Document BvQdaxGkj5Qw0Gx5v7b8Y9MpJ

AR226-1523 FINAL REPORT RECEIVED OPPT NCIC 03 SEP 30 PM1:00 PROTOCOL 418-028 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OFT-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST SPONSOR'S STUDY NUMBER: T-7706.1 FINAL REPORT DATE: 31 JULY 2003 PROTOCOL 418-028 - ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OFT-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST SPONSOR'S STUDY NUMBER: T-7706.1 TABLE OF CONTENTS SUBJECT 1. SUMMARY AND CONCLUSION 1.1. Methods 1.2. Results 1.3. Conclusion 2. DESCRIPTION OF TEST PROCEDURES 2.1. Conduct of Study . 2.2. Test Substance Information 2.3. Vehicle Information 2.4. Test Substance Preparation and Storage Conditions 2.5. Test System 2.6. Husbandry 2.7. Methods 3. RESULTS - Male Rats 3.1. Mortality, Clinical and Necropsy Observations 3.2. Terminal Body Weights and Organ Weights and Ratios(%) of Organ Weight to Terminal Body Weight and Brain Weight PAGE 1-1 1-1 1-3 1-6 2-1 2-1 2-4 2-4 2-5 2-6 2-7 2-10 3-1 3-1 3-2 11 SUBJECT PAGE 3.3. Hematology and Clinical Chemistry 3-2 3.4. Body Weights and Body Weight Changes 3-3 3.5. Absolute (g/day) and Relative (g/kg/day) Feed Consumption Values 3-3 3.6. Mating and Fertility 3-3 3.7. Functional Observational Battery 3-3 3.8. Motor Activity 3-4 3.9. Sperm 3-4 4. RESULTS - Female Rats 4-1 4.1. Mortality, Clinical and Necropsy Observations 4-1 4.2. Terminal Body Weights, Organ Weights and Ratios(%) of Organ Weight to Terminal Body Weight and Brain Weight and Primordial Follicle Counts 4-2 4.3. Hematology and Clinical Chemistry 4-2 4.4. Body Weights and Body Weight Changes 4-3 4.5 Absolute (g/day) and Relative (g/kg/day) Feed Consumption Values 4-3 4.6. Estrous Cycling, Mating and Fertility 4-4 4.7. Functional Observational Battery 4-4 4.8. Motor Activity 4-4 4.9. Natural Delivery and Litter Observations 4-5 4.10. Pup Clinical and Necropsy Observations 4-5 4.11. Pup Liver Weight and Ratio of Liver Weight to Terminal Body Weight 4-5 REFERENCES 4-6 APPENDIX A - REPORT FIGURES Figure 1. Fo Generation Male Rats A-1 iii SUBJECT PAGE Figure 2. Fo Generation Female Rats A-2 Figure 3. Motor Activity - Number of Movements - Fo Generation Male Rats A-3 Figure 4. Motor Activity- Time Spent in Movement - Fo Generation Male Rats A-4 Figure 5. Motor Activity- Number of Movements - Fo Generation Female Rats A-5 Figure 6. Motor Activity- Time Spent in Movement - Fo Generation Female Rats A-6 APPENDIX B - REPORT TABLES - Fo GENERATION MALE RATS Table B1. Clinical Observations - Summary - Fo Generation Male Rats B-1 Table B2. Necropsy Observations - Summary - Fo Generation Male Rats B-2 Table B3. Terminal Body Weights and Organ Weights - Summary- Fo Generation Male Rats B-3 Table B4. Ratios(%) of Organ Weight to Terminal Body Weight - Summary- Fo Generation Male Rats B-5 Table BS. Ratios(%) of Organ Weight to Brain Weight - Summary- Fo Generation Male Rats B-7 Table B6. Hematology - Summary - Fo Generation Male Rats B-9 Table B7. Clinical Chemistry- Summary- Fo Generation Male Rats B-12 Table B8. Body Weights - Summary- Fo Generation Male Rats B-15 Table B9. Body Weight Changes - Summary- Fo Generation Male Rats B-16 Table BIO. Absolute Feed Consumption Values (g/day) - Summary - Fo Generation Male Rats B-17 Table Bl 1. Relative Feed Consumption Values (g/kg/day) - Summary- Fo Generation Male Rats B-18 Table B12. Mating and Fertility- Summary- Fo Generation Male Rats B-19 Table B13. Functional Observational Battery Observations - Summary Fo Generation Male Rats B-20 iv SUBJECT PAGE Table B14. Motor Activity- Summary- Fo Generation Male Rats B-26 Table B15. Sperm Motility, Count and Density- Summary- Fo Generation Male Rats B-28 Table B16. Sperm Morphology- Summary- Fo Generation Male Rats B-29 Table B17. Clinical Observations - Individual Data- Fo Generation Male Rats B-30 Table B18. Necropsy Observations - Individual Data- Fo Generation Male Rats B-33 Table B19. Terminal Body Weights and Organ Weights and Ratios(%) of Organ Weight to Terminal Body Weight - Individual Data - Fo Generation Male Rats B-38 Table B20. Organ Weights and Ratios(%) Of Organ Weight to Brain Weight - Individual Data - Fo Generation Male Rats B-48 Table B21. Body Weights - Individual Data- Fo Generation Male Rats B-58 Table B22. Feed Consumption Values - Individual Data - Fo Generation Male Rats B-68 Table B23. Mating and Fertility - Individual Data - Fo Generation Male Rats B-71 Table B24. Functional Observational Battery Observations - Individual Data - Fo Generation Male Rats B-74 Table B25. Motor Activity - Individual Data - Fo Generation Male Rats B-79 Table B26. Sperm Motility, Count and Density - Individual Data - Fo Generation Male Rats B-89 Table B27. Sperm Morphology- Individual Data - Fo Generation Male Rats B-92 APPENDIX C - REPORT TABLES - Fo GENERATION FEMALE RATS Table Cl. Clinical Observations - Summary - Fo Generation Female Rats C-1 Table C2. Necropsy Observations - Summary- Fo Generation Female Rats C-4 Table C3. Terminal Body Weights and Organ Weights and Primordial Follicle Count - Summary - Fo Generation Female Rats C-5 v SUBJECT Table C4. Table C5. Table C6. Table C7. Table C8. Table C9. Table ClO. Table Cl 1. Table Cl2. Table C13. Table C14. Table C15. Table C16. Table Cl7. Table C18. PAGE Ratios (%) of Organ Weight to Terminal Body Weight - Summary - Fo Generation Female Rats C-7 Ratios(%) of Organ Weight to Brain Weight- Summary- Fo Generation Female Rats C-8 Hematology - Summary - Fo Generation Female Rats C-9 Clinical Chemistry - Summary - Fo Generation Female Rats C-12 Body Weights - Precohabitation - Summary - Fo Generation Female Rats C-15 Body Weight Changes - Precohabitation - Summary - Fo Generation Female Rats C-16 Maternal Body Weights - Gestation - Summary- Fo Generation Female Rats C-17 Maternal Body Weight Changes - Gestation - Summary - Fo Generation Female Rats C-19 Maternal Body Weights - Lactation - Summary- Fo Generation Female Rats C-20 Maternal Body Weight Changes - Lactation - Summary- Fo Generation Female Rats C-22 Absolute Feed Consumption Values (g/day) - Precohabitation - Summary- Fo Generation Female Rats C-23 Relative Feed Consumption Values (g/kg/day) - Precohabitation - Summary- Fo Generation Female Rats C-24 Maternal Absolute Feed Consumption Values (g/day) - Gestation - Summary- Fo Generation Female Rats C-25 Maternal Relative Feed Consumption Values (g/kg/day) - Gestation - Summary- Fo Generation Female Rats C-26 Maternal Absolute Feed Consumption Values (g/day) - Lactation - Summary - Fo Generation Female Rats C-27 vi SUBJECT Table Cl9. Table C20. Table C21. Table C22. Table C23. Table C24. Table C25. Table C26. Table C27. Table C28. Table C29. Table C30. Table C31. Table C32. Table C33. PAGE Maternal Relative Feed Consumption Values (g/kg/day) - Lactation - Summary - Fo Generation Female Rats C-28 Mating and Fertility, Estrous Cycling and Days in Cohabitation - Summary - Fo Generation Female Rats C-29 Functional Observational Battery- Summary - Fo Generation Female Rats C-31 Motor Activity - Summary - Fo Generation Female Rats C-37 Natural Delivery Observations - Summary- Fo Generation Female Rats C-39 Litter Observations (Naturally Delivered Pups) - Summary Fl Generation Litters C-40 Clinical Observations from Birth to Day 22 Postpartum - Summary - Fl Generation Pups C-43 Necropsy Observations - Summary - Fl Generation Pups C-44 Pup Liver Weights - Summary- Fl Generation Pups C-45 Clinical Observations - Individual Data - Fo Generation Female Rats C-46 Necropsy Observations - Individual Data - Fo Generation Female Rats C-51 Terminal Body Weights and Organ Weights and Ratios (%) of Organ Weight to Terminal Body Weight - Individual Data - Fo Generation Female Rats C-55 Organ Weights and Ratios(%) Of Organ Weight to Brain Weight - Individual Data - Fo Generation Female Rats C-60 Primordial Follicle Count - Individual Data - Fo Generation Female Rats C-65 Body Weights - Precohabitation - Individual Data - Fo Generation Female Rats C-67 vii SUBJECT PAGE Table C34. Maternal Body Weights - Presumed Gestation - Individual Data Fo Generation Female Rats C-70 Table C35. Maternal Body Weights - Lactation - Individual Data Fo Generation Female Rats C-75 Table C36. Feed Consumption Values - Precohabitation - Individual Data Fo Generation Female Rats C-80 Table C37. Maternal Feed Consumption Values - Presumed Gestation - Individual Data - Fo Generation Female Rats C-83 Table C38. Maternal Feed Consumption Values - Lactation - Individual Data - Fo Generation Female Rats C-86 Table C39. Mating and Fertility, Estrous Cycling and Days in Cohabitation Individual Data- Fo Generations Female Rats C-89 Table C40. Functional Observational Battery - Individual Data Fo Generation Female Rats C-92 Table C41. Motor Activity- Individual Data - Fo Generation Female Rats C-97 Table C42. Natural Delivery, Implantation Sites, and Pup Viability and Sex Individual Data - Fo Generation Female Rats/Fl Generation Litters C-107 Table C43. Pup Body Weight Litter Averages from Birth to Day 22 Postpartum - Individual Data - Fl Generation Litters C-110 Table C44. Pup Body Weights from Birth to Day 22 Postpartum Individual Data - Fl Generation Pups C-113 Table C45. Pup Vital Status and Sex from Birth to Day 22 Postpartum Individual Data - Fl Generation Pups C-125 Table C46. Clinical Observations from Birth to Day 22 Postpartum Individual Data - Fl Generation Pups C-128 Table C47. Necropsy Observations - Individual Data - Fl Generation Pups C-130 Table C48. Pup Liver Weights - Individual Date - Fl Generation Pups C-136 APPENDIX D - PROTOCOL AND AMENDMENTS D-1 to D-52 viii SUBJECT PAGE APPENDIX E - DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY E-1 to E-3 APPENDIX F- CERTIFICATE OF ANALYSIS F-1 to F-3 APPENDIX G- ANALYTICAL AND BIOANALYTICAL REPORT G-1 to G-153 APPENDIX H - TEMPERATURE AND RELATIVE HUMIDITY REPORT H-1 APPENDIX I- POSITIVE CONTROL DATA I-1 to I-4 APPENDIX J - HISTOPATHOLOGY REPORT J-1 to J-105 APPENIDX K - HEMATOLOGY AND CLINICAL CHEMISTRY REPORTS K-1 to K-150 APPENDIX L - STATEMENT OF THE STUDY DIRECTOR L-1 APPENIDIX M - QUALITY ASSURANCE STATEMENT M-1 to M-2 ix 418-028:PAGE 1-1 TITLE: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST ARGUS RESEARCH PROTOCOL NUMBER: 418-028 SPONSOR'S STUDY NUMBER: T-7706.1 1. SUMMARY AND CONCLUSION 1.1. Methodsa Seventy-five Crl:CD(SD)IGS VAF/Plus rats per sex were assigned to five dosage groups (Groups I through V), 15 rats per sex per group. An additional three rats per sex per group were assigned to Groups I through V for toxicokinetic sample collection. The test substance, T-7706 [Perfluorohexane Sulfonate Potassium Salt (PFHS)], or vehicle, aqueous 0.5% carboxymethylcellulose (CMC), was administered via gavage to male rats once daily beginning 14 days before cohabitation and continuing through the day before sacrifice, after completion of the cohabitation period, after a minimum of 42 days of administration, and to female rats once daily beginning 14 days before cohabitation and continuing through the day before sacrifice, day 21 of lactation (DL 21) or day 25 of presumed gestation (DG 25, rats that did not deliver a litter). Dosages were 0, 0.3, 1, 3 and 10 mg/kg/day. The dosage volume, 10 mL/kg, was adjusted daily on the basis of the individual body weights recorded before intubation. Fl generation pups were not directly administered the test substance or vehicle. Within each dosage group, rats were assigned to cohabitation, one male rat per female rat. Rats were observed for viability at least twice each day of the study. Observations for clinical signs of effects of the test substance and deaths were made on the first day of dosage at approximately hourly intervals for the first four hours and at the end of the normal working day. Observations for clinical signs of effects of the test substance and deaths were made on subsequent days daily before dosage and approximately 60 10 minutes after dosage administration and on the day of sacrifice. Once before the first dosage and at least once weekly thereafter, detailed clinical observations were conducted for all male and female rats assigned to the main study. a. Detailed descriptions of all procedures used in the conduct of this study are provided in the appropriate sections of this report and in APPENDIX D (PROTOCOL AND AMENDMENTS). 418-028:PAGE 1-2 Body weights were recorded daily during the dosage period and at sacrifice. Feed consumption values for male rats assigned to the main study were recorded weekly during the dosage period. Feed consumption values for female rats assigned to the main study were recorded weekly to cohabitation, on DGs 0, 7, 10, 12, 15, 18, 20 and 25 (if necessary) and on DLs 1, 5, 8 and 15. During cohabitation, individual values were not recorded or tabulated. Estrous cycling was evaluated in rats assigned to the main study by examination of vaginal cytology beginning with the day after the first administration and then until spermatozoa were observed in a smear of the vaginal contents and/or a copulatory plug was observed in situ during the cohabitation period. Estrous cycling was evaluated in rats assigned to the toxicokinetic study during the cohabitation period until spermatozoa were observed in a smear of the vaginal contents and/or a copulatory plug was observed in situ. Female rats were evaluated for adverse clinical signs observed during parturition, duration of gestation, litter sizes and pup viability at birth. Maternal behavior was evaluated on DLs 1, 5, 8, 15 and 22. Shortly before scheduled sacrifice, a functional observational battery (FOB) was conducted and motor activity was evaluated on 10 male and 10 female rats per group. On days 14 and 42 of study, blood samples were collected from each male rat assigned to the toxicokinetic sample collection portion of the study and on day 14 of study and DG 21, blood samples were collected from each female rat assigned to the toxicokinetic sample collection portion of the study. Each litter was evaluated for viability at least twice daily. The pups in each litter were counted once daily. Clinical observations were recorded once daily. Pup body weights were recorded on DLs 1, 8, 15 and 22. Male and female rats assigned to the toxicokinetic study were sacrificed on day 42 of study and DG 21, respectively. Liver weights were recorded. The median liver lobe was shipped for analysis. Blood samples were collected from each fetus and pooled by litter and serum was shipped for analysis. The liver from each fetus was collected, pooled per litter and shipped for analysis. The number of implantation sites was recorded. Male and female rats assigned to the main study were sacrificed after a minimum of 42 days of dosage and on DL 22, respectively. A gross necropsy of the thoracic, abdominal and pelvic viscera was performed. The number of implantation sites were recorded. Gross lesions were examined histologically. Ten rats per sex per group assigned to functional observational battery and motor activity tests were assigned to histological evaluations. The following organs were individually weighed: liver, kidneys, adrenals, thymus, testes, right epididymis, left epididymis (corpus and caput), seminal vesicles (with and without fluid), prostate, spleen, brain, heart, ovaries and uterus (with cervix). The following tissues or representative samples 418-028:PAGE 1-3 were retained: brain, small and large intestines, lungs, lymph nodes, peripheral nerve, stomach, kidneys, spleen, thymus, trachea, urinary bladder, spinal cord, liver, adrenals, heart, thyroid/parathyroid, bone marrow, testes, prostate, seminal vesicles, ovaries, uterus, vagina, mammary gland (female rats only) and gross lesions. Histological examination of retained tissues, including reproductive organs, was conducted for the assigned ten rats per sex from the control and high dosage groups. A quantitative evaluation of primordial follicles was conducted for Fo generation female rats. Sperm evaluations (concentration, motility and morphology) were performed for 10 male rats in each dosage group. At scheduled sacrifice, blood samples were collected from the 10 male and 10 female rats per group assigned to hematology and clinical chemistry sample collection. The following hematologic parameters were evaluated: erythrocyte count, hematocrit, hemoglobin, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume, total leukocyte count, differential leukocyte count, platelet count, mean platelet volume and cell morphology. Two blood smear slides were prepared for measurements of differential leukocyte count. Plasma samples evaluated for prothrombin time and activated partial thromboplastin time. Sera samples were evaluated for total protein, triglycerides, albumin, globulin, albumin/globulin ratio, glucose, cholesterol, total bilirubin, urea nitrogen, creatinine, creatinine kinase, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, calcium, phosphorus, sodium, potassium and chloride. On DL 22, pups were sacrificed and examined for gross lesions. Necropsy included a single cross-section of the head at the level of the frontal-parietal suture and examination of the cross-sectioned brain for apparent hydrocephaly. Blood samples were collected from five pups per sex per litter from the 10 female rats per group selected for FOB and motor activity assessment, blood sample collection for hematology and clinical chemistry and histological evaluations. Sera was shipped for analysis. The liver from each selected pup was weighed. 1.2. Results 1.2.1. Male Rats All male rats survived to scheduled sacrifice and all clinical and necropsy observations were considered unrelated to the test substance. Body weight gains were significantly reduced in the 0.3, 3 and 10 mg/kg/day dosage groups on study days (DSs) 29 to 36. Significantly reduced body weight gain occurred in the 0.3, 1, 3 and 10 mg/kg/day dosage groups on study days DS 29 to termination. Body weight gain was also significantly reduced for the 10 mg/kg/day dosage group for the entire dosage period. Absolute and relative feed consumption values for the male rats were unaffected by dosages of the test substance as high as 10 mg/kg/day. 418-028:PAGE 1-4 Terminal body weights of the male rats were slightly reduced in the 10 mg/kg/day dosage group. The absolute weights of the liver, the ratios of the liver weights to terminal body weights and ratios of the Iiver weights to brain weight were significant!y increased in the 3 and 10 mg/kg/day dosage groups. The ratio of the heart weights to brain weight was significantly decreased in the 10 mg/kg/day dosage group. Hemoglobin concentrations were significantly decreased in the 1, 3 and 10 mg/kg/day dosage groups and average values for red blood cells and hematocrit were significantly decreased in the 3 and 10 mg/kg/day dosage groups. Prothrombin time was significantly increased in the 0.3, 3 and 10 mg/kg/day dosage groups. Average values for cholesterol were significantly decreased in the 0.3, 1, 3 and 10 mg/kg/day dosage groups and the average values for triglycerides was significantly decreased in the 10 mg/kg/day dosage group. Albumin, blood urea nitrogen, alkaline phosphatase, calcium and albumin/globulin ratio levels were significantly increased in the 10 mg/kg/day dosage group. Treatment-related microscopic changes were observed in the liver and thyroid gland of male rats in the 3 and 10 mg/kg/day dosage groups. The treatment-related microscopic changes in the liver consisted of minimal to moderate enlargement of centrilobular hepatocytes and in the thyroid gland as an increased incidence of hypertrophy of follicular cells and hyperplasia. These microscopic changes are consistent with the known effects of compounds that cause microsomal enzyme induction where the hepatocellular hypertrophy results in a compensatory hypertrophy and hyperplasia of the thyroid due to increased plasma turnover of thyroxine and associated stimulation of thyroid-stimulating hormone in ratscl). There were no treatment-related microscopic changes observed in the liver of the Fl generation pups from the dams given up to 10 mg/kg/day of the test substance. All mating and fertility parameters were unaffected by dosages of the test substance as high as 10 mg/kg/day. There were no other statistically significant or biologically important differences among the four dosage groups in the measures of the functional observational battery (FOB) or motor activity on DSs 36 through 39. Sperm motility was unaffected by dosages of the test substance as high as 10 mg/kg/day. The sperm count and sperm density were comparable among the five dosage groups. 1.2.2. Female Rats All female rats survived to scheduled sacrifice and all clinical and necropsy observations were considered unrelated to the test substance. Body weights, body weight gains, and absolute and relative feed consumption values were comparable and did not differ significantly during the precohabitation, gestation or lactation periods at dosages of the test substance up to 10 mg/kg/day. Terminal body weights, absolute and relative weights of the reproductive organs, brain, liver, left and right kidneys and adrenals, spleen, thymus and heart of the female rats were 418-028:PAGE 1-5 comparable among dosage groups. Average primordial follicle counts for the 10 mg/kg/day dosage group were comparable to the control group. No treatment-related microscopic changes were observed in any of the female rats administered up to 10 mg/kg/day of the test substance. There were no treatment-related microscopic changes observed in the liver of the Fl generation pups from the dams given up to 10 mg/kg/day of the test substance. Dosages as high as 10 mg/kg/day did not affect any hematology or clinical chemistry values evaluated. The average numbers of estrous stages per 13 days were comparable among the five dosage groups. All mating and fertility parameters, including the gestation index, viability index and lactation indices were unaffected by dosages of the test substance as high as 10 mg/kg/day. There were no statistically significant or biologically important differences among the five dosage groups in the measures of the functional observational battery (FOB) or motor activity on DL 17. All pregnant dams delivered a litter of one or more live pups. Values for the numbers of dams delivering litters, the duration of gestation, averages for implantation sites per delivered litter, the numbers of dams with stillborn pups, the numbers of dams with no liveborn pups, dams with all pups dying, were comparable among the five dosage groups. The number of pups surviving per litter, pup sex ratios, litter size and pup body weights per litter were comparable among the five dosage groups. No clinical or necropsy observations in the Fl generation pups were attributable to dosages of the test substance as high as 10 mg/kg/day. Fl generation male and female pup terminal body weights, absolute liver weight and ratio of liver weight to terminal body weight were comparable across all five dosage groups. 418-028:PAGE 1-6 1.3. Conclusion On the basis of these data, the maternal no-observable-adverse-effect-level (NOAEL) for T-7706 [Perfluorohexane Sulfonate Potassium Salt] is greater than 10 mg/kg/day (the 10 mg/kg/day dosage caused no deaths, adverse clinical or necropsy/pathology observations, changes in body weight, feed consumption, or hematology or clinical chemistry values throughout precohabitation, gestation or lactation. The paternal NOAEL is less than 0.3 mg/kg/day (the 0.3 and 1 mg/kg/day dosages caused significant differences in body weight gain, hematology and clinical chemistry values and the 3 and 10 mg/kg/day dosages caused significant changes in absolute and relative organ weights and microscopic changes in the liver and thyroid gland). The reproductive NOAEL is greater than 10 mg/kg/day (the 10 mg/kg/day dosage had no effect on the durations of gestation and parturition or any mating and fertility parameters. There was no effect on the sperm parameters in the male rats). The NOAEL for viability and growth in the offspring is also greater than 10 mg/kg/day (dosages of 10 mg/kg/day had no effect on perinatal mortality, clinical or necropsy observations or body or liver weights in the Fl generation offspring). -~c:._ __ J~----------------~-(_--_~_~:t!_;J Alan M. Hoberman, Ph.D., DABT Date Director of Research Study Director Date Ass ate Directo Study Director 418-028:PAGE 2-1 2. 2.1. 2.1.1. DESCRIPTION OF TEST PROCEDURES Conduct of Study Sponsor 3M Corporate Toxicology, 3M Center, Building 220-2E-02, St. Paul, Minnesota 55144-1000 2.1.2. Testing Facility Argus Research, 905 Sheehy Drive, Building A, Horsham, Pennsylvania 19044-1297 2.1.3. Study Number 418-028 2.1.4. Sponsor's Study Number T-7706.1 2.1.5. Purpose of the Study The purpose of this study was to provide information on the possible health hazards that may result from repeated exposure of Crl:CD(SD)IGS BR VAF/Plus male and female rats to a test substance beginning before cohabitation, through mating and continuing for at least 42 days (male rats) or through parturition until day 21 of lactation (female rats). This repeated dose study incorporated a reproduction/developmental toxicity screening test that can be used to provide initial information on possible effects on male and female reproductive performance (e.g., gonadal function, mating behavior, conception, development of the conceptus and parturition). The study also placed emphasis on neurological effects as a specific endpoint and should identify the neurotoxic potential of a test substance, which may warrant further in-depth investigation. Because of the selectivity of the endpoints and the short duration of the study, the screening test did not provide evidence for definitive claims of no reproductive/ developmental effects. In particular, it offered only limited means of detecting postnatal manifestations of prenatal exposure or effects that may be induced during postnatal exposure. 2.1.6. Study Design The requirements of the Organisation for Economic Co-operation and Development (OECDP) were used as the basis for study design. 2.1.7. Regulatory Compliance This study was conducted in compliance with Good Laboratory Practice (GLP) regulations of the OECD(3),U.S. Food and Drug Administration (FDAi4), the Japanese 418-028:PAGE 2-2 Ministry of Health and Welfare (MHW)(5). There were no deviations from the GLP regulations that affected the quality or integrity of the study. Quality Assurance Unit findings derived from the inspections during the conduct of this study are documented and have been provided to the Study Director and the Testing Facility Management. 2.1.8. Ownership of the Study The Sponsor owns the study. All raw data, analyses, reports and preserved tissues are the property of the Sponsor. 2.1.9. Study Monitor John Butenhoff, Ph.D., CIH, DABT 2.1.10. Study Director Raymond G. York, Ph.D., DABT (Associate Director of Research) Address as cited previously for Testing Facility. 2.1.11. Technical Performance John F. Barnett, B.S. (Director of Laboratory Operations) Joseph W. Lech, B.S. (Senior Research Associate) Mary P. Howard, B.S. (Team Leader- General Laboratory) Jaclyn S. Fox, B.S. (Laboratory Technician) Josette M. Provost, B.S. (Necropsy Laboratory Technician/Fixed Tissue Coordinator) Christopher K. Ruppert, B.S. (Formulation Laboratory Technician) 2.1.12. Report Preparation Raymond G. York, Ph.D., DABT Jo Ann Frazee, M.S. (Study Coordinator) JoAnne M. Conklin, B.S. (Data Management Specialist) Cristina Petrescu (Report Administrator) 2.1.13. Report Review Valerie A. Sharper, M.S. (Director of Study Management) 2.1.14. Date Protocol Signed 26 March 2002 2.1.15. Dates of Technical Performance 2.1.15.1. Male Rats Rat Arrival Dosage Period (14 days before cohabitation and through a 14-day cohabitation period until sacrifice after at least 42 days of dosage) FOB and Motor Activity Evaluation Toxicokinetic Sample Collections DSa 14 DS42 Scheduled Sacrifice - Toxicokinetic Study Scheduled Sacrifice - Main Study 2.1.15.2. Female Rats Rat Arrival Dosage Period (14 days before cohabitation through DLb 21) Cohabitation Period Male 1 Male2 Toxicokinetic Sample Collections DS 14 DGC21 DGO DG 25 Sacrifice (Rats that did not deliver a litter) Delivery Periodd (DL 1) FOB and Motor Activity Evaluation DL 22 Sacrifice Female Rats and Pups 418-028:PAGE 2-3 26MAR02 01 APR02-16MAY02 06 MAY 02 - 09 MAY 02 14APR02 12MAY02 12MAY02 13 MAY 02-17 MAY 02 26MAR02 01 APR 02 - 09 JUN 02 14 APR 02 PM - 21APR02 AM 21 APR 02 PM - 28 APR 02 AM 14APR02 06MAY02-19MAY02 15 APR 02 - 28 APR 02 10 MAY 02- 23 MAY 02 07 MAY 02- 20 MAY 02 23 MAY02- 26 MAY 02 28MAY02-10JUN02 a. DS is an abbreviation used for day of study. b. DL is an abbreviation used for day of lactation/postpartum. c. DG is an abbreviation used for day of (presumed) gestation. d. The day of birth is designated lactation day 0 (postpartum day 0) in the Health Effects Test Guidelines - Reproduction and Fertility Effects (Office of Prevention, Pesticides and Toxic Substances 870.3800, August, 1998) and in the OECD Guideline for the Testing of Chemicals - Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (Section 4, No. 422, 22 March 1966). This same day is designated day 1 postpartum (day 1 of lactation) in the Standard Operating Procedures of the Testing Facility. Throughout this study, the day of birth was designated as day 1 postpartum (day 1 of lactation) and all subsequent ages of the Fl generation rats and days of the lactation period were determined and cited accordingly. 418-028:PAGE 2-4 2.1.16. Records Maintained The original report, raw data and reserve samples of each lot of bulk test substance and bulk vehicle components are retained in the archives of Argus Research. Any preserved tissues are retained in the archives of the Testing Facility for one year after the mailing of the draft final report, after which time the Sponsor will decide their final disposition. All unused prepared formulations were discarded at the Testing Facility. All remaining bulk test substance was returned to the Sponsor. 2.2. 2.2.1. Test Substance Information Description T-7706 [Perfluorohexane Sulfonate Potassium Salt (PFHS)] - a white powder 2.2.2. Date Received and Storage Conditions The test substance was received on 11 March 2002 and stored at room temperature. 2.2.3. Special Handling Instructions Standard safety precautions (use of protective clothing, gloves, dust-mist/HEPA-filtered mask, safety goggles or safety glasses and a face-shield) were taken during formulation preparation and dosage. A half-face respirator was worn during formulation preparation. 2.2.4. Analysis of Purity Information to document or certify the identity, composition, method of synthesis, strength and purity of the test substance was provided by the Sponsor to the Testing Facility. A Certificate of Analysis is available in APPENDIX F. 2.3. Vehicle Information 2.3.1. Description Aqueous 0.5% carboxymethylcellulose (CMC) (sodium salt; medium viscosity) prepared using carboxymethylcellulose (sodium salt; medium viscosity), an off-white powder, and reverse osmosis membrane processed deionized water (R.O. deionized water). 2.3.2. Lot Number 120K0252 2.3.3. Date Received and Storage Conditions The carboxymethylcellulose was received from Sigma Chemical Co., St. Louis, Missouri, on 11 September 2001 and stored at room temperature. R.O. deionized water is available from a continuous source at the Testing Facility and is maintained at room temperature. 418-028:PAGE 2-5 2.3.4. Special Handling Instructions Standard safety precautions (use of protective clothing, gloves, dust-mist/HEPA-mtered mask, safety goggles or safety glasses and a face-shield) were taken when handling the vehicle components and prepared vehicle. 2.3.5. Analysis of Purity Neither the Sponsor nor the Study Director was aware of any potential contaminants likely to have been present in the vehicle that would have interfered with the results of this study. The expiration date for the carboxymethylcellulose is September 2005. 2.4. Test Substance Preparation and Storage Conditions Formulations were prepared weekly at the Testing Facility. Prepared test substance and vehicle formulations were stored refrigerated (2C to 8C). 2.4.1. Sample Information Sample Type Date Size Retained Storage Conditions Shipped To/ Shipping Conditions Date Shipped Bulk Test Substancea lg 09JUN02 Room temperature Exygenb/ Ambient 10 JUN02 Homogeneityc (all levels) 2mL 29MAR02 Refrigerated conditions Sponsor/ Refrigerated 01APR02 Concentration (all levels) Stabilityg 2mL 2mL 24MAY02e 07 JUN02f 29MAR02 Refrigerated Refrigerated Exygenb/ Refrigerated Sponsor/ 28MAY02 10 JUN02 01APR02 Refrigerated Bulk Test Substance Reserve lg 10 JUN02 Room temperature Testing Facility 10JUN02 Archives Vehicle Components Reserve Room temperature Testing Facility Archives Carboxymethylcellulose R.O. deionized water lg 5mL 10JUN02 10 JUN02 10JUN02 10JUN02 a. A sample of the test article was retained on the last day of treatment and shipped for analysis. b. Exygen Research, State College, Pennsylvania. c. Quadruplicate samples were taken from the top, middle and bottom of each concentration on the first day of preparation. Two samples from each quadruplicate set were shipped for analysis. The remaining samples were retained at the Testing Facility as backup samples. d. Quadruplicate samples were taken from each concentration on the last day of preparation. Two samples from each quadruplicate set were shipped for analysis. The remaining samples were retained at the Testing Facility as backup samples. e. Samples for 0.03, 0.1 and 1 mg/mL concentrations only. f. Samples for 0 and 0.3 mg/mL concentrations only. g. Two sets of duplicate samples from each concentration were taken on the first day of preparation. One sample of each duplicate set was shipped on the day of preparation. These samples were analyzed as soon as possible after preparation and ten days after the first analysis. The remaining samples were retained at the Testing Facility as backup samples. 418-028:PAGE 2-6 2.4.2. Analytical Results Results of the analytical analyses are available in APPENDIX G. 2.5. Test System 2.5.1. Species Rat 2.5.2. Strain Crl:CD(SD)IGS VAF/Plus 2.5.3. Supplier (Source) Charles River Laboratories, Inc. Male Rats - St. Constant, Quebec, CANADA Female Rats - Raleigh, North Carolina 2.5.4. Sex Male and Female 2.5.5. Rationale for Test System The Crl:CD(SD)IGS BR VAF/Plus rat was selected as the Test System because: 1) it is one mammalian species accepted for use in toxicity studies and it has been widely used throughout industry; 2) this strain of rat has been demonstrated to be sensitive to reproductive and developmental toxins; and 3) historical data and experience exist at the Testing Facility<6-8). 2.5.6. Test System Data 2.5.6.1. Male Rats Number of Rats Approximate Date of Birth Approximate Age at Arrival Weight (g) the Day after Arrival Weight (g) at Study Assignment 100 20JAN02 66 days 277 - 318 305 - 348 2.5.6.2. Female Rats Number of Rats Approximate Date of Birth Approximate Age at Arrival Weight (g) the Day after Arrival Weight (g) at Study Assignment 100 21JAN02 65 days 195 - 227 207 - 230 418-028:PAGE 2-7 2.5.7. Method of Randomization Upon arrival, the male and female rats were assigned to individual housing on the basis of computer-generated random units. During an acclimation period of at least five days, male and female rats were selected for study on the basis of physical appearance and body weights recorded during acclimation. The ratswere assigned to five dosage groups (Groups i through V), 15 rats per sex per group, using a computer-generated (weight- ordered) randomization procedure. An additional three rats per sex per group were assigned to Groups I through V for toxicokinetic sample collection. At study initiation, the weight variation of the rats did not exceed 20% of the mean weight of each sex. Litters were not culled during the lactation period because random selection of pups for culling could have resulted in potential biases in pup viabilities and body weight gains over this period. Within each dosage group, consecutive order was used to assign the first 10 male and the first 10 female Fo generation rats to a functional observational battery (FOB) and motor activity assessment, blood sample collection for clinical chemistry and hematology and histological evaluations. On DL 22, a table of random units was used to select five male and five female pups per litter for blood sample and liver collection. These pups were only selected from the 10 dams selected for FOB, motor activity, clinical chemistry and hematology and histological evaluation. 2.5.8. System of Identification Male and female rats were assigned temporary numbers at receipt and given unique permanent identification numbers when assigned to the study before administration of the first dosage. Rats were permanently identified using a Monel self-piercing ear tag (Gey Band and Tag Co., Inc., No. MSPT 20101). Cage tags were marked with the study number, permanent rat number, sex, test substance identification, generation, dosage group and dosage level. Pups were not individually identified during lactation; all parameters were evaluated in terms of the litter. 2.6. Husbandry 2.6.1. Research Facility Registration USDA Registration No. 14-R-0144 under the Animal Welfare Act, 7 U.S.C. 2131 et seq. 2.6.2. Study Room The study room was maintained under conditions of positive airflow relative to a hallway and independently supplied with a minimum of ten changes per hour of 100% fresh air that had been passed through 99.97% HEPA filters. Room temperature and humidity 418-028:PAGE 2-8 were monitored constantly throughout the study. Room temperature was targeted at 64F to 79F (18C to 26C); relative humidity was targeted at 30% to 70%a. 2.6.3. Housing Rats were individually housed in stainless steel, wire-bottomed cages except during cohabitation and postpartum periods. During cohabitation, each pair of male and female rats was housed in the male rat's cage. Beginning no later than DG 20, Fo generation female rats were individually housed in nesting boxes until they either naturally delivered litters or were sacrificed (DG 25). Each dam and delivered litter was housed in a common nesting box during the postpartum period. All cage sizes and housing conditions were in compliance with the Guide for the Care and Use ofLaboratory Animali9). Argus Research is an AAALAC-accredited facility. 2.6.4. Lighting An automatically-controlled fluorescent light cycle was maintained at 12-hours light: 12-hours dark, with each dark period beginning at 1900 hours EST. 2.6.5. Sanitization Cage pan liners were changed at least three times weekly. Cages were changed approximately every other week. Bedding was changed as often as necessary to keep the rats dry and clean. 2.6.6. Feed Rats were given ad libitum access to Certified Rodent Diet#5002 (PMI Nutrition International, Inc., St. Louis, Missouri) in individual feeders. Feed was removed the evening prior to the scheduled sacrificeb. 2.6.7. Feed Analysis Analyses were routinely performed by the feed supplier. No contaminants at levels exceeding the maximum concentration for certified feed or deviations from expected nutritional requirements were detected by these analyses. Copies of the results of the feed analyses are available in the raw data. Neither the Sponsor nor the Study Director was aware of any potential contaminants likely to have been present in the feed at concentrations that would have interfered with the results of this study. a. See APPENDIX H (TEMPERATURE AND RELATIVE HUMIDITY REPORT). b. See APPENDIX E (DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY), item 1. 418-028:PAGE 2-9 2.6.8. Water Local water that had been processed by passage through a reverse osmosis membrane (R.O. water) was available to the rats ad libitum from individual water bottles attached to the cages and/or from an automatic watering access system. Chlorine was added to the processed water as a bacteriostat. 2.6.9. Water Analysis The processed water is analyzed twice annually for possible chemical contamination (Lancaster Laboratories, Lancaster, Pennsylvania) and monthly for possible bacterial contamination (Analytical Laboratories, Inc., Chalfont, Pennsylvania). Copies of the results of the water analyses are available in the raw data. Neither the Sponsor nor the Study Director was aware of any potential contaminants likely to have been present in the water that would have interfered with the results of this study. 2.6.10. Bedding Material Bed-o'cobs bedding (The Andersons Industrial Products Group, Maumee, Ohio) was used as the nesting material. 2.6.11. Bedding Analysis Analyses for possible contamination are conducted semi-annually. Copies of the restults of the bedding analyses are available in the raw data. Neither the Sponsor nor the Study Director was aware of any potential contaminants likely to have been present in the bedding that would have interfered with the results of this study. 418-028:PAGE 2-10 2. 7. Methods 2.7.1. Dosage Administration Dosage Dosage Number Dosagea Concentration Volume of Rats Assigned Numbers Group (mg/kg/day) (mg/mL) (mL/kg) per Sex Male Rats Female Rats I 0 0 10 15 + 3 Main Study: Main Study: 19109, 19115, 19116, 19119, 19010, 19012, 19019, 19021, 19122, 19125, 19131, 19132, 19023, 19041, 19042, 19044, 19134, 19135, 19143, 19151, 19050, 19053, 19065, 19068, 19157, 19161, 19167 19072, 19074, 19075 Toxicokinetic Study: Toxicokinetic Study: 19176- 19178 19076 - 19078 II 0.3 0.03 10 15 + 3 Main Study: Main Study: 19102, 19106, 19108, 19110, 19004, 19009, 19016, 19018, 19113, 19120, 19129, 19136, 19026, 19036, 19037, 19043, 19138, 19139, 19147, 19153, 19047, 19048, 19052, 19055, 19164, 19165, 19171 19061, 19067, 19071 Toxicokinetic Study: Toxicokinetic Study: 19179 - 19181 19079 - 19081 III 1 0.1 10 15 + 3b Main Study: Main Study: 19101, 19105, 19107, 19112, 19003, 19007, 19008, 19013, 19114, 19121, 19123, 19130, 19014, 19015, 19017, 19024, 19137, 19146, 19155, 19159, 19029, 19034, 19038, 19056, 19172, 19173, 19174 19057, 19060, 19064 Toxicokinetic Study: Toxicokinetic Study: 19182 - 19184 19082 - 19084 IV 3 0.3 10 15 + 3b Main Study: Main Study: 19100, 19103, 19104, 19118, 19002, 19005, 19035, 19039, 19133, 19141, 19142, 19144, 19040, 19045, 19046, 19051, 19148, 19150, 19156, 19160, 19054, 19058, 19062, 19063, 19162, 19163, 19166 19066, 19069, 19073 Toxicokinetic Study: Toxicokinetic Study: v 10 19185 - 19187 1 10 15 + 3b Main Study: 19085 - 19087 Main Study: 19111, 19117, 19124, 19126, 19001, 19006, 19011, 19020, 19127, 19128, 19140, 19145, 19022, 19025, 19027, 19028, 19149, 19152, 19154, 19158, 19030, 19031, 19032, 19033, 19168, 19169, 19170 19049, 19059, 19070 Toxicokinetic Study: Toxicokinetic Study: 19188 - 19190 19088 - 19090 a. The test substance was considered 100% pure for the purpose of dosage calculations. b. Three additional rats per sex were assigned to toxicokinetic sample collection. 2.7.2. Rationale for Dosage Selection Dosages were selected by the Sponsor based on previous studies conducted with the test substance, taking into account possible differences in sensitivity between pregnant and nonpregnant rats. The highest dosage was expected to cause toxic effects but not mortality or obvious suffering. The descending sequence of the lower dosage levels was selected for the purpose of demonstrating any dosage-related response, with no adverse effects expected at the lowest level. 418-028:PAGE 2-11 2.7.3. Route and Rationale for Route of Administration The oral (gavage) route was selected for use because: 1) in comparison with the dietary route, the exact dosage can be accurately administered; and 2) it is one of the possible routes for environmental exposure. 2.7.4. Frequency of Administration 2.7.4.1. Fo Generation Rats Male rats were administered the test substance or the vehicle once daily beginning 14 days before cohabitation (maximum 14 days) and continuing through the day before sacrifice, after completion of the cohabitation period, after a minimum of 42 days of administration. Female rats were administered the test substance or the vehicle once daily beginning 14 days before cohabitation (maximum 14 days) and continuing through the day before sacrifice, DL 21 or DG 24 (rats that did not deliver a litter). The dosage volume was adjusted daily on the basis of the individual body weights recorded before intubation. The rats were intubated once daily at approximately .the same time each day. The first day of dosage was designated as DS 1. Dams in the process of delivering pups were not intubated until completion of parturition, in order to preclude possible disruption of maternal behavior and/or cannibalization of pups. Consequently, some dams were not administered one daily dosage during the delivery period. No dam missed more than one daily dosage. 2.7.4.2. Fl Generation Pups Fl generation pups were not directly administered the test substance or vehicle, but may have been possibly exposed to the test substance or vehicle during maternal gestation (in utero exposure) or via maternal milk during the lactation period. 2.7.5. Method of Study Performance 2.7.5.1. Fo Generation Rats Within each dosage group, consecutive order was used to assign rats to cohabitation, one male rat per female rat. The cohabitation period consisted of a maximum of 14 days. Female rats with spermatozoa observed in a smear of the vaginal contents and/or a copulatory plug in situ were considered to be DG 0 and assigned to individual housing. Female rats not mated with a male rat within the first seven days of cohabitation were assigned an alternate male rat that had mated (same dosage group) and remained in cohabitation for a maximum of seven additional days. Rats were observed for viability at least twice each day of the study. Rats were examined for clinical observations and general appearance weekly during the acclimation period. Observations for clinical signs of effects of the test substance and deaths were made on the first day of dosage at approximately hourly intervals for the first four hours and at the end of the normal working day. Observations for clinical signs of effects of the test 418-028:PAGE 2-12 substance and deaths were made on subsequent days daily before dosage and approximately 60 10 minutes after dosage administration and on the day of sacrificea. Once before the first dosage and at least once weekly thereafter, detailed clinical observations were conducted for all male and female rats assigned to the main studyb. These observations were made outside the cage in a standard arena at the same time each day of conduct. Effort was made to ensure that variations in the test conditions were minimal and that observations were conducted by observers unaware of treatment groups. The rats were observed for (but observations were not limited to) the following signs: changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions and autonomic activity (e.g., lacrimation, piloerection, pupil size, unusual respiratory pattern). Changes in gait, posture and response to handling as well as the presence of clonic or tonic movements, stereotypic behavior (e.g., excessive grooming, repetitive circling), difficult or prolonged parturition or bizarre behavior (e.g., self-mutilation, walking backwards) were also recorded. Body weights were recorded weekly during the acclimation period, daily during the dosage period and at sacrifice. Feed consumption values for male rats assigned to the main study were recorded weekly during the dosage period. Feed consumption values for female rats assigned to the main study were recorded weekly to cohabitation, on DGs 0, 7, 10, 12, 15, 18, 20 and 25 (if necessary) and on DLs 1, 5, 8 and 15c. Because pups begin to consume maternal feed on or about DL 15, feed consumption values were not tabulated after DL 15. During cohabitation, when two rats occupied the same cage with one feed jar, replenishment of the feed jars was documented but individual values were not recorded or tabulated. Estrous cycling was evaluated in rats assigned to the main study by examination of vaginal cytology beginning with the day after the first administration and then until spermatozoa were observed in a smear of the vaginal contents and/or a copulatory plug was observed in situ during the cohabitation period. Estrous cycling was evaluated in rats assigned to the toxicokinetic study during the cohabitation period until spermatozoa were observed in a smear of the vaginal contents and/or a copulatory plug was observed in situ. Female rats were evaluated for adverse clinical signs observed during parturition, duration of gestation (DG 0 to the day the first pup was observed), litter sizes (all pups delivered) and pup viability at birth. Maternal behavior was evaluated on DLs 1, 5, 8, 15 and 22. Variations from expected maternal behavior were recorded, if and when present, on all other days of the postpartum period. On one occasion during the course of the study, a functional observational battery (FOB)(l0-l3) was conducted on 10 male and 10 female rats per group. For male rats, this assessment was conducted shortly before scheduled sacrifice, but prior to blood sample a. See APPENDIX E, items 2 and 3. b. See APPENDIX E, item 4. c. See APPENDIX E, item 5. 418-028:PAGE 2-13 collection for hematology and clinical chemistry evaluations. Female rats were tested during the lactation period, shortly before scheduled sacrifice. The FOB evaluation was conducted by an observer unaware of the group assignment of the rat. The following parameters were assessed: 1. Lacrimation, salivation, palpebral closure, prominence of the eye, pupillary reaction to light, piloerection, respiration, and urination and defecation (autonomic functions). 2. Sensorimotor responses to visual, auditory, tactile and painful stimuli (reactivity and sensitivity). 3. Reactions to handling and behavior in the open field (excitability). 4. Gait pattern in the open field, severity of gait abnormalities, air righting reaction and landing foot splay (gait and sensorimotor coordination). 5. Forelimb and hindlimb grip strength. 6. Abnormal clinical signs including but not limited to convulsions, tremors and other unusual behavior, hypotonia or hypertonia, emaciation, dehydration, unkempt appearance and deposits around the eyes, nose or mouth. The ability of this battery to detect the effects of positive control substances has been established (Testing Facility Positive Control Data) and is available in APPENDIX I. Motor activity was evaluated on 10 male and 10 female rats per group once, shortly before scheduled sacrifice, prior to blood sample collection. The movements of each rat were monitored by a passive infrared sensor mounted outside a stainless steel, wirebottomed cage (40.6 x 25.4 x 17.8 cm). Each test session was 1.5 hours in duration with the number of movements and time spent in movement tabulated at each five-minute interval. The apparatus monitored a rack of up to 32 cages and sensors during each session, with each rat tested in the same location on the rack across test sessions. Groups were counterbalanced across testing sessions and cages. Data demonstrating that the test system is capable of detecting increases in activity produced by positive control substances (Testing Facility Positive Control Data) is available in APPENDIX I. On DSs 14 and 42, blood samples (approximately 1 mL each) were collected from each male rat assigned to the toxicokinetic sample collection portion of the study (three rats per group) and on DS 14 and DG 21, blood samples (approximately 1 mL each) were collected from each female rat assigned to the toxicokinetic sample collection portion of the study (three rats per group). Samples were collected prior to dosage on DS 14. The time of each blood collection was recorded in the raw data. Blood was collected from the orbital sinus on DS 14 of the study and from the vena cava on DS 42 of study (male rats) and DG 21 (female rats). The samples were transferred into EDTA-coated (purple top) tubes and spun in a centrifuge. The resulting serum was transferred into polypropylene 418-028:PAGE 2-14 tubes labeled with the protocol number, Sponsor study number, rat number, sex, group number, dosage level, day of study, collection interval, date of collection, species, generation and storage conditions. All samples were immediately frozen on dry ice and maintained frozen (~-70C) until shipment to Exygen Research, State College, Pennsylvania, for analysis. Results of these analyses are available in APPENDIX G. 2.7.5.2. Fl Generation Pups Day 1 of lactation (postpartum) was defined as the day of birth and was also the first day on which all pups in a litter were individually weighed (pup body weights were recorded after all pups in a litter were delivered and groomed by the dam). Each litter was evaluated for viability at least twice daily. The pups in each litter were counted once daily. Clinical observations were recorded once daill. Pups were observed if they were warm and clean, for evidence of a nest and if pups were grouped together and nursing or had milk in stomach. Each pup was examined for general shape of the head, trunk, limbs, tail and presence of anus. Pup body weights were recorded on DLs 1, 8, 15 and 22 (terminal weight). 2.7.6. Gross Necropsy 2.7.6.1. Fo Generation Rats Male and female rats assigned to the toxicokinetic study were sacrificed by carbon dioxide asphyxiation on DS 42 and DG 21, respectively. Blood samples were collected from the rats as previously described. After sacrifice, the liver of each rat was excised and the liver weight was recorded. The median liver lobe was frozen and stored (~-20C) until shipment for analysisb. The fetuses were removed from the uterus and blood samples were collected from each fetus via decapitation. Blood was placed into tubes, pooled per litter, allowed to clot and spun in a centrifuge. The resulting serum was transferred into labeled polypropylene tubes. All samples were immediately frozen on dry ice and maintained frozen (~-70C) until shipment for analysis. The liver from each fetus was collected, pooled per litter and placed into labeled tubes. The samples were frozen and stored (~-20C) until shipment for analysis. The number of implantation sites was recorded. Carcasses were discarded without further evaluation. The livers were shipped to Exygen Research, State College, Pennsylvania, for analysis. Results of the analyses are available in APPENDIX G. Male and female rats assigned to the main study were sacrificed by carbon dioxide asphyxiation following the last dosage administration, after a minimum of 42 days of dosage and on DL 22, respectively. A gross necropsy of the thoracic, abdominal and pelvic viscera was performed. Gross necropsy included an initial physical examination of external surfaces and all orifices, as well as the cranial, thoracic and abdominal cavities and their contents. Special attention was paid to the organs of the reproductive system. The ovaries and the uterus with cervix of each female rat were weighed, and the a. See APPENDIX E, items 6 and 7. b. See APPENDIX E, item 8. 418-028:PAGE 2-15 ovaries, uterus, vagina and a mammary gland were retained in neutral buffered 10% formalin. The number of implantation sites were recorded. Uteri of apparently nonpregnant rats were examined after being pressed between glass plates to confirm the absence of implantation sites and were retained in neutral buffered 10% formalin. Gross lesions were retained in neutral buffered 10% formalin and examined histologically. Representative photographs of gross lesions are available in the raw data. Tissue trimming and histopathology were performed under the supervision of or by a Board Certified Veterinary Pathologist. Ten rats per sex per group assigned to functional observational battery and motor activity tests were assigned to histological evaluations. The following organs were excised, trimmed and individually weighed as soon as possible after excision to avoid drying: liver, kidneys, adrenals, thymus, testes, right epididymis, left epididymis (corpus and caput), seminal vesicles (with and without fluid), prostate, spleen, brain, heart, ovaries and uterus (with cervix). The following tissues or representative samples were retained in neutral buffered 10% formalin: brain (representative regions including cerebrum, cerebellum, pons), small and large intestines (including Peyer's patches), lungs (perfused with neutral buffered 10% formalin), lymph nodes (submandibular and mediastinal), peripheral nerve (sciatic or tibial), stomach, kidneys, spleen, thymus, trachea, urinary bladder, spinal cord (cervical, thoracic and lumbar), liver, adrenals, heart, thyroid/parathyroid, bone marrow (sternum), testes (fixed in Bouin's solution for 48 to 96 hours before being retained in neutral buffered 10% formalin), prostate, seminal vesicles (with coagulating gland), the remaining portion of the left epididymis (corpus and caput), the right epididymis, ovaries, uterus, vagina, mammary gland (female rats only) and gross lesions. Histological examination of retained tissues, including reproductive organs, was conducted for the assigned ten rats per sex from the control and high dosage groups. A quantitative evaluation of primordial follicles was conducted for Fo generation female rats. Examination included enumeration of number of primordial follicles, which were combined with small growing follicles, for comparison of ovaries of rats assigned to treated and control groups. Tissues that were examined histologically were shipped to Research Pathology Services, Inc., New Britain, Pennsylvania, for evaluation. Results of the histological evaluation are available in APPENDIX J. To assess the potential toxicity of the test substance on the male reproductive system, sperm evaluations were performed for 10 male rats in each dosage group. Sperm concentration and motility were evaluated using computer-assisted sperm analysis (CASA). Motility was evaluated by the Hamilton Thorne IVOS by collection of a sample from the left vas deferens. A homogenate was prepared from the left cauda epididymis for evaluation by the Hamilton Thome IVOS to determine sperm concentration (sperm per gram of tissue weight). The remaining portion of the left cauda epididymis was used to manually evaluate sperm morphology. Sperm morphology evaluations included the following: 1) determination of the percentage of normal sperm in a sample of at least 200; and 2) qualitative evaluation of abnormal sperm, including such categories as abnormal head, abnormal tail, and abnormal head and tail. 418-028:PAGE 2-16 At scheduled sacrifice, the 10 male and 10 female rats per group assigned to hematology and clinical chemistry sample collection were exsanguinated from the inferior vena cava following sacrifice. Rats were fasted overnight before sacrificea. Approximately 5 mL of blood was collected. The tubes containing the samples were labeled with the protocol number, Sponsor study number, rat number, sex, group number, dosage level, day of study, collection interval, date of collection, species, generation and storage conditions. Approximately 1 mL of blood was collected into EDTA-coated tubes and maintained on wet ice or refrigerated until shipment for analysis of the following hematologic parameters: erythrocyte count (RBC), hematocrit (HCT), hemoglobin (HGB), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), total leukocyte count (WBC), differential leukocyte count, platelet count (PLAT), mean platelet volume (MPV) and cell morphology. Two blood smear slides were prepared at the Testing Facility for each sample for measurements of differential leukocyte count. Approximately 1.8 mL of blood was added to a tube containing 0.2 mL of sodium citrate (0.129 M). The contents were mixed and maintained on wet ice until the tubes were centrifuged (within 30 minutes of the collection time). The resulting plasma was transferred to 2.0 mL polypropylene tubes and immediately frozen. Plasma samples were maintained on dry ice or in a freezer (~-70C) until shipment for measurement of prothrombin time (PT) and activated partial thromboplastin time (APTT). Approximately 2 mL of blood was collected into serum separator tubes and centrifuged. The resulting sera samples were immediately frozen on dry ice and maintained frozen (~-70C) until shipment for analysis of the following parameters: total protein (TP), triglycerides (TRI), albumin (A), globulin (G), albumin/globulin Ratio (A/G), glucose (GLU), cholesterol (CHOL), total bilirubin (TBILI), urea nitrogen (BUN), creatinine (CREAT), creatinine kinase (CK), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALK), calcium (CA), phosphorus (PHOS), sodium (NA), potassium (K) and chloride (CL). Samples for hematology and clinical chemistry analyses were shipped to Redfield Laboratories, A Division of CRL-DDS, Redfield, Arkansas. Samples were shipped on dry ice and slides were shipped at ambient conditions. Results of these analyses are available in APPENDIX K. Female rats that did not deliver a litter were sacrificed on DG 25. Gross necropsy, examination and tissue retention were conducted as described above for rats at scheduled sacrifice. Gross lesions were preserved in neutral buffered 10% formalin for possible future evaluation. Representative photographs of gross lesions are available in the raw data. a. See APPENDIX E, item 1. 418-028:PAGE 2-17 2.7.6.2. Fl Generation Pups On DL 22, pups were sacrificed by carbon dioxide asphyxiation and examined for gross lesions. Necropsy included a single cross-section of the head at the level of the frontalparietal suture and examination of the cross-sectioned brain for apparent hydrocephaly. Gross lesions were preserved in neutral buffered 10% formalin for possible future evaluation. Representative photographs of gross lesions are available in the raw data. Blood samples were collected from each selected pup (five per sex per litter from the 10 female rats per group selected for FOB and motor activity assessment, blood sample collection for hematology and clinical chemistry and histological evaluations) from the vena cava. The blood was placed into tubes, pooled per litter, allowed to clot and spun in a centrifuge; the resulting serum was transferred into labeled polypropylene tubes. All samples were immediately frozen on dry ice and maintained frozen (::=;-70C) until shipment for analysis. The liver from each selected pup was excised and the organ weight recordeda. The median lobe was frozen and stored (::=;-20C) until shipment for possible analysis. The remaining portion of each liver was retained in neutral buffered 10% formalin for possible histological evaluation. The livers were processed and evaluated histologically as described for the Fo generation rats. Pups that died before initial examination of the litter for pup viability were evaluated for vital status at birth. The lungs were removed and immersed in water. Pups with lungs that sink were identified as stillborn; pups with lungs that float were identified as liveborn, and to have died shortly after birth. Pups found dead were examined for gross lesions and for the cause of death. 2.7.7. Data Collection and Statistical Analyses Data generated during the course of this study were recorded either by hand or using the Argus Automated Data Collection and Management System, the Vivarium Temperature and Relative Humidity Monitoring System, the Coulbourn Instruments Passive Infrared Motor Activity System, the Coulbourn Instruments Auditory Startle System, the Coulbourn Instruments Spatial Delayed Alternation System, and/or the passive avoidance software. All data were tabulated, summarized and/or statistically analyzed using the Argus Automated Data Collection and Management System, the Vivarium Temperature and Relative Humidity Monitoring System, Microsoft Excel [part of Microsoft Office 97 (version SR-2)] and/or The SAS System (version 6.12). a. See APPENDIX E, item 9. 418-028:PAGE 2-18 Averages and percentages were calculated. Litter values were used where appropriate. The following schematic represents the statistical analyses of the data: I. Parametric A. Bartlett's Test 0 Type of Testa II. Nonparametricb A. Kruskal-W allis Test (s. 75% ties at any concentration) Significant at p~0.001 Not Significant Significant at p~0.05 Not Significant Nonparametric Analysis of Variance Significant at p~0.05 Dunnett's Test Not Significant Dunn's Test B. Fisher's Exact Test on Proportion of Ties (>75% ties at any concentration) B. Analysis of Variance with Repeated Measures Significant at p~0.05 Not Significant (Dosage) Dunnett's Test (Dosage x Block Interaction) One-way ANOVA for each block Significant at p~0.05 Not Significant Dunnett's Test Ill. Test for Proportion Data Variance Test for Homogeneity of the Binomial Distribution a. Statistically significant probabilities are reported as either p:S0.05 or p:S0.01. b. Proportion data are not included in this category. c. Test for homogeneity of variance. 418-028:PAGE 2-19 Adult data was evaluated with the individual rat as the unit measured. Litter values were used in evaluation of pup data, as appropriate. Variables with interval or ratio scales of measurement, such as body weights, feed consumption values, latency and errors per trial scores in behavioral tests and percent mortality per litter were analyzed as described under the Parametric heading of the schematic. Bartlett's Test of Homogeneity of Variances<14) was used to estimate the probability that the dosage groups have different variances. A non-significant result (p>0.001) indicated that an assumption of homogeneity of variance was not inappropriate, and the data was compared using the Analysis of Variance<15>_ If that test was significant (p::::;;0.05), the groups given the test substance were compared with the control group using Dunnett's Test<16>. If Bartlett's Test was significant (p::::;;0.001), the Analysis of Variance Test was not appropriate, and the data was analyzed as described under the Nonparametric heading of the schematic. When 75% or fewer of the scores in all the groups were tied, the Kruskal-Wallis Test<17) was used to analyze the data, and in the event of a significant result (p::::;;0.05), Dunn's Test(lS) was used to compare the groups given the test substance with the control group. When more than 75% of the scores in any dosage group were tied, Fisher's Exact Tes{19) was used to compare the proportion of ties in the groups. Data from the motor activity test, with measurements recorded at intervals (Blocks) throughout each test session, were analyzed using an Analysis of Variance with Repeated Measures<20), as described under that heading in the schematic. A significant result (p::::;;0.05) in that test could have appeared as effect of Concentration (differences among dosage groups in the totals of all measurements in a session) or as an interaction between Concentration and Block (differences in the patterns of dosage group values across the measurement periods). If the Concentration effect was significant, the totals for the control group and the groups given the test substance were compared using Dunnett's Test<16). If the Concentration x Block interaction was significant, an Analysis of Variance<15) was used to evaluate the data at each measurement period, and a significant result (p::::;;0.05) was followed by a comparison of the dosage groups using Dunnett's Test<16>. . Variables that had graded or count scores, such as litter size, the number of trials to a criterion in a behavioral test or the day a developmental landmark appeared, were analyzed using the procedures described under the Nonparametric heading of the schematic. Clinical observation incidence data, as well as the descriptive and quanta! data from the FOB, were analyzed as contingency tables using the Variance Test for Homogeneity of the Binomial Distribution<21). Sperm motility data were expressed as percentages and analyzed, as indicated above, by parametric methods. 418-028:PAGE 3-1 3. RESULTS - Male Rats 3.1. Mortality, Clinical and Necropsy Observations (Summaries - Tables Bl and B2; Individual Data - Tables Bl7 and Bl8) 3.1.1. Mortality All male rats survived to scheduled sacrifice. 3.1.2. Clinical Observations All clinical observations were considered unrelated to the test substance because: 1) the incidences were not dosage-dependent; and/or 2) the observation occurred in only one or two male rats in any dosage group. These observations included chromorhinorrea, missing/broken or misaligned incisors, chromodacryorrhea, lacrimation, localized alopecia on the head, underside or limbs, dry, brown perioral substance, soft or liquid feces, scab on head and dehydration. 3.1.3. Necropsy Observations All necropsy observations were considered unrelated to the test substance because the incidences were not dosage-dependent; and/or 2) the observation occurred in only one or two male rats in any dosage group. These observations included discolored/mottled kidneys, slight pelvic dilation of the left kidney, small epididymides, small testes and diverticulum jejunum. 3.1.4. Histopathology (APPENDIX J) No treatment-related microscopic changes were observed in any of the male rats administered 0.3 or 1 mg/kg/day of the test substance. Treatment-related microscopic changes were observed in the liver and thyroid gland of male rats in the 3 and 10 mg/kg/day dosage groups. The treatment-related microscopic changes in the liver consisted of minimal to moderate enlargement (hypertrophy) of centrilobular hepatocytes. The affected hepatocytes were enlarged with an increased amount of dense eosinophilic granular cytoplasm. The treatment-related microscopic changes in the thyroid gland consisted of an increased incidence of the male rats in the 3 and 10 mg/kg/day dosage groups with hypertrophy (enlargement) of follicular cells and hyperplasia (increased follicular cells and small follicles). Although the incidence in the 10 mg/kg/day dosage group was minimally increased over the control group values, the hypertrophy and hyperplasia could have been associated with the liver-cell changes. 418-028:PAGE 3-2 3.2. Terminal Body Weights and Organ Weights and Ratios (% ) of Organ Weight to Terminal Body Weight and Brain Weight (Summaries - Tables B3 through BS; Individual Data -Tables B19 and B20) Terminal body weights of the male rats were slightly reduced (approximately 6%), albeit not significantly, in the 10 mg/kg/day dosage group, as compared with control group values. The absolute weights of the liver, the ratios of the liver weights to terminal body weights and ratios of the liver weights to brain weight were significantly increased (p~0.05 and/or p~0.01) in the 3 and 10 mg/kg/day dosage groups, as compared with the control group value. The ratio of the heart weights to brain weight was significantly decreased (p~0.05) in the 10 mg/kg/day dosage group, as compared with the control group value. The absolute and relative (terminal body and brain) weights of the male reproductive organs (left and right epididymes, left cauda epididymes, left and right testes, seminal vesicles with and without fluid and prostate), brain, left and right kidneys and adrenals, spleen, thymus and heart (except relative heart weight as described above) were comparable across dosage groups and did not differ significantly. 3.3. Hematology and Clinical Chemistry (Summaries - Tables B6 and B7; Individual Data - APPENDIX K) Hemoglobin concentrations (HGB) were significantly decreased (p~0.05 or p~O.Ol) in the 1, 3 and 10 mg/kg/day dosage groups and average values for red blood cells (RBC) and hematocrit (HCT) were significantly decreased (p~0.05 or p~0.01) in the 3 and 10 mg/kg/day dosage groups, as compared with the control group values. Prothrombin time (PT) was significantly increased (p~0.05 or p~0.01) in the 0.3, 3 and 10 mg/kg/day dosage groups. Dosages of the test substance as high as 10 mg/kg/day did not affect mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelets (PLAT), mean platelet volume (MPV), volume, white blood counts (WBC), activated partial thromboplastin time (APTT), nucleated red blood cell count (NRBC), lymphocytes, segmented neutrophils, bands, monocytes, eosinophils, basophils and abnormal lymphocytes in male rats. These values were comparable among the four dosage groups and did not differ significantly. Average values for cholesterol (CHOL) were significantly decreased (p~0.05 or p~O.Ol) in the 0.3, 1, 3 and 10 mg/kg/day dosage groups and the average values for triglycerides (TRIG) was significantly decreased (p~0.01) in the 10 mg/kg/day dosage group. Albumin (A), blood urea nitrogen (BUN), alkaline phosphatase (ALK), calcium (CA) and albumin/globulin ratio (A/G) levels were significantly increased (p~0.01) in the 10 mg/kg/day dosage group. Clinical chemistry values for total protein (TP), glucose (GLU), total bilirubin (TBILI), creatinine (CREAT), creatinine kinase (CK), alanine aminotransferase (ALT), aspartate 418-028:PAGE 3-3 aminotransferase (AST), phosphorus (PROS), sodium (NA), potassium (K), chloride (CL) and globulin (G) in male rats were comparable among the four dosage groups and did not differ significant!y. 3.4. Body Weights and Body Weight Changes (Figure 1; Summaries - Tables BS and B9; Individual Data - Table B21) Body weight gains were significantly reduced (p:::;0.05 or p:::;0.01) in the 0.3, 3 and 10 mg/kg/day dosage groups on study days (DSs) 29 to 36. As a result of these reductions, significantly reduced (p:::;0.05 or p:::;0.01) body weight gain occurred in the 0.3, 1, 3 and 10 mg/kg/day dosage groups on study days DS 29 to termination. Body weight gain was also significantly reduced (p:::;0.01) for the 10 mg/kg/day dosage group for the entire dosage period (calculated as DS 1 to termination). 3.5. Absolute (g/day) and Relative (g/kg/day) Feed Consumption Values (Summaries - Tables BlO and Bll; Individual Data - Table B22) Absolute (g/day) and relative (g/kg/day) feed consumption values for the male rats were up.affected by dosages of the test substance as high as 10 mg/kg/day. 3.6. Mating and Fertility (Summary - Table B12; Individual Data - Table B23) All mating and fertility parameters (numbers of days in cohabitation, rats that mated, fertility index, rats with confirmed mating dates during the first and second week of cohabitation and the number of pregnant rats per number of rats in cohabitation) were unaffected by dosages of the test substance as high as 10 mg/kg/day. 3. 7. Functional Observational Battery (Summary - Table B13; Individual Data - Table B24) Home cage behavior of sleeping and immobile/awake were significantly different (p:::;0.01) in the 3 mg/kg/day dosage group, compared to the control group. These increases were not considered treatment-related because they were not dosage-dependent. There were no other statistically significant or biologically important differences among the four dosage groups in the measures of the functional observational battery (FOB). There were no alterations in autonomic functions (lacrimation, salivation, palpebral closure, prominence of the eye, pupillary reaction to light, piloerection, respiration, defecation and urination), sensorimotor functions [responses to visual, auditory, tactile and painful stimuli (reactivity and sensitivity)], excitability (reactions to handling and behavior in the open field), gait and sensorimotor coordination (gait pattern in the open field, severity of gait abnormalities, air righting reaction and landing foot splay) and forelimb and hindlimb grip strength and abnormal clinical observations including but not limited to: convulsions, tremors, unusual behavior, hypotonia or hypertonia, emaciation, dehydration, unkempt appearance and deposits around the eyes, nose or mouth. 418-028:PAGE 3-4 Body weights recorded during the functional operational battery for the treated groups were not significantly different than the control group for the male rats. 3.8. Motor Activity (Figures 3 and 4; Summary - Table B14; Individual Data - Table B25) There were no statistically significant or biologically important differences among the five dosage groups in the number of movements or time (in seconds) spent in movement measures of motor activity on DSs 36 through 39. 3.9. Sperm (Summary - Tables B15 and B16; Individual Data - Tables B26 and B27) 3.9.1. Sperm Motility Sperm motility was unaffected by dosages of the test substance as high as 10 mg/kg/day. Group mean values were comparable among the five dosage groups and ranged from 85.5% to 93.2% motile sperm. 3.9.2. Sperm Count and Sperm Density The sperm count and sperm density were comparable among the five dosage groups. No treatment-related differences were observed. 3.9.3. Sperm Morphology A low incidence of head and/or tail abnormalities was observed for the male rats in all dosage groups. No treatment-related differences were observed. 418-028 PAGE 4-1 4. 4.1. 4.1.1. RESULTS - Female Rats Mortality, Clinical and Necropsy Observations (Summaries - Tables Cl and C2; Individual Data - Tables C28 and C29) Mortality All female rats survived to scheduled sacrifice. 4.1.2. Clinical Observations All clinical observations were considered unrelated to the test substance because: 1) the incidences were not dosage-dependent; and/or 2) the observation occurred in only one female rat in any dosage group except for localized alopecia which is a common finding in rats that are allowed to deliver. These observations included brown perioral substance, rales, localized alopecia on the limbs, back or head, urine-stained abdominal fur, miosis, abdominal distention, emaciation, cold to touch, swollen nose, scab or ulceration on back or head, dehydration and tip of tail missing. 4.1.3. Necropsy Observations All necropsy observations were considered unrelated to the test substance because: 1) the incidences were not dosage-dependent; and/or 2) the observation occurred in only one female rat in each of the 1, 3 and 10 mg/kg/day dosage groups. These observations included the cortex of the right kidney adhered to the right lateral liver lobe in a 1 mg/kg/day dosage group female rat (19907), small left ovaries (0.003g) in one 3 mg/kg/day dosage group female rat (19051) that was not pregnant, outer capsule of spleen adhered to the omentum in another 3 mg/kg/day dosage group female rat (19063) and the large and small intestines distented with gas, small spleen and thymus, large adrenals, and approximately 12 black areas (pinpoint to 0.3 cm) on the fundic mucosa! surface of the stomach in a 10 mg/kg/day dosage group female rat (19020). 4.1.4. Histopathology (APPENDIX J) No treatment-related microscopic changes were observed in any of the female rats administered up to 10 mg/kg/day of the test substance. There were no treatment-related microscopic changes observed in the liver of the Fl generation pups from the dams given up to 10 mg/kg/day of the test article. There were a few microscopic changes observed in the various organs and tissues which were considered to have occurred spontaneously and not to be treatment-related. 418-028:PAGE 4-2 4.2. Terminal Body Weights, Organ Weights and Ratios (% ) of Organ Weight to Terminal Body Weight and Brain Weight and Primordial Follicle Counts (Summaries - Tables C3 through C5; Individual Data - Tables C30 through C32) Terminal body weights of the female rats were comparable among dosage groups and did not differ significantly. The absolute and relative weights (to terminal body and to brain weight) of the female reproductive organs (left and right ovaries and uterus with cervix), brain, liver, left and right kidneys and adrenals, spleen, thymus and heart were comparable across dosage groups and did not differ significantly (except on one occasion). The ratio of the left kidney to the brain weight of the female rats in the 3 mg/kg/day dosage group was significantly increased (p~0.05) over the corresponding control group value. This significant finding was not considered treatment-related because: 1) the incidence was not dosage-dependent; and/or 2) the observation was a single occurrence. Average primordial follicle counts for the 10 mg/kg/day dosage group were comparable to the control group and did not differ significantly. 4.3. Hematology and Clinical Chemistry (Summaries - Tables C6 and C7; Individual Data - APPENDIX K) Dosages as high as 10 mg/kg/day did not affect any hematology or clinical chemistry values evaluated. Average values for red blood cells (RBC), white blood cells (WBC), hemoglobin concentration (HGB), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelets (PLAT), mean platelet volume (MPV), prothrombin time (PT), activated partial thromboplastin time (APTT), nucleated red blood cell count (NRBC), lymphocytes, segmented neutrophils, bands, monocytes, eosinophils, basophils, abnormal 1ymphocytes in female rats were comparable among the five dosage groups and did not differ significantly (except on one occasion). The concentration of WBCs (1ymphocytes) for of the female rats in the 0.3 mg/kg/day dosage group was significantly increased (p~0.05) over the corresponding control group value. This significant finding was not considered treatment-related because: 1) the incidence was not dosage-dependent; and/or 2) the observation was a single occurrence. Average values for total protein (TP), albumin (A), glucose (GLU), cholesterol (CHOL), total bilirubin (TBILI), blood urea nitrogen (BUN), creatinine (CREAT), creatinine kinase (CK), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALK), calcium (CA), phosphorus (PROS), triglycerides (TRIG), sodium (NA), potassium (K), chloride (CL), globulin (G) and albumin/globulin ratio (A/G) in female rats were comparable among the five dosage groups and did not differ significantly (except on two occasions). The concentration of G was significantly decreased (p~0.01) and the concentration of NG was significantly increased (p~0.01) for of the female rats in the 0.3 mg/kg/day dosage group over the corresponding control group values. These significant findings were not considered treatment-related because: 418-028:PAGE 4-3 1) the incidences were not dosage-dependent; and/or 2) the observations were a single occurrence for both parameters. 4.4. Body Weights and Body Weight Changes (Figure 2; Summaries - Tables CS through C13; Individual Data - Tables C33 through C35) 4.4.1. Precohabitation Body weights and body weight gains were comparable and did not differ significantly during the precohabitation period at dosages of the test substance up to 10 mg/kg/day. 4.4.2. Gestation Body weights and body weight gains were comparable and did not differ significantly during the gestation period at dosages of the test substance up to 10 mg/kg/day. 4.4.3. Lactation Body weight gains were not significantly affected by dosages of the test substance up to 10 mg/kg/day during lactation. Body weights were significantly reduced (p::;0.05 or p::;0.01) on days of lactation (DLs) 4, 6 through 8, 11 and 13 in the 0.3 mg/kg/day dosage group, DLs 7 and 8 in the 3 mg/kg/day dosage group, DLs 4, 6 through 9, 11, 13 and 14 in the 10 mg/kg/day dosage group. These significant findings were not considered treatment-related because they were not dosage-dependent or they did not persist. 4.5. Absolute (g/day) and Relative (g/kg/day) Feed Consumption Values (Summaries - Tables C14 through C19; Individual Data - Tables C36 through C38) 4.5.1. Precohabitation Absolute (g/day) and relative (g/kg/day) feed consumption values were not significantly affected by dosages of the test substance up to 10 mg/kg/day during the precohabitation period. 4.5.2. Gestation Absolute (g/day) and relative (g/kg/day) feed consumption values were not significantly affected by dosages of the test substance up to 10 mg/kg/day during the gestation period. 4.5.3. Lactation Absolute and relative feed consumption values were not affected by dosages of the test substance up to 10 mg/kg/day during lactation. 418-028:PAGE 4-4 Absolute feed consumption values were significantly reduced (p::;0.05 or p::;0.01) on DLs 1to5 and 8 to 15 in the 0.3 mg/kg/day dosage group, DLs 1to5 and 8 to 15 in the 3 mg/kg/day dosage group and DLs 8 to 15 in the 10 mg/kg/day dosage group. Relative feed consumption values were significantly reduced (p::;0.01) on DLs 1to5 in the 0.3 mg/kg/day and DLs 5 to 8 in the 3 mg/kg/day dosage group. These significant findings were not considered treatment-related because they were not dosage-dependent and they did not persist. 4.6. Estrous Cycling, Mating and Fertility (Summary - Table C20; Individual Data - Table C39) The average numbers of estrous stages per 13 days were comparable among the five dosage groups and did not significantly differ. The number of rats with six or more consecutive days of diestrus or estrus did not differ significantly. All mating and fertility parameters (numbers of days in cohabitation, rats that mated, fertility ~ndex, rats with confirmed mating dates during the first and second week of cohabitation and the number of pregnant rats per number of rats in cohabitation) were unaffected by dosages of the test substance as high as 10 mg/kg/day. 4. 7. Functional Observational Battery (Summary - Table C21; Individual Data - Table C40) There were no statistically significant or biologically important differences among the five dosage groups in the measures of the functional observational battery (FOB). There were no alterations in home cage behavior, autonomic functions (lacrimation, salivation, palpebral closure, prominence of the eye, pupillary reaction to light, piloerection, respiration, defecation and urination), sensorimotor functions [responses to visual, auditory, tactile and painful stimuli (reactivity and sensitivity)], excitability (reactions to handling and behavior in the open field), gait and sensorimotor coordination (gait pattern in the open field, severity of gait abnormalities, air righting reaction and landing foot splay) and forelimb and hindlimb grip strength and abnormal clinical observations including but not limited to: convulsions, tremors, unusual behavior, hypotonia or hypertonia, emaciation, dehydration, unkempt appearance and deposits around the eyes, nose or mouth. Body weights recorded during the functional operational battery for the treated groups were not significantly different than the control group for the female rats. 4.8. Motor Activity (Figures 5 and 6; Summary - Table C22; Individual Data - Table C41) There were no statistically significant or biologically important differences among the five dosage groups in the measures of number of movements or time (in seconds) spent in movement motor activity on DL 17. 418-028:PAGE 4-5 4.9. Natural Delivery and Litter Observations (Summary - Tables C23 and C24; Individual Data - Tables C42 through C45) Pregnancy occurred in all 15 (100%) rats assigned to the 0 (Vehicle), 0.3 and 10 mg/kg/day dosage groups and 13 (88.7%) of the rats assigned to the 1 and 3 mg/kg/day dosage groups. All pregnant dams delivered a litter of one or more liveborn pups. Values for the numbers of dams that delivered litters, the duration of gestation (calculated in days), averages for implantation sites per delivered litter, the numbers of dams with stillborn pups, the numbers of dams with no liveborn pups, dams with all pups dying days 1to4 and 5 to 22, were comparable among the five dosage groups and did not significantly differ. The number of liveborn pups, the number of pups found dead or presumed cannibalized on day 1, and days 2 to 8, 9 to 15 and 16 to 22 postpartum were comparable among the five dosage groups and did not significantly differ. The gestation index (number of dams with one or more liveborn pups per number of pregnant rats), viability index (number of live pups on DL 8 per number of liveborn pups on DL 1) and lactation index (number of live pups on DL 22 per number of liveborn pups on DL 8) were compared to the control group value and did not differ significantly. The number of pups surviving per litter, pup sex ratios, litter size and pup body weights per litter on DLs 1, 8, 15 and 22 were comparable among the five dosage groups and did not significantly differ. 4.10. Pup Clinical and Necropsy Observations (Summary - Tables C25 and C26; Individual Data - Tables C46 and C47) No clinical or necropsy observations in the Fl generation pups were attributable to dosages of the test substance as high as 10 mg/kg/day because: 1) the incidences were not dosage-dependent; and 2) the observation occurred in only one to two litters. These clinical observations included: not nursing, emaciation, dehydration, whole body discolored purple, scab, cold to touch, left eye discolored purple, right eye enlarged, laceration on right hindlimb, bruise on back, not nesting, pale in appearance and corneal opacity of right eye. Necropsy observations of 228, 203, 196, 172 and 211 pups in the five respective dosage groups on postpartum days 5 and 22 were limited to moderate dilation of the renal pelvis of one pup from a 0.3 mg/kg/day dosage group litter. 4.11. Pup Liver Weight and Ratio of Liver Weight to Terminal Body Weight (Summary - Table C27; Individual Data - Table C48) Fl generation male and female pup terminal body weights, absolute liver weight (by sex) and ratio of liver weight to terminal body weight (by sex) were comparable across all five dosage groups and did not differ significant!y. 418-028:PAGE 4-6 REFERENCES 1. Sanders, J.E., Eigenberg, D.A., Bracht, L.J., Wang, W.R., and Zwieten, M.J. (1988): Thyroid and liver trophic changes in rats secondary to liver microsomal enzyme induction caused by an experimental leukotriene antagonist (L-649,923). Toxicology and Pharmacology, 95: 378-387. 2. Organisation for Economic Co-operation and Development (1996). OECD Guideline for Testing of Chemicals. Section 4, No. 422: Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, adopted 22 March 1996. 3. Organisation for Economic Co-operation and Development (1998). The Revised OECD Principles of Good Laboratory Practices [C(97)186/Final]. 4. U.S. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule. 21 CFR Part 58. 5. Japanese Ministry of Health and Welfare (1997). Good Laboratory Practice Standard for Safety Studies on Drugs, MHW Ordinance Number 21, March 26, 1997. 6. Christian, M.S. and Voytek, P.E. (1982). In Vivo Reproductive and Mutagenicity Tests. Environmental Protection Agency, Washington, D.C. National Technical Information Service, U.S. Department of Commerce, Springfield, VA 22161. 7. Christian, M.S. (1984). Reproductive toxicity and teratology evaluations of naltrexone. (Proceedings of Naltrexone Symposium, New York Academy of Sciences, November 7, 1983), J. Clin. Psychiat. 45(9):7-10. 8. Lang, P.L. (1988). Embryo and Fetal Developmental Toxicity (Teratology) Control Data in the Charles River Crl:CDBR Rat. Charles River Laboratories, Inc., Wilmington, MA 01887-0630. (Data base provided by Argus Research Laboratories, Inc.) 9. Institute of Laboratory Animal Resources (1996). Guide for the Care and Use of Laboratory Animals. National Academy Press, Washington, D.C. 10. Haggerty, G.C. (1989). Development of Tier I neurobehavioral testing capabilities for incorporation into pivotal rodent safety assessment studies. J. Amer. Col. Toxicol. 8:53-70. 11. Irwin, S. (1968). Comprehensive observational assessment: Ia. A systemic quantitative procedure for assessing the behavioral and physiologic state of the mouse. Psychopharmacologia (Berlin) 13:222-257. 12. Moser, V.C. (1989). Screening approaches to neurotoxicity: A functional observational battery. J. Amer. Col. Toxicol. 8:85-94. 418-028:PAGE 4-7 13. O'Donoghue, J.L. (1989). Screening for neurotoxicity using a neurologically based examination and neuropathology. J. Amer. Col. Toxicol. 8:97-116. 14. Sokal, R.R. and Rohlf, F.J. (1969). Bartlett's test of homogeneity of variances.Biometry, W.H. Freeman and Co., San Francisco, pp. 370-371. 15. Snedecor, G.W. and Cochran, W.G. (1967). Analysis of Variance. Statistical Methods, 6th Edition, Iowa State University Press, Ames, pp. 258-275. 16. Dunnett, C.W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Amer. Stat. Assoc. 50:1096-1121. 17. Sokal, R.R. and Rohlf, F.J. (1969). Kruskal-Wallis Test. Biometry, W.H. Freeman and Co., San Francisco, pp. 388-389. 18. Dunn, 0.J. (1964). Multiple comparisons using rank sums. Technometrics 6(3):241-252. 19. Siegel, S. (1956). Nonparametric Statistics for the Behavioral Sciences. Fisher's Exact. McGraw-Hill Co., New York, pp. 96-105. 20. SAS Institute, Inc. (1988). Repeated measures analysis of variance. SAS/STATfM User's Guide, Release 6.03 Edition, Cary, NC, pp. 602-609. 21. Snedecor, G.W. and Cochran, W.G. (1967). Variance test for homogeneity of the binomial distribution. Statistical Methods, 6th Edition, Iowa State University Press, Ames, pp. 240-241. APPENDIX A REPORT FIGURES PROTOCOL 418-Q28: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-77Q6 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-77Q6.1) BODY WEIGHTS Fo GENERATION MALE RATS Figure 1 SQQ-----,-~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 48Q 46Q __.___ Q MG/KG/DAY -.-- Q.3 MG/KG/DAY 44Q ~42Q II (9 w 4QQ $ 38Q ------0--- 1 MG/KG/DAY -------- 3 MG/KG/DAY ----k- 1Q MG/KG/DAY 36Q - a. Last value recorded before cohabitation. 34Q b. First value recorded .,J::.. after cohabitation. 00 c. Terminal body weight. I 0 N 00 32Q----'---~~--,-~~~~~~~~~~~~~~~~~.-~~~~-.~~~~~--,-~~~~~~~--' 8 c ~ 14a 29b 36 43 DAY OF STUDY ->>0tr1I PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) BODY WEIGHTS Fo GENERATION FEMALE RATS Figure 2 450--.--~~~~~~~~~~-,------~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ -----'W--- 0 MG/KG/DAY 400 ----A---- 0.3 MG/KG/DAY 350 : II (9 sUJ 300 -0------- 1 MG/KG/DAY -------- 3 MG/KG/DAY ~ 10 MG/KG/DAY 250 a. Last value recorded before cohabitation. I *p~o.os I +::.. ~ 00 I ;*p~o.01J I 200~~~~--.--~~~~--,--~-+----.~~~~~--.--~~~~--.--~~~~f----T-~~~~~~~--.--~~~~~~~ 0 N 00 ~ 1 3 5 7 9 11 13 1 3 5 7 9 11 13 15 17 19 2 4 6 8 10 12 14 16 18 20 22 > 2 4 6 8 1O 12 14a O 2 4 6 8 1O 12 14 16 18 20 1 3 5 7 9 11 13 15 17 19 21 0 DAY OF STUDY DAY OF GESTATION DAY OF LACTATION t'!1 > I N PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) MOTOR ACTIVITY - NUMBER OF MOVEMENTS - Fo GENERATION MALE RATS Figure 3 so~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~----. 70 ____._____ 0 MG/KG/DAY 60 (/) 61z- w 50 ~ w ~ 40 u.. 0 0w::: ~ CD 30 :::> z 20 -A- 0.3 MG/KG/DAY ---0-- 1 MG/KG/DAY -----3 MG/KG/DAY ~ 10 MG/KG/DAY 10 .a:::. ......... 00 I Q-+-~~~---.~~~------.~~~~.---~~~-.-~~~-.-~~~---,--~~~-----.~~~-,~~~------.,--~~--; 0 N 00 ~ 0 10 20 30 40 50 60 70 80 90 100 > TIME (MINUTES) 0 tr.I >wI PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) MOTOR ACTIVITY - TIME SPENT IN MOVEMENT - Fo GENERATION MALE RATS Figure 4 250 II _,.,__ -1 >z~ 200 LU ~ LU 0 ~ z 150 I !~: h \\~ \ ~\ \ '\'X:~ \ /---{ I I 0 MG/KG/DAY 11 -AI I 0.3 MG/KG/DAY I I ----0I I 1 MG/KG/DAY Iz - aLU.. J Cl) Cii 0z 100 0 (.) LU ~ LU ~ ~ 50 ~ \ \X~ ~ -\/- "" ~"" ~ _A\ \-/---. ~__() ~ I \ _.. ~ L/"W"" \ "Ir I I -------I I 3 MG/KG/DAY II~ I I 10 MG/KG/DAY J ..J:::. -00 I 0 0 tv 00 0 20 40 60 80 100 ~ TIME (MINUTES) >>~I ..J:::. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) MOTOR ACTIVITY - NUMBER OF MOVEMENTS - Fo GENERATION FEMALE RATS Figure 5 80--,-~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ __.____ 70 0 MG/KG/DAY 60 6 ~ z UJ 50 ::E UJ ::E 40 LL 0 a::: UJ co 30 ::E :::> z 20 ~ 0.3 MG/KG/DAY -0- ---1 MG/KG/DAY 3 MG/KG/DAY ~ 10 MG/KG/DAY 10 ..j.:.:.:.:.... 00 I O--+-~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~------< 0 tv 00 0 10 20 30 40 50 60 70 80 90 100 ~ > TIME (MINUTES) >a3I Vl PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) MOTOR ACTIVITY - TIME SPENT IN MOVEMENT - Fo GENERATION FEMALE RATS Figure 6 200 I I ~ CJ) I- I zw 150 :w? > 0 :? z - I Iz- 0w.. 100 CJ) CJ) Cl z 0 (.) w ~ w 50 :? ~ i \__ ~\ \\\ \ \\\ . \ \\ \ \ ~ ~ ~\ ""\ \\9 ~~~ ~-------- ~/?-~ . ~1?' -~~ =1:. 0 0 20 40 60 TIME (MINUTES) 0 MG/KG/DAY I I -A- 0.3 MG/KG/DAY ------0--- ---1 MG/KG/DAY I I 3 MG/KG/DAY ~ 10 MG/KG/DAY I ~ ~ 00 I 0 tv 00 80 100 ~ > 0 tT1 > I 0\ APPENDIXB REPORT TABLES - Fo GENERATION MALE RATS PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE Bl (PAGE 1) : CLINICAL OBSERVATIONS - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II III IV v 0 0.3 1 3 10 MAXIMUM POSSIBLE INCIDENCE 680/ 15 680/ 15 680/ 15 680/ 15 680/ 15 MORTALITY 0 0 0 0 0 CHROMORHINORRHEA 0/ 0 1/ 1 1/ 1 1/ 1 2/ 2 INCISORS: TOTAL MISSING/BROKEN MISALIGNED 2/ 1 2/ 1 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 13/ 1 6/ 1 13/ 1 13/ 1 13/ 1 0/ 0 CHROMODACRYORRHEA 0/ 0 0/ 0 3/ 1 9/ 1 2/ 1 LACRIMATION 0/ 0 0/ 0 0/ 0 0/ 0 1/ 1 LOCALIZED ALOPECIA: TOTAL HEAD UNDERSIDE LIMBS 0/ 0 0/ 0 0/ 0 0/ 0 27/ 2 16/ 1 0/ 0 11/ 1 3/ 2 0/ 0 2/ 1 1/ 1 14/ 1 14/ 1 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 DRY, BROWN PERIORAL SUBSTANCE 0/ 0 1/ 1 0/ 0 0/ 0 0/ 0 SOFT OR LIQUID FECES 0/ 0 1/ 1 0/ 0 0/ 0 0/ 0 HEAD: SCAB 8/ 1 0/ 0 0/ 0 0/ 0 0/ 0 DEHYDRATION 7/ 1 0/ 0 0/ 0 0/ 0 0/ 0 STATISTICAL ANALYSES OF CLINICAL OBSERVATION DATA WERE RESTRICTED TO THE NUMBER OF RATS WITH OBSERVATIONS. ..i;::.. MAXIMUM POSSIBLE INCIDENCE= (DAYS x RATS)/NUMBER OF RATS EXAMINED PER GROUP. ........ N/N = TOTAL NUMBER OF OBSERVATIONS/NUMBER OF RATS WITH OBSERVATION. 00 I 0 t-.J ;0.,0:; >~td ..I...... PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B2 (PAGE 1) : NECROPSY OBSERVATIONS - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II III IV v 0 0.3 1 3 10 RATS EXAMINED a N 15 15 15 15 15 MORTALITY N 0 0 0 0 0 APPEARED NORMAL N 14 12 15 14 14 KIDNEYS: BILATERAL, MOTTLED, MOTTLED TAN AND RED OR MOTTLED DARK RED N 1 2 0 0 0 LEFT, PELVIS, SLIGHT DILATION N 0 1 0 0 0 EPIDIDYMIDES: BILATERAL, SMALL N 0 0 0 1 0 LEFT CAUDA, SMALL N 0 0 0 1 0 TESTES: BILATERAL, SMALL N 0 0 0 1 0 JEJUNUM: DIVERTICULUM N 0 0 0 0 1 a. Refer to the individual clinical observations table (Table B17) for external observations confirmed at necropsy. ~ t--l 00 I 0 N 00 ~ ~ tT.1 OJ I N PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B3 (PAGE 1) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP I II III IV v DOSAGE (MG/KG/DAY) 0 0.3 1 3 10 ------------------------------------------------------------------------------------------------------------------------------------ RATS TESTED N 10 10 10 10 10 TERMINAL BODY WEIGHT MEANS.D. 469.7 31. 6 448.8 37.8 455.8 55.2 472. 3 38.3 440.8 12.6 EPIDIDYMIS LEFT MEANS.D. 0.6476 0.0367 0.6358 0.0397 0.6277 0.0505 0.5916 0.1092 0. 6134 0. 0472 CAUDA EPIDIDYMIS LEFT MEANS.D. 0.3308 0.0294 0.3182 0.0266 0.3232 0.0285 0.2913 0.0650 0.3041 0.0309 TESTIS LEFT MEANS.D. 1.6591 0.0879 1.7154 0.1239 1. 6717 0 .1646 1.6116 0.3330 1. 7483 0 .1549 SEMINAL VESICLES WITH FLUID MEANS.D. 1. 7055 0. 23 70 1.5439 0.2672 1.6385 0.2912 1.5473 0.3182 1. 4424 0. 2669 SEMINAL VESICLES WITHOUT FLUID MEANS.D. 0.8440 0.1038 0.8118 0.111? 0.7965 0.1068 0.7670 0.1477 0. 7772 0 .1163 EPIDIDYMIS RIGHT MEANS.D. 0.6745 0.0424 0.6546 0.0409 0.6534 0.0555 0.6106 0.1218 0.6261 0.0409 TESTIS RIGHT MEANS.D. 1.6777 0.0936 1. 7281 0 .1287 1. 6922 0 .1642 1.6175 0.3393 1.7604 0.1447 PROSTATE MEANS.D. 1.2902 0.2968 1.2000 0.1297 1.2267 0.2694 1. 2734 0 .1659 1.1918 0. 2344 BRAIN MEANS.D. 2.40 0.11 2.44 0.11 2.38 0.09 2.38 0.09 2.40 0.10 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . ..f:::.. -00 I 0 N 00 ~ ~mcoI tJ.) PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B3 (PAGE 2) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS - SUMMARY - Fo GENERATION MALE RATS ------------------------------------------------------------------------------------------------------------------------------------ DOSAGE GROUP I II III IV v DOSAGE (MG/KG/DAY) 0 0.3 1 3 10 ------------------------------------------------------------------------------------------------------------------------------------ RATS TESTED N 10 10 10 10 10 TERMINAL BODY WEIGHT MEANS.D. 469.7 31. 6 448.8 37.8 455.8 55.2 472. 3 38.3 440.8 12.6 LIVER MEANS.D. 14.63 1. 81 14.22 1. 58 15.94 3.56 17.60 1.64* 22.83 2.73** KIDNEY LEFT MEANS.D. 1. 98 0.25 1. 86 0.12 1.96 0.26 2.04 0.17 2.01 0 .18 KIDNEY RIGHT MEANS.D. 2.02 0.26 1. 90 0.15 2.00 0.24 2.13 0.18 2.04 0.14 ADRENAL LEFT MEANS.D. 0.035 0.007 0.035 0.007 0.034 0.005 0.032 0.006 0.032 0.004 ADRENAL RIGHT MEANS.D. 0.034 0.006 0.034 0.006 0.030 0.007 0.032 0.007 0.029 0.007 SPLEEN MEANS.D. 0.79 0.14 0.81 0.07 0.76 0.12 0.88 0.19 0.78 0.10 THYMUS MEANS.D. 0.41 0.12 0.45 0.09 0.36 0.10 0.42 0.09 0.42 0.05 HEART MEANS.D. 1.55 0.10 1. 52 0.12 1.54 0.13 1.60 0.13 1.44 0.07 ------------------------------------------------------------------------------------------------------------------------------------ ALL WEIGHTS WERE RECORDED IN GRAMS (G) . * Significantly different from the Group I value (p~0.05). ** Significantly different from the Group I value (p~0.01). ..J..:.:.... 00 I ~ 0 N 00 ~ t:tJ I .J::.. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B4 (PAGE 1) : RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II III IV v 0 0.3 1 3 10 RATS TESTED N 10 10 10 10 10 TERMINAL BODY WEIGHT MEANS.D. 469.7 31. 6 448.8 37.8 455.8 55.2 472.3 38.3 440.8 12.6 EPIDIDYMIS LEFT MEANS.D. 0.138 0.014 0.142 0.015 0.138 0.018 0.126 0.027 0.138 0.011 CAUDA EPIDIDYMIS LEFT MEANS.D. 0.068 0.009 0.071 0.012 0.071 0.007 0.063 0.015 0.068 0.008 TESTIS LEFT MEANS.D. 0.354 0.024 0.385 0.047 0.370 0.041 0.342 0.078 0.397 0.041 SEMINAL VESICLES WITH FLUID MEANS.D. 0.366 0.064 0.348 0.073 0.359 0.063 0.329 0.081 0.326 0.062 SEMINAL VESICLES WITHOUT FLUID MEANS.D. 0.181 0.031 0.183 0.038 0.176 0.022 0.163 0.038 0.176 0.026 EPIDIDYMIS RIGHT MEANS.D. 0.143 0.016 0.147 0.018 0.145 0.016 0.127 0.028 0.141 0.012 TESTIS RIGHT MEANS.D. 0.357 0.030 0.386 0.049 0.374 0.042 0.344 0.078 0.400 0.035 PROSTATE MEANS.D. 0.276 0.073 0.267 0.022 0.271 0.061 0.274 0.052 0.270 0.054 BRAIN MEANS.D. 0.510 0.030 0.546 0.053 0.528 0.050 0.506 0.041 0.545 0.027 ------------------------------------------------------------------------------------------------------------------------------------ ALL WEIGHTS WERE RECORDED IN GRAMS (G). RATIOS (%) = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. ....(.;.:.:.a... ~00 I 0 N 00 ~ t"I.1 Oj I Ul PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B4 (PAGE 2): RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II 0 0.3 RATS TESTED N 10 10 TERMINAL BODY WEIGHT MEANS.D. 469.7 31.6 448.8 37.8 LIVER MEANS.D. 3.109 0.264 3.165 0.208 KIDNEY LEFT MEANS.D. 0.419 0.032 0.415 0.033 KIDNEY RIGHT MEANS.D. 0.428 0.036 0.426 0.044 ADRENAL LEFT a MEANS.D. 7.419 1.226 7.837 1.573 ADRENAL RIGHT a MEANS.D. 7.202 1.181 7.587 1.353 SPLEEN MEANS.D. 0.168 0.025 0.180 0.024 THYMUS MEANS.D. 0.086 0.024 0.099 0.017 HEART MEANS.D. 0.331 0.021 0.339 0.014 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Value was multiplied by 1000. ** Significantly different from the Group I value (p~0.01). III IV v 1 3 10 10 10 10 455.8 55.2 472.3 38.3 440.8 12.6 3.466 0.396 3.728 0.212** 5.190 0.702** 0.429 0.030 0.433 0.025 0.456 0.042 0.441 0.030 0.450 0.032 0.463 0.034 7.427 1.196 6.929 1.461 7.280 0.836 6.603 1.636 6.788 1.503 6.680 1.514 0.167 0.019 0.183 0.030 0.177 0.023 0.077 0.019 0.089 0.019 0.095 0.013 0.340 0.024 0.337 0.015 0.327 0.012 RATIOS (%) = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. ..J:::.. -00 I 0 N 00 ~ ~ m OJ I 0'-1 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1} TABLE BS (PAGE 1): RATIOS (%} OF ORGAN WEIGHT TO BRAIN WEIGHT - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP I DOSAGE (MG/KG/DAY) 0 RATS TESTED N 10 BRAIN WEIGHT MEANS.D. 2.40 0.11 EPIDIDYMIS LEFT MEANS.D. 27.10 2.14 CAUDA EPIDIDYMIS LEFT MEANS.D. 13.83 1.28 TESTIS LEFT MEANS.D. 69.36 4.17 SEMINAL VESICLES WITH FLUID MEANS.D. 71. 40 11. 06 SEMINAL VESICLES WITHOUT FLUID MEANS.D. 35.34 4.98 EPIDIDYMIS RIGHT MEANS.D. 28.22 2.23 TESTIS RIGHT MEANS.D. 70.19 5.17 PROSTATE MEANS.D. 54.35 14.08 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . II 0.3 10 2.44 0.11 26.11 1.77 13.05 0.96 70.39 4.40 III 1 10 2.38 0.09 26.39 1.99 13.59 1.18 70.28 6.50 IV 3 10 2.38 0.09 24.77 4.51 12.20 2.80 67.41 13.64 v 10 10 2.40 0.10 25.55 2.21 12.66 1.32 72.79 6.71 63.64 12.45 68.84 12.04 64.77 12.58 59.83 10.03 33.48 5.71 26.90 2.06 70.94 5.02 49.41 6.63 33.44 4.03 32.14 5.94 32.30 4.57 27.47 2.16 25.57 5.13 26.08 2.00 71.14 6.42 67.66 13.99 73.30 6.34 51. 57 11. 28 53.52 7.70 49.48 RATIOS (%) = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. 9.23 ,+_;:.:...... ~00 I 0 tv 00 ~ to I -l PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE BS (PAGE 2): RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II 0 0.3 RATS TESTED N 10 10 BRAIN WEIGHT MEANS.D. 2.40 0.11 2.44 0.11 LIVER MEANS.D. 611.89 79.55 584.43 68.39 KIDNEY LEFT MEANS.D. 82.68 9.11 76.46 5.95 KIDNEY RIGHT MEANS.D. 84.22 9.20 77.94 6.26 ADRENAL LEFT MEANS.D. 1.46 0.27 1.44 0.31 ADRENAL RIGHT MEANS.D. 1.41 0.25 1.40 0.26 SPLEEN MEANS.D. 32.90 5.93 33.34 3.91 THYMUS MEANS.D. 17.22 5.29 18.37 4.02 HEART MEANS.D. 64.91 3.78 62.49 5.04 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . * Significantly different from the Group I ** Significantly different from the Group I value value (p~0.05). (p~0.01). III IV v 1 3 10 10 10 10 2.38 0.09 2.38 0.09 2.40 0.10 667.08 129.02 739.11 73.28** 948.61 95.12** 82.16 9.05 85.78 7.04 83.64 8.05 84 .13 7. 94 89.26 6.52 85.00 6.56 1.42 0.24 1.36 0.25 1.34 0.18 1.26 0.33 1.34 0.26 1.23 0.29 31.83 4.39 36.64 7.27 32.44 3.96 14.93 4.04 17.75 3.63 17.46 2.39 64.67 4.56 66.89 4.77 59.97 3.51* RATIOS (%) = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. ~ 0"'""0"" I 0 N 00 ~ @ l:d I 00 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B6 (PAGE 1) : HEMATOLOGY - SUMMARY - Fo GENERATION MALE RATS (See abbreviations on the last page of this table.) DOSAGE GROUP I II III IV V __r:~~.s!~_J.!'2.~~.!<..~!?~-~L-----------------------------------9----------------------2-~~----------------------!-----------------------2-----------------------~-o---------- RATS TESTED N 10 10 10 10 10 WBC (THSN/CU MM) MEAN S.D. 15.3 1.63 14.9 3.03 13.8 2.84 16.2 3.97 14.7 3.07 RBC (MILL/CU MM) MEAN S.D. 7.51 0. 648 7.33 0. 3 96 7.32 0. 441 6.93 0.305* 6.99 0.442* HGB (GRAMS/DL) HCT (%) MCV (CU MICRONS) MCH (PICO GRAMS) MCHC (%) PLAT (THSN/CU MM) MEAN S.D. 16.5 MEAN S.D. 43.5 MEAN S.D. 57.9 MEAN S.D. 22.0 MEAN S.D. 38.0 MEAN S.D. 1179 1.16 3.48 1. 89 0.87 0.93 130. 9 15.9 42.2 57.7 21. 8 37.7 1131 0.42 1.57 2.27 1.13 1.15 183. 7 15.7 0. 59* 42.0 2.22 57.4 1. 78 21. 5 0.75 37.5 0.79 1115 149. 2 15.4 40.2 57.9 22.2 38.4 1104 0.67** 2.29** 1.15 0.45 0.80 91.4 15.6 0.81* 40.7 1.81* 58.3 1.37 22.3 38.3 1148 0.56 0.70 159. 9 _!2.~Y--L~:!-!2.!~~~~l_____________~~~-i--~~P~----~~-~----~----~~_s-~-------~~~-----t-----~~~-------~~.?_____! ____~.?-~------!l-~~----l----2-~Z~-------~~2-----~----~~.?-9__, * Significantly different from the Group I value (p~0.05). ** Significantly different from the Group I value (p~0.01). ,~ ........ ~00 I 0 l'....J 00 ~ tT1 t:C I ' PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B6 (PAGE 2) : HEMATOLOGY - SUMMARY - Fo GENERATION MALE RATS (See abbreviations on the last page of this table.) DOSAGE GROUP I II III IV V -.P..~~<!~--~~~l.!<~~!'.?:L___________________________________9______________________2_~~----------------------!-----------------------]_______________________}_o__________, RATS TESTED N 10 10 10 10 10 PT (SECONDS) MEAN S.D. 13.4 0.24 14.2 0.27** 13.6 0.23 13.8 0. 40* 14.0 0.47** APTT (SECONDS) MEAN S.D. 21.0 3.09 22.1 4.41 20.6 2.38 21.2 2.24 21. 3 1.43 NRBC COUNT MEAN S.D. 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 Lymphocytes (THSN/CU MM) MEAN S.D. 11.9 1. 72 11. 0 2.68 10.8 2.02 12.1 3.57 12.4 2.75 Segmented (THSN/CU MM) MEAN S.D. 2.2 0.73 2.9 1.18 2.0 1. 06 2.8 0.73 1.6 0.78 Bands (THSN/CU MM) MEAN S.D. 0.0 0.00 0.0 0.00 0.0 0.03 0.0 0.03 0.0 0.00 Monocytes (THSN/CU MM) MEAN S.D. 0.8 0.56 0.7 0.50 0.6 0.51 0.8 0.67 0.5 0.33 Eosinophils (THSN/CU MM) MEAN S.D. 0.3 0.20 0.3 0.21 0.3 0.21 0.3 0.26 0.2 0.15 Basophils (THSN/CU MM) MEAN S.D. 0.0 0.00 0.0 0.00 0.0 0.00 0.0 0.00 0.0 0.00 Abnormal L (THSN/CU MM) MEAN S.D. 0.1 0.20 0.1 0.14 0.1 0.07 0.2 0.22 0.1 0.21 ____ ___ _____ _______ _____ -~~~~-::,_JJ!!.~~l-<:.q_~L----------~E!~-~--~~P~----9~_o_ ! ____9~--~--------~9 :1;.____o_~92 ~~-0_____! ____~---------2-~~----.!. 2_~~9-------~~2 !----~~2--- .+...:..:..-. * Significantly different from the Group I value (p$0.05). 00 I ** Significantly different from the Group I value (p$0.0l). 0 t...J 00 ~ ~t:C I ......... 0 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B6 (PAGE 3): HEMATOLOGY - SUMMARY - Fo GENERATION MALE RATS KEY TO HEMATOLOGY TABLE _2!,~~~~~!~-1:~~!:1----------------------------------------------------------1:~~-~~~.!'-~~~--------------------------------------------------------------------------------- WBC White Blood Cells (Leukocytes) RBC Red Blood Cells (Erythrocytes) HGB Hemoglobin HCT Hematocrit (Packed Cell Volume) MCV Mean Corpuscular Volume MCH Mean Corpuscular Hemoglobin MCHC Mean Corpuscular Hemoglobin Concentration PLAT Platelet Count MPV Mean Platelet Volume PT Prothrombin Time APTT Activated Partial Thromboplastin NRBC Nucleated Red Blood Cell Count ,~ _.... Segmented Segmented Neutrophils 00 I 0 N Abnormal L Abnormal Lymphocytes 00 ;-t; ~ Other Other Cells tT.I t:C ,,__I........ PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B7 (PAGE 1) : CLINICAL CHEMISTRY - SUMMARY - Fo GENERATION MALE RATS (See abbreviations on the last page of this table.) DOSAGE GROUP I II III IV V o________________________ _p_~~~,9-~_J!;'I.9.!..~9l~~!l_______________________________ ~~..3- _______________________ !-------------------------~------------------------~~---------- RATS TESTED N 10 10 10 10 10 TP (G/DL) A (G/DL) GLU (MG/DL) CHOL (MG/DL) TBILI (MG/DL) MEAN S.D. MEAN S.D. MEAN S.D. MEAN S.D. MEAN S.D. 6.3 0.36 4.3 0.22 145 16.8 57 8.3 0.2 0.07 6.1 0.28 4.1 0.19 141 26.0 41 11.l** 0.1 0.05 6.3 0.33 4.3 0.15 182 58.2 46 11. 6* 0.1 0.06 6.2 0.28 4.2 0.17 162 25.2 43 13.1** 0.1 0.05 6.3 0.28 4.5 0.20** 165 33.7 33 7. 2** 0.2 0. 06 BUN (MG/DL) MEAN S.D. 16 1. 5 16 0.8 16 1. 8 17 1. 6 21 2.4** CREAT (MG/DL) MEAN S.D. 0.3 0. 04 0.3 0. 05 0.3 0.06 0.3 0.03 0.3 0.05 CK (U/L) MEAN S.D. 288 172.6 246 111. 5 239 112 .9 196 53.5 243 117 .4 _.!!.J:.!__~l!/..~l---------------~~~--t-~~~~------~~------t----!i-~~---------~~-----~----..6~:~--------!i_o______! ____2J..~~--------~2______:t___~~-~~~--------~~-----..t.----Z~-o___, * Significantly different from the Group I value (p~0.05). ** Significantly different from the Group I value (p~0.01). ,~ _... 00 I 0 N 00 ;-t; ~tx:l ,_I ... N PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B7 (PAGE 2): CLINICAL CHEMISTRY - SUMMARY - Fo GENERATION MALE RATS (See abbreviations on the last page of this table.) DOSAGE GROUP I II I II IV V _.RA.~T~S~9-T~E_SJT!:E'Dl.?.!..~9!.P..1.!~l---N---------------------1-0--------------------------1-0---9~..3-------------------1-0----~----------------------1-0--~------------------------1~0~---------- AST (U/L) MEAN S.D. 96 22.4 121 92.6 117 40.9 198 248. 7 97 15.6 ALK (U/L) MEAN S.D. 105 14.3 111 36.9 100 12.4 115 25.1 144 37.5** CA (MG/DL) MEAN S.D. 10.9 0.48 10.7 0.44 11.1 0.44 11.1 0.34 11.5 0.38** PHOS (MG/DL) MEAN S.D. 9.5 1.40 9.4 1.11 9.9 2.09 9.7 1.43 10.2 1. 33 TRI (MG/DL) MEAN S.D. 52 21. 8 47 17.2 36 13.8 36 27.9 17 8.0** NA (MMOL/L) MEAN S.D. 146 1.4 146 1.3 147 1. 6 147 1. 0 146 2.2 K (MMOL/L) MEAN S.D. 6.6 2.10 6.1 0.89 6.5 1.27 6.0 0.60 6.9 1. 55 CL (MMOL/L) MEAN S.D. 98 2.7 99 1. 5 100 2.3 100 2.7 100 1. 2 G (G/DL) MEAN S.D. 2.0 0.19 2.0 0.16 2.0 0.24 2.0 0.16 1. 8 0.13 ____ -~.L~--~~<2~~1--------------~~~--=t-~~.P..~-----~-~~-----=t----~~~~--------~~-1_____.,t_____o_~~~--------~~~-----! 9~-='-~-------f-~~-----=t----~~~_s--------~~-~----1=---E-~~z::.. ** Significantly different from the Group I value (pS0.01). ~ ~ ~00 I 0 N 00 ~ tT.l t:O I ~ (J.) PROTOCOL 418-028: ORAL {GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST {SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B7 {PAGE 3): CLINICAL CHEMISTRY - SUMMARY - Fo GENERATION MALE RATS KEY TO CLINICAL CHEMISTRY TABLE ABBREVIATION TP TERMINOLOGY Total Protein A Albumin GLU Glucose CHOL Cholesterol TB I LI Total Bilirubin BUN Blood Urea Nitrogen CREAT Creatinine ALT Alanine Aminotransferase AST Aspartate Aminotransferase ALK Alkaline Phosphatase CA Calcium PHOS Phosphorus TRI Triglycerides +::-. I--' NA Sodium 00 I 0 K Potassium t'-..J 00 ~ CL Chloride >~ G Globulin tP I -~.!..~------------------------------------------------------------------------2!.~~~!,ll~~L9}_~~~2--~~-~!1..1:.~9---------------------------------------------------------------- I--' +::-. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B8 (PAGE 1) : BODY WEIGHTS - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP I II III IV v DOSAGE (MG/KG/DAY) 0 0.3 1 3 10 ------------------------------------------------------------------------------------------------------------------------------------ RATS TESTED N 15 15 15 15 15 BODY WEIGHT (G) DAY 1 MEANS.D. 342.7 12.6 338.9 13.l 341.9 14.7 345.6 11.2 343.3 12.4 DAY 8 MEANS.D. 382.7 22.2 376.1 19.5 380.5 21.6 386.6 21.5 376.7 11.7 DAY 14a MEANS.D. 407.3 25.4 400.7 23.7 404.3 29.8 412.9 25.4 397.3 12.3 DAY 29b MEANS.D. 456.6 38.9 450.3 30.9 456.6 44.6 468.5 32.0 437.7 15.4 DAY 36 MEANS.D. 480.2 38.2 466.5 32.6 476.8 47.7 481.1 33 .1 454.1 16.6 DAY 43 MEANS.D. 490.5 37.2 475.1 38.3 482.5 53.l 490.5 40.2 462.1 22.0 TERMINAL BODY WEIGHT MEANS.D. 472.5 33.9 453.7 34.3 463.1 48.2 468.3 37.1 441.5 16.5 ------------------------------------------------------------------------------------------------------------------------------------ DAY = DAY OF STUDY a. Last value recorded before cohabitation. b. First value recorded after cohabitation. ~ ~ 00 I 0 N 00 ~ ~ tT.l to I ~ Vl PROTOCOL 418-028: ORAL {GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST {SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B9 {PAGE 1) : BODY WEIGHT CHANGES - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II III IV v 0 0.3 1 3 10 RATS TESTED N 15 15 15 15 15 BODY WEIGHT CHANGE {G) DAYS 1 - 8 MEANS.D. +39.9 12.3 +37. 2 11. 0 +38.5 10.0 +41.0 12.1 +33. 4 5.6 DAYS 8 - 14a MEANS.D. +24.7 6.8 +24.6 5.0 +23.8 11.1 +26.3 8.2 +20.6 4.8 DAYS 1 - 14a MEANS.D. +64.6 16.5 +61.8 14.6 +62.3 18.3 +67.3 16.3 +54.0 7.0 DAYS 29b- 36 MEANS.D. +23.6 8.6 +16.2 7.8* +20.2 5.6 +12.6 5.4** +16.5 8.4* DAYS 36 - 43 MEANS.D. +10.3 10.8 +8. 7 11. 2 +5.7 14.4 +9.4 12.9 +7.9 13.7 DAYS 29bTERMINATION MEANS.D. +15.9 11.7 +3 .4 7.9** +6.5 10.1* -0.2 7.7** +3.8 11.8** DAYS 1 - TERMINATION MEANS.D. +129.8 25.5 +114.8 27.5 +121.2 37.7 +122.7 30.0 +98.2 13.9** ------------------------------------------------------------------------------------------------------------------------------------ DAY(S) = DAY(S) OF STUDY a. Last value recorded before cohabitation. b. First value recorded after cohabitation. * Significantly different from the Group I value {p~0.05). ** Significantly different from the Group I value {p~0.01). ~ -00 I 0 N 00 ~ >~txJ I O"'""""'I" PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE BlO (PAGE 1) : ABSOLUTE FEED CONSUMPTION VALUES (G/DAY) - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP I DOSAGE (MG/KG/DAY) 0 RATS TESTED N 15 FEED CONSUMPTION (G/DAY) DAYS 1 - Sa MEANS.D. 28.4 3.1 DAYS 29b- 36 MEANS.D. 30.2 2.6 [ 14) c DAYS = DAYS OF STUDY [ ] = NUMBER OF VALUES AVERAGED a. Last value recorded before cohabitation. b. First value recorded after cohabitation. c. Excludes values that were associated with spillage. II 0.3 15 27.8 2.0 28.8 2.5 III 1 15 29.1 3.3 29.8 2.5 IV 3 15 28.8 2.6 29.3 2.8 v 10 15 26.9 1. 4 28.2 2.2 .,i::.. ~ 00 I 0 l'...J 00 ~ >~tx' I ~ -.J PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE Bll (PAGE 1) : RELATIVE FEED CONSUMPTION VALUES (G/KG/DAY) - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP I DOSAGE (MG/KG/DAY) 0 RATS TESTED N 15 FEED CONSUMPTION (G/KG/DAY) DAYS 1 - Sa MEANS.D. 78.3 7.2 DAYS 29b- 36 MEANS.D. 64.2 3.2 [ 14] c DAYS = DAYS OF STUDY [ ] = NUMBER OF VALUES AVERAGED a. Last value recorded before cohabitation. b. First value recorded after cohabitation. c. Excludes values that were associated with spillage. II 0.3 15 77. 7 3.9 62.8 4.5 III 1 15 80.1 6.9 64.1 4.2 IV 3 15 78.2 4.3 61.7 3.7 v 10 15 74.7 3 .3 63.2 3 .6 +::-. lo--" 00 I 0 tv 00 ~ >~OJ I lo--" 00 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B12 (PAGE 1) : MATING AND FERTILITY - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II III 0 0.3 1 RATS IN COHABITATION N 15 15 15 DAYS IN COHABITATION a MEANS.D. 3.2 1.4 1. 9 1.2 2.8 1. 2 RATS THAT MATED N(%) 14 ( 93. 3) 15(100.0) 15(100.0) FERTILITY INDEX b N/N 14/ 14 (%) (100.0) 15/ 15 (100. O) 13/ 15 ( 86.7) RATS WITH CONFIRMED MATING DATES f N 14 15 15 MATED WITH FIRST FEMALE c DAYS 1-7 N(%) 14(100.0) 15(100.0) 15(100.0) RATS PREGNANT/RATS IN COHABITATION N/N 14/ 15 (%) ( 93.3) 15/ 15 (100.0) 13/ 15 ( 86.7) a. Restricted to rats with a confirmed mating date and rats that did not mate. b. Number of pregnancies/number of rats that mated. c. Includes only one mating for each male rat. IV 3 15 3.1 2.0 13( 86.7) 12/ 13 ( 92.3) 13 13(100.0) 12/ 15 ( 80.0) v 10 15 2.5 1.4 15(100.0) 15/ 15 (100.0) 15 15(100.0) 15/ 15 (100.0) ~ ~ ~00 I 0 l'...J 00 ~ ~ I ~ \D PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE Bl3 (PAGE 1) : FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP I II III IV V --~Q!\_q_~_J!:'LG./..~QLP~'!.L------------------------------------2----------------------2~}-----------------------~------------------------]-------------------------~~----------- MALE RATS N 10 10 10 10 10 HOME CAGE BEHAVIOR 1: Sleeping N 2 3 3 2: Awake, Immobile N 8 7 7 3: Normal movement N 0 0 0 4: Unusual posture N 0 0 0 5: Unusual behavior N 0 0 0 8** 2 2** 8 0 0 0 0 0 0 ALTERATIONS (HOME CAGE) 1: None N 9 10 10 10 10 2: Stereotyped behavior N la 0 0 0 0 3: Bizarre behavior N 0 0 0 0 0 4: Limb twitches/tremor N 0 0 0 0 0 5: Whole body tremor/spasm N 0 0 0 0 0 6: Unusual posture N 0 0 0 0 0 7: Tonic-clonic seizure N 0 0 0 0 0 REACTION TO REMOVAL (1) Sits quietly N 10 10 10 10 10 (2) Vocalization N 0 0 0 0 0 (3) Runs or freezes N 0 0 0 0 0 (4) Tail or throat rattles N 0 0 0 0 0 MEAN SCORE 1. 0 1. 0 1. 0 1. 0 1. 0 .,i::.. 0"'""0"' I REACTION TO HANDLING 0 t-...) (1) No resistance N 10 10 10 10 10 00 (2) Vocalization N 0 0 0 0 0 ~ (3) Tense N 0 0 0 0 0 ~ (4) Squirming N O 0 0 O O ______________________ ___________ ------------------------------------~~~-_f_q_~~----------l~----------------------l~-----------------------!~2 1~_0_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ !~2 tlj n: = Category number for descriptive test item. I t-...) (n) = Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score 0 and then dividing the sum of the products by the total number of rats a. Excludes a value for rat 19131, which appeared incorrectly recorded. ** Significantly different from the Group I value (p~0.01). PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B13 (PAGE 2) : FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION MALE RATS DOSAGE GRQUP I II III IV V --~Ql\_q_~-j~_G_l~Qj,P_J!~l-----------------------------------------------------------~-l----------------------!------------------------2-------------------------1_~----------- MALE RATS N 10 10 10 10 10 REARS IN OPEN FIELD DEFECATION IN OPEN 1: None 2: Feces normal 3: Soft or liquid FIELD feces MEANS.D. 3.3 2.5 N 10 N 0 N 0 6.2 3.2 8 2 0 3.9 1. 9 7 3 0 4.5 2.1 9 1 0 4.5 3.1 9 1 0 URINATION IN OPEN FIELD (1) None N 6 1 6 2 3 (2) Normal urination N 4 9 4 8 7 (3) Excess urination N 0 0 0 0 0 MEAN SCORE 1.4 1. 9 1.4 1. 8 1. 7 LEVEL OF AROUSAL (1) Stuporous N 0 0 0 0 0 (2) Sluggish N 0 0 0 0 0 (3) Apparently normal N 10 10 10 10 10 (4) Sudden darting N 0 0 0 0 0 (5) Freezing, vocalization N 0 0 0 0 0 MEAN SCORE 3.0 3.0 3.0 3.0 3.0 ALTERATIONS (OPEN FIELD) ..j:::.. ~ 1: None N 10 10 10 10 10 00 I 2: Stereotyped behavior N 0 0 0 0 0 0 tv 3: Bizarre behavior N 0 0 0 0 0 00 4: Limb twitches/tremor N 0 0 0 0 0 ~ > 5: Whole body tremor/spasm N 0 0 0 0 0 6: Unusual posture N 0 0 0 0 0 F6 --Zl---!~~iE_-_s19EJ_c;,_~~j.-~~E~------------l!.-----------------------------------------------------------------2------------------------2------------------------------------- t;O I n: = Category number for descriptive test item. tv (n) = Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score ~ and then dividing the sum of the products by the total number of rats PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B13 (PAGE 3): FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP I II III IV V __J2.Ql\i!.~_Jt'J9.L.~QLP.!!.~~-----------------------------------------------------------2~-3..----------------------~------------------------]-------------------------:l.:.~----------- MALE RATS N 10 10 10 10 10 GAIT PATTERN 1: Apparently normal N 10 10 10 10 10 2: Ataxic N 0 0 0 0 0 3: Limbs splay or drag N 0 0 0 0 0 4: Spastic, tip-toe N 0 0 0 0 0 5: Duck-walk N 0 0 0 0 0 6: Scissors gait N 0 0 0 0 0 GAIT ABNORMALITY, SEVERITY (1) Normal gait N 10 10 10 10 10 (2) Slight N 0 0 0 0 0 (3) Moderate N 0 0 0 0 0 (4) Extreme N 0 0 0 0 0 MEAN SCORE 1. 0 1.0 1. 0 1. 0 1. 0 PALPEBRAL CLOSURE (1) Wide open N 10 10 10 10 10 (2) Slightly drooping N 0 0 0 0 0 (3) Half-closed N 0 0 0 0 0 (4) Completely shut N 0 0 0 0 0 MEAN SCORE 1. 0 1. 0 1.0 1.0 1. 0 ,.,_i::_:... PROMINENCE OF THE EYE 00 I 1: Normal N 10 10 10 10 10 0 t-J 2 : Exophthalmos N 0 0 0 0 0 00 > --~~---Elll~~l1-t_1l~1.!!1..0_~--------------------..!'!-----------------------------------------------------------------2------------------------2-------------------------2------------ ~ n: = Category number for descriptive test item. ~ (n) = Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score and then dividing the sum of the products by the total number of rats td I t-J t-J PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE Bl3 (PAGE 4): FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP I II III IV V --~Ql\_q_~_Jfl.2/..~QLP_J!~l-----------------------------------------------------------2~-l----------------------!------------------------1------------------------2-~----------- MALE RATS N 10 10 10 10 LACRIMATION (1) No excess N 10 10 10 10 10 (2) Excess at eyelid margin N 0 0 0 0 0 (3) Margin persistently damp N 0 0 0 0 0 (4) Extends beyond margin N 0 0 0 0 0 MEAN SCORE 1. 0 1. 0 1. 0 1.0 1. 0 SALIVATION (1) No excess N 10 10 10 10 10 (2) Margin of mouth wet N 0 0 0 0 0 (3) 1/4 to 1/2 submandibular N 0 0 0 0 0 (4) Entire submandibular N 0 0 0 0 0 MEAN SCORE 1. 0 1.0 1. 0 1.0 1. 0 PILOERECTION N 0 0 0 0 0 ABNORMAL RESPIRATION N 0 0 0 0 0 APPEARANCE (1) Clean and groomed N 10 10 10 10 10 (2) Unkempt N 0 0 0 0 0 (3) Urine and/or fecal stain N 0 0 0 0 0 MEAN SCORE 1.0 1. 0 1. 0 1. 0 1.0 ..j::::. ...... VISUAL REACTION 00 I 0 (1) None N 0 0 0 0 0 tv (2) Orienting N 10 10 10 10 10 00 ~ (3) Startle N 0 0 0 0 0 > (4) More energetic reaction N 0 0 0 0 ~ (5) At tacks N 0 0 O 0 0 ____________________________________f1!!_1!I:!_s_q,~~----------3~_q_____________________3~_q______________________~~2______________________ __________ 3~------------------------~~2 _ to I n: = Category number for descriptive test item. wtv (n) = Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score and then dividing the sum of the products by the total number of rats PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B13 (PAGE 5) : FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION MALE RATS --D-O--S-A-G-E--G--R-O-U-P---------------------------------------------I-----------------------I-I-----------------------I-I--I-----------------------I-V--------------------------V------------ --~2l\_C!~_J!:19.L~gLP-1!~l-----------------------------------------------------------2~-~----------------------~------------------------]--------~----------------~~----------- MALE RATS N 10 10 10 10 10 TACTILE REACTION (1) None N 0 0 0 0 0 (2) Orienting N 10 10 10 10 10 (3) Startle N 0 0 0 0 0 (4) More energetic reaction N 0 0 0 0 0 (5) Attacks N 0 0 0 0 0 MEAN SCORE 2.0 2.0 2.0 2.0 2.0 AUDITORY REACTION (1) None N 0 0 0 0 0 (2) Orienting N 0 0 0 0 0 (3) Startle N 10 10 10 10 10 (4) More energetic reaction N 0 0 0 0 0 (5) Intense vocalization N 0 0 0 0 0 MEAN SCORE 3.0 3.0 3.0 3.0 3.0 TAIL-PINCH REACTION (1) None N 0 0 0 0 0 (2) Orienting N 10 10 10 10 10 (3) Startle N 0 0 0 0 0 (4) More energetic reaction N 0 0 0 0 0 (5) Attacks N 0 0 0 0 0 ..f.::.:-.. ------------------------------------!:'1!!_1!1::!_s_q,~~----------~~-~--------------------~~-~---------------------~~2______________________ 3~------------------------~~2___________ 00 I n: = Category number for descriptive test item. 0 (n) = Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score t'V 00 and then dividing the sum of the products by the total number of rats ~ >~t;O I t'V .f:::.. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B13 (PAGE 6): FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP I II III IV V --~Q!\~~-Jt19.L.~gLp_~~~-----------------------------------------------------------2~-3..----------------------!------------------------]_________________________1;.~----------- MALE RATS N 10 10 10 10 10 AIR RIGHTING RESPONSE (1) All feet land on ground N 10 10 10 10 10 (2) Lands on side N 0 0 0 0 0 (3) Lands on back N 0 0 0 0 0 MEAN SCORE 1. 0 1. 0 1. 0 1. 0 1. 0 PUPIL RESPONSE TO LIGHT N 10 10 10 10 10 FORELIMB GRIP TEST Maximum (G) Average (G) MEANS.D. MEANS.D. 444.0 410.5 49.6 52.7 451.5 400.6 57. 5 62. 7 456.0 409.4 111.1 93.7 418.5 367.5 125.8 109.0 406.5 359.2 120.7 104.6 HINDLIMB GRIP TEST Maximum (G) Average (G) MEANS.D. MEANS.D. 386.0 128.8 360.9 121.8 456.0 400.8 109.4 101.1 457.0 419.5 102.5 97.8 414.5 364.5 58.9 67.5 467.5 439 .4 113 .4 95.8 LANDING FOOT SPLAY Average (CM) MEANS.D. 7.5 1.0 8.6 2 .2 9.0 1. 3 8.6 1. 9 8.0 2.1 __ --~QPJ t;!~I.9.!!!_JgJ _______________________~--------!~j-~~---___ _______ ~j~-l------~..?_~~---1----l~~------J-II~l----i----~~~ 4_~~~~----i----~~-~------j_6_l~2 ____ t ____ l]~-~--- - n: = Category number for descriptive test item. (n) = Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score ..J::.. and then dividing the sum of the products by the total number of rats 00 I 0 t..J 00 ~ ~>t:o I t..J V'l PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE Bl4 (PAGE 1) : MOTOR ACTIVITY - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) II III IV v 0 0.3 1 3 10 NUMBER OF MALE RATS N 10 10 10 10 10 NUMBER OF MOVEMENTS BLOCK 1 MEAN S.D 64.8 6 .6 64.3 6.7 63.5 8.6 62.1 10.0 64.0 8.0 BLOCK 2 MEAN S.D 66.9 9.4 63.6 11.5 64.6 9.0 73.5 4 .4 69.6 7 .2 BLOCK 3 MEAN S.D 69.1 6. 8 59.8 16.2 65.1 8.3 71. 6 11. 7 67.5 7.8 BLOCK 4 MEAN S.D 72.3 10. 5 61.2 20.0 68.2 12.1 65.4 11.9 56.0 11. 7 BLOCK 5 MEAN S.D 60.1 12. 0 54.7 23.1 65.6 5.4 63.1 16. 5 56.9 15 .6 BLOCK 6 MEAN S.D 48.3 25 .4 52.8 26.8 64.2 12.8 59.9 14. 9 57.4 9. 9 BLOCK 7 MEAN S.D 39.4 21. 0 50.0 25.8 59.8 14.7 60.6 8.2 56.8 11.5 BLOCK 8 MEAN S.D 37.9 34. 6 46.7 24.8 54.0 19.9 57.0 19 .4 49.7 22 .2 BLOCK 9 MEAN S.D 27.6 25. 2 49. 2 22.8 49.7 23.4 55.3 20 .4 52.2 16. 9 BLOCK 10 MEAN S.D 25.0 30. 2 53.1 20.5 47.0 28.9 50.0 23 .1 49.6 15. 6 BLOCK 11 MEAN S.D 24.2 27 .1 35.1 28.3 51.2 25.5 51. 7 26. 7 41. 5 21.2 BLOCK 12 MEAN S.D 37.8 28. 0 35.1 25.7 45.5 25.9 49.1 26. 0 47.6 13. 0 BLOCK 13 MEAN S.D 42.1 31. 9 43.0 34.6 44.0 35.4 50.4 25. 6 43.0 22 .3 BLOCK 14 MEAN S.D 37.6 30. 7 43.8 29.4 36.5 26.3 59.2 19. 0 43.8 29 .6 BLOCK 15 MEAN S.D 23.3 26. 0 35.5 22.3 39.8 36.2 51. 3 21.1 43.0 25 .4 BLOCK 16 MEAN S.D 23.6 31.2 37.6 28.5 31.2 31.0 50.9 22. 7 42.5 29 .4 BLOCK 17 MEAN S.D 23.6 26. 8 39.2 30.2 29.1 25.9 53.5 24 .3 37.3 29 .6 BLOCK 18 MEAN S.D 22.8 24. 7 34.4 23.6 35.9 30.2 42.4 27. 0 34.2 23 .1 TOTAL MEAN S.D 746.4 217. 7 859.1 251. 7 914.9 212.7 1027.0 176.0 912.6 139. 0 ,._.p_.... TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 00 I 0 t-.J 00 > ~ ~tO I t-.J O'\ PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B14 (PAGE 2) : MOTOR ACTIVITY - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP I II III IV v DOSAGE (MG/KG/DAY) 0 0.3 1 3 10 ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- NUMBER OF MALE RATS N 10 10 10 10 10 TIME (SECONDS) SPENT IN MOVEMENT BLOCK 1 MEAN S.D 201.1 24 .1 201. 8 17.8 214.8 13.0 204.6 23. 7 194.8 27 .2 BLOCK 2 MEAN S.D 187.4 22. 6 174.4 32.9 195.8 33. 8 180.2 20. 9 170.1 32 .5 BLOCK 3 MEAN S.D 155.5 26 .2 140.3 63.3 172.5 35. 6 140.6 27 .5 148.7 39 .4 BLOCK 4 MEAN S.D 141.4 33. 3 138 .3 53.0 142.4 24. 7 140. 9 34 .1 130.9 50. 6 BLOCK 5 MEAN S.D 100.7 28. 5 131.1 71.4 150.3 20 .6 119 .2 29. 0 113. 8 45. 7 BLOCK 6 MEAN S.D 91.2 54. 3 89.7 52.6 118 .4 41.2 109.7 48. 8 102.7 40. 8 BLOCK 7 MEAN S.D 70.2 44 .2 90.2 55.5 110 .2 46. 9 118 .6 45. 9 107.9 38. 8 BLOCK 8 MEAN S.D 61.3 60. 8 83.7 55.9 109.9 52. 7 116 .1 50. 9 72.0 35. 9 BLOCK 9 MEAN S.D 44.0 46 .2 80.9 40.5 93.6 59 .3 103.6 56.4 93.6 47 .3 BLOCK 10 MEAN S.D 48.9 68. 7 86.6 40.3 77.4 55.3 83.1 47. 0 76.8 44 .1 BLOCK 11 MEAN S.D 40.2 59. 5 71.4 63.0 86.0 49 .1 97.7 61. 8 67.2 40. 0 BLOCK 12 MEAN S.D 58.1 46 .2 67.1 60.9 91. 7 62.1 81.1 49 .1 72.9 33. 7 BLOCK 13 MEAN S.D 66.9 56. 7 86.9 82.2 52.1 44. 8 80.2 41.2 70.5 48. 9 BLOCK 14 MEAN S.D 65.6 58. 7 75.7 55.9 54.1 47 .4 107.8 40. 9 73.3 59. 7 BLOCK 15 MEAN S.D 39.1 49. 7 53.1 46.5 68.0 65. 3 74.2 35.4 64.2 36. 9 BLOCK 16 MEAN S.D 31. 9 45 .1 55.5 47.5 60.3 73.9 87.2 43. 5 77.1 68 .2 BLOCK 17 MEAN S.D 32.0 38. 5 62.5 56.4 46.9 53 .5 91.4 49. 7 51. 0 44. 8 BLOCK 18 MEAN S.D 30.5 39. 6 47.4 46.1 56.3 54. 7 66.9 43 .5 54.1 41. 8 TOTAL MEAN S.D 1466.0 453. 9 1736.6 607.9 1900.7 469. 7 2003.1 453. 4 1741. 6 463. 4 ..j:::.. ~ TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 00 I 0 l'V 00 ~ >~t:d I l'V -..J PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B15 (PAGE 1): SPERM MOTILITY, COUNT AND DENSITY - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP I II III IV V __p_~!!.~~--i~~!'.'.!<~!'.'.P-~~1-------------------------------2----------------------------~.:]____________________________}_____________________________]____________________________2--~----------- RATS TESTED N 10 10 10 10 10 NUMBER MOTILE MOTILE PERCENT MEANS.D. MEANS.D. 289.1 51.3 92.1 3.1 307.4 77.3 93.3 2.8 312.0 80.2 92.5 3.4 307.3 85.5 149.6 22.3 325.4 81.5 91.1 7.4 STATIC COUNT (NONMOTILE) TOTAL COUNT a SPERM COUNT b MEANS.D. MEANS.D. MEANS.D. 25.2 11.3 314.3 57.7 170.1 48.8 23.5 14.4 330.9 89.7 158.2 55.2 23.1 7.8 335.1 75.6 161.0 41.6 32.7 340.0 124.6 15.3 152.4 50.2 32.4 23.4 357.8 81.2 174.5 37.9 --S--P-E-R-M----D-E--N-S-I-T--Y---c-------M--E-A--N--S--.D--.-----1--4-9--4-.-2-6---------4--4-0-.-4--0------1-4--3-0--.2--0---------4--5-8-.-0--1------1-4--4-1--.8--9----------3-4--4-.-2-8------1--2-1--4-.-6-8----------4-0-7--.-7-1------1--6-6--4-.-0-3---------3-7--0-.-3-0-- a. Sum of number motile and static count. Groups of five fields were evaluated until a sperm count of at least 200 was achieved or 20 fields were evaluated. b. Sperm count used in the calculation of sperm density. Ten fields were evaluated. c. The sperm density was calculated by dividing the sperm count by the volume in the image area (34.3 x 10-6 mL), multiplying by 2 (dilution factor) and multiplying by 10-6 to obtain the sperm co~centration. The calculated sperm concentration value (rounded to 1 decimal place) was multiplied by 50 (volume) and divided by the weight of the left cauda epididymis (see Table B19 for the weight of the left cauda epididymis) to obtain the sperm density. The calculated value will vary by approximately 0.8% from the Computer Automated Sperm Analysis because the digital image evaluated is slightly smaller (4 pixels) than the actual field causing a slight underestimate of the actual volume and an overestimate of the concentration. .~ ..... 00 I 0 l'V 00 1-d >~toI l'V 00 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B16 (PAGE 1) : SPERM MORPHOLOGY - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP I II III IV v DOSAGE (MG/KG/DAY) 0 0.3 1 3 10 ------------------------------------------------------------------------------------------------------------------------------------ RATS TESTED N 10 10 10 10 10 NORMAL MEANS.D. 192.3 3.1 193.3 3.0 193.3 3.5 173.8 59.8 193.3 3.1 DETACHED HEAD MEANS.D. 3.7 2.4 3.6 2.2 3.1 2.0 6.8 11.0 3.8 2.6 NO HEAD MEANS.D. 3.4 1. 7 2.1 1. 2 2.6 1.4 10.5 23.1 1. 8 1.3 BROKEN FLAGELLUM MEANS.D. 0.4 0.5 0.8 0.8 0.7 0.7 8.5 24.8 1.0 0.9 BENT FLAGELLUM MEANS.D. 0.2 0.4 0.2 0.4 0.3 0.7 0.4 1.3 0.1 0.3 PERCENT ABNORMAL MEANS.D. 3.8 1. 5 3.4 1. 5 3.4 1. 8 13.1 29.9 3.4 1.6 ------------------------------------------------------------------------------------------------------------------------------------ +:::- ~ 00 I 0 t--.) ;0-c0, ~ tr1 ~ I t--.) \0 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B17 (PAGE 1): CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT # DESCRIPTION DOSAGE GROUP I 0 MG/KG/DAY 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 19143 19151 19157 19161 19167 DS ( 25- 32) DS ( 43- 44) DS ( 23- 29) NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS HEAD: SCAB (0.5 CM IN DIAMETER) INCISORS: MISSING/BROKEN DEHYDRATION DOSAGE GROUP II 0. 3 MG/KG/DAY 19102 NO ADVERSE FINDINGS 19106 DS( 23 CHROMORHINORRHEA 19108 NO ADVERSE FINDINGS 19110 NO ADVERSE FINDINGS 19113 NO ADVERSE FINDINGS 19120 NO ADVERSE FINDINGS 19129 NO ADVERSE FINDINGS 19136 NO ADVERSE FINDINGS ~ 19138 NO ADVERSE FINDINGS 19139 NO ADVERSE FINDINGS 0""""0"" I 19147 NO ADVERSE FINDINGS 0 19153 DS ( 36- 46) LOCALIZED ALOPECIA: LIMBS a tv 00 19164 NO ADVERSE FINDINGS ~ 19165 DS( 6 ) SOFT OR LIQUID FECES > DS( 11 ) DRY, BROWN PERIORAL SUBSTANCE 19171 DS ( 17- 32) LOCALIZED ALOPECIA: HEAD ~td DS = DAY OF STUDY I a. Observation confirmed at necropsy. l;..l 0 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B17 (PAGE 2): CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT # DESCRIPTION DOSAGE GROUP III 1 MG/KG/DAY 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 19155 19159 19172 19173 19174 DS( 43 DS ( 11- 13) DS( 41 DS ( 46- 47) NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: NO ADVERSE FINDINGS CHROMODACRYORRHEA NO ADVERSE FINDINGS CHROMORHINORRHEA NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: NO ADVERSE FINDINGS LIMBS a UNDERSIDE a DOSAGE GROUP IV 3 MG/KG/DAY 19100 NO ADVERSE FINDINGS 19103 NO ADVERSE FINDINGS 19104 NO ADVERSE FINDINGS 19118 NO ADVERSE FINDINGS 19133 NO ADVERSE FINDINGS 19141 NO ADVERSE FINDINGS 19142 DS( 41 ) CHROMORHINORRHEA 19144 19148 NO ADVERSE FINDINGS NO ADVERSE FINDINGS .~ .._. 19150 DS ( 34- 39) INCISORS: MISSING/BROKEN 00 I DS ( 34- 42) CHROMODACRYORRHEA 0 DS ( 34- 46) INCISORS: MISALIGNED a l'J 00 ;-c, 19156 NO ADVERSE FINDINGS 19160 NO ADVERSE FINDINGS > 19162 DS ( 19- 32) LOCALIZED ALOPECIA: HEAD ~ 19163 NO ADVERSE FINDINGS 19166 NO ADVERSE FINDINGS t:d I DS = DAY OF STUDY v....._>. a. Observation confirmed at necropsy. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE Bl7 (PAGE 3): CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP V RAT # 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 19154 19158 19168 19169 19170 DS( 7- 8) DS( 34 ) DS( 25 ) DS ( 25- 37) DS( 34 ) DS = DAY OF STUDY 10 MG/KG/DAY DESCRIPTION NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS CHROMODACRYORRHEA NO ADVERSE FINDINGS LACRIMATION NO ADVERSE FINDINGS NO ADVERSE FINDINGS CHROMORHINORRHEA INCISORS: MISSING/BROKEN CHROMORHINORRHEA NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS -~ 00 I 0 N 00 > ~ ~ t:o w I N PROTOCOL 418-028: ORAL (GAVAGE} COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST {SPONSOR'S STUDY NUMBER: T-7706.1} TABLE Bl8 (PAGE l} : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY} RAT NUMBER DAY OF DOSES NECROPSY ADMINISTERED OBSERVATIONS a I 0 19109 DS 43 42 ALL TISSUES APPEARED NORMAL. 19115 DS 43 42 ALL TISSUES APPEARED NORMAL. 19116 DS 44 43 KIDNEYS: BILATERAL, MOTTLED TAN AND RED. ALL OTHER TISSUES APPEARED NORMAL. 19119 DS 44 43 ALL TISSUES APPEARED NORMAL. 19122 DS 44 43 ALL TISSUES APPEARED NORMAL. 19125 DS 45 44 ALL TISSUES APPEARED NORMAL. 19131 DS 45 44 ALL TISSUES APPEARED NORMAL. 19132 DS 45 44 ALL TISSUES APPEARED NORMAL. 19134 DS 46 45 ALL TISSUES APPEARED NORMAL. 19135 DS 46 45 ALL TISSUES APPEARED NORMAL. 19143 DS 47 46 ALL TISSUES APPEARED NORMAL. 19151 DS 47 46 ALL TISSUES APPEARED NORMAL. 19157 DS 47 46 ALL TISSUES APPEARED NORMAL. 19161 DS 47 46 ALL TISSUES APPEARED NORMAL. 19167 DS 47 46 ALL TISSUES APPEARED NORMAL. DS = DAY OF STUDY a. Refer to the individual clinical observations table (Table Bl7} for external observations confirmed at necropsy. -~ 00 I 0 tv 00 > ~ ~ to w I w PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B18 (PAGE 2) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) RAT NUMBER DAY OF DOSES NECROPSY ADMINISTERED OBSERVATIONS a II 0.3 19102 DS 43 42 KIDNEYS: BILATERAL, MOTTLED TAN AND DARK RED. ALL OTHER TISSUES APPEARED NORMAL. 19106 DS 43 42 ALL TISSUES APPEARED NORMAL. 19108 DS 44 43 ALL TISSUES APPEARED NORMAL. 19110 DS 44 43 ALL TISSUES APPEARED NORMAL. 19113 DS 44 43 KIDNEYS: LEFT, PELVIS, SLIGHT DILATION. ALL OTHER TISSUES APPEARED NORMAL. 19120 DS 45 44 ALL TISSUES APPEARED NORMAL. 19129 DS 45 44 ALL TISSUES APPEARED NORMAL. 19136 DS 45 44 KIDNEYS: BILATERAL, MOTTLED. ALL OTHER TISSUES APPEARED NORMAL. 19138 DS 46 45 ALL TISSUES APPEARED NORMAL. 19139 DS 46 45 ALL TISSUES APPEARED NORMAL. 19147 DS 47 46 ALL TISSUES APPEARED NORMAL. 19153 DS 47 46 ALL TISSUES APPEARED NORMAL. 19164 DS 47 46 ALL TISSUES APPEARED NORMAL. 19165 DS 47 46 ALL TISSUES APPEARED NORMAL. 19171 DS 47 46 ALL TISSUES APPEARED NORMAL. DS = DAY OF STUDY a. Refer to the individual clinical observations table (Table B17) for external observations confirmed at necropsy. .~ ........ 00 I 0 lV 00 ~ >~to w I ~ PROTOCOL 418-028: ORAL {GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B18 {PAGE 3): NECROPSY OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP RAT DAY OF DOSES DOSAGE {MG/KG/DAY} NUMBER NECROPSY ADMINISTERED OBSERVATIONS a ------------------------------------------------------------------------------------------------------------------------------------ III 1 19101 DS 43 42 ALL TISSUES APPEARED NORMAL. 19105 DS 43 42 ALL TISSUES APPEARED NORMAL. 19107 DS 43 42 ALL TISSUES APPEARED NORMAL. 19112 DS 44 43 ALL TISSUES APPEARED NORMAL. 19114 DS 44 43 ALL TISSUES APPEARED NORMAL. 19121 DS 45 44 ALL TISSUES APPEARED NORMAL. 19123 DS 45 44 ALL TISSUES APPEARED NORMAL. 19130 DS 46 45 ALL TISSUES APPEARED NORMAL. 19137 DS 46 45 ALL TISSUES APPEARED NORMAL. 19146 DS 46 45 ALL TISSUES APPEARED NORMAL. 19155 DS 47 46 ALL TISSUES APPEARED NORMAL. 19159 DS 47 46 ALL TISSUES APPEARED NORMAL. 19172 DS 47 46 ALL TISSUES APPEARED NORMAL. 19173 DS 47 46 ALL TISSUES APPEARED NORMAL. 19174 DS 47 46 ALL TISSUES APPEARED NORMAL. DS = DAY OF STUDY a. Refer to the individual clinical observations table {Table B17) for external observations confirmed at necropsy. ~ 0""'"0"" I 0 tv 00 > ~ ~to w I Vl PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B18 (PAGE 4) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) RAT NUMBER DAY OF DOSES NECROPSY ADMINISTERED OBSERVATIONS a IV 3 19100 DS 43 42 ALL TISSUES APPEARED NORMAL. 19103 DS 43 42 ALL TISSUES APPEARED NORMAL. 19104 DS 44 43 ALL TISSUES APPEARED NORMAL. 19118 DS 44 43 ALL TISSUES APPEARED NORMAL. 19133 DS 44 43 ALL TISSUES APPEARED NORMAL. 19141 DS 45 44 ALL TISSUES APPEARED NORMAL. 19142 DS 45 44 EPIDIDYMIDES: BILATERAL, SMALL; LEFT CAUDA, SMALL. TESTES: BILATERAL, SMALL. ALL OTHER TISSUES APPEARED NORMAL. 19144 DS 45 44 ALL TISSUES APPEARED NORMAL. 19148 DS 46 45 ALL TISSUES APPEARED NORMAL. 19150 DS 46 45 ALL TISSUES APPEARED NORMAL. 19156 DS 47 46 ALL TISSUES APPEARED NORMAL. 19160 DS 47 46 ALL TISSUES APPEARED NORMAL. 19162 DS 47 46 ALL TISSUES APPEARED NORMAL. 19163 DS 47 46 ALL TISSUES APPEARED NORMAL. 19166 DS 47 46 ALL TISSUES APPEARED NORMAL. DS = DAY OF STUDY a. Refer to the individual clinical observations table (Table B17) for external observations confirmed at necropsy. -~ 00 I 0 l:V 00 ~ >~toI (.;.) ' PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B18 (PAGE 5) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) v 10 RAT NUMBER 19111 DAY OF DOSES NECROPSY ADMINISTERED OBSERVATIONS a DS 43 42 JEJUNUM: DIVERTICULUM (1.5 CM X 0.6 CM X 0.4 CM). ALL OTHER TISSUES APPEARED NORMAL. 19117 DS 43 42 ALL TISSUES APPEARED NORMAL. 19124 DS 43 42 ALL TISSUES APPEARED NORMAL. 19126 DS 44 43 ALL TISSUES APPEARED NORMAL. 19127 DS 44 43 ALL TISSUES APPEARED NORMAL. 19128 DS 45 44 ALL TISSUES APPEARED NORMAL. 19140 DS 45 44 ALL TISSUES APPEARED NORMAL. 19145 DS 46 45 ALL TISSUES APPEARED NORMAL. 19149 DS 46 45 ALL TISSUES APPEARED NORMAL. 19152 DS 46 45 ALL TISSUES APPEARED NORMAL. 19154 DS 47 46 ALL TISSUES APPEARED NORMAL. 19158 DS 47 46 ALL TISSUES APPEARED NORMAL. 19168 DS 47 46 ALL TISSUES APPEARED NORMAL. 19169 DS 47 46 ALL TISSUES APPEARED NORMAL. 19170 DS 47 46 ALL TISSUES APPEARED NORMAL. DS = DAY OF STUDY a. Refer to the individual clinical observations table (Table B17) for external observations confirmed at necropsy. -~ 00 I 0 l:V 00 ~ >~tt:I w I .......J PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B19 (PAGE 1) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP I 0 MG/KG/DAY RAT TERMINAL BODY NUMBER WEIGHT EPIDIDYMIS LEFT ABS. REL. WT. % TBW CAUDA EPIDIDYMIS LEFT ABS. REL. WT. % TBW TESTIS LEFT ABS. REL. WT. % TBW SEMINAL VESICLES WITH FLUID ABS. REL. WT. % TBW SEMINAL VESICLES WITHOUT FLUID ABS. REL. WT. % TBW EPIDIDYMIS RIGHT ABS. REL. WT. % TBW 19109 1911S 19116 19119 19122 1912S 19131 19132 19134 1913S 438. 466. 490. sos. 4Sl. S08. 499. 439. 419. 482. 0.6013 0.6976a 0.6499 0.6S41 0.6661 0.6160 0.6482 0. 7103 0.6278 0.60S2 0.14 O.lS 0.13 0.13 O.lS 0.12 0.13 0 .16 O.lS 0.12 0.2822 0.3438 0.3209 0.3489 0. 3724 0.3260 0. 3140 0.3684 0.3368 0.2942 0.06 0.07 0.06 0.07 0.08 0.06 0.06 0.08 0.08 0.06 l.S706 1. 6971 1. 6213 1.7174 1.67S4 1. 6621 1.686S 1.8079 1. 4801 1. 6728 0.36 0.36 0.33 0.34 0.37 0.33 0.34 0.41 0.3S 0.3S 1.3331 2.1021 1. S369 1. 6464 1.937S 1.6300 1. S772 1. 9409 1.8240 1. S266 0.30 0 .4S 0. 31 0.33 0.43 0.32 0.32 0.44 0.44 0.32 0.7867 1. 0227 0.6846 0.8014 0.9217 0.7377 0. 7764 0.9312 0.9106 0.8672 0.18 0.22 0.14 0.16 0.20 0.14 0.16 0.21 0.22 0.18 0.6317a 0.72S2 0.6497 0.6728 0.7436 0.6362 0.6767 0.7249 0.6S40 0.6302 0.14 0.16 0.13 0.13 0.16 0.12 0.14 0.16 0.16 0.13 RAT TERMINAL BODY NUMBER WEIGHT TESTIS RIGHT ABS. REL. WT. % TBW PROSTATE ABS. WT. REL. % TBW BRAIN ABS. WT. REL. % TBW LIVER ABS. WT. REL. % TBW KIDNEY LEFT ABS. REL. WT. % TBW KIDNEY RIGHT ABS. REL. WT. % TBW 19109 438. 1. 6S29 0.38 1.18S4 0.27 2.29 O.S2 14.18 3.24 1. Sl 0.34 1. Sl 0.34 1911S 466. 1.6847 0.36 1.4274 0 .31 2.27 0.49 16. 71 3.S8 1. 99 0.43 1. 99 0.43 19116 19119 490. sos. 1.6820 1. 6364 0.34 0.32 1. S838 0.7632 0.32 O.lS 2.28 2.63 0.46 O.S2 15.18 14.66 3.10 2.90 2.16 2.26 0.44 0 .4S 2.12 2.38 0.43 0.47 19122 4Sl. 1. 69S6 0.38 1. 0942 0.24 2.4S O.S4 13.10 2.90 1. 92 0.42 1. 81 0 .40 1912S S08. 1. 6796 0.33 1.1823 0.23 2.44 0.48 16.13 3.18 2.31 0.4S 2.29 0 .45 19131 499. 1.6S34 0.33 1. 2496 0.2S 2.4S 0.49 16.94 3.39 2.13 0.43 2.22 0.44 ..j::::.. ~ 19132 439. 1. 8S32 0.42 1. 8S97 0.42 2.34 O.S3 11. 94 2. 72 1. 78 0.40 1. 89 0.43 00 I 19134 419. 1. 4818 0.3S 1. 38S8 0.33 2.3S 0.56 12.01 2.87 1. 76 0.42 1. 84 0.44 0 1913S 482. 1.7S70 0.36 1.1710 0.24 2.4S 0.51 lS.48 3.21 2.00 0.41 2.lS 0 .45 t-J 00 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . ABS. WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. ~ > a. Damaged during processing (weight not affected). t~oI t;..l 00 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B19 (PAGE 2): TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP I 0 MG/KG/DAY ADRENAL ADRENAL SPLEEN THYMUS HEART RAT TERMINAL BODY LEFT RIGHT NUMBER WEIGHT ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. REL. WT. % TBW a WT. % TBW a WT. % TBW WT. % TBW WT. % TBW ------------------------------------------------------------------------------------------------------------------------------------ 19109 438. 0.027 6.16 0.027 6.16 O.S6 0.13 0 .37 0.08 1.41 0.32 1911S 466. 0.041 8.80 0.040 8.S8 0.77 0.16 0.41 0.09 1. 62 0.3S 19116 19119 490. sos. 0.03S 0.048 7.14 9.SO 0.03S 0.046 7.14 9.11 0.9S 0.79 0.19 0.16 0.49 0.30 0.10 0.06 1.Sl 1. 62 0.31 0.32 19122 4Sl. 0.033 7.32 0.031 6.87 0.79 0.18 0.33 0.07 1. 68 0.37 1912S S08. 0.034 6.69 0.031 6.10 0.76 O.lS 0.70 0.14 1.S4 0.30 19131 499. 0.041 8.22 0.036 7.21 1. 03 0.21 0.47 0.09 1. 67 0.33 19132 439. 0.036 8.20 0.038 8.66 0.73 0.17 0.27 0.06 1.40 0.32 19134 419. 0.024 S.73 0.02S S.97 0.60 0.14 0.44 0.10 1.46 0.3S 1913S 482. 0.031 6.43 0.030 6.22 0.90 0.19 0.33 0.07 1. 63 0.34 ------------------------------------------------------------------------------------------------------------------------------------ ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. a. Value was multiplied by 1000. ..i::.. ~ 00 I 0 tv 00 > ~ ~to w I \0 PROTOCOL 418-028: ORAL {GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B19 (PAGE 3): TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS {%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP II 0.3 MG/KG/DAY RAT TERMINAL BODY NUMBER WEIGHT EPIDIDYMIS LEFT ABS. REL. WT. % TBW CAUDA EPIDIDYMIS LEFT ABS. REL. WT. % TBW TESTIS LEFT ABS. REL. WT. % TBW SEMINAL VESICLES WITH FLUID ABS. REL. WT. % TBW SEMINAL VESICLES WITHOUT FLUID ABS. REL. WT. % TBW EPIDIDYMIS RIGHT ABS. REL. WT. % TBW 19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 428. 476. 474. 453. 444. 486. 435. 495. 365. 432. 0.6197 0.6623 0.6465 0. 5411 0.6310 0.6180 0.6644 0.6785 0.6686 0.6280 0.14 0.14 0.14 0.12 0.14 0.13 0.15 0.14 0.18 0.14 0.2867 0. 2962 0.3502 0.2779 0.3379 0.3209 0.3181 0.3219 0.3604 0. 3114 0.07 0.06 0.07 0.06 0.08 0.07 0.07 0.06 0.10 0.07 1. 5498 1. 6495 1. 8847 1. 4915 1. 7844 1.6588 1.8000 1. 7629 1.7956 1. 7773 0.36 0.35 0.40 0.33 0.40 0.34 0.41 0.36 0.49 0.41 1.7556 1. 0913 1. 2460 1. 8646 1. 7236 1.6952 1. 7928 1. 2650 1. 5421 1. 4625 0.41 0.23 0.26 0.41 0.39 0.35 0.41 0.26 0.42 0.34 0.9426 0.5991 0.7062 0.8697 0.8319 0.8335 0.8254 0.6950 0. 8728 0.9423 0.22 0.12 0.15 0.19 0.19 0.17 0.19 0.14 0.24 0.22 0.6523 0.6675 0.6572 0.5439 0.6568 0. 6724 0.6538 0.6914 0.6831 0.6675 0.15 0.14 0.14 0.12 0.15 0.14 0.15 0.14 0.19 0.15 RAT TERMINAL BODY NUMBER WEIGHT TESTIS RIGHT ABS. REL. WT. % TBW PROSTATE ABS. WT. REL. % TBW BRAIN ABS. WT. REL. % TBW LIVER ABS. WT. REL. % TBW KIDNEY LEFT ABS. REL. WT. % TBW KIDNEY RIGHT ABS. REL. WT. % TBW 19102 428. 1. 5930 0.37 1. 2374 0.29 2.19 0.51 14.53 3.39 1. 92 0.45 1. 95 0 .46 19106 476. 1. 6779 0.35 1. 0360 0.22 2.57 0.54 17.19 3.61 1. 97 0 .41 2.00 0.42 19108 474. 1. 9171 0.40 1.1892 0.25 2.52 0.53 14.75 3 .11 1. 90 0.40 1. 98 0.42 19110 453. 1.4694 0.32 1.1812 0.26 2.42 0.53 13.95 3.08 1. 96 0.43 2.00 0.44 19113 444. 1. 7350 0.39 1. 2130 0.27 2.58 0.58 13.08 2.94 1. 96a 0.44 2 .11 0.48 19120 486. 1.6765 0.34 1. 4290 0.29 2.38 0.49 14.26 2. 93 1. 72 0.35 1. 76 0 .36 19129 435. 1. 8164 0.42 1.1232 0.26 2.45 0.56 13.37 3.07 1. 89 0.43 1. 90 0.44 .,J:::.. !--" ~ 19136 495. 1.8039 0.36 1. 3313 0.27 2.41 0.49 15.75 3.18 1. 83 0.37 1.69 0.34 00 I 19138 365. 1. 7840 0.49 0.9939 0.27 2.46 0.67 11.25 3.08 1. 58 0.43 1.66 0 .45 0 19139 432. 1.8078 0.42 1.2660 0.29 2.40 0.56 14.10 3.26 1. 88 0.44 1. 93 0 .45 t..J 00 ALL WEIGHTS WERE RECORDED IN GRAMS {G). ABS. WT. = ORGAN WEIGHT. REL. % TBW = {ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. ~ a. Rat 19113 had slight dilation of the pelvis of the left kidney. See the individual necropsy observations table {Table B18) . tx:l I ~ PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE Bl9 (PAGE 4) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP II 0.3 MG/KG/DAY RAT TERMINAL BODY NUMBER WEIGHT ADRENAL LEFT ABS. REL. WT. % TBW a ADRENAL RIGHT ABS. REL. WT. % TBW a SPLEEN ABS. WT. REL. % TBW THYMUS ABS. WT. REL. % TBW HEART ABS. WT. REL. % TBW 19102 428. 0.041 9.58 0.038 8.88 0.89 0.21 0.52 0.12 1. 38 0.32 19106 476. 0.024 5.04 0.024 5.04 0.86 0.18 0.42 0.09 1. 56 0.33 19108 474. 0.030 6.33 0.030 6.33 0.73 0.15 0.47 0.10 1. 64 0.34 19110 453. 0.037 8.17 0.038 8.39 0.85 0.19 0 .41 0.09 1. 59 0.35 19113 444. 0.046 10 .36 0.044 9.91 0.81 0.18 0.48 0.11 1.47 0.33 19120 486. 0.042 8.64 0.038 7.82 0.83 0.17 0.40 0.08 1. 56 0.32 19129 435. 0.037 8.50 0.034 7.82 0.76 0.17 0.34 0.08 1. 55 0.36 19136 495. 0.033 6.67 0.034 6.87 0.72 0.14 0.58 0.12 1. 71 0.34 19138 365. 0.028 7.67 0.027 7.40 0.73 0.20 0.30 0.08 1.30 0.36 19139 432. 0.032 7 .41 0.032 7.41 0.92 0.21 0.54 0.12 1.46 0.34 ------------------------------------------------------------------------------------------------------------------------------------ ALL WEIGHTS WERE RECORDED IN GRAMS (G) . ABS. WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. a. Value was multiplied by 1000. .+..:..:.-... ~00 I 0 N 00 ~ t:n tXl .+.I.:.:.-... PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B19 (PAGE 5) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP III 1 MG/KG/DAY RAT TERMINAL BODY NUMBER WEIGHT EPIDIDYMIS LEFT ABS. REL. WT. % TBW CAUDA EPIDIDYMIS LEFT ABS. REL. WT. % TBW TESTIS LEFT ABS. REL. WT. % TBW SEMINAL VESICLES WITH FLUID ABS. REL. WT. % TBW SEMINAL VESICLES WITHOUT FLUID ABS. REL. WT. % TBW EPIDIDYMIS RIGHT ABS. REL. WT. % TBW 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 353. 505. 437. 452. 430. 567. 464. 434. 443. 473. 0.6021 0.7012 0.5355a 0.6158 0.5678 0.6466 0.6675 0.6775 0.6420 0.6207 0.17 0.14 0.12 0.14 0.13 0.11 0.14 0.16 0.14 0.13 0.2993 0.3377 0.2667 0.3199 0.2915 0.3316 0.3384 0. 3513 0.3467 0.3492 0.08 0.07 0.06 0.07 0.07 0.06 0.07 0.08 0.08 0.07 1. 6371 2.0077 1. 4816 1.6088 1. 4232 1. 8123 1. 7221 1. 7366 1. 6457 1. 6423 0.46 0.40 0.34 0.36 0.33 0.32 0.37 0.40 0.37 0.35 1.1004 1. 7433 2.2034 1. 6734 1.6586 1. 6481 1. 7452 1. 7430 1.3000 1. 5693 0.31 0.34 0.50 0.37 0.38 0.29 0.38 0.40 0.29 0.33 0.5923 0.7941 0. 9613 0.8909 0.7345 0.8330 0.9021 0.7931 0.7387 0.7248 0.17 0.16 0.22 0.20 0.17 0.15 0.19 0.18 0.17 0.15 0. 6071 0.7481 0.5625 0.6460 0.6091 0.6559 0.6825 0.7227 0.6680 0.6320 0.17 0.15 0 .13 0.14 0.14 0.12 0.15 0.17 0.15 0 .13 RAT TERMINAL BODY NUMBER WEIGHT TESTIS RIGHT ABS. REL. WT. % TBW PROSTATE ABS. WT. REL. % TBW BRAIN ABS. WT. REL. % TBW LIVER ABS. WT. REL. % TBW KIDNEY LEFT ABS. REL. WT. % TBW KIDNEY RIGHT ABS. REL. WT. % TBW 19101 353. 1.5806 0.45 0.8460 0.24 2.22 0. 63 11.34 3.21 1. 50 0.42 1. 56 0.44 19105 505. 2.0016 0.40 1.5220 0.30 2.40 0.48 17.13 3.39 2.37 0.47 2.29 0.45 19107 437. 1. 5096 0.34 1. 5754 0.36 2.35 0.54 13.84 3.17 1. 71 0.39 1. 71 0 .39 19112 452. 1. 6041 0.35 1.3786 0.30 2.41 0.53 14.51 3.21 2.09 0 .46. 1. 97 0.44 19114 430. 1.4506 0.34 1.1497 0.27 2.36 0.55 14.34 3.33 1. 84 0.43 1. 92 0 .45 19121 567. 1. 7745 0 .31 1.0712 0.19 2.54 0 .45 23.98 4.23 2.20 0.39 2.25 0 .40 19123 464. 1.8031 0.39 0.9914 0.21 2.43 0.52 19.27 4.15 2.17 0 .47 2.22 0.48 .,J:::.. I--' 19130 434. 1. 8184 0.42 1. 6000 0.37 2.37 0.55 13.79 3.18 1. 88 0.43 1. 98 0 .46 00 I 19137 443. 1. 6928 0.38 1. 0622 0.24 2.45 0.55 14.59 3.29 1. 88 0.42 2.14 0.48 0 19146 473. 1. 6866 0.36 1. 0704 0.23 2.26 0.48 16.57 3.50 1. 94 0 .41 2.01 0.42 tv 00 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . ABS. WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. ~ > a. Damaged during processing (weight not affected). ~tP I ~ PROTOCOL 418-028: ORAL {GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST {SPONSOR'S STUDY NUMBER: T-7706.1) TABLE Bl9 {PAGE 6) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP III 1 MG/KG/DAY ADRENAL ADRENAL SPLEEN THYMUS HEART RAT TERMINAL BODY LEFT RIGHT NUMBER WEIGHT ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. REL. WT. % TBW a WT. % TBW a WT. % TBW WT. % TBW WT. % TBW ------------------------------------------------------------------------------------------------------------------------------------ 19101 3S3. 0.028 7.93 0.026 7.36 o.ss 0.16 0.23 0.06 1. 33 0.38 1910S sos. 0.034 6.73 0.027 S.3S 0.74 O.lS 0.47 0.09 1. 66 0.33 19107 19112 437. 4S2. 0.039 0.026 8.92 S.7S 0.038 0.022 8.70 4.87 0.69 0.6S 0.16 0.14 0.26 o.ss 0.06 0.12 1. 36 1.48 0.31 0.33 19114 430. 0.033 7.67 0.031 7.21 0.68 0.16 0.32 0.07 1. S2 0.3S 19121 S67. 0.032 S.64 0.03S 6.17 0.92 0.16 0.44 0.08 1. 70 0.30 19123 464. 0.040 8.62 0.02S S.39 0.78 0.17 0.40 0.09 1. S6 0.34 19130 434. 0.030 6.91 0.033 7.60 0.87 0.20 0.33 0.08 1.48 0.34 19137 443. 0.032 7.22 0.019 4.29 0.91 0.20 0.29 0.06 1. 6S 0.37 19146 473. 0.042 8.88 0.043 9.09 0.80 0.17 0.28 0.06 1. 6S 0.3S ------------------------------------------------------------------------------------------------------------------------------------ ALL WEIGHTS WERE RECORDED IN GRAMS {G). ABS. WT. = ORGAN WEIGHT. REL. % TBW = {ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. a. Value was multiplied by 1000. .~ ........ 00 I 0 tv 00 ~ ~>tD I w ~ PROTOCOL 418-028: ORAL (GAVAGE} COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1} TABLE B19 (PAGE 7) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%} OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP IV 3 MG/KG/DAY RAT TERMINAL BODY NUMBER WEIGHT EPIDIDYMIS LEFT ABS. REL. WT. % TBW CAUDA EPIDIDYMIS LEFT ABS. REL. WT. % TBW TESTIS LEFT ABS. REL. WT. % TBW SEMINAL VESICLES WITH FLUID ABS. REL. WT. % TBW SEMINAL VESICLES WITHOUT FLUID ABS. REL. WT. % TBW EPIDIDYMIS RIGHT ABS. REL. WT. % TBW 19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 421. 487. 476. 442. 448. 545. 479. 523. 454. 448. 0.6712 0.6486 0.6201 0.5834 0.5667 0.6531 0.3058a 0.5626 0.6884 0.6161 0.16 0.13 0.13 0.13 0.13 0.12 0.06 0.11 0.15 0.14 0.3355 0.2909 0.2961 0.3022 0.2961 0.3098 0.1333a 0.2529 0.3851 0.3111 0.08 0.06 0.06 0.07 0.07 0.06 0.03 0.05 0.08 0.07 1.7129 1.6530 1.7770 1.5495 1.7262 1. 7814 0.6988a 1.6357 1.8767 1.7049 0.41 0.34 0.37 0.35 0.38 0. 33 0.14 0.31 0.41 0.38 2.0456 2.0607 1.4443 1. 6316 1. 7327 1. 4610 1.1736 1. 3813 1.3721 1.1701 0.48 0.42 0.30 0.37 0.39 0.27 0.24 0.26 0.30 0.26 1. 0125 1. 0014 0.7874 0.7381 0. 8511 0.7077 0.6729 0.6369 0.6888 0.5734 0.24 0.20 0.16 0.17 0.19 0.13 0.14 0.12 0.15 0.13 0.6970 0.6457 0.5846 0.6169 0.5492 0.6801 0.3002a 0.6547 0.7389 0.6388 0.16 0.13 0.12 0.14 0.12 0.12 0.06 0.12 0.16 0.14 RAT TERMINAL BODY NUMBER WEIGHT TESTIS RIGHT ABS. REL. WT. % TBW PROSTATE ABS. WT. REL. % TBW BRAIN ABS. WT. REL. % TBW LIVER ABS. WT. REL. % TBW KIDNEY LEFT ABS. REL. WT. % TBW KIDNEY RIGHT ABS. REL. WT. % TBW 19100 421. 1. 7274 0.41 1.5079 0.36 2.40 0.57 15.67 3.72 1. 82 0.43 1. 91 0.45 19103 487. 1. 7657 0.36 1.4347 0.29 2.39 0.49 19.28 3. 96 2.40 0 .49 2.39 0.49 19104 476. 1. 7025 0.36 1. 2209 0.26 2.43 0.51 17.78 3.74 1. 98 0.42 2.16 0 .45 19118 442. 1. 6129 0.36 1. 3183 0.30 2.42 0.55 15.97 3.61 1. 90 0.43 2.12 0.48 19133 448. 1. 7045 0.38 1. 2429 0.28 2.47 0.55 15.06 3.36 2.08 0 .46 2.24 0.50 19141 545. 1. 7406 0.32 1.0238 0.19 2.52 0.46 20.42 3.75 2.18 0.40 2.20 0 .40 ,+::... 19142 479. 0.6700a 0.14 1.0863 0.23 2.23 0 .46 17.61 3.68 2.00 0.42 2.07 0.43 >---' 19144 523. 1.6766 0.32 1.1080 0.21 2.40 0.46 18.23 3.48 2.21 0.42 2.36 0 .45 00 I 19148 454. 1.8681 0.41 1.4524 0.32 2.24 0.49 18.08 3.98 1. 91 0.42 1. 92 0.42 0 19150 448. 1.7068 0.38 1.3391 0.30 2.35 0.52 17.94 4.00 1. 97 0.44 1. 92 0.43 t-...J 00 ALL WEIGHTS WERE RECORDED IN GRAMS (G} . ABS . WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. ~ > a. Rat 19142 had small testes, epididymides and left cauda epididymis. See the individual necropsy observations table (Table B18} . ~txj I +::>. +::>. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B19 (PAGE 8) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP IV 3 MG/KG/DAY ADRENAL ADRENAL SPLEEN THYMUS HEART RAT TERMINAL BODY LEFT RIGHT NUMBER WEIGHT ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. REL. WT. % TBW a WT. % TBW a WT. % TBW WT. % TBW WT. % TBW ------------------------------------------------------------------------------------------------------------------------------------ 19100 421. 0.028 6.65 0.032 7.60 0.86 0.20 0.40 0.10 1.42 0.34 19103 487. 0.040 8.21 0.046 9.44 0.88 0.18 0.39 0.08 1. 56 0.32 19104 476. 0.030 6 .30 0.026 5.46 1.10 0.23 0.40 0.08 1. 64 0.34 19118 442. 0.030 6.79 0.032 7.24 0.69 0.16 0.37 0.08 1.44 0.32 19133 448. 0.043 9.60 0.041 9.15 0.74 0.16 0.36 0.08 1. 60 0.36 19141 545. 0.024 4.40 0.030 5.50 1.15 0.21 0.57 0.10 1. 84 0.34 19142 479. 0.028 5.84 0.028 5.84 0.74 0.15 0.48 0.10 1. 54 0.32 19144 523. 0.037 7.07 0.032 6.12 1.15 0.22 0.34 0.06 1. 74 0.33 19148 454. 0.028 6.17 0.026 5.73 0.78 0.17 0.35 0.08 1. 55 0.34 19150 448. 0.037 8.26 0.026 5.80 0.67 0.15 0.57 0.13 1. 62 0.36 ------------------------------------------------------------------------------------------------------------------------------------ ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. a. Value was multiplied by 1000. .J::.. -00 I 0 N 00 ~ e;tT.l t:C I .J::.. Vl PROTOCOL 418-028: ORAL {GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B19 {PAGE 9): TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS {%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP V 10 MG/KG/DAY RAT TERMINAL BODY NUMBER WEIGHT EPIDIDYMIS LEFT ABS. REL. WT. % TBW CAUDA EPIDIDYMIS LEFT ABS. REL. WT. % TBW TESTIS LEFT ABS. REL. WT. % TBW SEMINAL WITH ABS. WT. VESICLES FLUID REL. % TBW SEMINAL VESICLES WITHOUT FLUID ABS. REL. WT. % TBW EPIDIDYMIS RIGHT ABS. REL. WT. % TBW 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 432. 462. 426. 426. 434. 445. 442. 441. 439. 461. 0.5886 0.5554a 0.7041 0.5648 0.5950 0.5787 0.6181 0.6705 0.6384 0.6200 0.14 0.12 0.16 0.13 0.14 0.13 0.14 0.15 0.14 0.13 0.2814 0. 2921 0.3378 0.2550 0.3045 0. 2725 0.2951 0.3537 0.3200 0.3288 0.06 0.06 0.08 0.06 0.07 0.06 0.07 0.08 0.07 0.07 1.7973 1. 5902 1. 9441 1.5950 1.7552 1. 5509 1.6009 1.8102 1. 9607 1. 8784 0.42 0.34 0.46 0.37 0.40 0.35 0.36 0.41 0.45 0.41 1. 4923 1. 4692 1. 6428 0.9950 1. 6404 1.1019 1.5387 1. 8705 1. 4543 1.2190 0.34 0.32 0.38 0.23 0.38 0.25 0.35 0.42 0.33 0.26 0. 7724 0.8619 0.8490 0.5749 0.7509 0.6009 0.8782 0.9316 0.8120 0.7403 0.18 0.19 0.20 0 .13 0.17 0.14 0.20 0.21 0.18 0.16 0.6626 0.5723 0.6631 0.5576 0.5793 0.6242 0.6487 0.6428 0.6610 0.6498 0.15 0.12 0.16 0.13 0.13 0.14 0.15 0.14 0.15 0 .14 RAT TERMINAL BODY NUMBER WEIGHT TESTIS RIGHT ABS. REL. WT. % TBW PROSTATE ABS. WT. REL. % TBW BRAIN ABS. WT. REL. % TBW LIVER ABS. WT. REL. % TBW KIDNEY LEFT ABS. REL. WT. % TBW KIDNEY RIGHT ABS. REL. WT. % TBW 19111 432. 1. 7246 0.40 1. 0515 0.24 2.48 0.57 24.36 5.64 2.00 0.46 2.13 0 .49 19117 462. 1. 6160 0.35 1. 0954 0.24 2.43 0.52 24.11 5.22 2.22 0.48 2.26 0 .49 19124 426. 1. 8910 0.44 1. 5146 0.36 2.38 0.56 25.72 6.04 2.21 0.52 2.18 0.51 19126 426. 1. 6044 0.38 0. 7260 0.17 2.28 0.54 22.94 5.38 2.04 0.48 2.04 0.48 19127 434. 1.7997 0.41 1.4010 0.32 2.62 0.60 27.38 6.31 1. 90 0.44 1. 95 0 .45 19128 445. 1. 5952 0.36 0.9706 0.22 2 .31 0.52 21.74 4.88 1. 78 0.40 1. 82 0 .41 19140 442. 1. 6407 0.37 1. 223 9 0.28 2.42 0.55 20.21 4.57 1. 93 0.44 1. 88 0.42 ...,.i:.:.:..... 19145 441. 1. 8340 0.42 1.3756 0.31 2.40 0.54 23.20 5.26 2.27 0.51 2.16 0 .49 00 I 19149 439. 1. 9989 0.46 1.2522 0.28 2.38 0.54 20.06 4.57 1. 76 0.40 1. 92 0.44 0 19152 461. 1.8997 0.41 1.3077 0.28 2.34 0.51 18.58 4.03 1. 97 0.43 2.07 0 .45 l'.J 00 ALL WEIGHTS WERE RECORDED IN GRAMS {G) . ABS. WT. = ORGAN WEIGHT. REL. % TBW = {ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. ~ > a. Damaged during processing {weight not affected). ~to I ~ O"\ PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE Bl9 (PAGE 10): TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP V 10 MG/KG/DAY ADRENAL ADRENAL SPLEEN THYMUS HEART RAT TERMINAL BODY LEFT RIGHT NUMBER WEIGHT ABS. REL. ABS. REL. ABS. REL. ABS. REL. ABS. REL. WT. % TBW a WT. % TBW a WT. % TBW WT. % TBW WT. % TBW ------------------------------------------------------------------------------------------------------------------------------------ 19111 432. 0.025 5.79 0.024 5.56 0.73 0.17 0.37 0.08 1.38 0.32 19117 462. 0.030 6.49 0.014 3.03 0.75 0.16 0.36 0.08 1. 60 0.35 19124 426. 0.035 8.22 0.034 7.98 0. 72 0.17 0.36 0.08 1.40 0.33 19126 426. 0.029 6.81 0.028 6.57 0.64 0.15 0.47 0.11 1. 38 0.32 19127 434. 0.031 7.14 0.031 7.14 0.81 0.19 0.47 0.11 1.43 0.33 19128 445. 0.036 8.09 0.034 7.64 0.74 0.17 0.40 0.09 1.42 0.32 19140 442. 0.036 8.14 0.028 6.33 0.86 0.19 0.44 0.10 1. so 0.34 19145 441. 0.034 7. 71 0.033 7.48 0.88 0.20 0.38 0.09 1.36 0.31 19149 439. 0.029 6.60 0.030 6.83 0.97 0.22 0.43 0.10 1.46 0.33 19152 461. 0.036 7.81 0.038 8.24 0.70 0.15 0.51 0.11 1.47 0.32 ------------------------------------------------------------------------------------------------------------------------------------ ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. a. Value was multiplied by 1000. -~ 00 I 0 tv 00 ~ >t~oI ~ -.......} PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B20 (PAGE 1) : ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP I 0 MG/KG/DAY RAT NUMBER BRAIN WEIGHT EPIDIDYMIS LEFT ABS. REL. WT. % BRW CAUDA EPIDIDYMIS LEFT ABS. REL. WT. % BRW TESTIS LEFT ABS. REL. WT. % BRW SEMINAL VESICLES WITH FLUID ABS. REL. WT. % BRW SEMINAL VESICLES WITHOUT FLUID ABS. REL. WT. % BRW EPIDIDYMIS RIGHT ABS. REL. WT. % BRW 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 2.29 2.27 2.28 2.63 2.45 2.44 2.45 2.34 2.35 2.45 0.6013 0.6976a 0.6499 0.6541 0.6661 0.6160 0.6482 0.7103 0.6278 0.6052 26.26 30.73 28.50 24.87 27.19 25.24 26.46 30.35 26.71 24.70 0.2822 0.3438 0.3209 0.3489 0.3724 0.3260 0.3140 0.3684 0.3368 0.2942 12.32 15.14 14.07 13.27 15.20 13.36 12.82 15.74 14.33 12.01 1. 5706 1. 6971 1. 6213 1.7174 1. 6754 1. 6621 1. 6865 1. 8079 1. 4801 1. 6728 68. 58 74. 76 71.11 65.30 68. 38 68 .12 68. 84 77. 26 62. 98 68. 28 1.3331 2.1021 1. 5369 1. 6464 1.9375 1.6300 1.5772 1.9409 1. 8240 1.5266 58.21 92.60 67. 41 62. 60 79.08 66.80 64.38 82.94 77. 62 62.31 0.7867 1. 0227 0.6846 0.8014 0.9217 0.7377 0.7764 0.9312 0.9106 0.8672 34.35 45. 05 30.03 30.47 37.62 30.23 31.69 39.79 38.75 35.40 0.6317a 0.7252 0.6497 0.6728 0.7436 0.6362 0.6767 0.7249 0.6540 0.6302 27.58 31.95 28.50 25.58 30.35 26.07 27.62 30.98 27.83 25.72 RAT NUMBER BRAIN WEIGHT TESTIS RIGHT ABS. REL. WT. % BRW PROSTATE ABS. WT. REL. % BRW LIVER ABS. WT. REL. % BRW KIDNEY LEFT ABS. REL. WT. % BRW KIDNEY RIGHT ABS. REL. WT. % BRW ADRENAL LEFT ABS. REL. WT. % BRW 19109 2.29 1.6529 72.18 1.1854 51. 76 14.18 619.21 1.51 65.94 1.51 65.94 0.027 1.18 19115 2.27 1.6847 74.22 1. 4274 62. 88 16. 71 736.12 1. 99 87.66 1. 99 87.66 0. 041 1. 81 19116 2.28 1. 6820 73. 77 1. 5838 69. 46 15.18 665.79 2.16 94.74 2.12 92.98 0.035 1.54 19119 2.63 1. 6364 62. 22 0.7632 29.02 14.66 557.41 2.26 85.93 2.38 90.49 0.048 1. 82 19122 2.45 1. 6956 69. 21 1. 0942 44. 66 13.10 534.69 1. 92 78.37 1.81 73.88 0.033 1.35 19125 2.44 1. 6796 68. 84 1.1823 48.45 16.13 661.06 2.31 94.67 2.29 93.85 0.034 1.39 19131 19132 2.45 2.34 1. 6534 67. 48 1. 8532 79. 20 1. 2496 51. 00 1.8597 79.47 16.94 11.94 691.43 510.26 2.13 1. 78 86.94 76.07 2.22 1. 89 90.61 80. 77 0. 041 0.036 1. 67 1.54 ....J..:.:.... ~ 19134 2.35 1.4818 63.06 1.3858 58.97 12.01 511. 06 1. 76 74.89 1.84 78.30 0.024 1. 02 00 I 19135 2.45 1. 7570 71. 71 1.1710 47.80 15.48 631. 84 2.00 81. 63 2.15 87.76 0.031 1.26 0 ~ 00 ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. ~ a. Damaged during processing (weight not affected). tT.l t;O I ..J::.. 00 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B20 (PAGE 2): ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP I 0 MG/KG/DAY RAT NUMBER BRAIN WEIGHT ADRENAL RIGHT ABS. REL. WT. % BRW SPLEEN ABS. WT. REL. % BRW THYMUS ABS. WT. REL. % BRW HEART ABS. WT. REL. % BRW 19109 2.29 0.027 1.18 0.56 24.45 0.37 16.16 1.41 61. 57 19115 2.27 0.040 1. 76 0.77 33.92 0.41 18.06 1. 62 71.36 19116 2.28 0.035 1. 54 0.95 41.67 0 .49 21.49 1. 51 66.23 19119 2.63 0.046 1. 75 0.79 30.04 0.30 11.41 1. 62 61. 60 19122 2.45 0.031 1.26 0.79 32.24 0.33 13.47 1. 68 68.57 19125 2.44 0.031 1.27 0.76 31.15 0.70 28.69 1. 54 63 .11 19131 2.45 0.036 1.47 1. 03 42.04 0.47 19.18 1. 67 68.16 19132 2.34 0.038 1. 62 0.73 31.20 0.27 11.54 1.40 59.83 19134 2.35 0.025 1. 06 0.60 25.53 0.44 18. 72 1.46 62.13 19135 2.45 0.030 1.22 0.90 36.73 0.33 13.47 1. 63 66.53 ------------------------------------------------------------------------------------------------------------------------------------ ALL WEIGHTS WERE RECORDED IN GRAMS (G) . ABS. WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. ~ 0"""0"'" I 0 tv 00 ~ >~tp 'I ~ PROTOCOL 418-028: ORAL {GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST {SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B20 {PAGE 3): ORGAN WEIGHTS AND RATIOS {%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP I I 0. 3 MG/KG/DAY RAT NUMBER BRAIN WEIGHT EPIDIDYMIS LEFT ABS. REL. WT. % BRW CAUDA EPIDIDYMIS LEFT ABS. REL. WT. % BRW TESTIS LEFT ABS. REL. WT. % BRW SEMINAL VESICLES WITH FLUID ABS. REL. WT. % BRW SEMINAL VESICLES WITHOUT FLUID ABS. REL. WT. % BRW EPIDIDYMIS RIGHT ABS. REL. WT. % BRW 19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 2.19 2.57 2.52 2.42 2.58 2. 38 2.45 2 .41 2.46 2.40 0.6197 0.6623 0.6465 0.5411 0.6310 0.6180 0.6644 0.6785 0.6686 0.6280 28.30 25.77 25.65 22.36 24.46 25.97 27.12 28.15 27.18 26.17 0.2867 0.2962 0.3502 0.2779 0.3379 0.3209 0.3181 0.3219 0.3604 0.3114 13.09 11.52 13.90 11.48 13.10 13.48 12.98 13.36 14.65 12.98 1.5498 1.6495 1.8847 1. 4915 1.7844 1. 6588 1.8000 1. 7629 1. 7956 1. 7773 70.77 64.18 74.79 61. 63 69.16 69. 70 73.47 73 .15 72. 99 74. 05 1.7556 1.0913 1.2460 1. 8646 1.7236 1.6952 1.7928 1. 2650 1.5421 1.4625 80.16 42.46 49.44 77. 05 66.81 71.23 73.18 52. 49 62.69 60.94 0.9426 0.5991 0.7062 0.8697 0.8319 0.8335 0.8254 0.6950 0.8728 0.9423 43.04 23.31 28.02 35.94 32.24 35.02 33.69 28.84 35.48 39.26 0.6523 0.6675 0.6572 0.5439 0.6568 0.6724 0.6538 0.6914 0.6831 0.6675 29.78 25.97 26.08 22.48 25.46 28.25 26.68 28.69 27.77 27.81 RAT NUMBER BRAIN WEIGHT TESTIS RIGHT ABS. REL. WT. % BRW PROSTATE ABS. WT. REL. % BRW LIVER ABS. WT. REL. % BRW KIDNEY LEFT ABS. REL. WT. % BRW KIDNEY RIGHT ABS. REL. WT. % BRW ADRENAL LEFT ABS. REL. WT. % BRW 19102 2.19 1.5930 72.74 1.2374 56.50 14.53 663.47 1. 92 87.67 1. 95 89.04 0. 041 1.87 19106 2.57 1.6779 65.29 1.0360 40.31 17.19 668.87 1. 97 76.65 2.00 77.82 0.024 0.93 19108 2.52 1.9171 76.08 1.1892 47.19 14.75 585.32 1. 90 75.40 1. 98 78.57 0.030 1.19 19110 2.42 1.4694 60.72 1.1812 48.81 13. 95 576.45 1. 96 80.99 2.00 82.64 0.037 1.53 19113 2.58 1.7350 67.25 1.2130 47.02 13.08 506.98 1.96a 75.97 2.11 81. 78 0.046 1. 78 19120 2.38 1. 6765 70. 44 1. 4290 60. 04 14.26 599.16 1. 72 72 .27 1. 76 73.95 0.042 1. 76 19129 2.45 1. 8164 74 .14 1.1232 45. 84 13.37 545. 71 1. 89 77 .14 1. 90 77.55 0.037 1.51 .p.. 19136 2.41 1. 8039 74. 85 1.3313 55.24 15.75 653.53 1. 83 75.93 1.69 70.12 0.033 1.37 ~ 19138 2.46 1.7840 72.52 0.9939 40.40 11.25 457.32 1. 58 64.23 1. 66 67.48 0.028 1.14 00 I 19139 2.40 1. 8078 75. 32 1.2660 52.75 14.10 587.50 1. 88 78.33 1. 93 80.42 0.032 1.33 0 t..J 00 ALL WEIGHTS WERE RECORDED IN GRAMS {G). ABS. WT. = ORGAN WEIGHT. REL. % TBW = {ORGAN WEIGHT/BRAIN WEIGHT) X 100. ~ a. Rat 19113 had slight dilation of the pelvis of the left kidney. See the individual necropsy observations table {Table B18) . >~tO I Vl 0 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B20 (PAGE 4) : ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP II 0. 3 MG/KG/DAY RAT NUMBER BRAIN WEIGHT ADRENAL RIGHT ABS. REL. WT. % BRW SPLEEN ABS. WT. REL. % BRW THYMUS ABS. WT. REL. % BRW HEART ABS. WT. REL. % BRW 19102 2.19 0.038 1.74 0.89 40. 64 0.52 23.74 1. 38 63.01 19106 2.57 0.024 0.93 0.86 33.46 0.42 16.34 1. 56 60.70 19108 2.52 0.030 1.19 0.73 28.97 0.47 18.65 1.64 65.08 19110 2.42 0.038 1. 57 0.85 35.12 0.41 16.94 1. 59 65.70 19113 2.58 0.044 1. 70 0.81 31.40 0.48 18.60 1.47 56.98 19120 2.38 0.038 1. 60 0.83 34.87 0 .40 16.81 1. 56 65.55 19129 2.45 0.034 1.39 0.76 31. 02 0.34 13.88 1. 55 63.26 19136 2.41 0.034 1.41 0. 72 29.88 0.58 24.07 1. 71 70.95 19138 2.46 0.027 1.10 0.73 29.67 0.30 12.20 1. 30 52.84 19139 2.40 0.032 1.33 0.92 38.33 0.54 22.50 1.46 60.83 ------------------------------------------------------------------------------------------------------------------------------------ ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. ~ ~ 00 I 0 t-J 00 > ~ ~to I V"I ~ '" PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B20 (PAGE 5) : ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP III 1 MG/KG/DAY RAT NUMBER BRAIN WEIGHT EPIDIDYMIS LEFT ABS. REL. WT. % BRW CAUDA EPIDIDYMIS LEFT ABS. REL. WT. % BRW TESTIS LEFT ABS. REL. WT. % BRW SEMINAL VESICLES WITH FLUID ABS. REL. WT. % BRW SEMINAL VESICLES WITHOUT FLUID ABS. REL. WT. % BRW EPIDIDYMIS RIGHT ABS. REL. WT. % BRW 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 2.22 2.40 2.35 2.41 2.36 2.54 2.43 2.37 2.45 2.26 0.6021 0.7012 0.5355a 0.6158 0.5678 0.6466 0.6675 0.6775 0.6420 0.6207 27.12 29.22 22.79 25.55 24.06 25.46 27.47 28.59 26.20 27.46 0.2993 0.3377 0.2667 0.3199 0.2915 0.3316 0.3384 0.3513 0.3467 0.3492 13.48 14.07 11.35 13.27 12.35 13.06 13.92 14.82 14.15 15.45 1.6371 2.0077 1.4816 1. 6088 1. 4232 1.8123 1. 7221 1. 7366 1.6457 1. 6423 73.74 83.65 63.05 66. 76 60. 30 71.35 70. 87 73. 27 67.17 72. 67 1.1004 1.7433 2.2034 1.6734 1. 6586 1.6481 1. 7452 1. 7430 1.3000 1.5693 49.57 72.64 93.76 69.44 70. 28 64.88 71. 82 73. 54 53.06 69.44 0.5923 0.7941 0.9613 0.8909 0.7345 0.8330 0.9021 0.7931 0.7387 0.7248 26.68 33.09 40.91 36.97 31.12 32.80 37.12 33.46 30.15 32.07 0.6071 0.7481 0.5625 0.6460 0.6091 0.6559 0.6825 0.7227 0.6680 0.6320 27.35 31.17 23.94 26.80 25.81 25.82 28.09 30.49 27.26 27.96 RAT NUMBER BRAIN WEIGHT TESTIS RIGHT ABS. REL. WT. % BRW PROSTATE ABS. WT. REL. % BRW LIVER ABS. WT. REL. % BRW KIDNEY LEFT ABS. REL. WT. % BRW KIDNEY RIGHT ABS. REL. WT. % BRW ADRENAL LEFT ABS. REL. WT. % BRW 19101 2.22 1. 5806 71. 20 0.8460 38.11 11.34 510.81 1. 50 67.57 1. 56 70.27 0.028 1.26 19105 2.40 2.0016 83.40 1. 5220 63. 42 17 .13 713.75 2.37 98.75 2.29 95.42 0.034 1.42 19107 2.35 1.5096 64.24 1. 5754 67. 04 13.84 588.94 1. 71 72. 76 1. 71 72.76 0.039 1.66 19112 2.41 1. 6041 66. 56 1.3786 57.20 14.51 602.07 2.09 86. 72 1. 97 81. 74 0.026 1.08 19114 2.36 1. 4506 61. 4 7 1.1497 48.72 14.34 607.63 1. 84 77.97 1.92 81. 36 0.033 1.40 19121 2.54 1. 7745 69. 86 1.0712 42.17 23.98 944.09 2.20 86.61 2.25 88.58 0.032 1.26 19123 2.43 1. 8031 74. 20 0.9914 40.80 19.27 793.00 2.17 89.30 2.22 91. 36 0.040 1.65 ~ 19130 2.37 1. 8184 76. 72 1. 6000 67. 51 13. 79 581.86 1. 88 79.32 1. 98 83.54 0.030 1.26 - 19137 2.45 1. 6928 69. 09 1. 0622 43. 36 14.59 595.51 1. 88 76.73 2.14 87.35 0.032 1.31 00 I 19146 2.26 1. 6866 74. 63 1.0704 47.36 16.57 733.18 1. 94 85.84 2.01 88.94 0.042 1.86 0 tv 00 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . ABS. WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. ~ a. Damaged during processing (weight not affected). >c~oI Vl tv PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B20 (PAGE 6) : ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP III 1 MG/KG/DAY RAT NUMBER BRAIN WEIGHT ADRENAL RIGHT ABS. REL. WT. % BRW SPLEEN ABS. WT. REL. % BRW THYMUS ABS. WT. REL. % BRW HEART ABS. WT. REL. % BRW 19101 2.22 0.026 1.17 0.55 24.77 0.23 10.36 1.33 59.91 19105 2.40 0.027 1.12 0.74 30.83 0.47 19.58 1. 66 69.17 19107 2.35 0.038 1. 62 0.69 29.36 0.26 11. 06 1.36 57.87 19112 2 .41 0.022 0.91 0.65 26.97 0.55 22.82 1.48 61.41 19114 2.36 0.031 1. 31 0.68 28.81 0.32 13 .56 1. 52 64.41 19121 2.54 0.035 1.38 0.92 36.22 0.44 17.32 1. 70 66.93 19123 2.43 0.025 1. 03 0.78 32.10 0.40 16.46 1. 56 64.20 19130 2.37 0.033 1. 39 0.87 36. 71 0.33 13 .92 1.48 62.45 19137 2.45 0.019 0.78 0.91 37.14 0.29 11.84 1. 65 67.35 19146 2.26 0.043 1. 90 0.80 35.40 0.28 12.39 1.65 73.01 ------------------------------------------------------------------------------------------------------------------------------------ ALL WEIGHTS WERE RECORDED IN GRAMS (G) . ABS. WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) x 100. ,+:.. 1--" 00 I 0 N 00 ~ >~to I Vl t;.l PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B20 (PAGE 7) : ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP IV 3 MG/KG/DAY RAT NUMBER BRAIN WEIGHT EPIDIDYMIS LEFT ABS. REL. WT. % BRW CAUDA EPIDIDYMIS LEFT ABS. REL. WT. % BRW TESTIS LEFT ABS. REL. WT. % BRW SEMINAL VESICLES WITH FLUID ABS. REL. WT. % BRW SEMINAL VESICLES WITHOUT FLUID ABS. REL. WT. % BRW EPIDIDYMIS RIGHT ABS. REL. WT. % BRW 19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 2.40 2.39 2.43 2.42 2.47 2.52 2.23 2.40 2.24 2.35 0.6712 0.6486 0.6201 0.5834 0.5667 0.6531 0.3058a 0.5626 0.6884 0.6161 27.97 27.14 25.52 24.11 22.94 25.92 13.71 23.44 30.73 26.22 0.3355 0.2909 0.2961 0.3022 0.2961 0.3098 0.1333a 0.2529 0.3851 0.3111 13.98 12.17 12.18 12.49 11.99 12.29 5.98 10.54 17.19 13.24 1.7129 1.6530 1.7770 1.5495 1. 7262 1.7814 0.6988a 1.6357 1. 8767 1.7049 71.37 69.16 73.13 64.03 69. 89 70.69 31.34 68.15 83. 78 72.55 2.0456 2.0607 1.4443 1.6316 1. 7327 1. 4610 1.1736 1.3813 1.3721 1.1701 85.23 86.22 59.44 67.42 70 .15 57. 98 52.63 57.55 61.25 49.79 1. 0125 1. 0014 0.7874 0.7381 0.8511 0.7077 0.6729 0.6369 0.6888 0.5734 42 .19 41. 90 32.40 30.50 34.46 28.08 30.17 26.54 30.75 24.40 0.6970 0.6457 0.5846 0.6169 0.5492 0.6801 0.3002a 0.6547 0.7389 0.6388 29.04 27.02 24.06 25.49 22.23 26.99 13.46 27.28 32.99 27.18 RAT NUMBER BRAIN WEIGHT TESTIS RIGHT ABS. REL. WT. % BRW PROSTATE ABS. WT. REL. % BRW LIVER ABS. WT. REL. % BRW KIDNEY LEFT ABS. REL. WT. % BRW KIDNEY RIGHT ABS. REL. WT. % BRW ADRENAL LEFT ABS. REL. WT. % BRW 19100 2.40 1. 7274 71. 98 1.5079 62.83 15.67 652. 92 1. 82 75.83 1. 91 79.58 0.028 1.17 19103 2.39 1. 7657 73. 88 1.4347 60.03 19.28 806.69 2.40 100.42 2.39 100.00 0.040 1. 67 19104 2.43 1. 7025 70. 06 1. 2209 so. 24 17.78 731.69 1. 98 81.48 2.16 88.89 0.030 1. 23 19118 2.42 1.6129 66.65 1.3183 54.48 15.97 659.92 1. 90 78.51 2 .12 87.60 0.030 1.24 19133 2.47 1. 7045 69. 01 1.2429 50.32 15.06 609. 72 2.08 84.21 2.24 90.69 0.043 1. 74 - 19141 2.52 1. 7406 69. 07 1.0238 40.63 20.42 810.32 2.18 86.51 2.20 87.30 0.024 0.95 1199114424 22..2430 10..66776060a 3609..0846 11..10088603 4486..1771 1187..2631 778599..6598 22..0201 8992..0689 22..3067 9982..3832 00..002387 11.. 2546 ..J:::.. 19148 2.24 1. 8681 83. 40 1. 4524 64. 84 18.08 807.14 1. 91 85.27 1. 92 85. 71 0.028 1. 25 00 I 19150 2.35 1. 7068 72. 63 1.3391 56.98 17.94 763.40 1. 97 83.83 1. 92 81. 70 0.037 1. 57 0 l'-..) ~00 ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. ~ a. Rat 19142 had small testes, epididymides and left cauda epididymis. See the individual necropsy observations table (Table B18) . txj I Vl ..J:::.. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B20 (PAGE 8) : ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP IV 3 MG/KG/DAY RAT NUMBER BRAIN WEIGHT ADRENAL RIGHT ABS. REL. WT. % BRW SPLEEN ABS. WT. REL. % BRW THYMUS ABS. WT. REL. % BRW HEART ABS. WT. REL. % BRW 19100 2.40 0.032 1.33 0.86 35.83 0.40 16.67 1.42 59.17 19103 2.39 0.046 1. 92 0.88 36.82 0.39 16.32 1. 56 65.27 19104 2.43 0.026 1. 07 1.10 45.27 0.40 16.46 1. 64 67.49 19118 2.42 0.032 1.32 0.69 28.51 0.37 15.29 1.44 59.50 19133 2.47 0.041 1. 66 0.74 29.96 0.36 14.57 1. 60 64.78 19141 2.52 0.030 1.19 1.15 45.63 0.57 22.62 1. 84 73.02 19142 2.23 0.028 1.26 0.74 33.18 0.48 21. 52 1. 54 69.06 19144 2.40 0.032 1.33 1.15 47.92 0.34 14.17 1. 74 72.50 19148 2.24 0.026 1.16 0.78 34.82 0.35 15.62 1. 55 69.20 19150 2.35 0.026 1.11 0.67 28.51 0.57 24.26 1. 62 68.94 ------------------------------------------------------------------------------------------------------------------------------------ ALL WEIGHTS WERE RECORDED IN GRAMS (G) . ABS. WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) x 100. .~ ...... ~00 I 0 N 00 ~ o:i I U"I U"I PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B20 (PAGE 9) : ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP V 10 MG/KG/DAY RAT NUMBER BRAIN WEIGHT EPIDIDYMIS LEFT ABS. REL. WT. % BRW CAUDA EPIDIDYMIS LEFT ABS. REL. WT. % BRW TESTIS LEFT ABS. REL. WT. % BRW SEMINAL VESICLES WITH FLUID ABS. REL. WT. % BRW SEMINAL VESICLES WITHOUT FLUID ABS. REL. WT. % BRW EPIDIDYMIS RIGHT ABS. REL. WT. % BRW 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 2.48 2.43 2.38 2.28 2.62 2 .31 2.42 2.40 2.38 2.34 0.5886 0.5554a 0.7041 0.5648 0.5950 0.5787 0.6181 0.6705 0.6384 0.6200 23.73 22.86 29.58 24.77 22.71 25.05 25.54 27.94 26.82 26.50 0.2814 0.2921 0.3378 0.2550 0.3045 0.2725 0.2951 0.3537 0.3200 0.3288 11.35 12.02 14.19 11.18 11.62 11.80 12.19 14.74 13.44 14.05 1.7973 1.5902 1.9441 1. 5950 1. 7552 1.5509 1. 6009 1. 8102 1.9607 1. 8784 72.47 65.44 81.68 69. 96 66. 99 67.14 66 .15 75. 42 82.38 80. 27 1.4923 1. 4692 1. 6428 0.9950 1. 6404 1.1019 1. 5387 1.8705 1. 4543 1. 2190 60.17 60. 46 69. 02 43.64 62. 61 47.70 63. 58 77.94 61.10 52. 09 0.7724 0.8619 0.8490 0.5749 0.7509 0.6009 0.8782 0.9316 0.8120 0.7403 31.14 35.47 35.67 25.21 28.66 26.01 36.29 38.82 34.12 31.64 0.6626 0.5723 0.6631 0.5576 0.5793 0.6242 0.6487 0.6428 0.6610 0.6498 26.72 23.55 27.86 24.46 22.11 27.02 26.80 26.78 27.77 27.77 RAT NUMBER BRAIN WEIGHT TESTIS RIGHT ABS. REL. WT. % BRW PROSTATE ABS. WT. REL. % BRW LIVER ABS. WT. REL. % BRW KIDNEY LEFT ABS. REL. WT. % BRW KIDNEY RIGHT ABS. REL. WT. % BRW ADRENAL LEFT ABS. REL. WT. % BRW 19111 2.48 1. 7246 69. 54 1. 0515 42. 40 24.36 982.26 2.00 80.64 2.13 85.89 0.025 1.01 19117 2.43 1. 6160 66. 50 1. 0954 45. 08 24 .11 992.18 2.22 91.36 2.26 93.00 0.030 1.23 19124 2.38 1. 8910 79. 45 1.5146 63.64 25.72 1080.67 2.21 92.86 2.18 91. 60 0.035 1.47 19126 2.28 1.6044 70.37 0.7260 31.84 22.94 1006.14 2.04 89.47 2.04 89.47 0.029 1.27 19127 2.62 1. 7997 68. 69 1.4010 53.47 27.38 1045.04 1. 90 72.52 1. 95 74.43 0.031 1.18 19128 2.31 1. 5952 69. 06 0.9706 42.02 21. 74 941.12 1. 78 77.06 1. 82 78.79 0.036 1.56 1199114405 22..4420 11.. 86344007 6776.. 4820 11..23273596 5570..3527 2230..2201 893656..1627 12..2973 9794..7558 21..1868 7970..0608 00..003346 11..4429 ~ - 19149 2.38 1. 9989 83. 99 1. 2522 52. 61 20.06 842.86 1. 76 73.95 1. 92 80.67 0.029 1.22 00 I 19152 2.34 1. 8997 81.18 1.3077 55.88 18.58 794.02 1. 97 84.19 2.07 88.46 0.036 1.54 0 lV ALL WEIGHTS WERE RECORDED IN GRAMS (G) . ABS. WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. 00 ~ a. Damaged during processing (weight not affected). >~t:xJ I Vl O"\ PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B20 (PAGE 10): ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP V 10 MG/KG/DAY RAT NUMBER BRAIN WEIGHT ADRENAL RIGHT ABS. REL. WT. % BRW SPLEEN ABS. WT. REL. % BRW THYMUS ABS. WT. REL. % BRW HEART ABS. WT. REL. % BRW 19111 2.48 0.024 0.97 0.73 29.44 0.37 14. 92 1.38 55.64 19117 2.43 0.014 0.58 0.75 30.86 0.36 14.81 1. 60 65.84 19124 2.38 0.034 1.43 0. 72 30.25 0.36 15.13 1.40 58.82 19126 2.28 0.028 1.23 0.64 28.07 0.47 20.61 1. 38 60.53 19127 2.62 0.031 1.18 0.81 30.92 0.47 17.94 1.43 54.58 19128 2.31 0.034 1.47 0.74 32.03 0.40 17.32 1.42 61.47 19140 2.42 0.028 1.16 0.86 35.54 0.44 18.18 1. so 61. 98 19145 2.40 0.033 1.38 0.88 36.67 0.38 15.83 1. 36 56.67 19149 2.38 0.030 1.26 0.97 40.76 0.43 18.07 1.46 61.34 19152 2.34 0.038 1. 62 0.70 29.91 0.51 21. 79 1.47 62.82 ------------------------------------------------------------------------------------------------------------------------------------ ALL WEIGHTS WERE RECORDED IN GRAMS (G) . ABS. WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. ~ I-"" ~00 I 0 N 00 ~ tx:J I Vl -.l PROTOCOL 418-028: ORAL (GAVAGE} COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1} TABLE B21 (PAGE 1} : BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT # DOSAGE GROUP I 0 MG/KG/DAY DAY 1 2 3 4 5 6 7 8 9 10 11 12 13 14a 15 16 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 19143 19151 19157 19161 19167 322. 357. 347. 350. 328. 359. 341. 338. 332. 358. 338. 346. 331. 362. 332. 326. 361. 348. 356. 329. 364. 350. 339. 330. 359. 334. 350. 337. 373. 340. 334. 370. 360. 370. 320. 372. 357. 343. 342. 372. 344. 362. 344. 385. 347. 342. 374. 363. 378. 312. 382. 362. 347. 345. 380. 347. 366. 350. 392. 351. 344. 377. 372. 388. 336. 384. 375. 348. 350. 381. 357. 370. 355. 399. 359. 352. 388. 378. 394. 346. 392. 384. 356. 356. 391. 358. 378. 362. 411. 365. 357. 385. 385. 400. 350. 400. 388. 361. 358. 393. 363. 380. 363. 417. 372. 359. 393. 388. 414. 354. 409. 388. 359. 358. 398. 366. 387. 370. 424. 373. 355. 402. 389. 420. 358. 414. 403. 353. 366. 395. 365. 389. 369. 425. 382. 363. 408. 394. 424. 366. 420. 400. 363. 367. 398. 374. 392. 377. 416. 382. 370. 412. 402. 431. 372. 428. 407. 363. 370. 408. 381. 400. 378. 436. 388. 374. 417. 402. 446. 379. 431. 407. 369. 373. 403. 381. 404. 384. 433. 391. 380. 423. 408. 450. 380. 436. 419. 370. 373. 416. 387. 407. 394. 436. 391. 380. 427. 403. 454. 382. 440. 417. 376. 380. 417. 390. 406. 393. 446. 399. 376. 422. 410. 449. 389. 435. 418. 376. 357. 416. 387. 404. 384. 449. 396. 384. 430. 416. 452. 396. 435. 418. 376. 378. 424. 388. 408. 392. 457. 401. DAY 17 18 19 20 21 22 23 24 25 26 27 28 29b 30 31 32 19109 390. 391. 392. 398. 400. 398. 396. 403. 406. 409. 420. 420. 421. 427. 430. 435. 19115 429. 442. 443. 451. 449. 455. 458. 460. 465. 463. 462. 453. 472. 469. 479. 472. 19116 413. 422. 420. 425. 431. 432. 442. 448. 448. 452. 461. 469. 462. 466. 476. 479. 19119 455. 463. 470. 476. 478. 485. 483. 492. 494. 504. 513. 511. 504. 510. 518. 516. 19122 396. 399. 399. 405. 406. 409. 413. 420. 419. 421. 426. 432. 432. 434. 440. 441. 19125 435. 434. 442. 448. 452. 452. 465. 471. 478. 482. 486. 489. 491. 493. 500. 498. 19131 417. 432. 425. 438. 435. 440. 447. 450. 456. 458. 470. 470. 479. 479. 484. 494. 19132 384. 392. 393. 410. 415. 406. 407. 406. 418. 420. 424. 426. 428. 428. 431. 438. 19134 371. 377. 377. 380. 385. 381. 381. 387. 388. 394. 396. 404. 404. 406. 415. 419. ~ ......... 19135 426. 432. 430. 440. 437. 440. 442. 446. 449. 453. 464. 465. 468. 469. 470. 477. 00 I 19143 392. 393. 400. 406. 408. 407. 413. 414. 417. 426. 432. 440. 435. 440. 444. 453. 0 19151 411. 413. 408. 423. 424. 428. 430. 434. 446. 445. 450. 452. 463. 461. 457. 464. l'V 00 1199115671 436934.. 436987.. 349746.. 441803.. 440858.. 440999.. 451012.. 452008.. 452147.. 452198.. 453322.. 450399.. 453486.. 453444.. 453498.. 454551.. ~ > 19167 410. 409. 419. 425. 422. 378. 368. 363. 373. 389. 396. 405. 406. 414. 398. 421. ~ DAY = DAY OF STUDY ~ ALL WEIGHTS WERE RECORDED IN GRAMS (G} . I a. Last value recorded before cohabitation. V00I b. First value recorded after cohabitation. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B21 (PAGE 2): BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT # DOSAGE GROUP I DAY 33 34 35 36 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 19143 19151 19157 19161 19167 442. 439. 477. 521. 437. 503. 492. 444. 421. 485. 458. 473. 441. 557. 424. 446. 482. 485. 532. 451. 509. 497. 446. 424. 486. 456. 466. 443. 561. 426. 452. 485. 490. 538. 449. 517. 501. 446. 426. 493. 466. 461. 447. 560. 438. 443. 476. 491. 533. 455. 517. 513. 448. 433. 490. 468. 474. 455. 566. 441. DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . 37 451. 490. 490. 523. 458. 527. 512. 450. 438. 504. 472. 481. 458. 567. 445. 38 447. 487. 492. 526. 467. 517. 506. 439. 431. 494. 470. 474. 459. 571. 446. 0 MG/KG/DAY 39 40 450. 491. 494. 527. 467. 528. 514. 454. 434. 496. 477. 481. 460. 564. 445. 455. 490. 501. 529. 468. 528. 516. 458. 436. 502. 478. 482. 463. 571. 451. 41 463. 498. 501. 526. 468. 528. 515. 465. 441. 502. 476. 482. 470. 562. 451. 42 466. 499. 503. 537. 475. 534. 520. 466. 444. 504. 486. 484. 473. 556. 456. 43 438. 466. 509. 538. 474. 534. 528. 463. 436. 504. 491. 482. 478. 559. 458. 44 490. 505. 451. 543. 530. 474. 446. 511. 493. 490. 483. 569. 458. 45 508. 499. 439. 445. 509. 495. 500. 491. 575. 462. 46 419. 482. 499. 503. 486. 583. 472. 47 469. 470. 462. 549. 441. ,+::... 1--" 00 I 0 t--.,) ;0-c0, > ~ to I Vl \0 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B21 (PAGE 3): BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT # DOSAGE GROUP II 0.3 MG/KG/DAY DAY 1 2 3 4 5 6 7 8 9 10 11 12 13 14a 15 16 19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 19147 19153 19164 19165 19171 315. 360. 340. 348. 328. 355. 333. 346. 314. 339. 331. 346. 338. 342. 348. 321. 356. 351. 356. 340. 358. 340. 352. 323. 343. 335. 345. 338. 347. 353. 322. 369. 361. 358. 344. 368. 346. 367. 319. 348. 346. 337. 344. 355. 356. 328. 379. 371. 368. 352. 376. 354. 370. 326. 350. 348. 362. 352. 357. 355. 336. 383. 377. 372. 354. 381. 361. 378. 326. 356. 356. 365. 360. 362. 363. 339. 398. 386. 385. 362. 387. 368. 389. 328. 366. 362. 371. 362. 359. 367. 348. 400. 389. 385. 368. 389. 367. 392. 331. 362. 366. 375. 369. 367. 368. 349. 405. 396. 389. 369. 396. 373. 396. 330. 369. 375. 379. 379. 371. 365. 353. 408. 401. 391. 369. 402. 366. 402. 330. 374. 370. 381. 382. 382. 366. 362. 415. 405. 392. 375. 404. 377. 404. 333. 378. 379. 392. 386. 384. 366. 367. 424. 415. 400. 389. 412. 386. 414. 336. 381. 387. 392. 395. 388. 368. 370. 432. 417. 404. 388. 414. 387. 413. 338. 385. 389. 398. 399. 392. 372. 365. 433. 422. 410. 396. 421. 392. 426. 344. 388. 397. 405. 404. 400. 378. 366. 438. 427. 416. 390. 423. 398. 421. 348. 391. 399. 409. 402. 400. 382. 363. 437. 428. 387. 391. 421. 388. 414. 334. 385. 397. 404. 407. 401. 375. 376. 441. 426. 390. 396. 433. 391. 414. 336. 388. 397. 417. 414. 409. 385. DAY 17 18 19 20 21 22 23 24 25 26 27 28 29b 30 31 32 19102 375. 382. 389. 396. 399. 396. 403. 407. 411. 415. 421. 413. 424. 426. 430. 431. 19106 438. 444. 443. 446. 452. 453. 457. 459. 467. 469. 470. 476. 484. 485. 489. 482. 19108 429. 435. 436. 446. 442. 439. 444. 447. 451. 456. 461. 464. 471. 466. 483. 478. 19110 404. 410. 418. 422. 420. 423. 437. 431. 439. 442. 444. 447. 450. 453. 454. 461. 19113 396. 396. 406. 408. 412. 410. 417. 423. 421. 429. 433. 434. 436. 442. 447. 449. 19120 433. 441. 438. 447. 451. 454. 458. 457. 459. 467. 477. 479. 483. 481. 486. 490. 19129 402. 408. 408. 411. 417. 417. 424. 425. 429. 430. 433. 436. 445. 440. 449. 448. 19136 420. 429. 435. 440. 446. 446. 454. 455. 458. 465. 472. 480. 480. 481. 487. 491. ..i:::. 19138 340. 343. 346. 353. 358. 352. 353. 360. 360. 364. 370. 368. 371. 372. 372. 380. - 19139 385. 392. 395. 403. 407. 406. 410. 412. 416. 419. 424. 430. 427. 432. 433. 433. 00 I 19147 396. 403. 412. 419. 420. 428. 430. 432. 434. 445. 447. 452. 459. 452. 462. 466. 0 19153 418. 425. 423. 433. 439. 444. 444. 449. 450. 457. 463. 469. 473. 470. 480. 481. N 00 19164 411. 423. 429. 433. 442. 439. 453. 454. 453. 451. 463. 470. 472. 465. 476. 480. ~ 19165 406. 412. 411. 422. 429. 424. 434. 434. 442. 448. 454. 459. 460. 455. 462. 468. 19171 384. 393. 386. 399. 395. 396. 401. 406. 408. 411. 415. 412. 419. 423. 423. 423. ~ DAY = DAY OF STUDY cc ALL WEIGHTS WERE RECORDED IN GRAMS (G) . I ' a. Last value recorded before cohabitation. 0 b. First value recorded after cohabitation. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B21 (PAGE 4): BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT # DOSAGE GROUP II DAY 33 34 35 36 19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 19147 19153 19164 19165 19171 431. 489. 483. 465. 451. 491. 448. 503. 375. 433. 466. 482. 487. 470. 426. 436. 488. 484. 464. 453. 496. 451. 506. 380. 442. 474. 486. 490. 466. 420. 440. 488. 490. 464. 453. 497. 451. 508. 379. 451. 471. 490. 497. 464. 425. 443. 486. 486. 461. 464. 503. 456. 511. 383. 450. 475. 494. 489. 468. 428. DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . 37 455. 499. 489. 462. 458. 509. 450. 513. 389. 451. 478. 495. 501. 470. 428. 38 450. 501. 479. 471. 456. 493. 440. 504. 382. 451. 469. 498. 504. 473. 431. 0. 3 MG/KG/DAY 39 40 41 455. 508. 485. 473. 460. 506. 455. 524. 382. 447. 478. 498. 493. 478. 424. 461. 502. 485. 474. 463. 508. 460. 523. 387. 461. 480. 500. 495. 467. 424. 453. 501. 488. 474. 466. 509. 461. 522. 386. 450. 484. 505. 500. 476. 427. 42 456. 506. 495. 481. 464. 505. 463. 528. 390. 462. 497. 502. 509. 480. 435. 43 428. 476. 498. 480. 468. 517. 459. 534. 388. 458. 481. 504. 516. 486. 434. 44 474. 453. 444. 524. 466. 537. 389. 462. 496. 511. 512. 490. 443. 45 486. 435. 495. 396. 464. 499. 513. 517. 489. 444. 46 365. 432. 498. 506. 521. 492. 453. 47 470. 487. 484. 455. 421. ~.~ ..... 00 I 0 N 00 ~ tT.1 tx:l I .C..J..'..., PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B21 (PAGE 5) : BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT # DOSAGE GROUP III 1 MG/KG/DAY DAY 1 2 3 4 5 6 7 8 9 10 11 12 13 14a 15 16 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 19155 19159 19172 19173 19174 309. 368. 344. 345. 325. 359. 337. 345. 329. 354. 337. 346. 350. 351. 330. 308. 372. 350. 353. 331. 368. 339. 346. 330. 357. 341. 351. 350. 355. 334. 312. 383. 356. 360. 334. 381. 350. 354. 342. 367. 347. 367. 362. 363. 343. 317. 388. 367. 363. 338. 389. 356. 356. 349. 374. 354. 368. 373. 373. 346. 317. 395. 368. 371. 343. 403. 365. 363. 353. 379. 356. 376. 378. 376. 353. 320. 404. 380. 374. 348. 409. 371. 369. 355. 384. 367. 385. 388. 383. 360. 322. 411. 382. 378. 352. 403. 375. 371. 364. 393. 371. 390. 398. 388. 362. 324. 399. 387. 381. 353. 408. 386. 374. 367. 394. 374. 396. 402. 393. 369. 323. 420. 393. 386. 356. 433. 384. 378. 372. 396. 381. 390. 411. 395. 374. 318. 422. 390. 388. 359. 428. 386. 383. 370. 400. 370. 389. 415. 391. 377. 325. 418. 395. 387. 365. 444. 397. 385. 371. 407. 376. 398. 428. 402. 376. 327. 428. 400. 393. 364. 452. 404. 387. 383. 408. 380. 408. 430. 405. 383. 333. 432. 394. 400. 369. 452. 411. 392. 381. 412. 388. 403. 420. 410. 389. 335. 432. 411. 405. 371. 465. 415. 389. 387. 413. 398. 413. 434. 408. 388. 319. 429. 403. 406. 363. 445. 407. 384. 386. 405. 383. 401. 414. 409. 373. 326. 439. 414. 398. 361. 477. 415. 386. 393. 412. 396. 409. 437. 413. 386. DAY 17 18 19 20 21 22 23 24 25 26 27 28 29b 30 31 32 19101 326. 337. 333. 340. 343. 335. 345. 341. 343. 346. 350. 353. 355. 359. 363. 365. 19105 430. 443. 454. 453. 455. 462. 461. 469. 473. 478. 481. 491. 497. 500. 509. 509. 19107 415. 413. 415. 424. 432. 428. 436. 438. 434. 441. 439. 442. 447. 451. 450. 450. 19112 407. 415. 415. 423. 424. 433. 433. 435. 444. 445. 451. 452. 458. 456. 458. 461. 19114 366. 367. 374. 370. 381. 379. 389. 390. 397. 400. 407. 408. 411. 422. 422. 423. 19121 474. 480. 488. 499. 502. 511. 522. 528. 528. 533. 538. 547. 557. 558. 568. 571. 19123 414. 418. 426. 433. 439. 438. 439. 448. 446. 454. 455. 460. 461. 468. 466. 468. 19130 389. 393. 397. 405. 406. 411. 415. 418. 419. 421. 428. 434. 433. 425. 438. 438. +:-. 19137 401. 402. 404. 406. 410. 417. 421. 424. 428. 429. 440. 436. 443. 443. 452. 449. ~ ~ 19146 409. 419. 426. 428. 435. 430. 444. 444. 452. 449. 457. 460. 462. 470. 471. 473. 00 I 19155 401. 405. 409. 416. 418. 422. 429. 437. 442. 443. 454. 457. 458. 457. 467. 471. 0 19159 416. 409. 417. 417. 428. 428. 431. 435. 433. 448. 463. 458. 462. 454. 460. 463. N 00 19172 435. 440. 447. 456. 461. 464. 470. 479. 484. 487. 493. 500. 505. 506. 506. 514. ~ 19173 426. 430. 432. 436. 442. 441. 443. 442. 448. 456. 459. 459. 463. 456. 460. 466. 19174 388. 388. 396. 401. 406. 411. 414. 418. 420. 428. 431. 433. 437. 437. 444. 447. DAY = DAY OF STUDY ~ ALL WEIGHTS WERE RECORDED IN GRAMS (G) . I a. Last value recorded before cohabitation. O'I N b. First value recorded after cohabitation. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B21 (PAGE 6) : BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT # DOSAGE GROUP III DAY 33 34 35 36 19101 1910S 19107 19112 19114 19121 19123 19130 19137 19146 191SS 191S9 19172 19173 19174 369. SlS. 4S4. 468. 428. S73. 472. 449. 4S3. 478. 467. 470. S14. 467. 449. 370. S22. 4SS. 463. 430. S76. 474. 447. 4S7. 478. 474. 466. S08. 471. 4S3. 374. S19. 461. 471. 435. S79. 481. 4SO. 4S6. 479. 475. 476. 520. 476. 4S7. 369. S28. 4S7. 470. 436. S84. 483. 449. 462. 481. 479. 480. 528. 486. 460. DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . 37 373. S38. 4S8. 474. 442. S98. 478. 4S2. 469. 481. 477. 480. 534. 485. 4S7. 38 373. 537. 449. 473. 442. S90. 469. 4S4. 46S. 483. 481. 482. S31. 483. 462. 1 MG/KG/DAY 39 40 374. 536. 449. 480. 446. 602. 482. 448. 461. 47S. 481. 485. 534. 482. 461. 379. S35. 4S3. 480. 44S. 600. 483. 4S2. 474. 480. 486. 483. S31. 466. 4S7. 41 37S. 533. 456. 480. 4SO. 606. 489. 464. 474. 493. 492. 484. S32. 477. 461. 42 379. S32. 460. 478. 451. 606. 491. 466. 471. 493. 494. 494. S38. 483. 461. 43 3S3. sos. 437. 482. 454. 603. 497. 466. 473. 495. 493. 494. S41. 483. 461. 44 4S2. 430. 616. 494. 461. 473. 496. S02. 484. S47. 485. 466. 4S S67. 464. 470. 468. 499. soo. 498. S49. 483. 471. 46 434. 443. 473. S04. S06. 5S6. 486. 473. 47 481. 47S. 526. 4S9. 448. ~ ~ 00 I 0 tv 00 ~ > ~ a:; I V"J' PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B21 (PAGE 7) : BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT # DOSAGE GROUP IV 3 MG/KG/DAY DAY 1 2 3 4 5 6 7 8 9 10 11 12 13 14a 15 16 19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 19156 19160 19162 19163 19166 332. 363. 351. 342. 338. 363. 334. 348. 336. 356. 333. 351. 331. 350. 356. 332. 363. 360. 352. 338. 374. 338. 357. 343. 360. 330. 351. 333. 356. 359. 341. 379. 366. 358. 339. 382. 345. 368. 342. 372. 333. 364. 334. 364. 373. 344. 386. 375. 362. 347. 391. 354. 378. 355. 377. 337. 375. 338. 368. 385. 348. 393. 383. 363. 354. 396. 363. 386. 360. 384. 346. 376. 341. 379. 388. 356. 403. 389. 370. 357. 406. 368. 393. 366. 390. 358. 388. 344. 387. 398. 363. 415. 398. 374. 362. 414. 374. 405. 376. 391. 361. 395. 347. 393. 404. 363. 417. 401. 376. 364. 422. 379. 410. 378. 396. 360. 392. 351. 394. 396. 366. 428. 405. 380. 368. 426. 389. 418. 388. 399. 368. 392. 352. 401. 415. 366. 425. 400. 383. 372. 431. 387. 422. 378. 395. 366. 396. 354. 405. 416. 378. 434. 408. 389. 384. 438. 391. 434. 388. 404. 384. 404. 358. 418. 430. 377. 436. 412. 394. 393. 451. 398. 436. 389. 407. 386. 401. 369. 412. 430. 376. 439. 412. 397. 393. 450. 400. 430. 393. 410. 382. 412. 366. 410. 439. 381. 446. 423. 399. 388. 457. 410. 436. 398. 411. 394. 417. 369. 422. 443. 375. 435. 426. 399. 386. 452. 407. 434. 395. 406. 385. 396. 365. 412. 437. 382. 441. 432. 394. 395. 466. 415. 437. 403. 419. 395. 417. 372. 419. 447. DAY 17 18 19 20 21 22 23 24 25 26 27 28 29b 30 31 32 19100 390. 391. 396. 400. 403. 405. 404. 408. 411. 414. 418. 425. 428. 428. 431. 432. 19103 451. 458. 457. 470. 468. 470. 479. 489. 483. 486. 488. 490. 492. 498. 497. 499. 19104 438. 439. 436. 452. 454. 454. 458. 461. 467. 464. 471. 478. 479. 481. 481. 481. 19118 398. 406. 409. 419. 425. 426. 430. 429. 433. 434. 442. 444. 446. 449. 447. 451. 19133 395. 404. 410. 415. 421. 421. 432. 427. 439. 440. 441. 445. 449. 446. 443. 451. 19141 462. 473. 476. 476. 486. 490. 499. 502. 505. 512. 519. 518. 531. 526. 533. 539. 19142 420. 425. 431. 435. 441. 438. 448. 450. 455. 463. 469. 471. 472. 475. 485. 490. 19144 435. 451. 444. 456. 459. 462. 471. 474. 480. 494. 497. 497. 509. 518. 519. 517. ~ 19148 405. 412. 417. 421. 421. 424. 431. 434. 437. 438. 450. 452. 455. 451. 457. 465. ~ 19150 418. 427. 432. 441. 440. 436. 448. 442. 454. 450. 462. 462. 464. 458. 467. 474. 00 I 19156 396. 392. 402. 411. 411. 409. 416. 417. 419. 423. 422. 430. 436. 436. 435. 438. 0 19160 421. 424. 427. 434. 437. 431. 446. 442. 449. 450. 461. 470. 464. 468. 475. 473. N 00 19162 377. 376. 381. 382. 390. 392. 397. 402. 400. 408. 409. 410. 415. 414. 415. 417. ~ 19163 429. 434. 438. 453. 455. 448. 462. 463. 459. 463. 468. 478. 484. 476. 481. 479. 19166 456. 460. 465. 473. 480. 480. 480. 487. 488. 493. 500. 502. 503. 505. 505. 505. ~ DAY = DAY OF STUDY OJ ALL WEIGHTS WERE RECORDED IN GRAMS (G) . I ' a. Last value recorded before cohabitation. ~ b. First value recorded after cohabitation. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B21 (PAGE 8) : BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT # DOSAGE GROUP IV DAY 33 34 35 36 19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 19156 19160 19162 19163 19166 435. 497. 484. 448. 452. 537. 494. 524. 460. 468. 438. 473. 419. 491. 511. 438. 502. 488. 452. 453. 537. 489. 524. 461. 463. 442. 475. 418. 483. 511. 440. 503. 484. 459. 454. 543. 491. 528. 469. 466. 441. 479. 426. 490. 517. 441. 499. 486. 458. 461. 545. 496. 531. 473. 470. 448. 479. 424. 492. 513. DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . 37 445. 508. 497. 457. 457. 556. 510. 539. 482. 470. 446. 485. 429. 494. 519. 38 447. 513. 499. 459. 464. 557. 497. 533. 482. 472. 450. 488. 427. 492. 525. 3 MG/KG/DAY 39 40 448. 516. 506. 464. 470. 566. 501. 546. 481. 472. 447. 486. 431. 497. 525. 455. 509. 506. 467. 474. 570. 504. 536. 489. 463. 452. 480. 433. 492. 520. 41 449. 511. 502. 464. 470. 567. 500. 547. 485. 478. 452. 483. 435. 500. 522. 42 454. 516. 506. 469. 475. 564. 504. 552. 486. 481. 457. 481. 434. 503. 523. 43 421. 487. 509. 470. 484. 574. 505. 547. 482. 476. 453. 478. 435. 508. 528. 44 476. 442. 448. 585. 515. 553. 495. 472. 447. 496. 441. 516. 535. 45 545. 479. 523. 495. 479. 455. 493. 449. 513. 531. 46 454. 448. 460. 491. 445. 512. 537. 47 433. 461. 415. 486. 506. -~ 00 I 0 tv 00 ~ >~t:d I V"t' PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B21 (PAGE 9) : BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT # DOSAGE GROUP V 10 MG/KG/DAY DAY 1 2 3 4 5 6 7 8 9 10 11 12 13 14a 15 16 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 19154 19158 19168 19169 19170 326. 363. 345. 344. 329. 358. 331. 348. 325. 347. 346. 350. 329. 358. 350. 334. 365. 346. 349. 335. 358. 328. 349. 324. 360. 346. 351. 329. 360. 353. 339. 375. 354. 356. 342. 367. 347. 358. 331. 358. 354. 362. 338. 365. 359. 346. 381. 360. 360. 351. 372. 346. 366. 339. 367. 355. 368. 341. 372. 365. 351. 382. 365. 365. 357. 376. 353. 375. 339. 371. 363. 373. 342. 375. 368. 360. 387. 372. 370. 366. 382. 359. 375. 346. 378. 369. 379. 352. 379. 382. 370. 393. 372. 371. 365. 382. 362. 382. 352. 384. 376. 384. 356. 381. 382. 370. 393. 379. 371. 370. 385. 366. 386. 354. 385. 371. 387. 359. 388. 386. 374. 390. 382. 377. 376. 389. 373. 388. 352. 382. 378. 389. 360. 390. 386. 382. 392. 389. 377. 378. 394. 379. 393. 359. 388. 381. 385. 369. 391. 390. 390. 404. 389. 384. 379. 390. 380. 395. 368. 394. 388. 398. 376. 403. 396. 389. 401. 379. 383. 383. 406. 387. 398. 367. 396. 385. 395. 378. 403. 395. 391. 408. 389. 391. 387. 409. 388. 406. 367. 401. 394. 394. 380. 409. 402. 393. 416. 393. 389. 395. 408. 393. 406. 369. 405. 401. 401. 378. 410. 402. 389. 405. 385. 386. 362. 411. 386. 387. 368. 399. 397. 398. 374. 411. 400. 396. 416. 397. 390. 394. 415. 396. 394. 375. 407. 409. 408. 385. 424. 396. DAY 17 18 19 20 21 22 23 24 25 26 27 28 29b 30 31 32 19111 401. 403. 407. 410. 412. 414. 426. 424. 427. 429. 437. 436. 438. 440. 440. 442. 19117 410. 424. 423. 427. 428. 430. 438. 446. 444. 445. 456. 456. 463. 460. 464. 466. 19124 403. 397. 402. 409. 409. 410. 415. 410. 413. 416. 419. 425. 430. 429. 428. 433. 19126 394. 393. 394. 400. 402. 400. 400. 400. 406. 407. 415. 420. 418. 422. 420. 423. 19127 388. 382. 384. 398. 402. 405. 464.c 417. 416. 421. 432. 436. 436. 435. 440. 446. 19128 414. 425. 429. 429. 430. 434. 436. 433. 430. 440. 439. 443. 444. 444. 451. 449. 19140 401. 407. 415. 417. 424. 417. 420. 428. 430. 436. 434. 442. 440. 446. 450. 448. 19145 19149 399. 383. 401. 376. 407. 383. 414. 386. 418. 396. 414. 399. 421. 402. 424. 405. 424. 406. 430. 407. 435. 417. 437. 417. 440. 422. 440. 422. 447. 433. 453. 434. .~ ...... 19152 412. 415. 416. 418. 426. 399. 406. 410. 417. 424. 430. 432. 430. 440. 445. 449. 00 I 19154 408. 409. 411. 412. 417. 416. 414. 415. 419. 427. 437. 437. 443. 448. 452. 463. 0 19158 412. 412. 414. 422. 427. 428. 432. 431. 432. 439. 440. 447. 447. 443. 446. 450. tv 00 19168 390. 394. 388. 391. 394. 390. 387. 392. 390. 396. 403. 404. 405. 404. 409. 414. ~ 19169 424. 429. 431. 438. 438. .436. 446. 447. 444. 447. 454. 456. 463. 466. 461. 468. > 19170 407. 412. 410. 418. 421. 420. 424. 428. 428. 433. 443. 443. 446. 448. 452. 455. ~ DAY = DAY OF STUDY tO ALL WEIGHTS WERE RECORDED IN GRAMS (G) . I a. Last value recorded before cohabitation. O"I O"I b. First value recorded after cohabitation. c. Value appeared incorrectly recorded and was excluded from group averages and statistical analyses. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B21 (PAGE 10) : BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT# DOSAGE GROUP V DAY 33 34 35 36 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 19154 19158 19168 19169 19170 446. 465. 434. 430. 448. 458. 452. 454. 443. 450. 458. 449. 412. 471. 456. 456. 467. 437. 436. 456. 457. 449. 451. 442. 455. 466. 448. 414. 469. 460. 449. 473. 443. 431. 448. 459. 456. 455. 444. 458. 468. 450. 418. 472. 459. 449. 467. 438. 435. 454. 461. 453. 455. 451. 461. 472. 453. 414. 484. 465. DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . 37 457. 477. 448. 429. 444. 473. 464. 460. 453. 464. 479. 461. 417. 485. 460. 38 456. 481. 445. 438. 454. 463. 454. 463. 460. 463. 477. 458. 423. 485. 462. 10 MG/KG/DAY 39 40 41 455. 484. 449. 437. 453. 473. 466. 459. 454. 464. 480. 456. 423. 479. 466. 461. 480. 445. 445. 458. 469. 465. 465. 463. 476. 491. 460. 420. 471. 457. 468. 486. 448. 446. 455. 472. 466. 464. 460. 479. 488. 462. 412. 474. 452. 42 466. 483. 450. 452. 470. 470. 469. 471. 459. 483. 496. 469. 416. 486. 457. 43 432. 462. 426. 452. 467. 481. 473. 473. 462. 485. 490. 474. 416. 479. 459. 44 426. 434. 486. 486. 477. 466. 498. 496. 461. 421. 477. 463. 45 445. 442. 466. 468. 491. 498. 478. 421. 482. 467. 46 441. 439. 461. 498. 471. 425. 480. 471. 47 466. 453. 402. 448. 445. ....J..:.:.:.... 00 I 0 N 00 ~ ~ tx:l I 0-. ....-J PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B22 (PAGE 1) : FEED CONSUMPTION VALUES - INDIVIDUAL DATA - Fo GENERATION MALE RATS DAYS 1- Sa 29b-36 RAT # DOSAGE GROUP I 0 MG/KG/DAY 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 19143 19151 19157 19161 19167 229. 187. 188. 236. 164. 212. 213. 169. 184. 199. 196. 195. 195. 235. 187. c 199. 209. 238. 204. 235. 222. 189. 198. 208. 220. 190. 212. 244. 191. RAT # DOSAGE GROUP II 0. 3 MG/KG/DAY 19102 193. 200. 19106 212. 192. 19108 222. 216. 19110 199. 202. 19113 200. 203. 19120 200. 195. 19129 196. 190. 19136 212. 226. ~ 19138 169. 179. ~ 19139 184. 201. 00 I 19147 189. 203. 0 19153 188. 201. N 00 19164 196. 246. ~ 19165 178. 189. 19171 187. 178. ~tT.1 DAY = DAY OF STUDY t:xJ ALL WEIGHTS WERE RECORDED IN GRAMS (G) . I a. Last value recorded before cohabitation. 00 ' b. First value recorded after cohabitation. c. Spilled feed precluded the calculation of this value. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B22 (PAGE 2) : FEED CONSUMPTION VALUES - INDIVIDUAL DATA - Fo GENERATION MALE RATS DAYS 1- 8a 29b-36 RAT # DOSAGE GROUP III 1 MG/KG/DAY 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 19155 19159 19172 19173 19174 153. 207. 211. 209. 188. 224. 192. 190. 207. 190. 194. 251. 240. 206. 195. 186. 219. 204. 209. 199. 253. 204. 192. 219. 194. 208. 231. 222. 192. 197. RAT # DOSAGE GROUP IV 3 MG/KG/DAY 19100 186. 191. 19103 222. 218. 19104 204. 209. 19118 181. 188. 19133 194. 208. 19141 233. 236. 19142 195. 232. 19144 227. 238. +::- 19148 199. 212. ~ 19150 214. 181. 00 I 19156 176. 177. 0 19160 214. 207. N 00 19162 171. 181. ~ 19163 206. 197. 19166 200. 201. ~tT1 DAY = DAY OF STUDY tp ALL WEIGHTS WERE RECORDED IN GRAMS (G) . I a. Last value recorded before cohabitation. l...O ' b. First value recorded after cohabitation. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B22 (PAGE 3): FEED CONSUMPTION VALUES - INDIVIDUAL DATA - Fo GENERATION MALE RATS DAYS 1- 8a 29b-36 RAT # DOSAGE GROUP V 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 19154 19158 19168 19169 19170 193. 183. 191. 181. 198. 197. 177. 191. 170. 187. 198. 202. 175. 198. 189. 186. 206. 178. 188. 198. 218. 193. 194. 206. 200. 227. 191. 168. 216. 198. DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Last value recorded before cohabitation. b. First value recorded after cohabitation. 10 MG/KG/DAY ~ 1--" 00 I 0 tv 00 ~ >~to I ......J 0 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B23 (PAGE 1) : MATING AND FERTILITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT # DAYS IN COHABITATION MATING STATUS MATING DATE FEMALE PREGNANCY STATUS DOSAGE GROUP I 0 MG/KG/DAY 19109 7 19115 2 19116 3 19119 2 19122 4 19125 4 19131 3 19132 1 19134 4 19135 3 19143 3 19151 2 19157a 4 19157b 7 19161 2 19167 4 DID NOT MATE - M c M c M c M c M c M c M c M c M c M c M c M c M c M c M c - (19010) P(19012) P(19019) P(19021) P(l9023) P(19041) P(19042) P(19044) P(19050) P(19053) P(19065) P(19068) P(19072) P(19010) P(19074) P(19075) DOSAGE GROUP II 0. 3 MG/KG/DAY ~ 19102 4 M c P(19004) 19106 1 M c P(l9009) 19108 1 M c P(19016) 19110 2 M c P(19018) 19113 4 M c P(19026) 19120 1 M c P(19036) 19129 2 M c p (1903 7) ..j::::.. lo--" 19136 1 M c P(19043) 00 19138 1 M c P(19047) I 0 19139 4 M c P(19048) tv 00 19147 1 M c P(19052) ~ 19153 1 M c P(19055) 19164 2 M c P(19061) 19165 3 M c P(19067) 19171 1 M c P(19071) tO I M = MATED ( ) = FEMALE RAT NUMBER ......J ~ C = CONFIRMED P = PREGNANT NP = NOT PREGNANT a. Result of first cohabitation period. b. Result of second cohabitation period. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B23 (PAGE 2): MATING AND FERTILITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT # DAYS IN COHABITATION MATING STATUS MATING DATE FEMALE PREGNANCY STATUS DOSAGE GROUP III 1 MG/KG/DAY 19101 3 19105 3 19107 4 19112 2 19114 1 19121 4 19123 1 19130 4 19137 2 19146 3 19155 1 19159 4 19172 4 19173 2 19174 4 M c M c M c M c M c M c M c M c M c M c M c M c M c M c M c P(19003) P(l9007) P(19008) P(19013) NP(19014) P(19015) p (19017) P(19024) P(19029) P(19034) NP(19038) P(19056) P(19057) P(19060) P(19064) DOSAGE GROUP IV 3 MG/KG/DAY 19100 7 DID NOT MATE - -(19002) 19103 4 M c P(19005) 19104 4 M c P(19035) 19118 2 M c P(19039) 19133 4 M c P(19040) 19141 1 M c P(19045) 19142 1 M c NP (19046) .a;::. 19144 7 DID NOT MATE - - (19051) ........ 19148 3 M c P(19054) 00 19150 1 M c P(19058) I 0 19156a 4 M c P(19062) !:'...,) 00 19156b 6 M c P(19002) ~ 19160 2 M c P(19063) 19162 4 M c P(19066) ~ 19163a 2 M c P(19069) 19163b 7 DID NOT MATE - -(19051) ec 19166 1 M c P(19073) I -..l !:'...,) M = MATED ( ) = FEMALE RAT NUMBER C = CONFIRMED p = PREGNANT NP = NOT PREGNANT a. Result of first cohabitation period. b. Result of second cohabitation period. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B23 (PAGE 3): MATING AND FERTILITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT # DAYS IN COHABITATION DOSAGE GROUP V 19111 1 19117 3 19124 4 19126 4 19127 4 19128 3 19140 4 19145 1 19149 4 19152 1 19154 4 19158 1 19168 1 19169 1 19170 1 M = MATED ( ) = FEMALE RAT NUMBER C = CONFIRMED p PREGNANT NP = NOT PREGNANT MATING STATUS 10 MG/KG/DAY M M M M M M M M M M M M M M M MATING DATE c c c c c c c c c c c c c c c FEMALE PREGNANCY STATUS p (19001) P(19006) P(19011) P(19020) P(19022) P(l9025) P(19027) P(19028) P(l9030) P(19031) P(19032) P(19033) p (19049) P(19059) P(19070) ,.._J:_:::... 00 I 0 tv 00 ;-c, >~Cd I -..J U-l PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B24 (PAGE 1) : FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - Fo GENERATION MALE RATS __ p~~~9_E2,_9~~q~--~-------------------------------------------------------------------------------------~-!:'l~~gj_~~,Y__________________________________________________ _ RAT # 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 -H--O-M-E---C-A-G--E--B-E--H-A-V--IO--R-------------------2-----------2------------2-----------2------------2-----------2------------1-----------2-----------2------------1----------------------- ALTERATIONS (HOME CAGE) 1 1 1 1 1 1 2a 1 1 1 REACTION TO REMOVAL 1 1 1 1 1 1 1 1 1 1 REACTION TO HANDLING 1 1 1 1 1 1 1 1 1 1 REARS IN OPEN FIELD 2 5 3 4 3 6 1 1 8 0 DEFECATION IN OPEN FIELD 1 1 1 1 1 1 1 1 1 1 URINATION IN OPEN FIELD 2 1 1 2 1 2 1 2 1 1 LEVEL OF AROUSAL 3 3 3 3 3 3 3 3 3 3 ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1 1 GAIT PATTERN 1 1 1 1 1 1 1 1 1 1 GAIT ABNORMALITY, SEVERITY 1 1 1 1 1 1 1 1 1 1 PALPEBRAL CLOSURE 1 1 1 1 1 1 1 1 1 1 PROMINENCE OF THE EYE 1 1 1 1 1 1 1 1 1 1 LACRIMATION 1 1 1 1 1 1 1 1 1 1 SALIVATION 1 1 1 1 1 1 1 1 1 1 PILOERECTION 0 0 0 0 0 0 0 0 0 0 ABNORMAL RESPIRATION 0 0 0 0 0 0 0 0 0 0 APPEARANCE 1 1 1 1 lb 1 1 1 1 1 VISUAL REACTION 2 2 2 2 2 2 2 2 2 2 TACTILE REACTION 2 2 2 2 2 2 2 2 2 2 AUDITORY REACTION 3 3 3 3 3 3 3 3 3 3 TAIL-PINCH REACTION 2 2 2 2 2 2 2 2 2 2 AIR RIGHTING RESPONSE 1 1 1 1 1 1 1 1 1 1 PUPIL RESPONSE TO LIGHT 1 1 1 1 1 1 1 1 1 1 ...i.:.:..:... FORELIMB GRIP TEST #1 (G) 355 460 500 360 340 470 315 415 295 315 00 I FORELIMB GRIP TEST #2 (G) 460 510 420 395 375 350 465 465 430 370 0 t-.J HINDLIMB GRIP TEST #1 (G) 450 320 620 315 315 490 255 300 280 345 00 HINDLIMB GRIP TEST #2 (G) 415 380 690 220 330 390 255 325 250 275 ~ > LANDING FOOT SPLAY #1 (CM) 6.7 9.8 8.8 7.9 4.5 8.5 7.8 8.0 7.7 8.4 LANDING FOOT SPLAY #2 (CM) 6.8 7.6 7.7 7.6 5.7 7.1 7.2 6.8 7.5 8.4 ________ ________ ~ --~~~!-.!'!.~!9!!.!._J~~--------------------~~.? j_~Z--------~2.:>________,:;_~Z--------~j________,;;_~~--------~2..7 j_'!~--------~2..3________ ,;;_~~--------------------- tx:1 vALuEs ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY. I -..l a. Value appeared incorrectly recorded; value excluded from group averages and statistical analyses. .i:::. b. Chromorhinorrhea. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B24 (PAGE 2) : FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - Fo GENERATION MALE RATS -P~~9-~-g~~~~--I_! ____________________________________________________________________________________~~}__~gL_~~LP2!~------------------------------------------------ -~!-~--------------------------------~~}_o_~ _____ }_9_~~------~~}_o_~ _____ }_9_~~2------~~}}_~ _____ }_9_~~2------~~}3_~ _____ }_9_~~------~~}]_~ _____ }_9_~~2-------------------- HOME CAGE BEHAVIOR 2 2 2 2 2 2 2 1 1 1 ALTERATIONS (HOME CAGE) 1 1 1 1 1 1 1 1 1 1 REACTION TO REMOVAL 1 1 1 1 1 1 1 1 1 1 REACTION TO HANDLING 1 1 1 1 1 1 1 1 1 1 REARS IN OPEN FIELD 11 8 3 11 9 4 4 3 4 5 DEFECATION IN OPEN FIELD 1 1 1 1 2 2 1 1 1 1 URINATION IN OPEN FIELD 2 1 2 2 2 2 2 2 2 2 LEVEL OF AROUSAL 3 3 3 3 3 3 3 3 3 3 ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1 1 GAIT PATTERN 1 1 1 1 1 1 1 1 1 1 GAIT ABNORMALITY, SEVERITY 1 1 1 1 1 1 1 1 1 1 PALPEBRAL CLOSURE 1 1 1 1 1 1 1 1 1 1 PROMINENCE OF THE EYE 1 1 1 1 1 1 1 1 1 1 LACRIMATION 1 1 1 1 1 1 1 1 1 1 SALIVATION 1 1 1 1 1 1 1 1 1 1 PILOERECTION 0 0 0 0 0 0 0 0 0 0 ABNORMAL RESPIRATION 0 0 0 0 0 0 0 0 0 0 APPEARANCE 1 1 1 1 1 1 1 1 1 1 VISUAL REACTION 2 2 2 2 2 2 2 2 2 2 TACTILE REACTION 2 2 2 2 2 2 2 2 2 2 AUDITORY REACTION 3 3 3 3 3 3 3 3 3 3 TAIL-PINCH REACTION 2 2 2 2 2 2 2 2 2 2 AIR RIGHTING RESPONSE 1 1 1 1 1 1 1 1 1 1 PUPIL RESPONSE TO LIGHT 1 1 1 1 1 1 1 1 1 1 ~ I--' FORELIMB GRIP TEST #1 (G) 355 375 395 415 455 245 250a 505 215 435 00 I ;,:, FORELIMB GRIP TEST #2 (G) 400 490 360 470 465 410 365 390 465 550 0 N HINDLIMB GRIP TEST #1 (G) 345 435 610 365 315 250 315 155 435 465 00 HINDLIMB GRIP TEST #2 (G) 460 505 575 450 520 550 345b 220 365 335 > LANDING FOOT SPLAY #1 (CM) 11.6 9.5 7.6 8.0 6.8 6.2 12.5 7.6 8.0 9.9 LANDING FOOT SPLAY #2 (CM) 9.7 8.4 6.5 7.8 6.5 4.8 12.7 7.8 9.2 11.5 ________ _______ ________ ________ ~ -~~~!-!!.~!9.!!.!_J~L--------------------~~} !;.~~--------~2-0________ }_~Z--------~!;. }_~~--------~~] _s_~Z--------~~_s !;.~~--------------------- ttJ vALuEs ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY. I .......J a. Vocalization and aggression observed during forelimb grip test. VI b. Soft or liquid feces observed during hindlirnb grip test. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B24 (PAGE 3): FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - Fo GENERATION MALE RATS -P~~~9_E2,_~!<-~':!~--~!!_________________________________________________________________________________}__1::'.19J_~~f.?-~!---------------------------------------------------- RAT # 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 -H--O-M-E---C-A-G--E--B-E--H-A-V--IO--R-------------------2-----------2------------2-----------2------------2-----------2------------2-----------1-----------1------------1----------------------- ALTERATIONS (HOME CAGE) 1 1 1 1 1 1 1 1 1 1 REACTION TO REMOVAL 1 1 1 1 1 1 1 1 1 1 REACTION TO HANDLING 1 1 1 1 1 1 1 1 1 1 REARS IN OPEN FIELD 3 3 7 2 2 3 2 5 6 6 DEFECATION IN OPEN FIELD 2 1 2 1 1 1 2 1 1 1 URINATION IN OPEN FI.ELD 2 2 2 1 2 1 1 1 1 1 LEVEL OF AROUSAL 3 3 3 3 3 3 3 3 3 3 ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1 1 GAIT PATTERN 1 1 1 1 1 1 1 1 1 1 GAIT ABNORMALITY, SEVERITY 1 1 1 1 1 1 1 1 1 1 PALPEBRAL CLOSURE 1 1 1 1 1 1 1 1 1 1 PROMINENCE OF THE EYE 1 1 1 1 1 1 1 1 1 1 LACRIMATION 1 1 1 1 1 1 1 1 1 1 SALIVATION 1 1 1 1 1 1 1 1 1 1 PILOERECTION 0 0 0 0 0 0 0 0 0 0 ABNORMAL RESPIRATION 0 0 0 0 0 0 0 0 0 0 APPEARANCE 1 1 la 1 1 1 1 1 1 1 VISUAL REACTION 2 2 2 2 2 2 2 2 2 2 TACTILE REACTION 2 2 2 2 2 2 2 2 2 2 AUDITORY REACTION 3 3 3 3 3 3 3 3 3 3 TAIL-PINCH REACTION 2 2 2 2 2 2 2b 2 2 2 AIR RIGHTING RESPONSE 1 1 1 1 1 1 1 1 1 le PUPIL RESPONSE TO LIGHT 1 1 1 1 1 1 1 1 1 1 .....J.:.:..:.. FORELIMB GRIP TEST #1 (G) 215 500 480 490 270 550 405 395 340 570 00 I FORELIMB GRIP TEST #2 (G) 175 430 545 400 430 395 395 515 330 360 0 tv HINDLIMB GRIP TEST #1 (G) 520 480 540 415 395 465 375 280 305 220 00 HINDLIMB GRIP TEST #2 (G) 545 580 415 525 395 475 490 435 255 280 ~ > LANDING FOOT SPLAY #1 (CM) 8.2 8.7 9.7 6.8 9.0 11.8 8.5 9.7 11.1 8.7 LANDING FOOT SPLAY #2 (CM) 6.7 7.5 10.3 7.5 8.8 10.2 9.5 7.8 10.7 7.6 ~ -~~~!-~~!.9!!.! __(_<!L--------------------~7_s________ _s_~~--------~2..9________ !_~~--------~~..9________ _?_~!--------~7_6________ J:_~Z--------~..7________ !_~~--------------------- to vALuEs ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY. I -.......) a. Localized alopecia: lower midline - right side (4.0 cm x 1.5 cm). O"'I b. Soft or liquid feces observed during tail-pinch reaction. c. Vocalization to touch and aggressive behavior observed during air righting response. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B24 (PAGE 4): FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - Fo GENERATION MALE RATS __-p-~-~-~-9---~---~-~-~-l-2-:-~-----~-~-------------------------------------------------------------------------------------------------------------------------------------------------------------------]-_-_-l-'-;-!-~-l-~-~-~-P-l-!-~--------------------------------------------------------------------------------------------------------- _____ _____ _____ _____ --~!_J________________________________~~!--~-----!..9_~~2------~~!_D_'!, !_9_~~------~~!_3_~ !_9_~~!------~~!J_~ !..9_~~~------~~!J_~ !..9_~~2-------------------- HOME CAGE BEHAVIOR 2 2 2 2 2 2 1 2 2 1 ALTERATIONS (HOME CAGE) 1 1 1 1 1 1 1 1 1 1 REACTION TO REMOVAL 1 1 1 1 1 1 1 1 1 1 REACTION TO HANDLING 1 1 1 1 1 1 1 1 1 1 REARS IN OPEN FIELD 7 6 1 4 4 2 6 7 3 5 DEFECATION IN OPEN FIELD 1 2 1 1 1 1 1 1 1 1 URINATION IN OPEN FIELD 2 2 1 2 2 1 2 2 2 2 LEVEL OF AROUSAL 3 3 3 3 3 3 3 3 3 3 ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1 1 GAIT PATTERN 1 1 1 1 1 1 1 1 1 1 GAIT ABNORMALITY, SEVERITY 1 1 1 1 1 1 1 1 1 1 PALPEBRAL CLOSURE 1 1 1 1 1 1 1 1 1 1 PROMINENCE OF THE EYE 1 1 1 1 1 1 1 1 1 1 LACRIMATION 1 1 1 1 1 1 1 1 1 1 SALIVATION 1 1 1 1 1 1 1 1 1 1 PILOERECTION 0 0 0 0 0 0 0 0 0 0 ABNORMAL RESPIRATION 0 0 0 0 0 0 0 0 0 0 APPEARANCE 1 1 1 1 1 1 1 1 1 la VISUAL REACTION 2 2 2 2 2 2 2 2 2 2 TACTILE REACTION 2 2 2 2 2 2 2 2 2 2 AUDITORY REACTION 3 3 3 3 3 3 3 3 3 3 TAIL-PINCH REACTION 2 2 2 2 2 2 2 2 2 2 AIR RIGHTING RESPONSE 1 1 1 1 1 1 lb 1 1 1 PUPIL RESPONSE TO LIGHT 1 1 1 1 1 1 1 1 1 1 FORELIMB GRIP TEST #1 (G) 450 355 330 270 335 120 390 355 465 260 FORELIMB GRIP TEST #2 (G) 540 315 465 475 365 220 365 255 675 345 HINDLIMB GRIP TEST #1 (G) 425 520 450 380 350 270 215 200 405 270 HINDLIMB GRIP TEST #2 (G) 385 420 335 415 265 420 365 340 485 375 LANDING FOOT SPLAY #1 (CM) 7.6 10.8 6.6 9.0 6.6 6.8 9.7 8.5 11. 9 9.4 LANDING FOOT SPLAY #2 (CM) 6.9 9.7 7.8 8.5 4.5 6.7 9.6 9.2 12.2 9.6 ____________________ _______ ________ -!3~~~-.!'!.~!9~!_J.s!L ~~-1--------..5-~~--------~2..4.. ..4..~~--------~2..9 _s_~~--------~2-6________ _s_~~--------~_1________ J_~~--------------------- vALuEs ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY. a. Chromodacryorrhea - right eye and incisors misaligned - upper bilateral. b. Vocalization and aggression observed during air righting response. .i;:::.. ~ 00 I 0 t'.J 00 ~ @ tJ:j I -..l -..l PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B24 (PAGE 5): FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - Fo GENERATION MALE RATS ,-_-p-.--~-~--E-2-.---~-~---~-l-!-~---~---------------------------------------------------------------------------------------------------------------------------------------------------------------~-2-----r-:-!-~-f---~-~-~-P-.!-!-.-!-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_--_ RAT # 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 -H--O-M-E---C-A-G-E---B-E--H-A-V--IO--R-------------------2-----------2------------2-----------1-----------2------------2------------2-----------2-----------2------------1----------------------- ALTERATIONS (HOME CAGE) 1 1 1 1 1 1 1 1 1 1 REACTION TO REMOVAL 1 1 1 1 1 1 1 1 1 1 REACTION TO HANDLING 1 1 1 1 1 1 1 1 1 1 REARS IN OPEN FIELD 6 6 2 8 2 0 6 5 9 1 DEFECATION IN OPEN FIELD 1 1 1 1 2 1 1 1 1 1 URINATION IN OPEN FIELD 2 2 1 2 2 1 2 2 2 1 LEVEL OF AROUSAL 3 3 3 3 3 3 3 3 3 3 ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1 1 GAIT PATTERN 1 1 1 1 1 1 1 1 1 1 GAIT ABNORMALITY, SEVERITY 1 1 1 1 1 1 1 1 1 1 PALPEBRAL CLOSURE 1 1 1 1 1 1 1 1 1 1 PROMINENCE OF THE EYE 1 1 1 1 1 1 1 1 1 1 LACRIMATION 1 1 1 1 1 1 1 1 1 1 SALIVATION 1 1 1 1 1 1 1 1 1 1 PILOERECTION 0 0 0 0 0 0 0 0 0 0 ABNORMAL RESPIRATION 0 0 0 0 0 0 0 0 0 0 APPEARANCE 1 1 1 1 1 1 1 1 1 1 VISUAL REACTION 2 2 2 2 2 2 2 2 2 2 TACTILE REACTION 2 2 2 2 2 2 2 2 2 2 AUDITORY REACTION 3 3 3 3 3 3 3 3 3 3 TAIL-PINCH REACTION 2 2 2 2 2 2 2 2 2 2 AIR RIGHTING RESPONSE 1 1 1 1 1 1 1 1 1 1 PUPIL RESPONSE TO LIGHT 1 1 1 1 1 1 1 1 1 1 ..,.i.:.::.:.... FORELIMB GRIP TEST #1 (G) 355 335 320 580 415 300 285 165 165 510 00 I FORELIMB GRIP TEST #2 (G) 365 450 350 470 470 450 450 155 275 320 0 HINDLIMB GRIP TEST #1 (G) 500 420 510 485 440 430 430 500 250 305 t-..J 00 HINDLIMB GRIP TEST #2 (G) 485 660 555 400 450 505 440 480 215 330 ~ > LANDING FOOT SPLAY #1 (CM) 8.1 7.5 8.1 8.8 9.1 5.3 13.0 8.1 5.8 8.5 LANDING FOOT SPLAY #2 (CM) 7.6 6.8 8.3 7.6 9.7 5.0 12.7 6.5 6.2 7.6 ________ ________ ________ ________ ~ __(_<!L____________________ ________ to ._!l.~~-!!.~!.9!!.! ~2_s J..~~--------~~2 }_~~--------~..3 J..~~--------~.? }_~~--------~_6 J..~~--------------------- vALuEs ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY. I -..l 00 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B25 (PAGE 1) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP I 0 MG/KG/DAY RAT NUMBER 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 --N-U-M--B-E-R---O-F--M--O-V--E-M-E-N--T-S----------------------------------------------------------------------------------------------------------------------------------------------- BLOCK 1 71 60 64 68 67 72 58 62 73 53 BLOCK 2 78 74 56 64 56 61 83 67 71 59 BLOCK 3 59 66 58 72 76 66 76 76 73 69 BLOCK 4 68 80 71 66 70 55 83 70 93 67 BLOCK 5 61 46 56 71 72 75 55 47 73 45 BLOCK 6 64 0 55 62 55 61 78 52 5 51 BLOCK 7 29 9 69 45 50 29 56 50 4 53 BLOCK 8 50 0 76 9 7 97 24 62 0 54 BLOCK 9 3 1 33 1 44 70 0 40 30 54 BLOCK 10 1 1 12 1 5 59 0 31 73 67 BLOCK 11 0 0 2 36 7 71 0 47 20 59 BLOCK 12 33 55 0 0 71 72 3 46 43 55 BLOCK 13 6 58 61 0 59 82 20 73 0 62 BLOCK 14 0 72 15 0 56 44 68 50 0 71 BLOCK 15 0 7 0 0 37 61 61 12 5 50 BLOCK 16 0 0 6 1 56 83 60 25 0 5 BLOCK 17 5 0 0 1 47 49 72 44 16 2 BLOCK 18 0 0 7 36 35 71 14 53 8 4 .,i::.. ~ TOTAL 528 529 641 533 870 1178 811 907 587 880 00 I > 0 --T-O-T--A-L---=--S-U-M---O-F---B-L-O--C-K--S-; --E-A-C--H--B-L--O-C-K---C-O--N-S-I-S-T-S---O-F---A--5---M-I-N-U--T-E---P-E-R-I-O--D-.--------------------------------------------------------------------------------------- t-...J 00 ~ ~tc I -....J \0 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B25 (PAGE 2): MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP I 0 MG/KG/DAY RAT NUMBER 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 --T-I-M--E---(S--E-C-O--N-D-S-)---S-P-E--N-T---IN---M--O-V-E-M--E-N-T------------------------------------------------------------------------------------------------------------------------------- BLOCK 1 185 217 193 169 161 194 229 219 224 220 BLOCK 2 182 182 133 186 191 201 188 184 217 210 BLOCK 3 161 115 110 181 149 162 183 178 173 143 BLOCK 4 144 127 106 166 190 88 139 129 134 191 BLOCK 5 106 54 113 132 129 140 92 69 94 78 BLOCK 6 91 0 125 111 71 158 133 135 1 87 BLOCK 7 70 6 140 82 125 48 65 80 2 84 BLOCK 8 99 0 87 8 10 124 18 165 0 102 BLOCK 9 0 0 31 0 113 118 0 53 50 75 BLOCK 10 0 0 11 1 4 122 0 43 122 186 BLOCK 11 0 0 0 36 6 169 0 58 12 121 BLOCK 12 38 91 0 0 84 114 1 72 62 119 BLOCK 13 9 90 60 0 95 116 21 126 0 152 BLOCK 14 0 67 9 0 151 127 104 90 0 108 BLOCK 15 0 5 0 0 105 118 99 10 3 51 BLOCK 16 0 0 5 0 79 102 106 24 0 3 BLOCK 17 4 0 0 0 100 57 72 70 16 1 BLOCK 18 0 0 6 46 44 125 23 56 2 3 ,+::. I--' ~ TOTAL 1089 954 1129 1118 1807 2283 1473 1761 1112 1934 00 I 0 --T-O-T--A-L---=--S-U-M---O--F--B-L--O-C-K--S-;--E-A-C--H--B-L--O-C-K---C-O--N-S-I-S-T-S---O-F---A--5---M--IN-U--T-E---P-E-R--IO--D-.--------------------------------------------------------------------------------------- t-..J 00 ~ tT.1 txJ I 00 0 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B25 (PAGE 3): MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP II 0.3 MG/KG/DAY RAT NUMBER 19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 NUMBER OF MOVEMENTS BLOCK 1 64 55 64 64 71 69 52 64 74 66 BLOCK 2 69 55 61 60 56 94 58 57 61 65 BLOCK 3 68 59 47 66 24 82 67 72 50 63 BLOCK 4 63 68 65 73 15 93 67 47 60 61 BLOCK 5 44 60 61 59 0 93 61 55 51 63 BLOCK 6 32 24 51 70 0 86 77 70 55 63 BLOCK 7 5 54 71 65 0 59 70 62 63 51 BLOCK 8 3 45 60 57 2 74 59 67 48 52 BLOCK 9 34 77 37 64 0 70 48 45 70 47 BLOCK 10 6 75 60 37 51 65 56 48 56 77 BLOCK 11 0 53 3 0 16 64 72 63 40 40 BLOCK 12 1 64 0 51 1 45 66 51 35 37 BLOCK 13 5 58 65 0 12 0 74 54 78 84 BLOCK 14 14 61 64 22 0 8 59 61 81 68 BLOCK 15 51 53 39 20 0 17 27 78 25 45 BLOCK 16 36 81 51 65 0 2 2 57 33 49 BLOCK 17 64 78 52 46 0 0 3 63 22 64 BLOCK 18 63 58 41 40 0 38 6 53 1 44 ~ I--' > TOTAL 622 1078 892 859 248 959 924 1067 903 1039 00 I 0 --T-O-T--A-L---=--S-U-M---O-F---B-L-O--C-K--S-; --E-A-C--H--B-L--O-C-K---C-O--N-S-I-S-T-S---O-F---A--5---M-I-N-U--T-E---P-E-R-I-O--D-.--------------------------------------------------------------------------------------- tv 00 ~ 0 t.d tx1 I 00 I--' PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B25 (PAGE 4): MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP II 0.3 MG/KG/DAY RAT NUMBER 19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 --T-I-M--E---(S--E-C-O--N-D-S-)---S-P-E--N-T---I-N--M--O-V-E-M--E-N-T------------------------------------------------------------------------------------------------------------------------------- BLOCK 1 215 201 192 192 176 197 240 216 191 198 BLOCK 2 133 164 152 182 138 160 238 209 170 198 BLOCK 3 150 126 71 150 24 211 223 203 144 101 BLOCK 4 116 140 162 201 16 144 209 129 143 123 BLOCK 5 35 147 166 116 0 171 214 197 83 182 BLOCK 6 40 31 103 142 0 135 157 125 76 88 BLOCK 7 1 125 136 98 0 148 153 102 71 68 BLOCK 8 1 77 81 55 0 162 117 146 69 129 BLOCK 9 33 105 99 85 0 117 116 63 125 66 BLOCK 10 4 114 78 42 94 94 137 95 75 133 BLOCK 11 0 117 4 0 49 135 177 123 58 51 BLOCK 12 0 72 0 60 0 90 146 181 62 60 BLOCK 13 1 88 86 0 7 0 190 135 207 155 BLOCK 14 26 90 120 29 0 2 114 152 122 102 BLOCK 15 113 59 60 17 0 26 28 146 15 67 BLOCK 16 57 125 63 84 0 0 1 121 28 76 BLOCK 17 93 151 66 56 0 0 0 117 21 121 BLOCK 18 111 54 37 41 0 43 2 139 1 46 ..,.i.:.:.:.... TOTAL 1129 1986 1676 1550 504 1835 2462 2599 1661 1964 00 I 0 --T-O-T--A-L---=--S-U-M---O--F--B-L--O-C-K--S-;--E-A--C-H--B--L-O-C-K---C-O--N-S-I-S-T-S---O-F---A--5---M-I-N-U--T-E---P-E-R-I-O--D-.--------------------------------------------------------------------------------------- tv 00 ~ >~tP I 00 tv PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B25 (PAGE 5) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP III 1 MG/KG/DAY RAT NUMBER 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 --N-U-M--B-E-R---O-F---M-O-V--E-M-E-N--T-S----------------------------------------------------------------------------------------------------------------------------------------------- BLOCK 1 67 57 63 79 60 74 60 51 56 68 BLOCK 2 55 57 63 76 57 67 69 55 81 66 BLOCK 3 76 72 52 71 56 70 59 57 71 67 BLOCK 4 80 68 63 73 61 71 79 43 84 60 BLOCK 5 62 63 66 61 66 75 60 71 72 60 BLOCK 6 72 57 52 60 47 78 64 52 74 86 BLOCK 7 74 57 52 47 65 71 69 28 76 59 BLOCK 8 57 68 51 6 66 78 49 43 68 54 BLOCK 9 59 86 64 22 31 69 22 31 74 39 BLOCK 10 56 73 66 14 35 75 17 47 85 2 BLOCK 11 21 44 52 2 69 74 84 73 50 43 BLOCK 12 71 8 37 14 12 79 60 60 59 55 BLOCK 13 109 5 54 49 8 70 22 37 81 5 BLOCK 14 29 17 81 0 29 55 0 53 57 44 BLOCK 15 27 69 71 1 2 85 0 65 75 3 BLOCK 16 50 72 5 0 0 66 3 47 64 5 - BLOCK 17 72 55 1 18 0 54 5 13 27 46 BLOCK 18 73 65 0 55 5 57 1 42 2 59 +::-- TOTAL 1110 993 893 648 669 1268 723 868 1156 821 00 I > 0 --T-O-T--A-L---=--S-U-M---O-F---B-L-O--C-K--S-; --E-A-C--H--B-L--O-C-K---C-O--N-S-I-S-T--S--O-F---A--5---M-I-N-U--T-E---P-E-R-I-O--D-.--------------------------------------------------------------------------------------- t-.J 00 ~ ~to I 0w 0 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B25 (PAGE 6) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP III 1 MG/KG/DAY RAT NUMBER 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 --T-I-M--E---(S-E--C-O-N--D-S-)---S-P-E-N--T---IN---M--O-V-E-M--E-N-T------------------------------------------------------------------------------------------------------------------------------- BLOCK 1 212 226 218 207 194 201 228 236 219 207 BLOCK 2 219 224 129 144 197 198 220 230 202 195 BLOCK 3 145 156 92 160 177 197 203 187 202 206 BLOCK 4 127 125 109 138 169 138 141 167 188 122 BLOCK 5 148 191 147 134 160 157 115 151 166 134 BLOCK 6 65 110 87 93 91 164 139 99 201 135 BLOCK 7 164 79 104 60 175 112 146 29 141 92 BLOCK 8 103 139 151 2 160 161 73 51 132 127 BLOCK 9 116 154 102 18 39 208 25 82 116 76 BLOCK 10 98 120 97 6 59 153 11 99 131 0 BLOCK 11 36 76 77 0 134 170 125 99 81 62 BLOCK 12 165 8 37 11 48 180 138 109 111 110 BLOCK 13 103 1 87 54 5 113 34 24 98 2 BLOCK 14 18 20 104 0 30 95 0 136 65 73 BLOCK 15 47 135 79 0 1 139 0 140 138 1 BLOCK 16 52 100 11 0 0 152 5 71 211 1 BLOCK 17 90 81 0 16 0 162 3 18 23 76 BLOCK 18 100 156 0 76 5 85 0 43 1 97 ~ I--" TOTAL 2008 2101 1631 1119 1644 2785 1606 1971 2426 1716 00 I > 0 --T-O-T--A-L---=--S-U-M---O-F---B-L-O--C-K--S-; --E-A-C--H--B-L--O-C-K---C-O--N-S-I-S-T-S---O-F---A--5---M-I-N-U--T-E--P--E-R-I-O--D-.--------------------------------------------------------------------------------------- tv 00 ~ ~toI 00 ~ PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B25 (PAGE 7) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP IV 3 MG/KG/DAY RAT NUMBER 19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 NUMBER OF MOVEMENTS BLOCK 1 80 55 61 54 47 63 73 66 54 68 BLOCK 2 84 74 72 73 69 69 76 75 70 73 BLOCK 3 54 69 87 87 81 69 67 54 74 74 BLOCK 4 57 57 75 86 78 71 55 48 63 64 BLOCK 5 67 43 85 71 37 74 77 71 42 64 BLOCK 6 29 67 62 79 41 66 59 64 74 58 BLOCK 7 47 60 66 62 71 56 49 70 66 59 BLOCK 8 62 43 64 44 12 63 71 80 69 62 BLOCK 9 55 53 69 27 14 69 83 60 63 60 BLOCK 10 32 69 65 85 0 51 50 49 58 41 BLOCK 11 1 50 76 74 8 58 65 70 68 47 BLOCK 12 1 46 89 60 18 54 66 57 69 31 BLOCK 13 3 14 77 77 54 73 56 62 53 35 BLOCK 14 58 69 63 10 71 69 80 53 61 58 BLOCK 15 75 63 71 3 40 54 54 49 67 37 BLOCK 16 54 74 61 70 0 57 56 67 45 25 BLOCK 17 72 62 63 72 20 48 66 65 67 0 BLOCK 18 67 16 57 61 5 47 34 74 63 0 .,i::.. - TOTAL 898 984 1263 1095 666 1111 1137 1134 1126 856 00 I 0 --T-O-T--A-L---=--S-U-M---O-F---B-L-O--C-K--S-; --E-A-C-H---B-L-O--C-K---C-O--N-S-I-S-T-S---O-F---A--5---M-I-N-U--T-E---P-E-R-I-O--D-.--------------------------------------------------------------------------------------- t-..) 00 ~ > 0 tT.l tx:l I 00 Vl PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B25 (PAGE 8) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP IV 3 MG/KG/DAY RAT NUMBER 19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 --T-I-M--E---(S--E-C-O-N--D-S-)---S-P-E-N--T---IN---M--O-V-E-M--E-N-T------------------------------------------------------------------------------------------------------------------------------- BLOCK 1 198 244 235 219 171 200 206 182 211 180 BLOCK 2 136 202 171 163 200 206 184 182 183 175 BLOCK 3 83 105 159 138 138 143 153 160 175 152 BLOCK 4 120 193 156 139 181 114 86 125 174 121 BLOCK 5 120 90 131 137 55 145 120 144 145 105 BLOCK 6 30 129 109 128 57 154 65 146 187 92 BLOCK 7 59 186 187 87 141 142 65 122 113 84 BLOCK 8 87 223 108 59 43 131 120 123 161 106 BLOCK 9 82 196 114 27 9 93 152 151 109 103 BLOCK 10 30 155 94 120 0 126 55 107 77 67 BLOCK 11 0 83 155 92 3 143 158 143 148 52 BLOCK 12 0 114 136 101 14 71 84 125 128 38 BLOCK 13 0 18 100 102 87 105 118 124 76 72 BLOCK 14 106 136 102 14 107 106 163 96 153 95 BLOCK 15 113 111 97 1 43 60 69 107 82 59 BLOCK 16 58 134 100 61 0 114 112 134 110 49 BLOCK 17 146 127 95 91 13 109 111 143 79 0 BLOCK 18 108 36 88 78 2 65 58 115 119 0 ..J:::.. ~ TOTAL 1476 2482 2337 1757 1264 2227 2079 2429 2430 1550 00 I > 0 --T-O-T--A-L---=--S-U-M---O-F---B-L-O--C-K--S-;--E-A-C--H--B--L-O-C-K---C-O--N-S-I-S-T-S---O-F---A--5---M-I-N-U--T-E---P-E-R-I-O--D-.--------------------------------------------------------------------------------------- N 00 ~ ~ t:c I 00 CJ'\ PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B25 (PAGE 9) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP V 10 MG/KG/DAY RAT NUMBER 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 NUMBER OF MOVEMENTS BLOCK 1 62 69 57 61 72 68 64 49 77 61 BLOCK 2 68 66 67 72 63 75 87 63 65 70 BLOCK 3 67 56 63 76 61 78 72 60 77 65 BLOCK 4 58 50 73 63 68 37 41 48 59 63 BLOCK 5 62 49 65 42 25 51 62 76 76 61 BLOCK 6 39 50 59 51 67 56 55 66 57 74 BLOCK 7 59 63 62 62 30 49 54 52 68 69 BLOCK 8 55 74 24 61 12 54 78 44 67 28 BLOCK 9 46 37 42 35 75 41 87 56 47 56 BLOCK 10 73 40 47 51 64 23 47 67 52 32 BLOCK 11 44 0 45 50 33 23 82 54 43 41 BLOCK 12 28 39 57 37 67 39 43 64 44 58 BLOCK 13 44 31 64 30 86 42 21 62 39 11 BLOCK 14 77 0 29 64 66 62 16 56 68 0 BLOCK 15 75 0 39 62 57 41 61 39 56 0 BLOCK 16 43 0 66 61 3 49 69 64 68 2 BLOCK 17 71 0 72 49 56 34 6 68 14 3 BLOCK 18 65 1 58 31 63 38 1 31 35 19 +::>- !--" > TOTAL 1036 625 989 958 968 860 946 1019 1012 713 00 I 0 --T-O-T--A-L---=--S-U-M---O-F---B-L-O--C-K--S-; --E-A-C-H---B-L--O-C-K---C-O--N-S-I-S-T--S--O-F---A--5---M-I-N-U--T-E---P-E-R--IO--D-.--------------------------------------------------------------------------------------- t-..) 00 ~ ~t;d I 00 -.l PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B25 (PAGE 10): MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP V 10 MG/KG/DAY RAT NUMBER 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 --T-I-M--E---(S-E--C-O-N--D-S-)---S-P-E-N--T---IN---M--O-V-E-M--E-N-T------------------------------------------------------------------------------------------------------------------------------- BLOCK 1 206 161 173 169 212 192 181 243 230 181 BLOCK 2 170 174 143 116 149 205 176 233 158 177 BLOCK 3 141 110 118 141 109 128 197 231 146 166 BLOCK 4 175 169 118 115 103 42 86 220 126 155 BLOCK 5 153 75 124 111 30 65 108 158 173 141 BLOCK 6 64 67 97 96 87 134 64 196 94 128 BLOCK 7 98 81 112 102 39 104 107 195 121 120 BLOCK 8 74 101 36 64 7 116 90 100 98 34 BLOCK 9 51 63 47 47 107 81 125 196 129 90 BLOCK 10 140 64 80 47 67 27 49 165 87 42 BLOCK 11 87 . 0 98 102 33 17 126 80 60 69 BLOCK 12 37 94 59 65 105 37 42 138 57 95 BLOCK 13 75 54 107 40 163 48 29 135 38 16 BLOCK 14 150 0 32 66 106 90 14 155 120 0 BLOCK 15 103 0 60 74 68 66 100 95 76 0 BLOCK 16 54 0 77 95 0 132 142 203 68 0 - BLOCK 17 93 0 98 86 70 42 5 108 6 2 BLOCK 18 110 0 91 21 106 69 0 69 55 20 ~ TOTAL 1981 1213 1670 1557 1561 1595 1641 2920 1842 1436 00 I > 0 --T-O-T--A-L---=--S-U-M---O-F---B-L-O--C-K--S-; --E-A-C--H--B-L--O-C-K---C-O--N-S-I-S-T-S---O-F---A--5---M-I-N-U--T-E---P-E-R-I-O--D-.--------------------------------------------------------------------------------------- tv 00 ~ ~tt1 I 00 00 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B26 (PAGE 1): SPERM MOTILITY, COUNT AND DENSITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS (See footnotes on the last page of this table.) RAT NUMBER MOTILE STATIC COUNT TOTAL SPERM SPERM ------~~!!.~---------------~9.!.!~~-----------------,!>!!.~~~!!.! ______________ ~:r;:~~~!}_I:.,~l---------------C:.~~-~-~-----------------~9~!-~---------------~~~!3-~!~--~----- ______.~!!.C!~_9_~~~!__! _________________________9__~~L.!<_C!l~~-~---------------------------------------------------------------------------------------------------------- 19109 276 89 33 309 166 1701. 6 19115 254 97 8 262 190 1598.6 19116 323 92 27 350 159 1433.3 19119 328 90 38 366 178 1475.8 19122 210 91 21 231 126 978.7 19125 256 91 25 281 121 1073.7 19131 375 94 23 398 271 2496.6 19132 302 88 41 343 222 1743.2 19134 235 97 7 242 156 1339.9 19135 332 92 29 361 112 1101. 2 -_-_-_-_-__--.P-.-.-<2--~--q-,~-_-9-_~-<-2~-,-!>-_-_-!-!-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-9-~-_-3-_-_-~-9-1-..-~-~-l-.-P-.-.-1-.-!-~----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- 19102 232 93 17 249 139 1402.5 19106 367 89 47 414 149 1455.1 19108 333 93 25 358 232 1916.4 19110 257 97 7 264 101 1051. 3 19113 334 90 37 371 177 1515.3 19120 469 92 39 508 220 1983.2 19129 293 95 15 308 231 2100.6 19136 338 92 30 368 95 853.7 19138 223 98 4 227 148 1187.9 19139 228 94 14 242 90 836.0 ,~ __.. 00 I 0 N 00 ;-t; ~tP I 00 ' PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B26 (PAGE 2): SPERM MOTILITY, COUNT AND DENSITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS (See footnotes on the last page of this table.) RAT NUMBER MOTILE STATIC COUNT TOTAL SPERM SPERM ______ !!,~~!!-~---------------~9_1:~~~-----------------!'-~~~~!!.! ______________ ~l';!~~~!}_~~l _______________<:,~~-1:-~-----------------~9~!-~--------------.?..~!:J'!3_~!~__c: _____. ______.~,!\-_<!~_g_~~~J__!EJ___________________________~-~-<!L~!..~~.:------------------------------------------------------------------------------------------------------- 19101 198 89 25 223 163 1575.4 19105 265 87 38 303 186 1593.3 19107 265 90 31 296 121 1312.4 19112 341 95 19 360 173 1564.4 19114 475 97 16 491 130 1290.1 19121 319 96 12 331 248 2163.4 19123 246 90 26 272 164 1401.9 19130 309 93 23 332 190 1564.5 19137 298 92 25 323 114 951.2 19146 404 96 16 420 121 1002. 3 -_-__-_-_-_--.?-.-,<-2-,-!\---S!-~-.9---~<-2~-,-!'-_-_!-y--_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-]-_-_-~-.-9!-.-.-~-9-1-.-?-.-.-~-~------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- 19100 301 91 28 329 141 1215.7 19103 372 86 60 432 171 1700.4 19104 244 95 14 258 131 1279.8 19118 286 95 16 302 86 823.2 19133 552 97 46 598 143 1397.0 19141 313 23 17 330 217 2026.2 19142 15 90 49 64 33 716.1 19144 298 92 32 330 88 1006.6 19148 495 88 36 531 119 893.9 19150 197 98 29 226 117 1087.9 .i:::.. 0""'"0"" I 0 t..J 00 ~ >~t:x:1 I \0 0 PROTOCOL 418-028: ORAL {GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST {SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B26 {PAGE 3): SPERM MOTILITY, COUNT AND DENSITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT NUMBER MOTILE STATIC COUNT TOTAL SPERM SPERM ------!!.~~~-~---------------~9.!.~~~-----------------!'-~~~~.!'!.! ______________ ~~~!-l-~<.2!!_!;,~l---------------C:.<.2~-'1:-~-----------------~9~!-~--------------.?..~!;:1'.'_~!Y__c:, _____ , ______ .<.2~-q,~_g_~<.2'!!.!'__;:________________________________________ ~2--~S::i_~~LPl!~------------------------------------------------------------------------------------------ 19111 304 94 21 325 229 2354.1 19117 286 90 33 319 189 1871. 7 19124 461 91 38 499 174 1490. 0 19126 264 93 12 276 91 1032.3 19127 339 72 26 365 190 1805.0 19128 231 95 92 323 163 1730.3 19140 464 95 27 491 161 1578.2 19145 360 96 30 390 146 1194 .1 19149 289 87 39 328 198 1789.9 19152 256 98 6 262 204 1794. 7 --a-.----S-u-m---o--f--n-u-m--b-e--r --m--o-t-i-l-e--a--n-d---s-t-a-t-i--c--c--o-u-n--t-. ---G--r-o-u-p--s--o-f---f-i-v-e---f-i-e-l-d--s---w-e--r -e--e-v--a-l-u-a--t-e-d--u--n--t-i-l--a---s-p-e-r-m---c-o--u-n-t--o--f--a--t--l-e-a--s-t---2-0-0--w--a-s---a-c-h--i e--v-e-d---o-r--- 20 fields were evaluated. b. Sperm count used in the calculation of sperm density. Ten fields were evaluated. c. The sperm density was calculated by dividing the sperm count by the volume in the image area (34.3 x 10-6 mL), multiplying by 2 {dilution factor) and multiplying by 10-6 to obtain the sperm concentration. The calculated sperm concentration value {rounded to 1 decimal place) was multiplied by 50 {volume) and divided by the weight of the left cauda epididymis {see Table B19 for the weight of the left cauda epididymis) to obtain the sperm density. The calculated value will vary by approximately 0.8% from the Computer Automated Sperm Analysis because the digital image evaluated is slightly smaller (4 pixels) than the actual field causing a slight underestimate of the actual volume and an overestimate of the concentration. ..j::::.. 1--' 00 I 0 N 00 ~ >~txJ I \0 1--' PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B27 (PAGE 1) : SPERM MORPHOLOGY - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT NUMBER NORMAL DOSAGE GROUP I 19109 186 19115 194 19116 189 19119 190 19122 192 19125 195 19131 194 19132 193 19134 196 19135 194 DOSAGE GROUP II 19102 189 19106 196 19108 195 19110 192 19113 196 19120 190 19129 189 19136 196 19138 195 19139 195 DETACHED HEAD 0 MG/KG/DAY 6 2 7 8 3 2 3 2 1 3 0.3 MG/KG/DAY 5 1 1 3 3 8 6 3 3 3 NO HEAD 7 4 4 2 5 2 2 4 2 2 4 1 2 3 1 2 4 1 1 2 BROKEN FLAGELLUM 1 0 0 0 0 1 0 0 1 1 2 1 1 2 0 0 1 0 1 0 BENT FLAGELLUM 0 0 0 0 0 0 1 1 0 0 0 1 1 0 0 0 0 0 0 0 PERCENT ABNORMAL 7.0 3.0 5.5 5.0 4.0 2.5 3.0 3.5 2.0 3.0 5.5 2.0 2.5 4.0 2.0 5.0 5.5 2.0 2.5 2.5 ~ ......... 00 I 0 N 00 ~ >~tx:1 I \0 t-...) PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B27 (PAGE 2): SPERM MORPHOLOGY - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT NUMBER NORMAL DETACHED HEAD NO HEAD BROKEN FLAGELLUM BENT FLAGELLUM PERCENT ABNORMAL DOSAGE GROUP III 1 MG/KG/DAY 19101 198 1 1 0 19105 197 1 1 1 19107 189 5 3 1 19112 197 1 1 1 19114 191 6 3 0 19121 196 2 2 0 19123 192 2 5 1 19130 188 5 4 2 19137 192 3 4 1 19146 193 5 2 0 0 1. 0 0 1. 5 2 5.5 0 1. 5 0 4.5 0 2.0 0 4.0 1 6.0 0 4.0 0 3.5 DOSAGE GROUP IV 3 MG/KG/DAY 19100 196 0 3 1 19103 192 4 4 0 19104 198 2 0 0 19118 188 4 7 1 19133 192 3 3 2 19141 192 5 2 1 19142 4 37 76 79 19144 184 10 6 0 19148 194 3 2 1 19150 198 0 2 0 0 2.0 0 4.0 0 1. 0 0 6.0 0 4.0 0 4.0 4 98.0 0 8.0 0 3.0 0 1. 0 -~ 00 I 0 N ;0-c0; ~tT.I t:J:j I \.0 (J.) PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B27 (PAGE 3): SPERM MORPHOLOGY - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT NUMBER NORMAL DOSAGE GROUP V 19111 198 19117 197 19124 192 19126 196 19127 189 19128 191 19140 191 19145 196 19149 192 19152 191 DETACHED HEAD 10 MG/KG/DAY 1 1 6 2 6 2 8 2 3 7 NO HEAD 1 1 1 2 2 5 1 1 3 1 BROKEN FLAGELLUM 0 1 1 0 3 2 0 1 1 1 BENT FLAGELLUM 0 0 0 0 0 0 0 0 1 0 PERCENT ABNORMAL 1. 0 1.5 4.0 2.0 5.5 4.5 4.5 2.0 4.0 4.5 ~ ~ 00 I 0 N 00 ~ @ cc I "~ APPENDIXC REPORT TABLES - Fo GENERATION FEMALE RATS PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE Cl (PAGE 1) : CLINICAL OBSERVATIONS - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP I II III IV v DOSAGE (MG/KG/DAY) 0 0.3 1 3 10 ------------------------------------------------------------------------------------------------------------------------------------ PRECOHABITATION (DAY 1 OF STUDY TO THE DAY OF COHABITATION) : MAXIMUM POSSIBLE INCIDENCE 210/ 15 210/ 15 210/ 15 210/ 15 210/ 15 MORTALITY 0 0 0 0 0 BROWN PERIORAL SUBSTANCE 0/ 0 0/ 0 0/ 0 0/ 0 7/ 1 RALES 0/ 0 0/ 0 0/ 0 0/ 0 7/ 1 LOCALIZED ALOPECIA: TOTAL HEAD LIMBS 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 4/ 1 0/ 0 4/ 1 4/ 1 4/ 1 0/ 0 URINE-STAINED ABDOMINAL FUR 0/ 0 0/ 0 0/ 0 0/ 0 3/ 1 MI OS I S 0/ 0 0/ 0 0/ 0 0/ 0 2/ 1 ABDOMINAL DISTENTION 0/ 0 0/ 0 0/ 0 0/ 0 2/ 1 EMACIATION 0/ 0 0/ 0 0/ 0 0/ 0 2/ 1 COLD TO TOUCH 0/ 0 0/ 0 0/ 0 0/ 0 1/ 1 ------------------------------------------------------------------------------------------------------------------------------------ STATISTICAL ANALYSES OF CLINICAL OBSERVATION DATA WERE RESTRICTED TO THE NUMBER OF RATS WITH OBSERVATIONS. MAXIMUM POSSIBLE INCIDENCE= (DAYS x RATS)/NUMBER OF RATS EXAMINED PER GROUP. N/N = TOTAL NUMBER OF OBSERVATIONS/NUMBER OF RATS WITH OBSERVATION. ~ ~ 00 I 0 N 00 ~ > ~ (1 I ~ PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE Cl (PAGE 2): CLINICAL OBSERVATIONS - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP I II III IV v DOSAGE (MG/KG/DAY) 0 0.3 1 3 10 ------------------------------------------------------------------------------------------------------------------------------------ PRESUMED GESTATION: a MAXIMUM POSSIBLE INCIDENCE 330/ 15 329/ 15 338/ 15 312/ 14 330/ 15 MORTALITY 0 0 0 0 0 LOCALIZED ALOPECIA: TOTAL LIMBS HEAD 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 2/ 1 2/ 1 0/ 0 30/ 2 30/ 2 0/ 0 21/ 1 14/ 1 7/ 1 NOSE: SWOLLEN 0/ 0 0/ 0 0/ 0 1/ 1 0/ 0 BACK: SCAB 13/ 1 0/ 0 0/ 0 0/ 0 0/ 0 BACK: ULCERATION 1/ 1 0/ 0 0/ 0 0/ 0 0/ 0 STATISTICAL ANALYSES OF CLINICAL OBSERVATION DATA WERE RESTRICTED TO THE NUMBER OF RATS WITH OBSERVATIONS. MAXIMUM POSSIBLE INCIDENCE= (DAYS x RATS)/NUMBER OF RATS EXAMINED PER GROUP. N/N = TOTAL NUMBER OF OBSERVATIONS/NUMBER OF RATS WITH OBSERVATION. a. Restricted to rats with a confirmed mating date. ..J::... ~ 00 I 0 tv 00 ;.-t; n>~I tv PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE Cl (PAGE 3): CLINICAL OBSERVATIONS - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP I II III IV v DOSAGE (MG/KG/DAY) 0 0.3 1 3 10 ------------------------------------------------------------------------------------------------------------------------------------ MAXIMUM POSSIBLE INCIDENCE 330/ 15 330/ 15 286/ 13 286/ 13 330/ 15 LACTATION: MORTALITY 0 0 0 0 0 LOCALIZED ALOPECIA: TOTAL LIMBS HEAD BACK 39/ 3 30/ 2 9/ 1 0/ 0 20/ 1 20/ 1 0/ 0 0/ 0 28/ 2 22/ 1 7/ 2 0/ 0 32/ 3 28/ 2 0/ 0 4/ 1 27/ 2 21/ 1 6/ 1 0/ 0 ABDOMINAL DISTENTION 0/ 0 0/ 0 0/ 0 0/ 0 16/ 1 RALES 0/ 0 0/ 0 0/ 0 0/ 0 9/ 1 EMACIATION 0/ 0 0/ 0 0/ 0 0/ 0 7/ 1 BACK OR HEAD: SCAB 13/ 3 23/ 2 0/ 0 0/ 0 6/ 1 DEHYDRATION 0/ 0 0/ 0 0/ 0 0/ 0 1/ 1 TIP OF TAIL MISSING 0/ 0 0/ 0 0/ 0 6/ 1 0/ 0 ------------------------------------------------------------------------------------------------------------------------------------ STATISTICAL ANALYSES OF CLINICAL OBSERVATION DATA WERE RESTRICTED TO THE NUMBER OF RATS WITH OBSERVATIONS. MAXIMUM POSSIBLE INCIDENCE= (DAYS x RATS)/NUMBER OF RATS EXAMINED PER GROUP. N/N = TOTAL NUMBER OF OBSERVATIONS/NUMBER OF RATS WITH OBSERVATION. -..t:;::.. 00 I 0 t-...J 00 > ~ ~() I VJ PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C2 (PAGE 1) : NECROPSY OBSERVATIONS - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II III IV v 0 0.3 1 3 10 RATS EXAMINED a N 15 15 15 15 15 MORTALITY N 0 0 0 0 0 APPEARED NORMAL N 15 15 14 13 14 KIDNEYS: RIGHT, CORTEX ADHERED TO RIGHT LATERAL LIVER LOBE N 0 0 1 0 0 OVARIES: LEFT, SMALL N 0 0 0 1 0 SPLEEN: OMENTUM ADHERED TO THE LENGTH OF THE OUTER CAPSULE N 0 0 0 1 0 LARGE AND SMALL INTESTINES: DISTENDED WITH GAS N 0 0 0 0 1 THYMUS: SMALL N 0 0 0 0 1 SPLEEN: SMALL N 0 0 0 0 1 ADRENALS: BILATERAL, LARGE N 0 0 0 0 1 ,.J:::.. .......... STOMACH: 00 I FUNDIC MUCOSAL SURFACE CONTAINED 0 lV APPROXIMATELY 12 BLACK AREAS N 0 0 0 0 1 00 >~>-d a. Refer to the individual clinical observations table (Table C27) for external observations confirmed at necropsy. () I ,.J:::.. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C3 (PAGE 1) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND PRIMORDIAL FOLLICLE COUNT - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II III IV v 0 0.3 1 3 10 TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS RATS TESTED N 15 15 15 15 15 PREGNANT N 15 15 13 13 15 TERMINAL BODY WEIGHT MEANS.D. 306.3 26.0 324.3 27.1 311. 2 35.0 319.6 40.4 303.5 37.9 BRAIN LIVER KIDNEY LEFT KIDNEY RIGHT ADRENAL LEFT ADRENAL RIGHT SPLEEN THYMUS OVARY LEFT MEANS.D. MEANS.D. MEANS.D. MEANS.D. MEANS.D. MEANS.D. MEANS.D. MEANS.D. MEANS.D. 2.16 0.08 [ lO]a 14.38 2.24 [ 10] a 1. 39 0.14 [ lO]a 1.47 0.12 [ 10] a 0.052 0.009 [ lO]a 0.043 0.007 [ lO]a 0.63 0.08 [ 10] a 0.21 0.07 [ lO]a 0.055 0.014 2 .11 0.09 [ 10] a 15.98 2. 71 [ 10] a 1.47 0.14 [ 10] a 1.52 0.16 [ 10] a 0.051 0.009 [ 10] a 0.041 0.010 [ 10] a 0.65 0.09 [ 10] a 0.21 0.06 [ 10] a 0.056 0.020 2.10 0.09 [ 10] a 14.70 2.92 [ lO]a 1. 38 0.14 [ lO]a 1.45 0.13 [ 10] a 0.051 0.009 [ lO]a 0.050 0.011 [ 10] a 0.60 0.11 [ 10] a 0.18 0.04 [ 10) a 0.053 0.014 2.08 0.18 [ 10] a 15 .11 3.28 [ lO]a 1.49 0.19 [ lO]a 1.52 0.13 [ 10] a 0.053 0.012 [ 10] a 0.049 0.006 [ 10] a 0.75 0.31 [ 10) a 0.20 0.10 [ 10] a 0.053 0.012 2.12 0.10 [ 10] a 13.64 3.18 [ 10] a 1. 39 0.10 [ 10] a 1.41 0.15 [ 10] a 0.053 0.009 [ 10] a 0.046 0.008 [ 10] a 0.54 0.10 [ 10) a 0.18 0.04 [ 10) a 0.054 0.015 OVARY RIGHT MEANS.D. 0.062 0.015 0.060 0.019 0.060 0.021 0.054 0.012 0.054 0.018 ..f:::. UTERUS WITH CERVIX MEANS.D. 0.53 0.09 0.56 0.12 0.50 0.13 0.62 0.15 0.56 0.16 0"""0'"" I HEART MEANS.D. 1.40 0.17 1.26 0 .13 1.35 0.11 1.40 0.13 1.33 0.25 0 tv [ 10) a [ 10) a [ 10) a [ lO]a [ 10) a 00 ~ ALL WEIGHTS WERE RECORDED IN GRAMS (G) . > [ ] = NUMBER OF VALUES AVERAGED ~ a. Only ten rats were tested. n I V'l PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C3 (PAGE 2): TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND PRIMORDIAL FOLLICLE COUNT - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II III 0 0.3 1 PRIMORDIAL FOLLICLE COUNT RATS TESTED N 15 PREGNANT N 15 OVARY #1 OVARY #2 MEANS.D. MEANS.D. 12.58 11.01 [ 10] a 12. 94 9.01 [ lO]a ALL WEIGHTS WERE RECORDED IN GRAMS [ ] = NUMBER OF VALUES AVERAGED a. Only ten rats were tested. (G) . IV v 3 10 15 15 12.40 6.24 [ lO]a 10.14 2.29 [ 10] a -~ 00 I 0 lV 00 ~ > ~ ('"'.:) I O"'I PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C4 (PAGE 1) : RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II III IV v 0 0.3 1 3 10 RATS TESTED N 15 15 15 15 15 PREGNANT N 15 15 13 13 15 TERMINAL BODY WEIGHT MEANS.D. 306.3 26.0 324.3 27.1 311. 2 35.0 319.6 40.4 303.5 37.9 BRAIN LIVER KIDNEY LEFT KIDNEY RIGHT ADRENAL LEFT b ADRENAL RIGHT b SPLEEN THYMUS OVARY LEFT b MEANS.D. MEANS.D. MEANS.D. MEANS.D. MEANS.D. MEANS.D. MEANS.D. MEANS.D. MEANS.D. 0.711 0.062 [ 10] a 4.703 0.450 [ lO]a 0.459 0.049 [ 10] a 0.482 0.043 [ 10] a 17.095 2.132 [ 10] a 13.984 1.612 [ 10] a 0.208 0.024 [ 10] a 0.070 0.022 [ 10] a 18.005 4.064 0.659 0.055 [ 10] a 4.947 0.703 [ 10] a 0.460 0.053 [ lO]a 0.472 0.052 [ lO]a 15.856 2.913 [ lO]a 12.842 3.379 [ 10] a 0.205 0.028 [ lO]a 0.065 0.018 [ 10] a 17.632 6.782 0.684 0.082 [ lO]a 4.697 0.512 [ lO]a 0.446 0.054 [ lO]a 0.467 0.042 [ lO]a 16.799 4.091 [ lO]a 16.479 4.381 [ lO]a 0.194 0.035 [ lO]a 0.059 0.016 [ lO]a 17.053 3.559 0.675 0.099 [ 10] a 4.795 0.517 [ 10] a 0.479 0.070 [ 10] a 0.492 0.058 [ lO]a 16.867 3.532 [ 10] a 15.743 2.727 [ 10] a 0.238 0.076 [ 10] a 0.065 0.037 [ 10] a 16.883 4.629 0.732 0.102 [ 10] a 4.582 0.541 [ 10] a 0.477 0.040 [ 10] a 0.484 0.043 [ 10] a 18.402 4.737 [ 10] a 15.959 4.763 [ 10] a 0.181 0.026 [ 10] a 0.059 0.016 [ lO]a 17.611 3.620 OVARY RIGHT b MEANS.D. 20.307 4.390 18.514 5.844 19.152 6.400 17.025 3.632 17.529 5.247 UTERUS WITH CERVIX MEANS.D. 0.175 0.031 0.175 0.042 0.162 0.046 0.198 0.063 0.185 0.055 HEART MEANS.D. 0.459 0.067 0.392 0.057 0.436 0.054 0.457 0.073 0.453 0.056 .~ ...... [ 10] a [ 10] a [ lO]a [ lO]a [ 10] a 00 I 0 tv ALL WEIGHTS WERE RECORDED IN GRAMS (G) . RATIOS (%) = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. 00 [ ] = NUMBER OF VALUES AVERAGED ~ a. Only ten rats were tested. >~ b. Value was multiplied by 1000. ('j I ......J PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE CS (PAGE 1) : RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II III IV v 0 0.3 1 3 10 RATS TESTED N 10 10 10 10 10 BRAIN WEIGHT MEANS.D. 2.16 0.08 2 .11 0.09 2.10 0.09 2.08 0.18 2.12 0.10 LIVER MEANS.D. 664.58 96.72 757.16 127.78 701.88 155.49 729.66 165.57 641.86 141.49 KIDNEY LEFT MEANS.D. 64.31 5.18 69. 72 4.89 65.73 6.72 71. 48 6.75* 65.57 3.88 KIDNEY RIGHT MEANS.D. 67.75 4.49 71. 72 6.50 68.95 7.09 73.35 5.96 66.53 5.96 ADRENAL LEFT MEANS.D. 2.42 0.42 2.40 0 .35 2.44 0.39 2.54 0.58 2.49 0.40 ADRENAL RIGHT MEANS.D. 1.98 0.31 1.95 0.46 2.39 0.48 2.36 0.40 2.15 0.40 SPLEEN MEANS.D. 29.20 3.42 30.95 4.47 28.56 5.09 36.15 15.02 25.16 4.18 THYMUS MEANS.D. 9. 72 3.12 9.96 2.95 8.43 1. 96 9.68 4.96 8.35 2.13 OVARY LEFT MEANS.D. 2.68 0.75 2.85 0.84 2.47 0.43 2.55 0.58 2.58 0.78 OVARY RIGHT MEANS.D. 2.83 0. 72 3.09 0.93 2.82 0.98 2.55 0.57 2.37 0.89 UTERUS WITH CERVIX MEANS.D. 26.20 4.17 28.44 4.18 24 .14 6. 72 31. 96 7.43 27. 71 6.59 HEART MEANS.D. 64.52 7.00 59.50 6.15 64.03 5.41 67.44 6.68 62.58 10.73 ------------------------------------------------------------------------------------------------------------------------------------ ALL WEIGHTS WERE RECORDED IN GRAMS (G) . RATIOS (%) = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. * Significantly different from the Group I value (p~0.05). ..j::::.. ~ 00 I 0 tv 00 >a3;.c, ('") I 00 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C6 (PAGE 1) : HEMATOLOGY - SUMMARY - Fo GENERATION FEMALE RATS (See abbreviations on the last page of this table.) DOSAGE GROUP I II III IV V _.?..~~~~--(_~S!i.!<~~~.!.L ___________________________________ 9______________________ 2_~~----------------------~-----------------------]-----------------------I----------- RATS TESTED N 10 10 10 10 10 WBC (THSN/CU MM) RBC (MILL/CU MM) MEAN S.D. 9.0 MEAN S.D. 6.51 3.09 0 .461 13.8 6.22 5. 73* 0. 423 11.1 6.40 2.98 0. 554 10.8 6.39 3.14 0. 532 8.9 6.42 3.48 0. 538 HGB (GRAMS/DL) HCT (%) MCV (CU MICRONS) MEAN S.D. 15.5 0.95 MEAN S.D. 40.5 2.93 MEAN S.D. 62.2 1.19 15.0 0. 77 39.3 2. 72 63.3 2.01 15.2 0.91 39.5 3.24 61. 8 1. 50 15.2 0.90 40.1 3.02 62.9 2.04 15.3 0. 77 40 .4 3.15 63.0 1. 60 MCH (PICO GRAMS) MCHC (%) PLAT (THSN/CU MM) MEAN S.D. 23.9 MEAN S.D. 38.4 MEAN S.D. 1419 0.55 0.76 153. 0 24.2 38.3 1240 0.76 0.94 208 .1 23.9 38.7 1274 0.88 1.29 226. 3 23.8 37.8 1305 1.25 1.22 207. 2 23.8 37.8 1355 1.05 1. 37 176. 8 -~~Y--L~~-~~~~S2.:t:!l-------------~~~-~--~~!?~----~~-3..____!----~~-4-~-------8..~~-----_____o_~~~-------~~]_____!----~~..8-~------..8-~~----l----2-~~~-------~~.?-----~----~~.?-4-_. * Significantly different from the Group I value (p~0.05). -..j:::.. 00 I 0 l'V 00 ~ > ~ (') I \0 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C6 (PAGE 2) : HEMATOLOGY - SUMMARY - Fo GENERATION FEMALE RATS (See abbreviations on the last page of this table.) 9______________________ _______________________]_______________________ DOSAGE GROUP I _.<2~-'!~--~~L.!<~~~.X.L ___________________________________ II III 2_~~----------------------! IV V }_o__________, RATS TESTED N 10 1a la 1a 10 PT (SECONDS) MEAN S.D. 13.2 0.41 13.4 a.29 13.2 a.37 13.5 a.42 13.8 1.12 APTT (SECONDS) MEAN S.D. 21.7 2.36 NRBC COUNT MEAN S . D . 0 0.0 Lymphocytes (THSN/CU MM) MEAN S.D. 6.6 2.44 23.9 a 9.8 3.19 a. 0 3. 44* 23.5 a 8.4 2.35 a.a 2.6a 25.2 0 8.2 2.45 o.a 2.52 25.2 3.81 a a.6 6.a 2.77 Segmented (THSN/CU MM) Bands (THSN/CU MM) Monocytes (THSN/CU MM) MEAN S.D. 2.2 MEAN S.D. 0.0 MEAN S.D. 0.1 0.90 0.00 0.15 3.6 3.69 a.a a.aa a.3 a.49 2.4 a.93 a.a a.aa a.2 a.13 2.4 a.96 a.a a.a9 a.2 a.11 2.6 0.82 a.a a.aa a.2 a.14 Eosinophils (THSN/CU MM) MEAN S.D. 0.1 Basophils (THSN/CU MM) MEAN S.D. 0.0 Abnormal L (THSN/CU MM) MEAN S.D. o.a 0.10 0.00 a.a5 a.1 a.13 a.a a.aa a.a a.aa 0.1 a.13 o.a a.aa a.1 a.a7 a.1 a.la a.a a.oa a.a a.1a 0.1 a.15 o.a a.aa a.a a.a5 -~~~~-::._J.!.!!.~~l-C:.'C!-~L----------~~~-~--~~!?~----2~-~----~----~~-~~--------~~-----t-----~~2-------~~-a_____! ____~--~--------~____.;t____2_~9_______~~------~----~~2--- ~ ~ * Significantly different from the Group I value (p~O.a5). 00 I 0 lV 00 > ~ ~ ~ I ~ 0 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C6 (PAGE 3): HEMATOLOGY - SUMMARY - Fo GENERATION FEMALE RATS KEY TO HEMATOLOGY TABLE ABBREVIATION WBC TERMINOLOGY White Blood Cells (Leukocytes) RBC Red Blood Cells (Erythrocytes) HGB Hemoglobin HCT Hematocrit (Packed Cell Volume) MCV Mean Corpuscular Volume MCH Mean Corpuscular Hemoglobin MCHC Mean Corpuscular Hemoglobin Concentration PLAT Platelet Count MPV Mean Platelet Volume PT Prothrombin Time APTT Activated Partial Thromboplastin NRBC Nucleated Red Blood Cell Count ~ ~ Segmented Segmented Neutrophils 00 I >;-c;0 lV Abnormal L Abnormal Lymphocytes 00 Other Other Cells ------------------------------------------------------------------------------------------------------------------------------------------------------------------------ ~ CJ I ~ ~ PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C7 (PAGE 1): CLINICAL CHEMISTRY - SUMMARY - Fo GENERATION FEMALE RATS (See abbreviations on the last page of this table.) DOSAGE GROUP I II III IV V _p_~~~.9_1!_J!:'1.9.l..~9i.?..~!l _______________________________o_ _______________________ 2~}________________________!_________________________~------------------------~~---------- RATS TESTED N 10 10 10 10 10 TP (G/DL) A (G/DL) GLU (MG/DL) CHOL (MG/DL) TBILI (MG/DL) MEAN S.D. MEAN S.D. MEAN S.D. MEAN S.D. MEAN S.D. 6.1 0.52 4.1 0.42 152 19.8 77 27.8 0.2 0.07 5.5 0.50 4.0 0.34 162 20.0 72 14.0 0.2 0.03 5.9 0.41 4.1 0.24 155 18.7 71 20.0 0.2 0.05 5.8 0.32 4.0 0.29 146 16.2 62 14.2 0.1 0.05 5.8 0.29 4.0 0.31 140 35.5 61 19.8 0.1 0.05 BUN (MG/DL) MEAN S.D. 28 4.4 24 4.7 28 6.7 25 4.4 30 15.4 CREAT (MG/DL) MEAN S.D. 0.4 0.05 0.4 0.05 0.3 0.05 0.4 0.08 0.3 0.06 CK (U/L) MEAN S.D. 202 54.1 250 85.6 192 21. 7 213 80.4 252 101. 6 _.!!_I:.!__~~~~l---------------l':!~~--~-~~.?..~-----2--2-~-----:1;.----~!~..7--------!~..3-----i-----2-~~2--------~~~-----~----~J-~~--------1-2-Z _____:t;. ____~~~..7--------!J_~----i____ _2_~~~-- ........j::::.. 00 I ?a>0 tv 00 ~ n ..I.... tv PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C7 (PAGE 2): CLINICAL CHEMISTRY - SUMMARY - Fo GENERATION FEMALE RATS (See abbreviations on the last page of this table.) DOSAGE GROUP I II III IV V _P..,<2,~~9-~_i!:1.9.L~~i.?..1.!~l-------------------------------~-----------------------~~]------------------------~-------------------------~------------------------~~---------- RATS TESTED N 10 10 10 10 10 AST (U/L) MEAN S.D. 142 22.8 135 21. 6 137 11. 8 124 12.1 156 40.7 ALK (U/L) MEAN S.D. 145 88.7 159 81. 7 136 107.3 178 131.0 128 44.7 CA (MG/DL) MEAN S.D. 10.6 0.72 11.2 0.63 10.4 0.87 10.4 0.46 10.4 0.82 PHOS (MG/DL) MEAN S.D. 8.8 1.33 7.9 1. 94 9.0 2.80 8.7 2.88 10.1 1. 64 TRI (MG/DL) MEAN S.D. 54 19.9 50 10.2 49 29.4 45 19.5 44 18.3 NA (MMOL/L) MEAN S.D. 143 6.3 143 2.4 142 2.5 142 2.6 142 2.6 K (MMOL/L) MEAN S.D. 5.8 0.67 5.6 0.58 5.6 0.32 6.1 0.70 6.2 0.90 CL (MMOL/L) MEAN S.D. 96 3.4 94 2. 7 95 3.8 95 3.4 94 3.1 G (G/DL) MEAN S.D. 1. 9 0.22 1. 6 0.26** 1. 8 0.21 1. 7 0.13 1. 8 0.21 -~.!..~--~~~~~1--------------~~~--t-~~.?..~-----~-~~-----t----~~!_!l________~~-6-----~---2~-'!.~::_______~~!_____!----~~-2-~-------~-~~-----t----~~!_6________~~]_____i _____o_~~2--. ** Significantly different from the Group I value (p~0.01). ~ I--" 00 I 0 tv 00 > ~ ~(J I wI--" PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C7 (PAGE 3): CLINICAL CHEMISTRY - SUMMARY - Fo GENERATION FEMALE RATS KEY TO CLINICAL CHEMISTRY TABLE --A-B--B-R-E-V--I-A-T-I-O-N---------------------------------------------------------------T-E--R-M-I-N-O--L-O-G-Y------------------------------------------------------------------------------ TP Total Protein A Albumin GLU Glucose CHOL Cholesterol TBILI Total Bilirubin BUN Blood Urea Nitrogen CREAT Creatinine ALT Alanine Aminotransferase AST Aspartate Aminotransferase ALK Alkaline Phosphatase CA Calcium PHOS Phosphorus TRI Triglycerides ~ 1--' NA Sodium 00 I 0 K Potassium lV 00 ~ CL Chloride >~ G Globulin (j I -~~~------------------------------------------------------------------------2'!.~~~.T...~~i9..1_c:.~~2--~~-~,!i..';.~9---------------------------------------------------------------- 1--' ~ PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE CB (PAGE 1) : BODY WEIGHTS - PRECOHABITATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP I DOSAGE (MG/KG/DAY) 0 RATS TESTED N 15 BODY WEIGHT (G) DAY 1 MEANS.D. 228.6 8.0 DAY 2 MEANS.D. 228.2 8.7 DAY 3 MEANS.D. 233.5 7.2 DAY 4 MEANS.D. 236.6 7.7 DAY 5 MEANS.D. 239.0 10.0 DAY 6 MEANS.D. 241.2 10.8 DAY 7 MEANS.D. 245.3 10.4 DAY 8 MEANS.D. 250.5 11.5 DAY 9 MEANS.D. 250.4 12.1 DAY 10 MEANS.D. 251.6 14.3 DAY 11 MEANS.D. 256.4 14.6 DAY 12 MEANS.D. 256.9 14.0 DAY 13 MEANS.D. 256.3 16.3 DAY 14a MEANS.D. 258.5 16.1 DAY = DAY OF STUDY a. Last value recorded before cohabitation. II 0.3 15 224.7 8.1 226.2 9.1 228.5 9.5 233.8 9.4 234. 6 11. 0 235.4 11.2 238.5 10.7 243.4 10.6 244.l 10.8 243.4 12.6 246.1 12.2 250.8 12.4 250.4 12.8 250.7 12.6 III 1 15 226.3 7.7 227.3 9.2 231.1 10.1 234.2 9.8 236.9 9.8 241. 0 10. 8 244.3 10.8 246.5 11.6 248.3 11.8 250.0 12.8 254.9 13.3 254.8 12.5 255.0 13.2 257.9 13.6 IV 3 15 226.8 7.9 227.3 7.6 231.5 8.0 234.5 8.3 235.3 9.3 237.7 9.1 241.0 9.4 245.8 9.6 245.8 10.5 246.3 12.5 248.6 11.5 252.1 11.3 252.9 12.8 253.0 13.2 v 10 15 226.9 8.0 228.3 10.0 231.5 10.0 235.7 10.5 235.1 12.3 236.3 14.9 238.4 15.2 243.5 18.4 242.3 20.8 243.3 20.9 248.3 19.3 252.0 18.4 251.9 17.9 251.1 18.0 .,i:::.. 1--' 00 I 0 t-.J 00 ~ @ ("'.) I 1--' Vl PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C9 (PAGE 1) : BODY WEIGHT CHANGES - PRECOHABITATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II III IV v 0 0.3 1 3 10 RATS TESTED N 15 15 15 15 15 BODY WEIGHT CHANGE (G) DAYS 1 - 8 MEANS.D. +21. 9 8.3 +18.7 6.3 +20.3 5.7 +19.0 4.3 +16.7 16.0 DAYS 8 - 14a MEANS.D. +7.9 7.4 +7.3 4.2 +11. 3 6.1 +7.2 6.4 +7.5 8.9 DAYS 1 - 14a MEANS.D. +29.9 13.7 +25.9 7.2 +31. 6 8.4 +26.2 8.3 +24.2 14.4 ------------------------------------------------------------------------------------------------------------------------------------ DAYS = DAYS OF STUDY a. Last value recorded before cohabitation. ~ ~ 00 I 0 lV 00 ~ > ~ n I ~ O"'I PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE ClO (PAGE 1) : MATERNAL BODY WEIGHTS - GESTATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP I II III IV v DOSAGE (MG/KG/DAY) 0 0.3 1 3 10 ------------------------------------------------------------------------------------------------------------------------------------ RATS TESTED N 15 15 15 15 15 PREGNANT N 15 15 13 13 15 MATERNAL BODY WEIGHT (G) DAY 0 MEANS.D. 270.1 14.3 259.4 12.0 270.9 15.6 265.6 15.4 260.9 18.2 DAY 1 MEANS.D. 273.7 19.9 264.7 11.5 274.6 13.4 270.9 14.5 266.9 19.2 DAY 2 MEANS.D. 280.5 20.2 269.9 12.8 278.2 14.7 275.4 15.6 269.1 18.1 DAY 3 MEANS.D. 283.4 20.6 274.3 12.4 284.5 14.0 278.8 16.0 275.7 18.0 DAY 4 MEANS.D. 286.5 22.2 278.9 12.9 285.7 16.6 282.7 17.7 277.7 20.8 DAY 5 MEANS.D. 291.3 20.3 283.1 13.9 290.2 17.3 286.3 16.8 280.9 19.4 DAY 6 MEANS.D. 294.1 18.7 287.3 14.2 292.2 18.0 288.5 18.1 283.7 19.8 DAY 7 MEANS.D. 298.0 16.1 290.4 14.9 295.2 18.4 291.3 19.1 287.7 20.6 DAY 8 MEANS.D. 303.3 18.0 294.6 13.2 300.5 18.6 296.2 22.1 292.2 21.0 DAY 9 MEANS.D. 307.9 16.8 299.3 15.3 305.3 20.1 301.0 22.3 295.9 20.6 DAY 10 MEANS.D. 314.1 17.2 304.2 15.5 311.7 20.5 306.3 22.6 302.1 22.1 ------------------------------------------------------------------------------------------------------------------------------------ .~ ...... DAY = DAY OF GESTATION 00 I 0 tv 00 > ~ ~ (") ..I..... .......J PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE ClO (PAGE 2) : MATERNAL BODY WEIGHTS - GESTATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II III IV v 0 0.3 1 3 10 RATS TESTED N 15 15 15 15 15 PREGNANT N 15 15 13 13 15 MATERNAL BODY WEIGHT (G) DAY 11 MEANS.D. 320.7 19.6 311.7 16.5 318.5 20.6 313.6 22.0 308.6 23.3 DAY 12 MEANS.D. 325.6 19.8 318.3 16.8 325.1 19.8 319.6 26.0 315.0 23.9 DAY 13 MEANS.D. 331.1 19.0 321.3 16.9 328.3 21.6 323.2 25.8 319.3 23.3 DAY 14 MEANS.D. 338.8 17.9 328.5 16.8 334.2 20.7 329.2 26.1 324.1 23.1 DAY 15 MEANS.D. 345.7 18.4 336.1 17.7 342.5 20.6 335.2 26.3 331.2 24 .1 DAY 16 MEANS.D. 353.1 23.8 345.1 17.8 350.1 20.8 342.8 29.0 337.7 24.6 DAY 17 MEANS.D. 365.3 26.7 357.7 19.8 364.8 19.4 356.0 30.6 353.3 24.6 DAY 18 MEANS.D. 383.5 27.1 370.3 21.5 380.4 20.8 365.2 25.2 365.0 25.9 DAY 19 MEANS.D. 398.1 31.0 380.3 27.4 393.0 22.7 380.4 24.7 378.0 27.8 DAY 20 MEANS.D. 412.0 35.0 397.4 27.8 412.1 21.7 398.8 27.6 395.1 28.1 ------------------------------------------------------------------------------------------------------------------------------------ DAY = DAY OF GESTATION ~ ~ 00 I 0 tv 00 ii; > ~ (J I ~ 00 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE Cll (PAGE 1) : MATERNAL BODY WEIGHT CHANGES - GESTATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP I II III IV v DOSAGE (MG/KG/DAY) 0 0.3 1 3 10 ------------------------------------------------------------------------------------------------------------------------------------ RATS TESTED N 15 15 15 15 15 PREGNANT N 15 15 13 13 15 MATERNAL BODY WEIGHT CHANGE (G) DAYS 0 - 7 MEANS.D. +27.9 6.7 +31. 0 7.4 +24.3 6.3 +25.7 10.3 +26.9 5.8 DAYS 7 - 10 MEANS.D. +16.1 4.9 +13.8 3.4 +16.5 5.3 +15.0 6.1 +14.4 3.7 DAYS 10 - 12 MEANS.D. +11. 5 4.2 +14.1 3.3 +13.4 4.2 +13. 3 5.8 +12.9 6.2 DAYS 12 - 15 MEANS.D. +20.1 4.3 +17.7 3.6 +17.4 4.0 +15.5 5.5 +16.2 4.1 DAYS 15 - 18 MEANS.D. +37.9 10.6 +34.2 7.9 +37.9 5.2 +30.0 12.5 +33.8 5.7 DAYS 18 - 20 MEANS.D. +28.5 16.6 +27.1 13.2 +31. 7 6.7 +33.6 9.2 +30.1 8.9 DAYS 0 - 20 MEANS.D. +141. 9 29. 0 +138.0 27.4 +141. 2 14 .1 +133. 2 21. 9 +134.2 16.9 ------------------------------------------------------------------------------------------------------------------------------------ DAYS = DAYS OF GESTATION ,~ __. 00 I 0 tv 00 ~ > ~ (") ,_I _. \0 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C12 (PAGE 1) : MATERNAL BODY WEIGHTS - LACTATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II III IV v 0 0.3 1 3 10 RATS TESTED N 15 15 15 15 15 PREGNANT N 15 15 13 13 15 DELIVERED A LITTER N 15 15 13 13 15 MATERNAL BODY WEIGHT (G) DAY 1 MEANS.D. 313.1 22.6 302.2 16.8 309.5 20.6 304.7 23.2 296.3 19.9 DAY 2 MEANS.D. 313.1 24.6 300.1 17.2 305.4 18.9 304.2 22.2 298.9 19.8 DAY 3 MEANS.D. 316.1 22.6 300.2 18.6 310.4 18.1 305.0 23.1 300.3 20.0 [ 13] a [ ll]a [ 12] a [ 14]a DAY 4 MEANS.D. 321.5 22.7 303.4 17.2* 314.2 19.8 310.2 22.5 299.3 19.7* [ 13]a [ 12] a [ 12] a [ 13] a DAY 5 MEANS.D. 326.0 20.5 307.3 14.2 314.9 21.1 311.523.0 308.4 15.7 [ 12]a [ 12]a [ 13] a DAY 6 MEANS.D. 332.7 26.1 312.9 11.9* 323.9 18.2 316.9 16.1 306.0 26.9** [ 12] a [ ll]a DAY 7 MEANS.D. 340.4 20.8 321.4 12.6* 331.2 18.3 317. 7 21. 6** 315.2 25.4** [ 12]a DAY 8 MEANS.D. 342.3 19.8 320.7 12.6* 333.6 19.6 322.2 21.5* 318.1 26.0** [ 12] a DAY 9 MEANS.D. 349.9 25.6 331.7 11.9 337.4 17.3 331.8 21.2 324.7 29.7** [ 14]a [ 14] a DAY 10 MEANS.D. 353.6 17.9 334.9 17.5 345.5 18.2 333.5 23.0 327.4 38.3 +::- [ 13] a [ 12] a I--" DAY 11 MEANS.D. 354.4 18.5 331.9 25.7* 349.2 20.3 336.4 24.6 330.2 30.8* 00 I [ 14] a [ 12] a [ 12] a 0 ------------------------------------------------------------------------------------------------------------------------------------ tv 00 DAY = DAY OF LACTATION ;.ci [ ] = NUMBER OF VALUES AVERAGED > a. Excludes values that appeared incorrectly recorded, as well as those associated with interrupted water access. ~ * Significantly different from the Group I value (p~0.05). ** Significantly different from the Group I value (p~0.01). n I tv 0 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE Cl2 (PAGE 2): MATERNAL BODY WEIGHTS - LACTATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II III IV v 0 0.3 1 3 10 RATS TESTED N 15 15 15 15 15 PREGNANT N 15 15 13 13 15 DELIVERED A LITTER N 15 15 13 13 15 MATERNAL BODY WEIGHT (G) DAY 12 DAY 13 DAY 14 DAY 15 DAY 16 DAY 17 DAY 18 MEANS.D. MEANS.D. MEANS.D. MEANS.D. MEANS.D. MEANS.D. MEANS.D. 355.7 20.2 364.l 18.5 [ 14]a 359.8 21.5 355.3 31.2 360.7 22.0 351. 7 21.4 360.3 21.5 344.2 13.6 [ 14] a 342.9 17.2* [ 14] a 342.7 14.5 [ 14]a 342.4 10.4 [ 14] a 345.7 12.9 341.1 16. 9 346.4 15.6 352.6 20.1 [ 12]a 353.5 20.2 [ 12] a 353.1 17.3 343.2 17.2 [ 12] a 353.2 18.0 346.5 17.8 [ 12]a 352.2 21.5 347.5 24.4 [ 12]a 352.0 21.8 [ 12]a 345.1 19.5 348.7 21.4 [ 12] a 348.4 21.3 339.3 26.4 352.2 21.8 334.2 32.5 [ 14] a 340.1 30.8* 335.2 32.2** [ 13] a 333.4 33.6 [ 14] a 337.8 34.3 [ 14]a 333.0 33.4 340.6 34.3 DAY 19 DAY 20 MEANS.D. MEANS.D. 360.1 21.4 359.6 19.0 347.9 15.1 344.6 16.1 355.0 19.6 348.8 20.6 357.5 25.1 352.9 24.0 339.5 32.3 [ 14]a 338.9 34.9 DAY 21 MEANS.D. 350.1 26.9 335.7 18.7 343.4 19.8 344.4 25.8 334.4 35.9 [ 14] a [ 14]a ....j:.:.:.:.:... DAY 22 MEANS.D. 306.3 26.0 324.3 27.1 311.2 35.0 319.6 40.4 303.5 37.9 00 ------------------------------------------------------------------------------------------------------------------------------------ I 0 DAY = DAY OF LACTATION t0 00 [ ] = NUMBER OF VALUES AVERAGED ~ a. Excludes values that appeared incorrectly recorded, as well as those associated with interrupted water access. > * Significantly different from the Group I value (p~0.05). ~ ** Significantly different from the Group I value (p~0.01). (J I t0 .......... PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C13 (PAGE 1) : MATERNAL BODY WEIGHT CHANGES - LACTATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II III IV v 0 0.3 1 3 10 RATS TESTED N 15 15 15 15 15 PREGNANT N 15 15 13 13 15 DELIVERED A LITTER N 15 15 13 13 15 MATERNAL BODY WEIGHT CHANGE (G) DAYS 1 - 5 DAYS 5 - 8 DAYS 8 - 11 DAYS 11 - 15 DAYS 15 - 18 DAYS 18 - 22 MEANS.D. MEANS.D. MEANS.D. MEANS.D. MEANS.D. MEANS.D. +12.9 10.2 +16.3 9.6 +13. 9 7.1 [ 14) a -0.7 22.4 [ 14]a +4.9 21.8 -54.0 25.3 +5.1 10.7 +13.5 7.4 +11.1 19.2 +12.8 19.9 [ 14) a +2. 2 11. 9 [ 14) a -22.1 26.7 +7.2 12.7 [ 12]a +17.3 7.6 [ ll]a +14.4 5.6 [ ll]a -3.7 13.2 [ ll]a +7.9 18.0 [ 12) a -41.1 33 .6 +7.7 14.8 [ 12) a +11. 0 11. 0 [ 12) a +13.6 10.6 [ 12) a +13.8 9.7 [ ll]a +4.1 6.3 [ 12) a -32.5 28.2 +7.8 15.1 [ 13) a +16.5 10.1 [ 13) a +12.1 10.8 +3. 7 11. 2 [ 14) a +7 .4 11.4 [ 14) a -37.1 29.8 DAYS 1 - 22 MEANS.D. -6.9 28.4 +22.1 26.0 +1.7 28.0 +14. 9 31. 8 +7.3 29.3 ------------------------------------------------------------------------------------------------------------------------------------ DAYS = DAYS OF LACTATION [ ] = NUMBER OF VALUES AVERAGED a. Excludes values that appeared incorrectly recorded, as well as those associated with interrupted water access. +::>. -00 I 0 tv 00 ;-c, >~nI tv tv PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C14 (PAGE 1) : ABSOLUTE FEED CONSUMPTION VALUES (G/DAY) - PRECOHABITATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II III 0 0.3 1 RATS TESTED N 15 15 15 FEED CONSUMPTION (G/DAY) DAYS 1 - 8 MEANS.D. 20.4 1.8 [ 13] a 19.5 1. 6 20.7 2.0 DAYS = DAYS OF STUDY [ ] = NUMBER OF VALUES AVERAGED a. Excludes values that were not recorded, as well as those associated with spillage. IV 3 15 19.5 1. 8 v 10 15 19.6 3.0 ~ ~ 00 I 0 tv 00 ~ > ~ (":) I wtv PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE Cl5 (PAGE 1) : RELATIVE FEED CONSUMPTION VALUES (G/KG/DAY) - PRECOHABITATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II III 0 0.3 1 RATS TESTED N 15 15 15 FEED CONSUMPTION (G/KG/DAY) DAYS 1 - 8 MEANS.D. 86.1 5.5 [ 13] a 83.4 5.6 87.9 7.0 DAYS = DAYS OF STUDY [ ] = NUMBER OF VALUES AVERAGED a. Excludes values that were not recorded, as well as those associated with spillage. IV 3 15 83.0 5.2 v 10 15 83.3 10.0 .~ ........ 00 I 0 tv 00 > ~ n ~ I tv ~ PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C16 (PAGE 1) : MATERNAL ABSOLUTE FEED CONSUMPTION VALUES (G/DAY) - GESTATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP I II III IV v DOSAGE (MG/KG/DAY) 0 0.3 1 3 10 ------------------------------------------------------------------------------------------------------------------------------------ RATS TESTED N 15 15 15 15 15 PREGNANT N 15 15 13 13 15 MATERNAL FEED CONSUMPTION (G/DAY} DAYS 0 - 7 MEANS.D. 25.4 3.3 25.0 2.5 24.3 2.7 25.2 3.6 24.0 2.7 DAYS 7 - 10 MEANS.D. 27.7 2.8 26.8 2.8 26.3 3.4 26.3 5.0 25.8 2.5 DAYS 10 - 12 DAYS 12 - 15 MEANS.D. MEANS.D. 32.0 10.5 [ 14) a 28.4 2.8 27.0 3.2 27.5 2.4 28.0 3.2 27.5 2.1 26.6 3.9 26.7 3.9 27.0 2.8 27.5 2.6 DAYS 15 - 18 MEANS.D. 25.4 4.0 26.7 3.1 25.9 2.1 25.3 3.6 26.0 3.3 DAYS 18 - 20 MEANS.D. 26.6 5.7 22.8 6.2 25.8 3.2 25.0 3.7 26.1 4.8 DAYS 0 - 20 MEANS.D. 26.9 3.2 25.9 2.4 25.8 2.0 25.7 3.0 25.6 2.3 ------------------------------------------------------------------------------------------------------------------------------------ DAYS = DAYS OF GESTATION [ ] = NUMBER OF VALUES AVERAGED a. Excludes values that were associated with spillage. ~ ~ 00 I 0 tv 00 ~ n>~I tv VI PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C17 (PAGE 1): MATERNAL RELATIVE FEED CONSUMPTION VALUES (G/KG/DAY) - GESTATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP I II III IV v DOSAGE (MG/KG/DAY) 0 0.3 1 3 10 ------------------------------------------------------------------------------------------------------------------------------------ RATS TESTED N 15 15 15 15 15 PREGNANT N 15 15 13 13 15 MATERNAL FEED CONSUMPTION (G/KG/DAY) DAYS 0 - 7 MEANS.D. 88.8 8.4 90.4 7.1 85.6 6.9 89.8 9.3 86.8 5.5 DAYS 7 - 10 MEANS.D. 90.5 7.4 90.0 7.0 86 .4 7.4 87.7 12.7 87.6 5.4 DAYS 10 - 12 DAYS 12 - 15 MEANS.D. MEANS.D. 99.0 28.7 [ 14] a 84.9 7.3 86.5 8.0 84.4 5.8 87.9 6.1 82.7 4.9 84.8 7.0 81. 5 6.9 87.3 4.3 85.6 7.2 DAYS 15 - 18 MEANS.D. 70.0 8.5 75.6 6.9 72 .3 6.2 72.2 7.4 75.1 8.3 DAYS 18 - 20 MEANS.D. 66.4 12.4 59.3 15.4 65.4 7.9 66.1 11. 8 68.7 10.7 DAYS 0 - 20 MEANS.D. 83.3 6.6 82.6 5.6 80.5 3.1 81. 6 5.4 82.5 4.0 ------------------------------------------------------------------------------------------------------------------------------------ DAYS = DAYS OF GESTATION [ ] = NUMBER OF VALUES AVERAGED a. Excludes values that were associated with spillage. .~ ...... 00 I 0 t-..> 00 ~ >n~I t-..> O"I PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C18 (PAGE 1) : MATERNAL ABSOLUTE FEED CONSUMPTION VALUES (G/DAY) - LACTATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II 0 0.3 RATS TESTED N 15 15 PREGNANT N 15 15 DELIVERED A LITTER N 15 15 MATERNAL FEED CONSUMPTION (G/DAY) DAYS 1 - 5 DAYS 5 - 8 MEANS.D. MEANS.D. 38.5 7.1 61.2 6.4 27.6 8.7** [ 14]a 53.7 6.6 DAYS 8 - 15 MEANS.D. 71.6 8.6 68.3 8.3* DAYS 1 - 15 MEANS.D. 59.9 7.0 54.3 7.1 DAYS = DAYS OF LACTATION [ ] = NUMBER OF VALUES AVERAGED a. Excludes values that were associated with spillage. * Significantly different from the Group I value (p~0.05). ** Significantly different from the Group I value (p~0.01). III 1 15 13 13 33.2 4.0 [ 12] a 55.9 4.4 69.2 4.0 56.9 4.9 IV v 3 10 15 15 13 15 13 15 31.4 5.5* 49.4 10.2 69.6 9.5** 54.4 7.2 34.4 7.9 [ 14]a 52.3 9.0 68.2 9.4** 55.7 8.2 -.i;::.. 00 I 0 tv 0;.c0; >fJ(') I tv -...l PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST {SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C19 (PAGE 1) : MATERNAL RELATIVE FEED CONSUMPTION VALUES (G/KG/DAY) - LACTATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II III IV v 0 0.3 1 3 10 RATS TESTED N 15 15 15 15 15 PREGNANT N 15 15 13 13 15 DELIVERED A LITTER N 15 15 13 13 15 MATERNAL FEED CONSUMPTION (G/KG/DAY) DAYS 1 - 5 DAYS 5 - 8 DAYS 8 - 11 DAYS 11 - 15 DAYS 1 - 15 MEANS.D. MEANS.D. MEANS.D. MEANS.D. MEANS.D. 121.1 21.3 183.0 20.6 176.1 134.6 [ 14]a 222.6 97.5 [ 14]a 176.7 19.5 91. 8 27.8** [ 14] a 170.4 23.5 176.1 109.9 225.3 64.3 [ 14]a 166.9 22.6 [ 14] a 107.6 15.0 [ 12] a 170.6 12.2 [ ll]a 101. 9 97.9 [ ll]a 276.0 76.3 [ ll]a 172.4 11.5 [ 12]a 102.7 21.2 [ 12] a 155.2 32.4** [ 12] a 155.4 134.0 [ 12] a 245.4 89.7 [ ll]a 166.6 20.2 [ 12] a 118. 7 22.1 [ 12]a 168.2 20.0 [ 12]a 138.4 127.0 248.7 81. 6 [ 14]a 175.1 14. 9 [ 14]a DAYS = DAYS OF LACTATION [ ] = NUMBER OF VALUES AVERAGED a. Excludes values that appeared incorrectly recorded, as well as those associated with interrupted water access or spillage. ** Significantly different from the Group I value (p~0.01). ~ ~ 00 I ~ 0 N ;0-c0, (') I N 00 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C20 (PAGE 1): MATING AND FERTILITY, ESTROUS CYCLING AND DAYS IN COHABITATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) ESTROUS CYCLING OBSERVATIONS RATS EVALUATED N ESTROUS STAGES/ 13 DAYS MEANS.D. RATS WITH 6 OR MORE CONSECUTIVE DAYS OF DIESTRUS N RATS WITH 6 OR MORE CONSECUTIVE DAYS OF ESTRUS N I 0 15 2.7 0.9 1 0 II 0.3 15 2.8 0.9 0 0 III 1 15 3.3 0.6 0 0 IV 3 15 2.9 0.8 0 1 v 10 15 2.1 1. 2 1 0 ~ ~ ~00 I 0 tv 00 ~ ("") I tv \0 PROTOCOL 418-028: ORAL {GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST {SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C20 {PAGE 2): MATING AND FERTILITY, ESTROUS CYCLING AND DAYS IN COHABITATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE {MG/KG/DAY) I II III 0 0.3 1 RATS IN COHABITATION N 15 15 15 DAYS IN COHABITATION a MEANS.D. 3.7 3.0 1.9 1.2 2.8 1.2 RATS THAT MATED N(%) 15(100.0) 15(100.0) 15(100.0) FERTILITY INDEX b N/N 15/ 15 {%) (100.0) 15/ 15 (100.0) 13/ 15 ( 86.7) RATS WITH CONFIRMED MATING DATES N 15 15 15 MATED BY FIRST MALE c DAYS 1-7 N(%) 14 { 93. 3) 15(100.0) 15(100.0) MATED BY SECOND MALE c DAYS 8-14 N{%) 1 ( 6. 7) 0 ( 0. 0) 0 ( 0. O) RATS PREGNANT/RATS IN COHABITATION N/N 15/ 15 (%) (100.0) 15/ 15 (100.0) 13/ 15 ( 86. 7) a. Restricted to rats with a confirmed mating date and rats that did not mate. b. Number of pregnancies/number of rats that mated. c. Restricted to rats with a confirmed mating date. IV 3 15 4.0 4.0 14 { 93. 3) 13/ 14 ( 92. 8) 14 13( 92.8) 1( 7.2) 13/ 15 ( 86. 7) v 10 15 2.5 1.4 15(100.0) 15/ 15 (100.0) 15 15(100.0) 0 { 0. 0) 15/ 15 (100.0) .~ ...... 00 I 0 l:V 00 > ~ ~( j I (.;.) 0 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C21 (PAGE 1) : FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP I II III IV V --~Ql\.2.~_J!:'l.9.L.~gLp~~L------------------------------------2----------------------Q~-3-----------------------!------------------------]-------------------------~~----------- FEMALE RATS N 10 10 10 10 10 HOME CAGE BEHAVIOR 1: Sleeping N 1 4 4 4 1 2: Awake, Immobile N 1 2 1 3 4 3: Normal movement N 8 4 5 3 5 4: Unusual posture N 0 0 0 0 0 5: Unusual behavior N 0 0 0 0 0 ALTERATIONS (HOME CAGE} 1: None N 10 10 10 10 10 2: Stereotyped behavior N 0 0 0 0 0 3: Bizarre behavior N 0 0 0 0 0 4: Limb twitches/tremor N 0 0 0 0 0 5: Whole body tremor/spasm N 0 0 0 0 0 6: Unusual posture N 0 0 0 0 0 7: Tonic-clonic seizure N 0 0 0 0 0 REACTION TO REMOVAL (1) Sits quietly N 10 10 10 10 10 (2) Vocalization N 0 0 0 0 0 (3) Runs or freezes N 0 0 0 0 0 (4) Tail or throat rattles N 0 0 0 0 0 MEAN SCORE 1. 0 1. 0 1. 0 1. 0 1. 0 REACTION TO HANDLING (1) No resistance N 10 10 10 10 10 (2) Vocalization N 0 0 0 0 0 (3) Tense N 0 0 0 0 0 ____________________________________ ____________________ _____________________ ______________________ (4) Squirming N 0 :1!;.~__f_q_~~----------1-~-q_ 0 l~_q_ 0 0 ~~2----------------------~~-Q. 0 !~.9__________ _ n: = Category number for descriptive test item. (n} = Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score and then dividing the sum of the products by the total number of rats ..j:::.. I--" 00 I 0 t-...J 00 ~ @ (1 I v..> I--" PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C21 (PAGE 2) : FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP I II III IV V __12,Q!\.Q.~_j!:1_G.f..~gLp_~~~------------------------------------2----------------------Q~}-----------------------!------------------------]-------------------------3:_~----------- FEMALE RATS N 10 10 10 10 10 REARS IN OPEN FIELD DEFECATION IN OPEN 1: None 2: Feces normal 3: Soft or liquid FIELD feces MEANS.D. 12.0 3.6 N 8 N 2 N 0 13.0 2.7 10 0 0 11.6 3.5 8 1 1 10.7 2.3 8 1 1 10.9 2.6 8 2 0 URINATION IN OPEN FIELD (1) None N 6 7 7 10 8 (2) Normal urination N 4 3 3 0 2 (3) Excess urination N 0 0 0 0 0 MEAN SCORE 1.4 1.3 1. 3 1. 0 1.2 LEVEL OF AROUSAL (1) Stuporous N 0 0 0 0 0 (2) Sluggish N 0 0 0 0 0 (3) Apparently normal N 10 10 10 10 10 (4) Sudden darting N 0 0 0 0 0 (5) Freezing, vocalization N 0 0 0 0 0 MEAN SCORE 3.0 3.0 3.0 3.0 3.0 ALTERATIONS (OPEN FIELD) .f;::.. ......... 1: None N 10 10 10 10 10 00 I 2: Stereotyped behavior N 0 0 0 0 0 0 l'V 3: Bizarre behavior N 0 0 0 0 0 00 4: Limb twitches/tremor N 0 0 0 0 0 ~ > 5: Whole body tremor/spasm N 0 0 0 0 0 ~ 6: Unusual posture N 0 0 0 0 0 n --nZ~: --=.!~C~ai.tse:g.o:_ryS12nEuJm-_bs_e~r~jf.o-r~~Ed~e--s-c-r-i-p--t-i-v-e-I't.e!-s-t---it-e-m---. -------o-----------------------.9------------------------2------------------------2-------------------------2------------ w I (n) = Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score l'V and then dividing the sum of the products by the total number of rats PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C21 (PAGE 3): FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP I II I II IV V __J2.Q!\.2.J2._J.t19..l~gLp~~~-----------------------------------------------------------2~-3..----------------------!------------------------]-------------------------~~----------- FEMALE RATS N 10 10 10 10 10 GAIT PATTERN 1: Apparently normal N 10 10 10 10 8 2: Ataxic N 0 0 0 0 0 3: Limbs splay or drag N 0 0 0 0 0 4: Spastic, tip-toe N 0 0 0 0 2 5: Duck-walk N 0 0 0 0 0 6: Scissors gait N 0 0 0 0 0 GAIT ABNORMALITY, SEVERITY (1) Normal gait N 10 10 10 10 8 (2) Slight N 0 0 0 0 2 (3) Moderate N 0 0 0 0 0 (4) Extreme N 0 0 0 0 0 MEAN SCORE 1. 0 1. 0 1. 0 1. 0 1.2 PALPEBRAL CLOSURE (1) Wide open N 10 10 10 10 10 (2) Slightly drooping N 0 0 0 0 0 (3) Half-closed N 0 0 0 0 0 (4) Completely shut N 0 0 0 0 0 MEAN SCORE 1. 0 1. 0 1. 0 1. 0 1. 0 .~ ...... PROMINENCE OF THE EYE 00 I 1: Normal N 10 10 10 10 10 0 tv 2 : E x o p h t h a l m o s N _____________________1'!, ________________ 0 _o_______________________ 0 _o________________________ 90________________________ 9O_________________________ 20___________ _ --~l---~~g~,!l_t_12_~!!!12_~ 00 ~ > n: = Category number for descriptive test item. (n) = Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score ~ and then dividing the sum of the products by the total number of rats ('j w I w PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C21 (PAGE 4): FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP I II I II IV V --DFOESMAGAE"(LMEG-/KRG.A/D-A;;Y8)---------------------------N----------------i0o______________________0i.o3______________________i_1o_______________________i3o________________________1io0 ___________ LACRIMATION (1) No excess N 10 10 10 10 10 (2) Excess at eyelid margin N 0 0 0 0 0 (3) Margin persistently damp N 0 0 0 0 0 (4) Extends beyond margin N 0 0 0 0 0 MEAN SCORE 1. 0 1.0 1. 0 1.0 1. 0 SALIVATION (1) No excess N 10 10 10 10 10 (2) Margin of mouth wet N 0 0 0 0 0 (3) 1/4 to 1/2 submandibular N 0 0 0 0 0 (4) Entire submandibular N 0 0 0 0 0 MEAN SCORE 1. 0 1.0 1. 0 1.0 1. 0 PILOERECTION N 0 0 0 0 0 ABNORMAL RESPIRATION N 0 0 0 0 1 APPEARANCE (1) Clean and groomed N 10 10 9 9 10 (2) Unkempt N 0 0 1 0 0 (3) Urine and/or fecal stain N 0 0 0 1 0 MEAN SCORE 1.0 1. 0 1.1 1.2 1. 0 ....J..:.:.:.... VISUAL REACTION 00 I (1) None N 0 0 0 0 0 0 tv (2) Orienting N 10 10 10 10 10 00 ~ (3) Startle N 0 0 0 0 0 > (4) More energetic reaction N 0 0 0 0 0 ~ (5) Attacks N 0 0 0 0 0 ____________________________________ ____________________ _____________________ ___________ ty_E:_~_.f_C2_~~----------3~_q_ 3~_q_ ~~9----------------------~~------------------------~~.9 n n: = Category number for descriptive test item. w I (n) = Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score ..J:::.. and then dividing the sum of the products by the total number of rats PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C21 (PAGE 5): FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP I II III IV V --~2!\.2.~-J~9.J..~gL.P.!!.!~-----------------------------------------------------------g~-~----------------------~------------------------2-------------------------~~----------- FEMALE RATS N 10 10 10 10 10 TACTILE REACTION (1) None N 0 0 0 0 0 (2) Orienting N 10 10 10 10 10 (3) Startle N 0 0 0 0 0 (4) More energetic reaction N 0 0 0 0 0 (5) Attacks N 0 0 0 0 0 MEAN SCORE 2.0 2.0 2.0 2.0 2.0 AUDITORY REACTION (1) None N 0 0 0 0 0 (2) Orienting N 0 0 0 1 1 (3) Startle N 10 10 10 9 9 (4) More energetic reaction N 0 0 0 0 0 (5) Intense vocalization N 0 0 0 0 0 MEAN SCORE 3.0 3.0 3.0 2.9 2.9 TAIL-PINCH REACTION (1) None N 0 0 0 0 0 (2) Orienting N 8 9 8 10 9 (3) Startle N 2 1 2 0 1 (4) More energetic reaction N 0 0 0 0 0 (5) Attacks N 0 0 0 0 0 .i::::.. ~ 00 I ------------------------------------~-E-~__f_q_~~----------~~-~--------------------3~-~---------------------~~~----------------------~~------------------------~~-1:_ _________ _ 0 tv n: = Category number for descriptive test item. 00 (n) = Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score ~ >~ and then dividing the sum of the products by the total number of rats (") w I Vl PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C21 (PAGE 6): FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP I II III IV v __J2Q!\.2.~-J~2.L.~gLp_~~~-----------------------------------------------------------2~-l----------------------~------------------------~-------------------------~~----------- FEMALE RATS N 10 10 10 10 10 AIR RIGHTING RESPONSE (1) All feet land on ground N 10 10 10 10 10 (2) Lands on side N 0 0 0 0 0 (3) Lands on back N 0 0 0 0 0 MEAN SCORE 1.0 1. 0 1.0 1. 0 1.0 PUPIL RESPONSE TO LIGHT N 10 10 10 10 10 FORELIMB GRIP TEST Maximum (G) Average (G) HINDLIMB GRIP TEST Maximum (G) Average (G) MEANS.D. MEANS.D. 509.5 455.9 161. 7 136.7 396.5 319.8 125.7 100.6 492.5 423.9 257.7 207.3 493.0 452.5 112. 3 103.4 518.5 460.3 161. 9 166.4 MEANS.D. MEANS.D. 462.0 423.0 111. 3 113. 7 412.5 366.5 104.7 77.3 455.5 87.7 418.3 79.4 397.0 67.5 362.8 79.8 485.5 427.3 71. 5 52.2 LANDING FOOT SPLAY Average (CM) MEANS.D. 7.7 1. 8 6.7 1.0 7.7 1.5 7.1 1.4 8.1 1. 7 __________________ ___ ____ ______ --~QPI--t:!~~S::.!!,!_J.s;J ~~~-t~~P~----~2]_~'!.------~3~-<2.------~j-~~~---.t- ______ l!~ ]_s_~~____ i----~~~-------~!2~1 .;!:____ ~2~_<2, ]_2_~~~----~----~j~-~--- n: = Category number for descriptive test item. (n) = Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score .,_p_... and then dividing the sum of the products by the total number of rats 00 I 0 tv 00 ~ >fnJI VJ ' PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C22 (PAGE 1): MOTOR ACTIVITY - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II III IV v 0 0.3 1 3 10 NUMBER OF FEMALE RATS N 10 10 10 10 10 NUMBER OF MOVEMENTS BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 BLOCK 7 BLOCK 8 BLOCK 9 BLOCK 10 BLOCK 11 BLOCK 12 BLOCK 13 BLOCK 14 BLOCK 15 BLOCK 16 BLOCK 17 BLOCK 18 TOTAL MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN 72.0 53.8 50.4 28.6 27.5 23.9 11.6 19.3 21.4 19.6 9.2 18.1 12.1 16.0 22.2 23.2 32.2 25.9 487.0 6.9 25.7 26.5 34.7 24.0 26.5 16.0 18.1 21. 0 22.1 10.6 25.5 18.3 19.0 30.6 27.2 33.8 28.5 244.9 67.1 7.6 53.6 20.8 41.2 34.2 30.7 25.5 21.2 23.6 19.4 20.7 17.8 23.2 13.2 18.6 10.5 24.3 6.5 7.2 7.0 16.6 5.9 5.3 15.0 22.1 19.0 19.6 13.0 15.7 15.0 16.7 11. 7 18.6 10.8 14.7 378.6 202.4 TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 68.3 6. 8 66.6 12. 4 50.2 17. 0 43.9 26. 8 43.6 26 .4 42.6 29. 5 44.5 21.3 38.0 20 .5 28.1 25 .4 29.4 29. 3 26.9 28 .2 21.1 26 .2 24.3 26. 3 24.4 30. 8 23.6 25. 9 24.5 28. 2 24.7 27. 9 17.9 18. 9 642.6 295.6 65.7 9. 7 57.1 18 .2 49.3 21.4 39.0 25 .1 33.9 24 .2 35.0 26. 8 38.3 29 .4 44.5 18. 0 34.0 19. 0 25.9 23 .5 23.5 22. 7 21. 8 20 .4 19.8 25. 0 24.4 26 .2 19.8 24. 9 27.2 29. 0 21. 9 23 .2 19.0 25 .3 600.1 292.0 68.4 42.5 31.1 20.5 18.6 19.7 14.0 32.6 27.9 15.5 19.7 29.7 22.1 16.8 15.1 19.2 18.3 22.6 454.3 9.8 19.9 24.6 22.9 22.4 18.0 17.3 26.2 24.6 16.5 22.6 21.4 25.5 18.3 20.2 18.9 25.6 20.9 261.4 ..J:::.. -00 I 0 N 00 ~ ~nmI (.;.> -.J PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C22 (PAGE 2): MOTOR ACTIVITY - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II III IV v 0 0.3 1 3 10 NUMBER OF FEMALE RATS N 10 10 10 10 10 TIME (SECONDS) SPENT IN MOVEMENT BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 BLOCK 7 BLOCK 8 BLOCK 9 BLOCK 10 BLOCK 11 BLOCK 12 BLOCK 13 BLOCK 14 BLOCK 15 BLOCK 16 BLOCK 17 BLOCK 18 TOTAL MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN 154.8 27.4 95.3 50.4 65.7 36.2 30.6 41.4 33.6 36.5 27.5 37.9 11. 7 18.4 25.4 29.0 25.5 28.6 25.2 30.0 11.8 14.7 22.9 35.7 14.0 23.3 14.8 20.2 30.1 46.0 27.0 33.9 40.7 46.3 38.2 45.8 694. 8 331. 8 141.5 94.0 60.1 48.0 27.5 31. 0 21.4 15.5 13.8 6.2 8.3 4.2 14.7 24.1 15.5 17.6 13.7 9.6 566.7 46.3 54.4 48.0 48.9 30.6 41. 8 31. 9 26.5 37.1 9.6 21.8 3.7 21.0 27.9 23.7 24.1 27.6 14.8 350.6 154.4 32 .2 114 .4 24 .2 88.5 56. 9 70.2 52.2 63.4 42. 7 56.1 41.1 69.0 46 .5 60.7 36 .2 37.9 41.2 38.7 44 .1 39.7 44 .2 34.4 48. 6 38.4 52 .5 34.5 48 .1 36.4 44 .5 36.1 42 .1 37.8 48. 8 18.1 23. 2 1028.7 477.6 181. 0 119 .5 94.4 73.0 52.0 56.7 65.3 70.1 66.6 41. 6 37.2 26.6 33.4 33.1 33.0 38.6 34.9 29.3 1086.3 36 .4 56. 0 55. 9 61.1 47 .4 47 .1 59. 7 26. 6 58. 8 49. 9 46 .8 25. 8 49. 6 42. 5 54. 3 40. 7 46. 8 48. 7 711.3 146.2 96.6 52.3 34.6 27.6 31. 0 16.5 41. 7 40.1 14.1 24.6 38.7 32.7 25.6 17.3 18.5 21. 7 27.6 707.4 26.1 63.6 51. 5 45.9 35.5 30.6 29.0 38.3 38.6 16.3 33.0 34.5 43.3 30.6 25.7 23.1 33.6 30.1 442. 6 TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. -~ 00 I 0 tv 00 ~ > Fri () w I 00 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C23 (PAGE 1) : NATURAL DELIVERY OBSERVATIONS - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II III IV v 0 0.3 1 3 10 RATS ASSIGNED TO NATURAL DELIVERY N 15 15 15 15 15 PREGNANT N(%) 15(100.0) 15(100.0) 13( 88.7) 13( 88.7) 15(100.0) DELIVERED LITTERS N(%) 15(100.0) 15(100.0) 13(100.0) 13(100.0) 15(100.0) DURATION OF GESTATION a MEANS.D. 22.5 0.5 22.7 0.4 22.7 0.5 22.8 0.4 22.6 0.5 IMPLANTATION SITES PER DELIVERED LITTER N MEANS.D. 251 16.7 1.3 230 15.3 2.9 206 15.8 1. 3 192 14.8 2.8 231 15.4 2.3 DAMS WITH STILLBORN PUPS N(%) 0 ( 0.0) 0 ( 0.0) 1 ( 7. 7) 3 ( 23 .1) 2 ( 13. 3) DAMS WITH NO LIVEBORN PUPS N 0 ( 0. 0) 0 ( 0.0) 0 ( 0. O) 0 ( 0.0) 0 ( 0.0) GESTATION INDEX b % N/N 100.0 15/ 15 100.0 15/ 15 100.0 13/ 13 100.0 13/ 13 100.0 15/ 15 DAMS WITH ALL PUPS DYING DAYS 1-4 POSTPARTUM N(%) 0 ( 0. 0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) DAMS WITH ALL PUPS DYING DAYS 5-22 POSTPARTUM N(%) 0 ( 0. 0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) a. Calculated as the time (in days) elapsed between confirmed mating (arbitrarily defined as day O) and the time (in days) the first pup was delivered. .,i:::.. b. Number of rats with live offspring/number of pregnant rats. ....... 00 I 0 tv 00 ~ > ~ n 'wI PROTOCOL 418-028: ORAL (GAVAGE} COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C24 (PAGE 1) : LITTER OBSERVATIONS (NATURALLY DELIVERED PUPS} - SUMMARY - Fl GENERATION LITTERS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY} I II III IV v 0 0.3 1 3 10 DELIVERED LITTERS WITH ONE OR MORE LIVEBORN PUPS N 15 15 13 13 15 PUPS DELIVERED (TOTAL} N MEANS.D. 235 15.7 1. 7 214 14.3 3.2 201 15.5 1.4 181 13.9 3.1 220 14.7 2.5 LIVEBORN MEANS.D. N(%} 15.7 1. 7 235(100.0} 14.3 3.2 214(100.0} 15.4 1. 6 200( 99.5) 13.6 3.2 177( 97.8) 14.5 2.4 218( 99.1) STILLBORN MEANS.D. N(%) 0.0 0.0 0 ( 0.0) 0.0 0.0 0 ( 0. 0) 0.1 0.3 1 ( 0.5) 0.2 0.4 3 ( 1. 6) 0.1 0.4 2 ( 0.9) UNKNOWN VITAL STATUS N 0 0 0 1 0 PUPS FOUND DEAD OR PRESUMED CANNIBALIZED DAY DAYS DAYS DAYS 1 2- 8 9-15 16-22 N/N(%) N/N(%) N/N(%) N/N(%) 1/235( 6/234 ( 0/228 ( 0/228( 0.4) 2. 6) 0.0) 0. 0) 2/214 ( 6/212 ( 2/206 ( 0/204 ( 0.9) 2.8) 1. 0) 0.0) 0/200( 3/200( 1/197( 0/196 ( 0. 0) 1. 5) 0. 5) 0.0) 2/177( 2/175 ( 1/173 ( 0/172 ( 1.1) 1.1) 0. 6) 0.0) 3/218( 3/215( 1/212 ( 0/211 ( 1.4) 1.4) 0.5) 0. O) VIABILITY INDEX a % 97.0 N/N 228/235 96.3 206/214 98.5 197/200 97.7 173/177 97.2 212/218 LACTATION INDEX b % 100.0 99.0 99.5 99 .4 99.5 N/N 228/228 204/206 196/197 172/173 211/212 - DAY(S} = DAY(S) POSTPARTUM .i;::.. a. Number of live pups on day 8 postpartum/number of liveborn pups on day 1 postpartum. 00 I b. Number of live pups on day 22 postpartum/number of live pups on day 8 postpartum. 0 l'-.) ~00 ~ n I ~ PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C24 (PAGE 2): LITTER OBSERVATIONS (NATURALLY DELIVERED PUPS) - SUMMARY - Fl GENERATION LITTERS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) I II III IV v 0 0.3 1 3 10 DELIVERED LITTERS WITH ONE OR MORE LIVEBORN PUPS N 15 15 13 13 15 SURVIVING PUPS/LITTER a DAY 1 MEANS.D. 15.7 1. 7 14.3 3.2 15.4 1. 6 13.6 3.2 14.5 2.4 DAY 8 MEANS.D. 15.2 1. 8 13.7 2.9 15.2 1. 5 13.3 3.3 14.l 2.1 DAY 15 MEANS.D. 15.2 1. 8 13.6 2.8 15.1 1. 3 13.2 3.2 14.1 2.2 DAY 22 MEANS.D. 15.2 1. 8 13.6 2.8 15.1 1. 3 13. 2 3.2 14.1 2.2 PERCENT MALE PUPS PER NUMBER OF PUPS SEXED DAY 1 MEANS.D. 45.2 12.4 51.9 13.1 51. 6 6.8 43.6 13.4 51.4 13 .4 DAY 8 MEANS.D. 45.2 13.0 52.7 12.0 51. 8 6.3 42.9 13.1 51.4 13.9 DAY 15 MEANS.D. 45.2 13.0 53 .1 11. 8 52.0 6.2 43 .1 13. 0 51. 8 14. 2 DAY 22 MEANS.D. 45.2 13.0 53.1 11.8 52.0 6.2 43.1 13.0 51.8 14.2 ------------------------------------------------------------------------------------------------------------------------------------ DAY = DAY POSTPARTUM a. Average number of live pups per litter, including litters with no surviving pups. b. Includes pups born alive, found dead day 1 postpartum. .....i.:.:.:..... 00 I 0 tv 00 ~ >n~I ..i:::.. ......... PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C24 (PAGE 3): LITTER OBSERVATIONS (NATURALLY DELIVERED PUPS) - SUMMARY - Fl GENERATION LITTERS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) I II III IV v 0 0.3 1 3 10 DELIVERED LITTERS WITH ONE OR MORE LIVEBORN PUPS N 15 15 13 13 15 LIVE LITTER SIZE AT WEIGHING DAY 1 MEANS.D. 15.6 1. 8 14.1 3.1 15.4 1. 6 13 .5 3.3 14.3 2.2 DAY 8 MEANS.D. 15.2 1. 8 13.7 2.9 15.2 1. 5 13 .3 3.3 14.1 2.1 DAY 15 MEANS.D. 15.2 1. 8 13.6 2.8 15.1 1. 3 13.2 3.2 14.1 2.2 DAY 22 MEANS.D. 15.2 1. 8 13.6 2.8 15.1 1.3 13.2 3.2 14.1 2.2 PUP WEIGHT/LITTER (GRAMS) DAY 1 MEANS.D. 6.3 0.3 6.3 0.5 6.4 0.3 6.5 0.7 6 .3 0.5 DAY 8 MEANS.D. 14.3 1. 6 13.3 1. 7 13.8 1. 0 14.1 3.1 13.1 1.5 DAY 15 MEANS.D. 26.2 2.8 26.3 3.9 25.9 2.6 27.4 5.7 25.1 3.3 DAY 22 MEANS.D. 37.4 4.7 39. 3 6.9 38.0 5.7 40.0 7.9 36.2 7.7 ------------------------------------------------------------------------------------------------------------------------------------ DAY = DAY POSTPARTUM ..(:::.. ~ 00 I 0 N 00 ~ Q~..(:::.. N PROTOCOL 418-028: ORAL {GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST {SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C25 {PAGE 1) : CLINICAL OBSERVATIONS FROM BIRTH TO DAY 22 POSTPARTUM - SUMMARY - Fl GENERATION PUPS MATERNAL DOSAGE GROUP I II III IV v MATERNAL DOSAGE {MG/KG/DAY) 0 0.3 1 3 10 LITTERS EXAMINED {N) 15 15 13 13 15 ------------------------------------------------------------------------------------------------------------------------------------ TRANSIENT CLINICAL OBSERVATIONS: a TOTAL FREQUENCY {DAYS X PUPS)/LITTERS WITH OBSERVATIONS NOT NURSING N/N 0/0 1/1 0/0 0/0 13/1 EMACIATION N/N 0/0 0/0 0/0 0/0 13/1 DEHYDRATION N/N 0/0 4/1 2/2 0/0 13/1 WHOLE BODY, EXCLUDING HEAD, DISCOLORATION, PURPLE N/N 0/0 0/0 0/0 0/0 6/1 SCAB b N/N 0/0 0/0 0/0 6/1 3/1 COLD TO TOUCH N/N 0/0 2/2 0/0 0/0 1/1 LEFT EYE, PERIORBITAL DISCOLORATION, PURPLE N/N 0/0 0/0 0/0 8/1 0/0 RIGHT EYE, ENLARGED N/N 0/0 0/0 0/0 3/1 0/0 RIGHT HINDLIMB, LACERATION N/N 0/0 0/0 0/0 1/1 0/0 BACK, BRUISE N/N 2/1 4/1 0/0 0/0 0/0 NOT NESTING N/N 0/0 1/1 0/0 0/0 0/0 PALE IN APPEARANCE N/N 3/2 0/0 0/0 0/0 0/0 _~.. 00 I RIGHT EYE, CORNEAL OPACITY N/N 5/1 0/0 0/0 0/0 0/0 0 t-,.) 00 a. Tabulation restricted to adverse observations; all other pups appeared normal. ~ b. Right hindlimb or head. >n~I w ~ PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C26 (PAGE 1) : NECROPSY OBSERVATIONS - SUMMARY - Fl GENERATION PUPS MATERNAL DOSAGE GROUP I II III IV v MATERNAL DOSAGE (MG/KG/DAY) 0 0.3 1 3 10 LITTERS EXAMINED (N) 15 15 13 13 15 TOTAL PUPS STILLBORN, OR FOUND DEAD a,b N 6 5 2 4 3 STILLBORN N 0 0 1 2 2 FOUND DEAD N 6 5 1 2 1 NO MILK IN STOMACH c N(%) 2 ( 33. 3) 5(100.0) 0 ( 0.0) 1( 50.0) 0 ( 0.0) PUPS SACRIFICED AND NECROPSIED ON DAYS 5 AND 22 POSTPARTUM c LITTERS EVALUATED PUPS EVALUATED N 15 15 13 N 228 204 196 13 15 172 211 APPEARED NORMAL LITTER INCIDENCE PUP INCIDENCE N(%) 15(100.0) N(%) 228(100.0) 14( 93.3) 203( 99.5) 13(100.0) 196(100.0) 13(100.0) 172(100.0) 15(100.0) 211(100.0) KIDNEYS: RIGHT, PELVIS, MODERATE DILATION LITTER INCIDENCE PUP INCIDENCE N(%) N(%) 0 ( 0.0) 0 ( 0.0) 1 ( 6.7) 1 ( 0.5) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) a. Restricted to pups in which complete necropsies were performed. Complete necropsies were not performed on pups in which autolysis or cannibalization precluded evaluation. - b. Refer to the individual pup clinical observations table (Table C44) for external clinical observations confirmed at necropsy. c. Analysis restricted to pups found dead and necropsied. ..J:::. 00 I 0 N 00 &;~ tT.I Cl I ..J:::. ..J:::. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C27 (PAGE 1) : PUP LIVER WEIGHTS - SUMMARY - Fl GENERATION PUPS DOSAGE GROUP DOSAGE (MG/KG/DAY) LITTERS EXAMINED TERMINAL BODY WEIGHT WEIGHT/LITTER MALE PUPS FEMALE PUPS N MEAN+S.D. MEAN.S.D. MEAN.S.D. I 0 10 37.42 + 4.53 38.17 . 4.72 36.67 + 4.44 II 0.3 10 40.00 + 8.08 41.57 . 8.53 38.35 . 7.94 III 1 10 38.56 + 4.78 40.27 . 4.60 36.86 . 5.30 IV 3 10 40.11 + 8.35 41. 04 + 8 .18 39.22 . 8.57 v 10 10 34.70 . 8.26 35.33 + 8.27 34.07 . 8.30 LIVER WEIGHT/LITTER MALE PUPS FEMALE PUPS MEAN.S.D. MEAN+S.D. MEAN+S.D. 1. 54 . 0. 24 1.48 . 0.26 1.59 + 0.24 1.65 + 0.41 1. 64 . 0. 43 1.65 . 0.40 1.60 . 0.28 1.62 + 0.31 1.58 . 0.31 1.70 . 0.38 1.65 . 0.40 1.75 . 0.39 1.40 + 0.40 1.37 + 0.40 1.44 + 0.40 RATIOS (%) OF LIVER TO TERMINAL BODY WEIGHT WEIGHT/LITTER MEAN.S.D. 4.10 . 0.24 4.10 . 0.28 4.14 + 0.33 4.23 . 0 .37 3.98 + 0.34 MALE PUPS MEAN.S.D. 3.86 + 0.27 3.91 0.33 4.02 + 0.44 4.01 . 0.47 3.79 . 0.37 FEMALE PUPS MEAN+S.D. 4.33 . 0.24 4.28 . 0.26 4.26 + 0.34 4.46 . 0.35 4.17 + 0.36 ------------------------------------------------------------------------------------------------------------------------------------ ~ RATIOS (%) = (LIVER WEIGHT/TERMINAL BODY WEIGHT) X 100. 0""'"0"" ALL WEIGHTS WERE RECORDED IN GRAMS (G) . I 0 tv 00 ~ > ~ ("') I ~ Vl PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C28 (PAGE 1) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP I 0 MG/KG/DAY RAT # DESCRIPTION 19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075 DG( 9 ) DG( 9- 21) DL( 1- 2) DL( 9- 13) DL( 9- 22) DL( 9- 13) DL( 14- 22) DL( 22 ) DL( 7- 22) NO ADVERSE FINDINGS BACK: ULCERATION (1.5 CM X 1.0 CM) BACK: SCAB (DID NOT EXCEED 2.0 CM X 1.0 CM) BACK: SCAB (2.0 CM X 1.0 CM) BACK: SCAB (2.0 CM X 0.5 CM) LOCALIZED ALOPECIA: LIMBS a NO ADVERSE FINDINGS HEAD: SCAB (0.2 CM IN DIAMETER) LOCALIZED ALOPECIA: HEAD a HEAD: SCAB (0.2 CM X 0 .4 CM)b NO ADVERSE FINDINGS LOCALIZED ALOPECIA: LIMBS a NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS DS = DAY OF STUDY DG = DAY OF PRESUMED GESTATION a. Observation confirmed at necropsy. b. First observed at necropsy. DL = DAY OF LACTATION ..J::.. ~ 00 I 0 N 00 ~ ~ tT1 (1 I ..J::.. 0-.. PROTOCOL 418-028: ORAL (GAVAGE} COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1} TABLE C28 (PAGE 2} : CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP II 0. 3 MG/KG/DAY RAT # DESCRIPTION 19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071 DL ( 5- 21} DL ( 3- 22} DL ( 17- 22} NO ADVERSE FINDINGS NO ADVERSE FINDINGS HEAD: SCAB (0.3 CM NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: TAIL: SCAB (3.0 CM NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS X 1.0 CM} LIMBS a X 0.8 CM}a DS = DAY OF STUDY DG = DAY OF PRESUMED GESTATION a. Observation confirmed at necropsy. DL = DAY OF LACTATION -~ 00 I 0 tv 00 ~ n~>I ~ .......J PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C28 (PAGE 3): CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP III 1 MG/KG/DAY RAT # DESCRIPTION 19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064 DL ( 17- 22) DG ( 20- 21) DL( 1- 22) DL( 22 ) NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: LOCALIZED ALOPECIA: LOCALIZED ALOPECIA: NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS HEAD a LIMBS LIMBS a HEAD b DS = DAY OF STUDY DG = DAY OF PRESUMED GESTATION a. Observation confirmed at necropsy. b. First observed at necropsy. DL = DAY OF LACTATION _~.. 00 I 0 tv 00 > ~ ~() I ~ 00 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C28 (PAGE 4): CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP IV 3 MG/KG/DAY RAT # DESCRIPTION 19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073 DL ( 19- 22) DG( 14 ) DG ( 18- 21) DL( 1- 22) DS( 11- 14) DG( 0- 25) DL ( 17- 22) DL ( 17- 22) LOCALIZED ALOPECIA: NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NOSE: SWOLLEN LOCALIZED ALOPECIA: LOCALIZED ALOPECIA: LOCALIZED ALOPECIA: LOCALIZED ALOPECIA: NO ADVERSE FINDINGS LOCALIZED ALOPECIA: NO ADVERSE FINDINGS TIP OF TAIL MISSING NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS BACK a LIMBS LIMBS a LIMBS LIMBS a LIMBS a a DS = DAY OF STUDY DG = DAY OF PRESUMED GESTATION a. Observation confirmed at necropsy. DL = DAY OF LACTATION .~ ,_... 00 I ~ 0 N 00 ~ (') I ~ "' PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C28 (PAGE 5) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP V 10 MG/KG/DAY RAT # DESCRIPTION 19001 NO ADVERSE FINDINGS 19006 NO ADVERSE FINDINGS 19011 NO ADVERSE FINDINGS 19020 DS( 6- 12) BROWN PERIORAL SUBSTANCE DS( 6- 12) RALES DS ( 10- 12) URINE-STAINED ABDOMINAL FUR DS( 11 ) COLD TO TOUCH DS ( 11- 12) MI OS I S DS ( 11- 12) ABDOMINAL DISTENTION DS ( 11- 12) EMACIATION DS ( 11- 17) LOCALIZED ALOPECIA: HEAD DG( 0- 6) LOCALIZED ALOPECIA: HEAD DG( 7- 20) LOCALIZED ALOPECIA: LIMBS DL( 2- 22) LOCALIZED ALOPECIA: LIMBS a DL( 7- 22) ABDOMINAL DISTENTION a DL ( 14- 15) EMACIATION DL ( 14- 22) RALES DL( 17 ) DEHYDRATION DL ( 18- 22) EMACIATION a 19022 NO ADVERSE FINDINGS 19025 NO ADVERSE FINDINGS 19027 NO ADVERSE FINDINGS 19028 NO ADVERSE FINDINGS 19030 DL ( 17- 22) HEAD: SCAB (0.3 CM X 0.3 CM)a DL ( 17- 22) LOCALIZED ALOPECIA: HEAD a 19031 NO ADVERSE FINDINGS 19032 NO ADVERSE FINDINGS ..J:::. ~ 19033 NO ADVERSE FINDINGS 00 I 19049 NO ADVERSE FINDINGS 0 19059 NO ADVERSE FINDINGS tv 00 19070 NO ADVERSE FINDINGS ;>,:, DS = DAY OF STUDY DG = DAY OF PRESUMED GESTATION a. Observation confirmed at necropsy. DL = DAY OF LACTATION n ~ I Vl 0 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C29 (PAGE 1) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) RAT NUMBER DAY OF PREGNANCY DOSES NECROPSY STATUS ADMINISTERED OBSERVATIONS a I 0 19010 DL 22 p 70 ALL TISSUES APPEARED NORMAL. 19012 DL 22 p 58 ALL TISSUES APPEARED NORMAL. 19019 DL 22 p 59 ALL TISSUES APPEARED NORMAL. 19021 DL 22 p 58 ALL TISSUES APPEARED NORMAL. 19023 DL 22 p 60 ALL TISSUES APPEARED NORMAL. 19041 DL 22 p 59 ALL TISSUES APPEARED NORMAL. 19042 DL 22 p 58 ALL TISSUES APPEARED NORMAL. 19044 DL 22 p 56 ALL TISSUES APPEARED NORMAL. 19050 DL 22 p 60 ALL TISSUES APPEARED NORMAL. 19053 DL 22 p 59 ALL TISSUES APPEARED NORMAL. 19065 DL 22 p 58 ALL TISSUES APPEARED NORMAL. 19068 DL 22 p 57 ALL TISSUES APPEARED NORMAL. 19072 DL 22 p 58 ALL TISSUES APPEARED NORMAL. 19074 DL 22 p 59 ALL TISSUES APPEARED NORMAL. 19075 DL 22 p 59 ALL TISSUES APPEARED NORMAL. II 0.3 19004 DL 22 p 59 ALL TISSUES APPEARED NORMAL. 19009 DL 22 p 57 ALL TISSUES APPEARED NORMAL. 19016 DL 22 p 57 ALL TISSUES APPEARED NORMAL. 19018 DL 22 p 57 ALL TISSUES APPEARED NORMAL. 19026 DL 22 p 60 ALL TISSUES APPEARED NORMAL. 19036 DL 22 p 57 ALL TISSUES APPEARED NORMAL. 19037 DL 22 p 58 ALL TISSUES APPEARED NORMAL. 19043 DL 22 p 57 ALL TISSUES APPEARED NORMAL. 19047 DL 22 p 57 ALL TISSUES APPEARED NORMAL. 19048 DL 22 p 60 ALL TISSUES APPEARED NORMAL. .J::.. >--' 19052 DL 22 p 56 ALL TISSUES APPEARED NORMAL. 00 19055 DL 22 p 57 ALL TISSUES APPEARED NORMAL. I s 19061 DL 22 p 56 ALL TISSUES APPEARED NORMAL. 00 19067 DL 22 p 58 ALL TISSUES APPEARED NORMAL. ;.t; 19071 DL 22 p 57 ALL TISSUES APPEARED NORMAL. > DG = DAY OF PRESUMED GESTATION DL = DAY OF LACTATION ~ P = PREGNANT NP = NOT PREGNANT n a. Refer to the individual clinical observations table (Table C27) for external observations confirmed at necropsy. I Vl ~ PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C29 (PAGE 2): NECROPSY OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP RAT DAY OF PREGNANCY DOSES DOSAGE (MG/KG/DAY) NUMBER NECROPSY STATUS ADMINISTERED OBSERVATIONS a -----------------------------------------------------------------------------------------------------------------------------------III 1 19003 DL 22 p 58 ALL TISSUES APPEARED NORMAL. 19007 DL 22 p 59 KIDNEYS: RIGHT, CORTEX ADHERED TO RIGHT LATERAL LIVER LOBE. ALL OTHER TISSUES APPEARED NORMAL. 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064 DL 22 p DL 22 p DG 25 NP DL 22 p DL 22 p DL 22 p DL 22 p DL 22 p DG 25 NP DL 22 p DL 22 p DL 22 p DL 22 p 59 ALL TISSUES APPEARED NORMAL. 58 ALL TISSUES APPEARED NORMAL. 39 ALL TISSUES APPEARED NORMAL. 59 ALL TISSUES APPEARED NORMAL. 57 ALL TISSUES APPEARED NORMAL. 59 ALL TISSUES APPEARED NORMAL. 58 ALL TISSUES APPEARED NORMAL. 58 ALL TISSUES APPEARED NORMAL. 39 ALL TISSUES APPEARED NORMAL. 59 ALL TISSUES APPEARED NORMAL. 59 ALL TISSUES APPEARED NORMAL. 57 ALL TISSUES APPEARED NORMAL. 60 ALL TISSUES APPEARED NORMAL. DG = DAY OF PRESUMED GESTATION P = PREGNANT NP = NOT PREGNANT DL = DAY OF LACTATION a. Refer to the individual clinical observations table (Table C27) for external observations confirmed at necropsy. ~ ~ 00 I 0 1:-.J 00 > ~ ~CJ I VI 1:-.J PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C29 (PAGE 3): NECROPSY OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) RAT NUMBER DAY OF PREGNANCY DOSES NECROPSY STATUS ADMINISTERED OBSERVATIONS a IV 3 19002 DL 22 p 69 ALL TISSUES APPEARED NORMAL. 19005 DL 22 p 59 ALL TISSUES APPEARED NORMAL. 19035 DL 22 p 59 ALL TISSUES APPEARED NORMAL. 19039 DL 22 p 57 ALL TISSUES APPEARED NORMAL. 19040 DL 22 p 58 ALL TISSUES APPEARED NORMAL. 19045 DL 22 p 57 ALL TISSUES APPEARED NORMAL. 19046 DG 25 NP 39 ALL TISSUES APPEARED NORMAL. 19051 DG 25 NP 52 OVARIES: LEFT, SMALL (0.003 G). ALL OTHER TISSUES APPEARED NORMAL. 19054 19058 19062 DL 22 p DL 22 p DL 22 p 59 ALL TISSUES APPEARED NORMAL. 57 ALL TISSUES APPEARED NORMAL. 59 ALL TISSUES APPEARED NORMAL. 19063 DL 22 p 58 SPLEEN: OMENTUM ADHERED TO THE LENGTH OF THE OUTER CAPSULE. ALL OTHER TISSUES APPEARED NORMAL. 19066 19069 19073 DL 22 P DL 22 P DL 22 P 59 ALL TISSUES APPEARED NORMAL. 58 ALL TISSUES APPEARED NORMAL. 57 ALL TISSUES APPEARED NORMAL. DG = DAY OF PRESUMED GESTATION DL = DAY OF LACTATION P = PREGNANT NP = NOT PREGNANT a. Refer to the individual clinical observations table (Table C27) for external observations confirmed at necropsy. _f;::.. 1--4 00 I ~ 0 N 00 ~ tT.l (1 I Ul (.>.) PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C29 (PAGE 4) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP RAT DAY OF PREGNANCY DOSES DOSAGE (MG/KG/DAY) NUMBER NECROPSY STATUS ADMINISTERED OBSERVATIONS a ------------------------------------------------------------------------------------------------------------------------------------ v 10 19001 DL 22 p 57 ALL TISSUES APPEARED NORMAL. 19006 DL 22 p 58 ALL TISSUES APPEARED NORMAL. 19011 DL 22 p 59 ALL TISSUES APPEARED NORMAL. 19020 DL 22 p 59 LARGE AND SMALL INTESTINES: DISTENDED WITH GAS. THYMUS: SMALL. SPLEEN: SMALL. ADRENALS: BILATERAL, LARGE. STOMACH: FUNDIC MUCOSAL SURFACE CONTAINED APPROXIMATELY 12 BLACK AREAS (PINPOINT TO 0.3 CM IN DIAMETER). ALL OTHER TISSUES APPEARED NORMAL. 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070 DL 22 p DL 22 p DL 22 p DL 22 p DL 22 p DL 22 p DL 22 p DL 22 p DL 22 p DL 22 p DL 22 p 60 ALL TISSUES APPEARED NORMAL. 59 ALL TISSUES APPEARED NORMAL. 59 ALL TISSUES APPEARED NORMAL. 57 ALL TISSUES APPEARED NORMAL. 60 ALL TISSUES APPEARED NORMAL. 56 ALL TISSUES APPEARED NORMAL. 59 ALL TISSUES APPEARED NORMAL. 56 ALL TISSUES APPEARED NORMAL. 57 ALL TISSUES APPEARED NORMAL. 56 ALL TISSUES APPEARED NORMAL. 57 ALL TISSUES APPEARED NORMAL. DG = DAY OF PRESUMED GESTATION DL = DAY OF LACTATION P = PREGNANT NP = NOT PREGNANT .,i::.. a. Refer to the individual clinical observations table (Table C27) for external observations confirmed at necropsy. ....... 00 I 0 tv 00 ~ > ~ n I VI .,i::.. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C30 (PAGE 1) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP I 0 MG/KG/DAY RAT TERMINAL BODY NUMBER WEIGHT 19012 p 19019 p 19021 p 19023 p 19041 p 19042 p 19044 p 190SO p 190S3 p 1906S p 33S. 309. 270. 280. 30S. 302. 360. 290. 299. 301. BRAIN ABS. WT. REL. % TBW 2.22 2.22 2.21 2 .11 2.09 2.2S 2.17 2 .11 2.2S 2.00 0.66 0. 72 0.82 0.7S 0.68 0.74 0.60 0.73 0.7S 0.66 LIVER ABS. WT. REL. % TBW 16.17 lS.21 14.21 13 .09 12.lS 14 .31 19.73 12.84 13 .17 12.97 4.83 4 .92 S.26 4.68 3.98 4.74 S.48 4.43 4.40 4.31 KIDNEY LEFT ABS. REL. WT. % TBW 1. S3 1.43 1. so 1.23 1.24 1. 60 1. Sl 1.32 1.26 1. 30 0.46 0.46 O.S6 0.44 0 .41 O.S3 0.42 0.46 0.42 0.43 KIDNEY RIGHT ABS. REL. WT. % TBW 1. 66 1.46 1. SS 1.39 1. 3S 1. S7 1. 60 1.41 1.34 1.33 o.so 0.47 O.S7 o.so 0.44 O.S2 0.44 0.49 0 .4S 0.44 ADRENAL LEFT ABS. REL. WT. % TBW a o.oso o.oss 0.04S O.OS4 0.048 O.OS6 0.076 0.048 0.049 0.042 14.92 17.80 16.67 19.28 lS.74 18.S4 21.11 16.SS 16.39 13.9S ADRENAL RIGHT ABS. REL. WT. % TBW a 0.047 0.047 0.040 0.028 0.044 0.046 O.OS3 0.036 0.043 0.044 14.03 lS. 21 14. 81 10.00 14.43 lS.23 14. 72 12 .41 14. 38 14. 62 RAT TERMINAL BODY NUMBER WEIGHT SPLEEN ABS. WT. REL. % TBW THYMUS ABS. WT. REL. % TBW OVARY LEFT ABS. REL. WT. % TBW a OVARY RIGHT ABS. REL. WT. % TBW a UTERUS WITH CERVIX ABS. REL. WT. % TBW HEART ABS. WT. REL. % TBW 19010 p 299. 0.03S 11. 70 0.042 14.0S 0.48 0.16 19012 p 19019 p 33S. 309. 0.78 0.64 0.23 0.21 0.23 0.31 0.07 0.10 0.092 0.044 27.46 14.24 0.073 0.064 21. 79 20. 71 O.S7 O.Sl 0.17 0.16 1.32 1. SS 0.39 o.so 19021 p 270. O.S8 0 .21 0.11 0.04 0.044 16.30 0.040 14.81 O.S3 0.20 1.31 0.48 19023 p 280. O.S8 0 .21 0.16 0.06 0.039 13. 93 0.062 22.14 0.62 0.22 1. 62 O.S8 19041 p 30S. O.S4 0.18 0.16 o.os 0.062 20.33 0.037 12 .13 0.46 O.lS 1.3S 0.44 ~ 19042 p 302. 0.64 0.21 0.33 0.11 O.OS9 19.S4 O.OS7 18.87 0.68 0.22 1.64 O.S4 ....... 19044 p 360. 0.67 0.19 0.27 0.08 0.070 19.44 0.081 22.SO O.S6 0.16 1.4S 0.40 00 I 190SO p 290. 0.74 0 .26 0.20 0.07 0.044 lS.17 0. 048 16.SS O.S6 0.19 1.19 0 .41 0 190S3 p 299. 0.61 0.20 0.17 0.06 O.OS8 19.40 0.08S 28.43 0.47 0.16 1.41 0.47 l'-.J 00 1906S p 301. O.S4 0.18 0.17 0.06 0.068 22.S9 0.066 21. 93 0.69 0.23 1.13 0.38 ;.t; 19068 p 360. 0.048 13 .33 0.07S 20.83 o.ss O.lS > 19072 p 292. O.OSl 17.46 0.060 20.SS 0.36 0.12 ~ 19074 p 297. O.OS7 19.19 0.073 24.S8 O.S3 0.18 1907S p 29S. O.OS9 20.00 0.073 24.74 0.44 O.lS (j I ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. Vl Vl P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) a. Value was multiplied by 1000. PROTOCOL 418-028: ORAL {GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C30 (PAGE 2) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP II 0. 3 MG/KG/DAY RAT TERMINAL BODY NUMBER WEIGHT BRAIN ABS. WT. REL. % TBW LIVER ABS. WT. REL. % TBW KIDNEY LEFT ABS. REL. WT. % TBW KIDNEY RIGHT ABS. REL. WT. % TBW ADRENAL LEFT ABS. REL. WT. % TBW a ADRENAL RIGHT ABS. REL. WT. % TBW a 19004 p 19009 p 19016 p 19018 p 19026 p 19036 p 19037 p 19043 p 19047 p 19048 p 276. 346. 314. 338. 296. 359. 309. 356. 325. 306. 1. 99 2 .11 2.17 2.04 2.12 2 .13 2.09 2.23 2.00 2.24 0.72 0.61 0.69 0.60 0. 72 0.59 0.68 0.63 0.62 0.73 11. 23 16.15 18.06 19.18 15.44 16.63 18.25 18.19 14.85 11.85 4.07 4.67 5.75 5.67 5.22 4.63 5.91 5.11 4.57 3.87 1.34 1.38 1.41 1.41 1. 65 1.45 1.43 1. 77 1. 35 1. 55 0.48 0.40 0.45 0.42 0.56 0.40 0.46 0.50 0.42 0.51 1.40 1.37 1.43 1.42 1. 70 1.54 1. 53 1. 87 1.47 1.42 0.51 0.40 0.46 0.42 0.57 0.43 0.50 0.52 0.45 0.46 0.043 0.038 0.059 0.052 0.054 0.042 0.056 0.065 0.044 0.055 15.58 10.98 18.79 15.38 18.24 11. 70 18.12 18.26 13 .54 17.97 0.049 0.033 0.048 0.041 0.045 0.044 0.047 0.053 0.027 0.024 17.75 9.54 15.29 12.13 15.20 12.26 15.21 14.89 8.31 7.84 RAT TERMINAL BODY NUMBER WEIGHT SPLEEN ABS. WT. REL. % TBW THYMUS ABS. WT. REL. % TBW OVARY LEFT ABS. REL. WT. % TBW a OVARY RIGHT ABS. REL. WT. % TBW a UTERUS WITH CERVIX ABS. REL. WT. % TBW HEART ABS. WT. REL. % TBW 19004 p 276. 0.60 0.22 0.24 0.09 0.083 30.07 0.071 25.72 0.65 0.24 1. 35 0.49 19009 p 346. 0.61 0.18 0.31 0.09 0.067 19.36 0.072 20.81 0.51 0.15 1. 51 0.44 19016 p 314. 0.53 0.17 0.16 0.05 0.063 20.06 0.081 25.80 0.70 0.22 1.23 0.39 19018 p 338. 0.74 0.22 0.21 0.06 0.064 18.93 0.068 20.12 0.64 0.19 1.16 0.34 19026 p 296. 0.70 0.24 0.18 0.06 0.048 16.22 0.075 25.34 0.73 0.25 1.35 0.46 19036 p 359. 0.74 0.21 0.28 0.08 0.077 21.45 0.095 26.46 0.58 0.16 1.20 0.33 19037 p 309. 0.74 0.24 0.21 0.07 0.062 20.06 0.046 14.89 0.45 0.14 1.15 0.37 ~ 19043 p 356. 0.77 0.22 0.10 0.03 0.052 14.61 0.056 15.73 0.63 0.18 1.31 0.37 0""""0"" I 19047 p 325. 0.55 0.17 0.21 0.06 0.057 17.54 0.059 18.15 0.55 0.17 1.05 0.32 0 19048 p 306. 0.55 0.18 0.19 0.06 0.024 7.84 0.026 8.50 0.56 0.18 1. 25 0.41 lV 00 19052 p 19055 p 320. 336. 0.093 29.06 0.055 17.19 0.45 0.14 ~ 0.032 9.52 0.052 15.48 0.28 0.08 > 19061 p 315. 0.038 12.06 0.025 7.94 0.53 0.17 19067 p 294. 0.061 20.75 0.059 20.07 0.50 0.17 ~ 19071 p 374. 0.026 6.95 0.058 15.51 0. 71 0.19 (') I ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. = ORGAN WEIGHT. REL. % TBW = {ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. Vl O'\ P = PREGNANT NP = NOT PREGNANT {VALUES EXCLUDED FROM AVERAGES) a. Value was multiplied by 1000. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C30 (PAGE 3): TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP III 1 MG/KG/DAY RAT TERMINAL BODY NUMBER WEIGHT BRAIN ABS. WT. REL. % TBW LIVER ABS. WT. REL. % TBW KIDNEY LEFT ABS. REL. WT. % TBW KIDNEY RIGHT ABS. REL. WT. % TBW ADRENAL LEFT ABS. REL. WT. % TBW a ADRENAL RIGHT ABS. REL. WT. % TBW a 19003 p 19007 p 19008 p 19013 p 19015 p 19017 p 19024 p 19029 p 19034 p 19056 p 284. 303. 292. 389. 274. 350. 309. 332. 287. 292. 2 .13 2.16 2.01 2.05 2.21 2.15 2.23 1. 98 2.10 2.02 0.75 0. 71 0.69 0.53 0.81 0.61 0. 72 0.60 0.73 0.69 12.51 13.07 12.76 19.40 12.50 16 .49 14. 95 19.93 12.83 12.62 4.40 4.31 4.37 4.99 4.56 4. 71 4.84 6.00 4.47 4.32 1. 31 1.62 1.24 1.44 1.14 1.45 1. 53 1. 28 1. 34 1.47 0.46 0.53 0.42 0.37 0.42 0 .41 0.50 0.38 0.47 0.50 1.37 1.66b 1. 31 1. 64 1.24 1.45 1.45 1.45 1.41 1. 50 0.48 0.55 0.45 0.42 0 .45 0 .41 0.47 0.44 0.49 0.51 0.054 0.067 0.045 0.050 0.066 0.039 0.053 0.049 0.051 0.040 19.01 22.11 15 .41 12.85 24.09 11.14 17.15 14.76 17.77 13.70 0.060 0.071 0.041 0.049 0.058 0.038 0.042 0.049 0.056 0.040 21.13 23.43 14.04 12.60 21.17 10.86 13.59 14.76 19.51 13.70 RAT TERMINAL BODY NUMBER WEIGHT SPLEEN ABS. WT. REL. % TBW THYMUS ABS. WT. REL. % TBW OVARY LEFT ABS. REL. WT. % TBW a OVARY RIGHT ABS. REL. WT. % TBW a UTERUS WITH CERVIX ABS. REL. WT. % TBW HEART ABS. WT. REL. % TBW 19003 p 284. 0.62 0.22 0.14 0.05 0.054 19.01 0.079 27.82 0.48 0.17 1.29 0.45 19007 p 303. 0.82 0.27 0.12 0.04 0.053 17.49 0.086 28.38 0.79 0.26 1. 30 0.43 19008 p 292. 0.49 0.17 0.17 0.06 0.050 17.12 0.055 18.84 0.53 0.18 1.17 0.40 19013 p 389. 0.65 0.17 0.22 0.06 0.068 17.48 0.080 20.56 0.58 0.15 1. 35 0.35 19015 p 274. 0.42 0.15 0.24 0.09 0.043 15.69 0.048 17.52 0.48 0.18 1.51 0.55 19017 p 350. 0.60 0.17 0 .13 0.04 0.053 15.14 0.048 13. 71 0.35 0.10 1.36 0.39 19024 p 309. 0.61 0.20 0.19 0.06 0.043 13.92 0.020 6.47 0.42 0.14 1.40 0.45 ~ 19029 p 332. 0.60 0.18 0.16 0.05 0.041 12.35 0.058 17.47 0.34 0.10 1.48 0.44 ~ ~ 19034 p 287. 0.54 0.19 0.18 0.06 0.062 21. 60 0.074 25.78 0.44 0.15 1.21 0.42 00 I 19056 p 292. 0.65 0.22 0.22 0.08 0.051 17.46 0.043 14.73 0.66 0.23 1.39 0.48 0 19057 p 287. 0.034 11. 85 0.041 14.28 0.35 0.12 N 00 19060 p 357. 0.089 24.93 0.092 25.77 0.61 0.17 ~ 19064 p 289. 0.051 17.65 0.051 17.65 0.44 0.15 ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. =ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. tT.I P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) Cl a. Value was multiplied by 1000. I b. Dam 19007 had the cortex of the right kidney adhered to the right lateral lobe of the liver . See the individual necropsy Ul -l observations table (Table C28) . PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C30 (PAGE 4) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP IV 3 MG/KG/DAY RAT TERMINAL BODY NUMBER WEIGHT BRAIN ABS. WT. REL. % TBW LIVER ABS. WT. REL. % TBW KIDNEY LEFT ABS. REL. WT. % TBW KIDNEY RIGHT ABS. REL. WT. % TBW ADRENAL LEFT ABS. REL. WT. % TBW a ADRENAL RIGHT ABS. REL. WT. % TBW a 19005 p 19035 p 19039 p 19040 p 19045 p 19054 p 19058 p 19062 p 19063 p 19066 p 285. 261. 315. 294. 385. 287. 350. 290. 369. 292. 1. 81 2.04 2.09 2.05 2.15 2.49 2.15 2.13 2.03 1. 91 0.64 0.78 0.66 0.70 0.56 0.87 0.61 0.73 0.55 0.65 13.80 12.06 16.01 13 .33 17. 71 11.54 19.11 13.59 21.27 12.70 4.84 4.62 5.08 4.53 4.60 4.02 5.46 4.69 5.76 4.35 1.16 1. 54 1.27 1. 54 1. 63 1. 65 1. 61 1. 58 1. 67 1.26 0 .41 0.59 0.40 0.52 0.42 0.57 0.46 0.54 0.45 0.43 1. 26 1. 56 1.40 1.48 1. 66 1.55 1. 57 1. 61 1. 69 1.47 0.44 0.60 0.44 0.50 0.43 0.54 0.45 0.56 0.46 0.50 0.044 0.064 0.055 0.052 0.063 0.041 0.064 0.046 0.067 0.031 15.44 24.52 17.46 17.69 16.36 14.28 18.28 15.86 18.16 10.62 0.046 0.055 0.055 0.051 0.042 0.038 0.049 0.046 0.059 0.045 16.14 21. 07 17.46 17.35 10.91 13.24 14 .00 15.86 15.99 15.41 RAT TERMINAL BODY NUMBER WEIGHT SPLEEN ABS. WT. REL. % TBW THYMUS ABS. WT. REL. % TBW OVARY LEFT ABS. REL. WT. % TBW a OVARY RIGHT ABS. REL. WT. % TBW a UTERUS WITH CERVIX ABS. REL. WT. % TBW HEART ABS. WT. REL. % TBW 19002 p 302. 0.058 19.20 0.052 17.22 0.46 0.15 19005 p 285. 0.54 0.19 0.14 0.05 0.049 17.19 0.056 19.65 0.80 0.28 1.16 0.41 19035 p 261. 0.66 0.25 0.16 0.06 0.051 19.54 0.055 21. 07 0. 71 0.27 1.45 0.56 19039 p 315. 0. 71 0.22 0.25 0.08 0.079 25.08 0.062 19.68 0.46 0.15 1.20 0.38 19040 p 294. 0.64 0.22 0.24 0.08 0.058 19.73 0.046 15.65 0.50 0.17 1. 55 0.53 19045 p 385. 0.61 0.16 0.13 0.03 0.046 11. 95 0.057 14.80 0.53 0.14 1.47 0.38 19054 p 287. 0.84 0.29 0.36 0.12 0.064 22.30 0.048 16.72 0.75 0.26 1.48 0.52 ~ 19058 p 350. 0.77 0.22 0.12 0.03 0.052 14.86 0.066 18.86 0.74 0.21 1.39 0.40 -t:::. 19062 p 290. 0.62 0.21 0.14 0.05 0.058 20.00 0.058 20.00 0.78 0.27 1.41 0.49 1--' 19063 p 369. 1.59b 0.43 0.09 0.02 0.049 13.28 0.057 15.45 0.56 0.15 1. 39 0.38 00 I 19066 p 292. 0.55 0.19 0.39 0.13 0.028 9.59 0.025 8.56 0.78 0.27 1.51 0.52 0 19069 p 362. 0.057 15.74 0.076 20.99 0.57 0.16 N 00 19073 p 363. 0.040 11. 02 0.046 12.67 0 .37 0.10 ~ ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. =ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) tr1 a. Value was multiplied by 1000. Cl b. Dam 19063 had omentum adhered to the entire length of the outer capsule of the spleen. See the individual necropsy I observations table (Table C28) . Ul 00 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C30 (PAGE 5) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP V 10 MG/KG/DAY RAT TERMINAL BODY NUMBER WEIGHT BRAIN ABS. WT. REL. % TBW LIVER ABS. WT. REL. % TBW KIDNEY LEFT ABS. REL. WT. % TBW KIDNEY RIGHT ABS. REL. WT. % TBW ADRENAL LEFT ABS. REL. WT. % TBW a ADRENAL RIGHT ABS. REL. WT. % TBW a 19001 p 19006 p 19011 p 19020 p 19022 p 19025 p 19027 p 19028 p 19030 p 19031 p 278. 304. 283. 210. 294. 291. 266. 339. 314. 361. 2.00 2.13 2.05 2.00 2.18 2 .13 2.27 2.02 2.18 2.24 0.72 0.70 0.72 0.95 0.74 0.73 0.85 0.60 0.69 0.62 12 .11 14.39 14.24 7.01 12.61 13. 99 12 .11 15.89 14.52 19.51 4.36 4.73 5.03 3.34 4.29 4.81 4.55 4.69 4.62 5.40 1. 36 1.44 1.41 1.14 1.45 1. 36 1. 38 1. 38 1.46 1. 52 0.49 0.47 0.50 0.54 0.49 0.47 0.52 0.41 0.46 0.42 1. 35 1.55 1. 36 1. 09 1. 63 1.40 1.35 1.41 1. 50 1.47 0.48 0.51 0.48 0.52 0.55 0.48 0.51 0.42 0.48 0.41 0.041 0.057 0.045 0.058b 0.064 0.061 0.053 0.044 0.062 0.042 14.75 18.75 15.90 27.62 21.77 20.96 19.92 12.98 19.74 11.63 0.031 0.055 0.045 0.056 0.041 0.055 0.047 0.041 0.046 0.038 11.15 18.09 15.90 26.67 13. 94 18.90 17.67 12.09 14.65 10.53 RAT TERMINAL BODY NUMBER WEIGHT SPLEEN ABS. WT. REL. % TBW THYMUS ABS. WT. REL. % TBW OVARY LEFT ABS. REL. WT. % TBW a OVARY RIGHT ABS. REL. WT. % TBW a UTERUS WITH CERVIX ABS. REL. WT. % TBW HEART ABS. WT. REL. % TBW 19001 p 278. 0.57 0.20 0.18 0.06 0.048 17.27 0.047 16.91 0.64 0.23 0.92 0.33 19006 p 304. 0.54 0.18 0.15 0.05 0.056 18.42 0.074 24.34 0.46 0.15 1. 57 0.52 19011 p 283. 0.50 0.18 0.15 0.05 0.046 16.25 0.036 12. 72 0.68 0.24 1.24 0.44 19020 p 210. 0.28b 0.13 O.llb 0.05 0.036 17.14 0.047 22.38 0.50 0.24 0.90 0.43 19022 p 294. 0.53 0.18 0.14 0.05 0.060 20.41 0.035 11.90 0.74 0.25 1. 54 0.52 19025 p 291. 0.56 0.19 0.25 0.08 0.053 18.21 0.058 19.93 0.53 0.18 1.38 0.47 ..p.. 19027 p 266. 0.61 0.23 0.23 0.09 0. 039 14 .66 0.018 6.77 0.44 0.16 1.32 0.50 ~ ~ 19028 p 339. 0.54 0.16 0.23 0.07 0.087 25.66 0.053 15.63 0.37 0.11 1. 56 0.46 00 I 19030 p 314. 0.58 0.18 0.17 0.05 0.045 14.33 0.048 15.29 0.78 0.25 1.37 0 .44 0 19031 p 361. 0.64 0.18 0.16 0.04 0.076 21. 05 0.087 24.10 0.74 0.20 1. 50 0.42 N 00 19032 p 19033 p 287. 328. 00..006391 1210..8004 00..004736 1243..1978 00..3832 00..2151 ~ 19049 p 330. 0.050 15.15 0.073 22.12 0.50 0.15 19059 p 19070 p 317. 351. 0.061 19.24 0.063 19.87 0.39 0.12 t'I1 0.051 14.53 0.045 12.82 0.47 0 .13 (") I ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. =ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. U'l \0 P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) a. Value was multiplied by 1000. b. Dam 19020 had a large left adrenal, small spleen, and small thymus. See the individual necropsy observations table (Table C28) . PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C31 (PAGE 1) : ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP I 0 MG/KG/DAY RAT NUMBER BRAIN WEIGHT LIVER ABS. WT. REL. % BRW KIDNEY LEFT ABS. REL. WT. % BRW KIDNEY RIGHT ABS. REL. WT. % BRW ADRENAL LEFT ABS. REL. WT. % BRW ADRENAL RIGHT ABS. REL. WT. % BRW SPLEEN ABS. WT. REL. % BRW 19012 p 19019 p 19021 p 19023 p 19041 p 19042 p 19044 p 19050 p 19053 p 19065 p 2.22 2.22 2.21 2 .11 2.09 2.25 2.17 2 .11 2.25 2.00 16.17 15.21 14.21 13.09 12.15 14. 31 19.73 12.84 13.17 12.97 728.38 685.14 642.99 620.38 581. 34 636.00 909.22 608.53 585.33 648.50 1. 53 1.43 1. so 1. 23 1.24 1. 60 1. 51 1.32 1.26 1.30 68.92 64.41 67.87 58.29 59.33 71.11 69.58 62.56 56.00 65.00 1. 66 1.46 1. 55 1. 39 1.35 1. 57 1. 60 1.41 1.34 1.33 74.77 65.76 70.14 65.88 64.59 69.78 73.73 66.82 59.56 66.50 0.050 0.055 0.045 0.054 0.048 0.056 0.076 0.048 0.049 0.042 2.25 2.48 2.04 2.56 2.30 2.49 3.50 2.27 2.18 2.10 0.047 0.047 0.040 0.028 0.044 0.046 0.053 0.036 0.043 0.044 2.12 2.12 1. 81 1. 33 2.10 2.04 2.44 1. 71 1. 91 2.20 0.78 0.64 0.58 0.58 0.54 0.64 0.67 0.74 0.61 0.54 35.14 28.83 26.24 27.49 25.84 28.44 30.88 35.07 27.11 27.00 RAT NUMBER BRAIN WEIGHT THYMUS ABS. WT. REL. % BRW OVARY LEFT ABS. REL. WT. % BRW OVARY RIGHT ABS. REL. WT. % BRW UTERUS WITH CERVIX ABS. REL. WT. % BRW HEART ABS. WT. REL. % BRW 19012 p 2.22 0.23 10.36 0.092 4.14 0.073 3.29 0.57 25.68 1.32 59.46 19019 p 2.22 0.31 13.96 0.044 1. 98 0. 064 2.88 0.51 22.97 1. 55 69.82 19021 p 2.21 0.11 4.98 0.044 1. 99 0.040 1. 81 0.53 23.98 1.31 59.28 19023 p 2 .11 0.16 7.58 0.039 1. 85 0.062 2.94 0.62 29.38 1. 62 76.78 19041 p 2.09 0.16 7.66 0.062 2.97 0.037 1. 77 0.46 22.01 1.35 64.59 19042 p 2.25 0.33 14.67 0.059 2.62 0.057 2.53 0.68 30.22 1. 64 72.89 ...... 19044 p 2.17 0.27 12.44 0.070 3.22 0.081 3.73 0.56 25.81 1.45 66.82 19050 p 2 .11 0.20 9.48 0.044 2.08 0.048 2.27 0.56 26.54 1.19 56.40 ~ 19053 p 2.25 0.17 7.56 0.058 2.58 0.085 3.78 0.47 20.89 1.41 62.67 00 I 19065 p 2.00 0.17 8.50 0.068 3.40 0.066 3.30 0.69 34.50 1.13 56.50 0 tv ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. 00 ~ P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) >~(') I O"\ 0 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C31 (PAGE 2) : ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP II 0. 3 MG/KG/DAY RAT NUMBER BRAIN WEIGHT LIVER ABS. WT. REL. % BRW KIDNEY LEFT ABS. REL. WT. % BRW KIDNEY RIGHT ABS. REL. WT. % BRW ADRENAL LEFT ABS. REL. WT. % BRW ADRENAL RIGHT ABS. REL. WT. % BRW SPLEEN ABS. WT. REL. % BRW 19004 p 19009 p 19016 p 19018 p 19026 p 19036 p 19037 p 19043 p 19047 p 19048 p 1. 99 2.11 2.17 2.04 2.12 2.13 2.09 2.23 2.00 2.24 11. 23 16.lS 18 .06 19.18 lS.44 16.63 18.2S 18.19 14.8S 11.8S S64.32 76S.40 832.26 940.20 728. 30 780.7S 873.20 81S.70 742.SO S29.02 1. 34 1. 38 1.41 1.41 1. 6S 1.4S 1.43 1. 77 1.3S 1. SS 67.34 6S.40 64.98 69.12 77.83 68.08 68.42 79.37 67.SO 69.20 1.40 1. 37 1.43 1.42 1. 70 1. S4 1. S3 1. 87 1.47 1.42 70.3S 64. 93 6S.90 69.61 80.19 72.30 73.20 83.86 73.SO 63.39 0.043 0.038 O.OS9 O.OS2 O.OS4 0.042 O.OS6 0.06S 0.044 o.oss 2.16 1. 80 2. 72 2.SS 2.SS 1. 97 2.68 2.91 2.20 2.46 0.049 0.033 0.048 0. 041 0.04S 0.044 0.047 O.OS3 0.027 0.024 2.46 1. S6 2.21 2.01 2.12 2.06 2.2S 2.38 1.3S 1. 07 0.60 0.61 O.S3 0.74 0.70 0.74 0.74 0.77 o.ss o.ss 30.lS 28.91 24.42 36.27 33.02 34.74 3S.41 34.S3 27.SO 24.SS RAT NUMBER BRAIN WEIGHT THYMUS ABS. WT. REL. % BRW OVARY LEFT ABS. REL. WT. % BRW OVARY RIGHT ABS. REL. WT. % BRW UTERUS WITH CERVIX ABS. REL. WT. % BRW HEART ABS. WT. REL. % BRW 19004 p 1. 99 0.24 12.06 0.083 4.17 0 .071 3.S7 0.6S 32.66 1.3S 67.84 19009 p 2.11 0.31 14.69 0.067 3.18 0. 072 3.41 O.Sl 24.17 1.Sl 71. S6 19016 p 2.17 0.16 7 .37 0.063 2.90 0.081 3.73 0.70 32.26 1.23 S6.68 19018 p 2.04 0.21 10.29 0.064 3.14 0.068 3.33 0.64 31. 37 1.16 S6.86 19026 p 2.12 0.18 8 .49 0.048 2.26 0.07S 3.S4 0.73 34.43 1.3S 63.68 19036 p 2.13 0.28 13.14 0.077 3.62 0.09S 4.46 O.S8 27.23 1. 20 S6.34 19037 p 2.09 0.21 10.0S 0.062 2.97 0.046 2.20 0 .4S 21. S3 1. lS SS.02 .p.. 19043 p 2.23 0.10 4.48 O.OS2 2.33 O.OS6 2.Sl 0.63 28.2S 1.31 S8.74 ........ 19047 p 2.00 0.21 10.SO O.OS7 2.8S O.OS9 2.9S o.ss 27.SO 1. OS S2.SO 00 I 19048 p 2.24 0.19 8.48 0.024 1. 07 0.026 1.16 O.S6 2S.OO 1.2S SS.80 0 t-..J ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. 00 ~ P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) n>~I .O.....'.\. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C31 (PAGE 3) : ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP III 1 MG/KG/DAY RAT NUMBER BRAIN WEIGHT LIVER ABS. WT. REL. % BRW KIDNEY LEFT ABS. REL. WT. % BRW KIDNEY RIGHT ABS. REL. WT. % BRW ADRENAL LEFT ABS. REL. WT. % BRW ADRENAL RIGHT ABS. REL. WT. % BRW SPLEEN ABS. WT. REL. % BRW 19003 p 19007 p 19008 p 19013 p 19015 p 19017 p 19024 p 19029 p 19034 p 19056 p 2 .13 2.16 2.01 2.05 2.21 2.15 2.23 1. 98 2.10 2.02 12.51 13.07 12.76 19.40 12.50 16.49 14.95 19.93 12.83 12.62 587.32 605.09 634.82 946.34 565.61 766.98 670.40 1006.56 610.95 624.75 1.31 1. 62 1. 24 1.44 1.14 1.45 1. 53 1.28 1.34 1.47 61. 50 75.00 61. 69 70.24 51. 58 67.44 68.61 64.65 63.81 72.77 1. 37 1. 66a 1.31 1. 64 1.24 1.45 1.45 1.45 1.41 1.50 64.32 76.85 65.17 80.00 56 .11 67.44 65.02 73.23 67.14 74.26 0.054 0.067 0.045 0.050 0.066 0.039 0.053 0.049 0.051 0.040 2.54 3.10 2.24 2.44 2.99 1. 81 2.38 2.47 2.43 1. 98 0.060 0 .071 0.041 0.049 0.058 0.038 0.042 0.049 0.056 0.040 2.82 3.29 2.04 2.39 2.62 1. 77 1. 88 2.47 2.67 1. 98 0.62 0.82 0 .49 0.65 0.42 0.60 0.61 0.60 0.54 0.65 29.11 37. 96 24.38 31. 71 19.00 27.91 27.35 30.30 25. 71 32.18 RAT NUMBER BRAIN WEIGHT THYMUS ABS. WT. REL. % BRW OVARY LEFT ABS. REL. WT. % BRW OVARY RIGHT ABS. REL. WT. % BRW UTERUS WITH CERVIX ABS. REL. WT. % BRW HEART ABS. WT. REL. % BRW 19003 p 2.13 0.14 6.57 0.054 2.54 0.079 3. 71 0.48 22.54 1.29 60.56 19007 p 2.16 0.12 5.56 0.053 2.45 0.086 3.98 0.79 36.57 1.30 60.18 19008 p 2.01 0.17 8.46 0.050 2.49 0.055 2.74 0.53 26.37 1.17 58.21 19013 p 2.05 0.22 10.73 0.068 3.32 0.080 3.90 0.58 28.29 1.35 65.85 19015 p 2.21 0.24 10.86 0.043 1. 94 0.048 2.17 0.48 21. 72 1. 51 68.32 19017 p 2.15 0.13 6.05 0.053 2.46 0.048 2.23 0.35 16.28 1.36 63.26 19024 p 2.23 0.19 8.52 0.043 1. 93 0.020 0.90 0.42 18.83 1.40 62.78 ..s;:::.. 19029 p 1. 98 0.16 8.08 0.041 2.07 0.058 2.93 0.34 17.17 1.48 74.75 ~ 19034 p 2.10 0.18 8.57 0.062 2.95 0.074 3.52 0.44 20.95 1.21 57.62 00 I 19056 p 2.02 0.22 10.89 0.051 2.52 0.043 2.13 0.66 32.67 1.39 68.81 0 N 00 ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. ~ P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) a. Dam 19007 had the cortex of the right kidney adhered to the right lateral lobe of the liver . See the individual necropsy ~ observations table (Table C28). tT.l n I "N PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C31 (PAGE 4) : ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP IV 3 MG/KG/DAY RAT NUMBER BRAIN WEIGHT LIVER ABS. WT. REL. % BRW KIDNEY LEFT ABS. REL. WT. % BRW KIDNEY RIGHT ABS. REL. WT. % BRW ADRENAL LEFT ABS. REL. WT. % BRW ADRENAL RIGHT ABS. REL. WT. % BRW SPLEEN ABS. WT. REL. % BRW 19005 p 19035 p 19039 p 19040 p 19045 p 19054 p 19058 p 19062 p 19063 p 19066 p 1. 81 2.04 2.09 2.05 2.15 2.49 2.15 2 .13 2.03 1.91 13.80 12.06 16.01 13.33 17.71 11.54 19.11 13.59 21.27 12.70 762.43 591.18 766.03 650.24 823.72 463.45 888.84 638.03 1047.78 664.92 1.16 1. 54 1.27 1. 54 1. 63 1. 65 1. 61 1. 58 1. 67 1.26 64.09 75.49 60.76 75.12 75.81 66.26 74.88 74.18 82.27 65.97 1.26 1. 56 1.40 1.48 1. 66 1. 55 1. 57 1. 61 1. 69 1.47 69.61 76.47 66.98 72 .20 77.21 62.25 73.02 75.59 83.25 76.96 0.044 0.064 0.055 0.052 0.063 0.041 0.064 0.046 0.067 0.031 2.43 3 .14 2.63 2.54 2.93 1.65 2.98 2.16 3.30 1. 62 0.046 0.055 0.055 0.051 0.042 0.038 0.049 0.046 0.059 0.045 2.54 2.70 2.63 2.49 1. 95 1. 53 2.28 2.16 2 .91 2.36 0.54 0.66 0. 71 0.64 0.61 0.84 0.77 0.62 1.59a 0.55 29.83 32.35 33.97 31. 22 28.37 33.73 35.81 29.11 78.32 28.80 RAT NUMBER BRAIN WEIGHT THYMUS ABS. WT. REL. % BRW OVARY LEFT ABS. REL. WT. % BRW OVARY RIGHT ABS. REL. WT. % BRW UTERUS WITH CERVIX ABS. REL. WT. % BRW HEART ABS. WT. REL. % BRW 19005 p 1. 81 0.14 7.73 0.049 2. 71 0.056 3.09 0.80 44.20 1.16 64.09 19035 p 2.04 0.16 7.84 0.051 2.50 0.055 2.70 0. 71 34.80 1.45 71. 08 19039 p 2.09 0.25 11.96 0.079 3.78 0.062 2.97 0.46 22.01 1. 20 57.42 19040 p 2.05 0.24 11.71 0.058 2.83 0.046 2.24 0.50 24.39 1. 55 75.61 19045 p 2.15 0.13 6.05 0.046 2.14 0.057 2.65 0.53 24.65 1.47 68.37 19054 p 2.49 0.36 14.46 0.064 2.57 0.048 1. 93 0.75 30.12 1.48 59.44 19058 p 2.15 0.12 5.58 0.052 2.42 0.066 3.07 0.74 34.42 1.39 64.65 ~ 19062 p 2.13 0.14 6.57 0.058 2.72 0.058 2. 72 0.78 36.62 1.41 66.20 ........ 19063 p 2.03 0.09 4.43 0.049 2.41 0.057 2.81 0.56 27.59 1. 39 68.47 00 I 19066 p 1. 91 0.39 20.42 0.028 1.46 0.025 1.31 0.78 40.84 1. 51 79.06 0 tv ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. 00 ~ P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) > a. Dam 19063 had omentum adhered to the entire length of the outer capsule of the spleen. See the individual necropsy ~ observations table (Table C28). CJ I w ' PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C31 (PAGE 5) : ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP V 10 MG/KG/DAY RAT NUMBER BRAIN WEIGHT LIVER ABS. WT. REL. % BRW KIDNEY LEFT ABS. REL. WT. % BRW KIDNEY RIGHT ABS. REL. WT. % BRW ADRENAL LEFT ABS. REL. WT. % BRW ADRENAL RIGHT ABS. REL. WT. % BRW SPLEEN ABS. WT. REL. % BRW 19001 p 19006 p 19011 p 19020 p 19022 p 19025 p 19027 p 19028 p 19030 p 19031 p 2.00 2 .13 2.05 2.00 2.18 2.13 2.27 2.02 2.18 2.24 12 .11 14.39 14.24 7.01 12.61 13.99 12.11 15.89 14.52 19.51 605.50 675.59 694.63 350.50 578.44 656.81 533.48 786.63 666.06 870.98 1.36 1.44 1.41 1.14 1.45 1. 36 1.38 1. 38 1.46 1. 52 68.00 67.60 68.78 57.00 66.51 63.85 60.79 68.32 66.97 67.86 1.35 1. 55 1.36 1. 09 1.63 1.40 1.35 1.41 1.50 1.47 67.50 72.77 66.34 54.50 74.77 65.73 59.47 69.80 68.81 65.62 0.041 0.057 0.045 0.058a 0.064 0.061 0.053 0.044 0.062 0.042 2.05 2.68 2.20 2.90 2.94 2.86 2.33 2.18 2.84 1. 88 0.031 0.055 0.045 0.056 0.041 0.055 0.047 0.041 0.046 0.038 1. 55 2.58 2.20 2.80 1. 88 2.58 2.07 2.03 2 .11 1. 70 0.57 0.54 0.50 0.28a 0.53 0.56 0.61 0.54 0.58 0.64 28.50 25.35 24.39 14.00 24.31 26.29 26.87 26.73 26.60 28.57 RAT NUMBER BRAIN WEIGHT THYMUS ABS. WT. REL. % BRW OVARY LEFT ABS. REL. WT. % BRW OVARY RIGHT ABS. REL. WT. % BRW UTERUS WITH CERVIX ABS. REL. WT. % BRW HEART ABS. WT. REL. % BRW 19001 p 2.00 0.18 9.00 0.048 2.40 0.047 2.35 0.64 32.00 0.92 46.00 19006 p 2 .13 0.15 7.04 0.056 2.63 0.074 3.47 0.46 21. 60 1. 57 73. 71 19011 p 2.05 0.15 7.32 0.046 2.24 0.036 1. 76 0.68 33.17 1.24 60.49 19020 p 2.00 O.lla 5.50 0.036 1. 80 0.047 2.35 0.50 25.00 0.90 45.00 19022 p 2.18 0.14 6.42 0.060 2.75 0.035 1. 60 0.74 33.94 1.54 70.64 19025 p 2 .13 0.25 11.74 0.053 2.49 0.058 2.72 0.53 24.88 1.38 64.79 19027 p 2.27 0.23 10 .13 0.039 1. 72 0.018 0.79 0.44 19.38 1.32 58.15 19028 p 2.02 0.23 11.39 0.087 4.31 0.053 2.62 0.37 18.32 1.56 77.23 _..j:.::... 19030 p 2.18 0.17 7.80 0.045 2.06 0.048 2.20 0.78 35.78 1.37 62.84 00 I 19031 p 2.24 0.16 7.14 0.076 3.39 0.087 3.88 0.74 33.04 1. 50 66.96 0 tv ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. 00 ;..e; P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) > a. Dam 19020 had a large left adrenal, small spleen, and small thymus. See the individual necropsy observations table (Table C28) . ~("') I "..j:::.. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C32 (PAGE 1) : PRIMORDIAL FOLLICLE COUNT - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS _________o\TA.R.Y"-#2----------------- DOSAGE GROUP I 0 MG/KG/DAY ---------------:RAT--#-----------0v-JCRy-1ri---------0v-~R:.Y-1r2-------------------------------------------------RA"-r-#-----------o-v.ARY.--#i ---------------1-9--0-1-2----------------3--1-----------------2--1------------------------------------------------------1-9-0-4-2-----------------1-------------------1-8--------------------- 37 46 0 9 46 34 1 9 33 36 6 16 34 36 3 13 AVERAGE 36.2 34.6 AVERAGE 2.2 13.0 19019 4 0 1 5 2 2 0 2 1 7 AVERAGE 1.6 3.2 19044 3 5 11 8 9 8 13 9 51 17 AVERAGE 17.4 9.4 19021 AVERAGE 16 16 21 20 14 17.4 4 4 12 17 30 13.4 19050 3 1 5 5 2 3 4 6 3 10 AVERAGE 3.4 5.0 19023 7 22 19053 24 3 14 11 11 11 10 13 27 16 14 27 27 20 AVERAGE 19041 11 11.2 7 14 2 6 15.8 4 3 4 25 38 ~ AVERAGE 22.8 17.6 0""'"0""' I 19065 4 7 0 lV 3 15 00 9 11 ~ > 5 6 7 9 3 12 14 16 ~ AVERAGE 7 . 0 5 . 2 AVERAGE 6 .6 12 . 2 ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------- (") I "'Ul PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C32 (PAGE 2) : PRIMORDIAL FOLLICLE COUNT - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS ------.?..~~!:.~R~A-T9-~#~~,:i--~----O--V-A-R-Y---#-1-----------O-V-A--R-Y--#--2-------~2--~9i_~~LP~~------------------------------R-A--T--#-------------O-V-A-R--Y--#--1----------O--V-A-R-Y---#-2------------------ ---------------1--9-0-0-1-----------------3-------------------6-------------------------------------------------------1-9-0-2--5----------------1-1------------------4---------------------- 4 5 12 6 9 6 6 15 6 17 6 25 23 20 7 12 AVERAGE 9.0 10.8 AVERAGE 8.4 12.4 19006 AVERAGE 27 11 23 26 21 21.6 5 6 19 20 20 14.0 19027 6 0 6 5 17 8 13 12 43 8 AVERAGE 17.0 6.6 19011 6 1 16 0 8 12 16 24 37 8 AVERAGE 16.6 9.0 19028 3 1 2 7 2 13 5 13 7 10 AVERAGE 3.8 8.8 19020 5 2 19030 9 3 4 1 21 13 15 2 24 6 8 12 22 7 20 20 AVERAGE 10.4 7.4 19022 9 9 2 4 5 11 26 20 .i::. AVERAGE 20.4 9.8 ~ <X> I 19031 11 7 0 lV 15 4 <X> 11 14 ~ > 1 17 7 19 9 11 14 17 ~ AVERAGE 4. 8 12. 0 AVERAGE 12. 0 10. 6 '' ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------- n I PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C33 (PAGE 1) : BODY WEIGHTS - PRECOHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DAY 1 2 3 4 5 6 7 8 9 10 11 12 13 14a RAT # DOSAGE GROUP I 0 MG/KG/DAY 19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075 213. 235. 230. 231. 219. 245. 227. 231. 220. 234. 223. 232. 222. 235. 232. 218. 239. 232. 236. 213. 239. 225. 230. 222. 238. 223. 229. 217. 238. 224. 223. 238. 240. 237. 222. 247. 232. 233. 226. 243. 230. 236. 228. 238. 229. 225. 236. 242. 240. 227. 252. 236. 235. 229. 244. 232. 247. 229. 241. 234. 224. 247. 244. 244. 223. 252. 238. 242. 229. 246. 234. 256. 228. 244. 234. 229. 246. 251. 248. 222. 249. 236. 238. 232. 255. 241. 260. 228. 247. 236. 235. 250. 254. 245. 228. 258. 236. 240. 236. 260. 245. 265. 239. 246. 242. 237. 251. 261. 250. 232. 264. 244. 247. 245. 262. 247. 277. 244. 253. 244. 238. 261. 256. 253. 229. 266. 247. 249. 243. 262. 244. 275. 238. 251. 244. 239. 261. 263. 258. 224. 260. 248. 243. 240. 269. 250. 281. 238. 254. 246. 246. 267. 269. 258. 233. 268. 248. 246. 245. 272. 255. 291. 247. 254. 247. 251. 258. 269. 260. 235. 272. 242. 245. 251. 274. 255. 288. 250. 258. 246. 246. 270. 272. 264. 235. 268. 249. 249. 246. 271. 254. 288. 242. 263. 227. 249. 267. 277. 266. 234. 264. 250. 250. 247. 277. 261. 293. 240. 260. 242. RAT # DOSAGE GROUP II 0. 3 MG/KG/DAY 19004 205. 203. 214. 215. 214. 216. 220. 226. 222. 219. 226. 228. 226. 223. 19009 231. 234. 236. 246. 248. 252. 252. 263. 257. 260. 260. 265. 264. 265. 19016 222. 224. 225. 227. 231. 232. 234. 234. 240. 238. 239. 247. 243. 244. 19018 222. 228. 228. 233. 232. 230. 240. 239. 244. 241. 241. 246. 246. 247. 19026 221. 227. 232. 236. 231. 233. 237. 239. 236. 241. 246. 251. 249. 249. 19036 230. 235. 239. 243. 247. 249. 249. 255. 260. 262. 263. 269. 271. 268. 19037 217. 217. 222. 228. 228. 227. 236. 241. 244. 237. 240. 240. 242. 249. 19043 227. 228. 233. 237. 238. 237. 245. 248. 246. 244. 253. 253. 252. 252. ~ 19047 219. 213. 207. 217. 211. 212. 213. 223. 224. 217. 219. 229. 228. 227. - 19048 228. 230. 235. 240. 239. 240. 246. 244. 245. 245. 253. 255. 252. 253. 00 I 19052 228. 228. 226. 235. 240. 234. 236. 245. 246. 244. 247. 254. 255. 251. 0 19055 235. 231. 228. 239. 249. 243. 241. 253. 258. 253. 255. 264. 266. 262. lV 00 19061 219. 225. 225. 227. 233. 238. 237. 241. 244. 248. 242. 241. 246. 250. ~ 19067 237. 238. 245. 246. 240. 246. 251. 252. 245. 250. 258. 259. 254. 259. > 19071 230. 232. 232. 238. 238. 242. 241. 248. 251. 252. 250. 261. 262. 261. ~ DAY = DAY OF STUDY () ALL WEIGHTS WERE RECORDED IN GRAMS (G) . I ' a. Last value recorded before cohabitation. ........] PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C33 (PAGE 2): BODY WEIGHTS - PRECOHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DAY 1 2 3 4 5 6 7 8 9 10 11 12 13 14a RAT # DOSAGE GROUP III 1 MG/KG/DAY 19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064 213. 244. 224. 229. 221. 228. 226. 234. 219. 231. 219. 230. 224. 233. 219. 218. 248. 222. 233. 219. 227. 221. 242. 219. 234. 220. 229. 226. 233. 218. 220. 254. 223. 237. 226. 227. 231. 241. 214. 239. 223. 238. 234. 236. 224. 218. 258. 233. 240. 228. 231. 234. 244. 221. 239. 227. 240. 234. 238. 228. 219. 256. 239. 243. 229. 235. 236. 253. 229. 243. 227. 240. 236. 240. 228. 227. 262. 244. 251. 231. 239. 233. 259. 233. 250. 230. 240. 238. 247. 231. 230. 269. 242. 249. 237. 237. 239. 262. 234. 252. 237. 245. 242. 252. 237. 229. 273. 243. 256. 241. 236. 246. 265. 234. 250. 238. 250. 245. 250. 242. 227. 270. 250. 262. 240. 237. 246. 267. 242. 255. 237. 251. 246. 253. 241. 234. 274. 254. 261. 240. 239. 243. 276. 246. 257. 236. 249. 246. 254. 241. 234. 280. 261. 264. 246. 241. 249. 282. 250. 261. 243. 257. 251. 256. 249. 229. 276. 254. 264. 250. 244. 257. 278. 246. 264. 244. 258. 251. 256. 251. 232. 281. 254. 271. 245. 239. 259. 269. 250. 266. 240. 256. 253. 260. 250. 236. 285. 264. 272. 250. 240. 250. 273. 256. 266. 244. 258. 253. 270. 251. RAT # DOSAGE GROUP IV 3 MG/KG/DAY 19002 224. 220. 228. 232. 238. 241. 246. 251. 251. 250. 255. 257. 258. 256. 19005 239. 238. 248. 250. 246. 248. 251. 255. 252. 256. 260. 260. 256. 259. 19035 225. 226. 233. 237. 230. 231. 242. 243. 243. 240. 248. 251. 247. 249. 19039 224. 222. 223. 227. 233. 234. 230. 236. 241. 242. 242. 242. 245. 248. 19040 218. 220. 226. 227. 226. 231. 234. 240. 236. 238. 243. 251. 245. 246. 19045 231. 227. 230. 236. 240. 237. 243. 250. 250. 250. 256. 261. 262. 262. 19046 214. 217. 221. 227. 227. 228. 232. 235. 237. 237. 237. 237. 247. 242. 1199005541 223179.. 223243.. 224204.. 224243.. 224299.. 225451.. 225384.. 223662.. 226451.. 227404.. 227415.. 227464.. 228414.. 224863.. ..s::::. - 19058 224. 233. 231. 235. 228. 229. 238. 241. 239. 232. 235. 240. 248. 242. 00 I 19062 222. 220. 229. 229. 224. 229. 235. 241. 234. 237. 242. 246. 240. 242. 0 19063 240. 241. 244. 248. 249. 248. 254. 265. 260. 264. 263. 266. 269. 268. N 00 19066 223. 223. 226. 227. 225. 226. 227. 236. 230. 227. 230. 238. 232. 232. ~ 19069 235. 237. 240. 241. 248. 250. 251. 252. 261. 264. 258. 261. 268. 269. 19073 227. 229. 229. 234. 238. 237. 240. 244. 247. 243. 244. 251. 252. 251. ~ DAY = DAY OF STUDY tT.1 n ALL WEIGHTS WERE RECORDED IN GRAMS (G) . I a. Last value recorded before cohabitation. O'. 00 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C33 (PAGE 3): BODY WEIGHTS - PRECOHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS ------------------------------------------------------------------------------------------------------------------------------------ DAY 1 2 3 4 5 6 7 8 9 10 11 12 13 14a ------------------------------------------------------------------------------------------------------------------------------------ RAT # DOSAGE GROUP V 10 MG/KG/DAY ------------------------------------------------------------------------------------------------------------------------------------ 19001 215. 214. 217. 217. 208. 212. 218. 220. 215. 214. 218. 221. 218. 213. 19006 231. 234. 238. 235. 236. 241. 242. 246. 250. 258. 258. 257. 259. 266. 19011 228. 230. 234. 238. 236. 243. 244. 248. 242. 241. 249. 249. 245. 243. 19020 226. 224. 222. 229. 231. 203. 199. 192. 186. 188. 203. 212. 220. 221. 19022 221. 221. 227. 230. 226. 230. 239. 240. 236. 236. 247. 247. 241. 243. 19025 229. 236. 240. 244. 239. 249. 259. 267. 271. 272. 283. 285. 280. 282. 19027 218. 220. 224. 228. 226. 229. 231. 235. 231. 235. 238. 240. 238. 238. 19028 232. 232. 232. 241. 242. 244. 243. 250. 253. 251. 252. 258. 259. 259. 19030 220. 220. 227. 230. 228. 232. 237. 242. 238. 241. 249. 253. 249. 251. 19031 245. 252. 255. 262. 264. 262. 255. 263. 264. 266. 268. 272. 277. 269. 19032 227. 229. 234. 240. 239. 243. 251. 258. 255. 256. 262. 266. 263. 264. 19033 225. 224. 228. 231. 234. 231. 233. 245. 244. 241. 246. 250. 256. 252. 19049 226. 228. 234. 237. 237. 240. 245. 254. 254. 252. 257. 262. 264. 257. 19059 240. 242. 243. 246. 250. 252. 250. 254. 256. 258. 256. 262. 263. 260. 19070 220. 218. 218. 227. 231. 233. 230. 239. 239. 241. 238. 246. 246. 248. DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Last value recorded before cohabitation. .~ ....... 00 I 0 lV 00 >;-t; ~() I \0' PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C34 (PAGE 1) : MATERNAL BODY WEIGHTS - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP I 0 MG/KG/DAY PREGNANCY STATUS DAY 0 1 2 3 4 5 6 7 8 9 10 11 12 19010 p 19012 p 19019 p 19021 p 19023 p 19041 p 19042 p 19044 p 19050 p 19053 p 19065 p 19068 p 19072 p 19074 p 19075 p 293. 273. 267. 276. 250. 291. 259. 256. 258. 284. 279. 287. 254. 268. 257. 304. 281. 284. 279. 244. 290. 265. 265. 248. 299. 286. 290. 257. 273. 240. 309. 281. 286. 283. 257. 304. 271. 270. 270. 300. 289. 302. 268. 285. 232. 312. 291. 293. 285. 261. 312. 270. 280. 269. 303. 289. 297. 272. 284. 233. 313. 295. 301. 291. 262. 308. 276. 277. 272. 310. 293. 307. 272. 290. 230. 312. 301. 310. 291. 267. 314. 285. 283. 274. 309. 300. 312. 273. 294. 244. 310. 300. 309. 296. 265. 318. 293. 288. 280. 311. 298. 320. 268. 295. 261. 313. 308. 304. 302. 271. 320. 294. 291. 282. 313. 300. 320. 280. 300. 272. 313. 312. 308. 304. 273. 324. 306. 297. 290. 323. 314. 331. 289. 298. 268. 324. 315. 311. 301. 280. 332. 314. 303. 292. 318. 318. 333. 291. 306. 280. 328. 321. 316. 314. 283. 337. 320. 306. 300. 329. 325. 338. 301. 311. 282. 336. 327. 324. 320. 286. 343. 329. 312. 305. 342. 334. 345. 307. 319. 281. 339. 333. 331. 330. 287. 347. 337. 321. 307. 338. 340. 352. 308. 326. 288. DAY 13 14 15 16 17 18 19 20 21 22 23 24 25 19010 p 344. 350. 358. 365. 378. 398. 416. 436. 453. 19012 p 338. 343. 350. 355. 369. 386. 408. 424. 445. 19019 p 336. 348. 357. 365. 379. 396. 420. 426. 445. 19021 p 331. 337. 347. 354. 365. 373. 352. 344. 385. 19023 p 299. 305. 314. 318. 298. 325. 341. 357. 366. 19041 p 354. 358. 366. 371. 392. 416. 425. 449. 19042 p 338. 348. 354. 374. 378. 397. 414. 430. 443. 19044 p 325. 340. 337. 349. 362. 380. 392. 420. ~ 19050 p 316. 320. 328. 305. 338. 360. 374. 388. 403. 0"""0""' I 19053 p 350. 359. 366. 373. 391. 415. 429. 449. 458. 0 19065 p 346. 348. 360. 376. 386. 411. 432. 446. tv 00 1199007628 pp 335140.. 335291.. 336257.. 338325.. 335904.. 346190.. 433844.. 444013.. ~ 19074 p 332. 340. 345. 356. 370. 377. 397. 408. 424. 419. ~ 19075 p 294. 306. 311. 318. 329. 340. 353. 359. 382. n P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) I DAY = DAY OF PRESUMED GESTATION -..) 0 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C34 (PAGE 2): MATERNAL BODY WEIGHTS - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP II 0.3 MG/KG/DAY PREGNANCY STATUS DAY 0 1 2 3 4 5 6 7 8 9 10 11 12 19004 p 19009 p 19016 p 19018 p 19026 p 19036 p 19037 p 19043 p 19047 p 19048 p 19052 p 19055 p 19061 p 19067 p 19071 p 239. 269. 249. 255. 268. 271. 260. 255. 232. 271. 259. 267. 259. 273. 264. 245. 275. 250. 262. 259. 281. 268. 265. 244. 273. 269. 277. 259. 270. 274. 252. 278. 258. 266. 273. 288. 274. 275. 241. 282. 262. 284. 266. 268. 281. 262. 281. 260. 269. 273. 292. 272. 274. 248. 287. 274. 289. 264. 283. 286. 265. 283. 266. 278. 285. 296. 280. 278. 248. 288. 272. 294. 271. 288. 292. 269. 286. 260. 281. 288. 301. 287. 285. 251. 291. 285. 300. 278. 289. 295. 270. 291. 269. 286. 290. 304. 290. 295. 255. 295. 288. 306. 278. 289. 304. 276. 294. 270. 292. 298. 313. 292. 292. 256. 303. 288. 307. 279. 294. 302. 280. 298. 281. 295. 296. 321. 296. 295. 264. 299. 293. 305. 288. 299. 309. 288. 299. 277. 299. 302. 324. 301. 305. 264. 306. 299. 318. 291. 300. 316. 292. 304. 282. 309. 311. 330. 302. 310. 270. 309. 305. 322. 290. 308. 319. 301. 310. 291. 318. 327. 332. 310. 318. 274. 312. 309. 334. 296. 312. 331. 306. 315. 296. 322. 329. 342. 319. 328. 279. 317. 318. 339. 306. 321. 338. DAY 13 14 15 16 17 18 19 20 21 22 23 24 25 19004 p 310. 320. 325. 334. 349. 361. 383. 396. 19009 p 321. 321. 330. 335. 343. 349. 326. 334. 361. 19016 p. 299. 310. 312. 325. 338. 348. 361. 380. 395. 19018 p 326. 332. 339. 348. 363. 373. 391. 408. 422. 19026 p 336. 349. 346. 361. 378. 394. 418. 432. 452. 19036 p 343. 348. 357. 367. 383. 398. 410. 424. 422. 19037 p 321. 325. 328. 342. 351. 364. 377. 393. 399. ~ 19043 p 329. 338. 346. 357. 372. 387. 389. 405. 417. ......... 19047 p 280. 289. 297. 304. 314. 329. 334. 364. 380. 00 I ~ 19048 p 321. 329. 336. 336. 348. 358. 358. 375. 382. 0 19052 p 322. 330. 338. 350. 366. 377. 391. 409. tv 00 19055 p 341. 349. 358. 371. 384. 401. 411. 433. 452. ~ 19061 p 308. 315. 325. 338. 345. 351. 367. 382. 19067 p 324. 325. 340. 344. 351. 370. 379. 395. 414. 19071 p 339. 348. 364. 365. 380. 394. 409. 431. 444. (J P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) I DAY = DAY OF PRESUMED GESTATION .......J ......... ALL WEIGHTS WERE RECORDED IN GRAMS (G) . PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C34 (PAGE 3): MATERNAL BODY WEIGHTS - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP III 1 MG/KG/DAY PREGNANCY STATUS DAY 0 1 2 3 4 5 6 7 8 9 10 11 12 19003 p 19007 p 19008 p 19013 p 19014 NP 19015 p 19017 p 19024 p 19029 p 19034 p 19038 NP 19056 p 19057 p 19060 p 19064 p 244. 293. 283. 291. 250. 250. 258. 291. 266. 266. 237. 272. 269. 276. 263. 252. 297. 282. 289. 259. 259. 262. 294. 267. 274. 243. 277. 271. 271. 275. 252. 302. 293. 294. 263. 262. 261. 292. 278. 280. 254. 282. 269. 278. 274. 258. 304. 296. 296. 264. 264. 275. 304. 275. 284. 262. 285. 281. 288. 288. 258. 312. 302. 304. 270. 266. 269. 305. 277. 289. 261. 290. 279. 277. 286. 260. 310. 310. 311. 276. 265. 275. 311. 283. 292. 265. 287. 282. 295. 291. 262. 315. 312. 310. 281. 259. 278. 309. 284. 294. 273. 292. 289. 301. 294. 264. 318. 317. 310. 280. 264. 283. 318. 284. 300. 278. 293. 290. 302. 295. 267. 324. 323. 320. 290. 275. 288. 316. 280. 308. 281. 299. 296. 306. 305. 269. 332. 327. 317. 291. 275. 292. 329. 285. 313. 282. 308. 301. 314. 307. 271. 340. 335. 328. 295. 287. 298. 330. 290. 321. 285. 313. 307. 320. 312. 287. 345. 344. 333. 295. 291. 301. 340. 294. 334. 291. 315. 310. 329. 317. 286. 350. 345. 341. 299. 298. 316. 342. 306. 339. 296. 318. 318. 334. 333. DAY 13 14 15 16 17 18 19 20 21 22 23 24 25 19003 p 291. 301. 308. 320. 335. 354. 365. 386. 19007 p 354. 360. 369. 380. 391. 412. 431. 444. 420. 19008 p 352. 358. 368. 370. 389. 411. 423. 439. 19013 p 350. 358. 361. 372. 386. 398. 409. 432. 450. 19014 NP 297. 298. 303. 306. 312. 310. 310. 310. 316. 313. 305. 293. 287. 19015 p 290. 298. 310. 315. 329. 346. 360. 374. 386. 19017 p 314. 323. 332. 338. 358. 364. 385. 406. 421. .,J::::.. 19024 p 341. 345. 355. 358. 374. 388. 368. 416. 400. ~ 19029 p 317. 317. 323. 336. 355. 363. 376. 393. 403. 00 I 19034 p 340. 346. 359. 364. 369. 390. 400. 413. 432. 0 19038 NP 294. 294. 288. 284. 287. 288. 281. 282. 281. 286. 288. 288. 302. tv 00 19056 p 324. 326. 338. 342. 355. 368. 384. 395. 420. ~ 19057 p 318. 328. 333. 337. 357. 375. 388. 402. 424. > 19060 p 346. 347. 353. 371. 379. 392. 409. 425. 19064 p 331. 337. 343. 348. 366. 384. 411. 432. 445. n~ P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) I DAY = DAY OF PRESUMED GESTATION .......J tv ALL WEIGHTS WERE RECORDED IN GRAMS (G) . PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C34 (PAGE 4) : MATERNAL BODY WEIGHTS - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT# DOSAGE GROUP IV 3 MG/KG/DAY PREGNANCY STATUS DAY 0 1 2 3 4 5 6 7 8 9 10 11 12 19002 p 19005 p 19035 p 19039 p 19040 p 19045 p 19046 NP 19051 NP 19054 p 19058 p 19062 p 19063 p 19066 p 19069 p 19073 p 295. 276. 264. 249. 266. 269. 247. MATING 248. 258. 256. 284. 246. 284. 258. 294. 299. 276. 286. 270. 273. 253. 253. 270. 274. 279. 282. 254. 258. NOT CONFIRMED 260. 260. 266. 271. 266. 268. 289. 294. 244. 254. 289. 298. 266. 268. 299. 284. 272. 256. 277. 288. 269. 258. 280. 274. 300. 258. 304. 275. 305. 284. 273. 256. 281. 293. 267. 262. 283. 278. 308. 262. 311. 279. 306. 285. 280. 260. 283. 294. 268. 267. 293. 279. 310. 267. 314. 284. 307. 284. 281. 264. 288. 290. 273. 264. 293. 289. 314. 266. 322. 288. 310. 287. 282. 264. 292. 296. 275. 268. 300. 292. 318. 264. 324. 290. 316. 290. 273. 267. 294. 313. 281. 276. 303. 292. 326. 268. 336. 296. 320. 292. 277. 269. 298. 313. 274. 280. 313. 304. 330. 274. 341. 302. 325. 297. 282. 274. 306. 320. 282. 284. 320. 307. 335. 278. 346. 308. 323. 303. 296. 281. 313. 324. 280. 291. 322. 316. 345. 290. 358. 315. 333. 300. 293. 287. 317. 340. 296. 296. 328. 320. 355. 290. 370. 326. DAY 13 14 15 16 17 18 19 20 21 22 23 24 25 19002 p 338. 341. 352. 350. 371. 380. 394. 406. 429. 19005 p 306. 316. 319. 326. 338. 357. 372. 389. 400. 19035 p 296. 297. 306. 307. 323. 336. 354. 383. 390. 19039 p 291. 296. 303. 314. 324. 329. 348. 362. 19040 p 320. 329. 337. 343. 357. 370. 390. 412. 19045 p 336. 342. 347. 363. 382. 392. 402. 423. 441. 19046 NP 290. 294. 293. 288. 284. 283. 284. 279. 274. 281. 280. 284. 274. .,i:::.. 19051 NP MATING NOT CONFIRMED ......... 19054 p 296. 302. 299. 307. 304. 316. 328. 337. 344. 00 I 19058 p 329. 340. 346. 350. 365. 383. 396. 414. 424. 0 19062 p 322. 332. 336. 340. 356. 376. 391. 415. 304. t-J 00 19063 p 362. 368. 369. 383. 392. 393. 407. 424. 440. ~ 19066 p 301. 302. 314. 321. 335. 351. 368. 381. 394. > 19069 p 375. 378. 387. 404. 413. 384. 408. 436. 454. ~ 19073 p 330. 336. 342. 349. 368. 380. 387. 402. 420. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) (') I DAY = DAY OF PRESUMED GESTATION -.l (.;..> ALL WEIGHTS WERE RECORDED IN GRAMS (G) . PROTOCOL 418-028: ORAL {GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST {SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C34 (PAGE 5): MATERNAL BODY WEIGHTS - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP V 10 MG/KG/DAY PREGNANCY STATUS DAY 0 1 2 3 4 5 6 7 8 9 10 11 12 19001 p 19006 p 19011 p 19020 p 19022 p 19025 p 19027 p 19028 p 19030 p 19031 p 19032 p 19033 p 19049 p 19059 p 19070 p 223. 268. 254. 236. 267. 293. 248. 265. 273. 281. 281. 249. 256. 267. 252. 229. 280. 261. 234. 271. 303. 252. 271. 271. 290. 279. 260. 267. 276. 259. 233. 281. 260. 249. 266. 303. 251. 278. 272. 285. 292. 258. 278. 271. 259. 237. 282. 263. 254. 282. 307. 260. 283. 286. 297. 292. 263. 281. 278. 270. 235. 292. 264. 256. 290. 314. 256. 283. 278. 298. 299. 262. 287. 286. 266. 242. 293. 264. 259. 293. 313. 260. 288. 284. 303. 300. 267. 284. 289. 275. 239. 296. 275. 257. 293. 316. 269. 292. 284. 303. 301. 272. 295. 291. 272. 243. 298. 278. 263. 294. 324. 270. 289. 288. 313. 309. 278. 296. 297. 276. 251. 306. 275. 269. 298. 329. 272. 297. 286. 322. 310. 279. 302. 301. 286. 250. 311. 287. 276. 303. 333. 274. 301. 292. 318. 315. 285. 307. 299. 287. 251. 318. 297. 283. 311. 342. 282. 304. 299. 327. 323. 288. 309. 308. 290. 255. 323. 289. 311. 316. 351. 287. 308. 307. 337. 331. 292. 312. 314. 296. 266. 333. 292. 293. 320. 352. 290. 318. 315. 346. 341. 304. 329. 325. 301. DAY 13 14 15 16 17 18 19 20 21 22 23 24 25 19001 p 271. 278. 283. 289. 303. 309. 320. 334. 343. 19006 p 336. 347. 353. 366. 379. 397. 422. 436. 451. 19011 p 308. 305. 309. 320. 340. 354. 375. 386. 406. 19020 p 293. 300. 303. 306. 321. 332. 349. 362. 19022 p 321. 328. 337. 345. 361. 369. 389. 416. 391. 19025 p 359. 354. 364. 372. 384. 401. 409. 413. 425. 19027 p 296. 299. 303. 308. 326. 341. 353. 373. 386. .,i::.. 19028 p 324. 327. 338. 344. 354. 365. 377. 394. 411. ~ ~ 19030 p 314. 321. 328. 332. 345. 354. 368. 382. 397. 00 I 19031 p 348. 357. 366. 371. 389. 398. 414. 436. 0 19032 p 344. 350. 355. 355. 375. 390. 404. 417. 447. N 00 19033 p 303. 312. 324. 328. 344. 358. 370. 390. ~ 19049 p 332. 338. 338. 346. 369. 373. 386. 410. 425. 19059 p 329. 333. 344. 352. 363. 376. 383. 405. 427. 19070 p 311. 313. 323. 332. 347. 358. 351. 372. 404. tT:1 (1 P = PREGNANT NP = NOT PREGNANT {VALUES EXCLUDED FROM AVERAGES) I DAY = DAY OF PRESUMED GESTATION -.J .,i::.. ALL WEIGHTS WERE RECORDED IN GRAMS (G) . PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C35 (PAGE 1) : MATERNAL BODY WEIGHTS - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT# DOSAGE GROUP I 0 MG/KG/DAY DAY 1 2 3 4 5 6 7 8 9 10 11 12 13 19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075 334. 316. 324. 302. 279. 337. 335. 301. 285. 324. 332. 338. 311. 313. 266. 330. 319. 309. 266. 294. 347. 334. 300. 285. 327. 340. 344. 298. 319. 284. 332. 322. 320. 289. 299. 346. 329. 303. 285. 338. 337. 349. 300. 313. 279. 334. 327. 337. 288. 302. 352. 340. 312. 290. 336. 345. 348. 305. 320. 287. 341. 323. 337. 310. 310. 358. 338. 321. 300. 339. 343. 347. 299. 336. 288. 344. 331. 342. 272. 319. 371. 346. 319. 305. 359. 351. 360. 324. 345. 303. 351. 347. 343. 324. 316. 363. 346. 330. 304. 367. 362. 362. 334. 352. 305. 351. 346. 340. 320. 318. 367. 344. 340. 313. 367. 361. 371. 337. 348. 311. 368. 349. 360. 291. 331. 383. 350. 339. 330. 374. 364. 381. 288.a 358. 321. 353. 295.a 360. 326. 338. 371. 354. 341. 327. 377. 377. 366. 340. 367. 297.a 360. 353. 365. 328. 345. 381. 354. 352. 335. 312.a 377. 377. 345. 369. 321. 356. 359. 352. 316. 336. 380. 362. 352. 335. 380. 365. 379. 360. 378. 325. 345. 366. 374. 350. 340. 390. 362. 356. 342. 392. 391. 380. 359. 350. 280.a DAY 14 15 16 17 18 19 20 21 22b 19010 352. 353. 362. 359. 360. 349. 347. 353. 299. 19012 365. 381. 386. 362. 378. 356. 354. 373. 335. 19019 388. 371. 384. 363. 394. 379. 384. 372. 309. 19021 347. 352. 355. 331. 344. 346. 354. 307.a 270. 19023 335. 331. 323. 322. 329. 338. 332. 317. 280. 19041 378. 396. 385. 376. 359. 367. 375. 362. 305. 19042 370. 370. 371. 346. 382. 365. 365. 355. 302. 19044 368. 354. 367. 327. 354. 359. 376. 366. 360. 19050 337. 339. 343. 329. 338. 337. 336. 341. 290. ..J..::.:.a... 19053 374. 378. 360. 367. 381. 377. 366. 285. 299. 00 I 19065 385. 393. 376. 346. 370. 371. 356. 345. 301. 0 19068 382. 382. 386. 398. 382. 403. 388. 386. 360. l'-J 00 1199007742 336337.. 323948.. 334486.. 335655.. 335613.. 336746.. 335840.. 336579.. 229927.. ~ > 19075 316. 298. 318. 330. 319. 314. 327. 320. 295. ~ DAY = DAY OF LACTATION (') ALL WEIGHTS WERE RECORDED IN GRAMS (G) . I a. Value appeared incorrectly recorded and was excluded from group averages and statistical analyses. .V....1.J b. Dams were fasted prior to sacrifice. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C35 (PAGE 2): MATERNAL BODY WEIGHTS - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP II 0. 3 MG/KG/DAY DAY 1 2 3 4 5 6 7 8 9 10 11 12 13 19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071 290. 286. 295. 302. 318. 304. 267. 314. 281. 306. 302. 320. 309. 305. 334. 293. 306. 297. 308. 296. 294. 272. 314. 269. 300. 297. 326. 290. 306. 334. 296. 273. 298. 311. 273.a 297. 277. 311. 271. 305. 261.a 320. 297. 311. 335. 301. 251.a 306. 311. 320. 296. 269. 316. 276. 302. 264.a 332. 293. 310. 312. 303. 301. 310. 318. 314. 296. 288. 316. 287. 307. 285. 332. 309. 314. 329. 317. 312. 320. 320. 311. 309. 292. 321. 284. 315. 315. 332. 307. 319. 320. 310. 324. 323. 325. 326. 319. 296. 332. 304. 320. 316. 348. 315. 331. 332. 316. 318. 321. 327. 331. 303. 301. 325. 296. 327. 317. 332. 323. 335. 339. 330. 325. 323. 336. 333. 318. 318. 342. 311. 336. 331. 353. 277.a 346. 342. 331. 331. 318. 347. 347. 334. 321. 349. 312. 343. 330. 363. 297. 352. 348. 333. 329. 324. 339. 341. 335. 251. 346. 318. 336. 339. 354. 319. 350. 364. 334. 342. 328. 332. 338. 347. 230.a 354. 318. 351. 350. 364. 340. 356. 365. 330. 343. 329. 342. 355. 352. 298. 352. 264.a 345. 340. 360. 332. 367. 356. DAY 14 15 16 17 18 19 20 21 22b 19004 349. 337. 345. 317. 332. 344. 325. 304. 276. 19009 349. 348. 343. 341. 345. 349. 342. 336. 346. 19016 342. 341. 336. 330. 327. 329. 324. 308. 314. 19018 336. 337. 341. 341. 353. 349. 340. 343. 338. 19026 360. 354. 356. 355. 341. 353. 358. 360. 296. 19036 344. 355. 356. 343. 345. 358. 344. 351. 359. 19037 310. 326. 332. 312. 332. 326. 342. 321. 309. 19043 355. 342. 338. 333. 344. 349. 344. 348. 356. .,I:::.. 19047 323. 321. 330. 318. 324. 317. 319. 308. 325. ~ 19048 355. 346. 349. 338. 356. 365. 368. 350. 306. 00 I ~ 19052 315.c 352. 353. 349. 345. 351. 346. 346. 320. 0 19055 331. 348. 363. 366. 372. 367. 368. 350. 336. N 00 19061 338. 335. 322. 348. 338. 337. 334. 327. 315. ~ 19067 344. 352. 352. 360. 371. 358. 343. 308.a 294. 19071 362. 316.a 369. 365. 371. 367. 372. 348. 374. tr:l DAY = DAY OF LACTATION (") .ALL WEIGHTS WERE RECORDED IN GRAMS (G) . I a. Value appeared incorrectly recorded and was excluded from group averages and statistical analyses. -.l 0\ b. Dams were fasted prior to sacrifice. c. Water access was interrupted; value excluded from group averages and statistical analyses. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C35 (PAGE 3): MATERNAL BODY WEIGHTS - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP III 1 MG/KG/DAY DAY 1 2 3 4 5 6 7 8 9 10 19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064 285. 284. 303. 309. 331. 326. 346. 334. NOT PREGNANT 281. 266. 320. 307. 295. 312. 282. 284. 311. 320. NOT PREGNANT 317. 311. 305. 294. 336. 318. 311. 305. 287. 316. 328. 315.a 283. 310. 321. 281. 323. 316. 278.a 330. 319. 293. 316. 335. 348. 288. 312. 327. 283. 322. 282.a 300. 328. 318. 300. 316. 316.a 349. 277. 313. 332. 290. 328. 321. 311. 342. 300. 308. 337. 341. 354. 295. 322. 332. 301. 309.a 319. 320. 345. 313. 312. 339. 350. 350. 302. 324. 342. 305. 354. 331. 324. 353. 319. 317. 348. 355. 357. 296. 339. 344. 309. 345. 311.a 324. 348. 321. 316. 347. 351. 359. 313. 341. 354. 309. 338. 339. 321. 358. 340. 330. 354. 361. 372. 321. 352. 361. 309. 345. 339. 339. 366. 342. DAY 14 15 16 17 18 19 20 21 22b 19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064 344. 336. 369. 331. 361. 370. 391. 379. NOT PREGNANT 339. 323. 336. 343. 364. 326.a 323. 326. 359. 352. NOT PREGNANT 347. 341. 351. 337. 362. 350. 344. 330. 335. 359. 358. 387. 322. 366. 368. 332. 358. 343. 343. 371. 349. 333. 354. 340. 369. 304. 343. 351. 299.a 339. 346. 352. 373. 354. 330. 377. 360. 380. 312. 363. 366. 321. 371. 348. 337. 351. 363. 335. 369. 356. 386. 323. 373. 369. 332. 356. 329. 356. 372. 359. 315. 352. 350. 381. 316. 358. 367. 317. 358. 350. 354. 351. 366. 338. 355. 350. 374. 312. 360. 354. 322. 352. 338. 305. 352. 352. 284. 303. 292. 389. 274. 350. 309. 332. 287. 292. 287. 357. 289. DAY = DAY OF LACTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Value appeared incorrectly recorded and was excluded from group averages and statistical analyses. b. Dams were fasted prior to sacrifice. 11 274.a 364. 368. 372. 311. 350. 368. 318. 349. 346. 336. 369. 340. 12 281.a 363. 361. 389. 310. 356. 369. 326. 351. 352. 350. 360. 344. 13 320. 373. 358. 390. 344. 363. 348. 323. 355. 343. 352. 373. 302.a ~ ~ 00 I 0 N 00 i-d @ (1 I -.l -.l PROTOCOL 418-028: ORAL {GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST {SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C35 (PAGE 4): MATERNAL BODY WEIGHTS - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP IV 3 MG/KG/DAY DAY 1 2 3 4 5 6 7 8 9 10 11 12 13 19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073 335. 330. 284. 295. 271. 267. 271. 269. 321. 299. 315. 315. NOT PREGNANT NOT PREGNANT; 280. 296. 309. 320. 304. 308. 331. 332. 290. 280. 332. 329. 318. 315. 328. 297. 276. 265. 299. 315. MATING NOT 291. 276.a 318. 341. 288. 332. 310. 337. 307. 285. 270. 314. 318. CONFIRMED 296. 268.a 317. 348. 292. 332. 306. 338. 317. 289. 272. 315. 304.a 297. 300. 326. 354. 297. 330. 303. 340. 322. 286. 254.a 323. 315. 304. 309. 322. 341. 303. 288.a 321. 345. 320. 292. 283. 328. 310. 303. 313. 332. 357. 301. 275.a 328. 356. 325. 292. 278. 339. 318. 312. 319. 334. 351. 314. 320. 330. 338. 328. 309. 292. 350. 352. 312. 329. 347. 370. 313. 333. 340. 348. 328. 309. 288. 350. 346. 357. 328. 305. 293. 348. 348. 368. 340. 316. 300. 356. 368. 367. 336. 332. 306. 356. 376. 313. 340. 351. 368. 315. 288.a 346. 306. 337. 348. 378. 304.a 337. 352. 290.a 351. 349. 385. 322. 353. 362. 333. 353. 368. 381. 351. 365. 290.a DAY 14 15 16 17 18 19 20 21 22b 19002 361. 358. 360. 369. 358. 376. 378. 359. 302. 19005 341. 342. 351. 320. 344. 352. 350. 333. 285. 19035 315. 322. 314. 306. 322. 326. 315. 312. 261. 19039 311. 310. 310. 296. 320. 317. 313. 317. 315. 19040 360. 355. 350. 334. 365. 361. 367. 356. 294. 19045 349. 377. 361. 353. 380. 402. 386. 398. 385. - 19046 NOT PREGNANT 19051 NOT PREGNANT; MATING NOT CONFIRMED ~ 19054 335. 332. 333. 313. 328. 326. 322. 323. 287. 19058 331. 302.c 345. 350. 345. 364. 363. 324. 350. 00 I 19062 369. 358. 356. 335. 352. 355. 354. 342. 290. 0 19063 377. 380. 383. 370. 384. 388. 377. 385. 369. tv 00 19066 338. 332. 332. 325. 336. 341. 340. 328. 292. ;.c; 19069 349. 361. 366. 365. 373. 375. 358. 352. 362. > 19073 350. 357. 368. 375. 371. 364. 365. 348. 363. ~ DAY = DAY OF LACTATION () ALL WEIGHTS WERE RECORDED IN GRAMS (G) . I -......) a. Value appeared incorrectly recorded and was excluded from group averages and statistical analyses. 00 b. Dams were fasted prior to sacrifice. c. Water access was interrupted; value excluded from group averages and statistical analyses. PROTOCOL 418-028: ORAL {GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C35 {PAGE 5): MATERNAL BODY WEIGHTS - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP V 10 MG/KG/DAY DAY 1 2 3 4 5 6 7 8 9 10 11 12 13 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070 256. 308. 291. 260. 278. 310. 281. 313. 307. 316. 317. 295. 310. 312. 290. 257. 308. 286. 268. 300. 318. 283. 302. 301. 324. 330. 292. 304. 313. 297. 254. 313. 290. 279. 310. 326. 278. 307. 304. 289.a 327. 292. 308. 314. 302. 254. 317. 302. 274. 314. 315.a 274. 310. 309. 286.a 319. 299. 305. 312. 302. 234.a 322. 303. 271. 317. 331. 242.a 310. 318. 319. 309. 305. 286.a 313. 305. 262. 324. 308. 243. 322. 349. 276. 311. 320. 329. 307. 308. 302. 317. 312. 261. 328. 302. 269. 335. 358. 294. 315. 327. 340. 326. 320. 318. 322. 313. 265. 330. 321. 266. 343. 347. 283. 315. 331. 340. 335. 326. 320. 327. 323. 259. 331. 321. 268. 344. 361. 291. 325. 348. 354. 339. 329. 326. 338. 337. 273. 346. 331. 262. 361. 365. 238. 331. 340. 362. 343. 342. 339. 348. 330. 281. 344. 338. 253. 341. 368. 296. 334. 346. 366. 328. 339. 335. 347. 337. 278. 339. 326. 268. 360. 381. 304. 331. 346. 371. 284.a 335. 331. 352. 357. 286. 348. 345. 259. 355. 379. 322. 338. 348. 371. 354. 344. 348. 350. 355. DAY 14 15 16 17 18 19 20 21 22b 19001 287. 288. 286. 278. 304. 302. 296. 292. 278. 19006 367. 366. 366. 356. 373. 373. 378. 373. 304. 19011 332. 294.a 318. 326. 338. 350. 330. 330. 283. 19020 270. 246. 252. 246. 252. 251. 246. 228. 210. 19022 360. 348. 352. 352. 359. 363. 349. 349. 294. 19025 384. 373. 358. 355. 392. 363. 358. 346. 291. 19027 317. 312. 309. 306. 302. 321. 315. 315. 266. 19028 318. 335. 294.C 329. 340. 348. 330. 346. 339. .i::::. 19030 357. 355. 353. 344. 346. 346. 365. 355. 314. 19031 316.c 362. 365. 364. 375. 373. 381. 371. 361. 0""""0"" I 19032 351. 336. 359. 343. 356. 319.a 341. 344. 287. 0 tv 19033 347. 341. 338. 332. 329. 332. 323. 323. 328. 00 19049 348. 346. 358. 341. 347. 334. 349. 349. 330. ~ 19059 320. 322. 357. 358. 345. 339. 360. 343. 317. > 19070 303.c 337. 358. 365. 351. 358. 363. 352. 351. ~ DAY = DAY OF LACTATION () ALL WEIGHTS WERE RECORDED IN GRAMS {G) . I -.....) a. Value appeared incorrectly recorded and was excluded from group averages and statistical analyses. \0 b. Dams were fasted prior to sacrifice. c. Water access was interrupted; value excluded from group averages and statistical analyses. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C36 (PAGE 1) : FEED CONSUMPTION VALUES - PRECOHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DAYS 1- Sa RAT # DOSAGE GROUP I 0 MG/KG/DAY 19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075 140. 142. 162. 147. 124. b 138. 144. 123. c 151. 167. 132. 146. 138. RAT # DOSAGE GROUP II 0.3 MG/KG/DAY 19004 132. 19009 156. 19016 126. 19018 137. 19026 144. 19036 136. 19037 138. 19043 153. ..p. 19047 110. I-"" 19048 131. 00 I 19052 123. 0 19055 147. t--.J 00 19061 134. ~ 19067 139. e; 19071 139. tr.I DAY = DAY OF STUDY n ALL WEIGHTS WERE RECORDED IN GRAMS (G) . I a. Last value recorded before cohabitation. 00 0 b. Spilled feed precluded the calculation of this value. c. Value was not recorded. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C36 (PAGE 2): FEED CONSUMPTION VALUES - PRECOHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DAYS 1- Ba RAT # DOSAGE GROUP III 1 MG/KG/DAY 19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064 124. 150. 155. 150. 136. 142. 127. 169. 153. 149. 130. 141. 143. 174. 138. RAT # DOSAGE GROUP IV 3 MG/KG/DAY 19002 145. 19005 150. 19035 125. 19039 118. 19040 133. 19045 134. 19046 132. 19051 160. +::-. 19054 135. i-- 19058 128. 00 I 19062 129. 0 19063 153. t--J 00 ~ 19066 124. ~ 19069 153. 19073 134. tT.l DAY = DAY OF STUDY (1 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . I a. Last value recorded before cohabitation. 00 i-- PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C36 (PAGE 3): FEED CONSUMPTION VALUES - PRECOHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DAYS 1- 8a RAT # DOSAGE GROUP V 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070 107. 119. 139. 92. 133. 151. 135. 163. 136. 180. 147. 148. 141. 138. 132. DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Last value recorded before cohabitation. 10 MG/KG/DAY ..i::. -00 I 0 tv 00 > ~ ~ () I 00 tv PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C37 (PAGE 1): MATERNAL FEED CONSUMPTION VALUES - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS PREGNANCY STATUS DAYS 0 - 7 7 - 10 10 - 12 12 - 15 15 - 18 18 - 20 RAT # DOSAGE GROUP I 0 MG/KG/DAY 19010 p 19012 p 19019 p 19021 p 19023 p 19041 p 19042 p 19044 p 19050 p 19053 p 19065 p 19068 p 19072 p 19074 p 19075 p 184. 85. 50. 77. 76. 53. 178. 82. 55. 83. 81. 59. 188. 90. 82. 95. 75. 56. 182. 85. 58. 93. 78. 21. 140. 66. 44. 76. 47. 51. 190. 82. 127. 81. 83. 58. 192. 91. 69. 101. 88. 66. 189. 91. 59. 93. 90. 54. 158. 70. 49. 73. 56. 53. 188. 77. 64. 84. 76. 58. 203. 92. 73. 94. 88. 68. 191. 93. 57. 86. 86. 55. 171. 75. a 77. 74. 58. 193. 89. 63. 90. 82. 51. 117. 78. 46. 77. 65. 36. RAT # DOSAGE GROUP II 0. 3 MG/KG/DAY 19004 p 186. 83. 58. 86. 81. 60. 19009 p 178. 79. 49. 91. 82. 17. 19016 p 137. 65. 45. 70. 71. 42. 19018 p 176. 85. 59. 90. 85. 55. 19026 p 179. 81. 58. 90. 86. 59. 19036 p 193. 93. 56. 82. 78. 40. 19037 p 185. 83. 59. 77. 67. 39. ..s:::.. 19043 p 170. 84. 57. 84. 95. 54. ~ 19047 p 150. 67. 43. 70. 72. 46. 00 I 19048 p 164. 67. 44. 76. 69. 46. 0 19052 p 162. 79. 49. 77. 79. 46. N 00 19055 p 198. 91. 63. 90. 97. 49. ~ 19061 p 170. 80. 51. 86. 81. 52. 19067 p 173. 79. 58. 80. 69. 22. ~ 19071 p 203. 90. 60. 90. 88. 57. n P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) I DAYS = DAYS OF PRESUMED GESTATION 00 t>l ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Spilled feed precluded the calculation of this value. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C37 (PAGE 2): MATERNAL FEED CONSUMPTION VALUES - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS PREGNANCY STATUS DAYS 0 - 7 7 - 10 10 - 12 12 - lS lS - 18 18 - 20 RAT # 19003 p 19007 p 19008 p 19013 p 19014 NP 1901S p 19017 p 19024 p 19029 p 19034 p 19038 NP 190S6 p 190S7 p 19060 p 19064 p DOSAGE GROUP III 1 MG/KG/DAY 144. 6S. 49. 77. 66. so. 179. 83. 60. 86. 78. S3. 213. 94. 64. 86. 79. 60. 160. 78. 64. 8S. 86. S4. 17S. 83. so. 73. 78. 41. 142. 71. 49. 73. 79. SS. 149. 70. so. 74. 86. Sl. 181. 91. S6. 84. 7S. 46. 17S. 63. 49. 89. 80. 4S. 182. 87. 6S. 90. 76. 36. 1S3. 76. 53. 68. 71. 6S. 167. 76. S3. 77. 71. S4. 174. 80. 53. 79. 80. S3. 172. 92. 64. 92. 86. 59. 177. 74. S3. 79. 69. SS. RAT # DOSAGE GROUP IV 3 MG/KG/DAY 19002 p 167. 62. 49. 70. 79. 47. 1900S p 16S. 68. 48. 75. 70. 5S. 1903S p lSS. S6. 44. 63. 62. 51. 19039 p 142. 6S. 44. 71. 70. S4. 19040 p 187. 79. S7. 87. 77. S9. 1904S p 186. 91. S9. 83. 94. S2. 19046 NP 170. 72. S2. 73. S4. 27. ~ 19051 NP MATING NOT CONFIRMED ~ 190S4 p 160. 7S. 49. 68. S6. S2. 00 I 190S8 p 196. 92. 51. 81. 88. 49. 0 19062 p 181. 80. 56. 81. 72. SS. N 00 1199006636 pp 124249.. 69S6.. 4673.. 7967.. 7841.. 4S8l.. ~ 19069 p 220. 106. 70. 104. 74. 28. ~ 19073 p 164. 91. 56. 86. 90. 49. tT.1 n P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) I DAYS = DAYS OF PRESUMED GESTATION 00 ~ ALL WEIGHTS WERE RECORDED IN GRAMS (G) . PROTOCOL 418-028: ORAL {GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C37 (PAGE 3) : MATERNAL FEED CONSUMPTION VALUES - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS PREGNANCY STATUS DAYS 0 - 7 7 - 10 10 - 12 12 - 15 15 - 18 18 - 20 RAT # DOSAGE GROUP V 10 MG/KG/DAY 19001 p 19006 p 19011 p 19020 p 19022 p 19025 p 19027 p 19028 p 19030 p 19031 p 19032 p 19033 p 19049 p 19059 p 19070 p 127. 63. 42. 71. 70. 41. 165. 74. 55. 85. 72. 61. 146. 69. 48. 69. 75. 56. 162. 77. 53. 79. 64. 51. 185. 75. 57. 88. 81. 69. 202. 88. 65. 73. 64. 50. 144. 73. 47. 81. 65. 41. 184. 82. 56. 93. 84. 55. 175. 71. 54. 78. 73. 57. 182. 91. 59. 94. 89. 54. 180. 84. 59. 93. 94. 62. 164. 82. 57. 89. 85. 55. 176. 83. 54. 81. 81. 52. 169. 75. 54. 84. 86. 50. 156. 75. 50. 82. 88. 30. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . -~ 00 I 0 l'-J 00 > ~ ~() I 00 Vl PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C38 (PAGE 1) : MATERNAL FEED CONSUMPTION VALUES - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DAY 1 - 5 5 - 8 8 - 15 RAT # DOSAGE GROUP I 0 MG/KG/DAY 19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075 131. 155. 137. 99. 158. 176. 137. 196. 144. 165. 191. 149. 125. 202. 144. 158. 178. 186. 181. 168. 183. 150. 207. 182. 206. 203. 184. 161. 216. 191. 387. 498. 540. 478. 488. 549. 468. 628. 506. 511. 579. 502. 427. 521. 433. RAT # DOSAGE GROUP II 0. 3 MG/KG/DAY 19004 158. 165. 513. 19009 85. 141. 400. 19016 140. 167. 495. 19018 120. 167. 486. 19026 25. 173. 374. 19036 101. 145. 533. 19037 85. 211. 561. 19043 138. 180. 516. ~ ...... 19047 114. 154. 460. 19048 114. 137. 447. 00 I 19052 82. 154. 497. 0 19055 145. 172. 493. tv 00 ;.c;, 19061 99. 138. 366. 19067 142. 170. 520. > 19071 a 142. 512. Fri DAY = DAY OF LACTATION n ALL WEIGHTS WERE RECORDED IN GRAMS (G) . I a. Spilled feed precluded the calculation of this value. 00 CJ'\ PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C38 (PAGE 2) : MATERNAL FEED CONSUMPTION VALUES - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DAY 1 - 5 5 - 8 8 - 15 RAT # DOSAGE GROUP III 1 MG/KG/DAY 19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064 155. 164. 156. 181. a 183. 120. 183. NOT PREGNANT 117. 158. 114. 166. 135. 163. 138. 148. 149. 143. NOT PREGNANT 113. 169. 117. 168. 138. 185. 143. 168. 439. 508. 527. 517. 474. 475. 461. 473. 470. 513. 471. 513. 455. RAT # DOSAGE GROUP IV 3 MG/KG/DAY 19002 113. 132. 427. 19005 175. 159. 497. 19035 108. 112. 438. 19039 146. 145. 436. 19040 140. 189. 542. 19045 130. 160. 584. 19046 NOT PREGNANT 19051 NOT PREGNANT; MATING NOT CONFIRMED .J::.. 19054 113. 125. 360. ........ 19058 98. 184. 496. 00 I 19062 147. 175. 560. 0 19063 131. 160. 568. l'V 00 19066 110. 139. 453. ~ 19069 106. 81. 451. > 19073 114. 167. 523. ~ DAY = DAY OF LACTATION (J ALL WEIGHTS WERE RECORDED IN GRAMS (G) . I a. Spilled feed precluded the calculation of this value. 00 -......) PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C38 (PAGE 3) : MATERNAL FEED CONSUMPTION VALUES - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DAY 1 - 5 5 - 8 8 - 15 RAT # DOSAGE GROUP V 10 MG/KG/DAY 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070 87. 154. 114. 137. 191. 187. 99. 126. 154. 92. 147. 143. a 144. 150. 119. 178. 157. 91. 184. 195. 132. 143. 158. 178. 149. 166. 169. 167. 167. 381. 558. 445. 319. 520. 553. 427. 454. 503. 559. 481. 499. 474. 494. 492. DAY = DAY OF LACTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Spilled feed precluded the calculation of this value. +::>- ~ 00 I 0 t-.J 00 ~ ~ n I 00 00 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C39 (PAGE 1) : MATING AND FERTILITY, ESTROUS CYCLING AND DAYS IN COHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # ESTROUS STAGES/ 13 DAYS DAYS IN COHABITATION MATING STATUS MATING DATE PREGNANCY STATUS DOSAGE GROUP I 0 MG/KG/DAY 19010 2 14 19012 2 2 19019 3 3 19021 3 2 19023 4 4 19041 4 4 19042 1 3 19044 2 1 19050 4 4 19053 2 3 19065 3 3 19068 2a 2 19072 2 4 19074 3 2 19075 3 4 M c p M c p M c p M c p M c p M c p M c p M c p M c p M c p M c p M c p M c p M c p M c p DOSAGE GROUP II 0. 3 MG/KG/DAY 19004 4 4 M c p 19009 3 1 M c p 19016 3 1 M c p 19018 3 2 M c p 19026 1 4 M c p 19036 2 1 M c p 19037 3 2 M c p 19043 4 1 M c p ..J:::.. I--" 19047 2 1 M c p 00 I 19048 4 4 M c p 0 19052 2 1 M c p t'-.J 00 19055 2 1 M c p ~ 19061 3 2 M c p > 19067 3 3 M c p ~ 19071 3 1 M c p M = MATED C = CONFIRMED P = PREGNANT NP = NOT PREGNANT (") I a. Six or more consecutive days of diestrus were observed. 00 \0 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C39 (PAGE 2) : MATING AND FERTILITY, ESTROUS CYCLING AND DAYS IN COHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # ESTROUS STAGES/ 13 DAYS DAYS IN COHABITATION MATING STATUS MATING DATE PREGNANCY STATUS DOSAGE GROUP III 1 MG/KG/DAY 19003 3 3 M c p 19007 3 3 M c p 19008 3 4 M c p 19013 3 2 M c p 19014 4 1 M c NP 19015 2 4 M c p 19017 3 1 M c p 19024 3 4 M c p 19029 3 2 M c p 19034 3 3 M c p 19038 3 1 M c NP 19056 4 4 M c p 19057 4 4 M c p 19060 4 2 M c p 19064 4 4 M c p DOSAGE GROUP IV 3 MG/KG/DAY ~ 19002 4 13 M c p 19005 3 4 M c p 19035 3 4 M c p 19039 3 2 M c p 19040 4 4 M c p 19045 3 1 M c p 19046 2 1 M c NP ..f:::.. 19051 la 14 19054 3 3 DID NOT MATE M c p 0'"""0"" I 19058 2 1 M c p 0 19062 4 4 M c p N 00 19063 3 2 M c p ~ 19066 3 4 M c p 19069 3 2 M c p 19073 3 1 M c p t'I'.l (1 M = MATED C = CONFIRMED P = PREGNANT NP = NOT PREGNANT I a. Six or more consecutive days of estrus were observed. \0 0 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C39 (PAGE 3): MATING AND FERTILITY, ESTROUS CYCLING AND DAYS IN COHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # ESTROUS STAGES/ 13 DAYS DAYS IN COHABITATION MATING STATUS DOSAGE GROUP V 10 MG/KG/DAY 19001 3 1 M 19006 2 3 M 19011 3 4 M 19020 0 4 M 19022 3 4 M 19025 la 3 M 19027 3 4 M 19028 1 1 M 19030 0 4 M 19031 1 1 M 19032 3 4 M 19033 3 1 M 19049 2 1 M 19059 3 1 M 19070 3 1 M M = MATED C = CONFIRMED P = PREGNANT NP = NOT PREGNANT a. Six or more consecutive days of diestrus were observed. MATING DATE c c c c c c c c c c c c c c c PREGNANCY STATUS p p p p p p p p p p p p p p p -~ 00 I 0 tv 00 -~ >~("') I \0 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C40 (PAGE 1) : FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS __ p~~~9-~-g~~~~--I--------------------------------------------------------------------------------------~-~~~,9j_~~_:---------------------------------------------------- RAT # 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 -H--O-M-E---C-A-G--E--B-E--H-A-V--IO--R-------------------3-----------2------------3-----------3------------3-----------3------------3-----------3-----------3------------1----------------------- ALTERATIONS (HOME CAGE) 1 1 1 1 1 1 1 1 1 1 REACTION TO REMOVAL 1 1 1 1 1 1 1 1 1 i REACTION TO HANDLING 1 1 1 1 1 1 1 1 1 1 REARS IN OPEN FIELD 10 12 12 19 7 13 15 7 14 11 DEFECATION IN OPEN FIELD 1 1 1 2 1 1 2 1 1 1 URINATION IN OPEN FIELD 1 1 2 2 1 2 2 1 1 1 LEVEL OF AROUSAL 3 3 3 3 3 3 3 3 3 3 ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1 1 GAIT PATTERN 1 1 1 1 1 1 1 1 1 1 GAIT ABNORMALITY, SEVERITY 1 1 1 1 1 1 1 1 1 1 PALPEBRAL CLOSURE 1 1 1 1 1 1 1 1 1 1 PROMINENCE OF THE EYE 1 1 1 1 1 1 1 1 1 1 LACRIMATION 1 1 1 1 1 1 1 1 1 1 SALIVATION 1 1 1 1 1 1 1 1 1 1 PILOERECTION 0 0 0 0 0 0 0 0 0 0 ABNORMAL RESPIRATION 0 0 0 0 0 0 0 0 0 0 APPEARANCE 1 1 la 1 lb 1 1 1 1 le VISUAL REACTION 2 2 2 2 2 2 2 2 2 2 TACTILE REACTION 2 2 2 2 2 2 2 2 2 2 AUDITORY REACTION 3 3 3 3 3 3 3 3 3 3 TAIL-PINCH REACTION 2 2 2 3 2 3 2 2 2 2 AIR RIGHTING RESPONSE 1 1 1 1 1 1 1 1 1 1 PUPIL RESPONSE TO LIGHT 1 1 1 1 1 1 1 1 1 1 +::a- ~ FORELIMB GRIP TEST #1 (G) 410 325 240 550 370 655 330 275 505 430 00 I FORELIMB GRIP TEST #2 (G) 465 650 345 500 355 845 375 350 545 600 0 tv HINDLIMB GRIP TEST #1 (G) 245 365 450 335 675 565 520 295 405 315 00 HINDLIMB GRIP TEST #2 (G) 335 445 420 300 670 475 350 350 530 415 ~ > LANDING FOOT SPLAY #1 (CM) 12.1 8.8 8.0 4.4 6.4 6.5 9.5 4.0 9.3 7.0 LANDING FOOT SPLAY #2 (CM) 9.6 8.0 8.3 6.0 5.7 5.7 8.0 6.4 9.4 7.7 ~ --~~~~-.!'!.~!.9.!!!_J~L--------------------~73________ _3_~~--------~}_4_ _______ _3_~Z--------~~3________ _3_~~--------~~3________ ..3_'!.~--------~2-1________ _3_~~--------------------- (") vALuEs ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY. I \0 a. Localized alopecia: head (1.0 cm x 0.4 cm). tv b. Localized alopecia: left forepaw and forelimb (1.5 cm x 0.6 cm) and right forelimb (0.6 cm x 0.7 cm). c. Ears torn: both pinnae. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C40 (PAGE 2): FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS __-P-!-?-.-~-~-9-_-1--.-_-g-~-~-q-~-----~-!------------------------------------------------------------------------------------------------------------------------------------------------------------------------~-~-]_-_-f-:!-g-f_-~-S-!-i-P-!-!-.-~----------------------------------------------------------------------------------------------- --~!-~--------------------------------~~9.9_'!, _____ ~_9-~~2------~~9}_~-----~..9-~~~------~~9}_~-----~..9-~~------~~9]_~-----~-9-~~~------~~9J_~-----~..9-~~~-------------------- HOME CAGE BEHAVIOR 3 1 3 2 1 3 2 1 3 1 ALTERATIONS (HOME CAGE) 1 1 1 1 1 1 1 1 1 1 REACTION TO REMOVAL 1 1 1 1 1 1 1 1 1 1 REACTION TO HANDLING 1 1 1 1 1 1 1 1 1 1 REARS IN OPEN FIELD 10 12 12 9 11 14 14 15 18 15 DEFECATION IN OPEN FIELD 1 1 1 1 1 1 1 1 1 1 URINATION IN OPEN FIELD 1 2 1 1 1 1 1 2 1 2 LEVEL OF AROUSAL 3 3 3 3 3 3 3 3 3 3 ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1 1 GAIT PATTERN 1 1 1 1 1 1 1 1 1 1 GAIT ABNORMALITY, SEVERITY 1 1 1 1 1 1 1 1 1 1 PALPEBRAL CLOSURE 1 1 1 1 1 1 1 1 1 1 PROMINENCE OF THE EYE 1 1 1 1 1 1 1 1 1 1 LACRIMATION 1 1 1 1 1 1 1 1 1 1 SALIVATION 1 1 1 1 1 1 1 1 1 1 PILOERECTION 0 0 0 0 0 0 0 0 0 0 ABNORMAL RESPIRATION 0 0 0 0 0 0 0 0 0 0 APPEARANCE 1 1 la 1 1 1 1 1 1 1 VISUAL REACTION 2 2 2 2 2 2 2 2 2 2 TACTILE REACTION 2 2 2 2 2 2 2 2 2 2 AUDITORY REACTION 3 3 3 3 3 3 3 3 3 3 TAIL-PINCH REACTION 2 2 2 2 2 2 2 2 3 2 AIR RIGHTING RESPONSE 1 1 1 1 1 1 1 1 1 1 PUPIL RESPONSE TO LIGHT 1 1 1 1 1 1 1 1 1 1 ..s;::.. t--' FORELIMB GRIP TEST #1 (G) 165 510 285 275 325 155 120 400 220 305 00 I ~ FORELIMB GRIP TEST #2 (G) 390 333 140 450 530 145 475 535 325 310 0 N HINDLIMB GRIP TEST #1 (G) 335 365 375 385 365 270 420 255 320 410 00 HINDLIMB GRIP TEST #2 (G) 315 380 525 355 285 365 665 375 240 325 ~ LANDING FOOT SPLAY #1 (CM) 6.0 8.7 7.9 5.2 6.3 6.2 6.5 5.2 6.2 5.8 LANDING FOOT SPLAY #2 (CM) 7.9 9.0 6.9 6.8 7.4 6.7 7.0 5.4 5.7 6.5 --~!?.~~-!!.~!9!!.!_J~~--------------------~~..7________ ]_~~--------~~_?________ ]_~~--------~~!;. _______ ]_~~--------~~_;;________ ]_~~--------~~_;;________ ]_~~--------------------- (1 VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY. I \D a. Localized alopecia: head (0.4 cm x 0.5 cm). t.;J PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C40 (PAGE 3): FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS ---P-~-~-~-.9---~---~-~-~-q-~-----:-i-:-.-~-!----------------------------------------------------------------------------------------------------------------------------------------------------------------~---~-.-9-1-.-.-~-~-!-.-?-.-.-~-!_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_-_--_ _____ _____ --~'E_!________________________________~~9--~-----~..9-~~2------~~9--~-----~..9-~~2------~~92--~-----~..9-~~2------~~9]_'!. ~..9-~~2------~~9]_'!. ~..9-~~~-------------------- HOME CAGE BEHAVIOR 3 3 1 3 1 3 3 1 2 1 ALTERATIONS (HOME CAGE) 1 1 1 1 1 1 1 1 1 1 REACTION TO REMOVAL 1 1 1 1 1 1 1 1 1 1 REACTION TO HANDLING 1 1 1 1 1 1 1 1 l 1 REARS IN OPEN FIELD 14 9 10 8 6 13 14 10 16 16 DEFECATION IN OPEN FIELD 1 1 1 1 1 1 1 3 1 2 URINATION IN OPEN FIELD 1 1 1 1 2 1 1 1 2 2 LEVEL OF AROUSAL 3 3 3 3 3 3 3 3 3 3 ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1 1 GAIT PATTERN 1 1 1 1 1 1 1 1 1 1 GAIT ABNORMALITY, SEVERITY 1 1 1 1 1 1 1 1 1 1 PALPEBRAL CLOSURE 1 1 1 1 1 1 1 1 1 1 PROMINENCE OF THE EYE 1 1 1 1 1 1 1 1 1 1 LACRIMATION 1 1 1 1 1 1 1 1 1 1 SALIVATION 1 1 1 1 1 1 1 1 1 1 PILOERECTION 0 0 0 0 0 0 0 0 0 0 ABNORMAL RESPIRATION 0 0 0 0 0 0 0 0 0 0 APPEARANCE 1 1 la 1 lb 2 1 le 1 1 VISUAL REACTION 2 2 2 2 2 2 2 2 2 2 TACTILE REACTION 2 2 2 2 2 2 2 2 2 2 AUDITORY REACTION 3 3 3 3 3 3 3 3 3 3 TAIL-PINCH REACTION 2 2 2 2 2 3 2 2 2 3 - AIR RIGHTING RESPONSE 1 1 1 1 1 1 1 1 1 1 PUPIL RESPONSE TO LIGHT 1 1 1 1 1 1 1 1 1 1 ~ FORELIMB GRIP TEST #1 {G) 325 975 85 200 420 330 695 320 610 255 00 I FORELIMB GRIP TEST #2 (G) 245 535 75 365 455 720 665 395 505 300 0 tv HHIINNDDLLIIMMBB GGRRIIPP TTEESSTT ##21 ((GG)) 249455 238105 332700 447905 434755 455300 444605 453250 465055 329605 ;0.-0c, > LANDING FOOT SPLAY #1 (CM) 5.4 7.0 6.2 10.8 6.8 7.7 8.8 6.2 7.4 8.3 ~ LANDING FOOT SPLAY #2 (CM) 6.3 8.5 5.8 10.6 7.2 6.4 10.4 8.0 7.5 8.4 ________ ________ ________ ________ --~~~!_.!!.~!.9!!.!_J~L--------------------~~] ]_~~--------~~_o________]_~~--------~~.? ]_~~--------~~..9 ]_~~--------~~J ]_~~--------------------- (') vALuEs ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY. I ' a. Chromorhinorrhea. ~ b. Localized alopecia: head (0.3 cm in diameter). c. Localized alopecia: both forepaws and forelimbs (2.8 cm x 0.5 cm) and head (0.3 cm x 0.5 cm). PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C40 (PAGE 4) : FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS ,_!?S?.~~9-~-~~S?.~~--Y:.':___________________________________________________________________________________3__~9j_~~i.?..1.!!____________________________________________________ RAT # 19005 19035 19039 19040 19045 19054 19058 19062 19063 19066 -H--O-M-E---C-A-G-E---B-E-H--A-V--IO--R-------------------3-----------1------------2-----------3------------1-----------2-----------3------------2-----------1------------1----------------------- ALTERATIONS (HOME CAGE) 1 1 1 1 1 1 1 1 1 1 REACTION TO REMOVAL 1 1 1 1 1 1 1 1 1 1 REACTION TO HANDLING 1 1 1 1 1 1 1 1 1 1 REARS IN OPEN FIELD 11 7 15 12 13 10 10 11 8 10 DEFECATION IN OPEN FIELD 3 1 1 1 2 1 1 1 1 1 URINATION IN OPEN FIELD 1 1 1 1 1 1 1 1 1 1 LEVEL OF AROUSAL 3 3 3 3 3 3 3 3 3 3 ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1 1 GAIT PATTERN 1 1 1 1 1 1 1 1 1 1 GAIT ABNORMALITY, SEVERITY 1 1 1 1 1 1 1 1 1 1 PALPEBRAL CLOSURE 1 1 1 1 1 1 1 1 1 1 PROMINENCE OF THE EYE 1 1 1 1 1 1 1 1 1 1 LACRIMATION 1 1 1 1 1 1 1 1 1 1 SALIVATION 1 1 1 1 1 1 1 1 1 1 PILOERECTION 0 0 0 0 0 0 0 0 0 0 ABNORMAL RESPIRATION 0 0 0 0 0 0 0 0 0 0 APPEARANCE 1 1 1 1 la 3b 1 le 1 1 VISUAL REACTION 2 2 2 2 2 2 2 2 2 2 TACTILE REACTION 2 2 2 2 2 2 2 2 2 2 AUDITORY REACTION 3 3 3 2 3 3 3 3 3 3 TAIL-PINCH REACTION 2 2 2 2 2 2 2 2 2 2 AIR RIGHTING RESPONSE 1 1 1 1 1 1 1 1 1 1 PUPIL RESPONSE TO LIGHT 1 1 1 1 1 1 1 1 1 1 .,f:::.. lo--" FORELIMB GRIP TEST #1 (G) 415 355 445 490 560 525 260 310 545 495 00 I FORELIMB GRIP TEST #2 (G) 685 360 395 465 555 605 435 225 530 390 0 l'-J HINDLIMB GRIP TEST #1 (G) 465 255 190 355 340 350 220 400 465 270 00 ;,:; HINDLIMB GRIP TEST #2 (G) 470 295 315 430 435 325 365 460 485 365 > LANDING FOOT SPLAY #1 (CM) 8.0 5.5 5.4 6.5 8.0 7.5 7.4 7.5 7.0 4.0 LANDING FOOT SPLAY #2 (CM) 8.3 5.8 6.3 7.2 9.4 9.6 9.0 7.0 7.5 5.0 ________ ~ -~S?.~!_!!.~!9!!.!_J~L--------------------~2-0_________3_~~--------~}..7 _3_~~--------~~---------..3-~~--------~~-5________ _3_~~--------~2_8________ _3_~2--------------------- () VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY. I ' a. Localized alopecia: left axilla (4.0 cm x 3.0 cm). Vl b. Localized alopecia: right forepaw and forelimb (1.7 cm x 0.6 cm). c. Tip of tail missing. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C40 (PAGE 5) : FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS -P~~~9_E]._g~~l!~-~----------------------------------------------------------------------------------2----~9i_~gf.R,1:!~---------------------------------------------------- RAT # 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 -H--O-M-E---C-A-G--E--B-E--H-A-V--I-O-R-------------------2-----------2------------2-----------3------------2-----------3------------1-----------3------------3-----------3----------------------- ALTERATIONS (HOME CAGE) 1 1 1 1 1 1 1 1 1 1 REACTION TO REMOVAL 1 1 1 1 1 1 1 1 1 1 REACTION TO HANDLING 1 1 1 1 1 1 1 1 1 1 REARS IN OPEN FIELD 12 9 9 9 9 10 14 8 15 14 DEFECATION IN OPEN FIELD 1 1 1 1 1 1 1 2 1 2 URINATION IN OPEN FIELD 1 1 1 1 1 1 2 2 1 1 LEVEL OF AROUSAL 3 3 3 3 3 3 3 3 3 3 ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1 1 GAIT PATTERN 4a 1 1 4a 1 1 1 1 1 1 GAIT ABNORMALITY, SEVERITY 2 1 1 2 1 1 1 1 1 1 PALPEBRAL CLOSURE 1 1 1 1 1 1 1 1 1 1 PROMINENCE OF THE EYE 1 1 1 1 1 1 1 1 1 1 LACRIMATION 1 1 1 1 1 1 1 1 1 1 SALIVATION 1 1 1 1 1 1 1 1 1 1 PILOERECTION 0 0 0 0 0 0 0 0 0 0 ABNORMAL RESPIRATION 0 0 0 le 0 0 0 0 0 0 APPEARANCE 1 lb 1 ld 1 1 1 1 le 1 VISUAL REACTION 2 2 2 2 2 2 2 2 2 2 TACTILE REACTION 2 2 2 2 2 2 2 2 2 2 AUDITORY REACTION 2 3 3 3 3 3 3 3 3 3 TAIL-PINCH REACTION 2 2 2 2 2 2 2 2 2 3 AIR RIGHTING RESPONSE 1 1 1 1 1 1 1 1 1 1 PUPIL RESPONSE TO LIGHT 1 1 1 1 1 1 1 1 1 1 ~ ~ FORELIMB GRIP TEST #1 (G) 170 785 525 205 560 535 315 270 595 270 00 I FORELIMB GRIP TEST #2 (G) 290 735 465 240 645 540 600 525 495 440 0 N HINDLIMB GRIP TEST #1 (G) 385 410 330 435 385 520 265 305 405 410 00 HINDLIMB GRIP TEST #2 (G) 380 530 490 370 630 430 410 480 530 445 ;-t; LANDING FOOT SPLAY #1 (CM) 4.8 6.3 9.0 8.8 10.5 10.0 6.3 8.7 6.2 10.4 ~ LANDING FOOT SPLAY #2 (CM) 5.8 7.0 9.4 8.7 8.5 9.0 6.5 9.2 7.0 9.2 tT.1 __ ____________________ _______ ________ _______ n -~.?-P-~-!!.~!9.!!.! ~'!L ~~-o________ _3_~~--------~~2- 3_~~--------~~-6________ _3_~~--------~}_s _3_~~--------~2_2_ ..3_:~--------------------- vALuEs ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY. I '../:) ' a. Tip-toe walk. b. Ear torn: right pinna. c. Rales. d. Localized alopecia: both forepaws and forelimbs (1.0 cm x 0.4 cm); Dehydration; Abdominal distention. e. Scab: head (0.3 cm in diameter); Localized alopecia: head (0.5 cm in diameter). PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C41 (PAGE 1) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP I 0 MG/KG/DAY RAT NUMBER 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 NUMBER OF MOVEMENTS BLOCK 1 84 77 76 63 74 73 73 69 60 71 BLOCK 2 86 17 67 0 66 52 61 59 65 65 BLOCK 3 83 30 65 0 72 64 18 64 63 45 BLOCK 4 70 7 25 2 23 3 33 9 108 6 BLOCK 5 65 3 43 2 49 4 54 9 33 13 BLOCK 6 76 3 11 0 57 2 34 10 6 40 BLOCK 7 39 41 20 0 4 1 3 4 4 0 BLOCK 8 32 53 23 0 0 11 24 1 10 39 BLOCK 9 12 37 7 0 13 55 54 29 1 6 BLOCK 10 20 41 4 20 1 5 71 8 1 25 BLOCK 11 17 4 10 1 2 0 30 0 23 5 BLOCK 12 71 5 10 2 1 1 19 9 59 4 BLOCK 13 57 4 21 1 1 1 2 2 27 5 BLOCK 14 40 1 9 0 37 2 8 4 8 51 BLOCK 15 67 2 2 1 75 6 3 3 7 56 BLOCK 16 83 2 3 0 47 5 1 39 22 30 BLOCK 17 81 4 5 37 79 4 0 70 39 3 BLOCK 18 59 12 10 0 36 4 0 59 74 5 ~ I--" TOTAL 1042 343 411 129 637 293 488 448 610 469 00 I 0 --T-O-T--A-L---=--S-U-M---O-F---B-L-O--C-K--S-; --E-A-C-H---B-L-O--C-K---C-O--N-S-I-S-T-S---O-F---A--5---M-I-N-U--T-E---P-E-R-I-O--D-.--------------------------------------------------------------------------------------- tv 00 ~ >~nI \0 -..l PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C41 (PAGE 2) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP I 0 MG/KG/DAY RAT NUMBER 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 TIME (SECONDS) SPENT IN MOVEMENT BLOCK 1 191 138 161 108 167 180 157 185 125 136 BLOCK 2 157 34 147 0 116 84 100 147 85 83 BLOCK 3 119 41 75 0 96 98 29 81 71 47 BLOCK 4 113 7 25 3 17 2 27 10 101 1 BLOCK 5 83 4 48 0 43 1 105 8 31 13 BLOCK 6 111 1 6 0 75 1 37 12 1 31 BLOCK 7 37 50 23 0 1 1 2 1 2 0 BLOCK 8 35 93 28 0 0 8 31 0 12 47 BLOCK 9 5 60 6 0 14 67 62 41 0 0 BLOCK 10 26 50 5 36 0 4 95 7 0 29 BLOCK 11 22 6 10 2 4 0 29 0 43 2 BLOCK 12 74 3 10 3 0 1 18 12 103 5 BLOCK 13 68 2 21 0 2 0 0 0 42 5 BLOCK 14 42 1 9 0 36 1 5 1 1 52 BLOCK 15 77 1 0 0 119 5 1 4 5 89 BLOCK 16 71 1 0 0 74 4 0 79 17 24 BLOCK 17 100 2 3 38 92 3 0 113 56 0 BLOCK 18 114 21 7 0 40 6 0 106 84 4 ,.._J:_::... > TOTAL 1445 515 584 190 896 466 698 807 779 568 00 I 0 --T-O-T--A-L---=--S-U-M---O-F---B-L-O--C-K--S-; --E-A-C--H--B-L--O-C-K---C-O--N-S-I-S-T-S---O-F---A--5---M-I-N-U--T-E--P--E-R-I-O--D-.--------------------------------------------------------------------------------------- l'-J 00 ~ ~ (') I \0 00 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C41 (PAGE 3) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP II 0.3 MG/KG/DAY RAT NUMBER 19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 NUMBER OF MOVEMENTS BLOCK 1 65 68 53 60 75 73 73 65 77 62 BLOCK 2 36 75 61 55 55 64 68 27 16 79 BLOCK 3 31 104 3 6 57 58 50 3 22 78 BLOCK 4 49 41 7 1 54 20 27 16 10 82 BLOCK 5 29 46 0 9 30 12 8 5 0 73 BLOCK 6 22 45 1 7 3 0 30 28 0 58 BLOCK 7 3 18 4 22 3 29 9 12 0 78 BLOCK 8 13 59 2 2 0 2 29 8 0 17 BLOCK 9 0 79 0 1 1 3 10 5 2 4 BLOCK 10 1 22 4 12 5 2 14 2 0 3 BLOCK 11 0 1 6 1 54 0 1 4 0 3 BLOCK 12 7 1 5 11 10 0 7 2 0 16 BLOCK 13 4 6 1 7 38 12 4 6 2 70 BLOCK 14 40 2 14 8 41 0 30 0 4 51 BLOCK 15 30 3 0 6 17 5 50 2 10 7 BLOCK 16 42 32 1 6 3 4 42 3 9 8 BLOCK 17 4 63 13 13 0 4 6 2 10 2 BLOCK 18 6 41 3 1 0 27 25 0 4 1 ..j::::.. ~ TOTAL 382 706 178 228 446 315 483 190 166 692 00 I 0 --T-O-T--A-L---=--S-U-M---O--F--B-L-O--C-K--S-;--E-A-C--H--B-L--O-C-K---C-O--N-S-I-S-T-S---O-F---A--5---M-I-N-U--T-E---P-E-R--IO--D-.--------------------------------------------------------------------------------------- tv 00 ~ > ~ (") I \0 \0 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C41 (PAGE 4): MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP II 0.3 MG/KG/DAY RAT NUMBER 19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 --T-I-M--E---(S-E--C-O-N--D-S-)---S-P-E-N--T---IN---M--O-V-E-M--E-N-T------------------------------------------------------------------------------------------------------------------------------- BLOCK 1 131 213 85 76 152 181 120 120 133 204 BLOCK "2 41 168 93 49 96 136 140 41 19 157 BLOCK 3 47 135 3 7 82 92 91 1 35 108 BLOCK 4 67 56 4 0 116 12 60 18 8 139 BLOCK 5 32 55 0 9 51 15 19 1 0 93 BLOCK 6 20 76 0 7 0 0 60 25 0 122 BLOCK 7 1 11 3 31 3 46 8 9 0 102 BLOCK 8 12 84 2 1 0 2 36 4 0 14 BLOCK 9 0 119 0 0 1 1 12 3 0 2 BLOCK 10 0 29 1 11 4 1 15 0 0 1 BLOCK 11 0 0 6 3 70 0 2 0 0 2 BLOCK 12 6 0 4 7 9 0 6 1 0 9 BLOCK 13 2 3 0 4 42 19 3 10 2 62 BLOCK 14 33 0 17 13 72 0 36 0 1 69 BLOCK 15 43 1 0 3 22 1 71 1 8 5 BLOCK 16 62 36 0 4 1 2 55 0 9 7 BLOCK 17 BLOCK 18 2 91 12 11 0 3 11 0 6 1 4 40 0 0 0 28 22 0 1 1 .+..:..-... 00 TOTAL 503 1117 230 236 721 539 767 234 222 1098 I 0 N --T-O-T--A-L---=--S-U-M---O-F---B-L-O--C-K--S-;--E-A-C--H--B--L-O-C-K---C-O--N-S-I-S-T--S--O-F---A--5---M-I-N-U--T-E---P-E-R-I-O--D-.--------------------------------------------------------------------------------------- 00 ~ ~tT.1 n..I..... 0 0 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C41 (PAGE 5) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP III 1 MG/KG/DAY RAT NUMBER 19003 19007 19008 19013 19015 19017 19024 19029 19034 19056 --N-U-M--B-E-R---O-F---M-O-V--E-M-E-N--T-S----------------------------------------------------------------------------------------------------------------------------------------------- BLOCK 1 76 74 55 71 69 70 74 69 58 67 BLOCK 2 61 40 63 70 68 59 85 81 68 71 BLOCK 3 65 65 70 19 30 37 59 48 48 61 BLOCK 4 40 60 48 3 61 19 61 56 6 85 BLOCK 5 18 27 89 5 64 25 60 70 43 35 BLOCK 6 37 49 78 1 84 36 58 65 9 9 BLOCK 7 46 50 70 1 74 40 55 44 22 43 BLOCK 8 49 57 64 2 40 38 53 38 34 5 BLOCK 9 9 53 57 2 8 51 24 65 10 2 BLOCK 10 5 85 74 0 2 27 24 38 27 12 BLOCK 11 0 57 64 1 1 29 58 53 1 5 BLOCK 12 3 1 71 10 3 16 59 41 2 5 BLOCK 13 45 9 78 0 3 27 26 50 1 4 BLOCK 14 58 1 77 0 2 32 6 64 1 3 BLOCK 15 52 7 59 1 1 61 10 39 4 2 BLOCK 16 43 1 85 19 6 39 1 46 0 5 BLOCK 17 51 7 60 0 8 43 1 70 1 6 ..j::;:.. BLOCK 18 47 4 42 1 5 10 28 39 1 2 ~ 00 TOTAL 705 647 1204 206 529 659 742 976 336 422 0I t'.J >5 --T-O-T--A-L---=--S-U-M---O--F--B-L-O--C-K--S-; --E-A-C--H--B-L--O-C-K---C-O--N-S-I-S-T--S--O-F---A--5---M-I-N-U--T-E---P-E-R--IO--D-.--------------------------------------------------------------------------------------- ;0.c0, a I ~ 0 ~ PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C41 (PAGE 6) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP III 1 MG/KG/DAY RAT NUMBER 19003 19007 19008 19013 19015 19017 19024 19029 19034 19056 --T-I-M--E---(S-E--C-O-N--D-S-)---S-P-E-N--T--I-N---M--O-V-E-M--E-N-T------------------------------------------------------------------------------------------------------------------------------- BLOCK 1 180 153 118 150 153 201 174 97 186 132 BLOCK 2 96 69 139 109 138 129 123 85 119 137 BLOCK 3 128 109 143 19 21 66 176 30 136 57 BLOCK 4 64 99 85 2 78 22 98 66 9 179 BLOCK 5 23 27 136 11 123 49 84 88 53 40 BLOCK 6 59 75 102 0 119 53 81 59 2 11 BLOCK 7 65 55 140 0 154 63 70 61 24 58 BLOCK 8 69 90 123 0 78 65 56 49 69 8 BLOCK 9 13 68 109 0 7 87 14 71 10 0 BLOCK 10 4 122 112 0 1 36 27 47 26 12 BLOCK 11 0 77 100 1 0 41 93 84 0 1 BLOCK 12 3 0 93 10 1 22 136 73 4 2 BLOCK 13 71 7 158 0 2 29 24 90 0 3 BLOCK 14 60 0 125 0 1 47 4 106 0 2 BLOCK 15 80 9 109 0 0 97 11 56 2 0 BLOCK 16 69 0 116 24 9 57 0 83 0 3 BLOCK 17 91 9 138 0 12 47 0 77 0 4 ~ BLOCK 18 56 1 52 0 0 7 22 42 1 0 .......... 00 TOTAL 1131 970 2098 326 897 1118 1193 1264 641 649 I 0 tv >~ --T-O-T--A-L---=--S-U-M---O-F---B-L-O--C-K-S--; --E-A-C-H---B-L--O-C-K---C-O--N-S-I-S-T-S---O-F---A--5---M-I-N-U--T-E---P-E-R-I-O--D-.--------------------------------------------------------------------------------------- 00 ~ (') I .......... 0 tv PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C41 (PAGE 7) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP IV 3 MG/KG/DAY RAT NUMBER 19005 19035 19039 19040 19045 19054 19058 19062 19063 19066 NUMBER OF MOVEMENTS BLOCK 1 59 82 75 62 55 68 67 49 71 69 BLOCK 2 63 77 58 18 66 75 48 69 37 60 BLOCK 3 52 51 63 11 67 75 27 41 32 74 BLOCK 4 51 33 64 2 79 62 13 40 32 14 BLOCK 5 54 37 73 1 50 52 5 33 6 28 BLOCK 6 64 7 15 15 56 56 2 54 12 69 BLOCK 7 78 5 4 57 66 48 2 57 11 55 BLOCK 8 66 34 28 29 44 75 22 49 36 62 BLOCK 9 57 27 9 1 52 43 39 55 33 24 BLOCK 10 55 0 9 0 59 43 18 49 22 4 BLOCK 11 50 6 5 0 59 35 3 47 26 4 BLOCK 12 54 3 3 32 53 6 16 35 14 2 BLOCK 13 68 1 0 3 55 37 3 21 7 3 BLOCK 14 60 0 9 11 53 52 3 53 3 0 BLOCK 15 46 5 3 1 69 25 1 44 1 3 BLOCK 16 58 4 39 2 50 4 1 31 81 2 BLOCK 17 54 19 17 4 57 2 0 10 52 4 .j::::.. - BLOCK 18 50 3 2 0 76 0 14 24 17 4 00 TOTAL 1039 394 476 249 1066 758 284 761 49~ 481 I 0 tv --T-O-T--A-L---=--S-U-M---O-F---B-L-O--C-K--S-;--E-A-C--H--B--L-O-C-K---C-O--N-S-I-S-T-S---O-F---A--5---M-I-N-U--T-E---P-E-R-I-O--D-.--------------------------------------------------------------------------------------- 00 ~ >~(") I -0 (.;.) PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C41 (PAGE 8) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP IV 3 MG/KG/DAY RAT NUMBER 19005 19035 19039 19040 19045 19054 19058 19062 19063 19066 --T-I-M--E---(S--E-C-O-N--D-S-)---S-P-E--N-T---I-N--M--O-V-E-M--E-N-T------------------------------------------------------------------------------------------------------------------------------- BLOCK 1 241 163 158 215 236 181 154 143 150 169 BLOCK 2 167 129 110 23 188 184 67 158 63 106 BLOCK 3 106 63 100 26 196 155 45 69 41 143 BLOCK 4 130 42 89 1 192 133 23 52 43 25 BLOCK 5 108 29 87 0 140 58 16 60 4 18 BLOCK 6 120 5 29 22 131 64 5 82 20 89 BLOCK 7 117 2 2 79 150 73 1 149 12 68 BLOCK 8 108 42 45 37 76 73 60 98 56 106 BLOCK 9 112 31 14 0 194 65 56 109 68 17 BLOCK 10 83 0 10 0 154 39 29 79 21 1 BLOCK 11 83 2 3 0 137 31 5 77 31 3 BLOCK 12 63 1 2 38 66 2 24 47 22 1 BLOCK 13 135 0 0 0 112 33 11 36 5 2 BLOCK 14 100 0 4 6 101 40 6 73 1 0 BLOCK 15 58 4 0 0 150 9 1 107 0 1 BLOCK 16 83 2 54 1 81 1 2 62 98 2 BLOCK 17 105 23 13 1 119 0 0 10 77 1 BLOCK 18 73 1 1 0 152 0 24 27 14 1 ....J..:.:.:.... 00 TOTAL 1992 539 721 449 2575 1141 529 1438 726 753 0I t..J --T-O-T--A-L---=--S-U-M---O-F---B-L-O--C-K--S-;--E-A-C--H--B-L--O-C-K---C-O--N-S-I-S-T--S--O-F---A--5---M-I-N-U--T-E---P-E-R-I-O--D-.--------------------------------------------------------------------------------------- 00 ~ n>~..I...... 0 ..J:::.. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C41 (PAGE 9) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP V 10 MG/KG/DAY RAT NUMBER 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 --N-U-M--B-E-R---O-F--M--O-V--E-M-E-N--T-S----------------------------------------------------------------------------------------------------------------------------------------------- BLOCK 1 72 76 61 75 63 83 52 78 65 59 BLOCK 2 30 4 59 28 59 45 27 45 64 64 BLOCK 3 20 8 63 3 63 9 41 7 58 39 BLOCK 4 7 2 52 0 56 5 42 1 5 35 BLOCK 5 5 1 64 0 46 27 31 2 4 6 BLOCK 6 6 18 59 0 39 29 17 6 10 13 BLOCK 7 6 1 57 1 23 7 23 16 3 3 BLOCK 8 61 1 61 48 63 49 19 3 3 18 BLOCK 9 57 4 61 3 44 54 0 9 14 33 BLOCK 10 43 2 30 35 28 4 4 7 2 0 BLOCK 11 43 4 65 1 41 1 7 24 5 6 BLOCK 12 52 7 64 48 38 1 34 30 9 14 BLOCK 13 46 4 62 5 46 1 1 51 2 3 BLOCK 14 16 4 38 1 47 2 0 40 3 17 BLOCK 15 7 3 44 0 40 3 0 48 0 6 BLOCK 16 5 1 52 39 36 32 2 17 6 2 BLOCK 17 1 2 67 50 46 10 0 2 2 3 .,J:::.. BLOCK 18 6 24 52 44 39 47 1 5 4 4 ....... 00 TOTAL 483 166 1011 381 817 409 301 391 259 325 I 0 tv --T-O-T--A-L---=--S-U-M---O-F---B-L-O--C-K--S-; --E-A-C-H---B-L-O--C-K---C-O--N-S-I-S-T-S---O-F---A--5---M-I-N-U--T-E---P-E-R-I-O--D-.--------------------------------------------------------------------------------------- 00 ~ f>Jn ..I..... 0 Vl PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C41 (PAGE 10) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP V 10 MG/KG/DAY RAT NUMBER 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 --T-I-M--E---(S-E--C-O-N--D-S-)---S-P-E-N--T---IN---M--O-V-E-M--E-N-T------------------------------------------------------------------------------------------------------------------------------- BLOCK 1 162 128 132 104 152 151 148 147 134 204 BLOCK 2 17 1 120 16 157 119 121 104 123 188 BLOCK 3 13 14 122 0 125 6 58 4 107 74 BLOCK 4 6 1 60 0 126 1 66 0 2 84 BLOCK 5 3 3 87 0 86 29 55 0 2 11 BLOCK 6 6 25 100 0 49 56 35 6 14 19 BLOCK 7 1 1 94 0 21 2 25 20 1 0 BLOCK 8 52 0 84 54 106 76 23 1 2 19 BLOCK 9 78 5 94 2 81 72 0 3 16 50 BLOCK 10 34 0 39 19 35 1 2 11 0 0 BLOCK 11 54 2 98 0 53 0 5 17 4 13 BLOCK 12 90 7 81 65 68 0 39 20 4 13 BLOCK 13 49 4 121 4 86 0 0 55 1 7 BLOCK 14 28 2 51 0 89 0 0 47 1 38 BLOCK 15 3 2 58 0 54 0 0 51 0 5 BLOCK 16 1 0 65 27 34 45 0 9 3 1 BLOCK 17 0 1 86 61 61 4 0 2 1 1 ._p.... BLOCK 18 1 34 78 35 50 69 0 3 3 3 00 TOTAL 598 230 1570 387 1433 631 577 500 418 730 I 0 t....J --T-O-T--A-L---=--S-U-M---O-F---B-L-O--C-K--S-; --E-A-C--H--B-L--O-C-K---C-O--N-S-I-S-T-S---O-F---A--5---M-I-N-U--T-E--P--E-R-I-O--D-.--------------------------------------------------------------------------------------- 00 ~ n~_I .. 0 ' PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C42 (PAGE 1): NATURAL DELIVERY, IMPLANTATION SITES, AND PUP VIABILITY AND SEX - INDIVIDUAL DATA Fo GENERATION FEMALE RATS/Fl GENERATION LITTERS RAT/ LITTER NUMBER DURATION OF GESTATION (DAYS) N LITTER DELIVERED LIVE STILL- TOTAL BORN BORN BORN N N N 1 M F NUMBER OF LIVE PUPS AT COMPLETION OF DAY POSTPARTUM 8 15 22 M F M F M F MATERNAL DOSAGE GROUP I 0 MG/KG/DAY 19010 23 19012 23 19019 23 19021 23 19023 22 19041 22 19042 23 19044 22 19050 22 19053 23 19065 22 19068 22 19072 22 19074 23 19075 23 14 0 14 16 0 16 15 0 15 14 0 14 13 0 13 18 0 18 15 0 15 17 0 17 15 0 15 16 0 16 20 0 20 15 0 15 16 0 16 15(1) 0 15 16 0 16 4 10 5 11 8 7 9 5 7 6 6 12 6 9 8 9 5 10 9 7 9 11 6 9 8 8 4 10 11 5 4 9 5 11 8 7 9 5 7 5 6 12 6 9 8 8 5 10 8 7 9 10 5 9 8 8 4 10 11 5 4 9 5 11 8 7 9 5 7 5 6 12 6 9 8 8 5 10 8 7 9 10 5 9 8 8 4 10 11 5 4 9 5 11 8 7 9 5 7 5 6 12 6 9 8 8 5 10 8 7 9 10 5 9 8 8 4 10 11 5 MATERNAL DOSAGE GROUP II 0. 3 MG/KG/DAY 19004 22 19009 23 19016 23 19018 23 19026 23 19036 22 19037 23 19043 23 19047 23 19048 23 19052 22 19055 23 19061 22 19067 23 19071 23 18 0 18 7 0 7 15 0 15 14 0 14 19 0 19 16(1) 0 16 16 0 16 13 0 13 13 0 13 9 0 9 17 0 17 16 (1) 0 16 13 0 13 14 0 14 14 0 14 8 10 2 5 12 3 8 6 10 9 6 9 8 8 7 6 7 6 5 4 6 11 10 5 8 5 6 8 8 6 8 9 2 5 12 3 8 6 10 8 6 8 8 8 7 6 7 6 5 4 6 10 10 5 7 5 6 7 8 6 M = MALE F = FEMALE ( ) = NUMBER OF PUPS DYING PRIOR TO WEIGHING ON DAY 1 POSTPARTUM. 8 9 2 5 12 3 8 6 10 8 6 7 8 7 7 6 7 6 5 4 6 10 10 5 7 5 6 7 8 6 8 9 2 5 12 3 8 6 10 8 6 7 8 7 7 6 7 6 5 4 6 10 10 5 7 5 6 7 8 6 TOTAL IMPLANTATIONS N 15 17 17 16 16 18 17 18 17 16 20 15 16 17 16 19 8 15 16 ._.J.;.:.::.... 20 00 16 I 0 17 l'-.) 1145 0~0 12 18 ~ 16 n 13 16 ..I..... 15 0 -...) PROTOCOL 418-028: ORAL {GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST {SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C42 {PAGE 2): NATURAL DELIVERY, IMPLANTATION SITES, AND PUP VIABILITY AND SEX - INDIVIDUAL DATA Fo GENERATION FEMALE RATS/Fl GENERATION LITTERS RAT/ LITTER NUMBER DURATION OF GESTATION {DAYS) N LITTER DELIVERED LIVE STILL- TOTAL BORN BORN BORN N N N 1 M F NUMBER OF LIVE PUPS AT COMPLETION OF DAY POSTPARTUM 8 15 22 M F M F M F TOTAL IMPLANTATIONS N MATERNAL DOSAGE GROUP III 1 MG/KG/DAY 19003 22 16 0 16 8 8 8 8 8 8 8 8 17 19007 22 18 0 18 7 11 7 10 7 10 7 10 18 19008 22 15 0 15 7 8 7 7 7 7 7 7 16 19013 23 15 0 15 9 6 9 6 9 6 9 6 15 19014 NOT PREGNANT 19015 23 15 0 15 9 6 9 6 9 6 9 6 15 19017 23 14 0 14 6 8 6 8 6 8 6 8 14 19024 23 15 0 15 9 6 9 6 9 6 9 6 16 19029 23 16 0 16 9 7 8 7 8 7 8 7 17 19034 23 13 1 14 6 7 6 7 6 7 6 7 15 19038 NOT PREGNANT 19056 23 14 0 14 7 7 7 7 7 7 7 7 14 19057 23 17 0 17 9 8 9 8 9 8 9 8 17 19060 22 14 0 14 8 6 8 6 8 6 8 6 15 19064 23 18 0 18 9 9 9 9 9 8 9 8 17 MATERNAL DOSAGE GROUP IV 3 MG/KG/DAY 19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073 23 10 (1) 1 11 23 16 0 16 23 14 0 14 22 15 0 15 22 17 0 17 23 15 0 16 [l] NOT PREGNANT NOT PREGNANT; MATING NOT CONFIRMED 23 5 0 5 23 13 0 13 22 15 0 15 23 13 1 14 23 13 (1) 1 14 23 17 0 17 23 14 0 14 3 6 6 10 6 8 6 9 7 10 6 9 3 2 8 5 9 6 2 11 5 7 6 11 8 6 3 6 6 10 6 8 5 9 7 10 6 9 3 2 8 5 9 6 2 11 5 7 6 11 7 6 3 6 6 10 6 8 5 9 7 10 6 9 3 2 8 5 9 6 2 11 5 7 6 10 7 6 3 6 6 10 6 8 5 9 7 10 6 9 3 2 8 5 9 6 2 11 5 7 6 10 7 6 14 16 16 15 .+..:.:.-... 17 00 16 I 0 1:-.J 00 6 ~ > 14 15 fdn 16 15 17 ..I..... 15 0 00 M = MALE F = FEMALE { ) = NUMBER OF PUPS DYING PRIOR TO WEIGHING ON DAY 1 POSTPARTUM. [ ] = NUMBER OF PUPS IN WHICH CANNIBALIZATION AND/OR AUTOLYSIS PRECLUDED THE DETERMINATION OF VIABILITY. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C42 (PAGE 3): NATURAL DELIVERY, IMPLANTATION SITES, AND PUP VIABILITY AND SEX - INDIVIDUAL DATA Fo GENERATION FEMALE RATS/Fl GENERATION LITTERS ------------------------------------------------------------------------------------------------------------------------------------ DURATION OF LITTER DELIVERED NUMBER OF LIVE PUPS AT TOTAL RAT/ GESTATION LIVE STILL- TOTAL COMPLETION OF DAY POSTPARTUM IMPLAN- LITTER (DAYS) BORN BORN BORN 1 8 15 22 TAT IONS NUMBER N N N N M F M F M F M F N ------------------------------------------------------------------------------------------------------------------------------------ MATERNAL DOSAGE GROUP V 10 MG/KG/DAY ------------------------------------------------------------------------------------------------------------------------------------ 19001 23 11 0 11 4 7 4 7 4 7 4 7 11 19006 23 19 (1) 1 20 6 12 5 12 5 12 5 12 20 19011 23 13 0 13 7 6 7 6 7 6 7 6 14 19020 22 13 0 13 8 5 8 5 8 5 8 5 14 19022 23 16 (1) 0 16 9 6 9 5 9 5 9 5 16 19025 22 20 0 20 13 7 13 7 13 7 13 7 20 19027 23 14 0 14 4 10 4 10 4 10 4 10 14 19028 23 12 1 13 5 7 5 7 5 7 5 7 15 19030 22 13 0 13 6 7 6 7 6 7 6 7 16 19031 22 15 0 15 8 7 7 7 7 7 7 7 15 19032 23 14 0 14 7 7 7 7 7 7 7 7 17 19033 22 14 0 14 6 8 6 8 6 8 6 8 14 19049 23 15 0 15 11 4 11 4 11 4 11 4 16 19059 23 15 0 15 10 5 10 5 10 5 10 5 15 19070 22 14 (1) 0 14 8 5 8 5 8 4 8 4 14 M = MALE F = FEMALE ( ) = NUMBER OF PUPS DYING PRIOR TO WEIGHING ON DAY 1 POSTPARTUM. -.i:::. 00 I 0 tv 00 > ~ ~(J I 0'""'""" \0 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C43 (PAGE 1) : PUP BODY WEIGHT LITTER AVERAGES FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - Fl GENERATION LITTERS RAT/ LITTER NUMBER DAY 1 M F T DAY 8 M F T DAY 15 M F T DAY 22 M F T MATERNAL DOSAGE GROUP I 0 MG/KG/DAY 19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075 6.8 6.6 6.6 16.4 15.9 16.1 28.4 27.7 27.9 41.9 40.0 40.6 6.6 6.4 6.5 13.8 13.6 13.7 26.5 25.5 25.8 42.7 40.6 41.2 6.6 6.2 6.4 15.4 14.4 14.9 28.6 26.5 27.6 40.0 37.2 38.7 6.4 5.9 6.2 12. 7 11. 9 12. 4 23.4 22.1 22.9 35.8 33.8 35.1 6.3 6.2 6.2 16.8 16.5 16.7 32.8 32.1 32.5 46.1 44.4 45.4 6.2 6.0 6.1 13.0 13.0 13.0 24.1 23.8 23.9 32.6 32.5 32.5 6.5 6.4 6.4 14.1 13.6 13.8 26.4 26.3 26.4 36.4 35.6 35.9 5.7 6.0 5.8 13.8 13.0 13.4 26.8 25.2 26.0 42.6 40.5 41.5 6.6 6.2 6.3 14.6 13.7 14.0 27.1 25.7 26.2 36.4 35.1 35.6 6.4 6.4 6.4 15.6 15.4 15.5 29.3 28.2 28.8 35.9 35.5 35.7 6.0 5.7 5.8 13.2 12.2 12.7 24.8 23.4 24.0 32.4 30.8 31.6 6.8 6.4 6.6 17.2 15.8 16.3 29.7 27.4 28.2 47.7 45.1 46.0 5.9 5.5 5.7 12.3 11.9 12.1 22.7 21.6 22.2 31.7 30.0 30.8 7.1 6.7 6.8 17.7 16.8 17.0 27.4 27.4 27.4 35.2 34.0 34.4 6.2 6.3 6.2 12.9 13.0 12.9 22.3 23.1 22.6 36.1 36.1 36.1 MATERNAL DOSAGE GROUP II 0.3 MG/KG/DAY 19004 5.7 5.4 5.5 13.5 11.9 12.7 24.5 22.3 23.3 31.1 28.8 29.9 19009 7.2 7.0 7.0 15.4 15.5 15.5 34.4 33.5 33.8 56.4 53.2 54.1 19016 6.4 6.1 6.4 14.6 12.9 14.2 27.7 23.1 26.8 46.3 38.1 44.6 19018 7.1 6.5 6.8 15.3 14.4 14.9 28.3 25.6 27.2 45.6 41.6 43.8 19026 7.1 6.5 6.8 13.7 12.1 13.0 25.0 22.7 24.0 31.8 29.4 30.7 19036 6.2 5.6 5.8 11. 6 9. 6 10. 4 26.9 24.1 25.4 41.1 36.8 38.8 ..f.;.:.:.... 19037 5.6 5.4 5.5 11. 5 11. 2 11. 4 18.3 18.0 18.2 31.2 29.2 30.3 00 19043 6.6 6.2 6.4 14.0 13.4 13.7 29.4 28.3 28.9 46.4 43.7 45.2 I 0 19047 7.2 6.8 7.0 15.3 14.4 14.9 28.2 27.0 27.6 38.2 37.3 37.8 tv 1199005428 66..42 56..29 66..30 1116..10 1106..28 1106..18 3223..61 3222..84 3222..88 4395..08 4365..49 4375..89 0~0 > 19055 6.7 6.4 6.6 14.3 13.1 13.9 26.4 25.1 26.0 39.8 37.2 38.9 19061 5.8 5.6 5.7 13 . 8 12 . 8 13 . 4 24.8 24.6 24.8 32.2 33.8 32.8 ~ 19067 7.0 6.5 6.7 13 . 7 13 . 3 13 . 5 29.4 28.l 28.7 40.2 38.8 39.4 n 19071 6.5 6.7 6.6 11. 4 11. 7 11. 5 24.8 24.5 24.7 40.0 39.7 39.9 I ............ M = MALE F = FEMALE T = TOTAL (SUM OF PUP WEIGHTS/NUMBER OF LIVE PUPS) DAY = DAY POSTPARTUM 0 ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C43 (PAGE 2) : PUP BODY WEIGHT LITTER AVERAGES FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - Fl GENERATION LITTERS RAT/ LITTER NUMBER DAY 1 M F T DAY 8 M F T DAY 15 M F T DAY 22 M F T MATERNAL DOSAGE GROUP III 1 MG/KG/DAY 19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064 6.6 6.0 6.3 6.3 5.8 6.0 6.2 5.7 6.0 7.0 6.4 6.8 NOT PREGNANT 6.7 6.2 6.5 7.4 6.9 7.1 6.2 5.8 6.1 6.3 5.8 6.1 6.8 6.4 6.6 NOT PREGNANT 6.8 6.6 6.7 6.6 6.4 6.5 6.9 6.4 6.7 6.7 6.2 6.5 13.5 13.7 14.7 15.2 12.1 12.3 14.1 13.9 12.8 12.9 14.4 14.7 14.0 14.8 14.5 14.1 15.3 13.1 14.4 13.4 12.2 14.3 13.7 14.5 14.1 13.2 14.8 15.1 13.1 14.8 12 .1 14.8 12.9 13.4 11. 5 14.9 13.0 14.2 11. 8 23.2 24.5 29.2 27.9 21.3 21.7 28.1 25.1 22.2 22.9 28.6 26.8 26.3 27.6 27.4 26.3 30.4 24.9 25.8 25.4 22.2 28.6 25.8 26.6 26.6 24.4 29.4 29.6 23.6 29.2 22.8 28.8 23.2 26.4 22.2 29.2 23.4 28.0 22.5 30.4 33.6 41.5 47.0 28.1 30.5 39.0 42.3 29.2 31.8 40.2 45.1 38.4 45.8 40.0 43.7 41.2 35.9 44.2 37.5 34.6 39.0 37.4 44.9 39.0 39.5 40.0 41.4 32.7 46.6 27.8 39.8 32.0 42.8 30.2 40.6 32.4 45.0 28.9 MATERNAL DOSAGE GROUP IV 3 MG/KG/DAY 19002 7.6 7.1 7.3 19.1 17.9 18.3 35.5 33.1 33.9 48.0 45.4 46.3 19005 6.5 5.8 6.0 13 . 2 13 . 0 13 . 1 24.2 23.7 23.9 33.2 31.7 32.2 19035 7.2 6.7 6.9 12.9 12.5 12.6 23.3 22.5 22.8 33.8 32.3 32.9 19039 5.9 5.4 5.6 11.1 10.2 10.6 22.9 21.2 21.8 35.1 32.4 33.4 19040 5.4 5.1 5.2 11.6 10.9 11.2 25.2 23.4 24.1 31.7 29.3 30.3 19045 6.5 6.6 6.6 11.7 12.0 11.9 24.0 23.6 23.8 37.6 36.2 36.7 ~ 19046 NOT PREGNANT 0"""0""' 19051 NOT PREGNANT; MATING NOT CONFIRMED I 0 19054 7.4 7.5 7.4 20.1 21.2 20.6 41.2 40.4 40.9 57.1 56.6 56.9 tv 19058 19062 6.6 6.5 6.6 14.9 14.6 14.8 27.8 27.2 27.6 46.4 45.1 45.9 6.9 6.6 6.8 16.7 15.8 16.3 30.7 29.4 30.2 42.4 40.1 41.4 00 ~ > 19063 7.0 6.9 6.9 14.6 15.2 15.1 29.8 30.0 29.9 47.6 46.2 46.4 19066 6.5 6.3 6.4 15.8 15.9 15.9 30.9 30.8 30.8 43.8 43.0 43.3 ~ 19069 5.9 5.7 5.8 10.3 9.7 9.9 19.3 20.4 20.0 30.1 33.4 32.2 n 19073 7.2 6.8 7.0 13.9 12.8 13.4 27.7 25.6 26.8 44.3 40.9 42.8 I M = MALE F = FEMALE T = TOTAL (SUM OF PUP WEIGHTS/NUMBER OF LIVE PUPS) DAY = DAY POSTPARTUM """""' """""' ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS. """""' PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C43 (PAGE 3) : PUP BODY WEIGHT LITTER AVERAGES FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - Fl GENERATION LITTERS RAT/ LITTER NUMBER DAY 1 M F T DAY 8 M F T DAY 15 M F T DAY 22 M F T MATERNAL DOSAGE GROUP V 10 MG/KG/DAY 19001 6.8 6.6 6.6 14. 0 14.3 14.2 26.6 26.6 26.6 44.1 44.0 44.1 19006 6.5 6.1 6.2 13. 8 13 .1 13.3 25.4 23.7 24.2 35.2 32.7 33.4 19011 6.9 6.6 6.8 13. 9 13.6 13.8 26.2 25.5 25.9 36.4 35.5 36.0 19020 5.8 5.5 5.7 9.2 9.1 9.2 15.7 15.4 15.6 15.4 15.5 15.5 19022 6.0 5.7 5.9 15.3 14. 9 15.2 29.0 27.0 28.3 36.3 34.5 35.7 19025 5.4 5.0 5.3 12.9 11. 0 12.3 24.2 20.4 22.9 30.8 26.8 29 .4 19027 7.3 6.5 6.8 12.6 12.l 12.2 23.6 21. 9 22.4 33.0 31.1 31. 6 19028 6.7 6.3 6.4 13 .1 13.2 13.2 25.9 25.9 25.9 39.8 40.1 40.0 19030 6.4 6.1 6.2 15.0 14.3 14.6 29.5 28.1 28.7 40.1 38.2 39.1 19031 5.9 5.7 5.8 12.3 11. 9 12.1 27.6 25.7 26.6 44.8 41.1 43.0 19032 7.3 6.9 7.1 14. 6 13.2 13.9 25.9 24.4 25.2 35.9 34.2 35.1 19033 6.6 6.0 6.2 13.8 12.6 13.1 27.4 25.2 26.2 44.1 41. 0 42.4 19049 6.7 6.2 6.6 12.6 11.0 12.2 25.4 22.8 24.7 36.8 32.9 35.7 19059 7.0 6.5 6.9 12.3 11. 0 11.9 24.9 21.3 23.7 34.6 30.4 33.2 19070 6.5 6.3 6.4 15.4 14.8 15.2 29.8 28.0 29.2 49. 6 46.8 48.7 ------------------------------------------------------------------------------------------------------------------------------------ M = MALE F = FEMALE T = TOTAL (SUM OF PUP WEIGHTS/NUMBER OF LIVE PUPS) DAY = DAY POSTPARTUM ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS. ~ ~ 00 I 0 t....:> 00 ~ ~nI ~ ~ t....:> PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C44 (PAGE 1) : PUP BODY WEIGHTS FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - Fl GENERATION PUPS PUP # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 RAT/ LITTER # MATERNAL DOSAGE GROUP I 0 MG/KG/DAY POSTPARTUM DAY 1 19010 19012 19019 19021 19023 19041 19042 19044 19050 "19053 19065 19068 19072 19074 19075 6.8 7.0 7.4 6.0 6.9 6.8 7.3 6.9 5.1 6.5 6.8 7.0 6.3 6.0 6.5 6.3 6.5 6.9 7.0 6.4 6.1 6.5 6.8 6.2 6.6 6.2 6.7 6.6 6.1 6.4 6.8 6.2 6.5 6.6 6.4 6.9 6.7 6.8 6.3 6.4 6.3 6.0 6.2 6.3 6.0 6.7 6.4 6.5 6.7 6.7 6.1 6.4 6.4 6.2 5.6 5.5 6.1 6.2 6.0 6.9 6.2 6.2 5.8 6.1 6.2 6.5 6.0 6.1 6.2 6.1 6.2 6.3 6.3 5.8 6.1 6.3 6.1 6.6 6.5 5.9 6.0 6.6 6.4 6.3 5.9 5.8 6.0 6.0 5.4 5.6 6.2 7.2 6.9 6.3 6.5 6.1 6.3 6.4 6.4 7.0 6.5 6.1 6.3 6.5 6.1 5.8 5.0 5.7 5.8 5.9 6.1 6.1 5.3 5.4 6.3 6.1 6.7 6.0 6.6 6.3 5.4 5.1 6.9 6.6 6.9 6.5 6.2 5.9 6.3 5.7 6.2 6.5 6.0 6.1 6.1 6.4 6.5 6.5 6.6 6.5 6.1 6.2 6.9 6.5 6.8 6.0 6.2 6.5 6.4 6.3 6.6 6.3 6.3 5.9 5.8 5.6 5.9 6.0 5.9 6.1 6.0 6.7 5.2 5.7 6.0 6.2 5.8 5.4 5.4 5.9 5.7 5.6 5.7 7.0 6.6 6.6 7.0 6.8 7.0 6.2 6.8 6.7 6.3 6.5 6.0 6.0 6.6 6.7 5.9 5.7 6.1 6.0 5.5 6.0 6.1 6.0 5.5 5.7 5.5 5.4 5.6 5.6 5.2 5.5 6.9 7.2 7.3 7.0 MD 1 7.0 6.8 7.1 6.6 7.1 7.0 6.0 6.6 6.3 6.7 6.4 6.1 5.5 6.4 5.8 6.4 6.4 6.3 6.5 6.5 6.2 6.4 6.3 6.3 6.0 6.3 RAT/ LITTER # MATERNAL DOSAGE GROUP II 0. 3 MG/KG/DAY POSTPARTUM DAY 1 19004 5.6 5.9 5.9 5.8 5.9 5.2 5.5 5.8 5.0 5.5 5.7 5.3 6.1 5.2 5.3 4.9 5.8 5.4 19009 7.5 7.0 6.7 6.9 7.1 6.8 7.4 19016 6.6 6.3 6.5 6.1 6.9 6.7 6.4 6.7 6.3 6.0 5.9 6.8 5.7 6.2 6.5 19018 7.2 6.7 7.2 6.9 7.2 7.2 7.7 6.9 6.1 6.6 6.4 6.4 6.9 6.5 19026 6.7 7.1 7.3 7.3 6.9 6.7 7.4 7.1 7.4 7.0 6.7 6.9 6.6 6.4 6.1 6.7 5.7 6.6 6.5 19036 6.1 6.4 6.6 6.0 6.2 5.6 6.6 5.7 4.9 5.8 4.6 5.5 5.6 5.9 5.7 FD 1 .J::.. - 19037 5.7 5.9 5.6 5.6 5.9 5.6 5.6 4.9 5.1 5.8 5.9 5.3 5.0 5.4 5.3 5.4 00 19043 6.8 6.7 6.1 6.9 6.8 6.7 6.6 6.3 5.8 6.2 6.4 6.2 6.0 I 0 19047 7.1 7.7 7.9 7.6 6.6 6.5 7.1 6.8 6.5 6.8 6.7 6.7 7.5 t-.J 1199005428 66..70 66..61 66..34 66..33 56..39 66..21 66..21 56..46 55..89 6.5 5.4 6.3 6.1 5.6 6.0 5.7 5.7 0~0 > 19055 6.8 6.5 7.2 6.6 7.0 6.8 6.4 6.6 6.7 6.4 MD 1 6.8 6.6 6.2 6.3 6.0 19061 5.9 5.9 5.8 5.6 5.7 6.3 5.7 5.6 5.8 5.6 5.7 5.6 5.3 ~ 19067 7.2 6.8 7.3 6.9 7.1 7.0 6.5 7.0 6.2 6.2 6.6 6.8 6.5 6.2 n 19071 6.6 6.3 5.4 7.4 6.6 6.9 6.7 6.4 7.0 6.5 6.5 6.5 6.9 6.9 I - ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS. (J..l FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED) NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C44 (PAGE 2): PUP BODY WEIGHTS FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - Fl GENERATION PUPS PUP # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 RAT/ LITTER # MATERNAL DOSAGE GROUP III 1 MG/KG/DAY POSTPARTUM DAY 1 19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064 7.2 7.0 6.8 6.5 6.5 6.6 6.3 5.8 6.7 6.0 6.1 6.3 5.8 5.1 5.7 5.9 6.4 6.3 6.5 5.8 6.3 6.6 6.2 6.6 5.6 5.6 5.6 5.9 5.7 6.1 5.4 5.9 5.6 5.6 6.4 6.0 6.0 6.5 5.9 6.3 6.6 6.1 5.6 6.2 6.2 6.1 6.3 5.7 3.5 7.4 7.1 6.8 7.3 7.3 7.0 6.5 7.0 6.8 6.5 7.3 5.9 6.1 6.5 6.4 NOT PREGNANT 6.5 7.2 6.6 6.5 6.4 6.7 6.9 6.8 6.5 6.2 6.3 6.2 6.3 6.3 5.9 7.1 7.2 7.8 7.7 7.3 7.2 6.7 7.1 6.7 7.2 6.5 8.1 7.4 5.7 5.7 6.4 6.2 5.8 6.5 6.2 6.3 6.4 6.8 5.4 5.6 6.3 5.7 5.6 6.4 6.6 6.2 6.4 6.5 6.1 6.4 6.8 6.1 5.8 6.0 5.9 6.0 5.7 5.4 6.3 5.7 7.1 6.9 6.6 6.8 6.8 6.6 6.4 6.4 6.9 7.1 5.9 6.2 6.3 FS NOT PREGNANT 6.8 6.9 6.4 6.9 6.7 6.7 7.5 6.7 6.1 6.3 6.4 6.9 6.9 6.6 6.8 6.5 6.5 6.9 6.6 6.7 6.1 6.6 6.6 6.1 6.3 6.8 6.5 6.8 6.2 5.8 6.6 7.0 6.8 6 .4 6.5 7.1 7.3 7.2 6.8 6.1 5.8 6.6 6.8 6.5 6.4 6.8 6.9 6.6 6.9 6.8 6.1 6.5 6.9 7.0 6.0 6.5 6.2 6.4 6.7 6.1 5.9 6.4 6.1 RAT/ LITTER # MATERNAL DOSAGE GROUP IV 3 MG/KG/DAY POSTPARTUM DAY 1 19002 7.7 7.6 7.5 MS 7.2 7.1 6.9 7.2 7.3 7.1 FD 1 19005 6.9 6.2 7.0 5.9 6.4 6.4 6.2 5.9 5.6 5.4 5.6 6.0 5.7 6.0 6.0 5.7 19035 7.3 7.3 7.4 7.2 6.9 6.9 6.6 6.6 6.6 7.0 6.7 6.5 6.7 6.8 19039 6.4 5.8 5.4 5.9 5.7 6.4 5.4 5.9 5.5 5.5 5.5 4.8 5.4 6.0 5.1 19040 5.5 5.1 5.8 4.9 5.7 5.3 5.3 5.2 5.1 5.2 5.3 5.4 5.4 5.4 4.8 4.8 4.5 19045 6.5 7.1 6.5 7.1 5.4 6.5 6.2 6.7 6.5 6.8 6.8 6.3 6.3 6.4 7.2 uu ~ - 19046 NOT PREGNANT 00 19051 NOT PREGNANT; MATING NOT CONFIRMED I 0 19054 7.0 7.5 7.7 7.6 7.4 t'...J 19058 6.2 7.0 6.9 6.3 6.6 6.6 6.3 7.1 6.7 6.4 6.1 6.8 6.6 00 ~ 19062 7.2 6.9 6.9 6.9 6.9 6.9 7.0 7.3 6.4 6.1 6.6 6.6 6.6 6.7 6.7 19063 6.7 7.3 7.6 6.8 6.5 6.5 6.8 6.6 6.5 7.3 6.7 7.1 7.4 FS 19066 6.4 7.2 6.6 6.1 6.2 6.3 MD 1 6.2 5.9 6.0 6.7 6.3 6.5 FS ~ 19069 6.1 5.8 6.1 5.1 6.1 6.0 6.3 5.7 5.2 5.8 5.7 6.2 4.5 5.8 5.8 5.8 5.8 n 19073 7.2 7.0 6.8 7.8 6.9 7.2 7.7 7.4 7.0 6.7 6.4 6.6 7.1 6.7 I - ALL WEIGHTS WERE RECORDED IN GRAMS (G) . MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS. ~ FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED) NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C44 (PAGE 3): PUP BODY WEIGHTS FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - Fl GENERATION PUPS PUP # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 RAT/ LITTER # MATERNAL DOSAGE GROUP V 10 MG/KG/DAY POSTPARTUM DAY 1 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070 6.9 6.4 6.8 7.0 6.7 6.1 6.5 6.6 6.8 6.5 6.7 7.0 6.3 6.6 7.0 6.1 5.8 5.9 6.1 6.4 6.5 5.6 6.5 6.2 6.0 6.7 5.9 6.0 5.9 FD 1 FS 7.4 7.3 6.3 7.0 6.9 6.7 6.8 7.1 6.7 6.5 6.2 6.6 6.3 6.3 6.0 6.1 6.7 4.5 5.4 5.7 5.6 4.9 5.2 5.5 5.4 6.3 6.2 6.0 5.8 6.1 5.7 6.5 5.9 6.0 6.1 MD 1 5.4 5.5 5.4 5.9 5.9 6.0 5.1 5.0 5.2 5.4 5.4 5.4 5.6 6.1 5.1 5.6 5.7 5.5 4.8 5.2 4.8 5.2 5.2 4.9 5.0 5.0 7.3 6.9 8.1 6.9 7.2 6.0 6.4 6.8 6.8 6.6 5.9 6.3 6.9 6.5 6.8 7.1 6.1 6.8 6.6 6.2 5.9 6.6 6.5 6.5 6.5 5.9 FS 6.6 5.9 6.8 6.9 6.0 6.4 5.9 6.3 4.9 6.5 6.3 6.1 6.7 6.2 6.3 6.2 5.0 5.9 5.8 5.9 5.9 6.1 5.7 5.5 5.5 5.5 5.9 5.9 7.6 7.4 7.2 7.4 7.2 7.1 7.4 6.9 6.9 7.2 7.0 7.1 6.7 6.7 6.4 6.7 6.5 6.9 6.4 6.6 6.0 5.9 5.9 6.1 6.0 5.8 6.4 5.9 7.0 6.4 7.0 6.4 7.3 6.6 6.8 6.4 6.7 6.3 7.2 6.8 6.0 6.1 5.9 7.2 7.0 6.6 6.8 7.2 7.0 7.4 7.0 7.3 6.8 6.5 6.5 6.4 6.5 6.8 6.8 6.6 6.0 6.5 6.5 6.4 6.3 6.7 6.2 5.7 6.6 6.7 6.4 FD 1 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED) NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED. PUPS. .~ ....... 00 I 0 t-....) 00 ~ n~..I...... ........ V'l PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C44 (PAGE 4): PUP BODY WEIGHTS FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - Fl GENERATION PUPS PUP # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 RAT/ LITTER # MATERNAL DOSAGE GROUP I 0 MG/KG/DAY POSTPARTUM DAY 8 19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075 15.9 14.2 15.2 13.3 16.5 10.5 13.9 14.5 13.8 15.6 14.7 17.7 10.9 16.7 14.1 16.5 14.2 15.1 13.2 18.1 14.9 15.7 13.2 13.9 14.6 14.8 17.0 11.8 18.1 13.3 15.9 13.3 15.7 13.1 17.2 12.5 13.8 15.2 14.6 15.7 13.4 17.0 12.4 18.2 13.3 17.3 14.4 15.1 13 . 5 16.9 13 . 5 12.9 13.5 15.2 16.5 12.4 16.9 13.2 17.8 10.8 17.0 12.9 16.2 12 . 0 15.7 13 . 9 14.9 15.1 15.7 14.9 11.8 17.4 13.2 MD 1 13.0 14.7 13.7 15.9 13 . 0 17.2 12 . 8 13.5 15.6 12.6 16.0 15.1 MD 2 11.2 17.5 14.2 18.2 13.1 14.7 13.3 16.0 12.7 13. 7 12.2 11. 6 15.6 13 .2 16.9 12.8 16.2 10.8 12.1 13 .4 15.0 11.8 16.3 14.1 14.9 10.9 12.6 16. 0 13.0 15.7 13.1 16.6 13.5 16.2 13. 3 13.8 11.4 15.8 13.7 13.5 12.1 15.1 MD 5 10.0 16.4 11.6 17.8 12.5 16.0 13.9 14.5 12.5 16.1 14 .1 13. 9 13.4 15.0 15.3 12.9 15. 6 11.1 15.3 14. 2 16.7 13.7 15.3 12.0 17.3 12. 9 12. 9 11.7 15.6 15.7 12.6 15. 6 12. 0 17.4 11. 9 16.1 14.1 14. 9 11.8 17.1 11.6 12.7 13.8 13. 4 16.6 14.9 15.3 12. 6 17.5 10.7 16.3 12.1 12. 9 11.6 FD 4 11.4 13.2 14.2 14. 4 14.8 10.6 15.0 11. 8 15.9 13.4 FD 3 14.1 14.7 11. 7 13.4 13 .4 14.0 12.8 15.2 11. 7 15.8 12.5 18.2 13.5 13.4 14.8 15.8 13. 9 10.7 13 .6 15.5 10.4 16.1 11. 9 15.4 13. 8 14.8 11. 8 13.8 14. 8 12.7 11.4 13.5 11. 6 FM 2 12 .1 13.5 11. 3 13 .2 FD 5 RAT/ LITTER # MATERNAL DOSAGE GROUP II 0. 3 MG/KG/DAY POSTPARTUM DAY 8 19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071 15.2 15.3 15.9 15.9 14.4 12.1 12.0 13.5 14.5 16.6 11.5 14.0 14.3 13.5 10.1 11.5 15.5 15.2 15.6 12.8 11.3 9.3 14.1 16.0 17.2 10.3 13.4 13.7 14.6 9.2 14.9 16.9 15.5 14.5 14.3 12.5 11.2 13.0 14.0 16.3 10.2 14.3 13.5 14.3 11.6 11.8 15.4 13.2 15.2 13.2 10.1 12.2 14.7 15.5 15.4 11.9 13.8 12.8 12.6 10.8 13.6 15.3 14.5 15.5 15.8 11.5 12.5 13.9 16.1 15.2 11.1 13.8 13.9 13.8 12.0 14.5 15.4 15.0 15.0 13.4 11.8 11.7 14.0 15.3 16.4 10.8 14.2 13.9 13.4 11.3 13.8 14.6 14.8 15.4 13.3 10.5 10.7 14.6 15.7 15.8 10.7 16.1 14.3 12.5 13.4 13.0 13.0 15.2 13.9 7.5 12.7 14.2 11.4 16.2 11.4 14.3 MD 3 13.5 12.9 12.3 13.8 15.7 12.1 11.3 12.1 13.6 14.5 16.2 11.6 15.4 13.2 13.3 12.1 12.6 14.3 13.1 13.4 13.3 10.8 13.2 14.3 10.5 13.7 12.1 13.2 10.4 12.4 14.8 13.8 13.9 6.4 11.8 13.6 15.6 10.4 MD 1 13.0 13.1 12.5 13.3 15.0 15.8 12.0 8.6 10.7 12.3 16.0 11.0 11.4 12.7 13.5 13.2 12.3 14.0 13.9 12.1 7.6 11.4 13.3 14.5 11. 0 14 .2 12.8 14.1 9.5 10.0 14.7 13.8 11. 7 11.5 9.3 10. 6 14 .2 FD 8 12.5 13.6 10.1 11. 4 FD 2 11.7 11.6 12.9 10.6 12.6 FD 1 12.0 9.0 13.0 10.3 11.2 FD 5 FM 6 11. 6 FD 8 ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED) NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED. PUPS. -.J:::.. 00 I 0 t-....) ;0.c0; -~ n I 0\ PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C44 (PAGE 5) : PUP BODY WEIGHTS FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - Fl GENERATION PUPS PUP # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 RAT/ LITTER # MATERNAL DOSAGE GROUP III 1 MG/KG/DAY POSTPARTUM DAY 8 19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064 13.9 13.6 14.3 14.1 13.7 13.3 13.7 14.8 15.4 15.8 14.9 14.0 NOT PREGNANT 13.9 14.5 14.3 14.l 15.7 15.7 14.6 14.2 14.7 14.3 14.l 13.5 15.1 15.0 15.5 NOT PREGNANT 15.0 14.9 16.0 13.2 13.1 12.6 16.1 14.9 16.2 11.1 11.6 14.3 11.1 13.7 15.6 15.1 14.2 14.4 13.8 14.3 15.4 14.6 13. 5 14.9 10.1 13.5 12.5 15.1 15.1 15.2 15.0 14.3 14.4 15.7 15.4 12. 8 13.2 10.8 14.1 14.8 14.7 15.3 13.5 13.6 14.9 13.7 15.0 14.3 13.0 14.1 10.9 13.5 13.9 13.7 15.9 14.1 13.6 14.0 13.8 14.1 15.4 13.2 14.0 13.8 13.7 11.7 14.8 15.4 12.9 15.3 15.1 14.9 12.7 14.1 12.4 14.6 11. 7 11.7 13.5 14.0 15.6 13.9 12.3 14.9 MM 2 14.6 15.4 13.8 12.9 14.9 12.9 11.2 13.6 14.2 11.1 15.3 13.6 12.7 14.8 14.5 14.0 12.2 9.7 12.3 12.7 14.6 12.6 13.2 15.1 12.7 10.9 15.2 15.5 14.2 14.5 11.5 11.1 11.9 15.2 15.3 13.8 15.2 13.3 12.6 14.0 15.2 12.1 13. 0 10.7 10.9 12.2 14.0 12.7 13.8 14.2 15.5 11.7 14.8 14.5 11. 9 15.8 11. 3 11.5 12.9 12.5 13.4 13.3 13.8 13.5 13.0 FS 14.3 12.1 12.0 13.8 14.2 11.7 FM 2 15.0 13.2 12.1 11.8 12.0 9.3 12.5 12.8 12.7 13.9 13.6 12.5 12.8 10.3 FD 2 13.4 RAT/ LITTER # MATERNAL DOSAGE GROUP IV 3 MG/KG/DAY POSTPARTUM DAY 8 19002 19.8 19.2 18.4 MS 18.3 17.9 17.3 17.9 17.9 18.2 FD 1 19005 13.6 11.9 14.8 12.2 12.5 14.0 13.4 12.2 12.8 13. 9 13. 3 13.9 13.1 12.9 12.3 12.7 19035 13.0 13.2 12.9 13.2 12.3 12.6 12.2 11.0 13.5 12.7 12.1 13.6 12.9 11.8 19039 10.4 11.2 12.1 11.6 10.1 MD 2 9.0 8.9 11.5 9.8 9.9 9.9 10.8 11.2 11.3 ~ 19040 12.5 10.5 11.8 13.0 9.7 12.0 11.8 9.8 11. 3 8. 5 11. 2 12.8 9.9 12.7 12.0 11.1 10.1 19045 12.0 12.8 11.5 11.7 9.8 12.4 12.3 12.7 11. 9 11.1 11. 3 13.1 12.9 11. 8 11. 0 uu .+..:.:.-... 19046 NOT PREGNANT 00 19051 NOT PREGNANT; MATING NOT CONFIRMED I 0 19054 20.7 20.4 19.2 21.5 21.0 N 1199006528 1146..42 1173..39 1174..38 1174..16 1166..67 1174..48 1164..46 1155..20 1156..97 1145..27 1146..29 1163..27 1155..51 15.6 15.2 0~0 19063 15.7 13.4 15.3 14.0 16.3 15.9 16.7 13.4 14.8 15.3 15.1 16.1 13.8 FS 1199006669 1160..66 1150..27 1151..54 1150..91 185..35 1161..50 MD9.81 1150..71 1170..41 186..43 1150..38 1150..30 1150..47 F6S.2 9.4 10.0 10.4 rd 19073 15.4 13.4 13.6 13.5 13.5 14.5 13.6 MM 3 12.9 13.3 12.4 13.3 12.7 11.9 (..I.1.... ......... ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS. -.l FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED) NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C44 (PAGE 6) : PUP BODY WEIGHTS FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - Fl GENERATION PUPS PUP # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 RAT/ LITTER # MATERNAL DOSAGE GROUP V 10 MG/KG/DAY POSTPARTUM DAY 8 19001 14.3 13.6 13.2 14.8 14.4 14.3 14.0 15.3 14.1 14.3 13.7 19006 12.9 13.5 13.8 14.8 14.2 MD 2 13.4 14.0 13.0 12.7 12.8 12.1 13. 7 11. 5 12.8 15.4 12.8 13.4 FD 1 FS 19011 13.9 14.2 13.8 14.3 13,.3 14.1 13.7 13.0 13.4 13 .2 14.9 13 .2 14 .1 19020 8.5 9.3 9.1 8.8 8.6 8.4 10.8 9.8 7.7 8.3 9.4 9.5 10.8 19022 15.8 15.3 16.2 14.8 15.3 15.2 14.8 15.6 14.5 MD 1 14.5 15.7 14.1 14.3 16.0 FM 2 19025 12.5 10.6 14.5 12.7 12.3 13.7 12.6 15.0 9.9 12.1 12.4 15.3 14.4 11. 5 11. 9 12.3 10.5 10.5 10.3 10.2 19027 12.0 13.2 13.1 12.2 10.8 11. 8 11. 8 11. 6 12.2 13.5 12.6 12.8 12.6 10.9 19028 13 .1 13. 7 13.3 11. 7 13. 8 13.2 12.9 13.7 12.6 14.5 13.4 12.4 FS 19030 15.6 14.5 14.9 15.7 13.7 15.3 15.0 14.4 14.5 11. 9 13.3 15.5 15.4 19031 12.7 10.7 12.4 11.3 13.6 12.9 12.6 MM 2 13.1 11.8 11.0 13.8 12.4 10.3 10.8 19032 13.6 15.2 15.0 14.6 15.2 13.4 14. 9 12.5 14.0 14.1 13.0 12. 5 13.4 13.1 19033 13.5 13.9 13.5 14.7 14.0 13.3 12.7 12.3 13.5 12.2 12.6 12 .1 13.0 12.4 19049 11. 5 13.7 13.1 11. 0 14 .1 12.8 12.5 12.1 14.8 12.7 10.4 12.5 12.7 9.3 9.4 19059 10.3 11. 5 12.8 13.1 12.5 13.0 12.3 13.0 12.1 12.4 9.9 11.5 11.4 11. 9 10.5 19070 15.8 13.2 14.3 15.2 16.1 16.4 15.8 16.0 14.7 16.9 14.8 14. 9 12.9 FD 1 ------------------------------------------------------------------------------------------------------------------------------------ ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS. FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED) NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED. ,._p_..... 00 I 0 t0 00 ~ > ~ (") ,,__I__.... 00 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C44 (PAGE 7) : PUP BODY WEIGHTS FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - Fl GENERATION PUPS PUP # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 RAT/ LITTER # MATERNAL DOSAGE GROUP I 0 MG/KG/DAY POSTPARTUM DAY 15 19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075 28.0 26.2 28.9 23.3 31.0 26.0 26.9 23.6 26.3 29.0 29.2 29.4 20.6 29.1 23.7 28.9 25.8 29.3 23.1 31.6 21.6 26.5 30.7 26.8 31.0 25.1 29.5 23.4 28.8 23.8 26.7 26.8 25.2 24.8 34.7 22.9 28.3 22.2 28.3 28.4 23.3 28.3 21.2 27.6 21.6 29.8 27.4 30.6 22.8 33.2 26.1 26.1 26.1 28.3 28.6 25.1 30.0 23.3 24.0 20.5 28.3 26.2 28.4 21.4 32.3 23.7 23.4 26.2 25.8 27.1 22.5 31.3 24.0 MD 1 23.0 30.1 26.1 29.1 23.5 34.8 24.3 27.3 29.8 26.9 31.1 24.2 MD 2 25.6 28.2 19.4 27.6 26.2 27.7 23.2 31.8 24.3 26.3 29.8 25.0 29.6 19.6 29.2 20.0 26.2 23.1 27.1 22.3 29.7 24.0 31.0 27.1 29.4 25.9 24.8 29.5 27.8 26.5 23.8 28.2 24.0 27.0 26.7 27.2 24.1 32.8 25.4 28.3 25.6 23.1 MD 5 26.8 28.2 23.1 27.6 21.9 28.6 25.2 25.4 21.3 32.8 20.5 26.2 27.2 27.5 27.1 27.2 27.6 20.4 26.3 22.2 28.2 23.7 22.9 22.8 32.6 25.6 27.0 21. 6 25.5 26.9 25.0 28.4 21. 3 26.8 22.6 28.9 25.9 28.6 21. 8 31.1 25.0 22.5 25.3 26.4 27.7 24.6 25.6 22.3 27.2 24.5 23.5 28.9 25.5 22.6 FD 4 25.8 26.2 26.1 26.0 28.7 22.9 26.7 20.7 25.8 22.7 FD 3 23.9 28.8 22.2 23.6 24.8 25.8 27.7 28.8 25.8 27.3 21.4 28.2 22.2 23.3 27.0 23.4 26.1 26.9 23.9 28.1 19.9 27.5 21. 9 29.0 21. 0 28.0 23.2 23.1 30.4 20.8 21. 5 24.9 19.6 FM 2 25.5 22.4 22.2 19.6 FD 5 RAT/ LITTER # MATERNAL DOSAGE GROUP II 0.3 MG/KG/DAY POSTPARTUM DAY 15 19004 22.4 25.9 25.7 24.5 20.9 26.3 23.6 26.5 18.7 21.1 19.0 21.5 26.8 23.0 22.6 23.2 24.6 FM 6 19009 34.4 34.4 32.6 32.8 33.2 35.0 33.9 19016 27.5 29.1 27.8 23.7 28.5 29.6 30.0 27.1 28.2 26.3 26.1 29.0 25.4 17.1 26.7 19018 29.6 27.0 28.1 30.5 26.6 27.1 28.8 28.8 26.3 23.1 28.4 26.4 24.9 24.6 19026 29.2 24.0 23.0 27.3 26.1 24.3 22.3 24.0 23.9 25.8 24.9 22.2 23.6 22.9 21.3 21. 8 23.2 21. 7 FD 8 19036 25.4 27.0 28.0 27.2 27.1 26.8 25.0 18.3 25.6 29.0 20.2 27.3 23.3 FMll FD 2 FD 1 .~ ....... 19037 18.8 18.6 16.8 19.2 15.6 19.5 20.2 17.9 19.3 19.7 15.9 17.8 19.6 17.5 15.9 FD15 00 19043 29.4 30.6 28.6 28.3 29.7 29.1 30.2 27.8 27.9 27.5 28.3 28.9 29.3 I 0 19047 29.5 28.7 29.2 29.5 26.9 28.0 25.8 26.5 23.3 29.0 28.8 29.3 24.8 tv 1199005428 3213..48 3213..59 3221..09 3234..48 2354..07 1380..97 3231..39 2343..89 3243..31 21.1 24.9 22.7 23.3 23.3 19.3 21.5 FD 5 0~0 > 19055 26.2 27.8 27.4 26.5 24.7 26.1 28.0 26.5 23.7 27.5 MD 1 25.0 24.4 23.6 26.8 25.6 19061 24.5 24.8 25.5 25.1 24.5 25.0 24.6 MD 3 24.9 24.3 24.8 24.1 25.1 &3 19067 29.5 29.9 29.9 29.4 29.0 28.9 29.4 27.9 26.8 27.7 28.6 27.5 28.6 FD 8 (") 19071 26.1 24.7 24.9 27.3 26.0 22.2 22.8 24.7 25.0 18.1 27.0 26.7 22.7 27.4 ..I...... ........ ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS. \0 FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED) NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C44 (PAGE 8): PUP BODY WEIGHTS FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - Fl GENERATION PUPS PUP # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 RAT/ LITTER # MATERNAL DOSAGE GROUP III 1 MG/KG/DAY POSTPARTUM DAY 15 19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064 24.4 21.2 23.5 24.8 25.5 25.5 31.1 28.7 29.9 29.0 27.3 27.4 NOT PREGNANT 27.5 25.0 29.2 27.1 28.9 28.4 26.0 27.7 28.8 26.9 27.4 23.1 30.5 30.5 30.8 NOT PREGNANT 28.7 30.6 30.8 21.9 24.4 22.8 27.7 31.8 29.9 21.6 25.0 21.1 25.1 25.1 26.9 28.4 23.2 27.9 29.8 26.1 29.8 29.5 24.6 30.3 23.9 23.5 25.3 28.3 28.8 25.9 27.8 26.4 27.0 30.9 27.8 22.2 27.2 26.5 24.8 24.1 29.2 29.4 24.7 25.7 26.3 25.8 29.8 31.3 24.6 29.0 21.9 24.5 21.5 30.5 28.3 27.7 28.2 26.7 26.7 27.6 28.2 24.1 28.5 22.6 18.8 23.4 29.2 27.9 26.7 28.1 25.7 27.4 28.2 29.7 24.3 29.3 20.8 21.2 21.4 27.8 25.0 27.2 26.4 28.9 MM 2 27.8 27.6 23.3 28.7 22.0 19.1 23.6 26.8 24.3 28.2 26.4 27.9 20.1 29.8 27.7 22.8 29.5 21.9 23.3 23.9 29.8 24.1 25.0 28.4 25.2 20.6 29.9 30.1 23.5 25.1 26.4 19.6 21.3 26.9 26.6 20.5 26.4 24.7 20.9 26.9 30.1 24.2 23.5 16.8 21.9 19.6 29.9 28.0 24.9 18.1 26.1 22.4 29.8 27.9 24.3 27.1 17.4 20.3 20.2 26.2 25.8 26. 5 24.8 24.9 24.5 FS 28.3 22.9 24.6 21. 6 21.3 21.0 FM 2 22.0 24.2 23.8 23.3 21. 9 24.3 23.4 21.1 23.8 22.9 26.7 21.4 22.8 22.1 FD 2 FMll RAT/ LITTER # MATERNAL DOSAGE GROUP IV 3 MG/KG/DAY POSTPARTUM DAY 15 19002 34.5 36.4 35.7 MS 33.1 33.6 32.9 32.4 33.7 33.0 FD 1 19005 23.1 26.5 23.4 24.8 22.1 25.2 24.8 23.7 24.2 24.0 24.0 25.1 21.1 24.7 22.5 23.0 19035 23.6 23.5 23.2 23.0 22.4 24.1 23.3 22.5 21.3 22.7 23.1 23.4 21.6 21.9 19039 24.7 19.3 24.0 23.5 23.0 MD 2 18.8 20.6 19.4 23.6 17.0 21.8 22.6 22.1 24.8 19040 26.1 26.l 26.3 27.4 22.4 24.2 23.9 22.4 27.3 24.6 22.6 21.4 27.5 25.6 24.4 20.1 18.1 19045 23.4 24.9 21.7 25.4 24.5 24.0 23.0 22.7 26.3 25.0 21.9 24.6 23.7 22.0 23.2 uu ..J:::.. ~ 19046 NOT PREGNANT 00 19051 NOT PREGNANT; MATING NOT CONFIRMED I 0 19054 39.0 41.2 43.5 40.1 40.8 t-...) 19058 19062 30.7 26.7 29.1 27.6 24.9 27.1 28.4 28.0 26.5 26.3 26.2 28.0 29.0 31.4 31.3 30.4 31.2 31.2 30.0 31.3 28.9 30.3 30.3 30.0 29.9 29.0 28.7 28.7 00 ~ > 19063 28.3 31.3 31.6 29.9 29.2 32.0 30.0 27.6 29.2 31. 9 30.7 26.8 30.8 FS 19066 31.4 31.2 30.0 32.0 30.1 30.0 MD 1 30.8 30.2 31.9 30.9 29.5 32.1 FS ~ 19069 16.8 21.7 19.4 19.6 18.2 19.9 19.5 21.8 17.0 21.4 22.3 21.5 20.9 20.0 19.8 19.9 FDlO 19073 26.7 27.5 29.3 27.1 28.0 28.1 27.3 MM 3 25.3 26.1 26.3 25.6 25.2 25.3 (j I ~ ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS. t-...) 0 FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED) NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C44 (PAGE 9) : PUP BODY WEIGHTS FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - Fl GENERATION PUPS PUP # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 RAT/ LITTER # MATERNAL DOSAGE GROUP V 10 MG/KG/DAY POSTPARTUM DAY 15 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070 27.5 23.2 27.0 17.0 30.9 25.6 23.5 28.5 29.1 25.3 25.9 27.4 27.2 26.4 30.1 26.3 26.7 25.9 13.8 27.6 24.5 24.2 22.7 29.3 24.6 26.9 28.2 26.1 24.3 29.4 26.2 26.2 27.1 15.3 30.0 24.4 25.0 27.8 29.7 30.7 26.4 27.1 25.8 28.1 31.0 26.2 25.7 26.2 14.8 29.7 23.7 21.9 25.5 30.9 28.8 23.9 27.0 26.1 25.6 30.4 26.6 25.4 25.8 16.6 28.7 26.2 21.7 25.1 29.3 27.8 26.7 27.1 24.5 23.8 29.7 26.2 MD 2 24.3 15.1 25.7 23.4 23.2 26.3 28.5 26.9 26.2 27.9 26.6 25.5 28.5 26.1 22.5 27.5 17.0 29.3 18.7 22.1 26.6 29.4 29.2 25.3 25.8 20.8 23.3 29.5 28.0 25.2 25.8 15.9 27.5 24.0 21.6 25.8 28.8 MM 2 25.5 25.3 25.2 22.7 30.1 26.4 27.5 24.2 14.9 31.4 23.8 22.2 27.4 24.0 26.4 24.5 25.4 24.0 24.1 30.5 25.8 23.6 25.7 15.8 MD 1 21.4 20.0 25.1 29.7 23.6 26.5 24.8 27.6 25.2 25.1 27 .3 24.9 25.1 15.2 25.6 25.3 22.7 24.6 29.0 26.5 24.6 26.6 25.1 22.1 27.3 26.3 24.6 16.2 27.0 26.8 21.4 25.5 28.0 26.2 23.4 24.3 26.1 17.4 29.3 22.1 27.5 15.1 29.2 27.4 24.0 FS 28.0 27.0 23.7 24.7 20.3 22.2 FD13 22.0 25.1 23.6 20.5 25.1 22.9 24.5 24.5 20.4 FD 1 25.1 28.3 20.8 25.1 20.1 24.3 23.2 FM 2 20.0 21. 3 22.4 21.2 17.7 FD 1 19.2 FS 19.1 ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED) NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED. PUPS. .~ ....... 00 I 0 t'...J 00 ~ n~..I...... .t.'.......J.. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C44 (PAGE 10) : PUP BODY WEIGHTS FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - Fl GENERATION PUPS PUP # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 RAT/ LITTER # MATERNAL DOSAGE GROUP I 0 MG/KG/DAY POSTPARTUM DAY 22 19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075 43.0 43.0 39.6 34.5 44.0 37.0 38.7 48.1 37.9 34.8 41.2 47.9 34.0 35.4 34.4 44.2 43.7 41.8 34.4 45.6 31.l 37.4 48.4 37.4 39.9 25.4 46.2 33.7 37.2 38.5 41.1 40.3 36.2 39.4 47.2 34.9 37.5 25.8 37.1 37.9 30.1 48.8 27.0 38.8 35.5 39.4 44.2 39.0 35.8 44.0 29.4 36.4 43.9 35.0 33.8 36.9 50.0 29.9 29.2 37.1 39.0 42.2 39.9 35.0 48.9 32.6 35.0 45.5 34.7 39.2 33.3 45.5 33.7 MD 1 30.8 39.5 37.9 42.5 35.6 46.4 30.4 33.1 43.1 34.5 32.3 30.9 MD 2 33.5 32.9 35.5 40.7 41.6 41.2 38.3 46.9 31.4 34.6 36.4 38.4 35.3 31.5 45.4 32.9 35.1 38.5 33.4 41.1 39.7 36.0 44.6 33.3 37.6 49.3 34.3 34.1 33.6 45.9 28.6 32.5 35.4 42.7 39.0 37.6 33.2 44.2 33.9 35.3 43.6 32.4 MD 5 29.0 45.9 28.0 33.6 40.7 40.0 36.9 35.4 34.1 45.4 33.4 35.7 41.6 37.1 34.7 32.8 46.8 28.9 33.5 36.0 41. 6 41. 8 38.6 34.9 44.6 35.4 34.4 41.1 38.5 35.2 30.9 42.5 33.0 34.7 34.5 41. 6 36.7 39.6 32.1 43.1 37.9 37.2 37.8 34.3 34.3 31.5 44.2 33.7 35.2 33.8 41.4 42.6 36.3 34.5 FD 4 29.6 35.7 36.6 34.5 38.3 32.4 47.1 30.3 34.7 37.4 FD 3 41.0 37.6 33.4 35.7 32.8 40.0 32.6 37.1 35.7 45.0 28.6 33.0 36.0 42.1 35.4 26.8 36.7 43.1 34.6 31. 7 31. 7 43.1 28.6 35.1 38.6 45.4 35.8 40.2 37.1 28. 9 29.1 34.5 25.3 FM 2 23.9 31. 8 33.0 26.8 FD 5 RAT/ LITTER # MATERNAL DOSAGE GROUP II 0.3 MG/KG/DAY POSTPARTUM DAY 22 19004 33.4 34.4 26.5 33.6 29.0 30.4 33.2 28.5 33.3 26.3 32.4 24.0 28.9 29.9 26.4 29.4 29.l FM 6 19009 57.1 55.6 51.3 51.4 57.7 53.8 51.8 19016 46.5 47.4 48.5 44.5 44.2 44.4 45.8 47.6 49.3 50.3 41.3 45.4 45.1 25.8 43.4 19018 48.4 47.0 45.9 46.3 44.8 43.4 44.6 44.0 45.6 45.0 39.2 38.1 41. 0 40.6 19026 32.3 32.5 39.1 30.7 30.1 34.9 29.3 29.6 28.7 30.7 29.1 31.2 29.3 27.6 34.6 28.6 27.1 27.5 FD 8 19036 39.7 40.9 43.1 42.9 42.1 38.1 29.l 35.7 42.7 43.2 39.2 30.5 37.0 FMll FD 2 FD 1 ~ ~ 19037 33.1 25.3 30.5 31.8 31.6 34.6 31.0 31.9 30.8 29.l 32.9 27.9 31. 9 27.0 24.9 FD15 00 19043 46.0 46.4 47.2 46.2 48.4 44.9 45.8 43.2 44.6 43.7 45.2 42.9 42.6 I 0 19047 38.9 39.1 34.4 37.1 39.3 39.5 39.5 41.3 39.7 36.9 40.5 33.0 32.2 tv 19048 19052 46.5 51.0 49.7 47.1 50.5 47.0 48.0 45.8 45.0 38.6 38.6 31.7 33.6 37.3 35.2 40.1 35.4 31.1 34.0 37.8 40.5 36.9 37.5 29.9 36.2 FD 5 00 ~ > 19055 40.7 40.1 41.3 40.2 39.6 38.1 42.9 38.5 36.3 40.3 MD 1 38.9 39.4 34.5 37.8 35.6 19061 33.8 30.7 32.2 31.1 34.4 30.2 32.7 MD 3 35.9 31.5 34.2 32.7 34.6 ~ 19067 41.4 39.9 40.2 40.8 39.6 39.3 40.5 39.4 37.5 39.1 37.0 40.2 37.7 FD 8 n 19071 40.7 42.3 42.1 40.5 44.4 34.9 40.0 35.3 36.9 41.3 43.3 42.6 43.1 31.1 I ~ ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS. tv tv FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED) NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C44 (PAGE 11) : PUP BODY WEIGHTS FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - Fl GENERATION PUPS PUP # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 RAT/ LITTER # MATERNAL DOSAGE GROUP III 1 MG/KG/DAY POSTPARTUM DAY 22 19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064 35.4 31.5 30.7 34.7 35.5 35.5 43.6 40.5 42.9 45.7 45.8 49.6 NOT PREGNANT 39.1 39.8 41.8 49.7 42.2 45.8 39.0 39.8 39.7 46.5 41.8 44.0 41.4 40.9 41.2 NOT PREGNANT 39.3 41.4 41.4 34.2 33.7 32.2 47.4 47.0 49.2 3.0 34.7 28.0 26.0 30.4 41.5 42.0 40.0 47.5 38.5 41.8 41.4 39.5 33.7 45.8 36.4 32.3 27.9 40.8 49.1 37.1 48.8 38.2 46.1 40.6 42.6 30.9 48.8 29.4 31.9 36.0 38.6 46.6 33.5 40.5 43.4 47.6 41.9 41.6 32.3 46.4 33.0 24.2 35.0 42.5 50.2 38.6 47.3 37.3 44.3 38.9 44.1 32.1 45.5 29.4 31.3 31.2 37.2 45.5 37.3 48.8 42.8 37.7 40.2 38.5 32.5 42.8 28.2 28.4 29.3 41.3 48.4 38.4 44.4 41.4 MM 2 40.4 41.5 33.0 46.7 28.4 30.2 28.0 38.4 41.8 38.8 45.0 37.1 38.6 40.4 41.2 31.5 42.7 36.9 25.0 31.0 38.4 39.5 36.2 47.1 41.3 32.0 38.7 39.6 34.6 48.8 28.4 28.6 29.0 42.5 42.8 38.1 41.9 35.6 31.7 37.5 41.6 31.1 40.6 30.3 26.6 31.8 39.9 46.1 35.8 30.8 35.6 38.0 37.0 38.0 33.9 39.5 34.2 31.6 30.1 35.5 37.9 30.1 48.3 38.5 37.6 FS 38.1 30.7 38.5 35.6 28.2 33.8 FM 2 45.5 36.4 36.8 34.2 33.9 27.5 26.1 27.4 30.3 29.7 24.0 33.8 30.3 24.6 FD 2 FMll RAT/ LITTER # MATERNAL DOSAGE GROUP IV 3 MG/KG/DAY POSTPARTUM DAY 22 19002 47.2 47.4 49.4 MS 44.4 46.3 45.3 46.0 45.4 45.0 FD 1 19005 31.3 36.4 34.3 31.3 32.7 33.1 28.9 32.0 32.7 31.5 29.6 33.0 33.2 33.4 28.1 34.5 19035 32.8 35.2 33.6 33.2 34.6 33.3 32.2 30.6 33.9 30.6 34.7 29.9 34.4 32.1 19039 36.0 39.4 36.2 34.0 30.1 MD 2 32.8 35.6 31.7 36.8 31. 7 28.5 32.7 33.7 27.8 ~ 19040 32.8 30.6 32.9 32.0 33.6 31.6 28.3 26.9 27.1 28.3 31.7 30.0 32.9 35.5 32.1 24.7 23.7 19045 37.1 41.2 37.1 33.5 39.4 37.1 38.3 35.8 36.0 37.8 36.4 30.6 36.0 39.9 34.8 uu ..p:. ....... 19046 NOT PREGNANT 00 19051 NOT PREGNANT; MATING NOT CONFIRMED I 0 19054 57.5 59.1 54.8 55.5 57.6 t-J 1199006528 4531..30 4443..76 4411..20 4427..99 4415..06 4470..61 4474..50 4452..79 4424..71 4417..35 4405..48 4412..27 3458..32 39.9 39.5 0~0 19063 48.7 46.5 46.1 48.6 45.9 49.4 48.4 44.0 42.8 50.l 47.2 39.7 46.2 FS 19066 43.5 44.3 43.8 44.3 42.9 45.7 MD 1 43.5 43.5 40.9 42.5 41.4 43.2 FS 19069 31.7 28.5 28.1 30.5 32.5 29.3 33.2 33.4 35.7 27.5 33.0 37.2 36.8 32.3 33.8 31.4 FDlO (') 19073 44.5 44.2 44.0 43.8 45.6 46.2 42.0 MM 3 39.5 38.6 42.7 41.3 42.2 41.2 ..I..... ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS. t-J VJ FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED) NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C44 (PAGE 12): PUP BODY WEIGHTS FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - Fl GENERATION PUPS PUP # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 RAT/ LITTER # MATERNAL DOSAGE GROUP V 10 MG/KG/DAY POSTPARTUM DAY 22 19001 43.5 45.6 43.0 44.3 45.4 43.3 44.0 43.0 42.9 44.2 45.6 19006 33.2 36.3 35.4 34.5 36.6 MD 2 31. 6 32.2 31. 7 32.0 30.9 36.9 34.9 34.8 34.4 28.9 29.9 34.2 FD 1 FS 19011 37.9 38.1 33.7 35.8 38.9 34.9 35.5 35.6 37.9 35.7 35.0 33.7 34.9 19020 15.1 15.8 16.0 16.2 14 .4 16.0 15.3 14. 8 14.5 18.1 14.9 15.9 14.2 19022 32.3 33.5 37.9 39 .1 39.3 35.4 35.3 37.0 37.2 MD 1 34.6 36.3 35.6 32.5 33.3 FM 2 19025 31.2 30.6 29.9 30.5 27.0 35.9 25.0 31. 7 30.2 34.5 30.6 31. 8 31. 5 30.5 24.4 27.6 26.8 31. 0 23.8 23.8 19027 34.8 33.3 32.3 31. 8 29.3 32.4 32.5 29.0 31.1 30.6 31.1 31. 7 30.1 33.0 19028 39.9 43.1 38.4 44.4 33.2 39.6 40.4 40.6 39.5 35.6 42.5 42.4 FS 19030 39.1 38.9 40.8 43.3 40.0 38.4 39.8 42.0 39.6 32.2 38.7 37.6 37.9 19031 43.4 45.6 45.0 50.8 40.4 40.9 47.8 MM 2 44.3 39.5 41.2 39.2 44.0 38 .4 40.9 19032 37.3 34.6 36.4 33.5 36.7 37.4 35.6 32.4 34.5 33.8 35.2 36.1 32.9 34.9 19033 45.7 40.7 43.6 45.8 45.1 43.8 41.2 44.2 42.6 39.1 41. 0 41. 0 40.2 39. 0 19049 37.8 34.6 35.3 37.1 36.1 39.9 39.6 33.9 39.1 31. 2 39.9 36.2 38.6 32.4 24.4 19059 35.2 33.3 33.8 37 .4 37.4 33.6 35.5 33.7 35.0 31. 0 33.8 27.5 25.6 32.2 32.9 19070 48.6 51. 7 54.1 47.6 49.5 52.l 46.9 46.5 47.5 46.8 43.9 48.8 FD13 FD 1 ------------------------------------------------------------------------------------------------------------------------------------ ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS. FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED) NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED. ~ !--" 00 I 0 N 00 ~ >n~..I..... N ~ PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C45 (PAGE 1) : PUP VITAL STATUS AND SEX FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - Fl GENERATION PUPS PUP # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 RAT/ LITTER # MATERNAL DOSAGE GROUP I 0 MG/KG/DAY 19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075 M A M A M A M A F A F A F A F A F A F A F A F A F A FD 3 MA MA MA MA MA FA FA FA FA FA FA FA FA FA FA FA MA MA MA MA MA MA MA MA FA FA FA F A F A F A F A MA MA MA MA MA MA MA MA MA FA FA F A F A F A MA MA MA MA MA MA MA F A F A FA FA F A FD 4 MA MA MA MA MA MA FA FA FA FA FA F A F A F A FA F A FA F A MA MA MA MA MA MA FA FA FA FA FA FA FA FA FA M A M A M A M A M A M A M A M A F A F A F A F A F A F A F A F A FM 2 MA MA MA MA MA F A F A F A F A F A F A F A F A F A F A M A M A M A M A M A M A M A M A MD 5 F A F A F A F A F A F A F A M A M A M A M A M A M A M A M A M A F A F A F A F A F A F A F A F A F A F A FD 5 M A M A M A M A M A MD 2 F A F A F A F A F A F A F A F A F A MA MA MA MA MA MA MA MA FA FA FA FA FA FA FA FA M A M A M A M A MD 1 F A F A F A F A F A F A F A F A F A F A MA MA MA MA MA MA MA MA MA MA MA FA FA FA FA FA RAT/ LITTER # MATERNAL DOSAGE GROUP II 0. 3 MG/KG/DAY 19004 MA MA MA MA MA MA MA MA FA FA FA FA F A F A F A F A F A FM 6 19009 MA MA FA FA FA FA FA 19016 MA MA MA MA MA MA MA MA MA MA MA MA FA FA FA 19018 MA MA MA MA MA MA MA MA FA FA FA FA F A F A 19026 MA MA MA MA MA MA MA MA MA MA FA FA F A F A F A F A F A F A FD 8 19036 MA MA MA MA MA MA FA FA FA FA FA FA F A FMll FD 2 FD 1 .,i:::.. - 19037 MA MA MA MA MA MA MA MA FA FA FA FA F A F A F A FD15 00 19043 MA MA MA MA MA MA MA FA FA FA FA FA F A I 0 19047 MA MA MA MA MA MA MA FA FA FA FA FA F A ~ 19048 19052 MA MA MA MA MA FA FA FA FA MA MA MA MA MA MA FA FA FA FA FA FA F A F A F A F A FD 5 00 ~ 19055 MA MA MA MA MA MA MA MA M A M A MD 1 F A F A F A F A F A 19061 MA MA MA MA MA MA MAMD3 F A F A F A F A F A ~ 19067 MA MA MA MA MA MA FA FA F A F A F A F A F A FD 8 n 19071 MA MA MA MA MA MA MA MA FA FA FA FA FA FA I - FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE ~ Vl SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED) NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C45 (PAGE 2): PUP VITAL STATUS AND SEX FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - Fl GENERATION PUPS PUP # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 RAT/ LITTER # MATERNAL DOSAGE GROUP III 1 MG/KG/DAY 19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064 MA MA MA MA MA MA MA MA FA FA FA FA FA FA FA FA M A M A M A M A M A M A M A F A F A F A F A F A F A F A F A F A F A FD 2 M A M A M A M A M A M A M A F A F A F A F A F A F A F A FM 2 MA MA MA MA MA MA MA MA MA FA FA FA FA FA FA NOT PREGNANT MA MA MA MA MA MA MA MA MA FA FA FA FA FA FA MA MA MA MA MA MA FA FA FA FA FA FA FA FA MA MA MA MA MA MA MA MA MA FA FA FA FA FA FA MA MA MA MA MA MA MA MAMM2 FA FA FA FA FA FA FA MA MA MA MA MA MA F A F A F A F A F A F A F A F S NOT PREGNANT MA MA MA MA MA MA MA FA FA FA FA FA FA FA MA MA MA MA MA MA MA MA MA FA FA FA FA FA FA FA FA MA MA MA MA MA MA MA MA FA FA FA FA FA FA M A M A M A M A M A M A M A M A M A F A F A F A F A F A F A F A F A FMll RAT/ LITTER # MATERNAL DOSAGE GROUP IV 3 MG/KG/DAY 19002 M A M A M A M S F A F A F A F A F A F A FD 1 19005 MA MA MA MA MA MA FA FA FA FA FA FA FA FA FA FA 19035 MA MA MA MA MA MA FA FA FA FA FA FA FA FA 19039 MA MA MA MA MAMD2 FA FA FA FA FA FA FA FA FA 19040 MA MA MA MA MA MA MA FA FA FA FA FA FA FA FA FA FA 19045 MA MA MA MA MA MA FA FA FA FA FA FA FA FA FA UU _J:::.. - 19046 NOT PREGNANT 00 19051 NOT PREGNANT; MATING NOT CONFIRMED I 0 19054 MA MA MA FA FA N 19058 19062 MA MA MA MA MA MA MA MA FA FA FA FA FA MA MA MA MA MA MA MA MA MA FA FA FA FA FA FA 00 ~ 19063 M A M A F A F A F A F A F A F A F A F A F A F A F A F S 19066 M A M A M A M A M A F A MD 1 F A F A F A F A F A F A F S ~ 19069 M A M A M A M A M A M A F A F A F A F A F A F A F A F A F A F A FDlO 19073 MA MA MA MA MA MA MAMM3 FA FA FA FA FA FA Cl I - FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE N SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED) " NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED. PROTOCOL 418-028: ORAL (GAVAGE} COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C45 (PAGE 3): PUP VITAL STATUS AND SEX FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - Fl GENERATION PUPS PUP # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 RAT/ LITTER # MATERNAL DOSAGE GROUP V 10 MG/KG/DAY 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070 MA MA MA MA FA FA FA FA FA FA FA M A M A M A M A M A MD 2 F A F A F A F A F A F A F A F A F A F A F A F A FD 1 F S MA MA MA MA MA MA MA FA FA FA FA FA FA MA MA MA MA MA MA MA MA FA FA FA FA FA M A M A M A M A M A M A M A M A M A MD 1 F A F A F A F A F A FM 2 MA MA MA MA MA MA MA MA MA MA MA MA MA FA FA FA FA FA FA FA MA MA MA MA F A F A F A F A F A F A F A F A F A F A MA MA MA MA MA F A F A F A F A F A F A F A F S MA MA MA MA MA MA FA FA FA FA FA FA FA M A M A M A M A M A M A M A MM 2 F A F A F A F A F A F A F A MA MA MA MA MA MA MA FA FA FA FA FA FA FA MA MA MA MA MA MA FA FA FA FA FA FA FA FA MA MA MA MA MA MA MA MA MA MA MA FA FA FA FA MA MA MA MA MA MA MA MA MA MA FA FA FA FA FA M A M A M A M A M A M A M A M A F A F A F A F A FD13 FD 1 FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED} NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED. ~ ~ ~00 I 0 N 00 ~ tT:1 (1 I ~ N -l PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C46 (PAGE 1) : CLINICAL OBSERVATIONS FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - Fl GENERATION PUPS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) LITTER NUMBER DAY POSTPARTUM OBSERVATIONS a I 0 19010 1- 2 1/14 PUPS: PALE IN APPEARANCE. 19044 1- 2 1/17 PUPS: BACK, BRUISE (2. 5 CM X 2. 0 CM) . 19050 1 1/15 PUPS: PALE IN APPEARANCE. 19072 18-22 1/16 PUPS: RIGHT EYE, CORNEAL OPACITY.b II 0.3 19004 8 1/17 PUPS: COLD TO TOUCH; NOT NESTING OR NURSING. 19036 1- 4 1/14 PUPS: BACK, BRUISE (2.0 CM IN DIAMETER). 19037 18 4/15 PUPS: DEHYDRATION. 19071 11 1/14 PUPS: COLD TO TOUCH. III 1 19003 17 1/16 PUPS: DEHYDRATION. 19064 9 1/18 PUPS: DEHYDRATION. a. Tabulation restricted to adverse observations; all other pups appeared normal. b. Confirmed at necropsy. .p. ~ 00 I 0 t-.J 00 ~ >n~I ~ t-.J 00 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C46 (PAGE 2): CLINICAL OBSERVATIONS FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - Fl GENERATION PUPS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) LITTER NUMBER DAY POSTPARTUM OBSERVATIONS a IV 3 19039 9- 16 1/14 PUPS: LEFT EYE, PERIORBITAL DISCOLORATION, PURPLE. 19054 1 2- 7 1/15 PUPS: 1/ 5 PUPS: RIGHT HINDLIMB I LACERATION. RIGHT HINDLIMB, SCAB (0.1 CM X 1.0 CM). 19058 20-22 1/13 PUPS: RIGHT EYE, ENLARGED.b v 10 19006 11 1/17 PUPS: COLD TO TOUCH. 19020 22 13/13 PUPS: NOT NURSING; DEHYDRATION b; EMACIATION b. 19049 2- 4 2/15 PUPS: WHOLE BODY, EXCLUDING HEAD, DISCOLORATION, PURPLE. 19070 8- 10 1/13 PUPS: HEAD, SCAB (DID NOT EXCEED 0.1 CM X 0.5 CM). a. Tabulation restricted to adverse observations; all other pups appeared normal. b. Confirmed at necropsy. .~ ....... ~00 I 0 t-J 00 ~ (1 '...I..... t-J PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C47 (PAGE 1) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - Fl GENERATION PUPS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) LITTER NUMBER DAY POSTPARTUM OBSERVATIONS a I 0 19010 3 1 PUP: FOUND DEAD. NO MILK IN STOMACH. ALL OTHER TISSUES APPEARED NORMAL. 22 13 PUPS: APPEARED NORMAL. 19012 22 16 PUPS: APPEARED NORMAL. 19019 22 15 PUPS: APPEARED NORMAL. 19021 22 14 PUPS: APPEARED NORMAL. 19023 4 1 PUP: FOUND DEAD. ALL TISSUES APPEARED NORMAL. 22 12 PUPS: APPEARED NORMAL. 19041 22 18 PUPS: APPEARED NORMAL. 19042 22 15 PUPS: APPEARED NORMAL. 19044 22 16 PUPS: APPEARED NORMAL. 19050 22 15 PUPS: APPEARED NORMAL. 19053 5 1 PUP: FOUND DEAD. ALL TISSUES APPEARED NORMAL. 22 15 PUPS: APPEARED NORMAL. 19065 5 1 PUP: FOUND DEAD. NO MILK IN STOMACH. ALL OTHER TISSUES APPEARED NORMAL. 22 19 PUPS: APPEARED NORMAL. 19068 2 1 PUP: FOUND DEAD. ALL TISSUES APPEARED NORMAL. 22 14 PUPS: APPEARED NORMAL. .+...:.-.... 19072 22 16 PUPS: APPEARED NORMAL. 00 I 0 19074 1 1 PUP: FOUND DEAD. ALL TISSUES APPEARED NORMAL. l'...> 22 14 PUPS: APPEARED NORMAL. 00 ~ 19075 22 16 PUPS: APPEARED NORMAL. ~ a. Complete necropsies were not performed on pups in which autolysis or cannibalization precluded evaluation. Refer to the n individual pup clinical observations table (Table C44) for external clinical observations confirmed at necropsy. I ........ v.> 0 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C47 (PAGE 2) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - Fl GENERATION PUPS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) LITTER NUMBER DAY POSTPARTUM OBSERVATIONS a II 0.3 19004 22 17 PUPS: APPEARED NORMAL. 19009 22 7 PUPS: APPEARED NORMAL. 19016 22 15 PUPS: APPEARED NORMAL. 19018 22 14 PUPS: APPEARED NORMAL. 19026 8 1 PUP: FOUND DEAD. NO MILK IN STOMACH. ALL OTHER TISSUES APPEARED NORMAL. 22 18 PUPS: APPEARED NORMAL. 19036 1 1 PUP: FOUND DEAD. NO MILK IN STOMACH. ALL OTHER TISSUES APPEARED NORMAL. 2 1 PUP: FOUND DEAD. AUTOLYSIS PRECLUDED FURTHER EVALUATION. 22 13 PUPS: APPEARED NORMAL. 19037 15 1 PUP: FOUND DEAD. NO MILK IN STOMACH. AUTOLYSIS PRECLUDED FURTHER EVALUATION. 22 1 PUP: KIDNEYS: RIGHT, PELVIS, MODERATE DILATION. ALL OTHER TISSUES APPEARED NORMAL. 14 PUPS: APPEARED NORMAL. 19043 22 13 PUPS: APPEARED NORMAL. 19047 22 13 PUPS: APPEARED NORMAL. 19048 22 9 PUPS: APPEARED NORMAL. 19052 5 1 PUP: FOUND DEAD. NO MILK IN STOMACH. .~ ....... ALL OTHER TISSUES APPEARED NORMAL. 00 22 16 PUPS: APPEARED NORMAL. I 0 tv a. Complete necropsies were not performed on pups in which autolysis or cannibalization precluded evaluation. Refer to the individual pup clinical observations table (Table C44) for external clinical observations confirmed at necropsy. 00 ~ >n~..I...... VJ ........ PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C47 (PAGE 3) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - Fl GENERATION PUPS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) LITTER NUMBER DAY POSTPARTUM OBSERVATIONS a II 0.3 cont. 19055 1 1 PUP: FOUND DEAD. NO MILK IN STOMACH. ALL OTHER TISSUES APPEARED NORMAL. 22 15 PUPS: APPEARED NORMAL. 19061 3 1 PUP: FOUND DEAD. AUTOLYSIS PRECLUDED FURTHER EVALUATION. 22 12 PUPS: APPEARED NORMAL. 19067 8 1 PUP: FOUND DEAD. NO MILK IN STOMACH. ALL OTHER TISSUES APPEARED NORMAL. 22 13 PUPS: APPEARED NORMAL. 19071 22 14 PUPS: APPEARED NORMAL. a. Complete necropsies were not performed on pups in which autolysis or cannibalization precluded evaluation. Refer to the individual pup clinical observations table (Table C44) for external clinical observations confirmed at necropsy. -..f;:=.. 00 I 0 tv 00 ~ > ~ n I -VJ tv PROTOCOL 418-028: ORAL (GAVAGE} COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1} TABLE C47 (PAGE 4) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - Fl GENERATION PUPS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY} LITTER NUMBER DAY POSTPARTUM OBSERVATIONS a III 1 19003 22 16 PUPS: APPEARED NORMAL. 19007 2 1 PUP: FOUND DEAD. ALL TISSUES APPEARED NORMAL. 22 17 PUPS: APPEARED NORMAL. 19008 19013 19015 19017 19024 19029 22 14 PUPS: APPEARED NORMAL. 22 15 PUPS: APPEARED NORMAL. 22 15 PUPS: APPEARED NORMAL. 22 14 PUPS: APPEARED NORMAL. 22 15 PUPS: APPEARED NORMAL. 22 15 PUPS: APPEARED NORMAL. 19034 1 1 PUP: STILLBORN. ALL TISSUES APPEARED NORMAL. 22 13 PUPS: APPEARED NORMAL. 19056 19057 19060 19064 22 14 PUPS: APPEARED NORMAL. 22 17 PUPS: APPEARED NORMAL. 22 14 PUPS: APPEARED NORMAL. 22 17 PUPS: APPEARED NORMAL. a. Complete necropsies were not performed on pups in which autolysis or cannibalization precluded evaluation. Refer to the individual pup clinical observations table (Table C44} for external clinical observations confirmed at necropsy. .,i::.. -00 I 0 ~ 00 ~ >n~I VJ -VJ PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C47 (PAGE 5) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - Fl GENERATION PUPS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) LITTER NUMBER DAY POSTPARTUM OBSERVATIONS a IV 3 19002 1 1 PUP: FOUND DEAD. ALL TISSUES APPEARED NORMAL. 1 PUP: STILLBORN. AUTOLYSIS PRECLUDED FURTHER EVALUATION. 22 9 PUPS: APPEARED NORMAL. 19005 19035 22 16 PUPS: APPEARED NORMAL. 22 14 PUPS: APPEARED NORMAL. 19039 2 1 PUP: FOUND DEAD. AUTOLYSIS PRECLUDED FURTHER EVALUATION. 22 14 PUPS: APPEARED NORMAL. 19040 19045 19054 19058 19062 22 17 PUPS: APPEARED NORMAL. 22 15 PUPS: APPEARED NORMAL. 22 5 PUPS: APPEARED NORMAL. 22 13 PUPS: APPEARED NORMAL. 22 15 PUPS: APPEARED NORMAL. 19063 1 1 PUP: STILLBORN. ALL TISSUES APPEARED NORMAL. 22 13 PUPS: APPEARED NORMAL. 19066 1 1 PUP: FOUND DEAD. NO MILK IN STOMACH. ALL OTHER TISSUES APPEARED NORMAL. 1 PUP: STILLBORN. ALL TISSUES APPEARED NORMAL. 22 12 PUPS: APPEARED NORMAL. ,.J_:_::i.. 19069 10 1 PUP: FOUND DEAD. NO MILK IN STOMACH. 00 AUTOLYSIS PRECLUDED FURTHER EVALUATION. I 0 22 16 PUPS: APPEARED NORMAL. N 00 19073 22 13 PUPS: APPEARED NORMAL. ~ ~ a. Cinodmipvliedtue anl epcurop pcslieins icwaelreonboset rpveartfioornmsedtabonlepu(pTsabilne wC4h4i)chfoaur teoxlytesrins aol rcclianninciablaloizbasteirovnatpiornecslucdoendfiremveadluaattionne.croRpseyf.er to the tTl n,_I _. v.> .J:::i. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C47 (PAGE 6) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - Fl GENERATION PUPS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) v 10 LITTER NUMBER 19001 DAY POSTPARTUM 22 OBSERVATIONS a 11 PUPS: APPEARED NORMAL. 19006 1 1 PUP: FOUND DEAD. ALL TISSUES APPEARED NORMAL. 1 PUP: STILLBORN. ALL TISSUES APPEARED NORMAL. 2 1 PUP: FOUND DEAD. AUTOLYSIS PRECLUDED FURTHER EVALUATION. 22 17 PUPS: APPEARED NORMAL. 19011 19020 22 13 PUPS: APPEARED NORMAL. 22 13 PUPS: APPEARED NORMAL. 19022 1 1 PUP: FOUND DEAD. AUTOLYSIS PRECLUDED FURTHER EVALUATION. 22 14 PUPS: APPEARED NORMAL. 19025 19027 22 20 PUPS: APPEARED NORMAL. 22 14 PUPS: APPEARED NORMAL. 19028 1 1 PUP: STILLBORN. ALL TISSUES APPEARED NORMAL. 22 12 PUPS: APPEARED NORMAL. 19030 19031 19032 19033 19049 19059 22 13 PUPS: APPEARED NORMAL. 22 14 PUPS: APPEARED NORMAL. 22 14 PUPS: APPEARED NORMAL. 22 14 PUPS: APPEARED NORMAL. 22 15 PUPS: APPEARED NORMAL. 22 15 PUPS: APPEARED NORMAL. 19070 1 1 PUP: FOUND DEAD. AUTOLYSIS PRECLUDED FURTHER EVALUATION. 13 1 PUP: FOUND DEAD. AUTOLYSIS PRECLUDED FURTHER EVALUATION. 22 12 PUPS: APPEARED NORMAL. a. Complete necropsies were not performed on pups in which autolysis or cannibalization precluded evaluation. Refer to the individual pup clinical observations table (Table C44) for external clinical observations confirmed at necropsy. -..i:::.. 00 I 0 N 00 ~ @ -(l I (.;.) Vl PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C48 (PAGE 1) : PUP LIVER WEIGHTS - INDIVIDUAL DATA - Fl GENERATION PUPS ----RA.-..ri---------------------------------------------------------------------------------------------------------------------------------------------------------------- LITTER LIVER TERMINAL BODY WEIGHT NUMBER M F T M F T -"DosA""G'E-C3R'ou"P--1-------------------------------o--iVi8i-K'8iD".AY--------------------------------------------------------------------------------------------------------- ----1-9oi2--------i~86-.;-------2:a-08-------i~9-36--------------------42-~68-------4-2~24--------4-2:4-6------------------------------------------------------------------- 19019 1.436 1.636 1.536 39.70 37.50 38.60 19021 1. 360 1. 558 1.459 34.74 33.80 34.27 19023 1. 814 1.878 1.846 46.02 44.38 45.20 19041 1.114 1. 232 1.173 33.00 31. 02 32.01 19042 1.390 1.552 1.471 36.12 36.16 36.14 19044 1.798 1.736 1.767 44.30 39.82 42.06 19050 1. 336 1.406 1.371 36.42 34.86 35.64 19053 1.438 1.562 1. 500 35.60 35.92 35.76 19065 1. 266 1.354 1. 310 33.08 31. 00 32.04 :~~~~=9~~~~::!!::::::::::::::::::::::::::::::2::~:b:~z~:~f(~~~:::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: 19004 1.138 1.246 1.192 30.78 30.12 30.45 19009 2.350 2.356 2.354 56.35 53.20 54.10 19016 1.874 1. 633 1. 784 45.32 38.10 42.61 19018 1.768 1.752 1.760 45.50 41.70 43.60 19026 1. 062 1.214 1.138 32.30 30.04 31.17 19036 1. 596 1. 596 1. 596 40.74 34.30 37.52 19037 1.170 1.182 1.176 30.66 29.16 29. 91 19043 2.098 2.074 2.086 46.34 43.80 45.07 19047 1. 510 1.462 1.486 38.78 36.62 37.70 19048 1.826 1.985 1.897 48.96 46.45 47.84 =~~~~=~~~~~::!!1:::::::::::::::::::::::::::::2-:~91:~~2~~i::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: 19003 1.268 0.998 1.133 30.78 27.58 29.18 19007 1. 324 1.278 1.301 35.34 29.70 32.52 .f;:>.. - 19008 1.516 1.732 1.624 41. 82 40.10 40.96 00 19013 1.976 1. 736 1. 856 46.36 42.36 44.36 I 0 19015 1.416 1. 510 1.463 38.06 35.84 36.95 N 00 19017 2.102 2.188 2.145 44.96 43.88 44.42 ~ 19024 1.504 1. 550 1.524 40. 04 37.62 38.83 ~ 19029 2.076 1.456 1.766 43.22 33.24 38.23 19034 1.550 1.670 1.610 41.24 38.76 40.00 tT.1 19056 1.500 1.646 1.573 40.88 39.48 () I 19005 1.296 1.312 1.304 33.56 30.84 32.20 - --M---=--M--A-L-E----------F---=--F-E-M--A-L-E----------T---=--T-O--T-A-L--------------------------------------------------------------------------------------------------------------------- (J.) ' ALL WEIGHTS WERE RECORDED IN GRAMS (G) . PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C48 (PAGE 2) : PUP LIVER WEIGHTS - INDIVIDUAL DATA - Fl GENERATION PUPS ----RA"T'i---------------------------------------------------------------------------------------------------------------------------------------------------------------- L I TTER LIVER TERMINAL BODY WEIGHT NUMBER M F T M F T :~~~~~:9:~~~:!'::~y-::::::::::::::::::::::::::::::]::~9?:~~2P~~::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: 19035 1.192 1.316 1.254 33.82 32.04 32.93 19039 1.540 1.380 1.460 35.14 31.46 33.30 1. 226 1. 582 1. ~W4 31.48 30.28 30.88 19045 1.624 1. 730 1. 677 37.66 37.18 37.42 19054 2.137 2.495 2.280 57.13 56.55 56.90 2.364 2 .110 2.2!3377 47.80 45.08 46.44 19062 1.470 1.702 1. 55886 42.50 39.86 41.18 19063 2.040 2.132 2.1: 06 47.60 46.10 46.53 19066 1.582 1.702 1.642 43.76 42.82 43.29 :~~~~~:Sf:~~~:!'::i:::::::::::::::::::::::::::::::l:~:B9"".i.:~9?~~~:::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: 19001 1.855 1.902 1.881 44.10 44.24 44.18 19006 1. 358 1. 512 1.435 35.20 32.84 34.02 19011 1. 290 1.434 1. 362 36.28 35.44 35.86 19020 0.454 0.540 0.497 15.30 15.52 15.41 19022 1. 336 1.286 1.311 36.60 34.46 35.53 19025 1.098 1.160 1.129 30.00 26.70 28.35 19027 1. 283 1.286 1.284 33.05 31.46 32.17 19028 1.550 1.742 1.646 39.80 40.10 39.95 19030 1.594 1. 632 1. 613 39.94 39.16 39.55 19031 1.842 1.870 1.856 43.06 40.80 41.93 ------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ..r;::.. 0"""0""' I 0 N 00 ~ @ (1 I V""""J"' -.l APPENDIXD PROTOCOL AND AMENDMENTS 418-028:PAGE D-1 905 Sheehy Drive, Bldi A Horsham. PA 19044 Telephone: (215) 443~710 Telefax: (21 SJ 443-8587 ~~.......... ARGUS RESEARCH Charles River Laboratories Discovery and Development Services PROTOCOL 418-028 SPONSOR'S STUDY NUMBER: T-7706.1 STUDY TITLE: Oral (Gavage) Combined Repeated Dose Toxicity Study ofT-7706 with the Reproduction/Developmental Toxicity Screening Test PURPOSE: The purpose of this study is to provide information on the possible health hazards that may result from repeated exposure ofCrl:CD(SD)IGS BR VAF/Plus male and female rats to a test substance beginning before cohabitation, through mating and continuing for at least 42 days (male rats) or through parturition until day 21 of lactation (female rats). This repeated dose study incorporates a reproduction/developmental toxicity screening test that can be used to provide initial information on possible effects on male and female reproductive performance (e.g., gonadal function, mating behavior, conception, development ofthe conceptus and parturition). The study also places emphasis on neurological effects as a specific endpoint and should identify the neurotoxic potential of a test substance, which may warrant further in-depth investigation. TESTING FACILITY: Because ofthe selectivity of the endpoints and the short duration of the study, the screening test will not provide evidence for definitive claims of no reproduction/developmental effects. In particular, it offers o!lly limited means of detecting postnatal manifestations ofprenatal exposure or effects that may be induced during postnatal exposure. Argus Research 905 Sheehy Drive, Building A Horsham, Pennsylvania 19044-1297 Telephone: (215) 443-8710 Telefax: (215) 443-8587 STUDY DIRECTOR: Raymond G. York, Ph.D., DABT Associate Director ofResearch Email: raymond.york@criver.com Address as cited above for Testing Facility SPONSOR: 3M Corporate Toxicology 3M Center, Building 220-2E-02 St. Paul, Minnesota 55144-1000 418-028:PAGE D-2 STUDY MONITOR: John Butenhoff, Ph.D., DABT, CIH 3M Corporate Toxicology 3M Medical Department Telephone: (651) 733-1962 Telefax: (651) 733-1773 Email: jlbutenhoff~.com Protocol 418-028 Page2 REGULATORY CITATIONS: Organisation for Economic Co-operation and Development (1996). OECD Guideline/or Testing ofChemicals. Section 4, No. 422: Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, adopted 22 March 1996. Organisation for Economic Co-operation and Development ( 1998). The Revised OECD Principles of Good Laboratory Practices [C(97)186/Final]. U.S. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule. 21 CFRPart58. Japanese Ministry of Health and Welfare (1997). Good Laboratory Practice Standardfor Safety Studies on Drugs, MHW Ordinance Number 21, March 26, 1997. REGULATORY COMPLIANCE: This study will be conducted in compliance with the Good Laboratory Practice (GLP) regulations cited above. All changes or revisions of this protocol shall be documented, signed by the Study Director and the Sponsor, dated and maintained with the protocol. The Testing Facility's Quality Assurance Unit (QAU) will audit the protocol, the raw data and the report, and will inspect critical phases ofthose portions of the study conducted at the Testing Facility in accordance with the Standard Operating Procedures ofthe Testing Facility. The final report will include a compliance statement signed by the Study Director that the report accurately reflects the raw data obtained during the performance of the study and that all applicable GLP regulations were followed in the conduct of the study. Should significant deviations from GLP regulations occur, each will be described in detail, together with how the deviation might affect the quality or integrity of the study. Should any portion ofthe study be conducted by a subcontractor or by the Sponsor, the Study Director will ensure that a qualified Principal hlvestigator is identified by the facility conducting that portion of the study. The QAU for this facility will conduct critical phase inspections and audit respective results and reports for that study portion according to the SOPs of that facility. Such critical phase inspection reports and report audits will be submitted by the facility to the Principal Investigator and the Study Director. The dates of the inspections and report submissions will be incorporated into a QAU Statement generated by that facility and provided 418-028:PAGE D-3 Protocol 418-028 Page3 to the Testing Facility for inclusion in the final report. In addition, this facility will provide a statement of GLP compliance, as described above, signed by the Principal Investigator for inclusion in the final report. SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE: See ATTACHMENT 1 to the protocol. TEST SUBSTANCE AND VEHICLE: Identification: Test Substance: T-7706 [Perfluorohexane Sulfonate Potassium Salt (PFHS)] Lot identification will be documented in the raw data. The Sponsor will provide to the Testing Facility documentation or certification of the identity, composition, method of synthesis, strength and activity/purity ofthe test substance. This documentation will be included in the final report. Vehicle: Aqueous 0.5% carboxymethlycellulose (CMC) (medium viscosity) prepared using reverse osmosis membrane processed deionized water (R.O. deionized water). Lot identification and Supplier will be documented in the raw data. Neither the Sponsor nor the Study Director is aware ofany potential contaminants likely to be present in the vehicle that would interfere with the results ofthis study. Therefore, no analyses other than those mentioned in this protocol will be conducted. Safety Precautions: Gloves, dust-mist/HEPA-filtered mask, appropriate eye protection and uniform/lab coat to be worn during formulation preparation and dosage. The Material Safety Data Sheet (MSDS) is attached to the protocol (ATTACHMENT 2). Storage: Bulk Test Substance: Bulk Vehicle Components: Prepared Test Substance and Vehicle Formulations: Room temperature. Room temperature. Refrigerated (2C to 8C). All test substance shipments should be addressed to the attention ofJulian Gulbinski, Manager of Formulation Laboratory, at the previously cited Testing Facility address and telephone number. 418-028 :PAGE D-4 Protocol 418-028 Page4 Shipments should include information concerning storage conditions and shipping cartons should be labeled appropriately. The recipient should be notified in advance of shipment. FORMULATION: Frequency of Preparation: Formulations (suspensions) will be prepared weekly at the Testing Facility. Detailed preparation procedures will be attached to this protocol (ATTACHMENT 3). Adjustment for Purity: The test substance will be considered 100% pure for the purpose of dosage calculations. Testing Facility Reserve Samples: The Testing Facility will reserve a sample of each lot ofbulk test substance (approximately 1 g) and bulk vehicle components (approximately 1gor5 mL) used during the course of the study. Samples will be stored under the previously cited conditions. ANALYSES: Results ofrequired analyses will be provided to the Testing Facility for inclusion in the study report. Samples additional to those described below may be taken if deemed necessary during the course ofthe study. Additional analyses, ifrequired, will be documented by protocol amendment. Bulk Test Substance Sampling: A sample of approximately 1 g of the test substance will be taken on the last day of treatment and sent (ambient conditions) to: Principal Investigator: Lisa Clemen 3M Environmental Technology and Safety Services Building 2-3E-09 St. Paul, Minnesota 55133-3331 Telephone: (651) 778-5568 Telefax: (651) 778-6176 Email: laclemen@mmm.com The recipient will be notified in advance of sample shipment. 4 l 8-028:PAGE D-S Analyses of Prepared Formulations: Protocol 418-028 Page5 Concentration and Homogeneity: Concentration and homogeneity of the prepared formulations will be verified during the course ofthis study. Quadruplicate samples (2 mL each) will be taken from the top, middle and bottom of each concentration on the first day ofpreparation. Two samples from each quadruplicate set will be shipped for analysis; the remaining samples will be retained at the Testing Facility as backup samples. Quadruplicate samples will be taken from each concentration on the last day of preparation. Two samples from each quadruplicate set will be shipped for analysis; the remaining samples will be retained as backup samples. Backup samples will be stored under the previously cited conditions and discarded at the Testing Facility upon the request of the Sponsor. Stabilitv: Stability of the prepared formulations will be documented during this study. Two sets of duplicate samples (2 mL each) from each concentration will be taken on the first day of preparation. One sample of each duplicate set will be shipped on the day of preparation. These samples will be analyzed at the following time points: as soon after preparation as possible and ten days after the first analysis. The remaining samples will be retained at the Testing Facility as backup samples. Backup samples will be stored under the previously cited conditions and discarded at the Testing Facility upon the request of the Sponsor. Shipping Instructions: Samples to be analyzed will be shipped (refrigerated) to: Principal Investigator: Lisa Clemen 3M Environmental Technology and Safety Services Building 2-3E-09 St. Paul, Minnesota SS 133-3331 Telephone: (6Sl) 778-S568 Telefax: (6Sl) 778-6176 Email: laclemen@mmm.com The recipient will be notified in advance of sample shipment. DISPOSITION: Prepared formulations will be discarded at the Testing Facility. All remaining bulk test substance will be returned to: Dan Hakes 3M EHSR - Auto & Chem Grp 3M Center, Building 236-lB-10 St. Paul, Minnesota S5144-1000 Telephone: (651) 733-2392 418-028:PAGE D-6 TEST SYSTEM: Protocol 418-028 Page6 Species/Strain and Reason for Selection: The Crl:CD(SD)IGS BR VAF/Plus rat was selected as the Test System because: 1) it is one mammalian species accepted for use in toxicity studies and it has been widely used throughout industry; 2) this strain of rat has been demonstrated to be sensitive to reproductive and developmental toxins; and 3) historical data and experience exist at the Testing Facility<1-3> Number: Initial population acclimated: Population selected for main study: Population selected for toxicokinetic study: 100 male and 100 virgin female rats. 75 male and 75 virgin female rats (15 per sex per dosage group). 15 male and 15 female rats (three per sex per dosage group). Body Weight and Age: Male rats will be ordered to weigh from 275 g to 300 g each at receipt, at which time they will be expected to be at least 60 days of age. Female rats will be ordered to weigh from 200 g to 225 g each at receipt, at which time they will be expected to be at least 56 days of age. Actual body weights will be recorded the day after receipt and will be documented in the raw data. The weight ranges will be included in the final report. At study initiation, the weight variation of the rats will not exceed 20% of the mean weight of each sex. Sex: Both male and female rats will be evaluated. Charles River Laboratories, Inc. The rats will be shipped in filtered cartons by air freight and/or truck from Charles River Laboratories, Inc., to the Testing Facility. Identification: Rats are permanently identified using Monel self-piercing ear tags (Gey Band and Tag Co., Inc., No. MSPT 20101). Male and female rats are assigned temporary numbers at receipt and given unique permanent identification numbers when assigned to the study before administration of the first dosage. Pups will not be individually identified during lactation; all parameters will be evaluated in terms of the litter. 418-028:PAGE D-7 ANIMAL HUSBANDRY: Protocol 418-028 Page 7 All cage sizes and housing conditions are in compliance with the Guide for the Care and Use of Laboratory Animali4>. Argus Research is an AAALAC-accredited facility. Housing: Fo generation rats will be individually housed in stainless steel wire-bottomed cages except during the cohabitation and postpartum periods. During cohabitation, each pair of rats will be housed in the male rat's cage. Beginning no later than day 20 ofpresumed gestation, Fo generation female rats will be individually housed in nesting boxes. Each dam and delivered litter will be housed in a common nesting box during the postpartum period. Nesting Material: Nesting material (bed-o'cobs) will be provided. Bedding will be changed as often as necessary to keep the animals dry and clean. Analyses for possible contamination are conducted semi-annually and documented in the raw data. Room Air, Temperature and Humidity: The animal room is independently supplied with at least ten changes per hour of 100% fresh air that has been passed through 99.97% HEPA filters. Room temperature will be maintained at 64F to 79F (18C to 26C) and monitored constantly. Room humidity will also be monitored constantly and maintained at 30% to 70%. Light: An automatically controlled 12-hour light:12-hour dark fluorescent light cycle will be maintained. Each dark period will begin at 1900 hours EST. The light cycle may be adjusted by the Study Director or designee if deemed necessary to accommodate scheduled laboratory activities. Any such adjustment will be documented in the raw data. Diet: Rats will be given Certified Rodent Diet #5002 (PMI Nutrition International) available ad libitum from individual feeders. Feed will be removed the evening prior to the scheduled sacrifice. Water: Water will be available ad libitum from individual bottles attached to the cages or from an automatic watering access system. All water will be from a local source and passed through a reverse osmosis membrane before use. Chlorine will be added to the processed water as a bacteriostat; processed water is expected to contain no more than 1.2 ppm chlorine at the time of analysis. Water is analyzed monthly for possible bacterial contamination and twice annually for possible chemical contamination. 418-028:PAGE D-8 Protocol 415-026 Page8 Contaminants: Neither the Sponsor nor the Study Director is aware of any potential contaminants likely to be present in the certified diet, in the drinking water or in the nesting materials at levels that would interfere with the results ofthis study. Therefore, no analyses other than those routinely performed by the feed supplier or those mentioned in this protocol will be conducted. DAY NUMBERING SYSTEM: Gestation day 0 is defined as the day spermatozoa are observed in a smear of the vaginal contents and/or a copulatory plug observed in situ. The day of birth is designated lactation day 0 (postpartum day 0) in the Health Effects Test Guidelines - Reproduction and Fertility Effects (Office ofPrevention, Pesticides and Toxic Substances 870.3800, August, 1998) and in the OECD Guideline for the Testing of Chemicals Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (Section 4, No. 422, 22 March 1966). This same day is designated day 1 postpartum (day 1 oflactation) in the Standard Operating Procedures ofthe Testing Facility. Throughout this protocol, the day ofbirth will be designated day 1 postpartum (day 1 of lactation) and all subsequent ages of the Fl generation rats and days of the lactation period will be determined and cited accordingly. RANDOMIZATION AND COHABITATION: Upon arrival, rats will be assigned to individual housing on the basis of computer-generated random units. During an acclimation period of at least five days, male and female rats will be selected for study on the basis ofphysical appearance and body weights recorded during acclimation. The rats will be assigned to dosage groups based on computer-generated (weightordered) randomization procedures. Within each dosage group, consecutive order will be used to assign rats to cohabitation, one male rat per female rat. The cohabitation period will consist of a maximum of 14 days. Female rats with spermatozoa observed in a smear ofthe vaginal contents and/or a copulatory plug observed in situ will be considered to be at day 0 of presumed gestation and assigned to individual housing. Female rats not mated within the first seven days ofcohabitation will be assigned alternate male rats that have mated (same dosage group) and will remain in cohabitation for a maximum of seven additional days. Day 1 of lactation (postpartum) is defined as the day ofbirth and is also the first day on which all pups in a litter are individually weighed (pup body weights will be recorded after all pups in a litter are delivered and groomed by the dam). Litters will not be culled during the lactation period, because random selection ofpups for culling could result in potential biases in pup viabilities and body weight gains over this period. 418-028:PAGE D-9 Protocol 418-028 Page9 Within each dosage group, consecutive order will be used to assign the first 10 male and the first 10 female rats to a functional observational battery (FOB) and motor activity assessment, blood sample collection for clinical chemistry and hematology (CC&H), and histological evaluations. On day 22 postpartum, a table ofrandom units will be used to select five male and five female pups per litter for blood sample and liver collection; these pups will only be selected from the ten dams selected for FOB, motor activity, CC&H and histological evaluation. ADMINISTRATION: Route and Reason for Choice: The oral (gavage) route was selected for use because: 1) in comparison with the dietary route, the exact dosage can be accurately administered; and 2) it is one of the possible routes for environmental exposure. Method and Frequency: Dosages will be adjusted daily for body weight changes and given at approximately the same time each day. The first day of dosage is designated as day 1 of study. Male rats will be given the test substance once daily beginning 14 days before a cohabitation period that consists of a maximum 14 days. Dosage will continue through the day before sacrifice, after completion of the cohabitation period, after a minimum of42 days of administration. Female rats will be given the test substance once daily beginning 14 days before a cohabitation period that consists of a maximum of 14 days. Dosage will continue through the day before scheduled sacrifice (day 21 oflactation). Rationale for Dosage Selection: Dosages were selected by the Sponsor based on previous studies conducted with the test substance, taking into account possible differences in sensitivity between pregnant and nonpregnant rats. The highest dosage will be expected to cause toxic effects but not mortality or obvious suffering. The descending sequence of the lower dosage levels will be selected for the purpose of demonstrating any dosage-related response, with no adverse effects expected at the lowest level. 418-028:PAGE D-10 Dosage Levels, Concentrations and Volumes: Protocol 418-028 Page 10 Dosage Group Number of Rats Per Sex Dosage (me/kl!lday) Concentration (ml!lmLl Dosage Volume (rn1Jk2) Argus Batch Number I 15 +lb 0 0 10 B-418-028-A(Day.Month.Year) II 15 +3b 0.3 0.03 10 8-418-028-B(Day.Month.Year) III )5+3b I 0.1 IO B-418-028-C(Day.Month.Year) IV 15 +3b 3 0.3 v 15+3b IO I 10 B-418-028-D(Day.Month. Year) 10 B-418-028-E(Day.Montr.. Year) a. The test substance wtll be considered 100% pure for the purpose of dosage calculahOns. b. Three additional rats per sex per dosage group will be assigned to toxicokinetic sample collection. TESTS, ANALYSES AND MEASUREMENTS - Fo GENERATION: Viability - Male and Female Rats: All Periods: At least twice daily. Clinical Observations and/or General Appearance - Male and Female Rats: Acclimation Period: Weekly. Dosage Period: Daily before dosage. On the first day of dosage, postdosage observations will be recorded at approximately hourly intervals for the first four hours and at the end of the normal working day. Subsequent postdosage observations will be recorded at intervals deemed appropriate by the Study Director or designee after determination ofpeak toxicologic effects. Maternal Behavior: Days 1, 5, 8, 15 and 22 postpartum. Observed abnormal behavior recorded daily. Clinical observations may be recorded more frequently than cited above, if deemed appropriate by the Study Director and/or Study Monitor. Data collected for rats assigned to toxicokinetic sample collection will not be summarized or analyzed statistically. Detailed Clinical Observations - Male and Female Rats: Once before the first dosage and at least once weekly thereafter, detailed clinical observations will be conducted for all male and female rats. These observations will be made outside the cage in a standard arena at the same time each day ofconduct. Effort will be made to ensure that variations in the test conditions are minimal and that observations are conducted by observers unaware of treatment groups. Signs noted should include, but not be limited to: changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions and autonomic activity (e.g., lacrimation, piloerection, pupil size, unusual respiratory pattern). Changes in gait, posture 418-028:PAGE D-11 Proiocol 418-028 Page 11 and response to handling as well as the presence of clonic or tonic movements, sterotypic behavior (e.g., excessive grooming, repetitive circling), difficult or prolonged parturition or bizarre behavior (e.g., self-mutilation, walking backwards) should also be recorded. Body Weights - Male and Female Rats: Acclimation Period: Weekly. Dosage Period: Daily. Sacrifice: Terminal weight. Feed Consumption Values - Male Rats (recorded and tabulated): Dosage Period: Weekly. Feed Consumpdon Values - Female Rats (recorded and tabulated): Dosage Period: Weekly to cohabitation. Gestation Period: Days 0, 7, 10, 12, 15, 18, 20 and 25 (if necessary). Postpartum Period: Days 1, 5, 8 and 15. Feed consumption not tabulated after day 15 postpartum, when it is expected that pups will begin to consume maternal feed. Feed Consumption Values - Male and Female Rats: Feed consumption values may be recorded more frequently than cited above if it is necessary to replenish the feed. During cohabitation, when two rats occupy the same cage with one feed jar, replenishment ofthe feed jars will be documented. Individual values will not be recorded or tabulated. Toxicokinedc Sample Collection: On day 14 and 42 of study, blood samples (approximately 1 mL each) will be collected from each male rat assigned to the toxicokinetic sample collection portion ofthe study (3 pet group). On day 14 of study and day 21 of presumed gestation, blood samples (approximately 1 mL each) will be collected from each female rat assigned to the toxicokinetic sample collection portion of the study (3 per group). Samples will be collected prior to dosage on day 14 ofstudy. The time of each blood collection will be recorded in the raw data. 418-028:PAGE D-12 Protocol 418-028 Page 12 Blood will be collected from the orbital sinus. Ifnecessary, blood may be collected from an alternate site; if so, the alternate site will be documented in the raw data.) The samples will be transferred into EDTA-coated (purple top) tubes and spun in a centrifuge. The resulting serum will be transferred into polypropylene tubes labeled with the protocol number, Sponsor study number, animal number, sex, group number, dosage level, day of study, collection interval, date of collection, species, generation and storage conditions. All samples will be immediately frozen on dry ice and maintained frozen (S-70C) until shipment for analysis. After the last blood sample collection, rats will be sacrificed and samples of the liver will be collected for analysis. Shipping Instructions: Samples to be analyzed will be shipped on dry ice to: Principal Investigator: Lisa Clemen 3M Environmental Technology and Safety Services Building 2-3E-09 St. Paul, Minnesota 55133-3331 Telephone: (651) 778-5568 Telefax: (651) 778-6176 Email: laclemen@mmm.com The recipient will be notified in advance of sample shipment. Estrous Cycling and Mating: Estrous cycling will be evaluated by examination of vaginal cytology beginning with the day after the first administration and then until spermatozoa are observed in a smear of the vaginal contents and/or a copulatory plug is observed in situ during the cohabitation period. Caesarean-Sectioning - Toxicokinetic Study: On day 21 ofpresumed gestation, blood and liver samples will be collected from all female rats designated for toxicokinetic sample collection. Blood samples will be collected from the rats as previously described. After sacrifice, the liver of each rat will be excised and the liver weight will be recorded. The median liver lobe will be frozen and stored ($-20C) until shipment for possible analysis. The fetuses will be removed from the uterus and blood samples will be collected from each fetus via decapitation. Blood will be placed into tubes, pooled per litter, allowed to clot and spun in a centrifuge; the resulting serum will be transferred into labeled polypropylene tubes. All samples will be immediately frozen on dry ice and maintained frozen ($-70C) until shipment for analysis. 418-028:PAGE D-13 Protocol 418-028 Page 13 The liver from each fetus will be collected, pooled per litter and placed into labeled tubes. The samples will be frozen and stored (:S-20C) until shipment for analysis. Samples will be shipped on dry ice to Lisa Clemen at the previously cited address. Natural Delivery: Female rats will be evaluated for: Adverse Clinical Signs Observed During Parturition. Duration of Gestation (day 0 of presumed gestation to the time the first pup is observed). Litter Size (defined as all pups delivered). Pup Viability at Birth. Functional Observational Battery: On one occasion during the course of the study, a functional observational battery (FOBi53>will be conducted on 10 male and 10 female rats per group. For male rats, this assessment will be conducted shortly before scheduled sacrifice, but prior to blood sample collection for hematology and clinical chemistry evaluations. Female rats should be tested during the lactation period, shortly before scheduled sacrifice. The FOB, to be conducted by an observer unaware of the group assignment ofthe rat, will assess the following parameters: 1. Lacrimation, salivation, palpebral closure, prominence ofthe eye, pupillary reaction to light, piloerection, respiration, and urination and defecation (autonomic functions). 2. Sensorimotor responses to visual, auditory, tactile and painful stimuli (reactivity and sensitivity). 3. Reactions to handling and behavior in the open field (excitability). 4. Gait pattern in the open field, severity ofgait abnormalities, air righting reaction, and landing foot splay (gait and sensorimotor coordination). 5. Forelimb and hindlimb grip strength. 6. Abnormal clinical signs including but not limited to convulsions, tremors and other unusual behavior, hypotonia or hypertonia, emaciation, dehydration, unkempt appearance and deposits around the eyes, nose or mouth. 418-028:PAGE D-14 Protocol 418-028 Page 14 Evidence of the ability of this battery to detect the effects ofpositive control substances will be provided (Testing Facility Positive Control Data). Data will also be provided to document interobserver reliability if more than one observer is involved in the testing. Motor Activity Test: Motor activity will be evaluated on 10 male and 10 female rats per group once during the course of the study. This assessment will be conducted shortly before scheduled sacrifice, but prior to blood sample collection. The movements of each rat will be monitored by a passive infrared sensor mounted outside a stainless-steel wire-bottomed cage (40.6 x 25.4 x 17.8 cm). Each test session will be 1.5 hours in duration with the number of movements and time spent in movement tabulated at each fiveminute interval. The apparatus will monitor a rack of up to 32 cages and sensors during each session, with each rat tested in the same location on the rack across test sessions. Groups will be counterbalanced across testing sessions and cages. Data will be provided to demonstrate that the test system is capable of detecting increases in activity produced by positive control substances (Testing Facility Positive Control Data). HEMATOLOGY AND CLINICAL CHEMISTRY: At scheduled sacrifice, the rats (fasted) assigned to hematology and clinical chemistry (H&CC) sample collection will be exsanguinated from the inferior vena cava following sacrifice by carbon dioxide asphyxiation. Approximately 5 mL ofblood will be collected and processed as described below. Determinations additional to those described below maybe conducted tfthe known properties of the test substance may, or are suspected to, affect related metabolic profiles (e.g., calcium, phosphate, fasting triglycerides and fasting glucose, specific hormones, and cholinesterase). Hematology: Approximately 1 mL ofblood will be collected into EDTA-coated tubes and maintained on wet ice or refrigerated until shipment for analysis ofthe following hematologic parameters: Erythrocyte Count (RBC) Hematocrit (HCT) Hemoglobin (HGB) Mean Corpuscular Hemoglobin (MCH) Mean Corpuscular Hemoglobin Concentration (MCHC) Mean Corpuscular Volume (MCV) Leukocyte Count, Total (WBC) Leukocyte~-. Differential Platelet Count (PLAT) Mean Platelet Volume (MPV) Cell Morphology Two blood smear slides will be prepared at the Testing Facility for each sample for measurements ofdifferential leukocyte count. All samples (on wet ice) and slides (ambient conditions) will be shipped to Redfield Laboratories at the following address. Approximately 1.8 mL of blood will be added to a tube containing 0.2 mL of sodium citrate (0.129 M). The contents will be mixed and maintained on wet ice until the tubes are centrifuged 418-028:PAGE D-15 Protocol 418-028 Page 15 (within 30 minutes of the collection time). The resulting plasma will be transferred 2.0 mL polypropylene tubes labeled with study number, Sponsor's study number, rat number, dosage level, day of study, collection interval, date of collection, species, generation and storage. All samples will be frozen on dry ice and maintained frozen (~70C) until shipment on dry ice by overnight courier for measurement ofprothrombin time (PT) and activated partial thromboplastin time (APTT). Clinical Chemistry: Approximately 2 mL of blood will be collected into serum separator tubes and centrifuged. The resulting sera samples will be immediately frozen on dry ice and maintained frozen (~-70C) until shipment for analysis of the following parameters: Total Protein (TP) Triglycerides (TRI) Albumin(A) Globulin (G) Albumin/Globulin Ratio Glucose (GLU) Cholesterol (CHOL) Total Bilirubin (TBILI) Urea Nitrogen (BUN) Creatinine (CREAT) (A/G) Creatinine Kinase (CK) Alanine Aminotransferase (ALT) Aspartate Aminotransferase (AST) Alkaline Phosphatase (ALK) Calcium (CA) Phosphorus (PHOS) Sodium(NA) Potassium (K) Chloride (CL) Samples will be shipped (on dry ice) to Redfield Laboratories at the following address. Shioping Instructions: Samples will be shipped to arrive on Monday through Friday according to the conditions described above to: Principal Investigator: Ms. Phyllis Powell Redfield Laboratories A Division ofCRL-DDS 100 East Boone Street P.O. Box 308 Redfield, Arkansas 72132 Telephone: (501) 397-2540 Telefax: (501) 397-2002 The recipient will be notified in advance of sample shipment. URINALYSIS: Urinalysis will not be conducted unless indicated based on expected or observed toxicity ofthe test substance. 418-028:PAGE D-16 METHOD OF SACRIFICE: Protocol 418-028 Page 16 Fo generation rats will be sacrificed by carbon dioxide asphyxiation. GROSS NECROPSY AND HISTOPATHOLOGY - Fo GENERATION RATS: Scheduled Sacrifice - Toxicokinetic Study: Scheduled sacrifice of male rats will be conducted on day 42 of study. Scheduled sacrifice of female rats will be conducted on day 21 of presumed gestation. Blood samples will be collected from the rats as previously described. After sacrifice, the liver of each rat will be excised and the liver weight will be recorded. The median liver lobe will be frozen and stored (=5-20C) until shipment for analysis. Fetal samples will be collected as previously described. Carcasses will be discarded without further evaluation. Samples will be shipped on dry ice to Lisa Clemen at the previously cited address. Scheduled Sacrifice - Main Study: Scheduled sacrifice of male rats will be conducted on the day following the last dosage administration, after a minimum of 42 days of dosage. Scheduled sacrifice of female rats will be conducted on day 22 of lactation. Gross necropsy of all male and female rats will include an initial physical examination of external surfaces and all orifices, as well as the cranial, thoracic and abdominal cavities and their contents. Special attention will be paid to the organs ofthe reproductive system. The number of implantation sites and corpora lutea will be recorded. Male and female rats will be examined for gross lesions. Gross lesions will be retained in neutral buffered 100/o formalin and examined histologically. Tissue trimming and histopathology will be performed under the supervision ofor by a Board-Certified Veterinary Pathologist. The ovaries and the uterus with cervix of each female rat will be weighed, and ovaries, uterus, vagina and a mammary gland will be retained in neutral buffered 10% formalin. Uteri of apparently nonpregnant rats will be examined after being pressed between glass plates to confirm the absence of implantation sites, and retained in neutral buffered 10% formalin. 418-028:PAGE D-17 Sperm Evaluations ofMale Rats: Protocol 418-028 Page 17 To assess the potential toxicity of the test article on the male reproductive system, the endpoints listed below will be evaluated from the first 10 male rats in each dosage group. Organ Weights: The following organs will be individually weighed: right testis, left testis, left epididymis (whole and cauda), right epididymis, seminal vesicles (with and without fluid) and prostate. Sperm Evaluations: Sperm concentration and motility will be evaluated using computerassisted sperm analysis (CASA). Motility will be evaluated by the Hamilton Thome IVOS by collection of a sample from the left vas deferens. A homogenate wiIJ be prepared from the left cauda epididymis for evaluation by the Hamilton Thome IVOS to determine sperm concentration (sperm per gram oftissue weight). The remaining portion of the left cauda epididymis will be used to manually evaluate sperm morphology. Sperm morphology evaluations will include the following: 1) determination of the percentage of normal sperm in a sample of at least 200; and 2) qualitative evaluation of abnormal sperm, including such categories as abnormal head, abnormal tail, and abnormal head and tail. See ATTACHMENT 4 for additional tissues to be weighed and retained from the ten rats per sex per group assigned to histological sample collection and evaluation. All other tissues will be discarded. Scheduled Sacrifice of Female Rats that Do Not Deliver Litters: Rats that do not deliver a litter will be sacrificed on day 25 ofpresumed gestation. Gross necropsy, examination and tissue retention will be conducted as described previously for rats at scheduled sacrifice. Dams with No Surviving Pups: Dams with no surviving pups will be sacrificed after the last pup is found dead, missing or presumed cannibalized. Gross necropsy, examination and tissue retention will be conducted as described above for rats at scheduled sacrifice. 418-028:PAGE D-18 Rats Found Dead or Moribund: Protocol 418-028 Page 18 Rats that die or are sacrificed because of moribund condition, abortion or premature delivery will be examined for the cause ofdeath or moribund condition on the day the observation is made. The rats will be examined for gross lesions. Testes and epididymides of male rats will be excised and paired organ weights will be recorded. The epididymides will be retained in neutral buffered 10% formalin. The testes will be fixed in Bouin's solution for 48 to 96 hours and then retained in neutral buffered 10% formalin. Pregnancy status and uterine contents of female rats will be recorded. Aborted fetuses and/or delivered pups will be examined to the extent possible. Uteri of apparently nonpregnant rats will be examined after being pressed between glass plates to confirm the absence of implantation sites. Ovaries and uteri will be retained in neutral buffered 10% formalin. TESTS, ANALYSES AND MEASUREMENTS - Fl GENERATION: Viability: Preweaning Period: Litters will be observed for dead pups at least twice daily. The pups in each litter will be counted once daily. Clinical Observations and/or General Appearance: Preweaning Period: Once daily. Pups will be observed ifthey are warm and clean, for evidence of a nest and ifpups are grouped together and nursing or have milk in stomach. Each pup will be examined for general shape of the head, trunk, limbs, tail and presence of anus. Clinical observations may be recorded more frequently than cited above, if deemed appropriate by the Study Director and/or the Study Monitor. Body Weights: Preweaning Period: Days 1 (birth), 8, 15 and 22 postpartum. Sacrifice: Terminal weight. Feed Consumption Values (recorded and tabulated): Preweaning Period: Not recorded. METHOD OF SACRIFICE - Fl GENERATION PUPS: Fl generation pups will be sacrificed by carbon dioxide asphyxiation. 418-028:PAGE D-19 Protocol 418-028 Page 19 NECROPSY - Fl GENERATION: Gross lesions will be retained in neutral buffered 10% formalin for possible future evaluation. Unless specifically cited below, all other tissues will be discarded. Pups Found Dead on Day 1 Postpartum: Pups that die before examination of the litter for pup viability will be evaluated for vital status at birth. The lungs will be removed and immersed in water. Pups with lungs that sink will be identified as stillborn; pups with lungs that float will be identified as livebom, and to have died shortly after birth. Pups with gross lesions will be preserved in Bouin's solution for possible future evaluation. Pups Found Dead or Moribund on Days 2 to 4 Postpartum: Pups found dead or sacrificed because of moribundity will be examined for gross lesions and for the cause of death or the moribund condition. Pups with gross lesions will be preserved in Bouin's solution for possible future evaluation. Scheduled Sacrifice: On day 22 postpartum, pups will be will be sacrificed and examined for gross lesions; gross lesions will be preserved in neutral buffered 10% formalin. Necropsy will include a single crosssection of the head at the level ofthe frontal-parietal suture and examination of the crosssectioned brain for apparent hydrocephaly. Blood samples will be collected from each selected pup (5 per sex per litter from the 10 females per group selected for FOB and motor activity assessment, blood sample collection for H&CC, and histological evaluations) from the vena cava. The blood will be placed into tubes, pooled per litter, allowed to clot and spun in a centrifuge; the resulting serum will be transferred into labeled polypropylene tubes. All samples will be immediately frozen on dry ice and maintained frozen (:5-70C) until shipment for analysis. The liver from each selected pup will be collected excised and the organ weight recorded. The median lobe will be frozen and stored (:5-20C} until shipment for possible analysis. Frozen samples will be shipped to Lisa Clemen at the previously cited address. The remaining portion ofeach liver will be retained in neutral buffered 10% fonnalin for possible histological evaluation. The livers will be processed and evaluated histologically as described for the Fo generation rats in Histological Evaluation in ATTACHMENT 4. 418-028:PAGE D-20 PROPOSED STATISTICAL TESTs<9-16): The following schematic represents statistical analyses of the data. Protocol 418-028 Page20 I. Parametric A. Bartlett's Test c: Type of Testa II. Nonparametric b A. l<ruskal-Wallis Test C:s 75% ties al any concenlratfon) Significant at p~o.001 Not Significant Significant at p~0.05 Not Significant Nonparametric Analysis of Variance Significant at p~0.05 Dunnett's Test Not Significant Dunn's Test B. Fisher's Exad Test on Proportion of Ties (>75% Mes at any concentration) B. Analysis of Variance with Repeated Measures Significant at p~0.05 Not Significant (Dosage) Dunnett's Test (Dosage x Block lnteradion) One-way ANOVA for each block Significant atp5,0.05 Not Significant Dunnett's Test Ill. Test for Proportion Data Variance Test for Homogeneity of the Binomial Distribution a. Statistically significant probabilities are reported as eitherp ::::; 0.05 orp ~ 0.01. b. Proportion data are not included in this category. c. Test for homogeneity of variance. 418-028:PAGE D-21 Protocol 418-028 Page21 Test items in the FOB using interval scales, such as the grip-strength tests and the landing foot splay test, as well as body weight data and feed consumption values will be analyzed as described under the Parametric heading of the schematic. Bartlett's Test of Homogeneity of Variances<9>will be used to estimate the probability that the groups had different variances. A nonsignificant result (p>0.001) will indicate that an assumption ofhomogeneity ofvariance is not inappropriate, and the data will be compared using the Analysis of Variance Test<10). If that test is significant (p:50.05), the groups exposed to the test article/substance will be compared with the control group using Dunnett's Test<11J. IfBartlett's Test is significant (p:50.001), the Analysis of Variance Test is not appropriate, and the data will be analyzed as described under the Nonparametric heading of the schematic. When 75% or fewer of the scores in all the groups are tied, the Kruskal-Wallis Test02>will be used to analyze the data, and in the event of a significant result (p:50.05), Dunn's Test<13>will be used to compare the groups exposed to the test article/substance with the control group. When more than 75% of the scores in any group are tied, Fisher's Exact Test<14>will be used to compare the proportion ofties in the groups. Data from the motor activity test, with repeated measurements within a session, will be analyzed using an Analysis of Variance with Repeated Measures<15>, as described under that heading in the schematic. A significant effect (p:50.05) in that test can appear as effect of Concentration (a difference between groups in the total across all measurements in a session) or as an interaction between Concentration and Block (a difference between groups at specific measurement periods). Ifthe Concentration effect is significant, the totals for the control group and the groups given the test article/substance will be compared using Dunnett's Test. Ifthe Concentration x Block interaction is significant, an Analysis of Variance Test will be used to evaluate the data at each measurement period, and a significant result (p:50.05) will be followed by a comparison of the groups using Dunnett's Test. Test items in the FOB having graded or count scores will be analyzed using the procedures described under the Nonparametric heading of the schematic. Clinical observation incidence data, as well as the descriptive and quantal data from the FOB, will be analyzed as contingency tables using the Variance Test for Homogeneity of the Binomial Distribution<16>. Alternate or additional statistical evaluations may be performed ifdeemed necessary or appropriate. 418-028:PAGE D-22 Protocol 418-028 Page 22 DATA ACQUISITION, VERIFICATION AND STORAGE: Data generated during the course ofthis study will be recorded either by hand or using the Argus Automated Data Collection and Management System, the Vivarium Temperature and Relative Humidity Monitoring System, the Coulbourn Instruments Passive Infrared Motor Activity System, the Coulbourn Instruments Auditory Startle System, the Coulbourn Instruments Spatial Delayed Alternation System, and/or the passive avoidance software. All data will be tabulated, summarized and/or statistically analyzed using the Argus Automated Data Collection and Management System, the Vivarium Temperature and Relative Humidity Monitoring System, Microsoft Excel [part of Microsoft Office 97 (version SR-2)] and/or The SAS System (version 6.12). Records will be reviewed by the Study Director and/or appropriate management personnel within 21 days after generation. All original records will be stored in the archives of the Testing Facility. All original data will be bound and indexed. A copy of all raw data will be supplied to the Sponsor upon request. Preserved tissues will be stored at the Testing Facility at no charge for one year after mailing ofthe draft final report, after which time the Sponsor will be contacted to determine the disposition of these materials. KEY PERSONNEL: Executive Director ofResearch: Mildred S. Christian, Ph.D., Fellow, ATS Director of Research: Alan M. Hobennan, Ph.D., DABT Associate DirectorofResearch and Study Director: Raymond G. York, Ph.D., DABT Director of Operations and Compliance: Barbara J. Patterson, B.A. Director of Laboratory Operations: John F. Barnett, B.S. Director of Study Management: Valerie A. Sharper, M.S. Manager ofAnimal Operations: Dena C. Lebo, V.M.D. Chairperson, Institutional Animal Care and Use Committee: Douglas B. Learn, Ph.D. Consultant, Veterinary Pathology: W. Ray Brown, D.V.M., Ph.D., ACVP 418-028:PAGE D-23 RECORDS TO BE MAINTAINED: Protocol 418-028 Page23 Protocol and Amendments. Test Substance, Vehicle and/or Reagent Receipt, Preparation and Use. Animal Acquisition. Randomization Schedules. Mating History. Treatment (ifprescribed by Staff Veterinarian). General Comments. Clinical Observations and/or General Appearance. Body Weights. Feed Consumption Values. Natural Delivery Observations. FOB and Motor Activity Observations. Blood Sample Collection, Processing and Shipment. Gross Necropsy Observations. Organ Weights. Photographs (if required). Study Maintenance (room and environmental records). Feed and Water Analyses. Packing and/or Shipment Lists. FINAL REPORT: The Study Director will provide periodic updates of study progress to the Sponsor. Draft summary tables of unaudited computer-recorded data may accompany these updates. Statistical analyses will not be performed on these interim data. A comprehensive draft final report will be prepared on completion of the study and will be fmalized following consultation with the Sponsor. The report will include the following: Summary and Conclusion. Experimental Design and Method. Evaluation ofTest Results. Appendices: Figures, Summary and Individual Tables Summarizing the Above Data, Protocol and Associated Amendments and Deviations, Study Director's GLP Compliance Statement, Reports of Supporting Data (ifappropriate) and QAU Statement. The Sponsor will receive one copy of the draft report and two copies of the final report. Data will be hand- and/or computer-recorded. Records will be reviewed by the Study Director and/or appropriate management personnel within 21 days after generation. All original records will be stored in the archives ofthe Testing Facility. All original data will be bound and indexed. A copy of all raw data will be supplied to the Sponsor upon request. Preserved tissues will be stored at the Testing Facility at no charge for one year after mailing of the draft final report, after which time the Sponsor will be contacted to determine the disposition of these materials. 418-028:PAGE D-24 Protocol 418-028 Page 24 INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE STATEMENT: The procedures described in this protocol have been reviewed by the Testing Facility's Institutional Animal Care and Use Committee. All procedures described in this protocol that involve study animals will be conducted in a manner to avoid or minimize discomfort, distress or pain to the animals. The Sponsor's signature below documents the fact that information concerning the necessity for conducting this study and the fact that this is not an unnecessarily duplicative study may be obtained from the Sponsor. No alternative (in vitro) procedures were available for meeting the stated pwposes of the study. REFERENCES: 1. Christian, M.S. and Voytek, P.E. (1982). In Vivo Reproductive and Mutagenicity Tests. Environmental Protection Agency, Washington, D.C. National Technical Information Service, U.S. Department of Commerce, Springfield, VA 22161. 2. Christian, M.S. (1984). Reproductive toxicity and teratology evaluations of naltrexone (Proceedings ofNaltrexone Symposium, New York Academy of Sciences, November 7, 1983), J. Clin. Psychiat. 45(9):7-10. 3. Lang, P.L. (1988). Embryo and Fetal Developmental Toxicity (Teratology) Control Data in the Charles River Crl:CDBR Rat. Charles River Laboratories, Inc., Wilmington, MA 01887-0630. (Data base provided by Argus Research Laboratories, Inc.) 4. Institute of Laboratory Animal Resources (1996). Guidefor the Care and Use of Laboratory Animals. National Academy Press, Washington, D.C. 5. Haggerty, G.C. (1989). Development of Tier I neurobehavioral testing capabilities for incorporation into pivotal rodent safety assessment studies. J. Amer. Col. Toxicol. 8:5370. 6. Irwin, S. (1968). Comprehensive observational assessment: Ia. A systemic quantitative procedure for assessing the behavioral and physiologic state of the mouse. Psychopharmacologia (Berlin) 13:222-257. 7. Moser, V.C. (1989). Screening approaches to neurotoxicity: A functional observational battery. J. Amer. Col. Toxicol. 8:85-94. 8. O'Donoghue, J.L. (1989). Screening for neurotoxicity using a neurologically based examination and neuropathology. J. Amer. Col. Toxicol. 8:97-116. 9. Sokal, R.R. and Rohlf, F.J. (1969). Bartlett's test ofhomogeneity ofvariances. Biometry, W.H. Freeman and Co., San Francisco, pp. 370-371. 418-028 :PAGE D-25 Protocol 418-028 Page 25 10. Snedecor, G.W. and Cochran, W.G. (1967). Analysis of Variance. Statistical Methods, 6th Edition, Iowa State University Press, Ames, pp. 258-275. 11. Dunnett, C.W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Amer. Stat. Assoc. 50:1096-1121. 12. Sokal, R.R. and Rohlf, F.J. (1969). Kruskal-Wallis Test. Biometry, W.H. Freeman and Co., San Francisco, pp. 388-389. 13. Dunn, O.J. (1964). Multiple comparisons using rank sums. Technometrics.6(3):241-252. 14. Siegel, S. (1956). Nonparametric Statistics for the Behavioral Sciences, McGraw-Hill, New York, pp. 96-104. 15. SAS Institute, Inc. (1988). Repeated measures analysis ofvariance. SAS/STATTM User's Guide, Release 6.03 Edition, Cary, NC, pp. 602-609. 16. Snedecor, G.W. and Cochran, W.G. (1967). Variance test for homogeneity ofthe binomial distribution. Statistical Methods, 6th Edition, Iowa State University Press, Ames, pp. 240-241. 418-028:PAGE D-26 PROTOCOL APPROVAL: FOR THE TESTING FACILITY ---(---k--~-----L------l-~\---~----.------------------------------- Alan M. Hobennan, Ph.D., DABT Director ofResearch Protocol 418-028 Page26 Date -----~-f!?.J!!_IJP:___~_f!R_b________ Date r ~~~~~---------------- Member, Institutional Animal Care and Use Committee __?:_!f-___r:..1..c::;e____{~:.~_?:_____________ Date FOR THE SPONSOR John Butenhoff, Ph.D., DABT, CUI Study Monitor and Sponsor's Representative Date 418-028:PAGE D-27 ATTACHMENT I SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE 418-028:PAGE D-28 ATTACHMENT 1 STUDY SCHEMATIC Protocol 418-028 Page 1 of3 COMBINED REPEAT DOSE AND REPRODUCTIVE/DEVELOPMENTAL TOXICITY SCREENa First Day of Test Substance Dosage Male Rats Premating 2 Weeks Last Day ofTest Substance Dosage: Cohabitation 2 Weeks Female Rats Motor Activity/FOBb 2 Weeks 2 Weeks Presumed Gestation 3 Weeks Last Day ofTest Substance Dosagee Natural Delivery Postpartum Period Day 21 Day 22e I I Motor Activity/FOBd - Dosage Period a. For additional details see "Tests, Analyses and Measurements" section of the protocol. b. FOB and motor activity evaluations conducted on ten males per group. c. Male rats sacrificed after completion of at least 42 days of dosage; necropsy and retention of male reproductive organs. Hematology, clinical biochemistry and histological samples collected from ten male rats per group. d. Ten female rats per group assigned to FOB evaluation and motor activity evaluation. e. Ten female rats per group and their litters sacrificed on day 22 postpartum; necropsy and retention of female reproductive organs. Hematology, clinical biochemistry and histological samples collected. Remaining female rats sacrificed on day 22 postpartwn and discarded. ATTACHMENT 1 418-028:PAGE D-29 Protocol 418-028 Page 2 of3 SCHEDULE8 26MAR02 01 APR02 01APR02 -12 JUN 02 14 APR 02 PM - 21 APR 02 AM 21 APR 02 PM - 28 APR 02 AM 14APR02 15 APR02 28APR02 06MAY02 19MAY02 06 MAY 02 - 07 MAY 02 Animal Receipt - Acclimation Begins. Start ofDosage Period - Male Rats (14 days before cohabitation and through a 14-day cohabitation period until the day before sacrifice after at least 42 days ofdosage). Dosage Period - Female Rats (14 days before cohabitation through Day 22 oflactation). Cohabitation Period (Maximum of 14 days). Male 1 (7 days) Male 2 (7 days) Day 14 Toxicokinetic Sample Collection First Possible Day 0 ofPresumed Gestation. Last Possible Day 0 ofPresumed Gestation. First Possible Day 21 ofPresumed Gestation Toxicokinetic Sample Collection and Sacrifice Toxicokinetic Study Female Rats Last Possible Day 21 ofPresumed Gestation Toxicokinetic Sample Collection and Sacrifice Toxicokinetic Study Female Rats FOB and Motor Activity Evaluation - I0 Male Rats per Group a. The start date of the study is the day the Study Director signs the protocol. b. Throughout this schedule, the day ofbirth is designated day 1 postpartum (day 1 of lactation) and all subsequent ages ofthe Fl generation rats and days ofthe lactation period will be determined and cited accordingly; as described above the protocol section, "Day Numbering System." 418-028:PAGE D-30 AITACHMENT 1 06MAY02 23MAY02 10MAY02 23MAY02 12 MAY02 13 MAY02 23 MAY 02 -09 JUN 02 27 MAY 02-13 JUN 02 24SEP02 Protocol 418-028 Page 3 of3 First Possible Delivery (Day 21 of presumed gestation). Last Possible Delivery (Day 25 ofpresumed gestation). First Possible Day 25 ofPresumed Gestation Female Sacrifice. Last Possible Day 25 ofPresumed Gestation Female Sacrifice. Day 42 Toxicokinetic Sample Collection and Scheduled Sacrifice - Toxicokinetic Study Male Rats Scheduled Sacrifice - Main Study Male Rats (Earliest possible date). Hematology, Clinical Biochemistry and Histological Sample Collection of Selected Male Rats. FOB and Motor Activity Evaluation - 10 Female Rats per Group. Day 22 Postpartum - Sacrifice Female Rats and Pups. Hematology, Clinical Chemistry and Histological Sample Collection ofSelected Female Rats and Pups. Draft Final Report 418-028:PAGE D-31 ATTACHMENT? MATERIAL SAFETY DATA SHEET 418-028:PAGE D-32 MATERIAL SAFETY DATA SHEET (Experimental) 3M 3M center St. Paul, Minnesota 55144-1000 1-800-364-3577 or (651) 737-6501 (24 hours) Copyright, 1999, Minnesota Mining and Manufacturing Copany. All rights reserved. Copying and/or downloading of this inforation for the purpose of properly utilizing 3M products is allowed provided that: 1) the information is copied in full with no changes unless prior agreeent is obtained fro 3M, and 2) neither the copy nor the original is resold or otherwise distributed with the intention of earning a profit thereon. DIVISION: 3M SPECIALTY MATERIALS MATERIAL: L-9051 DEVELOPMENTAL PRODUCT ISSUED: December 07, 1999 SUPERSEDES: May 17, 1999 DOCUMENT: 04-5470-2 1. INGREDIENT C.A.S. NO. PERCENT POTASSIUM PERFLUOROHEXANE SULFONATE..... 3871-99-6 RESIDUAL ORGANIC FLUOROCHEMICALS........ Mixture 100.0 Unknown This material is not listed on the TSCA inventory and should be used for research and development purposes only under the direct supervision of a technically qualified individual. 2. PHYSICAL DATA BOILING POINT: ......... VAPOR PRESSURE: ..... VAPOR DENSITY: ... EVAPORATION RATE: . SOLUBILITY IN WATER: ... SPECIFIC GRAVITY: .... PERCENT VOLATILE: .... pH: . VISCOSITY: . . . . . . . . . . . . . MELTING POINT: ............. N/A Negligible N/A Negligible slight ca.-1.0 Water=t (Bulk) Negligible N/A N/O N/D APPEARANCE ANO ODOR: Off.white crystalline solid, sharp odor. Abbreviations: N/0 - Not Determined NIA Not Applicable CA Approximately 418-028:PAGE D-33 MSOS: L-9051 DEVELOPMENTAL PRODUCT December 07, 1999 PAGE 2 --3-.--F-I-R-E--A-N-O--E-X--P-L-O-S-IO-N---H-A-Z-A-R-D--D-AT-A------------------------------------------------------------------------------------------------------------------- ~LASH f'U!N f : > i1 ~ ,. Setaflash Setaflash Closed Cup FLAMMABLE LIMITS - LEL: ....... N/A FLAMMABLE LIMITS - UEL: .. N/A AUTOIGNITION TEMPERATURE: ...... N/D EXTINGUISHING MEDIA: Water, Carbon dioxide, Dry chemical, Foam SPECIAL FIRE FIGHTING PROCEDURES: Wear full protective clothing, including helmet, self-contained, positive pressure or pressure demand breathing apparatus, bunker coat and pants, bands around aN1s, waist and legs, face ask, and protective covering for exposed areas of the head. UNUSUAL FIRE AND EXPLOSION HAZARDS: See Hazardous Decomposition section for products of combustion. 4. REACTIVITY DATA STABILITY: Stable INCOMPATIBILITY MATERIALS/CONDITIONS TO AVOID: None known. HAZARDOUS POLYMERIZATION: Hazardous polymerization will not occur. HAZARDOUS DECOMPOSITION PRODUCTS: May produce fluorocarbon gases if exposed to very high temperatures (over 300 C). 5. ENVIRONMENTAL INFORMATION SPILL RESPONSE: Observe precautions from other sections. Collect spilled material. Use wet sweeping compound or water to avoid dusting. Clean up residue. Place in a closed container. RECOMMENDED DISPOSAL: Incinerate in an industrial or commercial facility in the presence of a combustible material. Combustion products will include HF. Disposal alternative: Dispose of waste product in a facility permitted to accept chemical waste. ----------------------------------------------------------------- Abbreviations: N/D - Not Determined N/A Not Applicable CA Approximately 418-028:PAGE D-34 MSDS: L-9051 DEVELOPMENTAL PRODUCT December 07, 1999 PAGE 3 5. ENVIRONMENTAL INFORMATION (continued) t:NVIRUNMENlAL OAlA; Not deterined. REGULATORY INFORMATION: Volatile Organic Compounds: N/D. VOC Less H20 & Exempt Solvents: N/D. Since regulations vary, consult applicable regulations or authorities before disposal. U.S. EPA Hazardous Waste Nuber = None (Not U.S. EPA Hazardous). OTHER ENVIRONMENTAL INFORMATION: This product ay contain one or more organic f luorochemicals that have the potential.to resist degradation and persist in the environment. EPCRA HAZARD CLASS: FIRE HAZARD: No PRESSURE: No REACTIVITY: No ACUTE: Yes CHRONIC: No 6. SUGGESTED FIRST AID ----------------------------------------------------------------------------- EYE CONTACT: Immediately flush eyes with large amounts of water. Get immediate medical attention. SKIN CONTACT: Flush skin with large amounts of water. If irritation persists, get medical attention. INHALATION: If signs/symptoms occur, remove person to fresh air. If signs/symptoms continue, call a physician. IF SWALLOWED: If swallowed. call a physician immediately. Only induce vomiting at the instruction of a physician. Never give anything by mouth to an unconscious person. 7. PRECAUTIONARY INFORMATION EYE PROTECTION~ Avoid eye contact. Avoid eye contact with vapor, spray, or mist. The following should be worn alone or in combination, as appropriate, to prevent eye contact: Wear vented goggles. Abbreviations: N/D- Not Determined N/A - Not Applicable CA - Approximately 418-028:PAGE D-35 MSDS: L-9051 DEVELOPMENTAL PRODUCT December 07, 1999 PAGE 4 -------------------------------------------------------------------------- 7. PRECAUTIONARY INFORMATION (continued) SKIN PROTECTION; Avoid skin contact. Hear appropriate gloves when handling this material. A pair of gloves ade from the followiBg aterial(s) are recommended: butyl rubber, polyethylene/polyvinylidene chloride (Saranex). Use one or more of the following personal protection items as necessary to prevent skin contact: head covering, coveralls. Protective garents (other than gloves) should be made of either of the following materials: polyethylene/polyvinylidene chloride (Saranex). RECOMMENDED VENTILATION: Use with appropriate local exhaust ventilation. Provide appropriate local exhaust ventilation at transfer points. Use in a well- ventilated area. Provide sufficient ventilation to aintain emissions below recommended exposure liits. If exhaust ventilation is not adequate, use appropriate respiratory protection. Provide ventilation adequate to control vapor concentrations below recommended exposure limits and/or control spray or mist. Local exhaust ventilation is recommended where the mes airborne. material beco RESPIRATORY PROTECTION: Avoid breathing of airborne material. Select one of the following NIOSH approved respirators based on airborne concentration of contaminants and in accordance with OSHA regulations: half-mask supplied air respirator, full-face supplied air respirator. PREVENTION OF ACCIDENTAL INGESTION: Do not eat, drink or smoke when using this product. Wash exposed areas thoroughly with soap and water. Wash hands after handling and before eating. RECOMMENDED STORAGE: Store at room temperature. closed when not in use. Keep container dry. Keep container FIRE AND EXPLOSION AVOIDANCE: Not determined. EXPOSURE LIMITS INGREDIENT VALUE UNIT TYPE AUTH SKIN* POTASSIUM PERFLUOROHEXANE SULFONATE ................... 0 .1 MG/M3 TWA 3M v RESIDUAL ORGANIC FLUOROCHEMICALS..... 0.1 MG/M3 TWA 3M v ~ SKIN NOTATION: L1sted substances indicated with v under SKIN refer to Abbreviations: N/D - Not Determined N/A - Not Applicable CA Approximately 418-028:PAGE D-36 MSDS: L-9051 DEVELOPMENTAL PRODUCT December 07, 1999 PAGE 5 EXPOSURE LIMITS (continued) INGREDIENT VALUE UNIT TYPE AUTH SKIN* t-h-e--p--o-t-e-n-t-i-a-l-c--o-n-t-d-b-u--ti-u-n---to---th--e--u-v-e-r-a-l-l--ex--p-u-s-u-re--b-y--t-h-e--c-u-t-a-ne-o-u-s--r-o-ut-e----- including mucous embrane and eye, either by airborne or, ore particularly, by direct contact with the substance. Vehicles can alter skin absorption. SOURCE OF EXPOSURE LIMIT DATA: - 3M: 3M Recommended Exposure Guidelines --------------------------------------------------------------------------8. HEALTH HAZARD DATA ----------------------------------------------------------------------------- EYE CONTACT: No information was found regarding effects fro eye contact. Single exposure may cause: Mild Eye Irritation: signs/symptoms can include redness, swelling, pain, and tearing. SKIN CONTACT: No information was found regarding effects from skin contact. May be absorbed through the skin and persist in the body for an extended time. Single exposure may cause: Moderate Skin Irritation: signs/symptoms can include redness, swelling, itching, and dryness. INHALATION: No information was found regarding effects fro inhalation exposure. May be absorbed by inhalation and persist in the body for an extended ti.llte. Single overexposure, above recommended guidelines, may cause: Irritation (upper respiratory): signs/symptoms can include soreness of the nose and throat, coughing and sneezing. IF SWALLOWED: Ingestion is not a likely route of exposure to this product. No information was found regarding effects from swallowing. Animal studies conducted on organic fluorochemicals which may be present in this product indicate effects including liver disturbances, weight loss, loss of appetite, lethargy, and neurological, pancreatic, adrenal and hematologic effects. There are no known human health Abbreviations: N/O - Not Determined NIA - Not Applicable CA Approximately 418-028:PAGE D-37 MSOS: L-9051 DEVELOPMENTAL PRODUCT December 07, 1999 PAGE 6 8. HEALTH HAZARD DATA (continued) effects fro anticipated exposure to tnese organic f luorochemicals when used as intended and instructed. OTHER HEALTH HAZARD INFORMATION: This product may contain one or ore organic f luorocheicals that have the potential to be absorbed and reain in the body for long periods of time, either as the parent olecule or as metabolites, and may accumulate with repeated exposures. There are no known human health effects fro anticipated exposure to these organic fluorochemicals when used as intended and instructed. The presence of organic f luorocheicals in the blood of the general population and subpopulations, such as workers, has been published dating back to the 1970's. 3M's epidemiological study of its own workers indicates no adverse effects. SECTION CHANGE DATES ------------------------------------------------------------------------ PRECAUTIONARY INFO. SECTION CHANGED SINCE Hay 171 1999 ISSUE Abbreviations: N/0 - Not Determined N/A - Not Applicable CA - Approximateiy The information in this Material Safety Data Sheet (HSDS) is believed to be correct as of the date issued. 3M HAKES NO WARRANTIES, EXPRESSED OR IMPLIED, INCLUDING, BUT NOT LIMITED TO, MY IMPLIED WARRNJTY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE OR COURSE OF PERFORMANCE OR USAGE OF TRADE. user is responsible for determining whether the 3M product is fit for a particular purpose and suitable for user's method of use or application. Given the variety of factors that can affect the use and application of a 3M product, some of which are uniquely within the user's knowledge and control, it is essential that the user evaluate the 3M product to determine whether it is fit for a particular purpose and suitable for users Method of use or application. 3M provides information in electronic form as a service to its customers. Due to the remote possibility that electronic transfer may have resulted in errors, omissions or alterations in this information, 3M makes no representations as to its completeness or accuracy. In addition, information obtained from a database may not be as current as the information in the MSDS available directly from 3M. 418-028:PAGE D-38 ATTACHMENT3 TEST SUBSTANCE PREPARATION PROCEDURE 4 l 8-028:P AGE D-39 ATTACHMENT 3 Protocol 418-028 Version: 418-028(19 MAR 02) Page 1of2 TEST SUBSTANCE PREPARATION PROCEDURE Test Substance: T-7706 Vehicle: Aqueous 0.5% CMC (medium viscosity) A. Purpose: The purpose of this procedure is to provide a method for the preparation of dosage suspensions of T-7706 for oral (gavage) administration to rats on Argus Research Study number 418-028. B. General Information: 1. All suspension containers will be labeled and color-coded. Each label will specify the protocol number, test substance identification, Argus batch number, concentration, dosage level, preparation date, expiration date and storage conditions. 2. Suspensions will be prepared: Daily L Weekly _For_ days of use Approximately every ten days By Sponsor 3. Suspensions will be administered at a final dosage volume of 1O mUkg. 4. Safety: L Gloves, uniform/lab coat, goggles or safety glasses with side shields L Dust-mist/HEPA-filtered Mask Half-Face Respirator if not used in a chemical fume hood Full-Face Respirator/Positive Pressure Hood Tyvek Suit or tyvek apron and sleeves 5. Dosage suspensions adjusted for % Activity/Purity or Correction Factor: Yes .lL No (Calculations based on 100%) % Activity _ o/o Purity _ Correction Factor 6. Sampling requirements: Cited in protocol 7. Storage: Cited in protocol 418-028:PAGE D-40 ATTACHMENT 3 Protocol 418-028 Version: 418-028(19 MAR 02) Page2 of2 TEST SUBSTANCE PREPARATION PROCEDURE NOTE: Prior to test substance preparation accurately measure the required amount of the appropriate vehicle (R.O. deionized water should be used for calibration purposes) in a graduated cylinder, pour the required amount of veh.icle into a beaker. Carefully mark each beaker at the menjscus. This mark will be used during the preparation to bring the test substance slurry up to volume. C. Dosage Suspension Preparation: 1. Weigh the required amount of test substance on a piece of weigh paper or into an. appropriately sized mortar (see PREPARATION CALCULATIONS). 2. If weigh paper is used, transfer the test substance to an appropriately sized mortar. If necessary, grind the test substance into a fine powder. Slowly add a small amount of vehicle and grind. Continue to add vehicle slowly and grind the vehicle and the test substance together to form a fine slurry. Transfer the vehicle/test substance slurry to a marked beaker. 3. Rinse the mortar and pestle with additional vehicle to remove any remaining test substance. Transfer rinse to beaker. 4. Add additional vehicle to the beaker to bring volume up to the m;:irk. Place on magnetic stir plate and agitate prior to and during sampling, aliquotting and/or administration. 5. Repeat steps (1) through (4) for each concentration. _Yes [see attached clarification form] Initial/Date: __C:...:...fl--=-__....1._/3__..JI...;o.3.::;;.. I 418-028:PAGE D-41 ATTACHMENT4 TISSUES TO BE WEIGHED, RETAINED AND EXAMINED HISTOLOGICALLY 418-028:PAGE D-42 ATTACHMENT 4 Protocol 418-028 Page I of2 TISSUES TO WEIGHED AND RETAINED FOR POSSIBLE EXAMINATION FROM TEN RATS PER SEX PER GROUP The ten rats per sex per group assigned to functional observational battery and motor activity tests will be assigned to hematology, clinical biochemistry and histological evaluations. Tissues to be Weighed: The following organs will be excised, trimmed and individually weighed as soon as possible after excision to avoid drying. liver spleen kidneys brain adrenals heart thymus ovaries testes uterus (with cervix) right epididymis prostate left epididymis (whole and cauda) seminal vesicles (with and without fluid) Tissues to be Retained: The following tissues or representative samples will be retained in neutral buffered 10% fonnalin. brain (representative regions including cerebrum, cerebellum, pons) small and large intestines (including Peyer's patches) lungs (perfused with neutral buffered 10% formalin) lymph nodes (submandiblar and mediastinal) peripheral nerve (sciatic or tibial) gross lesions spinal cord (cervical, thoracic and lumbar) stomach liver kidneys adrenals spleen heart thymus thyroid/parathyroid trachea uterus urinary bladder bone marrow (sternum) testes* ovaries prostate uterus seminal vesicles (with coagulating gland) vagina mammary gland (female rats only) * Testes will be fixed in Bouin's solution for 48 to 96 hours before being retained in neutral buffered 10% formalin. Additionally, the remaining portion ofthe left epididymis (corpus and caput), as well as the right epididymis will be fixed in neutral buffered 10% formalin. 418-028:PAGE D-43 ATTACHMENT 4 Protocol 418-028 Page 2 of2 Histological Examination: Histological examination ofretained tissues, including reproductive organs, will be couducted for the assigned ten rats per sex from the control and high dosage groups and from the Fl generation pups (livers) from the control and high dosage groups. Iflesions attributed to the test substance are observed in the rats exposed to the high test substance concentration, the same tissues will be examined from the assigned ten rats per sex exposed to the lower test substance concentrations. Should results warrant examination ofthe lower dosage groups and conduct of quantitative evaluation, scheduled report date and prices will be adjusted accordingly. The postlactional ovary should contain primordial and growing follicles as well as the large corpora lutea of lactation. Histopathological examination may detect qualitative depletion of the primordial follicle population. A quantitative evaluation ofprimordial follicles will be conducted for Fo generation female rats; the number of rats, ovarian section selection and section sample size will be statistically appropriate for the evaluation procedure used. Examination will include enumeration of the number ofprimordial follicles, which can be combined with small growing follicles, for comparison of ovaries of rats assigned to treated and control groups. Shipping Instructions: Tissues to be examined histologically will be shipped (ambient conditions) to: Principal Investigator: W. Ray Brown, D.V.M., Ph.D., ACVP Veterinary Pathologist Research Pathology Services, Inc. 438 E. Butler Avenue New Britain, Pennsylvania 18901 Telephone: (215) 345-7070 Telefax: (215) 345-4326 Email: WRBRPS@concentric.net The recipient will be notified in advance of sample shipment. 418-028:PAGE D-44 905 Sheehy Orive. atdf. A Horsham, PA I 90.f" Telephone: (215) 443-8710 Telefax: (215} 443-8587 ARGUS RESEARCH Charles River Laboratories Discovery and Development Services PROTOCOL 418-028 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OFT-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST SPONSOR'S STUDY NUMBER: T-7706.l Amendment I - 17 April 2002 1. Detailed Clinical Observations - Male and Female Rats (page 10 ofthe protocol): [Effective Date: 1 April 2002] Detailed clinical observations will not be recorded for male and female rats assigned to toxicokinetic sampling. Reason for Change: This change was made because sufficient data for evaluation ofdetailed clinical observations will be available from the rats assigned to the main study. 2. Feed Consumption Values - Male Rats and Female Rats (page 11 ofthe protocol): [Effective Date: l April 2002] Feed consumption values will not be recorded or tabulated for male and female rats assigned to toxicokinetic sampling. Reason for Change: This change was made because sufficient data for evaluation of feed consumption will be available from the rats assigned to the main study. Any revisions made to this finalized amendment must be made by subsequent amendment. 418-028:PAGE D-45 3. Estrous Cycling and Mating (page 12 of the protocol): Protocol 418-028 Amendment 1 Page2 [Effective Date: I April 2002] For the rats assigned to toxicokinetic sampling, estrous cycling will be evaluated during the cohabitation period until spermatozoa are observed in a smear ofthe vaginal contents and/or a copulatory plug is observed in situ, but not during the dosage period, prior to cohabitation. Reason for Change: This change was made because sufficient data for evaluation of estrous cycling will be available from the rats assigned to the main study. 4. Scheduled Sacrifice - Toxicokinetic Study (page 16 of the protocol): [Effective Date: S April 2002) The number of implantation sites and corpora lutea will be recorded. Carcasses will be discarded without further evaluation. Reason of Change: This change was made in order to provide more information about possible toxicity of the test substance in pregnant rats. 5. Scheduled Sacrifice - Main Study (page 16 of the protocol): [Effective Date: 27 March 2002) The number of implantation sites will be recorded, rather than the number ofimplantation sites and corpora lutea will be recorded. Reason of Change: The number of corpora lutea will not be recorded because corpora lutea regress at a rapid rate and are not counted on studies at weaning. 6. Scheduled Sacrifice (page 19 ofthe protocol): [Effective Date: 4 April 2002] The liver from each selected pup will be excised and the organ weight recorded, rather than the liver from each selected pup will be collected excised and the organ weight recorded. Any revisions made to this ftnalized amendment must be made by subsequent amendment. 418-028:PAGE D-46 Protocol 418-028 Amendment 1 Page3 Reason for Change: This change clarifies the protocol by removing an extraneous word. ~~~~~ ~~0~~2;;7;; DirectorofResearch Associate Director ~;earch Study Director Theresa H. Woodard, D.V.M. Member, Institutional Animal Care and Use Committee Date John Butenhoff, Ph.D., DABT, Cffi Date Study Monitor and Sponsor's Representative Any revisions made to this finalized amendment must be made by subsequent amendment. 418-028:PAGE D-47 905 Sheehy Drive. 81df. A Horsham. PA 19044 Telephone: (215) 443-8710 Telefax: (21SJ 443-8587 ARGUS RESEARCH Charles River l..oboratorles Discovery and Development Services PROTOCOL 418-028 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST SPONSOR'S STUDY NUMBER: T-7706.1 Amendment 2 - 15 July 2002 1. Safety Precautions (page 3 ofthe protocol and Attachment 3 page 1 of the protocol): [Effective Date: 29 April 2002] A half face respirator will be worn in addition to gloves, appropriate eye protection and a uniform/lab coat during formulation preparation of the bulk test substance. Reason for Change: This change was made to match the bulk test .substance text with the text located within the Material Safety Data Sheet. 2. Study Schedule (Attachment 1page2 ofthe protocol): [Effective Date: 29 April 2002] The dates for FOB and motor activity evaluations have been extended to four days (06 MAY 02 - 09 MAY 02) rather than two days (06 MAY 02 - 07 MAY 02). Any revisions to this finalized amendment must be made by subsequent amendment. 418-028:PAGE D-48 Protocol 418-028 Amendment2 Page2 Reason for Change: This change was made because more time is needed to evaluate animals assigned to FOB and motor activity evaluations. --=ifl_~,-..,-~-l"liJ~~_I ! QA . _(~ZN~ obennan, Ph.D.,DABT Date ~G. Yor Ph. ., DABT Date Associate Director o esearch Study Director Jr-~~~~~d~~~-_!_U_~~~~L ]~~~?~~~;;7U Z,q_ Member, Institutional Animal Care Study Monitor and and Use Committee Sponsor's Representative Any revisions to this finalized amendment must be made by subsequent amendment. 418-028:PAGE D-49 905 Sheehy Drive,, Bldf. A Horsham,, PA 19044 Telephone: (215) 443-8710 Tele(oJC: (21 SJ 443-8581 ARGUS RESEARCH Charles River Laboratories Discovery and Development Services PROTOCOL 418-028 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST SPONSOR'S STUDY NUMBER: T-7706.1 Amendment 3 - 17 July 2002 1. Bulk Test Substance Sampling, Shipping Instructions, Shi1-ming Instructions, Caesarean-Sectioning - Toxicokinetic Study, Scheduled Sacrifice - Toxicokinetic Study, and Scheduled Sacrifice, (pages 4, 5, 12, 13, 16 and 19, respectively of the protocol) [Effective Date: 29 May 2002] Samples forperfluorohexanesulfonate (PFHS) analysis shipped to Lisa Clemen at 3M Environmental Technology and Safety Services will be reshipped and remaining samples, that were to be shipped to Lisa Clemen and have not yet been shipped, will be shipped to: John Flaherty, Ph.D. (Principal Investigator) Exygen Research 3058 Research Drive State College, Pennsylvania 16801 Telephone: (814) 272-1039, ext. 122 Telefax: (814) 231-1580 Email: john.flaherty@exygen.com Any revisions to this finalized amendment must be made by subsequent amendment. 418-028:PAGE D-50 Protocol 418-028 Amendment3 Page2 These samples include: Bulk test substance sampling (page 4 ofthe protocol) Concentration and homogeneity (page S of the protocol) Stability (page S ofthe protocol) Plasma toxicokinetic samples (page 11 to 12 and page 16 of the protocol) Plasma samples, rather than serum samples, were retained. Liver toxicokinetic samples (pages 12 and 16 of the protocol) Pooled fetal serum toxicok.inetic samples (pages 12 and 16 of the protocol) Pooled fetal liver toxicokinetic samples (pages 13 and 16 ofthe protocol) Pooled pup serum toxicokinetic samples (page 19 of the protocol) Pup liver toxicokinetic samples (page 19 of the protocol) The ar,ialyses will be subcontracted to Exygen by the Sponsor and the Quality Assurance Unit for Exygen Research will conduct critical phase inspections and audit the respective results and reports according to the Standard Operating procedures of that facility. Such critical phase inspection reports and audit reports will be submitted by that facility to the Study Director, Raymond G. York. The date ofthe inspections and report submissions will be incorporated into a QAU statement generated by Exygen Research for inclusion in the final report for Protocol 418-028. Reason for Change: This change was made at the request ofthe Sponsor because 3M is not able to complete the formulation analysis with their current staffing. ~ _ --~-- _ _ -~~.-"'"!''1.~xl?~~A~-.-,~-'~_1-7-Jk'i..([l . f/J - !B{.':1- --1. rman, Ph.D., DABT Date Ra . d G. York, ~Il.D., ABT Date f Director ofResearch Asso ate Director oK~es ch Study Director r ~~~~-~~-l-1z.h~~ Member, Institutional Animal Care and Use Committee z .. a~ ~/,./U' IYJU. z~ --Z=----------~~Q----------------- John Butenhoff, Ph.D., DABT, CIH Date Study Monitor and Sponsor's Representative Any revisions to this finalized amendment must be made by subsequent amendment. 418-028:PAGE D-51 905 _,,, DfiVt, 8Jdr. A HOtsholtJ.J'A lt(U!f, . r.,,fiOn~ (215J443~7:f0 tele(Ox: (ll5J 44341587 PROTOCOL 418-028 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OFT-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST SPONSOR'S STUDY NUMBER: T-7706.1 Amendment 4 - 20 March 2003 1. Bulk Test Substance Sampling, Shipping Instructions, Shipping Instructions, Caesarean-Sectioning - Toxicokinetic. Study, Scheduled Sacrifice - Toxicokinetic Study, and Scheduled Sacrifice, (pages 4, 5, 12, 13, 16 and 19, respectively of the protocol) and Amendment 3, Item 1: Bulk Test Substance Sampling, Shigping Instructions, Shiooing Instructions, Caesarean-Sectioning - Toxicokinetic Study, Scheduled Sacrifice -Toxicokinetic Study, and Scheduled Sacrifice (page 1 of Amendment 3) [Effective Date: 27 February 2003] The analyses performed by Exygen Research will be done according to Exygen Method ExM-023-071 Revision 1, entitled "Method of Analysis for the Determination of Perfluorohexanesulfonate (PFHS), Perfluorooctanesulfonate (PFOS) and Pentadecafluorooctanoic Acid (PFOA) in Rat Liver, Serum and Urine Revision l". Any revisions to this finalized amendment must be made by subsequent amendment. 418-028:PAGE D-52 Protocol 418-028 Amendment4 Page2 Reason for Change: This change was made at the request of the Exygen Research in order to clarify the method of analysis. Do gla . Learn, Ph.D. Chair, Institutional Animal Care and Use Committee John Butenhoff, Ph.D., DABT, CIB Date Study Monitor and Sponsor's Representative Any revisions to this finalized amendment must be made by subsequent amendment. APPENDIXE DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY 418-028: PAGE E-1 DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY 1. The following rats were not fasted overnight prior to necropsy. Dosage Group I Dosage (mg/kg/day) 0 II 0.3 III 1 IV 3 v 10 Date of Necropsy 28MAY02 29MAY02 28 MAY02 29MAY02 28 MAY02 29MAY02 28MAY02 29MAY02 28 MAY02 Sex Female Female Female Female Female Female Female Female Female Rat Numbers 19044 19012, 19021, 19068 19009, 19016, 19036, 19043, 19047, 19052, 19055, 19061, 19071 19018, 19037 19017 19013, 19029, 19060 19045, 19058, 19073 19039, 19063, 19069 19001, 19028, 19031, 19033, 19049, 19059, 19070 This deviation did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter and there were no indications of toxicity in clinical chemistry parameters for the female rats. 2. Postdosage observations were performed out of the range of 60 10 minutes on the following dates. Dosage Group I IV Dosage (mg/kg/day) 0 3 Date 09 APR02 03 JUN02 03 JUN02 Number of Rats Male Rats Female Rats 4 - - 1 - 1 Range of Time Deviated (minutes) +1 to +2 +8 +7 These deviations did not adversely affect the outcome or interpretation of the study because the extent of the deviation was less than 10 minutes. 3. On day 39 of study (DS 39) (9 May 2002), a postdosage clinical observation was not recorded for one male rat in the 0.3 mg/kg/day dosage group (19153). This deviation did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter. 4. On DS 44 (14 May 2002), dosage volume was not recorded for one male rat in the 3 mg/kg/day dosage group (19156). This deviation did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter. 418-028: PAGE E-2 5. On DS 46 (16 May 2002), postdosage clinical observations and dosage volumes were not recorded for two male rats in the 0 mg/kg/day dosage group (19161 and 19167). These deviations did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter. 6. Detailed clinical observations were not recorded weekly for the following rats. Dosage Group I II III IV v Dosage (mg/kg/day) 0 0.3 1 3 10 Date 09MAY02 09MAY02 09MAY02 09MAY02 09MAY02 Sex Female Female Female Female Female Rat Numbers 19023, 19041, 19050 19004 19008 19054, 19062 19020, 19030 These deviations did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter. 7. On DS 13 (13 April 2002), feed left values were not recorded for all rats before they were placed into cohabitation. This deviation did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter. 8. On days 1 and 2 of lactation (DLs 1 and 2) (10 May 2002 and 11 May 2002, respectively), one pup in the 0 mg/g/day dosage group (litter 19050) was recorded as having an adverse clinical observation without the sex being recorded. This deviation did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter. 9. On DL 3 (12 May 2002), one litter in the 10 mg/kg/day dosage group (19022) was not recorded as having been observed. All pups appeared normal on DL 4. This deviation did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter. 10. On DL 5 (12 May 2002), maternal observation was not recorded for one rat in the 0.3 mg/kg/day dosage group (19018). Maternal behavior on DL 8 was normal for this rat. This deviation did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter. 11. On 19 May 2002, the frozen liver sample for one female rat with a non-confirmed date of mating in the 0 mg/kg/day dosage group (19077) was lost before sample shipment. This deviation did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter. 418-028: PAGE E-3 12. On DL 22 (31 May 2002) the liver weight of one pup in the 1 mg/kg/day dosage group (pup 9 in litter 19024) was not recorded. This deviation did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter. All deviations are documented in the raw data. Ray Associate Director o......_..... ""C"~T>.... Study Director Date APPENDIXF CERTIFICATE OF ANALYSIS 418-028:PAGE F-1 Certificate of Analysis Nominal Product: Potassium perfluorohexanesulfonate: C~13SO{) K(+) Product Code: PFHS; 127498-80 AprillS,2002 Tom Kestner and Joel Miller The sample of 127498-80 PFHS was analyzed using LCMS, 19F-NMR and 1H-NMR analysis techniques. The overall qualitative and quantitative compositional results that were derived from these combined analyses are summarized below in TABLE-I. TABLE-1 Sample: 127498-80: PFHS Overall Quantitative Compositional Results by LCMS, 19F-NMR, and H-NMR Analvses Component Identities * Relative Wt.% Concentrations (single trial measurements, excludin2 anv water) CF3CF2CF2CF2CF2CF2So{> Kc+> 88.93% (NMR) (CF3)2-CF-(CF2)3-SO{J Kc+> 6.83%(NMR) CF3CF2-CF(CF3)-CF2CF2-So{> K<+> 2.75%(NMR) CF3CF2CF2CF2-CF(CF3)-SQ3(-J K(+J 0.83%(NMR) CF3CF2CF2CF(CF3)-CF2-SO{> K<+> 0.56%(NMR) (CF3)3-C-CFi-CF2Sot> K<+> C~12HSO{' K(+J 0.078% (NMR) 0.009% (LCMS) C1F1sSO{' K(+J 0.006% (LCMS) C4F9SQ3l-J Kl+> 0.004% (LCMS) Probable CnH2n+2 hydrocarbons 0.0034% (NMR) Other components Sum of C6FuSot> :W+> Isomers Sum of Known Impurities * Trace amounts of other unassigned components were also detected. <0.001% (LCMS) 99.98% 0.021 o/o Page 1of1 File Reference: CofA_PFHS_127498-80.doc 418-028:PAGE F-2 3M SPECIALTY MATERIALS MANUFACTURING DMSION ANALYTICAL LABORATORY Reguest No. GID:32537 To: Dan Hakes - (3-2392)-EHSR-Auto & Chem Group- 236-lB-10 From: Subject: Tom Kestner - (3-5633) - SMMD Analytical Lab - 236-2B-l l Chemical Characterization of PFHS (127498-80) by 1H-NMR & 19F-NMR Spectroscopy Date: April 15, 2002 SAMPLE DESCRIPTION: 127498-80: PFHS made by George Moore and to be used for toxicological testing. Nominal product =C6Fn-So3<-> K(+) (white powder). OBJECTIVE: This sample was subjected to 1H-NMR and 19F-NMR spectral analyses to determine the purity of the nominal product and to characterize as many impurity components as possible. Joel Miller also performed an LC/MS analysis and his results were reported to you previously. EXPERIMENTAL: A portion of the sample (-400 mg) was totally dissolved in deuterated dimethylsulfoxide (DMSO-d6) and then the solution was spiked with a small amount of 1,4-bis(trifluoromethyl)benzene (p-HFX) for NMR analysis. A 400 MHz 1H-NMR spectrum(# h32537.GID.401) and a 376 MHz 19F-NMR spectrum(# f32537.GID.401) were acquired.at room temperature using a Varian UNITYplus 400 FT-NMR spectrometer. The p-HFX was used as a 1HJ19F-NMR cross integration standard to permit the cross correlation of the relative 1H and 19F signal intensities for evaluation of the overall sample composition. RESULTS: The combined NMR spectral data indicated the sample of 127498-80 consisted of a high purity form of the nominal isomeric product mixture, CnF2n+1-Sol> M<+>, where 'n' was mainly 6 and where the metal cation ['M(+h] was assumed to be K<+>. Trace-levels ofprobable aliphatic hydrocarbon impurity components were also observed and quantified. The qualitative and quantitative compositional results that were derived from the single trial 1H/19F-NMR cross integration analysis are summarized in TABLE-1 on the following page. Any water that may have been present in the sample was ignored for calculation purposes. The relative weight percent concentrations shown in TABLE-I should be very close to their respective absolute weight percent values. Trace amounts ofother unidentified impurity components were also detected in the NMR spectra, but additional work would be needed in an effort to assign or quantify the unassigned impurities. Copies of the NMR spectra are attached with the paper copy of this report for your reference. Ifyou have any questions about these results, or if any further work is needed, please let me know. Tom Kestner c: Joel Miller George Moore RickPayfer File Reference: dh32537.GID.doc/93 Page 1 of2 418-028:P AGE F-3 April 15, 2002 3M SMMD Analytical Lab Request# GID:32537 TABLE-1 Sample: 127498-80: PFHS made by George Moore and to be used for toxicological testing. Overall Quantitative Compositional Results by lHI19F-NMR Cross lntearation Analysis Identified Components* 19F/1H-NMR Relative Wt.% Concentrations (single trial measurement) CF3CF2CF2CF2CF2CF2SOt' Kl+> 88.94% (CF3)2-CF-(CF2)3-SOtJ Kl+J 6.83% CF3CF2-CF(CF3)-CF2CF2-sot> Kl+J 2.75% CF3CF2CF2CF2-CF(Cf3)-SOt> Kl+> 0.83% CF3CF2CF2CF(CF3)-CF2-S03l-J K<+> 0.56% (CF3)3-C-CF2-CF2S03l-> K(+J 0.078% Probable CnH2n+2 hydrocarbons 0.0034% * Trace amounts of other unassigned components were also detected in the NMR spectra. Study No. FACT-TCR008 Page 2 of2 APPENDIXG ANALYTICAL AND BIOANALYTICAL REPORT 418-028:PAGE G-1 ANALYTICAL PHASE STUDY TITLE Oral (Gavage) Combined Repeated Dose Toxicity Study of T-7706 with the Reproduction/Developmental Toxicity Screening Test DATA REQUIREMENTS OECD Principles on Good Laboratory Practice. ENV/MC/CHEM{98}17, U.S. Food and Drug Administration 21 CPR Part 58, MHW Good Laboratory Practice Standard for Safety Studies on Drugs Ordinance Number 21, March 26, 1997 STUDY DIRECTOR Raymond G. York ANALYTICAL REPORT COMPLETION DATE July 21, 2003 PERFORMING LABORATORY Exygen Research 3058 Research Drive State College, PA 16801 Phone:814-272-1039 TESTING FACILITY Argus Research 905 Sheehy Drive, Building A Horsham, PA 19044-1297 Phone:215-443-8710 STUDY SPONSOR 3M Corporate Toxicology Building 220-2E-02 St. Paul, MN 55144-1000 PROJECT Protocol Number: 418-028 Sponsor's Study Number: T-7706.1 Exygen Study Number: 023-072 Total Pages: 153 418-028:PAGE G-2 Exygen Study No.: 023-072 GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT Exgyen Study Number 023-072, entitled "Oral (Gavage) Combined Repeated Dose Toxicity Study of T-7706 with the Reproduction/Developmental Toxicity Screening Test," conducted for 3M Corporate Toxicology, was performed in compliance with U.S. Food and Drug Administration Good Laboratory Practice Regulations 21 CFR Part 58, OECD Principles on Good Laboratory Practice. ENV/MC/CHEM(98)17 and MHW Good Laboratory Practice Standards for Safety Studies on Drugs Ordinance Number 21 by Exygen Research. Date John Butenhoff Study Monitor 3M Corporate Toxicology Exygen Research z.. y .:.j1/1- z vP:I Date Page 2of153 418-028:PAGE G-3 Exygen Study No.: 023-072 QUALITY ASSURANCE STATEMENT Exygen Research's Quality Assurance Unit reviewed Exygen Study Number 023-072, entitled, "Oral (Gavage) Combined Repeated Dose Toxicity Study of T-7706 with the Reproduction/Developmental Toxicity Screening Test". All reviewed phases were inspected for conduct according to Exygen Research's Standard Operating Procedures, the Study Protocol, and all applicable Good Laboratory Practice Standards. All findings were reported to the Exygen Principal Investigator and Management and to the Study Director. Phase Date Inspected Date Reported to Date Reported to Principal Exygen Date Reported to Investigator Management Study Director I. Protocol Review 09/24/02 11/20/02 11/22/02 01/20/03 2. Extraction, Fortification 09124102 11/21/02 12/18/02 01/20/03 3. Raw Data Review and Draft Analytical Report Review 02/03-07/03 and 02/10-11/03 02/24/03 02/28/03 03/07/03 4. Final Analytical Report Review 07/21/03 07/21/03 07/21/03 07/21/03 Date Exygen Research Page 3 of153 418-028:PAGE G-4 Exygen Study No.: 023-072 CERTIFICATION OF AUTHENTICITY This report, for Exygen Study Number 023-072, is a true and complete representation of the raw data for the study. Submitted by: Exygen Research 3058 Research Drive State College, PA 16801 (814) 272-1039 Principal Investigator, Exygen: ~~~;r= Date Exygen Research Exygen Research Facility Management: Al~ Date President Exygen Research Study Monitor, 3M: Jo~Butenhoff 3M Corporate Toxicology Exygen Research Z 8 -Y VI- 2-&1v .J Date Page 4of153 418-028:PAGE G-5 Exygen Study No.: 023-072 STUDY IDENTIFICATION Oral (Gavage) Combined Repeated Dose Toxicity Study ofT-7706 with the Reproduction/Developmental Toxicity Screening Test PROTOCOL NUMBER: 418-028 SPONSOR'S STUDY NUMBER: T-7706.1 EXYGEN STUDY NUMBER: 023-072 TYPE OF STUDY: Residue SAMPLE MATRIX: Rat Liver, Serum, and Plasma TEST SUBSTANCE: Perfluorohexanesulfonate (PFHS) SPONSOR: 3M Corporate Toxicology Building 220-2E-02 St. Paul, MN 55144-1000 STUDY DIRECTOR: Raymond G. York Argus Research 905 Sheehy Drive, Building A Horsham, PA 19044-1297 TESTING FACILITY: Argus Research 905 Sheehy Drive, Building A Horsham, PA 19044-1297 STUDY MONITOR: John Butenhoff 3M Corporate Toxicology Building 220-2E-02 St. Paul, MN 55144-1000 PERFORMING LABORATORY: Exygen Research 3058 Research Drive State College, PA 16801 ANALYTICAL PHASE TIMETABLE: Study Initiation Date: 03/26/02 Analytical Start Date: 09/16/02 Analytical Termination Date: 11/13/02 Analytical Report Completion Date: 07/21/03 Exygen Research Page 5 of 153 418-028:PAGE G-6 Exygen Study No.: 023-072 PROJECT PERSONNEL The Study Director for this project was Raymond G. York at Argus Research. The following personnel from Exygen Research were associated with various phases of the study: Name John Flaherty Karen Risha Paul Connolly Xiaoming Zhu Lawrence Ord Rickey Kelley Amy Sheehan Emily Decker Mark Neeley Title Vice President Scientist Technical Lead-LC/MS Technician Sample Custodian Sample Custodian Technician Scientist Scientist Exygen Research Page 6of153 418-028:PAGE G-7 Exygen Study No.: 023-072 TABLE OF CONTENTS Page TITLE PAGE ....................................................................................................................... 1 GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT..............................2 QUALITY ASSURAN"CE STATEMENT ...........................................................................3 CERTIFICATION OF AUTHENTICITY...........................................................................4 STUDY IDENTIFICATION ...............................................................................................5 PROJECT PERSONNEL ....................................................................................................6 TABLE OF CONTENTS.....................................................................................................7 LIST OF TABLES ...............................................................................................................8 LIST OF FIGURES .............................................................................................................9 LIST OF APPENDICES .................................................................................................... 10 1.0 SUMMARY................................................................................................................ 11 2.0 OBJECTIVE ............................................................................................................... 11 3.0 INTRODUCTION ...................................................................................................... 11 4.0 ANALYTICAL TEST SAMPLES ............................................................................. 12 5.0 REFERENCE MATERIAL ........................................................................................ 13 6.0 DESCRIPTION OF ANALYTICAL METHOD........................................................ 13 6.1. Extraction Procedure ............................................................................................... 13 6.2 Preparation of Standards and Fortification Solutions............................................... 14 6.3 Chromatography ....................................................................................................... 14 6.4 Instrument Sensitivity............................................................................................... 14 6.5 Description of LC/MS/MS Instrument and Operating Conditions........................... IS 6.6 Quantitation and Example Calculation..................................................................... 15 7.0 EXPERIMENTAL DESIGN ...................................................................................... 17 8.0 RESULTS ................................................................................................................... 18 9.0 CONCLUSIONS......................................................................................................... 18 10.0 RETENTION OF DATA AND SAMPLES ............................................................. 19 Exygen Research Page 7of153 418-028:PAGE G-8 Exygen Study No.: 023-072 Table I. LIST OF TABLES Page Summary of PFHS in Control Rat Plasma Samples .......................................21 Table II. Summary of PFHS in Control Rat Serum Samples ........................................21 Table Ill. Summary of PFHS in Control Rat Liver Samples..........................................21 Table IV. Summary of PFHS Fortification Recoveries in Rat Plasma...........................22 Table V. Summary of PFHS Fortification Recoveries in Rat Serum ............................22 Table VI. Summary of PFHS Fortification Recoveries in Rat Liver..............................23 Table VII. Summary of PFHS Residues in Rat Plasma Samples.....................................24 Table VIII. Summary of PFHS Residues in Rat Serum Samples......................................26 Table IX. Summary of PFHS Residues in Rat Liver Samples........................................28 Table X. Summary of PFHS Residues in Dosing Solutions..........................................40 Table XI. Summary of PFHS Residues in Stability Samples .........................................41 Table XII. Summary of PFHS Residues in Homogeneity Samples .................................42 Exygen Research Page 8of153 418-028:PAGE G-9 Exygen Study No.: 023-072 Figure 1. LIST OF FIGURES Page Typical Calibration Curve for PFHS ..............................................................44 Figure 2. Chromatogram Representing a 0.1 ng/mL standard for PFHS .......................45 Figure 3. Chromatogram Representing a Control Rat Plasma Sample for PFHS (Exygen ID 0202913 Control, Data Set: 091602B)........................................46 Figure 4. Chromatogram Representing a Control Rat Serum Sample for PFHS (Exygen ID: 0202987 Control, Data Set: 091902B) ......................................47 Figure 5. Chromatogram Representing a Control Rat Liver Sample for PFHS, (Exygen ID: 0202877 Control, Data Set: 100202A) .....................................48 Figure 6. Chromatogram Representing Control Rat Plasma Sample Fortified with 10 ppb of PFHS (Exygen ID: 0202913 Spk A, Data Set: 091602B)......49 Figure 7. Chromatogram Representing Control Rat Serum Sample Fortified with 10 ppb of PFHS (Exygen ID: 0202987 Spk A, Data Set: 09 l 902B)......50 Figure 8. Chromatogram Representing Control Rat Liver Sample Fortified with 10 ppb of PFHS (Exygen ID: 0202877 Spk A, Data Set: 100202A) .....51 Figure 9. Chromatogram Representing Rat Plasma Sample Analyzed for PFHS (Exygen ID: 0201816, Sponsor ID: 19176 GROUP I, Data Set: 091602B) ..52 Figure 10. Chromatogram Representing Rat Serum Sample Analyzed for PFHS, DF=lO (Exygen ID: 0201863, Sponsor ID: 19079 GROUP II, Data Set: 091902BR) ......................................................................................53 Figure 11. Chromatogram Representing Rat Liver Sample Analyzed for PFHS (Exygen ID: 0202050, Sponsor ID: 19018 GROUP II Male 1, Data Set: 100202A) ................................................................................................. 54 Exygen Research Page 9of153 418-028:PAGE G-10 Exygen Study No.: 023-072 LIST OF APPENDICES Appendix A Study Protocol 418-028 (Exygen Study No. 023-072) and Amendments, Deviation and Note to File..................................................55 Appendix B Analytical Method: Method ofAnalysis for the Determination of Perfluorohexanesulfonate (PFHS), Perfluorooctanesulfonate (PFOS) and Pentadecafluorooctanoic Acid (PFOA) in Rat Liver, Serum and Urine Revision 1 (Exygen Method No. Ex.M-023-071Revision1) .................110 Exygen Research Page 10 of 153 418-028:PAGE G-11 Exygen Study No.: 023-072 1.0 SUMMARY Exygen Resarch extracted and analyzed rat liver, serum, and plasma samples for the determination of perfluorohexanesulfonate (PFHS) according to Exygen Method ExM023-071 Revision 1 (Appendix B). The limit of quantitation for PFHS in rat liver was 10 ng/g and 10 ng/mL in rat serum and plasma. The LOQ for each matrix was determined in a method validation study performed at Exygen (Exygen Study No: 023-073). PFHS in the rat plasma samples ranged from non-detected levels to 237,000 ng/mL. PFHS in the rat serum samples ranged from non-detected levels to 189,000 ng/mL. PFHS in the rat liver samples ranged from non-detected levels to 675,000 ng/g. The average percent recoveries standard deviations for PFHS in rat plasma, serum, and liver samples were 84% 7%, 95% 12%, and 86% 13%, respectively. PFHS residues in the dosing solutions, stability samples and homogeneity samples were all within 70% to 125% of their known concentrations. 2.0 OBJECTIVE The objective of the analytical part of this study was to determine levels of perfluorohexanesulfonate (PFHS) in specimens of rat liver, serum and plasma samples, bulk test substance, concentration and homogeneity formulations, and stability solutions according to Protocol 418-028 (Appendix A). 3.0 INTRODUCTION This report details the results of the analysis for the determination of PFHS in rat liver, serum and plasma samples, bulk test substance, concentration and homogeneity formulations, and stability solutions using the analytical method entitled, "Method of Analysis for the Determination of Perfluorohexanesulfonate (PFHS), Perfluorooctanesulfonate (PFOS) and Pentadecafluorooctanoic Acid (PFOA) in Rat Liver, Serum and Urine Revision 1." The study was initiated on March 26, 2002, when the study director signed protocol number 418-028. The analytical start date was September 16, 2002, and the analytical termination date was November 13, 2002. Exygen Research Page 11 of153 418-028:PAGE G-12 Exygen Study No.: 023-072 4.0 ANALYTICAL TEST SAMPLES The control rat liver (Exygen ID 0202877) used for the matrix blanks and matrix fortifications was received frozen on dry ice on August 7, 2002 from Pel-Freez Biologicals, Rogers, Arkansas. The control rat plasma (Exygen ID 0202912 and 0202913) used for the matrix blanks and matrix fortifications was received frozen on dry ice on August 8, 2002 from Pel-Freez Biologicals, Rogers, Arkansas. The control rat serum (Exygen ID 0202987) used for the matrix blanks and matrix fortifications was received frozen on dry ice on August 15, 2002 from Pel-Freez Biologicals, Rogers, Arkansas. Dosage solution/suspension samples (Exygen ID 0201753-0201755) were received refrigerated at Exygen from Argus Research on May 29, 2002. Dosage solution/suspension samples (Exygen ID 0201757-0201758) were received refrigerated at Exygen from Argus Research on June 11, 2002. These samples were logged in by Exygen personnel and placed in refrigerated storage. Bulk TA/S sample (Exygen ID 0201756) was received ambient at Exygen from Argus Research on June 11, 2002. This sample was logged in by Exygen personnel and placed in refrigerated storage. Median liver lobe (Exygen ID 0201759-0201787), pooled fetal liver (Exygen ID 0201788-0201800), plasma (Exygen ID 0201801-0201860), pooled fetal serum (Exygen ID 0201861-0201874), pooled pup serum (Exygen ID 0201875-0201924), and pup livers (Exygen ID 0201925-0202408) were received frozen on dry ice at Exygen from Argus Research on June 18, 2002. These samples were logged in by Exygen personnel and placed in frozen storage. Median liver lobe (Exygen ID 0203650) and pooled fetal liver (Exygen ID 0203651) were received frozen on dry ice at Exygen from Argus Research on September 11, 2002 and logged in by Exygen personnel and placed in frozen storage. Prepared formulations (Exygen ID 0203923-0203962) were received frozen from 3M on September 19, 2002 and logged in by Exygen personnel and placed in frozen storage. Sample log-in and chain of custody information can be found in the raw data package associated with this study. Storage records will be kept at Exygen Research. Exygen Research Page 12of153 418-028:PAGE G-13 Exygen Study No.: 023-072 5.0 REFERENCE MATERIAL The analytical standard PFHS was received at Exygen on January 26, 2000 from 3M Environmental Technology and Services. The available information for the reference material is listed below. The reference material was stored frozen. Compound PFHS Exygen Inventory No.. SP244 TCRNo. SE036 Purity (%) Expiration Date 99.99 01/01/10 The molecular structures oftest substance is given below: Name:PFHS Chemical Name: Perfluorohexanesulfonate Molecular Weight: 399 F F F F F F F 6.0 DESCRIPTION OF ANALYTICAL METHOD The analytical method ExM-023-071Revision1 was used for-this study. 6.1. Extraction Procedure A 1 mL aliquot of the serum and plasma and 1 g of liver were used for the extraction procedure for the laboratory controls and fortifications. Due to insufficient sample size, a 100 L aliquot of the serum and plasma and 0.1 g of the liver were used for the extraction procedure for the study samples. After fortification of appropriate samples, the serum samples were brought up to 20 mL with Type I Water and the liver samples were brought up to 10 mL with Type I Water. The serum samples were vortexed for - 1 minute and the liver samples were homogenized with a tissuemizer for - I minute. An aliquot of one milliliter was transferred from each sample and 5 mL of acetonitrile was added and the samples were shaken for - 20 minutes. The samples were centrifuged and the supernatant was decanted onto a conditioned SPE column. Then the samples were eluted with 2 mL of methanol. Each sample was analyzed by LC/MS/MS electrospray. An extraction procedure was not necessary for the bulk test substance, concentration and homogeneity formulations, and the stability solutions. 10 mg of the bulk test substance was weighed and brought to volume with methanol in a 100-mL volumetric flask. The Exygen Research Page 13 of 153 418-028:PAGE G-14 Exygen Study No.: 023-072 sample was then diluted 100000 times with methanol to fit in the range of the analytical curve and analyzed by LC/MS/MS electrospray. The concentration and homogeneity formulations and the stability solutions were all diluted appropriately with methanol and analyzed by LC/MS/MS electrospray. 6.2 Preparation of Standards and Fortification Solutions A stock standard solution of PFHS was prepared on August 20, 2002 as specified in Exygen method ExM-023-071Revision1. The stock standard solution was prepared at a concentration of 100 g/mL by dissolving 10 mg of each standard (corrected for purity only) in methanol. From this solution, a 1.0 g/mL fortification standard solution was prepared by talcing 1 mL of the stock and bringing the volume up to 100 mL with methanol. A 0.1 g/mL fortification standard was prepared by taking 10 mL of the 1.0 g/mL fortification standard and bringing the volume up to 100 mL with methanol. A set of standards containing PFHS was prepared via dilution of the 0.1 g/mL and various calibration solutions in the following manner: Initial Cone. (g/mL) 1 0.1 0.1 0.1 0.005 0.002 0.001 1 ofPFHS Volume(mL) 5 2 1 10 10 10 Diluted to (mL) 100 100 100 100 100 100 Final Cone. (g/mL) 0.005 0.002 0.001 0.0005 0.0002 0.0001 The stock standard solution and all fortification and calibration standard solutions were stored in a refrigerator (4 2C) when not in use. Documentation of standard preparation can be found in the raw data associated with this report. 6.3 Chromatography Quantification of PFHS was accomplished by LC/MS/MS electrospray. The retention time of PFHS was -- 8.3 min. Peaks above the LOQ were not detected in any of the control samples corresponding to the analyte retention time. 6.4 Instrument Sensitivity The smallest standard amount injected during the chromatographic run had a concentration of0.0001 g/mL of PFHS. Exygen Research Page 14 ofl53 418-028:PAGE G-15 Exygen Study No.: 023-072 6.5 Description of LC/MS/MS Instrument and Operating Conditions Instrument: Micromass Quattro Ultima (Micromass) Interface: Electrospray (Micromass) Computer: COMPAQ Professional Workstation AP200 Software: Windows NT, Masslynx 3.3 HPLC: Hewlett Packard (HP) Series 1100 HP QuatPump HP Vacuum Degasser HP Autosampler HP Column Oven HPLC Column:Genesis C8 (Jones Chromatography), 2.1 mm x 50 mm, 4 Column Temp.: 35 C Injection Vol.: 15 L Mobile Phase (A): 2 mM Ammonium Acetate in type I water Mobile Phase (B): Methanol Time %A 0.0 90 2.0 90 5.0 10 9.0 10 9.5 0 14.0 0 14.5 90 20.0 90 %B Flow Rate (mL/min) 10 0.3 10 0.3 90 0.3 90 0.3 100 0.3 100 0.3 10 0.3 10 0.3 Ions monitored: Analyte PFHS Mode Negative Transition Monitored 399--+ 80 Approximate Retention Time (min) -8.3 min. 6.6 Quantitation and Example Calculation Fifteen microliters of sample or calibration standard were injected into the LC/MS/MS. The peak area was measured and the standard curve was generated (using 1/x fit weighted linear regression) by Masslynx software using six concentrations of standards. The concentration was detennined from the equations below. Equation 1 calculated the amount of analyte found (in ng/mL, based on peak area) using the standard curve (linear regression parameters) generated by the Masslynx software Exygen Research Page 15of153 418-028:PAGE G-16 Exygen Study No.: 023-072 program. Then Equation 2 calculated the amount of analyte found in ng/g for liver and ng/mL for serum and plasma. Equation 1: Analyte found (ng/mL) =(Peale area- intercept) x DF x AF slope Where: AF = Aliquot Factor DP = Dilution Factor Equation2: Analyte found (ppb, ng/g for liver and ng/mL for serum and plasma)= analyte found (ng/mL) x FY (mL) sample volume (mL) or sample weight (g) Where: FY = Final Volume For samples fortified with known amounts of PFHS prior to extraction, Equation 3 calculated the percent recovery. Equation 3: Recovery (%) = ((analyte found (ppb) - analyte in control (ppb)) xl00% amount added (ppb) To find the total analyte found corrected for the salt content Equation 4 was used. Equation4: Total Analyte Found Corrected (ppb) = analyte found (ppb) x salt correction factor Where the salt correction factor= 0.91. An example of a calculation using an actual sample follows: Rat liver sample Exygen ID 0202877 Spk A (Set: 100202A), fortified at 10 ng/g where: peak area = 2125 intercept = 41.0365 slope = 4728.12 dilution factor = 1 ppb added (fort level) 10 avg. amt in controls = 0 (Not Detected) final volume = 2mL aliquot factor = 10 sample weight 1.0 g Exygen Research Page 16 ofl 53 418-028:PAGE G-17 Exygen Study No.: 023-072 From equation 1: Analyte found (ng/mL) From equation 2: Analyte found (ppb) From equation 3: % Recovery From equation 4: Analyte Found Corrected (ppb) = [2125 - 41.0365] x I x IO 4728.12 4.41 ng/mL = (4.41nglmLx2 mL) (1.0 g) 8.82 ppb ((8.821mb - on12b) x 100% IOppb 88% 8.82 ppb x 0.91 = 8.03 ppb 7.0 EXPERIMENTAL DESIGN Each set of samples (liver, serum or plasma) consisted of one matrix blank, two matrix blanks fortified at known concentrations, and - 20 samples. Each sample was extracted using the method and then analyzed in duplicate. Exygen Research Page 17of153 418-028:PAGE G-18 Exygen Study No.: 023-072 8.0 RESULTS The PFHS found in the control rat plasma, serum, and liver samples are listed in Tables 1-111. Peaks were not detected in any of the control plasma or serum samples corresponding to the analyte retention time. Some peaks were detected in the control liver samples corresponding to the analyte retention time; however, the peaks detected were all below the LOQ of 10 ppb. Fortification recoveries for PFHS in the rat plasma, serum, and liver samples are detailed in Tables IV-VI. The average percent recoveries standard deviations for PFHS in rat plasma, serum, and liver samples were 84% 7%, 95% 12%, and 86% 13%, respectively. PFHS in the rat plasma samples ranged from non-detected levels to 237,000 ng/mL. Individual results are listed in Table VII. PFHS in the rat serum samples ranged from non-detected levels to 189,000 ng/mL. Individual results are listed in Table VIII. PFHS in the rat liver samples ranged from non-detected levels to 675,000 ng/g. Individual results are listed in Table IX. PFHS residues in the dosing solutions ranged from 88% to 125% of their known concentrations. The results are listed in Table X. PFHS residues found in the stability samples ranged from 91 % to 122% of their known concentrations. The results are listed in Table XI. PFHS residues found in the homogeneity samples ranged from 70% to 116% of their known concentrations. The results are listed in Table XII. 9.0 CONCLUSIONS The rat liver, serum, and plasma samples were successfully extracted and analyzed for PFHS according to analytical method ExM-023-071 Revision 1. The bulk test substance, concentration and homogeneity formulations, and stability solutions were also successfully analyzed for PFHS according to analytical method ExM-023-071 Revision 1. Exygen Research Page 18 of153 418-028:PAGE G-19 Exygen Study No.: 023-072 10.0 RETENTION OF DATA AND SAMPLES When the final analytical report is complete, all original paper data generated by Exygen Research will be shipped to the sponsor. This does not include facility-specific raw data such as instrument or temperature logs. Exact copies of all raw data, as well as a signed copy of the final analytical report and all original facility-specific raw data, will be retained in the Exygen Research archives for the period of time specified in 21 CFR Part 58, OECD ENV/MC/CHEM(98)17, and MHW Ordinance Number 21. Retained samples of reference substances are archived by the sponsor. Exygen Research Page 19 ofl53 418-028:PAGE G-20 Exygen Study No.: 023-072 TABLES Exygen Research Page 20of153 418-028:PAGE G-21 Exygen Study No.: 023-072 Table I. Summary of PFBS in Control Rat Plasma Samples Sponsor ID LOT 17824 LOT 17824 LOT05024 LOT 17824 Exygen ID 0202913 Control 0202913 Control 0202912 Control 0202913 Control Set Number 091602AR 091602B 091802A 091902A PFHS Found (ppb) ND ND ND ND Table II. Summary of PFHS in Control Rat Serum Samples Sponsor ID 36119-3 36119-3 36119-3 36119-3 36119-3 Exygen ID 0202987 Control 0202987 Control 0202987 Control 0202987 Control 0202987 Control Set Number 091902B 092002A 092002B 092302A 101102A PFHS Found (ppb) ND ND ND ND ND Table III. Summary of PFHS in Control Rat Liver Samples Sponsor ID LOT21824 LOT21824 LOT21824 LOT21824 LOT21824 LOT21824 LOT21824 LOT21824 LOT21824 LOT21824 LOT21824 LOT21824 LOT21824 LOT21824 LOT21824 LOT21824 Exygen ID 0202877 Control 0202877 Control A 0202877 Control A 0202877 Control 0202877 Control 0202877 Control 0202877 Control 0202877 Control 0202877 Control 0202877 Control 0202877 Control 0202877 Control 0202877 Control 0202877 Control 0202877 Control 0202877 Control Set Number 092802A 092602A 092602B 092702A 092702B 100202A 100102A 100302A 100402A 100402BR 100902AR 100902BR 101002A 101002B 101102AR 101402A PFHS Found(ppb) ND ND 2.32 (NQ) 3.84 (NQ) 3.85 (NQ) ND ND ND ND 2.09 (NQ) 3.95 (NQ) 2.01 (NQ) 1.85 (NQ) 3.95 (NQ) 4.73 (NQ) 3.37 (NQ) ND= Not Detected (Area less than the lowest concentration of the calibration standards (0.1 ng/mL)) NQ = Not Quantifiable (Area is greater than 0.1 ng/mL but less than LOQ (10 ng/mL)) Exygen Research Page 21 of 153 418-028:PAGE G-22 Exygen Study No.: 023-072 Table IV. Summary of PFHS Fortification Recoveries in Rat Plasma Sponsor ID LOT 17824 LOT 17824 19176 GROUP 1 LOT 17824 LOT 17824 19176 GROUP I LOT05024 LOT05024 19076 GROUP I LOT 17824 LOT 17824 19076 GROUP I Exygen ID 0202913 Spk A 0202913 Spk B 0201801 Spk C 0202913 Spk A 0202913 Spk B 0201816 Spk C 0202912 Spk A 0202912 Spk B 0201846 Spk C 0202913 Spk A 0202913 Spk B 0201831 Spk C Set Number Amount Added(p!b} 091602A 10 091602A 50 091602A 5000 091602B 10 091602B 50 091602B 5000 091802A 10 091802A 50 091802A 5000 091902A 10 091902A 50 091902A 5000 Average: Standard Deviation: Relative Standard Deviation: % Recove!l 91 84 77 86 84 78 88 86 89 71 96 82 84 7 8 Table V. Summary of PFHS Fortification Recoveries in Rat Serum Sponsor ID 36119-3 36119-3 19076 GROUP I 36119-3 36119-3 19012 GROUP I 36119-3 36119-3 19036 GROUP II 36119-3 36119-3 19005 GROUP IV 36119-3 36119-3 Exygen ID 0202987 Spk A 0202987 Spk 8 0201861 Spk C 0202987 Spk A 0202987 Spk 8 0201875 Spk C 0202987 Spk A 0202987 Spk B 0201890 Spk C 0202987 Spk A 0202987 Spk B 0201905 Spk C 0202987 Spk A 0202987 Spk 8 Set Number Amount Added(ppb) 0919028 10 0919028 50 0919028 5000 092002A 10 092002A 50 092002A 5000 092002B 10 092002B 50 092002BR 5000 092302A 10 092302A 50 101102A 200000 101102A 10 101102A 50 Average: Standard Deviation: Relative Standard Deviation: % Recove!l 92 96 94 106 105 90 97 97 120 90 101 88 78 72 95 12 12 Exygen Research Page 22 of 153 418-028:PAGE G-23 Exygen Study No.: 023-072 Table VI. Summary of PFHS Fortification Recoveries in Rat Liver Sponsor ID LOT21824 LOT21824 19176 GROUP I LOT21824 LOT21824 19076 GROUP I LOT21824 LOT21824 19076 GROUP I LOT21824 LOT21824 19012 GROUP I, Male 1 LOT21824 LOT21824 19021 GROUP I, Male 1 LOT21824 LOT21824 19018 GROUP II, Male 1 LOT21824 LOT21824 19041 GROUP I, Male 1 LOT21824 LOT21824 19036 GROUP II, Male 1 LOT21824 LOT21824 19003 GROUP III, Male 1 LOT 21824 LOT21824 19008 GROUP III, Male 1 LOT21824 LOT 21824 19015 GROUP III, Male 1 LOT21824 LOT21824 19035 GROUP IV, Male 1 LOT21824 LOT21824 19040 GROUP IV, Male 2 LOT 21824 LOT21824 19006 GROUP V, Male 1 LOT21824 LOT 21824 19020 GROUP V, Male 2 LOT21824 LOT 21824 19025 GROUP V, Male 1 Exygen ID 0202877 Spk A 0202877 Spk B 0201759 Spk C 0202877 Spk A 0202877 Spk B 0201774 SpkC 0202877 Spk A 0202877 SpkB 0201788 Spk C 0202877 Spk A 0202877 Spk B 0201925 Spk C 0202877 Spk A 0202877 SpkB 0201945 SpkC 0202877 Spk A 0202877 Spk B 0202050 Spk C 0202877 Spk A 0202877 Spk B 0201965 Spk C 0202877 SpkA 0202877 Spk B 0202070 Spk C 0202877 SpkA 0202877 Spk B 0202119 Spk C 0202877 SpkA 0202877 Spk B 0202139 Spk C 0202877 SpkA 0202877 Spk B 0202159 Spk C 0202877 Spk A 0202877 Spk B 0202229 Spk C 0202877 Spk A 0202877 Spk B 0202249 Spk C 0202877 Spk A 0202877 Spk B 0202320 Spk C 0202877 Spk A 0202877 Spk B 0202340 Spk C 0202877 Spk A 0202877 Spk B 0202360 SEk C Exygen Research Set Number Amount Added(ppb) 092802A 10 092802A 092802A 50 5000 092602A 10 092602A 50 092602A 092602B 5000 10 092602B 092602B 092702A 50 5000 10 092702A 092702A 50 5000 092702B 10 092702B 50 092702B 100202A 100202A 100202A 100102A 100102A 100102A 5000 10 50 5000 IO 50 5000 100302A 100302A 100302A 100402A 10 50 5000 IO 100402A 100402A 50 5000 100402BR 100402BR 100402BR 100902AR 10 50 5000 10 100902AR 100902AR 100902BR 100902BR 100902BR 50 5000 10 50 5000 101002A 10 101002A 50 101002AR 101002B 101002B 101002BR 5000 10 50 5000 101102AR 10 101102AR 50 101102AR 25000 101402A 10 101402A so 101402ARR 5000 Average: Standard Deviation: Relative Standard Deviation: % Recovery 83 87 96 125 110 100 104 87 111 75 93 94 83 100 109 88 71 76 74 77 76 98 81 77 81 79 62 70 78 86 72 81 79 72 70 72 96 93 84 97 72 90 88 75 83 95 77 110 86 13 16 Page 23 of 153 418-028:PAGE G-24 Exygen Study No.: 023-072 Table VII. Summary of PFHS Residues in Rat Plasma Samples Sponsor ID 19176 GROUP I 19176 GROUP J 19177 GROUP I 19177GROUP1 19178 GROUP I 19178GROUP1 19179 GROUP II 19179GROUP11 19180 GROUP II 19180GROUP11* 19181 GROUP II 19181 GROUP II 19182 GROUPW 19182 GROUP m 19183 GROUP m 19183 GROUP m 19184 GROUP m 19184 GROUP m 19185 GROUP IV 19185 GROUP IV* 19186 GROUP IV 19186 GROUP IV 19187 GROUP IV 19187 GROUP IV 19188 GROUP V 19188 GROUP V 19189 GROUP V 19189 GROUP V* 19190 GROUP V 19190 GROUP v 19176 GROUP I 19176GROUP1 19177 GROUP I 19177 GROUP I* 19178 GROUP I 19178 GROUP I 19179 GROUP II 19179 GROUP n 19180 GROUP II 19180GROUP11 19181 GROUP II 19181 GROUP II 19182 GROUP III 19182 GROUP m 19183 GROUP III 19183 GROUP 111 19184 GROUP III 19184 GROUP III* 19185 GROUP IV 19185GROUP IV 19186 GROUP IV 19186 GROUP IV 19187 GROUP IV 19187 GROUP IV 19188 GROUP V 19188 GROUP V* 19189 GROUP V 19189 GROUP v 19190 GROUP V 19190 GROUP V Exygen ID 0201801 0201801 Dup lnj. 0201802 0201802 Dup lnj. 0201803 0201803 Dup lnj. 0201804 0201804 Dup lnj. 0201805 0201805 Dup lnj. 0201806 0201806 Dup lnj. 0201807 0201807 Dup htj. 0201808 0201808 Dup Inj. 0201809 0201809 Dup Inj. 0201810 0201810 Dup Inj. 0201811 0201811 Dup htj. 0201812 0201812 Dup Inj. 0201813 0201813 Dup Inj. 0201814 0201814 Dup lnj. 0201815 0201815 Dup lnj 0201816 0201816 Dup Inj 0201817 0201817 Dup Inj 0201818 0201818 Dup lnj 0201819 0201819 Dup Inj 0201820 0201820 Dup laj 0201821 0201821 Dup Jnj 0201822 0201822 D up lnj 0201823 0201823 Dup Inj 0201824 0201824 Dup Inj 0201825 0201825 Dup Inj 0201826 0201826 Dup htj 0201827 0201'827 Dup Inj 0201828 0201828 Dup Jnj 0201829 0201829 Dup htj 0201830 0201830 Dup Inj Matrix PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA Collection Date 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/0i 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 5112102 5/12/02 5/12102 5/12/02 S/12/02 5/12102 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12102 5/12/02 5/12/02 S/12/02 5/12102 S/12/02 5/12/02 S/12102 S/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12102 5/12/02 S/12/02 Set Number 091602A 091602A 091602A 091602A 091602A 091602A 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 0916028 0916028 0916028 0916028 0916028 0916028 0916028R 091602BR 0916028R 091602BR 091602BR 091602BR 091602BR 0916028R 0916028R 091602BR 091602BR 091602BR 091602BR 0916028R 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR PFHS Found (nglmL) 182 172 103 108 46.5"" 43.3"" 18300 19400 15700 15300 20000 20400 58000 58000 68300 69500 117000 115000 70400 71900 126000 125000 237000 228000 197000 182000 187000 183000 177000 170000 245 256 382 376 74.7"" 65.4"" 57400 60200 35700 36400 37100 38500 91000 85900 90300 87500 90700 89300 119000 119000 137000 142000 128000 127000 188000 188000 224000 225000 191000 193000 AAAlthough the method used allows for alternate sample volumes or weights and all the peak area responses are within the calibration curve limits, the precision for the 0.1 mL or 0.1 g samples below 100 ppb has not been validated. * Duplicate Injection Exygen Research Page 24 of 153 418-028:PAGE G-25 Exygen Study No.: 023-072 Table VII (cont'd). Summary of PFHS Residues in Rat Plasma Samples Sponsor ID 19076 GROUP I 19076 GROUP I* 19077 GROUP I 19077 GROUP I* 19078 GROUP I 19078 GROUP I* 19079 GROUP II 19079 GROUP 11* 19080 GROUP II 19080 GROUP II* 19081 GROUP II 19081 GROUP II* 19082 GROUP Ill 19082 GROUP Ill* 19083 ORO~ III 19083 GROUPIII* 19084 GROUP III 19084 GROUP Ill* 19085 GROUP IV 19085 GROUP IV* 19086 GROUP IV 19086 GROUP IV* 19087 GROUP IV 19087 GROUP IV* 19088 GROUP V 19088 GROUPV* 19089 GROUP V 19089 GROUP V* 19090 GROUP V 19090 GROUP V* 19076 GROUP I 19076 GROUP I* 19077 GROUP I 19077 GROUP I* 19078 GROUP I 19078 GROUP I* 19079 GROUP II 19079 GROUP II* 19080 GROUP II 19080 GROUP II* 19081 GROUP II 19081 GROUP II* 19082 GROUP III 19082 GROUP III* 19083 GROUP Ill 19083 GROUP III* 19084 GROUP III 19084 GROUP Ill* 19085 GROUP IV 19085 GROUP IV* 19086 GROUP IV 19086 GROUP IV* 19087 GROUP IV 19087 GROUP IV* 19088 GROUP V 19088 GROUP V* 19089 GROUP V 19089 GROUPV* 19090 GROUP V 19090 GROUP V* * Duplicate Injection Exygen ID 0201846 0201846 Dup lnj 0201847 0201847 Dup lnj 0201848 0201848 Dup luj 0201849 0201849 Dup lnj 0201850 0201850 Dup lnj 0201851 0201851 Dup luj 0201852 0201852 Dup lnj 0201853 0201853 Dup luj 0201854 0201854 Dup lnj 0201855 0201855 Dup lnj 0201856 0201856 Dup lnj 0201857 0201857 Dup luj 0201858 0201858 Dup lnj 0201859 0201859 Dup Jnj 0201860 0201860 Dup lnj 0201831 0201831 Dup luj 0201832 0201832 Dup Jnj 0201833 0201833 Dup lnj 0201834 0201834 Dup lnj 0201835 0201835 Dup lnj 0201836 0201836 Dup lnj 0201837 0201837 Dup Inj 0201838 0201838 Dup lnj 0201839 0201839 Dup luj 0201840 0201840 Dup htj 0201841 0201841 Dup htj 0201842 0201842 Dup lnj 0201843 0201843 Dup lnj 0201844 0201844 Dup htj 0201845 0201845 Dup luj Matrix GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA PD 14 PLASMA Collection Date 5/9/02 519102 5/19/02 5119102 517/02 517102 5/9/02 5/9/02 5/9/02 519102 5/10/02 5/10/02 519102 519102 517102 5/7102 519102 519102 516102 516102 516102 516102 516102 516102 519102 519102 519102 519102 5/9/02 519102 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4114/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4114/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 Set Number 091802A 091802A 091802A 091802A 091802A 091802A 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091902A 091902A 091902A 091902A 091902A 091902A 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR PFHS Found (nglmL) ND ND ND ND ND ND 4150 4000 3240 3230 2640 2670 7150 7280 18000 18100 6490 6900 24800 25400 40700 40800 32500 32300 72600 73600 53200 54400 52200 52800 ND ND 386 398 ND ND 3800 3530 2600 2630 2040 2090 10400 10100 13100 14000 5540 5980 16900 17900 24800 25200 19200 20000 43900 43000 47100 48200 34000 35900 ND= Not Detected (Area less than lowest calibration standard ofO.l ng/mL) Exygen Research Page 25 of 153 418-028:PAGE G-26 Exygen Study No.: 023-072 Table VIII. Summary of PFHS Residues in Rat Serum Samples Sponsor ID 19076 GROUP I 19076 GROUP 1 19078 GROUP I 19078 GROUP 1 19079 GROUP Il 19079 GROUP o 19080GROUP II 19080 GROUP II 19081 GROUP II 19081 GROUP II* 19082 GROUP III 19082 GROUP III* 19083 GROUP III 19083 GROUP III 19084 GROUP III 19084 GROUP III 19085 GROUP IV 19085 GROUP IV 19086 GROUP IV 19086 GROUP IV 19087 GROUP IV 19087 GROUP IV* 19088 GROUP V 19088 GROUP V* 19089 GROUP V 19089GROUP v 19090GROUP V 19090 GROUP V* 19012 GROUP I 19012 GROUP 1 19019 GROUP I 19019 GROUP I* 19021 GROUP I 19021 GROUP J 19023 GROUP I 19023 GROUP I* 19041 GROUP I 19041 GROUP I* 19042 GROUP I 19042 GROUP 1 19044 GROUP I 19044 GROUP I* 19050 GROUP I 19050 GROUP I* 19053 GROUP I 19053 GROUP I* 19065 GROUP I 19065 GROUP I* 19004GROUP II 19004 GROUP n 19009GROUP Il 19009 GROUP Il* 19016 GROUP Il 19016 GROUP II* 19018 GROUP Il 19018 GROUP II 19026 GROUP II 19026 GROUP II* 19036 GROUP 0 19036 GROUP II* Exygen ID 0201861 0201861 Dup Inj 0201862 0201862 Dup lnj 0201863 0201863 Dup Inj 0201864 0201864 Dup Inj 0201865 0201865 Dup lnj 0201866 0201866 Dup Inj 0201867 0201867 Dup lnj 0201868 0201868 Dup lnj 0201869 0201869 Dup Inj 0201870 0201870 Dup Inj 0201871 0201871 Dup Inj 0201872 0201872 Dup Inj 0201873 0201873 Dup Inj 0201874 0201874 Dup lnj 0201875 0201875 Dup Inj 0201876 0201876 Dup Inj 0201877 0201877 Dup lnj 0201878 0201878 Dup lnj 0201879 0201879 Dup lnj 0201880 0201880 Dup lnj 0201881 0201881 Dup Inj 0201882 0201882 Dup Inj 0201883 0201883 Dup Inj 0201884 0201884 Dup lnj 0201885 0201885 Dup Inj 0201886 0201886 Dup Inj 0201887 0201887 Dup lnj 0201888 0201888 Dup Inj 0201889 0201889 Dup lnj 0201890 0201890 Dup Inj Matrix Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Collection Date 519/02 519/02 5mo2 5mo2 5/9/02 519/02 519/02 5/9/02 5/10/02 5110102 519/02 519/02 5n102 5n102 519102 519/02 516102 5/6/02 5/6/02 5/6/02 516102 5/6/02 519102 519/02 5/9/02 5/9/02 519/02 519/02 5129/02 5129102 5130/02 5/30/02 5/29/02 5129/02 5131102 5/31102 5131/02 5131/02 5130/02 5130/02 5/28/02 5/28/02 5131/02 5131/02 5/30/02 5/30/02 5/30/02 5130/02 5131102 5/31/02 5/28/02 5/28/02 5/28/02 5/28/02 5129/02 5129/02 S/31102 5/31/02 5/28/02 5/28/02 Set Number 0919028 0919028 0919028 0919028 091902BR 0919028R 091902BR 091902BR 091902BR 091902BR 0919028R 0919028R 0919028R 0919028R 0919028R 0919028R 0919028R 091902BR 0919028R 0919028R 0919028R 091902BR 0919028R 091902BR 091902BR 0919028R 0919028R 0919028R 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002AR. 092002AR 092002AR 092002AR 092002AR 092002AR 092002AR 092002AR 092002AR 092002AR 092002BR 092002BR PFHS Found (ng/mL) ND ND ND ND 6460 6800 3940 4040 5280 5370 12600 13500 15700 15700 11700 11600 38600 40200 33000 34700 36900 39200 35700 38400 44900 47900 47900 51200 ND ND 65.3"" 68.9"" 81.1"" 86.0"" 45.6"" 42.7"" ND ND ND ND ND ND ND ND ND ND ND ND 9650 9560 7940 7940 8490 8200 8630 8720 5490 5420 6300 6370 AAAlthough the method used allows for alternate sample volumes or weights and all the peak area responses are within the calibration curve limits, the precision for the 0.1 mL or 0.1 g samples below 100 ppb has not been validated. *Duplicate Injection ND= Not Detected (Area less than lowest calibration standard of0.1 ng/mL) Exygen Research Page 26of153 418-028:PAGE G-27 Exygen Study No.: 023-072 Table VIII (cont'd). Summary of PFHS Residues in Rat Serum Samples Sponsor ID 19037 GROUP II 19037 GROUP II* 19043 GROUP II 19043 GROUP II* 19047 GROUP II 19047 GROUP II* 19048 GROUP II 19048 GROUP ll* 19003 GROUP III 19003 GROUP Ill* 19007 GROUP III 19007 GROUP III* 19008 GROUP III 19008 GROUP Ill* 19013 GROUP Ill 19013 GROUP Ill* 19015 GROUP III 19015 GROUP III* 19017GROUPIII 19017 GROUP Ill* 19024 GROUP III 19024 GROUP III* 19029 GROUP Ill 19029 GROUP Ill* 19034 GROUP Ill 19034 GROUP III* 19056 GROUP III 19056 GROUP III* 19005 GROUP IV 19005 GROUP IV* 19035 GROUP IV 19035 GROUP IV* 19039 GROUP IV 19039 GROUP IV* 19040 GROUP IV 19040 GROUP IV* 19045 GROUP IV 19045 GROUP IV* 19054 GROUP IV 19054 GROUP IV* 19058 GROUP IV 19058 GROUP IV* 19062 GROUP IV 19062GROUP IV* 19063 GROUP IV 19063 GROUP IV* 19066 GROUP IV 19066 GROUP IV* 19001 GROUP V 19001 GROUP V* 19006 GROUP V 19006 GROUP V* 19011 GROUP V 19011 GROUP V* 19020 GROUP V 19020 GROUP V* 19022 GROUP V 19022 GROUP V* 19025 GROUP V 19025 GROUP V* 19027 GROUP V 19027GROUP V* 19028 GROUP V 19028 GROUP V* 19030 GROUP V 19030 GROUP V* 19031 GROUP V 19031 GROUP V* * Duplicate Injection Exygen ID 0201891 0201891 Dup Inj 0201892 0201892 Dup Inj 0201893 0201893 Dup Inj 0201894 0201894 Dup IJtj 0201895 0201895 Dup IJtj 0201896 0201896 Dup Inj 0201897 0201897 Dup Inj 0201898 0201898 Dup Inj 0201899 0201899 Dup lnj 0201900 0201900 Dup IJtj 0201901 0201901 Dup lnj 0201902 0201902 Dup lnj 0201903 0201903 Dup lnj 0201904 0201904Dup IJtj 0201905 0201905 Dup Inj 0201906 0201906 Dup lnj 0201907 0201907 Dup lnj 0201908 0201908 Dup lnj 0201909 0201909 Dup lnj 0201910 0201910 Dup lnj 0201911 0201911 Dup lnj 0201912 0201912 Dup Inj 0201913 0201913 Dup lnj 0201914 0201914 Dup Inj 0201915 0201915 Dup lnj 0201916 0201916 Dup lnj 0201917 0201917 Dup lnj 0201918 0201918 Dup Inj 0201919 0201919 Dup IJtj 0201920 0201920 Dup Inj 0201921 0201921 Dup IJtj 0201922 0201922 Dup Inj 0201923 0201923 Dup lnj 0201924 0201924 Duf lnj Matrix Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled PuE Serum Collection Date 5129102 5129102 5/28/02 5128102 5/28/02 5/28/02 5/31/02 5/31/02 5/30/02 5/30/02 5/30/02 S/30/02 5/31/02 5/31/02 S/29102 S/29102 5/31/02 5/31/02 5/28/02 5/28/02 5131/02 5/31/02 5/29/02 5/29/02 S/30/02 5/30/02 5/31/02 5/31/02 5/31102 5/31/02 5/31/02 5/31/02 5/29/02 5129102 5130102 5/30/02 5/28/02 5/28/02 5/31/02 5/31/02 5128102 5128102 5/31102 5/31102 5/29/02 5129102 5/31/02 5/31/02 5/13/02 5/13/02 5/13/02 5/13/02 5/13/02 5/13/02 5/14/02 5/14/02 5/31/02 S/31/02 5/30/02 5/30/02 5/31/02 5/31/02 5/28/02 5/28/02 5/31/02 5/31/02 5/28/02 5128102 Set Number 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR PFHS Found (ng!'.mL} 12800 13000 5750 5970 8990 8810 11700 11700 37300 37400 47300 46300 44000 45400 24300 24600 36900 37000 20800 21200 42900 45000 24900 22600 45000 43700 19700 20500 30900 30800 34600 33500 22600 22800 40700 38400 27800 29300 42900 43800 25800 25800 41200 41100 19800 19100 36800 39300 29000 32700 47900 52400 162000 164000 72800 76200 84100 89400 50200 53900 57200 53700 162000 163000 184000 189000 71200 76200 Exygen Research Page 27 of 153 418-028:PAGE G-28 Exygen Study No.: 023-072 Table IX. Summary of PFHS Residues in Rat Liver Samples Sponsor ID 19176 GROUP I 19176GROUP1 19177 GROUP I 19177 GROUP I"' 19178 GROUP I 19178 GROUP I"' 19179 GROUP II 19179 GROUP 11 19180 GROUP II 19180 GROUP n 19181 GROUP II 19181 GROUP II"' 19182 GROUP III 19182 GROUP III"' 19183 GROUP III 19183 GROUP III"' 19184 GROUP III 19184 GROUP 111 19185 GROUP N 19185 GROUP 1v 19186 GROUP N 19186 GROUP IV"' 19187 GROUP IV 19187 GROUP IV"' 19188 GROUP V 19188 GROUP V 19189 GROUP V 19189 GROUP v 19190 GROUP V 19190 GROUP v 19076 GROUP I 19076 GROUP 1 19077 GROUP I 19077 GROUP I 19078 GROUP I 19078 GROUP 1 19081 GROUP Il Female 1 19081 GROUP II Female t 19079 GROUP II 19079 GROUP 11 19080 GROUP II 19080 GROUP 11 19082 GROUP III 19082 GROUP m 19083 GROUP III 19083 GROUP III 19084 GROUP III 19084 GROUP 111 19085 GROUP IV 19085 GROUP IV 19086 GROUP IV 19086 GROUP IV Exygen ID 0201759 0201759 Dup laj 0201760 0201760 Dup lnj 0201761 0201761 Dup lnj 0201762 0201762 Dup Inj 0201763 0201763 Dup lnj 0201764 0201764 Dup Inj 0201765 0201765 Dup Inj 0201766 0201766 Dup Inj 0201767 0201767 Dup laj 0201768 0201768 Dup Iitj 0201769 0201769 Dup Inj 0201770 0201770 Dup Inj 0201771 0201771 Dup Inj 0201772 0201772 Dup lnj 0201773 0201773 Dup lnj 0201774 0201774 Dup Inj 0201775 0201775 Dup lnj 0201776 0201776 Dup Iitj 0203650 0203650 Dup lnj 0201777 0201777 Dup Inj 0201778 0201778 Dup Inj 0201779 0201779 Dup Inj 0201780 0201780 Dup lnj 0201781 0201781 Dup Inj 0201782 0201782 Dup Inj 0201783 0201783 Dup lnj Matrix Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Collection Date 5112102 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5112102 5/12/02 5112102 5/12/02 5/12/02 5/12/02 5112102 5/12/02 5112102 5112102 5/12/02 5/12/02 5/12/02 5/12/02 5112102 5/12/02 5112102 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 519102 519102 5/19/02 5119102 517102 517102 5/10/02 5/10/02 5/9/02 519102 519102 5/9/02 5/9/02 519102 517102 517102 S/9102 5/9/02 516102 5/6/02 5/6/02 5/6/02 Set Number 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092602A 092602A 092602A 092602A 092602A 092602A 092602A 092602A 092602AR 092602AR 092602AR 092602AR 092602AR 092602AR 092602AR 092602AR 092602AR 092602AR 092602AR 092602AR 092602AR 092602AR PFHS Found (nglmL) 606 576 138 141 326 335 40100 42300 36800 37900 52900 52800 149000 154000 124000 121000 172000 177000 194000 187000 408000 407000 416000 420000 501000 51IOOO 659000 675000 612000 603000 ND ND 8221\1\ 82.41\1\ ND ND 628 633 1040 974 762 125 1960 2080 3070 3090 2700 2750 6360 6640 9740 9370 AAAlthough the method used allows for alternate sample volumes or weights and all the peak area responses are within the calibration curve limits, the precision for the 0.1 mL or 0.1 g samples below I00 *ppb has not been validated. Duplicate Injection ND= Not Detected (Area less than lowest calibration standard ofO.l ng/mL) Exygen Research Page 28 of 153 418-028:PAGE G-29 Exygen Study No.: 023-072 Table IX. (cont'd). Summary of PFHS Residues in Rat Liver Samples Sponsor ID 19087 GROUP IV 19087 GROUP IV 19088 GROUP V 19088 GROUP v 19089 GROUP V 19089 GROUP v 19090 GROUP V 19090 GROUP v 19076 GROUP I 19076 GROUP 1 19078 GROUP I 19078 GROUP I* 19081GROUP11Female2 19081 GROUP II Female 2 19079 GROUP II 19079 GROUP 11 19080 GROUP II 19080 GROUP rr 19082 GROUP III 19082 GROUP III"' 19083 GROUP III 19083 GROUP III"' 19084 GROUP III 19084 GROUP 111 19085 GROUP IV 19085 GROUP N 19086 GROUP IV 19086 GROUP N 19087 GROUP N 19087 GROUP IV"' 19088 GROUP V 19088 GROUP V"' 19089 GROUP V 19089 GROUP V"' 19090 GROUP V 19090 GROUP v 19012 GROUP I, Male l 19012 GROUP I, Male 1* 19012 GROUP I, Male 2 19012 GROUP I, Male2"' 19012 GROUP I, Male3 19012 GROUP I, Male3"' 19012 GROUP I, Male4 19012 GROUP I, Male4* 19012 GROUP I, Male 5 19012 GROUP I, Male 5 19012 GROUP I, Female 7 19012 GROUP I, Female 7 19012 GROUP I, Female 8 19012 GROUP I, Female 8"' 19012 GROUP I, Female 14 19012 GROUP I, Female 14"' Exygen ID 0201784 0201784 Dup lnj 0201785 0201785 Dup lnj 0201786 0201786 Dup lnj 0201787 0201787 Dup Inj 0201788 0201788 Dup Inj 0201789 0201789 Dup Inj 0203651 0203651 Dup lnj 0201790 0201790 Dup Inj 0201791 0201791 Dup Inj 0201792 0201792 Dup lnj 0201793 020 l 793 Dup Inj 0201794 0201794 Dup Inj 0201795 0201795 Dup Inj 0201796 0201796 Dup Inj 0201797 0201797 Dup Inj 0201798 0201798 Dup Inj 0201799 0201799 Dup lnj 0201800 0201800 Dup Inj 0201925 0201925 Dup Inj 0201926 0201926 Dup Inj 0201927 0201927 Dup Inj 0201928 0201928 Dup lnj 0201929 0201929 Dup Inj 0201930 0201930 Dup Inj 0201931 0201931 Dup lnj 0201932 0201932 Dup Inj Matrix Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Median Liver Lobe Pooled Fetal Liver Pooled Fetal Liver Pooled Fetal Liver Pooled Fetal Liver Pooled Fetal Liver Pooled Fetal Liver Pooled Fetal Liver Pooled Fetal Liver Pooled Fetal Liver Pooled Fetal Liver Pooled Fetal Liver Pooled Fetal Liver Pooled Fetal Liver Pooled Fetal Liver Pooled Fetal Liver Pooled Fetal Liver Pooled Fetal Liver Pooled Fetal Liver Pooled Fetal Liver Pooled Fetal Liver Pooled Fetal Liver Pooled Fetal Liver Pooled Fetal Liver Pooled Fetal Liver Pooled Fetal Liver Pooled Fetal Liver Pooled Fetal Liver Pooled Fetal Liver Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Collection Date 5/6/02 5/6/02 5/9/02 5/9/02 519102 5/9/02 519102 5/9/02 5/9/02 519102 517/02 5/7/02 5/10/02 5/10/02 5/9/02 5/9/02 5/9/02 5/9/02 5/9/02 5/9/02 517/02 5/7/02 5/9/02 5/9/02 5/6/02 5/6/02 5/6/02 5/6/02 516102 5/6/02 5/9/02 5/9/02 519102 519102 519102 5/9/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5129102 5/29/02 5/29/02 5/29/02 5/29/02 5129102 5/29/02 5/29/02 5/29/02 5/29/02 Set Number 092602AR 092602AR 092602AR 092602AR 092602AR 092602AR 092602AR 092602AR 092602B 092602B 092602B 092602B 092602B 092602B 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092602BR 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A PFHS Found !n~mL) 7500 7210 19000 20000 15100 15300 14700 15100 27,7AA 25.7AA ND ND 789 821 1460 1480 1810 1880 2180 2290 4560 4550 3020 3150 7320 7170 8510 8590 5630 5920 22200 22800 20100 19800 14700 13600 ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND AAAlthough the method used allows for alternate sample volumes or weights and all the peak area responses are within the calibration curve limits, the precision for the 0.1 mL or 0.1 g samples below 100 ppb has not been validated. * Duplicate Injection ND= Not Detected (Area less than lowest calibration standard of0.1 ng/mL) Exygen Research Page 29 of 153 418-028:PAGE G-30 Exygen Study No.: 023-072 Table IX. (cont'd). Summary of PFHS Residues in Rat Liver Samples Sponsor ID 19012 GROUP I, Female 15 19012 GROUP I, Female 15* 19012 GROUP I, Female 16 19012 GROUP I, Female 16* 19019 GROUP I, Male l 19019 GROUP I, Male l* 19019 GROUP I, Male 2 19019 GROUP I, Male2* 19019 GROUP I, Male 3 19019 GROUP I, Male 3* 19019 GROUP I, Male 7 19019 GROUP I, Male 7* 19019 GROUP I, Male 8 19019 GROUP I, Male 8* 19019 GROUP I, Female 11 19019 GROUP I, Female 11* 19019 GROUP I, Female 12 19019 GROUP I, Female 12 19019 GROUP I, Female 13 19019 GROUP I, Female 13* 19019 GROUP I, Female 14 19019 GROUP I, Female 14* 19019 GROUP I, Female 15 19019 GROUP I, Female 15* 19021 GROUP I, Male l 19021 GROUP I, Male 1* 19021 GROUP I, Male 2 19021 GROUP I, Male 2* 19021 GROUP I, Male 6 19021 GROUP I, Male 6* 19021 GROUP I, Male 8 19021 GROUP I, Male 8 19021 GROUP I, Male 9 19021 GROUP I, Male 9* 19021 GROUP I, Female 11 19021 GROUP I, Female 11* 19021 GROUP I, Female 12 19021 GROUP I, Female 12* 19021 GROUP I, Female 13 19021 GROUP I, Female 13* 19021 GROUP I, Female 14 19021 GROUP I, Female 14"' 19023 GROUP I, Male I 19023 GROUP I, Male l * 19023 GROUP I, Male 2 19023 GROUP I, Male 2"' 19023 GROUP I, Male 3 19023 GROUP I, Ma1e3* 19023 GROUP I, Male 6 19023 GROUP I, Male 6"' 19023 GROUP I, Male 7 19023 GROUP I, Male 7"' Exygen ID 0201933 0201933 Dup Inj 0201934 0201934 Dup lnj 0201935 0201935 Dup Inj 0201936 0201936 Dup Inj 0201937 0201937 Dup lnj 0201938 0201938 Dup Inj 0201939 0201939 Dup Inj 0201940 0201940 Dup Inj 0201941 0201941 Dup lnj 0201942 0201942 Dup lnj 0201943 0201943 Dup lnj 0201944 0201944 Dup lnj 0201945 0201945 Dup lnj 0201946 0201946 Dup Inj 0201947 0201947 Dup Inj 0201948 0201948 Dup lnj 0201949 0201949 Dup Inj 0201951 0201951 Dup lnj 0201952 0201952 Dup Inj 0201953 0201953 Dup lnj 0201954 020 I954 Dup Inj 0201955 0201955 Dup lnj 0201956 0201956 Dup Inj 0201957 0201957 Dup lnj 0201958 0201958 Dup Inj 0201959 0201959 Dup lnj Matrix Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Collection Date 5/29/02 5/29/02 5/29/02 5129102 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 S/30/02 5/30/02 5/30/02 5/30/02 S/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/29/02 5/29/02 5/29/02 5/29/02 5129102 5129/02 5129102 5129102 5/29/02 5/29/02 5129102 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/31/02 5/31/02 5/31/02 5/31/02 5131102 S/31/02 5/31/02 5/31/02 5/31/02 5/31/02 Set Number 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702B 0927028 092702B 0927028 0927028 092702B 092702B 092702B 092702B 0927028 0927028 092702B 0927028 0927028 0927028 0927028 0927028 092702B 0927028 0927028 0927028 0927028 0927028 0927028 0927028 0927028 092702B 0927028 PFHS Found (ng/mL) ND ND ND ND ND ND ND ND 21.7"" 18.3"" 20.5"" 18.9"" ND ND ND ND ND ND 34.0"" 30.6"" ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND 50.6"" 53.S"" 34.0"" 37.0"" 19.6"" 24.l"" ND ND 30.8"" 34.01\1\ Al\Although the method used allows for alternate sample volumes or weights and all the peak area responses are within the calibration curve limits, the precision for the 0.1 mL or 0.1 g samples below 100 ppb has not been validated. * Duplicate Injection ND= Not Detected (Area less than lowest calibration standard of0.1 ng/mL) Exygen Research Page 30of153 418-028:PAGE G-31 Exygen Study No.: 023-072 Table IX. (cont'd). Summary of PFHS Residues in Rat Liver Samples Sponsor ID 9 19023 GROUP I, Female s 19023 GROUP I, Female 9 19023 GROUP I, Female 9 19023 GROUP I, Female 10 19023 GROUP I, Female 10* 19023 GROUP I, Female 11 19023 GROUP I, Female 11 19023 GROUP I, Female 12 19023 GROUP I, Female 12* 19021 GROUP I, Female 10 19021 GROUP I, Female 10* 19041 GROUP I, Male 1 19041 GROUP I, Male 1 19041 GROUP I, Male 2 19041 GROUP I, Male 2* 19041 GROUP I, Male 3 19041 GROUP I, Male 3* 19041 GROUP I, Male 4 19041 GROUP I, Male 4* 19041 GROUP I, Male 5 19041 GROUP I, Male S* 19041 GROUP I, Female 8 19041 GROUP I, Female 8* 19041 GROUP I, Female 9 19041 GROUP I, Female 9* 19041 GROUP I, Female 15 19041 GROUP I, Female IS* 19041 GROUP I, Female 16 19041 GROUP I, Female 16* 19041 GROUP I, Female 17 19041 GROUP I, Female 17* 19004 GROUP II, Male 2 19004 GROUP II, Male 2* 19004 GROUP II, Male 3 19004 GROUP II, Male 3* 19004 GROUP II, Male 4 19004 GROUP II, Male4* 19004 GROUP II, Male 5 19004 GROUP II, Male 5* 19004 GROUP II, Male 6 19004 GROUP II, Male 6* 19004 GROUP II, Female 9 19004 GROUP II, Female 9* 19004 GROUP II, Female 11 19004 GROUP Il, Female 11 * 19004 GROUP II, Female 15 19004 GROUP Il, Female 15* 19004 GROUP II, Female 16 19004 GROUP II, Female 16* 19004 GROUP II, Female 17 19004 GROUP II, Female 17* Exygen ID 0201960 0201960 Dup Inj 0201961 0201961 Dup lnj 0201962 0201962 Dup lrtj 0201963 0201963 Dup Inj 0201964 0201964 Dup lnj 0201950 0201950 Dup Inj 0201965 0201965 Dup lnj 0201966 0201966 Dup Inj 0201967 0201967 Dup Inj 0201968 0201968 Dup Inj 0201969 0201969 Dup Inj 0201970 0201970 Dup lnj 0201971 0201971 Dup lnj 0201972 0201972 Dup lnj 0201973 0201973 Dup Inj 0201974 0201974 Duplnj 0202025 0202025 Dup Inj 0202026 0202026 Dup lnj 0202027 0202027 Dup Inj 0202028 0202028 Dup lnj 0202029 0202029 Dup Inj 0202030 0202030 Dup Inj 0202031 0202031 Dup lnj 0202032 0202032 Dup Inj 0202033 0202033 Dup Inj 0202034 0202034 Dup Inj Matrix Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Collection Date 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5129102 5129102 5/31/02 5/31/02 5/31/02 5/31102 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31102 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 Set Number 0927028 0927028 0927028 0927028 0927028 0927028 0927028 0927028 0927028 0927028 092702BR 092702BR 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR 100102AR PFHS Found (n~mL) ND ND ND ND ND ND ND ND ND ND ND ND ND ND 24.41\1\ 26.6JV\ 26.0JV\ 24.71\1\ ND ND ND ND ND ND 30.6JV\ 30.81\1\ ND ND ND ND ND ND 1220 1160 1160 1120 2380 2480 1670 1670 2070 2000 1870 1880 1740 1710 1070 1060 1450 1530 946 983 N\Although the method used allows for alternate sample volumes or weights and all the peak area responses are within the calibration curve limits, the precision for the 0.1 mL or 0.1 g samples below 100 *ppb has not been validated. Duplicate Injection ND =Not Detected (Area less than lowest calibration standard ofO. l ng/mL) Exygen Research Page 31 ofl 53 418-028:PAGE G-32 Exygen Study No.: 023-072 Table IX. (cont'd). Summary of PFHS Residues in Rat Liver Samples Sponsor m 19018 GROUP II, Male 1 19018 GROUP Il,Male l* 19018 GROUP Il, Male 4 19018 GROUP Il, Male4* 19018 GROUP II, Male 5 19018 GROUP n, Males 19018 GROUP II, Male 6 19018 GROUP II, Male 6* 19018 GROUP Il, Male 7 19018 GROUP Il, Male 7* 19018 GROUP II, Female 9 19018 GROUP Il, Female 9* 19018 GROUP II, Female 10 19018 GROUP Il, Female 10* 19018 GROUP Il, Female 11 19018 GROUP II, Female 11 * 19018 GROUP II, Female 12 19018 GROUP Il, Female 12* 19018 GROUP II, Female 14 19018 GROUP Il, Female 14* 19026 GROUP II, Male 5 19026 GROUP II, Male 5* 19026 GROUP II, Male 1 19026 GROUP II, Male l * 19026 GROUP II, Male 3 19026 GROUP II, Male 3* 19026 GROUP Il, Male 4 19026 GROUP II, Male4* 19026 GROUP II, Male 7 19026 GROUP II, Male 7* 19026 GROUP II, Female 12 19026 GROUP Il, Female 12* 19026 GROUP II, Female 13 19026 GROUP Il, Female 13* 19026 GROUP II, Female 14 19026 GROUP II, Female 14* 19026 GROUP II, Female 15 19026 GROUP II, Female 15* 19026 GROUP II, Female 18 19026 GROUP Il, Female ts 19036 GROUP II, Male l 19036 GROUP II, Male l * 19036 GROUP II, Male 2 19036 GROUP II, Male 2 19036 GROUP Il, Male 4 19036 GROUP Il, Male 4 19036 GROUP II, Male 5 19036 GROUP II, Male 5 19036 GROUP Il, Male 6 19036 GROUP Il, Male 6* 19036 GROUP II, Female 7 19036 GROUP II, Female 7* Exygen m 0202050 0202050 Dup hrj 0202051 0202051 Dup lnj 0202052 0202052 Dup Inj 0202053 0202053 Dup Inj 0202054 0202054 Dup Iaj 0202055 0202055 Dup lnj 0202056 0202056 Dup lnj 0202057 0202057 Dup Inj 0202058 0202058 Dup Inj 0202059 0202059 Dup Inj 0202063 0202063 Dup Inj 0202060 0202060 Dup lnj 0202061 0202061 Dup Inj 0202062 0202062 Dup Inj 0202064 0202064 Dup laj 0202065 0202065 Dup lnj 0202066 0202066 Dup Iaj 0202067 0202067 Dup lnj 0202068 0202068 Dup lnj 0202069 0202069 Dup lnj 0202070 0202070 Dup lnj 0202071 0202071 Dup Inj 0202072 0202072 Dup lnj 0202073 0202073 Dup Inj 0202074 0202074 Dup Inj 0202075 0202075 Dup Inj Matrix Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Collection Date 5/29/02 5129102 5/29/02 5129102 5129102 5129102 5129102 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5129102 5/29/02 5/29/02 5129102 5/29/02 5129102 5/29/02 5/29/02 5/31/02 5/31/02 5131102 5/31/02 5131102 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 Set Number 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A l00202A l00202A l00202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202AR 100202AR 100202AR 100202AR 100202AR 100202AR 100202AR 100202AR 100202AR 100202AR 100202AR 100202AR 100202AR 100202AR 100202AR 100202AR 100202AR 100202AR 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A PFHS Found ln~mL) 839 816 788 818 886 872 868 888 523 514 556 596 804 785 649 664 743 751 788 815 937 928 1130 1130 1170 1150 1140 1130 1050 1010 946 956 928 919 1040 1140 1780 1830 1270 1310 746 748 169 174 707 693 965 946 667 649 622 620 * Duplicate Injection ND = Not Detected (Area less than lowest calibration standard of 0.1 ng/mL) Exygen Research Page 32 of 153 418-028:PAGE G-33 Exygen Study No.: 023-072 Table IX. (cont'd). Summary of PFHS Residues in Rat Liver Samples Sponsor ID 19036 GROUP II, Female 8 19036 GROUP II, Female 8* 19036 GROUP II, Female 11 19036 GROUP II, Female 11 * 19036 GROUP II, Female 12 19036 GROUP II, Female 12"' 19036 GROUP II, Female 13 19036 GROUP II, Female 13* 19037 GROUP II, Male 6 19037 GROUP II, Male 6"' 19037 GROUP II, Female 15 19037 GROUP II, Female 15* 19037 GROUP Il, Male 2 19037 GROUP n, Male 2"' 19037 GROUP II, Male 3 19037 GROUP II, Male 3* 19037 GROUP n, Male 7 19037 GROUP II, Male 7"' 19037 GROUP II, Male 8 19037 GROUP Il,Male 8"' 19037 GROUP II, Female 10 19037 GROUP Il, Female IO* 19037 GROUP II, Female 11 19037 GROUP Il, Female 11"' 19037 GROUP II, Female 13 19037 GROUP II, Female 13* 19037 GROUP II, Female 14 19037 GROUP Il, Female 14* 19003 GROUP III, Male 1 19003 GROUP III, Male l * 19003 GROUP III, Male 3 19003 GROUP III, Male 3* 19003 GROUP III, Male 5 19003 GROUP III, Male 5"' 19003 GROUP III, Male 7 19003 GROUP III, Male 7"' 19003 GROUP III, Male 8 19003 GROUP III, Male 8* 19003 GROUP III, Female 9 19003 GROUP III, Female 9* 19003 GROUP III, Female IO 19003 GROUP III, Female 10* 19003 GROUP III, Female 11 19003 GROUP III, Female 11 * 19003 GROUP III, Female 15 19003 GROUP Ill, Female 15* 19003 GROUP III, Female 16 19003 GROUP Ill, Female 16* 19007 GROUP III, Male l 19007 GROUP Ill, Male l"' 19007 GROUP III, Male 2 19007 GROUP Ill, Male 2* Exygen ID 0202076 0202076 Dup lnj 0202077 0202077 Dup Inj 0202078 0202078 Dup lnj 0202079 0202079 Dup Inj 0202082 0202082 Dup lnj 0202089 0202089 Dup lnj 0202080 0202080 Dup Inj 0202081 0202081 Dup Inj 20831983 0202083 Dup Inj 0202084 0202084 Dup Inj 0202085 0202085 Dup Inj 0202086 0202086 Dup Inj 0202087 0202087 Dup lnj 0202088 0202088 Dup lnj 0202119 0202119 Dup Inj 0202120 0202120 Dup Inj 0202121 0202121 Dup Inj 0202122 0202122 Dup lnj 0202123 0202123 Dup lnj 0202124 0202124 Dup Inj 0202125 0202125 Dup Inj 0202126 0202126 Dup Inj 0202127 0202127 Dup Inj 0202128 0202128 Dup lnj 0202129 0202129 Dup lnj 0202130 0202130 Dup lnj Matrix Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Collection Date 5128/02 5/28/02 5/28/02 5/28/02 5128102 5/28/02 5128102 5128102 5129102 5129102 5129102 5129102 5/29/02 5129102 5/29/02 5129102 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5130102 5/30/02 5/30/02 5/30/02 Set Number 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302AR 100302AR 100302AR 100302AR 100302AR 100302AR l00302AR 100302AR 100302AR 100302AR 100302AR 100302AR 100302AR 100302AR 100302AR 100302AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR PFHS Found (n~mL2 668 650 554 543 676 642 494 490 906 900 956 965 1670 1670 1430 1380 1280 1270 1760 1770 1150 1160 1300 1320 1680 1670 1330 1350 4640 4730 6250 6320 4490 4650 4540 4440 5820 5840 4100 4170 4400 4340 3270 3240 4810 4920 5430 5630 3030 3090 4310 4400 * Duplicate Injection ND= Not Detected (Area less than lowest calibration standard ofO.l ng/mL) Exygen Research Page 33 of 153 418-028:PAGE G-34 Exygen Study No.: 023-072 Table IX. (cont'd). Summary of PFHS Residues in Rat Liver Samples Sponsor ID 19007 GROUP m, Male 3 19007 GROUP III, Male 3 19007 GROUP III, Male 6 19007 GROUP III, Male 6 19007 GROUP ill, Male 7 19007 GROUP III, Male 7 19007 GROUP III, Female 9 19007 GROUP III, Female 9 19007 GROUP ill, Female 11 19007 GROUP III, Female 11 19007 GROUP III, Female 12 19007 GROUP Ill, Female 12* 19007 GROUP Ill, Female 13 19007 GROUP III, Female 13 19007 GROUP Ill, Female 16 19007 GROUP III, Female 16* 19008 GROUP III, Male 1 19008 GROUP III, Male 1 19008 GROUP III, Male 3 19008 GROUP m, Male 3 19008 GROUP IIT, Male 4 19008 GROUP III, Male 4* 19008 GROUP III, Male 6 19008 GROUP III, Male 6 19008 GROUP III, Male 7 19008 GROUP III, Male 7* 19008 GROUP III, Female 9 19008 GROUP III, Female 9 19008 GROUP Ill, Female 10 19008 GROUP Ill, Female 1O* 19008 GROUP III, Female 11 19008 GROUP III, Female 11 * 19008 GROUP Ill, Female 12 19008 GROUP III, Female 12* 19008 GROUP III, Female 13 19008 GROUP Ill, Female 13* 19013 GROUP UI, Male l 19013 GROUP III, Male i 19013 GROUP III, Male 4 19013 GROUP III, Male 4* 19013 GROUP III, Male 5 19013 GROUP III, Male 5* 19013 GROUP III, Male 6 19013 GROUP III, Male 6* 19013 GROUP III, Male 9 19013 GROUP III, Male 9* 19013 GROUP III, Female 11 19013 GROUP III, Female 11 * 19013 GROUP III, Female 12 19013 GROUP III, Female 12* 19013 GROUP Ill, Female 13 19013 GROUP III, Female 13* Exygen ID 0202131 0202131 Dup lnj 0202132 0202132 Dup Inj 0202133 0202133 Dup lnj 0202134 0202134 Dup Inj 0202135 0202135 Dup Inj 0202136 0202136 Dup Inj 0202137 020213 7 Dup Inj 0202138 0202138 Dup Inj 0202139 0202139 Dup Inj 0202140 0202140 Dup lnj 0202141 0202141 Dup Iaj 0202142 0202142 Dup Inj 0202143 0202143 Dup lnj 0202144 0202144 Dup Inj 0202145 0202145 Dup lnj 0202146 0202146 Dup lnj 0202147 0202147 Dup Inj 0202148 0202148 Dup lnj 0202149 0202149 Dup Inj 0202150 0202150 Dup lnj 0202151 0202151 Dup lnj 0202152 0202152 Dup lnj 0202153 0202153 Dup lnj 0202154 0202154 Dup Inj 0202155 0202155 Dup lnj 0202156 0202156 Dup Inj Matrix Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Collection Date 5/30/02 5/30/02 5130102 5/30/02 5/30/02 5/30/02 5130102 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/31102 5/31/02 5/31/02 5131102 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31102 5/31102 5/31/02 5/31/02 5/31102 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/29/02 . 5129102 5/29/02 5/29/02 5129102 5/29/02 5/29/02 5/29/02 5129102 5129102 5/29/02 5/29/02 5/29/02 5129102 5/29/02 5129102 Set Number 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR PFHS Found (ng/mL) 4450 4370 4430 4600 5630 5720 6340 6330 3850 3820 5230 5130 6630 6870 5720 5690 3920 3810 5080 5070 4090 4070 4810 4750 4690 4380 5190 5050 3070 2770 4120 3760 2790 2480 2440 2340 1590 1790 1950 2050 2030 2090 2420 2480 2180 2280 2130 2150 2000 2010 1680 1780 *Duplicate Injection ND= Not Detected (Area less than lowest calibration standard of0.1 ng/mL) Exygen Research Page 34 of 153 418-028:PAGE G-35 Exygen Study No.: 023-072 Table IX. (cont'd). Summary of PFHS Residues in Rat Liver Samples Sponsor ID 19013 GROUP ID, Female 14 19013 GROUP Ill, Female 14* 19013 GROUP ID, Female IS 19013 GROUP Ill, Female IS* 1901 S GROUP III, Male 1 19015 GROUP m, Male I* 1901S GROUP Ill, Male 3 19015 GROUP ID, Male 3* 1901S GROUP Ill, Male 6 19015 GROUP III, Male 6* 19015 GROUP III, Male 7 1901 S GROUP III, Male 7* 19015 GROUP III, Male 8 19015 GROUP Ill, Male 8* 1901S GROUP ill, Female 10 19015 GROUP ill, Female 10* 1901S GROUP m, Female 12 1901S GROUP III, Female 12* 19015 GROUP III, Female 13 1901 S GROUP ID, Female 13* 19015 GROUP ID, Female 14 1901S GROUP Ill, Female 14* 19015 GROUP ID, Female 15 19015 GROUP III, Female 15* 19005 GROUP IV, Male 1 19005 GROUP IV, Male I* 1900S GROUP IV, Male 2 1900S GROUP IV, Male 2* 19005 GROUP IV, Male 3 19005 GROUP IV, Male 3* 19005 GROUP IV, Male 5 19005 GROUP IV, Male 5* 19005 GROUP IV, Male 6 19005 GROUP IV, Male 6* 19005 GROUP IV, Female 8 19005 GROUP IV, Female 8* 19005 GROUP IV, Female 10 19005 GROUP IV, Female 10* 19005 GROUP IV, Female 11 19005 GROUP IV, Female 11 * 19005 GROUP IV, Female 12 19005 GROUP IV, Female 12* 19005 GROUP IV, Female 15 19005 GROUP IV, Female 15* 19035 GROUP IV, Male 1 19035 GROUP IV, Male l * 1903S GROUP IV, Male 2 19035 GROUP IV, Male2* 19035 GROUP IV, Male 4 19035 GROUP IV, Male 4* 19035 GROUP IV, Male S 1903S GROUP IV, Male S* Exygen ID 0202157 02021 S7 Dup Inj 0202158 0202158 Dup Inj 0202159 0202159 Dup Inj 0202160 0202160 Dup Inj 0202161 0202161 Dup lnj 0202162 0202162 Dup Inj 0202163 0202163 Dup Inj 0202164 0202164 Dup Inj 020216S 0202 l 6S Dup Inj 0202166 0202166 Dup lnj 0202167 0202167 Dup Inj 0202168 0202168 Dup lnj 0202219 0202219 Dup Inj 0202220 0202220 Dup lnj 0202221 0202221 Dup lnj 0202222 0202222 Dup lnj 0202223 0202223 Dup lnj 0202224 0202224 Dup Inj 0202225 0202225 Dup lnj 0202226 0202226 Dup Inj 0202227 0202227 Dup lnj 0202228 0202228 Dup Inj 0202229 0202229 Dup Inj 0202230 0202230 Dup Inj 0202231 0202231 Dup Inj 0202232 0202232 Dup Inj Matrix Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Collection Date 5n9102 5/29/02 S/29/02 S/29/02 5/31/02 S/31/02 S/31/02 5/31/02 5/31102 5/31/02 S/31/02 5/31/02 5/31/02 S/31/02 S/31102 5/31/02 5/31102 S/31/02 5/31/02 5/31/02 S/31/02 S/31/02 5/31/02 5/31/02 5/31/02 5/31/02 S/31/02 S/31102 5/31/02 5/31/02 S/31/02 S/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 S/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 S/31/02 Set Number 100402BR 100402BR 100402BR 100402BR 100902AR 100902AR 100902AR 100902AR 100902AR l00902AR 100902AR 100902AR 100902AR 100902AR l00902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR l00902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR PFHS Found (n~mL) 2290 2300 2000 2070 2950 2840 2780 2840 2860 2940 3150 3220 4680 4710 3800 3800 4280 4180 4000 3950 3800 3890 5330 5420 8860 8800 9280 9370 10500 lllOO 8340 9100 11200 10900 11400 11500 12300 12800 12600 12800 9010 9100 11800 12000 11500 12000 14500 14500 13700 13600 11300 10800 *Duplicate Injection ND= Not Detected (Area less than lowest calibration standard ofO.l ng/mL) Exygen Research Page 35of153 418-028:PAGE G-36 Exygen Study No.: 023-072 Table IX. (cont'd). Summary of PFHS Residues in Rat Liver Samples Sponsor ID 19035 GROUP IV, Male 6 19035 GROUP IV, Male 6* 19035 GROUP IV, Female 8 19035 GROUP IV, Female 8* 19035 GROUP IV, Female IO 19035 GROUP IV, Female IO* 19035 GROUP IV, Female 11 19035 GROUP IV, Female 11* 19035 GROUP IV, Female 12 19035 GROUP IV, Female 12* 19035 GROUP IV, Female 13 19035 GROUP IV, Female 13* 19039 GROUP IV, Male I 19039 GROUP IV, Male l* 19039 GROUP IV, Male2 19039 GROUP IV, Male 2* 19039 GROUP IV, Male 3 19039 GROUP IV, Male 3* 19039 GROUP IV, Male 4 19039 GROUP IV, Male 4* 19039 GROUP IV, Male 5 19039 GROUP IV, Male 5* 19039 GROUP IV, Female 8 19039 GROUP IV, Female 8* 19039 GROUP IV, Female 11 19039 GROUP IV, Female 11 * 19039 GROUP IV, Female 12 19039 GROUP IV, Female 12* 19039 GROUP IV, Female 14 19039 GROUP IV, Female 14* 19039 GROUP IV, Female 15 19039 GROUP IV, Female 15* 19040 GROUP IV, Male 2 19040 GROUP IV, Male 2* 19040 GROUP IV, Male 3 19040 GROUP IV, Male3* 19040 GROUP IV, Male 4 19040 GROUP IV, Male 4* 19040 GROUP IV, Male 5 19040 GROUP JV, Male 5* 19040 GROUP IV, Male 7 19040 GROUP IV, Male 7* 19040 GROUP IV, Female 11 19040 GROUP IV, Female 11 * 19040 GROUP IV, Female 12 19040 GROUP IV, Female 12* 19040 GROUP IV, Female 13 19040 GROUP IV, Female 13* 19040 GROUP IV, Female 15 19040 GROUP IV, Female 15* 19040 GROUP IV, Female 16 19040 GROUP IV, Female 16* Exygen ID 0202233 0202233 Dup Irtj 0202234 0202234 Dup lnj 0202235 0202235 Dup Inj 0202236 0202236 Dup lnj 0202237 0202237 Dup Inj 0202238 0202238 Dup Inj 0202239 0202239 Dup lnj 0202240 0202240 Dup Inj 0202241 0202241 Dup lnj 0202242 0202242 Dup Inj 0202243 0202243 Dup Inj 0202244 0202244 Dup Inj 0202245 0202245 Dup lnj 0202246 0202246 Dup lnj 0202247 0202247 Dup Inj 0202248 0202248 Dup Inj 0202249 0202249 Dup lnj 0202250 0202250 Dup Inj 0202251 0202251 Dup Inj 0202252 0202252 Dup Inj 0202253 0202253 Dup Inj 0202254 0202254 Dup lnj 0202255 0202255 Dup Inj 0202256 0202256 Dup lnj 0202257 0202257 Dup lnj 0202258 0202258 Dup lnj Matrix Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Collection Date 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5131/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/29/02 5/29/02 5/29/02 5129102 5129102 5/29/02 5/29/02 5129102 5129102 5129102 5/29/02 5129102 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 Set Number 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR PFHS Found (l!mL) 10600 I0500 12000 13300 IOOOO I0400 18500 18400 12600 12000 17300 17300 5320 5200 6160 6310 5300 5150 5870 6130 6500 6430 4910 5010 3510 3710 4550 4620 4310 4180 5110 4920 6480 7690 11500 11200 7540 7750 13000 12200 11100 lllOO 12100 11200 10600 10700 14IOO 14000 12400 12300 14900 15700 * Duplicate Injection ND = Not Detected (Area less than lowest calibration standard of 0.1 ng/mL) Exygen Research Page 36of153 418-028:PAGE G-37 Exygen Study No.: 023-072 Table IX. (cont'd). Summary of PFHS Residues in Rat Liver Samples Sponsor ID 19045 GROUP IV, Male I 19045 GROUP IV, Male 1 19045 GROUP IV, Male 2 19045 GROUP IV, Male2 19045 GROUP IV, Male4 19045 GROUP IV, Male 4 19045 GROUP IV, Male 5 19045 GROUP IV, Male 5 19045 GROUP IV, Male 6 19045 GROUP IV, Male 6 19045 GROUP IV, Female 8 19045 GROUP IV, Female 8 19045 GROUP IV, Female 9 19045 GROUP IV, Female 9 19045 GROUP IV, Female 10 19045 GROUP IV, Female 10* 19045 GROUP IV, Female 11 19045 GROUP IV, Female 11 19045 GROUP IV, Female 14 19045 GROUP IV, Female 14* 19006 GROUP V, Male 1 19006 GROUP V, Male 1 19006 GROUP V, Male 2 19006 GROUP V, Male 2* 19006 GROUP V, Male 3 19006 GROUP V, Male3* 19006 GROUP V, Male 4 19006 GROUP V, Male4 19006 GROUP V, Male 5 19006 GROUP V, Male 5* 19006 GROUP V, Female 8 19006 GROUP V, Female 8* 19006 GROUP V, Female 10 19006 GROUP V, Female 10 19006 GROUP V, Female 11 19006 GROUP V, Female 11* 19006 GROUP V, Female 13 19006 GROUP V, Female 13 19006 GROUP V, Female 18 19006 GROUP V, Female 18* 19011 GROUP V, Male 2 19011 GROUP V, Male 2* 19011 GROUP V, Male 3 19011 GROUP V, Male 3 19011 GROUP V, Male4 19011 GROUP V, Male4* 19011 GROUP V, Male 5 19011 GROUP V, Male 5 19011 GROUP V, Male 6 19011 GROUP V, Male 6* 19011 GROUP V, Female 9 19011 GROUP V, Female 9* Exygen ID 0202259 0202259 Dup lnj 0202260 0202260 Dup Inj 0202261 0202261 Dup lnj 0202262 0202262 Dup lnj 0202263 0202263 Dup Inj 0202264 0202264 Dup lnj 0202265 0202265 Dup Inj 0202266 0202266 Dup Inj 0202267 0202267 Dup lnj 0202268 0202268 Dup Inj 0202320 0202320 Dup lnj 0202321 0202321 Dup lnj 0202322 0202322 Dup Inj 0202323 0202323 Dup lnj 0202324 0202324 Dup Inj 0202325 0202325 Dup lnj 0202326 0202326 Dup Inj 0202327 0202327 Dup lnj 0202328 0202328 Dup lnj 0202329 0202329 Dup Inj 0202330 0202330 Dup lnj 0202331 0202331 Dup Inj 0202332 0202332 Dup Inj 0202333 0202333 Dup lnj 0202334 0202334 Dup Inj 0202335 0202335 Dup Inj Matrix Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Collection Date 5128102 5/28/02 5/28/02 5/28/02 5128102 5128102 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5128102 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5130102 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/31/02 5/31/02 5/31102 5/31/02 S/31/02 5131102 S/31102 5/31/02 5/31102 5/31/02 5/31/02 5131102 Set Number 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR I01002BR 101002BR IOI002BR IOl002BR 101002BR 101002BR 101002BR 101002BR I01002BR 101002BR 101002BR IOI002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR PFHS Found (nEmL) 6200 6210 4830 4900 7820 7510 5700 5750 4840 4970 7350 7350 6510 6740 8350 8010 6520 6380 6030 5870 13500 13700 16500 16700 25800 26100 30100 29400 30200 29800 23300 22500 17700 16400 25000 25000 16700 16500 20700 20200 19200 20000 18700 19900 19300 19000 18600 19300 14000 14100 20800 21100 * Duplicate Injection ND= Not Detected (Area less than lowest calibration standard ofO.l ng/mL) Exygen Research Page 37of153 418-028:PAGE G-38 Exygen Study No.: 023-072 Table IX. (cont'd). Summary of PFHS Residues in Rat Liver Samples Sponsor ID 19011 GROUP V, Female 10 19011 GROUP V, Female 10 19011 GROUP V, Female 11 19011 GROUP V, Female 11 19011 GROUP V, Female 12 19011 GROUP V, Female 12 19011 GROUP V, Female 13 19011 GROUP V, Female 13 19020 GROUP V, Male 2 19020 GROUP V, Male 2 19020 GROUP V, Male 4 19020 GROUP V, Male 4 19020 GROUP V, Male 5 19020 GROUP V, Male 5 19020 GROUP V, Male 7 19020 GROUP V, Male 7 19020 GROUP V, Male 8 19020 GROUP V, Male 8"' 19020 GROUP V, Female 9 19020 GROUP V, Female9 19020 GROUP V, Female IO 19020 GROUP V, Female 10 19020 GROUP V, Female 11 19020 GROUP V, Female 11"' 19020 GROUP V, Female 12 19020 GROUP V, Female 12 19020 GROUP V, Female 13 19020 GROUP V, Female 13* 19022 GROUP V, Male I 19022 GROUP V, Male l 19022 GROUP V, Male4 19022 GROUP V, Male 4* 19022 GROUP V, Male 5 19022 GROUP V, Male 5"' 19022 GROUP V, Male 7 19022 GROUP V, Male 7* 19022 GROUP V, Male 8 19022 GROUP V, Male 8* 19022 GROUP V, Female 11 19022 GROUP V, Female 11 19022 GROUP V, Female 12 19022 GROUP V, Female 12 19022 GROUP V, Female 13 19022 GROUP V, Female 13 19022 GROUP V, Female 14 19022 GROUP V, Female 14 19022 GROUP V, Female 15 19022 GROUP V, Female 15* 19025 GROUP V, Male 2 19025 GROUP V, Male 2"' 19025 GROUP V, Male 7 19025 GROUP V, Male 7"' Exygen ID 0202336 0202336 Dup Inj 0202337 0202337 Dup Inj 0202338 0202338 Dup Inj 0202339 0202339 Dup lnj 0202340 0202340 Dup Inj 0202341 0202341 Dup Inj 0202342 0202342 Dup lnj 0202343 0202343 Dup Inj 0202344 0202344 Dup Inj 02021345 0202345 Dup Inj 0202346 0202346 Dup lnj 0202347 0202347 Dup lnj 0202348 0202348 Dup Inj 0202349 0202349 Dup lnj 0202350 0202350 Dup Inj 0202351 0202351 Dup Inj 0202352 0202352 Dup lnj 0202353 0202353 Dup Inj 0202354 0202354 Dup lnj 0202355 0202355 Dup lnj 0202356 0202356 Dup Inj 0202357 0202357 Dup lnj 0202358 0202358 Dup Inj 0202359 0202359 Dup lnj 0202361 0202361 Dup Inj 0202362 0202362 Dup lnj Matrix Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Collection Date 5/31/02 5/31/02 5/31/02 5131102 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31102 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5131102 5/31/02 5131/02 5/31/02 5131102 5/31/02 5/31/02 5/31/02 5/30/02 5/30/02 5/30/02 5/30/02 Set Number 101002BRR 101002BRR 101002BRR 101002BRR 101002BRR 101002BRR 101002BRR 101002BRR l01102AR 101102AR l01102AR 101102AR 101102AR 101102AR 101102AR 101102AR l01102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR l01102AR 101102AR I01102AR l01102AR 101102AR 101102AR 101102AR 101102AR I01102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101402AR 101402AR 101402AR 101402AR PFHS Found (ng/m.L) 18700 20000 23500 22400 21900 22500 21000 21400 11800 11300 9460 9190 8130 8510 9280 9050 8750 8750 14800 14300 12200 12600 14400 14300 15600 15300 20900 21300 11100 11000 12700 12400 12500 12800 11800 11600 14400 14300 13700 14100 17400 17500 12200 11600 15700 15300 14100 14200 21700 21900 18600 18600 *Duplicate Injection ND= Not Detected (Area less than lowest calibration standard ofO.l ng/mL) Exygen Research Page 38of153 418-028:PAGE G-39 Exygen Study No.: 023-072 Table IX. (cont'd). Summary of PFBS Residues in Rat Liver Samples Sponsor ID 19025 GROUP V, Male 8 19025 GROUP V, Male 8"' 19025 GROUP V, Male 13 19025 GROUP V, Male 13"' 19025 GROUP V, Female 14 19025 GROUP V, Female 14"' 19025 GROUP V, Female 15 19025 GROUP V, Female 15"' 19025 GROUP V, Female 18 19025 GROUP V, Female 18"' 19025 GROUP V, Female 19 19025 GROUP V, Female 19* 19025 GROUP V, Female 20 19025 GROUP V, Female 20"' 19025 GROUP V, Male 1 19025 GROUP V, Male 1* Exygen ID 0202363 0202363 Dup lnj 0202364 0202364 Dup lnj 02021365 0202365 Dup Inj 0202366 0202366 Dup Inj 0202367 0202367 Dup lnj 0202368 0202368 Dup Inj 0202369 0202369 Dup lnj 0202360 0202360 Dup Inj Matrix Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Pup Livers Collection Date 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 Set Number 101402AR 101402AR 101402AR 101402AR 101402AR 101402AR 101402AR 101402AR 101402AR 101402AR 101402AR 101402AR 101402AR 101402AR 101402ARR 101402ARR PFHS Found {ng/mL~ 21400 21800 18300 19400 14700 15300 26400 26500 19800 19500 18900 18800 16800 17600 13300 14400 * Duplicate Injection ND =Not Detected (Area less than lowest calibration standard of 0.1 ng/mL) Exygen Research Page 39 of153 418-028:PAGE G-40 Exygen Study No.: 023-072 Table X. Summary of PFHS Residues in Dosing Solutions Sample Description B-418-028-A (07.Jun.02) 0 mg/mL 1 of4 B-418-028-A (07.Jun.02) 0mg/mL1 of4 B-418-028-B (24.May.02) 0.03 mg/mL 1 of 4 B-418-028-B (24.May.02) 0.03 mg/mL 1 of4 B-418-028-C (24.May.02) 0.1 mg/mL 1 of4 B-418-028-C (24.May.02) 0.1 mg/mL 1 of4 B-418-028-D (07.Jun.02) 0.3 mg/mL I of4 B-418-028-D (07.Jun.02) 0.3 mg/mL 1 of4 B-418-028-E (24.May.02) 1mg/mL1 of4 B-418-028-E (24.May.02) 1 mg/mL I of4 Bulk TA/S Sample (09.Jun.02) Bulk TNS Sample (09.Jun.02) Set Number 110702C 110702C 110702C 110702C 110702C 110702C 110702C l 10702C 110702CR 110702CR 110702C 110702C PFHS PFHS Known Concentration (ng/mL) Found (ng/mL) 0 ND 0 ND 30000 26500 30000 27300 100000 88900 100000 91000 300000 268000 300000 278000 1000000 1000000 100000 100000 1010000 1000000 125000 122000 PFHS Recovery(%) 88 91 89 91 89 93 101 100 125 122 ND= Not Detected (Area less than lowest calibration standard ofO. l ng/mL) Exygen Research Page 40of153 418-028:PAGE G-41 Exygen Study No.: 023-072 Table XI. Summary of PFHS Residues in Stability Samples 3M ID E02-0514-38611 * E02-0514-38611 E02-0514-38612 E02-0514-38612* E02-0514-38613 E02-0514-38613* E02-0514-38614 E02-0514-38614* E02-0514-38615 E02-0514-38615* E02-0514-38616 E02-0514-38616* E02-0Sl4-38617 E02-0514-381i17* E02-0514-38618 E02-0514-38618* E02-0514-38619 E02-0514-38619* E02-0514-38620 E02-05 l 4-38620* Exygen ID 0203923 0203923 Dup lnj 0203924 0203924 Dup lnj 0203925 0203925 Dup Inj 0203926 0203926 Dup lnj 0203927 0203927 Dup lnj 0203928 0203928 Dup lnj 0203929 0203929 Dup lnj 0203930 0203930 Dup lnj 0203931 0203931 Dup lnj 0203932 0203932 Dup lnj Sample Desc!!J!tion B-418-028 A (29 Mar02)0 mg/mL l of4 B-418-028 A (29 Mar 02) 0 mg/mL 1 of4 B-418-028 A (29 Mar 02) 0 mg/mL 2 of4 B-418-028 A (29 Mar 02) 0 mg/mL 2 of4 B-418-028 B (29 Mar02) 0.03mglmL1 of4 B-418-028 B (29 Mar 02) 0.03 mglmL 1 of4 B-418-028 B (29 Mar 02) 0.03 mglmL 2 of4 B-418-028 B (29 Mar 02) 0.03 mg/mL 2 of4 B-418-028 C (29 Mar 02) 0.1 mglmL 1 of4 B-418-028 C (29 Mar 02) 0.1 mglmL 1 of4 B-418-028 C (29 Mar02) 0.1mglmL2 of4 B-418-028 C (29 Mar 02) 0.1 mg/mL 2 of4 B-418-028 D (29 Mar 02) 0.3 mglmL I of4 B-418-028 D (29 Mar 02) 0.3 mg/mL 1 of4 B-418-028 D (29 Mar02) 0.3 mg/mL2 of4 B-418-028 D (29 Mar 02) 0.3 mg/mL 2 of4 B-418-028 E (29 Mar02) 1mg/mL1 of4 B-418-028 E (29 Mar02) 1mglmL1 of4 B-418-028 E (29 Mar02) 1mg/mL2 of4 B-418-028 E (29 Mar 02) I mB:'.'.mL 2 of4 Set Number ll0502A ll0502A 110502A 110502A 110502A 110502A 110502A 110502A 110502A 110502A 110502A 110502A 110S02A 110502A 110502A 110502A 110702AR 110702AR 110702AR ll0702AR PFHS Known Cone. (nglmL} 0 0 0 0 30000 30000 30000 30000 100000 100000 100000 100000 300000 300000 300000 300000 1000000 1000000 1000000 1000000 PFHS Found {nglmL} ND ND ND ND 29700 29600 29700 29500 122000 117000 100000 100000 308000 316000 326000 324000 910000 919000 1030000 1010000 PFHS Recovery !%} 99 99 99 98 122 117 100 100 103 105 109 108 91 92 103 IOI *Duplicate Injection ND= Not Detected (Area less than lowest calibration standard of0.1 ng/mL) Exygen Research Page 41 of 153 418-028:PAGE G-42 Exygen Study No.: 023-072 Table XII. Summary of PFHS Residues in Homogeneity Samples 3M ID E02-0514-38621 E02-0514-38621* E02-0514-38622 E02-0514-38622* E02-0514-38623 E02-0514-38623 * E02-0514-38624 E02-0514-38624* E02-0514-38625 E02-0514-38625* E02-05 l 4-38626 E02-0514-38626* E02-0514-38627 E02-0514-38627* E02-0514-38628 E02-0514-38628* E02-0514-3 8629 E02-0514-38629* E02-0514-38630 E02-0514-38630* E02-0514-38631 E02-0514-38631* E02-0514-38632 E02-0514-38632* E02-0514-38633 E02-0514-38633* E02-0514-38634 E02-0514-38634* E02-0514-38635 E02-0514-38635* E02-0514-38636 E02-0514-38636* E02-0514-38637 E02-0514-38637* E02-0514-38638 E02-0514-38638* E02-0514-38639 E02-0514-38639* E02-0514-38640 E02-0514-38640* E02-0514-38641 E02-0514-38641 * E02-0514-38642 E02-0514-38642* E02-0514-38643 E02-0514-38643* E02-0514-38644 E02-0514-38644* E02-0514-38645 E02-0514-38645* E02-0514-38646 E02-0514-38646* E02-0514-38647 E02-0514-38647* E02-0514-38648 E02-0514-38648* E02-0514-38649 E02-0514-38649* E02-0514-38650 E02-0514-3 8650* Exygen ID 0203933 0203933 Dup laj 0203934 0203934 Dup htj 0203935 0203935 Dup Inj 0203936 0203936 Dup Iaj 0203937 0203937 Dup htj 0203938 0203938 Dup Inj 0203939 0203939 Dup Inj 0203940 0203940 Dup Inj 0203941 0203941 Dup laj 0203942 0203942 Dup Inj 0203943 0203943 Dup htj 0203944 0203944 Dup Inj 0203945 0203945 Dup Inj 0203946 0203946 Dup laj 0203947 0203947 Dup lnj 0203948 0203948 Dup laj 0203949 0203949 Dup htj 0203950 0203950 Dup htj 0203951 0203951 Dup Inj 0203952 0203952 Dup Inj 0203953 0203953 Dup laj 0203954 0203954 Dup lnj 0203955 0203955 Dup Inj 0203956 0203956 Dup Inj 0203957 0203957 Dup lnj 0203958 0203958 Dup lnj 0203959 0203959 Dup laj 0203960 0203960 Dup htj 0203961 0203961 Dup lnj 0203962 0203962 Du2 Inj Sample Descri2ti.on B-418-028-A (29Mar02) 0 mg/mL 1 of 12T B-418-028-A (29Mar02) 0 mg/mL 1 of 12T B-418-028-A (29Mar02) 0 mg/mL 2 of12T B-418-028-A (29Mar02) 0 mg/mL 2 of 12T B-418-028-A (29Mar02) 0 mg/mL 5 of 12M B-418-028-A (29Mar02) 0 mg/mL 5 of 12M B-418-028-A (29Mar02) 0 mg/mL 6 ofl2M B-418-028-A (29Mar02) 0 mg/mL 6 of l 2M B-418-028-A (29Mar02) 0 mg/mL 9of12B B-418-028-A (29Mar02) 0 mg/mL 9of12B B-418-028-A (29Mar02) 0 mg/mL 10 of 12B B-418-028-A (29Mar02) 0 mg/mL I0 of 12B B-418-028-B (29Mar02) 0.03 mg/mL I of 12T B-418-028-B (29Mar02) O.Q3 mg/ml.. I of 12T B-418-028-B (29Mar02) 0.03 mg/mL 2of12T B-418-028-B (29Mar02) 0.03 mg/mL 2 of 12T B-418-028-B (29Mar02) 0.03 mg/mL S of 12M B-418-028-B (29Mar02) 0.03 mg/mL S o12M B-418-028-B (29Mar02) 0.03 mg/mL 6 of 12M B-418-028-B (29Mar02) 0.03 mg/mL 6 of 12M B-418-028-B (29Mar02) 0.03 mg/mL 9of12B B-418-028-B (29Mar02) O.o3 mg/mL 9 of12B B-418-028-B (29Mar02) 0.03 mg/mL 10 of 12B B-418-028-B (29Mar02) 0.03 mg/mL 10 of 12B B-418-028-C (29Mar02) 0.1 mg/mL I of l 2T B-418-028-C (29Mar02) 0.1mg/mL1 of12T B-418-028-C (29Mar02) 0.1mg/mL2of12T B-418-028-C {29Mar02) 0.1 mg/mL 2 of 12T B-418-028-C (29Mar02) 0.1 mg/mL 5 of 12M B-418-028-C (29Mar02) 0.1 mg/mL 5 of l 2M B-418-028-C (29Mar02) 0.1 mg/mL 6 of 12M B-418-028-C (29Mar02) 0.1 mg/mL 6 of 12M B-418-028-C (29Mar02) 0.1mg/mL9of12B B-418-028-C (29Mar02) 0.1 mg/mL 9 of l 2B B-418-028-C (29Mar02) 0.1 mg/mL IO of 12B B-418-028-C (29Mar02) 0.1 mg/mL IO of12B B-418-028-D (29Mar02) 0.3 mg/ml.. I of12T 8-418-028-D (29Mar02) 0.3 mg/mL 1 of 12T B-418-028-D {29Mar02) 0.3 mg/mL 2 of 12T B-418-028-D (29Mar02) 0.3 mg/mL2 ofl2T B-418-028-D (29Mar02) 0.3 mg/mL 5of12M B-418-028-D (29Mar02) 0.3 mg/mL 5 of l 2M B-418-028-D {29Mar02) 0.3 mg/mL 6 of l 2M B-418-028-D (29Mar02) 0.3 mg/mL 6of12M B-418-028-D (29Mar02) 0.3 mg/mL 9 of 12B B-418-028-D (29Mar02) 0.3 mg/mL 9 ofl2B B-418-028-D (29Mar02) 0.3 mg/mL 10 of 128 B-418-028-D {29Mar02) 0.3 mg/mL 10 of 128 B-418-028-E (29Mar02) 1mg/mL1 ofl2T B-418-028-E (29Mar02) 1 mg/mL 1 of 12T B-418-028-E (29Mar02) 1 mg/mL2 ofl2T B-418-028-E {29Mar02) 1 mg/mL2 ofl2T B-418-028-E {29Mar02) 1 mg/mL 5 of 12M B-418-028-E (29Mar02) 1 mg/mL 5 of l 2M B-418-028-E {29Mar02) 1 mg/mL 6 of 12M 8-418-028-E (29Mar02) 1mg/mL6 of12M 8-418-028-E (29Mar02) 1mg/ml..9 of12B B-418-028-E (29Mar02) 1mg/mL9 ofl28 B-418-028-E (29Mar02) 1 mg/mL 10 of 128 B-418-028-E (29Mar02l l ms!'.mL 10 of l 2B Set Number 110702A 110702A 110702A 110702A 110702A 110702A 110702A 110702A 110702A 110702A 110702A 110702A 110702A 110702A 110702A 110702A 110702A 110702A 110702A 110702A 110702A 110702A 110702A 110702A 110702A 110702A 110702A 110702A 110702AR 110702AR 110702A 110702A 110702A 110702A 110702AR 110702AR 110702A l 10702A 110702A l 10702A 1107028 110702B l 10702B 110702B 1107028 110702B 1107028 110702B 1107028 110702B l 10702B l 10702B 1107028 1107028 l 10702B 1107028 1107028 1107028 1107028 l 10702B PFHS Known Cone. (nWmL} 0 0 0 0 0 0 0 0 0 0 0 0 30000 30000 30000 30000 30000 30000 30000 30000 30000 30000 30000 30000 100000 100000 100000 100000 100000 100000 100000 100000 100000 100000 100000 100000 300000 300000 300000 300000 3'00000 300000 300000 300000 300000 300000 300000 300000 1000000 1000000 1000000 1000000 1000000 1000000 1000000 1000000 1000000 1000000 1000000 1000000 PFHS Found ~ng!mL} ND ND ND ND ND ND ND ND ND ND ND ND 24400 23700 26900 25800 25500 26100 25800 25800 24200 24400 24800 24500 75400 73800 76300 74700 93300 95100 69800 72300 84400 83700 95700 92800 270000 268000 270000 279000 254000 266000 241000 239000 255000 250000 280000 293000 1020000 1090000 987000 980000 1160000 1170000 1040000 994000 1090000 1100000 1110000 1070000 PFHS Recovery ~"l 81 79 90 86 85 87 86 86 81 81 83 82 75 74 76 15 93 95 70 72 84 84 96 93 90 89 90 93 85 89 80 80 85 83 93 98 102 109 99 98 116 117 104 99 109 110 111 107 * Duplicate Injection ND= Not Detected (Area less than lowest calibration standard ofO.l ng/mL) Exygen Research Page 42 of 153 418-028:PAGE G-43 Exygen Study No.: 023-072 FIGURES Exygen Research Page 43 of 153 418-028:PAGE G-44 Exygen Study No.: 023-072 Figure 1. Typical Calibration Curve for PFHS Compound 1 name: PFHS Coefficient of Determination: 0.999484 Calibration curve: 2633.68 * x + 44.4695 Response type: External Std, Area Curve type: Linear, Origin: Exclude, Weighting: 1/x, Axis trans: rt>ne 1.32e4 Response O-i'li'l....,..,..,..........,.........,...............................,...,.........~--........- - . _ . . ................,....._ _~,...,..._..nwmL 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 Exygen Research Page 44 ofl53 418-028:PAGE G-45 Exygen Study No.: 023-072 Figure 2. Chromatogram Representing a 0.1 ng/mL standard for PFHS C0820026, 0.1 ng/ml Standard 0919028-2012 Sm (Mn.2x3) 100 21-Sep-2002 10:34:30 LC/MS/MS#7 MRM of 1 Channel ES- 8.84 399 > 80 299 4.21e3 Area % 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.0D 11.00 Exygen Research Page 45 of 153 418-028:PAGE G-46 Exygen Study No.: 023-072 Figure 3. Chromatogram Representing a Control Rat Plasma Sample for PFHS (Exygen ID 0202913 Control, Data Set: 091602B) 0202913 Control 0916028-207 Sm (Mn. 2x3) 10 0.17 3.66 3.57 0.29 % 3.00 1.22 1.81 2.33 2.91 3.27 17-Sep-2002 22:52:59 LC/MS/MS#7 MRM of 1 Channel ES 9.09 399>8( 386 9.13 B. 7.24 5.45 6.69 9.22 .55 10.21 B.55 9.81 1063 11.90 6.51 6.75 7.78 7.898.07 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 Exygen Research Page 46 of 153 418-028:PAGE G-47 Exygen Study No.: 023-072 Figure 4. Chromatogram Representing a Control Rat Serum Sample for PFHS (Exygen ID: 0202987 Control, Data Set: 091902B) 0202987 Control A 09190282006 Sm (Mn, 2x3) 100 1.54 % 0.85 0.45 1.39 1.88 1.97 2.99 3.30 l8.93 21-Sep-2002 09:07:34 LC/MS/MS#7 MRM of 1 Channel ES- 10.18 399 :> 80 289 11.34 8.84 8.77 8.37 6.53 6.63 6.16 7.22 7.54 819 9.29 9.55 .75 10.46 11.42 11.08 11.82 11.94 O Time 1.00 2.00 3.DO 4.00 5.DO 6.00 7.00 8.00 9.00 10.00 11.00 12.DO Exygen Research Page47 of153 418-028:PAGE G-48 Exygen Study No.: 023-072 Figure 5. Chromatogram Representing a Control Rat Liver Sample for PFHS, (Exygen ID: 0202877 Control , Data Set: 100202A) 0202877 Control 100202A-208 Sm (Mn, 2x3) 10 03-0ct-2002 08:12:19 LC/MS/MS#7 MRM of 1 Channel ES- 8.33 399 > 80 539 2.00e3 Area 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 Exygen Research Page 48 of 153 418-028:PAGE G-49 Exygen Study No.: 023-072 Figure 6. Chromatogram Representing Control Rat Plasma Sample Fortified with 10 ppb of PFHS (Exygen ID: 0202913 Spk A, Data Set: 0916028) 0202913 Spk A, 10 ppb 0916028-208 Sm (Mn, 2x3) 10 17-Sep-2002 23:14:44 LC/MSIMS#7 MRM of 1 Channel E~ 9.08 399>8( 937 8.25e! Area % Exygen Research Page 49 of 153 418-028:PAGE G-50 Exygen Study No.: 023-072 Figure 7. Chromatogram Representing Control Rat Serum Sample Fortified with 10 ppb of PFHS (Exygen ID: 0202987 Spk A, Data Set: 091902B) 0202987 Spk A, 10 ppb 0919028-2009 Sm (Mn, 2x3) 100 21-Sep-2002 09:29:14 LCIMSIMS#7 MRM of 1 Channel ES- 8.84 399>80 649 1.04e4 Area % Exygen Research Page 50 of 153 418-028:PAGE G-51 Exygen Study No.: 023-072 Figure 8. Chromatogram Representing Control Rat Liver Sample Fortified with 10 ppb of PFHS (Exygen ID: 0202877 Spk A, Data Set: 100202A) 0202877 Spk A, 10 ppb 100202A-209 Sm (Mn, 2x3) 100 03-0ct-2002 08:33:57 LC/MS/MS#7 MRM of 1 Channel ES- 8.30 399 >80 2125 1.08e4 Area 1.u......\~~-~~~-~-----~~:ii:...,::;::;:~~~<=4'-l~-~,,..,.,..,Time 1.00 2.00 3.oo 4.oo 5.oo a.oo 1.00 e.oo 9.oo 10.00 11.00 12.00 Exygen Research Page 51 ofl 53 418-028:PAGE G-52 Exygen Study No.: 023-072 Figure 9. Chromatogram Representing Rat Plasma Sample Analyzed for PFHS (Exygen ID: 0201816, Sponsor ID: 19176 GROUP I, Data Set: 091602B) 0201816 0916028-212 Sm (Mn, 2x3) 100 18-Sep2002 00:41:24 LC/MSIMS#7 MRM of 1 Channel ES- 9.07 399 >BO 2772 2.16e4 Area % ...............................................- ~-,.,._,.,.,..,..,.....,....,_,,..,.__,..,.,,.,_.......,..,..,....,...~.,.,...... . ...................,..,,;-.-..-.-.-;~--...........,.,.,....,,,Time 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00 Exygen Research Page 52 of 153 418-028:PAGE G-53 Exygen Study No.: 023-072 Figure 10. Chromatogram Representing Rat Serum Sample Analyzed for PFHS, DF=lO (Exygen ID: 0201863, Sponsor ID: 19079 GROUP II, Data Set: 091902BR) 0201863, DF10 091902BR-308 Sm (Mn, 2x3) 100 24-Sep-2002 02:50:15 LCIMSIMS#7 MRM of 1 Channel ES- 8.80 399 > 80 2488 3.91e4 Area % 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 Exygen Research Page 53 of 153 418-028:PAGE G-54 Exygen Study No.: 023-072 Figure 11. Chromatogram Representing Rat Liver Sample Analyzed for PFHS (Exygen ID: 0202050, Sponsor ID: 19018 GROUP II Male 1, Data Set: 100202A) 0202050 100202A-213 Sm (Mn, 2x3) 100 8.28 21849 03.0ct-2002 10:00:52 LCIMS/MS#7 MRM of 1 Channel ES399 > 80 1.19e5 Area % o Time 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00 Exygen Research Page 54 of 153 418-028:PAGE G-55 Exygen Study No.: 023-072 APPENDIX A Study Protocol 418-028 (Exygen Study No. 023-072) and Amendments, Deviation and Note to File Exygen Research Page 55 of 153 418-028:PAGE G-56 Exygen Study No.: 023-072 90S Sheehy O-. lldr. A Horsham, M 190U Telephone: (21 S) 443-8710 Telejbr. fZ IS} 44J-8SB1 ......r~w? ARGUS ~EARCH Charles River Laboratories Oiscovery and Development SelVices PROTOCOL 418-028 SPONSOR'S STUDY NUMBER: T-7706.1 STUDY TITLE: Oral (Gavage) Combined Repeated Dose Toxicity Study ofT-7706 with the Reproduction/Developmental Toxicity Screening Test PURPOSE: - TESTING FACILITY: The purpose ofthis study is to provide information on the possible health hazards that may result from repeated exposure of Crl:CD(SD)IGS BR VAF/Plus male and female rats to a test substance beginning before cohabitation, through mating and continuing for at least 42 days (male rats) or through parturition until day 21 oflactation (female rats). This repeated dose study incoiporates a reproduction/developmental toxicity screening test that can be used to provide initial information on possible effects on male and female reproductive performance (e.g., gonadal function. mating behavior, conception, development ofthe conceptus and parturition). The study also places emphasis on neurological effects as a specific endpoint and should identify the neurotoxic potential ofa test substance, which may warrant further in-depth investigation. Because ofthe selectivity ofthe endpoints and the short duration ofthe study, the screening test will not provide evidence for definitive claims of no reproduction/developmental effects. In particular, it offers o!tly limited means ofdetecting postnatal manifestations ofprenatal exposure or-effects that may be induced during postnatal exposure. Argus Research 90S Sheehy Drive, Building A Horsham, Pennsylvania 19044-1297 Telephone: (215) 443-8710 Telefax: (215) 443-8587 STUDY DIRECTOR: Raymond G. York, Ph.D., DABT Associate Director ofResearch Email: raymond.york@criver.com Address as cited above for Testing Facility SPONSOR: 3M Corporate Toxicology 3M Center, Building 220-2E-02 St. Paul, Minnesota 55144-1000 Exygen Research Page 56 of 153 418-028:PAGE G-57 Exygen Study No.: 023-072 Protocol 41&-028 Pagc2 STUDY MONITOR: John Butenhoff: Ph.D., DABT, Clll 3M Co:rporate Toxicology 3M Medical Department Telephone: (651) 733-1962 Telefax: (651) 733-1773 Email: jlbutenhoff@mmm.com REGULATORY CITATIONS: Organisation for Economic Co-operation and Development (1996). OECD Guidelinefor Testing ofChemicals. Section 4, No. 422: Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, adopted 22 March 1996. Organisation for Economic Co-operation and Development (1998). The Revised OECD Principles ofGood Laboratory Practices [C(97)186/Final]. U.S. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule. 21CFRPart58. Japanese Ministry ofHealth and Welfare (1997). Good Laboratory Practice Standard/or Safety Studies on Dmgs, MHW Ordinance Number 21, March 26, 1997. REGULATORY COMPLIANCE: This study will be conducted in compliance with the Good Laboratory Practice (GLP) regulations cited above. AU changes or revisions ofthis protocol shall be documented, signed by the Study Director and the Sponsor, dated and maintained with the protocol. The Testing Facility's Quality Assurance Unit (QAU) will audit the protocol, the raw data and the report, and will inspect critical phases of those portions ofthe study conducted at the Testing Facility in accordance with the Standard Operating Procedures ofthe Testing Facility. The final report will include a compliance statement signed by the Study Director that :he report accurately reflects the raw data obtained during the perfonnance ofthe study and that all applicable GLP regulations were followed in the conduct ofthe study. Should significant de\fi~ons from GLP regulations occur, each will be described in detail, together with how the deviation might affect the quality or integrity ofthe study. Should any portion ofthe study be conducted by a subcontractor or by the Sponsor, the Study Director will ensure that a qualified. Principal Investigator is identified by the facility conducting that portion ofthe study. The QAU for this facility will conduct critical phase inspections and ,,,.,.... audit respective results and reports for that study portion according to the SOPs ofthat facility. Such critical phase inspection reports and report audits will be submitted by the facility to the Principal Investigator and the Study Director. The dates ofthe inspections and report submissions will be incorporated into a QAU Statement generated. by that fllcility and provided Exygen Research Page 57 of 153 418-028:PAGE G-58 Exygen Study No.: 023-072 Protocol 4 J8-028 Pagc3 to the Testing Facility for inclusion in the final report. In addition, this facility will provide a statement of GLP compliance, as described above, signed by the Principal Investigator for inclusion in the final report. SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE: See ATTACHMENT I to the protocol. TEST SUBSTANCE AND VEMCLE: Identification: Test Substance: T-7706 [Perfluorohexanc Sulfonate Potassium Salt (PFHS)] Lot identification will be documented in the raw data. The Sponsor will provide to the Testing Facility documentation or certification ofthe identity, composition, method of synthesis, strength and activity/purity ofthe test substance. This documentation will be included in the final report. Vehicle: Aqueous O.S% carboxymethlycellulose (CMC) (medium viscosity) prepared using reverse osmosis membrane processed deionized water (R.O. deionized water). Lot identification and Supplier will be documented in the raw data. Neither the Sponsor nor the Study Director is aware of any potential contaminants likely to be present in the vehicle that would interfere with the results ofthis study. Therefore, no analyses other than those mentioned in this protocol will be conducted. Safety Precautions: Gloves, dust-mist/HEPA-filtered mask, appropriate eye protection and unifonn/lab coat to be wom during formulation preparation and dosage. The Material Safety Data Sheet (MSDS) is attached to the protocol (AITACHMENT 2). Storage: Bulle Test Substance: Bulk Vehicle Components: Prepared Test Substance and Vehicle Formulations: Room temperature. Room temperature. Refrigerated (2<>C to s<>C). - All test substance shipments should be addressed to the attention ofJulian Gulbinski, Manager of Formulation Laboratory, at the previously cited Testing Facility address and telephone number. Exygen Research Page 58of153 418-028:PAGE G-59 Exygen Study No.: 023-072 Protocol 418-028 Pagc4 Shipments should include infonnation concerning storage conditions and shipping cartons should be labeled appropriately. The recipient should be notified in advance ofshipment. FORMULATION: Frequency of Preparation: Formulations (suspensions) will be prepared weekly at the Testing Facility. Detailed preparation procedures will be attached to this protocol (ATIACHMENT 3). Adjustment for Purify: The test substance will be considered 100% pure for the pwpose ofdosage calculations. Testing Facility Reserve Samples: The Testing Facility will reserve a sample of each lot ofbulk test substance (approximately 1 g) and bulk vehicle components (approximately 1 g or S mL) used during the course ofthe study. Samples will be stored under the previously cited conditions. ANALYSES: Results ofrequired analyses will be provided to the Testing Facility for inclusion in the study report. Samples additional to those described below may be taken ifdeemed necessary during the course ofthe study. Additional analyses, ifrequired, will be documented by protocol amendment. Bulk Test Substance Sam.pli!g: A sample ofapproximately 1 g ofthe test substance will be taken on the last day oftreatment and sent (ambient conditions) to: Principal Investigator: Lisa Clemen 3M Environmental Technology and Safety Services Building 2-3E-09 St. Paul, Minnesota SS 133-3331 Telephone: (651) 778-SS68 Telefax: (651) 778-6176 Email: laclemen@mmm.com The recipient will be notified in advance of sample shipment. Exygen Research Page 59 of 153 418-028:PAGE G-60 Exygen Study No.: 023-072 ~ Analvses of Prepared Formulations: Protocol 418-028 PagcS Concentration and Homogeneity: Concentration and homogeneity ofthe prepared formulations will be verified during the course ofthis study. Quadruplicate samples (2 mL each) will be taken from the top, middle and bottom ofeach concentration on the first day ofpreparation. Two samples ftom each quadruplicate set will be shipped for analysis; the remaining samples will be retained at the Testing Facility as backup samples. Quadruplicate samples will be taken :from each concentration on the last day of preparation. Two samples ftom each quadruplicate set will be shipped for analysis; the remaining samples will be retained as backup samples. Backup samples will be stored under the previously cited conditions and discarded at the Testing Facility upon the request ofthe Sponsor. Stability ofthe prepared formulations will be documented during this study. Two sets of duplicate samples (2 mL each) from each concentration will be taken on the first day of preparation. One sample ofeach duplicate set will be shipped on the day ofpreparation. These samples will be analyzed at the following time points: as soon after preparation as possible and ten days after the first analysis. The remaining samples will be retained at the Testing Facility as backup samples. Backup samples will be stored under the previously cited conditions and discarded at the Testing Facility upon the request ofthe Sponsor. Shipping Instructions: Samples to be analyzed will be shipped (refrigerated) to: Principal Investigator: Lisa Clemen 3M Environment.al Technology and Safety Services Building 2-3E-09 St. Paul, Minnesota 55133-3331 Telephone: (651) 778-5568 Telefax: (651) 778-6176 Email: laclemen@mmm.com The recipient will be notified in advance of sample shipment. DISPOSITION: Prepared fonnulations will be discarded at the Testing Facility. All remaining bulk test substance will be returned to: Dan Hakes - 3M EHSR- Auto & Chem Grp 3M Center, Building 236-lB-10 St. Paul, Minnesota 55144-1000 Telephone: (651) 733-2392 Exygen Research Page 60of153 418-028:PAGE G-61 Exygen Study No.: 023-072 ,,_. TEST SYSTEM: Protocol 418-028 Page6 Species/Strain and Reason for Selection: The Crl:CD(SD)IGS BR VAF/Plus rat was selected as the Test System because: 1) it is one mammalian species accepted for use in toxicity studies and it has been widely used throughout industry; 2) this strain ofrat has been demonstrated to be sensitive to reproductive and developmental toxins; and 3) historical data and experience exist at the Testing FacilityC13> Number: Initial population acclimated: Population selected for main study: Population selected for toxicokinctic study: 100 male and 100 virgin female rats. 75 male and 75 virgin female rats (lS per sex per dosage group). 15 male and 15 female rats (three per sex per dosage group). Body Weight and Age: Male rats will be ordered to weigh from 215 g to 300 g each at receipt, at which time they will be expected to be at least 60 days ofage. Female rats will be ordered to weigh from 200 g to 225 g each at receipt, at which time they will be expected to be at )east 56 days of age. Actual body weights will be recorded the day after receipt and will be documented in the raw data. The weight ranges will be included in the final report. At study initiation, the weight variation of the rats will not exceed ::1:20% ofthe mean weight ofeach sex. .g: Both male and female rats will be evaluated. Source: Charles River Laboratories, Inc. The rats will be shipped in filtered cartons by air freight and/or truck from Charles River Laboratories, Inc., to the Testing Facility. Identification: Rats are permanently identified using Monel self-piercing ear tags (Gey Band and Tag Co., Inc., No. MSPT 20101). Male and female rats are assigned temporary numbers at receipt and given unique pennancnt identification numbers when assigned to the study before administration of the first dosage. Pups will not be individually identified during lactation; all parameters will - be evaluated in terms ofthe litter. Exygen Research Page 61 of153 418-028:PAGE G-62 Exygen Study No.: 023-072 ANIMAL HUSBANDRY: Protocol 418-028 Page? All cage sizes and housing conditions are in compliance with the Guidefor the Care and Use of Laboratory Anima1s<4>_ Argus Research is an AAALAC-accredited facility. Rousing: Fo generation rats will be individually housed in stainless steel wire-bottomed cages except during the cohabitation and postpartum periods. During cohabitation, each pair ofrats will be housed in the male rat's cage. Beginning no later than day 20 ofpresumed gestation, Fo generation female rats will be individually housed in nesting boxes. Bach dam and delivered litter will be housed in a common nesting box during the postpartum period. Nesting Material: Nesting material (bed-ocobs) will be provided. Bedding will be changed as often as necessary to keep the animals dry and clean. Analyses for possible contamination are conducted semi-annually and documented in the raw data. Room Air. Temperature and Humidity: The animal room is independently supplied with at least ten changes per hour of 100% fresh air that has been passed through 99.97% HEPA filters. Room temperature will be maintained at 64F to 79F (18C to 26C) and monitored constantly. Room humidity will also be monitored constantly and maintained at 30% to 70%. Light: An automatically controlled 12-hour light: 12-hour dark fluorescent light cycle will be maintained. Bach dark period will begjn at 1900 hours EST. The light cycle may be adjusted by the Study Director or designee ifdeemed necessary to accommodate scheduled laboratory activities. Any such adjustment will be documented in the raw data. ~: Rats will be given Certified Rodent Diet #5002 (PMI Nutrition International} available ad /ibitum from individual feeders. Feed will be removed the evening prior to the scheduled sacrifice. Water will be available ad libitum from individual bottles attached to the cages or from an automatic watering access system. All water will be ftom a local source and passed through a reverse osmosis membrane before use. Chlorine wilJ be added to the processed water as a bacteriostat; processed. water is expected to contain no more than 1.2 ppm chlorine at the time of analysis. Water is analyzed monthly for possible bacterial. contamination and twice annually for possible chemical contamination. Exygen Research Page 62 of 153 418-028:PAGE G-63 Exygen Study No.: 023-072 - Contaminants: Protocol 418-028 Pages Neither the Sponsor nor the Study Director is aware of any potential contaminants likely to be present in the certified diet, in the drinking water or in the nesting materials at levels that would interfere with the results ofthis study. Therefore, no analyses other than those routinely perform.ed by the feed supplier or those mentioned in this protocol will be conducted. DAY NUMBERING SYSTEM: Gestation day 0 is defined as the day spermatozoa are observed in a smear ofthe vaginal contents and/or a copulatory plug observed in situ. The day ofbirth is designated lactation day 0 (postpartum day 0) in the Health Effects Test Guidelines - Reproduction and Fertility Effects (Office ofPrevention, Pesticides and Toxic Substances 870.3800, August, 1998) and in the OECD Guideline for the Testing ofChemicals Combined Repeated Dose Toxicity Study with the Rc;production/Developmental Toxicity Screening Test (Section 4, No. 422, 22 March 1966). This same day is designated day 1 postpartum (day 1 oflactation) in the Standard Operating Procedures ofthe Testing Facility. Throughout this protocol, the day ofbirth will be designated day 1 postpartum (day 1 of lactation) and all subsequent ages of the Fl generation rats and days ofthe lactation period will be determined and cited accordingly. RANDOMIZATION AND COBABITATION: Upon arrival, rats will be assigned to individual housing on the basis ofcomputer-generated random units. During an acclimation period ofat least five days, male and female rats will be selected for study on the basis ofphysical appearance and body weights recorded during acclimation. The rats will be assigned to dosage groups based on computer-generated (weightordered) randomization procedures. Within each dosage group, consecutive order will be used to assign rats to cohabitation, one male rat per female rat. The cohabitation period will consist ofa maximum of 14 days. Female rats of with spermatozoa observed in a smear ofthe vaginal contents and/or a copulatory plug observed tn situ will be considered to be at day 0 presumed gestation and assigned to individual housing. Female rats not mated within the .first seven days ofcohabitation will be assigned alternate male rats that have mated (same dosage group) and will remain in cohabitation for a maximum ofseven additional days. Day 1 oflactation (postpartum) is de.fined as the day ofbirth and is also the first day on which all pups in a litter are individually weighed (pup body weights will be recorded after all pups in a litter are delivered and groomed by the dam). Litters will not be culled during the lactation period, because random selection ofpups for - culling could result in potential biases in pup viabilities and body weight gains over this period. Exygen Research Page 63 of 153 418-028:PAGE G-64 Exygen Study No.: 023-072. Protocol 418-028 Page9 Within each dosage group, consecutive order will be used to assign the first 10 male and the first 10 female rats to a tbnctional observational battery (FOB) and motor activity assessment, blood sample collection for clinical chemisb:y and hematology (CC&H), and histological evaluations. On day 22 postpartum, a table ofrandom units will be used to select five male and five female pups per litter for blood sample and liver collection; these pups will only be selected from the ten dams selected for FOB, motor activity, CC&H and histological evaluation. ADMINISTRATION: Route aud Reason for Choice: The oral (gavage) route was selected for use because: 1) in comparison with the dietary route, the exact dosage can be accurately administered; and 2) it is one ofthe possible routes for environmental exposure. Method and Frequency: Dosages will be adjusted daily for body weight changes and given at approximately the same time each day. The first day of dosage is designated as day 1 of study. Male rats will be given the test substance once daily beginning 14 days before a cohabitation period that consists ofa maximum 14 days. Dosage will continue through the day before sacrifice, after completion ofthe cohabitation period, after a minimum of42 days of administration. Female rats will be given the test substance once daily beginning 14 days before a cohabitation period that consists of a maximum of 14 days. Dosage will continue through the day before scheduled sacrifice (day 21 oflactation). Rationale for Dosage Selection: Dosages were selected by the Sponsor based on previous studies conducted with the test substance, taking into accowit possible differences in sensitivity between pregnant and nonpregnant rats. The highest dosage will be expected to cause toxic effects but not mortality or obvious suffering. The descending sequence ofthe lower dosage levels will be selected for the pmpose ofdemonstrating any dosage-related response, with no adverse effects expected at the lowest level. Exygen Research Page 64 of 153 418-028:PAGE G-65 Exygen Study No.: 023-072 .- Dosage Levels. Concentrations and Volumes: Protocol 418-028 Page 10 Doaae Orouo Number of Rau Per Sn Douse (nurJkir/dav) Conc:entnatioa (nlR/mLl Dasage Volume (mlJbl Anm Blleh NUlllbcr I 15+3' 0 0 10 B-418-028-A(Day.Mondl.Year) u 15+3' O.l 0.03 JO B-418--028-B(Day.Mantll.Ycar) ID lS+J' 1 0.1 10 B-418-028-C(Day.Manlb.Year) IV 15+3' 3 0.3 v 15+3' 10 I 10 B-418-028-D(D&y.Monlh. Year) 10 B-418-028-E(Dly.Mont.'"-..Yar) a. The tat substance will be llOlllidered 100% pure for 1he puq11111e ofdolage calculaliDlll. b. 1hree ldditional rats per sex per dotage BR1up will be ulipal ID toxicalcinetlc 1111q1le coDection. TESTS, ANALYSES AND MEASUREMENTS - Fo GENERATION: Viability - Male and Female Rats: All Periods: At least twice daily. Clinical Observations and/or General Appearance - Male and Female Rats: Acclimation Period: Weekly. Dosage Period: Daily before dosage. On the fust day of dosag~ postdosage observations will be recorded at approximately hourly intervals for the first four hoUTS and at the end ofthe normal working day. Subsequent postdosage observations will be recorded at intervals deemed appropriate by the Study Director or designcc after dctcnnination ofpeak toxicologic effects. Matern.al Behavior: Days l, S, 8, IS and 22 postpartum. Observed abnonnal behavior recorded daily. Clinical observations may be recorded more frequently than cited above, if deemed appropriate by the Study Director and/or Study Monitor. Data collected for rats assigned to toxicokinetic sample collection will not be summarized or analyzed statistically. Detailed Clinical Observations - Male and Female Rats: Once before the first dosage and at least once weekly thereafter, detailed clinical observations will be conducted for all male and fem.ale rats. These observations will be made outside the cage in a standard arena at the same time each day ofconduct. Effort will be made to ensure that variations in the test conditions are minimal and that observations are conducted by observers - unaware of treatment groups. Signs noted should include, but not be limited to: changes in skin, fur, eyes, mucous membranes, occummce ofsecretions and excretions and autonomic activity (e.g., lacrimation, piloerection, pupil size, unusual respiratory pattern). Changes in gait. posture Exygen Research Page 65 of 153 418-028:PAGE G-66 Exygen Study No.: 023-072 Protocol 418-028 -- Page 11 and response to handling as well as the presence ofclonic or tonic movements, sterotypic behavior (e.g., excessive grooming, repetitive circling), difficult or prolonged parturition or bizarre behavior (e.g., self-mutilation, walking backwards) should also be recorded. Bodv Weights - Male and Female Rats: Acclimation Period: Weekly. Dosage Period: Daily. Sacrifice: Tenninal weight. Feed Consumption Values - Male Rats (recorded and tabulated): Dosage Period: Weekly. Feed Consumption Values - Female Rats (recorded and tabulated): Dosage Period: Weekly to cohabitation. Gestation Period: Days 0, 7, 10, 12, 15, 18, 20 and25 (ifnecessary). Postpartum Period: Days 1, 5, 8 and 15. Feed consumption not tabulated after day 1S postpartum, when it is expected that pups will begin to consume maternal feed. Feed ConsuJDDtion Values - Male and Female Rats: Feed consumption values may be recorded more frequently than cited above ifit is necessary to replenish the feed. During cohabitation, when two rats occupy the same cage with one feed jar, replenishment of the feed jars will be documented. Individual values will not be recorded or tabulated. Toxlcoldnetic Sample Collection: On day 14 and 42 of study, blood samples (approximately 1 mL each) will be collected :from each male rat assigned to the toxicokinetic sample collection portion ofthe study (3 pet group). On day 14 ofstudy and day 21 ofpresumed gestation, blood samples (approximately 1 mL each) will be collected from each female rat assigned to the toxicokinetic sample collection portion of the study (3 per group). Samples will be collected prior to dosage on day 14 of study. The time - ofeach blood collection will be recorded in the raw data. Exygen Research Page 66of153 418-028:PAGE G-67 Exygen Study No.: 023-072 Protocol 418-028 Page 12 Blood will be collected from the orbital sinus. Ifnecessary, blood may be collected from an alternate site; ifso, the alternate site will be documented. in the raw data.) The samples will be transferred into EDTA-coated (pwple top) tubes and spwi in a centrifuge. The resulting scrum will be transferred into polypropylene tubes labeled with the protocol number, Sponsor study number, animal number, sex, group number, dosage level, day ofstudy, collection interval. date of collection, species, generation and storage conditions. All samples will be immediately frozen on dry ice and maintained frozen (S-70C) until shipment for analysis. After the last blood sample collection, rats will be sacrificed and samples ofthe liver will be collected for analysis. Shipping Instructions: Samples to be analyzed will be shipped on dry ice to: Principal Investigator: Lisa Clemen 3M Bnviroomental Technology and Safety Services Building 2-3E-09 St. Paul, Minnesota 55133-3331 Telephone: (651) 778-5568 Telefax: (651) 778-6176 Email: laclemen@mmm.com The recipient will be notified in advance of sample shipment. Estrous Cycling and Mating: Estrous cycling will be evaluated by examination ofvaginal cytology beginning with the day after the first administration and then until spermatozoa arc observed in a smear ofthe vaginal contents and/or a copulatory plug is observed in situ during the cohabitation period Caesarean-Sectioning Toxicokinetic Studv: On day 21 of presumed gestation, blood and liver samples will be collected from all female rats designated for toxicokinetic sample collection. Blood samples will be collected from the rats as previously described. After sacrifice, the liver of each rat will be excised and the liver weight will be recorded. The median liver lobe will be frozen and stored (~20C) until shipment for possible analysis. The fetuses wiJl be removed from the uterus and blood samples will be collected from each fetus via deoapitation. Blood will be placed into tubes, pooled per litter, allowed to clot and spun in a centrifuge; the resulting serum will be transferred into labeled polypropylene tubes. All samples wi11 be immediately frozen on dry ice and maintained frozen ($-70C) until shipment for analysis. Exygen Research Page 67of153 418-028:PAGE G-68 Exygen Study No.: 023-072 Protocol 418-028 - Page 13 The liver .from each fetus will be collected, pooled per litter and placed into labeled tubes. The samples will be .frozen and stored (~20C) until shipment for analysis. Samples will be shipped on dry ice to Lisa Clemen at the previously cited address. Natural Deliverv: Female rats will be evaluated for: Adverse Clinical Signs Obse.rved During Parturition. Duration of Gestation (day 0 ofpresumed gestation to the time the first pup is observed). Litter Size (defined as all pups delivered). Pup Viability at Birth. Functional Observational Battery: On one occasion during the course ofthe study, a functional obsCIVational battery (FOBf5-9>will be conducted on 10 male and 10 female rats per group. For male rats, this assessment will be conducted shortly before scheduled sacrifice, but prior to blood sample collection for hematology and clinical chemistry evaluations. Female rats should be tested during the lactation period, shortly before scheduled sacrifice. The FOB, to be conducted by an observer unaware ofthe group assignment ofthe rat, will assess the following parameters: 1. Lacrimation, salivation, palpebral closure, prominence ofthe eye, pupillary reaction to light, piloerection, respiration, and urination and defecation (autonomic functions). 2. Sensorimotor responses to visual, auditory, tactile and painful stimuli (reactivity and sensitivity). 3. Reactions to handling and behavior in the open field (excitability). 4. Gait pattern in the open field, severity of gait abnormalities, air righting reaction, and landing foot splay (gait and sensorimotor coordination). s. Forelimb and hindlimb grip strength. 6. Abnormal clinical signs including but not limited to conwlsions. tremors and other unusual behavior, hypotonia or hypertonia, emaciation, dehydration, unkempt appearance and deposits around the eyes, nose or mouth. Exygen Research Page 68 of 153 418-028:PAGE G-69 Exygen Study No.: 023-072 Protocol 418..o28 Pago 14 ,-... Evidence ofthe ability ofthis battery to detect the effects ofpositive control substances will be provided. (Testing Facility Positive Control Data). Data will also be provided. to document interobserver reliability ifmore than one observer is involved in the testing. Motor Activity Test: Motor activity will be evaluated on 10 male and 10 female rats per group once during the course ofthe study. This assessment will be conducted shortly before scheduled sacrifice, but prior to blood sample collection. The movements ofeach rat will be monitored by a passive inftared sensor mounted outside a stainless-steel wire-bottomed cage (40.6 x 25.4 x 17.8 cm). Each test session will be l.S hours in duration with the number ofmovements and time spent in movement tabulated. at each five-minute interval. The apparatus will monitor a rack ofup to 32 cages and sensors during each session, with each rat tested in the same location on the rack across test sessions. Groups will be counterbalanced across testing sessions and cages. Data will be provided. to demonstrate that the test system is capable ofdetecting increases in activity produced. by positive control substances (resting Facility Positive Control Data). HEMATOLOGY AND CLINICAL CHEMISTRY: At scheduled sacrifice, the rats (fasted) assigned to hematology and clinical chcmis1ry (H&CC) sample collection will be exsanguinated from the inferior vena cava following sacrifice by carbon dioxide asphyxiation. Approximately S mL ofblood will be collected and processed as described below. Detenninations additional to those described below may be conducted Ifthe known properties ofthe test substance may, or are suspected to, affect related metabolic profiles (e.g., calcium, phosphate, fasting triglycerides and fasting glucose, specific honnones, and cholinesterase). Hematology: Approximately 1 mL ofblood will be collected into EDTA-coated tubes and maintained on wet ice or refrigerated until shipment for analysis ofthe following hematologic parameters: Erythrocyte Count (RBC) Hcmatocrit (HCT) Hemoglobin (HGB) Mean Corpuscular Hemoglobin (MCH) Mean Corpuscular Hemoglobin Concentration (MCHC) Mean Corpuscular Volume (MCV) Leukocyte Count, Total (WBC) Leukocyte Count, Differential Platelet Count (PLAT) Mean Platelet Volume (MPV) Cell Morphology Two blood smear slides will be prepared at the Testing Facility for each sample for measurements ofdifferential leukocyte count. All samples (on wet ice) and slides (ambient conditions) will be shipped to Redfield Laboratories at the following address. Approximately 1.8 mL ofblood will be added to a tube containing 0.2 mL ofsodium citrate (0.129 M). The contents will be mixed and maintained on wet ice until the tubes are centrifuged Exygen Research Page 69 of 153 418-028:PAGE G-70 Exygen Study No.: 023-072 - Protocol 418-028 Page 15 (within 30 minutes ofthe collection time). The resulting plasma will be transfem:d 2.0 mL polypropylene tubes labeled with study number, Sponsor's study number, rat number, dosage level, day of study. collection interval, date ofcollection, species, generation and storage. All samples will be frozen on dry ice and maintained frozen (~70C) until shipment on dry ice by overnight courier for measurement ofprothrombin time (PT) and activated partial thromboplastin time (APTT). Clinical Chemistrv: Approximately 2 mL ofblood will be collected into serum separator tubes and centrifuged. The resulting sera samples will he immediately frozen on dry ice and maintained frozen ($-70C) until shipment for analysis ofthe following parameters: Total Protein (TP) Triglycerides (TRI) Albumin(A) Globulin (G) Albumin/Globulin Ratio (A/G) Glucose (GLU) Cholesterol (CHOL) Total Bilirubin (TBil.I) Urea Nitrogen (BUN) Creatinine (CREAT) Creatinine Kinase (CK) Alanine Aminotransferase (ALT) Aspartatc Aminotransferase (AST) Alkaline Phosphatase (ALK) Calcium (CA) Phosphorus (PHOS) Sodium(NA) Potassium (K) Chloride (CL) Samples will be shipped (on dry ice) to Redfield Laboratories at the following address. Sbipoing Instructions: Samples will be shipped to arrive on Monday through Friday according to the conditions described above to: Principal Investigator: Ms. Phyllis Powell Redfield Laboratories A Division of CRL-DDS 100 East Boone Street P.O.Box308 Redfield, Arkansas 72132 Telephone: (501) 397-2540 Telefax: (501) 397-2002 The recipient will be notified in advance of sample shipment. URINALYSIS: Urinalysis will not be conducted unless indicated based on expected or observed. toxicity ofthe test substance. Exygen Research Page 70of153 418-028:PAGE G-71 Exygen Study No.: 023-072 Protoc:iol 418-028 Page 16 METHOD OF SACRIFICE: Fo generation rats will be sacrificed by carbon dioxide asphyxiation. GROSS NECROPSY AND IDSTOPATIIOLOGY - Fo GENERATION RATS; Scheduled Sacrifice - To:licokigetic Studv: Scheduled sacrifice ofmale rats will be conducted on day 42 ofstudy. Scheduled sacrifice of female rats will be conducted on day 21 ofpresumed gestation. Blood samples will be collected from the rats as previously described. After sacrifice, the liver ofeach rat will be excised and the liver weight will be recorded. The median liver lobe will be frozen and stored (5-20C) until shipment for analysis. Fetal samples will be collected as previously described. Carcasses will be discarded without further evaluation. Samples will be shipped on dry ice to Lisa Clemen at the previously cited address. Scheduled Sacrifice - Main Study: Scheduled sacrifice ofmale rats wilJ be conducted on the day following the last dosage administration, after a minimum of42 days ofdosage. Scheduled sacrifice of female rats will be conducted on day 22 oflactation. Gross necropsy ofall male and female rats will include an initial physical examination of external sUJfaces and all orifices, as well as the cranial, thoracic and abdominal cavities and their contents. Special attention will be paid to the organs ofthe reproductive system. The number of implantation sites and cotpora lutea will be recorded. Male and female rats will be examined for gross lesions. Gross lesions will be retained in neutral buffered 10% formalin and examined histologically. Tissue trimming and histopathology will be performed under the supervision ofor by a Board-Certified Veterinary Pathologist. The ovaries and the uterus with cervix ofeach female rat will be weighed, and ovaries, uterus, vagina and a mammary gland will be retained in neutral buffered 10% formalin. Uteri of apparently nonpregnant rats will be examined after being pressed between glass plates to confirm the absence of implantation sites, and retained in neutral buffered 10% formalin. - Exygen Research Page 71 of 153 418-028:PAGE G-72 Exygen Study No.: 023-072 Spemi Evaluations ofMale Rats: Protocol 418-028 Page 17 To assess the potential toxicity of the test article on the male reproductive system, the endpoints listed below will be evaluated from the first 10 male rats in each dosage group. Organ Weights: The fo1lowing organs will be individually weighed: right testis, left testis, le.ft epididymis {whole and cauda), right epididymis, seminal vesicles {with and without fluid) and prostate. Spenn Evaluations: Spenn concentration and motility will be evaluated using computcrassisted spenn analysis {CASA). Motility will be evaluated by the Hamilton Thome IVOS by collection ofa sample from the left vas deferens. A homogenate will be prepared from the left cauda epid.idymis for evaluation by the Hamilton Thome IVOS to determine sperm concentration (spenn per gram oftissue weight). The remaining portion ofthe left cauda epididymis will be used to manually evaluate sperm moiphology. Sperm mo1phology evaluations will include the following: l) determination ofthe percentage ofnonnal sperm in a sample ofat least 200; and 2) qualitative evaluation of abnonnal sperm, including such categories as abnormal head, abnormal tail, and abnormal head and tail. See ATIACHMENT 4 for additional tissues to be weighed and retained from the ten rats per sex per group assigned to histological sample collection and evaluation. All other tissues will be discarded. Scheduled Sacrifice of Female Rats that Do Not Deliver Litters: Rats that do not deliver a litter will be sacrificed on day 2S ofpresumed gestation. Gross necropsy, examination and tissue retention will be conducted as described previously for rats at scheduled sacrifice. Dams with No Surviving Pups: Dams with no surviving pups will be sacrificed after the last pup is found dead, missing or presumed cannibalized. Gross necropsy. examination and tissue retention will be conducted as described above for rats at scheduled sacrifice. Exygen Research Page 72 of 153 418-028:PAGE G-73 Exygen Study No.: 023-072 Protocol 418-028 Page 18 - Rats Found Dead or Moribund: Rats that die or are sacrificed because ofmoribund condition, abortion or premature deiivery will be examined for the cause ofdeath or moribund condition on the day the observation is made. The rats will be examined for gross lesions. Testes and epiclidymides ofmale rats will be excised and paired organ weights will be recorded. The epididymides will be retained in neutral buffered lOOAt formalin. The testes will be fixed in Bouin's solution for 48 to 96 hours and then retained in neutral buffered 10% fonnalin. Pregnancy status and uterine contents of female rats will be recorded. Aborted fetuses and/or delivered pups will be examined to the extent possible. Uteri of apparently nonpregnant rats will be examined. after being pressed between glass plates to confirm the absence ofimplantation sites. Ovaries and uteri will be retained in neutral buffered 100/u formalin. TESTS. ANALYSES AND MEASUREMENTS - Fl GENERATION: Viability: Preweaning Period: Litters will be observed for dead pups at least twice daily. The pups in each litter will be counted once daily. Clinical Observations and/or General Appearance: Preweaning Period: Once daily. Pups will be observed ifthey are warm and clean, for evidence of a nest and ifpups are grouped together and nursing or have milk in stomach. Each pup will be examined for general shape of the head, trunk, limbs, tail and presence of anus. Clinical observations may be recorded more frequently than cited above, ifdeemed appropriate by the Study Director and/or the Study Monitor. Body Weights: Preweaning Period: Days 1 (birth), 8, 1S and 22 postpartum. Sacrifice: Terminal weight Feed Consumption Values (recorded and tabulated): Preweaning Period: Not recorded. METHOD OF SACRIFICE - Fl GENERATION PUPS: Fl generation pups will be sacrificed by carbon dioxide asphyxiation. Exygen Research Page 73 of 153 418~028:PAGE G-74 Exygen Study No.: 023-072 - NECROPSY - Fl GENERATION: Protocol 418-028 Page 19 Gross lesions will be retained in neutral buffered 10% fonnalin for possible future evaluation. Unless specifically cited below, all other tissues will be discarded. Pups Found Dead OD Dav 1 Postpartum: Pups that die before examination of the litter for pup viability will be evaluated for vital status at birth. The lungs will be removed and immersed in water. Pups with lungs that sink will be identified as stillborn; pups with lungs that float will be identified as livebom, and to have died shortly after birth. Pups with gross lesions will be preserved in Bouin's solution for pcssible future evaluation. Pups Found Dead or Moribund oD Davs 2 to 4 Postpartum: Pups found dead or sacrificed because ofmoribundity will be examined for gross lesions and for the cause of death or the moribund condition. Pups with gross lesions will be preserved in Bouin's solution for possible future evaluation. Scheduled Sacrifice: On day 22 postpartu~ pups will be will be sacrificed and examined for gross lesions; gross lesions will be preserved in neutral buffered 10% formalin. Necropsy will include a single crosssection ofthe head at the level ofthe frontal-parietal suture and examination ofthe crosssectioned brain for apparent hydrocephaly. Blood samples will be collected from each selected pup (5 per sex per litter from the 10 females per group selected for FOB and motor activity assessment, blood sample collection for H&CC, and histological evaluations) from the vena cava. The blood will be placed into tubes, pooled per litter, allowed to clot and spun in a centrifuge; the resulting serum will be transferred into labeled polypropylene tubes. All samples will be immediately frozen on dry ice and maintained frozen (~70C) until shipment for analysis. The liver from each selected pup will be collected excised and the organ weight recorded. The median lobe will be frozen and stored (~-20C) until shipment for possible analysis. Frozen samples will be shipped to Lisa Clemen at the previously cited address. The remaining portion ofeach liver will be retained in neutral buffered 10% formalin for possible histological evaluation. The livers will be processed and evaluated histologically as described for the Fo generation rats in Histological Evaluation in ATIACHMENT 4. Exygen Research Page 74of153 418-028:PAGE G-75 Exygen Study No.: 023-072 - PROPOSED STATISTICAL TESTSC9-l6): The following schematic represents statistical analyses ofthe data. Protocol 418-028 Pagc20 I. Parametric A. Bara.tra Tat c Type of Test II. Nonparametricb A. Kruaklll-Vllillk Test l!Mlolllll'-*"">nl Significant -~.001 NotSIQnllicant Slgnlllcanl at p~0.05 Not Significant Signlllcant t ~0.05 Dunnell' Tat NotSlgnftlc:llnt Ounn'aTe.t a. Fillher'a Exact Te.ton PropcxUon ofTlea ~15,. . . lltlr/_,._. B. Analyal8 OfVaflanc:e With Repeated Measures SIQnificant at P,50.05 NotSillflibnt (Dauge} DunnetrTest (Dosage x Bicek lnteradion) OM-way AHOVA for 8111111 bloak Slgniftcant -~.05 NolSlgnlficllnl DunnetraTeat Ill. Test for Proportion pata Variance Test for Homogeneity of the Binomial Dlstribullon a. Statistically significant probabilities are reported as either p S 0.05 or p S 0.01. b. Proportion data are not included in this category. c. Test for homogeneity ofvariance. Exygen Research Page 75of153 418-028:PAGE G-76 Exygen Study No.: 023-072 Protocol 418-028 - Pagc21 Test items in the FOB using interval scales, such as the grip-strength tests and the landing foot splay test, as well as body weight data and feed consumption values will be analyzed as described under the Parametric heading ofthe schematic. Bartlett's Test ofHomogeneity of Variances") will be used to estimate the probability that the groups bad different variances. A nonsigniticant result (p>0.001) will indicate that an assumption ofhomogeneity ofvariance is not inappropriate, and the data will be compared using the Analysis ofVariance Test<10>. Ifthat test is significant (pS).OS), the groups exposed to the test article/substance will be compared with the control group using Dunnett's Te.sr11'. IfBartlett's Test is significant (pS).001), the Analysis ofVariance Test is not appropriate, and the data will be analyzed as described under the Nonoarametric heading ofthe schematic. When 75% or fewer ofthe scores in all the groups are tied, the Kruskal-Wallis TestU2>will be used to analyze the data, and in the event ofa significant resuJt (p;S>.05), Dunn's Test{IJ) will be used to compare the groups exposed to the test article/substance with the control group. When more than 75% ofthe scores in any group are tied, Fisher's Exact Test<14>will be used to compare the proportion ofties in the groups. Data from the motor activity test, with repeated measurements within a session, will be analyzed using an Analysis ofVariance with Repeated Measures<1., as described under that heading in the schematic. A significant effect (pS>.OS) in that test can appear as effect of Concentration (a difference between groups in the total ac:ross all measurements in a session) or as an interaction between Concentration and Block (a difference between groups at specific measurement periods). Ifthe Concentration effect is significant, the totals for the control group and the groups given the test article/substance will be compared using Dwmett's Test. Ifthe Concentration x Block interaction is significant, an Analysis ofVariance Test will be used to evaluate the data at each measurement period, and a significant result (p;S>.OS) will be followed by a comparison of the groups using Dunnett's Test. Test items in the FOB having graded or count scores will be analyzed using the procedures described under the Nonparametric heading ofthe schematic. Clinical observation incidence data, as weJl as the descriptive and quanta! data from the FOB, will be analyzed as contingency tables using the Variance Test for Homogeneity ofthe Binomial Distribution<t6>. Alternate or additional statistical evaluations may be perfonned if deemed necessary or appropriate. - Exygen Research Page 76of153 418-028:PAGE G-77 Exygen Study No.: 023-072 Protocol 418-028 .- Page22 DATA ACQUISmON. VERIFICATION AND STORAGE: Data generated during the course ofthis study will be recorded either by hand or using the Argus Automated Data Collection and Management System, the Vivarium Temperature and Relative Humidity Monitoring System, the Coulbourn Instruments Passive l'IJ{raredMotor Activity System, the Coulbourn Instruments Auditory Startle System, the Coulbourn Instruments Spatial Delayed Alternation System. and/or the passive avoidance software. All data will be tabulated, swnmarized and/or statistically analyzed using the Argus AutomatedData Collection and Management System, the Vivarium Temperature and Relative Humidity Monitoring System, Microsoft Excel [part of Microsoft Office 97 (version SR-2)] and/or The &4.S System (version 6.12). Records will be reviewed by the Study Director and/or appropriate management penonnel within 21 days after generati9n. All original records will be stored in the archives ofthe Testing. Facility. All original data will be bound and indexed. A copy ofall raw data will be supplied to the Sponsor upon request. Preserved tissues will be stored at the Testing Facility at no charge for one year after mailing ofthe draft final report, after which time the Sponsor will be contacted to determine the disposition ofthese materials. - KEY PERSONNEL: Executive Director ofResearch: Mildred S. Christian, Ph.D., Fellow, ATS Director ofResearch: Alan M. Hobennan, Ph.D., DABT Associate Director ofResearch and Study Director: Raymond G. Yo~ Ph.D., DABT Director ofOperations and Compliance: Barbara J. Patterson, B.A. Director of Laboratory Operations: John F. Barnett, B.s. Director ofStudy Management: Valerie A. Sharper, M.S. Manager ofAnimal Operations: Dena C. Lebo, V.M.D. Chairperson, Institutional Animal Care and Use Committee: Douglas B. Learn, Ph.D. Consultant, Veterinary Pathology: W. Ray Brown, D.V.M., Ph.D., ACVP Exygen Research Page 77 of 153 418-028:PAGE G-78 Exygen Study No.: 023-072 RECORDS TO BE MAINTAINED: Protocol 418-028 Page23 Protocol and Amendments. Test Substance, Vehicle and/or Reagent Receipt, Preparation and Use. Animal Acquisition. Randomization Schedules. Mating History. Treatment (ifprescribed by StaffVeterinarian). General Comments. Clinical Observations and/or General Appearance. Body Weights. Feed Consumption Values. Natural Delivery Observations. FOB and Motor Activity Observations. Blood Sample Collection, Processing and Shipment Gross Necropsy ObservB:tions. Organ Weights. Photographs (ifrequired). Study Maintenance (room and environmental records}. Feed and Water Analyses. Packing and/or Shipment Lists. .- FINAL REPORT: The Study Director will provide periodic updates of study progress to the Sponsor. Draft summary tables ofunaudited computer-recorded data may accompany these updates. Statistical analyses will not be perfonned on these interim data. A comprehensive draft final report will be prepared on completion ofthe study and will be finalized following consultation with the Sponsor. The report will include the following: Summary and Conclusion. Experimental Design and Method. Evaluation ofTest Results. Appendices: Figures, Summary and Individual Tables Summarizing the Above Data. Protocol and Associated. Amendments and Deviations, Study Director's OLP Compliance Statement, Reports ofSupporting Data (if appropriate} and QAU Statement. The Sponsor will receive one copy ofthe draft report and two copies ofthe final report. Data will be hand- and/or computer-recorded. Records will be reviewed by the Study Director and/or appropriate management personnel within 21 days after generation. All original records will be stored in the archives ofthe Testing Facility. All original data will be bound and indexed. A copy ofall raw data will be supplied to the Sponsor upon request. Preserved tissues will be stored at the Testing Facility at no charge for one year after mailing ofthe draft :final - report, after which time the Sponsor will be contacted to determine the disposition ofthese materials. Exygen Research Page 78of153 418-028:PAGE G-79 Exygen Study No.: 023-072 Protocol 418-028 Page24 - INSTITUTIONAL ANIMAL CARE AND USE COMMl'ITEE STATEMENT: The procedures described in this protocol have been reviewed by the Testing Facility's Institutional Animal Care and Use Committee. All procedures described in this protocol that involve study animals will be conducted in a manner to avoid or minimize discomfort, distress or pain to the animals. The Sponsor's signature below docwnents the fact that infomiation concerning the necessity for conducting this study and the fact that this is not an unnecessarily duplicative study may be obtained from the Sponsor. No alternative (in vitro) procedures were available for meeting the stated purposes of the study. REFERENCES: 1. Christian, M.S. and Voytek, P.B. (1982). In Vivo Reproductive and Mutagenicily Tests. Environmental Protection Agency, Washington, D.C. National Technical Jnfonnation Service, U.S. Department of~otnmerce, Springfield, VA 22161. 2. Christian, M.S. (1984). Reproductive toxicity and teratology evaluations of naltrexone (Proceedings ofNal1rexone Symposium, New York Academy ofSciences, November 7, 1983), 1. Clin. Psychiat. 45(9):7-10. 3. Lang, P.L. (1988). Embryo and Fetal Developmental Toxicity (Teratology) Control Data in the Charles River Crl:CDBR Rat. Charles River Laboratories, Inc., Wilmington, MA 01887-0630. (Data base provided by Argus Research Laboratories, Inc.) 4. Institute ofLaboratory Animal Resources (1996). Guidefor the Care and Use of Laboratory Animals. National Academy Press, Washington, D.C. 5. Haggerty, G.C. (1989). Development ofTier I neurobeha,.;oral testing capabilities for incorporation into pivotal rodent safety assessment studies. J. Amer. Col. Toxicol. 8:5370. 6. Irwin, S. (1968). Comprehensive observational assessment: la. A systemic quantitative procedure for assessing the behavioral and physiologic state ofthe mouse. Psychopharmacologia (Berlin) 13:222-257. 7. Moser, V.C. (1989). Screening approaches to neurotoxicity: A functional observational battery. J. Amer. Col. Toxicol. 8:85-94. 8. O'Donoghue, J.L. (1989). Screening for neurotoxicity using a neurologically based examination and neuropathology. J. Amer. Col. Toxicol. 8:97-116. 9. Sokal. R.R. and Rohlf, F.J. (1969). Bartlett's test ~fhomogeneity of variances. Biometry, W.H. Freeman and Co., San Francisco, pp. 370-371. Exygen Research Page 79 of 153 418-028:PAGE G-80 Exygen Study No.: 023-072 Protocol 418-028 - Page2S 10. Snedecor, G.W. and Cochran, W.G. (1967). Analysis ofVariancc. Statistical Methods, 6th Edition, Iowa State University Press, Ames, pp. 258-275. 11. Dunnett, C.W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Amer. Stat. Assoc. 50:1096-1121. 12. Sokal, R.R. and Rohlf, F.J. (1969). Kruskal-Wallis Test. Biometry, W.H. Freeman and Co., San Francisco, pp. 388-389. 13. Dwm, O.J. (1964). Multiple comparisons using rank sums. Tcchnometrics 6(3):241-252. 14. Siegel, S. (1956). Nonparametric Statistics/or the Behavioral Sciences, McGraw-Hill, New York, pp. 96-104. IS. SAS Institute. Inc. (1988). Repeated measures aualysis ofvariance. SA.S/STATTM User's Guide, Release 6~03 Edition, Cary, NC, pp. 602-609. 16. Snedecor, G. W. and Cochran, W.G. (1967). Variance test for homogeneity ofthe binomial distribution. Statistical Methods, 6th Edition, Iowa State University Press, Ames, pp. 240-241. Exygen Research Page 80 of 153 418-028:PAGE G-81 Exygen Study No.: 023-072 PROTOCOL APPROVAL: FOR THE TESTING FACll..ITY Alan M. Haberman, PhD DABT Director of Research Protocol 418-028 Page26 ___ ______, ' Date . ,, (' ~ ,; i.:.. ;- , -:; ' J_,t..J_/ ~-(-'. -""""'-----~------ -k- Theresa H. Woodard, D. l - 1, Member, Institutional Animal Care and Use Committee Date. _i~_f~!c..r:__;.!__~ .;l. - - Date FOR THE SPONSOR John Butcnhoft: PhD., DABT, Cill Date Study Monitor and Sponsor's Representative Exygen Research Page 81 of 153 418-028:PAGE G-82 Exygen Study No.: 023-072 - ATTACHMENT 1 SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE Exygen Research Page 82 of 153 418-028:PAGE G-83 Exygen Study No.: 023-072 AITACHMENT I - STUDY SCHEMATIC Protocol 4 t 8-028 Page I of3 COMBINED REPEAT DOSE AND REPRODUCTIVE/DEVELOPMENTAL TOXICITY SCREEN First Day of Test Substance Dosage Male Rats Premati.ng Last Day ofTest Substance Dosagcc Last Day ofTest Substance Dosage- 2 Weeks Motor Activity/FOB" Natural Delivery Presumed Gestation Postpartum Period Female Rats 2Weeks 2Weeks 3 Weeks I I Day21 DayllO Motor ActivityJFOBd - Dosage Period a. For additional details see "Tests, Analyses and Measurements" section ofthe protocol. b. FOB and motor activity evaluations conducted on ten males per group. c. Male rats sacrificed after completion ofat least 42 days of dosage; necropsy and retention ofmale reproductive organs. Hematology, clinical biochemistry and histological samples collected from ten male rats per group. d. Ten female rats per group assigned to FOB evaluation and motor activity evaluation. e. Ten female rats per group and their litters sacrificed on day 22 postpartum; necropsy and retention of female reproductive organs. Hematology, clinical biochemistry and histological samples collected. Remaining female rats sacrificed on day 22 postpartum and discarded. Exygen Research Page 83 of 153 418-028:PAGE G-84 Exygen Study No.: 023-072 AITACHMENT 1 Protocol 418..028 Page2 of3 SCHEDULE 26MAR.02 01 APR02 01 APR 02 - 12 JUN 02 14 APR 02 PM- 21APR02 AM 21APR02 PM- 28 APR 02 AM 14APR02 15APR02 28APR02 06MAY02 19MAY02 06 MAY 02 - 07 MAY 02 Animal Receipt - Accfunation Begins. Start ofDosage Period -Male Rats (14 days before cohabitation and through a 14-da.y cohabitation period until the day before sacrifice after at least 42 days ofdosage). Dosage Period - Female Rats (14 days before cohabitation through Day 22 oflactation). Cohabitation Period (Maximum of 14 days). Male 1 (7 days) Male 2 (7 days) Day 14 Toxicokinetic Sample Collection First Possible Day OofPresumed Gestation. Last Possible Day 0 ofPresumed Gestation. First Possible Day 21 ofPresumed Gesta"i.ion Toxicokinetic Sample Collection and Sacrifice Toxicokinetic Study Female Rats Last Possible Day 21 ofPresumed Gestation Toxicokinetic Sample Collection and Sacrifice Toxicokinetic Study Female Rats FOB and Motor Activity Evaluation - 10 Male Rats per Group a. The start date ofthe study is the day the Study Director signs the protocol. b, Throughout this schedule, the day ofbirth is designated day 1 postpartum (day 1 of lactation) and all subsequent ages ofthe Fl generation rats and days ofthe lactation period will be detennined and cited accordingly, as described above the protocol section. "Day Numbering System." Exygen Research Page 84 of 153 418-028:PAGE G-85 Exygen Study No.: 023-072 ATTACHMENT I -. 06MAY02 23MAY02 10MAY02 23MAY02 12MAY02 13MAY02 23 MAY02-09JUN02 27 MAY 02 - 13 JUN 02 24SEP02 Protocol 418-028 Pagel of3 First Possible Delivery (Day 21 ofpresumed gestation). Last Possible Delivery (Day 25 ofpresumed gestatibn). First Possible Day 25 ofPresumed Gestation Female Sacrifice. Last Possible Day 25 ofPresumed Gestation Female Sacrifice. Day 42 Toxicokinetic Sample Collection and Scheduled Sacrifice - Toxicokinetic Study Male Rats Scheduled Sacrifice - Main Study Male Rats (Earliest possible date). Hematology, Clinical. Biochemistry and Histological Sample Collection of Selected. Male Rats. FOB and Motor Activity Evaluation - 10 Female Rats per Group. Day 22 Postpartum - Sacrifice Female Rats and Pups. Hematology. Clinical Chemistry and Histological Sample Collection ofSelected Female Rats and Pups. Draft Final Report Exygen Research Page 85 of 153 418-028:PAGE G-86 Exygen Study No.: 023-072 - ATTACHMENT 2 MATERIAL SAFETY DATA SHEET - Exygen Research Page 86 of 153 418-028:PAGE G-87 Exygen Study No.: 023-072 - MATERIAL SAFETY DATA SHEET (Experimental) 3H 3M Center St. Paul, Minnesota 55144-1000 1-800-3843577 or (851) 737-6501 {24 hours) T170(p Copyright, 1999, Minnesota Mining and Manufacturing Co.tpany. All rights reserved. Copying and/or downloading of this inforation for the purpose of properly utilizing 3M products ia allowed provided th1t: 1) the infonaation is copied in full with no changes unless prior agreeaent is obtained fra. 3M, and 2) neither the copy nor the original is resold or otherwise distributed with the intention of earning a profit thereon. DIVISION: 3H SPECIALTY MATERIALS MATERIAL: L9051 DEVELOPMENTAL PRODUCT ISSUED: Dec..ber 07, 1989 SUPERSEDES: May 17, 1999 DOCUMENT: 0454702 1. INGREDIENT C.A.S. NO. PERCENT POTASSIUM PERFLUOROHEXANE SULFONATE..... 387199-6 RESIDUAL ORGANIC FLUOROCHEMICALS........ Mixture 100.D Unknown This material is not listed on the TSCA inventory and should be used for research and development purposes only under the direct. supervision of a technically qualified individual. 2. PHYSICAL DATA BOILING POINT: .. VAPOR PRESSURE: VAPOR DENSITY: . EVAPORATION RATE: SOLUBILITY IN WATER: SPECIFIC GRAVITY: .. PERCENT VOLATILE: pH: , VISCOSITY: . MELTING POINT: , .......... NIA Negligible NIA Negligible slipht ca. 1.0 Watera1 (Bulk) Negligible N/A N/D N/D APPEARANCE AND ODOR: Off-white crystalline solid, sharp odor. Abbreviations: N/D Nat Oeter"lli.ned N/A Not Applicable CA - AppraxiHtely Exygen Research Page 87of153 418-028:PAGE G-88 Exygen Study No.: 023-072 MSDS: L-9051 DEVELOPMENTAL PRODUCT Deceber 07, 1999 PAGE 2 3. FIRE AND EXPLOSION HAZARD DATA FLASH POINT: .... > 212 F Setaflash Setatlash Closed Cup FLAMMABLE LIMITS LEL: . N/A FLAfl'ASLE Ll"ITS - UEL: N/A AUTOIGNITION TEMPERATURE: . N/D EXTINGUISHING MEDIA: water, Carbon dioxide, Dry chemical, Foam SPECIAL FIRE FIGHTING PROCEDURES: Wear full protective clothing, .including helllet, self-contained, positive pressure or pressure daand breathing apparatus, bunker coat and pan~s, bands around ants, Nlist and legs, face ask, and protective covering for exposed areaa of the head. UNUSUAL FIRE AND EXPLOSION HAZARDS: See Hazardous Decoposition section for products of C011bustion. 4, REACTIVITY DATA STABILITY: Stable INCOMPATIBILITY - MATERIALS/CONDITIONS TO AVOID: None known. HAZARDOUS POLYMERIZATION: Hazardous polymerization will not occur. HAZARDOUS DECOMPOSITION PRODUCTS: May produce fluorocarbon gases if exposed to very high t ..peratures (over 300 C}. 5. ENVIRONMENTAL INFORMATION SPILL RESPONSE: Observe precautions fro other sections. Collect spilled material. Use wet sweeping compound or water to avoid dusting. Clean up residue. Place in a closed container. RECOMMENDED DISPOSAL: Incinerate in an industrial or coercial facility in the presence of a combustible material. C011bustion products will include HF. Disposal lternative: D1spase of waste prod~ct in a facility pel'lllitted to accept chemical waste. Abbreviations: N/D - Not Deterined N/A - Not Applicable CA Approxillately Exygen Research Page 88 of 153 418-028:PAGE G-89 Exygen Study No.: 023-072 HSDS: L9051 DEVELOPMENTAL PRODUCT December 071 1999 PAGE 3 5. ENVIRONMENTAL INFORMATION (continued) ENVIRONMENTAL DATA: Not de"te,..ined. REGULATORY INFORMATION: Volatile Organic Capaunds: N/D. VOC Lesa H20 I Ex..pt Solvents: NfD. Since regulations vary. consult applicable regulations or authorities before disposal. U.S. EPA Hazardous Waste Nuber None (Not u.s. EPA Hazardous). OTHER ENVIRONMENTAL INFORMATION: This product Y contain one or aore organic f luoroch..icala that have the potential.ta resist degradation and persist in the environent. EPCRA HAZARD CLASS: FIRE HAZARD: No PRESSURE: No REACTIVITY: No ACUTE: Yes CHRONIC: No 6. SUGGESTED FIRST AID EVE CONTACT: Immediately flush eyes with large aounta of water. Get illmediate medical attention. SKIN CONTACT: Flush skin with large 11111ounts of water. If irritation peraists, get medical attention. INHALATION: If signs/symptos occur, remove person to fresh air. If signs/symptos continue, call a physician. IF SWALLOWED: If swallowed, call a physician illediatel,y. Only induce vomiting at the instruction of a physician. Never give anything by outh to an unconscious person. 7. PRECAUTIONARY INFOAHATION EVE PROTECTION: Avoid eye contact. Avoid eye contact with vapor, spray, or ist. The following should b1 worn alone or in COllbination, as appropriate, to prevent eye contact: Wear vented goggles. Abbreviations: N/D - Not Detel'llined N/A - Not Applicable CA - Appro~.iltately Exygen Research Page 89 of 153 418-028:PAGE G-90 Exygen Study No.: 023-072 - HSDS: L-9051 DEVELOPMENTAL PAOOUCT Deceber 07, 1999 PAGE 4 7. PRECAUTIONARY INFORMATION (continued) SKIN PROTECTION: Avoid skin contact. wear appropriate gloves when handling this aterial. A pair of gloves ade fro the following aterial() are recoended: butyl rubber, polyethylene/polyvinylidtne chloride {Saranex). Use one or ore of the following personal protection items as necessary to prevent skin contact: head covering, coveralls. Protective gar11ents (other than gloves) should be de of either of the following terials: polyethylene/polyvinylidene chloride (Saranex). AECOtfilENDED VENTILATION: Use with appropriate local exhaust ventilation. Provide appropria~e local exhaust ven'tilaUon at transfer points. UH in a well ventilated area. Provide sufficient ventilation ta intain esissions below recommended exposure lillita. If exhaust ventilation is not adequate, use appropriate respiratory protection. Provide ventilation adequate to control vapor concentrations below recamended exposure llllits and/or control spr1v or aist. Local exhaust ventilation is rec011111ended where the es airborne. aterial beco RESPIRATORY PROTECTION: Avoid breathing of airborne material. Select one of the following NIOSH approved respirators based on airborne concentration of contaainants and in accordance with OSHA regulations: halt-ask supplied air respirator, full-face supplied air respirator. PREVENTION OF ACCIDENTAL INGESTION: Do not eat, drink or smoke when using this product. Hash exposed areas thoroughly with soap and water. Wash hands after handling and before eating. RECOMMENDED STORAGE: Store at roo teperature. closed when not in use. Keep container dry. Keep container FIRE AND EXPLOSION AVOIDANCE: Not deterined. EXPOSUftE LIMITS INGREDIENT VALUE UNIT 'TYPE AUTH SKIN* POTASSIUM PERFLUOROHEXANE SULFONATE . 0.1 MG/H3 TWA SM v RESIDUAL ORGANIC FLUOROCHEHICALS 0.1 HG/H3 TWA 3M y * SKIN NOTATION: Listed substances indicated with y under SKIN refer to Abbreviations: N/D Not Determined N/A - Not Applicable CA Approxiately Exygen Research Page 90 of 153 418-028:PAGE G-91 Exygen Study No.: 023-072 - MSDS: L-9051 DEVELOPMENTAL PRODUCT December 07, 1999 PAGE 5 EXPOSURE LIMITS (continuad) INGREDIENT VALUE UNIT TVPE AUTH SKIN the potential contribution to th overall exposure by the cutaneous route including ucous brane nd ay1, tither by airborne or, ore particularly, by direct contact with th substance. Vehicles can altar skin absorption. SOURCE OF EXPOSURE LIMIT DATA: - 3M: 3M Reca..ended Exposure Guidelin1s 8. HEALTH HAZARD DATA EYE CONTACT: No info,..ation was found regarding effac~s fro eya contact. Single exposure Y cause: Mild Eye Irritation: signs/syptos can include redness, swelling, pain, ~nd tearing. SKIN CONTACT: . No infol"llation was found regarding effects fro skin contact. Hay be absorbed through the skin and persist in the body for an extended ti.lie. Single exposure may cause: Moderate Skin Irritation: signs/syaptaa can include redness, swelling. itching, and dryness. INHALATION: No infol"llation was found regarding effects fro inhalation exposure. Hay be absorbed by inhalation and persist in the body for an axtndd the. Single overexposure, above recoaanded guidelines, may cause: Irritation (upper respiratory): signs/symptos can include soreness of the nose and throat, coughing and sneezing. IF SWALLOWED: Ingestion is not a likely route of exposure to this product. No infor11tation was found regarding effects fro swallowing. - Anillal studies conducted on organic fluorochemicals Which Y be present in this product indicate effects including liver disturbances, weight loss, loss of appetite, lethargy, and neurological, pancreatic, adrenal and hematologic effects. There are no known huan hea~th Abbreviations: N/D - Not Deterained NIA - Not Applicable CA - Approximately Exygen Research Page 91 of 153 418-028:PAGE G-92 Exygen Study No.: 023-072 - MSDS: L-9051 DEVELOPMENTAL PRODUCT December 07, 1999 PAGE El 8. HEALTH HAZARD DATA (continued) effects frOll anticipated exposure to these organic fluorocheicals when used as intended and instructed. OTHER HEALTH HAZARD INFORMATION: This product Y contain one or more organic f luoroahaicals that have the potential to be absorbed and rin in the body for long periods of till, either as the parent 110lecula or as tabolites, and ay accU111ulate with repeated exposures. There are no known huan health effects fro anticipated exposure to these organic fluorocheicals when used as intended and instructed. The presence of organic fluorocheicals in the blood of the gen.ral population and subpopulations. such aa workers, has been published dating back ta the 197D's. 3M' epideiological study of its own workers indicates no adverse effects. SECTION CHANGE DATES PRECAUTIONARY INFO. SECTION CHANGED SINCE May 17 1999 ISSUE Abbreviations: N/D Not Deterined NIA Not Applicable CA Approxillat1ly --------------------~------------------~------------------------------ The information in this Material Safety Data Sheet (HSDS) is belieyed ta be correct as of the date issued. 3H MAKES NO WARRANTIES, EXPRESSED OR IMPLIED, INCLUDING, BUT NOT LIMITED TO, flMY IMPLIED WARRNITY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE DA COURSE OF PERFORMANCE OR USAGE OF TRADE. User is responsible for detenaintna whether the 3H product is fit for a prticular purpose and suitable for user's method of use or application. Given the Yariety of factors that can affect the use and application of a 3M product, SOiie of which are uniquely within the user's knowledge and control, it is essential that the user evaluate the 3H product to deter11ine whether it is fit for a particular purpose and suitable for user's ethod of use or application. 3H provides information in electronic fora as a service to its cust1>11ers. Due to the remote possibility that electronic transfer ay ha~ resulted in errors, omissions or alterations in this infor11ation, 3M makes no representations as to its completeness or accuracy. In addition, infor11ation obtained from a database nay not be as current as the infornation in the HSDS available directly fro 3M. Exygen Research Page 92 of 153 418-028:PAGE G-93 Exygen Study No.: 023-072 ATIACHMENT 3 TEST SUBSTANCE PREPARATION PROCEDURE Exygen Research Page 93 of 153 418-028:PAGE G-94 Exygen Study No.: 023-072 ATI'ACHMENT 3 Protocol 418-028 Version: 418-028(19 MAR 02> Page 1 of2 TEST SUBSTANCE PREPARATION PROCEDURE Test Substance: T-7706 Vehicle: Aqueous 0.5% CMC (medium viscosity) A. Purpose: The purpose of this procedure is to provide a method for the preparation of dosage suspensions of T-7706 for oral (gavage) administration to rats on Argus Research Study number 418-028. B. General Information: 1. All suspension containers will be labeled and color-coded. Each label will specify the protocol number, test substance identification, Argus batch number, concentration, dosage level, preparation date, expiration date and storage conditions. 2. Suspensions will be prepared: Daily 1L Weekly _ For_ days of use Approximately every ten days By Sponsor 3. Suspensions will be administered at a final dosage volume of ..1Q.. mUkg. 4. Safety: l L Gloves, uniformnab coat, goggles or safety glasses with side shields L Oust-mist/HEPA-filtered Mask Half-Face Respirator if not used in a chemical fume hood Full-Face Respirator/Positive Pressure Hood Tyvek Suit or tyvek apron and sleeves 5. Dosage suspensions adjusted for % Activity/Purity or Correction Factor. Yes .lL No (Calculations based on 100%) % Actiyity _ % Purity _ Correction Factor 6. Sampling requirements: Cited in protocol 7. Storage: Cited in protocol Exygen Research Page 94 of 153 418-028:PAGE G-95 Exygen Study No.: 023-072 - ATTACHMENT 3 Protocol 418-028 Version: 418-028'19 MAR 02) Page 2 of2 TEST SUBSTANCE PREPARATION PROCEDURE NOTE: Prior to test substance preparation accurately measure the required amount of the appropriate vehicle (R.O. deionized water should be used for calibration purposes) in a graduated cylinder, pour the required amount of vehicle into a beaker. Carefully mark each beaker at the meniscus. This mark w!H be used during the preparation to bring the test substance slurry up to volume. C. Dosage Suspension Preparation: 1. Weigh the required amount of test substance on a piece of weigh paper or into an appropriately sized mortar (see PREPARATION CALCULATIONS). 2. If weigh paper is used, transfer the test substance to an appropriately sized mortar. If necessary, grind the test substance into a fine powder. Slowly add a small amount of vehicle and grind. Continue to add vehicle slowly and grind the vehicle and the test substance together to fonn a fine sluny. Trans~r the vehicle/test substance slurry to a marked beaker. 3. Rinse the mortar and pesUe with additional vehicle to remove any remaining test substance. Transfer rinse to beaker. 4. Add additional vehicle to the beaker to bring volume up to the m:=uk. Place on magnetic stir plate and agitate prior to and during sampling, aliquotting and/or administration. 5. Repeat steps (1) through (4) for each concentration. '")A ; I f ./J. Written By: l't"'f+Lyj. ,ffllk~ ~~ ~ Appmved (j) _No~Y~ Clarification: Data: U l'HLIJZc-[see -ched clarification form] .- Initial/Date: - - - - - - - Exygen Research Page 95 of 153 418-028:PAGE G-96 Exygen Study No.: 023-072 - ATTACHMENT 4 TISSUES TO BE WEIGHED, RETAINED AND EXAMINED msTOLOGICALLY Exygen Research Page 96 of 153 418-028:PAGE G-97 Exygen Study No.: 023-072 AITACHMENT 4 Protocol 418-028 Page 1 of2 - TISSUES TO WEIGHED AND RETAINED FOR POSSIBLE EXAI\UNATION FROM TEN RATS PER SEX PER GROUP The ten rats per sex per group assigned to functional observational battery and motor activity tests will be assigned to hematology, clinical biochemistry and histological evaluations. Tissues to be Weighed: The following organs will be excised, trimmed and individually weighed as soon as possible after excision to avoid drying. liver spleen kidneys brain adrenals heart thymus ovaries testes uterus (with cervix) right epididymis prostate left epididymis (whole and cauda) seminal vesicles (with and without fluid) Tissues to be Retained: The following tissues or representative samples will be retained in neutral buffered 1OOA. formalin .. brain (representative regions including cerebrum, cerebellum, pons) small and large intestines (including Peyer's patches) lungs (perfused with neutral buffered 10% formalin) lymph nodes (submandiblar and mediastinal) peripheral nerve (sciatic or tibial) gross lesions spinal cord (cervical, thoracic and lumbar) stomach liver kidneys adrenals spleen heart thymus thyroid/parathyroid trachea uterus urinary bladder bone marrow (sternum) testes* ovaries prostate uterus seminal vesicles (with coagulating gland) vagina mammary gland (female rats only) * Testes will be fixed in Bouin's solution for 48 to 96 hours before being retained in neutral buffered 10% formalin. Additionally, the remaining portion of the left epididymis {corpus and caput), as well as the right epididymis will be fixed in neutral buffered 10% formalin. Exygen Research Page 97 of 153 418-028:PAGE G-98 Exygen Study No.: 023-072 AlTACHMENT 4 Protocol 418-028 Page2 of2 - Histological Examination: Histological examination ofretained tissues, including reproductive organs, will be conducted for the assigned ten rats per sex ftom the control and high dosage groups and from the Fl generation pups (livers) from the control and high dosage groups. lflesions attributed to the test substance are observed in the rats exposed to the high test substance concentration, the same tissues will be examined from the assigned ten rats per sex exposed to the lower test substance concentrations. Should results warrant examination of the lower dosage groups and conduct of quantitative evaluation, scheduled report date and prices will be adjusted accordingly. The postlactional ovary should contain primordial and growing follicles as well as the large corpora lutea of lactation. Histopathological examination may detect qualitative depletion of the primordial follicle population. A quantitative evaluation ofprimordial follicles will be conducted for Fo generation female rats; the number ofrats, ovarian section selection and section sample size will be statistically appropriate for the evaluation procedure used. Examination will include enumeration ofthe number ofprimordial follicles, which can be combined with small growing follicles, for comparison of ovaries of rats assigned to treated and control groups. ShiPPing Instructions: Tissues to be examined histologically will be shipped (ambient conditions) to: Principal Investigator: W. Ray Brown, D.V.M., PhD., ACVP Veterinary Pathologist Research Pathology Services, Inc. 438 E. Butler Avenue New Britain. Pennsylvania 18901 Telephone: (215) 345-7070 Telefax: (215) 345-4326 Email: WRBRPS@concentric.net The recipient will be notified in advance of sample shipment. Exygen Research Page 98 of 153 418-028:PAGE G-99 Exygen Study No.: 023-072 - 905 Sllethy Dme. lldf. A . Han11om. PA 1904.f Tefepllant: (llS) 443..a710 Tefejilr. (ZIS} .f.f3.SSB7 ~~~ ARGUS RESEARCH Charles River L.oboratorie~ Omwry and Development Semces PROTOCOL 418-028 ORAL (GAVAGE) CO:MBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST SPONSOR'S STUDY NUMBER: T-7706.1 Amendment 1 - 17 April 2002 1. Detailed Clinical Observations-Male and Female Rats (page 10 ofthe protocol): [Effective Date: 1 April 2002] Detailed clinical obsmvations will not be recorded for male and female rats assigned to toxicokinctic sampling. Reason for Ghange: This change was made because sufficient data for evaluation of detailed clinical observations will be available ftom the rats assigned to the main study. 2. Feed Consumption Va}ues - Male Rats and Female Rats (page 11 ofthe protocol): [Effective Date: I April 2002] Feed consumption values will not be recorded or tabulated for male and female rats assigned to toxicokinctic sampling. Reason for Change: This change was made because sufficient data for evaluation of feed consumption will be available from the rats assigned to the main study. Any revisions made to this finalized amendment must be made by subsequent amendment. Exygen Research Page 99of153 418-028:PAGE G-100 Exygen Study No.: 023-072 Protcx:ol 418-028 Amendment I - 3. Estrous Cycling and Mating (page 12 ofthe protocol): Page2 [Effective Date: 1 ~pril 2002] For the rats assigned to toxicokinetic sampling, estrous cycling will be evaluated during the cohabitation period until spermatozoa are observed in a smear ofthe vaginal contents and/or a copulatory plug is observed in situ, but not during the dosage period, prior to cohabitation. Reason for Change: Tills change was made because sufficient data for evaluation of estrous cycling will be available from the rats assigned to the main study. 4. Scheduled Sacrifice -Toxicoldnetic Study (page 16 ofthe protocol): [Effective Date: S April 2002] The number ofimplantation sites and coipora Iutea will be recorded. Carcasses will be discarded without turtb.cr evaluation. Reason ofChange: This change was made in order to provide more information about possible toxicity of the test substance in pregnant rats. S. Scheduled Sacrifice- Main Study(page 16 ofthe protocol): [Effective Date: 27 March 2002] The number ofimplantation sites will be recorded, rather than the number ofimplantation sites and corpora lutea will be recorded. Reason 'of Change: The number ofcorpora lutea will not be recorded because corpora lutea regress at a rapid rate and are not counted on studies at weaning. 6. Scheduled Sacrifice (page 19 ofthe protocol): [Effective Date: 4 April 2002] The liver from each selected pup will be excised and the organ weight recorded, rather than the liver from each selected pup will be collected excised and the organ weight recorded. Any revisions made to this finalized amendment must be made by subsequent amendment. Exygen Research Page 100of153 418-028:PAGE G-101 Exygen Study No.: 023-072 Protocol 418-028 Amendmmt 1 Pa.pl Reason for Change: This change clarifies the protocol by removing an extraneous word. c~ ~ ~~-..!1::1.L-.P...:b- Alan M. Hobennan, Ph.D., v-!7 DABT """-- Date ;~~ b. ., DABT Date Director ofResearch Associate Director o esearch Study Director Theresa H. Wo~ D.V.M. Member, Institutional Animal Care and Use Committee Date John Butenhoff, Ph.D., DABT. cm: Date Study Monitor and Sponsor's Representative - . Aay revisions made to this fiulizec:l ameadment mast be made by subsequent amendment. Exygen Research Page 101 of 153 418-028:PAGE G-102 Exygen Study No.: 023-072 905 Sheehy 0rM. atdi A HlllShom. PA 19044 TeJepllone: (2 I 5) 44.J.87 I 0 .Telefilt: (215} 443-8581 ~~~ ARGUS RESEARCH Charles River Laboratories Disawel)' and Development Set'YKes PROTOCOL 418-028 ORAL {GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST SPONSOR'S STUDY NUMBER: T-7706.1 Amendment 2 15 July 2002 1. Safety Precautions (page 3 of the protocol and Attachment 3 page 1 of the protocol): [Effective Date: 29 April 2002) A halfface respirator will be wom in addition to gloves, appropriate eye protection and a unifonnllab coat during fonnulation preparation ofthe bulk test substance. Reason for Change: This change was made to match the bulk test substance text with the text located within the Material Safety Data Sheet. 2. Studv Schedule {Attachment 1 page 2 ofthe protocol): [Effective Date: 29 April 2002] The dates for FOB and motor activity evaluations have been extended to four days (06 MAY 02 - 09 MAY 02) rather than two days (06 MAY 02 - 07 MAY 02). - Any revisions to this finalized amendment must be made by subsequent amendment. --&----------------------------------- Exygen Research Page 102of153 418-028:PAGE G-103 Exygen Study No.: 023-072 Protocol 418-028 Amendment2 Page2 Reason for Change: This change was made because more time is needed to evaluate animals assigned to FOB and motor activity evaluations. o~I _/J JIA~-~~!.S~t?.-ZML - an M oberman. Ph.D., DABT Date ~ G. Yor Ph. DABT Date Directo ofResearch Associate Director esearch Study Director ~~IY.\M:-.!~L~~~df;f~3U ~ Member, Institutional Animal Care Study Monitor and and Use Committee Sponsor's Representative ,.- - Any revisions to this finalized amendment must be made by subsequent amendment. ------------------------' ________,.... Exygen Research Page 103of153 418-028:PAGE G-104 Exygen Study No.: 023-072 - 905 Slleehy DIM. lrdf. A HGIShom. PA I9044 Telephone: (215) 443.a710 Telefax: {l ISJ 44J.BSB7 ~~~ ARGUS RESEARCH Charles River Laboratories Discovery and Development Services PROTOCOL 418-028 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST SPONSOR'S STUDY NUMBER: T-7706.1 Amen~ent 3 -17 JuJy 2002 1. Bulle Test Substance Sampling. Shipping Instructions, ShiPPing Instructions. Caesarean-Sectioning - Toxicokinetic Study, Scheduled Sacrifice - Toxicokinetic Study, and Scheduled Sacrifice, (pages 4, S, 12, 13, 16 and 19, respectively of the protocol) [Effective Date: 29 May 2002] Samples for perfluorohexanesulfonate (PFHS) analysis shipped to Lisa Clemen at 3M Environmental Technology and Safety Services will be reshipped and remaining samples, that were to be shipped to Lisa Clemen and have not yet been shipped, will be shipped to: John Flaherty, Ph.D. (Principal Investigator) Exygen Research 3058 Research Drive State College, Pennsylvania 16801 Telephone: (814) 272-1039, ext. 122 Telefax: (814) 231-1580 Email: john.flaherty@exygen.com - Any revisions to this finalized amendment must be made by subsequent amendment. ----------------------- ----------. Exygen Research Page 104of153 418-028:PAGE G-105 Exygen Study No.: 023-072 Protocol 418-028 Amendment3 Page2 These samples include: Bulk test substance sampling (page 4 ofthe protocol) Concentration and homogeneity {page 5 ofthe protocol) Stability (page 5 ofthe protocol) Plasma toxicokinetic samples (page 11 to 12 and page 16 of the protocol) Plasma samples, rather than scrum samples, were retained. Liver toxicokinetic samples (pages 12 and 16 ofthe protocol) Pooled fetal serum toxicokinetic samples (pages 12 and 16 of the protocol) Pooled fetal liver toxicokinetic samples (pages 13 and 16 of the protocol) Pooled pup serum toxicokinetic samples (page 19 ofthe protocol) Pup Jivertoxicokinetic samples (page 19 ofthe protocol) The analyses will be subcontracted to Exygen by the Sponsor and the Quality Assurance Unit for Exygen Research will conduct critical phase inspections and audit the respective results and reports according to the Standard Operating procedures of that facility. Such critical phase inspection reports and audit reports will be submitted by that facility to the Study Director, Raymond G. York. The date ofthe inspections and report submissions will be incorporated into a QAU statement generated by Exygen Research for inclusion in the final report for Protocol 418-028. Reason for Change: This change was made at the request ofthe Sponsor because 3M is not able to complete the formulation analysis with their current staffing. L I '_ L/} OA~- ~~~ ~ t!a:~~.. - _'::;.JJ.J};J.fl:l 4.b Ra~~G. rman,Ph.D.,DABT /-' Director ofResearch Date ~=: ~irYecotrokr.oi,~hR.Des., ABT h Date Study Director - r _:t_lJz_k____ -~-..AJ..:_(1.J..L_____ ThcresHH. Woodard,b.v.M. Member. Institutional Animal Care t'.'.:74,. 2r. _7;-/.JU Ii' JU. Z4P'\. -7-=--------~P--------------Date John Butenhoff, Ph.D., DABT, Clll Date Study Monitor and and Use Committee Sponsor's Representative Any revisions to this finalized amendment must be made by subsequent amendment. Exygen Research Page 105of153 418-028:PAGE G-106 Exygen Study No.: 023-072 PROTOCOL 418-028 ORAL (GAVAGB) CO:MBINBD REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THB REPRODUCTION/DBVELOPMBNTAL TOXICITYSCREENING TEST SPONSOR'S STUDYNU.MBBR: T-7706.1 Amendnient 4 - 20 March 2003 1. Bulle Test Substance Sanmling. Shimdng Instructions, Shipping Jnstmctions. Caes~oning -Toxjcokipetic Stady~ Scbeduled Sacrifice -Toxicokinetic ~ and Scheduled Sacrifice. (pages 4. S, 12. 13, 16 and 19, respectively of the protocol) and Amendment 3. Item. 1: BuJk. Test Substance Sampling. Shipping Instructions, Sbipping Jnstmctions. Caesarean-Sectioning - Toxicokinetic Study. Scheduled Sacrifice - T2xicommcStudy. and Scheduled Sacrifice (page 1 of Amend:m.ent 3) . [Effective Date: 27 February 2003) The analyses performed by Bxygen Research will be done according to Bxygen Method ExM-023-071 Revision 1, entitled ..Method of Analysis for the Determination of Pertluorohexanesulfonate (PFllS). PerfluorooctanesuJfonatc (PPOS) and Pentadecafluorooctanoic Acid (PFOA) in Rat Uver, Serum and Urine Revision 1". Any revisions to this finalized amendment must be made by subsequent amendment. ----------------------- Exygen Research Page 106of153 418-028:PAGE G-107 Exygen Study No.: 023-072 Protocol 418-028 Amendmeat.4 Page2 Reason for Change: This change was made at the request of the Bxygen Resean:h in order to ~ the method of analysis. --~~J M=:2tt?!J~~~~--..!!.D"'1.lfA.~ Date Date ~.-a. fu~--~-3 John Butenhoff, Ph.D. DABT, Cill Date Study Monitor and Sponsor's Representative Any revisions to this fb.lalized amendment must be made by subsequent amendment. - ., . ------~-- Exygen Research Page 107of153 418-028:PAGE G-108 Exygen Study No.: 023-072 E~-enTM RESEARCH Precise Research. \._ Proven Results. Page _1_ of __1_ PROTOCOL DEVIATION .. Deviation Number: _1_ _ _ _ _ __ Date of Occurrence: ..1...0_./.1..4...._/_0.2....- - - - - Exygen ~dy Number: 023072 Protocol Number: 418028 .. DESCRIPTION OF DEVIATION A recovery Of 62% for PFHS is being accepted for the 5000 ppb sp1ke (0202119 Spk C) in data set 100402A. \ Deviation Issued. ACTIONS TAKEN tor example - deviation issued sop revision etc Recorded By: IMpAC(T ON srupy The 10 ppb and 50 ppb control matrix spi~ included with the set gave acceptable recoveries. Date 7Ub/<J3 Date o7I17 /ioo~ Date U:\Fonns\PROTOC~l,..DEV!ATION.doc I Exygen QAU _Review _\A.y:__:....,.___ -""1 _?/_ ..15_'"/o_:":>J _ 9125/200215 ........ o\E: ntts l.\JtA11w 1s BEi~Ct ~.,ssu~ ~u.e TO Sf>fC..TE~LeeCf oR.l~lNAL. ~01l1s/03 8 Research Drive re College, PA 16801, USA T: 800.281.3219 F: 814.272.1019 exygen.com - - - - - - -..----- - ... ----------- - - .... - - - - Exygen Research Page 108of153 418-028:PAGE G-109 Exygen Study No.: 023-072 3058 Research Drive State College, PA 16801 Phone: 8142721039 Fax: 814231-1580 NOTE TO FILE Date: 01/14103 Exygen Research Study# _ _,0=2=3...,-0-.7=2__ PROTOCOL#~~~4~1~8-~02~8...__ _~~- NOTE: The PFHS stock solution was inadvertently not corrected for salt content when prepared. The stock solution was used to make the fortification and calibration standards used for the study. Due to the large amount of data associated with this study, the concentrations of fortification and calibration solutions listed throughout the raw data were left uncorrected for the salt content. The final PFHS values recorded were corrected to reflect the difference in PFHS concentration due to the salt content. The correction was performed by multiplying the final ppb value found by 0.91. Signature: Dk+iJ Date: Ot)Jyl 0 ~ Exygen Research July 31, 200110 Page 109of153 418-028:PAGE G-110 Exygen Study No.: 023-072 APPENDIXB Analytical Method: Method of Analysis for the Determination of Perfluorohexanesulfonate (PFHS), Perfluorooctanesulfonate (PFOS) and Pentadecafluorooctanoic Acid (PFOA) in Rat Liver, Serum and Urine Revision 1 (Exygen Method No. ExM-023-071 Revision 1) Exygen Research Page 110 ofl 53 418-028:PAGE G-111 Exygen Study No.: 023-072 Method of Analysis for the Detennination of Perfluorohexanesulfonate (PFHS). Perfluorooctanesulfonate (PFOS) and Pentadecafluorooctanoic Acid (PFOA) in Rat Liver, Serum and Urine Revision I AUTHORS John Flaherty, Karen Risha. and Emily Decker DATEissUED November 20, 2002 SPONSOR 3M Medical Department Corporate ToxicoJogy 3M Center, Building 220-2E-02 St. Paul, MN 55144-1000 PERFORMING LABORATORY Exygen Research 3058 Research Drive State College, PA 16801 METHOD NUMBER ExM-023-071Revision1 TOTAL NUMBER OF PAGES 43 Exygen Research Page 111 of 153 418-028:PAGE G-112 Exygen Study No.: 023-072 Exygen Method No: ExM-023-071 Revision I MANAGEMENT APPROVAL oL /1'1r1.al~-r ~ohn Flaherty " Date Laboratory Manager Exygen Research John L. Butenhoff Date Sponsor Representative 3M Medical Department Corporate Toxicology ~ygen Research Exygen Research Page2 of43 Page 112 of153 418-028:PAGE G-113 Exygen Study No.: 023-072 Exygen Method No: ExM023-07 I Revision 1 TABLE OF CONTENTS TirLE ................................................................................................................................. 1 MANAGEMENT APPROVAL .......................................................................................... 2 TABLE OF CON'I'EN'I'S .................................................................................................... 3 UST OF TABLES .............................................................................................................. 4 LIST OF FIGURES ............................................................................................................. S 1. SUMMARY ..................................................................................................................7 2. EXPERIMENTAL COMPOtJNDS .............................................................................. 8 3. ClfEMICALS AND SlJPPIJES ...................................................................................9 3.1. CHEMICALS ...........................................................................................................9 3.2. STANDARDS ..........................................................................................................9 3.3. EQUIPt.mNT AND SUPPLIES ....................................................................................9 3.4. SOLUTIONS .......................................................................................................... 10 3.5. PREPARATION OF STANDARD SOLUTIONS ........................................................... 10 3.5.1. Stock solution ......................................................................................... 11 3.5.2. Fortification Solutions ............................................................................ 11 3.5.3. Calibration Standards ............................................................................. 11 4. ME'I'HOD .................................................................................................................... 12 4.1. FI.ow DIAGRAM .................................................................................................. 12 4.2. S.A)dPLE PROCESSING .......................................................................................... 12 4.3. BATCHSETUP ..................................................................................................... 13 4.4. S~ ExTRACTION ......................................................................................... 13 4.4.1. LiverEx.traction...................................................................................... 13 4.4.2. Serum and Urine Ex.traction ................................................................... 13 4.4.3. SPE Column Conditioning ..................................................................... 14 4.5. QUANTITATION ................................................................................................... 14 4.5.1. LC/MS/MS System and Operating Conditions...................................... 14 4.5.2. Calibration Curve Procedures ................................................................ 15 4.5.3. Sample Analysis ..................................................................................... 16 4.6. ACCEPTANCE CRITBRIA......................................................................................... 17 4.7. PERFORMANCECRITERIA ..................................................................................... 17 4.8. TIME REQUIRED FOR ANALYSIS ........................................................................... 18 S. CALClil..ATIONS ...................................................................................................... 18 6. SAFETY ...................................................................................................................... 19 ;Exygen Research Page3 of43 Exygen Research Page 113of153 418-028:PAGE G-114 Exygen Study No.: 023-072 Exygen Method No: Ex.M-023-071 Revision 1 LIST OF TABLES Table 1. Recovery Summary of PFHS in Rat liver and Serum...................................... 20 Table 2. Recovery Summary of PFOS in Rat Liver, Serum and Urine ........................... 21 Table 3. Recovery Summary of PFOA in Rat Liver, Scrum and Urine...........................22 Exygen Research Exygen Research Pagc4of43 Page 114 ofl 53 418-028:PAGE G-115 Exygen Study No.: 023-072 Exygen Method No: ExM-023-071 Revision 1 LIST OF FIGURES Figure 1. Calibration Curve for PFHS ............................................................................ 23 Figure 2. Calibration Curve for PFOS ............................................................................24 Figure 3. Calibration Curve for PFOA ........................................................................... 25 Figure 4. Representative Chromatogram of a 0.1 ng/mL Standard Containing PFIIS.............................................................................................26 Figure 5. Representative Chromatogram of a 0.1 ng/mL Standard Containing PFOS...26 Figure 6. Representative Chromatogram of a 0.1 nglmL Standard Containing PFOA .. 27 Figure 7. Representative Chromatogram of a 0.5 ng/mL Standard Containing PFHS... 27 Figu~ 8. Representative Chromatogram of a 0.5 nglmL Standard Containing PFOS... 28 Figure 9. Representative Chromatogram of a O.S ngfmL Standard Containing PFOA .. 28 Figure 10. Representative Chromatogram of a 5.0 nglmL Standard Containing PFHS... 29 Figure 11. Representative Chromatogram of a 5.0 ngfmL Standard Containing PFOS... 29 Figure 12. Representative Chromatogram of a 5.0 nglmL Standard Containing PFOA .. 30 Figure 13. Representative Chromatogram of a Reagent Blank Sam.pie Analyzed for PFIIS ............................................................................................................... 30 Figure 14. Representative Chromatogram of a Reagent Blank Sample Analyzed for PFOS ............................................................................................................... 31 Figure 15. Representative Chromatogram of a Reagent Blank Sample Analyzed for PFOA ............................................................................................................... 31 Figure 16. Representative Chromatogram of a Control Liver Sample Analyzed for PFIIS .......................................................................................................... 32 Figure 17. Representative Chromatogram of a Control Liver Sample Analyzed forPFOS .......................................................................................................... 32 Figure 18. Representative Chromatogram of a Control Liver Sample Analyzed forPFOA ......................................................................................................... 33 Figure 19. Representative Chromatogram of a Control Serum Sample Analyzed for PFIIS.......................................................................................................... 33 Figure 20. Representative Chromatogram of a Control Serum Sample Analyzed forPFOS .......................................................................................................... 34 Figure 21. Representative Chromatogram of a Control Serum Sample Analyzed forPFOA ......................................................................................................... 34 Figure 22. Representative Chromatogram of a Control Urine Sample Analyzed forPFOS .......................................................................................................... 35 Figure 23. Representative Chromatogram of a Control Urine Sample Analyzed forPFOA ......................................................................................................... 35 Figure 24. Representative Chromatogram of a Control Liver Sample Fortified at 10 ng/g with PFliS ...................................................................................... 36 Exygen Research Pages of43 Exygen Research Page 115 of153 418-028:PAGE G-116 Exygen Study No.: 023-072 Exygen Method No: ExM-023071 Revision I LIST OF FIGURES (continued) Figure 25. Representative Chromatogram of a Control Liver Sample Fortified at 10 ng/g with PFOS ...................................................................................... 36 Figure 26. Representative Chromatogram of a Control Liver Sample Fortified at 10 ng/g with PFOA...................................................................................... 37 Figure 27. Representative Chromatogram of a Control Liver Sample Fortified at 50 ng/g with PFIIS ......................................................................................37 Figure 28. Representative Chromatogram of a Control Liver Sample Fortified at 50 nglg with PFOS ...................................................................................... 38 Figure 29. Representative Chromatogram of a Control Liver Sample Fortified at 50 ng/g with PFOA...................................................................................... 38 Figure 30. Representative Chromatogram of a Control Serum Sample Fortified at 10 ng/mL with PFllS ................................................................................... 39 Figure 31. Representative Chromatogram of a Control Serum Sample Fortified at 10 ngfmL '!ith PFOS ..........;........................................................................ 39 Figure 32. Representative Chromatogram of a Control Serum Sample Fortified at 10 nglmL with PFOA .................................................................................. 40 Figure 33. Representative Chromatogram of a Control Serum Sample Fortified at 50 ng/mL with PFIIS ................................................................................... 40 Figure 34. Representative Chromatogram of a Control Serum Sample Fortified at SO ng/mL with PFOS ................................................................................... 41 Figure 35. Representative Chromatogram of a Control Serum Sample Fortified at 50 ng/mL with PFOA .................................................................................. 41 Figure 36. Representative Chromatogram of a Control Urine Sample Fortified at 10 ng/mL with PFOS ................................................................................... 42 Figure 37. Representative Chromatogram of a Control Urine Sample Fortified at 10 ng/ml.. with PFOA .................................................................................. 42 Figure 38. Representative Chromatogram of a Control Urine Sample Fortified at 50 ng/mL with PFOS ................................................................................... 43 Figure 39. Representative Chromatogram of a Control Urine Sample Fortified at 50 ng/ml.. with PFOA .................................................................................. 43 Exygen Research Exygen Research Pagc6 of43 Page 116 ofl 53 418-028:PAGE G-117 Exygen Study No.: 023-072 Exygen Method No: ExM-023-071 Revision 1 1. SUMMARY This report details a method of analysis for residues of Perfluorohexanesulfonate (PFllS), Perfluorooctanesulfonate (PFOS) and Pentadecafluorooctanoic Acid (PFOA) in Rat Liver, Serum and Urine. Residues of PFHS, PFOS and PFOA are extracted from each matrix with acetonitrile. The acetonitrile extract is added to water and loaded onto a conditioned C18 solid phase extraction (SPE) cartridge. Analyte residues are eluted with 2 mL of methanol. Quantification of PFHS, PFOS and PFOA is accomplished by liquid chromatography/tandem mass spectrometry (LCIMSJMS) analysis using multiple reaction monitoring (MRM). The proposed limit of quantitation (LOQ; the lowest fortification specified by the method which gives adequate recovery according to EPA guidelines) for this methOd is 10 ng/g (parts-per-billion) each for PFlIS, PFOS and PPOA. The theoretical limit of detection (LOD) will be based on the signal to noise ratio and will be at least greater than 3 times the level of noise, based on the instrumentation system used. For all analytes, the lowest analytical standard corresponds to 0.1 ng/mL. This method was developed using rat liver, serum and urine. Typical percent recoveries standard deviations (at 10 and SO ng/g) are shown below: Fortification Level n 10 so PFIIS Recovery in Rat Liver 115% 9.9% (n=3 98% 3.59' n=3 Fortification Level n mL 10 so PFHS Recovery in Rat Scrum 1089" 4.7% n=3) 111% 9.6% n=3 Fortification Level 10 so PFOS Recovery in Rat Liver 96% 8.5% n=3 889' 1.5% n=J Fortification Level n mL 10 so PFOS Recovery in Rat Serum 88% 9.8% n=3 120% 2.1% n=3 PFOS Recovery in Rat Urine 939' 4.7% n=3 799' 1.2% n=3 Fortification Level (nir/a) 10 50 PFOA Recovery in Rat Liver 98% 3.1 qr, (n=3) 949' 2.5% (n=J) Fortification Level (nst/mL) 10 50 PFOA Recovery in Rat Serum 117% 1.S% (n=3) 111% 4.0% {n=3) PFOA Recovery in Rat Urine 89% 2.S% Cn=3) 87'6 2.1 % Cn=3) Representative calibration curves are shown in Figures 1-3. Representative chromatograms are shown in Figures 4 to 39. ;Bxygen Research Page7of43 Exygen Research Page 117of153 418-028:PAGE G-118 Exygen Study No.: 023-072 Exygen Method No: ExM-023-071 Revision 1 2. EXPERIMENTAL COMPOUNDS The structures for PFIIS, PFOS and PFOA are given below. PFHS Chemical Name = Perfluorohexanesulfonate Molecular weight 399, as shown F-+Hffiso,. F F F PFIIS. is supplied as the potassium salt (4F13S03-K:+), molecular weight= 438 PFOS Chemical Name = Molecular weight Perfluorooctanesulfonate 499, as shown PFOS is supplied as the potassium salt (CsF11S03-K+) molecular weight = 538 PFOA Chemical Name Molecular weight Pentadecafluorooctanoic Acid 413. as shown ~ygcn Research Exygen Research Pagc8 of43 Page 118 of153 418-028:PAGE G-119 Exygen Study No.: 023-072 Ex:ygen Method No: ExM-023-071 Revision 1 3. CBEMICALSANDSUPPLIES 3.1. CHEMICALS Chemical Methanol (MeOH) Ammonium Acetate Water Acetonitrile Grade HPLC Reagent Type I HPLC Source EM Science IT Baker Exygen EM Science Catalog No. MX0475-1 0596-01 NA AX0145-1 Type I water= electrical resistivity, minimum of 16.67 MWcm at 25 C, from a Labconco Waterpro"TM workstation. 3.2. STANDARDS Standard Perfluorohexanesulfonate (PFHS) Perfluorooctanesulfonate (PFOS) Pentadecafluorooctanoic Acid(PFOA) TCRNumber SB-036 SD-018 Lot No: 08316DO Purit,I ~%) 99.99 all isomers, 84.36 straight chain 86.9 96 Source 3M 3M Aldrich Chem 33.EQUIPMENTANDSUPPLIES Eguipment Balance, analytical (display at least 0.0001 g) 125-mL I.DPB narrow mouth bottles Disposable glass micropipets (S0-100 & 100-200 L) Tissumizer Wrist action shaker Sorvall RC SC plus Centrifuge 50 mL disposable polypropylene centrifuge tubes 15 mL disposable polypropylene centrifuge tubes Visiprep vacuum manifold Sep Pak Vac 6 cc (lg) tC18 cartridges (part# WAT 036795 2-mL clear HPLC vial Kit (cat# 5181-3400) Class A pipets and volumetric flasks Standard Jab equipment (graduated cylinders, disposabie tubes etc.) Stand-alone drop-in guard cartridge holder {part #844017-400) Hypercarb drop-in guard column (4 mm) (part# 844017-400) HPLC Pump (LC-lOAD) LC/MS/MS and HPLC systems Supplier Mettler Nalgene Drummond (VWR) Tekmar Burrell Scientific Dupont vWR VWR Supclco Waters Hewlett-Packard various suppliers various suppliers Keystone Scientific Keystone Scientific Shimadzu As described in section 4.5. :Exygen Research Page9 of43 Exygen Research Page 119of153 418-028:PAGE G-120 Exygen Study No.: 023-072 Exygen Method No: ExM-023-071 Revision 1 Notes: 1. 2. 3. 4. S. In order to avoid contamination, the use of disposable labware (containers, tubes, pipettes, etc.) is highly recommended. Teflon or Teflon-lined containers or equipment should not be used. It may be necessary to check the solvents (acetonitrile, methanol) for the presence of contaminants (es~ially PFOA) by LC/MS/MS before use. Certain lot numbers have been found to be unsuitable for use. Use disposable micropipettes or pipettes to aliquot standard solutions when preparing standards and samples for extraction. Equivalent materials may be substituted for those specified in this method. 3.4. SOLUTIONS (1) 2 mM ammonium acetate in water is prepared by weighing 0.154 g of ammonium acetate and dissolving in lL of water. (2) Hypercarb filtered type I water is prepared by filtering type I water through a Hypercarb guard column using a HPLC pump at -2-3 mIJmin. Before use, wash the guard cart.ridge with -25 mL of HPLC grade acetonitrile, then - 25 mL of type I water, then begin collecting the filtered type I water eluate for use in the extraction. Repeat the wash after filtering -2L of water. Note: The aforementioned example is provided for guidance, alternative volumes may be prepared as long as the appropriate ratios of the solvent to solute are maintained. 3.5. PREPARATION OF STANDARD SOLUTIONS Analytical standards are used for three purposes: I. Calibration Standards - These standards arc prepared in methanol and are used to calibrate the response of the detector used in the analysis. 2. Laboratory Control Spikes - These fortifications are prepared at concentrations corresponding to the LOQ and 5x LOQ and are used to detennine analytical recovery. Laboratory control spikes are prepared in control matrix. 3. Matrix Spikes - These fortifications are prepared by spiking into the field samples at a known concentration. Matrix spikes are used to evaluate the effect of the sample matrix on analytical recovery and are prepared at the client's request. The analyst may vary the absolute volumes of the standards as long as the correct proportions of solute to solvent are maintained. ~xygcn Research Page 10of43 Exygen Research Page 120of153 418-028:PAGE G-121 Exygen Study No.: 023-072 Exygen Method No: ExM-023-071 Revision l 3.5.1. Stock solution Prepare individual stock solutions at 100 g/mL for PHIS, PFOS and PFOA by weighing out 10 mg of each analytical standard (corrected for purity and if necessary, salt content) and dilute to 100 mL with methanol in separate 100-mL volumetric flasks. The stock solutions (in 125-mL LOPE bottles) are to be stored in a refrigerator at 2C to 6C and are stable for a maximum period of one year from the date of preparation. 3.5.2. Fortification Solutions a. Prepare a mixed fortification standard at 1.0 g/mL (1000 ngfmL) of PFIIS, PFOS and PFOA by adding 1.0 mL of each of the 100 g/mL stock solutions into a 100-mL volumetric flask and bring up to volume with methanol. b. Prepare a mixed fortification standard at 0.1 g/mL (100 nglmL) of PFIIS, PFOS and PFOA _by diluting 10.0 mL of the 1.0 glmL mixed fortification solution to 100 mL with methanol in a volumetric flask. Example: one hundred microliters of the 0.1 g/mL solution spiked into 1 g of liver or 1 mL of serum/urine is equivalent to a 10 ppb (10 ng/mL or nglg) fortification. Store all fortification standard solutions in a refrigerator (in 125-mL IDPE bottles) at 2C to 6C for a maximum period of one year from the date of preparation. Note also that additional concentrations may be prepared if necessary. 3.5.3. Calibration Standards LC/MS/MS calibration standards containing PFEIS, PFOS and PFOA are prepared at 0.1, 0.2, 0.5, 1.0, 2.0 and 5.0 nglmL in methanoJ via dilution of the 0.1 glmL mixed fortification solution (section 3.5.2.b). The following is a typical example; additional concentrations may be prepared as needed. Initial Cone. (ng/mL) 100 100 100 5.0 2.0 1.0 Volume (mL) 5.0 2.0 1.0 10.0 10.0 10.0 Diluted to (mL) 100 100 100 100 100 100 Final Cone. (ng/mL) 5.0 2.0 1.0 o.s 0.2 0.1 The standards may be used for a period of one year (in 125-mL IDPE bottles) when stored refrigerated (at 2C to 6C). ~xygen Research Page 11 of43 Exygen Research Page 121 of 153 418-028:PAGE G-122 Exygen Study No.: 023-072 Exygen Method No: ExM-023-071 Revision l 4. METHOD 4.1. Fl.ow DIAGRAM The flow diagram of the method is given below, foUowed by a detailed description of each step. Method Flow Diagram Weigh appropriate amount of liver or measure appropriate volume of serum or urine (fortify samples designated as matrix spikes and laboratory control spikes) J. Add water to liver for a final volume of 10 mL, add water to serum and urine for a final volume of 20 mL, homogenize J. Remove 1 mL and add S mL of ACN, shake .J. Centrifuge J. Decant supernatant into 35 mL of water J. Load onto conditioned SPE J. Elute with 2 mL methanol J. LC/MS/MS Analysis 4.2. SAMPLE PROCESSING For liver samples, place frozen samples in a food processor and homogenize with dry ice. Then place samples in containers and leave open in frozen storage overnight to allow for C02 sublimation. Seal and place the samples in frozen storage below -l0C until time of extraction. Alternately, if there is an insufficient amount of sample (- less than 5 g), then no processing is necessary and the sample can be used as supplied. No sample processing is needed for serum and urine samples. However, frozen serum and urine samples must be allowed to completely thaw to room temperature before use. ~xygen Research Page 12of43 Exygen Research Page 122 of153 418-028:PAGE G-123 Exygen Study No.: 023-072 Exygen Method No: ExM-023-071 RcYision 1 4.3. BATCH SET UP a. A batch of samples should not contain more than 20 field samples. b. Each batch of samples analyzed must include at least one control (method blank using control matrix) and two matrix controls fortified at lmown concentrations (typically 10 and SO ng/g for liver or ng/mL for serum and urine) to verify procedural recovery for the batch. c. At least one field sample in each batch must also be separately fortified at a known concentration and carried through the procedure to verify recovery. Additional samples in the batch may also be fortified if desired. d. All samples require duplicate injections. 4A. SAMPLEEXTRACTION 4.4.1. Liver Extraction a. Weigh I g of liver sample into a 50 mL disposable centrifuge tube and fortify, if appropriate. Note that alternate weights of liver may be measured depending on the sample size available for use. b. Add water to the sample for a final volume of 10 mL. Cap tightly. c. Homogenize sample using a tissuemizer for -1 minute. d. Transfer 1 mL of the sample using a disposable pipette into 15 mL disposable centrifuge tubes. Add 5 mL of ACN and shake for -20 minutes on a wrist action shaker. e. Centrifuge tubes at -3000 Ipm for - S minutes. Carefully decant supernatant into a 50 mL disposable centrifuge tube and add 35 mL of water. f. Load the sample onto a conditioned SPE column (for conditioning details, see section 4.4.3.). Discan:l the eluate. Any analyte residues will be trapped on the SPE column at this point. g. Elute with 2 mL of methanol. Collect 2 mL of elute into a graduated 15 mL centrifuge tube. h. Analyze samples using electrospray LC/MS/MS. 4.4.2. Serum and Urine Extraction a. Measure 1 mL of serum or urine sample into a 50 mL disposable centrifuge tube and fortify, if appropriate. Note that alternate volumes of serum and urine may be measured depending on sample size available for use. ~ygen Research Page 13 of43 Exygen Research Page 123of153 418-028:PAGE G-124 Exygen Study No.: 023-072 Exygen Method No: ExM-023-071Revision1 b. Add water to sample for a final volume of 20 mL. Cap tightly and vortex for-1 minute. Then continue with steps d-h in section 4.4.1. 4.4.3. SPE Column Conditioning Place the unconditioned SPE columns on the vacuum manifold. Condition the SPE columns by passing - 10 mL of methanol through the column followed by - 5 mL of water. The washes may be pulled through the SPE column using vacuum at a flow rate of -1 drop/sec or may be allowed to pass through the column unaided. Discard all washes. Do not allow the column to dry. 4.5. QUANTITATION 4.5.J. LC/MS/MS System and Operating Conditions Mass Spec: Interface: Computer: Software: Micromass Quattro Ultima {Micromass) E1ectrospray (Micromass) Harvard infusion pump (Harvard Instruments), for tuning COMPAQ Professional Workstation AP200 Windows NT, Masslynx 3.3 HPLC: Hewlett Packard (HP) Series 1100 HPQuatPump HP Vacuum Degasser HP Autosampler HP Column Oven Note: A 4 x 10 mm hypercarb drop in guard cartridge is attached on-line after the purge valve and before the sample injector port to trap any residue contaminant.s that may be in the mobile phase and/or HPLC system. HPLC Column: Genesis Cs (Jones Chromatography), 2.1 mm x 50 mm, 4 Column Temperature: 35 C Injection Volume: 15 L Mobile Phase (A): 2 mM Ammonium Acetate in Type I water Mobile Phase (B): Methanol Time %A 0.0 90 2.0 90 5.0 10 9.0 10 9.5 0 14.0 0 14.5 90 20.0 90 .2Ul Flow Rate CmIJminl 10 0.3 10 0.3 90 0.3 90 0.3 100 0.3 100 0.3 10 0.3 10 0.3 ~xygen Research Page 14of43 Exygen Research Page 124of153 418-028:PAGE G-125 Exygen Study No.: 023-072 Exygen Method No: ExM-023-071 Revision 1 It may be necessary to adjust the HPLC gradient in order to optimize instrument performance. Columns with different dimensions (e.g. 2.1 x 30) and also columns from different manufacturers (Keystone Betasil C1s etc.) could be used, provided equivalent chromatography is obtained. Ions monitored: Analyte PFIIS PFOS PFOA Mode Negative Negative Negative Transition Monitoreci 399~ 80 499~99 413~369 Approximate Retention Time -8.2min. -8.Smin -8.6min The retention times may vary, on a day to day basis, depending on the batch of mobile phase etc. Drift in retention times (up to 4 %) is acceptable within an analytical run, as long as the drift continues through the entire analysis and the standards are included at the beginning and end of the analytical run. Note: An alternative LC/MS/MS system may be used once demonstrated to be equivalent. The mass spectrometer is tuned for each analyte by infusing a - 1.0 glmL standard solution (at 10 Umin, using an infusion pump) via a 'T" into a stream of mobile phase containing 50% methanol and 50% 2m.M ammonium acetate in water at 0.2 mUmin flow rate. Each analyte is initially tuned for the parent ion and then tuned for the product ion. Once the instrument is tuned, the optimized parameters are saved as a tune file. This tune file is then used during routine analysis. 4.5.2. Calibration Curve Procedu.res a. Inject the same aliquot {between 10 to SO L) of each calibration standard (ranging from the lowest level standard to the highest level prepared), into the LC/MS/MS. b. Use weighted linear standard curves for quantitation. Linear standard curves are generated for each analyte by linear regression using 1/x weighting of peak area versus calibration standard concentration using Masslynx (or equivalent) software system. Any calibration standard found to be a statistical outlier by using an appropriate outlier test, may be excluded from the calculation of the calibration curve. However, the total number of calibration standards that may be excluded must not exceed 20% of the total number of standards injected. c. The correlation coefficient (R) for calibration curves generated must be ~.9925 (R2 ~.985). If calibration results fall outside these limits, then appropriate steps must be taken to adjust instrument operation, and the standards or the relevant set of samples should be reanalyzed. ~xygen Research Page IS of43 Exygen Research Page 125of153 418-028:PAGE G-126 Exygen Study No.: 023-072 Exygen Method No: ExM-023-071 Revision 1 Typical calibration curves forPFHS, PFOS and PFOA can be found in Figures 13. 4.5.3 Sample Analysis a. Inject the same aliquot (between 10 to SO L) of each standard, sample, recovery, control, etc. into the LC/MS/MS system. b. Standards corresponding to at least five or more concentration levels (starting with the LOQ level or below) must be included in an analytical set. c. An entire set of calibration standards should be injected at the beginning of a set followed by calibration standards interspersed approximately every S-10 samples (to account for a second set of extracted standards). As an alternative, an entire set of calibration standards may be included at the beginning and at the end of a sample set. In either case, calibration standards must be the first and last injection in a sample set. d. The concentration of each sample/fortification/control is determined from the standard curve, based on the peak area of each analyte. The standard responses should bracket responses of the residue found in each sample set. Results may be quantitated up to 10% outside the curve by extrapolation. If necessary, dilute the samples to give a response within the standard curve range. e. Fortification recoveries falling within 70 to 130% are considered acceptable. f. Samples must be stored refrigerated between 2C to 6C until analysis. g. Samples in which either no peaks are detected or peaks less than the lowest concentration of the calibration standards are detected at the corresponding analyte retention time will be reported as ND (not detected). Samples in which peaks are detected at the corresponding analyte retention time that are less than the LOQ and greater than or equal to the lowest concentration of the calibration standards will be reported as NQ (not quantifiable). The analysis perfonned dudng the method development included fortifications at 10 and SO ng/g of PFHS in rat liver, 10 and 50 nglmL of PFHS in serum, 10 and 50 ng/g of PFOS and PFOA in rat liver and 10 and 50 ng/mL of PFOS and PFOA in serum and urine. Typical chromatograms can be found in Figures 4-39. ;Exygen Resc:an:h Page 16of43 Exygen Research Page 126of153 418-028:PAGE G-127 Exygen Study No.: 023-072 Exygen Method No: ExM-023-071 Revision 1 4.6. ACCEPTANCE CRITERIA The following criteria must be met to ensure the presence of PFllS, PFOS and PFOA: 1. The chromatogram must show a peak of a daughter ion at 80 amu from a parent of 399 amu for PFIIS, a daughter ion at 99 amu from a parent of 499 amu for PFOS, and a daughter ion at 369 amu from a parent of 413 amu for PFOA. 2. Method blanks must not contain analyte at levels greater than the LOQ. 'If a blank contains the analyte at levels greater than 10 nglmL, then a new blank sample must be obtained and the entire set must be re-extracted. 3. Recoveries of control spikes and matrix spikes (if any) must be between 70-130% of their known values. 'If a control spike falls outside the acceptable limits, the entire set of samples should be re-extracted. Any matrix spike outside 70-130% should be evaluated by the analyst to detennine if re-extraction is warranted. 4. Any calibration standard found to be a statistical outlier by using the Huge Enor Test, may be excluded from the calculation of the calibration curve. However, the total number of calibration standards that could be excluded must not exceed 20% of the total number of standards injected. 5. The correlation coefficient (R) for calibration curves generated must be ~0.9925 (R2 ~.985). If calibration results fall outside these limits. then appropriate steps must be taken to adjust instrument operation. and the standards or the relevant set of samples should be reanalyzed. 6. Retention times between standards and samples must not drift more than 4 % within an analytical run. If retention time drift exceeds this li~l within an analytical run then the set must be reanalyzed. 4.7. PERFORMANCE CRITERIA The following two criteria must be perfonned once as a system suitability test. before the commencement of analysis, when using an instrumentation set-up that has not been used for this method. Fust Criterion: Run a standard solution on LC/MS/MS corresponding to the estimated LOQ (10 nglmL) in matrix and obtain a signal to noise ratio for the analyte transition of at least 9:1, compared to a reagent blank. If this criterion cannot be met, optimize and change instrument operating parameters (or increase the injection volume, if appropriate). ~xygen Research ---------------- ---- Page 17 of43 Exygen Research Page 127of153 418-028:PAGE G-128 Exygen Study No.: 023-072 Exygen Method No: ExM..023-071 Revision 1 Second Criterion: Run a set of standards of five or more concentration levels, from at or below the LOQ, up to the highest concentration level to be included in the analysis. Generate a calibration curve for the analyte and obtain a linear regression with a coefficient of determination (R2) of at least 0.985 for the analyte. Once this criterion is met, samples may be analyzed with standards interspersed. 4.8. TJME REQUIRED FOR ANALYSIS One person can take a set of 20 samples through the sample preparation procedure in approximately 4 hours. The LC/MS/MS analysis of the set (containing 20 field samples, 1 matrix blank, 2 laboratory control spikes, 1 matrix spike and 12 standard injections) will take approximately 14 hours. 5. CALCULATIONS a. Use Equation 1 to calculate the amount of analyte found (in nglmL, based on peak area) using the standard curve (1/x weighted linear regression parameters) generated by the Masslynx software program. Equation 1: Analyte found (ng/mL) =(peak area - intercept) x DF x aliquot factor slope DF =factor by which the final volume was diluted, if necessary. Aliquot factor= 10 for liver, 20 for serum and urine b. For samples fortified with known amounts of analyte prior to extraction, use Equation 2 to calculate the percent recovery. Eguation 2: Recovery(%) = [ total analyte found (ng/mL) - analyte found in control (nglmL)] x 100 analyteadded (nglmL) Note: Subtract analyte found in control (ng/mL) from analyte found (nglmL), if nglmL in control is greater than LOQ. ~xygen Research Page 18 of43 Exygen Research Page 128of153 418-028:PAGE G-129 Exygen Study No.: 023-072 Bxygen Method No: ExM023-071 Revision 1 c. Use Equation 3 to calculate the amount of analyte found (in ppb) Equation 3: = Analyte found (nglg or nglmL) Cana.Lvte found <nglml.> x FV CmL) sample wei1bt (g) or sample volume (mL) FV =final volume For reporting purposes, samples in which either no peaks are detected or peaks less than the lowest concentration of the calibration standards are detected at the corresponding analyte retention time will be reported as ND (not detected). Samples in which peaks are detected at the corresponding analyte retention time that arc less than the LOQ and greater than or equal to the lowest concentration of the calibration standards will be reported as NQ (not quantifiable). 6. SAFETY The analyst should read the material safety data sheets for all standards and reagents before performing this method. Use universal precautions when handling standards and reagents, including working in fume hoods and wearing laboratory coats, safety glasses, and gloves. ~xygcn Research . ------------ Exygen Research Page 19of43 Page 129of153 418-028:PAGE G-130 Exygen Study No.: 023-072 Exygen Method No: ExM-023-071 Revision l Table 1. Recovery Summary of PFHS in Rat Liver and Serum Recovery Summary of PFHS In Rat Liver Sample ID 0201684 Spk A 0201684 Spk 8 0201684 Spk C Analyte Added (ng/g) 10 10 10 Average: Standard Deviation: Percent Recovery (%) 108 110 126 115 9.9 Sample ID 0201684 Spk D 0201684 Spk E 0201684 Spk F AnalYte Added (ng/g) 50 50 50 Average: Standard Deviation: Percent Recove7 (%) 101 98 94 98 3.5 Recovery Summary of PFHS In Rat Serum Sample ID 0201682 Spk A 0201682 Spk B 0201682 Spk C Analyt& Added (ng/ml) 10 10 10 Average: Standard Deviation: Percent Recovery (%) 112 103 110 108 4.7 Sample ID 0201682 Spk D 0201682 Spk E 0201682 Spk F Analyte Added (ng/mL) 50 50 50 Average: Standard Deviation: Percent Recovery (%) 107 104 122 111 9.6 ~xygen Research Exygen Research Pagc20of43 Page 130of153 418-028:PAGE G-131 Exygen Study No.: 023-072 Exygcn Method No: ExM-023-071 Revision l Table 2. Recovery Summary of PFOS in Rat Liver, Serum and Urine Recovery Summary of PFOS In Rat Uver Sample ID 0201684 Spk A 0201684 Spk B 0201684 SpkC Analrta Added (ng/g) 10 10 10 Average: Standard Deviation: Percent Recove7 (%) 88 95 105 96 8.5 Sample ID 0201684 Spk D 0201684 Spk E 0201684 Spk F AnalY!e Added (na(ll) 50 50 50 Average: Standard DevlaUon: Percent Recovery(%) 90 88 87 88 1.5 Recovery Summary of PFOS In Rat Serum Sample ID 0201682 Spk A 0201682 Spk B 0201682 SpkC Analy!e Added <ng/mL) 10 10 10 Average: Standard DevlaUon: Percent Recoverx (%) 80 85 99 88 9.8 Sample ID 0201682 Spk D 0201682 Spk E 0201682 Spk F Analyta Added CnplmL) 50 50 50 Average: S1andard Deviation: Percent Recovery(%) 118 122 121 120 2.1 Recovery Summary of PFOS In Rat Urine Sample ID 0201682 Spk A 0201682 Spk B 0201682 Spk C Analyta Added (np/mL) 10 10 10 Average: Standard Deviation: Percent Recovery(%) 98 89 91 93 4.7 Sample ID 0201682 Spk D 0201682 Spk E 0201682 Spk F Analyte Added (ng/mL) 50 50 50 Average: Standard Deviation: Percent Recove7 (%l so 78 78 79 1.2 ~xygen Research Page21 of43 Exygen Research Page 131 ofl 53 418-028:PAGE G-132 Exygen StudY, No.: 023-072 Exygen Method No: ExM-023-071 Revision l Table 3. Recovery Summary of PFOA in Rat Liver, Serum and Urine Recovery Summary of PFOA In Rat Liver SamplalD 0201684 Spk A 0201684 Spk B 0201684 Spk C Analyte Added (npfg) 10 10 10 Average: Standard Deviation: Percent Recove7 (%) 95 101 99 98 3.1 Sample ID 0201684 Spk D 0201684 Spk E 0201684 Spk F Analyta Added (ng/g) 50 so 50 Average: Standard Deviation: Percent Recoveq (%> 97 82 94 94 2.5 Recovery Summary of PFOA In Rat Serum Sample ID 0201682 Spk A 0201682 Spk B 0201682 Spk C Analv!a Added CnplmL) 10 10 10 Average: Standard Deviation: Percent Recovery(%) 118 117 115 117 1.5 Sample ID 0201682 Spk D 0201682 Spk E 0201682 Spk F Analvta Added (ng/mL) 50 50 60 Average: Standard Deviation: Percent Recove7 (%) 107 112 116 111 4.0 Recovery Summary of PFOA in Rat Urine Sample ID 0201682 Spk A 0201882 Spk B 0201682 Spk C AnalyJ: Added (ng/mL) 10 10 10 Average: Standard Deviation: Percent Recovery(%) 88 91 89 89 2.5 Sample ID 0201682 Spk D 0201682 Spk E 0201682 Spk F AnMe Added (nplmL) 50 50 50 Average: Standard Deviation: Percent Recovery(%) 89 88 as 87 2.1 ~ygen Research -------- -- ------- Page 22 of43 Exygen Research Page 132of153 418-028:PAGE G-133 Exygen Study No.: 023-072 Exygen Method No: ExM-023-071 Revision 1 Figure 1. Calibration Curve for PFHS Compound 1 name: PFHS Coafflolent of Detisnninatlan: 0.996485 CallbraUon curve: 1918.28 x +9.14134 Response type: Extemal Sid, Area Curve type: Unear, Origin: E.ll:lude, Weighting: 1hr, Aids trans: None 9.9883 o.o 0.5 1.0 1.5 2.0 3.0 3.5 4.0 4.5 ~xygen Research Exygen Research Pagc23 of43 Page 133of153 418-028:PAGE G-134 Exygen Study No.: 023-072 Exygen Method No: ExM-023-071 Revision 1 Figure 2. Calibration Curve for PFOS Compound 2 name: PFOS Coefficient of Determination: 0.997009 CaHbration curve: 3211.30 x + 48.9285 Response type: Extemal Std, Area Curve type: Linear, Origin: E>lclude, Weighting: 1/x, Alis trans: None 1.62e4 Respons ~~_.................................,...,.._,........,...._..,.....,..,..,..,..,.........,,...,..,.........._..._____ n~rrL. 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 ~xygen Research Exygen Research Page24of43 Page 134of153 418-028:PAGE G-135 Exygen Study No.: 023-072 Exygen Method No: BxM-023-071 Revision 1 Figure 3. Calibration Curve for PFOA COl'1'JOUnd 1 name: PFOA Coefficient of Determination: 0.995945 Cafibratlon curve: 31270.9 x + 3675.36 Response type: E>Cternal Std, Area CUrve type: linear, Origin: E>elude, Weighting: 1Ix, Axis trans: None 1.66e5 ~xygcn Research Exygen Research Page 25of43 Page 135of153 418-028:PAGE G-136 Exygen Study No.: 023-072 Exygen Method No: ExM-023-071 Revision 1 Figure 4. Representative Chromatogram of a 0.1 ng/mL Standard Containing PFHS COl21111.f, o.1 ngl'mL l'FHS ,ORIDZA-101 5111 lMl,212) 2....un4!11112 tl:112:IO LCIMSIMSn 1 MRM1111ClllllllllES- I.II :llllhollll 2.i'la'I "'- 1.1111 2.00 3.00 of.Oii Figure 5. Representative Chromatogram of a 0.1 ng/mL Standard Containing PFOS COG5GZ-I, 0.1 nglml. PFOA llfld PFOS 070ell2lr101Sm(~2'121 ' aa.Jul-21111211:25:21 -l.07 LCJMS/MS17 -012a..-rsa1h111 alllleS "'- 1.0D z.oa a.oa .oa a.oa 1.1111 1.00 e.oo 1.oa 111.00 11.00 ~xygen Research Page26of43 Exygen Research Page 136of153 418-028:PAGE G-137 Exygen Study No.: 023-072 Exygen Method No: ExM-023-071 Revision l Figure 6. Representative Chromatogram of a 0.1 ng/mL Standard Containing PFOA COl25CIH, Q,1 ng(tnL Pf'OA- PFOS ,07011112A-112 Sm (Mn. 212) -.... 11Wv14llOl 12t17:41 l.CIMSIMSt7 MAM Of 2 Chlllllllt ES 413>38l 4.8294 Mii Figure 7. Representative Chromatogram of a 0.5 ng/mL Standard Containing PFHS CC182102'4, OJI ng{JN. PFHS 0821UIA1113 Sm(..,, 21r2) 1 2....,u1140Clll 11:41:11 LC/MSIM8t7 1,.._- MAMd1C,,.,.,..ES. 1.17 31111>80 1111 ~xygcn Research ------------ Exygen Research Pagc27of43 Page 137 ofl53 418-028:PAGE G-138 Exygen Study No.: 023-072 Exygen Method No: ExM-023-071 Revision 1 Figure 8. Representative Chromatogram of a 0.5 ng/mL Standard Containing PFOS CllU5DM, O.S nQfml.. PFOAand PFO& 01'1111J:ZA.1D3 Siii (Ml. 2'c2) I 08.lul-211112 19:07:17 Lc.tlSIMSl7 MAMalZa-...IE&o .... 4119>111 .-.... IUI 1.41114 Figure 9. Representative Chromatogram of a 0.5 ng/mL Standard Containing PFOA COl2502-4, 0.5 nWmL PFOA.Md PFOS ,070902A-103 Sm (Mn, 2112) ;Exygen Research Exygen Research Page28 of43 Page 138of153 418-028:PAGE G-139 Exygen Study No.: 023-072 Exygen Method No: ExM-023-071 Revision 1 Figure 10. Representative Chromatogram of a 5.0 ng/mL Standard Containing PFllS CllU10Z.1, 5.0 ng/'lllL PFH& O!l21112A10lllnl(l.tl,21r21 1 24.lun-20Q2 17:51::11 "" "'"" LCIMSft\1817 ,,...al 1Chnlll El- 1.17 lllllh llO 1.13111 .,.._.....,...,.._.,.._,...._,,_..,,.....,........,.......,......,..._.,..-.,..._,....._,_-,.-.,-...,._.,...-,_..,,.......,........,.......,.......,Time 1.00 2.llO 3.00 4.00 5.CO UICI 7.llO 1.00 II.CO I D.00 11.00 12.00 Figure 11. Representative Chromatogram of a 5.0 ng/mL Standard Containing PFOS CGRSGll-1, S.D ngflnL PFOA .nd PFOS ll7Gll02A-108Sm(Mn,2X2) 1 11Wul4002 20:10:51 - I.GI 111111 LCIMSIMSll1 MRMo12~ES .ilH>llt t.18t5 ~xygen Research Exygen Research Page29 of43 Page 139of153 418-028:PAGE G-140 Exygen Study No.: 023-072 Exygen Method No: ExM-023-071 Revision I Figure 12. Representative Chromatogram of a 5.0 ng/mL Standard Containing PFOA C09251J2.1, 5.D nwin. PFOA and PFOS D71111C12A-tOBa..(Mn.2":1) ' Olhlul40ll2 20:1D:51 -.... LCIMSIMSt7 MAM al 2Chlmell E$. 413>311 1.IM Ala o.1-.....c:;.......-....-....,._-,-...,......,.....,.......,.........,.....,......,.............,_..,.....,...l!!f!:.;;;;;;:;:;:;;:;;;;;:;:;;=;,....._Tlme 2.DD S.DD 4.1111 5. I.OD 7.llO I.DD 11.1111 111.111 ti.DD Figure 13. Representative Chromatogram of a Reagent Blank Sample Analyzed for PFHS ReagantBlmnkA 012102A-IOB Sm (Mn. 2121 I .. - twun2G02 11:34:40 LCIMSIMSlll MRM .. 1Cllallnll l!SM> 811 I.DO ~xygen Research Exygen Research Pagc30of43 Page 140of153 418-028:PAGE G-141 Exygen Study No.: 023-072 Exygen Method No: ExM-023-071 Revision 1 Figure 14. Representative Chromatogram of a Reagent Blank Sample Analyzed for PFOS DS-.lu1411112 2D:S3:11 4,,-.., LCIMSIMSn MAUalla......ESI.II 1111 Figure 15. Representative Chromatogram of a Re.agent Blank Sample Analyzed for PFOA Ruganl Bl1m A 070llD2A-108Sm1Mn.~ 1 IJll..JUHllllZ 2D:51:11 LCIM!IMSff MRM DI 2 Chlnnelt ES- 413>3111 l.1G114 ""- ~xygen Research Exygen Research Pagc31 of43 Page 141 of153 418-028:PAGE G-142 Exygen Study No.: 023-072 Exygen Method No: ExM-023-071 Revision 1 Figure 16. Representative Chromatogram of a Control Liver Sample Analyzed for PFHS IXIDlll4LmrBllllkA 08211121r110lllll(Mn.21121 I 14-Jun-2Dll2 11:17:57 l.CIMWSn MllMG11 CllonnllES- 7.111 !lllt>IO 1.llllS I.GI 7.11 117 1.21 Figure 17. Representative Chromatogram ofa Control Liver Sample Analyzed for PFOS 0201114 Uvar BlmnkA 071181121rl10Snt CMn.2121 1 -1.12 Ol.Jul~DllZ21:35:17 LCIMSIM&f7 MRMo12CllilMllllES- 4111>111 S.37.a AIM ~xygcn Research Exygen Research Page 32of43 Page 142 of153 418-028:PAGE G-143 Exygen Study No.: 023-072 Exygen Method No: ExM-023..07 I Revision 1 Figure 18. Representative Chromatogram of a Control Liver Sample Analyzed for PFOA ll201114UverBl1nkA .... lmle02A-110Sm IMn. 2IQ) 1 am Figure 19. Representative Chromatogram of a Control Serum Sample Analyzed for PFHS 0201112 Serum Blnk A OS!!OV..122 Sm ...... 2'121 I 11.17 Z.WUll40Cl2 23:38:22 LCIMSIMSt7 MRMd1 a . - ES- 31111> llO 250 !CUii 1.21 1.11 1.a UI 1.11 1.54 & 1.15 U7 Ml UI n.1 11.511 11.71 ~xygen Research Page33 of43 Exygen Research Page 143of153 418-028:PAGE G-144 Exygen Study No.: 023-072 Exygen Method No: ExM-023-071 Remian 1 Figure 20. Representative Chromatogram of a Control Serum Sample Analyzed for PFOS 070llll2A.122 Siii (Mn, 2112) 1 I.Ill :m Figure 21. Representative Chromatogram of a Control Serum Sample Analyzed for PFOA 0201612 Smrum Bl111k A D7111D2A-122 Sm(..... 21121 1 ..-. lllhlu141111Z 01 :41:00 LCIMSIMSt7 -OIZCI-*' ES13>3111 2.8714 "'- ~xygen Research Exygen Research Page34of43 Page 144of153 418-028:PAGE G-145 Exygen Study No.: 023-072 Exygen Method No: Ex.M-023-07 I Revision 1 Figure 22. Representative Chromatogram of a Control Urine Sample Analyzed for PFOS D20tlll3 Urine Blank A ,070802A-f34 Sm ("'1, 212) .. ....,Ul-2CIGIOl:C12.."21 LCIMSlllS t7 MRM Ol 2 Cllltnnllla ES- I.Gt 99>911 l.35d kfla Figure 23. Representative Chromatogram of a Control Urine Sample Analyzed for PFOA 020111&1 Uri... Blank B 0111eOZA-135 Sm {Mn. 21QI 1 -1.1111 lll-Jul-QD02 08:23:31 LCIMSIMSl7 MRMllllClllMll1 ES411> 311 7.11194 Miii ~xygcn Re.search ------------------------- Page3S of43 Exygen Research Page 145of153 418-028:PAGE G-146 Exygen Study No.: 023-072 ExygenMethod No: ExM-023-071Revision1 Figure 24. Representative Chromatogram of a Control Liver Sample Fortified at 10 ng/g with PFHS 0201A4 Lfwl' Spk"' 10 ppb Gll21112""11Um(Mn,21QJ I - a.~1111..211112 20:23:00 LCIUtnlln MAMdlChlnftllES 3111> .. UlllM Figure 25. Representative Chromatogram of a Control Liver Sample Fortified at 10 ng/g with PFOS 02011M Ll'9r$plcA, 1Dppb IJ1'0802A..113Sm(Mn,212) I oa.Jul-:&Om 22:31:51 Lc.MSIMStn -all~ES. .... 4llll>M '-- 11111 ~xygen Research Exygen Research Page36of43 Page 146of153 418-028:PAGE G-147 Exygen Study No.: 023-072 Exygen Method No: ExM-023-071 Revision 1 Figure 26. Representative Chromatogram of a Control Liver Sample Fortified at 10 ng/g with PFOA Ga01114UVll'SpkA, 10ppll 1DllllD2A-t1S h IMn. Ml 1 1.00 2.00 3.llO ol.00 I.GO I.GO 1.1111 l.llO ll.llO 10.UD 11.CIO Figure 27. Representative Chromatogram of a Control Liver Sample Fortified at SO ng/g with PFHS 02ot1u uwr Siik o. so pplJ 1111210i2Aot18S..CU...21<21 1 l~Un-2002 21:21:01 t.u 11411 -LC/MSllllS ff -Gl1CllMnefE5 31111>111 7.11514 oJ....,..,......1...a..a.....,..2..a.a.,,_...a.o.o....,..4_.0,0.._,...s.._a,a......e...a,a......1..1-11.1--.,..a..o-.a--,~~~a"m"".'t':.1"0..a.a..,...n...a~a..,...1.2~.1~1l0lm ~xygcn Research Page37 of43 Exygen Research Page 147of153 418-028:PAGE G-148 Exygen Study No.: 023-072 Exygen Method No: ExM-023-071 Revision l Figure 28. Representative Chromatogram of a Control Liver Sample Fortified at SO nglg with PFOS 1120HNM Lhw Spic D, SCI ppb a11111lZA-11esm1r.tt.2'121 I - llWul-2002 23:412:12 LCIMSIMSR aoe MllM al 2 Chlnnlll ES S.""4 Arla Figure 29. Representative Chromatogram of a Control Liver Sample Fortified at SO ng/g with PFOA 02011184 u - Spk D, 50 ppb G'IDell2A-118Sm(Mn.212) 1 Ga.I~ 2:1:42:12 ..... ...... IU79 LCIMSIMSt7 MRMDl2Cll-ES- 413"381 11.51115 ;Exygen Research Exygen Research Page 38 of43 Page 148of153 418-028:PAGE G-149 Exygen Study No.: 023-072 Exygen Method No: ExM-023-071 Revision 1 Figure 30. Representative Chromatogram of a Control Serum Sample Fortified at 10 ng/mL with PFHS 02D1112 s"um Spk a, 10 ppti .... Clll2102A-128 l!m (Mn, 2112) I ID! Figure 31. Representative Chromatogram of a Control Serum Sample Fortified at 10 ng/mL with PFOS m01112 S.rum Spk a, 10 ppb 071111D2A-12DSm(Mn.2"2J 1 U7 1 I. 2.00 :S.00 4.00 5.00 II.Oil ~xygen Research Pagc39 of43 Exygen Research Page 149of153 418-028:PAGE G-150 Exygen Study No.: 023-072 Exygen Method No: ExM-023-071 Revision 1 Figure 32. Representative Chromatogram of a Control Serum Sample Fortified at 10 ngfmL with PFOA oaotem Serum Sp~ A, 1Dppll 11711102k125 Sm (Mn, 2112) 1 m.Jul-lllllRDl:ll2:21 LCINSIMS,,, MAM al 2 ChanMls Eli 411b311 1.G2t! ArM Figure 33. Representative Chromatogram of a Control Serum Sample Fortified at SO ng/mL with PFHS CIZl>181Z s.rwn Spic D, llO PPll Oll21112A-121Sm(Mn.2"2) I Z&Jun2002 01:48:311 -. ,. -LCIMS/MS'7 - al 1 CllMnll ES3118> IO 4.1714 ~xygen Research - - - - - -----"------ _,,___ .. Pagc40 of43 Exygen Research Page 150of153 418-028:PAGE G-151 Exygen Study No.: 023-072 Ex~ Method No: ExM-023-071 Revision 1 Figure 34. Representative Chromatogram of a Control Serum Sample Fortified at SO ng/mL with PFOS 112CH182a.wa&pkD,,50ppb ,G7111112A-111Sn!(lltt,2d) ...... Figure 35. Representative Chromatogram of a Control Serum Sample Fortified at 50 ng/mL with PFOA D201112 Serunt lpk E, ID ppll ,~121Smtl*l.2112) -.... ~xygen Research Exygen Research Page41 of43 Page 151 of153 418-028:PAGE G-152 Exygen Study No.: 023-072 Exygcn Method No: ExM-023-071 Revision l Figure 36. Representative Chromatogram of a Control Urine Sample Fortified at 10 ng/m.L with PFOS Q20lll3i.tneSpkA,.10ppb lmllll'lA-1S7 Sm (Mn, Zd) ' ...... Figure 37. Representative Chromatogram of a Control Urine Sample Fortified at 10 nglmL with PFOA D201tallrlnelSplCB,.10ppb 11101112A-131Sm(Mn,2112) 1 ~ul-21m07:lll:U ....lll7S1 -Lf:Ml/llS17 MllMIJl2-U. 411> l.4'18C ~xygcn Research Exygen Research Page42of43 Page 152of153 418-028:PAGE G-153 Exygen Study No.: 023-072 Exygen Method No: ExM-023-071 Revision 1 Figure 38. Representative Chromatogram of a Control Urine Sample Fortified at 50 nglmL with PFOS ll201113 lktn. Spk D, llO ppb cmmzA-14119111 (Mn.112) 1 -UI' Figure 39. Representative Chromatogram of a Control Urine Sample Fortified at 50 nglmL with PFOA G21l1113 ~n Spic D, SO ppb llJlllCl2M40&n (Mii, 21121 1 II.a 3"11 ~xygcn Research Exygen Research Page43 of43 Page 153of153 APPENDIXH TEMPERATURE AND RELATIVE HUMIDITY REPORTS ARGUS 418-028:PAGE H-1 Temperature and Relative Humidity Report Location: Room 05 Protocol Number: 418-028 Range of Dates: 26-Mar-2002 14:20to10-Jun-2002 08:59 Target Range: Species: Rat Total Number of Days: Total Number of Hours: Total Number of Data Points: Temperature 64F to 79F 77 1818.25 1817 Relative Humidity 30% to 70% 77 1818.25 1817 Mean( SD): Maximum: Median: Minimum: Number of Points in Range (%): Number of Points High (%): Number of Points Low (%): 69.2 71.0 69.2 66.0 1817 0 0 ( 0.7) (100.0) (0.0) (0.0) 54.6 64.5 55.3 36.4 1817 0 0 (4.4) (100.0) (0.0) (0.0) Report Generated: 1O-Jun-2002 at 13:26 REVIEWED BY: in:;J;. m . (_.J.g DATE: {g lt:> ~ :J APPENDIX I POSITIVE CONTROL DATA 418-028:PAGE 1-1 Historical Control Data This Functional Observation Battery Standard Operating Procedure and Studies conducted to document the training and competency of the technical staff and Motor Activity Negative Control Data and Positive Control Data are available at the Testing Facility. Page 1 418-028:PAGE 1-2 Summary Information for Functional Observation Battery Study Number - Title In-Life Start Test Substance Dosage Information mg/k~ mUka Number of Dosages 012-006- Validation ofFunctional Observational Battery and Motor Activity Measure Using Positive Test Substances 12/89 acryJamide 50 7 physostigmine 0.75 1.5 DDT 15 012-014- Neurotoxicity Evaluation of Positive Control Substances in Crl:CDBR VAF/Plus Rats 9/91 acrylamide 40 9 IDPN 200 3 carbaryl 15 s DDT 15 s t:J.iadimefon 200 5 012-015- Neurotoxicity Evaluation of DDT in Crl:CDBR VAF/Plus Rats 3/92 DDT 15 012-017- Neurotoxicity Evaluation of Positive Control Substances in Crl:CDBR VAF/Plus Rats 5192 acrylamide 40 9 IDPN 200 3. carbaryl 40 5 DDT 15 d-amphetamine 4.0 012-022 - Neurotoxicity Evaluation of Carbaryl in Crl:CDBR VAF/Plus Rats 10/92 carbaryl 40,200 5 012-031 - Neurotoxicity Evaluation of Positive Control Substances in Crl:CDBR VAF/Plus Rats 7/93 acrylamide 45 10 IDPN 250 4 carbaryl 40 5 DDT 75 d-amphetamine 4 Page2 012-056- Neurotoxicity Evaluation of Positive Control Substances in Crl:CDBR VAF/Plus Rats 012-075 - Neurotoxicity Evaluation of Positive Control Substances in Crl:CDBR VAF/Plus Rats 012-081-Neurotoxicity Evaluation of Positive Control Substances in Crl:CDBR VAF/Plus Rats 418-028:PAGE 1-3 11195 acrylamide 45 IO IDPN 250 s carbaryl 40 DDT 15 d-amphetamine 4.0 3/98 acrylamide 30 17 trimethyltin 8 MK-801 0.3 carbaryl 100 4 DDT 100 2 11/01 acrylamide 30 10 IDPN 250 d-amphetamine 40 carbaryl 100 4 DDT 100 2 5 Page3 418-028:PAGE I-4 Summary Information for Motor Activity Study - Title In-Life Start O12-011 - The Assessment of Motor Activity in Neonatal and Adult Rodents using Passive Infrared Sensors 5/91 012-014- Neurotoxicity Evaluation of Positive Control Substances in Crl:CDBR VAF/Plus Rats 9/91 012-016 - Motor Activity Evaluation in Crl:CDBR VAF/Plus Rats Administered Chlorpromazine and dAmphetamine (Positive Control Study) 012-058-Neurotoxicity Evaluation of Positive Control Substances in Crl:CDBR VAF/Plus Rats 4196 Test Substance Dosage Information Number of mg/kg ml/kg Dosages d-amphetamine chlorpromazine 0.75, l.5,4 1,2,4 aczylamide 40 9 IDPN 200 3 carbaryl 75 5 DDT 15 5 triadimefon 200 5 d...amphetamine chlorpromazine 0.5, l,4 1,2,4 acrylamide 45 10 d-amphetamine 0.75 trimethyltin 8 MK-801 10 Page4 APPENDIXJ HISTOPATHOLOGY REPORT 418-028:PAGE J-1 RESEARCH PATHOLOGY SERVICES, INC. 438 East Butler Avenue, New Britain, PA 18901 Phone: 215-345-7070 Fax: 215-345-4326 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCEENING TEST PROTOCOL 418-028 SPONSOR'S STUDY NUMBER T-7706.1 HISTOPATHOLOGY REPORT SUBMITTED TO: Raymond G. York, Ph.D., D.A.B.T. Argus Research 905 Sheehy Drive Horsham, PA 19044 SUBMITTED BY: July 3, 2003 418-028:PAGE J-2 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-028 SPONSOR'S STUDY NUMBER T-7706.1 HISTOPATHOLOGY REPORT TABLE OF CONTENTS REPORT Page Method ....................................................................................................................... 1 Results .......................................................................................................................3 Summary ....................................................................................................................5 Quality Assurance Unit Statement ............................................................................. 6 Good Laboratory Practice Compliance Statement ..................................................... 7 TABLE 1. Incidence and Degree of Severity of Histomorphologic Observations .................... 8 APPENDICES I. Histomorphologic Observations ...............................................................1-1 to 1-12 Key to Histomorphologic Observations ............................................................... 1-1 Tables 1-1. Histomorphologic Observations - Group I Male Rats ............................... 1-2 1-2. Histomorphologic Observations - Group II Male Rats .............................. 1-4 1-3. Histomorphologic Observations - Group Ill Male Rats ............................. 1-5 1-4. Histomorphologic Observations - Group IV Male Rats ............................. 1-6 1-5. Histomorphologic Observations - Group V Male Rats .............................. 1-7 1-6. Histomorphologic Observations - Group I Female Rats ........................... 1-9 1-7. Histomorphologic Observations - Group V Female Rats ........................ 1-11 II. Individual Animal Gross and Histomorphology Data .............................. 11-1 to 11-70 Ill. Histomorphologic Observations in the Liver - F1 Generation Pups ....... 111-1 to 111-2 Tables 111-1. Histomorphologic Observations in the Liver- Group I F1 Generation Pups ............................................................................... 111-2 111-2. Histomorphologic Observations in the Liver- Group V F1 Generation Pups ............................................................................... 111-3 418-028:PAGE J-3 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-028 SPONSOR'S STUDY NUMBER T-7706.1 HISTOPATHOLOGY REPORT METHOD Microscopic examination was made of the specified tissues from 50 adult male and 20 adult female Crl:CD(SD)IGS BR VAF/Plus rats from five groups in an oral (gavage) combined repeated dose toxicity study of T-7706 (PFHS) with the reproduction/developmental toxicity screening test. In addition, microscopic examination was made of the liver of 10 pups in each of the control and high dosage groups of the F1 Generation. A brief outline of the study design showing the dose group identification, number of rats per sex per group, and dosage levels of the control and test substances are shown below. DOSAGE GROUP I NUMBER OF RATS PER SEXa 15 + 3c DOSAGE (mg/kg/day) 0 CONCENTRATIONb (mg/ml) 0 DOSE VOLUME (mUkg) 10 II 15 + 3c 0.3 0.03 10 Ill 15 + 3c 1 0.1 10 IV 15 + 3c 3 0.3 10 v 15 + 3c 10 1 10 a.Ten male and ten female rats of Groups I and V were assigned for h1stopatholog1c evaluation. bThe test substance was considered to be 100% active for the purpose of dosage calculations. crhree additional rats per sex per dosage group were assigned to toxicokinetic sample collection. Male rats were given the test substance once daily beginning 14 days before a cohabitation period that consisted of a maximum of 14 days. Dosing continued through the day before sacrifice, after completion of a cohabitation period, after a minimum of 42 days of administration. Female rats were given the test substance once daily beginning 14 days before a cohabitation period that consisted of a maximum of 14 days. Dosing continued through the day before scheduled sacrifice (Day 22 of lactation). Dosages were adjusted daily for body weight changes and were given at approximately the same time each day. The first day of dosing was desig- Research Pathology Services, Inc. -1 418-028:PAGE J-4 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-028 SPONSOR'S STUDY NUMBER T-7706.1 HISTOPATHOLOGY REPORT nated as Day 1 of the study. Pups were sacrificed and necropsied on Day 22 postpartum. All rats were necropsied and the specified tissues were collected and placed in 10% neutral buffered formalin for fixation. The testes were fixed in Bouin's solution for 48 to 96 hours and then retained in 10% neutral buffered formalin. The in-life portion of the study, necropsies, and recording of the gross necropsy observations were performed by the staff of Argus Research, Horsham, PA. The tissue processing, microscopic slide preparation and histopathologic evaluation were performed by Research Pathology Services, Inc. The tissues specified for microscopic evaluation from 10 male and 10 female rats of Groups I and V included: brain, duodenum, jejunum, ileum, cecum, colon, rectum, Peyer's patch, lung, submandibular and mediastinal lymph nodes, sciatic nerve, stomach, kidneys, spleen, thymus, trachea, urinary bladder, testes, epididymides, seminal vesicles, coagulating gland, prostate, spinal cord (cervical, lumbar and thoracic), liver, adrenal glands, heart, thyroid, parathyroid, uterus, bone marrow (sternum), ovaries, uterus, vagina, mammary gland (female rats) and all other tissues with gross changes. In addition, the liver and thyroid of 10 male and 10 female rats in each of the intermediate dosage groups were examined. The liver of 9 or 10 pups F1 generation pups from each of the 10 selected control and high dosage female rats were also examined. Representative samples of these tissues were routinely processed, embedded in paraffin, sectioned, and stained with hematoxylin and eosin for microscopic evaluation. In addition, sections of the testes from the control and high dosage group male rats were stained with periodic acid-Schiff (PAS) reaction and examined. The study was initiated on June 24, 2002 and completed on July 3, 2003. Upon completion of the project, all raw data (remaining wet tissue, paraffin blocks, microscopic slides and histology records) will be returned to Argus Research for archiving. Research Pathology Services, Inc. -2 418-028:PAGE J-5 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-028 SPONSOR'S STUDY NUMBER T-7706.1 HISTOPATHOLOGY REPORT RESULTS The type, incidence and degree of severity of the histomorphologic changes in the specified tissues for the male and female rats are presented in Table 1. The microscopic observations in each rat are summarized in tabular form in Appendix I (Tables 1-1 to 1-7). A key to the histomorphologic observations precedes Table 1-1. The gross necropsy observations, detailed descriptions of the microscopic observations, and a correlation of the microscopic findings with the gross changes in these rats, when applicable, are contained in Appendix II. The histomorphologic observations in the liver of the F1 Generation pups of the control and high dosage groups are summarized in tabular form in Appendix Ill (Tables 111-1 and 111-2). A key to the histomorphologic observations is included on Tables 111-1 and 111-2. No treatment-related microscopic changes were observed in any of the male rats given 0.3 or 1 mg/kg/day of the test substance or in female rats given 1O mg/kg/day of T-7706. Treatment-related microscopic changes were observed in the liver and thyroid gland of male rats of the 3 and 10 mg/kg/day dosage groups. The treatment-related microscopic change in the liver consisted of minimal to moderate enlargement (hypertrophy) of centrilobular hepatocytes (Table 1). The affected hepatocytes were enlarged with an increased amount of dense eosinophilic granular cytoplasm. The treatment-related effect in the thyroid gland consisted of an increased incidence of male rats of the 3 and 10 mg/kg/day dosage groups with hypertrophy (enlargement) of follicular cells and hyperplasia (increased follicular cells and small follicles) in male rats (Table 1). Although the incidence in Group IV was minimally increased over the controls, the hypertrophy and hyperplasia in this group of rats could have been associated with the liver-cell changes. These microscopic changes in the liver and thyroid are consistent with the known effects of compounds that cause microsomal enzyme induction where the hepatocellular hypertrophy results in a compensatory hypertrophy and hyperplasia of Research Pathology Services, Inc. -3 418-028:PAGE J-6 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-028 SPONSOR'S STUDY NUMBER T-7706.1 HISTOPATHOLOGY REPORT the thyroid due to increased plasma turnover of thyroxine and an associated stimulation of thyroid-stimulating hormone in rats. 1 There were no compound-related microscopic changes observed in the liver of the F1 generation pups from the dams given 10 mg/kg/day of the test substance. There were a few other microscopic changes observed in the various organs and tissues which were considered to have occurred spontaneously and to be incidental and unrelated to compound administration. The type, incidence and severity of these changes were not influenced by compound administration. These changes also are listed in the attached histomorphology tables. 1 Sanders, J.E., Eigenberg, D.A., Bracht, L..J., Wang, W.R., and van Zwieten, M.J., Thyroid and Liver Trophic Changes in Rats Secondary to Liver Microsomal Enzyme Induction Caused by an Experimental Leukotriene Antagonist (L-649,923), Toxicology and Pharmacology 95, 378-387 (1988) Research Pathology Services, Inc. -4 418-028:PAGE J-7 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-028 SPONSOR'S STUDY NUMBER T-7706.1 HISTOPATHOLOGY REPORT SUMMARY Microscopic examination was made of the SJ:>ecified tissues from five groups of male and female Crl:CD(SD)IGS BR VAF/Plus rats used in an oral (gavage) combined repeated dose toxicity study of T-7706 with the reproduc;.. tion/developmental toxicity screening test. The five groups of rats had been given the vehicle (aqueous 0.5% carboxymethylcellulose), or 0.3, 1, 3 or 10 mg/kg/day of T-7706, orally by gavage, once daily for the protocol-specified number of days. In addition, the liver was examined microscopically from 9 or 10 pups of the F1 generation from 10 dams each of the control and high dosage groups. No treatment-related microscopic changes were observed in female rats given 10 mg/kg/day of T-7706 or in male rats given 0.3 or 1 mg/kg/day of T-7706. Treatment-related microscopic changes were observed in the liver and thyroid of male rats of the 3 and 10 mg/kg/day dosage groups. The treatment-related change in the liver consisted of minimal to moderate hypertrophy of centrilobular hepatocytes and the effect in the thyroid was an increased incidence of male rats with a compensatory hypertrophy and hyperplasia of the follicular epithelium in these groups of male rats. No treatment-related microscopic changes were observed in the liver of the F1 generation pups from dams given 10 mg/kg/day of T-7706. All other microscopic changes were considered to be spontaneous in origin and not treatment-related. The type, incidence or severity of these changes were not considered to be influenced by administration of the test substance. Research Pathology Services, Inc. -5 418-028:PAGE J-8 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-028 SPONSOR'S STUDY NUMBER T-7706.1 HISTOPATHOLOGY REPORT QUALITY ASSURANCE UNIT STATEMENT All aspects of the tissue processing, microscopic slide preparation, histopathologic evaluation and report preparation for the study listed above have been performed according to the Standard Operating Procedures of Research Pathology Services, Inc. and were audited in accordance with the procedures established by the Quality Assurance Unit of Research Pathology Services, Inc. in compliance with the Good Laboratory Practice regulations specified in the protocol. Organisation for Economic Cooperation and Development (1996). OECD Guideline for Testing of Chemicals. Section 4, No. 422: Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, adopted 22March1996. Organisation for Economic Cooperation and Development (1998). The Revised OECD Principles of Good Laboratory Practices [C(97)186/Final). US Food and Drug Administration. Good Laboratory Practice Regulations: Final Rule. 21 CFR Part 58. Japanese Ministry of Health and Welfare (1997). Good Laboratory Practice Standard for Safety Studies on Drugs, MHW Ordinance Number 21, March 26, 1997. Quality assurance unit study-based inspections were performed as shown below. There were no devia- tions from the protocol, standard operating procedures and/or appropriate good laboratory practice regulations noted during the conduct of the study. The summary report of QA inspections is included in the final report sub- mitted to the study director on July 3, 2003. Dates of Dates Reported to Date Reported Inspection Study Phase Management to Study Director 12/16/02 12/16/02 01/07/03 01/09/03 01/11/03 01/13/03 01/13/03 01/31/03 01/31/03 02/21/03 02/24/03 02126103 02127103 02/28/03 07103103 Master Schedule Pre-initiation Trimming Embedding Microtomy Staining Organization & Review Histopathology Data Entry Data Verification Data Processing Report Preparation Pre-submission Audit Draft report Final report 12/31/02 12/31/02 01/30/03 01/31/03 01/31/03 01/31/03 01/27/03 01/31/03 02/27/03 02/27/03 02127103 02127103 02127103 02/28/03 07103103 02/28/03 02/28/03 02/28/03 02/28/03 02/28/03 02/28/03 02/28/03 02128103 02/28/03 02/28/03 02/28/03 02/28/03 02/28/03 02/28/03 07103103 Research Pathology Services, Inc. 1 Date -6 418-028:PAGE J-9 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-028 SPONSOR'S STUDY NUMBER T-7706.1 HISTOPATHOLOGY REPORT GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT All aspects of the above-referenced study performed by Research Pathology Services, Inc. were conducted according to: Organisation for Economic Cooperation and Development (1996). OECD Guideline for Testing of Chemicals. Section 4, No. 422: Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, adopted 22 March 1996. Organisation for Economic Cooperation and Development (1998). The Revised OECD Principles of Good Laboratory Practices [C(97) 186/Final]. US Food and Drug Administration. Good Laboratory Practice Regulations: Final Rule. 21 CFR Part 58. Japanese Ministry of Health and Welfare (1997). Good Laboratory Practice Standard for Safety Studies on Drugs, MHW Ordinance Number 21, March 26, 1997. No deviations were noted that had any significant impact on the validity of the study. Date Research Pathology Services, Inc. -7 418-028:PAGE J-10 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 TABLE 1 Incidence and Degree of Severity of Histomorphologic Observations Dose Group: Sex: Number of Animals/GrouQ: I II III IV v M M M M M 10 10 10 10 10 ADRENAL GLANDS: NO. EXAMINED NO. NORMAL 10 0 0 0 10 7 0 0 0 9 -degeneration. cystic, cortex. multifocal mild [OJ [OJ [OJ [0] [0] 0 0 0 0 0 -hypertrophy/vacuolation, cortex, multifocal mild [0] [0] [0] [0] [OJ 0 0 0 0 0 -necrosis, cortex, focal mild [0] [OJ [0] [OJ [0] 0 0 0 0 0 -vacuolation, cortex, diffuse minimal mild [3] [OJ [OJ [OJ [1] 2000 0 1 0 0 0 1 -vacuolation, zona glomerulosa mild [0] [0] [OJ [0] [0] 0 0 0 0 0 BONE MARROW (STERNUM): NO. EXAMINED NO. NORMAL 10 0 0 0 10 10 0 0 0 10 BRAIN: NO. EXAMINED NO. NORMAL 10 0 0 0 10 10 0 0 0 10 CECUM: NO. EXAMINED NO. NORMAL 10 0 0 0 10 8 0 0 0 9 -inflammation, mucosa, chronic mild moderate [2J [0] [0] [OJ [1] 0 0001 2 0 0 0 0 COAGULATING GLAND: NO. EXAMINED NO. NORMAL 10 0 0 0 10 10 0 0 0 10 COLON: NO. EXAMINED NO. NORMAL 10 0 0 0 10 9 0 0 0 10 -inflammation, mucosa. chronic mild [1] [OJ [OJ [OJ [0] 1 0 0 0 0 DUODENUM: NO. EXAMINED NO. NORMAL 10 0 0 0 10 10 0 0 0 10 EPIDIDYMIDES: NO. EXAMINED NO. NORMAL 10 0 0 1 10 6 0 0 0 9 [ ] = Total incidence of specified lesion, all grades. I v F F 10 10 10 10 8 7 [0] [1] 0 1 [0] [1] 0 1 [OJ [1] 0 1 [0] [0] 0 0 0 0 [2J [OJ 2 0 10 10 10 10 10 10 10 10 10 10 8 10 [2J [OJ 1 0 1 0 10 10 10 10 [0] [OJ 0 0 10 10 10 10 8 418-028:PAGE J-11 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 TABLE 1 (Continued) Incidence and Degree of Severity of Histomorphologic Observations Dose Group: Sex: Number of Animals/GrouQ: I II III IV v M M M M M 10 10 10 10 10 EPIDIDYMIDES (Continued): -exfoliated spermatogenic cells moderate [OJ [OJ [OJ [lJ [OJ 0 0 0 1 0 -hypospermia marked [OJ [OJ [OJ [lJ [OJ 0 0 0 1 0 -infiltration, mononuclear-cell, focal minimal [4J [OJ [OJ [OJ [lJ 4 0 0 0 1 HEART: NO. EXAMINED NO. NORMAL 10 0 0 0 10 8 0 0 0 9 -i nfl ammati on, chronic. foca 1 minimal mild [2J [OJ [OJ [OJ [lJ 1 0 0 0 1 1 0 0 0 0 ILEUM: NO. EXAMINED NO. NORMAL 10 0 0 0 10 10 0 0 0 10 JEJUNUM: NO. EXAMINED NO. NORMAL 10 0 0 0 10 10 0 0 0 9 -diverticulum 0 0 0 0 1 KIDNEYS: NO. EXAMINED NO. NORMAL 10 3 0 0 10 7 1 0 0 7 -basophilia/degeneration, cortical tubules, focal/multifocal minimal [OJ [OJ [OJ [OJ [lJ 0 0 0 0 1 -cyst(s), medulla 1 0002 -dilatation, pelvis minimal mild [OJ [2J [OJ [OJ [OJ 0 1 0 0 0 0 1 0 0 0 -infiltration, mononuclear-cell. focal/multifocal minimal [2J [OJ [OJ [OJ [2J 2 0002 -mineralization, multifocal minimal [OJ [OJ [OJ [OJ [OJ 0 0 0 0 0 I v F F 10 10 10 10 10 10 [OJ [OJ 0 0 0 0 10 10 10 10 10 10 10 10 0 0 10 10 9 8 [OJ [OJ 0 0 0 0 [OJ [OJ 0 0 0 0 [OJ [OJ 0 0 [OJ [lJ 0 1 [ J = Total incidence of specified lesion, all grades. -9 418-028:PAGE J-12 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 TABLE 1 (Continued) Incidence and Degree of Severity of Histomorphologic Observations Dose Group: Sex: Number of Animals/Grau~: I II III IV v M M M M M 10 10 10 10 10 KIDNEYS (Continued): -nephritis, chronic, focal minimal [OJ [OJ [OJ [OJ [lJ 0 0 0 0 1 LIVER: NO. EXAMINED NO. NORMAL 10 10 10 10 10 23 200 -hypertrophy, hepatocellular, centrilobular minimal mild moderate [OJ [OJ [OJ [9J [lOJ 0008 4 0 0 0 1 5 0 0 0 0 1 -i nfl ammati on. chronic, focal/multifocal minimal mild [BJ [6J [7J [6J [SJ 54 765 3 2000 -lipidosis. tension, focal 0 2 0 0 0 -necrosis, focal minimal [OJ [OJ [OJ [OJ [OJ 0 0 0 0 0 -vacuolation, hepatocellular, midzonal mild [OJ [OJ [lJ [OJ [OJ 0 0 1 0 0 -vacuolation, hepatocellular, multifocal minimal mild [OJ [lJ [lJ [OJ [OJ 0 1 0 0 0 0 0 1 0 0 LUNG: NO. EXAMINED NO. NORMAL 10 0 0 0 10 10 0 0 0 10 -infiltration, polymorphonuclear. perivascular/peribronchial mild [OJ [OJ [OJ [OJ [OJ 0 0 0 0 0 -inflammation. interstitial, focal minimal [OJ [OJ [OJ [OJ [OJ 0 0 0 0 0 -macrophages, alveoli. focal minimal [OJ [OJ [OJ [OJ [OJ 0 000 0 LYMPH NODE, MEDIASTINAL: NO. EXAMINED NO. NORMAL 8 0 0 0 10 70 008 -congestion minimal [OJ [OJ [OJ [OJ [OJ 0 0 0 0 0 [ J = Total incidence of specified lesion, all grades. I v F F 10 10 [lJ [lJ 1 1 10 10 8 7 [OJ [OJ 0 0 0 0 0 0 [2J [lJ 2 1 0 0 0 0 [OJ [2J 0 2 [OJ [OJ 0 0 [OJ [OJ 0 0 0 0 10 10 9 9 [lJ [OJ 1 0 [OJ [lJ 0 1 [OJ [lJ 0 1 10 10 7 10 [2] [OJ 2 0 -10 418-028:PAGE J-13 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 TABLE 1 (Continued) Incidence and Degree of Severity of Histomorphologic Observations Dose Group: Sex: Number of Animals/GrouQ: I II III IV v M M M M M 10 10 10 10 10 LYMPH NODE. MEDIASTINAL (Continued): hyperplasia, lymphocytic/plasmacytic mild [OJ [OJ [OJ [OJ [OJ 0 0 0 0 0 -mastocytosis minimal [lJ [OJ [OJ [OJ [2J 1 0 0 0 2 LYMPH NODE. SUBMANDIBULAR: NO. EXAMINED NO. NORMAL 10 0 0 0 10 5 0 0 0 4 -hyperplasia, lymphocytic/plasmacytic minimal mild moderate [5J [OJ [OJ [OJ [6J 1 0 0 0 2 2 0 0 0 0 2 0 0 0 4 MAMMARY GLAND: NO. EXAMINED NO. NORMAL -necrosis, focal minimal NERVE. SCIATIC: NO. EXAMINED NO. NORMAL 10 0 0 0 10 10 0 0 0 10 OVARIES: NO. EXAMINED NO. NORMAL -cyst(s), intraovarian PARATHYROID: NO. EXAMINED NO. NORMAL 10 0 0 0 10 10 0 0 0 10 PEYER'S PATCH: NO. EXAMINED NO. NORMAL 10 0 0 0 10 10 0 0 0 9 mineralization, focal minimal [OJ [OJ [OJ [OJ [lJ 0 0 0 0 1 PROSTATE: NO. EXAMINED NO. NORMAL 10 0 0 0 10 6 0 0 0 6 I v F F 10 10 [lJ [OJ 1 0 [lJ [OJ 1 0 10 9 4 3 [6J [6J 1 0 3 5 2 1 10 10 10 9 [OJ [lJ 0 1 10 9 10 9 10 10 9 10 1 0 10 10 10 10 10 10 10 10 [OJ [OJ 0 0 [ J = Total incidence of specified lesion, all grades. 11 418-028:PAGE J-14 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418028 SPONSOR'S STUDY NUMBER T-7706.1 TABLE 1 (Continued) Incidence and Degree of Severity of Histomorphologic Observations Dose Group: Sex: Number of Animals/GrouQ: I II III IV v M M M M M 10 10 10 10 10 PROSTATE (Continued): -atrophy, focal/multifocal minimal moderate [lJ [OJ [OJ [OJ [2J 1 0 0 0 1 0 0 0 0 1 inflammation. chronic. focal/multifocal minimal [3J [OJ [OJ [OJ [3J 3 0 0 0 3 RECTUM: NO. EXAMINED NO. NORMAL 10 0 0 0 10 9 0009 inflammation. mucosa. chronic minimal mild [lJ [OJ [OJ [OJ [lJ 0 0 0 0 1 1 0 0 0 0 SEMINAL VESICLES: NO. EXAMINED NO. NORMAL 10 0 0 0 10 10 0 0 0 10 SKIN (GROSS LESION): NO. EXAMINED NO. NORMAL 0 0 0 0 0 0 0 0 0 0 -dermatitis. chronic. focal minimal mild [OJ [OJ [OJ [OJ [OJ 0 0 0 0 0 0 0 0 0 0 SPINAL CORD. CERVICAL: NO. EXAMINED NO. NORMAL 10 0 0 0 10 10 0 0 0 10 SPINAL CORD, LUMBAR: NO. EXAMINED NO. NORMAL 10 0 0 0 10 10 0 0 0 10 SPINAL CORD. THORACIC: NO. EXAMINED NO. NORMAL 10 0 0 0 10 10 0 0 0 10 SPLEEN: NO. EXAMINED NO. NORMAL 10 0 0 0 10 10 0 0 0 10 -atrophy mild [OJ [OJ [OJ [OJ [OJ 0 0 0 0 0 STOMACH: NO. EXAMINED NO. NORMAL 10 0 0 0 10 8 0009 [ J = Total incidence of specified lesion, all grades. I v F F 10 10 10 10 10 10 [OJ [OJ 0 0 0 0 1 1 0 0 [lJ [lJ 0 1 1 0 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 9 [OJ [lJ 0 1 10 10 7 6 -12 418-028:PAGE J-15 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 TABLE 1 (Continued) Incidence and Degree of Severity of Histomorphologic Observations Dose Group: Sex: Number of Animals/GrouQ: I II III IV v M M M M M 10 10 10 10 10 STOMACH (Continued): -dilatation. mucosal glands minimal [lJ [OJ [OJ [OJ [OJ 1 0 0 0 0 -edema/inflammation, submucosa, forestomach mild [lJ [OJ [OJ [OJ [lJ 1 0 0 0 1 -edema/inflammation, submucosa, glandular area minimal mild moderate [2J [OJ [OJ [OJ [OJ 1 0000 0 0 0 0 0 1 0 0 0 0 -erosion(s). glandular mucosa moderate [OJ [OJ [OJ [OJ [OJ 0 0 0 0 0 TESTIS CH&E): NO. EXAMINED NO. NORMAL 10 0 0 1 10 10 0 0 0 10 -degeneration, multifocal mild [OJ [OJ [OJ [lJ [OJ 0 0 0 1 0 TESTIS (PAS): NO. EXAMINED NO. NORMAL 10 0 0 1 10 10 0 0 0 10 -degeneration, multifocal mild [OJ [OJ [OJ [lJ [OJ 0001 0 THYMUS: NO. EXAMINED NO. NORMAL 10 0 0 0 10 10 0 0 0 10 -atrophy moderate marked [OJ [OJ [OJ [OJ [OJ 0 0 0 0 0 0 0 0 0 0 THYROID: NO. EXAMINED NO. NORMAL 10 10 10 10 10 5 35 5 3 -hypertrophy/hyperplasia, follicular epithelium minimal mild moderate [2J [3J [2J [4J [7J 0 1 1 2 0 221 23 0 0 0 0 4 -ultimobranchial body/cyst 3 4 4 2 2 TRACHEA: NO. EXAMINED NO. NORMAL 10 0 0 0 10 6 0009 [ J = Total incidence of specified lesion, all grades. I v F F 10 10 [lJ [lJ 1 1 [OJ [lJ 0 1 [2J [3J 0 0 1 3 1 0 [OJ [lJ 0 1 10 10 9 9 [lJ [lJ 1 0 0 1 10 10 5 5 [OJ [OJ 0 0 0 0 0 0 5 5 10 10 10 9 13 418-028:PAGE J-16 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 TABLE 1 (Continued) Incidence and Degree of Severity of Histomorphologic Observations Dose Group: Sex: Number of Animals/GrouQ: I II III IV v M M M M M 10 10 10 10 10 TRACHEA (Continued): -inflammation, chronic, focal minimal mild [4J [OJ [OJ [OJ [lJ 2 0 0 0 0 2 0 0 0 1 URINARY BLADDER: NO. EXAMINED NO. NORMAL 10 0 0 0 10 10 0 0 0 10 -inflammation. chronic. focal minimal [OJ [OJ [OJ [OJ [OJ 0 0 0 0 0 UTERUS: NO. EXAMINED NO. NORMAL -distention. lumen mild moderate -macrophages. pigmented minimal mild moderate marked VAGINA: NO. EXAMINED NO. NORMAL I v F F 10 10 [OJ [lJ 0 1 0 0 9 10 8 10 [lJ [OJ 1 0 10 10 0 1 [OJ [2J 0 1 0 1 [lOJ [8J 1 0 2 2 7 5 0 1 10 10 10 10 [ J = Total incidence of specified lesion, all grades. -14 418-028:PAGE J-17 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-028 SPONSOR'S STUDY NUMBER T-7706.1 HISTOPATHOLOGY REPORT APPENDIX I HISTOMORPHOLOGIC OBSERVATIONS 418-028:PAGE J-18 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-028 SPONSOR'S STUDY NUMBER T-7706.1 HISTOPATHOLOGY REPORT KEY TO HISTOMORPHOLOGIC OBSERVATIONS = No change (not remarkable, within normal histologic limits or indicated change not present). = * Tissue not available (specified tissue missing, insufficient tissue in plane of section, artifact precludes evaluation, or specified tissue not present in section). <> = Microscopic finding(s) in tissue(s) with gross observation(s). = <-> Within normal limits [no microscopic change(s) to correlate with the gross observation(s)]. p = Indicated change or lesion present 1 = Minimal degree or amount of indicated change or lesion. 2 = Mild degree or amount of indicated change or lesion. 3 = Moderate degree or amount of indicated change or lesion. 4 = Marked degree or amount of indicated change or lesion. SS = Scheduled Sacrifice 1-1 418-028:PAGE J-19 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 TABLE I-1 Histomorphologic Observations Dose Group: Animal Number: Sex: Death Type: I I I I I I I I I I 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 M M M M M M M M M M SS SS SS SS SS SS SS SS SS SS ADRENAL GLANDS: -vacuolation, cortex, diffuse 1 1 2 BONE MARROW (STERNUM): BRAIN: CECUM: ~mmation, mucosa, chronic 3 3 COAGULATING GLAND: COLON: :-rnfiammation, mucosa, chronic 2 DUODENUM: EPIDIDYMIDES: -infiltration, mononuclear-cell, focal HEART: -inflammation, chronic, focal 2 .!!J.1!!:t. JEJUNUM: KIDNEYS: -cyst(s), medulla <-> p -infiltration, mononuclear-cell, focal/multifocal <-> LIVER: -inflammation, chronic, focal/multifocal 1 2 2 2 LUNG: LYMPH NODE. MEDIASTINAL: -mastocytosis * * LYMPH NODE. SUBMANDIBULAR: -hyperplasia, lymphocytic/plasmacytic 3 2 1 3 2 NERVE. SCIATIC: PARATHYROID: PEYER'S PATCH: PROSTATE: -atrophy, focal/multifocal I-2 418-028:PAGE J-20 ORAL {GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 TABLE I-1 {Continued) Histomorphologic Observations Dose Group: Animal Number: Sex: Death Type: I I I I I I I I I I 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 M M M M M M M M M M SS SS SS SS SS SS SS SS SS SS PROSTATE (Continued): -inflammation, chronic, focal/multifocal RECTUM: :rnr=ra-mmation, mucosa, chronic 2 SEMINAL VESICLES: SPINAL CORD. CERVICAL: SPINAL CORD. LUMBAR: SPINAL CORD. THORACIC: SPLEEN: STOMACH: -dilatation, mucosal glands -edema/inflammation, submucosa, forestomach - -edema/inflammation, submucosa, glandular area 1 2 3 TESTIS (H&E): TESTIS (PAS): THYMUS: THYROID: -hypertrophy/hyperplasia, follicular epithelium -ultimobranchial body/cyst 2 p 2 p p TRACHEA: -inflammation, chronic, focal 2 1 2 URINARY BLADDER: I-3 418-028:PAGE J-21 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 TABLE 1-2 Histomorphologic Observations Dose Group: Animal Number: Sex: Death Type: II II II II II II II II II II 19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 M M M M M M M M M M SS SS SS SS SS SS SS SS SS SS KIDNEYS: -dilatation, pelvis <-> <2> <1> LIVER: -inflammation, chronic, focal/multifocal -lipidosis, tension, focal 2 2 1 p -vacuolation, hepatocellular, multifocal 1 p 1 THYROID: -hypertrophy/hyperplasia, follicular epithelium 2 -ultimobranchial body/cyst p p 2 p p I-4 418-028:PAGE J-22 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 TABLE I-3 Histomorphologic Observations Dose Group: Animal Number: Sex: Death Type: III III III III III III III III III III 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 M M M M M M M M M M SS SS SS SS SS SS SS SS SS SS LIVER: -inflammation, chronic, focal/multifocal 1 1 -vacuolation, hepatocellular, midzonal 2 -vacuolation, hepatocellular, multifocal 2 THYROID: -hypertrophy/hyperplasia, follicular epithelium -ultimobranchial body/cyst 1 2 p p p p 1-5 418-028:PAGE J-23 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 TABLE I-4 Histomorphologic Observations Dose Group: Animal Number: Sex: Death Type: IV IV IV IV IV IV IV IV IV IV 19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 M M M M M M M M M M SS SS SS SS SS SS SS SS SS SS EPIDIDYMIDES: -exfoliated spermatogenic cells <3> -hypospermia <4> LIVER: -hypertrophy, hepatocellular, centrilobular -inflammation, chronic, focal/multifocal 2 1 1 1 1 1 1 1 TESTIS (H&E): -degeneration, multifocal <2> TESTIS (PAS): -degeneration, multifocal <2> THYROID: -hypertrophy/hyperplasia, follicular epithelium -ultimobranchial body/cyst 1 p p 2 2 I-6 418-028:PAGE J-24 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 TABLE I-5 Dose Group: Animal Number: Sex: Death Type: Histomorphologic Observations v v v v v v v v v v 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 M M M M M M M M M M SS SS SS SS SS SS SS SS SS SS ADRENAL GLANDS: -vacuolation, cortex, diffuse 2 BONE MARROW (STERNUM): BRAIN: CECUM: -inflammation, mucosa, chronic 2 COAGULATING GLAND: COLON: DUODENUM: EPIDIDYMIDES: -infiltration, mononuclear-cell, focal JillBI.:. -inflammation, chronic, focal 1liJ1M.:. JEJUNUM: -diverticulum <P> KIDNEYS: -basophilia/degeneration, cortical tubules, focal/multi focal -cyst(s), medulla 1 P p -infiltration, mononuclear-cell, focal/multifocal -nephritis, chronic, focal LIVER: -hypertrophy, hepatocellular, centrilobular 2 2 2 3 2 1 2 1 -inflammation, chronic, focal/multifocal 1 1 1 1 1 LUNG: LYMPH NODE. MEDIASTINAL: -mastocytosis 1 LYMPH NODE. SUBMANDIBULAR: -hyperplasia, lymphocytic/plasmacytic 1 3 3 3 3 NERVE. SCIATIC: PARATHYROID: PEYER'S PATCH: -mineralization, focal I-7 418-028:PAGE J-25 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 TABLE I-5 (Continued) Dose Group: Animal Number: Sex: Death Type: Histomorphologic Observations v v v v v v v v v v 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 M M M M M M M M M M SS SS SS SS SS SS SS SS SS SS PROSTATE: -atrophy, focal/multifocal 3 -inflammation, chronic, focal/multifocal RECTUM: -inflammation, mucosa, chronic 1 SEMINAL VESICLES: SPINAL CORD. CERVICAL: SPINAL CORD. LUMBAR: SPINAL CORD. THORACIC: SPLEEN: STOMACH: -edema/inflammation, submucosa, forestomach - 2 TESTIS (H&El: TESTIS (PAS): THYMUS: THYROID: -hypertrophy/hyperplasia, follicular epithelium 3 2 2 3 3 3 2 -ultimobranchial body/cyst p p TRACHEA: -inflammation, chronic, focal 2 URINARY BLADDER: I-8 418-028:PAGE J-26 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 TABLE I-6 Histomorphologic Observations Dose Group: Animal Number: Sex: Death Type: I I I I I I I I I I 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 F F F F F F F F F F SS SS SS SS SS SS SS SS SS SS ADRENAL GLANDS: -vacuolation, zona glomerulosa 2 2 BONE MARROW (STERNUM): BRAIN: CECUM: :-rrif'i'ammation, mucosa, chronic 3 2 ~ DUODENUM: HEART: ill.!:!!:t. JEJUNUM: KIDNEYS: -nephritis, chronic, focal LIVER: -inflammation, chronic, focal/multifocal LUNG: -infiltration, polymorphonuclear, perivascular/peribronchial 2 LYMPH NODE. MEDIASTINAL: -congestion 1 -hyperplasia, lymphocytic/plasmacytic 2 -mastocytosis LYMPH NODE. SUBMANDIBULAR: -hyperplasia, lymphocytic/plasmacytic 2 3 3 2 2 MAMMARY GLAND: NERVE. SCIATIC: OVARIES: -cyst(s), intraovarian p PARATHYROID: PEYER'S PATCH: RECTUM: SKIN (GROSS LESION): -dermatitis, chronic, focal <2> I-9 418-028:PAGE J-27 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 TABLE I-6 (Continued) Histomorphologic Observations Dose Group: Animal Number: Sex: Death Type: I I I I I I I I I I 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 F F F F F F F F F F SS SS SS SS SS SS SS SS SS SS SPINAL CORD. CERVICAL: SPINAL CORD. LUMBAR: SPINAL CORD. THORACIC: SPLEEN: STOMACH: -dilatation, mucosal glands 1 -edema/inflammation, submucosa, glandular area 2 3 THYMUS: -atrophy 3 THYROID: -ultimobranchial body/cyst p p p p p TRACHEA: URINARY BLADDER: -inflammation, chronic, focal UTERUS: -macrophages, pigmented * 3 2 3 3 3 3 3 3 2 I-10 418-028:PAGE J-28 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 TABLE 1-7 Dose Group: Animal Number: Sex: Death Type: Histomorphologic Observations v v v v v v v v v v 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 F F F F F F F F F F SS SS SS SS SS SS SS SS SS SS ADRENAL GLANDS: -degeneration, cystic, cortex, multifocal -hypertrophy/vacuolation, cortex, multi focal -necrosis, cortex, focal <2> 2 2 BONE MARROW (STERNUM}: BRAIN: CECUM: <-> COLON: <-> DUODENUM: <-> HEART: ILEUM: <-> JEJUNUM: <-> KIDNEYS: -mineralization, multifocal 1 -nephritis, chronic, focal LIVER: -inflammation, chronic, focal/multifocal -necrosis, focal LUNG: -inflammation, interstitial, focal -macrophages, alveoli, focal LYMPH NODE. MEDIASTINAL: LYMPH NODE. SUBMANDIBULAR: -hyperplasia, lymphocytic/plasmacytic MAMMARY GLAND: -necrosis, focal 2 2 2 2 3 * 2 1 NERVE. SCIATIC: * OVARIES: PARATHYROID: PEYER'S PATCH: RECTUM: <-> 1-11 418-028:PAGE J-29 ORAL {GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 TABLE 1-7 {Continued) Dose Group: Animal Number: Sex: Death Type: Histomorphologic Observations v v v v v v v v v v 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 F F F F F F F F F F SS SS SS SS SS SS SS SS SS SS SKIN (GROSS LESION): -dermatitis, chronic, focal <1> SPINAL CORD. CERVICAL: SPINAL CORD. LUMBAR: SPINAL CORD. THORACIC: SPLEEN: -atrophy <2> STOMACH: -dilatation, mucosal glands -edema/inflammation, submucosa, forestomach -edema/inflammation, submucosa, glandular area -erosion(s), glandular mucosa <2> <2> 2 2 <3> THYMUS: -atrophy <4> THYROID: -ultimobranchial body/cyst p p p p p TRACHEA: -inflammation, chronic, focal URINARY BLADDER: UTERUS: -distention, lumen -macrophages, pigmented 2 3 2 3 4 2 3 3 3 3 1-12 418-028:PAGE J-30 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-028 SPONSOR'S STUDY NUMBER T-7706.1 HISTOPATHOLOGY REPORT APPENDIX II INDIVIDUAL ANIMAL GROSS AND HISTOMORPHOLOGY DATA 418-028:PAGE J-31 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19109 DOSE GROUP: I SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LYMPH NODE, MEDIASTINAL: LYMPH NODE, SUBMANDIBULAR: PROSTATE: THYROID: mastocytosis (minimal) hyperplasia, lymphocytic/plasmacytic (moderate) inflammation, chronic, focal/multifocal (minimal) hypertrophy/hyperplasia, follicular epithelium (mild) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COAGULATING GLAND HEART LIVER PEYER'S PATCH SPINAL CORD, LUMBAR TESTIS (H&E) URINARY BLADDER BONE MARROW (STERNUM) COLON ILEUM LUNG RECTUM SPINAL CORD, THORACIC TESTIS (PAS) End of Record- 19109 BRAIN DUODENUM JEJUNUM NERVE, SCIATIC SEMINAL VESICLES SPLEEN THYMUS CECUM EPIDIDYMIDES KIDNEYS PARATHYROID SPINAL CORD, STOMACH TRACHEA CERVICAL 11-1 418-028:PAGE J-32 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19115 DOSE GROUP: I SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: ADRENAL GLANDS: EPIDIDYMIDES: HEART: LIVER: THYROID: TRACHEA: vacuolation, cortex, diffuse (minimal) infiltration, mononuclear-cell, focal {minimal) inflammation, chronic, focal {minimal) inflammation, chronic, focal/multifocal {minimal) ultimobranchial body/cyst inflammation, chronic, focal {mild) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: BONE MARROW {STERNUM) COLON KIDNEYS NERVE, SCIATIC RECTUM SPINAL CORD, THORACIC TESTIS (PAS) BRAIN DUODENUM LUNG PARATHYROID SEMINAL VESICLES SPLEEN THYMUS End of Record- 19115 CECUM ILEUM LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD, CERVICAL STOMACH URINARY BLADDER COAGULATING GLAND JEJUNUM LYMPH NODE, SUBMANDIBULAR PROSTATE SPINAL CORD, LUMBAR TESTIS (H&E) 11-2 418-028:PAGE J-33 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19116 DOSE GROUP: I SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): KIDNEYS: Mottled tan and red, bilateral. No microscopic change to correlate HISTOMORPHOLOGIC OBSERVATIONS: KIDNEYS: LIVER: LYMPH NODE, SUBMANDIBULAR: No microscopic change to correlate inflammation, chronic, focal/multifocal (minimal) hyperplasia, lymphocytic/plasmacytic (mild) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COAGULATING GLAND HEART LUNG PEYER'S PATCH SPINAL CORD, CERVICAL STOMACH THYROID BONE MARROW (STERNUM) COLON ILEUM LYMPH NODE, MEDIASTINAL PROSTATE SPINAL CORD, LUMBAR TESTIS (H&E) TRACHEA End of Record- 19116 BRAIN DUODENUM JEJUNUM NERVE, SCIATIC RECTUM SPINAL CORD, THORACIC TESTIS (PAS) URINARY BLADDER CECUM EP ID IDYM IDES KIDNEYS PARATHYROID SEMINAL VESICLES SPLEEN THYMUS II-3 418-028:PAGE J-34 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19119 DOSE GROUP: I SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: ADRENAL GLANDS: CECUM: COLON: KIDNEYS: LIVER: RECTUM: vacuolation, cortex, diffuse (minimal) inflammation, mucosa, chronic (moderate) inflammation, mucosa, chronic (mild) infiltration, mononuclear-cell, focal/multifocal inflammation, chronic, focal/multifocal (mild) inflammation, mucosa, chronic (mild) (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: BONE MARROW (STERNUM) EPIDIDYMIDES LUNG PARATHYROID SPINAL CORD, CERVICAL STOMACH THYROID BRAIN HEART LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD, LUMBAR TESTIS (H&E) TRACHEA End of Record- 19119 COAGULATING GLAND ILEUM DUODENUM JEJUNUM LYMPH NODE, SUBMANDIBULAR NERVE, SCIATIC PROSTATE SEMINAL VESICLES SPINAL CORD, THORACIC TESTIS (PAS) SPLEEN THYMUS URINARY BLADDER II-4 418-028:PAGE J-35 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19122 DOSE GROUP: I SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: EPIDIDYMIDES: LIVER: LYMPH NODE, SUBMANDIBULAR: TRACHEA: infiltration, mononuclear-cell, focal (minimal) inflammation, chronic, focal/multifocal (minimal) hyperplasia, lymphocytic/plasmacytic (minimal) inflammation, chronic, focal (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COAGULATING GLAND ILEUM NERVE, SCIATIC RECTUM SPINAL CORD, THORACIC TESTIS (PAS) BONE MARROW (STERNUM) COLON JEJUNUM PARATHYROID SEMINAL VESICLES SPLEEN THYMUS BRAIN DUODENUM KIDNEYS PEYER'S PATCH SPINAL CORD, CERVICAL STOMACH THYROID CECUM HEART LUNG PROSTATE SPINAL CORO, LUMBAR TESTIS (H&E) URINARY BLADDER TISSUE(S) NOT AVAILABLE FOR EVALUATION: LYMPH NODE, MEDIASTINAL End of Record- 19122 II-5 418-028:PAGE J-36 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19125 SEX: M DOSE GROUP: DEATH TYPE: I Sacrifice-Scheduled GROSS OBSERVATION(S): GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION(S): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: CECUM: LIVER: LYMPH NODE, SUBMANDIBULAR: PROSTATE: THYROID: inflammation, mucosa, chronic (moderate) inflammation, chronic, focal/multifocal (minimal) hyperplasia, lymphocytic/plasmacytic (moderate) atrophy, focal/multifocal (minimal) ultimobranchial body/cyst THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON ILEUM LYMPH NODE, MEDIASTINAL RECTUM SPINAL CORD, THORACIC TESTIS (PAS) BONE MARROW (STERNUM) DUODENUM JEJUNUM NERVE, SCIATIC SEMINAL VESICLES SPLEEN THYMUS End of Record- 19125 BRAIN EPIDIDYMIDES KIDNEYS PARATHYROID SPINAL CORD, STOMACH TRACHEA CERVICAL COAGULATING GLAND HEART LUNG PEYER'S PATCH SPINAL CORD, LUMBAR TESTIS (H&E) URINARY BLADDER II-6 418-028:PAGE J-37 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19131 DOSE GROUP: I SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: ADRENAL GLANDS: EPIDIDYMIDES: HEART: LIVER: LYMPH NODE, SUBMANDIBULAR: PROSTATE: TRACHEA: vacuolation, cortex, diffuse (mild) infiltration, mononuclear-cell, focal (minimal) inflammation, chronic, focal (mild) inflammation, chronic, focal/multifocal (mild) hyperplasia, lymphocytic/plasmacytic (mild) inflammation, chronic, focal/multifocal (minimal) inflammation, chronic, focal (mild) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: BONE MARROW (STERNUM) COLON KIDNEYS PARATHYROID SPINAL CORD, CERVICAL STOMACH THYROID BRAIN DUODENUM LUNG PEYER'S PATCH SPINAL CORD, LUMBAR TESTIS (H&E) URINARY BLADDER End of Record- 19131 CECUM ILEUM LYMPH NODE, MEDIASTINAL RECTUM SPINAL CORD, THORACIC TESTIS (PAS) COAGULATING GLAND JEJUNUM NERVE. SCIATIC SEMINAL VESICLES SPLEEN THYMUS 11-7 418-028:PAGE J-38 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19132 DOSE GROUP: I SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: STOMACH: THYROID: inflammation, chronic, focal/multifocal (mild) edema/inflammation, submucosa, glandular area (moderate) ultimobranchial body/cyst THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COAGULATING GLAND HEART LUNG PEYER 's PATCH SPINAL CORO, CERVICAL TESTIS (H&E) URINARY BLADDER BONE MARROW (STERNUM) BRAIN COLON DUODENUM ILEUM JEJUNUM LYMPH NODE, SUBMANDIBULAR NERVE, SCIATIC PROSTATE RECTUM SPINAL CORD, LUMBAR SPINAL CORD, THORACIC TESTIS (PAS) THYMUS CECUM EPIDIDYMIDES KIDNEYS PARATHYROID SEMINAL VESICLES SPLEEN TRACHEA TISSUE(S) NOT AVAILABLE FOR EVALUATION: LYMPH NODE, MEDIASTINAL End of Record- 19132 II-8 418-028:PAGE J-39 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19134 SEX: M DOSE GROUP: DEATH TYPE: I Sacrifice-Scheduled =========================================================================================~============= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: EPIDIDYMIDES: KIDNEYS: STOMACH: THYROID: TRACHEA: infiltration, mononuclear-cell, focal (minimal) cyst(s), medulla dilatation, mucosal glands (minimal) edema/inflammation, submucosa, glandular area (minimal) edema/inflammation, submucosa, forestomach (mild) hypertrophy/hyperplasia, follicular epithelium (mild) inflammation, chronic, focal (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COAGULATING GLAND ILEUM LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD, CERVICAL TESTIS (H&E) BONE MARROW (STERNUM) BRAIN COLON DUODENUM JEJUNUM LIVER LYMPH NODE, SUBMANDIBULAR NERVE, SCIATIC PROSTATE RECTUM SPINAL CORD, LUMBAR SPINAL CORD, THORACIC TESTIS (PAS) THYMUS End of Record- 19134 CECUM HEART LUNG PARATHYROID SEMINAL VESICLES SPLEEN URINARY BLADDER II-9 418-028:PAGE J-40 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19135 DOSE GROUP: I SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: KIDNEYS: LIVER: PROSTATE: infiltration, mononuclear-cell, focal/multifocal (minimal) inflammation, chronic, focal/multifocal (minimal) inflammation, chronic, focal/multifocal (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COAGULATING GLAND HEART LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD, LUMBAR TESTIS (H&E) TRACHEA BONE MARROW (STERNUM) COLON ILEUM LYMPH NODE, SUBMANDIBULAR RECTUM SPINAL CORD, THORACIC TESTIS (PAS) URINARY BLADDER BRAIN DUODENUM JEJUNUM NERVE, SCIATIC SEMINAL VESICLES SPLEEN THYMUS End of Record- 19135 CECUM EPIDIDYMIDES LUNG PARATHYROID SPINAL CORD, STOMACH THYROID CERVICAL 11-10 418-028:PAGE J-41 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19102 DOSE GROUP: I I SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): KIDNEYS: Bilateral- mottled. No microscopic change to correlate HISTOMORPHOLOGIC OBSERVATIONS: KIDNEYS: LIVER: THYROID: No microscopic change to correlate inflammation, chronic, focal/multifocal (mild) ultimobranchial body/cyst THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: KIDNEYS End of Record- 19102 I I-11 418-028:PAGE J-42 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19106 SEX: M DOSE GROUP: DEATH TYPE: II Sacrifice-Scheduled GROSS OBSERVATION(S): GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION(S): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: End of Record- 19106 inflammation, chronic, focal/multifocal (mild) ultimobranchial body/cyst Il-12 418-028:PAGE J-43 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19108 DOSE GROUP: I I SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: lipidosis, tension, focal inflammation, chronic, focal/multifocal (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: THYROID End of Record- 19108 Il-13 418-028:PAGE J-44 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19110 DOSE GROUP: II SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION{S): HISTOMORPHOLOGIC OBSERVATION{S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: End of Record- 19110 inflammation, chronic, focal/multifocal (minimal} hypertrophy/hyperplasia, follicular epithelium (mild) II-14 418-028:PAGE J-45 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19113 DOSE GROUP: I I SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): KIDNEYS: Left- pelvis, slight dilation. dilatation, pelvis HISTOMORPHOLOGIC OBSERVATIONS: KIDNEYS: dilatation, pelvis (mild) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: LIVER THYROID End of Record- 19113 II-15 418-028:PAGE J-46 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19120 DOSE GROUP: II SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION($): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: inflammation, chronic, focal/multifocal (minimal) lipidosis, tension, focal THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: THYROID End of Record- 19120 II-16 418-028:PAGE J-47 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19129 DOSE GROUP: I I SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: End of Record- 19129 inflammation, chronic, focal/multifocal (minimal) hypertrophy/hyperplasia, follicular epithelium {minimal) 11-17 418-028:PAGE J-48 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19136 DOSE GROUP: I I SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION{S): HISTOMORPHOLOGIC OBSERVATION(S): KIDNEYS: Bilateral- mottled. dilatation, pelvis HISTOMORPHOLOGIC OBSERVATIONS: KIDNEYS: LIVER: THYROID: End of Record- 19136 dilatation, pelvis (minimal) vacuolation, hepatocellular, multifocal (minimal) ultimobranchial body/cyst II-18 418-028:PAGE J-49 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19138 SEX: M DOSE GROUP: DEATH TYPE: I I Sacrifice-Scheduled GROSS OBSERVATION(S): GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION(S): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: THYROID: ultimobranchial body/cyst THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: LIVER End of Record- 19138 Il-19 418-028:PAGE J-50 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19139 DOSE GROUP: II SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION{S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: THYROID: hypertrophy/hyperplasia, follicular epithelium (mild) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: LIVER End of Record- 19139 II-20 418-028:PAGE J-51 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19101 DOSE GROUP: III SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: LIVER THYROID End of Record- 19101 II-21 418-028:PAGE J-52 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19105 DOSE GROUP: I II SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: inflammation, chronic, focal/multifocal (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: THYROID End of Record- 19105 II-22 418-028:PAGE J-53 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19107 DOSE GROUP: II I SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: End of Record- 19107 inflammation, chronic, focal/multifocal (minimal) hypertrophy/hyperplasia, follicular epithelium (minimal) ultimobranchial body/cyst II-23 418-028:PAGE J-54 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19112 DOSE GROUP: I I I SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: End of Record- 19112 inflammation, chronic, focal/multifocal (minimal) ultimobranchial body/cyst II-24 418-028:PAGE J-55 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19114 DOSE GROUP: I II SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: End of Record- 19114 inflammation, chronic, focal/multifocal (minimal) ultimobranchial body/cyst II-25 418-028:PAGE J-56 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19121 DOSE GROUP: I II SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: End of Record- 19121 inflammation, chronic, focal/multifocal (minimal) vacuolation, hepatocellular, multifocal (mild) ultimobranchial body/cyst II-26 418-028:PAGE J-57 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19123 DOSE GROUP: I I I SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: inflammation, chronic, focal/multifocal (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: THYROID End of Record- 19123 II-27 418-028:PAGE J-58 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19130 DOSE GROUP: I II SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION{S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: End of Record- 19130 inflammation, chronic, focal/multifocal (minimal) hypertrophy/hyperplasia, follicular epithelium (mild} II-28 418-028:PAGE J-59 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19137 DOSE GROUP: I II SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: LIVER THYROID End of Record- 19137 II-29 418-028:PAGE J-60 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19146 SEX: M DOSE GROUP: DEATH TYPE: I I I Sacrifice-Scheduled GROSS OBSERVATION(S): GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION(S): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: vacuolation, hepatocellular, midzonal (mild) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: THYROID End of Record- 19146 II-30 418-028:PAGE J-61 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19100 DOSE GROUP: IV SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: End of Record- 19100 hypertrophy, hepatocellular, centrilobular (minimal) inflammation, chronic, focal/multifocal (minimal) hypertrophy/hyperplasia, follicular epithelium (minimal) II-31 418-028:PAGE J-62 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19103 DOSE GROUP: IV SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: hypertrophy, hepatocellular, centrilobular (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: THYROID End of Record- 19103 Il-32 418-028:PAGE J-63 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19104 SEX: M DOSE GROUP: DEATH TYPE: IV Sacrifice-Scheduled GROSS OBSERVATION(S): GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION(S): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: inflammation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (mild) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: THYROID End of Record- 19104 II-33 418-028:PAGE J-64 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19118 SEX: M DOSE GROUP: DEATH TYPE: IV Sacrifice-Scheduled GROSS OBSERVATION(S): GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION(S): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: inflammation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: THYROID End of Record- 19118 II-34 418-028:PAGE J-65 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19133 DOSE GROUP: IV SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: End of Record- 19133 hypertrophy, hepatocellular, centrilobular (minimal) hypertrophy/hyperplasia, follicular epithelium (minimal) ultimobranchial body/cyst II-35 418-028:PAGE J-66 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19141 DOSE GROUP: IV SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: End of Record- 19141 hypertrophy, hepatocellular, centrilobular (minimal) ultimobranchial body/cyst 11-36 418-028:PAGE J-67 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19142 DOSE GROUP: IV SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): EPIDIDYMIDES: Bilateral- small; cauda epididymis, 1eft, small. TESTES: Bilateral- small. hypospermia exfoliated spermatogenic cells degeneration, multifocal, TESTIS (PAS) degeneration, multifocal, TESTIS (H&E) HISTOMORPHOLOGIC OBSERVATIONS: EPIDIDYMIDES: LIVER: TESTIS (H&E): TESTIS (PAS): hypospermia (marked) exfoliated spermatogenic cells (moderate) inflammation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (minimal) degeneration, multifocal (mild) degeneration, multifocal (mild) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: THYROID End of Record- 19142 11-37 418-028:PAGE J-68 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19144 DOSE GROUP: IV SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: inflammation, chronic, focal/multifocal (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: THYROID End of Record- 19144 II-38 418-028:PAGE J-69 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19148 DOSE GROUP: IV SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: End of Record- 19148 inflammation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (minimal) hypertrophy/hyperplasia, follicular epithelium (mild) 11-39 418-028:PAGE J-70 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19150 DOSE GROUP: IV SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: End of Record- 19150 hypertrophy, hepatocellular, centrilobular (minimal) hypertrophy/hyperplasia, follicular epithelium (mild) II-40 418-028:PAGE J-71 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19111 DOSE GROUP: v SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GASTROINTESTINAL TRACT: Jejunum- diverticulum, 1.5x0.6x0.4cm. diverticulum, JEJUNUM HISTOMORPHOLOGIC OBSERVATIONS: JEJUNUM: KIDNEYS: LIVER: LYMPH NODE, SUBMANDIBULAR: PEYER'S PATCH: PROSTATE: THYROID: diverticulum basophilia/degeneration, cortical tubules, focal/multifocal (minimal) cyst(s). medulla infiltration, mononuclear-cell, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (mild) inflammation, chronic, focal/multifocal (minimal) hyperplasia, lymphocytic/plasmacytic (minimal) mineralization, focal (minimal) inflammation, chronic, focal/multifocal (minimal) ultimobranchial body/cyst hypertrophy/hyperplasia, follicular epithelium (moderate) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COAGULATING GLAND HEART NERVE, SCIATIC SPINAL CORD, CERVICAL STOMACH TRACHEA BONE MARROW (STERNUM) COLON ILEUM PARATHYROID SPINAL CORD, LUMBAR TESTIS (H&E) URINARY BLADDER End of Record- 19111 BRAIN DUODENUM LUNG RECTUM SPINAL CORD, TESTIS (PAS) THORACIC CECUM EPIDIDYMIDES LYMPH NODE, MEDIASTINAL SEMINAL VESICLES SPLEEN THYMUS 11-41 418-028:PAGE J-72 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19117 DOSE GROUP: v SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: LYMPH NODE, MEDIASTINAL: LYMPH NODE, SUBMANDIBULAR: STOMACH: hypertrophy, hepatocellular, centrilobular (minimal) mastocytosis (minimal) hyperplasia, lymphocytic/plasmacytic (moderate) edema/inflammation, submucosa, forestomach (mild) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COAGULATING GLAND HEART LUNG PROSTATE SPINAL CORD, LUMBAR TESTIS (PAS) URINARY BLADDER BONE MARROW (STERNUM) COLON ILEUM NERVE, SCIATIC RECTUM SPINAL CORD, THORACIC THYMUS End of Record- 19117 BRAIN DUODENUM JEJUNUM PARATHYROID SEMINAL VESICLES SPLEEN THYROID CECUM EPIDIDYMIDES KIDNEYS PEYER'S PATCH SPINAL CORD, CERVICAL TESTIS (H&E) TRACHEA 11-42 418-028:PAGE J-73 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19124 DOSE GROUP: v SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: EPIDIDYMIDES: KIDNEYS: LIVER: LYMPH NODE, MEDIASTINAL: THYROID: infiltration, mononuclear-cell, focal (minimal) nephritis, chronic, focal (minimal) cyst(s), medulla hypertrophy, hepatocellular, centrilobular (mild) mastocytosis (minimal) hypertrophy/hyperplasia, follicular epithelium (mild) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COAGULATING GLAND ILEUM NERVE, SCIATIC RECTUM SPINAL CORD, THORACIC TESTIS (PAS) BONE MARROW (STERNUM) COLON JEJUNUM PARATHYROID SEMINAL VESICLES SPLEEN THYMUS End of Record- 19124 BRAIN DUODENUM LUNG PEYER'S PATCH SPINAL CORD, CERVICAL STOMACH TRACHEA CECUM HEART LYMPH NODE, SUBMANDIBULAR PROSTATE SPINAL CORD, LUMBAR TESTIS (H&E) URINARY BLADDER II-43 418-028:PAGE J-74 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19126 DOSE GROUP: v SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION{S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: PROSTATE: inflammation, chronic, focal/multifocal (minimal} hypertrophy, hepatocellular, centrilobular (mild) inflammation, chronic, focal/multifocal (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COAGULATING GLAND HEART LUNG PARATHYROID SPINAL CORD, CERVICAL STOMACH THYROID BONE MARROW (STERNUM) COLON ILEUM LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD, LUMBAR TESTIS (H&E) TRACHEA End of Record- 19126 BRAIN DUODENUM JEJUNUM CECUM EPIDIDYMIDES KIDNEYS LYMPH NODE, SUBMANDIBULAR NERVE, SCIATIC RECTUM SEMINAL VESICLES SPINAL CORD, THORACIC SPLEEN TESTIS (PAS) THYMUS URINARY BLADDER II-44 418-028:PAGE J-75 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19127 SEX: M DOSE GROUP: DEATH TYPE: v Sacrifice-Scheduled GROSS OBSERVATION(S): GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION(S): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: ADRENAL GLANDS: LIVER: LYMPH NODE, SUBMANDIBULAR: THYROID: vacuolation, cortex, diffuse (mild) hypertrophy, hepatocellular, centrilobular (moderate) hyperplasia, lymphocytic/plasmacytic (minimal) hypertrophy/hyperplasia, follicular epithelium (mild) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: BONE MARROW (STERNUM) COLON ILEUM LYMPH NODE, MEDIASTINAL PROSTATE SPINAL CORD, LUMBAR TESTIS (H&E) URINARY BLADDER BRAIN DUODENUM JEJUNUM NERVE, SCIATIC RECTUM SPINAL CORD, THORACIC TESTIS (PAS) End of Record- 19127 CECUM EPIDIDYMIDES KIDNEYS PARATHYROID SEMINAL VESICLES SPLEEN THYMUS COAGULATING GLAND HEART LUNG PEYER 'S PATCH SPINAL CORD, CERVICAL STOMACH TRACHEA 11-45 418-028:PAGE J-76 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19128 DOSE GROUP: v SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: CECUM: LIVER: LYMPH NODE, SUBMANDIBULAR: PROSTATE: THYROID: inflammation, mucosa, chronic (mild) inflammation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (mild) hyperplasia, lymphocytic/plasmacytic (moderate) atrophy, focal/multifocal (moderate) hypertrophy/hyperplasia, follicular epithelium (moderate) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON ILEUM LYMPH NODE, MEDIASTINAL RECTUM SPINAL CORD, THORACIC TESTIS (PAS) BONE MARROW (STERNUM) DUODENUM JEJUNUM NERVE, SCIATIC SEMINAL VESICLES SPLEEN THYMUS End of Record- 19128 BRAIN EPIDIDYMIDES KIDNEYS PARATHYROID SPINAL CORD, STOMACH TRACHEA CERVICAL COAGULATING GLAND HEART LUNG PEYER'S PATCH SPINAL CORD, LUMBAR TESTIS (H&E) URINARY BLADDER Il-46 418-028:PAGE J-77 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19140 DOSE GROUP: v SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: inflammation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular {minimal) hypertrophy/hyperplasia, follicular epithelium (moderate) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COAGULATING GLAND HEART LUNG PARATHYROID SEMINAL VESICLES SPLEEN THYMUS BONE MARROW (STERNUM) COLON ILEUM LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD, CERVICAL STOMACH TRACHEA End of Record- 19140 BRAIN DUODENUM JEJUNUM LYMPH NODE, SUBMANDIBULAR PROSTATE SPINAL CORD, LUMBAR TESTIS (H&E) URINARY BLADDER CECUM EPIDIDYMIDES KIDNEYS NERVE, SCIATIC RECTUM SPINAL CORD, THORACIC TESTIS (PAS) II-47 418-028:PAGE J-78 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19145 DOSE GROUP: v SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: KIDNEYS: LIVER: LYMPH NOOE, SUBMANDIBULAR: RECTUM: TRACHEA: infiltration, mononuclear-cell, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (mild) hyperplasia, lymphocytic/plasmacytic (moderate) inflammation, mucosa, chronic (minimal) inflammation, chronic, focal (mild) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COAGULATING GLAND HEART LYMPH NODE, MEDIASTINAL PROSTATE SPINAL CORO, THORACIC TESTIS (PAS) BONE MARROW (STERNUM) COLON ILEUM NERVE I SCIATIC SEMINAL VESICLES SPLEEN THYMUS End of Record- 19145 BRAIN DUODENUM JEJUNUM PARATHYROID SPINAL CORD, STOMACH THYROID CERVICAL CECUM EPIDIDYMIDES LUNG PEYER'S PATCH SPINAL CORD, LUMBAR TESTIS (H&E) URINARY BLADDER 11-48 418-028:PAGE J-79 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19149 DOSE GROUP: v SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: hypertrophy, hepatocellular, centrilobular (minimal) ultimobranchial body/cyst hypertrophy/hyperplasia, follicular epithelium (moderate) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COAGULATING GLAND HEART LUNG PARATHYROID SEMINAL VESICLES SPLEEN THYMUS BONE MARROW (STERNUM) COLON ILEUM LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD, CERVICAL STOMACH TRACHEA End of Record- 19149 BRAIN DUODENUM JEJUNUM LYMPH NODE, SUBMANDIBULAR PROSTATE SPINAL CORD, LUMBAR TESTIS (H&E) URINARY BLADDER CECUM EPIDIDYMIDES KIDNEYS NERVE, SCIATIC RECTUM SPINAL CORD, THORACIC TESTIS (PAS) II-49 418-028:PAGE J-80 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19152 DOSE GROUP: v SEX: M DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: HEART: LIVER: LYMPH NODE, SUBMANDIBULAR: PROSTATE: THYROID: inflammation, chronic, focal (minimal) inflammation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (minimal) hyperplasia, lymphocytic/plasmacytic (moderate) inflammation, chronic, focal/multifocal (minimal) atrophy, focal/multifocal (minimal) hypertrophy/hyperplasia, follicular epithelium (mild) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COAGULATING GLAND ILEUM LYMPH NODE, MEDIASTINAL RECTUM SPINAL CORD, THORACIC TESTIS (PAS) BONE MARROW (STERNUM) COLON JEJUNUM NERVE, SCIATIC SEMINAL VESICLES SPLEEN THYMUS End of Record- 19152 BRAIN DUODENUM KIDNEYS PARATHYROID SPINAL CORD, STOMACH TRACHEA CERVICAL CECUM EPIDIDYMIDES LUNG PEYER'S PATCH SPINAL CORD, LUMBAR TESTIS (H&E) URINARY BLADDER II-50 418-028:PAGE J-81 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19012 DOSE GROUP: I SEX: F DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: STOMACH: THYROID: UTERUS: dilatation, mucosal glands (minimal) ultimobranchial body/cyst macrophages, pigmented (moderate) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON JEJUNUM LYMPH NODE, MEDIASTINAL OVARIES SPINAL CORD, CERVICAL THYMUS BONE MARROW (STERNUM) BRAIN DUODENUM KIDNEYS HEART LIVER LYMPH NODE, SUBMANDIBULAR MAMMARY GLAND PARATHYROID PEYER'S PATCH SPINAL CORD, LUMBAR TRACHEA SPINAL CORO, THORACIC URINARY BLADDER End of Record- 19012 CECUM ILEUM LUNG NERVE, RECTUM SPLEEN VAGINA SCIATIC II-51 418-028:PAGE J-82 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19019 DOSE GROUP: I SEX: F DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LYMPH NODE, SUBMANDIBULAR: UTERUS: hyperplasia, lymphocytic/plasmacytic (mild) macrophages, pigmented (mild) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON JEJUNUM LYMPH NODE, MEDIASTINAL PARATHYROID SPINAL CORD, LUMBAR THYMUS VAGINA BONE MARROW (STERNUM) DUODENUM KIDNEYS MAMMARY GLAND PEYER'S PATCH SPINAL CORD, THORACIC THYROID End of Record- 19019 BRAIN HEART LIVER NERVE, SCIATIC RECTUM SPLEEN TRACHEA CECUM ILEUM LUNG OVARIES SPINAL CORD, CERVICAL STOMACH URINARY BLADDER II-52 418-028:PAGE J-83 ORAL (GAVAGE} COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19021 DOSE GROUP: I SEX: F DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): HEAD: Head- scab, 0.2cmx0.4cm. dermatitis, chronic, focal, SKIN (GROSS LESION) HISTOMORPHOLOGIC OBSERVATIONS: LIVER: LYMPH NODE, MEDIASTINAL: SKIN (GROSS LESION}: THYROID: UTERUS: inflammation, chronic, focal/multifocal congestion (minimal) dermatitis, chronic, focal (mild) ultimobranchial body/cyst macrophages, pigmented (moderate) (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON JEJUNUM MAMMARY GLAND PEYER'S PATCH SPINAL CORD, THORACIC TRACHEA BONE MARROW (STERNUM) DUODENUM KIDNEYS NERVE, SCIATIC RECTUM SPLEEN VAGINA BRAIN HEART LUNG OVARIES SPINAL CORD, STOMACH CERVICAL CECUM ILEUM LYMPH NODE, SUBMANDIBULAR PARATHYROID SPINAL CORD, LUMBAR THYMUS TISSUE(S) NOT AVAILABLE FOR EVALUATION: URINARY BLADDER End of Record- 19021 II-53 418-028:PAGE J-84 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19023 SEX: F DOSE GROUP: DEATH TYPE: I Sacrifice-Scheduled GROSS OBSERVATION(S): GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION(S): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LUNG: LYMPH NODE, MEDIASTINAL: STOMACH: UTERUS: infiltration, polymorphonuclear, perivascular/peribronchial (mi 1d) mastocytosis (minimal) edema/inflammation, submucosa, glandular area (mild) macrophages, pigmented (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON JEJUNUM MAMMARY GLAND PEYER'S PATCH SPINAL CORD, THORACIC TRACHEA BONE MARROW (STERNUM) DUODENUM KIDNEYS NERVE, SCIATIC RECTUM SPLEEN URINARY BLADDER End of Record- 19023 BRAIN HEART LIVER OVARIES SPINAL CORD, THYMUS VAGINA CERVICAL CECUM ILEUM LYMPH NODE, SUBMANDIBULAR PARATHYROID SPINAL CORD, LUMBAR THYROID II-54 418-028:PAGE J-85 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19041 DOSE GROUP: I SEX: F DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LYMPH NODE, SUBMANDIBULAR: STOMACH: THYROID: UTERUS: hyperplasia, lymphocytic/plasmacytic (moderate) edema/inflammation, submucosa, glandular area (moderate) ultimobranchial body/cyst macrophages, pigmented (moderate) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON JEJUNUM LYMPH NODE, MEDIASTINAL PARATHYROID SPINAL CORD, LUMBAR TRACHEA BONE MARROW (STERNUM) DUODENUM KIDNEYS MAMMARt GLAND PEYER'S PATCH SPINAL CORD, THORACIC URINARY BLADDER End of Record- 19041 BRAIN HEART LIVER NERVE, SCIATIC RECTUM SPLEEN VAGINA CECUM ILEUM LUNG OVARIES SPINAL CORD, THYMUS CERVICAL II-55 418-028:PAGE J-86 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19042 DOSE GROUP: I SEX: F DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: OVARIES: THYROID: UTERUS: cyst(s), intraovarian ultimobranchial body/cyst macrophages, pigmented (moderate) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON JEJUNUM LYMPH NOOE, MEDIASTINAL PARATHYROID SPINAL CORD, LUMBAR THYMUS BONE MARROW (STERNUM) DUODENUM KIDNEYS LYMPH NOOE, SUBMANDIBULAR PEYER'S PATCH SPINAL CORD, THORACIC TRACHEA BRAIN HEART LIVER MAMMARY RECTUM SPLEEN URINARY GLAND BLADDER End of Record- 19042 CECUM ILEUM LUNG NERVE, SCIATIC SPINAL CORD, CERVICAL STOMACH VAGINA II-56 418-028:PAGE J-87 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19044 DOSE GROUP: I SEX: F DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: KIDNEYS: LYMPH NODE, MEDIASTINAL: LYMPH NODE, SUBMANDIBULAR: UTERUS: nephritis, chronic, focal (minimal) congestion (minimal) hyperplasia, lymphocytic/plasmacytic (mild) hyperplasia, lymphocytic/plasmacytic (moderate) macrophages, pigmented (moderate) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON JEJUNUM NERVE, SCIATIC RECTUM SPLEEN TRACHEA BONE MARROW (STERNUM) DUODENUM LIVER OVARIES SPINAL CORD, CERVICAL STOMACH URINARY BLADDER End of Record- 19044 BRAIN HEART LUNG PARATHYROID SPINAL CORD, THYMUS VAGINA LUMBAR CECUM ILEUM MAMMARY GLAND PEYER'S PATCH SPINAL CORO, THORACIC THYROID II-57 418-028:PAGE J-88 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19050 DOSE GROUP: I SEX: F DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: ADRENAL GLANDS: LYMPH NODE, SUBMANDIBULAR: UTERUS: vacuolation, zona glomerulosa (mild) hyperplasia, lymphocytic/plasmacytic (minimal) macrophages, pigmented (moderate) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: BONE MARROW (STERNUM) DUODENUM KIDNEYS MAMMARY GLAND PEYER'S PATCH SPINAL CORD, THORACIC THYROID BRAIN HEART LIVER NERVE, SCIATIC RECTUM SPLEEN TRACHEA End of Record- 19050 CECUM ILEUM LUNG OVARIES SPINAL CORD, CERVICAL STOMACH URINARY BLADDER COLON JEJUNUM LYMPH NODE, MEDIASTINAL PARATHYROID SPINAL CORD, LUMBAR THYMUS VAGINA II-58 418-028:PAGE J-89 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19053 DOSE GROUP: I SEX: F DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: ADRENAL GLANDS: CECUM: LYMPH NODE, SUBMANDIBULAR: THYMUS: THYROID: UTERUS: vacuolation, zona glomerulosa (mild) inflammation, mucosa, chronic (moderate) hyperplasia, lymphocytic/plasmacytic (mild) atrophy (moderate) ultimobranchial body/cyst macrophages, pigmented (moderate) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: BONE MARROW (STERNUM) HEART LIVER NERVE, SCIATIC RECTUM SPLEEN VAGINA BRAIN ILEUM LUNG OVARIES SPINAL CORD, STOMACH CERVICAL End of Record- 19053 COLON JEJUNUM LYMPH NODE, MEDIASTINAL PARATHYROID SPINAL CORD, LUMBAR TRACHEA DUODENUM KIDNEYS MAMMARY GLAND PEYER'S PATCH SPINAL CORD, THORACIC URINARY BLADDER II-59 418-028:PAGE J-90 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19065 DOSE GROUP: I SEX: F DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION{S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: CECUM: LIVER: LYMPH NODE, SUBMANDIBULAR: URINARY BLADDER: UTERUS: inflammation, mucosa, chronic (mild) inflammation, chronic, focal/multifocal (minimal) hyperplasia, lymphocytic/plasmacytic (mild) inflammation, chronic, focal (minimal) macrophages, pigmented (mild) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS DUODENUM KIDNEYS NERVE, SCIATIC RECTUM SPLEEN TRACHEA BONE MARROW (STERNUM) HEART LUNG OVARIES SPINAL CORD, CERVICAL STOMACH VAGINA End of Record- 19065 BRAIN ILEUM LYMPH NODE, MEDIASTINAL PARATHYROID SPINAL CORO, LUMBAR THYMUS COLON JEJUNUM MAMMARY GLAND PEYER'S PATCH SPINAL CORD, THORACIC THYROID II-60 418-028:PAGE J-91 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19001 SEX: F DOSE GROUP: DEATH TYPE: v Sacrifice-Scheduled GROSS OBSERVATION($): GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION(S): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LUNG: TRACHEA: UTERUS: inflammation, interstitial, focal (minimal) macrophages, alveoli, focal (minimal) inflammation, chronic, focal (minimal) macrophages, pigmented (moderate) distention, lumen (mild) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS BONE MARROW (STERNUM) COLON DUODENUM JEJUNUM KIDNEYS LYMPH NODE, SUBMANDIBULAR MAMMARY GLAND PARATHYROID PEYER'S PATCH SPINAL CORD, LUMBAR THYMUS SPINAL CORD, THORACIC THYROID End of Record- 19001 BRAIN HEART LIVER NERVE, SCIATIC RECTUM SPLEEN URINARY BLADDER CECUM ILEUM LYMPH NODE, MEDIASTINAL OVARIES SPINAL CORD, CERVICAL STOMACH VAGINA 11-61 418-028:PAGE J-92 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19006 DOSE GROUP: v SEX: F DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LYMPH NODE, SUBMANDIBULAR: THYROID: UTERUS: hyperplasia, lymphocytic/plasmacytic (mild) ultimobranchial body/cyst macrophages, pigmented (mild} THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON JEJUNUM LYMPH NODE, MEDIASTINAL PARATHYROID SPINAL CORD, LUMBAR THYMUS BONE MARROW (STERNUM) DUODENUM KIDNEYS MAMMARY GLAND PEYER'S PATCH SPINAL CORD, THORACIC TRACHEA End of Record- 19006 BRAIN HEART LIVER NERVE, SCIATIC RECTUM SPLEEN URINARY BLADDER CECUM ILEUM LUNG OVARIES SPINAL CORD, STOMACH VAGINA CERVICAL II-62 418-028:PAGE J-93 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19011 DOSE GROUP: v SEX: F DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: ADRENAL GLANDS: LIVER: UTERUS: necrosis, cortex, focal (mild) Not remarkable macrophages, pigmented (moderate) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: BONE MARROW (STERNUM) DUODENUM KIDNEYS MAMMARY GLAND PEYER'S PATCH SPINAL CORD, THORACIC THYROID BRAIN HEART LUNG NERVE, SCIATIC RECTUM SPLEEN TRACHEA End of Record- 19011 CECUM ILEUM LYMPH NODE, MEDIASTINAL OVARIES SPINAL CORD, CERVICAL STOMACH URINARY BLADDER COLON JEJUNUM LYMPH NODE, SUBMANDIBULAR PARATHYROID SPINAL CORD, LUMBAR THYMUS VAGINA 11-63 418-028:PAGE J-94 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19020 DOSE GROUP: v SEX: F DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): ADRENAL GLANDS: Bilateral- large. GASTROINTESTINAL TRACT: Abdominal distention, large and small intestines distended with gas. SPLEEN: Small. ~: Fundic mucosa surface contains approximately 12 black areas ranging in size from pinpoint to 0.3cm in diameter. THYMUS: Small. degeneration, cystic, cortex, multifocal No microscopic change to correlate, DUODENUM No microscopic change to correlate, JEJUNUM No microscopic change to correlate, ILEUM No microscopic change to correlate, COLON No microscopic change to correlate, CECUM No microscopic change to correlate, RECTUM atrophy edema/inflammation, submucosa, glandular area edema/inflammation, submucosa, forestomach erosion(s), glandular mucosa atrophy HISTOMORPHOLOGIC OBSERVATIONS: ADRENAL GLANDS: CECUM: COLON: DUODENUM: ILEUM: JEJUNUM: LIVER: LYMPH NODE, SUBMANDIBULAR: RECTUM: SPLEEN: STOMACH: THYMUS: THYROID: UTERUS: degeneration, cystic, cortex, multifocal (mild) No microscopic change to correlate No microscopic change to correlate No microscopic change to correlate No microscopic change to correlate No microscopic change to correlate necrosis, focal (minimal) hyperplasia, lymphocytic/plasmacytic (mild) No microscopic change to correlate atrophy (mild) erosion(s), glandular mucosa (moderate) edema/inflammation, submucosa, glandular area (mild) edema/inflammation, submucosa, forestomach (mild) atrophy (marked) ultimobranchial body/cyst macrophages, pigmented (marked) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: BONE MARROW (STERNUM) DUODENUM KIDNEYS NERVE, SCIATIC RECTUM TRACHEA BRAIN HEART LUNG OVARIES SPINAL CORD, CERVICAL URINARY BLADDER End of Record- 19020 CECUM ILEUM LYMPH NODE, MEDIASTINAL PARATHYROID SPINAL CORD, LUMBAR VAGINA COLON JEJUNUM MAMMARY GLAND PEYER'S PATCH SPINAL CORD, THORACIC 11-64 418-028:PAGE J-95 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19022 DOSE GROUP: v SEX: F DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: LYMPH NODE, SUBMANDIBULAR: MAMMARY GLAND: THYROID: UTERUS: inflammation, chronic, focal/multifocal (minimal) hyperplasia, lymphocytic/plasmacytic (mild) necrosis, focal (minimal) ultimobranchial body/cyst macrophages, pigmented (mild) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON JEJUNUM NERVE, SCIATIC RECTUM SPLEEN URINARY BLADDER BONE MARROW (STERNUM) DUODENUM KIDNEYS OVARIES SPINAL CORD, CERVICAL STOMACH VAGINA End of Record- 19022 BRAIN HEART LUNG PARATHYROID SPINAL CORD, THYMUS LUMBAR CECUM ILEUM LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD, THORACIC TRACHEA 11-65 418-028:PAGE J-96 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19025 DOSE GROUP: v SEX: F DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: ADRENAL GLANDS: KIDNEYS: STOMACH: UTERUS: hypertrophy/vacuolation, cortex, multifocal (mild) nephritis, chronic, focal (minimal) edema/inflammation, submucosa, glandular area (mild) macrophages, pigmented (moderate) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: BONE MARROW (STERNUM) DUODENUM LIVER MAMMARY GLAND PEYER'S PATCH SPINAL CORD, THORACIC TRACHEA BRAIN HEART LUNG NERVE, SCIATIC RECTUM SPLEEN URINARY BLADDER End of Record- 19025 CECUM ILEUM LYMPH NODE, MEDIASTINAL OVARIES SPINAL CORD, CERVICAL THYMUS VAGINA COLON JEJUNUM LYMPH NODE, SUBMANDIBULAR PARATHYROID SPINAL CORD, LUMBAR THYROID II-66 418-028:PAGE J-97 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19027 DOSE GROUP: v SEX: F DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: KIDNEYS: LYMPH NOOE, SUBMANDIBULAR: STOMACH: THYROID: mineralization, multifocal (minimal) hyperplasia, lymphocytic/plasmacytic (mild) edema/inflammation, submucosa, glandular area (mild) ultimobranchial body/cyst THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON JEJUNUM MAMMARY GLAND RECTUM SPLEEN UTERUS BONE MARROW (STERNUM) DUODENUM LIVER OVARIES SPINAL CORO, CERVICAL THYMUS VAGINA BRAIN HEART LUNG PARATHYROID SPINAL CORD, TRACHEA LUMBAR CECUM ILEUM LYMPH NOOE, MEDIASTINAL PEYER'S PATCH SPINAL CORO, THORACIC URINARY BLADDER TISSUE(S) NOT AVAILABLE FOR EVALUATION: NERVE, SCIATIC End of Record- 19027 II-67 418-028:PAGE J-98 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19028 DOSE GROUP: v SEX: F DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LYMPH NODE, SUBMANDIBULAR: STOMACH: UTERUS: hyperplasia, lymphocytic/plasmacytic (moderate) dilatation, mucosal glands (minimal) macrophages, pigmented (moderate) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON JEJUNUM LYMPH NODE, MEDIASTINAL PARATHYROID SPINAL CORD, LUMBAR THYROID BONE MARROW (STERNUM) DUODENUM KIDNEYS MAMMARY GLAND PEYER'S PATCH SPINAL CORD, THORACIC TRACHEA End of Record- 19028 BRAIN HEART LIVER NERVE, SCIATIC RECTUM SPLEEN URINARY BLADDER CECUM ILEUM LUNG OVARIES SPINAL CORD, THYMUS VAGINA CERVICAL Il-68 418-028:PAGE J-99 ORAL {GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 ANIMAL NUMBER: 19030 SEX: F Appendix II Individual Animal Gross and Histomorphology Data DOSE GROUP: DEATH TYPE: v Sacrifice-Scheduled GROSS OBSERVATION(S): HEAD: Head- scab, 0.3cm x 0.3cm. HISTOMORPHOLOGIC OBSERVATION(S): dermatitis, chronic, focal, SKIN (GROSS LESION) HISTOMORPHOLOGIC OBSERVATIONS: LIVER: SKIN (GROSS LESION): THYROID: UTERUS: Not remarkable dermatitis, chronic, focal (minimal) ultimobranchial body/cyst macrophages, pigmented (moderate) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON JEJUNUM MAMMARY GLAND PEYER'S PATCH SPINAL CORD, THORACIC TRACHEA BONE MARROW (STERNUM) DUODENUM KIDNEYS NERVE, SCIATIC RECTUM SPLEEN URINARY BLADDER BRAIN HEART LUNG OVARIES SPINAL CORD, STOMACH VAGINA CERVICAL CECUM ILEUM LYMPH NODE, MEDIASTINAL PARATHYROID SPINAL CORD, LUMBAR THYMUS TISSUE(S) NOT AVAILABLE FOR EVALUATION: LYMPH NODE, SUBMANDIBULAR End of Record- 19030 II-69 418-028:PAGE J-100 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19031 DOSE GROUP: v SEX: F DEATH TYPE: Sacrifice-Scheduled ======================================================================================================= GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: LYMPH NODE, SUBMANDIBULAR: UTERUS: necrosis, focal (minimal) hyperplasia, lymphocytic/plasmacytic (mild) distention, lumen (moderate) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON JEJUNUM MAMMARY GLAND PEYER'S PATCH SPINAL CORD, THORACIC THYROID BONE MARROW (STERNUM) DUODENUM KIDNEYS NERVE, SCIATIC RECTUM SPLEEN TRACHEA End of Record- 19031 BRAIN HEART LUNG OVARIES SPINAL CORD, CERVICAL STOMACH URINARY BLADDER CECUM ILEUM LYMPH NODE, MEDIASTINAL PARATHYROID SPINAL CORD, LUMBAR THYMUS VAGINA II-70 418-028:PAGE J-101 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-028 SPONSOR'S STUDY NUMBER T-7706.1 HISTOPATHOLOGY REPORT APPENDIX Ill HISTOMORPHOLOGIC OBSERVATIONS IN THE LIVER F1 GENERATION PUPS 418-028:PAGE J-102 ORAL (GAVAGE) COMBINED REPEATED DOSE STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Table 111-1 Histomorphologic Observations in the Liver - Group I - F1 Generation Pups Dose Group: Dam Number: Pup Number: I I I I I I I I I I 19012 19012 19012 19012 19012 19012 19012 19012 19012 19012 1 2 3 4 5 7 8 14 15 16 Dose Group: Dam Number: Pup Number: I I I I I I I I I I 19019 19019 19019 19019 19019 19019 19019 19019 19019 19019 1 2 3 7 8 11 12 13 14 15 Dose Group: Dam Number: Pup Number: I I I I I I I I I I 19021 19021 19021 19021 19021 19021 19021 19021 19021 19021 1 2 6 8 9 10 11 12 13 14 Dose Group: Dam Number: Pup Number: I I I I I I I I I I 19023 19023 19023 19023 19023 19023 19023 19023 19023 19023 1 2 3 6 7 8 9 10 11 12 Dose Group: Dam Number: Pup Number: I I I I I I I I I I 19041 19041 19041 19041 19041 19041 19041 19041 19041 19041 1 2 3 4 5 8 9 15 16 17 111-1 418-028:PAGE J-103 ORAL (GAVAGE) COMBINED REPEATED DOSE STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Table 111-1 (Continued) Histomorphologic Observations in the Liver - Group I - F1 Generation Pups Dose Group: Dam Number: Pup Number: I I I I I I I I I I 19042 19042 19042 19042 19042 19042 19042 19042 19042 19042 1 2 4 5 6 7 8 10 12 13 Dose Group: Dam Number: Pup Number: I I I I I I I I I I 19044 19044 19044 19044 19044 19044 19044 19044 19044 19044 1 2 5 6 7 9 11 12 13 14 Dose Group: Dam Number: Pup Number: I I I I I I I I I I 19050 19050 19050 19050 19050 19050 19050 19050 19050 19050 1 2 3 4 5 6 7 8 13 14 Dose Group: Dam Number: Pup Number: Dose Group: Dam Number: Pup Number: I I I I I I I I I I 19053 19053 19053 19053 19053 19053 19053 19053 19053 19053 1 3 4 5 6 10 11 12 13 14 I I I I I I I I I I 19065 19065 19065 19065 19065 19065 19065 19065 19065 19065 3 4 5 7 8 10 11 14 15 17 111-2 418-028:PAGE J-104 ORAL (GAVAGE) COMBINED REPEATED DOSE STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Dose Group: Dam Number: Pup Number: LIVER : Table 111-2 Histomorphologic Observations in the Liver - Group V- F1 Generation Pups v v v v v v v v v 19001 19001 19001 19001 19001 19001 19001 19001 19001 1 2 3 4 5 6 7 9 11 Dose Group: Dam Number: Pup Number: LIVER : v v v v v v v v v v 19006 19006 19006 19006 19006 19006 19006 19006 19006 19006 1 2 3 4 5 8 10 11 13 18 Dose Group: Dam Number: Pup Number: LIVER : v v v v v v v v v v 19011 19011 19011 19011 19011 19011 19011 19011 19011 19011 2 3 4 5 6 9 10 11 12 13 Dose Group: Dam Number: Pup Number: LIVER : v v v v v v v v v v 19020 19020 19020 19020 19020 19020 19020 19020 19020 19020 2 4 5 7 8 9 10 11 12 13 Dose Group: Dam Number: Pup Number: LIVER : v v v v v v v v v v 19022 19022 19022 19022 19022 19022 19022 19022 19022 19022 1 4 5 7 8 11 12 13 14 15 111-3 418-028:PAGE J-105 ORAL (GAVAGE) COMBINED REPEATED DOSE STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Dose Group: Dam Number: Pup Number: LIVER : Table 111-2 (Continued) Histomorphologic Observations in the Liver - Group V- F1 Generation Pups v v v v v v v v v v 19025 19025 19025 19025 19025 19025 19025 19025 19025 19025 1 2 7 8 13 14 15 18 19 20 Dose Group: Dam Number: Pup Number: LIVER : v v v v v v v v v 19027 19027 19027 19027 19027 19027 19027 19027 19027 1 2 3 4 5 6 7 13 14 Dose Group: Dam Number: Pup Number: LIVER : v v v v v v v v v v 19028 19028 19028 19028 19028 19028 19028 19028 19028 19028 1 2 3 4 5 6 7 10 11 12 Dose Group: Dam Number: Pup Number: LIVER : Dose Group: Dam Number: Pup Number: LIVER : v v v v v v v v v v 19030 19030 19030 19030 19030 19030 19030 19030 19030 19030 1 2 4 5 6 8 9 11 12 13 v v v v v v v v v v 19031 19031 19031 19031 19031 19031 19031 19031 19031 19031 1 2 3 5 6 9 11 12 14 15 111-4 APPENDIXK HEMATOLOGY AND CLINICAL CHEMISTRY REPORTS 418-028:PAGE K-1 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY Ii): ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ---------------~------------------------------------------------------------------------------------------------------- Animal ID WBC RBC HGB HCT MCV MCH MCHC PLT THSN/CU MM MILL/CU MM GRAMS/DL % CU MICRONS PICO GRAMS % THSN/CU MM ----------------------------------------------------------------------------------------------------------------------- GROUP: 1-M 19109 13.5 7.10 15.4 40.6 57.2 21.7 37.9 1219 19115 15.9 8.58 19.0 50.0 58.3 22.1 38.0 1072 19116 15.1 6.95 16.3 42.6 61.3 23.5 38.3 964 19119 12.7 7.16 16.2 42.1 58.8 22.6 38.5 1354 19122 16.4 6.77 15.7 40.6 59.9 23.2 38.7 1074 19125 17.6 7.61 16.2 41.4 54.4 21.3 39.1 1322 19131 17.7 7.37 16.3 41.6 56.5 22.1 39.2 1049 19132 14.9 7.45 16.3 43.3 58.1 21.9 37.6 1264 19134 15.0 7.43 15.6 42.7 57.5 21.0 36.5 1269 19135 14.3 8.71 18.2 49.7 57.1 20.9 36.6 1203 19143 19151 19157 19161 19167 MEAN 15.3 7.51 16.5 43.5 57.9 22.0 38.0 1179 SD 1.63 0.648 1.16 3.48 1.89 0.87 0.93 130.9 N 10 10 10 10 10 10 10 10 (--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-2 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID WBC RBC HGB HCT MCV MCH MCHC PLT THSN/CU MM MILL/CU MM GRAMS/DL % CU MICRONS PICO GRAMS % THSN/CU MM GROUP: 2-M 19102 10.9 7.55 16.2 43.6 57.7 21.5 37.2 926 19106 17.0 6.93 15.2 39.6 57.1 21.9 38.4 970 19108 12.7 7.02 16.1 40.3 57.4 22.9 40.0 959 19110 13.1 8.20 15.9 43.9 53.5 19.4 36.2 1468 19113 15.7 6.80 16.1 42.0 61.8 23.7 38.3 1170 19120 18.4 7.42 16.4 44.4 59.8 22.1 36.9 1382 19129 14.7 7.29 15.9 43.2 59.3 21.8 36.8 1184 19136 10.5 7.32 15.4 41.3 56.4 21.0 37.3 1183 19138 17.2 7.53 16.4 42.2 56.0 21.8 38.9 1069 19139 19.0 7.20 15.5 41.7 57.9 21.5 37.2 994 19147 19153 19164 19165 19171 MEAN 14.9 7.33 15.9 42.2 57.7 21.8 37.7 1131 SD 3.03 0.396 0.42 1.57 2.27 1.13 1.15 183.7 N 10 10 10 10 10 10 10 10 (--) - Data Unavailable .LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-3 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-069 SEX: MALE ----------------------------------------------------------~------------------------------------------------------------ Animal ID WBC RBC HGB HCT MCV MCH MCHC PLT THSN/CU MM HILL/CU HM GRAMS/DL % CU MICRONS PICO GRAMS % THSN/CU MM ----------------------------------------------------------------------------------------------------------------------- GROUP: 3-M 19101 13.1 7.38 16.0 42.4 57.4 21.7 37.7 958 19105 11.0 7.28 16.3 43.2 59.3 22.4 37.7 960 19107 12.5 7.59 16.1 44.4 58.5 21.2 36.3 993 19112 13.3 7.20 15.4 40.1 55.7 21.4 38.4 1002 19114 11.2 7.72 15.7 42.6 55.2 20.3 36.9 1253 19121 20.9 7.23 15.4 40.5 56.0 21.3 38.0 1340 19123 14.1 6.69 15.0 39.1 58.4 22.4 38.4 1143 19130 13.9 7.96 16.4 43.8 55.0 20.6 37.4 1123 19137 12.2 7.60 16.3 45.0 59.2 21.4 36.2 1046 19146 15.4 6.54 14.7 38.8 59.4 22.5 37.9 1336 19155 19159 19172 19173 19174 MEAN SD N 13.8 7.32 15.7 42.0 57.4 21.5 37.5 1115 2.84 0.441 0.59 2.22 1. 78 0.75 0.79 149.2 10 10 10 10 10 10 10 10 <--> - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-4 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 Animal ID WBC THSN/CU MM RBC MILL/CU MM HGB GRAMS/DL HCT MCV % CU MICRONS MCH PICO GRAMS MCHC PLT % THSN/CU MM GROUP: 4-M 19100 12.6 6.59 14.6 38.2 57.9 22.2 38.2 1072 19103 21.0 6.73 15.0 39.0 58.0 22.3 38.5 1144 19104 18.1 6.75 15.6 39.3 58.2 23.1 39.7 1029 19118 12.0 6.83 14.8 38.4 56.2 21.7 38.5 1274 19133 22.0 7.50 16.8 45.5 60.7 22.4 36.9 1124 19141 17.4 7.07 15.5 40.3 57.0 21.9 38.5 1125 19142 12.8 6.87 15.0 39.9 58.1 21.8 37.6 998 19144 19.6 7.37 16.1 42.4 57.5 21.8 38.0 962 19148 15.6 6.97 15.6 40.6 58.2 22.4 38.4 1155 19150 11.1 6.62 15.0 38.1 57.6 22.7 39.4 1161 19156 19160 19162 19163 19166 MEAN SD N 16.2 6.93 15.4 40.2 57.9 22.2 38.4 1104 3.97 0.305 0.67 2.29 1.15 0.45 0.80 91.4 10 10 10 10 10 10 10 10 <--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:.PAGE K-5 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID WBC RBC HGB HCT MCV MCH MCHC PLT THSN/CU MM MILL/CU MM GRAMS/DL % CU MICRONS PICO GRAMS % THSN/CU MM --------------------------------------------------------------------------------------~------------------------------ GROUP: 5-M 19111 15.7 7.20 16.1 41.7 57.9 22.4 38.6 1013 19117 14.3 6.72 15.7 39.8 59.2 23.4 39.4 1181 19124 10.8 6.68 15.0 39.0 58.4 22.5 38.5 1249 19126 12.5 8.07 17.3 44.4 55.0 21.4 39.0 1142 19127 11.0 6.61 14.7 38.1 57.6 22.2 38.6 1040 19128 14.2 7.09 15.5 41.1 58.0 21.9 37.7 1001 19140 15.2 7.05 16.2 41.9 59.5 23.0 38.7 1059 19145 20.7 7.13 15.7 41.4 58.1 22.0 37.9 1523 19149 18.3 6.66 14.8 39.8 59.8 22.2 37.2 1234 19152 13.9 6.68 14.8 39.5 59.2 22.2 37.5 1041 19154 19158 19168 19169 19170 MEAN 14.7 6.99 15.6 40.7 58.3 22.3 38.3 1148 SD 3.07 0.442 0.81 1.81 1.37 0.56 0.70 159.9 N 10 10 10 10 10 10 10 10 (--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-6 Study Report for Hematology INDIVIDUAL ANIMAL REPORT BY GROUP -----------------------------------------------------------------------------------------------------~----------------- PERIOD TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID WBC RBC HGB HCT MCV MCH MCHC PLT THSN/CU MM MILL/CU MM GRAMS/DL % CU MICRONS PICO GRAMS % THSN/CU MM -----------------------------------------------------~----------------------------------------------------------------- GROUP: 1-F 19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 15.9 5.60 14.0 35.2 62.9 25.0 39.8 1421 6.6 6.95 16.4 42.5 61.1 23.6 38.6 1344 7.4 7.10 16.7 44.7 63.0 23.5 37.4 1199 7.3 6.62 16.3 42.4 64.1 24.6 38.4 1352 8.0 6.86 16.2 42.4 61.8 23.6 38.2 1529 6.8 6.45 15.1 40.2 62.3 23.4 37.6 1225 10.6 6.09 14.3 37.6 61.7 23.5 38.0 1343 8.2 6.64 16.0 42.2 63.6 24.1 37.9 1629 6.6 6.08 14.7 37.5 61.6 24.2 39.2 1524 12.5 6.67 15.7 40.2 60.2 23.5 39.1 1623 19068 19072 19074 19075 MEAN SD N 9.0 6.51 15.5 40.5 62.2 23.9 38.4 1419 3.09 0.461 0.95 2.93 1.19 0.55 0.76 153.0 10 10 10 10 10 10 10 10 C--) - Data unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-7 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- XNDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 Animal ID WBC THSN/CU MM RBC MILL/CU MM HGB GRAMS/DL HCT MCV % CU MICRONS MCH PICO GRAMS MCHC PLT % THSN/CU MM GROUP: 2-F 19004 7.8 7.07 16.6 43.8 62.0 23.5 37.9 1540 19009 14.6 5.90 14.8 38.3 64.9 25.1 38.6 1157 19016 17.0 6.32 14.9 38.5 60.9 23.6 38.7 1529 19018 13.3 5.61 14.1 35.3 63.0 25.1 39.9 1057 19026 9.1 6.36 15.5 41.6 65.4 24.4 37.3 1443 19036 18.0 6.30 14.5 38.9 61.7 23.0 37.3 1166 19037 26.3 6.23 14.8 37.8 60.6 23.8 39.2 1257 19043 13.5 5.83 14.7 38.3 65.7 25.2 38.4 942 19047 11.1 5.93 14.5 37.5 63.3 24.5 38.7 1041 19048 7.1 6.60 16.0 43.4 65.8 24.2 36.9 1264 19052 19055 19061 19067 19071 MEAN SD N 13.8 6.22 15.0 39.3 63.3 24.2 38.3 1240 5.73 0.423 0.77 2.72 2.01 0.76 0.94 208.1 10 10 10 10 10 10 10 10 <--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-8 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ------------------------------------------------------------------------------~-------------------------------------- Animal 10 wee RBC HGB HCT MCV MCH MCHC PLT THSN/CU MM MILL/CU MM GRAMS/DL % CU MICRONS PICO GRAMS % THSN/CU MM ----------------------------------------------------------------------------------------------------------------------- GROUP: 3-F 19003 11.1 6.43 15.7 40.0 62.2 24~4 39.3 1165 19007 7.9 6.31 15.4 39.9 63.3 24.4 38.6 1450 19008 7.0 6.71 15.7 40.5 60.3 23.4 38.8 1319 19013 16.6 5.53 13.8 33.1 59.9 25.0 41.7 1167 19014 19015 7.4 6.41 15.1 39.8 62.1 23.6 37.9 1671 19017 12.9 6.03 14.4 38.0 63.0 23.9 37.9 866 19024 10.5 6.93 15.6 42.1 60.8 22.5 37.1 1424 19029 12.5 5.69 14.0 35.6 62.6 24.6 39.3 1062 19034 12.1 6.54 16.1 41.9 64.1 24.6 38.4 1231 19038 19056 12.7 7.38 16.6 44.2 59.9 22.5 37.6 1380 19057 19060 19064 MEAN SD N 11.1 6.40 15.2 39.5 61.8 23.9 38.7 1274 2.98 0.554 0.91 3.24 1.50 0.88 1.29 226.3 10 10 10 10 10 10 10 10 (--) - Data Unavailable . LABCAT HE4. 43 27-JUN-2002 418-028:PAGE K-9 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- INDiVIDUAL ANiMAL REPORT BY GROUP PERXOD TERMXNAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 Animal ID WBC THSN/CU MM RBC MILL/CU MM HGB GRAMS/DL HCT MCV % CU MICRONS MCH PICO GRAMS MCHC % PLT THSN/CU MM GROUP: 4-F 19002 19005 9.5 6.51 15.8 42.0 64.5 24.3 37.6 1479 19035 9.6 6.81 16.2 42.4 62.3 23.8 38.2 1527 19039 12.8 6.48 14.8 38.9 60.1 22.8 38.0 1066 19040 10.0 6.48 15.8 41.3 63.8 24.4 38.3 1333 19045 9.7 5.77 13.7 36.7 63.6 23.7 37.3 1148 19046 19051 19054 14.9 7.33 15.7 44.1 60.2 21.4 35.6 1497 19058 15.7 5.94 14.2 37.2 62.6 23.9 38.2 1094 19062 6.2 6.86 15.7 43.3 63.1 22.9 36.3 1399 19063 12.9 5.68 14.0 35.2 61.9 24.6 39.8 999 19066 7.1 6.01 15.7 40.3 67.0 26.1 39.0 1506 19069 19073 MEAN SD N 10.8 6.39 15.2 40.1 62.9 23.8 37.8 1305 3.15 0.532 0.90 3.02 2.04 1.25 1.22 207.2 10 10 10 10 10 10 10 10 <--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-10 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ---~------------------------------------------------------------------------------------------------------------------- Animal ID WBC RBC HGB HCT MCV MCH MCHC PLT THSN/CU MM MILL/CU MM GRAMS/DL % CU MICRONS PICO GRAMS % THSN/CU MM GROUP: 5-F 19001 15 .1 5.90 14.3 37.3 63.2 24.2 38.3 1131 19006 7.6 6.33 15.4 39.0 61.6 24.3 39.5 1312 19011 6.4 6.46 15.7 40.5 62.7 24.3 38.8 1254 19020 4.2 7.49 16.1 46.8 62.5 21.5 34.4 1549 19022 5.4 6.79 16.0 43.0 63.4 23.6 37.2 1448 19025 7.3 6.47 15.1 39.7 61.3 23.3 38.0 1391 19027 12.3 6.69 15.9 42.2 63.1 23.8 37.7 1667 19028 10.2 5.76 13.8 35.8 62.2 24.0 38.5 1286 19030 8.1 6.62 15.6 41.4 62.6 23.6 37.7 1417 19031 12.3 5.72 14.7 38.4 67.1 25.7 38.3 1099 19032 19033 19049 19059 19070 MEAN 8.9 6.42 15.3 40.4 63.0 23.8 37.8 1355 SD 3.48 0.538 0.77 3.15 1.60 1.05 1.37 176.8 N 10 10 10 10 10 10 10 10 (--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-11 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID MPV PT APTT NRBC Lymphocyte Segmented Bands Monocytes CU MICRON seconds seconds COUNT THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM GROUP: 1-M 19109 8.0 13.2 13.2 19115 8.0 13.3 21.5 19116 7.2 13.7 22.4 19119 7.5 13.6 23.0 19122 8.2 13.1 19.8 19125 8.9 13.6 Z0.8 19131 8.2 13.2 19.8 19132 8.0 13.7 21.8 19134 8.4 13.2 23.9 19135 8.8 13.2 23.6 19143 19151 19157 19161 19167 0 9.7 2.0 0.0 1.1 0 11.4 2.7 0.0 1.6 0 11.6 3.0 0.0 0.3 0 9.1 2.2 0.0 1.3 0 14.1 1.5 0.0 0.2 0 14.3 1.4 0.0 1.1 0 13.1 2.7 0.0 1.6 0 12.7 1.5 0.0 0.4 0 11.0 3.5 0.0 0.5 0 12.2 1.6 0.0 0.3 MEAN SD N 8.1 13.4 21.0 0.52 0.24 3.09 10 10 10 0 11.9 2.2 0.0 0.8 0.0 1. 72 0.73 0.00 0.56 10 10 10 10 10 (--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-12 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ---------------------------------------------~---------------------------------------------------------------~--------- Animal ID MPV PT APTT NRBC Lymphocyte Segmented Bands Monocytes CU MICRON seconds seconds COUNT THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM GROUP: 2-M 19102 7.5 14.0 22.1 19106 7.6 14.0 22.0 19108 8.4 14.6 24.6 19110 8.4 14.2 26.2 19113 7.2 14.4 20.0 19120 7.6 14.4 17.5 19129 7.2 14.3 20.8 19136 8.8 14.2 19.3 19138 8.1 13.7 16.6 19139 7.8 14.5 31.4 19147 19153 19164 19165 19171 0 6.5 2.7 0.0 1.0 0 12.1 2.9 0.0 1.4 0 10.9 1.4 0.0 0.1 0 10.0 2.0 0.0 0.7 0 11.1 3.6 0.0 0.8 0 13.4 3.1 0.0 1.5 0 9.4 4.0 0.0 0.7 0 8.6 1.4 0.0 0.3 0 11.4 5.2 0.0 0.2 0 16.3 2.5 0.0 0.2 MEAN SD N 7.9 14.2 22.1 0.54 0.27 4.41 10 10 10 0 11.0 2.9 0.0 0.7 0.0 2.68 1.18 0.00 0.50 10 10 10 10 10 (--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-13 Study Report for Hematology ---~------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ------------------------------------------------------------~-------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID MPV PT APTT NRBC Lymphocyte Segmented Bands Monocytes CU MICRON seconds seconds COUNT THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM GROUP: 3-M 19101 8.0 19105 7.4 19107 8.0 19112 9.9 19114 8.3 19121 8.3 19123 8.1 19130 8.9 19137 7.8 19146 7.6 19155 19159 19172 19173 19174 13.9 13.7 13.6 13.6 13.5 13.2 13.7 13.7 13.4 14.0 18.3 24.6 22.0 22.1 19.8 21.2 18.1 22.3 20.6 16.7 0 10.1 2.1 0.0 0.5 0 8.8 1.9 0.0 0.2 0 9.8 0.6 0.1 1.5 0 11.0 1.3 0.0 0.5 0 7.8 2.7 0.0 0.6 0 14.8 4.0 0.0 1.5 0 10.4 3.4 0.0 0.1 0 11.7 1.7 0.0 0.4 0 10.6 1.1 0.0 0.2 0 13.1 1.4 0.0 0.3 MEAN SD N 8.2 13.6 20.6 0.72 0.23 2.38 10 10 10 0 10.8 2.0 0.0 0.6 0.0 2.02 1.06 0.03 0.51 10 10 10 10 10 (--) - Data Unavailable l.ABCAT HE4.43 27-JUN-2002 418-028:PAGE K-14 Study Report for Hematology INDIVIDUAL ANIMAL REPORT BY GROUP -------------------------------------------------------------------------------~--------------------------------------- PERIOD TERM~NAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID MPV PT APTT NRBC Lymphocyte Segmented Bands Monocytes CU MICRON seconds seconds COUNT THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM ----------------------------------------------------------------------------------------------------------------------- GROUP: 4-M 19100 7.1 13.5 19.8 0 7.7 4.0 0.0 0.6 19103 8.2 14.6 26.3 0 16.4 2.3 0.0 1. 7 19104 7.9 14.0 23.0 0 12.1 3.1 0.0 2.2 19118 8.3 13.9 21.4 0 9.4 1.4 0.0 0.5 19133 7.4 14.0 19.1 0 17.4 2.9 0.0 0.7 19141 8.4 13.6 21.5 0 12.7 3.7 0.0 0.5 19142 7.5 13.5 20.8 0 8.6 2.8 0.1 1.0 19144 9.3 13.9 21.5 0 15.9 2.7 0.0 0.6 19148 8.7 13.8 19.7 0 12.3 3.1 0.0 0.0 19150 9.3 13.1 18.6 0 8.3 2.4 0.0 0.2 19156 19160 19162 19163 19166 MEAN SD N 8.2 0.76 10 13.8 0.40 10 21.2 2.24 10 0 12.1 2.8 0.0 0.8 0.0 3.57 0.73 0.03 0.67 10 10 10 10 10 (--> - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-15 Study Report for Hematology INDIVIDUAL ANIMAL REPORT BY GROUP -------------------------------------------------------~------------------------------------------------------------- PERIOD TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 Animal ID MPV PT APTT NRBC lymphocyte Segmented Bands Monocytes CU MICRON seconds seconds COUNT THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM ----------------------------------------------------------------------------------------------------------------------- GROUP: 5-M 19111 7.7 13.9 23.6 0 13.0 1.4 0.0 0.6 19117 7.5 15.1 23.3 0 11.3 1. 7 0.0 0.9 19124 7.3 13.8 20.8 0 10.2 0.3 0.0 0.2 19126 9.0 13.7 21.8 0 10.1 1.1 0.0 0.9 19127 8.8 14.1 20.7 0 8.0 2.4 0.0 0.2 19128 8.6 13.5 21.6 0 12.4 1.4 0.0 0.3 19140 8.0 13.9 19.6 0 12.2 2.1 0.0 0.2 19145 7.5 14.3 21.9 0 17.2 2.5 0.0 0.8 19149 7.8 13.5 19.5 0 16.1 2.2 0.0 0.0 19152 8.2 13.7 20.0 0 13.1 0.4 0.0 0.4 19154 19158 19168 19169 19170 MEAN SD N 8.0 14.0 21.3 0.59 0.47 1.43 10 10 10 0 12.4 1.6 0.0 0.5 0.0 2.75 0.78 0.00 0.33 10 10 10 10 10 <--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-16 Study Report for Hematology INDIVIDUAL ANIMAL REPORT BY GROUP --------------------------------------------------------------~------------------------------------------------------ PERIOD TERMINAL STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID MPV PT APTT NRBC Lymphocyte Segmented Bands Monocytes CU MICRON seconds seconds COUNT THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM GROUP: 1-F 19010 19012 7.7 13.9 26.6 19019 8.9 13.0 20.4 19021 7.8 13.8 24.2 19023 7.9 12.9 21.9 19041 9.1 13.4 19.3 19042 8.4 12.8 21.8 19044 8.4 12.8 18.5 19050 8.2 13.1 20.5 19053 8.1 13.3 22.5 19065 8.9 12.8 21.6 19068 19072 19074 19075 0 12.6 2.7 0.0 0.5 0 4.4 2.0 0.0 0.2 0 5.7 1.4 0.0 0.0 0 6.1 0.9 0.0 0.1 0 5.0 2.9 0.0 0.1 0 5.3 1.5 0.0 0.0 0 7.3 3.1 0.0 0.1 0 6.1 1.8 0.0 0.2 0 4.7 1.8 0.0 0.0 0 8.4 3.8 0.0 0.1 MEAN SD N 8.3 13.2 21.7 0.49 0.41 2.36 10 10 10 0 6.6 2.2 0.0 0.1 0.0 2.44 0.90 0.00 0.15 10 10 10 10 10 (--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-17 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 Animal ID MPV CU MICRON PT seconds APTT seconds NRBC COUNT Lymphocyte THSN/CU MM Segmented THSN/CU MM Bands THSN/CU MM Monocytes THSN/CU MM GROUP: 2-F 19004 9.6 13.3 27.5 19009 7.2 13.8 21.3 19016 8.8 13.3 29.2 19018 8.2 13.7 22.6 19026 8.4 12.8 20.3 19036 7.8 13.5 24.3 19037 8.1 13.3 20.0 19043 8.0 13.2 26.8 19047 6.9 13.5 25.3 19048 7.0 13.1 22.1 19052 19055 19061 19067 19071 0 5.8 2.0 0.0 0.1 0 12.7 1.6 0.0 0.1 0 13.6 3.1 0.0 0.0 0 10.9 2.3 0.0 0.0 0 7.7 1.4 0.0 0.0 0 15.1 2.2 0.0 0.4 0 11.0 13.7 0.0 1.6 0 9.6 3.5 0.0 0.3 0 6.2 4.6 0.0 0.2 0 5.4 1.6 0.0 0.0 MEAN SD N 8.0 13.4 23.9 0.84 0.29 3.19 10 10 10 0 9.8 3.6 0.0 0.3 0.0 3.44 3.69 0.00 0.49 10 10 10 10 10 (--> - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-18 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD TERMINAL ------------------------------------------------------------------------------------------~-------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID MPV PT APTT NRBC Lymphocyte Segmented Bands Monocytes CU MICRON seconds seconds COUNT THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM ----------------------------------------------------------------------------------------------------------------------- GROUP: 3-F 19003 7.2 12.9 22.7 0 6.5 4.0 0.0 0.3 19007 7.3 12.9 21.7 0 5.7 2.0 0.0 0.2 19008 9.3 12.8 22.6 0 5.0 1.9 0.0 0.0 19013 8.5 13.7 22.7 0 12.3 3.8 0.0 0.3 19014 19015 19017 19024 19029 19034 19038 19056 9.0 13.6 27.6 7.8 13.3 21.9 8.8 12.9 22.1 7.4 13.3 24.4 8.1 12.7 21.2 9.3 13.6 27.6 0 5.7 1.6 0.0 0.1 0 9.8 2.6 0:0 0.1 0 7.4 2.6 0.0 0.2 0 10.3 2.1 0.0 0.0 0 10.9 1.0 0.0 0.1 0 10.2 2.2 0.0 0.4 19057 19060 19064 MEAN SD N 8.3 13.2 23.5 0.82 0.37 2.35 10 10 10 0 8.4 2.4 0.0 0.2 0.0 2.60 0.93 0.00 0.13 10 10 10 10 10 ---------------~----------------------------------------------------------------------------------------------------- (--> - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-19 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ---------------------------------------------------------------------------------------.~------------------------------ STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID MPV PT APTT NRBC Lymphocyte Segmented Bands Monocytes CU MICRON seconds seconds COUNT THSN/CU HM THSN/CU MM THSN/CU MM THSN/CU MM ----------------------------------------------------------------------------------------------------------------------- GROUP: 4-F 19002 19005 7.8 13.1 21.4 0 7.7 1.6 0.0 0.1 19035 9.0 13.4 24.5 0 7.1 2.3 0.0 0.1 19039 7.8 13.4 23.7 0 9.6 2.8 0.0 0.3 19040 8.1 12.9 27.9 0 7.7 2.2 0.0 0.1 19045 7.6 13.0 21.9 0 5.4 3.8 0.3 0.2 19046 19051 19054 7.5 14.1 27.1 0 12.2 1.9 0.0 0.4 19058 7.5 13.5 25.7 0 11.5 3.9 0.0 0.2 19062 9.1 13.9 25.2 0 4.8 1.4 0.0 0.1 19063 8.5 14.0 26.2 0 9.8 2.6 0.0 0.3 19066 7.4 13.5 28.9 0 6.0 1.0 0.0 0.1 19069 19073 MEAN 8.0 13.5 25.3 0 8.2 2.4 0.0 0.2 SD 0.63 0.42 2.45 0.0 2.52 0.96 0.09 0.11 N 10 10 10 10 10 10 10 10 C--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-20 Study Report for Hematology INDIVIDUAL ANIMAL REPORT BY GROUP ------------------------------------------------------------------------------------~---------------------------------PERIOD: TERMINAL -------------------------------------------------------------------------------------------------------------------~--- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 Animal ID MPV CU MICRON PT seconds APTT seconds NRBC COUNT Lymphocyte THSN/CU MM Segmented THSN/CU MM Bands THSN/CU MM Monocytes THSN/CU MM GROUP: 5-F 19001 6.9 13.8 30.4 19006 9.2 12.8 22.1 19011 7.4 12.9 22.3 19020 7.0 16.8 27.6 19022 7.6 13.7 21.6 19025 8.3 13.5 25.3 19027 7.3 13.2 27.5 19028 8.1 13.6 22.2 19030 7.9 13.7 31.5 19031 6.8 13.5 21.6 19032 19033 19049 19059 19070 0 10.1 4.2 0.0 0.5 0 4.6 2.7 0.0 0.2 0 4.4 1.8 0.0 0.1 2 2.2 1.9 0.0 0.1 0 3.1 2.0 0.0 0.2 0 5.2 2.0 0.0 0.1 0 10.2 2.0 0.0 0.1 0 7.1 2.8 0.0 0.3 0 5.2 2.8 0.0 0.1 0 8.2 3.7 0.0 0.0 MEAN SD N 7.7 13.8 25.2 0.74 1.12 3.81 10 10 10 0 6.0 2.6 0.0 0.2 0.6 2.77 0.82 0.00 0.14 10 10 10 10 10 (--) - Data Unavailable . LABCAT HE4. 43 27-JUN-2002 418-028:PAGE K-21 Study Report for Hematology INDIVIDUAL ANIMAL REPORT BY GROUP ----------------------------------------------------------~------------------------------------------------------------ PERIOD TERMINAL STUDY ID: ARGUS 418.-028 STUDY NO: 060-069 SEX: MALE Animal ID Eosinophil THSN/CU MM Basophils THSN/CU MM Abnormal L Other THSN/CU MM THSN/CU MM GROUP: 1-M 19109 0.7 0.0 0.0 0.0 19115 0.2 0.0 0.0 0.0 19116 0.2 0.0 0.0 0.0 19119 0.1 0.0 0.0 0.0 19122 0.2 0.0 0.5 0.0 19125 0.5 0.0 0.4 0.0 19131 0.2 0.0 0.2 0.0 19132 0.0 0.0 0.3 0.0 19134 0.2 0.0 0.0 0.0 19135 0.3 0.0 0.0 0.0 19143 19151 19157 19161 19167 MEAN SD N 0.3 0.0 0.1 0.0 0.20 0.00 0.20 0.00 10 10 10 10 (--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-22 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ------------------------------------------------------------~---------------------------------------------------------- Animal ID Eosinophil Basophils Abnormal L Other THSN/CU MM THSN/CU MM THSN/CU f1M THSN/CU MM ----------------------------------------------------------------------------------------------------------------------- GROUP: 2-M 19102 0.3 0.0 0.3 0.0 19106 0.5 0.0 0.2 0.0 19108 0.0 0.0 0.3 0.0 19110 0.3 0.0 0.3 0.0 19113 0.2 0.0 0.0 0.0 19120 0.4 0.0 0.0 0.0 19129 0.6 0.0 0.0 0.0 19136 0.2 0.0 0.0 0.0 19138 0.5 0.0 0.0 0.0 19139 0.0 0.0 0.0 0.0 19147 19153 19164 19165 19171 MEAN SD N 0.3 0.0 0.1 0.0 0.21 0.00 0.14 0.00 10 10 10 10 (--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-23 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL -----------------------------------------------------------------------------------~--------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 Animal ID Eosinophil Basophils Abnormal L Other THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM ----------------------------------------------------------------------------------------------------------------------- GROUP: 3-M 19101 0.3 0.0 0.1 0.0 19105 0.0 0.0 0.1 0.0 19107 0.5 0.0 0.0 0.0 19112 0.3 0.0 0.1 0.0 19114 0.1 0.0 0.0 0.0 19121 0.4 0.0 0.2 0.0 19123 0.0 0.0 0.1 0.0 19130 0.1 0.0 0.0 0.0 19137 0.2 0.0 0.0 0.0 19146 0.6 0.0 0.0 0.0 19155 19159 19172 19173 19174 MEAN SD N 0.3 0.0 0.1 0.0 0.21 0.00 0.07 0.00 10 10 10 10 (--} - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-24 Study Report for Hematology ---------------------------------------------------------------------------------------~-------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 Animal ID Eosinophil THSN/CU MM Basophi ls THSN/CU MM Abnormal L Other THSN/CU MM THSN/CU MM GROUP: 4-M 19100 0.1 0.0 0.1 0.0 19103 0.0 0.0 0.6 0.0 19104 0.4 0.0 0.4 0.0 19118 0.2 0.0 0.5 0.0 19133 0.9 0.0 0.2 0.0 19141 0.3 0.0 0.2 0.0 19142 0.1 0.0 0.1 0.0 19144 0.4 0.0 0.0 0.0 19148 0.2 0.0 0.0 0.0 19150 0.1 0.0 0.0 0.0 19156 19160 19162 19163 19166 MEAN SD N 0.3 0.0 0.2 0.0 0.26 0.00 0.22 0.00 10 10 10 10 C--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-25 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------~---------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ---------------------------------------------------------------------------------------------------------~------------- Animal ID Eosinophil Basophils Abnormal L Other THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM GROUP: 5-M 19111 0.2 0.0 0.5 0.0 19117 0.4 0.0 0.0 0.0 19124 0.1 0.0 0.0 0.0 19126 0.4 a.o 0.0 0.0 19127 a.1 o.a 0.2 a.o 19128 0.1 0.0 0.0 0.0 19140 0.3 0.0 0.5 a.a 19145 0.2 a.o 0.0 0.0 19149 0.0 0.0 0.0 0.0 19152 0.0 0.0 0.0 0.0 19154 19158 19168 19169 19170 MEAN SD N 0.2 0.0 0.1 0.0 0.15 0.00 0.21 0.00 10 10 10 10 <--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-26 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD TERMINAL --------------------------------------------------------------~----------------------------~----------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID Eosinophil Basophils Abnormal L Other THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM ----------------------------------------------------------------------------------------------------------------------- GROUP: 1-F 19010 19012 0.2 0.0 0.0 0.0 19019 0.0 0.0 0.0 0.0 19021 0.3 0.0 0.0 0.0 19023 0.1 0.0 0.1 0.0 19041 0.0 0.0 0.0 0.0 19042 0.0 0.0 0.0 0.0 19044 0.1 0.0 0.0 0.0 19050 0.1 0.0 0.0 a.a 19053 0.0 0.0 0.1 0.0 19065 0.1 0.0 0.1 0.0 19068 19072 19074 19075 MEAN SD N 0.1 0.10 10 0.0 0.00 10 0.0 0.05 10 0.0 0.00 10 (--) - Data Unavailable .LABCAT HE4. 43 27-JUN-2002 418-028:PAGE K-27 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 Animal ID Eosinophil THSN/CU MM Basophils THSN/CU MM Abnormal L THSN/CU MM Other THSN/CU MM GROUP: 2-F 19004 0.0 0.0 0.0 0.0 19009 0.1 0.0 0.0 0.0 19016 0.3 0.0 0.0 0.0 19018 0.1 0.0 0.0 0.0 19026 19036 0.0 0.0 0.0 0.0 0.4 0.0 o.o o.o 19037 0.0 0.0 0.0 0.0 19043 0.1 0.0 0.0 0.0 19047 0.1 0.0 0.0 0.0 19048 0.1 0.0 0.0 0.0 19052 19055 19061 19067 19071 MEAN SD N 0.1 0.0 0.0 0.0 0.13 0.00 0.00 0.00 10 10 10 10 <--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-28 Study Report for Hematology ----------------------------------------------------------------------------~---~---------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD TERMINAL ---------------------------------------------------------~---------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID Eosinophil Basophils Abnormal L Other THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM GROUP: 3-F 19003 0.1 0.0 0.1 0.0 19007 0.0 0.0 0.1 0.0 19008 0.0 0.0 0.1 0.0 19013 0.0 0.0 0.2 0.0 19014 19015 0.0 0.0 0.0 0.0 19017 0.4 0.0 0.0 0.0 19024 0.2 0.0 0.1 0.0 19029 0.1 0.0 0.0 0.0 19034 0.1 0.0 0.0 0.0 19038 19056 0.0 0.0 0.0 0.0 19057 19060 19064 MEAN SD N 0.1 0.0 0.1 0.0 0.13 0.00 0.07 0.00 10 10 10 10 (--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-29 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD TERMINAL -----------------------------------------------~-------------------------------------~------------------------------- STUDY ID: ARGUS 418-028 SEX: FEl"'IALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID Eosinophil Basophils Abnormal L Other THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM GROUP: 4-F 19002 19005 0.1 0.0 0.0 0.0 19035 0.0 0.0 0.1 0.0 19039 0.1 0.0 0.0 0.0 19040 0.0 0.0 0.0 0.0 19045 0.0 0.0 0.0 0.0 19046 19051 19054 0.0 0.0 0.3 0.0 19058 0.2 0.0 0.0 0.0 19062 0.0 0.0 0.0 0.0 19063 0.3 0.0 0.0 0.0 19066 0.0 0.0 0.1 0.0 19069 19073 MEAN SD N 0.1 0.0 0.1 0.0 0.11 0.00 0.10 0.00 10 10 10 10 (--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-30 Study Report for Hematology --------------------------------------------------------------------------------------------~------------------------ INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ------------------------------------------------------------------------------------------------------------------------ STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID Eosinophil Basophils Abnormal L Other THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM GROUP: 5-F 19001 0.3 0.0 0.0 0.0 19006 0.0 0.0 0.0 0.0 19011 0.0 0.0 0.1 0.0 19020 0.0 0.0 0.0 0.0 19022 0.1 0.0 0.0 0.0 19025 0.0 0.0 0.1 0.0 19027 0.0 0.0 0.0 0.0 19028 0.0 0.0 0.0 0.0 19030 0.0 0.0 0.1 0.0 19031 0.4 0.0 0.0 0.0 19032 19033 19049 19059 19070 MEAN SD N 0.1 0.0 0.0 0.0 0.15 0.00 0.05 0.00 10 10 10 10 (--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-31 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- SUMMARY REPORT PERIOD TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE --------------------------------------~------------------------------------------------------------------------------ TESTCs): WBC RBC HGB HCT MCV MCH MCHC PLT MPV UNITS: THSN/CU MM MILL/CU MM GRAMS/DL % CU MICRONS PICO GRAMS % THSN/CU MM CU MICRON ----------------------------------------------------------------------------------------------------------------------- Group: 1-M MEAN 15.3 7.51 16.5 43.5 57.9 22.0 38.0 1179 8.1 SD 1.63 0.648 1.16 3.48 1.89 0.87 0.93 130.9 0.52 N 10 10 10 10 10 10 10 10 10 Group: 2-M MEAN 14.9 7.33 15.9 42.2 57.7 21.8 37.7 1131 7.9 SD 3.03 0.396 0.42 1.57 2.27 1.13 1.15 183.7 0.54 N 10 10 10 10 10 10 10 10 10 Group: 3-M MEAN 13.8 7.32 15.7 42.0 57.4 21.5 37.5 1115 8.2 SD 2.84 0.441 0.59 2.22 1. 78 0.75 0.79 149.2 0.72 N 10 10 10 10 10 10 10 10 10 Group: 4-M MEAN 16.2 6.93* 15.4** 40.2* 57.9 22.2 38.4 1104 8.2 SD 3.97 0.305 0.67 2.29 1.15 0.45 0.80 91.4 0.76 N 10 10 10 10 10 10 10 10 10 Group: 5-M MEAN 14.7 6.99* 15.6* 40.7* 58.3 22.3 38.3 1148 8.0 SD 3.07 0.442 0.81 1.81 1.37 0.56 0.70 159.9 0.59 N 10 10 10 10 10 10 10 10 10 *-Significant Difference from Control P < .05 LABCAT HE4.43 tt-Significant Difference from Control P < .01 27-JUN-2002 418-028:PAGE K-32 Study Report for Hematology SUMMARY REPORT ----------------------------------~---------~---------------------------------------------------------------------PERIOD TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE ----------------------------------------------------------------------------------------------------------------------- TEST(s): PT APTT NRBC lymphocyte Segmented Bands 1'1onocytes Eosinophil Basophils UNITS: seconds seconds COUNT THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM ----------------------------------------------------------------------------------------------------------------------- Group: 1-M MEAN 13.4 21.0 0 11. 9 2.2 0.0 0.8 0.3 0.0 SD 0.24 3.09 0.0 1.72 0.73 0.00 0.56 0.20 0.00 N 10 10 10 10 10 10 10 10 10 Group: 2-M MEAN SD N 14.2** 22.1 0.27 4.41 10 10 0 11.0 2.9 0.0 0.7 0.3 0.0 0.0 2.68 1.18 0.00 0.50 0.21 0.00 10 10 10 10 10 10 10 Group: 3-M MEAN 13.6 20.6 SD 0.23 2.38 N 10 10 0 10.8 2.0 0.0 0.6 0.3 0.0 0.0 2.02 1.06 0.03 0.51 0.21 0.00 10 10 10 10 10 10 10 Group: 4-M MEAN SD N 13.8* 21.2 0.40 2.24 10 10 0 12.1 2.8 0.0 0.8 0.3 0.0 0.0 3.57 0.73 0.03 0.67 0.26 0.00 10 10 10 10 10 10 10 Group: 5-M MEAN SD N 14.0** 21.3 0.47 1.43 10 10 0 12.4 1.6 0.0 0.5 0.2 0.0 0.0 2.75 0.78 0.00 0.33 0.15 0.00 10 10 10 10 10 10 10 *-Significant Difference from Control P < .OS . LABCAT HE4. 43 **-Significant Difference from Control P < .01 27-JUN-2002 418-028:PAGE K-33 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- SUMMARY REPORT TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE TEST(s): UNITS: Abnormal L Other THSN/CU MM THSN/CU MM Group: 1-M MEAN 0.1 0.0 SD 0.20 0.00 N 10 10 Group: 2-M MEAN 0.1 0.0 SD 0.14 0.00 N 10 10 Group: 3-M MEAN 0.1 0.0 SD 0.07 0.00 N 10 10 Group: 4-M MEAN 0.2 0.0 SD 0.22 0.00 N 10 10 Group: 5-M MEAN 0.1 0.0 SD 0.21 0.00 N 10 10 LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-34 Study Report for Hematology -------------------------------------------------------------------------------------------------------------------------------- SUMMARY REPORT PERIOD TERMINAL --------------------------------------------------------------------------~----------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE -------------------------------------------------------------------------------------------------------------------------------- White Blood Count Std. DUNNETT'S DUNNETT'S RANGES Degree Sum of Mean Group N Total Mean Dev. 't' LO -95%- HI LO -99%- HI Source Fdm Squares Square -------------------------------------------------------------------------------------------------------------------------------- 1-M 10 153.1 15.3 1.63 TREATMENTS 4 32.41 8.10 2-M 10 149.2 14.9 3.03 0.29 11.9 18.7 11.1 19.5 ERROR 45 406.23 9.03 3-M 10 137.6 13.8 2.84 1.15 11.9 18.7 11.1 19.5 -------------------------------------- 4-M 10 162.2 16.2 3.97 0.68 11.9 18.7 11.1 19.5 TOTAL 49 438.64 5-M 10 146.6 14.7 3.07 0.48 11.9 18.7 11.1 19.5 F Ratio = 0.90 IF' table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % = 20.065 Dunnetts 'T' table values P.01 = 3.12 P.05 = 2.51 Red B l o o d C o u n t --------------------------------------------------------------------------------------~--------------------------------------- -------------------------------------------------------------------------------------------------------------------------------- 1-M 10 75.13 7.51 0.648 TREATMENTS 4 2.44 0.61 2-M 10 73.26 7.33 0.396 0.91 7.00 8.03 6.87 8.16 ERROR 45 9.54 0.21 3-M 10 73.19 7.32 0.441 0.94 7.00 8.03 6.87 8.16 -------------------------------------- 4-M 10 69.30 6.93 0.305 2.83 7.00 8.03* 6.87 8.16 TOTAL 49 11.98 5-M 10 69.89 6.99 0.442 2.54 7.00 8.03* 6.87 8.16 F Ratio= 2.88 IF' table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. %0 -- 6.381 Dunnetts 'T' table values P.01 = 3.12 P.05 = 2.51 ---------------------------------------------------------------------------------------------------------~-------------------- Hemoglobin 1-M 10 165.2 16.5 1.16 TREATMENTS 4 7.40 1.85 2-M 10 159.1 15.9 0.42 1.77 15.7 17.4 15.4 17.6 ERROR 45 26.78 0.60 3-M 10 157.3 15.7 0.59 2.29 15.7 17.4 15.4 17.6 -------------------------------------- 4-M 10 154.0 15.4 0.67 3.25 15.7 17.4* 15.4 17.6** TOTAL 49 34.18 5-M 10 155.8 15.6 0.81 2.72 15.7 17.4* 15.4 17.6 F Ratio = 3.11 IF' table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % = 4.874 Dunnett's 'T' table values P.01 = 3.12 P.05 = 2.51 *-Significant Difference from Control P < .05 tt-Signif icant Difference from Control P < .01 Error-within groups LABCAT HE4.43 Source-Source of Variation Treatments-between groups 27-JUN-2002 418-028:PAGE K-35 Study Report for Hematology SUMMARY REPORT ------------~------------------------------------------------------------------------------------------------------------------PERIOD TERMINAL ----------------------------------------------------------~----------------------------------~------------------------------ STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE Hematocrit Group N Total Mean Std. DUNNETT'S Dev. 't' DUNNETT'S RANGES LO -95%- HI LO -99%- HI Degree Source Fdm Sum of Squares Mean Square 1-M 10 434.6 43.5 3.48 TREATMENTS 4 68.54 17.13 2-M 10 422.2 42.2 1.57 1.17 40.8 46.1 40.2 46.8 ERROR 45 252.15 5.60 3-M 10 419.9 42.0 2.22 1.39 40.8 46.1 40.2 46.8 -------------------------------------- 4-M 10 401.7 40.2 2.29 3.11 40.8 46.1* 40.2 46.8 TOTAL 49 320.69 5-M 10 406.7 40.7 1.81 2.64 40.8 46.1* 40.2 46.8 F Ratio = 3.06 IF I table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % - 5.676 Ounnett's 'T' table values P.01 = 3.12 P.05 = 2.51 Mean Corpuscular Volume 1-M 10 579.1 57.9 1.89 2-M 10 576.9 57.7 2.27 0.28 56.0 59.9 3-M 10 574.1 57.4 1.78 0.64 56.0 59.9 4-M 10 579.4 57.9 1.15 0.04 56.0 59.9 5-M 10 582.7 58.3 1.37 0.46 56.0 59.9 F Ratio = Coeff. Var. % = 0.34 3.006 IF I table values Dunnett's 'T' table values F.01 = P.01 = Mean Corpuscular Hemoglobin TREATMENTS 4 4.07 1.02 55.5 60.3 ERROR 45 136.05 3.02 55.5 60.3 -------------------------------------- 55.5 60.3 TOTAL 49 140.12 55.5 60.3 3.78 F.05 = 2.58 3.12 P.05 = ' 2.51 1-M 10 220.3 22.0 0.87 2-M 10 217.6 21.8 1.13 0.76 21.1 22.9 3-M 10 215.2 21.5 0.75 1.44 21.1 22.9 4-M 10 222.3 22.2 0.45 0.57 21.1 22.9 5-M 10 223.2 22.3 0.56 0.82 21.1 22.9 F Ratio = Coeff. Var. % = 1. 77 3.593 IF I table values Ounnett's 'T' table values F.01 = P.01 = 20.9 20.9 20.9 20.9 23. 1 23.1 23.1 23.1 TREATMENTS 4 4.40 1.10 ERROR 45 28.04 0.62 ------~------------------------------ TOTAL 49 32.44 3.78 F.05 = 2.58 3.12 P.05 = 2.51 *-Significant Difference from Control P < .05 Error-within groups LABCAT HE4.43 Source-Source of Variation Treatments-between groups 27-JUN-2002 418-028:PAGE K-36 Study Report for Hematology SUMMARY REPORT -----------------------------------~-------------------------------------------------------------------------------------------- PERIOD TERMINAL -------------------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE -------------------------------------------------------------------------------------------------------------------------------- Mean Corpuscular Hem. Cone. Std. DUNNETT'S DUNNETT'S RANGES Degree Sum of Hean Group N Total Mean Dev. 1 t' LO -95%- HI LO -99%- HI Source Fdm Squares Square -------------------------------------------------------------------------------------------------------------------------------- 1-M 10 380.4 38.0 0.93 TREATMENTS 4 5.72 1.43 2-M 10 377.2 37.7 1.15 0.80 37.0 39.0 36.8 39.3 ERROR 45 35.64 0.79 3-M 10 374.9 37.5 0.79 1.38 37.0 39.0 36.8 39.3 4-M 10 383.7 38.4 0.80 0.83 37.0 39.0 36.8 39.3 TOTAL 49 41.36 5-M 10 383.1 38.3 0.70 0.68 37.0 39.0 36.8 39.3 = F Ratio = 1.81 'F' table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % 2.343 ounnett 1 s 'T' table values P.01 = 3.12 P.05 = 2.51 Platelets 1-M 10 11790 1179 130.9 2-M 10 11305 1131 183.7 0.74 1015 1343 3-M 10 11154 1115 149.2 0.97 1015 1343 4-M 10 11044 1104 91.4 1.14 1015 1343 5-M 10 11483 1148 159.9 0.47 1015 1343 F Ratio = Coeff. Var. % = 0.40 12.888 IF I table values ounnett's 'T' table values F.01 = P.01 = TREATMENTS 4 34523 8631 975 1383 ERROR 45 963815 21418 975 1383 -------------------------------------- 975 1383 TOTAL 49 998339 975 1383 3.78 F.05 = 2.58 3.12 P.05 = 2.51 MEAN PLATELET VOLUME 1-M 10 81.2 8.1 0.52 TREATMENTS 4 0.90 0.23 2-M 10 78.6 7.9 0.54 0.92 7.4 8.8 7.2 9.0 ERROR 45 18.03 0.40 3-M 10 82.3 8.2 0.72 0.39 7.4 8.8 7.2 9.0 -------------------------------------- 4-M 10 82.1 8.2 0.76 0.32 7.4 8.8 7.2 9.0 TOTAL 49 18.94 5-M 10 80.4 8.0 0.59 0.28 7.4 8.8 7.2 9.0 F Ratio = 0.56 IF I table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % = 7.823 Dunnett 1 s 'T' table values P.01 = 3.12 P.05 = 2.51 Error-within groups Source-Source of Variation LABCAT HE4.43 Treatments-between groups 27-JUN-2002 418-028:PAGE K-37 Study Report for Hematology SUMMARY REPORT ----------------------------------------------------------------~------------------------------------------------------------PERIOD TERMINAL -------------------------------------------------------------~----------------------------------------------------------------- STUDY ID: ARGUS 418~028 SEX: MALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE -----------------------------------------------------~------------------------------------------------------------------------ Prothrombin Std. DUNNETT 1 S DUNNETT'S RANGES Degree Sum of Mean Group N Total Mean Dev. 1t 1 LO -95%- HI LO -99%- HI Source Fdm Squares Square --------------------------------------------------------------------------------------------------------------------------~--- 1-M 10 133.8 13.4 0.24 TREATMENTS 4 4.13 1.03 2-M 10 142.3 14.2 0.27 5.63 13.0 13.8* 12.9 13.9** ERROR 45 5.13 0.11 3-M 10 136.3 13.6 0.23 1.66 13.0 13.8 12.9 13.9 -------------------------------------- 4-M 10 137.9 13.8 0.40 2.71 13.0 13.8* 12.9 13.9 TOTAL 49 9.26 5-M 10 139.5 14.0 0.47 3.77 13.0 13.8* 12.9 13.9** F Ratio = 9.05 IF' table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % = 2.448 Dunnett 1 s 'T' table values P.01 = 3.12 P.05 = 2.51 -------------------------------------------------------------------------~------------------------------------------------------ Act. Part. Thromboplastin Time ----~--------------------------------------------------------------------------------------------------------------------------- 1-M 10 209.8 21.0 3.09 TREATMENTS 4 11. 75 2.94 2-M 10 220.5 22.1 4.41 0.83 17.7 24.2 17.0 25.0 ERROR 45 374.92 8.33 3-M 10 205.7 20.6 2.38 0.32 17.7 24.2 17.0 25.0 -------------------------------------- 4-M 10 211. 7 21.2 2.24 0.15 17.7 24.2 17.0 25.0 TOTAL 49 386.66 5-M 10 212.8 21.3 1.43 0.23 17.7 24.2 17.0 25.0 F Ratio = 0.35 IF I table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % = 13.609 Dunnett's 'T' table values P.01 = 3.12 P.05 = 2.51 -------------------------------------------------------------~--------------------------------------------~--------------~-- Nucleated Red Cells ----------------------------------------------------------------~------------------------------------------------------------- 1-M 10 0 0 0.0 TREATMENTS 4 0.00000 0.00000 2-M 10 0 0 0.0 0.00 0 a 0 0 ERROR 45 0.00000 0.00000 3-M 10 0 0 0.0 0.00 0 0 0 0 -------------------------------------- 4-M 10 0 0 0.0 0.00 a 0 0 0 TOTAL 49 0.00000 5-M 10 0 0 0.0 0.00 0 0 0 0 F Ratio = Coeff. Var. % = 0.00 IF' table values F.01 0.000 Dunnett's 1 T1 table values P.01 3.78 F.05 = 2.58 3.12 P.05 = 2.51 ----------------------------------------------~------------------------------------------------------------------------------- *-Significant Difference from Control P < .05 Source-Source of Variation **-Significant Difference from Control P < .01 Treatments-between groups Error-within groups LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-38 Study Report for Hematology -------------------------------------------------------------------------------------------------------------------------------- SUMMARY REPORT PERIOD TERMINAL -----------------------------------------------------------~-------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE -------------------------------------------------------------------------------------------------------------------------------- Lymphocytes Std. DUNNETT'S DUNNETT'S RANGES Degree Sum of Mean Group N Total Mean Dev. 't' LO -95%- HI LO -99%- HI Source Fdm Squares Square ---------------------------------------------------------~---------------------------------------------------------------------- 1-M 10 119.2 11.9 1. 72 TREATMENTS 4 19.27 4.82 2-M 10 109.7 11.0 2.68 0.81 9.0 14.9 8.3 15.6 ERROR 45 311.29 6.92 3-M 10 108.1 10.8 2.02 0.94 9.0 14.9 8.3 15.6 -------------------------------------- 4-M 10 120.8 12.1 3.57 0.14 9.0 14.9 8.3 15.6 TOTAL 49 330.56 5-M 10 123.6 12.4 2.75 0.37 9.0 14.9 8.3 15.6 F Ratio = 0.70 IF' table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % = 22.619 Dunnett' s 'T' table values P.01 = 3.12 P.05 = 2.51 -------------------------------------------------------------------------------------------------------------------------------- Segmented Neutrophils -------------------------------------------------------------------------------------------------------------------------~------ 1-M 10 22.1 2.2 0.73 TREATMENTS 4 12.77 3.19 2-M 10 28.8 2.9 1.18 1.63 1.2 3.2 0.9 3.5 ERROR 45 37.87 0.84 3-M 10 20.2 2.0 1.06 0.46 1.2 3.2 0.9 3.5 -------------------------------------- 4-M 10 28.4 2.8 0.73 1.54 1.2 3.2 0.9 3.5 TOTAL 49 50.64 5-M 10 15.5 1.6 0.78 1.61 1.2 3.2 0.9 3.5 F Ratio = Coeff. Var. % = 3.79 39.885 IF' table values Dunnett's 'T' table values F.01 = P.01 = 3.78 F.05 = 2.58 3.12 P.05 = 2.51 ----------------------------------------------------------------------------------------------------------------------------~---- Bands -----------------------------------------------------------------------------------------------------------------~------------ 1-M 10 0.0 0.0 0.00 TREATMENTS 4 0.0012 0.0003 2-M 10 0.0 0.0 0.00 0.00 0.0 0.0 0.0 0.0 ERROR 45 0.0180 0.0004 3-M 10 0.1 0.0 0.03 1.12 0.0 0.0 0.0 0.0 ------------------------------------.~- 4-M 10 0.1 0.0 0.03 1.12 0.0 0.0 0.0 0.0 TOTAL 49 0.0192 5-M 10 0.0 0.0 0.00 0.00 0.0 0.0 0.0 0.0 F Ratio = 0.75 IF I table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % = 500.000 Dunnett 1 s 'T' table values P.01 = 3.12 P.05 = 2.51 ------------------------------------------------------------------~------------------------------------------------------------- Error-within groups Source-Source of Variation LAB CAT HE4. 43 Treatments-between groups 27-JUN-2002 418-028:PAGE K-39 Study Report for Hematology -------------------------------------------------------------------------------------------------------------------------------- SUMMARY REPORT PERIOD TERMINAL -------------------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE -------------------------------------------------------------------------------------------------------------------------------- Monocytes Std. DUNNETT'S DUNNETT'S RANGES Degree Sum of Mean Group N Total Mean Dev. 1t 1 LO -95%- HI LO -99%- HI Source Fdm Squares Square -------------------------------------------------------------------------------------------------------------------------------- 1-M 10 8.4 0.8 0.56 TREATMENTS 4 1.03 0.26 2-M 10 6.9 0.7 0.50 0.64 0.2 1.4 0.1 1.6 ERROR 45 12.43 0.28 3-M 10 5.8 0.6 0.51 1.11 0.2 1.4 0.1 1.6 ~--------------~-------------------- 4-M 10 8.0 0.8 0.67 0.17 0.2 1.4 0.1 1.6 TOTAL 49 13.46 5-M 10 4.5 0.5 0.33 1.66 0.2 1.4 0.1 1.6 = F Ratio = = = Coeff. Var. % 0.93 78.222 IF I table values Dunnett's 'T1 table values F.01 = P.01 3.78 3.12 F.05 = P.05 2.58 2.51 -------------------------------------------------------------------------------------------------------------------------------- Eosinophils -------------------------------------------------------------------------------------------------------------------------------- 1-M 10 2.6 0.3 0.20 TREATMENTS 4 0.08 0.02 2-M 10 3.0 0.3 0.21 0.43 0.0 0.5 0.0 0.5 ERROR 45 1.93 0.04 3-M 10 2.5 0.3 0.21 0.11 0.0 0.5 0.0 0.5 -------------------------------------- 4-M 10 2.7 0.3 0.26 0.11 0.0 0.5 0.0 0.5 TOTAL 49 2.00 5-M 10 1.8 0.2 0.15 0.86 0.0 0.5 0.0 0.5 F Ratio = Coeff. Var. % = 0.46 82.096 IF I table values Dunnett 1 s 'T' table values F.01 = P.01 = = 3.78 F.05 2.58 3.12 P.05 = 2.51 Basophils 1-M 10 2-M 10 3-M 10 4-M 10 5-M 10 F Ratio = Coeff. Var. % = 0.0 0.0 0.00 0.0 0.0 0.00 0.00 0.0 0.0 0.00 0.00 0.0 0.0 0.00 0.00 0.0 0.0 0.00 0.00 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.00 0.000 IF I table values Dunnett's 'T' table values F.01 = P.01 = TREATMENTS 4 0.00000 0.00000 0.0 0.0 ERROR 45 0.00000 0.00000 0.0 0.0 -------------------------------------- 0.0 0.0 TOTAL 49 0.00000 0.0 0.0 3.78 F.05 = 2.58 3.12 P.05 = 2.51 Error-within groups Source-Source of Variation LABCAT HE4.43 Treatments-between groups 27-JUN-2002 418-028:PAGE K-40 Study Report for Hematology ------------------------------------------------------------------------------------------------------------------------------- SUMMARY REPORT PERIOD TERMINAL -------------------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE --------------------------------------------------------~----------------------------------------------------------------------- Lymphocytes Std. DUNNETT'S DUNNETT'S RANGES Degree Sum of Mean Group N Total Mean Dev. 't' LO -95%- HI LO -99%- HI Source Fdm Squares Square ------------------------------------------------------------~------------------------------------------------------------------- 1-M 10 1.4 0.1 0.20 TREATMENTS 4 0.12 0.03 2-M 10 1.1 0.1 0.14 0.38 -.1 0.3 -.1 0.4 ERROR 45 1.40 0.03 3-M 10 0.6 0.1 0.07 1.01 -.1 0.3 -.1 0.4 4-M 10 2.1 0.2 0.22 0.89 -.1 0.3 -.1 0.4 TOTAL 49 1.52 5-M 10 1.2 0.1 0.21 0.25 -.1 0.3 -.1 0.4 F Ratio = 0.95 IF I table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % = 137.898 Dunnett's 'T' table values P.01 = 3.12 P.05 = 2.51 -------------------------------------------------------------------------------------------------------------------------------- Other -------------------------------------------------------------------------------------------------------------------------------- 1-M 10 0.0 0.0 0.00 TREATMENTS 4 0.00000 0.00000 2-M 10 0.0 0.0 0.00 0.00 0.0 0.0 0.0 0.0 ERROR 45 0.00000 0.00000 3-M 10 0.0 0.0 0.00 0.00 0.0 0.0 0.0 0.0 -------------------------------------- 4-H 10 0.0 0.0 0.00 0.00 0.0 0.0 0.0 0.0 TOTAL 49 0.00000 5-M 10 0.0 0.0 0.00 0.00 0.0 0.0 0.0 0.0 F Ratio = 0.00 IF' table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % = 0.000 Dunnett's 'T' table values P.01 = 3.12 P.05 = 2.51 -------------------------------------------------------------------------------------------------------------------------------- Error-within groups Source-Source of Variation LABCAT HE4.43 Treatments-between groups 27-JUN-2002 418-028:PAGE K-41 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- SUMMARY REPORT PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE ----------------------------------------------------------------------------------------------------------------------- TEST(s): WBC RBC HGB HCT MCV MCH MCHC PLT MPV UNITS: THSN/CU MM MILL/CU MM GRAMS/DL % CU MICRONS PICO GRAMS % THSN/CU MM CU MICRON ----------------------------------------------------------------------------------------------------------------------Group: 1-F MEAN 9.0 6.51 15.5 40.5 62.2 23.9 38.4 1419 8.3 SD 3.09 0.461 0.95 2.93 1.19 0.55 0.76 153.0 0.49 N 10 10 10 10 10 10 10 10 10 Group: 2-F MEAN 13.8* 6.22 15.0 39.3 63.3 24.2 38.3 1240 8.0 SD 5.73 0.423 0.77 2.72 2.01 0.76 0.94 208.1 0.84 N 10 10 10 10 10 10 10 10 10 Group: 3-F MEAN 11.1 6.40 15.2 39.5 61.8 23.9 38.7 1274 8.3 SD 2.98 0.554 0.91 3.24 1.50 0.88 1.29 226.3 0.82 N 10 10 10 10 10 10 10 10 10 Group: 4-F MEAN 10.8 6.39 15.2 40.1 62.9 23.8 37.8 1305 8.0 SD 3.15 0.532 0.90 3.02 2.04 1.25 1.22 207.2 0.63 N 10 10 10 10 10 10 10 10 10 Group: 5-F MEAN 8.9 6.42 15.3 40.4 63.0 23.8 37.8 1355 7.7 SD 3.48 0.538 0.77 3.15 1.60 1.05 1.37 176.8 0.74 N 10 10 10 10 10 10 10 10 10 *-Significant Difference from Control P < .05 LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-42 Study Report for Hematology SUMMARY REPORT -----------------------------------~-------------------------------~------------------------------------------------PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT 1 S PROCEDURE ----------------------------------------------------------------------------------------------------------------------- TEST Cs): PT APTT NRBC Lymphocyte Segmented Bands Honocytes Eosinophil Basophils UNITS: seconds seconds COUNT THSN/CU MM THSN/CU MM THSN/CU MH THSN/CU HM THSN/CU MM THSN/CU MM ----------------------------------------------------------------------------------------------------------------------- Group: 1-F MEAN 13.2 21. 7 0 6.6 2.2 0.0 0.1 0.1 0.0 SD 0.41 2.36 0.0 2.44 0.90 0.00 0.15 0.10 0.00 N 10 10 10 10 10 10 10 10 10 Group: 2-F HEAN 13.4 23.9 SD 0.29 3.19 N 10 10 0 9.8* 3.6 0.0 0.3 0.1 0.0 0.0 3.44 3.69 0.00 0.49 0.13 0.00 10 10 10 10 10 10 10 Group: 3-F HEAN 13.2 23.5 SD 0.37 2.35 N 10 10 0 8.4 2.4 0.0 0.2 0.1 0.0 0.0 2.60 0.93 0.00 0.13 0.13 0.00 10 10 10 10 10 10 10 Group: 4-F MEAN 13.5 25.3 SD 0.42 2.45 N 10 10 0 8.2 2.4 0.0 0.2 0.1 0.0 0.0 2.52 0.96 0.09 0.11 0.11 0.00 10 10 10 10 10 10 10 Group: 5-F MEAN 13.8 25.2 SD 1.12 3.81 N 10 10 0 6.0 2.6 0.0 0.2 0.1 0.0 0.6 2.77 0.82 0.00 0.14 0.15 0.00 10 10 10 10 10 10 10 *-Significant Difference from Control P < .05 LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-43 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- SUMMARY REPORT PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 06~069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE ----------------------------------------------------------------------------------------------------------------------- TEST(s): Abnormal L Other UNITS: THSN/CU MM THSN/CU MM ----------------------------------------------------------------------------------------------------------------------Group: 1-F MEAN 0.0 0.0 SD 0.05 0.00 N 10 10 Group: 2-F MEAN 0.0 0.0 SD 0.00 0.00 N 10 10 Group: 3-F MEAN 0.1 0.0 SD 0.07 0.00 N 10 10 Group: 4-F MEAN 0.1 0.0 SD 0.10 0.00 N 10 10 Group: 5-F MEAN 0.0 0.0 SD 0.05 0.00 N 10 10 LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-44 Study Report for Hematology ------------------------------------------------------------------------------------------------------------------------------- SUMMARY REPORT PERIOD: TERMINAL ------------------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE White Blood Count -------------------------------------------------------------------------------------------------------------------------------~ Std. DUNNETT'S DUNNETT'S RANGES Degree Sum of Hean Group N Total Mean Dev. 't' LO -95%- HI LO -99%- HI Source Fdm Squares Square -------------------------------------------------------------------------------------------------------------------------------- 1-F 10 89.9 9.0 3.09 TREATMENTS 4 158.42 39.61 2-F 10 137.8 13.8 5.73 2.80 4.7 13.3* 3.6 14.3 ERROR 45 659.12 14.65 3-F 10 110.7 11.1 2.98 1.22 4.7 13.3 3.6 14.3 -------------------------------------- 4-F 10 108.4 10.8 3.15 1.08 4.7 13.3 3.6 14.3 TOTAL 49 817.54 5-F 10 88.9 8.9 3.48 0.06 4.7 13.3 3.6 14.3 = = = F Ratio 2.70 IF I table values F.01 3.78 F.05 2.58 = = = Coeff. Var. % 35.721 Dunnett's 'T' table values P.01 3.12 P.05 2.51 -------------------------------------------------------------------------------------------------------------------------------- Red Blood Count -------------------------------------------------------------------------------------------------------------------------------- 1-F 10 65.06 6.51 0.461 TREATMENTS 4 0.45 0.11 2-F 10 62.15 6.22 0.423 1.29 5.94 7.07 5.80 7.21 ERROR 45 11.44 0.25 3-F 10 63.96 6.40 0.554 0.49 5.94 7.07 5.80 7.21 4-F 10 63.87 6.39 0.532 0.53 5.94 7.07 5.80 7.21 TOTAL 49 11.89 5-F 10 64.23 6.42 0.538 0.37 5.94 7.07 5.80 7.21 = F Ratio = 0.44 'F' table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % = 7.896 Dunnett's 'T' table values P.01 = 3.12 P.05 2.51 -------------------------------------------------------------------------------------------------------------------------------- Hemoglobin -------------------------------------------------------------------------------------------------------------------------------- 1-F 10 155.4 15.5 0.95 TREATMENTS 4 1.36 0.34 2-F 10 150.4 15.0 0.77 1.29 14.6 16.5 14.3 16.7 ERROR 45 33.62 0.75 3-F 10 152.4 15.2 0.91 0.78 14.6 16.5 14.3 16.7 -------------------------------------- 4-F 10 151.6 15.2 0.90 0.98 14.6 16.5 14.3 16.7 TOTAL 49 34.98 5-F 10 152.6 15.3 0.77 0.72 14.6 16.5 14.3 16.7 F Ratio = Coeff. Var. % = 0.46 5.669 IF I table values Dunnett 1 s 'T' table values F.01 = P.01 = 3.78 F.05 = 2.58 3.12 P.05 = 2.51 *-Significant Difference from Control P < .OS Error-within groups LABCAT HE4.43 Source-Source of Variation Treatments-between groups 27-JUN-2002 418-028:PAGE K-45 Study Report for Hematology ------------------------------------------------------------------------------------------------------------------------------- SUMMARY REPORT PERIOD: TERMINAL ------------------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE ------------------------------------------------------------------------------------------------------------------------------- Hematocrit Std. DUNNETT'S DUNNETT'S RANGES Degree Sum of Mean Group N Total Mean Dev. 't' LO -95%- HI LO -99%- HI Source Fdm Squares Square -------------------------------------------------------------------------------------------------------------------------------- 1-F 10 404.9 40.5 2.93 TREATMENTS 4 11.01 2.75 2-F 10 393.4 39.3 2.72 0.85 37.1 43.9 36.3 44.7 ERROR 45 409.80 9.11 3-F 10 395.1 39.5 3.24 0.73 37.1 43.9 36.3 44.7 -------------------------------------- 4-F 10 401.4 40.1 3.02 0.26 37.1 43.9 36.3 44.7 TOTAL 49 420.81 5-F 10 404.1 40.4 3.15 0.06 37.1 43.9 36.3 44.7 = F Ratio = 0.30 IF' table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. %= 7.548 Dunnett's 'T' table values P.01 = 3.12 P.05 2.51 Mean Corpuscular Volume -------------------------------------------------------------------------------------------------------------------------------- 1-F 10 622.3 62.2 1.19 TREATMENTS 4 14.98 3.74 2-F 10 633.3 63.3 2.01 1.45 60.3 64.1 59.9 64.6 ERROR 45 129.67 2.88 3-F 10 618.2 61.8 1.50 0.54 60.3 64.1 59.9 64.6 -------------------------------------- 4-F 10 629.1 62.9 2.04 0.90 60.3 64.1 59.9 64.6 TOTAL 49 144.64 5-F 10 629.7 63.0 1.60 0.97 60.3 64.1 59.9 64.6 = F Ratio = 1.30 IF' table values F.01 = 3.78 F.05 2.58 = = Coeff. Var. % = 2.709 Dunnett's 'T' table values P.01 3.12 P.05 2.51 Mean Corpuscular Hemoglobin 1-F 10 239.0 23.9 0.55 TREATMENTS 4 1.28 0.32 2-F 10 242.4 24.2 0.76 0.82 22.9 24.9 22.6 25.2 ERROR 45 38.92 0.86 3-F 10 238.9 23.9 0.88 0.02 22.9 24.9 22.6 25.2 4-F 10 237.9 23.8 1.25 0.26 22.9 24.9 22.6 25.2 TOTAL 49 40.21 5-F 10 238.3 23.8 1.05 0.17 22.9 24.9 22.6 25.2 F Ratio = 0.37 'F' table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % = 3.886 Dunnett's 'T' table values P.01 = 3.12 P.05 = 2.51 Error-within groups Source-Source of Variation LABCAT HE4.43 Treatments-between groups 27-JUN-2002 418-028:PAGE K-46 Study Report for Hematology -------------------------------------------------------------------------------------------------------------------------------- SUMMARY REPORT PERIOD: TERMINAL -------------------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT 1 S PROCEDURE -------------------------------------------------------------------------------------------------------------------------------- Mean Corpuscular Hem. Cone. Std. DUNNETT 1 S DUNNETT 1 S RANGES Degree Sum of Mean Group N Total Mean Dev. 1t 1 LO -95%- HI LO -99%- HI Source Fdm Squares Square -------------------------------------------------------------------------------------------------------------------------------- 1-F 10 384.2 38.4 0.76 TREATMENTS 4 5.34 1.34 2-F 10 382.9 38.3 0.94 0.26 37.1 39.7 36.8 40.0 ERROR 45 58.25 1.29 3-F 10 386.6 38.7 1.29 0.47 37.1 39.7 36.8 40.0 -------------------------------------- 4-F 10 378.3 37.8 1.22 1.16 37.1 39.7 36.8 40.0 TOTAL 49 63.60 5-F 10 378.4 37.8 1.37 1.14 37.1 39.7 36.8 40.0 = F Ratio = 1.03 I Fl table values F.01 = 3.78 F.05 2.58 = Coeff. Var. % = 2.978 Dunnett 1 s 1 T1 table values P.01 = 3.12 P.05 2.51 -------------------------------------------------------------------------------------------------------------------------------- Platelets -------------------------------------------------------------------------------------------------------------------------------- 1-F 10 14189 1419 153.0 TREATMENTS 4 198797 49699 2-F 10 12396 1240 208.1 2.05 1199 1639 1145 1692 ERROR 45 1729216 38427 3-F 10 12735 1274 226.3 1.66 1199 1639 1145 1692 -------------------------------------- 4-F 10 13048 1305 207.2 1.30 1199 1639 1145 1692 TOTAL 49 1928012 5-F 10 13554 1355 176.8 0.72 1199 1639 1145 1692 F Ratio = 1.29 If 1 table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % = 14.868 Dunnett's 1 T1 table values P.01 = 3.12 P.05 = 2.51 MEAN PLATELET VOLUME 1-F 10 83.4 8.3 0.49 TREATMENTS 4 2.95 0.74 2-F 10 80.0 8.0 0.84 1.06 7.5 9.1 7.3 9.3 ERROR 45 23.11 0.51 3-F 10 82.7 8.3 0.82 0.22 7.5 9.1 7.3 9.3 4-F 10 80.3 8.0 0.63 0.97 7.5 9.1 7.3 9.3 TOTAL 49 26.06 5-F 10 76.5 7.7 0.74 2.15 7.5 9.1 7.3 9.3 = F Ratio = 1.44 IF I table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % = 8.894 Dunnett 1 s 'T 1 table values P.01 = 3.12 P.05 2.51 Error-within groups Source-Source of Variation LABCAT HE4.43 Treatments-between groups 27-JUN-2002 418-028:PAGE K-47 Study Report for Hematology -------------------------------------------------------------------------------------------------------------------------------- SUMMARY REPORT PERIOD: TERMINAL -------------------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE -------------------------------------------------------------------------------------------------------------------------------- Prothrombin Std. DUNNETT'S DUNNETT'S RANGES Degree Sum of Mean Group N Total Mean Dev. 1t 1 LO -95%- HI LO -99%- HI Source Fdm Squares Square -------------------------------------------------------------------------------------------------------------------------------- 1-F 10 131.8 13.2 0.41 TREATMENTS 4 2.32 0.58 2-F 10 133.5 13.4 0.29 0.63 12.5 13.9 12.3 14.0 ERROR 45 16.48 0.37 3-F 10 131. 7 13.2 0.37 0.04 12.5 13.9 12.3 14.0 -------------------------------------- 4-F 10 134.8 13.5 0.42 1.11 12.5 13.9 12.3 14.0 TOTAL 49 18.80 5-F 10 137.5 13.8 1.12 2.11 12.5 13.9 12.3 14.0 = = = F Ratio 1.58 IF' table values F.01 3.78 F.05 2.58 = = = Coeff. Var. % 4.521 Dunnett 1s 'T' table values P.01 3.12 P.05 2.51 -------------------------------------------------------------------------------------------------------------------------------- Act. Part. Thromboplastin Time -------------------------------------------------------------------------------------------------------------------------------- 1-F 10 217.3 21.7 2.36 TREATMENTS 4 84.50 21.13 2-F 10 239.4 23.9 3.19 1. 71 18.5 25.0 17.7 25.8 ERROR 45 375.66 8.35 3-F 10 234.5 23.5 2.35 1.33 18.5 25.0 17.7 25.8 -------------------------------------- 4-F 10 252.5 25.3 2.45 2.72 18.5 25.0* 17.7 25.8 TOTAL 49 460.17 5-F 10 252.1 25.2 3.81 2.69 18.5 25.0* 17.7 25.8 = = = F Ratio 2.53 IF' table values F.01 3.78 F.05 2.58 = = = Coeff. Var. % 12.081 Dunnett 1 s 1 T1 table values P.01 3.12 P.05 2.51 -------------------------------------------------------------------------------------------------------------------------------- Nucleated Red Cells -------------------------------------------------------------------------------------------------------------------------------- 1-F 10 0 0 0.0 TREATMENTS 4 0.32 0.08 2-F 10 0 0 0.0 0.00 0 0 0 0 ERROR 45 3.60 0.08 3-F 10 0 0 0.0 0.00 0 0 0 0 4-F 10 0 0 0.0 0.00 0 0 0 0 TOTAL 49 3.92 5-F 10 2 0 0.6 1.58 0 0 0 0 = = F Ratio 1.00 IF I table values F.01 = = = Coeff. Var. % 707 .107 Dunnett 1s 1 T1 table values P.01 3.78 F.05 = 2.58 3.12 P.05 2.51 -------------------------------------------------------------------------------------------------------------------------------- -------------------------------------------------------------------------------------------------------------------------------- *-Significant Difference from Control P < .05 Source-Source of Variation Error-within groups Treatments-between groups LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-48 Study Report for Hematology SUMMARY REPORT ---------------------------------------------------------------------------------------~-------------------------------------PERIOD: TERMINAL -------------------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE -------------------------------------------------------------------------------------------------------------------------------- Lymphocytes Std. DUNNETT'S DUNNETT'S RANGES Degree Sum of Mean Group N Total Mean Dev. 1 t' LO -95%- HI LO -99%- HI Source Fdm Squares Square -------------------------------------------------------------------------------------------------------------------------------- 1-F 10 65.6 6.6 2.44 TREATMENTS 4 91.51 22.88 2-F 10 98.0 9.8 3.44 2.61 3.4 9.7* 2.7 10.4 ERROR 45 347.60 7.72 3-F 10 83.8 8.4 2.60 1.46 3.4 9.7 2.7 10.4 -------------------------------------- 4-F 10 81.8 8.2 2.52 1.30 3.4 9.7 2.7 10.4 TOTAL 49 439.11 5-F 10 60.3 6.0 2.77 0.43 3.4 9.7 2.7 10.4 F Ratio = 2.96 IF' table values F.01 = 3.78 F.05 = 2.58 coeff. Var. % = 35.677 Dunnett 1s 'T' table values P.01 = 3.12 P.05 = 2.51 -------------------------------------------------------------------------------------------------------------------------------- Segmented Neutrophils 1-F 10 21.9 2.2 0.90 2-F 10 36.0 3.6 3.69 1.72 0.1 4.3 3-F 10 23.8 2.4 0.93 0.23 0.1 4.3 4-F 10 23.5 2.4 0.96 0.19 0.1 4.3 5-F 10 25.9 2.6 0.82 0.49 0.1 4.3 F Ratio = Coeff. Var. % = 0.95 70.025 IF I table values Dunnett's r table values F.01 = P.01 = TREATMENTS 4 12.77 3.19 -.4 4.8 ERROR 45 151.70 3.37 -.4 4.8 -------------------------------------- -.4 4.8 TOTAL 49 164.47 -.4 4.8 3.78 F.05 = 2.58 3.12 P.05 = 2.51 Bands 1-F 10 2-F 10 3-F 10 4-F 10 5-F 10 F Ratio = Coeff. Var. % = 0.0 0.0 0.00 0.0 0.0 0.00 0.00 0.0 0.0 0.00 0.00 0.3 0.0 0.09 1.58 0.0 0.0 0.00 0.00 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1.00 707.107 If I table values Dunnett 1 s ITI table values F;01 = P.01 = TREATMENTS 4 0.0072 0.0018 -.1 0.1 ERROR 45 0.0810 0.0018 -.1 0.1 -------------------------------------- -.1 0.1 TOTAL 49 0.0882 -.1 0.1 3.78 F.05 = 2.58 3.12 P.05 = 2.51 *-Significant Difference from Control P < .05 Error-within groups LABCAT HE4.43 Source-Source of Variation Treatments-between groups 27-JUN-2002 418-028:PAGE K-49 Study Report for Hematology SUMMARY REPORT -------------------------------------------------------~---------------------------------------------------------------------- PERIOD: TERMINAL -------------------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE -------------------------------------------------------------------------------------------------------------------------------- Monocytes Std. DUNNETT'S DUNNETT'S RANGES Degree Sum of Mean Group N Total Hean Dev. 't' LO -95%- HI LO -99%- HI Source Fdm Squares Square -~----------------------------------------------------------------------------------------------------------------------------- 1-F 10 1.3 0.1 0.15 TREATMENTS 4 0.11 0.03 2-F 10 2.7 0.3 0.49 1.26 -.1 0.4 -.2 0.5 ERROR 45 2.79 0.06 3-F 10 1. 7 0.2 0.13 0.36 -.1 0.4 -.2 0.5 4-F 10 1.9 0.2 0.11 0.54 -.1 0.4 -.2 0.5 TOTAL 49 2.90 5-F 10 1.7 0.2 0.14 0.36 -.1 0.4 -.2 0.5 = F Ratio = 0.43 IF' table values F.01 = 3.78 F.05 2.58 = Coeff. Var. % = 133.942 Dunnett's 'T' table values P.01 = 3.12 P.05 2.51 -------------------------------------------------------------------------------------------------------------------------------- Eosinophils 1-F 10 0.9 0.1 0.10 2-F 10 1.2 0.1 0.13 0.54 0.0 0.2 3-F 10 0.9 0.1 0.13 0.00 0.0 0.2 4-F 10 0.7 0.1 0.11 0.36 0.0 0.2 5-F 10 0.8 0.1 0.15 0.18 0.0 0.2 = F Ratio = Coeff. Var. % 0.23 137.686 IF' table values Dunnett's 'T' table values F.01 = P.01 = Basophils TREATMENTS 4 0.014 0.004 -.1 0.3 ERROR 45 0.691 0.015 -.1 0.3 -------------------------------------- -.1 0.3 TOTAL 49 0.705 -.1 0.3 3.78 F.05 = 2.58 3.12 P.05 = 2.51 1-F 10 2-F 10 3-F 10 4-F 10 5-F 10 F Ratio = Coeff. Var. %0 -- 0.0 0.0 0.00 0.0 0.0 0.00 0.00 0.0 0.0 0.00 0.00 0.0 0.0 0.00 0.00 0.0 0.0 0.00 0.00 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.00 0.000 IF' table values Dunnett's 'T' table values F.01 = P.01 = 0.0 0.0 0.0 0.0 3.78 3.12 TREATMENTS 4 0.00000 0.00000 0.0 ERROR 45 0.00000 0.00000 0.0 -------------------------------------- 0.0 TOTAL 49 0.00000 0.0 F.05 = 2.58 P.05 = 2.51 Error-within groups Source-Source of Variation LABCAT HE4.43 Treatments-between groups 27-JUN-2002 418-028:PAGE K-50 Study Report for Hematology -------------------------------------------------------------------------------------------------------------------------------- SUMMARY REPORT PERIOD: TERMINAL -------------------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE -------------------------------------------------------------------------------------------------------------------------------- Abnormal Lymphocytes Group N Total Hean Std. DUNNETT'S Dev. 1t 1 DUNNETT'S RANGES LO -95%- HI LO -99%- HI Degree Source Fdm Sum of Squares Hean Square ------------------------------~------------------------------------------------------------------------------------------------- 1-F 10 0.3 0.0 0.05 TREATMENTS 4 0.021 0.005 2-F 10 0.0 0.0 0.00 1.09 0.0 0.1 -.1 0.1 ERROR 45 0.171 0.004 3-F 10 0.6 0.1 0.07 1.09 0.0 0.1 -.1 0.1 -------------------------------------- 4-F 10 0.5 0.1 0.10 0.73 0.0 0.1 -.1 0.1 TOTAL 49 0.192 5-F 10 0.3 0.0 0.05 0.00 0.0 0.1 -.1 0.1 = F Ratio = 1.39 IF' table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. %= 181.306 Dunnett's 'T' table values P.01 = 3.12 P.05 2.51 -------------------------------------------------------------------------------------------------------------------------------- Other -------------------------------------------------------------------------------------------------------------------------------- 1-F 10 0.0 0.0 0.00 TREATMENTS 4 0.00000 O.oClooo 2-F 10 0.0 0.0 0.00 0.00 0.0 0.0 0.0 0.0 ERROR 45 0.00000 0.00000 3-F 10 0.0 0.0 0.00 0.00 0.0 0.0 0.0 0.0 -------------------------------------- 4-F 10 0.0 0.0 0.00 0.00 0.0 0.0 0.0 0.0 TOTAL 49 0.00000 5-F 10 0.0 0.0 0.00 0.00 0.0 0.0 0.0 0.0 . = F Ratio = 0.00 IF' table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % -- 0.000 Dunnett's 'T' table values P.01 = 3.12 P.05 2.51 -------------------------------------------------------------------------------------------------------------------------------- Error-within groups Source-Source of Variation LABCAT HE4.43 Treatments-between groups 27-JUN-2002 418-028:PAGE K-51 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTiAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 1-M SEX: MALE Animal ID TERMINAL CNT ABS 19109 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 72 9.7 15 2.0 0 0.0 8 1.1 5 0.7 0 0.0 0 0.0 0 0.0 13.5 19115 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 72 11.4 17 2.7 0 0.0 10 1.6 1 0.2 0 0.0 0 0.0 0 0.0 15.9 19116 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 n 11.6 20 3.0 0 0.0 2 0.3 1 0.2 0 0.0 0 0.0 0 0.0 15.1 LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-52 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 1-M SEX: MALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19119 Nucleated Red Cells 0 Lymphocytes 72 9.1 Segmented Neutrophils 17 2.2 Bands 0 0.0 Monocytes 10 1.3 Eosinophils 1 0.1 Basophils 0 0.0 Abnormal Lymphocytes 0 0.0 Other wee 0 0.0 12.7 19122 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 86 14.1 9 1.5 0 0.0 0.2 1 0.2 0 0.0 3 0.5 0 0.0 16.4 19125 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 81 14.3 8 1.4 0 0.0 6 1.1 3 0.5 0 0.0 2 0.4 0 0.0 17.6 LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-53 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 1-M SEX: MALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19131 Nucleated Red Cells 0 Lymphocytes 74 13.1 Segmented Neutrophils 15 2.7 Bands 0 0.0 Monocytes 9 1.6 Eosinophils 1 0.2 BasopMls 0 0.0 Abnormal Lymphocytes 0.2 Other wee 0 0.0 17.7 19132 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 85 12.7 10 1.5 0 0.0 3 0.4 0 0.0 0 0.0 2 0.3 0 0.0 14.9 19134 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 73 11.0 23 3.5 0 0.0 3 0.5 1 0.2 0 0.0 0 0.0 0 0.0 15.0 LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-54 Study Report for Hematology WHITE DIFFERENTIAL DATA -----------------------------------~----------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 1-M SEX: MALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19135 Nucleated Red Cells 0 Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 85 12.2 11 1.6 0 0.0 2 0.3 2 0.3 0 0.0 0 0.0 0 0.0 14.3 19143 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 wee 19151 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 wee (--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-55 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 1-M SEX: MALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19157 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosfoophi ls 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 wee 19161 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 wee 19167 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 wee ----------------------------------------------------------------------------------------------------------------------- C--> - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-56 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARG~S 418-028 STUDY NO: 060-069 GROUP: 2-M SEX: MALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19102 Nucleated Red Cells 0 Lymphocytes 60 6.5 Segmented Neutrophils 25 2.7 Bands 0 0.0 Monocytes 9 1.0 Eosinophils 3 0.3 Basophils 0 0.0 Abnormal Lymphocytes 3 0.3 Other wee 0 0.0 10.9 19106 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophi ls Abnormal Lymphocytes Other wee 0 71 12.1 17 2.9 0 0.0 8 1.4 3 0.5 0 0.0 1 0.2 0 0.0 17.0 19108 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other WBC 0 86 10.9 11 1.4 0 0.0 1 0.1 0 0.0 0 0.0 2 0.3 0 0.0 12.7 LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-57 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 2-H SEX: MALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19110 Nucleated Red Cells 0 Lymphocytes 76 10.0 Segmented Neutrophils 15 2.0 Bands 0 0.0 Monocytes 5 0.7 Eosinophils 2 0.3 Basophils 0 0.0 Abnormal Lymphocytes 2 0.3 Other wee 0 0.0 13.1 19113 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 71 11.1 23 3.6 0 0.0 5 0.8 1 0.2 0 0.0 0 0.0 0 0.0 15.7 19120 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 73 13.4 17 3.1 0 0.0 8 1.5 2 0.4 0 0.0 0 0.0 0 0.0 18.4 LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-58 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 2-M SEX: MALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19129 Nucleated Red Cells 0 Lymphocytes 64 9.4 Segmented Neutrophils 27 4.0 Bands 0 0.0 Monocytes 5 0.7 Eosinophils 4 0.6 Basophils 0 0.0 Abnormal Lymphocytes 0 0.0 Other 0 0.0 WBC 14.7 19136 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 82 8.6 13 1.4 0 0.0 3 0.3 2 0.2 0 0.0 0 0.0 0 0.0 10.5 19138 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other WBC 0 66 11.4 30 5.2 0 0.0 1 0.2 3 0.5 0 0.0 0 0.0 0 0.0 17.2 LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-59 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 2-M SEX: MALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19139 Nucleated Red Cells 0 Lymphocytes 86 16.3 Segmented Neutrophils 13 2.5 Bands 0 0.0 Monocytes 0.2 Eosinophils 0 0.0 Basophils 0 0.0 Abnormal Lymphocytes 0 0.0 Other 0 0.0 wee 19.0 19147 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 wee 19153 Nuc Leated Red Ce LLs 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 wee (--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-60 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY IO: ARGUS 418-028 STUDY NO: 060-069 GROUP: 2-M SEX: MALE ----------------------------------------------------------------------------------------------------------------------- Animal IO TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19164 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 wee 19165 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 wee 19171 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 wee (--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-61 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 3-M SEX: HALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS 19101 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 77 10.1 16 2.1 0 0.0 4 0.5 2 0.3 0 0.0 1 0.1 0 0.0 13.1 19105 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosi nophils Basophils Abnormal Lymphocytes Other wee 0 80 8.8 17 1.9 0 0.0 2 0.2 0 0.0 0 0.0 1 0.1 0 0.0 11.0 19107 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other WBC 0 78 9.8 5 0.6 1 0.1 12 1.5 4 0.5 0 0.0 0 0.0 0 0.0 12.5 LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-62 Study Report for Hematology ------------------------------------------------------------------------------------------------------------~---------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 3-M SEX: MALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19112 Nucleated Red Cells 0 Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 83 11.0 10 1.3 0 0.0 4 0.5 2 0.3 0 0.0 1 0.1 0 0.0 13.3 19114 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 70 7.8 24 2.7 0 0.0 5 0.6 1 0.1 0 0.0 0 0.0 0 0.0 11.2 19121 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 71 14.8 19 4.0 0 0.0 7 1.5 2 0.4 0 0.0 1 0.2 0 0.0 20.9 'LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-63 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 3-M SEX: MALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19123 Nucleated Red Cells 0 Lymphocytes 74 10.4 Segmented Neutrophils 24 3.4 Bands 0 0.0 Monocytes 1 0.1 Eosinophils 0 0.0 Basophils 0 0.0 Abnormal Lymphocytes 1 0.1 Other wee 0 0.0 14.1 19130 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 84 11. 7 12 1. 7 0 0.0 3 0.4 0.1 0 0.0 0 0.0 0 0.0 13.9 19137 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other WBC 0 87 10.6 9 1.1 0 0.0 2 0.2 2 0.2 0 0.0 0 0.0 0 0.0 12.2 LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-64 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 3-11 SEX: HALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19146 Nucleated Red Cells 0 Lymphocytes 85 13.1 Segmented Neutrophils 9 1.4 Bands 0 0.0 f'lonocytes 2 0.3 Eosinophils 4 0.6 Basophils 0 0.0 Abnormal Lymphocytes 0 0.0 Other 0 0.0 wee 15.4 19155 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 WBC 19159 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 WBC <--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-65 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 3-M SEX: MALE Animal ID TERMINAL CNT ABS 19172 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 WBC 19173 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 WBC 19174 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 WBC <--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-66 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 4-M SEX: MALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS 19100 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 61 7.7 32 4.0 0 0.0 5 0.6 1 0.1 0 0.0 1 0.1 0 0.0 12.6 19103 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 78 16.4 11 2.3 0 0.0 8 1. 7 0 0.0 0 0.0 3 0.6 0 0.0 21.0 19104 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other WBC 0 67 12.1 17 3.1 0 0.0 12 2.2 2 0.4 0 0.0 2 0.4 0 0.0 18.1 LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-67 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 4-M SEX: MALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19118 Nucleated Red Cells 0 Lymphocytes 78 9.4 Segmented Neutrophils 12 1.4 Bands 0 0.0 Monocytes 4 0.5 Eosinophils 2 0.2 Basophils 0 0.0 Abnormal Lymphocytes 4 0.5 Other wee 0 0.0 12.0 19133 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 79 17.4 13 2.9 0 0.0 3 0.7 4 0.9 0 0.0 1 0.2 0 0.0 22.0 19141 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other WBC 0 73 12.7 21 3.7 0 0.0 3 0.5 2 0.3 0 0.0 1 0.2 0 0.0 17.4 LABCAT HE4. 43 27-JUN-2002 418-028:PAGE K-68 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 4-M SEX: MALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19142 Nucleated Red Cells 0 Lymphocytes 67 8.6 Segmented Neutrophils 22 2.8 Bands 1 0.1 Monocytes 8 1.0 Eosinophils 1 0.1 Basophils 0 0.0 Abnormal Lymphocytes 1 0.1 Other wee 0 0.0 12.8 19144 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other WBC 0 81 15.9 14 2.7 0 0.0 3 0.6 2 0.4 0 0.0 0 0.0 0 0.0 19.6 19148 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other WBC 0 79 12.3 20 3.1 0 0.0 0 0.0 1 0.2 0 0.0 0 0.0 0 0.0 15.6 LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-69 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 4-M SEX: HALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ------------------------------------------------------------------------------------------------------~---------------- 19150 Nucleated Red Cells 0 Lymphocytes 75 8.3 Segmented Neutrophils 22 2.4 Bands 0 0.0 Monocytes 2 0.2 Eosinophils 1 0.1 Basophils Abnormal Lymphocytes 0 0.0 0 0.0 Other wee 0 0.0 11.1 19156 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 WBC 19160 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 wee (--> - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-70 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 4-M SEX: MALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19162 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 wee 19163 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 EosinopM ls 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 WBC 19166 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 wee <--> - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-71 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 5-M SEX: MALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ------------------------------------------------------------------------------~-------------------------------------- 19111 Nucleated Red Cells 0 Lymphocytes 83 13.0 Segmented Neutrophils 9 1.4 Bands 0 0.0 Monocytes 4 0.6 Eosinophils 0.2 Basophils 0 0.0 Abnormal Lymphocytes 3 0.5 Other 0 0.0 WBC 15.7 19117 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophi ls Abnormal Lymphocytes Other wee 0 79 11.3 12 1.7 0 0.0 6 0.9 3 0.4 0 0.0 0 0.0 0 0.0 14.3 19124 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophi ls Abnormal Lymphocytes Other WBC 0 94 10.2 3 0.3 0 0.0 2 0.2 1 0.1 0 0.0 0 0.0 0 0.0 10.8 LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-72 Study Report for Hematology WHITE DIFFERENTIAL DATA -----------------------------------~----------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 5-M SEX: MALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19126 Nucleated Red Cells 0 Lymphocytes 81 10.1 Segmented Neutrophils 9 1.1 Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 0.0 7 0.9 3 0.4 0 0.0 0 0.0 0 0.0 12.5 19127 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophi ls Abnormal Lymphocytes Other WBC 0 73 8.0 22 2.4 0 0.0 2 0.2 1 0.1 0 0.0 2 0.2 0 0.0 11.0 19128 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 87 12.4 10 1.4 0 0.0 2 0.3 1 0.1 0 0.0 0 0.0 0 0.0 14.2 LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-73 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 5-H SEX: HALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19140 Nucleated Red Cells 0 Lymphocytes 80 12.2 Segmented Neutrophils 14 2.1 Bands 0 0.0 Monocytes 0.2 Eosinophils 2 0.3 Basophils 0 0.0 Abnormal Lymphocytes 3 0.5 Other 0 o.a WBC 15.2 19145 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other WBC 0 83 17.2 12 2.5 0 0.0 4 0.8 1 0.2 0 a.a 0 a.a 0 0.0 2a.7 19149 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 88 16.1 12 2.2 0 0.0 0 0.0 0 a.a 0 0.0 0 0.0 a 0.0 18.3 LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-74 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 5-M SEX: MALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19152 Nucleated Red Cells 0 Lymphocytes 94 13.1 Segmented N~utrophils 3 0.4 Bands 0 0.0 Monocytes 3 0.4 Eosinophils 0 0.0 Basophils 0 0.0 Abnormal Lymphocytes 0 0.0 Other 0 0.0 WBC 13.9 19154 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 WBC 19158 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 WBC <--> - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-75 Study Report for Hematol?9Y WHITE DIFFERENTIAL DATA --------------------------------------~-------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 5-M SEX: MALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19168 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 WBC 19169 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 WBC 19170 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 WBC <--> - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-76 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA -------------------------------------------------------------------------------------------------------------------~--- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 1-F SEX: FEMALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------~------------------------------------------------------------------------ 19010 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 wee 19012 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 79 12.6 17 2.7 0 0.0 3 0.5 1 0.2 0 0.0 0 0.0 0 0.0 15.9 19019 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 66 4.4 31 2.0 0 0.0 3 0.2 0 0.0 0 0.0 0 0.0 0 0.0 6.6 LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-77 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 1-F SEX: FEMALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19021 Nucleated Red Cells 0 Lymphocytes 77 5.7 Segmented Neutrophils 19 1.4 Bands 0 0.0 Monocytes 0 0.0 Eosinophils 4 0.3 Basophils 0 0.0 Abnormal Lymphocytes 0 0.0 Other 0 0.0 WBC 7.4 19023 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Honocytes Eosinophi Ls Basophils Abnormal Lymphocytes Other WBC 0 83 6.1 12 0.9 0 0.0 2 0.1 2 0.1 0 0.0 0.1 0 0.0 7.3 19041 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 63 5.0 36 2.9 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 0 0.0 8.0 LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-78 Study Report for Hematology WHITE DIFFERENTIAL DATA ----------------------------------~------------------------------------------------------------------------------------ ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 1-F SEX: FEMALE Animal ID TERMINAL CNT ABS 19042 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 78 5.3 22 1.5 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 6.8 19044 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils easophils Abnormal Lymphocytes Other wee 0 69 7.3 29 3.1 0 0.0 1 0.1 1 0.1 0 0.0 0 0.0 0 0.0 10.6 19050 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 74 6.1 22 1.8 0 0.0 3 0.2 1 0.1 0 0.0 0 0.0 0 0.0 8.2 LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-79 Study Report for Hematology WHITE DIFFERENTIAL DATA ---------------------------------------------------------------------~----------------------------------------------- ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 1-F SEX: FEMALE Animal ID TERMINAL CNT ABS 19053 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophi ls Abnormal Lymphocytes Other wee 0 71 4.7 28 1.8 0 0.0 0 0.0 0 0.0 0 0.0 1 0.1 0 0.0 6.6 19065 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 67 8.4 30 3.8 0 0.0 1 0.1 0.1 0 0.0 1 0.1 0 0.0 12.5 19068 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophi ls 0 Abnormal Lymphocytes 0 Other 0 wee <--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-80 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------~------------------------------------------~--------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 1-F SEX: FEMALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19072 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 wee 19074 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 wee 19075 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 easophils 0 Abnormal Lymphocytes 0 Other 0 wee (--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-81 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 2-F SEX: FEMALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19004 Nucleated Red Cells 0 Lymphocytes 74 5.8 Segmented Neutrophils 25 2.0 Bands 0 0.0 Monocytes 1 0.1 Eosinophils 0 0.0 Basophils 0 0.0 Abnormal Lymphocytes 0 0.0 Other 0 0.0 WBC 7.8 19009 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Honocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 87 12.7 11 1.6 0 0.0 1 0.1 1 0.1 0 0.0 0 0.0 0 0.0 14.6 19016 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other WBC 0 80 13.6 18 3.1 0 0.0 0 0.0 2 0.3 0 0.0 0 0.0 0 0.0 17.0 LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-82 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 2-F SEX: FEMALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS 19018 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Honocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 82 10.9 17 2.3 0 0.0 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 13.3 19026 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophi ls Basophils Abnormal Lymphocytes Other wee 0 85 7.7 15 1.4 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 9.1 19036 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 84 15.1 12 2.2 0 0.0 2 0.4 2 0.4 0 0.0 0 0.0 0 0.0 18.0 LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-83 Study Report for Hematology ----------------------------------------~------------------------------------------------------------------------------ WHITE DIFFERENTIAL DATA -----------------------------------------------------------------------------------------------------------~----------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 2-F SEX: FEMALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS -------------------------------------------------------------------------------~--------------------------------------- 19037 Nucleated Red Cells 0 Lymphocytes 42 11.0 Segmented Neutrophils 52 13.7 Bands 0 0.0 Monocytes 6 1.6 Eosinophils 0 0.0 Basophils 0 0.0 Abnormal Lymphocytes 0 0.0 Other wee 0 0.0 26.3 19043 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 71 9.6 26 3.5 0 0.0 2 0.3 1 0.1 0 0.0 0 0.0 0 0.0 13.5 19047 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 56 6.2 41 4.6 0 0.0 2 0.2 1 0.1 0 0.0 0 o.o 0 0.0 11.1 LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-84 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 2-F SEX: FEMALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19048 Nucleated Red Cells 0 Lymphocytes 76 5.4 Segmented Neutrophils 23 1.6 Bands 0 0.0 Monocytes 0 0.0 Eosinophils 1 0.1 Basophils 0 0.0 Abnormal Lymphocytes 0 0.0 Other 0 0.0 WBC 7.1 19052 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 WBC 19055 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 WBC (--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-85 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 2-F SEX: FEMALE Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19061 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 WBC 19067 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 WBC 19071 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 WBC (--> - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGEK-86 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 3-F SEX: FEMALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19003 Nucleated Red Cells 0 Lymphocytes 59 6.5 Segmented Neutrophils 36 4.0 Bands 0 0.0 Monocytes 3 0.3 Eosinophils 1 0.1 Basophils 0 0.0 Abnormal Lymphocytes 0.1 Other wee 0 0.0 11.1 19007 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 72 5.7 25 2.0 0 0.0 2 0.2 0 0.0 0 0.0 1 0.1 0 0.0 7.9 19008 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 72 5.0 27 1.9 0 0.0 0 0.0 0 0.0 0 0.0 0.1 0 0.0 7.0 . LABCAT HE4. 43 27-JUN-2002 418-028:PAGE K-87 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 3-F SEX: FEMALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS 19013 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 74 12.3 23 3.8 0 0.0 2 0.3 0 0.0 0 0.0 1 0.2 0 0.0 16.6 19014 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 wee 19015 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other WBC 0 77 5.7 22 1.6 0 0.0 0.1 0 0.0 0 0.0 0 0.0 0 0.0 7.4 <--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-88 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 3-F SEX: FEMALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19017 Nucleated Red Cells 0 Lymphocytes 76 9.8 Segmented Neutrophils 20 2.6 Bands 0 0.0 Honocytes 1 0.1 Eosinophils 3 0.4 Basophils 0 0.0 Abnormal Lymphocytes 0 0.0 Other 0 0.0 WBC 12.9 19024 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 70 7.4 25 2.6 0 0.0 2 0.2 2 0.2 0 0.0 1 0.1 0 0.0 10.5 19029 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Honocytes Eosinophils Basophils Abnormal Lymphocytes Other WBC 0 82 10.3 17 2.1 0 0.0 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 12.5 LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-89 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 3-F SEX: FEMALE Animal ID TERMINAL CNT ABS 19034 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Honocytes Eosinophils Basophi ls Abnormal Lymphocytes Other wee 0 90 10.9 8 1.0 0 0.0 1 0.1 1 0.1 0 0.0 0 0.0 0 0.0 12.1 19038 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 wee 19056 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other WBC 0 80 10.2 17 2.2 0 0.0 3 0.4 0 0.0 0 0.0 0 0.0 0 0.0 12.7 <--> - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-90 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 3-F SEX: FEMALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19057 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils o Abnormal Lymphocytes 0 Other 0 wee 19060 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 WBC 19064 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 wee (--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-91 Study Report for Hematology WHITE DIFFERENTIAL DATA -----------------------------------~----------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 4-F SEX: FEMALE Animal ID TERMINAL CNT ABS 19002 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 wee 19005 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other WBC 0 81 7.7 17 1.6 0 0.0 1 0.1 1 0.1 0 0.0 0 0.0 0 0.0 9.5 19035 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 74 7.1 24 2.3 0 0.0 1 0.1 0 0.0 0 0.0 1 0.1 0 0.0 9.6 LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-92 Study Report for Hematology WHITE DIFFERENTIAL DATA --------------------------------------------~------------------------------------------------------------------------ ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 4-F SEX: FEMALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19039 Nucleated Red Cells 0 Lymphocytes 75 9.6 Segmented Neutrophils 22 2.8 Bands 0 0.0 Monocytes 2 0.3 Eosinophils 0.1 Basophils Abnormal Lymphocytes 0 0.0 0 0.0 Other wee 0 0.0 12.8 19040 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 n 7.7 22 2.2 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 0 0.0 10.0 19045 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 56 5.4 39 3.8 3 0.3 2 0.2 0 0.0 0 0.0 0 0.0 0 0.0 9.7 C--) - Data Unavailable LABCAT HE4. 43 27-JUN-2002 418-028:PAGE K-93 Study Report for Hematology WHITE DIFFERENTIAL DATA --------------------------------------------------------~------------------------------------------------------------ ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 4-F SEX: FEMALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS 19046 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 wee 19051 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 wee 19054 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other WBC 0 82 12.2 13 1.9 0 0.0 3 0.4 0 0.0 0 0.0 2 0.3 0 0.0 14.9 (--> - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-94 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 4-F SEX: FEMALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS 19058 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 73 11.5 25 3.9 0 0.0 1 0.2 1 0.2 0 0.0 0 0.0 0 0.0 15.7 19062 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 77 4.8 22 1.4 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 0 0.0 6.2 19063 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other WBC 0 76 9.8 20 2.6 0 0.0 2 0.3 2 0.3 0 0.0 0 0.0 0 0.0 12.9 LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-95 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 4-F SEX: FEMALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19066 Nucleated Red Cells 0 Lymphocytes 84 6.0 Segmented Neutrophils 14 1.0 Bands 0 0.0 Monocytes 1 0.1 Eosinophils 0 0.0 Basophils 0 0.0 Abnormal Lymphocytes 1 0.1 Other 0 0.0 WBC 7.1 19069 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 wee 19073 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 wee (--> - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-96 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA -----------------------------------------------------------------------------------~--------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 5-F SEX: FEMALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19001 Nucleated Red Cells 0 Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils easophi ls Abnormal Lymphocytes Other wee 67 10.1 28 4.2 0 0.0 3 0.5 2 0.3 0 0.0 0 0.0 0 0.0 15.1 19006 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 61 4.6 36 2.7 0 0.0 3 0.2 0 0.0 0 0.0 0 0.0 0 0.0 7.6 19011 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Honocytes Eosinophils Basophils Abnormal Lymphocytes Other WBC 0 69 4.4 28 1.8 0 0.0 2 0.1 0 0.0 0 0.0 1 0.1 0 0.0 6.4 LABCAT HE4.43 27-JUN-2002 418-028 :PAGE K-97 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 5-F SEX: FEMALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19020 Nucleated Red Cells 2 Lymphocytes 52 2.2 Segmented Neutrophils 46 1.9 Bands 0 0.0 Monocytes 2 0.1 Eosinophils 0 0.0 Basophils 0 0.0 Abnormal Lymphocytes 0 0.0 Other wee 0 0.0 4.2 19022 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 58 3.1 37 2.0 0 0.0 3 0.2 2 0.1 0 0.0 0 0.0 0 0.0 5.4 19025 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 71 5.2 27 2.0 0 0.0 1 0.1 0 0.0 0 0.0 1 0.1 0 0.0 7.3 LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-98 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 5-F SEX: FEMALE --------------------------------------------------------------------------------------------------------------------~ Animal ID TERMINAL CNT ABS ----------------------------------------------------------------------------------------------------------------------- 19027 Nucleated Red Cells 0 Lymphocytes 83 10.2 Segmented Neutrophils 16 2.0 Bands 0 0.0 Monocytes 1 0.1 Eosinophils 0 0.0 Basophils 0 0.0 Abnormal Lymphocytes 0 0.0 Other wee 0 0.0 12.3 19028 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 70 7.1 27 2.8 0 0.0 3 0.3 0 0.0 0 0.0 0 0.0 0 0.0 10.2 19030 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other wee 0 64 5.2 34 2.8 0 0.0 1 0.1 0 0.0 a 0.0 1 0.1 0 0.0 8.1 LABCAT HE4.43 27-JUN-2002 418-028:PAGE ~-99 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 5-F SEX: FEMALE ----------------------------------------------------------------------------------------------------------------------- Animal ID TERMINAL CNT ABS 19031 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other WBC 0 67 8.2 30 3.7 0 0.0 0 0.0 3 0.4 0 0.0 0 0.0 0 0.0 12.3 19032 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 WBC 19033 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 WBC C--> - Data Unavailable .LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-100 Study Report for Hematology ----------------------------------------------------------------------------------------------------------------------- WHITE DIFFERENTIAL DATA ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 5-F SEX: FEMALE Animal ID TERMINAL CNT ABS 19049 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 wee 19059 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophils 0 Abnormal Lymphocytes 0 Other 0 WBC 19070 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophi ls 0 Abnormal Lymphocytes 0 Other 0 wee C--) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-101 Study Report for Clinical Chemistry ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- An;mal ID TP ALB GLU CHOL T-BIL BUN CREAT CK g/dL g/dL mg/dL mg/dL mg/dL mg/dL mg/dl U/L ----------------------------------------------------------------------------------------------------------------------- GROUP: 1-H 19109 5.9 3.9 164 46 0.1 16 0.3 263 19115 6.5 4.4 165 62 0.2 19 0.4 164 19116 5.8 4.0 119 61 0.2 16 0.3 330 19119 6.0 4.1 134 44 0.1 14 0.3 105 19122 6.2 4.3 140 62 0.1 15 0.3 177 19125 6.5 4.3 169 56 0.3 15 0.4 260 19131 6.5 4.2 128 59 0.1 18 0.3 385 19132 6.1 4.3 141 51 0.1 15 0.3 250 19134 6.3 4.3 140 56 0.2 15 0.3 722 19135 7.0 4.7 153 72 0.2 15 0.3 221 19143 19151 19157 19161 19167 MEAN SD N 6.3 4.3 145 0.36 0.22 16.8 10 10 10 57 0.2 8.3 0.07 10 10 16 0.3 288 1.5 0.04 172.6 10 10 10 <--> - Data Unavailable LABCAT CC4.43 27-JUN-2002 418-028:PAGE K-102 Study Report for Clinical Chemistry -----------------------------------------~----------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID TP ALB GLU CHOL T-BIL BUN CREAT CK g/dL g/dl mg/dL mg/dl mg/dL mg/dL mg/dL U/L ----------------------------------------------------------------------------------------------------------------------- GROUP: 2-M 19102 6.1 4.1 172 40 0.2 16 0.3 .169 19106 6.2 4.0 166 44 0.1 17 0.3 151 19108 5.8 3.9 152 38 0.1 15 0.3 235 19110 6.1 4.1 104 33 0.1 16 0.3 307 19113 5.6 3.9 157 30 0.1 16 0.3 133 19120 6.5 4.3 115 28 0.2 17 0.4 350 19129 5.7 3.9 149 33 0.1 17 0.3 292 19136 6.2 4.3 123 52 0.1 17 0.3 134 19138 6.3 4.4 108 60 0.2 15 0.4 478 19139 6.1 4.2 165 55 0.2 16 0.4 213 19147 19153 19164 19165 19171 MEAN SD N 6.1 4.1 141 41 0.1 0.28 0.19 26.0 11.1 0.05 10 10 10 10 10 16 0.3 246 0.8 0.05 111.5 10 10 10 C--) - Data Unavailable LABCAT CC4.43 27-JUN-2002 418-028:PAGE K-103 Study Report for Clinical Chemistry ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID TP ALB GLU CHOL T-BIL BUN CREAT CK g/dL g/dL mg/dL mg/dL mg/dl mg/dL mg/dL U/L ----------------------------------------------------------------------------------------------------------------------GROUP: 3-M 19101 6.2 H 4.0 H 304 H 27 H 0.3 H 18 H 0.4 H 129 H 19105 6.1 4.3 254 52 0.1 16 0.3 118 19107 5.8 4.1 198 50 0.1 15 0.3 132 19112 6.3 4.3 137 46 0.1 12 0.3 286 19114 6.3 4.3 142 65 0.1 16 0.3 250 19121 6.6 4.4 121 45 0.1 18 0.4 289 19123 6.2 4.4 156 46 0.1 17 0.2 329 19130 5.7 4.1 149 34 0.1 17 0.3 480 19137 6.7 4.4 158 59 0.1 17 0.3 200 19146 6.6 4.4 204 35 0.1 16 0.3 175 19155 19159 19172 19173 19174 MEAN 6.3 4.3 182 46 0.1 16 0.3 239 SD 0.33 0.15 58.2 11.6 0.06 1.8 0.06 112.9 N 10 10 10 10 10 10 10 10 C--> - Data Unavailable LABCAT CC4.43 H - Hemolyzed 27-JUN-2002 418-028:PAGE K-104 Study Report for Clinical Chemistry ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID TP ALB GLU CHOL T-BIL BUN CREAT CK g/dL g/dL mg/dL mg/dL mg/dL mg/dL mg/dL U/L ----------------------------------------------------------------------------------------------------------------------- GROUP: 4-M 19100 6.0 4.0 175 42 0.1 16 0.3 111 19103 5.7 4.0 202 28 0.1 20 0.3 145 19104 5.9 4.1 167 42 0.1 16 0.3 196 19118 6.0 4.2 131 39 0.1 20 0.4 187 19133 6.3 4.4 179 49 0.1 17 0.3 146 19141 6.2 4.3 147 70 0.2 16 0.3 182 19142 6.6 4.4 132 56 0.2 17 0.3 270 19144 6.2 4.1 130 29 0.1 18 0.3 242 19148 6.5 4.4 175 42 0.1 16 0.3 267 19150 6.4 4.4 181 30 0.2 18 0.3 218 19156 19160 19162 19163 19166 MEAN 6.2 4.2 162 43 0.1 17 0.3 196 SD 0.28 0.17 25.2 13.1 0.05 1.6 0.03 53.5 N 10 10 10 10 10 10 10 10 <--> - Data Unavailable LABCAT CC4.43 27-JUN-2002 418-028:PAGE K-105 Study Report for Clinical Chemistry ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- TP ALB GLU CHOL T-BIL BUN CREAT CK g/dl g/dl mg/dL mg/dL mg/dl mg/dl mg/dl U/L ----------------------------------------------------------------------------------------------------------------------GROUP: 5-M 19111 6.6 H 4.6 H 173 H 38 H 0.2 H 26 H 0.4 H 211 H 19117 6.1 H 4.3 H 177 H 37 H 0.3 H 23 H 0.3 H 269 H 19124 6.6 4.8 226 25 0.1 20 0.4 94 19126 6.4 4.6 165 29 0.1 20 0.3 156 19127 6.6 4.6 156 47 0.2 22 0.3 379 19128 6.5 4.8 181 35 0.2 21 0.4 472 19140 6.0 4.3 110 24 0.2 18 0.3 304 19145 6.4 4.5 134 27 0.2 19 0.3 239 19149 6.3 4.5 195 38 0.2 19 0.3 175 19152 5.8 4.2 132 31 0.2 19 0.3 128 19154 19158 19168 19169 19170 MEAN so N 6.3 4.5 165 0.28 0.20 33.7 10 10 10 33 0.2 7.2 0.06 10 10 21 0.3 243 2.4 0.05 117.4 10 10 10 (--> - Data Unavailable LABCAT CC4.43 H - Hemolyzed 27-JUN-2002 418-028:PAGE K-106 Study Report for Clinical Chemistry ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID TP ALB GLU CHOL T-BIL BUN CREAT CK g/dL g/dl mg/dL mg/dL mg/dl mg/dL mg/dL U/L ----------------------------------------------------------------------------------------------------------------------GROUP: 1-F 19010 19012 5.4 3.7 149 63 0.2 32 0.4 166 19019 6.3 4.3 139 92 0.1 29 0.3 212 19021 7.1 4.9 157 136 0.1 33 0.4 210 19023 6.1 4.3 156 85 0.2 26 0.4 222 19041 19042 5.9 4.3 165 6.3 4.3 155 62 0.2 n 0.1 28 0.3 201 25 0.4 178 19044 6.6 4.4 144 93 0.3 27 0.4 332 19050 5.8 3.9 184 78 0.2 34 0.3 198 19053 5.5 3.7 108 43 0.1 28 0.3 123 19065 5.7 3.5 163 40 0.1 19 0.3 175 19068 19072 19074 19075 MEAN SD N 6.1 4.1 152 n 0.2 0.52 0.42 19.8 27.8 0.07 10 10 10 10 10 28 0.4 202 4.4 0.05 54.1 10 10 10 (--) - Data Unavailable LABCAT CC4.43 27-JUN-2002 418-028:PAGE K-107 Study Report for Clinical Chemistry ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID TP ALB GLU CHOL T-BIL BUN CREAT CK g/dL g/dL mg/dL mg/dL mg/dl mg/dL mg/dL U/L ----------------------------------------------------------------------------------------------------------------------GROUP: 2-F 19004 5.9 4.3 178 56 0.2 20 0.3 144 19009 5.7 3.9 166 62 0.2 26 0.4 311 19016 5.5 4.2 173 83 0.2 26 0.3 237 19018 5.6 4.2 152 77 0.2 27 0.4 151 19026 5.5 3.9 170 85 0.1 32 0.3 208 19036 5.9 4.2 203 84 0.2 22 0.4 228 19037 5.0 3.5 153 54 0.2 22 0.3 369 19043 5.7 3.8 149 92 0.2 21 0.4 269 19047 4.3 3.3 135 57 0.2 16 0.3 392 19048 5.9 4.2 142 73 0.2 29 0.4 186 19052 19055 19061 19067 19071 MEAN SD N 5.5 4.0 162 72 0.2 0.50 0.34 20.0 14.0 0.03 10 10 10 10 10 24 0.4 250 4.7 0.05 85.6 10 10 10 (~) - Data Unavailable LABCAT CC4.43. 27-JUN-2002 418-028:PAGE K-108 Study Report for Clinical Chemistry --------------------------------~------------------------------------------------------------------------------------ INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 Animal ID TP ALB GLU CHOL T-BIL BUN CREAT CK g/dL g/dL mg/dL mg/dl mg/dL mg/dL mg/dL U/L GROUP: 3-F 19003 5.6 3.9 179 54 0.1 19007 5.3 3.8 121 45 0.1 19008 5.7 4.0 171 56 0.1 19013 5.8 4.1 146 59 0.2 19014 19015 5.6 3.7 155 61 0.2 19017 5.8 4.1 164 87 0.2 19024 6.7 4.5 140 96 0.2 19029 5.8 4.0 142 79 0.2 19034 6.4 4.3 151 105 0.1 19038 19056 6.1 4.2 179 63 0.1 19057 19060 19064 36 0.3 199 41 0.3 159 20 0.3 206 24 0.4 160 28 0.3 212 22 0.4 190 33 0.4 215 26 0.3 212 23 0.4 169 28 0.3 197 MEAN SD N 5.9 4.1 155 71 0.2 0.41 0.24 18.7 20.0 0.05 10 10 10 10 10 28 0.3 192 6.7 0.05 21.7 10 10 10 (--> - Data Unavailable LABCAT CC4.43 27-JUN-2002 418-028:PAGE K-109 Study Report for Clinical Chemistry ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 Animal ID TP ALB GLU CHOL T-BIL BUN CREAT CK g/dL g/dL mg/dL mg/dl mg/dl mg/dl mg/dl U/L GROUP: 4-F 19002 19005 6.1 4.3 167 19035 5.7 4.0 161 19039 5.5 4.0 163 19040 5.8 3.9 127 19045 5.6 3.7 160 19046 19051 19054 6.3 4.5 129 19058. 5.6 3.9 150 19062 6.0 4.4 127 19063 5.2 3.6 145 19066 5.9 4.1 132 19069 19073 70 0.2 47 0.1 71 0.2 63 0.1 91 0.2 41 0.1 64 0.1 49 0.1 62 0.1 63 0.1 30 0.4 259 27 0.4 193 26 0.4 160 20 0.3 233 25 0.5 398 25 0.4 124 20 0.3 267 34 0.3 176 23 0.4 172 22 0.2 147 MEAN SD N 5.8 4.0 146 62 0.1 0.32 0.29 16.2 14.2 0.05 10 10 10 10 10 25 0.4 213 4.4 0.08 80.4 10 10 10 C--> - Data Unavailable LABCAT CC4.43 27-JUN-2002 418-028:PAGE K-110 Study Report for Clinical Chemistry ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID TP ALB GLU CHOL T-BlL BUN CREAT CK g/dl g/dL mg/dL mg/dL mg/dL mg/dL mg/dL U/L ----------------------------------------------------------------------------------------------------------------------GROUP: 5-F 19001 5.5 4.0 165 55 0.1 23 0.3 341 19006 5.7 4.0 119 58 0.1 19 0.3 373 19011 5.8 4.3 154 48 0.1 29 0.4 149 19020 5.6 3.5 53 33 0.2 73 0.2 438 19022 5.8 4.1 132 60 0.1 25 0.3 186 19025 5.8 3.7 133 49 0.1 28 0.4 143 19027 5.5 3.8 152 71 0.1 27 0.3 252 19028 5.9 4.0 159 70 0.2 23 0.3 261 19030 6.3 4.5 180 58 0.1 26 0.3 168 19031 6.3 4.4 157 108 0.2 25 0.3 210 19032 19033 19049 19059 19070 MEAN 5.8 4.0 140 61 0.1 30 0.3 252 SD 0.29 0.31 35.5 19.8 0.05 15.4 0.06 101.6 N 10 10 10 10 10 10 10 10 (--> - Data Unavailable LABCAT CC4.43 27-JUN-2002 418-028:PAGE K!.111 Study Report for Clinical Chemistry ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID ALT AST ALP CA PHOS TRIG NA K U/L U/L U/L mg/dL mg/dL mg/dL mmol/L mmol/L ----------------------------------------------------------------------------------------------------------------------GROUP: 1-M 19109 36 78 91 10.6 12.0 23 143 10.3 19115 38 77 77 11.8 11.6 48 146 10.5 19116 40 93 102 10.3 9.7 59 145 6.6 19119 33 83 112 10.8 7.9 43 147 4.6 19122 51 86 103 11.3 9.4 28 146 5.9 19125 49 113 115 10.6 8.7 65 145 5.5 19131 39 116 107 11.1 7.9 93 146 4.9 19132 42 80 98 11.1 9.8 45 146 6.2 19134 49 146 126 10.4 8.5 36 147 5.7 19135 43 85 119 11.4 9.2 76 148 5.5 19143 19151 19157 19161 19167 MEAN 42 96 105 10.9 9.5 52 146 6.6 SD 6.0 22.4 14.3 0.48 1.40 21.8 1.4 2.10 N 10 10 10 10 10 10 10 10 <--> - Data Unavailable LABCAT CC4.43 27-JUN-2002 418-028:PAGE K-112 Study Report for Clinical Chemistry ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: HALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID ALT AST ALP CA PHOS TRIG NA K U/L U/L U/L mg/dL mg/dL mg/dL mmol/L mmol/L GROUP: 2-M 19102 37 84 101 10.5 10.3 19106 38 77 70 11.6 12.0 19108 37 81 99 10.3 9.1 19110 57 116 141 10.3 8.9 19113 40 91 130 11.2 8.9 19120 46 111 91 10.7 9.3 19129 48 104 99 10.6 9.3 19136 34 80 88 10.7 8.8 19138 261 382 199 10.3 7.8 19139 33 87 95 11.1 9.3 19147 19153 19164 19165 19171 26 145 6.8 60 144 8.0 62 145 6.0 44 146 5.4 43 147 5.2 29 146 5.5 27 145 6.2 78 144 6.9 57 147 5.5 43 148 5.5 MEAN 63 121 111 10.7 9.4 47 146 6.1 SD 69.9 92.6 36.9 0.44 1.11 17.2 1.3 0.89 N 10 10 10 10 10 10 10 10 (--) - Data Unavailable LABCAT CC4.43 27-JUN-2002 418-028:PAGE K-113 Study Report for Clinical Chemistry ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID ALT AST ALP CA PHOS TRIG NA K U/L U/L U/L mg/dL mg/dl mg/dl mmol/L mmol/L ----------------------------------------------------------------------------------------------------------------------- GROUP: 3-M 19101 60 H 124 H 101 H 11.5 H 10.4 H 20 H 143 H 8.9 H 19105 35 70 107 11.5 9.5 56 147 5.6 19107 35 82 97 11.5 15.6 34 148 8.4 19112 45 99 92 10.2 8.8 51 147 6.5 19114 141 197 108 10.8 9.9 35 145 7.0 19121 42 92 88 10.7 9.0 56 147 5.5 19123 101 171 80 11.2 9.4 21 146 6.1 19130 55 140 124 10.7 9.4 34 148 5.4 19137 44 102 108 11.3 8.3 22 146 5.7 19146 42 94 96 11.3 8.8 35 148 5.4 19155 19159 19172 19173 19174 MEAN 60 117 100 11.1 9.9 36 147 6.5 SD 34.4 40.9 12.4 0.44 2.09 13.8 1.6 1.27 N 10 10 10 10 10 10 10 10 <--) - Data Unavailable LABCAT CC4.43 H - Hemolyzed 27-JUN-2002 418-028:PAGE K-114 Study Report for Clinical Chemistry ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ---------------------------------------------------------~----------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID ALT AST ALP CA PHOS TRIG NA K U/L U/L U/L mg/dL mg/dl mg/dl mmol/L mmol/L ------------------------------------------------------------------~-------------------------------------------------- GROUP: 4-M 19100 51 91 122 10.9 8.3 14 146 5.5 19103 37 83 76 11.0 13.3 19 147 6.6 19104 50 107 98 11.5 8.6 35 148 5.6 19118 439 887 154 10.8 9.8 23 148 6.9 19133 19141 54 106 152 11. 7 9.3 32 147 5.3 46 91 93 10.7 10.7 113 145 6.4 19142 45 108 98 10.7 8.8 35 148 5.3 19144 48 119 124 11.2 9.8 30 147 5.5 19148 138 277 112 11.2 9.2 28 147 6.1 19150 46 107 123 11.3 9.3 32 146 6.5 19156 19160 19162 19163 19166 MEAN 95 198 115 11.1 9.7 36 147 6.0 SD 124.1 248.7 25.1 0.34 1.43 27.9 1.0 0.60 N 10 10 10 10 10 10 10 10 C--) - Data Unavailable LABCAT CC4.43 27-JUN-2002 418-028:PAGE K-115 Study Report for Clinical Chemistry ------------------------------------------------------------------------~-------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID ALT AST ALP CA PHOS TRIG NA K U/L U/L U/L mg/dl mg/dL mg/dL mmol/L mmol/L ----------------------------------------------------------------------------------------------------------------------- GROUP: 5-M 19111 38 H 86 H 115 H 11. 7 H 12.9 H 7 H 142 H 10.7 H 19117 49 H 114 H 153 H 11.0 H 9.2 H 18 H 144 H 6.6 H 19124 33 76 204 11.9 9.8 2 147 5.5 19126 52 88 159 11.3 9.6 17 146 6.8 19127 49 104 182 11.8 11.1 21 147 7.1 19128 50 112 83 11.6 8.4 17 148 6.0 19140 40 95 169 10.9 9.0 23 148 5.5 19145 54 125 137 11.3 10.8 16 143 7.9 19149 40 87 140 12.0 10.2 16 147 7.1 19152 42 87 99 11.8 11.3 31 148 5.8 19154 19158 19168 19169 19170 MEAN 45 97 144 11.5 10.2 17 146 6.9 SD 7.0 15.6 37.5 0.38 1.33 8.0 2.2 1.55 N 10 10 10 10 10 10 10 10 C--) - Data Unava;Lable LABCAT CC4.43 H - Hemolyzed 27-JUN-2002 418-028:PAGE K-116 Study Report for Clinical Chemistry ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 Animal ID ALT AST ALP CA PHOS TRIG NA K U/L U/L U/L mg/dl mg/dL mg/dl mmol/L mmol/L GROUP: 1-F 19010 19012 144 123 217 10.5 6.8 19019 136 182 77 10.9 11.4 19021 177 167 345 11.8 8.3 19023 115 114 89 10.3 8.6 19041 142 154 171 9.9 9.2 19042 104 121 82 10.2 8.7 19044 153 149 100 11. 7 8.3 19050 156 157 202 10.5 10.4 19053 87 123 92 9.6 7.6 19065 80 133 73 10.1 8.2 19068 19072 19074 19075 70 143 6.0 65 142 5.8 47 159 5.4 91 140 5.5 46 140 6.2 44 138 5.7 70 149 4.8 51 140 7.4 40 140 5.7 20 143 5.6 MEAN SD N 129 142 145 10.6 8.8 54 31.7 22.8 88.7 0.72 1.33 19.9 10 10 10 10 10 10 143 5.8 6.3 0.67 10 10 <--) - Data Unavailable LABCAT CC4.43 27-JUN-2002 418-028:PAGE K,_117 Study Report for Clinical Chemistry --------------------------------------------------------------~------------------------------------------------------ INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID ALT AST ALP CA PHOS TRIG NA K U/L U/L U/L mg/dL mg/dl mg/dl mmol/L mmol/L ----------------------------------------------------------------------------------------------------------------------GROUP: 2-F 19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 97 133 80 11.3 8.4 116 110 193 11. 7 7.6 150 141 242 11.6 7.8 136 102 240 11.6 6.7 145 142 183 10.7 9.6 176 125 200 11.9 8.5 115 181 48 10.9 5.3 150 139 252 11.5 8.3 117 131 46 10.0 5.3 132 147 102 10.4 11.8 45 139 5.3 60 144 5.9 68 147 5.4 45 144 5.0 45 141 5.0 47 145 5.4 43 143 5.2 55 142 6.1 55 142 5.6 32 140 6.9 19055 19061 19067 19071 HEAN SD N 133 135 159 11.2 7.9 50 23.0 21.6 81. 7 0.63 1.94 10.2 10 10 10 10 10 10 143 5.6 2.4 0.58 10 10 <--> - Data Unavailable . LABCAT CC4.43 27-JUN-2002 418-028:PAGE K-118 Study Report for Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP -----------------------------------------------------------~--------------------------------------------------------- PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 Animal ID ALT AST ALP CA PHOS TRIG NA K U/L U/L U/L mg/dL mg/dl mg/dl mmol/L mmol/L GROUP: 3-F 19003 182 134 101 9.6 9.7 26 19007 90 113 60 9.3 9.2 17 19008 107 143 64 9.7 7.3 28 19013 137 125 154 10.6 5.6 65 19014 19015 178 137 97 9.3 14.3 116 19017 166 153 418 11.3 5.9 33 19024 121 139 60 11.3 11.5 46 19029 189 151 190 11.5 6.1 53 19034 124 140 108 11.0 10.5 72 19038 19056 130 133 111 10.7 9.9 34 19057 19060 19064 MEAN SD N 142 137 136 10.4 9.0 49 34.2 11.8 107.3 0.87 2.80 29.4 10 10 10 10 10 10 142 5.5 139 5.8 139 5.7 144 5.4 141 4.9 145 5.4 142 6.0 147 5.4 141 5.5 142 5.9 142 5.6 2.5 0.32 10 10 C--> - Data Unavailable LABCAT CC4.43 27-JUN-2002 418-028:PAGE K-119 Study Report for Clinical Chemistry ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ---------------------------------------------~----------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID ALT AST ALP CA PHOS TRIG NA K U/L U/L U/L mg/dL mg/dL mg/dL mmol/L mmol/L ----------------------------------------------------------------------------------------------------------------------GROUP: 4-F 19002 19005 19035 19039 19040 19045 19046 134 127 108 10.6 9.6 115 128 107 10.0 9.2 174 125 228 11.0 4.4 134 132 90 9.7 10.8 157 149 432 11.1 8.6 49 142 6.2 67 142 5.5 62 147 5.8 n 138 7.0 55 145 5.9 19051 19054 19058 19062 19063 19066 19069 94 107 70 10.0 10.1 124 117 171 10.7 5.4 98 129 102 10.3 10.7 119 114 388 10.7 5.0 116 112 88 10.3 13.2 28 139 6.5 30 142 5.3 18 144 7.1 34 143 5.1 33 142 6.6 19073 MEAN 127 124 178 10.4 8.7 45 142 6.1 SD 24.7 12.1 131.0 0.46 2.88 19.5 2.6 0.70 N 10 10 10 10 10 10 10 10 (--) - Data Unavailable LABCAT CC4.43 27-JUN-2002 418-028:PAGE K-120 Study Report for Clinical Chemistry ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------~---------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID ALT AST ALP CA PHOS TRIG NA K U/L U/L U/L mg/dl mg/dl mg/dl mmol/L mmol/L ----------------------------------------------------------------------------------------------------------------------- GROUP: 5-F 19001 116 133 135 10.1 10.7 37 141 6.8 19006 160 149 71 10.1 9.0 49 138 6.8 19011 132 131 131 10.3 8.2 53 142 5.2 19020 151 263 138 9.8 13.7 7 143 6.9 19022 143 167 101 10.3 10.0 38 145 6.4 19025 113 141 142 9.6 9.4 30 142 5.4 19027 149 138 58 9.6 10.6 44 141 7.6 19028 19030 179 127 122 12.0 9.2 156 1n 171 10.9 11.6 45 147 5.1 n 139 6.3 19031 148 138 211 11.6 8.6 57 143 5.1 19032 19033 19049 19059 19070 MEAN 145 156 128 10.4 10.1 44 142 6.2 SD 20.0 40.7 44.7 0.82 1.64 18.3 2.6 0.90 N 10 10 10 10 10 10 10 10 -----------------------------------------------------------------------------------------------------------------~~-- <--> - Data Unavailable LABCAT CC4.43 27-JUN-2002 418-028:PAGE K-121 Study Report for Clinical Chemistry ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID CL GLOB A/G mmol/L g/dL none ----------------------------------------------------------------------------------------------------------------------GROUP: 1-M 19109 103 2.0 2.0 19115 100 2.1 2.1 19116 98 1.8 2.2 19119 100 1.9 2.2 19122 97 1.9 2.3 19125 96 2.2 2.0 19131 98 2.3 1.8 19132 99 1.8 2.4 19134 98 2.0 2.2 19135 93 2.3 2.0 19143 19151 19157 19161 19167 MEAN SD N 98 2.0 2.1 2.7 0.19 0.18 10 10 10 (--> - Data Unavailable LABCAT CC4.43 27-JUN-2002 418-028:PAGE K-122 Study Report for Clinical Chemistry ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 Animal ID CL GLOB A/G mmol/L g/dl none GROUP: 2-H 19102 98 2.0 2.1 19106 99 2.2 1.8 19108 101 1.9 2.1 19110 101 2.0 2.1 19113 98 1.7 2.3 19120 96 2.2 2.0 19129 99 1.8 2.2 19136 99 1.9 2.3 19138 99 1.9 2.3 19139 98 1.9 2.2 19147 19153 19164 19165 19171 MEAN SD N 99 2.0 2.1 1.5 0.16 0.16 10 10 10 <--> - Data Unavailable LABCAT CC4.43 27-JUN-2002 418-028:PAGE K.-123 Study Report for Clinical Chemistry ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 Animal ID CL GLOB A/G mmol/L g/dL none ----------------------------------------------------------------------------------------------------------------------GROUP: 3-M 19101 101 H 2.2 H 1.8 H 19105 96 1.8 2.4 19107 105 1. 7 2.4 19112 100 2.0 2.2 19114 99 2.0 2.2 19121 99 2.2 2.0 19123 100 1.8 2.4 19130 100 1.6 2.6 19137 98 2.3 1.9 19146 99 2.2 2.0 19155 19159 19172 19173 19174 MEAN 100 2.0 2.2 SD 2.3 0.24 0.26 N 10 10 10 <--> - Data Unavailable . LABCAT CC4.43 H - Hemolyzed 27-JUN-2002 418-028:PAGE K-124 Study Report for Clinical Chemistry ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: f1ALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID CL GLOB A/G mmol/L g/dl none GROUP: 4-M 19100 104 2.0 2.0 19103 104 1. 7 2.4 19104 100 1.8 2.3 19118 103 1.8 2.3 19133 98 1.9 2.3 19141 99 1.9 2.3 19142 96 2.2 2.0 19144 99 2.1 2.0 19148 98 2.1 2.1 19150 99 2.0 2.2 19156 19160 19162 19163 19166 MEAN SD N 100 2.0 2.2 2.7 0.16 0.15 10 10 10 c--> - Data Unavailable LABCAT CC4.43 27-JUN-2002 418-028:PAGE K-125 Study Report for Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP ----------------------------------------------~------------------------------------------------------------------------ PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID CL GLOB A/G mmol/L g/dL none ----------------------------------------------------------------------------------------------------------------------- GROUP: 5-M 19111 101 H 2.0 H 2.3 H 19117 101 H 1.8 H 2.4 H 19124 99 1.8 2.7 19126 100 1.8 2.6 19127 19128 19140 19145 19149 19152 19154 101 2.0 2.3 98 1. 7 2.8 101 1. 7 2.5 98 1.9 2.4 100 1.8 2.5 99 1.6 2.6 19158 19168 19169 19170 MEAN SD N 100 1.8 2.5 1.2 0.13 0.17 10 10 10 C--> - Data Unavailable LABCAT CC4.43 H - Hemolyzed 27-JUN-2002 418-028:PAGE K-126 Study Report for Clinical Chemistry -----------------------------------------~-------------------------------------~--------~------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ---------------------------------------------------------~----------------------------------------------------------- Animal ID CL GLOB A/G mmol/L g/dL none ----------------------------------------------------------------------------------------------------------------------GROUP: 1-F 19010 19012 96 1. 7 2.2 19019 92 2.0 2.2 19021 100 2.2 2.2 19023 91 1.8 2.4 19041 93 1.6 2.7 19042 92 2.0 2.2 19044 96 2.2 2.0 19050 99 1.9 2.1 19053 99 1.8 2.1 19065 98 2.2 1.6 19068 19072 19074 19075 MEAN 96 1.9 2.2 SD 3.4 0.22 0.28 N 10 10 10 (--> - Data Unavailable LABCAT CC4.43 27-JUN-2002 418-028:PAGE K-127 Study Report for Clinical Chemistry -----------------------------------~----------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 Animal ID CL GLOB A/G mmol/L g/dL none GROUP: 2-F 19004 89 1.6 2.7 19009 93 1.8 2.2 19016 98 1.3 3.2 19018 97 1.4 3.0 19026 94 1.6 2.4 19036 95 1.7 2.5 19037 96 1.5 2.3 19043 91 1.9 2.0 19047 93 1.0 3.3 19048 95 1.7 2.5 19052 19055 19061 19067 19071 MEAN 94 1.6 2.6 SD 2.7 0.26 0.43 N 10 10 10 <--) - Data Unavailable LABCAT CC4.43 27-JUN-2002 418-028:PAGE K-128 Study Report for Clinical Chemistry --------------------------------------~---~------------------------------------------------------------------------ INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID CL GLOB A/G mmol/L g/dL none ----------------------------------------------------------------------------------------------------------------------- GROUP: 3-F 19003 92 1.7 2.3 19007 97 1.5 2.5 19008 96 1. 7 2.4 19013 97 1. 7 2.4 19014 19015 92 1.9 1.9 19017 99 1. 7 2.4 19024 94 2.2 2.0 19029 101 1.8 2.2 19034 88 2.1 2.0 19038 19056 93 1.9 2.2 19057 19060 19064 MEAN 95 1.8 2.2 SD 3.8 0.21 0.21 N 10 10 10 <--> - Data Unavailable LABCAT CC4.43 27-JUN-2002 418-028:PAGE K-.129 Study Report for Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP ----------------------------------------------------------------~---------------------------------------------------- PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 Animal ID CL GLOB A/G mmol/L g/dl none GROUP: 4-F 19002 19005 90 1.8 2.4 19035 96 1. 7 2.4 19039 101 1.5 2.7 19040 91 1.9 2.1 19045 97 1.9 1.9 19046 19051 19054 94 1.8 2.5 19058 97 1. 7 2.3 19062 98 1.6 2.8 19063 97 1.6 2.3 19066 93 1.8 2.3 19069 19073 MEAN SD N 95 1. 7 2.4 3.4 0.13 0.26 10 10 10 C--> - Data Unavailable LABCAT CC4.43 27-JUN-2002 418-028:PAGE K-130 Study Report for Clinical Chemistry ----------------------------------------------------------------------------------------------------------------------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ----------------------------------------------------------------------------------------------------------------------- Animal ID CL GLOB A/G mmol/L g/dL none GROUP: 5-F 19001 91 1.5 2.7 19006 93 1.7 2.4 19011 92 1.5 2.9 19020 91 2.1 1. 7 19022 100 1.7 2.4 19025 94 2.1 1.8 19027 96 1. 7 2.2 19028 95 1.9 2.1 19030 95 1.8 2.5 19031 89 1.9 2.3 19032 19033 19049 19059 19070 MEAN SD N 94 1.8 2.3 3.1 0.21 0.37 10 10 10 (--> - Data Unavailable LABCAT CC4.43 27-JUN-2002 418-028:PAGE K-131 Study Report for Clinical Chemistry ----------------------------------------------------------------------------------------------------------------------- SUMMARY REPORT PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE ----------------------------------------------------------------------------------------------------------------------- TEST(s): TP ALB GLU CHOL T-BIL BUN CREAT CK ALT UNITS: g/dl g/dL mg/dL mg/dL mg/dL mg/dL mg/dl U/L U/L ----------------------------------------------------------------------------------------------------------------------- Group: 1-M MEAN 6.3 4.3 145 57 0.2 16 0.3 288 42 SD 0.36 0.22 16.8 8.3 0.07 1.5 0.04 172.6 6.0 N 10 10 10 10 10 10 10 10 10 Group: 2-M MEAN 6.1 4.1 141 41** 0.1 SD 0.28 0.19 26.0 11.1 0.05 N 10 10 10 10 10 16 0.3 246 63 0.8 0.05 111.5 69.9 10 10 10 10 Group: 3-M MEAN 6.3 4.3 182 46 0.1 SD 0.33 0.15 58.2 11.6 0.06 N 10 10 10 10 10 16 0.3 239 60 1.8 0.06 112.9 34.4 10 10 10 10 Group: 4-M MEAN 6.2 4.2 162 43* 0.1 SD 0.28 0.17 25.2 13.1 0.05 N 10 10 10 10 10 17 0.3 196 95 1.6 0.03 53.5 124.1 10 10 10 10 Group: 5-M MEAN 6.3 4.5** 165 33** 0.2 21** 0.3 243 45 SD 0.28 0.20 33.7 7.2 0.06 2.4 0.05 117.4 7.0 N 10 10 10 10 10 10 10 10 10 *-Significant Difference from Control P < .05 LABCAT CC4.43 **-Significant Difference from Control P < .01 27-JUN-2002 418-028:PAGE K-132 Study Report for Clinical Chemistry ------------------------------------------~------------------------~------------------------------------------------- SUMMARY REPORT PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE ----------------------------------------------------------------------------------------------------------------------- TESTCs): AST ALP CA PHOS TRIG NA K CL GLOB UNITS: U/L U/L mg/dL mg/dL mg/dL mmol/L mmol/L mmol/L g/dL ----------------------------------------------------------------------------------------------------------------------Group: 1-M MEAN 96 105 10.9 9.5 52 146 6.6 98 2.0 SD 22.4 14.3 0.48 1.40 21.8 1.4 2.10 2.7 0.19 N 10 10 10 10 10 10 10 10 10 Group: 2-M MEAN 121 111 10.7 9.4 47 SD 92.6 36.9 0.44 1.11 17.2 N 10 10 10 10 10 146 6.1 1.3 0.89 10 10 99 2.0 1.5 0.16 10 10 Group: 3-M MEAN 117 100 11.1 9.9 36 SD 40.9 12.4 0.44 2.09 13.8 N 10 10 10 10 10 147 6.5 1.6 1.27 10 10 100 2.0 2.3 0.24 10 10 Group: 4-M MEAN 198 115 11.1 9.7 36 SD 248.7 25.1 0.34 1.43 27.9 N 10 10 10 10 10 147 6.0 1.0 0.60 10 10 100 2.0 2.7 0.16 10 10 Group: 5-M MEAN 97 144** 11.5** 10.2 SD 15.6 37.5 0.38 1.33 N 10 10 10 10 17** 146 6.9 8.0 2.2 1.55 10 10 10 100 1.8 1.2 0.13 10 10 **-Significant Difference from Control P < .01 LABCAT CC4.43 27-JUN-2002 418-028:PAGE K-133 Study Report for Clinical Chemistry ----------------------------------------------------------------------------------------------------------------------- SUMMARY REPORT PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT 1 S PROCEDURE TEST(s): A/G UNITS: none Group: 1-M MEAN 2.1 SD 0.18 N 10 Group: 2-M MEAN 2.1 SD 0.16 N 10 Group: 3-M MEAN 2.2 SD 0.26 N 10 Group: 4-M MEAN 2.2 SD 0.15 N 10 Group: 5-M MEAN SD N 2.5** 0.17 10 **-Significant Difference from Control P < .01 LABCAT CC4.43 27-JUN-2002 418-028:PAGE K-134 Study Report for Clinical Chemistry SUMMARY REPORT ------------------------------------~--------------------------------~------------------------------------------------------ PERIOD: TERMINAL -------------------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE -------------------------------------------------------------------------------------------------------------------------------- Total Protein Std. DUNNETT'S DUNNETT'S RANGES Degree Sum of Hean Group N Total Mean Dev. 't' LO -95%- HI LO -99%- HI Source Fdm Squares Square -------------------------------------------------------------------------------------------------------------------------------- 1-M 10 62.8 6.3 0.36 TREATMENTS 4 0.44 0.11 2-M 10 60.6 6.1 0.28 1.60 5.9 6.6 5.9 6.7 ERROR 45 4.26 0.09 3-M 10 62.5 6.3 0.33 0.22 5.9 6.6 5.9 6.7 -------------------------------------- 4-M 10 61.8 6.2 0.28 0.73 5.9 6.6 5.9 6.7 TOTAL 49 4.70 5-M 10 63.3 6.3 0.28 0.36 5.9 6.6 5.9 6.7 = F Ratio = 1.16 IF' table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % = 4.948 Dunnett's 'T' table values P.01 = 3.12 P.05 2.51 -------------------------------------------------------------------------------------------------------------------------------- Albumin -------------------------------------------------------------------------------------------------------------------------------- 1-M 10 42.5 4.3 0.22 TREATMENTS 4 0.90 0.22 2-M 10 41.1 4.1 0.19 1.66 4.0 4.5 4.0 4.5 ERROR 45 1.59 0.04 3-M 10 42.7 4.3 0.15 0.24 4.0 4.5 4.0 4.5 -------------------------------------- 4-M 10 42.3 4.2 0.17 0.24 4.0 4.5 4.0 4.5 TOTAL 49 2.49 5-M 10 45.2 4.5 0.20 3.21 4.0 4.5* 4.0 4.5** = = F Ratio = 6.35 IF' table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % = 4.399 Dunnett's 'T' table values P.01 3.12 P.05 2.51 -------------------------------------------------------------------------------------------------------------------------------- Glucose -------------------------------------------------------------------------------------------------------------------------------- 1-M 10 1453 145 16.8 TREATMENTS 4 10942 2735 2-M 10 1411 141 26.0 0.27 106 185 96 194 ERROR 45 55071 1224 3-M 10 1823 182 58.2 2.37 106 185 96 194 -------------------------------------- 4-M 10 1619 162 25.2 1.06 106 185 96 194 TOTAL 49 66013 5-M 10 1649 165 33.7 1.25 106 185 96 194 = F Ratio = 2.24 IF I table values F.01 = 3.78 F.05 2.58 Coeff. Var. % = 21.988 Dunnett's 'T' table values P.01 = 3.12 P.05 = 2.51 -------------------------------------------------------------------------------------------------------------------------------- *-Significant Difference from Control P < .OS Source-Source of Variation **-Significant Difference from Control P < .01 Treatments-between groups Error-within groups LABCAT CC4.43 27-JUN-2002 418-028:PAGE :&-135 Study Report for Clinical Chemistry -------------------------------------------------------------------------------------------------------------------------------SUMMARY REPORT PERIOD: TERMINAL -------------------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: HALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE -------------------------------------------------------------------------------------------------------------------------------- Cholesterol Std. DUNNETT'S DUNNETT'S RANGES Degree Sum of Mean Group N Total Mean Dev. 't' LO -95%- HI LO -99%- HI Source Fdm Squares Square -------------------------------------------------------------------------------------------------------------------------------- 1-M 10 569 57 8.3 TREATMENTS 4 2978.08 744.52 2-M 10 413 41 11.1 3.32 45 69* 42 72** ERROR 45 4954.90 110.11 3-M 10 459 46 11.6 2.34 45 69 42 72 -------------------------------------- 4-M 10 427 43 13.1 3.03 45 69* 42 72 TOTAL 49 7932.98 5-M 10 331 33 7.2 5.07 45 69* 42 72** = F Ratio = 6.76 IF' table values F.01 = 3.78 F.05 2.58 = = = Coeff. Var. % 23.859 Dunnett's 'T' table values P.01 3.12 P.05 2.51 -------------------------------------------------------------------------------------------------------------------------------- Total Bilirubin -------------------------------------------------------------------------------------------------------------------------------- 1-M 10 1.6 0.2 0.07 TREATMENTS 4 0.031 0.008 2-M 10 1.4 0.1 0.05 0.76 0.1 0.2 0.1 0.2 ERROR 45 0.154 0.003 3-M 10 1.2 0.1 0.06 1.53 0.1 0.2 0.1 0.2 -------------------------------------- 4-M 10 1.3 0.1 0.05 1.15 0.1 0.2 0.1 0.2 TOTAL 49 0.185 5-M 10 1.9 0.2 0.06 1.15 0.1 0.2 0.1 0.2 F Ratio = 2.25 IF' table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % = 39.527 Dunnett's 'T' table values P.01 = 3.12 P.05 = 2.51 -------------------------------------------------------------------------------------------------------------------------------- Blood Urea Nitrogen -------------------------------------------------------------------------------------------------------------------------------- 1-M 10 158 16 1.5 TREATMENTS 4 162.32 40.58 2-M 10 162 16 0.8 0.53 14 18 13 18 ERROR 45 129.30 2.87 3-M 10 162 16 1.8 0.53 14 18 13 18 -------------------------------------- 4-M 10 174 17 1.6 2.11 14 18 13 18 TOTAL 49 291.62 5-M 10 207 21 2.4 6.46 14 18* 13 18** = = F Ratio 14.12 IF I table values F.01 = 3.78 F.05 2.58 = = Coeff. Var. % = 9.821 Dunnett's 'T' table values P.01 3.12 P.05 2.51 -------------------------------------------------------------------------------------------------------------------------------- *-Significant Difference from Control P < .05 **-Significant Difference from Control P < .01 Error-within groups LABCAT CC4.43 Source-Source of Variation Treatments-between groups 27-JUN-2002 418-028:PAGE K-136 Study Report for Clinical Chemistry -------------------------------------------------------------------------------------------------------------------------------- SUMMARY REPORT PERIOD: TERMINAL -------------------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE -------------------------------------------------------------------------------------------------------------------------------- Creatinine Std. DUNNETT'S DUNNETT'S RANGES Degree Sum of Hean Group N Total Mean Dev. 't' LO -95%- HI LO -99%- HI Source Fdm Squares Square -------------------------------------------------------------------------------------------------------------------------------- 1-M 10 3.2 0.3 0.04 TREATMENTS 4 0.0040 0.0010 2-M 10 3.3 0.3 0.05 0.48 0.3 0.4 0.3 0.4 ERROR 45 0.0960 0.0021 3-M 10 3.1 0.3 0.06 0.48 0.3 0.4 0.3 0.4 -------------------------------------- 4-M 10 3.1 0.3 0.03 0.48 0.3 0.4 0.3 0.4 TOTAL 49 0.1000 5-M 10 3.3 0.3 0.05 0.48 0.3 0.4 0.3 0.4 = = F Ratio 0.47 IF I table values F.01 = 3.78 F.05 2.58 = = Coeff. Var. % 14.434 Dunnett's 'T' table values P.01 = 3.12 P.05 2.51 -------------------------------------------------------------------------------------------------------------------------------- Creatine Kinase -------------------------------------------------------------------------------------------------------------------------------- 1-M 10 2877 288 172.6 TREATMENTS 4 41956 10489 2-M 10 2462 246 111.5 0.78 153 422 121 455 ERROR 45 644538 14323 3-M 10 2388 239 112.9 0.91 153 422 121 455 -------------------------------------- 4-H 10 1964 196 53.5 1. 71 153 422 121 455 TOTAL 49 686494 5-M 10 2427 243 117.4 0.84 153 422 121 455 = = F Ratio = = = Coeff. Var. % 0.73 IF' table values F.01 49.381 Dunnett 1 s 'T' table values P.01 3.78 F.05 = 2.58 3.12 P.05 2.51 Alanine Aminotransferase -------------------------------------------------------------------------------------------------------------------------------- 1-M 10 420 42 6.0 TREATMENTS 4 18155 4539 2-M 10 631 63 69.9 0.72 -32 116 -so 134 ERROR 45 194111 4314 3-M 10 600 60 34.4 0.61 -32 116 -50 134 -------------------------------------- 4-M 10 954 95 124.1 1.82 -32 116 -50 134 TOTAL 49 212266 5-M 10 447 45 7.0 0.09 -32 116 -50 134 = = F Ratio 1.05 IF' table values F.01 = 3.78 F.05 2.58 = = = Coeff. Var. % 107.598 Dunnett 1s 'T' table values P.01 3.12 P.05 2.51 Error-within groups Source-Source of Variation LABCAT CC4.43 Treatments-between groups 27-JUN-2002 418-028:PAGE K-137 Study Report for Clinical Chemistry -------------------------------------------------------------------------------------------------------------------------------- SUMMARY REPORT PERIOD: TERMINAL -------------------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: HALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE -------------------------------------------------------------------------------------------------------------------------------- Aspartate Aminotransferase Std. DUNNETT'S DUNNETT'S RANGES Degree Sum of Hean Group N Total Hean Dev. 't' LO -95%- HI LO -99%- HI Source Fdm Squares Square -------------------------------------------------------------------------------------------------------------------------------- 1-M 10 957 96 22.4 TREATMENTS 4 69637 17409 2-M 10 1213 121 92.6 0.47 -40 231 -73 264 ERROR 45 655378 14564 3-H 10 1171 117 40.9 0.40 -40 231 -73 264 -------------------------------------- 4-H 10 1976 198 248.7 1.89 -40 231 -73 264 TOTAL 49 725015 5-M 10 974 97 15.6 0.03 -40 231 -73 264 F Ratio = 1.20 IF I table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % -- 95.916 Dunnett's 'T' table values P.01 = 3.12 P.05 = 2.51 -------------------------------------------------------------------------------------------------------------------------------- Alkaline Phosphatase -------------------------------------------------------------------------------------------------------------------------------- 1-M 10 1050 105 14.3 TREATMENTS 4 11825 2956 2-M 10 1113 111 36.9 0.51 74 136 67 143 ERROR 45 33780 751 3-M 10 1001 100 12.4 0.40 74 136 67 143 -------------------------------------- 4-M 10 1152 115 25.1 0.83 74 136 67 143 TOTAL 49 45604 5-H 10 1441 144 37.5 3.19 74 136* 67 143** F Ratio = 3.94 IF' table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % = 23.795 Dunnett's 'T' table values P.01 = 3.12 P.05 = 2.51 Calcium -------------------------------------------------------------------------------------------------------------------------------- 1-H 10 109.4 10.9 0.48 TREATMENTS 4 3.45 0.86 2-H 10 107.3 10.7 0.44 1.12 10.5 11.4 10.4 11.5 ERROR 45 7.97 0.18 3-M 10 110.7 11.1 0.44 0.69 10.5 11.4 10.4 11.5 -------------------------------------- 4-M 10 111.0 11.1 0.34 0.85 10.5 11.4 10.4 11.5 TOTAL 49 11.42 5-M 10 115.3 11.5 0.38 3.14 10.5 11.4* 10.4 11.5** F Ratio = 4.87 IF I table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % -- 3.800 Dunnett's 'T' table values P.01 = 3.12 P.05 = 2.51 *-Significant Difference from Control P < .05 **-Significant Difference from Control P < .01 Error-within groups LABCAT CC4.43 Source-Source of Variation Treatments-between groups 27-JUN-2002 418-028:PAGE K-138 Study Report for Clinical Chemistry -----------------------------------------;.._---------------------~------------------------------------------------------------- SUMMARY REPORT PERIOD: TERMINAL -------------------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE -------------------------------------------------------------------------------------------------------------------------------- Phosphorus Std. DUNNETT'S DUNNETT'S RANGES Degree Sum of Mean Group N Total Hean Dev. 't' LO -95%- HI LO -99"1.- HI Source Fdm Squares Square -------------------------------------------------------------------------------------------------------------------------------- 1-H 10 94.7 9.5 1.40 TREATMENTS 4 4.80 1.20 2-M 10 93.7 9.4 1.11 0.15 7.8 11.2 7.4 11.6 ERROR 45 102.32 2.27 3-M 10 99.1 9.9 2.09 0.65 7.8 11.2 7.4 11.6 -------------------------------------- 4-M 10 97.1 9.7 1.43 0.36 7.8 11.2 7.4 11.6 TOTAL 49 107.12 5-M 10 102.3 10.2 1.33 1.13 7.8 11.2 7.4 11.6 F Ratio = 0.53 IF I table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % = 15.485 Dunnett's 'T' table values P.01 = 3.12 P.05 = 2.51 T r i g l y c e r i d e s ---~---------------------------------------------------------------------------------------------------------------------------- -------------------------------------------------------------------------------------------------------------------------------- 1-H 10 516 52 21.8 TREATMENTS 4 7188 1797 2-M 10 469 47 17.2 0.55 30 73 25 78 ERROR 45 16244 361 3-M 10 364 36 13.8 1. 79 30 73 25 78 -------------------------------------- 4-H 10 361 36 27.9 1.82 30 .73 25 78 TOTAL 49 23432 5-M 10 168 17 8.0 4.10 30 73* 25 78** F Ratio = 4.98 IF' table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % = 50.584 ounnett's 'T' table values P.01 = 3.12 P.05 = 2.51 -------------------------------------------------------------------------------------------------------------------------------- Sodium 1-H 10 1459 146 1.4 2-M 10 1457 146 1.3 0.29 144 148 3-H 10 1465 147 1.6 0.86 144 148 4-M 10 1469 147 1.0 1.44 144 148 5-M 10 1460 146 2.2 0.14 144 148 F Ratio = Coeff. Var. % = 1.00 1.062 IF I table values Dunnett's 'T' table values F.01 = P.01 = TREATMENTS 4 9.60 2.40 144 148 ERROR 45 108.40 2.41 144 148 -------------------------------------- 144 148 TOTAL 49 118.00 144 148 3.78 F.05 = 2.58 3.12 P.05 = 2.51 *-Significant Difference from Control P < .05 **-Significant Difference from Control P < .01 Error-within groups LABCAT CC4.43 Source-Source of Variation Treatments-between groups 27-JUN-2002 418-028:PAGE K-139 Study Report for Clinical Chemistry -------------------------------------------------------------------------------------------------------------------------------- SUMMARY REPORT PERIOD: TERMINAL -------------------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: MALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT 1 S PROCEDURE -------------------------------------------------------------------------------------------------------------------------------- Potassium Group N Total Mean Std. DUNNETT'S Dev. 1t 1 DUNNETT'S RANGES LO -95%- HI LO -99%- HI Degree Source Fdm Sum of Squares Mean Square ---------------------------------------~---------------------------------------------------------------------------------------- 1-M 10 65.7 6.6 2.10 TREATMENTS 4 5.56 1.39 2-M 10 61.0 6.1 0.89 0.76 5.0 8.1 4.6 8.5 ERROR 45 86.21 1.92 3-M 10 64.5 6.5 1.27 0.19 5.0 8.1 4.6 8.5 4-M 10 59.7 6.0 0.60 0.97 5.0 8.1 4.6 8.5 TOTAL 49 91.n 5-M 10 69.0 6.9 1.55 0.53 5.0 8.1 4.6 8.5 = F Ratio = 0.73 IF' table values F.01 = 3.78 F.05 2.58 Coeff. Var. % = 21.633 Dunnetts 1 T1 table values P.01 = 3.12 P.05 = 2.51 -------------------------------------------------------------------------------------------------------------------------------- Chloride -------------------------------------------------------------------------------------------------------------------------------- 1-M 10 982 98 2.7 TREATMENTS 4 23.60 5.90 2-M 10 988 99 1.5 0.62 96 101 95 101 ERROR 45 212.90 4.73 3-M 10 997 100 2.3 1.54 96 101 95 101 -------------------------------------- 4-M 10 1000 100 2.7 1.85 96 101 95 101 TOTAL 49 236.50 5-M 10 998 100 1.2 1.64 96 101 95 101 F Ratio = 1.25 IF I table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % = 2.190 Ounnett 1 s 1 T1 table values P.01 = 3.12 P.05 = 2.51 -------------------------------------------------------------------------------------------------------------------------------- Globulin -------------------------------------------------------------------------------------------------------------------------------- 1-M 10 20.3 2.0 0.19 TREATMENTS 4 0.27 0.07 2-M 10 19.5 2.0 0.16 0.99 1.8 2.2 1.8 2.3 ERROR 45 1.46 0.03 3-M 10 19.8 2.0 0.24 0.62 1.8 2.2 1.8 2.3 -------------------------------------- 4-M 10 19.5 2.0 0.16 0.99 1.8 2.2 1.8 2.3 TOTAL 49 1.72 5-M 10 18.1 1.8 0.13 2.73 1.8 2.2* 1.8 2.3 F Ratio = 2.06 IF' table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % = 9.253 Dunnett's 'T' table values P.01 = 3.12 P.05 = 2.51 -------------------------------------------------------------------------------------------------------------------------------- *-Significant Difference from Control P < .05 Error-within groups LABCAT CC4.43 Source-Source of Variation Treatments-between groups 27-JUN-2002 418-028:PAGE K-140 Study Report for Clinical Chemistry -------------------------------------------------------------------------------------------------------------------------------- SUMMARY REPORT PERIOD: TERMINAL -------------------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: HALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE -------------------------------------------------------------------------------------------------------------------------------- Albumin/Globulin Ratio Std. DUNNETT'S DUNNETT'S RANGES Degree Sum of Hean Group N Total Mean Dev. 't' LO -95%- HI LO -99%- HI Source Fdm Squares Square -------------------------------------------------------------------------------------------------------------------------------- 1-M 10 21.2 2.1 0.18 TREATMENTS 4 1.02 0.25 2-M 10 21.4 2.1 0.16 0.24 1.9 2.3 1.9 2.4 ERROR 45 1.57 0.03 3-M 10 21.9 2.2 0.26 0.84 1.9 2.3 1.9 2.4 -------------------------------------- 4-M 10 21.9 2.2 0.15 0.84 1.9 2.3 1.9 2.4 TOTAL 49 2.59 5-M 10 25.1 2.5 0.17 4.67 1.9 2.3* 1.9 2.4** F Ratio = 7.31 IF I table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % = 8.368 Dunnett's 'T' table values P.01 = 3.12 P.05 = 2.51 -------------------------------------------------------------------------------------------------------------------------------- *-Significant Difference from Control P < .OS **-Significant Difference from Control P < .01 Error-within groups LABCAT CC4.43 Source-Source of Variation Treatments-between groups 27-JUN-2002 418-028:PAGE K-141 Study Report for Clinical Chemistry ----------------------------------------------------------------------------------------------------------------------- SUMMARY REPORT PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT 1 S PROCEDURE ----------------------------------------------------------------------------------------------------------------------- TESTCs): TP ALB GLU CHOL T-BIL BUN CREAT CK ALT UNITS: g/dL g/dl mg/dL mg/dL mg/dL mg/dL mg/dL U/L U/L ----------------------------------------------------------------------------------------------------------------------Group: 1-F MEAN 6.1 4.1 152 n 0.2 28 0.4 202 129 SD 0.52 0.42 19.8 27.8 0.07 4.4 0.05 54.1 31.7 N 10 10 10 10 10 10 10 10 10 Group: 2-F MEAN 5.5 4.0 162 72 0.2 SD 0.50 0.34 20.0 14.0 0.03 N 10 10 10 10 10 24 0.4 250 133 4.7 0.05 85.6 23.0 10 10 10 10 Group: 3-F MEAN 5.9 4.1 155 71 0.2 SD 0.41 0.24 18.7 20.0 0.05 N 10 10 10 10 10 28 0.3 192 142 6.7 0.05 21.7 34.2 10 10 10 10 Group: 4-F MEAN SD N 5.8 4.0 146 62 0.1 0.32 0.29 16.2 14.2 0.05 10 10 10 10 10 25 0.4 213 127 4.4 0.08 80.4 24.7 10 10 10 10 Group: 5-F MEAN 5.8 4.0 140 61 0.1 30 0.3 252 145 SD 0.29 0.31 35.5 19.8 0.05 15.4 0.06 101.6 20.0 N 10 10 10 10 10 10 10 10 10 LABCAT CC4.43 27-JUN-2002 418-028:PAGE K-142 Study Report for Clinical Chemistry ----------------------------------------------------------------------------------------------------------------------- SUMMARY REPORT PERIOD: TERMINAL ----------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE ----------------------------------------------------------------------------------------------------------------------- TEST(s): AST ALP CA PHOS TRIG NA K CL GLOB UNITS: U/L U/L mg/dL mg/dL mg/dL mmol/L mmol/L mmol/L g/dl ----------------------------------------------------------------------------------------------------------------------Group: 1-F MEAN 142 145 10.6 8.8 54 143 5.8 96 1.9 SD 22.8 88.7 0.72 1.33 19.9 6.3 0.67 3.4 0.22 N 10 10 10 10 10 10 10 10 10 Group: 2-F MEAN 135 159 11.2 7.9 50 SD 21.6 81. 7 0.63 1.94 10.2 N 10 10 10 10 10 143 5.6 2.4 0.58 10 10 94 1.6** 2.7 0.26 10 10 Group: 3-F MEAN 137 136 10.4 9.0 49 SD 11.8 107.3 0.87 2.80 29.4 N 10 10 10 10 10 142 5.6 2.5 0.32 10 10 95 1.8 3.8 0.21 10 10 Group: 4-F MEAN 124 178 10.4 8.7 45 SD 12.1 131.0 0.46 2.88 19.5 N 10 10 10 10 10 142 6.1 2.6 0.70 10 10 95 1. 7 3.4 0.13 10 10 Group: 5-F MEAN 156 128 10.4 10.1 44 SD 40.7 44.7 0.82 1.64 18.3 N 10 10 10 10 10 142 6.2 2.6 0.90 10 10 94 1.8 3.1 0.21 10 10 tt-signif icant Difference from Control P < .01 LABCAT CC4.43 27-JUN-2002 418-028:PAGE K-143 Study Report for Clinical Chemistry ----------------------------------------------------------------------------------------------------------------------- SUMMARY REPORT PERIOD: TERMINAL ------------------------------------------------------------------------------------------------------~---------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE ----------------------------------------------------------------------------------------------------------------------- TEST(s): A/G UNITS: none ----------------------------------------------------------------------------------------------------------------------Group: 1-F MEAN 2.2 SD 0.28 N 10 Group: 2-F HEAN SD N 2.6* 0.43 10 Group: 3-F MEAN 2.2 SD 0.21 N 10 Group: 4-F HEAN 2.4 SD 0.26 N 10 Group: 5-F HEAN 2.3 SD 0.37 N 10 *-Significant Difference from Control P < .05 LABCAT CC4.43 27-JUN-2002 418-028:PAGE K-144 Study Report for Clinical Chemistry -------------------------------------------------------------------------------------------------------------------------------- SUMMARY REPORT PERIOD: TERMINAL -------------------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE -------------------------------------------------------------------------------------------------------------------------------- Total Protein Std. DUNNETT'S DUNNETT'S RANGES Degree Sum of Mean Group N Total Mean Dev. 't' LO -95%- HI LO -99%- HI Source Fdm Squares Square -----------------------------------------------------~-------------------------------------------------------------------------- 1-F 10 60.7 6.1 0.52 TREATMENTS 4 1.70 0.43 2-F 10 55.0 5.5 0.50 3.04 5.6 6.5* 5.5 6.7 ERROR 45 7.91 0.18 3-F 10 58.8 5.9 0.41 1.01 5.6 6.5 5.5 6.7 4-F 10 57.7 5.8 0.32 1.60 5.6 6.5 5.5 6.7 TOTAL 49 9.62 5-F 10 58.2 5.8 0.29 1.33 5.6 6.5 5.5 6.7 = = F Ratio = = Coeff. Var. % 2.42 IF I table values F.01 7.220 Dunnett's 'T' table values P.01 3.78 F.05 = 2.58 3.12 P.05 = 2.51 Albumin 1-F 10 41.3 4.1 0.42 TREATMENTS 4 0.17 0.04 2-F 10 39.5 4.0 0.34 1.24 3.8 4.5 3.7 4.6 ERROR 45 4.78 0.11 3-F 10 40.6 4.1 0.24 0.48 3.8 4.5 3.7 4.6 -------------------------------------- 4-F 10 40.4 4.0 0.29 0.62 3.8 4.5 3.7 4.6 TOTAL 49 4.94 5-F 10 40.3 4.0 0.31 0.69 3.8 4.5 3.7 4.6 = = = F Ratio 0.39 IF' table values F.01 3.78 F.05 2.58 = = = Coeff. Var. % 8.059 Dunnett's 'T' table values P.01 3.12 P.05 2.51 -------------------------------------------------------------------------------------------------------------------------------- Glucose -------------------------------------------------------------------------------------------------------------------------------- 1-F 10 1520 152 19.8 TREATMENTS 4 2750 687 2-F 10 1621 162 20.0 0.98 126 178 120 184 ERROR 45 24006 533 3-F 10 1548 155 18.7 0.27 126 178 120 184 -------------------------------------- 4-F 10 1461 146 16.2 0.57 126 178 120 184 TOTAL 49 26756 5-F 10 1404 140 35.5 1.12 126 178 120 184 = = = F Ratio 1.29 IF I table values F.01 3.78 F.05 2.58 = = = Coeff. Var. % 15.288 ounnett's 'T' table values P.01 3.12 P.05 2.51 *-Significant Difference from Control P < .05 Error-within groups LABCAT CC4.43 Source-Source of Variation Treatments-between groups 27-JUN-2002 418-028:PAGE K-145 Study Report for Clinical Chemistry -------------------------------------------------------------------------------------------------------------------------------- SUMMARY REPORT PERIOD: TERMINAL -------------------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE -------------------------------------------------------------------------------------------------------------------------------- Cholesterol Std. DUNNETT'S DUNNETT'S RANGES Degree Sum of Mean Group N Total Mean Dev. 't' LO -95%- HI LO -99%- HI Source Fdm Squares Square -------------------------------------------------------------------------------------------------------------------------------- 1-F 10 769 77 27.8 TREATMENTS 4 1862 465 2-F 10 723 72 14.0 0.52 55 99 49 105 ERROR 45 17702 393 3-F 10 705 71 20.0 0.72 55 99 49 105 4-F 10 621 62 14.2 1.67 55 99 49 105 TOTAL 49 19564 5-F 10 610 61 19.8 1.79 55 99 49 105 F Ratio = 1.18 IF I table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % = 28.929 Dunnett's 'T' table values P.01 = 3.12 P.05 = 2.51 -------------------------------------------------------------------------------------------------------------------------------- Total Bilirubin -------------------------------------------------------------------------------------------------------------------------------- 1-F 10 1.6 0.2 0.07 TREATMENTS 4 0.025 0.006 2-F 10 1.9 0.2 0.03 1.30 0.1 0.2 0.1 0.2 ERROR 45 0.120 0.003 3-F 10 1.5 0.2 0.05 0.43 0.1 0.2 0.1 0.2 --------------------------~--------- 4-F 10 1.3 0.1 0.05 1.30 0.1 0.2 0.1 0.2 TOTAL 49 0.145 5-F 10 1.3 0.1 0.05 1.30 0.1 0.2 0.1 0.2 F Ratio = 2.33 IF' table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % = 33.974 Dunnett's 'T' table values P.01 = 3.12 P.05 = 2.51 -------------------------------------------------------------------------------------------------------------------------------- Blood Urea Nitrogen 1-F 10 2-F 10 3-F 10 4-F 10 5-F 10 F Ratio = Coeff. Var. % = 281 28 4.4 241 24 4.7 1.08 281 28 6.7 0.00 252 25 4.4 0.78 298 30 15.4 0.46 19 37 19 37 19 37 19 37 0.79 30.672 IF I table values Dunnett's 'T' table values F.01 = P.01 = TREATMENTS 4 218.92 54.73 17 40 ERROR 45 3099.90 68.89 17 40 -------------------------------------- 17 40 TOTAL 49 3318.82 17 40 3.78 F.05 = 2.58 3.12 P.05 = 2.51 Error-within groups Source-Source of Variation LABCAT CC4.43 Treatments-between groups 27-JUN-2002 418-028:PAGE K-146 Study Report for Clinical Chemistry -------------------------------------------------------------------------------------------------------------------------------- SUMMARY REPORT PERIOD: TERMINAL -------------------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE -------------------------------------------------------------------------------------------------------------------------------- Creatinine Std. DUNNETT'S DUNNETT'S RANGES Degree Sum of Hean Group N Total Hean Dev. 't' LO -95%- HI LO -99%- HI Source Fdm Squares Square -------------------------------------------------------------------------------------------------------------------------------- 1-F 10 3.5 0.4 0.05 TREATMENTS 4 0.015 0.004 2-F 10 3.5 0.4 0.05 0.00 0.3 0.4 0.3 0.4 ERROR 45 0.167 0.004 3-F 10 3.4 0.3 0.05 0.37 0.3 0.4 0.3 0.4 -------------------------------------- 4-F 10 3.6 0.4 0.08 0.37 0.3 0.4 0.3 0.4 TOTAL 49 0.182 5-F 10 3.1 0.3 0.06 1.47 0.3 0.4 0.3 0.4 = = = F Ratio 1.00 IF I table values F.01 3.78 F.05 2.58 = = = Coeff. Var. % 17.813 Dunnett's 'T' table values P.01 3.12 P.05 2.51 -------------------------------------------------------------------------------------------------------------------------------- Creatine Kinase -------------------------------------------------------------------------------------------------------------------------------- 1-F 10 2017 202 54.1 TREATMENTS 4 30624 7656 2-F 10 2495 250 85.6 1.44 118 285 98 305 ERROR 45 247619 5503 3-F 10 1919 192 21.7 0.30 118 285 98 305 -------------------------------------- 4-F 10 2129 213 80.4 0.34 118 285 98 305 TOTAL 49 278244 5-F 10 2521 252 101.6 1.52 118 285 98 305 = = = F Ratio 1.39 IF' table values F.01 3.78 F.05 2.58 = = = Coeff. Var. % 33.472 Dunnett's 'T' table values P.01 3.12 P.05 2.51 -------------------------------------------------------------------------------------------------------------------------------- Alanine Aminotransferase -------------------------------------------------------------------------------------------------------------------------------- 1-F 10 1294 129 31. 7 TREATMENTS 4 2546 637 2-F 10 1334 133 23.0 0.33 99 160 91 167 ERROR 45 33396 742 3-F 10 1424 142 34.2 1.07 99 160 91 167 -------------------------------------- 4-F 10 1265 127 24.7 0.24 99 160 91 167 TOTAL 49 35942 5-F 10 1447 145 20.0 1.26 99 160 91 167 = = = F Ratio = = Coeff. Var. % 0.86 IF' table values F.01 20.138 Dunnett's 'T' table values P.01 3.78 F.05 2.58 3.12 P.05 = 2.51 -------------------------------------------------------------------------------------------------------------------------------- -------------------------------------------------------------------------------------------------------------------------------- Error-within groups Treatments-between groups Source-Source of Variation LABCAT CC4.43 27-JUN-2002 418-028:PAGE K--147 Study Report for Clinical Chemistry -------------------------------------------------------------------------------------------------------------------------------- SUMMARY REPORT PERIOD: TERMINAL -------------------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE -------------------------------------------------------------------------------------------------------------------------------- Aspartate Aminotransferase Std. DUNNETT'S DUNNETT'S RANGES Degree Sum of Mean Group N Total Mean Dev. 't' LO -95%- HI LO -99%- HI Source Fdm Squares Square 1-F 10 1423 142 22.8 2-F 10 1351 135 21.6 0.67 115 169 3-F 10 1368 137 11.8 0.51 115 169 4-F 10 1240 124 12.1 1.69 115 169 5-F 10 1564 156 40.7 1.30 115 169 F Ratio = Coeff. Var. %= 2.38 17.422 IF I table values Dunnett's 1 T1 table values F.01 = P.01 = Alkaline Phosphatase TREATMENTS 4 5587 1397 109 176 ERROR 45 26359 586 109 176 -------------------------------------- 109 176 TOTAL 49 31946 109 176 3.78 F.05 = 2.58 3.12 P.05 = 2.51 1-F 10 1448 145 88.7 2-F 10 1586 159 81.7 0.32 38 252 3-F 10 1363 136 107.3 0.20 38 252 4-F 10 1784 178 131.0 0.79 38 252 5-F 10 1280 128 44.7 0.40 38 252 F Ratio = Coeff. Var. % = 0.44 63.733 IF' table values Dunnett's 'T' tablevalues F.01 = P.01 = Calcium TREATMENTS 4 15762 3941 12 277 ERROR 45 406995 9044 12 2n -------------------------------------- 12 2n TOTAL 49 422757 12 2n 3.78 F.05 = 2.58 3.12 P.05 = 2.51 1-F 10 105.5 10.6 0.72 2-F 10 111.6 11.2 0.63 1.90 9.7 11.4 3-F 10 104.3 10.4 0.87 0.37 9.7 11.4 4-F 10 104.4 10.4 0.46 0.34 9.7 11.4 5-F 10 104.3 10.4 0.82 0.37 9.7 11.4 F Ratio = Coeff. Var. % = 1.94 6.760 IF I table values Dunnett's 'T' table values F.01 = P.01 = TREATMENTS 4 3.99 1.00 9.5 11.6 ERROR 45 23.11 0.51 9.5 11.6 -------------------------------------- 9.5 11.6 TOTAL 49 27.11 9.5 11.6 3.78 F.05 = 2.58 3.12 P.05 = 2.51 Error-within groups Source-Source of Variation . LABCAT CC4.43 Treatments-between groups 27-JUN-2002 418-028:PAGE K-148 Study Report for Clinical Chemistry -------------------------------------------------------------------------------------------------------------------------------- SUMMARY REPORT PERIOD: TERMINAL -------------------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE -------------------------------------------------------------------------------------------------------------------------------- Phosphorus Std. DUNNETT'S DUNNETT'S RANGES Degree Sum of Mean Group N Total Mean Dev. 't' LO -95%- HI LO -99%- HI Source Fdm Squares Square -------------------------------------------------------------------------------------------------------------------------------- 1-F 10 87.5 8.8 1.33 TREATMENTS 4 24.53 6.13 2-F 10 79.3 7.9 1.94 0.83 6.3 11.2 5.7 11.8 ERROR 45 219.09 4.87 3-F 10 90.0 9.0 2.80 0.25 6.3 11.2 5.7 11.8 -------------------------------------- 4-F 10 87.0 8.7 2.88 0.05 6.3 11.2 5.7 11.8 TOTAL 49 243.62 5-F 10 101.0 10.1 1.64 1.37 6.3 11.2 5.7 11.8 = = = F Ratio 1.26 IF I table values F.01 3.78 F.05 2.58 = = = Coeff. Var. % 24.803 Dunnett's 'T' table values P.01 3.12 P.05 2.51 Triglycerides 1-F 10 544 54 19.9 TREATMENTS 4 693 173 2-F 10 495 so 10.2 0.54 32 77 26 83 ERROR 45 18711 416 3-F 10 490 49 29.4 0.59 32 77 26 83 4-F 10 453 45 19.5 1.00 32 77 26 83 TOTAL 49 19404 5-F 10 437 44 18.3 1.17 32 77 26 83 = = = F Ratio = = Coeff. Var. % 0.42 IF' table values F.01 42.148 Dunnett's 'T' table values P.01 3.78 F.05 2.58 3.12 P.05 = 2.51 Sodium 1-F 10 1434 143 6.3 2-F 10 1427 143 2.4 0.43 139' 147 3-F 10 1422 142 2.5 0.74 139 147 4-F 10 1424 142 2.6 0.62 139 147 5-F 10 1421 142 2.6 0.80 139 147 F Ratio = Coeff. Var. %= 0.21 2.534 IF' table values Dunnett's 'T' table values F.01 = P.01 = 138 138 138 138 3.78 3.12 TREATMENTS 4 10.92 2.73 148 ERROR 45 587.40 13.05 148 -------------------------------------- 148 TOTAL 49 598.32 148 F.05 = 2.58 P.05 = 2.51 Error-within groups Source-Source of Variation LABCAT CC4.43 Treatments-between groups 27-JUN-2002 418-028:PAGE K-149 Study Report for Clinical Chemistry -------------------------------------------------------------------------------------------------------------------------------- SUMMARY REPORT PERIOD: TERMINAL -------------------------------------------------------------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE -------------------------------------------------------------------------------------------------------------------------------- Potassium Std. DUNNETT'S DUNNETT'S RANGES Degree Sum of Mean Group N Total Mean Dev. 't' LO -95%- HI LO -99%- HI Source Fdm Squares Square -------------------------------------------------------------------------------------------------------------------------------- 1-F 10 58.1 5.8 0.67 TREATMENTS 4 3.23 0.81 2-F 10 55.8 5.6 0.58 0.78 5.1 6.6 4.9 6.7 ERROR 45 19.67 0.44 3-F 10 55.5 5.6 0.32 0.88 5.1 6.6 4.9 6.7 -------------------------------------- 4-F 10 61.0 6.1 0.70 0.98 5.1 6.6 4.9 6.7 TOTAL 49 22.90 5-F 10 61.6 6.2 0.90 1.18 5.1 6.6 4.9 6.7 = F Ratio = 1.84 IF' table values F.01 = 3.78 F.05 2.58 = Coeff. Var. % = 11.322 Dunnett's 'T' table values P.01 3.12 P.05 = 2.51 -------------------------------------------------------------------------------------------------------------------------------- Chloride -------------------------------------------------------------------------------------------------------------------------------- 1-F 10 956 96 3.4 TREATMENTS 4 29.08 7.27 2-F 10 941 94 2.7 1.01 92 99 91 100 ERROR 45 493.00 10.96 3-F 10 949 95 3.8 0.47 92 99 91 100 -------------------------------------- 4-F 10 954 95 3.4 0.14 92 99 91 100 TOTAL 49 522.08 5-F 10 936 94 3.1 1.35 92 99 91 100 = = F Ratio = 0.66 IF' table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % 3.494 Dunnett's 'T' table values P.01 = 3.12 P.05 2.51 G l o b u l i n ----------------------------------------------------------------------------------------------------------------~------------- -------------------------------------------------------------------------------------------------------------------------------- 1-F 10 19.4 1.9 0.22 TREATMENTS 4 0.82 0.20 2-F 10 15.5 1.6 0.26 4.12 1.7 2.2* 1.6 2.2** ERROR 45 2.02 0.04 3-F 10 18.2 1.8 0.21 1.27 1.7 2.2 1.6 2.2 -------------------------------------- 4-F 10 17.3 1. 7 0.13 2.22 1.7 2.2 1.6 2.2 TOTAL 49 2.83 5-F 10 17.9 1.8 0.21 1.59 1.7 2.2 1.6 2.2 F Ratio = 4.56 IF' table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % = 11.982 Dunnett 1 s 'T' table values P.01 = 3.12 P.05 = 2.51 -------------------------------------------------------------------------------------------------------------------------------- -------------------------------------------------------------------------------------------------------------------------------- *-Significant Difference from Control P < .05 Source-Source of Variation **-Significant Difference from Control P < .01 Treatments-between groups Error-within groups LABCAT CC4.43 27-JUN-2002. 418-028:PAGE K-150 Study Report for Clinical Chemistry -----------------------------------------~-------------------------------------------------------------------------------------- SUMMARY REPORT PERIOD: TERMINAL ----------------------------------------------------~------------------------------------------------------------------------- STUDY ID: ARGUS 418-028 SEX: FEMALE STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE -------------------------------------------------------------------------------------------------------------------------------- Albumin/Globulin Ratio Std. DUNNETT'S DUNNETT'S RANGES Degree Sum of Hean Group N Total Hean Dev. 1t 1 LO -95%- HI LO -99%- HI Source Fdm Squares Square -------------------------------------------------------~---------------------------------------------------------------------- 1-F 10 21.7 2.2 0.28 TREATMENTS 4 1.16 0.29 2-F 10 26.1 2.6 0.43 3.07 1.8 2.5* 1.7 2.6 ERROR 45 4.63 0.10 3-F 10 22.3 2.2 0.21 0.42 1.8 2.5 1.7 2.6 -------------------------------------- 4-F 10 23.7 2.4 0.26 1.39 1.8 2.5 1.7 2.6 TOTAL 49 5.80 5-F 10 23.0 2.3 0.37 0.91 1.8 2.5 1.7 2.6 = = F Ratio = 2.83 IF' table values F.01 = 3.78 F.05 = 2.58 Coeff. Var. % 13.734 Dunnett 1 s 1 T' table values P.01 3.12 P.05 = 2.51 *-Significant Difference from Control P < .05 Error-within groups LABCAT CC4.43 Source-Source of Variation Treatments-between groups 27-JUN-2002 APPENDIXL STATEMENT OF THE STUDY DIRECTOR 905 Sheehy Drive, Bklr A Horsham, PA I 9CU4 Telephone: (215) 443..8710 Telefax: (215) 443-8587 418-028:PAGE L-1 ARGUS RESEARCH Charles River Laboratories Discovery and Development Services PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OFT-7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST SPONSOR'S STUDY NUMBER: T-7706.1 STATEMENT OF THE STUDY DIRECTOR This final report accurateIy reflects the raw data obtained during the performance of the study. No deviations from the U.S. Food and Drug Administration (FDA) Good Laboratory Practice Regulations; Final Rule\ the Japanese Ministry of Health and Welfare (MHW) Good Laboratory Practice Standard for Safety Studies on Drugsb, the Organisation for Economic Co-operation and Development (OECD). The Revised OECD Principles of Good Laboratory Practicesc and the Organisation for Economic Co-operation and Development (OECD), The OECD Guideline for Testing of Chemicalsd occurred that affected the quality or integrity of the study. Study Director Argus Research a. U.S. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule. 21 CFR Part 58. b. Japanese Ministry of Health and Welfare (1997). Good Laboratory Practice Standard for Safety Studies on Drugs, MHW Ordinance No. 21, March 26, 1997. c. Organisation for Economic Co-operation and Development (1998). The Revised OECD Principles of Good Laboratory Practices [C(97)186/Final]. d. Organisation for Economic Co-operation and Development (1996). OECD Guideline for Testing of Chemicals. Section 4, No. 422: Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, adopted 22 March 1996. APPENDIXM QUALITY ASSURANCE STATEMENT 905 Sheehy OriYe, 81cJr. A Horshorn. PA 19044 Telephone: (215) 44343710 Telefax: (215) 443-8587 418-028:PAGE M-1 ~~ .... ARGUS RESEARCH Charles River Laboratories Discovery and Development Services QUALITY ASSURANCE STATEMENT Argus Protocol: 418-028 Sponsor's Study Number: T-7706.1 Study Director: Raymond G. York, Ph.D., DABT The protocol, critical phases, raw data and draft final report were inspected by the Quality Assurance Unit (QAU), to assure conformance with: Organisation for Economic Co-operation and Development (1998). The Revised OECD Principles of Good Laboratory Practices [C(97)186/Final]. U.S. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule. 21 CFR Part 58. Japanese Ministry of Health and Welfare (1997). Good Laboratory Practice Standard for Safety Studies on Drugs, MHW Ordinance Number 21, March 26, 1997. The undersigned indicate that the report is an accurate representation of the raw data. Data provided by the Sponsor or a subcontractor were not audited by the Argus Research Quality Assurance Unit. 418-028:PAGE M-2 The QAU inspection and report audit dates are listed below: lns,gection Phase Ins,gection Date(s} Protocol 22MAR02 Test Substance Administration 04APR02 Test Substance Preparation 05APR02 Motor Activity 08MAY02 Blood Collection 09MAY02 Fetal Blood Collection 09MAY02 Fetal Liver Collection 09MAY02 Satellite Caesarean- Sectioning 09MAY02 Male Sacrifice 14MAY02 Male Blood Collection 14MAY02 Sperm Evaluation 14MAY02 Litter Observations 17MAY02 Functional Observational Battery 24MAY02 Blood Collection 30MAY02 Dam/Litter Sacrifice 30MAY02 In-Life Data 11-20 SEP 02 Necropsy Data 13-20 SEP 02 Formulation Data 17 SEP 02 Report Tables 16-23 SEP 02 24 SEP 02 Report Text 19,22-23 SEP 02 25 SEP 02 Revised Report 06NOV02 Date(s) Findings Submitted to Study Director 22MAR02 05 APR02 06APR02 16MAY02 10MAY02 13MAY02 13MAY02 13MAY02 14MAY02 14MAY02 14MAY02 17MAY02 24MAY02 04JUN02 04JUN02 23 SEP 02 20 SEP 02 17 SEP02 23 SEP 02 24 SEP 02 23 SEP 02 25 SEP 02 06NOV02 Date(s) Findings Submitted to Management 22MAR02 05 APR02 06APR02 16MAY02 10MAY02 13MAY02 13MAY02 13MAY02 14MAY02 14MAY02 14MAY02 17MAY02 24MAY02 04JUN02 04JUN02 23 SEP 02 20 SEP 02 17 SEP02 23 SEP 02 24 SEP02 23 SEP 02 25 SEP 02 06NOV02 Matthew J. Vaneman, B.S. Date Manager of Regulatory Compliance