Document oD81D3yjGQBBnrMJz7a38Yr

RECiiiVEO O P P NC IC 200*4MAY 12 AH 9= 10 -4&224r mo FINAL REPORT 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 FINAL REPORT DATE: 31 JULY 2003 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 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-M aleRats 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 h SUBJECT 3.3. Hematology and Clinical Chemistry PAGE 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 3.6. Mating and Fertility 3-3 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 -l in SUBJECT Figure 2. Fo Generation Female Rats PAGE 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 B 1. Table B2. Clinical Observations - Summary - Fo Generation Male Rats Necropsy Observations - Summary - Fo Generation Male Rats B-1 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 B5. 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-l 6 Table BIO. Absolute Feed Consumption Values (g/day) - Summary Fo Generation Male Rats B -l7 Table B 11. Relative Feed Consumption Values (g/kg/day) - Summary Fo Generation Male Rats B -l8 Table B12. Mating and Fertility - Summary - Fo Generation Male Rats B-19 Table B 13. Functional Observational Battery Observations - Summary Fo Generation Male Rats B-20 IV SUBJECT PAGE Table B 14. Motor Activity - Summary - Fo Generation Male Rats B-26 Table B15. Sperm Motility, Count and Density - Summary Fo Generation Male Rats B-28 Table B 16. Sperm Morphology - Summary - Fo Generation Male Rats B-29 Table B 17. Clinical Observations - Individual Data - Fo Generation Male Rats B-30 Table B 18. 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 C l. Table C2. Clinical Observations - Summary - Fo Generation Female Rats Necropsy Observations - Summary - Fo Generation Female Rats C-l 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. PAGE Ratios (%) of Organ Weight to Terminal Body Weight - Summary - Fo Generation Female Rats C-7 Table C5. Ratios (%) of Organ Weight to Brain Weight - Summary Fo Generation Female Rats C-8 Table C6. Hematology - Summary - Fo Generation Female Rats C-9 Table C7. Clinical Chemistry - Summary - Fo Generation Female Rats C-12 Table C8. Body Weights - Precohabitation - Summary - Fo Generation Female Rats C-15 Table C9. Body Weight Changes - Precohabitation - Summary - Fo Generation Female Rats C-16 Table CIO. Maternal Body Weights - Gestation - Summary - Fo Generation Female Rats C-17 Table C l 1. Maternal Body Weight Changes - Gestation - Summary Fo Generation Female Rats C-19 Table C12. Maternal Body Weights - Lactation - Summary Fo Generation Female Rats C-20 Table C13. Maternal Body Weight Changes - Lactation - Summary Fo Generation Female Rats C-22 Table C14. Absolute Feed Consumption Values (g/day) - Precohabitation Summary - Fo Generation Female Rats C-23 Table CIS. Relative Feed Consumption Values (g/kg/day) - Precohabitation - Summary - Fo Generation Female Rats C-24 Table C l6. Maternal Absolute Feed Consumption Values (g/day) - Gestation - Summary - Fo Generation Female Rats C-25 Table C17. Maternal Relative Feed Consumption Values (g/kg/day) - Gestation - Summary - Fo Generation Female Rats C-26 Table C l8. Maternal Absolute Feed Consumption Values (g/day) - Lactation - Summary - Fo Generation Female Rats C-27 vi SUBJECT PAGE Table C19. Maternal Relative Feed Consumption Values (g/kg/day) - Lactation - Summary - Fo Generation Female Rats C-28 Table C20. Mating and Fertility, Estrous Cycling and Days in Cohabitation - Summary - Fo Generation Female Rats C-29 Table C21. Functional Observational Battery - Summary Fo Generation Female Rats C-31 Table C22. Motor Activity - Summary - Fo Generation Female Rats C-37 Table C23. Natural Delivery Observations - Summary - Fo Generation Female Rats C-39 Table C24. Litter Observations (Naturally Delivered Pups) - Summary FI Generation Litters C-40 Table C25. Clinical Observations from Birth to Day 22 Postpartum Summary - FI Generation Pups C-43 Table C26. Necropsy Observations - Summary - FI Generation Pups C-44 Table C27. Pup Liver Weights - Summary - FI Generation Pups C-45 Table C28. Clinical Observations - Individual Data Fo Generation Female Rats C-46 Table C29. Necropsy Observations - Individual Data Fo Generation Female Rats C-51 Table C30. Terminal Body Weights and Organ Weights and Ratios (%) of Organ Weight to Terminal Body Weight - Individual Data - Fo Generation Female Rats C-55 Table C31. Organ Weights and Ratios (%) Of Organ Weight to Brain Weight - Individual Data - Fo Generation Female Rats C-60 Table C32. Primordial Follicle Count - Individual Data - Fo Generation Female Rats C-65 Table C33. 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 - FI Generation Litters C-110 Table C44. Pup Body Weights from Birth to Day 22 Postpartum Individual Data - FI Generation Pups C-113 Table C45. Pup Vital Status and Sex from Birth to Day 22 Postpartum Individual Data - FI Generation Pups C-125 Table C46. Clinical Observations from Birth to Day 22 Postpartum Individual Data - FI Generation Pups C-128 Table C47. Necropsy Observations - Individual Data - FI Generation Pups C-130 Table C48. Pup Liver Weights - Individual Date - FI Generation Pups C-136 APPENDIX D - PROTOCOL AND AMENDMENTS D -ltoD -52 SUBJECT PAGE APPENDIX E - DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY E-l to E-3 APPENDIX F - CERTIFICATE OF ANALYSIS F -lto F -3 APPENDIX G - ANALYTICAL AND BIOANALYTICAL REPORT G-l to G-153 APPENDIX H - TEMPERATURE AND RELATIVE HUMIDITY REPORT H -l APPENDIX I - POSITIVE CONTROL DATA I-lto I-4 APPENDIX J - HISTOPATHOLOGY REPORT J-l to J-105 APPENIDX K - HEMATOLOGY AND CLINICAL CHEMISTRY REPORTS K-l to K-150 APPENDIX L - STATEMENT OF THE STUDY DIRECTOR L-l APPENIDIX M QUALITY ASSURANCE STATEMENT M -l 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 SCREENINGTEST ARGUS RESEARCH PROTOCOL NUMBER: 418-028 SPONSOR'S STUDY NUMBER: T-7706.1 1. SUMMARY AND CONCLUSION 1.1. Methods8 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. FI 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 ,1 0 ,1 2 ,1 5 ,1 8 ,2 0 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 liver weights to brain weight were significantly 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 rats(1). There were no treatment-related microscopic changes observed in the liver of the FI 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 FI 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 livebom 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 FI generation pups were attributable to dosages of the test substance as high as 10 mg/kg/day. FI 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 FI generation offspring). Alan M. Hoberman, Ph.D., DABT Director of Research Study Director Date Raymond G. YorkfPh.D , DABT Associate Directono f Research Study Director 418-028:PAGE 2-1 2. DESCRIPTION OF TEST PROCEDURES 2.1. Conduct of Study 2.1.1. 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 made 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 (OECD)(2) 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 (FDA)<4), 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 DS 42 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 Male 2 Toxicokinetic Sample Collections DS 14 DGC21 DGO DG 25 Sacrifice (Rats that did not deliver a litter) Delivery Period*1(DL 1) FOB and Motor Activity Evaluation DL 22 Sacrifice Female Rats and Pups 418-028:PAGE 2-3 26 MAR 02 01 APR 0 2 -1 6 MAY 02 06 MAY 02 - 09 MAY 02 14 APR 02 12 MAY 02 12 MAY 02 13 MAY 0 2 -1 7 MAY 02 26 MAR 02 01 APR 02 - 09 JUN 02 14 APR 02 PM - 21 APR 02 AM 21 APR 02 PM - 28 APR 02 AM 14 APR 02 06 MAY 0 2 -1 9 MAY 02 15 APR 02 -2 8 APR 02 10 MAY 02 -2 3 MAY 02 07 MAY 02 - 20 MAY 02 23 MAY 02 - 26 MAY 02 28 MAY 02- 10 JUN 02 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 FI 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. Test Substance Information 2.2.1. 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-fikered 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 Substance" l g 09JU N 02 Room temperature Exygen*1/ Ambient 10 JUN 02 Homogeneity" 2 mL 29 MAR 02 Refrigerated conditions Sponsor/ 01 APR 02 (all levels) Refrigerated Concentration'1 (all levels) Stability8 2mL 2 mL 24 MAY 02e Refrigerated 07 JUN 02f 29 MAR 02 Refrigerated Exygen" / Refrigerated Sponsor/ Refrigerated 28 MAY 02 10 JUN 02 01 APR 02 Bulk Test Substance Reserve l g 10 JUN 02 Room temperature Testing Facility 10 JUN 02 Archives Vehicle Components Reserve Carboxymethylcellulose R.O. deionized water lg 5 mL 10 JUN 02 10 JUN 02 Room temperature Testing Facility Archives 10 JUN 02 10 JUN 02 a. A sample o f the test article was retained on the last day o f 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 o f duplicate samples from each concentration were taken on the first day o f preparation. One sample o f each duplicate set was shipped on the day o f 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 20 JAN 02 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 21 JAN 02 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 rats were assigned to five dosage groups (Groups I through V), 15 rats per sex per group, using a computer-generated (weightordered) 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 Guidefo r the Care and Use o f Laboratory Animals(9). 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 Number Dosage Dosage1 Concentration Volume of Rats Assigned Numbers Group (mg/kg/day) (mg/mL) (mL/kg) per Sex Male Rats Female Rats I0 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 1 5 + 3d 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: 19179-19181 Toxicokinetic Study: 19079 -19081 in 1 0.1 10 15 + 3 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 1 5 + 3 6 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: 19185 -19187 19085 - 19087 V 10 1 10 15 + 3" Main Study: 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. Hie 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 die 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. FI Generation Pups FI 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.I. 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 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 study6. 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 ,1 0 ,1 2 ,1 5 ,1 8 ,2 0 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)00-135 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 semm 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. FI 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 daily8. 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.I. 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 analysis1*. 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 Thome 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 sacrifice". 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 2.1 .6 .2 . FI 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 die 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 recorded. 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 livebom, 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 A rg u s A u to m a te d D a ta C o lle c tio n a n d M a n a g em en t S ystem , the V ivarium T em peratu re a n d R e la tiv e H u m id ity M o n ito rin g S ystem , the C o u lb o u m In stru m en ts P a ssiv e In fra re d M o to r A c tiv ity S ystem , the C o u lb o u m In stru m en ts A u d ito ry S ta rtle S ystem , the C o u lb o u m In stru m ents S p a tia l D e la y e d A ltern a tio n S ystem , and/or the passive avoidance software. All data were tabulated, summarized and/or statistically analyzed using the A rg u s A u to m a te d D a ta C o lle c tio n a n d M a n a g em en t S ystem , the V ivarium T em p era tu re a n d R ela tiv e H u m id ity M o n ito rin g System , M ic ro so ft E xcel [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: ' Parametric Type of Test8 ll. Nonparametricb A. Bartlett's Test r Significant at pi.0.001 l Not Significant A. Kruskal-Wallls Test (.7SK ties at any concentration) Significant at p&O.OS Not Significant Nonparametric Analysis of Variance r Significant at ps.0.05 i Not Significant Dun nett's Test Dunn's Test B. Fisher's Exact Test on Proportion of Ties (>75% tie* at any caneantratlon) B. Analysis of Variance with Repeated Measures Significant at ps.0.05 Not Significant r (Dosage) Dunnett's Test 1 (Dosage x Block Interaction) One-way ANOVA for each block Significant at p<S>.05 Not Significant Dunnett's Test III. Test for Proportion Data Variance Test (or Homogeneity of the Binomial Distribution o ' ja Statistically significant probabilities are reported as either p<0.05 or p<0.01. 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(18) 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 Test(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(I5) was used to evaluate the data at each measurement period, and a significant was followed by a comparison of the dosage groups using Dunnett's 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 quantal 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-M aleRats 3.1. Mortality, Clinical and Necropsy Observations (Summaries - Tables B1 and B2; Individual Data - Tables B17 and B18) 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 B5; 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 /?<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 /?<X).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<0.01) 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 (PHOS), sodium (NA), potassium (K), chloride (CL) and globulin (G) in male rats were comparable among the four dosage groups and did not differ significantly. 3.4. Body Weights and Body Weight Changes (Figure 1; Summaries - Tables B8 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 ip<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 B10 and B ll; Individual Data - Table B22) Absolute (g/day) and relative (g/kg/day) feed consumption values for the male rats were unaffected 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 Bcxly 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. RESULTS - Female Rats 4.1. Mortality, Clinical and Necropsy Observations (Summaries - Tables C l and C2; Individual Data - Tables C28 and C29) 4.1.1. 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 mucosal 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 FI 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 lymphocytes in female rats were comparable among the five dosage groups and did not differ significantly (except on one occasion). The concentration of WBCs (lymphocytes) 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 (PHOS), 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 A/G 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. 4.4.1. Body Weights and Body Weight Changes (Figure 2; Summaries Tables C8 through C13; Individual Data - Tables C33 through C35) 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 (pO.OS or p^O.Ol) 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^O.Ol) on DLs 1 to 5 and 8 to 15 in the 0.3 mg/kg/day dosage group, DLs 1 to 5 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 1 to 5 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 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. 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 livebom 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 livebom pups, dams with all pups dying days 1 to 4 and 5 to 22, were comparable among the five dosage groups and did not significantly differ. The number of livebom 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 livebom pups per number of pregnant rats), viability index (number of live pups on DL 8 per number of livebom pups on DL 1) and lactation index (number of live pups on DL 22 per number of livebom 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 FI 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 comeal 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) FI 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 significantly. 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 Guidelinefor Testing o f 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 Standardfor 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, YA 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). Guidefor the Care and Use o f 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: la. 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. ODonoghue, 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, O.J. (1964). Multiple comparisons using rank sums. Technometrics 6(3):241-252. 19. Siegel, S. (1956). Nonparametric Statisticsfor 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/STATTM 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 418-028: 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 F o G E N E R A T IO N M ALE R A T S Figure 1 DAY OF STUDY 0 MG/KG/DAY 0.3 MG/KG/DAY 1 MG/KG/DAY 3 MG/KG/DAY 10 MG/KG/DAY a. Last value recorded before cohabitation. b. First value recorded after cohabitation. c. Terminal body weight. 418-028:PAGE A- PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITYSTUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) BODY WEIGHTS F o G E N E R A T IO N FEM A LE R A T S Figure 2 0 MG/KG/DAY 0.3 MG/KG/DAY 1 MG/KG/DAY 3 MG/KG/DAY --- X--- 10 MG/KG/DAY a. Last value recorded before cohabitation. *p<0.05 2 4 6 8 10 12 14a 0 2 4 6 8 10 12 14 16 18 20 1 3 5 7 9 11 13 15 17 19 21 DAY OF STUDY DAY OF GESTATION DAY OF LACTATION **p < 0 .0 1 418-028:PAGE A-2 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY O F 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 80 70 0 MG/KG/DAY 60 - (f> iz UJ 50 E * oLL ttL UJ |3 0 Z 20 0.3 MG/KG/DAY 1 MG/KG/DAY 3 MG/KG/DAY 10 MG/KG/DAY 10 418-028:PAGE A-3 --\ ! | | | |- T~ 10 20 30 40 50 60 70 80 90 100 TIME (MINUTES) 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 {2 200 Z LU 2 L>U o 2 z 150 h- Z LQU. CD CQO 100 Oo UJ CO UJ 2 p 50 0 MG/KG/DAY 0.3 MG/KG/DAY 1 MG/KG/DAY 3 MG/KG/DAY 10 MG/KG/DAY 418-028:PAGE A-4 20 40 60 80 100 TIME (MINUTES) PROTOCOL 41B-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 0 MG/KG/DAY 0.3 MG/KG/DAY 1 MG/KG/DAY 3 MG/KG/DAY 10 MG/KG/DAY 418-028-.PAGE A-5 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-7708.1) MOTOR ACTIVITY - TIME SPENT IN MOVEMENT - Fo GENERATION FEMALE RATS Figure 6 0 MG/KG/DAY CID- Z LU 0.3 MG/KG/DAY 2 >OLU 1 MG/KG/DAY Z LOU. CD 3 MG/KG/DAY COD Z O OLU 10 MG/KG/DAY CD 20 40 60 80 100 TIME (MINUTES) 418-028:PAGE A-6 APPENDIX B 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 B1 (PAGE I) : CLINICAL OBSERVATIONS - SUMMARY - FO GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II III IV 0 0.3 13 MAXIMUM POSSIBLE INCIDENCE 680/ 15 680/ 15 680/ 15 680/ 15 MORTALITY 0 0 00 CHROMORHINORRHEA 0/ 0 1/ 1 1/ 1 1/ 1 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 CHROMODACRYORRHEA 0/ 0 0/ 0 3/ 1 9/ 1 LACRIMATION 0/ 0 0/ 0 0/ 0 0/ 0 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 DRY, BROWN PERIORAL SUBSTANCE 0/ 0 1/ 1 0/ 0 0/ 0 SOFT OR LIQUID FECES 0/ 0 1/ 1 0/ 0 0/ 0 HEAD: SCAB 8/ 1 0/ 0 0/ 0 0/ 0 DEHYDRATION 7/ 1 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. V 10 680/ 15 0 2/ 2 13/ 1 13/ 1 0/ 0 2/ 1 1/ 1 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 418-028-.PAGEB- 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 N0 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 00 LEFT, PELVIS, SLIGHT DILATION N 0 1 0 00 EPIDIDYMIDES: BILATERAL, SMALL N0 0 0 10 LEFT CAUDA, SMALL N0 0 0 10 TESTES: BILATERAL, SMALL N0 0 0 10 JEJUNUM: DIVERTICULUM N0 0 0 01 a. Refer to the individual <clinical observations table (Table B17) for external observations 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 B3 (PAGE 1) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I 0 RATS TESTED N 10 TERMINAL BODY WEIGHT MEANS.D. 469.7 t 31.6 EPIDIDYMIS LEFT MEANtS.D. 0.6476 i0.0367 CAUDA EPIDIDYMIS LEFT MEANtS.D. 0.3308 t 0 .0294 TESTIS LEFT MEANtS.D. 1.6591 t0.0879 SEMINAL VESICLES WITH FLUID MEANtS.D. 1.7055 t 0 .2370 SEMINAL VESICLES WITHOUT FLUID MEANS.D. 0.8440 t 0 .1038 EPIDIDYMIS RIGHT MEANS.D. 0.6745 iO.0424 TESTIS RIGHT MEANtS.D. 1.6777 t O .0936 PROSTATE MEANtS.D. 1.2902 t O .2968 BRAIN MEANtS.D. 2.40 t 0.11 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . II 0.3 10 448.8 i 37.8 0.6358 t O .0397 0.3182 tO.0266 1.7154 t O .1239 1.5439 i0.2672 0.8118 i0 .1117 0.6546 t O .0409 1.7281 0 .1287 1.2000 t O .1297 2.44 t 0.11 III 1 10 455.8 i 55.2 0.6277 iO.0505 0.3232 t O .0285 1.6717 t O .1646 1.6385 t O .2912 0.7965 10.1068 0.6534 t O .0555 1.6922 t O .1642 1.2267 iO.2694 2.38 t 0.09 rv 3 10 472.3 i 38.3 0.5916 t O .1092 0.2913 t O .0650 1.6116 iO.3330 1.5473 10.3182 0.7670 t O .1477 0.6106 t O .1218 1.6175 t O .3393 1.2734 t O .1659 2.38 t 0.09 V 10 10 440.8 i 12.6 0.6134 t O .0472 0.3041 tO.0309 1.7483 t O .1549 1.4424 t O .2669 0.7772 iO.1163 0.6261 t O .0409 1.7604 iO.1447 1.1918 tO.2344 2.40 t 0.10 PROTOCOL 418-028: ORAL (OAVAGE) 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 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. 14.63 i 1.81 14.22 1.58 KIDNEY LEFT MEANS.D. 1.98 0.25 1.86 0.12 KIDNEY RIGHT MEANS.D. 2.02 0.26 1.90 0.15 ADRENAL LEFT MEANS.D. 0.035 0.007 0.035 0.007 ADRENAL RIGHT SPLEEN MEANS.D. MEANS.D. 0.034 0.006 0.79 0.14 0.034 0.006 0.81 0.07 THYMUS MEANS.D. 0.41 0.12 0.45 0.09 HEART MEANS.D. 1.55 0.10 1.52 0.12 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). III 1 10 455.8 55.2 15.94 3.56 1.96 0.26 2.00 0.24 0.034 0.005 0.030 0.007 0.76 0.12 0.36 0.10 1.54 0.13 IV 3 10 472.3 38.3 17.60 1.64* 2.04 0.17 2.13 0.18 0.032 0.006 0.032 0.007 0.88 0.19 0.42 0.09 1.60 0.13 V 10 10 440.8 12.6 22.83 2.73** 2.01 0.18 2.04 0.14 0.032 0.004 0.029 0.007 0.78 0.10 0 .42 0.05 1.44 0.07 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 0 RATS TESTED N 10 TERMINAL BODY WEIGHT MEANS.D. 469.7 31.6 EPIDIDYMIS LEFT MEANS.D. 0.138 0.014 CAUDA EPIDIDYMIS LEFT MEANS.D . 0.068 0.009 TESTIS LEFT MEANS.D. 0.354 0.024 SEMINAL VESICLES WITH FLUID MEANS.D. 0.366 t 0.064 SEMINAL VESICLES WITHOUT FLUID MEANS.D. 0.181 0.031 EPIDIDYMIS RIGHT MEANS.D. 0.143 0.016 TESTIS RIGHT MEANS.D. 0.357 i 0.030 PROSTATE MEANS.D. 0.276 0.073 BRAIN MEANS.D. 0.510 0.030 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . II 0 .3 10 448.8 37.8 0.142 0.015 0.071 0.012 0.385 0.047 III 1 10 455.8 55.2 0.138 0.018 0.071 0.007 0.370 0.041 IV 3 10 472.3 38.3 0.126 0.027 0.063 0.015 0.342 0.078 V 10 10 440.8 + 12.6 0.138 0.011 0.068 0.008 0.397 0.041 0.348 0.073 0.359 0.063 0.329 0.081 0.326 0.062 0.183 0.038 0.147 0.018 0.386 0.049 0.267 0.022 0.546 0.053 0.176 0.022 0.163 0.038 0.176 0.026 0.145 0.016 0.127 0.028 0.141 0.012 0.374 0.042 0.344 0.078 0.400 0.035 0.271 0.061 0.274 0.052 0.270 0.054 0.528 0.050 0.506 0.041 0.545 0.027 RATIOS (%) = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. 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 MEANtS.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<0.0l). 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. 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 B5 (PAGE 1): RATIOS (%) OF ORGAN WEIGHT1 TO BRAIN WEIGHT SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I 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 9.23 RATIOS {%) = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. 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 B5 (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 MEANtS.D. 2.40 0.11 2.44 i 0.11 LIVER MEANS.D. 611.89 79.55 584.43 t 68.39 KIDNEY LEFT MEANtS.D, 82.68 9.11 76.46 t 5.95 KIDNEY RIGHT MEANS.D. 84.22 9.20 77.94 1 6.26 ADRENAL LEFT MEANtS.D. 1.46 0.27 1.44 i 0.31 ADRENAL RIGHT MEANtS.D. 1.41 0.25 1.40 0.26 SPLEEN MEANS.D. 32.90 5.93 33.34 3.91 THYMUS MEANtS.D. 17.22 5.29 18.37 t 4.02 HEART MEANtS.D. 64.91 3.78 62.49 t 5.04 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) . III rv 13 V 10 10 10 10 2.38 0.09 2.38 0.09 2.40 i 0.10 667.08 il29.02 739.11 73.28** 948.61 i 95.12** 82.16 9.05 85.78 7.04 83.64 t 8.05 84.13 7.94 89.26 6.52 85.00 i 6.56 1.42 0.24 1.36 0.25 1.34 i 0.18 1.26 0.33 1.34 0.26 1.23 t 0.29 31.83 4.39 36.64 7.27 32.44 i 3.96 14.93 4.04 17.75 3.63 17.46 i 2.39 64.67 4.56 66.89 4.77 59.97 t 3.51* RATIOS (%) = (ORGAN WBIGHT/BRAIN WEIGHT) X 100. 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 DOSAGE (MG/KG/DAY) RATS TESTED I 0 N 10 II III 0.3 1 10 10 IV 3 10 V 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 0.396 7.32 0.441 6.93 0.305* 6.99 0.442* HGB (GRAMS/DL) MEAN S.D. 16.5 1.16 15.9 0.42 15.7 0.59* 15.4 t 0.67** 15.6 0.81* HCT (%) MEAN S.D. 43.5 3.48 42.2 1.57 42.0 2.22 40.2 t 2.29** 40.7 1.81* MCV (CU MICRONS) MEAN S.D. 57.9 1.89 57.7 2.27 57.4 1.78 57.9 1.15 58.3 1.37 MCH (PICO GRAMS) MEAN S.D. 22.0 0.87 21.8 1.13 21.5 0.75 22.2 0.45 22.3 0.56 MCHC (%} MEAN S.D. 38.0 0.93 37.7 1.15 37.5 0.79 38.4 i 0.80 38.3 0.70 PLAT (THSN/CU MM) MEAN S.D. 1179 130.9 1131 183.7 1115 149.2 1104 t 91.4 1148 159.9 MPV (CU MICRONS) MEAN S.D. 8.1 0.52 7.9 * Significantly different from the Group I value (pS0.05). ** Significantly different from the Group I value (pSO.Ol). 0.54 8.2 0.72 8.2 t 0.76 8.0 0.59 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 DOSAGE (MG/KG/DAY) 0 RATS TESTED N 10 II III 0.3 1 10 10 IV 3 10 V 10 10 PT (SECONDS) MEAN S.D. 13.4 0.24 14.2 0.27** APTT (SECONDS) MEAN S.D. 21.0 3.09 22.1 4.41 NRBC COUNT MEAN S.D. 0 t 0.0 0 0.0 Lymphocytes (THSN/CU MM) MEAN t S.D. 11.9 1.72 11.0 2.68 Segmented (THSN/CU MM) MEAN S.D. 2.2 0.73 2.9 1.18 Bands (THSN/CU MM) MEAN S.D. 0.0 0.00 0.0 t 0.00 Monocytes (THSN/CU MM) MEAN S.D. 0.8 0.56 0.7 0.50 Eosinophils (THSN/CU MM) MEAN S.D. 0.3 0.20 0.3 0.21 Basophils (THSN/CU MM) MEAN S.D. 0.0 t 0.00 0.0 0.00 Abnormal L (THSN/CU MM) MEAN S.D. 0.1 0 .20 0.1 0.14 Other (THSN/CU MM) MEAN S.D. 0.0 0.00 0.0 * Significantly different from the Group I value (p0.05). ** Significantly different from the Group I value (p<0.01). 0.00 13.6 0.23 20.6 2.38 0 t 0.0 10.8 2.02 2.0 1.06 0.0 0.03 0.6 0.51 0.3 0.21 0.0 0.00 0.1 0.07 0.0 0.00 13.8 0.40* 21.2 2.24 0 0.0 12.1 3.57 2.8 0.73 0.0 0.03 0.8 0.67 0.3 0.26 0.0 0.00 0.2 0.22 0.0 0.00 14.0 0.47** 21.3 1.43 0 0.0 12.4 2.75 1.6 0.78 0.0 i 0.00 0.5 0.33 0.2 0.15 0.0 0.00 0.1 0.21 0.0 0.00 418-028-.PAGEB-10 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 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 93OV<i-8Z0-8It> Segmented Segmented Neutrophils Abnormal L Abnormal Lymphocytes Other Other Cells 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 h i IV V DOSAGE (MG/KG/DAY) 0 0.3 i 3 10 RATS TESTED N 10 10 10 10 10 TP (G/DL) A (G/DL) GLU (MG/DL) CHOL (MG/DL) 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 6.1 0.28 4.1 0.19 141 26.0 41 11.1** 6.3 0.33 4.3 0.15 182 58.2 46 11.6* 6.2 0.28 4.2 t 0.17 162 25.2 43 13.1** 6.3 0.28 4.5 0.20** 165 33.7 33 7.2** TBILI (MG/DL) MEAN S.D. 0.2 0.07 0.1 0.05 0.1 0.06 0.1 0.05 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 CK (U/L) MEAN S.D. 288 172.6 246 ALT (U/L) MEAN S.D. 42 6.0 63 * Significantly different from the Group I value (pSO.05). ** Significantly different from the Group I value (pSO.01). 0.05 111.5 69.9 0.3 0.06 239 112.9 60 34.4 0.3 0.03 196 53.5 95 124.1 0.3 0.05 243 117.4 45 7.0 418-028:PAGE B-12 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 DOSAGE (MG/KG/DAY) RATS TESTED N I 0 10 II III 0.3 1 10 10 IV 3 10 V 10 10 AST (U/L) ALK (U/L) CA (MG/DL) PHOS (MG/DL) MEAN S.D. MEAN S.D. MEAN S.D. MEAN S.D. 96 22.4 105 14.3 10.9 0.48 9.5 1.40 121 92.6 111 36.9 10.7 0.44 9.4 1.11 117 40.9 100 t 12.4 11.1 0.44 9.9 2.09 198 248.7 115 25.1 11.1 0.34 9.7 1.43 97 15.6 144 37.5** 11.5 0.38** 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 t 1.0 146 2.2 K (MMOL/L) MEAN t 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 G (G/DL) MEAN S.D. 2.0 0.19 2.0 0.16 2.0 t 0.24 2.0 A/G (NONE) MEAN S.D. ___ 2_._1___ ____0.18_____ 2.1 -- ** Significantly different from the Group I value rP5o.Ol7. 0.16____ _2;2_____ 0.26 __ 2.2 2.7 100 1.2 0.16 1.8 0.13 0.15____ __2.5 _ 0 17*_* 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 A GLU CHOL TERMINOLOGY Total Protein Albumin Glucose Cholesterol TBILI Total Bilirubin BUN CREAT Blood Urea Nitrogen Creatinine ALT AST ALK CA PHOS TRI NA K Alanine Aminotransferase Aspartate Aminotransferase Alkaline Phosphatase Calcium Phosphorus Triglycerides Sodium Potassium 418-028-.PAGEB-14 CL Chloride G Globulin A/G Albumin/Globulin Ratio 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 DOSAGE (MG/KG/DAY) I 0 RATS TESTED N 15 BODY WEIGHT (G) DAY 1 MEANS.D. 342.7 12.6 DAY 8 MEANS.D. 382.7 22.2 DAY 14a MEANS.D. 407.3 25.4 DAY 29b MEANS.D. 456.6 38.9 DAY 36 MEANS.D. 480.2 38.2 DAY 43 TERMINAL BODY WEIGHT MEANS.D. MEANS.D. 490.5 37.2 472.5 33.9 DAY - DAY OF STUDY a. Last value recorded before cohabitation. b. First value recorded after cohabitation. II 0 .3 15 338.9 13.1 376.1 19.5 400.7 23.7 450.3 30.9 466.5 32.6 475.1 38.3 453.7 34.3 III 1 15 341.9 14.7 380.5 21.6 404.3 29.8 456.6 + 44.6 476.8 47.7 482.5 53.1 463.1 48.2 IV 3 15 345.6 11.2 386.6 21.5 412.9 25.4 468.5 32.0 481.1 33.1 490.5 40.2 468.3 37.1 V 10 15 343.3 12.4 376.7 11.7 397.3 12.3 437.7 15.4 454.1 16.6 462.1 22.0 441.5 16.5 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 0 0 .3 RATS TESTED N 15 15 BODY WEIGHT CHANGE (G) DAYS 1 - 8 MEANS.D. +39.9 12.3 +37.2 11.0 DAYS 8 - 14a MEANS.D. +24.7 6.8 +24.6 5.0 DAYS 1 - 14a MEANS.D. +64.6 16.5 +61.8 14.6 DAYS 29b- 36 MEANS.D. +23.6 8.6 +16.2 7.8 + DAYS 36 - 43 MEANS.D. +10.3 10.8 +8.7 11.2 DAYS 29bTERMINATION MEANS.D. +15.9 11.7 +3.4 7.9** DAYS 1 TERMINATION MEANS.D. +129.8 25.5 +114.8 i 27.5 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 ** Significantly different from the Group I value (p<0.05). (p<0.01). III 1 15 +38.5 10.0 +23.8 11.1 +62.3 18.3 +20.2 5.6 +5.7 14.4 +6.5 10.1* +121.2 37.7 IV 3 15 +41.0 12.1 +26.3 8.2 +67.3 16.3 +12.6 5.4** +9.4 12.9 -0.2 7.7** +122.7 30.0 V 10 15 +33.4 5.6 +20.6 4.8 +54.0 7.0 +16.5 8.4* +7.9 13.7 +3.8 11.8** +98.2 13.9** 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 BIO (PAGE 1) : ABSOLUTE FEED CONSUMPTION VALUES (G/DAY) - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I 0 RATS TESTED N 15 FEED CONSUMPTION (G/DAY) DAYS 1 - 8a MEANS.D. 28.4 3.1 DAYS 29b- 36 MEANS.D. 30.2 2.6 [ 14] C DAYS = DAYS OF STUDY [ ] = NUMBER OF VALDES 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 28.2 1.4 2.2 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 DOSAGE (MG/KG/DAY) I 0 RATS TESTED N 15 FEED CONSUMPTION (G/KG/DAY) DAYS 1 - 8a 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 61.7 4.3 3.7 V 10 15 74.7 63.2 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 MEANtS.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 (100.0) 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 PREGNNT/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) 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 1) : FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) MALE RATS I 0 N 10 II 0.3 10 III 1 10 HOME CAGE BEHAVIOR 1 Sleeping 2 Awake, Immobile 3 Normal movement 4 Unusual posture 5 Unusual behavior N N N N N 2 8 0 0 0 3 7 0 0 0 3 7 0 0 0 ALTERATIONS (HOME CAGE) 1 None 2 Stereotyped behavior 3 Bizarre behavior 4 Limb twitches/tremor 5 Whole body tremor/spasm e Unusual posture 7 Tonic-clonic seizure N N N N N N N 9 la 0 0 0 0 0 10 0 0 0 0 0 0 10 0 0 0 0 0 0 IV 3 10 8** 2** 0 0 0 10 0 0 0 0 0 0 V 10 10 2 8 0 0 0 10 0 0 0 0 0 0 418-028-.PAGEB-20 REACTION TO REMOVAL (1) Sits quietly N 10 10 10 10 (2) Vocalization N0 0 0 0 (3) Runs or freezes N 0 0 0 0 (4) Tail or throat rattles N 0 0 0 0 MEAN SCORE 1.0 1.0 1.0 1.0 10 0 0 0 1.0 REACTION TO HANDLING (1) No resistance N 10 10 10 10 (2) Vocalization N0 0 0 0 10 0 (3) Tense N0 0 0 0 (4) Squirming N0 0 0 0 MEAN SCORE 1.0 1.0 1.0 1.0 0 0 1.0 ! 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 a. Excludes a value for rat 19131, which appeared incorrectly recorded. ** Significantly different from the Group I value (pSO.Ol) . 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 GROUP DOSAGE (MG/KG/DAY) MALE RATS I 0 N 10 II 0.3 10 III 1 10 IV 3 10 V 10 10 REARS IN OPEN FIELD MEANS.D. 3.3 2.5 6.2 3.2 3.9 1.9 4.5 2.1 4.5 3.1 DEFECATION IN OPEN FIELD 1 : None 2 : Feces normal 3: Soft or liquid feces N N N 10 0 0 8 2 0 7 3 0 9 1 0 9 1 0 URINATION IN OPEN FIELD (1) None N6 1 6 2 (2) Normal urination N 4 9 4 8 (3) Excess urination N 0 0 0 0 MEAN SCORE 1.4 1.9 1.4 1.8 3 7 0 1.7 LEVEL OF AROUSAL (1) Stuporous (2) Sluggish (3) Apparently normal (4) Sudden darting (5) Freezing, vocalization N N N N N MEAN SCORE 0 0 10 0 0 3.0 0 0 10 0 0 3.0 0 0 10 0 0 3.0 0 0 10 0 0 3.0 0 0 10 0 0 3.0 418-028:PAGE B-21 ALTERATIONS (OPEN FIELD) 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 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 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 DOSAGE (MG/KG/DAY) 0 0.3 1 MALE RATS N 10 10 10 IV 3 10 V 10 10 GAIT PATTERN 1 : Apparently normal 2: Ataxic 3: Limbs splay or drag 4: Spastic, tip-toe 5: Duck-walk 6: Scissors gait N N N N N N 10 0 0 0 0 0 10 0 0 0 0 0 10 0 0 0 0 0 10 0 0 0 0 0 10 0 0 0 0 0 GAIT ABNORMALITY, SEVERITY (1) Normal gait (2) Slight (3) Moderate (4) Extreme N N N N MEAN SCORE 10 0 0 0 1.0 10 0 0 0 1.0 10 0 0 0 1.0 10 0 0 0 1.0 10 0 0 0 1.0 PALPEBRAL CLOSURE (1) Wide open (2) Slightly drooping (3) Half-closed (4) Completely shut N N N N MEAN SCORE 10 0 0 0 1.0 10 0 0 0 1.0 10 0 0 0 1.0 10 0 0 0 1.0 10 0 0 0 1.0 418-028:PAGE B-22 PROMINENCE OF THE EYE 1 : Normal N 10 10 10 10 10 2 : Exophthalmos N0 0 0 0 0 _3: __Enophthalmos______ ___ N 0 0 0 0 0 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 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 4) : FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) MALE RATS I 0 N 10 II 0.3 10 III 1 10 IV 3 10 V 10 10 LACRIMATION (1) No excess N (2) Excess at eyelid margin N (3) Margin persistently damp N (4) Extends beyond margin N MEAN SCORE 10 0 0 0 1.0 10 0 0 0 1.0 10 0 0 0 1.0 10 0 0 0 1.0 10 0 0 0 1.0 SALIVATION (1) No excess N (2) Margin of mouth wet N (3) 1/4 to 1/2 submandibular N (4) Entire submandibular N MEAN SCORE 10 0 0 0 1.0 10 0 0 0 1.0 10 0 0 0 1.0 10 0 0 0 1.0 10 0 0 0 1.0 PILOERECTION N0 0 0 0 0 ABNORMAL RESPIRATION N 0 0 0 0 0 APPEARANCE (1) Clean and groomed N (2) Unkempt N (3) urine and/or fecal stain N MEAN SCORE 10 0 0 1.0 10 0 0 1.0 10 0 0 1.0 10 0 0 1.0 10 0 0 1.0 VISUAL REACTION (1) None N0 0 0 0 0 (2! Orienting N 10 10 10 10 10 (3) Startle N0 0 0 0 0 (4) More energetic reaction N 0 (5) Attacks N0 MEAN SCORE 2.0 n: * Category number for descriptive test item, 0 0 2.0 0 0 2.0 0 0 2.0 0 0 2.0 (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 418-028:PAGE B-23 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 __ . . . . DOSAGE GROUP ------- I II Ill DOSAGE (MG/KG/DAY) 0 0.3 1 MALE RATS N 10 10 10 IV 3 10 V 10 10 TACTILE REACTION (1) None N (2) Orienting N (3) Startle N (4) More energetic reaction N (5) Attacks N MEAN SCORE 0 10 0 0 0 2.0 0 10 0 0 0 2.0 0 10 0 0 0 2.0 0 10 0 0 0 2.0 0 10 0 0 0 2.0 AUDITORY REACTION (1) None N (2) Orienting N (3) Startle N (4) More energetic reaction N (5) Intense vocalization N MEAN SCORE 0 0 10 0 0 3.0 0 0 10 0 0 3.0 0 0 10 0 0 3.0 0 0 10 0 0 3.0 0 0 10 0 0 3.0 TAIL--PINCH REACTION (1) None N0 0 0 0 0 (2) Orienting N 10 10 10 10 10 (3) Startle N0 0 0 0 0 (4) More energetic reaction N 0 0 0 0 0 (5 Attacks N0 0 0 0 0 MEAN SCORE 2.0 2.0 2.0 2.0 2.0 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 sura of the products by the total number of rats 418-028:PAGE B-24 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 DOSAGE (MG/KG/DAY) 0 0.3 1 MALE RATS N 10 10 10 IV 3 10 V 10 10 AIR RIGHTING RESPONSE (1) All feet land on ground N (2) Lands on side N (3) Lands on back N MEAN SCORE 10 0 0 1.0 10 0 0 1.0 10 0 0 1.0 10 0 0 1.0 10 0 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 49.6 410.5 52.7 451.5 57.5 400.6 62.7 456.0 111.1 409.4 93.7 418.5 125.8 367.5 109.0 406.5 359.2 120.7 104.6 HINDLIMB GRIP TEST Maximum (G) Average (G) MEANS.D. MEANS.D. 386.0 128.8 360.9 121.8 456.0 109.4 400.8 101.1 457.0 102.5 419.5 97.8 414 .5 58.9 364.5 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 BODY WEIGHT (G) N 484.2 34.1 n: * Category number for descriptive test item. 465.5 36.8 477.1 . . . t -- 58.8 493 .2 36.6 461.9 (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 13.0 418-028:PAGEB-25 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 1) : MOTOR ACTIVITY - SUMMARY - FO GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II 0 0.3 NUMBER OF MALE RATS N 10 10 NUMBER OF MOVEMENTS BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK TOTAL 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 MEAN S.D MEAN t S.D MEAN S.D MEAN t S.D MEAN S.D MEAN S.D MEAN t S.D MEAN S.D MEAN t S.D MEAN t S.D MEAN S.D MEAN S.D MEAN S.D MEAN S.D MEAN S.D MEAN S.D MEAN S.D MEAN S.D MEAN S.D 64.8 66.9 69.1 72.3 60.1 48.3 39.4 37.9 27.6 25.0 24.2 37.8 42.1 37.6 23.3 23.6 23.6 22.8 746.4 6.6 9.4 6.8 10.5 12.0 25.4 21.0 i 34.6 25.2 30.2 27.1 28.0 31.9 30.7 26.0 31.2 26.8 24.7 217.7 64.3 63.6 59.8 61.2 54.7 52.8 50.0 46.7 49.2 53.1 35.1 35.1 43.0 43.8 35.5 37.6 39.2 34.4 859.1 t 6.7 t 11.5 t 16.2 20.0 23.1 26.8 25.8 24.8 22.8 20.5 28.3 25.7 34.6 t 29.4 22.3 28.5 30.2 23.6 251.7 TOTAL - SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. III IV 13 10 10 63.5 8.6 64.6 9.0 65.1 8.3 68.2 12.1 65.6 5.4 64.2 12.8 59.8 14.7 54.0 19.9 49.7 23.4 47.0 28.9 51.2 25.5 45.5 25.9 44.0 35.4 36.5 26.3 39.8 36.2 31.2 31.0 29.1 25.9 35.9 i 30.2 914.9 212.7 62.1 t 10.0 73.5 t 4.4 71.6 11.7 65.4 t 11.9 63.1 16.5 59.9 14.9 60.6 t 8.2 57.0 19.4 55.3 20.4 50.0 t 23.1 51.7 26.7 49.1 26.0 50.4 25.6 59.2 19.0 51.3 21.1 50.9 t 22.7 53.5 24.3 42.4 27.0 1027.0 176.0 V 10 10 64.0 8.0 69.6 7.2 67.5 7.8 56.0 + 11.7 56.9 15.6 57.4 9.9 56.8 11.5 49.7 22.2 52.2 16.9 49.6 15.6 41.5 21.2 47.6 13.0 43.0 22.3 43.8 29.6 43.0 25.4 42.5 29.4 37.3 29.6 34.2 23.1 912.6 139.0 418-028:PAGE B-26 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 DOSAGE (MG/KG/DAY) I II 0 0.3 NUMBER OF MALE RATS N 10 10 TIME (SECONDS) SPENT IN MOVEMENT BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK TOTAL 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 MEAN t S.D MEAN S.D MEAN S.D MEAN S.D MEAN S.D MEAN S.D MEAN S.D MEAN S.D MEAN S.D MEAN S.D MEAN S.D MEAN S.D MEAN S.D MEAN S.D MEAN S.D MEAN S.D MEAN S.D MEAN S.D MEAN S.D 201.1 187.4 155.5 141.4 100.7 91.2 70.2 61.3 44.0 48.9 40.2 58.1 66.9 65.6 39.1 31.9 32.0 30.5 1466.0 24.1 22.6 26.2 33.3 28.5 54.3 44.2 60.8 46.2 68.7 59.5 46.2 56.7 58.7 49.7 45.1 38.5 39.6 453.9 201.8 174.4 140.3 138.3 131.1 89.7 90.2 83.7 80.9 86.6 71.4 67.1 86.9 75.7 53.1 55.5 62.5 47.4 1736.6 17.8 32.9 63.3 53.0 t 71.4 52.6 55.5 55.9 40.5 40.3 63.0 60.9 82.2 55.9 46.5 47.5 56.4 46.1 607.9 TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. III 1 10 214.8 195.8 172.5 142.4 150.3 118.4 110.2 109.9 93.6 77.4 86.0 91.7 52.1 54.1 68.0 60.3 46.9 56.3 1900.7 13.0 33.8 35.6 24.7 20.6 41.2 46.9 52.7 59.3 55.3 49.1 62.1 44.8 t 47.4 65.3 73.9 53.5 54.7 t 469.7 IV 3 10 204.6 23.7 180.2 20.9 140.6 27.5 140.9 34.1 119.2 29.0 109.7 48.8 118.6 45.9 116.1 50.9 103.6 56.4 83.1 47.0 97.7 61.8 81.1 49.1 80.2 41.2 107.8 40.9 74.2 35.4 87.2 43.5 91.4 49.7 66.9 43.5 2003.1 453.4 V 10 10 194.8 27.2 170.1 32.5 148.7 39.4 130.9 50.6 113.8 45.7 102.7 40.8 107.9 38.8 72.0 35.9 93.6 47.3 76.8 44.1 67.2 40.0 72.9 33.7 70.5 48.9 73.3 59.7 64.2 36.9 77.1 68.2 51.0 44.8 54.1 41.8 1741.6 463 .' 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 BIS (PAGE 1) : SPERM MOTILITY, COUNT AND DENSITY - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP I II III IV DOSAGE (MG/KG/DAY) 0 0.3 1 3 RATS TESTED N 10 10 10 10 V 10 10 NUMBER MOTILE MEANS.D. 289.1 51.3 307.4 77.3 312.0 80.2 307.3 149.6 325.4 81.5 MOTILE PERCENT MEANS.D. 92.1 3.1 93.3 2.8 92.5 3.4 85.5 22.3 91.1 7.4 STATIC COUNT (NONMOTILE) MEANS.D. 25.2 11.3 23.5 14.4 23.1 7 .B 32.7 15.3 32.4 23.4 TOTAL COUNT a MEANS.D. 314.3 57.7 330.9 89.7 335.1 75.6 340.0 152.4 357.8 81.2 SPERM COUNT b MEANS.D. 170.1 48.8 158.2 55.2 161.0 41.6 124.6 50.2 174.5 37.9 SPERM DENSITY C MEANS.D. 1494.26 440.40 1430.20 458.01 1441.89 344.28 1214.68 407.71 1664.03 370.30 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"s 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. 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 DOSAGE (MG/KG/DAY) RATS TESTED NORMAL DETACHED HEAD NO HEAD BROKEN FLAGELLUM BENT FLAGELLUM PERCENT ABNORMAL N MEANS.D. MEANS.D, MEANS.D. MEANS.D. MEANS.D. MEANlS.D. I 0 10 192.3 3.1 3.7 2.4 3.4 1.7 0.4 0.5 0.2 0.4 3.8 1.5 II 0.3 10 193.3 3.0 3.6 2.2 2.1 1.2 0.8 0.8 0.2 0.4 3.4 1.5 III 1 10 193.3 3.5 3.1 2.0 2.6 1.4 0.7 0.7 0.3 0.7 3.4 1.8 IV 3 10 173.8 59.8 6.8 11.0 10.5 23.1 8.5 24.8 0.4 1.3 13.1 29.9 V 10 10 193.3 3.1 3.8 2.6 1.8 1.3 1.0 0.9 0.1 0.3 3.4 1.6 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/XG/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 19106 19108 19110 19113 19120 19129 19136 19138 19139 19147 19153 19164 19165 19171 DS ( 23 ) DS ( 36- 46) DS { 6 ) DS{ 11 ) DS ( 17- 32) NO ADVERSE FINDINGS CHROMORHINORRHEA 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 LOCALIZED ALOPECIA: LIMBS a NO ADVERSE FINDINGS SOFT OR LIQUID FECES DRY, BROWN PERIORAL SUBSTANCE LOCALIZED ALOPECIA: HEAD DS = DAY OF STUDY a. Observation confirmed at necropsy. 418-028:PAGE B-30 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 19103 19104 19118 19133 19141 19142 19144 19148 19150 19156 19160 19162 19163 19166 DS{ 41 ) DS ( 34- 39) DS ( 34- 42) DS { 34- 46) DS { 19- 32) NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS CHROMORHINORRHEA NO ADVERSE FINDINGS NO ADVERSE FINDINGS INCISORS: MISSING/BROKEN CHROMODACRYORRHEA INCISORS: MISALIGNED a NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: HEAD NO ADVERSE FINDINGS NO ADVERSE FINDINGS DS = DAY OF STUDY a. Observation confirmed at necropsy. 418-028:PAGE B-31 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-770S WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE B17 (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 418-028:PAGE B-32 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 1): NECROPSY OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) RAT NUMBER DAY OF DOSES NECROPSY ADMINISTERED OBSERVATIONS a I 19209 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 B17) for external observations confirmed at necropsy. 418-028:PAGE B-33 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 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. 418-028:PAGE B-34 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 DOSAGE (MG/KG/DAY) RAT NUMBER DAY OF DOSES NECROPSY ADMINISTERED OBSERVATIONS a III 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. 418-028:PAGE B-35 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. 418-028:PAGE B-36 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) RAT NUMBER DAY OF DOSES NECROPSY ADMINISTERED OBSERVATIONS a V 10 19111 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 Refer to the individual clinical observations table (Table B17) for external observations confirmed at necropsy. 418-028:PAGE B-37 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-770G.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 19115 19116 19119 19122 19125 19131 19132 19134 19135 438. 466. 490. 505. 451. 508. 499. 439. 419. 482. 0.6013 0.6976a 0.6499 0.6541 0.6661 0.6160 0.6482 0.7103 0.6278 0.6052 0.14 0.15 0.13 0.13 0.15 0.12 0.13 0.16 0.15 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 1.5706 1.6971 1.6213 1.7174 1.6754 1.6621 1.6865 1.8079 1.4801 1.6728 0.36 0.36 0.33 0.34 0.37 0.33 0.34 0.41 0.35 0.35 1.3331 2.1021 1.5369 1.6464 1.9375 1.6300 1.5772 1.9409 1.8240 1.5266 0.30 0.45 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 0.7252 0.6497 0.6728 0.7436 0.6362 0.6767 0.7249 0.6540 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 19115 19116 19119 19122 19125 19131 19132 19134 19135 438. 466. 490. 505. 451. 508. 499. 439. 419. 482. 1.6529 1.6847 1.6820 1.6364 1.6956 1.6796 1.6534 1.8532 1.4818 1.7570 0.38 0.36 0.34 0.32 0.38 0.33 0.33 0.42 0.35 0.36 1.1854 1.4274 1.5838 0.7632 1.0942 1.1823 1.2496 1.8597 1.3858 1.1710 0.27 0.31 0.32 0.15 0.24 0.23 0.25 0.42 0.33 0.24 2.29 2.27 2.28 2.63 2.45 2.44 2.45 2.34 2.35 2.45 0.52 0.49 0.46 0.52 0.54 0.48 0.49 0.53 0.56 0.51 14.18 16.71 15.18 14.66 13.10 16.13 16.94 11.94 12.01 15.48 3.24 3.58 3.10 2.90 2.90 3.18 3.39 2.72 2.87 3.21 1.51 1.99 2.16 2.26 1.92 2.31 2.13 1.78 1.76 2.00 0.34 0.43 0.44 0.45 0.42 0.45 0.43 0.40 0.42 0.41 1.51 1.99 2.12 2.38 1.81 2.29 2.22 1.89 1.84 2.15 0.34 0.43 0.43 0.47 0.40 0.45 0.44 0.43 0.44 0.45 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . ABS. WT. - ORGAN WEIGHT. a. Damaged during processing (weight not affected). REL. %TBW (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. 418-028:PAGE B-38 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OP 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 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 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 438. 466. 490. 505. 451. 508. 499. 439. 419. 482. 0.027 0.041 0.035 0.048 0.033 0.034 0.041 0.036 0.024 0.031 6.16 8.80 7.14 9.50 7.32 6.69 8.22 8.20 5.73 6.43 0.027 0.040 0.035 0.046 0.031 0.031 0.036 0.038 0.025 0.030 6.16 8.58 7.14 9.11 6.87 6.10 7.21 8.66 5.97 6.22 0.56 0.77 0.95 0.79 0.79 0.76 1.03 0.73 0.60 0.90 0.13 0.16 0.19 0.16 0.18 0.15 0.21 0.17 0.14 0.19 0.37 0.41 0.49 0.30 0.33 0.70 0.47 0.27 0.44 0.33 0.08 0.09 0.10 0.06 0.07 0.14 0.09 0.06 0.10 0.07 1.41 1.62 1.51 1.62 1.68 1.54 1.67 1.40 1.46 1.63 0.32 0.35 0.31 0.32 0.37 0.30 0.33 0.32 0.35 0.34 ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Value was multiplied by 1000. ABS. WT. = ORGAN WEIGHT. REL. % TBW - (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 10O. 418-028:PAGE B-39 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 19106 19108 19110 19113 19120 19129 19136 19138 19139 428. 476. 474. 453. 444. 486. 435. 495. 365. 432. 1.5930 1.6779 1.9171 1.4694 1.7350 1.6765 1.8164 1.8039 1.7840 1.8078 0.37 0.35 0.40 0.32 0.39 0.34 0.42 0.36 0.49 0.42 1.2374 1.0360 1.1892 1.1812 1.2130 1.4290 1.1232 1.3313 0.9939 1.2660 0.29 0.22 0.25 0.26 0.27 0.29 0.26 0.27 0.27 0.29 2.19 2.57 2.52 2.42 2.58 2.38 2.45 2.41 2.46 2.40 0.51 0.54 0.53 0.53 0.58 0.49 0.56 0.49 0.67 0.56 14.53 17.19 14.75 13.95 13.08 14.26 13.37 15.75 11.25 14.10 3.39 3.61 3.11 3.08 2.94 2.93 3.07 3.18 3.08 3.26 1.92 1.97 1.90 1.96 1.96a 1.72 1.89 1.83 1.58 1.88 0.45 0.41 0.40 0.43 0.44 0.35 0.43 0.37 0.43 0.44 1.95 2.00 1.98 2.00 2.11 1.76 1.90 1.69 1.66 1.93 0.46 0.42 0 .42 0.44 0.48 0.36 0.44 0.34 0.45 0.45 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 le ft kidney. See the individual necropsy observations table (Table B18). 418-028:PAGE B-40 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 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 19106 19108 19110 19113 19120 19129 19136 19138 19139 428. 476. 474 . 453. 444. 486. 435. 495. 365. 432. 0.041 0.024 0.030 0.037 0.046 0.042 0.037 0.033 0.028 0.032 9.58 5.04 6.33 8.17 10.36 8.64 8.50 6.67 7.67 7.41 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Value was multiplied by 1000. 0.038 0.024 0.030 0.038 0.044 0.038 0.034 0.034 0.027 0.032 8.88 5.04 6.33 8.39 9.91 7.82 7.82 6.87 7.40 7.41 0.89 0.86 0.73 0.85 0.81 0.83 0.76 0.72 0.73 0.92 0.21 0.18 0.15 0.19 0.18 0.17 0.17 0.14 0.20 0.21 0.52 0.42 0.47 0.41 0.48 0.40 0.34 0.58 0.30 0.54 0.12 0.09 0.10 0.09 0.11 0.08 0.08 0.12 0.08 0.12 1.38 1.56 1.64 1.59 1.47 1.56 1.55 1.71 1.30 1.46 0.32 0.33 0.34 0.35 0.33 0.32 0.36 0.34 0.36 0.34 ABS. WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. 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. RBL. 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 19105 19107 19112 19114 19121 19123 19130 19137 19146 353. 505. 437. 452. 430. 567. 464. 434 . 443. 473. 1.5806 2.0016 1.5096 1.6041 1.4506 1.7745 1.8031 1.8184 1.6928 1.6866 0.45 0.40 0.34 0.35 0.34 0.31 0.39 0.42 0.38 0.36 0.8460 1.5220 1.5754 1.3786 1.1497 1.0712 0.9914 1.6000 1.0622 1.0704 0.24 0.30 0.36 0.30 0.27 0.19 0.21 0.37 0.24 0.23 2.22 2.40 2.35 2.41 2.3$ 2.54 2.43 2.37 2.45 2.26 0.63 0.48 0.54 0.53 0.55 0.45 0.52 0.55 0.55 0.48 11.34 17.13 13.84 14.51 14.34 23.98 19.27 13.79 14.59 16.57 3.21 3.39 3.17 3.21 3.33 4.23 4.15 3.18 3.29 3.50 1.50 2.37 1.71 2.09 1.84 2.20 2.17 1.88 1.88 1.94 0.42 0.47 0.39 0.46 0.43 0.39 0.47 0.43 0.42 0.41 1.56 2.29 1.71 1.97 1.92 2.25 2.22 1.98 2.14 2.01 0.44 0.45 0.39 0.44 0.45 0.40 0.48 0.46 0.48 0.42 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . ABS. WT. = ORGAN WEIGHT. a. Damaged during processing (weight not affected). REL. %TBW= (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. 418-028:PAGE B-42 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 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 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 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 353. 505. 437. 452. 430. 567. 464 . 434. 443 . 473. 0.028 0.034 0.039 0.026 0.033 0.032 0.040 0.030 0.032 0.042 7.93 6.73 8.92 5.75 7.67 5.64 8.62 6.91 7.22 8.88 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Value was multiplied by 1000. 0.026 0.027 0.038 0.022 0.031 0.035 0.025 0.033 0.019 0.043 7.36 5.35 8.70 4.87 7.21 6.17 5.39 7.60 4.29 9.09 0.55 0.74 0.69 0.65 0.68 0.92 0.78 0.87 0.91 0.80 0.16 0.15 0.16 0.14 0.16 0.16 0.17 0.20 0.20 0.17 0.23 0.47 0.26 0.55 0.32 0.44 0.40 0.33 0.29 0.28 0.06 0.09 0.06 0.12 0.07 0.08 0.09 0.08 0.06 0.06 1.33 1.66 1.36 1.48 1.52 1.70 1.56 1.48 1.65 1.65 0.38 0.33 0.31 0.33 0.35 0.30 0.34 0.34 0.37 0.35 ABS. WT. = ORGAN WEIGHT. REL. %TBW- (ORGAN NEIGHT/TERMINAL BODY WEIGHT) X 100. 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 19103 19104 19118 19133 19141 19142 19144 19148 19150 421. 487. 476. 442. 448 . 545. 479. 523. 454. 448. 1.7274 1.7657 1.7025 1.6129 1.7045 1.7406 0.6700a 1.6766 1.8681 1.7068 0.41 0.36 0.36 0.36 0.38 0.32 0.14 0.32 0.41 0.38 1.5079 1.4347 1.2209 1.3183 1.2429 1.0238 1.0863 1.1080 1.4524 1.3391 0.36 0.29 0.26 0.30 0.28 0.19 0.23 0.21 0.32 0.30 2.40 2.39 2.43 2.42 2.47 2.52 2.23 2.40 2.24 2.35 0.57 0.49 0.51 0.55 0.55 0.46 0.46 0.46 0.49 0.52 15.67 19.28 17.78 15.97 15.06 20.42 17.61 18.23 18.08 17.94 3.72 3.96 3.74 3.61 3.36 3.75 3.68 3.48 3.98 4.00 1.82 2.40 1.98 1.90 2.08 2.18 2.00 2.21 1.91 1.97 0.43 0.49 0.42 0.43 0.46 0.40 0.42 0.42 0.42 0.44 1.91 2.39 2.16 2.12 2.24 2.20 2.07 2.36 1.92 1.92 0.45 0.49 0.45 0.48 0.50 0.40 0.43 0.45 0.42 0.43 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 le ft cauda epididymis. See the individual necropsy observations table (Table B18). 418-028:PAGE B-44 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 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 19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 421. 487. 476. 442. 448. 545. 479. 523. 454 . 448. 0.028 0.040 0.030 0.030 0.043 0.024 0.028 0.037 0.028 0.037 6.65 8.21 6.30 6.79 9.60 4.40 5.84 7.07 6.17 8.26 0.032 0.046 0.026 0.032 0.041 0.030 0.028 0.032 0.026 0.026 7.60 9.44 5.46 7.24 9.15 5.50 5.84 6.12 5.73 5.80 0.86 0.88 1.10 0.69 0.74 1.15 0.74 1.15 0.78 0.67 0.20 0.18 0.23 0.16 0.16 0.21 0.15 0.22 0.17 0.15 0.40 0.39 0.40 0.37 0.36 0.57 0.48 0.34 0.35 0.57 0.10 0.08 0.08 0.08 0.08 0.10 0.10 0.06 0.08 0.13 1.42 1.56 1.64 1.44 1.60 1.84 1.54 1.74 1.55 1.62 0.34 0.32 0.34 0.32 0.36 0.34 0.32 0.33 0.34 0.36 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Value was multiplied by 1000. ABS. WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. 418-028:PAGE B-45 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 VESICLES WITH FLUID ABS. REL. WT. % 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. WT. REL. % 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 19117 19124 19126 19127 19128 19140 19145 19149 19152 432. 462. 426. 426. 434. 445. 442. 441. 439. 461. 1.7246 1.6160 1.8910 1.6044 1.7997 1.5952 1.6407 1.8340 1.9989 1.8997 0.40 0.35 0.44 0.38 0.41 0.36 0.37 0.42 0.46 0.41 1.0515 1.0954 1.5146 0.7260 1.4010 0.9706 1.2239 1.3756 1.2522 1.3077 0.24 0.24 0.36 0.17 0.32 0.22 0.28 0.31 0.28 0.28 2.48 2.43 2.38 2.28 2.62 2.31 2.42 2.40 2.38 2.34 0.57 0.52 0.56 0.54 0.60 0.52 0.55 0.54 0.54 0.51 24.36 24.11 25.72 22.94 27.38 21.74 20.21 23.20 20.06 18.58 5.64 5.22 6.04 5.38 6.31 4.88 4.57 5.26 4.57 4.03 2.00 2.22 2.21 2.04 1.90 1.78 1.93 2.27 1.76 1.97 0.46 0.48 0.52 0.48 0.44 0.40 0.44 0.51 0.40 0.43 2.13 2.26 2.18 2.04 1.95 1.82 1.88 2.16 1.92 2.07 0.49 0.49 0.51 0.48 0.45 0.41 0.42 0.49 0.44 0.45 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . ABS. WT. = ORGAN WEIGHT. a. Damaged during processing (weight not affected). REL. %TBW= (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. 418-028:PAGE B-46 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 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 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 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 432. 462. 426. 426. 434. 445. 442. 441. 439. 461. 0.025 0.030 0.035 0.029 0.031 0.036 0.036 0.034 0.029 0.036 5.79 6.49 8.22 6.81 7.14 8.09 8.14 7.71 6.60 7.81 ALL WEIGHTS WERE RECORDED IN GRAMS (G) a. Value was multiplied by 1000. 0.024 0.014 0.034 0.028 0.031 0.034 0.028 0.033 0.030 0.038 5.56 3.03 7.98 6.57 7.14 7.64 6.33 7.48 6.83 8.24 0.73 0.75 0.72 0.64 0.81 0.74 0.86 0.88 0.97 0.70 0.17 0.16 0.17 0.15 0.19 0.17 0.19 0.20 0.22 0.15 0.37 0.36 0.36 0.47 0.47 0.40 0.44 0.38 0.43 0.51 0.08 0.08 0.08 0.11 0.11 0.09 0.10 0.09 0.10 0.11 1.38 1.60 1.40 1.38 1.43 1.42 1.50 1.36 1.46 1.47 0.32 0.35 0.33 0.32 0.33 0.32 0.34 0.31 0.33 0.32 ABS. WT ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. 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. t 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 26.26 0.6976a 30.73 0.6499 28.50 0.6541 24.87 0.6661 27.19 0.6160 25.24 0.6482 26.46 0.7103 30.35 0.6278 26.71 0.6052 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 27.58 0.7252 31.95 0.6497 28.50 0.6728 25.58 0.7436 30.35 0.6362 26.07 0.6767 27.62 0.7249 30.98 0.6540 27.83 0.6302 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 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 1.6529 1.6847 1.6820 1.6364 1.6956 1.6796 1.6534 1.8532 1.4818 1.7570 72.18 74.22 73.77 62.22 69.21 68.84 67.48 79.20 63.06 71.71 1.1854 1.4274 1.5838 0.7632 1.0942 1.1823 1.2496 1.8597 1.3858 1.1710 51.76 62.88 69.46 29.02 44 .66 48.45 51.00 79.47 58.97 47.80 14.18 16.71 15.18 14.66 13.10 16.13 16.94 11.94 12.01 15.48 619.21 736.12 665.79 557.41 534.69 661.06 691.43 510.26 511.06 631.84 1.51 1.99 2.16 2.26 1.92 2.31 2.13 1.78 1.76 2.00 65.94 87.66 94.74 85.93 78.37 94.67 86.94 76.07 74.89 81.63 1.51 1.99 2.12 2.38 1.81 2.29 2.22 1.89 1.84 2.15 65.94 87.66 92.98 90.49 73.88 93.85 90.61 80.77 78.30 87.76 0.027 0.041 0.035 0.048 0.033 0.034 0.041 0.036 0.024 0.031 ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. = ORGAN WEIGHT. a. Damaged during processing (weight not affected). REL. %TBW= (ORGAN WEIGHT/BRAIN WEIGHT) X 100. 1.18 1.81 1.54 1.82 1.35 1.39 1.67 1.54 1.02 1.26 418-028:PAGE B-48 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 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 0.027 0.040 0.035 0.046 0.031 0.031 0.036 0.038 0.025 0.030 1.18 1.76 1.54 1.75 1.26 1.27 1.47 1.62 1.06 1.22 0.56 0.77 0.95 0.79 0.79 0.76 1.03 0.73 0.60 0.90 24.45 33.92 41.67 30.04 32.24 31.15 42.04 31.20 25.53 36.73 0.37 0.41 0.49 0.30 0.33 0.70 0.47 0.27 0.44 0.33 16.16 18.06 21.49 11.41 13.47 28.69 19.18 11.54 18.72 13.47 1.41 1.62 1.51 1.62 1.68 1.54 1.67 1.40 1.46 1.63 61.57 71.36 66.23 61.60 68.57 63.11 68.16 59.83 62.13 66.53 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . ABS. WT. > ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. 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 31 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 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 1.5930 1.6779 1.9171 1.4694 1.7350 1.6765 1.8164 1.8039 1.7840 1.8078 72.74 65.29 76.08 60.72 67.25 70.44 74.14 74.85 72.52 75.32 1.2374 1.0360 1.1892 1.1812 1.2130 1.4290 1.1232 1.3313 0.9939 1.2660 56.50 40.31 47.19 48.81 47.02 60.04 45.84 55.24 40.40 52.75 14.53 17.19 14.75 13.95 13.08 14.26 13.37 15.75 11.25 14.10 663.47 668.87 585.32 576.45 506.98 599.16 545.71 653.53 457.32 587.50 1.92 1.97 1.90 1.96 1.96a 1.72 1.89 1.83 1.58 1.88 87.67 76.65 75.40 80.99 75.97 72.27 77.14 75.93 64.23 78.33 1.95 2.00 1.98 2.00 2.11 1.76 1.90 1.69 1.66 1.93 89.04 77.82 78.57 82.64 81.78 73.95 77.55 70.12 67.48 80.42 0.041 0.024 0.030 0.037 0.046 0.042 0.037 0.033 0.028 0.032 1.87 0.93 1.19 1.53 1.78 1.76 1.51 1.37 1.14 1.33 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 le ft kidney. See the individual necropsy observations table (Table B18) . OS-HHOVd;8ZO-8W 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 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 0.038 0.024 0.030 0.038 0.044 0.038 0.034 0.034 0.027 0.032 1.74 0.93 1.19 1.57 1.70 1.60 1.39 1.41 1.10 1.33 0.89 0.86 0.73 0.85 0.81 0.83 0.76 0.72 0.73 0.92 40.64 33.46 28.97 35.12 31.40 34.87 31.02 29.88 29.67 38.33 0.52 0.42 0.47 0.41 0.48 0.40 0.34 0.58 0.30 0.54 23.74 16.34 18.65 16.94 18.60 16.81 13.88 24.07 12.20 22.50 1.38 1.56 1.64 1.59 1.47 1.56 1.55 1.71 1.30 1.46 63.01 60.70 65.08 65.70 56.98 65.55 63.26 70.95 52.84 60.83 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . ABS. WT. = ORGAN WEIGHT. REL. % TBW (ORGAN WEIGHT/BRAIN WEIGHT) X 100. 418-028:PAGEB-51 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/DY RAT NUMBER BRAIN WEIGHT EPIDIDYMIS LEFT ABS. REL. WT. 1 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 27.12 0.7012 29.22 0.53S5a 22.79 0.6158 25.55 0.5678 24.06 0.6466 25.46 0.6675 27.47 0.6775 28.59 0.6420 26.20 0.6207 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. t 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 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 1.5806 2.0016 1.5096 1.6041 1.4506 1.7745 1.8031 1.8184 1.6928 1.6866 71.20 83.40 64.24 66.56 61.47 69.86 74.20 76.72 69.09 74.63 0.8460 1.5220 1.5754 1.3786 1.1497 1.0712 0.9914 1.6000 1.0622 1.0704 38.11 63.42 67.04 57.20 48.72 42.17 40.80 67.51 43.36 47.36 11.34 17.13 13.84 14.51 14.34 23.98 19.27 13.79 14.59 16.57 510.81 713.75 588.94 602.07 607.63 944.09 793.00 581.86 595.51 733.18 1.50 2.37 1.71 2.09 1.84 2.20 2.17 1.88 1.88 1.94 67.57 98.75 72.76 86.72 77.97 86.61 89.30 79.32 76.73 85.84 1.56 2.29 1.71 1.97 1.92 2.25 2.22 1.98 2.14 2.01 70.27 95.42 72.76 81.74 81.36 88.58 91.36 83.54 87.35 88.94 0.028 0.034 0.039 0.026 0.033 0.032 0.040 0.030 0.032 0.042 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . ABS. WT. - ORGAN WEIGHT. a. Damaged during processing (weight not affected). REL. %TBW= (ORGAN WEIGHT/BRAIN WEIGHT) X 100. 1.26 1.42 1.66 1.08 1.40 1.26 1.65 1.26 1.31 1.86 418-028:PAGE B-52 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 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 0.026 0.027 0.038 0.022 0.031 0.035 0.025 0.033 0.019 0.043 1.17 1.12 1.62 0.91 1.31 1.38 1.03 1.39 0.78 1.90 0.55 0.74 0.69 0.65 0.68 0.92 0.78 0.87 0.91 0.80 24.77 30.83 29.36 26.97 28.81 36.22 32.10 36.71 37.14 35.40 0.23 0.47 0.26 0.55 0.32 0.44 0.40 0.33 0.29 0.28 10.36 19.58 11.06 22.82 13.56 17.32 16.46 13.92 11.84 12.39 1.33 1.66 1.36 1.48 1.52 1.70 1.56 1.48 1.65 1.65 59.91 69.17 57.87 61.41 64.41 66.93 64.20 62.45 67.35 73.01 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . ABS. WT. ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. 418-028:PAGE B-53 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. <t 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 27.97 0.6486 27.14 0.6201 25.52 0.5834 24.11 0.5667 22.94 0.6531 25.92 0.3058a 13.71 0.5626 23.44 0.6884 30.73 0.6161 26.22 0.3355 13.98 0.2909 12.17 0.2961 12.18 0.3022 12.49 0.2961 11.99 0.3098 12.29 0.1333a 5.98 0.2529 10.54 0.3851 17.19 0.3111 13.24 1.7129 71.37 1.6530 69.16 1.7770 73.13 1.5495 64.03 1.7262 69.89 1.7814 70.69 0.6988a 31.34 1.6357 68.15 1.8767 83.78 1.7049 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 29.04 0.6457 27.02 0.5846 24.06 0.6169 25.49 0.5492 22.23 0.6801 26.99 0.3002a 13.46 0.6547 27.28 0.7389 32.99 0.6388 27.18 RAT NUMBER BRAIN WEIGHT TESTIS RIGHT ABS. REL. WT. 1It 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 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 1.7274 71.98 1.7657 73.88 1.7025 70.06 1.6129 66.65 1.7045 69.01 1.7406 69.07 0.6700a 30.04 1.6766 69.86 1.8681 83.40 1.7068 72.63 1.5079 1.4347 1.2209 1.3183 1.2429 1.0238 1.0863 1.1080 1.4524 1.3391 62.83 60.03 50.24 54 .48 50.32 40.63 48.71 46.17 64.84 56.98 15.67 19.28 17.78 15.97 15.06 20.42 17.61 18.23 18.08 17.94 652.92 806.69 731.69 659.92 609.72 810.32 789.69 759.58 807.14 763.40 1.82 2.40 1.98 1.90 2.08 2.18 2.00 2.21 1.91 1.97 75.83 100.42 81.48 78.51 84.21 86.51 89.69 92.08 85.27 83.83 1.91 2.39 2.16 2.12 2.24 2.20 2.07 2.36 1.92 1.92 79.58 100.00 88.89 87.60 90.69 87.30 92.82 98.33 85.71 81.70 0.028 0.040 0.030 0.030 0.043 0.024 0.028 0.037 0.028 0.037 1.17 1.67 1.23 1.24 1.74 0.95 1.26 1.54 1.25 1.57 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . ABS. WT. - ORGAN WEIGHT. a. Rat 19142 had small testes, epididymides and left cauda epididymis. (Table B18). REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. See the individual necropsy observations table 418-028-.PAGEB-54 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 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 0.032 0.046 0.026 0.032 0.041 0.030 0.028 0.032 0.026 0.026 1.33 1.92 1.07 1.32 1.66 1.19 1.26 1.33 1.16 1.11 0.86 0.88 1.10 0.69 0.74 1.15 0.74 1.15 0.78 0.67 35.83 36.82 45.27 28.51 29.96 45.63 33.18 47.92 34.82 28.51 0.40 0.39 0.40 0.37 0.36 0.57 0.48 0.34 0.35 0.57 16.67 16.32 16.46 15.29 14.57 22.62 21.52 14.17 15.62 24.26 1.42 1.56 1.64 1.44 1.60 1.84 1.54 1.74 1.55 1.62 59.17 65.27 67.49 S9.50 64.78 73.02 69.06 72.50 69.20 68.94 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . ABS. WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. 418-028-.PAGEB-55 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 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 EPIDIDYMIS LEFT ABS. REL. WT. % BRW CAUDA EPIDIDYMIS LEFT ABS. REL. WT. % BRW 0.5886 23.73 0.5554a 22.86 0.7041 29.58 0.5648 24.77 0.5950 22.71 0.5787 25.05 0.6181 25.54 0.6705 27.94 0.6384 26.82 0.6200 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 TESTIS LEFT ABS. REL. WT. % BRW SEMINAL VESICLES WITH FLUID ABS. REL. WT. % BRW SEMINAL VESICLES WITHOUT FLUID ABS. REL. WT. % BRW 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 EPIDIDYMIS RIGHT ABS. REL. WT. % BRW 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. )r 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 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 1.7246 1.6160 1.8910 1.6044 1.7997 1.5952 1.6407 1.8340 1.9989 1.8997 69.54 66.50 79.45 70.37 68.69 69.06 67.80 76.42 83.99 81.18 1.0515 1.0954 1.5146 0.7260 1.4010 0.9706 1.2239 1.3756 1.2522 1.3077 42.40 45.08 63.64 31.84 53.47 42.02 50.57 57.32 52.61 55.88 24.36 24.11 25.72 22.94 27.38 21.74 20.21 23.20 20.06 18.58 982.26 992.18 1080.67 1006.14 1045.04 941.12 835.12 966.67 842.86 794.02 2.00 2.22 2.21 2.04 1.90 1.78 1.93 2.27 1.76 1.97 80.64 91.36 92.86 89.47 72.52 77.06 79.75 94.58 73.95 84.19 2.13 2.26 2.18 2.04 1.95 1.82 1.88 2.16 1.92 2.07 85.89 93.00 91.60 89.47 74.43 78.79 77.68 90.00 80.67 88.46 0.025 0.030 0.035 0.029 0.031 0.036 0.036 0.034 0.029 0.036 ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. = ORGAN WEIGHT. a. Damaged during processing (weight not affected). REL. %TBW= (ORGAN WEIGHT/BRAIN WEIGHT) X 100. 1.01 1.23 1.47 1.27 1.18 1.56 1.49 1.42 1.22 1.54 418-028:PAGE B-56 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 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 0.024 0.014 0.034 0.028 0.031 0.034 0.028 0.033 0.030 0.038 0.97 0.58 1.43 1.23 1.18 1.47 1.16 1.38 1.26 1.62 0.73 0.75 0.72 0.64 0.81 0.74 0.86 0.88 0.97 0.70 29.44 30.86 30.25 28.07 30.92 32.03 35.54 36.67 40.76 29.91 0.37 0.36 0.36 0.47 0.47 0.40 0.44 0.38 0.43 0.51 14.92 14.81 15.13 20.61 17.94 17.32 18.18 15.83 18.07 21.79 1.38 1.60 1.40 1.38 1.43 1.42 1.50 1.36 1.46 1.47 55.64 65.84 58.82 60.53 54.58 61.47 61.98 56.67 61.34 62.82 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . ABS. WT. ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. 418-028:PAGEB-57 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 DAY 1 2 3 4 5 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. DAY 17 18 19 20 21 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 19143 19151 19157 19161 19167 390. 429. 413. 455. 396. 435. 417. 384. 371. 426. 392. 411. 394. 463 . 410. 391. 442. 422. 463. 399. 434. 432. 392. 377. 432. 393. 413. 397. 468. 409. 392. 443 . 420. 470. 399. 442. 425. 393. 377. 430. 400. 408. 396. 474. 419. 398. 451. 425. 476. 405. 448. 438. 410. 380. 440. 406. 423. 410. 483. 425. 400. 449. 431. 478. 406. 452. 435. 415. 385. 437. 408. 424. 405. 488. 422. DAY - DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Last value recorded before cohabitation. b. First value recorded after cohabitation. 6 352. 388. 378. 394. 346. 392. 384. 356. 356. 391. 358. 378. 362. 411. 365. 22 398. 455. 432. 485. 409. 452. 440. 406. 381. 440. 407. 428. 409. 499. 378. 0 MG/KG/DAY 7 8 9 10 357. 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. 23 24 25 26 396. 458. 442. 483. 413. 465. 447. 407. 381. 442. 413. 430. 411. 502. 368. 403. 460. 448. 492 . 420. 471. 450. 406. 387. 446. 414. 434. 420. 508. 363. 406. 465. 448. 494. 419. 478. 456. 418. 388. 449. 417. 446. 424. 517. 373. 409. 463. 452. 504. 421. 482. 458. 420. 394. 453. 426. 445. 429. 518. 389. 11 370. 412. 402. 431. 372. 428. 407. 363. 370. 408. 381. 400. 378. 436. 388. 27 420. 462. 461. 513. 426. 486. 470. 424. 396. 464. 432. 450. 432. 532. 396. 12 13 14a 15 16 374. 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. 28 29b 30 31 32 420. 453. 469. 511. 432. 489. 470. 426. 404 . 465. 440. 452. 409. 539. 405. 421. 472. 462. 504. 432. 491. 479. 428. 404. 468. 435. 463. 438. 546. 406. 427. 469. 466. 510. 434. 493. 479. 428. 406. 469. 440. 461. 434 . 544 . 414. 430. 479. 476. 518. 440. 500. 484. 431. 415. 470. 444. 457. 439. 548. 398. 435. 472. 479. 516. 441, 498. 494. 438 . 419. 477. 453. 464. 441. 555. 421. 418-028:PAGE B-58 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 37 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. 451. 490. 490. 523. 458. 527. 512. 450. 438. 504. 472. 481. 458. 567. 445. DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . 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 44 45 438. 466. 509. 538. 474. 534. 528 . 463. 436. 504 . 491. 482. 478. 559. 458. 490 . 505. 451. 543. 530. 474. 446. 511. 493. 490. 483 . 569. 458. 508. 499. 439. 445. 509. 495. 500. 491. 575. 462. 46 419. 482. 499. 503. 486. 583. 472. 47 469. 470. 462. 549. 441. 418-028:PAGE B-59 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 DAY 1 2 3 4 5 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. DAY 17 18 19 20 21 19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 19147 19153 19164 19165 19171 375. 438. 429. 404. 396. 433. 402. 420. 340. 385. 396. 418. 411. 406. 384. 382. 444. 435. 410. 396. 441. 408. 429. 343. 392. 403. 425. 423. 412. 393. 389. 443. 436. 418. 406. 438. 408. 435. 346. 395. 412. 423. 429. 411. 386. 396. 446. 446. 422. 408. 447. 411. 440. 353. 403. 419. 433. 433. 422. 399. 399. 452. 442. 420. 412. 451. 417. 446. 358. 407. 420. 439. 442. 429. 395. DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Last value recorded before cohabitation. b. First value recorded after cohabitation. 0.3 MG/KG/nAY 6789 339. 398. 386. 385. 362. 387. 368. 389. 328. 366. 362. 371. 362. 359. 367. 348. 400. 389. 385. 368. 389. 367. 3 92. 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. 22 23 24 25 396. 453. 439. 423. 410. 454. 417. 446. 352 . 406. 428. 444. 439. 424. 396. 403 . 457. 444. 437. 417. 458. 424 . 454. 353 . 410. 430. 444. 453. 434. 401. 407. 459. 447. 431. 423. 457. 425. 455. 360. 412. 432. 449. 454. 434. 406. 411. 467. 451. 439. 421. 459. 429. 458. 360. 416. 434. 450. 453. 442. 408. 10 11 362. 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. 26 27 415. 469. 456. 442 . 429. 467. 430. 465. 364. 419. 445. 457. 451. 448. 411. 421. 470. 461. 444. 433. 477. 433. 472. 370. 424. 447. 463. 463. 454. 415. 12 370. 432. 417. 404. 388. 414. 387. 413. 338. 385. 389. 398. 399. 392. 372. 28 413. 476. 464. 447. 434. 479. 436. 480. 368. 430. 452. 469. 470. 459. 412. 13 365. 433. 422. 410. 396. 421. 392. 426. 344. 388. 397. 405. 404. 400. 378. 29b 424. 484. 471. 450. 436. 483. 445. 480. 371. 427. 459. 473. 472. 460. 419. 14a 15 16 366. 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. 30 31 32 426. 485. 466. 453 . 442. 481. 440. 481. 372. 432. 452. 470. 465. 455. 423. 430. 489. 483. 454. 447. 486. 449. 487. 372 . 433 . 462. 480. 476. 462. 423. 431. 482. 478. 461. 449. 490. 448 . 491. 380. 433. 466. 481. 480. 468. 423. 418-028:PAGE B-60 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 37 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. 455. 499. 489. 462. 458. 509. 450. 513. 389. 451. 478. 495. 501. 470. 428. DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . 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 44 45 428. 476. 498. 480. 468. 517. 459. 534. 388. 458. 481. 504. 516. 486. 434 . 474. 453 . 444. 524. 466. 537. 389. 462. 496. 511. 512. 490. 443. 486. 435. 495. 396. 464. 499. 513. 517. 489. 444. 46 47 365. 432. 498. 506. 521. 492. 453 . 470. 487. 484 . 455. 421. 418-028-.PAGEB-61 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 Ill DAY 1 2 3 4 5 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. DAY 17 18 19 20 21 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 19155 19159 19172 19173 19174 326. 430. 415. 407. 366. 474. 414. 389. 401. 409. 401. 416. 435. 426. 388. 337. 443. 413. 415 . 367. 480. 418. 393. 402 . 419. 405. 409. 440. 430. 388. 333. 454. 415. 415. 374. 488. 426. 397. 404. 426. 409. 417. 447. 432. 396. 340. 453. 424. 423. 370. 499. 433. 405. 406. 428. 416. 417. 456. 436. 401. 343. 455. 432. 424. 381. 502. 439. 406. 410. 435. 418. 428. 461. 442. 406. DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Last value recorded before cohabitation. b. First value recorded after cohabitation. 1 MG/KG/DAY 6 7 8 9 10 11 12 13 320. 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. 22 23 24 25 26 27 28 29b 335. 462. 428. 433 . 379. 511. 438. 411. 417. 430. 422. 428. 464. 441. 411. 345. 461. 436. 433 . 389. 522. 439. 415. 421. 444. 429. 431. 470. 443 . 414. 341. 469. 438. 435. 390. 528. 448. 418. 424. 444. 437. 435. 479. 442. 418. 343. 473. 434. 444. 397. 528. 446. 419. 428. 452. 442. 433. 484. 448. 420. 346. 478. 441. 445. 400. 533. 454. 421. 429. 449. 443 . 448. 487. 456. 428. 350. 481. 439. 451. 407. 538. 455. 428. 440. 457. 454. 463. 493. 459. 431. 353. 491. 442. 452. 408. 547. 460. 434. 436. 460. 457. 458. 500. 459. 433. 355. 497. 447. 458. 411. 557. 461. 433. 443. 462. 458. 462. 505. 463. 437. 14a 15 16 335. 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. 30 31 32 359. 500. 451. 456. 422. 558. 468. 425. 443. 470. 457. 454. 506. 456. 437. 363. 509. 450. 458. 422. 568. 466. 438. 452. 471. 467. 460. 506. 460. 444. 365. 509. 450. 461. 423 . 571. 468. 438. 449. 473 . 471. 463. 514. 466. 447. 418-028:PAGEB-62 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OP 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 Ill DAY 33 34 35 36 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 19155 19159 19172 19173 19174 369. 515. 454. 468. 428. 573. 472. 449. 453. 478. 467. 470. 514. 467. 449. 370. 522. 455. 463. 430. 576. 474. 447. 457. 478. 474 . 466. 508. 471. 453. 374. 519. 461. 471. 435. 579. 481. 450. 456. 479. 475. 476. 520. 476. 457. 369. 528. 457. 470. 436. 584. 483. 449. 462. 481. 479. 480. 528. 486. 460. DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). 37 373. 538. 458. 474. 442. 598. 478. 452. 469. 481. 477. 480. 534. 485. 457. 38 373. 537. 449. 473. 442. 590. 469. 454. 465. 483. 481. 482. 531. 483. 462. 1 MG/KG/DAY 39 40 41 374. 536. 449. 480. 446. 602. 482. 448. 461. 475. 481. 485. 534. 482. 461. 379. 535. 453. 480. 445 . 600 . 483. 452. 474 . 480. 486. 483. 531. 466. 457. 375. 533. 456. 480. 450. 606. 489. 464. 474. 493. 492. 484. 532. 477. 461. 42 43 379. 532. 460. 478. 451. 606. 491. 466. 471. 493. 494. 494. 538. 483 . 461. 353. 505. 437. 482. 454. 603. 497. 466. 473. 495. 493. 494. 541. 483. 461. 44 45 46 47 452. 430. 616. 494 . 461. 473. 496. 502. 484. 547. 485. 466. 567. 464 . 470. 468. 499. 500. 498. 549. 483. 471. 434 . 443 . 473. 504 . 506. 556. 486. 473. 481. 475. 526. 459. 448. 418-028:PAGE B-63 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 DAY 1 2 3 4 5 6 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. DAY 17 18 19 20 21 22 19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 19156 19160 19162 19163 19166 390. 451. 438. 398. 395. 462. 420. 435. 405. 418. 396. 421. 377. 429. 456. 391. 458. 439. 406. 404. 473 . 425. 451. 412. 427. 392. 424. 376. 434. 460. 396. 457. 436. 409. 410. 476 . 431. 444. 417. 432. 402. 427. 381. 438. 465. 400. 470. 452. 419. 415. 476. 435. 456. 421. 441. 411. 434. 382. 453. 473. 403. 468. 454 . 425. 421. 486. 441. 459. 421. 440. 411. 437. 390. 455. 480. 405. 470. 454. 426. 421. 490. 438. 462. 424. 436. 409. 431. 392. 448. 480. DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Last value recorded before cohabitation. b. First value recorded after cohabitation. 3 MG/KG/DAY 7 8 9 10 11 363. 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. 23 24 25 26 27 404. 479. 458. 430. 432. 499. 448. 471. 431. 448. 416. 446. 397. 462. 480. 408. 489. 461. 429. 427. 502. 450. 474. 434. 442 . 417. 442 . 402. 463. 487 . 411. 483. 467. 433 . 439. 505. 455. 480. 437. 454 . 419. 449. 400. 459. 488. 414. 486. 464. 434. 440. 512. 463. 494. 438. 450. 423. 450. 408. 463. 493. 418. 488. 471. 442. 441. 519. 469. 497. 450. 462. 422. 461. 409. 468. 500. 12 13 14a 15 16 377. 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 . 28 29b 30 31 32 425. 490. 478. 444. 445. 518 . 471. 497. 452. 462. 430. 470. 410. 478. 502. 428. 492 . 479. 446. 449. 531. 472. 509. 455. 464. 436. 464. 415. 484. 503. 428. 498. 481. 449. 446. 526. 475. 518. 451. 458. 436. 468. 414 . 476. 505. 431. 497. 481. 447. 443 . 533 . 485. 519. 457. 467. 435. 475 . 415. 481. 505 . 432 . 499. 481. 451. 451. 539. 490. 517. 465. 474 . 438. 473. 417. 479. 505. 418-028-.PAGEB-64 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. 3 MG/KG/DAY 38 39 40 41 447. 513. 499. 459. 464 . 557. 497. 533. 482. 472. 450. 488. 427. 492. 525. 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. 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 44 421. 487. 509. 470. 484 . 574. 505. 547. 482. 476. 453 . 478. 435. 508. 528. 476. 442. 448. 585. 515. 553. 495. 472. 447. 496. 441. 516. 535. 45 46 47 545. 479. 523 . 495. 479. 455. 493. 449. 513. 531. 454 . 448. 460. 491. 445. 512. 537. 433. 461. 415. 486. 506. 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 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. DAY 17 18 19 20 21 22 23 24 25 26 27 28 29b 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 19154 19158 19168 19169 19170 401. 410. 403. 394. 388. 414. 401. 399. 383. 412. 408. 412. 390. 424 . 407. 403. 424 . 397. 393. 382. 425. 407. 401. 376. 415. 409. 412. 394. 429. 412. 407. 423. 402. 394. 384. 429. 415. 407. 383. 416. 411. 414. 388. 431. 410. 410. 427. 409. 400. 398. 429. 417. 414. 386. 418. 412. 422. 391. 438. 418. 412. 428. 409. 402. 402. 430. 424. 418. 396. 426. 417. 427. 394. 438. 421. 414. 430. 410. 400. 405. 434 . 417. 414 . 399. 399. 416. 428. 390. 436. 420. 426. 438. 415. 400. 464. c 436. 420. 421. 402. 406. 414. 432. 387. 446. 424 . 424. 446. 410. 400. 417. 433 . 428. 424. 405. 410. 415. 431. 392. 447. 428. 427. 444. 413. 406. 416. 430. 430. 424. 406. 417. 419. 432. 390. 444. 428. 429. 445. 416. 407. 421. 440. 436. 430. 407. 424. 427. 439. 396. 447. 433. 437. 456. 419. 415. 432. 439. 434. 435. 417. 430. 437. 440. 403. 454. 443. 436. 456. 425. 420. 436. 443 . 442. 437. 417. 432 . 437. 447. 404 . 456. 443. 438. 463. 430. 418. 436. 444. 440. 440. 422. 430. 443. 447. 405. 463. 446. DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Last value recorded before cohabitation. b. First value recorded after cohabitation. c. Value appeared incorrectly recorded and was excluded from group averages and statistical analyses. 14a 15 16 393. 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. 30 31 32 440. 460. 429. 422. 435. 444. 446. 440 . 422. 440. 448. 443. 404. 466. 448. 440. 464. 428. 420. 440. 451. 450. 447. 433. 445. 452. 446. 409. 461. 452. 442. 466. 433. 423 . 446. 449. 448. 453 . 434 . 449. 463. 450. 414 . 468. 455. 418-028:PAGE B-66 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 10 MG/KG/DAY DAY 33 34 35 36 37 38 39 40 41 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. 457. 477. 448. 429. 444. 473 . 464. 460. 453. 464. 479. 461. 417. 485. 460. 456. 481. 445. 438. 454. 463. 454. 463. 460. 463. 477 . 458. 423. 485. 462. 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. DAY - DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) 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 45 46 426. 434 . 486. 486. 477. 466. 498. 496. 461. 421. 477. 463. 445. 442. 466. 468. 491. 498. 478 . 421. 482. 467. 441. 439. 461. 498. 471. 425. 480. 471. 47 466. 453. 402 . 448. 445. 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- 8a 29b-36 RAT # DOSAGE GROUP I 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 19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 19147 19153 19164 19165 19171 193. 212. 222. 199. 200. 200. 196. 212. 169. 184. 189. 188. 196. 178. 187. 200. 192. 216. 202. 203. 195. 190. 226. 179. 201. 203. 201. 246. 189. 176. DAY - DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Last value recorded before cohabitation. b. First value recorded after cohabitation. C. Spilled feed precluded the calculation of this value. 0 MG/KG/DAY 0.3 MG/KG/DAY 418-028:PAGE B-68 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 2 9b- 36 RAT # DOSAGE GROUP Ill 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 19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 19156 19160 19162 19163 19166 186. 222. 204 . 181. 194. 233. 195. 227. 199. 214. 176. 214. 171. 206. 200. 191. 218. 209. 188. 208. 236. 232. 238. 212. 181. 177. 207. 181. 197. 201. DAY - DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Last value recorded before cohabitation. b. First value recorded after cohabitation. 1 MG/KG/DAY 3 MG/KG/DAY 418-028-.PAGEB-69 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 418-028:PAGEB-70 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 DOSAGE GROUP I 0 MG/KG/DAY 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 19143 19151 19157a 19157b 19161 19167 7 2 3 2 4 4 3 1 4 3 3 2 4 7 2 4 DID NOT MATE M M M M M M M M M M M M M M M DOSAGE GROUP II 0.3 MG/KG/DAY 19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 19147 19153 19164 19165 19171 4 1 1 2 4 1 2 1 1 4 i i 2 3 1 M M M M M M M M M M M M M M M M * MATED ( ) = FEMALE RAT NUMBER C - CONFIRMED P = PREGNANT NP = NOT PREGNANT a. Result of first cohabitation period. b. Result of second cohabitation period. MATING DATE _ C C c c c c c c c c c c c c c c c c c c c c c c c c c c c c FEMALE PREGNANCY STATUS -(19010) P(19012) P(19019) P(19021) P(19023) P(19041) P9042) P(19044) P(19050) P19053) P(19065) P9068) P(19072) P(19010) P(19074) P(19075) P(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) P19067) P(19071) 418-028:PAGEB-71 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 DOSAGE GROUP III 1 MG/KG/DAY 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 19155 19159 19172 19173 19174 3 3 4 2 1 4 1 4 2 3 1 4 4 2 4 M M M M M M M M M M M M M M M DOSAGE GROUP IV 3 MG/KG/DAY 19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 19156a 19156b 19160 19162 19163a 19163b 19166 7 4 4 2 4 i i 7 3 1 4 6 2 4 2 7 i DID NOT MATE M M M M M M DID NOT MATE M M M M M M M DID NOT MATE M M = MATED ( ) = FEMALE RAT NUMBER C = CONFIRMED P = PREGNANT NP = NOT PREGNANT a. Result of first cohabitation period. b. Result of second cohabitation period. MATING DATE C C C C C C C C C C C C C C C - c C C C c c - c c c c c c c - c FEMALE PREGNANCY STATUS P (19003) P19007) P19008) P(19013) NP(19014) P(19015) P(19017) P(19024) P(19029) P(19034) NP(19038) P(19056) P(19057) FU9060) P(19064) -(19002) P(19005) P(19035) P(19039) P (19040) P (19045) NP(19046) -(19051) P(19054) P(19058) P(19062) P19002) P (19063) P (19066) P19069) -(19051) P19073) 418-028-.PAGEB-72 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 19117 19124 19126 19127 19128 19140 19145 19149 19152 19154 19158 19168 19169 19170 1 3 4 4 4 3 4 1 4 1 4 1 1 1 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(19025) P (19027) P(19028) P(19030) P (19031) P(19032) P(19033) P (19049) P (19059) P(19070) L'fl HOYd*8l0"8It 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 DOSAGE GROUP I "'m/KG/DK RAT # 19109 19115 19116 19119 19122 19125 19131 19132 19134 HOME CAGE BEHAVIOR 2222 2 2 12 2 ALTERATIONS (HOME CAGE) 1 1 1 1 1 1 2a 1 1 REACTION TO REMOVAL 1111 1 1i1 1 REACTION TO HANDLING 1111 1 1i1 1 REARS IN OPEN FIELD 2 5 34 3 6 i1 8 DEFECATION IN OPEN FIELD 1 1 1 1 1 1 i 1 1 URINATION IN OPEN FIELD 2112 12 i2 1 LEVEL OF AROUSAL 3333 3 333 3 ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1 GAIT PATTERN 1111 1 1 111 GAIT ABNORMALITY, SEVERITY 1 1 1 1 1 1 1 1 1 PALPEBRAL CLOSURE 11 11 1 1 11 1 PROMINENCE OF THE EYE 1111 1 111 1 LACRIMATION 11 11 1 1 11 1 SALIVATION 11 11 1 1 11 1 PILOERECTION 0000 0000 0 ABNORMAL RESPIRATION 0000 0 0 00 0 APPEARANCE 1 1 1 1 lb 1 1 1 1 VISUAL REACTION 22222 2222 TACTILE REACTION 22 22 2 2 22 2 AUDITORY REACTION 3333 3333 3 TAIL-PINCH REACTION 22222 222 2 AIR RIGHTING RESPONSE 11 1 11 1 11 1 PUPIL RESPONSE TO LIGHT 1111 1 1 11 1 FORELIMB GRIP TEST #1 (G) 355 460 500 360 340 470 315 415 295 FORELIMB GRIP TEST #2 (G) 460 510 420 395 375 350 465 465 430 HINDLIMB GRIP TEST #1 (G) 450 320 620 315 315 490 255 300 280 HINDLIMB GRIP TEST #2 (G) 415 380 690 220 330 390 255 325 250 LANDING FOOT SPLAY #1 (CM) 6.7 9.8 8.8 7.9 4.5 8.5 7.8 8.0 7.7 LANDING FOOT SPLAY #2 (CM) 6.8 7.6 7.7 7.6 5.7 7.1 7.2 6.8 7.5 BODY WEIGHT (G) 452 487 4 95 527 464 529 507 445 433 VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY. a. Value appeared incorrectly recorded; value excluded from group averages and statistical analyses. b . Chromorhi norrhea. 19135 1 1 1 1 0 1 1 3 1 1 1 1 1 1 1 0 0 1 2 2 3 2 1 1 315 370 345 275 8.4 8.4 503 418-028:PAGE B-74 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OP 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 DOSAGE GROUP II 0i.3 MG/KG/DAY RAT # 19102 19106 19108 19110 19113 19120 19129 19136 19138 HOME CAGE BEHAVIOR 222222211 ALTERATIONS (HOME CAGE) 11 11 11 11 1 REACTION TO REMOVAL 11111111 1 REACTION TO HANDLING 11111111 1 REARS IN OPEN FIELD 11 8 3 11 9 4 4 3 4 DEFECATION IN OPEN FIELD 1 1 1 1 2 2 1 1 1 URINATION IN OPEN FIELD 21222222 2 LEVEL OF AROUSAL 3 333 3 3 33 3 ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1 GAIT PATTERN 1 1 11 1 111 1 GAIT ABNORMALITY, SEVERITY 1 1 1 1 1 1 1 1 1 PALPEBRAL CLOSURE 1 1 11 1 11 1 1 PROMINENCE OF THE EYE 11 111 111 1 LACRIMATION 11111111 1 SALIVATION 11111111 1 PILOERECTION 0 0000 000 0 ABNORMAL RESPIRATION 00 00 0 000 0 APPEARANCE 11 111 111 1 VISUAL REACTION 22 222 222 2 TACTILE REACTION 2 2 22 2222 2 AUDITORY REACTION 3333 3 333 3 TAIL-PINCH REACTION 2 222 2222 2 AIR RIGHTING RESPONSE 11111111 1 PUPIL RESPONSE TO LIGHT 1 1 1 1 1 1 11 1 FORELIMB GRIP TEST #1 (G) 355 375 395 415 455 245 250a 505 215 FORELIMB GRIP TEST #2 (G) 400 490 360 470 465 410 365 390 465 HINDLIMB GRIP TEST #1 (G) 345 435 610 365 315 250 315 155 435 HINDLIMB GRIP TEST #2 (G) 460 505 575 450 520 550 345b 220 365 LANDING FOOT SPLAY #1 (CM) 11.6 9.5 7.6 8.0 6.8 6.2 12.5 7.6 8.0 LANDING FOOT SPLAY #2 (CM) 9.7 8.4 6.5 7.8 6.5 4.8 12.7 7.8 9.2 BODY WEIGHT (G) 444 489 490 467 464 496 443 517 385 VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY. a. Vocalization and aggression observed during forelimb grip test. b. Soft or liquid feces observed during hindlimb grip test. 19139 1 1 1 1 5 1 2 3 1 1 1 1 1 1 1 0 0 1 2 2 3 2 1 1 435 550 465 335 9.9 11.5 460 418-028:PAGEB-75 PROTOCOL 4X8-028: 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 DOSAGE GROUP III 1 MG/KG/DAY RAT # 19101 19105 19107 19112 19114 19121 19123 19130 19137 HOME CAGE BEHAVIOR 222222 211 ALTERATIONS (HOME CAGE) 111 111 111 REACTION TO REMOVAL 1111 11 111 REACTION TO HANDLING 11111 1 111 REARS IN OPEN FIELD 33 722 3 256 DEFECATION IN OPEN FIELD 2 1 2 1 1 1 2 1 1 URINATION IN OPEN FIELD 222121 111 LEVEL OF AROUSAL 333333 333 ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1 GAIT PATTERN 111111 111 GAIT ABNORMALITY, SEVERITY 1 1 1 1 1 1 1 1 1 PALPEBRAL CLOSURE 111 11 1 11 1 PROMINENCE OF THE EYE 111 111 111 LACRIMATION SALIVATION 111111 111 11111 1 11 1 PILOERECTION 000000 000 ABNORMAL RESPIRATION 00000 0 000 APPEARANCE 1 1 la 1 1 1 1 1 1 VISUAL REACTION 222222 222 TACTILE REACTION 222222 222 AUDITORY REACTION 333 333 333 TAIL-PINCH REACTION 2 2 2 2 2 2 2b 2 2 AIR RIGHTING RESPONSE 111111 111 PUPIL RESPONSE TO LIGHT 111111 111 FORELIMB GRIP TEST #1 (G) 215 500 480 490 270 550 405 395 340 FORELIMB GRIP TEST #2 (G) 175 430 545 400 430 395 395 515 330 HINDLIMB GRIP TEST #1 (G) 520 480 540 415 395 465 375 280 305 HINDLIMB GRIP TEST #2 (G) 545 580 415 525 395 475 490 435 255 LANDING FOOT SPLAY #1 (CM) 8.2 8.7 9.7 6.8 9.0 11.8 8.5 9.7 11.1 LANDING FOOT SPLAY #2 (CM) BODY WEIGHT (G) 6.7 375 7.5 10.3 7.5 532 459 482 8.8 10.2 9.5 439 601 476 7.8 10.7 457 467 VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY. a. Localized alopecia: lower midline - right side (4.0 cm x 1.5 cm). b. Soft or liquid feces observed during tail-pinch reaction. c. Vocalization to touch and aggressive behavior observed during air righting response. 19146 1 1 1 1 6 1 1 3 1 1 1 1 1 1 1 0 0 1 2 2 3 2 lc 1 570 360 220 280 8.7 7.6 483 418-028:PAGEB-76 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 DOSAGE GROUP IV 3 MG/KG/DAY RAT # 19100 19103 19104 19118 19133 19141 19142 19144 19148 HOME CAGE BEHAVIOR 2222 2212 2 ALTERATIONS (HOME CAGE) 1111 1111 1 REACTION TO REMOVAL 1111 1111 1 REACTION TO HANDLING 111 1 1111 1 REARS IN OPEN FIELD 7614 426 7 3 DEFECATION IN OPEN FIELD i 21 1 11 1 i 1 URINATION IN OPEN FIELD 2 212 212 2 2 LEVEL OF AROUSAL 3333 3333 3 ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1 GAIT PATTERN 1111 111 11 GAIT ABNORMALITY, SEVERITY 1 11 1 11 1 1 1 PALPEBRAL CLOSURE 1111 111 1 1 PROMINENCE OF THE EYE 1111 11111 LACRIMATION 1111 1111 1 SALIVATION 1111 1111 1 PILOERECTION 0000 0000 0 ABNORMAL RESPIRATION 0000 0000 0 APPEARANCE 1111 1111 1 VISUAL REACTION 2222 22222 TACTILE REACTION 2222 22222 AUDITORY REACTION 3333 3333 3 TAIL-PINCH REACTION 2222 2222 2 AIR RIGHTING RESPONSE 1 1 1 1 1 1 lb 1 1 PUPIL RESPONSE TO LIGHT 1111 1111 1 FORELIMB GRIP TEST #1 (G) 450 355 330 270 335 120 390 355 465 FORELIMB GRIP TEST #2 (G) 540 315 465 475 365 220 365 255 675 HINDLIMB GRIP TEST #1 (G) 425 520 450 380 350 270 215 200 405 HINDLIMB GRIP TEST #2 (G) 385 420 335 415 265 420 365 340 485 LANDING FOOT SPLAY #1 (CM) 7.6 10.8 6.6 9.0 6.6 6.8 9.7 8.5 11.9 LANDING FOOT SPLAY #2 (CM) 6.9 9.7 7.8 8.5 4.5 6.7 9.6 9.2 12.2 BODY WEIGHT (G) 441 505 494 472 459 563 506 538 481 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. 19150 1 1 1 1 5 1 2 3 1 1 1 1 1 1 1 0 0 la 2 2 3 2 1 1 260 345 270 375 9.4 9.6 473 U-930Vd:8fl)-8Il7 PROTOCOL 418-028: ORAL (GAVASE) 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 S) : FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP V 10 MG/KG/DAY RAT # 19111 19117 19124 19126 19127 19128 19140 19145 19149 HOME CAGE BEHAVIOR 22 212 2222 ALTERATIONS (HOME CAGE) 11111 1111 REACTION TO REMOVAL 1 1 11 1 1 11 1 REACTION TO HANDLING 1 1 111 1 111 REARS IN OPEN FIELD 66282 0659 DEFECATION IN OPEN FIELD 1 1 1 1 2 1 1 1 1 URINATION IN OPEN FIELD 22 122 1222 LEVEL OF AROUSAL 3 3 333 3333 ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1 GAIT PATTERN 11 111 1111 GAIT ABNORMALITY, SEVERITY 1 1 1 1 1 1 1 1 1 PALPEBRAL CLOSURE 11 111 1111 PROMINENCE OF THE EYE 11 111 1111 LACRIMATION 1 1 111 11 11 SALIVATION 1 1 11 1 1 111 PILOEEECTION 00 000 0000 ABNORMAL RESPIRATION 0 0 000 0000 APPEARANCE VISUAL REACTION 11 111 1111 2 2 222 2222 TACTILE REACTION 2 2 222 222 2 AUDITORY REACTION 333333333 TAIL-PINCH REACTION 22 222 222 2 AIR RIGHTING RESPONSE 11111 1111 PUPIL RESPONSE TO LIGHT 1 1111 1111 FORELIMB GRIP TEST #1 (G) 355 335 320 580 415 300 285 165 165 FORELIMB GRIP TEST #2 (G> 365 450 350 470 470 450 450 155 275 HINDLIMB GRIP TEST #1 (G) 500 420 510 485 440 430 430 500 250 HINDLIMB GRIP TEST #2 (G) 485 660 555 400 450 505 440 480 215 LANDING FOOT SPLAY #1 (CM) 8.1 7.5 8.1 8.8 9.1 5.3 13.0 8.1 5.8 LANDING FOOT SPLAY #2 (CM) 7.6 6.8 8.3 7.6 9.7 5.0 12.7 6.5 6.2 BODY WEIGHT (G) 458 475 440 439 463 470 462 473 466 VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY. 19152 1 1 1 1 1 1 1 3 1 1 1 1 1 1 1 0 0 1 2 2 3 2 1 1 510 320 305 330 8.5 7.6 473 418-028:PAGEB-78 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 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 71 60 64 68 67 78 74 56 64 56 59 66 58 72 76 68 80 71 66 70 61 46 56 71 72 64 0 55 62 55 29 9 69 45 50 50 0 76 9 7 3 1 33 1 44 1 1 12 1 5 0 0 2 36 7 33 55 0 0 71 6 58 61 0 59 0 72 15 0 56 0 7 0 0 37 0 0 6 1 56 5 0 0 1 47 0 0 7 36 35 528 529 641 533 870 TOTAL = SUMOF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 19125 72 61 66 55 75 61 29 97 70 59 71 72 82 44 61 83 49 71 1178 19131 58 83 76 83 55 78 56 24 0 0 0 3 20 68 61 60 72 14 811 19132 62 67 76 70 47 52 50 62 40 31 47 46 73 50 12 25 44 53 907 19134 73 71 73 93 73 5 4' 0 30 73 20 43 0 0 5 0 16 8 587 19135 53 59 69 67 45 51 53 54 54 67 59 55 62 71 50 5 2 4 880 418-028-.PAGEB-79 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 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 185 217 193 169 161 182 182 133 186 191 161 115 110 181 149 144 127 106 166 190 106 54 113 132 129 91 0 125 111 71 70 6 140 82 125 99 0 87 a 10 0 0 31 0 113 0 0 11 1 4 0 0 0 36 6 38 91 0 0 84 9 90 60 0 95 0 67 9 0 151 0 5 0 0 105 0 0 5 0 79 4 0 0 0 100 0 0 6 46 44 1089 954 1129 1118 1807 TOTAL - SUMOF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 19125 194 201 162 88 140 158 48 124 118 122 169 114 116 127 118 102 57 125 2283 19131 229 188 183 139 92 133 65 18 0 0 0 1 21 104 99 106 72 23 1473 19132 219 184 178 129 69 135 80 165 53 43 58 72 126 90 10 24 70 56 1761 19134 224 217 173 134 94 1 2 0 50 122 12 62 0 0 3 0 16 2 1112 19135 220 210 143 191 78 87 84 102 75 186 121 119 152 108 51 3 1 3 1934 418-028:PAGEB-80 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 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 64 55 64 64 71 69 55 61 60 56 68 59 47 66 24 63 68 65 73 15 44 60 61 59 0 32 24 51 70 0 5 54 71 65 0 3 45 60 57 2 34 77 37 64 0 6 75 60 37 51 0 53 3 0 16 1 64 0 51 1 5 58 65 0 12 14 61 64 22 0 51 53 39 20 0 36 81 51 65 0 64 78 52 46 0 63 58 41 40 0 622 1078 892 859 248 TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 19120 69 94 82 93 93 86 59 74 70 65 64 45 0 8 17 2 0 38 959 19129 52 58 67 67 61 77 70 59 48 56 72 66 74 59 27 2 3 6 924 19136 64 57 72 47 55 70 62 67 45 48 63 51 54 61 78 57 63 53 1067 19138 74 61 50 60 51 55 63 48 70 56 40 35 78 81 25 33 22 1 903 19139 66 65 63 61 63 63 51 52 47 77 40 37 84 68 45 49 64 44 1039 418-028:PAGEB-l OO 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 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 215 133 150 116 35 40 1 1 33 4 0 0 1 26 113 57 93 111 1129 201 164 126 140 147 31 125 77 105 114 117 72 88 90 59 125 151 54 1986 192 152 71 162 166 103 136 81 99 78 4 0 86 120 60 63 66 37 1676 192 182 150 201 116 142 98 55 85 42 0 60 0 29 17 84 56 41 1550 176 138 24 16 0 0 0 0 0 94 49 0 7 0 0 0 0 0 504 TOTAL = SUMOF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 19120 197 160 211 144 171 135 148 162 117 94 135 90 0 2 26 0 0 43 1835 19129 240 238 223 209 214 157 153 117 116 137 177 146 190 114 28 1 0 2 2462 19136 216 209 203 129 197 125 102 146 63 95 123 181 135 152 146 121 117 139 2599 19138 191 170 144 143 83 76 71 69 125 75 58 62 207 122 15 28 21 1 1661 19139 198 198 101 123 182 88 68 129 66 133 51 60 155 102 67 76 121 46 1964 418-028:PAGEB-82 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 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 67 57 63 79 60 55 57 63 76 57 76 72 52 71 56 80 68 63 73 61 62 63 66 61 66 72 57 52 60 47 74 57 52 47 65 57 68 51 6 66 59 86 64 22 31 56 73 66 14 35 21 44 52 2 69 71 8 37 14 12 109 5 54 49 8 29 17 81 0 29 27 69 71 1 2 50 72 5 0 0 72 55 1 18 0 73 65 0 55 5 1110 993 893 648 669 TOTAL - SUMOF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 19121 74 67 70 71 75 78 71 78 69 75 74 79 70 55 85 66 54 57 1268 19123 60 69 59 79 60 64 69 49 22 17 84 60 22 0 0 3 5 1 723 19130 51 55 57 43 71 52 28 43 31 47 73 60 37 53 65 47 13 42 868 19137 56 81 71 84 72 74 76 68 74 85 50 59 81 57 75 64 27 2 1156 19146 68 66 67 60 60 86 59 54 39 2 43 55 5 44 3 5 46 59 821 418-028:PAGE B-83 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 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 212 219 145 127 148 65 164 103 116 98 36 165 103 18 47 52 90 100 2008 226 224 156 125 191 110 79 139 154 120 76 8 1 20 135 100 81 156 2101 218 129 92 109 147 87 104 151 102 97 77 37 87 104 79 11 0 0 1631 207 144 160 138 134 93 60 2 18 6 0 11 54 0 0 0 16 76 1119 194 197 177 169 160 91 175 160 39 59 134 48 5 30 1 0 0 5 1644 TOTAL SUMOF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 19121 201 198 197 138 157 164 112 161 208 153 170 180 113 95 139 152 162 85 2785 19123 228 220 203 141 115 139 146 73 25 11 125 138 34 0 0 5 3 0 1606 19130 236 230 187 167 151 99 29 51 82 99 99 109 24 136 140 71 18 43 1971 19137 219 202 202 188 166 201 141 132 116 131 81 111 98 65 138 211 23 1 2426 19146 207 195 206 122 134 135 92 127 76 0 62 110 2 73 1 1 76 97 1716 418-028:PAGEB-84 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 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 80 55 61 54 47 84 74 72 73 69 54 69 87 87 81 57 57 75 86 78 67 43 85 71 37 29 67 62 79 41 47 60 66 62 71 62 43 64 44 12 55 53 69 27 14 32 69 65 85 0 1 50 76 74 8 1 46 89 60 18 3 14 77 77 54 58 69 63 10 71 75 63 71 3 40 54 74 61 70 0 72 62 63 72 20 67 16 57 61 5 898 984 1263 1095 666 TOTAL - SUMOF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 19141 63 69 69 71 74 66 56 63 69 51 58 54 73 69 54 57 48 47 1111 19142 73 76 67 55 77 59 49 71 83 50 65 66 56 80 54 56 66 34 1137 19144 66 75 54 48 71 64 70 80 60 49 70 57 62 53 49 67 65 74 1134 19148 54 70 74 63 42 74 66 69 63 58 68 69 53 61 67 45 67 63 1126 19150 68 73 74 64 64 58 59 62 60 41 47 31 35 58 37 25 0 0 856 418-028:PAGEB-85 PROTOCOL 418-028: ORAL (GAVAGE1 COMBINED REPEATED DOSE TOXICITY STUDY OP 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 --r - - , , L 19100 19103 19104 . . .i,. _ _______ _____ ._ TIME (SECONDS) SPENT IN MOVEMENT 19118 ____ 19133 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 198 136 83 120 120 30 59 87 82 30 0 0 0 106 113 58 146 108 1476 244 202 105 193 90 129 186 223 196 155 83 114 18 136 111 134 127 36 2482 235 171 159 156 131 109 187 108 114 94 155 136 100 102 97 100 95 88 2337 219 163 138 139 137 128 87 59 27 120 92 101 102 14 1 61 91 78 1757 171 200 138 181 55 57 141 43 9 0 3 14 87 107 43 0 13 2 1264 TOTAL SUMOF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 19141 200 206 143 114 145 154 142 131 93 126 143 71 105 106 60 114 109 65 2227 19142 206 184 153 86 120 65 65 120 152 55 158 84 118 163 69 112 111 58 2079 19144 182 182 160 125 144 146 122 123 151 107 143 125 124 96 107 134 143 115 2429 19148 211 183 175 174 145 187 113 161 109 77 148 128 76 153 82 110 79 119 2430 19150 180 175 152 121 105 92 84 106 103 67 52 38 72 95 59 49 0 0 1550 oo 8 oo T3 > g owIo On 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 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 62 69 57 61 72 68 66 67 72 63 67 56 63 76 61 58 50 73 63 68 62 49 65 42 25 39 50 59 51 67 59 63 62 62 30 55 74 24 61 12 46 37 42 35 75 73 40 47 51 64 44 0 45 50 33 28 39 57 37 67 44 31 64 30 86 77 0 29 64 66 75 0 39 62 57 43 0 66 61 3 71 0 72 49 56 65 1 58 31 63 1036 625 989 958 968 TOTAL * SUMOF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD 19128 68 75 78 37 51 56 49 54 41 23 23 39 42 62 41 49 34 38 860 19140 64 87 72 41 62 55 54 78 87 47 82 43 21 16 61 69 6 1 946 19145 49 63 60 48 76 66 52 44 56 67 54 64 62 56 39 64 68 31 1019 19149 77 65 77 59 76 57 68 67 47 52 43 44 39 68 56 68 14 35 1012 19152 61 70 65 63 61 74 69 28 56 32 41 58 11 0 0 2 3 19 713 418-028:PAGEB-87 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 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 206 170 141 175 153 64 98 74 51 140 87 37 75 150 103 54 93 110 1981 161 174 110 169 75 67 81 101 63 64 0 94 54 0 0 0 0 0 1213 173 143 118 118 124 97 112 36 47 80 98 59 107 32 60 77 98 91 1670 169 116 141 115 111 96 102 64 47 47 102 65 40 66 74 95 86 21 1557 212 149 109 103 30 87 39 7 107 67 33 105 163 106 68 0 70 106 1561 TOTAL = SUMOF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 19128 192 205 128 42 65 134 104 116 81 27 17 37 48 90 66 132 42 69 1595 19140 181 176 197 86 108 64 107 90 125 49 126 42 29 14 100 142 5 0 1641 19145 243 233 231 220 158 196 195 100 196 165 80 138 135 155 95 203 108 69 2920 19149 230 158 146 126 173 94 121 98 129 87 60 57 38 120 76 68 6 55 1842 19152 181 177 166 155 141 128 120 34 90 42 69 95 16 0 0 0 2 20 1436 418-028:PAGE B-88 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 DOSAGE GROUP I 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 DOSAGE GROUP II 19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 NUMBER MOTILE 276 254 323 328 210 256 375 302 235 332 232 367 333 257 334 469 293 338 223 228 MOTILE PERCENT 0 MG/KG/DAY 89 97 92 90 91 91 94 88 97 92 0.3 MG/KG/DAY 93 89 93 97 90 92 95 92 98 94 STATIC COUNT (NONMOTILE) 33 8 27 38 21 25 23 41 7 29 17 47 25 7 37 39 15 30 4 14 TOTAL COUNT a 309 262 350 366 231 281 398 343 242 361 249 414 358 264 371 508 308 368 227 242 SPERM COUNT b 166 190 159 178 126 121 271 222 156 112 139 149 232 101 177 220 231 95 148 90 SPERM DENSITY c 1701.6 1598.6 1433.3 1475.8 978.7 1073.7 2496.6 1743.2 1339.9 1101.2 1402.5 1455.1 1916.4 1051.3 1515.3 1983.2 2100.6 853.7 1187.9 836.0 418-028:PAGE B-89 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 DOSAGE GROUP III 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 DOSAGE GROUP IV 19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 NUMBER MOTILE 198 265 265 341 475 319 246 309 298 404 301 372 244 286 552 313 15 298 495 197 MOTILE PERCENT 1 MG/KG/DAY 89 87 90 95 97 96 90 93 92 96 3 MG/KG/DAY 91 86 95 95 97 23 90 92 88 98 STATIC COUNT (NONMOTILE) 25 38 31 19 16 12 26 23 25 16 28 60 14 16 46 17 49 32 36 29 TOTAL COUNT a 223 303 296 360 491 331 272 332 323 420 329 432 258 302 598 330 64 330 531 226 SPERM COUNT b 163 186 121 173 130 248 164 190 114 121 141 171 131 86 143 217 33 88 119 117 SPERM DENSITY c 1575.4 1593.3 1312.4 1564.4 1290.1 2163.4 1401.9 1564.5 951.2 1002.3 1215.7 1700.4 1279.8 823.2 1397.0 2026.2 716.1 1006.6 893.9 1087.9 418-028:PAGE B-90 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 NUMBER MOTILE PERCENT (NONMOTILE) COUNT a COUNT b DENSITY c DOSAGE GROUP V 10 MG/KG/DAY 19111 304 94 21 325 229 2354.1 19117 286 90 33 319 189 1871.7 19124 19126 19127 461 264 339 91 93 72 38 499 174 1490.0 12 276 91 1032.3 26 365 190 1805.0 19128 231 95 92 323 163 1730.3 19140 464 95 27 4 91 161 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 . Sum of number motile and static count. Groups of five fields were evaluated until a sperm count of at least 200 was achieved i 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's 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. 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 NIMBER NORMAL DOSAGE GROUP I 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 186 194 189 190 192 195 194 193 196 194 DOSAGE GROUP II 19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 189 196 195 192 196 190 189 196 195 195 DETACHED HEAD NO HEAD 0 MG/KG/DAY 67 24 74 82 35 22 32 24 12 32 0.3 MG/KG/DAY 54 11 12 33 31 82 64 31 31 32 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 2.5 418-028:PAGE B-92 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OP 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 DOSAGE GROUP III 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 198 197 189 197 191 196 192 188 192 193 DOSAGE GROUP IV 19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 196 192 198 188 192 192 4 184 194 198 DETACHED HEAD 1 MG/KG/DAY 1 1 5 1 6 2 2 5 3 5 3 MG/KG/DAY 0 4 2 4 3 5 37 10 3 0 NO HEAD 1 1 3 1 3 2 5 4 4 2 3 4 0 7 3 2 76 6 2 2 BROKEN FLAGELLUM 0 1 1 1 0 0 1 2 1 0 1 0 0 1 2 1 79 0 1 0 BENT FLAGELLUM 0 0 2 0 0 0 0 1 0 0 0 0 0 0 0 0 4 0 0 0 PERCENT ABNORMAL 1.0 1.5 5.5 1.5 4.5 2.0 4.0 6.0 4.0 3.5 2.0 4.0 1.0 6.0 4.0 4.0 98.0 8.0 3.0 1.0 418-028-.PAGEB-93 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 19117 19124 19126 19127 19128 19140 19145 19149 19152 198 197 192 196 189 191 191 196 192 191 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 4.5 418-028:PAGEB-94 APPENDIX C 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 DOSAGE (MG/KG/DAY) I II 0 0.3 III IV 13 PRECOHABITATION (DAY 1 OF STUDY TO THE DAY OF COHABITATION): MAXIMUM POSSIBLE INCIDENCE 210/ 15 210/ 15 210/ 15 210/ 15 MORTALITY 0 0 00 BROWN PERIORAL SUBSTANCE 0/ 0 0/ 0 0/ 0 0/ 0 RALES 0/ 0 0/ 0 0/ 0 0/ 0 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 URINE-STAINED ABDOMINAL FUR 0/ 0 0/ 0 0/ 0 0/ 0 MIOSIS 0/ 0 0/ 0 0/ 0 0/ 0 ABDOMINAL DISTENTION EMACIATION 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 COLD TO TOUCH 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. V 10 210/ 15 0 7/ 1 7/ 1 4/ 1 4/ 1 0/ 0 3/ 1 2/ 1 2/ 1 2/ 1 1/ 1 418-028:PAGE C -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 Cl (PAGE 2) : CLINICAL OBSERVATIONS - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II III IV 0 0.3 13 PRESUMED GESTATION: a MAXIMUM POSSIBLE INCIDENCE 330/ 15 329/ 15 338/ 15 312/ 14 MORTALITY 0 0 00 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 NOSE: SWOLLEN 0/ 0 0/ 0 0/ 0 1/ 1 BACK: SCAB 13/ 1 0/ 0 0/ 0 0/ 0 BACK: ULCERATION 1/ 1 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. V 10 330/ 15 0 21/ 1 14/ 1 7/ 1 0/ 0 0/ 0 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 Cl (PAGE 3): CLINICAL OBSERVATIONS - SUMMARY - Fo GENERATION FEMALE RATS >o HI DOSAGE GROUP DOSAGE (MG/KG/DAY) I II III IV 0 0.3 13 MAXIMUM POSSIBLE INCIDENCE 330/ 15 330/ 15 286/ 13 286/ 13 LACTATION: MORTALITY 0 0 00 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 ABDOMINAL DISTENTION 0/ 0 0/ 0 0/ 0 0/ 0 RALES 0/ 0 0/ 0 0/ 0 0/ 0 EMACIATION 0/ 0 0/ 0 0/ 0 0/ 0 BACK OR HEAD: SCAB 13/ 3 23/ 2 0/ 0 0/ 0 DEHYDRATION 0/ 0 0/ 0 0/ 0 0/ 0 TIP OF TAIL MISSING 0/ 0 0/ 0 0/ 0 6/ 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. 330/ 15 0 27/ 2 21/ 1 6/ 1 0/ 0 16/ 1 9/ 1 7/ 1 6/ 1 1/ 1 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 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 N0 0 0 0 0 APPEARED NORMAL N 15 15 14 13 14 KIDNEYS: RIGHT, CORTEX ADHERED TO RIGHT LATERAL LIVER LOBE N0 0 1 00 OVARIES: LEFT, SMALL N 0 0 0 1 0 SPLEEN: OMENTUM ADHERED TO THE LENGTH OF THE OUTER CAPSULE N0 0 0 10 LARGE AND SMALL INTESTINES: DISTENDED WITH GAS N0 0 0 01 THYMUS: SMALL N0 0 0 0 1 SPLEEN: SMALL N0 0 0 0 1 ADRENALS: BILATERAL, LARGE N0 0 0 01 STOMACH: FUNDIC MUCOSAL SURFACE CONTAINED APPROXIMATELY 12 BLACK AREAS N 0 0 0 01 a. Refer to the individual clinical observations table (Table C27) for external observations confirmed at necropsy. 418-028:PAGE C-4 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 418-028:PAGE C-5 H 00 o CM DOSAGE GROUP DOSAGE (MG/KG/DAY) I 0 TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS RATS TESTED N 15 PREGNANT N 15 TERMINAL BODY WEIGHT MEANS.D. 306.3 26.0 BRAIN LIVER KIDNEY LEFT KIDNEY RIGHT ADRENAL LEFT ADRENAL RIGHT SPLEEN THYMUS OVARY LEFT MEANS.D. MEANS.D. MEANS.D. MEANS.D. MEAN+S.D. MEANS.D. MEANS.D. MEANS.D. MEANS.D. 2 .16 0 .08 [ 10] a 14 .38 2 .24 t 10] a 1 .39 0 .14 [ 10] a 1 .47 0 .12 [ 10] a 0. 052 0. 009 [ 10] a 0. 043 0. 007 [ 10] a 0 .63 0 .08 [ 10] a 0 .21 0 .07 [ 10] a 0. 055 0. 014 OVARY RIGHT MEANS.D. 0. 062 0. 015 UTERUS WITH CERVIX MEANS.D. 0 .53 0 .09 HEART MEANS.D. 1 .40 0 .17 [ 10] a ALL WEIGHTS WERE RECORDED IN GRAMS (G). [ ] = NUMBER OF VALUES AVERAGED a. Only ten rats were tested. II 0.3 15 15 324.3 27.1 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 0. 060 0. 019 0 .56 0 .12 1 .26 0 .13 [ 10] a III 1 15 13 311.2 35.0 2 .10 0 .09 [ 10] a 14 .70 2 .92 [ 10] a 1 .38 0 .14 ( 10] a 1 .45 0 .13 [ 10] a 0. 051 0. 009 [ 10] a 0. 050 0. Oil [ 10] a 0 .60 0 .11 [ 10] a 0 .18 0 .04 [ 10] a 0. 053 0. 014 0. 060 0. 021 0 .50 0 .13 1 .35 0 .11 [ 10] a IV 3 15 13 319.6 40.4 0 .18 [ 10] a 15.11 3 .28 [ 10} a 1.49 0 .19 ( 10} 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 0.054 0. 012 0.62 0 .15 1.40 0 .13 [ 10] a V 10 15 15 303.5 37.9 2 .12 0 .10 [ 10] a 13 .64 3 .18 i 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 0. 054 0. 018 0 .56 0 .16 1 .33 0 .25 [ 10] a 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 0 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 [ 10] a ALL WEIGHTS WERE RECORDED IN GRAMS (G). [ 1 NUMBER OF VALUES AVERAGED a. Only ten rats were tested. II 0.3 III 1 IV V 3 10 15 15 12.40 + 6.24 [ 10] a 10.14 2.29 [ 10] a 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 0 RATS TESTED N 15 PREGNANT N 15 TERMINAL BODY WEIGHT MEANS.D. 306.3 l 26.0 BRAIN LIVER KIDNEY LEFT KIDNEY RIGHT ADRENAL LEFT b ADRENAL RIGHT b SPLEEN THYMUS OVARY LEFT b MEANS.D. MEANlS.D. MEANS.D . MEANS.D. MEANS.D. MEANlS.D. MEANS.D. MEANlS.D. MEANlS.D. 0.711 i 0.062 [ 10] a 4.703 1 0.450 C 10] a 0.459 l 0.049 I 10] a 0.482 l 0.043 [ 10] a 17.095 i 2.132 [ 10] a 13.984 i 1.612 ( 10] a 0.208 l 0.024 [ 10] a 0.070 1 0.022 [ 10] a 18.005 1 4.064 OVARY RIGHT b MEANlS.D. 20.307 1 4.390 UTERUS WITH CERVIX MEANlS.D. 0.175 1 0.031 HEART MEANlS.D. 0.459 1 0.067 [ 10] a HT.T. WEIGHTS WERE RECORDED IN GRAMS [ ] * NUMBER OF VALUES AVERAGED a. Only ten rats were tested. b. Value was multiplied by 1000. (G) . II 0.3 15 15 324.3 1 27.1 0.659 i 0.055 [ 10] a 4.947 t 0.703 [ 10] a 0.460 0.053 [ 10] a 0.472 0.052 [ 10] a 15.856 2.913 [ 10] a 12.842 3.379 [ 10] a 0.205 0.028 t 10] a 0.065 0.018 [ 10] a 17.632 6.782 18.514 5.844 0.175 0.042 0.392 0.057 [ 10] a III IV 13 V 10 15 15 15 13 13 15 311.2 35.0 319.6 40.4 303.5 37.9 0.684 0.082 [ 10] a 4.697 0.512 [ 10] a 0.446 0.054 [ 10] a 0.467 0.042 [ 10] a 16.799 4.091 [ I0]a 16.479 4.381 [ 10]a 0.194 0.035 [ 10] a 0.059 0.016 [ 10] a 17.053 3.559 0.675 0.099 ( 10] a 4.795 0.517 t 10] a 0.479 0.070 [ 10] a 0.492 0.058 [ 10] 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 t 10] a 0.484 0.043 [ 10] a 18.402 4.737 t 10] a 15.959 4.763 [ 10] a 0.181 0.026 [ 10] a 0.059 0.016 [ 10] a 17.611 3.620 19.152 6.400 17.025 3.632 17.529 5.247 0.162 0.046 0.198 0.063 0.185 0.055 0.436 0.054 [ 10] a 0.457 0.073 t 10] a 0.453 0.056 ( 10] a RATIOS (%) = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. 418-028:PAGE C-7 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 C5 (PAGE 1) : RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II 0 0.3 RATS TESTED N 10 10 BRAIN WEIGHT MEANS.D. 2.16 0.08 2.11 0.09 LIVER MEANlS.D. 664.58 96.72 757.16 1127.78 KIDNEY LEFT MEANlS.D. 64.31 5.18 69.72 4.89 KIDNEY RIGHT MEANlS.D. 67.75 1 4.49 71.72 6.50 ADRENAL LEFT MEANS.D. 2.42 1 0.42 2.40 1 0.35 ADRENAL RIGHT MEANS.D. 1.98 1 0.31 1.95 0.46 SPLEEN MEANtS.D. 29.20 1 3.42 30.95 4.47 THYMUS OVARY LEFT OVARY RIGHT MEANS.D. MEANS.D. MEANS.D. 9.72 3.12 2.68 0.75 2.83 1 0.72 9.96 2.95 2.85 0.84 3.09 0.93 UTERUS WITH CERVIX HEART MEANlS.D. MEANlS.D. 26.20 1 4.17 64.52 7.00 28.44 1 4.18 59.50 6.15 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . * Significantly different from the Group I value (p<0.05). III IV 13 V 10 10 10 10 2.10 1 0.09 2.08 1 0.18 2.12 0.10 701.88 1155.49 729.66 1165.57 641.86 1141.49 65.73 6.72 71.48 6.75* 65.57 1 3.88 68.95 7.09 73.35 1 5.96 66.53 1 5.96 2.44 0.39 2.54 0.58 2.49 0.40 2.39 0.48 28.56 1 5.09 2.36 1 0.40 36.15 15.02 2.15 1 0.40 25.16 4.18 8.43 1.96 9.68 1 4.96 8.35 2.13 2.47 0.43 2.55 0.58 2.58 1 0.78 2.82 0.98 2.55 1 0.57 2.37 0.89 24.14 1 6.72 31.96 1 7.43 27.71 6.59 64.03 5.41 67.44 6.68 62.58 10.73 RATIOS (%) = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. 418-028:PAGE C-8 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 DOSAGE (MG/KG/DAY) 0 RATS TESTED N 10 II III 0.3 1 10 10 IV 3 10 V 10 10 WBC (THSN/CU MM) RBC (MILL/CU MM) HGB (GRAMS/DL) HCT (%) MEAN S.D. 9.0 3.09 MEAN S.D. 6.51 0.461 MEAN S.D. 15.5 0.95 MEAN S.D. 40.5 2.93 13.8 5.73* 6.22 0.423 15.0 0.77 39.3 2.72 11.1 t 2.98 6.40 0.554 15.2 0.91 39.5 3.24 10.8 3.14 6.39 0.532 15.2 0.90 40.1 3.02 8.9 3.48 6.42 0.538 15.3 0.77 40.4 3.15 MCV (CU MICRONS) MEAN S.D. 62.2 1.19 63.3 2.01 61.8 1.50 62.9 2.04 63.0 1.60 MCH (PICO GRAMS) MEAN S.D. 23.9 0.55 24.2 0.76 23.9 0.88 23.8 1.25 23.8 1.05 MCHC (%) MEAN S.D. 38.4 0.76 38.3 0.94 PLAT (THSN/CU MM) MEAN 1 S.D. 1419 153.0 1240 208.1 MPV (CU MICRONS) MEAN 1 S.D. 8.3 0.49 8.0 * Significantly different from the Group I value (pSO .05) . 0.84 38.7 1.29 1274 226.3 8.3 0.82 37.8 1.22 1305 207.2 8.0 0.63 37.8 1.37 1355 176.8 7.7 0.74 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.) DOSAGE GROUP DOSAGE (MG/KG/DAY) RATS TESTED I 0 N 10 II III 0.3 1 10 10 IV 3 10 V 10 10 PT (SECONDS) MEAN S.D. 13.2 0.41 13.4 0.29 13.2 0.37 13.5 0.42 13.8 1.12 APTT (SECONDS) MEAN S.D. 21.7 2.36 23.9 3.19 23.5 2.35 25.2 2.45 25.2 3.81 NRBC COUNT MEAN S.D. 0 0.0 0 0.0 0 0.0 0 i 0.0 0 0.6 Lymphocytes (THSN/C MM) MEAN S.D. 6.6 2 .44 9.8 3.44* 8.4 2.60 8.2 2.52 6.0 2.77 Segmented (THSN/CU MM) MEAN S.D. 2.2 0.90 3.6 3.69 2.4 0.93 2.4 0.96 2.6 0.82 Bands (THSN/CU MM) MEAN S.D. 0.0 0.00 0.0 0.00 0.0 0.00 0.0 0.09 0.0 0.00 Monocytes (THSN/CU MM) MEAN S.D. 0.1 0.15 Eosinophils (THSN/CU MM) MEAN S.D. 0.1 0.10 Basophils (THSN/CU Ml) MEAN S.D. 0.0 0.00 Abnormal L (THSN/CU MM) MEAN i S.D. 0.0 0.05 0.3 0.49 0.1 0.13 0.0 0.00 0.0 0.00 0.2 0.13 0.1 0.13 0.0 0.00 0.1 0.07 0.2 0.11 0.1 0.10 0.0 0.00 0.0 0.10 0.2 0.14 0.1 0.15 0.0 0.00 0.0 0.05 418-028:PAGE C-10 Other (THSN/CU m m ) MEAN S.D. 0.0 0.00 0.0 * Significantly different from the Group I value (pSO.05) . 0.00 0.0 0.00 0.0 0.00 0.0 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 C6 (PAGE 3): HEMATOLOGY - SUMMARY - Fo GENERATION FEMALE RATS KEY TO h t OLOGY 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 U-DHOVd:8CO-8lfr Segmented Segmented Neutrophils Abnormal L Abnormal Lymphocytes Other Other Cells 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.) o <j DOSAGE GROUP DOSAGE (MG/KG/DAY) RATS TESTED N I 0 10 II III 0.3 1 10 10 XV 3 10 10 TP (G/DL) MEAN S.D. 6.1 0.52 5.5 0.50 5.9 0.41 5.8 0.32 5.8 0.29 A (G/DL) MEAN S.D. 4.1 0.42 4.0 0.34 4.1 0.24 4.0 0.29 4.0 0.31 GLU (MG/DL) MEAN S.D. 152 19.8 162 20.0 155 18.7 146 16.2 140 35.5 CHOL (MG/DL) MEAN S.D. 77 27.8 72 14.0 71 20.0 62 14.2 61 19.8 TBILI (MG/DL) MEAN S.D. 0.2 0.07 0.2 0.03 0.2 0.05 0.1 0.05 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 t 0.08 0.3 0.06 CK (O/L) MEAN S.D. 202 54.1 250 85.6 192 21.7 213 80.4 252 101.6 ALT (U/L) MEAN S.D. 129 31.7 133 23.0 142 34.2 127 24.7 145 20.0 418-028:PAGE C-12 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 DOSAGE (MG/KG/DAY) RATS TESTED N I 0 10 II III 0.3 1 10 10 IV 3 10 V 10 10 t(oO CD AST (U/L) MEAN S.D. 142 135 i 21.6 137 11.8 124 12.1 156 40.7 ALK (U/L) MEAN S.D. 145 88.7 159 81.7 CA (MG/DL) MEAN S.D. 10.6 0.72 11.2 0.63 PHOS (MG/DL) MEAN S.D. 8.8 1.33 7.9 1.94 TRI (MG/DL) MEAN S.D. 54 19.9 50 10.2 NA (MMOL/L) MEAN S.D. 143 6.3 143 i 2.4 K (MMOL/L) MEAN S.D. 5.8 0.67 5.6 0.58 CL (MMOL/L) MEAN S.D. 96 3.4 94 2.7 G (G/DL) MEAN S.D. 1.9 0.22 1.6 0.26** A/G (NONE) MBAN S.D. 2.2 t 0.28 2.6 ** Significantly different from the Group I value (pSO.Ol). 0.43** 136 107.3 10.4 0.87 9.0 2.80 49 29.4 142 2.5 5.6 0.32 95 3.8 1.8 * 0.21 2.2 0.21 178 131.0 10.4 0.46 8.7 2.88 45 19.5 142 2.6 6.1 0.70 95 3.4 1.7 0.13 2.4 0.26 128 44.7 10.4 0.82 10.1 1.64 44 18.3 142 2.6 6.2 0.90 94 3.1 1.8 0.21 2.3 0.37 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 CLTNICAL ^CHEMISTRY TABLE ABBREVIATION_______________ TP A GLU CHOL TBILI Total Protein Albumin Glucose Cholesterol Total Bilirubin BUN CREAT ALT AST ALK CA PHOS TRI NA K CL G A/G Blood Urea Nitrogen Creatinine Alanine Aminotransferase Aspartate Aminotransferase Alkaline Phosphatase Calcium Phosphorus Triglycerides Sodium Potassium Chloride Globulin Albumin/Globulin Ratio 418-028:PAGE C-14 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 C8 (PAGE 1) : BODY WEIGHTS - PRECOHABITATION - SUMMARY - Fo GENERATION FEMALE RATS 418-028:PAGE C-15 o CO DOSAGE GROUP DOSAGE (MG/KG/DAY) I 0 RATS TESTED N 15 BODY WEIGHT (G) DAY 1 MEANS.D. 228.6 DAY 2 MEANS.D. 228.2 8.7 DAY 3 DAY 4 DAY 5 MEANS.D. MEANS.D. MEANS.D. 233.5 7.2 236.6 7.7 239.0 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 DAY 14a MEANS.D. MEANS.D. 256.3 16.3 258.5 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 10.6 244.1 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 TV 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 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 0 RATS TESTED N 15 BODY WEIGHT CHANGE (G) DAYS 1 - 8 MEANtS.D. +21.9 8.3 DAYS 8 - 14a MEANS.D. +7.9 7.4 DAYS 1 - 14a MEANS.D. +29.9 13.7 DAYS = DAYS OF STUDY a. Last value recorded before cohabitation. II 0.3 15 +18.7 6.3 +7.3 4.2 +25.9 7.2 III 1 15 +20.3 5.7 +11.3 6.1 +31.6 8.4 IV 3 15 +19.0 4.3 +7.2 6.4 +26.2 8.3 V xo 15 +16.7 16.0 +7.5 8.9 +24.2 14.4 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-770G.1) TABLE CIO (PAGE 1) : MATERNAL BODY WEIGHTS - GESTATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) RATS TESTED N PREGNANT N MATERNAL BODY WEIGHT (G) DAY 0 MEANS.D. DAY 1 MEANS.D. DAY 2 MEANS.D. DAY 3 MEANS.D. DAY 4 MEANS.D. DAY 5 MEANS.D. DAY 6 MEANS.D. DAY 7 MEANS.D, DAY 8 MEANS.D. DAY 9 MEANS.D . DAY 10 MEANS.D. DAY = DAY OF GESTATION I 0 15 15 270.1 14.3 273.7 19.9 280.5 20.2 283 .4 20.6 286.5 22.2 291.3 20.3 294.1 18.7 298.0 16.1 303.3 18.0 307.9 16.8 314.1 17.2 II 0 .3 15 15 259.4 12.0 264.7 11.5 269.9 12.8 274.3 12.4 278.9 12.9 283.1 i 13.9 287.3 14.2 290.4 14.9 294.6 13.2 299.3 15.3 304.2 15.5 III 1 15 13 270.9 15.6 274.6 13.4 278.2 14.7 284.5 14.0 285.7 16.6 290.2 17.3 292.2 18.0 295.2 18.4 300.5 18.6 305.3 20.1 311.7 20.5 IV 3 15 13 265.6 15.4 270.9 14.5 275.4 15.6 278.8 16.0 282.7 17.7 286.3 16.8 288.5 18.1 291.3 19.1 296.2 22.1 301.0 22.3 306.3 22.6 V 10 15 15 260.9 18.2 266.9 19.2 269.1 18.1 275.7 18.0 277.7 20.8 280.9 19.4 283.7 19.8 287.7 20.6 292.2 21.0 295.9 20.6 302.1 22.1 418-028:PAGE C-17 PROTOCOL 418-028: ORAL (GA.VAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE CIO (PAGE 2) : MATERNAL BODY WEIGHTS - GESTATION - SUMMARY - Fo GENERATION :FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) RATS TESTED N PREGNANT N MATERNAL BODY WEIGHT (G) DAY 11 MEANS.D. DAY 12 MEAN+S.D. DAY 13 MEANS.D. DAY 14 MEAN+S.D. DAY 15 MEANS.D. DAY 16 MEANS.D. DAY 17 MEANS.D. DAY 18 MEANtS.D. DAY 19 MEANS.D. DAY 20 MEANS.D. DAY = DAY OF GESTATION I 0 15 15 320.7 19.6 325.6 19.8 331.1 19.0 338.8 17.9 345.7 18.4 353.1 23.8 365.3 26.7 383.5 27.1 398.1 31.0 412.0 35.0 II 0 .3 15 15 311.7 16.5 318.3 16.8 321.3 16.9 328.5 16.8 336.1 17.7 345.1 17.8 357.7 19.8 370.3 21.5 380.3 27.4 397.4 + 27.8 III 1 15 13 318.5 20.6 325.1 19.8 328.3 21.6 334.2 20.7 342.5 20.6 350.1 20.8 364.8 19.4 380.4 20.8 393.0 22.7 412.1 21.7 IV 3 15 13 313.6 22.0 319.6 26.0 323.2 25.8 329.2 26.1 335.2 26.3 342.8 29.0 356.0 30.6 365.2 25.2 380.4 24.7 398.8 27.6 V 10 15 15 308.6 23.3 315.0 23.9 319.3 23.3 324.1 23.1 331.2 24.1 337.7 24.6 353.3 24.6 365.0 25.9 378.0 27.8 395.1 28.1 418-028:PAGE C-18 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 DOSAGE (MG/KG/DAY) RATS TESTED N PREGNANT N MATERNAL BODY WEIGHT CHANGE (G) DAYS 0 - 7 MEANS.D. DAYS 7 - 10 MEANS.D. DAYS 10 - 12 ' MBANS.D. DAYS 12 - 15 MEANS.D. DAYS 15 - 18 MEANS.D. DAYS 18 - 20 MEANS.D. DAYS 0 - 20 MEANS.D. DAYS = DAYS OF GESTATION I 0 15 15 +27.9 6.7 +16.1 4.9 +11.5 4.2 +20.1 4.3 +37.9 10.6 +28.5 + 16.6 +141.9 29.0 II 0.3 15 15 +31.0 7.4 +13.8 3.4 +14.1 3.3 +17.7 3.6 +34.2 7.9 +27.1 13.2 +138.0 27.4 III 1 15 13 +24.3 6.3 +16.5 5.3 +13.4 4.2 +17.4 4.0 +37.9 5.2 +31.7 6.7 +141.2 14.1 IV 3 15 13 +25.7 10.3 +15.0 6.1 +13.3 5.8 +15.5 5.5 +30.0 12.5 +33.6 9.2 +133.2 21.9 V 10 15 15 +26.9 5.8 +14.4 3.7 +12.9 6.2 +16.2 jfc 4.1 +33.8 5.7 +30.1 8.9 +134.2 16.9 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 0 0.3 1 IV 3 V 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 2 2 . 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 DAY 4 DAY 5 DAY 6 DAY 7 DAY 8 DAY 9 DAY 10 DAY 11 MEANS.D. MEANS.D. MEANS.D. MEANS.D. MEANS.D. MEANS.D. MEANS.D. MEANS.D. MEANS.D. 316.1 22.6 321.5 22.7 326.0 20.5 332.7 26.1 340.4 20.8 342.3 19.8 349.9 25.6 [ 14] a 353.6 1 7 . 9 ( 13]a 354.4 18.5 t 14] a 300.2 18.6 [ 13] a 303.4 17.2* [ 13] a 307.3 14.2 312.9 11.9* 321.4 12.6* 320.7 12.6* 331.7 11.9 [ 14] a 334.9 17.5 331.9 25.7* 310.4 18.1 C 111a 314.2 19.8 ( 12] a 314.9 21.1 t 12] a 323.9 18.2 ( 12] a 331.2 18.3 333.6 19.6 [ 12] a 337.4 17.3 345.5 18.2 349.2 20.3 [ 12] a 305.0 23.1 [ 12]a 310.2 22.5 [ 12] a 311.5 23.0 [ 12] a 316.9 1 6 . 1 t 11] a 317.7 21.6** [ 12] a 322.2 21.5* 331.8 21.2 333.5 23.0 C 12] a 336.4 24.6 [ 12] a 300.3 20.0 [ 14] a 299.3 19.7* [ 13] a 308.4 15.7 ( 13] a 306.0 26.9** 315.2 25.4** 318.1 26.0** 324.7 29.7** 327.4 38.3 330.2 30.8* DAY = DAY OF LACTATION [ ] = 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). 418-028:PAGE C-20 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STODY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C12! (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 20.2 364.1 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 1 3 . 6 t 14] a 342.9 17.2' [ 14] a 342.7 1 4 . 5 [ 14] a 342.4 10.4 [ 14] a 345.7 1 2 . 9 341.1 16.9 346.4 15.6 352.6 20.1 I 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 t 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 DAY 22 MEANS.D. MEANS.D. 350.1 26.9 ( 14] a 306.3 26.0 335.7 18.7 [ 14] a 324.3 2 7 . 1 343.4 19.8 311.2 35.0 344.4 25.8 319.6 40.4 334.4 35.9 303.5 37.9 DAY - DAY OF LACTATION [ ] = 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). 418-028:PAGE C-21 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 - Fa GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II III 0 0.3 1 IV 3 V 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 - 1 1 DAYS 11 - 15 DAYS 15 - 18 DAYS 18 - 22 MEANS.D. MEANS.D. MEANS.D. MEAN+S.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 [ 11] a +14.4 5.6 C 11] a -3.7 13.2 [ 11] a +7.9 18.0 1 12] a -41.1 33.6 +7.7 14.8 [ 12] a +11.0 1 1 . 0 [ 12] a +13.6 1 0 . 6 [ 12] a +13.8 9.7 [ 11] a +4.1 6.3 [ 12] a -32.5 28.2 +7.8 15.1 [ 13] a +16.5 10.1 f 13] a +12.1 1 0 . 8 +3.7 11,2 t 14] a +7.4 11.4 t 14] a -37.1 29.8 DAYS 1 - 2 2 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 valueB that appeared incorrectly recorded, as well as those associated with interrupted water access. 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 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 CIS (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 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 DOSAGE (MG/KG/DAY) I 0 RATS TESTED N 15 PREGNANT N 15 MATERNAL FEED CONSUMPTION (G/DAY) DAYS 0 - 7 MEANS.D. 25.4 3.3 DAYS 7 - 1 0 MEANS.D. 27.7 2.8 DAYS 10 - 12 DAYS 1 2 - 1 5 MEANS.D. MEANS.D. 32.0 10.5 t 14] a 28.4 2.8 DAYS 15 - 18 MEANS.D. 25.4 4.0 DAYS 18 - 20 MEANS.D. 26.6 5.7 DAYS 0 - 2 0 MEANtS.D. 26.9 3.2 DAYS = DAYS OF GESTATION [ ] = NUMBER OF VALUES AVERAGED a. Excludes values that were associated with spillage. II 0.3 15 15 25.0 2.5 26.8 2.8 27.0 i 3.2 27.5 2.4 26.7 3.1 22.8 6.2 25.9 2.4 III 1 15 13 24.3 2.7 26.3 3.4 28.0 3.2 27.5 2.1 25.9 2.1 25.8 3.2 25.8 2.0 IV 3 15 13 25.2 3.6 26.3 5.0 26.6 + 3.9 26.7 3.9 25.3 3.6 25.0 3.7 25.7 3.0 V 10 15 15 24.0 2.7 25.8 2.5 27.0 2.8 27.5 + 2.6 26.0 3.3 26.1 4.8 25.6 2.3 418-028:PAGE C-25 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-770S. 1) TABLE C17 (PAGE 1) : MATERNAL RELATIVE FEED CONSUMPTION VALUES (G/KG/DAY) - GESTATION - SUMMARY - FO GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I 0 RATS TESTED N 15 PREGNANT N 15 MATERNAL FEED CONSUMPTION (G/KG/DAY) DAYS 0 - 7 MEANS.D. 88.8 8.4 DAYS 7 - 1 0 MEANS.D. 90.5 7.4 DAYS 10 - 12 DAYS 12 - 15 MEANS.D. MEANS.D. 99.0 28.7 [ 14] a 84.9 7.3 DAYS 15 - 18 MEANS.D. 70.0 8.5 DAYS 18 - 20 MEANS.D. 66.4 12.4 DAYS 0 - 2 0 MEANS.D. 83.3 6.6 DAYS DAYS OF GESTATION [ ] = NUMBER OF VALUES AVERAGED a. Excludes values that were associated with spillage. II 0.3 15 15 90.4 7.1 90.0 7.0 86.5 8.0 84.4 5.8 75.6 6.9 59.3 15.4 82.6 5.6 III 1 15 13 85.6 6.9 86.4 7.4 87.9 6.1 82.7 4.9 72.3 6.2 65.4 7.9 80.5 3.1 IV 3 15 13 89.8 9.3 87.7 12.7 84.8 7.0 81.5 6.9 72.2 7.4 66.1 11.8 81.6 5.4 V 10 15 15 86.8 5.5 87.6 5.4 87.3 4.3 85.6 7.2 75.1 8.3 68.7 10.7 82.5 4.0 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 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 61.2 7.1 6.4 27.6 8.7* * [ 14]a 53.7 6.6 DAYS 8 - 1 5 MEANS.D. 71.6 8.6 68.3 t 8.3* DAYS 1 - 1 5 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 LZ-0 39Vd:80'8lt7 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 Cl9 (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 0 0.3 1 IV 3 V 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 - S DAYS 5 - 8 DAYS 8 - 1 1 DAYS 11 - 15 DAYS 1 - 1 5 MEANS.D. MEANS.D. MEANS.D. MEANS.D. MEANS.D. 121.1 t 21.3 183.0 t 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 [ 11] a 101.9 97.9 ( 11] a 276.0 76.3 [ 11] 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 [ 11] a 166.6 20.2 [ 123 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 t ] = 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). 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 PROTOCOL 4X8-028: 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 MEANtS.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 IS 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( 0.0) 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. TV 3 15 4.0 4.0 14( 93.3) 13/ 14 ( 92.8) 14 13( 92.8) M 7.2) 13/ 15 ( 86.7) V 10 15 2.5 t 1.4 15(100.0) 15/ 15 (100.0) 15 15(100.0) 0( 0.0) 15/ 15 (100.0) PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OP T-7706 KITH 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 DOSAGE (MG/KG/DAY) FEMALE RATS I 0 N 10 XI 0.3 10 III 1 10 IV 3 10 V 10 10 HOME CAGE BEHAVIOR 1 Sleeping 2 Awake, Immobile 3 Normal movement 4 Unusual posture 5 Unusual behavior N N N N N ALTERATIONS (HOME CAGE) 1 None 2 Stereotyped behavior 3 Bizarre behavior 4 Limb twitches/tremor 5 Whole body tremor/spasm 6 Unusual posture 7 Tonic-clonic seizure N N N N N N N REACTION TO REMOVAL (1) Sits quietly (2) Vocalization (3) Runs or freezes (4) Tail or throat rattles N N N N MEAN SCORE 1 1 8 0 0 10 0 0 0 0 0 0 10 0 0 0 1.0 4 2 4 0 0 10 0 0 0 0 0 0 10 0 0 0 1.0 4 1 5 0 0 10 0 0 0 0 0 0 10 0 0 0 1.0 4 3 3 0 0 10 0 0 0 0 0 0 10 0 0 0 1.0 1 4 5 0 0 10 0 0 0 0 0 0 10 0 0 0 1.0 l-3H9V^8lO-8It? REACTION TO HANDLING (1) No resistance N 10 10 10 10 10 (2) Vocalization N0 0 0 0 0 (3) Tense N0 0 0 0 0 (4) Squirming H0 0 0 0 0 MEAN SCORE 1.0 1.0 1.0 1.0 1.0 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 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.I) TABLE C21 (PAGE 2) : FUNCTIONAL OBSERVATIONAL BATTERY - SIMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) FEMALE RATS I 0 N 10 II 0.3 10 III 1 10 REARS IN OPEN FIELD MEANS.D. 12.0 3.6 13.0 2.7 11.6 3.5 DEFECATION IN OPEN FIELD 1 : None 2 : Feces normal 3 : Soft or liquid feces N N N 8 2 0 10 0 0 8 1 i IV 3 10 10.7 2.3 ' V 10 10 10.9 2.6 88 i2 X0 URINATION IN OPEN FIELD (1) None (2) Normal urination (3) Excess urination N N N MEAN SCORE LEVEL OF AROUSAL (1) Stuporous (2) Sluggish (3) Apparently normal (4) Sudden darting (5) Freezing, vocalization N N N N N MEAN SCORE 6 4 0 1.4 0 0 10 0 0 3.0 ' 7 3 0 1.3 0 0 10 0 0 3.0 7 3 0 1.3 0 0 10 0 0 3.0 10 0 0 1.0 0 0 10 0 0 3.0 8 2 0 1.2 0 0 10 0 0 3.0 418-028:PAGE C-32 ALTERATIONS (OPEN FIELD) 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 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 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 DOSAGE (MG/KG/DAY) FEMALE RATS I 0 N 10 II 0.3 10 III 1 10 IV 3 10 V 10 10 GAIT PATTERN 1: Apparently normal N 10 10 10 10 2: Ataxic N0 0 0 0 3: Limbs splay or drag N 0 0 0 0 4: Spastic, tip-toe N 0 0 0 0 5: Duck-walk N0 0 0 0 6: Scissors gait N0 0 0 0 8 0 0 2 0 0 GAIT ABNORMALITY, SEVERITY (1) Normal gait N 10 10 10 10 (2) Slight N0 0 0 0 (3) Moderate N0 0 0 0 (4) Extreme N0 0 0 0 MEAN SCORE 1.0 1.0 1.0 1.0 8 2 0 0 1.2 PALPEBRAL CLOSURE (1) Wide open N 10 10 10 10 (2) Slightly drooping N 0 0 0 0 (3) Half-closed N0 0 0 0 (4) Completely shut N 0 0 0 0 MEAN SCORE 1.0 1.0 1.0 1.0 10 0 0 0 1.0 418-028:PAGE C-33 PROMINENCE OF THE EYE 1: Normal N 10 10 10 10 10 2 : Exophthalmos N0 0 0 0 0 3 : Enophthalmos N0 0 0 0 0 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 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 DOSAGE (MG/KG/DAY)_______________ FMAL RATS ~N LACRIMATION (1) No excess N (2) Excess at eyelid margin N (3) Margin persistently damp (4) Extends beyond margin N N MEAN SCORE I 0_______________ 10 II 0.3 10 10 10 00 00 00 1.0 1.0 III 1 10 10 0 0 0 1.0 IV 3 10 10 0 0 0 1.0 V 10 10 10 0 0 0 1.0 SALIVATION (1) No excess N (2) Margin of mouth wet N (3) 1/4 to 1/2 submandibular (4) Entire submandibular N N MEAN SCORE 10 0 0 0 1.0 10 0 0 0 1.0 10 0 0 0 1.0 10 0 0 0 1.0 10 0 0 0 1.0 PILOERECTION N0 0 0 0 0 ABNORMAL RESPIRATION N APPEARANCE (1) Clean and groomed (2) Unkempt N N (3) Urine and/or fecal stain N MEAN SCORE 0 10 0 0 1.0 0 10 0 0 1.0 0 9 1 0 1.1 0 9 0 1 1.2 1 10 0 0 1.0 418-028:PAGE C-34 VISUAL REACTION (1) None N0 0 0 0 0 (2) Orienting (3) Startle (4) More energetic reaction N N N 10 0 0 10 0 0 10 0 0 10 0 0 10 0 0 (5) Attacks N0 0 0 0 0 MEAN SCORE 2.0 2.0 2.0 2.0 2.0 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 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 DOSAGE (MG/KG/DAY) FEMALE RATS I 0 N 10 ii 0.3 10 III 1 10 IV 3 10 V 10 10 TACTILE REACTION (1) None N0 0 0 0 (2) Orienting N 10 10 10 10 (3) Startle N0 0 0 0 (4) More energetic reaction N 0 0 0 0 (5) Attacks N0 0 0 0 MEAN SCORE 2.0 2.0 2.0 2.0 0 10 0 0 0 2.0 AUDITORY REACTION (1) None N0 0 0 0 (2) Orienting N0 0 0 1 (3) Startle N 10 10 10 9 (4) More energetic reaction N 0 0 0 0 (5) Intense vocalization N 0 0 0 0 MEAN SCORE 3.0 3.0 3.0 2.9 0 1 9 0 0 2.9 TAIL--PINCH REACTION (1) None N0 0 0 0 (2) Orienting N8 9 8 10 (3) Startle N2 X 2 0 (4) More energetic reaction N 0 0 0 0 (5) Attacks N0 0 0 0 0 9 1 0 0 418-028:PAGE C-35 MEAN SCORE 2.2 2.1 2.2 2.0 2.1 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 DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY R'S STUDY NUMBER: T-7706.1) Y - SUMMARY - Fo GENERATION FEMALE RATS ii III 0.3 1 10 10 IV 3 10 V 10 10 10 10 00 00 1.0 1.0 10 10 10 0 0 1.0 10 10 0 0 1.0 10 1.7 16.7 396.5 319.8 125.7 100.6 492.5 423.9 257.7 207.3 493.0 452.5 112.3 103.4 518.5 460.3 161.9 166.4 .1.3 .3.7 412.5 366.5 104.7 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 8 6.7 1.0 7.7 1.5 7.1 1.4 8.1 1.7 1.0 347.2 14.8 350.6 22.8 345 .2 20.0 328.3 44.7 as calculated by multiplying each score by the number of rats with that score total number of rats 528: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) 3E 1) : MOTORACTIVITY - SUMMARY - Fo GENERATION FEMALE RATS 'DAY) I II 0 0.3 kLE RATS N 10 10 SMENTS MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN t 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 53.6 41.2 30.7 21.2 19.4 17.8 13.2 10.5 6.5 7.0 5.9 15.0 19.0 13.0 15.0 11.7 10.8 378.6 7.6 20.8 34.2 25.5 23.6 + 20.7 23.2 18.6 24.3 7.2 16.6 5.3 22.1 19.6 15.7 16.7 18.6 14.7 202.4 BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD III 1 10 68.3 66.6 50.2 43.9 43.6 42.6 44.5 38.0 28.1 29.4 26.9 21.1 24.3 24.4 23.6 24.5 24.7 17.9 642.6 6.8 12.4 17.0 26.8 26.4 29.5 21.3 20.5 25.4 29.3 28.2 26.2 26.3 30.8 25.9 28.2 27.9 18.9 295.6 IV V 3 10 10 10 65.7 57.1 49.3 39.0 33.9 35.0 38.3 44.5 34.0 25.9 23.5 21.8 19.8 24.4 19.8 27.2 21.9 19.0 600.1 9.7 18.2 21.4 25.1 24.2 26.8 29.4 t 18.0 19.0 23.5 22.7 + 20 .4 25.0 26.2 24.9 29.0 23.2 25.3 292.0 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 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 11 III 0 0.3 1 NUMBER OF FEMALE RATS N 10 10 10 TIME (SECONDS) SPENT IN MOVEMENT BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK TOTAL 1 2 3 4 S 6 7 8 9 10 11 12 13 14 15 16 17 18 MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN t 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 t 331.8 141.5 46.3 154.4 32.2 94.0 54.4 114.4 24.2 60.1 48.0 88.5 + 56.9 48.0 48.9 70.2 52.2 27.5 30.6 63.4 42.7 31.0 41.8 56.1 41.1 21.4 31.9 69.0 46.5 15.5 26.5 60.7 36.2 13.8 37.1 37.9 41.2 6.2 9.6 38.7 44.1 8.3 21.8 39.7 44.2 4.2 3.7 34.4 48.6 14.7 21.0 38.4 52.5 24.1 27.9 34.5 48.1 15.5 23.7 36.4 44.5 17.6 24.1 36.1 42.1 13.7 27.6 37.8 48.8 9.6 14.8 18.1 23.2 566.7 350.6 1028.7 t 477.6 TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD IV V 3 10 10 10 181.0 119.5 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 26.1 96.6 63.6 52.3 51.5 34.6 45.9 27.6 35.5 31.0 30.6 16.5 29.0 41.7 38.3 40.1 38.6 14.1 16.3 24.6 33.0 38.7 34.5 32.7 43.3 25.6 30.6 17.3 + 25.7 18.5 23.1 21.7 33.6 27.6 30.1 707.4 442.6 8-DHOVd:80-8W 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 rv V 0 0.3 1 3 10 RATS ASSIGNED TO NATURAL DELIVERY N 15 15 IS 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 N PER DELIVERED LITTER 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) K 7.7) 3( 23.1) 2{ 13.3) DAMS WITH NO LXVEBORN PUPS N 0( 0.0) 0( 0.0) 0( 0.0) 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 0) and the time (in days) the first pup was delivered. b. Number of rats with live offspring/number of pregnant rats. 6-OH9V<reO-m 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 - FI GENERATION LITTERS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) I II III 0 0.3 1 DELIVERED LITTERS WITH ONE OR MORE LIVEBORN PUPS N 15 15 13 PUPS DELIVERED (TOTAL) N MEANS.D. 235 15.7 1.7 214 14.3 3.2 201 15.5 1.4 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) STILLBORN MEANS.D. N(%> 0.0 0.0 0( 0.0) 0.0 0.0 0( 0.0) 0.1 0.3 M 0.5) UNKNOWN VITAL STATUS N 0 0 0 PUPS FOUND DEAD OR PRESUMED CANNIBALIZED DAY 1 DAYS 2 - 8 DAYS 9-15 DAYS 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) VIABILITY INDEX a % 97.0 N/N 228/235 96.3 206/214 98.5 197/200 LACTATION INDEX b % 100.0 N/N 228/228 99.0 204/206 99.5 196/197 DAY(S) DAY (S) POSTPARTUM a. Number of live pups on day 8 postpartum/number of l i v e b o m pups on day 1 postpartum. b. Number of live pups on day 22 postpartum/number of live pups on day 8 postpartum. IV 3 13 181 13.9 3.1 13.6 3.2 177( 97.8) 0.2 0.4 3{ 1.6) 1 2/177 ( 2/175 ( 1/173( 0/172( 1.1) 1.1) 0.6) 0.0) 97.7 173/177 99.4 172/173 V 10 15 220 14.7 2.5 14.5 2.4 218( 99.1) 0.1 0.4 2( 0.9) 0 3/218( 3/215( 1/212( 0/211( 1.4) 1.4) 0.5) 0.0) 97.2 212/218 99.5 211/212 418-028-.PAGEC40 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 - FI GENERATION LITTERS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) I II III 0 0.3 1 DELIVERED LITTERS WITH ONE OR MORE LIVEBORN PUPS N 15 15 13 SURVIVING PUPS/LITTER a DAY 1 MEANS.D. 15.7 1.7 14.3 3.2 15.4 1.6 DAY 8 MEANS.D. 15.2 1.8 13.7 2.9 15.2 1.5 DAY 15 MEANS.D. 15.2 1.8 13.6 2.8 15.1 + 1.3 DAY 22 MEANS.D. 15.2 1.8 13.6 2.8 15.1 1.3 PERCENT MALE PUPS PER NUMBER OF PUPS SEXED DAY 1 MEANS.D. 45.2 12.4 51.9 13.1 51.6 6.8 DAY 8 MEANS.D. 45.2 13.0 52.7 + 12.0 51.8 6.3 DAY 15 MEANS.D, 45.2 13.0 53.1 11.8 52.0 6.2 DAY 22 MEANS.D. 45.2 13.0 53.1 11.8 52.0 6.2 DAY = DAY POSTPARTUM a. Average number of live pups per litter, including litters with no surviving pups. b. includes pups b o m alive, found dead day 1 postpartum. IV 3 13 13.6 3.2 13.3 3.3 13.2 3.2 13.2 3.2 43.6 13.4 42.9 13.1 43.1 13.0 43.1 13.0 V 10 15 14.5 2.4 14.1 2.1 14.1 2.2 14.1 2.2 51.4 13.4 51.4 13.9 51.8 14.2 51.8 14.2 -3HDV<mO-8lfr 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 - FI GENERATION LITTERS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) DELIVERED LITTERS WITH ONE OR MORE LIVEBORN PUPS N LIVE LITTER SIZE AT WEIGHING DAY 1 MEANS.D. DAY 8 MEANS.D. DAY 15 MEANS.D. DAY 22 MEANS.D. PUP WEIGHT/LITTER (GRAMS) DAY 1 MEANtS.D. DAY 8 MEANS.D. DAY 15 MEANS.D. DAY 22 MEANS.D. DAY = DAY POSTPARTUM I 0 15 15.6 1.8 15.2 1.8 15.2 1.8 15.2 1.8 6.3 0.3 14.3 1.6 26.2 2.8 37.4 4.7 II 0.3 15 14.1 3.1 13.7 2.9 13.6 2.8 13.6 2.8 6.3 0.5 13.3 1.7 26.3 3.9 39.3 6.9 III 1 13 15.4 1.6 15.2 1.5 15.1 1.3 15.1 1.3 6.4 0.3 13.8 1.0 25.9 2.6 38.0 5.7 IV 3 13 13.5 3.3 13.3 3.3 13.2 3.2 13.2 3.2 6.5 0.7 14.1 3.1 27.4 5.7 40,0 7.9 V 10 15 14.3 2.2 14.1 2.1 14.1 2.2 14.1 2.2 6.3 0.5 13.1 1.5 25.1 3.3 36.2 7.7 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 - FI GENERATION PUPS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) LITTERS EXAMINED (N) I II III 0 0.3 1 15 15 13 IV 3 13 TRANSIENT CLINICAL OBSERVATIONS : a TOTAL FREQUENCY (DAYS X PUPS)/LITTERS WITH OBSERVATIONS NOT NURSING EMACIATION N/N 0/0 1/1 0/0 0/0 N/N 0/0 0/0 0/0 0/0 DEHYDRATION N/N 0/0 4/1 2/2 0/0 WHOLE BODY, EXCLUDING HEAD, DISCOLORATION, PURPLE N/N 0/0 0/0 0/0 0/0 SCAB b N/N 0/0 0/0 0/0 6/1 COLD TO TOUCH N/N 0/0 2/2 0/0 0/0 LEFT EYE, PERIORBITAL DISCOLORATION, PURPLE N/N 0/0 0/0 0/0 8/1 RIGHT EYE, ENLARGED N/N 0/0 0/0 0/0 3/1 RIGHT HINDLIMB, LACERATION N/N 0/0 0/0 0/0 1/1 BACK, BRUISE N/N 2/1 4/1 0/0 0/0 NOT NESTING N/N 0/0 1/1 0/0 0/0 PALE IN APPEARANCE N/N 3/2 0/0 0/0 0/0 RIGHT EYE, CORNEAL OPACITY N/N 5/1 0/0 0/0 0/0 a. Tabulation restricted to adverse observations; all other pups appeared normal. b. Right hindlimb or head. V 10 15 13/1 13/1 13/1 6/1 3/1 1/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 tt-D3OVd:80-8lfr PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-770S WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-770S.1) TABLE C26 (PAGE 1) : NECROPSY OBSERVATIONS - SUMMARY - FI GENERATION PUPS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) I II III 0 0.3 1 IV 3 V 10 LITTERS EXAMINED (N) 15 15 13 13 15 TOTAL PUPS STILLBORN, OR FOUND DEAD a,b N6 5 2 4 STILLBORN N0 0 1 2 FOUND DEAD N6 5 1 2 3 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(t> 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) M 6.7) M 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. 418-028;PAGEC-44 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 - FI GENERATION PUPS DOSAGE GROUP DOSAGE (MG/KG/DAY) LITTERS EXAMINED TERMINAL BODY WEIGHT WEIGHT/LITTER MALE PUPS FEMALE PUPS I 0 N 10 MEAN+S.D . MEAN+S.D. MEAN+S.D. 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 MALE PUPS MEAN+S.D. 3.86 + 0.27 FEMALE PUPS MEAN+S.D. 4.33 + 0.24 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . 4.10 + 0.28 3.91 + 0.33 4.28 + 0.26 4.14 + 0.33 4.23 + 0.37 3.98 + 0.34 4.02 + 0.44 4.01 + 0.47 3.79 + 0.37 4.26 + 0.34 4.46 + 0.35 4.17 + 0.36 RATIOS (%) = (LIVER WEIGHT/TERMINAL BODY WEIGHT) X 100. 418-028:PAGE C-45 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 ( DG ( DL( DL{ DL ( 9) 9- 21) 1- 2) 9- 13) 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 418-028:PAGEC-46 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 X 1.0 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: LIMBS a TAIL: SCAB (3.0 CM X 0.8 CM)a NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS DS = DAY OF STUDY DG = DAY OF PRESUMED GESTATION a. Observation confirmed at necropsy. DL = DAY OF LACTATION 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 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: BACK a NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NOSE : SWOLLEN LOCALIZED ALOPECIA: LIMBS LOCALIZED ALOPECIA: LIMBS a LOCALIZED ALOPECIA: LIMBS LOCALIZED ALOPECIA: LIMBS a NO ADVERSE FINDINGS LOCALIZED ALOPECIA: LIMBS a NO ADVERSE FINDINGS TIP OF TAIL MISSING a 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. DL - DAY OF LACTATION 418-028:PAGE C-49 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 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070 DS( 6- 12) DS ( 6- 12) DS ( 10- 12) DS ( 11 ) DS ( 11- 12) DS ( 11- 12) DS ( 11- 12) DS ( 11- 17) DG ( 0- 6) DG ( 7- 20) DL( 2- 22) DL( 7- 22) DL( 14- 15) DL( 14- 22) DL{ 17 ) DL( 18- 22) DL( 17- 22) DL( 17- 22) NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS BROWN PERIORAL SUBSTANCE RALES URINE-STAINED ABDOMINAL FUR COLD TO TOUCH MIOSIS ABDOMINAL DISTENTION EMACIATION LOCALIZED ALOPECIA: HEAD LOCALIZED ALOPECIA: HEAD LOCALIZED ALOPECIA: LIMBS LOCALIZED ALOPECIA: LIMBS a ABDOMINAL DISTENTION a EMACIATION RALES DEHYDRATION EMACIATION a NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS HEAD: SCAB (0.3 CM X 0.3 CM)a LOCALIZED ALOPECIA: HEAD a 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. DL DAY OF LACTATION 418-028:PAGE C-50 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. 190S0 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. 19052 DL 22 P 56 ALL TISSUES APPEARED NORMAL. 19055 DL 22 P 57 ALL TISSUES APPEARED NORMAL. 19061 DL 22 P 56 ALL TISSUES APPEARED NORMAL. 19067 DL 22 P 58 ALL TISSUES APPEARED NORMAL. 19071 DL 22 P 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. 418-028:PAGE C-5 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 DOSAGE (MG/KG/DAY) RAT NUMBER DAY OF PREGNANCY DOSES NECROPSY STATUS ADMINISTERED OBSERVATIONS a III 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 DL 22 DG 25 DL 22 DL 22 DL 22 DL 22 DL 22 DG 25 DL 22 DL 22 DL 22 DL 22 P P NP P P P P P NP P P P 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 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. HOVd'80-8Ifr 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 DL 22 DL 22 P P 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 DL 22 DL 22 P P P 59 ALL TISSUES APPEARED NORMAL. 58 ALL TISSUES APPEARED NORMAL. 57 ALL TISSUES APPEARED NORMAL. DG = DAY OF PRESUMED GESTATION DL a DAY OF LACTATION P a PREGNANT NP - NOT PREGNANT a. Refer to the individual clinical observations table (Table C27) for external observations confirmed at necropsy. 418-028:PAGE C-53 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 DOSAGE (MG/KG/DAY) RAT NUMBER DAY OF PREGNANCY DOSES 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 DL 22 DL 22 DL 22 DL 22 DL 22 DL 22 DL 22 DL 22 DL 22 DL 22 P P P P P P P P P P 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 a. Refer to the individual clinical observations table (Table C27) for external observations confirmed at necropsy. 418-028:PAGE C-54 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-770S.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 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 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 P P P P P P P P P P 335. 309. 270. 280 . 305. 302. 360. 290. 299. 301. 2.22 2.22 2.21 2.11 2.09 2.25 2.17 2.11 2.25 2.00 0.66 0.72 0.82 0.75 0.68 0.74 0.60 0.73 0.75 0.66 16.17 15.21 14.21 13.09 12.15 14.31 19.73 12.84 13.17 12.97 4.83 4.92 5.26 4.68 3.98 4.74 5.48 4.43 4.40 4.31 1.53 1.43 1.50 1.23 1.24 1.60 1.51 1.32 1.26 1.30 0.46 0.46 0.56 0.44 0 .41 0.53 0.42 0.46 0.42 0.43 1.66 1.46 1.55 1.39 1.35 1.57 1.60 1.41 1.34 1.33 0.50 0.47 0.57 0.50 0.44 0.52 0.44 0.49 0.45 0.44 0.050 0.055 0.045 0.054 0.048 0.056 0.076 0.048 0.049 0.042 14.92 17.80 16.67 19.28 15.74 18.54 21.11 16.55 16.39 13.95 0.047 0.047 0.040 0.028 0.044 0.046 0.053 0.036 0.043 0.044 14.03 15.21 14.81 10.00 14.43 15.23 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 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075 P P P P P P P P P P P P P P P 299. 335. 309. 270. 280. 305. 302. 360. 290. 299. 301. 360. 292. 297. 295. 0.78 0.64 0.58 0.58 0.54 0.64 0.67 0.74 0.61 0.54 0.23 0.21 0.21 0.21 0.18 0.21 0.19 0.26 0.20 0.18 0.23 0.31 0.11 0.16 0.16 0.33 0.27 0.20 0.17 0.17 0.07 0.10 0.04 0.06 0.05 0.11 0.08 0.07 0.06 0.06 0.035 0.092 0.044 0.044 0.039 0.062 0.059 0.070 0.044 0.058 0.068 0.048 0.051 0.057 0.059 11.70 27.46 14.24 16.30 13.93 20.33 19.54 19.44 15.17 19.40 22.59 13.33 17.46 19.19 20.00 0.042 0.073 0.064 0.040 0.062 0.037 0.057 0.081 0.048 0.085 0.066 0.075 0.060 0.073 0.073 14.05 21.79 20.71 14.81 22.14 12.13 18.87 22.50 16.55 28.43 21.93 20.83 20.55 24.58 24.74 0.48 0.57 0.51 0.53 0.62 0.46 0.68 0.56 0.56 0.47 0.69 0.55 0.36 0.53 0.44 0.16 0.17 0.16 0.20 0.22 0.15 0.22 0.16 0.19 0.16 0.23 0.15 0.12 0.18 0.15 1.32 1.55 1.31 1.62 1.35 1.64 1.45 1.19 1.41 1.13 0.39 0.50 0.48 0.58 0.44 0.54 0.40 0.41 0.47 0.38 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . ABS. WT. = ORGAN WEIGHT. P PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) a. Value was multiplied by 1000. REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. 418-028:PAGE C-55 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 19009 19016 19018 19026 19036 19037 19043 19047 19048 P P P P P P P P P 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 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071 P P P P P P P P P P P P P P P 276. 346. 314. 338. 296. 359. 309. 356. 325. 306. 320. 336. 315. 294. 374. 0.60 0.61 0.53 0.74 0.70 0.74 0.74 0.77 0.55 0.55 0.22 0.18 0.17 0.22 0.24 0.21 0.24 0.22 0.17 0.18 0.24 0.31 0.16 0.21 0.18 0.28 0.21 0.10 0.21 0.19 0.09 0.09 0.05 0.06 0.06 0.08 0.07 0.03 0.06 0.06 0.083 0.067 0.063 0.064 0.048 0.077 0.062 0.052 0.057 0.024 0.093 0.032 0.038 0.061 0.026 30.07 19.36 20.06 18.93 16.22 21.45 20.06 14.61 17.54 7.84 29.06 9.52 12.06 20.75 6.95 0.071 25.72 0.072 20.81 0.081 25.80 0.068 20.12 0.075 25.34 0.095 26.46 0.046 14.89 0.056 15.73 0.059 18.15 0.026 8.50 0.055 17.19 0.052 . 15.48 0.025 7.94 0.059 20.07 0.058 15.51 0.65 0.51 0.70 0.64 0.73 0.58 0.45 0.63 0.55 0.56 0.45 0.28 0.53 0.50 0.71 0.24 0.15 0.22 0.19 0.25 0.16 0.14 0.18 0.17 0.18 0.14 0.08 0.17 0.17 0.19 1.35 1.51 1.23 1.16 1.35 1.20 1.15 1.31 1.05 1.25 0.49 0.44 0.39 0.34 0.46 0.33 0.37 0.37 0.32 0.41 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . ABS. WT. = ORGAN WEIGHT. P - PREGNANT NP - NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) a. Value was multiplied by 1000. REL. % TBW - (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. 418-028:PAGE C-56 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 19007 19008 19013 19015 19017 19024 19029 19034 19056 P P P P P P P P P 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 19007 19008 19013 19015 19017 19024 19029 19034 19056 19057 19060 19064 P P P P P P P P P P P P P 284. 303. 292. 389. 274. 350. 309. 332. 287. 292. 287. 357. 289. 0.62 0.82 0.49 0.65 0.42 0.60 0.61 0.60 0.54 0.65 0.22 0.27 0.17 0.17 0.15 0.17 0.20 0.18 0.19 0.22 0.14 0.12 0.17 0.22 0.24 0.13 0.19 0.16 0.18 0.22 0.05 0.04 0.06 0.06 0.09 0.04 0.06 0.05 0.06 0.08 0.054 0.053 0.050 0.068 0.043 0.053 0.043 0.041 0.062 0.051 0.034 0.089 0.051 19.01 17.49 17.12 17.48 15.69 15.14 13.92 12.35 21.60 17.46 11.85 24.93 17.65 0.079 0.086 0.055 0.080 0.048 0.048 0.020 0.058 0.074 0.043 0.041 0.092 0.051 27.82 28.38 18.84 20.56 17.52 13.71 6.47 17.47 25.78 14.73 14.28 25.77 17.65 0.48 0.79 0.53 0.58 0.48 0.35 0.42 0.34 0.44 0.66 0.35 0.61 0.44 0.17 0.26 0.18 0.15 0.18 0.10 0.14 0.10 0.15 0.23 0.12 0.17 0.15 1.29 1.30 1.17 1.35 1.51 1.36 1.40 1.48 1.21 1.39 0.45 0.43 0.40 0.35 0.55 0.39 0.45 0.44 0.42 0.48 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) a. Value was multiplied by 1000. b. 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). 418-028:PAGE C-57 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 EIGHTS AND ORGAN EIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY EIGHT 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. T. % TBW a 19005 19035 19039 19040 19045 19054 19058 19062 19063 19066 P P P P P P P P P 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 EIGHT SPLEEN ABS. WT. REL. % TBW THYMUS ABS. iT, REL. % TBW OVARY LEFT ABS. REL. T. % TBW a OVARY RIGHT ABS. REL. T. % TBW a UTERUS WITH CERVIX ABS. REL. WT. % TBW HEART ABS. T. REL. % TBW 19002 19005 19035 19039 19040 19045 19054 19058 19062 19063 19066 19069 19073 P P P P P P P P P P P P P 302 . 285. 261. 315. 294. 385. 287. 350. 290. 369. 292. 362. 363. 0.54 0.66 0.71 0.64 0.61 0.84 0.77 0.62 1.59b 0.55 0.19 0.25 0.22 0.22 0.16 0.29 0.22 0.21 0.43 0.19 0.14 0.16 0.25 0.24 0.13 0.36 0.12 0.14 0.09 0.39 0.05 0.06 0.08 0.08 0.03 0.12 0.03 0.05 0.02 0.13 0.058 0.049 0.051 0.079 0.058 0.046 0.064 0.052 0.058 0.049 0.028 0.057 0.040 19.20 17.19 19.54 25.08 19.73 11.95 22.30 14.86 20.00 13.28 9.59 15.74 11.02 0.052 0.056 0.055 0.062 0.046 0.057 0.048 0.066 0.058 0.057 0.025 0.076 0.046 17.22 19.65 21.07 19.68 15.65 14.80 16.72 18.86 20.00 15.45 8.56 20.99 12.67 0.46 0.80 0.71 0.46 0.50 0.53 0.75 0.74 0.78 0.56 0.78 0.57 0.37 0.15 0.28 0.27 0.15 0.17 0.14 0.26 0.21 0.27 0.15 0.27 0.16 0.10 1.16 1.45 1.20 1.55 1.47 1.48 1.39 1.41 1.39 1.51 0.41 0.56 0.38 0.53 0.38 0.52 0.40 0.49 0.38 0.52 418-028:PAGE C-58 ALL EIGHTS ERE RECORDED IN GRAMS (G) . ABS. WT. = ORGAN WEIGHT. P - PREGNANT NF = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY EIGHT) X 100 . a. Value was multiplied by 1000. b. Dam 19063 had omentum adhered to the entire length of the outer capsule of the spleen. 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 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 19006 19011 19020 19022 19025 19027 19028 19030 19031 P P P P P P P P P 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 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070 P P P P P P P P P P P P P P P 278. 304. 283. 210. 294. 291. 266. 339. 314. 361. 287. 328. 330. 317. 351. 0.57 0.54 0.50 0.28b 0.53 0.56 0.61 0.54 0.58 0.64 0.20 0.18 0.18 0.13 0.18 0.19 0.23 0.16 0.18 0.18 0.18 0.15 0.15 0.11b 0.14 0.25 0.23 0.23 0.17 0.16 0.06 0.05 0.05 0.05 0.05 0.08 0.09 0.07 0.05 0.04 0.048 0.056 0.046 0.036 0.060 0.053 0.039 0.087 0.045 0.076 0.031 0.069 0.050 0.061 0.051 17.27 18.42 16.25 17.14 20.41 18.21 14.66 25.66 14.33 21.05 10.80 21.04 15.15 19.24 14.53 0.047 0.074 0.036 0.047 0.035 0.058 0.018 0.053 0.048 0.087 0.043 0.076 0.073 0.063 0.045 16.91 24.34 12.72 22.38 11.90 19.93 6.77 15.63 15.29 24.10 14.98 23.17 22.12 19.87 12.82 0.64 0.46 0.68 0.50 0.74 0.53 0.44 0.37 0.78 0.74 0.33 0.82 0.50 0.39 0.47 0.23 0.15 0.24 0.24 0.25 0.18 0.16 0.11 0.25 0.20 0.11 0.25 0.15 0.12 0.13 0.92 1.57 1.24 0.90 1.54 1.38 1.32 1.56 1.37 1.50 0.33 0.52 0.44 0.43 0.52 0.47 0.50 0.46 0.44 0.42 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . ABS. WT. - ORGAN WEIGHT. 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. (Table C28). REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. See the individual necropsy observations table 418-028:PAGE C-59 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 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 P P P P P P P P P P 2.22 2.22 2.21 2.11 2.09 2.25 2.17 2.11 2.25 2.00 LIVER ABS. WT. REL. t BRW 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 KIDNEY LEFT ABS. REL. WT. % BRW 1.53 1.43 1.50 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 KIDNEY RIGHT ABS. REL. WT. % BRW 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 ADRENAL LEFT ABS. REL. WT. % BRW 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 ADRENAL RIGHT ABS. REL. WT. % BRW 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 SPLEEN ABS. WT. REL. % BRW 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. <t BRW UTERUS WITH CERVIX ABS. REL. WT. % BRW HEART ABS. WT. REL. % BRW 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 P P P P P P P P P P 2.22 2.22 2.21 2.11 2.09 2.25 2.17 2.11 2.25 2.00 0.23 0.31 0.11 0.16 0.16 0.33 0.27 0.20 0.17 0.17 10.36 13.96 4.98 7.58 7.66 14.67 12.44 9.48 7.56 8.50 0.092 0.044 0.044 0.039 0.062 0.059 0.070 0.044 0.058 0.068 4.14 1.98 1.99 1.85 2.97 2.62 3.22 2.08 2.58 3.40 0.073 0.064 0.040 0.062 0.037 0.057 0.081 0.048 0.085 0.066 3.29 2.88 1.81 2.94 1.77 2.53 3.73 2.27 3.78 3.30 0.57 0.51 0.53 0.62 0.46 0.68 0.56 0.56 0.47 0.69 25.68 22.97 23.98 29.38 22.01 30.22 25.81 26.54 20.89 34.50 1.32 1.55 1.31 1.62 1.35 1.64 1.45 1.19 1.41 1.13 59.46 69.82 59.28 76.78 64.59 72.89 66.82 56.40 62.67 56.50 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . ABS. WT. = ORGAN WEIGHT. P = PREGNANT NP - NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. 418-028:PAGE C-60 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. !t BRW ADRENAL LEFT ABS. REL. WT. % BRW ADRENAL RIGHT ABS. REL. WT. % BRW SPLEEN ABS. WT. REL. % BRW 19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 P P P P P P P P P P 1.99 2.11 2.17 2.04 2.12 2.13 2.09 2.23 2.00 2.24 11.23 16.IS 18.06 19.18 15.44 16.63 18.25 18.19 14.85 11.85 564.32 765.40 832.26 940.20 728.30 780.75 873.20 815.70 742.50 529.02 1.34 1.38 1.41 1.41 1.65 1.45 1.43 1.77 1.35 1.55 67.34 65.40 64.98 69.12 77.83 68.08 68.42 79.37 67.50 69.20 1.40 1.37 1.43 1.42 1.70 1.54 1.53 1.87 1.47 1.42 70.35 64.93 65.90 69.61 80.19 72.30 73.20 83.86 73.50 63.39 0.043 0.038 0.059 0.052 0.054 0.042 0.056 0.065 0.044 0.055 2.16 1.80 2.72 2.55 2.55 1.97 2.68 2.91 2.20 2.46 0.049 0.033 0.048 0.041 0.045 0.044 0.047 0.053 0.027 0.024 2.46 1.56 2.21 2.01 2.12 2.06 2.25 2.38 1.35 1.07 0.60 0.61 0.53 0.74 0.70 0.74 0.74 0.77 0.55 0.55 30.15 28.91 24.42 36.27 33.02 34.74 35.41 34.53 27.50 24.55 RAT NUMBER BRAIN WEIGHT THYMUS ABS. WT. REL. % BRW OVARY LEFT ABS. REL. WT. % BRW OVARY RIGHT ABS. REL. WT. 1 BRW UTERUS WITH CERVIX ABS. REL. WT. % BRW HEART ABS. WT. REL. % BRW 19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 P P P P P P P P P P 1.99 2.11 2.17 2.04 2.12 2.13 2.09 2.23 2.00 2.24 0.24 0.31 0.16 0.21 0.18 0.28 0.21 0.10 0.21 0.19 12.06 14.69 7.37 10.29 8.49 13.14 10.05 4.48 10.50 8.48 0.083 0.067 0.063 0.064 0.048 0.077 0.062 0.052 0.057 0.024 4.17 3.18 2.90 3.14 2.26 3.62 2.97 2.33 2.85 1.07 0.071 0.072 0.081 0.068 0.075 0.095 0.046 0.056 0.059 0.026 3.57 3.41 3.73 3.33 3.54 4.46 2.20 2.51 2.95 1.16 0.65 0.51 0.70 0.64 0.73 0.58 0.45 0.63 0.55 0.56 32.66 24.17 32.26 31.37 34.43 27.23 21.53 28.25 27.50 25.00 1.35 1.51 1.23 1.16 1.35 1.20 1.15 1.31 1.05 1.25 67.84 71.56 56.68 56.86 63.68 56.34 55.02 58.74 52.50 55.80 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . ABS. WT. = ORGAN WEIGHT. P PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) REL. % TBW - (ORGAN WEIGHT/BRAIN WEIGHT) X 100. 418-028:PAGE C-61 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. (fc 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 19007 19008 19013 19015 19017 19024 19029 19034 19056 P P P P P P P P P 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. iir BRW OVARY RIGHT ABS. REL. WT. * BRW UTERUS WITH CERVIX ABS. REL. WT. % BRW HEART ABS. WT. REL. % BRW 19003 19007 19008 19013 19015 19017 19024 19029 19034 19056 P P P P P P P P P P 2.13 2.16 2.01 2.05 2.21 2.15 2.23 1.98 2.10 2.02 0.14 0.12 0.17 0.22 0.24 0.13 0.19 0.16 0.18 0.22 6.57 5.56 8.46 10.73 10.86 6.05 8.52 8.08 8.57 10.89 0.054 0.053 0.050 0.068 0.043 0.053 0.043 0.041 0.062 0.051 2.54 2.45 2.49 3.32 1.94 2.46 1.93 2.07 2.95 2.52 0.079 0.086 0.055 0.080 0.048 0.048 0.020 0.058 0.074 0.043 3.71 3.98 2.74 3.90 2.17 2.23 0.90 2.93 3.52 2.13 0.48 0.79 0.53 0.58 0.48 0.35 0.42 0.34 0 .44 0.66 22.54 36.57 26.37 28.29 21.72 16.28 18.83 17.17 20.95 32.67 1.29 1.30 1.17 1.35 1.51 1.36 1.40 1.48 1.21 1.39 60.56 60.18 58.21 65.85 68.32 63.26 62.78 74.75 57.62 68.81 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). 418-028-.PAGEC-62 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. 1: BRW ADRENAL LEFT ABS. REL. WT. % BRW ADRENAL RIGHT ABS. REL. WT. % BRW SPLEEN ABS. WT. REL. % BRW 19005 19035 19039 19040 19045 19054 19058 19062 19063 19066 P P P P P P P P P 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 19035 19039 19040 19045 19054 19058 19062 19063 19066 P P P P P P P P P P 1.81 2.04 2.09 2.05 2.15 2.49 2.15 2.13 2.03 1.91 0.14 0.16 0.25 0.24 0.13 0.36 0.12 0.14 0.09 0.39 7.73 7.84 11.96 11.71 6.05 14.46 5.58 6.57 4.43 20.42 0.049 0.051 0.079 0.058 0.046 0.064 0.052 0.058 0.049 0.028 2.71 2.50 3.78 2.83 2.14 2.57 2.42 2.72 2.41 1.46 0.056 0.055 0.062 0.046 0.057 0.048 0.066 0.058 0.057 0.025 3.09 2.70 2.97 2.24 2.65 1.93 3.07 2.72 2.81 1.31 0.80 0.71 0.46 0.50 0.53 0.75 0.74 0.78 0.56 0.78 44.20 34.80 22.01 24.39 24.65 30.12 34.42 36.62 27.59 40.84 1.16 1.45 1.20 1.55 1.47 1.48 1.39 1.41 1.39 1.51 64.09 71.08 57.42 75.61 68.37 59.44 64.65 66.20 68.47 79.06 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 19063 had omentum adhered to the entire length of the outer capsule of the spleen. See the individual necropsy observations table (Table C28). 418-028:PAGE C-63 PROTOCOL 4X8-028: 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. t 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 19006 19011 19020 19022 19025 19027 19028 19030 19031 P P P P P P P P P 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. t BRW UTERUS WITH CERVIX ABS. REL. WT. % BRW HEART ABS. WT. REL. % BRW 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 P P P P P P P P P P 2.00 2.13 2.05 2.00 2.18 2.13 2.27 2.02 2.18 2.24 0.18 0.15 0.15 0.11a 0.14 0.25 0.23 0.23 0.17 0.16 9.00 7.04 7.32 5.50 6.42 11.74 10.13 11.39 7.80 7.14 0.048 0.056 0.046 0.036 0.060 0.053 0.039 0.087 0.045 0.076 2.40 2.63 2.24 1.80 2.75 2.49 1.72 4.31 2.06 3.39 0.047 0.074 0.036 0.047 0.035 0.058 0.018 0.053 0.048 0.087 2.35 3.47 1.76 2.35 1.60 2.72 0.79 2.62 2.20 3.88 0.64 0.46 0.68 0.50 0.74 0.53 0.44 0.37 0.78 0.74 32.00 21.60 33.17 25.00 33.94 24.88 19.38 18.32 35.78 33.04 0.92 1.57 1.24 0.90 1.54 1.38 1.32 1.56 1.37 1.50 46.00 73.71 60.49 45.00 70.64 64.79 58.15 77.23 62.84 66.96 ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. = ORGAN WEIGHT. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) a. Dam 19020 had a large left adrenal, small spleen, and small thymus. (Table C28). REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. See the individual necropsy observations table 418-028:PAGE C-64 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 ____ DOSAGE GROUP I " r a t "# 19012 AVERAGE OVARY #1 31 37 46 33 34 36.2 0 MG/KG/DAY OVARY #2 21 46 34 36 36 34.6 RAT # 19042 AVERAGE OVARY #1 1 0 1 6 3 2.2 OVARY #2 18 9 9 16 13 13.0 19019 AVERAGE 4 1 2 0 1 1.6 0 5 2 2 7 3.2 19044 AVERAGE 3 11 9 13 51 17.4 5 8 8 9 17 9.4 19021 AVERAGE 16 16 21 20 14 17.4 4 4 12 17 30 13.4 19050 AVERAGE 3 5 2 4 3 3.4 1 5 3 6 10 5.0 19023 AVERAGE 7 14 10 14 11 11.2 22 11 13 27 6 15.8 19053 AVERAGE 24 11 27 27 25 22.8 3 11 16 20 38 17.6 418-028:PAGE C-65 19041 AVERAGE 7 14 2 5 7 ____ 7.0 4 3 4 6 9 5.2 19065 AVERAGE 4 3 9 3 14 6.6 7 15 11 12 16 12.2 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 DOSAGE GROUP V RAT # 19001 AVERAGE OVARY #1 3 4 9 6 23 9.0 OVARY #2 6 5 6 17 20 10.8 10 MG/KG/DAY RAT # 19025 AVERAGE OVARY #1 11 12 6 6 7 8.4 OVARY #2 4 6 15 25 12 12.4 19006 AVERAGE 27 11 23 26 21 21.6 5 6 19 20 20 14.0 19027 AVERAGE 6 6 17 13 43 17.0 0 5 8 12 8 6.6 19011 AVERAGE 6 16 8 16 37 16.6 1 0 12 24 8 9.0 19028 AVERAGE 3 2 2 5 7 3.8 1 7 13 13 10 8.8 19020 AVERAGE 5 4 15 8 20 10.4 2 1 2 12 20 7.4 19030 AVERAGE 9 21 24 22 26 20.4 3 13 6 7 20 9.8 418-028:PAGE C- 19022 AVERAGE 9 2 5 1 7 4.8 9 4 11 17 19 12.0 19031 AVERAGE 11 15 11 9 14 12.0 7 4 14 11 17 10.6 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 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. RAT # DOSAGE GROUP II 0.3 MG/KG/DAY 19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071 205. 231. 222. 222. 221. 230. 217. 227. 219. 228. 228. 235. 219. 237. 230. 203. 234. 224. 228. 227. 235. 217. 228. 213. 230. 228. 231. 225. 238. 232. 214. 236. 225. 228. 232. 239. 222. 233. 207. 235. 226. 228. 225. 245. 232. 215. 246. 227. 233. 236. 243. 228. 237. 217. 240. 235. 239. 227. 246. 238. 214. 248. 231. 232. 231. 247. 228. 238. 211. 239. 240. 249. 233. 240. 238. 216. 252. 232. 230. 233. 249. 227. 237. 212. 240. 234. 243 . 238. 246. 242. 220. 252. 234. 240. 237. 249. 236. 245. 213. 246. 236. 241. 237. 251. 241. 226. 263. 234. 239. 239. 255. 241. 248. 223. 244. 245. 253 . 241. 252. 248. 222. 257. 240. 244. 236. 260. 244. 246. 224. 245. 246. 258. 244. 245. 251. 219. 260. 238. 241. 241. 262. 237. 244 . 217. 245. 244. 253. 248. 250. 252. 226. 260. 239. 241. 246. 263. 240. 253. 219. 253. 247. 255. 242. 258. 250. DAY DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Last value recorded before cohabitation. 12 251. 258. 269. 260. 235. 272. 242. 245. 251. 274. 255. 288. 250. 258. 246. 228. 265. 247. 246. 251. 269. 240. 253. 229. 255. 254. 264. 241. 259. 261. 13 246. 270. 272. 264. 235. 268. 249. 249. 246. 271. 254. 288. 242. 263. 227. 226. 264. 243. 246. 249. 271. 242. 252. 228. 252. 255. 266. 246. 254. 262. 14a 249. 267. 277. 266. 234. 264. 250. 250. 247. 277. 261. 293. 240. 260. 242. 223 . 265. 244. 247. 249. 268. 249. 252. 227. 253. 251. 262. 250. 259. 261. 418-028:PAGE C-67 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 RAT # DOSAGE GROUP III 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. RAT # DOSAGE GROUP rv 19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073 224. 239. 225. 224. 218. 231. 214. 237. 219. 224. 222. 240. 223. 235. 227. 220. 238. 226. 222. 220. 227. 217. 234. 223. 233. 220. 241. 223. 237. 229. 228. 248. 233. 223. 226. 230. 221. 240. 224. 231. 229. 244. 226. 240. 229. 232. 250. 237. 227. 227. 236. 227. 244. 223. 235. 229. 248. 227. 241. 234. 238. 246. 230. 233. 226. 240. 227. 249. 229. 228. 224. 249. 225. 248. 238. DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Last value recorded before cohabitation. 6789 1 MG/KG/DAY 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. 3 MG/KG/DAY 241. 248. 231. 234. 231. 237. 228. 255. 241. 229. 229. 248. 226. 250. 237. 246. 251. 242 . 230. 234. 243. 232. 258. 234. 238. 235. 254. 227. 251. 240. 251. 255. 243. 236. 240. 250. 235. 262. 236. 241. 241. 265. 236. 252. 244. 251. 252. 243. 241. 236. 250. 237. 265. 241. 239. 234. 260. 230. 261. 247. 10 11 234. 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. 250. 256. 240. 242 . 238. 250. 237. 270. 244. 232. 237. 264. 227. 264. 243. 255. 260. 248. 242. 243. 256. 237. 271. 245. 235. 242. 263. 230. 258. 244. 12 13 229. 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. 257. 260. 251. 242. 251. 261. 237. 276. 244. 240. 246. 266. 238. 261. 251. 258. 256. 247. 245. 245. 262. 247. 281. 244. 248. 240. 269. 232. 268. 252. 14a 236. 285. 264. 272. 250. 240. 250. 273. 256. 266. 244. 258. 253 . 270. 251. 256. 259. 249. 248. 246. 262. 242. 283 . 246. 242. 242. 268. 232. 269. 251. 418-028:PAGE C-68 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 RAT # DOSAGE GROUP V 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070 215. 231. 228. 226. 221. 229. 218. 232. 220. 245. 227. 225. 226. 240. 220. 214. 234. 230. 224. 221. 236. 220. 232. 220. 252. 229. 224. 228. 242. 218. 217. 238. 234. 222. 227. 240. 224. 232. 227. 255. 234. 228. 234. 243. 218. 217. 235. 238. 229. 230. 244 . 228. 241. 230. 262. 240. 231. 237. 246. 227. 208. 236. 236. 231. 226. 239. 226. 242. 228. 264. 239. 234. 237. 250. 231. DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Last value recorded before cohabitation. 6 7 8 9 10 10 MG/KG/DAY 212. 241. 243. 203. 230. 249. 229. 244. 232. 262. 243 . 231. 240. 252. 233. 218. 242. 244. 199. 239. 259. 231. 243. 237. 255. 251. 233. 245. 250. 230. 220. 246. 248. 192. 240. 267. 235. 250. 242. 263. 258. 245. 254. 254. 239. 215. 250. 242. 186. 236. 271. 231. 253. 238. 264. 255. 244 . 254. 256. 23 9. 214. 258. 241. 188. 236. 272. 235. 251. 241. 266. 256. 241. 252. 258. 241. 11 218. 258. 249. 203. 247. 283. 238. 252. 249. 268. 262. 246. 257. 256. 238. 12 221. 257. 249. 212. 247. 285. 240. 258. 253. 272. 266. 250. 262. 262. 246. 13 218. 259. 245. 220. 241. 280. 238. 259. 249. 277. 263. 256. 264. 263. 246. 14a 213. 266. 243. 221. 243. 282. 238. 259. 251. 269. 264. 252. 257. 260. 248. 418-028:PAGE C-69 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 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. DAY 13 14 15 16 17 18 19 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 344. 338. 336. 331. 299. 354. 338. 325. 316. 350. 346. 354. 310. 332. 294. 350. 343. 348. 337. 305. 358. 348. 340. 320. 359. 348. 359. 321. 340. 306. 358. 350. 357. 347. 314. 366. 354. 337. 328. 366. 360. 365. 327. 345. 311. 365. 355. 365. 354. 318. 371. 374. 349. 305. 373. 376. 382. 335. 356. 318. 378. 369. 379. 365. 298. 392. 378. 362. 338. 391. 386. 394. 350. 370. 329. 398. 386. 396. 373. 325. 416. 397. 380. 360. 415. 411. 410. 369. 377. 340. 416. 408. 420. 352. 341. 425. 414. 392. 374. 429. 432. 434. 384. 397. 353. P PREGNANT NP - NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). 7 313. 308. 304. 302. 271. 320. 294. 291. 282. 313. 300. 320. 280. 300. 272. 20 436. 424. 426. 344. 357. 449. 430. 420. 388. 449. 446. 441. 403. 408. 359. 8 313. 312. 308. 304. 273. 324. 306. 297. 290. 323. 314. 331. 289. 298. 268. 21 453. 445. 445. 385. 366. 443. 403. 458. 424. 382. 9 324. 315. 311. 301. 280. 332. 314. 303. 292. 318. 318. 333. 291. 306. 280. 22 419. 10 328. 321. 316. 314. 283. 337. 320. 306. 300. 329. 325. 338. 301. 311. 282. 23 11 336. 327. 324. 320. 286. 343. 329. 312. 305. 342. 334. 345. 307. 319. 281. 24 12 339. 333 . 331. 330 . 287. 347. 337. 321. 307. 338. 340 . 352 . 308 . 326 . 288. 25 418-028-.PAGE C-70 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 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. DAY 13 14 15 16 17 18 19 19004 P 19009 P 19016 P19018 P 19026 P 19036 P 19037 P 19043 P 19047 P 19048 P 19052 P 19055 P 19061 P 19067 P 19071 P 310. 321. 299. 326. 336. 343. 321. 329. 280. 321. 322. 341. 308. 324. 339. 320. 321. 310. 332. 349. 348. 325. 338. 289. 329. 330. 349. 315. 325. 348. 325. 330. 312. 339. 346. 357. 328. 346. 297. 336. 338. 358. 325. 340. 364. 334. 335. 325. 348. 361. 367. 342. 357. 304. 336. 350. 371. 338. 344. 365. 349. 343. 338. 363. 378. 383. 351. 372. 314. 348. 366. 384. 345. 351. 380. 361. 349. 348. 373. 394. 398. 364. 387. 329. 358. 377. 401. 351. 370. 394. 383. 326. 361. 391. 418. 410. 377. 389. 334. 358. 391. 411. 367. 379. 409. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY - DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . 7 276. 294. 270. 292. 298. 313. 292. 292. 256. 303. 288. 307. 279. 294 . 302. 20 396. 334. 380. 408. 432. 424. 393. 405. 364. 375. 409. 433. 382. 395. 431. 8 280. 298. 281. 295. 296. 321. 296. 295. 264. 299. 293. 305. 288. 299. 309. 21 361. 395. 422. 452. 422. 399. 417. 380. 382. 452. 414. 444. 9 288. 299. 277. 299. 302. 324. 301. 305. 264. 306. 299. 318. 291. 300. 316. 22 10 292. 304. 282309. 311. 330. 302. 310. 270. 309. 305. 322. 290. 308. 319. 23 11 301. 310. 291. 318. 327. 332. 310. 318. 274 . 312. 309. 334. 296. 312. 331. 24 12 306. 315. 296. 322. 329. 342 . 319. 328. 279. 317. 318. 339. 306. 321. 338. 25 418-028:PAGE C-71 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 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. DAY 13 14 15 16 17 18 19 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 291. 354. 352. 350. 297. 290. 314. 341. 317. 340. 294. 324. 318. 346. 331. 301. 360. 358. 358. 298. 298. 323 . 345. 317. 346. 294. 326. 328. 347. 337. 308. 369. 368. 361. 303. 310. 332. 355. 323. 359. 288. 338. 333. 353. 343. 320. 380. 370. 372. 306. 315. 338. 358. 336. 364. 284. 342. 337. 371. 348. 335. 391. 389. 386. 312. 329. 358. 374. 355. 369. 287. 355. 357. 379. 366. 354. 412. 411. 398. 310. 346. 364. 388. 363. 390. 288. 368. 375. 392. 384. 365. 431. 423. 409. 310. 360. 385. 368. 376. 400. 281. 384. 388. 409. 411. P PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY - DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . 7 264. 318. 317. 310. 280. 264. 283. 318. 284. 300. 278. 293. 290. 302. 295. 20 386. 444. 439. 432. 310. 374. 406. 416. 393. 413. 282. 395. 402. 425. 432. 8 267. 324. 323. 320. 290. 275. 288. 316. 280. 308. 281. 299. 296. 306. 305. 21 420. 450. 316. 386. 421. 400. 403. 432. 281. 420. 424. 445. 9 269. 332. 327. 317. 291. 275. 292. 329. 285. 313. 282. 308. 301. 314. 307. 22 313. 286. 10 271. 340. 335. 328. 295. 287. 298. 330. 290. 321. 285. 313. 307. 320. 312. 23 305. 288. 11 287. 345. 344 . 333. 295. 291. 301. 340. 294 . 334. 291. 315. 310. 329. 317. 24 12 286. 350. 345. 341. 299. 298. 316. 342. 306. 339. 296. 318. 318 . 334. 333. 25 293 . 287. 288. 302. 418-028:PAGE C-72 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 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. 294. 299. 276. 276. 286. 264. 270. 273 . 249. 253. 253. 266. 270. 274. 269. 279. 282. 247. 254. 258. MATING NOT CONFIRMED 248. 260. 260. 258. 266. 271. 256. 266. 268. 284. 289. 294. 246. 244. 254. 284. 289. 298. 258. 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. DAY 13 14 15 16 17 18 19 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 338. 341. 352. 306. 316. 319. 296. 297. 306. 291. 296. 303. 320. 329. 337. 336. 342. 347. 290. 294. 293. MATING NOT CONFIRMED 296. 302. 299. 329. 340. 346. 322. 332. 336. 362. 368. 369. 301. 302. 314. 375. 378. 387. 330. 336. 342. 350. 326. 307. 314. 343. 363. 288. 307. 350. 340. 383. 321. 404. 349. 371. 338. 323. 324. 357. 382. 284. 304. 365. 356. 392. 335. 413. 368. 380. 357. 336. 329. 370. 392. 283. 316. 383. 376. 393. 351. 384. 380. 394. 372. 354. 348. 390. 402. 284. 328. 396. 391. 407. 368. 408. 387. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . 7 310. 287. 282. 264. 292. 296. 275. 268. 300. 292. 318. 264. 324. 290. 20 406. 389. 383. 362. 412. 423. 279. 337. 414. 415. 424. 381. 436. 402. 8 316. 290. 273. 267. 294. 313. 281. 276. 303. 292. 326. 268. 336. 296. 21 429. 400. 390. 441. 274. 344. 424. 440. 394. 454. 420. 9 320. 292. 277. 269. 298. 313. 274. 280. 313. 304. 330. 274. 341. 302. 22 281. 304. 10 325 . 297. 282. 274. 306. 320. 282. 284. 320. 307. 335. 278. 346. 308. 23 11 323. 303. 296. 281. 313. 324. 280. 291. 322. 316. 345. 290. 358. 315. 24 280. 284. 12 333 . 300. 293 . 287. 317 . 340. 296. 296. 328 . 320. 355 . 290 . 370 . 326. 25 274 . 418-028-.PAGE C-73 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 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. DAY 13 14 15 16 17 18 19 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 271. 336. 308. 293. 321. 359. 296. 324. 314. 348. 344. 303. 332. 329. 311. 278. 347. 305. 300. 328. 354. 299. 327. 321. 357. 350. 312. 338. 333. 313. 283. 353. 309. 303. 337. 364. 303. 338. 328. 366. 355. 324. 338. 344. 323. 289. 366. 320. 306. 345. 372. 308. 344. 332. 371. 355. 328. 346. 352. 332. 303. 379. 340. 321. 361. 384. 326. 354. 345. 389. 375. 344. 369. 363. 347. 309. 397. 354. 332. 369. 401. 341. 365. 354. 398. 390. 358. 373. 376. 358. 320. 422. 375. 349. 389. 409. 353. 377. 368. 414. 404. 370. 386. 383. 351. P - PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). 7 243. 298. 278. 263. 294. 324. 270. 289. 288. 313. 309. 278. 296. 297. 276. 20 334. 436. 386. 362. 416. 413. 373. 394. 382. 436. 417. 390. 410. 405. 372. 8 251. 306. 275. 269. 298. 329. 272. 297. 286. 322. 310. 279. 302. 301. 286. 21 343. 451. 406. 391. 425. 386. 411. 397. 447. 425. 427. 404. 9 250. 311. 287. 276. 303. 333. 274. 301. 292. 318. 315. 285. 307. 299. 287. 22 10 251. 318. 297. 283. 311. 342. 282. 304 . 299. 327. 323. 288. 309. 308. 290. 23 11 255. 323. 289. 311. 316. 351. 287. 308 . 307. 337. 331. 292 . 312. 314. 296. 24 12 266. 333 . 292 . 293 . 320. 352 . 290. 318 . 315. 346 . 341. 304 . 329. 325. 301. 25 418-028-.PAGEC-74 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 FIMALE RATS RAT # DOSAGE GROUP I 0 MG/KG/DAY DAY 1 2 3 4 5 6 7 8 9 10 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 DAY 14 15 16 17 18 19 20 21 22b 19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075 352. 365. 388. 347. 335. 378. 370. 368. 337. 374. 385. 382. 363. 337. 316. 353. 381. 371. 352. 331. 396. 370. 354. 339. 378. 393. 382. 294. 338. 298. 362. 386. 384. 355. 323. 385. 371. 367. 343. 360. 376. 386. 348. 346. 318. 359. 362. 363. 331. 322. 376. 346. 327. 329. 367. 346. 398. 355. 365. 330. 360. 378. 394. 344. 329. 359. 382. 354. 338. 381. 370. 382. 351. 363. 319. 349. 356. 379. 346. 338. 367. 365. 359. 337. 377. 371. 403. 364. 376. 314. 347. 354. 384. 354. 332. 375. 365. 376. 336. 366. 356. 388. 354. 380. 327. 353. 373. 372. 307.a 317. 362. 355. 366. 341. 285. 345. 386. 367. 359. 320. 299. 335. 309. 270. 280. 305. 302. 360. 290. 299. 301. 360. 292. 297. 295. 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. 11 360. 353. 365. 328. 345. 381. 354. 352. 335. 312.a 377. 377 . 345. 369. 321. 12 356. 359. 352. 316. 336. 380. 362. 352. 335. 380. 365. 379. 360. 378. 325. 13 345. 366 . 374 . 350. 340. 390. 362 . 356. 342 . 392 . 391. 380 . 359. 350. 280 .a 418-028:PAGE C-75 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 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. DAY 14 15 16 17 18 19 20 21 22b 19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071 349. 349. 342 . 336. 360. 344. 310. 355. 323. 355. 315.C 331. 338. 344. 362. 337. 348. 341. 337. 354. 355. 326. 342. 321. 346. 352. 348. 335. 352. 316.a 345. 343. 336. 341. 356. 356. 332. 338. 330. 349. 353. 363. 322. 352. 369. 317. 341. 330. 341. 355. 343. 312. 333. 318. 338. 349. 366. 348. 360. 365. 332. 345. 327. 353. 341. 345. 332. 344 . 324. 356. 345. 372. 338. 371. 371. 344 . 349. 329. 349. 353. 358. 326. 349. 317. 365. 351. 367. 337. 358. 367. 325. 342. 324. 340. 358. 344. 342. 344. 319. 368. 346. 368. 334. 343. 372. 304. 336. 308. 343. 360. 351. 321. 348. 308. 350. 346. 350. 327. 308.a 348. 276. 346. 314, 338. 296. 359. 309. 356. 325. 306. 320. 336. 315. 294. 374. 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. c. Water access was interrupted; value excluded from group averages and statistical analyses. 11 333. 329. 324 . 339. 341. 335. 251. 346. 318. 336. 339. 354. 319. 350. 364. 12 334. 342. 328. 332. 338. 347. 230.a 354. 318. 351. 350. 364. 340. 356. 365. 13 330. 343 . 329. 342. 355. 352 . 298. 352. 264 .a 345. 340. 360. 332 . 367. 356. 418-028:PAGE C-76 PROTOCOL 4X8-028: 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. 3 90. 344. 363. 348. 323 . 355. 343. 352. 373. 302 .a 418-028:PAGE C-77 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 19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073 335. 330, 328. 337. 284. 295. 297. 307. 271. 267, 276. 285. 271, 269. 265. 270. 321. 299. 299. 314. 315. 315. 315. 318. NOT PREGNANT NOT PREGNANT;; MATING NOT CONFIRMED 280. 296. 291. 296. 309. 320, 276.a 268.a 304. 308. 318. 317. 331. 332. 341. 348. 290. 280. 288. 292. 332, 329. 332. 332. 318. 315. 310. 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. 313. 340. 351. 368. 315. 288.a 346. DAY 14 15 16 17 18 19 20 21 22b 19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073 361. 358. 360. 369. 341. 342. 351. 320. 315. 322. 314. 306. 311. 310. 310. 296. 360. 355. 350. 334. 349. 377. 361. 353. NOT PREGNANT NOT PREGNANT;: MATING NOT CONFIRMED 335. 332. 333. 313. 331. 302. C 345. 350. 369. 358. 356. 335. 377. 380. 383. 370. 338. 332. 332. 325. 349. 361. 366. 365. 350. 357. 368. 375. 358. 344. 322. 320. 365. 380. 328. 345. 352. 384 . 336. 373. 371. 376. 352. 326. 317. 361. 402. 326. 364 . 355. 388. 341. 375. 364. 378. 350. 315. 313. 367. 386. 322. 363 . 354. 377. 340. 358. 365. 359. 333. 312. 317. 356. 398. 323. 324. 342. 385. 328. 352. 348. 302. 285. 261. 315. 294. 385. 287. 350. 290. 369. 292. 362. 363. 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. c. Water access was interrupted; value excluded from group averages and statistical analyses. 11 357. 328. 305. 293. 348. 348. 306. 337. 348. 378. 304.a 337. 352. 12 368. 340. 316. 300. 356. 368. 290.a 351. 349. 385. 322 . 353. 362. 13 367. 336. 332. 306. 356. 376. 333. 353. 368. 381. 351. 365. 290.a 418-028:PAGE C-78 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 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. DAY 14 15 16 17 18 19 20 21 22b 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070 287. 367. 332. 270. 360. 384. 317. 318. 357. 316.c 351. 347. 348. 320. 303.c 288. 366. 294.a 246. 348. 373. 312. 335. 355. 362. 336. 341. 346. 322. 337. 286. 366. 318. 252. 352. 358. 309. 294. c 353. 365. 359. 338. 358. 357. 358. 278. 356. 326. 246. 352. 355. 306. 329. 344. 364. 343. 332. 341. 358. 365. 304. 373. 338. 252. 359. 392. 302. 340. 346. 375. 356. 329. 347. 345. 351. 302. 373 . 350. 251. 363. 363. 321. 348. 346. 373. 319.a 332. 334. 339. 358. 296. 378. 330. 246. 349. 358. 315. 330. 365. 381. 341. 323. 349. 360. 363. 292. 373. 330. 228. 349. 346. 315. 346. 355. 371. 344. 323. 349. 343. 352. 278. 304. 283. 210. 294. 291. 266. 339. 314. 361. 287. 328. 330. 317. 351. 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. c. Water access was interrupted; value excluded from group averages and statistical analyses. 11 281. 344. 338. 253. 341. 368. 296. 334. 346. 366. 328. 339. 335. 347. 337. 12 278. 339. 326. 268. 360. 381. 304 . 331. 346. 371. 284 .a 335. 331. 352. 357. 13 286. 348. 345 . 259. 355. 379. 322. 338. 348. 371. 354. 344 . 348 . 350. 355. 418-028:PAGE C-79 PROTOCOL 4X8-028: 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- 8a RAT # DOSAGE GROUP I 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 19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071 132. 156. 126. 137. 144. 136. 138. 153. 110. 131. 123. 147. 134. 139. 139. DAY - DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Last value recorded before cohabitation. b. Spilled feed precluded the calculation of this value. c. Value was not recorded. 0 MG/KG/DAY 0.3 MG/KG/DAY 418-028:PAGE C-80 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.I) TABLE C36 (PAGE 2): FEED CONSUMPTION VALUES - PRECOHABITATION - INDIVIDUAL DATA - FO GENERATION FEMALE RATS DAYS 1- 8a RAT # DOSAGE GROUP III 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 19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073 145. 150. 125. 118. 133. 134. 132. 160. 135. 128. 129. 153. 124. 153. 134. DAY - DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Last value recorded before cohabitation. 1 MG/KG/DAY 3 MG/KG/DAY 418-028:PAGE C-81 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE EEPRODUCTION/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 418-028:PAGE C-82 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 - 1 0 10 - 12 12 - 15 15 - 18 18 - 20 RAT # DOSAGE GROUP I 0 MG/XG/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 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 186. 83. 58. 86. 81. 60. 178 . 79. 49. 91. 82. 17. 137. 65. 45. 70. 71. 42. 176. 85. 59. 90. 85. 55. 179. 81. 58. 90. 86. 59. 193. 93. 56. 82. 78. 40. 185. 83. 59. 77. 67. 39. 170. 84. 57. 84. 95. 54. 150. 67. 43. 70. 72. 46. 164. 67. 44. 76. 69. 46. 162. 79. 49. 77. 79. 46. 198. 91. 63. 90. 97. 49. 170. 80. 51. 86. 81. 52. 173. 79. 58. 80. 69. 22 . 203. 90. 60. 90. 88. 57. P - PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Spilled feed precluded the calculation of this value. 418-028:PAGE 0 8 3 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 - 1 0 10 - 12 12 - 15 15 - 18 18 - 20 RAT # DOSAGE GROUP III 1 MG/KG/DAY 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 144. 65. 49. 77. 66. SO. 179. 83. 60. 86. 78. 53. 213. 94. 64. 86. 79. 60. 160. 78. 64. 85. 86. 54. 175. 83. 50. 73. 78. 41. 142. 71. 49. 73. 79. 55. 149. 70. 50. 74. 86. 51. 181. 91. 56. 84. 75. 46. 175. 63. 49. 89. 80. 45. 182. 87. 65. 90. 76. 36. 153. 76. 53. 68. 71. 65. 167. 76. 53. 77. 71. 54. 174. 80. 53. 79. 80. 53. 172. 92. 64. 92. 86. 59. 177. 74. 53. 79. 69. 55. RAT # DOSAGE GROUP TV 3 MG/KG/DAY 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 167. 62. 49. 70. 79. 47. 165. 68. 48. 75. 70. 55. 155. 56. 44. 63. 62. 51. 142. 65. 44. 71. 70. 54. 187. 79. 57. 87. 77. 59. 186. 91. 59. 83. 94. 52. 170. 72. 52. 73. 54. 27. MATING NOT CONFIRMED 160. 75. 49. 68. 56. 52. 196. 92. 51. 81. 88. 49. 181. 80. 56. 81. 72. 55. 224. 95. 63. 97. 81. 48. 149. 66. 47. 76. 74. 51. 220. 106. 70. 104. 74. 28. 164. 91. 56. 86. 90. 49. P - PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS - DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). 418-028:PAGE C-84 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 - 1 0 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) . 418-028:PAGE D-42 ATTACHMENT 4 Protocol 418-028 Page 1 o f 2 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 w ill be assigned to hematology, clinical biochemistry and histological evaluations. Tissues to be W eighed: The following organs w ill 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 w ill be 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 (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 w ill be fixed in Bouin's solution for 48 to 96 hours before being retained in neutral buffered 10% formalin. Additionally, the remaining portion o f the left epididymis (corpus and caput), as well as the right epididymis w ill be fixed in neutral buffered 10% formalin. 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 1 H H 98"3 39Yd:8lO` 8l 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 0.3 MG/KG/DAY 19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071 158. 85. 140. 120. 25. 101. 85. 138. 114. 114. 82. 145. 99. 142. a 165. 141. 167. 167. 173. 145. 211. 180. 154. 137. 154. 172. 138. 170. 142. 513. 400. 495. 486. 374. 533. 561. 516. 460. 447. 497. 493. 366. 520. 512. DAY - DAY OF LACTATION 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 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 rv 3 MG/KG/DAY 19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073 113. 132. 427. 175. 159. 497. 108. 112. 438. 146. 145. 436. 140. 189. 542. 130. 160. 584. NOT PREGNANT NOT PREGNANT; MATING NOT CONFIRMED 113. 125. 360. 98. 184. 496. 147. 175. 560. 131. 160. 568. 110. 139. 453. 106. 81. 451. 114. 167. 523. DAY - DAY OF LACTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Spilled feed precluded the calculation of this value. 418-028:PAGE C-87 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. 418-028:PAGE C-88 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 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 M M M M M M M M M M M M M M DOSAGE GROUP II 0.3 MG/KG/DAY 19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071 4 3 3 3 1 2 3 4 2 4 2 2 3 3 3 4M 1M 1M 2M 4M 1M 2M 1M 1M 4M 1M 1M 2M 3M 1M 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 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 P P P P P P P P P P P P P P P 418-028:PAGE C-89 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 DOSAGE GROUP III 1 MG/KG/DAY 19003 3 3 M 19007 3 3 M 19008 3 4 M 19013 3 2 M 19014 4 1M 19015 2 4 M 19017 3 1 M 19024 3 4 M 19029 3 2 M 19034 3 3 M 19038 3 1M 19056 4 4 M 19057 4 4 M 19060 4 2 M 19064 4 4 M DOSAGE GROUP IV 3 MG/KG/DAY 19002 4 13 19005 3 4 19035 3 4 19039 3 2 19040 4 4 19045 19046 3 2 1 1 19051 la 14 19054 3 3 19058 2 1 19062 4 4 19063 3 2 19066 3 4 19069 3 2 19073 3 1 M M M M M M M DID NOT MATE M M M M M M M M - MATED C = CONFIRMED P = PREGNANT NP = NOT PREGNANT a. Six or more consecutive days of estrus were observed. MATING DATE C C C C C C C C C C c c c c c c c c c c c c - c c c c c c c PREGNANCY STATUS P P P P ' NP P P P P P NP P P P P P P P P P P NP - P P P P P P P 418-028:PAGE C-90 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 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070 3 2 3 0 3 la 3 1 0 1 3 3 2 3 3 1 3 4 4 4 3 4 1 4 1 4 1 1 1 1 M M M M M M M M M M M M M M 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 418-028:PAGE C-91 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 ,.22^?_E -9SS.-L.1 __ _ RAT # ___ . 19012 19019 19021 19023 19041 0 MG/KG/DAY 19042 19044 19050 19053 HOME CAGE BEHAVIOR 32 333 3333 ALTERATIONS (HOME CAGE) 111111111 REACTION TO REMOVAL 1 1 11 1 1 11 1 REACTION TO HANDLING 111111111 REARS IN OPEN FIELD 10 12 12 19 7 13 15 7 14 DEFECATION IN OPEN FIELD 1 1 1 2 1 1 2 1 1 URINATION IN OPEN FIELD 112212211 LEVEL OF AROUSAL 3 3 33 3 3 33 3 ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1 GAIT PATTERN 11111 1111 GAIT ABNORMALITY, SEVERITY 1 1 1 1 1 1 1 1 1 PALPEBRAL CLOSURE 111111111 PROMINENCE OF THE EYE 1 1 11 1 1 1 1 1 LACRIMATION 1 11111111 SALIVATION 1 1111 1111 PILOERECTION 000000000 ABNORMAL RESPIRATION 0 0 00 0 0000 APPEARANCE 1 1 la 1 lb 1 1 1 1 VISUAL REACTION 2 2 22 2 2 222 TACTILE REACTION 2 2 22 2 2 222 AUDITORY REACTION 3 3 33 3 3 33 3 TAIL-PINCH REACTION 22232 3222 AIR RIGHTING RESPONSE 1 1 11 1 1 1 11 PUPIL RESPONSE TO LIGHT 1 1111 1111 FORELIMB GRIP TEST #1 (G) 410 325 240 550 370 655 330 275 505 FORELIMB GRIP TEST #2 (G) 465 650 345 500 355 845 375 350 545 HINDLIMB GRIP TEST #1 (G) 245 365 450 335 675 565 520 295 405 HINDLIMB GRIP TEST #2 (G) 335 445 420 300 670 475 350 350 530 LANDING FOOT SPLAY #1 (CM) 12.1 8.8 8.0 4.4 6.4 6.5 9.5 4.0 9.3 LANDING FOOT SPLAY #2 (CM) 9.6 8.0 8.3 6.0 5.7 5.7 8.0 6.4 9.4 BODY WEIGHT (G) 372 374 314 327 382 366 342 342 351 VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY. a. Localized alopecia: head (1.0 cm x 0.4 cm). 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. 19065 1 1 J. 1 11 1 1 3 1 1 1 1 1 1 1 0 0 lc 2 2 3 2 1 1 430 600 315 415 7.0 7.7 364 418-028:PAGE C-92 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.I) TABLE C40 (PAGE 2): FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP II_______________________________________ _____ _____ _________ _____ 0.3 MG/KG/DAY RAT # 19004 19009 19016 19018 19026 19036 19037 19043 19047 HOME CAGE BEHAVIOR 31 32 1 3213 ALTERATIONS (HOME CAGE) 111 111111 REACTION TO REMOVAL 1111 11111 REACTION TO HANDLING 1111 11111 REARS IN OPEN FIELD 10 12 12 9 11 14 14 15 18 DEFECATION IN OPEN FIELD 1 1 1 1 1 1 1 1 1 URINATION IN OPEN FIELD 12 1 1 1 112 1 LEVEL OF AROUSAL 333 3 3 3333 ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1 GAIT PATTERN 111 1 11111 GAIT ABNORMALITY, SEVERITY 1 1 1 1 1 1 1 1 1 PALPEBRAL CLOSURE 111 111111 PROMINENCE OF THE EYE 1111 11111 LACRIMATION 1111 11111 SALIVATION 1111 1 1111 PILOERECTION 00000 000 0 ABNORMAL RESPIRATION 0000 00000 APPEARANCE 1 1 la 1 1 1 1 1 1 VISUAL REACTION 222 2 2 222 2 TACTILE REACTION 2222 22222 AUDITORY REACTION 3333 33333 TAIL-PINCH REACTION 22222222 3 AIR RIGHTING RESPONSE 111111111 PUPIL RESPONSE TO LIGHT 1111 11111 FORELIMB GRIP TEST #1 (G) 165 510 285 275 325 155 120 400 220 FORELIMB GRIP TEST #2 (G) 390 333 140 450 530 145 475 535 325 HINDLIMB GRIP TEST #1 (G) 335 365 375 385 365 270 420 255 320 HINDLIMB GRIP TEST #2 (G) 315 380 525 355 285 365 665 375 240 LANDING FOOT SPLAY #1 (CM) 6.0 8.7 7.9 5.2 6.3 6.2 6.5 5.2 6.2 LANDING FOOT SPLAY #2 (CM) 7.9 9.0 6.9 6.8 7.4 7.0 5.4 5.7 BODY WEIGHT (G) 317 356 352 350 334 362 335 356 345 VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY, a. Localized alopecia: head (0.4 cm x 0.5 cm). 19048 1 1 1 1 15 1 2 3 1 1 1 1 1 1 1 0 0 1 2 2 3 2 1 1 305 310 410 325 5.8 6.5 365 418-028-.PAGEC-93 r* VP 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 DOSAGE GROUP III 1 MG/KG/DAY RAT # 19003 19007 19008 19013 19015 19017 19024 19029 19034 HOME CAGE BEHAVIOR 33 1313 312 ALTERATIONS (HOME CAGE) 111 111111 REACTION TO REMOVAL 111111111 REACTION TO HANDLING 1 1 1 1 1 1 1 1 1 REARS IN OPEN FIELD 14 9 10 8 6 13 14 10 16 DEFECATION IN OPEN FIELD 1 1 1 1 1 1 1 3 1 URINATION IN OPEN FIELD 11 112 1112 LEVEL OF AROUSAL 33 3 333 33 3 ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1 GAIT PATTERN 11 1 1i1 11 1 GAIT ABNORMALITY, SEVERITY 1 1 1 1 i 1 1 1 1 PALPEBRAL CLOSURE 111 1i1111 PROMINENCE OF THE EYE 11 1 1i 111 1 LACRIMATION 11 1 1i 1 11 1 SALIVATION 1 1 1 1i 1 111 PILOERECTION 000 000000 ABNORMAL RESPIRATION 000 000000 APPEARANCE 1 1 la 1 lb 2 1 1C 1 VISUAL REACTION 222 222222 TACTILE REACTION 22 2 22 2 22 2 AUDITORY REACTION 33 3333333 TAIL-PINCH REACTION 22 2 22 3 22 2 AIR RIGHTING RESPONSE 11 1 11 11i1 PUPIL RESPONSE TO LIGHT 1 1 1 11 1 1i 1 FORELIMB GRIP TEST #1 (G) 325 975 85 200 420 330 695 320 610 FORELIMB GRIP TEST #2 (G) 245 535 75 365 455 720 665 395 505 HINDLIMB GRIP TEST #1 (G) 295 280 370 495 445 450 465 435 455 HINDLIMB GRIP TEST #2 (G) 445 315 320 470 375 530 440 520 605 LANDING FOOT SPLAY #1 (CM) 5.4 7.0 6.2 10.8 6.8 7.7 8.8 6.2 7.4 LANDING FOOT SPLAY #2 (CM) 6.3 8.5 5.8 10.6 7.2 6.4 10.4 8.0 7.5 BODY WEIGHT (G) 323 365 360 386 325 369 359 316 344 VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY. 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) . 19056 1 1 1 1 16 2 2 3 1 1 1 1 1 1 1 0 0 1 2 2 3 3 1 1 255 300 290 365 8.3 8.4 359 418-028:PAGE C-94 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 DOSAGE GROUP IV 3 MG/KG/DAY RAT # 19005 19035 19039 19040 19045 19054 19058 19062 19063 HOME CAGE BEHAVIOR 3123 12 32 1 ALTERATIONS (HOME CAGE) 1 111 1 1 11 1 REACTION TO REMOVAL 111111111 REACTION TO HANDLING 1 11 1 1 1 11 1 REARS IN OPEN FIELD 11 7 15 12 13 10 10 11 8 DEFECATION IN OPEN FIELD 3 1 1 1 2 1 1 1 1 URINATION IN OPEN FIELD 1 11 1 11 11 1 LEVEL OF AROUSAL 3 33 3 3 3 33 3 ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1 GAIT PATTERN 1 11 11 1 111 GAIT ABNORMALITY, SEVERITY 1 1 1 1 1 1 1 1 1 PALPEBRAL CLOSURE 1 111 1 1 11 1 PROMINENCE OF THE EYE 111111111 LACRIMATION 1 11 1 11 11 1 SALIVATION 1 11 11 111 1 PILOERECTION 00000000 0 ABNORMAL RESPIRATION 00000000 0 APPEARANCE 1 1 1 1 la 3b 1 1c 1 VISUAL REACTION 2 22 2 2 2 2 2 2 TACTILE REACTION 222222222 AUDITORY REACTION 333233 333 TAIL-PINCH REACTION 2 222 2 2 22 2 AIR RIGHTING RESPONSE 1 11 1 1 1 11 1 PUPIL RESPONSE TO LIGHT 1111 11 111 FORELIMB GRIP TEST #1 (G) 415 355 445 490 560 525 260 310 545 FORELIMB GRIP TEST #2 (G) 685 360 395 465 555 605 435 225 530 HINDLIMB GRIP TEST #1 (G) 465 255 190 355 340 350 220 400 465 HINDLIMB GRIP TEST #2 (G) 470 295 315 430 435 325 365 460 485 LANDING FOOT SPLAY #1 (CM) 8.0 5.5 5.4 6.5 8.0 7.5 7.4 7.5 7.0 LANDING FOOT SPLAY #2 (CM) 8.3 5.8 6.3 7.2 9.4 9.6 9.0 7.0 7.5 BODY WEIGHT (G) 330 322 317 353 380 339 355 351 368 VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY. a. Localized alopecia: left axilla (4.0 cm x 3.0 cm). b. Localized alopecia: right forepaw and forelimb (1.7 cm x 0.6 c m ) . c. Tip of tail missing. 19066 1 1 1 1 10 1 1 3 1 1 1 1 1 1 1 0 0 1 2 2 3 2 1 1 495 390 270 365 4.0 5.0 337 418-028:PAGE C-95 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 -22S-SH..552H?TM___________ _____ _ RAT # 19001 _ 19006 19011 19020 19022 ' *"i o "m g /k g /d a y 19025 19027 19028 19030 HOME CAGE BEHAVIOR ALTERATIONS (HOME CAGE) 222 3 2 313 3 1111 1 111 1 REACTION TO REMOVAL 1111 1111 1 REACTION TO HANDLING 11111111 1 REARS IN OPEN FIELD 12 9 9 9 9 10 14 8 15 DEFECATION IN OPEN FIELD 1 1 1 1 1 1 1 2 1 URINATION IN OPEN FIELD 11111 122 1 LEVEL OF AROUSAL 3333 3 333 3 ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1 GAIT PATTERN 4a 1 1 4a 1 1 1 1 1 GAIT ABNORMALITY, SEVERITY 2 1 1 2 1 1 1 1 1 PALPEBRAL CLOSURE 11111111 1 PROMINENCE OF THE EYE 1111 1 111 1 LACRIMATION 1 1 1 1 1 1 1 1 1 SALIVATION 11111111 1 PILOERECTION 00000 000 0 ABNORMAL RESPIRATION 0 0 0 lc 0 0 0 0 0 APPEARANCE 1 lb 1 Id 1 1 1 1 le VISUAL REACTION 2222 22222 TACTILE REACTION 2222 2 222 2 AUDITORY REACTION 23333 3333 TAIL-PINCH REACTION 2222 22222 AIR RIGHTING RESPONSE 11111 111 1 PUPIL RESPONSE TO LIGHT 1111 1 1111 FORELIMB GRIP TEST #1 (G) 170 785 525 205 560 535 315 270 595 FORELIMB GRIP TEST #2 (G) 290 735 465 240 645 540 600 525 495 HINDLIMB GRIP TEST #1 (G) 385 410 330 435 385 520 265 305 405 HINDLIMB GRIP TEST #2 (G) 380 530 490 370 630 430 410 480 530 LANDING FOOT SPLAY #1 (CM) 4.8 6.3 9.0 8.8 10.5 10.0 6.3 8.7 6.2 LANDING FOOT SPLAY #2 (CM) 5.8 7.0 9.4 8.7 8.5 9.0 6.5 9.2 7.0 BODY WEIGHT (G) 250 365 320 254 366 362 318 343 332 VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY. a. Tip-toe walk. b. Ear t o m : 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). 19031 3 1 1 1 14 2 1 3 1 1 1 1 1 1 1 0 0 1 2 2 3 3 1 1 270 440 410 445 10.4 9.2 373 418-028:PAGEC-96 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 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 84 77 76 63 74 86 17 67 0 66 83 30 65 0 72 70 7 25 2 23 65 3 43 2 49 76 3 11 0 57 39 41 20 0 4 32 53 23 0 0 12 37 7 0 13 20 41 4 20 1 17 4 10 1 2 71 5 10 2 1 57 4 21 1 1 40 1 9 0 37 67 2 2 1 75 83 2 3 0 47 81 4 5 37 79 59 12 10 0 36 1042 343 411 129 637 TOTAL SUMOF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD 19042 73 52 64 3 4 2 1 11 55 5 0 1 1 2 6 5 4 4 293 19044 73 61 18 33 54 34 3 24 54 71 30 19 2 8 3 1 0 0 488 19050 69 59 64 9 9 10 4 1 29 8 0 9 2 4 3 39 70 59 448 19053 60 65 63 108 33 6 4 10 1 1 23 59 27 8 7 22 39 74 610 19065 71 65 45 6 13 40 0 39 6 25 5 4 5 51 56 30 3 5 469 418-028:PAGE C-97 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 C4I (PAGE 2) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP I 0 MG/KG/DAY RAT NUMBER 19012 19019 19021 19023 19041 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 191 138 161 108 167 157 34 147 0 116 119 41 75 0 96 113 7 25 3 17 83 4 48 0 43 111 1 6 0 75 37 50 23 0 1 35 93 28 0 0 5 60 6 0 14 26 50 5 36 0 22 6 10 2 4 74 3 10 3 0 68 2 21 0 2 42 1 9 0 36 77 1 0 0 119 71 1 0 0 74 100 2 3 38 92 114 21 7 0 40 1445 515 584 190 896 TOTAL = SUMOF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 19042 180 84 98 2 1 1 1 8 67 4 0 1 0 1 5 4 3 6 466 19044 157 100 29 27 105 37 2 31 62 95 29 18 0 5 1 0 0 0 698 19050 185 147 81 10 8 12 1 0 41 7 0 12 0 1 4 79 113 106 807 19053 125 85 71 101 31 1 2 12 0 0 43 103 42 1 5 17 56 84 779 19065 136 83 47 1 13 31 0 47 0 29 2 5 5 52 89 24 0 4 568 418-028:PAGE C-98 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 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 65 68 53 60 75 36 75 61 55 55 31 104 3 6 57 49 41 7 1 54 29 46 0 9 30 22 45 1 7 3 3 18 4 22 3 13 59 2 2 0 0 79 0 1 1 1 22 4 12 5 0 1 6 1 54 7 1 5 11 10 4 6 1 7 38 40 2 14 8 41 30 3 0 6 17 42 32 1 6 3 4 63 13 13 0 6 41 3 1 0 382 706 178 228 446 TOTAL = SUMOF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 19036 73 64 58 20 12 0 29 2 3 2 0 0 12 0 5 4 4 27 315 19037 73 68 50 27 8 30 9 29 10 14 1 7 4 30 50 42 6 25 483 19043 65 27 3 16 5 28 12 8 5 2 4 2 6 0 2 3 2 0 190 19047 77 16 22 10 0 0 0 0 2 0 0 0 2 4 10 9 10 4 166 19048 62 79 78 82 73 58 78 17 4 3 3 16 70 51 7 8 2 1 692 418-028:PAGE C-99 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 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 131 213 85 76 152 41 168 93 49 96 47 135 3 7 82 67 56 4 0 116 32 55 0 9 51 20 76 0 7 0 1 11 3 31 3 12 84 2 1 0 0 119 0 0 1 0 29 1 11 4 0 0 6 3 70 60479 2 3 0 4 42 33 0 17 13 72 43 1 0 3 22 62 36 0 4 1 2 91 12 11 0 4 40 0 0 0 503 1117 230 236 721 TOTAL = SUMOF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 19036 181 136 92 12 15 0 46 2 1 1 0 0 19 0 1 2 3 28 539 19037 120 140 91 60 19 60 8 36 12 15 2 6 3 36 71 55 11 22 767 19043 120 41 1 18 1 25 9 4 3 0 0 1 10 0 1 0 0 0 234 19047 133 19 35 8 0 0 0 0 0 0 0 0 2 1 8 9 6 1 222 19048 204 157 108 139 93 122 102 14 2 1 2 9 62 69 5 7 i i 1098 418-028:PAGE C-100 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 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 76 74 55 71 69 61 40 63 70 68 65 65 70 19 30 40 60 48 3 61 18 27 89 5 64 37 49 78 1 84 46 50 70 1 74 49 57 64 2 40 9 53 57 2 8 5 85 74 0 2 0 57 64 1 1 3 1 71 10 3 45 9 78 0 3 58 1 77 0 2 52 7 59 1 1 43 1 85 19 6 51 7 60 0 8 47 4 42 1 5 705 647 1204 206 529 TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 19017 70 59 37 19 25 36 40 38 51 27 29 16 27 32 61 39 43 10 659 19024 74 85 59 61 60 58 55 S3 24 24 58 59 26 6 10 1 1 28 742 19029 69 81 48 56 70 65 44 38 65 38 53 41 50 64 39 46 70 39 976 19034 58 68 48 6 43 9 22 34 10 27 i 2 1 1 4 0 1 1 336 19056 67 71 61 85 35 9 43 5 2 12 5 5 4 3 2 5 6 2 422 418-028:PAGE C- 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 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 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 180 153 118 150 96 69 139 109 128 109 143 19 64 99 85 2 23 27 136 11 59 75 102 0 65 55 140 0 69 90 123 0 13 68 109 0 4 122 112 0 0 77 100 1 3 0 93 10 71 7 158 0 60 0 125 0 80 9 109 0 69 0 116 24 91 9 138 0 56 1 52 0 1131 970 2098 326 153 138 21 78 123 119 154 78 7 1 0 1 2 1 0 9 12 0 897 TOTAL - SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 19017 201 129 66 22 49 53 63 65 87 36 41 22 29 47 97 57 47 7 1118 19024 174 123 176 98 84 81 70 56 14 27 93 136 24 4 11 0 0 22 1193 19029 97 85 30 66 88 59 61 49 71 47 84 73 90 106 56 83 77 42 1264 19034 186 119 136 9 53 2 24 69 10 26 0 4 0 0 2 0 0 1 641 19056 132 137 57 179 40 11 58 8 0 12 1 2 3 2 0 3 4 0 649 418-028:PAGE C-102 PROTOCOL 4X8-028: 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 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 59 82 75 62 55 63 77 58 18 66 52 51 63 11 67 51 33 64 2 79 54 37 73 1 50 64 7 15 15 56 78 5 4 57 66 66 34 28 29 44 57 27 9 1 52 55 0 9 0 59 50 6 5 0 59 54 3 3 32 53 68 1 0 3 55 60 0 9 11 53 46 5 3 1 69 58 4 39 2 50 54 19 17 4 57 50 3 2 0 76 1039 394 476 249 1066 TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 19054 68 75 75 62 52 56 48 75 43 43 35 6 37 52 25 4 2 0 758 19058 67 48 27 13 5 2 2 22 39 18 3 16 3 3 1 1 0 14 284 19062 49 69 41 40 33 54 57 49 55 49 47 35 21 53 44 31 10 24 761 19063 71 37 32 32 6 12 11 36 33 22 26 14 7 3 1 81 52 17 493 19066 69 60 74 14 28 69 55 62 24 4 4 2 3 0 3 2 4 4 481 418-028:PAGE C-103 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OP 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 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 IS BLOCK 16 BLOCK 17 BLOCK 18 TOTAL 241 163 158 215 236 167 129 110 23 188 106 63 100 26 196 130 42 89 1 192 108 29 87 0 140 120 5 29 22 131 117 2 2 79 150 108 42 45 37 76 112 31 14 0 194 83 0 10 0 154 83 2 3 0 137 63 1 2 38 66 135 0 0 0 112 100 0 4 6 101 58 4 0 0 150 83 2 54 1 81 105 23 13 1 119 73 1 1 0 152 1992 539 721 449 2575 TOTAL = SUMOF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 19054 181 184 155 133 58 64 73 73 65 39 31 2 33 40 9 1 0 0 1141 19058 154 67 45 23 16 5 1 60 56 29 5 24 11 6 1 2 0 24 529 19062 143 158 69 52 60 82 149 98 109 79 77 47 36 73 107 62 10 27 1438 19063 150 63 41 43 4 20 12 56 68 21 31 22 5 1 0 98 77 14 726 19066 169 106 143 25 18 89 68 106 17 1 3 1 2 0 1 2 1 1 753 418-028:PAGE C-104 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OP 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 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 72 76 61 75 63 30 4 59 28 59 20 8 63 3 63 7 2 52 0 56 5 1 64 0 46 6 18 59 0 39 6 1 57 1 23 61 1 61 48 63 57 4 61 3 44 43 2 30 35 28 43 4 65 1 41 52 7 64 48 38 46 4 62 5 46 16 4 38 1 47 7 3 44 0 40 5 1 52 39 36 1 2 67 50 46 6 24 52 44 39 483 166 1011 381 817 TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 19025 83 45 9 5 27 29 7 49 54 4 1 1 1 2 3 32 10 47 409 19027 52 27 41 42 31 17 23 19 0 4 7 34 1 0 0 2 0 1 301 19028 78 45 7 1 2 6 16 3 9 7 24 30 51 40 48 17 2 5 391 19030 65 64 58 5 4 10 3 3 14 2 5 9 2 3 0 6 2 4 259 19031 59 64 39 35 6 13 3 18 33 0 6 14 3 17 6 2 3 4 325 418-028:PAGE C-105 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 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 162 128 132 104 152 17 1 120 16 157 13 14 122 0 125 6 1 60 0 126 3 3 87 0 86 6 25 100 0 49 1 1 94 0 21 52 0 84 54 106 78 5 94 2 81 34 0 39 19 35 54 2 98 0 53 90 7 81 65 68 49 4 121 4 86 28 2 51 0 89 3 2 58 0 54 1 0 65 27 34 0 1 86 61 61 1 34 78 35 50 598 230 1570 387 1433 TOTAL = SUMOF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 19025 151 119 6 1 29 56 2 76 72 1 0 0 0 0 0 45 4 69 631 19027 148 121 58 66 55 35 25 23 0 2 5 39 0 0 0 0 0 0 577 19028 147 104 4 0 0 6 20 1 3 11 17 20 55 47 51 9 2 3 500 19030 134 123 107 2 2 14 1 2 16 0 4 4 1 1 0 3 1 3 418 19031 204 188 74 84 11 19 0 19 50 0 13 13 7 38 5 1 1 3 730 418-028-.PAGE C-106 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/F1 GENERATION LITTERS RAT/ LITTER NUMBER DURATION OF GESTATION (DAYS) N LITTER DELIVERED LIVE STILL- TOTAL BORN BORN BORN NNN 1 MF NUMBER OF LIVE PUPS AT COMPLETION OF DAY POSTPARTUM 8 15 22 MF MF MF MATERNAL DOSAGE GROUP I 0 MG/KG/DAY 19010 19012 . 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075 23 23 23 23 22 22 23 22 22 23 22 22 22 23 23 14 16 15 14 13 18 15 17 15 16 20 15 16 15(1) 16 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 14 16 15 14 13 18 15 17 IS 16 20 15 16 15 16 4 10 5 11 87 95 76 6 12 69 89 5 10 97 9 11 69 88 4 10 11 5 49 5 11 87 95 75 6 12 69 88 5 10 87 9 10 59 88 4 10 11 5 49 5 11 87 95 75 6 12 69 88 5 10 87 9 10 59 88 4 10 11 5 49 5 11 87 95 75 6 12 69 88 5 10 87 9 10 59 88 4 10 11 5 MATERNAL DOSAGE GROUP II 0.3 MG/KG/DAY 19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071 22 23 23 23 23 22 23 23 23 23 22 23 22 23 23 18 7 15 14 19 16(1) 16 13 13 9 17 16(1) 13 14 14 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 18 7 15 14 19 16 16 13 13 9 17 16 13 14 14 8 10 25 12 3 86 10 9 69 88 76 76 54 6 11 10 5 85 68 86 89 25 12 3 86 10 8 68 88 76 76 54 6 10 10 5 75 67 86 89 25 12 3 86 10 8 67 87 76 76 54 6 10 10 5 75 67 86 89 25 12 3 86 10 8 67 87 76 76 54 6 10 10 5 75 67 86 M = MALE F - FEMALE ( ) - NUMBER OF PUPS DYING PRIOR TO WEIGHING ON DAY 1 POSTPARTUM. TOTAL IMPLAN TATIONS N 15 17 17 16 16 18 17 18 17 16 20 15 16 17 16 19 8 15 16 20 16 17 15 14 12 18 16 13 16 15 418-028-.PAGE C-107 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/F1 GENERATION LITTERS RAT/ LITTER NUMBER DURATION OF GESTATION (DAYS) N LITTER DELIVERED LIVE STILL- TOTAL BORN BORN BORN NNN 1 MF NUMBER OF LIVE PUPS AT COMPLETION OF DAY POSTPARTUM 8 15 22 MF MF MF MATERNAL DOSAGE GROUP III 1 MG/KG/DAY 19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064 22 22 22 23 NOT PREGNANT 23 23 23 23 23 NOT PREGNANT 23 23 22 23 16 18 15 15 15 14 15 16 13 14 17 14 18 0 16 0 18 0 15 0 15 0 15 0 14 0 15 0 16 1 14 0 14 0 17 0 14 0 18 88 7 11 78 96 96 68 96 97 67 77 98 86 99 88 7 10 77 96 96 68 96 87 67 77 98 86 99 88 7 10 77 96 96 68 96 87 67 77 98 86 98 88 7 10 77 96 96 68 96 87 67 77 98 86 98 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 [1] 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 36 6 10 68 69 7 10 69 32 85 96 2 11 57 6 il 86 36 6 10 68 59 7 10 69 32 85 96 2 11 57 6 11 76 36 6 10 68 59 7 10 69 32 85 96 2 11 57 6 10 76 36 6 10 68 59 7 10 69 32 85 96 2 11 57 6 10 76 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. TOTAL IMPLANTATIONS N 17 18 16 15 15 14 16 17 15 14 17 15 17 14 16 16 15 17 16 6 14 15 16 15 17 15 418-028:PAGE C-108 PROTOCOL 418-028! ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE EEPRODUCTION/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/F1 GENERATION LITTERS RAT/ LITTER NUMBER DURATION OF GESTATION (DAYS) N LITTER DELIVERED LIVE STILL TOTAL BORN BORN BORN N NN 1 MF NUMBER OF LIVE PUPS AT COMPLETION OF DAY POSTPARTUM 8 15 22 MF MF MF MATERNAL DOSAGE GROUP V 10 MG/KG/DAY 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070 23 23 23 22 23 22 23 23 22 22 23 22 23 23 22 11 19(1) 13 13 16(1) 20 14 12 13 15 14 14 IS 15 14(1) 0 1 0 0 0 0 0 1 0 0 0 0 0 0 0 11 20 13 13 16 20 14 13 13 15 14 14 15 15 14 47 6 12 76 85 96 13 7 4 10 57 67 87 77 68 11 4 10 5 85 47 5 12 76 85 95 13 7 4 10 57 67 77 77 68 11 4 10 5 85 47 5 12 76 85 95 13 7 4 10 57 67 77 77 68 11 4 10 5 84 47 5 12 76 85 95 13 7 4 10 57 67 77 77 68 11 4 10 5 84 M = MALE F FEMALE ( ) = NUMBER OF PUPS DYING PRIOR TO WEIGHING ON DAY 1 POSTPARTUM. TOTAL IMPLAN TATIONS N 11 20 14 14 16 20 14 15 16 15 17 14 16 15 14 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 - FI GENERATION LITTERS RAT/ LITTER NUMBER DAY 1 MFT DAY 8 M FT DAY 15 MFT DAY 22 M FT 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 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071 5.7 5.4 5.5 13.5 11.9 12.7 24.5 22.3 23.3 31.1 28.8 29.9 7.2 7.0 7.0 15.4 15.5 15.5 34.4 33.5 33.8 56.4 53.2 54.1 6.4 6.1 6.4 14.6 12.9 14.2 27.7 23.1 26.8 46.3 38.1 44.6 7.1 6.5 6.8 15.3 14.4 14.9 28.3 25.6 27.2 45.6 41.6 43.8 7.1 6.5 6.8 13.7 12.1 13.0 25.0 22.7 24.0 31.8 29.4 30.7 6.2 5.6 5.8 11.6 9.6 10.4 26.9 24.1 25.4 41.1 36.8 38.8 5.6 5.4 5.5 11.5 11.2 11.4 18.3 18.0 18.2 31.2 29.2 30.3 6.6 6.2 6.4 14.0 13.4 13.7 29.4 28.3 28.9 46.4 43.7 45.2 7.2 6.8 7.0 15.3 14.4 14.9 28.2 27.0 27.6 38.2 37.3 37.8 6.4 6.2 6.3 16.1 16.2 16.1 33.1 32.4 32.8 49.0 46.4 47.8 6.2 5.9 6.0 11.0 10.8 10.8 22.6 22.8 22.8 35.8 35.9 35.9 6.7 6.4 6.6 14.3 13.1 13.9 26.4 25.1 26.0 39.8 37.2 38.9 5.8 5.6 5.7 13.8 12.8 13.4 24.8 24.6 24.8 32.2 33.8 32.8 7.0 6.5 6.7 13.7 13.3 13.5 29.4 28.1 28.7 40.2 38.8 39.4 6.5 6.7 6.6 11.4 11.7 11.5 24.8 24.5 24.7 40.0 39.7 39.9 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. 0U"3 H9Vd:80_8It7 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODDCTION/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 - FI GENERATION LITTERS RAT/ LITTER NUMBER DAY 1 M FT DAY 8 M FT DAY 15 MFT DAY 22 M FT 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 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073 7.6 7.1 7.3 19.1 17.9 18.3 6.5 5.8 6.0 13.2 13.0 13.1 7.2 6.7 6.9 12.9 12.5 12.6 5.9 5.4 5.6 11.1 10.2 10.6 5.4 5.1 5.2 11.6 10.9 11.2 6.5 6.6 6.6 11.7 12.0 11.9 NOT PREGNANT NOT PREGNANT; MATING NOT CONFIRMED 7.4 7.5 7.4 20.1 21.2 20.6 6.6 6.5 6.6 14.9 14.6 14.8 6.9 6.6 6.8 16.7 15.8 16.3 7.0 6.9 6.9 14.6 15.2 15.1 6.5 6.3 6.4 15.8 15.9 15.9 5.9 5.7 5.8 10.3 9.7 9.9 7.2 6.8 7.0 13.9 12.8 13.4 35.5 24.2 23.3 22.9 25.2 24.0 33.1 23.7 22.5 21.2 23.4 23.6 33.9 23.9 22.8 21.8 24.1 23.8 41.2 27.8 30.7 29.8 30.9 19.3 27.7 40.4 27.2 29.4 30.0 30.8 20.4 25.6 40.9 27.6 30.2 29.9 30.8 20.0 26.8 48.0 33.2 33.8 35.1 31.7 37.6 45.4 31.7 32.3 32.4 29.3 36.2 46.3 32.2 32.9 33.4 30.3 36.7 57.1 46.4 42.4 47.6 43.8 30.1 44.3 56.6 45.1 40.1 46.2 43.0 33.4 40.9 56.9 45.9 41.4 46.4 43.3 32.2 42.8 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. IIK) H9Vd:80-8Itr 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 - FI GENERATION LITTERS RAT/ LITTER NUMBER DAY 1 M FT DAY 8 M FT DAY 15 M FT DAY 22 M FT MATERNAL DOSAGE GROUP V 10 MG/KG/DAY 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070 6.8 6.6 6.6 14.0 14.3 14.2 26.6 26.6 26.6 44.1 44.0 44.1 6.5 6.1 6.2 13.8 13.1 13.3 25.4 23.7 24.2 35.2 32.7 33.4 6.9 6.6 6.8 13.9 13.6 13.8 26.2 25.5 25.9 36.4 35.5 36.0 5.8 5.5 5.7 9.2 9.1 9.2 15.7 15.4 15.6 15.4 15.5 15.5 6.0 5.7 5.9 15.3 14.9 15.2 29.0 27.0 28.3 36.3 34.5 35.7 5.4 5.0 5.3 12.9 11.0 12.3 24.2 20.4 22.9 30.8 26.8 29.4 7.3 6.5 6.8 12.6 12.1 12.2 23.6 21.9 22.4 33.0 31.1 31.6 6.7 6.3 6.4 13.1 13.2 13.2 25.9 25.9 25.9 39.8 40.1 40.0 6.4 6.1 6.2 15.0 14.3 14.6 29.5 28.1 28.7 40.1 38.2 39.1 5.9 5.7 5.8 12.3 11.9 12.1 27.6 25.7 26.6 44.8 41.1 43.0 7.3 6.9 7.1 14.6 13.2 13.9 25.9 24.4 25.2 35.9 34.2 35.1 6.6 6.0 6.2 13.8 12.6 13.1 27.4 25.2 26.2 44.1 41.0 42.4 6.7 6.2 6.6 12.6 11.0 12.2 25.4 22.8 24.7 36.8 32.9 35.7 7.0 6.5 6.9 12.3 11.0 11.9 24.9 21.3 23.7 34.6 30.4 33.2 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. zu-3aov<m o-8ifr 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 - FI 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 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071 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 7.5 7.0 6.7 6.9 7.1 6.8 7.4 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 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 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 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 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 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 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 6.7 6.6 6.4 6.3 5.9 6.2 6.2 6.4 5.9 6.0 6.1 6.3 6.3 6.3 6.1 6.1 5.6 5.8 6.5 5.4 6.3 6.1 5.6 6.0 5.7 5.7 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 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 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 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 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. e it-3 H0Vd:8O-8W 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 - FI 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 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 RAT/ LITTER # MATERNAL DOSAGE GROUP IV 3 MG/KG/DAY POSTPARTUM DAY 1 19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073 7.7 7.6 7.5 MS 7.2 7.1 6.9 7.2 7.3 7.1 FD 1 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 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 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 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 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 NOT PREGNANT NOT PREGNANT; MATING NOT CONFIRMED 7.0 7.5 7.7 7.6 7.4 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 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 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 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 CO in 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 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 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 - FI 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 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. SU-OHDVd`-8K)r8ft 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 - FI 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 12.4 14.3 13.1 13.4 13.3 10.8 13.2 14.3 14.8 13.8 13.9 6.4 11.8 13.6 15.6 10.5 13.7 12.1 13.2 10.4 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 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. 911-0 aOVr.8ZQ-8lfr 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 - FI GENERATION PUPS PUP # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 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 14.1 15.7 15.7 14.6 14.2 14.7 14.3 14.1 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 rv 3 MG/KG/DAY POSTPARTUM DAY 8 19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073 19.8 19.2 18.4 MS 18.3 17.9 13.6 11.9 14.8 12.2 12.5 14.0 13.0 13.2 12.9 13.2 12.3 12.6 10.4 11.2 12.1 11.6 10.1 MD 2 12.5 10.5 11.8 13.0 9.7 12.0 12.0 12.8 11.5 11.7 9.8 12.4 NOT PREGNANT NOT PREGNANT; MATING NOT CONFIRMED 20.7 20.4 19.2 21.5 21.0 14.4 13.9 14.8 14.6 16.6 14.8 16.2 17.3 17.3 17.1 16.7 17.4 15.7 13.4 15.3 14.0 16.3 15.9 16.6 15.7 15.5 15.9 15.5 16.5 10.6 10.2 11.4 10.1 8.3 11.0 15.4 13.4 13.6 13.5 13.5 14.5 17.3 13.4 12.2 9.0 11.8 12.3 14.6 16.4 16.7 MD 1 9.8 13.6 17.9 12.2 11.0 8.9 9.8 12.7 15.2 15.0 13.4 15.7 10.1 MM 3 17.9 12.8 13.5 11.5 11.3 11.9 15.9 16.7 14.8 17.1 10.4 12.9 18.2 13.9 12.7 9.8 8.5 11.1 14.2 15.7 15.3 16.3 8.4 13.3 FD 1 13.3 12.1 9.9 11.2 11.3 14.2 16.9 15.1 15.3 10.8 12.4 13.9 13.6 9.9 12.8 13.1 13.7 16.2 16.1 15.0 10.3 13.3 13.1 12.9 10.8 9.9 12.9 15.1 15.5 13.8 15.4 10.7 12.7 12.9 11.8 11.2 12.7 11.8 15.6 FS FS 6.2 11.9 12.3 11.3 12.0 11.0 15.2 9.4 12.7 11.1 UU 10.0 10.1 10.4 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. 19 20 Ul-OaOVd:8ZO-8tt 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 - FI 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 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070 14.3 12.9 13.9 8.5 15.8 12.5 12.0 13.1 15.6 12.7 13.6 13.5 11.5 10.3 15.8 13.6 13.5 14.2 9.3 15.3 10.6 13.2 13.7 14.5 10.7 15.2 13.9 13.7 11.5 13.2 13.2 13.8 13.8 9.1 16.2 14.5 13.1 13.3 14.9 12.4 15.0 13.5 13.1 12.8 14.3 14.8 14.8 14.3 8.8 14.8 12.7 12.2 11.7 15.7 11.3 14.6 14.7 11.0 13.1 15.2 14.4 14.2 1.3.3 8.6 15.3 12.3 10.8 13.8 13.7 13.6 15.2 14.0 14.1 12.5 16.1 14.3 MD 2 14.1 8.4 15.2 13.7 11.8 13.2 15.3 12.9 13.4 13.3 12.8 13.0 16.4 14.0 13.4 13.7 10.8 14.8 12.6 11.8 12.9 15.0 12.6 14.9 12.7 12.5 12.3 15.8 15.3 14.0 13.0 9.8 15.6 15.0 11.6 13.7 14.4 MM 2 12.5 12.3 12.1 13.0 16.0 14.1 13.0 13.4 7.7 14.5 9.9 12.2 12.6 14.5 13.1 14.0 13.5 14.8 12.1 14.7 14.3 12.7 13.2 8.3 MD 1 12.1 13.5 14.5 11.9 11.8 14.1 12.2 12.7 12.4 16.9 13.7 12.8 14.9 9.4 14.5 12.4 12.6 13.4 13.3 11.0 13.0 12.6 10.4 9.9 14.8 12.1 13.2 9.5 15.7 15.3 12.8 12.4 15.5 13.8 12.5 12.1 12.5 11.5 14.9 13.7 14.1 10.8 14.1 14.4 12.6 FS 15.4 12.4 13.4 13.0 12.7 11.4 12.9 11.5 14.3 11.5 10.9 10.3 13.1 12.4 9.3 11.9 FD 1 12.8 16.0 11.9 10.8 9.4 10.5 15.4 FM 2 12.3 12.8 10.5 13.4 10.5 FD 1 10.3 FS 10 .2 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. 81I'D HOVd:8ZX)"8It? 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-770S.1) TABLE C44 (PAGE 7): PUP BODY WEIGHTS FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - FI 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 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071 22.4 34.4 27.5 29.6 29.2 25.4 18.8 29.4 29.5 31.8 23.4 26.2 24.5 29.5 26.1 25.9 34.4 29.1 27.0 24.0 27.0 18.6 30.6 28.7 33.9 21.5 27.8 24.8 29.9 24.7 25.7 32.6 27.8 28.1 23.0 28.0 16.8 28.6 29.2 31.9 22.0 27.4 25.5 29.9 24.9 24.5 32.8 23.7 30.5 27.3 27.2 19.2 28.3 29.5 33.8 24.4 26.5 25.1 29.4 27.3 20.9 33.2 28.5 26.6 26.1 27.1 15.6 29.7 26.9 34.0 25.7 24 .7 24.5 29.0 26.0 26.3 35.0 29.6 27.1 24.3 26.8 19.5 29.1 28.0 30.9 18.7 26.1 25.0 28.9 22.2 23.6 33.9 30.0 28.8 22.3 25.0 20.2 30.2 25.8 31.9 23.3 28.0 24.6 29.4 22.8 26.5 27.1 28.8 24.0 18.3 17.9 27.8 26.5 33.9 24.8 26.5 MD 3 27.9 24.7 18.7 28.2 26.3 23.9 25.6 19.3 27.9 23.3 33.1 24.3 23.7 24.9 26.8 25.0 21.1 26.3 23.1 25.8 29.0 19.7 27.5 29.0 21.1 27.5 24.3 27.7 18.1 19.0 26.1 28.4 24.9 20.2 15.9 28.3 28.8 24.9 MD 1 24.8 28.6 27.0 21.5 29.0 26.4 22.2 27.3 17.8 28.9 29.3 22.7 25.0 24.1 27.5 26.7 26.8 25.4 24.9 23.6 23.3 19.6 29.3 24.8 23.3 24.4 25.1 28.6 22.7 23.0 17.1 24.6 22.9 FM11 17.5 23.3 23.6 FD 8 27.4 22.6 26.7 21.3 FD 2 15.9 19.3 26.8 23.2 21.8 FD 1 FD15 21.5 25.6 24.6 23.2 FD 5 FM 6 21.7 FD 8 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. 6 1 3OYd:80"8lt' PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-770G 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 - FI GENERATION PUPS PUP # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 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 FM11 RAT/ LITTER # MATERNAL DOSAGE GROUP IV 3 MG/KG/DAY POSTPARTUM DAY 15 19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073 34.5 36.4 35.7 MS 33.1 33.6 23.1 26.5 23.4 24.8 22.1 25.2 23.6 23.5 23.2 23.0 22.4 24.1 24.7 19.3 24.0 23.5 23.0 MD 2 26.1 26.1 26.3 27.4 22.4 24.2 23.4 24.9 21.7 25.4 24.5 24.0 NOT PREGNANT NOT PREGNANT; MATING NOT CONFIRMED 39.0 41.2 43.5 40.1 40.8 30.7 26.7 29.1 27.6 24.9 27.1 31.4 31.3 30.4 31.2 31.2 30.0 28.3 31.3 31.6 29.9 29.2 32.0 31.4 31.2 30.0 32.0 30.1 30.0 16.8 21.7 19.4 19.6 18.2 19.9 26.7 27.5 29.3 27.1 28.0 28.1 32.9 24.8 23.3 18.8 23.9 23.0 28.4 31.3 30.0 MD 1 19.5 27.3 32.4 23.7 22.5 20.6 22.4 22.7 28.0 28.9 27.6 30.8 21.8 MM 3 33.7 24.2 21.3 19.4 27.3 26.3 26.5 30.3 29.2 30.2 17.0 25.3 33.0 24.0 22.7 23.6 24.6 25.0 26.3 30.3 31.9 31.9 21.4 26.1 FD 1 24.0 23.1 17.0 22.6 21.9 26.2 30.0 30.7 30.9 22.3 26.3 25.1 23.4 21.8 21.4 24.6 28.0 29.9 26.8 29.5 21.5 25.6 21.1 21.6 22.6 27.5 23.7 29.0 29.0 30.8 32.1 20.9 25 .2 24.7 21.9 22.1 25.6 22.0 28.7 FS FS 20.0 25.3 22.5 24.8 24.4 23.2 28.7 19.8 23.0 20.1 UU 19.9 18.1 FD10 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. 19 20 418-028:PAGE C-120 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 - FI 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 25.1 28.3 23.6 20.8 20.5 2S.1 22.9 24.5 24.5 20.4 FD 1 25.1 20.1 24.3 23.2 FM 2 20.0 21.3 22.4 21.2 17.7 FD 1 FS 19.2 19.1 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. 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 - FI 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 31.1 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 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071 33.4 57 .1 46.5 48.4 32.3 39.7 33.1 46.0 38.9 46.5 38.6 40.7 33.8 41.4 40.7 34.4 55.6 47.4 47.0 32.5 40.9 25.3 46.4 39.1 51.0 38.6 40.1 30.7 39.9 42.3 26.5 51.3 48.5 45.9 39.1 43.1 30.5 47.2 34.4 49.7 31.7 41.3 32.2 40.2 42.1 33.6 51.4 44.5 46.3 30.7 42.9 31.8 46.2 37.1 47.1 33.6 40.2 31.1 40.8 40.5 29.0 57.7 44.2 44.8 30.1 42.1 31.6 48.4 39.3 50.5 37.3 39.6 34.4 39.6 44.4 30.4 53.8 44.4 43.4 34.9 38.1 34.6 44.9 39.5 47.0 35.2 38.1 30.2 39.3 34.9 33.2 51.8 45.8 44.6 29.3 29.1 31.0 45.8 39.5 48.0 40.1 42.9 32.7 40.5 40.0 28.5 47.6 44.0 29.6 35.7 31.9 43.2 41.3 45.8 35.4 38.5 MD 3 39.4 35.3 33.3 49.3 45.6 28.7 42.7 30.8 44.6 39.7 45.0 31.1 36.3 35.9 37.5 36.9 26.3 50.3 45.0 30.7 43.2 29.1 43.7 36.9 34.0 40.3 31.5 39.1 41.3 32.4 41.3 39.2 29.1 39.2 32.9 45.2 40.5 37.8 MD 1 34.2 37.0 43.3 24.0 45.4 38.1 31.2 30.5 27.9 42.9 33.0 40.5 38.9 32.7 40.2 42.6 28.9 45.1 41.0 29.3 37.0 31.9 42.6 32.2 36.9 39.4 34.6 37.7 43.1 29.9 25.8 40.6 27.6 FM11 27.0 37.5 34.5 FD 8 31.1 26.4 43 .4 34.6 FD 2 24.9 29.9 37.8 29.4 28.6 FD 1 FD15 36.2 35.6 29.1 27.1 FD 5 FM 6 27.5 FD 8 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. 418-028:PAGE C-122 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 - FI GENERATION PUPS PUP # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 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 FM11 RAT/ LITTER # MATERNAL DOSAGE GROUP IV 3 MG/KG/DAY POSTPARTUM DAY 22 19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073 47.2 47.4 49.4 MS 44.4 46.3 31.3 36.4 34.3 31.3 32.7 33.1 32.8 35.2 33.6 33.2 34.6 33.3 36.0 39.4 36.2 34.0 30.1 MD 2 32.8 30.6 32.9 32.0 33.6 31.6 37.1 41.2 37.1 33.5 39.4 37.1 NOT PREGNANT NOT PREGNANT; MATING NOT CONFIRMED 57.5 59.1 54.8 55.5 57.6 51.3 44.7 41.2 47.9 45.6 47.6 43.0 43.6 41.0 42.9 41.0 40.1 48.7 46.5 46.1 48.6 45.9 49.4 43.5 44.3 43.8 44.3 42.9 45.7 31.7 28.5 28.1 30.5 32.5 29.3 44.5 44.2 44.0 43.8 45.6 46.2 45.3 28.9 32.2 32.8 28.3 38.3 47.5 44.0 48.4 MD 1 33.2 42.0 46.0 32.0 30.6 35.6 26.9 35.8 45.7 42.9 44.0 43.5 33.4 MM 3 45.4 32.7 33.9 31.7 27.1 36.0 44.1 42.7 42. B 43.5 35.7 39.5 45.0 31.5 30.6 36.8 28.3 37.8 47.5 41.3 50.1 40.9 27.5 38.6 FD 1 29.6 34.7 31.7 31.7 36.4 45.8 40.4 47.2 42.5 33.0 42.7 33.0 29.9 28.5 30.0 30.6 42.7 41.2 39.7 41.4 37.2 41.3 33.2 34.4 32.7 32.9 36.0 45.3 38.2 46.2 43.2 36.8 42.2 33.4 32.1 33.7 35.5 39.9 39.9 FS FS 32.3 41.2 28.1 27.8 32.1 34.8 39.5 33.8 34.5 24.7 UU 31.4 23.7 FD10 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. 19 20 418-028:PAGE C-123 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 - FI 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 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070 43.5 33.2 37.9 15.1 32.3 31.2 34.8 39.9 39.1 43.4 37.3 45.7 37.8 35.2 48.6 45.6 36.3 38.1 15.8 33.5 30.6 33.3 43.1 38.9 45.6 34.6 40.7 34.6 33.3 51.7 43.0 35.4 33.7 16.0 37.9 29.9 32.3 38.4 40.8 45.0 36.4 43.6 35.3 33.8 54.1 44.3 34.5 35.8 16.2 39.1 30.5 31.8 44.4 43.3 50.8 33.5 45.8 37.1 37.4 47.6 45.4 36.6 38.9 14.4 39.3 27.0 29.3 33.2 40.0 40.4 36.7 45.1 36.1 37.4 49.5 43.3 MD 2 34.9 16.0 35.4 35.9 32.4 39.6 38.4 40.9 37.4 43.8 39.9 33.6 52.1 44.0 31.6 35.5 15.3 35.3 25.0 32.5 40.4 39.8 47.8 35.6 41.2 39.6 35.5 46.9 43.0 32.2 35.6 14.8 37.0 31.7 29.0 40.6 42.0 MM 2 32.4 44.2 33.9 33.7 46.5 42.9 31.7 37.9 14.5 37.2 30.2 31.1 39.5 39.6 44.3 34.5 42.6 39.1 35.0 47.5 44.2 32.0 35.7 18.1 MD 1 34.5 30.6 35.6 32.2 39.5 33.8 39.1 31.2 31.0 46.8 45.6 30.9 35.0 14.9 34.6 30.6 31.1 42.5 38.7 41.2 35.2 41.0 39.9 33.8 43.9 36.9 33.7 15.9 36.3 31.8 31.7 42.4 37.6 39.2 36.1 41.0 36.2 27.5 48.8 34.9 34.9 14.2 35.6 31.5 30.1 FS 37.9 44.0 32.9 40.2 38.6 25.6 FD13 34.8 34.4 32.5 33.3 30.5 24.4 33.0 38.4 34.9 39.0 32.4 32.2 FD 1 40.9 24.4 32.9 28.9 FM 2 27.6 29.9 26.8 34.2 31.0 FD 1 23.8 FS 23.8 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 C45 (PAGE 1) : PUP VITAL STATUS AND SEX FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - FI 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 FA FA FA FA MA MA M A 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 F A F A F A F A F A FD 4 MA MA MA M A MA MA FA FA FA FA FA FA FA FA FA FA FA MA M A M A M A M A 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 FA 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 MD 5 F A F A F A F A F A F A F A MA 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 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 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071 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 FM 6 MA MA FA FA FA FA FA MA MA MA MA MA MA MA MA MA MA MA MA FA FA FA MA MA MA MA MA MA MA M A FA FA FA FA FA FA M 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 FD 8 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 FM11 FD 2 FD 1 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 FD15 MA MA M A MA M A MA MA FA FA FA FA FA FA MA MA MA MA MA MA MA FA FA FA FA FA FA MA MA MA MA MA FA FA FA FA 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 M A M A M A M A M A MD 1 F A F A F A F A F A M A M A M A M A M A M A M A MD 3 F A F A F A F A F 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 FD 8 MA MA MA M A M A MA MA M A FA FA FA FA FA FA 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. 418-028:PAGE C-125 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 - FI GENERATION PUPS PUP # 12 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 M A M A MA M A 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 M A M A MA M A MA MA MA MA FA FA FA FA FA FA NOT PREGNANT MA M A M A MA MA MA MA MA MA FA FA FA FA FA FA M A MA M A 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 M A 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 FA FA FA FA FA FA FA FS NOT PREGNANT MA MA MA MA M A MA MA FA FA FA FA FA FA FA MA M A MA MA MA MA MA MA MA FA FA FA FA FA FA FA FA MA MA MA M A 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 FM11 RAT/ LITTER # MATERNAL DOSAGE GROUP IV 3 MG/KG/DAY 19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073 M A M A M A M S F A F A F A F A F A F A FD 1 M A M A MA MA MA MA FA FA FA FA FA FA FA FA FA FA MA MA MA MA MA MA FA 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 MA MA MA MA MA MA MA FA FA FA FA FA FA FA FA FA FA M A MA M A MA MA MA FA FA FA FA FA FA FA FA FA U U NOT PREGNANT NOT PREGNANT; MATING NOT CONFIRMED MA MA MA FA FA M A MA MA MA MA MA MA M A FA FA FA FA FA M A M A MA MA MA MA MA MA M A FA FA FA FA FA FA MA MA FA FA FA FA FA FA FA FA FA FA FA FS 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 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 FD10 M A M A M A M A M A M A M A MM 3 F A F A F A F A F A F A 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. 418-028:PAGE C-126 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 - FI GENERATION PUPS PUP # 12 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 M A 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 M A MA MA MA MA MA FA FA FA FA FA FA M A M A MA M A MA MA M A 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 M A MA M A MA MA MA MA MA M A MA MA MA FA FA FA FA FA FA FA M A M A M A M A F A FA FA FA FA FA FA FA FA FA MA M A MA M A MA FA FA FA FA FA FA FA 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 M A MA MA M A MA FA FA FA FA FA FA FA FA MA MA MA MA MA MA M A MA MA MA MA FA FA FA FA MA M A 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. 418-028:PAGE C-127 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 - FI 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 C M ) . 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 X 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. 418-028:PAGE C-128 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 - FI 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: RIGHT HINDLIMB, LACERATION. 1/ 5 PUPS: 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 C M ) . a. Tabulation restricted to adverse observations; all other pups appeared normal. b. 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 C47 (PAGE 1) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - FI GENERATION PUPS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) LITTER NUMBER DAY POSTPARTUM OBSERVATIONS a 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. 190S0 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. 19074 1 1 PUP: FOUND DEAD. ALL TISSUES APPEARED NORMAL 22 14 PUPS: APPEARED NORMAL. 19075 22 16 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. 418-028:PAGE C-130 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 - FI GENERATION PUPS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) LITTER NUMBER DAY POSTPARTUM OBSERVATIONS a 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. 22 16 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. 418-028-.PAGE C- U-> 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 - FI 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. 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 - FI GENERATION PUPS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) LITTER NUMBER DAY POSTPARTUM OBSERVATIONS a III 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. PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-770S WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1) TABLE C47 (PAGE 5): NECROPSY OBSERVATIONS - INDIVIDUAL DATA - FI GENERATION PUPS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) LITTER NUMBER DAY POSTPARTUM OBSERVATIONS a 19002 1 1 PUP: FOUND DEAD. ALL TISSUES APPEARED NORMAL 1 PUP: STILLBORN. AUTOLYSIS PRECLUDED FURTHER EVALUATION. 22 9 PUPS: APPEARED NORMAL. 1900S 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. 19069 10 1 PUP: FOUND DEAD. NO MILK IN STOMACH. AUTOLYSIS PRECLUDED FURTHER EVALUATION. 22 16 PUPS: APPEARED NORMAL. 19073 22 13 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. 418-028:PAGEC-134 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 - FI GENERATION PUPS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) LITTER NUMBER DAY POSTPARTUM OBSERVATIONS a 19001 22 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 IS 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. 418-028:PAGE C-135 PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OP 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 - FI GENERATION PUPS RAT/ LITTER LIVER NUMBER M F T DOSAGE GROUP I 0 MG/KG/DAY 19012 1.864 2.008 1.936 19019 1.436 1.636 1.536 19021 1.360 1.558 1.459 19023 1.814 1.878 1.846 19041 1.114 1.232 1.173 19042 1.390 1.552 1.471 19044 1.798 1.736 1.767 19050 1.336 1.406 1.371 19053 1.438 1.562 1.500 19065 1.266 1.354 1.310 DOSAGE GROUP II 0.3 MG/KG/DAY 19004 1.138 1.246 1.192 19009 2.350 2.356 2.354 19016 1.874 1.633 1.784 19018 1.768 1.752 1.760 19026 1.062 1.214 1.138 19036 1.596 1.596 1.596 19037 1.170 1.182 1.176 19043 2.098 2.074 2.086 19047 1.510 1.462 1.486 19048 1.826 1.985 1.897 DOSAGE GROUP III 1 MG/KG/DAY 19003 1.268 0.998 1.133 19007 1.324 1.278 1.301 19008 1.516 1.732 1.624 19013 1.976 1.736 1.856 19015 1.416 1.510 1.463 19017 2.102 2.188 2.145 19024 1.504 1.550 1.524 19029 2.076 1.456 1.766 19034 1.550 1.670 1.610 19056 1.500 1.646 1.573 19005 1.296 1.312 1.304 M = MALE F FEMALE T = TOTAL ALL WEIGHTS WERE RECORDED IN GRAMS (G) . TERMINAL BODY WEIGHT M FT 42.68 39.70 34.74 46.02 33.00 36.12 44.30 36.42 35.60 33.08 42.24 37.50 33.80 44.38 31.02 36.16 39.82 34.86 35.92 31.00 42.46 38.60 34.27 45.20 32.01 36.14 42.06 35.64 35.76 32.04 30.78 56.35 45.32 45.50 32.30 40.74 30.66 46.34 38.78 48.96 30.12 53.20 38.10 41.70 30.04 34.30 29.16 43.80 36.62 46.45 30.45 54.10 42.61 43.60 31.17 37.52 29.91 45.07 37.70 47.84 30.78 35.34 41.82 46.36 38.06 44.96 40.04 43.22 41.24 40.88 33.56 27.58 29.70 40.10 42.36 35.84 43.88 37.62 33.24 38.76 39.48 30.84 29.18 32.52 40.96 44.36 36.95 44.42 38.83 38.23 40.00 40.18 32.20 418-028:PAGE C-136 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 - FI GENERATION PUPS RAT/ LITTER NUMBER M DOSAGE GROUP IV 19035 1.192 19039 1.540 19040 1.226 19045 1.624 19054 2.137 19058 2.364 19062 1.470 19063 2.040 19066 1.582 DOSAGE GROUP V 19001 1.855 19006 1.358 19011 1.290 19020 0.454 19022 1.336 19025 1.098 19027 1.283 19028 1.550 19030 1.594 19031 1.842 LIVER F 1.316 1.380 1.582 1.730 2.495 2.110 1.702 2.132 1.702 1.902 1.512 1.434 0.540 1.286 1.160 1.286 1.742 1.632 1.870 T 3 MG/KG/DAY 1.254 1.460 1.404 1.677 2.280 2.237 1.586 2.106 1.642 10 MG/KG/DAY 1.881 1.435 1.362 0.497 1.311 1.129 1.284 1.646 1.613 1.856 TERMINAL BODY WEIGHT M FT 33.82 35.14 31.48 37.66 57.13 47.80 42.50 47.60 43.76 32.04 31.46 30.28 37.18 56.55 45.08 39.86 46.10 42.82 32.93 33.30 30.88 37.42 56.90 46.44 41.18 46,53 43.29 44.10 35.20 36.28 15.30 36.60 30.00 33.05 39.80 39.94 43.06 44.24 32.84 35.44 15.52 34.46 26.70 31.46 40.10 39.16 40.80 44.18 34.02 35.86 15.41 35.53 28.35 32.17 39.95 39.55 41.93 LI-3aDVa*K0-8Ifr APPENDIX D PROTOCOL AND AMENDMENTS 418-028:PAGE D -l 90S Shccty D rin , Bk)g. A Honham, PA 19044 Telephone;(2J5J 44347 iO Ttfeftec (215) 443-8587 ARGUS RESEARCH Charles River Laboratories D iscovery and D evelopm ent Services PROTOCOL 418-028 SPONSOR'S STUDY NUMBER: T-7706.1 STUIW TITI F. Oral (Gavage) Combined Rqjeated Dose Toxicity Study o f T-7706 with the Reproduction/Developmental Toxicity Screening Test PURPOSE: The purpose o f this study is to provide information on the possible health hazards that may result from repeated exposure o f 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 o f 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 o f the cohceptus and parturition). The study also places emphasis on neurological effects as a specific endpoint and should identify the neurotoxic potential o f a test substance, which may warrant further in-depth investigation. TESTING FACILITY: Because o f the selectivity o f the endpoints and die short duration o f foe study, the screening test w ill not provide evidence for definitive claims o f no reproduction/developmental effects. In particular, it offers only limited means o f detecting postnatal manifestations o f prenatal 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 PBHBETOlfc Raymond G. York, P h D ., DABT Associate Director o f Research Email: raymond.york@criver.com Address as cited above for Testing Facility SPONSOR: 3M Corporate Toxicology 3M Crater, Building 220-2E-02 St. Paul, Minnesota 55144-1000 418-028:PAGE D-2 STUDY M O N IT O R : John Buteohoff, Ph.D., DABT, CIH 3M Corporate Toxicology 3M Medical Department Telephone: (651) 733-1962 Telefax: (651)733-1773 Email: jlbutenhofi@ m nim .com Protocol 418-028 Page 2 REGULATORY CITATIONS: Organisation for Economic Co-operation and Development (1996). OECD Guidelinefo r Testing o f Chemicals. 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 o f Good Laboratory Practices [C(97)186/Final]. U.S. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule. 21 CFRPart58. Japanese Ministry o f Health and Welfare (1997). Good Laboratory Practice Standardfo r Safety Studies on Drugs, MHW Ordinance Number 21, March 26,1997. REGULATORY COMPLIANCE: This study w ill be conducted in compliance with the Good Laboratory Practice (GLP) regulations cited above. All changes or revisions o f 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) w ill audit the protocol, the raw data and the report, and w ill inspect critical phases o f those portions o f the study conducted at the Testing Facility in accordance w ith the Standard Operating Procedures o f the Testing Facility. The final report w ill include a compliance statement signed by the Study Director that the report accurately reflects the raw data obtained during the performance o f the study and that all applicable GLP regulations were followed in die conduct o f the study. Should significant deviations from GLP regulations occur, each w ill be described in detail, together with how the deviation might affect the quality or integrity o f the study. Should any portion o f the study be conducted by a subcontractor or by the Sponsor, the Study Director w ill ensure that a qualified Principal Investigator is identified by the facility conducting that portion o f the study. The QAU for this facility w ill conduct critical phase inspections and audit respective results and reports for that study portion according to the SOPs o f that facility. Such critical phase inspection reports and report audits w ill be submitted by the facility to the Principal Investigator and the Study Director. The dates o f the inspections and report submissions w ill be incorporated into a QAU Statement generated by that facility and provided 418-028:PAGE D-3 Protocol 418-028 Page 3 to the Testing Facility for inclusion in the final report. In addition, this facility w ill provide a statement o f 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-. Tg lSabstange: T-7706 [Perfluorohexane Sulfonate Potassium Salt (PFHS)] Lot identification w ill be documented in the raw data. The Sponsor w ill provide to the Testing Facility documentation or certification o f fire identity, composition, method o f synthesis, strength and activity/purity o f the test substance. This documentation will be included in the final report. V eh icle: Aqueous 0.5% carboxymethlycellulose (CMC) (medium viscosity) prepared using reverse osm osis membrane processed deionized water (R.O. deionized water). Lot identification and Supplier w ill be documented in the raw data. Neither the Sponsor nor die Study Director is aware o f any potential contaminants likely to be present in the vehicle that would interfere with fire results o f this study. Therefore, no analyses other than those mentioned in this protocol w ill 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). Sfirag: Bulk Test Substance: Bulk Vehicle Components: Prepared Test Substance and Vehicle Formulations: Room temperature. Room temperature. Refrigerated (2C to 8eC). A ll test substance shipments should be addressed to the attention o f Julian Gulbinslri, Manager o f Formulation Laboratory, at the previously cited Testing Facility address and telephone number. 418-028-.PAGED-4 Protocol 418-028 Page 4 Shipments should include information concerning storage conditions and shipping cartons should be labeled appropriately. The recipient should be notified in advance o f shipment. FO R M U LA TIO N : Frequency o f Preparation: Formulations (suspensions) w ilt be prepared weekly at the Testing Facility. Detailed preparation procedures w ill be attached to this protocol (ATTACHMENT 3). Adjustment for Puritv : The test substance w ill be considered 100% pure for the purpose o f dosage calculations. Testing Facility Reserve Sam ples: The Testing Facility w ill reserve a sample o f each lot o f bulk test substance (approximately 1 g) and bulk vehicle components (approximately 1 g or 5 mL) used during the course o f the study. Samples w ill be stored under the previously cited conditions. ANALYSES: Results o f required analyses w ill 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 o f die study. Additional analyses, if required, w ill be documented by protocol amendment. Bulk Test Substance Sam pling: A sample o f approximately 1 g o f the test substance w ill be taken on the last day o f treatment and sent (ambient conditions) to: Principal Investigator: Lisa Clemen 3M Environmental Technology and Safety Services Building 2-3E-09 S t Paul, Minnesota 55133-3331 Telephone: (651)778-5568 Telefax: (651)778-6176 Email: laclemen@nunm.com The recipient w ill be notified in advance o f sample shipment. 418-028.-PAGE Analyses of Prepared Formulations: Protocol 418-028 Page 5 Concentration and Homogeneity: Concentration and homogeneity o f the prepared formulations w ill be verified during the course o f this study. Quadruplicate samples (2 mL each) w ill be taken from the top, middle and bottom o f each concentration on the first day o f preparation. Two samples from each quadruplicate set w ill be shipped for analysis; the remaining samples w ill be retained at file Testing Facility as backup samples. Quadruplicate samples w ill be taken from each concentration on the last day o f preparation. Two samples from each quadruplicate set w ill be shipped for analysis; the remaining samples w ill be retained as backup samples. Backup samples w ill be stored under die previously cited conditions and discarded at the Testing Facility upon the request o f the Sponsor. Stability: Stability o f the prepared formulations w ill be documented during this study. Two sets o f duplicate samples (2 mL each) from each concentration w ill be taken on the first day o f preparation. One sample o f each duplicate set w ill be shipped on the day o f preparation. These samples w ill be analyzed at the following time points: as soon after preparation as possible and ten days after the first analysis. The remaining samples w ill be retained at the Testing Facility as backup samples. Backup samples w ill be stored under the previously cited conditions and discarded at the Testing Facility upon the request o f the Sponsor. Shipping Instructions: Samples to be analyzed w ill be shipped (refrigerated) to: Principal Investigator Lisa Clemen 3M Environmental Technology and Safety Services Building 2-3E-09 S t Paul, Minnesota 55133-3331 Telephone: (651) 778-5568 Telefax: (651) 778-6176 Email: laclemen@mmm.com The recipient w ill be notified in advance o f sample shipment. DISPOSITION: Prepared formulations w ill be discarded at the Testing Facility. A ll remaining bulk test substance w ill be returned to: Dan Hakes 3M EHSR - Auto & Chem Grp 3M Center, Building 236-1B-10 St. Paul, Minnesota 55144-1000 Telephone: (651) 733-2392 418-028:PAGE D-6 TEST SYSTEM: Protocol 4184)28 Page 6 Species/Strain and Reason for Selection: The Crl:CD(SD)IGS BR VAF/Phis rat was selected as the Test System because: 1) it is one mammalian species accepted for use in toxicity studies and it has been w idely used throughout industry, 2) this strain o f 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: 100 male and 100 virgin female rats. Population selected for main study: 75 male and 75 virgin female rats (15 per sex per dosage group). Population selected for toxicokinetic study: 15 male and 15 female rats (three per sex per dosage group). Body Weight and Age: Male rats w ill be ordered to weigh from 275 g to 300 g each at receipt, at which time they w ill be expected to be at least 60 days o f age. Female rats w ill be ordered to weigh from 200 g to 225 g each at receipt, at which time they w ill be expected to be at least 56 days o f age. Actual body weights w ill be recorded the day after receipt and w ill be documented in the raw data. The weight ranges w ill be included in die final report. At study initiation, the weight variation o f the rats w ill not exceed 20% o f the mean weight o f each sex. Sex: Both male and female rats w ill be evaluated. Source: Charles River Laboratories, Inc. The rats w ill 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., hie., 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 o f the first dosage. Pups w ill not be individually identified during lactation; all parameters w ill be evaluated in terms o f die litter. 418-028:PAGE D-7 ANIMAL HUSBANDRY: Protocol 418-028 Page 7 All cage sizes and housing conditions are in compliance with the Guidefo r the Care and Use o f LaboratoryA nim als^. Argus Research is an AAALAC-accredited facility. Housing: Fo generation rats w ill be individually housed in stainless steel wire-bottomed cages except during the cohabitation and postpartum periods. During cohabitation, each pair o f rats w ill be housed in the male rat's cage. Beginning no later than day 20 o f presumed gestation, Fo generation female rats w ill be individually housed in nesting boxes. Each dam and delivered litter w ill be housed in a common nesting box during the postpartum period. Nesting Material: Nesting material (bed-o'cobs) w ill 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 A ir. Tem perature and Humidity: The animal room is independently supplied with at least ten changes p a hour o f 100% fresh air that has been passed through 99.97% HEPA filters. Room temperature w ill be maintained at 64F to 79F (18C to 26C) and monitored constantly. Room humidity w ill also be monitored constantly and maintained at 30% to 70%. An automatically controlled 12-hour light: 12-hour dark fluorescent light cycle w ill be maintained. Each dark period w ill begin at 1900 hours EST. The light cycle may be adjusted by the Study Director or designee i f deemed necessary to accommodate scheduled laboratory activities. Any such adjustment w ill be documented in the raw data. D iet: Rats w ill be given Certified Rodent Diet #3002 (PMI Nutrition International) available ad libitum from individual feeders. Feed w ill 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. A ll water w ill be from a local source and passed through a reverse osmosis membrane before use. Chlorine w ill be added to the processed water as a bacteriostat; processed water is expected to contain no m o than 12 ppm chlorine at the time o f analysis. Water is analyzed monthly for possible bacterial contamination and twice annually for possible chemical contamination. 418-028;PAGE D-8 Protocol 418-028 Page 8 Contam inants: Neither the Sponsor nor the Study Director is aware o f 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 w ith the results o f this study. Therefore, no analyses other than those routinely performed by the feed supplier or those mentioned in this protocol w ill be conducted. DAY NUM BERING SYSTEM: Gestation day 0 is defined as the day spermatozoa are observed in a smear o f the vaginal contents and/or a copulatory plug observed in situ. The day o f birth is designated lactation day 0 (postpartum day 0) in the Health Effects Test Guidelines - Reproduction and Fertility Effects (O ffice o f Prevention, Pesticides and Toxic Substances 870.3800, August, 1998) and in the OECD Guideline for the Testing o f Chemicals Combined Repeated Dose Toxicity Study with the Reproduction/Developmcntal Toxicity Screening Test (Section 4, No. 422,22 March 1966). This same day is designated day 1 postpartum (day 1 o f lactation) in the Standard Operating Procedures o fth e Testing Facility. Throughout this protocol, the day o f birth w ill be designated day 1 postpartum (day 1 o f lactation) and all subsequent ages o f the FI generation rats and days o f the lactation period w ill be determined and cited accordingly. RANDOM IZATION AND COHABITATION: Upon arrival, rats w ill be assigned to individual housing on the basis o f computer-generated random units. During an acclimation period o f at least five days, male and fem ale rats w ill be selected for study on the basis o f physical appearance and body weights recorded during acclimation. The rats w ill be assigned to dosage groups based on computer-generated (weightordered) randomization procedures. Within each dosage group, consecutive order w ill be used to assign rats to cohabitation, one male rat per fem ale rat. The cohabitation period w ill consist o f a maximum o f 14 days. Female rats with spermatozoa observed in a smear o f the vaginal contents and/or a copulatory plug observed in situ w ill be considered to be at day 0 o f presumed gestation and assigned to individual housing. Fem ale rats not mated within the first seven days o f cohabitation w ill be assigned alternate m ale rats that have mated (same dosage group) and w ill remain in cohabitation for a maximum o f seven additional days. Day 1 o f lactation (postpartum) is defined as the day o f birth and is also the first day on which all pups in a litter are individually weighed (pup body weights w ill be recorded after all pups in a litter are delivered and groomed by the dam). Utters w ill not be culled during the lactation period, because random selection o f pups 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 Page 9 Within each dosage group, consecutive order w ill 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 o f random units w ill be used to select five male and five fem ale pups per litter for blood sample and liver collection; these pups w ill only be selected from the ten dams selected for FOB, motor activity, CC&H and histological evaluation. A D M IN IS T R A T IO N : Route and Reason for C hoice: 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 o f the possible routes for environmental exposure. Method and Frequency: Dosages w ill be adjusted daily for body weight changes and given at approximately the same time each day. The first day o f dosage is designated as day 1 o f study. Male rats w ill be given the test substance once daily beginning 14 days before a cohabitation period that consists o f a maximum 14 days. Dosage w ill continue through the day before sacrifice, after completion o f the cohabitation period, after a minimum o f 42 days o f administration. Female rats w ill be given the test substance once daily beginning 14 days before a cohabitation period that consists o f a maximum o f 14 days. Dosage w ill continue through the day before scheduled sacrifice (day 21 o f lactation). 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 w ill be expected to cause toxic effects but not mortality or obvious suffering. The descending sequence o f the lower dosage levels w ill be selected for the purpose o f demonstrating any dosage-related response, with no adverse effects expected at the lowest level. 418-028:PAGE D-10 Dosage Level. C oncentrations and Volume: Protocol 418-028 Page 10 Dosage Grin Number o f Rats Per Sex Doaacc (m g/kgttay) Concentration* (im /n d j rV niyi Volume (m lA g) Angui Batch Number I 15 + 3* 0 0 10 B -418^>28-A(Dey.Mooth.Year) II 15 + 3* 0.3 0.03 10 B -4l8428-B (D ay.M ailh.Y ear) UI 15 + 3* 1 0.1 ID B-41M28-CCDay.Month.Year) IV 15 + 3* 3 0.3 10 B -418-02*-D(Day.M onth.Year) V 15 + 3* 10 l to B-4 IM 2S-E(D ay.Month.Year) b. Three addltk a l rata per ex per dosage group w ill be asaigned to toxicokinetic sample collection. TESTS. ANALYSES AND MEASUREMENTS - Fo GENERATION: All Periods: m l Fem ale K afr At least twice daily. Clinical Observation and/or General Appearance - M ale aad Fem ale Rats: Acclimation Period: W eekly. Dosage Period: Daily before dosage. On die first day o f dosage, postdosage observations w ill be recorded at approximately hourly intervals for the first four hours and at the end o f the normal working day. Subsequent postdosage observations w ill be recorded at intervals deemed appropriate by the Study Director or designee after determination o f peak toxicologic effects. Maternal Behavior: Days 1 ,5 ,8 ,1 5 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 w ill not be summarized or analyzed statistically. Detailed Clinical O bservations - M ale and F tw sfe ttats- Once before the first dosage and at least once weekly thereafter, detailed clinical observations w ill be conducted for all male and female rats. These observations w ill be made outside the cage in a standard arena at the same time each day o f conduct. Effort w ill be made to ensure that variations in the test conditions are minimal and that observations are conducted by observers unaware o f treatment groups. Signs noted should include, but not be limited to: changes in skin, fur, eyes, mucous membranes, occurrence o f secretions and excretions and autonomic activity (e.g., lacrimation, piloerection, pupil size, unusual respiratory pattern). Changes in gait, posture 418-028-.PAGED-11 Protocol 415-028 Page 11 and response to handling as w ell as the presence o f 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 W eights - M ale and Fem ale Rats: Acclimation Period: Weekly. Dosage Period: Daily. Sacrifice: Terminal weight. Feed Consum ption Values - M ale B ats (recorded and tabulated): Dosage Period: Weekly. Feed Consum ption Values - Fem ale Rats (recorded and tabulated): Dosage Period: Weekly to cohabitation. Gestation Period: Days 0 ,7 ,1 0 ,1 2 , IS, 1 8,20 and 25 (if necessary). Postpartum Period: Days 1 ,5 ,8 and 15. Feed consumption not tabulated after day IS postpartum, when it is expected that pups w ill begin to consume maternal feed. Feed Consum ption Values - M ale an d Fem ale R at, Feed consumption values may be recorded more frequently than cited above if it iBnecessary to replenish the feed. During cohabitation, when two rats occupy the same cage with one feed jar, replenishment o f the feed jars w ill be documented. Individual values w ill not be recorded or tabulated. Toxicokinetic Sam ple Collection: On day 14 and 42 o f study, blood samples (approximately 1 mL each) w ill be collected from each male rat assigned to the toxicokinetic sample collection portion o f the study (3 pet group). On day 14 o f study and day 21 o f presumed gestation, blood samples (approximately 1 mL each) will be collected from each female rat assigned to the toxicokinetic sample collection portion o f the study (3 per group). Samples w ill be collected prior to dosage on day 14 o f study. The time o f each blood collection w ill be recorded in die raw data. 418-028:PAGE D-12 Protocol 418-028 Page 12 Blood w ill be collected from the orbital sinus. I f necessary, blood may be collected from an alternate site; if so, the alternate site w ill be documented in the raw data.) The samples w ill be transferred into EDTA-coated (purple top) tubes and spun in a centrifuge. The resulting serum w ill be transferred into polypropylene tubes labeled with the protocol number, Sponsor study number, animal number, sex, group number, dosage level, day o f study, collection interval, date o f collection, species, generation and storage conditions. All samples w ill be immediately frozen on dry ice and maintained frozen C-70C) until shipment for analysis. After the last blood sample collection, rats w ill be sacrificed and samples o f the liver w ill be collected for analysis. Shipping Instructions: Samples to be analyzed w ill be shipped on dry ice to: Principal Investigator: Lisa Clemen 3M Environmental Technology and Safety Services Building 2-3E-09 S t Paul, Minnesota 55133-3331 Telephone: (651) 778-5568 Telefkx: (651) 778-6176 Email: laclemen@mmm.com The recipient w ill be notified in advance o f sample shipment Estrone Cycling and Mating. Estrous cycling w ill be evaluated by examination o f vaginal cytology beginning with the day after the first administration and then until spermatozoa are observed in a smear o f the vaginal contents and/or a copulatory plug is observed in situ during the cohabitation period. Caesarean-Sectioning - Toxicokinetic Study: On day 21 o f presumed gestation, blood and liver samples w ill be collected from all female rats designated for toxicokinetic sample collection. Blood samples w ill be collected from the rats as previously described. After sacrifice, the liver o f each rat w ill be excised and tire liver weight w ill be recorded. The median liver lobe w ill be frozen and stored (<-20C) until shipment for possible analysis. The fetuses w ill be removed from the uterus and blood samples w ill be collected from each fetus via decapitation. Blood w ill be placed into tubes, pooled per litter, allowed to clot and spun in a centrifuge; the resulting serum w ill be transferred into labeled polypropylene tubes. A ll samples will be immediately frozen on dry ice and maintained frozen (<-70C) until shipment for analysis. 418-028:PAGE D-13 Protocol 418-028 P age 13 The liver from each fetus w ill be collected, pooled per litter and placed into labeled tubes. The samples w ill be frozen and stored (<-20C) until shipment for analysis. Samples w ill be shipped on dry ice to Lisa Clemen at the previously cited address. Natural Delivery: Female rats w ill be evaluated for: Adverse Clinical Signs Observed During Parturition. Duration o f Gestation (day 0 o f 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 o f the study, a functional observational battery (FOB)<5_8)w ill be conducted on 10 m ale and 10 female rats per group. For male rats, this assessment dll 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 o f the group assignment o f the rat, w ill assess the following parameters: 1. Lacrimation, salivation, palpebral closure, prominence o f 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 o f gait abnormalities, air righting reaction, and landing foot splay (gait ami 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 hypotonia, emaciation, dehydration, unkempt appearance and deposits around the eyes, nose or mouth. 418-028:PAGE D-14 Protocol 418-028 Page 14 Evidence o f the ability o f this battery to detect the effects o f positive control substances w ill be provided (Testing Facility Positive Control Data). Data w ill also be provided to document interobserver reliability i f more than one observer is involved in the testing. M otor A ctivity Test: Motor activity will be evaluated on 10 male and 10 female rats per group once during the course o f the study. This assessment w ill be conducted shortly before scheduled sacrifice, but prior to blood sample collection. The movements o f each rat w ill 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 w ill be 1.5 hours in duration with the number o f movements and time spent in movement tabulated at each fiveminute interval. The apparatus w ill monitor a rack o f up to 32 cages and sensors during each session, with each rat tested in the same location on the rack across test sessions. Groups w ill be counterbalanced across testing sessions and cages. Data w ill be provided to demonstrate that the test system is capable o f 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 w ill be exsanguinated from the inferior vena cava follow ing sacrifice by carbon dioxide asphyxiation. Approximately 5 mL o f blood w ill be collected and processed as described below. Determinations additional to those described below m ay be conducted i f the known properties o f 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). H em atology: Approximately 1 mL o f blood w ill be collected into EDTA-coated tubes and maintained on wet ice or refrigerated until shipment for analysis o f foe 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^lHHtf* Differential Platelet Count (PLAT) Mean Platelet Volume (MPV) Cell Morphology Two blood smear slides w ill be prepared at foe Testing Facility for each sample for measurements o f differential leukocyte count. A ll samples (on wet ice) and slides (ambient conditions) w ill be shipped to Redfield Laboratories at foe following address. Approximately 1.8 mL o f blood w ill be added to a tube containing 0.2 mL o f sodium citrate (0.129 M). The contents w ill be mixed and maintained on wet ice until foe tubes are centrifuged 418-028 :PAGE D-15 Protocol 418-028 Page IS (within 30 minutes o f the collection time). The resulting plasma w ill be transferred 2.0 mL polypropylene tubes labeled with study number, Sponsor's study number, rat number, dosage level, day o f study, collection interval, date o f collection, species, generation and storage. A ll samples w ill be frozen on dry ice and maintained frozen (<-70C) until shipment on dry ice by overnight courier for measurement o f prothrombin time (PT) and activated partial thromboplastin time (APTT). CBniol Chemistry: Approximately 2 mL o f blood w ill be collected into serum separator tubes and centrifuged. The resulting sera samples w ill be immediately frozen on dry ice and maintained frozen (<*70C) until shipment for analysis o f 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) Chloride (CL) Samples w ill be shipped (on dry ice) to Redfield Laboratories at the following address. Shipping InstjntjfflBs: Samples w ill be shipped to arrive on Monday through Friday according to the conditions described above to: Principal Investigator: Ms. Phyllis Powell Redfield Laboratories A Division o f CRL-DDS 100 East Boone Street P.O .B ox 308 Redfield, Arkansas 72132 Telephone: (501) 397-2540 Telefax: (501)397-2002 The recipient w ill be notified in advance o f sample shipment UHNALYSIS: Urinalysis w ill not be conducted unless indicated based on expected or observed toxicity o f the test substance. 418-028:PAGE D-16 METHOD OF SACRIFICE: Protocol 418-028 Page 16 Fo generation rats w ill be sacrificed by carbon dioxide asphyxiation. GROSS NECROPSY AND HISTOPATHOLOGY - Fo GENERATION RATS: Scheduled Sacrifice - Toricokinetic Study: Scheduled sacrifice o f male rats w ill be conducted on day 42 o f study. Scheduled sacrifice o f female rats w ill be conducted on day 21 o f presumed gestation. Blood samples w ill be collected from the rats as previously described. After sacrifice, the liver o f each rat w ill be excised and the liver weight w ill be recorded. The median liver lobe w ill be frozen and stored (<~20C) until shipment for analysis. Fetal samples w ill be collected as previously described. Carcasses w ill be discarded without further evaluation. Samples w ill be shipped on dry ice to lis a C lone at the previously cited address. Scheduled Sacrifice - Main Study: Scheduled sacrifice o f male rats w ill be conducted on the day following the last dosage administration, after a minimum o f 42 days o f dosage. Scheduled sacrifice o f female rats w ill be conducted on day 22 o f lactation. Gross necropsy o f all male and female rats w ill include an initial physical examination o f external surfaces and all orifices, as w ell as foe cranial, thoracic and abdominal cavities and their contents. Special attention w ill be paid to the organs o f the reproductive system. The number o f implantation rites and corpora lutea w ill be recorded. Male and female rats w ill be examined for gross lesions. Gross lesions w ill be retained in neutral buffered 10% formalin and examined histologically. Tissue trimming and histopafoology w ill be performed under the supervision o f or by a Board-Certified Veterinary Pathologist The ovaries and foe uterus with cervix o f each female rat w ill be weighed, and ovaries, uterus, vagina and a mammary gland w ill be retained in neutral buffered 10% formalin. Uteri o f apparently nonpregnant rats w ill be examined after being pressed between glass plates to confirm the absence o f implantation sites, and retained in neutral buffered 10% formalin. 418-028-.PAGED-17 Sperm Evaluation? ofM aleJBats: Protocol 418-028 Page 17 To assess the potential toxicity o f the test article on the male reproductive system, the endpoints listed below w ill be evaluated from the first 10 male rats in each dosage group. Organ Weights: The follow ing organs w ill be individually weighed: right testis, left testis, left epididymis (w hole and canda), right epididymis, seminal vesicles (with and without fluid) and prostate. Sperm Evaluations: Sperm concentration and motility w ill be evaluated using computerassisted sperm analysis (CASA). M otility w ill be evaluated by die Hamilton Thome IVOS by collection o f a sample from the left vas deferens. A homogenate w ill be prepared from the left cauda epididymis for evaluation by the Hamilton Thome IVOS to determine sperm concentration (sperm per gram o f tissue weight). The remaining portion o f the left cauda epididymis w ill be used to manually evaluate sperm morphology. Sperm morphology evaluations w ill include tire following: 1) determination o f the parentage o f normal sperm in a sample o f at least 200; and 2) qualitative evaluation o f 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 firm the ten rats per sex per group assigned to histological sample collection and evaluation. A ll other tissues w ill be discarded. Scheduled Sacrifice f ffemale Rate that Do Not Deliver U tters: Rats that do not deliver a litter w ill be sacrificed on day 25 o f presumed gestation. Gross necropsy, examination and tissue retention w ill be conducted as described previously for rats at scheduled sacrifice. Pam s with No Surviving Puna: Dams with no surviving pups w ill be sacrificed after the last pup is found dead, m issing or presumed cannibalized. Gross necropsy, examination and tissue retention w ill be conducted as described above for rats at scheduled sacrifice. 418-028:PAGE D-18 Rate Fonnd Dead or M oribund: Protocol 418-028 Page 18 Rats that die or are sacrificed because o f moribund condition, abortion or premature delivery w ill be examined for the cause o f death or moribund condition on the day the observation is made. The tats w ill be examined for gross lesions. Testes and epididymides o f male rats w ill be excised and paired organ weights w ill be recorded. The epididymides w ill be retained in neutral buffered 10% formalin. The testes w ill be fixed in Bourn's solution for 48 to 96 hours and then retained in neutral buffered 10% formalin. Pregnancy status and uterine contents o f female rats will be recorded. Aborted fetuses and/or delivered pups w ill be examined to the extent possible. Uteri o f apparently nonpregnant rats w ill be examined after being pressed between glass plates to confirm the absence o f implantation sites. Ovaries and uteri w ill be retained in neutral buffered 10% formalin. TESTS. ANALYSES AND MEASUREMENTS - FI GENERATION: V iability: Preweaning Period: Litters w ill be observed for dead pups at least twice daily. The pups in each litter w ill be counted once daily. Clinical Observations and/or General Appearance: Preweaning Period: Once daily. P ips w ill be observed if they are warm and clean, for evidence o f a nest and i f p ip s are grouped together and nursing or have milk in stomach. Each pup w ill be examined for general shape o f the head, trunk, limbs, tail and presence o f 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 w eight Feed Consum ption V alues (recorded and tabulated): Preweaning Period: Not recorded. METHOD OF SACRIFICE - FI GENERATION PUPS: FI generation pups w ill be sacrificed by carbon dioxide asphyxiation. 418-028:PAGE D-19 Protocol 418-028 Page 19 N E C R O P S Y - F I G E N E R A T IO N : Gross lesions w ill be retained in neutral buffered 10% formalin for possible future evaluation. Unless specifically cited below, all other tissues w ill be discarded. Pups Fonnd Dead on Pay 1 Postpartum: Pups that die before examination o f the litter for pup viability w ill be evaluated for vital status at birth. The lungs w ill be removed and immersed in water. Pups with lungs that sink w ill be identified as stillborn; pups with lungs that float w ill be identified as livebom, and to have died shortly after birth. Pups with gross lesions w ill be preserved in Bouin's solution for possible future evaluation. Pups Fonnd Dead or Moribund on Days 2 to 4 Postpartum: Pups found dead or sacrificed because o f moribundity w ill be examined for gross lesions and for the cause o f death or the moribund condition. Pups with gross lesions w ill be preserved in Bouin's solution for possible future evaluation. Scheduled Sacrifice: On day 22 postpartum, pups w ill be w ill be sacrificed and examined for gross lesions; gross lesions w ill be preserved in neutral buffered 10% formalin. Necropsy w ill include a single crosssection o f the head at the level o f the frontal-parietal suture and examination o f the crosssectioned brain for apparent hydrocephaly. Blood samples w ill 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 w ill be placed into tubes, pooled per litter, allowed to clot and spun in a centrifuge; the resulting serum w ill be transferred into labeled polypropylene tubes. A ll samples w ill be immediately frozen on dry ice and maintained frozen (<-70C) until shipment for analysis. The liver from each selected pup w ill be collected excised and the organ weight recorded. The median lobe w ill be frozen and stored (<-20C) until shipment for possible analysis. Frozen samples w ill be shipped to Lisa Clemen at the previously cited address. The remaining portion o f each liver w ill be retained in neutral buffered 10% formalin for possible histological evaluation. The livers w ill be processed and evaluated histologically as described for the Fo generation rats in H istological Evaluation in ATTACHMENT 4. 418-028:PAGE D-20 PROPOSED STATISTICAL T E S T S ^ : The following schematic represents statistical analyses o f the data Protocol 418-028 Page 20 I- P aranretrfc IX ESjO ast' II. Nonparatnetrict A . B artM T aT eit* A. KruaM -W M toTM rt tsT W tn rfv y m n n ln laii) i SlgnMcant at p<o.ooi Not Significant I SlgnMcant at p<0.05 Not SlgnMcant Nonpaiamatrie Analytte of Variance I----- " Significant a t p<0.06 Not StgnHicant D unnetfiTest D u n n ' T e *t B. F h h a rt Exact Teat on Proportion ofTie P T W --Ma y mnaa e atoi) B. Analyst* ofVariance with Repeated Measures ' SlgnMcant at po.os Not SlgnMcant (Doaaga) D um atrsTaat (Dotage x Block Interaction) O new ay ANOVA lor each block SlgnMcant at RSD.06 Not SlgnMcant D um atrsTaat III- Teat for Proportion Data Variance Test for Homogeneity of the Binomial Distribution Statistically significant probabilities are reported as eitherp < 0.05 or/ < 0.01. Proportion data are not included in this category, c. Test for homogeneity o f variance. $r p 418-028:PAGED-21 Protocol 418-028 Page 21 Test items in the FOB using interval scales, such as the grip-strength tests and the landing foot splay test, as w ell as body weight data and feed consumption values w ill be analyzed as described under the Parametric heading o f the schematic. Bartlett's Test o f Homogeneity o f Variances'9*w ill be used to estimate the probability that die groups had diffrait variances. A nonsignificant result (pXl.OOl) w ill indicate dial an assumption o f homogeneity o f variance is not inappropriate, and the data w ill be compared using the Analysis o f Variance Test'10*. If that test is significant (p<0.05), the groups exposed to the test article/substance w ill be compared with the control group using Dunnett's Test(11). If Bartlett's Test is significant (p<0.001), the Analysis o f Variance Test is not appropriate, and die data w ill be analyzed as described under the Nonparametric heading o f the schematic. When 75% or fewer o f the scores in all the groups are tied, the Kruskal-Wallis Test'12*w ill be used to analyze the data, and in the event o f a significant result (p<0.05), Dunn's Test'13*w ill be used to compare the groups exposed to the test article/substance with the control group. When more than 75% o f the scores in any group are tied, Fisher's Exact Test'14*w ill be used to compare the proportion o f ties in the groups. Data from the motor activity test, with repeated measurements within a session, w ill be analyzed using an Analysis o f Variance with Repeated Measures'15*, as described under dial heading in the schematic. A significant effect (p<0.05) in dud test can appear as effect o f 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). If the Concentration effect is significant, the totals for the control group and the groups given the test article/substance w ill be compared using Dunnett's Test. If the Concentration x Block interaction is significant, an Analysis o f Variance Test w ill be used to evaluate the data at each measurement period, and a significant result (p<0.05) w ill be followed by a comparison o f the groups using Dunnett's Test. Test items in the FOB having graded or count scores w ill be analyzed using the procedures described under the Nonparametric heading o f the schematic. Clinical observation incidence data, as w ell as the descriptive and quantal data from the FOB, w ill be analyzed as contingency tables using foe Variance Test for Homogeneity o f the Binomial Distribution'16*. Alternate or additional statistical evaluations may be performed i f deemed necessary or appropriate. 418-028:PAGED-22 Protocol 418-028 Page 22 DATA ACQUISITION, VERIFICATION AND STORAGE: Data generated duiing the course o f this study w ill be recorded either by hand or using the Argus Automated Data Collection and Management System, the Vivarium Temperature and Relative Humidity Monitoring System, the Coulboum Instruments Passive Infrared M otor Activity System, the Coulboum Instruments Auditory Startle System, the Coulboum Instruments Spatial Delayed Alternation System, and/or the passive avoidance software. A ll data w ill 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 o f Microsoft Office 97 (version SR-2)] and/or The SAS System (version 6.12). Records w ill be reviewed by the Study Director and/or appropriate management personnel within 21 days after generation. A ll original records w ill be stored in the archives o f the Testing Facility. A ll original data w ill be bound and indexed. A copy o f all raw data w ill be supplied to the Sponsor upon request. Preserved tissues w ill be stored at the Testing Facility at no charge for one year after mailing o f the draft final report, after which time the Sponsor w ill be contacted to determine file disposition o f these materials. KEY PERSONNEL: Executive Director o f Research: Mildred S. Christian, FhJD., Fellow, ATS Director o f Research: Alan M. Hoberman, Ph.D., DABT Associate Director o f Research and Study Director: Raymond G. York, Ph.D., DABT Director o f Operations and Compliance: Barbara J. Patterson, B.A. Director o f Laboratory Operations: John F. Barnett, B.S. Director o f Study Management: Valerie A Sharper, M.S. Manager o f Animal 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 Page 23 Protocol and Amendments. Test Substance, Vehicle and/or Reagent Receipt, Preparation and Use. Animal Acquisition. Randomization Schedules. Mating History. Treatment (if prescribed 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 o f study progress to die Sponsor. Draft summary tables o f unaudited computer-recorded data may accompany these updates. Statistical analyses w ill not be performed on these interim data. A comprehensive draft final report w ill be prepared on completion o f the study and w ill be finalized following consultation with the Sponsor. The report w ill include the following: Summary and Conclusion. Experimental Design and Method. Evaluation o f Test Results. Appendices: Figures, Summary and Individual Tables Summarizing the Above Data, Protocol and Associated Amendments and Deviations, Study Director's GLP Compliance Statement, Reports o f Supporting Data (if appropriate) and QAU Statement The Sponsor w ill receive one copy o f the draft report and two copies o f the final report. Data w ill be hand- and/or computer-recorded. Records w ill be reviewed by the Study Director and/or appropriate management personnel within 21 days after generation. A ll original records w ill be stored in the archives o f the Testing Facility. A ll original data w ill be bound and indexed. A copy o f all raw data w ill be supplied to the Sponsor upon request. Preserved tissues w ill be stored at the Testing Facility at no charge for one year after mailing o f the draft final report, after which time the Sponsor w ill be contacted to determine the disposition o f these materials. 418-028-.PAGED-24 Protoco] 418-028 Page 24 INSTITUTIONAL ANIM AL CARE AND USE COML i l l M U STATEM ENT: The procedures described in this protocol have been reviewed by die Testing Facility's Institutional Animal Care and Use Committee. A ll procedures described in this protocol that involve study animals w ill be conducted in a manner to avoid or minimize discomfort, distress or The Sponsor's signature below documents the fact that information concerning the necessity for conducting this study and foe fact that this is not an unnecessarily duplicative study may be obtained from foe Sponsor. No alternative (in vitro) procedures were available for meeting foe stated purposes o f foe 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 o f Commerce, Springfield, VA 22161. 2. Christian, M .S. (1984). Reproductive toxicity and teratology evaluations o f naltrexone (Proceedings o f Naltrexone Symposium, New York Academy o f 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:CD<EBR Rat. Charles River Laboratories, Inc., Wilmington, MA 01887-0630. (Data base provided by Argus Research Laboratories, Inc.) 4. Institute o f Laboratory Animal Resources (1996). Guidefo r the Care and Use o f Laboratory Animals. National Academy Press, Washington, D.C. 5. Haggerty, G.C. (1989). Development o f 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: la. A systemic quantitative procedure fin assessing foe behavioral and physiologic state o f foe 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. ODonoghue, 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 o f homogeneity o f variances. Biometry, W.H. Freeman and Co., San Francisco, pp. 370-371. 418-028:PAGED-25 Protocol 418-028 Page 25 10. Snedecor, G.W. and Cochran, W.G. (1967). Analysis o f 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 Statisticsfo r the Behavioral Sciences, McGraw-Hill, New York, pp. 96-104. 15. SAS Institute, Inc. (1988). Repeated measures analysis o f variance. 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 o f the binomial distribution. Statistical Methods, 6th Edition, Iowa State University Press, Ames, pp. 246-241. PROTOCOL APPROVAL: FOR THE TESTING FACILITY Alan M. Hoberman, Ph.D., DABT Director o f Research Study Director . LUL. T heta H. WoodairndL, D .V M . Member, Institutional Animal Care and Use Committee FOR THE SPONSOR John Butenhoff, P hD ., DABT, O H Study Monitor and Sponsor's Representative 48-028-.PAGED-26 Protocol 418-028 Page 26 ~l lu Date 2-Q> fO/fQ. 2-OQ2-. Date Date Date 418-028-.PAGED-27 ATTACHMENT 1 SCHEM ATIC O F STUDY DESIGN AND STUDY SCHEDULE 418-028:PAGED-28 ATTACHMENT! STUDY SCHEMATIC Protocol 4184)28 Page 1o f3 COMBINED REPEAT DOSE AND REPRODI)CTIVE/DEVELOPM ENTAL TO XICITY SCREEN* F irst D a y o f Test S u b sta n ce D osage M a le R ats P re m a tin g La st D a y o f Test Su b sta n ce D o sage* C o h a b ita tio n Last D ay o f Test Su b sta n ce 1 2 W eeks 2 W eeks M otor ..... - A ctiv ity / F O B " ' N atural D e liv e ry Presum ed G e statio n P o stp a rtu m P e rio d Fe m a le R a ts 2 W eeks 2 W eeks 3 W eeks D a y 21 D a y 22* Motor A ctiv ity / F O B d m Dosage Period a. For additional details see "Tests, Analyses and Measurements" section o f the protocol. b. FOB and motor activity evaluations conducted on ten males per group. c. Male rats sacrificed after completion o f at least 42 days o f dosage; necropsy and retention o f 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 o f female reproductive organs Hematology, clinical biochemistry and histological samples collected. Remaining female rats sacrificed cm day 22 postpartum and discarded. 418-028:PAGED-29 ATTACHMENT! Protocol 418-028 Page 2 o f3 SCHEDULE* 26 MAR 02 01 APR 02 01 APR 02 -1 2 JUN 02 14 APR 02 P M -2 1 APR 02 AM 21 APR 02 P M -2 8 APR 02 AM 14 APR 02 15 APR 02 28 APR 02 06 MAY 02 19 MAY 02 06 MAY 02 - 07 MAY 02 Animal Receipt - Acclimation Begins. Start o f Dosage Period - Male Rats (14 days before cohabitation and through a 14-day cohabitation period until the day before sacrifice after at least 42 days o f dosage). Dosage Period - Female Rats (14 days before cohabitation through Day 22 o f lactation). Cohabitation Period (Maximum o f 14 days). M ale 1 (7 days) M ale2(7days) Day 14 Toxicokinetic Sample Collection First Possible Day 0 o f Presumed Gestation. Last Possible Day 0 o f Presumed Gestation. First Possible Day 21 o f Presumed Gestation Toxicokinetic Sample Collection and Sacrifice Toxicokinetic Study Female Rats Last Possible Day 21 o f Presumed Gestation Toxicokinetic Sample Collection and Sacrifice Toxicokinetic Study Female Rats FOB and Motor Activity Evaluation -1 0 M ale Rats per Group a. The start date o f the study is the day the Study Director signs the protocol. b. Throughout this schedule, the day o f birth is designated day 1 postpartum (day 1 o f lactation) and all subsequent ages o f the FI generation rats and days o f the lactation period w ill be determined and cited accordingly, as described above the protocol section, "Day Numbering System." 418-028:PAGE D-30 ATTACHMENT! 06 MAY 02 23 MAY 02 10 MAY 02 23 MAY 02 12 MAY 02 13 MAY 02 23 MAY 02 - 09 JUN 02 27 MAY 0 2 - 13 JUN 02 24 SEP 02 Protocol 418-028 Page 3 o f3 First Possible Delivery (Day 21 o f presumed gestation). Last Possible Delivery (Day 25 o f presumed gestation). First Possible Day 25 o f Presumed Gestation Female Sacrifice. Last Possible Day 25 o f Presumed Gestation Female Sacrifice. Day 42 Toxicokinetic Sample Collection and Scheduled Sacrifice - Toxicokinetic Study Male Rats Scheduled Sacrifice - Main Study M ale Rats (Earliest posable date). Hematology, Clinical Biochemistry and H istological Sample Collection o f Selected Male Rats. FOB and Motor A ctivity Evaluation - 10 Female Rats per Group. Day 22 Postpartum - Sacrifice Female Rats and Pups. Hematology, Clinical Chemistry and Histological Sample Collection o f Selected Female Rats and Pups. Draft Final Report 418-028:PAGE D -31 ATTACHMENT 2 MATERIAL SAFETY DATA SHEET 418-028:PAGE D-32 MATERIAL SAFETY DATA SHEET (Experimental) 3M an center St. Paul, Minnesota 55144-1000 1-800-364-3577 or (651) 737-6501 (24 hours) Copyright, 1999, Minnesota Mining and Manufacturing Company. All rights reserved. Copying and/or downloading of this information for the purpose of properly utilizing 3M products is allowed provided that: 1) the information is copied in full with no changes unless prior agreement is obtained from 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 HATER: SPECIFIC GRAVITY:... PERCENT VOLATILE:... pH :............................... VISCOSITY:....... MELTING POINT:.... N/A Negligible N/A Negligible slight ca. 1.0 Hatsr*l (Bulk) Negligible N/A N/D N/D APPEARANCE AND ODOR: Off-white crystalline solid, sharp odor. Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately 418-028-.PAGE D-33 MSDS: L-9051 DEVELOPMENTAL PRODUCT December 07, 1999 PAGE 2 3. FIRE AND EXPLOSION HAZARD DATA FLASH PoiNi:.............. 212 F Setafiash Setaflash Closed Cup FLAMMABLE LIMITS - LEL:..... N/A FLAMMABLE LIMITS UEL:.....N/A AUTOIGNITION TEMPERATURE:....N/D EXTINGUISHING MEDIA: Mater, Carbon dioxide, Dry chemical, Foam SPECIAL FIRE FIGHTING PROCEDURES: Hear full protective clothing, Including helmet, self-contained, positive pressure or pressure demand breathing apparatus, bunker coat and pants, bands around arms, waist and legs, face mask, 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 PROOUCTS: Hay produce fluorocarbon gases if exposed to vary 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 comercial 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 M8D8: L-9051 DEVELOPMENTAL PROOUCT Oeceaber 07, 1999 PAGE 3 5. ENVIRONMENTAL INFORMATION (continued) ENVIRONMENTAL DATA: Not dotsrained. REGULATORY INFORMATION: Volatile Organic Coapounds: N/D. VOC Lees H20 & Exeapt Solvents: N/D. Since regulations vary, consult applicable regulations or authorities before disposal. U.S. EPA Hazardous Haste Nuaber * None (Not U.S. EPA Hazardous). OTHTEhiRsEpNrVoIdRuOcNtMEmNTaAyLcoInNtFOaRiMnAToInOeN:or aore organic fluorocheaieals that have the potential to resist degradation and persist in the environaent. EPCRA HAZARD CLASS: FIRE HAZARD: No PRESSURE: No REACTIVITY: No ACUTE: Yes CHRONIC: No 6. SUGGESTED FIRST AID EYE CONTACT: Iaaedlately flush eyes with large aaounts of water. Get iaaediate aedical attention. SKIN CONTACT: Flush skin with large aaounts of water. If irritation persists, get medical attention. INHALATION: If signs/syaptoas occur, remove person to fresh air. If signs/syaptoas continue, call a physician. IF SHALLOWEO: If swallowed, call a physician immediately. Only induce vomiting at the instruction of a physician. Never give anything by aouth to an unconscious person. 7. PRECAUTIONARY INFORMATION EYE PROTECTION: Avoid eye contact. Avoid eye contact with vapor, spray, or aist. The following should be worn alone or in combination, as appropriate, to prevent eye contact: Hear vented goggles. Abbreviations: N / D N o t Determined N/A - Not Applicable CA - Approximately 418-028-.PAGED-35 MSOS: L-9051 DEVELOPMENTAL PRODUCT December 07, 1999 PAGE 4 7. PRECAUTIONARY INFORMATION (continued) SKIN PROTECTION; Avoid skin contact. Near appropriate flloves when handling this saterial. A pair of gloves aade froa the following material(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 garments (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 alocal exhaust ventilation at transfer points. Use in well* ventilated area. Provide sufficient ventilation to maintain eoissions below recommended exposure limits. 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 reeoamended where the aes 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. Hash exposed areas thoroughly with soap and water. Hash hands after handling and before eating. RECOMMENDED STORAGE: Store at room temperature. Keep container dry. Keep container closed when not in use. FIRE AND EXPLOSION AVOIDANCE: Not determined. EXPOSURE LIMITS INGREDIENT VALUE UNIT TYPE AUTH SKIN* POTASSIUM PERFLUOROHEXANE SULFONATE.................. .. RESIDUAL ORGANIC FLUOROCHEMICALS--- 0.1 MG/M3 0.1 MQ/M3 TWA 3M TWA 3M Y Y * SKIN NOTATION: Listed substances indicated with `Y` under SKIN refer to Abbreviations: N/0 - Not Determined N/A - Not Applicable CA Approximately 418-028:PAGE D-36 NSOS: L-9051 DEVELOPMENTAL PROOUCT December 07, 1999 PAGE 5 EXPOSURE LIMITS (continued) INGREDIENT VALUE UNIT TYPE AUTH SKIN* the potential contribution to the overall exposure by the cutaneous route including mucous membrane and eye, either by airborne or, more 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 from 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 froe inhalation exposure. May be absorbed by inhalation and persist in the body for an extended time. Single overexposure, above recommended guidelines, may cause: Irritation (upper respiratory): signs/symptoms can include soreness of the nose and throat, coughing and sneezing. IF SHALLOWED: Ingestion is not a likely route of exposure to this product. No information was found regarding effects from swallowing. Animal studies conducted on organic fluorooheaicals which nay bo 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 Oetemined N/A - Not Applicable CA - Approximately 418-028:PAGE D-37 USDS: L-9051 DEVELOPMENTAL PROOUCT December 07, 1999 PAGE 6 8. HEALTH HAZARD DATA (continued) effects fro anticipated exposure to these organic fiuorocheeicals when used as intended and instructed. OTHER HEALTH HAZARO INFORMATION: This product ay contain one or ore organic fiuorocheeicals that have the potential to be absorbed and reeain in the body for long periods of time, either as the parent Molecule or as Metabolites, and aay accuaulate with repeated exposures. There are no known huaan health effects fro anticipated exposure to these organic fiuorocheeicals when used as intended and instructed. The presence of organic fluoroehemicals 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 OATES PRECAUTIONARY INFO. SECTION CHANGED SINCE May 17, 1999 ISSUE Abbreviations: N/D Not Determined N/A > Not Applicable CA Approximately The information in this Material Safety Data Sheet (MSDS) is believed to be correct as of the date issued. 3M MAKES NO WARRANTIES, EXPRESSED OR IMPLIED, INCLUDING, BUT NOT LIMITED TO, ANY IMPLIED WARRANTY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE OR COURSE OF PERFORMANCE OR USAGE OF TRADE. User is responsible for deterining 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, soe 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 user's method of use or application. 3M provides information in electronic fora as a service to its customers. Due to the remote possibility that electronic transfer may hays 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-.PAGED-38 ATTACHMENT 3 TEST SUBSTANCE PREPARATION PROCEDURE 418-028:PAGE D-39 ATTACHMENT 3 Protocol 418-028 Version: 418-028^19 MAR 021 Page 1 o f2 TE S T 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 X Weekly __ For_ days of use __ Approximately every ten days __ By Sponsor 3. Suspensions will be administered at a final dosage volume of 10 mL/kg. 4. Safety: X Gloves, uniform/lab coat, goggles or safety glasses with side shields X 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 J L No (Calculations based on 100% ) __ % Activity __% P u rity __ 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 021 Page 2 of 2 TE S T 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 will be used during the preparation to bring the test substance slurry up to volume. C. Dosage Suspension Preparation: 1. W eigh the required amount of test substance on a piece of weigh paper or into an appropriately sized mortar (see PREPARATION C A L C U L A T IO N S ). 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 vehide/test substance slurry to a marked beaker. 3. Rinse the mortar and pestle with additional vehide to remove any remaining test substance. Transfer rinse to beaker. 4. Add additional vehide to the beaker to bring volume up to the mark. Place on magnetic stir plate and agitate prior to and during sampling, aliquotting and/or administration. Repeat steps (1) through (4) for each concentration. Written By: Approved bv:|^ L ^ ^ L ^ = Date: Clarification: v/ ' n o " r e s [see attached clarification form] Initial/Date : C(L 7 / j / ^ 0 3 4 1 8 -0 2 8 :P A G E D -4 l ATTACHMENT 4 TISSUES TO BE WEIGHED, RETAINED AND EXAMINED HISTOLOGICALLY 418-028:PAGE D-43 ATTACHMENT 4 Protocol 418-028 Page 2 o f 2 Histological Examination: Histological examination o f retained tissues, including reproductive organs, w ill be conducted for the assigned ten rats per sex from the control and high dosage groups and from the FI generation pups (livers) from the control and high dosage groups. If lesions attributed to the test substance are observed in the rats exposed to the high test substance concentration, die same tissues w ill be examined from the assigned ten rats per sex exposed to die lower test substance concentrations. Should results warrant examination o f the lower dosage groups and conduct o f 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 ltea o f lactation. Histopathological examination may detect qualitative depletion o f the primordial follicle population. A quantitative evaluation o f primordial follicles will be conducted for Fo generation female rats; the number o f rats, ovarian section selection and section sample size will be statistically appropriate for the evaluation procedure used. Examination w ill include enumeration o f the number o f primordial follicles, which can be combined with small growing follicles, for comparison o f ovaries o f 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 w ill be notified in advance o f sample shipment. 418-028:PAGE D-44 90S Shtehy Drive). B k& A Horsham, PA 19044 Telephone: (215)443-87/0 TefejSwr (215) 4 4 3 * 5 8 7 ARGUS RESEARCH Chartes River Laboratories Discovery and Developm ent 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 1- 17 April 2002 1. Detailed Clinical Observations - Male and Female Rats (page 10 o f the 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 o fdetailed clinical observations will be available from foe rats assigned to foe main study. 2. Feed Consumption Values - Male Rats and Female Rats (page 11 o f foe protocol): [Effective Date: 1 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 datafor evaluation o f feed consumption will be available from foe rats assigned to foe main study. Any revisions made to this finalized amendment must be made by subsequent am endm ent 418-028-.PAGED-45 3. Estrous Cycling and Mating (page 12 o f the protocol): Protocol 418-028 Amendment 1 Page 2 [Effective Date: 1 April 2002] For the rats assigned to toxicokinetic sampling, estrous cycling w ill be evaluated during the cohabitation period until spermatozoa are observed in a smear o f the 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 o f estrous cycling w ill be available from the rats assigned to the main study. 4. Scbeduled_SflCrifice . Tpsipokmctic Study (page 16 o f the protocol): [Effective Date: 5 April 2002] The number o f implantation sites and coipora lutea w ill be recorded. Carcasses w ill be discarded without further evaluation. Reason o f Change: This change was made in order to provide more information about possible toxicity o f the test substance in pregnant rats. 5. Scheduled Sacrifice - Main Study (page 16 o f the protocol): [Effective Date: 27 March 2002] The number o f implantation sites w ill be recorded, rather than the number o f implantation sites and corpora lutea w ill be recorded. Reason o f Change: The number o f coipora lutea w ill not be recorded because corpora lutea regress at a rapid rate and are not counted on studies at weaning. 6. Scheduled Sacrifice (page 19 o f the protocol): [Effective Date: 4 April 2002] The liver from each selected pup w ill be excised and the organ weight recorded, rather than the liver from each selected pup w ill be collected excised and the organ weight recorded. Any revisions made to this finalized amendment must be made by subsequent amendment 418-028:PAGE D-46 Protocol 418-028 Amendment I Page 3 RmmM .Qmisf- This change clarifies the protocol by removing an extraneous word. W 7 ~o Alan M. Hoberman, PhD ., DABT Director o f Research Date Raymond G. York, Associate Director Study Director DABT Date lzPK. Theresa H. Woodard, D.V.M. Member, Institutional Animal Care and U se Committee Date John Butenhofl; Ph-D., DABT, CIH Date Study Monitor and Sponsor's Representative Any revisions made to this finalized amendment mnst be made by subsequent amendment 418-028PAGE D-47 905 Sheehy Drive, Bldg. A Horsham. PA 19044 Telephone: (2 15 ) 4 4 3-3 7 10 Telefax: (2 1 5 )4 4 3 -8 5 8 7 ARGUS RESEARCH Otaries 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 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. R eason for Change: This change was made to match the bulk test substance text with die text located within the Material Safety Data Sheet. 2. Study Schedule (Attachment 1page 2 of die 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 Amendment 2 Page 2 Reason for Change: This change was made because more time is needed to evaluate animals assig n s to FOB and motor activity evaluations. !an Mfoberman, Ph.D., DABT Director o f Research DABT Date Associate Director i Research Study Director ^-ThereM H. Woodard, DiV.M. Member, Institutional Animal Care and Use Committee * 7 2nd 2*% , Date John Butenhoff, P h D ., DABT, CIH Date Study Monitor and Sponsor's Representative Any revisions to this finalized amendment mast be made by subsequent amendment 418-028:PAGE D-49 9 05 Sheehy Drive, Bkfa. A H orsham , PA 1 9 0 4 4 Telephone: (215) 443-87 10 T tk fisc (215) 443-8587 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 - 1 7 July 2002 1. Bulk Test Substance Sampling. Shipping Instructions. Shipping Instructions. Caesarean-Sectioning - Toxicokinetic Study. Scheduled Sacrifice - Toxicoldnetic Study, and Scheduled Sacrifice, (pages 4,5,12,13,16 and 19, respectively o f 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 lis a 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 amendm ent m ust be made by subsequent am endm ent 418-028:PAGE D-50 Protocol 418-028 Amendments Page 2 These samples include: Bulk test substance sampling (page 4 o f the protocol) Concentration and homogeneity (page 5 o f the protocol) Stability (page 5 o f the protocol) Plasma toxicokinetic samples (page 11 to 12 and page 16 o f the protocol) Plasma samples, rather than serum samples, were retained. Liver toxicokinetic samples (pages 12 and 16 o f the protocol) Pooled fetal serum toxicokinetic samples (pages 12 and 16 o f the protocol) Pooled fetal liver toxicokinetic samples (pages 13 and 16 o f the protocol) Pooled pup serum toxicokinetic samples (page 19 o f the protocol) Pup liver toxicokinetic samples (page 19 o f the protocol) The analyses w ill be subcontracted to Exygen by the Sponsor and the Quality Assurance Unit for Exygen Research w ill conduct critical phase inspections and audit the respective results and reports according to the Standard Operating procedures o f that facility. Such critical phase inspection reports and audit reports w ill be submitted by that facility to the Study Director, Raymond G. York. The date o f the inspections and report submissions w ill 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 o f the Sponsor because 3M is not able to complete the formulation analysis with their current staffing. Study Director Member, Institutional Animal Care and Use Committee 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 V ARGUS RESEARCH Charted ftfaer Laboratories 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 4 - 2 0 March 2003 1. Bulk Test Substance Sampling. Shipping Instructions. Shipping Instructions. Caesarean-Sectioninp - Toxicokinetic Study. Scheduled Sacrifice - Toxicokinp.ticStudv. and Scheduled Sacrifice, (pages 4,5,12,13,16 and 19, respectively of the protocol) and Amendment 3, Item 1: Bulk Test Substance Sampling. Shipping Instructions. Shipping 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 1". Any revisions to this finalized amendment must be made by subsequent amendment. Reason for Change: 418-028:PAGE D-52 Protocol 418-028 Amendment 4 Page 2 This change was made at the request of the Exygen Research in order to clarify the method of analysis. Chair, Institutional Animal Care and Use Committee Jo n d G . Yc Associate Directe Study Director .D., DABT Date esearch John Butenhoff, Ph.D., DABT, CM Date Study Monitor and Sponsor's Representative Any revisions to tins finalized amendment must be made by subsequent am endm ent APPENDIX E DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY 418-028: PAGE E -l DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY The following rats were not fasted overnight prior to necropsy. Dosage Group I Dosage (mg/kg/day) 0 n 0.3 m1 IV 3 V 10 Date of Necropsy 28 MAY 02 29 MAY 02 28 MAY 02 29 MAY 02 28 MAY 02 29 MAY 02 28 MAY 02 29 MAY 02 28 MAY 02 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. Postdosage observations were performed out of the range of 60 10 minutes on the following dates. Dosage Dosage Group (mg/kg/day) I0 IV 3 Date 09 APR 02 03 JUN 02 03 JUN 02 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. 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. 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 m IV V Dosage (mg/kg/day) 0 0.3 1 3 10 Date 09 MAY 02 09 MAY 02 09 MAY 02 09 MAY 02 09 MAY 02 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. Study Director APPENDIX F CERTIFICATE OF ANALYSIS 4 18-028-.P A G E F -1 C ertificate o f A n alysis Nom inal Product: Potassium perfluorohexanesulfonatc: C6Fi3S 0 3w K(+) Product Code: PFHS; 127498-80 April 15,2002 Tom Kestner and Joel M iller The sample o f 127498-80 PFHS was analyzed using LCMS, 19F-NMR and lH-NMR analysis techniques. The overall qualitative and quantitative compositional results that w o e derived from these combined analyses are summarized below in TABLE-1. TABLE-1 Sample: 127498-80: PFHS Overall Quantitative Compositional Results by LCMS, 19F-NMR, and 'H-NMR Analyses Component Identities * R elative W t% Concentrations (single trial measurements, excluding any water) CF3CF2CF2 CF2 CF2 CF2SO3 0 Kl+) 88.93% (NMR) (CF3)2.CF.(CFj)3. S03(-) k i+> 6.83% (NMR) CF3CF2-CF(CF3)-CF2CF2-S03(') k (+) 2.75% (NMR) CF3CF2CF2CF2-CF(CF3)-S03('>Kl+> 0.83% (NMR) CF3CF2CF2CF(CF3)-CF2-S03WKt+) 0.56% (NMR) (0F 3)3-C-CF2-CF2SO3(-5k w CeFl2HS0 3(-JK(+) 0.078% (NMR) 0.009% (LCMS) C rF isS O ^ K ^ 0.006% (LCMS) 0.004% (LCMS) Probable CnH2n+2 hydrocarbons 0.0034% (NMR) Other components Sam ofC iF isSO s^ Isomers Sum o f Known Im purities * T ra ce am ounts o f oth er u n a ssign e d com ponents w ere a lso detected. <0.001% (LCMS) 99.98% 0.021% Page 1 o f 1 F ile R e fe re n ce : C o fA P F H S 1 2 7 4 9 8 -8 0 .d o c 418-028.PA G EF-2 3M SPECIALTY MATERIALS M ANUFACTURING DIVISION ANALYTICAL LABORATORY Request No. G ID:32537 To: Dan Hakes - (3-2392) ~ EHSR - Auto & Chem Group - 236-1B -10 From: Tom Kestner - (3-5633) - SMMD Analytical Lab - 236-2B -11 Subject: Chem ical Characterization o f PFHS (127498-80) by 'H-NM R & 19F-NM R Spectroscopy Date: April 15,2002 SAMPLE DESCRIPTION: 127498-80: PFHS made by George Moore and to be used for toxicological testing. Nominal product C eFu-SO ^ K(+) (white powder). OBjrsqpvB: This sample w as subjected to `H-NMR and ,9F-NMR spectral analyses to determine the purity o f the nominal product and to characterize as many impurity components as possible. Joel M iller also performed an LC/MS analysis and his results were reported to you previously. EXPERIM ENTAL; A portion o f the sample (-4 0 0 mg) was totally dissolved in deuterated dim ethylsulfoxide (DMSO-ds) and then the solution was spiked with a small amount o f 1,4-bis(trifluoromethyl)benzene (p-HFX) for NMR analysis. A 400 MHz fH-NMR spectrum (# h32537.GID.401) and a 376 MHz ,9F-NMR spectrum (# f32537.G ID.401) were acquired, at room temperature using a Varian UNITYplus 400 FT-NMR spectrometer. The p-HFX was used as a 'H />9F-NMR cross integration standard to permit die cross correlation o f the relative *H and I9F signal intensities for evaluation o f the overall sample composition. RESULTS; The combined NMR spectral data indicated the sample o f 127498-80 consisted o f a high purity form o f the nominal isom eric product mixture, CnFjn+i-SC^'* MTM, where V was mainly 6 and where the metal cation was assumed to be K(+). Trace-levels o f probable aliphatic hydrocarbon impurity components were also observed and quantified. The qualitative and quantitative compositional results that were derived from the single trial >H /I9F-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-1 should be very close to their respective absolute weight percent values. Trace amounts o f other unidentified impurity components were also detected in the NMR spectra, but additional work would be needed in an effort to assign or quantity the unassigned impurities. Copies o f the NMR spectra are attached with the paper copy o f this report for your reference. If you have any questions about these results, or if any further work is needed, please let m e know. Tom Kestner c : Jo e l M ille r G e o rge M oore Rick Payfer File Reference: dh32537.GID.ctoc/93 Page 1 of2 418-028`.PAGE F-3 April 15,2002 3M SMMD Analytical Lab Request # GID:32537 TABLE-1 Sample: 127498-80: PFHS made by George M oore and to be used for toxicological testing. Overall Quantitative Compositional Results by `H /^ -N M R Cross Integration Analysis Identified Components * 1sF/'H-NMR Relative Wt.% Concentrations (single trial measurement) CF3CF2CF2CF2CF2CF2S 0 3w K(+) 88.94% (CF3)2-CF-(CF2)3-S03<') k (+) 6.83% CF3CF2-CF(CF3)-CF2CF2-S03Wk w 2.75% CF3CF2CF2CF2-CF(CF3)-S 0 3w k (+) 0.83% CF3CF2CF2CF(CF3)-CF2-S03(*) k(+) 0.56% (CF3)3-C-CF2-CF2S03^ Kt+) 0.078% Probable CnH2n+2 hydrocarbons 0.0034% * T ra ce am ounts o f oth er u n a ssign e d com ponents w ere a lso detected in the N M R sp e ctra. Study No. FACT-TCR008 Page 2 o f2 APPENDIX G ANALYTICAL AND BIOANALYTICAL REPORT 418-028.PAGE G -l 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 CFR 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:PA G E G -2 Exygen Study No.: 023-072 G O O D L A B O R A T O R Y P R A C T IC E C O M PL IA N C E ST A T E M E N T 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 Numb: 21 by Exygen Research. Principal Investigator Exygen Research John ButenhofF Study Monitor 3M Corporate Toxicology Exygen Research Z Y & v t , ZOO3 Date Date Page 2 o f 153 418-028:PAGE G-3 Exygen Study No.: 023-072 Q U A L IT Y A SSU R A N C E ST A T E M E N T 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 1. Protocol R eview D ate Insoected 09/24/02 Date Reported to Date Reported to Principal Exygen Date Reported to ayestifator Maaagsmsnt Study Director 11/20/02 11/22/02 01/20/03 2. Extraction, Fortification 09/24/02 11/21/02 12/18/02 01/20/03 3. Raw Data R eview 02/03-07/03 and Draft Analytical and 02/10-11/03 Report R eview 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 o n fxifa Date Exygen Research Page 3 of 153 418-028:PAGE G-4 Exygen Study No.: 023-072 C E R T IF IC A T IO N O F A U T H E N T IC IT Y 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: John Flaherty Vice President Exygen Research Exygen Research Facility Management: Date Jf-JUL-Q'Z Date Study Monitor, 3M: John ButenhofF 3M Corporate Toxicology _____ Exygen Research y J U L ZQ0JZ Date ZB JV*- 2-*vj Date Page 4 of 153 418-028.PA G EG -5 Exygen Study No.: 023-072 STU D Y ID E N T IFIC A T IO N 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 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 PR O JE C T PERSONN EL 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 6 of 153 418-028:PAGE G-7 Exygen Stady No.: 023-072 TABLE OF CONTENTS Page TITLE PAGE....................................................................................................................I GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT.............................2 QUALITY ASSURANCE 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 o f 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..........................15 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 7 of 153 418-028:PAGE G-8 Exygcn Study No.: 023-072 LIST OF TABLES Page Table I. Summary of PFHS in Control Rat Plasma Samples.....................................21 Table II. Summary of PFHS in Control Rat Serum Samples...................................... 21 Table III. 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 8 of 153 418-028:PAGE G-9 Exygen Study No.: 023-072 LIST OF FIGURES Page Figure 1. 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 ED: 0202987 Control, Data Set: 091902B)....................................47 Figure 5. Chromatogram Representing a Control Rat Liver Sample for PFHS, (E xygen ID: 0 2 0 2 8 7 7 C o n tro l, D ata Set: 1 0 0 2 0 2 A )................................... ......... 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: 091902B) 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=10 (Exygen ID: 0201863, Sponsor ID: 19079 GROUP II, Data Set: 091902BR).................................................................................. 53 Figure 11. Chromatogram Representing Rat Liver Sample Analyzed for PFHS (Exygen ED: 0202050, Sponsor ID: 19018 GROUP II Male 1, Data Set: 100202A).............................................................................................54 Exygen Research Page 9 of 153 418-028:PAGE G-10 Exygen Study No.: 023-072 LIST OF APPENDICES Page Appendix A Study Protocol 418-028 (Exygen Study No. 023-072) and Amendments, Deviation and Note to File................................................ 55 Appendix B 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 ) ................110 Exygen Research Page 10 of 153 418-028:PAGE G -l 1 Exygen Study No.: 023-072 1.0 S U M M A R Y 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 o f 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). PFH S in th e rat plasm a sam p les ranged from non-detected le v e ls to 237,000 ng/m L . PFH S in th e rat serum sam ples ranged from non-detected le v e ls to 189,000 ng/m L . PFH S in the rat liv er sam ples ranged from non-detected lev els to 6 75,000 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 O B JE C T IV E 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 IN T R O D U C T IO N 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 of 153 418-028:PAGE G-12 Exygen Study No.: 023-072 4.0 A N A L Y T IC A L T E S T S A M P L E S The control rat liver (Exygen ED 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 12 of 153 418-028:PAGE G-13 Exygen Study No.: 023-072 5.0 R E F E R E N C E M A T E R IA L 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 Exygen Inventory No.. PFHS SP244 TCR No. SE036 Purity (%) Expiration Date 99.99 01/01/10 The molecular structures of test substance is given below: Name: PFHS Chemical Name: Perfluorohexanesulfonate Molecular Weight: 399 6.0 D E S C R IP T IO N O F A N A L Y T IC A L M E T H O D The analytical method ExM-023-071 Revision 1 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 die extraction procedure for the laboratory controls and fortifications. Due to insufficient sample size, a 100 pL aliquot of the serum and plasma and 0.1 g ofthe 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 ~ 1 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-023-071 Revision 1. The stock standard solution was prepared at a concentration of 100 pg/mL by dissolving 10 mg of each standard (corrected for purity only) in methanol. From this solution, a 1.0 pg/mL fortification standard solution was prepared by taking 1 raL of the stock and bringing the volume up to 100 mL with methanol. A 0.1 pg/mL fortification standard was prepared by taking 10 mL of the 1.0 pg/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 pg/mL and various calibration solutions in the following manner: Initial Cone. (ug/mL) 1 0.1 0.1 0.1 0.005 0 .0 0 2 0.001 1 of PFHS Volume (mL) 5 2 1 10 10 10 Diluted to (mL) 100 100 100 100 100 100 Final Cone. (ujs/mL) 0.005 0 .0 0 2 0.001 0.0005 0 .0 0 0 2 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. 63 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 o f0.0001 pg/mL of PFHS. Exygen Research Page 14 of 153 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) Computen COMPAQ Professional Workstation AP200 Software: Windows NT, Masslynx 3.3 HPLC: Hewlett Packard (HP) Series 1100 HP Quat Pump HP Vacuum Degasser HP Autosampler HP Column Oven HPLC Column:Genesis C8 (Jones Chromatography), 2.1 mm x 50 mm, 4jn Column Temp.: 35 C Injection Voi.: 15 pL Mobile Phase (A): 2 mM Ammonium Acetate in type I water Mobile Phase (B): Methanol Time 0.0 2.0 5.0 9.0 9.5 14.0 14.5 20.0 %A 90 90 10 10 0 0 90 90 Flow Rate faiL/minl 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: Analvte PFHS Mode Negative Approximate TransitjpaMPflitoigd Retention Time (mini 399 -> 80 ~8.3 min. 6.6 Quantitation and Example Calculation Fifteen microliters of sample or calibration standard wore 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 determined from the equations below. Equation 1 calculated the amount of analyte found (in ng/mL, based on peak area) using die standard curve (linear regression parameters) generated by the Masslynx software Exygen Research Page 15 of 153 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) = (Peak area - intercept) x DF x AF Where: AF = Aliquot Factor slope DF = Dilution Factor Equation 2: Analyte found (ppb, ng/g for liver and ng/mL for serum and plasma) = analyte found (ng/mU x FV (mLl sample volume (mL) or sample weight (g) Where: FV = Final Volume For samples fortified with known amounts o f PFHS prior to extraction, Equation 3 calculated the percent recovery. Equation 3: Recovery (%) = (fanalvte found fpnbl - analyte in control (ppbYl x l00% amount added (ppb) To find the total analyte found corrected for the salt content Equation 4 was used. Equation 4: 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 ppb added (fort level) 110 avg. amt in controls 0 (Not Detected) final volume 2 mL aliquot factor 10 sample weight l.Og Exygen Research Page 16 of 153 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) 212S--41.0365) x 1 x 10 4728.12 4.41 ng/mL (4.41 nc/mL x 2 mi:> (1-0 g) 8.82 ppb ((8.82 ppb - Oppb) x 100% 10 ppb 88% 8.82 ppb x 0.91 8.03 ppb 7.0 E X P E R IM E N T A L D E S IG N 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 17 of 153 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 I-IH. 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-VJL The average percent recoveries standard deviations for PFHS in rat plasma, swum, 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/inL. 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 VHI. 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 XL 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 C O N C L U S IO N S 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 of 153 418-028:PAGE G-19 Exygen Study No.: 023-072 10.0 R E T E N T IO N O F D A T A A N D S A M P L E S 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 o f time specified in 21 CFR Part 58, OECD ENV/MC/CHEM(98)17, and MHW Ordinance Number 21. Retained samples ofreference substances are archived by the sponsor. Exygen Research Page 19 of 153 418-028:PAGE G -20 Exygen Study No.: 023-072 TABLES Exygen Research Page 20 of 153 418-028:PAGE G-21 Exygen Study No.: 023-072 Table I. Summary o f PFHS in Control Rat Plasma Samples S p o n so r ID LOT 17824 LOT 17824 LOT 05024 LOT 17824 Exygen ID 0202913 Control 0202913 Control 0202912 Control 0202913 Control Set N um ber 091602AR 091602B 091802A 091902A PFH S F o u n d (p p b ) ND ND ND ND T a b le II. S u m m ary o f P F H S in C o n tro l R a t S eru m S am ples Sp o n so r IP 36119-3 36119-3 36119-3 36119-3 36119-3 Exygen ID 0202987 Control 0202987 Control 0202987 Control 0202987 Control 0202987 Control Set N um ber 091902B 092002A 092002B 092302A 101102A PFH S F o u n d (p i ND ND ND ND ND T a b le III. S u m m ary o f P F H S in C o n tro l R a t L iv e r S am ples S p o n so r ID LOT 21824 LOT 21824 LOT 21824 LOT 21824 LOT 21824 LOT 21824 LOT 21824 LOT 21824 LOT 21824 LOT 21824 LOT 21824 LOT21824 LOT21824 LOT21824 LOT 21824 LOT 21824 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 N um ber 092S02A 092602A 092602B 092702A 092702B 100202A 100102A 100302A 100402A 100402BR 100902A R 100902BR 101002A 101002B 101102AR 101402A PFH S F o u n d (p p b ) ND ND 2 .3 2 (N Q ) 3 .8 4 (N Q ) 3 .8 5 (N Q ) ND ND ND ND 2 .0 9 (N Q ) 3 .9 5 (N Q ) 2 .0 1 (N Q ) 1.85 (N Q ) 3 .9 5 (N Q ) 4 .7 3 (N Q ) 3 .3 7 (N O ) N D - N o t D e te cte d (A re a le ss th a n d ie lo w e st co n ce n tra tio n o f d ie c a lib ra tio n sta n d a rd s (0 .1 n g / m L )) N Q = N o t Q u a n tifia b le (A re a is g re a te r th a n 0 .1 n g / m L b u t le ss th a n L O Q (1 0 n g / m L )) Exygen Research Page 21 of 153 418-028:PA G EG -22 Exygen Study No.: 023-072 Table IV. Summary o f PFHS Fortification Recoveries in Rat Plasma S p o n so r ID LO T 17824 L O T 17824 19176 G R O U P 1 L O T 17824 L O T 17824 19176 G R O U P I LO T 05024 LO T 05024 19076 G R O U P I L O T 17824 L O T 17824 19076 G R O U P I Exygen m 0202913 Spk A 0202913 Spk B 0201801 S p k C 0202913 Spk A 0202913 Spk B 0201816 Sp k C 0202912 Spk A 0202912 Spk B 0201846 S p k C 0202913 Spk A 0202913 Spk B 0201831 S p k C Set N um ber Am ount A d d e d (p p b ) 091602A 091602A 091602A 091602B 091602B 091602B 091802A 091802A 091802A 091902A 091902A 091902A 10 50 5000 10 50 5000 10 50 5000 10 50 5000 A ve rage : S ta n d a rd D e v ia tio n : R e la tiv e S ta n d a rd D e v ia tio n : % R eco ve ry 91 84 77 86 84 78 88 86 89 71 96 82 84 7 8 T ab le V . S u m m ary o f P F H S F o rtific a tio n R ecoveries in R a t S eru m S p o n so r ID 3 6 1 1 9 -3 36U 9-3 19076 G R O U P 1 3 6 1 1 9 -3 3 6 1 1 9 -3 19012 G R O U P 1 3 6 1 1 9 -3 3 6 1 1 9 -3 19036 G R O U P II 3 6 1 1 9 -3 3 6 1 1 9 -3 19005 G R O U P IV 3 6 1 1 9 -3 3 6 1 1 9 -3 Exygen n> 0 2 0 2 9 8 7 Side A 0202987 Sp kB 0201861 S p k C 0202987 Spk A 0202987 S p k B 0201875 S p k C 0 2 0 2 9 8 7 Side A 0202987 S p kB 0 2 0 1 8 9 0 Side C 0202987 Spk A 0202987 Sp kB 0201905 S p k C 0202987 Spk A 0202987 Sp kB Set N um ber Am ount A d d e d (p p b ) 091902B 091902B 091902B 092002A 092002A 092002A 092002B 092002B 092002BR 092302A 092302A 101102A 101102A 101102A 10 50 5000 10 50 5000 10 50 5000 10 50 200000 10 50 A ve rage : S ta n d a rd D e v ia tio n : R e la tiv e S ta n d a rd D e v ia tio n : % R eco ve ry 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 Sp o n so r ID LOT21824 LOT21824 19176 GROUPI LOT21824 LOT21824 19076GROUP I LOT21824 LOT21824 19076 GROUP I LOT21824 LOT21824 19012 GROUP I, Male 1 LOT21824 LOT21824 19021 GROUPLMale 1 LOT21824 LOT21824 19018 GROUPn, Male 1 LOT21824 LOT21824 19041 GROUP LMale 1 LOT21824 LOT21824 19036 GROUPH, Male 1 LOT21824 LOT21824 19003 GROUPm,Male 1 LOT21824 LOT21824 19008 GROUPm,Male 1 LOT21824 LOT21824 19015 GROUP m, Male 1 LOT21824 LOT21824 19035 GROUP IV.Male 1 LOT21824 LOT21824 19040 GROUPIV, Male2 LOT21824 LOT 21824 19006GROUPV, Male 1 LOT 21824 LOT 21824 19020GROUP V, Male2 LOT21824 LOT21824 19025 GROUPV, Male 1 Exygen ID 0202877 SpkA 0202877 SpkB 0201759 SpkC 0202877 SpkA 0202877 SpkB 0201774 SpkC 0202877 Si* A 0202877 SpkB 0201788 SpkC 0202877 Sf* A 0202877 SpkB 0201925 SpkC 0202877 SpkA 0202877 SpkB 0201945 Sj* C 0202877 SpkA 0202877 SpkB 0202050 SpkC 0202877 SpkA 0202877 SpkB 0201965 SpkC 0202877 SpkA 0202877 SpkB 0202070 SpkC 0202877 SpkA 0202877 SpkB 0202119 SpkC 0202877 SpkA 0202877 SpkB 0202139 SpkC 0202877 SpkA 0202877 SpkB 0202159 SpkC 0202877 SpkA 0202877 SpkB 0202229 SpkC 0202877 SpkA 0202877 SpkB 0202249 SpkC 0202877 SpkA 0202877 SpkB 0202320 SpkC 0202877 SpkA 0202877 SpkB 0202340 SpkC 0202877 SpkA 0202877 SpkB 0202360 SpkC Exygen Research Sot Number Amount Added (ppb) 0928Q2A 092802A 092802A 092602A 092602A 092602A 092602B 092602B 092602B 092702A 092702A 092702A 092702B 092702B 092702B 100202A 1002Q2A 100202A 100102A 100102A 100102A 100302A 100302A 100302A 100402A 100402A 100402A 100402BR 100402BR 100402BR 100902AR 100902AR 10 50 5000 10 50 5000 10 50 5000 10 50 5000 10 50 5000 10 50 5000 10 50 5000 10 50 5000 10 50 5000 10 50 5000 10 50 100902AR 1D0902BR 100902BR 100902BR 101002A 101002A 101002AR 101002B 101002B 101002BR 101102AR 101102AR 101102AR 101402A 101402A 101402ARR 5000 10 50 5000 10 50 5000 10 50 5000 10 50 25000 10 50 5000 Average: Standard Deviation: Relative Standard Deviation: % Recove 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 S p o a isr ID 19176 GROUP I 19176 GROUP 1* 19177 GROUP I 19177GROUP I* 19178 GROUP I 19178GROUP I* 19179 GROUP U 19179CROUP U* 19180 GROUP n 19180GROUP II* 19181 GROUP H 19181 GROUP n * 19182 GROUP m 19182 GROUP m* 19183 GROUP Dl 19183 GROUP m * 19184 GROUP in 19184 GROUP m 19183GROUP IV 191S5GROUP IV * 19186 GROUP IV 19186GROUP IV * 19187GROUP IV 19187GROUP IV 19188 GROUP V 19188 GROUP V * 19189 GROUP V 19189 GROUP V * 19190 GROUP V 19190 CROUP V* 19176GROUP I 19176 GROUP 1* 19177GROUP 1 19177GROUP I* 19178 GROUP! 19178GROUP I* 19179 GROUP O 19179GROUP O* 19180 GROUP n 19180GROUP U* 19181 GROUP U 19181 GROUP n* 19182 GROUP m 19182 GROUP ID* 19183 GROUPID 19183 GROUP m* 19184 GROUP HI 19184 GROUPm * 19185OROUPIV 19185 GROUP IV * 19186GROUP IV 19186 GROUP IV * 19187 GROUP IV 19187GROUP IV * 19188 GROUP V 19188 GROUP V* 19189 GROUP V 19189 GROUP V * 19190 OROUP V 19190 GROUP V * Kspga ID 0201801 Dup Inj. 0201802 0201802 Dap taj. 0201803 0201803 Dup by. 0201*04 0201804Dup hy. 0201805 0201805 Dup by. 0201806 0201806 Dup Rtf. 0201807 0201807 Dup hq. 0201808 0201808 Dup by. 0201809 0201809 Dap by. 0201810 020)B10Dup by. 0201811 0201811 Dup 0201812 0201812 Dup by. 0201813 0001813 Dup by. 0201814 0201814 Dup by. 0201815 0201815 Dup Iqj 0201816 0201816 Dup by 0201817 Q20!8l7Dupby 0201818 02018I8DupIqj 0201819 O Q 018J9D upluJ 0201820 0201820 Dup b 0201821 0201821 Dup by 0201822 0201822Dupby 0201B23 0201823 Dup by 0201824 0201824 Dup by 0201825 0201825 Dup by 0201826 0201826 Dup hg 0201827 0201827 Dup by 0201828 0201828 Dup by 0201829 0201829 Dup by 0201830 0201830Dup by M atrix PD 14PLASMA PD 14 PLASMA PD 14PLASMA PD 14PLASMA PD 14 PLASMA PD 14 PLASMA PD14 PLASMA PD 14PLASMA PD 14PLASMA PD 14PLASMA PD 14PLASMA PD 14PLASMA PD 14PLASMA PD 14PLASMA PD 14PLASMA PD 14 PLASMA PD 14PLASMA FD 14PLASMA PD 14PLASMA PD 14 PLASMA PD 14PLASMA PD 14 PLASMA FD 14 PLASMA PD 14 PLASMA PD 14PLASMA PD 14 PLASMA PD 14PLASMA PD 14PLASMA PD 14 PLASMA PD 14 PLASMA PD 42 PLASMA PD 43 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 PD42 PLASMA PD42 PLASMA PD 42 PLASMA PD42 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 PD42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA C u lc rtlu D ate 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 m Am 4/14/02 4/1402 4/14/02 4/1402 4/14/02 4/14/02 4/14/02 4/14/02 414/02 414/02 41402 414/02 4/14/02 41402 4/14/02 4/14/02 4/14/02 4/144)2 4/1402 4/14/02 414412 414412 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/124)2 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/124)2 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12412 Sat N atelirr 091602A 091602A 09I602A 091602A 0916Q2A 091602A 091602AR 09I602AR 091602AR 091602AR 091602AR 09I602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 0916Q2AR 09I602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 0916Q2B 091602B 091602B 091602B 091602B 091602B 09I602BR 0916Q2BR 091602BR 0916Q2BR 091602BR 09I6Q2BR 091602BR 091602BR 091602BR 09I602BR 09I602BR 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 09I602BR 091602BR 091602BR 09I602BR 091602BR 091602BR PFHS Fauad M a il) 1S2 172 103 10S 46.5TM 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 245 236 382 376 74.7a* 65.4a* 57400 60200 35700 56400 371OD 38500 91000 85900 90300 87500 90700 89300 119000 119000 137000 142000 128000 127000 188000 188000 224000 225000 191000 193000 ^Although the method used allows for alternate sample volumes or weights and all the peak area responses are within the calibration curve limits, die precision for the 0.1 m LorO .l g samples below 100 ppb has not been validated. * Duplicate Injection Exygen Research Page 24 of 153 418-028:PAGE G-25 Exygea Study No.: 023-072 Table VII (cont'd). Summary of PFHS Residues in Rat Plasma Samples SpoaMr ID 19076 GROUP 1 19076 GROUP 1* 19077 GROUP 1 19077 GROUP I* 19078 GROUP 1 19078 GROUP I* 19079 GROUP H 19079 GROUP H* 19080 GROUP D 19080 GROUP D* 19081 GROUP D 19081 GROUP D* 19082 GROUP m 19082 GROUP H I* 19083 GROUP ID 19083 GROUPm * 19084 GROUP in 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 19089 GROUP V * 19090GROUP V 19090 GROUP V * 19076 GROUP I 19076 GROUP I* 19077 GROUP! 19077 GROUP 1* 19078 GROUP 1 19078 GROUP I* 19079 GROUP H 19079 GROUP H* 19080 GROUP n 19080 GROUP n* 19081 GROUP n 19081 GROUP II* 19082 GROUP m 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 19089 GROUP V * 19090 GROUP V 19090 GROUP V * * D u p lic a te In je c tio n Exygen ID 0201846 0201846 Dopili) 0201847 0201847 Dop ay 0201848 0201848 Dnp by 0201849 0201849 Dap Ini 0201850 0201850Dap h j 0201851 0201831 Dap by 0201852 0201852 Dap by 0201853 0201BS3 Dap by 0201854 0201854 Dap h j 0201855 0201B55Dapbi 0201856 0201856 Dapbti 0201857 0201857 Dap h j 0201858 0201858 Dap h j 0201859 0201859 Dup fag 0201860 0201860 D isiai 0201831 0201831 Dap h j 0201832 0201832 Dap In) 0201833 0201833 Dup laj 0201834 0201834 Dup by 0201835 0201835 Dap h|j 0201836 0201836 Dap iqj 0201837 0201837 Dup 0201838 0201838 Dap Iqj 0201839 0201839 Dap Iqj 0201840 0201840 Dap h i 0201841 0201841 Dapbti 0201842 0201842 Dap Ip) 0201843 0201843 Dap h i 0201844 0201844 Dap bd 0201845 0201845 Dap h i Matrix GD21 PLASMA GD 21 PLASMA GD21 PLASMA GD21 PLASMA GD21 PLASMA GD21 PLASMA GD 21 PLASMA GD 21 PLASMA GD21 PLASMA GD21 PLASMA GD 21 PLASMA GD21 PLASMA GD21 PLASMA GD 21 PLASMA OD 21 PLASMA GD21 PLASMA OD 21 PLASMA GD21 PLASMA GD2I PLASMA GD21 PLASMA GD 21 PLASMA GD 21 PLASMA GD21 PLASMA GD 21 PLASMA GD 21 PLASMA GD21 PLASMA GD 21 PLASMA GD 21 PLASMA GD 21 PLASMA GD21 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 14PLASMA 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 Calkctiaa Dote 5/9702 5/9/02 5/19/02 5/19/02 5/7/02 5/7/02 5/9/02 5/9/02 5/9/02 5/9/02 5/10/02 5/10/02 5/9/02 5/9/02 5/7/02 5/7/02 5/9m 5/9/02 5/6/02 5/6/02 5/6/02 5/6/02 5/6/02 5/6/02 5/9/02 5/9/02 5/9/02 5/9/02 5/9/02 5/9/02 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 4/14/02 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 act Number 091802A 091802A 091802A 091802A 091S02A 091802A 091802AR 091802AR 091B02AR 091802AR 09IS02AR 091B02AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 09I802AR 091802AR 091S02AR 091B02AR 091902A 091902A 091902A 091902A 091902A 091902A 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR. 09I902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR PEHS F cm tftaM U ND ND ND ND ND ND 41S0 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 S540 5980 16900 17900 24800 25200 19200 20000 43900 43000 7100 48200 34000 35900 N D = N o t D e te cte d (A re a le sa th a n lo w e st c a lib ra tio n sta n d a rd o f 0 .1 n g / m L ) Exygen Research Page 25 of 153 418-028.PAGE G-26 Exygen Study No.: 023-072 Table VIII. Summary o f PFHS Residues in Rat Serum Samples SpWMW ID 19076 GROUP 1 19076 GROUP 1* 19078 GROUP! 19078 GROUP P* 19079GROUP U 19079 GROUP II* 19080GROUP H 19060 GROUP 0* 19081 GROUP n 19081 GROUP n* 19082 GROUP m 19082 GROUP ID* 19083 GROUP m 19083 GROUP m * 19084GROUP m 19084 GROUP ffl* 19085 GROUP IV 19085 GROUP IV * 190*6 GROUP IV 19086 GROUP IV * 19087 GROUP IV 19087 GROUP IV * 19088GROUP V 19088 GROUP V* 19089GROUP V 19089 GROUP V * 19090GROUP V 19090GROUP V* 19012 GROUP 1 19012 GROUP I* 19019 GROUP I 19019 GROUP I* 19021 GROUP I 19021 GROUP 1* 19023 GROUP I 19023 GROUP I* 19041 GROUP I 19041 GROUP 1 19042 GROUP I 19042 GROUP I* 19044 GROUP I 19044 GROUP 1* 19050 GROUP 1 19050 GROUP I* 19053 GROUP I 19053 GROUP I* 19065 GROUP I 19065 GROUP I* 19004GROUP n 19004 GROUP tl* 19009GROUP D 19009 GROUP B* 19016GROUP 0 19016 GROUP H* 19018 OROUPO 19018 GROUP n* 19026GROUP 11 19026 GROUP n* 19036 OROUPO 19036 GROUP II* Exygea n> 0201861 0201861 D i* Ol 0201862 0201862 Dup h j 0201863 0201863 Dup Iqj 0201864 0201864 Dup by 0201865 0201865 D i I*) 0201866 0201866 Dup b j 0201867 0201867 Dup by 0201868 0201868 Dup Iqj 0201869 0201869 DupIqj 0201870 0201870 Duplo] 0201871 0201871 Duplqj 0201872 0201872 Dup by 0201873 0201873 Dup by 0201874 0201874 Diy>h j 0201875 0201875 Dupby 0201876 0201576 Dup tai 0201877 0201877 Dup hj 0201878 0201878 Dupbj 0201879 0201879 Dup lm 0201880 0201880 Dup iy 0201881 0201881 Duplqj 0201882 0201882 Dup by 0201883 0201883 DuphU 0201884 0201884 Dup Iqj 0201885 0201885 Dup by 0201886 0201886 Duplqj 0201887 0201887 Dup Iqj 0201888 0201888 Dup by 0201889 0201889 Dup liU 0201890 g '9 9 tR . M u tril Pooled Fetal Scrum Pooled Fetal Serum PooledFetal Scrum Pooled Petal Senim Pooled Fetal Seran PooledPetal Scrum Pooled Fetal Scram Pooled FetalSen PooledFetal Serum PooledFetal Scrum PooledPetal Serum Pooled Fetal Serum Pooled Fetal Serum PooledPetal Serum Pooled Fetal Serum Pooled Fetal Seran FooledFetal Serum Pooled Fetal Serna PooledFetalSerum Fooled Fetal Scrum Pooled Fetal Scrum Pooled Fetal Scrum Pooled Fetal Serum Fooled PetalSerum Pooled Fetal Scram Pooled Fetal Serum Pooled Fetal Scran Pooled Fetal Sorum PooledPqp Seram PooledPup Serum PooledPup Serum PooledPup Scrota PooledPup Seram PooledPup Scrum PooledPup Scrum PooledPup Scrum PooledPup Serum PooledPup Scrum PooledPup Scrum PooledP19 Scrum PooledPup Serum PooledPup Scrum FooledPup Serum PooledPup Serum FooledPup Serum PooledPup Seram PooledPop Scrum PooledPup Serum PooledPup Scrum PooledPup Scram PooledPup Sena* PooledPup Seram PooledPap Seram PooledPup Scrum PooledPup Scram PooledPup Serum PooledPup Serum FooledPup Serum Pooledr upStrum PooledPud Serna Collection Date SM2 5/9/02 srw2 5/72 5/9102 5/9 2 5/9/02 5/9/02 5/10/02 5/1002 5/9/02 5/9/52 5/7/02 5/7/02 5/9/02 5/9/02 5/6/02 5/6/02 5/6/02 5/6/02 5/62 5/62 5/9/02 5/9/02 5/9/02 5/9/02 5/9/02 5/9/02 5/29/02 5/29/02 5/3002 5/30/02 5/29/02 5/29/02 5/31/02 5/31/02 5/31/02 5/31/02 5/30/02 5/30812 5/28/02 5/28/02 5/31/02 5/31/02 5/30/02 5/30/02 3/30/02 5/30/02 5/31/02 5/31/02 5/28/02 5/28/02 5/28/02 5/28/02 5/29/02 5/29/02 5/31/02 5/31/02 5/28/02 5/28/02 Set W ither 09I90ZB 091902B 091902B 091902B 09I902BR 091902BR 09I902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 09I902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 09I902BR 091902BR 091902BR 091902BR 09I902BR 0919Q2BR 091902BR 09I9Q2BR 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 IM M iU 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 65.3a* 68.9" 81.1" 86.0" 456" 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 ^ A lt h o u g h d ie m e th o d u se d a llo w s fo r a lte rn a te sa m p le v o lu m e s o r w e ig h ts a n d a ll th e p e a k a re a re sp o n se s a re w ith in th e c a lib ra tio n c u rv e lim its , d ie p re c is io n fo r the 0 .1 m L o r 0 .1 g sa m p le s b e lo w 100 p p b h a s n o t b e e n v a lid a te d . * D u p lic a te In je c tio n N D = N o t D e te cte d (A re a le s s th a n lo w e st c a lib ra tio n sta n d a rd o f 0 .1 n g / m L ) Exygen Research Page 26 of 153 418-028-.PAGE G-27 Exygen Study No.: 023-072 Table VIII (cont'd). Summary o f PFHS Residues in Rat Serum Samples Sparnr n> i97 m o u rn W037(m ou rn * 19043 GROUPH 19043 GROUP n * 19047 GROUPn 19047 GROUP II* 19041 oR ourn 19048 GROUPU* 19003 GROUP HI 19003GROUP m* 19007GROUPm 19007GROUP at* 19008GROUPin 19008 GROUP ID* 19013 GROUP m 19013 GROUPm* 19015GROUP in 19015 GROUPm* 19017 GROUPm 19017GROUP m * 19024 GROUPm 19024GROUP m* 19029 GROUP Cl 19029OROUP 01* 19034 GROUPffl 19034GROUPm* 19055 OROUP m 19056GROUPm* 19005 GROUP IV 19005GROUP IV* 19035GROUP IV 19035OROUP IV* 19039 OROUP nr 19039OROUP IV* 19040GROUP IV 19040GROUP IV* 19045GROUP IV 19045GROUP IV* 19034 GROUP IV 19054OROUP IV * 19051GROUP IV 19051 GROUP IV* 19062OROUP IV 19062GROUP IV* 19063GROUP IV 19063 GROUPIV* 19066 GROUP IV 19065GROUP IV* 19001 GROUPV 19001 GROUP V* 19006 GROUPV 19006 GROUP V * 19011 OROUPV 19011 GROUP V* 19020 GROUPV 19020GROUP V* 19022 OROUPV 19022 GROUP V * 19023 GROUPV 19025OROUP V* 19027 GROUPV 19027 GROUP V * 1902* GROUPV 19028GROUP V* 19030 GROUPV 19030GROUP V* 19031 GROUPV 19031 GROUPV* * D u p lic a te In je c tio n bua n> 0201891 0201891 Dup b 0201892 0201092Dap h 0201093 0201093 D up la 0201894 0201894 Dtp 0201895 0201095Dap b 0201896 0201896Dop Ini 0201097 0201897Dop bO 0201898 0201898 Dup lai 0201199 0201899 Deph* 0201900 0201900Dup Iqj 0201901 0201901 Dup b|) 0201902 0201902 Dup lq 0201903 0201903Dup b4 0201904 0201904Dup bg 0201905 02019Q3Dop Iq 0201906 0201906Dtp tq 0201907 0201907 Dup Iq 0201900 0201908Dop Ib 0201909 0201909Dup Iqj 0201910 0201910Dop bg 0201911 0201911 Dop Iqj 0201912 0001912Dup by 0201913 0201913 Dup Iqj 0201914 0201914Dup Iqj 0201915 0201915Dop 1* 0201916 0201916Dup Jty 0201917 0201917 Dup bg 0201918 0201918Dup Ir 0201919 0201919 Dup bfl 0201920 0201920Dup Inj 0201921 0201921 Dup H 0201922 0201922Dup Iq 0201923 0201923Dup bfj 0201924 0201924 Dup Ini M urta Poolnl Pup Scram PooledPupSerum PooledPupScram Pooled Pup Serum PooledPupSerum PooladPapSana Pooled Pup Sena PooledPupSeram Poded PupSerum Poded PupScram PooledPupScram PooledPupSeram PooledPapSena Poded PupScrum PooledPupSaum PooledPupSeram PooledPapSerum Poded PupSerum PooledPupSeram Poded Pup Seram Poded PupSeram Peded Pup Serum PooledPupSerum Poded Pap Seram PodedPupSerum PodedPupSeram PodedPupSerum Poded Pup Scram PodedPupSeram PooledP^> Serum PodedPupSerum PooledPupSerum PooledPupSerin PodadPupScram PooledPup Serum Poded PupSerum PodedPip Serum PooledPupSeram PodedPupSerum PooledPupSeram PodedPupSeram Poded Pup Serum PodedPupSmum PodedPup Seram PodedPupSeram PodedPupScrum PodedPupScrum Poded Pup Scrum PodedPupSeram PodedPupScrum Poded PupSeram Poded PupSerum Pooled Pup Seram PooledPupScram Poded Pup Serum PooledPupSerum Poded PapScrum PodedPupSerum PodedPupSeram Poded Pup Scram PodedPupSerum Poded Pup Seram Poded PupSeram Poded Pup Seram Poded Pup Seram Poded Pep Seram PodedPupScram PodedPupSeram Concedes Date 5/29/02 5/29/02 5/28/02 5/28/02 5/28/02 5/28/02 5/31/02 5/31/02 5/30/02 5/30/02 5/30/02 5/30/02 5/31/02 5/31/02 5/29/02 5/29/02 S/31/02 5/31/02 5/28/02 5/28/02 5/31/02 5/31/02 5/29/02 5/29/02 5/3002 5/3002 3/31/02 5/31/02 5/31/02 S/31/02 5/31/02 5/31/02 5/29/02 3/29/02 5/30/02 5/30/02 5/28/02 5/28/02 S/31/02 5/31/02 5/28/02 5/28/02 5/31/02 5/31/02 5/29/02 5/29/02 5/31/02 5/31/02 5/13/02 5/13/02 5/13! 5/13/02 5/13/02 5/13/03 5/14/02 5/14/02 5/31/02 5/31/02 5/30/02 5/30/02 5/31/02 5/31/02 5/28/02 S/28/02 5/31/02 5/31/02 5/28/02 5/28/02 Set Maabei- 092002BR 092002BR 092002HR 092002BR 092002BR 092002BR 092002HR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR Q92002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 093002BR 092002BR 092002BR 092002BR 092002BR 092302AR 092302AR 092302AR 092302AR Q9230ZAR 092302AR 0923G2AR O92302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 0923C2AR 092302AR 092303AR 092302AR 092302AR 092302AR 092302AR 0923Q2AR 092302AR 092302AR Q923Q2AR 092302AR 0923Q2AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092303AR 092302AR PFHS F taadfaz/nU 12100 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 23800 25800 41200 41100 19800 wioo 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 o f PFHS Residues in Rat Liver Samples Sponsor ID 19176 GROUP I 19176 GROUP 1* 19177 GROUP 1 19177 GROUP J* 1917 GROUP I 19178 GROUP 1* 19179 GROUP U 19179 GROUP U* 19180 GROUP H 19180 GROUP n* 19181 GROUP H 19181 GROUP H* 19182 GROUP m 19182 GROUP n i* 19183 GROUP HI 19183 GROUP IB* 19184 GROUP m 19184 GROUP 1H* 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* 19076 GROUP I 19076 GROUP 1* 19077 GROUP I 19077 GROUP I* 19078 GROUP I 19078 GROUP I* 19081 GROUP D Fem ale 1 19081 GROUP U Fem ale 1* 19079 GROUP II 19079 GROUP n* 19080 GROUP H 19080 GROUP U* 19082 GROUP m 19082 GROUP m * 19083 GROUP m 19083 GROUP m * 19084 GROUP 01 19084 GROUP m * 19085 GROUP IV 19085 GROUP IV* 19086 GROUP IV 19086 GROUP IV* Exygen ID 0201759 0201759 D up Iqj 0201760 0201760 D up Iiy 0201761 0201761 D u p ln j 0201762 0201762 D uplnj 0201763 0201763 D ap Inj 0201764 0201764 D uplnj 0201765 0201765 D ap Inj 0201766 0201766 D uplnj 0201767 0201767 D up Inj 0201768 0201768 D ap by 0201769 0201769 D up Iqj 0201770 0201770 D ap fay 0201771 0201771 D up Iqj 0201772 0201772 Dup by 0201773 0201773 D ap by 0201774 0201774 D up Iqj 0201775 0201775 Dup Inj 0201776 0201776 Dup by 0203650 0203650 Dup Iqj 0201777 0201777 D up Iqj 0201778 0201778 D ap Inj 0201779 0201779 D ap Iqj 0201780 0201780 D up Iqj 0201781 0201781 Dup Iqj 0201782 0201782 D up Iqj 02017B3 0201783 Dup Iqj M atrix M edian L iver Lobe M edian L iver Lobe M edian L iver Lobe M edian L iver L obe M edian L iver Lobe M edian L iver L obe M edian L iver L obe M edian Liver Lobe M edian L iver Lobe M edian liv e r Lobe M edian L iver L obe M edian L iver Lobe M edian L iver L obe M edian liv e r L obe M edian L iver Lobe M edian L iver Lobe M edian L iver Lobe M edian liv e r L obe M edian L iver Lobe M edian L iver Lobe M edian L iver Lobe M edian liv e r L obe M edian L iver Lobe M edian L iver L obe M edian L iver Lobe M edian L iver Lobe M edian L iver Lobe M edian L iver L obe M edian L iver Lobe M edian liv e r Lobe M edian liv e r Lobe M edian liv e r Lobe M edian L iver Lobe M edian L iver Lobe M edian L iver Lobe M edian L iver L obe M edian L iver L obe M edian L iver Lobe M edian L iver Lobe M edian liv e r Lobe M edian L iver L obe M edian L iver L obe M edian liv e r Lobe M edian L iver Lobe M edian liv e r Lobe M edian L iver L obe M edian Laver L obe M edian liv e r Lobe M edian liv e r Lobe M edian liv e r Lobe M edian L iver Lobe M edian liv e r Lobe Collection D ate 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/D2 5/12/02 5/12/02 5/12/02 1 2 /0 2 5/12/02 5/12/02 1 2 /0 2 1 2 /0 2 1 2 /0 2 1 2 /0 2 1 2 /0 2 1 2 /0 2 1 2 /0 2 1 2 /0 2 1 2 /0 2 1 2 /0 2 12/02 1 2 /0 2 9 /02 mm 1 9 /0 2 1 9 /0 2 5/7/02 mm 1 0 /0 2 5/10/02 mm mm 5/9m mm mm mm 5/7/02 5/7/02 mm mm 5/6/02 5/6/02 5/6/02 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 0926Q2AR 092602AR 092602AR 092602AR 092602AR 092602AR 092602AR 092602AR 092602AR 092602AR 092602AR PFHS Fornai (ng/naL) 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 511000 659000 675000 612000 603000 ND ND 82J2AA 8 2 .4 'A ND ND 628 633 1040 974 762 725 1960 2080 3070 3090 2700 2750 6360 6640 9740 9370 ^ A lt h o u g h th e m e th o d u se d a llo w s fo r a lte rn a te sa m p le v o lu m e s o r w e ig h ts a n d a ll d ie p e a k area re sp o n se s a re w ith in th e c a lib ra tio n c u rv e lim its , th e p re c is io n fo r th e 0 .1 m L o r 0 .1 g sa m p le s b e lo w 1 0 0 p p b h a s n o t b e e n v a lid a te d . * D u p lic a te In je c tio n N D = N o t D e te cte d (A re a le ss th an lo w e st c a lib ra tio n sta n d a rd o f 0 .1 n g / m L ) 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 n> 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 I* 19078 GROUP I 19078 GROUP 1* 19081 GROUP C Fem ale 2 19081 GROUP II F an n ie 2* 19079 GROUP II 19079 GROUP H* 19080 GROUP II 19080 GROUP D* 19082 GROUP m 19082 GROUP m * 19083 GROUP m 19083 GROUP HI* 19084 GROUP m 19084 GROUP m * 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 GROUP V* 19090 G RO UPV 19090 GROUP V* 19012 GROUP 1. M ale 1 19012 GROUP I, S tale 1* 19012 GROUP I, M ale 2 19012 GROUP I, M ale 2* 19012 GROUP I, M ale 3 19012 GROUP I, M ale3* 19012 GROUP 1, M ale 4 19012 GROUP I, M ale 4* 19012 GROUP I, M ale 5 19012 GROUP I, M ale 5* 19012 GROUP I, Fem ale 7 19012 GROUP I, Fem ale 7* 19012 GROUP I, Fem ale 8 19012 GROUP I, Fem ale 8* 19012 O R O U PI, Fem ale 14 19012 GROUP 1. Fem ale 14* Exygen ID 0201784 0201784 Dup by 0201785 0201785 D ap by 0201786 0201786 Dup by 0201787 0201787 D up bij 0201788 0201788 Dup by 0201789 0201789 D up by 0203651 0203651 Dup by 0201790 0201790 Dup by 0201791 0201791 Dup by 0201792 0201792 Dup by 0201793 0201793 Dup by 0201794 0201794 Dup by 0201795 0201795 Dup Inj 0201796 0201796 Dup by 0201797 0201797 D up bij 0201798 0201798 Dup by' 0201799 0201799 Dup by 0201800 0201800 Dup by 0201925 0201925 Dup by . 0201926 0201926 Dup Inj 0201927 0201927 Dup by 0201928 0201928 Dup by 0201929 0201929 Dup by 0201930 0201930 Dup by 0201931 0201931 Dup by 0201932 0201932 D ue Inj M atrix M edian L iver Lobe M edian L iver L obe M edian L iver L obe M edian Liver L obe M edian L iver L obe M edian L iver Lobe M edian L iver L obe M edian L iver L obe Pooled Fetal L iver Pooled Fetal L iver P ooled F etal L iver Pooled Fetal L iver Pooled Fetal liv e r Pooled Fetal liv e r P ooled F etal L iver Pooled F etal liv e r Pooled Fetal L iver Pooled Fetal L iver Pooled F etal liv e r P ooled F etal L iver Pooled Fetal L iver Pooled Fetal L iver Pooled F etal liv e r Pooled F etal L iver Pooled Feta] L iver Pooled F etal L iver Pooled F etal liv e r Pooled Fetal L iver Pooled Fetal L iver Pooled Fetal L iver Pooled F etal liv e r Pooled Fetal L iver Pooled Fetal L iver Pooled Fetal L iver Fooled F etal L iv a Pooled F etal L iver Pup L iven Pup L iv en Pup L iv en Pup L iven Pup L iv en Pup L iv en Pup liv e n Pup L iv en Pup L iv en Pup L iven Pup liv e n Pup L iven Pup L iven Pup L iv en Pup L iv en Pup L iven C ollection D ate 5/6/02 5/6/02 5/9/02 5/9/02 5/9/02 5/9/02 5/9/02 S/9/02 5/9/02 5/9/02 5/7/02 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 5/7/02 5/7/02 5/9/02 5/9/02 5/6/02 5/6/02 5/6/02 5/6/02 5/6/02 5/6/02 5/9/02 5/9/02 5/9/02 5/9/02 5/9/02 S/9/02 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 5/29/02 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 0926Q2BR 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*AnL) 7500 7210 19000 20000 15100 15300 14700 15100 2 7 .7 AA 2 5 .7 "' 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 ^ Although fhe 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 of 0.1 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 Exygw H> 19012 GROUP I. Fem ale 15 19012 GROUP I, Fem ale 15* 19012 GROUP I, Fem ale 16 19012 GROUP I, Fem ale 16* 19019 GROUP 1M ale 1 19019 GROUP 1, M ale 1* 19019 GROUP I, M ale 2 19019 GROUP I, M ale 2* 19019 GROUP I, M ale 3 19019 GROUP I, M ale 3* 19019 GROUP I, M ale 7 19019 GROUP I, M ale 7* 19019 GROUP 1, M ale* 19019 GROUP I. M aleS* 19019 GROUP 1, Fem ale 11 19019 GROUP I. Fem ale 11* 19019 GROUP I. Fem ale 12 19019 GROUP I, Fem ale 12* 19019 GROUP I, Fem ale 13 19019 GROUP I, Fem ale 13* 19019 GROUP I. Fem ale 14 19019 GROUP I, Fem ale 14* 19019 GROUP I, Fem ale 15 19019 GROUP I, Fem ale 15* 19021 GROUP I, M ale 1 19021 GROUP I. M ale 1* 19021 G R O U P!, M ale 2 19021 GROUP I, M ale 2* 19021 GROUP I, M ale 6 19021 GROUP I, M ale 6* 19021 GROUP I, M ale 8 19021 GROUP I, M ale 8* 19021 GROUP I. M ale 9 19021 GROUP I, M ale 9* 19021 GROUP I, Fem ale 11 19021 GROUP I, Fem ale 11* 19021 GROUP I, Fem ale 12 19021 GROUP I, Fem ale 12* 19021 GROUP I, Fem ale 13 19021 GROUP I, Fem ale 13* 19021 GROUP I, Fem ale 14 19021 GROUP I, Fem ale 14* 19023 GROUP I, M ale 1 19023 GROUP I, M ale 1* 19023 GROUP I, M ale 2 19023 GROUP I, M ale 2* 19023 GROUP 1, M ale 3 19023 GROUP I, M ale 3* 19023 GROUP I, M ale 6 19023 GROUP I. M ale 6* 19023 GROUP I, M ale 7 19023 GROUP l M ale 7* 0201933 0201933 D up Inj 0201934 0201934 D uplnj 0201935 0201935 D u p ln j 0201936 0201936 D uplnj 0201937 0201937 D upfaj 0201938 0201938 D up In) 0201939 0201939 D uplnj 0201940 0201940 D up lpj . 0201941 0201941 D uplnj 0201942 0201942 D up lpj 0201943 0201943 D up Inj 0201944 0201944 D up Inj 0201945 0201945 Dup Inj 0201946 0201946 D up Inj 0201947 0201947 Dup Inj 0201948 0201948 D up lpj 0201949 0201949 Dup lpj 0201951 0201951 Dup lpj 0201952 0201952 Dup Inj 0201953 0201953 D up Inj 0201954 0201954 D up Inj 0201955 0201955 Dup by 0201956 0201956 D up Inj 0201957 0201957 D up liy 0201958 0201958 D up Inj 0201959 0201959 D up Ini M atrix Pup liv er* P up L iv en Pup L iv en Pup L iv en Pup liv e n Pup L iv en Pup L iven Pup L iven Pup L iv en Pup L iv en P up L iven Pup L iv en Pup L iv en Pup liv e n Pup L iv en Pup L iv en Pup L iven Pup L iven Pup L iv en Pup L iv en Pup L iven Pup L iv en Pup L iven Pup L iv en Pup L iv en Pup L iv en Pup liv e n Pup L iv en Pup L iven Pup L iv en Pup L iv en Pup L iv en Pup L iven Pup L iv en Pup L iv en Pup L iv en Pup liv e n Pup L iv en P up L iven Pup L iv en Pup L iven Pup L iven P up L iv en Pup L iven P up L iven Pup L iven Pup L iven Pup L iv en Pup L iv en P up L iven Pup L iven Pup L iven C ottactk D ate 5129/02 5/29/02 5/29/02 5/29/02 S/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 S/30/02 5/30/02 5/30/02 S/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 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 S/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 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 Set N um ber 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 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B PFHS FomkI (ug/m L) ND ND ND ND ND ND ND ND 2 1 .7 113" 2 0 .5 1 8 .9 '"' ND ND ND ND ND ND 3 4 .0 3 0 .6 ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND 5 0 .6 5 3 .5 3 4 .0 3 7 .0 1 9 .6 2 4 .1 ND ND 3 0 .8 3 4 .0 **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 o f 0.1 ng/mL) Exygen Research Page 30 o f 153 418-028:PAGE G-31 Exygen Study No.: 023-072 Table IX. (cont'd). Summary of PFHS Residues in Rat Liver Samples Spouor ID 9 19023 GROUP I, Fem ale 8* 19023 GROUP I. Fem ale 9 19023 GROUP ! F em ale 9* 19023 GROUP I, Fem ale 10 19023 GROUP ! Fem ale 10* 19023 GROUP I, Fem ale 11 19023 GROUP I, Fem ale 11* 19023 GROUP 1, Fem ale 12 19023 GROUP I. Fem ale 12* 19021 GROUP I, Fem ale 10 19021 GROUP ! Fem ale 10* 19041 GROUP I, M ale 1 19041 GROUP I, M ale 1* 19041 GROUP I, M ale 2 19041 GROUP I, M ale 2* 19041 GROUP I, M ale 3 19041 GROUP I. M ale 3* 19041 GROUP I, M ale 4 19041 GROUP I, M ale 4* 19041 GROUP 1, M ale 5 19041 GROUP I, M ale S* 19041 GROUP I, Fem aleS 19041 GROUP l Fem ale 8* 19041 GROUP 1, Fem ale 9 19041 GROUP I. Fem ale 9* 19041 GROUP 1, Fem ale IS 19041 GROUP I, Fem ale 15* 19041 GROUP 1, Fem ale 16 19041 GROUP 1. Fem ale 16* 19041 GROUP I. Fem ale 17 19041 GROUP ! Fem ale 17* 19004 GROUP 0 . M ale 2 19004 GROUP II, M ale 2* 19004 GROUP 0 , M ale 3 19004 GROUP n . M ale 3* 19004 GROUP n , M ale 4 19004 GROUP n, M ale 4* 19004 GROUP n . M ale 5 19004 GROUP II, M ale 5* 19004 GROUP II, M ale 6 19004 GROUP H, M ale 6* 19004 GROUP 11. Fem ale 9 19004 GROUP U, Fem ale 9* 19004 GROUP 1 ! Fem ale 11 19004 GROUP 0 . Fem ale 11* 19004 GROUP n , Fem ale 15 19004 GROUP 11, Fem ale 15* 19004 GROUP O , Fem ale 16 19004 GROUP 0 , Fem ale 16* 19004 GROUP II. Fem ale 17 19004 GROUP n . Fem ale 17* E xygen n> 0201960 0201960 D up Inj 0201961 0201961 D u p ly j 0201962 0201962 D u p ly j 0201963 0201963 D u p ln j 0201964 0201964 D u p ln j 0201950 0201950 Dup by 0201965 0201965 Dup by 0201966 0201966 D u p ln j 0201967 0201967 D ap by 0201968 0201968 D up Inj 0201969 0201969 D ap by 0201970 0201970 Dup by 0201971 0201971 Dup Ud 0201972 0201972 Dup by 0201973 0201973 Dup by 0201974 0201974 Dup Inj 0202025 0202025 Dup by 0202026 0202026 Dup by 0202027 0202027 Dup by 0202028 0202028 Dup by 0202029 0202029 Dup by 0202030 0202030 Dup by 0202031 0202031 D u p lq j 0202032 0202032 Dup by 0202033 0202033 Dup by 0202034 0202034 Dup by M a trix P u p L iv ers P u p L iv ers P up L iv en P u p L iv ers P up L iv en P u p L ivers P u p L iv ers P up L iv en P u p L iv ers P ly) L iv e n P u p L iv ers Pup liv e n P u p L iv ers P u p L ivers P up L iv e n P up L iv e n Pup liv e n P up L iv en P u p L ivers Pup liv e n P up L iv e n P up L iv en P up L iv en P up L iv e n P up L iv e n P up L iv e n P u p L ivers Pup liv e rs P up L iv en Pup L iv e n P u p L iv ers P up L iv e n P u p L iv ers P up L iv e n Pup L iv en Piy> L iv ers P up L iv e n Pup liv e n P up L iv en P up L iv ers Pup liv e n P up L iv ers P u p L iv ers Pup liv e n P up L iv ers P up L iv e n P up L iv e n P up L iv e n P u p L iv ers P up L iv e n P up L iv e n P u p L iv ers C o llectio n D ate 5 /3 1 /0 2 5 /31/02 5/3 1 /0 2 5 /31/02 5 /3 1 /0 2 5 /3 1 /0 2 5 /31/02 5 /31/02 5 /31/02 5/3 1 /0 2 5 /29/02 5 /29/02 5 /31/02 5/3 1 /0 2 5 /31/02 5/3 1 /0 2 5 /31/02 5 /3 1 /0 2 5 /31/02 5 /31/02 5 /31/02 5/3 1 /0 2 5 /3 1 /0 2 5 /31/02 5/3 1 /0 2 5/3 1 /0 2 5 /31/02 5 /31/02 5/3 1 /0 2 5 /31/02 5 /31/02 5 /31/02 5 /31/02 5/3 1 /0 2 5/3 1 /0 2 5 /31/02 5 /31/02 5/3 1 /0 2 5 /31/02 5 /31/02 5 /3 1 /0 2 5 /31/02 5/3 1 /0 2 5 /31/02 5 /31/02 5 /3 1 /0 2 5 /31/02 5/3 1 /0 2 5 /31/02 5 /31/02 5 /31/02 5/3 1 A 2 Set N um ber 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B R 092702B R 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A R 100102A R 100102A .R 100102A R 100102A R 100102A R 100102A R 100102A R 100102A R 100102A R 100102A R I00102A R 100102A R 100102A R 100102A R 100102A R 100102A .R 100102A R 100102A R 100102A R PFH S F ew ad (u s/m L l ND ND ND ND ND ND ND ND ND ND ND ND ND ND 2 4 .4 AA 2 6 .6 2 6 .0 2 4 .7 ND ND ND ND ND ND 3 0 .6 3 0 .8 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 ^Although the method used allows for alternate sample volumes or weights and all die peak area responses are within die calibration curve limits, die 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 o f 0.1 ng/mL) Exygen Research Page 31 of 153 418-028:PAGE G-32 Exygen Study No.: 023-072 Table IX. (cont'd). Summary o f PFHS Residues in Rat Liver Samples S p o n so r E xygen m n> 19018 GROUP a M ale 1 0202050 19018 GROUP H, M ale 1* 0202050 D u p lq j 19018 GROUP n . M ale 4 0202051 19018 GROUP n , M ale 4* 19018 GROUP II, M ale 3 0202051 D up Inj 0202052 19018 GROUP II, M ale 5* 0202052 D up Inj 19018 GROUP O, M ale 6 19018 GROUP H, M ale 6* 0202053 0202053 D up Inj 19018 GROUP D, M ale 7 19018 GROUP n , M ale 7* 19018 GROUP D, Fem ale 9 0202054 0202054 Dup Inj 0202055 19018 GROUP n . Fem ale 9* 0202055 D op Iqj 19018 GROUP 0 , Fem ale 10 0202056 19018 GROUP n , Fem ale 10* 0202056 D up Iqj 19018 GROUP K, Fem ale 11 0202057 19018 GRO UP n , Fem ale 11* 0202057 D up Inj 19018 GROUP D , Fem ale 12 0202058 19018 GROUP n , Fem ale 12* 0202058 D up Inj 19018 GROUP n , Fem ale 14 0202059 19018 GRO UP n . Fem ale 14* 0202059 D up Iqj 19026 GROUP D, M ale 3 0202063 19026 GROUP H M ale 5* 19026 GROUP H, M ale 1 0202063 Dup Iqj 0202060 19026 GROUP n . M ale 1* 0202060 D u p lq j 19026 GROUP n . M ale 3 0202061 19026 GROUP n . M ale 3* 0202061 D up Inj 19026 GROUP II, M ale 4 0202062 19026 GROUP D, M ale 4* 0202062 D up by 19026 GROUP a M ale 7 0202064 19026 GROUP a M ale 7* 0202064 D u p lq j 19026 GROUP a Fem ale 12 0202065 19026 GRO UP a Fem ale 12* 0202065 D u p lq j 19026 GROUP a Fem ale 13 0202066 19026 GROUP a Fem ale 13* 0202066 D u p lq j 19026 GROUP a Fem ale 14 0202067 19026 GROUP a Fem ale 14* 19026 GROUP a Fem ale 15 19026 GROUP a Fem ale 15* 19026 GROUP a Fem ale 18 0202067 Dup Inj 0202068 0202068 D uplqj 0202069 19026 GROUP a Fem ale 18* 0202069 D up Inj 19036 GROUP a M ale 1 0202070 19036 GROUP a M ale 1* 0202070 D u p lq j 19036 GROUP a M ale 2 0202071 19036 GROUP a M ale 2* 19036 GROUP a M ale 4 0202071 D uplqj 0202072 19036 GROUP a M ale 4* 0202072 D u p lq j 19036 GROUP a M ale 5 0202073 19036 GROUP a M ale 5* 0202073 D u p lq j 19036 GROUP a M ale 6 0202074 19036 GROUP a M ale 6* 0202074 D up Inj 19036 GROUP a Fem ale 7 0202075 19036 GROUP a Fem ale 7* 0202075 D up Ini M a triz Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera PupU ven Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera C o llcctio B D ate 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 snm i 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5 0 9 /0 2 5/29/02 5/29/02 5/29/02 5/29/02 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 5/31/02 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 S et N um ber 100202A 100202A 100202A I00202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 10D202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 10O2O2AR 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 PFH S F o u n d f n |/n l^ 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 of0.1 ng/mL) Exygen Research Page 32 of 153 418-028:PAGE G-33 Exygen Study No.: 023-072 Table IX. (cont'd). Summary o f PFHS Residues in Rat Liver Samples Sponsor ID Exygen ID 19036 GROUP n . Fem ale 8 19036 GROUP H , Fem ale 8* 19036 GROUP 0 , Fem ale 11 19036 GROUP n , Fem ale 11* 19036 GROUP II, Fem ale 12 19036 GROUP II, Fem ale 12* 19036 GROUP O, Fem ale 13 19036 GROUP n , Fem ale 13* 19037 GROUP 0 , M ale 6 19037 GROUP 0 . M ale 6* 19037 GROUP II. Fem ale IS 19037 GROUP II, Fem ale IS* 19037 GROUP O, M ale 2 19037 GROUP H, M ale 2* 19037 GROUP H. M ale 3 19037 GROUP 11, M ale 3* 19037 GROUP n , M ale 7 19037 GROUP U, M ale 7* 19037 GROUP II, M ale 8 19037 GROUP n , M ale 8* 19037 GROUP II, Fem ale 10 19037 GROUP n , Fem ale 10* 19037 GROUP II, Fem ale 11 19037 GROUP U, Fem ale 11 * 19037 GROUP II, Fem ale 13 19037 GROUP O , Fem ale 13* 19037 GROUP II, Fem ale 14 19037 GROUP n . Fem ale 14* 19003 GROUP m , M ale 1 19003 GROUP ID, M ale 1* 19003 GROUP H I, M ale 3 19003 GROUP m , M ale 3* 19003 GROUP III, M ale 5 0202076 0202076 D ap by 0202077 0202077 D ap Inj 0202078 0202078 Dup by 0202079 0202079 Dup by 0202082 0202082 Dup by 0202089 0202089 D op Inj 0202080 0202080 Dup by 0202081 0202081 D ap by 20831983 0202083 Dup by 0202084 0202084 Dup Iqj 0202083 0202083 Dup by 0202086 0202086 Dup by' 0202087 0202087 Dup by 0202088 0202088 Dup by 0202119 0202119 Dup by 0202120 0202120 Dup by 0202121 19003 GROUP m , M ale 5* 19003 GROUP m , M ale 7 19003 GROUP III, M ale 7* 19003 GROUP H I, M ale 8 19003 GROUP m , M ale 8* 19003 GROUP DI, Fem ale 9 19003 GROUP in . Fem ale 9* 19003 GROUP m , Fem ale 10 19003 GROUP DI, Fem ale 10* 19003 GROUP m , Fem ale 11 19003 GROUP III, Fem ale 11* 19003 GROUP in , Fem ale IS 0202121 Dup by 0202122 0202122 Dup by 0202123 0202123 Dup Iqj 0202124 0202124 Dup by 020212S 0202125 Dup by 0202126 0202126 Dup by 0202127 19003 GROUP m , Fem ale IS* 19003 GROUP m , Fem ale 16 19003 GROUP m , Fem ale 16* 19007 GROUP HI, M ale 1 19007 GROUP H I, M ale 1* 19007 GROUP H I, M ale 2 19007 GROUP m , M ale 2* 0202127 D up Iqj 0202128 0202128 Dup Iqj 0202129 0202129 Dup Iqj 0202130 0202130 Dup by M atriz Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Piq) U vera Pup U vera Pup U vera Piq> U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Piq> U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera Pup U vera CoUectfoa D a ta 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/29/02 3/29/02 5/29/D2 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 29 /0 2 5/29/02 3/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5Q 9/02 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 5/30/02 5/30/02 5/30/02 5/30/02 Set N am ber 100302A 100302A 100302A 10Q302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302AR 100302AR 100302AR 100302AR 100302A R 100302AR 100302AR 100302AR 100302AR 100302AR 100302AR 100302AR 100302A R 100302A R 100302AR 100302AR 100402AR 100402A R 100402AR I00402A R 100402AR 100402AR 100402AR 100402AR 100402A R 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402A R 100402AR 100402AR 100402A R PFHS 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 of 0.1ng/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 Exygen n> ID 19007 GROUP m, M ale 3 0202131 19007 GROUP ffl, M ale 3* 0202131 D up b y 19007 GROUP H I, M ale 6 0202132 19007 GROUP m , M ale 6* 0202132 D up b y 19007 GROUP m, M ale 7 0202133 19007 GROUP H I. M ale 7* 0202133D u p Iq | 19007 GROUP m , Fem ale 9 0202134 19007 GROUP m . Fem ale 9* 0202134 D up b y 19007 GROUP m , F o n ale 11 0202135 19007 GROUP HI, Fem ale 11* 0202135 D up by 19007 GROUP IH , Fem ale 12 0202136 1907 GROUP m . Fem ale 12* 0202136 D ap Inj 19007 GROUP H I, Fem ale 13 0202137 19007 GROUP H I. Fem ale 13* 0202137 D ap by 19007 GROUP m . Fem ale 16 0202138 19007 GROUP m , Fem ale 16* 0202138 D up by 19008 GROUP m . M ale 1 0202139 19008 GROUP IH , M ale 1* 0202139 D ap b y 19008 GROUP DI, M ale 3 0202140 19008 GROUP m , M ale 3* 0202140 D up Inj 19008 GROUP m , M ale 4 0202141 19008 GROUP ID , M ale 4* 0202141 D up Inj 19008 GROUP m , M ale 6 0202142 19008 GROUP m . M ale 6* 0202142 D up Inj 19008 GROUP H I, M ale 7 0202143 19008 GROUP m , M ale 7* 0202143 D up Iqj 19008 GROUP m, Fem ale 9 0202144 19008 GROUP IH , Fem ale 9* 0202144 D ap Iqj 19008 GROUP m . Fem ale 10 0202145 19008 OROUP m . Fem ale 10* 0202145 D up btf 19008 GROUP m . Fem ale 11 0202146 19008 GROUP D I, Fem ale 11 * 0202146 D ap liy 19008 GROUP m , Fem ale 12 0202147 19008 GROUP H I, Fem ale 12* 0202147 D ap b y 19008 GROUP m , Fem ale 13 0202148 19008 GROUP H I. Fem ale 13* 0202148 D ap by 19013 GROUP m , M ale 1 0202149 19013 GROUP 111, M ale 1* 0202149 D up b y 19013 GROUP m , M ale 4 0202150 19013 GROUP m , M ale 4* 0202150 D up Iqj 19013 GROUP m , M ale 3 0202151 19013 GROUP IH , M aleS* 0202151 D ap by 19013 GROUP H I, M ale 6 0202152 19013 GROUP IQ , M ale 6* 0202152 D up Iqj 19013 GROUP H I, M ale 9 0202153 19013 GROUP m . M ale 9* 0202153 D up Iqj 19013 GROUP m . Fem ale 11 0202154 19013 GROUP HI, Fem ale 11* 0202154 D up by 19013 GROUP ffl. Fem ale 12 0202155 19013 GROUP H I, Fem ale 12* 0202155 D up ly i 19013 GROUP D l, Fem ale 13 0202156 19013 GROUP H I, Fem ale 13* 0202156 D up by M atrix Pup L iv en Pup Livers Pup L iven Pup L iv en Pup L iv en Pup L iven Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en P up L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L ivers Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L ivers Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iven Pup L iv en C etlectloa D a te 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/304)2 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 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 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/29/02 5/29/02 5/29/02 5/29/02 S/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 Set N um ber I00402A R 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402AR 100402BR 100402BR 100402BR 100402BR 100402BR I0 0 4 0 2 B R 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 10O4O2BR 100402BR 100402BR 100402BR I00402B R 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR 100402BR PFHS FwumK ic M U 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 4 t2 0 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 of 0.1 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 Exygen ID n > 19013 GROUP m , Fem ale 14 0202157 19013 GROUP O I, Fem ale 14* 0202157 D u p ln j 19013 GROUP IH . Fem ale 15 0202158 19013 GROUP D I, Fem ale 15* 0202158 D up bo 19015 GROUP m . M ale 1 0202159 19015 GROUP m . M ale 1* 0202159 D u p ln j 19015 GROUP m , M ale 3 190IS GROUP ID, M ale 3* 0202160 0202160 Dup by 19015 GROUPED, M ale 6 19015 GROUP ffl, M ale 6* 19015 GROUP m , M ale 7 0202161 0202161 D u p iq j 0202162 19015 GROUP in , M ale 7* 0202162 D up by 19015 GROUP H I, M ale 8 19015 GROUP ID ,M ale * 19015 GROUP m . Fem ale 10 19015 GROUP ID , Fem ale 10* 0202163 0202163 Dup by 0202164 0202164 Dup by 19015 GROUP m . Fem ale 12 0202165 19015 GROUP m , Fem ale 12* 0202165 D up b y 19015 GROUP m , Fem ale 13 0202166 19015 GROUP m . Fem ale 13* 0202166 D up by 19015 GROUP m . Fem ale 14 0202167 19015 GROUP D I, Fem ale 14* 0202167 D up by 19015 GROUP m . Fem ale IS 0202168 1901$ GROUP m , Fem ale 15* 0202168 D up by 19005 GROUP IV , M ale 1 19005 GROUP IV , M ale 1* 19005 GROUP IV , M ale 2 0202219 0202219 Dup by 0202220 19005 GROUP IV , M ale 2* 0202220 D up liy 19005 GROUP IV , M ale 3 0202221 19005 GROUP IV , M ale 3* 0202221 D up by 19005 GROUP IV , M ale 5 0202222 19005 GROUP IV , M ale 5* 0202222 D u p ln j 19005 GROUP IV , M ale 6 0202223 19005 GROUP IV , M ale 6* 19005 GROUP IV , F em ale 8 19005 GROUP IV , Fem ale 8* 0202223 D up by 0202224 0202224 Dup by 19005 GROUP IV , Fem ale 10 0202225 19005 GROUP IV , F o n ale 10* 0202225 D u p ln j 19005 GROUP IV , Fem ale 11 0202226 19005 GROUP IV , Fem ale 11* 0202226 D up by 19005 GROUP IV , Fem ale 12 0202227 19005 GROUP IV , Fem ale 12* 0202227 D up by 19005 GROUP IV , Fem ale IS 0202228 19005 GROUP IV , Fem ale 15* 0202228 D up Inj 19035 GROUP TV, M a le! 0202229 19035 GROUP IV , M ale 1* 0202229 D up lu j 19035 GROUP IV , M ale 2 0202230 19035 GROUP IV , M ale 2* 0202230 D up Inj 19035 GROUP IV , M ale 4 0202231 19035 GROUP IV , M ale 4* 0202231 D up Iqj 19035 GROUP IV , M ale 5 0202232 19035 GROUP IV , M ale 5 0202232 D up by M atrix PupU vcxe Pup Lven Pup Lven Pup lv en Pup lv en Pup lv en P u p lv en Pup lv en Pup lv en Pup lv en P u p lv en P q ) lv en Pup lv en Pup lv en Pup lven Pup lv en Pup lv en Pup lven P u p lv en Pup lven Pup lv en Pup lv en Piip l v e n Pup lv en Pup lv en P u p lv en Pup lven P u p lv en Pup lv en Pup lv en Pup lv en P u p lv en P u p lv en Pup lv en Pup lv en Pup U vera Pup U vera Pup lv en Pup lven Pup U vera Pup U vera Pup lv en Pup lv en Pup lv en Pup lv en Pup lv en Pup lv en Pup lv en Pup Lven Pup lven Pup lv en P u p lv en C oB ectioa D ate 5/29/02 5/29/02 5/29/02 5/29/02 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 5/31/02 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 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 Set Number 100402BR 1D0402BR 100402BR 100402BR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 1Q0902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902A R 1009Q2AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902AR 100902A R 100902AR 100902AR 100902AR 100902AR 100902AR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR PFHS Fm od b a M 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 11100 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 of 0.1 ng/mL) Exygen Research Page 35 of 153 418-028:PAGE G-36 Exygen Study No.: 023-072 Table IX. (coat'd). Summary of PFHS Residues In Rat Liver Samples Sponsor ID Exygen n> 19035 GROUP IV , M ale 6 0202233 19035 GROUP IV , M ale 6* 19035 GROUP IV , Fem ale 8 19035 GROUP IV , Fem ale 8 0202233 Dup Iqj 0202234 0202234 Dup hg 19035 GROUP IV , Fem ale 10 0202235 19035 GROUP IV , Fem ale 10* 0202235 D up Inj 19035 GROUP IV , Fem ale 11 0202236 19035 GROUP IV , Fem ale 11* 0202236 D up Inj 19035 GROUP IV , Fem ale 12 0202237 19035 GROUP IV , Fem ale 12* 0202237 D up Inj 19035 GROUP IV , Fem ale 13 0202238 19035 GROUP IV , Fem ale 13* 0202238 D up Inj 19039 GROUP r v , M ale 1 19039 GROUP IV , M ale 1* 19039 GROUP IV , M ale 2 0202239 0202239 D up Iqj 0202240 19039 GRO UP IV , M ale 2* 0202240 D up Iqj 19039 GROUP IV , M ale 3 0202241 19039 GROUP IV , M ale 3* 0202241 D up Inj 19039 GROUP IV , M ale 4 0202242 19039 GROUP IV , M ale 4* 0202242 D up by 19039 GROUP IV , M ale 5 0202243 19039 GROUP IV , M ale 5* 0202243 D up Inj 19039 GROUP IV , Fem ale 8 0202244 19039 GROUP IV , Fem ale 8* 0202244 D up by 19039 GROUP IV , Fem ale 11 0202245 19039 G RO UP IV , Fem ale 11* 0202245 D up Iq j 19039 GROUP IV , Fem ale 12 0202246 19039 GROUP IV , Fem ale 12* 0202246 D up Iqj 19039 GROUP IV , Fem ale 14 0202247 19039 GROUP IV , Fem ale 14* 0202247 D up Iqj 19039 GROUP IV , Fem ale 15 0202248 19039 GROUP IV , Fem ale 15* 0202248 D up Inj 19040 GROUP IV , M ale 2 0202249 19040 G RO UP IV , M ale 2* 0202249 D up Iqj 19040 GRO UP IV , M ale 3 0202250 19040 GROUP IV , M ale 3* 0202250 D up Inj 19040 GROUP IV , M ale 4 0202251 19040 GROUP IV , M ale 4* 0202251 D up Inj 19040 GROUP IV , M ale 5 0202252 19040 GROUP IV , M ale 5* 0202252 Dup Iqj 19040 GROUP IV , M ale 7 0202253 19040 GROUP IV , M ale 7* 0202253 D up Iqj 19040 GROUP IV , Fem ale 11 0202254 19040 GROUP IV , Fem ale 11* 0202254 D up Inj 19040 GROUP IV , Fem ale 12 0202255 19040 GROUP IV , Fem ale 12* 0202255 D up Iqj 19040 GROUP IV , Fem ale 13 0202256 19040 GROUP IV , Fem ale 13* 0202256 D up Iqj 19040 GROUP IV , Fem ale 15 0202257 19040 GROUP IV , Fem ale 15* 0202257 D up Iqj 19040 GRO UP IV , Fem ale 16 0202258 19040 GROUP IV . Fem ale 16* 0202258 D up Iqj M atrix Pop lven Pup Lven Pup Lven Pup Lven Pup Lven P u p lv en P u p lv en Pup lv en Pup Lven Pup Lven Pup Lven Pup lven Pup Lven Pup Lven Pup Lven Pup lv en Pup lv en Pup lven P u p lv en Pup lv en Pup lv en Pup Lven P u p lv en Pup lven Pup Lven P u p lv en Pup Lven Pup lv en Pup lv en Pup Lven Pup Lven Pup lv en P u p lv en Pup Lven Pup Lven P u p lv en Pup lv en Pup lv en Pup lv en Pup Lven Pup Lven Pup Lven Pup Lven Pup Lven Pup Lven Pup Lven P u p lv en Pup Lven Pup Lven Pup Lven Pup Lven Pup Lven CoUecttnn D a te 5/31/02 5/31/02 5/31/02 5/31/02 . 5/31/02 5/31/02 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 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 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5/29/02 5 0 0 /0 2 5 0 0 /0 2 5 0 0 /0 2 5 0 0 /0 2 5 0 0 /0 2 5 0 0 /0 2 5 0 0 /0 2 5 0 0 /0 2 5 0 0 /0 2 5 0 0 /0 2 5 0 0 /0 2 5 0 0 /0 2 5 0 0 /0 2 5 0 0 /0 2 5/30/02 5 0 0 /0 2 5 0 0 /0 2 5 0 0 /0 2 5/30/02 5 0 0 /0 2 Set N um ber 100902BR IQQ9Q2BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR I00902B R 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR 100902BR I01002A R 101002A R 101002AR 101002AR 101002AR 101002AR 101002AR 10100ZAR 10I002A R 101002AR 101002AR 101002AR 101002A R I0I002A R 101002AR 10I002A R 101002AR 101002AR 101002AR 101002A R FFHS Fm w dtaa/m l.-i 10600 10500 12000 13300 10000 10400 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 11100 12100 11200 10600 10700 14100 14000 12400 12300 14900 15700 * Duplicate Injection ND = Not Detected (Area less than lowest calibration standard of0.1 ng/mL) Exygen Research Page 36 of 153 418-028:PAGE G-37 Exygen Study No.: 023-072 Table IX . (cont'd). Summary o f PFHS Residues in Rat Liver Samples Sponsor ID K q iea ID 19045 GROUP IV , M ale 1 0202259 19045 G RO U P IV . M ale 1* 0202259 D up Iqj 19045 GROUP IV . M ale 2 19045 GROUP IV , M ale 2* 19045 GROUP IV . M ale 4 0202260 0202260 D up Iqj 0202261 19045 GROUP IV , M ale 4* 0202261 D up Iqj 19045 GROUP IV . M ale 5 19045 GRO UP IV . M ale 5* 19045 GROUP IV , M ale 6 0202262 0202262 D up Iqj 0202263 19045 GRO UP IV , M ale 6* 0202263 D ap by 19045 GROUP IV , Fem ale 8 0202264 19045 GROUP IV , Fem ale 8* 0202264 D ap Iqj 19045 GRO UP IV , Fem ale 9 0202265 19045 GRO UP IV . Fem ale 9 0202265 D ap Iqj 19045 GROUP IV , Fem ale 10 0202266 19045 GRO UP IV , Fem ale 10* 0202266 D ap Iqj 19045 GRO UP IV , Fem ale 11 0202267 19045 GROUP IV , Fem ale 11 * 0202267 D up Iqj 19045 GROUP IV , Fem ale 14 0202268 19045 GRO UP IV , Fem ale 14* 0202268 D up Iqj 19006 GROUP V , M ale 1 0202320 19006 GROUP V . M ale 1* 0202320 D up Iqj 19006 GROUP V , M ale 2 19006 GROUP V , M ale 2* 0202321 0202321D upIq 19006 G RO UP V , M ale 3 0202322 19006 GROUP V , M ale 3* 0202322 D up toj 19006 GROUP V , M ale 4 19006 GROUP V , M ale 4* 19006 G RO UP V , M ale 5 19006 GROUP V , M ale 5* 0202323 0202323 D ap Iqj 0202324 0202324 Dup Inj 19006 GROUP V , Fem ale 8 0202325 19006 GROUP V , Fem ale 8* 0202325 D ap Iqj 19006 GROUP V , Fem ale 10 0202326 19006 GROUP V , Fem ale 10* 0202326 D up Iqj 19006 GROUP V , Fem ale 11 0202327 19006 GROUP V , Fem ale 11* 0202327 D up Iqj 19006 GROUP V , Fem ale 13 0202328 19006 GROUP V , Fem ale 13* 0202328 D ap Iqj 19006 GROUP V , Fem ale 18 0202329 19006 GRO UP V , Fem ale 18* 0202329 Dup Iqj 19011 GROUP V , M ale 2 0202330 19011 GROUP V , M ale 2* 0202330 D up Iqj 19011 GROUP V , M ale 3 19011 GROUP V , M ale 3* 0202331 0202331 Dup Iqj 19011 GROUP V , M ale 4 0202332 19011 GROUP V , M ale 4* 0202332 D up Iqj 19011 GROUP V , M ale 5 0202333 19011 GROUP V , M ale 5* 0202333 Dup Iqj 19011 GROUP V , M ale 6 0202334 19011 GROUP V , M ale 6* 0202334 D ap Iqj 19011 GROUP V , Fem ale 9 0202335 19011 GROUP V , Fem ale 9* 0202335 Dup Inj M atrix P up L iv en P ap L iv en P up Livers Pup L iv en Pup L iv en Pup Livers Pup L iv en Pup L iv en P ap L iv en P ap L iven P ap L iv en Pup L iv en Pup L iv en Pup L iv en Pup liv e n Pup L iv en Pup L iv en Pup L iven Pup L iv en Pup liv e n Pup liv e n Pup L iv en Pup L iv en Pup L iv en Pup L iven Pup U ven Pup L iv en Pup L iv en Pup L iv en Pup L iv en P ap L iv en Pup L iv en P ap L iv en P ap L iv en Pup L iven Pup L iv en Pup L iv en Pup L iven Pup L iven Pup L iv en Pup L iven Pup L iv en P up L iven Pup L iven Pup L iv en Pup L iv en P up L iv en P up L iven Pup L iv en Pup L iv en P ap L iven Pup L iven CoBcctfcm D ata 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 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 5/28/02 sana sama 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 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 0 1 /0 2 5/31/02 5/31/02 Set N um ber 101002AR 101002AR 101002AR 101002AR 1010Q2AR 101002AR 101002AR I01002A R 101002AR 101002A R 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 101002AR 10I002A R 101002AR 101002BR 101002BR 1 0 I002B R 101002BR 101002BR 101002BR 101002BR 101002BR 10I002B R 101002BR 101002BR 10I002B R I0 1002B R 101002BR 101002BR IO I002B R 101002BR 101002BR 101002BR 101002BR I0 1002B R 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR 101002BR PFHS V a u S ta k L ) 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 of 0.1 ng/mL) Exygen Research Page 37 of 153 418-028:PAGE G-38 Exygen Study No.: 023-072 Table IX. (cont'd). Summary of PFHS Residues in Rat Liver Samples S p ontr ID Exygca ID 19011 GROUP V , Fem ale 10 0202336 19011 GROUP V , Fem ale 10* 0202336 D up Inj 19011 GROUP V . Fem ale 11 0202337 19011 GROUP V . Fem ale 11* 0202337 D up Iqj 19011 GROUP V , Fem ale 12 0202338 19011 GROUP V , Fem ale 12* 0202338 D u p lq j 19011 GROUP V , Fem ale 13 0202339 19011 GROUP V, Fem ale 13* 0202339 D up Iqj 19020 GROUP V , M ale 2 0202340 19020 GROUP V . M ale 2* 0202340 D uplat) 19020 GROUP V , M ale 4 0202341 19020 GROUP V . M ale 4* 19020 GROUP V , M ale 5 19020 GROUP V . M ale 5* 0202341 Dup by 0202342 0202342 D uplq} 19020 GROUP V , M ale 7 0202343 19020 GROUP V , M ale 7* 0202343 D up Iqj 19020 GROUP V .M ale 8 0202344 19020 GROUP V . M ale 8* 0202344 D up Iqj 19020 GROUP V , Fem ale 9 02021345 19020 GROUP V, Fem ale 9* 0202345 D up Iqj 19020 GROUP V , Fem ale 10 0202346 19020 GROUP V , Fem ale 10 0202346 D up Inj 19020 GROUP V. Fem ale 11 0202347 19020 GROUP V , Fem ale 11* 0202347 D up Iqj 19020 GROUP V , Fem ale 12 0202348 19020 GROUP V , Fem ale 12* 0202348 D up Inj 19020 GROUP V . Fem ale 13 0202349 19020 GROUP V , Fem ale 13* 0202349 D up Iqj 19022 GROUP V , M ale 1 0202350 19022 GROUP V , M ale 1* 0202350 D up Iqj 19022 GROUP V .M ale4 0202351 19022 GROUP V .M ale4* 0202351 D up lq j 19022 GROUP V .M ale 5 0202352 19022GROUP V .M ale3* 0202352 D up Iqj 19022GROUP V .M ale7 0202353 19022 GROUP V .M ale 7* 0202353 D up Iqj 19022 GROUP V .M ale8 19022 GROUP V . M ale 8* 0202354 0202354 Dup by 19022 GROUP V , Fem ale 11 0202355 19022 GROUP V , Fem ale 11* 0202355 D up Iqj 19022 GROUP V. Fem ale 12 0202356 19022 GROUP V ,F em ale 12* 0202356 D up In j 19022 GROUP V, Fem ale 13 0202357 19022 GROUP V , Fem ale 13* 0202357 D up Iqj 19022 GROUP V , Fem ale 14 0202358 19022 GROUP V . Fem ale 14* 0202358 D up Iqj 19022 GROUP V, Fem ale IS 0202359 19022 GROUP V , F em ale 15* 0 2 0 2 3 5 9 D u p lq 19025GROUP V .M ale2 0202361 19025 GROUP V .M ale 2* 0202361 D u p lq j 19025 GROUP V .M ale7 0202362 19025 GROUP V .M ale 7* 0202362 D up Ini M atrix Pup L ivers Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en P up L ivers Pup L iv en Pup L iv en Pup L iv en Pup L iv en P u p L iv m Pup L iv en Pup liv e n Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L ivers Pup L iven Pup L iv en Pup L iv en Pup L iv en Pup L iven Pup L iv en Pup Livers Pup L iv en Pup L iven Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en P ip L iven Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en Pup L iv en P u p liv en Pup L iven P up L iv en Pup L ivers Pup L iv en C oB ectien D ate 5/31/02 5/31/02 501 /0 2 5 0 1 /0 2 501 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 501 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 $ 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 1 /0 2 5 0 0 /0 2 5 0 0 /0 2 5 0 0 /0 2 5 0 0 /0 2 Set Number 101002BRR 101002BKR 101002BRR 101002BRR I01002B R R 101002BRR 101002HRR 101002BRR 10I102A R 101102AR 101102AR 101102AR 10U 02A R 101102AR 101102AR 10I102A R 1Q1KOAR 10U 02A R 101102AR 101102AR 10U 02A R 101102AR 10U 02A R 10I102A R 10I102A R 101102AR 101102AR 101102AR 10U 02A R 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 101102AR 10I102A R 10I102A R 101102AR 101102AR 101102AR 101102AR 101102AR 1011O2AR 101102AR 101102AR 101102AR 101102AR 101402AR 101402AR 101402AR 101402AR PFHS Found (ao/atL ) 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 1110Q 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 of 0.1 ng/mL) Exygen Research Page 38 of 153 418-028:PAGE G-39 Exygen Study No.: 023-072 Table IX. (cont'd). Summary o f PFHS Residues in Rat Liver Samples Sponsor m 19025 GROUP V , M ale* 19025 GROUP V , M ile* * 19025 GROUP V , M ale 13 19025 GROUP V . M ale 13* 19025 GROUP V . P an ale 14 19025 GROUP V , Fem ale 14* 19025 GROUP V , F o n ale 15 19025 GROUP V , Fem ale 15* 19025 GROUP V , F o n d e 18 19025 GROUP V . Fem ale 18* 19025 GROUP V . Fem ale 19 19025 GROUP V , Fem ale 19* 19025 GROUP V , Fem ale 20 19025 GROUP V , Fem ale 20* 19025 GROUP V . M ale 1 19025 GROUP V , M ale 1 Esygen n> 0202363 0202363 Dop bq 0202364 0202364 D uplnj 02021365 0202365 D uplnj 0202366 0202366 D uplnj 0202367 0202367 D u p ln j 0202368 0202368 Dup by 0202369 0202369 Dup by 0202360 0202360 Dup bo M atrix Pup L iv en Pup L iv en Pup L ivers Pup L iv en Pup L iv en Pup L iv en P up L iv en Pup L iv en Pup Livers Pup liv ers Pup liv ers Pup liv ers Pup L iv en Pup L iv en Pup L iv en Pup L iven C ollection D o te 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 0 0 /0 2 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 5/30/02 Set N uotar 101402A R 1014Q2AR 101402A R 101402AR 101402AR 101402AR 101402AR 101402AR 101402AR 101402AR 101402AR 101402AR 101402AR 101402AR 101402A K R I01402A RR PFHS F enod (nx/auL) 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 o f 0.1 ng/mL) Exygen Research Page 39 of 153 418-028:PAGE G-40 Exygen Study No.: 023-072 Table X. Summary of PFHS Residues in Dosing Solutions Sam ple D eK ripttM B -4 1 8 -0 2 8 -A (0 7 Ju n .0 2 )0 m g/m L 1 o f 4 B -4 18-028-A (07Jim .02) 0 m g/m L 1 o f 4 B -418-028-B (24.M ay.02) 0.03 m g/m L 1 o f 4 B -418-028-B (24.M ay.02) 0 .03 m g/m L 1 o f 4 B -418-028-C (24.M ay.02) 0.1 m g/m L 1 o f 4 B -418-028-C (24.M ay.02) 0.1 m g/m L 1 o f 4 B-418- 28-D (07Ju n .0 2 ) 0 .3 mgAnL 1 o f4 B -418-028-D (07 Ju n .0 2 ) 0 .3 m g/m L 1 o f 4 B -418-028-E (24.M ay.02) 1 m g/m L 1 o f 4 B -418-028-E (24.M ay.02) 1 m g/m L 1 o f 4 B ulk T A /S Sam ple (09Ju n .0 2 ) B ulk T A /S Sam ple (09Ju n .0 2 ) Set N um ber 110702C 1I0702C 110702C 110702C 110702C 110702C 110702C 110702C 110702CR 110702CR 110702C 110702C PFHS PFHS PFHS Km w b C oncentration (ng/m L) Found (ng/m L) R ecovery (% ) 0 ND . 0 ND . 30000 26500 88 30000 27300 91 100000 88900 89 100000 91000 91 300000 268000 89 300000 1000000 1000000 278000 1010000 1000000 93 101 100 100000 100000 125000 122000 125 122 ND = Not Detected (Area less than lowest calibration standard o f 0.1 ng/mL) Exygen Research Page 40 of 153 418-028:PAGE G-41 Exygen Study No.: 023-072 Table XI. Summary o f PFHS Residues in Stability Samples 3M m 602-0514-38611 602-0514-38611* 6024)514-38612 E02-0514-38612* 602-0514-38613 602-0514-38613* 602-0514-38614 602-0514-38614* 602-0514-38615 E02-0514-38615* 602-0514-38616 602-051438616* E02-0514-38617 602-051438617* 602-051438618 602-051438618* 602-051438619 602-051438619* 602-051438620 602-051438620* E xjw m 0203923 0203923 D opili 0203924 0203924 Dap by 0203923 020392$ Dap fay 0203926 0203926 Dyp by 0203927 0203927 Dap fay 0203928 0203928 Dap by 0203929 0203929 Dap fay 0203930 0203930 Dnptaj 0203931 0203931 Dnp by 0203932 0203932 DudW S e n p ie S d o fa ta 64184128 A (29 MarGZ)0ai8taL 1of4 6418-828 A (29 fatar02)0 ay/nL 1of4 64184)28 A (19 fatar02)0aM L 2 of4 6418-028 A (29 fatar02)0 msW . 2 of4 64184128 B (29 fatar02)0.03 inptaL 1of4 6-418-028 B (29 fatar02)0.03 OBybal. 1of4 64184)28 B (29 fatar02) 0.03 ra*taL2of4 B-418-028 B (29 fatar02) 0.03 aWL 2 of4 B-418-028 C (29 fatar 02) O .lia p b L I of4 64184)28 C (29 fatar 02) 0.1 n*/mL 1of4 64184128 C (29 fate 02) 0.1 mglmL 2 of4 6418-028 C (29 fatar02) 0.1 a |M L 2 of4 B-418-028 D (29 Mar 02)0.3 m tfaL 1of4 B-418-028 D (29 fatar02)0.3 KtgbnL 1of4 B-418-028 D(29 Mar 02) 0J n y M .2 of4 B418-028 D (29 fatar02) 03 oWL 2 at4 B-4184128 6(29 Mar 02) 1mgtaL 1 of4 6418-028 B (29 fatar02) 1m t/aL 1of4 6418-028 6 (29 M v02) 1agM L2 0f4 B-418-028 6(29 Mar02) 1 mK/mL2of4 Set N w bor 11Q502A 110502A 110502A 110502A 110502A 110902A 110S02A 110502A 1105Q2A 110502A 110502A 110502A I10J02A 1105Q2A 110502A 110502A 110702AR I10702AK 110702AR 110702AR PFHS K aaira Coae. 8 0 0 0 30000 30000 30000 30000 100000 100000 100000 100000 300000 300000 300000 300000 1000000 1000000 1000000 1000000 PFHS Foaad (asftaL ) 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 too 103 105 109 108 91 92 103 101 * Duplicate Injection ND - Not Dctccted (Area lesa than lowest calibratimi standard o f 0.1 ng/mL) Exygen Research Page 41 of 153 418-028:PAGE G-42 Exygen Study No.: 023-072 Table XII. Summary o f PFHS Residues in Homogeneity Samples 3M ID E02-0514-38621 E02-O514-38621* E02-0514-38622 B02-0514-38622* 02-0514-38623 E02-0514-38623* E02-0514-38624 02-0514-38624* B02-0514-38625 02-0514-38625* 02-0514-38626 02-0514-38626* G02-0514-38627 02-0514-38627* 02-0514-38628 02-0514-38628* 02-0514-3862 02-0514-38629* 02-0514-38630 02-0514-38630* E02-0514-38631 02-0514-38631* 02-0514-38632 02-0514-38632* 02-0514-38633 02-0514-38633* 02-0514-38634 02-0514-38634* G02-0514-38635 02-0514-38635* 02-0514-38636 02-0514-38636* 02-0514-38637 E02-0514-38637* 02-0514-38638 02-0514-38638* 02-0514-38639 02-0514-38639* 02-0514-38640 02-0514-38640* 02-0514-38641 02-0514-38641* 02-0514-38642 02-0514-38642* 02-0514-38643 02-0514-38643* 02-0514-38644 E02-0514-38644* 02-0514-38645 02-0514-38645* 02-0514-38646 02-0514-38646* 02-0514-38647 02-0514-38647* E02-05I4-38648 02-0514-38648* 02-0514-38649 B02-0514-38649* 02-0514-38650 02-0514-38650* Exygem ID S am ple D m d p th w Set N um ber 0203933 0203933 Dup by 0203934 0203934 Dup by 0203935 0203935 Dop Inj 0203936 0203936 Dup lnj B -418-028-A {29M m 02) 0 m g/m L 1 o f 12T B -418-028-A (29M ar02) 0 m g/m L 1 o f 12T B -418-028-A (2 9 M v 0 2 ) 0 m g/m L 2 o f l2 T B -4 18-028-A (29M sr02) 0 m g/m L 2 o f 12T B -418028-A (29M ai02) 0 mg/mL 5 o fl2 M B -4 18-028-A (2 9 M s0 2 ) 0 m g/m L 5 o fl2 M B -418-028-A (29M arf)2) 0 ag/m L 6 o f 12M B -418-028-A (29M arf)2)0 m g/m L 6 o f 12M 110702A 110702A 110702A 110702A 110702A 110702A 110702A 110702A 0203937 B -418-028-A (29M ar02) 0 m g/m L 9 o f 12B 0203937 Dup Iqj B -418-028-A (29M ar02) 0 m g/m L 9 o f 12B 110702A 110702A 0203938 B -418-028-A (2 9 M u 0 2 ) 0 mgAnL 10 o f 12B 110702A 0203938 Dqp by B -418-028-A (29M ai02) 0 m g/m L 10 o f 12B 110702A 0203939 B -418-028-B (29M ar02) 0.03 m g/m L 1 o f 12T 110702A 0203939 Dup lnj B -418-028-B (2 9 M a0 2 ) 0.03 m g/m L 1 o f 12T 110702A 0203940 B -418-028-B (2 9 M n 0 2 ) 0.03 m g/m L 2 o f 12T 0203940 Dup Inj B -418-028-B (29M 02) 0.03 m g/m L 2 o fl2 T 0203941 B -418-028-B (2 9 M n 0 2 ) 0.03 m g/m L 5 o f I2 M 0203941 Dq> Iqj B -418-028-B (2 9 M a0 2 ) 0.03 m g/m L 5 o f 12M 0203942 B -418-028-B (29M m 02) 0.03 m g/m L 6 o f 12M 0203942 Dup Iqj B -418-028-B (2 9 M o 0 2 ) 0.03 m g/m L 6 o f l2 M 0203943 B-418-028-B (29M at02) 0.03 mg/mL 9 o f 12B 0203943 Dup Iqj B -418-028-B (29M ui02) 0.03 m g/m L 9 o f 12B 0203944 B -418-028-B (2 9 M u 0 2 ) 0.03 m g to L 10 o fl2 B 0203944 Dup Iqj B -4 1 8 -0 2 8 B (29M m 02) 0.03 m g/m L 10 o f 12B 0203945 B -418-028-C (29M m 0 2 ) 0.1 mg/mL 1 o f 12T 110702A 110702A 110702A 110702A 110702A 110702A J10702A I10702A 110702A 110702A 110702A 0203945 Dup Iqj B -418-028-C (29M m 02) 0.1 m g/m L 1 o f 12T 110702A 0203946 B -418-028-C (29M i02) 0.1 m g/m L 2 o f 12T I10702A 0203946 Dup Iqj B -4I8-028-C (29M m 02) 0.1 m g/m L 2 o f 12T 110702A 0203947 B -418-028-C (29M m 02) 0.1 m g/m L 5 o f 12M 110702A R 0203947 Dup Iqj B -418-028-C (29M ar02) 0.1 m g/m L 5 o f 12M 110702A R 0203948 B -418-028-C (29M 02) 0.1 m g/m L 6 o f 12M 110702A 0203948 Dup Iqj B -418-028-C (29M art>2) 0.1 m g/m L 6 o fl2 M 110702A 0203949 B -418-028-C (29M ar02) 0.1 m g/m L 9 o f 12B 110702A 0203949 Dup Iqj B -418-028-C (29 M m 0 2 )0 .1 m g /m L 9 o f 12B 110702A 0203950 B -418-028-C (2 9 M 0 2 ) 0.1 m g/m L 10 o f 12B 110702A R 0203950 Dup Iqj B -418-028-C (2 9 M u 0 2 ) 0.1 m g/m L 10 o f 12B 110702A R 0203951 B -418-028-D (2 9 M n 0 2 ) 0.3 m g/m L 1 o f 12T 110702A 0203951 Dup Inj B -418-028-D (2 9 M n 0 2 ) 0.3 m g/m L 1 o f 12T I10702A 0203952 B -418-028-D (29M ai02) 0.3 m g/m L 2 o f 12T 110702A 0203952 Dup Iqj B -418-028-D (29M ar02) 0.3 m g/m L 2 o f I2 T 110702A 0203953 B -418-028-D (29M ar02) 0.3 m g/m L 5 o f 12M 110702B 0203953 Dup Iqj B -418-028-D (29M at02) 0.3 m g/m L S o f 12M 110702B 0203954 B -418-028-D (29M m 02) 0.3 m g/m L 6 o f 12M 110702B 0203954 Dup Iqj B -418-028-D (29M n02) 0 3 m g/m L 6 o f 12M 110702B 0203955 B -418-028-D (29M ai02) 0.3 m g/m L 9 o f 12B 110702B 0203955 Dup lnj B -418-028-D (29M m 02) 0.3 m g/m L 9 o f 12B 110702B 0203956 B-41B-028-D (29M ju02) 0 .3 m g/m L 10 o f 12B 110702B 0203956 Dup Iqj B -418-028-D (2 9 M n 0 2 ) 0 .3 m g/m L 10 o fl2 B 110702B 0203957 B -418-028-H (29M m 02) 1 m g/m L 1 o f 12T 110702B 0203957 Dup Iqj B -418-028-E (29M ai02) I m g/m L 1 o f 12T 110702B 0203958 B -418-028-E (29M m 02) 1 m g/m L 2 o f I2 T 110702B 0203958 Dup Inj B -418-028-E (29M ar02) 1 m g /m L 2 o fl2 T 0203959 B -418-028-E (29M ai02) 1 m g/m L i o f 12M 110702B 110702B 0203959 Dup Iqj B -418-028-E (29M ai02) 1 m g/m L S o f 12M 110702B 0203960 B -4 18-028-E (29M m 02) 1 m g/m L 6 o f 12M 110702B 0203960 Dup by B -418-028-E (2 9 M u 0 2 ) 1 m g/m L 6 o f 12M 110702B 0203961 B -418-028-E (29M ai02) 1 m g/m L 9 o f 12B I10702B 0203961 Dup Iqj 0203962 0203962 Dup Iqj B -418-028-E (29M m 02) 1 m g/m L 9 o f 12B B -418-028-E (29M m 0 2 ) 1 m g/m L 10 o f 12B B -418-028-E (2 9 M u 0 2 ) 1 m g/m L 10 o f 12B 1I0702B 110702B 110702B PFHS K nown Coac. < ua/*L > 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 300000 300000 300000 300000 300000 300000 300000 300000 1000000 1000000 1000000 1000000 1000000 1000000 1000000 1000000 1000000 1000000 1000000 1000000 PFHS F m um I (SM L) 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 nooooo 1110000 1070000 PFHS R ecovery (% ) 81 7 90 8$ 85 87 86 86 81 81 83 82 75 74 76 75 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 of 0.1 ng/mL) Exygen Research Page 42 of 153 418-028.PAGE G-43 Exygeu Study No.: 023-072 FIGURES Exygen Research Page 43 o f 153 418-028:PAGE G-44 Exygen Study No.: 023-072 F ig u re 1. T y p ical C a lib ra tio n C u rv e fo r P F H S 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: 1fx, Arts trans: None Exygen Research Page 44 of 153 418-028:PAGE G-45 Exygen Study No.: 023-072 F ig u re 2 . C h ro m a to g ra m R e p re s e n tin g a 0.1 n g /m L s ta n d a r d f o r PFHS C0929O24B,0.1 ngfrnL Standard 0019028*2012 Sm (Mn. 2x3) 10Ch 21*Sap*20Q21*34:30 Lcssfifl#y M R M ef 1 Channel ES390 >80 4 21 *3 V 1 .0 0 2.0 0 3 .0 0 4X0 5 .0 0 6X0 7 .0 0 ^ 8 p ^ <^ A *H v ^ >fi>rf><irCiVrVWi.K ^W K T im . 8.00 8.00 10X0 11X0 1X00 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 I 17-ep-2M 22:32:3* L C M M K fr Exygen Research Page 46 of 153 418-028:PAGE G-47 Exygen Study No.: 023-072 F ig u re 4. C h ro m ato g ram R ep resen tin g a C o n tro l R a t S erum S am p le fo r P F H S (E xygen ID : 0202987 C o n tro l, D a ta S et: 091902B) Exygen Research Page 47 of 153 418-028:PAGE G-48 Exygen Study No.: 023-072 F ig u re 5. C h ro m ato g ram R ep resen tin g a C o n tro l R a t L iv e r S am p le fo r P F H S , (E xygen ID : 0202877 C o n tro l, D ata S et: 100202A ) 0202877 Control VOct-2002 08:12:18 LC M M SC T 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: 091602B) 0202313 Spk A, IS ppb 17-*p-2002 23:14:44 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 o f PFHS (Exygen ID: 0202987 Spk A, Data Set: 091902B) 02029*7 Spk A, 10 p |* 0910029-2009 3m(Mo.2x3) 21-Sp-20Q2 09:29:14 LCAISAW 47 MRMoflChmalES- 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 o f PFHS (Exygen ID: 0202877 Spk A, Data Set: 100202A) (02*7785* A, 10 ppb 10020Z*r209 3m (Mn,23) 0 3 0 0 -2 0 0 2 0 *3 3 :5 7 LC M 8M 807 MRMo# 1Charm* ES- Exygen Research Page 51 of 153 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) 020181* 0916QQ&-212 Sm (Mnr 2k3) 1 M p J 0 0 2 00:41:24 iaunmn t MRMof 1Channel E5- 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=10 (Exygen ID: 0201863, Sponsor ID: 19079 GROUP D , Data Set: 091902BR) 0201863, D F 1 0 24-8*1-2002 02.90:13 LCM 8M 807 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 10Q2Q2A-213Sm (Mn,2x3) 10O-i ta 21840 0VOCU29021 0*0 :5 2 LC A NM M #7 MRM o fl Channel ES- 369>00 1.1085 %- 11I " i>i| i'i-i i* n i p|f " ir ' 1.00 2.00 aoo i '*'"H' ' 4D0 5.00 Too 6.QQ 9.00 WLflO iiS" 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 M5SMrOiftl%A IW 4 T ^ tp h tm (ilS )4 O 8 7 l0 7M *k ( ili) *0-85*7 PROTOCOL 418408 ARGUS RESEARCH U KVi S n W r U HM M wOrKI ,Ssrtdoss STUDYTITLE: SPONSOR'SSTUDYNUMBER: T-7706.1 Oral (Garage) CombinedRepealedDose ToxicityStudyofT-7706with the Reproduction/Dcvelopmental ToxicityScreeningTot PURPOSE: Thepuipoee ofthis studyis toprovideinformationan thepossiblehealth hazards thatmayrecult fromrepeatedexposureofCrl;CDO(SD)IGSBR VAF/Phmaleandfemalertfs toatestsubstancebeginningbefore cohabitation, throughmatingandcootiiuiingfor at lent 42 days (mate rata)orthroughparturitionuntilday21 oflactation(femalerata). This repeateddosestudyincorporatesa reproduction/deVBtopinentaltoxicity screeningtest thatcanbeusedtoprovideinitial information onpossible effectsonmaleand femalereproductiveperformance(e.g^ gonadal taction, matingbehavior, conception, developmentofthe oonceptu*and parturition). Thestudyalsoplaces emphasisonneurological effects as a specific endpoint and should identifytheneorotoxicpotential ofa test substance, whichmaywarrant furtherin-depthinvestigation. TESTING FACILITY: Becauseofthe selectivityoftheendpointsanddie shortdurationofthe study, the screeningtestwillnotprovideevidencefor definitiveclaims of no reproduction/developmentaleffects. Inparticular, it oShraonlyHmited meansofdetectingpostestri manifestationsofprenatal exposureorSects thatmaybe inducedduringpostnatal exposure. Argus Research 90S SheehyDrive, Budding A Horsham, Pemsyivama 19044-1297 Telephone: (215)443-8710 Telofcx: (213)443-8587 5XSB3C DIRECTOR: Raymond G. York,Ph-D.,DABT Associate Director ofResearch Email: raymond.york@criw.com Addressascited above forTestingFacility BffflftQR: 3MCorporateToxicology 3MCenter, Building220-2E-02 St Paul, Minnesota 33144-1000 Exygen Research Page 56 of 153 418-028:PAGE G-57 Exygen Study No.: 023-072 FrotacoM lS^O S su m M O NITO R. John ButenhofE, PhJD., DABT, CIH 3M Corporate Toxicology 3M Medical Deportment Telephone: (631)733-1962 Telefax: (651)733-1773 Em ail: jlbttteaihofl@ iiiniin.cam REGULATORY C ITATIO N S: Organisation fo r Economic Co-operation and Development(1996). OECD Guidelinefor Testing ofCkmdath. Section 4 , No. 422: Combined Repealed D oie T o xicity Study w ith the Repnxiuction/DeveJopmentalT oxicity ScreeningTest, adopted 22 March 1996. Organisation fo r Economic Co-operation and Development(1998). The Revised OECD Principle o fGood Laboratory Practices [C(97)186/Rnal]. U.S. Food and Drug Adm inistration. Good Laboratory Practice Regulation; FinalRule. 21C FR Pait58. Japanese M inim y o fHealth and W elftm (1997). GoodLaboratoryPracticeStandardfar Safety Studiesoh Drug*, MHW Ordinance Nnmber21,Match 26,1997. BK2BliA3BffiXSB9SSBtoMS$3$' This study w ill be conducted in compliance w ith the Good Laboratory Practice (GLF) regulations cited above. A ll changes or reviaoM o fthis protocol shallbe documented, signed by the Study D irector snd the Sponsor, dated and maintained w ith the protocol. The Testing F a cility^ Q uality Assurance U nit (QAU) w ill audit the protocol, the raw data and Ihe report, and w ill inspect critical phases o fth o ie portions o fth e study conducted at the Testing Facility in accordance w ith the Standard Operating Procedures o f the T esting Facility, The fin a l report w ill include a compliance statement signed by the Study D irector thatthe report accurately reflects the raw data obtained during the performance o fthe study and that a ll applicable GLP regulations were followed in die conduct o fthe study. Should significant deviations from GLP regulations occur, eachw ill be described in detail, togetherw ith how the deviation m ight affect the quality or integrity o fthe study. Should airy portion o fthe study be conducted by a subcontractoror by the Sponsor, the Study Director w in ensure that a qualified Principal Investigator is identified by the fa c ility conducting thatportion o fthe study. The QAU fo r this fh tih ty w ill conductcritica l phase inspections and auditrespective results and reports fa r thatstudyportion according to the SOPso fthat fh c ilily . Such critica l phase inspection reports and report audita w ill be submitted by the fa c ility to the Principal Investigator and the Study D irector. The dates o fthe inspections and report submissions w ill be incorporated into a QAU Statementgenerated by that ftc ility and provided Exygen Research Page 57 of 153 418-028:PAGE G-58 Exygen Study No.: 023-072 Pn*ooot 418-028 P{c3 to the Testing F a tih tyfo in ch n rio n in the fin a l report. In addition, this fa c ility w ill provide a statemento f GLP complisnca, as dcacribed above, signed by the P rincipal hrveatigator fixinclusion in the 8m I report. ssm m iK & m sm sm sn Am m mxM m m A - SeeATTACHMENT 1 to the protocol. TEST 8CWTAHCIAfflP IdotHfcettoe: Test SnbeUnce: T-7706 [Perfluorohexane Sulfonate Potassium S ilt (PFHS)] L ot identification w ill be documented in the n w data. The Sponsor w ill provide to the Totting Facility documentation or certification o f the identity, com position, method o f synthesis, strength and activity/purity o f the test substance. T hu documentation w ill be inclndcd in the fo a l report. V ehicle; Aqueous 0.5% carbaxymethlycelluloae (CMC) (medium viscosity)prepared using reverse osmosis membrane processed deionized water(R.O. deionized w ater). Lot identification and Supplierw in be documented in die taw data. Neither the Sponsornor the Study D irector is aware o f anypotentialcontaminants lik e ly to be presentin fee vehicle thatwould interfere w ith the result o ffins study. Therefore, no analyses otherthan thoae mentioned in this protocol w ill be conducted. fofrtr froiHuagM- Gkrves, dust-m ist/HEPA-filtered mask, appropriate eye protection and umfbrm/Iab coat to be worn during form ulation preparation sad dosage. The M aterial Safety Datasheet (MSDS)is attached to the protocol (ATTACHMENT 2). B ulk Teat Substance: Bulk Vehicle Components; Prepared TestSubstance and Vehicle Formulations: Room temperature. Room temperature. Refrigerated (2C to S X ). A ll test substance dpments should be addressed to the attention o fJulian O ulhinaki, Managero f Formulation Laboratory, at the previously cited Testing F a cility address and telephone number. Exygen Research Page 38 of 153 418-028:PAGE G-59 Exygen Study No.: 023-072 Protocol 4 1S-02S P ip 4 Shipment houldincludemfixmationconccnungstorageconditionsrod hippingcartonshould be labeledappropriately. Therecipientshouldbe notified in advanceofshipment TiTTTtt) Frequency ofPreparation: Formulation*(suspensions) willbepreparedweeklyat die TestingFacility. Detailedpreparationprocedural willbe attachedto thisprotocol (ATTACHMENT3). Adtitts.ftLRnrltr Theteatanbataneewillbe conaidered 100%pure fordiepiupoacofdosage calculations. Twite Wffltm hwtfff T h e T earin g F a c ility w ill re se rv e a am ple n f each lo t n fh n llr M t n h s ta n e . { y m i .M l .l y 1 j ) andbalk vehiclecomponents (approximately 1gor 5niL)usedduringthe courseofdie atudy. Sampleswill bestaredunderthepreviouslycitedconditions. MMXm: Result* ofrequiredanalyseswill beprovidedto the TestingFacility flarinclusion inthe study report# Samplesadditional to thosedescribedbetowmaybe takenifdeemednecessaryduringdie comae oftbeatndy. Additional analyses, ifrequired,willbedocumentedbyprotocol anendmeat. Ptefc.T-- t gamHiir Asampleofapproximately 1gofthetest substancewill be takenon dielast dayoftreatment and sent(ambientcondition*)to: Principal Investigator. lisa Clemen 3MEnvironmental Technologyand Safety Services Building 2-3E-09 St Paul, Minnesota35133-3331 Telephone: (651)778-5568 Telefax: (651)778-6176 Email: laeIcmon(ghwmm.com The recipientwillbenotifiedin advanceofsampleshipment Exygen Research Page 59 of 153 418-028:PAGE G-60 Exygen Study No.: 023-072 MitTWHrffrfiwrp Fnnwihtfr: P ro to n i 41S-02S P tge 5 CfflBMnttition Concentrationandhomogeneityofthe[pored formulations will beverified duringthecourse ofthis study. Quadruplicatesamples(2mLetch)willbetaken fromthe top. middleandbottom ofeachconcentration onthe firstdayofpreparation. Twosamples fromeachquadruplicateset willbe shipped foranalysis; theremainingsampleswillhe retainedat theTestingFacilitym backupsamples. Quadruplicatesampleswill betaken fromeach concentrationonthe lastdayof preparation. Two samples fromeachquadruplicate actwillbe dripped foranalysis;the remainingsampleswill beretained as backupsamples. Backupsampleswill be storedunderthe previouslycitedconditionsanddiscardedat theTestingFacilityupon therequest ofthe Sponsor. Stability. Stabilityoftheprepared formulations willbedocumentedduringthis study. Twosets of duplicatesamples (2 mLcadi) fromeachconcentrationwillbetaken onthe firstdayof preparation. One sampleofeachduplicateset willbeshippedon die dayofpreparation. These sampleswillbe analyzedatthefollowingtimepoints: as soonafterpreparationaspossibleand tendaysafterthe tint analysis. Theremainingsampleswill be retainedatthe TestingFacilityas backupsamples. Backupsampleswillbestored underthepreviouslycitedconditionand discardedattheTestingFacilityupontherequestofthe Sponsor. Samplestobe analyzedwillbe shipped(refrigerated)to: Principal Investigator LisaClemen 3MEnvironmental TechnologyandSafetyServices Building 2-3E-09 St Paul, Minnesota55133-3331 Telephone: (651) 778-5568 Telefax: (651)77S-6176 Email- laelemenQiTimmiMm Therecipientwill benotifiedinadvanceofsampleshipment moo Preparedibnnulationi will bediscardedat theTestingFacility. AUremainingbulktest subetenoe will be returned to: DanHakes 3MEHSR- Auto &ChemGrp 3MCenter, Building236-1B-10 St Paul, Minnesota55144-1000 Telephone: (651)733-2392 Exygen Research Page 60 of 153 418-028:PAGE G-61 Exygen Study No.: 023-072 TEST SYSTEM: Protocol 418-028 Page6 TheCrl:CD(SD)IGSBRVAF/Pluaretwas electedas the Test Systembecause: 1)itis one mammalianspecies acceptedforuse intoxicitystudies andithas been widelyusedthroughout industry; 2) this strainofist hasbeendemonstratedto bosensitivBto reproductive and developmental toxins; and3)historical dataandexperienceexist attheTestingFacility^1"5* Initial populationacclimated: 100maleand 100virgin femalerata. Populationselected formainstudy: 75maleand 73virgin femalerats (15 persrocper dosage group). Populationselectedfixtoxicoldncticstudy: 15maleaod 15 femalerata (timepersot per dosage group). BodyWeight and Age: Maleratiwillbeorderedto weighfrom27Sg to 300g each atreceipt, at whichtimetheywillbe expectedto be atleast60day*ofage. Femaleratswillbe orderedto weighfrom200gto 225g eachat receipt, atwhichtimetheywillbeexpectedtobe atkrat 56days ofage. Actualbody weightswillbe recordedthe dayafterreceipt andwill bedocumentedin theraw data. The weightranges willbe includedindie finalreport Atstudyinitiation, theweightvariationofthe tatswillnot exceed20%ofdiemen weightofeachsot. Bothmaleand Sanale ratswill be evaluated. Claries KiverLaboratories, Inc. Therats willbe shippedin filteredcartonsby air freightand/ortruck fromCharles River Laboratories,Inc.,to theTestingFacility. PqrtiflartNi: Rats arepermanentlyidentifiedusingMonelseif-piercing eartags (GeyBand andTagCo., Inc.,No. MSPT20101). Maleand femaleratsawassignedtemporatynumbersat receiptand g iv en u n iq u e p e n n a n e n t id e n tific a tio n m im h m w h en M aig n ad to file rn d y b aS n ia itw iitiia traH ofthe first dosage. Pupswill notbeindividuallyidentifiedduringlactation; allparameterswill be evaluated in tetma ofthe litter. Exygen Research Page 61 of 153 418-028:PAGE G-62 Exygen Study No.: 023-072 Protocol 41w a s Page? Allcagesizesandhousingconditiausreincompliancewiththe G uidefa r th e C art and U se o f L aboratory A nim al/ . ArgusResearchis anAAALAC-accreditedfacility. Fo generationratiwill beindividuallyhousedin stainlessiteeiwire-bottomedcages except duringthecohabitation andpostpartumperiods. Daringcohabitation, eachpair ofratewillbe housedindiemolen fs cage. Beginningno later thanday20 ofpresumedgestation, Fo generation femaleralwill be individuallyhoused innestingboxes. Eachdmnanddelivered litterwill behousedin a commonnestingbox duringthepostpartumperiod. Nesting Material: Nestingmaterial (bcd-o'cobe)willbeprovided. Beddingwill bechangedasoftenas necessaryto keep Acanimaldryandclean. Analytes finpossiblecontamination arcconductedsemi-annuallyanddocumentedinthe raw data. 5&fiBBjAtejL22SflBBfiE3tBEOfcJUUEhyBltSfiP Theanimal roomis independentlysuppliedwithat leastten changesperhoarof 100%freshair thathasbeenpassedthrough99.97%HBPAfitters. Roomtemperaturewillbemaintainedat 64*Fto 79F(18Cto 26C) andmonitoredconstantly. Roomhumiditywill alsobemonitored constantlyandmaintained at 30%to 70%. Llaht: AnautomaticallycootioUed 12-hourlight12-hourdarkfluorescent lightcyclewillbe maintained, Eachdarkperiodwillbegin at 1900hoursEST. Thelightcyclemaybeadjustedby theStudyDirectorofdadgnee ifdeemednecessaryto accommodate scheduled laboratory activities. Anysuchadjustmentwill bedocumentedintherawdata. Ratawill begivenCertifiedRodentDiet#5002(PMINutrition International)availablead libitum fromindividual feeders. Peedwill beremovedtheeveningprior to the achednled sacrifice. Water: Waterwillbe availablead libitum fromindividual bottles attachedto the cages or froman automaticwateringaccess system. All waterwillbe fix a local source andpassedthrougha reverse osmosismembranebeforeuse. Chlorinewillbe addedto theprocessedwateraaa bacteriostat; processedwateris expectedto containnomorethan 1.2ppm chlorine atthe timeof analysis. Water is analyzedmonthlyforpossiblebacterialcontamination,andtwiceannually for possiblechemical oootaniiiiatioiL Exygen Research Page 62 of 153 418-028:PAGE G-63 Exygen Study No.: 023-072 Protocol 419-028 Fife8 Neither the Sponsornot the Study D irector is aware o faoy potential contaminsnts lik o ly to be presentin the certified diet, in the drinking wateror in die nesting materials at level thatwould interfere w ith the results o fth is study. Therefore, no analyses otherthan those routinely performed by the &ed supplier or those mentioned in this protocol w ill be conducted. PAY NUMBERING SYSTEM: Gestation day 0 is defined as file day spermatozoa are observed in a smear o ftbe vaginal contents and/or a copulatory plug observed in situ. The day o fb irth is designated Jactation day 0 (postpartum day 0) in the Health Effects Test Guidelines - Reproduction and F e rtility Effects (O ffice o fPrevention. Pesticides and Toxic Substances 870.3800, August, 1998)and in the OECD Guideline fa r the Testing o fChemicals Combined RepeatedDose Tenacity Studyw ith tbe ReproductkiivTtevelnprriaatalTenacity Screening Test (Section 4, No.422,22 March 1966). This sameday is designated day 1 postpartum (day 1 afla cta tio n ) in the Standard Operating Procedures o fthe Testing F acility. Throughoutthis protocol, the day o fb irth w ill be designated day l postpartum (day 1 o f lactation) and a ll subsequent ages o fdie F I generation ra ti and days o fthe lactation period w ill be determined and cited accordingly. RANDO M IZATIO N AND C O H ABITATIO N: Upon arrival, rats w ill be assigned to individual housing on the basis o fcomputer-generated random units. During an acclim ation period o fat less five days,male and female rata w ill be selected fo r study on the basis o fphyaical appearance andbody weights recorded during acclimation. The ra t) w ill be assigned to dotage groups based on computer-generated (weightordered) randomization procedures. W ithin each dosage group, consecutive orderw ill be used to assign rats to cohabitation, one mi> ratper female is t The cohabitation period w ill consisto fa maximum o f 14 days. Femalerats w ith spermatozoa observed in a smearo fthe vaginalcontents and/ora copulatory phtg observed insituw ill be considered to be atday 0 o fpresumed gestation sod assigned to individual housing. Female rsts notmated w ithin die firs t seven dayso fcohabitation w ill be assigned alternate male rats that have mated (same dosage group) and w ill remain in cohabitation fo r a maximum o fseven additional days. Day 1o flactation (postpartum) is defined asthe day o fbirth and i l also the firs t day on which a ll pupa in a litte r arc individually weighed (pup body weights w ill be recorded after a ll pups in a Utter are delivered and groomed by the dam). Littera w ill not be culled during the lactation period, becauserandom selection o fpups fo r culling could resultin potentialbiases in pup via b ilitie s and body weight gains o va th is period. Exygen Research Page 63 of 153 418-028:PAGE G-64 Exygen Study No.: 023-072. Protocol 41M2S t* fi9 W ithin each dosage group, consecutive orderw ill be uied to assign the firs t 10 male aod the firs t 10 female rat to a functional observational battery (FOB) and m otor a ctivity assessment, Mood sample collection fo r clin ica l chemistry andhematology(CC&H), and histological evaluations. On day 22 postpartum, a table o frandom units w ill be used to select five male and fire female pups per Utter & r blood sample cod live r collection; thesepaps w ill only be selected from the ten dams selected fo r FOB, m otor activity, CC&H tad histological evaluation. KIRI* NATION: Bmw m l Waww for artw= The oral (gavage) route was selected torus* because: 1) in comparison w ith the dietary route, the exactdosage can be accurately administered;and 2) it is one o fth e possible routs* fix environmental exposure. Dosages w ill be adjusted d a ily fo r body w e i# it changes tad given t t approximately the none tim e each day. The firs t dayo f dosage is designated asday 1 o fstudy. Male rata w ill be given the test substance once daily beginning 14 days before a cohabitation period that consist* o fa nucriim an 14 days. Dotage w ill continue through the daybefore sacrifice, after com pletion ofthe cohabitation period, after a minimum of42daya o f Female n ta w ill be given the test substance once daily beginning 14 days before a cohabitation period that corunsts o fa maximum o f 14 days. Dosagew ill caat&ue through ft daybefore scheduled sacrifice (d iy 2 l o flactation). IMbiMtelhnpMKQm: Dosages were selected by tiw Sponsorbased on previous studies conducted w ith the test substance, taking in to accountpossible diffisrences in sensitivity between pregnantaod nonpregnant rat*. The highest dosage w ill be expected to came toxic effects but notm ortality or obvious suffering. The descending sequenceo fthe lower dosage le v e li w ill be selected fo r the purpose o fdemonstrating any dosage-related response, w ith no adverse effects expected atthe lowest level. Exygen Research Page 64 of 153 418-028:PAGE G-65 Exygen Study No.: 023-072 Protocol 4IW H 8 hge 10 JQOIB0> aTM I a m IV --V Mim Ttai to tal 15+3* 15+3^ IS** 1S+* IJ+3* DaNC ( H I 0 0J 04 1 6.1 J *j I itomM Hmfw M w i teteM M M Dm p Votant 10 10 20 10 10 im tatahlknb* a^!M SSA (D nJisH k.yM M S S H tls M aSUsI B - it4 u s tn ajaean .v M *ll+ BS -0< D ;M w aY w 1 M H n a p e tta a tH TESTS. ANALYSES ANDMEASUREMENTS- Fo GENERATION: A ll Periods: At least twicecUily. Acclim ation Period: W eekly. iMefcKtiUtoatitei: Dosage P eriod: Maternal Behavior D aily before dosage. On the firs t day o fdosage. poatdoaage observations w ill be recorded at yp ra rim std y houriy intervals fo r the firs t four h o rn and atdie eod o fthe noraalw orking day. Subsequentpoetdoeage obeervationa w ill be recorded at intervals deemed appropriate by die StudyD irector ordesignee afterdetanrinattoa o fpeak toxicologie effects. Days 1.5,8,15 and 22 postpartum. Observed abnormal behaviorrecorded daily. C linical observations may be recorded more frequently than cited above, i f deemed appropriate by the Study D irector and/or Study M onitor. Data collected fo r rats asiigned to toxicokkietic m aple coBectioo w ill not be summarized or analyzed statistically. Detailed C lin ica l Observations - M ale an* p-- Oncebefore the firs t dosage and at leastonce weekly thereafter, detailed clin ica lobservations w ill be cooducted fo r a ll male and female rats. These observations w ill be made outside the cage in a standard arena at the same time each day o fconduct. E ffo rt w ill be made to ensure that variations in the test conditions are m inim al and that observations are conducted by observers unaware o ftreatment groups. Signs noted should include, butnotbe lim ited to : changes in alrin, fur, eyes, mucous membranes, occurrence o fsecretions and exactions and autonomic a ctivity (e.g., lscrixnation, friloerectkm , pupil size, unusual respiratory pattern). Changea in gait, posture Exygen Research Page 65 of 153 418-028:PAGE G-66 Exygen Study No.: 023-072 Protocol4I&4K28 Page 11 andresponseto handlingaswell as thepretence ofclonic ortonicmovements, sterotypic behavior(e.g.,excessivegrooming,repetitive ending), difficultorprolongedparturitionor bizarrebehavior(e.g., self-tnutation,walkingbackwards) shouldalso be recorded. BodyWcfrhta - Mal .d demote Bo*.: Acclimation Period: Weekly. Dosage Period: D aily. Sacrifice: Terminal weight D osage Period: Weddy. Dosage Period: Weeklyto cohabitation. GestationPeriod: Days 0,7,10,12,15,18,20 and25 (ifnecessary). Postpartum Period: Days 1,5,8 and 15. Feed consumptionnottabulatedafterday 13postpartum,whenit iaexpectedthatpupswillbegin to consumematernal feed. Fwflcpwmtft*yum- MMfradftroMaJtefr- Feedconsumptionvaluesmayberecordedmore frequentlythancitedaboveif it ianecessaryto replenishfile feed. Duringcohabitation,whentworats occupythe samecagewithone feedjar, replenishmentofthe feedjars will be documented. Individual valueswill notbe recordedor tabulated. Onday 14and42 ofstudy, bloodsample*(approximately 1mLeach) wifibecollectedfrom eachmalerat assignedto thetoxicokinctic samplecollectionportionofthe study(3 per group). Onday 14ofrtudyand day21 ofpresumedgestation, blood samples(approximately 1mLeach) will be collectedfromeach femalerat aasignod to thetoxicokincticsamplecollectionportion of the study(3 per group). Samplewillbe collectedpriorto dosageeraday H ofstudy. Thetime ofeachbloodcollectionwillberecorded in the rawdata. Exygen Research Page 66 of 153 418-028.PAGE G-67 Exygen Study No.: 023-072 Protocol 418-OZ* Pap 12 Bloodwillbe collectedfromthe orbital sinus. Ifnecessary,bloodmayhe collectedfroman alternateit; ifto, the alternate rite willbedocumented in therawdata.) Tbs sample*will be transferredintoEDTA-ooated(purple top)tubetod qsunina centrifuge. Theresaltingacnim will betransferredinto polypropylenetube labeledwiththeprotocolnumber, Sponsorstudy number,animalnumber, sear,group number, dotage level, dayof(tody, collection interval, date ofcollection, species, generation andstorage conditions. Allsamples will be immediatelyfrozen ondry ice endmaintainedfrozen(S-70C)until thipraentfor analysis. Afterthe lastbloodsamplecollection, rail willbe sacrificedandtemplet ofthe liver willbe collected for analyat*. Sampleatobeanalyzedwillbe ihippedoodryiceto: PrincipalInvestigator Liu Clemen 3MEnvironmentalTechnologyand SafetyServices Building2-3E-09 S t Paul. M innesota 55133-3331 Teleplume; (651) 778-5568 Telefax: (631)7784176 Email; laclemen@mnim.com Therecipient will benotified inadvanceofsampleshipment. Ifotrmffnaw * Mittir Estrooscyclingwillbe evaluatedby examination ofvaginalcytologybeginningwithtbe day afterthe first administrationandthenuntil spermatozoaare observedma smear ofthe vaginal contentsand/ora copulatoryplugis observed in tin t duringtbecohabitationperiod. Onday21 ofpresumedgestation,bloodand liversampleswill be collected fromall femalerats riwMgm rtflrf --m pl f Bloodsampleswill becollectedfromtherats aspreviouslydescribed. Aftersacrifice,the liver ofeachratwillbeexcisedandthe liverweightwillbe recorded. Themedianliver lobewillbe frozenandstored(<-20C)until shipment forpossibleanalysis. The fetuseswill beremovedfromtheuterus andbloodsampleswill be collected fromeachfetus viadecapitation. Bloodwillbeplacedintotubes,pooledperlitter, allowedto clotsod spunin a centrifiige; the resultingserumwill betransferred intolabeledpolypropylene tabes. All samples willbe immediatelyfrozenondryice andmaintained frozen (g-70*C)until shipment for analysis. Exygen Research Page 67 of 153 418-028:PAGE G-68 Exygen Study No.: 023-072 Protocol i t W )2i P*I 13 Theliverfromeach fetuawillbecollected,pooledperlitter andplaced into labeledtube*. The ample*willbe frozensad ctored(<-20C)until ahipment for analysis. Simplewill be chippedon dryice to Lin Clemenat thepreviouslycited address. CtauaLfi&XSX: Femalerats will be evaluatedfor; Adverts Clinical SignsObservedDuringParturition. DurationofGestation(day0ofpreaumodgeatationto the time the firstpup is observed). UtterSize (definedu all pup*delivered). Pup Viability at Birth. PuiffttoMl P *rrviffiwm ftftttrr Onone occasionduringthe courseofthe study, a functional observational battery(FOB)i5'*>will boconductedon 10maleand 10femaleret*pergroup. Formile rate, thii mewntent will be oanductodihartlybefore schedulednaifice, but priorto bloodsimple collectionfor hematologysnd clinical chemiitryevaluations. Femalerate ihcrnidbe toted duringthe lactation period, shortlybefore icheduledsacrifice. TheFOB,to be conductedby anobserverunawareofthe group assignmentofdierat, will assess the followingparameters: 1. Lacrimation, salivation, palpebral closure, prominenceofthe eye,pupillary reaction to tight,piloereetkm,respiration, andurinationanddefecation (Autonomic ftmetioos). 2. Sensorimotorresponsesto viaoal, auditory, tactileand painful titnuli(reactivity andsensitiviry). 3. Reaction*to handling andbehaviorinthe openfield(excitability). 4. Gaitpatternin theopen field, severityofgait abnormalities, airrightingreaction, andlanding footaplay(gaitand sensorimotorcoordination). 5. Forehmbandhindlunb grip strength. 6. Abnormalclinical signs includingbut not limitedto convulsions, tremorsand otherunusual behavior, hypotoniaorhypertonia, emaciation, dehydration, unkemptappearanceanddepositsaround the eyes,noaeor mouth. Exygen Research Page 68 of 153 418-028:PAGE G-69 Exygen Study No.: 023-072 Protocol 418-028 hpu Evidenceoftheabilityofthisbatteryto detectthe effectofpositivecontrol substanceswillbe provided.(TextingFacilityPositiveControlDot). Datawillalsobeprovidedto document interobserverreliabilityifmorethan oneobserverit involved inthetesting. 2SflimihS^id$Ei3CflEt Motoractivitywill boevaluatedon 10maleand 10female ratspergrouponceduringdiecoot ofthe atndy. Thiassesamontwillbeconductedshortlybefore scheduled sacrifice. butpriorto blood sample collection. Themovementofeachratwillbemonitoredbya paarivBinfraredsensormountedoutsidea stainkss-fted wire-bottomedcage(40.fi x25.4 x 17.8 cm). Eachtetsessionwillbe 1.5hours in durationwith(tienumberofmovementtod time spentinmovementtabulatedat each fiveminuteinterval. Theapparatuswillmonitora rack ofupto 32cagesand season duringeach session, witheachrat testedindie aarnelocationon therackacrosstest sessions. Groupswillbe npTfflitinting wwhiim ffnnpygi Oatswillbeprovidedto demonstratethatthe test systemis capableofdetectingincreasesin activityproducedbypositivecontrol substances(TestingFacilityPositiveControl Data). HtCMATOLOGY AND fl.IN lC A L C H K M IS l'itY ; A t c W n lw t a erifiea , thg ra h (fa cta ri) --s ig n ! to lM M h ln g y Mid r.lim ra.1 d m ir iity ( m f V ) Baublecollectionwillbe exsanguinatedfromthe interiorvcoacavafollowingsacrificeby carbondioxide asphyxiation. Approximately5mL ofbloodwillbecollectedandprocessedas describedbelow. Dctenninalxmaadditionalto those describedbelowmaybe conductedifthe knownpropertiesofthe test substancemay, or are suspectedto, affectrelatedmetabolicprofiles (c.r., calcium, phosphate, lastingtriglyceridesand fastingglucose, specifichormones, and cholinesterase). Approximately 1mLofblood willbocollectedinto EDTA-costodtubes andmaintainedonwet ice orrefrigerateduntilshipment foranalysisofthe followinghematologicparameters: Erythrocyte Count (RBC) Hematocrit (HCT) Hemoglobin (HGB) Mean Corpuscular Hemoglobin (MCH) Mean CorpuscularHemoglobin Concentration (MCHQ Mean Corpuscular Volume (MCV) LeukocyteCount,Totad(WBQ Leukocyte Count, Differential Platelet Count (PLAT) Mean Platelet Volume (MPV) Coll Morphology Twobloodsmear slides will beprepared at the TestingFacility toreachsamplefor measurementsofdifferential leukocytecount. All samples(onwet ice) andslides (ambient conditions) willbe shippedtoRedfldd Laboratories at the followingaddress. Approximately1.8mLofblood willbe addedto a tubecontaining0 2 mLofsodiumcitrate (0.129M). Thecontentswill bemixedand maintainedonwet iceuntil the tubes are centriftiged Exygen Research Page 69 of 153 418-028:PAGE G-70 Exygen Study No.: 023-072 Protocol 4 18-02S Fa(elS (within30mmntes oftits collectiontime). Theresultingplasmawillbe transferred2.0mL polypropylenetubelabeledwith studynumber. Sponsor'studynumber,ratnumber, dongs level, dayofstudy, collection interval, dateofcoUectkm,species,generationrod storage. AH sampleswill befranca on dryice andmaintainedfrozen(<-70C) until shipmenton dryice by overnightcourier formeasurement ofprothrombintime(FT) andactivatedpartial thromboplastintime (APTT). Clinical Chcndstn r: Approximately2 mLofbloodwinbecollectedinto seromseparatortabesandcentrifuged. The resultingserasamples will be immediately frozenondryice andmaintainedfrozen(S-70C) untilshipment foranalysisofthe followingparameters: Total Protein (TP) Triglycerides (TRI) Albumin (A) Globulin(G) Albumin/GlobulinRatio (A/G) Glucose (GLU) Cholesterol (CHOL) Total Bilirubin(TBILI) Una Nitrogen(BUN) Creatinine (CREAT) CreatinineKinase (CK) Alanine Aminotransferase (ALT) Aspartate Aminotransferase (AST) AlkalinePhosphatase(ALK) Calcium(CA) Phosphorus (PHOS) Sodium(NA) Potassium(K) Chlorid*(CL) Sampleswill beshipped(ondryice) toRedfieklLaboratories atthe following address. Shipping Samples will be shippedto arriveonMondaythroughFridayaccordingto the cotxiitians described above to: Principal Investigator. Ms. PhylHsPowell RedfialdLaboratories A Division ofCRL-DDS 100 Beat Boone Street P.O. Box 308 Redfield, Arkansas 72132 Telephone; (301)397-2540 Telefax: (501)397-2002 Therecipientwill benotifiedin advaoceofsample shipment 1ZBSSAUGSI&* Urinalysis will notbe conducted unlessindicated basedon expected orobservedtoxicityofthe tost substancc. Exygen Research Page 70 of 153 418-028:PAGE G-71 Exygen Study No.: 023-072 Protocol 418-P2S P ig s 16 MgmOR-QOA Fogenerationratswill be sacrificedby cartondioxideasphyxiation. GROSS NECROPSYANP EHSTOPATHOLQCV- FoCENRRATIONRATS; StiMwMSawitey,:JnkfthMitte Scheduledsacrificeofmalerat*willbe conductedonday42 ofstudy. Scheduledsacrificeof femalerata will beconductedonday21 ofpresumedgestation. Blood ample* willbe collectedfromdie rat*aspreviouslydescribed. Aftersacrifice, the liver ofeachrmtwillbeexcisedsnd the liverweightWillberecorded. ThemedianBvtxlobewillbe frozenand stored(<-20C) until shipmentfor analysis. Fetal sampleswill be collected as previouslydescribed. Carcasseswillbediscardedwithout further evaluation. Sampleswillbeshippedondryice to lisa Clemenatthepreviouslycitedaddress. Scheduled Sscrlflce- Mah Stadv: Scheduledsacrificeofmalerats willbe conductedonthe dayfollowingthe last dosage administration,aftera minimumof42 days ofdosage. Scheduledsacrificeoffemalerats will be conducted onday22 oflactation. Grossnecropsyofall maleand femaleratswill includean initial physicalexaminationof external surfacesandall orifices, si well asthe cranial,thoracic andabdominal cavities andtheir contents. Special attentionwillbe paidto dieorgansofthereproductivesystem. Thenumberof implantation sites and corpora ltea will be reootded. Maleand femaleratswillbe examined forgross lesions. Grosslesions willberetained inneutral buffered 10%formalinandexaminedhistologically. Tissuetrimmingandhistopathologywillbe performedunderthesupervisionofor by aBoard-CertifiedVeterinaryPathologist Theovaries andtheuteruswithcervixofeachfemaleratwill beweighed, andovaries, uterus, vaginaanda mammarygland will beretainedinneutralbuffered 10%formalin. Uteriof apparentlynonpregnantrats will be examined afterbeingpressedbetweenglass platesto confirm the absenceofimplantationsites, andretainedis neutralbuffered 10%formalin. Exygen Research Page 71 of 153 418-028:PAGE G-72 Exygen Study No.: 023-072 Protocol 4M-QZS Hg>n To assessthe potential toxicityofthetest articleonthemalereproductivesystem, the endpoints lilted belowwillbeevaluatedfromthe first 10mile rate ineachdoaagegroup. Organ Weights: Tbefbflowingorgm wifibe individuallyweighed: righttestis, left testis, left epididymis (wholeandcauda),right epididymis,seminalvesicle(withand without fluid)andprostate. SpermEvaluations: Spermconcentration mdmotilitywill beevaluatedusingcomputerassistedspenn analysis (CASA). Motilitywillbe evaluatedby theHamiltonThome 1VOSby collectionofa ample fromthe leftvu deferens. Ahomogenatewill be preparedfromtheleft caudaepididymis foeevaluationbythe HamiltonThomeIVOSto determinespermconcentration(spam pergramoftissue weight). Theremainingportion ofthe leftcaudaepididymiswill beusedto manuallyevaluate spermmorphology. Spennmorphologyevaluationswillincludethe following: 1)determinationofthe percentageofnormalspennin a sampleofat least200; and2) qualitative evaluationof abnormal sperm, includingsuchcategoric! as abnormal head, abnormaltail, and abnormal beadand tail. SeeATTACHMENT4 foradditional tisauea to beweighedandretained from the tenrataperBex pergroupasaigned tohistological samplecollectionandevaluation. Allothertissueswillbe discarded. ScheduledSacrifice offm * * fct NotDeUverLitter: Ratthat donotdelivera Litterwill besacrificedonday25ofpresumedgestation. Gross necropsy,examinationand tissueretentionwillbeconductedasdescribedpreviouslyforrats at scheduled sacrifice. P llf fffft fft SerWvfcatPuns: Dams withno survivingpups will be sacrificedafterdie lastpup is founddead, missingor presumedcannibalized. Groasnecropsy,examinationand tissue retentionwill be conductedg describedaboveforrats at scheduledsacrifice. Exygen Research Page 72 of 153 418-028:PAGE G-73 Exygen Study No.: 023-072 Protocol 418-028 Page 18 Bltt EBBrt.PMtf W M r t l W i : Rats thatlieor oresacrificedbecauseofmoribundcondition, abortionorprematuredeliverywill beexaminedforthecameofdeathormoribundconditiononthe daythe observationiamade. Therad will beexamined to r grots leaiom. Teste*and epididymidesofmaterate will be excisedandpairedorganweightswinberecorded. Theepididymides willberetaiiied inneutral buffered 10%formalin. Thetesteswillbe fixed inBauin'saohiikxi fix'48 to96boon andthen retainedinneutral buffered 10%formalin. Pregnancystatusenduterinecontentsoffemalerats willbe recorded. Abortedfetuses and/ordeliveredpups win be examinedto Cheextentpossible. Uteri ofapparentlynonpregnantnia winbe examinedafterbeingpressedbetweenglassplates to confirmtheabsenceofimplantationsites. Ovaries anduteri willberetainedin neutralbuffered 10%formalin. TKTStAftAfcYMS 4WP VUbUltv: H fiBfffiBAUQK' PreweaningPeriod: litter* willbeobservedlordeadpep* at leasttwicedaily. The pups in each litter will be counted once daily. *Ffimlhw -V" rm n tl A m m atr PreweaningPeriod: Oncedaily. Pupawill beobservediftheyarewarmanddean, forevidenceofa nestandifpupa are grouped togetherandnursingorhavemilkin stomach. Eachpupwill beexaminedfor generalshapeof thehead, trank, limbs, tail andpresenceofanna. Clinical observationsmayberecordedmorefrequentlythan dted above, ifdeemedappropriate bythe StudyDirectorand/orthe StudyMonitor. loHrmMIfrPrewoaningPeriod: Dayi 1(birth), 8,15 and22postpartum. Sacrifice: Terminal weight Feed (recorded PreweamngPeriod: Not recorded. METHOD OF SACRIFICE - F I GENERATION PDFS: FI generationpupawill besacrificedbycarbondioxide asphyxiation. Exygen Research Page 73 of 153 418-028:PAGE G-74 Exygen Study No.: 023-072 Protocol 4 1 *4 2 8 19 e s c w w l b wm&noti- Grosslesionswill beretainedinneutral buffered 10%fbnnslin forpossiblefutureevaluation. Unless specificallycitedbek>w,all othertiuueswillbe discarded. FufffjUMtf m Pm 1Fwtwmutt-' Pupthat diebeforeexaminationofthe litter forpop viabilitywill beevaluatedforvital statueat With. The lungswillberemovedsad immeraedinwater. Pups withlungs that link winbe identifiedas stillborn; pups withlungs that {lootwillbeidentified at Kvdiaro, andto have died shortlyafterbirth. Popswithgross lesions will bepreserved inBonin'ssolutionforpossible futureevaluation. fw EimrfJBw4 MMflwn4m P m lA .it gwttwrtw Pups founddeador sacrificedbecause ofmoribunditywillbe examinedforgrow lesions rod for thecauseofdeathorthemoribundcondition. Pupwith gran lesionswillbe preservedin Bourn's solution forpossiblefutureevaluation. Stiw4M Staffer Onday22 postpartum,popwill bewill be sacrificed andexaminedfor gross lesion; gross lesionswQlbepreserved inneutral buffered 10%formalin. Necropsywill includea singlecrocssectionoftheheadatthe level offoefrontal-parietal sutureandexaminationofthecrosssectionedbrain forapparenthydrocephaly. Bloodsampleswill be collectedfromeachselectedpup(3 persexper litterfromtire 10females pergroupselectedforFOBsad motor activityassessment,bloodsaapio collection forH&CC, andhistological evaluations) fromthevenacava. Thebloodwillbeplacedinto tubes, pooledper litter, allowedto clotandspuninacentrifuge; theresultingserumwillbe transferredintolabeled polypropylenetubes. All sampleswillbe immediatelyfrozenondryice sodmaintainedfrozen (S-7(PQ until shipment foranalysis. The liverfromeachselectedpupwillbecollected excised andthe organweightrecorded. Themedianlobewillbe frozenandstored (<-20*C)until shipment forpossibleanalysis. Frozensampleswillbeshippedto LisaClemen st the previously citedaddress. Theremsinmgportionofeach liver-willbe retainedinneutralbuffered 10% formalin forpossiblehistological evaluation. Theliven willbe processedandevaluated histologicallyai describedforthe Fogenerationratsin Histological Evaluation in ATTACHMENT4. Exygen Research Page 74 of 153 418-028:PAGE G-75 Exygen Study No.: 023-072 ~ PROPOSED S TA TIS TIC A L TESTS1" : Thefollowingschematic reprsentastatistical analysesofthedata. Protocol41&-02* Fib 20 Emanatesi lyca.QfTjat* U- ttefwgnrtriB* itWiNlEMV r IWMR tWpMiRMR l> WirtBMniwtai M I M ri '| OmnMtkTM Ona-asrANOVAtaraariitMi CkmanTM ih- TMtfar-PnaBwHaiCM VWIanoalM * r HMnagMM% oi HwHnomMOtaMbulon Statisticallysignificantprobabilitiesarereportedas eitherp< 0.05 or/><0.01. Proportiondataare not includedin this category. Test for homogeneity of variance. PF Exygen Research Page 75 of 153 418-028:PAGE G-76 Exygen Study No.: 023-072 Protocol 41t-Q2> P l o 2 i Test items is HieFOBusing interval scales, suchasthe grip-strengthtest*aodthe landing foot splaytest, as well as bodyweightdotssodfeedconsumptionvalueswillbe analyzedas describedunderthe Panmctac headingoftheacbcmotic. Bartlett'sTostofHomogeneityof Variances1*'will beusedto estimatetheprobabilityfeat thegroups bad different variances. A nonsignificantresult (p>0.001) willindicatethat anassumptionofhomogeneityofvariance is not inappropriate, and the datawill becompetedusingtheAnalysis ofVarianceTest*18*. Iffeat teat is significant (p^).05), thegroups exposedto theteat srticte/substancowill be comparedwith thecontrol groupusing DurmetfsTest*11'. IfBsrtletf*Test is significant(p<0.001\ theAnalysis ofVarianceTestis not appropriate, andfeedatawillbeanalysedas describedunderfits Nonoaramgtrieheading ofthe schematic. When7S%or feweroffee scoresin all fee groupsare tied, fee Kruskal-WaOisTest?51'willbe usedto analyzethe data, and in feeevent ofa significant result(pSO.OS),Dunn'sTest"11willbeusedto comparethe groupsexposed tothetest articlc/substanccwiththe control group. Whenmarcthan75%offeescons in any groupare tied, Fisher'sExact Test0*1will beusedto comparefeeproportionofties infee groups. Data fromfee motoractivity test,wiferepealedmeasurementswithina session,will be analyzed usinganAnalysis ofVariancewifeRepeatedMeasure*035, as describedunderthatheadingin fee schematic. Aprificanteffect(p3>05)inthattest canappearas effect ofConcentration(a differencebetweengroupsinthetotal acrossall measurements ina session)oras an interaction betweenConcentrationandBlock(adifieraacebetweengtonpa at specificmeasurement periods). Iffee Concentrationeffect is significant, feetotals torfee control group andfee groups givenfeetest article/substaoce will becomparedusingDunnetfsTest IffeeConcentrationx Blockinteraction is significant, anAnalysisofVarianceTeatwillbe usedto evaluatethe dataat eachmeasorementperiod, and a significantresult(p jfj.0 5 ) will befollowedby a comparisonof feegroupsusingDunnetfs Test Testitemsin the FOBhavinggraded or countscoreswillbe analyzed usingfeeprocedures described under the Nonnaramotric heading of the schematic. Clinical observation incidence data, aswell asthedescriptiveandquintal data fromtheFOB, will be analyzedas contingencytables usingfeeVarianceTestforHomogeneityoffeeBinomial Distribution*1*'. Alternateor additional statistical evaluationsmaybeperftsmedifdeemednecessaryor appropriate. Exygen Research Page 76 of 153 418-028.PAGE G-77 Exygen Study No.: 023-072 Protocol 41S-028 PH*!! DATA ACQUISITION. VERIFICATION ANDSTORAGE: Dot*generatedduringthecourseofthis studywillbe recordedeitherbyband orusing theA rgus A utom ated D ata C ollection and M anagem entSystem , the Vivarium T em perature andR ela tive H um idityM onitoring System , the C oulbount Instrum ents P asstve In fraredM otor A ctivity S ystem , the C oulboum Instrum ents A uditory S ta rtle System , die Coulboum Instrum ents S patial D elayed A lternation System , and/orthepassive avoidancesoftware. Alldatawillbetabulated, summarizedand/orstatisticallyanalyzedusingtheA rgus Autom ated D ata C ollection and M anagem ent System , the Vivarium Tem perature and R elative H um idity M onitoring System , M icrosoftE xcel [part ofMicrosoft Office97(version SR-2)] and/or 77m SAS .System (version 6.12). Recordswill bereviewedbythe StudyDirector and/or appropriatemanagementpersonnelwithin 21 days aftergeneration. All origina] records willbe storedin the archivesofthe Testing Facility. All origina]datawill beboundandindexed. Acopyofall rawdatawillbesuppliedto the Sponsor uponrequest Preservedtissueswillbe stared attheTestingFacility atdo charge for one yearaftermailingofthedraftfinal report, afterwhichtimedie Sponsorwillbecontactedto determine tho disposition ofthese nurtcriilf. mxwmiomt: ExecutiveDirectorofResearch; MildredS. Christian, Fh.D,,Fellow, ATS DirectorofResearch: AlanM. Hobcrman,FhJ)., DABT AssociateDirectorofResearchandStudyDirector RaymondG. York,PhD., DABT DirectorofOperation* andCompliance: BarbaraJ. Patterson,BA. DirectorofLaboratoryOperations; JohnF. Barnett, B.S. DirectorofStudyManagement: ValerieA Sharper,MJ5. ManagerofAnimal Operations: DonaC. Lobo, VJM-D. Chairperson, Institutional Animal CateandUacCommittee: DouglasB. Learn, PhD. Consultant,VeterinaryPathology; W.RayBrown,D.VJv.,PhD., ACVP Exygen Research Page 77 of 153 418-028:PAGE G-78 Exygen Study No.: 023-072 SESrWBS,Iff 11 HmWAOTP- Protocol and Amendments. TortSubstance,Vehicleand/orReagentReceipt, Preparation andUse. Animal Acquisition. Randomization Schedule. Mating History. Treatment (ifprescribed by StaffVeterinarian). General Comments. Clinical Observation*and/orGeneralAppearance. BodyWeights. Feed Consumption Values. NaturalDeliveryObservations. FOBandMotorActivityObservations. BloodSampleCollection,Processingand Shipment OroesNecropsyObservations. OrganWeight*. Photographs(ifrequired). StudyMaintenance(roomand environmentalrecords). Feed andWaterAnalyses. Packing anchor Shipment List*. Protocol 418-028 F ige 23 FINAL REPORT: TheStudyDirectorwillprovideperiodicupdate*ofstudyprogress to the Sponsor. Draft summarytable*ofunauditedcomputer-recordeddatamayacoompanythawupdate*. Statistical analyseswinnotbe performedontheseinterimdata. Acomprehensivedraftfinal reportwillbe prepared oncompletionofthestudyandwill be finalizedfollowingconsultationwiththe Sponsor. Thereportwill includethe following: SummarysaidConclusion. Experimental DesignandMethod. Evaluation ofTeat Results. Appendices: Figure*, Summary*nd IndividualTablesSummarizingthe AboveData, Protocol andAssociatedAmendment*md Deviations, StudyDirector's GLPCompliance Statement, ReportsofSupportingData(ifappropriate) andQAUStatement TheSponsorwill receiveonecopyofthe draftreportandtwocopies offlicfinal report Datawill behand- and/orcomputer-recorded. Record*willbe reviewedby dieStudyDirector and/orappropriatemanagementpersonnel within 21 daya aftergeneration. All original records willbe storedinthearchive*offt* TestingFacility. All original datawill beboundand indexed. Acopyofallrawdatawill be suppliedto dieSponsoruponrequeit Preservedtissues willbe stared atthe TestingFacilityatno charge foroneyearaftermailingofthedraftfinal report, alterwhichtime theSponsorwill be contactedto determinethe dispositionofthese materials. Exygen Research Page 78 of 153 418-028:PAGE G-79 Exygen Study No.: 023-072 ~ msnjMt'JU'ivAL ANIMALAIM AMP.BW8ttBfflfflnCHB STA3 Protocol 41140$ Pago 24 Theprocedure*describedinthi*protocol havebeenreviewedbythe TestingFacility's Institutional Animal CareandUseC om m ittee. All pcooedurea describedinthis protocolthat involvetodyminiaiwiDbe conductedin mannertoavoidorminimize discomfort, distressor paintotheanimals. TheSponsor'ssignaturebelowdocumentsthe fhetthat informationconcerningthenocessityfor conductingthisstudyandthe fret that this isnot anunnecessarilyduplicative studymaybe obtainedfromthe Sponsor. No alternative(avitro ) proceduresworeavailable tormeetingthe statedpurposes ofthe study. RBidURBiNCRSt 1. Christian, MS. andVoytek, P.E. (1982). In V ivo R eproductive and M utagenicity T ata. E n v iro n m en tal P ro te c tio n A gency. W ash in g to n , n . f l N a tio n a l T e c h n ic a l ftifo m ro fa n Service, U.S. DepartmentofCommerce, Springfield. VA 22161. 2. Christian,M.S. (1984). Reproductivetoxicityandteratologyevaluations of naltrexone(ProceedingsofNalttwane Symposium,NewYorkAcademyofSciences, November7,1983), J. din. PsychiaL45(9):7-10. 3. Lang,PX. (1988). Em bryo and F etal D evelopm ental T oxicity (T eratology) C ontrolD ata in th e C harles R iver Cri:CDQ&R B at. ChartesRiver Laboratories,Inc., Wilmington, MA 01887-0630. (DatabaseprovidedbyArgusResearch Laboratories, Inc.) 4. InstituteofLaboratoryAnimalResources (1996). G uidefo r the C are and U se <jf L aboratory A nim ais. NationalAcademyPress, Washington, D.C. 5. Haggerty, G.C. (1989). DevelopmentofTierI neurobchavionl testingcapabilities for incorporationintopivotalrodent safetyassessment studies. J. Atner. Col.ToxicoL8:5370. 6. Irwin, S. (1968). Comprehensiveobservational assessment: la. Asystemicquantitative procedureforassessingthebehavioral andphysiologicstateofthe mouse. Psycbopharmacologia(Berlin) 13:222-257. 7. Moaer,V.C. (1989). Screeningapproachesto neurotoxicity: A functional observational battery. J. Amer. CoLToxicoL8:85-94. 8. CDonoghuc, J.L. (1989). Screening forneurotoxicityusing a neurologicallybased examination andneuropathology. J. Amer. CoLToxicoL 8:97-116. 9. Sokal, R.R. andRohli FJ. (1969). Bartlett's test ofhomogeneityofvariances. Biom etry, W E Freeman andCo., SanFritncisco,pp. 370-371. Exygen Research Page 79 of 153 418-028:PAGE G-80 Exygen Study No.: 023-072 PruM sot 418-028 P igs 23 10. Sncdecor, G.W. andCochran, W,G. (1967). Analysis ofVariance. S ta tistica lM ethods, 6thEdition, Iowa StateUniversityPress,Amo, pp. 258-275. 11. Durmett,C.W. (1955). Amultiplecomparisonprocedureforcomparingseveral treatments with a control. J. Amer. Stat Assoc. 50:1096-1121. 12. Sokal,RJL and Rnhlf, FJ. (1969). Knukat-Wallis Teat B iom etry, WM . Freemanand Co, SanFrancisco, pp. 388-389. 13. Dunn, O.J. (1964). Multiplecomparisonusingranksums. Technomotrica6(3):241-252. 14. Siegel,S. (1956). N onparam eiric S ta tisticsfo r the B ehavioral S d en a a , McGraw-Hill, NewYork, pp. 96-104. 15. SASInstitute, Inc. (1988). Repeatedmeasure*analysisofvariance. SAS/STATTM U ser's G uide, Release6.03 Edition, Cary, NC, pp. 602-609. 16. Snedecor, G.W. andCochran, W.G.(1967) Variancetest forhomogeneityofthe binomial distribution. S ta tistica lM ethods, 6th Edition, IowaStateUniversityPress, Ames,pp. 240-241. Exygen Research Page 80 of 153 P R Q J 2 C 9 L XUfSXyMtFOR THE TESTING FACOLTTY {U-~ --- - AlanM. Hobennan,FhJD., DABT DirectorofResearch IG.Yodc, i Djreotorof. Study Director I _ ---- ^ Theres Woodard,D .v k -- I- Member,InstitutionalAnimalCareand U*eCommittee FOR T H I SPONSOR JohnButenhoS;PhJX, DABT. CIH Study Monitor and Sponaar*Representative 418-028:PAGE G-81 Exygen Study No.: 023-072 Protocol 4 1 S 4 2 S hpU T< Dste <*/> Z0P2_ Dite Ji. Date Date Exygen Research Page 81 of 153 418-028:PAGE G-82 Exygen Study No.: 023-072 ATTACHMENT 1 SCHEMATIC OF STUDYDESIGNANDSTUDYSCHEDULE Exygen Research Page 82 of 1S3 418-028:PAGE G-83 Exygen Study No.: 023-072 ATTACHMENT! SftfcMATI Protocol 418-028 Page 1 o f3 COMBINEDREPEATDOSE ANDREPRODUCTIVE/DEVELOPMENTALTOXICITY SCREEN* F irst D ay o f Test ft|^unpn Dotage L ast Day o fT est QnhnU npn Dotici L ast Day o f Test M ale R a ta P esale R a ts M olar Activity/FO B* 2Weeks 2 W orin N atural D drvery G estation P o stp a rtu m P eriod 3 W eeks D ay 21 D ay 22* M otor A erirty/FO B * D osage Period For additional details aee 'Testa, A nalyses and Measurements* section o f the protocol. FOB and motor activity evaluation conducted on ten male per groop. M ale rata sacrificed after com pletion o f at least 42 days o f dosage, necropsy and retention o f male reproductive organa. H em atology, clinical biochem istry and histological samples collected from ten male rats per group. Ten fem ale rats per group nssigned to FOB evaluation and motor activity evaluation. Ten fem ale rata p a group and their Httssa sacrificed on day 22 postpartum; necropsy and retention o f female reproductive organs. Hem atology, clinical biochem istry and histological sam ples collected. Rem aining fem ale rats sacrificed on day 22 postpartum and discarded. p p- P P" P Exygen Research Page 83 of 153 418-028:PAGE G-84 Exygen Study No.: 023-072 ATTACHMENT 1 Protocol 41M ) P s*B 2of3 SCHEDULE* 26 MAH02 Animal Receipt - AcclimationBogin. 01 APR02 Start ofDoeagePeriod - MaleRata(14daysbefore cohabitationandthrough a 14-daycohabitation perioduntil the daybeforesacrificeafter atleast42 days ofdosage). 01 APR02-12 JUN02 DosagePeriod FemaleRata(14daysbefore cohabitation throughPay 22oflactation). 14APR02 PM- 21 APR02AM 21 APR02 PM- 28APR02AM CohabitationPeriod(Maximumof 14days). Male 1(7 days) Male2 (7 days) 14APR02 Day 14ToxicolrineticSampleCollection ~ 15 APR 02 FirstPossibleDay0ofPresumedGestation. 28 APR02 LastPossibleDay0 ofPresumedGestation. 06 MAY 02 19MAY02 FirstPossibleDay21 ofPresumedGestation ToxicolrineticSampleCollection andSacrificeToxicolrineticStudyFemaleRats LastPossibleDay21 ofPresumedGestation Toxicolrinetic Sample Collection end Sacrifice Toxicolrinetic Study Female Rata 06MAY02-07 MAY02 FOBandMotorActivityEvaluation- 10MaleRata per Group a. Thestartdtoofthe studyIsthedaythe StudyDirectorsignstheprotocol. b. Throughoutthis schedule, thedayofbirthis designatedday t postpartum(day 1of lactation)and >11subsequentagesoftbeFI generationrati anddays ofthe lactation periodwill bedeterminedandcited accordingly, as describedabovethe protocol section, "DayNumbering System." Exygen Research Page 84 of 153 418-028:PAGE G-85 Exygen Study No.: 023-072 ATTACHMENT 1 06 MAY 02 23 MAY02 10MAY02 23 MAY02 12MAY02 13 MAY 02 23MAY02 - 09JUN02 -- 27MAY02-13 JUN02 24 SEP02 Protocol 4 1 * 4 2 8 Page 3 o f3 First PossibleDelivery(Day21 ofpresumed gestation). LastPossibleDelivery(Day25 ofpresumed gestation). FirstPossibleDay25 ofPresumedGestation FemaleSacrifice. LadPosableDay25 ofPresumedGestation FemaleSacrifice. Day42 Taxicokinetic Sample Collection and ScheduledSacrifice- Toricokiwctic StudyMale Kata ScheduledSacrifice- MainStudyMaleRata (Earliestpossibledate). Hematology, Clinical BiochemistryandHistological SampleCollectionof SelectedMale Rata. FOBandMotorActivityEvaluation- 10Female RataperGroup. Day22Postpartum- Sacrifice FemaleRataand Pupa. Hematology,ClinicalChemistryand HistologicalSampleCollection ofSelectedFemale Rats andPupa. Draft Final Report Exygen Research Page 85 of 153 418-028.PAGE G-86 Exygen Study No.: 023-072 ATTACHMENT 2 M A TE R IA L SAFETY DATA SHEET Exygen Research Page 86 of 153 418-028:PAGE G-87 Exygen Study No.: 023-072 MATERIAL 8APETY DATA SHEET (E xp erlaen tal) m Center S t . Maul, M iuw aota S S 1 4 4 -1 IM 1 - 8 0 0 - 3 8 4 - 3 5 7 7 OP ( E S I ) 737-0M 1 (24 (M an) T C o p y rig h t, 1 8 S S , M innesota M ining and M anu facturing Coapany. A l l r ig h t r e s e r v e d . Copying a n d /o r dow nloading o f t h is I n f o n a a t i o n f o r t h o parpooa o f p r o p o r ly u t i l i z i n g 3M p r o d u c t* l a allow ed prov id ed th a t: 1 ) th o in fo rm a tio n l a oapiod in f u l l w ith no changes w ilo a* p r io r ag raao o n t l a oM alnod f r e e 3H, and 2 ) n e ith e r th e copy nor the o rig in a l l a re a e ld o r otharuiae d is tr ib u te d w ith th e In ten tio n o f earn in g a p r o fit th ereon . D IV ISIO N : m SPECIALTY MATERIALS MATERIAL: L -M S 1 DEVELOPMENTAL PRODUCT ISSUED: O eeaab er 0 7 , 1 0 8 S SUPERSEDES: May 1 7 , 1 0 0 0 OOCUMENT: 0 4 - 5 4 7 0 - 2 -n o i 1 . UKREDIENT C .A .S . NO. PERCENT POTASSIUM PERFLUOROHEXANE SULFONATE........... RESIDUAL ORGANIC FLUONOCHEMXCALS.................. 3871 -0 0 -8 M ixture 1 0 0 .0 Unkmaoi T h la a a t o r l a l 1 * n o t l l o t o d on th o T8CA I n v e n t o r y end ih o u ld bo m o d f o r resoaroh and dovolepnont purpose* o n ly under th o d ir e c t supervision o f a te c h n ic a lly q u alified in d iv id u al. 2 . PHYSICAL DATA BOXL1NB PO IN T :............. VAPOR PRESSURE:........... VAPOR D EN SITY:............. EVAPORATION RA TE:. . . SOLUBILITY IN HATER: SPECIFIC GRAVITY:. . . PERCENT VOLATILE:. . . pH :............................... V IS C O S IT Y :........................ HELTINS PO IN T :............. N/A sagliQlhla N/A N eg lig ib le alig h t oa. 1 .0 W ater-1 (B u lk ) N eg lig ib le N/A R/D R/0 APPEARANCE ANO ODOR: O ff-w h its c r y s t a llin e s o lid , sharp odor. A b b r e v ia t i e n e : n/D Mot D eterm in ed N/A - N et A p p l ic a b l e CA A p p r e x la o ts ly Exygen Research Page 87 of 153 418-028:PAGE G-88 Exygen Study No.: 023-072 8 0 S : L -9 0 S 1 DEVELOPMENTAL mOCUCT O M H b*r *7 , f 999 PfSC 2 3 . F IR E A M EXPLOSION HAZARD DATA FLASH PO IN T!...............................................> * 1 2 P S s t a f l a a l l S a t a f ls a H C lo s s d Cup FLAMHASLE LIM ITS L E L :.................. N/A FLAMBASI LIM ITS - U E L :.................. N/A AVTDIBWmON TEMPERATURE:.............N/D EXTINGUISHINS MEDIA: tta ta r, Carbon d i x id o , Dry ch a o io a l, Foao SPECIAL F IR E F IS H R N S PROCEDURES: Haar f u l l p r o ta c tiv a e lo tR ln a , Inoluding h a la a t , aalf-carrtain ad , poa l t i v a p ra a su ra o r pr a s s u r a dsaand b rsa tM n g a p p a ra tu s, banksr c o s t and p a n ts , banda around an a s, u a is t and l a s * , T aos a a tk , and p ro ta ctiv a o avarlng f o r axpoaad arasa v f tb s hsad. UNUSUAL FINE ANO EXPLOSION HAZARDS: Saa Hazardous D so o ap aaitio a aaetian fo r p rod u cts o f oanb u stian . 4 . REACTIVITY DATA STABILITY: S ta b la INCOMPATIBILITY - MATERIAL8/C0N0ITI0NS TO AVOID: Nona kncaai. HAZARDOUS POLYMERIZATION: H azard os* p e ly s s H L z a tio n M i l l s o t o o o u r. HAZARDOUS DECOMPOSITION PRODUCTS; Hay p r o d u c t f l u o r o c a r b o n p a s t a I f tx p o sa d t o v a r y h ig h t a a p o ro tu r a a (ovar 310 C ). t . ENVIRONMENTAL INFORMATION SPILL RESPONSE: Obsarvo p ra ea u tio n a fr o a o tb a r a a etio n a . C o lla o t sp U la d a a t a r la l. U ta u a t SMa a pln p ooopound o r u a ita r t o a v o id d u s t i n g . C ls a n up raaid u s. P lace in a cloaad contalnar. recommended d i s p o s a l : In ein arata in an in d u s tr ia l o r saaaro ial f a c i l i t y in th a praaanca e f a c o a b u a t i b l a a a t a r l a l . C a a b u s tlo a p ro d u ct w i l l i n d u d a HP. o is p a s a l a l t a m a t i v a : Olapoaa a f uaata produet in a f a c i l i t y p a ra ltta d to aooapt c h a a lc a i H tata. A b b r e v ia tio n a : N/D - H ot O a ta r a ln a d N/A - N at A p p lie O b la CA Approxl a s t s l y Exygen Research Page 88 of 153 418-028:PAGE G-89 Exygen Study No.: 023-072 3 0 8 : 1 .-0 0 5 1 DEVELOPMENTAL PAOOUCT D ecM tXr 07, 1098 Past 3 5 . ENVIRONMENTAL INFORMATION (co n tin u e d ) ENVIRONMENTAL DATA: Not d s te ra in e d . REBULATORV INFORMATION: V o la t ile O rgan le Coapounds: n/ d. VOC t e a * HOO 0 E x a a p t S o l v e n t s : HID. Sin e# re g u la tio n s vary, co n su lt applicable reg u latio n s o r a u th o ritie s b e f o r e d i s p o s a l . U .8. CPA H azardous H a s t* N uabar - Nona (N at U.O. EM H azardout). OTHER ENVIRONMENTAL INFORMATION: T his product say c o o te ln ena o r o r organic flu o ro cfte a ia a ls ttia t have th e p o te n tia l t o r a o la t degradation and p e r s i s t in th e e n v lro n a e n t. EPCRA HAZARD CLASS! FIR E HAZARD: No PRESSURE: No REACTIVITY: No ACUTE: Y SS CHRONIC: No 0 . aUGBESTEO F IR S T AID EVE CONTACT: la u d l a t e ly flu s h a y es w ith la rg e aaovnta o f H a ter. O at la a s d ia ta asd io al a tte n tio n . SKIN CONTACT: Flush sh in w ith la r g e aaounta o f w ater, i f I r r it a t io n p ars l e t s , g at aed ioal a tte n tio n . XWMLATION: I f sig n s/sy e p to a s o o cu r. renova parson to fre sh a i r . I f slg n s/sy a p to a a o on tln u a, c a l l a p hysician. I F SHALLOWED: I f aw all m aul, c a l l a p h y sicl a s la a s d la ts ly . Only Ind ues v a a itin g a t th e In s tr u c tio n o f a p h y sic ia n . Never g ive anything by aouth t o an unconscious parson. 7 . PRECAUTIONARY INFORMATION EYE PROTECTION: Avoid oyo d o n ta e t. Avoid ty e c o n ta ct w ith vapor, sp ra y , o r s l a t . The fo llo w in g sh ou ld be worn s la n t o r In e o a b ln a tlo n , a s a p p ro p ria te, to p reven t oyo c o n ta c t: Hoar vested goggles. A b b r e v i a t i o n s : H/D - N ot D o te r in e d N/A - Not A p p lic a b le CA A p p ro a ld o ta ly Exygen Research Page 89 of 153 418-028:PAGE G-90 Exygen Study No.: 023-072 H S U : L -M 5 1 DEVELOPMENTAL PRQOUCT D scaabar 07, IB M 7 . PRECAUTIONARY INFORMATION (o o n tln o o d ) PARE 4 SKIN PROTECTION: A v o id s k i n c o n t a c t . H o a r a p p r o p r i a t e g lo v e s when h o o d lin g t h i s a t t r ia l. A p a ir o f giovoa aada fro a th e follow ing o o to rla l(o ) aro ro o o a a ondo d i b u t y l r u b b a r , p o ly o th y ls n o /p o ly v ln y lid a n s o h l a r i d a (S a ra n a x ). Uao ana o r ao ro o f th e fo llo w in g poraonal p ro to o tia n ita a a aa naoaaaary to p rev an t akin co n ta c t: htad co v trin g , co v sr a i l s . P r a ta a tiv a g a r a a a tt (o th e r th an g lo w s ) should to aada o f e ith e r o r tM fo llo w in g a a te r la ia : palytthylano/polyvlnyU d sno ch lo rid e (Saranax). RCCOMHP B E P VENTILATION: Use M ith a p p ro p ria te l o e a l tx h a u a t v a n tila tlo n . Provide a p p ro p riate lo o a l axhaaat v e n til at i on a t tr a a a fe r p o in ts, use in a w eilvan tl i t tad a re a . Prov id e a n ffia ia n t v e n tila tio n t o a a in ta ln ta ia a io n a to low raooaaandod axpoaara l i n i t t . i f axhaaat v e n tila tio n i s n o t adoqoata, uaa ap p rop riate rv ap irato ry p ro ta a tlto . Provide v a n tila tlo n ad eq u ate t o c o n tr o l vapor a o n o an tratio n a below r e c n-- en ded e x p o s u r e U n i t s a n d /o r c o n t r o l s p r a y o r a i s t . L o c a l e x h a u st v a n t i l a t l a n i s r a no aaandad id iara th a ana airb o rn e. s a t * r ia l bvco RESPIRATORY PROTECTION: Avoid b re a th in g o f a ir t o m o n o t a r ia l, s a l t o t on# o f th a fo llo w in g RIOSH ap p rov ed r e s p i r a t o r b a a a d on a i r b o r n e e o n a e o tr a t io n o f c o n ta a i n a n t s and I n a c c o r d a n c e w ith OSHA r s g u l s t i o n a i h a l f -o a a k su p p lied a i r r a a p ir a to r , f u l l - f a c a auppliad a i r re p in to r . PREVENTION O f ACCIDENTAL INGESTION: Do n o t o a t , d r in k o r a a o k a whan u s in g t h i n p r o d u c t. Hash oxp oasd a r e a s th o r o u g h ly w ith s o a p and w a te r . Wash hands a f t e r h a n d lin g and before satin g . RECOMMENDED STORAGE: O tors a t ro cs te a p e ra tu m . c l o s e d whan n o t i n n a n . Knap e o n ta in a r d r y . Kaap o o n ta ia a r E IR E AND EXPLOSION AVOIDANCE: Not d e tera ln ed . EXPOSURE LIM ITS 1NNRE0IENT VALUE UNIT POTASSIUM PERFLUQMHEXANE SULPONATE............................................................... a.i m m HESIOUAL ORGANIC FLUOROCMEMICAiS.......... (.1 m im TYPE Aunt SION* THA THA SM 3M V Y SKIN NOTATION: L i s t n d s u b s t a n c e s i n d i c a t e d w ith `V under SKIN r i f a r t o A b b r e v i a t i o n s : N/O N ot O o ttr a ln o d N/A - Not A p p lie a U o CA - A p p r o x ln a to ly Exygen Research Page 90 o f 153 418-028:PAGE G-91 Exygen Study No.: 023-072 8 0 S : L -9 0 5 1 DEVELOPHENTAL PRODUCT D M M ter 7, I9M PAK 9 EXPOSURE LIM ITS (c o n tin u e d ) IN SR E O ieifT VALUE UNIT TYPE AUTH SKIM* t h * p o te n tia l c o n trib u tio n t o th # o v e ra ll axpoaura by th # cutanaoui ro u ta in clu d in g Jtacous a a a b n n t and aya, e it h e r by airb o rn e o r . aora p a r tic u la r ly , by d iro n t o o n ta o t w ith th a aubatanoa. v a h ic la s oan a lt a r akin a b ao rp tlan . SOURCE OP EXPOSURE LIM IT DATA: - SM: SM R a ce-- a n d s d E x p o a u ra QuldaJLlnaa S . HEALTH HAZARD DATA EYE CONTACT: No i n f o r m a t i o n w as fo u n d ra g a r d ln g a f f o c t a f r o a ay a o o n ta o t. 8 in g le oxpoaura say cau sa: H ild Eya I r r i t a t i o n : algna/ayaptona oan in clud e rednaaa, s n a llin g , p a in , and te a rin g . SION CONTACT! Mo i n f o r m a t i o n w aa fo u n d r a g a r d ln g a f f a o t a f r o a a k in o o n ta o t. nay bo a b so rb ed th ro u g h t h a ak in and p a r a le t in th a body f o r an extended tin e . S in g le expoeura sa y oauaa: M oderate s k in I r r i t a t i o n : algna/aynptoaa can in clud e rednaaa, SM ellliig, itc h in g , and dryneas. INHALATION: No i n f o r m a t i o n u a o fo u n d r e g a r d in g a f f a o t a f r o o i n h a l a t i o n o xp o a u ro . May b o a b s o rb e d b y i n h a l a t i o n and p e r * l e t i n t h a body f o r an e x te n d e d tin s. S in g le o v e re x p o s u r e , above rso o a a sa ded g u id el i n n , nay c a u sa : I r r it a t io n (upper re s p ira to ry ): sig n s/syap too * can include ao ran aas o f th o n ose and th ro a t, coughing and annexing. I P SHALLOWED: In g ea tio n i s n ot a lik e ly ro u ts o f axposura to t h is produet. No in f o r m a t io n w as fo u n d r e g a rd in g o f f s e t * f r o o s u a l l a u i n g . Anl e a l at u p l e s o o n d u eta d on o r g a n ic f l u o m n h s o i o a la u h ie h n ay be p resen t in t h is produot in d iea ta a ffa o ta includ ing liv e r d istu rban ces, w eigh t l o s s , l o t * o f a p p e tite , le th a r g y , and n e u ro lo g ic a l, p a n c r e a tic , a d r a r w l and h s a a t o l o g l c a f f a c t a . T h a r* a r e no known hsoan h e a l t h A b b r e v i a t i o n s : n/D N ot D o tc ro in a d N/A - N et A p p lic a b le CA A p p r o x lo a ta ly Exygen Research Page 91 of 153 418-028:PAGE G-92 Exygen Study No.: 023-072 M B S : L - M S 1 DEVELOPMENTAL PROOUCT Oeoeober * 7 , IS M pane a a . H EALTH HAZARD DATA (c o n tim i !} e f f e c t s fro a a n ticlp a ta d sxpoaurs to these organic flu o ro oh aeio ala u h m ueed m intandod and l n i t n a t u . OTHER HEALTH HAZARD INFORMATION: T h is p red u et Bay co n ta in ana o r ooro organic Y loero oh eaioal* th a t hava th a p a ta n tia X t o ba absorbed and raa a ia l a th a body f o r ie n a p e rie d a o f t i a a , e i t h e r a a th e p aren t aoieeuXa o r aa e e t i b o l i t e a , and a a y a c o u a u i a t t u l t h r e p e a t e d e x p o s u r e * . T h ere a r e n o known htaean h ea lth e ffa o ta fro n a a tle ip a te d exposure to th eae organlo f lu o r o c h a a lo a la when aeed a a in ten d ed and In r t r e s t e d . Tha p reaan oa o f o rg a n ic f lu o ro che a l e a l in th a Mood o f th e g en e ra i p o p u la tio n and su b p o p u latio n e , aaob aa Harfeere, has been p u b lished d a t i n g b a c h t o t h a 19 7 S ' . W a a p i d a a l a i n g i o a l stu d y o f i t a awn w orkers In d ica tes no adverse e ffe c ts . SECTION CHANGE BATES PRECAUTIONARY M R ) . SECTION CHAWED SINCE Nay 1 7 , 1 S H ISSUE A b b r e v i a t i o n s : N/D N ot O s t a r e in e d H/A Not A p p lic a b l e CA A p p r o x la a t tly Tha i n f o n s e t Io n in t h i a H a te r la l S a fe ty Data S h eet (M M ) l a b e liev ed to b a c o r r e c t a a o f th e d a t a i s s u e d , m N U BS NO WARRANTIES, EXPRESSED OR IM PLIED, O C U JD IM , BUT HOT UN ITED 7 0 , ANY XW UED WARRANTY OP HERCHANTAULITV OR FITN ESS FDR A PARTICULAR PURPOSE OR COURSE OP PERFORMANCE OR USABE OF TRADE. U se r i s r e s p o n s i b l e f o r d e te r m in in g w h e th e r t h e 3M p r e d u e t i s f i t f o r e p a r t i c u l a r p u rp o se and s u i t a b l e f o r u s e r 's aeth o d o f use a r a p p lic a tio n . Given th e v e r ie ty o f fa c to r a th a t c a n a f f e c t t h e u ae end a p p l i c a t i o n o f a 3M p r o d u c t, t o e s o f w hich a r e u n iq u ely w ith in th e u s e r 'a knowledge and c o n tr o l, i t la e a a a n tla l th a t t h e u s e r e v a l u a t e t h e 3M p r o d u c t t o d e te r a ln a w h eth er i t l a f i t f o r e p a r tic u la r purpose and s u ita b le fa r u se r'a aethod o f uae o r a p p lica tio n . 3H p r o v id e s in fo r m a tio n in a l e e t r o n l e f o r a as a s a rv io a t o i t s e u a te o a ra . Due t o th e re n o te p o s s i b i l it y th a t e le c tr o n ic tr a n s fe r m y hay re s u lte d i n e r r o r s , m i s s i o n s e r a l t e r a t i o n s In t h i s i n f e r a a t i o n , SM e a k a e no re p re sen ta tio n * aa to i t s eeap latenata or accuracy, is ad d ition , In fe ra a tio n obtained fro a a database aay not ba aa cu rran t aa th e in f o r m a t io n i n t h e HSOS a v a i l a b l e d i r e e t l y f r o a 3M. Exygen Research Page 92 of 153 418-028:PAGE G-93 Exygen Study N o.: 023-072 ATTACHMENTS TEST SUBSTANCE PREPARATION PROCEDURE Exygen Research Page 93 of 153 418-028:PAGE G-94 Exygen Study No.: 023-072 ATTACHMENTS V artan: TEST SUBSTANCE PREPARATION PROCEDURE Test Substance: T-7706 Vehicle: Aqueous 0.5% CMC (medium viscoeJty) Protocol 41B-02B A . Purpose: The p u rp o s e d this procedure is to provide a method for the preparation o f dosage suspensions o f T-7706 for oral (gevage) administration to rata on Argua Research Study number 418-028. B. General Information: 1. All suspension containers wM be (abated and color-coded. Each label wU specify the protocol number, test substance IdenMBcaBon, A r y batch number, concentration, dosage level, preparation date, expiration date and storage conditions. 2. Suspensions wfll be prepared: __ Daily X W eekly _F o r_d ayso fu se _ Approximately every ten days __ By Sponsor 3. Suspensions w be administered a t a final dosage volume of J O . mL/kg. 4 . Safety. J&_ Gloves. unlfbmVtab coat, goggles or safety glass* with side shields X Duat-mM/HEPA-fiKerad Mask __ Half-Face Respirator if not used In a chemical fam e hood ___ Ful-Faoe RespiratorfPositive Pressure Hood ___ Tyvek Suit or tyvek apron and sleeves 5. Dosage suspensions adjusted for % ActrvXy/PurHy o r Correction Factor __ Y es _X _ No (Calculations based on 100% ) __ % Activity __ % P u rity __ 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 VwikwdUjSEllJiefi^B Pag* 2 of2 TESTSUBSTANCE PREPARATION PROCEDURE NOTE: Prior to test substance preparation accurately measure th e required amount o f th e appropriate vehicle (R .O . deionized w ater should be used for calibration purposes) In a graduated cylinder, pour the required amount o f vehicle Into a beaker. Carefully mark each beaker a t die meniscus. This m ark will be used during the preparation to bring the test substance slurry up to volume. C. Dosage Suspension Preparation: 1. W eigh th e required amount o f test substance on a piece o f weigh paper or Into an appropriately sized mortar (see PREPARATION C A L C U L A T IO N S ). 2. If weigh paper Is ueed, transfer th e test substance to an appropriately sized mortar, if necessary, grind the test substance Into a fine powder. Slowly add a small amount o f vehicle and grind. Continue to add vehicle slowly and grind the vehicle and the test substance together to form a fine slurry. Transfer the vehJde/test substance slurry to a marked beaker. 3. Rinse the m ortar and pestle with additional vehicle to remove any remaining test substance. Transfer rinse to beaker. 4. Add additional vehicle to toe beaker to bring volume up to the mark. Place on magnetic stir plate and agitate prior to and during sampling, aliquottlng and/or administration. 5. Repeat steps (1 ) through (4 ) for each concentration. Written By. Clarification:___ No Yes [see attached clarification forni] Initlal/Date : 3 tn-03 Exygen Research Page 95 of 153 418-028:PAGE G-96 Exygen Study No.: 023-072 ATTACHMENT4 TISSUESTO BEWEIGHED,RETAINEDANDEXAMINEDHISTOLOGICALLY Exygen Research Page 96 of 153 418-028.PAGE G-97 Hxygen Study No.: 023-072 ATTACHMENT 4 Protocol 41S-028 Pag 1 o f 2 TISSUESTO WEIGHEDANDRETAINEDFORPOSSIBLE EXAMINATION FROM TENRATSFIR SEXPERGROUT Thetenratsper sexpergroupassignedto functional observational battery andmotoractivity testawillbe assignedto hematology, clinical biochemistryandhistological evaluations. TfrffttthW ritM : Thefollowingorganswill be excised,trimmedand individuallyweighedas soonaspossible afterexcisionto avoiddrying. liver spleen kidneys brain adrenals heart thymus ovaries testes uteres (with cervix) right epididymis prostate leftepididymis(whole andcauda) seminal vesicles (withsndwithoutSaid) The followingtissues orrepresentativesampleswill beretainedin neutralbuffered 10% fbnnalin. brain (representative regions includingcerebrum, cerebellum, pons) smallandhuge fat*TM(includingPayor'spatches) hmgs(perfusedwithneutralbuffered 1OKformalin) lymph nodes(submandiblar mediastinal} peripheral nerve (sciaticor tibial) gross lesions spinal cord(cervical,thoracic andlumbar) stomach liver kidneys adrenals spleen heart thymus thyroid/parathyroid trachea rtotry urinarybladder bonetnamrw (sternum) testes* ovaries prostate uterus seminalvesicles (withcoagulatinggland) vagina mammarygland (femalerats only) Testes willbe fixedin Bouin's solution for48 to 96hoursbeforebeingretainedinneutral buffered 10%formalin. Additjanally, dieremainingportion offee left epididymis(corpus andcaput),as well as theright epididymiswillbe fixed inneutralbuffered 10%formalin. Exygen Research Page 97 o f 153 418-028:PAGE G-98 Exygen Study No.: 023-072 ATTACHMENT 4 Protocol 41& 028 P * * elo T 2 HlrtoioricM Examlaath: Histological examinationofretained tusues, includingreproductive organs,willbeconducted forthe assignedten rati persex fromthecontroltod highdotagegroupand fromthe FI generationpups Givers)fromthecontrol andhighdosage group. Ifiesiom attributedtothe test suhstanceare observedin thetab exposedtothehighte*tsubstanceconccutrstion,the tame tissueswin be examinedfromtheassignedtenratapersex exposedto the lowerto* substance concentration*. Shouldresults warrantexaminationofthe lowerdosagegroupsandconducto f quantitative evaluation, scheduledreportdateandpriceswill be adjustedaccordingly. TheposUactiooal ovary shouldcontainprimordial andgrowingfollicles a*wellasthe Urge corporalutea oflactation. Histopathological examinationmaydetectqualitative depletionofthe primordial folliclepopulation. A.quantitativeevaluation ofprimordial follicleswillbe conducted forFogenerationfemalerats; thenumberofrats,ovariansectionselectionandsection samplesizewill bestatisticallyappropriate forthe evaluationprocedureused. Bxamtnatiopwill includeenumeration ofdienumberofprimordial follicles, whichcanbecombinedwithsmall growingfollicles, fix comparisonofovaries ofrats assignedtotreated andcoitirol group*. Tissues to be examinedhiatologicaltywill beshipped(ambientconditions)to: Principal Investigator. W.RayBrown, D.V.M.,PhD., ACVP VeterinaryPathologist ResearchPathologyServices, Inc. 438B. Butler Avenue NewBritain,Pconsylvama 18901 Telephone: (213)343-7070 Telefax: (213)343-4323 p.rnait- WRBRJPS@concentric.net Therecipient will benotifiedin advanceofsampleshipment Exygen Research Page 98 o f 153 418-028:PAGE G-99 Exygen Study No.: 023-072 m a r n a r M m. aui. a - I M M M IKH4 TH*wefZI3)44M7IO T+m e {2IS)4434M7 ARGUS RESEARCH Charles River Laboratori** Oteoteey a r i Devetopcnew Services PROTOCOL418-028 ORAL (GAVAGE) COMBINED REPEATEDDOSE TOXICITY STUDY OFT-7706 WITHTHEREPRODUCTIOWDEVELCHPMENTAL TOXICITYSCREENINGTEST SPONSOR'S STUDYNUMBER: T-7706.1 Amendment 1-17 April2002 > Detailed Clinical Observation-H ilf BKIHf -- h BlUf' n r ,n [EffectiveDate: 1April2002] Detailedclinical observationswill not be recorded formaleand femalerats assigned to toxicofcingticsampling. RtMgnfrcQiiw This changewas madebecausewflBcicntdatafcr evahiatio#ofdetailedclinical observationswillbeavailablefromtbe rats assignedto the mainctudy. 2- Feed ConauiwntionVahid - M*1 *fr*f" 11 n' th" P"*"*"1*' [EffectiveDate: 1April2002] Feedconsumptionvahieawillnotbe recoededor t a V ila M fiw m a U mnA f t im U w h to*wtfiAftK n^ 'g w w |iT tn | BaasrnforChBiffp: Thischangewas madebecausesufficientdata fix-evaluationoffeedconsumption willbe available flam die rats assignedto tbe mainstudy. A ay revisions m ade to this fln a lto d am endm ent m ust be aaade by se b ae q aan t amen dm e n t Exygen Research Page 99 of 153 418-028:PAGE G -100 Exygen Study No.: 023-072 3 . E a tro m C y c lin g anA M u tin y / y e 11 o f Am pm ftrvnTV Protocol41*40* Anaodowatl hpl [Effective Data: 1April 2002] FnrthgrmtmigTveritn trariealnngti* nmplmy estrooi cyclingwill be evaluatedduringfl cohabitationperioduntapennatozoe are observed in a tear ofthe vaginalcontentsand/ora copulatoryplugis observedin situ , but not duringthe dosageperiod, priorto cohabitation. B e a m for Change: Thigchangewasmadebecame imfRramtdatafix evaluationofcstroua cycling willbe available fromthe rati alignedto themain atudy. 4. M lffliu M SlCri.ffct - T W tiW ^e fe Study fpaaa l o ftha protncolV: [EffectiveDate: 5 April 2002] Thenomberofimplantationsitesandcapon tutea.will berecorded. Carcasses winbe discardedwithoutfartherevaluation. Itew n9fflw ngff Thiachangewasmade in ordertoprovidemoreinformationaboutpossible toxicityofthetest aubstancein pregnantrata. 3- ScheduledStmfiy - Mlin StdY(Pg H>Oftheprotocol): [Effective Date: 27 March2002] Tbenornberofimplantationaitei willbe recorded, ratherthan thenumberofimplantationaiteaandcorporabtteawiBbe recorded. Bfflata'gfi3aBgg The numberofcorporaluteawill not berecordedbecausecorporahitearegressat arapid rate and arenotcountedoo atndiea atweaning. 6. 19oftheprotocol): [EffectiveDate: 4 April 2002] The liverfromeachselectedpupwillbe exciied andtbe organweight recorded, ratherthantbeliver fromeachselectedpupwill be collected excisedand the organweightrecorded. A ny revisions Exygen Research Page 100 of 153 418-028:PAGE G-101 Exygen Study No.: 023-072 Reasonfor r hamgg- Protocol4li-028 nnunt 1 P*b 3 Thiclange clarifies theprotocol byremovinganextraneousword. c d JL Aim M. Hoberman,PhJ>.,DAflT DirectorofResearch Date RaymondG. York, Associate Director i StndyDirector H-J Z-TpZr DABT Data TheresaH. Woodard, D.VAI Date JohnButenfcofPhJD.,DABT, CIHDate Member, InstitutionalAnimai Care StudyMonitor and and Uae Committee Sponsor'sRepresentative Exygen Research Page 101 of 153 418-028:PAGE G-102 Exygen Study No.: 023-072 t05SMvCMK.B%A M M M * M 19044 T * flm t:(ltS )4 4 }S 7 IO Tifcffcc f2rS)44^8SS7 ARGUS RESEARCH ChorksKrer Laboratories D ltam y and D m to p m m t S erried PROTOCOL418-028 ORAL(GAVAGE) COMBINEDREPEATEDDOSETOXICITYSTUDY OFT-7706WITHTHEREPRODUCTION/DEVELOPMENTAL TOXICITYSCREENINGTEST SPONSOR'SSTUDYNUMBER: T-7706.1 Amendment 2> IS July2002 1. SafetyPrecautions (pane3oftheprotocoland Attachment 3pape 1of the protocol): [Effective Date: 29 April 2002] Ahalffitccrespiratorwillbe wornin additionto glove*, appropriateeyeprotectionandaunifonn/labcoat duringformulation preparation ofthebulkta t substance. Re4 m ferClimge: This changewas madeto matchthebalk test sidwtancetextwiththe text located withinthe Material Safety DataSheet 2 . S tu d y S ch ed u le (A tta c h m e n t 1 fia p e 1 n f th e p m tn c n l)- [EffectiveDate: 29 April2002] Thedates to r FOB andmotoractivity evaluations havebeen extendedto fourdays (06MAY02 - 09MAY02) ratter than twoday*(06MAY02 - 07MAY02). A ay revisions to d its du alized am endm ent m ost b e m ade by subsequent am endm ent. Exygen Research Page 102 of 153 418-028:PAGE G-103 Exygen Study No.: 023-072 Protocol 4 1*-028 Amendment 2 Page 2 tomtftrOBMg Thiachangewasmadebecausemore timeis neededto evaluateanimals assigned to FOB andmotoractivityevaluations. GJSl a IanM^hoberman, PhD., DABT ofResearch Date G. Yorl AssocialeDirector' StudyDirector iSjjUOe. B L kt^ ,l* J u L f2 tCJ. ,y ^-Therefl H. Woodard, D #M . Date JohnButenhoft PhD., DABT, CIHDate Member, Institutional AnimalCare StudyMonitor and and Use Committee Sponsor's Representative *** Any revisions to th is ttnalto d am endm ent m eat be m ade by subsequent am asdn en t Exygen Research Page 103 of 153 418-028:PAGE G-104 Exygen Study No.: 023-072 MfSMrM*a*A Hm Im M WOW Ww*piJ)4M7#P TW*e pIS}MUSST ARGUS RESEARCH Chartes R tn r Laboratories O taM ryortf Development Sendees PROTOCOL418-028 ORAL(GAVAGE) COMBINEDREPEATEDDOSETOXICITYSTUDY OFT-7706 WITHTHEREPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST SPONSOR'SSTUDYNUMBER; T-7706.1 Amendment 3-17 July2002 BulkTest SubstanceSampling. ShippingInstructions. ShippingInstructions. QtWMmSwfoaiHg- TffnkmhimrticStudy. Sriwfotat Swrificc - TwiwIiiinBis study, andSdWdWkd SuCTlfe (P*b s 4 ,5 .1 2 .1 3 .1 6 and 19. respectivelyofthe protocol) [EffectiveDate; 29 May2002] Sample* for perfluorohexanesuifonote(PFHS) analyaiaducted to Lin Clemenat3MEnvironmentalTechnologyandSafety Service*willbereahippodandremainingsamples, thatwereto be shipped to Lisa Clemenandhavenot yet been shipped,willhe shippedto: JohnFlaherty, PhD. (Principal Investigator) ExygenResearch 3058 Research Drive StateCollege, Pennsylvania 16801 Telephone: (814) 272-1039, ext 122 Telefax: (814)231-1380 Email; john.flaherty@exygen.com Any revision* to Ola flaaUxed amendment mast bemade by snbseqaaat amendment Exygen Research Page 104 of 153 418-028:PAGE G-105 Exygen Study No.: 023-072 Protocol 418-028 Amendment 3 Page 2 These samples include: Butt tot substance gangling (page4ofdieprotocol) Concentrationandhomogeneity(page5 oftheprotocol) Stability(page 5 ofthe protocol) Plasms toxicoltinetic ample(page 11 to 12amipage 16ofthe protocol) Plasma samples,ratherthanserumsamples, wereretained. Livertoxicokineticsamples (pages 12and 16oftheprotocol) Pooled fetal serumtoxicokinetic samples (pages 12and 16ofthe protocol) Pooled fetal liver toxicokineticsamples(pages 13and 16oftheprotocol) Pooled pup scram toxicokineticsamples (page 19offeeprotocol) Puplivertoxicokinetic sample (page 19oftheprotocol) Theanalyseswill be subcontractedto Exygenby the Sponsorandfee Quality AssuranceUnitforExygenResearchwill conductcritical phaseinspections and auditthe respectiveresults and reports accordingto the StandardOperating proceduresofthat facility. Suchcriticalphaseinspection reportand audit reports willbesubmittedbythat facilitytofeeStudyDirector,RaymondG. Yotk. The dateofthe inapectionsami reportsubmissionswillbe incorporatedinto a QAU statementgenerated byExygenResearchforinclusionin the finalreport for Protocol 418-028. Reason for Change: Thiachangewasmadeat therequest offeeSponsorbecause 3Mis not able to completethoformulationanalysis withtheirennentstaffing. ^ BJanM. J&bcrman,Ph.D., DABT Director of Research Date 1G. York, HhX>,, a}JLnTOCwTO--If1 StudyDirector j - Q J J L ____ A_ TheraBH,. Woodard,D.VAt Dato JohnButenhoff, PhJD., DABT, CIHDate t Member, Institutional Animal Care StudyMonitor and andUse Committee Sponsor's Representative Any revisions to this finalized amendment unit be wide by subsequentamendment Exygen Research Page 105 of 153 418-028:PAGE G-106 Exygen Study No.: 023-072 PROTOCOL 418-028 ORAL(GAVAGB) CQMBINBDREPBATBDDOSETOXHCTTYSTUDY OF T-7706 WTTHTHBRHPRCMXJCrrON/DBVELOPMENTAL TOXKTTYSCRKBNINOTEST SPONSORS STUDYNUMBBR: T-7706.1 Ameodment4-20 March2003 L Hnllr T--*S a M m a i S m alto . SMnning Trumetinm. SMpnhw S r f w A i k ! M i r i l i - T m I b U m A . Stndv. iMuAJwi Rxwtfr ftw a 5.12.13.16 ind 19. reroocthndv ofthe nrntncoDandAnifln<tnicnt3-liteni UBidfcTMtSahtmcBSmnHng. Shiming ftmnictitm- Shfotrint Imtrocdon. CiwniTffWhSectkTOjffr- TmrtQHBPtic StBfty. SstwduM Sacrifice - Ttatafrtnstte Stwiy. d Sfifo*taM Sunfisg (page i of A m endrtw w t3) [E ffe c tiv e D a te ; 2 7 F e b n ia ry 2 0 0 3 ] I t e a n a lyse s p e rfo rate cib y E x ig e a R e se a rch w illb e d o n e a c c o c d in g to E x y g e n M e th o d B xM -0 2 3 -0 7 1 R v is a l.e n f ifle d "M e th o d a f A n a ly sis f o t t e D e ta tn d o a lk n a fP crfto a to fa e x a n e su lfb n a te fP F H S ), P e rfh ro ro o cttiie su tfb o a te (P F O S ) nd P cm toctecaflu orooctan oic A c id (F F O A ) in R a t L iv e r , S ru m and U rin o R e v is k n 1*. Aay rerlgtoM to tfafaftaaHml aM ifaw ita m itb ta iid tliy iiilii H piw tiiaaad B n it Page 106 o f 153 418-028:PAGE G-107 Exygen Study No.: 023-072 ReM cnfncnummi- Protocol418-028 ABMNtfedBMSt4 P*(b2 THchange wamadeatthe requeatofdieBsygm Remoth in odor to clarify tbe methodofanalysis. CL jc Jo -fU s*- -- AlanM. PU>.,OABT J Date SfiHlyrHroctwr Chair, Institutional Annual Cara and Use Committee *<<** * g JohnBurcnhaff, PhJ)., DABT, CIHDate StodyMonitor and SpniBOi*!Rflpteteptitive i i Exygen Research Page 107 of 153 418-028:PAGE G-108 Exygen Study No.: 023-072 n RESEARCH Precise Research. \ Praw n Results. PROTOCOL DEVIATION deviation Number: 1 Date ofOccurrence: 10/14/02 Pepe 1 of 1 Exygen 'Study Number 023-072 Protocol Number 418-028 A recovery of 62%for PFH5 is being accepted for the 5000 ppb splke (0202119 Spk C) In data se t 100402A. \ Deviation Issued. 3iPP17.T1 liWMf WblWI.tifc Recorded By: 0^ Date:c CF7|lslo3 IMPACTON3TUSt The 10 ppb and 50 ppb control matrix spinas Included with the set gave acceptable recoveries. Date m r a l r e c k S ig natur* 1 z A A . Date f J r -L - M anagern? -?/a/a3 Dele (Sponsor) <~? Study Monitor 07 /f l/t o p - j. \ b a te Exvuen QAU Review / K 7 / fS'/ o 3 JIriFomwtPROTOCOl^^ieVlATION.doo . "."'"""... .V ... . -.... nr2i9l/r3si0f0i2f/l9r cft-. msteJlWl'oOlSBEiNfrff-lSSUGs W E , TO SUSPECTE^Lce&ef CR&INM-. l|lS'|3 3058 R oeaich Drive [Stete Cclqga. PA 16801, USA Y mt & m , exygBn.com Exygen Research Page 108 of 153 418-028:PAGE G-109 Exygen Study No.: 023-072 3058 Research Drive Sute College, PA 16801 Phone; 814-272-1039 Fax: 814-231-1980 NOTE TO FILE Pate: JM 4 3___ Exygen Research Study * ___ $835 7 2 . PROTOCOL # 418-028 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, th e concentrations o f fortification and calibration solutions listed throughout th e raw data w ere le ft uncorrected for th e salt content. The final PFHS values recorded w ere corrected to reflect th e difference in PFHS concentration due to the sa lt content. The correction was perform ed by multiplying the final ppb value found by 0.91. D ate: 0 l|) 4 |o 3 > Exygen Research July 31, 2001/0 Page 109 of 153 418-028:PAGE G-110 Exygen Study No.: 023-072 APPENDIX B 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 of 153 418-028:PAGE G -l 11 Exygen Study No.: 023-072 TITLE MethodofAnalysis fortheDeterminationofPcrfhiorohcxancsulfciiiate(PFHS), Perfloorooctanesulfooaie(PFOS) andPratadecafiuorooctanoicAcid(PFOA)inRat liver. Saura andUrineRevision I A I JB Q B S JohnFlaherty. KarenRistia, andEmilyDecker Noverai 20.2002 S fQ N S Q R 3MMedical DepartmentCapente Toxicology 3MCentex.Building 220-2E-02 St Paul,MN55144-1000 & LA BO RA TO R Y BxygenResearch 3058 Research Drive StateCollege. PA16801 BxM-023-071 Revision 1 TQ TA kH KM PBRO F FA gB S 43 Exygen Research Page 111 of 153 418-028:PAGE G -l 12 Exygen Study No.: 023-072 Exygen M tthod No: ExM-023^771 Reyfaio 1 MANAGEMENT APPROVAL Exygen Research -- 7. Im Z L I'/tf JohnL. Butenhoff Date SponsorReprwentative 3MMedicalDepartment CorporateToxicology Exyfen Reaeoch Exygen Research Page 2 o f 43 Page 112 of 153 418-028:PAGE G -l 13 Exygen Study No.: 023-072 E x y jtai M ethod N o; ExM-023417 I Ravtatoo 1 TABLE OF CONTENTS TTTLB. MANAGEMENTAPPROVAL.. TABLE OF CONTENTS. LISTOFTABLES .1 -.2 .3 LISTOFFIGURES.. .5 1. SUMMARY. 2. EXPERIMENTALCOMPOUNDS. .7 .8 3. CHEMICALS ANDSUPPLIES------- >t -- a 3 3.1. CHBMKALS 9 3.2. Standards 9 3.3. Equipment and Supples 9 3.4. Solutions 3.5. Preparation o f Standard So u iu q n s 10 10 3.5.1. Stocksolution 11 3.5.2. Fortification Solutions 11 3.5.3. Calibration Standards 11 METHOD 12 4.1. FLOWDlAOKAM 12 a aaaaaa|*af*aa*ataa*taaN a aw aaaa aaaM n#ata*M a*4aw *w a> 4.2. S a m p l e P r o c e s s in g M aaaaaaiiH aaaaaaaaataiaaaaaH aaa a** i* a a a12 43. B a t c h S e t u p .. 4.4. S a m p l e E x t r a c t io n . 4.4.1. liver Extraction.. .13 .13 .13 45. 4.4.2. Scrum and UrineExtraction 13M iM M iiM M iaaaaitiaaiaaaaaaaaiM aa> H aiaa> aM ai> aiH aa 4.4.3. SPE Column Conditioning 14tfMMaa<aaMaaaaaN*aMaaM aaaaa>aHaaaaaHaai*a aaaaaaaiaaaaaaa Q u a n t it a t io n ......... aia*aaaaa>aiaaa>aaaM ai>aa iaiM>aaa ................................................................... .. 14 45.1. LC7MS/MSSystemandOperatingCondition*-- ------- ----------- 14 45.X CalibrationCurveProcedure* ............. ....... --............... 15 45.3. Sample Analysis.................... ........................................... ..... 16 4.6. Acceptance Criteria.......... ............................................... .............................. 17 4.7. P er fo r m a n c e CsnsaiA.................. .............................. - ......................... 17 4.8. Time Required f o r A n a l y s is ................................ - ............................. ............. - ............ 18 5. CALCULATIONS. 18i**aa*a*4aM aaaaM aai*aaaaaa>iaaaiiaaaatuaaaa*M aaiaM aaaaaaaaa aaaaiaaaaaaaaaaaaaifaatii 6. SAFETY.. .1 9 Esyp ealt aw re h P lR B 3of43 Exygen Research Page 113 of 153 418-028:PAGE G-114 Exygen Study No.: 023-072 1E x y g n M rtn d N o; ExM 423-071 R m U m LIST OF TABLES Table 1. RecoverySummaryofPFHSinRatLiverandSenna............................... 20 Table2. RecoverySummary ofPFOSInRatliver, SerumandUrine..................... 21 Table3. RecoverySummaryofFFOAInRatLiver, SerumandUrine___________ 22 ExygenResearch Exygen Research P ig c4 o f4 3 Page 114 of 153 418-028:PA GE G -l 15 Exygen Study No.: 023-072 E q raea M ethod N o: BxM -023-071 Rm rUoa 1 LIST OF FIGURES Figure 1. CalibrationCurveforPFHS...................... ................................ ..... . 23 Figure 2. C a lib ra tio n C u rve forPFOS....... ....... ........................................ ..........................24 Kgure3. Calibration Curve forPFOA............................ ............. .................. 25 Figure 4. RepresentativeChromatogramof a 0.1 ng/mLStandard ContainiugFFH5.... ................ ............................... .............. ........26 H gure5. Representative Chromatogramofa 0.1 n^mL StandardContainingPFOS...26 Figure 6. RepresentativeChromatogramofa 0.1 ng/mLStandardContainingPFOA..27 Figure 7. RepresentativeChromatogramofa 0.5ng/mLStandardContainingPFHS...27 Figure 8. RepresentativeChromatogramofa0.5 ng/mLStandardContainingFFOS...28 Figures. RepresentativeChromatogramof a0.5 ng/mLStandardContainingPFOA..28 Figure 10. RepresentativeChromatograma t a S.Ong/mLStandardContainingFFHS...29 Figure 11. RepresentativeChromatogramof a S.Ong/mLStandardContainingPFOS...29 Figure 12. RepresentativeChromatogramofa S.Ong/mLStandardContainingPFOA..30 Figure 13. RepresentativeChromatogramofa ReagentBlank SampleAnalyzedfor FFHS............................... .......................................................... 30 Figure 14. RepresentativeChromatogramof aReagent Blank SampleAnalyzedfor PFOS..... ............................ ......... ............................ ,,............,,...31 Figure IS. RepresentativeChromatogramofa ReagentBlankSampleAnalyzedfor PFOA............................................................... ..........................31 Figure 16. RepresentativeChromatogramof aControl LiverSample Analyzed forPFHS.-.................................................. .................. ...... 32 Figure 17. Representative Chromatogram o f a Control L ive r Sample Analyzed forPFO S-..................... .............................. ................................. .32 Figure 18. RepresentativeChromatogramof a Control Liver SampleAnalyzed forPFO A ....................................................... 33 Figure 19. RepresentativeChromatogramof a Control SerumSampleAnalyzed for FFHS........................................................................ - ........ - .............................. 33 Figure 20. RepresentativeChromatogramofa Control SerumSampleAnalyzed forPFOS-------- --------- 34 Figure 21. RepresentativeChromatogramof a Control SerumSampleAnalyzed for PFOA............................... 34 Figure 22. RepresentativeChromatogramofa Control Urine SampleAnalyzed forPFOS....................................................... 35 Figure 23. RepresentativeChromatogramofa Control Urine Sample Analyzed forFFO A ............................- ....................... .................... ........... ............................35 Figure 24. RepresentativeChromatogramofa Control Liver SampleFortified at 10n^g withFFHS........................................................ 36 ExyiM Research P a je 5 o f 43 Exygen Research Page 115 o f 153 418-028:PAGE G-116 Exygen Study No.: 023-072 Bxnn MethodNo:BXM-4B3-071Reridon1 LIST OF FIGURES (continued) Figure25. RepresentativeChromatogramofa Control LiverSampleFortified at 10ng/gwithPFOS.... ........... ....................................... Figure26. RepresentativeChromatogramofaControl Liver SampleFortified at 10ng/gwithFFOA....... ............... .......... --.......... . Figure27. RepresentativeChromatogramofa Control LiverSampleFortified at 50ng/gwithPFHS......... .................. .............................. Figure 28. Representative Chromatogramofa ControlLiverSampleFortified at 50 ng/g with PFOS __ ............................................. Figure29. RepresentativeChromatogramofa Control LiverSampleFortified at 50ng/gwithPFOA....... ................ --.... ......................... Figure30. RepresentativeChromatogramofa Control SerumSample Fortified at 10ng/mLwithPISS.......... ...... ..................... .................. Figure31. RepresentativeChromatogramofa Control SerumSampleFortified at 10ng/mLwithFFOS.....-- .... ...........................--......... .... Figure32. RepresentativeChromatogramofa Control SerumSampleFortified at 10ngftnLwithFFOA............ -.......................................... Figure 33. RepresentativeChromatogramofa Control SerumSampleFortified at 50ng/mLwithPFKS--------- --------------------- .... ........... Figure 34. RepresentativeChromatogramoft Control SerumSampleFortified at 50ng/mLwithPFOS.......................................................... Figure 35. RepresentativeChromatogramof a Control SerumSampleFortified at 50ng/mLwithFFOA------------------------------------------- Figure 36. RepresentativeChromatogramof aControl Urine SampleFortified at 10ng/mLwithPFOS...... ............... --........................... Figure37. RepresentativeChromatogramofaControl Urine SampleFortified at 10ng/mLwithPFOA................ ........................................ Figure 38. RepresentativeChromatogramof aControl UrineSampleFortified at50ng/mLwithPFOS ......... ....... ...----------------------- Figure 39. RepresentativeChromatogramofa Control Urine SampleFortified at 50ng/mLwithPFOA.............. .............. ...... ..... ..... ...... . 36 37 37 38 38 39 39 40 40 41 41 42 42 43 43 ExygenRaearch Exygen Research Page6of43 Page 116 of 153 418-028.PAGE G -l 17 Exygen Study No.: 023-072 B xyjen M ethod N o: BxM -023-071 R eviiioo ] 1. SUMMARY This repost details a method of analysis for residues ofPeriluorohexanesulfonate (PFHS), PeriluorooctsiKaulfonare (PFOS) and Pentadecafluorooctanoic Arid (PFOA)in RatLiver, SerumnodUrine. Residues of PFHS, PPOS and PFOA ate extracted from each matrix with acetonitrile. The acetonitrile extract is added to water and loaded onto s conditioned C18 solid phase extraction (SPB) cartridge. Analyte residues are eluted with 2 mL of methanol. Quantification of PFHS. PFOS and PFOA is accomplishedby liquid chromatography/landem mass spectrometry (LCVMS/MS) analysis usingmultiplereactionmonitoring(MRM). The proposed limit ofquantitation(LOQ; the lowestfortification specified bythe method which gives adequate recovery according to EPA guidelines) for this methodis 10ng/g (parts-per-billion) eachforPFHS, PFOS andPFOA. The theoretical limit of detection (LOD) will be basedon the signal to noise ratio and will be at least greater than 3 tunes the level of noise, based on the instrumentation system used. For all analytes, die lowest analytical standard caaesponds to0.1 ng/mL. This method was developed using rat liver, serum and urine. Typical percent recoveries standarddeviations (at 10and30ng/g) are shownbelow: Portiflcatkm L evd (natal 10 30 PFHS Recovery in R at L iv er 113 9 .9 (i 3 ) 98% 3 .5 (n-31 F orttfeatioa L evd (oa/m L) 10 50 PFHS R ecovery in R at Serum 1 0 8 * 4 .7 * (-31 111* 9 .3 fa-3 ) F o rtificatio n Level (n s/sl . 10 30 PFOS Recovery in Rat L iver 9 6 * 8 5 * fo-31 W U fa-3 ) F o c d fie stio a Level (n aftn L ) 10 30 9 F 0 8 R ecovery la R d Serum 8 8 * 9 .8 * (m 3) 120* i l * fn-31 PPOS R ecovery In Rnl U rine 9 3 4 .7 * fa-3) 7 9 ft lJ* tD -3 1 F o rtific a tio n Levd (n a ta l 10 30 PFO A Recovery in Rat L iver 9 8 * 3 .1 * (o-3) 9 4 * 2 .5 * (d -3> ForiM eition Level (tvdm U 10 30 PPOA Recovery in R at Seram 1 1 7 * lJ* (n -3 ) 111*1441* fa-3) PFOA R ecovery in R at U rine 8 9 * 2 J* (n -3 ) 8 7 2 .1 * ftt-3 ) Representative calibration curves are shown in Figures 1-3. Representative chromatograms are shown inFigures 4to 39. E xyfeti Research P sge7of43 418-028:PAGE G -l 18 Exygen Study No.: 023-072 1Exygen M ethod N o; BXMOZ3-071 K erin o a 2. EXPERIMENTAL COMPOUNDS The structures forPFHS, PFOSandPFOA aregiven below. PFHS ChemicalName * Molecularweight = Perfiuorohexaneaulfonatc 399, as shown F f_F PFHSi*suppliedas thepotassiumsalt (CFi>SOj'K*).molecularweight 438 pros ChemicalName = Molecularweight = Perfluorooctanesulfonate 499,as shown PFOSis supplied as the potassiumsalt (CjFitSOjTC)molecularweight 338 PFOA Chemical Name Molecularweight = Pentsdecafluesooctanoic Acid 413, as shown 0 Exygen Research Page I o f43 Exygen Research Page 118 of 153 418-028:PAGE G-119 Exygen Study No.: 023-072 ExygenMethod No:ExM-023-071 Rendon 1 3. CHEMICALS AND SUPPLIES 3 X Chemicals_________________________________________________ Chondral Grade Source Catalog No. Methanol (MeOH) HPLC EM Science AmmoniumAcetateReagent JT Baker Water TypeI Exygen Acetonitrile HPLC EM Science MX0475-1 0596-01 NA AX0145-1 Type I water= electrical resistivity, minimumof 16.67MQ/cm at 25 "C, froma LabconcoWaterpro1* workstation. 3.2. Standards Sta n d a rd Perfluorohexanesulfcmate (FEHS) Periluorooctanesulfonate (PFOS) Pentadscafluorooctanoic Acid (PPOA) T C R N um ber SE-036 SD-018 LotNo: 08316DO P u rity (W ) 99.99ell isomers. 84.36straightchain 86.9 96 Som e 3M 3M Aldrich Chem 3 3 . EQVIFatKNTANDSUPPLIES Balance, analytical (displayat least0.0001 g) 125-mLLDFE narrow mouth bottles Disposable glass micropipets(50-100& 100-200pL) Tissumizer Wrist action shaker Sorvali RC5Cplus Centrifuge 50mLdisposablepolypropylenecentrifuge tubes 15mLdisposablepolypropylenecentrifuge tubes Visiprep vacuummanifold SepPakVec6cc(lg) tC18cartridges(part#WAT 036795 2-mLclearHPLCvial Kit (cat# 5181-3400) Class A pipetsandvolumetricflasks Standardlabequipment (graduatedcylinders. disposable tubes etc.) Stand-alone drop-in guard cartridge holder (part #844017-400) Hypercarb drop-inguardcolumn (4mm) (part # 844017-400) HPLC Pump (LC-10AD) LC/MS/MS and HPLC systems Sumiller Mettler Nalgene Drummond (VWR) Tekmar Burrell Scientific Dupont VWR VWR Supeko Waten Hewlett-Packard various suppliers various suppliers Keystone Scientific Keystone Scientific Shimadzu As described in section 4.5. ExygenResearch Page9of43 Exygen Research Page 119 of 153 418-028:PAGE G-120 Exygen Study No.: 023-072 E x y g n M ethod N o: E x M 2 3 -m a M o a l Notes: 1. In order to avoidcontamination, the use of disposablelabware (containers, tabes,pipettes, etc.) is highlyrecommended 2. TfcflanorTeflon-linedcontainersorequipmentshouldnotbe used. 3. It may be necessary to check the solvents (acetonitrile, methanol) fior the presence of contaminants (especially PFOA) by LC/MS/MS before use. Certainlot numbershavebeen foundto be unsuitablefor use. 4. Use disposable micropipettes or pipettes to aliquot standard solutions when preparingstandards andsamplesfortraction. 5. Equivalent materials maybe substitutedforthosespecifiedin diis method. M . Solutions (1) - 2 mM ammonium acetate in water is prepared by weighing 0.154 gof ammoniumacetate anddissolvingIn 1L ofwater. (2) Hypercaib filtered type I water is prepared by filtering type I water through a Hypercaib guard column using a HPLCpump at -2-3 mL/min Before use, wash the guard cartridge with -25 mL of HPLC grade acetonitrile, then - 25 mL of type I water, then begin collecting the filteredtype I water eluatefearuse io the extraction. Repeat die wash alter filtering -2L ofwater. Note: The aforementionedexampleis providedforguidance, alternative volumes may be prepared as long as the appropriate ratios of the solvent to solute are maintained. 3.5. Preparation o p Standard Solutions Analytical standardsareusedforthreepurposes: 1. Calibration Standards-Ihese standards are preparedIn methanol and are usedto calibratethe response of the detectorusedin the analysis. 2. Laboratory Control Spikes - These fortifications are prepared at concentrations corresponding to die LOQ and Sx LOQ and are used to determine analytical recovery. Laboratory control spikes are prepared in control matrix. 3. Matrix Spikes- These fortifications arepreparedby spikinginto the field samples at aknown concentration. Matrix spikes me usedto 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 ofsolute tosolventare maintained. ExygenResearch Page 10 o f 43 Exygen Research Page 120 o f 153 418-028:PAGE G-121 Exygen Study No.: 023-072 ExygenMethodNo: ExM-023-071 Rstmoq1 3.5.1. Stock solution Prepare individual stock solutions at 100 figfmL far PFHS, PKXS and FFOA by weighing out 10 mg of each analytical standard (corrected for purity and if necessary, salt content) anddilute to 100 mL with methanol in separate 100-mL volumetric flasks. The stock solutions Cm 12S-mL LDFE bottles) an to be stored in a refrigerator at 2C to 6*C and are stablefor a maximumperiodof one yearfromthe dateofpreparation. 3.5.2. Fortification Solutions a. Prepare a mixed fortification standard at 1.0 pgfrnL (1000 ngftnL) of PFHS. PPOS end PPOA by adding IX)mL of each of the lOOpg/mL stock solutions into a 100-mLvolumetric flaskandbringupto volume with methanol. b. Prepare a mixed fortification standard at 0.1 pgftnL (100 ngfrnL) of PFHS, PPOS and PPOAby diluting 10.0 mLofthe 1.0 pgtaL mixed fortification solutionto 100mLwithmethanolin a volumetricflask. Example: one hundred microliterof the 0.1 pgfmL solutionspiked into 1 g of liver or 1mL of serumAnine is equivalent to a 10 ppb (10 ng/mLor ng/g) fortification. Store all fortificationstandardsolutionsin arefrigerator (in 125-mLLDPE bottles) at 2C to 6C for a maximumperiod 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 PFHS, PFOS and PPOA are preparedat0.1,0.2,0.5,1.0,2.0 and5.0ngfinLin methanol viadilutionof the0.1 pg/mLmixedfortification solution(section 3.5.2.b). The following is a typical example; additional concentrations may be prepared asneeded. Initial Cone. (nntaL) 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. _ (ngftnL) 5JO ZO 1.0 05 0.2 0.1 The standards may be used for a period of one year (in 123-mL LDPE bottles) whenstaredrefrigerated(at 2Cto 6C). Exygen Research Page 11 o f 43 Exygen Research Page 121 of 153 418-028:PAGE G-122 Exygen Study No.: 023-072 B x y g n M ethod N o: B *M -t& 3-0711tevU an] 4. METHOD 4.1. Flow Diagram The flow diagram of the method is given below, followed by a descriptionofeach step. MethodFlowDiagram Weighappropriateamount ofliverormeasureappropriate volumeofscrumor urine (fortifysamples designatedas matrix spikes andlaboratorycontrol spikes) 4 Addwatertoliverfor a final volumeof 10mL, add waterto serum andurine fars final volume of20mL,homogenize 4 Remove 1mLand*dd5mLof ACN, shake i Centrifuge Decantsupernatant into 33mLof water i Load ontoconditionedSPE 4- Elute with2 mLmethanol i LC/MS/MS Analysis 4 0 . Sam ple P rocsssing For liversamples, place frozen samples in a food processor andhomogenise with dry ice. Then place samples in containers and leave open in frozen storage overnight to allow for COj sublimation. Seal and place the samples in frozen storage below -1QC until time of extraction. Alternately, if there is an insufficient amount of sample (- less than S g), then no processing is necessity and the sample can be used as supplied. No sample processing is needed for serum and urine samples. However, frozen serum end urine samples must be allowedto completely thawtoroomtemperaturebeforeuse. BsjffniResearch F a r of 43 Exygen Research Page 122 of 153 418-028:PAGE G-123 Exygen Study No.: 023-072 E xygra M ethod No: E xM -02W m K svislo* I 4 3 . Ba tc h Se t u p a. Abatchofsamples shouldnot containmare than 20fieldsamples. b. Each batch of samples analyzed must include at least one control (method blank using control matrix) and two matrix controls fortified at known concentrations (typically 10 and SOn g /g far liver or ng/mL for serum and urine) toverify procedural recoveryforthe 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 thebatch mayalsobefortifiedif desired. d. All samples requireduplicateinjections. U S a m t u c E x t r a c t io n 4,4.1. liv e r Extraction a. Weigh 1 g of liver sample into a 30 mL disposable centrifuge tube and fortify, if appropriate. Note that alternate weights of liver may be measureddependingonthe samplesizeavailablefornse. b. Addwaterto foe sample fora final vdhmieof 10mL. Captightly. c. Homogenizesamplewringa tUsuemizerfor -1 minute. d Transfer 1 mL of the sample using a disposable pipette into 13 mL disposable centrifuge tubes. Add 5 mL of ACN and shake for -20 minutesona wrist actionshaker. e. Centrifuge tubes at -3000 rpra for - S minutes. Carefully decant supernatant into a SOmL disposable centrifuge tube and add 35 mL of water. f. Load the sampleonto a conditioned SPEcolumn (forconditioningdetails, see section 4.4.3.). Discard the eluate. Any analyte residues will be trappedon the SHEcolumnat thispoint. g. Elute with 2 mL of methanol Collect 2 mLof elute into a graduated IS mLcentrifuge tube. h. AnalyzesamplesusingelectrosprsyLC/MS/M5. 4.4.2. Scrum and U rine 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 serumand urine maybe measured depending on sample size available for E xyanR esonb Page 13 of 43 Exygen Research Page 123 of 153 418-028.PAGE G-124 Exygen Study No.: 023-072 BxygenMethodNoeBsM*023-07IRevision! b. Addwaterto samplefor a finaj volume of 20 mL. Cap tightly and voit for-1 minute. Thencontnuewith topd-hin section4.4.1. 4.4.3. SPE Column Conditioning Placethe unconditionedSPEcolumnsos the vacuummanifold. Condition die 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 vacuumat a flowrate of -1 drop/sec or maybe allowedto pass through the columnunaided. Discard all washes. Do not allow thecolumn to dry. U Quantitation 4.5.1. LC/MS/MS System and O perating Conditions Mass Spec: Micromass Quattro Ultima (Micromass) Interface: Electrospray(Micromass) Harvardinfiisioupump(HarvardInstruments), for tuning Computer COMPAQProfessional Workstation AP200 Software: WindowsNT,Masaiynx33 HPLC: HewlettPackard (HP) Series 1100 HP Qust Pump HPVacuumDegasser HPAutosampler HPColumn Oven Note: A4 x 10mmhypercarb dropin guardcartridge is attachedon-line after the purge valveandbefore the sampleinjectorport to trap anyresidue contaminants that maybe in die mobilephase and/orHPLCsystem. HPLCColumn: GenesisC| (JonesChromatography), 2.1 mmx 50mm,4|i ColumnTemperature:35 C Injection Volume: 13pL MobilePhase (A): 2mMAmmoniumAcetatein Type I water MobileRuse (B): Methanol Eme S tA 0.0 90 2.0 90 5.0 10 9.0 10 9.5 0 14.0 0 14.5 90 20.0 90 S tS . Plow Rate fmL/minl 10 03 10 03 90 03 90 0.3 100 03 100 0.3 10 03 10 03 ExygaiResearch Page 14 o f 43 Exygen Research Page 124 of 153 418-028:PAGE G-125 Exygen Study No.: 023-072 Bxyge* M ethod N o: E *M -023-07l R ovino 1 It may be necessary to adjust the HPLC gradient in order to optimize instrument performance. Column*withdifferentdimensions (e.g. 2.1 x 30) andalsocohmms from different manufacturers (Keystooe Betaail Ch etc.) could be used, provided equivalentchromatographyis obtained. femjnKMiitoBBd* Analyte FFHS EPOS PFOA Mode TramMonMonitored Negative 399-80 Negative 499-99 Negative 413-> 369 Approximate Retention Time -851mm. - 8.8min -845 min The retention times may vary, on s 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 standardsamincludedat thebeginningandendof 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 infosing a - 1.0 (i^mL standard solution (at 10 pL/min, using an infusion pump) via a "V into a stream of mobile phase containing 50% methanol and 50% 2mM ammonium acetate in water at 0.2 mL/mmflow rate. Each analyte 1initially 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. 4.3.Z Cditbratian Curve Procedure a. Inject the same aliquot (between 10 to 50 pL) of each calibration standard (ranging fromthe lowest level standardto the hipest level prepared), intothe LC/MS/MS. b. Use weighted linear standard curves for quantitation. Linear standard curves are generated for each analyte by linear regression using IAt weighting of peak area versus calibration standard concentration using Maaslynx (or equivalent) software system. Anycalibration standardfoundto be a statistical outlier by using an appropriate outlier test, may be excluded from the calculation of the calibtadoo curve. However, the total number of calibration standards that maybe excluded must not exceed 20% of die total number of standards injected. c. The correlation coefficient (R) for calibration curves generated must be 205)925 (R* 20.985). If calibration results fall outside these limits, (hen appropriate steps must be taken to ad)ust instrument operation, and the standards or therelevant set ofsamples shouldbe reanalyzed. Exygen R asso d i Page 15 o f 43 Exygen Research Page 125 of 153 418-028:PAGE G-126 Exygen Study No.: 023-072 1E x y g n M ethod K o: BxM -Q234m RevM oa Typical calibrationcurvesforPFHS,PPOS andPFOAcn be foundin Figures 1- 4.5.3 Sample Analysis i Inject the same aliquot (between 10 to SO pL) of each (Undent, sample, recovery, control,etc. intotheLC7MS/MSlystem. b. Standards correspondingto at least five or more concentration levels (darting with ft LOQlevel orbelow)mustbeincludedin an analytical let c. Ac entire set ofcalibration standards should be injected at the beginning of t set followed by calibration standards interspersed approximately every 5-10 samples (to account for a second set of extracted standards). As m alternative, an entire set of calibration standards may be included at the beginning and at the end of a sample seL In either case, calibration standards mostbethe first andlastinjectionin a sampleset. d. The concentration ofeach samplc/fortification/control is determined bom 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 19 to 10%outside the curve by extrapolation. If necessary, dilute the samples to give a response within the standard curve range. e. Fortificationrecoveriesfallingwithin70 to 130%are consideredacceptable. f. Sample*must bestoredrefrigeratedbetween2C to 6Cuntil 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 se ND (not detected). Samples fat which peaks are detected at the corresponding analyte retention time that are less than the LOQandgreaterthan or equal to the lowest concentration of the calibrationstandards willbe reportedasNQ (notquantifiable). The analysis performedduring the method development included fortifications at 10 and 50ng/j ofPFHS in rat liver, 10 and 50ng/mL of FFHS in serum, 10and 50 ng/gofFFOS andPFOAin ratliver and 10 and50 ngfmLofFFOS andFFOA in serum andurine. Typical chromatogramscanbe foundin Figures4-39. Exyfen Research Pam 16 o f 43 Exygen Research Page 126 of 153 418-028:PAGE G-127 Exygen Study No.: 023-072 Baygea MethodNoeB*M-0234>71Rsvinoal 4.6. Acxxptanck Cr iter ia The fallowing criteria moat be met to easure the presence of FFHS, PPOS and PFOA: 1. Thechromatogramoust show a peak ofa daughterion at BOamn from a patent of 399 amu for FFHS, a daughter ion at 99 amu lima a patent of 499 amu for PFOS, and a daughter it at 369 amufrom a patent of 413 amufor PFOA. 2. Methodblank* mustnot contain analyteat level*greaterthanthe LOQ. If a blank containa dm analyte at levels greater than 10ng/mL, then a new blank samplemustbeobtainedandthe entiresetmustbere-extracted. 3. Recoveries of conttol spikes and matrix spikes (if any) must be between 70-130% of their known values. V a control spike falls outride the acceptable limits, the entire set of samples should be re-extracted. Any matrix spike outride 70-130% should be evaluated by the analyst to determineif re-extraction is warranted. 4. Anycalibration standardfoundto be a statistical outlierby usingthe Huge Error Test, may be excluded from thecalculation ofthe calibration curve. However, the total numberof calibration standards thatcould be excluded mustnotexceed 20%ofthe total numberof standardsinjected. 5. The correlation coefficient (R) for calibration curves generated must be 0.9925 (R10.985). If calibration results Dill outride these limits, then appropriate steps must be taken to adjust instrument operation, and the standards orthe relevant set a t samples shouldbe reanalyzed. 6. Retention times between standards and samples must not drift more than 4 % within an analytical run. If retention time drift exceeds this limit within ananalyticalrunthen the setmustbereanalyzed. 4.7. PERFORMANCE CRITERIA The following two criteria must be perfumed once as s system suitability teat, before the commencement of analysis, when using an instrumentation set-up that hasnot beenusedfarthis method. FirstCritcoad: Run a standard solution on LC/M&/MS corresponding to the estimated LOQ (10ngtaiL) in matrix andobtain a signal tonoise ratio fertile analyte transition of atleast 9:1, compared to a reagentblank. If this criterioncannot be met,optimize and change instrument operating parameters (or increase the injection volume, if appropriate). ExygenResearch Page 17 o f 43 Exygen Research Page 127 of 153 418-028:PAGE G-128 Exygen Study No.: 023-072 Exy*enMethodNo:ExM-fl2:W)71 Bevtaa 1 SecondCritcritm: Run s set of standards of five or more concentration levels, fromat or below the LOQ, up to the highest concentntioa level to be included in the analysis. Generate a calibration curve far the analyte and obtain a linear regression with a coefficient of determination (R1) of at least 0.965 for the analyte. Once this criterion is met, samples maybe analyzedwithstandards interspersed. U Tim e Req u ired fo r Analysis Oneperson can take a set of20samplesthroughthe samplepreparationprocedure in approximately4 hours. TheLC/MS/MS analysis ofthe set (containing20field samples, 1 matrix blank, 2 laboratory control spikes, 1 matrix spike and 12 standardinjections)will take approximately 14hours. 5. CALCULATIONS a. Use Equation 1to calculate die amount of analyte found (in ng/mL, based on peak area) using the standard curve (1/x weighted linear regression parameters) generatedbydieMasslynx softwareprogram. E quation 1: Anslyt franwt .1=Ipfl.ll;.M intercept! xDFx aliquotfactor slope DF= factor bywhichthe final volumewas diluted, if necessary. Aliquotfactors 10for fiver, 20forserum endurine b. For samples fortified with known amounts of analyte prior to extraction, use Equation2 to calculatethe percent recovery. 7' Recovery{%) = [totalanalytefound(ng/mL) - analytefoundincontrol(ng/mL)] j[10Q analyteadded(ng/mL) Notet Subtract analyte foundin control (ng/mL) Gramanalyte found(ng/mL), ifng/niLin control is greaterthanLOQ. ExyfeaResearch P SelB o f Exygen Research Page 128 of 153 418-028:PAGE G-129 Exygen Study No.: 023-072 1Bxygsa M a te d Noe E x M -m 0 7 1 R eviiioa c. UseEquation 3 to calculateCheamount af analyte found(in ppb) F^utfinn A M lyteftnM l (a |fe or n a ta l} - simfmpolehwnoefigohunt(d(](momrtma LolpkFvVahrtm- no (mL) FV=final volume For reporting pupates, 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 repotted as ND (not detected). Sample* in which peaks are detected at the corresponding analyte retention time that areless than theLOQ andgreaterthan orequal to dielowestconcentrationof thecalibrationstandardswill bereported asNQ(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 fame hoods and wearing laboratorycoats, safety glasses,and gloves. Exygen Research Exygen Research P ige 191*43 Page 129 o f 153 418-028:PAGE G-130 Exygen Study No.: 023-072 E x y tn M ethod N o: E*M-C23-071 Revieron 1 Table 1. Recovery Summary of PFHS in Rat Liver and Serum Recovery Sum m ary o f PFHS In R al liv e r BamotID 0201684 Spk A 0201684 SpkB 0201684 Sok C Analvta Added fnc/o) 10 10 10 AVMQK Standard DavW on: Percent Raeovarv (%t ..... t U M f 110 126 IIS 8J Sam el* ID 02016B4 Spk D 0201684 Spk E 0201684 SokF Analyte Added (noto) SO SO SO Av u iq k Standard Deviation; Percent Raeovarv (%) 101 98 84 88 &S Recovery Sum m ary o f PFHS In Rat Serum lID 0201682 SpkA 0201682 SpkB 0201682 SokC 10 10 10 Average: Standard Deviation: 112 109 110 108 4.7 SkuaolalD 0201682 Spk 0 0201682 8pkE 0201682 SokF Analvta Added (mVmU SO 50 SO Average; Standard Deviation: Pareen* Raeovarv (%1 107 104 122 111 8.6 Exygen R a catth Exygen Research Pae 20 o f *3 Page 130 of 153 418-028-.PAGE G-131 Exygen Study No.: 023-072 Bxyjen M elted No:ExM-023-071 Rcviikxi 1 Table 2. Recovery Summary ofPFOS in Rat Liver, Serum and Urine Recovery Summary of PFO * In Rot U ver t a m ia ID 0201684 Spk A 0201984 Spk B 0201684 SofcC A m M iM M In a U 10 10 10 A v arajai ^vaaimnaaevasBeemmnnem^eoa F an an t R aw varvnu M 08 10S M U Sam plalO 0201664 Spk D 0201684 Bpk E 0201684 81* F Analvta Addad tna/O ) SO so so b u n w uwf--lwmw--un-a-mn F an an t Raeavary n u so 88 87 88 1J R e co v e ry Su m m ary o f P F O S In R e t S e ru m t a r a i ID 0201682 Spk A 0201682 Spk S 0201682 Sok e Analvla A S M (M rtaL) 10 10 10 A varaga: Standard D avtatlon: P a n a n t n aco M rv MU 80 es so as M ta e h D 0201682 Spk D 0201682 SpkE 0201882 Sok F A naM aA driadfaaA nU 60 SO SO A varaga: Standard DavtaDorc F a n a n t Raoovarv fltt 118 12a 21 120 2 .1 Recovery Summary of P F08 In Rat Urine SSi*L**SSSlSiSiS6i!RSS*JSSS^S-5ti2SL 0201682 Bpk A 10 " """ " 0201682 Spk B 10 88 0201882 SDkC 10 SI Ammwooc 83 Standard OavtetlOR: 4 .7 ta a w la lD 0201682 8pkD 0201862 Spk E 0201882 81* F A naM a Addad (noftnU 50 60 so Avwo(6K Standard D avtatlon: F a n a n t Raoovarv n u 80 78 78 78 U Exygen Research Pape 21 o f 43 Exygen Research Page 131 of 153 418-028:PAGE G-132 Exygen Study No.: 023-072 E x y p a M ethod No: ExM-0234>71 RaW doa 1 Tabic 3. Recovery Summary of PFOA in Rat Liver, Scrum and Urine Raoovory Summery of PFOA in Rat Uvmr to rn a to lo c e o ie s is p k A 0 1 8 8 4 Bpk B 01684 SakC am ai* ID 02016648pkD 0201684 Bpk E 0201664 Sak F 10 10 10 to lto ! H m M O a M ta i A m iv i* Addad (n atal 60 60 M a n ta s tunw tard Davtodon: Panant M w varvnu 101 M M 3.1 PtorcMn n N P V trv i% ) it 04 04 U Recovary Summary of PFOA In Rat Sarum p i 0 2 0 1 8 8pk A 0201682 SpkB 0201882 SokC lu n a to ID 0201682 8pk D 0201662 Sok E 0 2 0 1 6 in k F A m ivto Asktod (noknO 10 10 10 to n iQ n a n d a td D avtattan: A m M a Addad (noftnU BO BO BO A v aiajai n u m ffrt rtowtoltnn P an an t R aaaw ry (% l 118 117 118 117 1M P a n a n t R aoavaryfK ) 107 112 116 111 4 .0 Racovory Summary of PFOA in Rat Urin m u ta to 0201682 Spk A 0 2 0 1 6 Sok B 02016 SakC A natott Addad InakaU 10 10 10 A w nga: 8tandw d Davtodom P arean t Asm h w v f% ) 88 81 H 69 U Sain oto IO 0201662 SpkD 0 2 0 1 6 Bpk E 0 2 0 1 8 Sak F Anahda Addad (aakn U 60 SO 50 Standard Dawtaflon: Paraant R aenvacvnU W 88 86 7 2.1 Exygen R n u rc h F ife 22 of43 Exygen Research Page 132 of 153 418-028:PAGE G-133 Exygen Study No.: 023-072 Exyam MethodNo:ExM-023-071 lUvWoo 1 Figure 1. Calibration Curve for PFHS Oumpointl m P FM ( aMMmtHMtmiMtaK M M I O H * cumifMUl *xaM m ^^ttaottt ^IkL4^tt Owm pcUrn,Mate M W Montas:Vx,A* W * Msn ExygeoRexetfCb Exygen Research P tge23of43 Page 133 of 153 418-028:PAGE G-134 Exygen Study No.: 023-072 Exygen M ethod N o: E*M -023-071 R orido I F ^uic2. Calibration Curve for FFOS Cornsound2 mum: PFO S CoaffictenlofMarrrtwtton: 0M70B Catbrattoft cwvk 9811.30 **+ 4M M 6 S S O T S S S K tt Hxygen Reaearcti Exygen Research Page 24 o f 43 Page 134 of 153 418-028.PAGE G-135 Exygen Study No.: 023-072 BaygenMethodNosBxM-023-071 Revision 1 Figure 3. Calibration Curve for PFOA Compound 1 name: PFOA C oaffidant o f D ata u rin a ftin : 0.098946 CaSbndkx) curva: 31270.9 * x + 3675.38 Raaponaa type: Edama) Std, Araa Curve type: Unaar, O rigin: B adato, Watghttng: 1/x, A jto tra iw Nona E x y g n Research Exygen Research Page 25 o f 43 Page 135 of 153 418-028-.PAGE G-136 Exygen Study No.: 023-072 E x y jen M ethod N : BxM -033-071 R svM oa I F igured Representative Chromatogram o f a 0.1 ng/mL Standard Containing PFHS GMBMMltlKIM.ITIK nraMMn\M) mmckM US I t M u,,.W Xij L IhggM. kJ L h ilj Illijjji fcj*"#jj Figure 5. Representative Chromatogram of a 0.1 ng/mL Standard Containing PFOS ExycoeRoeaich Exygen Research P a r 26 of43 Page 136 of 153 418-028:PAGE G-137 Exygen Study No.: 023-072 Ex.ytBB M ethod No: BiM -OC&On R e v iik * 1 Figure 6. Representative Chromatogram o f a 0.1 ng/mL Standard Containing PFOA Figure 7. Representative Chromatogram o f a 0.5 ng/mL Standard Containing FFHS C M 1M , * J to* mi IIh e - m m i i in-- w#r i- MK ill 'M* tr'fck 1l4* "**"' MO US MUM \?J# 'ImST* Exygen R esearch Page 27 o f 43 Exygen Research Page 137 of 153 418-028:PAGE G-138 Exygen Study No.: 023-072 Exygen M ethod N o: B*M -Q23-?1 R evirion I Figure 8. Representative Chromatogram of a 0.5 ug/mL Standard Containing FFOS Figure 9. Representative Chromatogram of a 0.5 ng/mL Standard Containing PFOA Exyte a Research Exygen Research Pace 28 of 43 Page 138 of 153 418-028.PAGE G-139 Exygen Study No.: 023-072 E x y g M sthod N o; ExM-023-(m R o ritio o 1 Figure 10. Representative Chromatogram of a 5.0 ngAnL Standard Containing PFHS o w m i, u " * * - m u --m ,h ii inw m Figure 11. Representative Chromatogram of a 5.0 ngftnL Standard Containing PFOS E xycnR eaarch Exygen Research F ife 29 o f *3 Page 139 of 153 418-028.PAGE G-140 Exygen Study No.: 023-072 Exyieo Method N: H*M 4334m Revisloo I Figure 12. Representative Chromatogram of a 5.0 ng/mL Standard Containing PFOA Figure 13. Representative Chromatogram of a Reagent Blank Sample Analyzed for FFHS Rm (M BUnkA ExygcnReaurch Exygen Research P tgc 30 o f 43 Page 140 of 153 418-028:PAGE G-141 Exygen Study No.: 023-072 Ejyien MethodNo:ExM-Q23-07i Rcvioo 1 Figure 14. Representative Chromatogram o f a ReagentBlank Rampi Analyzed for PFOS Figure 15. .. ni Exygen R u e n cli Exygen Research E*|e31 of43 Page 141 of 153 418-028:PAGE G-142 Exygen Study No.: 023-072 1B x y im M ethod Nos ExM -023-071 Revision figure 16. Representative Chromatogram ofa Control Liver Sample Analyzed for PFHS mHLInrMlA Figure 17. Representative Chromatogram Analyzed for PFOS ofa Control Liver Samp]e ExygenRaeaick Exygen Research Page 32 o f 43 Page 142 of 153 418-028:PAGE G-143 Exygen Study No.: 023-072 ExygenMethod No: BxM42347l Keviafan 1 Exygen R aearch Exygen Research P w 33 of43 Page 143 of 153 418-028:PAGE G-144 Exygen Study No.: 023-072 Exygen M ethod No: ExM -0ZW 71 Revixioo 1 Figure 20. Representative Chromatogram of a Control Serum Sample Analyzed for PFOS Figure 21. Representative Chromatogram of a Control Serum Sample Analyzed for PFOA Exygen Research Exygen Research Page 34 o f 43 Page 144 of 153 418-028:PAGE G-145 Exygen Study No.: 023-072 SXHPO M ethod N o: EM-Q33-OJI R evine l Figure 22. Representative Chromatogram of a Control Urine Sample Analyzed for PFOS Figure 23. Representative Chromatogram of a Control Urine Sample Analyzed for PFOA Exygen Research Exygen Research Page 35 o f 43 Page 145 of 153 418-028:PAGE G-146 Exygen Study No.: 023-072 Exygen M ethod N o: E xM -023^71 R evision I Figure 24. Representative Chromatogram of a Control Liver Sample Fortified at 10 ng/g with PFHS Figure 25. Representative Chromatogram of a Control liv e r Sample Fortified at 10 ngfe with FFOS ExygenRceesrch Exygen Research Psge 3 o f43 Page 146 of 153 418-028:PAGE G-147 Exygen Study No.: 023-072 Exygen kfahod No:ExM-023-071 Ksvinoa 1 Figure 26. Representative Chromatogram o f a Control Liver Sample Fortified at 10 ng/g with FFOA figure 27. Representative Chromatogram of a Control Liver Sample Fortified at 50 ng/g with PFHS ExygenReicarch Exygen Research P i* 37 of 43 Page 147 of 153 418-028:PAGE G-148 Exygen Study No.: 023-072 E x y fea M ethod No: ExM -023-071 R evU tm 1 Figure 28. Representative Chromatogram of a Control Liver Sample Fortified at 50 ng/g -with PFOS Figure 29. Representative Chromatogram of a Control Liver Sample Fortified at 50 ng/g with PFOA Exygen Reneerch Exygen Research Page 38 o f 43 Page 148 of 153 418-028:PAGE G-149 Exygen Study No.: 023-072 Eiqiien MethodNo: 0014234)71 Sevwioi 1 Figure 30. Representative Chromatogram of a Control Serum Sample Fortified at 10 ng/mL with FFHS Figure 31. Representative Chromatogram o f a Control Serum Sample Fortified at 10 ng/mL with FFOS Exyiej]Research Exygen Research P its 39 of43 Page 149 of 153 418-028:PAGE G-150 Exygen Study No.: 023-072 Bxygcn M ethod N o; ExM O J34)71 R crU itw 1 Figure 32. Representative Chromatogram of a Control Serum Sample Fortified at 10 ng/mL with FFOA Figure 33. Representative Chromatogram of a Control Serum Sample Fortified at SOng/mL with PFHS Exygen B acarch Exygen Research Page 40 o f 43 Page 150 of 153 418-028.PAGE G-151 Exygen Study No.: 023-072 1E xyjeo M ethod N o: E xM -0234m RovW oo Figure 34. Representative Chromatogram of a Control Serum Sample Fortified at SO ngAnL with PFOS Figure 35. Representative Chromatogram of a Control Serum Sample Fortified at 50 ngfanL with PFOA E ayfee R atearci Exygen Research Ffcae41of43 Page 151 of 153 418-028:PAGE G-152 Exygen Study No.: 023-072 BxjrgH)MethodNo:ExM-OTHm Revtaion1 R giire36. Reprraentaty Chromatogram of a Control Urine Sanmle Fortified at 10 ng/mL with PFOS * lg u 3 7 . Representative Chromatogram of * Control Urine Sannite Fortified at 10 ng/mL with PFOA ^r^ar1* v x iiiiU" B xytealtaam ieh Page42 of43 Exygen Research Page 152 of 153 418-028:PAGE G-153 Exygen Study No.: 023-072 & W MethodNo: ExM-023-071 RerUoa 1 Figure 38. Representative Chromatogram o f a Control Urine Sample Fortified at 50 ug/mL with FFOS MBiMwa**,* TS 1 1 t.1*t. U * a. r " X "" ^ ..... Figure 39. Representative Chromatogram a ta Control Urine Sample Fortified at 50 ng/mL with PFOA amMiMMUttMenb E x y in lte m ic h H ' M Exygen Research P*e43of43 Page 153 o f 153 APPENDIX H TEMPERATURE AND RELATIVE HUMIDITY REPORTS ARGUS 418-028:PAGE H -l Tem perature and R elative Hum idity Report Location: Room 05 Protocol Num ber: 418-028 Range o f Dates: 26-M ar-2002 14:20 to 10-Jun-2002 08:59 Tamet 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: 10-Jun-2002 at 13:26 COMMENTS: REVIEWED BY: DATE: (q IP -oa APPENDIX I POSITIVE CONTROL DATA 418-028:PAGE 1-1 H isto rica l C o n tro l D ata This Functional Observation Battery Standard Operating Procedure and Studies conducted to document the training and competency o f die technical staff and M otor 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 rng/kn Numberof mUkg. Dosaees 012-006-Validation ofFunctional ObservationalBatteryand Motor Activity Measure Using Positive Test Substances 12/89 acrylamide 50 1 7 physostigmine 0.75 1.5 1 DDT 75 I I 012-014- NeurotoxicityEvaluationof Positive Control Substances in CrI:CDBRVAF/Plus Rats 9/91 acrylamide 40 1 9 IDPN 200 1 3 carbaryl 75 5 1 DDT 75 5 1 triadimefbo 200 5 1 012-013- NeurotoxicityEvaluationof DDTin Crl:CDBRVAF/PlusRats 3/92 DDT 75 1 1 012r017- Neurotoxicity Evaluationof Positive Control Substances in CrLCDBRVAF/PlusRats 012-022- NeurotoxicityEvaluationof Carbary! in Cri-CDBRVAF/PlusRats 012-031 - NeurotoxicityEvaluationof Positive Control Substances in Crl:CDBR VAF/Plus Rats 5/92 acrylamide 40 EDPN 200 carbaryl 40 DDT 75 d-amphetamine 4.0 10/92 carbaryl 40,200 7/93 acrylamide 45 IDPN 250 carbaryl 40 DDT 75 d-amphetamine 4 1 1 5 1 1 5 1 1 5 1 1 9 3 1 1 1 1 10 4 1 1 1 Page 2 012-056- Neurotoxicity Evaluationof PositiveControlSubstances in Cri:CDBRVAF/PlusRats 012-075 -Neurotoxicity Evaluation of PositiveCantrolSubstances in Crl:CDBR VAF/Plus Rats 012-081- NeurotoxicityEvaluationof PositiveControl Substancesin Crl.CDBRVAF/PlusRats 418-028:PAGE 1-3 11/95 acrylamide 45 IDPN 250 carbaryl 40 DDT 75 d-amphetamine 4.0 1 1 1 1 1 3/98 acrylamide 30 1 trimetfayitin 8 1 MK-801 0.3 1 carbaryl 100 4 DDT 100 2 11/01 aaylaniide 30 IDPN 250 d-amphetamine 40 carbaryl 100 DDT 100 1 1 1 4 2 10 5 1 1 1 17 1 1 l 1 10 1 1 1 5 Page 3 418-028:PAGE 1-4 Summary Information for Motor Activity Study-T itle In-Life Start 012-011 - Tin AssessmentofMotor Activityin Neonatal andAdultRodents usingPassive Infrared Sensors 5/91 012-014-Neurotoxicity Bvalnation of PositiveControlSubstances in Gri:CDBRVAF/Phu Rats 9/91 012-016- MotorActivityEvaluationin CrL-CDtSBRVAF/PhisRata Administered Chlotpromazmc and d- 012-058- NeurotoxicityEvaluation of PositiveControlSubstances in Crl:CDBR VAF/Phis Rots 4/96 Test Dosage Information Substance ___ ragfcg____ nlAg Numberof Dosages d-amphetamine chlorpromazine 0.75,1.5,4 1,2,4 1 1 1 1 acrylamide 40 1 IDFN 200 1 cartwryl 75 5 DDT 75 5 triadimfifbn 200 5 9 3 1 1 t chlorpromazine 0.5, 1,4 1,2,4 1 1 1 1 acrylamide d-amphetamine trimethyhin MK-801 45 0.75 8 10 1 1 1 1 10 1 1 1 Page 4 APPENDIX J HISTOPATHOLOGY REPORT 418-028:PAGE J-l RESEARCH PATHOLOGY SERVICES, INC. 438 East Butler Avenue, New Britain, PA 18901 Phone: 215-345-7070 Fax: 215-345-4326 O R A L (G A V A G E ) C O M B IN E D R E P E A T E D D O S E T O X IC IT Y S T U D Y O F T -7 7 0 6 W IT H T H E R E P R O D U C T IO N /D E V E L O P M E N T A L TO X IC ITY SC E E N IN G T E S T PR O T O C O L 418-028 S P O N S O R 'S S T U D Y N U M B E R T - 7 7 0 6 .1 H IST O PA T H O L O G Y R E P O R T SUBMITTED TO: Raymond G. York, Ph.D., D.A.B.T. Argus Research 905 Sheehy Drive Horsham, PA 19044 SUBMITTED BY: Veterinary Pathologist July 3, 2003 418-028-.PAGE J-2 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 W ITH 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 R esu lts................................................................................................................................... 3 Summary............................................................................................................................... 5 Quality Assurance Unit Statem ent.................................................................................... 6 Good Laboratory Practice Compliance Statem ent.......................................................... 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 R ats...................................I-2 I-2. Histomorphologic Observations - Group II Male R ats................................. I-4 I-3. Histomorphologic Observations - Group III Male R ats................................ I-5 I-4. Histomorphologic Observations - Group IV Male Rats................................ I-6 I-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 D ata................................ 11-1 to II-70 III. Histomorphologic Observations in the Liver - F1 Generation Pups.......111-1 to III-2 Tables MI-1. MI-2. Histomorphologic Observations in the Liver - Group I F1 Generation Pups.......................................................................................MI-2 Histomorphologic Observations in the Liver - Group V F1 Generation Pups.......................................................................................MI-3 418-028:PAGE J-3 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 W ITH THE REPRODUCTION/DEVELOPMENTAL TO XICITY 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 exami nation 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 con trol and test substances are shown below. DOSAGE GROUP I NUMBER OF RATS PER SEX* 15 + 3 DOSAGE (mg/kg/day) 0 CONCENTRATION11 (mg/mL) 0 DOSE VOLUME (mL/kg) 10 II 15 + 3C 0.3 0.03 10 III 15 + 3C 1 0.1 10 10 IIV 15 + 3 3 0.3 IV 15 + 3 10 1 10 `Ten male and ten female rats of Groups I and V were assigned for histopathologicevaluation. The test substance was considered to be 100% active for the purpose of dosage calculations. `Three additional rats per sex per dosage groupwere assignedto toxicokineticsample 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 maxi mum 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 TO XICITY STUDY OF T-7706 W ITH THE REPRODUCTION/DEVELOPMENTAL TO XICITY 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 post partum. 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 solu tion 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 process ing, 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, epididy mides, 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 tis sues 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 TO XICITY STUDY OF T-7706 W ITH 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 I-7). A key to the histomorphologic observations precedes Table 1-1. The gross necropsy observations, detailed descriptions of the microscopic observa tions, and a correlation of the microscopic findings with the gross changes in these rats, when applicable, are contained in Appendix II. The histomorphologic observa tions in the liver of the F1 Generation pups of the control and high dosage groups are summarized in tabular form in Appendix III (Tables 111-1 and III-2). A key to the histomorphologic observations is included on Tables 111-1 and ill-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 10 mg/kg/day of T-7706. Treatment-related microscopic changes were observed in the liver and thy roid 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 TO XICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TO XICITY 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 inci dental 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 Experi mental 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 TO XICITY STUDY OF T-7706 W ITH 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 specified 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 reproduce 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 gen eration 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 in creased 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 TO XICITY STUDY OF T-7706 W ITH THE REPRODUCTION/DEVELOPMENTAL TO XICITY 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 Pro cedures 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. Organisationfor EconomicCooperation and Development (1996). OECD Guideline for Testing of Chemicals. Section 4, No. 422: Combined Repealed DoseToxidty Studywith the Reproduction/Developmental Toxicity Screening Test, adopted 22 March 1996. Organisation for EconomicCooperation and Development (1998). The Revised OECD Principles of Good Laboratory Practices [C(97)186/Finall. US Food and DrugAdministration. 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 Dwgs, MHWOrdinance Number21, 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 InsDection Studv Phase Management to Studv 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 02/26/03 02/27/03 02/28/03 07/03/03 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 02/27/03 02/27/03 02/27/03 02/28/03 07/03/03 02/28/03 02/28/03 02/28/03 02/28/03 02/28/03 02/28/03 02/28/03 02/28/03 02/28/03 02/28/03 02/28/03 02/28/03 02/28/03 02/28/03 07/03/03 Research Pathology Services, Inc. !\9 ukuJ Karen W . Harkins, BS Quality Assurance Unit Date -6 418-028:PAGE J-9 ORAL (GAVAGE) COMBINED REPEATED DOSE TO XICITY STUDY OF T-7706 W ITH THE REPRODUCTION/DEVELOPMENTAL TO XICITY 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 Studywiththe Reproduction/Developmental ToxicityScreening Test, adopted 22 March 1996. Organisation for EconomicCooperation and Development (1998). The Revised OECD Principles of Good Laboratory Practices [C(97)186/Final]. US Food and DrugAdministration. Good Laboratory Practice Regulations: Final Rule. 21CFR Part58. Japanese Ministry of Health and Welfare (1997). Good Laboratory Practice Standard for Safety Studies on Drugs, MHWOrdinance Number 21, March 26,1997. No deviations were noted that had any significant impact on the validity of the study. 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/Group: I _nMM 10 10 III " I F " V MMM 10 10 10 ADRENAL GLANDS: NO. EXAMINED NO. NORMAL 10 0 0 0 10 70009 -degeneration, cystic, cortex, multifocal mild [0] [0] [0] [0] [0] 00000 -hypertrophy/vacuolation, cortex, multifocal mild [0] 0 [0] 0 [0] 0 [0] 0 [0] 0 -necrosis, cortex, focal mild -vacuolation. cortex, diffuse minimal mild [0] [0] [0] [0] [0] 00000 [3] 2 [0] 0 [0] 0 [0] 0 [1] 0 10001 -vacuolation, zona glomerulosa mild [0] CO] [0] [0] [0] 00000 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 80009 -inflammation, mucosa, chronic mild moderate [2] [0] [0] [0] [1] 00001 20000 COAGULATING GLAND: NO. EXAMINED NO. NORMAL 10 0 0 0 10 10 0 0 0 10 COLON: N. examined NO. NORMAL 10 0 0 0 10 9 0 0 0 10 -inflammation, mucosa, chronic mild [1] [0] [0] [0] [0] 10000 DUODENUM: no. Examined NO. NORMAL 10 0 0 0 10 10 0 0 0 10 EPIDIDYMIDES: NO. G X M N Q ) NO. NORMAL 10 0 0 1 10 60009 [ ] Total incidence of specified lesion, all grades. IV FF 10 10 10 10 87 [0] 0 [I] 1 [0] [1] 01 [0] 0 [1] 1 [0] CO] 00 00 [2] [0] 20 10 10 10 10 10 10 10 10 10 10 8 10 [2] [0] 10 10 10 10 10 10 [0] [0] 00 10 10 10 10 -8 418-028:PAGE J-ll 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/GrouD: EPIDIDYMIDES (Continued): I II III ~ W ~ V MMMMM 10 10 10 10 10 -exfoliated spermatogenic cells moderate -hypospermia marked -infiltration, mononuclear-cell, focal minimal HEART: NO. EXAMINED NO. NORMAL -inflammation, chronic, focal minimal mild ILEUM: NOTE5CAMINED NO. NORMAL JEJUNUM: NO. EXAMINED NO. NORMAL [0] [0] [0] [1] [0] 00010 [0] [0] [0] [1] [0] 00010 [4] 4 [0] 0 [0] 0 CO] 0 [1] 1 10 0 0 0 10 80009 [2] 1 [0] 0 [0] 0 [0] 0 [1] 1 10 000 10 0 0 0 10 10 0 0 0 10 10 0 0 0 10 10 0 0 0 9 -diverticulum 00001 KIDNEYS: NO. EXAMINED NO. NORMAL 10 3 0 0 10 71007 -basophilia/degeneration, cortical tubules, focal/multifocal minimal -cyst(s), medulla -dilatation, pelvis minimal mild [0] 0 [0] 0 [0] 0 [0] 0 [1] 1 10002 [0] C2] [0] [0] [0] 0 10 0 0 01000 -infi1tration. mononuclear-cel1. focal/multifocal minimal [2] 2 [0] 0 [0] 0 [0] 0 [2] 2 -mineralization, multifocal minimal [0] [0] [0] [0] [0] 00000 IV FF 10 10 10 10 10 10 [0] [0] 00 00 10 10 10 10 10 10 10 10 00 10 10 98 [0] [0] 00 00 [0] [0] 00 00 [0] [0] 00 [0] [1] 01 [ ] - 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/Group: I " T T I T Iv ----MMMMM 10 10 10 10 10 KIDNEYS (Continued): -nephritis, chronic, focal minimal [0] [0] [0] CO] Cl] 00001 LIVER: NO. EXAMINED NO. NORMAL 10 10 10 10 10 23200 -hypertrophy, hepatocellular, centrilobular minimal mild moderate [0] 0 [0] 0 [0] 0 [9] 8 CIO] 4 00015 00001 r~> LO UJ -inflammation, chronic, focal/multifocal minimal mild (8] [6] [71 [6] 547 6 3200 5 0 -lipidosis, tension, focal 02000 -necrosis, focal minimal [0] CO] r.o] CO] [0] 00000 -vacuolation, hepatocellular, midzonal mild [0] [0] [i] CO] CO] 00i 00 -vacuolation, hepatocellular, multifocal minimal mild [0] [1] ci] CO] CO] 0100 0 00100 LUNG: NO. EXAMINED NO. NORMAL 10 0 0 0 10 10 0 0 0 10 -infiltration, polymorphonuclear, perivascular/peribronchial mild [0] [0] CO] [0] co] 00000 -inflammation, interstitial, focal minimal [0] [0] [0] [0] CO] 00000 -macrophages, alveoli, focal minimal CO] [0] CO] CO] CO] 00 000 LYMPH NODE, MEDIASTINAL: NO. EXAMINED NO. NORMAL 8 0 0 0 10 70008 -congestion minimal [0] [0] CO] CO] CO] 00000 IV FF 10 10 ci] ci] 11 10 10 87 CO] CO] 00 00 00 C2] Cl] 21 00 00 [0] C2] 02 CO] [0] 00 CO] CO] 00 00 10 10 99 [11] CO] 0 CO] [1] 01 CO] 0 Cl1] 10 10 7 10 C2] coi 20 [ ] Total incidence of specified lesion, all grades. -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/GrouD: I II III Iv V MMMMM 10 10 10 10 10 LYMPH NODE. MEDIASTINAL (Continued): -hyperplasia, lymphocytic/plasmacytlc mild [0] [0] [0] [0] [0] 00000 -mastocytosis minimal [1] [0] [0] [0] [2] 10002 LYMPH NODE. SUBMANDIBULAR: NO. EXAMINED NO. NORMAL 10 0 0 0 10 5 0004 -hyperplasia. 1ymphocytic/plasmacytic minimal mild moderate [5] [0] [0] [0] [6] 10002 2 0000 2 00 04 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: n o . Ex a m i n e d NO. NORMAL 10 0 0 0 10 10 0 0 0 9 -mineralization, focal minimal [0] [0] [0] [0] [1] 00001 PROSTATE: NO. EXAMINED NO. NORMAL 10 0 0 0 10 6 0006 IV FF 10 10 [1] [0] 10 [1] [0] 10 10 9 43 C6] [6] 10 35 21 10 10 10 9 [0] [1] 01 10 9 10 9 10 10 9 10 10 10 10 10 10 10 10 10 10 [0] [0] 00 [ ] - 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 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/Grouo: PROSTATE (Continued): I I III V V MMMMM 10 10 10 10 10 -atrophy, focal/multifocal minimal moderate -inflammation, chronic, focal/multifocal minimal RECTUM: NO. EXAMINED NO. NORMAL -inflammation, mucosa, chronic minimal mild SEMINAL VESICLES: NO. EXAMINED NO. NORMAL SKIN (GROSS LESION): NO. EXAMINED NO. NORMAL Cl] 1 [0] 0 [03 0 [0] 0 [213 00001 [33 3 [03 0 [03 0 [03 0 [33 3 10 0 0 0 10 90009 [1] 0 [0] 0 [03 0 [0] 0 [13 1 10000 10 0 0 0 10 10 0 0 0 10 00000 0 0000 -dermatitis, chronic, focal minimal mild [0] 0 [0] 0 [03 0 [0] 0 [03 0 00000 SPINAL CORD. CERVICAL: No. xaM1Nd NO. NORMAL 10 0 0 0 10 10 0 0 0 10 SPINAL CORD. LUMBAR: NO. EXAMINED NO. NORMAL SPINAL CORD. THORACIC: NO. EXAMINED NO. NORMAL SPLEEN: nO. Examined NO. NORMAL -atrophy mild 10 0 0 0 10 10 0 0 0 10 10 0 0 0 10 10 0 0 0 10 10 0 0 0 10 10 0 0 0 10 [03 [03 [0] [03 [03 00000 STOMACH: no. Examined NO. NORMAL 10 0 0 0 10 8 0009 [ ] - Total incidence of specified lesion, all grades. IV FF 10 10 10 10 10 10 [03 0 [003 00 11 00 [13 0 [113 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 9 [03 [13 01 10 10 76 -12 418-028:PAGE J-15 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRQDUCTION/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/GrouD: I r r ~ Hi Iv V MMMMM 10 10 10 10 10 STOMACH (Continued): -dilatation, mucosal glands minimal [1] 1 [0] CO] co] 000 CO] 0 -edema/inflammation, submucosa, forestomach mild [1] [0] to] co] ci] 10 001 -edema/inflammation, submucosa, glandular area minimal mild moderate [2] [0] CO] CO] CO] 10000 00000 10000 erosion(s), glandular mucosa moderate [0] [0] CO] C0] CO] 00000 TESTIS (H&E): NO. EXAMINED NO. NORMAL 10 0 0 1 10 10 0 0 0 10 -degeneration, multifocal mild [0] [0] CO] ci] CO] 00010 TESTIS (PAS): NO. EXAMINED NO. NORMAL 10 0 0 1 10 10 0 0 0 10 -degeneration, multifocal mild CO] [0] CO] ci] CO] 00010 THYMUS: N. EXAMINED NO. NORMAL 10 0 0 0 10 10 0 0 0 10 -atrophy moderate marked [0] [0] CO] CO] [0] 00000 00000 THYROID: NO. EXAMINED NO. NORMAL 10 10 10 10 10 53553 -hypertrophy/hyperplasia, follicular epithelium minimal mild moderate [2] [3] C2] C4] C7] 0 112 0 22 12 3 00004 -ultimobranchial body/cyst 34422 TRACHEA: NO. EXAMINED NO. NORMAL 10 0 0 0 10 60009 t ] - Total incidence of specified lesion, all grades. IV FF 10 10 ci] ci] 11 CO] Cl] 01 C2] C3] 00 13 10 CO] Cl] 01 10 10 99 Cl] Cl] 10 01 10 10 55 CO] CO] 00 00 00 55 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/GrouD: I II n r IV V MMMMM 10 10 10 10 10 TRACHEA (Continued): -inflammation, chronic, focal minimal mild [4] [0] [0] [0] Cl] 20000 20001 URINARY BLADDER: NO. EXAMINEb NO. NORMAL 10 0 0 0 10 10 0 0 0 10 -inflammation, chronic, focal minimal [0] [0] [0] [0] [0] 00000 UTERUS: n. Examined NO. NORMAL -distention, lumen mild moderate -macrophages, pigmented minimal mild moderate marked VAGINA: N. EXAMINED NO. NORMAL I ~T~ FF 10 10 [0] 0 [1] 1 00 9 10 8 10 [1] [0] 10 10 10 01 [0] [2] 01 01 [10] [8] 10 22 75 01 10 10 10 10 [ ] - Total incidence of specified lesion, all grades. -14 418-028:PAGE J-17 ORAL (GAVAGE) COMBINED REPEATED DOSE TO XICITY STUDY OF T-7706 W ITH THE REPRODUCTION/DEVELOPMENTAL TO XICITY 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 W ITH THE REPRODUCTION/DEVELOPMENTAL TO XICITY 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 (6AVA6E) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T -7 7 0 6 .1 TABLE 1-1 Histom orphologic Observations Dose Group: Animal Number: SDeexa:th Tvoe: ADRENAL GLANDS: -vacuolation, cortex, d iffu se I M19109 SS I M19115 SS I M19116 SS I 19119 M SS I M19122 SS 1I 9125 MSS I 19131 M SS I 19132 M SS 1I 9134 MSS I 19135 M $S 1- 1 2 __ BONE MARROW (STERNUMl: ---------- BRAIN: ---------- C-iEnCfUlaMm: n a tlo n , mucosa, c h ro n ic -- -3-3- -- - COAGULATING GLAND: ---------- g-.iQnLfOla.Nm: m a tio n , mucosa, c h ro n ic - - - 2- - - - - DUODENUM: ---------- EPIDIDYMIDES: - in filtr a tio n , m ononuclear-cell, focal - 1- - 1- 1- 1- HEART: -Inflam m ation, chronic, focal - 1- - - - 2- - - ILEUM: JEJUNUM: ------------------- KIDNEYS: -c y s t(s ), m edulla - in filt r a tio n , m ononuclear-cell, fo ca l/m u ltifo c a l <-> P - - <-> 1 - - - - - 1 LIVER: -inflam m ation, chronic, fo c a l/m u ltifo c a l - 112 1122 - 1 LYMPH NODE, MEDIASTINAL: -m astocytosis ---------1- - - * - - * - - LYMPH NODE. SUBMANDIBULAR: -h y p e rp la s 1a , 1ymphocy11c /p lasm acyt i c 3- 2- 132- - - NERVE. SCIATIC: ---------- PARATHYROID: ----- - - - - - PEYER'S PATCH: -- -- -- --- - -PaRtOroSTpAhTyE,: fo c a l/m u ltifo c a l - - - - - 1- - - - 1-2 418-028-.PAGEJ-20 ORAL (SAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST SPONPSROORT'OSCSOTLUDNYUMNBUEMRB4ER18T-0-2787 0 6 .1 TABLE 1-1 (C ontinued) Histom orphologic Observations ADonsime aGl roNuupm:ber : Sex: Death Tvoe: I19109 M SS I19115 M SS I19116 1I 9119 MM ss_____ SS____ I 19122 M ss I19125 1I 9131 MM SS_____ SS____ I 19132 MSS I19134 MSS I 19135 MSS PROSTATE (C o n tin u e d ): -inflam m ation, chronic, fo c a l/m u lti focal 1 - _ 1 __1 R-IEnCfTlaUmM:m a tio n , mucosa, c h ro n ic - - - 2- - - - - - SEMINAL VESICLES: ---------- SPINAL CORD. CERVICAL: ---------- SPINAL CORD. LUMBAR: ---------- SPINAL CORD. THORACIC: ---------- SPLEEN: ---------- STOMACH: - d ila ta tio n , mucosal glands -e d e m a /in flarm ati on, submucosa, forestomach - -edem a/Infiam m aiIo n, submucosa, g landular - - - - - - - 1 2 - area - - - - - - - 3 1 - TESTIS (H&E): ---------- TESTIS (PAS): ---------- THYMUS: ---------- THYROID: -h yeppeitrhterolipuhmy /h y p e rp la s la , f o ilic u la r -ultim obranchial body/cyst 2 - P- P- P 2- T-IRnAfClaHmEAm: a tio n , c h ro n ic , fo c a l - 2- - 1- 2- 1- URINARY BLADDER: ---------- 418-028:PAGE J-21 ORAL (GAVA6E) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T -7 7 0 6 .1 TABLE 1-2 Hi stom orphologi c O b servt1ons OAnoismeaGl roNuupm:ber Sex: Death Type: II II II II II II II II II II 19102 19106 1910819110 19113 19120 19129 19136 19138 19139 MSS MSS M SS MSS M SS M SS M SS M SS M SSM SS KIDNEYS: -d ila ta tio n , p elvis <-> < 2> < 1 > LIVER: -Inflam m ation, chronic, fo c a l/m u ltifo c a l -lip id o s is , tension, focal -vacuolation, hep atocellular, m ultifoc al 2 - 2 - 1 P 1 - 1P 1 1 THYROID: -hypertrophy/hyperplasla, fo llic u la r e p ith e liu m -ultim obranchial body/cyst "-PP- 2 1 -P -P 2- 1-4 418-028:PAGE J-22 ORAL (SAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T -7 7 0 6 .1 TABLE 1-3 Hfstom orphologic Observations Dose Group: III III III III III III III III III III Animal Number: 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 SDeexa:th Type:___________________________________________ SMS MSS MSS MSS M SS M SS M SS M SS M SSM SS LIVER: -inflam m ation, chronic, fo c a l/m u ltifo c a l -v a c u o la tio n , h e p a to c e llu la r, mldzonal -vacuolation, hep atocellular, m ultifoc al 11 2 THYROID: -hypertrophy/hyperplasia, fo llic u la r epi t h e l1urn -ultim obranchial body/cyst 1P -P -P -P -- 2- 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 1-4 Histomorphologic Observations Dose Group: Animal Number: Sex: Death Tvoe: EPIDIDYMIDES: -exfoliated spermatogenic cells -hypospermla IV IV IV IV IV IV IV IV IV IV 19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 MMMMMMMMMM 55 SS SS SS SS SS SS SS SS SS <3> <4> LIVER: -hypertrophy, hepatocellular, centrllobular 1 1 2 1 1 1 i - 11 -inflammation, chronic, focal/multifocal 1- 11"-i 11- TESTIS (H&E): -degeneration, multifocal <2> TESTIS fPAS 1: -degeneration, multifocal <2> THYROID: -hypertrophy/hyperplasia, fol11cular epithelium -ultimobranchial body/cyst 1 - -1 - 22 --- - PP-- -- 1-6 418-028:PAGEJ-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 1-5 Dose Group: Animal Number: Sex: Death Tvoe: ADRENAL GLANDS: -vacuolation, cortex, diffuse Hlstomorphologic Observations VVVVVVVVVV 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 MMHM M MM MM H SS s SS SS SS SS SS SS SS SS _ _2 .. BONE MARROW (STERNUM1: -- - - - - - -- - BRAIN: - - - - - - -- -- CECUM: -inflamnation, mucosa, chronic -----2 --- - COAGULATING GLAND: CQl,0N: DUODENUM: ------ - - - - --- - -- - ------------ EPIDIDYMIDES: -Infiltration, mononuclear-cell, focal --1------- ijEARTi -Inflammation, chronic, focal v.m-- JEJUNUM: -diverticulum ---- -----1 ---------- <P> - - - - - * - - - KIDNEYS: -basophlUa/degeneratlon, cortical tubules, focal/multi focal 1 ---- -- - -- -cyst(s), medulla P "P -"---- -infiltration, mononuclear-cell, focal/multi focal 1 - - -- - - 1- - -nephritis, chronic, focal - 1 ----"- UVffl; -hypertrophy, hepatocellular, centrilobular 2 1 2 2 32 1 2 1 1 -Inflammation, chronic, focal/multifocal 1 -"1 -1 1- 1 ---- - -- - - - LYMPH,NODE..HEPIftSHNAL: -mastocytosis -1 1 ------- LYMPH NODE. SUBMANDIBULAR: -hyperplasia, lymphocytic/plasmacytic NERVE. SCIATIC: parathyroid PEYER'S PATCH: -mineralization, focal 13--1 3-3-3 --- -- --- ----------- 1 --------- 1-7 418-028-.PAGE J-25 ORAL (GAVASE) 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 1-5 (Continued) Hlstomorphologlc Observations Dose 6roup: Animal Number: Sex: Death Type:______________________ VVVVVVVVVV 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 MMMMMMMMMM SS SS SS SS SS SS SS SS SS SS PROSTATE: -atrophy, focal/multi focal -inflammation, chronic, focal/multi focal -----3---1 1t 111 lilil lilil i 11\ t \ lilil lilil lilil I I 1 1 1 # -- lilil lilil RECTUM: -inflammation, mucosa, chronic SEMINAL VESICLES: SPINAL CORD. CERVICAL: SPINAL CORD. LUMBAR: SPINAL CORD. THORACIC: SPLEEN: STOMACH: -edema/1nf1ammation, submucosa, forestomach - 2 TESTIS fH&E): TESTIS (PA?.): .............................. THYMUS: I.HYJP.1D: -hypertrophy/hyperplasa, folli cular epithelium -ultimobranchial body/cyst TRACHEA: -inflammation, chronic, focal 3-2-233-32 P .................................... P - .................................... 2 URINARY BLADDER: 1-8 418-028:PAGE J-26 ORAL (GAVAGE) COMBINED REPEATED OQSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 TABLE 1-6 H1stomorpho1og1c Observations Dose 6roup: Animal Number: Sex: Death Tvoe: ADRENAL GLANDS: -vacuolation, zona glomerulosa IIIIIIIIII 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 ss ssF F F F F F SS SS____SS___ SS SS FF ss FF SS SS _- _22 BONE MARROW fSTERNUM): ---------- BRAIN; CECUM: -Inflammation, mucosa, chronic ---------- --- -----32 COLON: ---------- DUODENUM: --- - -- - --- HEART: ---------- ILEUM: ---------- JEJUNUM: --- -- -- --- KIDNEYS: -nephritis, chronic, focal --- - -- 1-- - LIVER: -Inflammation, chronic, focal/multifocal - - 1 - - - - - - 1 LUNG: -Infiltration, polymorphonuclear, peri vascular/per1bronchi al _ 2 __ _ _ LYMPH NODE. MEDIASTINAL: -congestion -hyperplasia, lymphocytlc/plasmacytlc -mastocytosi s 11 ------2*-- - 1* - "- - LYMPH NODE. SUBMANDIBULAR: -hyperplas1a , 1ymphocyt1c/plasmacyt1c MAMMARY GLAND: -2 --3 -3 1 22 ---------- NERVE. SCIATIC: ---------- OVARIES: -cyst(s), Intraovarian -----P- --- PARATHYROID: - --- - - - - -- PEYER'S PATCH: ---------- RECTUM: ------- --- SKIN (GROSS LESION): -dermatitis, chronic, focal <2> 1-9 418-028:PAGEJ-27 ORAL (6AVA6E) 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 1-6 (Continued) Histomorphologic Observations Dose Group: Animal Number: Sex: Death Tvoe:___________ II I1 I 1I II I 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 FFFFFFFFFF SS SS SS SS SS SS SS SS SS SS SPINAL CORD. CERVICAL: SPINAL CORD, LUMBAR: SPINAL CORD. THORACIC: SPLEEN: STOMACH: -dilatation, mucosal glands -edema/1nflammat1on, submucosa, glandular area THYMUS: -atrophy THYROID: -ultlmobranchlal body/cyst TRACHEA: 1---- --- P-P ... ------23----- -----3- -PP--P.................................... URINARY BLADDER: -Inflammation, chronic, focal --*------1 UTERUS: -macrophages, pigmented 3231333332 VAGINA: ...................................................... 1-10 418-028:PAGE J-28 ORAL (SAVAGE) 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.I TABLE 1-7 Histomorphologic Observations Dose Group: Animal Number: Sex: Death Tvoe: ADRENAL GLANDS: -degeneration, cystic, cortex, multifocal -hypertrophy/vacuolati on, cortex, multifocal -necrosis, cortex, focal VVVVVVVVVV 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 FFFFFFFFFF SS 55 SS SS SS S$ SS SS SS SS " <2 " """ - - --2- - -2 - --" BONE MARROW (STERNUM): BRAIN: CECUM: COLON: ---------- - -_ _ _ - _ __ . <-> . <-> DUODENUM: - - - <-> - - - - - - HEART: IL^M; JEJUNUM: ---------- - - <-> - - - - - - - - <-> - - - - - - KIDNEYS: -mineralization, multifocal -nephritis, chronic, focal --"-- 1 1--- - UVER: -inflammation, chronic, focal/multifocal -necrosis, focal LUNGi -Inflammation, interstitial, focal -macrophages, alveoli, focal LYMPH NODE. MEDIASTINAL: - 1 1 _ 1 1 -- - - -1 ---- _ LYMPH NODE. SUBMANDIBULAR: -hyperplasia, lymphocytic/plasmacytic - 2-22- 23*2 MAMMARY GLAND: -necrosis, focal NERVE. SCIATIC: ---- 1- ---- ------*--- OVARIES: ---------- PARATHYROID: ---------- PEYER'S PATCH: RECTUM: ---- - --- -- - <-> ""-- 1-11 418-028:PAGE J-29 ORAL (GAVA6E) 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) Hlstomorphologlc Observations Dose Group: Animal Number: Sex: Death Type:_________ VVVVVVVVVV 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 FFFFFFFFFF 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/lnfl animation, submucosa, forestomach -edema/1nflammation, submucosa, glandular area -erosion(s), glandular mucosa - < 2> 2< > - 22 - - <3> - THYMUS: -atrophy <4> THYROID: -ultimobranchlal body/cyst -P PP-P-P TRACHEA: -inflammation, chronic, focal 1 URINARY BLADDER: UTERUS: -distention, lumen -macrophages, pigmented 2 32 3 33 VASINA: 1-12 418-028:PAGE 1-30 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 (QAVA6E) 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 SEX: M DOSE GROUP: DEATH TYPE: I Sacrifice-Scheduled GROSS OBSERVATION (SI: GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATIONS!: 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) BRAIN DUODENUM JEJUNUM NERVE, SCIATIC SEMINAL VESICLES SPLEEN THYMUS End of Record- 19109 CECUM EPIDIDYMIDES KIDNEYS PARATHYROID SPINAL CORD, CERVICAL STOMACH TRACHEA II-l 418-028-.PAGEJ-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 SEX: M DOSE GROUP: DEATH TYPE: I Sacrifice-Scheduled GROSS OBSERVATIONfS): GENERAL: No gross changes. HIST0M0RPH0L06IC OBSERVATIONiSi : 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 TISSUEfS) 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 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) End of Record- 19115 II-2 418-028-.PAGE J-33 ORAL (SAVAGE) COMBINED REPEATEO DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUM8ER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19116 SEX: M DOSE GROUP: DEATH TYPE: I Sacrifice-Scheduled GROSS OBSERVATIONfS): KIDNEYS: Mottled tan and red, bilateral. HISTOMORPHOLOGIC OBSERVATION!Si: No microscopic change to correlate HISTOMORPHOLOGIC OBSERVATIONS: KIDNEYS: LIVER: LYMPH NODE, SU8MANDIBULAR: 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 BRAIN DUODENUM JEJUNUM NERVE, SCIATIC RECTUM SPINAL CORD, THORACIC TESTIS (PAS) URINARY BLADDER End of Record- 19116 CECUM EPIDIDYMIDES KIDNEYS PARATHYROID SEMINAL VESICLES SPLEEN THYMUS 11-3 418-028-.PAGE J-34 ORAL (GAVA6E) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPROOUCTIOH/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 SEX: M DOSE GROUP: DEATH TYPE: I Sacrifice-Scheduled GROSS OBSERVATION!Si : GENERAL: No gross changes. HIST0M0RPH0L06IC OBSERVATIONfSl: Not applicable HISTQMORPHOLOGIC OBSERVATIONS: ADRENAL GLANDS: CECUM: COLON: KIDNEYS: LIVER: RECTUM: vacuolatlon, cortex, diffuse (minimal) inflammation, mucosa, chronic (moderate) inflammation, mucosa, chronic (mild) Infiltration, mononuclear-cell, focal/multifocal (minimal) inflammation, chronic, focal/multifocal (mild) Information, mucosa, chronic (mild) 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 C0A6ULATING GLAND DUODENUM ILEUM JEJUNUM LYMPH NODE, SUBMANDIBULAR NERVE, SCIATIC PROSTATE SEMINAL VESICLES SPINAL CORD, THORACIC SPLEEN TESTIS (PAS) THYMUS URINARY BLADDER End of Record- 19119 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 SEX: M GROSS OBSERVATION(S): GENERAL: No gross changes. DOSE GROUP: I DEATH TYPE: Sacrifice-Scheduled ts & s a s ta s s B s s s s H a a s e s s B a s c e s K B a ia B S B B s s s a s a s s B B a is a HISTOMORPHOLOGIC OBSERVATION!Si : 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 TISSUEfSl 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 CORD, LUMBAR TESTIS (H&E) URINARY BLADDER TISSUEfSl NOT AVAILABLE FOR EVALUATION: LYMPH NODE, MEDIASTINAL End of Record- 19122 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 OBSERVATIONfSi : GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATIONS! : 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 TISSUEfSl 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 BRAIN EPIDIDYMIDES KIDNEYS PARATHYROID SPINAL CORD, CERVICAL STOMACH TRACHEA End of Record- 19125 COAGULATING GLAND HEART LUNG PEYER'S PATCH SPINAL CORD, LUMBAR TESTIS (H&E) URINARY BLADDER 418-028-.PAGEJ-37 ORAL (SAVAGE) 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 SEX: M DOSE GROUP: DEATH TYPE: I Sacrifice-Scheduled GROSS OBSERVATIONfS): GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATIONfS): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: ADRENAL GLANDS: EPIDIDYMIDES: HEART: LIVER: LYMPH NODE, SUBMANDIBULAR: PROSTATE: TRACHEA: vacuolatlon, 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 CECUM ILEUM LYMPH NODE, MEDIASTINAL RECTUM SPINAL CORD, THORACIC TESTIS (PAS) End of Record- 19131 COAGULATING GLAND JEJUNUM NERVE, SCIATIC SEMINAL VESICLES SPLEEN THYMUS 11--7 418-028:PAGE J-38 ORAL (GAVASE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELQPMENTAL TOXICITY SCREENINQ TEST PROTOCOL NUMBER 416-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and HIstomorphology Data ANIMAL NUMBER: 19132 SEX: M GROSS OBSERVATION(S): GENERAL: No gross changes. DOSE GROUP: DEATH TYPE: I Sacrifice-Scheduled ISSSSSSSSBBSBSSSSaBKaSSSSSSBBBSBSSSSBSieSSSSSaSSSESSSSSSaSXSB HIST0MQRPH0L06IC OBSERVATIONS): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: STOMACH: THYROID: inflammation, chronic, focal/multifocal (mild) edema/inflammation, submucosa, glandular area (moderate) ultimobranchial body/cyst THE FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COAGULATING GLAND HEART LUNG PEYER'S PATCH SPINAL CORD, 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 CORO, THORACIC TESTIS (PAS) THYMUS CECUM EPIDIDYMIDES KIDNEYS PARATHYROID SEMINAL VESICLES SPLEEN TRACHEA TISSUEfSl NOT AVAILABLE FOR EVALUATION: LYMPH NODE, MEDIASTINAL End of Record- 19132 II-8 418-028:PAGE J-39 ORAL (SAVAGE) 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 GROSS OBSERVATION(S): GENERAL: No gross changes. DOSE GROUP: I DEATH TYPE: Sacrifice-Scheduled 8SSBSSB3*BSSBBse*assaHsaBBssaaaasa8asssas8aBS8M8SES3saB HISTOMORPHOLOGIC OBSERVATION(S): 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/inflairmation, submucosa, forestomach (mild) hypertrophy/hyperplasia, follicular epithelium (mild) inflammation, chronic, focal (minimal) THE FOLLOWING TISSUEfS) 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 11-9 418-028:PAGE J-40 ORAL (6AVAGE) 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 SEX: M DOSE GROUP: DEATH TYPE: I Sacrifice-Scheduled GROSS OBSERVATION(S) : GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATIONS! : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: KIDNEYS: LIVER: PROSTATE: infiltration, mononuclear-cell, focal/multifocal (minimal) inflammation, chronic, focal/mult1focal (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) BRAIN COLON DUODENUM ILEUM JEJUNUM LYMPH NODE, SUBMANDIBULAR NERVE, SCIATIC RECTUM SEMINAL VESICLES SPINAL CORD, THORACIC SPLEEN TESTIS (PAS) THYMUS URINARY BLADDER End of Record- 19135 CECUM EPIDIDYMIDES LUNG PARATHYROID SPINAL CORD, CERVICAL STOMACH THYROID 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 SEX: M DOSE GROUP: DEATH TYPE: II Sacrifice-Scheduled GROSS OBSERVATIONfS): KIDNEYS: Bilateral- mottled. HISTOMORPHOLOGIC OBSERVATIONfS1: 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 TISSUEfS) WERE WITHIN NORMAL LIMITS: KIDNEYS End of Record- 19102 11-11 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 OBSERVATIONfS): GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATIONS! : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: End of Record- 19106 Inflammation, chronic, focal/multifocal (mild) ultimobranchlal body/cyst 11-12 418-028-.PAGEJ-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 SEX: M GROSS OBSERVATION!SI : GENERAL: No gross changes. DOSE GROUP: DEATH TYPE: II Sacri fice-Scheduled lesnaBaBSSsssiBBsssssssasasBssss HISTOMORPHOLOGIC OBSERVATION(Si : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: lipidosis, tension, focal inflammation, chronic, focal/multifocal (minimal) THE FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS: THYROID End of Record- 19108 11-13 418-028:PAGEJ-44 ORAL (SAVAGE) 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 SEX: M GROSS OBSERVATIONS): GENERAL: No gross changes. DOSE GROUP: DEATH TYPE: II Sacri fice-Scheduled SSSSBSSSSSSSSSBBBBBSSSBSSBSSW8B8 HISTOMORPHOLOGIC OBSERVATIONfS): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: End of Record- 19110 Inflammation, chronic, focal/multlfocal (minimal) hypertrophy/hyperplasia, follicular epithelium (mild) 11-14 418-028-.PAGEJ45 ORAL (SAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEYELOPMENTAL 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 SEX: M DOSE GROUP: DEATH TYPE: II Sacrifice-Scheduled GROSS OBSERVATION(S): KIDNEYS: Left- pelvis, slight dilation. HISTOMORPHOLOSIC OBSERVATIONfSl: dilatation, pelvis HISTOMORPHOLOGIC OBSERVATIONS: KIDNEYS: dilatation, pelvis (mild) THE FOLLOWING TISSUEtS) WERE WITHIN NORMAL LIMITS: LIVER THYROID End of Record- 19113 11-15 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 SEX: M DOSE GROUP: DEATH TYPE: II Sacrifice-Scheduled GROSS OBSERVATIONfSi: GENERAL: No gross changes. HISTOMORPHOLOGIC.OBSERVATION): 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 11-16 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 SEX: M DOSE GROUP: DEATH TYPE: II Sacrifice-Scheduled GROSS OBSERVATION(Si : GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION!Si : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: End of Record- 19129 inflammation, chronic, focal/multi focal (minimal) hypertrophy/hyperplasia, follicular epithelium (minimal) 11-17 418-028:PAGE 3-48 ORAL (GAVA6E) COMBINED REPEATED DOSE TOXICITY STUDY OF T-770B WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENINQ TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Hlstomorphology Data ANIMAL NUMBER: 19136 SEX: M DOSE GROUP: DEATH TYPE: II Sacrifice-Scheduled GROSS OBSERVATIONS!: KIDNEYS: Bilateral- mottled. HISTOMORPHOLOGIC OBSERVATION ISi: dilatation, pelvis HISTOMORPHOLOGIC OBSERVATIONS: KIDNEYS: LIVER: THYROID: End of Record- 19136 dilatation, pelvis (minimal) vacuolatlon, hepatocellular, multifocal (minimal) ultimobranchlal body/cyst 11-18 418-028-.PAGEJ-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 GROSS OBSERVATION!Si : GENERAL: No gross changes. DOSE GROUP: II DEATH TYPE: Sacrifice-Scheduled c sa iisa n sB S E B S S B a sa ia iB a ssB ssa a sa a ia B sssa B a B a sisssG E B B sa HISTOMORPHOLOGIC OBSERVATION!Si: Not applicable HISTOMORPHOLOGIC OBSERVATIONS: THYROID: ultimobranchial body/cyst THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: LIVER End of Record- 19138 11-19 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 SEX: M DOSE GROUP: DEATH TYPE: II Sacrifice-Scheduled GROSS OBSERVATION!SI: GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION!SI: Not applicable HISTOMORPHOLOGIC OBSERVATIONS: THYROID: hypertrophy/hyperplasia, follicular epithelium (mild) THE FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS: LIVER End of Record- 19139 11-20 418-028:PAGE J-51 ORAL (GAVA6E) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENINQ TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19101 SEX: M SSS=3SS3SSCS3S3SSSaBBS3BBSSSSB&=SS8SS3BSSSi GROSS OBSERVATION!Si: GENERAL: No gross changes. DOSE GROUP: III DEATH TYPE: Sacrifice-Scheduled HISTOMORPH0LO6IC OBSERVATIONSi: Not applicable THE FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS: LIVER THYROID End of Record- 19101 iSBBB 11-21 418-028:PAGEJ-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 SEX: M DOSE 6R0UP: DEATH TYPE: III Sacrifice-Scheduled GROSS OBSERVATION!SI: GENERAL: No gross changes. HIST0M0RPH0L06IC OBSERVATION!Si : Not applicable HISTOMORPHOLOGIC 0BSERVATI0NS: LIVER: Inflammatlon, chronlc, focal/multifocal (minima!) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: THYROID End of Record- 19105 11-22 418-028-.PAGEJ-53 ORAL (6AVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7708.1 Appendix II Individual Animal Gross and Hlstomorphology Data ANIMAL NUMBER: 19107 SEX: M DOSE GROUP: DEATH TYPE: III Sacri fice-Scheduled GROSS OBSERVATION(S): GENERAL: No gross changes. HIST0M0RPH0L06IC OBSERVATION!Si: Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: End of Record- 19107 Inflammation, chronic, focal/multifocal (minimal) hypertrophy/hyperplasia, follicular epithelium (minimal) ultlmobranchial body/cyst 11-23 418-028-.PAGEJ-54 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-0Z8 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and H1stomorphology Data ANIMAL NUMBER: 19112 SEX: M DOSE GROUP: DEATH TYPE: III Sacrifice-Scheduled GROSS OBSERVATIONS: GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATIONS): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: End of Record- 19112 Inflanrnation, chronic, focal/multifocal (minimal) ultlmobranchlal body/cyst 11-24 418-028-.PAGEJ-55 ORAL (GAVASE) 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 H1stomorphology Data ANIMAL NUMBER: 19114 SEX: M DOSE GROUP: DEATH TYPE: III Sacrifice-Scheduled GROSS OBSERVATION!SI: GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION!Si: Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: End of Record- 19114 Inflammation, chronic, focal/multifocal (minimal) ultlmobranchial body/cyst 11-25 418-028:PAGE J-56 ORAL (6AVAGE) 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 SEX: M DOSE GROUP: DEATH TYPE: III Sacrifice-Scheduled GROSS OBSERVATIONS: GENERAL: No gross changes. HIST0H0RPH0L06IC OBSERVATION! SI : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: End of Record- 19121 inflanmatlon, chronic, focal/multifocal (minimal) vacuolatlon, hepatocellular, multifocal (mild) ultimobranchial body/cyst 11-26 418-028.PAGE J-57 ORAL (6AVASE) 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: III SEX: M DEATH TYPE: Sacrifice-Scheduled sssssaBsss3BBasBssssssaBsssassss0*8aa==BBssssssss8ss8SS*CBsssBsssa8snssBasssBB9saasasssssss3ssssnaaB GROSS OBSERVATION(S): HIST0M0RPH0L06IC OBSERVATIONS!: GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: inflammation, chronic, focal/multifocal (minimal) M E FOLLOWING- TISSUE(S) WERE WITHIN NORMAL LIMITS: THYROID End of Record- 19123 11-27 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 SEX: M GROSS OBSERVATIONS) : GENERAL: No gross changes. isssssssnaessssss: DOSE GROUP: DEATH TYPE: III Sacri fice-Schedul ed SSSSSBSSSSBasaSSBSCSBBSBCSBSflSBS HIST0M0RPH0L06IC OBSERVATION!Si : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: End of Record- 19130 Inflammation, chronic, focal/multifocal (minimal) hypertrophy/hyperplasia, follicular epithelium (mild) 11-28 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 SEX: M GROSS OBSERVATION!SI: GENERAL: No gross changes. DOSE GROUP: DEATH TYPE: III Sacri fice-Schedul ed ISSSSSSSSSSSaSBHIBSSBSSSSSSSSSSS HISTOMORPHOLOGIC OBSERVATIONS): Not applicable THE FOLLOWING TISSUEtS) WERE WITHIN NORMAL LIMITS: LIVER THYROID End of Record- 19137 11-29 418-028:PAGE J-60 ORAL (SAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/OEVELOPMENTAL 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 DOSE GROUP: III SEX: M DEATH TYPE: Sacrifice-Scheduled ssBssaaaaa8ssssaaBs&3aasaa8ssassaiissBsasB8ssBa8BsBsssBasBBSsa3aBssBsssss8BS8aBBBsssBaaaBSBSss GROSS OBSERVATION(S1: HISTOMORPHOLOGIC OBSERVATION!Si: GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: vacuolation, hepatocellular, midzonal (mild) THE FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS: THYROID End of Record- 19146 11-30 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 Hlstomorphology Data ANIMAL NUMBER: 19100 SEX: M DOSE GROUP: DEATH TYPE: IV Sacrifice-Scheduled GROSS OBSERVATIONfSl: GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATIONfSl: Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: End of Record- 19100 hypertrophy, hepatocellular, centrllobular (minimal) inflammation, chronic, focal/multlfocal (minimal) hypertrophy/hyperplasla, follicular epithelium (minimal) 11-31 418-028:PAGE J-62 ORAL (6AVAGE) 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 Hlstomorphology Data ANIMAL NUMBER: 19103 DOSE GROUP: IV SEX: M DEATH TYPE: Sacrifice-Scheduled essasBSsaaBsasssBSBsssssasasBsssBSSsassasasasssssaassBssssBssassBBiSBSsainasaBessssassBSBBSaBBsssBsssBssB GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATIONS: GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: hypertrophy, hepatocellular, centrilobular (minimal) THE-FOILOWINB TISSUE(S) WERE WITHIN NORMAL LIMITS: THYROID End of Record- 19103 11-32 418-028.PAGE J-63 ORAL (6AVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTIQN/DEVELOPMENTAL TOXICITY SCREENIN6 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 GROSS OBSERVATION!Si : GENERAL: No gross changes. DOSE GROUP: DEATH TYPE: IV Sacrifice-Scheduled IBBSSSSSSSS8BBaSBSSSSSSBaasSSaBSSSSBSSB>BXSBSas HISTOMORPHOLOGIC OBSERVATION!Si: Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: inflammation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrllobular (mild) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: THYROID End of Record- 19104 11-33 418-028.PAGE J-64 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPROOUCTIQN/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 Sacrif1ce-Scheduled GROSS OBSERVATIONS!: GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATIONS!: Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: Inflammation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrllobular (minimal) THE FOLLOWING TISSUE(S1 WERE WITHIN NORMAL LIMITS: THYROID End of Record- 19118 11-34 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 SEX: M DOSE GROUP: DEATH TYPE: IV Sacrifice-Scheduled GROSS OBSERVATIONS!: GENERAL: No gross changes. HIST0M0RPH0L06IC OBSERVATION!Si : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: End of Record- 19133 hypertrophy, hepatocellular, centrl1obular (minimal) hypertrophy/hyperplasia, follicular epithelium (minimal) ultimobranchial body/cyst 11-35 418-028.PAGEJ-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 Bssssassssssssass3SBSsaEsasssssr=s*ss3sssB8S3saaasassssBMBassssssaaBaBsnss3BssssaBCBSSBsssss3saB88SBss GROSS OBSERVATIONiS): GENERAL: No gross changes. HISTOHORPHOLQ6IC OBSERVATION!S): 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 (GAVA6E) COMBINED REPEATED DOSE TOXICITY STUDY OF T-770B WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENINS TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19142 SEX: M DOSE GROUP: DEATH TYPE: IV Sacri flce-Scheduled GROSS OBSERVATIONfS): EPIDIDYMIDES: Bilateral- small; cauda epididymis, left, small. TESTES: Bilateral- small. HIST0M0RPH0L06IC OBSERVATIONfSI: hypospermla exfoliated spermatogenlc cells degeneration, multifocal, TESTIS (PAS) degeneration, multifocal, TESTIS (H&E) HIST0M0RPH0LQGIC OBSERVATIONS: EPIDIDYMIDES: LIVER: TESTIS (H&E): TESTIS (PAS): hypospermla (marked) exfoliated spermatogenlc cells (moderate) inflammation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrllobular (minimal) degeneration, multifocal (mild) degeneration, multifocal (mild) THE FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS: THYROID End of Record- 19142 11-37 ifI M l ORAL (SAVAGE) 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 Hlstomorphology Data ANIMAL NUMBER: 19144 SEX: M GROSS OBSERVATION(Si : GENERAL: No gross changes. DOSE GROUP: IV DEATH TYPE: Sacrifice-Scheduled B B B B B s s s s s s s s B s s B a s s s B B B S B B W B B B B e B S B S s c s s B a s B B S B S B S B s ts s B S B S B s s B B B B S B HISTOMORPHOLOGIC OBSERVATIONS) : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: inflammation, chronic, focal/multifocal (minimal) t h e I PHWlMfi TjS&iEisJ WEREJUTHIN n o rm al LIMITS: THYROID End of Record- 19144 418-028:PAGE J-69 ORAL (SAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-770B WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19148 SEX: M GROSS OBSERVATIONfS): GENERAL: No gross changes. DOSE GROUP: DEATH TYPE: IV Sacrifice-Scheduled :B3SSSSS*S=S3S=3a8BaBSSS=SSS8aS==SSSaSSaSSS3=SB HISTOMORPHOLOGIC OBSERVATION!Si: Not applicable HI.SISMOR L H m iO gSL RyATjONS: LIVER: THYROID: End of Record- 19148 Inflammation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (minimal) hypertrophy/hyperplasla, follicular epithelium (mild) 11-39 418-028.PAGE 3-70 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 SEX: M DOSE GROUP: DEATH TYPE: IV Sacrifice-Scheduled GROSS OBSERVATION!SI : GENERAL: No gross changes. HISTOHORPHOLOGIC OBSERVATION!Si : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: End of Record- 19150 hypertrophy, hepatocellular, centrilobular (minimal) hypertrophy/hyperplasia, follicular epithelium (mild) 11-40 418-028-.PAGEJ-71 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-77Q6 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 SEX: M DOSE GROUP: DEATH TYPE: V Sacrifice-Scheduled GROSS OBSERVATIONS: GASTROINTESTINAL TRACT: Jejunum- diverticulum, 1.5x0.6x0.4cm. HISTOMORPHOLOGIC OBSERVATION!S): diverticulum, JEJUNUM HISTQMORPHOLQGIC 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, 1ymphocyt1c/plasmacytic (minimal) mineralization, focal (minimal) inflammation, chronic, focal/multifocal (minimal) ultimobranchial body/cyst hypertrophy/hyperplasia, follicular epithelium (moderate) THE FOLLOWING TISSUEfS) 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 BRAIN DUODENUM LUNG RECTUM SPINAL CORD, THORACIC TESTIS (PAS) End of Record- 19111 CECUM EPIDIDYMIDES LYMPH NODE, MEDIASTINAL SEMINAL VESICLES SPLEEN THYMUS 11-41 418-02S-.PAGE 3-72 ORAL (SAVAGE) COMBINED REPEAfED 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 SSB=SSaSBSSSSSSaHB3BZS8SBSSM3SSSSSSSSaSBSS3SSSSSSBBBS3SSSSaBSBBaBSSSa!SSBS8aBBBSSBSSS*B8airaaBCSSS GROSS OBSERVATION(S): HIST0M0RPH0L06IC OBSERVATIONfS): 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/inflanimation, submucosa, forestomach (mild) THE FOLLOWING TISSUEfS) 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 BRAIN DUODENUM JEJUNUM PARATHYROID SEMINAL VESICLES SPLEEN THYROID End of Record- 19117 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 REPRQDUCTION/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 SEX: M DOSE GROUP: DEATH TYPE: V Sacrifice-Scheduled GROSS OBSERVATION!Si: GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION!SI: 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 HARROW (STERNUM) COLON JEJUNUM PARATHYROID SEMINAL VESICLES SPLEEN THYMUS BRAIN DUODENUM LUNG PEYER'S PATCH SPINAL CORD, CERVICAL STOMACH TRACHEA End of Record- 19124 CECUM HEART LYMPH NODE, SUBMANDIBULAR PROSTATE SPINAL CORD, LUMBAR TESTIS (H&E) URINARY BLADDER 11-43 418-028:PAGE J-74 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELQPMENTAL 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 SEX: M DOSE GROUP: DEATH TYPE: V Sacrifice-Scheduled GROSS OBSERVATION(S): GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATIONS): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: PROSTATE: inflammation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (mild) Inflammation, chronic, focal/multifocal (minimal) THE FOLLOWING TISSUEfS) 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 BRAIN CECUM DUODENUM EPIDIDYMIDES JEJUNUM KIDNEYS LYMPH NODE, SUBMANDIBULAR NERVE, SCIATIC RECTUM SEMINAL VESICLES SPINAL CORD, THORACIC SPLEEN TESTIS (PAS) THYMUS URINARY BLADDER End of Record- 19126 11-44 418-028-.PAGEJ-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 NLW4BER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19127 SEX: M DOSE GROUP: DEATH TYPE: V Sacrifice-Scheduled GROSS OBSERVATIONS!: GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION!SI : 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) CECUM EPIDIDYMIDES KIDNEYS PARATHYROID SEMINAL VESICLES SPLEEN THYMUS End of Record- 19127 COAGULATING 6LAND 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/DEVELOPHENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Hlstomorphology Data ANIMAL NUMBER: 19128 SEX: M GROSS OBSERVATION!SI: GENERAL: No gross changes. DOSE GROUP: V DEATH TYPE: Sacrifice-Scheduled eS B S aS S K B S B fltS B aN IB S S S aE M B aaM N m B S S S B S S M atS S H B M B asS B S S S S S S S S E HISTOMORPHOLOGIC OBSERVATIONS!: Not applicable HISTOMORPHOLOGIC OBSERVATIONS: CECUM: LIVER: LYMPH NODE, SUBMANDIBULAR: PROSTATE: THYROID: Inflammation, mucosa, chronic (mild) inflamnation, chronic, focal/multi focal (minimal) hypertrophy, hepatocellular, centrllobular (mild) hyperplasia, lymphocytic/plasmacytic (moderate) atrophy, focal/multifocal (moderate) hypertrophy/hyperplasla, follicular epithelium (moderate) THE FOLLOWING TISSUEfS) 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 BRAIN EPIDIDYMIDES KIDNEYS PARATHYROID SPINAL CORD. CERVICAL STOMACH TRACHEA End of Record- 19128 COAGULATING GLAND HEART LUNG PEYER'S PATCH SPINAL CORD, LUMBAR TESTIS (H&E) URINARY BLADDER 11-46 418-028:PAGE J-77 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELQPMENTAL 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 SEX: M DOSE GROUP: DEATH TYPE: V Sacri fice-Scheduled GROSS OBSERVATIONfS): GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATIONS: Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: 1nfl airmailon, chronic, focal/multi focal (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 BRAIN CECUM DUODENUM EPIDIDYMIDES JEJUNUM KIDNEYS LYMPH NODE, SUBMANDIBULAR NERVE, SCIATIC PROSTATE RECTUM SPINAL CORD, LUMBAR SPINAL CORD, THORACIC TESTIS (H&E) TESTIS (PAS) URINARY BLADDER End of Record- 19140 11-47 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 SEX: M DOSE GROUP: DEATH TYPE: V Sacrifice-Scheduled GROSS OBSERVATION(S): GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATIONfSl: Not applicable HISTOMORPHOLOGIC OBSERVATIONS: KIDNEYS: LIVER: LYMPH NODE, 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 TISSUEfSl WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COAGULATING GLAND HEART LYMPH NODE, MEDIASTINAL PROSTATE SPINAL CORD, THORACIC TESTIS (PAS) BONE MARROW (STERNUM) COLON ILEUM NERVE, SCIATIC SEMINAL VESICLES SPLEEN THYMUS BRAIN DUODENUM JEJUNUM PARATHYROID SPINAL CORD, CERVICAL STOMACH THYROID End of Record- 19145 CECUM EPIDIDYMIDES LUNG PEYER'S PATCH SPINAL CORD, LUMBAR TESTIS (H&E) URINARY BLADDER 11-48 418-028:PAGE J-79 ORAL (SAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTIPORON/TODECVOELLONPUMMEBNETRAL41T8O-0X2I8CITY SCREENING TEST SPONSOR' S STUDY NUMBER T -7 7 0 6 .1 Appendix I I In d iv id u a l Animal Gross and Histom orphology Data ANIMAL NUMBER: 19149 SEX: M DOSE GROUP: DEATH TYPE: S a c rif 1ce-Scheduled GROSS OBSERVATION(S): GENERAL: No g ross changes. HISTOMORPHOLOGIC OBSERVATION(S): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: hypertrophy, h e p a to c e llu la r, c e n trilo b u la r (m inim al) ultim obranchial body/cyst hypertrophy/hyperplasia, fo llic u la r e p ith elium (moderate) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIM ITS: ADRENAL GLANDS COAGULATING GLAND HEART LUNG PARATHYROID SEMINAL VESICLES SPLEEN THYMUS BONE MARROW (STERNUM) COLON ILEUM PLYEMYPEHR'SNOPDAET,CHMEDIASTINAL SSTPOINMAACLHCORD. CERVICAL TRACHEA End o f Record- 19149 BRAIN CECUM DUODENUM EPIDIDYMIDES JEJUNUM KIDNEYS LYMPH NODE, SUBMANDIBULAR NERVE, SCIATIC PROSTATE RECTUM SPINAL CORD, LUMBAR SPINAL CORD, THORACIC TESTIS (H&E) TESTIS (PAS) URINARY BLADDER 11-49 418-028:PAGE J-80 OWRAITLH (GTHAEVARGEEP) RCOODMUBCITNIEODN/DREEVPEELAOTPEMDEDNOTASLE TTOOXXIICCIITTYY SSCTURDEYENOINFGTT-7E7S0T6 PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T -7 7 0 6 .1 Appendix I I In d ivid u a l Animal Gross and Histom orphology Data ANIMAL NUMBER: 19152 SEX: M DOSE GROUP: V DEATH TYPE: S a c rific e -S c h e d u le d s s s s B S s s s s s a s s s s s s s a s s s s r x s s a a s s s rB S S X S X B B B B X X B X X X S B B B X X S X X B B B B B B B X B X B B K X S S B B B X X B X S S X X X B B B B X S S X B S X X B S X B GROSS OBSERVATION(S): HISTOMORPHOLOGIC OBSERVATION(S): GENERAL: No aro ss chanaes. Not applicable H1ST0M0RPH0L0GIC OBSERVATIONS: HEART: LIVER: LYMPH NODE, SUBMANDIBULAR: PROSTATE: THYROID: inflam m ation, chronic, focal (m inim al) Inflam m ation, chronic, fo c a l/m u ltifo c a l (m inim al) hypertrophy, h e p a to c e llu la r, c e n trllo b u la r (m inim al) hyperplasia, lym phocytlc/plasm acytlc (moderate) Inflam m ation, chronic, fo c a l/m u ltifo c a l (m inim al) atrophy, fo c a l/m u ltifo c a l (m inim al) hypertrophy/hyperplasia, fo llic u la r ep ithelium (m ild ) THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIM ITS: ADRENAL GLANDS COAGULATING GLAND ILEUM RLYEMCTPUHMNODE, MEDIASTINAL SPINAL CORD, THORACIC TESTIS (PAS) BONE MARROW (STERNUM) COLON JEJUNUM NERVE, SCIATIC SSPELMEIENNAL VESICLES THYMUS End o f Record- 19152 BRAIN KDUIDONDEENYUSM SPAPRINAATLHYCROORIDD, CERVICAL TSRTOAMCHACEHA CECUM LEUPNIDGIDYMIDES SPPEIYNEARL'S COPARTDC, HLUMBAR TESTIS (H&E) URINARY BLADDER 11-50 418-028:PAGE J-81 OWRAITLH (GTHAEVAR6EEP)RCOODMUCBITNIOEDN/DREEVPEELAOTPEMDEDNOTASEL TTOOXXIICCIITTYY SSTCURDEYENOINFGTT-7E7S0T6 PROTOCOL NUMBER 418-028 SPONSOR' S STUDY NUMBER T -7 7 0 6 .1 Appendix I I In d iv id u a l Animal Gross and Histom orphology Data ANIMAL NUMBER: 19012 SEX: F DOSE GROUP: I DEATH TYPE: S a c ri f i ce-Scheduled GROSS OBSERVATION^ h GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATIONS! : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: TSHTOYMRAOCIDH:: UTERUS: udlitllamtoabt iroann,c hmiaulcobsoald yg/claynsdts (m in im a l) macrophages, pigmented (moderate) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIM ITS: ADRENAL GLANDS COLON JEJUNUM LYMPH NODE, MEDIASTINAL OVARIES SPINAL CORD. CERVICAL THYMUS BONE MARROW (STERNUM) BRAIN DUODENUM HEART KIDNEYS LIVER LYMPH NODE, SUBMANDIBULAR MAMMARY GLAND PARATHYROID PEYER'S PATCH SPINAL CORD. LUMBAR SPINAL CORO, THORACIC TRACHEA URINARY BLADDER End o f Record- 19012 CECUM ILEUM LUNG NERVE, SCIATIC RECTUM SPLEEN VAGINA 11-51 418-028:PAGE J-82 OWRAITLH (6TAHVEAGREEP) RCOOOMUBCITNIEODN/DREEVPEELAOTPEMDENDOTASLE TTOOXXIICCIITTYY SSTCURDEYENOINFGTT-7E7S0T6 PROTOCOL NUMBER 418-028 SPONSOR' S STUDY NUMBER T -7 7 0 6 .1 Appendix I I In d iv id u a l Animal Gross and Histom orphology Data ANIMAL NUMBER: 19019 SEX: F GROSS OBSERVATIONfS): GENERAL: No gross changes. DOSE GROUP: 1 DEATH TYPE: S a c rific e -S c h e d u le d B B S B B B S B B S B S B S sB B B B B B B isa B sa ssssssss sB ssB S B B B B B B m ss HISTOMORPHOLOGIC OBSERVATIONS!: Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LYMPH NODE, SUBMANDIBULAR: UTERUS: hyperplasia, lym phocytic/plasm acytic (m ild ) macrophages, pigmented (m ild ) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIM ITS: ACODLROENNAL GLANDS JEJUNUM LYMPH NODE, MEDIASTINAL PARATHYROIO SPINAL CORD, LUMBAR TVHAYGMINUAS BONE MARROW (STERNUM) DUODENUM MKAIDMNMEAYRSY GLAND PEYER'S PATCH SPINAL CORD, THORACIC THYROID End o f Record- 19019 BHERAARINT LIVER NERVE, SCIATIC RECTUM SPLEEN TRACHEA CECUM ILEUM LUNG OVARIES SPINAL CORD, CERVICAL STOMACH URINARY BLADDER 11-52 418-028:PAGE J-83 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTPIORONT/DOECVOELLONPUMMEBNERTA4L1T8O-0X2I8CITY SCREENING TEST SPONSOR' S STUDY NUMBER T -7 7 0 6 .1 Appendix I I In d iv id u a l Animal Gross and Histom orphology Data ANIMAL NUMBER: 19021 SEX: F DOSE GROUP: I DEATH TYPE: S a c rific e -S c h e d u le d GROSS OBSERVATIONS!: HEAD: Head- scab, 0.2cmx0.4cm. HISTOMORPHOLOGIC OBSERVATION!SI : d e rm a titis , c h ro n ic , fo c a l, SKIN (GROSS LESION) HISTOMORPHOLOGIC OBSERVATIONS: LIVER: LYMPH NODE, MEDIASTINAL: SKIN (GROSS LESION): THYROID: UTERUS: cinofnlagmesmtiaotnio n(m, icn ihmroanl)ic , fo c a l/m u ltifo c a l (m in im a l) d e rm a titis, chronic, focal (m ild) ultim obranchlal body/cyst macrophages, pigmented (moderate) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIM ITS: ADRENAL GLANDS JCEOJLUONNUM MAMMARY GLAND PEYER' S PATCH TSRPAINCAHLEACORD, THORACIC BONE MARROW (STERNUM) DKUIDONDEENYUSM NERVE, SCIATIC RECTUM VSAPLGEINENA BRAIN HEART OLUVNAGRIES SPINAL CORD, CERVICAL STOMACH CILEECUUMM LYMPH NODE, SUBMANDIBULAR PSAPRINAATHLYCROORIDD, LUMBAR THYMUS TISSUE(S) NOT AVAILABLE FOR EVALUATION: URINARY BLADDER End o f Record- 19021 11-53 418-028-.PAGE J-84 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTIPORNO/TDOECVOELLQNPUMMEBNERTA4L1T8O-0X2I8CITY SCREENING TEST SPONSOR'S STUDY NUMBER T -7 7 0 6 .1 Appendix I I In d iv id u a l Animal Gross and Histom orphology Data ASNEIXM: AL NUMBER: F19023 GROSS OBSERVATIONfS): GENERAL: No gross changes. DOSE GROUP: I DEATH TYPE: S a c rific e -S c h e d u le d :x3SSBiB8aaanaiBa33Q38aaiBSsssaB3zsssBssBsssss8 HISTOMORPHOLOGIC OBSERVATIONfSl: Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LUNG: SLTYOMMPHACNHO: DE, MEDIASTINAL: UTERUS: i n(fmi litlrda) t i o n , polym orphonuclear,p e riv a s c u la r/p e rib ro n c h ia l medaesmtoac/yintoflasmis m(amtlionnim, aslu)bmucosa, g la n d u la r area (m ild ) macrophages, pigmented (m inim al) THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIM ITS: ADRENAL GLANDS COLON JEJUNUM MAMMARY GLAND PEYER' S PATCH SPINAL CORD, THORACIC TRACHEA BONE MARROW (STERNUM) DKUIDONDEENYUSM NREECRTVUEM, SCIATIC SPLEEN URINARY BLADDER End o f Record- 19023 BRAIN HEART LIVER OVARIES SPINAL CORD, CERVICAL TVHAYGMINUAS CECUM ILEUM LYMPH NODE, SUBMANDIBULAR PARATHYROIO SPINAL CORD, LUMBAR THYROID 11-54 418-028 :PAGE J-85 ORAL (GAVA6E) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTPIROONT/ODCEOVELLONUPMMBEENRTA4l1T8O-0X2I8CITY 5CREENIN6 TEST SPONSOR' S STUDY NUMBER T -7 7 0 6 .1 Appendix I I In d ivid u a l Animal Gross and Histom orphology Data ANIMAL NUMBER: 19041 SEX: F DOSE GROUP: I DEATH TYPE: S a c rific e -S c h e d u le d GROSS OBSERVATION^!: GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATIONS! : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LYMPH NODE, SUBMANDIBULAR: STOMACH: THYROID: UTERUS: hyperplasia, lym phocytic/plasm acytlc (moderate) e d em a/in fla im a tio n , submucosa, g lan d ular area (moderate) ultim obranchial body/cyst macrophages, pigmented (moderate) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIM ITS: ADRENAL GLANDS COLON JEJUNUM LYMPH NODE, MEDIASTINAL SPAPRINAATLHYCROORIDD. LUMBAR TRACHEA BONE MARROW (STERNUM) DKUIDONDEENYUSM MPAEMYMERAR'SY GPALATCNDH SPINAL CORD, THORACIC URINARY BLADDER End o f Record- 19041 BRAIN HEART LNIEVREVRE, SCIATIC RECTUM SPLEEN VAGINA CECUM ILEUM LUNG OVARIES SPINAL CORD, CERVICAL THYMUS 11-55 418-028 .PAGE J-86 OWRAITLH(GTAHVEAGREEP) RCOODMUBCITNIEOON/DREEVPEELAOTPEMDEDNOTASEL TTOOXXIICCIITTYY SSTCURDEYENOINFGTT-7E7S0T6 PROTOCOL NUMBER 418-028 SPONSOR' S STUDY NUMBER T -7 7 0 6 .1 In d iv id u a l Animal GArpopsesndaindx HIIistom orp hology Data ANIMAL NUMBER: 19042 SEX: F DOSE GROUP: I DEATH TYPE: S a c rific e -S c h e d u le d GROSS OBSERVATION'S): GENERAL: No g ross changes. HISTOMORPHOLOGIC OBSERVATIONS!: Not applicable HISTOMORPHOLOGIC OBSERVATIONS: OTHVYARROIEIDS:: UTERUS: uc lytismt(osb)r,a nincthrataol v ab rolda yn/cyst macrophages, pigmented (moderate) THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIM ITS: ADRENAL GLANDS CJEOJLUONNUM LYMPH NODE, MEDIASTINAL PARATHYROID TSHPYINMAULS CORD, LUMBAR BDOUONEDENMUAMRROW (STERNUM) BHREAARINT KIDNEYS LIVER LPYEMYPEHR'SNOPDAET,CHSUBMANDIBULAR RMEACMTMUMARY GLAND SPINAL CORO, THORACIC SPLEEN TRACHEA URINARY BLADDER End o f Record- 19042 CECUM LILUENUGM SNPEIRNVAEL, CSOCRIADT, ICCERVICAL SVTAOGMINAACH 11-56 418-028:PAGE J-87 OWRAITLH (GTHAEVARGEEP) RCOODMUBCITNIOEDN/DREEVPEELAOTPEMDEDNOTASLE TTOOXXIICCIITTYY SSCTURDEYENOINFGTT-7E7S0T6 SPONPSROORT'OSCSOTLUDNUYMNBUERMB4ER18T-0-2787 0 6 .1 Appendix I I In d ivid u a l Animal Gross and Histom orphology Data ANIMAL NUMBER: 19044 SEX: F DOSE GROUP: DEATH TYPE: I Sacri f i ce-Schedul ed GROSS OBSERVATIONS!: GENERAL: No g ross changes. HISTOMORPHOLOGIC OBSERVATION( S ) : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: KLYIDMNPHEYNSO: DE. MEDIASTINAL: LYMPH NODE, SUBMANDIBULAR: UTERUS: cnoenpghersittiiosn, c(mh rinoinmica,l) fo c a l {m in im a l) hyperplasia, lym phocytlc/plasm acytlc (m ild) hyperplasia, lym phocytlc/plasm acytlc (moderate) macrophages, pigmented (moderate) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIM ITS: ADRENAL GLANDS CJEOJLUONNUM NREECRTVUEM, SCIATIC SPLEEN TRACHEA BONE MARROW (STERNUM) DUODENUM LIVER OVARIES SSTPOINMAACLHCORD, CERVICAL URINARY BLADDER BRAIN HLUENAGRT PARATHYROID SPINAL CORD, LUMBAR TVHAYGMINUAS End o f Record- 19044 CECUM ILEUM MAMMARY GLAND PEYER'S PATCH STHPYINRAOLIDCORD, THORACIC 11-57 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 -7 7 0 6 .1 Appendix I I In d ivid u a l Animal Gross and Histom orphology Data ANIMAL NUMBER: 19050 SEX: F DOSE GROUP: I DEATH TYPE: S a c rific e -S c h e d u le d GROSS OBSERVATION(SI: GENERAL: No c ro ss chanoes. HISTOMORPHOLOGIC OBSERVATIO N (S ): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: ADRENAL GLANDS: LYMPH NODE. SUBMANDIBULAR: UTERUS: vhay cp ueorplalatlsoina ,, zlyomnap hgolocmytelcru/plolassam(amc iyldtlc) (m in im a l) macrophages, pigmented (moderate) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIM ITS: BONE MARROW (STERNUM) DUODENUM KIDNEYS MSPPAEMIYNMEARALR'SYCGOPALRATDCN,HDTHORACIC THYROID BRAIN HEART LIVER RSNEPECLRETVUEEMN. SCIATIC TRACHEA End o f Record- 19050 CECUM ILEUM LUNG OSPVIANRAIELSCORD, CERVICAL USTROINMAACRHY BLADDER COLON JLEYJMUPNHUMNODE, MEDIASTINAL SPAPRINAATLHYCROORIDD, LUMBAR TVHAYGMINUAS 11-58 418-028.PAGE J-89 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTIPROON/TODCEVOELLONPUMMEBNETRAL41T8O-0X2I8CITY SCREENING TEST SPONSOR'S STUDY NUMBER T -7 7 0 6 .1 Appendix I I In d iv id u a l Animal Gross and Histom orphology Data ANIMAL NUMBER: 19053 SEX: F GROSS OBSERVATION(S): GENERAL: No gross changes. DOSE GROUP: I D 8ESASTHS e 8T Y B P S E S : S a a a S Sacr nSSB if B ic B e B - B S8ca i 8h 8eBdBu le d BBS B HIST0M0RPH0L06IC OBSERVATION(S): Not applicable HISTOMORPHOLOSIC OBSERVATIONS: ACDECRUENMA: L GLANDS: LYMPH NODE, SUBMANDIBULAR: THYMUS: THYROID: UTERUS: vac uo lation , zona glom erulosa (m ild) inflam m ation, mucosa, chronic (moderate) hyperplasia, lym phocytic/plasm acytlc (m ild ) atrophy (moderate) ultim obranchial body/cyst macrophages, pigmented (moderate) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIM ITS: BONE MARROW (STERNUM) HEART LIVER NERVE, SCIATIC RECTUM SPLEEN VAGINA BRAIN ILEUM LUNG OVARIES SSTPOINMAACLHCORD, CERVICAL End o f Record- 19053 COLON JEJUNUM LYMPH NODE, MEDIASTINAL PARATHYROID SPINAL CORD, LUMBAR TRACHEA DUODENUM KIDNEYS MPAEMYMEARR'SY GPALATCNHD SUPRIINNAARLYCOBLRADD, DTEHRORACIC 11-59 418-028;PAGE J-90 OWRAITLH (6TAHVEAGREEP)RCOODMUCBITNIOEDN/DREEVPEELAOTPEMDEDNOTASLE TTOOXXIICCIITTYY SSTCURDEYENOINFGTT-7E7S0T6 PROTOCOL NUMBER 418-028 SPONSOR' S STUDY NUMBER T -7 7 0 6 .1 Appendix I I In d iv id u a l Animal Gross and Histom orphology Data ANIMAL NUMBER: 19065 SEX: F 6R0SS OBSERVATIONS: GENERAL: No g ross changes. DOSE GROUP: I DEATH TYPE: S a c rific e -S c h e d u le d :sssiiB B B S s s s sB a iia sB B S S B z s s a a B iE s s s 8 z rs s sa B rc B S B s s 3 is a a HISTOMORPHOLOGIC OBSERVATION!SI : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: CECUM: LIVER: ULYRMINPAHRYNOBDLEA, DSDUEBRM: ANDIBULAR: UTERUS: inflam m ation, mucosa, chronic (m ild ) hinyfplaemrpmlaastiioan, , 1ycmh rpohnoiccy,t1cfo/pclaa sl/mmaucltyitf1occ a(ml il(dm)in im a l) inflam m ation, chronic, focal (m inim al) macrophages, pigmented (m ild ) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIM ITS: ADRENAL GLANDS DKUIDONDEENYUSM NERVE, SCIATIC RECTUM STRPALECEHNEA BONE MARROW (STERNUM) HEART LUNG OSPVIANRAIELS CORD, CERVICAL VSTAOGMINAACH End o f Record- 19065 BRAIN LILYEMUPMH NODE, MEDIASTINAL PSAPRINAATLHYCROORIDD, LUMBAR THYMUS COLON JEJUNUM MPAEMYMEARR'SY GPALATCNHD TSHPYINRAOLIDCORD, THORACIC 11-60 418-028:PAGE J-91 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTIPROON/TODCEOVELLONPUMMEBNETRAL41T8O-0X2I8CITY SCREENING TEST SPONSOR'S STUDY NUMBER T -7 7 0 6 .1 Appendix I I In d ivid u a l Animal Gross and Histom orphology Data ANIMAL NUMBER: 19001 SEX: F DOSE GROUP: V DEATH TYPE: S a c rific e -S c h e d u le d GROSS OBSERVATION!Si : GENERAL: No gross changes. HISTOMORPHOL06IC OBSERVATIONfS): Not applicable HIST0M0RPH0L06IC OBSERVATIONS: LUNG: UTRTAECRUHSE:A: Inmfalacmromphaatgioens,, ai nlvt ee or slit,i t fioacl ,a l fo(cmainl im(ma li)n im a l) mInaflcarmopmhaagtieosn,, pcighmroennitce,d f(omcoadl er(amtein) im a l) d is te n tio n , lumen (m ild ) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIM ITS: ADRENAL GLANDS BONE MARROW (STERNUM) JCEOJLUONNUM KDUIDONDEENYUSM LPYAMRPAHTHNYORODEID, SUBMANDIBULAR PMEAYMEMRA'RSY PGALTACNHD STHPYINMAULS CORD, LUMBAR STHPYINRAOLIDCORD, THORACIC End o f Record- 19001 BRAIN HEART LNIEVREVRE, SCIATIC RECTUM SPLEEN URINARY BLADDER CECUM LILYEMUPMH NODE, MEDIASTINAL OVARIES SPINAL CORD, CERVICAL STOMACH VAGINA 11-61 418-028:PAGE J-92 ORAL (SAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTPIORONT/DOECVOELLONPUMMEBNERTA4L1T6O-0X2I8CITY SCREENING TEST SPONSOR'S STUDY NUMBER T -7 7 0 6 .1 Appendix I I In d ivid u a l Animal Gross and Hlstom orphology Data ANIMAL NUMBER: 19006 SEX: F DOSE GROUP: DEATH TYPE: S a c rif 1ce-Schedul ed GROSS OBSERVATIONfSi: GENERAL: No gross changes. HIST0M0RPHQL06IC OBSERVATION(S): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: TLYHMYPRHOIDNO: DE, SUBMANDIBULAR: UTERUS: hulyt1pme ropblraasniac,h1laylmbpohdoyc/yctylcs/tp la s m a c ytlc (m ild ) macrophages, pigmented (m ild ) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIM ITS: ADRENAL GLANDS COLON JEJUNUM LYMPH NODE, MEDIASTINAL SPAPRINAATLHYCROORIDD, LUMBAR THYMUS BONE MARROW (STERNUM) KDUIDONDEEYNUSM MPAEMYMEARR'SY GPALATCNHD TSRPAINCAHLEACORD, THORACIC End o f Record- 19006 BRAIN HEART LIVER NREECRTVUEM, SCIATIC SPLEEN URINARY BLADDER CECUM ILEUM OLUVNAGRIES SPINAL CORD. CERVICAL STOMACH VAGINA 11-62 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 SEX: F GROSS OBSERVATION!Si : GENERAL: No gross changes. DOSE GROUP: V DEATH TYPE: Sacrifice-Scheduled eaaiat3B S!SssssssssaB 3B flt*ssasB B n!8SB 3satS3ssS3SSB aiB ss3sss:asssasssae HIST0M0RPH0L06IC PBSERVATIQN(S): 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 CECUM ILEUM LYMPH NODE, MEDIASTINAL OVARIES SPINAL CORO, CERVICAL STOMACH URINARY BLADDER End of Record- 19011 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 SEX: F S B s s s s s s s a B a B s a s s s s B s s s a a is s tB B S B a s s s s s a s B B B S S B S B : GROSS OBSERVATION(S): ADRENAL GLANDS: Bilateral- large. GASTROINTESTINAL TRACT: Abdominal distention, large and small intestines distended with gas. SPLEEN: Small. STOMACH: Fundic mucosa surface contains approximately 12 black areas ranging 1n size from pinpoint to 0.3cm 1n diameter. THYMUS: Small. DOSE GROUP: DEATH TYPE: V Sacrifice-Scheduled :8aB8BBa88S3BSBSSSSSB8BBaBB8BBBa88BBSB38SSSaC8SE HISTOMORPHOLOGIC OBSERVATION!S): 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/1nf1ammat1on, 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) ultimobranchlal 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 CECUM ILEUM LYMPH NODE. MEDIASTINAL PARATHYROID SPINAL CORD, LUMBAR VAGINA End of Record- 19020 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 SEX: F DOSE GROUP: DEATH TYPE: V Sacrifice-Scheduled GROSS OBSERVATIONfSl: GENERAL : No gross changes. HISTOMORPHOLOGIC OBSERVATION!S): 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 BRAIN HEART LUNG PARATHYROID SPINAL CORD, LUMBAR THYMUS End of Record- 19022 CECUM ILEUM LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD, THORACIC TRACHEA 11-65 418-028-.PAGE J-96 ORAL (GAVA6E) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUOY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19025 SEX: F DOSE GROUP: DEATH TYPE: V Sacrifice-Scheduled GROSS OBSERVATION(S): GENERAL: No gross changes. HISTOMORPHOLOGIC OSSERVATION[SI : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: ADRENAL GLANDS: KIDNEYS: STOMACH: UTERUS: hypertrophy/vacuolation, cortex, multifocal (mild) nephritis, chronic, focal (minimal) edema/inflaimiation, submucosa, glandular area (mild) macrophages, pigmented (moderate) THE FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS: BONE MARROW (STERNUM) DUODENUM LIVER MAMMARY GLAND PEYER'S PATCH SPINAL COW), THORACIC TRACHEA BRAIN HEART LUNG NERVE, SCIATIC RECTUM SPLEEN URINARY BLADDER CECUM ILEUM LYMPH NODE, MEDIASTINAL OVARIES SPINAL CORD, CERVICAL THYMUS VAGINA End of Record- 19025 COLON JEJUNUM LYMPH NODE. SUBMANDIBULAR PARATHYROID SPINAL CORD, LUMBAR THYROID 11-66 418-028-.PAGEJ-97 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPROOUCTION/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 8 B B X B S = S S S 8 S 8 a a B a B 3 S S S 3 = S 3 8 B B B S S S S S S S S S iB 3 S a S M S S a S S = S B S S a C B S B S U B V S S S S a S 3 = S a 8 S B S a iB B B B B H B S S B S B S B = B S S B S S GROSS OBSERVATIONfSI: HIST0M0RPH0L06IC OBSERVATIONS) ; GENERAL: No gross changes. Not applicable HISTOMORPHOLOGIC OBSERVATIONS: KIDNEYS: LYMPH NODE. SUBMANDIBULAR: STOMACH: THYROID: mineralization, multifocal (minimal) hyperplasia, 1ymphocyt1c/plasmacytic (mild) edema/1nf1ammat1on, 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 CORD, CERVICAL THYMUS VAGINA BRAIN HEART LUNG PARATHYROID SPINAL CORD, LUMBAR TRACHEA CECUM ILEUM LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD, THORACIC URINARY BLADDER TISSUE(S) NOT AVAILABLE FOR EVALUATION: NERVE, SCIATIC End of Record- 19027 11-67 418-028-.PAGE J-98 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRQDUCTIQN/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Hlstomorphology Data ANIMAL NUMBER: 19028 SEX: F DOSE GROUP: DEATH TYPE: V Sacrifice-Scheduled QROS$,opSEBVfflQHf); GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATIONS): 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 BRAIN HEART LIVER NERVE, SCIATIC RECTUM SPLEEN URINARY BLADDER End of Record- 19028 CECUM ILEUM LUNG OVARIES SPINAL CORD, CERVICAL THYMUS VAGINA 11-68 418-028;PAGE J-99 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPROOUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTXOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Appendix II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 19030 SEX: F DOSE GROUP: DEATH TYPE: V Sacrifice-Scheduled GROSS OBSERVATIONS): HEAD: Head- scab, 0.3cm x 0.3cm. HISTOMORPHOLOGIC OBSERVATIONS!: dermatitis, chronic, focal, SKIN (GROSS LESION) HISTOMORPHOLOGIC OBSERVATIONS: LIVER: SKIN (GROSS LESION): THYROID: UTERUS: Not remarkable dermatitis, chronic, focal (minimal) ultlmobranchial body/cyst macrophages, pigmented (moderate) THE FOLLOWING TISSUEfS) 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 MPAGT LUNG OVARIES SPINAL CORD. CERVICAL STOMACH VAGINA CECUM Tl Clu LYMPH NODE,MEDIASTINAL PARATHYROID SPINAL CORD, LUMBAR THYMUS TISSUE(S) NOT AVAILABLE FOR EVALUATION: LYMPH NODE, SUBMANDIBULAR End of Record- 19030 11-69 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 SEX: F DOSE GROUP: DEATH TYPE: V Sacri flee-Scheduled GROSS OBSERVATIONfSI: GENERAL: No gross changes. HIST0M0RPH0L06IC OBSERVATIONfSi : Not applicable HIST0M0RPH0L06IC OBSERVATIONS: LIVER: LYMPH NODE. SUBMANDIBULAR: UTERUS: necrosis, focal (minimal) hyperplasia, lymphocytic/plasmacytlc (mild) distention, lumen (moderate) THE FOLLOWING TISSUE! 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 BRAIN HEART LUNG OVARIES SPINAL CORD, CERVICAL STOMACH URINARY BLADDER End of Record- 19031 CECUM ILEUM LYMPH NODE, MEDIASTINAL PARATHYROID SPINAL CORD, LUMBAR THYMUS VAGINA 11-70 418-028:PAGE J-101 ORAL (GAVAGE) COMBINED REPEATED DOSE TO XICITY STUDY OF T-7706 W ITH THE REPRODUCTION/DEVELOPMENTAL TO XICITY SCREENING TEST PROTOCOL 418-028 SPONSOR'S STUDY NUMBER T-7706.1 HISTOPATHOLOGY REPORT APPENDIX III 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 HistomorphologicObservationsinthe Liver- GroupI - F1 Generation Pups Dose Group: IIII IIIII I Dam Number 19012 19012 19012 19012 19012 19012 19012 19012 19012 19012 Pud Number:________________ 1 2 3 4 5 7 8 14 15 16 LIVER: .............................................................................................. Dose Group: IIIII IIIII Dam Number: 19019 19019 19019 19019 19019 19019 19019 19019 19019 19019 Pud Number_________________1 2 3 7 8 11 12 13 14 15 LIVER: .............................................................................................. Dose Group: III III III I Dam Number: 19021 19021 19021 19021 19021 19021 19021 19021 19021 19021 Pud Number:_________________1 2 6 8 9 10 11 12 13 14 LIVER: .............................................................................................. Dose Group: IIIIIII III DamNumber: 19023 19023 19023 19023 19023 19023 19023 19023 19023 19023 Pud Number________________ 1 2 3 6 7 8 9 10 11 12 LIVER: .............................................................................................. Dose Group: III IIII II I Dam Number: 19041 19041 19041 19041 19041 19041 19041 19041 19041 19041 Pud Number:________________ 1 2 3 4 5 8 9 15 16 17 LIVER: .............................................................................................. 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: I IIIIII III Dam Number: 19042 19042 19042 19042 19042 19042 19042 19042 19042 19042 PudNumber:________________ 1 2 4 5 6 7 8 10 12 13 LIVER: ............................................................... Dose Group: IIII III III Dam Number: 19044 19044 19044 19044 19044 19044 19044 19044 19044 19044 Pud Number:_________________1 2 5 6 7 9 11 12 13 14 LIVER: .............................................................................................. Dose Group: IIIIIIIII I Dam Number 19050 19050 19050 19050 19050 19050 19050 19050 19050 19050 PudNumber:________________ 1 2 3 4 5 6 7 8 13 14 LIVER: .............................................................................................. Dose Group: IIIII IIII I Dam Number: 19053 19053 19053 19053 19053 19053 19053 19053 19053 19053 PudNumber:_________________1 3 4 5 6 10 11 12 13 14 LIVER: .............................................................................................. Dose Group: IIIIIIIIII Dam Number. 19065 19065 19065 19065 19065 19065 19065 19065 19065 19065 PudNumber_________________3 4 5 7 8 10 11 14 15 17 LIVER: .............................................................................................. HI-2 418-028PAGE 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 Table III-2 Histomorphologic Observations in the Liver - Group V - F1 Generation Pups Dose Group: VVVVVVVVV Dam Number. 19001 19001 19001 19001 19001 19001 19001 19001 19001 Pup Number:______________________ 1 2 3 4 5 6 7 9 11 LIVER : .................................................................................... Dose Group: VVVVVVVVVV Dam Number: 19006 19006 19006 19006 19006 19006 19006 19006 19006 19006 Pup Number________________ 1 2 3 4 5 8 10 11 13 18 LIVER : .............................................................................................. Dose Group: VVVVVVVVVV Dam Number 19011 19011 19011 19011 19011 19011 19011 19011 19011 19011 Pup Number:_________________2 3 4 5 6 9 10 11 12 13 LIVER : .............................................................................................. DoseGroup: VVVVVVVVVV Dam Number 19020 19020 19020 19020 19020 19020 19020 19020 19020 19020 Pup Number________________ 2 4 5 7 8 9 10 11 12 13 LIVER : .............................................................................................. Dose Group: Dam Number: Pup Number LIVER : VVVVVVVVVV 19022 19022 19022 19022 19022 19022 19022 19022 19022 19022 1 4 5 7 9 11 12 13 14 15 - III-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 Table III-2 (Continued) HistomorphologicObservationsinthe Liver- GroupV- F1 Generation Pups Dose Group: VVVVVVVVVV Dam Number: 19025 19025 19025 19025 19025 19025 19025 19025 19025 19025 Pud Number_____________________ 1 2 7 8 13 14 15 18 19 20 LIVER : .............................................................................................. Dose Group: VVVVVVVVV Dam Number: 19027 19027 19027 19027 19027 19027 19027 19027 19027 Pup Number:______________________ 1 2 3 4 5 6 7 13 14 LIVER : .................................................................................... Dose Group: DamNumber: Pup Number:____________ LIVER : VVVVVVVVVV 19028 19028 19028 19028 19028 19028 19028 19028 19028 19028 1 2 3 4 5 6 7 10 11 12 .............................................................................................. Dose Group: VVVVVVVVVV Dam Number. 19030 19030 19030 19030 19030 19030 19030 19030 19030 19030 Pup Number________________ 1 2456 8 9 11 12 13 LIVER : .............................................................................................. Dose Group: Dam Number Pud Number LIVER : VVVVVVVVVV 19031 19031 19031 19031 19031 19031 19031 19031 19031 19031 1 2 3 5 6 9 11 12 14 15 -- III-4 APPENDIX K HEM ATO LO G Y A N D C LIN IC A L C H EM ISTR Y REPORTS Study Report for Hematology INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Animal ID UBC THSN/CU HR RBC HILL/CU HH GROUP: 1-M 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 19143 19151 19157 19161 19167 13.5 15.9 15.1 12.7 16.4 17.6 17.7 14.9 15.0 14.3 -- -- -- -- -- 7.10 8.58 6.95 7.16 6.77 7.61 7.37 7.45 7.43 8.71 -- -- -- -- -- MEAN SD N 15.3 1.63 10 7.51 0.648 10 mu TOO GRAHS/DL 15.4 19.0 16.3 16.2 15.7 16.2 16.3 16.3 15.6 18.2 -- -- -- -- -- 16.5 1.16 10 HCT HCV HCH X CU MICRONS PICO GRAMS 40.6 50.0 42.6 42.1 40.6 41.4 41.6 43.3 42.7 49.7 -- -- -- -- -- 43.5 3.48 10 57.2 58.3 61.3 58.8 59.9 54.4 56.5 58.1 57.5 57.1 ----- . -- -- -- -- 57.9 1.89 10 21.7 22.1 23.5 22.6 23.2 21.3 22.1 21.9 21.0 20.9 -- -- -- -- -- 22.0 0.87 10 418-028.PAGE K-l SEX: HALE MCHC X PLT THSN/CU MM 37.9 38.0 38.3 38.5 38.7 39.1 39.2 37.6 36.5 36.6 _ _ -- 38.0 0.93 10 1219 1072 964 1354 1074 1322 1049 1264 1269 1203 . _ __ -- 1179 130.9 10 (-- ) - Data Unavailable LABCAT HE4.43 27-JUN--2002 Study Report for Hematology IN D IV ID U A L ANIMAL REPORT BY GROUP PE R IO D : TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Aniaal ID WBC THSN/CU HH RBC MILL/CU NH GROUP: 2-M 19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 19147 19153 19164 19165 19171 10.9 17.0 12.7 13.1 15.7 18.4 14.7 10.5 17.2 19.0 -- -- -- -- -- 7.55 6.93 7.IE 8.20 6.80 7.42 7.29 7.32 7.53 7.20 -- --- -- -- MEAN SD N 14.9 3.03 10 7.33 0.396 10 HGB GRAMS/DL 16.2 15.2 16.1 15.9 16.1 16.4 15.9 15.4 16.4 15.5 -- -- -- -- -- 15.9 0.42 10 HCT HCV HCH X CU MICRONS PICO GRANS 43.6 39.6 40.3 43.9 42.0 44.4 43.2 41.3 42.2 41.7 -- -- -- -- -- 42.2 1.57 10 57.7 57.1 57.4 53.5 61.8 59.8 59.3 56.4 56.0 57.9 -- -- -- -- -- 57.7 2.27 10 21.5 21.9 22.9 19.4 23.7 22.1 21.8 21.0 21.8 21.5 -- -- -- -- -- 21.8 1.13 10 418-028:PAGE K-2 SEX: m a l e NCHC X PLT THSN/CU HH 37.2 38.4 40.0 36.2 38.3 36.9 36.8 37.3 38.9 37.2 -- -- -- -- -- 37.7 1.15 10 926 970 959 1468 1170 1382 1184 1183 1069 994 __ -- -- -- 1131 183.7 10 (-- ) - Data Unavailable LABCAT HE4.43 27-JUN-2002 Study Report for Hematology INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL 418-028:PAGE K-3 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 SEX: HALE Animal ID NBC THSN/CU HH RBC NILL/CU MH GROUP: 3-H 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 19155 19159 19172 19173 19174 13.1 11.0 12.5 13.3 11.2 20.9 14.1 13.9 12.2 15.4 -- -- -- -- -- 7.38 7.28 7.59 7.20 7.72 7.23 6.69 7.96 7.60 6.54 -- -- -- -- -- KEAN SD N 13.8 2.84 10 7.32 0.441 10 HGB GRAHS/DL 16.0 16.3 16.1 15.4 15.7 15.4 15.0 16.4 16.3 14.7 -- -- __ -- -- 15.7 0.59 10 HCT HCV HCH X CU MICRONS PICO GRANS 42.4 43.2 44.4 40.1 42.6 40.5 39.1 43.8 45.0 38.8 -- ~ -- -- -- 42.0 2.22 10 57.4 59.3 58.5 55.7 55.2 56.0 58.4 55.0 59.2 59.4 -- -- -- -- -- 57.4 1.78 10 21.7 22.4 21.2 21.4 20.3 21.3 22.4 20.6 21.4 22.5 -- -- -- -- -- 21.5 0.75 10 HCHC X PLT THSN/CU HK 37.7 37.7 36.3 38.4 36.9 38.0 38.4 37.4 36.2 37.9 -- -- -- -- 37.5 0.79 10 958 960 993 1002 1253 1340 1143 1123 1046 1336 -- 1115 149.2 10 (-- ) - Data Unavailable LABCAT HE4.43 27-JUN-2QQ2 418-028:PAGE K-4 Study Report for Hematology INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL STUDY ID: ARGUS VI8-028 STUDY NO: 060-069 SEX: HALE An inai ID WBC THSN/CU MM RBC MILL/CU HH GROUP: 4-M 19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 19156 19160 19162 19163 19166 12.6 21.0 18.1 12.0 22.0 17.4 12.8 19.6 15.6 11.1 -- -- -- -- -- 6.59 6.73 6.75 6.83 7.50 7.07 6.87 7.37 6.97 6.62 -- -- -- -- -- MEAN SD N 16.2 3.97 10 6.93 0.305 10 KGB GRANS/DL 14.6 15.0 15.6 14.8 16.8 15.5 15.0 16.1 15.6 15.0 -- -- -- -- 15.4 0.67 10 HCT HCV KCH X CU MICRONS PICO GRAMS 38.2 39.0 39.3 38.4 45.5 40.3 39.9 42.4 40.6 38.1 -- -- -- -- -- 40.2 2.29 10 57.9 58.0 58.2 56.2 60.7 57.0 58.1 57.5 58.2 57.6 _ _ -- -- -- 57.9 1.15 10 22.2 22.3 23.1 21-7 22.4 21.9 21.8 21.8 22.4 22.7 -- -- -- -- -- 22.2 0.45 10 MCHC X PLT THSN/CU MN 38.2 38.5 39.7 38.5 36.9 38.5 37.6 38.0 38.4 39.4 -- --- -- -- -- 38.4 0.80 10 1072 1144 1029 1274 1124 1125 998 962 1155 1161 __ -- ~ 1104 91.4 10 (-- ) - Data Unavailable LABCAT HE4.43 27-JUN-20Q2 Study Report for Hematology INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Aniaal ID UBC THSN/CU HH RBC MIU./CU MM GROUP: 5- 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 19154 19158 19168 19169 19170 MEAN SO N 15.7 14.3 10.8 12.5 11.0 14.2 15.2 20.7 18.3 13.9 -- -- -- -- -- 14.7 3.07 10 7.20 6.72 6.68 8.07 6.61 7.09 7.05 7.13 6.66 6.68 -- -- -- -- -- 6.99 0.442 10 HGB GRANS/DL 16.1 15.7 15.0 17.3 14.7 15.5 16.2 15.7 14.8 14.8 -- -- -- -- 15.6 0.81 10 HCT HCV MCH X CU MICRONS PICO GRAMS 41.7 39.8 39.0 44.4 38.1 41.1 41.9 41.4 39.8 39.5 -- -- -- -- -- 40.7 1.81 10 57.9 59.2 58.4 55.0 57.6 58.0 59.5 58.1 59.8 59.2 -- -- -- -- ---- 58.3 1.37 10 22.4 23.4 22.5 21.4 22.2 21.9 23.0 22.Q 22.2 22.2 -- -- -- -- -- 22.3 0.56 10 418-028-.PAGEK-5 SEX: HALE NCHC X PLT THSN/CU MM 38.6 39.4 38.5 39.0 38.6 37.7 38.7 37.9 37.2 37.5 --- -- -- -- 38.3 0.70 10 1013 1181 1249 1142 1040 1001 1059 1523 1234 1041 -- -- -- -- . ---- 1148 159.9 10 (-- ) - Data Unavailable LABCAT HE4.43 27-JUN-2Q02 Study Report for Hematology INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Aniaal ID UBC TH5N/CU MM RBC MILL/CU MM GROUP: 1-F 19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075 15.9 6.6 7.4 7.3 8.0 6.8 10.6 8.2 6.6 12.5 -- -- -- -- 5.60 6.95 7.10 6.62 6.86 6.45 6.09 6.64 6.08 6.67 -- -- -- -- KGB GRAHS/DL 14.0 16.4 16.7 16.3 16.2 15.1 14.3 16.0 14.7 15.7 -- -- -- -- HCT MCV MCH X CU MICRONS PICO 6RAMS 35.2 42.5 44.7 42.4 42.4 40.2 37.6 42.2 37.5 40.2 -- __ -- -- 62.9 61.1 63.0 64.1 61.8 62.3 61.7 63.6 61.6 60.2 -- -- -- -- 25.0 23.6 23.5 24.6 23.6 23.4 23.5 24.1 24.2 23.5 -- -- -- -- MEAN SD N 9.0 3.09 10 6.51 0.461 10 15.5 0.95 10 40.5 2.93 10 62.2 1.19 10 23.9 0.55 10 418-028:PAGE K-6 SEX: FEMALE MCHC X PLT THSN/CU MM 39.8 38.6 37.4 38.4 38.2 37.6 38.0 37.9 39.2 39.1 -- -- -- -- 38.4 0.76 10 1421 1344 1199 1352 1529 1225 1343 1629 1524 1623 ____ ___ _. -- 1419 153.0 10 (-- > - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-7 Study Report for Hematology INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Aninal ID WBC THSN/CU MM RBC MILL/CU MM HGB GRAMS/DL HCT MCV MCH X CU MICRONS PICO GRAMS SEX: FEMALE MCHC X PLT THSN/CU MM GROUP: 2-F 19004 19009 19016 19018 19026 19036 19Q37 19043 19047 19048 19052 19055 19061 19067 19071 MEAN SO N 7.8 14.6 17.0 13.3 9.1 18.0 26.3 13.5 11.1 7.1 -- -- -- -- -- 13.8 5.73 10 7.07 5.90 6.32 5.61 6.36 6.30 6.23 5.83 5.93 6.60 -- -- -- -- -- 6.22 0.423 10 16.6 14.8 14.9 14.1 15.5 14.5 14.8 14.7 14.5 16.0 -- -- -- -- -- 15.0 0.77 10 43.8 38.3 38.5 35.3 41.6 38.9 37.8 38.3 37.5 43.4 -- -- -- -- -- 39.3 2.72 10 62.0 64.9 60.9 63.0 65.4 61.7 60.6 65.7 63.3 65.8 __ __ -- -- -- 63.3 2.01 10 23.5 25.1 23.6 25.1 24.4 23.0 23.8 25.2 24.5 24.2 -- -- -- -- -- 24.2 0.76 10 37.9 38.6 38.7 39.9 37.3 37.3 39.2 38.4 38.7 36.9 -- -- -- -- -- 38.3 0.94 10 1540 1157 1529 1057 1443 1166 1257 942 1041 1264 -- -- -- -- -- 1240 208.1 10 <-- ) - Data Unavailable LABCAT HE4.43 27-JUN-2002 Study Report for Hematology IN D IV ID U A L ANIMAL REPORT BY GROUP PE R IO D : TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Aniaal ID UBC THSN/CU MM RBC MILL/CU MM GROUP: 3-F 19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064 KEAN SD N 11.1 7.9 7.0 16.6 -- 7.4 12.9 10.5 12.5 12.1 -- 12.7 -- -- -- 11.1 2.98 10 6.43 6.31 6.71 5.53 -- 6.41 6.03 6.93 5.69 6.54 -- 7.38 --- -- 6.40 0.554 10 HGB GRAMS/DL T5.7 15.4 15.7 13.8 -- 15.1 14.4 15.6 14.0 16.1 -- 16.6 -- __ -- 15.2 0.91 10 HCT MCV KCH % CU MICRONS PICO GRAMS 40.0 39.9 40.5 33.1 -- 39.8 38.0 42.1 35.6 41.9 -- 44.2 -- -- -- 39.5 3.24 10 62.2 63.3 60.3 59.9 -- 62.1 63.0 60.8 62.6 64.1 -- 59.9 -- -- -- 61.8 1.50 10 24:4 24.4 23.4 25.0 -- 23.6 23.9 22.5 24.6 24.6 -- 22.5 -- -- -- 23.9 0.88 10 418-028:PAGE K-8 SEX: FEMALE MCHC X PLT THSN/CU MM 39.3 38.6 38.8 41.7 -- 37.9 37.9 37.1 39.3 38.4 -- 37.6 -- __ -- 38.7 1.29 10 1165 1450 1319 1167 -- 1671 866 1424 1062 1231 -- 1380 -- -- -- 1274 226.3 10 C-- ) - Data Unavailable LABCAT HE4.43 27-JUN-2002 Study Report for Hematology INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL STUDY ID; ARGUS 418-028 STUDY NO: 060-069 A n i m i ID WBC THSN/CU MM RBC MILL/CU MM HGB GRANS/DL HCT HCV MCH X CU MICRONS PICO GRAMS GROUP: 4-F 19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073 9.5 9.6 12.8 10.0 9.7 -- -- 14.9 15.7 6.2 12.9 7.1 -- -- 6.51 6.81 6.48 6.48 5.77 -- -- 7.33 5.94 6.86 5.68 6.01 -- -- 15.8 16.2 14.8 15.8 13.7 -- -- 15.7 14.2 15.7 14.0 15.7 -- -- 42.0 42.4 38.9 41.3 36-7 ---- 44.1 37.2 43.3 35.2 40.3 -- -- 64.5 62.3 60.1 63.8 63.6 -- -- 60.2 62.6 63.1 61.9 67.0 -- -- 24.3 23.8 22.8 24.4 23.7 -- -- 21.4 23.9 22.9 24.6 26.1 __ -- MEAN SD N 10.8 3.15 10 6.39 0.532 10 15.2 0.90 10 40.1 3.02 10 62.9 2.04 10 23.8 1.25 10 418-028:PAGE K-9 SEX: FERALE MCHC X PLT THSN/CU MM 37.6 38.2 38.0 38.3 37.3 -- -- 35.6 38.2 36.3 39.8 39.0 -- -- 37.8 1.22 10 1479 1527 1066 1333 1148 1497 1094 1399 999 1506 -- -- 1305 207.2 10 C-- ) - Data Unavailable LABCAT HE4.43 27-JUN-2002 Study Report for Hematology 418-028:PAGE K-10 IN D IV ID U A L ANIMAL REPORT BY GROUP PERIO D: TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-069 SEX: FEMALE Aninal ID UBC THSN/CU KM RBC MILL/CU HK GROUP: 5-F 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070 15.1 7.6 6.4 4.2 5.4 7.3 12.3 10.2 8.1 12.3 -- -- -- -- -- 5.90 6.33 6.46 7.49 6.79 6.47 6.69 5.76 6.62 5.72 -- -- -- -- --- KEAN SD N 8.9 3.48 10 6.42 0.538 10 HGB GRAHS/DL 14.3 15.4 15.7 16.1 16.0 15.1 15.9 13.8 15.6 14.7 -- -- -- -- 15.3 0.77 10 HCT KCV HCH % CU KICRONS PICO GRAMS 37.3 39.0 40.5 46.8 43.0 39.7 42.2 35.8 41.4 38.4 -- -- _ -- -- 40.4 3.15 10 63.2 61.6 62.7 62.5 63.4 61.3 63.1 62.2 62.6 67.1 -- -- -- -- -- 63.0 1.60 10 24.2 24.3 24.3 21.5 23.6 23.3 23.8 24.0 23.6 25.7 -- -- -- -- -- 23.8 1.05 10 MCHC X PLT THSN/CU MM 38.3 39.5 38.8 34.4 37.2 38.0 37.7 38.5 37.7 38.3 -- -- -- -- -- 37.8 1.37 10 1131 1312 1254 1549 1448 1391 1667 1286 1417 1099 ..... -- -- 1355 176.8 10 <-- > - Data Unavailable LABCAT HE4.43 27-JUM-2002 418-028:PAGE K -ll Study Report for Hematology INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-069 SEX: BALE Animal ID MPV CU MICRON GROUP: 1-M 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 19143 19151 19157 19161 19167 8.0 8.0 7.2 7.5 8.2 8.9 8.2 8.0 8.4 8.8 -- -- -- -- -- MEAN SD N 8.1 0.52 10 PT seconds 13.2 13.3 13.7 13.6 13.1 13.6 13.2 13.7 13.2 13.2 -- -- -- -- -- 13.4 0.24 10 APTT seconds 13.2 21.5 22.4 23.0 19.8 20.8 19.8 21.8 23.9 23.6 -- -- -- -- *-- 21.0 3.09 10 NRBC COUNT Lyapbocyte THSN/CU m Segmented THSN/CU MM Bands THSN/CU MM Monocytes THSN/CU MM 0 9.7 2.0 0 11.4 0 11.6 0 9.1 0 14.1 0 14.3 0 13.1 0 12.7 0 11.0 2.7 3.0 2.2 1.5 1.4 2.7 1.5 3.5 0 12.2 ---- 1.6 -- ---- -- -- -- -- ------ ------ 0.0 1.1 0.0 1.6 0.0 0.3 0.0 1.3 0.0 0.2 0.0 1.1 0.0 1.6 0.0 0.4 0.0 0.5 0.0 0.3 -- -- -- -- -- .-- 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 Study Report for Hematology 418-028-.PAGEK-12 IN D IV ID U A L ANIM AL REPORT BY GROOP PER IO D : TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-069 SEX: MALE Aniaal ID HPV CU MICRON GROUP: 2-M 19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 19147 19153 19164 19165 19171 7.5 7.6 8.4 8.4 7.2 7.6 7.2 8.8 8.1 7.8 -- -- -- MEAN SD N 7.9 0.54 10 PT seconds 14.0 14.0 14.6 14.2 14.4 14.4 14.3 14.2 13.7 14.5 -- -- -- -- -- 14.2 0.27 10 APTT seconds 22.1 22.0 24.6 26.2 20.0 17.5 20.8 19.3 16.6 31.4 -- -- -- -- -- 22.1 4.41 10 NRBC COUNT Lyaphocyte THSN/CU MM Segmented THSN/CU MM Bands THSN/CU MM Monocytes THSN/CU MM 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 Q.O 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 -- ------ -- -- ------ -- -- -- -- __ -- --_-- -- -- -- -- -- .-- 0 11.0 2.9 0.0 0.7 0.0 2.68 1.18 0.00 0.50 TO 10 10 10 10 (-- ) - Data Unavaitable LABCAT HE4.43 27-JUN-20Q2 418-028:PAGE K-13 Study Report for Hematology INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-069 SEX: HALE Animal ID KPV CU HICRON GROUP: 3-H 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 19155 19159 19172 19173 19174 8.0 7.4 8.0 9.9 8.3 8.3 8.1 8.9 7.8 7.6 -- -- -- -- HEAN SD N 8.2 0.72 10 PT seconds 13.9 13.7 13.6 13.6 13.5 13.2 13.7 13.7 13.4 14.0 -- __ -- -- -- 13.6 0.23 10 APTT seconds 18.3 24.6 22.0 22.1 19.8 21.2 18.1 22.3 20.6 16.7 -- -- -- -- -- 20.6 2.38 10 NRBC COUNT Lymphocyte THSN/CU HH Segmented THSN/CU HH Bands THSN/CU HR Nonocytes THSN/CU HH 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 Q.O 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 -------- -------- -------- -------- ---------- 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 LABCAT HE4.43 27-JUN-2002 STUDY XD: ARGUS 418-028 STUDY NO: 060-069 418-028:PAGE K-14 Study Report for Hematology INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL Animal ID MPV CU MICRON GROUP: 4-M 19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 19156 19160 19162 19163 19166 7.1 8.2 7.9 8.3 7.4 8.4 7.5 9.3 8.7 9.3 -- -- -- -- -- MEAN SD N 8.2 0.76 10 PT seconds 13.5 14.6 14.0 13.9 14.0 13.6 13.5 13.9 13.8 13.1 -- --- -- -- 13.8 0.40 10 APTT seconds 19.8 26.3 23.0 21.4 19.1 21.5 20.8 21.5 19.7 18.6 21.2 2.24 10 NR8C COUNT Lymphocyte THSN/CU MM Segmented THSN/CU MH Bands THSN/CU MM Monocytes THSM/CU MM 0 7.7 4.0 0.0 0.6 0 16.4 2.3 Q.O 1.7 0 12.1 3.1 0.0 2.2 0 9.4 1.4 0.0 0.5 0 17.4 2.9 0.0 0.7 0 12.7 3.7 0.0 0.5 0 8.6 2.8 0.1 1.0 0 15.9 2.7 0.0 0.6 0 12.3 3.1 0.0 0.0 0 8.3 2.4 0.0 0.2 ---- -- -- -- -- mmmm ---- 0 12.1 2.8 0.0 0.8 0.0 3.57 0.73 0.03 0.67 10 10 10 10 10 C-- ) - Data Unavailable LABCAT HE4.43 27-JUN-2002 Study Report for Hematology 418-Q28:PAGE K-15 IN D IV ID U A L ANIMAL REPORT BY GROUP P E R IO D : TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Animal ID MPV CU MICRON GROUP: 5-H 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 19154 19158 19168 19169 19170 7 .7 7.5 7.3 9 .0 8 .8 8 .6 8 .0 7.5 7 .8 8.2 -- -- -- -- -- MEAN SD N 8 .0 0 .5 9 10 PT seconds 13.9 15.1 13.8 13.7 14.1 13.5 13.9 14.3 13.5 13.7 -- -- -- -- -- 14.0 0.47 1Q APTT seconds 23.6 23.3 20.8 21.8 20.7 2 1 .6 19.6 21.9 19.5 2 0 .0 __ -- __ _ -- 21.3 1.43 10 NRBC Lymphocyte Segmented Bands Monocytes COUNT THSN/CU MH THSN/CU HN THSN/CU MM THSN/CU MM 0 13.0 0 11.3 0 10.2 0 10.1 0 8.0 0 12.4 0 12.2 0 17.2 0 16.1 0 13.1 ---- ---- ---- ---- -- -- 0 12.4 0.0 2.75 10 10 1.4 1.7 0 .3 1.1 2 .4 1 .4 2.1 2.5 2.2 0 .4 -- __ . -- 1.6 0.78 10 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 -- -- 0 .0 0.00 10 0 .6 0 .9 0 .2 0 .9 0 .2 0 .3 0 .2 0 .8 0 .0 0 .4 __ _ -- 0.5 0 .3 3 10 (-- ) - Data Unavailable LABCAT HE4.43 27-JUN-2002 Study Report for Hematology 418-028:PAGE K-16 INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-069 SEX: FEMALE Animal ID KPV CU MICRON GROUP: 1-F 19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075 7.7 8 .9 7.8 7 .9 9.1 8.4 8 .4 8 .2 8.1 8 .9 -- -- -- -- KEAN SO N 8 .3 0.49 10 PT seconds 13.9 13.0 13.8 12.9 13.4 12.8 12.8 13.1 13.3 12.8 _ -- -- -- 13.2 0.41 10 APTT seconds 26.6 20.4 24.2 2 1 .9 19.3 2 1 .8 18.5 20.5 22.5 2 1 .6 -- __ -- -- 2 1 .7 2 .3 6 10 NRBC Lymphocyte Segmented Bands Monocytes COUNT THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM 0 12.6 0 4.4 0 5.7 0 6.1 0 5.0 0 5.3 0 7.3 0 6.1 0 4.7 0 8.4 -- -- ---- ---- ---- 0 6.6 0.0 2.44 10 10 2 .7 2 .0 1.4 0 .9 2 .9 1 .5 3.1 1 .8 1 .8 3 .8 -- -- -- -- 2 .2 0 .9 0 10 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 -- -- -- -- 0 .0 0.00 10 0.5 0.2 0 .0 0.1 0.1 0 .0 0.1 0 .2 0 .0 Q.1 ... __ -- 0.1 0.15 10 (-- ) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-17 Study Report for Hematology IN D IV ID U A L ANIMAL REPORT BY GROUP PE R IO D : TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Animal ID MPV CU MICRON PT seconda APTT seconds SEX: FEMALE NRBC ly a p b o c y te Segmented Bands Monocytes COUNT THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM GROUP: 2-F 19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071 MEAN SD N 9 .6 7.2 8 .8 8.2 8.4 7 .8 8.1 8 .0 6.9 7 .0 -- -- -- -- -- 8.0 0.84 10 13.3 13.8 13.3 1 3 .7 12.8 13.5 13.3 13.2 13.5 13.1 -- --- --- 13.4 0 .2 9 10 27.5 21.3 29.2 22.6 20.3 2 4 .3 20.0 26.8 25.3 22.1 -- -- -- -- -- 2 3 .9 3 .1 9 10 0 5.8 0 12.7 0 13.6 0 10.9 0 7.7 0 15.1 0 11.0 0 9.6 0 6.2 0 5.4 ---- -- ---- ---- -- 0 9.8 0.0 3.44 10 10 2 .0 1.6 3.1 2.3 1.4 2 .2 13.7 3.5 4.6 1.6 -- -- -- -- -- 3 .6 3 .6 9 10 0.0 0 .0 0 .0 0 .0 O.Q 0 .0 0 .0 0 .0 0 .0 0 .0 -- -- -- -- -- 0 .0 0 .0 0 10 0.1 0.1 Q.O 0 .0 0 .0 0 .4 1 .6 0 .3 0 .2 0 .0 -- -- -- -- -- 0.3 0 .4 9 10 (-- ) - Data Unavailable LABCAT HE4.43 27-JUN-2002 Study Report for Hematology 418-028:PAGE K-18 INDIVIDUAI ANIMAL REPORT BY GROUP PERIOD: TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Animal ID MPV CU MICRON GROUP: 3-F 19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064 7.2 7 .3 9 .3 8.5 -- 9 .0 7 .8 8 .8 7 .4 8.1 -9 .3 -- -- -- MEAN SD N 8 .3 0.82 10 PT seconds 12.9 12.9 12.8 13.7 -- 13.6 13.3 12.9 13.3 12.7 -- 13.6 -- -- -- 13.2 0 .3 7 10 APTT seconds 22.7 21.7 22.6 22.7 -- 27.6 21.9 22.1 24.4 21.2 -- 27.6 -- -- 23.5 2.35 10 NR8C Lymphocyte Segmented Bands Monocytes COUNT THSN/CU MM THSN/CU MM THSN/CU MH THSN/CU MM 0 6.5 4.0 0 .0 0.3 0 5.7 2.0 0.0 0.2 0 5.0 1.9 0.0 0.0 0 12.3 3 .8 0.0 0 .3 -- -- -- -- __ 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 __ -- -- ------ 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 STUDY ID : ARGUS 418-028 STUDY NO: 060-069 Study Report for Hematology 418-028:PAGE K -19 INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL SEX: PENALE A n im i ID HPV CU MICRON PT seconds APTT seconds NRBC Lymphocyte Segmented Bands Monocytes COUNT THSN/CU NH THSN/CU MM THSN/CU MM THSN/CU MM GROUP: 4 - F 19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073 MEAN SD N -- 7 .8 9 .0 7 .8 8.1 7 .6 -- -- 7.5 7.5 9.1 8.5 7 .4 -- -- 8 .0 0.63 10 -- 13.1 13.4 13.4 12.9 13.0 -- __ 14.1 13.5 13.9 14.0 13.5 -- -- 13.5 0.42 10 -- 21.4 24.5 23.7 27.9 21.9 -- -- 27.1 25.7 25.2 26.2 28.9 -- -- 25.3 2.45 10 ------ -- 0 7 .7 1 .6 0.0 0.1 0 7.1 2 .3 0.0 0.1 0 9.6 2 .8 0.0 0.3 0 7 .7 2 .2 0 .0 0.1 0 5.4 3.8 0.3 0.2 -- -- -- -- __ _ ---- -- 0 12.2 1.9 0 .0 0 .4 0 11.5 3 .9 0 .0 0 .2 0 4 .8 1.4 0.0 0.1 0 9.8 2.6 0.0 0.3 0 6 .0 1 .0 0.0 0.1 ------ -- -- -- ------ 0 8.2 2.4 0.0 0.2 0 .0 2.52 0.96 0 .0 9 0.11 10 10 10 10 10 {-- ) - Data Unavailable LABCAT HE4.43 27-JUN-2002 Study Report for Hematology 418-028:PAGE K-20 INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL STUDY ID: AHSUS 418-028 STUDY NO: 060-069 Animal ID HPV CU MICRON GROUP: 5-F 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19Q7Q 6 .9 9.2 7 .4 7 .0 7 .6 8 .3 7 .3 8.1 7 .9 6 .8 -- -- -- -- -- MEAN SD N 7 .7 0.74 10 PT seconds 13.8 12.8 12.9 16.8 13.7 13.5 13.2 13.6 13.7 13.5 -- -- __ -- -- 13.8 1.12 10 APTT seconds 30.4 22.1 22.3 27.6 21.6 25.3 27.5 22.2 31.5 21.6 -- -- -- -- -- 25.2 3.81 10 NRBC Lymphocyte Segmented Bands Monocytes COUNT THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM 0 10.1 4 .2 Q.Q 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 Q.Q 0 .3 0 5.2 2.8 0.0 0.1 0 8.2 3.7 0.0 0.0 -- -- -- --_ ---- -- -- ---- -- _ rr ---- -- __ __ -- -------- 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 U navailable 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 Animal ID E o sin o p h il B a so p h ils Abnormal L O th er THSN/CU MB THSN/CU rot THSN/CU rot THSN/CU rot GROUP: 1-M 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 19143 19151 19157 19161 19167 MEAN SD N 0 .7 0.2 0.2 0.1 0.2 0.5 0 .2 0.0 0.2 0 .3 -- -- -- -- -- 0 .3 0.20 10 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 -- -- -- -- -- 0.0 0.00 10 0.0 0.0 Q.O 0.0 0.5 0.4 0.2 0.3 0.0 0.0 -- -- -- -- -- 0.1 0.20 10 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0 .0 0.0 -- -- --- -- 0.0 0.00 10 SEX: BALE <-- ) - Data Unavailable LABCAT HE4.43 27-JUN-2Q02 418-028:PAGE K-22 Study Report for Hematology INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-069 SEX: HALE Animal ID E o sin o p h il B a so p h ils Abnormal L O th er THSN/CU NH THSN/CU HH THSN/CU NH THSN/CU HH GROUP: 2-H 19102 0 .3 0.0 0 .3 0.0 19106 19108 0 .5 0.0 0 .2 0.0 0.0 0 .3 0.0 0.0 19110 19113 19120 19129 19136 19138 19139 0 .3 0.0 0 .3 0.0 0 .2 0.0 0.0 0.0 0 .4 0.0 0.0 0.0 0 .6 0.0 0.0 0.0 0 .2 0.0 0 .0 0.0 0 .5 0.0 0.0 0.0 0.0 0.0 0.0 0.0 19147 -- -- ---- 19153 19164 19165 -- -- ---- __ -- ---- _-- ---- 19171 ' --- -- -- -- HEAN SD N 0 .3 0.21 10 0.0 0 .0 0 10 0.1 0.14 10 0.0 0.00 10 (-- ) - Data Unavailable LABCAT HE4.43 27-JUN-20Q2 Study Report for Hematology 418-028:PAGE K-23 INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-069 SEX; HALE Arris a l ID E o sin o p h il B a so p h ils Abnormal L O th er THSN/CU UH THSN/CU HH THSN/CU HM THSN/CU HH GROUP: 3-H 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 19155 19159 19172 19173 19174 MEAN SD N 0.3 0.0 0.5 0.3 0.1 0.4 0.0 0.1 0.2 0 .6 -- -- -- -- -- 0.3 0.21 10 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 -- -- -- -- -- 0.0 0.00 10 0.1 0.1 0.0 0.1 0.0 0.2 0.1 0.0 0.0 0.0 -- -- -- -- -- 0.1 0.07 10 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 -- -- -- -- __ 0.0 0.00 10 (-- ) - Data Unavailable LABCAT HE4.43 27-JUN-21002 418-028:PAGE K-24 Study Report for Hematology INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-069 SB(; HALE Animal ID E o sin o p h il THSN/CU nn B asophiIs Abnormal L O th er THSN/CU HN THSN/CU nn thsn/ cu nn GROUP: 4-H 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 Q.5 0 .0 19133 19141 0.9 0 .0 0.2 0 .0 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 0.26 10 0 .0 0.00 10 0 .2 0 .2 2 10 0 .0 0.00 10 (-- ) _ Data unavailable LABCAT HE4.43 27-JUN-20Q2 Study Report for Hematology 418-028:PAGE K-25 INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL STUDY ID: ARGUS 18-028 STUDY NO: 060-069 SEX: HALE Animal ID E o s in o p h il B a so p h ils Abnormal L O th er THSN/CU HM THSN/CU HH THSN/CU HH THSN/CU NH GROUP: 5-H 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 19154 19158 19168 19169 19170 MEAN SD N 0 .2 0 .4 0.1 0 .4 0.1 0.1 0.3 0 .2 0 .0 0 .0 -- -- -- -- -- 0 .2 0.15 10 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 -- -- -- -- -- 0 .0 0.00 10 0.5 0.0 0 .0 0 .0 0.2 0 .0 0.5 0 .0 0.0 O.Q -- -- -- -- -- 0.1 0.21 10 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 -- -- -- -- -- 0 .0 0 .0 0 10 (-- ) - Data Unavailable LABCAT HEA.43 27-JUN~20Q2 Study Report for Hematology 418-028:PAGE K-26 INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Animal ID E o sin o p h il B a so p h ils Abnormal L O th er THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM GROUP: 1-F 19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075 MEAN SD N 0 .2 0 .0 0.3 0.1 0.0 0.0 0.1 0.1 0.0 0.1 -- -- -- 0.1 0.10 10 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 O.Q 0.0 -- -- -- -- 0.0 0.00 10 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0 .0 0.1 0.1 .-- -- _ -- 0.0 0.05 10 0.0 0 .0 0.0 0.0 0 .0 0 .0 0.0 0.0 Q.O 0.0 -- -- -- -- 0.0 0 .0 0 10 SEX: FEMALE (-- ) - Data Unavaitable LABCAT HE4.43 27-JUN-200Z Study Report for Hematology 418-028:PAGE K-27 IN D IV ID U A L ANIMAL REPORT BY GROUP PERIOD.* TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-0 6 9 SEX: FEMALE Ani n a i ID E o sin o p h il B a so p h iIs Abnormal L O th er THSN/CU Mff THSN/CU MK THSN/CU NH THSN/CU HH GROUP: 2-F 19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0 .3 0 .0 0 .0 Q.O 0.1 0 .0 0 .0 0 .0 0.0 0.0 0.0 0.0 0 .4 0.0 0.0 0 .0 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.1 0 .0 0.Q 0 .0 0.1 0.0 0.0 0 .0 ------ -- 19055 ---- -- -- 19061 ---- -- -- 19067 ---- -- -- 19071 ~ -- -- -- MEAN SD N 0.1 0.13 10 0 .0 0.00 10 0 .0 0.00 10 0 .0 0 .0 0 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 4 1 8 -0 2 8 STUDY NO: 060-069 1 ! ID E o s in o p h il THSN/CU KM B a s o p h i Is THSN/CU HR A bnorm al L THSN/CU MM O th er THSN/CU HH 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 0.13 10 0 .0 0.00 10 0.1 0.07 10 0 .0 0.00 10 SEX: FEMALE (-- ) - Data Unavailable LABCAT HE4.43 27-JUN-2002 Study Report for Hematology 418-028:PAGE K-29 INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-069 SEX: FERALE Animal ID Eosinophil THSN/Cli MR BasophiIs THSN/CU MR Abnormal L THSN/CU HR Other THSN/CU HR 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 Q.O 0.0 0.0 19040 0.0 0.0 0.0 0.0 19045 0.0 0.0 0.0 Q.O 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 Q.O 0.0 19066 0.0 0.0 0.1 0.0 19069 -- -- -- . -- 19073 -- -- ---- MEAN SD N 0.1 0.11 10 Q.O 0.00 10 0.1 0.10 10 Q.O 0.00 10 C-- ) - Data Unavailable LABCAT HE4.43 27-JUH-20Q2 418-028:PAGE K-30 Study Report for Hematology INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-069 SEX: FEMALE Aninai ID Eosinophil THSK/CU MM Basophils THSN/CU MM Abnormal L Other THSN/CU MM THSN/CU MM GROUP: 5-F 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 0.3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.0 Q.O 0.0 0.0 Q.O 0.0 0.0 0.0 0.0 0.0 0.1 Q.O 0.4 0.0 0.0 0.0 19032 -- -- -- -- 19033 -- -- -- -- 19049 -- -- -- -- 19059 -- -- -- -- 19070 -- -- __ -- MEAN SD N 0.1 0.15 10 0.0 0.00 IQ 0.0 0.05 10 0.0 0.00 10 (-- ) - Data Unavailable LABCAT HE4.43 27-JUN-2002 Study Report for Hematology SUMMARY REPORT PERIOD; TERMINAL 418-028:PAGE K-31 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE SEX: ALE TESTCs): UNITS: WBC RBC THSN/CU MM MILL/CU MM HGB GRAMS/DL HCT MCV NCH X CU MICRONS PICO GRAMS MCHC PLT MPV X THSN/CU MM CU MICRON Group: 1-M KEAN SD N 15.3 1.63 10 7.51 0.648 10 16.5 1.16 10 43.5 3.48 10 57.9 1.89 10 22.0 0.87 10 38.0 0.93 10 1179 130.9 10 8.1 0.52 10 Group: 2-H MEAN SD N 14.9 3.03 10 7.33 0.396 10 15.9 0.42 10 42.2 1.57 10 57.7 2.27 10 21.8 1.13 TO 37.7 1.15 10 1131 183.7 10 7.9 0.54 10 Group: 3-M MEAN SD N 13.8 2.84 10 7.32 0.441 10 15.7 0.59 10 42.0 2.22 10 57.4 1.78 10 21.5 0.75 10 37.5 0.79 10 1115 149.2 10 8.2 0.72 TO Group: 4-M MEAN SD N 16.2 3.97 10 6.93* 0.305 10 15.4** 0.67 10 40.2* 2.29 10 57.9 1.15 10 22.2 0.45 10 38.4 Q.8Q 10 1104 91.4 10 8.2 0.76 IQ Group: 5-M MEAN SD N 14.7 3.07 10 6.99* 0.442 10 15.6* 0.81 10 40.7* 1.81 10 58.3 1.37 10 22.3 0.56 10 38.3 0.70 10 1148 159.9 10 8.0 0.59 1Q -Significant Difference fro Control P < .05 LABCAT HE4.43 **-Significant Difference fro Control P < .01 27-JUN-2002 Study Report for Hematology SUMMARY REPORT PERIOD: TERMINAL 418-028:PAGE K-32 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE TEST(a): UNITS: PT seconds APTT seconds Group: 1-M MEAN SD N 13.4 0.24 10 21.0 3.09 10 Group: 2-H MEAN SD N 14.2 0.27 10 22.1 4.41 10 Group: 3-M MEAN SD N 13.6 0.23 10 20.6 2.38 10 Group: 4-M MEAN SD N 13.8* 0.40 10 21.2 2.24 10 Group: 5-M MEAN SD N 14.0 0.47 10 21.3 1.43 10 NRBC Lymphocyte Segmented Bands Monocytes Eosinophil Basophils COUNT THSN/CU MM TMSN/CU MH THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM 0 11.9 2.2 0.0 0.8 0.3 0.0 0.0 1.72 0.73 0.00 0.56 0.20 0.00 10 10 10 10 10 10 10 0 11.0 2.9 0.0 0.7 0.3 0.0 Q.O 2.68 1.18 0.00 0.50 0.21 0.00 10 10 10 10 10 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 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 0 12.4 1.6 0.0 0.5 0.2 0.0 0.0 2.75 0.78 0.00 Q.33 0.15 0.00 10 10 10 10 10 10 10 *-Significant Difference from Control P < .05 LABCAT HE4.43 -Significant Difference from Control P < .01 27-JUN-20O2 STUDY 10: ARGUS 418-028 STUDY NO: 060-069 Study Report for Hematology SUMMARY REPORT PERIOD; TERMINAL 418-028:PAGE K-33 ANALYSIS OF VARIANCE FOLLOWED BY 0UNNETT'S PROCEDURE TEST(s): Abnormal L Other UNITS: THSN/CU HH THSN/CU HH Group: 1-M MEAN SD N 0.1 0.20 10 0.0 0.00 10 Group: 2-H MEAN SD N 0.1 0.14 10 0.0 0.00 10 Group: 3-H MEAN SD N 0.1 0.07 10 0.0 0.00 10 Group: 4-H MEAN SD N 0.2 0.22 10 0.0 0.00 10 Group: 5-H MEAN SD N 0.1 0.21 10 0.0 0.00 10 SEX: HALE LABCAT HE4.43 27-JUN-2002 Study Report for Hematology SUMMARY REPORT PERIOD: TERMINAL 418-028:PAGE K-34 STUDY ID: ARGUS 418-028 STUOY NO: 060-069 ANALYSIS OF VARIANCE FOLLOVED BY DUNNETT'S PROCEDURE SEX: MALE White Blood Count Std. Group N Total Mean Dev. DUNNETT'S 't' DUNNETT'S RANGES LO -95%- HI LO -99X- HI Degree Source Fda Su m of Squares Mean Square 1-M 10 153.1 15.3 1.63 2-N 10 149.2 14.9 3.03 0.29 11.9 18.7 3-M 10 137.6 13.8 2.84 1.15 11.9 18.7 4-M 10 162.2 16.2 3.97 0.68 11.9 18.7 5-M 10 146.6 14.7 3.07 0.48 11.9 18.7 F Ratio = C oe f f . Var. X = 0.90 20.065 'F* table values Dunnett's 'T' table values F.01 = P.01 = Red Blood Count 11.1 11.1 11.1 11.1 19.5 19.5 19.5 19.5 TREATMENTS ERROR TOTAL 4 45 49 3.78 3.12 F.05 = P.05 2.58 2.51 32.41 406.23 438.64 8.10 9.03 1-M 10 75.13 7.51 0.648 2-M 10 73.26 7.33 0.396 0.91 7.00 8.(0 3-M 10 73.19 7.32 0.441 0.94 7.00 8.03 4-M 10 69.30 6.93 0.305 2.83 7.00 8.03* 5-M 10 69.89 6.99 0.442 2.54 7.00 8.03* F Ratio = Coeff. Var. X 2.88 6.381 'F* table values Dunnett's 'T* table values F.01 = P.01 = Hemoglobin 6.87 6.87 6.87 6.87 8.16 8.16 8.16 8.16 TREATMENTS ERROR TOTAL 4 45 49 3.78 3.12 F.05 -- P.05 = 2.58 2.51 2.44 9.54 11.98 0.61 0.21 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 = Coeff. Var. X = 3.11 4.874 'F' table values Dunnett's 'T* table values F.01 * P.01 = 3.78 3.12 F.05 = P.05 2.58 2.51 -Significant Difference from Control P < .05 **-Significant Difference fro Control P < .01 Error-within groups LABCAT HE4.43 Source-Source of Variation Treatnents-between groups 27-JUN-2002 Study Report for Hematology SUMMARY REPORT PERIOD: TERMINAL 418-028:PAGE K-35 STUDY ID: ARGUS 418-0Z8 STUDY NO: 060-069 ANALYSIS 0F VARIANCE F0LL0WED BY DUNNETT'S PROCEDURE SEX: HAL Hematocrit Group N Total Mean 1-N 10 434.6 43.5 2-M 10 422.2 42.2 3-M 10 419.9 42.0 4-H 10 401.7 40.2 5-n 10 406.7 40.7 Std. DUNNETT'S Dev. 't' 3.48 1.57 2.22 2.29 1.81 1.17 1.39 3.11 2.64 DUNNETT'S RANGES L0 -95X- NI L0 -99X- HI Degree Source Fdn 40.8 40.8 40.8 40.8 46.1 46.1 46.1* 46.1* 40.2 40.2 40.2 40.2 46.8 46.8 46.8 46.8 TREATMENTS ERROR TOTAL 4 45 49 Sim of Squares 68.54 252.15 320.69 Mean Square 17.13 5.60 F Ratio = Coeff. Var. % = 3.06 5.676 'F' table values Dunnett's *T' table values Mean Corpuscular Volume F.01 P.01 = 3.78 3.12 F.05 = P.05 = 2.58 2.51 1-H 10 579.1 57.9 1.89 2-N 10 576.9 57.7 2.27 0.28 56.0 59.9 3-K 10 574.1 57.4 1.78 0.64 56.0 59.9 4-H 10 579.4 57.9 1.15 0.04 56.0 59.9 5-H 10 582.7 58.3 1.37 0.46 56.0 59.9 F Ratio =: Coeff. Var. X = 0.34 3.006 'F' table values Dunnett's *T' table values F.01 = P.01 = Mean Corpuscular Hemoglobin 55.5 55.5 55.5 55.5 60.3 60.3 60.3 60.3 TREATMENTS ERROR TOTAL 4 45 49 3.78 3.12 F.05 = P.05 = 2.58 2.51 4.07 136.05 140.12 1.02 3.02 1-M 10 220.3 22.0 0.87 TREATMENTS 4 4.40 1.10 2-M 10 217.6 21.8 1.13 0.76 21.1 22.9 20.9 23.1 ERROR 45 28.04 0.62 3-M 10 215.2 21.5 0.75 1.44 21.1 22.9 20.9 23.1 --- 4-M 10 222.3 22.2 0.45 0.57 21.1 22.9 20.9 23.1 TOTAL 49 32.44 5-H 10 223.2 22.3 0.56 0.82 21.1 22.9 20.9 23.1 F Ratio = Coeff., Var. X = 1.77 3.593 'F ` table values Dunnett's 'T' table values F .01 = P.01 = 3.78 3.12 F.05 = P.05 = 2.58 2.51 -Significant Difference fro control P < .05 Error-within groups LABCAT HE4.43 Source-Source of Variation Treataents-between groups. 27-JUN-2002 Study Report for Hematology SUMMARY REPORT PERIOD: TERMINAL 418-028:PAGE K-36 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE Mean Corpuscular Hero. Cone. Std. 1DUNNETT'S Group N Total Bean Dev. *t' DUNNETT* S RANGES L0 -95X- HI L0 -99X- HI Degree Source Fdm 1-N 10 380.4 38.0 0.93 TREATBENTS 4 2-H 10 377.2 37.7 1.15 0.80 37.0 39.0 36.8 39.3 ERROR 45 3-B 10 374.9 37.5 0.79 1.38 37.0 39.0 36.8 39.3 - 4-B 10 383.7 38.4 0.80 0.83 37.0 39.0 36.8 39.3 TOTAL 49 5-H 10 383.1 38.3 0.70 0.68 37.0 39.0 36.8 39.3 F Ratio = Coeff. Var. % = 1.81 2.343 Platelets 'F ' table values Dunnett's *T ' table values F.d = P.01 = 3.78 3.12 F.05 = P.05 = 2. 58 2. 51 1-H 10 11790 1179 130.9 TREATBENTS 4 2-H 10 11305 1131 183.7 0.74 1015 1343 975 1383 ERROR 45 3-B 10 11154 1115 149.2 0.97 1015 1343 975 1383 --- 4-B 10 11044 1104 91.4 1.14 1015 1343 975 1383 TOTAL 49 5-H 10 11483 1148 159.9 0.47 1015 1343 975 1383 F Ratio = Coeff. Var. X = 0.40 12.888 F ' table values Dunnett's 'T' table values MEAN PLATELET VOLUME F.Q1 = P.01 = 3.78 3.12 F.05 = P.05 = 2.58 2.51 SEX: BALE Sua of Squares 5.72 35.64 41.36 Bean Square 1.43 0.79 34523 963815 998339 8631 21418 1-H 10 81.2 8.1 0.52 2-H 10 78.6 7.9 0.54 0.92 7.4 8.8 3-B 10 82.3 8.2 0.72 0.39 7.4 8.8 4-B 10 82.1 8.2 0.76 0.32 7.4 8.8 5-H 10 80.4 8.0 0.59 0.28 7.4 8.8 F Ratio = Coeff. Var. % = 0.56 7.823 'F ' table values Dunnett's 'T' table values F.01 = P.01 = TREATBENTS 4 7.2 9.0 ERROR 45 7.2 9.0 7.2 9.0 TOTAL 49 7.2 9.0 3.78 3.12 F.05 = P.05 = 2.58 2.51 0.90 18.03 18.94 0.23 0.40 Erroi-- within groups Source-Source of Variation LABCAT HE4.43 Treataents-between groups 27-JUN-2002 Study Report for Hematology SUMMARY REPORT PERIOD: TERMINAL 418-028:PAGE K-37 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE Prothrombin Group N Total Mean Std. DUNNETT'S Dew. *t' DUNNETT'SI RANGES L0 -95X- HI L0 -99X- HI Degree Source Feta Sum of Squares Mean Square 1-M 10 133.8 13.4 0.24 TREATMENTS 4 4.13 1.03 2-N 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-H 10 137.9 13.8 0.40 2.71 13.0 13.8* 12.9 13.9 TOTAL 49 9.26 5-N 10 139.5 14.0 0.47 3.77 13.0 13.8* 12.9 13.9** F Ratio == Coeff. Var. % * 9.05 2.448 'F' table values Dunnett's 'T` table values F.01 = P.01 3.78 3.12 F.05 = P.05 = 2.58 2.51 Act. Part. Thromboplastin Time 1-M 10 209.8 21.0 3.09 2-M 10 220.5 22.1 4.41 0.83 17.7 24.2 3-M 10 205.7 20.6 2.38 0.32 17.7 24.2 4-M 10 211.7 21.2 2.24 0.15 17.7 24.2 5-M 10 212.8 21.3 1.43 0.23 17.7 24.2 F Ratio >= Coeff. Var. X * 0.35 13.609 'F' table values Dunnett's 'T* table values F.01 * P.01 Nucleated Red Cells 17.0 17.0 17.0 17.0 25.0 25.0 25.0 25.0 TREATMENTS ERROR TOTAL 4 45 49 3.78 3.12 F.Q5 = P.05 = 2.58 2.51 11.75 374.92 386.66 2.94 8.33 1-M 10 2-M 10 3-M 10 4-M 10 5-M IQ F Ratio = Coeff., Var. X = 0 0 Q.O 0 0 0.0 0.00 0 0 0 .0 0.00 0 0 0.0 0.00 0 0 0.0 0.00 00 00 00 00 0.00 0.000 `F' table values Dunnett's 'T* table values F.01 = P.01 = 0 0 0 0 3.78 3.12 TREATMENTS 4 0.00000 0 ERROR 45 0.00000 0 --------------- 0 TOTAL 49 0.00000 0 0.00000 0.00000 F.05 = P.05 = 2.58 2.51 -Significant Difference fro Control P < .05 -Significant Difference fro Control P < .01 Error-within groups LABCAT HE4.43 Source-Source of Variation Treatments-between group 27-JUN-20Q2 Study Report for Hematology SUMMARY REPORT PERIOD: TERMINAL 418-02&PAGE K-38 STUDY IB: ARGUS 418-028 STUDY NO: 060-069 ANALYSIS 0F VARIANCE FOLLOWED BY DUNNETT1S PROCEDURE SEX: MALE Lymphocytes Group N Total Mean sto. DUNNETT'S Dev. 't' DUNNETT' S RANGES L0 -95X- HI L0 -99X- HI Degree Source Fdm Sum of Squares Mean Square 1-H 10 119.2 11.9 1.72 2-M 10 109.7 11.0 2.68 0.81 9.0 14.9 3-M 10 108.1 10.8 2.02 0.94 9.0 14.9 4-M 10 120.8 12.1 3.57 0.14 9.0 14.9 5-N 10 123.6 12.4 2.7S 0.37 9.0 14.9 F Ratio = Coeff. Var. % * 0.70 22.619 F' table values Dunnett's 'T* table values F.01 = P.01 = Segmented Neutrophils TREATMENTS 4 8.3 15.6 ERROR 45 8.3 15.6 - 8.3 15.6 TOTAL 49 8.3 15.6 3.78 3.12 F .05 = P.05 = 2.58 2.51 19.27 311.29 330.56 4.82 6.92 ---- ---- 1-M 10 22.1 2.2 0.73 2-M 10 28.8 2.9 1.18 1.63 1.2 3.2 3-M 10 20.2 2.0 1.06 0.46 1.2 3.2 4-M 10 28.4 2.8 0.73 1.54 1.2 3.2 5-M 10 15.5 1.6 0.78 1.61 1.2 3.2 F Ratio = Coeff. Var. X ~ 3.79 39.885 F' table values Dunnett's 'T' table values F.01 = P.01 = TREATMENTS 4 0.9 3.5 ERROR 45 0.9 0.9 3.5 TOTAL 49 0.9 3.5 3.78 3.12 F.05 = P.05 = 2.58 2.51 12.77 37.87 50.64 3.19 0.84 B ands 1-H 10 0.0 0.0 0.00 2-M 3-M 10 10 0_.0 0.1 0.0 0.0 0.00 0.03 0.00 1.12 0.0 0.0 4-M 10 0.1 0.0 0 .0 3 1.12 0.0 0.0 5-M 10 Q.O 0.0 0.00 0.00 0.0 0.0 F Ratio = Coeff. Var. X ~ 0.75 500.000 'F* table values Dunnett's 'T' table values F.01 = P.01 = TREATMENTS 4 0.0 0.0 ERROR 45 0.0 0.0 0.0 TOTAL 49 0.0 0.0 3.78 3.12 F.05 = P.05 = 2.58 2.51 0.0012 0.0180 0.0192 0.0003 0.0004 Error-within groups Source-Source of Variation LABCAT HE4.43 Trestmems-betveen groups 27-JUN-20Q2 Study Report for Hematology SUMMARY REPORT PERIOD: TERMINAL 418-028.PAGE K-39 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE SEX: MALE Monocytes Group N Total Mean 1-M 10 8.4 0.8 2-M 10 6.9 0.7 3-M 10 5.8 0.6 4-H 10 8.0 0.8 5-M 10 4.5 0.5 Std. DUNNETT* S Dev. t' 0.56 0.50 0.51 0.67 0.33 Q.64 1.11 0.17 1.66 DUNNETT' S RANGES L0 -95Z- HI LO -99Z- HI Degree Source Fdn Sun of Squares 0.2 1.4 0.2 1.4 0.2 1.4 0.2 1.4 TREATMENTS 4 1.03 0.1 1.6 ERROR 45 12.43 0.1 1 . 6 ------------------- 0.1 1.6 0.1 1.6 TOTAL 49 13.46 Mean Square 0.26 Q.28 F Ratio = Coeff. Var. Z = 0.93 78.222 Eosinophils F* table values Dunnett's 'T` table values F.01 * P.01 = 3.78 3.12 F.05 = P.05 = 2.58 2.51 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-H 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. Z = 0.46 82.096 Basophils 1F ` table values Dunnett's *T' table values F.01 = P.01 = 3.78 3.12 F.05 = P.05 = 2.58 2.51 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.Q 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-M 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 = Coeff. Var. Z = 0.00 0.000 F* table values Dunnett's 'T' table values F.01 = P.01 * 3.78 3.12 F.05 = P.05 = 2.58 2.51 Error-within groups Source-Source of Variation LABCAT HE4.43 Treatnents-between groups 27-JUN-2002 Study Report for Hematology SUMMARY REPORT PERIOD: TERMINAL 418-028:PAGE K-40 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 ANALYSIS 0F VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE Abnormal Lymphocytes Std DUNNETT'S Group N Total Mean Dev. 't' DUNNETT'S RANGES L0 -95X- HI L0 -99X- HI Degree Source Fdm 1-M 2-M 10 1.4 0.1 0.20 10 1.1 0.1 0.14 0.38 -.1 0.3 TREATMENTS 4 -.1 0.4 ERROR 45 3-M 4-M 10 0.6 0.1 0.07 1.01 10 2.1 0.2 0.22 0.89 -.1 0.3 -.1 0.3 -.1 0.4 -.1 0.4 TOTAL 49 5-M 10 1.2 0.1 0.21 .25 -.1 0.3 -.1 0.4 F Ratio = Coeff. Var. X = 0.95 137.898 'F' table value Dunnett's 'T* table values F.01 P.01 3.78 3.12 F .05 = P.05 * 2.58 2.51 Other 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 Q .Q 0.0 0.0 0.0 0.0 0.0 0 .0 0 0.000 'F' table values Dunnett's 'T' table values F.01 = P.01 = TREATMENTS 4 0.0 0.0 ERROR 45 0.0 0.0 0.0 0.0 TOTAL 49 0.0 0.0 3.78 3.12 F.05 = P.05 = 2.58 2.51 Suis of Squares Mean Square 0.12 1.40 0.03 0.03 1.52 0.00000 0.00000 0.00000 0.00000 0.00000 Error-- within groups Source-Source of Variation LABCAT HE4.43 Treataents-between groups 27-JUN-2002 Study Report for Hematology 418-028:PAGE K-41 SUMMARY REPORT PERIOD: TERMINAL STUDY ID: ARGUS 418-028 STUDY N0: 060-069 ANALYSIS 0F VARIANCE FOLLOUED BY DUNNETT'S PROCEDURE TEST(s): UNITS: WBC RBC THSN/CU HH MILL/CU MM HGB 6RAMS/DL Group: 1-F MEAN SO N 9.0 3.09 10 6.51 0.461 10 15.5 0.95 10 Group: 2-F MEAN SD N 13.8* 5.73 10 6.22 0.423 10 15.0 0.77 10 Group: 3-F MEAN SD N 11.1 2.98 10 6.40 0.554 10 15.2 0.91 10 Group: 4-F MEAN SD N 10.8 3.15 10 6.39 0.532 10 15.2 0.90 10 Group: 5-F MEAN SD N 8.9 3.48 10 6.42 0.538 10 15.3 0.77 10 HCT MCV MCH X CU MICRONS PICO GRAMS 40.5 2.93 10 62.2 1.19 10 23.9 0.55 10 39.3 2.72 10 63.3 2.01 10 24.2 0.76 10 39.5 3.24 10 61.8 1.50 10 23.9 0.88 10 40.1 3.02 10 62.9 2.04 10 23.8 1.25 10 40.4 3.15 10 63.0 1.60 10 23.8 1.05 10 MCHC PLT MPV X THSN/CU MM CU MICRON 38.4 0.76 10 1419 153.0 10 8.3 0.49 10 38.3 0.94 10 1240 208.1 10 8.0 0.84 10 38.7 1.29 10 1274 226.3 10 37.8 1.22 10 1305 207.2 10 8.3 0.82 10 8.0 0.63 10 37.8 1.37 10 1355 176.8 10 7.7 0.74 10 -Significant Difference fro Control P < .05 LABCAT HE4.43 27-JUN-2002 Study Report for Hematology SUMMARY REPORT PERIOD: TERMINAL 418-028:PAGE K-42 STUDY 1D: ARGUS 418-028 STUDY N0: 060-069 ANALYSIS OF VARIANCE F0LL0UED BY DUNNETT'S PROCEDURE SEX: FENALE TEST(s): UNITS: PT seconds APTT seconds NRBC Lymphocyte Segmented Bands Monocytes Eosinophil Basophils COUNT THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM Group: 1-F MEAN SD N Group: 2-F MEAN SD N Group: 3-F MEAN SD N Group: 4-F MEAN SD N Group: 5-F MEAN SD N 13.2 0.41 10 13.4 0.29 10 13.2 0.37 10 13.5 0.42 10 13.8 1.12 10 21.7 2.36 10 23.9 3.19 10 23.5 2.35 10 25.3 2.45 10 25.2 3.81 10 0 6.6 2.2 0.0 0.1 0.1 0.0 0.0 2.44 0.90 0.00 0.15 0.10 0.00 10 10 10 10 10 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 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 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 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 STUDY ID: ARGUS A18-028 STUDY N0: 060-069 Study Report for Hematology SUMMARY REPORT PERIOD: TERMINAL ANALYSIS OF VARIANCE FOLLOVED BY DUNNETT'S PROCEDURE TEST(s): Abnormal L o th e r UNITS: THSN/CU NM THSN/CU NM Group: 1-F MEAN SD N 0 .0 0.05 10 0 .0 0.00 10 Group: 2-F MEAN SD N 0 .0 0 .0 0 10 0 .0 0.00 10 Group: 3-F MEAN SD N 0.1 0.07 10 0 .0 0.00 10 Group: A-F MEAN SD N 0.1 0 .1 0 10 0 .0 0.00 10 Group: 5-F MEAN SD N 0 .0 0.05 10 0 .0 0 .0 0 10 418-028:PAGE K-43 SEX: FEMALE LABCAT HEA.A3 27-JUN-20Q2 Study Report for Hematology SUMMARY REPORT PERIO D : TERMINAL 418-028:PAGE K-44 STUDY 10: ARGUS 418-028 STUDY N0: 060-069 ANALYSIS OF VARIANCE FOLLOUEO BY DUNNETT'S PROCEDURE SEX: FEMALE White Blood Count S td . DUNNETT'S Group N T otal Mean Dev. t' 1-F 10 89.9 9 .0 3.09 2-F 10 137.8 13.8 5.73 2.80 3-F 10 110.7 11.1 2.98 1.22 4-F 10 108.4 10.8 3.15 1.08 5 -F 10 88.9 8 .9 3 .48 0 .06 DUNNETT' S RANGES L0 -95%- HI LO -99%- HI Degree S ource Fetal 4 .7 13.3* 4 .7 13.3 4 .7 13.3 4.7 13.3 TREATMENTS 4 3 .6 14.3 ERROR 45 3 .6 14.3 - 3 .6 14.3 TOTAL 49 3 .6 14.3 Sun o f Squares 158.42 659.12 817.54 Mean Square 39.61 14.65 F R atio = C oeff. Var. % = 2.70 35.721 'F ' ta b le values D unnett's 'T ' ta b le values Red Blood Count F.01 = P.01 3.78 3.12 F.05 * P.05 2.58 2.51 1-F 10 65.06 6.51 0.461 2-F 10 62.15 6.22 0.423 1.29 5.94 7.07 3-F 10 63.96 6.40 0.554 0.49 5.94 7.07 4-F 10 63.87 6.39 0.532 0.53 5.94 7.07 5-F 10 64.23 6.42 0.538 0 .3 7 5.94 7.07 F R atio * C oeff. Var. X = 0.44 7.896 F* t a b l e v a lu e s D unnett's 'T ' ta b le valu es F.01 = P.01 * Hemoglobin 5.80 5.80 5.80 5.80 7.21 7.21 7.21 7.21 TREATMENTS 4 ERROR 45 TOTAL 49 3.78 3.12 F.05 P.05 * 2. 58 2.51 0.45 11.44 11.89 0.11 0 .2 5 1-F 10 155.4 15.5 0.95 TREATMENTS 4 1 .3 6 0 .3 4 2-F 10 150.4 15.0 0.77 1.29 14.6 16.5 14.3 16.7 ERROR 45 33.62 0 .7 5 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 R atio = C oeff. Var. % = 0.46 5.669 1F ' t a b l e v a lu e s D u n n e tt's 1T 1 t a b l e v a lu e s F.01 P.01 3.78 3.12 F.05 = P.05 2.58 2.51 -Significant Difference froa Control P < .05 Error-- within groups LABCAT HE4.43 Source-Source of Variation Treataents-between groups 27-JUN-200B Study Report for Hematology SUMMARY REPORT PER IO D : TERMINAL 418-028:PAGE K-45 STUDY ID: ARGUS 418-028 STDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOUED BY DUNNETT'S PROCEDURE Hematocrit Group N Total Hean S td . DUNNETT'S Dev. 't ' DUNNETT'! RANGES L0 -95%- HI L0 -99%- HI Degree Source Fda 1-F 10 404.9 40.5 2.93 TREATMENTS 4 2 -F 10 393.4 39.3 2.72 0.85 37.1 43.9 36.3 44.7 ERROR 45 3-F 10 395.1 39.5 3.24 0.73 37.1 43.9 3 6 .3 4 4 . 7 ----- 4-F 10 401.4 40.1 3.02 0.26 37.1 43.9 36.3 44.7 TOTAL 49 5-F 10 404.1 40.4 3.15 0.06 37.1 43.9 36.3 44.7 F Ratio = C oeff. Var. % = 0.30 7.548 F' ta b l e v a lu e s D unnett's 'T ' ta b le values Mean Corpuscular Volume F .01 = P. 01 = 3.78 3.12 F .05 P .05 - 2 .5 8 2.51 SEX; f EMALE Sua of Squares 11.01 409.80 420.81 Mean Square 2 .7 5 9.11 1-F 10 622.3 62.2 1.19 2 -F 10 633.3 63.3 2.01 1.45 60.3 64.1 3-F 10 618.2 61.8 1.50 0.54 60.3 64.1 4-F 10 629.1 62.9 2.04 0.90 60.3 64.1 5-F 10 629.7 63.0 1.60 0.97 60.3 64.1 F Ratio C oeff. Var. % 1.30 2.709 F1 t a b l e v a lu e s D u n n e tt's 'T* t a b l e v a lu e s F .01 P .01 Mean Corpuscular Hemoglobin 1-F io 239.0 23.9 0.55 2 -F 10 242.4 24.2 0.76 0.82 22.9 24.9 3-F 10 238.9 23.9 0.88 0.02 22.9 24.9 4-F 10 237.9 23.8 1.25 0.26 22.9 24.9 5-F 10 238.3 23.8 1.05 0.17 22.9 24.9 59.9 59.9 59.9 59.9 64.6 64.6 64.6 64.6 TREATMENTS ERROR ----TOTAL 4 45 49 3.78 3.12 F .05 * P .05 X 2 .5 8 2.51 - 22.6 22.6 22.6 22.6 25.2 25.2 25.2 25.2 TREATMENTS ERROR ----TOTAL 4 45 49 14.98 129.67 144.64 1.28 38.92 40.21 3 .7 4 2 .8 8 0 .3 2 0 .8 6 F R atio = C oeff. Var. X = 0.37 3.886 F' ta b le values D unnett's 'T ' ta b le values F .01 = P .01 = 3.78 3.12 F .05 * P .05 X 2 .5 8 2.51 Error-within groups Source-Source of Variation LABCAT HE4.43 Treataents-between groups 27-JUN-20Q2 418-028:PAGE K-46 Study Report for Hematology SUMMARY REPORT PERIOD*. TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-069 ANALYSIS 0F VARIANCE F0LL0HED BY DUNNETT'S PROCEDURE SEX: FEMALE Mean Corpuscular Hem. Conc. S td . DUNNETT'S Group N Total Mean Dew. 'f DUNNETT'S RANGES LO -95%- HI LO -99X - HI Degree S ource Fdm 1-F 10 384.2 3 8 .4 0.76 2-F 10 382.9 3 8 .3 0.94 0.26 37.1 39.7 VF 10 386.6 3 8 .7 1.29 0.47 37.1 39.7 4-F 10 378.3 3 7 .8 1.22 1.16 37.1 39.7 5-F 10 378.4 3 7 .8 1.37 1.14 37.1 39.7 F R atio = C oeff. Var. % = 1. 03 2.978 'F ' tab le values D unnett's 'T ' ta b le valu es F .01 = P .01 * 3 6 .8 36.8 36.8 36.8 TREATMENTS 40.0 ERROR 4 0 . 0 ------ 40.0 TOTAL 40.0 4 45 49 3 .7 8 3 .1 2 F .05 * P .05 =* 2.58 2.51 Platelets 1-F 10 14189 1419 153.0 p -f 10 12396 1240 208.1 2.05 1199 1639 3 -9 10 12735 1274 226.3 1.66 1199 1639 4-F 10 13048 1305 207.2 1.30 1199 1639 5-F 10 13554 1355 176.8 0.72 1199 1639 F R atio = Coeff.. Var. X = 1 .29 14.868 'F ' ta b le values D unnett's 'T ' ta b le values F .01 * P .01 * 1145 1145 1145 1145 1692 1692 1692 1692 TREATMENTS ERROR ----TOTAL 4 45 49 3 .7 8 3.12 F.05 P .05 - 2.58 2.51 MEAN PLATELET VOLUME 1-F 10 83.4 8 .3 0.49 2-F 10 80.0 8 .0 0.84 1.06 7 .5 9.1 3-F 10 82.7 8.3 0.82 0.22 7 .5 9.1 10 80.3 8 .0 0.63 0.97 7.5 9.1 5-F 10 76.5 7 .7 0.74 2.15 7 .5 9.1 F R atio = C oeff . V ar. X *> 1 .44 8.894 'F ta b le v alu es D u n n ett's 'T'1 ta b le v alu es F. 01 * P .01 * TREATMENTS 4 7.3 9.3 ERROR 45 7 .3 9 .3 ----- 7.3 9.3 TOTAL 49 7.3 9.3 3 .7 8 3.12 F .05 = P .05 * 2.58 2.51 Sua of Squares Mean Square 5 .3 4 58.25 1 .3 4 1 .2 9 63.60 198797 1729216 1928012 49699 38427 2.95 23.11 26.06 0 .7 4 0.51 Erpor-within groups Source-Source of Variation LABCAT HE4.43 Treatments-betveen groups 2 7 -JUN-2002 Study Report for Hematology SUMMARY REPORT PE R IO D : TERMINAL 418-028:PAGE K-47 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE SEX: FEMALE Prothrombin Group N T otal Hean 1-F 10 131.8 13.2 2-F 10 133.5 13.4 3-F 10 131.7 13.2 4-F 10 134.8 13.5 5-F 10 137.5 13.8 S td . DUNNETT'S Dev. t* 0.41 0.29 0.37 0.42 1.12 0.63 0.04 1.11 2.11 DUNNETT'S RANGES L0 -95X - HI LO -99X - HI Degree S o u rce Fda 12.5 12.5 12.5 12.5 13.9 13.9 13.9 13.9 12.3 12.3 12.3 12.3 14.0 14.0 14.0 14.0 TREATMENTS ERROR TOTAL 4 45 49 Sua of Squares 2.32 16.48 18.80 Mean Square 0 .5 8 0 .3 7 F R atio = C oeff. Var. X = 1.58 4.521 F* t a b l e v a lu e s D u n n e tt's 'T* t a b l e v a lu e s Act. Part. Thromboplastin Time F.01 = P.01 = 3.78 3.12 F.05 = P.05 = 2.58 2.51 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 R atio = C oeff. Var. X = 2.53 12.081 F* t a b l e v a lu e s D unnett's 'T ' ta b le valu es Nucleated Red Cells F.01 P.01 a 3.78 3.12 F.05 = P.05 * 2.58 2.51 1-F 10 0 0 0 .0 2-F 10 0 0 0 .0 0.00 0 0 3-F 10 0 0 0 .0 0.00 0 0 4-F 10 0 0 0 .0 0.00 0 0 5-F 10 2 0 0 .6 1.58 0 0 F R atio a C oeff. Var. X = 1.00 707.107 ' F' ta b le values D unnett's 'T ' ta b le values F.01 * P.01 = 0 0 0 0 3.78 3.12 TREATMENTS 4 0 ERROR 45 00 TOTAL 49 0 F.05 * P.05 a 2.58 2.51 0.32 3.60 3.92 0 .0 8 0 .0 8 -Significant Difference froa Control P < .05 Error-within groups LABCAT HE4.43 Source-Source of Variation Treataents-between groups 27-JUN-2002 418-028:PAGE K-48 Study Report for Hematology SUMMARY REPORT PERIOD: TERMINAI. STUDY 10: ARGUS 418-028 STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOUED BY DUNNETT' S PROCEDURE SEX: FEMALE Lymphocytes Group N Total Mean S td . DUNNETT'S Dev. 't ' DUNNETT'S RANGES L0 -95X - HI LO -99X - HI Degree Source Fda Sua o f Squares Mean Square 1-F 10 65.6 6 .6 2 .44 2-F 10 98.0 9 .8 3.44 2.61 3.4 9.7* 3-F 10 83.8 8.4 2.60 1.46 3.4 9.7 4-F 10 81.8 8 .2 2 .52 1.30 3.4 9.7 5-F 10 60.3 6.0 2.77 0.43 3.4 9.7 F R a tio =' C o e ff. V ar. X == 2.96 35.677 'F ' ta b le values D u n n e tt's 'T* t a b l e v a lu e s F.01 = P.01 Segmented Neutrophils TREATMENTS 4 2 .7 10.4 ERROR 45 2 .7 10.4 - 2 .7 10.4 TOTAL 49 2 .7 10.4 3 .7 8 3 .1 2 F.05 * P.05 2.58 2.51 91.51 347.60 439.11 2 2 .8 8 7 .7 2 1-F 10 21.9 2 .2 0.90 2-F 10 3 6.0 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 R a tio : C o e ff. V ar. X 1= 0.95 70.025 'F` ta b le values D unnett's 'T ' ta b le values F.01 = P.01 Bands TREATMENTS 4 - .4 4.8 ERROR 45 -.4 4.8 -.4 4.8 TOTAL 49 -.4 4.8 3 .7 8 3.12 F.05 P.05 - 2.58 2.51 12.77 151.70 164.47 3 .1 9 3 .3 7 1-F 10 2-F 10 3-F 10 4-F 10 5-F 10 F R atio = C oeff. Var. X * 0.0 0.0 0.00 0.0 0.0 0.00 0.00 0 .0 Ut 0.3 0.0 0.09 1.58 0.0 0.0 0.00 0.00 0.0 0 .0 n n n ft 0.0 0.0 0.0 0 .0 1.00 707.107 F' ta b le values D unnett's 'T ' ta b le values F.01 P.01 TREATMENTS 4 -.1 0.1 ERROR 45 n 1 . -- -.1 0.1 -.1 0.1 TOTAL 49 3.78 3.12 F.05 * P.05 2.58 2.51 0.0072 0.0810 0.0882 0.0018 0.0018 -Significant Difference fro m Control P < .05 Error-within groups LABCAT HE4.43 Source-Source of Variation Treataents-between groups 27-JUN-2002 Study Report for Hematology SUMMARY REPORT PERIOD: TERMINAL 418-028:PAGE K-49 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE SEX: FEMALE Monocytes Group N T otal Mean 1-F 10 1.3 0.1 2-F 10 2.7 0 .3 3-F 10 1.7 0 .2 4-F 10 1.9 0.2 5-F 10 1.7 0 .2 S td . DUNNETT' S Dev. 't* DUNNETT' S RANGES LO -95X - HI L0 -99X- HI Degree S o u rce Fd a 0.15 0.49 0.13 0.11 0.14 1.26 0.36 0.54 0 .3 6 -.1 0.4 -.1 0.4 -.1 0.4 -.1 0.4 TREATMENTS 4 -.2 0.5 ERROR 45 - . 2 0 .5 ----- -.2 0.5 TOTAL 49 -.2 0.5 Sua of Squares 0.11 2 .7 9 2.90 Mean Square 0 .0 3 0 .0 6 F R atio * C oeff. Var. X 0.43 133.942 Eosinophils 'F ' ta b le values D u n n e tt's 'r* t a b l e v a lu e s F.01 P.01 * 3.78 3.12 F.05 * P.05 = 2 .5 8 2.51 1-F 10 0 .9 0.1 0.10 2-F 10 1.2 0.1 0.13 0.54 0.0 0.2 5--r n o A <1 0 .1 3 0 .0 0 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. X * 0.23 137.686 F' table values Dunnett's 'T' table values F.01 P.01 Basophils TREATMENTS 4 -.1 0.3 ERROR 45 - 1 0.3 -.1 0.3 TOTAL 49 -.1 0.3 3.78 3.12 F.05 * P.05 = 2 .5 8 2.51 0.014 0.691 0.705 0.004 0.015 1-F 10 0.0 0.0 0 .0 0 TREATMENTS 4 0.00000 0.00000 2-F 10 0.0 0.0 0 .0 0 0.00 0.0 0.0 0.0 0.0 ERROR 45 0.00000 0.00000 3-F 10 0.0 0.0 0 .0 0 0.00 0.0 0.0 0.0 0.0 4-F 10 0.0 0.0 0 .0 0 0 .0 0 0.0 0.0 0.0 0.0 TOTAL 49 0.00000 5-F 10 0.0 0.0 0 .0 0 0 .0 0 0.0 0.0 0.0 0.0 F R atio * Coeff.. Var. X * 0.00 0.000 F' t a b l e v a lu e s D u n n ett's `T' ta b le v alu es F.01 = P.01 * 3.78 3.12 F.05 * P.05 * 2.58 2.51 Error-within groups Source-Source of Variation LABCAT HE4.43 Treataents-between groups 27-JUM-20Q2 Study Report for Hematology SUMMARY REPORT PERIO D : TERMINAL 418-028:PAGE K-50 STUDY ID: ARGUS 418-028 STUDY MO: 060-069 ANALYSIS 0F VARIANCE FOLLOUED BY DUNNETT1S PROCEDURE SEX: FEHALE Abnormal Lymphocytes S td . DUNNETT' S Group N Total Mean Dev. 't ' DUNNETT' S RANGES L0 -95X - HI L0 -99X - HI D egree S ource Fdm Sum o f Squares Mean 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 .1 0 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 R atio * C oeff. Var. X ~ 1. 39 181.306 Other 'F ' ta b le values D u n n e tt's 'T* t a b l e v a lu e s F .01 P. 01 * 3.78 3.12 F .05 * P .05 2 .5 8 2.51 1-F 10 0.0 0.0 0 .0 0 TREATMENTS 4 0.00000 0.00000 2-F 10 0.0 0.0 0 .0 0 0.00 0.0 0.0 0.0 0.0 ERROR 45 0.00000 0.00000 3-F 10 U.U n n n nn 0 .0 0 0 .0 0.0 0.0 n n 4-F 10 0.0 0.0 0 .0 0 0 .0 0 0.0 0.0 0.0 0.0 TOTAL 49 0.00000 5-F 10 0.0 0.0 0 .0 0 0 .0 0 0.0 0.0 0.0 0.0 F Ratio = Coeff,. Var. X = 0.00 0.000 F' t a b l e v a lu e s D unnett's 'T ' ta b le values F .01 = P .01 = 3.78 3.12 F .05 P .05 = 2.58 2.51 Error-uithin groups Source-Source of Variation LABCAT HE4.43 Treataents-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 Animal ID GROUP: 1-M TERMINAL CNT ABS SEX: MALE 19109 19115 N u c le a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands M onocytes E o sin o p h iIs B aso p h iIs Abnormal Lymphocytes O ther UBC N u c le a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands M onocytes E o sin o p h iIs B aso p h iIs Abnormal Lymphocytes O ther UBC 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 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 N u c le a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h iIs B aso p h iIs Abnormal Lymphocytes O th er UBC 0 77 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 Study Report for Hematology WHITE DIFFERENTIAL DATA 418-028:PAGE K-52 STUDY ID: ARSUS 4 18-028 STUDY NO: 060-069 A n im i ID GROUP: 1-M TERMINAL CNT ABS SEX: MALE 19119 19122 N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h iIs B asophils Abnormal Lymphocytes O ther UBC N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h ils B aso p h iIs Abnormal Lymphocytes o th e r UBC 0 72 9.1 17 2.2 0 0.0 10 1.3 1 0.1 0 0.0 0 0.0 0 0.0 12.7 0 86 14.1 9 1.5 0 0.0 1 0.2 1 0.2 0 0.0 3 0.5 0 0.0 16.4 19125 N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h ils B aso p h iIs Abnormal Lymphocytes O ther UBC 0 81 1 4 .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 Study Report for Hematology WHITE DIFFERENTIAL DATA 418-028:PAGE K-53 STUDY ID: ARGUS 418-028 STUDY HO: 0 6 0 -0 6 9 6R0UP: 1-M SEX: MALE Animal ID TERMINAL CNT ABS 19131 19132 19134 N u c le a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h iIs B asophiIs Abnormal Lymphocytes O th er UBC N u cle a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h iIs B asophiIs Abnormal Lymphocytes O th er UBC N u cle a te d Red C e lls Lymphocytes Segmented N eutrophils Bands M onocytes Eosinophi Is B aso p h ils Abnormal Lymphocytes O th er UBC 0 74 13.1 15 2 .7 0 0.0 9 1.6 1 0.2 0 0.0 1 0.2 0 0.0 17.7 0 85 1 2 .7 10 1 .5 0 0.0 3 0.4 0 0.0 0 0.0 2 0.3 0 0.0 14.9 0 73 1 1 .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 Ania a l ID 19135 19143 19151 GROUP: 1-H N u cle a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands M onocytes E o sin o p h ils B aso p h ils Abnormal Lymphocytes O th er WBC N u cle a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h ils B aso p h iIs Abnormal Lymphocytes O ther WBC N u cle a te d Red C e lls Lymphocytes Segmented N eutrophils Bands Monocytes E o sin o p h ils B asophiIs Abnormal Lymphocytes O th er WBC TERMINAL CNT ABS 0 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 0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0-- -- 0 0-- 0-- 0-- 0-- 0-- 0_ 0-- 0-- -- SEX: HALE (-- ) - Data U navailable LABCAT HE4.43 27-JUN-2002 Study Report for Hematology WHITE D IFFE R E N T IA L DATA 418-028:PAGE K-55 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 A n im i ID GROUP: 1-M TERMINAL CNT ABS SEX: HALE 19157 N u c le a te d Red C e lls Lymphocytes Segmented N eutrophils Bands M onocytes E osinophils B aso p h ils Abnormal Lymphocytes O th er UBC 0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0-- -- 19161 N u c le a te d Red C e lls Lymphocytes Segmented N eutrophils Bands M onocytes E o sin o p h iIs B aso p h iIs Abnormal Lymphocytes O th er UBC 0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0-- -- 19167 N u c le a te d Red C e lls Lymphocytes Segmented N eutrophils Bands Monocytes E o sin o p h ils B aso p h ils Abnormal Lymphocytes O th er UBC 0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0-- (-- ) - Data U navailable LABCAT HEA.43 27-JUN-2002 418-028:PAGE K-56 Study Report for Hematology WHITE D IFFE R E N T IA L DATA STUDY ID: ARGUS 418-028 STUDY MO: 060-069 Anin a l ID GROUP: 2-M TERMINAL CNT ABS SEX: MALE 19102 19106 N u cleated Red C e lls Lynphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h iIs B aso p h ils Abnormal Lymphocytes O th er UBC N u cleated Red C e lls Lymphocytes Segmented N eutrophils Bands Monocytes E o sin o p h iIs B aso p h ils Abnormal Lymphocytes O th er UBC 0 60 6 .5 25 2 .7 0 0.0 9 1.0 3 0.3 0 0.0 3 0.3 0 0.0 10.9 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 N ucleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h iIs B a so p h iIs Abnormal Lymphocytes O th er UBC 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 Study Report for Hematology WHITE DIFFERENTIAL DATA 418-028:PAGE K-57 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Animal ID GROUP: 2-H TERMINAL CNT ABS SEX: MALE 19110 N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h ils B aso p h iIs Abnormal Lymphocytes O th er WBC 0 76 10.0 15 2 .0 0 0.0 5 0.7 2 0.3 0 0.0 2 0.3 0 0.0 13.1 19113 N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h ils B a so p h iIs Abnormal Lymphocytes O th er WBC 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 N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h ils B aso p h ils Abnormal Lymphocytes O ther WBC 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-JUH-2002 418-028:PAGE K-58 Study Report for Hematology WHITE DIFFERENTIAL DATA STUDY ID: ARGUS 4 18-028 STUDY NO: 060-069 GROUP: 2-N SEX: NALE Animal ID TERMINAL CNT ABS 19129 19136 19138 N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes Eosinophi Is B aso p h ils Abnormal Lymphocytes O th er WBC N ucleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h ils B aso p h ils Abnormal Lymphocytes O th er UBC N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h ils B aso p h ils Abnormal Lymphocytes O th er WBC 0 64 9 .4 27 4 .0 0 0.0 5 0.7 4 0.6 0 0.0 0 0.0 0 0.0 14.7 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 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-JUM-20G2 418-028:PAGE K-59 Study Report for Hematology WHITE DIFFERENTIAL DATA STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Animai ID GROUP: 2-M 19139 19147 19153 N ucleated Red C e lls Lyaphocytes Segaented N eutrophils Bands Monocytes E o sin o p h iIs B aso p h ils Abnormal Lyaphocytes O th er UBC N u cle a te d Red C e lls Lyaphocytes Segaented N eutrophils Bands M onocytes E o sin o p h ils B asophiIs Abnormal Lyaphocytes O th er UBC N u c le a te d Red C e lls Lyaphocytes Segmented N eu tro p h ils Bands Monocytes E osinophils B aso p h iIs Abnormal Lyaphocytes O th er UBC TERMINAL CNT ABS 0 86 16.3 13 2 .5 0 0.0 1 0.2 0 0.0 0 0.0 0 0.0 0 0.0 19.0 0 0_ 0-- 0-- 0-- 0-- 0-- 0-- 0_ -- 0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0-- -- SEX: HALE <-- > - Data U n a v a ila b le LABCAT HE4.43 27-JUN-202 Study Report for Hematology WHITE DIFFERENTIAL DATA 418-028:PAGE K-60 STUDY ID: ARSUS 418-028 STUDY NO: 060-069 Anin a l ID GROUP: 2-H 19164 19165 19171 N u c le a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands M onocytes E o sin o p h iIs B aso p h iIs Abnormal Lymphocytes O th er UBC N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h iIs B aso p h iIs Abnormal Lymphocytes O ther UBC N u c le a te d Red C e lls Lymphocytes Segmented N eutrophils Bands Monocytes E osinophils B aso p h iIs Abnormal Lymphocytes O th er UBC TERMINAL CNT ABS 0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0 -- -- 0 0-- 0-- 0-- 0-- 0-- 0 -0-- 0-- -- 0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0-- SEX: MALE (-- ) - Data Unavailable LABCAT HE4.43 27-JUH-2002 418-028:PAGE K-61 Study Report for Hematology WHITE DIFFERENTIAL DATA STUDY ID: ARGUS A18-028 STUDY HO: 060-069 A n im i ID 19101 19105 19107 GROUP: 3-H n u c le a te d Red C e lls Lyaphocytes Segtented N eutrophils Bands Monocytes E o sin o p h ils B aso p h iIs Abnormal Lymphocytes O th er UBC N u cleated Red C e lls Lyaphocytes Segm nted N eutrophils Bands Monocytes E o sin o p h ils B aso p h ils Abnormal Lymphocytes O th er UBC N u cleated Red C e lls Lymphocytes Segmnted N eutrophils Bands Monocytes Eosirtophi Is B aso p h ils Abnormal Lyaphocytes O th er UBC TERMINAL CNT ABS 0 77 10.1 16 2.1 0 0 .0 A 0.5 2 0.3 0 0 .0 1 0.1 0 0 .0 13.1 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 0 78 9.8 5 0.6 1 0.1 12 1.5 A 0.5 0 0 .0 0 0 .0 0 0 .0 12.5 SEX: MALE LABCAT HEA.A3 27-JUH-2002 Study Report for Hematology WHITE DIFFERENTIAL DATA 418-028-.PAGEK-62 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 A n im i ID 19112 19114 19121 GROUP: 3-H N u c le a te d Red C e lls lym phocytes Segmented N eutrophils Bands Monocytes E o sin o p h ils B asophiIs Abnormal Lymphocytes O ther UBC N u cle a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Honocytes Eosinophi Is B aso p h iIs Abnormal Lymphocytes o th e r UBC N u cleated Red c e l l s Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h ils B aso p h ils Abnormal Lymphocytes O th er UBC TERMINAL CNT ABS 0 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 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 0 71 1 4 .8 19 4 .0 0 0.0 7 1.5 2 0.4 0 0.0 1 0.2 0 0.0 20.9 SEX: HALE LABCAT HEA.43 27-JUN-2002 Study Report for Hematology WHITE DIFFERENTIAL DATA 418-028:PAGE K-63 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 A n im i ID GROUP: 3-H 19123 19130 19137 N ucleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h iIs B asophils Abnormal Lymphocytes O th er KBC N u cle a te d Red C e lls Lymphocytes Segmented N eutrophils Bands Monocytes E o sin o p h iIs B asophils Abnormal Lymphocytes O th er VBC N u c le a te d Red C e lls Lymphocytes Segmented N eutrophils Bands Monocytes E o sin o p h iIs B aso p h ils Abnormal Lymphocytes O th er UBC TERMINAL CNT ABS 0 74 10.4 24 3 .4 0 0.0 1 0.1 0 0.0 0 0.0 1 0.1 0 0.0 14.1 0 84 11.7 12 1 .7 0 0.0 3 0.4 1 0.1 0 0.0 0 0.0 0 0.0 13.9 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 SEX: HALE LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-64 Study Report for Hematology WHITE DIFFERENTIAL DATA STUDY ID: ARGUS 418-026 STUDY NO: 060-069 A n iaal ID GROUP: 3-M TERMINAL CNT ABS SEX: MALE 19146 19155 N u c le a te d Red C e lls Lyaphocytes Segaented N eutrophils Bands M onocytes E o sin o p h ils B aso p h iIs Abnoraal Lyaphocytes O ther WBC N u c le a te d Red C e lls L y ap h o cy tes Segaented N eutrophils Bands M onocytes E o sin o p h iIs B aso p h iIs Abnoraal Lyaphocytes O ther WBC 0 85 13.1 9 1.4 0 0.0 2 0.3 4 0.6 0 0.0 0 0.0 0 0.0 15.4 0 0-- 0-- 0-- 0-- 0_ 0-- 0-- 0-- -- 19159 N u c le a te d Red C e lls Lyaphocytes Segaented N eutrophils Bands Monocytes E o sin o p h iIs B asophiIs Abnoraal Lyaphocytes O ther WBC 0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0-- (-- ) - Data Unavailable LABCAT HE4.43 27-JUN-2002 Study Report for Hematology WHITE DIFFERENTIAL DATA 418-028:PAGE K-65 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 A n ia a l ID GROUP: 3-N TERMINAL CNT ABS SEX: MALE 19172 N u c le a te d Red C e lls Lymphocytes Segmented N eutrophils Bands Monocytes E o sin o p h iIs B aso p h iIs Abnormal Lymphocytes O ther VBC 0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0-- --' 19173 N u c le a te d Red C e lls Lymphocytes Segmented N eutrophils Bands M onocytes E o sin o p h iIs B asophils Abnormal Lymphocytes O th er VBC 0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0-- -- 19174 N u c le a te d Red C e lls Lymphocytes Segmented N eutrophils Bands Monocytes E o sin o p h ils B aso p h iIs Abnormal Lymphocytes O th er UBC 0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0-- (-- ) - Data U navailable LABCAT HE4.43 27-JUN-2002 Study Report for Hematology WHITE DIFFERENTIAL DATA STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 4-H Animal ID TERHINAL CNT ABS 19100 19103 N u cle a te d Red C e lls Lymphocytes Segmented N eutrophils Bands Nonocytes E o sin o p h ils B asophiIs Abnormal Lymphocytes O th er WBC N u c le a te d Red C e lls Lymphocytes Segmented N eutrophils Bands N o nocytes E o sin o p h iIs B asophiIs Abnormal Lymphocytes O th er WBC 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 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 2 1 .0 19104 N ucleated Red C e lls Lymphocytes Segmented N eutrophils Bands N onocytes E o sin o p h iIs B aso p h ils Abnormal Lymphocytes O th er 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 18.1 418-028:PAGE K-66 SEX: NALE LABCAT HE4.43 27-JUN-2002 Study Report for Hematology WHITE DIFFERENTIAL DATA 418-028:PAGE K-67 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Animal ID GROUP: 4-M 19118 19133 19141 N u cle a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands H o nocytes E o sin o p h ils B aso p h ils Abnormal Lymphocytes O th er UBC N u cle a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Honocytes E o sin o p h ils B aso p h ils Abnormal Lymphocytes O th er UBC N u c le a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h ils B aso p h iIs Abnormal Lymphocytes O th er UBC TERMINAL CNT ABS 0 78 9.4 12 1 .4 0 0.0 4 O.S 2 0.2 0 0.0 4 0.5 0 0.0 12.0 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 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 SEX: MALE LABCAT HE4.43 27-JUN-20Q2 Study Report for Hematology WHITE DIFFERENTIAL DATA 418-028:PAGE K-68 STUDY ID: ARGUS 4 18-028 STUDY HO: 060-069 Animal ID GROUP: 4-M 19142 19144 19148 N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E osinophils B aso p h iIs Abnormal Lymphocytes O th er WBC N u c le a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E osinophils B aso p h ils Abnormal Lymphocytes O th er WBC N u c le a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h iIs B aso p h ils Abnormal Lymphocytes O th er WBC TERMINAL CNT ABS 0 67 8 .6 22 2 .8 1 0.1 8 1.0 1 0.1 0 0.0 1 0.1 0 0.0 12.8 0 81 1 5 .9 14 2 .7 0 0.0 3 0.6 2 0.4 0 0.0 0 0.0 0 0.0 19.6 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 SEX: MALE LABCAT HE4.43 27-JUN-2002 Study Report for Hematology WHITE DIFFERENTIAL DATA 418-028:PAGE K-69 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Anin a l ID GROUP: 4-H TERMINAL CNT ABS SEX: MALE 19150 19156 N u c le a te d Red C e lls Lynphocytes Segmented N eu tro p h ils Bands M onocytes E o sin o p h ils B asophiIs Abnormal Lymphocytes O ther UBC N u c le a te d Red C e lls Lynphocytes Segmented N eu tro p h iIs Bands M onocytes E o sin o p h iIs B aso p h iIs Abnormal Lynphocytes O th er UBC 0 75 8 .3 22 2 .4 0 0.0 2 0.2 1 0.1 0 0.0 0 0.0 0 0.0 11.1 0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0-- -- 19160 N u c le a te d Red C e lls Lynphocytes Segmented N eu tro p h iIs Bands Monocytes E o sin o p h ils B aso p h ils Abnormal Lynphocytes O th er UBC 0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0-- (-- > - Data U navailable LABCAT HE4.43 27-JUH-2002 418-028:PAGE K-70 Study Report for Hematology WHITE DIFFERENTIAL DATA STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Animal ID GROUP: 4-H 19162 19163 19166 N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h ils B aso p h ils Abnormal Lymphocytes O th er UBC N u cleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E o sin o p h ils B aso p h iIs Abnormal Lymphocytes O th er VffiC N u cle a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h ils B aso p h iIs Abnormal Lymphocytes O th er WBC TERMINAL CNT ABS 0 0-- 0-- 0-- 0-- 0 -0-- 0-- 0-- -- 0 0-- 0-- 0 -0-- 0-- 0-- 0-- 0-- -- 0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0-- SEX: MALE ( -- ) - Data U navailable LABCAT HEA.43 27-JUN-2002 Study Report for Hematology 418-028`.PAGE K-71 WHITE D IF F E R E N T IA L DATA STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 5-M SEX: MALE A n im i ID TERMINAL CNT ABS 19111 N ucleated Red C e lls Lynphocytes Segaented N eu tro p h ils Bands Monocytes E o sin o p h ils B aso p h ils Abnorml Lyaphocytes O ther UBC 0 83 13.0 9 1.4 0 0.0 4 0.6 1 0.2 0 0.0 3 0.5 0 0.0 15.7 19117 19124 N u cleated Red C e lls Lymphocytes Segaented N eu tro p h ils Bands Monocytes E o sin o p h ils B aso p h iIs Abnormal Lymphocytes O ther UBC N u cleated Red C e lls Lyaphocytes Segaented N eu tro p h ils Bands Monocytes E o sin o p h iIs B aso p h iIs Abnorml Lyaphocytes O ther UBC 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 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 S tudy R ep o rt f o r Hem atology WHITE D IFFER E N T IA L DATA STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 5-M SEX: HALE A n im i ID 19126 19127 19128 N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h iIs B aso p h ils Abnormal Lymphocytes O ther WBC N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h iIs B asophils Abnormal Lymphocytes O th er use N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h ils B aso p h ils Abnormal Lymphocytes O th er UBC TERMINAL CNT ABS 0 81 10.1 9 1.1 0 0.0 7 0.9 3 0.4 0 0.0 0 0.0 0 0.0 12.5 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 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 Study Report for Hematology WHITE DIFFERENTIAL DATA 418-028-.PAGE K-73 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Animal ID GROUP: 5-H TERMINAL CNT ABS SEX: MALE 19140 N u c le a te d Red C e lls Lymphocytes Segmented N eutrophils Bands Monocytes E o sin o p h ils B aso p h ils Abnormal Lymphocytes O th er UBC 0 80 12.2 14 2.1 0 0.0 1 0.2 2 0.3 0 0.0 3 0.5 0 0.0 15.2 19145 N u cle a te d Red C e lls Lymphocytes Segmented N eutrophils Bands Monocytes E o sin o p h iIs B aso p h iIs Abnormal Lymphocytes O th er UBC 0 83 17.2 12 2 .5 0 0.0 4 0.8 1 0.2 0 0.0 0 0.0 0 0.0 20.7 19149 N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h ils B aso p h ils Abnormal Lymphocytes O th er UBC 0 88 16.1 12 2 .2 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 18.3 LABCAT HE4.43 27-JUM-2002 S tu d y R ep ort f o r H em atology WHITE DIFFERENTIAL DATA 418-028:PAGE K-74 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Animal ID 19152 19154 19158 N u cle a te d Red C e lls Lymphocytes Segmented N eutrophils Bands Monocytes E o sin o p h ils B aso p h ils Abnormal Lymphocytes O th er UBC N u c le a te d Red C e lls Lymphocytes Segmented N eutrophils Bands Monocytes E o sin o p h iIs B asophiIs Abnormal Lymphocytes O th er UBC N u cle a te d Red C e lls Lymphocytes Segmented N eutrophils Bands Monocytes E o sin o p h ils B aso p h iIs Abnormal Lymphocytes O th er UBC TERMINAL CNT ABS 0 94 13.1 3 0.4 0 0.0 3 0.4 0 0.0 0 0.0 0 0.0 0 0.0 13.9 0 0-- 0 -- 0_ 0-- 0-- 0 --0 -~ 0-- " 0 0-- 0-- 0 --** 0-- 0 0 ---- 0-- 0 -- SEX: HALE (-- ) - Data Unavailable LABCAT HE4.43 2 7 -JUN-2002 418-028:PAGE K-75 Study Report for Hematology WHITE DIFFERENTIAL DATA STUDY ID: ARGUS 418-028 STUDY NO: 060-069 A n ia a l ID GROUP: 5-M TERMINAL CNT ABS SEX: MALE 19168 N u cleated Red C e lls Lymphocytes Segmented N eutrophils Bands Monocytes E o sin o p h ils B aso p h ils Abnormal Lymphocytes O th er UBC 0 0-- 0-- 0-- 0_ 0-- 0~ 0-- 0 __ -- 19169 N u cleated Red C e lls Lymphocytes Segmented N eutrophils Bands Monocytes E o sin o p h iIs B aso p h iIs Abnormal Lymphocytes O th er UBC 0 0 __ 0_ 0-- 0-- 0-- 0-- 0-- 0-- -- 19170 N u cleated Red C e lls Lymphocytes Segmented N eutrophils Bands Monocytes E o sin o p h iIs B aso p h iIs Abnormal Lymphocytes O th er UBC 0 0-- 0-- 0~ 0 -0-- 0-- 0-- 0 -- (-- ) - Data U navailable LABCAT HE4.43 27-JUN-2002 Study Report for Hematology 418-028:PAGE K-76 WHITE D IFFE R E N T IA L DATA STUDY ID: AR6US 418-028 STUDY NO: 060-069 A n im i ID GROUP: 1-F TERMINAL CNT ABS SEX: FEMALE 19010 N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h iIs B aso p h iIs A bnorm l Lymphocytes O ther UBC 0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0-- -- 19012 N u cleated Red C e lls Lyaphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h iIs B aso p h ils Abnormal Lyaphocytes O th er UBC 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 N u cleated Red C e lls Lyaphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h ils B asophils Abnormal Lymphocytes O ther UBC 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 DIFFERENTIA L DATA STUDY ID: ARGUS 418-028 STUDY HO: 060-069 A n im i ID 19021 19023 19041 GROUP: 1-F N u cleated Red C e lls Lymphocytes Segmented N eutrophils Bands Monocytes E o sin o p h ils B aso p h ils Abnormal Lymphocytes O th er UBC N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Nonocytes E o sin o p h ils B aso p h iIs Abnormal Lymphocytes O th er UBC N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Nonocytes E o sin o p h ils B a so p h iIs Abnormal Lymphocytes O th er UBC TERMINAL CNT ABS 0 77 5 .7 19 1.4 0 0.0 0 0.0 4 0.3 0 0.0 0 0.0 0 0.0 7 .4 0 83 6.1 12 0 .9 0 0.0 2 0.1 2 0.1 0 0.0 1 0.1 0 0.0 7 .3 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 SEX: FEMALE LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-78 Study Report for Hematology WHITE D IFFER E N T IA L DATA STUDY ID: ARGUS 418-028 STUDY NO: 060-06 9 GROUP: 1-F SEX: FEMALE A n im i ID TERMINAL CNT ABS 19042 N ucleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands M onocytes E o sin o p h iIs B asophils Abnormal Lymphocytes O th er UBC 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 N u cle a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h iIs B aso p h ils Abnormal Lymphocytes O th er UBC 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 N u c le a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands M onocytes E o sin o p h ils B asophiIs Abnormal Lymphocytes O th er UBC 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 DIFFERENTIA L DATA STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 1-F SEX: FEMALE A n in al ID TERMINAL CNT ABS 19053 N u c le a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands M onocytes E osinophils B asophils Abnormal Lymphocytes O th er UBC 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 N ucleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands M onocytes E osinophils B asophils Abnormal Lymphocytes O ther UBC 0 67 8 .4 30 3 .8 0 0.0 1 0.1 1 0.1 0 0.0 1 0.1 0 0.0 12.5 19068 N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands M onocytes E osinophils B asophils Abnormal Lymphocytes O th er UBC 0 0-- 0-- 0-- 0_ 0-- 0-- 0-- 0-- C-- ) - Bata Unavailable LABCAT HE4.43 27-JUN-2002 418-028:PAGE K-80 Study Report for Hematology WHITS DIFFERENTIAL DATA STUDY ID: ARGUS 418-028 STUDY NO: 060-069 A n im i ID GROUP: 1-F 19072 19074 19075 N u cle a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E osinophils B aso p h ils Abnormal Lymphocytes O th er WBC N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h ils B asophiIs Abnormal Lymphocytes O ther WBC N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h iIs B asophiIs Abnormal Lymphocytes O th er WBC TERMINAL CNT ABS 0 0-- 0-- 0-- 0-- 0_ 0-- 0-- 0-- -- 0 0-- 0-- 0-- 0_ 0-- 0-- 0-- 0-- -- 0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0-- SEX: FEMALE (-- ) - Data U n available LABCAT HE4.43 27-JUN-2002 Study Report for Hematology WHITE DIFFERENTIA L DATA 418-028:PAGE K-81 STUDY ID: ARGUS A18-Q28 STUDY NO: 060-069 A n im i ID GROUP: 2-F TERMINAL CNT ABS SEX: FEMALE 190QA 19009 N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h ils B asophils Abnormal Lymphocytes O ther WBC N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h ils B aso p h ils Abnormal Lymphocytes O th er WBC 0 7A 5 .8 25 2 .0 0 0.0 1 0.1 0 0.0 0 0 .0 0 0.0 0 0.0 7 .8 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 1A.6 19016 N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h ils B aso p h ils Abnormal Lymphocytes O ther 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 HEA.A3 27-JUN-2002 418-028JPAGE K-82 Study Report for Hematology WHITE DIFFERENTIAL DATA STUDY ID: ARGUS 418-028 STUDY NO: 060-069 A n im i ID GROUP: 2-F 19018 19026 19036 N u cleated Red C e lls L ym phocytes Segmented N eu tro p h ils Bands Honocytes E o sin o p h ils B aso p h ils Abnormal Lymphocytes O th er UBC N u cle a te d Red C e lls Lymphocytes Segmented N eutrophils Bands Monocytes EosinopM Is B aso p h ils Abnormal Lymphocytes O th er UBC N u cleated Red C e lls Lymphocytes Segmented N eutrophils Bands Nonocytes E o sin o p h ils B aso p h iIs Abnormal Lymphocytes O th er UBC TERMINAL CNT ABS 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 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 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 SEX: FEMALE LABCAT HE4.43 27-JUN"2002 418-028-.PAGEK-83 Study Report for Hematology WHITE D IFFER E N T IA L DATA STUDY ID: ARGUS 418-028 STUDY NO: 060-069 A n im i ID GROUP: 2-F TERHINAL CNT ABS SEX: FEHALE 19037 190 N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Honocytes E o sin o p h ils Basophi Is A bnorm l Lymphocytes O th er use N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Honocytes E o sin o p h ils B a so p h iIs A bnorm l Lymphocytes O ther WBC 0 42 11 .0 52 1 3 .7 0 0.0 6 1.6 0 0.0 0 0.0 0 0.0 0 0.0 26.3 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 N u cleated Red C e lls Lymphocytes Segmented N eutrophils Bands Honocytes E o sin o p h ils B a so p h iIs A bnorm l Lymphocytes O th er UBC 0 56 6 .2 41 4 .6 0 0.0 2 0.2 1 0.1 0 0.0 0 0.0 0 0.0 11.1 LASCAT HE4.43 27-JUN-2002 Study Report for Hematology 418-028-.PAGEK-84 WHITE D IF F E R E N T IA L DA.T.A. STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Animal ID GROUP: 2-F TERMINAL CNT ABS SEX: FEMALE 19048 19052 19055 N u c le a te d Red C e lls Lyaphocytes Segmented N eu tro p h ils Bands M onocytes E osinophils B aso p h iIs Abnormal Lymphocytes O th er UBC N u c le a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands M onocytes E o sin o p h iIs B asophils Abnormal Lyaphocytes O th er UBC N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands M onocytes E o sin o p h ils B aso p h ils Abnormal Lymphocytes O ther UBC 0 76 5.4 23 1 .6 0 0.0 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 7.1 0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0-- -- 0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0-- -- (-- ) - Data Unavailable LABCAT HE4.43 27-JUN-2002 418-028-.PAGEK-85 Study Report for Hematology WHITE DIFFERENTIAL DATA STUDY ID: ARGUS 418-028 STUDY NO: 060-069 A n iaal ID GROUP: 2-F TERMINAL CNT ABS SEX: FEMALE 19061 N ucleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E osinophils B aso p h iIs Abnormal Lymphocytes O th er UBC 0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0-- -- 19067 N ucleated Red C e lls Lymphocytes Segmented N eutrophils Bands Monocytes E o sin o p h ils B aso p h iIs Abnormal Lymphocytes O th er UBC 0 0-- 0-- 0-- 0 __ 0-- 0-- 0-- 0 -- -- 19071 N u c le a te d Red C e lls Lymphocytes Segmented N eutrophils Bands Monocytes E o sin o p h ils B aso p h ils Abnormal Lymphocytes O th er UBC 0 0-- 0-- 0-- 0-- 0-- 0 '-- 0-- 0 --- (-- j _ Qata Unavailable LABCAT HE4.43 27-JUN-20Q2 Study Report for Hematology WHITE DIFFERENTIAL DATA STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 3-F A n ia a l ID TERMINAL CNT ABS 19003 N u c le a te d Red C e llt Lymphocytes Segmented N eutrophils Bands Monocytes E osinophils B aso p h lIs Abnormal Lymphocytes O ther UBC 0 59 6.5 36 4.0 0 0.0 3 0.3 1 0.1 0 0.0 1 0.1 0 0.0 11.1 19007 N u c le a te d Red C e lls Lymphocytes Segmented N eutrophils Bands M onocytes E osinophils B aso p h lIs Abnormal Lymphocytes O ther UBC 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 N u c le a te d Red C e lls Lymphocytes Segmented N eutrophils Bands M onocytes E osinophils B aso p h lIs Abnormal Lymphocytes O ther UBC 0 72 5.0 27 1.9 0 0.0 0 0.0 0 0.0 0 0.0 1 0.1 0 0.0 7 .0 418-028:PAGE -K-86 SEX: FEMALE LABCAT HE4.43 27-JUN-2002 Study Report for Hematology WHITE DIFFERENTIAL DATA 418-028:PAGE K-87 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Animal ID GROUP: 3-F 19013 19014 19015 N u c le a te d Red C e lls Lymphocytes Segmented NeutrophiLs Bands Monocytes E o sin o p h ils B aso p h iIs Abnormal Lymphocytes O th er WBC N u c le a te d Red C e lls Lymphocytes Segmented N eutrophils Bands Monocytes E o sin o p h ils B aso p h iIs Abnormal Lymphocytes O th er WBC N u c le a te d Red C e lls Lymphocytes Segmented N eutrophils Bands M onocytes E o sin o p h iIs B asophils Abnormal Lymphocytes O th er WBC TERMINAL CNT ABS 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 0 0-- 0-- 0-- 0-- 0_ 0-- 0-- 0-- -- 0 77 5.7 22 1 .6 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 0 0.0 7.4 SEX: FEMALE C-- ) - Data Unavailable LABCAT HE4.43 27-JUN-20Q2 Study Report for Hematology WHITE DIFFERENTIAL DATA 418-028*.PAGE K-88 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 A n im i ID GROUP: 3-F TERMINAL CUT ABS SEX: FEMALE 19017 N u cle a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h ils B asophiIs Abnormal Lymphocytes O th er UBC 0 76 9 .8 20 2.6 0 0.0 1 0.1 3 0.4 0 0.0 0 0.0 0 0.0 12.9 19024 19029 N u c le a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h ils B aso p h ils Abnormal Lymphocytes o th e r UBC N u c le a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h iIs B aso p h iIs Abnormal Lymphocytes O th er UBC 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 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 Study Report for Hematology WHITE DIFFERENTIAL DATA 418-028:PAGE K-89 STUDY ID: ARGUS 418-028 STUDY HO: 060-069 Animal ID GROUP: 3-F TERH1NAL CNT ABS SEX: PENALE 19034 19038 19056 N u c le a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands N onocytes E o sin o p h ils B aso p h iIs Abnormal Lymphocytes O th er UBC N u cle a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands N onocytes E o sin o p h ils B asophils Abnormal Lymphocytes O th er UBC N u c le a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands N onocytes E osinophils B asophils Abnormal Lymphocytes O th er UBC 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 0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0-- -- 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 U navailable LABCAT HE4.43 27-JUN-2002 Study Report for Hematology WHITE DIFFERENTIAL DATA 418-028-.PAGE K-90 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Animal ID GROUP: 3-F 19057 19060 19064 N u c le a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h iIs B aso p h iIs Abnormal Lymphocytes O th er WBC N ucleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands M onocytes E o sin o p h ils B aso p h iIs AbnormaL Lymphocytes O ther WBC N u cleated Red C a lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h ils B aso p h ils Abnormal Lymphocytes O th er U8C TERMINAL c m ABS 0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0-- -- 0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0-- --r 0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0-- SEX: FEMALE (-- ) - Data U navailable LABCAT HE4.43 27-JUN-2002 Study Report for Hematology WHITE DIFFERENTIAL DATA 418-028:PAGE K-91 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Animal ID GROUP: 4-F TERMINAL CNT ABS SEX: FEMALE 19002 N ucleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h iIs B aso p h iIs Abnormal Lymphocytes O th er WBC 0 0-- 0-- 0-- 0 0-- 0-- 0-- 0-- -- 19005 N ucleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands M onocytes E o sin o p h iIs B aso p h ils Abnormal Lymphocytes O ther 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 N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E osinophils B aso p h iIs Abnormal Lymphocytes O th er WBC 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 Study Report for Hematology WHITE DIFFERENTIAL DATA 418-028:PAGE K-92 STUDY ID: ARGUS 418-028 STUDY HO: 060-069 GROUP: 4-F SEX: FEMALE Ani M l ID TERMINAL CNT ABS 19039 N u c le a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands M onocytes E o sin o p h ils B aso p h iIs Abnormal Lymphocytes O th er UBC 0 75 9 .6 22 2 .8 0 0.0 2 0.3 1 0.1 0 0.0 0 0.0 0 0.0 12.8 19040 N u cleated Red C e lls Lymphocytes Segmented N eutrophils Bands M onocytes E o sin o p h ils B aso p h iIs Abnormal Lymphocytes O ther UBC 0 77 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 N u c le a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands M onocytes E o sin o p h iIs B asophils Abnormal Lymphocytes O ther UBC 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 (-- ) - Data Unavailable LABCAT HE4.43 27-JUN-2002 Study Report for Hematology WHITE DIFFERENTIAL DATA 418-028:PAGE K-93 STUDY ID: ARGUS *18-028 STUDY NO: 060-069 Animal ID GROUP: 4-F 19046 19051 19054 N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes Eosirtophi Is B a so p h iIs Abnormal Lymphocytes O th er UBC N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h ils B aso p h ils Abnormal Lymphocytes O ther UBC N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h iIs B a so p h iIs Abnormal Lymphocytes O ther UBC TERMINAL CNT ABS 0 0-- 0 --* 0-- 0-- 0-- 0-- 0 0-- 0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0-- 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 SEX: FEMALE (-- ) - Data Unavailable LABCAT HE4.43 27-JUM-2002 418-028:PAGEK-94 Study Report for Hematology WHITE DIFFERENTIAL DATA STUDY ID: ARGUS 418-028 STUDY NO: 060-0 6 9 GROUP: 4 - F SEX: FERALE Animat. ID TERMINAL CNT ABS 19058 N ucleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h ils B aso p h ils Abnormal Lymphocytes O th er UBC 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 N ucleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h ils B aso p h iIs Abnormal Lymphocytes O th er WBC 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 N ucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E o sin o p h iIs B asophils Abnormal Lymphocytes O th er UBC 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 Study Report for Hematology WHITE DIFFERENTIAL DATA 418-028:PAGE K-95 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Animal ID GROUP: 4-F TERMINAL CNT ABS SEX: FEMALE 19066 19069 N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h ils B aso p h iIs Abnormal Lymphocytes O th er UBC N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h iIs B aso p h iIs Abnormal Lymphocytes O th er UBC 0 84 6 .0 14 1 .0 0 0.0 1 0.1 0 0.0 0 0.0 1 0.1 0 0.0 7.1 0 0 -0-- 0-- 0-- 0-- 0-- 0-- 0-- -- 19073 N u cle a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands Monocytes E o sin o p h ils B aso p h iIs Abnormal Lymphocytes O th er UBC 0 0-- 0-- 0 -0-- 0-- 0-- 0-- 0-- -- (-- > - Data Unavailable LABCAT HE4.43 27-JUN-20Q2 Study Report for Hematology WHITE DIFFERENTIAL DATA 418-028:PAGE K-96 STUDY ID : ARGUS 418-028 STUDY NO: 060-069 A n im i ID GROUP: 5-F TERMINAL CNT ABS SEX: FEMALE 19001 N ucleated Red C e lls ly a p h o c y te s Segmented N e u tro p h ils Bends Monocytes E o sin o p h iIs B asophils A b n o rm l Lymphocytes O ther UBC 0 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 19011 N ucleated Red C e lls Lyaphocytes Segmented N e u tro p h ils Bands Monocytes E osin o p h iIs B asophils A bnorm l Lyaphocytes O ther UBC N ucleated Red C e lls Lyaphocytes Segmented N e u tro p h ils Bands Monocytes E osinophiIs B asophils A bnorm l Lyaphocytes O th e r UBC 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 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 HEA.43 27-JUN-2002 418-028:PAGE K-97 Study Report for Hematology WHITE DIFFERENTIAL DATA STUDY ID: ARGUS 18-028 STU D Y NO: 060-069 Anim al ID GROUP: 5 -F TERMINAL CNT ABS S E X : FERALE 19020 19022 19025 N ucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E osinophiIs B asophils Abnormal Lymphocytes O ther UBC N ucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E o sin o p h ils B a s o p h iIs Abnormal Lymphocytes O th e r UBC N ucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E o sin o p h ils BasophiLs Abnormal Lymphocytes O ther UBC 2 52 2.2 46 1.9 0 0.0 2 0.1 0 0.0 0 0.0 0 0.0 0 0.0 .2 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 . 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 HE.3 27-JUN-20Q2 Study Report for Hematology WHITE DIFFERENTIAL DATA 418-028:PAGE K-98 STUDY ID : ARGUS 418-028 STUDY NO: 060-069 GROUP: 5-F SEX: FEMALE Anistal ID TERMINAL CNT ABS 19027 19028 19030 N ucleated Red C e lls Lyaphocytes Segaented N e u tro p h ils Bands Monocytes E o sin o p h iIs B asophils Abnormal Lyaphocytes O ther UBC N ucleated Red C e lls Lyaphocytes Segaented N e u tro p h ils Bands Monocytes E o sin o p h ils B asophils Abnoraal Lyaphocytes O ther WBC N ucleated Red C e lls Lyaphocytes Segaented N e u tro p h ils Bands Monocytes E o sin o p h ils B asophils Abnoraal Lyaphocytes O ther UBC 0 83 10.2 16 2 .0 0 0 .0 1 0.1 0 0 .0 0 0 .0 0 0 .0 0 0 .0 12.3 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 1 0 .2 0 64 5 .2 34 2 .8 0 0 .0 1 0.1 0 0 .0 0 0 .0 1 0.1 0 0 .0 8 .1 LABCAT HE4.43 27-JUH-2002 Study R ep o rt f o r H em atology 418-028-.PAGE K-99 WHITE D IFFER E N T IA L DATA STUDY ID: ARGUS 418-028 STUDY NO: 060-069 GROUP: 5-F SEX: FEMALE A n i m i ID TERMINAL CNT ABS 19051 19032 19033 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other NBC Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other UBC Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other UBC 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 0 0-- 0-- 0-- 0~ 0-- 0-- 0-- 0-- -- 0 0 __ 0-- 0-- 0-- 0-- 0-- 0 -0-- __ (-- ) - Data Unavailable LABCAT HE4.43 27-JUN-2002 Study Report for Hematology 418-028:PAGE K-100 WHITE D IFF E R E N T IA L DATA STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Animal ID GROUP: 5-F TERMINAL CNT ABS SEX: FEMALE 19049 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophi Is Abnormal Lymphocytes Other WBC 0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0-- -- 19059 19070 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other WBC Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other WBC 0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0-- -- 0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0 -- (-- ) - Data Unavailable U B C A T HE4.43 27-JUN-2002 STUDY ID: ARGUS 418-028 STUDY HO: 060-069 Animal ID TP g/dL GROUP: 1-H 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 19143 19151 19157 19161 19167 5.9 6.5 5.8 6.0 6.2 6.5 6.5 6.1 6.3 7.0 -- -- -- -- -- HEAN SD N 6.3 0.36 10 418-028-.PAGE K-101 Study Report for Clinical Chemistry IN D IV ID U A L ANIMAL REPORT BY GROUP PERIO D : TERMINAL SEX: HALE ALB g/dL 6LU g/dL CHOL g/dL T-BIL g/dL BUN g/dL CREAT g/dL CK U/L 3.9 4.4 4.0 4.1 4.3 4.3 4.2 4.3 4.3 4.7 -- -- -- -- -- 4.3 0.22 10 164 165 119 134 140 169 128 141 140 153 -- -- -- -- 145 16.8 10 46 0.1 62 0.2 61 0.2 44 0.1 62 0.1 56 0.3 59 0.1 51 0.1 56 0.2 72 0.2 ---- ---- -- __ ---- -- 57 0.2 8.3 0.07 10 10 16 0.3 263 19 0.4 164 16 0.3 330 14 0.3 105 15 0.3 177 15 0.4 260 18 0.3 385 15 0.3 250 15 0.3 722 15 0.3 221 ---- _ ---- ---- -- _ ------ ---- -- 16 0.3 288 1.5 0.04 172.6 10 10 10 (-- ) - Data Unavailable LABCAT CC4.43 27-JUN-2002 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 A n i m i ID TP 9/dL GROUP: 2-H 19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 19147 19153 19164 19165 19171 6.1 6.2 5.8 6.1 5.6 6.5 5.7 6.2 6.3 6.1 -- -- -- -- -- HEAN SD N 6.1 0.28 10 418-028:PAGE K -102 Study Report for Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL SEX: HALE ALB g/dL GLU g/dL CHOL g/dL T-BIL g/dL BUN g/dL CREAT g/dL CK U/L 4.1 4.0 3.9 4.1 3.9 4.3 3.9 4.3 4.4 4.2 -- -- -- -- -- 4.1 0.19 10 172 166 152 104 157 115 149 123 108 165 -- _ -- -- -- 141 26.0 10 40 44 38 33 30 28 33 52 60 55 -- -- -- -- -- 41 11.1 10 0.2 0.1 0.1 0.1 0.1 0.2 0.1 0.1 0.2 0.2 -- -- -- -- -- 0.1 0.05 10 16 0.3 169 17 0.3 15 0.3 16 0.3 151 235 307 16 0.3 133 17 0.4 350 17 0.3 292 17 0.3 134 15 0.4 478 16 0.4 213 ---- -- ---- -- ---- -- _ -- -- -- -- .-- 16 0.3 246 0.8 0.05 111.5 10 10 10 (-- ) - Data Unavailable LABCAT CC4.43 27-JUN-20Q2 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 A n ia a l ID TP g /d L GROUP: 3-M 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 19155 19159 19172 19173 19174 6 .2 H 6.1 5 .8 6 .3 6 .3 6 .6 6 .2 5 .7 6 .7 6 .6 -- -- -- -- -- HEAN SD N 6 .3 0 .3 3 10 418-028:PAGE K-103 Study Report for Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL SEX: HALE ALB g /d L GLU g/dL CHOL ng/dL T-B IL g/dL BUN g/dL CREAT g /d L CK U /L 4 .0 H 4 .3 4 .1 4 .3 4 .3 4 .4 4 .4 4.1 4 .4 4 .4 -- -- -- -- -- 4 .3 0 .1 5 10 304 H 254 198 137 142 121 156 149 158 204 -- -- -- -- -- 182 58.2 10 27 H 52 50 46 65 45 46 34 59 35 -- -- -- -- -- 46 1 1 .6 10 0.3 H 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 -- -- -- -- -- 0.1 0 .0 6 10 18 H 16 15 12 16 18 17 17 17 16 -- -- -- -- -- 16 1 .8 10 0 .4 H 0 .3 0 .3 0 .3 0 .3 0 .4 0 .2 0 .3 0 .3 0 .3 ... -- -- 0 .3 0 .0 6 10 129 H 118 132 286 250 289 329 480 200 175 - mmm-. T. i -- 239 112.9 10 (-- ) - Data Unavailable LABCAT CC4.43 H - Heaolyzed 27-JUN-2002 STUDY ID: ARGUS 418-028 STUDY HO: 060-069 Animal ID TP g /d L GROUP: 4-M 19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 19156 19160 19162 19163 19166 6 .0 5 .7 5 .9 6 .0 6 .3 6 .2 6 .6 6 .2 6 .5 6 .4 -- -- -- -- HEAN SD N 6 .2 0 .2 8 10 418-028:PAGE K-104 Study Report for Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL SEX: HALE ALB g /d L GLU g /d L CHOL ag/dL T -B IL ag/dL BUN ag/dL CREAT ag/dL CK U /L 4 .0 4 .0 4.1 4 .2 4 .4 4 .3 4 .4 4 .1 4 .4 4 .4 -- -- -- -- -- 4 .2 0 .1 7 10 175 202 167 131 179 147 132 130 175 181 -- _ -- -- 162 2 5 .2 10 42 28 42 39 49 70 56 29 42 30 -- --- -- 43 13.1 10 0.1 0.1 0.1 0.1 0.1 0 .2 0 .2 0 .1 0.1 0 .2 -- -- -- -- --* 0.1 0.05 10 16 0 .3 20 0 .3 16 0 .3 20 0.4 17 0 .3 16 0 .3 17 0.3 18 0 .3 16 0.3 18 0.3 ---- ---- ---- ---- ---- 111 145 196 187 146 182 270 242 267 218 -- -- -- -- -- 17 0.3 196 1 .6 0.03 53.5 10 10 10 (-- ) - Data Unavailable LABCAT CC4.43 27-JUM-2002 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Anim al ID TP g /d L GROUP: 5-M 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 19154 19158 19168 19169 19170 6 .6 H 6.1 H 6 .6 6 .4 6 .6 6 .5 6 .0 6 .4 6 .3 5 .8 -- -- -- -- -- MEAN SD N 6 .3 0 .2 8 10 418-028:PAGE K -105 Study Report for Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL SEX: HALE ALB g /d L GLU g/dL CHOL g/dL T -B IL g/dL BUN mg/dL CREAT g/dL CK U /L 4 .6 H 4 .3 H 4 .8 4 .6 4 .6 4 .8 4 .3 4 .5 4 .5 4 .2 -- -- -- -- -- 4 .5 0 .2 0 10 173 H 177 H 226 165 156 181 110 134 195 132 -- -- -- -- -- 165 3 3 .7 10 38 H 37 H 25 29 47 35 24 27 38 31 -- -- -- -- -- 33 7 .2 10 0 .2 H 0 .3 H 0.1 0 .1 0 .2 0 .2 0 .2 0 .2 0 .2 0 .2 -- -- -- -- -- 0 .2 0 .0 6 10 26 H 23 H 20 20 22 21 18 19 19 19 -- -- -- -- -- 21 2 .4 10 0 .4 H 0 .3 H 0 .4 0 .3 0 .3 0 .4 0 .3 0 .3 0 .3 0 .3 ___ -- 0 .3 0 .0 5 10 211 H 269 H 94 156 379 472 304 239 175 128 _ _ _--.. -- 243 117.4 10 C-- ) - Data Unavailable LABCAT CC4.43 H - Heaolyzed 27-JUN-2002 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 A nim al ID TP g/dL GROUP: 1-F 19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075 MEAN SD N 5.4 6.3 7.1 6.1 5.9 6.3 6.6 5.8 5.5 5.7 -- -- -- -- 6.1 0.52 10 418-028:PAGE K-106 Study Report for Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD.- TERMINAL SEX: FEMALE ALB g/dL GLU mg/dL CHOL ag/dL T-BIL ag/dL BUN mg/dL CREAT ag/dL CK U/L 3.7 4.3 4.9 4.3 4.3 4.3 4.4 3.9 3.7 3.5 -- -- -- -- 4.1 0.42 10 149 139 157 156 165 155 144 184 108 163 -- -- -- -- 152 19.8 10 63 92 136 85 62 77 93 78 43 40 -- -- -- -- 77 27.8 10 0.2 0.1 0.1 0.2 0.2 0.1 0.3 0.2 0.1 0.1 -- -- _ -- 0.2 0.07 10 32 0.4 166 29 0.3 212 33 0.4 210 26 0.4 222 28 0.3 201 25 0.4 178 27 0.4 332 34 0.3 198 28 0.3 123 19 0.3 175 ---- --_ ---- ------ 28 0.4 202 4.4 0.05 54.1 10 10 10 <-- ) - Data Unavailable LABCAT CCA.43 27-JUN-2002 STUDY 10: ARSUS 418-028 STUDY NO: 060-069 Aniaal ID TP g/dL GROUP: 2-F 19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071 5.9 5.7 5.5 5.6 5.5 5.9 5.0 5.7 4.3 5.9 -- -- -- -- -- MEAN SD N 5.5 0.50 10 418-028:PAGE K-107 Study Report for Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL SEX: FEMALE ALB g/dL GLU mg/dL CHOL ag/dL T-BIL mg/dL BUN ag/dL CREAT ag/dL CK U/L 4.3 3.9 4.2 4.2 3.9 4.2 3.5 3.8 3.3 4.2 -- -- -- -- -- 4.0 0.34 10 178 166 173 152 170 203 153 149 135 142 -- -- -- -- -- 162 20.0 10 56 62 83 77 85 84 54 92 57 73 -- -- -- -- 72 14.0 10 0.2 0.2 0.2 0.2 0.1 0.2 0.2 0.2 0.2 0.2 -- -- -- -- -- 0.2 0.03 10 20 0.3 144 26 0.4 311 26 0.3 237 27 0.4 151 32 0.3 208 22 0.4 228 22 0.3 369 21 0.4 269 16 0.3 392 29 0.4 186 ---- -- ---- -- ------ ------ ---- -- 24 0.4 250 4.7 0.05 85.6 10 10 10 (-- ) - Data Unavailable LABCAT CC4.43. 27-JUN-2002 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Animal ID TP g/dL GROUP: 3-F 19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064 5.6 5.3 5.7 5.8 -- 5.6 5.8 6.7 5.8 6.4 -- 6.1 -- -- -- MEAN SD N 5.9 0.41 10 418-028:PAGE K-108 Study Report for Clinical Chemistry IN D IV ID U A I. ANIMAL REPORT BY GROUP PERIOD: TERMINAL SEX: FERALE ALB g/dL GLU 9/dL CHOL g/dL T-BIL g/dL BUN ag/dL CREAT g/dL CK U/L 3.9 3.8 4.0 4.1 -- 3.7 4.1 4.5 4.0 4.3 -- 4.2 -- -- -- 4.1 0.24 10 179 121 171 146 -- 155 164 140 142 151 -- 179 -- -- -- 155 18.7 10 54 45 56 59 -- 61 87 96 79 105 -- 63 -- --- 71 20.0 10 0.1 0.1 0.1 0.2 -- 0.2 0.2 0.2 0.2 0.1 -- 0.1 -- -- -- 0.2 0.05 10 36 0.3 41 0.3 20 0.3 24 0.4 --_ 28 0.3 22 0.4 33 0.4 26 0.3 23 0.4 ---- 28 0.3 ---- ---- -- -- 28 0.3 6.7 0.05 10 10 199 159 206 160 -- 212 190 215 212 169 -- 197 -- -- -- 192 21.7 10 (-- ) - Data Unavailable LABCAT CC4.43 27-JUH-20Q2 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Animal ID TP g/dL GROUP: 4-F 19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073 6.1 5.7 5.5 5.8 5.6 -- -- 6.3 5.6 6.0 5.2 5.9 -- -- MEAN SD N 5.8 0.32 10 418-028:PAGE K-109 Study Report for Clinical Chemistry IN D IV ID U A L ANIMAL REPORT BY GROUP PERIOD: TERMINAL SEX: FEMALE ALB g/dL _ 4.3 4.0 4.0 3.9 3.7 -- __ 4.5 3.9 4.4 3.6 4.1 -- --- 4.0 0.29 10 GLU g/dL 167 161 163 127 160 -- -- 129 150 127 145 132 -- 146 16.2 10 CHOL g/dL 70 47 71 63 91 -- -- 41 64 49 62 63 -- -- 62 14.2 10 T-BIL 9/dL 0.2 0.1 0.2 0.1 0.2 -- -- 0.1 0.1 0.1 0.1 0.1 -- -- 0.1 0.05 10 BUN mg/dL 30 27 26 20 25 -- -- 25 20 34 23 22 -- -- 25 4.4 10 CREAT mg/dL 0.4 0.4 0.4 0.3 0.5 -- -- 0.4 0.3 0.3 0.4 0.2 -- -- 0.4 0.08 10 CK U/L 259 193 160 233 398 -- -- 124 267 176 172 147 -- -- 213 80.4 10 (-- ) - Data Unavailable LABCAT CC4.43 27-JUN-2002 STUDY ID: ARGUS 418-028 STUDY MO: 060-069 Aniaal ID TP g/dL GROUP: 5-F 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070 MEAN SD N 5.5 5.7 5.8 5.6 5.8 5.8 5.5 5.9 6.3 6.3 -- -- -- -- -- 5.8 0.29 10 418-028:PAGE K -l 10 Study Report for Clinical Chemistry IN D IV ID U A L ANIMAL REPORT BY GROUP PERIO D : TERMINAL SEX: FEMALE ALB g/dL 4.0 4.0 4.3 3.5 4.1 3.7 3.8 4.0 4.5 4.4 -- -- -- -- -- 4.0 0.31 10 GLU ag/dL 165 119 154 53 132 133 152 159 180 157 -- -- -- -- 140 35.5 10 CHOL ng/dL 55 58 48 33 60 49 71 70 58 108 --- -- -- ---- 61 19.8 10 T-BIL ag/dL 0.1 0.1 0.1 0.2 0.1 0.1 0.1 0.2 0.1 0.2 -- -- -- -- -- 0.1 0.05 10 BUN ag/dL 23 19 29 73 25 28 27 23 26 25 -- -- -- -- -- 30 15.4 10 CREAT ag/dL 0.3 0.3 0.4 0.2 0.3 0.4 0.3 0.3 0.3 0.3 -- -- -- -- -- 0.3 0.06 10 CK U/L 341 373 149 438 186 143 252 261 168 210 -- -- -- -- 252 101.6 10 (-- ) - Data Unavailable LABCAT CC4.43 27-JUN-20Q2 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Anial ID ALT U/L GROUP: 1-H 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 19143 19151 19157 19161 19167 36 38 40 33 51 49 39 42 49 43 -- -- -- -- -- MEAN SD N 42 6.0 10 418-028:PAGE K>111 Study Report for Clinical Chemistry IN D IV ID U A L ANIMAL REPORT BY GROUP PERIO D : TERMINAL SEX: MALE AST U/L 78 77 93 83 86 113 116 80 146 85 --- -- -- -- . 96 22.4 10 ALP U/L 91 77 102 112 103 115 107 98 126 119 -- -- -- -- 105 14.3 10 CA g/dL 10.6 11.8 10.3 10.8 11.3 10.6 11.1 11.1 10.4 11.4 --- -- -- 10.9 0.48 10 PHOS g/dL 12.0 11.6 9.7 7.9 9.4 8.7 7.9 9.8 8.5 9.2 -- -- -- -- -- 9.5 1.40 10 TRIG ng/dL 23 48 59 43 28 65 93 45 36 76 -- -- -- -- -- 52 21.8 10 NA mol/L 143 146 145 147 146 145 146 146 147 148 -- -- -- -- -- 146 1.4 10 K Wol/L 10.3 10.5 6.6 4.6 5.9 5.5 4.9 6.2 5.7 5.5 -- -- -- -- -- 6.6 2.10 10 (-- ) - Data Unavailable LABCAT CC4.43 27-JUN-2002 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Animal ID ALT U/L GROUP: 2-N 19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 19147 19153 19164 19165 19171 37 38 37 57 40 46 48 34 261 33 -- -- -- '-- -- MEAN SD N 63 69.9 10 418-028:PAGE K -l 12 Study Report for Clinical Chemistry IN D IV ID U A L ANIMAL REPORT BY GROUP PERIO D : TERMINAL SEX; MALE AST U/L 84 77 81 116 91 111 104 80 382 87 -- -- -- -- -- 121 92.6 10 ALP U/L 101 70 99 141 130 91 99 88 199 95 -- -- --- 111 36.9 10 CA mg/dL 10.5 11.6 10.3 10.3 11.2 10.7 10.6 10.7 10.3 11.1 -- -- -- -- -- 10.7 0.44 10 PHOS mg/dL 10.3 12.0 9.1 8.9 8.9 9.3 9.3 8.8 7.8 9.3 -- -- -- -- -- 9.4 1.11 10 TRIG mg/dL 26 60 62 44 43 29 27 78 57 43 -- -- -- -- -- 47 17.2 10 NA mmol/L 145 144 145 146 147 146 145 144 147 148 -- -- _ -- -- 146 1.3 10 K mmol/L 6.8 8.0 6.0 5.4 5.2 5.5 6.2 6.9 5.5 5.5 -- -- -- -- -- 6.1 0.89 10 (-- ) - Data Unavailable LABCAT CC4.43 27-JUN-2002 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 A n i al ID ALT U/L GROUP: 3-H 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 19155 19159 19172 19173 19174 60 H 35 35 45 141 42 101 55 44 42 -- -- -- -- -- MEAN SD N 60 34.4 10 418-028:PAGE K -l 13 Study Report for Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL SEX: HALE AST ALP CA PHOS TRIG NA K U/L U/L ag/dL *g/dL ag/dL aaol/L aw l/L 124 H 70 82 99 197 92 171 140 102 94 -- -- -- -- -- 117 4 0 .9 10 101 H 107 97 92 108 88 80 124 108 96 --- -- -- -- 100 12.4 10 11.5 H 11.5 11.5 10.2 10.8 10.7 11.2 10.7 11.3 11.3 -- -- -- -- -- 11.1 0.44 10 10.4 H 9.5 15.6 8.8 9 .9 9 .0 9 .4 9 .4 8 .3 8 .8 -- -- -- -- -- 9 .9 2 .0 9 10 20 H 56 34 51 35 56 21 34 22 35 -- -- -- -- -- 36 13.8 10 143 H 147 148 147 145 147 146 148 146 148 -- -- -- -- -- 147 1.6 10 8.9 H 5 .6 8 .4 6.5 7 .0 5.5 6.1 5 .4 5 .7 5 .4 -- -- -- 6 .5 1.27 10 (-- ) - Data Unavailable LABCAT CC4.43 H - Hcmolyzad 27-JUN-2002 418-028:PAGE K -l 14 Study Report for Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-069 SEX: HALE A n ia a l ID ALT U/L GROUP: 4-tt 19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 19156 19160 19162 19163 19166 51 37 50 439 54 46 45 48 138 46 -- -- -- -- -- MEAN SD N 95 124.1 10 AST U/L 91 83 107 887 106 91 108 119 277 107 -- -- -- -- -- 198 248.7 10 ALP U/L 122 76 98 154 152 93 98 124 112 123 -- -- -- -- -- 115 25.1 10 CA ag/dL 10.9 11.0 11.5 10.8 11.7 10.7 10.7 11.2 11.2 11.3 -- -- -- -- -- 11.1 0 .3 4 10 PHOS ag/dL 8.3 13.3 8 .6 9.8 9.3 10.7 8 .8 9 .8 9.2 9.3 _ -- -- -- -- 9 .7 1.43 10 TRIG ag/dL 14 19 35 23 32 113 35 30 28 32 -- -- -- -- -- 36 27.9 10 NA aaol/L 146 147 148 148 147 145 148 147 147 146 -- -- -- -- -- 147 1.0 10 K a a o l/L 5.5 6 .6 5 .6 6 .9 5.3 6 .4 5.3 5.5 6.1 6.5 Ml _ -- -- -- 6 .0 0 .6 0 10 (-- ) - Data Unavailable LABCAT C M . 43 27-JUN-2002 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 A n iaal ID ALT U/L GROUP: 5-N 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 19154 19158 19168 19169 19170 38 H 49 H 33 52 49 50 40 54 40 42 -- -- --- -- MEAN SD N 45 7 .0 10 418-028:PAGE K -l 15 Study Report for Clinical Chemistry IN D IV ID U A L ANIMAL REPORT BY GROUP PE R IO D : TERMINAL SEX: MALE AST ALP CA PHOS TRIG NA K U/L U/L g/dL ag/dL g/dL K .I/L m ol/L 86 H 114 H 76 88 104 112 95 125 87 87 -- -- -- -- --1 97 15.6 10 115 H 153 H 204 159 182 S3 169 137 140 99 -- -- --* -- 144 37.5 10 11.7 H 11.0 H 11.9 11.3 11.8 11.6 10.9 11.3 12.0 11.8 -- -- -- -- 11.5 0.38 10 12.9 H 9.2 H 9 .8 9.6 11.1 8 .4 9 .0 10.8 10.2 11.3 -- -- -- -- 10.2 1.33 10 7H 18 H 2 17 21 17 23 16 16 31 -- -- -- -- -- 17 8 .0 10 142 H 144 H 147 146 147 148 148 143 147 148 -- -- _ -- -- 146 2 .2 10 10.7 H 6.6 M 5.5 6 .8 7.1 6 .0 5.5 7 .9 7.1 5 .8 -- -- -- -- -- 6 .9 1.55 10 C-- > - Data UrtavailabLe LABCAT CCA.43 H - Heaolyzed 27-JUN-20Q2 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Aniaal ID ALT U/L 6R0UP: 1-F 19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075 144 136 177 115 142 104 153 156 87 80 -- -- -- -- MEAN SD N 129 31.7 10 418-028:PAGE K -l 16 Study Report for Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL SEX: FEMALE AST ALP CA PHOS TRIG NA K U/L U/L ag/dL ag/dL ag/dL amol/L anol/L 123 182 167 114 154 121 149 157 123 133 -- -- -- -- 142 22.8 10 217 77 345 89 171 82 100 202 92 73 -- -- -- -- 145 88.7 10 10.5 10.9 11.8 10.3 9.9 10.2 11.7 10.5 9.6 10.1 -- -- -- 10.6 0.72 10 6.8 11.4 8.3 8.6 9.2 8.7 8.3 10.4 7.6 8.2 -- -- -- -- 8.8 1.33 10 70 65 47 91 46 44 70 51 40 20 _ -- -- -- 54 19.9 10 143 6.0 142 5.8 159 5.4 140 5.5 140 6.2 138 5.7 149 4.8 140 7.4 140 5.7 143 5.6 ---- ---- ---- ---- 143 5.8 6.3 0.67 10 10 (-- ) - Data Unavailable LABCAT CC4.43 27-JUN-2002 STUDY ID: ARGUS 41&-028 STUDY NO: 060-069 Animal ID ALT U/L GROUP: 2-F 19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071 MEAN SD N 97 116 150 136 145 176 115 150 117 132 --- -- -- -- 133 23.0 10 418-028:PAGE K>-117 Study Report for Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL SEX: FEMALE AST ALP CA PHOS TRIG NA K U/L U/L ag/dL ag/dL ag/dL aaol/L amol/L 133 110 141 102 142 125 181 139 131 147 -- -- -- -- -- 135 21.6 10 80 193 242 240 183 200 48 252 46 102 -- -- -- -- "* 159 81.7 10 11.3 11.7 11.6 11.6 10.7 11.9 10.9 11.5 10.0 10.4 *-----1 -- ---- 11.2 0.63 10 8.4 7.6 7.8 6.7 9.6 8.5 5.3 8.3 5.3 11.8 -- 7.9 1.94 10 45 60 68 45 45 47 43 55 55 32 --- -- 50 10.2 10 139 5.3 144 5.9 147 5.4 144 5.0 141 5.0 145 5.4 143 5.2 142 6.1 142 5.6 140 6.9 -- 143 5.6 2.4 0.58 10 10 (-- ) - Data Unavailable LABCAT CC4.43 27-JUN-20Q2 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 Animal ID ALT U/L GROUP: 3-F 19003 19007 19008 19013 19014 19015 19017 19024 19029 19Q34 19038 19056 19057 19060 19064 182 90 107 137 -- 178 166 121 189 124 -- 130 -- -- -- MEAN SD N 142 34.2 10 418-028:PAGE K-118 Study Report for Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL SEX; FEMALE AST U/L 134 113 143 125 -137 153 139 151 140 __ 133 __ -- --1 137 11.8 10 ALP U/L 101 60 64 154 -- 97 418 60 190 108 -- 111 -- -- 136 107.3 10 CA g/dL 9.6 9.3 9.7 10.6 -- 9.3 11.3 11.3 11.5 11.0 -- 10.7 -- -- -- 10.4 0.87 10 PHOS mg/dL 9.7 9.2 7.3 5.6 _ 14.3 5.9 11.5 6.1 10.5 -- 9.9 -- -- -- 9.0 2.80 10 TRIG mg/dL 26 17 28 65 -- 116 33 46 53 72 -- 34 -- -- -- 49 29.4 10 HA maol/L 142 139 139 144 -- 141 145 142 147 141 __ 142 ---- 142 2.5 10 K maol/L 5.5 5.8 5.7 5.4 __ 4.9 5.4 6.0 5.4 5.5 5.9 -- -- -- 5.6 0.32 10 <-- ) - Data Unavailable LABCAT CC4.43 27-JUN-2002 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 AnInal ID ALT U/L GROUP: 4-F 19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073 MEAN SD N 134 115 174 134 157 -- -- 94 124 98 119 116 -- -- 127 24.7 10 418-028:PAGE K-119 Study Report for Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL SEX: FEMALE AST ALP CA PHOS TRIG NA K U/L U/L ng/dt g/dL ng/dL aol/L mol/L 127 128 125 132 149 -- -- 107 117 129 114 112 -- 124 12.1 10 108 107 228 90 432 -- -- 70 171 102 388 88 -- 178 131.0 10 10.6 10.0 11.0 9.7 11.1 -- _ 10.0 10.7 10.3 10.7 10.3 -- 10.4 0.46 10 9.6 9.2 4.4 10.8 8.6 -- -- 10.1 5.4 10.7 5.0 13.2 -- 8.7 2.88 10 49 67 62 77 55 -- __ 28 30 18 34 33 -- 45 19.5 10 142 6.2 142 5.5 147 5.8 138 7.0 145 5.9 ---- ---- 139 6.5 142 5.3 144 7.1 143 5.1 142 6.6 ---- """ 142 6.1 2.6 0.70 10 10 (-- ) - Data Unavailable LABCAT CC4.43 27-JUN-2002 STUDY ID: ARGUS 418-028 STUDY MO: 060-069 A n iaal ID ALT U/L GROUP: 5-F 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070 MEAN SD N 116 160 132 151 143 113 149 179 156 148 -- -- -- -- -- 145 20.0 10 418-028:PAGE K-120 Study Report for Clinical Chemistry IN D IV ID U A L ANIMAL REPORT BY GROUP PERIO D : TERMINAL SEX: FEMALE AST ALP CA PHOS TRIG NA tc U/L U/L g/dL ag/dL g/dL M l/L NOl/L 133 149 131 263 167 141 138 127 177 138 -- -- -- -- 156 40.7 10 135 71 131 138 101 142 58 122 171 211 -- -- -- -- 128 44.7 10 10.1 10.1 10.3 9 .8 10.3 9 .6 9 .6 12.0 10.9 11.6 -- -- -- -- 10.4 0.82 10 10.7 9.0 8.2 13.7 10.0 9 .4 10.6 9 .2 11.6 8 .6 -- -- -- 10.1 1.64 10 37 49 53 7 38 30 44 45 77 57 -- -- -- ~ 44 18.3 10 141 6 .8 138 6 .8 142 5.2 143 6 .9 145 6 .4 142 5 .4 141 7 .6 147 5.1 139 6 .3 143 5.1 --_ ---- ---- ---- . --* 142 6 .2 2 .6 0.90 10 10 <-- ) - Data Unavailable LABCAT CC4.43 27-JUN-2002 STUDY ID: ARGUS 4 18-028 STUDY NO: 060-069 418-028:PAGE K-121 Study Report for Clinical Chemistry IN D IV ID U A L ANIMAL REPORT BY GROUP PER IO D : TERMINAL SEX: HALE A nial ID CL ol/L GROUP: 1-H 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 19143 19151 19157 19161 19167 103 100 98 100 97 96 98 99 98 93 -- -- _ -- -- MEAN SD N 98 2 .7 10 GLOB g/dL 2.0 2.1 1.8 1.9 1.9 2 .2 2.3 1.8 2 .0 2.3 -- -- __ -- -- 2 .0 0.19 10 A/6 none 2 .0 2.1 2.2 2.2 2 .3 2 .0 1.8 2 .4 2.2 2 .0 -- -- -- -- -- 2.1 0.18 10 <-- ) - Data Unavailable LABCAT CC4.43 27-JUN-2002 STUDY ID: ARGUS 418-028 STUDY HO: 060-069 418-028:PAGE K-122 Study Report for Clinical Chemistry IN D IV ID U A L ANIMAL REPORT BY GROUP PERIOD: TERMINAL SEX: HALE A n ia a l ID CL m ol/L GROUP: 2-H 19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 19147 19153 19164 19165 19171 98 99 101 101 98 96 99 99 99 98 -- -- -- __ -- HEAN SD N 99 1 .5 10 GLOB 9/61 2 .0 2.2 1.9 2 .0 1.7 2 .2 1 .8 1.9 1.9 1 .9 -- -- -- -- --1 2 .0 0.16 10 A/G none 2.1 1.8 2.1 2.1 2.3 2.0 2.2 2 .3 2.3 2.2 _ -- -- -- -- 2.1 0 .1 6 10 (-- > - Data Unavailable LABCAT CC4.43 27-JUN-2002 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 418-028-.PA G EK 423 Study Report for Clinical Chemistry IN D IV ID U A L ANIMAL REPORT BY GROUP PE R IO D : TERMINAL SEX: MALE A n im i ID CL m ol/L GROUP: 3-M 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 19155 19159 19172 19173 19174 101 H 96 105 100 99 99 100 100 98 99 -- -- -- ~ -- MEAN SD N 100 2 .3 10 6L0B g/tJL 2.2 H 1 .8 1.7 2 .0 2 .0 2 .2 1 .8 1 .6 2 .3 2 .2 __ -- _ -- -- 2 .0 0.24 10 A/G none 1.8 H 2 .4 2 .4 2 .2 2 .2 2 .0 2 .4 2 .6 1 .9 2 .0 -- -- -- -- -- 2 .2 0.26 10 (-- > - Data Unavailable LABCAT CC4.43 H - Hemolyzed 27-JUN-20Q2 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 418-028:PAGE K-124 Study Report for Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL SEX: HALE Animal ID CL mmol/L GROUP: 4-H 19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 19156 19160 19162 19163 19166 104 104 100 103 98 99 96 99 98 99 -- -- -- -- -- HEAN SD N 100 2.7 10 GLOB 9/dL 2 .0 1.7 1 .8 1 .8 1 .9 1.9 2 .2 2.1 2.1 2 .0 --- -- -- -- 2 .0 0.16 10 A/6 none 2 .0 2 .4 2.3 2.3 2 .3 2.3 2.0 2 .0 2.1 2.2 -- _ _ -- 2 .2 0.15 10 (-- > - Data Unavailable LABCAT CCA.43 27-JUH-2002 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 418-028:PAGE K-125 Study Report for Clinical Chemistry IN D IV ID U A L ANIMAL REPORT BY GROUP P E R IO D : TERMINAL SEX: HALE A n ia a l ID CL naol/L GROUP: 5-H 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 19154 19158 19168 19169 19170 101 H 101 H 99 100 101 98 101 98 100 99 -- -- -- -- -- MEAN SD N 100 1.2 10 GLOB fl/dL 2.0 H 1.8 H 1.8 1.8 2.0 1.7 1.7 1.9 1.8 1.6 -- -- -- -- -- 1.8 0.13 10 A/G none 2.3 H 2.4 H 2 .7 2 .6 2 .3 2 .8 2.5 2 .4 2.5 2 .6 -- -- -- -- -- 2.5 0.17 10 (-- ) - Data Unavailable LABCAT CC4.43 H - Heaolyzed 27-JUN-2002 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 418-028:PAGE K-126 Study Report for Clinical Chemistry IN D IV ID U A L ANIMAL REPORT BY GROUP PE R IO D : TERMINAL SEX: FEMALE A n im l ID CL M M l/L GROUP: 1-F 19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075 -- 96 92 100 91 93 92 96 99 99 98 -- -- -- -- MEAN SD N 96 3 .4 10 GLOB fl/dL -- 1.7 2 .0 2 .2 1.8 1.6 2 .0 2.2 1.9 1.8 2.2 -- -- -- -- 1 .9 0.22 10 A/G none -- 2 .2 2.2 2 .2 2 .4 2 .7 2 .2 2.0 2.1 2.1 1.6 -- -- -- -- 2.2 0.28 10 (-- ) - Data Unavailable LABCAT CC4.43 27-JUN-20Q2 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 418-028-.PAGEK-127 Study Report for Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL SEX: FEMALE Anin a l ID CL m ol/L GROUP: 2-F 19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071 89 93 98 97 94 95 96 91 93 95 -- -- -- -- -- MEAN SD N 94 2 .7 10 GLOB g/dL 1 .6 1.8 1 .3 1 .4 1 .6 1 .7 1.5 1 .9 1 .0 1 .7 _ -- -- -- -- 1 .6 0.26 10 A/G none 2.7 2.2 3 .2 3 .0 2 .4 2.5 2 .3 2 .0 3 .3 2.5 -- -- -- -- -- 2 .6 0.43 10 (-- ) - Data Unavailable LABCAT CCA.43 Z7-JUN-2002 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 418-028:PAGE K-128 Study Report for Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL SEX: FEMALE A n iaal ID CL GROUP: 3-F 19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064 MEAN SD N 92 97 96 97 -- 92 99 94 101 88 -- 93 -- _ --" 95 3 .8 10 GLOB g/dL 1.7 1.5 1 .7 1.7 -- 1.9 1 .7 2 .2 1 .8 2.1 -- 1 .9 -- -- -- 1 .8 0.21 10 A/e none 2 .3 2.5 2 .4 2 .4 -- 1.9 2 .4 2 .0 2 .2 2 .0 -- 2 .2 -- -- -- 2 .2 0.21 10 (-- ) - Data Unavailable LABCAT CC4.43 27-JUW-2002 STUDY ID: ARGUS 418-028 STUDY HO: 060-069 418-028:PAGE K 429 Study Report for Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL SEX: FEMALE Animal ID CL maol/L GROUP: 4-F 19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073 90 96 101 91 97 -- -- 94 97 98 97 93 -- -- MEAN SD H 95 3.4 10 GLOB g/dL 1 .8 1 .7 1.5 1 .9 1 .9 -- -- 1 .8 1 .7 1.6 1 .6 1 .8 -- -- 1 .7 0.13 10 A/G none 2 .4 2 .4 2 .7 2.1 1 .9 -- -- 2.5 2.3 2 .8 2.3 2.3 __ -- 2 .4 0.26 10 C-- ) - Data Unavailable LABCAT CC4.43 27-JUN-2002 STUDY ID: AR6US *18-028 STUDY NO: 060-069 418-028:PAGE K-130 Study Report for Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL SEX: FEMALE A n ia a l ID CL -P l/L GROUP: 5-F 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070 91 93 92 91 100 94 96 95 95 89 -- -- -- -- MEAN SD N 94 3.1 10 GLOB g/dL 1.5 1.7 1.5 2.1 1.7 2.1 1.7 1 .9 1 .8 1 .9 -- -- -- -- -- 1.8 0.21 10 A/G none 2 .7 2 .4 2 .9 1.7 2 .4 1 .8 2.2 2.1 2.5 2 .3 -- -- -- -- -- 2.3 0.37 10 (-- > - Data Unavailable LABCAT CCA.A3 27-JUN-2002 418-028:PAGE K-131 Study Report for Clinical Chemistry SUMMARY REPORT PERIOD: TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOMED BY DUNNETT'S PROCEDURE SEX: HALE TEST(s): UNITS: Group: 1-M MEAN SD N Group: 2-M HEAN SD N Group: 3-M MEAN SD N Group: 4-H MEAN SD N Group: 5-H MEAN SD N TP g/dL 6.3 0.36 10 6.1 0.28 10 6 .3 0.33 10 6 .2 0.28 10 6.3 0.28 10 ALB GLU CHOL T-BIL BUN CREAT CK ALT g/dL g/dL g/dL g/dL g/dL g/dL U/L U/L 4 .3 0.22 10 145 16.8 10 57 0 .2 8.3 0.07 10 10 16 0 .3 288 1.5 0.04 172.6 10 10 10 42 6 .0 10 4.1 0.19 10 141 26.0 10 41** 11.1 10 0.1 0.05 10 16 0 .3 246 63 0 .8 0.05 111.5 6 9 .9 10 10 10 10 4 .3 0.15 10 182 58.2 10 46 11.6 10 0.1 0.06 10 16 0 .3 239 60 1 .8 0.06 112.9 3 4 .4 10 10 10 10 4 .2 0.17 10 162 25.2 10 43* 13.1 10 0.1 0.05 10 17 0 .3 196 95 1 .6 0.03 53.5 124.1 10 10 10 10 4.5** 0.20 10 165 33.7 10 33** 7.2 10 0.2 0.06 10 21** 2 .4 10 0 .3 0.05 10 243 117.4 10 45 7 .0 10 -Significant Difference froe control P < .05 LABCAT CC4.43 **-Significant Difference fro 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 STUDY N0: 060-069 ANALYSIS 0F VARIANCE F0LL0UED BY DUNNETT'S PROCEDURE SEX: ALE TEST(s): UNITS: Group: 1-H MEAN SD N Group: 2-H MEAN SD N Group: 3-M MEAN SD N Group: 4-M MEAN SD N Group: 5-M MEAN SD N AST U/L 96 22.4 10 121 92.6 10 117 4 0 .9 10 198 248.7 10 97 15.6 10 ALP CA PHOS TRI6 NA K CL U/L g/dL g/dL g/dL m o I/L naol/L nol/L 105 14.3 10 10.9 0.48 10 9.5 1.40 10 52 21.8 10 146 6 .6 1 .4 2.10 10 10 98 2 .7 10 111 36.9 10 10.7 0.44 10 9 .4 1.11 10 47 17.2 10 146 6.1 1.3 0.89 10 10 99 1.5 10 100 12.4 10 11.1 0.44 10 9 .9 2 .0 9 10 36 13.8 10 147 6.5 1.6 1.27 10 10 100 2 .3 10 115 25.1 10 11.1 0.34 10 9 .7 1.43 10 36 27.9 10 147 6.0 1.0 0.60 10 10 100 2 .7 10 144** 37.5 10 11.5** 0.38 10 10.2 1.33 10 17** 8 .0 10 146 2 .2 10 6.9 1.55 10 100 1.2 10 GLOB g/dL 2 .0 0 .1 9 10 2 .0 0 .1 6 10 2 .0 0 .2 4 10 2 .0 0.16 10 1 .8 0.13 10 **-Signifleant Difference froa Control P < .01 LABCAT CC4.43 27-JUN-20Q2 STUDY ID: ARGUS 41B-028 STUDY NO: 060-069 418-028:PAGE K-133 Study Report for Clinical Chemistry SUMMARY REPORT PERIOD: TERMINAL s EX: HALE ANALYSIS OF VARIANCE FOLLOWED BY DUHNETT'S PROCEDURE TEST(s): UNITS: A/G none Group: 1-H HEAN SD N 2.1 0.18 10 Group: 2-H HEAN SD N 2.1 0.16 10 Group: 3-H HEAN SD N Group: 4-H HEAN SD N 2.2 0.26 10 2.2 0.15 10 Group: 5-H HEAN SD N 2.5** 0.17 10 -Significant Difference froa 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 STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOUED BY DUNNETT'S PROCEDURE Total Protein Group N Total Mean S td . DUNNETT'S Dev. ' t ' DUNNETT'S RANGES LO -95X - HI L0 -99X - HI Degree S ource Fda 1-H 10 6 2 .8 6 .3 0 .3 6 TREATMENTS 4 2-M 10 6 0.6 6.1 0.28 1.60 5.9 6.6 5.9 6.7 ERROR 45 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 5 --M 10 63.3 6.3 0.28 0.36 5.9 6.6 5.9 6.7 F R atio = C oeff. Var. X - 1.16 4.948 r ta b le values D u n n e tt's 11r 1 t a b l e v a lu e s F.01 P.01 = 3.78 3.12 F.05 P.05 = 2 .5 8 2.51 Albumin SEX: MALE Sum o f Squares 0 .4 4 4 .2 6 4 .7 0 Mean Square 0.11 0 .0 9 1-M 10 4 2 .5 4 .3 0 .2 2 2-H 10 41.1 4.1 0.19 1.66 4 .0 4.5 3-M 10 42.7 4 .3 0.15 0.24 4.0 4.5 4-M 10 42.3 4.2 0.17 0.24 4 .0 4.5 5-M 10 45.2 4.5 0.20 3.21 4 .0 4.5* F R atio * Coeff., Var. X = 6.35 4.399 F' ta b le values D u n n e tt's 'T* t a b l e v a lu e s F.01 P.01 * Glucose 1-M 10 1453 145 1 6 .8 2-M 10 1411 141 2 6 .0 0 .2 7 106 185 3-M 10 1823 182 58.2 2.37 106 185 4-M 10 1619 162 25 .2 1.06 106 185 5-M 10 1649 165 3 3 .7 1.25 106 185 F Ratio = Coeff . Var. X = 2.24 21.988 F' t a b l e v a lu e s D u n n e tt's 1T* t a b l e v a lu e s F.01 = P.01 = TREATMENTS 4 4.0 4.5 ERROR 45 4 .0 4 . 5 -- 4.0 4.5 TOTAL 49 4.0 4.5* 3.78 3.12 F.05 P.05 2.58 2.51 TREATMENTS 4 96 194 ERROR 45 96 1 9 4 -- 96 194 TOTAL 49 96 194 3.78 3.12 F.05 = P.05 = 2.58 2.51 0 .9 0 1.59 2 .4 9 10942 55071 66013 0 .2 2 0 .0 4 2735 1224 -Significant Difference from Control P < .05 -Significant Difference froa Control P < .01 Error-within groups LABCAT CC4.43 Source-Source of Variation Treataents-betveen groups 27-JUN-2002 418-028:PAGE K-135 Study Report for Clinical Chemistry SUMMARY RSPORT PERIOD: TERMINAL STUDY ID: ARGUS 4 18-028 STUDY NO: 060-069 ANALYSIS OF VARIANCE F0U.0WED BY DUNNETT'S PROCEDURE SEX: HALE Cholesterol Group N T otal Mean S td . DUNNETT' S Dev. * f DUNNETT'S RANGES LO -95X - HI L0 -99X - HI Degree S o u rce Fdn Sua of Squares Mean Square 1-H 10 569 57 8 .3 TREATMENTS 4 2978.08 744.52 2-H 10 413 41 11.1 3 .3 2 45 69* 42 72** ERROR 45 4954.90 110.11 3-M 10 459 46 11.6 2.34 45 69 42 7 2 ------------------------------ 4-N 10 427 43 13.1 3.03 45 69* 42 72 TOTAL 49 7932.98 5-N 10 331 33 7.2 5.07 45 69* 42 72** F R atio = C oeff. Var. X * 6 .7 6 23.859 ' F* t a b l e v a lu e s D unnett's 'T ' ta b le values Total Bilirubin F.01 * P.01 * 3.78 3.12 F.0S = P.05 * 2 .5 8 2.51 1-M 10 1 .6 0 .2 0 .0 7 2-H 10 1.4 0.1 0.05 0.76 0.1 0.2 3-M 10 1 .2 0.1 0.06 1.53 0.1 0.2 4-M 10 1 .3 0.1 0.05 1.15 0.1 0 .2 5-M 10 1 .9 0 .2 0.06 1.15 0.1 0 .2 F R atio = Coeff.. Var. X 2.25 39.527 ' F' t a b l e v a lu e s D unnett's ' T' ta b le values F.01 * P.01 * Blood Urea Nitrogen TREATMENTS 4 0.031 0.1 0 .2 ERROR 45 0.154 0 .1 0 .2 ------------------------------ 0.1 0.2 TOTAL 49 0.185 0.1 0.2 3.78 3.12 F.05 P.05 * 2.58 2.51 .008 0.003 1-M 10 2-H 10 3-M 10 4-M 10 5-M 10 F R atio = Coeff. Var. X = 158 16 1.5 162 16 0 .8 0.53 162 16 1.8 0.53 174 17 1.6 2.11 207 21 2 .4 6 .4 6 14 18 14 18 14 18 14 18* 14.12 9.821 'F' ta b le values D u n n ett's 'T' ta b le values F.01 = P.01 = TREATMENTS 4 13 18 ERROR 45 13 18 ----- 13 18 TOTAL 49 13 18** 3.78 3.12 F.05 = P.05 = 2 .5 8 2.51 162.32 129.30 291.62 40.58 2 .8 7 -Significant Difference fro* Control P < .05 -Significant Difference froa Control P < .01 Error-within groups LABCAT CC4.43 Source-Source of Variation Treataenta-between groups 27-JUN-2002 418-028:PAGE K-136 Study Report for Clinical Chemistry SUMMARY REPORT PERIOD: TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE Creatinine Group N Total Mean S td . DUNNETT'S Dev. t' DUNNETT'S RANGES L0 -95X - HI L0 -99X - HI Degree S o u rce Fdm 1-H 10 3 .2 0 .3 0 .0 4 TREATHENTS 4 2-M 10 3.3 0.3 0.05 0.48 0.3 0.4 0.3 0.4 ERROR 45 3-H 10 3.1 0.3 0.06 0.48 0.3 0.4 0.3 0.4 4-N 10 3.1 0.3 0.03 0.48 0.3 0.4 0.3 0.4 TOTAL 49 5-H 10 3.3 0.3 0.05 0.48 0.3 0.4 0.3 0.4 F R atio * C oeff. Var. X = 0 .4 7 14.434 'F ' ta b le values D u n n e tt's *T' t a b l e v a lu e s Creatine Kinase F.01 * P.01 * 3.78 3.12 F.05 = P.05 2 .5 8 2.51 SEX: BALE Sum o f Squares 0.0040 0.0960 0.1000 Mean Square 0.0010 0.0021 1-M 10 2877 288 172.6 2-M 10 2462 246 111.5 0 .78 153 422 3-M 10 2388 239 112.9 0.91 153 422 4-H 10 1964 196 53.5 1.71 153 422 5-H 10 2427 243 117.4 0.84 153 422 F R atio * Coeff. Var. X * 0.73 49.381 F' tab le values D u n n e tt's 'T* t a b l e v a lu e s F.01 P.01 * Alanine Aminotransferase TREATHENTS 4 121 455 ERROR 45 121 455 121 455 TOTAL 49 121 455 3.78 3.12 F.05 P.05 * 2.58 2.51 41956 644538 686494 10489 14323 1-M 10 420 42 6 .0 TREATMENTS 4 18155 4539 2-M 10 631 63 69.9 0 .7 2 -32 116 -50 134 ERROR 45 194111 4314 3-M 10 600 60 34.4 0.61 -32 116 -5 0 134 ----- 4-H 10 954 95 124.1 1 .8 2 -32 116 -50 134 TOTAL 49 212266 5-N 10 447 45 7.0 0.09 -32 116 -50 134 F Ratio * Coeff.. Var. X * 1.05 107.598 ' F* t a b l e v a lu e s D unnett's ' T' ta b le v alu es F.01 = P.01 * 3.78 3.12 F.05 P.05 - 2.58 2.51 E rror--w ith in g ro u p s Source-Source of V ariation LABCAT CC4.43 Treataents-betw een groups 27-JUN-2002 418-028:PAGE K-137 Study Report for Clinical Chemistry SUMMARY REPORT PERIOD: TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-069 ANALYSIS 0F VARIANCE FOLLOWEO BY DUNNETT'S PROCEDURE $EX: rtALE Aspartate Aminotransferase S td . DUNNETT'S Group N Total Mean Dev. t ' DUNNETT' S RAMSES LO -95X - HI LO -99X - HI Degree Source Fda 1-M 10 957 96 22.4 TREATMENTS 4 2-N 10 1213 121 9 2 .6 0 .4 7 -4 0 231 -73 264 ERROR 45 3-M 10 1171 117 4 0 .9 0 .4 0 -4 0 231 -73 264 4-N 10 1976 198 248.7 1.89 -4 0 231 -73 264 TOTAL 49 5-H 10 974 97 15.6 0 .03 -4 0 231 -73 264 Sum o f Squares 69637 655378 725015 Mean Square 17409 14564 F R atio = C oeff. Var. X = 1.20 95.916 F ' t a b l e v a lu e s D unnett's 'T ' ta b le values Alkaline Phosphatase F.01 P.01 = 3.78 3.12 F.05 P.05 * 2.58 2.51 1-M 10 1050 105 1 4 .3 TREATMENTS 4 11825 2956 2-H 10 1113 111 3 6 .9 0.51 74 136 67 143 ERROR 45 33780 751 3-M 10 1001 100 1 2 .4 0 .4 0 74 136 67 1 4 3 ------------------------------ 4-M 10 1152 115 25.1 0 .8 3 74 136 67 143 TOTAL 49 45604 5-M 10 1441 144 3 7 .5 3 .1 9 74 136* 67 143** F R atio * Coeff.. Var. X = 3.94 23.795 Calcium F* t a b l e v a lu e s D unnett's `T' ta b le values F.01 P.01 = 3.78 3.12 F.05 P.05 * 2.58 2.51 1-M 10 109.4 10.9 0 .4 8 TREATMENTS 4 3.45 0 .8 6 2-H 10 107.3 10.7 0.44 1.12 10.5 11.4 10.4 11.5 ERROR 45 7.97 0 .1 8 3-M 10 110.7 11.1 0.44 0.69 10.5 11.4 1 0 .4 1 1 . 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 R atio = Coeff.. Var. X 4.87 3.800 *F' ta b le values D unnett's 'T ' ta b le values F.01 * P.01 = 3.78 3.12 F.05 * P.05 = 2.58 2.51 -Signifleant Difference fro* Control P < .05 -Significant Difference fro* Control P < .01 Error-within groups LABCAT CC4.43 Source-Source of Variation Treataents-between groups 27-JUN-2002 418-028:PAGE K-138 Study Report for Clinical Chemistry SUMMARY REPORT PERIOD*. TERMINAL STUDY XD: ARGUS 418-028 STUOY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY OUNNETT'S PROCEDURE Phosphorus Group N Total Mean S td . OUNNETT'S Dev. 'V DUNNETT'S RANGES L0 -95X - HI L0 -99%- HI Degree Source Fda 1-M 10 9 4 .7 9 .5 1 .4 0 2-M 10 93.7 9 .4 1.11 0.15 7 .8 11.2 3-H 10 99.1 9 .9 2.09 0.65 7 .8 11.2 4-H 10 97.1 9 .7 1.43 0.36 7 .8 11.2 5-H 10 102.3 10.2 1.33 1.13 7 .8 11.2 F Ratio * C o eff. Var. X - 0.53 15.485 1F1 t a b l e v a lu e s D u n n e tt's 'T* t a b l e v a lu e s F .01 = P.01 * Triglycerides TREATMENTS 4 7 .4 11.6 ERROR 45 7.4 11.6 7.4 11.6 TOTAL 49 7.4 11.6 3.78 3.12 F.05 P.05 2 .5 8 2.51 1-M 10 516 52 21.8 2-M 10 469 47 17.2 0.55 30 73 3-M IQ >90 ft 1 TO 30 73 4-N 10 361 36 2 7.9 1.82 30 73 5-M 10 168 17 8 .0 4.10 30 73A F Ratio = C o eff. Var. X = 4.98 50.584 *F' ta b le values D unnett's 'T ' ta b le values F.01 * P.01 = Sodium TREATMENTS 4 25 78 ERROR 45 25 7ft 25 78 TOTAL 49 25 7 8 * * 3.78 3.12 F.05 P.05 a 2 .5 8 2.51 1-M 10 1459 146 1.4 TREATMENTS 4 2-M 10 1457 146 1.3 0.29 144 148 144 148 ERROR 45 3-M 10 1465 147 1 .6 0.86 144 148 144 148 - 4-M 10 1469 147 1.0 1.44 144 148 144 148 TOTAL 49 5-M 10 1460 146 2.2 0.14 144 148 144 148 F R atio = Coeff.. Var. X = 1.00 1.062 'F' t a b l e v a lu e s D u n n ett's *7' ta b le values F.01 * P.01 = 3.78 3.12 F.05 > P.05 - 2.58 2.51 SEX: HALE Sua of Squares 4 .8 0 102.32 107.12 Mean Square 1 .2 0 2 .2 7 7188 16244 23432 1797 361 9 .6 0 108.40 118.00 2 .4 0 2.41 -Significant Difference fro* Control P < .05 -significant Difference free Control P < .01 Error-within groups LABCAT CC4.43 Source-Source of Variation Treatments-between groups 27-JUN-2002 STUDY 10: ARGUS 418-028 STUDY NO: 060-069 418-028-.PAGE K-139 Study Report for Clinical Chemistry SUMMARY REPORT PERIOD: TERMINAL ANALYSIS OF VARIANCE F0LL0UED BY DUNNETT'S PROCEDURE SEX: HALE Group N Total Mean S td . DUNNETT'S Dev. 't* DUNNETT1S RANGES LO -95X - HI L0 -99X - HI Degree Source Fda Su o f Squares 1-H 10 6 5 .7 6 . 6 2 .1 0 TREATMENTS 4 5.56 2-N 10 61.0 6.1 0.89 0.76 5.0 8.1 4.6 8.5 ERROR 45 86.21 3-M 10 64.5 6 .5 1.27 0.19 5.0 8.1 4 .6 8 . 5 ----------------------------- 4-H 10 59.7 6 .0 0.60 0.97 5.0 8.1 4 .6 8.5 TOTAL 49 91.77 5-H 10 69.0 6 .9 1.55 0.53 5.0 8.1 4 .6 8.5 F R atio C oe ff. Var. X = 0.73 21.633 Chloride *F` ta b l e v alu es D u rm ett's 'T ' t a b l e v a lu e s F.01 = P.01 * 3 .7 8 3.12 F .05 * P .05 * 2.58 2.51 1-H 10 982 98 2 .7 2-M 10 988 99 1.5 0.62 96 101 3-M 10 997 100 2.3 1.54 96 101 4-M 10 1000 100 2 .7 1.85 96 101 5-M 10 998 100 1.2 1.64 96 101 F R a tio * C oeff. Var. X = 1.25 2.190 F' t a b l e v a lu e s D u rm ett1s 'T ' t a b l e v a lu e s F.01 * P.01 Globulin TREATMENTS 4 23.60 95 101 ERROR 45 212.90 95 1 0 1 ----------------------------- 95 101 TOTAL 49 236.50 95 101 3 .7 8 3 .1 2 F .05 P.05 * 2.58 2.51 1-M 10 2 0 .3 2 .0 0 .1 9 TREATMENTS 4 0.27 2-H 10 19.5 2 .0 0 .16 0.99 1.8 2.2 1.8 2.3 ERROR 45 1.46 3-M 10 19.8 2 .0 0.24 0.62 1.8 2.2 1.8 2.3 - 4-H 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 = Coeff.. Var. X = 2.06 9.253 *F` ta b l e v a lu e s D unn ett's 'T1 ta b le values F .01 = P.01 = 3 .7 8 3 .1 2 F .05 P .05 * 2.58 2.51 Mean Square 1.39 1.92 .....- 5 .9 0 4.73 0 .0 7 0.03 -S ig n ific a n t D ifferen ce fr * C ontrol P < .05 Error-- within groups LABCAT CC4.43 Source-Source of V ariation T re a tn e n ts -b e tw e e n groups 27-JUN-2002 418-028.PAGE K-140 Study Report for Clinical Chemistry SUMMARY REPORT PERIOD: TERMINAL STUDY ID: ARGUS 418-028 STUOY HO: 060-0 6 9 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT' S PROCEDURE SEX: HALE Albumin/Globulin Ratio S td . DUNNETT'S Group N T otal Hean Dev. f DUNNETT'S RANGES L0 -95X - HI L0 -99X - HI Degree S ource Fda 1-M 10 2 1 .2 2 .1 0 .1 8 TREATMENTS 4 2-H 10 21.4 2.1 0.16 0.24 1.9 2.3 1.9 2.4 ERROR 45 3-M 10 21.9 2.2 0.26 0.84 1.9 2.3 1.9 2.4 - 4-H 10 21.9 2 .2 0.15 0.84 1.9 2.3 1.9 2.4 TOTAL 49 5-M 10 25.1 2.5 0.17 4.67 1.9 2.3* 1.9 2.4** F R atio = C oeff. Var. X * 7.31 8.368 *F' t a b l e v a lu e s Dunne* s T ta b le values f .01 * P.01 = 3 .7 8 3.12 F.05 P.05 - 2.58 2.51 Sue of Squares 1.02 1.57 2.59 Hean Square 0.25 0 .0 3 -Significant Difference fro* Control P < .05 -Significant Difference fro m C o n tro l P < .01 Error-vithin groups LABCAT CC4.43 Source-Source of Variation Treataents-betveen groups 27-JUN-2002 418-028:PAGE K-141 Study Report for Clinical Chemistry SUMMARY REPORT PERIOD: TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-069 TEST(s): UNITS: Group: 1-F MEAN SD N Group: 2-F MEAN SD N Group: 3-F MEAN SD N Group: 4-F MEAN SD N Group: 5-F MEAN SD N TP g/dL 6.1 0.52 10 5.5 0.50 10 5.9 0.41 10 5.8 0.32 10 5.8 0.29 10 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE ALB g/dL 6LU g/dL CHOL g/dL T-BIL g/dL BUN g/dL CREAT g/dL SEX: FERALE CK ALT U/L U/L 4.1 0.42 10 152 19.8 10 77 27.8 10 0.2 0.07 10 28 0.4 202 129 4.4 0.05 54.1 31.7 10 10 10 10 4.0 0.34 10 162 20.0 10 72 14.0 10 0.2 0.03 10 24 0.4 250 133 4.7 0.05 85.6 23.0 10 10 10 10 4.1 0.24 10 155 18.7 10 71 20.0 10 0.2 0.05 10 28 0.3 192 142 6.7 0.05 21.7 34.2 10 10 10 10 4.0 0.29 10 146 16.2 10 62 14.2 10 0.1 0.05 10 25 0.4 213 127 4.4 0.08 80.4 24.7 10 10 10 10 4.0 0.31 10 140 35.5 10 61 19.8 10 0.1 0.05 10 30 15.4 10 0.3 0.06 10 252 101.6 10 145 20.0 10 LABCAT CC4.43 27-JUN-2002 418-028:PAGE K-142 Study Report for Clinical Chemistry SUMMARY REPORT PERIOD: TERMINAL STUOY ID: ARGUS 418-028 STUDY NO: 060-069 ANALYSIS OP VARIANCE FOLLOWED BY OUNNETT'S PROCEDURE SEX: PENALE TEST(s): UNITS: Group: 1-F NEAN SD N Group: 2-F MEAN SD N Group: 3-F NEAN SD N Group: 4-F NEAN SD N Group: 5-F NEAN SD N AST U/L 142 22.8 10 ALP CA PHOS TRIG NA K CL U/L g/dL g/dL g/dL mol/L mrnol/L ol/L 145 88.7 10 10.6 0.72 10 8.8 1.33 10 54 19.9 10 143 5.8 6.3 0.67 10 10 96 3.4 10 GLOB g/dL 1.9 0.22 10 135 21.6 10 159 81.7 10 11.2 0.63 10 7.9 1.94 10 50 10.2 10 143 5.6 2.4 0.58 10 10 94 1.6** 2.7 0.26 10 10 137 11.8 10 136 107.3 10 10.4 0.87 10 9.0 2.80 10 49 29.4 10 142 5.6 2.5 0.32 10 10 95 1.8 3.8 0.21 10 10 124 12.1 10 178 131.0 10 10.4 0.46 10 8.7 2.88 10 45 19.5 10 142 6.1 2.6 0.70 10 10 95 1.7 3.4 0.13 10 10 156 40.7 10 128 44.7 10 10.4 0.82 10 10.1 1.64 10 44 18.3 10 142 6.2 2.6 0.90 10 10 94' 3.1 10 1.8 0.21 10 -Significant Difference from Control P < .01 LABCAT CC4.43 27-JUN-2002 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 418-028:PAGE K-143 Study Report for Clinical Chemistry SUMMARY REPORT PERIOD: TERMINAL ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE TESTCs): UNITS: A/G none Group: 1-F MEAN SD N Group: 2-F MEAN SD N 2.2 0.28 10 2.6* 0.43 10 Group: 3-F MEAN SD N 2.2 0.21 10 Group: 4-F MEAN SD N 2.4 0.26 10 Group: 5-F MEAN SD N 2.3 0.37 10 SEX: FENALE -Significant Difference fro* 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 STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOUED BY DUNNETT'S PROCEDURE sEX: FEHALE Total Protein Group N Total Kean 1-f 10 60.7 6.1 2-F 10 55.0 5.5 3-F 10 58.8 5.9 4-F 10 57.7 5.8 5-F 10 58.2 5.8 Std. DUNNETT'S Dev. t* 0.52 0.50 0.41 0.32 0.29 3.04 1.01 1.60 1.33 DUNNETT'S RANGES LO -95X- HI LO -99X- HI Degree Source Fda TREATMENTS 4 5.6 6.5* 5.5 6.7 ERROR 45 5.6 6.5 5.5 6.7 5.6 6.5 5.5 6.7 TOTAL 49 5.6 6.5 5.5 6.7 Sua of Squares 1.70 7.91 9.62 Mean Square 0.43 0.18 F Ratio = Coeff. Var. X - 2.42 7.220 Albumin 'F* table values Dunnett's `T ' table values F.01 = P.01 3.78 3.12 F.05 " P.05 2.58 2.51 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 = Coeff. Var. X = 0.39 8.059 Glucose F' table values Dunnett's 'T' table values F.01 * P.01 = 3.78 3.12 F.05 * P.05 2.58 2.51 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 = Coeff.. Ver. X = 1.29 15.288 'F' table values Dunnett's 'T' table values F.01 = P.01 3.78 3.12 F.05 P.05 2.58 2.51 -Significant Difference froa Control P < .05 Error-within groups LABCAT CC4.43 Source-Source of Variation Treataents-between groups 27-JUN-2002 418-028:PAGE K-145 Study Report for Clinical Chemistry SUMMARY REPORT PERIOD: TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE SEX: FEMALE Cholesterol Group N Total Mean Std. DUNNETT'S Dev. 't' DUNNETT' S RANGES L0 -95X- HI L0 -99X- HI Degree Source Fda Sua of Squares Mean Square 1-F 10 76 9 77 27.8 2-F 10 723 72 14.0 0.52 55 99 3-F 10 705 71 20.0 0.72 55 99 4-F 10 621 62 14.2 1.67 55 99 5-F 10 610 61 19.8 1.79 55 99 F Ratio Coeff. Var. X = 1.18 28.929 'F 1 table values Du nnetfs T table values F .01 * P.01 - Total Bilirubin TREATMENTS 4 49 105 ERROR 45 49 105 ---- 49 105 TOTAL 49 49 105 3.78 3.12 F.05 * P.05 * 2.58 2.51 1862 17702 19564 465 393 ------ 1-F 10 1.6 0.2 0.07 2-F 10 1.9 0.2 0.03 1.30 0.1 0.2 3-F 10 1.5 0.2 0.05 0.43 0.1 0.2 4-F 10 1.3 0.1 0.05 1.30 0.1 0.2 5-F 10 1.3 0.1 0.05 1.30 0.1 0.2 F Ratio * Coeff. Var. X = 2.33 33.974 1F' table values Dunnett's 'T* table values F.01 * P.01 Blood Urea Nitrogen 1-F 10 281 28 4.4 2-F 10 241 24 4.7 1.08 19 37 3-F 10 281 28 6.7 0.00 19 37 4-F 10 252 25 4.4 0.78 19 37 5-F 10 298 30 15.4 0.46 19 37 F Ratio " Coeff.. Var. X = 0.79 30.672 *F* table values Dunnett's '7' table values F.01 P.01 TREATMENTS 4 0.1 0.2 ERROR 45 0.1 0.2 --- 0.1 0.2 TOTAL 49 0.1 0.2 3.78 3.12 F.05 = P.05 2.58 2.51 0.025 0.120 0.145 TREATMENTS 4 17 40 ERROR 45 17 4 0 --- 17 40 TOTAL 49 17 40 3.78 3.12 F.05 * P.05 * 2.$8 2.51 218.92 3099.90 3318.82 0.006 0.003 54.73 68.89 Error-vfthin groups Source-Source of Variation LABCAT CC4.43 Treataent.-between groups 27-JUN-2002 STUDY ID: ARGUS 418-028 STUDY NO: 060-069 418-028:PAGE K-146 Study Report for Clinical Chemistry SUMMARY REPORT PERIOD: TERMINAL ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE SEX: FEMALE Group N Total Mean Std. DUNNETT'S Dev. 't' DUNNETT1S RANGES L0 -95X- HI L0 -99X- HI Degree Source Fdot 1-F 10 3.5 0.4 0.05 2-F 10 3.5 0.4 0.05 0.00 0.3 0.4 3-F 10 3.4 0.3 0.05 0.37 0.3 0.4 4-F 10 3.6 0.4 0.08 0.37 0.3 0.4 5-F 10 3.1 0.3 0.06 1.47 0.3 0.4 F Ratio = Coeff. Var. X = 1.00 17.813 *F` table value Dunnett's ''P table values F.01 P.01 = Cre&tizie Kinase TREATMENTS 4 0.3 0.4 ERROR 45 0.3 0.4 - 0.3 0.4 TOTAL 49 0.3 0.4 3.78 3.12 F.05 = P.05 2.58 2.51 1-F 10 2017 202 54.1 2-F 10 2495 250 85.6 1.44 118 285 3-F 10 1919 IT C M7 0.30 118 285 4-F 10 2129 213 80.4 0.34 118 285 5-F 1 0 2521 252 101.6 1.52 118 285 F Ratio Coeff . Var. X * 1.39 33.472 'F* table values Dunnett's 'T' table values F.01 * P.01 * Alanine Aminotransferase TREATMENTS 4 98 305 ERROR 45 98 vk -. 98 305 TOTAL 49 98 305 3.78 3.12 F.05 * P.05 * 2.58 2.51 1-F 10 1294 129 31.7 2-F 10 1334 133 23.0 0.33 99 160 3-F 10 1424 142 34.2 1.07 99 160 4-F 10 1265 127 24.7 0.24 99 160 5-F 10 1447 145 20.0 1.26 99 160 F Ratio * Coeff. Var. X = 0.86 20.138 'F* table values Dunnett's 'T' table values F.01 * P.01 TREATMENTS 4 91 167 ERROR 45 91 167 --- 91 167 TOTAL 49 91 167 3.78 3.12 F.05 * P.05 2.58 2.51 Su m of Squares 0.015 0.167 0.182 30624 247619 278244 2546 33396 35942 Mean Square 0.004 0.004 7656 5503 637 742 Error-vithin groups Source-Source of Variation LABCAT CC4.43 Trestent-between groups 27-JUN-2002 418-028-.PAGEK-147 Study Report for Clinical Chemistry SUMMARY REPORT PERIOD: TERMINAL STUDY ID: ARGUS 418r-028 STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE SEX: FEMALE Aspartate Aminotransferase Std. DUNNETT'S Group N Total Mean Dev. *t' 1-F 10 1423 142 22.8 2-F 10 1351 135 21.6 0.67 3-F 10 1368 137 11.8 0.51 4-F 10 1240 124 12.1 1.69 5-F 10 1564 156 40.7 1.30 DUNNETT' S RANGES L0 -95X- HI L0 -99%- HI Degree Source Fdn 115 169 115 169 115 169 115 169 TREATMENTS 4 109 176 ERROR 45 109 176 109 176 TOTAL 49 109 176 Su m of Squares 5587 26359 31946 Mean Square 1397 586 F Ratio = Coeff. Var. % * 2.38 17.422 *F* table values Dunnett's 'T* table values Alkaline Phosphatase F.01 = P.01 * 3.78 3.12 F.05 = P.05 * 2.58 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. X 0.44 63.733 F' table values Dunnett's 'T' table values P.01 * It TREATMENTS 4 15762 12 277 ERROR 45 406995 12 277 ------------------- 12 277 12 277 TOTAL 49 422757 3.78 3.12 F.05 = P.05 * 2.58 2.51 3941 9044 Calcium 1-F 10 105.5 10.6 0.72 TREATMENTS 4 3.99 1.00 2-F 10 111.6 11.2 0.63 1.90 9.7 11.4 9.5 11.6 ERROR 45 23.11 0.51 3-F 10 104.3 10.4 0.87 0.37 9.7 11.4 9.5 11.6 - 4-F 10 104.4 10.4 0.46 0.34 9.7 11.4 9.5 11.6 TOTAL 49 27.11 5-F 10 104.3 10.4 0.82 0.37 9.7 11.4 9.5 11.6 F Ratio = Coeff. Var. X = 1.94 6.760 'F* table values Dunnett's 'T' table values F.01 = P.01 = 3.78 3.12 F.05 = P.05 = 2.58 2.51 Error-within groups Source-Source of Variation LABCAT CC4.43 Treataents-between groups 27-JUN-2002 STU0Y 10: ARGUS 418-028 STUDY NO: 060-069 418-028:PAGE K-148 Study Report for Clinical Chemistry SUMMARY REPORT PERIOD: TERMINAL ANALYSIS OF VARIANCE F0LL0WED BY DUNNETT'S PROCEDURE SEX: FEHALE Group N Total Mean Std. DUNNETT'S Dev. t' DUNNETT'S RANGES L0 -95X- HI L0 -99%- HI Degree Source Fdm 1-F 10 87.5 8.8 1.33 TREATMENTS 4 2-F 10 79.3 7.9 1.94 0.83 6.3 11.2 5.7 11.8 ERROR 45 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 5-F 10 101.0 10.1 1.64 1.37 6.3 11.2 5.7 11.8 F Ratio = Coeff. Var. X * 1.26 24.803 'F* table values Dunnett'a 'T' table values Triglycerides F.01 * P.01 3.78 3.12 F.05 = P.05 * 2.58 2.51 1-F 10 544 54 19.9 TREATMENTS 4 2-F 10 495 50 10.2 0.54 32 77 26 83 ERROR 45 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 5-F 10 437 44 18.3 1.17 32 77 26 83 F Ratio = Coeff. Var. % = 0.42 42.148 F' table values Dunnett's 'T' table values F.01 = P.01 * 3.78 3.12 F.05 * P.05 * 2.58 2.51 Sodium 1-F 10 1434 143 6.3 TREATMENTS 4 2-F 10 1427 143 2.4 0.43 139 147 138 148 ERROR 45 3-F 10 1422 142 2.5 0.74 139 147 138 148 --- 4-F 10 1424 142 2.6 0.62 139 147 138 148 TOTAL 49 5-F 10 1421 142 2.6 0.80 139 147 138 148 F Ratio = Coeff. Var. % * 0.21 2.534 F' table values Dunnett's *T` table values F.01 * P.01 3.78 3.12 F.05 * P.05 = 2.58 2.51 Sus of Squares 24.53 219.09 243.62 693 18711 19404 10.92 587.40 598.32 Mean Square 6.13 4.87 173 416 2.73 13.05 Error-within groups Source-Source of Variation LABCAT CC4.43 Treatsents-between groups 27-JUN-2002 STUOY ID: ARGUS 418-028 STUOY NO: 060-069 418-028:PAGE K -149 Study Report for Clinical Chemistry SUMMARY REPORT PERIOD: TERMINAL ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT1S PROCEDURE SEX: FEHALE Group N Total Mean Std. DUNNETT'S Dev. 't' DUNNETT' S RANGES L0 -95X- HI L0 -99X- HI Degree Source Fd 1-F 10 58.1 5.8 0.67 2-F 10 55.8 5.6 0.58 0.78 5.1 6.6 3-F 10 55.5 5.6 0.32 0.88 5.1 6.6 4-F 10 61.0 6.1 0.70 0.98 5.1 6.6 5-F 10 61.6 6.2 0.90 1.18 5.1 6.6 F Ratio * Coeff. Var. X * 1.84 11.322 F* table values Dunnett's *T* table values F.01 P.01 Chloride TREATHENTS 4 4.9 6.7 ERROR 45 4.9 6 . 7 ----------- 4.9 6.7 TOTAL 49 4.9 6.7 3.78 3.12 F.05 * P.05 * 2. 58 2. 51 1-F 10 2-F 10 3-F 10 4-F 10 5-F 10 F Ratio = Coeff. Var. X * 956 96 3.4 941 94 2.7 1.01 949 95 3.8 0.47 954 95 3.4 0.14 936 94 3.1 1.35 92 99 92 99 92 99 92 99 0.66 3.494 'F' table values Dunnett's 'T' table values F.01 = P.01 = TREATMENTS 4 91 100 ERROR 45 91 100 --- 91 100 TOTAL 49 91 100 3.78 3,12 F.05 P.05 * 2.58 2.51 Globulin 1-F 10 19.4 1.9 0.22 2-F 10 15.5 1.6 0.26 4.12 1.7 2.2* 3-F 10 18.2 1.8 0.21 1.27 1.7 2.2 4-F 10 17.3 1.7 0.13 2.22 1.7 2.2 5-F 10 17.9 1.8 0.21 1.59 1.7 2.2 F Ratio Coeff., Var. X - 4.56 11.982 'F' table values Dunnett's 'T' table values F.01 * P.01 * TREATHENTS 4 1.6 2.2** ERROR 45 1.6 2.2 --- 1.6 2.2 TOTAL 49 1.6 2.2 3.78 3.12 F.05 * P.05 * 2.58 2.51 Su m of Squares 3.23 19.67 22.90 29.08 493.00 522.08 0.82 2.02 2.83 Hean Square 0.81 0.44 7.27 10.96 0.20 0.04 -Significant Difference fro Control P < .05 -Significant Difference fro Control P < .01 Error-within groups LABCAT CC4.43 Source-Source of Variation Treataents-betueen groups 27-JUN-20Q2 418-028:PAGE K-150 Study Report for Clinical Chemistry SUMMARY REPORT PERIOD: TERMINAL STUDY ID: ARGUS 418-028 STUDY NO: 060-069 ANALYSIS OF VARIANCE FOLLOWED BY DUHNETT'S PROCEDURE Albumin/Globulin Ratio Std. DUNNETT'S Group N Total Mean Dev. f DUNNETT'S RANGES LO -95X- HI LO -99X- HI Degree Source Fctoi 1-F 2-F 3-F 4-F 5-F 10 21.7 10 26.1 10 22.3 10 23.7 10 23.0 2.2 2.6 2.2 2.4 2.3 0.28 0.43 0.21 0.26 0.37 3.07 0.42 1.39 0.91 TREATMENTS 4 1.8 2.5* 1.7 2.6 ERROR 45 1.8 2.5 1.7 2.6 1.8 2.5 1.7 2.6 TOTAL 49 1.8 2.5 1.7 2.6 F Ratio = Coeff. Var. X 2.83 13.734 1F ` table values Dunnett's 'T' table values F.01 P.01 3.78 3.12 F .05 = P.05 * 2.58 2.51 Sin of Squares 1.16 4.63 5.80 Square 0.29 0.10 -Significant Difference froa Controt P < .05 Error-vithin groups LABCAT CC4.43 Source-Source of Variation Treataents-between groups 27-JUN-2002 APPENDIX L STATEMENT OF THE STUDY DIRECTOR 905 Sheehy Orive, Bldg. A H orsham , PA 1 9 0 4 4 Telephone: (2 1 5 ) 443-5710 Telefax: (2/5) 4 4 3 -8 5 8 7 418-028:PAGE L -l ARGUS RESEARCH Charles Hiver 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 STATEMENT OF THE STUDY DIRECTOR This final report accurately reflects the raw data obtained during the performance of the study. No deviations from the U.S. Food and Drag Administration (FDA) Good Laboratory Practice Regulations; Final Rulea, the Japanese Ministry of Health and Welfare (MHW) G o o d L a b o ra to ry P ra c tic e S ta n d a rd f o r S a fety S tu dies on D ru gs*, the Organisation for Economic Co-operation and Development (OECD). The Revised OECD Principles of Good Laboratory Practices and the Organisation for Economic Co-operation and Development (OECD), The OECD Guideline for Testing of Chemicals*1occurred that affected the quality or integrity of the study. Argus Research a. U.S. Food and Drag Administration. G o o d L a b o ra to ry P ra c tic e R egu lation s; F in al R ule. 21 CFR Part 58. b. Japanese Ministry of Health and Welfare (1997). G o o d L a b o ra to ry P ra c tic e S ta n d a rd f o r S afety S tu d ies on D ru gs, MHW Ordinance No. 21, March 26,1997. c. Organisation for Economic Co-operation and Development (1998). The R evised O E C D P rin c ip le s o f G o o d L a b o ra to ry P r a c tic e s [C(97)186/Final]. d. Organisation for Economic Co-operation and Development (1996). O E C D G uideline f o r Testing o f C hem icals. Section 4, No. 422: Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, adopted 22 March 1996. APPENDIX M QUALITY ASSURANCE STATEMENT 418-028:PAGE M -l 90S Sheehy Drive, Bldg. A Horsham. PA 19044 Telephone: (2 1 5 )4 4 1 3 7 1 0 Telefax: (215} 4 4 1 9 5 8 7 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 fo r 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: Date(s) Findings Submitted to Study Inspection Phase Insoection Datis) Director Protocol 22 MAR 02 22 MAR 02 Test Substance Administration 04 APR 02 05 APR 02 Test Substance Preparation 05 APR 02 06 APR 02 Motor Activity 08 MAY 02 16 MAY 02 Blood Collection 09 MAY 02 10 MAY 02 Fetal Blood Collection 09 MAY 02 13 MAY 02 Fetal Liver Collection 09 MAY 02 13 MAY 02 Satellite Caesarean- Sectioning 09 MAY 02 13 MAY 02 Male Sacrifice 14 MAY 02 14 MAY 02 Male Blood Collection 14 MAY 02 14 MAY 02 Sperm Evaluation 14 MAY 02 14 MAY 02 Litter Observations 17 MAY 02 17 MAY 02 Functional Observational Battery 24 MAY 02 24 MAY 02 Blood Collection 30 MAY 02 04 JUN 02 Dam/Litter Sacrifice 30 MAY 02 04 JUN 02 In-Life Data 11-20 SEP 02 23 SEP 02 Necropsy Data 13-20 SEP 02 20 SEP 02 Formulation Data 17 SEP 02 17 SEP 02 Report Tables 16-23 SEP 02 23 SEP 02 24 SEP 02 24 SEP 02 Report Text 19,22-23 SEP 02 23 SEP 02 25 SEP 02 25 SEP 02 Revised Report 06 NOV 02 06 NOV 02 Date(s) Findings Submitted to Management 22 MAR 02 05 APR 02 06 APR 02 16 MAY 02 10 MAY 02 13 MAY 02 13 MAY 02 13 MAY 02 14 MAY 02 14 MAY 02 14 MAY 02 17 MAY 02 24 MAY 02 04 JUN 02 04 JUN 02 23 SEP 02 20 SEP 02 17 SEP 02 23 SEP 02 24 SEP 02 23 SEP 02 25 SEP 02 06 NOV 02 Matthew J. Vaneman, B.S. Date Manager of Regulatory Compliance