Document X7qR337K2X5YdgxzGqkrpqBky

/!"R oL Q> _ I & I S FINAL REPORT PROTOCOL 418-027 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST SPONSOR'S STUDY NUMBER: T-7599 FINAL REPORT DATE: 25 MARCH 2003 PROTOCOL 418-027 - ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST SPONSOR'S STUDY NUMBER: T-7599 TABLE OF CONTENTS SUBJECT 1. SUMMARY AND CONCLUSION 1.1. Methods 1.2. Results - Males 1.3. Results - Females 1.4. Conclusion 2. DESCRIPTION OF TEST PROCEDURES 2.1. Conduct of Study 2.2. Test Substance Information 2.3. Vehicle Information 2.4. Test Substance Preparation and Storage Conditions 2.5. Test System 2.6. Husbandry 2.7. Methods 3. RESULTS - Male Rats 3.1. Mortality, Clinical and Necropsy Observations PAGE 1-1 1-1 1-3 1-3 1-5 2-1 2-1 2-3 2-4 2-5 2-6 2-8 2-10 3-1 3-1 li SUBJECT PAGE 3.2. Terminal Body Weights and Organ Weights and Ratios (%) of Organ Weight to Terminal Body Weight and Brain Weight 3-2 3.3. Hematology and Clinical Chemistry 3-2 3.4. Body Weights and Body Weight Changes 3-2 3.5. Absolute (g/day) and Relative (g/kg/day) Feed Consumption Values 3-3 3.6. Mating and Fertility 3-3 3.7. Functional Observational Battery 3-3 3.8. Motor Activity 3-3 4. RESULTS - Female Rats 4-1 4.1. Mortality, Clinical and Necropsy Observations 4-1 4.2. Terminal Body Weights and Organ Weights and Ratios (%) of Organ Weight to Terminal Body Weight and Brain Weight 4-2 4.3. Hematology and Clinical Chemistry 4-2 4.4. Body Weights and Body Weight Changes 4-2 4.5. Absolute (g/day) and Relative (g/kg/day) Feed Consumption Values 4-3 4.6. Estrous Cycling, Mating and Fertility 4-3 4.7. Functional Observational Battery 4-4 4.8. Motor Activity 4-4 4.9. Natural Delivery and Litter Observations 4-4 4.10. Pup Clinical and Necropsy Observations 4-5 REFERENCES 4-6 APPENDIX A - REPORT FIGURES Figure 1. Body Weights - Male Rats A-l iii SUBJECT PAGE Figure 2. Body Weights - Female Rats A-2 Figure 3. Motor Activity - Number of Movements - Male Rats A-3 Figure 4. Motor Activity - Time Spent in Movement - Male Rats A-4 Figure 5. Motor Activity - Number of Movements - Female Rats A-5 Figure 6. Motor Activity - Time Spent in Movement - Female Rats A-6 APPENDIX B - REPORT TABLES - Fo GENERATION MALE RATS Table Bl. Table B2. Clinical Observations - Summary - Fo Generation Male Rats Necropsy Observations - Summary - Fo Generation Male Rats B-l 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-4 Table B5. Ratios (%) of Organ Weight to Brain Weight - Summary Fo Generation Male Rats B-5 Table B6. Hematology - Summary - Fo Generation Male Rats B-6 Table B7. Clinical Chemistry - Summary - Fo Generation Male Rats B-9 Table B8. Body Weights - Summary - Fo Generation Male Rats B-12 Table B9. Body Weight Changes - Summary - Fo Generation Male Rats B-13 Table BIO. Absolute Feed Consumption Values (g/day) - Summary Fo Generation Male Rats B-14 Table Bl l. Relative Feed Consumption Values (g/kg/day) - Summary Fo Generation Male Rats B-15 Table B12. Mating and Fertility - Summary - Fo Generation Male Rats B-16 Table B13. Functional Observational Battery - Summary - Male Rats B-17 Table B 14. Motor Activity - Summary - Fo Generation Male Rats B-23 IV SUBJECT PAGE Table B 15. Clinical Observations - Individual Data - Fo Generation Male Rats B-25 Table B 16. Necropsy Observations - Individual Data - Fo Generation Male Rats B-30 Table B 17. Terminal Body Weights, Organ Weights and Ratios (%) of Organ Weight to Terminal Body Weight - Individual Data Fo Generation Male Rats B-34 Table B 18. Brain Weights, Organ Weights and Ratios (%) of Organ Weight to Brain Weight - Individual Data - Fo Generation Male Rats B-46 Table B 19. Body Weights - Individual Data - Fo Generation Male Rats B-54 Table B20. Feed Consumption Values - Individual Data - Fo Generation Male Rats B-66 Table B21. Mating and Fertility - Individual Data - Fo Generation Male Rats B-70 Table B22. Functional Observational Battery - Individual Data - Male Rats B-74 Table B23. Motor Activity - Individual Data - Fo Generation Male Rats B-78 APPENDIX C - REPORT TABLES - Fo GENERATION FEMALE RATS Table Cl. Clinical Observations - Summary - Fo Generation Female Rats Table C2. Necropsy Observations - Summary - Fo Generation Female Rats C-l C-4 Table C3. Terminal Body Weights and Organ Weights - Summary - Fo Generation Female Rats C-5 Table C4. Ratios (%) of Organ Weight to Terminal Body Weight - Summary - Fo Generation Female Rats C-6 Table C5. Ratios (%) of Organ Weight to Brain Weight - Summary Fo Generation Female Rats C-l Table C6. Hematology - Summary - Fo Generation Female Rats C-8 Table Cl. Clinical Chemistry - Summary - Fo Generation Female Rats C-l 1 Table C8. Body Weights - Precohabitation - Summary - Fo Generation Female Rats C-l4 v SUBJECT PAGE Table C9. Body Weight Changes - Precohabitation - Summary - Fo Generation Female Rats C-15 Table CIO. Maternal Body Weights - Gestation - Summary - Fo Generation Female Rats C-16 T ableC ll. Maternal Body Weight Changes - Gestation - Summary Fo Generation Female Rats C-18 Table C12. Maternal Body Weights - Lactation - Summary - Fo Generation Female Rats C-19 Table C13. Maternal Body Weight Changes - Lactation - Summary Fo Generation Female Rats C-20 Table 0 4 . Absolute Feed Consumption Values (g/day) - Precohabitation Summary - Fo Generation Female Rats C-21 Table 0 5 . Relative Feed Consumption Values (g/kg/day) - Precohabitation Summary - Fo Generation Female Rats C-22 Table 0 6 . Maternal Absolute Feed Consumption Values (g/day) - Gestation - Summary - Fo Generation Female Rats C-23 TableC17. Maternal Relative Feed Consumption Values (g/kg/day) - Gestation - Summary - Fo Generation Female Rats C-24 Table 0 8 . Maternal Absolute Feed Consumption Values (g/day) - Lactation - Summary - Fo Generation Female Rats C-25 Table 0 9 . Maternal Relative Feed Consumption Values (g/kg/day) - Lactation - Summary - Fo Generation Female Rats C-26 Table C20. Mating and Fertility, Estrous Cycling and Days in Cohabitation Summary - Fo Generation Female Rats C-27 Table C21. Functional Observational Battery - Summary - Female Rats C-29 Table C22. Motor Activity - Summary - Fo Generation Female Rats C-35 Table C23. Natural Delivery Observations - Summary - Fo Generation Female Rats C-37 VI SUBJECT PAGE Table C24. Litter Observations (Naturally Delivered Pups) - Summary FI Generation Litters C-38 Table C25. Clinical Observations from Birth to Day 5 Postpartum - Summary - FI Generation Pups C-41 Table C26. Necropsy Observations - Summary - FI Generation Pups C-42 Table C27. Clinical Observations - Individual Data - Fo Generation Female Rats C-43 Table C28. Necropsy Observations - Individual Data - Fo Generation Female Rats C-48 Table C29. Terminal Body Weights and Organ Weights and Ratios (%) of Organ Weight to Terminal Body Weight - Fo Generation Female Rats C-51 Table C30. Organ Weights and Ratios (%) of Organ Weight to Brain Weight - Individual Data - Fo Generation Female Rats C-59 Table C31. Body Weights - Precohabitation - Individual Data - Fo Generation Female Rats C-63 Table C32. Maternal Body Weights - Presumed Gestation - Individual Data Fo Generation Female Rats C-67 Table C33. Maternal Body Weights - Lactation - Individual Data - Fo Generation Female Rats C-71 Table C34. Feed Consumption Values - Precohabitation - Individual Data Fo Generation Female Rats C-75 Table C35. Maternal Feed Consumption Values - Presumed Gestation Individual Data - Fo Generation Female Rats C-79 Table C36. Maternal Feed Consumption Values - Lactation - Individual Data - Fo Generation Female Rats C-83 Table C37. Mating and Fertility, Estrous Cycling and Days in Cohabitation Individual Data - Fo Generation Female Rats C-87 Table C38. Functional Observational Battery - Individual Data - Female Rats C-89 vu SUBJECT PAGE Table C39. Motor Activity - Individual Data - Fo Generation Female Rats C-93 Table C40. Natural Delivery, Implantation Sites, and Pup Viability and Sex Individual Data - Fo Generation Female Rats/Fl Generation Litters C-101 Table C41. Pup Body Weight Litter Averages from Birth to Day 5 Postpartum - Individual Data - FI Generation Litters C-103 Table C42. Pup Body Weights from Birth to Day 5 Postpartum - Individual Data - FI Generation Pups C-105 Table C43. Pup Vital Status and Sex from Birth to Day 5 Postpartum - Individual Data - FI Generation Pups C-l 13 Table C44. Clinical Observations from Birth to Day 5 Postpartum Individual Data - FI Generation Pups C-l 17 Table C45. Necropsy Observations - Individual Data - FI Generation Pups C-l 18 APPENDIX D - PROTOCOL AND AMENDMENTS D-1 to D-42 APPENDIX E - DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY E-1 to E-2 APPENDIX F - CERTIFICATE OF ANALYSIS F-1 APPENDIX G - ANALYTICAL REPORT G-1 APPENDIX H - TEMPERATURE AND RELATIVE HUMIDITY REPORT H-1 APPENDIX I - POSITIVE CONTROL DATA I-1 to 1-4 APPENDIX J - HISTOPATHOLOGY REPORT J-l to J-110 APPENDIX K - HEMTOLOGY AND CLINICAL CHEMISTRY REPORTS K-ltoK-51 APPENDIX L - STATEMENT OF THE STUDY DIRECTOR L-1 APPENDIX M- QUALITY ASSURANCE STATEMENT M-l to M-2 vin 418-027 :PAGE 1-1 TITLE: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST ARGUS RESEARCH PROTOCOL NUMBER: 418-027 SPONSOR'S STUDY NUMBER: T-7599 1. SUMMARY AND CONCLUSION 1.1. Methods* Sixty male and sixty female Crl:CD(SD)IGS VAF/Plus rats were assigned to four dosage groups (Groups I through IV), 15 rats per sex per group. The test substance was T 7599.7 and the vehicle was aqueous 0.5% or 1.0% carboxymethylcellulose (CMC). The 0.5% CMC was used for the first four days of the study and the 1.0% CMC was used for the remainder of the study. The test substance or vehicle was administered to the male rats beginning 14 days before cohabitation and continuing until sacrifice, after completion of the cohabitation period, after a minimum of 28 days of dosage and to the female rats beginning 14 days before cohabitation and continuing until day 5 of lactation (DL 5). Dosages were 0 (Vehicle), 10, 50 and 250 mg/kg/day. The dosage volume was adjusted daily. Within each dosage group, consecutive order was be used to assign the first five male and the first five female rats to a functional observational battery (FOB) and motor activity assessment. The next five rats per sex in each group were assigned to hematology and clinical biochemistry evaluations. The last five rats per sex in each group were assigned to metabolite analysis. Histological evaluations were performed on the last ten rats per sex in each group. Rats were observed for viability at least twice each day of the study. Observations for clinical signs of effects of the test substance, abortions, premature deliveries and deaths were made daily before dosage. Postdosage observations were recorded 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. Body weights for male and female rats were recorded daily during the dosage period and at sacrifice. Feed consumption values for male rats were recorded weekly during the dosage period. Feed consumption values for female rats were recorded weekly to cohabitation and on gestation days (DGs) 0, 7, 10, 12, 15, 18, 20 and 25 (if necessary) and on lactation days (DLs) 1 and 5. 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). 418-027 :PAGE 1-2 Estrous cycling was evaluated 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. 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 and 5. Motor activity was evaluated on five male and five female rats per group once during the course of the study, before scheduled sacrifice. Day 1 of lactation was defined as the day of birth and was also the first day on which all pups in a litter were individually weighed. Each litter was evaluated for viability at least twice daily. The pups in each litter were counted twice daily. Clinical observations were recorded once daily. Pup body weights were recorded on DLs 1 and 5. After 36 days of dosage, all male rats were sacrificed and on DL 6, all surviving female rats were sacrificed. A gross necropsy was performed. The testes and epididymides of all male rats were weighed, and the testes, epididymides, seminal vesicles with coagulating gland and prostate were retained. The ovaries and the uterus with cervix of each female rat were weighed, and ovaries, uterus, vagina and a mammary gland were retained. The following organs were individually weighed: liver, kidneys, adrenals, thymus, testes, epididymides, spleen, brain, heart, ovaries and uterus. The following tissues or representative samples were retained: brain, small and large intestines, lungs, lymph nodes, peripheral nerve, stomach, kidneys, spleen, thymus, trachea, urinary bladder, testes, epididymides, seminal vesicles, prostate, spinal cord, liver, adrenals, heart, thyroid/parathyroid, uterus, bone marrow, ovaries, uterus, vagina, mammary gland (female rats only) and gross lesions. Histological examination was conducted for the assigned ten rats per sex from the control and high dosage groups. Histological evaluations were performed on the livers of ten male and ten female rats, the thymuses of ten female rats and the stomachs of ten male rats in the 10 and 50 mg/kg/day dosage groups. At scheduled sacrifice, blood was collected from the five male and five female rats per group assigned to hematology and clinical chemistry sample collection. One aliquot was analyzed for hematologic parameters. Two blood smear slides were prepared for each sample for measurements of differential leukocyte count. Plasma from another aliquot was measured for prothrombin time and activated partial thromboplastin time. Serum from a third aliquot was analyzed for clinical chemistry parameters. Blood samples were collected from the five rats per sex per group assigned to metabolite analysis. The liver was excised and the organ weight recorded. On DL 5, pups were sacrificed and examined for gross lesions. Pups found dead on DLs 2 to 4 were examined for gross lesions and for possible cause of death. 418-027 :PAGE 1-3 1.2. Results - Males All male rats survived to scheduled sacrifice. Significant increases in excess salivation, perioral substance and urine-stained abdominal fur occurred in the 250 mg/kg/day dosage group. All other clinical observations and all necropsy observations were considered unrelated to the test substance. Body weight gains were significantly reduced in the 250 mg/kg/day dosage group on DSs 1 to 8, 1 to 15 and 1 to 36. Body weight gains were also significantly decreased in the 50 mg/kg/day dosage group on DSs 1 to 36. Body weights were significantly reduced on DS 29 and 36 in the 250 mg/kg/day dosage group. Absolute feed consumption values were significantly reduced in the 50 and 250 mg/kg/day dosage groups on DSs 1 to 8 and significantly reduced in the 250 mg/kg/day dosage groups on DSs 1 to 15 and 1 to 36. Relative feed consumption values were significantly reduced on DSs 1 to 8 in the 50 and 250 mg/kg/day dosage groups. Terminal body weights of the male rats were significantly reduced in the 250 mg/kg/day dosage group. Absolute weights of the left and right kidneys were significantly increased in the 50 and 250 mg/kg/day dosage groups and the absolute weight of the liver was significantly increased in the 250 mg/kg/day dosage group. The ratios of the weights of these organs to terminal body weights were significantly increased in the 50 and 250 mg/kg/day dosage groups. Relative to the brain weight, only the liver weight in the 250 mg/kg/day dosage group was significantly increased. Treatment-related microscopic changes were observed in the liver of male rats in the 50 and 250 mg/kg/day dosage groups and in the stomach of male rats in the 250 mg/kg/day dosage group. Dosages of the test substance as high as 250 mg/kg/day did not affect any hematology or clinical chemistry values evaluated. All mating and fertility parameters were unaffected by dosages of the test substance as high as 250 mg/kg/day. There were no statistically significant or biologically important differences among the four dosage groups in the measures of the functional observational battery (FOB). Body weights recorded during the functional operational battery for the treated groups were not significantly different than the control group for the male rats. There were no statistically significant or biologically important differences among the four dosage groups in the measures of motor activity on DS 86. 1.3. Results - Females All female rats survived to scheduled sacrifice. All clinical and necropsy observations were considered unrelated to the test substance. Body weight gains were significantly reduced during the precohabitation period in the 250 mg/kg/day dosage group on DSs 1 to 8 and 1 to 15. Body weights and body weight gains were not significantly affected by dosages of the test substance during gestation or lactation. Terminal body weights of the female rats were reduced in the 250 mg/kg/day dosage group. Absolute liver weight was significantly increased in the 250 mg/kg/day dosage group. The ratios of the weight of this organ and the weight of the right kidney to 418-027 :PAGE 1-4 terminal body weights were significantly increased in the 250 mg/kg/day dosage group. Only the ratio of the liver weight to brain weight in the 250 mg/kg/day dosage group was significantly increased. Treatment-related microscopic changes were observed in the liver and thymus of female rats in the 250 mg/kg/day dosage group. Dosages as high as 250 mg/kg/day did not affect any hematology or clinical chemistry values evaluated. Absolute and relative feed consumption values were not significantly affected by dosages of the test substance during the precohabitation, gestation or lactation periods. All estrous, mating and fertility parameters were unaffected by dosages of the test substance as high as 250 mg/kg/day. There were no statistically significant or biologically important differences among the four dosage groups in the measures of the FOB. Body weights recorded during the functional operational battery for the treated groups were not significantly different than the control group for the female rats. There were no statistically significant or biologically important differences among the four dosage groups in the measures of motor activity on DS 86. The number of livebom pups was significantly reduced and number of stillborn pups was significantly increased in the 250 mg/kg/day dosage group. The number of pups found dead or presumed cannibalized on day 1 and days 2 to 5 postpartum was significantly increased in the 250 mg/kg/day dosage groups. The viability index and number of pups surviving per litter on postpartum day 5 were significantly reduced in the 250 mg/kg/day dosage group. Pup body weights per litter were also reduced in the 250 mg/kg/day dosage group on postpartum days 1 and 5. Values for the numbers of dams delivering litters, duration of gestation, averages for implantation sites per delivered litter, gestation index, numbers of dams with stillborn pups, dams with all pups dying, stillborn pups, surviving pups per litter on postpartum day 1 and pup sex ratios were comparable among the four dosage groups. No clinical or necropsy observations in the FI generation pups were attributable to dosages of the test substance as high as 250 mg/kg/day. 418-027 :PAGE 1-5 1.4. Conclusion On the basis of these data, the paternal no-observable-adverse-effect-level (NOAEL) for T 7599.7 is 10 mg/kg/day (the 50 mg/kg/day dosage caused reduced weight gain during precohabitation, reduced absolute and relative feed consumption values, increased absolute and relative liver and kidney weight, and liver histopathology). The maternal NOAEL is 50 mg/kg/day (the 250 mg/kg/day dosage caused reduced weight gain during precohabitation, reduced terminal body weights, increased absolute and relative liver weight, and histopathology of the liver and thymus). The reproductive NOAEL is greater than 250 mg/kg/day (all estrous, mating and fertility parameters were unaffected by dosages of the test substance as high as 250 mg/kg/day). The NOAEL for viability and growth in the offspring is 50 mg/kg/day (dosages of 250 mg/kg/day caused postnatal mortality and decreased pup body weights). Alan M. Hoberman, Ph.D., DABT Director of Research Date fmond G. York/ h.DL DABT Associate Director search Study Director Date 418-027 :PAGE 2-1 2. 2.1. 2.1.1. DESCRIPTION OF TEST PROCEDURES Conduct of Study Sponsor 3M Corporate Toxicology, 3M Center, Building 220-2E-02, St. Paul, Minnesota 55144-1000 2.1.2. Testing Facility Argus Research, 905 Sheehy Drive, Building A, Horsham, Pennsylvania 19044-1297 2.1.3. Study Number 418-027 2.1.4. T-7599 Sponsor's Study Number 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 28 days (male rats) or through parturition until day 5 of lactation (female rats). This repeated dose study incorporated a reproduction/developmental toxicity screening test to provide initial information on possible effects on male and female reproductive performance (e.g., gonadal function, mating behavior, conception, development of the conceptus and parturition). The study also placed emphasis on neurological effects as a specific endpoint and was designed to identify the neurotoxic potential of a test substance, which may warrant further in-depth investigation. 2.1.6. Study Design The requirements of the Organisation for Economic Co-operation and Development (OECD)(1) 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 Organisation for Economic Co-operation and Development (OECD)(2), U.S. Food and Drug Administration (FDA)(3) and the Japanese Ministry of Health and Welfare (MHW)(4). 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. 418-027 :PAGE 2-2 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 Paul H. Lieder, Ph.D., DABT 2.1.10. Study Director Raymond G. York, Ph.D., DABT, Associate Director of Research Address as cited above for Testing Facility 2.1.11. Technical Performance John F. Barnett, B.S. (Director of Laboratory Operations) Christine A. O'Brien (Research Associate) Loma A. Sinotte, B.S. (Laboratory Technician) Stephanie M. Dorizio, B.A. (Necropsy Laboratory Technician) 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) Jennifer M. Hughes (Report Administrator) 2.1.13. Report Review Mildred S. Christian, Ph.D., Fellow, ATS (Executive Director of Research) Alan M. Hoberman, Ph.D., DABT (Director of Research) 2.1.14. Date Protocol Signed 15 February 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 28 days of dosage) FOB and Motor Activity Evaluation Scheduled Sacrifice 12 FEB 02 18 FEB 02-25 MAR 02 19 MAR 02 - 20 MAR 02 26 MAR 02 418-027 :PAGE 2-3 2.1.15.2. Female Rats Rat Arrival 12 FEB 02 Dosage Period (14 days before cohabitation through DLa 5) 18 FEB 02 - 12 APR 02 Dosage Period Estrous Cycle Evaluation 19 FEB 02 - 04 MAR 02 Cohabitation Period Male 1 04 MAR 02 PM - 11 MAR 02 AM Male 2 11 MAR 02 PM - 18 MAR 02 AM DGb 0 05 MAR 02 - 17 MAR 02 Delivery Period0(DL 1) 27 MAR 02 - 08 APR 02 DG 25 Sacrifice (Rats that did not deliver a litter) 30 MAR 02 - 12 APR 02 FOB Evaluation and Motor Activity Evaluation 31 MAR 02- 12 APR 02 Pup Sacrifice (DL 5) 31 MAR 02- 12 APR 02 Scheduled Sacrifice (DL 6) 01 APR 02 - 13 APR 02 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. Unused bulk test substance will be returned to the Sponsor. 2.2. Test Substance Information 2.2.1. Description T 7599.7 - amber waxy solid a. DL is an abbreviation for day of lactation. b. DG is an abbreviation used for day of (presumed) gestation. c. 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 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. 418-027 :PAGE 2-4 2.2.2. 6 Lot Number 2.2.3. Date Received and Storage Conditions The test substance was received on 18 February 2002 and stored at room temperature, protected from light. 2.2.4. 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 worn during formulation preparation and dosage. A half-face respirator was worn when the bulk test substance was not being used in a chemical fume hood. 2.2.5. 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% or 1.0% carboxymethylcellulose (CMC) (medium viscosity) prepared carboxymethylcellulose, an off-white powder, and reverse osmosis membrane processed water. The 0.5% CMC was used for the first four days of the study. Beginning 22 February 2002, the 1.0% CMC was used for the remainder of the study. 2.3.2. Lot Number 120K0252 2.3.3. Date Received and Storage Conditions The carboxymethylcellulose was received on 11 September 2001 from Sigma Chemical Co., St. Louis, Missouri, 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. 418-027:PAGE 2-5 2.3.4. 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 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 of 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, protected from light. 418-027 :PAGE 2-6 2.4.1. Sample Information Sample Type Date Storage/Shipping Size Retained Conditions Shipped To Date Shipped Bulk Test Substance Concentrationd (all levels) 5g lg 2 mL 2 mL 26 FEB 02a 12 APR 02b 03 APR 02e 04 APR 02f Room temperature, protected from light Refrigerated, protected from light SRIC SRIC 26 FEB 02 15 APR 02 03 APR 02 04 APR 02 Homogeneity8 (all levels) 2 mL 18 FEB 02 2 mL 28 FEB 02 Refrigerated, SRIC protected from light 18 FEB 02 28 FEB 02 Stability11 2 mL 18 FEB 021 Refrigerated, SRIC 18 FEB 02 2 mL 28 FEB 02j protected from light 28 FEB 02 Bulk Test Substance Reserve 1 g 22 APR 02 Room temperature, Testing Facility 23 APR 02 protected from light Archives Vehicle Components Reserve Room temperature Testing Facility Archives Carboxymethylcellulose R.O. Deionized Water 1 g 22 APR 02 1 g 22 APR 02 23 APR 02 23 APR 02 a. A sample of the bulk test substance was retained for use in the preparation of analytical standards and for possible spectrophotometric analysis. b. A sample of the bulk test article was retained on the last day of dosage administration and shipped for analysis. c. Southern Research Institute, Birmingham, Alabama. 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. Sample for 1 mg/mL. f. Samples for 0, 5 and 25 mg/mL g. Quadruplicate samples were taken from the top, middle and bottom of each concentration on the first day of preparation. Two samples of each quadruplicate set were shipped for analysis. The remaining samples were retained at the Testing Facility as backup samples. h. Two sets of duplicate samples from each concentration were taken on the first day of preparation. One sample of each duplicate set was shipped for analysis. These samples were analyzed as soon after preparation as possible and ten days after the first analysis. The remaining samples were retained at the Testing Facility as backup samples. i. Prepared using 0.5% carboxymethylcellulose. j. Prepared using 1.0% carboxymethylcellulose. 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 BR VAF/Plus 418-027 :PAGE 2-7 2.5.3. Supplier (Source) Charles River Laboratories, Inc., 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(5~7)' 2.5.6. Test System Data 2.5.6.I. Male Rats Number of Rats Approximate Date of Birth Approximate Age at Arrival Weight (g) the Day after Arrival Weight (g) at Study Assignment 70 04 DEC 01 71 days 282 -333 303 -354 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 70 10 DEC 01 65 days 185 -226 210 -230 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. After 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 four dosage groups (Groups I through IV), 15 rats per sex per group, using a computer-generated (weightordered) randomization procedure. Within each dosage group, consecutive order was used to assign the first five male and the first five female rats to a functional observational battery (FOB) and motor activity assessment. The next five rats per sex in each group were assigned to hematology and clinical biochemistry evaluations. The last five rats per sex in each group were assigned 418-027 :PAGE 2-8 to metabolite analysis. Histological evaluations were performed on the last ten rats per sex in each group. 2.5.8. System of Identification Male and female rats assigned temporary numbers at receipt and given unique permanent identification numbers when assigned to the study. Rats were permanently identified using Monel self piercing ear tags (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 and dosage level. Pups were not individually identified during lactation; all parameters were evaluated in terms of the litter. 2.6. 2.6.1. Husbandry 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 were monitored constantly throughout the study. Room temperature was targeted at 66F to 77F (19C to 25C); relative humidity was targeted at 30% to 70%a. 2.6.3. Housing Fo generation rats were individually housed in stainless steel wire-bottomed cages except during cohabitation period 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. 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 Guidefor the Care and Use of Laboratory Animals(8). 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. a. See APPENDIX H (TEMPERATURE AND RELATIVE HUMIDITY REPORT). 418-027 :PAGE 2-9 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. Rats were fasted overnight before sacrifice. 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 that would have interfered with the results of this study. 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 an automatic watering access system and/or individual water bottles attached to the cages. 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. 418-027 :PAGE 2-10 2.6.11. Bedding Analysis Analyses for possible contamination are conducted semi-annually. Copies of the results 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. 2.7. 2.7.1. Methods Dosage Administration Dosage Dosage3 Group (mg/kg/day) Concentration (mg/mL) Dosage Volume (mL/kg) Number of Rats per Sex Assigned Numbers Male Rats Female Rats I 0 (Vehicle) 0 17601, 17602, 17603, 17604, 17662, 17672, 17673, 17674, 10 15 17607, 17608, 17618, 17630, 17680, 17681, 17690, 17694, 17631, 17639, 17648, 17652, 17695, 17703, 17713, 17715, 17656, 17658, 17660 17716, 17717, 17719 II 10 17615, 17616,17624,17626, 17663,17665, 17666, 17668, 1 10 15 17632,17634,17635,17638, 17671, 17675, 17679, 17684, 17642,17643, 17645,17649, 17688, 17698, 17702, 17704, 17651, 17653,17655 17707, 17708, 17710 III 50 17605,17610, 17611, 17613, 17661,17667,17669, 17670, 5 10 15 17619, 17620, 17623, 17627, 17676,17687, 17693, 17697, 17628, 17633, 17640, 17646, 17700, 17701, 17705, 17706, 17650, 17657,17659 17709, 17718, 17720 IV 250 17606,17609, 17612,17614, 17664,17677,17678, 17682, 25 10 15 17617,17621, 17622, 17625, 17683,17685,17686, 17689, 17629, 17636, 17637, 17641, 17691,17692, 17696,17699, 17644, 17647,17654 17711, 17712, 17714 a. The test substance was considered 100% pure for the pupose of dosage calculatons. 2.7.2. Rationale for Dosage Selection Dosages were selected by the Sponsor based on previous studies conducted with the test substance, taking into account possible differences in sensitivity between pregnant and nonpregnant rats. The highest dosage was expected to cause toxic effects but not mortality or obvious suffering. The descending sequence of the lower dosage levels were selected for the purpose of demonstrating any dosage-related response, with no adverse effects expected at the lowest level. 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 possible route of human exposure. 418-027 :PAGE 2-11 2.7.4. Method and Frequency of Administration 2.7.4.1. Fo Generation Rats Male rats were administered the test substance and/or the vehicle once daily beginning 14 days before cohabitation (maximum 14 days) and continuing until sacrifice, after completion of the cohabitation period, after a minimum of 28 days of dosage. Female rats were administered the test substance and/or the vehicle once daily beginning 14 days before cohabitation (maximum 14 days) and continuing until DL 5. The dosage volume was adjusted daily on the basis of the individual body weights recorded before intubation3. The rats were intubated once daily at approximately the same time each day. 2.7.4.2. FI Generation Pups FI generation pups were not directly administered the test substance and/or vehicle, but may have been possibly exposed to test substance and/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 that were 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, abortions, premature deliveries and deaths were made daily before dosage. On the first day of dosage, postdosage observations were recorded at approximately hourly intervals for the first four hours after administration. The observation at four hours after administration was at the end of the normal working day. Postdosage observations for subsequent days of dosage were recorded approximately 60 10 minutes after dosage administration and on the day of sacrifice15. Once before the first dosage and at least once weekly thereafter, detailed clinical observations were conducted for all male and female rats. These observations were made a. See APPENDIX E (DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY), item 1. b. See APPENDIX E, items 2 and 3. 418-027 :PAGE 2-12 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. Signs noted included, but were not limited to: changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions and autonomic activity (e.g., lacrimation, piloerection, pupil size, unusual respiratory pattern). Changes in gait, posture 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 for male and female rats were recorded weekly during the acclimation period, daily during the dosage period and at sacrifice. Feed consumption values for male rats were recorded weekly during the dosage period. Feed left was recorded on the day before sacrifice. Feed consumption values for female rats were recorded weekly to cohabitation and on DGs 0, 7, 10, 12, 15, 18, 20 and 25 (if necessary) and on DLs 1 and 5. Feed left was recorded on the day before sacrifice. During cohabitation, when two rats occupied the same cage with one feed jar, replenishment of feed jars was documented but individual values were not recorded or tabulated. Male and female rats were fasted overnight before sacrifice. Estrous cycling was evaluated 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. 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 and 5. 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, shortly before scheduled sacrifice, a functional observational battery (FOB)(912) was conducted on five male and five female rats per group. For male rats, this assessment was conducted approximately one week before scheduled sacrifice. Female rats were tested during the lactation period, the day before scheduled sacrifice. To avoid hyperthermia of pups, dams were separated from their litters for no longer than 30 to 40 minutes. 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). 418-027 :PAGE 2-13 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, visual placing response 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 five male and five female rats per group once during the course of the study. For male rats, this assessment was conducted approximately one week before scheduled sacrifice. Female rats were tested during the lactation period, the day before scheduled sacrifice. The movements of each rat were 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 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. 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 daily. Pup body weights were recorded on DLs 1 and 5 (terminal weight). 418-027 :PAGE 2-14 2.7.6. Gross Necropsy 2.7.6.I. Fo Generation Rats After 36 days of dosage, all male rats were sacrificed on the day following the last dosage, day 37 of study (DS 37) and on DL 6, all surviving female rats were sacrificed. Rats were sacrificed by carbon dioxide asphyxiation, and a gross necropsy of the thoracic, abdominal and pelvic viscera was performed. Gross necropsy of all male and female rats 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 number of implantation sites and corpora lutea were recorded. Tissue trimming and histopathology was performed under the supervision of or by a Board-Certified Veterinary Pathologist. Gross lesions were retained in neutral buffered 10% formalin and examined histologically. Representative photographs of gross lesions are available in the raw data. The testes and epididymides of all male rats were weighed, and the testes, epididymides, seminal vesicles with coagulating gland and prostate were retained in neutral buffered 10% formalin. The testes were fixed in Bouin's solution for 48 to 96 hours before being retained in neutral buffered 10% formalin. The ovaries and the uterus with cervix of each female rat were weighed, and ovaries, uterus, vagina and a mammary gland were retained in neutral buffered 10% formalin. Uteri of apparently nonpregnant rats were examined after being pressed between glass plates to confirm the absence of implantation sites, and retained in neutral buffered 10% formalin. Ten rats per sex per group not 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, epididymides, spleen, brain, heart, ovaries and uterus (with cervix)a. 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), stomach, kidneys, spleen, thymus, trachea, urinary bladder, testes (fixed in Bouin's solution for 48 to 96 hours before being retained in neutral buffered 10% formalin), epididymides, seminal vesicles (with coagulating gland), prostate, spinal cord (cervical, thoracic and lumbar), liver, adrenals, heart, thyroid/parathyroid, uterus, bone marrow, 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. Histological evaluations were performed on the livers of ten male and ten female rats, the thymuses of ten female rats and the stomachs of ten male rats in the 10 and 50 mg/kg/day dosage groups. Tissues to be examined a. See APPENDIX E, item 4. 418-027 :PAGE 2-15 histologically were shipped to Research Pathology Services, Inc., New Britain, Pennsylvania for evaluation. Results of the histological evaluation are available in APPENDIX J. At scheduled sacrifice, the five male and five 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, animal number, 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 a transport tube and immediately frozena. Plasma samples were maintained on dry ice or in a freezer (< -70C) until shipped 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), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALK), calcium (CA), phosphorus (PHOS), sodium (NA), potassium (K) and chloride (CL)a. Samples for hematology and clinical chemistry analyses were shipped to Redfield Laboratories, A Division of CRL-DDS, Redfield, Arkansas. Results of these analyses are available in APPENDIX K. Blood samples (approximately 3 mL) were collected from the five rats per sex per group assigned to metabolite analysis. Blood was collected from the vena cava. Each sample was divided into two aliquots. One aliquot of 2 mL was transferred into an EDTA-coated (purple top) tube and refrigerated. The second aliquot (approximately 1 mL) was a. See APPENDIX E, item 5. 418-027 :PAGE 2-16 transferred into a serum tube, allowed to clot and spun in a centrifuge. The resulting serum was transferred into polypropylene tubes labeled with the protocol number, Sponsor study number, animal number, 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 for analysis. The liver was excised and the organ weight recorded. One lobe (right lateral) was placed in a conical tube and flash frozen in an ice/alcohol bath. Liver samples were maintained frozen (<-70C) until shipment for analysis. Liver and serum samples were shipped on dry ice and whole blood will be shipped on ice packs. Samples to be analyzed were shipped to Southern Research Institute, Birmingham, Alabama, for analysis. 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. Dams with no surviving pups were sacrificed after the last pup was found dead, missing or presumed cannibalized. Gross necropsy, examination and tissue retention was 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. 2.7.6.2. FI Generation Pups On DL 5, 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. 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 sank were identified as stillborn; pups with lungs that floated were identified as livebom, and to have died shortly after birth. Pups found dead on DLs 2 to 4 were examined for gross lesions and for the cause of death. 418-027 :PAGE 2-17 2.7.7. Data Collection and Statistical Analyses Data generated during the course of this study were recorded either by hand or using the Argus Automated Data Collection and Management System, the Vivarium Temperature and Relative Humidity Monitoring System, the Coulbourn Instruments Passive Infrared Motor Activity System, the Coulbourn Instruments Auditory Startle System, the Coulbourn Instruments Spatial Delayed Alternation System, and/or the passive avoidance software. All data were tabulated, summarized and/or statistically analyzed using the Argus Automated Data Collection and Management System, the Vivarium Temperature and Relative Humidity Monitoring System, Microsoft Excel [part of Microsoft Office 97 (version SR-2)] and/or The SAS System (version 6.12). 418-027 :PAGE 2-18 Averages and percentages were calculated. Litter values were used where appropriate. The following schematic represents the statistical analyses of the data: I. Param etric Type of Test3 II. N o n p a ra m e tric b A. Bartlett's T e s t0 I S ig n ifica n t at p<.0.001 I Not S ignificant A - Kruskal-W allis Test (s.75% ties at any concentration) I S ignificant at p<0.05 I Not Significant Nonparam etric ,-- ,Analysis of Variance 1------------ Significant at p<0.05 Not Significant Dunn's Test B. Fisher's Exact T est on Proportion of Ties (>75% ties at any concentration) D unnett's Test B. A nalysis of V ariance with R epeated M easures S ig n ifica n t at p<_0.05 Not Significant (D osa g e ) D unnett's Test (Dosage x Block Interaction) One-way ANO VA for each block Significant at p < 0.05 Not Significant Dunnett's Test III. Test for Proportion Data Variance Test for Hom ogeneity of the Binom ial Distribution a. Statistically significant probabilities are reported as either p<0.05 or /?<0.001. b. Proportion data are not included in this category. c. Test for homogeneity of variance. 418-027: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(13) 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(14). If that test was significant (p<0.05), the groups given the test substance were compared with the control group using Dunnett's Test(1 . 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(16) was used to analyze the data, and in the event of a significant result (p<0.05), Dunn's Test(17) 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(18) 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(19), as described under that heading in the schematic. A significant result (p<0.05) in that test could have appeared as effect of Dosage (differences among dosage groups in the totals of all measurements in a session) or as an interaction between Dosage and Block (differences in the patterns of dosage group values across the measurement periods). If the Dosage effect was significant, the totals for the control group and the groups given the test substance were compared using Dunnett's Test(15). If the Dosage x Block interaction was significant, an Analysis of Variance(14) was used to evaluate the data at each measurement period, and a significant result (p<0.05) was followed by a comparison of the dosage groups using Dunnett's test(15). 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 were analyzed using the Variance Test for Homogeneity of the Binomial Distribution(20). 418-027 :PAGE 3-1 3. RESULTS - MALE RATS 3.1. Mortality, Clinical and Necropsy Observations (Summaries - Tables B1 and B2; Individual Data - Tables B15 and B16) 3.1.1. Mortality All male rats survived to scheduled sacrifice. 3.1.2. Clinical Observations Significant increases (/?<0.01) in the incidences of excess salivation, perioral substance and urine-stained abdominal fur occurred in the 250 mg/kg/day dosage group. All other 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, soft or liquid feces, missing/broken incisors, chromodacryorrhea, scabs on right forelimb, red substance on the penis and ulceration on right forelimb. 3.1.3. 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 male rat (17636) in the 250 mg/kg/day dosage group. These observations included a tan, firm, lobular mass (2.8 cm x 0.9 cm x 0.7 cm) on the right hemisphere of the prostate and a red ventral side of the same prostate gland. A cut surface of the mass revealed a tan smooth surface. Histomorphologic diagnosis was suppurative prostatitis. 3.1.4. Histopathology Treatment-related microscopic changes were observed in the liver of male rats in the 50 and 250 mg/kg/day dosage groups and in the stomach of male rats in the 250 mg/kg/day dosage group. The treatment-related microscopic changes in the liver consisted of minimal or mild enlargement (hypertrophy) of centrilobular hepatocytes in most of the male rats in the 250 mg/kg/day dosage group and 4 out of 10 in the 50 mg/kg/day dosage group. The enlargement was due to an increased amount of finely granular, dense eosinophilic cytoplasm. Also, in three of the affected rats in the 250 mg/kg/day dosage group, necrosis of individual enlarged hepatocytes was seen in the centrilobular areas. Microscopic examination of the stomach revealed focal erosions in the pyloric glandular mucosa of two rats in the 250 mg/kg/day dosage group. No treatment-related microscopic changes were observed in any of the male rats given 10 mg/kg/day of the test substance. 418-027: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 B17 and B18) Terminal body weights of the male rats were significantly reduced (p<0.01) in the 250 mg/kg/day dosage group, as compared with control group values. Absolute weights of the left and right kidneys were significantly increased (p<0.05 or p<0.01) in the 50 and 250 mg/kg/day dosage groups and the absolute weight of the liver was significantly increased (p<0.01) in the 250 mg/kg/day dosage group, as compared with the control group value. The ratios of the weights of these organs to terminal body weights were significantly increased (p<0.05 or /?<0.01) in the 50 and 250 mg/kg/day dosage groups. Relative to the brain weight, only the liver weight in the 250 mg/kg/day dosage group was significantly increased (p<0.01). 3.3. Hematology and Clinical Chemistry (Summaries - Tables B6 through B7) Dosages of the test substance as high as 250 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, volume, prothrombin and activated partial thromboplastin time (PT and APTT), mean platelet volume (MPV), nucleated red blood cell count (NRBC), lymphocytes, segmented neutrophils, bands, monocytes, eosinophils, basophils and abnormal lymphocytes in male rats were comparable among the four dosage groups and did not differ significantly. Average values for total protein (TP), albumin (A), glucose (GLU), cholesterol (CHOL), total bilirubin (TBILI), blood urea nitrogen (BUN), creatinine (CREAT), 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 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 B19) Body weight gains were significantly reduced (p<0.01) in the 250 mg/kg/day dosage group on study days (DSs) 1 to 8, 1 to 15 and 1 to 36. Body weight gains were also significantly decreased (p<0.05) in the 50 mg/kg/day dosage group on DSs 1 to 36. Body weights were significantly reduced (p<0.01) on DS 29 and 36 in the 250 mg/kg/day dosage group. Body weights and body weight gains of the male rats were unaffected by dosages of the test substance as high as 10 mg/kg/day. 418-027:PAGE 3-3 3.5. Absolute (g/day) and Relative (g/kg/day) Feed Consumption Values (Summaries - Tables BIO and B ll; Individual Data - Table B20) Absolute (g/day) feed consumption values were significantly reduced (p<0.05 or p<0.01) in the 50 and 250 mg/kg/day dosage groups on DSs 1 to 8 and significantly reduced (p<0.01) in the 250 mg/kg/day dosage groups on DSs 1 to 15 and 1 to 36. Absolute feed consumption values during the recovery period were comparable between the 0 (Vehicle) and 10 mg/kg/day dosage groups. Relative (g/kg/day) feed consumption values were significantly reduced (/?<0.05 or /?<0.01) on DSs 1 to 8 in the 50 and 250 mg/kg/day dosage groups. Relative feed consumption values of 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 B2I) 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, rats pregnant per rats in cohabitation and the number of pregnant rats per number of rats in cohabitation) were unaffected by dosages of the test substance as high as 250 mg/kg/day. 3.7. Functional Observational Battery (Summary - Table B13; Individual Data - Table B22) There were no 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 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 male rats. 3.8. Motor Activity (Figure 3 and 4; Summary - Table B14; Individual Data - Table B23) There were no statistically significant or biologically important differences among the four dosage groups in the measures of motor activity on DS 8. 418-027 :PAGE 4-1 4. RESULTS - Female Rats 4.1. Mortality, Clinical and Necropsy Observations (Summaries - Tables C l and C2; Individual Data - Tables C27 and C28) 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 or two female rats in any dosage group. These observations included perioral substance, excess salivation, bent tail, chromodacryorrhea, comeal opacity of right eye, localized alopecia on the limbs, underside or head, urine-stained abdominal fur, red perivaginal substance, soft or liquid feces, missing/broken incisors and dehydration. 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 the 50 mg/kg/day dosage group and one female rat in the 250 mg/kg/day dosage group. These observations included an absent right kidney in one 50 mg/kg/day dosage group female rat (17706) and a small thymus in one 250 mg/kg/day dosage group female rat (17696). The small thymus was not available for histomorphologic diagnosis. 4.1.4. Histopathology Treatment-related microscopic changes were observed in the liver and thymus of female rats in the 250 mg/kg/day dosage group. The treatment-related microscopic changes in the liver consisted of minimal or mild enlargement (hypertrophy) of centrilobular hepatocytes in most of the female rats in the 250 mg/kg/day dosage group. The enlargement was due to an increased amount of finely granular, dense eosinophilic cytoplasm. Microscopic examination of the thymus revealed an increased incidence and severity of atrophy of the thymic lobules in female rats in the 250 mg/kg/day dosage group. No treatment-related microscopic changes were observed in any of the female rats given 10 mg/kg/day of the test substance. 418-027 :PAGE 4-2 4.2. Terminal Body Weights and Organ Weights and Ratios (%) of Organ Weight to Terminal Body Weight and Brain Weight (Summaries - Tables C3 through C5; Individual Data - Tables C29 and C30) Terminal body weights of the female rats were reduced (-4.8%), albeit not significantly, in the 250 mg/kg/day dosage group, as compared with control group values. Absolute weights of the liver was significantly increased (p<0.01) in the 250 mg/kg/day dosage group, as compared with the control group value. The ratios of the weight of this organ and the weight of the right kidney to terminal body weights were significantly increased (p<0.01) in the 250 mg/kg/day dosage group. Only the ratio of the liver weight to brain weight in the 250 mg/kg/day dosage group was significantly increased (p<0.01) was considered treatment-related; the significantly increased (p<0.05) ratio of the liver weight to brain weight in the 10 mg/kg/day dosage group was not considered treatmentrelated because it was not dosage dependent. 4.3. Hematology and Clinical Chemistry (Summaries - Tables C6 and C7) Dosages as high as 250 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, prothrombin and activated partial thromboplastin time (PT and APTT), mean platelet volume (MPV), nucleated red blood cell count (NRBC), lymphocytes, segmented neutrophils, bands, monocytes, eosinophils, basophils, abnormal lymphocytes in female rats were comparable among the four dosage groups and did not differ significantly. Average values for total protein (TP), albumin (A), glucose (GLU), cholesterol (CHOL), total bilirubin (TBILI), blood urea nitrogen (BUN), creatinine (CREAT), 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 four dosage groups and did not differ significantly. 4.4. Body Weights and Body Weight Changes (Figure 1; Summaries - Tables C8 through C13; Individual Data - Tables C31 through C33) 4.4.1. Precohabitation Body weight gains were significantly reduced (p<0.05) during the precohabitation period in the 250 mg/kg/day dosage group on DSs 1 to 8 and 1 to 15. Body weights were not significantly affected by dosages of the test substance on any weight day during precohabitation. 418-027:PAGE 4-3 4.4.2. Gestation Body weights and body weight gains were not significantly affected by dosages of the test substance during gestation. Body weights gains were significantly reduced (p<0.05 or p<0.01) during gestation on days of gestation (DGs) 0 to 3 and 12 to 15 in the 50 mg/kg/day dosage group and on DGSs 12 to 15 in the 10 mg/kg/day dosage group. These significant reductions in body weight gain were not considered treatment-related because they were not dosagedependent. 4.4.3. Lactation Body weight gains were not significantly affected by dosages of the test substance during lactation. Body weights were significantly reduced (p<0.05) during lactation on day of lactation (DL) 1 in the 250 mg/kg/day dosage group but was not considered treatmentrelated because it did not persist. 4.5. Absolute (g/day) and Relative (g/kg/day) Feed Consumption Values (Summaries - Tables C14 through C19; Individual Data - Tables C34 through C36) 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 during the precohabitation period. 4.5.2. Gestation Absolute (g/day) feed consumption values were not significantly affected by dosages of the test substance during the gestation period. Relative (g/kg/day) feed consumption values were significantly increased (p<0.01) during gestation on DGs 15 to 18 in the 250 mg/kg/day dosage group but was not considered treatment-related because it did not persist. 4.5.3. Lactation Absolute and relative feed consumption values were not significantly affected by dosages of the test substance during lactation. 4.6. Estrous Cycling, Mating and Fertility (Summary - Table C20; Individual Data - Table C37) The average numbers of estrous stages per 14 days were comparable among the four dosage groups and did not significantly differ. The number of rats with six or more consecutive days of diestras or estras did not differ significantly. 418-027 :PAGE 4-4 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, rats pregnant per rats in cohabitation and the number of pregnant rats per number of rats in cohabitation) were unaffected by dosages of the test substance as high as 250 mg/kg/day. 4.7. Functional Observational Battery (Summary - Table C21; Individual Data - Table C38) There were no 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 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 C39) There were no statistically significant or biologically important differences among the four dosage groups in the measures of motor activity on DS 86. 4.9. Natural Delivery and Litter Observations (Summary - Tables C23 and C24; Individual Data - Tables C40 through C43) Pregnancy occurred in all 15 (100%) rats assigned to the 0 (Vehicle) and 50 mg/kg/day dosage groups, 14 (93.3%) of the rats assigned to the 10 mg/kg/day dosage group and 13 (86.7%) of the rats assigned to the 250 mg/kg/day dosage group. All pregnant dams delivered a litter of one or more livebom pups. The number of livebom pups was significantly reduced (/?<0.01) in the 250 mg/kg/day dosage group. The number of stillborn pups was significantly increased (p<0.01) in the 250 mg/kg/day dosage group. The number of pups found dead or presumed cannibalized on day 1 and days 2 to 5 postpartum was significantly increased (p<0.01) in the 250 mg/kg/day dosage groups. The viability index (81.5%) was significantly reduced (p<0.01) in the 250 mg/kg/day dosage group, compared to the control group value (99.1%). The number of pups surviving per litter on postpartum day 5 was significantly reduced (p<0.05) in the 250 mg/kg/day dosage group. Pup body weights per litter were also reduced, albeit not significantly, in the 250 mg/kg/day dosage group on postpartum days 1 and 5. These 418-027:PAGE 4-5 findings at 250 mg/kg/day were considered related to the test substance because they were dosage dependent. Values for the numbers of dams delivering litters, the duration of gestation, averages for implantation sites per delivered litter, the gestation index (number of dams with one or more livebom pups/number of pregnant rats), the numbers of dams with stillborn pups, dams with all pups dying, stillborn pups, surviving pups per litter on postpartum day 1 and pup sex ratios were comparable among the four dosage groups and did not significantly differ. 4.10. Pup Clinical and Necropsy Observations (Summary - Tables C25 and C26; Individual Data - Tables C44 and C45) No clinical or necropsy observations in the FI generation pups were attributable to dosages of the test substance as high as 250 mg/kg/day because: 1) the incidences were not dosage-dependent; and 2) the observation occurred in only one to three litters. These clinical observations included: not nursing, not nesting, pale and bruise on head, back, mouth, lower midline, chest and/or neck. Necropsy observations on postpartum day 5 was limited to slight dilation of the renal pelvis of one pup from a 10 mg/kg/day dosage group litter. 418-027:PAGE 4-6 REFERENCES 1. Organisation for Economic Co-operation and Development (1996). OECD Guideline for Testing of Chemicals. Section 4, No. 422: Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, adopted 22 March 1996. 2. Organisation for Economic Co-operation and Development (1998). The Revised OECD Principles of Good Laboratory Practices [C(97)186/Final]. 3. U.S. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule. 21 CFR Part 58. 4. Japanese Ministry of Health and Welfare (1997). Good Laboratory Practice Standardfor Safety Studies on Drugs, MHW Ordinance Number 21, March 26, 1997. 5. Christian, M.S. and Voytek, P.E. (1982). In Vivo Reproductive and Mutagenicity Tests. Environmental Protection Agency, Washington, D.C. National Technical Information Service, U.S. Department of Commerce, Springfield, VA 22161. 6. 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. 7. 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.) 8. Institute of Laboratory Animal Resources (1996). Guide for the Care and Use of Laboratory Animals. National Academy Press, Washington, D.C. 9. 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. 10. 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. 11. Moser, V.C. (1989). Screening approaches to neurotoxicity: Afunctional observational battery. J. Amer. Col. Toxicol. 8:85-94. 12. O'Donoghue, J.L. (1989). Screening for neurotoxicity using a neurologically based examination and neuropathology. J. Amer. Col. Toxicol. 8:97-116. 418-027 :PAGE 4-7 13. 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. 14. Snedecor, G.W. and Cochran, W.G. (1967). Analysis of Variance. Statistical Methods, 6th Edition, Iowa State University Press, Ames, pp. 258-275. 15. Dunnett, C.W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Amer. Stat. Assoc. 50:1096-1121. 16. Sokal, R.R. and Rohlf, F.J. (1969). Kruskal-Wallis Test. Biometry, W.H. Freeman and Co., San Francisco, pp. 388-389. 17. Dunn, O.J. (1964). Multiple comparisons using rank sums. Technometrics 6(3):241-252. 18. Siegel, S. (1956). Nonparametric Statisticsfor the Behavioral Sciences. Fisher's Exact. McGraw-Hill Co., New York, pp. 96-105. 19. SAS Institute, Inc. (1988). Repeated measures analysis of variance. SAS/STATTM User's Guide, Release 6.03 Edition, Cary, NC, pp. 602-609. 20. 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 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) BODY WEIGHTS - MALE RATS Figure 1 480 0 (VEHICLE) MG/KG/DAY 10 MG/KG/DAY 50 MG/KG/DAY 320 1 15a DAY OF STUDY 29b 250 MG/KG/DAY *p<0.05 >p<0.01 a. Last value recorded before cohabitation. b. First value recorded after cohabitation. 36 418-027:PAGE A- PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) BODY WEIGHTS - FEMALE RATS Figure 2 418-027 :PAGE A-2 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) MOTOR ACTIVITY - NUMBER OF MOVEMENTS - MALE RATS Figure 3 0 (VEHICLE) MG/KG/DAY 10 MG/KG/DAY 50 MG/KG/DAY 250 MG/KG/DAY 0 10 20 30 40 50 60 70 80 90 100 TIME (MINUTES) 418-027:PAGE A-3 TIME (SECONDS) SPENT IN MOVEMENTS PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) MOTOR ACTIVITY - TIME SPENT IN MOVEMENT - MALE RATS Figure 4 0 (VEHICLE) MG/KG/DAY 10 MG/KG/DAY 50 MG/KG/DAY 250 MG/KG/DAY 0 20 40 60 80 100 TIME (MINUTES) 418-027 :PAGE A- PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) MOTOR ACTIVITY - NUMBER OF MOVEMENTS - FEMALE RATS Figure 5 90 -- ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ ------------ -- n ----------------------------------------------- 0 20 40 60 80 100 TIME (MINUTES) 418-027 :PAGE A-5 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) MOTOR ACTIVITY - TIME SPENT IN MOVEMENT - FEMALE RATS Figure 6 250 418-027:PAGE A-6 40 60 TIME (MINUTES) 100 APPENDIX B REPORT TABLES - Fo GENERATION MALE RATS PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B1 (PAGE 1) : CLINICAL OBSERVATIONS - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I 0 (VEHICLE) II 10 III 50 MAXIMUM POSSIBLE INCIDENCE 555/ 15 555/ 15 555/ 15 MORTALITY 000 EXCESS SALIVATION 0/ 0 0/ 0 0/ 0 RED, SLIGHT PERIORAL SUBSTANCE 0/ 0 0/ 0 0/ 0 URINE-STAINED ABDOMINAL FUR CHROMORHINORRHEA 0/ 0 4/ 3 0/ 0 6/ 4 1/ 1 2/ 1 LOCALIZED ALOPECIA: LIMBS 0/ 0 0/ 0 6/ 1 CHROMODACRYORRHEA 0/ 0 0/ 0 1/ 1 SOFT OR LIQUID FECES 3/ 2 3/ 2 0/ 0 RIGHT FORELIMB: SCAB(S) 0/ 0 0/ 0 0/ 0 INCISORS : MISSING/BROKEN PENIS: RED SUBSTANCE RIGHT FORELIMB : ULCERATION 0/ 0 0/ 0 0/ 0 0/ 0 1/ 1 0/ 0 1/ 1 1/ 1 0/ 0 STATISTICAL ANALYSES OF CLINICAL OBSERVATION DATA WERE RESTRICTED TO THE NUMBER OF RATS WITH OBSERVATIONS. MAXIMUM POSSIBLE INCIDENCE = (DAYS X RATS)/NUMBER OF RATS EXAMINED PER GROUP. N/N = TOTAL NUMBER OF OBSERVATIONS/NUMBER OF RATS WITH OBSERVATION. ** Significantly different from the vehicle control group value (p<0.01). IV 250 555/ 15 0 24/ 10** 15/ 10** 14/ 4** 6/ 3 16/ 2 5/ 2 2/ 2 14/ 1 9/ 1 1/ 1 1/ 1 418-027:PAGEB- PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B2 (PAGE 1) : NECROPSY OBSERVATIONS - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) i 0 (VEHICLE) II 10 III 50 IV 250 RATS EXAMINED a N 15 15 15 15 MORTALITY N0 0 0 0 APPEARED NORMAL N 15 15 15 14 PROSTATE: RIGHT HEMISPHERE, TAN, FIRM, LOBULAR MASS N0 0 0 1 VENTRAL RIGHT SIDE, RED N 0 00 1 a. Refer to the individual clinical observations table (Table B15) for external observations confirmed at necropsy. PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B3 (PAGE 1) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I 0 (VEHICLE) II 10 RATS TESTED N 15 15 TERMINAL BODY WEIGHT MEANS.D . 447.1 + 34.7 439.0 21.3 EPIDIDYMIS LEFT MEANS.D . 0.74 + 0.06 0.72 0.09 TESTIS LEFT MEAN+S.D. 1.76 0.14 1.64 0.29 EPIDIDYMIS RIGHT MEANS.D. 0.76 0.06 0.74 0.10 TESTIS RIGHT MEAN+S.D. 1.74 0.14 1.72 0.12 BRAIN LIVER MEANS.D . MEAN+S.D. 2.31 0.10 [ 10] a 13.61 1.26 2 . 2 5 + 0.12 [ 10] a 13.79 1.74 KIDNEY LEFT KIDNEY RIGHT ADRENAL LEFT ADRENAL RIGHT SPLEEN THYMUS HEART MEAN+S.D. MEAN+S.D. MEAN+S.D . MEANS.D . MEAN+S.D . MEAN+S.D. MEAN+S.D . 1.94 0.16 [ 10] a 2.00 0.09 [ 10] a 0.030 0.003 [ 9]a,b 0.028 0.004 [ 10] a 0.89 0.09 [ 10] a 0.54 0.14 [ 10] a 1.51 0.13 [ 10] a 1.96 0.16 [ 10] a 2.02 + 0.21 [ 10] a 0.030 0.005 [ 10] a 0.032 0.005 [ 10] a 0.79 0.12 [ 10] a 0.43 0.13 [ 10] a 1.49 0.20 [ 10] a ALL WEIGHTS WERE RECORDED IN GRAMS (G) . [ ] = NUMBER OF VALUES AVERAGED. a. Results did not warrant examination of the five additional rats. b. Excludes a value for rat 17650, which had an organ damaged (weight affected). * Significantly different from the vehicle control group value (p<0.05). ** Significantly different from the vehicle control group value (p<0.01). III 50 15 428.6 32.2 0.72 0.08 1.73 0.15 0.73 0.09 1.74 0.15 2.36 0.09 [ 10] a 14.06 1.51 2.12 0.18* [ 10] a 2.16 0.18* [ 10] a 0.029 0.006 [ 10] a 0.029 0.002 [ 10] a 0.85 0.12 [ 10] a 0.43 0.14 [ 10] a 1.46 0.16 [ 10] a IV 250 15 412.3 16.0** 0.71 0.06 1.74 0.13 0.70 0.06 1.75 0.14 2.32 0.16 [ 10] a 18.31 2.27** 2.16 + 0.13** [ 10] a 2.18 0.13* [ 10] a 0.030 + 0.007 [ 10] a 0.028 0.004 [ 10] a 0.83 0.10 [ 10] a 0.40 0.12 [ 10] a 1.45 + 0.17 [ 10] a 418-027:PAGE B-3 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVE LOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B4 (PAGE 1) : RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II ill IV 0 (VEHICLE) 10 50 250 RATS TESTED N 15 15 15 15 EPIDIDYMIS LEFT MEANS.D. 0.165 + 0.016 0.165 0.019 0.167 0.023 0.173 0.018 TESTIS LEFT MEAN+S.D. 0.395 0.050 0.373 0.066 0.406 0.048 0.422 + 0.038 EPIDIDYMIS RIGHT MEANS.D . 0.169 0.019 0.167 0.025 0.171 0.026 0.171 0.017 TESTIS RIGHT MEANS.D . 0.392 0.046 0.393 0.027 0.409 0.047 0.425 0.041 BRAIN LIVER MEAN+S.D . MEAN+S.D. 0.521 0.039 [ 10] a 3.043 0.144 0.512 + 0.032 [ 10] a 3.133 0.278 0.547 0.033 ( 10] a 3.275 0.166** 0.555 0.050 [ 10] a 4.434 + 0.450** KIDNEY LEFT KIDNEY RIGHT ADRENAL LEFT b ADRENAL RIGHT b SPLEEN THYMUS HEART MEANS.D. MEANS.D . MEANS.D . MEAN+S.D. MEANS.D . MEAN+S.D. MEAN+S.D . 0.436 0.046 [ 10] a 0.451 0.037 [ 10] a 6.562 0.570 [ 9] a, C 6.325 0.938 [ 10] a 0.200 0.027 t 10] a 0.122 0.032 [ 10] a 0.341 0.027 [ 10] a 0.448 0.043 [ 10] a 0.462 0.051 [ 10] a 6.737 + 1.213 [ 10] a 7.215 1.194 [ 10] a 0.178 0.026 ( 10] a 0.099 + 0.030 [ 10] a 0.341 0.038 [ 10] a 0.493 0.056* [ 10] a 0.501 0.056* [ 10] a 6.690 1.451 [ 10] a 6.826 0.724 [ 10] a 0.197 0.033 [ 10] a 0.099 0.033 [ 10] a 0.338 0.039 [ 10] a 0.517 0.033** [ 10] a 0.521 + 0.031** [ 10] a 7.069 1.568 [ 10] a 6.598 1.005 [ 10] a 0.197 0.021 [ 10] a 0.096 0.029 [ 10] a 0.348 0.042 [ 10] a ALL WEIGHTS WERE RECORDED IN GRAMS (G) . RATIOS (%) = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. [ ] = NUMBER OF VALUES AVERAGED. a. Results did not warrant examination of the five additional rats. b. Value was multiplied by 1000. c. Excludes a value for rat 17660, which had an organ damaged (weight affected). * Significantly different from the vehicle control group value (p<0.05). ** Significantly different from the vehicle control group value (p^O.Ol). 418-027:PAGE B-4 PROTOCOL 418-027: ORAL (GAVAGK) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B5 (PAGE 1) : RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) i 0 (VEHICLE) II 10 III 50 IV 250 RATS TESTED N 10a 10a 10a 10a BRAIN WEIGHT MEANS.D. 2.31 0.10 2.25 0.12 2.36 + 0.09 2.32 + 0.16 EPIDIDYMIS LEFT MEAN+S.D . 31.28 2.24 32.08 + 3.44 29.98 + 3.37 29.86 + 2.87 TESTIS LEFT MEANS.D . 75.14 + 6.24 75.90 + 4.98 73.00 + 8.32 73.95 + 10.60 EPIDIDYMIS RIGHT MEAN+S.D. 31.97 + 2.81 32.63 + 3.73 30.38 + 3.16 29.72 + 3.60 TESTIS RIGHT MEANS.D . 74.42 5.96 76.90 + 3.34 72.98 + 6.85 73.87 9.89 LIVER MEANS.D . 594.63 42.79 620.48 + 81.18 603.91 + 53.24 807.37 123.75' KIDNEY LEFT MEAN+S.D. 83.88 7.32 87.59 7.45 90.39 9.47 93.84 + 9.85 KIDNEY RIGHT MEANS.D . 86.77 5.89 90.12 + 9.43 91.76 + 8.79 94.73 + 10.17 ADRENAL LEFT ADRENAL RIGHT MEANS.D . MEANS.D. 1.18 0.30 [ 9] b 1.22 0.16 1.32 + 0.27 1.42 + 0.29 1.22 + 0.25 1.25 + 0.11 1.29 + 0.38 1.19 + 0.18 SPLEEN MEANS.D . 38.72 5.38 35.15 + 4.75 36.13 5.76 35.99 6.32 THYMUS MEAN+S.D . 23.66 7.02 19.20 + 5.21 18.19 + 5.94 17.22 4.88 HEART MEANS.D. 65.48 7.01 66.42 + 7.27 61.92 + 6.70 63.19 + 9.74 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . RATIOS (%) = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. a. Results did not warrant examination of the five additional rats. b. Excludes a value for rat 17650, which had an organ damaged (weight affected). ** Significantly different from the vehicle control group value (p<0.01). 418-027`.PAGE B-5 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B6 (PAGE 1) : HEMATOLOGY - SUMMARY - Fo GENERATION MALE RATS (See last page of this table for abbreviations) DOSAGE GROUP DOSAGE (MG/KG/DAY) RATS TESTED WBC (THSN/CU MM) RBC (MILL/CU MM) HGB (GRAMS/DL) HCT (%) MCV (CU MICRONS) MCH (PICO GRAMS) MCHC (%) PLT (THSN/CU MM) PT (SECONDS) APTT (SECONDS) N MEANS .D . MEANS.D. MEAN+S.D. MEAN+S .D . MEAN+S .D . MEAN+S.D. MEAN+S.D MEANS.D . MEANS,D . MEAN+S.D. I 0 (VEHICLE) 5 14.7 3.61 7.55 0.493 15.8 0.26 43.7 1.82 57.9 2.09 21.0 1.15 36.3 0.97 1197 + 122.5 14.4 0.66 25.4 1.89 II 10 5 18.9 2.96 7.56 0.448 15.6 0.71 42.5 2.12 56.3 + 0.84 20.7 + 0.42 36.8 + 0.35 1172 + 54.0 13.7 0.39 25.9 + 2.33 III 50 5 15.3 3.36 7.27 0.291 15.2 0.40 41.4 1.30 56.9 1.94 20.9 0.70 36.6 1.17 1218 190.7 14.7 0.70 26.2 + 2.18 IV 250 5 19.3 + 7.90 7.17 + 0.270 15.1 + 0.65 40.5 1.88 56.5 1.44 21.1 0.88 37.4 + 1.25 1283 138.9 14.6 + 0.96 26.7 + 2.51 418-027:PAGE B-6 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B6 (PAGE 2) : HEMATOLOGY - SUMMARY - Fo GENERATION MALE RATS (See the page of this table for abbreviations) DOSAGE GROUP DOSAGE (MG/KG/DAY) RATS TESTED N MPV (CU MICRONS) MEANS.D . NRBC COUNT MEAN+S.D . Lymphocyte (THSN/CU MM) MEANS.D . Segmented (THSN/CU MM) MEAN+S.D . Bands (THSN/CU MM) MEAN+S .D . Monocytes (THSN/CU MM) MEAN+S .D . Eosinophil (THSN/CU MM) MEANS.D. Basophils (THSN/CU MM) MEAN+S .D . Abnormal L (THSN/CU MM) MEANS.D . Other (THSN/CU MM) MEAN+S .D . I 0 (VEHICLE) 5 9.2 0.32 0 0.0 12.6 3.67 1.9 0.26 0.0 0.00 0.1 0.07 0.1 0.05 0.0 0.00 0.0 0.00 0.0 0.00 II 10 5 9.7 0.79 0 0.0 15.8 3.21 2.8 0.87 0.0 0.00 0.2 0.20 0.2 0.11 0.0 0.00 0.0 0.00 0.0 0.00 III 50 5 9.5 1.03 0 0.0 13.3 3.24 1.8 0.41 0.0 0.00 0.1 0.09 0.2 0.15 0.0 0.00 0.0 0.00 0.0 0.00 IV 250 5 9.1 0.67 0 0.0 14.1 4.01 5.0 7.38 0.0 0.00 0.1 0.13 0.1 0.14 0.0 0.00 0.0 0.00 0.0 0.00 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B6 (PAGE 3): HEMATOLOGY - SUMMARY - Fo GENERATION MALE RATS KEY TO HEMATOLOGY TABLE ABBREVIATION WBC RBC HGB HCT MCV MCH MCHC PLAT MPV PT APTT NRBC Segmented Abnormal L Other TERMINOLOGY White Blood Cells (Leukocytes) Red Blood Cells (Erythrocytes) Hemoglobin Hematocrit (Packed Cell Volume) Mean Corpuscular Volume Mean Corpuscular Hemoglobin Mean Corpuscular Hemoglobin Concentration Platelets Mean Platelet Volume Prothrombin Time Activated Partial Thromboplastin Nucleated Red Blood Cell Count Segmented Neutrophils Abnormal Lymphocytes Other Cells 418-027 :PAGE B-8 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B7 (PAGE 1) : CLINICAL CHEMISTRY - SUMMARY - Fo GENERATION MALE RATS (See last page of this table for abbreviations) DOSAGE GROUP DOSAGE (MG/KG/DAY) RATS TESTED TP (G/DL) A (G/DL) GLU (MG/DL) CHOL (MG/DL) TBILI (MG/DL) BUN (MG/DL) CREAT (MG/DL) ALT (U/L) AST (U/L) N MEAN+S .D . MEANS .D . MEANS.D . MEANS.D . MEAN+S. D. MEANS .D . MEAN+S .D . MEANS.D . MEANS.D . I 0 (VEHICLE) 5 6.3 0.29 4.0 + 0.16 159 + 11.0 56 11.9 0.1 + 0.00 12 + 1.6 0.3 + 0.05 38 2.3 88 3.4 II 10 5 6.3 0.34 4.1 0.15 184 23.9 52 5.3 0.1 0.00 14 2.3 0.3 0.04 43 1.6 86 10.2 III 50 5 6.2 0.29 4.1 0.21 156 12.7 49 + 5.5 0.1 0.00 13 + 1.3 0.3 + 0.04 47 + 4.2 96 + 5.7 IV 250 5 6.3 0.16 4.2 + 0.43 108 11.5 29 8.2 0.1 0.00 17 + 5.9 0.4 + 0.09 48 + 6.5 102 + 8.3 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B7 (PAGE 2) : CLINICAL CHEMISTRY - SUMMARY - Fo GENERATION MALE RATS (See last page of this table for abbreviations) DOSAGE GROUP DOSAGE (MG/KG/DAY) RATS TESTED ALK (U/L) CA (MG/DL) PHOS (MG/DL) TRI (MG/DL) NA (MMOL/L) K (MMOL/L) CL (MMOL/L) G (G/DL) A/G N MEAN+S. D. MEANS.D . MEAN+S.D . MEAN+S.D . MEAN+S .D . MEAN+S.D . MEAN+S .D . MEAN+S.D . MEAN+S.D . I 0 (VEHICLE) 5 107 + 27.4 11.1 0.37 8.5 + 0.87 72 + 22.2 148 + 1.5 5.7 0.51 96 1.8 2.2 0.18 1.8 0.15 II 10 5 108 28.6 11.4 0.38 9.7 2.45 59 13.1 147 2.9 6.2 + 1.01 98 2.9 2.3 + 0.26 1.8 0.21 III 50 5 116 23.4 11.4 0.29 9.4 0.90 66 23.2 148 0.8 6.5 + 0.49 100 2.2 2.1 + 0.20 2.0 0.22 IV 250 5 123 + 20.0 11.3 0.14 10.0 1.51 31 9.5 148 2.8 6.5 0.80 99 2.9 2.1 0.41 2.0 0.49 418-027-.PAGEB-10 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B7 (PAGE 3): CLINICAL CHEMISTRY - SUMMARY -- Fo GENERATION MALE RATS KEY TO CLINICAL CHEMISTRY TABLE ABBREVATION TP A GLU CHOL TBILI BUN CREAT ALT AST ALK CA PHOS TRI NA K CL G A/G TERMINOLOGY Total Protein Albumin Glucose Cholesterol Total Bilirubin Blood Urea Nitrogen Creatinine Alanine Aminotransferase Aspartate Aminotransferase Alkaline Phosphatase Calcium Phosphorus (inorganic) Triglycerides Sodium Potassium Chloride Globulin Albumin/Globulin Ratio 418-027:PAGE B- PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B8 (PAGE 1) : BODY WEIGHTS - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I 0 (VEHICLE) II 10 RATS TESTED N 15 15 BODY WEIGHT (G) DAY 1 MEANS.D. 342.7 9.4 341.9 9.4 DAY 8 MEAN+S.D . 384.8 16.3 380.9 13.0 DAY 15a MEANS.D . 411.6 + 24.8 409.8 16.5 DAY 29b MEAN+S.D . 458.3 + 32.5 450.8 20.8 DAY 36 MEAN+S.D . 474.2 36.0 466.3 22.5 DAY = DAY OF STUDY a. Last value recorded before cohabitation. b. First value recorded after cohabitation. ** Significantly different from the vehicle control group value (p<0.01). III 50 15 343.8 13.1 380.0 20.1 403.4 24.4 440.7 31.7 455.9 32.2 IV 250 15 339.5 9.4 370.6 11.4 393.5 13.9 428.8 13.9** 443.5 14.9** 418-027 :PAGE B-12 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B9 (PAGE 1) : BODY WEIGHT CHANGES - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I 0 (VEHICLE) II 10 RATS TESTED N 15 15 BODY WEIGHT CHANGE (G) DAYS 1 - 8 MEANS.D . +42.1 9.1 +39.0 + 7.5 DAYS 8 - 15a MEANS.D . +26.8 + 10.1 +28.9 7.6 DAYS 1 - 15a MEANS.D . +68.9 17.8 +67.9 1 2 . 8 DAYS 29b- 36 MEANS.D . +15.9 6.0 +15.5 5.4 DAYS 1 - 3 6 MEAN+S.D. +131.5 29.6 +124.4+ 21.8 DAYS = DAYS OF STUDY a. Last value recorded before cohabitation. b. First value recorded after cohabitation. * Significantly different from the vehicle control group value ** Significantly different from the vehicle control group value (p<0.05). (p^O.Ol). III 50 15 +36.2 + 9.8 +23.4 6.8 +59.6 + 12.5 +15.2 7.1 +112.1+ 21.2* IV 250 15 +31.1 + 5.2** +22.9 + 6.8 +53.9 + 9.9** +14.7 3.7 +103.9 13.8** PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE BIO (PAGE 1) : ABSOLUTE FEED CONSUMPTION VALUES (G/DAY) - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I 0 (VEHICLE) II 10 RATS TESTED N 15 15 FEED CONSUMPTION (G) DAYS i - 8 MEANS.D . 27.4 2.0 26.2 1.6 DAYS 8 - 15a DAYS 1 - 15a DAYS 29c- 36 MEAN+S.D . MEAN+S.D . MEANS.D . 26.3 26.9 28.3 + 2.8 2.4 2.8 25.8 1.6 [ 14] b 26.1 1.4 [ 14] b 27.2 1.9 DAYS 1 - 36 MEAN+S.D. 27.3 2.4 26.4 1.5 DAYS = DAYS OF STUDY [ ] = NUMBER OF VALUES AVERAGED a. Last value recorded before cohabitation. b. Excludes values that were associated with spillage. c. First value recorded after cohabitation. * Significantly different from the vehicle control group value * * Significantly different from the vehicle control group value (p<0.05). (p<0.01). III 50 15 25.9 25.5 25.7 26.8 26.1 + 2.4* 2.6 2.3 2.8 2.3 IV 250 15 24.7 24.9 24.8 26.0 25.2 1.4** 1.9 1.4** 1.6 1.3** PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE Bll (PAGE 1) : RELATIVE FEED CONSUMPTION VALUES (G/KG/DAY) - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I 0 (VEHICLE) II 10 RATS TESTED FEED CONSUMPTION (G) N 15 15 DAYS 1 - 8 MEANS.D. 75.1 3.8 72.4 3.2 DAYS 8 - 15a DAYS 1 - 15a DAYS 29c- 36 M E A N S .D . M E A N + S .D . M E A N S .D . 66.0 4.5 70.4 3.9 60.6 3.2 65.1 3.4 [ 14] b 68.6 2.7 [ 14] b 59.5 2.8 DAYS 1 " 36 M E A N S .D . 65.3 2.7 63.9 DAYS = DAYS OF STUDY [ ] = NUMBER OF VALUES AVERAGED a. Last value recorded before cohabitation. b. Excludes values that were associated with spillage. c. First value recorded after cohabitation. * Significantly different from the vehicle control group value ** Significantly different from the vehicle control group value (p^O.05). (p<0.01). 2.2 III 50 15 71.4 65.2 + 68.2 59.9 + 64.0 4.9* 4.4 3.6 4.3 3.3 IV 250 15 70.0 65.2 + 67.5 59.8 63.5 3.1** 3.7 2.7 2.6 2.1 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B12 (PAGE 1) : MATING AND FERTILITY - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I 0 (VEHICLE) II 10 Ill 50 RATS IN COHABITATION N 15 15 15 DAYS IN COHABITATION a MEANS.D . 2.9 1.6 2.7 1.0 3.5 1.7 RATS THAT MATED b N (%) 14( 93.3) 15(100.0) 13( 86.7) FERTILITY INDEX c,d N/N (%) 14/14 (100.0) 14/15 ( 93.3) 13/13 (100.0) RATS WITH CONFIRMED MATING DATES N 14 15 13 MATED WITH FEMALE e DAYS 1 - 7 DAYS 8-14 N(%) N(%) 14(100.0) 0( 0.0) 15(100.0) 0( 0.0) 13(100.0) 0( 0.0) RATS PREGNANT/RATS IN COHABITATION d N/N (%) 14/15 ( 93.3) 14/15 ( 93.3) 13/15 ( 86.7) a. Restricted to rats with a confirmed mating date and rats that did not mate, b. Includes only one mating for each male rat. c. Number of pregnancies/number of rats that mated. d. Includes only one pregnancy for each rat that impregnated more than one female rat. e. Restricted to rats with a confirmed mating date. IV 250 15 2.8 2.1 13( 86.7) 12/13 ( 92.3) 13 13(100.0) 0( 0.0) 12/15 ( 80.0) PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B13 (PAGE 1) : FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - MALE RATS DOSAGE GROUP I II III IV DOSAGE (MG/KG/DAY) 0 (VEHICLE) 10 50 250 RATS N5 5 5 5 HOME CAGE BEHAVIOR 1 Sleeping 2 Awake, Immobile 3 Normal movement 4 Unusual posture 5 Unusual behavior N N N N N 0 5 0 0 0 0 5 0 0 0 0 5 0 0 0 0 5 0 0 0 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 5 0 0 0 0 0 0 5 0 0 0 0 0 0 5 0 0 0 0 0 0 5 0 0 0 0 0 0 REACTION TO REMOVAL (i) Sits quietly (2) Vocalization (3) Runs or freezes (4) Tail or throat rattles N N N N MEAN SCORE 5 0 0 0 1.0 5 0 0 0 1.0 5 0 0 0 1.0 5 0 0 0 1.0 418-027:PAGE B-17 REACTION TO HANDLING di No resistance N5 5 5 5 (2) Vocalization N0 0 0 0 ( ) Tense N0 0 0 0 (4) Squirming N0 0 0 0 MEAN SCORE 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 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCT ION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B13 (PAGE 2) : FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - MALE RATS DOSAGE GROUP I II III IV DOSAGE (MG/KG/DAY) 0 (VEHICLE) 10 50 250 RATS N5 5 5 5 REARS IN OPEN FIELD MEANS.D. 7.2 2.9 7.2 3.1 7.2 4.2 10.6 6.9 DEFECATION IN OPEN FIELD 1 : None N2 1 5 3 2 : Feces normal N2 4 0 1 3: Soft or liquid feces N 1 0 0 1 URINATION IN OPEN FIELD (1) None N1 0 3 3 (2) Normal urination N 4 5 2 2 (3) Excess urination N 0 0 0 0 MEAN SCORE 1.8 2.0 1.4 1.4 LEVEL OF AROUSAL (1) Stuporous N0 0 0 0 (2) Sluggish N0 0 0 0 (3) Apparently normal N 5 5 5 5 (4) Sudden darting N0 0 0 0 (5) Freezing, vocalization N 0 0 0 0 MEAN SCORE 1.0 3.0 3.0 3.0 418-027:PAGEB-18 ALTERATIONS (OPEN FIELD) 1: None N5 5 5 5 2: Stereotyped behavior N 0 0 0 0 3: Bizarre behavior N 0 0 0 0 4: Limb twitches/tremor N 0 0 0 0 5: Whole body tremor/spasm N 0 0 0 0 6: Unusual posture N0 0 0 0 7: Tonic-clonic seizure N 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 a. Excludes a value that was incorrectly recorded. PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B13 (PAGE 3) : FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) RATS I 0 (VEHICLE) N5 II 10 5 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 5 0 0 0 0 0 5 0 0 0 0 0 GAIT ABNORMALITY, SEVERITY (1) Normal gait (2) Slight (3) Moderate (4) Extreme N N N N MEAN SCORE 5 0 0 0 1.0 5 0 0 0 1.0 III 50 5 5 0 0 0 0 0 5 0 0 0 1.0 IV 250 5 5 0 0 0 0 0 5 0 0 0 1.0 418-027`.PAGE B-19 PALPEBRAL CLOSURE (1) Wide open (2) Slightly drooping (3) Half-closed (4) Completely shut N N N N MEAN SCORE 5 0 0 0 1.0 5 0 0 0 1.0 5 0 0 0 1.0 5 0 0 0 1.0 PROMINENCE OF THE EYE 1: Normal N5 5 5 5 2 : Exophthalmos N0 0 0 0 3 : Enophthalmos N0 0 0 0 n: = Category number for descriptive test item. in) = 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 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B13 (PAGE 4): FUNCTIONAL >OBSERVATIONAL BATTERY - SUMMARY - MALE RATS DOSAGE GROUP I II III IV DOSAGE (MG/KG/DAY) 0 (VEHICLE) 10 50 250 RATS N5 5 5 5 LACRIMATION (1) No excess N (2) Excess at eyelid margin N (3) Margin persistently damp N (4) Extends beyond margin N MEAN SCORE 5 0 0 0 1.0 5 0 0 0 1.0 5 0 0 0 1.0 5 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 5 0 0 0 1.0 5 0 0 0 1.0 5 0 0 0 1.0 5 0 0 0 1.0 PILOERECTION ABNORMAL RESPIRATION N N 0 0 0 0 0 0 0 0 APPEARANCE (1) Clean and groomed N (2) Unkempt N (3) Urine and/or fecal stain N MEAN SCORE 5 0 0 1.0 5 0 0 1.0 5 0 0 1.0 5 0 0 1.0 418-027:PAGE B-20 VISUAL REACTION (1) None N0 0 0 0 (2) Orienting (3) Startle N5 N0 5 0 5 0 5 0 (4) More energetic reaction N 0 0 0 0 (5) Attacks N MEAN SCORE 0 2.0 0 2.0 0 2.0 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 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B13 (PAGE 5) : FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - MALE RATS DOSAGE GROUP I II III IV DOSAGE (MG/KG/DAY) 0 (VEHICLE) 10 50 250 RATS N5 5 5 5 TACTILE REACTION ti) None N (2) Orienting N (3) Startle N (4) More energetic reaction N (5) Attacks N MEAN SCORE 0 5 0 0 0 2.0 0 5 0 0 0 2.0 0 5 0 0 0 2.0 0 5 0 0 0 2.0 AUDITORY REACTION (i) None N (2) Orienting N (3) Startle N (4) More energetic reaction N (5) Intense vocalization N MEAN SCORE 0 0 5 0 0 3.0 0 0 5 0 0 3.0 0 0 5 0 0 3.0 0 0 5 0 0 3.0 TAIL -PINCH REACTION tu None N (2) Orienting N (3) Startle N (4) More energetic reaction N (5) Attacks N MEAN SCORE . 0 5 0 0 0 2.0 0 5 0 0 0 2.0 0 5 0 0 0 2.0 0 5 0 0 0 2.0 418-027:PAGE B-21 VISUAL PLACING RESPONSE di Early extension N (2) Extension after contact N (3) No extension N MEAN SCORE 5 0 0 1.0 5 0 0 1.0 5 0 0 1.0 5 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 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B13 (PAGE 6) : FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - MALE RATS DOSAGE GROUP I II III IV DOSAGE (MG/KG/DAY) 0 (VEHICLE) 10 50 250 RATS N5 5 5 5 AIR RIGHTING RESPONSE (1) All feet land on ground N (2) Lands on side N (3) Lands on back. N MEAN SCORE 5 0 0 1.0 5 0 0 1.0 5 0 0 1.0 5 0 0 1.0 PUPIL RESPONSE TO LIGHT N 5 5 5 5 FORELIMB GRIP TEST Maximum (G) Average (G) HINDLIMB GRIP TEST Maximum (G) Average (G) MEAN+S.D. MEANS.D. 375.0 120.9 337.6 + 112.8 423.0 55.0 393.4 + 50.4 404.0 + 110.4 329.0 + 98.1 293.0 276.4 + 114.2 105.8 MEAN+S.D. MEANS.D. 387.0 + 123.0 355.0 + 105.3 341.0 + 66.8 309.0 + 55.1 420.0 382.8 + 99.7 + 96.0 354.0 315.0 + 104.0 + 418-027:PAGE B-22 CO ra-\> LANDING FOOT SPLAY Average (CM) MEAN+S.D. 8.6 1.5 9.6 2.2 8.0 1.3 7.9 + 1.3 BODY WEIGHT (G) N 464.6 37.3 457.5 19.9 438.6 + 28.4 422.4 + 12.3 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 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B14 (PAGE 1) : MOTOR ACTIVITY - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I 0 (VEHICLE) II 10 DAY 86 NUMBER OF RATS N 5 5 NUMBER OF MOVEMENTS BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 BLOCK 7 BLOCK 8 BLOCK 9 BLOCK 10 BLOCK 11 BLOCK 12 BLOCK 13 BLOCK 14 BLOCK 15 BLOCK 16 BLOCK 17 BLOCK 18 TOTAL MEAN 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. 65.4 9.9 72.0 7.6 69.8 4.1 58.0 18.9 29.8 29.2 31.2 28.8 35.0 35.3 44.8 27.6 35.0 34.2 18.8 23.7 20.0 27.0 31.8 38.6 26.0 31.5 14.8 25.5 11.2 21.8 14.8 22.6 13.8 25.9 12.4 23.9 604.6 292.0 67.0 10.0 67.8 9.0 70.4 15.1 62.4 14.6 63.4 19.9 51.6 30.9 41.4 28.8 50.2 31.9 41.4 23.7 36.4 30.2 33.0 22.8 24.6 19.5 22.8 29.9 27.2 26.2 18.6 24.3 18.0 21.1 4.8 5.3 3.8 5.0 704.8 280.9 TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. III 50 5 64.0 4.1 63.2 15.3 66.8 11.6 54.6 14.5 42.8 30.9 28.4 24.5 22.4 29.7 25.4 22.4 32.2 31.3 44.4 27.2 35.8 31.7 22.4 22.3 19.4 27.6 19.8 24.1 15.4 23.9 22.0 21.0 13.4 23.0 7.6 14.8 600.0 120.2 IV 250 5 65.6 72.2 62.0 61.2 25.6 16.0 10.8 8.2 1.4 10.8 26.0 22.6 7.4 3.8 8.0 16.2 3.8 3.4 425.0 5.3 12.2 9.0 10.8 29.2 22.4 21.4 13.1 1.7 20.9 24.2 27.8 7.7 6.8 12.5 24.2 6.9 4.7 91.8 418-027'.PAGE B-23 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B14 (PAGE 2): MOTOR ACTIVITY - SUMMARY - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I 0 (VEHICLE) II 10 DAY 86 NUMBER OF RATS N 5 5 TIME (SECONDS) SPENT IN MOVEMENT BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 BLOCK 7 BLOCK 8 BLOCK 9 BLOCK 10 BLOCK 11 BLOCK 12 BLOCK 13 BLOCK 14 BLOCK 15 BLOCK 16 BLOCK 17 BLOCK 18 TOTAL MEAN 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. 178.6 20.7 170.8 18.0 140.8 42.6 77.8 18.5 41.8 54.5 51.0 62.5 45.2 49.3 64.8 43.6 56.4 59.5 27.8 47.1 30.6 42.4 39.6 52.6 35.6 47.6 24.2 49.7 20.4 45.6 21.8 43.8 17.2 37.4 14.8 32.0 1059.2 547.0 204.8 16.2 167.4 10.1 140.2 23.4 101.8 22.4 101.4 39.2 85.4 50.9 66.4 61.9 70.4 48.2 75.0 46.2 47.0 39.9 40.0 36.4 35.3 35.6 30.0 39.9 27.8 28.4 20.2 29.9 22.2 30.4 4.0 6.2 2.6 4.3 1242.4 381.5 TOTAL o SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. III 50 5 188.4 19.3 135.0 31.2 123.4 20.5 101.6 30.8 56.2 43.7 33.2 28.1 33.4 50.3 26.8 31.0 38.2 39.3 72.6 55.4 60.4 64.3 26.2 27.9 21.8 31.0 22.6 30.9 19.4 34.8 26.4 28.4 20.0 36.4 12.2 26.2 1017.8 181.4 IV 250 5 17 9.6 22.4 152.6 29.4 111.6 23.8 109.2 52.2 32.2 38.2 24.0 45.5 13.6 30.4 5.0 9.1 0.6 0.9 14.2 28.0 32.8 34.1 30.6 43.0 5.8 8.0 2.2 4.9 6.6 11.3 28.0 40.6 4.0 3.9 1.2 2.7 753.8 146.0 418-027:PAGE B-24 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B15 (PAGE 1) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP I RAT # 17601 17602 17603 17604 17607 17608 17618 17630 17631 17639 17648 17652 17656 17658 17660 DS ( 35 ) DS ( 11 ) DS ( 14- 15) DS ( 34 ) DS ( 34- 35) DS = DAY OF STUDY VEHICLE DESCRIPTION NO ADVERSE FINDINGS NO ADVERSE FINDINGS CHROMORHINORRHEA NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS SOFT OR LIQUID FECES SOFT OR LIQUID FECES CHROMORHINORRHEA NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS CHROMORHINORRHEA 0 (VEHICLE) MG/KG/DAY 418-027:PAGE B-25 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B15 (PAGE 2) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP II RAT # 17615 17616 17624 17626 17632 17634 17635 17638 17642 17643 17645 17649 17651 17653 17655 DS ( 34 ) DS ( 34- 35) DS ( 14 ) DS( 35 ) DS ( DS ( DS ( 14 ) 10 ) 14 ) DS ( 15 ) DS ( 14 ) DS = DAY OF STUDY LOW DOSAGE DESCRIPTION PENIS : RED SUBSTANCE CHROMORHINORRHEA NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS CHROMORHINORRHEA CHROMORHINORRHEA NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS CHROMORHINORRHEA SOFT OR LIQUID FECES SOFT OR LIQUID FECES NO ADVERSE FINDINGS SOFT OR LIQUID FECES CHROMORHINORRHEA NO ADVERSE FINDINGS 10 MG/KG/DAY 418-027:PAGE B-26 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B15 (PAGE 3) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP III MIDDLE DOSAGE RAT # DESCRIPTION 17605 17610 17611 17613 17619 17620 17623 17627 17628 17633 17640 17646 17650 17657 17659 DS ( DS ( DS ( 14 ) 16 ) 27 ) DS ( DS ( DS ( 23 ) 23 ) 10 ) DS ( 32- 37) NO ADVERSE FINDINGS CHROMORHINORRHEA URINE-STAINED ABDOMINAL FUR CHROMORHINORRHEA NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS CHROMODACRYORRHEA INCISORS : MISSING/BROKEN PENIS : RED SUBSTANCE NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: LIMBS a NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS DS = DAY OF STUDY a. Observation confirmed at necropsy. 50 MG/KG/DAY 418-027:PAGE B-27 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B15 (PAGE 4) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP IV RAT # 17606 17609 17612 17614 17617 DS ( 10 ) DS ( 12- 13) DS ( 17 ) DS ( 23 ) DS ( 30- 31) DS ( 33 ) DS ( 12 ) DS ( 12- 13) DS ( 14 ) DS ( 14- 22) DS ( 16- 17) DS ( 32 ) DS ( 30 ) DS ( 35 ) DS ( 14- 15) DS ( 29 ) DS ( 1 ) DS ( 14 ) DS ( 14 ) DS ( 16 ) DS ( 29 ) DS ( 32 ) DS ( 37 ) DS = DAY OF STUDY HIGH DOSAGE DESCRIPTION EXCESS SALIVATION EXCESS SALIVATION RED, SLIGHT PERIORAL SUBSTANCE EXCESS SALIVATION EXCESS SALIVATION EXCESS SALIVATION CHROMORHINORRHEA CHROMODACRYORRHEA CHROMORHINORRHEA INCISORS: MISSING/BROKEN CHROMODACRYORRHEA EXCESS SALIVATION RED, SLIGHT PERIORAL SUBSTANCE PENIS: RED SUBSTANCE CHROMORHINORRHEA RED, SLIGHT PERIORAL SUBSTANCE EXCESS SALIVATION RED, SLIGHT PERIORAL SUBSTANCE URINE-STAINED ABDOMINAL FUR RED, SLIGHT PERIORAL SUBSTANCE EXCESS SALIVATION EXCESS SALIVATION URINE-STAINED ABDOMINAL FUR 250 MG/KG/DAY PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B15 (PAGE 5) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP IV HIGH DOSAGE 250 MG/KG/DAY RAT # DESCRIPTION 17621 17622 17625 17629 17636 17637 17641 17644 17647 17654 DS ( 25 ) DS ( 30 ) DS ( 31 ) DS ( 35 ) DS ( 16- 17) DS ( 23- 31) DS ( 32 ) DS ( 32 ) DS ( 33- 37) DS ( 37 ) DS ( 37 ) DS ( 32 ) DS ( 6- 7) DS ( 14 ) DS ( 19 ) DS ( 24 ) DS ( 30 ) DS ( 31- 35) DS ( 37 ) DS ( 14 ) DS ( 37 ) DS ( 15 ) DS ( 11 ) DS ( 15 ) DS ( 23- 37) DS ( 31 ) DS ( 33- 34) DS ( 17 ) DS ( 32- 35) DS ( 3 ) DS ( 10 ) DS ( 13 ) DS ( 3 ) DS ( 11 ) DS ( 29 ) RED, SLIGHT PERIORAL SUBSTANCE RED, SLIGHT PERIORAL SUBSTANCE EXCESS SALIVATION EXCESS SALIVATION RED, SLIGHT PERIORAL SUBSTANCE RIGHT FORELIMB: SCAB(S) (DID NOT EXCEED 2.5 CM X 0.5 CM) RIGHT FORELIMB: ULCERATION (1.0 CM IN DIAMETER) RED, SLIGHT PERIORAL SUBSTANCE RIGHT FORELIMB: SCAB(S) (DID NOT EXCEED 1.0 CM IN DIAMETER)a CHROMQDACRYORRHEA a LOCALIZED ALOPECIA: LIMBS a RED, SLIGHT PERIORAL SUBSTANCE CHROMORHINORRHEA URINE-STAINED ABDOMINAL FUR RED, SLIGHT PERIORAL SUBSTANCE RED, SLIGHT PERIORAL SUBSTANCE EXCESS SALIVATION URINE-STAINED ABDOMINAL FUR URINE-STAINED ABDOMINAL FUR EXCESS SALIVATION URINE-STAINED ABDOMINAL FUR EXCESS SALIVATION EXCESS SALIVATION EXCESS SALIVATION LOCALIZED ALOPECIA: LIMBS a EXCESS SALIVATION EXCESS SALIVATION RED, SLIGHT PERIORAL SUBSTANCE URINE-STAINED ABDOMINAL FUR SOFT OR LIQUID FECES EXCESS SALIVATION EXCESS SALIVATION SOFT OR LIQUID FECES EXCESS SALIVATION RED, SLIGHT PERIORAL SUBSTANCE DS = DAY OF STUDY a. Observation confirmed at necropsy. 418-027:PAGE B-29 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE BIS (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 0 (VEHICLE) 17601 DS 37 36 ALL TISSUES APPEARED NORMAL 17602 DS 37 36 ALL TISSUES APPEARED NORMAL 17603 DS 37 36 ALL TISSUES APPEARED NORMAL 17604 DS 37 36 ALL TISSUES APPEARED NORMAL 17607 DS 37 36 ALL TISSUES APPEARED NORMAL 17608 DS 37 36 ALL TISSUES APPEARED NORMAL 17618 DS 37 36 ALL TISSUES APPEARED NORMAL 17630 DS 37 36 ALL TISSUES APPEARED NORMAL 17631 DS 37 36 ALL TISSUES APPEARED NORMAL 17639 DS 37 36 ALL TISSUES APPEARED NORMAL 17648 DS 37 36 ALL TISSUES APPEARED NORMAL 17652 DS 37 36 ALL TISSUES APPEARED NORMAL 17656 DS 37 36 ALL TISSUES APPEARED NORMAL 17658 DS 37 36 ALL TISSUES APPEARED NORMAL 17660 DS 37 36 ALL TISSUES APPEARED NORMAL DS = DAY OF STUDY a. Refer to the individual clinical observations table (Table B15) for external observations confirmed at necropsy. PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B15 (PAGE 2) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) RAT NUMBER DAY OF DOSES NECROPSY ADMINISTERED OBSERVATIONS a II 10 17615 DS 37 36 ALL TISSUES APPEARED NORMAL. 17616 DS 37 36 ALL TISSUES APPEARED NORMAL. 17624 DS 37 36 ALL TISSUES APPEARED NORMAL. 17626 DS 37 36 ALL TISSUES APPEARED NORMAL. 17632 DS 37 36 ALL TISSUES APPEARED NORMAL. 17634 DS 37 36 ALL TISSUES APPEARED NORMAL. 17635 DS 37 36 ALL TISSUES APPEARED NORMAL. 17638 DS 37 36 ALL TISSUES APPEARED NORMAL. 17642 DS 37 36 ALL TISSUES APPEARED NORMAL. 17643 DS 37 36 ALL TISSUES APPEARED NORMAL. 17645 DS 37 36 ALL TISSUES APPEARED NORMAL. 17649 DS 37 36 ALL TISSUES APPEARED NORMAL. 17651 DS 37 36 ALL TISSUES APPEARED NORMAL. 17653 DS 37 36 ALL TISSUES APPEARED NORMAL. 17655 DS 37 36 ALL TISSUES APPEARED NORMAL. DS = DAY OF STUDY a. Refer to the individual clinical observations table (Table B15) for external observations confirmed at necropsy. 418-027:PAGE B-! UJ PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B16 (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 50 17605 DS 37 36 ALL TISSUES APPEARED NORMAL. 17610 DS 37 36 ALL TISSUES APPEARED NORMAL. 17611 DS 37 36 ALL TISSUES APPEARED NORMAL. 17613 DS 37 36 ALL TISSUES APPEARED NORMAL. 17619 DS 37 36 ALL TISSUES APPEARED NORMAL. 17620 DS 37 36 ALL TISSUES APPEARED NORMAL. 17623 DS 37 36 ALL TISSUES APPEARED NORMAL. 17627 DS 37 36 ALL TISSUES APPEARED NORMAL. 17628 DS 37 36 ALL TISSUES APPEARED NORMAL. 17633 DS 37 36 ALL TISSUES APPEARED NORMAL. 17640 DS 37 36 ALL TISSUES APPEARED NORMAL. 17646 DS 37 36 ALL TISSUES APPEARED NORMAL. 17650 DS 37 36 ALL TISSUES APPEARED NORMAL. 17657 DS 37 36 ALL TISSUES APPEARED NORMAL. 17659 DS 37 36 ALL TISSUES APPEARED NORMAL. DS = DAY OF STUDY a. Refer to the individual clinical observations table (Table B15) for external observations confirmed at necropsy. 418-027:PAGEB-32 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T- 7599) TABLE B16 (PAGE 4]1: NECROPSY OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) RAT NUMBER DAY OF DOSES NECROPSY ADMINISTERED OBSERVATIONS a IV 250 17606 DS 37 36 ALL TISSUES APPEARED NORMAL. 17609 DS 37 36 ALL TISSUES APPEARED NORMAL. 17612 DS 37 36 ALL TISSUES APPEARED NORMAL. 17614 DS 37 36 ALL TISSUES APPEARED NORMAL. 17617 DS 37 36 ALL TISSUES APPEARED NORMAL. 17621 DS 37 36 ALL TISSUES APPEARED NORMAL. 17622 DS 37 36 ALL TISSUES APPEARED NORMAL. 17625 DS 37 36 ALL TISSUES APPEARED NORMAL. 17629 DS 37 36 ALL TISSUES APPEARED NORMAL. 17636 DS 37 36 PROSTATE: RIGHT HEMISPHERE, TAN, FIRM, LOBULAR MASS (2.8 CM X 0.9 CM X 0.7 CM), CUT SURFACE REVEALED A TAN, SURFACE; VENTRAL RIGHT SIDE, RED. ALL OTHER TISSUES APPEARED NORMAL. SMOOTH 17637 17641 17644 17647 17654 DS 37 DS 37 DS 37 DS 37 DS 37 36 36 36 36 36 ALL TISSUES APPEARED NORMAL. ALL TISSUES APPEARED NORMAL. ALL TISSUES APPEARED NORMAL. ALL TISSUES APPEARED NORMAL. ALL TISSUES APPEARED NORMAL. DS = DAY OF STUDY a. Refer to the Individual clinical observations table (Table B15) for external observations confirmed at necropsy. 418-027 :PAGEB-33 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B17 (PAGE 1) : TERMINAL BODY WEIGHTS, ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP I RAT TERMINAL BODY NUMBER WEIGHT EPIDIDYMIS LEFT ABS. REL. WT . % TBW 17601 17602 17603 17604 17607 17608 17618 17630 17631 17639 17648 17652 17656 17658 17660 439. 512 . 446. 433 . 418 . 469. 422 . 448 . 439. 483 . 415 . 520 . 428 . 433 . 401. 0.82 0.80 0.74 0.80 0.73 0.84 0.71 0.75 0.67 0.69 0.77 0.72 0.71 0.63 0.74 0.19 0.16 0.16 0.18 0.17 0.18 0.17 0.17 0.15 0.14 0.18 0.14 0.16 0.14 0.18 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . VEHICLE 0 (VEHICLE) MG/KG/DAY TESTIS LEFT ABS. REL. WT . % TBW EPIDIDYMIS RIGHT ABS. REL. WT. % TBW TESTIS RIGHT ABS. REL. W T . % TBW BRAIN ABS. REL. W T . % TBW LIVER ABS. WT. REL. % TBW 1.70 1.76 1.80 1.96 1.78 1.77 1.69 1.80 1.68 1.51 1.87 1.68 2.02 1.51 1.84 0.39 0.34 0.40 0.45 0.42 0.38 0.40 0.40 0.38 0.31 0.45 0.32 0.47 0.35 0.46 0.79 0.82 0.76 0.82 0.81 0.88 0.76 0.78 0.64 0.70 0.81 0.75 0.69 0.70 0.68 0.18 0.16 0.17 0.19 0.19 0.19 0.18 0.17 0.14 0.14 0.20 0.14 0.16 0.16 0.17 1.73 1.78 1.71 1.99 1.73 1.72 1.61 1.79 1.78 1.50 1.90 1.71 1.92 1.50 1.77 0.39 0.35 0.38 0.46 0.41 0.37 0.38 0.40 0.40 0.31 0.46 0.33 0.45 0.35 0.44 2.42 2.32 2.39 2.28 2.12 2.23 2.46 2.36 2.25 2.29 0.52 0.55 0.53 0.52 0.44 0.54 0.47 0.55 0.52 0.57 12.36 15.56 13.86 11.86 12.97 14.64 13.24 13.82 13.55 14.04 11.97 16.55 13.25 13.27 13.17 2.82 3.04 3.11 2.74 3.10 3.12 3.14 3.08 3.09 2.91 2.88 3.18 3.10 3.06 3.28 ABS. WT. ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B17 (PAGE 2) : TERMINAL BODY WEIGHTS, ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP I VEHICLE 0 (VEHICLE) MG/KG/DAY RAT TERMINAL BODY NUMBER WEIGHT KIDNEY LEFT ABS. REL. W T . % TBW KIDNEY RIGHT ABS. REL. W T . % TBW ADRENAL LEFT ABS. REL. WT. % TBW a ADRENAL RIGHT ABS. REL. WT. % TBW a SPLEEN ABS. REL. WT . % TBW THYMUS ABS. REL. W T . % TBW 17608 17618 17630 17631 17639 17648 17652 17656 17658 17660 469. 422 . 448 . 439 . 483 . 415 . 520 . 428 . 433 . 401. 2.06 2.09 1.98 1.81 2.02 1.89 2.04 1.69 1.69 2.10 0.44 0.50 0.44 0.41 0.42 0.46 0.39 0.39 0.39 0.52 2.11 2.02 2.03 1.92 2.10 2.00 1.97 1.84 1.94 2.09 0.45 0.48 0.45 0.44 0.43 0.48 0.38 0.43 0.45 0.52 0.033 0.031 0.032 0.027 0.027 0.025 0.034 0.028 0.029 0.008b 7.04 7.34 7.14 6.15 5.59 6.02 6.54 6.54 6.70 2.00b 0.032 0.034 0.026 0.029 0.026 0.030 0.029 0.024 0.030 0.021 6.82 8.06 5.80 6.60 5.38 7.23 5.58 5.61 6.93 5.24 0.77 0.87 0.81 1.01 1.02 0.84 0.85 0.86 1.02 0.86 0.16 0.21 0.18 0.23 0.21 0.20 0.16 0.20 0.24 0.21 0.53 0.49 0.34 0.59 0.71 0.50 0.56 0.35 0.82 0.54 0.11 0.12 0.08 0.13 0.15 0.12 0.11 0.08 0.19 0.13 ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. a. Value was multiplied by 1000. b. Damaged during processing (weight affected); values excluded from group averages and statistical analyses. 418-027:PAGE B-35 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B17 (PAGE 3) : TERMINAL BODY WEIGHTS, ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP I RAT TERMINAL BODY NUMBER WEIGHT HEART ABS. WT. REL. % TBW 17608 17618 17630 17631 17639 17648 17652 17656 17658 17660 469 . 422 . 448 . 439. 483 . 415 . 520 . 428 . 433 . 401. 1.46 1.43 1.51 1.61 1.63 1.66 1.64 1.36 1.52 1.28 0.31 0.34 0.34 0.37 0.34 0.40 0.32 0.32 0.35 0.32 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . VEHICLE ABS. WT. ORGAN WEIGHT. 0 (VEHICLE) MG/KG/DAY REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B17 (PAGE 4) : TERMINAL BODY WEIGHTS, ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP II RAT TERMINAL BODY NUMBER WEIGHT EPIDIDYMIS LEFT ABS. REL. WT. % TBW 17615 17616 17624 17626 17632 17634 17635 17638 17642 17643 17645 17649 17651 17653 17655 424 . 437. 417 . 456. 457. 433 . 440. 452 . 413 . 494 . 440 . 440 . 434 . 442 . 406. 0.66 0.83 0.65 0.74 0.68 0.64 0.83 0.80 0.72 0.79 0.90 0.57 0.69 0.60 0.69 0.16 0.19 0.16 0.16 0.15 0.15 0.19 0.18 0.17 0.16 0.20 0.13 0.16 0.14 0.17 ALL WEIGHTS WERE RECORDED IN GRAMS (G). LOW DOSAGE 10 MG/KG/DAY TESTIS LEFT ABS. REL. WT. % TBW EPIDIDYMIS RIGHT ABS. REL. WT. % TBW TESTIS RIGHT ABS. REL. WT. % TBW BRAIN ABS. WT. REL. % TBW LIVER ABS. WT. REL. % TBW 1.76 1.71 0.69 1.68 1.76 1.51 1.69 1.88 1.70 1.86 1.91 1.47 1.58 1.76 1.70 0.42 0.39 0.16 0.37 0.38 0.35 0.38 0.42 0.41 0.38 0.43 0.33 0.36 0.40 0.42 0.70 0.91 0.68 0.69 0.71 0.70 0.87 0.79 0.76 0.80 0.86 0.59 0.68 0.55 0.75 0.16 0.21 0.16 0.15 0.16 0.16 0.20 0.17 0.18 0.16 0.20 0.13 0.16 0.12 0.18 1.75 1.73 1.57 1.67 1.83 1.60 1.80 1.88 1.72 1.84 1.91 1.47 1.68 1.70 1.69 0.41 0.40 0.38 0.37 0.40 0.37 0.41 0.42 0.42 0.37 0.43 0.33 0.39 0.38 0.42 2.29 2.31 2.45 2.21 2.26 2.40 2.02 2.20 2.18 2.15 0.53 0.52 0.54 0.54 0.46 0.54 0.46 0.51 0.49 0.53 12.66 14.57 12.06 14.49 13.60 13.01 14.06 14.20 12.00 18.47 16.04 12.55 11.98 14.34 12.82 2.98 3.33 2.89 3.18 2.98 3.00 3.20 3.14 2.90 3.74 3.64 2.85 2.76 3.24 3.16 ABS. WT. = ORGAN WEIGHT, REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. 418-027:PAGE B-37 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B17 (PAGE 5) : TERMINAL BODY WEIGHTS, ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP II RAT TERMINAL BODY NUMBER WEIGHT KIDNEY LEFT ABS. REL. W T . % TBW 17634 17635 17638 17642 17643 17645 17649 17651 17653 17655 433 . 440 . 452 . 413 . 494 . 440 . 440 . 434 . 442 . 406 . 1.97 2.10 1.87 1.82 2.10 2.14 1.83 1.72 1.91 2.19 0.45 0.48 0.41 0.44 0.42 0.49 0.42 0 .40 0.43 0.54 ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Value was multiplied by 1000. LOW DOSAGE 10 MG/KG/DAY KIDNEY RIGHT ABS. REL. W T . % TBW ADRENAL LEFT ABS. REL. WT. % TBW a ADRENAL RIGHT ABS. REL. WT. % TBW a SPLEEN ABS. WT. REL. % TBW THYMUS ABS. REL. W T . % TBW 1.89 2.21 1.97 1.89 2.26 2.14 1.81 1.78 1.90 2.37 0.44 0.50 0.44 0.46 0.46 0.49 0.41 0.41 0.43 0.58 0.027 0.031 0.029 0.026 0.028 0.026 0.037 0.038 0.022 0.031 6.24 7.04 6.42 6.30 5.67 5.91 8.41 8.76 4.98 7.64 0.029 0.029 0.032 0.032 0.034 0.029 0.041 0.040 0.027 0.024 6.70 6.59 7.08 7.75 6.88 6.59 9.32 9.22 6.11 5.91 0.69 0.84 0.75 0.85 0.94 0.99 0.58 0.70 0.74 0.83 0.16 0.19 0.16 0.20 0.19 0.22 0.13 0.16 0.17 0.20 0.53 0.61 0.53 0.48 0.53 0.37 0.24 0.24 0.36 0.45 0.12 0.14 0.12 0.12 0.11 0.08 0.05 0.06 0.08 0.11 ABS. WT. ORGAN WEIGHT. REL. % TBW (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B17 (PAGE 6) : TERMINAL BODY WEIGHTS, ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP II RAT TERMINAL BODY NUMBER WEIGHT HEART ABS. WT. REL. % TBW 17634 17635 17638 17642 17643 17645 17649 17651 17653 17655 433 . 440 . 452 . 413 . 494 . 440 . 440 . 434 . 442 . 406. 1.59 1.40 1.57 1.37 1.82 1.72 1.28 1.56 1.18 1.45 0.37 0.32 0.35 0.33 0.37 0.39 0.29 0.36 0.27 0.36 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . LOW DOSAGE A B S . WT. = ORGAN WEIGHT. 10 MG/KG/DAY REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B17 (PAGE 7) : TERMINAL BODY WEIGHTS, ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP III RAT TERMINAL BODY NUMBER WEIGHT EPIDIDYMIS LEFT ABS. REL. W T . % TBW 17605 17610 17611 17613 17619 17620 17623 17627 17628 17633 17640 17646 17650 17657 17659 392 . 467 . 422 . 411. 410 . 475 . 426 . 415 . 389 . 484 . 398 . 423 . 482 . 417 . 418 . 0.73 0.74 0.64 0.92 0.70 0.70 0.70 0.67 0.80 0.74 0.69 0.64 0.73 0.57 0.81 0.19 0.16 0.15 0.22 0.17 0.15 0.16 0.16 0.20 0.15 0.17 0.15 0.15 0.14 0.19 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . MIDDLE DOSAGE 50 MG/KG/DAY TESTIS LEFT ABS. REL. W T . % TBW EPIDIDYMIS RIGHT ABS. REL. W T . % TBW TESTIS RIGHT ABS. REL. W T . % TBW BRAIN ABS. REL. W T . % TBW LIVER ABS. WT. REL. % TBW 1.66 1.73 1.65 1.94 1.88 1.63 1.64 1.61 1.86 1.94 1.76 1.66 1.58 1.49 1.98 0.42 0.37 0.39 0.47 0.46 0.34 0.38 0.39 0.48 0.40 0.44 0.39 0.33 0.36 0.47 0.75 0.71 0.64 0.97 0.76 0.65 0.71 0.71 0.80 0.74 0.72 0.64 0.75 0.62 0.80 0.19 0.15 0.15 0.24 0.18 0.14 0.17 0.17 0.20 0.15 0.18 0.15 0.16 0.15 0.19 1.62 1.77 1.67 2.09 1.82 1.67 1.64 1.68 1.77 1.92 1.82 1.64 1.59 1.54 1.88 0.41 0.38 0.40 0.51 0.44 0.35 0.38 0.40 0.46 0.40 0.46 0.39 0.33 0.37 0.45 2.48 2.46 2.39 2.24 2.38 2.21 2.29 2.42 2.34 2.34 0.52 0.58 0.58 0.58 0.49 0.56 0.54 0.50 0.56 0.56 12.49 15.99 12.49 13.00 14.61 16.22 13.91 12.79 12.94 16.89 12.58 13.15 15.87 13.85 14.18 3.19 3 .42 2.96 3.16 3.56 3 .41 3 .26 3 .08 3 .33 3 .49 3.16 3.11 3 .29 3 .32 3 .39 A B S . WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B17 (PAGE 8) : TERMINAL BODY WEIGHTS, ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP III RAT TERMINAL BODY NUMBER WEIGHT KIDNEY LEFT ABS. REL. WT. % TBW 17620 17623 17627 17628 17633 17640 17646 17650 17657 17659 475 . 426 . 415 . 389 . 484 . 398 . 423 . 482 . 417 . 418 . 2.30 2.00 1.82 2.30 2.36 2.26 2.08 1.93 2.00 2.19 0.48 0.47 0.44 0.59 0.49 0.57 0.49 0.40 0.48 0.52 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Value was multiplied by 1000. MIDDLE DOSAGE 50 MG/KG/DAY KIDNEY RIGHT ABS. REL. WT. % TBW ADRENAL LEFT ABS. REL. WT. % TBW a ADRENAL RIGHT ABS. REL. WT. % TBW a SPLEEN ABS. WT. REL. % TBW THYMUS ABS. WT. REL. % TBW 2.37 2.09 1.92 2.29 2.37 2.29 2.00 1.92 2.09 2.23 0.50 0.49 0.46 0.59 0.49 0.58 0.47 0.40 0.50 0.53 0.027 0.029 0.035 0.032 0.033 0.030 0.014 0.031 0.027 0.030 5.68 6.81 8.43 8.23 6.82 7.54 3.31 6.43 6.47 7.18 0.026 0.031 0.033 0.030 0.031 0.028 0.028 0.033 0.026 0.028 5.47 7.28 7.95 7.71 6.40 7.04 6.62 6.85 6.24 6.70 0.83 0.68 0.77 1.05 1.02 0.70 0.83 0.85 0.81 0.95 0.17 0.16 0.18 0.27 0.21 0.18 0.20 0.18 0.19 0.23 0.24 0.62 0.49 0.23 0.55 0.31 0.62 0.40 0.45 0.38 0.05 0.14 0.12 0.06 0.11 0.08 0.15 0 .08 0.11 0.09 ABS. WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. 418-027:PAGE B- PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B17 (PAGE 9) : TERMINAL BODY WEIGHTS, ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP III RAT TERMINAL BODY NUMBER WEIGHT HEART ABS. WT. REL. % TBW 17620 17623 17627 17628 17633 17640 17646 17650 17657 17659 475 . 426. 415 . 389. 484 . 398. 423 . 482 . 417. 418 . 1.62 1.46 1.08 1.43 1.54 1.37 1.52 1.40 1.57 1.58 0.34 0.34 0.26 0.37 0.32 0.34 0.36 0.29 0.38 0.38 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . MIDDLE DOSAGE ABS. WT. ORGAN WEIGHT. 50 MG/KG/DAY REL. % TBW = (ORGAN WEIGHT/TEEMINAL BODY WEIGHT) X 100. PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B17 (PAGE 10) : TERMINAL BODY WEIGHTS, ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP IV RAT TERMINAL BODY NUMBER WEIGHT EPIDIDYMIS LEFT ABS. REL. W T . % TBW 17606 17609 17612 17614 17617 17621 17622 17625 17629 17636 17637 17641 17644 17647 17654 390. 407 . 388. 428 . 394 . 417 . 407. 431. 414 . 445 . 427 . 416. 407. 400 . 413 . 0.71 0.84 0.76 0.76 0.67 0.70 0.66 0.69 0.73 0.67 0.64 0.73 0.70 0.74 0.62 0.18 0.21 0.20 0.18 0.17 0.17 0.16 0.16 0.18 0.15 0.15 0.18 0.17 0.18 0.15 ALL WEIGHTS WERE RECORDED IN GRAMS (G). HIGH DOSAGE 250 MG/KG/DAY TESTIS LEFT ABS. REL. WT. % TBW EPIDIDYMIS RIGHT ABS. REL. W T . % TBW TESTIS RIGHT ABS. REL. W T . % TBW BRAIN ABS. WT. REL. % TBW LIVER ABS. WT. REL. % TBW 1.81 1.80 1.88 1.80 1.80 1.80 1.66 1.53 1.66 1.96 1.63 1.56 1.67 1.93 1.60 0.46 0.44 0.48 0.42 0.46 0.43 0.41 0.35 0.40 0.44 0.38 0.38 0.41 0.48 0.39 0.71 0.77 0.78 0.74 0.69 0.67 0.76 0.64 0.67 0.72 0.65 0.73 0.71 0.72 0.57 0.18 0.19 0.20 0.17 0.18 0.16 0.19 0.15 0.16 0.16 0.15 0.18 0.17 0.18 0.14 1.81 1.92 1.89 1.80 1.87 1.81 1.72 1.48 1.70 1.96 1.65 1.54 1.64 1.85 1.65 0.46 0.47 0.49 0.42 0.47 0.43 0.42 0.34 0.41 0.44 0.39 0.37 0.40 0.46 0.40 2.52 2.47 2.20 2.44 2.01 2.23 2.33 2.27 2.19 2.50 0.60 0.61 0.51 0.59 0.45 0.52 0.56 0.56 0.55 0.60 14.69 15.67 16.48 23.34 19.20 16.80 18.75 18.98 18.26 21.64 19.80 18.99 17.54 18.47 16.03 3.77 3.85 4.25 5.45 4.87 4.03 4.61 4.40 4.41 4.86 4.64 4.56 4.31 4.62 3.88 ABS. WT. ORGAN WEIGHT. REL. % TBW (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B17 (PAGE 11) : TERMINAL BODY WEIGHTS, ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP IV RAT TERMINAL BODY NUMBER WEIGHT KIDNEY LEFT ABS. REL. W T . % TBW 17621 17622 17625 17629 17636 17637 17641 17644 17647 17654 417. 407. 431. 414 . 445. 427 . 416. 407 . 400 . 413 . 2.09 2.17 2.15 1.94 2.21 2.11 2.39 2.34 2.08 2.13 0.50 0.53 0.50 0.47 0.50 0.49 0.57 0.57 0.52 0.52 ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Value was multiplied by 1000. HIGH DOSAGE 250 MG/KG/DAY KIDNEY RIGHT ABS. REL. W T . % TBW ADRENAL LEFT ABS. REL. WT. % TBW a ADRENAL RIGHT ABS. REL. WT. % TBW a SPLEEN ABS. REL. W T . % TBW THYMUS ABS. REL. W T . % TBW 2.29 2.05 2.12 2.02 2.29 2.19 2.34 2.35 2.09 2.07 0.55 0.50 0.49 0.49 0.51 0.51 0.56 0.58 0.52 0.50 0.030 0.031 0.020 0.023 0.045 0.032 0.034 0.022 0.028 0.031 7.19 7.62 4.64 5.56 10.11 7.49 8.17 5.40 7.00 7.51 0.029 0.028 0.018 0.027 0.027 0.029 0.034 0.028 0.028 0.027 6.95 6.88 4.18 6.52 6.07 6.79 8.17 6.88 7.00 6.54 0.75 0.70 1.05 0.80 0.89 0.84 0.70 0.82 0.84 0.87 0.18 0.17 0.24 0.19 0.20 0.20 0.17 0.20 0.21 0.21 0.51 0.43 0.60 0.36 0.20 0.37 0.40 0.25 0.40 0.49 0.12 0.10 0.14 0.09 0.04 0.09 0.10 0.06 0.10 0.12 ABS. WT. ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B17 (PAGE 12) : TERMINAL BODY WEIGHTS, ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP IV RAT TERMINAL BODY NUMBER WEIGHT HEART ABS. WT. REL. % TBW 17621 17522 17525 17629 17635 17537 17641 17644 17547 17654 417 . 407 . 431. 414 . 445 . 427. 416. 407. 400. 413 . 1.35 1.41 1.88 1.29 1.37 1.37 1.39 1.38 1.57 1.53 0.32 0.35 0.44 0.31 0.31 0.32 0.33 0.34 0.39 0.37 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . HIGH DOSAGE A B S . WT. = ORGAN WEIGHT. 250 MG/KG/DAY REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY- STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST {SPONSOR'S STUDY NUMBER: T-7599) TABLE B18 (PAGE 1) : BRAIN WEIGHTS, ORGAN WEIGHTS AND RATIOS {%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA Fo GENERATION MALE RATS DOSAGE GROUP I RAT NUMBER BRAIN WEIGHT EPIDIDYMIS LEFT ABS. REL. W T . % BRW 17608 17618 17630 17631 17639 17648 17652 17656 17658 17660 2.42 2.32 2.39 2.28 2.12 2.23 2.46 2.36 2.25 2.29 0.84 0.71 0.75 0.67 0.69 0.77 0.72 0.71 0.63 0.74 34.71 30.60 31.38 29.38 32.55 34.53 29.27 30.08 28.00 32.31 ALL WEIGHTS WERE RECORDED IN GRAMS (G). VEHICLE 0 (VEHICLE) MG/KG/DAY TESTIS LEFT ABS. REL. W T . % BRW EPIDIDYMIS RIGHT ABS. REL. W T . % BRW TESTIS RIGHT ABS. REL. W T . % BRW LIVER ABS. REL. W T . % BRW KIDNEY LEFT ABS. REL. W T . % BRW 1.77 1.69 1.80 1.68 1.51 1.87 1.68 2.02 1.51 1.84 73.14 72.84 75.31 73.68 71.23 83.86 68.29 85.59 67.11 80.35 0.88 0.76 0.78 0.64 0.70 0.81 0.75 0.69 0.70 0.68 36.36 32.76 32.64 28.07 33.02 36.32 30.49 29.24 31.11 29.69 1.72 1.61 1.79 1.78 1.50 1.90 1.71 1.92 1.50 1.77 71.07 69.40 74.90 78.07 70.75 85.20 69.51 81.36 66.67 77.29 14.64 13.24 13.82 13.55 14.04 11.97 16.55 13.25 13.27 13.17 604.96 570.69 578.24 594.30 662.26 536.77 672.76 561.44 589.78 575.11 2.06 2.09 1.98 1.81 2.02 1.89 2.04 1.69 1.69 2.10 85.12 90.09 82.84 79.38 95.28 84.75 82.93 71.61 75.11 91.70 ABS. WT. ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B18 (PAGE 2) : BRAIN WEIGHTS, ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA Fo GENERATION MALE RATS DOSAGE GROUP I VEHICLE 0 (VEHICLE) MG/KG/DAY RAT NUMBER BRAIN WEIGHT KIDNEY RIGHT ABS. REL. WT. % BRW ADRENAL LEFT ABS. REL. W T . % BRW ADRENAL RIGHT ABS. REL. WT. % BRW SPLEEN ABS. WT. REL. % BRW THYMUS ABS. WT. REL. % BRW' HEART ABS. WT. REL. % BRW 17608 17618 17630 17631 17639 17648 17652 17656 17658 17660 2.42 2.32 2.39 2.28 2.12 2.23 2.46 2.36 2.25 2.29 2.11 2.02 2.03 1.92 2.10 2.00 1.97 1.84 1.94 2.09 87.19 87.07 84.94 84.21 99.06 89.69 80.08 77.97 86.22 91.27 0.033 0.031 0.032 0.027 0.027 0.025 0.034 0.028 0.029 0.008a 1.36 1.34 1.34 1.18 1.27 1.12 1.38 1.19 1.29 0.35a 0.032 0.034 0.026 0.029 0.026 0.030 0.029 0.024 0.030 0.021 1.32 1.46 1.09 1.27 1.23 1.34 1.18 1.02 1.33 0.92 0.77 0.87 0.81 1.01 1.02 0.84 0.85 0.86 1.02 0.86 31.82 37.50 33.89 44.30 48.11 37.67 34.55 36.44 45.33 37.55 0.53 0.49 0.34 0.59 0.71 0.50 0.56 0.35 0.82 0.54 21.90 21.12 14.22 25.88 33.49 22.42 22.76 14.83 36.44 23.58 1.46 1.43 1.51 1.61 1.63 1.66 1.64 1.36 1.52 1.28 60.33 61.64 63.18 70.61 76.89 74.44 66.67 57.63 67.56 55.90 ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT . = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. a. Damaged during processing (weight affected); values excluded from group averages and statistical analyses. 418-027:PAGE B-47 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B18 (PAGE 3) : BRAIN WEIGHTS, ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA Fo GENERATION MALE RATS DOSAGE GROUP II RAT NUMBER BRAIN WEIGHT EPIDIDYMIS LEFT ABS. REL. WT. % BRW 17634 17635 17638 17642 17643 17645 17649 17651 17653 17655 2.29 2.31 2.45 2.21 2.26 2.40 2.02 2.20 2.18 2.15 0.64 0.83 0.80 0.72 0.79 0.90 0.57 0.69 0.60 0.69 27.95 35.93 32.65 32.58 34.96 37.50 28.22 31.36 27.52 32.09 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . LOW DOSAGE 10 MG/KG/DAY TESTIS LEFT ABS. REL. WT. % BRW EPIDIDYMIS RIGHT ABS. REL. WT. % BRW TESTIS RIGHT ABS. REL. WT. % BRW LIVER ABS. WT. REL. % BRW KIDNEY LEFT ABS. REL. WT. % BRW 1.51 1.69 1.88 1.70 1.86 1.91 1.47 1.58 1.76 1.70 65.94 73.16 76.73 76.92 82.30 79.58 72.77 71.82 80.73 79.07 0.70 0.87 0.79 0.76 0.80 0.86 0.59 0.68 0.55 0.75 30.57 37.66 32.24 34.39 35.40 35.83 29.21 30.91 25.23 34.88 1.60 1.80 1.88 1.72 1.84 1.91 1.47 1.68 1.70 1.69 69.87 77.92 76.73 77.83 81.42 79.58 72.77 76.36 77.98 78.60 13.01 14.06 14.20 12.00 18.47 16.04 12.55 11.98 14.34 12.82 568.12 608.66 579.59 542.99 817.26 668.33 621.29 544.54 657.80 596.28 1.97 2.10 1.87 1.82 2.10 2.14 1.83 1.72 1.91 2.19 86.03 90.91 76.33 82.35 92.92 89.17 90.59 78.18 87.61 101.86 A B S . WT. = ORGAN WEIGHT. R E L . % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. 418-027:PAGE B-48 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B18 (PAGE 4) : BRAIN WEIGHTS, ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA Fo GENERATION MALE RATS DOSAGE GROUP II RAT NUMBER BRAIN WEIGHT KIDNEY RIGHT ABS. REL. WT. % BRW 17634 17635 17638 17642 17643 17645 17649 17651 17653 17655 2.29 2.31 2.45 2.21 2.26 2.40 2.02 2.20 2.18 2.15 1.89 2.21 1.97 1.89 2.26 2.14 1.81 1.78 1.90 2.37 82.53 95.67 80.41 85.52 100.00 89.17 89.60 80.91 87.16 110.23 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . LOW DOSAGE 10 MG/KG/DAY ADRENAL LEFT ABS. REL. W T . % BRW ADRENAL RIGHT ABS. REL. WT. % BRW SPLEEN ABS. WT. REL. % BRW THYMUS ABS. WT. REL. % BRW HEART ABS. WT. REL. % BRW 0.027 0.031 0.029 0.026 0.028 0.026 0.037 0.038 0.022 0.031 1.18 1.34 1.18 1.18 1.24 1.08 1.83 1.73 1.01 1.44 0.029 0.029 0.032 0.032 0.034 0.029 0.041 0.040 0.027 0.024 1.27 1.26 1.31 1.45 1.50 1.21 2.03 1.82 1.24 1.12 0.69 0.84 0.75 0.85 0.94 0.99 0.58 0.70 0.74 0.83 30.13 36.36 30.61 38.46 41.59 41.25 28.71 31.82 33.94 38.60 0.53 0.61 0.53 0.48 0.53 0.37 0.24 0.24 0.36 0.45 23.14 26.41 21.63 21.72 23.45 15.42 11.88 10.91 16.51 20.93 1.59 1.40 1.57 1.37 1.82 1.72 1.28 1.56 1.18 1.45 69.43 60.61 64.08 61.99 80.53 71.67 63.37 70.91 54.13 67.44 ABS. WT . = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. 418-027:PAGE B-49 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B18 (PAGE 5) : BRAIN WEIGHTS, ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA Fo GENERATION MALE RATS DOSAGE GROUP III RAT NUMBER BRAIN WEIGHT EPIDIDYMIS LEFT ABS. REL. WT. % BRW 17620 17623 17627 17628 17633 17640 17646 17650 17657 17659 2.48 2.46 2.39 2.24 2.38 2.21 2.29 2.42 2.34 2.34 0.70 0.70 0.67 0.80 0.74 0.69 0.64 0.73 0.57 0.81 28.22 28.46 28.03 35.71 31.09 31.22 27.95 30.16 24.36 34.62 ALL WEIGHTS WERE RECORDED IN GRAMS (G). MIDDLE DOSAGE 50 MG/KG/DAY TESTIS LEFT ABS. REL. WT. % BRW EPIDIDYMIS RIGHT ABS. REL. WT. % BRW TESTIS RIGHT ABS. REL. WT. %: BRW LIVER ABS. WT. REL. % BRW KIDNEY LEFT ABS. REL. WT. % BRW 1.63 1.64 1.61 1.86 1.94 1.76 1.66 1.58 1.49 1.98 65.72 66.67 67.36 83.04 81.51 79.64 72.49 65.29 63.68 84.62 0.65 0.71 0.71 0.80 0.74 0.72 0.64 0.75 0.62 0.80 26.21 28.86 29.71 35.71 31.09 32.58 27.95 30.99 26.50 34.19 1.67 1.64 1.68 1.77 1.92 1.82 1.64 1.59 1.54 1.88 67.34 66.67 70.29 79.02 80.67 82.35 71.62 65.70 65.81 80.34 16.22 13.91 12.79 12.94 16.89 12.58 13.15 15.87 13.85 14.18 654.03 565.45 535.15 577.68 709.66 569.23 574.24 655.78 591.88 605.98 2.30 2.00 1.82 2.30 2.36 2.26 2.08 1.93 2.00 2.19 92.74 81.30 76.15 102.68 99.16 102.26 90.83 79.75 85.47 93.59 ABS. WT. ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B18 (PAGE 6) : BRAIN WEIGHTS, ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA Fo GENERATION MALE RATS DOSAGE GROUP III RAT NUMBER BRAIN WEIGHT KIDNEY RIGHT ABS. REL. W T . % BRW 17620 17623 17627 17628 17633 17640 17646 17650 17657 17659 2.48 2.46 2.39 2.24 2.38 2.21 2.29 2.42 2.34 2.34 2.37 2.09 1.92 2.29 2.37 2.29 2.00 1.92 2.09 2.23 95.56 84.96 80.33 102.23 99.58 103.62 87.34 79.34 89.32 95.30 ALL WEIGHTS WERE RECORDED IN GRAMS (G). MIDDLE DOSAGE 50 MG/KG/DAY ADRENAL LEFT ABS. REL. WT . % BRW ADRENAL RIGHT ABS. REL. W T . % BRW SPLEEN ABS. REL. W T . % BRW THYMUS ABS. REL. W T . % BRW HEART ABS. REL. W T . % BRW 0.027 0.029 0.035 0.032 0.033 0.030 0.014 0.031 0.027 0.030 1.09 1.18 1.46 1.43 1.39 1.36 0.61 1.28 1.15 1.28 0.026 0.031 0.033 0.030 0.031 0.028 0.028 0.033 0.026 0.028 1.05 1.26 1.38 1.34 1.30 1.27 1.22 1.36 1.11 1.20 0.83 0.68 0.77 1.05 1.02 0.70 0.83 0.85 0.81 0.95 33.47 27.64 32.22 46.87 42.86 31.67 36.24 35.12 34.62 40.60 0.24 0.62 0.49 0.23 0.55 0.31 0.62 0.40 0.45 0.38 9.68 25.20 20.50 10.27 23.11 14.03 27.07 16.53 19.23 16.24 1.62 1.46 1.08 1.43 1.54 1.37 1.52 1.40 1.57 1.58 65.32 59.35 45.19 63.84 64.70 61.99 66.38 57.85 67.09 67.52 A B S . WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. 418-027:PAGE B-51 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B18 (PAGE 7): BRAIN WEIGHTS, ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA Fo GENERATION MALE RATS DOSAGE GROUP IV RAT NUMBER BRAIN WEIGHT EPIDIDYMIS LEFT ABS. REL. WT. % BRW 17621 17622 17625 17629 17636 17637 17641 17644 17647 17654 2.52 2.47 2.20 2.44 2.01 2.23 2.33 2.27 2.19 2.50 0.70 0.66 0.69 0.73 0.67 0.64 0.73 0.70 0.74 0.62 27.78 26.72 31.36 29.92 33.33 28.70 31.33 30.84 33.79 24.80 ALL WEIGHTS w e r e :RECORDED IN 'GRAMS (G). HIGH DOSAGE 250 MG/KG/DAY TESTIS LEFT ABS. REL. WT. % BRW EPIDIDYMIS RIGHT ABS. REL. WT. % BRW TESTIS RIGHT ABS. REL. WT. % BRW LIVER ABS. WT. REL. % BRW KIDNEY LEFT ABS. REL. WT. % BRW 1.80 1.66 1.53 1.66 1.96 1.63 1.56 1.67 1.93 1.60 71.43 67.21 69.54 68.03 97.51 73.09 66.95 73.57 88.13 64.00 0.67 0.76 0.64 0.67 0.72 0.65 0.73 0.71 0.72 0.57 26.59 30.77 29.09 27.46 35.82 29.15 31.33 31.28 32.88 22.80 1.81 1.72 1.48 1.70 1.96 1.65 1.54 1.64 1.85 1.65 71.82 69.64 67.27 69.67 97.51 73.99 66.09 72.25 84.47 66.00 16.80 18.75 18.98 18.26 21.64 19.80 18.99 17.54 18.47 16.03 666.67 759.11 862.73 748.36 1076.62 887.89 815.02 772.69 843.38 641.20 2.09 2.17 2.15 1.94 2.21 2.11 2.39 2.34 2.08 2.13 82.94 87.85 97.73 79.51 109.95 94.62 102.58 103.08 94.98 85.20 ABS. WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. 418-027:PAGE B-52 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B18 (PAGE 8) : BRAIN WEIGHTS, ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA Fo GENERATION MALE RATS DOSAGE GROUP IV RAT NUMBER BRAIN WEIGHT KIDNEY RIGHT ABS. REL. W T . % BRW 17621 17622 17625 17629 17636 17637 17641 17644 17647 17654 2.52 2.47 2.20 2.44 2.01 2.23 2.33 2.27 2.19 2.50 2.29 2.05 2.12 2.02 2.29 2.19 2.34 2.35 2.09 2.07 90.87 83.00 96.36 82.79 113.93 98.21 100.43 103.52 95.43 82.80 ALL WEIGHTS WERE RECORDED IN GRAMS (G). HIGH DOSAGE 250 MG/KG/DAY ADRENAL LEFT ABS. REL. WT. % BRW ADRENAL RIGHT ABS. REL. W T . % BRW SPLEEN ABS. REL. W T . % BRW THYMUS ABS. WT. REL. % BRW HEART ABS. WT. REL. % BRW 0.030 0.031 0.020 0.023 0.045 0.032 0.034 0.022 0.028 0.031 1.19 1.26 0.91 0.94 2.24 1.43 1.46 0.97 1.28 1.24 0.029 0.028 0.018 0.027 0.027 0.029 0.034 0.028 0.028 0.027 1.15 1.13 0.82 1.11 1.34 1.30 1.46 1.23 1.28 1.08 0.75 0.70 1.05 0.80 0.89 0.84 0.70 0.82 0.84 0.87 29.76 28.34 47.73 32.79 44.28 37.67 30.04 36.12 38.36 34.80 0.51 0.43 0.60 0.36 0.20 0.37 0.40 0.25 0.40 0.49 20.24 17.41 27.27 14.75 9.95 16.59 17.17 11.01 18.26 19.60 1.35 1.41 1.88 1.29 1.37 1.37 1.39 1.38 1.57 1.53 53.57 57.08 85.45 52.87 68.16 61.43 59.66 60.79 71.69 61.20 A B S . WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. 418-027:PAGE B-53 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B19 (PAGE 1): BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT # DOSAGE GROUP I VEHICLE 0 (VEHICLE) MG/KG/DAY DAY 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15a 16 17601 17602 17603 17604 17607 17608 17618 17630 17631 17639 17648 17652 17656 17658 17660 333 . 362 . 342 . 349. 330. 353 . 343 . 347. 332 . 350. 333 . 349. 342. 345 . 331. 331. 371. 350 . 353 . 333 . 364 . 347. 352 . 337. 356. 340 . 362 . 348. 356. 338. 340. 380. 357. 363 . 341. 367. 351. 357. 346. 358. 350. 370. 352 . 360. 344 . 348 . 389. 364 . 368 . 348 . 379. 361. 366. 355 . 364 . 354. 380. 359. 363 . 343 . 367. 400. 369. 377. 354 . 379. 366. 374 . 360. 371. 359. 386. 364 . 368 . 350 . 365. 401. 373 . 376. 358. 388. 374 . 381. 364 . 380. 363 . 391. 371. 372 . 353 . 375. 410 . 379. 386. 360 . 393 . 376. 384 . 370 . 385. 374 . 399. 373 . 374 . 355 . 383 . 419. 383 . 389 . 364 . 396. 383 . 387. 376. 395. 372 . 410 . 380. 381. 354 . 380. 425 . 391. 399. 365 . 402. 379. 395 . 374 . 397. 370. 415 . 379. 378. 362 . 388. 431. 395. 396. 369. 404 . 384 . 402 . 380. 404 . 381. 425 . 380. 3 84. 360. 384 . 436. 398. 402 . 372 . 410 . 390. 408. 372. 407. 384. 430. 388 . 384 . 363 . 396. 441. 406 . 403 . 377 . 412 . 396. 412 . 389. 414 . 389. 438 . 386. 387. 367. 398 . 449. 408 . 412 . 379. 421. 394 . 416. 393 . 421. 390. 445 . 391. 391. 368. 401. 458 . 413 . 414 . 382 . 423 . 394 . 424 . 394 . 425 . 390 . 450. 393 . 392 . 374 . 409. 463 . 417. 418. 385. 428 . 398 . 421. 394 . 425 . 395. 456. 398 . 393 . 374 . 403 . 458 . 412 . 413 . 382 . 433 . 404 . 418 . 398. 427 . 391. 454 . 392 . 390 . 375. DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Last value recorded before cohabitation. 418-027:PAGEB-54 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B19 (PAGE 2): BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT # DOSAGE GROUP I VEHICLE 0 (VEHICLE) MG/KG/DAY DAY 17 18 19 20 21 22 23 24 25 26 27 28 29a 30 31 32 17601 17602 17603 17604 17607 17608 17618 17630 17631 17639 17648 17652 17656 17658 17660 414 . 464 . 424 . 418 . 388 . 436. 408 . 423 . 401. 431. 397. 459 . 394 . 400 . 379. 416 . 468 . 428 . 417. 395. 438. 405. 429. 406 . 432 . 391. 464 . 400. 400 . 379. 421. 476. 432 . 421. 398. 442 . 413 . 434 . 413 . 438. 396. 475 . 401. 402 . 382. 416 . 479. 434 . 423 . 402 . 445 . 414 . 436. 418 . 440. 397 . 473 . 406. 408 . 379. 418 . 479 . 439. 420 . 401. 444 . 413 . 439. 423 . 446 . 404 . 479 . 409. 414 . 382 . 427. 484 . 444 . 427 . 405. 448 . 420. 441. 428 . 446. 410 . 485 . 412 . 413 . 388. 428. 490 . 448 . 433 . 407 . 454 . 416. 446. 426. 452 . 405 . 487. 411. 418 . 393 . 433 . 493 . 447. 436. 410. 452 . 424 . 446. 433 . 452. 412 . 497. 416. 429 . 394 . 434 . 496. 453 . 430. 408. 456 . 428. 451. 436. 462 . 412 . 497. 418 . 425. 392 . 444 . 504 . 458. 435. 415 . 458 . 430. 454 . 440 . 463 . 416 . 506. 423 . 434 . 399. 438. 514 . 459. 438 . 417 . 463 . 428. 456. 437 . 465. 413 . 509. 427. 440 . 399. 444 . 514 . 468 . 438 . 418 . 467 . 436. 459. 449 . 475 . 422 . 511. 429 . 444 . 402 . 455. 522 . 471. 449 . 427 . 474 . 439. 459. 454 . 481. 426 . 524 . 435. 448 . 410 . 453 . 516. 473 . 450. 425 . 474 . 434 . 464 . 454 . 482 . 426 . 526. 438 . 448 . 404 . 466. 532 . 465 . 447. 424 . 477 . 439 . 468 . 457. 489. 432 . 531. 440 . 449 . 409. 460. 533 . 470 . 457 . 429. 480. 440 . 469. 467 . 490. 438 . 540. 444 . 451. 414 . DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. First value recorded after cohabitation. 418-027:PAGE B-55 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B19 (PAGE 3) : BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT # DOSAGE GROUP I VEHICLE DAY 33 34 35 36 37 17601 17602 17603 17604 17607 17608 17618 17630 17631 17639 17648 17652 17656 17658 17660 458 . 533 . 473 . 450 . 433 . 484 . 443 . 475 . 458. 495. 436. 537. 44 6. 449. 417 . 467 . 541. 471. 459 . 438 . 490. 443 . 475 . 466. 496. 436. 540 . 451. 457. 420 . 465. 545. 471. 462. 439. 495. 446. 476. 467. 503. 437. 547. 454 . 462 . 426. 473 . 544 . 476. 461. 436. 493 . 446. 474 . 469. 504 . 440 . 550 . 457. 463 . 427 . 439. 512 . 446. 433 . 418 . 469. 422 . 448 . 439. 483 . 415 . 520. 428. 433 . 401. DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). 0 (VEHICLE) MG/KG/DAY 9S"9HDV<R0-8lt7 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B19 (PAGE 4) : BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT # DOSAGE GROUP II LOW DOSAGE DAY 1 2 34 5 67 17615 17616 17624 17626 17632 17634 17635 17638 17642 17643 17645 17649 17651 17653 17655 328. 354 . 336. 344 . 334 . 357 . 337 . 347 . 328 . 350 . 336. 340 . 336. 353 . 349. 332 . 361. 339. 350 . 341. 362 . 341. 350. 331. 358 . 339. 348 . 341. 356. 348 . 334. 365. 343 . 360. 348 . 366. 350 . 358. 336. 362. 342 . 353 . 344 . 363 . 355. 342 . 374 . 352 . 370 . 356. 371. 353 . 368 . 342 . 374 . 352 . 360. 348. 368 . 361. 339. 380 . 358 . 376. 364 . 378 . 360. 373 . 339. 385 . 362 . 364 . 367. 374 . 370 . 350. 385 . 360 . 382 . 373 . 380. 368. 376. 351. 392. 366. 369. 370. 378 . 365 . 348 390 370 391 381 386 374 385 352 399 372 372 376 385 377 DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Last value recorded before cohabitation. 10 MG/KG/DAY 8 9 10 11 12 13 14 15a 16 354 . 396. 374 . 390. 387. 390. 373 . 390. 360. 402 . 376. 378. 375. 390. 379. 363 . 403 . 375 . 390. 391. 392 . 373 . 393 . 364 . 410 . 384 . 383 . 370. 393 . 380. 362 . 403 . 381. 394 . 399. 398. 385. 398. 363 . 419. 382 . 393 . 381. 404 . 388 . 367. 409. 378 . 403 . 401. 399. 381. 400 . 370 . 422 . 384 . 396. 381. 404 . 390. 368 . 410 . 382 . 404 . 414 . 402 . 387. 405. 375 . 435 . 388 . 398. 388 . 408 . 393 . 381. 413 . 385. 407 . 416 . 407 . 392 . 405. 376. 436. 400 . 401. 392 . 413 . 395. 383 . 416. 388 . 409 . 422 . 410 . 396. 406. 380 . 432 . 392 . 408. 394 . 420 . 396. 389. 420 . 394 . 415 . 428 . 416 . 404 . 417. 386. 449 . 401. 411. 395. 420 . 402 . 391 419 387 414 422 406 397 409 386 446 391 406 397 415 386 "H 3 9 V < m O -8 It7 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B19 (PAGE 5) : BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT # DOSAGE GROUP II LOW DOSAGE DAY 17 18 19 20 21 22 17615 17616 17624 17626 17632 17634 17635 17638 17642 17643 17645 17649 17651 17653 17655 393 . 427 . 396. 414 . 435 . 415 . 401. 407 . 388 . 456. 401. 407 . 406 . 426. 397 . 399. 422 . 405 . 415 . 425 . 415 . 404 . 416 . 393 . 451. 402 . 410. 410 . 425 . 386 . 399. 424 . 403. 424 . 434 . 420 . 408. 409. 399. 455. 410. 414 . 409. 427. 398. 406. 424 . 409. 429 . 434 . 425 . 411. 423 . 403 . 459. 415 . 410 . 412 . 432 . 400. 411. 428 . 413 . 434 . 436. 421. 416. 427. 408. 466. 416. 416. 413 . 431. 400. 414 . 427. 412 . 438 . 443 . 430. 419 . 429 . 410 . 472 . 419 . 424 . 417 . 430. 403 . DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. First value recorded after cohabitation. 23 408. 428 . 419. 446. 444 . 429 . 419 . 429 . 410 . 476. 417. 425. 417. 437. 409. 24 414 . 432 . 420 . 445. 451. 438. 429. 432 . 416. 486 . 426. 430. 425 . 442 . 413 . 25 415 . 436. 423 . 443 . 450 . 440 . 428 . 436. 417. 484 . 424 . 430 . 430 . 443 . 416. 10 MG/KG/DAY 26 27 28 417 423 . 424 . 436 445 . 443 . 423 426. 432 . 451 456 . 462 . 457 461. 464 . 445 440 . 443 . 436 438 . 447. 442 447 . 446 . 420 424 . 423 . 489 496 . 502 . 431 440 . 441. 433 439. 441. 434 441. 440 . 447 452 . 455. 408 418 . 415. 29a 430. 447. 432 . 463 . 471. 454 . 451. 455. 427 . 506. 453 . 452 . 447 . 455. 419 . 30 425 . 447 . 431. 471. 473 . 449 . 445 . 457 . 424 . 511. 452 . 446 . 450. 460 . 423 . 31 435 . 450 . 430. 469. 470 . 456. 456. 467 . 423 . 512 . 450 . 451. 455 . 461. 422 . 32 438 . 454 . 441. 473 . 484 . 460 . 453 . 473 . 425 . 516 . 458 . 455. 456. 465 . 426 . 418-027:PAGE B-58 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B19 (PAGE 6) : BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT # DOSAGE GROUP II LOW DOSAGE DAY 33 34 35 36 37 17615 17616 17624 17626 17632 17634 17635 17638 17642 17643 17645 17649 17651 17653 17655 440 . 458 . 440 . 473 . 484 . 455 . 457 . 470 . 423 . 513 . 454 . 452 . 453 . 464 . 420 . 444 . 460. 436. 467. 484 . 453 . 456. 475. 431. 522 . 463 . 455. 461. 464 . 430 . 448. 461. 444 . 478 . 486. 460. 459. 479. 438. 521. 465. 463. 459. 466. 431. 452 . 461. 443 . 476 . 488 . 460 . 466. 482. 440. 529. 464 . 464 . 464 . 468 . 438. 424 . 437. 417. 456 . 457 . 433 . 440. 452. 413 . 494 . 440 . 440 . 434 . 442 . 406. DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). 10 MG/KG/DAY 418-027:PAGE B-59 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B19 (PAGE 7): BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT # DOSAGE GROUP Ill MIDDLE DOSAGE 50 MG/KG/DAY DAY 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15a 16 17605 17610 17611 17613 17619 17620 17623 17627 17628 17633 17640 17646 17650 17657 17659 325. 363 . 339. 346. 330. 358 . 342 . 340. 328. 356. 338 . 349. 370 . 337. 336. 324 . 373 . 346. 350 . 334 . 364 . 346 . 337 . 332 . 366. 344 . 354 . 369. 338. 344 . 330. 381. 354 . 353. 336. 373 . 356. 342. 341. 374 . 345 . 363 . 376. 349. 346. 334 . 385 . 363. 366. 343 . 379. 356. 345. 345. 382 . 352 . 368. 386. 359. 349. 339. 388. 367. 374 . 348 . 386. 368. 347 . 342 . 393 . 358. 373 . 389. 362. 359. 342 . 394 . 375 . 377. 350 . 395 . 372 . 352 . 350. 402 . 361. 379. 389. 367. 359. 346. 401. 377. 385. 355. 404 . 373 . 358. 353 . 408 . 367. 381. 398 . 368 . 362. 353 . 406. 386. 396. 357. 412 . 380. 363 . 356. 404 . 371. 384 . 401. 365. 366 . 356. 416. 386. 392 . 360 . 416. 381. 363 . 352 . 400 . 371. 386 . 408 . 373 . 370 . 353 419 390 396 362 417 388 370 359 415 375 376 414 374 373 352 . 416. 394 . 396. 367. 424 . 389. 373 . 362 . 418 . 376. 386. 418 . 382 . 376. 360 . 423 . 398. 406. 368 . 429. 393 . 375. 366. 422 . 382 . 387. 422 . 389. 383 . 359. 425 . 398. 407. 373 . 430 . 397. 386. 365. 425. 380. 395 . 425 . 3 78. 384 . 365. 432 . 401. 412 . 378 . 436. 402 . 388 . 371. 427. 384 . 395 . 431. 380 . 389 . 367. 438 . 405. 415 . 380 . 435. 409. 391. 369. 435. 388 . 402 . 437 . 388 . 392 . 364 . 431. 396 . 412 . 374 . 441. 407 . 396. 371. 435 . 388 . 387. 431. 386 . 391. DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Last value recorded before cohabitation. 418-027:PAGE B-60 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B19 (PAGE 8): BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT # DOSAGE GROUP Ill MIDDLE DOSAGE 50 MG/KG/DAY DAY 17 18 19 20 21 22 23 24 25 26 27 28 29a 30 31 32 17605 17610 17611 17613 17619 17620 17623 17627 17628 17633 17640 17646 17650 17657 17659 367. 435. 403 . 417 . 384 . 443 . 411. 402 . 378. 445 . 387. 399. 448 . 391. 397. 376. 439. 400. 418 . 388. 446. 411. 400 . 374 . 443 . 388 . 400 . 452 . 393 . 402 . 381. 444 . 411. 420. 389. 452. 413 . 409. 379. 442. 391. 402. 459. 396. 399. 381. 448 . 408. 419 . 390 . 455 . 413 . 406 . 384 . 450. 391. 408 . 460 . 403 . 405. 385. 450 . 407. 419. 394 . 451. 415 . 406 . 385. 456. 395. 410 . 459. 400. 406. 389. 457 . 408 . 417 . 398. 457 . 414 . 408 . 386. 460. 395. 414 . 462 . 402 . 412 . 390. 462 . 410 . 421. 401. 464 . 422 . 402 . 389. 462 . 399. 407 . 464 . 405. 412 . 394 . 465. 415 . 422 . 399. 466. 423 . 415 . 392 . 468 . 402 . 417 . 472 . 410. 416 . 391. 464 . 415. 419 . 404 . 471. 421. 413 . 391. 467 . 402 . 422 . 469. 412 . 422 . 399 465 415 418 411 473 426 418 393 472 405 420 478 418 424 403 . 471. 420. 422 . 416. 481. 430. 418 . 390 . 478 . 407 . 430 . 480. 419. 422 . 406. 473 . 424 . 422 . 413 . 481. 432 . 421. 397. 484 . 408. 432 . 480. 422 . 423 . 407. 484 . 433 . 432 . 425. 485 . 438 . 421. 388. 488 . 416 . 437. 491. 433 . 432 . 406 . 482 . 429 . 433 . 420. 487 . 440 . 424 . 399. 489. 412 . 437. 496. 431. 431. 408 . 490. 432 . 426 . 420 . 489. 444 . 424 . 401. 492 . 416. 437 . 496. 435 . 436. 415. 489. 434 . 435 . 430 . 491. 446 . 430 . 403 . 502 . 420 . 444 . 504 . 439. 442 . DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. First value recorded after cohabitation. 418-027:PAGEB-61 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B19 (PAGE 9) : BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT # DOSAGE GROUP III MIDDLE DOSAGE DAY 33 34 35 36 37 17605 17610 17611 17613 17619 17620 17623 17627 17628 17633 17640 17646 17650 17657 17659 412 . 484 . 437 . 431. 428 . 496 . 444 . 429. 400. 499. 417 . 446 . 498 . 440 . 437 . 414 . 487 . 441. 427. 434 . 503 . 446. 430. 404 . 505. 420. 452 . 504 . 446 . 443 . 421. 490. 439. 434 . 433 . 505 . 44 7. 434. 409. 509. 420 . 454 . 509. 452 . 443 . 423 . 488 . 445 . 433 . 435 . 498 . 454 . 438 . 413 . 510. 426. 454 . 515. 457 . 449 . 392 . 467 . 422. 411. 410. 475. 426. 415 . 389. 484 . 398 . 423 . 482 . 417 . 418. DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . 50 MG/KG/DAY Z9"9 HDV<mO"8Ii7 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B19 (PAGE 10) : BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT # DOSAGE GROUP IV HIGH DOSAGE DAY 1 2 3 4 5 6 17606 17609 17612 17614 17617 17621 17622 17625 17629 17636 17637 17641 17644 17647 17654 321. 358 . 340. 348. 330. 347 . 336. 338 . 332 . 350 . 342 . 342 . 328 . 343 . 338. 328 . 358 . 340 . 343 . 329. 349. 336. 342 . 336. 350 . 346. 340 . 320. 349. 345 . 321. 360. 345. 338. 332. 351. 327. 338. 341. 350. 352. 344 . 316. 345. 341. 332 . 373 . 349 . 355 . 340 . 361. 349. 350. 348 . 357 . 358 . 350. 328. 354 . 352. 338. 375 . 354 . 360. 344 . 370. 353 . 357. 349. 366. 362 . 354 . 331. 360. 360. 343 . 382 . 356. 371. 354 . 373 . 364 . 366. 361. 368. 367. 362 . 341. 362 . 364 . DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Last value recorded before cohabitation. 7 348. 383 . 357. 376. 352 . 380. 367. 369. 361. 377. 370. 365. 346. 361. 370. 8 351. 388. 365. 382 . 354 . 387. 370. 376. 368. 380. 377 . 369. 355 . 366. 371. 9 355. 392 . 369. 389. 358. 386. 380. 389. 372 . 386. 374 . 368 . 353 . 363 . 381. 250 MG/KG/DAY 10 11 12 358 . 394 . 369. 396. 359. 392 . 379. 388 . 380. 396. 382 . 373 . 360. 370 . 374 . 365 . 397 . 374 . 394 . 362 . 392 . 385 . 390. 379. 402 . 382 . 378 . 363 . 371. 379 . 365. 400. 374 . 398 . 366 . 395. 389. 392 . 380 . 401. 387. 381. 367. 375 . 379. 13 366. 398 . 374 . 404 . 365 . 398 . 389. 398 . 387. 407 . 389. 383 . 368. 378 . 382 . 14 369. 392 . 378 . 408 . 367 . 401. 392 . 405 . 390 . 411. 393 . 392 . 373 . 377. 385. 15a 373 . 400. 379. 413 . 370 . 403 . 394 . 408. 396. 414 . 402 . 396. 380. 384 . 390 . 16 370. 409. 384 . 403 . 363 . 394 . 380 . 393 . 388. 403 . 390 . 392. 376. 381. 388 . 418-027:PAGE B-63 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B19 (PAGE 11): BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS 1 t i CM l l RAT # DOSAGE GROUP IV HIGH DOSAGE DAY 17 18 19 20 21 22 17606 17609 17612 17614 17617 17621 17622 17625 17629 17636 17637 17641 17644 17647 17654 379. 395 . 385 . 415 . 363 . 401. 389. 407 . 402 . 412 . 409. 396. 376. 384 . 391. 384 . 407. 384 . 418. 363 . 402 . 393 . 411. 405. 408. 400. 395. 386. 390. 392 . 385. 401. 389. 418. 368. 403. 399. 413. 406. 417. 403 . 402. 385. 394 . 398. 391 416 390 420 371 408 410 418 416 422 406 401 389 392 404 388 . 414 . 390. 426. 380 . 411. 410. 422 . 412 . 425 . 413 . 404 . 390 . 396. 414 . 394 . 416. 393 . 425 . 379. 407. 411. 424 . 412 . 429. 416. 409. 399. 403 . 409 . DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. First value recorded after cohabitation. 23 396. 417. 398. 430. 384 . 416. 405 . 426. 421. 429 . 415. 412 . 396. 398 . 407. 24 395. 421. 399. 432 . 381. 417. 412 . 430. 423 . 432 . 424 . 423 . 406. 404 . 415 . 25 399. 427. 401. 436. 389. 413 . 411. 430. 426 . 437. 430. 412 . 400 . 408 . 418 . Iof) MG/KG/DAY 26 27 28 398 404 . 403 . 424 422 . 432 . 401 406. 406. 434 432 . 431. 392 400. 404 . 423 424 . 421. 418 418 . 421. 438 447 . 453 . 425 426 . 432 . 439 442 . 445 . 428 437 . 435 . 420 426 . 430 . 405 407. 418. 408 412 . 419 . 419 426 . 431. 2 9a 405 . 427. 408. 442 . 409. 428 . 424 . 450 . 430. 443 . 442 . 442 . 421. 425 . 436. 30 402 . 426 . 406. 437 . 412 . 432 . 423 . 442 . 436 . 446 . 446 . 435 . 420 . 422 . 433 . 31 410 . 432 . 411. 430 . 412 . 432 . 424 . 445. 436. 463 . 447 . 438 . 427 . 420 . 438 . 32 408 433 410 449 411 437 423 456 436 466 449 442 428 430 439 418-027:PAGE B-64 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B19 (PAGE 12): BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT # DOSAGE GROUP IV HIGH DOSAGE DAY 33 34 35 36 37 17606 17609 17612 17614 17617 17621 17622 17625 17629 17636 17637 17641 17644 17647 17654 413 . 430. 412 . 447. 412 . 437. 428 . 447 . 437 . 460 . 452 . 439 . 422 . 425 . 446 . 415 . 433 . 414 . 452 . 416 . 436. 436 . 462 . 440 . 460. 452 . 445 . 430. 428 . 445 . 416. 438. 413. 449. 422 . 442 . 433. 466. 440. 470. 459. 449. 431. 436. 455. 421. 438. 418 . 453 . 427. 449. 438 . 469 . 444 . 462 . 458 . 453 . 436. 434 . 452 . 390. 407. 388. 428 . 394 . 417 . 407 . 431. 414 . 445 . 427 . 416. 407 . 400. 413 . DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). 250 MG/KG/DAY S9"9H9V(R0-8lt7 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B20 (PAGE 1): FEED CONSUMPTION VALUES - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT # DOSAGE GROUP I DAYS 1- 8 8- 15a 29b-36 17601 17602 17603 17604 17607 17608 17618 17630 17631 17639 17648 17652 17656 17658 17660 192 . 220 . 201. 195 . 181. 196. 183 . 206. 189. 194 . 184 . 216 . 177 . 178 . 169. 189. 219. 200. 193 . 167 . 190 . 176. 201. 177 . 184 . 164 . 218 . 159. 156 . 172 . 194 . 230. 196. 202 . 170 . 205. 175 . 190 . 207. 220. 186. 240 . 180 . 180 . 194 . DAYS = DAYS OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Last value recorded before cohabitation. b. First value recorded after cohabitation. VEHICLE 0 (VEHICLE) MG/KG/DAY 418-027:PAGE B-66 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B20 (PAGE 2): FEED CONSUMPTION VALUES - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT # DOSAGE GROUP II LOW DOSAGE DAYS 1- 8 8- 15a 29b-36 17615 17616 17624 17626 17632 17634 17635 17638 17642 17643 17645 17649 17651 17653 17655 158. 190 . 177 . 189. 200. 186. 191. 181. 171. 202 . 181. 173 . 181. 188 . 186 . 183 . 184 . 165. 176. 208 . 180. 184 . 169. c 196. 172 . 179. 172 . 183 . 180 . 189. 186. 178 . 188 . 209. 196. 196. 201. 168. 220. 190 . 191. 169. 188. 192 . DAYS = DAYS 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. 10 MG/KG/DAY PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B20 (PAGE 3) : FEED CONSUMPTION VALUES - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT # DOSAGE GROUP III DAYS 1- 8 8- 15a 29b-36 17605 17610 17611 17613 17619 17620 17623 17627 17628 17633 17640 17646 17650 17657 17659 184 . 195 . 184 . 198. 154 . 214 . 184 . 164 . 165. 207 . 175 . 186. 173 . 170. 167. 169. 207 . 170 . 183 . 157. 215. 168 . 177. 181. 200 . 162 . 155. 196 . 171. 171. 187. 199. 169. 169. 166. 229. 179. 165. 197. 216. 171. 187. 210. 191. 182 . DAYS = DAYS OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Last value recorded before cohabitation. b. First value recorded after cohabitation. MIDDLE DOSAGE 50 MG/KG/DAY 418-027:PAGE B-68 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B20 (PAGE 4) : FEED CONSUMPTION VALUES - INDIVIDUAL DATA - Fo GENERATION MALE RATS RAT # DOSAGE GROUP IV DAYS 1- 8 8- 15a 29b-36 17606 17609 17612 17614 17617 17621 17622 17625 17629 17636 17637 17641 17644 17647 17654 163 . 179 . 163 . 186. 165. 195. 168. 178 . 180 . 164 . 178 . 178 . 164 . 169 . 166. 165. 171. 157. 209. 162 . 179. 185 . 187. 167 . 190. 167. 170. 165. 176. 169. 157. 177 . 164 . 190. 178 . 188. 179. 192. 176 . 189. 185. 186. 180. 197. 194 . DAYS = DAYS OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Last value recorded before cohabitation. b. First value recorded after cohabitation. HIGH DOSAGE 200 MG/KG/DAY 418-027-.PAGE B-69 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B21 (PAGE 1): MATING AND FERTILITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP I VEHICLE 0 (VEHICLE) MG/KG/DAY RAT # DAYS IN COHABITATION MATING STATUS MATING DATE FEMALE PREGNANCY STATUS 17601 17602 17603 17604 17607 17608 17618 17630 17631 17639 17648 17652a 17652b 17656 17658 17660 3 4 1 1 3 3 3 1 2 3 3 4 2 4 1 7 M M M M M M M M M M M M M M M DID NOT MATE C C C C C C C C C C C C C C C - P (17662) P (17672) P (17673) P (17674) P (17680) P (17681) P (17690) P (17694) P (17695) P (17703) P (17713) P (17715) P (17719) P (17716) P (17717) - (17719) M = MATED ( ) = FEMALE RAT NUMBER C = CONFIRMED P = PREGNANT NP = NOT PREGNANT a. Result of first cohabitation period. b. Male rat mated early in the first cohabitation period and was cohabited with a second female rat. PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599. 7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B21 (PAGE 2): MATING AND FERTILITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP II RAT # DAYS :IN COHABITATION 17615 17616 17624 17626 17632 17634 17635 17638 17642 17643 17645 17649 17651 17653 17655 3 3 1 3 3 2 3 4 3 3 1 2 4 1 4 M = MATED ( ) = FEMALE RAT NUMBER C = CONFIRMED P = PREGNANT NP = NOT PREGNANT LOW DOSAGE MATING STATUS 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 10 MG/KG/DAY FEMALE PREGNANCY STATUS N P (17663) P (17665) P (17666) P (17668) P (17671) P (17675) P (17679) P (17684) P (17688) P (17698) P (17702) P (17704) P (17707) P (17708) P (17710) PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B21 (PAGE 3) : MATING AND FERTILITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP III MIDDLE DOSAGE 50 MG/KG/DAY RAT # DAYS IN COHABITATION MATING STATUS MATING DATE FEMALE PREGNANCY STATUS 17605 17610 17611 17613 17619 17620 17623 17627 17628a 17628b 17633 17640 17646 17650 17657 17659a 17659b 2 2 3 4 2 4 1 3 3 6 3 3 4 7 7 4 6 M M M M M M M M M M M M M DID NOT MATE DID NOT MATE M M C C C C C C C C C C C C C - - c c P (17661) P (17667) P (17669) P (17670) P (17676) P (17687) P (17693) P (17697) P (17700) P (17709) P (17701) P (17705) P (17706) - (17709) -(17718) P (17720) P (17718) M = MATED ( ) = FEMALE RAT NUMBER C = CONFIRMED P = PREGNANT NP = NOT PREGNANT a. Result of first cohabitation period. b. Male rat mated early in the first cohabitation period and was cohabited with a second female rat. PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B21 (PAGE 4) : MATING AND FERTILITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP IV HIGH DOSAGE 250 MG/KG/DAY RAT # DAYS IN COHABITATION MATING STATUS MATING DATE FEMALE PREGNANCY STATUS 17606 17609a 17609b 17612 17614 17617 17621 17622 17625 17629 17636 17637 17641a 17641b 17644 17647 17654 7 4 6 4 7 3 1 1 1 4 1 1 3 7 1 1 3 DID NOT MATE M M M DID NOT MATE M M M M M M M M DID NOT MATE M M M - C C c - c c c c c c c c - c c c -(17664) P (17677) P (17682) P (17678) -(17682) P (17683) P (17685) N P (17686) P (17689) P (17691) P (17692) P (17696) P (17699) -(17664) P (17711) P (17712) P (17714) M = MATED ( ) = FEMALE RAT NUMBER C = CONFIRMED P = PREGNANT NP = NOT PREGNANT a. Result of first cohabitation period. b. Male rat mated early in the first cohabitation period and was cohabited with a second female rat. PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B22 (PAGE 1) : FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - MALE RATS DOSAGE GROUP I 0 (VEHICLE~ MG/KG/DAY RAT # 17601 17602 17603 17604 17607 HOME CAGE BEHAVIOR 22222 ALTERATIONS (HOME CAGE) 11111 REACTION TO REMOVAL 11111 REACTION TO HANDLING 11111 REARS IN OPEN FIELD 89928 DEFECATION IN OPEN FIELD 1 2 3 2 1 URINATION IN OPEN FIELD 22212 LEVEL OF AROUSAL 33333 ALTERATIONS (OPEN FIELD) 11111 GAIT PATTERN 11111 GAIT ABNORMALITY, SEVERITY 1 1 1 1 1 PALPEBRAL CLOSURE 11111 PROMINENCE OF THE EYE 11111 LACRIMATION 11111 SALIVATION 11111 PILOERECTION 00000 ABNORMAL RESPIRATION 00000 APPEARANCE 11111 VISUAL REACTION 22222 TACTILE REACTION 22222 AUDITORY REACTION 33333 TAIL-PINCH REACTION 22222 VISUAL PLACING RESPONSE 111 11 AIR RIGHTING RESPONSE 11111 PUPIL RESPONSE TO LIGHT 11111 FORELIMB GRIP TEST #1 345 510 190 355 370 FORELIMB GRIP TEST #2 450 405 125 350 275 HINDLIMB GRIP TEST #1 445 375 310 200 360 HINDLIMB GRIP TEST #2 555 375 430 215 285 LANDING FOOT SPLAY #1 8.7 7.5 9.5 7.7 7.5a LANDING FOOT SPLAY #2 8.9 7.6 12.6 9.6 6.9 BODY WEIGHT (G) 455 525 469 449 425 VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY, a. Soft or liquid feces were observed during during landing foot splay testing. 418-027'.PAGE B-74 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B22 (PAGE 2): FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - MALE RATS DOSAGE GROUP II 10 MG/KG/DAY RAT # 17615 17616 17624 17626 17632 HOME CAGE BEHAVIOR 222 2 2 ALTERATIONS (HOME CAGE) 111 1 1 REACTION TO REMOVAL 111 1 1 REACTION TO HANDLING 11111 REARS IN OPEN FIELD 8 7 9 10 2 DEFECATION IN OPEN FIELD 2 2 2 2 1 URINATION IN OPEN FIELD 222 2 2 LEVEL OF AROUSAL 33333 ALTERATIONS (OPEN FIELD) 1 1 1 1 1 GAIT PATTERN 111 1 1 GAIT ABNORMALITY, SEVERITY 1 1 1 1 1 PALPEBRAL CLOSURE 111 1 1 PROMINENCE OF THE EYE 111 1 1 LACRIMATION 111 1 1 SALIVATION 11111 PILOERECTION 00000 ABNORMAL RESPIRATION 00000 APPEARANCE 11111 VISUAL REACTION 222 2 2 TACTILE REACTION 222 2 2 AUDITORY REACTION 333 3 3 TAIL-PINCH REACTION 2222 2 VISUAL PLACING RESPONSE 111 1 1 AIR RIGHTING RESPONSE 111 1 1 PUPIL RESPONSE TO LIGHT 11111 FORELIMB GRIP TEST #1 330 425 420 405 445 FORELIMB GRIP TEST #2 325 470 290 450 370 HINDLIMB GRIP TEST #1 410 335 345 205 365 HINDLIMB GRIP TEST #2 275 355 245 230 325 LANDING FOOT SPLAY #1 7.0 8.1 11.2 12.5 7.8 LANDING FOOT SPLAY #2 9.8 8.5 11.3 12.7 7.2 BODY WEIGHT (G) 433 450 441a 470 477 VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY, a. Value appeared incorrectly recorded and was excluded from group averages and statistical analyses. 418-027:PAGE B-75 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B22 (PAGE 3): FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - MALE RATS DOSAGE GROUP III 50 MG/KG/DAY RAT # 17605 17610 17611 17613 17619 HOME CAGE BEHAVIOR 2 2 222 ALTERATIONS (HOME CAGE) 1 1 111 REACTION TO REMOVAL 1 1111 REACTION TO HANDLING 1 1 11 1 REARS IN OPEN FIELD 10 10 7 9 0 DEFECATION IN OPEN FIELD 1 1 11 1 URINATION IN OPEN FIELD 1 1 22 1 LEVEL OF AROUSAL 3 3333 ALTERATIONS (OPEN FIELD) 1 1 1 1 1 GAIT PATTERN 1 1 111 GAIT ABNORMALITY, SEVERITY 1 1 1 1 1 PALPEBRAL CLOSURE 1 1111 PROMINENCE OF THE EYE 11 111 LACRIMATION 1 1 111 SALIVATION 1 1 111 PILOERECTION 0 0000 ABNORMAL RESPIRATION 0 0000 APPEARANCE 1 1111 VISUAL REACTION 2 2222 TACTILE REACTION 22 222 AUDITORY REACTION 3 3 333 TAIL-PINCH REACTION 22 222 VISUAL PLACING RESPONSE 1 1111 AIR RIGHTING RESPONSE 1 1111 PUPIL RESPONSE TO LIGHT 1 1111 FORELIMB GRIP TEST #1 205 395 315 380 195 FORELIMB GRIP TEST #2 270 575 410 400 365 HINDLIMB GRIP TEST #1 285 560 405 390 310 HINDLIMB GRIP TEST #2 360 465 480 345 230 LANDING FOOT SPLAY #1 7.2 7.2 9.9 7.0 8.1 LANDING FOOT SPLAY #2 7.1 7.4 9.7 6.5 9.3 BODY WEIGHT (G) 415 488 432 430 428 VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY. 418-027:PAGE B-76 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B22 (PAGE 4): FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - MALE RATS DOSAGE GROUP IV 250 MG/KG/DAY RAT # 17606 17609 17612 17614 17617 HOME CAGE BEHAVIOR 22 2 2 2 ALTERATIONS (HOME CAGE) 111 1 1 REACTION TO REMOVAL 111 1 1 REACTION TO HANDLING 111 11 REARS IN OPEN FIELD 13 19 12 9 0 DEFECATION IN OPEN FIELD 1 2 1 1 3 URINATION IN OPEN FIELD 21112 LEVEL OF AROUSAL 333 3 3 ALTERATIONS (OPEN FIELD) 1 1 1 1 1 GAIT PATTERN 1111 1 GAIT ABNORMALITY, SEVERITY 1 1 1 1 1 PALPEBRAL CLOSURE 1111 1 PROMINENCE OF THE EYE 1111 1 LACRIMATION 1111 1 SALIVATION 1111 1 PILOERECTION 0000 0 ABNORMAL RESPIRATION 0000 0 APPEARANCE 1 1 1 la 1 VISUAL REACTION 222 2 2 TACTILE REACTION 222 2 2 AUDITORY REACTION 33 3 3 3 TAIL-PINCH REACTION 2222 2 VISUAL PLACING RESPONSE 111 1 1 AIR RIGHTING RESPONSE 111 1 1 PUPIL RESPONSE TO LIGHT 111 1 1 FORELIMB GRIP TEST #1 210 275 400 170 285 FORELIMB GRIP TEST #2 200 310 465 140 310 HINDLIMB GRIP TEST #1 190 385 400 180 290 HINDLIMB GRIP TEST #2 410 405 460 205 225 LANDING FOOT SPLAY #1 7.6 6.6 6.9 8.7 LANDING FOOT SPLAY #2 10.2 7.8 6.5 6.7 10.0 BODY WEIGHT (G) 410 434 411 436 421 VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY"." a . Chromorhinorrhea. 418-027:PAGE B-77 o 00 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B23 (PAGE 1): MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY RAT NUMBER 17601 17602 17603 17604 DAY 86 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 58 75 54 79 70 81 65 72 63 70 70 63 33 76 74 36 0 7 74 1 6 41 72 0 2 79 62 2 55 72 61 0 81 6 57 0 26 9 57 28 4 3 64 77 1 6 71 67 3 7 53 9 2 3 60 0 0 6 50 4 2 14 54 3 1 5 60 1 0 6 55 518 407 566 1113 TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 17607 64 65 74 44 32 36 32 34 31 2 1 4 0 0 0 0 0 0 419 M -D Y& LZO rm PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B23 (PAGE 2): MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY RAT NUMBER 17601 17602 17603 17604 DAY 86 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 186 196 147 169 161 149 180 168 79 146 120 180 84 54 104 78 33 0 9 136 0 2 53 154 0 0 107 86 0 85 88 109 0 123 1 114 0 25 3 110 45 8 1 99 103 0 2 91 101 0 5 72 7 1 0 113 0 0 0 102 2 0 7 100 0 0 2 84 0 0 2 72 801 789 831 2037 TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 17607 195 196 179 69 31 46 33 42 44 1 0 2 0 0 0 0 0 0 838 418-027:PAGE B-79 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B23 (PAGE 3): MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP II 10 MG/KG/DAY RAT NUMBER 17615 17616 17624 17626 DAY 86 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 52 66 78 65 59 76 77 58 57 91 75 54 48 74 73 45 31 85 70 63 0 81 59 67 0 71 27 64 0 64 50 50 0 43 55 55 1 72 9 48 0 27 30 60 2 44 17 14 0 65 0 5 0 58 0 44 0 37 0 52 2 6 0 41 1 3 0 13 0 5 12 0 253 968 632 798 TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A. 5 MINUTE PERIOD. 17632 74 69 75 72 68 51 45 87 54 52 48 46 44 34 4 41 7 2 873 08-aaova^o-8it7 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B23 (PAGE 4): MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP II 10 MG/KG/DAY RAT NUMBER 17615 17616 17624 17626 DAY 86 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 233 196 195 196 182 154 164 170 135 169 160 120 85 122 94 79 45 136 127 123 0 107 78 119 0 143 12 112 0 94 55 73 0 86 77 127 0 74 7 74 0 28 20 93 1 68 15 15 0 91 0 9 0 66 0 42 0 29 0 69 1 5 0 70 0 0 0 14 0 3 10 0 682 1571 1014 1505 TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE p e r i o d . 17632 204 167 117 12 9 76 123 65 130 85 80 59 80 50 31 3 35 6 0 1440 418-027:PAGE B-: QO PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B23 (PAGE 5) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP III 50 MG/KG/DAY RAT NUMBER 17605 17610 17611 17613 DAY 86 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 66 64 63 69 67 37 64 75 64 51 81 63 70 40 43 50 69 22 0 52 41 0 11 28 41 2 1 2 2 52 29 3 4 34 43 2 1 68 66 48 0 40 80 48 0 37 51 1 1 31 63 0 0 55 34 0 5 57 14 1 54 31 11 0 14 53 0 0 1 34 0 2 500 708 654 444 TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A. 5 MINUTE PERIOD. 17619 58 73 75 70 71 62 66 41 78 39 11 23 2 10 0 14 0 1 694 418-027:PAGE B-82 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B23 (PAGE 6): MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP III 50 MG/KG/DAY RAT NUMBER 17605 17610 17611 17613 DAY 86 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 177 181 221 119 134 166 144 98 135 145 88 67 108 25 0 59 0 8 54 0 0 0 71 17 6 35 53 0 112 137 0 71 160 0 66 39 0 40 68 0 71 36 4 81 12 58 56 4 16 84 0 0 59 0 890 1272 1123 190 164 135 88 64 39 0 0 0 77 64 0 0 0 0 0 0 1 822 TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 17619 173 92 105 120 84 60 113 46 97 37 7 26 1 6 0 14 0 1 982 418-027:PAGE B-83 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OP T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B23 (PAGE 7): MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP IV 250 MG/KG/DAY RAT NUMBER 17606 17609 17612 17614 DAY 86 NUMBER OP 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 61 60 65 72 70 54 76 88 48 64 63 73 54 60 48 73 1 52 1 12 2 6 0 18 3 101 1 810 0 2 01 2 0 48 0 1 32 47 50 3 56 1 50 4 20 0 9 1 1 1 16 10 0 1 29 57 2 0 20 1 0 0 16 1 5 0 11 320 423 352 539 TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A. 5 MINUTE PERIOD. 17 617 70 73 62 71 62 54 49 31 4 4 0 3 4 0 0 2 2 0 491 418-027:PAGE B-84 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE B23 (PAGE 8) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS DOSAGE GROUP IV 250 MG/KG/DAY RAT NUMBER 17606 17609 17612 17614 DAY 86 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 192 197 181 187 163 173 108 180 82 114 95 142 122 146 44 167 0 70 0 14 0 5 0 10 0000 04 0 0 0100 0 0 64 0 0 33 79 52 1 92 0 60 1 19 0 8 0 0 0 11 7 0 0 26 89 0 0 51 0 0 0 20 0006 657 854 571 934 TOTAL = SUM OF BLOCKS t EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 17617 141 139 125 67 77 105 68 21 2 7 0 0 1 0 0 0 0 0 753 418-027:PAGE B-85 APPENDIX C REPORT TABLES - Fo GENERATION FEMALE RATS PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE Cl (PAGE 1): CLINICAL OBSERVATIONS - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I 0 (VEHICLE) II 10 III 50 MORTALITY 0 00 PRECOHABITATION (DAY 1 OF STUDY TO THE DAY OF COHABITATION): MAXIMUM POSSIBLE INCIDENCE 225/ 15 225/ 15 225/ 15 RED, SLIGHT PERIORAL SUBSTANCE 1/ 1 0/ 0 0/ 0 EXCESS SALIVATION 1/ 1 0/ 0 0/ 0 TAIL BENT 0/ 0 0/ 0 0/ 0 CHROMODACRYORRHEA 1/ 1 0/ 0 0/ 0 RIGHT EYE: CORNEAL OPACITY 0/ 0 0/ 0 12/ 1 LOCALIZED ALOPECIA: LIMBS 9/ 2 1/ 1 0/ 0 STATISTICAL ANALYSES OF CLINICAL OBSERVATION DATA WERE RESTRICTED TO THE NUMBER OF RATS WITH OBSERVATIONS. MAXIMUM POSSIBLE INCIDENCE = (DAYS x RATS)/NUMBER OF RATS EXAMINED PER GROUP. N/N = TOTAL NUMBER OF OBSERVATIONS/NUMBER OF RATS WITH OBSERVATION. IV 250 0 225/ 15 3/ 3 4/ 2 13/ 1 1/ 1 0/ 0 0/ 0 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE Cl (PAGE 2): CLINICAL OBSERVATIONS - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I 0 (VEHICLE) II 10 III 50 MORTALITY 0 00 PRESUMED GESTATION: a MAXIMUM POSSIBLE INCIDENCE 330/ 15 335/ 15 331/ 15 EXCESS SALIVATION 0/ 0 0/ 0 0/ 0 RED, SLIGHT OR MODERATE PERIORAL SUBSTANCE 0/ 0 0/ 0 0/ 0 LOCALIZED ALOPECIA: TOTAL LIMBS UNDERSIDE HEAD 43/ 2 43/ 2 0/ 0 0/ 0 40/ 3 40/ 3 0/ 0 0/ 0 26/ 2 26/ 2 0/ 0 0/ 0 URINE-STAINED ABDOMINAL FUR 0/ 0 0/ 0 0/ 0 TAIL BENT 0/ 0 0/ 0 0/ 0 RED PERIVAGINAL SUBSTANCE 0/ 0 0/ 0 0/ 0 CHROMODACRYORRHEA 0/ 0 0/ 0 2/ 1 INCISORS: MISSING/BROKEN SOFT OR LIQUID FECES 0/ 0 0/ 0 1/ 1 1/ 1 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. ** Significantly different from the vehicle control group value (p<0.01). IV 250 0 316/ 14 25/ 7** 16/ 6** 41/ 3 38/ 2 4/ 1 3/ 1 12/ 2 22/ 1 1/ 1 0/ 0 0/ 0 0/ 0 Z"3 3DV<T-LZ0-8Ii7 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE Cl (PAGE 3) : CLINICAL OBSERVATIONS - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I 0 (VEHICLE) II 10 III 50 MORTALITY 00 0 LACTATION: MAXIMUM POSSIBLE INCIDENCE 90/ 15 84/ 14 90/ 15 LOCALIZED ALOPECIA: TOTAL LIMBS UNDERSIDE 12/ 2 12/ 2 0/ 0 13/ 3 13/ 3 0/ 0 12/ 2 12/ 2 0/ 0 EXCESS SALIVATION 0/ 0 0/ 0 0/ 0 TAIL BENT 0/ 0 0/ 0 0/ 0 DEHYDRATION 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. IV 250 0 70/ 13 7/ 2 7/ 2 6/ 1 4/ 2 6/ 1 1/ 1 418-027:PAGE 0 3 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C2 (PAGE 1) : NECROPSY OBSERVATIONS - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II III IV 0 (VEHICLE) 10 50 250 RATS EXAMINED a N 15 15 15 15 MORTALITY N0 0 0 0 APPEARED NORMAL N 15 15 14 14 KIDNEYS: RIGHT, ABSENT N 0 0 1 0 THYMUS: SMALL N0 0 0 1 a. Refer to the individual clinical observations table (Table C27) for external observations confirmed at necropsy. 418-027:PAGE 0 4 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C3 (PAGE 1): TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I 0 (VEHICLE) II 10 RATS TESTED N 15 15 PREGNANT N 15 14 INCLUDED IN ANALYSES N 15 14 TERMINAL BODY WEIGHT M E A N S ..D. 299.1 24.7 304.0 + 18.9 BRAIN LIVER M E A N S .D. MEANS.D . 2.20 0.08 [ 10] b 11.22 1.26 2.19 + 0.07 [ 10] b 11.81 1.50 KIDNEY LEFT KIDNEY RIGHT ADRENAL LEFT ADRENAL RIGHT SPLEEN THYMUS OVARY LEFT M E A N S .D. MEANS.,D . M E A N S .D. M E A N + S ,.D. M E A N + S ,.D. M E A N S ,.D. M E A N + S ,.D. 1.20 0.13 [ 10] b 1.20 0.13 [ 10] b 0.042 0.004 [ 10] b 0.041 + 0.006 [ 10] b 0.70 + 0.06 [ 10] b 0.27 0.07 [ 10] b 0.080 0.017 1.29 0.14 [ 10] b 1.31 + 0.10 [ 10] b 0.046 + 0.008 [ 10] b 0.043 + 0.006 [ 10] b 0.74 0.14 [ 10] b 0.34 + 0.07 [ 10] b 0.079 + 0.012 OVARY RIGHT MEANS,.D . 0.081 0.014 0.083 + 0.013 UTERUS WITH CERVIX M E A H S .D. 0.80 0.11 0.79 0.10 HEART M E A N S .D. 1.08 0.11 [ 10] b 1.15 0.08 [ 10] b ALL WEIGHTS WERE RECORDED IN GRAMS (G). [ ] = NUMBER OF VALUES AVERAGED a. Excludes values for dams that were sacrificed due to no surviving pups. b. Results did not warrant examination of the five additional rats. c. Excludes rat 17706, which had an absent right kidney. ** Significantly different from the vehicle control group value (p<0.01). III 50 15 15 15 296.0 25.0 2.19 0.07 [ 10] b 11.66 1.28 1.31 0.32 [ 10] b 1.27 0.14 [ 9] b, c 0.041 0.008 [ 10] b 0.038 0.008 [ 10] b 0.76 0.10 [ 10] b 0.29 0.07 [ 10] b 0.079 0.015 0.084 0.015 0.78 0.09 1.11 0.14 [ 10] b IV 250 15 13 11a 284.8 11.1 2 .20 0.08 [ 9] b 13 .56 0.89** 1 .23 + 0.08 [ 9] b 1 .27 0.08 [ 9] b 0. 045 + 0.008 [ 9] b 0. 040 0.006 [ 9] b 0 .64 0.09 C 9] b 0 .22 + 0.05 [ 9] b 0 .076 0.010 0. 080 + 0.014 0 .70 0.06 1 .00 + 0.12 C 9] b 418-027:PAGE C-5 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C4 (PAGE 1): RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II III IV 0 (VEHICLE) 10 50 250 RATS TESTED N 15 15 15 15 PREGNANT N 15 14 15 13 INCLUDED IN ANALYSES N 15 14 15 11a TERMINAL BODY WEIGHT MEANS D. 299.1 24.7 304.0 18.9 296.0 25.0 284.8 11.1 BRAIN LIVER KIDNEY LEFT KIDNEY RIGHT ADRENAL LEFT c ADRENAL RIGHT c SPLEEN THYMUS OVARY LEFT C OVARY RIGHT c UTERUS WITH CERVIX HEART MEANS D. MEANS D. MEANS D. MEANS D. MEANS D. MEANS D. MEANS D. MEANS D. MEANS D. MEANS D. MEANS D. MEANS D. 0 .733 0 .059 ( 10] b 3 .753 0 .336 0 .397 0 .029 [ 10] b 0. 400 0 .036 [ 10] b 13 .994 2 004 [ 10] b 13 .767 2 .449 [ 10] b 0 .234 0 .021 [ 10] b 0 .092 0 .019 [ 10] b 26. 915 6 .046 27 .215 4 .339 0 .267 0 .034 0 .361 0 .019 [ 10] b 0 706 0 .029 [ 10] b 3 871 0 .318 0 416 + 0 .042 [ 10] b 0 421 0 .031 [ 10] b 14 906 2 .273 [ 10] b 13 951 l .699 [ 10] b 0 236 0 .037 [ 10] b 0 107 0 .019 [ 10] b 25 976 4 .034 27 123 3 .255 0 258 0 .035 0 371 0 .026 [ 10] b 0 728 0 .065 [ 10] b 3 935 0 .233 0 432 0 .096 [ 10] b 0 421 0 .042 [ 9] b d 13 476 1 .549 [ 10] b 12 481 1 930 [ 10] b 0 255 0 047 [ 10] b 0 094 0 020 [ 10] b 26 551 3 .476 28 301 4 .894 0 263 0 .028 0 366 0 .036 [ 10] b 0 778 0 .040 [ 9] b 4 763 0 .284** 0 434 0 .034 [ 9] b 0 449 0 .035** [ 9] b 15 943 3 .030 ( 9] b 14 297 2 .379 [ 9] b 0 227 0 .031 [ 9] b 0 076 0 .019 [ 9] b 26 802 3 .440 28 246 4 797 0 246 0 025 0 354 0 .034 [ 9] b ALL WEIGHTS WERE RECORDED IN GRAMS (G) . RATIOS (%) = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. [ ] = NUMBER OF VALUES AVERAGED a . Excludes values for dams that were sacrificed due to no surviving p ups. b . Results did not warrant examination of the five additional rats. c . Value was multiplied by 1000. d. Excludes rat 17706, which had an absent right kidney. ** Significantly different from the vehicle control group value (p<0.01). 418-027:PAGE C-6 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C5 (PAGE 1): RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II Ill IV 0 (VEHICLE) 10 50 250 RATS TESTED N 10 10 10 12 PREGNANT N 10 10 10 11 INCLUDED IN ANALYSES N 10 10 10 9a BRAIN WEIGHT M E A N S .D. 2 ,.20 0,.08 2 .19 0,.07 2 .19 0 .07 2 .20 0 .08 LIVER M E A N S .D. 521,.53 59 ,.00 564 ,.65 + 40,.68* 547,.24 48 .14 616 .82 + 35 .48** KIDNEY LEFT MEANS.D . 54 ,.44 5 .35 59,.07 5..87 59..77 14 .09 55,.99 + 2 ,.45 KIDNEY RIGHT ADRENAL LEFT M E A N S ,.D. M E A N S ,.D. 54 ,.59 5..44 1,.90 0 ,.20 59..89 + 4 ,.34 2 .11 0,.34 58..08 6 .21 ( 9] b 1..88 + 0 .36 57 .96 3 .10 2 .04 + 0 ,.34 ADRENAL RIGHT M E A N S ,.D. 1,.88 0..29 1,.98 0..28 1..74 + 0..38 1,.83 0..27 SPLEEN MEANS.D . 32 ,.11 3 .12 33 .76 6..06 34..92 + 4 ,.73 29..17 3 .90 THYMUS M E A N S ,.D. 12 ,.42 3 ,.30 15..40 2 .84 13 .18 3 ,.13 9,.85 2 ,.66 OVARY LEFT M E A N S .D. 3 ,.69 0 .86 3 ,.66 0,.59 3..82 0,.73 3 .42 0..44 OVARY RIGHT M E A N S ,.D. 3 ,.75 0..77 3 .94 0..42 3 ..95 0..67 3 .63 + 0 .73 UTERUS WITH CERVIX MEANS ,.D. 36..63 5..32 36..42 + 4 .93 36.,07 2 .57 32 .66 + 2 .24 HEART MEANS .D. 49..34 4 ,.16 52 ,.51 3 .48 50..74 6,.49 45 .77 + 5 .51 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . RATIOS (%) = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. [ ] = NUMBER OF VALUES AVERAGED a. Excludes values for dams that were sacrificed due to no surviving pups. b. Excludes rat 17706, which had an absent right kidney. * Significantly different from the vehicle control group value (p<0.05). * * Significantly different from the vehicle control group value (p<0.01). 418-027:PAGE C-7 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C6 (PAGE 1): HEMATOLOGY - SUMMARY - Fo GENERATION FEMALE RATS (See last page of this table for abbreviations) DOSAGE GROUP DOSAGE (MG/KG/DAY) I 0 (VEHICLE) RATS TESTED N5 INCLUDED IN ANALYSES N 4a WBC (THSN/CU MM) MEAN+S.D . 20.2 + 2.70 RBC (MILL/CU MM) MEANS.D . 5.86 + 0.466 HGB (GRAMS/DL) MEANS.D . 13.9 + 0.61 HCT (%) MEAN+S.D . 36.8 + 1.61 MCV (CU MICRONS) MEAN+S.D . 63.0 2.88 MCH (PICO GRAMS) MEANS.D . 23.8 1.21 MCHC (%) M E A N S .D 37.8 + 0.72 PLAT (THSN/CU MM) MEAN+S.D . 1534 + 140.4 PT (SECONDS) MEAN+S.D . 13.3 + 0.40 APTT (SECONDS) M E A N I S .D 21.2 + 2.32 [ ] = NUMBER OF VALUES AVERAGED a. Excludes values for rats that had clotted samples. II 10 5 5 14.9 1.92 6.00 + 0.246 14.3 + 0.46 38.2 + 1.08 63.6 2.77 23.8 + 1.08 37.4 + 0.17 947 531.0 13.3 + 0.34 [ 4] a 18.2 + 1.95 III 50 6 6 20.2 + 2.71 5.77 0.578 13.7 0.78 36.3 + 2.88 63.0 1.87 23.8 1.26 37.8 + 1.01 1598 423.9 13.2 0.16 [ 5] a 22.0 + 3.70 IV 250 4 4 21.6 2.83 5.76 + 0.371 13.2 + 0.68 34.1 2.46 59.2 + 1.38 22.9 + 0.46 38.7 + 1.36 1547 + 236.6 13.2 0.22 19.8 + 4.39 418-027'.PAGE C-8 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C6 (PAGE 2) : HEMATOLOGY - SUMMARY - Fo GENERATION FEMALE RATS (See last page of this table for abbreviations) DOSAGE GROUP DOSAGE (MG/KG/DAY) RATS TESTED INCLUDED IN ANALYSES I 0 (VEHICLE) N5 N 4a MPV (CU MICRONS) MEAN+S.D . 7.7 0 . 9 1 NRBC COUNT MEANS.D . 0 + 0.0 Lymphocyte (THSN/CU MM) MEAN+S.D . 15.9 + 1.81 Segmented (THSN/CU MM) MEANS.D . 3.9 1.38 Bands (THSN/CU MM) MEANS.D . 0.0 + 0.00 Monocytes (THSN/CU MM) MEAN+S.D. 0.3 + 0.34 Eosinophil (THSN/CU MM) MEANS.D . 0.1 + 0.12 Basophils (THSN/CU MM) MEAN+S.D . 0.0 + 0.00 Abnormal L (THSN/CU MM) MEAN+S.D . 0.1 0.10 Other (THSN/CU MM) MEAN+S.D . 0.0 + 0.00 [ ] = NUMBER OF VALUES AVERAGED a. Excludes values for rats that had clotted samples. II 10 5 5 8.8 2.08 [ 4] a 0 0.0 12.6 + 2.28 2.0 0.76 0.0 0.00 0.2 0 . 1 6 0.0 0.00 0.0 0.00 0.0 0.00 0.0 0.00 III 50 6 6 8.0 1.02 [ 5] a 0 0.0 15.5 2.48 4.4 1 . 5 4 0.0 0.00 0.2 0.27 0.1 0.17 0.0 0.00 0.0 0.00 0.0 0.00 IV 250 4 4 8.2 + 0.58 0 0.0 16.4 4.17 4.1 1.95 0.1 0.12 0.9 0.56 0.0 0.00 0.0 0.00 0.1 0.15 0.0 0.00 418-027'.PAGE C-9 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C6 (PAGE 3): HEMATOLOGY - SUMMARY - Fo GENERATION FEMALE RATS KEY TO HEMATOLOGY TABLE AB BREVATION WBC RBC HGB HCT MCV MCH MCHC PLAT MPV PT APTT NRBC Segmented Abnormal L Other TERMINOLOGY White Blood Cells (Leukocytes) Red Blood Cells (Erythrocytes) Hemoglobin Hematocrit (Packed Cell Volume) Mean Corpuscular Volume Mean Corpuscular Hemoglobin Mean Corpuscular Hemoglobin Concentration Platelets Mean Platelet Volume Prothrombin Time Activated Partial Thromboplastin Nucleated Red Blood Cell Count Segmented Neutrophils Abnormal Lymphocytes Other Cells 0K)3Dv<r-mmi7 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C7 (PAGE 1): CLINICAL CHEMISTRY - SUMMARY - Fo GENERATION FEMALE RATS (See last page of this table for abbreviations) DOSAGE GROUP DOSAGE (MG/KG/DAY) RATS TESTED TP (G/DL) A (G/DL) GLU (MG/DL) CHOL (MG/DL) TBILI (MG/DL) BUN (MG/DL) GREAT (MG/DL) ALT (U/L) AST (U/L) N MEANtS.D . MEAN+S.D . MEANS.D . MEAN+S.D . MEANS .D . MEANS.D . MEANiS.D . MEAN+S.D. MEAN+S.D . I 0 (VEHICLE) 5 6.5 0.45 4.2 + 0.30 125 + 26.9 52 + 11.8 0.1 + 0.05 20 3.6 0.4 + 0.04 60 + 7.4 100 + 9.1 II 10 5 6.5 + 0.61 4.2 + 0.25 138 + 6.6 61 7.5 0.1 + 0.04 18 + 3.3 0.3 + 0.09 57 13.0 94 18.8 III 50 6 6.2 + 0.44 4.1 + 0.33 124 27.4 58 14.5 0.1 0.00 19 3.3 0.3 0.04 62 13.3 117 20.0 IV 250 4 6.3 + 0.59 4.1 + 0.14 114 + 28.1 57 + 12.9 0.1 + 0.05 21 + 2.5 0.4 + 0.08 94 7.4 120 23.8 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C7 (PAGE 2): CLINICAL CHEMISTRY - SUMMARY - Fo GENERATION FEMALE RATS (See last page of this table for abbreviations) DOSAGE GROUP DOSAGE (MG/KG/DAY) RATS TESTED ALK (U/L) CA (MG/DL) PHOS (MG/DL) TRI (MG/DL) NA (MMOL/L) K (MMOL/L) CL (MMOL/L) G (G/DL) A/G N MEAN+S.D . MEAN+S.D . MEANS.D . MEAN+S.D . MEAN1S .D . MEANiS.D . MEAN+S.D . MEAN+S.D. MEAN+S.D . I 0 (VEHICLE) 5 63 19.5 11.8 + 0.37 9.3 + 0.13 56 12.5 143 2.1 6.7 + 0.37 97 3.0 2.3 + 0.19 1.8 + 0.11 II 10 5 51 + 9.5 11.7 0.54 8.1 + 0.85 57 22.2 142 + 1.1 6.4 + 0.74 98 1.2 2.4 + 0.38 1.8 + 0.20 III 50 6 54 + 23.0 11.5 0.31 8.8 + 1.54 48 22.2 143 1.0 6.7 0.51 101 + 1.8 2.2 0.13 1.9 0.12 IV 250 4 87 + 28.5 11.9 + 0.66 9.5 0.50 66 10.6 140 + 2.1 6.7 0.22 98 + 2.9 2.2 + 0.46 2.0 + 0.44 418-027:PAGE C-12 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C7 (PAGE 3): CLINICAL CHEMISTRY - SUMMARY -- Fo GENERATION FEMALE RATS KEY TO CLINICAL CHEMISTRY TABLE ABBREVATION TP A GLU CHOL TBILI BUN GREAT ALT AST ALK CA PHOS TRI NA K CL G A/G TERMINOLOGY Total Protein Albumin Glucose Cholesterol Total Bilirubin Blood Urea Nitrogen Creatinine Alanine Aminotransferase Aspartate Aminotransferase Alkaline Phosphatase Calcium Phosphorus (inorganic) Triglycerides Sodium Potassium Chloride Globulin Albumin/Globulin Ratio 418-027:PAGE C-13 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C8 (PAGE 1) : BODY WEIGHTS - PRECOHABITATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I 0 (VEHICLE) RATS TESTED N 15 BODY WEIGHT (G) DAY 1 MEANS.D . 227.2 7.9 DAY 8 MEANS.D . 248.2 11.8 DAY 15a MEANS.D . 262.3 14.7 DAY = DAY OF STUDY a. Last value recorded before cohabitation. II 10 15 227.3 7.5 248.8 9.1 262.3 13.5 III 50 15 226.5 5.9 248.5 12.1 260.7 1 4 . 6 IV 250 15 226.5 5.7 242.5 10.0 252.9 1 2 . 8 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C9 (PAGE 1): BODY WEIGHT CHANGES - PRECOHABITATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I 0 (VEHICLE) II 10 RATS TESTED N 15 15 BODY WEIGHT CHANGE (G) DAYS 1 - 8 MEANS.D . +21.0 6.2 +21.5 4.4 DAYS 8 - 15a MEAN+S.D . +14.1 + 5.2 +13.5 6.0 DAYS 1 - 15a MEANS.D . +35.1 10.0 +34.9 8.4 DAYS = DAYS OF STUDY a. Last value recorded before cohabitation. * Significantly different from the vehicle control group value (p<0.05). III 50 15 +21.9 + 7.5 +12.2 5.3 +34.1 + 10.4 IV 250 15 +16.0 6.5* +10.3 4.1 +26.3 8.9* 418-027'.PAGE C-15 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) 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 MEAN+S.D . DAY 2 MEANS.D . DAY 3 MEANS.D . DAY 4 MEANS.D . DAY 5 MEANS.D . DAY 6 MEANS.D . DAY 7 MEAN+S.D . DAY 8 MEANS.D . DAY 9 MEANS.D . DAY 10 MEANS.D . DAY 11 MEANS.D . DAY 12 MEANS.D . DAY 13 MEANS.D . DAY 14 MEANS.D . DAY = DAY OF GESTATION I 0 (VEHICLE) 15 15 268.5 13.4 276.3 + 14.5 281.8 + 15.5 284.4 + 15.6 288.0 15.0 292.1 + 16.4 295.8 17.9 299.7 18.4 303.5 18.9 306.0 + 20.0 312.5 + 20.6 319.3 21.8 325.3 + 22.7 329.8 + 24.6 338.3 + 26.4 II 10 15 14 272.9 13.0 277.6 + 14.8 282.7 15.0 286.5 17.4 289.4 15.9 291.9 17.3 295.8 17.7 298.7 16.5 301.9 + 17.4 306.8 19.2 311.8 + 20.1 318.4 + 19.6 327.1 21.6 329.2 21.8 336.9 23.8 III 50 15 15 2 1 2 . 1 + 17.0 276.8 16.8 280.6 17.7 282.5 17.6 287.6 19.0 289.8 18.5 2 92.0 18.4 296.8 19.3 299.0 20.6 302.4 21.2 308.1 21.9 315.3 22.2 322.9 + 24.1 324.9 + 24.1 331.3 + 23.6 IV 250 15 13 262.0 + 16.2 268.2 13.1 272.5 14.2 273.7 14.8 278.3 16.6 280.9 16.4 283.1 15.7 285.5 17.2 288.3 17.5 292.8 18.0 298.7 17.1 304.8 17.3 311.5 + 16.7 315.2 + 16.7 321.5 + 17.2 418-027PAGE C-16 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) 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 15 MEANS.D . DAY 16 MEANS.D. DAY 17 MEANS.D . DAY 18 MEANS.D . DAY 19 MEANS.D . DAY 20 MEAN+S.D . DAY = DAY OF GESTATION I 0 (VEHICLE) 15 15 345.4 25.9 355.7 25.5 368.6 27.4 386.9 29.4 400.6 29.7 418.1 34.5 II 10 15 14 341.4 24.5 354.2 25.9 368.8 26.5 387.1 29.6 400.9 30.7 416.5 32.8 III 50 15 15 338.8 24.0 350.5 23.4 363.9 24.5 380.1 24.1 395.7 24.2 411.4 + 26.7 IV 250 15 13 328.3 17.0 340.9 + 16.5 353.2 16.4 366.2 17.6 381.2 15.9 395.6 17.0 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR1'S STUDY NUMBER: T-7599) TABLE Cil (PAGE 1)1: MATERNAL BODY WEIGHT CHANGES - GESTATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I 0 (VEHICLE) II 10 RATS TESTED N 15 15 PREGNANT N 15 14 MATERNAL BODY WEIGHT CHANGE (G) DAYS 0 - 3 MEANS.D . +15.9 4.8 +13.6 5.7 DAYS 3 - 6 MEANS.D . +11.4 5.5 +9.4 4.9 DAYS 6 - 9 MEAN+S.D . +10.2 4.5 +11.0 3.8 DAYS 9 - 12 MEANS.D . +19.3 4.9 +20.3 5.3 DAYS 12 - 15 MEANS.D . +20.1 4.6 +14.3 6.2** DAYS 15 - 18 MEANS.D . +41.5 6.2 +45.7 9.2 DAYS 18 - 20 MEANS.D . +31.2 8.6 +29.4 6.7 DAYS 0 - 20 MEAN+S.D . +149.6+ 24.8 +143.6 23.0 DAYS = DAYS OF GESTATION * Significantly different from the vehicle control group value (p0.05). k k Significantly different from the vehicle control group value (p<0.01). III 50 15 15 +10.4 5.7* +9.5 4.2 +10.4 5.2 +20.5 4.2 +15.9 5.2* +41.3 5.5 +31.3 6.3 +139.3 17.1 IV 250 15 13 +11.7 5.4 +9.4 3.7 +9.7 4.3 +18.7 6.5 +16.8 4.1 +37.9 6.0 +29.4 5.6 +133.6 12.8 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C12 (PAGE 1) : MATERNAL BODY WEIGHTS - LACTATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) RATS TESTED N PREGNANT N DELIVERED A LITTER N MATERNAL BODY WEIGHT (G) DAY 1 MEANS.D . DAY 2 MEAN+S.D . DAY 3 MEAN+S.D . DAY 4 MEANS.D . DAY 5 MEANS.D . DAY 6 MEAN+S.D . I 0 (VEHICLE) 15 15 15 321.2 24.7 320.9 27.2 320.9 26.5 324.1 27.6 327.5 29.4 299.1 24.7 II 10 15 14 14 319.8 20.8 324.6 25.7 326.4 2 4 . 7 329.1 25.0 339.1 21.6 304.0 18.9 DAY = DAY OF LACTATION [ ] = NUMBER OF VALUES AVERAGED a. Excludes values for dams that were sacrificed due to no surviving pups. * Significantly different from the vehicle control group value (p<0.05). III 50 15 15 15 316.5 25.0 318.7 26.1 322.7 25.9 320.6 25.8 327.9 27.5 296.0 25.0 IV 250 15 13 13 296.3 25.7* 308.2 1 4 . 1 [ 11] a 308.4 15.0 [ 11] a 310.6 14.6 [ 11] a 317.4 12.3 [ 11] a 284.8 11.1 [ 11] a PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C13 (PAGE 1): MATERNAL BODY WEIGHT CHANGES - LACTATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) RATS TESTED PREGNANT DELIVERED A LITTER MATERNAL :BODY WEIGHT CHANGE (G) DAYS 1 - 2 DAYS 2 - 3 DAYS 3 - 4 DAYS 4 - 5 DAYS 5 - 6 DAYS 1 - 6 N N N MEANS.D . MEANS.D . MEANS.D . MEANS.D . MEANS.D . MEANS.D . I 0 (VEHICLE) 15 15 15 -0.3 9.3 -0.1 8.0 +3.3 6.4 +3.4 9.0 -28.4 8.6 -22.1 9.6 II 10 15 14 14 +4.7 8.2 +1.8 6.5 +2.7 8.3 +10.0 6.9 -35.1 8.5 -15.8 6.5 DAYS = DAYS OF LACTATION [ ] = NUMBER OF VALUES AVERAGED a. Excludes values for dams that were sacrificed due to no surviving pups. III 50 15 15 15 +2.2 7.2 +3.9 5.9 -2.1 6.0 +7.3 4.3 -31.9 5.8 -20.5 9.7 IV 250 15 13 13 +3.1 + 4.6 [ 11] a +0.3 + 6.3 [ 11] a +2.2 4.3 [ 11] a +6.8 7.7 [ 11] a -32.6 + 8.0 [ 11] a -20.3 13.3 [ 11] a 418-027:PAGE 020 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C14 (PAGE 1): ABSOLUTE FEED CONSUMPTION VALUES (G/DAY) - PRECOHABITATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) RATS TESTED N FEED CONSUMPTION (G/DAY) DAYS 1 - 8 MEANS.D . DAYS 8 - 15a MEANS.D . DAYS 1 - 15a MEANS.D . I 0 (VEHICLE) 15 19.4 2.8 20.3 2.5 19.8 2.6 DAYS = DAYS OF STUDY [ ] = NUMBER OF VALUES AVERAGED a. Last value recorded before cohabitation. b. Excludes values that were associated with spillage. II 10 15 19.4 1.7 20.7 2.1 20.0 1.8 III 50 15 19.8 20.3 20.0 2.8 2.8 2.7 IV 250 15 18.5 2.6 19.2 1.6 [ 14] b 18.6 1.6 [ 14] b PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C15 (PAGE 1): RELATIVE FEED CONSUMPTION VALUES (G/KG/DAY) - PRECOHABITATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) ! TESTED N ) CONSUMPTION (G/KG/DAY) DAYS 1 - 8 MEANS.D . DAYS 8 - 15a MEANS.D . DAYS 1 - 15a MEANS.D . I 0 (VEHICLE) 15 82.2 12.7 79.6 10.7 80.9 11.6 DAYS = DAYS OF STUDY [ ] = NUMBER OF VALUES AVERAGED a. Last value recorded before cohabitation. b. Excludes values that were associated with spillage. II 10 15 81.6 5.4 80.7 5.3 81.3 4.6 HI 50 15 83.4 79.5 81.5 9.3 7.3 7.9 IV 250 15 79.0 9.4 77.3 3.9 [ 14] b 77.2 4.0 [ 14] b PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) 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 (VEHICLE) RATS TESTED N 15 PREGNANT N 15 MATERNAL FEED CONSUMPTION (G/DAY) DAYS 0 - 7 MEANS.D . 23.3 1.9 DAYS 7 - 1 0 MEANS.D . 25.1 2.4 DAYS 1 0 - 1 2 MEANS.D . 25.4 2.9 DAYS 12 - 15 MEANS.D . 26.4 2.9 DAYS 15 - 18 MEANS.D . 26.8 3.1 DAYS 1 8 - 2 0 MEANS.D . 25.7 3.7 DAYS 0 - 2 0 MEANS.D . 25.0 2.3 DAYS = DAYS OF GESTATION [ ] = NUMBER OF VALUES AVERAGED a. Excludes values that were associated with spillage. II 10 15 14 23.3 25.2 25.6 26.5 28.3 25.3 25.2 2.7 2.7 4.0 3.8 3.2 3.4 2.7 III 50 15 15 22.6 3.2 23.7 3.6 25.0 3.2 25.7 4.2 26.9 3.7 25.8 2.8 24.4 3.0 IV 250 15 13 22.2 2.3 [ 12] a 24.2 2.7 26.5 3.4 26.4 2.3 28.1 3.2 25.0 2.8 24.8 1.8 418-027PAGE C-23 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) 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 (VEHICLE) II 10 RATS TESTED N 15 15 PREGNANT N 15 14 MATERNAL FEED CONSUMPTION (G/KG/DAY) DAYS 0 - 7 MEANS.D . 81.6 4.0 80.9 5.7 DAYS 7 - 10 MEANS.D . 82.1 5.0 82.4 6.2 DAYS 10 - 12 MEANS.D . 79.5 5.7 80.0 9.5 DAYS 12 - 15 MEANS.D . 78.8 4.9 79.1 7.2 DAYS 15 - 18 MEANS.D . 73.6 5.5 77.9 5.1 DAYS 18 - 20 MEANS.D . 64.0 7.4 62.9 6.2 DAYS 0 - 20 MEANS.D . 77.3 3.7 77.8 4.4 DAYS = DAYS OF GESTATION [ ] = NUMBER OF VALUES AVERAGED a. Excludes values that were associated with spillage. ** Significantly different from the vehicle control group value (p<0.01). III 50 15 15 79.0 7.1 78.4 8.3 79.3 8.9 77.7 10.1 75.0 8.1 65.1 4.7 76.1 6.0 IV 250 15 13 80.8 6.6 [ 12] a 83.2 8.1 86.8 10.3 82.8 5.9 81.2 9.1** 65.8 7.5 80.2 4.8 418-027:PAGE C-24 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C18 (PAGE 1): MATERNAL ABSOLUTE FEED CONSUMPTION VALUES (G/DAY) - LACTATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I 0 (VEHICLE) II 10 RATS TESTED N 15 15 PREGNANT N 15 14 DELIVERED A LITTER N 15 14 MATERNAL FEED CONSUMPTION (G/DAY) DAYS 1 - 5 MEANS.D . 31.4 5.6 36.4 4.2 [ 13] a DAYS = DAYS OF LACTATION [ ] = NUMBER OF VALUES AVERAGED a. Excludes values that were associated with spillage. b. Excludes values for dams that were sacrificed due to no surviving pups. III 50 15 15 15 33.0 5.6 [ 14] a IV 250 15 13 13 30.8 7.4 [ 11] b PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) 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 0 (VEHICLE) II 10 RATS TESTED N 15 15 PREGNANT N 15 14 DELIVERED A LITTER N 15 14 MATERNAL FEED CONSUMPTION (G/KG/DAY) DAYS 1 - 5 MEANS.D . 97.0 13.4 110.9 + 8.4 [ 13] a DAYS = DAYS OF LACTATION ( ] = NUMBER OF VALUES AVERAGED a. Excludes values that were associated with spillage. b . Excludes values for dams that were sacrificed due to no surviving pups. III 50 15 15 15 103.3 13.2 [ 14] a IV 250 15 13 13 99.2 22.8 [ 11] b PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) 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 PRECOHABITATION ESTROUS CYCLING ESTROUS STAGES/ 14 DAYS MEAN+S.D. RATS WITH 6 OR MORE CONSECUTIVE DAYS OF DIESTRUS N RATS WITH 6 OR MORE CONSECUTIVE DAYS OF ESTRUS N I 0 (VEHICLE) 15 3.1 + 1.1 1 0 II 10 15 3 . 4 + 0.8 0 0 III 50 15 2 + 1.0 1 0 IV 250 15 3 . 4 + 0.6 0 0 L Z ~3 39Y(R 0"8I17 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) 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 0 (VEHICLE) II 10 MATING OBSERVATIONS RATS IN COHABITATION N 15 15 DAYS IN COHABITATION a MEAN+S.D . 3 . 0 + 2.0 2.7 + 1.0 RATS THAT MATED N (%) 15(100.0) 15(100.0) FERTILITY INDEX b N/N 15/ 15 (%) (100.0) 14/ 15 ( 93.3) RATS WITH CONFIRMED MATING DATES N 15 15 MATED BY FIRST MALE c DAYS 1-7 N (%) 14 ( 93.3) 15(100.0) MATED BY SECOND MALE C DAYS 7-14 N (%) M 6.7) 0( 0.0) RATS PREGNANT/RATS IN COHABITATION N/N (%) 15/ 15 (100.0) 14/ 15 ( 93.3) 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. III 50 15 4 . 3 + 3..6 15(100.0) 15/ 15 (100.0) 15 13 ( 86.7) 2 ( 13.3) 15/ 15 (100.0) IV 250 15 3.7 + 4.2 14( 93.3) 13/ 14 ( 92.8) 14 13 ( 92.8) K 7.1) 13/ 15 ( 86.7) 418-027:PAGE C-28 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C21 (PAGE 1): FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - FEMALE RATS DOSAGE GROUP I II III IV DOSAGE (MG/KG/DAY) 0 (VEHICLE) 10 50 250 RATS N5 4 5 5 HOME CAGE BEHAVIOR 1 Sleeping 2 Awake, Immobile 3 Normal movement 4 Unusual posture 5 Unusual behavior N N N N N 3 2 0 0 0 2 2 0 0 0 0 5 0 0 0 2 3 0 0 0 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 5 0 0 0 0 0 0 4 0 0 0 0 0 0 5 0 0 0 0 0 0 5 0 0 0 0 0 0 REACTION TO REMOVAL (1) Sits quietly (2) Vocalization (3) Runs or freezes (4) Tail or throat rattles N N N N MEAN SCORE 5 0 0 0 1.0 4 0 0 0 1.0 5 0 0 0 1.0 5 0 0 0 1.0 418-027:PAGE C-29 REACTION TO HANDLING (1) No resistance N5 4 5 5 (2) Vocalization N0 0 0 0 (3) Tense N0 0 0 0 (4) Squirming N0 0 0 0 MEAN SCORE 1.0 1.0 1.0 1.0 n = Category number for descriptive test item. (n = Score assigned to gradee 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 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C21 (PAGE 2): FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - FEMALE RATS DOSAGE GROUP I II III IV DOSAGE (MG/KG/DAY) 0 (VEHICLE) 10 50 250 RATS N5 4 5 5 REARS IN OPEN FIELD DEFECATION IN OPEN FIELD 1: None 2: Feces normal 3: Soft or liquid feces MEANS.D. N N N 7.8 + 1.8 5 0 0 10.3 1.7 3 1 0 10.0 2.8 5 0 0 9.0 2.2 5 0 0 URINATION IN OPEN FIELD (1) None (2) Normal urination (3) Excess urination N N N MEAN SCORE 5 0 0 1.0 3 1 0 1.3 5 0 0 1.0 5 0 0 1.0 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 5 0 0 3.0 0 0 4 0 0 3.0 0 0 5 0 0 3.0 0 0 5 0 0 3.0 418-027:PAGE C-30 ALTERATIONS (OPEN FIELD) 1: None N4 4 5 5 2: Stereotyped behavior N 0 0 0 0 3: Bizarre behavior N 0 0 0 0 4: Limb twitches/tremor N 0 0 0 0 5: Whole body tremor/spasm 6: Unusual posture N N 0 0 0 0 0 0 0 0 7: Tonic-clonic seizure N 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 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C21 (PAGE 3): FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - FEMALE RATS DOSAGE GROUP I II III IV DOSAGE (MG/KG/DAY) 0 (VEHICLE) 10 50 250 RATS N5 4 5 5 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 5 0 0 0 0 0 4 0 0 0 0 0 5 0 0 0 0 0 5 0 0 0 0 0 GAIT ABNORMALITY, SEVERITY (1) Normal gait (2) Slight (3) Moderate (4) Extreme N N N N MEAN SCORE 5 0 0 0 1.0 4 0 0 0 1.0 5 0 0 0 1.0 5 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 5 0 0 0 1.0 4 0 0 0 1.0 5 0 0 0 1.0 5 0 0 0 1.0 3 3OV<R0-8It7 PROMINENCE OF THE EYE 1 : Normal N5 4 5 5 2 : Exophthalmos N0 0 0 0 3 : Enophthalmos N0 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 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C21 (PAGE 4) : FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - FEMALE RATS DOSAGE GROUP I ii III IV DOSAGE (MG/KG/DAY) 0 (VEHICLE) 10 50 250 RATS N5 4 5 5 LACRIMATION (1) No excess N (2) Excess at eyelid margin N (3) Margin persistently damp N (4) Extends beyond margin N MEAN SCORE 5 0 0 0 1.0 4 0 0 0 1.0 5 0 0 0 1.0 5 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 5 0 0 0 1.0 4 0 0 0 1.0 4 1 0 0 1.2 5 0 0 0 1.0 PILOERECTION N0 0 0 0 ABNORMAL RESPIRATION N 0 0 0 0 APPEARANCE (1) Clean and groomed N (2) Unkempt N (3) Urine and/or fecal stain N MEAN SCORE 5 0 0 1.0 4 0 0 1.0 5 0 0 1.0 5 0 0 1.0 418-027:PAGE C-32 VISUAL REACTION (1) None N0 0 0 0 (2) Orienting N5 4 5 5 (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 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 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C21 (PAGE 5): FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - FEMALE RATS DOSAGE GROUP I II III IV DOSAGE (MG/KG/DAY) 0 (VEHICLE) 10 50 250 RATS N5 4 5 5 TACTILE REACTION (1) None N (2) Orienting N (3) Startle N (4) More energetic reaction N (5) Attacks N MEAN SCORE 0 5 0 0 0 2.0 0 4 0 0 0 2.0 0 5 0 0 0 2.0 0 5 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 5 0 0 3.0 0 0 4 0 0 3.0 0 0 5 0 0 3.0 0 0 5 0 0 3.0 TAIL -PINCH REACTION (1) None (2) Orienting (3) Startle (4) More energetic reaction (5) Attacks N N N N N 0 5 0 0 0 0 4 0 0 0 0 5 0 0 0 0 5 0 0 0 aov<mo-8ii7 MEAN SCORE 2.0 2.0 2.0 2.0 VISUAL PLACING RESPONSE (1) Early extension N (2) Extension after contact N (3) No extension N MEAN SCORE 5 0 0 1.0 4 0 0 1.0 5 0 0 1.0 5 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 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C21 (PAGE 6): FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - FEMALE RATS DOSAGE GROUP I II III IV DOSAGE (MG/KG/DAY) 0 (VEHICLE) 10 50 250 RATS N5 4 5 5 AIR RIGHTING RESPONSE (1) All feet land on ground N (2) Lands on side N (3) Lands on back N MEAN SCORE 5 0 0 1.0 4 0 0 1.0 5 0 0 1.0 5 0 0 1.0 PUPIL RESPONSE TO LIGHT N 5 4 5 5 FORELIMB GRIP TEST Maximum (G) Average (G) MEAN+S.D. 316.0 53.4 MEAN+S.D . 296.2 43.2 303.8 + 105.5 276.8 101.7 260.0 240.6 40 .8 23 .2 381.0 358.0 114.9 108.7 HINDLIMB GRIP TEST Maximum (G } Average (G) MEANS.D. MEAN+S.D. 298.0 90.7 274.0 85.3 321.3 65.4 306.0 58.2 258.0 221.2 44 .2 38.6 359.0 328.8 106.5 119.0 LANDING FOOT SPLAY Average (CM) MEAN+S.D . 6.7 0.3 6.3 1.6 6.7 0.7 6.8 0.9 BODY WEIGHT (G) MEAN+S.D. 332.8 24.7 322.5 + 26.9 321.2 23 .8 313.8 25.9 n: = Category number for descriptive test item. (n) = Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score and then dividing the sum of the products by the total number of rats 418-027'.PAGE C-34 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REFRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C22 (PAGE 1): MOTOR ACTIVITY - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I 0 (VEHICLE) II 10 DAY 86 NUMBER OF RATS N 5 4 NUMBER OF MOVEMENTS BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 BLOCK 7 BLOCK 8 BLOCK 9 BLOCK 10 BLOCK 11 BLOCK 12 BLOCK 13 BLOCK 14 BLOCK 15 BLOCK 16 BLOCK 17 BLOCK 18 TOTAL MEAN 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. 75.0 8.5 80.8 12.8 69.8 17.3 58.0 29.8 65.4 30.3 65.0 33.3 63.6 28.6 38.4 + 30.4 46.8 32.4 56.0 30.4 60.2 39.1 47.6 36.6 50.2 25.2 60.4 17.9 55.2 10.1 53.4 14.3 69.8 28.0 54.4 13.4 1070.0 277.2 73.0 4.7 78.2 6.7 77.8 9.1 62.5 33.3 51.8 27.7 56.0 39.0 61.5 44.4 52.8 35.0 65.5 9.1 69.5 12.9 53.0 11.0 41.0 32.3 34.2 23.3 29.5 28.5 49.5 32.3 54.5 35.9 25.2 32.6 31.5 30.6 967.0 219.2 TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. III IV 50 250 55 66.8 12.8 72.0 16.8 54.8 38.4 46.4 41.6 47.4 37.8 51.6 29.8 72.4 8.2 54.2 10.1 45.4 39.6 52.4 13.0 52.6 23.6 33.8 25.0 35.0 27.1 43.2 25.8 54.4 30.2 46.6 29.1 55.4 29.1 39.2 29.7 923.6 256.7 77.0 13.0 77.6 23.7 75.2 13.7 74.6 16.5 69.2 20.8 64.0 16.8 63.6 23.8 63.4 31.0 39.8 30.4 47.0 32.1 61.6 23.4 73.2 17.7 50.0 27.4 34.8 27.6 42.4 37.8 39.0 27.3 38.4 32.9 50.2 27.7 1041.0 192.9 418-027 :PAGE C-35 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICTY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C22 (PAGE 2): MOTOR ACTIVITY - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I 0 (VEHICLE) II 10 DAY 86 NUMBER OF RATS N 5 4 TIME (SECONDS) SPENT IN MOVEMENT BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 BLOCK 7 BLOCK 8 BLOCK 9 BLOCK 10 BLOCK 11 BLOCK 12 BLOCK 13 BLOCK 14 BLOCK 15 BLOCK 16 BLOCK 17 BLOCK 18 TOTAL MEAN 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. 190.2 37.2 17 8.8 47.1 130.4 61.0 91.8 61.6 99.4 51.8 86.4 49.0 87.8 42.3 67.6 55.4 74.6 57.8 88.0 55.3 75.4 54.6 71.8 56.4 83.0 54.6 85.8 21.9 92.4 17.7 78.2 32.9 89.0 46.3 70.2 27.2 1740.8 585.8 183.2 29.5 150.8 22.8 137.2 43.1 103.8 71.5 81.5 62.8 76.0 50.8 85.0 57.7 84.2 64.3 119.0 23.8 107.8 20.2 104.0 73.8 74.2 80.8 45.5 40.1 48.2 65.4 69.0 53.1 77.0 54.6 44.2 74.1 55.5 69.8 1646.2 621.4 TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. III 50 5 220.4 29.9 141.6 54.2 84.2 72.6 62.8 62.9 77.2 80.6 77.0 48.4 110.8 17.4 87.6 49.7 72.0 71.9 64.2 36.6 82.6 46.8 45.2 39.6 56.8 48.8 69.0 39.3 87.6 48.4 68.6 52.8 86.6 47.4 56.2 50.4 1550.4 528.7 IV 250 5 178.6 23.4 154.2 29.9 124.6 33.6 110.0 38.5 107.4 40.2 89.2 30.8 96.2 35.6 81.0 43.6 62.4 56.7 61.0 43.3 89.8 46.8 114.8 15.0 68.8 44.3 42.6 38.6 65.0 62.0 49.8 39.2 52.4 47.0 66.4 + 40.0 1614.2 357.2 418-027:PAGE C-36 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C23 (PAGE 1): NATURAL DELIVERY OBSERVATIONS - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) I II III IV 0 (VEHICLE) 10 50 250 RATS ASSIGNED TO NATURAL DELIVERY N 15 15 15 15 PREGNANT N (%) 15(100.0) 14 ( 93.3) 15(100.0) 13( 86.7) DELIVERED A LITTER N (%) 15(100.0) 14(100.0) 15(100.0) 13(100.0) DURATION OF GESTATION a MEAN+S.D . 22.7 0.4 22.5 0.5 22.8 0.4 22.9 + 0.3 IMPLANTATION SITES N PER DELIVERED LITTER MEANS.D . 251 16.7 2.4 226 16.1 2.5 247 16.5 1.1 204 15.7 1.5 DAMS WITH STILLBORN PUPS N (%) M 6.7) 0( 0.0) 2( 13.3) 4 ( 30.8) DAMS WITH NO LIVEBORN PUPS N 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) GESTATION INDEX b % N/N 100.0 15/ 15 100.0 14/ 14 100.0 15/ 15 100.0 13/ 13 DAMS WITH ALL PUPS DYING DAYS 1-5 POSTPARTUM N (%) 0( 0.0) 0( 0.0) 0( 0.0) 3 ( 23.1)** 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. ** Significantly different from the vehicle control group value (p<0.01). PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C24 (PAGE 1): LITTER OBSERVATIONS (NATURALLY DELIVERED PUPS) - SUMMARY - FI GENERATION LITTERS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) I 0 (VEHICLE) II 10 III 50 DELIVERED LITTERS WITH ONE OR MORE LIVEBORN PUPS N 15 14 15 PUPS DELIVERED (TOTAL) N MEANS.D . 236 15.7 2.3 215 15.4 2.6 231 15.4 1.2 LIVEBORN MEAN+S.D . N (%) 15.7 2.2 235( 99.6) 15.4 2.6 215(100.0) 15.1 0.9 227 ( 98.3) STILLBORN MEANS.D . N(%) 0.1 0.2 M 0.4) 0.0 0.0 0( 0.0) 0.3 0.7 4( 1.7) UNKNOWN VITAL STATUS N 0 0 0 PUPS FOUND DEAD OR PRESUMED CANNIBALIZED DAY 1 DAYS 2 - 5 N/N (%) N/N {%) 2/235 ( 0.8) 0/233 ( 0.0) 0/215 ( 0.0) 2/215 ( 0.9) 0/227 ( 0.0) 2/227 ( 0.9) VIABILITY INDEX a % N/N 99.1 233/235 99.1 213/215 99.1 225/227 D A Y (S) = D A Y (S) POSTPARTUM a. Number of live pups on day 5 postpartum/number of liveborn pups on day 1 postpartum. ** Significantly different from the vehicle control group value (p<0.01). IV 250 13 183 14.1 2.8 13.3 3.3 173 ( 94.5)** 0.5 0.8 6( 3.3)** 4 4/173 ( 2.3) 28/169 ( 16.6) 81.5** 141/173 418-027:PAGE C-38 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C24 (PAGE 2): 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 SURVIVING PUPS/LITTER a DAY lb MEANS.D . DAY 5 MEANS.D . PERCENT MALE PUPS PER NUMBER OF PUPS SEXED DAY lb MEANS.D . DAY 5 MEANS.D . I 0 (VEHICLE) 15 15.7 2.2 15.5 2.1 53.0 9.2 53.1 9.7 II 10 14 15.4 2.6 15.2 2.4 5 2 . 1 12.2 52.9 12.2 DAY = DAY POSTPARTUM [ ] = NUMBER OF VALUES AVERAGED a. Average number of live pups per litter, including litters with no surviving pups. b. Includes pups born alive, found dead day 1 postpartum. c. Excludes values for dams that were sacrificed due to no surviving pups. * Significantly different from the vehicle control group value (p<0.05). III 50 15 15.1 0.9 15.0 1.0 52.2 17.0 52.8 17.4 IV 250 13 13.3 3.3 10.8 6.3* 44.2 16.2 47.0 17.4 [ 10] C 418-027:PAGE C-39 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) 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 MEAN+S.D . DAY 5 MEANS.D . I 0 (VEHICLE) 15 15.5 2.1 15.5 + 2.1 II 10 14 15.4 + 2.6 15.2 2.4 PUP WEIGHT/LITTER (GRAMS) DAY 1 MEANS.D . DAY 5 MEANS.D . 6.4 0.7 9.6 + 1.0 6.3 0.4 10.0 0.8 DAY = DAY POSTPARTUM [ ] = NUMBER OF VALUES AVERAGED a. Excludes values for dams that were sacrificed due to no surviving pups. III 50 15 15.1 0.9 15.0 1.0 6.5 0.3 10.0 1.0 IV 250 13 14.1 1.8 ( 12] a 14.1 1.7 [ 10] a 5.9 0.8 [ 12] a 9.3 1.3 [ 10] a PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C25 (PAGE 1): CLINICAL OBSERVATIONS FROM BIRTH TO DAY 5 POSTPARTUM - SUMMARY - FI GENERATION PUPS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) LITTERS EXAMINED (N) I 0 (VEHICLE) 15 II 10 14 III 50 15 TRANSIENT CLINICAL OBSERVATIONS: a TOTAL FREQUENCY (DAYS x PUPS)/LITTERS WITH OBSERVATIONS COLD TO TOUCH N/N 0/0 0/0 0/0 NOT NESTING N/N 0/0 0/0 0/0 NOT NURSING N/N 0/0 0/0 0/0 PALE N/N 0/0 2/1 0/0 BRUISE b N/N 2/1 9/1 2/1 STATISTICAL ANALYSES WERE RESTRICTED TO THE NUMBER OF LITTERS WITH OBSERVATIONS. a. Tabulation restricted to adverse observations; all other pups appeared normal. b. Head, back, mouth, lower midline, chest, and/or neck. IV 250 13 2/1 2/1 2/1 0/0 9/3 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C26 (PAGE 1) : NECROPSY OBSERVATIONS - SUMMARY - FI GENERATION PUPS MATERNAL DOSAGE GROUP I II III IV MATERNAL DOSAGE (MG/KG/DAY) 0 (VEHICLE) 10 50 250 LITTERS EXAMINED (N) 15 14 15 13 TOTAL PUPS STILLBORN OR FOUND DEAD a,b N2 04 5 STILLBORN N1 0 4 3 FOUND DEAD N1 0 0 2 NO MILK IN STOMACH C N(%) 1(100.0) 0( 0.0) 0( 0.0) 1( 50.0) PUPS SACRIFICED AND NECROPSIED ON DAY 5 POSTPARTUM b LITTERS EVALUATED PUPS EVALUATED N 15 14 15 10 N 233 213 225 141 APPEARED NORMAL LITTER INCIDENCE PUP INCIDENCE N (%) 15(100.0) N (%) 233 (100.0) 14(100.0) 212( 99.5) 15(100.0) 225(100.0) 10 (100.0) 141(100.0) KIDNEYS: BILATERAL, PELVIS, SLIGHT DILATION LITTER INCIDENCE N (%) PUP INCIDENCE N (%) 0( 0.0) 0( 0.0) M 7.1) M 0.5) 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. 418-027:PAGE C-42 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C27 (PAGE 1): CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP I VEHICLE 0 (VEHICLE) MG/KG/DAY RAT # DESCRIPTION 17662 17672 17673 17674 17680 17681 17690 17694 17695 17703 17713 17715 17716 17717 17719 DS ( 14 ) DS ( 3 ) DS ( 14 ) DS ( 11- 16) DG ( 0- 20) DL ( 1- 6) DS ( 12- 15) DG ( 0- 21) DL ( 1- 6) NO ADVERSE FINDINGS EXCESS SALIVATION NO ADVERSE FINDINGS CHROMODACRYORRHEA RED, SLIGHT PERIORAL SUBSTANCE NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: LIMBS LOCALIZED ALOPECIA: LIMBS LOCALIZED ALOPECIA: LIMBS a NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: LIMBS LOCALIZED ALOPECIA: LIMBS LOCALIZED ALOPECIA: LIMBS a NO ADVERSE FINDINGS DS = DAY OF STUDY DG = DAY OF PRESUMED GESTATION a. Observation confirmed at necropsy. DL = DAY OF LACTATION 418-027'.PAGE C-43 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C27 (PAGE 2): CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP II LOW DOSAGE 10 MG/KG/DAY RAT # DESCRIPTION 17663 17665 17666 17668 17671 17675 17679 17684 17688 17698 17702 17704 17707 17708 17710 DG ( 0 ) DG ( 9- 21) DL ( 1- 6) DG ( 14 ) DS( 13 ) DG ( 12- 19) DG ( 3- 21) DL ( 1- 5) DL ( 5- 6) SOFT OR LIQUID FECES NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: LIMBS LOCALIZED ALOPECIA: LIMBS a NO ADVERSE FINDINGS INCISORS : MISSING/BROKEN NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: LIMBS LOCALIZED ALOPECIA: LIMBS NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: LIMBS LOCALIZED ALOPECIA: LIMBS LOCALIZED ALOPECIA: LIMBS a NO ADVERSE FINDINGS DS = DAY OF STUDY DG = DAY OF PRESUMED GESTATION a. Observation confirmed at necropsy. DL = DAY OF LACTATION 418-027:PAGE C-44 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C27 (PAGE 3): CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP III MIDDLE DOSAGE 50 MG/KG/DAY RAT # DESCRIPTION 17661 17667 17669 17670 17676 17687 17693 17697 17700 17701 17705 17706 17709 17718 17720 DG ( 20- 21) DG ( 18- 21) DL ( 1- 6) DS ( 16 ) DS ( 3- 13) DS ( 15- 16) DS ( 17- 27) DG ( 0- 21) DL ( 1- 6) DS ( 16 ) CHROMODACRYORRHEA NO ADVERSE FINDINGS LOCALIZED ALOPECIA: LIMBS LOCALIZED ALOPECIA: LIMBS a URINE-STAINED ABDOMINAL FUR NO ADVERSE FINDINGS RIGHT EYE: CORNEAL OPACITY RIGHT EYE: CORNEAL OPACITY NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: LIMBS LOCALIZED ALOPECIA: LIMBS LOCALIZED ALOPECIA: LIMBS a NO ADVERSE FINDINGS URINE-STAINED ABDOMINAL FUR DS = DAY OF STUDY DG = DAY OF PRESUMED GESTATION a. Observation confirmed at necropsy. DL = DAY OF LACTATION 418-027:PAGE C-45 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C27 (PAGE 4): CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP IV HIGH DOSAGE RAT # DESCRIPTION 17664 17677 17678 17682 17683 17685 17686 DS ( 21- 28) DS ( 50 ) DS ( 16- 18) DG ( 0- 2) DS ( 17 ) DG ( 1 ) DG ( 13 ) DG ( 20 ) DS ( 23- 25) DG ( 3 ) DG ( 15 ) DG ( 5- 21) DG ( 18- 21) DL ( 1- 6) DL ( 1- 6) DS ( 12 ) DS ( 14- 15) DG ( 0- 7) DG ( 13- 16) DG ( 19- 20) DL ( 1 ) DL ( 3 ) DL ( 5 ) DS ( 15 ) DG ( 0 ) DG ( 3 ) DG( 6 ) DG ( 7- 14) DG ( 8- 9) DG ( 15 ) DG ( 16 ) DG ( 20- 22) DG ( 21 ) INCISORS : MISSING/BROKEN RED, SLIGHT PERIORAL SUBSTANCE URINE-STAINED ABDOMINAL FUR URINE-STAINED ABDOMINAL FUR RED, SLIGHT PERIORAL SUBSTANCE EXCESS SALIVATION RED, SLIGHT PERIORAL SUBSTANCE EXCESS SALIVATION EXCESS SALIVATION RED, SLIGHT PERIORAL SUBSTANCE RED, SLIGHT PERIORAL SUBSTANCE LOCALIZED ALOPECIA: LIMBS LOCALIZED ALOPECIA: UNDERSIDE LOCALIZED ALOPECIA: LIMBS a LOCALIZED ALOPECIA: UNDERSIDE a EXCESS SALIVATION EXCESS SALIVATION EXCESS SALIVATION EXCESS SALIVATION EXCESS SALIVATION EXCESS SALIVATION EXCESS SALIVATION EXCESS SALIVATION RED, SLIGHT PERIORAL SUBSTANCE RED, SLIGHT PERIORAL SUBSTANCE URINE-STAINED ABDOMINAL FUR RED, SLIGHT PERIORAL SUBSTANCE URINE-STAINED ABDOMINAL FUR RED, SLIGHT PERIORAL SUBSTANCE RED, SLIGHT PERIORAL SUBSTANCE EXCESS SALIVATION LOCALIZED ALOPECIA: HEAD EXCESS SALIVATION DAY OF STUDY DG = DAY OF PRESUMED GESTATION a. Observation confirmed at necropsy. DL = DAY OF 250 MG/KG/DAY 418-027:PAGE C-4 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C2 7 (PAGE 5) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP IV HIGH DOSAGE 250 MG/KG/DAY RAT # DESCRIPTION 17689 17691 17692 17696 17699 17711 17712 17714 DS ( DG ( DG ( DG ( DS ( DG ( DG ( DG ( DG ( DG ( DL ( 3) 11 ) 3) 7) 13 ) 1) 5) 9) 13 ) 16 ) 2) DS ( DG ( DG ( DG ( DG ( DG ( DG ( DG ( DL ( DL ( DS ( DS ( DG ( DG ( DG ( DL ( DL ( DL ( DS ( 14 ) 0) 4) 6) 9) 14 ) 15 ) 17 ) 1) 2) 3- 15) 15 ) 0- 21) 1- 21) 14 ) 1) 1) 1- 6) 17 ) NO ADVERSE FINDINGS CHROMODACRYORRHEA EXCESS SALIVATION RED, SLIGHT PERIORAL SUBSTANCE RED, SLIGHT PERIORAL SUBSTANCE EXCESS SALIVATION RED, SLIGHT PERIORAL SUBSTANCE EXCESS SALIVATION EXCESS SALIVATION EXCESS SALIVATION EXCESS SALIVATION SACRIFICED DUE TO NO SURVIVING PUPS NO ADVERSE FINDINGS RED, SLIGHT PERIORAL SUBSTANCE RED, SLIGHT PERIORAL SUBSTANCE RED, SLIGHT PERIORAL SUBSTANCE RED, SLIGHT PERIORAL SUBSTANCE RED, SLIGHT PERIORAL SUBSTANCE RED PERIVAGINAL SUBSTANCE RED, MODERATE PERIORAL SUBSTANCE EXCESS SALIVATION DEHYDRATION a SACRIFICED DUE TO NO SURVIVING PUPS TAIL BENT RED, SLIGHT PERIORAL SUBSTANCE TAIL BENT LOCALIZED ALOPECIA: LIMBS EXCESS SALIVATION EXCESS SALIVATION LOCALIZED ALOPECIA: LIMBS TAIL BENT a RED, SLIGHT PERIORAL SUBSTANCE DS = DAY OF STUDY DG = DAY OF PRESUMED GESTATION a. Observation confirmed at necropsy. DL = DAY OF LACTATION 418-027:PAGE C-47 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C28 (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 (VEHICLE) 17662 17672 17673 17674 17680 17681 17690 17694 17695 17703 17713 17715 17716 17717 17719 DL 6 DL 6 DL 6 DL 6 DL 6 DL 6 DL 6 DL 6 DL 6 DL 6 DL 6 DL 6 DL 6 DL 6 DL 6 P P P P P P P P P P P P P P P 44 ALL TISSUES APPEARED NORMAL. 45 ALL TISSUES APPEARED NORMAL. 42 ALL TISSUES APPEARED NORMAL. 42 ALL TISSUES APPEARED NORMAL. 44 ALL TISSUES APPEARED NORMAL. 44 ALL TISSUES APPEARED NORMAL. 44 ALL TISSUES APPEARED NORMAL. 42 ALL TISSUES APPEARED NORMAL. 41 ALL TISSUES APPEARED NORMAL. 42 ALL TISSUES APPEARED NORMAL. 44 ALL TISSUES APPEARED NORMAL. 45 ALL TISSUES APPEARED NORMAL. 45 ALL TISSUES APPEARED NORMAL. 42 ALL TISSUES APPEARED NORMAL. 49 ALL TISSUES APPEARED NORMAL. II 10 17663 DG 25 NP 42 ALL TISSUES APPEARED NORMAL. 17665 DL 6 P 43 ALL TISSUES APPEARED NORMAL. 17666 DL 6 P 42 ALL TISSUES APPEARED NORMAL. 17668 DL 6 P 44 ALL TISSUES APPEARED NORMAL. 17671 DL 6 P 44 ALL TISSUES APPEARED NORMAL. 17675 DL 6 P 43 ALL TISSUES APPEARED NORMAL. 17679 DL 6 P 44 ALL TISSUES APPEARED NORMAL. 17684 DL 6 P 45 ALL TISSUES APPEARED NORMAL. 17688 DL 6 P 43 ALL TISSUES APPEARED NORMAL. 17698 DL 6 P 43 ALL TISSUES APPEARED NORMAL. 17702 DL 6 P 42 ALL TISSUES APPEARED NORMAL. 17704 DL 6 P 43 ALL TISSUES APPEARED NORMAL. 17707 DL 6 P 45 ALL TISSUES APPEARED NORMAL. 17708 DL 6 P 42 ALL TISSUES APPEARED NORMAL. 17710 DL 6 P 45 ALL TISSUES APPEARED NORMAL. DS = DAY OF STUDY 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. SK) HDVd*ZZ0-8tt PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C28 (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 50 17661 DL 6 P 43 ALL TISSUES APPEARED NORMAL. 17667 DL 6 P 43 ALL TISSUES APPEARED NORMAL. 17669 DL 6 P 44 ALL TISSUES APPEARED NORMAL. 17670 DL 6 P 45 ALL TISSUES APPEARED NORMAL. 17676 DL 6 P 43 ALL TISSUES APPEARED NORMAL. 17687 DL 6 P 45 ALL TISSUES APPEARED NORMAL. 17693 DL 6 P 42 ALL TISSUES APPEARED NORMAL. 17697 DL 6 P 44 ALL TISSUES APPEARED NORMAL. 17700 DL 6 P 43 ALL TISSUES APPEARED NORMAL. 17701 DL 6 P 44 ALL TISSUES APPEARED NORMAL. 17705 DL 6 P 44 ALL TISSUES APPEARED NORMAL. 17706 DL 6 P 45 KIDNEYS: RIGHT, ABSENT. ALL OTHER TISSUES APPEARED NORMAL. 17709 17718 17720 DL 6 DL 6 DL 6 P P P 53 ALL TISSUES APPEARED NORMAL. 53 ALL TISSUES APPEARED NORMAL. 45 ALL TISSUES APPEARED NORMAL. IV 250 17664 DS 54 NP 53 ALL TISSUES APPEARED NORMAL. 17677 DL 6 P 46 ALL TISSUES APPEARED NORMAL. 17678 DL 6 P 45 ALL TISSUES APPEARED NORMAL. 17682 DL 6 P 53 ALL TISSUES APPEARED NORMAL. 17683 DL 6 P 44 ALL TISSUES APPEARED NORMAL. 17685 DL 6 P 42 ALL TISSUES APPEARED NORMAL. 17686 DG 25 NP 40 ALL TISSUES APPEARED NORMAL. 17689 DL 6 P 41 ALL TISSUES APPEARED NORMAL. 17691 DL 6 P 45 ALL TISSUES APPEARED NORMAL. 17692 DL 6 P 42 ALL TISSUES APPEARED NORMAL. DS = DAY OF STUDY 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. 418-027:PAGE C-49 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C28 (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 250 cont. 17696 DL 2 P 39 SACRIFICED DUE TO NO SURVIVING PUPS ON DAY 2 OF LACTATION. THYMUS : SMALL. ALL OTHER TISSUES APPEARED NORMAL. 17699 DL 6 P 44 ALL TISSUES APPEARED NORMAL. 17711 DL 2 P 39 SACRIFICED DUE TO NO SURVIVING PUPS ON DAY 2 OF LACTATION. ALL TISSUES APPEARED NORMAL. 17712 17714 DL 6 DL 6 P P 42 ALL TISSUES APPEARED NORMAL. 44 ALL TISSUES APPEARED NORMAL. DS = DAY OF STUDY 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. 418-027:PAGE C-50 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C2 9 (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 VEHICLE 0 (VEHICLE) MG/KG/DAY RAT TERMINAL BODY NUMBER WEIGHT BRAIN ABS. WT. REL. % TBW LIVER ABS. WT. REL. % TBW KIDNEY LEFT ABS. REL. W T . % TBW KIDNEY RIGHT ABS. REL. W T . % TBW ADRENAL LEFT ABS. REL. WT. % TBW a ADRENAL RIGHT ABS. REL. WT. % TBW a 17662 P 17672 P 17673 P 17674 P 17680 P 17681 P 17690 P 17694 P 17695 P 17703 P 17713 P 17715 P 17716 P 17717 P 17719 P 303 . 319. 271. 282 . 303 , 303 . 345 . 291. 271. 339. 292 . 328. 298 , 274 . 268, 2.04 2.27 2.28 2.16 2.27 2.26 2.22 2.15 2.15 2.16 0.67 0.66 0.78 0.80 0.67 0.77 0.68 0.72 0.78 0.80 9.58 12.34 10.17 10.10 11.66 11.10 12.40 11.10 10.63 13.19 9.91 11.72 13.55 9.57 11.30 3.16 3.87 3.75 3.58 3.85 3.66 3.59 3.81 3.92 3.89 3.39 3.57 4.55 3.49 4.22 1.13 1.28 1.21 1.08 1.51 1.03 1.24 1.19 1.15 1.14 0.37 0.37 0.42 0.40 0.44 0.35 0.38 0.40 0.42 0.42 1.19 1.31 1.33 1.00 1.43 1.03 1.17 1.21 1.15 1.17 0.39 0.38 0.46 0.37 0.42 0.35 0.36 0.41 0.42 0.44 0.034 0.047 0.041 0.039 0.042 0.037 0.041 0.044 0.049 0.044 11.22 13.62 14.09 14.39 12.39 12.67 12.50 14.76 17.88 16.42 0.034 0.047 0.042 0.033 0.044 0.034 0.041 0.042 0.054 0.041 11.22 13.62 14.43 12.18 12.98 11.64 12.50 14.09 19.71 15.30 ALL WEIGHTS WERE RECORDED IN iGRAMS (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. -O R D Y & L Z Q -m Ul PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C2 9 (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 I VEHICLE 0 (VEHICLE) MG/KG/DAY RAT TERMINAL BODY NUMBER WEIGHT SPLEEN ABS. WT. REL. % TBW THYMUS ABS. REL. W T . % TBW OVARY LEFT ABS. REL. WT. % TBW a OVARY RIGHT ABS. REL. WT. % TBW a UTERUS WITH CERVIX ABS. REL. W T . % TBW HEART ABS. WT. REL. % TBW 17662 P 17672 P 17673 P 17674 P 17680 P 17681 P 17690 P 17694 P 17695 P 17703 P 17713 P 17715 P 17716 P 17717 P 17719 P 303 . 319. 271. 282 . 303 . 303 . 345. 291. 271. 339. 292 . 328 . 298 . 274 . 268. 0.76 0.70 0.66 0.70 0.79 0.65 0.76 0.70 0.73 0.59 0.25 0.20 0.23 0.26 0.23 0.22 0.23 0.23 0.27 0.22 0.33 0.38 0.23 0.24 0.37 0.31 0.25 0.20 0.27 0.15 0.11 0.11 0.08 0.09 0.11 0.11 0.08 0.07 0.10 0.06 0.089 0.070 0.098 0.067 0.068 0.080 0.094 0.081 0.103 0 .Ill 0.044 0.066 0.080 0.068 0.083 29.37 21.94 36.16 23.76 22.44 26.40 27.25 27.84 38.01 32.74 15.07 20.12 26.84 24.82 30.97 0.075 0.080 0.068 0.095 0.081 0.096 0.078 0.070 0.090 0.113 0.057 0.096 0.071 0.071 0.079 24.75 25.08 25.09 33.69 26.73 31.68 22.61 24.05 33.21 33.33 19.52 29.27 23.82 25.91 29.48 0.71 0.82 0.71 0.77 0.93 0.74 0.84 0.77 0.96 0.95 0.74 0.98 0.68 0.62 0.77b 0.23 0.26 0.26 0.27 0.31 0.24 0.24 0.26 0.35 0.28 0.25 0.30 0.23 0.23 0.29 1.04 1.17 1.11 0.94 1.25 1.02 1.24 1.00 1.08 0.99 0.34 0.34 0.38 0.35 0.37 0.35 0.38 0.34 0.39 0.37 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . A B S . WT. = ORGAN WEIGHT. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) a. Value was multiplied by 1000. b. Damaged during processing (weight not affected). REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. ZS"D WYfrLZO-m PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C2 9 (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 II LOW DOSAGE 10 MG/KG/DAY RAT TERMINAL BODY NUMBER WEIGHT BRAIN ABS. WT. REL. % TBW LIVER ABS. WT. REL. % TBW KIDNEY LEFT ABS. REL. W T . % TBW KIDNEY RIGHT ABS. REL. W T . % TBW ADRENAL LEFT ABS. REL. WT. % TBW a ADRENAL RIGHT ABS. REL. WT. % TBW a 17663 NP 17665 P 17666 P 17668 P 17671 P 17675 P 17679 P 17684 P 17688 P 17698 P 17702 P 17704 P 17707 P 17708 P 17710 P 267 . 308 . 289. 299 . 256 . 297 . 295. 317 . 311. 299. 307 . 327 . 296 . 328. 327. 2.18 2.13 2.15 2.21 2.24 2.05 2.26 2.18 2.29 2.20 0.73 0.72 0.68 0.71 0.75 0.67 0.69 0.74 0.70 0.67 7.49 10.81 12.16 10.54 8.16 12.27 11.54 12.17 11.60 11.43 11.83 13.36 11.40 14.27 13.78 2.80 3.51 4.21 3.52 3.19 4.13 3.91 3.84 3.73 3.82 3.85 4.08 3.85 4.35 4.21 1.31 1.35 1.30 1.02 1.38 1.14 1.41 1.15 1.49 1.39 0.44 0.46 0.41 0.33 0.46 0.37 0.43 0.39 0.45 0.42 1.34 1.30 1.37 1.20 1.41 1.23 1.41 1.10 1.35 1.40 0.45 0.44 0.43 0.38 0.47 0.40 0.43 0.37 0.41 0.43 0.044 0.037 0.042 0.054 0.047 0.041 0.049 0.047 0.039 0.063 14.81 12.54 13.25 17.36 15.72 13.36 14.98 15.88 11.89 19.27 0.039 0.036 0.042 0.049 0.036 0.040 0.049 0.045 0.042 0.056 13.13 12.20 13.25 15.76 12.04 13.03 14.98 15.20 12.80 17.12 ALL WEIGHTS WERE RECORDED IN SRAMS (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. 418-027:PAGE C-53 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C29 (PAGE 4): TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP II LOW DOSAGE 10 MG/KG/DAY RAT TERMINAL BODY NUMBER WEIGHT SPLEEN ABS. REL. W T . % TBW THYMUS ABS. REL. W T . % TBW OVARY LEFT ABS. REL. WT. % TBW a OVARY RIGHT ABS. REL. WT. % TBW a UTERUS WITH CERVIX ABS. REL. W T . % TBW HEART ABS. WT. REL. % TBW 17663 NP 17665 P 17666 P 17668 P 17671 P 17675 P 17679 P 17684 P 17688 P 17698 P 17702 P 17704 P 17707 P 17708 P 17710 P 267. 308. 289. 299. 256 . 297 . 295. 317. 311. 299. 307. 327. 296. 328. 327. 0.75 0.55 0.74 0.64 0.66 0.71 0.98 0.60 0.82 0.95 0.25 0.19 0.23 0.20 0.22 0.23 0.30 0.20 0.25 0.29 0.36 0.29 0.36 0.26 0.30 0.29 0.37 0.29 0.50 0.36 0.12 0.10 0.11 0.08 0.10 0.09 0.11 0.10 0.15 0.11 0.053 0.078 0.067 0.082 0.073 0.078 0.063 0.080 0.090 0.110 0.071 0.074 0.077 0.069 0.091 19.85 25.32 23.18 27.42 28.52 26.26 21.36 25.24 28.94 36.79 23.13 22.63 26.01 21.04 27.83 0.062 0.094 0.076 0.073 0.053 0.086 0.071 0.090 0.086 0.092 0.082 0.100 0.086 0.072 0.097 23.22 30.52 26.30 24.41 20.70 28.96 24.07 28.39 27.65 30.77 26.71 30.58 29.05 21.95 29.66 0.48 0.62 0.91 0.80 0.74 0.89 0.71 0.84 0.76 0.70 0.92 0.95 0.66 0.78 0.75 0.18 0.20 0.31 0.27 0.29 0.30 0.24 0.26 0.24 0.23 0.30 0.29 0.22 0.24 0.23 1.13 1.00 1.19 1.23 1.26 1.16 1.18 1.08 1.10 1.16 0.38 0.34 0.38 0.40 0.42 0.38 0.36 0.36 0.34 0.35 ALL WEIGHTS WERE RECORDED IN GRAMS (G). A B S . W T . = 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. 418-027:PAGE C-54 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C29 (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 III MIDDLE DOSAGE 50 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 17661 P 17667 P 17669 P 17670 P 17676 P 17687 P 17693 P 17697 P 17700 P 17701 P 17705 P 17706 P 17709 P 17718 P 17720 P 280. 311. 296. 268. 265 . 337. 274 . 268. 310. 311. 330. 315. 262 . 295. 318 . 2.13 2.15 2.17 2.13 2.26 2.11 2.22 2.13 2.27 2.29 0.63 0.78 0.81 0.69 0.73 0.64 0.70 0.81 0.77 0.72 10.84 13.45 10.92 10.80 9.21 13.22 10.76 10.23 10.96 12.74 12.94 12.79 11.06 12.17 12.75 3.87 4.32 3.69 4.03 3.48 3.92 3.93 3.82 3.54 4.10 3.92 4.06 4.22 4.12 4.01 1.25 1.05 1.11 1.35 1.12 1.19 2.15 1.12 1.46 1.28 0.37 0.38 0.41 0.44 0.36 0.36 0.68 0.43 0.49 0.40 1.33 1.16 1.10 1.46 1.19 1.19 b 1.12 1.45 1.41 0.39 0.42 0.41 0.47 0.38 0.36 b 0.43 0.49 0.44 0.045 0.033 0.030 0.043 0.047 0.053 0.043 0.031 0.038 0.047 13.35 12.04 11.19 13.87 15.11 16.06 13.65 11.83 12.88 14.78 0.042 0.033 0.026 0.043 0.042 0.047 0.039 0.029 0.029 0.050 12.46 12.04 9.70 13.87 13.50 14.24 12.38 11.07 9.83 15.72 ALL WEIGHTS WERE RECORDED IN GRAMS (G). ABS. WT. = ORGAN WEIGHT REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) a. Value was multiplied by 1000. b. Dam 17706 had an absent right kidney. See the individual necropsy observations table (Table C28) X 100 418-027:PAGE C-55 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C29 (PAGE 6): TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP III MIDDLE DOSAGE 50 MG/KG/DAY RAT TERMINAL BODY NUMBER WEIGHT SPLEEN ABS. REL. W T . % 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. W T . % TBW HEART ABS. REL. W T . % TBW 17661 P 17667 P 17669 P 17670 P 17676 P 17687 P 17693 P 17697 P 17700 P 17701 P 17705 P 17706 P 17709 P 17718 P 17720 P 280 . 311. 296. 268 . 265. 337. 274 . 268. 310 . 311. 330. 315 . 262 . 295 . 318. 0.78 0.79 0.66 0.62 0.74 0.73 0.84 0.90 0.92 0.65 0.23 0.29 0.25 0.20 0.24 0.22 0.27 0.34 0.31 0.20 0.37 0.18 0.19 0.35 0.32 0.27 0.31 0.31 0.23 0.35 0.11 0.06 0.07 0.11 0.10 0.08 0.10 0.12 0.08 0.11 0.073 0.067 0.072 0.078 0.060 0.101 0.062 0.071 0.082 0.072 0.097 0.108 0.066 0.082 0.093 26.07 21.54 24.32 29.10 22.64 29.97 22.63 26.49 26.45 23.15 29.39 34.28 25.19 27.80 29.24 0.088 0.097 0.080 0.054 0.072 0.101 0.081 0.093 0.077 0.064 0.075 0 .Ill 0.090 0.074 0.097 31.43 31.19 27.03 20.15 27.17 29.97 29.56 34.70 24.84 20.58 22.73 35.24 34.35 25.08 30.50 0.63 0.94b 0.89 0.67 0.67 0.74 0.72b 0.85 0.82 0.86 0.83 0.82 0.72 0.76 0.76 0.22 0.30 0.30 0.25 0.25 0.22 0.26 0.32 0.26 0.28 0.25 0.26 0.27 0.26 0.24 1.05 0.99 0.98 1.12 1.17 1.38 1.11 0.91 1.28 1.10 0.31 0.36 0.36 0.36 0.38 0.42 0.35 0.35 0.43 0.34 ALL WEIGHTS WERE RECORDED IN iGRAMS (G). ABS. WT. = ORGAN WEIGHT. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) a. Value was multiplied by 1000. b. Damaged during processing (weight not affected). REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100. 418-027:PAGE C-56 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C29 (PAGE 7): TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP IV HIGH DOSAGE 250 MG/KG/DAY RAT TERMINAL BODY NUMBER WEIGHT 17664 NP 17677 P 17678 P 17682 P 17683 P 17685 P 17686 NP 17689 P 17691 P 17692 P 17696 P c 17699 p 17711 P c 17712 p 17714 p -- 287. 293 . 300 . 259 . 277 . 284. 285. 286. 277. -- 283 . -- 292 . 294 . BRAIN ABS. WT. -- REL. % TBW -- 2.23 2.19 2.31b 2.10 2.27 2.02 2.17 2.17 2.18 2.10 2.19 2.22 0.76 0.84 0.83 0.74 0.80 0.71 0.78 -- 0.77 -- 0.75 0.76 LIVER ABS. WT. 11.51 13.06 13.68 14.07 12.48 13.29 12.31 14.32 11.62 13.67 14.77 14.51 12.56 14.14 14.33 REL. % TBW -- 4.55 4.67 4.69 4.82 4.80 4.33 5.02 4.06 4.94 -- 5.13 -- 4.84 4.87 KIDNEY LEFT ABS. REL. WT . % TBW __ __ 1.23 1.17 1.37 1.30 1.30 1.12 1.22 1.28 1.30 1.38 1.21 1.16 0.42 0.45 0.49 0.46 0.46 0.39 0.44 -- 0.46 -- 0.41 0.39 KIDNEY RIGHT ABS. REL. W T . % TBW __ __ 1.25 1.28 1.40 1.31 1.27 1.21 1.21 1.24 1.40 1.38 1.22 1.22 0.43 0.49 0.50 0.46 0.44 0.42 0.44 -- 0.49 -- 0.42 0.41 ADRENAL LEFT ABS. REL. WT. % TBW a ___ ___ 0.050 0.054 0.043 0.037 0.045 0.037 0.031 0.053 0.055 0.059 0.041 0.049 17.06 20.85 15.52 13.03 15.79 12.94 11.19 19.43 14.04 16.67 ADRENAL RIGHT ABS. REL. WT. % TBW a ____ ____ 0.038 0.048 0.034 0.036 0.043 0.036 0.033 0.041 0.050 0.052 0.039 0.042 12.97 18.53 12.27 12.68 15.09 12.59 11.91 17.67 13.36 14.28 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. Damaged during processing (weight not affected). c. Dam was sacrificed due to no surviving pups on day 2 of lactation; values excluded from group averages and statistical analyses. 418-027:PAGE C-57 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C29 (PAGE 8): TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP IV HIGH DOSAGE 250 MG/KG/DAY RAT TERMINAL BODY NUMBER WEIGHT 17664 NP 17677 P 17678 P 17682 P 17683 P 17685 P 17686 NP 17689 P 17691 P 17692 P 17696 P c 17699 P 17711 P c 17712 P 17714 P -- 287 . 293 . 300. 259. 277 . 284 . 285 . 286. 277. -- 283 . -- 292 . 294 . SPLEEN ABS. WT. REL. % TBW ---- 0.81 0.28 0.60 0.54 0.48 0.70 0.54 0.66 0.49 0.67 0.39 0.69 0.56 0.23 0.19 0.17 0.24 0.19 0.24 -- 0.24 -- 0.24 0.19 THYMUS ABS. WT. REL. % TBW ---- 0.30 0.10 0.23 0.20 0.43 0.19 0.29 0.15 0.06d 0.23 0.23 0.20 0.15 0.09 0.07 0.15 0.07 0.10 0.05 -- 0.08 -- 0.07 0.05 OVARY LEFT ABS. REL. WT. % TBW a 0.068 0.072 0.074 0.092 0.074 0.079 0.058 0.072 0.066 0.057 0.070 0.090 0.062 0.088 0.076 25.09 25.26 30.67 28.57 28.52 20.42 25.26 23.08 20.58 31.80 30.14 25.85 OVARY RIGHT ABS. REL. WT. % TBW a 0.081 0.083 0.100 0.086 0.074 0.072 0.053 0.066 0.074 0.076 0.083 0.102 0.086 0.095 0.057 28.92 34.13 28.67 28.57 25.99 18.66 23.16 25.87 27.44 36.04 32.53 19.39 UTERUS WITH CERVIX ABS. REL. WT. % TBW 0.51b 0.68 0.76 0.58 0.68 0.70 0.42 0.82 0.67 0.71 1.71 0.64 2.15 0.77 0.71 _______ 0.24 0.26 0.19 0.26 0.25 0.15 0.29 0.23 0.26 -- 0.23 -- 0.26 0.24 HEART ABS. WT. _______ REL. % TBW ___ 1.21 0.41 0.90 0.94 1.09 0.99 0.94 0.84 0.85 1.00 1.04 1.18 1.05 0.35 0.34 0.38 0.35 0.33 0.30 -- 0.35 -- 0.40 0.36 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. Damaged during processing (weight not affected). c. Dam was sacrificed due to no surviving pups on day 2 of lactation; values excluded from group averages and statistical analyses. d. Dam 17696 had a small thymus. See the individual necropsy observations table (Table C28). 8SO 3D V <M 0-m PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C30 (PAGE 1) : ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP I VEHICLE 0 (VEHICLE) MG/KG/DAY RAT NUMBER BRAIN WEIGHT LIVER ABS. WT. REL. % BRW KIDNEY LEFT ABS. REL. WT. % BRW KIDNEY RIGHT ABS. REL. WT. % BRW ADRENAL LEFT ABS. REL. WT. % BRW ADRENAL RIGHT ABS. REL. WT. % BRW SPLEEN ABS. WT. REL. % BRW 17681 17690 17694 17695 17703 17713 17715 17716 17717 17719 P P P P P P P P P P 2.04 2.27 2.28 2.16 2.27 2.26 2.22 2.15 2.15 2.16 11.10 12.40 11.10 10.63 13.19 9.91 11.72 13.55 9.57 11.30 544.12 546.26 486.84 492.13 581.06 438.50 527.93 630.23 445.12 523.15 1.13 1.28 1.21 1.08 1.51 1.03 1.24 1.19 1.15 1.14 55.39 56.39 53.07 50.00 66.52 45.58 55.86 55.35 53.49 52.78 1.19 1.31 1.33 1.00 1.43 1.03 1.17 1.21 1.15 1.17 58.33 57.71 58.33 46.30 63.00 45.58 52.70 56.28 53.49 54.17 0.034 0.047 0.041 0.039 0.042 0.037 0.041 0.044 0.049 0.044 1.67 2.07 1.80 1.80 1.85 1.64 1.85 2.05 2.28 2.04 0.034 0.047 0.042 0.033 0.044 0.034 0.041 0.042 0.054 0.041 1.67 2.07 1.84 1.53 1.94 1.50 1.85 1.95 2.51 1.90 0.76 0.70 0.66 0.70 0.79 0.65 0.76 0.70 0.73 0.59 37.25 30.84 28.95 32.41 34.80 28.76 34.23 32.56 33.95 27.31 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 17681 17690 17694 17695 17703 17713 17715 17716 17717 17719 P P P P P P P P P P 2.04 2.27 2.28 2.16 2.27 2.26 2.22 2.15 2.15 2.16 0.33 0.38 0.23 0.24 0.37 0.31 0.25 0.20 0.27 0.15 16.18 16.74 10.09 11.11 16.30 13.72 11.26 9.30 12.56 6.94 0.080 0.094 0.081 0.103 0.111 0.044 0.066 0.080 0.068 0.083 3.92 4.14 3.55 4.77 4.89 1.95 2.97 3.72 3.16 3.84 0.096 0.078 0.070 0.090 0.113 0.057 0.096 0.071 0.071 0.079 4.70 3.44 3.07 4.17 4.98 2.52 4.32 3.30 3.30 3.66 0.74 0.84 0.77 0.96 0.95 0.74 0.98 0.68 0.62 0.77a 36.27 37.00 33.77 44.44 41.85 32.74 44.14 31.63 28.84 35.65 1.04 1.17 1.11 0.94 1.25 1.02 1.24 1.00 1.08 0.99 50.98 51.54 48.68 43.52 55.07 45.13 55.86 46.51 50.23 45.83 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . A B S . WT. = ORGAN WEIGHT. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) a. Damaged during processing (weight not affected). REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. 6S`3 3OVd:60"8It7 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C30 (PAGE 2): ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP II LOW DOSAGE 10 MG/KG/DAY RAT NUMBER BRAIN WEIGHT LIVER ABS. WT. REL. % BRW KIDNEY LEFT ABS. REL. WT. % BRW KIDNEY RIGHT ABS. REL. WT. % BRW ADRENAL LEFT ABS. REL. WT. % BRW ADRENAL RIGHT ABS. REL. WT. % BRW SPLEEN ABS. WT. REL. % BRW 17675 17679 17684 17688 17698 17702 17704 17707 17708 17710 P P P P P P P P P P 2.18 2.13 2.15 2.21 2.24 2.05 2.26 2.18 2.29 2.20 12.27 11.54 12.17 11.60 11.43 11.83 13.36 11.40 14.27 13.78 562.84 541.78 566.05 524.89 510.27 577.07 591.15 522.94 623.14 626.36 1.31 1.35 1.30 1.02 1.38 1.14 1.41 1.15 1.49 1.39 60.09 63.38 60.46 46.15 61.61 55.61 62.39 52.75 65.06 63.18 1.34 1.30 1.37 1.20 1.41 1.23 1.41 1.10 1.35 1.40 61.47 61.03 63.72 54.30 62.95 60.00 62.39 50.46 58.95 63.64 0.044 0.037 0.042 0.054 0.047 0.041 0.049 0.047 0.039 0.063 2.02 1.74 1.95 2.44 2.10 2.00 2.17 2.16 1.70 2.86 0.039 0.036 0.042 0.049 0.036 0.040 0.049 0.045 0.042 0.056 1.79 1.69 1.95 2.22 1.61 1.95 2.17 2.06 1.83 2.54 0.75 0.55 0.74 0.64 0.66 0.71 0.98 0.60 0.82 0.95 34.40 25.82 34.42 28.96 29.46 34.63 43.36 27.52 35.81 43.18 RAT NUMBER BRAIN WEIGHT THYMUS ABS. WT. REL. % BRW OVARY LEFT ABS. REL. WT. % BRW OVARY RIGHT ABS. REL. WT. % BRW UTERUS WITH CERVIX ABS. REL. WT. % BRW HEART ABS. WT. REL. % BRW 17675 17679 17684 17688 17698 17702 17704 17707 17708 17710 P P P P P P P P P P 2.18 2.13 2.15 2.21 2.24 2.05 2.26 2.18 2.29 2.20 0.36 0.29 0.36 0.26 0.30 0.29 0.37 0.29 0.50 0.36 16.51 13.62 16.74 11.76 13.39 14.15 16.37 13.30 21.83 16.36 0.078 0.063 0.080 0.090 0.110 0.071 0.074 0.077 0.069 0.091 3.58 2.96 3.72 4.07 4.91 3.46 3.27 3.53 3.01 4.14 0.086 0.071 0.090 0.086 0.092 0.082 0.100 0.086 0.072 0.097 3.94 3.33 4.19 3.89 4.11 4.00 4.42 3.94 3.14 4.41 0.89 0.71 0.84 0.76 0.70 0.92 0.95 0.66 0.78 0.75 40.82 33.33 39.07 34.39 31.25 44.88 42.04 30.28 34.06 34.09 1.13 1.00 1.19 1.23 1.26 1.16 1.18 1.08 1.10 1.16 51.83 46.95 55.35 55.66 56.25 56.58 52.21 49.54 48.03 52.73 ALL WEIGHTS WERE RECORDED IN GRAMS (G). A B S . WT. = ORGAN WEIGHT. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. 418-027:PAGE C-60 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C30 (PAGE 3): ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TCi BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP III MIDDLE DOSAGE 50 MG/KG/DAY RAT NUMBER BRAIN WEIGHT LIVER ABS. WT. REL. % BRW KIDNEY LEFT ABS. REL. WT. % BRW KIDNEY RIGHT ABS. REL. WT. % BRW ADRENAL LEFT ABS. REL. WT. % BRW ADRENAL RIGHT ABS. REL. WT. % BRW SPLEEN ABS. WT. REL. % BRW 17687 17693 17697 17700 17701 17705 17706 17709 17718 17720 P P P P P P P P P P 2.13 2.15 2.17 2.13 2.26 2.11 2.22 2.13 2.27 2.29 13.22 10.76 10.23 10.96 12.74 12.94 12.79 11.06 12.17 12.75 620.66 500.46 471.43 514.55 563.72 613.27 576.13 519.25 536.12 556.77 1.25 1.05 1.11 1.35 1.12 1.19 2.15 1.12 1.46 1.28 58.68 48.84 51.15 63.38 49.56 56.40 96.85 52.58 64.32 55.90 1.33 1.16 1.10 1.46 1.19 1.19 a 1.12 1.45 1.41 62.44 53.95 50.69 68.54 52.65 56.40 a 52.58 63.88 61.57 0.045 0.033 0.030 0.043 0.047 0.053 0.043 0.031 0.038 0.047 2.11 1.53 1.38 2.02 2.08 2.51 1.94 1.46 1.67 2.05 0.042 0.033 0.026 0.043 0.042 0.047 0.039 0.029 0.029 0.050 1.97 1.53 1.20 2.02 1.86 2.23 1.76 1.36 1.28 2.18 0.78 0.79 0.66 0.62 0.74 0.73 0.84 0.90 0.92 0.65 36.62 3 6.74 30.41 29.11 32.74 34.60 37.84 42.25 40.53 28.38 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 17687 17693 17697 17700 17701 17705 17706 17709 17718 17720 P P P P P P P P P P 2.13 2.15 2.17 2.13 2.26 2.11 2.22 2.13 2.27 2.29 0.37 0.18 0.19 0.35 0.32 0.27 0.31 0.31 0.23 0.35 17.37 8.37 8.76 16.43 14.16 12.80 13.96 14.55 10.13 15.28 0.101 0.062 0.071 0.082 0.072 0.097 0.108 0.066 0.082 0.093 4.74 2.88 3.27 3.85 3.18 4.60 4.86 3.10 3.61 4.06 0.101 0.081 0.093 0.077 0.064 0.075 0.111 0.090 0.074 0.097 4.74 3.77 4.28 3.62 2.83 3.55 5.00 4.22 3.26 4.24 0.74 0.72b 0.85 0.82 0.86 0.83 0.82 0.72 0.76 0.76 34.74 33.49 39.17 38.50 38.05 39.34 36.94 33.80 33.48 33.19 1.05 0.99 0.98 1.12 1.17 1.38 1.11 0.91 1.28 1.10 49.30 46.05 45.16 52.58 51.77 65.40 50.00 42.72 56.39 48.03 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . A B S . WT. = ORGAN WEIGHT. R E L . % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) a. Dam 17706 had an absent right kidney. See the individual necropsy observations table (Table C28). b. Damaged during processing (weight not affected). X 100. 418-027:PAGE C ON PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C3 0 (PAGE 4) : ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP IV HIGH DOSAGE 250 MG/KG/DAY RAT NUMBER BRAIN WEIGHT LIVER ABS. WT. REL. % BRW KIDNEY LEFT ABS. REL. WT. % BRW KIDNEY RIGHT ABS. REL. WT. % BRW ADRENAL LEFT ABS. REL. WT. % BRW ADRENAL RIGHT ABS. REL. WT. % BRW SPLEEN ABS. WT. REL. % BRW 17678 P 17683 P 17685 P 17686 NP 17689 P 17691 P 17692 P 17696b P 17699 P 17711b P 17712 P 17714 P 2.23 2.19 2.31a 2.10 2.27 2.02 2.17 2.17 2.18 2.10 2.19 2.22 13.68 12.48 13.29 12.31 14.32 11.62 13.67 14.77 14.51 12.56 14.14 14.33 613.45 569.86 575.32 586.19 630.84 575.25 629.95 680.64 665.60 598.10 645.66 645.50 1.23 1.17 1.37 1.30 1.30 1.12 1.22 1.28 1.30 1.38 1.21 1.16 55.16 53.42 59.31 61.90 57.27 55.44 56.22 58.99 59.63 65.71 55.25 52.25 1.25 1.28 1.40 1.31 1.27 1.21 1.21 1.24 1.40 1.38 1.22 1.22 56.05 58.45 60.61 62.38 55.95 59.90 55.76 57.14 64.22 65.71 55.71 54.95 0.050 0.054 0.043 0.037 0.045 0.037 0.031 0.053 0.055 0.059 0.041 0.049 2.24 2.46 1.86 1.76 1.98 1.83 1.43 2.44 2.52 2.81 1.87 2.21 0.038 0.048 0.034 0.036 0.043 0.036 0.033 0.041 0.050 0.052 0.039 0.042 1.70 2.19 1.47 1.71 1.89 1.78 1.52 1.89 2.29 2.48 1.78 1.89 0.81 0.60 0.54 0.48 0.70 0.54 0.66 0.49 0.67 0.39 0.69 0.56 36.32 27.40 23.38 22.86 30.84 26.73 30.41 22.58 30.73 18.57 31.51 25.22 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 17678 P 17683 P 17685 P 17686 NP 17689 P 17691 P 17692 P 17696b P 17699 P 17711b P 17712 P 17714 P 2.23 2.19 2.31a 2.10 2.27 2.02 2.17 2.17 2.18 2.10 2.19 2.22 0.30 0.23 0.20 0.43 0.19 0.29 0.15 0.06c 0.23 0.23 0.20 0.15 13.45 10.50 8.66 20.48 8.37 14.36 6.91 2.76 10.55 10.95 9.13 6.76 0.074 0.074 0.079 0.058 0.072 0.066 0.057 0.070 0.090 0.062 0.088 0.076 3.32 3.38 3.42 2.76 3.17 3.27 2.63 3.22 4.13 2.95 4.02 3.42 0.100 0.074 0.072 0.053 0.066 0.074 0.076 0.083 0.102 0.086 0.095 0.057 4.48 3.38 3.12 2.52 2.91 3.66 3.50 3.82 4.68 4.10 4.34 2.57 0.76 0.68 0.70 0.42 0.82 0.67 0.71 1.71 0.64 2.15 0.77 0.71 34.08 31.05 30.30 20.00 36.12 33.17 32.72 78.80 29.36 102.38 35.16 31.98 1.21 0.90 0.94 1.09 0.99 0.94 0.84 0.85 1.00 1.04 1.18 1.05 54.26 41.10 40.69 51.90 43.61 46.53 38.71 39.17 45.87 49.52 53.88 47.30 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . A B S . WT. = ORGAN WEIGHT. REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) a. Damaged during processing (weight not affected). b. Dam was sacrificed due to no surviving pups on day 2 of lactation; values excluded from group averages and statistical analyses. c. Dam 17696 had a small thymus. See the individual necropsy observations table (Table C28). 418-027:PAGE C-62 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C31 (PAGE 1): BODY WEIGHTS - PRECOHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP I VEHICLE 0 (VEHICLE) MG/KG/DAY DAY 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15a 17662 17672 17673 17674 17680 17681 17690 17694 17695 17703 17713 17715 17716 17717 17719 222 . 237. 225 . 229. 222 . 239. 224 . 226 . 216. 240. 230 . 237. 221. 224 . 216. 221. 241. 225. 230 . 220 . 235 . 226. 226. 220 . 238 . 229 . 238 . 222 . 227. 217 . 229. 240 . 224. 237. 229. 242 . 234. 230. 227. 248. 239. 247. 224. 232 . 221. 231. 243 . 229. 240. 232. 245. 237. 232 . 224 . 248 . 239. 249. 227. 229. 219. 234 . 254 . 232 . 242 . 233 . 244 . 242 . 237 . 226 . 256 . 240 . 246. 227. 234 . 219. 234. 250. 234 . 243 . 229. 247. 242 . 243 . 231. 252 . 237. 24 7 . 229. 240. 224 . 238. 253 . 228. 251. 235. 252 . 248 . 245 . 237. 260. 245 . 258 . 231. 246 . 228 . 241. 262 . 239. 254 . 245 . 257. 258 . 243 . 234 . 268. 252 . 259 . 233 . 250. 228. 243 . 266. 237 . 261. 246. 253 . 253 . 249. 233 . 266. 249. 261. 238 . 256. 227 . 239. 264 . 241. 264 . 243 . 256. 261. 251. 241. 266. 249. 262 . 235 . 262 . 230 . 246 . 267 . 236. 261. 247 . 260 . 262 . 253 . 244 . 273 . 253 . 270 . 233 . 260 . 233 . 247 . 276. 238. 270. 251. 262 . 262 . 251. 239. 279. 257 . 273 . 240 . 264 . 238 . 249 . 279 . 245 . 271. 256. 265 . 269. 257 . 244 . 283 . 252 . 271. 242 . 270 . 238 . 247. 279 . 247 . 277 . 250. 263 . 271. 264 . 254 . 278 . 254 . 269 . 242 . 270 . 234 . 252 . 275 . 246. 270 . 257 . 267 . 275 . 265 . 250 . 292 . 260 . 274 . 244 . 271. 237 . DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Last value recorded before cohabitation. 9-3 3DV<r-LZ0-8li7 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C31 (PAGE 2): BODY WEIGHTS - PRECOHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP II LOW DOSAGE 10 MG/KG/DAY DAY 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15a 17663 17665 17666 17668 17671 17675 17679 17684 17688 17698 17702 17704 17707 17708 17710 221. 234. 223 . 224 . 215 . 233 . 221. 228 . 225. 237. 223 . 233 . 218. 239. 236. 220. 232 . 226. 225 . 215 . 236. 225 . 234 . 226. 230. 230 . 232 . 224 . 238. 238 . 224 . 238. 233. 231. 222. 238. 231. 236. 229. 239. 227. 236. 220. 245. 239. 222 . 244 . 234 . 235. 222 . 238. 234 . 239 . 232 . 246 . 233 . 240. 226. 252 . 249 . 229 . 242 . 240 . 233 . 224 . 238. 236. 243 . 234 . 246. 240 . 246. 227. 254 . 246 . 223 . 238. 244 . 233 . 220 . 241. 236. 245 . 235, 242 . 246. 248, 230 , 254 . 251, 235. 245 . 248 . 236. 224 . 246. 240 . 247 . 240 . 250. 244 . 250 . 232 . 260. 256 . 235 . 250. 248. 240 . 236. 250 . 249. 251. 246 . 258. 250. 255. 237 . 266. 261. 237. 247. 256. 241. 230 . 248 . 246 . 259. 246. 258. 263 . 261. 235 . 270 . 264. 237. 247. 259 . 240 . 226 . 256. 248 . 260 . 250 . 255. 263 . 268 . 234 . 272 . 265 . 240 251 259 244 231 254 254 261 255 262 254 271 236 271 265 243 . 256. 259 . 247 . 235 . 253 . 257 . 264 . 258. 264 . 259. 267. 238 . 278 . 272 . 246. 256. 263 . 248 . 235. 253 . 257. 266. 256. 267 . 270. 273 . 243 . 283 . 280 . 247 . 257 . 269. 246 . 232 . 259. 260. 268. 261. 266. 269. 278 . 242 . 286. 278 . 247 . 262 . 268. 252 . 235 . 260. 262 . 264 . 265. 272 . 261. 280 . 245 . 285. 276 . DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Last value recorded before cohabitation. 418-027:PAGE C-64 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVE LOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C31 (PAGE 3) : BODY WEIGHTS - PRECOHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP Ill MIDDLE DOSAGE 50 MG/KG/DAY DAY 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15a 17661 17667 17669 17670 17676 17687 17693 17697 17700 17701 17705 17706 17709 17718 17720 218 . 232 . 231. 228 . 217 . 238. 222 . 225 . 225. 236 . 225 . 227 . 222 . 228 . 224 . 220 . 240 . 231. 226 . 218 . 238 . 226. 225 . 229. 235 . 225 . 231. 220. 231. 226 . 226. 247. 241. 229. 218. 248. 230. 230. 233. 244. 230. 234. 223. 230. 222. 222 . 249 . 242 . 234 . 223 . 252 . 234 . 235 . 238 . 248 . 235. 238. 224 . 234 . 229 . 222 . 244 . 244 . 238 . 226. 255. 237. 233 . 242 . 249 . 239. 243 . 228. 235. 233 . 229 . 252 . 242 . 238. 227. 256. 237. 232. 244 . 249 . 240 . 244 . 223 . 237. 235. 230 . 258 . 253 . 238. 225. 262 . 238. 237 . 249. 255 . 242 . 246. 229. 236. 245 . 226. 257. 257. 249. 231. 270. 249. 243 . 256. 261. 255. 253 . 232 . 243 . 245. 228 . 256. 258 . 247. 232 . 268 . 249. 241. 254 . 262 . 253 . 257. 233 . 244 . 253 . 234 . 263 . 258 . 245. 235 . 276. 250. 240 . 255. 264 . 248 . 259. 230. 248 . 258. 235 268 265 247 236 281 248 244 261 269 263 259 236 246 259 233 . 264 . 268. 249. 234 . 288. 246. 250 . 263 . 269. 262. 266. 240 . 250 . 264 . 232 . 262 . 267 . 258 . 238. 289. 256. 249 . 266. 271. 268. 266. 243 . 254 . 278. 237 . 270 . 267. 254 . 243 . 287. 255. 253 . 266. 272 . 261. 262 . 240 . 253 . 269. 239. 272 . 271. 249. 246. 289. 253 . 252 . 273 . 278 . 271. 266. 245 . 249. 257 . DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Last value recorded before cohabitation. 418-027:PAGE C-65 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C31 (PAGE 4): BODY WEIGHTS - PRECOHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP IV HIGH DOSAGE 250 MG/KG/DAY DAY 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15a 17664 17677 17678 17682 17683 17685 17686 17689 17691 17692 17696 17699 17711 17712 17714 217. 236. 228 . 224 . 222 . 233 . 227. 226. 229 . 222. 218 . 232 . 223 . 227 . 234 . 219 . 239. 227 . 233 . 220 . 233 . 225 . 226. 222 . 224 . 219. 234 . 222 . 228. 235 . 214. 244 . 229. 234. 226. 235. 227. 229. 215. 225. 218. 239. 223 . 221. 242. 219. 240 . 231. 235. 226. 230 . 228. 235. 223 . 224 . 225 . 243 . 224 . 228 . 248 . 225 . 249 . 236. 237. 228. 236. 229 . 238 . 233 . 231. 228 . 247 . 232 . 234 . 252 . 227. 255 . 238 . 242 . 226. 241. 230 . 238. 234 . 235 . 225 . 248. 234 . 237 . 252 . 223 . 257. 234 . 247 . 228 . 239. 228 . 241. 235 . 235 . 223 . 254 . 233 . 226 . 258. 232. 256. 244 . 248 . 234 . 241. 237. 247 . 243 . 236. 232 . 256. 234 . 234 . 264 . 233 . 251. 243 . 252 . 233 . 246 . 237. 248 . 244 . 241. 233 . 257 . 239. 238. 264 . 235 . 263 . 246. 253 . 236. 251. 235. 250 . 245. 244 . 236. 256. 239. 239. 264 . 232 . 264 . 242 . 256. 240 . 250 . 235. 252 . 243 . 243 . 234 . 260. 238. 236. 270 . 241. 273 . 249 . 256. 241. 246 . 242 . 256. 249. 241. 236. 260 . 240 . 235. 278 . 244 . 271. 251. 256. 240 . 253 . 241. 256. 248 . 246 . 241. 264 . 243 . 243 . 280. 244 . 270 . 248 . 256. 241. 257 . 243 . 256 . 253 . 247 . 235 . 260. 243 . 244 . 278 . 242 . 268 . 250 . 260. 243 . 258 . 244 . 260. 252 . 246. 234 . 267 . 241. 246. 282 . DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Last value recorded before cohabitation. 418-027:PAGE C-66 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C32 (PAGE 1) : MATERNAL BODY WEIGHTS - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP I VEHICLE PREGNANCY STATUS DAY 0 1 2 3 4 5 17662 P 17672 P 17673 P 17674 P 17680 P 17681 P 17690 P 17694 P 17695 P 17703 P 17713 P 17715 P 17716 P 17717 P 17719 P 255. 289. 248 . 272 . 268. 277 . 281. 265. 254 . 286. 260 . 288 . 253 . 269. 262 . 263 . 298 . 253 . 284 . 272 . 284 . 289. 274 . 259. 296. 269 . 298. 264 . 276. 266. 270. 299. 261. 290. 286. 286. 301. 277. 262 . 309. 274 . 300. 265 . 279 . 268 . 270 . 301. 265. 293 . 281. 287. 300. 278. 268. 313 . 276. 310. 271. 282. 271. 276. 304 . 267. 294 . 285. 292 . 307. 284 . 270 . 316. 283 . 308 . 276 . 284. 274 . 281. 312 . 269. 302 . 288. 298. 312 . 286. 278. 319. 279 . 316. 280. 286. 275 . DAY 13 14 15 16 17 18 17662 P 17672 P 17673 P 17674 P 17680 P 17681 P 17690 P 17694 P 17695 P 17703 P 17713 P 17715 P 17716 P 17717 P 17719 P 316. 354 . 304 . 341. 332 . 334 . 371. 325. 299. 370. 318. 360 . 313 . 310. 300. 323 . 360. 308 . 352 . 341. 346. 380. 338 . 307 . 387. 331. 364 . 316 . 318 . 304 . 329. 372 . 316. 360. 352 . 348 . 386. 344 . 319. 389. 333 . 373 . 327 . 324 . 309. 342 . 380. 326. 371. 360. 358. 400. 354 . 332 . 400. 345. 377. 337. 332. 321. 354 . 394. 336. 385. 377. 370 . 413 . 367. 341. 419 . 355 . 392 . 352 . 339. 335 . 367. 408. 351. 407. 397. 391. 440 . 383 . 362 . 439. 376. 410 . 361. 357. 354. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). 6 287 . 316. 275 . 304 . 289. 301. 324 . 295. 280. 327. 281. 316. 277 . 288. 277. 19 380. 424 . 364 . 429 . 412. 403 . 454 . 399. 372 . 448 . 380. 423 . 379. 367. 375 . 7 288 . 323 . 276. 308. 297 . 306. 328 . 292. 284 . 331. 292 . 320. 283 . 285 . 282 . 20 392 . 442 . 380. 453 . 438. 414 . 476. 417. 380. 477 . 392 . 444 . 392 . 381. 393 . 0 (VEHICLE) MG/KG/DAY 8 293 . 326. 283 . 315 . 300 . 309. 330 . 299. 280. 336. 2 93 . 327 . 285 . 291. 286. 21 406. 4 64 . 3 93 . 461. 458 . 427 . 512 . 437 . 9 300 . 324 . 284. 316. 304 . 312 . 340. 300 . 281. 341. 293 . 328. 292 . 292 . 283 . 22 10 303 . 336. 286. 321. 312 . 320 . 343 . 309. 292 . 347 . 302 . 337. 295 . 297. 287. 23 413 . 469 . 410 . 387 . 415 . 11 310 . 348 . 296 . 329. 320 . 328 . 351. 312 . 293 . 354 . 304 . 344 . 303 . 306. 291. 24 12 315. 346. 300 . 338. 328 . 334 . 361. 319. 305 . 362 . 317 . 352 . 307. 305 . 291. 25 418-027:PAGE C-67 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C32 (PAGE 2): MATERNAL BODY WEIGHTS - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP II LOW DOSAGE PREGNANCY STATUS DAY 0 1 2 3 4 5 17663 NP 17665 P 17666 P 17668 P 17671 P 17675 P 17679 P 17684 P 17688 P 17698 P 17702 P 17704 P 17707 P 17708 P 17710 P 258. 267 . 272 . 263 . 244 . 266. 271. 283 . 275 . 278 . 273 . 277 . 264 . 288 . 300. 253 . 271. 275 . 261. 251. 267. 277. 286. 281. 284 . 284 . 291. 261. 290. 308. 250. 274 . 279. 269. 255 . 272 . 282 . 294 . 285 . 298 . 286. 294 . 265. 294 . 311. 256. 280 . 284 . 276. 249. 277 . 279 . 294 . 288 . 300 . 291. 299. 270 . 301. 323 . 261. 284 . 286. 280 . 258. 278 . 284 . 298. 293 . 305. 292 . 298. 271. 303 . 322 . 261. 286. 278 . 279 . 260. 282 . 284 . 304 . 298 . 309. 289. 304 . 278 . 310. 326. DAY 13 14 15 16 17 18 17663 NP 17665 P 17666 P 17668 P 17671 P 17675 P 17679 P 17684 P 17688 P 17698 P 17702 P 17704 P 17707 P 17708 P 17710 P 268. 326 . 307 . 322 . 289 . 317. 313 . 348 . 332 . 340 . 329 . 349. 313 . 350 . 374 . 269. 336. 309. 338. 294 . 317 . 323 . 351. 351. 356. 332 . 356. 315 . 355. 384 . 270 . 339. 314 . 337. 300 . 321. 323 . 361. 344, 353 . 345 . 372 . 320. 363 . 388 . 272 . 354 . 326 . 353 . 310 . 335. 330 . 373 . 366. 364 . 357. 382 . 328 . 378 . 403 . 269. 368 . 339. 373 . 322 . 353 . 343 . 388. 387. 376 . 370. 399. 340 . 389. 416. 268 . 390 . 355 . 382 . 334 . 377 . 348 . 404 . 406. 397 . 389. 425 . 363 . 414 . 436. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). 6 259. 295 . 283 . 291. 263 . 283 . 286. 303 . 303 . 314 . 296. 306. 275. 312 . 332 . 19 267. 396. 371. 391. 346. 395. 362. 425. 419. 402 . 404 . 445 . 377. 431. 449. 7 260. 296. 288 . 290 . 265. 291. 291. 309. 305. 309. 299. 313 . 279. 320. 327. 20 269. 417 . 387 . 405 . 359. 411. 375 . 441. 432 . 413 . 416. 459. 389. 456 . 471. 10 MG/KG/DAY 8 262 . 297. 289. 294 . 271. 291. 290 . 311. 310. 317. 300. 316. 283 . 323 . 335. 21 277. 434 . 400 . 426. 371. 434 . 383 . 468 . 9 267. 300. 293 . 298 . 273 . 298 . 294 . 314 . 316. 321. 309. 324 . 283 . 328 . 345 . 22 279 . 436. 468. 408. 472 . 498. 10 271. 308 . 292 . 306. 280 . 299. 298. 324 . 324 . 334 . 306. 329 . 286. 332 . 347 . 23 281. 11 268 . 315 . 298. 314 . 281. 306 . 306 . 333 . 329 . 336. 316. 336. 299. 334 . 354 . 24 279 . 12 266. 324 . 303 . 324 . 292 . 313 . 316. 339. 336. 342 . 319. 348 . 304 . 349 . 371. 25 267. 418-027:PAGE C-68 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C32 (PAGE 3) : MATERNAL BODY WEIGHTS - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP III MIDDLE DOSAGE PREGNANCY STATUS DAY 0 1 2 3 4 5 17661 P 17667 P 17669 P 17670 P 17676 P 17687 P 17693 P 17697 P 17700 P 17701 P 17705 P 17706 P 17709 P 17718 P 17720 P 243 . 273 . 282 . 262 . 247 . 305 . 255 . 258 . 277. 293 . 280. 276 . 273 . 288 . 269. 251. 287 . 288 . 262 . 250 . 305 . 262 . 262 . 280. 298. 288. 282 . 272 . 292. 273 . 248 . 290 . 290. 265. 253 . 311. 265. 274 . 285. 299. 297. 283 . 276. 297. 276. 253 . 296 . 290 . 262 . 253 . 313 . 268. 274 . 288 . 301. 297. 286. 278 . 294 . 284 . 259. 295 . 294 . 269. 255 . 322 . 272 . 271. 293 . 311. 303 . 294 . 284 . 299. 293 . 258 . 299. 295 . 275 . 260. 326. 275 . 274 . 296. 311. 299. 301. 286. 298. 294 . DAY 13 14 15 16 17 18 17661 P 17667 P 17669 P 17670 P 17676 P 17687 P 17693 P 17697 P 17700 P 17701 P 17705 P 17706 P 17709 P 17718 P 17720 P 306. 337. 325 . 306. 284 . 370 . 301. 300 . 333 . 355. 350. 340 . 304 . 326. 336. 312 . 342 . 330 . 315. 291. 370 . 306. 310. 341. 365 . 359. 339. 308. 335 . 346. 326. 353 . 338 . 320. 298. 376. 312 . 318 . 352 . 366. 367. 351. 307 . 344 . 354 . 340 . 361. 348 . 337. 308 . 388 . 327. 326. 361. 383 . 377. 359. 324 . 352. 366. 355. 378 . 367 . 346. 324 . 403 . 330. 344 . 375. 388 . 394 . 377. 331. 367. 380. 376. 395. 386. 362 . 334 . 417. 351. 361. 390. 410. 407 . 377. 352 . 386. 397. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). 6 265 . 301. 293 . 274 . 261. 326. 279. 275. 297. 312 . 311. 302. 286. 301. 297 . 19 391. 412 . 403 . 380. 350. 434 . 369. 373 . 405. 423 . 418. 401. 362 . 402 . 413 . 7 276. 308. 301. 275 . 265 . 333 . 281. 275 . 300. 322. 316. 301. 293 . 304. 302 . 20 402 . 419 . 416 . 394 . 358. 450. 385. 386. 416. 442 . 443 . 423 . 379. 423 . 435 . 50 MG/KG/DAY 8 275. 313 . 305. 279. 262 . 336. 283 . 277 . 305 . 324 . 320. 306. 291. 305. 304 . 21 424 . 440 . 436. 416. 373 . 476. 405. 405 . 466. 467. 443 . 391. 454 . 9 279. 316 . 307. 287 . 265 . 337. 283 . 280 . 310 . 331. 325 . 314 . 287. 306. 309. 22 10 286 . 321. 309. 292 . 270 . 348 . 288 . 286. 312 . 341. 330. 317. 296. 311. 314 . 23 11 293 . 327 . 317 . 295 . 274 . 356. 298 . 297. 321. 346 . 338 . 324 . 301. 320 . 323 . 24 12 302 . 335 . 325 . 305 . 282 . 366. 302 . 298 . 328 . 354 . 352 . 337 . 300 . 324 . 333 . 25 418-027:PAGE C-69 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C32 (PAGE 4) : MATERNAL BODY WEIGHTS - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP IV HIGH DOSAGE PREGNANCY STATUS DAY 0 1 2 3 4 5 17664 NP 17677 P 17678 P 17682 P 17683 P 17685 P 17686 NP 17689 P 17691 P 17692 P 17696 P 17699 P 17711 P 17712 P 17714 P MATING NOT CONFIRMED 268. 276. 278. 263 . 269. 274 . 288 . 284. 288. 250 . 264 . 265. 262 . 268. 270 . 243 . 251. 259. 264. 268 . 267. 264 . 268 . 274 . 254 . 260. 262 . 231. 244 . 252 . 272 . 275 . 283 . 249 . 254 . 256. 250 . 261. 267. 291. 296. 306. 281. 283 . 290. 261. 275 . 265 . 268. 277. 264 . 252 . 282 . 256 . 264 . 305. 288. 284 . 293 . 264 . 280. 267. 270. 281. 269. 252. 289. 261. 271. 316. 290. 289. 292 . 267 . 282 . 268. 272 . 288. 269. 255. 292. 264 . 274 . 318 . DAY 13 14 15 16 17 18 17664 NP 17677 P 17678 P 17682 P 17683 P 17685 P 17686 NP 17689 P 17691 P 17692 P 17696 P 17699 P 17711 P 17712 P 17714 P MATING NOT CONFIRMED 319. 325 . 332. 330 . 332 . 338. 324 . 331. 341. 318 . 328 . 326. 313 . 319. 328 . 272 . 277. 275 . 316. 324 . 327 . 324 . 324 . 331. 298. 307. 315 . 284 . 290. 299. 326. 333 . 340 . 295 . 300. 305. 304 . 309. 320. 347. 358 . 366. 341. 347 . 355. 339 . 340 . 266. 350 . 340. 329. 311. 352 . 319. 333 . 376. 358. 364. 367. 348. 351. 270. 355. 351. 340. 323 . 366. 332 . 350. 387. 363 . 373 . 371. 369 . 373 . 278 . 369. 359. 357. 338. 380. 337. 366. 406. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). 6 286. 292 . 293 . 270 . 288. 272 . 276. 287 . 274 . 257. 299. 266. 275 . 317. 19 373 . 385 . 389. 380. 389. 284 . 389. 374 . 371. 356. 396. 355. 385 . 414 . 7 289. 297. 299 . 266. 289. 271. 282 . 295 . 278 . 256. 295. 268 . 276. 322 . 20 386. 405. 401. 396. 403 . 294 . 409. 381. 395. 369. 403 . 366. 399. 430 . 250 MG/KG/DAY 89 296, 299. 299. 278 . 290 . 278 , 288. 296. 276. 259. 296. 264 . 280. 327 . 21 297. 303 . 303 . 279. 295 . 284 . 290. 304 . 283 . 261. 302 . 271. 285 . 333 . 22 398 . 422 . 417 . 409. 290. 420. 391. 409. 377. 415 . 3 64. 408 . 443 . 381. 296. 370. 354 . 10 303 . 309. 308 . 293 . 299. 286. 293 . 309. 284 . 272 . 309. 278 . 288 . 338 . 23 299. 11 313 . 320 . 310 . 304 . 302 . 302 . 302 . 316. 291. 274 . 312 . 282 . 295 . 341. 24 298. 12 317. 327. 319. 315 . 305 . 293 . 305. 317 . 299. 282 . 321. 293 . 301. 348 . 25 284 . 418-027:PAGE 0 7 0 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C33 (PAGE 1): MATERNAL BODY WEIGHTS - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP I DAY 1 2 3 17662 17672 17673 17674 17680 17681 17690 17694 17695 17703 17713 17715 17716 17717 17719 304 . 339. 304 . 321. 331. 326. 360. 315. 294 . 366. 312 . 356. 305 . 291. 294 . 315 . 329. 287. 326. 331. 329 . 381. 317. 293 . 354 . 305 . 357. 306. 294 . 290. 321. 350. 290 . 321. 332 . 327. 366. 322 . 286 . 354 . 311. 353 . 302 . 293 . 285 . DAY = DAY OF LACTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). VEHICLE 45 328 . 354 . 301. 318. 339. 331. 372 . 328 . 298. 362 . 302 . 353 . 298. 286. 292 . 328 . 361. 295 . 306. 338 . 337 . 388. 317. 299. 371. 321. 350 . 307. 295 . 300. 6 303 . 319. 271. 282 . 303 . 303 . 345. 291. 271. 339. 292. 328 . 298. 274 . 268. 0 (VEHICLE) MG/KG/DAY PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C3 3 (PAGE 2) : MATERNAL BODY WEIGHTS - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP II DAY 1 2 3 17663 17665 17666 17668 17671 17675 17679 17684 17688 17698 17702 17704 17707 17708 17710 NOT PREGNANT 325 . 324 . 297 . 304 . 308. 312 . 276. 273 . 307. 313 . 322 . 313 . 332 . 345 . 332 . 339. 315 . 318. 328 . 327 . 342 . 350. 299. 299. 351. 357. 344 . 370. 327. 299. 323 . 270 . 323 . 307. 344 . 337. 328. 333 . 346. 309. 359. 364 . DAY = DAY OF LACTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). LOW DOSAGE 45 326. 301. 329. 262 . 325. 319. 339. 352 . 339. 340 . 349. 319. 344 . 363 . 335. 309. 342 . 290 . 335 . 328 . 348. 355. 341. 344 . 351. 330. 360. 379. 6 308 . 289. 299. 256. 297. 295 . 317. 311. 299. 307. 327 . 296. 328 . 327. 10 MG/KG/DAY ZL~D Z D V d 'L Z O -m PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C33 (PAGE 3) : MATERNAL BODY WEIGHTS - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP III DAY 1 2 3 17661 17667 17669 17670 17676 17687 17693 17697 17700 17701 17705 17706 17709 17718 17720 311. 331. 321. 294 . 269. 351. 294 . 295 . 334 . 351. 331. 337 . 282 . 314 . 333 . 299. 329. 322 . 297. 276 . 354 . 286 . 297. 343 . 348 . 349. 337 . 287 . 323 . 334 . 306. 332 . 319 . 294 . 287 . 359. 295 . 311. 344 . 350. 361. 337 . 284 . 320. 341. DAY = DAY OF LACTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). MIDDLE DOSAGE 45 297. 329. 325. 292 . 289. 354 . 299. 295. 335. 345 . 362 . 341. 286. 318. 342 . 306 . 341. 336. 294 . 294 . 364 . 302 . 304 . 348 . 348. 374 . 340. 290 . 326. 351. 6 280 . 311. 296. 268. 265 . 337. 274 . 268 . 310. 311. 330. 315 . 262 . 295. 318. 50 MG/KG/DAY 418-027:PAGE C-73 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C33 (PAGE 4) : MATERNAL BODY WEIGHTS - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP IV HIGH DOSAGE 250 MG/KG/DAY DAY 1 2 3 4 5 6 17664 17677 17678 17682 17683 17685 17686 17689 17691 17692 17696 17699 17711 17712 17714 NOT PREGNANT; MATING NOT' CONFIRMED 304 . 298. 304 . 304 . 304 . 287. 327. 324 . 332 . 328. 330. 293 . 306. 310. 317 . 321. 338. 300 . 298 . 302 . 296 . 294 . 304 . 259 . 293 . 304 . 295. 294 . 307. 277 . NOT PREGNANT 301, 302. 307. 312 . 324 . 285 . 303 . 308. 310. 307. 315. 286. 273 . 279. 282 . 291. 300. 277 . 248 . SACRIFICED DUE TO NO SURVIVING PUPS ON DAY 2 OF LACTATION 314 , 318 . 315. 320. 322 . 283 . 248 , SACRIFICED DUE TO NO SURVIVING PUPS ON DAY 2 OF LACTATION 307. 313 . 304 . 310 . 322 . 292 . 330 . 332 . 331. 336. 326. 294 . DAY = DAY OF LACTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). 418-027'.PAGE C-74 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C34 (PAGE 1) : FEED CONSUMPTION VALUES - PRECOHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP I DAYS 1- 8 8- 15a 17662 17672 17673 17674 17680 17681 17690 17694 17695 17703 17713 17715 17716 17717 17719 138. 141. 103 . 145 . 133 . 134 . 127 . 128 . 141. 136. 129 . 136 . 196 . 129. 123 . 132 . 150. 110. 150. 145 . 141. 146. 141. 13 9. 147. 130. 136 . 192 . 148 . 124 . DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Last value recorded before cohabitation. VEHICLE 0 (VEHICLE) MG/KG/DAY 418-027:PAGE C-75 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C34 (PAGE 2): FEED CONSUMPTION VALUES - PRECOHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP II DAYS 1- 8 8- 15a 17663 17665 17666 17668 17671 17675 17679 17684 17688 17698 17702 17704 17707 17708 17710 117 . 156. 134 . 126. 115. 128. 145 . 140 . 128 . 142 . 143 . 139 . 124 . 151. 145 . 139. 14 9. 141. 131. 112 . 143 . 151. 156. 153 . 141. 150. 162 . 122. 160. 164. DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Last value recorded before cohabitation. LOW DOSAGE 10 MG/KG/DAY 418-027:PAGE C-76 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C34 (PAGE 3): FEED CONSUMPTION VALUES - PRECOHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP III DAYS 1- 8 8- 15a 17661 17667 17669 17670 17676 17687 17693 17697 17700 17701 17705 17706 17709 17718 17720 123 . 130 . 150 . 138 . 119 . 187 . 140 . 129. 157. 160. 124 . 140 . 110 . 124 . 144 . 117. 132 . 146. 132 . 125 . 191. 133 . 136. 153 . 167. 150. 146 . 118. 133 . 158 . DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Last value recorded before cohabitation. MIDDLE DOSAGE 50 MG/KG/DAY 418-027:PAGE C-77 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C34 (PAGE 4) : FEED CONSUMPTION VALUES - PRECOHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP IV HIGH DOSAGE DAYS 1- 8 8- 15a 17664 17677 17678 17682 17683 17685 17686 17689 17691 17692 17696 17699 17711 17712 17714 125 . 147 . 123 . 178 . 118 . 133 . 121. 135. 113 . 126. 108 . 13 8. 119 . 109. 147 . 134 . 145 . 129 . b 122 . 149. 122 . 139. 141. 13 7. 124 . 141. 122 . 122 . 153 . 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. 250 MG/KG/DAY 8L" 3 3 D V < m O "8It7 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C35 (PAGE 1) : MATERNAL FEED CONSUMPTION VALUES - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP I VEHICLE PREGNANCY STATUS DAYS 0 - 7 7 - 1 0 10 - 12 12 - 15 15 - 18 18 - 20 17662 P 17672 P 17673 P 17674 P 17680 P 17681 P 17690 P 17694 P 17695 P 17703 P 17713 P 17715 P 17716 P 17717 P 17719 P 159. 171. 138. 171. 165. 159. 190. 168. 161. 183 . 154 . 176. 159. 148. 149. 80. 75 . 64 . 83 . 79. 77 . 89. 76. 72 . 84 . 74 . 77 . 66. 66. 67. 50 . 55 . 45 . 53 . 55. 53 . 61. 44 . 52 . 55 . 49. 58 . 48. 41. 43 . 74 . 85. 67. 85. 85. 82 . 94 . 80. 81. 85. 75. 90. 75 . 65. 66. 78 . 85 . 67. 92 . 91. 78. 99. 83 . 80. 91. 71. 75. 69. 75. 74 . 42 . 54 . 50 . 68 . 56. 49. 62 . 52 . 51. 47 . 39. 56. 52 . 44 . 50 . P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). 0 (VEHICLE) MG/KG/DAY 6"0 aova-Lzo-m PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C35 (PAGE 2) : MATERNAL FEED CONSUMPTION VALUES - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP II LOW DOSAGE PREGNANCY STATUS DAYS 0 - 7 7 - 1 0 10 - 12 12 - 15 15 - 18 18 - 20 17663 NP 17665 P 17666 P 17668 P 17671 P 17675 P 17679 P 17684 P 17688 P 17698 P 17702 P 17704 P 17707 P 17708 P 17710 P 139. 168. 135 . 157. 139. 152 . 164 . 170 . 165 . 168 . 166. 179 . 13 9. 172 . 207. 63 . 75 . 59. 83 . 69. 71. 75. 76 . 80. 81. 71. 82 . 63 . 87. 84 . 39. 56. 39. 55. 41. 47 . 52 . 57. 43 . 55. 42 . 60 . 51. 52. 67. 57. 78. 61. 81. 62. 69. 82 . 87. 74. 83 . 81. 98. 73 . 83 . 101. 56. 83 . 71. 88. 72 . 76 . 83 . 86. 101. 85 . 84 . 99. 74 . 95. 92 . 31. 45. 46. 44. 41. 51. 49. 58 . 55 . 40 . 58. 57. 48 . 61. 55. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). 10 MG/KG/DAY 418-027:PAGE C-80 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C35 (PAGE 3) : MATERNAL FEED CONSUMPTION VALUES - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP III MIDDLE DOSAGE pregnancy STATUS DAYS 0 - 7 7 - 1 0 10 - 12 12 - 15 15 - 18 18 - 20 17661 P 17667 P 17669 P 17670 P 17676 P 17687 P 17693 P 17697 P 17700 P 17701 P 17705 P 17706 P 17709 P 17718 P 17720 P 140 . 154 . 155 . 129 . 126. 207. 146 . 146 . 169. 188 . 167 . 178 . 143 . 152 . 172 . 71. 73 . 70. 60 . 58 . 87. 65. 64 . 81. 83 . 84 . 78. 52 . 62. 79. 58. 47 . 52 . 44 . 47. 58. 40. 48. 54 . 53 . 56. 53 . 38. 45 . 57. 86. 74 . 76. 73 . 66. 92 . 54 . 77. 91. 88. 85. 83 . 53 . 67. 91. 90. 80. 89. 70 . 65 . 81. 68. 86. 98 . 94. 94 . 75 . 65 . 72 . 84 . 58 . 50 . 48 . 50 . 41. 61. 52 . 44 . 52 . 58. 54 . 52 . 45 . 51. 58 . P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). 50 MG/KG/DAY I8-DH9V(T-ZZ0-8W PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C35 (PAGE 4): MATERNAL FEED CONSUMPTION VALUES - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP IV HIGH DOSAGE PREGNANCY STATUS DAYS 0 - 7 7 - 1 0 10 - 12 12 - 15 15 - 18 18 - 20 17664 NP 17677 P 17678 P 17682 P 17683 P 17685 P 17686 NP 17689 P 17691 P 17692 P 17696 P 17699 P 17711 P 17712 P 17714 P MATING NOT CONFIRMED 153 . 73 . 52 . 175. 73 . 58 . 170 . 72 . 68 . 13 6. 82 . 57. 174 . 76. 42 . 148 . 63 . 34 . 140 . 78 . 50. a 74. 46 . 152 . 67. 47 . 136. 60. 53 . 162 . 72 . 58 . 136 . 55. 47 . 174 . 82 . 54 . 164 . 82 . 56. 82 . 79. 77 . 85. 69. 50 . 76. 76 . 77. 72 . 87. 71. 89. 90 . 72 . 79. 80 . 93 . 86. 48 . 82 . 76. 84 . 79. 97. 75 . 106. 89. 45. 55. 52. 46. 51. 44 . 51. 42. 51. 47 . 49. 50 . 65. 47. 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. 250 MG/KG/DAY 8"3 HOVd'-tfXmfr PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C3 6 (PAGE 1) : MATERNAL FEED CONSUMPTION VALUES - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP I DAY 1 - 5 17662 17672 17673 17674 17680 17681 17690 17694 17695 17703 17713 17715 17716 17717 17719 144 . 143 . 93 . 97. 150. 129 . 168. 126. 118 . 127 . 100. 138 . 138 . 94 . 121. DAY = DAY OF LACTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). VEHICLE 0 (VEHICLE) MG/KG/DAY 8-OHOVd:/ZO-8lfr PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C3 6 (PAGE 2): MATERNAL FEED CONSUMPTION VALUES - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP II LOW DOSAGE DAY 1 - 5 17663 17665 17666 17668 17671 17675 17679 17684 17688 17698 17702 17704 17707 17708 17710 NOT PREGNANT 133 . 131. 158. 117. 153 . 118. 156. 147. a 13 9. 164 . 147. 166. 163 . DAY = DAY OF LACTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Spilled feed precluded the calculation of this value 10 MG/KG/DAY t?8"0 H9Yd-ilO"8It7 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C36 (PAGE 3): MATERNAL FEED CONSUMPTION VALUES - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP III MIDDLE DOSAGE DAY 1 - 5 17661 17667 17669 17670 17676 17687 17693 17697 17700 17701 17705 17706 17709 17718 17720 116 . 110. 141. 109. 13 0. 154 . 119. 110 . 167. 126 . a 150. 105. 141. 173 . DAY = DAY OF LACTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Spilled feed precluded the calculation of this value 50 MG/KG/DAY 418-027:PAGE C-85 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C3 6 (PAGE 4) : MATERNAL FEED CONSUMPTION VALUES - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # DOSAGE GROUP IV HIGH DOSAGE DAY 1 - 5 17664 17677 17678 17682 17683 17685 17686 17689 17691 17692 17696 17699 17711 17712 17714 NOT PREGNANT; MATING NOT CONFIRMED 74 . 111. 186. 109 . 114 . NOT PREGNANT 141. 133 . 106. SACRIFICED DUE TO NO SURVIVING PUPS ON DAY 2 OF LACTATION 113 . SACRIFICED DUE TO NO SURVIVING PUPS ON DAY 2 OF LACTATION 155. 113 . DAY = DAY OF LACTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). 250 MG/KG/DAY 418-027'.PAGE C-86 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C3 7 (PAGE 1) : MATING AND FERTILITY, ESTROUS CYCLING AND DAYS IN COHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT # PRECOHABITATION ESTROUS STAGES/ 14 DAYS DAYS IN COHABITATION MATING STATUS MATING DATE DOSAGE GROUP I VEHICLE 0 (VEHICLE) MG/KG/DAY 17662 3 3 M C 17672 4 4 M C 17673 2 1 M C 17674 3 1 M C 17680 4 3 M C 17681 3 3 M C 17690 4 3 M C 17694 3 1 M C 17695 2 2 M C 17703 4 3 M C 17713 4 3 M C 17715 4 4 M C 17716 4 4 M C 17717 la 1 M C 17719 1 9 M C DOSAGE GROUP II LOW DOSAGE 10 MG/KG/DAY 17663 4 3 M C 17665 3 3 M C 17666 3 1 M C 17668 4 3 M C 17671 4 3 M C 17675 3 2 M C 17679 3 3 M C 17684 4 4 M C 17688 4 3 M C 17698 4 3 M C 17702 1 1 M C 17704 3 2 M C 17707 3 4 M C 17708 4 1 M C 17710 4 4 M C M = MATED C = CONFIRMED P = PREGNANT NP = NOT PREGNANT a. Six or more consecutive days of diestrus were observed. PREGNANCY STATUS P P P P P P P P P P P P P P P NP P P P P P P P P P P P P P P 418-027:PAGE C-87 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C3 7 (PAGE 2) : MATING AND FERTILITY, ESTROUS CYCLING AND DAYS IN COHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS PRECOHABITATION ESTROUS STAGES/ 14 DAYS DAYS IN COHABITATION MATING STATUS MATING DATE DOSAGE GROUP III MIDDLE DOSAGE 50 MG/KG/DAY 17661 3 2 M C 17667 3 2 M C 17669 4 3 M c 17670 4 4 M c 17676 3 2 M c 17687 3 4 M c 17693 3 1 M c 17697 3 3 M c 17700 4 3 M c 17701 4 3 M c 17705 4 3 M c 17706 1 4 M c 17709 4 13 M c 17718 4 13 M c 17720 la 4 M c DOSAGE GROUP IV HIGH DOSAGE 250 MG/KG/DAY 17664 17677 17678 17682 17683 17685 17686 17689 17691 17692 17696 17699 17711 17712 17714 4 3 3 3 3 2 4 4 4 3 4 4 3 3 4 14 4 4 13 3 1 1 1 4 1 1 3 1 1 3 DID NOT MATE M M M M M M M M M M M M M M _ c c c c c c c c c c c c c c M = MATED C = CONFIRMED P = PREGNANT NP = NOT PREGNANT a. Six or more consecutive days of diestrus were observed. PREGNANCY STATUS P P P P P P P P P P P P P P P _ P P P P P NP P P P P P P P P 418-027:PAGE C-88 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C38 (PAGE 1): FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - FEMALE RATS DOSAGE GROUP I 0 (VEHICLE^ MG/KG/DAY RAT # 17662 17672 17673 17674 17680 HOME CAGE BEHAVIOR 211 12 ALTERATIONS (HOME CAGE) 1 1 1 11 REACTION TO REMOVAL 11 111 REACTION TO HANDLING 1 1 1 11 REARS IN OPEN FIELD 6 9 6 8 10 DEFECATION IN OPEN FIELD 1 1 1 1 1 URINATION IN OPEN FIELD 11 111 LEVEL OF AROUSAL 33 333 ALTERATIONS (OPEN FIELD) 1 1 1 1 4c GAIT PATTERN 11 111 GAIT ABNORMALITY, SEVERITY 1 1 1 1 1 PALPEBRAL CLOSURE 11 111 PROMINENCE OF THE EYE 11 111 LACRIMATION 11111 SALIVATION 11 1 11 PILOERECTION 00 000 ABNORMAL RESPIRATION 00 000 APPEARANCE 11111 VISUAL REACTION 2 2 2 22 TACTILE REACTION 22222 AUDITORY REACTION 33 333 TAIL-PINCH REACTION 2 2 2 22 VISUAL PLACING RESPONSE 11111 AIR RIGHTING RESPONSE 11 111 PUPIL RESPONSE TO LIGHT 1 1 1 11 FORELIMB GRIP TEST #1 310a 315 355 320b 225 FORELIMB GRIP TEST #2 355 325 255 285 220 HINDLIMB GRIP TEST #1 145 305 205 370 375 HINDLIMB GRIP TEST #2 190 325 215 220 390 LANDING FOOT SPLAY #1 6.6 6.1 7.2 6.7 6.7 LANDING FOOT SPLAY #2 7.7 6.8 5.5 6.8 6.8 BODY WEIGHT (G) 343 360 295 324 342 VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY. a. Soft or liquid feces were <observed during the forelimb grip testing. b. Animal fell aproximately 3 feet to floor, animal appeared normal c . Value appeared incorrectly recorded[ and was excluded from group averages and statistical analyses. 418-027:PAGE C-89 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C38 (PAGE 2) : FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - FEMALE RATS DOSAGE GROUP II 10 MG/KG/DAY RAT # 17665 17666 17668 17671 HOME CAGE BEHAVIOR 1 22 1 ALTERATIONS (HOME CAGE) 1 111 REACTION TO REMOVAL 1 11 1 REACTION TO HANDLING 1 11 1 REARS IN OPEN FIELD 12 8 11 10 DEFECATION IN OPEN FIELD 1 1 2 1 URINATION IN OPEN FIELD 1 121 LEVEL OF AROUSAL 3 33 3 ALTERATIONS (OPEN FIELD) 1 111 GAIT PATTERN 1 11 1 GAIT ABNORMALITY, SEVERITY 1 1 1 1 PALPEBRAL CLOSURE 1 111 PROMINENCE OF THE EYE 1 111 LACRIMATION 1 11 1 SALIVATION 1 111 PILOERECTION 0 000 ABNORMAL RESPIRATION 0 000 APPEARANCE la 1 1 lc VISUAL REACTION 2 22 2 TACTILE REACTION 2 222 AUDITORY REACTION 3 33 3 TAIL-PINCH REACTION 2 222 VISUAL PLACING RESPONSE 1 111 AIR RIGHTING RESPONSE 1 111 PUPIL RESPONSE TO LIGHT 1 111 FORELIMB GRIP TEST #1 210 385 175b 280 FORELIMB GRIP TEST #2 170 455 270 270 HINDLIMB GRIP TEST #1 285 370 335 220 HINDLIMB GRIP TEST #2 340 325 350 225 LANDING FOOT SPLAY #1 6.7 6.5 7.7 4.1 LANDING FOOT SPLAY #2 6.8 6.4 8.1 4.1 BODY WEIGHT (G) 335 310 353 292 VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY. a. Localized alopecia: both forepaws (0.5 cm :in diameter). b. Animal fell approximately 3 to 4 feet and appeared normal. c. Localized alopecia: both forepaws and forelimbs (2.0 cm x 0.5 cm ) . 06-0 m v & L io - m PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C38 (PAGE 3): FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - FEMALE RATS DOSAGE GROUP III Y 0 "m g 7kg"/DAY RAT # 17661 17667 17669 17670 17676 HOME CAGE BEHAVIOR 22222 ALTERATIONS (HOME CAGE) 1 1 11 1 REACTION TO REMOVAL 11111 REACTION TO HANDLING 11111 REARS IN OPEN FIELD 9 9 15 8 9 DEFECATION IN OPEN FIELD 1 1 1 1 1 URINATION IN OPEN FIELD 1 1 11 1 LEVEL OF AROUSAL 33333 ALTERATIONS (OPEN FIELD) 1 1 1 1 1 GAIT PATTERN 11111 GAIT ABNORMALITY, SEVERITY 1 1 1 1 1 PALPEBRAL CLOSURE 11111 PROMINENCE OF THE EYE 11 11 1 LACRIMATION 1 1 11 1 SALIVATION 2 1 11 1 PILOERECTION 00000 ABNORMAL RESPIRATION 00000 APPEARANCE 1 1 la 1 1 VISUAL REACTION 22222 TACTILE REACTION 22222 AUDITORY REACTION 33333 TAIL-PINCH REACTION 22222 VISUAL PLACING RESPONSE 11111 AIR RIGHTING RESPONSE 11111 PUPIL RESPONSE TO LIGHT 11 11 1 FORELIMB GRIP TEST #1 190 200 245 275 230 FORELIMB GRIP TEST #2 310 200 245 240 270 HINDLIMB GRIP TEST #1 270 180 280 310 135 HINDLIMB GRIP TEST #2 170 235 215 220 195 LANDING FOOT SPLAY #1 8.7 6.1 6.0 6.7 5.7 LANDING FOOT SPLAY #2 6.8 7.7 5.8 6.6 6.7 BODY WEIGHT (G) 308 346 347 295 310 VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY, a. Localized alopecia: both forepaws and forelimbs (2.0 cm x 0.5 cm). 16-3 W V& LZO-m PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C38 (PAGE 4): FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - FEMALE RATS DOSAGE GROUP IV 250 MG/KG/DAY RAT # 17677 17678 17682 17683 17691 HOME CAGE BEHAVIOR 12 2 12 ALTERATIONS (HOME CAGE) 111 11 REACTION TO REMOVAL 11 1 11 REACTION TO HANDLING 11 1 11 REARS IN OPEN FIELD 9 8 12 6 10 DEFECATION IN OPEN FIELD 1 1 1 1 1 URINATION IN OPEN FIELD 11 1 11 LEVEL OF AROUSAL 33 3 33 ALTERATIONS (OPEN FIELD) 1 1 1 1 1 GAIT PATTERN 111 11 GAIT ABNORMALITY, SEVERITY 1 1 1 1 1 PALPEBRAL CLOSURE 11 1 11 PROMINENCE OF THE EYE 111 11 LACRIMATION 111 11 SALIVATION 111 11 PILOERECTION 0 0 0 00 ABNORMAL RESPIRATION 000 00 APPEARANCE 1 1 1 la 1 VISUAL REACTION 222 22 TACTILE REACTION 22 2 22 AUDITORY REACTION 333 33 TAIL-PINCH REACTION 222 22 VISUAL PLACING RESPONSE 11 1 11 AIR RIGHTING RESPONSE 111 11 PUPIL RESPONSE TO LIGHT 111 11 FORELIMB GRIP TEST #1 405 200 455 350 455 FORELIMB GRIP TEST #2 330 190 410 290 495 HINDLIMB GRIP TEST #1 210 365 510 190 225 HINDLIMB GRIP TEST #2 345 360 535 270 280 LANDING FOOT SPLAY #1 5.5 6.3 6.2 7.6 6.5 LANDING FOOT SPLAY #2 6.8 7.4 5.2 8.6 7.6 BODY WEIGHT (G) 316 340 337 296 280 VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY. a. Localized alopecia: right forelimb (1.5 cm x 1.0 cm), right inguinal area (6.0 cm x 2.0 cm) and right hindlimb (2.0 cm x 2.0 cm). 16"3 aOV<T-L0"8It7 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C3 9 (PAGE 1) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY RAT NUMBER 17662 17672 17673 17674 DAY 86 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 70 70 78 84 56 84 40 51 25 77 14 50 42 76 47 5 75 29 76 64 37 77 7 74 40 60 38 75 44 58 46 44 28 63 34 61 797 1102 90 71 92 90 47 85 26 103 92 91 91 93 27 98 8 72 1 78 4 79 3 90 8 74 12 78 80 62 56 70 41 75 71 104 62 48 811 1461 TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A. 5 MINUTE PERIOD. 17680 74 60 77 70 42 77 75 60 51 57 94 75 61 47 43 61 83 67 1179 418-027-.PAGE C-93 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C3 9 (PAGE 2) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE 'GROUP I 0 (VEHICLE) MG/KG/DAY RAT NUMBER 17662 17672 17673 17674 DAY 86 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 179 172 135 58 16 9 55 89 158 146 38 7 42 63 95 114 28 47 1451 180 172 157 69 105 97 119 10 50 126 113 12 9 137 115 112 77 82 96 1946 139 231 113 193 27 146 20 164 105 159 75 113 30 118 7 108 0 90 2 83 1 92 17 91 9 116 95 65 68 105 26 78 67 146 62 44 863 2142 TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 17680 222 244 187 148 112 138 117 124 75 83 133 115 111 91 82 96 122 102 2302 418-027:PAGE C-94 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C39 (PAGE 3): MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP II 10 MG/KG/DAY RAT NUMBER 17665 17666 17668 17671 DAY 86 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 66 75 75 76 85 72 83 73 69 87 84 71 96 17 74 63 76 37 20 74 71 60 1 92 108 68 1 69 74 57 2 78 56 61 77 68 76 71 80 51 45 62 42 63 2 27 65 70 28 4 54 51 14 33 3 68 74 58 2 64 83 65 2 68 12 16 0 73 7 3 57 59 1042 873 722 1231 TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 418-027:PAGE C-95 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C39 (PAGE 4) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP II 10 MG/KG/DAY RAT NUMBER 17665 17666 17668 17671 DAY 86 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 194 176 194 151 91 104 125 101 99 128 63 0 21 5 89 77 7 6 1631 220 138 90 20 54 104 116 81 100 122 117 37 2 44 61 120 15 1 1442 156 163 13 9 70 17 0 0 0 129 93 34 73 77 2 0 0 0 64 1017 163 126 126 174 164 96 99 155 148 88 202 187 82 142 126 111 155 151 2495 TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 418-027:PAGE C-96 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C39 (PAGE 5): MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP III 50 MG/KG/DAY RAT NUMBER 17661 17667 17669 17670 DAY 86 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 81 78 75 68 60 66 64 84 61 64 59 61 52 68 67 65 60 1192 57 74 85 43 81 13 73 2 15 9 0 76 74 62 65 43 81 6 60 33 70 15 25 5 93 4 31 3 54 3 72 4 73 2 12 711 626 58 73 13 0 45 66 81 53 54 63 44 19 46 63 67 60 62 58 925 TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A. 5 MINUTE PERIOD. 17676 86 78 89 82 100 56 79 46 2 45 70 61 56 66 80 31 73 64 1164 418-027:PAGE C-97 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C39 (PAGE 6): MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP III 50 MG/KG/DAY RAT NUMBER 17661 17667 17669 17670 DAY 86 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 242 190 17 9 140 193 96 122 134 136 82 127 99 107 75 98 12 9 113 116 2378 251 177 116 67 17 0 86 144 154 67 118 27 10 1 2 1 3 2 1243 196 231 54 128 12 10 00 8 39 104 123 121 126 45 79 3 66 23 114 10 68 2 25 1 70 86 102 117 114 89 97 94 114 5 77 970 1583 TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 17676 182 159 104 107 129 62 99 36 1 35 90 73 96 81 107 27 109 81 1578 418-027:PAGE C-98 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C39 (PAGE 7): MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP IV 250 MG/KG/DAY RAT NUMBER 17677 17678 17682 17683 DAY 86 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 88 49 91 55 88 64 80 48 51 76 50 88 31 87 9 61 3 68 27 74 79 79 78 4 74 1 44 3 60 5 61 5 50 81 62 919 1026 59 76 57 105 69 77 80 96 80 98 73 79 82 69 77 73 12 52 0 68 21 63 90 43 67 55 11 65 0 77 14 53 2 73 6 54 800 1276 TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A. 5 MINUTE PERIOD. 17691 91 86 87 53 69 42 48 71 71 72 71 76 50 53 72 62 62 48 1184 66"0 H9V<T-LZ;0"8I17 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C3 9 (PAGE 8) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP IV 250 MG/KG/DAY RAT NUMBER 17 677 17678 17682 17683 DAY 86 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 160 133 98 73 53 126 114 100 78 72 102 121 0 0 3 2 4 85 1324 186 150 118 104 118 71 44 6 0 36 138 105 93 40 131 83 67 97 1587 225 155 122 142 112 92 128 107 10 0 15 109 117 10 0 13 2 3 1362 166 204 182 157 163 109 120 112 135 88 114 101 77 86 119 82 104 96 2215 TOTAL = SUM OF BLOCKS 1 EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD. 17691 156 129 103 74 91 48 75 80 89 109 80 138 57 77 72 69 85 51 1583 418-027:PAGE C-100 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C40 (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 NN N NUMBER OF LIVE PUPS AT COMPLETION OF DAY POSTPARTUM 15 MF MF DOSAGE GROUP I VEHICLE 0 (VEHICLE) MG/KG/DAY 17662 17672 17673 17674 17680 17681 17690 17694 17695 17703 17713 17715 17716 17717 17719 23 23 23 23 23 23 23 22 22 22 23 23 23 22 23 14 16 13 18 17 16 18 16(1) 15 20 (1) 14 13 14 13 18 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 14 16 13 18 17 16 18 16 15 21 14 13 14 13 18 86 10 6 58 12 6 89 97 99 10 5 96 8 11 68 85 86 58 99 86 10 6 58 12 6 89 97 99 10 5 96 8 11 68 85 86 58 99 DOSAGE GROUP II LOW DOSAGE 10 MG/KG/DAY 17663 17665 17666 17668 17671 17675 17679 17684 17688 17698 17702 17704 17707 17708 17710 NOT PREGNANT 23 22 23 22 23 23 22 22 22 22 23 23 22 23 15 14 16 13 18 9 16 14 16 15 19 15 16 19 0 15 0 14 0 16 0 13 0 18 09 0 16 0 14 0 16 0 15 0 19 0 15 0 16 0 19 87 4 10 79 58 12 6 45 97 95 97 87 13 6 69 97 13 6 87 4 10 79 58 12 6 45 97 95 96 87 13 6 69 97 12 6 M = MALE F = FEMALE ( ) = NUMBER OF PUPS DYING PRIOR TO WEIGHING ON DAY 1 POSTPARTUM. TOTAL IMPLANTATIONS N 15 17 15 18 18 18 20 18 15 22 15 15 14 13 18 15 15 16 14 18 10 16 17 17 15 20 16 17 20 418-027:PAGE C-101 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C40 (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 NUMBER OF LIVE PUPS AT COMPLETION OF DAY POSTPARTUM 15 MF MF DOSAGE GROUP III MIDDLE DOSAGE 50 MG/KG/DAY 17661 17667 17669 17670 17676 17687 17693 17697 17700 17701 17705 17706 17709 17718 17720 23 23 23 23 23 23 23 23 22 23 23 23 23 22 22 15 0 15 13 0 13 16 0 16 16 0 16 15 0 15 15 0 15 15 2 17 15 0 15 14 0 14 14 0 14 16 2 18 15 0 15 16 0 16 16 0 16 16 0 16 10 5 76 2 14 6 10 11 4 87 87 96 10 4 4 10 79 10 5 79 11 5 88 10 5 76 2 14 6 10 11 4 87 86 96 10 4 4 10 79 10 4 79 11 5 88 DOSAGE GROUP IV HIGH DOSAGE 250 MG/KG/DAY 17664 17677 17678 17682 17683 17685 17686 17689 17691 17692 17696 17699 17711 17712 17714 NOT PREGNANT; 23 23 22 23 23 NOT PREGNANT 23 23 23 23 23 23 23 23 MATING NOT CONFIRMED 4 (4) 0 7 [3] 12 0 12 14 0 14 16 0 16 16 1 17 17 0 18 [1] 12 0 12 14 2 16 13 2 15 14 0 14 12 1 13 13 0 13 16 0 16 -- 57 68 10 6 3 13 12 5 48 77 49 86 57 85 5 11 -- 57 68 10 6 2 13 12 5 48 77 -- 76 -- 85 5 10 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 16 15 17 16 15 16 17 16 16 19 18 16 16 18 16 13 15 15 16 17 18 13 16 17 16 15 16 17 418-027:PAGE C-102 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C41 (PAGE 1) : PUP BODY WEIGHT LITTER AVERAGES FROM BIRTH TO DAY 5 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION LITTERS RAT/ LITTER NUMBER DAY 1 M FT DAY 5 MFT MATERNAL DOSAGE GROUP I VEHICLE 0 (VEHICLE) MG/KG/DAY 17662 17672 17673 17674 17680 17681 17690 17694 17695 17703 17713 17715 17716 17717 17719 7.0 6.5 6.8 11.1 10.2 10.7 6.4 6.2 6.4 10.9 9.7 10.4 6.5 5.9 6.1 8.7 8.5 8.6 6.7 6.5 6.6 9.2 8.7 9.0 7.5 6.8 7.1 11.4 10.5 10.9 6.1 5.8 6.0 9.8 9.5 9.6 6.3 6.1 6.2 9.8 9.5 9.6 6.2 5.7 6.0 10.0 9.2 9.8 5.9 5.7 5.8 9.3 9.1 9.2 5.5 5.2 5.4 8.7 7.9 8.2 6.5 6.4 6.4 10.1 10.0 10.0 8.1 8.5 8.3 11.8 12.4 12.0 7.2 6.8 7.0 9.4 9.1 9.3 6.3 6.0 6.1 8.8 8.8 8.8 6.2 6.0 6.1 8.3 8.4 8.4 MATERNAL DOSAGE GROUP II LOW DOSAGE 10 MG/KG/DAY 17663 17665 17666 17668 17671 17675 17679 17684 17688 17698 17702 17704 17707 17708 17710 NOT PREGNANT 7.1 6.9 7.0 6.3 5.9 6.0 6.2 5.9 6.0 6.5 6.4 6.4 6.0 5.9 6.0 7.3 7.1 7.2 6.8 6.6 6.7 6.0 5.7 5.9 6.3 6.4 6.3 6.2 5.7 6.0 6.0 6.2 6.0 6.0 5.9 6.0 6.2 5.9 6.0 6.6 6.2 6.5 10.4 10.0 10.4 9.5 9.1 12.1 10.6 10.6 10.6 9.8 9.0 10.2 10.4 10.5 10.0 9.4 9.4 9.3 8.6 12.0 10.0 10.4 10.1 9.0 9.4 10.2 9.6 9.8 10.2 9.5 9.8 9.4 8.9 12.0 10.3 10.5 10.4 9.5 9.1 10.2 10.0 10.3 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. 0I-O 3DV<m 0"8lt/ PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVE LOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C41 (PAGE 2) : PUP BODY WEIGHT LITTER AVERAGES FROM BIRTH TO DAY 5 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION LITTERS RAT/ LITTER NUMBER DAY 1 M FT DAY 5 MFT MATERNAL DOSAGE GROUP III MIDDLE DOSAGE 50 MG/KG/DAY 17661 17667 17669 17670 17676 17687 17693 17697 17700 17701 17705 17706 17709 17718 17720 6.7 6.1 6.5 9.8 8.6 9.4 7.1 6.9 7.0 10.8 10.2 10.5 6.8 5.9 6.0 10.4 9.0 9.2 7.0 6.8 6.8 9.5 9.1 9.2 6.3 6.2 6.3 9.3 8.9 9.2 6.8 6.4 6.6 12.0 11.8 11.9 6.4 6.3 6.4 10.0 9.6 9.8 6.5 6.2 6.4 10.0 9.3 9.7 6.6 6.2 6.5 11.2 10.7 11.1 7.1 6.8 6.9 11.0 9.9 10.2 7.1 6.4 6.7 10.8 9.0 9.8 7.1 6.6 6.9 11.9 11.5 11.8 6.0 5.6 5.7 9.0 8.5 8.7 6.5 6.2 6.4 9.6 9.8 9.7 6.3 6.2 6.3 10.1 10.7 10.4 MATERNAL DOSAGE GROUP IV HIGH DOSAGE 250 MG/KG/DAY 17664 17677 17678 17682 17683 17685 17686 17689 17691 17692 17696 17699 17711 17712 17714 NOT PREGNANT; MATING NOT CONFIRMED NO ,SURVIVING PUPS ON DAY 1 OF LACTATION 7.0 6.5 6.7 10.9 10.4 10.6 6.8 6.8 6.8 11.5 11.2 11.3 6.2 6.1 6.2 7.7 7.2 7.5 5.5 5.4 5.4 7.4 7.7 7.7 NOT PREGNANT 5.8 5.8 5.8 9.2 9.2 9.2 7.2 7.0 7.0 9.8 9.6 9.7 5.7 5.5 5.6 8.1 8.0 8.1 4.8 4.5 4.6 NO ,SURVIVING PUPS ON DAY 2 OF LACTATION 5.8 5.5 5.7 9.0 8.8 8.9 4.9 4.5 4.7 NO SURVIVING PUPS ON DAY 2 OF LACTATION 6.5 6.0 6.3 11.0 9.9 10.5 7.0 6.1 6.4 10.5 9.2 9.6 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. 418-027:PAGE C-104 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C42 (PAGE 1): PUP BODY WEIGHTS FROM BIRTH TO DAY 5 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 VEHICLE 0 (VEHICLE) MG/KG/DAY POSTPARTUM DAY 1 17662 17672 17673 17674 17680 17681 17690 17694 17695 17703 17713 17715 17716 17717 17719 6.8 7.3 7.3 7.5 7.1 7.0 6.5 6.9 6.6 5.3 6.5 6.7 6.5 7.2 6.6 6.2 6.7 6.9 6.0 6.1 6.5 6.8 6.0 6.3 6.5 7.0 6.1 6.4 5.9 5.6 6.6 6.7 6.7 6.2 6.2 6.1 6.2 6.6 6.2 5.8 5.6 6.0 4.9 6.0 5.8 6.8 7.0 6.2 7.0 6.7 7.0 7.4 7.2 7.0 6.7 7.1 6.6 6.5 6.4 5.8 6.6 7.0 7.3 7.4 7.9 7.4 7.6 7.6 7.6 7.0 6.0 6.6 7.0 6.5 7.6 6.9 7.5 6.6 5.9 5.9 6.6 6.0 5.3 6.5 5.6 6.2 6.6 5.9 5.7 6.0 5.9 6.1 5.7 5.7 6.8 5.0 6.3 7.0 6.1 6.4 5.9 6.7 6.4 5.7 6.2 5.7 5.9 5.9 7.0 5.6 6.3 6.3 6.5 6.4 5.7 6.1 6.0 6.2 6.4 6.5 6.0 6.5 6.2 5.5 5.6 5.2 5.8 FD 1 5.9 6.0 6.2 6.0 5.6 6.1 5.6 5.7 5.7 5.9 5.8 5.2 5.7 5.8 5.7 5.7 5.8 5.6 5.7 5.4 5.2 5.7 5.1 MD 1 MS 5.8 4.7 5.5 5.3 5.5 5.0 5.4 5.1 5.5 5.3 4.6 6.6 6.6 6.5 6.8 6.3 6.3 6.1 6.7 6.3 6.3 6.1 6.2 6.9 6.2 7.0 9.0 8.0 7.1 8.9 7.3 8.9 8.8 8.4 9.0 8.5 8.6 8.0 7.4 7.1 7.1 7.2 7.3 7.3 6.9 7.3 6.9 6.8 6.6 6.1 7.3 6.8 6.0 6.2 6.5 6.5 6.1 5.3 5.9 5.9 6.4 5.8 6.4 6.4 6.0 6.3 6.3 6.6 6.0 6.8 5.2 5.7 6.6 6.2 5.5 5.9 6.2 6.6 5.6 6.2 6.1 5.9 6.1 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. 418-027:PAGE C-105 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C42 (PAGE 2): PUP BODY WEIGHTS FROM BIRTH TO DAY 5 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 II LOW DOSAGE 10 MG/KG/DAY POSTPARTUM DAY 1 17663 17665 17666 17668 17671 17675 17679 17684 17688 17698 17702 17704 17707 17708 17710 NOT PREGNANT 7.1 6.9 7.3 7.4 6.7 6.7 7.1 7.3 6.9 6.8 6.8 6.9 7.3 6.7 6.7 6.3 6.4 6.3 6.2 5.6 5.9 6.2 6.1 5.5 5.9 6.1 6.0 5.9 5.9 6.2 6.5 6.3 6.4 5.6 6.3 6.4 5.8 5.9 5.8 6.0 5.6 5.7 6.1 6.0 6.0 6.8 6.5 6.0 6.9 6.3 6.4 6.2 6.6 6.5 6.3 6.2 6.5 6.5 6.1 6.3 5.4 6.2 6.1 6.6 6.5 5.8 6.0 5.5 6.1 5.7 6.2 5.9 5.5 6.1 5.9 6.0 7.4 7.3 7.2 7.4 7.4 6.8 6.9 7.6 6.9 6.7 6.5 6.6 7.1 7.2 6.9 6.8 7.0 6.7 7.0 6.7 6.4 6.2 6.5 6.3 6.9 6.3 6.0 6.1 6.1 6.2 6.4 6.4 5.0 5.3 5.7 5.9 5.7 5.3 5.8 7.0 6.2 6.0 3.8 6.6 7.5 6.6 7.0 5.8 6.2 6.2 6.6 6.4 6.6 6.9 6.0 6.0 6.0 6.1 6.5 6.4 6.0 6.2 6.5 5.5 6.2 5.4 5.6 5.9 6.2 5.1 6.3 5.7 5.8 4.9 6.5 6.6 6.3 5.5 6.0 6.8 5.1 6.4 5.7 6.1 6.1 6.3 6.3 6.1 6.2 6.6 6.4 5.8 6.0 6.1 5.3 6.1 5.5 6.1 5.3 5.8 6.2 5.9 6.3 6.0 6.1 6.1 6.2 5.9 5.6 6.6 6.5 6.3 6.4 5.8 6.2 5.4 6.0 5.7 5.9 6.2 6.7 6.7 7.2 6.6 6.9 6.6 6.3 7.1 5.7 6.3 6.3 6.9 7.0 6.7 6.1 6.3 6.1 6.3 5.6 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. 418-027:PAGE C-106 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C42 (PAGE 3): PUP BODY WEIGHTS FROM BIRTH TO DAY 5 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 # 17661 17667 17669 17670 17676 17687 17693 17697 17700 17701 17705 17706 17709 17718 17720 MATERNAL DOSAGE GROUP III MIDDLE DOSAGE 50 MG/KG/DAY POSTPARTUM DAY 1 6.5 6.8 6.6 6.4 6.7 6.7 6.8 6.3 7.6 7.0 6.0 6.4 5.2 6.1 6.6 6.9 6.8 6.5 8.7 6.5 7.5 6.9 6.5 5.6 7.8 6.7 6.4 8.3 6.6 7.1 5.7 5.6 5.4 6.1 6.1 6.0 6.1 6.1 6.2 6.1 6.1 5.5 6.2 5.9 6.9 6.2 7.1 7.5 6.6 7.4 6.7 7.5 6.8 7.4 6.1 6.9 5.1 6.9 7.0 7.1 6.6 6.5 6.6 5.8 5.0 6.7 6.2 6.0 6.7 6.8 6.4 6.0 6.4 6.2 6.1 6.6 6.8 6.5 6.0 6.9 7.0 7.2 7.2 6.2 6.7 6.1 6.7 6.5 6.0 6.5 5.5 6.4 6.4 6.8 6.6 6.9 6.5 6.1 6.8 MS 6.3 6.3 6.6 6.1 6.0 6.1 FS 6.7 6.7 6.5 6.5 6.7 6.7 6.1 6.6 6.2 5.7 6.5 6.4 5.3 6.5 6.8 6.2 6.9 7.0 6.5 6.6 6.9 5.8 7.0 6.8 6.1 6.2 6.2 6.0 6.4 7.2 6.7 7.5 7.0 7.3 6.5 6.7 6.7 6.7 7.0 6.7 7.3 6.6 6.3 6.7 7.1 6.8 6.9 7.3 7.4 7.4 MS 6.4 7.1 6.7 6.4 6.7 6.5 4.6 6.4 6.6 FS 7.3 7.4 7.4 6.9 7.3 6.7 6.9 7.1 6.6 7.6 6.6 6.6 6.6 6.4 6.7 5.9 5.8 5.8 5.7 6.4 6.0 6.1 6.0 5.1 5.6 5.6 5.5 5.8 5.5 5.8 5.2 7.1 6.6 6.1 6.1 6.0 7.0 6.7 6.6 6.1 6.5 6.5 6.1 5.9 6.1 6.6 6.5 6.0 6.5 4.4 6.5 6.9 6.9 6.4 6.7 6.5 6.0 6.9 6.1 6.3 5.7 6.6 5.8 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 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C42 (PAGE 4): PUP BODY WEIGHTS FROM BIRTH TO DAY 5 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 IV HIGH DOSAGE 250 MG/KG/DAY POSTPARTUM DAY 1 17664 17677 17678 17682 17683 17685 17686 17689 17691 17692 17696 17699 17711 17712 17714 NOT PREGNANT; MATING NOT CONFIRMED MD 1 UU UU FD 1 FD 1 FD 1 UU 6.9 7.4 7.0 7.0 6.5 6.9 6.2 6.7 5.8 6.1 7.1 6.7 6.9 6.5 7.1 6.7 6.9 6.5 6.8 7.1 6.6 7.2 6.7 6.1 6.9 6.6 6.8 5.7 6.8 6.0 6.3 6.0 6.2 6.1 6.1 6.3 6.3 6.6 5.6 6.0 5.9 6.2 5.4 5.2 6.0 4.9 5.6 5.4 5.6 5.3 5.2 5.5 5.4 5.4 5.4 5.1 5.9 5.1 FS NOT PREGNANT 5.6 5.8 6.0 5.6 6.2 5.7 5.7 6.0 5.2 6.0 5.5 5.7 5.5 6.0 5.7 5.7 5.9 UU 7.1 7.8 6.6 7.3 6.9 7.4 6.4 7.1 6.5 6.9 7.4 7.3 6.0 5.4 5.4 5.6 5.3 6.7 5.7 MS MS 5.7 5.5 5.7 5.5 5.2 5.2 5.9 4.5 5.0 5.1 4.8 4.6 4.7 4.5 4.1 4.1 4.6 5.2 4.1 4.6 FS FS 5.8 5.5 6.2 5.5 5.4 6.2 5.4 6.5 5.4 5.2 5.8 5.4 5.5 5.6 5.0 4.9 4.8 4.9 4.8 MS 4.5 4.7 4.3 4.5 4.5 4.4 4.8 6.1 6.5 6.3 6.8 6.6 6.8 6.3 6.5 5.9 6.4 5.8 6.1 5.8 7.0 6.8 7.0 7.3 7.0 6.0 6.1 6.2 6.3 5.6 6.4 6.7 5.8 5.6 6.6 6.0 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. 418-027'.PAGE C-108 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C42 (PAGE 5): PUP BODY WEIGHTS FROM BIRTH TO DAY 5 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 VEHICLE 0 (VEHICLE) MG/KG/DAY POSTPARTUM DAY 5 17562 17672 17673 17674 17680 17681 17690 17694 17695 17703 11.6 11.1 10.2 10.5 11.7 11.1 11.2 11.7 11.6 8.2 10.2 10.5 10.3 10.4 9.8 10.8 11.2 11.0 11.6 10.5 10.5 11.1 11.6 10.6 9.0 9.1 9.7 10.0 10.6 9.7 8.4 7.7 8.8 9.0 9.8 8.2 9.3 8.9 8.8 8.7 8.0 8.4 8.0 9.3 9.7 8.1 9.8 8.7 9.5 9.5 8.8 9.8 9.7 8.2 9.6 8.6 8.4 8.8 9.0 8.7 8.6 11.8 11.6 10.8 11.9 11.7 10.8 11.4 11.0 10.8 10.9 10.6 11.4 9.7 10.1 11.7 9.7 10.0 10.1 10.6 9.7 9.2 10.9 9.1 9.1 11.0 8.2 9.4 9.0 9.6 9.9 9.9 9.6 9.2 10.7 10.2 10.5 10.5 7.0 10.5 9.2 10.2 9.5 10.9 9.2 9.3 9.4 9.4 9.3 9.2 9.6 9.0 10.9 10.5 9.9 10.4 10.0 9.5 8.6 10.1 11.0 9.5 10.5 9.7 8.4 9.0 8.5 FD 1 9.7 8.9 9.7 9.0 9.4 9.1 9.0 9.5 9.2 9.0 8.9 9.5 8.9 8.7 9.8 8.7 9.3 9.3 8.3 9.1 8.4 8.5 8.2 MD 1 MS 7.9 7.0 7.5 7.8 9.2 8.3 8.1 8.8 6.7 8.2 17713 17715 17716 17717 17719 10.1 10.4 9.5 9.3 10.9 10.4 10.0 9.8 9.6 10.6 10.1 10.0 10.2 9.5 12.2 11.1 10.8 12.4 12.5 12.7 12.2 10.4 12.6 12.3 12.6 12.3 12.3 9.6 9.9 9.7 8.5 9.7 8.9 9.6 9.4 8.2 9.5 9.4 10.0 8.4 9.2 8.6 7.6 9.9 9.2 8.9 8.6 8.6 8.5 9.0 9.5 8.3 8.9 9.3 9.2 8.6 6.7 7.9 6.6 9.0 9.8 7.0 9.7 7.8 8.6 7.5 8.8 8.3 8.8 8.0 9.4 8.8 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. 418-027:PAGE C-109 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C42 (PAGE 6): PUP BODY WEIGHTS FROM BIRTH TO DAY 5 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 II LOW DOSAGE 10 MG/KG/DAY POSTPARTUM DAY 5 17663 17665 17666 17668 17671 17675 17679 17684 17688 17698 17702 17704 17707 17708 17710 NOT PREGNANT 10.7 10.9 10.4 10.2 9.4 9.7 11.0 10.5 10.3 9.4 9.5 9.1 9.1 9.7 8.1 12.5 11.8 12.2 10.2 11.6 10.2 11.2 7.3 10.5 10.5 10.5 10.5 10.4 10.3 10.0 7.6 9.2 9.1 11.1 8.3 10.4 10.4 11.5 10.6 10.9 10.5 9.0 10.4 10.5 10.6 9.7 9.7 11.9 9.7 10.9 11.6 9.4 9.0 10.1 10.1 10.3 10.1 9.1 10.8 9.9 8.1 12.8 10.3 11.4 10.9 9.2 10.3 11.1 10.9 10.3 11.0 9.6 9.2 9.4 9.2 12.1 11.4 11.7 10.6 9.2 9.3 10.1 10.5 11.3 10.2 9.1 10.1 8.7 9.1 11.6 10.5 11.4 11.1 10.3 10.0 9.3 10.2 9.6 9.9 9.4 9.8 9.5 10.1 11.4 10.7 9.7 11.0 10.0 9.8 10.5 10.1 10.6 10.8 9.1 9.6 9.5 8.7 12.1 10.8 11.4 8.3 10.4 9.2 10.8 9.0 10.5 10.3 9.3 9.5 9.0 9.5 9.7 10.8 10.1 8.6 8.8 9.3 8.5 10.2 10.4 10.7 9.7 9.6 9.6 11.1 9.9 9.8 9.4 7.9 10.5 9.9 11.4 10.0 8.9 9.2 9.5 8.4 9.3 10.6 10.7 8.2 9.1 11.1 10.6 11.3 9.7 9.8 9.3 9.2 7.8 10.2 10.4 10.7 8.4 8.0 9.1 9.9 MM 2 9.6 8.8 9.2 9.0 9.8 10.4 9.2 9.2 8.5 10.7 9.3 10.3 9.2 9.5 8.9 9.7 10.1 9.2 10.7 10.3 9.2 10.3 9.3 8.7 10.0 FD 2 10.0 9.7 10.2 8.5 8.6 9.0 8.9 8.5 10.4 9.4 9.1 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. 418-027'.PAGE C-110 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C42 (PAGE 7) : PUP BODY WEIGHTS FROM BIRTH TO DAY 5 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 III MIDDLE DOSAGE 50 MG/KG/DAY POSTPARTUM DAY 5 17661 17667 17669 17670 17676 17687 17693 17697 17700 17701 17705 17706 17709 17718 17720 9.8 9.7 10.4 9.5 9.3 12.7 10.4 9.9 11.2 10.6 11.5 12.3 9.6 8.3 11.3 9.4 10.6 10.5 9.9 9.8 11.2 10.3 9.8 11.7 10.5 9.9 12.3 9.5 10.7 11.4 10.0 11.8 8.5 9.8 10.0 11.7 9.6 9.9 9.7 11.3 12.2 12.1 8.5 10.1 10.5 9.7 10.0 7.6 10.3 9.2 12.5 10.6 10.2 10.8 11.8 11.6 12.4 9.0 9.9 5.7 10.8 9.8 9.2 9.0 9.8 12.4 10.1 10.1 12.5 10.4 9.2 11.2 8.3 9.7 10.9 10.1 13.6 9.0 8.6 9.8 11.7 10.3 9.7 12.6 11.0 10.3 10.9 8.6 9.4 10.4 9.6 10.2 8.6 8.8 8.6 12.0 9.0 9.8 10.9 8.7 11.2 12.7 9.5 9.9 9.4 10.3 9.7 9.8 9.6 7.9 11.6 10.1 10.3 11.8 10.2 MS 12.8 8.6 10.5 11.4 9.4 12.0 9.3 9.2 9.2 12.1 9.3 9.9 10.5 10.6 9.2 11.3 8.3 10.6 10.7 9.3 7.8 9.0 9.8 9.6 11.7 MS 10.0 10.4 10.8 8.1 11.4 7.8 9.6 9.5 9.7 10.0 9.5 9.8 9.1 12.5 8.8 9.2 11.1 10.3 9.5 12.0 9.2 7.1 10.2 9.1 12.2 8.2 9.5 9.6 11.7 9.6 9.2 11.1 9.5 10.1 11.0 9.3 10.3 11.0 7.9 9.3 9.5 8.3 9.0 11.5 9.7 9.5 10.9 9.5 9.4 11.3 8.2 10.1 11.3 7.6 9.6 7.5 9.1 11.3 9.9 10.5 9.8 8.4 7.1 11.6 7.8 9.0 11.0 8.7 9.6 9.2 7.8 11.7 10.1 7.5 8.2 9.2 FM 3 9.7 FD 5 8.4 9.9 11.7 10.6 8.6 9.5 10.1 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. ui-O H O vd'-m m tr PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C42 (PAGE 8): PUP BODY WEIGHTS FROM BIRTH TO DAY 5 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 IV HIGH DOSAGE 250 MG/KG/DAY POSTPARTUM DAY 5 17664 17677 17678 17682 17683 17685 17686 17689 17691 17692 17696 17699 17711 17712 17714 NOT PREGNANT; MATING NOT CONFIRMED MD 1 UU UU FD 1 FD 1 FD 1 UU 11.0 10.5 11.2 10.7 11.3 10.5 9.4 10.3 10.4 11.4 9.8 11.0 11.7 11.6 11.9 11.4 11.4 10.8 11.0 11.9 11.5 10.6 11.4 11.4 10.9 10.5 8.4 8.5 7.7 7.3 7.7 8.2 7.0 7.3 7.0 7.5 7.6 7.2 7.3 7.1 7.3 6.9 7.2 7.6 MM 2 7.9 6.8 7.1 8.2 8.7 7.3 7.5 6.8 8.2 7.9 8.2 8.1 7.5 FS NOT PREGNANT 9.1 8.9 8.9 9.2 9.5 9.4 9.9 9.3 8.6 8.5 9.8 9.3 9.0 9.1 9.3 9.2 9.5 UU 9.9 9.3 9.4 10.8 10.3 10.2 10.0 10.2 9.5 8.6 8.2 10.1 8.1 7.9 8.1 8.8 7.8 7.8 8.5 MS MS 8.1 8.0 8.6 8.2 8.0 8.1 7.2 MD 2 MD 2 MD 2 MD 2 FD 2 FD 2 FD 2 FD 2 FD 2 FM 2 FM 2 FM 2 FM 2 FS FS 8.9 9.0 8.4 8.9 9.0 8.9 10.0 MM 2 8.7 9.0 9.2 8.8 8.4 8.6 MD 2 MD 2 MD 2 MD 2 MM 2 MS FD 2 FD 2 FD 2 FD 2 FD 2 FD 2 FD 2 11.4 10.9 10.6 11.5 10.8 10.1 10.8 11.6 9.4 9.8 11.0 9.7 9.4 10.7 9.9 10.3 10.8 11.0 8.4 8.7 9.3 9.0 9.7 9.8 9.5 8.7 9.4 9.6 FM 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. ni-oaovd: 10-811/ PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C43 (PAGE 1): PUP VITAL STATUS AND SEX FROM BIRTH TO DAY 5 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 I VEHICLE 0 (VEHICLE) MG/KG/DAY 17662 17672 17673 17674 17680 17681 17690 17694 17695 17703 17713 17715 17716 17717 17719 MA MA MA MA MA MA MA MA FA FA FA FA FA FA MA MA MA MA MA MA MA MA MA MA FA FA FA FA FA FA MA MA MA MA MA FA FA FA FA FA FA FA FA M A MA M A M A MA M A MA MA MA MA MA MA FA FA FA FA FA FA M A M A M A M A MA MA M A M A FA FA FA FA FA FA FA FA FA MA MA MA MA MA MA MA MA MA FA FA FA FA FA FA FA M A M A MA MA MA 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 M A M A F A F A F A F A F A FD 1 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 MD 1 M S F A 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 FA FA FA FA FA FA FA FA MA MA MA MA MA MA MA MA FA FA FA FA FA MA MA MA MA MA MA MA MA FA FA FA FA FA FA MA MA MA MA MA FA FA FA FA FA FA FA FA M A M A M A MA M A MA M A M A M A FA FA FA 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. Il-3 3DVd^0-8ll7 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE RE PRODUCTION/DEVE LOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C43 (PAGE 2): PUP VITAL STATUS AND SEX FROM BIRTH TO DAY 5 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 II LOW DOSAGE 10 MG/KG/DAY 17663 17665 17666 17668 17671 17675 17679 17684 17688 17698 17702 17704 17707 17708 17710 NOT PREGNANT MA MA MA MA MA MA MA MA FA FA FA FA FA FA FA MA MA MA M A FA FA FA FA FA FA FA FA FA FA MA MA MA M A MA MA MA FA FA FA FA FA FA FA FA FA MA MA MA M A MA FA FA FA FA FA FA FA FA M A M A M A M A M A MA M A M A M A M A M A M A F A F A FA FA FA F A MA MA MA MA FA FA FA FA FA MA MA MA MA MA MA MA MA MA FA FA FA FA FA FA FA MA MA MA MA MA MA MA MA MA FA FA FA FA FA 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 FD 2 MA MA MA MA MA MA MA MA FA FA FA FA FA FA FA M A M A M A M A M A MA M A MA MA M A M A M A M A FA FA FA FA FA MA M A MA MA MA MA FA FA FA FA FA FA FA FA FA MA M A MA M A 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 M A M A M A M A M A MM 2 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. n 1-3 30Vd- 10-8117 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C43 (PAGE 3): PUP VITAL STATUS AND SEX FROM BIRTH TO DAY 5 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 I I I MIDDLE DOSAGE 50 MG/KG/DAY 17661 17667 17669 17670 17676 17687 17693 17697 17700 17701 17705 17706 17709 17718 17720 MA MA MA MA MA MA MA MA MA MA FA FA FA FA FA MA MA MA MA MA MA MA FA FA FA FA FA FA MA M A FA FA FA FA FA FA FA FA FA FA FA FA FA FA MA MA MA MA MA MA FA FA FA FA FA FA FA FA FA FA MA MA MA MA MA MA MA MA MA MA MA FA FA FA FA MA MA MA MA MA MA MA MA 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 M S F A F A F A F A F A FM 3 MA MA MA MA MA MA MA MA MA FA FA FA FA FA FA MA MA MA MA MA MA MA MA MA MA FA FA FA FA MA MA MA MA FA FA FA FA FA FA FA FA FA FA MA MA MA MA MA MA MA M S FA FA 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 FD 5 MA MA MA MA MA MA MA FA FA FA FA FA FA FA FA FA MA MA MA MA MA MA MA MA MA MA MA FA FA FA FA FA MA MA MA MA MA MA MA MA FA FA 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. SU -D W D Y& LZQ -m PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C43 (PAGE 4) : PUP VITAL STATUS AND SEX FROM BIRTH TO DAY 5 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 IV HIGH DOSAGE 250 MG/KG/DAY 17664 NOT PREGNANT; MATING NOT1 CONFIRMED 17677 MD 1 U U U U FD 1 FD 1 FD 1 U U 17678 M A M A M A M A M A F A F A F A F A F A F A F A 17682 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 17683 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 17685 M A M A MM 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 F A F S 17686 NOT PREGNANT 17689 M A M A 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 U U 17691 M A M A M A M A F A F A F A F A F A F A F A F A 17692 M A M A M A M A M A M A M A M S M S M A F A F A F A F A F A F A 17696 MD 2 MD 2 MD 2 MD 2 FD 2 FD 2 FD 2 FD 2 FD 2 FM 2 FM 2 FM 2 FM 2 F S F S 17699 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 17711 MD 2 MD 2 MD 2 MD 2 MM 2 M S FD 2 FD 2 FD 2 FD 2 FD 2 FD 2 FD 2 17712 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 17714 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 FM 2 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 aOV<R0"8ll7 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C44 (PAGE 1) : CLINICAL OBSERVATIONS FROM BIRTH TO DAY 5 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) LITTER NUMBER DAY(S) POSTPARTUM OBSERVATIONS a I 0 (VEHICLE) 17690 1- 2 1/18 PUPS: HEAD, BRUISE (DID NOT EXCEED 0.8 CM X 0.3 CM) II 10 17688 1- 4 1/14 PUPS: BACK, BRUISE (DID NOT EXCEED 0.5 CM X 1.0 CM) 1- 2 1/14 PUPS: LOWER MIDLINE, BRUISE (DID NOT EXCEED 1.5 CM X 2.0 CM) ; PALE. 3- 5 1/14 PUPS: LOWER MIDLINE, BRUISE (DID NOT EXCEED 1.5 CM X 1.0 CM) . III 50 17720 1- 2 1/16 PUPS: NECK, BRUISE (DID NOT EXCEED 2.0 CM X 2.5 CM) IV 250 17683 1- 4 1/16 PUPS: BACK, BRUISE (DID NOT EXCEED 2.0 CM X 1.5 CM) 17685 1 2- 3 1/16 PUPS: CHEST AND NECK, BRUISE (1.0 CM IN DIAMETER). 1/15 PUPS: CHEST AND NECK, BRUISE (1.0 CM IN DIAMETER). 17696 1 2/15 PUPS: MOUTH,, BRUISE (0.2 CM X 0.1 CM). 17699 4 2/13 PUPS: COLD TO TOUCH; NOT NESTING OR NURSING. a. Tabulation restricted to adverse observations; all other pups appeared normal. PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C45 (PAGE 1) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - FI GENERATION PUPS MATERNAL DOSAGE GROUP .MATERNAL DOSAGE (MG/KG/DAY) LITTER NUMBER DAY POSTPARTUM OBSERVATIONS a I 0 (VEHICLE) 17662 17672 17673 17674 17680 17681 17690 5 14 PUPS APPEARED NORMAL. 5 16 PUPS APPEARED NORMAL. 5 13 PUPS APPEARED NORMAL. 5 18 PUPS APPEARED NORMAL. 5 17 PUPS APPEARED NORMAL. 5 16 PUPS APPEARED NORMAL. 5 18 PUPS APPEARED NORMAL. 17694 1 1 PUP FOUND DEAD. ALL TISSUES APPEARED NORMAL. 5 15 PUPS APPEARED NORMAL. 17695 5 15 PUPS APPEARED NORMAL. 17703 1 1 PUP STILLBORN. ALL TISSUES APPEARED NORMAL. 1 PUP FOUND DEAD. NO MILK IN STOMACH. 5 19 PUPS APPEARED NORMAL. 17713 17715 17716 17717 17719 5 14 PUPS APPEARED NORMAL. 5 13 PUPS APPEARED NORMAL. 5 14 PUPS APPEARED NORMAL. 5 13 PUPS APPEARED NORMAL. 5 18 PUPS APPEARED NORMAL. a. Complete necropsies were not performed on pups in which autolysis or cannibalization precluded evaluation. PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C45 (PAGE 2): NECROPSY OBSERVATIONS - INDIVIDUAL DATA - FI GENERATION PUPS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) LITTER NUMBER DAY POSTPARTUM OBSERVATIONS a 17665 17666 17668 17671 17675 17679 17684 17688 5 15 PUPS APPEARED NORMAL. 5 14 PUPS APPEARED NORMAL. 5 16 PUPS APPEARED NORMAL. 5 13 PUPS APPEARED NORMAL. 5 18 PUPS APPEARED NORMAL. 5 9 PUPS APPEARED NORMAL. 5 16 PUPS APPEARED NORMAL. 5 14 PUPS APPEARED NORMAL. 17698 2 1 PUP FOUND DEAD. AUTOLYSIS PRECLUDED FURTHER EVALUATION. 5 15 PUPS APPEARED NORMAL. 17702 5 15 PUPS APPEARED NORMAL. 17704 5 1 PUP KIDNEYS: BILATERAL, PELVIS, SLIGHT DILATION ALL OTHER TISSUES APPEARED NORMAL. 18 PUPS APPEARED NORMAL. 17707 17708 17710 5 15 PUPS APPEARED NORMAL. 5 16 PUPS APPEARED NORMAL. 5 18 PUPS APPEARED NORMAL. a. Complete necropsies were not performed on pups in which autolysis or cannibalization precluded evaluation. 6II"0 39V d:0"8117 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C4 5 (PAGE 3) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - FI GENERATION PUPS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) LITTER NUMBER DAY POSTPARTUM OBSERVATIONS a III 17661 5 15 PUPS APPEARED NORMAL. 17667 5 13 PUPS APPEARED NORMAL. 17669 5 16 PUPS APPEARED NORMAL. 17670 5 16 PUPS APPEARED NORMAL. 17676 5 15 PUPS APPEARED NORMAL. 17687 5 15 PUPS APPEARED NORMAL. 17693 1 2 PUPS STILLBORN. ALL TISSUES APPEARED NORMAL. 5 14 PUPS APPEARED NORMAL. 17697 17700 17701 5 15 PUPS APPEARED NORMAL. 5 14 PUPS APPEARED NORMAL. 5 14 PUPS APPEARED NORMAL. 17705 1 2 PUPS STILLBORN. ALL TISSUES APPEARED NORMAL. 5 16 PUPS APPEARED NORMAL. 17706 5 1 PUP FOUND DEAD. AUTOLYSIS PRECLUDED FURTHER EVALUATION. 14 PUPS APPEARED NORMAL. 17709 17718 17720 5 16 PUPS APPEARED NORMAL. 5 16 PUPS APPEARED NORMAL. 5 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. 418-027:PAGE C-120 PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7599) TABLE C45 (PAGE 4): NECROPSY OBSERVATIONS - INDIVIDUAL DATA - FI GENERATION PUPS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) LITTER NUMBER DAY POSTPARTUM OBSERVATIONS a 17677 1 1 PUP: FOUND DEAD. NO MILK IN STOMACH. ALL TISSUES APPEARED NORMAL. 1 PUP: FOUND DEAD. ALL TISSUES APPEARED NORMAL. 2 PUPS: FOUND DEAD. NO MILK IN STOMACH. AUTOLYSIS PRECLUDED FURTHER EVALUATION. 17678 17682 17683 5 12 PUPS: APPEARED NORMAL. 5 14 PUPS: APPEARED NORMAL. 5 16 PUPS: APPEARED NORMAL. 17685 1 1 PUP: STILLBORN. ALL TISSUES APPEARED NORMAL. 5 15 PUPS: APPEARED NORMAL. 17689 17691 5 17 PUPS: APPEARED NORMAL. 5 12 PUPS: APPEARED NORMAL. 17692 1 2 PUPS: STILLBORN. ALL TISSUES APPEARED NORMAL. 5 14 PUPS: APPEARED NORMAL. 17696 1 2 PUPS: STILLBORN. AUTOLYSIS PRECLUDED FURTHER EVALUATION. 2 3 PUPS: FOUND DEAD. AUTOLYSIS PRECLUDED FURTHER EVALUATION. 6 PUPS: FOUND DEAD. CANNIBALIZATION PRECLUDED FURTHER EVALUATION. 17699 5 13 PUPS: APPEARED NORMAL. 17711 1 1 PUP: STILLBORN. AUTOLYSIS PRECLUDED FURTHER EVALUATION. 2 11 PUPS: FOUND DEAD. AUTOLYSIS PRECLUDED FURTHER EVALUATION. 17712 17714 5 13 PUPS: APPEARED NORMAL. 5 15 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. 418-027 :PAGEC-121 APPENDIX D PROTOCOL AND AMENDMENTS 418-027'.PAGE D -l 90S Sheehy Drive, Bldg. A Horsham, PA 19044 Telephone: (215) 442-0710 Telefax: (215)443-8587 ARGUS RESEARCH Charles River Laboratories Discovery and Development Services PROTOCOL 418-027 SPONSOR'S STUDY NUMBER: T-7599 STUDY TITLE: Oral (Gavage) Combined Repeated Dose Toxicity Study of T 7599.7 with the Reproduction/Developmental Toxicity Screening Test PURPOSE: The purpose of this study is to provide information on the possible health hazards that may result from repeated exposure 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 28 days (male rats) or through parturition until day 4 or 5 of lactation (female rats). This repeated dose study incorporates a reproduction/developmental toxicity screening test that can be used to provide initial information on possible effects on male and female reproductive performance (e.g., gonadal function, mating behavior, conception, development of the conceptus and parturition). The study also places emphasis on neurological effects as a specific endpoint and should identify the neurotoxic potential of a test substance, which may warrant further in-depth investigation. Because of the selectivity of the endpoints and the short duration of the study, the screening test will not provide evidence for definitive claims of no reproduction/developmental effects. In particular, it offers only limited means of detecting postnatal manifestations of prenatal exposure or effects that may be induced during postnatal exposure. TESTING FACILITY: Argus Research 905 Sheehy Drive, Building A Horsham, Pennsylvania 19044-1297 Telephone: (215) 443-8710 Telefax: (215)443-8587 STUDY DIRECTOR: Raymond G. York, Ph.D., DABT Associate Director of Research Address as cited above for Testing Facility. Email: raymond.york@criver.com SPONSOR: 3M Corporate Toxicology 3M Center, Building 220-2E-02 St. Paul, Minnesota 55144-1000 418-027:PAGE D-2 Protocol 418-027 Page 2 STUDY MONITOR: Paul H. Lieder, PhD., DABT 3M Corporate Toxicology 3M Medical Department Telephone: (651) 737-2678 Telefax: (651) 733-1773 Email: phliederl @mmm.com REGULATORY CITATIONS: 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. 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 Standardfor Safety Studies on Drugs, MHW Ordinance Number 21, March 26, 1997. REGULATORY COMPLIANCE: This study will be conducted in compliance with the Good Laboratory Practice (GLP) regulations cited above with the exception of analysis ofblood and liver samples sent to Southern Research Institute for metabolite analysis. All changes or revisions of this protocol shall be documented, signed by the Study Director and the Sponsor, dated and maintained with the protocol. The Testing Facility's Quality Assurance Unit (QAU) will audit the protocol, the raw data and the report, and will inspect critical phases of those portions of the study conducted at the Testing Facility in accordance with the Standard Operating Procedures of the Testing Facility. The final report will include a compliance statement signed by the Study Director that the report accurately reflects the raw data obtained during the performance of the study and that all applicable GLP regulations were followed in the conduct of the study. Should significant deviations from GLP regulations occur, each will be described in detail, together with how the deviation might affect the quality or integrity of the study. 418-027 :PAGE D-3 Protocol 418-027 Page 3 Should any portion of the study be conducted by a subcontractor or by the Sponsor, the Study Director will ensure that a qualified Principal Investigator is identified by the facility conducting that portion of the study. The QAU for that facility will conduct critical phase inspections and audit respective results and reports for that study portion according to the SOPs of that facility. Such critical phase inspection reports and report audits will be submitted by that facility to the Principal Investigator and the Study Director. The dates of the inspections and report submissions will be incorporated into a QAU Statement generated by that facility and provided to the Testing Facility for inclusion in the final report. In addition, that facility will provide a statement of GLP compliance, as described above, signed by the Principal Investigator for inclusion in the final report. SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE: See ATTACHMENT 1 to the protocol. TEST SUBSTANCE AND VEHICLE: Identification: Test Substance: T 7599.7. Lot identification to be documented in the raw data. The Sponsor will provide to the Testing Facility documentation or certification of the identity, composition, method of synthesis, strength and activity/purity of the test substance. This documentation will be included in the final report. Vehicle: Aqueous 0.5% carboxymethylcellulose (CMC) (medium viscosity) prepared using reverse osmosis membrane processed deionized water (R.O. deionized water). Lot identification to be documented in the raw data. Neither the Sponsor nor the Study Director is aware of any potential contaminants likely to be present in the vehicle that would interfere with the results of this study. Therefore, no analyses other than those mentioned in this protocol will be conducted. Safety Precautions: Gloves, dust-mist/HEPA-filtered mask, appropriate eye protection and uniform/lab coat to be worn during formulation preparation and dosage. The Material Safety Data Sheet (MSDS) will be included in the raw data. Storage: 418-027:PAGE D-4 Protocol 418-027 Page 4 Bulk Test Substance: Bulk Vehicle Components: Prepared Test Substance and Vehicle Formulations: Room temperature, protected from light. Room temperature. Room temperature, protected from light. All test substance shipments to the Testing Facility should be addressed to the attention of Julian Gulbinski, Manager of Formulation Laboratory, at the previously cited address and telephone number. Shipments should include information concerning storage conditions and shipping cartons should be labeled appropriately. The recipient should be notified in advance of shipment. FORMULATION: Frequency of Preparation: Formulations (suspensions) will be prepared weekly at the Testing Facility. Detailed preparation procedures are attached to this protocol (ATTACHMENT 2). Adjustment for Purity: The test substance will be considered 100% pure for the purpose of dosage calculations. Testing Facility Reserve Samples: The Testing Facility will reserve a sample (approximately 1 g) of each lot of bulk test substance and bulk vehicle components used during the course of the study. Samples will be stored under the previously cited conditions. ANALYSES: Results of required analyses will be provided to the Testing Facility for inclusion in the study report. Samples additional to those described below may be taken if deemed necessary during the course of the study. Additional analyses, if required, will be documented by protocol amendment. Bulk Test Substance Sampling: 418-027:PAGED-5 Protocol 418-027 Page 5 A sample (approximately 1 g) of the test substance will be taken on the last day of treatment and sent (ambient conditions, protected from light) to the Sponsor for analysis. This sample will be sent to: Principal Investigator: Gregory S. Gorman, Ph.D. Staff Chemist Bioanalytical Chemistry Group Southern Research Institute 2000 Ninth Avenue South Birmingham, Alabama 35255-5305 Telephone: (205) 581-2725 Telefax: (205) 581-2044 Email: gorman@sri.org The recipient will be notified in advance of sample shipment. Analyses of Prepared Formulations: Concentration and Homogeneity: Concentration and homogeneity of the prepared formulations will be verified during the course of this study. Quadruplicate samples (2 mL each) will be taken from the top, middle and bottom of each concentration on the first day of preparation. Two samples from each quadruplicate set will be shipped for analysis; the remaining samples will be retained at the Testing Facility as backup samples. Quadruplicate samples will be taken from each concentration on the last day of preparation. Two samples from each quadruplicate set will be shipped for analysis; the remaining samples will be retained as backup samples. Backup samples will be stored under the previously cited conditions and discarded at the Testing Facility upon the request of the Sponsor. Stability: Stability of the prepared formulations will be documented during this study. Two sets of duplicate samples (2 mL each) from each concentration will be taken on the first day of preparation. One sample of each duplicate set will be shipped on the day of preparation. These samples will be analyzed at the following time points: as soon after preparation as possible and ten days after the first analysis. The remaining samples will be retained at the Testing Facility as backup samples. Backup samples will be stored under the previously cited conditions and discarded at the Testing Facility upon the request of the Sponsor. Shipping Instructions: 418-027:PAGE D-6 Protocol 418-027 Page 6 Samples to be analyzed will be shipped (ambient conditions) to: Gregory S. Gorman, Ph.D. Staff Chemist Bioanalytical Chemistry Group Southern Research Institute 2000 Ninth Avenue South Birmingham, Alabama 35255-5305 Telephone: (205) 581-2725 Telefax: (205) 581-2044 Email: gorman@sri.org The recipient will be notified in advance of sample shipment. DISPOSITION: Prepared formulations will be discarded at the Testing Facility. All remaining bulk test substance will be returned to the Sponsor at the previously cited address. TEST SYSTEM: Species/Strain and Reason for Selection: The Crl:CD(SD)IGS BR VAF/Plus rat was selected as the Test System because: 1) it is one mammalian species accepted for use in toxicity studies and it has been widely used throughout industry; 2) this strain of rat has been demonstrated to be sensitive to reproductive and developmental toxins; and 3) historical data and experience exist at the Testing Facility*1'3) Number: Initial population acclimated: Population selected for study: 70 male and 70 virgin female rats. 60 male and 60 virgin female rats (15 per sex per dosage group). Body Weight and Age: Male rats will be ordered to weigh from 300 g to 325 g each at receipt, at which time they will be expected to be at least 60 days of age. Female rats will be ordered to weigh from 200 g to 225 g each at receipt, at which time they will be expected to be at least 60 days of age. Actual body weights will be recorded the day after receipt and will be documented in the raw data. The weight ranges will be included in the final report. At study initiation, the weight variation of the rats will not exceed 20% of the mean weight of each sex. Sex: 418-027:PAGED-7 Protocol 418-027 Page 7 Both male and female rats will be evaluated. Source: Charles River Laboratories, Inc. The rats will be shipped in filtered cartons by air freight and/or truck from Charles River Laboratories, Inc., to the Testing Facility. Identification: Rats are permanently identified using Monel self-piercing ear tags (Gey Band and Tag Co., Inc., No. MSPT 20101). Male and female rats are assigned temporary numbers at receipt and given unique permanent identification numbers when assigned to the study before administration of the first dosage. Pups will not be individually identified during lactation; all parameters will be evaluated in terms of the litter. ANIMAL HUSBANDRY: All cage sizes and housing conditions are in compliance with the Guidefor the Care and Use of Laboratory Animals^. Housing: Fo generation rats will be individually housed in stainless steel, wire-bottomed cages, except during the cohabitation and postpartum periods. During cohabitation, each pair of rats will be housed in the male rat's cage. Beginning no later than day 20 of presumed gestation, Fo generation female rats will be individually housed in nesting boxes. Each dam and delivered litter will be housed in a common nesting box during the postpartum period. Nesting Material: Nesting material (bed-o'cobs) will be provided. Bedding will be changed as often as necessary to keep the animals dry and clean. Analyses for possible contamination are conducted semi-annually and documented in the raw data. Room Air. Temperature and Humidity: The animal room is independently supplied with at least ten changes per hour of 100% fresh air that has been passed through 99.97% HEPA filters. Room temperature will be maintained at 66F to 77F (19C to 25C) and monitored constantly. Room humidity will also be monitored constantly and maintained at 30% to 70%. Light: 418-027:PAGED-8 Protocol 418-027 Page 8 An automatically controlled 12-hour light: 12-hour dark fluorescent light cycle will be maintained. Each dark period will begin at 1900 hours EST. The light cycle may be adjusted by the Study Director or designee if deemed necessary to accommodate scheduled laboratory activities. Any such adjustment will be documented in the raw data. Diet: Rats will be given Certified Rodent Diet #5002 (PMI Nutrition International), available ad libitum from individual feeders except during fasting. Water: Water will be available ad libitum from individual bottles attached to the cages or from an automatic watering access system. All water will be from a local source and passed through a reverse osmosis membrane before use. Chlorine will be added to the processed water as a bacteriostat; processed water is expected to contain no more than 1.2 ppm chlorine at the time of analysis. Water is analyzed monthly for possible bacterial contamination and twice annually for possible chemical contamination. Contaminants: Neither the Sponsor nor the Study Director is aware of any potential contaminants likely to be present in the certified diet, in the drinking water or in the nesting materials at levels that would interfere with the results of this study. Therefore, no analyses other than those routinely performed by the feed supplier or those mentioned in this protocol will be conducted. DAY NUMBERING SYSTEM: Gestation day 0 is defined as the day spermatozoa are observed in a smear of the vaginal contents and/or a copulatory plug observed in situ. The day of birth is designated lactation day 0 (postpartum day 0) in the Health Effects Test Guidelines - Reproduction and Fertility Effects (Office 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 protocol, the day of birth will be designated day 1postpartum (day 1 of lactation) and all subsequent ages of the FI generation rats and days of the lactation period will be determined and cited accordingly. RANDOMIZATION AND COHABITATION: 418-027:PAGE D-9 Protocol 418-027 Page 9 Upon arrival, rats will be assigned to individual housing on the basis of computer-generated random units. After an acclimation period of at least five days, male and female rats will be selected for study on the basis of physical appearance and body weights recorded during acclimation. The rats will be assigned to dosage groups based on computer-generated (weight-ordered) randomization procedures. Within each dosage group, consecutive order will be used to assign rats to cohabitation, one male rat per female rat. The cohabitation period will consist of a maximum of 14 days. Female rats with spermatozoa observed in a smear of the vaginal contents and/or a copulatory plug observed in situ will be considered to be at day 0 of presumed gestation and assigned to individual housing. Female rats not mated within the first seven days of cohabitation will be assigned alternate male rats that have mated (same dosage group) and will remain in cohabitation for a maximum of seven additional days. Day 1 of lactation (postpartum) is defined as the day of birth and is also the first day on which all pups in a litter are individually weighed (pup body weights will be recorded after all pups in a litter are delivered and groomed by the dam). Within each dosage group, consecutive order will be used to assign the first five male and the first five female rats to a functional observational battery (FOB) and motor activity assessment. The next five rats per sex in each group will be assigned to hematology and clinical biochemistry evaluations. The last five rats per sex in each group will be assigned to metabolite analysis. Histological evaluations will be performed on the last ten rats per sex in each group. ADMINISTRATION: Route and Reason for Choice: The oral (gavage) route was selected for use because: 1) in comparison with the dietary route, the exact dosage can be accurately administered; and 2) it is one possible route of human exposure. Method and Frequency: Dosages will be adjusted daily for body weight changes and given at approximately the same time each day. Male rats will be given the test substance and/or the vehicle once daily beginning 14 days before cohabitation (maximum 14 days) and continuing until sacrifice, after completion of the cohabitation period, after a minimum of 28 days of dosage. 418-027 :PAGE D-10 Protocol 418-027 Page 10 Female rats will be given the test substance and/or the vehicle once daily beginning 14 days before cohabitation (maximum 14 days) and continuing until the day before scheduled sacrifice on day 6 of lactation. Pups will not be directly given the test substance or the vehicle but may be possibly exposed to the test substance during maternal gestation (in utero exposure) or via maternal milk during the lactation period. Rationale for Dosage Selection: Dosages will be selected by the Sponsor based on previous studies conducted with the test substance, taking into account possible differences in sensitivity between pregnant and nonpregnant rats. The highest dosage will be expected to cause toxic effects but not mortality or obvious suffering. The descending sequence of the lower dosage levels will be selected for the purpose of demonstrating any dosage-related response, with no adverse effects expected at the lowest level. Dosage Levels. Concentrations and Volumes: Dosage Group Number Of Rats Per Sex Dosage Concentration (mg/kg/day) (mg/mL) Dosage Volume (mL/kg) Argus Batch Number I 15 0 (Vehicle) 0 10 B-418-027-A(Day.Month.Year) II 15 10 1 10 B-418-027-B(Day.Month.Year) III 15 50 5 10 B-418-027-C(Day.Month.Year) IV 15 250 25 10 B-418-027-D(Day.Month.Year) The test substance will be considered 100% pure for the purpose of dosage calculations. TESTS. ANALYSES AND MEASUREMENTS - Fo GENERATION: Viability - Male and Female Rats: All Periods: At least twice daily. Clinical Observations and/or General Appearance - Male and Female Rats: Acclimation Period: Weekly. Dosage Period: 418-027'.PAGE D -l 1 Protocol 418-027 Page 11 Daily before dosage. On the first day of dosage, postdosage observations will be recorded at approximately hourly intervals after administration for the first four hours and at the end of the normal working day. Postdosage observations for subsequent days of dosage will be recorded at intervals determined appropriate by the Study Director and/or Study Monitor after determination of the onset of peak pharmacologic/toxicologic effects. Postdosage Period: Before sacrifice. Maternal Behavior: Days 1 and 5 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. Detailed Clinical Observations - Male and Female Rats: Once before the first dosage and at least once weekly thereafter, detailed clinical observations will be conducted for all male and female rats. These observations will be made outside the cage in a standard arena at the same time each day of conduct. Effort will be made to ensure that variations in the test conditions are minimal and that observations are conducted by observers unaware of treatment groups. Signs noted should include, but not be limited to: changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions and autonomic activity (e.g., lacrimation, piloerection, pupil size, unusual respiratory pattern). Changes in gait, posture 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) should also be recorded. Body Weights - Male and Female Rats: Acclimation Period: Weekly. Dosage Period: Daily. Sacrifice: Terminal weight. Feed Consumption Values - Male Rats (recorded and tabulated): Dosage Period: Weekly. Feed left recorded on the day before sacrifice. Rats will be fasted overnight before sacrifice. Feed Consumption Values - Female Rats (recorded and tabulated): 418-027:PAGE D-12 Protocol 418-027 Page 12 Dosage Period: Weekly to cohabitation. Days 0, 7, 10, 12,15, 18,20 and 25 (if necessary) of presumed gestation and days 1 and 5 postpartum. Feed left will be recorded on the day before sacrifice. Rats will be fasted overnight before sacrifice. Feed Consumption Values - Male and Female Rats: Feed consumption values may be recorded more frequently than cited above if it is necessary to replenish the feed. During cohabitation, when two rats occupy the same cage with one feed jar, replenishment of the feed j ars will be documented. Individual values will not be recorded or tabulated. Estrous Cycling and Mating: Estrous cycling will be evaluated by examination of vaginal cytology beginning with the day after the first administration and then until spermatozoa are observed in a smear of the vaginal contents and/or a copulatory plug is observed in situ during the cohabitation period. Natural Delivery: Female rats will be evaluated for: Adverse Clinical Signs Observed During Parturition. Duration of Gestation (day 0 of presumed gestation to the time the first pup is observed). Litter Size (defined as all pups delivered). Pup Viability at Birth. Functional Observational Battery: On one occasion during the course of the study, a functional observational battery (FOB)i5_8)will be conducted on five male and five female rats per group. For male rats, this assessment will be conducted shortly before scheduled sacrifice. Female rats should be tested during the lactation period, shortly before scheduled sacrifice. To avoid hyperthermia of pups, dams will be separated from their litters for no longer than 30 to 40 minutes. The FOB, to be conducted by an observer unaware of the group assignment of the rat, will assess the following parameters: 418-027'.PAGE D-13 Protocol 418-027 Page 13 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, visual placing response 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. Evidence of the ability of this battery to detect the effects of positive control substances will be provided (Testing Facility Positive Control Data). Data will also be provided to document interobserver reliability if more than one observer is involved in the testing. Motor Activity Test: Motor activity will be evaluated on five male and five female rats per group once during the course of the study. For male rats, this assessment will be conducted shortly before scheduled sacrifice. Female rats should be tested during the lactation period, shortly before scheduled sacrifice. The movements of each rat will be monitored by a passive infrared sensor mounted outside a stainless steel, wire-bottomed cage (40.6 x 25.4 x 17.8 cm). Each test session will be 1.5 hours in duration with the number of movements and time spent in movement tabulated at each five-minute interval. The apparatus will monitor a rack of up to 32 cages and sensors during each session, with each rat tested in the same iocation on the rack across test sessions. Groups will be counterbalanced across testing sessions and cages. Data will be provided to demonstrate that the test system is capable of detecting increases in activity produced by positive control substances (Testing Facility Positive Control Data). HEMATOLOGY ANP CLINICAL CHEMISTRY: 418-027:PAGE D -14 Protocol 418-027 Page 14 At scheduled sacrifice, the five male and five female rats per group assigned to hematology and clinical chemistry sample collection will be exsanguinated from the inferior vena cava following sacrifice by carbon dioxide asphyxiation. Rats will be fasted overnight before sacrifice. Approximately 5 mL of blood (fasted) will be collected and processed as described below. Determinations additional to those described below may be conducted if the known properties of the test substance may, or are suspected to, affect related metabolic profiles (e.g., calcium, phosphate, fasting triglycerides and fasting glucose, specific hormones, and cholinesterase). The tubes containing the samples will be labeled with the protocol number, Sponsor study number, animal number, group number, dosage level, day of study, collection interval, date of collection, species, generation and storage conditions. Hematology: Approximately 1 mL ofblood will be 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) Leukocyte Count, Total (WBC) Leukocyte Count, Differential Platelet Count (PLAT) Mean Platelet Volume (MPV) Cell Morphology Two blood smear slides will be prepared at the Testing Facility for each sample for measurements of differential leukocyte count. All samples (on wet ice) and slides (ambient conditions) will be shipped on the day of collection to Redfield Laboratories at the following address. Approximately 1.8 mL ofblood will be added to a tube containing 0.2 mL of sodium citrate (0.129 M). The contents will be mixed and maintained on wet ice until the tubes are centrifuged (within 30 minutes of the collection time). The resulting plasma will be transferred to a transport tube and immediately frozen. Plasma samples will be maintained on dry ice or in a freezer (<_70C) until shipped on dry ice to Redfield Laboratories at the following address, for measurement of prothrombin time (PT) and activated partial thromboplastin time (APTT). Clinical Chemistry: 418-027:PAGE D -15 Protocol 418-027 Page 15 Approximately 2 mL of blood will be collected into serum separator tubes and centrifuged. The resulting sera samples will be immediately frozen on dry ice and maintained frozen (<-70C) until shipment for analysis of the following parameters: Total Protein (TP) Triglycerides (TRI) Albumin (A) Globulin (G) Albumin/Globulin Ratio (A/G) Glucose (GLU) Cholesterol (CHOL) Total Bilirubin (TBILI) Urea Nitrogen (BUN) Creatinine (CREAT) Alanine Aminotransferase (ALT) Aspartate Aminotransferase (AST) Alkaline Phosphatase (ALK) Calcium (CA) Phosphorus (PHOS) Sodium (NA) Potassium (K) Chloride (CL) Samples will be shipped (on dry ice) to arrive on Monday through Friday at Redfield Laboratories at the following address. Shipping Instructions: Samples will be shipped according to the conditions described above to: Principal Investigator: Ms. Phyllis Powell Redfield Laboratories A Division of CRL-DDS 100 East Boone Street P.O. Box 308 Redfield, Arkansas 72132 Telephone: (501) 397-2540 Telefax: (501) 397-2002 The recipient will be notified in advance of sample shipment. URINALYSIS: Urinalysis will not be conducted unless indicated based on expected or observed toxicity of the test substance. METHOD OF SACRIFICE. Fo generation rats will be sacrificed by carbon dioxide asphyxiation. 418-027'.PAGE D-16 Protocol 418-027 Page 16 GROSS NECROPSY AND HISTOPATBOLOGY - Fo GENERATION RATS: Scheduled Sacrifice: Scheduled sacrifice of male rats will be conducted on the day following the last dosage administration, after a minimum of 28 days of dosage. Scheduled sacrifice of female rats will be conducted on day 6 of lactation. Gross necropsy of all male and female rats will include an initial physical examination of external surfaces and all orifices, as well as the cranial, thoracic and abdominal cavities and their contents. Special attention will be paid to the organs of the reproductive system. The number of implantation sites and corpora lutea will be recorded. Male and female rats will be examined for gross lesions. Gross lesions will be retained in neutral buffered 10% formalin and examined histologically. Tissue trimming and histopathology will be performed under the supervision of or by a Board-Certified Veterinary Pathologist. The testes and epididymides of all male rats will be weighed, and the testes, epididymides, seminal vesicles with coagulating gland and prostate will be retained in neutral buffered 10% formalin. The testes will be fixed in Bourn's solution for 48 to 96 hours before being retained in neutral buffered 10% formalin. The ovaries and the uterus with cervix of each female rat will be weighed, and ovaries, uterus, vagina and a mammary gland will be retained in neutral buffered 10% formalin. Uteri of apparently nonpregnant rats will be examined after being pressed between glass plates to confirm the absence of implantation sites, and retained in neutral buffered 10% formalin. Blood samples (approximately 3 mL) will be collected from the five rats per sex per group assigned to metabolite analysis. Blood will be collected from the vena cava. Each sample will be divided into two aliquots. One aliquot of 2 mL will be transferred into an EDTA-coated (purple top) tube and refrigerated. The second aliquot (approximately 1 mL) will be transferred into a serum tube, allowed to clot and spun in a centrifuge. The resulting serum will be transferred into polypropylene tubes labeled with the protocol number, Sponsor study number, animal number, group number, dosage level, day of study, collection interval, date of collection, species, generation and storage conditions. All samples will be immediately frozen on dry ice and maintained frozen (<-70C) until shipment for analysis. The liver will be excised and the organ weight recorded. One lobe (right lateral) will be placed in a conical tube and flash frozen in an ice/alcohol bath. Liver samples will be maintained frozen (<-70C) until shipment for analysis. Shipping Instructions: 418-027'.PAGE D-17 Protocol 418-027 Page 17 Liver and serum samples will be shipped on dry ice and whole blood will be shipped on ice packs. Samples to be analyzed will be shipped to: Principal Investigator: Gregory S. Gorman, Ph.D. Staff Chemist Bioanalytical Chemistry Group Southern Research Institute 200 Ninth Avenue South Birmingham, Alabama 35255-5305 Telephone: (205) 581-2725 Telefax: (205) 581-2044 Email: gorman@sri.org The recipient will be notified in advance of sample shipment. See ATTACHMENT 3 for additional tissues to be weighed and retained from the ten rats per sex per group assigned to histological sample collection and evaluation. All other tissues will be discarded. Scheduled Sacrifice of Female Rats that Do Not Deliver Litters: Rats that do not deliver a litter will be sacrificed on day 25 ofpresumed gestation. Gross necropsy, examination and tissue retention will be conducted as described above for rats at scheduled sacrifice. Dams with No Surviving Pups: Dams with no surviving pups will be sacrificed after the last pup is found dead, missing or presumed cannibalized. Gross necropsy, examination and tissue retention will be conducted as described above for rats at scheduled sacrifice. Rats Found Dead or Moribund: Rats that die or are sacrificed because of moribund condition, abortion or premature delivery will be examined for the cause of death or moribund condition on the day the observation is made. The rats will be examined for gross lesions. Testes and epididymides of male rats will be excised and paired organ weights will be recorded. The epididymides will be retained in neutral buffered 10% formalin. The testes will be fixed in Bouin's solution for 48 to 96 hours and then retained in neutral buffered 10% formalin. Pregnancy status and uterine contents of female rats will be recorded. Aborted fetuses and/or delivered pups will be examined to the extent possible. Uteri of apparently nonpregnant rats will be examined after being pressed between glass plates to confirm the absence of implantation sites. Ovaries and uteri will be retained in neutral buffered 10% formalin. 418-027'.PAGE D-18 Protocol 418-027 Page 18 TESTS. ANALYSES AND MEASUREMENTS - FI GENERATION: Viability: Preweaning Period: Litters will be observed for dead pups at least twice daily. The pups in each litter will be counted once daily. Clinical Observations and/or General Appearance: Preweaning Period: Once daily. 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) and 5 postpartum. Sacrifice: Terminal weight. Feed Consumption Values (recorded and tabulated): Preweaning Period: Not recorded. METHOD OF SACRIFICE - FI GENERATION PUPS: FI generation pups will be sacrificed by carbon dioxide asphyxiation. NECROPSY - FI GENERATION. Gross lesions will be retained in neutral buffered 10% formalin for possible future evaluation. Unless specifically cited below, all other tissues will be discarded. Pups Found Dead on Day 1 Postpartum: Pups that die before examination of the litter for pup viability will be evaluated for vital status at birth. The lungs will be removed and immersed in water. Pups with lungs that sink will be identified as stillborn; pups with lungs that float will be identified as livebom, and to have died shortly after birth. Pups with gross lesions will be preserved in Bouin's solution for possible future evaluation. Pups Found Dead or Moribund on Days 2 to 4 Postpartum: Pups found dead or sacrificed because of moribundity will be examined for gross lesions and for the cause of death or the moribund condition. Pups with gross lesions will be preserved in Bourn's solution for possible future evaluation. 4 1 8 -0 2 7 '.P A G E D -19 Protocol 418-027 Page 19 Scheduled Sacrifice: On day 5 postpartum, pups will be will be sacrificed and examined for gross lesions; gross lesions will be preserved in neutral buffered 10% formalin. Necropsy will include a single crosssection of the head at the level of the frontal-parietal suture and examination of the crosssectioned brain for apparent hydrocephaly. PROPOSED STATISTICAL TESTS: When possible results will be evaluated by appropriate and acceptable statistical methods. Because of the limited dimensions of the study, statistical analysis in the form of tests for significance are of limited value for many endpoints, particularly reproductive and neurological endpoints. Some of the most widely used methods, especially parametric tests for measures of central tendency, are inappropriate. If statistical analyses are to be conducted, the methods selected will be appropriate for the distribution of the variable examined and added to the protocol prior to finalization or by amendment. DATA ACQUISITION. VERIFICATION AND STORAGE: Data generated during the course of this study will be recorded either by hand or using the Argus Automated Data Collection and Management System, the Vivarium Temperature and Relative Humidity Monitoring System, the Coulboum Instruments Passive Infrared Motor Activity System, the Coulboum Instruments Auditory Startle System, the Coulboum Instruments Spatial Delayed Alternation System, and/or the passive avoidance software. All data will be tabulated, summarized and/or statistically analyzed using the Argus Automated Data Collection and Management System, the Vivarium Temperature and Relative Humidity Monitoring System, Microsoft Excel [part of Microsoft; Office 97 (version SR-2)] and/or The SAS System (version 6.12). Records will be reviewed by the Study Director and/or appropriate management personnel within 21 days after generation. All original records will be stored in the archives of the Testing Facility. All original data will be bound and indexed. A copy of all raw data will be supplied to the Sponsor upon request. Preserved tissues will be stored at the Testing Facility at no charge for one year after mailing of the draft final report, after which time the Sponsor will be contacted to determine the disposition of these materials. KEY PERSONNEL: 418-027`.PAGE D-20 Protocol 418-027 Page 20 Executive Director of Research: Mildred S. Christian, Ph.D., Fellow, ATS Director of Research: Alan M. Hoberman, Ph.D., DABT Associate Director of Research and Study Director: Raymond G. York, Ph.D., DABT Director of Operations and Compliance: Barbara J. Patterson, B.A. Director of Laboratory Operations: John F. Barnett, B.S. Director of Study Management: Valerie A. Sharper, M.S. Manager of 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 RECORDS TO BE MAINTAINED : Protocol and Amendments. Test Substance, Vehicle and/or Reagent Receipt, Preparation and Use. Animal Acquisition. Randomization Schedules. Mating History. Treatment (if prescribed by StaffVeterinarian). General Comments. Clinical Observations and/or General Appearance. Body Weights. Feed Consumption Values. Natural Delivery Observations. FOB and Motor Activity Observations. Blood Sample Collection, Processing and Shipment. Gross Necropsy Observations. Organ Weights. Photographs (if required). Study Maintenance (room and environmental records). Feed and Water Analyses. Packing and/or Shipment Lists. FINAL REPORT: Protocol 418-027 Page 21 The Study Director will provide periodic updates of study progress to the Sponsor. Draft summary tables of unaudited computer-recorded data may accompany these updates. Statistical analyses will not be performed on these interim data. A comprehensive draft final report will be prepared on completion of the study and will be finalized following consultation with the Sponsor. The report will include the following: Summary and Conclusion. Experimental Design and Method. Evaluation of 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 of Supporting Data (if appropriate) and QAU Statement. The Sponsor will receive one copy of the draft report and two copies of the final report. Data will be hand- and/or computer-recorded. Records will be reviewed by the Study Director and/or appropriate management personnel within 21 days after generation. All original records will be stored in the archives of the Testing Facility. All original data will be bound and indexed. A copy of all raw data will be supplied to the Sponsor upon request. Preserved tissues will be stored at the Testing Facility at no charge for one year after mailing of the draft final report, after which time the Sponsor will be contacted to determine the disposition of these materials. INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE STATEMENT: The procedures described in this protocol have been reviewed by the Testing Facility's Institutional Animal Care and Use Committee. All procedures described in this protocol that involve study animals will be conducted in amanner to avoid or minimize discomfort, distress or pain to the animals. The Sponsor's signature below documents the fact that information concerning the necessity for conducting this study and the fact that this is not an unnecessarily duplicative study may be obtained from the Sponsor. No alternative (in vitro) procedures were available for meeting the stated purposes of the study. REFERENCES: 418-027:PAGE D-22 Protocol 418-027 Page 22 1. Christian, M.S. and Voytek, P.E. (1982). In Vivo Reproductive and Mutagenicity Tests. Environmental Protection Agency, Washington, D.C. National Technical Information Service, U.S. Department of Commerce, Springfield, VA 22161. 2. Christian, M.S. (1984). Reproductive toxicity and teratology evaluations of naltrexone (Proceedings of Naltrexone Symposium, New York Academy of Sciences, November 7,1983), J. Clin. Psychiat. 45(9):7-10. 3. Lang, P.L. (1988). Embryo and Fetal Developmental Toxicity (Teratology) Control Data in the Charles River Crl:CDBR Rat. Charles River Laboratories, Inc., Wilmington, MA 01887-0630. (Data base provided by Argus Research Laboratories, Inc.) 4. Institute of Laboratory Animal Resources (1996). Guidefor the Care and Use of Laboratory Animals. National Academy Press, Washington, D.C. 5. Haggerty, G.C. (1989). Development of Tier I neurobehavioral testing capabilities for incorporation into pivotal rodent safety assessment studies. J. Amer. Col. Toxicol. 8:5370. 6. Irwin, S. (1968). Comprehensive observational assessment: la. A systemic quantitative procedure for assessing the behavioral and physiologic state of the mouse. Psychopharmacologia (Berlin) 13:222-257. 7. Moser, V.C. (1989). Screening approaches to neurotoxicity: A functional observational battery. J. Amer. Col. Toxicol. 8:85-94. 8. O'Donoghue, J.L. (1989). Screening for neurotoxicity using a neurologically based examination and neuropathology. J. Amer. Col. Toxicol. 8:97-116. PROTOCOL APPROVAL: FOR THE TESTING FACILITY 418-027:PAGE D-23 Protocol 418-027 Page 23 ________ Rebecca Altmann-Reilly, M.S. (j Member, Institutional Animal Care and Use Committee FOR THE SPONSOR __ ___________________________________ Paul H. Lieder, Ph.D., DABT Study Monitor and Sponsor's Representative 15 feb. Date ____ /*? Feb 2-d Date 418-027:PAGE D-24 ATTACHMENT 1 SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE ATTACHMENT 1 STUDY SCHEMATIC 418-027`.PAGE D-25 Protocol 418-027 Page 1 o f3 COMBINED REPEAT DOSE AND REPRODUCTIVE/DEVELOPMENTAL TOXICITY SCREEN3 First Day of Test Substance Dosage Male Rats Premating Last Day o f Test Substance Dosagtf Cohabitation i Last Day o f Test Substance Dosage 2 Weeks 2 Weeks Motor Activity/FOB' Natural Delivery Presumed Postpartum Female Rats Day 5 Day 6 Motor Activity/FOB? I Dosage Period For additional details see ''Tests, Analyses and Measurements" section of the protocol. FOB and motor activity evaluations conducted on five males per group. c. Male rats sacrificed after completion of at least 28 days of dosage; necropsy and retention of male reproductive organs. Hematology and clinical biochemistry samples (five male and five female rats per group) and histological samples (ten male and ten female rats per group) collected. d. Five female rats per group assigned to FOB evaluation on day 5 postpartum and motor activity evaluation on day 6 postpartum. e. Last day of dosage for female rats is day 5 postpartum. Pups sacrificed on day 5 postpartum. Female rats sacrificed on day 6 postpartum; necropsy and retention of female reproductive organs. Hematology, clinical biochemistry and histological samples collected. P* P ATTACHMENT 1 SCHEDULE8 418-027:PAGE D-26 Protocol 418-027 Page 2 o f3 12 FEB 02 18 FEB 02 18 FEB 02- 16 APR 02 19 FEB 02 - 04 MAR 02 04 MAR 02 PM- 11 MAR 02 AM 11 MAR 02 PM- 18 MAR 02 AM 05 MAR 02 18 MAR 02 19 MAR 02 - 22 MAR 02 25 MAR 02 Animal Receipt - Acclimation Begins. Start of Dosage Period - Male Rats (14 days before cohabitation and through a 14-day cohabitation period until the of sacrifice after at least 28 days of dosage). Dosage Period - Female Rats (14 days before cohabitation through Day 4 or Day 5 of lactation). Dosage Period Estrous Cycle Evaluation. Cohabitation Period (Maximum of 14 days). Male 1 (7 days) Male 2 (7 days) First Possible Day 0 of Presumed Gestation. Last Possible Day 0 of Presumed Gestation. FOB and Motor Activity Evaluation - Five Male Rats per Group Scheduled Sacrifice - Male Rats (Earliest possible date). Hematology, Clinical Biochemistry and Histological Sample Collection. a. The start date of the study is the day the Study Director signs the protocol. b. Throughout this schedule, the day of birth is designated day 1 postpartum (day 1 of lactation) and all subsequent ages of the FI generation rats and days of the lactation period will be determined and cited accordingly, as described above the protocol section, "Day Numbering System." ATTACHMENT 1 26 MAR 02 12 APR 02 30 MAR 02 12 APR 02 30 MAR 02- 16 APR 02 30 MAR 02 - 16 APR 02 31 MAR 02- 17 APR 02 31 MAR 02- 17 APR 02 01 AUG 02 418-027'.PAGE D-27 Protocol 418-027 Page 3 of 3 First Possible Delivery (Day 21 of presumed gestation). Last Possible Delivery (Day 25 of presumed gestation). First Possible Day 25 of Presumed Gestation Female Sacrifice. Last Possible Day 25 of Presumed Gestation Female Sacrifice. FOB Evaluation - Five Female Rats per Group. Day 5 Postpartum - Pups Sacrificed. Motor Activity Evaluation - Five Female Rats per Group. Day 6 Postpartum - Sacrifice of Female Rats. Hematology, Clinical Biochemistry and Histological Sample Collection. Draft Final Report 418-027'.PAGE D-28 ATTACHMENT 2 TEST SUBSTANCE PREPARATION PROCEDURE 418-027 :PAGE D-29 ATTACHMENT 2 Protocol 418-027 Version: 418-027(14 FEB 021 Page 1 of 2 TEST SUBSTANCE PREPARATION PROCEDURE Test Substance: T 7559.7 Vehicle: Aqueous 0.5% CMC (medium viscosity) A. Purpose: The purpose of this procedure is to provide a method for the preparation o f dosage suspensions of T 7559.7 fo r oral (gavage) administration to rats on Argus Research Study num ber 418-027. 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_ W eekly _ For_ days of use __ Approximately every ten days __ By Sponsor 3. Suspensions will be administered at a final dosage volume o f 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 R espirator 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 X No (Calculations based on 100%) __ % Activity __% Purity __ Correction Factor 6. Sampling requirements: Cited in protocol 7. Storage: Cited in protocol 418-027:PAGE D-30 ATTACHMENT 2 Protocol 418-027 Version: 418-027(14 FEB 02) Page 2 o f2 TEST SUBSTANCE PREPARATION PROCEDURE NOTE: Prior to test substance preparation accurately m easure the required am ount of the appropriate vehicle (R.O. deionized w ater should be used fo r calibration purposes) in a graduated cylinder, pour the required am ount o f vehicle into a beaker. Carefully mark each beaker at the meniscus. This m ark w ill be used during the preparation to bring the test substance slurry up to volum e. C. Dosage Suspension Preparation: 1. W eigh the required am ount o f test substance on a piece o f weigh paper or into an appropriately sized m ortar (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 sm all am ount 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 vehicle/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 the beaker to bring volum e up to the mark. Place on magnetic stir plate and agitate prior to and during aliquotting, adm inistration and/or sam pling. 5. Repeat steps (1) through (4) fo r each concentration. C larification: ^ No ___ Yes [see attached clarification form ] Initial/Date : cc f 418-027'.PAGE D-31 ATTACHMENT 3 TISSUES TO BE WEIGHED, RETAINED AND EXAMINED HISTOLOGICALLY ATTACHMENT 3 418-027'.PAGE D-32 Protocol 418-027 Page 1 o f2 TISSUES TO WEIGHED AND RETAINED FOR POSSIBLE EXAMINATION FROM TEN RATS PER SEX PER GROUP Ten rats per sex per group not assigned to functional observational battery and motor activity tests will be assigned to histological evaluations. Tissues to be Weighed: The following organs will be excised, trimmed and individually weighed as soon as possible after excision to avoid drying. liver kidneys adrenals thymus testes epididymides spleen brain heart ovaries uterus (with cervix) Tissues to be Retained: The following tissues or representative samples will 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 (submandibular and mediastinal) peripheral nerve (sciatic) gross lesions spinal cord (cervical, thoracic and lumbar) stomach liver kidneys adrenals spleen heart thymus thyroid/parathyroid trachea uterus urinary bladder bone marrow testes* ovaries epididymides uterus seminal vesicles (with coagulating gland) vagina prostate mammary gland (female rats only) Testes will be fixed in Bouin's solution for 48 to 96 hours before being retained in neutral buffered 10% formalin. ATTACHMENT 3 Histological Examination: 418-027:PAGE D-33 Protocol 418-027 Page 2 of 2 Histological examination of retained tissues, including reproductive organs, will be conducted for the assigned ten rats per sex 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 dosage, the same tissues will be examined from the assigned five rats per sex exposed to the lower test substance dosages. Should results warrant examination of the lower dosage groups and conduct of quantitative evaluation, scheduled report date and prices will be adjusted accordingly. 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 The recipient will be notified in advance of sample shipment. 418-027'.PAGE D-34 90S Shechy Drive, BMg. A Horsham, PA 19044 Telephone: (2/5) 443-8710 Telefax: (2IS) 443-8587 ARGUS RESEARCH Charles River Laboratories Discovery and Development Services PROTOCOL 418-027 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST SPONSOR'S STUDY NUMBER: T-7599 Amendment 1-15 March 2002 1. Purpose (page 1 of the protocol): [Effective Date: 1 March 2002] The purpose of this study is to provide information on the possible health hazards that may result from repeated exposure of Cri:CD(SD)IGS BR VAF/Plus male and female rats to a test substance beginning before cohabitation, through mating and continuing for at least 28 days (male rats), or through parturition until day 5, rather than day 4 or 5, of lactation (female rats). Reason for Change: This change corrects the protocol and is consistent with the method and frequency of administration to female rats on page 10 of the protocol. 2. Vehicle (page 3 of the protocol): [Effective Date: 22 February 2002] The vehicle will be aqueous 1.0% carboxymethylcellulose (CMC) (medium viscosity), rather than aqueous 0.5% carboxymethlycellulose. Reason for Change: This change was made because the test substance is precipitating out of suspension during shipment for analysis and cannot be analyzed. Any revisions to this finalized amendment must be made by subsequent amendment. 418-027'.PAGE D-35 Protocol 418-027 Amendment 1 Page 2 3. Safety Precautions (page 3 of the protocol): [Effective Date: 18 February 2002] A half-face respirator will be worn when the bulk test substance is not being used in a chemical fume hood. Reason for Change: This addition was made so that safety precautions are consistent with the MSDS. 4. Storage (page 4 of the protocol): [Effective Date: 18 February 2002] The prepared test substance and vehicle formulations will be stored refrigerated, protected from light, rather than at room temperature, protected from light. Reason for Change: This change was made at the request of the Sponsor based on the stability of the test substance. 5. Analyses (page 4 of the protocol): Additional analyses for concentration and homogeneity and stability will be performed on samples taken from the second test substance preparation using 1.0% carboxymethlycellulose. These samples will be taken and analyzed as described in the protocol. Reason for Change: This change was made to provide an analysis of samples prepared using 1.0% carboxymethylcellulose as the vehicle. 6. Bulk Test Substance Sampling (page 5 of the protocol) [Effective Date: 25 February 2002] The 1 g sample of the test substance taken on the last day of treatment will be sent directly to Southern Research Institute at the address in the protocol, rather than to the Sponsor, for analysis. Reason for Change: This change corrects the protocol to indicate that the sample will be sent to Southern Research Institute, rather than to the Sponsor. A ny revisions to this finalized amendment must be made by subsequent amendment. 418-027 :PAGE D-36 7. Bulk Test Substance Sampling (page 5 of the protocol) Protocol 418-027 Amendment 1 Page 3 [Effective Date: 25 February 2002] A sample (approximately 5 g) of the test substance will be taken and sent (ambient conditions, protected from light) for use in the preparation of analytical standards and for possible spectrophotometric analysis. The sample will be sent to: Principal Investigator, Gregory S. Gorman, Ph.D. Staff Chemist Bioanalytical Chemistry Group Southern Research Institute 2000 Ninth Avenue South Birmingham, Alabama 35255-5305 Telephone: (205) 581-2725 Telefax (205) 581-2044 Email: gorman@sri.org 8. Shipping Instructions (page 6 of the protocol): [Effective Date: 18 February 2002] The samples to be analyzed will be shipped refrigerated, protected from light, rather than at ambient conditions. Reason for Change: This change was made at the request of the Sponsor based on the stability of the test substance. 9. Schedule (Page 2 of Attachment 1 to the protocol): [Effective Date: 25 February 2002] The dosage period for female rats will be 14 days before cohabitation through Day 5 of lactation, rather than through Day 4 or 5 of lactation. Reason for Change: This change corrects the protocol and is consistent with the method and frequency of administration to female rats on page 10 of the protocol. 10. Safety (Page 1 of Attachment 2 to the protocol): [Effective Date: 18 February 2002] There should be an "X" before "Half-Face Respirator if not used in a chemical fume hood" to indicate an additional safety precaution. Any revisions to this f in a liz e d amendment must be made by subsequent amendment. 418-027:PAGE D-37 Reason for Change: Protocol 418-027 Amendment 1 Page 4 This addition was made so that safety precautions are consistent with the MSDS. Alan M. Hoberman, Ph.D., DABT Director of Research Date bnd G. Yo Associate Direct Study Director ABT Date ch __ Rebecca Altmann-Reilly, M.S. (j Member, Institutional Animal Care and Use Committee Date Paul H. Lieder, Ph.D., DABT Study Monitor Sponsor's Representative Date Any revisions to this finalized amendment must be made by subsequent amendment. 418-027:PAGE D-38 90S Shethy Drive, Bldg. A Horsham, PA 19044 Telephone (215) 443-8710 Telefax: (215) 443-8587 ARGUS RESEARCH Charles River Laboratories Discoveryand Development Services PROTOCOL 418-027 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST SPONSOR'S STUDY NUMBER: T-7599 Amendment 2 - 5 September 2002 1. Proposed Statistical Tests (page 19 of the protocol): [Effective Date: 25 June 2002]: Attachment 1 to this amendment describes the proposed statistical methods. Body weight data, feed consumption values and organ weights will be analyzed as described under the Parametric heading of the schematic. Bartlett's Test of Homogeneity of Varianees(9) will be used to estimate the probability that the groups had different variances. A nonsignificant result (p>Q.Q01) will indicate that an assumption of homogeneity of variance is not inappropriate, and the data will be compared using the Analysis of Variance Test(10). If that test is significant (p<0.05), the groups exposed to the test substance will be compared with the control group using Dunnett's Test(11). If Bartlett's Test is significant (p<0.001), the Analysis of Variance Test is not appropriate, and the data will be analyzed as described under the Nonparametric heading of the schematic. When 75% or fewer of the scores in all the groups are tied, the Kruskal-Wallis Test(12) will be used to analyze the data, and in the event of a significant result (p<0.05), Dunn's Test(13) will be used to compare the groups exposed to the test substance with the control group. When more than 75% of the scores in any group are tied, Fisher's Exact Tesr }will be used to compare the proportion of ties in the groups. Data from the motor activity test, with repeated measurements within a session, will be analyzed using an Analysis of Variance with Repeated Measures(l5), as described under that heading in the schematic. A significant effect (p<0.05) in that test can appear as effect of Concentration (a difference between groups in the total across all measurements in a session) or as an interaction between Any revisions to this finalized am endm ent m ust be made by subsequent am endm ent. CM CN 418-027:PAGE D-39 Protocol 418-027 Amendment Page 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 substance will be compared using Dunnett's Test. If the Concentration x Block interaction is significant, an Analysis of Variance Test will be used to evaluate the data at each measurement period, and a significant result (n<0.05) will be followed bv a comparison of the groups using Dunnett's Test. Test items in the FOB having graded or count scores will be analyzed using the procedures described under the Nonparametric heading of the schematic. Clinical observation incidence data will be analyzed as contingency tables using the Variance Test for Homogeneity of the Binomial Distribution16). Alternate or additional statistical evaluations may be performed if deemed necessary or appropriate. Reason for Change: The statistical methods were to be added by amendment. 2. References (page 22 of the protocol): [Effective Date: 25 June 2002J: The following references are added to the protocol. 9. 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. 10. Snedecor, G.W. and Cochran, W.G. (1967). Analysis of Variance. Statistical Methods, 6th Edition, Iowa State University Press, Ames, pp. 258-275.11. Dunnett, C.W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Amer. Stat. Assoc. 50:1096-1121. 11. Dunnett, C.W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Amer. Stat. Assoc. 50:1096-1129- 12. Sokal, R.R. and Rohlf, F.J. (1969). Kruskal-Wallis Test. Biometry, W.H. Freeman and Co., San Francisco, pp. 388-389. Any revisions to this finalized amendment m ust be m ade by subsequent am endm ent. 418-027 :PAGE D-40 Protocol 418-027 Amendment 2 Page 3 13. Dunn, O.J. (1964). Multiple comparisons using rank sums. Technometrics 6(3):241-252. 14. Siegel, S. (1956). Nonparametric Statisticsfor the Behavioral Sciences, McGraw-Hill, New York, pp. 96-105. 15. SAS Institute, Inc. (1988). Repeated measures analysis of 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 of the binomial distribution. Statistical Methods, 6th Edition, Iowa State University Press, Ames, pp. 240-241. Reason for Change: The proposed statistical tests cite these references. 3. Histological Examination (page 2 of Attachment 3 of the protocol): [Effective Date: 4 June 2002]: If lesions attributed to the test substance are observed in the rats exposed to the high test substance dosage, the same tissues will be examined from the assigned ten rats, rather than five rats, per sex exposed to the lower test substance dosages. Reason for Change: This change was made to correct the protocol. The Randomization and cohabitation section of the protocol, page 9, states that histological evaluations will be performed on the last ten rats per sex in each group exposed to the lower test substance dosages. 4. Histological Examination (page 2 of Attachment 3 of the protocol): [Effective Date: 4 June 2002]: Histological evaluations will be performed on the livers of ten male and ten female rats, the thymuses of ten female rats and the stomachs of ten male rats exposed to each of the lower test substance dosages. Any revisions to this finalized am endm ent m ust be m ade by subsequent am endm ent. Reason for Change: 418-027:PAGE D-41 Protocol 418-027 Amendment 2 Page 4 This change was made to clarify that additional histological evaluation w ould be performed because lesions of the livers, thymuses and stomachs were found in male and/or female rats assigned to the 250 mg/kg/day dosage group. ' .. Alan M. Hoberman, Ph.D., DABT Director of Research -v. Date Rayhfoil G. York, Ph.D. ABT Date Associate Director oi arch Study Director M tlu ^ -G J 2 -d L tJ J L __ Jt/sj Rebecca Altmann-Reilly, M.S.J Date Member, Institutional Animal Care and Use Committee Paul H. Lieder, PhJX, DABT Study Monitor Sponsor's Representative Date Any revisions to this finalized am endm ent m ust be made by subsequent am endm ent. PROPOSED STATISTICAL TESTS(9-16). 418-027:PAGE D-42 Protocol 418-027 Attachment 1 to Amendment 2 Page 1 The following schematic represents statistical analyses of the data. I. rarameme Type of Test3 il. iMunuaiamemc- A. Bartlett's T e s tc r Significant atp<0.001 1 Not Significant A. Kruskal-Wallis Test (< 75% tie s a t a n y concentration) r Significant atp<0.05 i Not Significant Nonparametric Analysis of Variance ----- Significant at p<0.05 Not Significant Dunn's Test B. Fisher's Exact Test on Proportion of Ties (>75% ties at any concentration) Dunnett's Test B. Analysis of Variance with R epeated Measures Significant atp<0.05 Not Significant r (Dosage) . Dunnett's T est 1 (Dosage x Block Interaction) O ne-way A N O V A for each block ! Significant atp<0.05 -------- "1 Not Significant Dunnett's Test III. Test for Proportion Data Variance Test for Homogeneity of the Binomial Distribution Statistically significant probabilities are reported as either p<0.05 or /><0.001. Proportion data are not included in this category, c. Test for homogeneity of variance. er p A ny revisions to this finalized am endm ent m ust be made by subsequent am endm ent. APPENDIX E DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILTY 418-027:PAGEE-1 DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY 1. On 25 March 2002, day 36 of study (DS 36), male rat 17632 in the 10 mg/kg/day dosage group refluxed approximately 1 mL of the 4.9 mL test substance that was administered. This deviation did not adversely affect the outcome or interpretation of the study because the rat was administered most of the dosage. 2. On 3 March 2002, DS 14, and on 26 March 2002, day 19 of presumed gestation (DG 19), the postdosage observations for female rats 17716 in the 0 (Vehicle) mg/kg/day dosage group and 17683 in the 250 mg/kg/day dosage group were performed one minute early from the range of 60 10 minutes. These deviations did not adversely affect the outcome or interpretation of the study because the extent of the deviation was minimal. 3. On 3 March 2002, DS 14, the postdosage observation for male rat 17630 in the 0 (Vehicle) mg/kg/day dosage group was not performed. This deviation did not adversely affect the outcome or interpretation of the study because sufficient data were available for evaluation of this parameter and it was a single event. 4. On 30 March 2002, DG 25, ovaries of female rat 17686 in the 250 mg/kg/day dosage group were not retained after necropsy. This deviation did not adversely affect the outcome or interpretation of the study because sufficient tissues were saved from other rats in this dosage group to evaluate ovaries. 5. On 4 April 2002, plasma and serum samples from the following rats were processed and immediately frozen on dry ice. On 5 April 2002, these samples were found in a styrofoam box after they had thawed because of insufficient dry ice to keep the samples frozen. Samples were immediately refrozen and transferred to a -70 C chest freezer for storage. Dosage Group I II III IV Dosage (mg/kg/day) 0 10 50 250 Rat Number 17715 17684 17707 17710 17687 17706 17720 17678 Sample Type Serum Serum and Plasma Serum Serum Serum and Plasma Serum Serum Serum 418-027 :PAGE E-2 This deviation did not adversely affect the outcome or interpretation of the study because sufficient samples were available for evaluation. All deviations are documented in the raw data. / ___ 1t3 l Rnyrfiond G. Yorf, Ph.y., DABT Associate Director fesearch Study Director Date APPENDIX F CERTIFICATE OF ANALYSIS 418-027:PAGEF-1 Certificate of Analysis N -M eFBSE [C 4F9S02N(CH3)CH2C H 20 H ] 41-2601-1878-5 Lot 6 30 January 2002 Gibbes Bailie Sample purity -- 95.55%. This sample was analyzed using GC, GC/MS, LC/MS, 1 H-NMR, and 1 9 F-NMR analyses techniques. The results of these tests show the sample to contain the following composition: C4 F9S 0 2 N(CH3)2 C4 F9S 0 2 N(CH3)H C4F9S 0 2N(CH3)C2 H40 C 4F8H C4F9S 0 2 N(CH3)CH2CH20 H C4F9S 0 2N(CH3)C2H4N(CH3)2 C4F9S 0 2 N(CH3)C2 H4 N(CH3)H C4 F8H S 0 2 N(CH3)CH2CH20 H C4 F9S 0 2 N(CH3)CH2CH20CH2CH20H C3F7C (0)N (C H 3)H C3 F7 C0 2 c 4f 9 s o 3- c4f8hso3- 0.009 % 0.63 % 0.14% 95.55 % %0 . 0 0 2 0.17% 1.80 % 1.71 % 0.0004 % < 30 ppm < 7 ppm 1 0 ppm Additionally, the isomer distribution of the C4 alcohol (C4 F9 S0 2 N(Me)-CH2 CH2 0 H) was determined using 1 9 F-NMR techniques and found to contain the following relative composition: CF3 CF2 CF2 CF2 S0 2 N(CH3 )CH2 CH2OH [linear! (CF3 )2 CFCF2 S0 2 N(CH3 )CH2 CH2OH [iso branch] CF3 CF2 CF(CF3 )S0 2 N(CH3 )CH2 CH2 0 H [alphabranch] 98.8 % 0.97 % %0 . 2 0 Gibbes Bailie APPENDIX G ANALYTICAL REPORT 418-027 :PAGE G -l FINAL REPORT ANALYSIS OF DOSING SOLUTIONS USED AT ARGUS RESEARCH LABORATORY FOR SPONSOR'S STUDY NUMBER T-7599.7 (ARGUS RESEARCH LABORATORY PROTOCOL NUMBER: 418-027), SOUTHERN RESEARCH INSTITUTE STUDY A536.2 STUDY ID: A536.2 SPONSOR STUDY NO. T-7599.7 (ARGUS RESEARCH LABORATORY PROTOCOL NUMBER: 418-027) Southern Research Institute 2000 Ninth Avenue South P.O. Box 55305 Birmingham, AL 35255-5305 Study Initiation Date: 3/15/02 Study Completion Date: 2/12/2003 Experimental Initiation Date: 3/11/02 Experimental Completion Date: 6/14/02 1 SUMMARY 418-027 :PAGE G-2 All samples were analyzed according to analytical method BACG-3592. A total of 8 formulated dose samples including vehicles ranging in concentration from 0 to 25 mg/mL were analyzed to determine the 10 day stability of 1-Butanesulfonamide, 1,1,2,2,3,3,4,4,4-nonafluoro-n-(2hydroxyethyl)-N-methyl (T-7599.7) in the formulated mixture. A total of 8 formulated dose samples including vehicles ranging in concentration from 0 to 25 mg/ml were analyzed to determine concentration of T-7599.7 in the formulated mixture. To test for homogeneity of dose formulation a total of 24 formulated dose samples including vehicles ranging in concentration from 0 to 25 mg/ml were analyzed to determine concentration of T-7599.7 in the top, middle and bottom of the formulated mixture. Samples were stored refrigerated as per sponsor's shipping recommendations. For the 10-day stability, study samples were found to be within 11% of the day 1 values except for the 5 mg/mL samples which were within 15% of the expected dose concentration but twice (204% and 196% of Day 1 values) that found on day 1. For the dose analysis, 1 mg/ml dose formulation samples were found to be within 15% of the reported concentrations but the 5 and 25 mg/mL samples were lower than expected, ranging from 55% to 69% of the expected value. For the homogeneity samples the 1 mg/mL and 5 mg/mL samples were lower than their expected concentrations ranging from 55% to 70%, but values between top, middle, and bottom samples differed by less than 16%. The 25 mg/mL dose samples were within 16% of expected values for both concentration and homogeneity between top, middle, and bottom samples. 2 KEY PERSONNEL Raymond G. York, Ph.D., D.A.B.T. Study Director Argus Research Laboratories Gregory S. Gorman, Ph.D. Manager Bioanalytical Chemistry Group Lara Cook, M.S. Research Associate II Bioanalytical Chemistry Group 418-027 :PAGE G-3 3 418-027 :PAGE G-4 1.0 Objective The objective of this study was to determine the stability, dose concentration, and homogeneity of dose formulations (top, middle and bottom samples) of 1-Butanesulfonamide, 1,1,2,2,3,3,4,4,4-nonafluoro-n-(2-hydroxyethyl)-N-methyl (T-7599.7) in the supplied dosing solutions received from the sponsor and to confirm the identity of the test solution. 2.0 Safety All necessary procedures to ensure safety of the analysts were based on information contained in the Material Safety and Data Sheets, provided by the producer of the test article and the study director. 3.0 Compliance The study described in this final report was conducted in accordance with the FDA Good Laboratory Practice Standards (21 CFR Part 58), OECD Principles of Good Laboratory Practices [C(97)186/Final], and Japanese Ministry of Health and Welfare (MHW Ordinance Number 21, March 26, 1997). The final report accurately reflects the raw data obtained during the performance of the study. There were no adverse circumstances that affected the quality or integrity of the study. 4.0 Experimental 4.1 Analytical Procedures The sample preparation and analysis procedures as described in the analytical method BACG-3592 were employed for all analyses. For the stability study each sample was allowed to warm to room temperature, was sonicated for about 15 minutes and was then vortexed well before being sampled. An aliquot was taken from each and diluted as described in the method. For samples that were analyzed for the dose analysis and homogeneity studies, samples were allowed to come to room temperature and sonicated for 15 minutes, but would not go into solution. Samples were then run under hot water and sonicated further but would not go into solution and remained instead a suspension. These samples were quantitatively transferred and diluted as described in the chemical analysis sheets. Multiple calibration curves were prepared over a concentration range of 500 to 10,000 ng/mL and analyzed along with the samples as described in the method. The correlation coefficient for each curve was equal to or greater than 0.9991. 4.2 Results The results of the identity testing confirmed that the found spectra (LC/MS, FT-IR and 13C NMR results) were consistent with the submitted substance, T-7599.7. The results of the formulation analyses are presented (Tables I - VII) corresponding to the sponsor's study number at the end of the report. 4 418-027:PAGE G-5 4.3 Calculations Calculations were performed using TurboQuan (Version 1.0). The amount of analyte in the diluted dose formulation samples (ng/mL) was back calculated using a calibration curve generated from a set of calibration standards containing the equivalent amount of carboxy methyl cellulose (CMC) as in the diluted samples. The calibration curve was generated by a regression analysis to determine the best fit curve (e.g., linear, quadratic, etc.) and amount of weighting. A quadratic fit with 1/X weighting was determined to be the best f it: where: y - ax2 + bx + c y = Peak area response of test article x = Concentration of the test article in standards. a, b, c - Constants derived from the regression analysis. 5.0 Storage A copy of the final report and all raw data will be stored in the Southern Research Institute archives. 6.0 Conclusion A total of 40 T-7599.7 dose formulation samples ranging in concentration from 0 to 25 m g/m T, were analyzed using method BACG-3592. For the 10-day stability study, samples were found to be within 11% of the Day 1 values except for the 5 mg/mL samples which were within 15% of the expected dose concentration but twice (204% and 196% of Day 1 values) that found on Day 1. This may have been due to the low values found for the 5 mg/mL samples on Day 1 (52% of expected concentration). For the dose analysis, the 1 mg/ml dose formulation samples were found to be within 15% of the reported concentrations but the 5 and 25 m g /mT. samples were lower than expected, ranging from 55% to 69% of the expected value. For the homogeneity samples the 1 mg/mL and 5 mg/mL samples were lower than their expected concentrations, ranging from 55% to 70% but values between top, middle, and bottom samples differed by less than 15%. The 25 mg/mL dose samples were within 16% of expected values for both concentration and homogeneity between top, middle, and bottom samples. The variation in expected concentrations may have been due to the fact that samples were in a suspension rather than in solution and instead of assisting in solubility the presence of the 1% CMC made the samples very viscous and quantitative transfer difficult to perform. Data presented in Tables I through VII are based on non-truncated numbers and may not be reproducible based on rounded numbers displayed. Values for each measured concentration are based on the average of two replicates per sample. 5 418-027:PAGE G-6 Table I Day 1 of the 10-Day Stability Study for a Dose Formulation Containing T-7599.7 1% CMC Sponsor Study Number T-7599.7 (Argus Research Laboratory Protocol Number: 418-027) Nominal Dose concentration (mg/mL) & Sample # 0(1 of 4) 0 (2 of 4) 1 (1 of 4) 1 (2 of 4) 5(1 of 4) 5 (2 of 4) 25(1 of 4) 25 (2 of 4) Target Dilution (ug/mL) Pay 1 Measured Cone. (ug/mL) Dose Conc.(mg/mL) % of Theoretical NA Not detected -- NA Not detected -- 3.0 2.3 0 . 8 3.0 2.5 0 .8 3.0 1.7 2 . 8 3.0 1.5 2 . 6 3.0 3.0 25.2 3.0 2 . 8 23.1 -- -- 78 83 55 51 101 93 Table II Day 10 of the 10-Day Stability Study for a Dose Formulation Containing T-7599.7 1% CMC Sponsor Study Number T-7599.7 (Argus Research Laboratory Protocol Number: 418-027) Nominal Dose concentration (mg/mL) & Sample # 0(1 of 4) 0 (2 of 4) 1 (1 o f 4) 1 (2 of 4) 5(1 of 4) 5 (2 of 4) 25 (1 o f 4) 25 (2 of 4) Target Dilution (ug/mL) Day 10 Measured Dose Cone. Conc.(mg/mL) (ug/mL) % 0f Theoretical % of Day 1 NA Not detected NA Not detected -- 3.0 2.3 0 .8 3.0 2 . 2 0.7 3.0 3.4 5.6 3.0 3.0 5.0 3.0 2.9 24.4 3.0 3.0 24.7 -- 76 98 75 89 113 204 1 0 1 196 98 97 99 107 6 418-027:PAGE G-7 Table II! Dose Formulation Analysis of T-7599.7 in 1% CMC Sponsor Study Number T-7599.7 (Argus Research Laboratory Protocol Number: 418-027) Nominal Dose concentration (mg/ml_) & Sam ple I.D. 0 (1 o f 4) 0 (2 of 4) 1 (1 of 4) 1 (2 of 4) 5(1 of 4) 5 (2 of 4) 25 (1 o f 4) 25 (2 o f 4) Target Dilution (ug/mL) NA NA 2 .8 2.9 3.0 3.0 3.0 3.0 Measured Concentration (ug/mL) Dose Concentration % o f (mg/mL) Theoretical not detected not detected 2 .8 3.3 2 .1 2 .1 1 .8 1.7 -- -- 1 .0 1 .1 3.4 3.4 14.9 13.7 -- -- 98 114 69 69 60 55 Tables IV, V, VI and VII Homogeneity Dose Formulation Analysis of T-7599.7 in 1% CMC Sponsor Study Number T-7599.7 (Argus Research Laboratory Protocol Number: 418-027) (In the sample ID, T = top, M = middle, and B = bottom) Table IV Controls (0 mg/ml) Nominal Target Measured Dose Dose concentration (m g/m l) & Sam ple I.D. Dilution (ug/mL) Concentration Concentration % o f (ug/mL) (mg/mL) Theoretical 0(1 of 12T) NA not detected -- 0 (2 of 12T) NA not detected -- -- 0 (5 of 12M) NA not detected -- -- 0 ( 6 of 12M) NA not detected -- -- 0 (9 of 12B) NA not detected -- -- 0 (10 of 12B) NA not detected -- -- Table V 1 mg/ml Nominal Target Measured Dose Dose concentration (mg/mL) & Sample I.D. Dilution (ug/mL) Concentration Concentration % o f (ug/mL) (mg/mL) Theoretical 1 (1 o f 12T) 3.0 2 .0 0.7 65 1 (2 o f 12T) 3.0 1 .8 0 . 6 61 1 (5 of 12M) 3.0 1.7 0 . 6 55 1 ( 6 of 12M) 3.0 1 .8 0 . 6 59 1 (9 of 12B) 3.0 2 .1 0.7 69 1 (10 of 12B) 3.0 2 .1 0.7 70 7 418-027 :PAGE G-8 Nominal Dose concentration (mg/mL) & Sample I.D. 5 (1 of 12T) 5 (2 of 12T) 5 (5 of 12M) 5 (6 of 12M) 5 (9 of 12B) 5 (10 of 12B) Target Dilution (ug/mL) 2.9 3.0 3.0 3.0 3.0 3.0 Table VI 5 mg/ml Measured Concentration (ug/mL) Dose Concentration % o f (mg/mL) Theoretical 1.7 2 . 8 56 1.7 2 . 8 56 1 . 8 2.9 58 1.9 3.2 63 2 . 0 3.4 67 1.9 3.2 64 Nominal Dose concentration (mg/mL) & Sample I.D. 25(1 of 12T) 25 (2 of 12T) 25 (5 of 12M) 2 5 (6 of 12M) 25 (9 o f 12B) 25 (10 of 12B) Target Dilution (ug/mL) 3.0 3.0 2.9 3.0 3.0 3.0 Table VII 25 mg/ml Measured Concentration (ug/mL) Dose Concentration % o f (mg/mL) Theoretical 3.0 24.6 98 3.1 25.6 103 3.4 28.9 116 2.7 22.5 90 2.9 23.9 96 3.0 25.7 103 Calculated values are based upon non-truncated numbers and may not be reproducible based on rounded numbers displayed in tables I through VII. 7.0 Approvals Lara Cook, M.S. Research Associate II Bioanalytical Chemistry Group Manager Bioanalytical Chemistry Group Charles D. Hbert, Ph.D., D.A.B.T. Director Safety Assessment Department -/h o ? Date u //// 3 > Date 2 -J/-03 Date RaymbjLd G. York, Ph.p., D.A.B.T. Study Director Argus Research Laboratories Date 418-027:PAGE G-10 ^R! 'ECCFY- P ^atm ' r,^ir,',>i; *tyFt#f; IjlmUu <33 QUALITY ASSURANCE STATEMENT Final Report On: Analysis of Dosing Solutions Used at Argus Research Laboratory For Sponsor's Study Number T-7599.7 (Argus Research Laboratory Protocol Number: 418-027), SRI Study A536.2 Study No.: A536.2 Listed below are the phases and/or procedures performed by Southern Research Institute that were inspected and audited by the Quality Assurance Unit during the study described in the report. Findings were reported to the study director and management periodically. P h a ses/P ro c ed u res Test Substance Characterization: Liquid Chromatography/Mass Spectrometry In sp e c tio n / A udit D ate 6/18/02 D ate M anagem ent D ate Study D irector N otified N otified 1/23/03 1/24/03 Final (Draft) Report Review And Data Audit 1/7/03-1/9/03; 1/13/03; 1/21/03 1/23/03 1/24/03 Final Report Review 2/11/03 2/11/03 2/11/03 The results presented in this final report accurately reflect the raw data. APPENDIX H TEMPERATURE AND RELATIVE HUMIDITY REPORT 418-027:PAGE H -l ARGUS Temperature and Relative Humidity Report Location: Room 01 Protocol Number: 418-027 Range o f Dates: 12-Feb-2002 13:35 to 13-Apr2002 09:59 Target Range: Species: Rat Total Number of Days: Total Number of Hours: Total Number of Data Points: Temperature 66F to 77F 61 1436.0 1436 Relative Humidity 30% to 70% 61 1436.0 1436 Mean ( SD): Maximum: Median: Minimum: Number of Points in Range (%): Number of Points High (%): Number of Points Low (%): 70.6 73.3 70.8 66.6 1436 0 0 (1.1) (100.0) (0.0) (0.0) 54.5 66.9 55.0 35.3 1436 0 0 ( 4.4) (100.0) (0.0) (0.0) R eport Generated: 24-Jun-2002 at 14:03 COMMENTS: ; umulative by Location (vMay-21-1999) APPENDIX I POSITIVE CONTROL DATA 418-027:PAGE 1-1 Historical Control Data This Functional Observation Battery Standard Operating Procedure and Studies conducted to document the training and competency of the technical staff and Motor Activity Negative Control Data and Positive Control Data are available at the Testing Facility. Page 1 418-027 :PAGE 1-2 Summary Information for Functional Observation Battery Study Number - Title In-Life Start Test Substance Dosage Information Number of mg/kg mL/kg Dosages 012-006 - Validation of Functional Observational Battery and Motor Activity Measure Using Positive Test Substances 12/89 acrylamide 50 1 7 physostigmine 0.75 1.5 1 DDT 75 1 1 012-014 - Neurotoxicity Evaluation of Positive Control Substances in Crl:CDBR VAF/Plus Rats 9/91 acrylamide 40 1 9 IDPN 200 1 3 carbaryl 75 5 1 DDT 75 5 1 triadimefon 200 5 1 012-015 - Neurotoxicity Evaluation of DDT in Crl:CDBR VAF/Plus Rats 3/92 DDT 75 1 1 012-017 - Neurotoxicity Evaluation of Positive Control Substances in Crl:CDBR VAF/Plus Rats 012-022 - Neurotoxicity Evaluation of Carbaryl in Crl:CDBR VAF/Plus Rats 012-031 - Neurotoxicity Evaluation of Positive Control Substances in Crl:CDBR VAF/Plus Rats 5/92 10/92 7/93 acrylamide IDPN carbaryl DDT d-amphetamine 40 200 40 75 4.0 carbaryl 40,200 acrylamide IDPN carbaryl DDT d-amphetamine 45 250 40 75 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 418-027'.PAGE 1-3 012-056 - Neurotoxicity Evaluation of Positive Control Substances in Crl:CDBR VAF/Plus Rats 012-075 - Neurotoxicity Evaluation of Positive Control Substances in Crl:CDBR VAF/Plus Rats 012-081 - Neurotoxicity Evaluation of Positive Control Substances in Crl:CDBR VAF/Plus Rats 11/95 acrylamide 1DPN carbaryl DDT d-amphetamine 45 250 40 75 4.0 1 1 1 1 1 3/98 acrylamide 30 1 trimethyltin 8 1 MK-801 0.3 1 carbaryl 100 4 DDT 100 2 11/01 acrylamide IDPN d-amphetamine carbaryl DDT 30 250 40 100 100 1 1 1 4 2 10 5 1 1 1 17 1 1 1 1 10 1 1 1 5 Page 3 418-027:PAGE 1-4 Summary Information for Motor Activity T Tf Study - Title Start 012-011 - The Assessment of Motor Activity in Neonatal and Adult Rodents using Passive Infrared Sensors 5/91 012-014 - Neurotoxicity Evaluation of Positive Control Substances in Crl:CDBR VAF/Plus Rats 9/91 012-016 - Motor Activity Evaluation in Crl:CDBR VAF/Plus Rats Administered Chlorpromazine and dAmphetamine (Positive Control Study) 012-058 - Neurotoxicity Evaluation of Positive Control Substances in Crl:CDBR VAF/Plus Rats 4/96 T Substance Dosage Information Number of mg/kg mL/kg Dosages d-amphetamine chlorpromazine 0.75,1.5,4 1,2,4 1 1 1 1 acrylamide 40 1 IDPN 200 1 carbaryl 75 5 DDT 75 5 triadimefon 200 5 9 3 1 1 1 d-amphetamine chlorpromazine 0.5, 1,4 1,2,4 1 1 1 1 acrylamide d-amphetamine trimethyltin MK-801 45 0.75 8 10 1 1 1 1 10 1 1 1 Page 4 APPENDIX J HISTOPATHOLOGY REPORT 418-027:PAGE J-l RESEARCH PATHOLOGY SERVICES, INC, 438 East Butler Avenue, New Britain, PA 18901 Phone: 215-345-7070 Fax: 215-345-4326 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCEENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 HISTOPATHOLOGY REPORT SUBMITTED TO: Raymond G. York, Ph.D., D.A.B.T. Argus Research 905 Sheehy Drive Horsham, PA 19044 SUBMITTED BY: kf & /-ww-- W. Ray Brown, D.V.M., Ph.D. Veterinary Pathologist .re-? February 25, 2003 418-027'.PAGE J-2 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 HISTOPATHOLOGY REPORT TABLE OF CONTENTS REPORT Page M ethod....................................... 1 R esults................................................................................................................................... 3 Sum m ary................................................................................................................................5 Quality Assurance Unit S tatem ent.....................................................................................6 table 1. Incidence and Degree of Severity of Histomorphologic Observations..................... 7 APPENDIX I. Histomorphologic Observations.................................................................... 1-1 to 1-13 Key to Histomorphologic Observations..................................................................... 1-1 Tables 1-1 .Histomorphologic Observations - Group I Male Rats........................................I-2 I-2.Histomorphologic Observations - Group II Male Rats...................................... I-4 I-3.Histomorphologic Observations - Group III Male Rats..................................... I-5 I-4. Histomorphologic Observations - Group IV Male R a ts.................................... I-6 I-5. Histomorphologic Observations - Group IFemale R a ts ................................... I-8 I-6.Histomorphologic Observations - Group IIFemale R a ts ................................ 1-10 I-7.Histomorphologic Observations - Group III Female R a ts ............................. 1-11 I-8. Histomorphologic Observations - Group IV Female R ats............................. 1-12 II. Individual Animal Gross and Histomorphology D ata..............................11-1 TO II-80 418-027:PAGE J-3 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 W)TH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 HISTOPATHOLOGY REPORT M ETHOD Microscopic examination was made of the specified tissues from 40 male and 40 female Crl:CD(SD)IGS BR VAF/Plus rats in an oral (gavage) combined repeated dose toxicity study of T 7599.7 with the reproduction/developmental toxicity screening test. A brief outline of the study design showing the dose group identifica tion, dosage levels of the test and control substances and number of male and female rats examined group are shown below. DOSAGE GROUP I NUMBER OF RATS PER SEX 10 DOSAGE (mg/kg/day) 0 (Vehicle) CONCENTRATION (mg/mL) 0 DOSE VOLUME (mL/kg) 10 II 10 10 1 10 III 10 50 5 10 IV 10 250 25 10 The test substance was considered to be 100% active for the purpose of dosage calculations. The rats were given the test substance and/or vehicle beginning before cohabitation, through mating and continued for at least 28 days (male rats), or through parturition until Day 5 of lactation (female rats). Dosages were adjusted daily for body weight changes and given at approximately the same time each day. Scheduled sacrifice of male rats was on the day following the last dosage administration, after a minimum of 28 days of dosage. Scheduled sacrifice of female rats was on Day 6 of lactation. 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. Research Pathology Services, Inc. -1 418-027:PAGE J-4 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 HISTOPATHOLOGY REPORT The tissues specified for microscopic evaluation from the male and female rats of Groups I and IV 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 tissues with gross changes. In addition, the liver of male and female rats, stomach of male rats and thymus of female rats were examined from the intermediate dosage groups. Representative samples of these tissues were routinely processed, embed ded in paraffin, sectioned, and stained with hematoxylin and eosin for microscopic evaluation. 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 418-027:PAGE J-5 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 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-8). 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. No treatment-related microscopic changes were observed in any of the male rats given 10 mg/kg/day or in female rats given 10 or 50 mg/kg/day of the test substance. Treatment-related microscopic changes were observed in the liver of male rats of the 50 and 250 mg/kg/day dosage groups and female rats of the 250 mg/kg/day dosage group, thymus of female rats of the 250 mg/kg/day dosage group and stomach of the male rats of the 250 mg/kg/day dosage group. The treatment-related microscopic change in the liver consisted of minimal or mild enlargement (hypertrophy) of centrilobular hepatocytes in most male and fe male rats of the 250 mg/kg/day dosage group and in 4/10 male rats of the 50 mg/kg/day dosage group. The enlargement was due to an increased amount of finely granular, dense eosinophilic cytoplasm. The incidence and severity of the change occurred in a dose-related manner. Also, in three of the affected high dose male rats, necrosis of individual enlarged hepatocytes was seen in centrilobular areas (Table 1). The treatment-related effect in the thymus consisted of an increased inci dence and severity of atrophy of the thymic lobules in female rats of the 250 mg/kg/day dosage group. Single incidences of thymic atrophy occurred in female rats of the control and lower dosage groups, but the increased incidence and severity of this effect in the high dosage group was considered to be treatmentrelated. Microscopic examination of the stomach revealed focal erosions in the pyloric glandular mucosa of two high dose male rats. Although the incidence was low, this Research Pathology Services, Inc. -3 418-027'.PAGE J-6 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 HISTOPATHOLOGY REPORT change may be treatment-related. Other changes observed in the stomach which occurred at a somewhat varied and sporadic incidence in the control and compoundtreated male rats included edema with or without inflammation (infiltrations of polymorphonuclear inflammatory cells) in the submucosa of the glandular and nonglandular (forestomach) areas. The very slight increased incidence and severity (Table 1) of these changes in these areas of the stomach of the high dose male rats may also be treatment-related. However, these changes were not clearly associated with the erosions. All other microscopic changes were considered to have occurred spontane ously and to be incidental and unrelated to compound administration. The type, in cidence and severity of these changes were not influenced by compound admini stration. These changes also are listed in the attached histomorphology tables. One high dosage group male rat had early lymphosarcoma in the spleen only. There was no evidence of disseminated involvement. Although this is a Group IV rat, it is still considered to have been incidental and a spontaneously-occurring effect. Research Pathology Services, Inc. -4 418-027'.PAGE J-7 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 HISTOPATHOLOGY REPORT SUMMARY Microscopic examination was made of the specified tissues from four groups of 10 male and 10 female Crl:CD@(SD)IGS BR VAF/Plus rats used in an oral (gavage) combined repeated dose toxicity study of T 7599.7 with the reproduction/developmental toxicity screening test. The four groups of rats had been given 0 (vehicle), or 10, 50 or 250 mg/kg/day of T 7599.7, orally by gavage, once daily for the protocol-specified number of days. No treatment-related microscopic changes were observed in the male rats given 10 mg/kg/day or female rats given 10 or 50 mg/kg/day of the test substance. Treatment-related microscopic changes were observed in the liver of male rats of the 50 and 250 mg/kg/day dosage groups and female rats of the 250 mg/kg/day dosage group, thymus of female rats given 250 mg/kg/day and stomach of male rats given 250 mg/kg/day of the test substance. The treatment-related effect in the liver consisted of minimal to mild hypertrophy of centrilobular hepatocytes in the mid and high dosage group male rats and in the high dosage group female rats. A low incidence of high dose male rats had individual-cell necrosis of affected centrilobular hepatocytes. The treatment-related change in the thymus was an increased incidence and severity of atrophy of the thymic lobules in female rats of the high dosage group. There were single incidences of atrophy in each of the control and lower dosage groups, but this increased incidence in the 250 mg/kg/day dosage group was con sidered to be treatment-related. The treatment-related change in the stomach in male rats of the high dosage group consisted of a low incidence of focal erosions of the pyloric glandular mucosa. A varied incidence of edema and inflammation of the submucosa of the nonglandular and glandular areas also was observed in a few rats at a slightly higher incidence and severity in Group 4 and this may also be related to compound-related. All other 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 T 7599.7. Research Pathology Services, Inc. -5 418-027:PAGE J-8 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 HISTOPATHOLOGY REPORT QUALITY ASSURANCE UNIT STATEMENT All aspects of the tissue processing, microscopic slide preparation, histo pathologic evaluation and report preparation for the study listed above have been performed according to the Standard Operating Procedures of Research Pathology Services, Inc. and were audited in accordance with the procedures established by the Quality Assurance Unit of Research Pathology Services, Inc. in compliance with the regulations as specified in the protocol. Quality Assurance inspections were performed on 04/08/02, 04/12/02, 04/18/02, 04/19/02, 04/23/02, 04/24/02, 05/22/02, 06/05/02, 06/07/02, 07/10/02, 07/11/02, 07/12/02, and 02/25/03 and findings were reported to management on 04/30/02, 05/31/02, 06/28/02 and 02/25/03. There were no deviations from the protocol, Standard Operating Procedures and/or appropriate Good Laboratory Practice regu lations noted during the conduct of the study that had an impact on study integrity. The summary report of QA inspections is included in the final report submitted to the Study Director on February 25, 2003. Research Pathology Services, Inc. Karen W. Harkins, BS Quality Assurance Unit Date 4 - - o 3 -6 418-027:PAGE J-9 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 TABLE 1 Incidence and Degree of Severity of Histomorphologic Observations Dose Group: Sex: Number of Animals/GrouD: I II III IV MMMM 10 10 10 10 I II FF 10 10 ADRENAL GLANDS: NO. E XAMINED NO. NORMAL 10 0 0 10 8006 10 0 90 -infilt r a t i o n , m o n o n u c l e a r - c e l l , multifocal CO] [0] [0] [0] minimal 0000 [1] [0] 10 -vacuolation, cortex minimal mild [2] [0] [0] [3] 1003 1000 [0] [0] 00 00 BONE MARROW (STERNUM!: NO. EXAMINED NO. NORM A L 10 0 0 10 10 0 0 10 10 0 10 0 BRAIN: NO. EXAMINED NO. NORMAL 10 0 0 10 10 0 0 10 10 0 10 0 CECUM: NO. EXAMINED NO. NORMAL 10 0 0 10 9 0 0 10 10 0 10 0 -inflammation, mucosa, chronic mild [1] [0] [0] [0] 1000 [0] [0] 00 COAGULATING GLAND: NO. EXAMINED NO. NORM A L 10 0 0 10 10 0 0 10 COLON: NO. EXAMINED NO. NORMAL 10 0 0 10 10 0 0 10 10 0 10 0 DUODENUM: NO. E XAMINED NO. NORMAL 10 0 0 10 10 0 0 10 10 0 10 0 EPIDIDYMIDES: NO. E XAMINED NO. NORMAL 10 0 0 10 8009 -infiltration, mononuclear-cell, focal minimal [2] [01 [0] [1] 2001 EXTREMITIES: NO. EXAMINED NO. NORMAL 000 1 0000 00 00 -dermatitis, ulcerative, focal mild [0] [0] [0] [1] 000 1 [0] [0] 00 HEART: NO. EXAMI N E D NO. NORMAL 10 0 90 [ ] = Total incidence of specified lesion, all grades. 0 0 10 9 10 0 90 III IV FF 10 10 0 10 0 10 [0] [0] 00 [0] [0] 00 00 0 10 0 10 0 10 0 10 0 10 0 10 [0] [0] 00 0 10 0 10 0 10 0 10 00 00 [0] [0] 00 0 10 09 -7 418-027:PAGE J-10 ORAL (SAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTIQN/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 S P O N S O R 'S STUDY N U M B E R T-7599 TABLE 1 (Continued) Incidence and Degree of Severity of Histomorphologic Observations Dose Group: Sex: Number of Animals/Grouo: I II III IV MMMM 10 10 10 10 I II III IV FFFF 10 10 10 10 HEART (Continued): -inflammation, subacute, focal/multifocal minimal mild -pericarditis, chronic, focal minimal ILEUM: NO. EXAMINED NO. NORMAL [1] [0] 00 10 CO] [0] 00 10 0 10 0 [0] [1] 01 00 [0] [0] 00 0 10 0 10 [0] [0] [0] [1] 0001 0000 [1] [0] [0] [0] 1000 10 0 0 10 10 0 0 10 JEJUNUM: NO. EXAMINED NO. NOR M A L 10 0 0 10 10 0 0 10 10 0 0 10 10 0 0 10 KIDNEYS: NO. EXAMINED NO. NORMAL - c y s t (s), me d u l l a 10 0 0 10 7006 0002 10 0 0 10 8006 0000 -dilatation, pelvis mild [1] [0] [0] [0] 1000 [0] [0] [0] [0] 0000 -edema, papillary minimal [1] [0] [0] [0] 1000 [0] [0] [0] [0] 0000 -infiltration, mononuclear-cell, focal minimal [1] [01 [0] [0] 1000 [0] [0] [0] [0] 0000 -mineralization, multifocal minimal [0] [0] [0] [1] 0001 [2] [0] [0] [2] 2002 -nephritis, chronic, focal minimal [0] [0] [0] [1] 0001 -pyelitis, chronic minimal [0] [0] [0] [0] 0000 - v a c u o !ation, cortical t u b u l a r e p i t h e l i u m [0] [0] [0] [0] mild 0000 [0] [0] [0] [0] 0000 [0] [0] [0] [1] 0001 [0] [0] [0] [1] 0001 LIVER: NO. EXAMINED NO. NORMAL 10 10 10 10 3 110 - h e m a t o poiesis, extram e d u l l a r y , multifocal [0] [0] [0] [0] minimal 0000 10 10 10 10 583 1 [0] [0] [1] [0] 00 10 [ ] = Total incidence of specified lesion, all grades. -8 418-027:PAGE M l ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 TABLE 1 (Continued) Incidence and Degree of Severity of Histomorphologic Observations Dose Group: Sex: Number of Animals/Group: I II III IV MMMM 10 10 10 10 I II FF 10 10 LIVER (Continued): - h ypertrophy, hepato c e l l u l a r , c e n t r i l o b u l a r [01 [0] [4] [10] minimal 004 2 mild 0008 [0] [0] 00 00 -inflammation, chronic, focal/multifocal minimal mild [7] [7] [6] [4] 6563 1201 [3] [2] 32 00 -lipidosis, tension, focal 0 10 1 00 -necrosis, focal minimal [0] [0] [0] [1] 0001 [1] [1] 11 -necrosis, individual hepatocytes minimal mild [0] [0] [0] [3] 0002 0001 [0] [0] 00 00 -vacuo!ation, hepatocellular, multifocal minimal [0] [0] [0] [0] 0000 [1] [0] 10 -vacuolation, hepatocellular, periportal minimal [1] [2] [0] [0] 1200 [0] [0] 00 LUNG: NO. EXAMINED NO. NORMAL 10 0 0 10 9 009 10 0 80 -inflammation, interstitial, multifocal minimal [1] [0] [0] [1] 100 1 [1] [0] 10 -macrophages, a l v e o l i , focal minimal [0] [0] [0] [1] 0001 [1] [0] 10 LYMPH NODE. MEDIASTINAL: NO. EXAMINED NO. NORMAL 9 0 0 10 8 008 90 70 -congest ion/eryt hrophagocytos is minimal mild [1] [0] [0] [2] 100 1 0001 [1] [0] 10 00 -hyperplasi a , 1ymphocyti c/plasmacyti c minimal [0] [0] [0] [0] 0000 [1] [0] 10 -macrophages, pigmented minimal LYMPH NODE. SUBMANDIBULAR: ( NO. EXAMINED NO. NORMAL [0] [0] [0] [0] 0000 10 0 0 10 5004 [2] [0] 20 10 0 10 III IV FF 10 10 [0] [8] 06 02 [6] [5] 65 00 01 [0] [01 00 [0] [0] 00 00 [0] [0] 00 [0] [1] 01 0 10 0 10 [0] [0] 00 [0] [0] 00 09 07 [0] [2] 00 02 [0] [0] 00 [0] [0] 00 0 10 02 [ ] = Total incidence of specified lesion, all grades. -9 418-027 :PAGE J-12 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTI0N/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 TABLE 1 (Continued) Incidence and Degree of Severity of Histomorphologic Observations Dose Group: Sex: Number of Animals/Grouo: I 11 III IV MMMM 10 10 10 10 I II FF 10 10 LYMPH NODE. SUBMANDIBULAR (Continued): -hyperplasi a , 1ymphocyti c/piasmacyt ic minimal mild moderate [5] [0] [0] [6] 3004 2001 0001 [9] [0] 40 30 20 MAMMARY GLAND: NO. EXAMINED NO. NORMAL 10 0 00 -hyperplasia, physiological 10 0 -inflammation, subacute mild [1] [0] 10 NERVE, SCIATIC: NO. EXAMINED NO. NORMAL 10 0 0 10 10 0 0 10 10 0 10 0 OVARIES: NO. EXAMINED NO. NORMAL 10 0 10 0 PARATHYROID: NO. E X A M I N E D NO. NORMAL 10 0 0 8 10 0 0 8 10 0 10 0 PEYER'S PATCH: NO. EXAMINED NO. NORMAL 10 0 0 10 10 0 0 9 10 0 10 0 -mineral ization minimal [0] [0] [0] [1] 0001 [0] [0] 00 PROSTATE: NO. EXAMINED NO. NORMAL 10 0 0 10 8006 -atrophy, focal minimal Cl] [0] [0] [1] 100 1 -inflammation, chronic, multifocal minimal [1] [0] [0] [2] 1002 -prostatitis, suppurative marked [0] [0] [0] [1] 000 1 RECTUM: NO. EXAMINED NO. NORMAL 10 0 0 10 9008 10 0 10 0 III IV FF 10 10 [0] [8] 01 03 04 0 10 00 0 10 [0] [0] 00 0 10 0 10 09 09 0 10 0 10 0 10 0 10 [0] [0] 00 0 10 0 10 [ ] = Total incidence of specified lesion, all grades. -10 418-027 -.PAGE J-13 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 TABLE 1 (Continued) Incidence and Degree of Severity of Histomorphologic Observations Dose Group: Sex: Number of Animals/GrouD: I II III IV MMMM 10 10 10 10 I II FF 10 10 RECTUM (Continued): -edema/inflammation, submucosa moderate -parasite(s) [1] [0] [0] [0] 10 0 0 0002 [0] [0] 00 00 SEMINAL VESICLES: NO. EXAMINED NO. NORMAL 10 0 0 10 10 0 0 10 SPINAL CORD. CERVICAL: NO. EXAMINED NO. NORMAL 10 0 0 10 10 0 0 10 10 0 10 0 SPINAL CORD. LUMBAR: NO. EXAMINED NO. NORMAL 10 0 0 10 10 0 0 10 10 0 10 0 SPINAL CORD. THORACIC: NO. EXAMINED NO. NORMAL 10 0 0 10 10 0 0 10 10 0 10 0 SPLEEN: NO. EXAMINED NO. NORMAL 10 0 0 10 10 0 0 8 10 0 60 -atrophy mild [0] [03 [0] [0] 0000 [0] [0] 00 -hema t o p o i e s i s , e x t r a m e dullary, in c r e a s e d [0] [01 [0] [1] minimal 0001 mild 0000 -lymphosarcoma 0001 [4] [0] 10 30 00 STOMACH: NO. EXAMINED NO. NORMAL -dilatation, mucosal glands minimal mild 10 10 10 10 6783 [3] [2] [2] [3] 3 122 0101 10 0 90 [1] [0] 10 00 -edema/infiammati on, submucosa, glandular area [2] [0] [2] [3] minimal 1020 mild 100 1 moderate 0002 [0] [0] 00 00 00 III IV FF 10 10 [0] CO] 00 00 0 10 0 10 0 10 0 10 0 10 0 10 0 10 06 [03 [1] 01 [0] [3] 03 00 00 0 10 0 10 [0] [0] 00 00 [0] [0] 00 00 00 [ ] = Total incidence of specified lesion, all grades. -11 418-027 :PAGE J -14 Dose Group: Sex: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 TABLE 1 (Continued) Incidence and Degree of Severity of Histomorphologic Observations I II III IV MMMM 10 10 10 10 I II FF 10 10 III IV FF 10 10 STOMACH (Continued): -edema/infiammati on, submucosa, nonglandular area minimal mild moderate [1] [1] [0] [4] 1002 0001 0 10 1 -erosion(s), glandular mucosa minimal mild [0] [0] [0] [2] 0001 0001 [0] [0] [0] [0] 0000 0000 0000 [0] [0] [0] [0] 0000 0000 TAIL: NO. EXAMINED NO. NORMAL TESTES: NO. EXAMINED NO. NORMAL THYMUS: NO. EXAMINED NO. NORMAL -atrophy minimal mild moderate THYROID: NO. EXAMINED NO. NORMAL -hypertrophy, follicular epithelium mild -ultimobranchial body/cyst 0000 0000 10 0 0 10 10 0 0 10 10 0 0 10 10 0 0 10 [0] [0] [0] [0] 0000 0000 0000 10 0 0 10 70 0 7 [1] [0] [0] [0] 1000 3 003 0001 0u01 10 10 10 9 9994 [1] [1] [1] C5] 1 112 0002 0001 10 0 0 10 70uD [0] [0] [0] [0] 0000 3 005 TRACHEA: NO. EXAMINED NO. NORMAL -inflammation, chronic, focal minimal URINARY BLADDER: NO. EXAMINED NO. NORMAL UTERUS : NO. EXAMINED NO. NORMAL 10 0 0 10 9 0 0 10 [1] [0] CO] [0] 1000 10 0 0 10 10 0 0 10 10 0 0 10 10 0 0 10 [0] [0] [0] [0] 0000 10 0 0 10 10 0 0 10 10 0 0 10 c 01 [ ] Total incidence of specified lesion, all grades. -12 418-027 :PAGE J-15 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTIQN/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 TABLE 1 (Continued) Incidence and Degree of Severity of Histomorphologic Observations Dose Group: Sex: Number of Animals/GrouD: I II III IV MMMM 10 10 10 10 I II FF 10 10 UTERUS (Continued): -distention, lumen minimal moderate [1] [0] 10 00 -hemorrhage, endometrium mild [0] [0] 00 -inflammation, endometrium, diffuse mild [0] [0] 00 -macrophages, minimal mild moderate pigmented -thrombus [8] [0] 10 00 70 20 VAGINA: NO. EXAMINED NO. NORMAL 10 0 80 -inflammation, acute moderate -mucification moderate marked [0] [0] 00 [2] 2 [0] 0 00 1 1 1L--o_ III IV FF 10 10 [1] 00 01 [0] [1] 01 [a] [1] 01 [0] [9] 02 02 05 01 0 10 08 [0] [1] 01 [0] [2] 01 01 [ ] = Total incidence of specified lesion, all grades. 418-027 :PAGE J-16 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 HISTOPATHOLOGY REPORT APPENDIX I HISTOMORPHOLOGIC OBSERVATIONS 418-027:PAGE J-17 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 HISTOPATHOLOGY REPORT KEY TO HISTQMORPHOLOGIC 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)]. XM Primary malignant neoplasm present. P Indicated change or lesion present 1 Minimal degree or amount of indicated change or lesion. 2 Mild degree or amount o f 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 418-027:PAGE J-18 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 T A B L E 1-1 Histomorphologic Observations Dose Group: Animal Number: Sex: Death Type: I 17608 M SS I 17618 M SS I 17630 M SS I 17631 M SS I 17639 M SS I 17648 M SS I 17652 M SS I 17656 M SS I 17658 M SS I 17660 M SS ADRENAL GLANDS: -vacuolation, cortex 2- 1- - - - -- - BONE MARROW (STERNUM): ---------- BRAIN: CECUM: -inflammation, mucosa, chronic COAGULATING GLAND: ---------- -2----------------- COLON: ---------- DUODENUM: ---------- EPIDIDYMIDES: -infiltration, mononuclear-cell, focal ----1--1-- HEART: -inflammation, subacute, focal/multifocal - - - - - 2 - - - - ILEUM: ---------- JEJUNUM: ---------- KIDNEYS: -dilatation, pelvis -edema, papillary -infiltration, mononuclear-cell, focal ---2------------1-- ----- 1---- LIVER: -inflammation, chronic, focal/multifocal -vacuolation, hepatocellular, periportal 12 11- 1 1- - 1 --- 1------ LUNG: -inflammation, interstitial, multifocal 1--------- LYMPH NODE. MEDIASTINAL: -congesti on/erythrophagocytosis --* - 1- - - -- LYMPH NODE. SUBMANDIBULAR: -hyperplasi a , 1ymphocyti c/plasmacyti c --- 212-1-1 NERVE, SCIATIC: ---------- PARATHYROID: ---------- PEYER'S PATCH: ---------- PROSTATE: -atrophy, focal ""-1 ""- " 1-2 418-027:PAGE J-19 ORAL (GAVA6E) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 TABLE 1-1 (Continued) Histomorphologic Observations Dose Group: Animal Number: Sex: Death Tvoe: I 17608 M SS I 17618 M SS I 17630 M SS I 17631 M SS I 17639 M SS I 17648 M SS I 17652 M SS I 17656 M SS I 17658 M SS I 17660 M SS PROSTATE (Continued): -inflammation, chronic, multifocal ___ __ _ 1_ RECTUM: -edema/inflammation, submucosa 3- - - - - - --- SEMINAL VESICLES: SPINAL CORD. CERVICAL: ---------- _ _ _ _ _ __ SPINAL C0R D r LUMBAR: SPINAL CORD. THORACIC: SPLEEN: --- - - - - - - - STOMACH: -dilatation, mucosal glands -11--1---- -edema/inflammation, submucosa, glandular area -edema/inflammation, submucosa, - 1- - - - 2- _ _ nonglandular area --1------- TESTES: --------- - THYMUS : --- - - - -- - - THYROID: -hypertrophy, follicular epithelium -ultimobranchial body/cyst 2 P- - P- - - - P- TRACHEA: -inflammation, chronic, focal 1- - - - - - - _ _ URINARY BLADDER: --- -- - - -- - 418-027`.PAGE J-20 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 TABLE 1-2 Dose Group: Animal Number: Sex: Death Tvoe: Histomorphologic Observations II 17634 M SS II 17635 M SS II 17638 M SS II 17642 M SS II 17643 M SS II 17645 M SS II 17649 M SS II 17651 M SS II 17653 M SS II 17655 M SS LIVER: -inflammation, chronic, focal/multifocal -lipidosis, tension, focal -vacuolation, hepatocellular, periportal 11 22 11 1 --P ------- -1 --- - -- 1 - STOMACH: -dilatation, mucosal - e d e m a / i n f i a m m a i ion, nonglandular area glands submucosa, 1 " 2" - - - - -- - 3 - -- 1-4 418-027 :PAGE J-21 ORAL (6AVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 TABLE 1-3 Histomorphologic Observations Dose Group: Animal Number: Sex: Death Type: III III III III III 17620 17623 17627 17628 17633 MMMMMM SS SS SS SS SS III 17640 M SS III 17646 M SS III 17650 M SS III 17657 M SS III 17659 SS LIVER: -hypertrophy, hepatocellular, centrilobular 1 - 1 -inflammation, chronic, focal/multifocal -11 1 STOMACH: -dilatation, mucosal -edema/infiammati on, area glands submucosa, glandular 1 1 1 1 1-5 418-027 :PAGE J-22 ORAL (GAVA6E) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 TABLE 1-4 Histomorphologic Observations Dose Group: Animal Number: Sex: Death Tvoe: IV 17621 M SS IV 17622 M SS IV 17625 M SS IV 17629 M SS IV 17636 M SS IV 17637 M SS IV 17641 M SS IV 17644 M SS IV 17647 M SS IV 17654 M SS ADRENAL GLANDS: -vacuolation, cortex 1---1-- 1-- BONE MARROW (STERNUM): ---------- BRAIN: ---------- CECUM: ---------- COAGULATING GLAND: ---------- COLON: ---------- DUODENUM: ---------- EPIDIDYMIDES: -infiltration, mononuclear-cell, focal 1 EXTREMITIES: -dermatitis, ulcerative, focal <2> HEART: -inflammation, subacute, focal/multifocal - - - - - - - - - 1 ILEUM: ---------- JEJUNUM: ---------- KIDNEYS: -cyst(s), medulla -mineralization, multifocal -nephritis, chronic, focal ---PP----------1--- ---------1 LIVER: -hypertrophy, hepatocellular, centrilobular 2 2 2 2 1 2 2 2 2 1 -inflammation, chronic, focal/multifocal -lipidosis, tension, focal -necrosis, focal 2---1- 1--1 -------_-P -- 1- -- - --- -necrosis, individual hepatocytes -- -- - 1 12- - LUNG: -inflammation, interstitial, multifocal -macrophages, alveoli, focal - - - 1- - ------1------ LYMPH NODE. MEDIASTINAL: -congestion/erythrophagocytosi s ----2- 1--- LYMPH NODE. SUBMANDIBULAR: -hyperplasi a , 1ymphocyti c/plasmacyti c 13 12 - - 1 1-- NERVE, SCIATIC: ---------- 1-6 418-027 :PAGE J-23 ORAL (GAVASE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 TABLE 1-4 (Continued) Hi stomorphologi c Obs e r v a t i o n s Dose Group: Animal Number: Sex: Death Type: PARATHYROID: IV 17621 M SS IV 17622 M SS IV 17625 M SS IV 17629 M SS IV 17636 M SS IV 17637 M SS IV 17641 M SS IV 17644 M SS IV 17647 M SS IV 17654 M SS - - - - * - - k - - PEYER'S PATCH: -mineralization ----- 1-- -- PROSTATE: -atrophy, focal -inflammation, chronic, multifocal -prostatitis, suppurative 1 - - - 1- - - l- - - - - <4> - - - - - RECTUM: -parasite(s) P--- P----- SEMINAL VESICLES: ---------- SPINAL CORD. CERVICAL: ---------- SPINAL CORD. LUMBAR: ---------- SPINAL CORD. THORACIC: ---------- SPLEEN: -hematopoiesis, extramedullary, increased - - - - - - - 1- - -lymphosarcoma <XM> - - - - - - - - - STOMACH: -dilatation, mucosal glands ---1- 12--- -edema/infiammati on, submucosa, glandular area - -- - 32- -3- -edema/inflanimation, submucosa, nonglandular area -- - 12 1 - -3 - -erosion(s), glandular mucosa 12 - - - - - - - - TESTES: ---------- THYMUS: ---------- THYROID: -ultimobranchial body/cyst ---PPP---- TRACHEA: ---------- URINARY BLADDER: 1-7 418-027 :PAGEJ-24 ORAL (SAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 TABLE 1-5 Dose Group: Animal Number: Sex: Death Tvoe: Histomorphologic Observations I 17681 F SS I 17690 F SS I 17694 F SS I 17695 F SS I 17703 F SS I 17713 F SS I 17715 F SS I 17716 F SS I 17717 F SS I 17719 F SS ADRENAL GLANDS: -infiltration, mononuclear-cell, multifocal _ _ __ _1 _ BONE MARROW (STERNUM): ---------- BRAIN: -------- - - CECUM: - - - ---- --- COLON: ---------- DUODENUM: ---------- HEART: -pericarditis, chronic, focal ILEUM: JEJUNUM: KIDNEYS: -mineralization, multifocal LIVER: -inflammation, chronic, focal/multifocal -necrosis, focal -vacuolation, hepatocellular, multifocal LUNG: -inflammation, interstitial, multifocal -macrophages, alveoli, focal LYMPH NODE. MEDIASTINAL: -congesti on/erythrophagocytosi s -hyperplasia, lymphocytic/plasmacytic -macrophages, pigmented LYMPH NODE. SUBMANDIBULAR: -hyperplasia, 1ymphocyti c/plasmacytic - - - - - 1- _- - ------- - - - - - -------- 1- - - 1- - - - - 1 11 - - - - - - - 1- - - - - - 1- - - - 1 - - 1- - - - - - - - - 1- - - - - - * - - - 1- - - - - k - - 11- - - --k 3 12- 3 12 121 MAMMARY GLAND: -hyperplasia, physiological -inflammation, subacute NERVE, SCIATIC: PPPPPPPPPP ---------2 __- _ _ __ - _ _ OVARIES: ---------- PARATHYROID: ---------- PEYER'S PATCH: ---------- 1-8 418-027 :PAGE J-25 ORAL (GAVA6E) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 TABLE 1-5 (Continued) Histomorphalogic Observations Dose Group: Animal Number Sex: Death Type: I II I I I 17681 17690 17694 17695 17703 17713 FFFFFFF SS SS SS____ SS____ SS____ SS I 17715 F SS I 17716 F SS I 17717 F SS I 17719 SS____ RECTUM: SPINAL CORD. CERVICAL: - SPINAL CORD. LUMBAR: - SPINAL CORD. THORACIC: - SPLEEN: -hematopoiesis, extramedullary, increased 2 - - 2 2 - 1 - - - STOMACH: -dilatation, mucosal glands -1-------- THYMUS: -atrophy ---------l THYROID: -ultimobranchial body/cyst TRACHEA: P---P---P__________ URINARY BLADDER: __________ UTERUS: -distention, lumen -macrophages, pigmented -thrombus VAGINA: -mucification 13 3 3 3 3 3 3 P- -- P 33 1-9 418-027 :PAGEJ-26 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 TABLE 1-6 Histomorphologic Observations Dose Group: Animal Number Sex: Death Type: II II II II II 17675 17679 17684 17688 17698 FFFFFF SS SS SS SS SS II 17702 F SS II 17704 F SS II 17707 F SS II 17708 F SS II 17710 SS LIVER: -inflammation, chronic, -necrosis, focal focal/multi focal ------11 -------1 THYMUS: -atrophy ----1--- 1-10 418-027 :PAGE J-27 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 TABLE 1-7 Histomorphologic Observations Dose Group: Animal Number: Sex: D eath Type:___________________________________ III III III III III 17687 17693 17697 17700 17701 FFFFFF SS SS SS SS SS III 17705 F SS III 17706 F SS III 17709 F SS III 17718 F SS III 17720 SS LIVER: -inflammation, chronic, focal/multifocal 1- 1111- - 1 THYMUS: -atrophy 1 1-11 418-027 :PAGE J-28 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELQPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 TABLE 1-8 Histomorphologic Observations Dose Group: Animal Number: Sex: Death Type: IV IV IV IV IV IV 17685 17686 17689 17691 17692 17696 FFFFFFF SS SS SS SS SS SS IV 17699 F SS IV 17711 F SS IV 17712 F SS IV 17714 SS ADRENAL GLANDS: BONE MARROW fSTERNUM): BRAIN: CECUM: COLON: DUODENUM: HEART: -inflammation, subacute, focal/multifocal ILEUM: JEJUNUM: KIDNEYS: -mineralization, multifocal -pyelitis, chronic -vacuo!ation, cortical tubular epithelium 1 1- 1 2 LIVER: -hypertrophy, hepatocellular,centrilobular -inflammation, chronic, focal/multifocal -lipidosis, tension, focal -vacuolation, hepatocellular, periportal 1 P 1 111-12 11- - 1- 12 1- LUNG: LYMPH NODE. MEDIASTINAL: -congesti on/erythrophagocytosi s 2-2----* LYMPH NODE. SUBMANDIBULAR: -hyperplasia, lymphocytic/plasmacytic MAMMARY GLAND: -hyperplasia, physiological 3 321323-2P PPPPPPPPP NERVE. SCIATIC: OVARIES: PARATHYROID: PEYER'S PATCH: RECTUM: SPINAL CORD. CERVICAL: 1-12 418-027 :PAGE J-29 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 TABLE 1-8 (Continued) Histomorphologic Observations Dose Group: Animal Number Sex: Death Type: IV IV IV IV IV 17685 17686 17689 17691 17692 FFFFFF SS SS SS SS SS IV 17696 F SS IV 17699 F SS IV 17711 F SS IV 17712 F SS IV 17714 SS SPINAL CORD. LUMBAR: SPINAL CORD. THORACIC: SPLEEN: -atrophy -hematopoiesis, extramedullary, increased -- - - 1- --- -2 1- -- -1 A 11 V STOMACH: TAIL: THYMUS: -atrophy A * V ---2 13 12 THYROID: -ultimobranchial body/cyst p -p-P P --P TRACHEA: --------- URINARY BLADDER: UTERUS: -distention, lumen -hemorrhage, endometrium -inflammation, endometrium, -macrophages, pigmented -thrombus diffuse - "_ 3 - 2 -2 123 333 23 -- - " - - - - P VAGINA: -inflammation, acute - m u c i fi c a t i o n -3 3 4 1-13 418-027 :PAGE J-30 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 HISTOPATHOLOGY REPORT APPENDIX II INDIVIDUAL ANIMAL GROSS AND HISTOMORPHOLOGY DATA 418-027 :PAGE J-31 ORAL (6AVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x 11 Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17608 SEX: M DOSE GROUP: DEATH TYPE: I Sacri fi ce-Schedul ed GROSS OSSERVATION(Si: GENERAL: No aross chanaes HISTOMORPHOLOGIC OBSERVATION(Si : Not appli cable HISTOMORPHOLOGIC OBSERVATIONS: ADRENAL GLANDS: LIVER: LUNG: THYROID: TRACHEA: vacuo!ation, cortex (mild) inflammation, chronic, focal/multifocal (minimal) inflammation, interstitial, multifocal (minimal) ultimobranchial body/cyst inflammation, chronic, focal (mi nimal ) THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS: BONE MARROW (STERNUM) COLON ILEUM LYMPH NODE, SUBMANDIBULAR PROSTATE SPINAL CORD, LUMBAR TESTES BRAIN DUODENUM JEJUNUM NERVE, SCIATIC RECTUM SPINAL CORD, THORACIC THYMUS CECUM EPIDIDYMIDES KIDNEYS PARATHYROID SEMINAL VESICLES SPLEEN URINARY BLADDER End of Record- 17608 COAGULATING GLAND HEART LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD, CERVICAL STOMACH II-l 418-027 :PAGE J-32 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17618 SEX: M DOSE GROUP: DEATH TYPE: I Sacrifice-Scheduled GROSS OBSERVATION(S): GENERAL: No gross changes. HISTOMQRPHOLOGIC OBSERVATION!Si : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: CECUM: LIVER: STOMACH: inflammation, mucosa, chronic (mild) inflammation, chronic, focal/multifocal (mild) dilatation, mucosal glands (minimal) edema/infiammati on, submucosa, glandular area (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON ILEUM LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD, CERVICAL TESTES URINARY BLADDER BONE MARROW (STERNUM) BRAIN DUODENUM EPIDIDYMIDES JEJUNUM KIDNEYS LYMPH NODE, SUBMANDIBULAR NERVE, SCIATIC PROSTATE RECTUM SPINAL CORD, LUMBAR SPINAL CORD, THORACIC THYMUS THYROID End of Record- 17618 COAGULATING GLAND HEART LUNG PARATHYROID SEMINAL VESICLES SPLEEN TRACHEA 418-027-.PAGE J-33 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17630 SEX: M DOSE GROUP: DEATH TYPE: I Sacrifice-Scheduled GROSS OBSERVATIONS! : GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATIONfS 1: Not applicable HISTOMORPHOLOGIC OBSERVATIONS: ADRENAL GLANDS: LIVER: STOMACH: vacuolati on, cortex (minimal) infiammati on, chronic, focal/multi focal (minimal) dilatation, mucosal glands (minimal) edema/infiammati on, submucosa, nonglandular area (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: BONE MARROW (STERNUM) BRAIN COLON DUODENUM ILEUM JEJUNUM LYMPH NODE, SUBMANDIBULAR NERVE, SCIATIC PROSTATE RECTUM SPINAL CORD, LUMBAR SPINAL CORD, THORACIC THYMUS THYROID CECUM EPIDIDYMIDES KIDNEYS PARATHYROID SEMINAL VESICLES SPLEEN TRACHEA COAGULATING GLAND HEART LUNG PEYER'S PATCH SPINAL CORD, CERVICAL TESTES URINARY BLADDER TISSUE(S) NOT AVAILABLE FOR EVALUATION: LYMPH NODE, MEDIASTINAL End of Record- 17630 11-3 418-027 :PAGE J-34 ORAL (GAVASE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17631 SEX: M DOSE GROUP: DEATH TYPE: I Sacrifice-Scheduled GROSS OBSERVATION!S): GENERAL: No gross changes. HISTOMORPHQLQGIC OBSERVATIONfS^: Not applicable HISTOMORPHQLQGIC OBSERVATIONS: KIDNEYS: LIVER: LYMPH NODE, SUBMANDIBULAR: PROSTATE: THYROID: dilatation, pelvis (mild) vacuolation, hepatocellular, periportal (minimal) inflammation, chronic, focal/multifocal (minimal) hyperplasia, lymphocytic/plasmacytic (mild) atrophy, focal (minimal) ultimobranchial body/cyst hypertrophy, follicular epithelium (mild) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COAGULATING GLAND HEART LYMPH NODE, MEDIASTINAL RECTUM SPINAL CORD, THORACIC THYMUS BONE MARROW (STERNUM) COLON ILEUM NERVE, SCIATIC SEMINAL VESICLES SPLEEN TRACHEA BRAIN DUODENUM JEJUNUM PARATHYROID SPINAL CORD, CERVICAL STOMACH URINARY BLADDER End of Record- 17631 CECUM EPIDIDYMIDES LUNG PEYER'S PATCH SPINAL CORD, LUMBAR TESTES 11-4 418-027 :PAGE J-35 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17639 SEX: M DOSE GROUP: DEATH TYPE: I Sacrifice-Scheduled GROSS OBSERVATIONfS1 : GENERAL: No qross chanaes. HISTOMORPHOLOGIC OBSERVATIONfSi : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: EPIDIDYMIDES: LYMPH NODE, MEDIASTINAL: LYMPH NODE, SUBMANDIBULAR:: infiltration, mononuclear-cell, focal (minimal) congestion/erythrophagocytosis (minimal) hyperplasia, 1ymphocytic/plasmacytic (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COAGULATING GLAND ILEUM LUNG PROSTATE SPINAL CORD, LUMBAR TESTES URINARY BLADDER BONE MARROW (STERNUM) COLON JEJUNUM NERVE, SCIATIC RECTUM SPINAL CORD, THORACIC THYMUS BRAIN DUODENUM KIDNEYS PARATHYROID SEMINAL VESICLES SPLEEN THYROID End of Record- 17639 CECUM HEART LIVER PEYER'S PATCH SPINAL CORD, CERVICAL STOMACH TRACHEA 11-5 418-027 :PAGE J-36 ORAL (6AVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17648 SEX: M DOSE GROUP: DEATH TYPE: I Sacrifice-Scheduled G ROSS O B S E R V A T I O N f S ): GENERAL: No gross changes. HIST0M0RPH0L06IC OBSERVATIONfS: Not applicable HISTOMORPHOLOGIC OBSERVATIONS: HEART: KIDNEYS: LIVER: LYMPH NODE, STOMACH: SUBMANDIBULAR: inflammation, subacute, focal/multifocal (mild) infiltration, mononuclear-cell, focal (minimal) inflammation, chronic, focal/multifocal (minimal) hyperplasia, 1ymphocytic/plasmacytic (mild) dilatation, mucosal glands (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COAGULATING GLAND ILEUM NERVE, SCIATIC RECTUM SPINAL CORD, THORACIC THYROID BONE MARROW (STERNUM) COLON JEJUNUM PARATHYROID SEMINAL VESICLES SPLEEN TRACHEA BRAIN DUODENUM LUNG PEYER'S PATCH SPINAL CORD, CERVICAL TESTES URINARY BLADDER End of Record- 17648 CECUM EPIDIDYMIDES LYMPH NODE, MEDIASTINAL PROSTATE SPINAL CORD, LUMBAR THYMUS 11-6 418-027-.PAGE J-37 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17652 SEX: M DOSE GROUP: DEATH TYPE: I Sacrifice-Scheduled GROSS OBSERVATIONS): GENERAL: No gross changes. HISTQMORPHOLOGIC OBSERVATION(S): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: RECTUM: STOMACH: inflammation, chronic, focal/multifocal (minimal) edema/inflammation, submucosa (moderate) edema/inflammation, submucosa, glandular area (mild) THE FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COAGULATING GLAND HEART LUNG PARATHYROID SPINAL CORD, CERVICAL TESTES URINARY BLADDER BONE MARROW (STERNUM) COLON ILEUM LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD, LUMBAR THYMUS BRAIN CECUM DUODENUM EPIDIDYMIDES JEJUNUM KIDNEYS LYMPH NODE, SUBMANDIBULAR NERVE, SCIATIC PROSTATE SEMINAL VESICLES SPINAL CORD, THORACIC SPLEEN THYROID TRACHEA End of Record- 17652 11-7 418-027-.PAGE J-38 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17656 SEX: M DOSE GROUP: DEATH TYPE: I Sacrifice-Scheduled GROSS OBSERVATION(Si ; GENERAL: No gross changes. HISTOMORPHOLOGIC 0BSERVATI0NS): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: EPIDIDYMIDES: KIDNEYS: LYMPH NODE, SUBMANDIBULAR PROSTATE: infiltration, mononuclear-cell, focal (minimal) edema, papillary (minimal) hyperplasia, 1ymphocytic/plasmacytic (minimal) inflammation, chronic, multifocal (minimal) THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS ADRENAL GLANDS COAGULATING GLAND ILEUM LYMPH NODE, MEDIASTINAL RECTUM SPINAL CORD, THORACIC THYMUS BONE MARROW (STERNUM) COLON JEJUNUM NERVE, SCIATIC SEMINAL VESICLES SPLEEN THYROID End of Record- 17656 BRAIN DUODENUM LIVER PARATHYROID SPINAL CORD, STOMACH TRACHEA CERVICAL CECUM HEART LUNG PEYER'S PATCH SPINAL CORD, LUMBAR TESTES URINARY BLADDER 11-8 418-027 :PAGE J-39 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17658 SEX: M DOSE GROUP: DEATH TYPE: I Sacrifice-Scheduled GROSS OBSERVATION!S): GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATIONfSi : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: THYROID: ultimobranchial body/cyst THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COAGULATING GLAND HEART LIVER NERVE, SCIATIC RECTUM SPINAL CORD, THORACIC THYMUS BONE MARROW (STERNUM) COLON ILEUM LUNG PARATHYROID SEMINAL VESICLES SPLEEN TRACHEA BRAIN DUODENUM JEJUNUM LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD, CERVICAL STOMACH URINARY BLADDER End of Record- 17658 CECUM EPIDIDYMIDES KIDNEYS LYMPH NODE, SUBMANDIBULAR PROSTATE SPINAL CORD, LUMBAR TESTES 11-9 418-027 :PAGE J-40 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17660 SEX: M DOSE GROUP: DEATH TYPE: I Sacrifice-Scheduled GROSS OBSERVATIONfSI: GENERAL: No gross changes. HISTOMORPHOLQGIC OBSERVATIONfS): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: LYMPH NODE, SUBMANDIBULAR:: inflammation, chronic, focal/multifocal (minimal) hyperplasia, 1ymphocytic/plasmacytic (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COAGULATING GLAND HEART LUNG PEYER'S PATCH SPINAL CORD, CERVICAL STOMACH TRACHEA BONE MARROW (STERNUM) COLON ILEUM LYMPH NODE, MEDIASTINAL PROSTATE SPINAL CORD, LUMBAR TESTES URINARY BLADDER BRAIN DUODENUM JEJUNUM NERVE, SCIATIC RECTUM SPINAL CORD, THORACIC THYMUS End of Record- 17660 CECUM EPIDIDYMIDES KIDNEYS PARATHYROID SEMINAL VESICLES SPLEEN THYROID 11-10 418-027 :PAGE J-41 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17634 SEX: M DOSE GROUP: DEATH TYPE: II Sacrifice-Scheduled GROSS OBSERVATIONfSI: GENERAL: No gross changes. HIST0M0RPH0L06IC OBSERVATIONfS): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: inflammation, chronic, focal/multifocal (minimal) THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS: STOMACH End of Record- 17634 11-11 418-027 :PAGE J-42 ORAL (GAVA6E) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17635 SEX M DOSE GROUP: DEATH TYPE: II Sacrifice-Scheduled GROSS OBSERVATIONS): GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATIONfSi : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: STOMACH: End of Record- 17635 vacuolation, hepatocellular, periportal inflammation, chronic, focal/multifocal dilatation, mucosal glands (minimal) (minimal) (minimal) 11-12 418-027 :PAGE J-43 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 S P O N S O R 'S STUDY N U M B E R T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17638 SEX: M DOSE GROUP: DEATH TYPE: II Sacrifice-Scheduled GROSS QBSERVATIQNfS): GENERAL: No gross changes. H I S T O M O R P H O L O G I C O B S E R V A T I O N f S 1): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: lipidosis, tension, focal THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS: STOMACH End of Record- 17638 11-13 418-027 :PAGE J-44 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17642 SEX: M DOSE GROUP: DEATH TYPE: II Sacrifice-Scheduled GROSS OBSERVATION(S): GENERAL: No gross changes. H I S T O M O R P H O L O G I C O B S E R V A T I O N ( S ): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: inflammation, chronic, focal/multifocal (mild) THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS: STOMACH End of Record- 17642 11-14 418-027 :PAGE J-45 ORAL (GAVA6E) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17643 SEX: M DOSE GROUP: DEATH TYPE: II Sacrifice-Scheduled GROSS OBSERVATION!S): GENERAL: No qross chanaes. HISTOMORPHOLOGIC OBSERVATION!S): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: STOMACH: End of Record- 17643 inflammation, chronic, focal/multifocal (mild) dilatation, mucosal glands (mild) 418-027 :PAGE J-46 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 S P O N S O R 'S STUDY N U M B E R T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17645 SEX: M DOSE GROUP: DEATH TYPE: II Sacrifice-Scheduled GROSS OBSERVATIONfST: GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATIONfSl: Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: inflammation, chronic, focal/multifocal (minimal) THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS: STOMACH End of Record- 17645 11-16 418-027 :PAGE J-47 ORAL (6AVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17649 SEX M DOSE GROUP: DEATH TYPE: II Sacrifice-Scheduled GROSS OBSERVATION!Si : GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION!Si : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: STOMACH: End of Record- 17649 inflammation, chronic, focal/multifocal (minimal) edema/inflanimation, submucosa, nonglandular area (moderate) 11-17 418-027 :PAGE J-48 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17651 SEX M DOSE GROUP: DEATH TYPE: II Sacrifice-Scheduled GROSS OBSERVATION(Si: GENERAL: No gross changes. HISTOMQRPHOLOGIC OBSERVATION^! : Not a p p i icab!e THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS: LIVER STOMACH End of Record- 17651 11-18 418-027 :PAGE J-49 ORAL (6AVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphol ogy Data ANIMAL NUMBER: 17653 SEX: M DOSE GROUP: DEATH TYPE: II Sacrifice-Scheduled GROSS OBSERVATIONfS^: GENERAL: No gross changes. H I S T O M O R P H O L O G I C O B S E R V A T I O N f S ): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: vacuolation, hepatocellular, periportal (minimal) THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS: STOMACH End of Record- 17653 11-19 418-027 :PAGE J-50 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17655 SEX: M DOSE GROUP: DEATH TYPE: II Sacrifice-Scheduled GROSS OBSERVATIONfSl; GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATIONfSl: Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: inflammation, chronic, focal/multifocal (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: STOMACH End of Record- 17655 11-20 418-027 :PAGE J-51 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17620 SEX M DOSE GROUP: DEATH TYPE: III Sacrifice-Scheduled GROSS OBSERVATION(Si: GENERAL: No gross changes. HISTOMORPHQLOGIC OBSERVATION(ST : Not applicable HISTOMORPHQLOGIC OBSERVATIONS: LIVER: STOMACH: End of Record- 17620 hypertrophy, hepatocellular, centrilobular (minimal) edema/infiammati on, submucosa, glandular area (minimal) dilatation, mucosal glands (minimal) 11-21 418-027 :PAGE J-52 ORAL (6AVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17623 SEX: M DOSE GROUP: DEATH TYPE: III Sacrifice-Scheduled GROSS OBSERVATIONfS1: GENERAL: No gross changes. HIST0M0RPH0L06IC OBSERVATIONfS^; Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: inflammation, chronic, focal/multifocal (minimal) THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS: STOMACH End of Record- 17623 11-22 418-027 :PAGE J-53 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17627 SEX: M DOSE GROUP: DEATH TYPE: III Sacrifice-Scheduled G R OSS O B S E R V A T I O N (Si: GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION^! : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: inflammation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (minimal) THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS: STOMACH End of Record- 17627 11-23 418-027 :PAGE J-54 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17628 SEX: M DOSE GROUP: DEATH TYPE: III Sacrifice-Scheduled GROSS OBSERVATIONfS): GENERAL: No gross changes. HISTOMORPHOLQGIC OBSERVATIONfS^: Not applicable HISTOMORPHOLQGIC OBSERVATIONS: LIVER: inflammation, chronic, focal/multifocal (minimal) THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS: STOMACH End of Record- 17628 11-24 418-027:PAGE J-55 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17633 SEX: M DOSE GROUP: DEATH TYPE: III Sacrifice-Scheduled GROSS O B S E R V A T I O N S : GENERAL: No gross changes. H I S T O M O R P H O L O G I C O B S E R V A T I O N ( S ): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: hypertrophy, hepatocellular, centrilobular (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: STOMACH End of Record- 17633 11-25 418-027:PAGE J-56 ORAL (GAVA6E) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17640 SEX M DOSE GROUP: DEATH TYPE: III Sacrifice-Scheduled GROSS OBSERVATION(S): GENERAL: No gross changes. HISTOMORPHOLQGIC OBSERVATIONfS: Not applicable THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: LIVER STOMACH End of Record- 17640 11-26 418-027:PAGE J-57 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17646 SEX: M DOSE GROUP: DEATH TYPE: III Sacrifice-Scheduled GROSS OBSERVATIONfSV: GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION!Si : Not applicable HIST0M0RPH0LQGIC OBSERVATIONS: LIVER: inflammation, chronic, focal/multifocal (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: STOMACH End of Record- 17646 11-27 418-027 :PAGE J-58 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17650 SEX M DOSE GROUP: DEATH TYPE: III Sacrifice-Scheduled GROSS OBSERVATION!S!: GENERAL: No gross changes. HIST0M0RPH0L06IC OBSERVATION(S): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: STOMACH: End of Record- 17650 hypertrophy, hepatocellular, centrilobular (minimal) dilatation, mucosal glands (minimal) edema/inflammation, submucosa, glandular area (minimal) 11-28 418-027 :PAGE J-59 ORAL (SAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17657 SEX: M DOSE GROUP: DEATH TYPE: III Sacrifice-Scheduled GROSS OBSERVATION(S): GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION(S): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: inflammation, chronic, focal/multifocal (minimal) THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS: STOMACH End of Record- 17657 11-29 418-027`.PAGE J-60 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17659 SEX: M DOSE GROUP: DEATH TYPE: III Sacrifice-Scheduled GROSS OBSERVATION(Si: GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATIONfSi: Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: inflammation, chronic, focal/multifocal (minimal) THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS: STOMACH End of Record- 17659 11-30 418-027 :PAGE J-61 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17621 SEX: M DOSE GROUP: DEATH TYPE: IV Sacrifice-Scheduled GROSS OBSERVATIONS! : SPLEEN: Nodule, 0.3cm (trimming observation). HISTOMORPHOLQGIC OBSERVATION(Si : lymphosarcoma HISTOMORPHOLOGIC OBSERVATIONS: ADRENAL GLANDS: LIVER: LYMPH NODE, RECTUM: SPLEEN: STOMACH: SUBMANDIBULAR: vacuolation, cortex (minimal) inflammation, chronic, focal/multifocal (mild) hypertrophy, hepatocellular, centrilobular (mild) hyperplasia, 1ymphocytic/plasmacytic (minimal) parasite(s) 1ymp h o s a r c o m a , m a l ignant erosion(s), glandular mucosa (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: BONE MARROW (STERNUM) COLON ILEUM LYMPH NODE, MEDIASTINAL PROSTATE SPINAL CORD, THORACIC TRACHEA BRAIN DUODENUM JEJUNUM NERVE, SCIATIC SEMINAL VESICLESi TESTES URINARY BLADDER CECUM EPIDIDYMIDES KIDNEYS PARATHYROID SPINAL CORD, CERVICAL THYMUS COAGULATING GLAND HEART LUNG PEYER'S PATCH SPINAL CORD, LUMBAR THYROID NEOPLASMS: SPLEEN End of Record- 17621 1y m p h o s a r c o m a , mal ignant 11-31 418-027-.PAGE J-62 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17622 SEX: M DOSE GROUP: DEATH TYPE: IV Sacrifice-Scheduled GROSS OBSERVATION!Si : EXTREMITIES: Right front leg- scab. HISTOMORPHOLOGIC OBSERVATION^) : dermatitis, ulcerative, focal HISTOMORPHOLOGIC OBSERVATIONS: EXTREMITIES: LIVER: LYMPH NODE, SUBMANDIBULAR:: PROSTATE: STOMACH: dermatitis, ulcerative, focal (mild) hypertrophy, hepatocellular, centrilobular (mild) hyperplasia, 1ymphocytic/piasmacytic (moderate) atrophy, focal (minimal) erosion(s). glandular mucosa (mild) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COAGULATING GLAND HEART LUNG PEYER'S PATCH SPINAL CORD, LUMBAR THYMUS BONE MARROW (STERNUM) COLON ILEUM LYMPH NODE, MEDIASTINAL RECTUM SPINAL CORD, THORACIC THYROID BRAIN DUODENUM JEJUNUM NERVE, SCIATIC SEMINAL VESICLES SPLEEN TRACHEA End of Record- 17622 CECUM EPIDIDYMIDES KIDNEYS PARATHYROID SPINAL CORD, CERVICAL TESTES URINARY BLADDER 11-32 418-027 :PAGE J-63 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17625 SEX: M DOSE GROUP: DEATH TYPE: IV Sacrifice-Scheduled GROSS OBSERVATION(S): GENERAL: No gross changes. HIST0M0RPHQLQ6IC OBSERVATIONfSl: Not applicable HISTOMORPHOLOGIC OBSERVATIONS: ADRENAL GLANDS: LIVER: LYMPH NODE, SUBMANDIBULAR: hypertrophy/vacuolation, zona glomerulosa (mild) necrosis, focal (minimal) hypertrophy, hepatocellular, centrilobular (mild) hyperplasia, 1ymphocytic/piasmacytic (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: BONE MARROW (STERNUM) COLON ILEUM LYMPH NODE, MEDIASTINAL PROSTATE SPINAL CORD, LUMBAR TESTES URINARY BLADDER BRAIN DUODENUM JEJUNUM NERVE, SCIATIC RECTUM SPINAL CORD, THORACIC THYMUS CECUM EPIDIDYMIDES KIDNEYS PARATHYROID SEMINAL VESICLES SPLEEN THYROID End of Record- 17625 COAGULATING GLAND HEART LUNG P E Y E R 'S PATCH SPINAL CORD, CERVICAL STOMACH TRACHEA 11-33 418-027 :PAGE J-64 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17629 SEX: M DOSE GROUP: DEATH TYPE: IV Sacrifice-Scheduled GROSS OBSERVATION!SI: GENERAL: No gross changes. HISTOMORPBOLQGIC OBSERVATION^! : Not applicable HISTOMQRPHOLOGIC OBSERVATIONS: KIDNEYS: LIVER: LUNG: LYMPH NODE, SUBMANDIBULAR: PROSTATE: STOMACH: THYROID: cyst(s), medulla hypertrophy, hepatocellular, centrilobular (mild) macrophages, alveoli, focal (minimal) inflammation, interstitial, multi focal (minimal) hyperplasia, 1ymphocytic/plasmacytic (mild) inflanimation, chronic, mul ti focal ( m i n i m a l ) edema/inflamnation, submucosa, nonglandular area (minimal) dilatation, mucosal glands (minimal) ultimobranchial body/cyst THE FOLLOWING TISSUEfS) ADRENAL GLANDS COAGULATING GLAND HEART NERVE, SCIATIC SEMINAL VESICLES SPLEEN URINARY BLADDER IRE W I T H I N NORMAL LIMITS: BONE MARROW (STERNUM) COLON ILEUM PARATHYROID SPINAL CORD, CERVICAL TESTES BRAIN DUODENUM JEJUNUM PEYER'S PATCH SPINAL CORD, LUMBAR THYMUS CECUM EPIDIDYMIDES LYMPH NODE, MEDIASTINAL RECTUM SPINAL CORD, THORACIC TRACHEA COMMENTS : STOMACH End of Record- 17629 The edema/ infl animation is most prominent at the limiting ridge. 11-34 418-027`.PAGE J-65 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17636 SEX: M DOSE GROUP: DEATH TYPE: IV Sacrifice-Scheduled GROSS OBSERVATIONfS^: PROSTATE: Right hemisphere- firm, lobular mass, tan in color, m e asuring 2.8cm x 0.9cm x 0.7cm, cut surface reveals tan, smooth surface, ventral right side red in color. HISTOMORPHOLOGIC OBSERVATION^Si: prostatitis, suppurative HISTOMORPHOLOGIC OBSERVATIONS: ADRENAL GLANDS: KIDNEYS: LIVER: LYMPH NODE, PROSTATE: RECTUM: STOMACH: MEDIASTINAL: THYROID: vacuo!ation, cortex (minimal) cyst(s), medulla inflammation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (minimal) congesti on/ e r y t h r o p h a g o c y t os i s (mi 1d) prostatitis, suppurative (marked) parasite(s) edema/infiammati on, submucosa, glandular area (moderate) edema/inflammation, submucosa, nonglandular area (mild) ultimobranchial body/cyst THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: BONE MARROW (STERNUM) COLON ILEUM NERVE, SCIATIC SPINAL CORD, LUMBAR THYMUS BRAIN DUODENUM JEJUNUM PEYER'S PATCH SPINAL CORD, THORACIC TRACHEA CECUM EPIDIDYMIDES LUNG SEMINAL VESICLES SPLEEN URINARY BLADDER COAGULATING GLAND HEART LYMPH NODE, SUBMANDIBULAR SPINAL CORD, CERVICAL TESTES TISSUE(S) NOT AVAILABLE FOR EVALUATION: PARATHYROID End of Record- 17636 11-35 418-027 .-PAGE J-66 ORAL (6AVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17637 SEX: M DOSE GROUP: DEATH TYPE: IV Sacrifice-Scheduled GROSS OBSERVATION(S): GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATIONS): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: PEYER'S PATCH: STOMACH: THYROID: necrosis, individual hepatocytes (minimal) hypertrophy, hepatocellular, centrilobular (mild) mineralization (minimal) edema/inflammation, submucosa, nonglandular area (minimal) edema/inflammation, submucosa, glandular area (mild) dilatation, mucosal glands (minimal) ultimobranchial body/cyst THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COAGULATING GLAND HEART LUNG PARATHYROID SPINAL CORD, CERVICAL TESTES BONE MARROW (STERNUM) COLON ILEUM LYMPH NODE, MEDIASTINAL PROSTATE SPINAL CORD, LUMBAR THYMUS BRAIN CECUM DUODENUM EPIDIDYMIDES JEJUNUM KIDNEYS LYMPH NODE, SUBMANDIBULAR NERVE, SCIATIC RECTUM SEMINAL VESICLES SPINAL CORD, THORACIC SPLEEN TRACHEA URINARY BLADDER End of Record- 17637 11-36 418-027 :PAGE J-67 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17641 SEX: M DOSE GROUP: DEATH TYPE: IV Sacrifice-Scheduled GROSS OBSERVATION(S) : GENERAL: No gross changes. H I S T O M O R P H O L O G I C O B S E R V A T I O N f S ): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: KIDNEYS: LIVER: LYMPH NODE, MEDIASTINAL: LYMPH NODE, SUBMANDIBULAR: STOMACH: mineralization, multifocal (minimal) inflammation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (mild) necrosis, individual hepatocytes (minimal) c o n g e s t ! o n / e r y t h r o ph a g o c y t o s i s (mi ni m a l ) hyperplasia, 1ymphocytic/plasmacytic (minimal) dilatation, mucosal glands (mild) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COAGULATING GLAND HEART NERVE, SCIATIC RECTUM SPINAL CORD, THORACIC THYROID BONE MARROW (STERNUM) COLON ILEUM PARATHYROID SEMINAL VESICLES SPLEEN TRACHEA BRAIN DUODENUM JEJUNUM PEYER'S PATCH SPINAL CORD, CERVICAL TESTES URINARY BLADDER End of Record- 17641 CECUM EPIDIDYMIDES LUNG PROSTATE SPINAL CORD, THYMUS LUMBAR 11-37 418-027 :PAGE J-68 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17644 SEX: M DOSE GROUP: DEATH TYPE: IV Sacrifice-Scheduled GROSS OBSERVATIONfS^: GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION!Si : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: ADRENAL GLANDS: LIVER: LYMPH NODE, SUBMANDIBULAR: PROSTATE: SPLEEN: vacuo!ation, cortex (minimal) hypertrophy, hepatocellular, centrilobular (mild) necrosis, individual hepatocytes (mild) hyperplasia, 1ymphocytic/plasmacytic (minimal) inflammation, chronic, multifocal (minimal) hematopoiesis, extramedullary, increased (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: BONE MARROW (STERNUM) COLON ILEUM LYMPH NODE, MEDIASTINAL SEMINAL VESICLES STOMACH TRACHEA BRAIN DUODENUM JEJUNUM NERVE. SCIATIC SPINAL CORD, CERVICAL TESTES URINARY BLADDER CECUM EPIDIDYMIDES KIDNEYS PEYER'S PATCH SPINAL CORD, LUMBAR THYMUS COAGULATING GLAND HEART LUNG RECTUM SPINAL CORD, THORACIC THYROID TISSUE(S) NOT AVAILABLE FOR EVALUATION: PARATHYROID End of Record- 17644 11-38 418-027 :PAGE J-69 ORAL (GAVASE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphol ogy Data ANIMAL NUMBER: 17647 SEX: M DOSE GROUP: DEATH TYPE: IV Sacrifice-Scheduled GROSS OBSERVATION!Si : GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION!S): Not a p p i icable HISTOMORPHOLOGIC OBSERVATIONS: EPIDIDYMIDES: LIVER: STOMACH: infiltration, mononuclear-cell, focal (minimal) hypertrophy, hepatocellular, centrilobular (mild) edema/inflammation, submucosa, nonglandular area (moderate) edema/inflammation, submucosa, glandular area (moderate) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COAGULATING GLAND ILEUM LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD, CERVICAL TESTES URINARY BLADDER BONE MARROW (STERNUM) BRAIN COLON DUODENUM JEJUNUM KIDNEYS LYMPH NODE, SUBMANDIBULAR NERVE, SCIATIC PROSTATE RECTUM SPINAL CORD, LUMBAR SPINAL CORD, THORACIC THYMUS THYROID End of Record- 17647 CECUM HEART LUNG PARATHYROID SEMINAL VESICLES SPLEEN TRACHEA 11-39 418-027 :PAGE J-70 ORAL (GAVA6E) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17654 SEX: M DOSE GROUP: DEATH TYPE: IV Sacrifice-Scheduled GROSS OBSERVATION(S): GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION(S): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: HEART: KIDNEYS: LIVER: inflammation, subacute, focal/multifocal (minimal) nephritis, chronic, focal (minimal) lipidosis, tension, focal inflammation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS BONE MARROW (STERNUM) COAGULATING GLAND COLON ILEUM JEJUNUM LYMPH NODE, SUBMANDIBULAR NERVE, SCIATIC PROSTATE RECTUM SPINAL CORD, LUMBAR SPINAL CORD, THORACIC TESTES THYMUS URINARY BLADDER BRAIN DUODENUM LUNG PARATHYROID SEMINAL VESICLES SPLEEN THYROID End of Record- 17654 CECUM EPIDIDYMIDES LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD, CERVICAL STOMACH TRACHEA 11-40 418-027 :PAGE J-71 ORAL (6AVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17681 SEX: F DOSE GROUP: DEATH TYPE: I Sacrifice-Scheduled GROSS OBSERVATIONfS^: GENERAL: No gross changes. HISTQMORPHOLQGIC OBSERVATIONfS') : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: KIDNEYS: LYMPH NODE, SUBMANDIBULAR: MAMMARY GLAND: SPLEEN: THYROID: VAGINA: mineralization, multifocal (minimal) hyperplasia, 1ymphocytic/plasmacytic (moderate) hyperplasia, physiological hematopoiesis, extramedullary, increased (mild) ul t imobranchi al bod y / c y s t mucification (moderate) THE FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON JEJUNUM NERVE, SCIATIC RECTUM STOMACH UTERUS BONE MARROW (STERNUM) DUODENUM LIVER OVARIES SPINAL CORD, CERVICAL THYMUS BRAIN HEART LUNG PARATHYROID SPINAL CORD, TRACHEA LUMBAR End of Record- 17681 CECUM ILEUM LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD, THORACIC URINARY BLADDER 11-41 418-027 :PAGE J-72 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17690 SEX: F DOSE GROUP: DEATH TYPE: I Sacrifice-Scheduled GROSS OBSERVATION(Si: GENERAL: No aross chanaes. HISTOMORPHOLOGIC OBSERVATION(Si : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: LYMPH NODE, SUBMANDIBULAR: MAMMARY GLAND: STOMACH: VAGINA: infl animation, chronic, focal/multi focal (minimal) hyperplasia, 1ymphocytic/plasmacytic (minimal) hyperplasia, physiological dilatation, mucosal glands (minimal) muc i fi cat ion ( m o d e r a t e ) THE FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON JEJUNUM NERVE, SCIATIC RECTUM SPLEEN URINARY BLADDER BONE MARROW (STERNUM) DUODENUM KIDNEYS OVARIES SPINAL CORD, CERVICAL THYMUS UTERUS BRAIN HEART LUNG PARATHYROID SPINAL CORD, THYROID LUMBAR End of Record- 17690 CECUM ILEUM LYMPH NODE, MEDIASTINAL P E Y E R 'S PATCH SPINAL CORD, THORACIC TRACHEA 11-42 418-027 :PAGE J-73 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17694 SEX: F DOSE GROUP: DEATH TYPE: I Sacrifice-Scheduled GROSS OBSERVATION(S): GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION!Si : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LUNG: LYMPH NODE, MEDIASTINAL: LYMPH NODE, SUBMANDIBULAR: MAMMARY GLAND: UTERUS: macrophages, alveoli, focal (minimal) macrophages, pigmented (minimal) congestion/erythrophagocytosis (minimal) hyperplasia, 1ymphocytic/plasmacytic (mild) hyperplasia, physiological thrombus macrophages, pigmented (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON JEJUNUM OVARIES SPINAL CORD, CERVICAL STOMACH URINARY BLADDER BONE MARROW (STERNUM) DUODENUM KIDNEYS PARATHYROID SPINAL CORD, LUMBAR THYMUS VAGINA BRAIN HEART LIVER PEYER'S PATCH SPINAL CORD, THORACIC THYROID End of Record- 17694 CECUM ILEUM NERVE, SCIATIC RECTUM SPLEEN TRACHEA 11-43 418-027:PAGE J-74 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17695 SEX: F DOSE GROUP: DEATH TYPE: I Sacrifice-Scheduled GROSS OBSERVATION(S): GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION^! : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LYMPH NODE, MEDIASTINAL: MAMMARY GLAND: SPLEEN: UTERUS: hyperplasia, 1ymphocytic/plasmacytic (minimal) macrophages, pigmented (minimal) hyperplasia, physiological hematopoiesis, extramedullary, increased (mild) macrophages, pigmented (moderate) THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS BONE MARROW (STERNUM) COLON DUODENUM JEJUNUM KIDNEYS LYMPH NODE, SUBMANDIBULAR NERVE, SCIATIC PEYER'S PATCH RECTUM SPINAL CORD,THORACIC STOMACH TRACHEA URINARY BLADDER BRAIN HEART LIVER OVARIES SPINAL CORD, THYMUS VAGINA CERVICAL End of Record- 17695 CECUM ILEUM LUNG PARATHYROID SPINAL CORD, THYROID LUMBAR 11-44 418-027 :PAGE J-75 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17703 SEX: F DOSE GROUP: DEATH TYPE: I Sacrifice-Scheduled GROSS O B S E R V A T I O N S : GENERAL: No gross changes. H I S T O M O R P H O L Q G I C OBS E R V A T I O N ! Si : Not applicable HISTOMORPHOLQGIC OBSERVATIONS: KIDNEYS: LIVER: LYMPH NODE, SUBMANDIBULAR: MAMMARY GLAND: SPLEEN: THYROID: UTERUS: mineralization, multifocal (minimal) inflammation, chronic, focal/multifocal (minimal) hyperplasia, 1ymphocytic/plasmacytic (moderate) hyperplasia, physiological hematopoiesis, extramedullary, increased (mild) ultimobranchial body/cyst macrophages, pigmented (moderate) THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON JEJUNUM OVARIES SPINAL CORD, CERVICAL THYMUS BONE MARROW (STERNUM) DUODENUM LUNG PARATHYROID SPINAL CORD, LUMBAR TRACHEA BRAIN HEART LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD, THORACIC URINARY BLADDER End of Record- 17703 CECUM ILEUM NERVE, SCIATIC RECTUM STOMACH VAGINA 11-45 418-027 :PAGE J-76 ORAL (SAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRGDUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17713 SEX: F DOSE GROUP: DEATH TYPE: I Sacrifice-Scheduled GROSS OBSERVATIONfS): GENERAL: No gross changes. HISTOMORPHOLQGIC OBSERVATION(S): Not appli cab!e HISTOMORPHOLOGIC OBSERVATIONS: HEART: LIVER: LYMPH NODE, SUBMANDIBULAR: MAMMARY GLAND: UTERUS: pericarditis, chronic, focal (minimal) vacuo!ation, hepatocellular, multifocal (minimal) hyperplasia, 1ymphocytic/plasmacytic (minimal) hyperplasia, physiological macrophages, pigmented (moderate) distention, lumen (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON KIDNEYS OVARIES SPINAL CORD, CERVICAL STOMACH URINARY BLADDER BONE MARROW (STERNUM) DUODENUM LUNG PARATHYROID SPINAL CORD, LUMBAR THYMUS VAGINA BRAIN ILEUM LYMPH NODE, MEDIASTINAL P E Y E R 'S PATCH SPINAL CORD, THORACIC THYROID End of Record- 17713 CECUM JEJUNUM NERVE, SCIATIC RECTUM SPLEEN TRACHEA 11-46 418-027:PAGE J-77 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17715 SEX: F DOSE GROUP: DEATH TYPE: I Sacrifice-Scheduled GROSS OBSERVATIONfS): GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION!Si: Not applicable HISTOMORPHOLOGIC OBSERVATIONS: ADRENAL GLANDS: LIVER: LYMPH NODE. SUBMANDIBULAR: MAMMARY GLAND: SPLEEN: UTERUS: infiltration, mononuclear-cell, multifocal (minimal) inflammation, chronic, focal/multifocal (minimal) hyperplasia, 1ymphocytic/plasmacytic (mild) hyperplasia, physiological hematopoiesis, extramedullary, increased (minimal) thrombus macrophages, pigmented (moderate) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: BONE MARROW (STERNUM) DUODENUM KIDNEYS OVARIES SPINAL CORD, CERVICAL THYMUS VAGINA BRAIN HEART LUNG PARATHYROID SPINAL CORD, THYROID LUMBAR CECUM ILEUM LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD, THORACIC TRACHEA End of Record- 17715 COLON JEJUNUM NERVE, SCIATIC RECTUM STOMACH URINARY BLADDER 11-47 418-027 :PAGE J-78 ORAL (GAVASE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17716 SEX: F DOSE GROUP: I DEATH TYPE:Sacrifice-Scheduled GROSS OBSERVATION(S): GENERAL: No gross changes. HISTOMORPHOLQGIC OBSERVATION(SI: Not applicable HISTOMORPHOLQGIC OBSERVATIONS: LIVER: LYMPH NODE, SUBMANDIBULAR: MAMMARY GLAND: UTERUS: necrosis, focal (minimal) hyperplasia, 1ymphocytic/plasmacytic hyperplasia, physiological macrophages, pigmented (moderate) (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON JEJUNUM NERVE, SCIATIC RECTUM SPLEEN TRACHEA BONE MARROW (STERNUM) DUODENUM KIDNEYS OVARIES SPINAL CORD, CERVICAL STOMACH URINARY BLADDER BRAIN HEART LUNG PARATHYROID SPINAL CORD, THYMUS VAGINA LUMBAR End of Record- 17716 CECUM ILEUM LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD, THORACIC THYROID 11-48 418-027 :PAGE J-79 ORAL (GAVA6E) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17717 SEX: F DOSE GROUP: DEATH TYPE: I Sacrifice-Scheduled GROSS OBSERVATION(Si: GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATIONfSi : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LUNG: LYMPH NODE, SUBMANDIBULAR: MAMMARY GLAND: THYROID: UTERUS: inflammation, interstitial, multifocal (minimal) hyperplasia, 1ymphocytic/plasmacytic (mild) hyperplasia, physiological ultimobranchial body/cyst macrophages, pigmented (moderate) 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 LIVER PARATHYROID SPINAL CORD, THYMUS LUMBAR End of Record- 17717 CECUM ILEUM LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD, THORACIC TRACHEA 11-49 418-027 :PAGE J-80 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphol ogy Data ANIMAL NUMBER: 17719 SEX: F DOSE GROUP: DEATH TYPE: I Sacrifice-Scheduled GROSS OBSERVATIONfSl: GENERAL: No aross chanaes. HISTOMORPHOLOGIC OBSERVATIONfS): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LYMPH NODE, SUBMANDIBULAR: MAMMARY GLAND: THYMUS: UTERUS: hyperplasia, 1ymphocytic/plasmacytic inflammation, subacute (mild) hyperplasia, physiological atrophy (minimal) macrophages, pigmented (moderate) (minimal) THE FOLLOWING TISSUEfS) 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 LIVER PARATHYROID SPINAL CORD, THYROID LUMBAR CECUM ILEUM LUNG PEYER'S PATCH SPINAL CORD, THORACIC TRACHEA TISSUEfS) NOT AVAILABLE FOR EVALUATION: LYMPH NODE, MEDIASTINAL End of Record- 17719 11-50 418-027 :PAGE J-81 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17675 SEX F DOSE GROUP: DEATH TYPE: II Sacrifice-Scheduled GROSS OBSERVATION(Si : GENERAL: No gross changes. H I S T O M O R P H O L O G I C OBSE R V A T I O N fS ) : Not applicable THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: LIVER THYMUS End of Record- 17675 11-51 418-027 :PAGE J-82 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17679 SEX F DOSE GROUP: DEATH TYPE: II Sacrifice-Scheduled GROSS O B S E R V A T I O N S : GENERAL: No gross changes. HISTQMORPHQLOGIC OBSERVATION(Si : Not applicable THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: LIVER THYMUS End of Record- 17679 11-52 418-027 :PAGE J-83 OkAL RAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17684 SEX F DOSE GROUP: DEATH TYPE: II Sacrifice-Scheduled GROSS O B S E R V A T I O N S : GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATIONfS1: Not applicable THE FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS: LIVER THYMUS End of Record- 17684 11-53 418-027 :PAGE J-84 ORAL (GAVA6E) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17688 SEX: F DOSE GROUP: DEATH TYPE: II Sacrifice-Scheduled GROSS OBSERVATIONS!: GENERAL: No gross changes HISTOMORPHOLOGIC OBSERVATIONfSi : Not appli cab!e THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS: LIVER THYMUS End of Record- 17688 11-54 418-027:PAGE J-85 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17698 SEX: F DOSE GROUP: DEATH TYPE: II Sacrifice-Scheduled GROSS OBSERVATION(Si: GENERAL: No gross changes. HISTQMQRPHOLOGIC OBSERVATION(Si : Not applicable HISTQMQRPHOLOGIC OBSERVATIONS: THYMUS: atrophy (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: LIVER End of Record- 17698 11-55 418-027 :PAGE J-86 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17702 SEX F DOSE GROUP: DEATH TYPE: II Sacrifice-Scheduled GROSS OBSERVATIONfS 1: GENERAL: No gross changes. HIST0MQRPH0L06IC OBSERVATION!Si : Not applicable THE FOLLOWING TISSUElSl WERE WITHIN NORMAL LIMITS: LIVER THYMUS End of Record- 17702 11-56 418-027 :PAGE J-87 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17704 SEX: F DOSE GROUP: DEATH TYPE: II Sacrifice-Scheduled GROSS OBSERVATION!Si: GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION(S): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: inflammation, chronic, focal/multifocal (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: THYMUS End of Record- 17704 11-57 418-027 :PAGE J-88 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17707 SEX: F DOSE GROUP: DEATH TYPE: II Sacrifice-Scheduled GROSS OBSERVATION(S): GENERAL: No qross chanaes. HISTOMORPHOLOGIC OBSERVATION^! : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: necrosis, focal (minimal) inflammation, chronic, focal/multifocal (minimal) THE FOLLOWING TISSUE!S) WERE WITHIN NORMAL LIMITS: THYMUS End of Record- 17707 11-58 418-027 :PAGE J-89 ORAL (GAVA6E) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17708 SEX F DOSE GROUP: DEATH TYPE: II Sacrifice-Scheduled GROSS O B S E R V A T I O N S : GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION!S): Not a p p i icab!e THE FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS: LIVER THYMUS End of Record- 17708 11-59 418-027 :PAGE J-90 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17710 SEX F DOSE GROUP: DEATH TYPE: II Sacrifice-Scheduled GROSS OBSERVATIONS!: GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION(Si : Not applicab!e THE FOLLOWING TISSUE!S) WERE WITHIN NORMAL LIMITS: LIVER THYMUS End of Record- 17710 11-60 418-027 :PAGE J-91 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17687 SEX F DOSE GROUP: DEATH TYPE: III Sacrifice-Scheduled GROSS OBSERVATION^!: GENERAL: No gross changes. HIST0M0RPH0L06IC OBSERVATION^!: Not applicable THE FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS: LIVER THYMUS End of Record- 17687 11-61 418-027 :PAGE J-92 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17693 SEX: F DOSE GROUP: DEATH TYPE: III Sacrifice-Scheduled GROSS O B S E R V A T I O N S : GENERAL: No gross changes. HISTOMQRPHOLOGIC OBSERVATIONfS) : Not applicable HISTOMQRPHOLOGIC OBSERVATIONS: LIVER: inflammation, chronic, focal/multifocal (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: THYMUS End of Record- 17693 11-62 418-027:PAGE J-93 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17697 SEX: F DOSE GROUP: DEATH TYPE: III Sacrifice-Scheduled GROSS OBSERVATION(S): GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION!S) : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: THYMUS: atrophy (minimal) THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS: LIVER End of Record- 17697 11-63 418-027:PAGE J-94 ORAL (SAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17700 SEX: F DOSE GROUP: DEATH TYPE: III Sacrifice-Scheduled GROSS OBSERVATION'S): GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION(S): Not appli cab!e HISTOMORPHOLOGIC OBSERVATIONS: LIVER: inflammation, chronic, focal/multifocal (minimal) THE FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS: THYMUS End of Record- 17700 11-64 418-027 :PAGE J-95 ORAL (GAVA6E) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 Appendi x 11 Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17701 SEX: F DOSE GROUP: DEATH TYPE: III Sacrifice-Scheduled GROSS OBSERVATIONS): GENERAL: No gross changes. HISTOMQRPHOLOGIC OBSERVATION!S): Not applicable HISTOMQRPHOLOGIC OBSERVATIONS: LIVER: inflammation, chronic, focal/multifocal (minimal) THE FOLLOWING TISSUE!S) WERE WITHIN NORMAL LIMITS: THYMUS End of Record- 17701 11-65 418-027:PAGE J-96 ORAL (GAVASE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17705 SEX: F DOSE GROUP: DEATH TYPE: III Sacrifice-Scheduled GROSS OBSERVATION(Si: GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION!Si : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: inflammation, chronic, focal/multifocal (minimal) THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS: THYMUS End of Record- 17705 11-66 418-027 :PAGE J-97 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17706 SEX: F DOSE GROUP: DEATH TYPE: III Sacrifice-Scheduled GROSS OBSERVATIONfS^: GENERAL: No gross changes. HISTOMORPHQLOGIC OBSERVATION(Si : Not applicable HISTOMORPHQLOGIC OBSERVATIONS: LIVER: inflammation, chronic, focal/multifocal (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: THYMUS End of Record- 17706 11-67 418-027:PAGE J-98 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17709 SEX F GROSS OBSERVATION(S): GENERAL: No gross changes. DOSE GROUP: DEATH TYPE: III Sacrifice-Scheduled H I S T O M O R P H O L O G I C O B S E R V A T I O N ! Si : Not applicable THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: LIVER THYMUS End of Record- 17709 11-68 418-027:PAGE J-99 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17718 SEX: F DOSE GROUP: DEATH TYPE: III Sacrifice-Scheduled GROSS OBSERVATIONfSl: GENERAL: No aross chanaes. HISTOMORPHOLOGIC OBSERVATIONfSi: Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: hematopoiesis, extramedullary, multifocal (minimal) THE FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS: THYMUS End of Record- 17718 11-69 418-027:PAGE J-100 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17720 SEX: F DOSE GROUP: DEATH TYPE: III Sacrifice-Scheduled GROSS OBS E R V A T I O N ^ ! : GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATIONfSl: Not applicab!e HISTOMORPHOLOGIC OBSERVATIONS: LIVER: inflammation, chronic, focal/multifocal (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: THYMUS End of Record- 17720 11-70 418-027 :PAGE J-101 ORAL (6AVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17685 SEX: F DOSE GROUP: DEATH TYPE: IV Sacrifice-Scheduled GROSS OBSERVATION!SI: GENERAL: No gross changes. HISTOMORPHOLQGIC OBSERVATION!S): Not applicable HISTOMORPHOLOGICOBS ERVATIONS: KIDNEYS: LIVER: LYMPH NODE, SUBMANDIBULAR: MAMMARY GLAND: UTERUS: pyelitis, chronic (minimal) lipidosis, tension, focal hypertrophy, hepatocellular, centrilobular (minimal) hyperplasia, 1ymphocytic/plasmacytic (moderate) hyperplasia, physiological macrophages, pigmented (minimal) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON JEJUNUM OVARIES SPINAL CORD, CERVICAL STOMACH URINARY BLADDER BONE MARROW (STERNUM) DUODENUM LUNG PARATHYROID SPINAL CORD, LUMBAR THYMUS VAGINA BRAIN HEART LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD, THORACIC THYROID End of Record- 17685 CECUM ILEUM NERVE, SCIATIC RECTUM SPLEEN TRACHEA 11-71 418-027:PAGE J-102 ORAL (SAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17686 SEX: F DOSE GROUP: DEATH TYPE: IV Sacrifice-Scheduled GROSS OBSERVATION(S): GENERAL: No aross chanaes. HISTOMORPHOLOGIC OBSERVATION(S): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: LYMPH NODE, SUBMANDIBULAR: MAMMARY GLAND: THYROID: UTERUS: VAGINA: inflammation, chronic, focal/multifocal (minimal) hyperplasia, 1ymphocytic/plasmacytic (moderate) hyperplasia, physiological ultimobranchial body/cyst macrophages, pigmented (minimal) mucification (moderate) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON JEJUNUM NERVE, SCIATIC SPINAL CORD, CERVICAL STOMACH BONE MARROW (STERNUM) DUODENUM KIDNEYS PARATHYROID SPINAL CORD, LUMBAR THYMUS BRAIN HEART LUNG PEYER'S PATCH SPINAL CORD, THORACIC TRACHEA TISSUE(S) NOT AVAILABLE FOR EVALUATION: OVARIES End of Record- 17686 CECUM ILEUM LYMPH NODE, MEDIASTINAL RECTUM SPLEEN URINARY BLADDER 11-72 418-027:PAGE J-103 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17689 SEX: F DOSE GROUP: DEATH TYPE: IV Sacrifice-Scheduled GROSS OBSERVATIONS: GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATION!Si : Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: LYMPH NODE, MEDIASTINAL: LYMPH NODE, SUBMANDIBULAR: MAMMARY GLAND: SPLEEN: UTERUS: inflammation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (minimal) congesti o n / e r y t h r o p h a g o c y t os i s (mi 1d) hyperplasia, 1ymphocytic/plasmacytic (mild) hyperplasia, physiological hematopoiesis, extramedullary, increased (minimal) macrophages, pigmented (mild) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON JEJUNUM OVARIES SPINAL CORD, CERVICAL THYMUS VAGINA BONE MARROW (STERNUM) DUODENUM KIDNEYS PARATHYROID SPINAL CORD, LUMBAR THYROID BRAIN HEART LUNG PEYER'S PATCH SPINAL CORD, THORACIC TRACHEA End of Record- 17689 CECUM ILEUM NERVE, SCIATIC RECTUM STOMACH URINARY BLADDER 11-73 418-027:PAGE J-104 ORAL (GAVAQE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal G r oss and Hi s t o m o r p h o l o g y Data ANIMAL NUMBER: 17691 SEX: F DOSE GROUP: DEATH TYPE: IV Sacrifice-Scheduled GROSS OBSERVATION?Si: GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATIONfS: Not applicable HISTOMORPHOLOGIC OBSERVATIONS: LIVER: LYMPH NODE, SUBMANDIBULAR: MAMMARY GLAND: THYROID: UTERUS: inflammation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (minimal) hyperplasia, 1ymphocytic/plasmacytic (minimal) hyperplasia, physiological ultimobranchial body/cyst macrophages, pigmented (moderate) 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, THYMUS LUMBAR End of Record- 17691 CECUM ILEUM LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD, THORACIC TRACHEA 11-74 418-027`.PAGE J-105 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17692 SEX: F DOSE GROUP: DEATH TYPE: IV Sacrifice-Scheduled GROSS OBSERVATION(Si: GENERAL: No gross changes. HISTOMORPHOLQGIC OBSERVATION!Si : Not applicable HISTOMORPHOLQGIC OBSERVATIONS: KIDNEYS: LIVER: LYMPH NODE, MEDIASTINAL: LYMPH NODE, SUBMANDIBULAR: MAMMARY GLAND: THYMUS: mineralization, multifocal (minimal) hypertrophy, hepatocellular, centrilobular (minimal) congesti on/erythrophagocytosis (mild) hyperplasia, 1ymphocytic/piasmacytic (moderate) hyperplasia, physiological atrophy (mild) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON JEJUNUM PARATHYROID SPINAL CORD, LUMBAR THYROID VAGINA BONE MARROW (STERNUM) DUODENUM LUNG PEYER'S PATCH SPINAL CORD, THORACIC TRACHEA BRAIN HEART NERVE, SCIATIC RECTUM SPLEEN URINARY BLADDER End of Record- 17692 CECUM ILEUM OVARIES SPINAL CORD, STOMACH UTERUS CERVICAL 11-75 418-027'.PAGE J-106 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17696 SEX: F DOSE GROUP: DEATH TYPE: IV Sacrifice-Scheduled GROSS OBSERVATIONiS): THYMUS: Small. HISTOMORPHOLQGIC OBSERVATION!S): Tissue not available HISTOMORPHOLQGIC OBSERVATIONS: HEART: LYMPH NODE, SUBMANDIBULAR: MAMMARY GLAND: THYROID: UTERUS: inflammation, subacute, focal/multifocal (minimal) hyperplasia, 1ymphocytic/plasmacytic (mild) hyperplasia, physiological ultimobranchial body/cyst inflammation, endometrium, diffuse (mild) macrophages, pigmented (moderate) di stention, lumen (moderate) THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON KIDNEYS NERVE, SCIATIC RECTUM SPLEEN VAGINA BONE MARROW (STERNUM) DUODENUM LIVER OVARIES SPINAL CORD, CERVICAL STOMACH BRAIN ILEUM LUNG PARATHYROID SPINAL CORD, TRACHEA LUMBAR CECUM JEJUNUM LYMPH NODE, MEDIASTINAL P E Y E R 'S PATCH SPINAL CORD, THORACIC URINARY BLADDER TISSUEfS) NOT AVAILABLE FOR EVALUATION: THYMUS End of Record- 17696 11-76 418-027 :PAGE J-107 ORAL (6AVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17699 SEX: F DOSE GROUP: DEATH TYPE: IV Sacrifice-Scheduled GROSS QBSERVATIONfSl: GENERAL: No gross changes. HISTOMORPHOLOGIC QBSERVATIONfSl: Not appli cable HISTOMORPHOLOGIC OBSERVATIONS: KIDNEYS: LIVER: LYMPH NODE, SUBMANDIBULAR: MAMMARY GLAND: SPLEEN: THYMUS: THYROID: UTERUS: mineralization, multifocal (minimal) inflammation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (minimal) hyperplasia, 1ymphocytic/plasmacytic (moderate) hyperplasia, physiological hematopoiesis, extramedullary, increased (minimal) atrophy (minimal) ultimobranchial body/cyst macrophages, pigmented (moderate) THE FOLLOWING TISSUE/S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON JEJUNUM OVARIES SPINAL CORD, CERVICAL TRACHEA BONE MARROW (STERNUM) DUODENUM LUNG PARATHYROID SPINAL CORD, LUMBAR URINARY BLADDER BRAIN HEART LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD. THORACIC VAGINA End of Record- 17699 CECUM ILEUM NERVE, SCIATIC RECTUM STOMACH 11-77 418-027:PAGE J-108 ORAL (6AVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17711 SEX: F DOSE GROUP: DEATH TYPE: IV Sacrifice-Scheduled GROSS OBSERVATION(Si : GENERAL: No aross chanaes HISTOMORPHOLQGIC OBSERVATION(S): Not applicable HISTOMORPHOLQGIC OBSERVATIONS: KIDNEYS: LIVER: MAMMARY SPLEEN: THYMUS: UTERUS: GLAND: VAGINA: vacuolation, cortical tubular epithelium (miId) hypertrophy, hepatocellular, centrilobular (mild) vacuolation, hepatocellular, periportal (minimal) hyperplasia, physiological atrophy (mild) atrophy (moderate) hemorrhage, endometrium (mild) macrophages, pigmented (moderate) inflammation, acute (moderate) mucification (marked) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON JEJUNUM NERVE, SCIATIC RECTUM STOMACH BONE MARROW (STERNUM) DUODENUM LUNG OVARIES SPINAL CORD, CERVICAL THYROID BRAIN HEART LYMPH NODE, MEDIASTINAL PARATHYROID SPINAL CORD, LUMBAR TRACHEA End of Record- 17711 CECUM ILEUM LYMPH NODE, SUBMANDIBULAR PEYER'S PATCH SPINAL CORD, THORACIC URINARY BLADDER 11-78 418-027:PAGE J-109 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17712 SEX: F DOSE GROUP: DEATH TYPE: IV Sacrifice-Scheduled GROSS OBSERVATION(S): TAIL: Bent. HISTOMORPHOLOGIC OBSERVATION!SI : No microscopic change to correlate HISTOMORPHOLOGIC OBSERVATIONS: LIVER: LYMPH NODE, SUBMANDIBULAR: MAMMARY GLAND: TAIL: THYMUS: UTERUS: inflammation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (minimal) hyperplasia, 1ymphocytic/plasmacytic (mild) hyperplasia, physiological No microscopic change to correlate atrophy (minimal) macrophages, pigmented (mild) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON JEJUNUM NERVE, SCIATIC RECTUM SPLEEN TRACHEA BONE MARROW (STERNUM) DUODENUM KIDNEYS OVARIES SPINAL CORD, CERVICAL STOMACH URINARY BLADDER BRAIN HEART LUNG PARATHYROID SPINAL CORD, TAIL VAGINA LUMBAR End of Record- 17712 CECUM ILEUM LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD, THORACIC THYROID 11-79 418-027'.PAGE J-110 ORAL (6AVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 A p p e n d i x II Individual Animal Gross and Histomorphology Data ANIMAL NUMBER: 17714 SEX: F DOSE GROUP: DEATH TYPE: IV Sacrifice-Scheduled GROSS OBSERVATION(SI: GENERAL: No qross chanaes HISTOMORPHOLOGIC OBSERVATIONS ): Not appiicab!e HISTOMORPHOLOGIC OBSERVATIONS: LIVER: MAMMARY GLAND: SPLEEN: THYMUS: THYROID: UTERUS: hypertrophy, hepatocellular, centri lobular (mild) hyperplasia, physiological hematopoiesis, extramedullary, increased (minimal) atrophy (mild) ultimobranchial body/cyst thrombus macrophages, pigmented (moderate) THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: ADRENAL GLANDS COLON JEJUNUM NERVE, SCIATIC RECTUM STOMACH BONE MARROW (STERNUM) DUODENUM KIDNEYS OVARIES SPINAL CORD, CERVICAL TRACHEA BRAIN HEART LUNG PARATHYROID SPINAL CORD, LUMBAR URINARY BLADDER TISSUE(S) NOT AVAILABLE FOR EVALUATION LYMPH NODE, MEDIASTINAL End of Record- 17714 CECUM ILEUM LYMPH NODE, SUBMANDIBULAR P E Y E R 'S PATCH SPINAL CORD, THORACIC VAGINA 11-80 APPENDIX K HEMATOLOGY AND CLINICAL CHEMISTRY REPORTS Study R eport fo r Hematology IN D IV ID U A L ANIMAL REPORT BY GROUP P E R IO D : T E R M IN A L STUDY ID : ARGUS #418-027 STUDY NO: 060-063 Animal ID WBC RBC THSN/CU MM MILL/CU MM HGB GRAMS/DL HCT MCV MCH % CU MICRONS PICO GRAMS GROUP: 1-M 17608 17618 17630 17631 17639 MEAN SD N 13.5 10.9 12.6 16.6 20.0 14.7 3.61 5 7.61 8.24 7.67 7.34 6.89 7.55 0.493 5 15.7 16.3 15.7 15.8 15.7 15.8 0.26 5 43.5 46.8 43.3 42.4 42.4 43.7 1.82 5 57.1 56.8 56.5 57.7 61.6 57.9 2.09 5 20.6 19.8 20.5 21.5 22.8 21.0 1.15 5 GROUP: 2-M 17634 17635 17638 17642 17643 MEAN SD N 19.1 16.9 16.5 18.3 23.9 18.9 2.96 5 8.05 7.98 7.45 7.29 7.01 7.56 0.448 5 16.3 16.3 15.5 15.5 14.6 15.6 0.71 5 45.0 44.0 42.1 41.9 39.5 42.5 2.12 5 55.9 55.2 56.5 57.5 56.3 56.3 0.84 5 20.2 20.4 20.8 21.3 20.8 20.7 0.42 5 GROUP: 3-M 17620 17623 17627 17628 17633 MEAN SD N 13.6 20.7 13.1 16.5 12.7 15.3 3.36 5 7.17 7.74 7.21 6.95 7.30 7.27 0.291 5 15.6 15.6 14.9 14.9 14.8 15.2 0.40 5 40.5 43.3 41.6 41.6 39.9 41.4 1.30 5 56.5 55.9 57.7 59.8 54.7 56.9 1.94 5 21.8 20.2 20.7 21.4 20.3 20.9 0.70 5 418-027:PAGE K -l SEX: MALE MCHC PLT % THSN/CU MM 36.1 34.8 36.3 37.3 37.0 36.3 0.97 5 1094 1406 1174 1126 1185 1197 122.5 5 36.2 37.0 36.8 37.0 37.0 36.8 0.35 5 1174 1237 1096 1204 1147 1172 54.0 5 38.5 36.0 35.8 35.8 37.1 36.6 1.17 5 1038 1326 1030 1219 1475 1218 190.7 5 LABCAT HE4.43 22-MAY-2002 Study Report fo r Hem atology IN D IV ID U A L ANIMAL REPORT BY GROUP P E R IO D : T E R M IN A L STUDY ID : ARGUS #418-027 STUDY NO: 060-063 Animal ID WBC RBC THSN/CU MM MILL/CU MM HGB GRAMS/DL HCT MCV MCH % CU MICRONS PICO GRAMS GROUP: 4-M 17621 17622 17625 17629 17636 MEAN SD N 17.2 11.0 14.5 22.3 31.3 19.3 7.90 5 7.54 6.87 7.24 7.25 6.94 7.17 0.270 5 16.1 14.7 14.5 14.9 15.5 15.1 0.65 5 43.5 38.6 41.0 39.4 40.2 40.5 1.88 5 57.7 56.2 56.6 54.3 57.9 56.5 1.44 5 21.4 21.4 20.0 20.6 22.3 21.1 0.88 5 418-027:PAGE K-2 SEX: MALE MCHC PLT 1 THSN/CU MM 37.0 38.1 35.4 37.8 38.6 37.4 1.25 5 1154 1352 1189 1492 1226 1283 138.9 5 LABCAT HE4.43 22-MAY-2002 Study Report fo r H em atology IN D IV ID U A L ANIMAL REPORT BY GROUP PERIO D: TERMINAL STUDY ID : ARGUS #418-027 STUDY NO: 060-063 Animal ID WBC RBC THSN/CU MM MILL/CU MM HGB GRAMS/DL HCT MCV MCH % CU MICRONS PICO GRAMS GROUP: 1-F 17694 17703 17681 17690 17695 16.8 23.3 19.8 20.9 CL 5.72 5.54 6.55 5.63 CL 14.2 13.1 14.5 13.8 CL 37.7 35.3 38.6 35.6 CL 65.9 63.7 59.0 63.2 CL 24.8 23.6 22.1 24.5 CL MEAN SD N 20.2 2.70 4 5.86 0.466 4 13.9 0.61 4 36.8 1.61 4 63.0 2.88 4 23.8 1.21 4 GROUP: 2-F 17675 17679 17688 17698 17684 MEAN SD N 16.9 13.3 14.5 16.8 12.8 14.9 1.92 5 6.10 6.32 5.72 6.09 5.79 6.00 0.246 5 14.1 14.7 14.7 14.2 13.6 14.3 0.46 5 37.8 39.3 39.2 37.9 36.7 38.2 1.08 5 61.9 62.2 68.5 62.3 63.3 63.6 2.77 5 23.1 23.3 25.7 23.3 23.5 23.8 1.08 5 GROUP: 3-F 17693 17697 17700 17701 17687 17709 MEAN SD N 24.0 16.3 18.0 21.2 21.2 20.6 20.2 2.71 6 5.26 5.71 6.80 5.81 5.19 5.85 5.77 0.578 6 13.4 13.2 14.9 13.6 12.7 14.2 13.7 0.78 6 34.1 35.3 41.1 36.0 33.2 38.0 36.3 2.88 6 64.8 61.8 60.4 62.0 64.0 65.0 63.0 1.87 6 25.5 23.1 21.9 23.4 24.5 24.3 23.8 1.26 6 418-027 :PAGE K-3 SEX: FEMALE MCHC PLT % THSN/CU MM 37.7 37.1 37.6 38.8 CL 37.8 0.72 4 1575 1648 1583 1329 CL 1534 140.4 4 37.3 37.4 37.5 37.5 37.1 37.4 0.17 5 1381 1259 128 1273 692 947 531.0 5 39.3 37.4 36.3 37.8 38.3 37.4 37.8 1.01 6 2292 1874 1375 1554 1101 1393 1598 423.9 6 CL - C lo tte d LABCAT HE4.43 22-MAY-2002 Study Report fo r H em atology IN D IV ID U A L ANIMAL REPORT BY GROUP PERIOD: TERMINAL STUDY ID : ARGUS #418--027 STUDY NO: 060-063 Animal ID WBC RBC THSN/CU MM MILL/CU MM HGB GRAMS/DL HCT MCV MCH % CU MICRONS PICO GRAMS GROUP: 4 - F 17685 17689 17692 17691 MEAN SD N 21.6 18.6 25.4 20.8 21.6 2.83 4 5.91 5.57 5.37 6.21 5.76 0.371 4 13.2 12.9 12.5 14.1 13.2 0.68 4 35.3 33.8 30.8 36.5 34.1 2.46 4 59.8 60.6 57.4 58.8 59.2 1.38 4 22.3 23.2 23.3 22.7 22.9 0.46 4 418-027:PAGE K-4 SEX: FEMALE MCHC PLT % THSN/CU MM 37.4 38.2 40.6 38.6 38.7 1.36 4 1570 1803 1230 1584 1547 236.6 4 LABCAT HE4.43 22-MAY-2002 Study R eport fo r Hematology 418-027:PAGE K-5 IN D IV ID U A L ANIMAL REPORT BY GROUP PERIOD : TERMINAL STUDY ID : ARGUS #418-027 STUDY NO: 060-063 SEX: MALE Anim al ID PT seconds APTT seconds MPV CU MICRONS NRBC Lymphocyte Segmented Bands Monocytes COUNT THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM GROUP: 1-M 17608 17618 17630 17631 17639 14.3 14.3 14.0 15.5 13.8 25.1 26.6 25.3 27.5 22.5 9.0 9.0 9.6 9.5 8.9 0 11.2 2 .0 0.0 0.1 0 8.8 1.9 0 .0 0.1 0 10.3 2 .0 0 .0 0.1 0 14.9 1.5 0 .0 0 .2 0 17.8 2.2 0 .0 0 .0 MEAN SD N 14.4 0.66 5 25.4 1.89 5 9.2 0.32 5 0 12.6 1.9 0 .0 0.1 0.0 3.67 0.26 0.00 0.07 555 55 GROUP: 2-M 17634 17635 17638 17642 17643 MEAN SD N 13.4 14.3 13.3 13.7 13.7 13.7 0.39 5 22.4 27.9 24.7 27.0 27.6 25.9 2.33 5 9 .6 9.5 9.3 9.1 11.1 9 .7 0.79 5 0 17.0 1.9 0 .0 0.0 0 12.7 4.1 0.0 0.2 0 13.9 2.1 0.0 0.2 0 14.6 2.9 0.0 0.5 0 20.8 2.9 0.0 0.0 0 15.8 2.8 0 .0 0.2 0 .0 3.21 0.87 0.00 0.20 555 55 GROUP: 3-M 17620 17623 17627 17628 17633 MEAN SD N 14.4 14.1 14.6 14.4 15.9 14.7 0.70 5 26.1 27.9 24.2 28.8 23.9 26.2 2.18 5 8.9 11.0 8.7 8 .7 10.1 9.5 1.03 5 0 11.4 2.0 0 .0 0 .0 0 18.2 2.3 0 .0 0 .0 0 10.9 1.8 0 .0 0.0 0 15.0 1.2 0 .0 0.2 0 10.9 1.7 0 .0 0.1 0 13.3 1.8 0 .0 0.1 0 .0 3.24 0.41 0.00 0.09 5 5 5 55 LABCAT HE4.43 22-MAY-2002 Study R eport fo r H em atology IN D IV ID U A L ANIMAL REPORT BY GROUP PERIOD: TERMINAL 418-027 :PAGE K-6 STUDY ID : ARGUS #418-027 STUDY NO: 060-063 Animal ID PT seconds APTT seconds MPV CU MICRONS SEX: I NRBC Lymphocyte Segmented Bands Monocytes COUNT THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM GROUP: 4-M 17621 17622 17625 17629 17636 MEAN SD N 16.0 13.5 14.9 14.0 14.4 14.6 0.96 5 30.7 26.1 27.3 24.0 25.6 26.7 2.51 5 9.5 8.4 9.5 9.8 8.4 9.1 0.67 5 0 15.8 1.0 0 .0 0.3 0 8.7 2.0 0.0 0.0 0 13.1 1.5 0 .0 0 .0 0 19.6 2.5 0 .0 0 .0 0 13.1 18.2 0 .0 0 .0 0 14.1 5 .0 0 .0 0.1 0 .0 4.01 7.38 0.00 0.13 555 5 5 LABCAT HE4.43 22-MAY-2002 Study Report fo r H em atology IN D IV ID U A L ANIMAL REPORT BY GROUP PERIOD : TERMINAL 418-027:PAGE K-7 STUDY ID : ARGUS #418-027 STUDY NO: 060-063 Anim al ID PT seconds APTT seconds MPV CU MICRONS SEX: FEMALE NRBC Lymphocyte Segmented Bands Monocytes COUNT THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM GROUP: 1-F 17694 17703 17681 17690 17695 MEAN SD N 12.8 13.3 13.9 13.5 13.2 13.3 0.40 5 18.2 24.0 22.2 21.6 19.3 21.1 2.32 5 7 .0 7 .0 7 .9 8.9 CL 7.7 0.91 4 0 13.6 0 17.0 0 15.2 0 17.6 CL -- 2.7 5.8 3 .8 3.1 -- 0.0 0 .3 0.0 0 .2 0.0 0 .8 0.0 0.0 ---- 0 15.9 3 .9 0.0 0 .3 0.0 1.81 1.38 0 .0 0 0.3 4 444 44 GROUP: 2-F 17675 17679 17688 17698 17684 MEAN SD N 12.8 13.6 13.4 13.2 CL 13.3 0.34 4 19.3 15.5 18.2 19.9 CL 18.2 1.95 4 9.2 7 .8 12.3 7.5 7 .3 8 .8 2.08 5 0 14.4 2 .2 0.0 0 .3 0 10.6 2 .7 0.0 0.0 0 11.9 2 .6 0.0 0.0 0 15.6 0 .8 0.0 0 .3 0 10.6 1 .9 0.0 0 .3 0 12.6 2 .0 0.0 0 .2 0.0 2.2 8 0.76 0.00 0.16 555 55 GROUP: 3-F 17693 17697 17700 17701 17687 17709 MEAN SD N 13.3 13.2 13.2 12.9 13.3 CL 13.2 0.16 5 21.5 19.7 23.6 17.7 27.3 CL 22.0 3.70 5 6 .8 7 .6 8 .4 7.3 8.2 9 .7 8 .0 1.02 6 0 17.8 5.5 0.0 0 .7 0 13.7 2 .6 0.0 0.0 0 12.2 5 .4 0.0 0.0 0 18.7 2 .3 0.0 0 .2 0 16.1 5.1 0.0 0.0 0 14.6 5 .6 0.0 0 .2 0 15.5 4 .4 0.0 0 .2 0.0 2.4 8 1.54 0 .0 0 0.2 7 6 66 66 ( -- ) - Data U n available LABCAT HE4.43 CL - C lo tte d 22-MAY-2002 Study Report fo r H em atology IN D IV ID U A L ANIMAL REPORT BY GROUP PERIOD: TERMINAL 418-027 :PAGE K-8 STUDY ID : ARGUS #418-027 STUDY NO: 060-063 SEX: FEMALE Animal ID PT seconds APTT seconds MPV CU MICRONS NRBC Lymphocyte Segmented Bands Monocytes COUNT THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM GROUP: 4-F 17685 17689 17692 17691 MEAN SD N 13.0 13.1 13.5 13.3 13.2 0.22 4 25.3 14.9 20.8 18.2 19.8 4.39 4 9.0 7.7 7.9 8.0 8.2 0.58 4 0 13.0 6 .9 0 .2 1.3 0 13.6 3.3 0.2 1.5 0 22.1 2.5 0 .0 0.5 0 16.8 3.5 0 .0 0 .4 0 16.4 4.1 0.1 0 .9 0.0 4.17 1.95 0.12 0.56 444 4 4 LABCAT HE4.43 22-MAY-2002 Study Report fo r H em atology IN D IV ID U A L ANIMAL REPORT BY GROUP PERIOD: TERMINAL STUDY ID : ARGUS #418-027 STUDY NO: 060-063 Animal ID E o sin o p h il BasophiIs Abnormal L Other THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM GROUP: 1-M 17608 17618 17630 17631 17639 MEAN SD N 0.1 0.1 0.1 0.0 0 .0 0.1 0.05 5 0.0 0.0 0.0 0.0 0.0 0.0 0.00 5 0.0 0.0 0.0 0.0 0.0 0.0 0.00 5 0.0 0.0 0.0 0.0 0.0 0.0 0.00 5 GROUP: 2-M 17634 17635 17638 17642 17643 MEAN SD N 0.2 0 .0 0.3 0.2 0.2 0.2 0.11 5 0.0 0.0 0.0 0.0 0.0 0.0 0.00 5 0.0 0.0 0.0 0.0 0.0 0.0 0.00 5 0.0 0.0 0.0 0.0 0.0 0.0 0.00 5 GROUP: 3-M 17620 17623 17627 17628 17633 MEAN SD N 0.1 0.2 0.4 0.2 0 .0 0.2 0.15 5 0.0 0.0 0.0 0.0 0.0 0.0 0.00 5 0.0 0.0 0.0 0.0 0.0 0.0 0.00 5 0.0 0.0 0.0 0.0 0.0 0.0 0.00 5 418-027:PAGE K-9 SEX: MALE LABCAT HE4.43 22-MAY-2002 Study Report fo r Hem atology IN D IV ID U A L ANIMAL REPORT BY GROUP PERIOD: TERMINAL STUDY ID : ARGUS #418-027 STUDY NO: 060-063 Anim al ID E o s in o p h il B asophiIs Abnormal L Other THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM GROUP: 4-M 17621 17622 17625 17629 17636 MEAN SD N 0.0 0.3 0.0 0.2 0.0 0.1 0.14 5 0.0 0.0 0.0 0.0 0.0 0.0 0.00 5 0.0 0.0 0.0 0.0 0.0 0.0 0.00 5 0.0 0.0 0.0 0.0 0.0 0.0 0.00 5 418-027:PAGE K-10 SEX: MALE LABCAT HE4.43 22-MAY-2002 Study R eport fo r Hem atology IN D IV ID U A L ANIMAL REPORT BY GROUP PERIOD : TERMINAL STUDY ID : ARGUS #418-027 STUDY NO: 060-063 Animal ID E o s in o p h il B a so p h iIs Abnormal L Other THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM GROUP: 1-F 17694 0.0 0.0 0.2 0.0 17703 0.2 0.0 0.0 0.0 17681 0.0 0.0 0.0 0.0 17690 0.2 0.0 0.0 0.0 17695 -- -- -- -- MEAN SD N 0.1 0.12 4 0 .0 0.00 4 0.1 0.10 4 0.0 0.00 4 418-027 :PAGE K-l 1 SEX: FEMALE GROUP: 2 - F 17675 17679 17688 17698 17684 MEAN SD N 0.0 0.0 0.0 0.0 0.0 0.0 0.00 5 0.0 0.0 0.0 0.0 0.0 0.0 0.00 5 0.0 0.0 0.0 0.0 0.0 0.0 0.00 5 0.0 0.0 0.0 0.0 0.0 0.0 0.00 5 GROUP: 3-F 17693 17697 17700 17701 17687 17709 MEAN SD N 0.0 0.0 0 .4 0.0 0.0 0.2 0.1 0.17 6 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.00 6 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.00 6 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.00 6 ( -- ) - Data Unavai ta b le LABCAT HE4.43 22-MAY-2002 Study R eport fo r Hematology IN D IV ID U A L ANIMAL REPORT BY GROUP PER IO D : TERMINAL- study ID : ARGUS #418-027 STUDY NO: 060-063 Animal ID E o s in o p h il B asophiIs Abnormal L O th e r THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM GROUP: 4 - F 17685 0.0 0.0 0.2 0.0 17689 0.0 0.0 0.0 0.0 17692 0.0 0.0 0.3 0.0 17691 0.0 0.0 0.0 0.0 MEAN SD N 0 .0 0.00 4 0 .0 0.00 4 0.1 0.15 4 0 .0 0.00 4 418-027 :PAGE K-12 SEX: FEMALE LABCAT HE4.43 22-MAY-2002 Study R eport fo r Hem atology SUMMARY REPORT PERIO D: TERMINAL STUDY ID : ARGUS #418-027 STUDY NO: 060-063 TESTCs): UNITS: WBC RBC HGB THSN/CU MM MILL/CU MM GRAMS/DL HCT MCV MCH % CU MICRONS PICO GRAMS Group: 1-M MEAN SD N 14.7 3.61 5 7.55 0.493 5 15.8 0.26 5 43.7 1.82 5 57.9 2.09 5 21.0 1.15 5 Group: 2-M MEAN SD N 18.9 2.96 5 7.56 0.448 5 15.6 0.71 5 42.5 2.12 5 56.3 0.84 5 20.7 0.42 5 Group: 3-M MEAN SD N 15.3 3.36 5 7.27 0.291 5 15.2 0.40 5 41.4 1.30 5 56.9 1.94 5 20.9 0.70 5 Group: 4-M MEAN SD N 19.3 7.90 5 7.17 0.270 5 15.1 0.65 5 40.5 1.88 5 56.5 1.44 5 21.1 0.88 5 418-027PAGE K-13 SEX: MALE MCHC PLT % THSN/CU MM PT seconds 36.3 0.97 5 1197 122.5 5 14.4 0.66 5 36.8 0.35 5 1172 54.0 5 13.7 0.39 5 36.6 1.17 5 1218 190.7 5 14.7 0.70 5 37.4 1.25 5 1283 138.9 5 14.6 0.96 5 LABCAT HE4.43 22-MAY-2002 Study Report fo r Hem atology SUMMARY REPORT PERIOD: TERMINAL 418-027 :PAGE K-14 STUDY ID: ARGUS #418-027 STUDY NO: 060-063 TEST(s): UNITS: APTT MPV seconds CU MICRONS SEX: MALE NRBC Lymphocyte Segmented Bands Monocytes E o s in o p h il B a so p h ils COUNT THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM Group: 1-M MEAN SD N 25.4 1.89 5 9.2 0.32 5 0 12.6 1.9 0 .0 0.1 0.1 0 .0 0.0 3.67 0.26 0.00 0.07 0.05 0.00 5555 55 5 Group: 2-M MEAN SD N 25.9 2.33 5 9 .7 0.79 5 0 15.8 2.8 0.0 0.2 0.2 0.0 0 .0 3.21 0.87 0.00 0.20 0.11 0.00 5555 55 5 Group: 3-M MEAN SD N 26.2 2.18 5 9.5 1.03 5 0 13.3 1.8 0 .0 0.1 0.2 0 .0 0 .0 3.24 0.41 0.00 0.09 0.15 0.00 55 55 55 5 Group: 4-M MEAN SD N 26.7 2.51 5 9.1 0.67 5 0 14.1 5.0 0 .0 0.1 0.1 0 .0 0 .0 4.01 7.38 0.00 0.13 0.14 0.00 55 55 55 5 LABCAT HE4.43 22-MAY-2002 STUDY ID : ARGUS #418-027 STUDY NO: 060-063 Study R eport fo r Hem atology SUMMARY REPORT PERIOD: TERMINAL TEST(s): UNITS: Abnormal L O th e r THSN/CU MM THSN/CU MM Group: 1-M MEAN SD N 0 .0 0.00 5 0 .0 0.00 5 Group: 2-M MEAN SD N 0 .0 0.00 5 0 .0 0.00 5 Group: 3-M MEAN SD N 0 .0 0.00 5 0 .0 0.00 5 Group: 4-M MEAN SD N 0 .0 0.00 5 0 .0 0.00 5 418-027:PAGE K -15 SEX: MALE LABCAT HE4.43 22-MAY-2002 Study Report fo r H em atology SUMMARY REPORT PERIOD: TERMINAL STUDY ID : ARGUS #418-027 STUDY NO: 060-063 TEST(s): UNITS: WBC RBC HGB THSN/CU MM MILL/CU MM GRAMS/DL HCT MCV MCH % CU MICRONS PICO GRAMS Group: 1-F MEAN SD N 20.2 2.70 4 5.86 0.466 4 13.9 0.61 4 36.8 1.61 4 63.0 2.88 4 23.8 1.21 4 Group: 2 - F MEAN SD N 14.9 1.92 5 6.00 0.246 5 14.3 0.46 5 38.2 1.08 5 63.6 2.77 5 23.8 1.08 5 Group: 3 - F MEAN SD N 20.2 2.71 6 5.77 0.578 6 13.7 0.78 6 36.3 2.88 6 63.0 1.87 6 23.8 1.26 6 Group: 4 - F MEAN SD N 21.6 2.83 4 5.76 0.371 4 13.2 0.68 4 34.1 2.46 4 59.2 1.38 4 22.9 0.46 4 418-027 :PAGE K-16 SEX: FEMALE MCHC PLT % THSN/CU MM PT seconds 37.8 0.72 4 1534 140.4 4 13.3 0.40 5 37.4 0.17 5 947 531.0 5 13.3 0.34 4 37.8 1.01 6 1598 423.9 6 13.2 0.16 5 38.7 1.36 4 1547 236.6 4 13.2 0.22 4 LABCAT HE4.43 22-MAY-2002 Study R eport fo r H em atology SUMMARY REPORT PE R IO D : TERMINAL 418-027;PAGE K-17 STUDY ID : ARGUS #418-027 STUDY NO: 060-063 TEST(s) UNITS: APTT MPV seconds CU MICRONS SEX: FEMALE NRBC Lymphocyte Segmented Bands Monocytes E o s in o p h il B a s o p h iIs 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 21.1 2.32 5 7 .7 0.91 4 0 15.9 3.9 0.0 0.3 0.1 0.0 0.0 1.81 1.38 0.00 0.34 0.12 0.00 4 4 444 4 4 Group: 2 - F MEAN SD N 18.2 1.95 4 8.8 2.08 5 0 12.6 2.0 0.0 0.2 0.0 0.0 0.0 2.28 0.76 0.00 0.16 0.00 0.00 5 5 555 5 5 Group: 3 - F MEAN SD N 22.0 3.70 5 8 .0 1.02 6 0 15.5 4 .4 0 .0 0.2 0.1 0 .0 0.0 2.48 1.54 0.00 0.27 0.17 0.00 6 6666 6 6 Group: 4 - F MEAN SD N 19.8 4.39 4 8.2 0.58 4 0 16.4 4.1 0.1 0 .9 0 .0 0 .0 0.0 4.17 1.95 0.12 0.56 0.00 0.00 4 4 444 4 4 LABCAT HE4.43 22-MAY-2002 STUDY ID : ARGUS #418-027 STUDY NO: 060-063 Study R eport fo r Hem atology SUMMARY REPORT PERIO D; TERMINAL TESTIs ) : Abnormal L Other UNITS: THSN/CU MM THSN/CU MM Group: 1-F MEAN SD N 0.1 0.10 4 0.0 0.00 4 Group: 2 - F MEAN SD N 0 .0 0.00 5 0.0 0.00 5 Group: 3 - F MEAN SD N 0 .0 0.00 6 0.0 0.00 6 Group: 4-F MEAN SD N 0.1 0.15 4 0.0 0.00 4 418-027:PAGE K -18 SEX: FEMALE LABCAT HE4.43 22-MAY-2002 Study R eport fo r H em atology WHITE DIFFERENTIAL DATA STUDY ID: ARGUS #418-027 STUDY NO: 060-063 GROUP: 1-M Animal ID TERMINAL CNT ABS 17608 Nucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E osinophiIs BasophiIs Abnormal Lymphocytes O th e r WBC 0 83 11.2 15 2 .0 0 0.0 1 0.1 1 0.1 0 0.0 0 0.0 0 0.0 13.5 17618 N ucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E o s in o p h iIs BasophiIs Abnormal Lymphocytes Other WBC 0 81 8 .8 17 1 .9 0 0.0 1 0.1 1 0.1 0 0.0 0 0.0 0 0.0 10.9 17630 N ucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E o s in o p h iIs B a s o p h iIs Abnormal Lymphocytes Other WBC 0 82 1 0.3 16 2 .0 0 0.0 1 0.1 1 0.1 0 0.0 0 0.0 0 0.0 12.6 418-027:PAGE K-19 SEX: MALE LABCAT HE4.43 22-MAY-2002 Study R eport fo r Hem atology WHITE D IFFERENTIAL DATA STUDY ID : ARGUS #418-027 STUDY NO: 060-063 GROUP: 1-M Animal ID TERMINAL CNT ABS 17631 17639 N ucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E o s in o p h iIs BasophiIs Abnormal Lymphocytes Other UBC N ucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E osinophiIs B a s o p h iIs Abnormal Lymphocytes O ther WBC 0 90 1 4.9 9 1.5 0 0.0 1 0.2 0 0.0 0 0.0 0 0.0 0 0.0 16.6 0 89 1 7 .8 11 2 .2 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 20.0 418-027:PAGE K-20 SEX: MALE LABCAT HE4.43 22-MAY-2002 Study Report fo r Hem atology WHITE DIFFERENTIAL DATA STUDY ID: ARGUS #418-027 STUDY NO: 060-063 GROUP: 2-M Animal ID TERMINAL CNT ABS 17634 Nucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E o s in o p h iIs BasophiIs Abnormal Lymphocytes O th e r UBC 0 89 1 7 .0 10 1 .9 0 0.0 0 0.0 1 0.2 0 0.0 0 0.0 0 0.0 19.1 17635 Nucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E osinophiIs B a s o p h iIs Abnormal Lymphocytes O th e r WBC 0 75 12 .7 24 4.1 0 0.0 1 0.2 0 0.0 0 0.0 0 0.0 0 0.0 16.9 17638 N ucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E osinophiIs BasophiIs Abnormal Lymphocytes O th e r WBC 0 84 1 3 .9 13 2.1 0 0.0 1 0.2 2 0.3 0 0.0 0 0.0 0 0.0 16.5 418-027'.PAGE K-21 SEX: MALE LABCAT HE4.43 22-MAY-2002 Study Report fo r H em atology WHITE DIFFER EN TIA L DATA STUDY ID : ARGUS #418-027 STUDY NO: 060-063 GROUP: 2-M Anim al ID TERMINAL CNT ABS 17642 N ucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E o s in o p h iIs BasophiIs Abnormal Lymphocytes Other WBC 0 80 1 4 .6 16 2 .9 0 0.0 3 0.5 1 0.2 0 0.0 0 0.0 0 0.0 18.3 17643 N ucleated Red C e lls Lymphocytes Segmented N e u tro p h iIs Bands Monocytes E o s in o p h iIs BasophiIs Abnormal Lymphocytes Other WBC 0 87 2 0 .8 12 2 .9 0 0.0 0 0.0 1 0.2 0 0.0 0 0.0 0 0.0 23.9 418-027PAGE K-22 SEX: MALE LABCAT HE4.43 22-MAY-2002 Study R eport fo r H em atology WHITE DIFFERENTIAL DATA STUDY ID: ARGUS #418-027 STUDY NO: 060-063 GROUP: 3-M Anim al ID TERMINAL CNT ABS 17620 N ucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E o s in o p h iIs BasophiIs Abnormal Lymphocytes Other WBC 0 84 11.4 15 2 .0 0 0.0 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 13.6 17623 N ucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E o s in o p h iIs B a s o p h iIs Abnormal Lymphocytes Other WBC 0 88 18.2 11 2 .3 0 0.0 0 0.0 1 0.2 0 0.0 0 0.0 0 0.0 20.7 17627 Nucleated Red C e lls Lymphocytes Segmented N e u tro p h iIs Bands Monocytes E osinophiIs B a s o p h iIs Abnormal Lymphocytes O th e r WBC 0 83 1 0.9 14 1 .8 0 0.0 0 0.0 3 0.4 0 0.0 0 0.0 0 0.0 13.1 418-027 :PAGE K-23 SEX: MALE LABCAT HE4.43 22-MAY-2002 Study R eport fo r Hem atology WHITE DIFFERENTIAL DATA STUDY ID: ARGUS #418-027 STUDY NO: 060-063 GROUP: 3-M Animal ID TERMINAL CNT ABS 17628 Nucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E o s in o p h iIs B a s o p h iIs Abnormal Lymphocytes Other WBC 0 91 15.0 7 1.2 0 0.0 1 0.2 1 0.2 0 0.0 0 0.0 0 0.0 16.5 17633 Nucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E o s in o p h iIs BasophiIs Abnormal Lymphocytes Other WBC 0 86 10.9 13 1 .7 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 0 0.0 12.7 418-027:PAGE K-24 SEX: MALE LABCAT HE4.43 22-MAY-20Q2 Study Report fo r Hem atology WHITE DIFFERENTIAL DATA STUDY ID: ARGUS #418-027 STUDY NO: 060-063 GROUP: 4-M Animal ID TERMINAL CNT ABS 17621 Nucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E o s in o p h iIs B a s o p h iIs Abnormal Lymphocytes Other WBC 0 92 15.8 6 1.0 0 0.0 2 0.3 0 0.0 0 0.0 0 0.0 0 0.0 17.2 17622 17625 N ucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E o s in o p h iIs BasophiIs Abnormal Lymphocytes Other WBC N ucleated Red C e lls Lymphocytes Segmented N e u tro p h iIs Bands Monocytes E o s in o p h iIs BasophiIs Abnormal Lymphocytes Other WBC 0 79 8 .7 18 2 .0 0 0.0 0 0.0 3 0.3 0 0.0 0 0.0 0 0.0 11.0 0 90 13.1 10 1.5 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 14.5 418-027:PAGE K-25 SEX: MALE LABCAT HE4.43 22-MAY-2002 Study Report fo r Hem atology W H IT E D IF F E R E N T IA L DATA STUDY ID : ARGUS #418-027 STUDY NO: 060-063 GROUP: 4-M Animal ID TERMINAL CNT ABS 17629 17636 N ucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E o s in o p h iIs BasophiIs Abnormal Lymphocytes Other WBC N ucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E osinophiIs B a s o p h iIs Abnormal Lymphocytes Other WBC 0 88 1 9.6 11 2 .5 0 0.0 0 0.0 1 0.2 0 0.0 0 0.0 0 0.0 22.3 0 42 13.1 58 18.2 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 31.3 418-027:PAGE K-26 SEX: MALE LABCAT HE4.43 22-MAY-2002 Study Report fo r H em atology WHITE DIFFERENTIAL DATA STUDY ID: ARGUS #418-027 STUDY NO: 060-063 Animal ID GROUP: 1-F TERMINAL CNT ABS 17694 N ucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E o s in o p h iIs B a s o p h iIs Abnormal Lymphocytes Other WBC 0 81 1 3.6 16 2 .7 0 0.0 2 0.3 0 0.0 0 0.0 1 0.2 0 0.0 16.8 17703 Nucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E osinophiIs BasophiIs Abnormal Lymphocytes O th e r WBC 0 73 1 7 .0 25 5 .8 0 0.0 1 0.2 1 0.2 0 0.0 0 0.0 0 0.0 23.3 17681 N ucleated Red C e lls Lymphocytes Segmented N e u tro p h iIs Bands Monocytes E o s in o p h iIs BasophiIs Abnormal Lymphocytes Other WBC 0 77 15.2 19 3 .8 0 0.0 4 0.8 0 0.0 0 0.0 0 0.0 0 0.0 19.8 418-027:PAGE K-27 SEX: FEMALE LABCAT HE4.43 22-MAY-2002 Study R eport fo r Hem atology WHITE DIFFERENTIAL DATA STUDY ID : ARGUS #418-027 STUDY NO: 060-063 GROUP: 1-F Animal ID TERMINAL CNT ABS 17690 N ucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E osinophiIs B a s o p h ils Abnormal Lymphocytes Other WBC 0 84 17.6 15 3.1 0 0.0 0 0.0 1 0.2 0 0.0 0 0.0 0 0.0 20.9 17695 N ucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E osinophiIs B a s o p h iIs Abnormal Lymphocytes Other WBC 0 0 0 0 0 0 0 0 0 418-027:PAGE K-28 SEX: FEMALE (-- ) - Data Unavailable LABCAT HE4.43 22-MAY-2002 Study Report fo r H em atology WHITE D IFFER EN TIA L DATA STUDY ID : ARGUS #418-027 STUDY NO: 060-063 GROUP: 2-F Animal ID TERMINAL CNT ABS 17675 N ucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E osinophiIs BasophiIs Abnormal Lymphocytes Other WBC 0 85 14.4 13 2 .2 0 0.0 2 0.3 0 0.0 0 0.0 0 0.0 0 0.0 16.9 17679 N ucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E o s in o p h iIs BasophiIs Abnormal Lymphocytes Other WBC 0 80 1 0.6 20 2 .7 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 13.3 17688 N ucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E osinophiIs BasophiIs Abnormal Lymphocytes Other WBC 0 82 11.9 18 2 .6 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 14.5 418-027`.PAGE K-29 SEX: FEMALE LABCAT HE4.43 22-MAY-2002 Study R eport fo r Hematology WHITE DIFFERENTIAL DATA STUDY ID: ARGUS #418-027 STUDY NO: 060-063 GROUP: 2-F Animal ID TERMINAL CNT ABS 17698 N ucleated Red C e lls Lymphocytes Segmented N e u tro p h iIs Bands Monocytes E o s in o p h iIs B a s o p h iIs Abnormal Lymphocytes Other UBC 0 93 15.6 5 0.8 0 0.0 2 0.3 0 0.0 0 0.0 0 0.0 0 0.0 16.8 17684 N ucle a ted Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E o s in o p h iIs B a s o p h iIs Abnormal Lymphocytes Other WBC 0 83 10.6 15 1 .9 0 0.0 2 0.3 0 0.0 0 0.0 0 0.0 0 0.0 12.8 418-027'.PAGE K-30 SEX: FEMALE LABCAT HE4.43 22-MAY-2002 Study R eport fo r Hematology WHITE D IFFER EN TIA L DATA STUDY ID : ARGUS #418-027 STUDY NO: 060-063 GROUP: 3-F Animal ID TERMINAL CNT ABS 17693 17697 N ucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E o s in o p h iIs B a s o p h iIs Abnormal Lymphocytes Other UBC N ucle a ted Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E o s in o p h iIs B a s o p h iIs Abnormal Lymphocytes Other WBC 0 74 17.8 23 5.5 0 0.0 3 0.7 0 0.0 0 0.0 0 0.0 0 0.0 24.0 0 84 13.7 16 2 .6 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 16.3 17700 N ucle a ted Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E o s in o p h iIs B a s o p h iIs Abnormal Lymphocytes Other WBC 0 68 12.2 30 5.4 0 0.0 0 0.0 2 0.4 0 0.0 0 0.0 0 0.0 18.0 418-027:PAGE K-31 SEX: FEMALE LABCAT HE4.43 22-MAY-2002 Study R eport fo r H em atology WHITE DIFFERENTIAL DATA STUDY ID: ARGUS #418-027 STUDY NO: 060-063 GROUP: 3-F Animal ID TERMINAL CNT ABS 17701 17687 Nucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E o s in o p h iIs BasophiIs Abnormal Lymphocytes Other WBC N ucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E o s in o p h iIs BasophiIs Abnormal Lymphocytes Other WBC 0 88 18.7 11 2 .3 0 0.0 1 0.2 0 0.0 0 0.0 0 0.0 0 0.0 21.2 0 76 16.1 24 5.1 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 21.2 17709 N ucleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E o s in o p h iIs BasophiIs Abnormal Lymphocytes O th e r WBC 0 71 14 .6 27 5.6 0 0.0 1 0.2 1 0.2 0 0.0 0 0.0 0 0.0 20.6 418-027 :PAGE K-32 SEX: FEMALE LABCAT HE4.43 22-MAY-2002 Study R eport fo r H em atology WHITE DIFFERENTIAL DATA STUDY ID : ARGUS #418-027 STUDY NO: 060-063 GROUP: 4-F Anim al ID TERMINAL CNT ABS 17685 N ucle a ted Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E osinophiIs BasophiIs Abnormal Lymphocytes O ther UBC 0 60 1 3.0 32 6 .9 1 0.2 6 1.3 0 0.0 0 0.0 1 0.2 0 0.0 21.6 17689 N ucle a ted Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E o s in o p h iIs B a s o p h iIs Abnormal Lymphocytes O ther WBC 0 73 1 3 .6 18 3 .3 1 0.2 8 1.5 0 0.0 0 0.0 0 0.0 0 0.0 18.6 17692 N u cle a ted Red C e lls Lymphocytes Segmented N e u tro p h ils Bands Monocytes E o s in o p h iIs B a s o p h iIs Abnormal Lymphocytes O th e r WBC 0 87 22.1 10 2 .5 0 0.0 2 0.5 0 0.0 0 0.0 1 0.3 0 0.0 25.4 418-027'.PAGE K-33 SEX: FEMALE LABCAT HE4.43 22-MAY-2002 Study Report fo r H em atology WHITE D IFFERENTIAL DATA STUDY ID : ARGUS #418-027 STUDY NO: 060-063 GROUP: 4-F Animal ID TERMINAL CNT ABS 17691 Nucleated Red C e lls Lymphocytes Segmented N e u tro p h iIs Bands Monocytes E o s in o p h iIs BasophiIs Abnormal Lymphocytes Other WBC 0 81 16.8 17 3 .5 0 0.0 2 0.4 0 0.0 0 0.0 0 0.0 0 0.0 20.8 418-027'.PAGE K-34 SEX: FEMALE LABCAT HE4.43 22-MAY-2002 Study Report fo r C lin ic a l C hem istry IN D IV ID U A L ANIMAL REPORT BY GROUP PERIOD TERMINAL STUDY ID: ARGUS #418-027 STUDY NO: 060-063 Animai ID TP g/dL ALB g/dL GLU mg/dL CHOL mg/dL T -B IL mg/dL BUN mg/dL GROUP: 1-M 17608 6 .6 4 .2 156 17618 5 .9 3 .9 143 17630 6 .5 4.1 163 17631 6.1 3 .8 173 17639 6.2 4.1 161 71 0.1 62 0.1 52 0.1 39 0.1 57 0.1 13 10 10 13 13 MEAN SD N 6.3 0.29 5 4 .0 0.16 5 159 11.0 5 56 11.9 5 0.1 0.00 5 12 1.6 5 418-027:PAGE K-35 CREAT mg/dL 0 .3 0.3 0.2 0.2 0.3 0.3 0.05 5 SEX: MALE ALT U/L 41 38 35 36 38 38 2.3 5 GROUP: 2-M 17634 17635 17638 17642 17643 MEAN SD N 6.2 6.7 6 .7 6 .0 6.1 6.3 0.34 5 3 .9 4.1 4 .3 4 .0 4.1 4.1 0.15 5 180 188 185 150 217 184 23.9 5 51 0.1 61 0.1 50 0.1 51 0.1 47 0.1 52 0.1 5.3 0.00 55 16 0 .3 11 0 .3 13 0 .3 12 0 .2 16 0 .3 14 0 .3 2.3 0.04 55 45 42 42 42 45 43 1.6 5 GROUP: 3-M 17620 17623 17627 17628 17633 MEAN SD N 6.1 6 .4 5.8 6.5 6.0 6.2 0.29 5 4 .2 4.1 3 .7 4 .2 4.1 4.1 0.21 5 154 178 153 145 151 156 12.7 5 43 0.1 47 0.1 49 0.1 48 0.1 58 0.1 49 0.1 5.5 0.00 55 11 0 .3 12 0 .4 14 0 .3 14 0 .3 12 0 .3 13 0 .3 1.3 0.04 55 50 45 50 48 40 47 4 .2 5 LABCAT CC4.43 22-MAY-2002 Study Report fo r C lin ic a l C hem istry IN D IV ID U A L ANIMAL REPORT BY GROUP PERIOD: TERMINAL STUDY ID : ARGUS #418-027 STUDY NO: 060-063 Animal ID TP 9/dL ALB 9/dL GLU mg/dL CHOL mg/dL T -B IL mg/dL BUN mg/dL GROUP: 4-M 17621 6 .5 4 .4 117 17622 6.1 4.3 90 17625 6 .2 4 .4 119 17629 6 .4 4 .3 106 17636 6 .2 3 .4 110 18 0.1 32 0.1 39 0.1 33 0.1 24 0.1 14 16 9 21 24 MEAN SD N 6.3 0.16 5 4.2 0.43 5 108 11.5 5 29 0.1 8.2 0.00 55 17 5.9 5 418-027 :PAGE K-36 CREAT mg/dL 0 .4 0 .4 0 .2 0 .4 0 .4 0 .4 0.09 5 SEX: MALE ALT U/L 38 51 54 45 52 48 6.5 5 LABCAT CC4.43 22-MAY-2002 Study Report fo r C lin ic a l C hem istry IN D IV ID U A L ANIMAL REPORT BY GROUP PERIOD: TERMINAL STUDY ID : ARGUS #418-027 STUDY NO: 060-063 Anim al ID GROUP: 1-F 17694 17695 17703 17681 17690 MEAN SD N TP g/dL 5.8 6.5 6 .7 7 .0 6.3 6.5 0.45 5 ALB g/dL 3 .7 4.3 4 .2 4.5 4.1 4 .2 0.30 5 GLU mg/dL 91 130 111 164 127 125 26.9 5 CHOL mg/dL 43 48 63 66 40 52 11.8 5 T -B IL mg/dL 0.1 0.1 0.1 0.2 0.2 0.1 0.05 5 BUN mg/dL 24 16 23 17 21 20 3 .6 5 418-027:PAGE K-37 SEX: FEMALE CREAT mg/dL ALT U/L 0.3 0 .4 0.4 0 .4 0 .4 0 .4 0.04 5 58 48 62 68 62 60 7 .4 5 GROUP: 2 - F 17675 7 .3 4 .5 138 17679 6 .3 4 .2 135 17684 5 .7 3 .8 144 17688 6 .4 4.1 129 17698 6 .9 4 .2 145 71 0 .2 58 0.1 65 0.1 51 0.1 61 0.1 19 0 .4 17 0 .2 14 0 .3 23 0 .4 17 0 .4 60 43 77 49 55 MEAN SD N 6.5 4 .2 138 61 0.1 18 0 .3 57 0.61 0.25 6 .6 7.5 0.04 3.3 0.09 13.0 555 5 555 5 GROUP: 3-F 17693 17687 17697 17700 17701 17709 MEAN SD N 6.2 6.5 6 .0 6 .9 6.2 5.6 6.2 0.44 6 4 .0 4.3 3 .8 4.5 4.1 3 .6 4.1 0.33 6 98 162 113 145 93 135 124 27.4 6 46 72 57 73 61 36 58 14.5 6 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.00 6 22 0 .3 13 0 .3 19 0 .4 18 0 .3 21 0 .3 21 0 .3 47 83 52 70 55 63 19 0 .3 62 3.3 0.04 13.3 666 LABCAT CC4.43 22-MAY-2002 Study R eport fo r C lin ic a l C hem istry IN D IV ID U A L ANIMAL REPORT BY GROUP PERIO D; TERMINAL STUDY ID : ARGUS #418-027 STUDY NO: 060-063 Anim al ID GROUP: 4-F 17685 17689 17692 17691 MEAN SD N Tp g/dL 6.5 6 .7 5.4 6.5 6.3 0.59 4 ALB g/dL 4.2 4.2 3 .9 4.1 4.1 0.14 4 GLU mg/dL 100 105 96 156 114 28.1 4 CHOL mg/dL 66 69 41 53 57 12.9 4 T -B IL mg/dL 0.1 0.2 0.1 0.1 0.1 0.05 4 BUN mg/dL 17 22 22 22 21 2.5 4 418-027:PAGE K-38 SEX: FEMALE CREAT mg/dL ALT U/L 0 .4 0 .4 0.3 0.5 0 .4 0.08 4 89 99 102 87 94 7.4 4 LABCAT CC4.43 22-MAY-2002 Study Report fo r C lin ic a l C hem istry IN D IV ID U A L ANIMAL REPORT BY GROUP PER IO D : TERMINAL STUDY ID : ARGUS #418-027 STUDY NO: 060-063 Animal ID AST U/L ALP U/L CA mg/dL PHOS mg/dL TRIG mg/dL NA tnmol/L GROUP: 1-M 17608 17618 17630 17631 17639 MEAN SD N 90 92 89 83 88 88 3 .4 5 106 63 131 129 106 107 27.4 5 11.6 10.6 11.2 11.2 10.9 11.1 0.37 5 8.3 7 .7 8.6 9 .9 7 .9 8.5 0.87 5 66 45 76 106 66 72 22.2 5 147 150 147 148 146 148 1.5 5 418-027:PAGE K-39 SEX: MALE K mmol/L CL mmol/L 5.5 6 .0 4 .9 5 .9 6 .2 5 .7 0.51 5 94 98 94 96 97 96 1.8 5 GROUP: 2-M 17634 17635 17638 17642 17643 MEAN SD N 101 86 80 89 74 86 10.2 5 74 88 118 113 148 108 28.6 5 11.5 11.0 11.9 11.0 11.4 11.4 0.38 5 9 .8 8.2 8.3 8.2 13.9 9 .7 2.45 5 39 69 69 66 53 59 13.1 5 144 6 .2 147 5 .0 151 6 .3 148 5 .9 144 7 .8 147 6 .2 2 .9 1.01 55 95 96 102 100 97 98 2 .9 5 GROUP: 3-M 17620 17623 17627 17628 17633 MEAN SD N 102 88 92 100 96 96 5.7 5 149 96 91 122 122 116 23.4 5 11.3 11.8 11.0 11.4 11.4 11.4 0.29 5 9 .2 8.0 9 .8 10.3 9 .9 9.4 0.90 5 48 68 52 56 105 66 23.2 5 147 5 .8 147 6 .7 148 7 .0 149 6 .9 148 6 .3 148 6 .5 0.8 0.49 55 97 100 103 101 99 100 2.2 5 LABCAT CC4.43 22-MAY-2002 Study Report fo r C lin ic a l C hem istry IN D IV ID U A L ANIMAL REPORT BY GROUP PERIOD : TERMINAL STUDY ID : ARGUS #418-027 STUDY NO: 060-063 Animal ID AST U/L ALP U/L CA mg/dL PH0S mg/dL TRIG mg/dL NA mmol/L GROUP: 4-M 17621 17622 17625 17629 17636 89 105 109 108 98 117 11.5 109 11.1 104 11.3 133 11.3 153 11.3 9 .3 8.9 9 .8 12.6 9 .2 24 151 30 147 47 150 24 144 28 147 MEAN SD N 102 123 11.3 10.0 31 148 8.3 20.0 0.14 1.51 9.5 2 .8 555 555 418-027'.PAGE K-40 SEX: MALE K mmol/L CL mmol/L 5.9 6.3 6.3 7 .9 6.1 6.5 0.80 5 100 100 103 95 98 99 2 .9 5 LABCAT CC4.43 22-MAY-2QQ2 Study Report fo r C lin ic a l C hem istry INDIV ID U A L ANIMAL REPORT BY GROUP PERIOD: TERMINAL STUDY ID : ARGUS #418-027 STUDY NO: 060-063 Animal ID AST U/L ALP U/L CA mg/dL PHOS mg/dL TRIG mg/dL NA mmol/L GROUP: 1-F 17694 17695 17703 17681 17690 MEAN SD N 102 92 99 114 92 100 9.1 5 49 59 59 51 97 63 19.5 5 11.5 11.5 11.8 12.4 11.8 11.8 0.37 5 9.5 9 .4 9 .2 9 .2 9.3 9.3 0.13 5 44 51 46 66 72 56 12.5 5 140 141 143 145 144 143 2.1 5 418-027:PAGE K-41 SEX: FEMALE K mmol/L CL mmol/L 7.0 7.0 6.1 6 .8 6.7 6.7 0.37 5 96 101 99 93 98 97 3.0 5 GROUP: 2 - F 17675 17679 17684 17688 17698 MEAN SD N 107 82 120 75 86 94 18.8 5 39 12.4 43 11.8 56 10.9 61 11.6 56 11.7 8 .0 9.3 7 .0 8.5 7 .8 84 27 47 72 53 51 11.7 8.1 57 9.5 0.54 0.85 22.2 55 5 5 141 141 141 143 143 142 1.1 5 6.0 7.4 6.1 5.5 6.8 6.4 0.74 5 96 98 99 98 99 98 1.2 5 GROUP: 3 - F 17693 17687 17697 17700 17701 17709 MEAN SD N 95 107 104 114 129 150 117 20.0 6 91 48 24 68 43 49 54 23.0 6 11.6 11.4 11.2 12.1 11.4 11.5 11.5 0.31 6 10.5 9.1 6 .7 10.6 8.1 7 .9 8 .8 1.54 6 36 91 37 36 34 52 48 22.2 6 141 6 .9 143 6 .2 143 7.1 143 6 .7 142 7 .3 144 6 .0 143 6 .7 1.0 0.51 66 102 100 102 98 103 100 101 1 .8 6 LABCAT CC4.43 22-MAY-2002 Study Report fo r C lin ic a l C hem istry IN D IV ID U A L ANIMAL REPORT BY GROUP PERIOD: TERMINAL STUDY ID : ARGUS #418-027 STUDY NO: 060-063 Animal ID AST U/L ALP U/L CA mg/dL PHOS mg/dL TRIG mg/dL NA mmol/L GROUP: 4-F 17685 17689 17692 17691 MEAN SD N 93 147 109 131 120 23.8 4 76 68 129 73 87 28.5 4 11.6 12.2 11.1 12.6 11.9 0.66 4 9.5 10.0 8 .8 9 .6 9.5 0.50 4 54 69 62 79 66 10.6 4 140 140 138 143 140 2.1 4 418-027:PAGE K-42 SEX: FEMALE K mmol/L CL mmol/L 6 .7 6 .8 6.4 6 .9 6 .7 0.22 4 98 98 102 95 98 2 .9 4 LABCAT CC4.43 22-MAY-2002 Study Report fo r C lin ic a l Chem istry IN D IV ID U A L ANIMAL REPORT BY GROUP PERIO D: TERMINAL STUDY ID : ARGUS #418-027 STUDY NO: 060-063 Animal ID GLOB g/dL A/G none GROUP: 1-M 17608 17618 17630 17631 17639 2.4 2 .0 2 .4 2.3 2.1 1.8 2.0 1.7 1.7 2.0 MEAN SD N 2.2 0.18 5 1.8 0.15 5 418-027'.PAGE K-43 SEX: MALE GROUP: 2-M 17634 17635 17638 17642 17643 MEAN SD N 2 .3 2 .6 2 .4 2 .0 2 .0 2.3 0.26 5 1.7 1.6 1.8 2.0 2.1 1.8 0.21 5 GROUP: 3-M 17620 17623 17627 17628 17633 MEAN SD N 1.9 2 .3 2.1 2 .3 1 .9 2.1 0.20 5 2.2 1.8 1.8 1.8 2.2 2 .0 0.22 5 LABCAT CC4.43 22-MAY-2002 Study Report fo r C lin ic a l C hem istry IN D IV ID U A L ANIMAL REPORT BY GROUP PER IO D : TERMINAL STUDY ID : ARGUS #418-027 STUDY NO: 060-063 Animal ID GLOB g/dL A/G none GROUP: 4-M 17621 17622 17625 17629 17636 2.1 1.8 1.8 2.1 2 .8 2.1 2.4 2.4 2.0 1.2 MEAN SD N 2.1 0.41 5 2.0 0.49 5 418-027 :PAGE K-44 SEX: MALE LABCAT CC4.43 22-MAY-2002 Study Report fo r C lin ic a l Chem istry I N D I V I D U A L ANIMAL R E P O R T B Y G R O U P PERIO D: TERMINAL STUDY ID : ARGUS #418-027 STUDY NO: 060-063 Animal ID GLOB g/dL A/G none GROUP: 1-F 17694 17695 17703 17681 17690 2.1 2.2 2.5 2.5 2 .2 1.8 2 .0 1.7 1.8 1.9 MEAN SD N 2 .3 0.19 5 1.8 0.11 5 418-027'.PAGE K-45 SEX: FEMALE GROUP: 2-F 17675 17679 17684 17688 17698 MEAN SD N 2 .8 2.1 1 .9 2 .3 2 .7 2.4 0.38 5 1.6 2.0 2.0 1.8 1.6 1 .8 0.20 5 GROUP: 3-F 17693 17687 17697 17700 17701 17709 MEAN SD N 2 .2 2.2 2.2 2 .4 2.1 2 .0 2 .2 0.13 6 1.8 2 .0 1.7 1.9 2 .0 1.8 1 .9 0.12 6 LABCAT CC4.43 22-MAY-2002 Study Report for Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL STUDY ID : ARGUS #418-027 STUDY NO: 060-063 Animal ID GLOB g/dL A/G none GROUP: 4-F 17685 17689 17692 17691 2.3 2.5 1.5 2.4 1 .8 1.7 2 .6 1 .7 MEAN SD N 2.2 0.46 4 2 .0 0.44 4 418-027:PAGE K-46 SEX: FEMALE LABCAT CCA.43 22-MAY-2QQ2 Study Report for Clinical Chemistry 418-027:PAGE K-47 SUMMARY REPORT PERIOD: TERMINAL STUDY ID : ARGUS #418-027 STUDY NO: 060-063 SEX: MALE TEST(s): UNITS: TP ALB GLU CHOL T -B IL BUN CREAT ALT AST g/dL g/dL mg/dL mg/dL mg/dL mg/dL mg/dL U/L U/L Group: 1-M MEAN 6 .3 4 .0 159 56 0.1 12 0 .3 38 88 SD 0.29 0.16 11.0 11.9 0.00 1.6 0.05 2.3 3.4 N 555 55555 5 Group: 2-M MEAN SD N 6 .3 0.34 5 4.1 0.15 5 184 23.9 5 52 0.1 5.3 0.00 55 14 0 .3 2.3 0.04 55 43 86 1.6 10.2 55 Group: 3-M MEAN 6 .2 4.1 156 49 0.1 13 0 .3 47 96 SD 0.29 0.21 12.7 5.5 0.00 1.3 0.04 4.2 5.7 N 555 5 5555 5 Group: 4-M MEAN 6 .3 4 .2 108 29 0.1 17 0 .4 48 102 SD 0.16 0.43 11.5 8.2 0.00 5.9 0.09 6.5 8 .3 N 555 5 5555 5 LABCAT CC4.43 22-MAY-2002 Study Report for Clinical Chemistry 418-027:PAGE K-48 SUMMARY REPORT PERIOD: TERMINAL STUDY ID : ARGUS #418-027 STUDY NO: 060-063 SEX: MALE TEST(s): UNITS: ALP CA PHOS TRIG NA K CL U/L mg/dL mg/dL mg/dL mmol/L mmol/L mmol/L GLOB 9/dL A/G none Group: 1-M MEAN SD N 107 27.4 5 11.1 0.37 5 8.5 0.87 5 72 22.2 5 148 5 .7 1.5 0.51 55 96 2 .2 1.8 1.8 0.18 0.15 555 Group: 2-M MEAN SD N 108 28.6 5 11.4 0.38 5 9 .7 2.45 5 59 13.1 5 147 6.2 2 .9 1.01 55 98 2.3 1.8 2 .9 0.26 0.21 555 Group: 3-M MEAN SD N 116 23.4 5 11.4 0.29 5 9.4 0.90 5 66 23.2 5 148 6.5 0.8 0.49 55 100 2.1 2 .0 2.2 0.20 0.22 555 Group: 4-M MEAN 123 11.3 1 0.0 31 148 6 .5 99 2.1 2 .0 SD 20.0 0.14 1.51 9.5 2.8 0.80 2 .9 0.41 0.49 N 555 5 555 55 LABCAT CC4.43 22-MAY-2002 Study Report for Clinical Chemistry SUMMARY R E P O R T PERIOD : TERMINAL 418-027:PAGE K-49 STUDY ID : ARGUS #418-027 STUDY NO: 060-063 SEX: FEMALE TEST(s): UNITS: TP ALB GLU CH0L T -B IL BUN CREAT ALT AST g/d>- 9/dL mg/dL mg/dL mg/dL mg/dL mg/dL U/L U/L Group: 1-F MEAN 6 .5 4 .2 125 52 0.1 20 0 .4 60 100 SD 0.45 0.30 26.9 11.8 0.05 3.6 0.04 7 .4 9.1 N 5555 555 5 5 Group: 2 - F MEAN 6.5 4 .2 138 61 0.1 18 0 .3 57 94 SD 0.61 0.25 6.6 7.5 0.04 3.3 0.09 13.0 18.8 N 5555555 55 Group: 3 - F MEAN SD N 6.2 0.44 6 4.1 0.33 6 124 27.4 6 58 14.5 6 0.1 0.00 6 19 0 .3 62 117 3.3 0.04 13.3 20.0 66 6 6 Group: 4 -F MEAN SD N 6.3 0.59 4 4.1 0.14 4 114 28.1 4 57 12.9 4 0.1 0.05 4 21 0 .4 2.5 0.08 44 94 120 7.4 23.8 44 LABCAT CC4.43 22-MAY-2002 Study Report for Clinical Chemistry 418-027`.PAGE K-50 SUMMARY REPORT PERIOD: TERMINAL STUDY ID: ARGUS #418-027 STUDY NO: 060-063 SEX: FEMALE TESTIs ): 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 ALP CA PHOS TRIG NA K CL U/L mg/dL mg/dL mg/dL mmol/L mmol/L mmol/L 63 19.5 5 11.8 0.37 5 9.3 0.13 5 56 12.5 5 143 6 .7 2.1 0.37 55 97 3.0 5 51 1 1 .7 8.1 57 9.5 0.54 0.85 22.2 5 555 142 6 .4 1.1 0.74 55 98 1.2 5 54 23.0 6 11.5 0.31 6 8.8 1.54 6 48 22.2 6 143 6 .7 1.0 0.51 66 101 1.8 6 87 28.5 4 11.9 0.66 4 9.5 0.50 4 66 10.6 4 140 6 .7 2.1 0.22 44 98 2 .9 4 GLOB g/dL 2.3 0.19 5 2.4 0.38 5 2.2 0.13 6 2.2 0.46 4 A/G none 1.8 0.11 5 1.8 0.20 5 1.9 0.12 6 2 .0 0.44 4 LABCAT CC4.43 22-MAY-2002 418-027:PAGE K -51 QUALITY ASSURANCE STATEMENT Study Number: 418-027 Redfield Study Number: 060-063 This study has been inspected and audited by the Quality Assurance Unit (QAU) as required by the Good Laboratory Practice (GLP) regulations promulgated by the U.S. Food and Drug Administration or U.S. Environmental Protection Agency or other international regulations, as required. The following is a record of the dates that audits/inspections were performed and reported by the QAU. Date of AU D IT/lN SPEC TlO N 05/17/02, 05/20/02 T y p e o f A udit/In spectio n Clinical Pathology D ates R eported to Stu d y Directo r and Ma nagem en t 05/20/02 APPROVED BY: Redfield Laboratories \3 o ^ - Date APPENDIX L STATEMENT OF THE STUDY DIRECTOR 905 Sheehy Drive, Bldg. A Horsham, PA 19044 Telephone: (215) 443-6710 Telefax: (215)443-8587 418-027:PAGE L -l ARGUS RESEARCH Charles River Laboratories Discovery and Development Services PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST SPONSOR'S STUDY NUMBER: T-7599 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 Drug Administration (FDA) Good Laboratory Practice Regulations; Final Rulea, the Japanese Ministry of Health and Welfare (MHW) Good Laboratory Practice Standard for Safety Studies on Drugsb, the Organisation for Economic Co-operation and Development (OECD), the Revised OECD Principles of Good Laboratory Practices0and the Organisation for Economic Co-operation and Development (OECD), The OECD Guideline for Testing of Chemicalsdoccurred that affected the quality or integrity of the study. Y *-< lond G. York, Ph.D,|DABT Associate Director oLResearch Study Director Argus Research Date a. U.S. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule. 21 CFR Part 58. b. Japanese Ministry of Health and Welfare (1997). Good Laboratory Practice Standard for Safety Studies on Drugs, MHW Ordinance No. 21, March 26, 1997. c. Organisation for Economic Co-operation and Development (1998). The Revised OECD Principles of Good Laboratory Practices [C(97)186/Final]. d. Organisation for Economic Co-operation and Development (1996). OECD Guideline for Testing of Chemicals. Section 4, No. 422: Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, adopted 22 March 1996. APPENDIX M QUALITY ASSURANCE STATEMENT 418-027:PAGE M -l 9 0 S Sheehy Drive, Bldg. A Horsham , PA 19 0 4 4 Telephone: ( 2 I S ) 4 4 3 -8 7/0 Telefax: (2 1 5 ) 4 4 3 -8 5 0 7 ARGUS RESEARCH Charles River Laboratories Discovery and Development Services QUALITY ASSURANCE STATEMENT Argus Protocol: 418-027 Sponsor's Study Number: T-7599 Study Director: Raymond G. York, Ph.D., DABT The protocol, critical phases, raw data and final report were inspected by the Quality Assurance Unit (QAU), to assure conformance with: Organisation for Economic Co-operation and Development (1998). The Revised OECD Principles of Good Laboratory Practices [C(97)186/Final]. U.S. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule. 21 CFR Part 58. Japanese Ministry of Health and Welfare (1997). Good Laboratory Practice Standard for Safety Studies on Drugs, MHW Ordinance Number 21, March 26, 1997. The undersigned indicate that the report is an accurate representation of the raw data. Data provided by the Sponsor or a subcontractor were not audited by the Argus Research Quality Assurance Unit. 418-027:PAGE M-2 The QAU inspection and report audit dates are listed below: Inspection Phase Protocol TS Administration TS Preparation Motor Activity FOB1 Natural Delivery/ Litter Observations Blood Collection Dam/Litter Sacrifice Male SacrificeRaw Data Check In-Life Data Necropsy Data Formulations Data Report Tables Report Text Inspection Date(s) 12 FEB 02 15 FEB 02 22 FEB 02 28 FEB 02 20 MAR 02 20 MAR 02 Date(s) Findings Submitted to Study Director 12 FEB 02 15 FEB 02 22 FEB 02 28 FEB 02 20 MAR 02 01 APR 02 Date(s) Findings Submitted to Management 12 FEB 02 15 FEB 02 22 FEB 02 28 FEB 02 20 MAR 02 01 APR 02 27 MAR 02 04 APR 02 04 APR 02 27 MAR 02 19 APR 02 19 APR 02 27 MAR 02 19 APR 02 19 APR 02 01 AUG 02 17-19, 22-24 JUL 02 18, 22 JUL 02 03,31 JUL 02 26-30 JUL 02 25-26 JUL 02 30 JUL 02 01 AUG 02 01 AUG 02 24 JUL 02 23 JUL 02 31 JUL 02 30 JUL 02 26 JUL 02 30 JUL 02 01 AUG 02 01 AUG 02 24 JUL 02 23 JUL 02 31 JUL 02 30 JUL 02 26 JUL 02 30 JUL 02 01 AUG 02 functional Observational Battery V \ a J ^ .72^ Matthew J. Vaneman, B.S. Date Manager of Regulatory Compliance 0%(uluaaji O'figuri asm m 3 Maureen O'Brien, B.S. Date Quality Assurance Associate and Principal Auditor