Document 3Oeo1Q7Lg9jqq0MD7KnVgLkD

._ _-____ 8) OECD 407, Repeat dose oral toxicity (with FOB & histopathology), 132-007 SANITIZED JAN 0 9 2004 A 28-Dav Oral Toxicitv Studv in SPraque-Dawlev Rats Studv Number: 132-007 SAN ITlZED A 28-DAY ORAL (GAVAGE) TOXICITY STUDY OF T-7485 IN SPRAGUE-DAWLEY RATS STUDY NUMBER: 132-007 SPONSOR 3M Corporate Toxicology 3M Center, Building 220-2E-02 P.O. Box 33220 St. Paul, MN 55133-3320 SPONSOR'S REPRESENTATIVE Senior Laboratorv Manager Telephone: FAX: TESTING FACILITY Primedica Redfield Mail: P..O.Box 308 Deliveries: 100 East Boone St. Redfield, AR 72132 Telephone: 501-397-2540 FAX: 501-397-2002 STUDY DATES Study Initiation: August 29, 2000 Animal Phase Initiation: August 31, 2000 Animal Phase Completion: October 13, 2000 Study Completion: August 2, 2001 Page 1 A 28-Dav Oral ToxiciW Studv in Soraque-Dawlev Rats Studv Number: 132-007 GLP COMPLIANCE STATEMENT Study Number: 132-007 I certify that this study was performed in compliance with the Organizationfor Economic Cooperation and Development (OECD) Guidelines [C(81)30 (Final)] with the following exception. The analyses of the formulated test materials were not performed in accordance with Good Laboratory Practice guidelines. The report accurately reflects the raw data. Stud$ Director ' Primedica Redfield Page 2 A 28-Dav Oral Toxicitv Studv in SDraaue-Dawlev Rats Studv Number: 132-007 QUALITY ASSURANCE STATEMENT Study Number: 132-007 This study has been inspected and audited by the Quality Assurance Unit (QAU) as required by the Organization for Economic Cooperation and Development (OECD) Guidelines [(C(81)30 (Final)]. The following is a record of the dates that audits/inspections were performed and reported by the QAU. AUDITANSPECTION TYPEOF AUDIT/~NSPECTION DATESREPORTEDTO STUDY DIRECTOARND MANAGEMENT 08/31/00 I Dosing Formulations Amendment #1 10/24/00, 10/26/00 Formulations Raw Data 10/24/00-10/26/00 ln-Life Flaw Data Individual Animal Necropsy Records Clinical Pathology p b 11/07/00 Gross Pathology 1 12/11/00-12/12/00 I II 07/24/10 Draft Report Final Report The report accurately reflects the original data. APPROVED BY: 08/31100 p 11/07/00 12112/00 07/24/01 Quality Assurance Auditor Primedica fledfield Page 3 A 28-Dav Oral Toxicitv Studv in Soraaue-Dawlev Rats Studv Number: 132-007 TITLE A 28-DAY ORAL (GAVAGE) TOXICITY STUDY OF T-7485 IN SPRAGUE-DAWLEY RATS APPROVED BY: Stud$ Director " Primedica Redfield Page 4 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 TABLE OF CONTENTS Page Cover Page........................................................................................................................................ 1 GLP Compliance Statement............................................................................................................. 2 Quality Assurance Statement........................................................................................................... 3 Title and Signature Page .................................................................................................................. 4 Table of Contents ............................................................................................................................. 5 Study Abstract .................................................................................................................................. 7 Objective........................................................................................................................................... 9 Materials and Methods ..................................................................................................................... 9 Archival Statement.......................................................................................................................... 11 Results............................................................................................................................................ 12 Conclusion ...................................................................................................................................... 13 Tables ............................................................................................................................................. 14 Table 1 - Summary of Clinical Observations ............................................................................. 15 Table 2 - Summary of Motor Activity Data................................................................................. 18 Table 3 - Summary of Body Weights......................................................................................... 21 Table 4 - Summary of Body Weight Changes ........................................................................... 24 Table 5 - Summary of Absolute Feed consumption.................................................................. 27 Table 6 - Summary of Hematology Data ................................................................................... 30 Table 7 - Summary of Clinical Chemistry Data.......................................................................... 44 Table 8 - Summary of Organ Weights ....................................................................................... 58 Appendices ..................................................................................................................................... 79 Appendix 1- Methods Used For Clinical Pathology Procedures............................................... 80 Appendix 2 - Individual Necropsy Observations........................................................................ 84 Appendix 3 - Histopathology Report.......................................................................................... 94 Appendix 4 - Individual Clinical Observation!; ......................................................................... 190 Appendix 5 - Individual Motor Activity Data ............................................................................. 196 Appendix 6 - Neurological Function Examination Results....................................................... 209 Appendix 7 - Individual Body Weights ..................................................................................... 218 Appendix 8 - Individual Feed Consumption............................................................................. 223 Appendix 9 - Individual Hematology Data ............................................................................... 228 Appendix 10 - IndividualClinical Chemistry Data.................................................................... 322 Appendix 11 - Historical Control Clinical Chemistry Data ....... ............................................... 348 Appendix 12 - Individual Organ Weights ................................................................................. 350 Page 5 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 TABLE OF CONTENTS (CONTINUED) Page Appendix 13 .Formulated Test Material Analysis Report....................................................... 371 Appendix 14 .Certificate of Analysis ....................................................................................... 392 Appendix 15 .Protocol and Amendment................................................................................. 394 Appendix 16 .Protocol Deviations .......................................................................................... 406 Appendix 17 - Key Personnel .................................................................................................. 408 Page 6 A 28-Dav Oral Toxicitv Studv in SDraaue-DawlevRats Studv Number: 132-007 A 28-DAY ORAL (GAVAGE) TOXICITY STUDY OF T-7485 IN SPRAGUE-DAWLEY RATS STUDY ABSTRACT The objective of this study was to evaluate the toxicity potential associated with oral (gavage) administration of T-7485 in Sprague-Dawley rats for a 28-day repeated dose with an approximate 14-day recovery period. Group Number 1 2 3 4 'Number Dosage Dosage Dosage Group Level Concentration Volume Designation (mg/kg) (mg/mL) (mUkg) Vehicle Control 0 0 25 Mid-dose 100 4 25 Mid-high dose 300 12 25 High-dose 900 36 25 in parentheses indicates the number of Recovery animals Number of c Animals* Males Females 10 (5) 10 10 (5) 10 10 10 10 (5) 10 (5) The animals were administered the test material or vehicle via oral gavage for 28 consecutive days. The first day of dosing was designated as Study Day 1. The dose volume was constant for all groups at 25 mUkg. Individual dose volumes were calculated based on the most recently recorded body weight for each animal. Five animals/sex/group in the vehicle control and highdose groups were designated as Recovery animals and allowed to recover for approximately 14 days. No mortality was recorded during the 28-day administration of T-7485 or during the recovery period. Clinical observations consisted of localized alopecia (back, limbs, neck, and underside), urine-stained abdominal fur, scabbed area on back and neck, and soft or liquid feces. These findings are considered incidental and unrelated to test materialadministration. Additional cageside observations were all normal. Assessment of neurological effects on animals treated with T-7485 included peripheral neuropathy, motor activity, and audio/visual evaluations. There were no test material-related effects on motor activity or audio/visual. Interpretation of peripheral neurological findings suggests no test material-relatedneuropathology, but within this evaluation the significant findings for the tail flick examination may suggest T-7485 induced a male-specific doseindependent hyperactivity. There were no treatment-related effects on body weight for either Main Study or Recovery animals. On Study Day 36, the mean body weight in males that received 900 mg/kg/day T-7485 was decreased by 7% when compared to the corresponding controls. This finding was considered incidental. Throughout the study, body weight changes and absolute feed consumption in treatment groups were calculated and compared to the corresponding control groups with no significant findings recorded for either Main Study or Recovery animals. The reported significant hematological findings are considered incidental and not associated with test materialadministration. Main Study clinical chemistry findings in males that received 2300 mg/kg/day T-7485 indicate significant decreases in serum phosphorus (approximately 16% of the control values) and potassium (approximately 20% of the control values). In contrast, an increase in chloride levels in Page 7 A 28-Dav Oral Toxicitv Studv in SDraaUe-DaWlev Rats Studv Number: 132-007 males that received 900 mg/kg/day T-7485 (4% above the control values) was recorded. In the absence of similar findings in Recovery animals, the changes in phosphorus, potassium, and chloride levels appear to be associated with test material administration but do not appear to be toxicologically or biologically significant. Other incidental findings do not appear to be related to administration of test material. Absolute and relative male liver (between 25'Y0to 30%) and female kidney (9Y0to 11%) weights were significantly increased in animals that received 900 mg/kg/day 1-7485 when compared to the corresponding controls. These significant changes were not recorded during the recovery period, and since there does not appear to be an effect of body weight on organ development, these data suggest the changes are test material-related. However, the biological and toxicological significance is unclear due to the lack of any supportive gross or histopathological findings. The remaining significant findings are considered incidental and unrelated to test material administration. Only one gross lesion was recorded at necropsy and was not considered to be test materialrelated. The microscopic lesions observed in the test animals are considered to be incidentaland in no way related to receiving the test material. Oral (gavage) administration of T-7485 in Sprague-Dawley rats for a 28-day repeated dose with an approximate 14-day recovery period resulted in no mortality or abnormal clinical observations as well as no changes in body weights, feed consumption, peripheral neuropathy, motor activity, audio/visual response, hematology, clinical chemistry, gross pathology, and histopathology. These data suggest that administration of 900 mg/kg/day T-7485 resulted in significant increases in male liver and female kidney weights when compared to control animals and establishes the n o - o b s e r v a b l e - a d v e r s e - e f f e c t - l e v e l ~ ( T~-7~4E85~. ~F~ur~the~rm~ o~re~, t~he~T~-7~4~85~ ~ non-dose-dependent hyper-reactivity effect is gender specific and is therefore difficult to interpret. Page 8 A 28-Dav Oral Toxicitv Studv in SDraaue-DawlevRats Studv Number: 132-007 OBJECTIVE The objective of this study was to evaluate the toxicity potential associated with oral (gavage) administrationof T-7485 in Sprague-Dawley rats for a 28-day repeated dose with an approximate 14-day recovery period. 3 MATERIALS AND METHODS TEST AND CONTROL MATERIALS: The test material and vehicle control materialwere identified as follows: Test Material: Lot Number: Dates Received: Physical Description: Storage: Amount Received:, T-7485 (PotassiumPerfluorobutane Sulfonate, PFBS) 2 April 6, 2000; August 30, 2000 White powder Room temperature, protectedfrom light Total of 900 grams Vehicle Material: Lot Number: Supplier: Physical Description: Storage: Carboxymethylcellulose (medium viscosity) 69H0028 Sigma Chemical Company White powder Room temperature The Sponsor assumed responsibility for characterization (identity, purity, and stability) determinations of the test material. The test materialwas inventoriedwhen received at Primedica Redfield, and a record of all test material usage was maintained. The Certificate of Analysis for the test material is in Appendix 14. Reserve samples of each lot of test and vehicle control materials were retained at Primedica Redfieldfor archiving in accordance with Good Laboratory Practices. The vehicle control material was prepared at Primedica Redfield by dissolving powdered carboxymethylcellulose in deionized water (from tap at Primedica Redfield) at a concentration of 1%. Test material solutions were prepared to the requiredconcentrations at Primedica Redfield by dissolving the test material in the prepared vehicle. Each batch of dosing solutions was prepared a maximum of 14 days prior to the last day of use. The formulated test materials were stored refrigerated in amber glass bottles. A sample (5 mL) of each concentration of the formulatedtest material and vehicle was retained predose and on the last day of dosing for each batch. The samples were frozen at approximately -20C. Prior to dosing, all predose samples were shipped to Southern Research Institution for analysis. All samples collected on the last day of dosing for each batch were shipped to Southern Research Institute for analysis after study termination. TEST ANIMALS: Healthy male and female Crl: CD@(SD) out-bredalbino rats were received from Charles River Laboratories, Inc., for use on the study. The animals were individually housed in screen-bottom stainless steel cages. Animal identification consisted of uniquely numbered ear tags and color-codedcage cards. On Study Day 1, the animals were approximately eight weeks old. The males weighed 209 to 253 grams, and the females weighed 178 to 212 grams. Teklad Certified Rodent Diet #8728 and filtered tap water were provided ad libitum. The feed and water were routinely analyzed for contaminants. There were no known contaminants in the feed or water that would be expected to affect the results of the study. The results of these analyses are on file at Primedica Redfield. Page 9 A 28-Dav Oral Toxicity Studv in Soraaue-Dawlev Rats Studv Number: 132-007 Environmental controls were set to maintain temperatures of 18" to 26C (64" to 79F) with a relative humidity of 30% to 70%. These parameters were recorded at least once daily. A 12:12 hour lightdark cycle was maintained in the animal room. GROUP DESIGNATION AND TREATMENT: The animals were acclimated for ten days prior to Study Day 1 and were examined by the Staff Veterinarian prior to being released for use on the study. Fifty males and fifty females were randomly assigned to groups by a computer generated weight-ordered distribution such that individual body weights did not exceed S O % of the mean weight for each sex. The study design was as follows: 1 Group 1 Group Dosage 1 Dosage Concentration I VDolsuamge I Number of Animals' I II 2 I Mid-dose 100 I 3 Mid-high dose 300 4 25 I 10 I 10 12 25 I 10 1 10 The animals were administered the test materialor vehicle via oral gavage for 28 consecutive days. The first day of dosing was designated as Study Day 1. The dose volume was constant for all groups at 25 mUkg. Individual dose volunies were calculated based on the most recently recorded body weight for each animal. Five mimals/sex/group in the vehicle control and highdose groups were designated as Recovery animals and allowed to recover for approximately 14 days. JUSTIFICATION FOR SPECIES SELECTION, ROUTE OF ADMINISTRATION, AND DOSE LEVEL: Rats are an animal model for studies of this type. In the assessment and evaluationof the toxic characteristics of a substance, determination of acute oral toxicity is usually an initial step. Dose levels were chosen by the Sponsor and based on the findings reported in Primedica Redfield Study Number 132-006. CLINICAL OBSERVATIONS: Observations for mortality and moribundity were recorded twice daily (a.m. and p.m.). Cageside observations were recorded at approximately one to two hours postdose daily and when a change was noted. Detailed clinical observations were recorded once before the first dose and at least weekly thereafter or when a change was noted. During Week 4, each animal was assessed far sensory reactivity to stimuli of different types (e.g., auditory and visual), grip strength, and rnotor activity. BODY WEIGHTS: Body weights were recorded pretest, on Study Day 1, approximately weekly, prior to terminal fasting, and prior to necropsy (fasted weight). The pretest body weights are not included in this report but are located in the raw data. The fasted body weights recorded prior to necropsy were used only for the calculation of relative organ weights. FEED CONSUMPTION: Feed consumption was measured approximately weekly. HEMATOLOGY: Blood samples for hematological analysis were obtained via cardiac puncture prior to necropsy. The animals were anesthetized with carbondioxide for the collection. Feed was withheld overnight prior to collection. The blood samples were evaluated for the following parameters: total and relative differential leukocyte counts, erythrocyte counts, hemoglobin concentration, hematocrit value, mean corpuscular volume, mean corpuscular hemoglobin, mean F'age 10 A 28-Dav Oral Toxicitv Studv in SDraQue-Dawlev Rats Studv Number: 132-007 corpuscular hemoglobin concentration, platelet counts, prothrombin time, and activated partial thromboplastin time. Specific methods for hematology analyses are located in Appendix 1. CLINICAL CHEMISTRY: Blood samples for clinical chemistry analysis were obtained via cardiac puncture prior to necropsy. The animals were anesthetized with carbon dioxide for the collection. Feed was withheld overnight prior to collection. The samples were processed and evaluated for the following parameters: total protein, alburnin, globulin, albumin/globulin ratio, glucose, cholesterol, triglycerides, total bilirubin, urea nitrogen, creatinine, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyltransferase, calcium, phosphorus, sodium, potassium, and chloride. Specific methods for clinical chemistry analyses are located in Appendix 1. NECROPSY AND ORGAN WEIGHTS: On !Study Day 29, all animals except for the Recovery animals were humanely euthanized via anesthesia with carbon dioxide to effect followed by exsanguinationand submitted for a complete necropsy examination. On Study Day 44/43 (males/females),the Recovery animals (five animals/sex/group in Groups 1 and 4) were humanely euthanized and submitted for a complete necropsy examination. A complete necropsy was defined as examination of the external surface of the body; all orifices; and the cranial, thoracic, and abdominal cavities and their contents. Organ weights were recorded for the following organs prior to fixation: adrenal glands, brain, heart, kidneys, liver, ovaries, spleen, thymus, and testes. Paired organs were weighed together. The following organs and tissues were examined in situ, dissected free, and fixed in 10% neutral buffered formalin: adrenal glands, aorta, bone marrow (sternum), brain (brain stem, cerebellum, cerebrum), cervix, epididymides, esophagus, eyes (with optic nerve), femur (with articular surface), gross lesions, Harderian gland, heart, large intestine (cecum, colon, rectum), small intestine (duodenum, ileum, jejunum), kidneys, lacrimal gland, liver, lungs (with bronchi), lymph nodes (mesenteric, mandibular), mammary gland, ovaries, oviducts, pancreas, pituitary gland, prostate gland, salivary gland (mandibular), sciatic nerve, seminal vesicles, skeletal muscle, spinal cord (cervical, thoracic, lumbar), spleen, stomach (forestomach, glandular), testes, thymus, thyroid/parathyroid, tongue, trachea, uterus, iurinary bladder, vagina, and Zymbal's gland. HISTOPATHOLOGY: Histopathologywas performed on all tissues from the vehicle control, high-dose, and Recovery animals and on all gross lesions. Fixed tissues were shipped to PathologyAssociates Internationalwhere they were processed through paraffin, sectioned at approximately five microns, and stained with hematoxylin and eosin. The slides were evaluated microscopically by John Pletcher, D.V.M., DACVP. STATISTICS: Means and standard deviations were calculated for all quantitative data. Treated groups of the same sex were compared to Group 1 (vehicle control) at common time points using an ANOVA with a post hoc Dunnett'st Test (Dunnett, C.W., J. Amer. Statis. Assoc., 50:10961121, 1955) or another appropriatetest. A two-sided a of 0.05 or 0.01 was used to determine if statistically significant differences existed between the vehicle control and the treated groups. ARCHIVAL STATEMENT All original data and the original final report will be retained at Primedica Redfield's archives, located at 100 East Boone Street, Redfield, Arkansas, for a period of five years after issuance of the final report. Wet tissues, slides, and blocks (as appropriate) will be retainedfor at least one year. After this time, the Sponsor will be contacted for disposition instructions. All data not generated at Primedica Redfield will be archived at a facility chosen by the Sponsor. Page 11 A 28-Dav Oral Toxicitv Studv in SDraque-Dawlev flats Studv Number: 132-007 RESULTS FORMULATEDTEST MATERIAL ANALYSIS: The formulated test material analysis report is located in Appendix 13. A total of 24 formulated dose samples including blanks ranging from 4 to 40 mg/rnL were analyzed to determine the concentration of T-7485 in the formulated mixture. All dose formulations were found to be acceptable by the Sponsor. CLINICAL OBSERVATIONS: The summary of clinical observations is in Table 1. The individual clinical observations are in Appendix 4. Clinical observations consisted of localized alopecia (back, limbs, neck, and underside), urinestained abdominal fur, scabbed area on back and neck, and soft or liquid feces. These findings are considered incidental and unrelatedto test materialadministration. Additionalcageside observations were all normal. NEUROLOGICAL'FUNCTION OBSERVATIONS: The results of the neurological function examinations performedduring Week 4 are located in Appendix 6. The summary and individual motor activity data are presented in Table 2 i2nd Appendix 5, respectively. Assessment of neurological effects on animals treated with T-7485 included peripheral neuropathy, motor activity, and audio/visual evaluations. There were no test material-related effects on motor activity or audio/visual. Interpretation of peripheral neurologicalfindings suggests no test material-relatedneuropathology, but within this evaluation the significant findings for the tail flick examinationmay suggest that T-7485 induces a male-specific doseindependent hyperreactivity. BODY WEIGHTS AND BODY WEIGHT CHANGES: The summaries of body weights and body weight changes are in Tables 3 and 4, respectively. The individual body weights are in Appendix 7. There were no treatment-relatedeffects on body weights for either Main Study or Recovery animals. On Study Day 36, the mean body weight in males that received900 mg/kg/day T-7485 was decreased by 7% when compared to the corresponding controls. This finding was considered incidental. Throughout the study, body weight changes in treatment groups were calculated and compared to the corresponding control groups with no s,ignificantfindings recorded for either Main Study or Recovery animals. FEED CONSUMPTION: The summary of absolute feed consumption is in Table 5. The individual data are in Appendix 8. Throughout the study, absolute feed consumption per treatment group was calculated and compared to the corresponding control groups with no significant findings recorded for either Main Study or Recovery animals. HEMATOLOGY: The summary of hematology data is in Table 6. The individual data are in Appendix 9. The reported significant hematological findings are consideredincidental and not associated with test materialadministration. CLINICAL CHEMISTRY: The summary of clinical chemistry data is in Table 7. The individual data are in Appendix 10. f'age 12 A 28-Dav Oral Toxicitv Studv in Spraoue-Dawlev Rats Studv Number: 132-007 Main Study findings in males that received 2300 mg/kg/day T-7485 indicate significant decreases in serum phosphorus (approximately 16% of the control values) and potassium (approximately 20% of the control values). In contrast, an increase in chloride levels in males that received 900 mg/kg/day T-7485 (4% above the control values) was recorded. In the absence of similar findings in Recovery animals, the changes in phosphorus, potassium, and chMride levels appear to be associated with test material administration but do not appear to be toxicologicallyor biologically significant, as indicated by historical data (Primedica, Appendix 11). Other incidental findings do not appear to be related to admiriistrationof the test material. NECROPSY: The individual necropsy observations are in Appendix 2. Only one gross lesion was recorded at necropsy and was not considered to be test materialrelated. ORGAN WEIGHTS: The summary of organ weights is in Table 8. The individual data are in Appendix 12. Absolute and relative male liver (between 25% to 30%) and female kidney (9% to 11%) weights were significantly increased in animals that received 900 mg/kg/day T-7485 when compared to the corresponding controls. These significant changes were not recorded during the recovery period, and since there does not appear to be an effect of body weight on organ development, these data suggest the changes are test material-related. However, the biological and toxicological significance is unclear due to the lack of any supportive gross or histopathological findings. The remaining significant findings are considered incidental and unrelated to test material administration. HISTOPATHOLOGY: The histopathology report is located in Appendix 3. The microscopic lesions observed in the test animals are considered to be incidental and in no way related to receiving the test material. CONCLUSION Oral (gavage) administration of T-7485 in Sprague-Dawley rats for a 28-day repeated dose with an approximate 14-day recovery period resulted in no mortality or abnormal clinical observations as well as no changes in body weights, feed consumption, peripheral neuropathy, motor activity, audio/visual response, hematology, clinical chemistry, gross pathology, and histopathology. These data suggest that administration of 900 mg/kg/day T-7485 resulted in significant increases in male liver and female kidney weights when compared to control animals and establishes the no-observable-adverse-effect-level (NOAEL) at 300 mg/kg/day T-7485. Furthermore, the T-7485 non-dose-dependent hyper-reactivity effect is gender specific and is therefore difficult to interpret. Page 13 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLES Study Number: 132-007 Page 14 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 TABLE 1 SUMMARY OF CLINICAL OBSERVATIONS Page 15 - LOCALIZED ALOPECIA, BACK o/ 0 LOCALIZED ALOPECIA, LIMBS 5/ 2 o/ 0 LOCALIZED ALOPECIA, NECK o/ 0 LOCALIZED ALOPECIA, UNDERSIDE SCABBED AREA, BACK o/ 0 o/ 0 S_C_AB_B_ED_A_RE_A_, _NE_C_K _________-------------------------------- N/N NUMBER OF OBSERVATIONS/NUHBER OF ANIMALS 2/ 1 6/ 2 o/ 0 10/ 2 1/ 1 o/ 0 o/ 0 8/ 2. s/ 1 o/ 0 o/ 0 5/ 1 o/ 0 16/ 4 o/ 0 1/ 1 o/ 0 o/ 0 rn l9n1 (D A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 TABLE 2 SUMMARY OF MOTOR ACTIVITY DATA Page 18 BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 TOTAL MEAN f S.D. MEAN f S.D. MEAN f S.D. MEAN f S.D. MEAN f S . D . MEAN f S.D. MEAN f S.D. 152.7 f 14.3 146.5 f 16.3 143.9 f 17.7 120.3 f 33.2 85.1 f 58.3 1 1 . 4 f 61.4 719.9 f 148.0 154.0 f 12.8 139.2 f 10.0 107.8 f 30.1 95.3 f 47.3 57.9 f 62.6 51.2 f 66.9 605.4 f 193.0 T I M E (SECONDS) S P E N T I N MOVEMENT BLOCK 1 MEAN f S.D. 308.5 f 47.8 306.1 f 40.5 BLGCR 2 XSE? f S.D. mc,. n LA)." i 60.5 ii4.4 f 49.0 BLOCK 3 MEAN f S.D. 232.1 f 60.6 167.1 f 79.3 BLOCK 4 MEAN i S.D. 175.7 f 10.4 137.5 f 93.6 BLOCK 5 MEAN f S.D. 111.3 f 97.4 74.0 f 90.8 BLOCK 6 MEAN f S . D . 93.2 f 9 8 . 1 68.2 f 97.7 - ...T.O.T.A.L...........M..EA.N...f..S..D... .............1.1.8.5..7..f...3.1.7..3........1.0.0.1...9..f..3..5.5.7 TOTAL SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 1 0 MINUTE PERIOD. There were no significant differences noted. 157.9 f 7.4 156.0 f 17.0 134.6 f 24.1 106.3 f 32.4 61.5 f 50.5 26.7 f 29.4 643.0 f 106.9 307.8 f 48.0 261.2 f 54.9 198.2 f 43.2 143.0 f 46.2 61.8 f 55.2 24.5 f 20.4 996.5 f 173.4 153.3 f 9.1 152.3 f 15.6 128.1 f 38.9 105.1 f 52.5 82.4 f 63.3 54.3 f 60.2 616.1 f 166.1 313.2 f 48.5 261.8 f 53.8 202.1 f 99.5 152.3 f 94.1 113.2 f 93.5 75.3 f 99.2 1118.5 f 423.3 PROTOCOL 132-007: A 28-DAY ORAL (GAVAGE) TOXICITY STUDY OF T-7485 IN SPRAGUE-DAWLEY RATS NUMBER OF MOVEMENTS BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 TOTAL MEAN f S.D. MEAN f S.D. MEAN f S.D. MEAN f S.D. MEAN f S.D. MEAN f S.D. MEAN f S.D. 150.1 f 14.0 144.3 f 13.9 138.3 f 14.3 121.3 f 22.5 103.9 f 44.5 80.4 f 52.7 738.4 f 130.3 152.0 f 14.2 147.3 i 18.0 137.3 f 24.6 124.9 f 34.5 90.7 f 45.4 76.2 f 46.9 728.4 f 124.8 148.3 f 148.6 f 118.2 f 104.8 f 86.3 f 61.4 i 667.6 f 13.5 17.1 29.2 34.2 24.5 413.9 77.9 153.9 i 12.8 144.5 f 13.7 132.9 f 32.7 116.5 f 42.3 102.2 f 51.9 87.3 i 5 8 . 4 737.3 f 177.4 TIME (SECONDS) SPENT IN MOVEMENT BLOCK 1 DLOCR 2 MEAN f S.D. "FIU .*LI.-... 2 s.E. 313.3 i 1co n * &"".I L 38.2 :6.8 313.1 f 47.1 269.9 i 56.i BLOCK 3 MEAN f S.D. 236.1 i 5 7 . 8 225.6 f 74.3 BLOCK 4 MEAN f S.D. 187.7 f 54.5 113.1 f 59.2 -BLOCK 5 HEAN f S.D. 139.3 f 79.1 117.3 f 79.4 h) 0 BLOCK 6 MEAN f S.D. 90.3 f 79.7 94.7 f 76.4 ...T.O.T.A.L...........M.E..A.N..f..S...D...............1.2.3.5...5..i..2.8.5...3.......1.1.9.4...3..f...31.6...4 TOTAL SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 10 MINUTE PERIOD. There were no significant differences noted. A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 TABLE 3 SUMMARY OF BODY WEIGHTS Page 21 SD 8 MEANfS .D 2E2.1 f 1 5 . 5 281.7 f 13.0 280.3 f 19.9 279.2 f 14.4 SD 15 MEANfS.D . 326.5 f 19.9 324.4 f 17.0 317.5 f 28.5 321.5 f 19.5 SD 22 MEANfS .D. 361.4 f 22.7 361.0 f 18.5 349.5 f 3 5 . 0 351.9 f 23.9 SD 2 8 MEANtS .D. 374.1 f 24.9 375.0 f 22.3 361.0 f 37.1 358.0 f 31.3 SD 36 MEANfS.D . 421.0 f 10.2 a t 5la SD 43 MEANfS .D . 419.6 f 20.1 a I 5la ...................................................................................... SD = STUDY DAY I 1 = Number of values averaged. a = Excludes values for animals that were a scheduled sacrifice. = Significantly different from Group1 at pi0.05. 393.0 f 24.4' I sla 421.4 f 29.9 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _!_ _5_!_1_ _ _ _ PROTOCOL 132-007: A 2E-DAY ORAL (GAVAGE) TOXICITY STUDY OF T-7485 IN SPRAGUE-DAWLEY RATS - - TABLE 3: BODY WEIGHTS SUMMARY F E W E RATS ____________________----------------------------------------------- DOSE GROUP 1 2 3 4 (MG/KG/DAY) 0 (VEHICLE) 100 300 900 ____________________----------------------------------------------- RATS - TESTED 15 10 10 15 BODY WEIGHT (GI SD 1 SD E . . MEANfS D MEANfS.D. 194.3 f 9.3 214.6 f 11.0 196.0 f 8.2 211.7 f 8.2 195.5 f 10.1 211.1 * 10.4 197.1 f 7.4 217.1 f 9.3 SD 15 SD 22 MEANfS.D. . MEANfS .D 227.5 f 15.2 239.5 f 12.6 221.0 f 10.2 235.0 f 8.5 232.2 f 11.3 245.4 f 15.7 231.6 f 8.7 243.1 f 11.9 SD 28 MEANft3.D. 241.1 f 16.1 236.2 f 10.4 242.4 f 13.7 242.5 f 12.2 S D 36 MEANfS .D . 254.8 f 17.0 a . . I 5la SD 42 MEANiS D 260.0 f 13.2 a - - [ sla ________________________________________-------------------------. SD STUDY DAY [ 1 Number of values averaged. a = Excludes values for animals that were a scheduled sacrifice. There were no significant differences noted. A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 TABLE 4 SUMMARY OF BODY WEIGHT CHANGES Page 24 SD 1 - 8 SD 8 - 15 SD 15 - 22 MEANfS.D . MEANfS.D . MEANfS.D . +50.9 f 8.0 +44.4 f 6 . 5 +34.9 f 6.7 + 5 0 . 6 f 4.7 +42.7 f 6.4 +36.6 f 5.8 SD 22 - 28 SD 28 - 36 SD 36 - 43 SD 1 - 28 MEANtS .D . HEANiS.D . MEANfS .D . MEANiS .D . +12.7 f 6.9 +32.8 f 3.1 I 51a +28.6 f 11.3 I 51a +142.9f 20.3 +14.0 f 4.8 a a +143.9f 16.7 SD 1 - 43 MEANfS.D. +217.2t 17.6 a I 5la _______________________________________r-----------------------------------------------------------------.-------------.------------ SD = STUDY DAY I I = Number of values averaged. a = Excludes values for animals that were a scheduled sacrifice. There were no significant differences noted. +49.5 f 8.6 +37.2 f 10.0 +32.0 f 7.8 + 1 1 . 5 f 5.9 a a +130.2f 26.5 a +47.5 f 7.8 +42.3 f 9.3 +30.4 f 6 . 5 +6.1 f 12.0 +32.0 f 2.7 I 5la +28.4 f 5.8 [ 5la +126.3f 27.3 +192.6f 24.5 I 5la PROTOCOL 132-007: A 28-DAY ORAL (GAVAGE) TOXICITY STUDY OF T-7485 IN SPRAGUE-DAWLEYRATS TABLE 4: BODY WEIGHT CHANGES - SUMMARY - FEMALE RATS .................................................................................................................................... DOSE GROUP 1 2 3 4 (MG/KG/DAY) ............ . . . . . . . . . . . . . . . . . . . . . . . . . . 0 .. (VEHICLE) .......... . . . . . . . . . . . . . . . . .1.0.0. . . . . . . . . . . . . . . . . . . . .3.0.0. . . . . . . . . . . . . . . . . . . . . 9.0.0. . . . . . . . . . . . . . . . . RATS - TESTED 15 10 10 15 BODY WEIGHT CHANGES (GI SD 1 - 8 . MEANfS D . +20.3 f 5.7 +15.7 f 7.0 +21.6 f 6.5 +19.9 f 6.7 SD 8 - 15 SD 15 - 22 SD 22 - 28 MEANfS.D. MEANfS.D . . MEANfS .D +12.9 f 7.4 +12.0 f 6.8 +1.7 f 7.2 +15.3 f 6.4 ' +8.0 f 5.4 +1.2 f 6.5 +15.1 f 5 . 8 +13.2 f 8.1 -3.0 f 7.3 +14.5 f 3.8 +12.1 f 6.7 -1.2 f 7.6 SD 28 - 36 SD 36 - 42 SD 1 - 28 MEANfS .D . MEANfS .D . MEANfS .D . +17.4 f 6 . 8 I Sla +5.2 f 9.1 I 51a +46.0 f 11.7 a a +40.2 f , 8.3 a a +46.9 f 9.5 +12.8 f 5.2 I 51a + 3 . a f 5.7 [ 51a +45.3 f 10.1 SD 1 - 4 2 MEANfS .D . + 6 5 . 6 f 10.2 a a +63.6 f 2.3 -. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .I. . .5.l.a. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .I. . .5.l.a. . . . . . . . . . . . . . . SD STUDY DAY I 1 I Number of values averaged. a I Excludes values for animals that were a scheduled sacrifice. There were no significant differences noted. A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 TABLE 5 SUMMARY OF ABSOLUTE FEED CONSUMPTION Page 27 SD 8 - 15 MEANfS.D. 27.0 f 2.5 28.3 f 2.1 26.13 i 2.7 28.5 f 2.9 SD 15 - 22 MEANfS .D . 28.6 f 2.4 29.6 * 2.13 213.1 i 3 . 3 29.6 f 2.7 SD 22 - 213 S D 28 - 36 SD 36 - 43 SD 1 - 28 MEANfS .D . MEANfS .D . MEANfS.D. MEANfS .D . 29.4 f 2.6 31.2 f 1.9 f 5la 34.1 f 2.3 I 51a 28.2 f 2.3 30.8 f 3.1 a a 29.0 f 2.3 28.7 f 3.6 a a 27.6 f 3.0 32.2 f 28.1 I 31.5 f 29.3 f 5.5 14lb i 3.5 5la f 3.3 51a f 2.6 2 - SD 1 43 MEANfS .D . 30.4 f 2.0 a a 29.1 f 2.9 In f 51a I 5la [D .................................................................................................................................... h, 03 S D i. STUDY DAY [ 1 = Number of values averaged. a = Excludes values for animals that were a scheduled sacrifice. -b Excludes valued for animals in which feed consumption could not be calculated, There were no significant differences noted. PROTOCOL 132-007: A 28-DAY ORAL (GAVAGE)TOXICITY STUDY OF T-7485 IN SPRAGUE-DAWLEYRATS TAELE 5 : ABSOLUTE FEED CONSUMPTION - SUHMARY - FEMALE RATS .................................................................................................................................... DOSE GROUP 1 2 3 4 .(.M.G./.K.G./.D.A.Y.). . . . . . . . . . . . . . . . . . . . . . . . . . . . .0. .(.V.E.H.I.C.L.E.1. . . . . . . . . . . . . . . . . .1.0.0. . . . . . . . . . . . . . . . . . . . .3.0.0. . . . . . . . . . . . . . . . . . . . .9.0.0. . . . . . . . . . . . . . . . RATS - TESTED 15 10 10 15 FEED CONSUMPTION (G/DAYl SD 1 - 8 SD 8 - 15 MEANfS.D . MEANfS.D . 21.0 f 1.7 20.9 f 2.1 20.5 f 1.3 21.1 f 1.7 21.5 f 1.2 21.2 f 1.7 21.5 f 1.1 21.9 f 1.0 SD 15 - 22 SD 22 - 28 . MEANS.D MEANfS .D . 21.4 f 2.2 22.5 f 1.9 21.7 f 1.7 21.8 f 2.5 22.2 f 1.9 21.7 f 2.3 22.3 f 1.7 22.3 f 1.8 SD 28 - 36 SD 36 - 42 SD 1 - 28 MEANfS.D . MEANfS.D. MEANfS.D. 20.5 f 5.2 [ 51.3 24.0 f 2.1 5la 21.4 f 1.7 a a 21.2 * 1.7 a a 21.7 f 1.6 22.0 f 0 . 8 [ 5la 23.7 f 1.7 [ 5la 22.0 f 1.2 SD 1 - 42 MEANfS.D. 21.8 f 2.1 a a 22.4 f 0 . 8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .I. . .5.1.a. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .I. . .5.1.a. . . . . . . . . . . . . SD I STUDY DAY I 1 = Number of values averaged. a = Excludes values for animals that were a scheduled sacrifice. There were n o significant differences noted. A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 TABLE 6 SUMMARY OF HEMATOLOGY DATA Page 30 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 KEY TO HEMATOLOGY TABLES ABBREVIATION TERM1NOLOGY UNITS WBC White Blood Cells (Leukocytes) 103/cumm RBC Red Blood Cells (Erythrocytes) 106/cumm HGB Hemoglobin g/dL HCT Hematocrit (Packed Cell Volume) % MCV Mean Corpuscular Volume fL or cu micron MCH Mean Corpuscular Hemoglobin pg or picograms MCHC , Mean Corpuscular Hemoglobin % Concentration PLT Platelets 103/cumm NRBC Nucleated Red Blood Cell Count Lymphocyte Lymphocytes 103/cu mm Segmented Segmented Neutrophils 1031cumm Eosinophil Eosinophils 103/cumm Abnormal L Abnormal Lymphocytes 103/cumm APT Activated Partial Thromboplastin Time seconds PT Other Prothrombin time Other Cells seconds 103/cumm Page 31 A 2 8 - D a y Oral Toxicity Study in Sprague-Dawley Rats 'TABLE 6 Study Number: 132-007 Group: I - M MEAN SO N Group: 2-M MEAN SO N Group: 3-M MEAN so N Group: 4-M MEAN SD n 10.0 4.44 10 6.91 0.805 10 12.2 2.99 10 7.02 0.473 10 10.4 2.99 10 6.90 0.328 10 9.5 1.91 10 6.65 0.617 10 15.5 1.54 10 15.8 0.54 10 15.6 0.46 10 15.0 I.os 10 42.1 4.87 10 42.8 2.24 10 41.6 1.27 10 39.8 3.02 10 60.9 2.69 10 61. O 1.45 10 60.5 2.41 10 59.9 2.09 10 22.5 1.01 10 22.5 1.02 10 22.6 0.87 10 22.6 0.89 10 36.9 1.25 10 1174 149.5 10 14.6 0.95 10 36.8 1.03 10 1242 101.9 10 15.3 0.69 9 37.4 0.44 10 I121 112.8 10 14.5 0.62 10 37.7 0.66 10 1w2* 139.8 10 14.6 0.88 9 *-Significant - -- Difference from Control P < .OS LAECAT HE4.41~ -- ---------- 03-NOV-2ooO Fage 32 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 6 Study Number: 132-007 G r w p : 1-H MEAN SD N G r o u p : 2-M HEAN SD N G r w p : 3-H HEAN SD N Grwp: 4-M HEAN SD N 25.9 7.66 10 24.9 2.77 9 22.9 3.70 10 25.1 5.06 9 0 9.2 0.6 0.0 0.0 0.1 0.0 0.0 0.3 3.96 0.44 0.03 0.07 0.13 0.00 0.00 10 10 10 10 10 10 10 10 0 10.5 1.6- 0.0 0.0 0.1 0.0 0.0 0.0 2.71 0.49 0.00 0.00 0.09 0.00 0.06 10 10 10 10 10 10 10 10 0 9.3 1.(I 0.0 0.0 0.1, 0.0 0.0 0.0 2.79 0.7'5 0.00 0.03 0.10 0.00 0.00 10 10 1I1 10 10 10 10 10 0 8.5 0.9 0.0 0.1- 0.0 0.0 0.0 0.0 1.87 0.36 0.00 0.09 0.07 0.00 0.00 10 10 10 10 10 10 10 10 _--___-___ + * - S i g n i f i c a n t D i f f e r e n c e froa C o n t r o l P < .01 - - I - - UBCAT HE4.41~ --- - 03-NOV-2ooO Page 33 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 6 Study Number: 132-007 Group: I - M MEAN SD N Group: 2-M MEAN SD N Group: 3-H MEAN SD N Group: 4-fl MEAN SD N 0.0 0.00 10 0.0 0.00 10 0.0 0.00 10 0.0 0.00 10 Page 34 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 6 Study Number: 132-007 STUDY I D : 28-DAY ORAL DOSEfRAT STUDY NO: 132-007 ANALYSIS OF VARIANCE FOLLOUED BY DUNNETT'S PROCEDURE SEX: MALE TEST(r): UBC RBC HGB HCT HCV MCH MCHC PLT PT --- UNITS: THSN/CU HM MILL/CU NH GRAMS/DL I CU MICRONS P I C 0 GRAMS X THSN/CU MM s e c o n d s - - - - - - -- __-I ___ - ---I - ---- - ----_II___ Group: 1-M MEAN SO N 13.4 7.07 15.1 40.a 56.8 21.3 37.6 1256 12.6 3.93 0.362 0.69 2.36 1.66 0.74 0.59 111.3 0.11 5 5 5 5 5 5 5 5 5 Group: 4-H MEAN SO N 11.5 3:66 5 7.28 0.462 5 15.4 0.89 5 41 .4 2.76 S 56.9 1.40 5 21.2 0.63 5 37.3 0.44 5 1118* 50.6 5 13.4* 0.11 5 - *-Significant D i f f e r e n c e from Control P < .05 LABCAT HE4.41c * - S i g n i f i c a n t D i f f e r e n c e fro4 C o n t r o l P < .01 03-NOV-2aoO Page 35 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 6 Study Number: 132-007 STUDY I D : 28-DAY ORAL DOSE/RAT STUDY NO: 132-007 SEX: HALE ---- ---A-N--A-L-Y-S--IS--O-F VARIANCE FO-L-L-O-UED BY ----- DUNNETT'S PROCEDURE TEST(t): APTT NRBC Lymphocyte Segmentd Bands Honocytes Eosinophil Basophils Abnormal L UNITS: seconds COUNT THSN/CU HH THSN/CU H f l THSN/CU HH THSN/CU HH MSN/CU HM THSN/CU MM THSN/CU HM -----I-- 1 - - - - 1 -------- _ _ --------- Group: 1-11 HEAN SD N 17.6 2.74 5 0 12.0 1 .:i 0.0 0.0 0.1 0.0 0.0 0.0 4.07 0.43 0.00 0.04 0.05 0.00 0.00 5 5 5 5 5 5 5 5 Group: 4-M HEAN SO N 22.3* 3.23 5 0 10.1 1.7 0.0 0.1 0.0 0.0 0.0 0.0 3.15 0.51 0.00 0.13 0.04 0.00 0.00 5 5 5 5 5 5 5 5 *-Significant Difference from Control P < .OS LABCAT H E 4 . 4 1 ~ 03-MOV-2O00 Page 36 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 6 Study Number: 132-007 Grwp: 1-M MEAN SD N Grwp: 4-L( MEAN SD N 0.0 0.00 5 0.0 0.00 5 -- -- UBCAT HE4.41c - - - - - - - - - - I _ - ---- 03-NOV-ZwO Page 37 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 6 Study Number: 132-007 STUDY I D : 20-DAY ORAL DOSE/RAT STUDY NO: 132-007 ANALYSIS OF VARIANCE FOLLOYED BY DUNNETT'S PROCEDURE SEX: FEMALE TEST( s 1 : UNITS: UBC RBC THSN/CU M I I MILL/CU MM HGe GRAMS/DL tic-r MCV MCH X CU MICRONS P I C 0 GRAMS MCHC PLT X THSN/CU MM PT seconds Group: 1-F MEAN SD N 9.2 4.42 10 6.70 0.290 10 15.4 0.32 10 41.4 1.15 10 61.9 1.80 10 23.0 0.65 10 37.1 0.56 10 1090 88.9 10 14.4 1.93 7 G r w p : 2-F MEAN SD N 11.. 2 3.47 9 6.89 0.490 9 15.3 0.67 9 41.8 2.26 51 60.8 2.06 9 22.3 0.84 9 36.7 0.65 9 1155 320.3 9 14.9 1.98 10 G r w p : 3-F MEAN SD N 7.4 3.02 10 6.74 0.437 10 15.3 1.01 10 41 .Y 2.68 10 62.2 2.22 10 22.7 0.82 10 36.5 0.80 10 1118 221.2 10 14.4 1.28 10 Grwp: 4-F MEAN SD N 8.8 3.00 10 6.66 0.286 10 15.2 0.66 10 41.1 2.16 io 61.6 2.11 10 22.8 0.68 10 37.0 0.68 10 1167 167.8 10 15.6 1.88 10 Page 38 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats 'TABLE 6 Study Number: 132-007 Group: I - F MEAN SD N Group: 2-F MEAN SD N Group: 3-F MEAN SD N Group: 4-F MEAN SO N 31.6 8.89 7 31.8 7.72 10 26.8 6.01 10 28.9 8.60 10 0 8.4 0.6 0.0 0.2 0.1 0.0 0.0 0.0 4.16 0.41 0.00 0.18 0.17 0.00 0.00 10 10 10 10 10 10 10 10 0 10.1 0.s 0.0 0.1 0.1 0.0 0.0 0.0 3.11 0.41) 0.03 0.11 0.12 0.00 0.00 9 9 9 9 9 9 9 9 0 6.4 0.9 0.0 0.W 0.0 0.0 0.0 0.0 2.60 0.61 0.00 0.03 0.05 0.00 0.03 10 10 10 10 10 10 10 10 0 7.7 0.9 0.0 0.1 0.1 0.0 0.0 0.3 2.86 0.4'7 0.00 0.11 0.12 0.00 0.03 10 10 10 10 10 10 10 10 --- -------- **-Significant Difference from Control P < .01 LABCAT HE4.41C 1 _ - - 03-NOV-2wO Page 39 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 6 Study Number: 132-007 Group: 2-F REAN SD N Group: 3-F MEAN SD N Group: 4-F HEAN SD N 0.0 0.00 9 0.0 0.00 10 0.0 0.00 10 Page 40 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 6 Study Number: 132-007 TESTCr): UNITS: UBC RBC THSN/CU MM MILL/CU M R ma GRAHS/DL Group: 1-F MEAN SD N 9.7 7.15 15.1 2.10 0.351 0.70 5 5 5 Group: 4-F MEAN SD N 8.6 6.89 15.0 4.'36 0.524 1.24 5 S 5 HCT MCV MCH L CU MICRONS PIC0 GRAMS 41.7 58.3 21.2 2.02 2.23 O.% '5 S 5 40.6 58.9 21.7 3.34 2.63 1.39 5 5 5 MCHC PLT X THSN/CU nM PT seconds 36.4 1239 12.3 0.42 143.9 0.45 S 5 5 36.8 0.70 5 994* 147.5 S 12.w 0.21 5 *-Significant I - Difference from Control _--- P < .OS LABCAT HE4.41 c I 03-NOV-2ooO Page 41 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 TABLE 6 - Study Report for Hem- atology ____-ell---------_--l-l_--__------- - - -__ _ _ -_ _ I _ _ _ _ _ _ I _I_ SUMMARY REPORT PERIOD: RECOVERY ____--___ __I_______-------------------- STUDY I D : 28-DAY ORAL DOSE/RAT STUDY No: 132-007 ANALYSIS OF VARIANCE FOLLWED BY DUNNETT'S PROCEDURE SEX: FEMALE _ _ I - - - c - _------------__-___----_____I_~----___- TEST(s) : UNITS: APTT seconds NREC Lymphocyte S e g m t e d Bands Monocytes E o s i n o p h i1 B a s o p h i 1s Abnormal L COUNT THSN/CU MH THSN/CU MM THSN/CU MH THSN/CU HH THSN/CU MM THSN/CU MM THSN/CU HM Group: I - F MEAN SD N 18.5 0.81 5 0 8.9 0.8 0.0 0.0 0.0 0.0 0.0 0.0 1.97 0.26 0.00 0.04 0.00 0.00 0.00 5 5 5 5 5 5 5 5 Group: 4-F MEAN SD N 21 .o* 0 7.5 1.0 0.0 0.1 0.0 0.0 0.0 1.60 0.0 4.20 0.51 0.00 0.09 0.00 , 0.00 0.00 5 5 5 fi 5 5 5 5 5 * - S i g n i f i c a n t D i f f e r e n c e f r o l C o n t r o l P < .05 LAECAT H E 4 . 4 1 ~ 03-NOV-2Mx) Page 42 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 6 Study Report for Hematology SUMMARY REPORT PERIOD : RECOVERY STUDY ID: 28-DAY ORAL DOSE/RAT STUDY NO: 132-007 ANALYSIS OF VARIANCE FOLLOYED BY DUNNETT'S PROCEDURE Study Number: 132-007 SEX: FERALE Group: 4-F MEAN SD N 0.0 0.00 5 UBCAT HE4.41C 03-NOV-2MM Page 43 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 TABLE 7 SUMMARY OF CLINICAL CHEMISTRY DATA Page 44 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 KEY TO CLINICAL CHEMISTRY TABLES ABBREVIAT10N TERMINOLOGY ALP Alkaline Phosphatase AST Aspartate Aminotransferase ALT Alanine Aminotransferase CHOL Cholesterol GLU Glucose BUN Blood Urea Nitrogen C R EAT Creatinine TRIG Triglycerides PHOS Phosphorus (inorganic) TP Total Protein ALB Albumin GLOB Globulin NG Albumin/Globulin Ratio CA Calcium CL Chloride NA Sodium K Potassium GGT Gamma-glutamyItransferase T-BIL Total Bilirubin UNITS U/L UIL U/L mg/dL mg1dL mg/dL mg/dL mg1dL mg1dL gld L g1dL g1dL mgld L mEq/L or mmol1L mEq/L or mmol/L mEq/L or mmol/L UIL mgldL Page 45 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 7 Study Number: 132-007 Group: 1-M MEAN SD N Group: 2-M MEAN SO N Group: 3-M MEAN SD N Group: 4-M MEAN SD N 6.4 0.47 10 4.4 0.33 10 6.2 0.23 10 4.2 0.25 10 6.4 0.35 10 4.3 0.23 10 6.3 0.30 10 4.4 0.28 10 161 42.7 10 169 46.7 10 147 22.1 10 137 19.6 10 64 18.8 10 0.2 0.07 10 61 15.0 10 0.2 0.07 10 63 19.9 10 0.2 0.08 10 50 11.2 10 0.2 0.09 10 18 0.3 2.4 0.05 10 10 35 110 5.9 18.1 10 10 18 0.3 1.7 0.05 10 10 37 111 8.4 20.3 10 10 19 0.3 53 138 2.7 0.06 40.0 71.3 10 10 10 10 20 0.3 46 133 2.1 0.04 16.5 44.9 10 10 10 10 Page 46 A 26-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 7 Study Number: 132-007 Group: 1-H HEAN SD N Group: 2-H HEAN SO N Group: 3-H HEAN SD N Group: 4-I! MEAN SO N 162 41.9 10 152 35.5 10 150 25.3 10 172 37.8 10 1 11.4 10.8 32 1.6 0.53 0.61 10.2 10 10 10 10 1 11.2 10.3 34 2.2 0.48 0.95 18.0 10 10 10 10 0 11.2 9.4* 2s 0.7 0.59 0.86 8.6 10 10 10 10 0 10.9 9.1* 23 0.0 0.62 0.92 10.3 10 10 10 10 146 7.7 2.4 1.52 10 10 96 2.0 2.6 0.20 10 10 146 7.0 1.4 1.24 10 10 98 2.0 2.8 0.13 10 10 147 6.4* 1.7 0.87 10 10 98 2.1 2.6 0.28 10 10 147 6.B loo* 1.9 2.0 1.10 1.9 0.19 10 10 10 10 - - - - - _ I - - - ------ *-Significant Difference f r o l Control P < .05 UBCAT CC4.41c *-Significant Difference f r o l Control - - - - I - - P < .01 03-NOV-2MM Page 47 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 7 Study Number: 132-007 Group: 2-M MEAN SD N Group: 3-n MEAN SQ N Group: 6-M MEAN SD N 2.1 0.21 10 2.1 0.33 10 2.4 0.30 10 UBCAT C C 4 . 4 1 ~ 03-NOV-2ooO Page 48 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 7 Study Number: 132-007 STUDY I D : STUDY NO: 28-DAY ORAL DOSE/RAT 132-007 ANALYSIS OF VARIANCE FOLLOUED BY DUNNETT'S PROCEDURE TEST( s) : UNITS: Group: 1-M MEAN SD N TP ALE GLU CHOL T-BIL BUN CREAT g/dL __-__-q_/d_L______w__/d_L____.__w_/_d_L______w_/_d_L______n_g_/dI_L---------w--/-d--L- 6.7 0.28 5 4.4 0.26 5 161 34.3 5 65 12.6 5 0.2 0.05 5 18 0.3 1.5 0.05 5 5 Group: 4-M MEAN SD N 67 0.38 5 4.5 0.36 5 158 46.1 5 75 21.6 5 0.1 0.04 5 17 0.3 1.2 0.10 5 5 SEX: MALE ALT AST U/L U/L 43 125 4.5 42.6 5 5 47 121 6.0 36.9 5 5 LABCAT CC4.41~ 03-NOV-2ooo Page 49 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 7 Study Number: 132-007 STUDY ID: 28-DAY ORAL WSE/RAT SEX: MALE STUDY NO: 132-007 ------- - ANALYSIS OF VARIANCE FOLLOUED BY DUNNETT'S PROCEDURE --_---_ - - - _ I _ I _ _ _ - - - _ - - I _ _ - TEST(s1: UNITS: ALP GGT CA PHOS TRIG NA K CL GLOB - U/L U/L mg/dL mg/dL mg/dL nml/L mol/L mnol/L g/dL __--.-__--_-_I-__- - - 1 - - Grwp: 1-M MEAN SO N 159 18.3 5 2 12.4 12.5 45 2.0 0.47 2.14 19.3 5 5 5 5 145 8.7 1.5 1.66 5 5 98 2.3 1.9 0.23 5 5 Grwp: 4-R MEAN SD N 149 22.7 5 2 12.5 11.8 55 2.2 0.69 1.211 39.8 5 5 5 5 147 8.3 2.1 1.68 5 5 99 2.2 3.3 0.12 5 5 Page 50 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 7 Study Number: 132-007 Group: 6-11 MEAN SD N 2.0 0.21 5 Page 51 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 TABLE 7 Study Report f o r Clinical Chemistry ___1___------1-----------I_--_------------------- --_---- --------------- SUMMARY REPORT PERIOD: TE--R--MI---N--A--L------- STUDY ID: 2&DAY ORAL DOSE/RAT STUDY No: 132-W7 ----------- ANALYSIS OF VARIANCE FOLLWED BY DUNNETT'S PROCEDURE .-__l--l-~ TEST(s): TP ALE GLU CHOL. T-BIL BUN CREAT ALT UNITS--:-------- g/dL g/dL ng/dL --_.-__-I- ng/dL ng/dL w / d L w / d L UIL Group: 1-F REAN SD N 6.6 0.35 10 4.8 0.27 10 155 25.4 10 73 12.5 10 0.2 0.03 10 19 0.4 43 3.0 0.05 14.7 10 10 10 - - SEX: FEMALE - AST U/L 124 30.6 10 Group: 2-F MEAN SD N 6.9 0.21 10 5.0 0.27 10 154 42.2 10 71 13.4 10 0.2 0.05 10 20 0.4 3.2 0.04 10 10 35 111 5.7 22.9 10 10 Group: 3-F MEAN SD N 6.0 0.34 10 4.7 0.34 10 143 29.4 10 62 15.0 10 0.2 0.06 10 21 0.4 1.9 0.06 10 10 3a 113 6.4 14.7 10 10 Group: 4-F HEAN SD N 6.6 0.36 10 4.6 0.43 10 129 20.1 10 73 13.7 10 0.2 0.05 10 21 0.4 2.8 0.05 10 10 36 109 3.0 10.9 10 10 -- LABCAT CC4.41~ -- 03-NOV-2OW Page 52 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 TABLE 7 Study Report f o r C l i n i c a l Chemistry SUMMARY REPORT PERIOD: TERMINAL STUDY ID: STUDY NO: 28-DAY ORAL DOSE/RAT 132-007 ANALYSIS OF VARIANCE FOLLWED BY DUNNETT'S PROCEDURE SEX: FEMALE ______________----------------------_I__ TEST(r): UNITS: ALP GGT CA PHOS TRIG NA K CL GLOB U/L U/L q/dL mg/dL q/dL ml/L ml/L mml/L g/dL __l_______________-_______l___________l_---- - - - - - I - - - - G r w p : 1-F MEAN 90 1 11.8 9.9 37 144 7.8 103 2.1 so 28.3 1.o 0.34 0.96 7.7 1.8 1.21 1 .8 0.18 N 10 10 10 10 10 10 10 10 10 G r w p : 2-F MEAN '79 1 11.9 10.1 31 143 9.1* 102 2.0 SD 20.7 1.6 0.33 0.70 7.9 1.6 1.42 2.5 0.13 N 10 10 10 10 10 10 10 10 10 Group: 3-F MEAN SD N 101 0 11.6 10.5 34 144 8.4 104 2.1 7.4 0.4 0.31 0.83 8.6 1.5 0.99 1.6 0.22 10 10 10 10 10 10 10 10 10 Group: 4-F MEAN SD 90 17.3 0 11.4 9.6 0.5 0.50 1.03 32 145 7.0 9.9 1.5 0.03 104 2.0 1.4 0.16 N 10 10 10 10 10 10 10 10 10 - I - - - - * - S i g n i f i c a n t D i f f e r e n c e frou C o n t r o l P < .Os LABCAT CC4.41c 03-NOV-2M)o Page 53 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 7 Study Number: 132-007 STUDY I D : STUDY No: 28-DAY ORAL DOSE/RAT 132-007 ANALYSIS OF VARIANCE FOLLGUED BY DUNNETT'S PROCEDURE Group: 1-F MEAN SO N Group: 2-F MEAN SD N Group: 3-F MEAN SD N G m p : 4-F MEAN SD N 2.3 0.23 10 2.5 0.29 10 2.3 0.32 10 2.4 0.38 10 SEX: FEMALE --- LABCAT CC4.41~ - 03-NOV-Moo Page 54 A 28-Day Oral Toxicity Study in Sprague-DawleyRats TABLE 7 Study Number: 132-007 STUDY I D : STUDY NO: 28-DAY ORAL DOSEIRAT 132-W7 ANALYSIS OF VARIANCE FOLLOUED BY DUNNETT'S PROCEDURE SEX: FEMALE TESTb): TP ALB ___U_NI_TS_: ___------g-/-d-L------ g/dL Group: I - F MEAN SD N 7.3 0.43 5 5.3 0.33 5 GLU r*l/dL 166 73.3 5 CHOL T-BIL q / d-L---- mg/dL 84 22.5 5 0.2 0.00 5 BUN CREAT ALT AST --__----------- w/dL W/dL U/L U/L __-I_- 21 0.4 53 194 6.0 0.11 14.3 63.9 5 5 5 5 Group: 4-F MEAN SO N 7.1 5.1 135 72 0.2 0.37 0.40 55.2 11.0 0.08 5 5 5 5 5 21 0.4 5.2 0.12 5 5 37* 189 5.1 78.4 5 5 -- *-Significant - - _ I - p D i f f e r m c e froa Control P < .os LABCAT CE4.41c - 03-NOV-2ooO Page 55 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 7 Study Number: 132-007 STUDY I D : 28-DAY ORAL WSEIRAT STUDY NO: 132-007 ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE SEX: FEHALE TESTCs): UNITS: ALP GGT CA PHOP TRIG NA K CL GLOB U/L U/L mg/dL mg/dl. mg/dL mml/L mml/L ml/L g/dL _ _ _ _ _ I _ - _ _ _I __ - ~----------------I--------- Group: 1-F MEAN SD N 83 10.3 5 1 12.9 12.3 45 0.8 0.40 1.05 14.2 5 5 5 5 144 9.2 1.7 1.52 5 5 102 2.0 2.9 0.38 5 5 Group: 4-F HEAN SD N 82 16:7 5 1 12.3 1.1 0.54 5 5 10.7 1.74 5 32 11.2 5 145 7.8 2.2 1.53 5 5 104 2.0 2.0 0.09 5 5 Page 56 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 7 Study Number: 132-007 Group: 4-F MEAN SD N 2.5 0.25 5 Page 57 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 TABLE 8 SUMMARY OF ORGAN WEIGHTS Page 58 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 8 Study Number: 132-007 BOOY YEIGHT (G)(ABSOLUTE) MEAN so 344.300 27.6970 N 10 348.900 21.9315 10 337.200 33.65 12 10 335.800 32.4886 10 ADRENAL GLANDS (G)(ABSOCUTE) MEAN 0.068 SO 0.0069 N 10 0.075 0.0118 10 0.067 0.0117 10 0.068 0.0133 10 BRA1N (G)(ABSOCUTE) MEAN SO N 1.992 0.1023 10 2.058 0.0824 10 2.061 0.1254 10 1 .992 0.1136 10 HEART (C)(ABMLUTE) MEAN SO N 1.219 0.0939 10 1.234 0.0852 10 1.185 0.1309 10 1.169 0.0895 10 KIDNEYS (G)(ABSOLUTE) MEAN SO N 2.751 0.2997 10 2.774 0.2146 10 2.899 0.4427 10 2.868 0.3493 10 LIVER (E)(ABSOLUTE) MEAN SO N 10.042 1.0649 10 SPLEEN (G)(ABSOLUTE) MEAN so N 0.652 0.0848 10 10.599 1.2931 10 0.720 0.1236 10 1o.m 1A978 10 0.708 0.0878 10 12.6721.6538 10 0.655 0.10% 10 Page 59 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 TABLE 8 ________________________________________--------.---- ORGAN WEIGHT SUMMARY (ABSOLUTE) ________..__GR_CUP_: __1-U___2-M-___3-M_.__4-M_____________------------ TESTES (G)(ABMLUTE) MEAN 3.233 2.946 3.271 3.250 SD 0.2537 0..3320 0.38% 0.1937 N 10 10 10 10 THYWS (G)(ABSOLUTE) MEAN SD N 0.507 0.0799 10 0.532 0.1231 10 0.4% 0.0600 10 0.516 0.1313 10 Page 60 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 8 Study Number: 132-007 BWY MIGHT (G)(ABSOLUTE) MEAN 424.800 SO 17.6692 N 5 ADRENAL GLANDS (G)(ABSOLUTE) MEAN 0.073 SO 0.0128 N 5 BRAIN (G)<ABSOLUTE) MEAN so N 2.142 0.0995 5 HEART (G)(ABSOLUTE) MEAN SO N 1.434 0.1301 5 KIDNEYS (G)(ABSOLUTE) MEAN SO N 3.488 0.1967 5 LIVER (G)(ABSOLUTE) MEAN SO N 15.145 1.1353 5 SPLEEN (G)(ABSOLUTE) MEAN SO N 0.844 0.13W 5 0.000 PA 0 0.000 NA 0 0.000 NA 0 0.000 NA 0 0.000 NA 0 0.000 NA 0 0.000 NA 0 0.000 NA 0 397.200 2a.2524 5 0.000 NA 0 0.069 0.0139 5 0.000 NA 0 2.200 0.0807 5 0.000 NA 0 1.459 0.1861 5 0.000 NA 0 3.594 0.3547 5 0.000 NA 0 14.697 1.9888 5 0.000 NA 0 0.711 0.1192 5 _____--___._----._______________________--.----- HA-Not Applicable PRIMEDICA REDFIELO STUDY W E E R 132-007 Page 61 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 8 Study Number: 132-007 GRWP: 1-H TESTES CG)(ABSOLUTE) MEAN u) N 3.038 0.2203 5 THYMUS (G)(ABSOLUTE) MEAN SO N 0.540 0.0557 5 2-M 0.000 NA 0 0.000 HA 0 3-n 4-M 0.000 NA 0 3.430. 0.2355 5 0.000 NA 0 0.543 0.0740 5 - ____________________------------.-------.--------------- * Significant diffcrmcc P<.O5 NA-Not Applicabla PRlMEDlU REOFIELO STWY NUMBER 132-007 Page 62 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 8 Study Number: 132-007 EWY WEIGHT (GICABSOLUTE) MEAN 225.300 SO 15.9028 N 10 ADRENAL GLANDS (G)(AESOLUTEI MEAN 0.084 SO 0.0151 N 10 BRAIN (G)(AESOLUTE) MEAN SO N 1.931 0.1029 10 HEART (G)(AESOLUTE) MEAN SO N 0.886 0.0573 10 K IONEYS (G) (ABSOLUTE) MEAN 1.820 SO 0.1718 N 10 LIVER (G)(ABSOLUTE) MEAN SO N 6.915 1.0021 10 OVARIES (C)(ABSOCUTE) MEAN SO N 0.108 0.0151 10 220.600 11.0675 10 0.081 0.0093 10 1,950 0.0684 10 0.890 0.0767 10 1.925 0.1152 10 7.100 0.5100 10 0.103 0.0135 10 227.300 15.2100 10 0.081 0.0103 10 1.930 0.0710 10 0.861 0.0881 10 1.864 0.1264 10 7.101 0.5348 10 0.109 0.0129 10 230.100 14.1378 10 0.079 0.0091 10 1.934 0. on0 10 0.848 0.0739 10 2.015** 0.1158 10 7.362 0.7272 10 0.109 0.0235 10 Page 63 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 8 Study Number: 132-007 GROUP: 1-F SPLEEN (G)(ABSOLUTE) MEAN SO N 0.496 0.0480 10 THYWS (G)(ABSOLUTE) MEAN u) N 0.446 0.0808 10 2- F 0.535 0.0920 10 0.461 0.0774 10 3-F 0.474 0.0625 10 0.432 0.0457 10 4-F 0.520 0.0542 10 0.434 0.0896 10 Page 64 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 8 Study Number: 132-007 BWY EIGHT (G)(ABSOLUTE) MEAN 243.200 SD 12.4780 N 5 ADRENAL GLANDS (G)(ABSOLUTE> MEAN 0.080 50 0.0124 N 5 BRAIN (G)(ABSOLUTE) MEAN SD N 1.978 0.0996 5 HEART (C)(ABSOLUTE) REAN SO N 0.959 0.0743 5 KIDNEYS (G)(ABSOLUTE) REAN SD N 2.135 0.2176 5 LIVER (G)(ABSOLUTE) MEAN SO N 8.547 1.1297 5 OVARIES (G)(&BSOLUTE) MEAN SD N 0.104 0.0196 5 0.000 NA 0 0.000 NA 0 0.000 NA 0 0.000 NA 0 0.000 NA 0 0.000 NA 0 0.000 NA 0 0.000 HA 0 242.000 4 3589 5 0.000 NA 0 0.089 0.0119 5 0.000 NA 0 1.967 0.0784 5 0.000 NA 0 0.934 0.06% 5 0.000 NA 0 2.227 0.2213 5 0.000 NA 0 8.825 0.9359 5 0.000 HA 0 0.102 0.0115 5 Page 65 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 8 Study Number: 132-007 __...________G_ROU_P: __1-_F ___2- F___3_-F ___4-_F ___________---------------- SPLEEN (G)(ABSOCUTE) MEAN 0.547 0.000 0.000 0.546 SD 0.0716 NA NA 0.0310 N 5 0 0 5 THYWS (G)(ABSOLUTE) MEAN 0.506 SO 0.1406 N 5 0.000 NA 0 0.000 NA 0 0.420 0.0834 5 _______________________________________ NA-Not Awlicable PRIMEDICA REDFIELO STWY W E E R 132-007 Page 66 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 8 Study Number: 132-007 ADRENAL GLANDS ( X Bmy EIGHT) MEAN 0.020 SO 0.0023 N 10 BRAIN ( X BOOY WEIGHT) MEAN 0.583 SO 0.0694 N 10 HEART ( X Ba)Y M I G H T ) MEAN 0.355 SO 0.0237 N 10 KIDNEYS ( X BOOY WEIGHT) MEAN 0.800 SO 0.OR4 N 10 LIVER ( X Bmy EIGHT) MEAN 2.913 SO 0.12n N 10 SPLEEN ( X E W Y E I G H T ) MEAN 0.189 so 0.0201 N 10 TESTES ( X BOOY UEIGHT) M A N 0.961 so 0.0665 N 10 0.021 0.0028 10 0.591 0.0355 10 0.355 0.0273 10 0.795 0,0261 10 3.030 0I2376 10 0.206 0.03oC 10 0.848 0.1201 10 0.020 0.0028 10 0.616 0.0631 10 0.352 0.0314 10 0.858 0.0886 10 3.208' 0.2470 10 0.210 0.0111 10 0.9m 0.0633 10 0.020 0.0030 10 0.596 0.0405 10 0.U9 0.0158 10 0.855 0.0775 10 3.?74" 0.3286 10 0.1% 0.0237 10 0.9?3 0.0794 10 Page 67 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 8 Study Number: 132-007 Page 68 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 8 Study Number: 132-007 AORENAL GLANDS ( X B W Y WEIGHT) MEAN 0.017 SD 0.0025 N 5 0.000 NA 0 BRAIN ( X BWY E I G H T ) MEAN 0.505 SD 0.0250 N 5 0.000 NA 0 HEART ( X BWY UEIGIIT) MEAN 0.337 SD 0.0249 N 5 0.000 NA 0 KIDNEYS ( X BWY E I G H T ) MEAN 0.824 SD 0.0809 N 5 0.000 NA 0 LIVER ( X BQ)Y MIGHT) MEAN 3.566 SD 0.2505 I 5 0.000 NA 0 SPLEEN ( X BWY UEIGHT) MEAN 0.199 SD 0.0328 N 5 TESTES ( x BWY MEAN SD N 0.716 0.0501 5 0.000 NA 0 0.000 NA 0 0.000 NA 0 0.017 0.oou 5 0.000 NA 0 0.556 0.0460 5 0.000 NA 0 0.367 0.0346 5 0.000 NA 0 0.905 0.0685 5 0.000 NA 0 3.691 0.3024 5 0.000 NA 0 0.181 0.0411 5 0.000 NA 0 0.866" 0.W 5 Page 69 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 8 Study Number: 132-007 ___.____.____GRW_P: __1_-11___2-_n ___3-11___4_-n ____________----.---------- THYMUS ( x amy EIGHT) MEAN 0.127 0.000 0.000 0.137 SO 0.0145 NA NA 0.0183 N 5 0 0 5 Page 70 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 8 Study Number: 132-007 ADRENAL GLANDS ( X BCOY WEIGHT) MEAN 0.037 SO 0.0055 N 10 0.037 0.0047 10 BRAIN ( X BODY WEIGHT) MEAN 0.859 SO 0.0531 N 10 0.886 0.0512 10 HEART ( X BODY UEICHT) MEAN 0.394 SO 0.0223 N 10 0.404 0.0360 10 KIDNEYS ( X BWY UEIGHT) MEAN 0.809 SD 0.- N 10 0.874 0.04T7 10 LIVER ( X BODY UEIGHT) MEAN 3.oM SD 0.3517 N 10 3.221 0.2249 10 OVARIES ( X BODY UEIGHT) 0.048 SD 0.0065 N 10 SPLEEN ( X BQ)Y UEIGHT) MEAN 0.220 SD 0.0155 N 10 0.047 0.0065 10 0.243 0.0419 10 0.036 0.0066 10 0.853 0.0639 10 0.373 0.0320 10 0.822 0.0592 10 3.130 0.2314 10 0.048 0.0055 10 0.208 0.0214 10 0.035 0.0049 10 0.844 0.0599 10 0.370 0.0397 10 0.879. O.OTJ3 10 3.203 0.2816 10 0.048 0.0098 10 0.226 0.0228 10 ________________._______________________-- Significant difference P<.05 ?PiMEOICA REOFlELO STWY W E E R 132-007 Page 71 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 8 Study Number: 132-007 GROUP: I-F 2-F 3-F 4- F _--_______-____-_---____________._______---------------------- THYMUS ( X BOOY YEIGHT) MEAN 0.198 u) 0.0320 N 10 0.210 o..0370 10 0.191 0.0234 10 0.188 0.0321 10 Page 72 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 8 Study Number: 132-007 ADRENAL GLANDS ( X BWY M I G H T ) MEAN 0.033 SD 0.0048 N 5 0.000 NA 0 BRAIN ( X BWY M I G H T ) MEAN 0.814 SD 0.0467 N 5 0.000 NA 0 HEART ( X BCOY E I G H T ) MEAN 0.3% SD 0.0149 N 5 0.000 NA 0 KIDNEYS (% BWY M I G H T ) MEAN 0.878 SD 0.0731 N 5 LIVER r x amy MIGHT) MEAN 3.512 SD 0.4185 N 5 0.000 NA 0 0.000 NA 0 OVARIES ( X BWY M I G H T ) MEAN 0.043 SD 0.0071 N 5 SPLEEN ( X rimy vEIoni) MEAN 0.225 SD 0.02% N 5 0.000 NA 0 0.000 NA 0 0.000 NA 0 0.037 0.0051 5 0.000 NA 0 0.813 0.0360 5 0.000 NA 0 0.387 0.0315 5 0.000 NA 0 0.920 0.0856 5 0.000 NA 0 3.648 0.4010 5 0.000 NA 0 0.042 0.0046 5 0.000 NA 0 0.226 0.0116 5 Page 73 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 8 Study Number: 132-007 ._______.______.________________________-------- NA-Not Applicable P R I M E D I U REDFIELD STWY NWBER 132-007 Page 74 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 8 Study Number: 132-007 ADRENAL GLANDS ( X MEAN SD N BRAIN UEIGHT) 3.448 0.3766 10 3.645 0.5446 10 3.237 0.5365 10 3.377 0.5620 10 HEART ( X BRAIN UEIGIIT) MEAN 61.471 SD 6.7103 N 10 59.996 4.2516 10 57.621 6.8870 10 50.R7 3.9519 10 KIDNEYS ( X BRAIN UEIGHT) MEAN 138.521 SD 17.6779 N 10 134.756 0.4422 10 140.611 19.4984 10 143.659 12.2345 10 LIVER ( X BRAIN UEIGHT) MEAN 506.171 SD 66.3457 N 10 514.455 53.3694 10 527.859 03.2392 10 634.112. 52.9397 10 SPLEEN ( X BRAIN UEIGHT) MEAN 32.839 SD L.0507 N 10 35.042 6.2017 10 34.455 4.4519 10 32.700 4.4595 10 TESTES ( X BRAIN UEIGHT) MEAN 162.754 SD 15.9430 N 10 143.109. 15.6906 10 159.161 20.9146 10 163.221 7.0780 10 THYWS ( X BRAIN WEIGHT) MEAN 25.550 SD 4.4202 N 10 25.886 6.1433 10 23.94 2.0155 10 25.784 5.8661 10 Page 75 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 8 Study Number: 132-007 ADRENAL GLANDS ( X BRAIN WIGHT) MEAN 3.410 SO 0.5265 N 5 0.000 NA 0 HEART ( X BRAIN E I G H T ) MEAN 66.964 m 5.9684 N 5 0.000 NA 0 KIDNEYS ( X BRAIN UEIGHT) MEAN 163.194 m 13.8442 N 5 0.000 NA 0 LIVER ( X BRAIN WIGHT) REAN 704.862 SO 41.2554 N 5 0.000 NA 0 SPLEEN ( X BRAIN E I G H T ) MEAN 39.630 SD 1.4456 N 5 0.000 NA 0 TESTES ( X BRAIN E I G H T ) MEAN 141.894 SD 9.3046 N 5 THYWS ( X BRAIN WIGHT) MEAN 25.224 SO 2.2726 N 5 0.000 NA 0 0.000 NA 0 0.000 NA 0 3.134 0.7291 5 0.000 HA 0 66.236 6.9501 5 0.000 NA 0 163 - 2 5 8 12.81 00 5 0.000 NA 0 668.866 95.8205 5 0.000 NA 0 32.354 53 0 3 5 0.000 HA 0 155.866' 8.3186 5 0.000 NA 0 24.720 3.4212 5 - -_--____.._._______-.-------------.------------------------- Significant difference P<.05 NA-Not Applicable PRIMEDICA REDFlELD STWY NWBER 132-007 Page 76 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats TABLE 8 Study Number: 132-007 ADRENAL GLANDS ( X MEAN SD N BRAIN UEIGHT) 4.341 0.8352 10 4.142 0.5258 10 4.222 0.5661 10 4.081 0.4782 10 HEART ( X BRAIN WEIGHT) MEAN 45.976 SO 2.9349 N 10 45.579 2.7052 10 44.656 4.8562 10 43.927 4.5627 10 KIDNEYS ( X BRAIN YEIGHT) MEAN 94.429 SD 9.5441 N 10 98.811 6.1946 10 96.744 8.1046 10 104.359 7.7444 10 LIVER ( X BRAIN YEIGHT) MEAN 358.130 SO 46.9672 N 10 364.641 30.7329 10 368.399 32.2870 10 381.530 45.0936 10 OVARIES ( X BRAIN YEIGHTI MEAN so 5.590 0.6268 N 10 5.294 0.6363 10 5.681 0. no0 10 5.656 1.2672 10 SPLEEN ( X BRAIN EIGHT) MEAN 25.666 SD 1.9341 N 10 THYWS ( X BRAIN E I G H T ) M A N 23.119 SD 3.8556 N 10 27.541 5.2675 10 23.730 4.4214 10 24.590 3.3877 10 22.422 2.6258 10 26.860 2.5176 10 22.631 4.5613 10 Page 77 TABLE 8 ADRENAL GLANDS ( X BRAIN WEIGHT) MEAN 4.036 SO 0.6184 N 5 0.000 HA 0 HEART ( X BRAIN WEIGHT) MEAN 48.492 SD 3.1436 N 5 0.000 NA 0 KIDNEYS CX BRAIN WEIGHT) MEAN 107.766 SO 6.7108 N 5 0.000 NA 0 LIVER ( X BRAIN WEIGHT) MEAN 432.210 SO 54.7403 N 5 0.000 NA 0 OVARIES ( X BRAIN WEIGHT) MEAN 5.254 SD 0 . m N 5 0.000 NA 0 SPLEEN ( X BRAIN WEIGHT) MEAN 27.666 SO 3.5032 N 5 0.000 NA 0 THYWS CX BRAIN YEIGHT> MEAN 25.744 SO 7.8943 N 5 0.000 NA 0 0.000 NA 0 4 .54a 0.6118 5 0.000 NA 0 47.576 4.0621 5 0.000 NA 0 113.046 7.9401 5 0.000 HA 0 448.022 33.2786 5 0.000 NA 0 5.174 0.39TI 5 0.000 NA 0 27.774 1 A843 5 0.000 HA 0 21.336 3.8449 5 Page 78 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDICES Page 79 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 1 METHODS USED FOR CLINICAL PATHOLOGY PROCEDURES Page 80 ~~ ~~ ~~ A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 HEMATOLOGY The Baker System 9110 + Plus Automated Cell Counter is used for complete blood counts. White Blood Cell (WBC), Red Blood Cell (RBC) and Platelet counts - The instrument electronically counts WBC, RBC, and platelets by employing the impedance principle. This principle of electronic counting and sizing is based on the difference in conductivity between blood cells and the diluent in which they are suspended. Pulse editing is used to discriminate between red blood cells and platelets. Mean Corpuscular Volume (MCV) - Measurementof MCV is based on the RBC impedance pulse amplitude. RBC pulses are sized according to their voltage and an average is taken. The average is then compared to the MCV reference that is set during the Hematocrit calibration. Hemoglobin - The hemoglobin determination is accomplished by a cyanmethemoglobin procedure. The color intensity of this reaction is measured by a photometric cell. - Hematocrit (HCT), Mean Corpuscular Hemoglobin (MCH) and Mean Corpuscular Hemoalobin Concentration lMCHCLl - calculated from the measured Darameters usina the I following formulas: HCT = MCV X RBC 10 MCH = HGB X 10 RBC MCHC = HGB X 100 HCT Differentials and RBC morphology are done manually. Stain used - VOLU-SOL Wright's stain. Page 81 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 COAGULATION MCA 110 - a fully integrated microprocessor driven instrument designed to perform coagulation tests on plasma specimens. The MCA 110 operates on the principles of optical density measurement enhanced by electronic light amplification, differentiation and signal processing. Utilizing light generated by light diodes and solid state photo-detectors. Prothrombin Time Bio/Data Corporation Plastinex Thromboplastin Reagent No. 101158 Activated Partial Thromboplastin Time Bio/Data Corporation Cephalinex Activated PTT Reagent (Silica Activated) No. 101162 Page 82 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 CLINICAL CHEMISTRY The Boehringer Mannheim Hitachi - 717 Analyzer is a fully automated computerized chemistry analyzer. It is a multi-channel, discrete instrument capable of performing potentiometric and photometric assays of a wide range of analyses. The Hitachi - 717 utilizes a unique reagent and sampling system which allows the analysis of 750 testlhour including Ion Selective Electrodes. Total Protein (Biuret) Colorimetric Determination BMC Albumin (Bromcresol Green) Colorimetric Determination BMC Glucose (Hexokinase) Enzymatic Determination BMC Cholesterol Enzymatic Determination BMC Blood Urea Nitrogen (RATE) Enzymatic Determination BMC Creatinine Kinetic Determination BMC Total Bilirubin Colorimetric Determination BMC Alanine Aminotransferase Kinetic Determination BMC Aspartate Aminotransferase Kinetic Determination BMC Alkaline Phosphatase Kinetic Determination BMC Creatine Kinase Kinetic Determination BMC Lactate Dehydrogenase Kinetic Determination BMC Gamma-Glutamy ltransferase Kinetic Determination BMC Triglyceride (GPO-Trinder) Enzymatic Determination BMC Calcium Colorimetric Determination BMC Phosphorus (Inorganic) Ultraviolet Determination BMC Direct Bilirubin Colorimetric Determination BMC Amylase/EPS Enzymatic Colorimetric Test BMC Lipase Ultraviolet Determination BMC Sorbitol Dehydrogenase Enzymatic Determination Sigma Sodium - Ion Selective Electrode, Boehringer Mannheim Procedure Potassium - Ion Selective Electrode, Boehringer Mannheim Procedure Chloride - Ion Selective Electrode, Boehringer Mannheim Procedure BMC = Boehringer Mannheim Corporation Reagents Page 83 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 2 J INDIVIDUAL NECROPSY OBSERVATIONS Page 84 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 REPORTS CODE TABLE TGL Trackable Gross Lesion PRlMEDlCA REDFIELD STUDY NUMBER 132-007 Page 85 INDIVIDUAL NECROPSY OBSERVATIONS 1 3 2 - 0 0 7 . A 28-DAY ORAL (GAVAGE) TOXICITY STUDY OF T-7485 I N SPRAGUE-DAWLEY RATS Group: 1 Dose: 0 Sex: Male Animal Number Mode O f Death 7569 SCHEDULED SACRIFICE 7571 SCHEDULE0 SACRIFICE 7573 SCHEDULED SACRIFICE 7575 SCHEWLED SACRIFICE 7577 SCHEWLED SACRIFICE 7579 SCHEDULED SACRIFICE 7581 SCHEDULED SACRIFICE 7583 SCHEDULED SACRIFICE 7585 SCHEDULED SACRIFICE 7587 SCHEWLED SACRIFICE 7589 SCHEDULED SACRIFICE 7591 SCHEDULED SACRIFICE 7593 SCHEDULED SACRIFICE 7595 SCHEWLED SACRIFICE 7597 SCHEDULED SACRIFICE Death Day (Week) O b s e r v a t i o n ( s ) No V i s i b l e Lesions No V i s i b l e L e s i o n s No V i s i b l e L e s i o n s No V i s i b l e Les'ions No V i s i b l e L e s i o n s No V i s i b l e L e s i o n s No V i s i b l e L e s i o n s No V i s i b l e L e s i o n s No V i s i b l e L e s i o n s No V i s i b l e Lesions No V i s i b l e L e s i o n s No V i s i b l e L e s i o n s No V i s i b l e L e s i o n s No V i s i b l e L e s i o n s No V i s i b l e L e s i o n s INOIVIWAL NECROPSY OBSERVATIONS 132-007 - A 28-DAY ORAL (GAVAGE) TOXICITY STUOY OF T-7485 I N SPRAGUE-OAWLEY RATS Group: 2 Dose: 100 Sex: M a l e Animal Number Mode O f Death Death Day (Week) O b s e r v a t i o n ( s ) 7599 SCHEWLEO SACRIFICE No V i s i b l e L e s i o n s 7601 SCHEWLEO SACRIFICE No V i s i b l e L e s i o n s 7603 SCHEWLED SACRIFICE No V i s i b l e L e s i o n s 7605 SCHEWLED SACRIFICE No V i s i b l e L e s i o n s 7607 SCHEWLED SACRIFICE TESTES; RIGHT; SMALL (TGL) Any r e m a i n i n g p r o t o c o l r e q u i r e d t i s s u e s , which have been examined, have no v i s i b l e l e s i o n s 7609 SCHEWLEO SACRIFICE No V i s i b l e L e s i o n s 7611 SCHEWLEO SACRIFICE No V i s i b l e Lesions 7613 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7615 SCHEWLEO SACRIFICE No V i s i b l e L e s i o n s , 7617 SCHEWLED SACRIFICE No V i s i b l e L e s i o n s INOIVIWAL NECROPSY OBSERVATIONS 132-007 - A ZB-OAY ORAL (GAVAGE) TOXICITY STUDY OF T-7485 I N SPRAGUE-DAWLEY RATS -~ ~ ~- Group: 3 Dose: 300 Sex: Male Animal Number Mode O f Death Death Day (Week) O b s e r v a t i o n ( s ) 7 6 1 9 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7621 SCHEWLED SACRIFICE No V i s i b l e L e s i o n s 7623 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7625 SCHEWLED SACRIFICE No V i s i b l e Lesions 7627 SCHEWLED SACRIFICE No V i s i b l e L e s i o n s 7629 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7631 SCHEWLED SACRIFICE No V i s i b l e L e s i o n s 03 7633 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 03 7635 SCHEWLED SACRIFICE No V i s i b l e Lesions 7637 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s INDIVIDUAL NECROPSY OBSERVATIONS 1 3 2 - 0 0 7 - A 26-DAY ORAL (GAVAGE) TOXICITY STUDY OF T - 7 4 6 5 I N SPRAGUE-DAWLEY RATS Group: 4 Dose: 900 Sex: Male Animal Number Mode O f Death Observation( s) 7 6 3 9 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7641 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7 6 4 3 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7 6 4 5 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7 6 4 7 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7 6 4 9 SCHEDULED SACRIFICE No V i s i b l e Lesions cn9 7651 SCHEDULED SACRIFICE No V i s i b l e Lesions 7 6 5 3 SCHEDULE0 SACRIFICE No V i s i b l e L e s i o n s 7 6 5 5 SCHEDULED SACRIFICE No V i s i b l e Lesions 7657 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7 6 5 9 SCHEDULED SACRIFICE No V i s i b l e Lesions 7661 SCHEDULED SACRIFICE No V i s i b l e Lesions 7 6 6 3 SCHEDULED SACRIFICE No V i s i b l e Lesions 7 6 6 5 SCHEDULED SACRIFICE 7667 SCHEDULED SACRIFICE No V i s i b l e Lesions No V i s i b l e Lesions INDIVIDUAL NECROPSY OBSERVATIONS 132-007 - A 28-DAY ORAL (GAVAGE) TOXICITY STUDY OF T-7485 I N SPRAGUE-DAWLEY RATS Group: 1 Dose: 0 Sex: Female Animal - Number Mode O f Death 7570 SCHEDULED SACRIFICE 7572 SCHEWLED SACRIFICE 7574 SCHEDULED SACRIFICE 7576 SCHEDULED SACRIFICE 7578 SCHEDULED SACRIFICE 7580 SCHEDULED SACRIFICE 7582 SCHEDULED SACRIFICE 7584 SCHEDULED SACRIFICE 7586 SCHEDULED SACRIFICE 7588 SCHEDULED SACRIFICE 7590 SCHEDULED SACRIFICE 7592 SCHEDULED SACRIFICE 7594 SCHEDULED SACRIFICE 7596 SCHEDULED SACRIFICE 7598 SCHEDULED SACRIFICE Death Day (Week) Observation(s) No V i s i b l e L e s i o n s No V i s i b l e L e s i o n s No V i s i b l e Lesions No V i s i b l e L e s i o n s No V i s i b l e Lesions NO V i s i b l e Lesions No V i s i b l e Lesions No V i s i b l e Lesions No V i s i b l e Lesions No V i s i b l e L e s i o n s No V i s i b l e Lesions No V i s i b l e Lesions No V i s i b l e Lesions No V i s i b l e Lesions No V i s i b l e Lesions INDIVIDUAL NECROPSY OBSERVATIONS 1 3 2 - 0 0 7 . A 28-DAY ORAL (GAVAGE) TOXICITY STUDY OF T-7485 I N SPRAGUE-DAWLEY RATS Group: 2 Dose: 100 Sex: Female Animal Number Node O f Death Death Day (Week) O b s e r v a t i o n ( s ) 7600 SCHEWLED SACRIFICE No V i s i b l e L e s i o n s 7602 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7604 SCHEWLED SACRIFICE No V i s i b l e L e s i o n s 7606 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7608 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7610 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7612 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7614 SCHEWLED SACRIFICE No V i s i b l e L e s i o n s 7616 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7618 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s INDIVIDUAL NECROPSY OBSERVATIONS 1 3 2 - 0 0 7 . A 28-DAY ORAL (GAVAGE) TOXICITY STUDY OF T-7485 I N SPRAGUE-DAWLEY RATS Group: 3 Dose: 300 Sex: Female Animal Number Mode O f D e a t h Death Day (Week) Observation(s) 7620 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7622 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7624 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7626 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7628 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7630 SCHEWLEO SACRIFICE No V i s i b l e L e s i o n s 9u3 7632 SCHEWLED SACRIFICE No V i s i b l e L e s i o n s (D (D 7634 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s h) 7636 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7638 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s INDIVIDUAL NECROPSY OBSERVATIONS 1 3 2 - 0 0 7 - A 28-DAY ORAL (GAVAGE) T O X I C I N STUDY OF T - 7 4 8 5 I N SPRAGUE-DAWLEY RATS Group: 4 Dose: 900 Sex: Female Animal Number Mode Of Death Death Day (Week) O b s e r v a t i o n ( s ) 7640 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7642 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7644 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7646 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7648 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7650 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7652 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7654 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7656 SCHEDULED SACRIFICE NO V i s i b l e Lesions 7658 SCHEDULED SACRIFICE No V i s i b l e Lesions 7660 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7662 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7664 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s 7666 SCHEDULED SACRIFICE 7668 SCHEDULED SACRIFICE No V i s i b l e L e s i o n s No V i s i b l e L e s i o n s A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 3 HISTOPATHOLOGY REPORT Page 94 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 -E4 PATHOLOGY ASSOCIATES A CHARLES RIVER COMPANY PATHOLOGY REPORT FOR A 28-DAY ORAL (GAVAGE) TOXICITY STUDY OF T-7485 IN SPRAGUE-DAWLEY RATS . PRlMEDlCA REDFIELD PROTOCOL NUMBER: 132-007 PREPARED FOR PRlMEDlCA REDFIELD 15 Worman's Mill Court, Suite I, Frederick, MD 21701 301.663.1644 FAX: 301.663.8994 www.paicriver.com Page 95 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 TABLE OF CONTENTS I. Pathology Narrative 1-1 Appendix .1: Reports Code Table Appendix 2: Abbreviations List II. Summary of Histologic Findings 11-1 Ill. Individual Animal Histologic Findings 111-1 IV. Gross & Microscopic Correlation of Findings 1v-1 V. Comment Report v-1 VI. Quality Assurance Statement v1-1 Page 96 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 1. Pathology Narrative Page 97 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 Final Pathology Report Redfield Laboratories, Inc.: 132-007 A 28-DAY ORAL (GAVAGE) TOXICITY STUDY OF T-7485 IN SPRAGUE-DAWLEY RATS Primedica Redfield Protocol Number 132-007 INTRODUCTION This report by Pathology Associates-A Charles River Company (PAI), formerly Pathology Associates International, for Primedica Redfield, 100 East Boone Street, Redfield, AR 72132, presents the results of pathology support for Protocol Number 132- 007, an oral toxicity study in rats. The objective of this study was to evaluate the toxicity potential associated with oral (gavage) administration of T-7485 in Sprague-Dawley rats for a 28-day repeated dose with an approximate 14-day recovery period. The portions of this study performed by Pathology Associates (PA) were conducted to the standards of the Organization for Economic Cooperation and Development (OECD) regulations, C(81)30 (Final). STUDY DESIGN AND METHODS One hundred Sprague-Dawley rats (50 males and 50 females) were randomly assigned to four groups and treated as is depicted in Table 1. Three dose levels of the test material and a vehicle control group were evaluated. Doses were administered via oral gavage for twenty-eight consecutive days. The dose volume was 25 mLkg. The dose for each animal was calculated based upon the most recent body weight. Rats (5hedgroup) in the vehicle control and high dose groups were allowed a recovery period of approximately fourteen days. On Study Day 29, the animals were sacrificed by rotating sequentially through groups for each sex. Recovery animals were sacrificed rotating sequentially through the groups for each sex on approximately Study Day 44. Animals were euthanized via carbon dioxide asphyxiation followed by exsanguination. Comprehensive necropsies were performed on all scheduled sacrifices by Primedica personnel. These included macroscopic examination of the external surface of the body, all orifices and the cranial, thoracic, and abdominal cavities and their contents. Specified organ weights were measured and gross lesions were recorded during the necropsies, and protocol specified tissues were collected and preserved in 10% neutral buffered formalin or other suitable fixative. Group Number Group Designation Dosage Level (mg/ke) 1 Vehicle Control 0 I I 2 Mid-dose 100 3 Mid-highdose 300 Dosage Concentration (mg/mL) 0 4 12 Dosage Volume Number o f Animals' (mmz) Males Females 25 lO(5) lO(5) 25 10 10 25 1 10 IO * Number in parenthesis indicates the number of recovery animals. 1 Page 98 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 Final Pathology Report Redfield Laboratories, Inc.: 132-007 Protocol specified tissues from animals in the control and high dose groups and on all gross lesions were sent to PAI's Frederick, Maryland facility where they were processed through paraffin, sectioned at approximately 5 microns, and stained with hematoxylin and eosin (H&E). Sections were then evaluated for pathological changes by the undersigned Study Pathologist. All microscopic lesions were graded according to the following severity scale: 1(minimal), 2(mild), 3(moderate),or 4(marked). RESULTS Unscheduled Deaths There were no early deaths. All study animals survived to their scheduled sacrifice date (Day 29 or Day 44). Gross Lesions Only one gross lesion was recorded at necropsy and was not considered to be test article-related. Microscouic Patholow Microscopic findings are presented in tabular format in Sections I1 and 111. Summary data are presented by gender, group and time point in the Summary of Histologic Findings (Section 11), while individual diagnoses can be found in the Individual Animal Histologic Findings (Section 111). The macroscopic lesions, as well as the corresponding microscopic correlates, when present, are recorded in Section IV of this report (Gross and Microscopic Correlation of Findings). Tissue comments, where applicable, are provided in the Comment Report (Section V). Symbols used for lesion severity and distribution are explained in the Reports Code Table (Appendix I), and abbreviations used in LABCAT tables are explained in Appendix 2. The microscopic lesions observed in the animals of this study are considered incidental and in no way related to receiving the test article. SUMMARY AND CONCLUSIONS One hundred Sprague-Dawleyrats were randomly assigned to four groups and treated as is depicted in Table 1. Doses were administered via oral gavage for twenty-eight consecutive days. Comprehensive necropsies were performed on all study animals by Prirnedica personnel. Protocol specified tissues were processed through paraEn and rendered to approximately 5 micron sections stained with H&E. These sections were then evaluated microscopically. The one gross lesion noted at necropsy is not considered to be related to receiving the test article. The microscopic lesions observed in the test animals are also considered to be incidental and in no way related to receiving the test article. Study Pathologist 2 Page 99 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 Appendix 1: Reports Code Table Page 100 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 PATHOLOGYASSOCIATES INTERNATIONAL A 28-DAY ORAL (GAVAGE) TOXICITY STUDY T-7485 IN SPRAGUE-DAWLEY RATS PRlMEDlCA REDFIELD PROTOCOL NUMBER: 132-007 Reports Code Table N Tissues within normal histological limits A Autolysis precluding adequate evaluation U Tissues unavailable/unsuitablefor evaluation R Recuffretrim requested * Tissues not submitted for evaluation 1 minimal 2 mild 3 moderate 4 marked 0 focal [I diffuse <> multifocal P Present B Neoplasm, Benign M Neoplasm, Malignant without Metastasis C Neoplasm, Malignant with Metastasis X Metastatic Site (+) L Unilateral I Bilateral Diagnosis not applicable to animal/tissue; no data entered Page 101 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 Appendix 2: Abbreviations List Page 102 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 PATHOLOGY ASSOCIATES INTERNATIONAL A 28-DAY ORAL (GAVAGE) TOXICITY STUDY T-7485 IN SPRAGUE-DAWLEY RATS PRlMEDlCA REDFIELD PROTOCOL NUMBER: 132-007 # EX MANDIB SM LG WI ARTIC Abbreviations List Number Examined Mandibular Small Large With Articular Page 103 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 It. Summary of Histologic Findings Page 104 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ESOPHAGUS MUSCULAR TUNIC- OEGENERATION # # EX 10 0 HEART CARDIOMYOPATHY # EX 10 2 KIDNEYS HYDRONEPHROSIS CORTEX- SUBACUTE INFLMHATION CY S T ( S ) # EX 10 2 1 1 LACRIMAL GLAND LYMPHOCYTE INFILTRATION # EX 10 0 LG INTESTINE, RECTUM # EX 10 MUSCULAR TUNIC- PERIVASCULAR INFLAMMATION 1 SUBMUCOSA- PERIVASCULAR INFLAMMATION 1 LIVER SUBACUTE INFLAMMATION # EX 10 10 LUNGS WITH BRONCHI ALVEOLI- EOSINOPHILIC CRYSTALS HEMORRHAGE I NFLAMMATION # EX 10 1 1 3 LYMPH NODES, MANDIBULAR HEMORRHAGE # EX 10 1 LYMPH NODES, MESENTERIC HEMORRHAGE # EX 10 0 PANCREAS SUBACUTE INFLAMMATION I EX 10 1 TESTES TUBULAR DEGENERATION # EX 10 0 # # 0 10 0 1 0 10 0 1 0 10 0 1 0 0 0 0 0 10 0 1 0 10 0 0 0 0 0 10 0 7 0 10 0 0 0 0 0 1 0 10 0 0 0 10 0 1 0 10 0 0 1 10 1 0 Page 105 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ___-__--_____-___-__--....------------------.-------- PRlMEDlCA REDFIELO STUDY NUMBER 132-007 ' Page 106 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ESOPHAGUS MUSCULAR TUNIC- DEGENERATION # # # EX 10 10 0 3 HARDERIAN GLAND SUBACUTE INFLAMMATION # EX 10 10 0 1 KIDNEYS MINERALIUTION TUBULAR DEGENERATION # EX 10 10 8 10 1 2 LIVER SUBACUTE INFLAMMATION # EX 10 10 9 7 LUNGS WITH BRONCHI I NFLAMMATI O N # EX 10 10 2 2 LYMPH NOOES, MESENTERIC HISTIOCYTOSIS # EX 10 10 1 0 PANCREAS SUBACUTE I N F L M T I O N # EX 10 10 1 0 PITUITARY GLAND # EX 10 10 PARS NERMSA- ECTOPIC EPITHELIAL REST 0 1 THYMUS HEMORRHAGE # EX 10 10 1 2 UTERUS HORNS- DILATED # EX 10 10 5 3 ____________________---..--.-----.---.----------"- PRIMEDICA REDFIELD STUDY NUMBER 132-007 Page 107 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 EPIDIDYMIDES GRANULOHA(S) KIDNEYS HYDRONEPHROSIS CYST(S) TUBULAR DEGENERATION LIVER SUBACUTE I N F L W T I O N NECROSIS LUNGS U I T H BRONCHI INFLAMMATION TESTES TUBULAR DEGENERATION THYMUS HEMORRHAGE # # EX 5 0 # EX 5 0 1 1 # EX 5 c 0 # EX 5 0 # EX 5 0 # EX 5 2 # 5 1 5 1 0 1 5 5 1 5 1' 5 1 5 0 Page 108 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 K IDNEYs HYDRONEPHROSIS MINERALIZATION TUBULAR DEGENERATION LIVER SUBACUTE INFLAHMTION LYMPH NOOES, MESENTERIC HEMORRHAGE UTERUS HORNS- 0ILATER # EX 5 5 0 1 2 3 0 1 # EX 5 5 5 4 # EX 5 5 1 0 # EX 5 5 1 2 Page 109 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 111. Individual Animal Histologic Findings Page 110 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ANIMAL ID: ADRENAL GLANDS AORTA BONE HARRW (STERNUH) BRAIN EPIDIDYMIDES ESOPHAGUS EYES WITH OPTIC NERVE FEMUR W/ ARTIC SURFACE HARDERIAN GLAND HEART CARD IOHYOPATHY KIDNEYS HYDRONEPHROSlS CORTEX- SUBACUTE INFLAHHATION LACRIHAL GLAND LG INTESTINE, CECUH LG INTESTINE, COLON LG INTESTINE, RECTUM MUSCULAR TUNIC- PERIVASCULAR I N F L A W A T I O N SUBWCOSA- PERIVASCULAR INFLAHMATION 7569 N N N N N N N N N 1 N N N N 2 7571 N N N N N N N N N N 1L N N N N 7573 N N N N N N N N N N 7575 N N N N N N N N N N N <l>I N N N N N N N 1 ------..-.--....--_----.----..-.-.-------------.-----------.------- See R e p o r t s Code T a b l e f o r S y n l ~ ~D le f i n i t i o n s PRIMEDICA REDFIELD STUDY NUMEER 132-007 Page 111 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ANIMAL ID: LIVER SUBACUTE INFLAMMATION LUNGS WITH BRONCHI ALVEOLI- EOSINOPHILIC CRYSTALS HEMORRHAGE INFLAMMATION . LYMPH NWES. MANDIBULAR LYMPH NWES, MESENTERIC MAMMARY GLAND PANCREAS SUBACUTE INFLAMMATION PARATHYROID PITUITARY GLAND PROSTATE GLAND SALIVARY GLAND, MANDIB S C I A T I C NERVE SEMINAL VESICLES SKELETAL MISCLE SM INTESTINE, DUOOENUM SM INTESTINE, ILEUM SM INTESTINE, JEJUNUM 7569 7571 7573 7575 <lD <l> 4, <l> N N (2) (31 <2> (1) N N N N N N N N N N N N N N N (1 I N N N U N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N ________.___________---------------.------------- S e e Reports C o d e T a b l e f o r S-1 Definitions PRIMEDICA REDFIELD STUDY NUMBER 132-007 Page 112 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ANIMAL ID: SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR SPINAL CORD, THORACIC SPLEEN S T W C H , FORESTWCH STCMACH, GLANDULAR TESTES THYMUS THYROID TONGUE TRACHEA URINARY BLADDER ZYMBALS GLAND 7569 N N N N N N N N N N N N N 7571 N N N N N N N N N N N N N 7573 N N N N N N N N N N N N N 7575 N N N N N N N N N N N N N ____________________--.------------------------ See Reports Code Table for S y n b l D e f i n i t i o n s PRIMEDICA REDFIELO STUDY NUMBER 132-DO7 Page 113 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ................................................................................................. _____I_ND_IV_ID_UA_L A.N-I-M-AL-_HI_ST_OLO_GI_C -F-I-ND-I-N-GS.-----------------------.- DRUG: T - 7 4 8 5 FATE: I n t e r i m s a c r i f i c e GROUP: 1M ________---------__-___________SEX:_MA_LE _______------- ANIMAL ID: 7 5TI 7579 7581 7583 ADRENAL GLANDS N N N N AORTA N N N N BONE MARROV (STERNUM) N N N N BRAIN N N N N EPIDIDYMIDES N N N N ESOPHAGUS N N N N EYES WITH OPTIC NERVE N N N N FEMUR W/ ARTIC SURFACE N N N N HARDERIAN GLAND N N N N HEART CARDlOnYOPATHY N N N 1 KIDNEYS HYDRONEPHROSIS N N N 1L LACRIMAL GLAND N N N N LG INTESTINE, CECUM LG INTESTINE, COLON N N N N N N N N LG INTESTINE, RECTUM N N N N LIVER SUBACUTE INFLAMMATION <l> <2> <l> <l> LUNGS WITH BRONCHI N N N N Page 114 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats I Study Number: 132-007 ANIMAL ID: LYMPH NWES, MANDIBULAR HEMORRHAGE LYMPH NWES, MESENTERIC MAMMARY GLAND . PANCREAS PARATHYROID PITUITARY GLAND PROSTATE GLAND SALIVARY GLAND, M N D I B SCIATIC NERVE SEMINAL VESICLES SKELETAL N S C L E SM INTESTINE, DUODENUM SM INTESTINE, I L E W SM INTESTINE, JEJ U N W SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR SPINAL CORD, THORACIC SPLEEN 7s77 7579 7581 75.93 N N N 1 N N N N N N N N N N N N N N U N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N ___________-____________________________ See Reports Code Table for S-1 Definitions PRIMEDICA REDFIELD STUDY NUMBER 132-OD7 Page 115 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ANIMAL ID: STORACH, FORESTOMACH STOMACH, GLANDULAR TESTES THYMUS HEMORRHAGE THYROID TONGUE TRACHEA URINARY BLADDER ZYHBALS'GLAND 7577 N N N N N N N N N 7579 N N N N N N N N N 7581 N N N N N N N N N 7583 N N N 1 N N N N N ___________.________.--.--.---------.---------------- See Reports C o d e T a b l e f o r S y n l w l Definitiont PRIHEDICA REDFIELD STUDY NUMBER 132-007 Page 116 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ANIMAL ID: ADRENAL GLANDS AORTA BONE MARROU (STERNUM) BRAIN EPIDIDYMIDES ESOPHAGUS EYES UITH OPTIC NERVE FEMUR U/ ARTIC SURFACE HARDERIAN GLAND HEART KIDNEYS CYST( S1 LACR IEIAL GLAND LG INTESTINE, CECUM LC INTESTINE, COLON LG INTESTINE, RECTUM LIVER SUBACUTE INFLAMMATION LUNGS UITH BRONCHI I NFLAWATIOW Ea5 7587 N N N N N N N N N N N N N N N N N N N N N 1L N N N N N N N N <2> <l> N (2) ____-_----------________________________------- See Reports Code Table for Synbol Definitions PRIMEDICA REDFIELD STUDY NUMBER 132-007 Page 117 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ANIMAL ID: LYMPH NODES, MANDIBULAR LYMPH NOOES, MESENTERIC MAMMARY GLAND PANCREAS PARATHYROID PITUITARY GLAND PROSTATE GLAND SALIVARY GLAND, MANDIB SCIATIC NERVE SEMINAL VESICLES SKELETAL MUSCLE SM INTESTINE, DUODENUM SM INTESTINE, ILEUM SM INTESTINE, JEJUNUM SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR SPINAL CORD, THORACIC SPLEEN N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N See R e p o r t s C o d e T a b l e f o r S-1 Definitions PRIMEDICA REDFIELD STUDY NUMBER 132-007 Page 118 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ANIMAL ID: STOFIACH, FORESTOMACH STOFIACH, GLANDULAR TESTES THYMUS HEMORRHAGE THYRDI D TONGUE TRACHEA URINARY BLADDER ZYMBALS GLAND 7585 N N N 7587 N N N 1 1 N N N N N N N N N N S e e R e p o r t s C o d e T a b l e f o r Synbal D e f i n i t i o n s PRIMEDICA REDFIELD STUDY NUMBER 132-007 ' Page 119 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 TESTES TUBULAR DEGENERATION 3L ____________________------------.-------------- See Reports Code Table for Symbol Definitions PRIMDICA REDFIELD STUDY NUMBER 132-007 Page 120 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ADRENAL GLANDS AORTA BONE MARROV (STERNUM) BRAIN EPIDIDYMIDES ESOPHAGUS MUSCULAR TUNIC- DEGENERATION EYES U I T H OPTIC NERVE FEMUR U/ ARTIC SURFACE HARDERIAN GLAND HEART KIDNEYS LACR I HAL GLAND LYMPHOCYTE INFILTRATION LG INTESTINE, CECUM LG INTESTINE, COLON LC INTESTINE, RECTUM LIVER SUBACUTE INFLAMMATION LUNGS U l T H B R W H I N N N N N N N N N N N N N N N N N N N N - N N N (2) N N N N N N N N N N N N N N N N N N N N N (111 N- N N N N N N N N N N N N N <I> <2> <2> N - N N N S e e R e p o r t s C o d e T a b l e f o r Symbol D e f i n i t i o n s PRIMEDICA REDFIELD STUDY NUMBER 1 3 2 - 0 0 7 Page 121 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ANIMAL ID: INFLAMMATION LYMPH NOOES, MANDIBULAR LYMPH NODES, MESENTERIC MAMMARY GLAND PANCREAS PARATHYROID PITUITARY GLAND PROSTATE GLAND SALIVARY GLAND, MANDIB SCIATIC NERVE SEMINAL VESICLES SKELETAL MUSCLE SM INTESTINE, DUODENUM 511 INTESTINE, ILEUM SM INTESTINE, JEJUNUM SPINAL CORD, CERVICAL SPINAL CORD, LUnBAR SPINAL CORD, THORACIC 7639 N N N N U N N N N N N N N N H N N 764 1 N N N N N N N N N N N N N N N N N 7643 N N N N U N N N N N N N N N N N N 7645 <2> N N N N U N N N N N N N N N N N N ________________________________________ See Reports Code Table for Syrbol D e f i n i t i o n s PRIMEDICA REDFIELD STUDY NUMBER 132-007 Page 122 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 SPLEEN STOMACH, FORESTOMClCH STOMACH, GLANDULAR TESTES THYMUS HEMORRHAGE THYROID TONGUE TRACHEA URINARY BLADDER ZYMBALS GLAND N N N N N N N N N N N N N N N N N N 1 2 N N N N N N N N N N N N N N N N N N N N ______________._________________________- See Reports Code Table for Synhl D e f i n i t i o n s PRIMEDICA REDFIELD STUDY NUMBER 132-007 Page 123 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ANIMAL ID: ADRENAL GLANDS AORTA BONE MARRCU (STERNUM) BRAIN EPIDIDYMIDES ESOPHAGUS EYES WITH OPTIC NERVE FEMUR W/ ARTIC SURFACE HARDERIAN GLAND HEART CARDIWYOPATHY KIDUEYS HYDRONEPHROSIS LACRIMAL GLAND LG INTESTINE, CECUM LG INTESTINE, COLON L C INTESTINE, RECTUM LIVER SUBACUTE INFLAMMATION LUNGS WITH BRONCHI 7667 7649 N N N N N N N N N N N N N N N N N N N 1 N 1L N N N N N N N N N <1> N N 765 1 N N N N N N N N N N 7653 N N N N N N N N N N N N N N N N N N N N <l> <1> N N _._________--___________________________--- See Reports Code Table for Sydml D e f i n i t i o n s PRIMEDICA REDFIELD STUDY NUMBER 132-007 ' Page 124 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ................................................................................................. INDIVIDUAL ANIMAL HISTOLOGIC FINDINGS ................................................................................................. DRUG: T - 7 4 8 5 FATE: I n t e r i m s a c r i f i c e GROUP: 4M __________-___-----.__________SEX_: M_ALE________-.-.-- ANIMAL ID: 7647 7649 765 1 7653 LYMPH NWES, MANDIBULAR N N N N LYMPH NWES, MESENTERIC N N N N MAMMARY GLAND N N N N PANCREAS N N N N PARATHYROID N N U N PITUITARY GLAND N N N N PROSTATE GLAND N N N N SALIVARY GLAND, HANDIB N N N N SCIATIC NERVE N N N N SEMINAL VESICLES N N N N SKELETAL MUSCLE N N N N SM INTESTINE, D U W E N W N N N N SM INTESTINE, ILEUM N N N N SM INTESTINE, JEJUNUM N N N N SPINAL CORD, CERVICAL N N N N SPINAL CORD, LUMBAR N N N N SPINAL CORD, THORACIC N N N N SPLEEN N N N N See Reparts Code T a b l e f a r Symbol D e f i n i t i o n s PRIMEDICA REDFIELD S T W Y NUMBER 132-007 Page 125 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ANIMAL ID: STOMACH, FORESTOMACH STOMACH, GLANDULAR TESTES THYMUS THYROID TONGUE TRACHEA URINARY BLADDER ZYMEALS GLAND 7647 N N N N N N N N N 7649 N N N N N N N N N 765 1 N N N N N N N N N 7653 N N N N N N N N N See Reports C o d e Table f o r Synbol D e f i n i t i o.n s PRIMEDICA REDFIELD S T W Y NUMBER 132-007 Page 126 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ANIMAL ID: ADRENAL GLANDS AORTA BONE MARRCU (STERNUM) BRAIN EPIDIDYMIDES ESOPHAGUS EYES UITH OPTIC NERVE FEMUR U/ ARTIC SURFACE HARDERIAN GLAND HEART KIDNEYS LACRIMAL GLAND LG INTESTINE, CECUM LG INTESTINE, COLON LG INTESTINE, RECTUM LIVER SUBACUTE INFLAMHATIW LUNGS YITH BRONCHI LYMPH W E S , MANDIBULAR 7655 N N N N N N N N N N N N N N N <1> N N 7657 N N N N N N N N N N N N N N N N N N _________________.--------.-.---------------.----- S e e R e p o r t s C o d e T a b l e f o r S-1 Definitions PRIMEDICA REDFIELD STUDY NUMBER 132-007 .- Page 127 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ANIMAL ID: LYMPH NODES, MESENTERIC HEMORRHAGE MAMMARY GLAND PANCREAS PARATHYROID PITUITARY GLAND PROSTATE GLAND SALIVARY GLAND, MANDIB SCIATIC NERVE SEMINAL VESICLES SKELETAL MUSCLE SM INTESTINE, DUODENUU SM INTESTINE, ILEUM SM INTESTINE, JEJUNUM SPINAL CORD, CERVICAL SPINAL CORD, LUMEAR SPINAL CORD, THORACIC SPLEEN STOMACH, FORESTOMACH 7655 N N N N N N N N N N N N N N N N N N 7657 2 N N N N N N N N N N N N N N N N N See Reports Code Table for Synbol D e f i n i t i o n s PRIMEDICA REDFIELD STUDY NUMBER 132-007 Page 128 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 STOMACH, GLANDULAR TESTES THYMUS THYROID TONGUE TRACHEA URINARY BLADDER ZYMBALS GLAND N N N N N N N N N N N N N N N N ___________________-___________________ See R e p o r t s C o d e T a b l e f o r Symbol D e f i n i t i o n s P R l M E D l C A REOFIELD STUDY N W B E R 132-007 Page 129 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ANIMAL ID: ADRENAL GLANDS AORTA BONE H A R R W (STERNUM) BRAIN CERVIX ESOPHAGUS EYES WITH OPTIC NERVE FEMUR W/ ARTIC SURFACE HARDERIAN GLAND HEART KIDNEYS MINERALIZATION LACRIMAL GLAND LG INTESTINE, CECUM LG INTESTINE, COLON LG INTESTINE, RECTUM LIVER SUBACUTE 1NFLA.FIFIATION LUNGS WITH BRONCHI INFLAMCIATlON 75 70 N N N N N N N N N N N N N N N 7572 N N N N N N N N N N N N N N N 75 76 N N N N N N N N N N 7576 N N N N N N N N N N <2>L N N N N <l>l N N N N <1> <l> < l > <l> N N <2> (1) See Reports Code T a b l e f o r S y n b l D e f i n i t i o n s PRIMEDICA REDFIELD STUDY NUMBER 132-007 Page 130 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ................................................................................................. _____I_ND_IV_IDU_AL_A_NI_MA-L _HI-S-TO_LO_GI_C _FI_ND_ING_S _______________ DRUG: 7 - 7 4 8 5 FATE: I n t e r i m s a c r i f i c e GROUP: 1 F . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S.E.X.:. .F.E.M. .A.LE ANIMAL ID: 7570 75 72 757 4 75 76 LYMPH NOOES, MANDIBULAR N N N N LYMPH NODES, MESENTERIC N N N N MAMMARY GLAND N N N N OVARIES N N N N OVIDUCTS N N N N PANCREAS SUBACUTE INFLAlWATION N N N (1) PARATHYROID N N N N PITUITARY GLAND N N N N SALIVARY GLAND, MANDIB N N N N SCIATIC NERVE N N N N SKELETAL MUSCLE N N N N SM INTESTINE, DUODENUM N N N N SM INTESTINE, ILEUM SM INTESTINE, JEJUNUM N N N N N N N N SPINAL CORD, CERVICAL N N N N SPINAL CORD, LUMBAR N N N N SPINAL CORD, THORACIC N N N N SPLEEN N N N N ________________.___------------------------------ See Reports Code Table f o r S-1 Definitions PRIMEDICA REDFIELD STUDY NUMBER 132-007 Page 131 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ANIMAL ID: STWACH, FORESTOMACH STWACH, GLANDULAR . THYMUS HEMORRHAGE THYROID TONGUE TRACHEA URINARY BLADDER UTERUS HORNS- DILATED VAG I NA ZYMEALS GLAND 7570 N N N N N N N N N N 7572 N N N N N N N 11 N N 7574 N N 1 N N N N 2L N N 75 76 N N N N N N N N N N __________________._-----.--.----.--.----.-.------- See R e p o r t s C o d e T a b l e f o r S y n b o l D e f i n i t i o n s PRIMEDICA REDFIELD STUDY NUMEER 132-007 Page 132 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ANIMAL ID: ADRENAL GLANDS AORTA BONE MARROV (STERNUM) BRAIN CERVIX ESOPHAGUS EYES U I T H OPTIC NERVE FEMUR U/ ARTIC SURFACE HARDERIAN GLAND HEART KIDNEYS MINERALIZATION LACRIMAL GLAND LG INTESTINE, CECUM LE INTESTINE, COLON LG INTESTINE, RECTUM LIVER SUBACUTE INFLAMMATION LUNGS U I T H BRONCHI 7 578 N N N N N N N N N N 7580 N N N N N N N N N N 7582 N N N N N N N N N N 7584 N N N N N N N N N N <2>1 <2>1 < 1 > I N N N N N N N N N N N N <l>l N N N N <l> <l> <2> <1> N N N N S e e R e p o r t s C o d e Table f o r S-1 Definitions PRIMEDICA REDFIELD STUDY NUMBER 132-007 Page 133 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ANIMAL ID: LYMPH NODES, MANDIBULAR LYMPH NCOES, MESENTERIC MAMMARY GLAND OVARIES OVIDUCTS PANCREAS PARATHYROID PITUITARY GLAND SALIVARY GLAND, MANDIB SCIATIC NERVE SKELETAL MUSCLE SM INTESTINE, DUOOENUM SM INTESTINE, ILEUM SM INTESTINE, JEJUNUM SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR SPINAL CORD, THORACIC SPLEEN 757a N N N N N N N N N N N N N N N N N N 7580 N N N N N N N N N N N N N N N N N N 7582 N N N N N N U N N N N N N N N NN N 7584 N N N N N N U N N N N N N N N N N N ____________----.--_____________________-- See Reports Cade T a b l e f o r S y h o l D e f i n i t i o n s PRIMEDICA REDFIELD STUDY NUMBER 132-007 Page 134 A 28-DayOral Toxicity Study in Sprague-DawleyRats Study Number: 132-007 STWCH, FORESTWCH STOMACH, GLANDULAR THYMUS THYROID TONGUE TRACHEA URINARY BLADDER UTERUS HORNS- DILATED VAG INA ZYMBALS GLAND N N N n N N N N N N N N N N N N N N N N N N N N N N N N N N N 31 N N N N N N N N See Reports Code Table for Symbol Definitions PRIMEDICA REDFIELD STUDY N M B E R 132-007 Page 135 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ................................................................................................. _____I_ND_IV_ID_UA_L -AN-I_MA_L _HI_ST.OL_OG_IC--F-IN-D-I-NG-S-------------------------- DRUG: 1-7405 FATE: I n t e r i m s a c r i f i c e CRCUP: 1 F . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S.E.X.:. .F.E.M. .A.LE ANIMAL ID: 7586 7588 ADRENAL GtANDS N N AORTA N N BONE HARROU (STERNUM) N N BRAI N N N CERVIX U N ESOPHAGUS N N EYES U I T H OPTIC NERVE N N FEMUR U/ ARTIC SURFACE N N HARDERIAN GLAND N N HEART N N KIDNEYS M INERALlU T I O N TUBULAR DEGENERATION <2>I <2>I 11 LACRIMAL GLAND N N LC INTESTINE, CECUM N N LG INTESTINE, COLON N N LG INTESTINE, RECTUM N N LIVER SUBACUTE INFLAMXATION N <l> LUNGS UITH BRONCHI N N Page 136 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ................................................................................................. _____I_ND_IV_IDU_A-L _AN_IM_AL_H_IS_TO-LO-G-I-C-F-I-N-DI-N.G.S-------.----------------- DRUG: T-7485 FATE: I n t e r i m s a c r i f i c e GROUP: 1 F ____________________-------S-EX-: -FE-MA-LE--.--------------- ANIMAL ID: 7586 naa LYMPH NODES, MANDIBULAR N N LYMPH NODES, MESENTERIC HISTlOCYTOSlS ElAEIMARY GLAND . N 3 N N OVARIES N N OVIDUCTS N N PANCREAS N N PARATHYROID U N PITUITARY GLAND N N SALIVARY GLAND, MANDIB N N SCIATIC NERVE N N SKELETAL MUSCLE N N SM INTESTINE, DUOOENM N N SH INTESTINE, ILEUM N N SW INTESTINE, JEJUNUM N N SPINAL CORD, CERVICAL N N SPINAL CORD, LUMBAR N N SPINAL CORD, THORACIC N N SPLEEN N N See Reports Code T a b l e for Symbol O e f i n i t i o n r PRIMEDICA REDFIELD STUDY NUMBER 132-007 Page 137 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 S T W C H , FORESTOMACH STOMACH, GLANDULAR THYMUS THYROID TONGUE TRACHEA URINARY BLADDER UTERUS HORNS- DILATED VAGINA ZYMEALS GLAND N N N N N N u N N N N N N N 21 21 N N n N Page 138 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ANIMAL ID: ADRENAL GLANDS AORTA BONE MARROU (STERNUM) BRAIN CERVIX ESOPHAGUS MUSCULAR TUNIC- DEGENERATION EYES U I T H OPTIC NERVE FEMUR U/ ARTIC SURFACE HARDERIAN GLAND SUBACUTE INFLAMMATION HEART KIDNEYS M INERALl ZATION TUBULAR DEGENERATION LACRIMAL GLAND LG INTESTINE, CECUM LG INTESTINE, COLON LG INTESTINE, RECTUM LIVER SUBACUTE INFLAMMATION 7640 N N N N N N N N N N 7642 N N N N N (1) N N N N 7644 N N N N N N 7646 N N N N N N N N N N N (1)L N N <2> I 3L N N N N <l> <2> I N N N N <l> I 3L N N N N N <l>I N N N N <l> _________---------__-------------------------------- S e e Reports Code T a b l e f o r S-1 Definitions PRIMEDICA REDFIELD STUDY NUMBER 132-007 Page 139 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 DRUG: ~ - 7 4 8 5 FATE: Interim sacrifice ANIMAL ID: LUNGS WITH BRONCHI INFLAMMATION LYMPH NODES, MANDIBULAR LYMPH NODES, MESENTERIC MAMMARY GLAND OVARIES OVIDUCTS PANCREAS PARATHYROID PITUITARY GLAND SALIVARY GLAND, MANDIE SCIATIC NERVE SKELETAL MUSCLE SM INTESTINE, DIJWENUM SM INTESTINE, ILEUM SM INTESTINE, JEJUNUM SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR SPINAL CORD, THORACIC 7640 7642 7644 7646 N N N (1) N N N N N N N N N N N N N N N N N N N N N N N N N N U U N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N -________-----.---..____________________------ See Reports Code Table f o r S W l Definitions PRIMEDICA REDFIELD STUDY NUMEER 132-OD7 Page 140 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ANIMAL ID: SPLEEN STOMACH, FORESTOnACH STOMACH, GLANDULAR THYMUS THYROID TONGUE TRACHEA URINARY BLADDER UTERUS HORNS- DILATED VAG INA ZYWALS GLAND 7640 N N N N N N N N 21 N N 7642 N N N N N N N N N N N 7644 N N N N N N N N N N N 7646 N N N N N N N N N N N ---------------_--_-------------.------------------------- See Reports Code T a b l e f o r S-1 Definitions PRIMEDICA REDFIELD STUDY NUMBER 132-007 Page 141 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ADRENAL GLANDS AORTA BONE MARROW (STERNUM) BRAI N CERVIX ESOPHAGUS MUSCULAR TUNIC- DEGENERATION EYES U I T H OPTIC NERVE FEMUR U/ ARTIC SURFACE HARDERIAN GLAND HEART KIDNEYS MINERALIUTION LACRIMAL GLAND LG INTESTINE, CECUM LG INTESTINE, COLON LG INTESTINE, RECTUM LIVER SUBACUTE INFLAMMATION LUNGS U I T H BRONCHI N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N <2> - <1> N N N N ____________________-----------------.-----.---.-- See Reports Code Table for Symbol D e f i n i t i o n s PRIMEDICA REDFIELD STUDY NUMEER 132-007 Page 142 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 DRUG: T-7485 FATE: I n t e r i m s a c r i f i c e ANIMAL ID: LYMPH NOOES, MANDIBULAR LYMPH NOOES, MESENTERIC MAMMARY GLAND OVAR I ES OVIDUCTS PANCREAS '8 HYROlD PITUITARY GLAND PARS NERVOSA- ECTOPIC EPITHELIAL REST SALIVARY GLAND, MANDIB S C I A T I C NERVE SKELETAL MUSCLE SM INTESTINE, DUOOENUM SM INTESTINE, ILEUM SM I N T E S T I Y E , JEJUNUM SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR SPINAL CORD, THORACIC SPLEEN 7648 N N N N N N U N N N N N N N N N N N 7650 N N N N N N U P N N N N N N N N N N 7652 N N N N N N N N N N N N N N N N N N GROUP: 4F SEX: FEMALE 7654 N N N N N N N N N N N N N N N N N N ____________.__________________________.--- See Reports Code T a b l e for Synbol D e f i n i t i o n s PRIMEDICA REDFIELD STUDY NUHBER 132-007 Page 143 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 STOFIACH, FORESTWACH STOEIACH, GLANDULAR . THYMUS HEMORRHAGE THYROID TONGUE TRACHEA URINARY BLADDER UTERUS HORNS- DILATED VAG INA ZYMBALS GLAND N N N N N N N N N N N 1 N N N N N N N N N N N N N N N N N N 21 21 N N N N N N N N ___.________-_______--.----..---.------------------ See Reports Code Table for S y n b l D e f i n i t i o n s PRIMEDICA REDFIELD STUDY NUMBER 132-007 Page 144 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ________-------_--------------------------.----------------- INDIVIDUAL ANIMAL HISTOLOGIC FINDINGS ................................................................................................. DRUG: f-7485 FATE: Interim sacrifice GRCUP: 4F . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S.E.X.:. .F.E. M. A. .LE ANIMAL ID: 7656 7658 ADRENAL GLANDS N N AORTA N N BONE MRRW (STERNUM) N N BRAIN N N CERVIX N N ESOPHAGUS N N EYES UITH OPTIC NERVE N N FEMUR U/ ARTIC SURFACE N N HARDERIAN GLAND N N HEART N N KIDNEYS MINERALIZATION <2> I <2>1 LACRIMAL GLAND N N LG INTESTINE, CECUM N N LG I N T E S T I N E , COLON N N LG INTESTINE, RECTUM N N LIVER SUBACIJTE INFLAMMATION <l> <l> LUNGS UITH BRONCHI INFLAMMATION N <l> Page 145 A 28-DayOral Toxicity Study in Sprague-DawleyRats Study Number: 132-007 ___-_--___---------------------.----.-----.--------------- _____I_ND_IV_ID_UA_L .A_NI_MAL--H_IS_TO_LO_GI-C_FI_ND_IN_GS___________.____- DRUG: 1-7485 FATE: Interim sacrifice GRWP: 4F . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S.E.X.:. .F.E.M.A.L.E. . ANIMAL ID: 7656 7658 LYMPH NWES, MANDIBULAR N N LYMPH NWES, MESENTERIC N N MAMMARY GLAND N N OVARIES N N OVIDUCTS N N PANCREAS N N PARATHYROID N N PITUITARY GLAND N N .`I GLAND, HANDIB N N SCIATIC NERVE N N SKELETAL MUSCLE N N SM INTESTINE, D U W E N U N N N S I I INTESTINE, ILEUM N N SM INTESTINE, JEJUNUM N N SPINAL CORD, CERVICAL N N SPINAL CORD, LUMBAR N N SPINAL CORD, THORACIC N N SPLEEN N N ................................................................................................. See Reports Code Table for S y n b l Definitions PRIMEDICA REDFIELD STUDY NUMBER 132-007 Page 146 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ____-__---------____---.---.------.------------------------- INDIVIDUAL ANIMAL HISTOLOGIC FINDINGS STOMACH, FORESTOMACH STOMACH, GLANDULAR THYWS HEMORRHAGE THYROID TONGUE TRACHEA URINARY BLADDER UTERUS VAGINA ZYMEALS GLAND N N N N N 1 N N N N N N N N N N N N N N Page 147 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ANIMAL ID: ADRENAL GLANDS AORTA BONE MARROU (STERNUM) BRAIN EPIDIDYMIDES ESOPHAGUS * t E S WITH OPTIC NERVE FEMUR W/ ARTIC SURFACE HARDERIAN GLAND HEART KIDNEYS CYST(S) TUBULAR DEGENERATION LACRIMAL GLAND LG INTESTINE, CECUM LG INTESTINE, COLON LG INTESTINE, RECTUM LIVER SUBACUTE INFLAMMATION 7589 N N N N N N N N N N N N N N N <2> 7591 N N N N N N N N N N 2L 7593 N N N N N N N N N N N N N N N N N N N <l> c2> 7595 N N N N N N N N N N (1)L N N N N N See Reports C o d e T a b l e far S-1 Definition8 PRIMEDICA REDFIELD STUDY NUMBER 132-007 Page 148 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 DRUG: T-7405 FATE: Terminal sacrifice ANIMAL ID: LUNGS WITH BRONCHI LYMPH NWES, MANDIBULAR LYMPH NWES, MESENTERIC MAMMARY GLAND PANCREAS PARATHYROID PITUITARY GLAND PROSTATE GLAND SALIVARY GLAND, HANDIB SCIATIC NERVE SEMINAL VESICLES SKELETAL MUSCLE SI! INTESTINE, DVOOENLAI SI4 INTESTINE, ILEUM SM INTESTINE, JEJUNUM SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR SPINAL CORD, THORACIC GROUP: 1M SEX: MALE -------_________ 7589 7591 7593 7595 N N N N N N N N N N N N N N N N N N N N N U N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N See Reports Code Tabla for S y n h l Definitions PRIMEDICA REDFIELD STUOY NUMBER 132-007 Page 149 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ................................................................................................. _____I-N-DI_VI-D-UA-L-A_NI_MA_L _HI-ST-O-L-OG_IC_F_IN_DI_NG_S ______________-- DRUG: 1-7485 FATE: T e r m i n a l s a c r i f i c e GROUP: 1H ________________--_______SE_X: _MALE___________ ANIMAL ID: 7589 mi 7593 7595 SPLEEN N N N N STOFUCH. FORESTOHACH N N N N STOMACH, GLANDULAR N N N N TESTES N N N N Tnywus HEMORRHAGE N N 1 1 THYROID N N N N TONGUE N N N N TRACHEA N N N N .ARY BLADDER N N N N ZYMBALS GLAND N N N N ____.__________________________________ See Reports Code Table for Synhl D e f i n i t i o n s PRIMEDICA REDFIELD STUDY NUMBER 132-001 Page 150 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ADRENAL GLANDS N AORTA N BONE MARROV (STERNUM) N BRA I N N EPIDIDYMIDES N ESOPHAGUS N ;S U I T H OPTIC NERVE N FEMUR U/ ARTIC SURFACE N HARDERIAN GLAND N HEART N KIDNEYS N LACRIMAL GLAND N LG INTESTINE, CECUM N LG INTESTINE, COLON N L t INTESTINE, RECTUM N LIVER SUBACUTE INFLAMMATION LUNGS U I T H BRONCHI N LYMPH NOOES, MANDIBULAR N Page 151 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 LYMPH N W E S , MESENTERIC N MAMMARY GLAND N PANCREAS N PARATHYROID . N PITUITARY GLAND N PROSTATE GLAND N SALIVARY GLAND, MANDIE N SCIATIC NERVE N iCLE N SM INTESTINE, DUODENUH N SM INTESTINE, ILEUM N SM INTESTINE, JEJUNUM N SPINAL CORD, CERVICAL N SPINAL CORD, LUMEAR N SPINAL CORD, THORACIC N SPLEEN N S T W C H , FORESTOMACH N ____________-___--_____________________ See Reports Code Table for S-1 Definitions PRIMEDICA REDFIELD STUDY N W E E R 132-007 Page 152 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 STOMACH, GLANDULAR N TESTES N THYMUS N THYROID N TONGUE N TRACHEA N URINARY BLADDER N ZYMBALS GLAND N Page 153 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ANIMAL ID: ADRENAL GLANDS AORTA BONE M R R W (STERNUM) BRA IN EPIDIDYMIDES GRANULOPU(S) ESOPHAGUS EYES WITH OPTIC NERVE FEMUR W/ ARTIC SURFACE HARDERIAN GLAND HEART KIDNEYS HYDRONEPHROSIS TUBULAR DEGENERATION LACRIMAL GLAND LG INTESTINE, CECUM LG INTESTINE, COLON LG INTESTINE, R E C T W LIVER SUBACUTE INFLAMMATION NECROSIS 7659 7661 7663 7665 N N N N N N N N N N N N N N N N N N N ZL N N N N N N N N N N N N N N N N N N N N N N 1L 1L N N N N N N N N N N N N N N N N <2> <l> <2> <1> <2> ______.__._____________________________ See Reports Code Table for S-1 Definitions PRIMEDICA REDFIELD STUDY NUMBER 132-007 Page 154 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ................................................................................................. ______IN_DI_VI_DU_AL_A_NI_MA_L _HI_ST-OL_OG_I_C F_IN_D_IN_GS________________- DRUG: 1-7485 FATE: Terminal sacrifice GROUP: 4M ____________-_-_-----------------S-EX-: -MA-LE------.----------- ANIMAL ID: 7659 7661 7663 7665 LUNGS UITH BRONCHI INFLAMMATION N N N (1) LYMPH NODES, MANDIBULAR N N N N LYMPH NWES, MESENTERIC N N N N MAWARY GLAND N N N N PANCREAS N N N N PARATHYROID N N U N PITUITARY GLAND N N N N PROSTATE GLAND N N N N SALIVARY GLAND, RAND16 N N N N SCIATIC NERVE N N N N SEMINAL VESICLES N N N N SKELETAL MUSCLE N N N N SM INTESTINE, DUODENUM N N N N St4 INTESTINE, ILEUM N N N N SM INTESTINE, JEJUNUM N N N N SPINAL CORD, CERVICAL N N N N SPINAL CORD, LUMEAR N N N N SPINAL CORD, THORACIC N N N N ________________.______________________ See Reports Code Table for S@l D e f i n i t i m PRIMEDICA REDFIELD STUDY NUMBER 132-007 Page 155 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 SPLEEN STOnACH, FORESTWCH STOEIACH, GLANDULAR TESTES TUBULAR DEGENERATION THYMUS THYROID TONGUE TRACHEA 4RY BLADDER ZYMBALS GLAND N N N N N N N N N N N N N N N 3L N N N N N N N N N N N N N N N N N N N N N N N N Page 156 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ADRENAL GLANDS N AORTA N BONE HARROU (STERNUM) N BRAIN N EPIDIDYMIDES N E SOP HA GUS N EYES WITH OPTIC NERVE N FEMUR W/ ARTIC SURFACE N HARDERIAN GLAND N ART N KIDNEYS N LACRIMAL GLAND N LG INTESTINE, CECVW N LG INTESTINE, COLON N LC INTESTINE, RECTUM N LIVER SUBACUTE INFLAMMATION LUNGS WITH BRONCHI N LYMPH NODES, MANDIBULAR N ___________.___.________________________-- See R e p o r t s Code T a b l e f o r S@oL D e f i n i t i o n s PRIMEDICA REDFIELD STUDY NUMBER 132-007 Page 157 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 LYMPH NWES, MESENTERIC N MAMMARY GLAND N PANCREAS N PARATHYROID PITUITARY GLAND PROSTATE GLAND SALIVARY GLAND, MANDIB SCIATIC NERVE N SEMINAL VESICLES N SKELETAL MUSCLE N SM INTESTINE, D U W E N U M N SM INTESTINE, ILEUM N SM INTESTINE, JEJUNUM N SPINAL CORD, CERVICAL N SPINAL CORD, LUMBAR N SPINAL CORD, THORACIC N SPLEEN N STCMACH, FORESTOMACH N See Reports Code Table for Sylnbol Definitions PRIMEDICA REDFIELD S T M Y NUMBER 132-007 Page 158 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 DRUG: 1-7485 FATE: T e r m i n a l s a c r i f i c e __________------------------------.------------- ANIMAL ID: STCMACH, GLANDULAR TESTES THYMUS THYROID TONGUE TRACHEA URINARY BLADDER ZYMBALS GLAND _________.__---_________________________ S e e R e p o r t s C o d e T a b l e for S y n h l Definitions P R I M E D I C A R E D F I E L D S T M Y NUMBER 132-007 Page 159 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ADRENAL GLANDS AORTA BONE MARRCU (STERNUM) BRAIN CERVIX ESOPHAGUS EYES UITH OPTIC NERVE FEMUR U/ ARTlC SURFACE HARDERIAN GLAND SUBACUTE INFLAMMATION HEART KIDNEYS MINERALIZATION LACRIMAL GLAND LG INTESTINE, C E M LG INTESTINE, COLON LG INTESTINE, RECTUM LIVER SUBACUTE INFLAMMATION LUNGS UITH BRONCHI N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N - N N N (2)L N N N N N N 21 21 N N N N N N N N N N N N N N N N N N N N ____________--___-__--------------.------.---.----- S e e R e p o r t s Code T a b l e f o r S-l Definitions PRIMEDICA REDFIELD STUDY NUMEER 132-007 Page 160 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ANIMAL ID: LYMPH N W E S , MANDIBULAR LYMPH NWES, MESENTERIC HEMORRHAGE MAMMARY GLAND . OVARIES OVIDUCTS PANCREAS PARATHYROID PITUITARY GLAND SALIVARY GLAND, MANDIE SCIATIC NERVE SKELETAL MUSCLE SM INTESTINE, DUWENUM SM INTESTINE, ILEUM SI( INTESTINE, JEJUNUM SPINAL CORD, CERVICAL SPINAL CMID, LUMBAR SPINAL CORD, THCRACIC SPLEEN 7590 7592 75 96 7596 N N N N N N N 1 N U N N N N N N N N N N N N N N N N N U N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N See Reports Code Table for Symbol Definitiona PRIMEDICA REDFIELD S T W Y NUMBER 132-007 Page 161 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 STOMACH, FORESTWACH STOMACH, GLANDULAR THYMUS THYROID TONCUE TRACHEA URINARY BLADDER UTERUS HORNS- DILATED VAGINA ZYMBALS GLAND N N N N N N N N N N N N N N N N N N N N N N N N 21 N N N N N N N N See R e p o r t s C o d e T a b l e f o r S&ml D e f i n i t i o n s PRIHEDICA REDFIELD STUDY NUMBER 132-007 Page 162 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ADRENAL GLANDS N AORTA N BONE MARRW (STERNUM) N BRAIN CERVIX ESOPHAGUS EYES WITH OPTIC NERVE FEMUR U/ ARTIC SURFACE HARDERIAN GLAND HEART KIDNEYS LACRIMAL GLAND LG INTESTINE, CECUM LG INTESTINE, COLON LG INTESTINE, RECTUM LIVER SUBACUTE INFLAJMATION LUNGS W I T H BRONCHI N LYMPH NOOES, MANDIBULAR N Page 163 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 LYMPH NWES, MESENTERIC N MAMMARY GLAND N OVARIES N OVIDUCTS N PANCREAS N PARATHYROID U :ITARY GLAND N SALIVARY GLAND, HANOIB N SCIATIC NERVE N SKELETAL MUSCLE N SM INTESTINE, DUOOENUn N SM INTESTINE, ILEUM N SM INTESTINE, J E J U N W N SPINAL CORD, CERVICAL N SPINAL CORD, LWEAR N SPINAL CORD, THORACIC N SPLEEN N STOIUCH, FORESTCMACH N S e e Reports C o d e T a b l e f o r S-1 Definitions PRIMEDICA REDFIELD STUDY NUMBER 132-OD7 Page 164 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 STOMACH, GLANDULAR N THYMUS N THYROID N TONGUE N TRACHEA N M Y BLADDER N UTERUS N VAGINA N ZYMBALS GLAND N __________--_--_.-__------.----------------------..-.. See Reports Code Table for S-1 Definitions PRIMEDICA REDFIELD STUDY NUMBER 132-007 Page 165 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ANIMAL ID: ADRENAL GLANDS AORTA BONE MARROV (STERNUM) BRAIN CERVIX ESOPHAGUS EYES WITH OPTIC NERVE FEMUR U/ ARTIC SURFACE HARDERIAN GLAND HEART KIDNEYS HVDRONEPHROSIS M i NERALIU T ION TUBULAR DEGENERATION LACRIMAL GLAND Lt INTESTINE, CECUM LG INTESTINE, COLW LG INTESTINE, RECTUM LIVER SUBACUTE INFLAMMATION 7660 N N N N N N N N N N 21 7662 N N N N N N N N N N N N N N N N N N N N <1> 7664 N N N N N N N N N N N N N N N 7666 N N N N N N N N N N 11 21 31 N N N N <l> <l> _____________.----__.--.---------------------------- S e e R e p o r t s Code T a b l e f o r S-1 Definitions PRIMEDICA REDFIELD STUDY NUM8ER 132-007 Page 166 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ANIHAL ID: LUNGS WITH BRONCHI LYMPH N W E S , MANDIBULAR LYMPH NOOES, MESENTERIC MAMMARY GLAND OVARIES OVIDUCTS PANCREAS PARATHYROID . PITUITARY GLAND SALIVARY GLAND, MANDIE SCIATIC NERVE SKELETAL W S C L E SM INTESTINE, DWDENUM SM INTESTINE, ILEUM St4 I N E S T INE, JEJUNUM SPINAL CORD, CERVICAL SPINAL CORD, LUMBAR SPINAL CORD, THORACIC 7660 7662 7664 7666 N N N N N N N N N N N N N N N N N N N N N N N N N N N N N U N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N See Reports Code Table for S ) d o l Definitions PRIMEDICA REDFIELD STUDY NUMBER 132-007 Page 167 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 SPLEEN STOMACH, FORESTWACH STOEUCH, GLANDULAR THYMUS THYROID TONGUE TRACHEA URINARY BLADDER UTERUS HORNS- DILATED ZYMBALS GLAND N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N 31 21 N N N N N N N N __________-___________________________ See Reports Code Table for Synbol Definitions PRIMEDICA REDFIELD STUDY NUMEER 132-OD7 Page 168 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 AORENAL GLANDS N AORTA N BONE MARRW (STERNUM) N BRAIN N CERVIX N ESOPHAGUS N EYES YlTH OPTIC NERVE N "JR W/ ARTIC SURFACE N HARDERIAN GLAND N HEART N KIDNEYS MINERALIZATION 11 LACRIMAL GLAND N LG INTESTINE, CECUM N LG INTESTINE, COLON N LG INTESTINE, RECTUM N LIVER SUBACUTE INFLAMMATION LUNGS WITH BRONCHI N ____________-__.____-.----..------------------------ See R e p o r t s Code T a b l e f o r S y n h l D e f i n i t i o n s P R I M E D I U REDFIELD STUDY NUMBER 132-007 Page 169 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 LYMPH NODES, MANDIBULAR N LYMPH NODES, MESENTERIC N MAMMARY GLAND N OVARIES N OVIDUCTS N PANCREAS N PARATHYROID N PITUITARY GLAND N SALIVARY GLAND, MANDIB N SCIATIC NERVE N SKELETAL MUSCLE N SM INTESTINE, DUWENUM N SM INTESTINE, ILEUM N SM INTESTINE, JEJUNUM N SPINAL CORD, CERVICAL N SPINAL CORD, LWEAR N SPINAL CORD, THORACIC N SPLEEN N ................................................................................................. See R e p o r t s Code T a b l e f o r S y n t u l D e f i n i t i o n s PRIMEDICA REDFIELD STUDY NUMBER 132-OD7 . Page 170 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 STOEUCH, FORESTOEUCH N STOMACH, GLAMDULAR N THYMUS N THYROID n TONGUE N TRACHEA N URINARY BLADDER N UTERUS N VAG I MA N ZYMEALS GLAND N S e e R e p o r t s C o d e T a b l e f o r S-1 Definitions P R I M E D I U REDFIELD STUDY NUMEER 132-007 Page 171 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 IV. Gross & MicroscopicCorrelation of Findings Page 172 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 No Gross Observations f o r any animal i n t h i s group Page 173 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 Animal ID: 7607 Animal Fate: Interim sacrifice Reference t o Necropsy Record: TESTES - RIGHT, SMALL Pathologist: JMP Related Histopathology: TESTES - TUBULAR DEGENERATION __________-.________----------------.------------- P R I K D I U REDFIELD STUDY NUMBER 132-007 Page 174 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 _______-_-----------.----.--------------.---------------- ____G_RO_SS_& _MI_CR_OS-CO-P-IC--C-OR-R-E-LA-T-IO-N--OF--FI-N-D-IN-G-S--------------.------ DRUG: T-7485 SEX: MALE GROUP: 4 : No Gross Observations for any animal i n t h i s group Page 175 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 _________------------------------------------------- . . . . . . . . . . . . . .G. .R. .O. .S.S. . . .&. . .M. .I.C. .R. .O.S. .C. .O. .P.I. .C. . .C. .O. .R.R. .E. .L. .A.T. .I. .O.N. . . .O.F. . . .F. .I.N. .D. .I.N. .G. .S. . . . . . . . . . . DRUG: 1-7485 SEX: FEMALE GROUP: 1: No Gross Observations f o r any animal i n t h i s group Page 176 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 __________---------------------------------.--------------- . . . . . . . . . . . . . .G. .R. .O. S. .S. . . .&. . .M. .I.C. .R. .O.S. .C. .O.P. .I. .C. . .C. .O. .R.R. .E. .L. .A.T. .I. .O.N. . . .O.F. . . .F. I. .N. .D. .I.N. .G. .S. . . . . . . . . . . DRUG: T-7485 SEX: FEMALE GROUP: 4: No Gross Observations for any a n i m l in t h i s group Page 177 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 __________----------------.------------------------- _____GR_OS_S _& _MI_CR-OS-C-O.P-I-C-C-O-R_RE_LA_TI_ON_O_F _FI_ND_IN_GS_._________------. DRUG: T-7485 SEX: MALE GROUP: 1: N o G r o s s Observations f o r any animal in t h i s group Page 178 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 No Gross Observations for any animal in this group ________._._________..-----.-.---.-------..----------- PRIMEDICA REDFIELD STLRY NUMBER 132-007 Page 179 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 No Gross Observations for any animal i n t h i s group Page 180 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 no Gross Observations f o r any animal in t h i s group Page 181 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 V. Comment Report Page 182 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ___________--------------------------------------------. COMMENT REPORT ................................................................................................. DRUG: T-7485 . . .SE.X.:. . M. .A.L.E. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .G.R.O.U.P.:. .1:. . . Animal ID: 7575 Animal Fate: Interim sacrifice Pathologist: .IMP TISSUE COMMENTS: ADRENAL GLANDS - ADRENAL MEDULLAS NOT AVAILABLE FOR EVALUATION _____________________________________ Animal ID: 7577 Patholog ist : JMP Animal Fate: Interim sacrifice TISSUE COCIMENTS: - THYROID - SCANT SECTION AVAILABLE FOR EVALUATION PARATHYROID SCANT SECTION AVAILABLE FOR EVALUATION Page 183 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats No Comnents f o r any animal in t h i s group Study Number: 132-007 Page 184 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 ______._____________--------------------------- __________--C.O.M-M-E-NT--R-EP-O-R-T------------------.-.-..--.--...----- DRUG: T-74a5 . . S. E.X.:. . .H.A.L.E. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .G.R.O.U.P.:. .4.:. . A n i m a l I D : 7639 P a t h o l o g i s t : JHP Animal Fate: I n t e r i m s a c r i f i c e - TISSUE COMMENTS: LYMPH N W E S , MANDIBULAR SCANT SECTION AVAILABLE FOR EVALUATION - TISSUE C W E N T S : THYROID SCANT SECTION AVAILABLE FOR EVALUATION ................................................................................................. A n i m a l ID: 7649 P a t h o l o g i s t : JHP Animal Fate: I n t e r i m s a c r i f i c e - TISSUE C W E N T S : MAMMARY GLAND SCANT SECTION AVAILABLE FOR EVALUATION _______..-----_-_--_____________________--- A n i m a l ID: 7659 P a t h o l o g i s t : JHP Animal Fate: Terminal s a c r i f i c e - TISSUE COPVIENTS: ZYHBALS GLAND SCANT SECTION AVAILABLE FOR EVALUATION ________._.--....-._-.---.-..-------------.------------------ A n i m a l ID: 7665 P a t h o l o g i s t : JHP Animal Fate: Terminal sacrifice - TISSUE COMMENTS: ADRENAL GLANDS ADRENAL MEDULLAS NOT AVAILABLE FOR EVALUATION Page 185 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 - TISSUE COMMENTS: OVARIES ONE OVARY AVAILABLE FOR EVALUATION ................................................................................................. Animal ID: 7588 P a t h o l o g i s t : JRP Animal Fate: Interim s a c r i f i c e TISSUE COMMENTS: EYES UITH OPTIC NERVE - OPTIC NERVES NOT AVAILABLE FOR EVALUATION ___________________-__________________ PRIREDICA REDFIELD STUDY NUMBER 132-007 Page 186 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 Animal IO: 76446 Animal Fate: Interim s a c r i f i c e TISSUE COMMENTS: ESOPHAGUS - PARTIAL SECTION AVAILABLE FOR EVALUATION P a t h o l o g i s t : JMP ................................................................................................. Animal ID: 7660 P a t h o l o g i s t : JMP Animal Fate: Terminal s a c r i f i c e TISSUE COMMENTS: EYES UlTH OPTIC NERVE - ONE EYE AVAILABLE FOR EVALUATIUN Page 187 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 VI. Quality Assurance Statement Page 188 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 PATHOLOGY ASSOCIATES A CHARLES RIVER COMPANY Pathology Report A 28-Day Oral (Gavage) Toxicity Study of T-7485 in Sprague-Dawley Rats Primedica Redfield Protocol Number: 132-007 QUALITY ASSURANCE STATEMENT This histopathology project has been inspected and audited by the PAI Quality Assurance Unit (QAU) as required by the Good Laboratory Practice (GLP) regulations promulgated by the Organization for Economic Cooperation and Development (OECD). The pathology report is an accurate reflection of the recorded data. The following table is a record of the inspectiondaudits performed and reported by the QAU. Date of Inspection 1o/ 10100 11/21/00 11/21/00 06/29/01 07/25/01 Phase Inspected Date Findings Reported to PAI ManagementjStudy Pathologist Tissue Trimming Individual Animal Data Draft PathologyReport Final Pathology Report Amended Final Pathology Report 10110100 11/21/00 11/21/00 06/29/01 07/25/01 -Dorahe Dundee QualityAssurance Specialist 15 Worman's Mill Court, Suite I, Frederick, MD 21701 301.663.1 644 FAX: 301.663.8994 www.paicriver.com Page 189 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 4 INDIVIDUAL CLINICAL OBSERVATIONS Page 190 -0 a, (D cb pet | ! i PROTOCOL 132-007: A 28-DAY ORAL (GAVAGE) T O X I C I T Y STUDY O F T-7485 I N SPRAGUE-DAWLEY RATS 7570 7572 7514 7576 7578 7580 7582 7584 7586 7588 7590 7592 7594 7596 7598 SDi 22 i S D ( 28- 29) SD( 43 ) ~~ LOCALIZED ALOPECIA; LOCALIZED ALOPECIA, NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE NO ADVERSE NO ADVERSE NO ADVERSE FINDINGS FINDINGS FINDINGS FINDINGS LOCALIZED ALOPECIA, NO ADVERSE FINDINGS NO ADVERSE FINDINGS LIMBS LIMBS LIMBS PROTOCOL 132-007: A 28-DAY ORAL (GAVAGE) TOXICITY STUDY O F T - 7 4 8 5 I N SPRAGUE-DAWLEY RATS 7640 7642 . -. NO ADVERSE FINDINGS 7644 SD( 8 ) LOCALIZED ALOPECIA, LIMBS SD( 15 LOCALIZED ALOPECIA, LIMBS SD( 22 ) LOCALIZED ALOPECIA, LIMBS SD( 28- 2 9 ) LOCALIZED ALOPECIA, LIMBS 7646 NO ADVERSE FINDINGS 7648 NO ADVERSE FINDINGS 7650 NO ADVERSE FINDINGS 7652 NO ADVERSE FINDINGS 7654 NO ADVERSE FINDINGS 7656 SD( 8 1 LOCALIZED ALOPECIA, LIMBS SD( 15 LOCALIZED ALOPECIA, LIMBS SD( 2 2 ) LOCALIZED ALOPECIA, LIMBS SD( 28- 2 9 ) LOCALIZED ALOPECIA, LIMBS 7658 NO ADVERSE FINDINGS 7660 SD( 4 3 ) LOCALlZED ALOPECIA, LIMBS 7662 NO ADVERSE FINDINGS 7664 SD( 22 ) LOCALIZED ALOPECIA, LIMBS SU( 28 ) LOCALIZED ALOPECIA, LIMBS S D ( 36 ) LOCALIZED ALOPECIA, LIMBS SD( 42- 43) LOCALIZED ALOPECIA, LIMBS 7666 NO ADVERSE FINDINGS -7. 6. .6.8. . . . . . . . . . . . . . . . . . . . . . . . .N.O. .A.D.V.E.R.S.E. .F.I N. .D.I N. .G.S. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S D STUDY DAY A n i m a l s w i t h NO ADVERSE FINDINGS w e r e normal u n t i l t h e i r scheduled s a c r i f i c e . A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 5 INDIVIDUAL MOTOR ACTIVITY DATA Page 196 BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 TOTAL 154 155 160 156 112 119 165 153 129 114 137 150 160 180 172 141 105 166 162 131 157 44 113 112 64 141 104 164 21 71 24 11 59 6 158 5 5 2 16 15 10 166 549 614 517 550 105 590 990 TIME (SECONDS) SPENT IN MOVEMENT BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BMCK 5 BLOCK 6 TOTAL 259 255 2 64 255 294 331 296 191 184 146 194 254 249 319 164 219 129 258 216 116 263 26 117 114 95 211 99 231 11 62 17 9 61 4 186 1 3 1 14 6 3 112 652 840 61 1 825 1102 868 1473 TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 10 MINUTE PERIOD. 159 133 154 141 146 148 159 148 124 132 144 157 111 149 123 161 78 126 21 141 2 111 82 115 620 199 683 935 215 299 355 312 218 295 282 314 166 200 248 234 152 210 191 241 79 193 24 196 0 159 78 214 890 1356 1178 1637 --- NUMBER OF MOVEMENTS BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 TOTAL 149 143 123 141 129 146 135 164 133 152 137 145 138 142 111 122 134 151 120 150 160 131 120 71 e43 865 746 193 TIME (SECONDS) SPENT IN MOVEMENT BLOCK 1 2 92 416 313 345 9 BLOCK 2 267 349 312 311 (13 BLOCK 3 244 296 371 237 CD BLOCK 4 240 266 215 215 BLOCK 5 184 263 249 222 BLOCK 6 232 181 185 89 - _ _TO_T_A_L _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _1_4_59_ _ _ _ _1_7_71_ _ _ _ _1_64_5_ _ _ - - 1- 4- 1- 9- - - - - - - - - - - - - - - - - - - - - TOTAL SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 10 MINUTE PERIOD. NUMBER OF MOVEMENTS BLOCK 1 BWK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 TOTAL 167 136 150 159 145 180 141 158 151 153 143 137 152 139 136 143 132 142 117 151 72 54 132 131 129 138 114 76 104 128 68 45 127 108 63 145 113 7 126 151 0 0 139 3 18 147 35 10 98 129 8 0 65 1 6 169 0 4 134 125 458 372 765 541 497 922 535 397 730 837 TIME (SECONDS) SPENT IN MOVEMENT s BLOCK 1 288 340 241 236 324 320 305 320 338 355 .BLOCK 2 250 219 195 178 307 276 256 320 234 309 BLOCK 3 70 54 211 134 218 299 144 112 174 255 ((P D BLOCK 4 63 51 213 121 54 287 164 3 184 235 BLOCK 5 0 0 167 1 9 258 51 2 134 118 BLOCK 6 3 0 65 0 0 243 0 1 204 166 TOTAL 674 664 1092 670 912 1683 920 758 - 1- 2- 6- 8 - - ..- - - - 1 - 4- 3 - 8 - - TOTAL = SUM OF BMCKS; EACH BLOCK CONSISTS OF A 10 MINUTE PERIOD. NUMBER OF MOVEMENTS BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BU)CK 5 BLOCK 6 TOTAL 154 152 166 159 161 164 148 146 163 166 159 135 137 147 164 152 138 169 184 175 100 88 143 127 169 146 134 145 145 149 78 95 97 102 168 108 139 135 62 79 54 51 41 100 127 111 123 6 1 1 25 5 0 37 91 64 11 9 16 9 570 526 584 672 880 745 693 610 571 579 TIME (SECONDS) SPENT IN MOVEMENT BLOCK 1 300 320 247 261 408 258 289 326 333 336 BWK 2 295 189 215 284 363 192 236 291 250 297 BLOCK 3 173 116 180 224 264 186 172 250 196 221 BLOCK 4 126 156 162 129 212 117 188 160 41 139 h) BLOCK 5 43 79 26 149 90 97 131 3 0 0 0 BLOCK 6 20 1 0. 40 83 63 11 5 15 7 0 _ _T_OT_A_L_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _9_57_ _ _ _ _ _86_1_ _ _ _ _8_3_0_ _ _ - -1-0-8-7- - - - - - -1-4-2-0- - - - - -----9_-1-_3- -_-_- -_-_-1--0-_2-7- - - 1035 835 1000 TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 10 MINUTE PERIOD. NUMBER OF MOVEMENTS BLOCK 1 BLOCK 2 BLOCK 3 BMCK 4 BLOCK 5 BLOCK 6 TOTAL 160 147 14 9 158 142 134 151 160 159 159 152 160 149 177 146 131 13 9 136 142 144 163 165 4 138 133 98 114 112 133 139 139 167 150 41 131 58 22 108 111 176 9 85 175 145 3 62 2 0 136 136 104 1 2 142 153 11 4 0 21 15 129 12 0 103 21 129 379 631 519 445 646 761 712 451 632 827 894 TIME (SECONDS) SPENT I N MOVEMENT BLOCK 1 280 292 226 BLOCK 2 170 226 251 BLOCK 3 3 236 101 BLOCK 4 41 193 52 BLOCK 5 0 76 0 BMCK 6 4 1 0 TOTAL 498 1024 630 ____________________---. TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 1 0 MINUTE 256 345 3 17 293 292 326 387 356 186 241 260 226 271 299 309 322 87 156 198 166 158 160 249 321 15 141 160 214 2 115 281 214 0 188 226 132 0 0 203 206 12 14 198 5 0 132 20 196 556 _ _ 10 _ 85 _ _ _ 1359 ___ _ _ 1 _ 0 - 36 _ _ _ _ 723 .__-__ _-- --_- -- _1--0--3- 2 -- -------- 1449 -- _ - -_- ._ 1615 _- __- . PERIOD. NUMBER OF MOVEMENTS BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 TOTAL 146 168 150 165 137 155 156 185 151 156 132 155 126 146 143 110 130 99 150 116 126 2 169 72 816 726 900 E 03 TIME (SECONDS) SPENT IN MOVEMENT BLOCK 1 307 296 417 308 BLOCK 2 269 260 387 250 BLOCK 3 313 266 383 244 BLOCK 4 219 in7 316 134 N BLOCK 5 195 109 234 129 0 N BLOCK 6 192 2 294 59 _ _TO_T_A_L_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _1_4_95_ _ _ _ _1_12_0_ _ _ _ _2_03_1_ _ _ - - -1~12-4- - - - - - - - - - - - - - - - - - - - - TOTAL I SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 10 MINUTE PERIOD. 9 N 7 k? Y BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 TOTAL 4 L -1 !2. 8 E!a Y-. 3 s 169 134 131 141 139 120 147 154 144 164 156 cn 119 146 141 119 160 144 136 156 136 138 138 Lu 159 155 149 128 115 121 134 141 140 142 141 (P c 164 130 130 111 122 112 124 134 81 112 125 ? 14 8 132 151 68 14 117 116 92 14 114 94 P 102 105 113 69 102 23 69 3 4 115 69 r 921 802 .e27 642 112 631 126 680 519 7 8 5 723 Ym P TIME (SECONDS) SPENT IN MOVEMENT BLOCK 1 iii 329 259 321 304 380 373 276 218 286 366 293 BLOCK 2 354 266 335 216 309 283 281 245 203 261 265 BLOCK 3 239 241 287 192 203 225 190 200 235 221 298 BLOCK 4 241 192 282 162 141 165 208 117 133 204 194 N BLOCK 5 181 192 222 13 81 136 170 81 11 131 121 0 w BLOCK 6 68 95 140 64 98 30 14 _ _TO_T_A_L _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _1_41_8_ _ _ _ _12_4_8_ _ _ _ 1_5_8_1 _ _ _ - -1-0-1-1- - - - - ---1--2--1--8------ - - - -1-2-1-2- 1199 0 1 112 58 987 -8_6_9- - - 1- 3 - 0 - 1 - - - - - - - 1- 2 - 3 5 TOTAL I SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 10 MINUTE PERIOD. E! a Y f 2 2. . A W 0 -4 BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 TOTAL 172 153 159 157 148 144 129 144 158 137 113 142 140 128 72 135 143 129 17 150 160 152 0 120 921 843 490 848 TIME (SECONDS) SPENT I N MOVEMENT BLOCK 1 296 342 319 277 BLOCK 2 290 3 03 188 234 BLOCK 3 3 14 364 160 163 BLOCK 4 180 2 98 98 134 BLOCK 5 170 311 14 177 BLOCK 6 225 283 0 107 TOTAL 1475 1901 779 1092 .................................................................. TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 10 MINUTE PERIOD. BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 TOTAL 150 156 148 122 155 160 148 168 141 172 137 163 169 12 1 160 168 144 140 12 0 151 143 170 137 91 162 128 150 120 113 159 75 147 103 114 196 150 125 88 120 131 30 152 45 64 95 102 121 109 36 153 85 145 37 12 0 135 49 74 85 15 17 620 933 639 632 903 757 762 710 545 783 TIME (SECONDS) SPENT IN MOVEMENT BLOCK 1 325 396 332 249 351 , 319 278 271 261 349 BLOCK 2 237 362 310 211 282 267 255 246 185 344 BLOCK 3 188 348 212 128 293 157 248 184 175 323 BLOCK 4 81 259 133 168 243 138 218 118 155 224 N BLOCK 5 26 265 51 59 133 105 178 141 24 191 0 VI BLOCK 6 97 218 32 153 195 40 79 122 3 8 _ _TO_T_AL_ - _ _ - _ - _ _ _ _ _ _. ._. _. ._. .- 95 .-.-. . 4 . . . . . . . 1 . 848 .... . . . . . 10 ... 7 . 0 . . . . . . . . 968 ... 1497 1026 1256 _-_----------_--- 1082 803 1439 TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 10 MINUTE PERIOD. BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 TOTAL 146 139 155 136 121 141 141 151 163 172 141 137 162 124 168 158 142 124 113 151 133 109 135 139 140 119 16 80 163 88 121 68 125 129 144 15 98 119 126 31 90 13 81 96 113 104 66 118 87 35 0 18 84 106 2 83 122 112 23 I 643 604 142 130 694 686 645 110 735 487 TIME (SECONDS) SPENT I N MOVEMENT BLCKK 1 315 296 231 356 442 320 256 290 281 260 BLOCK 2 274 246 167 250 346 211 208 191 234 215 BLOCK 3 BLOCK 4 183 180 111 239 293 186 100 91 191 123 191 94 140 210 181 98 136 14 5 138 31 BLOCK 5 113 75 11 109 144 106 100 119 95 22 BLOCK 6 0 107 71 131 0 85 146 122 14 1 - _T_OT_AL_ TOTAL ______ SUM OF BLOCKS; __ EACH 1016 ___ BLOCK , 998 _____- CONSISTS OF A 803 ------ 1 0 MINUTE 1301 ----- PERIOD. - - 1406 --- - - - --1--0-66- -_--.----- 9--4--6- - -- - - - _-9-6--4-_ -_ - - 95 -- 9 - - - - - 652 -. NUMBER OF MOVEMENTS BLCCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 TOTAL 141 164 157 167 124 158 140 155 151 150 174 14 5 148 146 142 119 155 154 162 160 137 148 37 101 160 144 131 137 158 12 0 120 152 142 6 98 148 94 112 131 150 119 135 149 99 7 53 177 83 101 145 130 102 119 77 105 0 10 153 132 71 127 114 109 94 8 62 336 574 94 1 762 658 853 846 767 779 673 730 TIME (SECONDS) SPENT IN MOVEMENT BLCCK 1 279 282 385 315 342 334 298 376 378 388 338 BLOCK 2 212 261 364 230 323 324 247 316 318 326 211 BLOCK 3 32 127 326 177 270 249 244 169 210 333 225 BLOCK 4 0 124 264 94 208 181 212 141 198 252 136 BLOCK 5 0 47 268 71 119 226 185 120 207 121 126 BMCK 6 0 _ _T O_T_A L _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ - 523 --- 5 249 846 1856 111 119 167 129 131 99 3 66 998 1381 1481 1315 1253 1410 1423 1102 ................................................................. TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 10 MINUTE PERIOD. BLOCK 1 BLOCK 2 BLOCK 3 BMCK 4 BLOCK 5 BLOCK 6 TOTAL 153 153 171 150 122 123 154 153 134 126 155 177 58 121 157 170 1 116 159 158 9 92 163 165 477 731 959 973 TIME (SECONDS) SPENT IN MOVEMENT BLOCK 1 363 367 341 308 BMCK 2 335 283 369 255 BMCK 3 282 211 285 310 BLOCK 4 69 113 280 299 BLOCK 5 0 133 236 225 BMCK 6 8 100 233 215 . . T. .O.T.A.L. . . . . . . . . . . . . . . . . . . . . . . . 105 .... 7 . . . . . . . 1327 .... . . . . . . 1744 ..... . . . . . . 1 . 6 . 1 . 2 . . TOTAL E SUM OF BLOCKS; EACH B M C K CONSISTS OF A 10 MINUTE PERIOD. A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 6 NEUROLOGICAL FUNCTION EXAMINATION RESULTS Page 209 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 6 Study Number: 132-007 MALES Group 1 Animal 7569 7571 7573 7575 7577 7579 7581 7583 7585 7587 7589 7591 7593 7595 7597 PERIPHERAL NEUROPATHY FUNCTIONAL EXAMS FOR WEEK 4 - 132-007 Tail Flick Latency (Time/Second) 4.4 2.9 3.2 4.6 3.2 4.3 2.6 4.0 3.0 4.3, 4.0 4.2 3.5 3.6 2.2 Forelimb Grip (Grams) 368.5 920.0 601.5 577.5 811.5 650.0 611.0 702.5 554.0 538.0 652.5 808.5 599.5 612.0 692.5 Hindlimb Grip (Grams) 500.0 537.0 613.5 793.0 683.0 773.5 847.5 762.5 731.0 620.0 648.0 830.5 638.0 719.0 809.5 Rotorod Latency (Seconds) 6.6 6.6 6.8 6.8 7.6 7.8 5.4 3.0 1.2 1.4 1.2 2.6 5.4 3.0 4.8 Foot Splay (Centimeters) 8.0 7.2 6.6 7.8 7.8 7.0 8.6 8.0 7.5 7.0 7.8 7.0 6.8 9.0 8.5 Mean 3.6 S.D. 0.7 646.6 700.4 4.7 7.6 131.6 106.0 2.4 0.7 MALES Group 2 Animal 7599 7601 7603 7605 7 607 7609 7611 7613 7615 7 617 Tail Flick Latency (Time/Second) 1.2 2.6 3.1 3.0 2.5 3.6 2.3 2.2 2.8 2.3 Forelimb Grip (Grams) 713.0 784.5 623.5 832.5 603.0 504.0 772.0 937.0 660.5 698.0 Hindlimb Grip (Grams) 685.0 861.5 792.0 897.0 698.5 574.0 871.5 881.0 838.0 733.0 Rotorod Latency (Seconds) 1.8 1.6 1.8 1.4 3.2 2.0 2.8 2.0 4.8 2.0 Foot Splay (Centimeters) 8.8 6.6 7.2 5.8 8.8 6.8 7.3 7.4 6.8 4.9 Mean 2.6** 712.8 783.2' 2.3 7.0 S.D. 0.6 124.6 106.8 1.0 1.2 - Significantly different from Group 1 at pc0.05. -* * Significantly different from Group 1 at p<O.Ol. Page 210 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 6 MALES Group 3 Animal 7619 7621 7623 7625 7627 7629 7631 7633 7635 7637 PERIPXERAL NEUROPATHY E'UNCTIONAL EXAMS FOR WEEK 4 - 132-007 Tail Flick Latency (Time/Second1 3.4 3.0 4.7 2.6 1.8 2.6 1.8 4.2 1.8 2.4 Forelimb Grip (Grams) 714.5 571.0 722.0 593.0 600.0 595.5 583.0 612.0 664.0 714.5 Hindlimb Grip (Grams) 708.0 693.0 790.5 716.0 803.0 727.5 810.0 954.5 814.5 807.0 Rotorod Latency (Seconds) 3.0 2.2 1.6 1.4 2.2 2.0 2.4 2.4 2.2 2.4 Foot Splay (Centimeters) 5.1 6.3 5.3 6.4 5.0 5.2 7.3 7.3 7.5 9.1 Mean 2.8' s.n. 1.0 637.0 782.4' 2.2' 6.5' 60.5 77.1 0.4 1.4 MALES Group 4 Animal 7639 7641 7643 7645 7647 7649 7651 7653 7655 7657 7659 7661 7663 7665 7667 Tail Flick Latency (Time/Second) 3.4 2.4 2.4 3.4 3.8 3.1 2.6 2.5 1.9 3.3 3.9 2.0 2.1 1.8 1.9 Forelimb Grip (Grams) 580.0 700.0 646.0 785.0 650.0 576.5 665.0 705.0 669.5 562.0 603.5 680.0 715.5 685.0 594.5 Hindlimb Grip (Grams) 744.0 760.5 835.5 828.5 730.0 805.5 788.0 945.0 045.5 780.5 718.0 730.0 758.0 747.5 725.0 Rotorod Latency (Seconds1 3.2 4.0 2.4 2.0 1.4 1.8 2.4 1.4 1.6 2.0 3.4 2.0 2.2 I. 6 1.4 Foot Splay (Centimeters) 8.2 8.2 7.2 5.2 7.2 5.5 5.3 6.8 6.6 7.2 8.0 5.5 6.0 6.3 7.2 Mean 2.7" 654.5 782.8. 2.2. 6.7, S.D. 0.7 62.0 61.3 0.8 1.0 - Significantly different from Group 1 at p<O.O5. -* * Significantly different from Group 1 at p<O.Ol. Page 211 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 6 Study Number: 132-007 FEMALES Group 1 Animal 7570 7572 7574 7576 7578 7580 7582 7584 7586 7588 7590 7592 7594 7596 7598 PERIPHERAL NEUROPATHY FUNCTIONAL EXAMS FOR WEEK 4 - 132-007 Tail Flick Latency (Time/Second) 1.5 2.6 1.0 2.5 1.7 1.8 1.4 1.1 2.7 2.2. 2.1 3.0 2.2 3.0 3.6 Forelimb Grip (Grams) 361.0 501.5 488.0 556.0 406.5 257.0 257.0 202.0 208.5 401.5 608.5 438.5 439.0 433.5 274.5 Hindlimb Grip (Grams) 266.5 236.5 289.5 419.5 343.0 272.0 309.5 256.0 321.0 307.0 432.5 353.5 335.5 232.5 285.0 Rotorod Latency (Seconds) 2.0 2.0 0.4 2.6 1.0 0.6 0.6 0.4 1.6 0.0 0.6 1.4 0.6 0.8 0.2 Foot Splay (Centimeters) 5.4 4.8 8.2 9.4 9.7 5.9 7.0 5.7 7.4 5.8 4.2 3.8 5.2 6.0 8.5 Mean 2.2 S.D. 0.8 388.9 310.6 1.0 6.5 126.0 59.4 0.8 1.8 FEMALES Group 2 Animal 7600 7602 7604 7606 7608 7610 7612 7 614 7616 7618 Tail Flick Latency (Time/Second) 2.5 1.4 2.7 1.6 2.1 0.5 1.2 2.8 1.4 1.8 Forelimb Grip (Grams) 156.0 293.5 190.5 187.5 459.0 561.5 319.0 410.0 393.0 285.0 Hindlimb Grip (Grams) 234.0 256.5 265.0 334.5 334.5 330.0 289.0 314.0 279.0 240.0 Rotorod Latency (Seconds) 1.4 1.0 1.6 2.2 2.2 0.2 5.4 2.2 8.8 1.6 Foot Splay (Centimeters) 6.9 6.7 6.1 7.6 6.2 5.8 4.8 5.8 9.2 5.8 Mean 1.8 S.D. 0.7 325.5 287.7 2.7 6.5 130.8 38.9 2.5 1.2 Page 212 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 6 FEMALES Group 3 Animal 7620 7622 7624 7626 7628 7630 7632 7634 7636 7638 PERIPHERAL NEUROPATHY FUNCTIONAL EXAMS FOR WEEK 4 - 132-007 Tail Flick Latency (Time/Second) 1.4 1.6 1.0 1.6 2.0 2.6 2.6 2.5 3.0 1.6 Forelimb Grip (Grams) 413.5 348.0 300.0 317.0 283.5 719.5 473.0 763.0 621.5 751.0 Hindlimb Grip (Grams) 361.5 422.0 377.0 300.0 244.0 863.5 222.0 837.5 332.5 767.5 Rotorod Latency (Seconds) 5.6 7.0 1.2 2.6 3.0 0.6 7.8 3.2 2.6 1.4 Foot Splay (Centimeters) 7.0 8.4 6.0 7.6 7.2 6.4 11.2 3.6 4.4 4.2 Mean 2.0 S.D. 0.7 505.0 472.8 3.5'* 6.6 204.5 249.8 2.5 2.3 FEMALES Group 4 Animal 7640 7642 7644 7646 7648 7650 7652 7654 7656 7658 7660 7662 7664 7666 7668 Tail Flick Latency (Time/Second) 3.0 1.8 1.0 1.9 2.1 2.3 1.2 2.4 0.6 2.4 2.0 1.2 1.8 1.4 1.8 Forelimb Grip (Grams) 506.0 375.0 224.0 580.0 532.5 655.0 251.0 671.0 329.5 705.5 581.0 249.0 614.5 498.5 413.0 Hindlimb Grip (Grdm.9 1 206.0 573.5 222.5 650.5 207.5 746.0 199.5 754.5 255.0 616.0 695.5 237.0 799.5 759.5 307.0 Rotorod Latency (Seconds) 2.2 3.4 4.4 2.6 6.4 11.0 3.6 2.4 1.4 2.6 4.2 3.2 1.6 1.8 2.6 Foot Splay (Centimeters) 5.6 5.1 7.6 8.3 6.3 5.1 7.2 4.2 6.2 5.0 4.8 9.5 5.0 7.8 5.5 Mean 1.8 S.D. 0.6 479.0 482.0 3.6" 6.2 162.5 248.3 2.4 1.5 * * - Significantly different from Group 1 at pCO.01. Page 213 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 6 AUDIO/VISUAL EXAMS - 132-007 Group 1 ANIMAL 7569 7571 7573 7575 7577 7579 7581 7583 7585 7587 7589 7591 7593 7595 7597 Group 2 ANIMAL 7599 7601 7603 7605 7607 7609 7611 7613 7615 7617 MALES AUDIO Response observed Response observed Response observed Response observed Response observed Response observed Response observed . Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed MALES AUDIO Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed VISUAL Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed VISUAL Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Study Number: 132-007 Page 214 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 6 AUDIO/VISUAL EXAMS - 132-007 Group 3 ANIMAL 7619 7621 7623 7625 7627 7629 7631 7633 7635 7637 Group 4 ANIMAL 7569 7571 7573 7575 7577 7579 7581 7583 7585 7587 7589 7591 1593 7595 7597 MALES AUDIO Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed MALES AUDIO Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed VISUAL Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed VISUAL Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Study Number: 132-007 Page 215 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 6 AUDIO/VISUAL EXAMS - 132-007 Group 1 ANIMAL 7570 7572 7574 7576 7578 7580 7582 7584 7586 7588 7590 7592 7594 7596 7598 FEMALES AUDIO Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Group 2 ANIMAL 7600 7602 7604 7606 7608 7610 7612 7614 7616 7618 FEMALES AUDIO Response observed Response observed Response Observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed VISUAL Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed VISUAL Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Study Number: 132-007 Page 216 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 6 AUDIO/VISUAL EXAMS - 132-007 Group 3 ANIMAL 7620 7622 7624 7626 7620 7630 7632 7634 7636 7638 Group 4 ANIMAL 7640 7642 7644 7646 7648 7650 7652 7654 7656 7658 7660 7662 7664 7666 7668 FEMALES AUDIO Response observed Response observed ReSpOnse observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed FEMALES AUDIO Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed ReSpOnSe observed Response observed Response observed Response observed VISUAL Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed VISUAL Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Response observed Study Number: 132-007 Page 217 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 7 INDIVIDUAL BODY WEIGHTS Page 218 N N 0 7570 7572 7574 7576 178. 202. 221. 225. 233. a 212. 236. 248. 258. 273. a 196. 226. 248. 261. 262. a 192. 204. 210. 223. 229. a 7578 178. 203. 220. 231. 233. a 7580 7582 203. 218. 237. 241. 249, a 199. 214. 226. 240. 238. a 7584 193. 213. 219. 244. 243. a 7586 7588 188. 204. 198. 222. 215. a 204. 228. 244. 252. 255. a 7590 7592 203. 194. 229. 210. 246. 228. 252. 234. 260. 239. 284. 249. 277. 266. 7594 188. 7596 195. 7-5-9-8- - - - - - - - - -1-9-2_.- - 211. 217. 218. 236. -2-0-3-.- - - - . 214. 238. 238. 244. 231. -- -2-2-7-.- .- --2-1-9-.- 248. 258. 253. 258. 240. 241. -----__------- SD 1 8 15 22 28 36 42 .................................................................................................................................... RAT # DOSE GROUP 2 100 MG/KG/DAY ____________________----------------------------------------------- 7600 182. 202. 216. 225. 226. a 7602 205. 203. 229. 235. 238. a 7604 194. 212. 236. 246. 245. a 7606 202. 221. 236. 241. 256. a 7608 184. 204. 208. 223. 226. a 7610 206. 221. 230. 247. 241. a 7612 194. 213. 229. 230. 231. a 7614 201. 222. 238. 239. 232. a 7616 193. 203. 216. 227. 223. a 7618 199. 216. 232. 237. 244. a ________________________________________----------------- SD = STUDY DAY ~ 1 w1eights were reported in grama (GI. a = Scheduled sacrifice. 7640 183. 198. 220. 230. 213. a 7642 212. 236. 252. 264. 260. a 7644 197. 223. 239. 261. 256. a 1646 193. 221. 234. 251. 253. a 7648 193. 218. 237. 254. 243. a 7650 207. 210. 223. 242. 237. a N 7652 198. 224. 239. 249. 252. a tNu 17665546 119918.. 221063.. 221375.. 224253.. 224293.. aa 7658 206. 224. 233. 238. 237. a 7660 191. 214. 227. 211. 240. 250. 255. 7662 196. 222. 234. 246. 242. 258. 263. 7664 195. 216. 230. 230. 242. 259. 259. 7666 204. 221. 228. 251. 240. 253. 265. * 7660 __ _ _ _ 193. ___ _ 210. __ _ _ 22 _ 6. _ _ 230. ___ _ -_2--4--2-.-- --_-_-2--58--.-- -- 255. -_-_- -_-.- - . SD = STUDY DAY All weights were reported in grams (GI. a E Scheduled sacrifice. A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 8 INDIVIDUAL FEED CONSUMPTION Page 223 3 Lo EL : ee ---------------- A 28-Day Oral Toxicity Study in Sprague-Dawiey Rats Study Number: 132-007 m N m N . . . . . . . . . . m m m w w r - r m m m WOW~~NNOWO dNdddNNNdN . . . . . . . . . . m ~ n r w m m d r * mm~mmooomo dddddNNNdN . . . . . . . . . . m m n ~ ~ w m o m o wmrmmoodwo dddddNNNdN . . . . . odo ~m .d+ do n NNNNN . . . . . m e w n w ~ m m m m m m m m m mN N o oN wN mN d . . . . . . . . . . . . . . w m n d m m m m ~ r ~ w w m mrunnmmdmmdwwomw Ndd ddNddNddNdd ............... ~mmwm~wmmodmwnw mmd~o~m~ommm~~m ddNdNNNNNNddNNd Page 225 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats I Study Number: 132-007 Page 226 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 I1 N0 I N * I, ONPW wwww wwww rrrr Page 227 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 9 INDIVIDUAL HEMATOLOGY DATA Page 228 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 KEY TO HEMATOLOGY TABLES AB BREVIAT10N TERMINOLOGY UNITS WBC White Blood Cells (Leukocytes) 103/cumm RBC Red Blood Cells (Erythrocytes) 106/cumm HGB Hemoglobin g/dL HCT Hematocrit (Packed Cell Volume) % MCV Mean Corpuscular Volume fL or cu micron MCH Mean Corpuscular Hemoglobin pg or picograms MCHC Mean Corpuscular Hemoglobin % Concentration PLT Platelets 103/cumm NRBC Nucleated Red Blood Cell Count Lymphocyte Lymphocytes 103/cumm Segmented Segmented Neutrophils 103/cu mm Eosinophil Eosinophils 103/cumm Abnormal L Abnormal Lymphocytes 1o3/cumrn APlT Activated Partial Thromboplastin Time seconds PT Prothrombin time seconds Other Other Cells IO~ICU mm ABS Absolute C NT Count Page 229 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 9 Study c_----I----------- ------ Report for Hematology c----------- --- - -- - -- - - - - - INDIVIDUAL ANIMAL REPORT BY ----- PERIOD: RECOVERY _ _ _ _ _ _ I - - GROUP --_--------_-__I__ STUDY I D : 28-DAY ORAL DOSEIRAT ---S--T-UDY NO: 1-3--2-----0--0--7-- Animal I D UBC RBC M S N / C U MM MILL/CU MM me GRAMS/DL SEX: MALE HCT % _ - - - - - - - - - - I - MCV CU MICRONS MCH P I C 0 GRAMS MCHC % PLT THSN/CU MM GROVP: 1-M 7569 7571 7573 7575 7577 7579 7581 7583 7585 7507 7589 7591 7593 7595 7597 e e e e e e e e e e 13.0 19.2 14.2 8.3 12.2 e e e e e e e e e e 7.08 7.10 6.79 7.65 6.74 e e e e e e e e e e 14.5 15.4 15.2 16.0 14.3 e e e e e e e e e e 38.6 41 .O 39.9 43.7 37.6 e e e e e e e e e e 54.5 57.8 58.7 57.1 55.8 e e e e e e e e e e 20.5 21.7 22.4 20.9 21.2 e e e 37.6 37.6 38.1 36.6 38.0 e e e e e e e e e e 1421 1134 1234 1188 1304 MEAN SO N 13.4 3.93 5 7.07 0.362 5 15.1 0.69 5 40.2 2.36 5 56.8 1.66 5 21.3 0.74 5 37.6 0.59 5 1256 111.3 5 e - Terminal Sacrifice LABCAT HE4.41c --- 03-NOV-2oM) Page 230 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 9 ---------------- ---- Study Report for Hematology __------I_ I _ _______ INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: RECOVERY STUDY I D : 28-DAY ORAL WSE/RAT STUDY NO: 132-007 Animal I D Yet -- - THSN/CU MM GROUP: 4-M 7639 e 7641 e 7643 e 7645 e 7647 e 7649 e 7651 e 7653 e 7655 e 7657 e 7659 11.5 7661 9.5 7663 7.0 7665 12.6 7667 16.8 RBC MILL/CU MM I_ e e e e e e e e e e 7.19 7.94 7.48 6.71 7.07 MEAN so N 11.5 3.66 5 7.28 0.462 5 me HCT MCV GRAMS/DL ___-___%_--C-U--M-IC--R-ONS MCH P I C 0 GRAMS e e e e e e e e e e 15.9 16.2 15.9 14.0 15.1 15.4 0.89 5 e e e e e e e e e e 42.5 44.4 42.6 37.2 40.3 41.4 2.76 5 e e e e e e e e e e 59.1 55.9 57.0 55.5 57.0 56.9 1.40 5 e e e e e e e e e e 22.1 20.4 21.3 20.9 21.4 21 .z 0.63 5 SEX: MALE MCHC PLT --_%- THSN/CU MN---- e e e e e e e e e e 37.4 36.5 37.3 37.6 37.5 e e e e e e e e e e 1088 1180 1161 1061 1098 37.3 0.44 5 1118 50.6 5 _ _ I - - - e - Terminal Sacrifice LABCAT HE4.41~ 03-NoV-2WO Page 231 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 9 Study Report Hematology f o r ------ ----- ----- _ __________I- - I - - _ - 1 - 1 - _ _ _ - - - _ - _ I - 1 -- - - - _ - _ __ INDIVIDUAL ANIMAL REPORT BY GROUP -_____-______----_-_-~__- PERIOD: RECOVERY -----~----I-_---I_---------- STUDY ID: 28-DAY ORAL DOSE/RAT _-S-T-U--D-Y--NO: 132-007 - - - I - - - I - _ - - - - - - - SEX: MALE ------- Animal ID PI APTT NRBC ---------- seconds seconds COUNT - - - I - - - - - - - Lymphocyte THSN/CU MM Segmented - THSN/CU MM Bands THSN/CU MM nonocytei THSN/CU M M Eosinophi 1 THSN/CU MM I - - I - GROUP: 1-I4 7569 7571 7573 7575 7577 7579 7581 7583 7505 7587 7589 7591 7593 7595 7597 e e e e e e e e e e 12.7 12.5 12.6 12.4 12.6 e e e e e e e . e e e 20.0 14.0 20.2 10.4 15.6 e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e 0 12.0 0.9 0.0 0.0 0.1 0 18.2 1.o 0.0 0.0 0.0 0 12.1 2.0 0.0 0.0 0.1 0 6.9 1.3 0.0 0.0 0.1 0 10.7 1.3 0.0 0.1 0.0 MEAN SD N 12.6 0.11 5 17.6 2.74 5 0 12.0 1.3 0.0 0.0 0.1 0.0 4.07 0.43 0.00 0.04 0.05 5 5 5 5 5 5 ---e Terminal Sacrifice LABCAT HE4.41c ----- -- 03-NOV-2ooO Page 232 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 9 _____~~~ Study Report f o r Hematology INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD : RECOVERY ~~ ~ ~ _ _ _ STUDY I D : 28-DAY ORAL DOSE/RAT STUDY NO: 132-007 SEX: nALE Animal I D PT seconds APTT seconds - - - - - - - - - - - - - _ I GRWP: 4-11 7639 7641 7643 7645 7647 7649 7651 7653 7655 7657 7659 7M1 7663 7665 7667 e e e e e e e e e e 13.4 13.4 13.4 13.6 13.3 e e e e e e e e e e 19.6 21.4 27.0 20.5 22.1 NREC COUNT Lymphocyte THSN/CU MM Segmented Bands Mcwcyter Eosinophil MSN/CU nN MSN/CU na THSN/CU MM _____-_-_____ THSN/CU M- M - e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e 0 10.2 1.3 0.0 0.0 0.0 0 8.7 0.7 0.0 0.0 0.1 0 6.2 0.7 0.0 0.1 0.0 0 10.7 1.6 0.0 0.3 0.0 0 14.8 1.8 0.0 0.2 0.0 MEAN SD N 13.4 0.11 5 22.3 3.23 5 0 10.1 1.2 0.0 0.1. 0.0 0.0 3.15 0.51 0.w 0.13 0.04 5 5 5 5 5 5 __--- e - Terminel.Sacrifice LABCAT HE4.41~ - - I _ 03-NOV-2ooO Page 233 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 STUDY ID: 28-DAY ORAL DOSEIRAT ---S-T-U--D-Y- NO: 132-007 SEX: MALE _ _ - I - - - - - - - - - - - - - I - - - - _ Animal I D Basophils THSN/CU MM Abnormal L THSN/CU MM Other THSN/CU MM GROUP: I - M 7569 e e e 7571 e e e 7573 e e e 7575 e e e 7577 e e e 7579 e e e 7501 e e e 7503 e e e 7585 e e e 7587 e e e 7589 0.0 0.0 0.0 7591 0.0 0.0 0.0 7593 0.0 0.0 0.0 7595 0.0 0.0 0.0 7597 0.0 0.0 0.0 MEAN SD N 0.0 0.00 5 0.0 0.00 5 0.0 0.00 5 UBCAT HE4.41c 03-NOV-2ooO Page 234 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 STUDY I D : 28-DAY ORAL DOSE/RAT STUDY NO: 132-007 ----- __---- Animal I D Basophils THSN/-C-U----M-M- GROUP: 4-N 7639 e 7641 e 7643 e 7645 e 7647 e 7649 e 7651 e 7653 e 7655 e 7657 e 7659 0.0 7661 0.0 7663 0.0 7665 0.0 7667 0.0 Abnormal L THSN/CU NM e e e e e e e e e e 0.0 0.0 0.0 0.0 0.0 Other THSN/CU MN e e e e e e e e e e 0.0 0.0 0.0 0.0 0.0 MAN SD N 0.0 0.00 5 0.0 0.00 5 0.0 0.00 5 SEX: MALE - - I - _ _ _ e - Terminal Sacrifice LABCAT ~ ~ 4 . 4 1 ~ 03-NOV-2oaO Page 235 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 9 Study Report for Hematology ------------ INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD : TERMINAL STUDY I D : 28-DAY ORAL DOSE/RAT ------S-TUDY NO: 132-007 - - - I ---~ Animal I D U8C THSN/CU nn RBC nxLL/cu nn HGB GRAns/DL HCT ncv ncn X CU MICRONS PIC0 G R A M SEX: MALE I - - - - nCHC X PLT THSN/CU MM GROUP: 1 - M 7569 7571 75T3 7575 75n 7579 7581 7583 7585 7587 7589 7591 7593 7595 7597 7.5 5.4 10.7 20.6 7.6 12.8 12.5 7.9 8.1 6.9 I - 7.16 7.14 7.71 7.37 7.69 . 6.29 7.62 6.82 5.98 --5.33 15.5 15.6 16.6 16.5 16.3 15.0 17.3 16.4 13.2 -12.5 -- I - 42.4 41.6 45.5 48.6 43.9 40.0 47.2 42.6 36.2 --- 32.6 I - 59.2 58.2 59.0 66.0 57.1 63.6 61.9 62.5 60.5 61.-1- - I - 21.6 21.8 21.5 22.4 21.2 23.8 22.7 24.0 22.1 - 23.5 - - - - 36.6 37.5 36.5 34.0 37.1 37.5 36.7 38.5 36.5 --38.3 - - - - 1057 1093 1303 1234 1011 1027 1242 1458 1275 10-4-4 - I - NEAN SD N 10.0 4.44 10 6.91 0.805 10 15.5 1.54 10 42.1 4.87 10 60.9 2.69 10 22.5 1.M 10 36.9 1.25 10 1174 149.5 10 GROUP: 2-M 7599 7601 7603 7605 7607 7.509 7611 7613 7615 7617 REAN SD N 10.8 11.6 13.9 17.5 14.3 11.8 8.3 11.1 7.7 14.6 12.2 2.99 10 7.44 7.23 6.70 7.94 7.06 6.69 6.46 6.44 7.30 6.98 7.02 0.473 10 16.6 15.7 15.2 16.0 16.3 15.5 15.4 15.0 16.4 15.5 15.8 0.54 10 45.2 43.2 41.4 46.4 44.4 41.9 40.2 39.2 44.2 41.7 42.8 2.24 10 60.8 59.8 61.8 58.4 62.9 62.7 62.3 61.3 60.5 59.8 61 .O 1.45 10 22.3 21.7 22.7 20.2 23.1 23.2 23.8 23.3 22.5 22.2 22.5 1.02 10 36.7 36.3 36.7 34.5 36.7 37.0 38.3 38.0 37.1 37.2 36.8 1.03 10 1014 1262 1185 1291 1199 1266 1409 1308 1261 1223 1242 101.9 10 ------ - (-) Data Unavailable LABCAT HE4.41 c -- 03-NOV-2oM) Page 236 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 9 --------------------- Study Report for Hematology ---ll------l_--___-------- _____ INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL - - - - - I _ - - - __-- STUDY I D : 28-DAY ORAL DOSEIRAT STUDY NO: 132-007 SEX: PIALE Animal I D UEC THSN/CU flM REC flILL/CU flM HGE GRAMS/DL HCT ncv MCH X CU flICRONS PIC0 G R A M MCHC X PLT THSN/CU MM GROUP: 3-fl 761 9 7621 7623 7625 7627 7629 7631 7633 7635 7637 9.0 10.0 8.6 10.9 14.2 9.1 14.4 14.5 7.0 6.6 7.01 6.70 7.66 6.85 6.91 6.82 6.40 , 6.70 7.09 6.85 15.4 15.1 16.6 15.4 14.9 15.9 15.6 15.7 15.7 15.5 40.8 41 .O 44.4 41.3 40.0 43.2 41.2 41.8 41.1 41.6 58.2 61.2 58.0 60.3 57.9 63.4 64.4 62.4 58.0 60.7 22.0 22.5 21.7 22.5 21.6 23.3 24.4 23.4 22.1 22.6 37.7 36.8 37.4 37.3 37.3 36.8 37.9 37.6 38.2 37.3 1019 1033 1380 1200 1051 1180 1155 1103 1063 1022 MAN SD N 10.4 2.99 10 6.90 0.328 10 GROUP: 4-fl 7639 7641 7643 7645 7647 7649 7651 7653 7655 7657 7659 7661 7663 7665 7667 10.0 12.3 8.2 11.5 6.8 7.8 9.7 7.9 12.0 9-.1 - -- - - 7.34 6.43 7.47 6.81 7.05 6.58 6.92 5.56 . 6.59 -5 .-n - - 15.6 0.46 10 15.9 14.6 15.6 15.6 15.8 14.9 15.4 13.0 15.9 -- 13.4 -- - -- 41.6 1.27 10 42.8 38.8 42.6 40.9 42.2 38.1 U.6 34.5 42.1 35-.-3-- - 60.5 2.41 10 22.6 0.87 10 58.3 60.4 57.0 60.0 59.8 57.9 58.7 62.1 63.9 -- 61.2 - - I 21.7 22.7 20.9 22.9 22.4 22.6 22.3 23.4 24.1 - 23.2 - -- 37.4 0.44 10 37.1 37.6 36.6 38.1 37.4 39.1 37.9 37.7 37.8 38.0 - 1 -- --- 1121 112.8 10 - 1118 981 915 1069 a47 1269 867 853 1119 -977 - - MEAN SD N 9.5 1.91 10 6.65 0.617 10 15.0 1.os 10 39.8 3.02 10 59.9 2.09 10 22.6 0.89 10 37.7 0.66 10 1002 139.8 10 -(-I - Data Unavailable LAECAT HE4.41~ -- o3-mv-~ooo Page 237 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 STUDY I D : 28-DAY ORAL DOSEIRAT STUDY NO: 132-007 SEX: MALE Animal I D PT APT1 NRBC Lymphocyte Segmented Bands ------ seconds seconds CWNT THSN/CU MM THSN/CU MM THSN/CU MM __l___-_I--__-l---- -__.-_--- - - _ I _ GROUP: 1-n 7569 15.2 22.3 0 7.1 0.4 0.0 7571 14.3 15.8 0 5.0 0.3 0.0 7573 15.0 29.4 0 10.3 0.2 0.0 7575 14.2 27.2 0 18.5 1.6 0.0 7577 16.5 40.4 0 7.1 0.5 0.0 7579 14.3 19.1 0 11.8 0.9 0.0 7581 15.3 36.0 0 11.4 1.1 0.0 7583 13.7 25.0 0 7.2 0.C 0.1 7585 14.0 24.5 0 7.3 0.7 0.0 7587 - - - -- - 7589 - - - - - 7591 - - -- 7593 -_ - - - - 7595 - - - - - 7597 13.2 19.7 1 6.4 0.4 0.0 _- I I Monocytes THSN/CU MM 0.0 0.0 0.2 0.0 0.0 0.1 0.0 0.0 0.1 0-.0- - - I I Eosinophi 1 --- THSN/CU MM 0.1 0.1 0.0 0.4 0.0 0.0 0.0 0.2 0.0 -0.1 - 1 MEAN SD N 14.6 0.95 10 25.9 7.66 10 0 9.2 0.6 0.0 0.0 0.1 0.3 3.96 0.44 0.03 0.07 0.13 10 10 10 10 10 10 GROUP: 2-M 7599 7601 7603 7605 7607 7609 7611 7613 7615 7617 MEAN so N CL 15.2 15.6 16.4 15.5 15.0 15.2 14.5 15.8 14.1 15.3 0.69 9 CL 25.7 27.9 28.2 30.8 29.6 26.2 24.5 27.4 21.6 26.9 2.77 9 0 9.5 1.2 0.0 0.0 0.1 0 9.6 1.9 0.0 0.0 0.1 0 11.8 2.1 0.0 0.0 0.0 0 15.6 1.8 0.0 0.0 0.0 0 12.9 1.4 0.0 0.0 0.0 0 9.8 1.9 0.0 0.0 0.1 0 6.6 1.6 0.0 0.0 0.1 0 9.8 1.3 0.0 0.0 0.0 0 7.1 0.5 0.0 0.0 0.1 0 12.3 2.0 0.0 0.0 0.3 0 10.5 1.6 0.0 0.0 0.1 0.0 2.71 0.49 0.00 0.00 0.09 10 10 10 ' 10 10 10 --- -- (-1 - Data Unavailable LABCAT HE&. 41C I CL - Clotted -- 03-liQV-2ooO Page 238 A 26-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 Animal I D PT seconds APTT seconds -------------------__I______ GROUP: 3-N 761 9 7621 7623 7625 7627 7629 7631 7633 7635 7637 14.6 14.6 14.4 13.6 13.3 15.3 14.8 14.8 14.3 15.1 26.7 20.0 15.9 20.1 26.3 . 27.9 23.4 20.8 24.4 23.2 REAN SO N 14.5 0.62 10 22.9 3.70 10 GROUP: 4-n 7639 7641 7643 7645 7647 7649 7651 7653 7655 7657 7659 7661 7663 7665 7667 NEAN SD N 14.7 13.3 14.6 14.0 16.5 14.6 CL 14.1 14.3 -- 15.1 -- --- 14.6 0.88 9 32.1 29.7 19.8 20.5 31.6 25.3 EL 22.5 25.6 --- 19.1 - I 25.1 5.06 9 --(-1 - Data Unavai table LABCAT HE4.41 c NRBC COUNT Lymphocyte THSN/CU NN Segmented ---THSN/CU NN Bands THSN/CU NM Nmocytes THSN/CU NN I - - - Eosinophil THSN/CU NN 0 8.1 0.9 0.0 0.0 0.0 0 9.5 0.5 0.0 0.0 0.0 0 8.0 0.6 0.0 0.0 0.0 0 9.8 1.1 0.0 0.0 0.0 0 12.1 1.8 0.0 0.0 0.3 0 6.5 2.6 0.0 0.0 0.0 0 12.7 1.6 0.0 0.0 0.1 0 13.9 0.3 0.0 0.1 0.1 0 6.5 0.5 0.0 0.0 0.0 0 6.1 0.4 0.0 0.0 0.1 0 9.3 1.0 0.0 0.0 0.1 0.0 2.79 0.75 0.00 0.03 0.10 10 10 10 10 10 10 0 8.5 1.5 0.0 0.0 0.0 0 11.2 0.9 0.0 0.2 0.0 0 7.8 0.4 0.0 0.0 0.0 0 9.8 1.4 0.0 0.3 0.0 0 5.8 0.7 0.0 0.1 0.1 0 6.9 0.8 0.0 0.1 0.0 0 8.7 0.7 0.0 0.1 0.2 0 6.6 1.1 0.0 0.2 0.0 0 11.4 0.5 0.0 0.1 0.0 --0 8.-0 0.-8 0.-0 0.-2 -0.1 - - - - - I - -- - -- - - - 1 - - - 1 -- 1 0 8.5 0.9 0.0 0.1 0.0 0.0 1.07 0.36 0.00 0.09 0.07 10 10 10 10 10 10 _ _ _ - - _ - I - CL - clotted 03-NOV-2OW Page 239 A 28-Day Oral Toxicity Study in Sprague-Daw@ Rats Study Number: 132-007 APPENDIX 9 Study Report Hematology f o r ___--- --------- _______ - _ - ^ _ I - - - - - - -- -_ - _ -- _ - _ - _ - _ - I -__-_-_-------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIO_D:__TE_RM_IN_AL -- - I STUDY I D : 2E-DAY ORAL M)SE/RAT _-S-TU_D_Y _NO_: --1-32407 __________-- Animal I D Basophils Abnormal L ------ --____----- THSN/CU MM THSN/CU MM GROUP: 1-M 7569 0.0 0.0 7571 0.0 0.0 7573 0.0 0.0 7575 0.0 0.0 75n 0.0 0.0 7579 0.0 0.0 7581 0.0 0.0 7583 0.0 0.0 7585 0.0 0.0 7587 - - 7589 - - 7591 - 7593 - - 7595 - - 7597 0.0 0.0 I SEX: NALE ---~__ Other TH-S-N-/C_U _NM _--__- 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 -0.0 - - -- - MEAN SD N 0.0 0.00 10 GROUP: 2-H 7599 7601 7603 7605 7607 7609 761 1 7613 76'15 7617 REAN SO N 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.00 10 0.0 0.00 10 0.0 0.0 0.0 0.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.06 10 0.0 0.00 10 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.00 10 LABCAT H E 4 . 4 1 ~ 03-Nov-2wo Page 240 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 GRWP: 3-H 7619 7621 7423 7625 7627 7629 7631 7633 7635 7637 MEAN SO N 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.00 10 GROUP: 4-H 7639 0.0 7641 0.0 7643 0.0 7645 0.0 7647 0.0 7649 0.0 7651 0.0 7653 0.0 7655 0.0 7657 7659 0-.0- 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.00 10 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.-0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.00 10 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 -0.0 MEAN so N (--) - Data Unavailable LABCAT HE4.41e 0.0 0.00 10 0.0 0.00 10 0.0 0.00 10 03-NOV-2ooO Page 241 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 GROUP: 1-H 7569 7571 7573 7575 7577 7579 7581 7583 7585 7587 7589 7591 7593 7595 7597 HEAN SD N e e e e e e e e e e 13.0 19.2 14.2 8.3 12.2 13.4 3.93 5 e e e e e e e e e e 7.M 7.10 6.79 7.65 6.74 7.07 0.362 5 e e e e e e e e e e 14.5 15.4 15.2 16.0 14.3 15.1 0.69 5 e e e e e e e e e e 38.6 41 .O 39.9 43.7 37.6 40.2 2.34 5 e e e e e e e e e e 54.5 57.8 58.7 57.1 55.8 56.8 1.M 5 e e e e e e e e e e 20.5 21.7 22.4 20.9 21.2 21.3 0.74 5 e e e e e e e e e e 37.6 37.6 38.1 36.6 38.0 37.6 0.59 5 e e e e e e e e e e 1421 1134 1234 1168 1304 1256 111.3 5 e - Terminal Sacrifice LABCAT HE4.41~ 03-NOV-2ooO Page 242 A 26-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 GRWP: 4-Pi 7639 7641 7643 7645 7647 7649 7651 7653 7655 7657 7659 7661 7663 7665 7667 MEAN SD N e e e e e e e e e e 11.5 9.5 7.0 12.6 16.0 11.5 3.66 5 e e e e e e e e e e 7.19 7.94 7.40 6.71 7.07 7.20 0.462 5 e e e e e e e e e e 15.9 16.2 15.9 14.0 15.1 15.4 0.89 5 e e e e e e e C e e 42.5 44.4 42.6 37.2 40.3 41.4 2.76 5 e e e e e e e e e e 59.1 55.9 57.0 55.5 57.0 56.9 1.40 5 e e e e e e e e e e 22.1 20.4 21.3 20.9 21.4 21.2 0.63 5 e e e e e e e e e e 37.4 36.5 37.3 37.6 37.5 37.3 0.44 5 e e e e e e e e e e 1088 1180 1161 lo61 1098 1118 50.6 5 e - Terminal Sacrifice LABCAT HE4.41~ I - - - 03-NOV-2ooO Page 243 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 9 _ _ _ _ ____ Study R e p o r t f o r Hematology _ _ ______l___l_______-___l________________l-------- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: RECOVERY I_____-_---_______- _ 1 - _ 1 - _ - - - _ - - - STUDY I D : 28-DAY ORAL WSE/RAT STUDY NO: 132-007 _--I--------__- ------------ SEX: MALE - - I _ Animal I D PT seconds APTT secoods NREC COUNT Lymphocyte THSN/CU MM Segmented THSN/CU MM Bands THSN/CU MM Monocytes THSN/CU MM Eosinophi 1 THSN/CU MM GROUP: 1-11 7569 7571 7573 7575 7577 7579 7581 7583 7585 7587 7589 7591 7593 7595 7597 MEAN SD N e e e e e e e e e e 12.7 12.5 12.6 12.4 12.6 12.6 0.11 5 . e e 20.0 14.0 20.2 18.4 15.6 17.6 2.74 5 e e e e e e e e e e e e 0 12.0 0.9 0.0 0.0 0.1 0 18.2 1 .o 0.0 0.0 0.0 0 12.1 2.0 0.0 0.0 0.1 0 6.9 1.3 0.0 0.0 0.1 0 10.7 1.3 0.0 0.1 0.0 0 12.0 1.3 0.0 0.0 0.1 0.0 4.07 0.43 0.00 0.04 0.05 5 5 5 5 5 5 -- -e Terminal Sacrifice UECAT H E 4 . 4 1 ~ 03-WV-2ooO Page 244 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Report for Hematology Study Number: 132-007 Animal I D PT seconds GROUP: 4-14 7639 7641 7643 7645 7647 7649 7651 7653 7655 7657 7659 7661 7663 7665 7667 e e e e e e e e e e 13.4 13.4 13.4 13.6 13.3 NEAN SD N 13.4 0.11 5 APTT seconds e e e e e e . e e e e 19.6 21.4 27.8 20.5 22.1 22.3 3,23 5 NRBC COUNT Lymphocyte THSN/CU Hf4 Segmented THSN/CU I411 Bands THSN/CU NN Hcnocytes THSN/CU NN Eosinaphi 1 THSN/CU NN e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e 0 10.2 1.3 0.0 0.0 0.0 0 8.7 0.7 0.0 0.0 0.1 0 6.2 0.7 0.0 0.1 0.0 0 10.7 1.6 0.0 0.3 0.0 0 14.8 1.8 0.0 0.2 0.0 0 10.1 1.2 0.0 0.1 0.0 0.0 3.15 0.51 0.00 0.13 0.04 5 5 5 5 5 5 e - Terminal Sacrifice LABCAT HE4.41 c 03-NOV-20M) Page 245 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 9 Study Report for Hematology ______----------_____l______l___________ __----___- INDIVIDUAL ANIMAL REPORT BY GROUP ---- --- PERIOD: RECOVERY _ _ _ _ _ _ - - I - - - - STUDY I D : 28-01'1 ORAL DOSE/RAT -_S-TU-DY NO: 132-007---__- SEX: MALE I Animal I D Basophils THSN/CU MM Abnormal L MSN/CU M R Other THSN/CU MI4 GROUP: 1-M 7569 C e e 7571 e e e 7573 c e e 7575 e e c 7577 e e e 7579 e C C 7581 e e c 7583 e e e 7585 e e e 7587 e e e 7589 0.0 0.0 0.0 7591 0.0 0.0 0.0 7593 0.0 0.0 0.0 7595 0.0 0.0 0.0 7597 0.0 0.0 0.0 MEAN SD N 0.0 0.0 0.0 0.00 0.w 0.w 5 5 5 ___- c - Terminal Sacrifice LABCAT HE4.41 c -~-- 03-NOV-2ooO Page 246 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Report for Hematology STUDY I D : 28-DAY ORAL DOSEIRAT STUDY NO: 132-007 Animal ID Basophils THSN/CU MH Abnormal L THSN/CU MM Other THSN/CU MM GROUP: 4-14 7639 e e e 7641 e e e 7643 e e e 7645 e e e 7647 C e e 7649 e e C 7651 e e e 7653 e e e 7655 C e 7657 e C e 7659 0.0 0.0 0.0 7661 0.0 0.0 0.0 7663 0.0 0.0 0.0 7665 0.0 0.0 0.0 7667 0.0 0.0 0.0 MEAN SD N 0.0 0.0 0.0 0.00 0.00 0.00 5 5 5 Study Number: 132-007 SEX: MALE - -------- I - - - - - - e - Terminal Sacrifice LABCAT HE4.41 c ~-- 03-NOV-2OW Page 247 A 28-Day Oral Toxicity Study in Sprague-DawleyRats APPENDIX 9 Study Number: 132-007 Animal I D UBC RBC HGB HCT THSN/CU MM R I L L / C U MM GRAMS/DL X _-II_________________-_I____-- GROUP: 1-F 7570 7572 7574 7576 7578 7560 7582 7584 7586 7588 7590 7592 7594 75% 7598 e e e e e C e e e e 10.1 10.0 7.1 12.8 8.7 C e c e e e e e e C 6.79 7.46 7.33 7.41 6.74 e e C e e c e e e e 15.1 15.0 14.9 16.3 14.4 e e e e e e e C c e 41.4 41.6 41.6 44.7 39.0 MCV CU MICRONS c e e e C e e e c c 60.9 55.7 56.8 60.3 57.9 MCH P I C 0 GRAMS MCHC X PLT THSN/CU MM --1__1_-- e e e C e e e e e e 22.2 20.1 20.3 22.0 21.4 e e e e e e e e e C 36.5 36.1 35.8 36.5 36.9 e e e e c e e e e e 1350 1349 1106 1330 1059 MEAN SD N 9.7 2.10 5 7.15 0.351 5 15.1 0.70 5 41.7 2.02 5 58.3 2.23 5 21.2 0.96 5 36.4 0.42 5 1239 143.9 5 e - Terminal Sacrifice LABCAT HE4.41c 03-NOV-Moo Page 248 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Report f o r Hematology Study Number: 132-007 STUDY ID: 2&DAY ORAL DOSEIRAT STUDY No: 132-007 Animal ID uac THSN/CU HM R8C BILL/CU HH GROUP: 4-F 7640 7642 76u 7646 7648 7650 7652 7654 7656 7658 7660 7662 7664 7666 7668 e e e e e e e e e e 6.0 5.4 16.1 6.9 8.5 e e e e e e e e e e 7.50 6.08 6.88 7.15 6.86 HEAN SD N 8.6 4.36 5 6.89 0.524 5 HGB GRAHS/DL e e e e e e e e e e 17.0 14.2 15.1 14.7 13.8 15.0 1.24 5 HCT HCV HCH X CU HICRONS PIC0 GRAHS e e e e e e e e e e 46.1 37.5 40.6 40.5 38.4 40.6 3.34 5 e e e e e e e e e e 61.5 61.6 59.0 56.6 56.0 58.9 2.63 5 e e e e e e e e e e 22.7 23.4 21.9 20.6 20.1 21.7 1.39 5 SEX: FEHALE HCHC X PLT THSN/CU HH e e e e e e e e e e 36.9 37.9 37.2 36.3 35.9 36.8 0.78 5 e e e e e e e e e e 968 801 967 1212 1024 994 147.5 5 -- -e Terminal Sacrifice LABCAT HE4.41~ -- - _ I - 03-NOV-2OOO Page 249 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 9 Study Report for Hematology INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD : RECOVERY STUDY I D : 28-DAY ORAL DOSE/RAT STUDY NO: 132-007 - - - - - - - - - - I _ - - - - - - Animal I D PT seconds APT1 seconds NREC CWNT ---- Lynphocyte Segmented THSN/CU MM THSN/CU MM Bands THSN/CU MM SEX: FEMALE - - - - I _ Monocytes MSN/CU MM Eotinophi 1 THSN/CU MM GROUP: 1-F 7570 7572 7574 7576 7578 7580 7582 7584 7586 7588 7590 7592 7594 75% 7590 e e e e e e e e e e 12.4 13.0 12.1 11.8 12.2 e e e e e e e e e e 17.8 19.9 18.1 18.6 18.3 e e e e e e e e e e e e e e e e e e e e e e e. e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e 0 9.5 0.6 0.0 0.0 0.0 0 8.7 1.2 0.0 0.1 0.0 0 6.5 0.6 0.0 0.0 0.0 0 11.8 1 .o 0.0 0.0 0.0 0 7.9 0.8 0.0 0.0 0.0 MEAN SD N 12.3 0.45 5 18.5 0.81 5 0 0.9 0.8 0.0 0.0 0.0 0.0 1.97 0.26 0.00 0.04 0.00 5 5 5 5 5 5 --e Terminal Sacrifice LAECAT HE4.41c -- 03-NOV-2ooO Page 250 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 9 Study Report f o r Hematology INDIVIDUAL ANIMAL REPORT BY GROUP ______________ PERIOD: RECOVERY -~------I------- STUDY I D : 20-QAY ORAL DOSEIRAT STUDY NO: 132-007 SEX: FEMALE Animal I D GROUP: 4-F 7640 7642 7644 7646 7.540 7650 7652 7654 7656 7658 7660 7662 7664 7656 7668 MEAN SD N PT seconds e e e e e e e e e e 12.7 13.2 12.9 12.7 12.8 12.9 0.21 5 APTT seconds e e e e e e . e e e e 21 .o 23.6 19.6 19.0 21.2 21.0 1.60 5 NRBC CWNT Lymphocyte THSN/CU MM Segmented THSN/CU MM Bands THSN/CU MM Monocytes THSN/CU MM Eosinophi 1 THSN/CU MM e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e 0 5.6 0.3 0.0 0.1 0.0 0 4.6 0.8 0.0 0.0 0.0 0 14.8 1.1 0.0 0.2 0.0 0 5.2 1.7 0.0 0.0 0.0 0 7.5 1.0 0.0 0.0 0.0 0 7.5 1.0 0.0 0.1 0.0 0.0 4.20 0.51 0.00 0.09 0.00 5 5 5 5 5 5 --e - Terminal Sacrifice LABCAT HE&.41c - I _ _ - - - 03-NOV-2ooO Page 251 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 9 _____~~ study Report f o r Hematology ~~ INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: RECOVERY STUDY I D : 28-DAY ORAL DOSEJRAT STUDY NO: 132-007 _ _ - ---A I _ - - - - - -- ----- SEX: FEMALE Animal I D L s o p h i l r Abnormal L Other --------- ----- THSN/CU MM THSN/CU MM THSN/CU MM _ _ _ _ _ _ _ _ _ l - - I - - - - - _ I - - - - I _ GRWP: 1-F 7570 e e e 7572 e e e 7574 e e e 7576 e e e 7578 e e e 7580 e e e 7582 e e e 7504 e e e 7586 e e e 7588 e e e 7590 0.0 0.0 0.0 7592 0.D 0.0 0.0 7594 0.0 0.0 0.0 7596 0.0 0.0 0.0 7598 0.0 0.0 0.0 HEAN SD N 0.0 0.00 5 0.0 0.00 5 0.0 0.00 5 - -e Terminal Sacrifice LABCAT HE4.41c I - -- 03-NOV-2ooO Page 252 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 GROUP: 4-F 7640 7642 7644 7646 7648 7650 7652 7654 7656 7658 7660 7662 7664 7666 7668 MEAN SD N e e e e e e e e e e 0.0 0.0 0.0 0.0 0.0 0.0 0.00 5 e e e e e e e e e e 0.0 0.0 0.0 0.0 0.0 0.0 0.00 5 t e e e e e e e e e 0.0 0.0 0.0 0.0 0.0 0.0 0.00 5 - --------e Terminal Sacrifice LABCAT HE4.41~ - - - - - - - - I _ _ - 03-NOV-2Mlo Page 253 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 Animal ID UBC RBC HGB HCT MCV MCH MCHC PLT ----------- THSN/CU MM MILL/CU MM GRAMS/DL X CU MICRONS PIC0 GRAMS X THSN/CU MM _-_----------I-___-- GROUP: 1-F 7570 8.8 6.63 15.4 41.3 62.3 23.2 37.3 1119 7572 9.9 6.49 14.9 40.1 61.8 23.0 37.2 1044 7574 3.4 6.27 15.1 41.3 65.9 24.1 36.6 1080 7576 7.1 7.34 16.0 64.1 60.1 21.8 36.3 1107 7578 5.1 6.91 15.4 42.2 61.1 22.3 36.5 1016 7580 15.2 6.47 15.3 41 .5 64.1 23.6 36.9 1044 7582 7584 7586 . 10.2 6.60 15.1 40.0 60.6 22.9 37.8 1231 14.9 6.74 15.6 41.6 61.7 23.1 37.5 922 14.0 6.74 15.6 41 .O 60.8 23.1 38.0 1172 7588 - - - - -- 7590 3.9 6.76 15.2 -- - 41.1 60.8 22.-5- 37.0 1163 -- - - - 7592 - - -- - - - - 7594 I - -- I - - - - -- 75% - - -- - - - - - - -- 7598 - - MEAN SD N 9.2 4.42 10 6.70 0.290 10 15.4 0.32 10 41.4 1.15 10 61.9 1.80 10 23.0 0.65 10 37.1 0.56 10 10% 88.9 10 GROUP: 2-F 7600 7602 7604 76423 7608 7610 7612 7614 761 6 7618 MEAN SO N 10.9 8.7 8.4 7.2 8.2 17.3 11.3 CL 14.1 14.6 11.2 3.47 9 7.00 6.41 6.41 7.16 6.59 7.19 7.53 CL 7.47 6.22 6.89 0.490 9 15.4 15.1 14.5 15.7 15.2 15.4 16.6 CL 15.8 14.4 15.3 0.67 9 42.7 41.2 39.7 43.1 41 .O 42.5 45.8 CL 42.5 37.8 41.8 2.26 9 61.0 64.3 61.9 60.2 62.2 59.1 60.8 CL 56.9 60.7 60.8 2.06 9 22.0 23.6 22.6 21.9 23.1 21.4 22.0 CL 21.2 23.2 22.3 0.84 9 36.1 36.7 36.5 36.4 37.1 36.2 36.2 CL 37.2 38.1 36.7 0.65 9 746 029 1760 1423 1337 1075 1094 CL 908 1225 1155 320.3 9 ~~~ (--) - Data Unavailable U8CAT HE4.41~ CL - Clotted 03-NOV-2000 Page 254 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 GROUP: 3-F 7620 7622 7624 7626 7628 7630 7632 7634 7636 7638 MEAN SD N 7.6 3.9 6.4 10.6 4.9 10.6 9.7 5.4 3.3 11.4 7.4 3.02 10 GROUP: 4-F 7640 7642 7644 7646 7648 7650 7652 7654 7656 7658 7.560 7662 7664 7666 7668 MEAN SD N 4.6 11.8 3.1 9.1 9.4 9.2 6.9 10.1 11.6 11.7 - - - - - 8.8 3.00 10 6.93 6.55 6.52 6.94 5.97 6.97 7.39 6.28 7.25 6.61 6.74 0.437 10 -- 6.93 6.51 6.37 6.42 7.17 6.37 6.65 6.52 7.03 - 6.67 - I - 6.66 0.286 10 15.1 15.4 14.1 16.5 13.4 15.8 16.6 14.6 15.7 15.6 15.3 1.01 10 16.2 15.3 14.7 15.1 15.9 14.3 14.6 14.4 15.5 -- 15.7 - I -- 15.2 0.66 10 - - - - I - (--) - Data Unavailable LABCAT HE4.41c 42.1 42.4 40.0 46.0 37.4 42.8 45.4 38.7 42.2 41.6 41.9 2.68 10 43.8 42.6 40.1 40.1 44.4 38.0 39.0 39.0 42.0 41.8 -- -_- - 41 .I 2.16 10 60.8 64.8 61.3 66.3 62.7 61.4 61.5 61.7 58.2 62.9 62.2 2.22 10 63.2 65.4 63.0 62.4 61.9 59.6 58.7 59.8 59.7 62.7 I - - - -- 61.6 2.11 10 21.8 23.5 21.6 23.8 22.4 22.7 22.5 23.2 21.7 23.6 22.7 0.82 10 35.9 36.3 35.3 35.9 35.8 36.9 36.6 37.7 37.2 37.5 36.5 0.80 10 1414 768 1164 1030 1095 1439 809 1112 1087 1260 1118 221.2 10 23.4 23.5 23.1 23.5 22.2 22.4 22.0 22.1 22.0 23.5 I -- - - 22.8 0.68 10 37.0 35.9 36.7 37.7 35.8 37.6 37.4 36.9 36.9 - 37.6 -- - -- 37.0 0.68 10 1270 1038 1413 1291 1404 1124 1098 947 977 - 1112 -__ -- 1167 167.8 10 ---- 03-NOV-2M)O Page 255 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 9 Study Report for Hematology INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ___-I__ -- _ -_ - _ - _ _ - I - - - _ - - - - I - _----__ STUDY ID: 28-DAY ORAL DOSE/RAT STUDY NO: 132-007 --- -- - -I- _-- I -- - --- - -_-I-------- SEX: FEMALE -__-_1--- Animal ID PT seconds APT1 seconds NRBC COUNT Lymphocyte THSN/CU MM Segmented THSN/CU MM Bands THSN/CU MM Monocytes THSN/CU MM Eosirwphi 1 THSN/CU MI4 GRWP: 1-F -- 7570 -- 7572 --I 0 7.7 0.6 0.0 0.4 0.2 0 9.0 0.7 0.0 0.2 0.0 7574 14.8 39.0 0 3.0 0.4 0.0 0.0 0.0 7576 18.1 47.4 0 5.8 1.1 0.0 0.2 0.0 7578 12.6 25.3 0 4.5 0.4 0.0 0.1 0.1 7580 7582 -13.3 23.9 I 0 14.0 0.3 0.0 0.5 0.5 0 9.5 0.5 0.0 0.1 0.1 7584 7586 7588 7590 15.4 33.3 13.3 27.9 13.0 24.2 0 14.3 0.3 0.0 0.0 0.3 0 12.2 1.5 0.0 0.3 0.0 -- 0 3.7 0.2 0.0 0.0 0.0 1 1 MEAN SD N 14.4 1.93 7 GROUP: 2-F 7600 7602 7604 7606 7608 7610 7612 . 7614 7616 7618 MEAN SO N 13.8 19.4 13.6 14.5 13.3 14.0 17.2 14.4 15.6 13.3 14.9 i.9a 10 31.6 8.89 7 30.9 46.4 30.9 25.9 20.6 30.2 34.5 30.9 42.3 25.4 31.8 7.72 10 (--) - Data unavailable LABCAT HE4.41~ 0 8.4 0.6 0.0 0.2 0.1 0.0 4.16 0.41 0.00 0.18 0.17 10 10 10 10 10 10 0 9.9 0.8 0.0 0.1 0.1 0 7.6 0.9 0.0 0.3 0.0 0 7.6 0.5 0.0 0.2 0.1 0 6.6 0.5 0.0 0.0 0.1 0 7.9 0.3 0.0 0.0 0.0 0 15.7 1.2 0.0 0.3 0.0 C0L 10-.1- 1-.o- 0-.0 0-.1 0-.1 0 13.3 0.4 0.0 0.1 0.3 0 12.6 1.5 0.1 0.1 0.3 0 10.1 0.8 0.0 0.1 0.1 0.0 3.11 0.40 0.03 0.11 0.12 9 9 9 9 9 9 --- CL - clotted -I-- 03-NOV-2ooO Page 256 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 GROUP: 3- F 7620 7622 7624 7626 7620 7630 7632 7634 7636 7630 MEAN SD N - GRWP: 4-F 7640 7642 7644 7646 7640 7650 7652 7654 7656 7650 7660 7662 7664 7.566 7668 MEAN SD N 14.6 14.1 14.1 17.5 12.5 14.9 14.3 14.9 13.6 13.9 14.4 1.20 10 14.3 15.4 14.1 17.5 17.3 15.2 13.9 16.0 10.9 --12.9 -_ --- - 15.6 1 .a 10 30.6 0 27.9 0 24.0 0 39.0 0 21.1 0 27.9 0 19.0 0 32.4 0 22.5 0 24.0 0 26.0 6.01 10 0 0.0 10 - 26.6 0 27.9 0 20.5 0 24.1 0 39.0 0 22.5 1 22.5 0 25.2 0 48.7 0 --23.4 - 0 -- - - --- I -- -- 28.9 0 0.60 0.3 10 10 --- (--I - Data Unavailable LAECAT HE4.41~ 6.9 3.4 5.4 9.6 4.1 0.1 0.0 5.0 3.1 10.1 6.4 2.60 10 4.4 11.2 2.5 7.4 8.4 7.5 5.6 0.4 10.9 -10.5 - ---- - 7.7 2.06 10 ---- 0.6 0.4 1.o 0.8 0.7 2.3 0.9 0.3 0.2 1.3 0.9 0.61 10 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.00 10 0.2 0.5 0.5 1.4 0.9 1.4 1.2 1.4 0.3 --0 . 8 - - I 0.9 0.47 10 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 --0.0 - --_ 0.0 0.00 10 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.03 10 0.0 0.0 0.0 0.1 0.0 0.2 0.0 0.0 0.3 0-.2_- - I - 0.1 0.11 10 0.1 0.0 0.0 0.1 0.0 0.1 0.0 0.0 0.0 0.0 0.0 0.05 10 - 1 0.0 0.1 0.0 0.3 0.1 0.1 0.0 0.3 0.0 0-.1 - _- 0.1 0.12 10 03-NOV-2ooO Page 257 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 Animal 10 Basophils THSN/CU MI! Abnormal L THSN/CU MI! Other THSN/CU MM ____--------__-----l___________l_____l_---- GROUP: 1-F 7570 0.0 0.0 0.0 7572 0.0 0.0 0.0 7574 0.0 0.0 0.0 7576 0.0 0.0 0.0 7578 0.0 0.0 0.0 7580 0.0 0.0 0.0 7582 0.0 0.0 0.0 7584 0.0 0.0 0.0 7586 0.0 0.0 0.0 7588 - - - 7590 - - -- 7592 - -- - 7594 -- - 7596 - - -- 7598 0.0 0.0 0.0 I MEAN SD N 0.0 0.00 10 0.0 0.M) 10 0.0 0.M) 10 GROUP: 2-F 76w 7602 760.4 7606 77610 761 2 761 4 7616 7610 MEAN SD N 0.0 0.0 0.0 0.0 0.0 0.0 0-.0 0.0 0.0 0.0 0.00 9 0.0 0.0 0.0 0.0 0.0 0.0 0.-0- 0.0 0.0 0.0 0.M) 9 0.0 0.0 0.0 0.0 0.0 0.0 0-.0 0.0 0.0 0.0 0.00 9 -- - - I (-) - Data Unavailable LABCAT H E 4 . 4 1 C - - - I 03-NOV-2ooO Page 258 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 STUDY I D : 28-DAY ORAL DOSE/RAT STUDY NO: 132-007 Animal I D Basophils Abnormal L Other - THSN/CU MH THSN/CU HH THSN/CU HI! ~----___----______-____ ---- GROUP: 3-F 7620 0.0 0.0 0.0 7622 0.0 0.0 0.0 7624 0.0 0.0 0.0 7626 0.0 0.0 0.0 7620 0.0 0.0 0.0 7630 0.0 0.1 0.0 7632 0.0 0.0 0.0 7634 0.0 0.0 0.0 7636 0.0 0.0 0.0 7638 0.0 0.0 0.0 HEAN SD N 0.0 0.00 10 0.0 0.03 10 0.0 0.00 10 GROUP: 4-F 7640 7642 7644 7646 764a 7650 7652 7656 7656 7658 7660 7662 ?t& 7666 7668 MEAN SD N 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0-.0 - - -- 0.0 0.00 10 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 I 0.0 0.03 10 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 -0.0 0.0 0.00 10 UBCAT HE4.41~ SEX: FEMALE ---_-___ 03-NOV-2oOO Page 259 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 STUDY I D : 28-DAY ORAL DOSEIRAT STUDY NO: 132407 SEX: FEMALE Animal I D UEC THSN/CU HH RBC HILL/CU HH me GRAHS/DL HCT HCV HCH X CU MICRONS PIC0 GRAMS HCHC X PLT THSN/CU HH __-_________-___1_1_111_--__-__--_----1-1_-------____- GROUP: I - F 7570 7572 7574 7576 7578 7580 7582 7584 7586 7588 7593 7592 7594 7596 7598 e e e e e c e e e e 10.1 10.0 7.1 12.8 8.7 e e e e e e . e e e e 6.79 7.46 7.33 7.41 6.74 e e e e e e e e e e 15.1 15.0 14.9 16.3 14.4 c C e e e e e e C e 41.4 41.6 41.6 44.7 39.0 e e e e e e e e e e 60.9 55.7 56.8 60.3 57.9 e e e e e e e e e e 22.2 20.1 20.3 22.0 21.4 e e e c e e e e e e 36.5 36.1 35.8 36.5 36.9 e e C e e e e e e e 1350 1349 1106 1330 1059 MEAN SD N 9.7 2.10 5 7.15 0.351 5 15.1 0.70 5 41.7 2.02 5 58.3 2.23 5 21.2 0.W 5 36.4 0.42 5 1239 143.9 5 _-- -e Terminal Sacrifice LABCAT HE4.41C - _ _ _ I _ - - - 03-NOV-2oaO Page 260 A 28-Day Oral Toxicity Study in Sprague-DawleyRats APPENDIX 9 Study Number: 132-007 STUDY ID: 28-DAY ORAL DOSE/RAT STUDY MY: 132-007 Animal ID UBC THSN/CU MM R8C MILL/CU MM GROUP: 4-F 7640 7642 7644 7646 7648 7650 7652 7654 7656 7658 7660 7662 7664 7666 7668 e e e e e e e e e e 6.0 5.4 16.1 6.9 8.5 e e e e e e e 'e e e 7.50 6.08 6.88 7.15 6.86 MEAN SD N 8.6 4.36 5 6.89 0.524 5 HG8 GRAMS/DL e e e e e e e e e e 17.0 14.2 15.1 14.7 13.8 15.0 1.24 5 HCT MCV MCH X CU MICRONS PIC0 GRAMS e e e e e e e e e e 46.1 37.5 40.6 40.5 38.4 40.6 3.34 5 e e e e e e e e e e 61.5 61.6 59.0 56.6 56.0 58.9 2.63 5 e e e e e e e e e e 22.7 23.4 21.9 20.6 20.1 21.7 1.39 5 SEX: FEMALE MCHC % PLT THSN/CU MM e e e e e e e e e e 36.9 37.9 37.2 36.3 35.9 36.8 0.78 5 e e e e e e e e e e 968 801 %7 1212 1024 994 147.5 5 LAECAT HE4.41 c 03-NOV-2M)o Page 261 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 STUDY I D : 28-DAY ORAL DOSE/RAT SEX: FEMALE STUDY NO: 132-007 _ _ _ I - _ _ ___ _ ____ - _-- - ---- - -I_ - _ - - - - Animal ID PT APTT NRBC Lylnphocyte Segmented Bands Monocytes Eosinophi 1 seconds seconds COUNT THSN/CU MH THSN/CU MH THSN/CU MH THSN/CU MM THSN/CU HH GROUP: I - F 7570 7572 7574 7576 7578 7580 7582 7584 7586 7588 7590 7592 7594 75% 7598 MEAN SO N e e e e e e e e e e 12.4 13.0 12.1 11.8 12.2 12.3 0.45 5 e e e e e e e ' e e e 17.8 19.9 18.1 18.6 18.3 18.5 0.81 5 e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e 0 9.5 0.6 0.0 0.0 0.0 0 8.7 1.2 0.0 0.1 0.0 0 6.5 0.6 0.0 0.0 0.0 0 11.8 1.o 0.0 0.0 0.0 0 7.9 0.8 0.0 0.0 0.0 0 8.9 0.8 0.0 0.0 0.0 0.0 1.97 0.26 0.00 0.04 0.00 5 5 5 5 S 5 _---- - e Terminal Sacrifice LABCAT HE4.41C _ - _ - I _ _ - - - - - - - - - - 03-NOV-2MM Page 262 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 9 Study Report for Hematology INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: RECOVERY STUDY I D : 28-DAY ORAL DOSEIRAT STUDY NO: 132-007 -- - - - - - - - - - - - - - - - - - I - - -----__I ---_ Animal I D PT seconds APTT seconds NRBC COUNT Lymphocyte THSN/CU MH Segmented THSN/CU HH Bands THSN/CU HH Monocytes THSN/CU HM SEX: FEMALE Eosinophil THSN/CU HH GROVP: 4- F 7640 7642 7644 7646 7648 7650 7652 7654 7656 7650 7660 7662 7664 7666 -7668 MEAN ' SD N e e e e e e e e e e 12.7 13.2 12.9 12.7 12.8 12.9 0.21 5 e e e e e e . e e e e 21 .o 23.6 19.6 19.0 21.2 21 .o 1.60 5 e e e e e e e e e e e e e e e e e e e e 0 5.6 0 4.6 0 14.8 0 5.2 0 7.5 0 7.5 0.0 4.20 5 5 e e e e e e e e e e 0.3 0.8 1.1 1.7 1.o 1.0 0.51 5 e 0.0 0.0 0.0 0.0 0.0 0.0 0.00 5 e e e e e e e e e e 0.1 0.0 0.2 0.0 0.0 0.1 0.09 5 e e e e e e e e e e 0.0 0.0 0.0 0.0 0.0 0.0 0.00 5 ---- d_- e - Terminal Sacrifice UBCAT HE4.41~ -- 03-NOV-2ooO Page 263 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 9 ___-__---_ ___-________S-t_u_d_y__R-e-p_o--r_t---f--o--r---H--e-m--a--t-o--l--o-g--y-_--_- INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: - - - - --------lll---_______--_l-_- -_-_ll_ - - I - RECOVERY ---- STUDY IO: &DAY ORAL DOSE/RAT SEX: FEMALE STUDY NO: 1 3 2 4 0 7 __________1-_1-___-___1__1______--I --- _--- Animal I D Basophils Abnormal L Other THSN/CU MM THSN/CU MM THSN/CU MM __-----__ _ _ _ _ __ _ _ _ __ __ GROUP: 1-F 7570 c e e 7572 C e e 7574 e C C 7576 e e e 7570 e e t 7580 e e e 7582 e c e 7584 e e e 7586 e e e 7588 e e e 7590 0.0 0.0 0.0 7592 0.0 0.0 0.0 7594 0.0 0.0 0.0 7596 0.0 0.0 0.0 7590 0.0 0.0 0.0 MEAN SD N 0.0 0.00 5 0.0 0.00 5 0.0 0.00 5 e - Terminal Sacrifice LAECAT H E 4 . 4 1 ~ 03-NOV-20M) Page 264 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 Animat I D Basophils Abnormal L Other ----- THSN/CU Mll THSN/CU MM THSN/CU flM - - - I - - - - - - - - -_ - - _ - ___---- - _ - I _ I_- ~ GROUP: 4-F 7640 e e e 7642 e e e 7644 e e e 7646 e e e 7- e e e 7650 e e e 7652 e e e 7654 e e e 7656 e e e 7658 e e e 7650 0.0 0.0 0.0 7662 0.0 0.0 0.0 7664 0.0 0.0 0.0 7666 0.0 0.0 0.0 7668 0.0 0.0 0.0 MEAN SD N 0.0 0.00 5 0.0 0.00 5 0.0 0.00 5 ----- e - Terminal Sacrifice LABCAT HE4.41~ 03-NOV-2ooO Page 265 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7569 7571 7573 Nucleated Red Cells Lymphocytes Segmented Neutrophi Ls Bands Monocytes Eosinophi 1s Basophi 1s Abnormal Lymphocytes Other UBC Nucleated Red Celts Lymphocyte$ Segmented Neutrophils Bands nonocyter Eosinophi 1s Basophils Abnormal Lymphocytes Other UBC Nucleated Red Cells Lymphocytes Segmented Neutrophi 1s Bands Monocytes Eosinophi 1s Basophi 1s AbnOrMl LymCytes Other UBC 0 94 7.1 5 0.4 0 0.0 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 7.5 0 93 5 .o 6 0.3 0 0.0 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 5.4 0 96 10.3 2 0.2 0 0.0 2 0.2 0 0.0 0 0.0 0 0.0 0 0.0 10.7 _____-- LABCAT HE4.41~ - 03-NOV-2ooO Page 266 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 STUDY ID: 28-DAY ORAL DOSEIRAT STUDY NO: 132-007 ----------- Animal ID --__--- 7575 7577 7579 GROUP: 1-M --- Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophi 1s Abnornal Lymphocytes Other UBC Nucleated Red Cells Lymphocytes Segmented Neutrophi 1s Bands Monocytes Eosinophi 1s Basophi 1s A b n o r M l LyDphocytes Other UBC Nucleated R e d Cells Lynphocytes Segmented Neutrophils Bands Monocytes Eorinophi 1s Rasophi 1s Abnormal Lymphocytes Other UBC TERMINAL - CNT ABS 0 90 18.5 8 1.6 0 0.0 0 0.0 2 0.4 0 0.0 0 0.0 0 0.0 20.6 0 93 7.1 7 0.5 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 7.6 0 92 11.8 7 0.9 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 0 0.0 12.8 -___- SEX: MALE -- LABCAT HE4.41c - - - - I _ - 03-NOV-2wO Page 267 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7581 7583 7585 Nucleated Red Cells Lymphocytes Segmented Neutrophi 1s Bands Monocytes Eosinophi 1s Basophils Abnormal Lymphocytes Other UEC Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophi 1s Basophi 1s Abnormal Lymphocytes Other UBC Nucleated Red C e l l s Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Batophi 1s Abnormal Lyaphocytes Other YBC 0 91 11.4 9 1.1 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 12.5 0 91 7.2 5 0.4 1 0.1 0 0.0 3 0.2 0 0.0 0 0.0 0 0.0 7.9 0 90 7.3 9 0.7 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 0 0.0 8.1 Page 268 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7587 Nucleated Red Cells 1 Lymphocytes 93 Segmented Neutrophils 6 Bands 0 Monocytes 0 Eosinophi 1s 1 Basophi 1s 0 Abnormal Lymphocytes 0 Other 0 UBC 7589 Nucleated Red Cells 0 Lynphocytes 0 Segmented Neutrophi 1s 0 Bands 0 tbnocytes 0 Eosin@+ 1s 0 Basophi 1s 0 Abnormal Lymphocytes 0 Other 0 UBC 7591 Nucleated Red Cells 0 Lynphocytes 0 Segmted Neutrophils 0 Bands 0 Mwcytcs 0 Eorinophi 1s 0 Basophi I s 0 Abnormal Lymphocytes 0 Other 0 YBC (--I - Data Unavailable LABCAT HE4.41c --- I _ _ _ - - 03-NOV-2WO Page 269 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7593 Nucleated R e d Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophi 1s 0 Basophi 1s 0 Abnormal Lymphocytes 0 Other 0 UBC 7595 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 monocytes 0 Eosinophils 0 Basophi 1s 0 Abnormal Lymphocytes 0 Other 0 UBC 7597 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophils 0 Basophi 1s 0 Abnormal Lymphocytes 0 Other 0 UBC LAECAT HE4.41c 03-NoV-2ooO Page 270 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7559 7601 7603 Nucleated Red Cells Lymphocytes Segmented Ncutrophi 1s Bands Monocytes E o s i m p h i 1s Easophi 1s Abnormal Lymphocytes Other uec Nucleated Red Cells Lynphocytes Segmented Neutrophils Band, Monocytes E o r i n q h i 1s Easophi 1s Abnormal Lymphocytes Other uec Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Momcytes Eosinophi 1s Basophi 1s Abnormal Lymphocytes Other uec 0 88 9.5 11 1.2 0 0.0 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 10.8 0 83 9.6 16 1.9 0 0.0 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 11.6 0 85 11.8 15 2.1 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 13.9 Page 271 A 26-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 __________--___St_ud_y_--R--e_-p-__o_r_t-_f_o-_r__H-e_m-atology WHITE DIFFERENTIAL DATA _ _ _ I - - - - - --- I - ___-----I___ STUDY I D : 28-DAY ORAL DOSE/RAT --- ----- STUDY No: 132-007 GROUP: 2-M SEX: MALE ___- - - - _ I _ - _ -I____ Animal ID TERMINAL _____-_--- _ 1 _ 1 - CNT ABS - 760s Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophi1s Easophi 1s Abnormal Lymptmcytes Other YEC 0 a9 15.6 10 1 .(I 0 0.0 0 0.0 0 0.0 0 0.0 1 0.2 0 0.0 17.5 7607 Nucleated Red Cells Lymphocytes Segmented Neutrophi 1s Bands Monocytes Eosinophi 1s brei1s A b n o r m a l Lymphocytes Other UEC 0 90 12.9 10 1.4 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 14.3 7609 Nucleated R e d Cells Lynphocytes Segmented N e u t r o p h i 1s Bands Monocytes Eosinophi 1s & s e i 1s Abnormal Lymphocytes Other YEC 0 a3 9.8 16 1.9 0 0.0 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 11.8 -- LAECAT HE4.41C I _ - - - - -- 03-NOV-2ooO Page 272 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 Animal I D 761 1 7613 7615 Nucleated Red Cells Lymphocytes Segmented Neutrophi 1s Bands Monocytes Eosinophi 1s Basophi 1s Abnormal Lynyhcytes Other WBC Nucleated R e d Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophi 1s Basaphi 1s Abnormal Lymphocytes Other YBC Nucleated Red Cells Lymphocytes Segmented Neutrophi 1s Bands Monocytes Eosinophi 1s Barophi 1s Abnormal Lynphocytes Other UEC TERMINAL CNT ABS 0 80 6.6 19 1.6 0 0.0 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 8.3 0 88 9.0 12 1.3 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 11.1 0 92 7.1 7 0.5 0 0.0 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 7.7 Page 273 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7617 Nucleated R e d Cells Lymphocytes Segmented Neutrophils Bad+ Monocytes Eorinophi 1s Basophi Ls Abnormal Lymphocytes Other UEC 0 84 12.3 14 2.0 0 0.0 0 0.0 2 0.3 0 0.0 0 0.0 0 0.0 14.6 -- I LABCAT HE4.41 c 03-NOV-2ooO Page 274 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7619 7621 7623 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophi 1s Basophil o Abnormal Lymphocytes Other UBC Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophi 1s Abnormal Lymphocytes Other UBC Nucleated Red C e l l s Lymphocytes Segmented Neutrophi 1s Bands Monocytes Eosinophi 1s Besophi 1s Abnormal Lymphocytes Other YBC 0 90 8.1 10 0.9 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 9.0 0 95 9.5 5 0.5 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 10.0 0 93 8.0 7 0.6 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 8.6 LABCAT HE4.41~ 03-NOV-2ooO Page 275 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7625 7627 7629 Nucleated Red Cells Lymphocytes Segmented Neutrophi 1s Bands Monocytes Eosinophils Basophi 1s Abnormal Lymphocytes Other YEC Nucleated Red Cells Lymphocytes Segmented Neutrophi 1s Bands Monocytes Eosinophils Basophi 1s Abnormal Lymphocytes Other YBC Nucleated Red Cells Lynphocytes Segmented Neutrophi 1s Bands Monocytes Eosinophils Bascphi ts Abnormal Lyaphocytes Other UBC 0 90 9.8 10 1.1 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 10.9 0 85 12.1 13 1.8 0 0.0 0 0.0 2 0.3 0 0.0 0 0.0 0 0.0 14.2 0 71 6.5 29 2.6 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 9.1 03-NOV-2OW Page 276 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 Animal I D ----__________ __ ---____I__ 7631 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands knocytes Eosinophi 1s Basophi 1s Abnormal Lymphocytes Other UEC 7633 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Umocytes Eosirmphi 1s 6asophi 1s Abnormal Lymphocytes Other UEC 7635 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophi 1s Easophi 1s Abnorlal Lynphocytes Other YBC TERMINAL ----_ CMT ABS ~ 0 88 12.7 11 1.6 0 0.0 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 14.4 0 96 13.9 2 0.3 0 0.0 1 0.1 1 0.1 0 0.0 0 0.0 0 0.0 14.5 0 93 6.5 7 0.5 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 7.0 -- -----_____ LABCAT H E 4 . 4 1 ~ 03-NOV-2ooO Page 277 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 9 Study Report for Hematology WHITE DIFFERENTIAL DATA STUDY I D : 28-DAY ORAL DOSE/RAT STUDY NO: 132-W7 ----- - ---- Animal ID 7637 GROUP: 3-M TERMINAL CNT ABS -~--I_------ Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basephi is Abnormal Lymphocytes Other UBC 0 93 6.1 6 0.4 0 0.0 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 6.6 SEX: MALE Page 278 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Report f o r Hematology WHITE DIFFERENTIAL DATA STUDY IO: 28-DAY ORAL DOSEIRAT STUDY NO: 132-007 GROUP: 4-tl Animal I D TERNINAL CNT ABS __-_----------_---I--I -- ---- -_ _ - - _- 7639 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands nonocytes Eosinophi 1s Batophi 1s Abnormal Lymphocytes Other UEC 0 as 8.5 15 1.5 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 10.0 7641 7643 Nucleated Red Cells Lynphocytes Segmented Neutrophils Bands nonocytes Eosinophils Basophi 1s Abnormal Lymphocytes other UEC Nucleated Red Cells Lymphocytes Segmented Neutrophils Bards nonocytes Eosincphi 1s Basophi 1s Abnormal Lynphocytes Other UBC 0 91 11.2 7 0.9 0 0.0 2 0.2 0 0.0 0 0.0 0 0.0 0 0.0 12.3 0 95 7.8 5 0.4 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 8.2 Study Number: 132-007 SEX: NALE Page 279 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7645 7647 7649 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands nonocytes Eosinophi 1s Basophi 1s Abnormal Lymphocytes Other UBC Nucleated Red Cells Lymphocytes Segmented Neutrophi 1s Bands Monocytes Eosinophils Basophi 1s Abnormal Lymphocytes Other uec Nucleated Red Cells Lymphocytes Segmented Neutrophi 1s Bands nonocytes Eosinophils Basophi 1s Abnormal Lynphocytes Other YBC 0 85 9.8 12 3.4 a 0.0 3 0.3 0 0.0 0 0.0 0 0.0 0 0.0 11.5 0 85 5.0 11 0.7 0 0.0 2 0.1 2 0.1 0 0.0 0 0.0 0 0.0 6.8 0 89 6.9 10 0.8 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 0 0.0 7.8 __-___I_- LABCAT HE4.41 t -____--- _-__I- 03-NOV-H)oo Page 280 A 26-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7651 7653 7655 Nucleated Rea Cells Lymphocytes Segmented Neutrophi 1s Bands Honocytes Eosinophi 1s Pasophi 1s Abnormal Ly-cytes Other UBC Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands mcyter Eosinophi 1s Basophi 1s Abnormal Lymphocytes Other UBC Nucleated Red Cells Lylnphocytes Segmented Neutrophi 1s Bands Nonocytes Eosinophi 1s Basophi 1s Abnormal Lymphocytes Other UBC 0 90 8.7 7 0.7 0 0.0 1 0.1 2 0.2 0 0.0 0 0.0 0 0.0 9.7 0 84 6.6 14 1.1 0 0.0 2 0.2 0 0.0 0 0.0 0 0.0 0 0.0 7.9 0 95 11.4 4 0.5 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 0 0.0 12.0 LABCAT HE4.41~ 03-NOV-2ooO Page 281 A 26-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 STUDY I D : 28-DAY ORAL DOSEfRAT STUDY NO: 132-007 Animal I D _ - - - _ I - - - - 7657 7659 7661 GROUP: 4-11 ------ Nucleated Red Cells Lymphocytes Segmented Neutrophi 1s Bands Monocytes Eosinophi 1s Basophi 1s Abnormal Lymphocytes Other UEC Nucleated R e d Cells Lyrnphocytes Segmented Neutrophils Bands Monocytes Eosinophi 1s Basophi 1s Abnorual Lymphocytes Other UBC Nucleated Red Cells Lymphocytes Segmented Neutrophils Band. bmcyter EosiMphi 1s Basophi 1s Abnormal Lynphocytes Other UBC TERMINAL CNT ABS 0 88 8.0 9 0.8 0 0.0 2 0.2 1 0.1 0 0.0 0 0.0 0 0.0 9.1 -- SEX: MALE . -- -_-- _--- - - (--) Data Unavailable LAECAT HE4.41 C 03-NOV-2UM Page 282 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7663 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophi 1s 0 BandS 0 Monocytes 0 Eosinophi 1s 0 Basophils 0 Abnormal LynphoCyteS 0 Other 0 UBC 7665 Nucleated Red C e l l s 0 Lymphocytes 0 Segmented Neutrophi 1s 0 Bands 0 Mcmocytes 0 Eosinophi 1s 0 Basophi 1s 0 Abnorml Ly-cytes 0 Other 0 UBC 7667 Nucleated Red Cells 0 Lyaphocytes 0 Segmented Neutrophi 1s 0 Bands 0 Monocytes 0 Eosinophi 1s 0 Basophi 1s 0 Abnormal Lylphocytes 0 Other 0 UBC --- (--) Data Unavailable UBCAT H E 4 . 4 1 ~ -- -- 03-NOV-2ooO Page 283 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7570 7572 7574 Nucleated Red Cells Lymphocytes segmented Neutrophils Bands Monocytes Eosinophi 1s Basophi 1s Abnormal Lymphocytes Other UBC Nucleated Red Cells Lymphocytes Segmented N e u t r o p h i 1s BandS Monocytes Eosinophi 1s B a e i 1s AbnorMl LyilphoCyteS Other UBC Nucleated R e d Cells Lymphocytes segmented Neutrophi 1s Bands Monccytes Eosimphi 1s Basophi 1s Abnormal Lynphocytes Other YBC 0 87 7.7 7 0.6 0 0.0 4 0.4 2 0.2 0 0.0 0 0.0 0 0-0 8.8 0 91 9.0 7 0.7 0 0.0 2 0.2 0 0.0 0 0.0 0 0.0 0 0.0 9.9 0 89 3.0 11 0.4 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 3.4 ---- _ _ - _ I _ - - - LABCAT HE4.41c ------ 03-NoV-N)oo Page 204 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7576 7578 7580 Nucleated Red Cells Lymphocytes Segmented Neutrophi 1s Bands Monocytes Eosinophils Basophi 1s Abnormal Lymphocytes Other UBC Nucleated R e d Cells Lylphocytes Segmented N e u t r o p h i 1s Bands Monocytes Eosinophils Basophi 1s Abnormal Lymphocytes Other UEC Nucleated Red Cells Lymphocytes Segmented Nautrophi 1s Bands Monocytes Eosinophils Basophi 1s Abnormal Lynphocytes Other UBC 0 82 5.8 15 1.1 0 0.0 3 0.2 0 0.0 0 0.0 0 0.0 0 0.0 7.1 0 89 4.5 8 0.4 0 0.0 2 0.1 1 0.1 0 0.0 0 0.0 0 0.0 5.1 0 92 14.0 2 0.3 0 0.0 3 0.5 3 0.5 0 0.0 0 0.0 0 0.0 15.2 Page 285 A 28-Day Oral Toxicity Study in Sprague-DawleyRats APPENDIX 9 Study Number: 132-007 7582 7584 7586 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophi 1s Barophi 1s Abnormal Lymphocytes Other UBC Nucleated Red Cells Lymphocytes Segmented Neutrophi 1s Bands Monocytes Eosinophi 1s Basophi 1s A h r m a l Lynphocytes Other UBC Nucleated Red Cells Lyllphocytes Segmented Neutrophils Bands Monocytes Eosinophi 1s Basophi 1s A b n O r M L Lylnphocytes Other UBC 0 93 9.5 5 0.5 0 0.0 1 0.1 1 0.1 0 0.0 0 0.0 0 0.0 10.2 0 96 14.3 2 0.3 0 0.0 0 0.0 2 0.3 0 0.0 0 0.0 0 0.0 14.9 0 07 12.2 11 1.5 0 0.0 2 0.3 0 0.0 0 0.0 0 0.0 0 0.0 14.0 ---- -- _I__________- --^---I LABCAT HE4. 41 C 03-WV-2MX) Page 286 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 _--------------- Animal I D TERMINAL --- CNT ABS -- --- 7588 Nucleated Red Cells 0 Lymphocytes 96 3.7 Segmented Neutrophi 1s 4 0.2 Bands 0 0.0 tlonocytes 0 0.0 Eosinophi 1s 0 0.0 Basophi 1s 0 0.0 A h r m l Lymphocytes 0 0.0 Other 0 0.0 UBC 3.9 7590 Nucleated Red Cells 0 Lymphocytes Segmented Neutrophils Bands nonocytes Eosinophi 1s Basophi 1s Abnorml Lymphocytes Other UBC 7592 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Ilonocytes Eosinophils Basophi 1s Abnoraal Lymphocytes Other UBC (--I - Data Unavaileble U B C A T HE4.41c 03-NOV-2OOO Page 287 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7594 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophi 1s 0 Bands 0 Monocytes 0 Eosinophi 1s 0 Basophi 1s 0 Abnormal Lymphocytes 0 Other 0 UEC 75% Nucleated R e d Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 nonocytes 0 Eosinophi 1s 0 Easophi 1s 0 Abnormal Lymphcytes 0 Other 0 UBC 7590 Nucleated Red C e l l s 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophi 1s 0 Basophi 1s 0 Abnormal Lymphocytes 0 Other 0 WBC LABCAT HE4.41~ 03-NOV-2000 Page 288 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7m 7602 7604 Nucleated Red Cells Lymphocytes Segmented Neutrophils Eands Monocytes Eosinophils Basophi 1s Abnormal Lymphocytes Other YBC Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophi 1s Basophi 1s Abnormal Lymphocytes Other YBC Nucleated Red Cells Lymphocytes Segmented Neutrophils BandS bonocytes Eosinophi 1s Basophi 1s Abnormal LyAphocytes Other UBC 0 91 9.9 7 0.8 0 0.0 1 0.1 1 0.1 0 0.0 0 0.0 0 0.0 10.9 0 87 7.6 10 0.9 0 0.0 3 0.3 0 0.0 0 0.0 0 0.0 0 0.0 8.7 0 91 7.6 6 0.5 0 0.0 2 0.2 1 0.1 0 0.0 0 0.0 0 0.0 8.4 --- __ I _ - - LABCAT HE4.41~ 03-WV-2oOO Page 289 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7606 7608 7610 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands nonocyter Eosinophi 1s Basophi 1s Abnormal Lymphocytes Other UBC Nucleated R e d Celts Lymphocytes Segmented Neutrophi 1s Bands nonocytes Eosinophils Basophi 1s Abnormal Lymphocytes Other UBC Nucleated R e d Cells Lymphocytes Segmented Neutrophils Bands Monacytes Eosinophi 1s Basophi 1s Abnormal Lynphocytes Other UBC 0 92 6.6 7 0.5 0 0.0 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 7.2 0 96 7.9 4 0.3 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 8.2 0 91 15.7 7 1.2 0 0.0 2 0.3 0 0.0 0 0.0 0 0.0 0 0.0 17.3 - - I - - - LABCAT HE&.41c l___l 03-NOV-2ooO Page 290 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9' Study Number: 132-007 7612 7614 7616 Nucleated Red Cells Lynphocytes Segmented Neutrophi 1s Bands nmcytes Eosinophi 1s Basophi 1s Abnormal Lymphocytes Other WBC Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands monocytes Eosinophi 1s BaDophi 1s Abnormal Lymphocytes Other UBC Nucleated R e d Cells Lymphocytes Segmented Neutrophi 1s Bands Nonocytes Eosinophils ' B a s e i 1s AbnorMl Lynphocytes Other UBC 0 89 10.1 9 1.0 0 0.0 1 0.1 1 0.1 0 0.0 0 0.0 0 0.0 11.3 0 0 - 0 -- 0 - -- 0 0 -- 0 -- 0 _- 0 -- 1 0 94 13.3 3 0.4 0 0.0 1 0.1 2 0.3 0 0.0 0 0.0 0 0.0 14.1 _-_______ (--) - Data Unavailable LABCAT HE4.41c I-_____-- 03-N0V-m Page 291 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 -- -------I LABCAT HE4.41c I - - - - - - 03-NOV-2OW Page 292 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7620 7622 7624 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lynphocytes Other UBC Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands mocytes E o s i r q h i 1s Basophi 1s Abnormal Lymphocytes Other UBC Nucleated Red Cells Lymphocytes Segmented Neutrophi 1s Bands monocytes E o s i r q h i 1s Basophi 1s Abnormal Lymphocytes Other UBC 0 91 6.9 0 0.6 0 0.0 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 7.6 0 88 3.4 11 0.4 0 0.0 0 0.0 1 0.0 0 0.0 0 0.0 0 0.0 3.9 0 84 5.4 16 1 .o 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 6.4 Page 293 A 26-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 9 Study Report f o r Hematology __----------- - STUDY I D : 28-DAY ORAL DOSE/RAT _-S-T-U-D-Y--N-O-:-_1_32_-0-0_7___---------- WHITE DIFFERENTIAL DATA ---------_ --~----___----- GROUP: 3-F SEX: FERALE -I--_______I_ Animal I D ---------_-___-----_____I TERRINAL CNT -- ABS --____ 7626 Nucleated Red Cells Lymphocytes Segmented Neutrcphi 1s Bands Monocytes Eosinophi 1s Basophi 1s Abnormal Lymphocytes Other UBC 0 91 9.6 a 0.8 0 0.0 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 10.6 7620 Nucleated Red Cells 0 Lymphocytes a3 4.1 Segmented Neutrophils 15 0.7 Bands 0 0.0 nonocytes 1 0.0 Eosinophi 1s 1 0.0 Bssophi 1s 0 0.0 Abnornal Lymphocytes 0 0.0 i Other YBC 0 0.0 4.9 7630 Nucleated Red Cells Lynphocytes Segmented Neutmphils Bands tbnocytes Eosinophi 1s Basophi 1s Abnormal Lyllphocyter Other WBC 0 76 0.1 22 2.3 0 0.0 0 0.0 1 0.1 0 0.0 1 0.1 0 0.0 10.6 UBCAT HE4.41 c 03-NOV-Moo Page 294 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7632 7634 7636 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophi 1s Basophi 1s Abnormal Lymphocytes Other UBC Nucleated R e d Cells Lymphocytes Segmented Neutrophi 1s Bands Monocytes Eosimphi 1s Basophi 1s Abnormal Lymphocytes Other UBC Nucleated R e d Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosimphi 1s Basophi 1s Abnormal Lymphocytes Other UBC 0 91 8.8 9 0.9 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 9.7 0 93 5.0 5 0.3 0 0.0 2 0.1 0 0.0 0 0.0 0 0.0 0 0.0 5.4 0 94 3.1 6 0.2 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 3.3 Page 295 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 9 Study Report f o r Hematology WHITE DIFFERENTIAL DATA STUDY I D : 2&DAY ORAL DOSEIRAT ------ STUDY NO: 132-007 GROUP: 3-F _--___I----__----_ Animal I D ___--__ll__-_---l---l_l______ 7638 Nucleated R e d Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eorinophi 1s Basophi 1s Abnormnl Lymphocytes Other UBC ----------_____ SEX: FEMALE - - I - - - TERMINAL CNT ABS I_--------------p 0 89 10.1 11 1.3 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 11.4 Page 296 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7640 7642 7664 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophi 1s AbnorML Lymphocytes Other WBC Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands hwcytes Eosinophi 1s Basophi 1s Abnormal Lymphocytes Other UBC Nucleated Red Cells Lynphocytes Segmented Neutrophils Bands Monocytes Eosincphils Basophi 1s Abnormal Lymphocytes Other UBC 0 95 4.4 4 0.2 0 0.0 1 0.0 0 0.0 0 0.0 0 0.0 0 0.0 4.6 0 95 11.2 4 0.5 0 0.0 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 11.8 0 82 2.5 16 0.5 0 0.0 1 0.0 1 0.0 0 0.0 0 0.0 0 0.0 3.1 LABCAT HE4.41~ --I_ -- - 03-NoV-HxM Page 297 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7646 7.548 7650 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophi 1s Basophils Abnormal Lymphocytes Other WBC Nucleated Red Cells Lymphocytes Segmented Neutrophi 1s Bands bnocytes Eosinophi 1s Basophi 1s Abnormal Lylphocytes Other WBC Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophi 1s &tophi 1s Abnormal Lynphocytes Other UBC 0 81 7.4 15 1.4 0 0.0 7 0.1 3 0.3 0 0.0 0 0.0 0 0.0 9.1 0 89 8.4 10 0.9 0 0.0 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 9.4 1 82 7.5 15 1.4 0 0.0 2 0.2 1 0.1 0 0.0 0 0.0 0 0.0 9.2 Page 298 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7652 7654 7656 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands mocytes Eosinophi 1s Basophi 1s Abnormal Lymphocytes Other WBC Nucleated Red Cells Lymphocytes Segmented Neutrophi 1s Bands mcytes Eosinophi 1s Basophi 1s Abnormal Lymphocytes Other UBC Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophi 1s AbnorML Lyl@?OCyteS Other UBC 0 a1 5.6 18 1.2 0 0.0 0 0.0 0 0.0 0 0.0 1 0.1 0 0.0 6.9 0 a3 8.4 14 1.4 0 0.0 0 0.0 3 0.3 0 0.0 0 0.0 0 0.0 10.1 0 94 10.9 3 0.3 0 0.0 3 0.3 0 0.0 0 0.0 0 0.0 0 0.0 11.6 Page 299 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7.560 7662 Nucleated R e d Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophi 1s Basophi 1s Abnormal Lymphocytes Other UBC Nucleated Red Cells Lymphocytes S e g m t e d Neutrophi 1s Bands Monocytes E O S i M p h i LS Basophi 1s Abnormal Lymphocytes Other UBC -- ---- - I - (--) - Data Unavailable LABCAT HE4.41~ - 03-NoV-2ooO Page 300 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7664 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophils 0 Bands 0 Monocytes 0 Eosinophi 1s 0 Basophi 1s 0 Abnormal Lymphocytes 0 Other 0 WBC 7666 Nucleated Red Cells 0 Lymphocytes 0 Segmented Neutrophi 1s 0 Bands 0 Mmcytes 0 Eosinophils 0 Basophi 1s 0 Abnormal Lymphocytes 0 Other 0 WBC 766a Nucleated Red Cells 0 Lymphocytes 0 Segmented Nwtrophi 1s 0 Bands 0 hocytcs 0 Eosinqahi 1s 0 Basophi Ls 0 Abnormal Ly+cytes 0 Other 0 WBC -- - (--) Data Unavailable LABCAT HE4.41c -- - - - - - - - - - - - - - I - - - - - 03-NOV-2000 Page 301 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7569 7571 7573 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands llonocytes Eosinophils Basophi 1s Abnormal Lymphocytes Other UBC Nucleated Red Cells Lynphocytes Segmented Neutrophils Bands Monocytes Eosinophi 1s Basophi 1s A b n O r M l Ly@lOCyteS Other UBC Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophi 1s AbnorMl LymphOCyteS Other UBC e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e c e (-) - Data Unavailable LABCAT HE4.41~ e - Terminal Sacrifice 03-NOV-2ooO Page 302 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7575 7577 7579 Nucleated Red Cells Lymphocytes Segmented Nwtrophi 1s Bands bcytes Eosinophi 1s Basophi 1s Abnormal Lymphocytes Other WBC Nucleated Red Cells LyPlphocytes Segmented Neutrophi 1s Bands llonocytes Eosinophils Basophi 1s Abnormal Lynphocytes Other UBC Nucleated Red Cells Lymphocytes S e g m t e d Neutrophi 1s Bands Mooocytes Eorinophi 1s Basophi 1s Abnormal Lymphocytes Other UBC e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e -- - - - I (-) - Data Unavailable LABCAT HE4.415 e - Terminal Sacrifice 03-NoV-2ooO Page 303 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7581 7583 7585 Nucleated R e d Cells Lymphocytes Segmented Neutrophi 1s Bands flonocyter Eosinophi 1s Besophi 1s Abnormal Lymphocytes Other UBC Nucleated R e d Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinqahils Basmi1s Abnormal Lymphocytes Other UBC Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophi 1s Basophi 1s Abnormal Lyaphocytes Other WBC e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e - - (--) Data Unavailable LABCAT HE4.41~ --___--- e Terminal Sacrifice 03-WV-2WO Page 304 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7589 7591 Nucleated Red Cells Lymphocytes Segmented Neutrophi 1s Bands Monocytes Eosinophi 15 Basophiis Abnormal Lymphocytes Other UBC Nucleated Red Cells Lylphocytes Segmented Neutrophi 1s Bands Honocytes Eosincphi 1s Basophi 1s Abnormal Lymphocytes Other UBC 0 92 12.0 7 0.9 0 0.0 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 13.0 0 95 18.2 5 1.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 19.2 -e - Terainal Sacrifice LABCAT HE4.41C -____-____---I_--- --- 03-NOV-2ooO Page 305 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 9 I I -- Study Report f--o---r Hematology ---I------ WHITE DIFFERENTIAL DATA - -------- - - - - -- --- - - --- - -I - - --- - - -_ I _ - _----I__ ~__- STUDY I D : .?&DAY ORAL DOSE/RAT __ST-U_DY-_No-:--1-3-2---0-0-7 _-__ GROUP: 1-M -ll-__l_____- ~ ___-_S_EX: _MAL_E __- Animal ID RECOVERY CNT ABS 7593 Nucleated Red Cells Lymphocytes Segmented Neutrophils Eands Monocytes Eorinophi 1s Basophils Abnormal Lymphocytes Other UEC 0 85 12.1 14 2.0 0 0.0 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 14.2 7595 Nucleated R e d Cells Lynphocytes Segmented Neutrophi 1s Bands Monocytes Eosinophils Basophi 1s Abnormal Lymphocytes Other UEC 0 03 6.9 16 1.3 0 0.0 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 8.3 7597 Nucleated Red C e l l s Lymphocytes Segmented Neutrophils Eands tbnocytes Eosinophils Easophi 1s Abnormal Lymphocytes Other UEC 0 88 10.7 11 1.3 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 0 0.0 12.2 LAECAT HE4.41~ 03-NoV-2OW Page 306 A 26-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7641 7643 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosincphi 1s Basophils Abnormal Lynphocyter Other WBC Nucleated Red Cetls Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophi 1s Abnormal Lymphocytes Other uac e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e - - ~ - (--) Data Unavailable LABCAT HE4.41 C e - Terminal Sacrifice ----- 03-NOV-ZOW Page 307 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 STUDY I D : 28-DAY ORAL DOSE/RAT STUDY NO: 132-007 GROUP: 4-n 7645 7647 7649 Nucleated Red Cells Lymphocytes Segmented Neutrophi 1s Bands Monocytes Eosinophi 1s Basophi 1s Abnormal Lymphocyte$ Other UEC Nucleated Red C e l l s Lymphocytes Segmented Neutrophi 1s Band. mcytes Eorimphi 1s Basophi 1s AbnOrMl LyaphoCyteS Other UEC Nucleated Red Cells Lymphocytes Segmented Neutrophi 1s BMds Ibmcytes Eosimphi 1s Bascphi 1s Abnarml Lymphocytes Other UBC e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e c SEX: MALE -- __ (--I Data Unavailable IAECAT HE4.41c - -_-_- e Terminal Sacrifice 03-NOV-ZM)O Page 308 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 Animal I D ----------___-_-----______________I 7651 Nucleated Red Cells Lymphocytes Segmented Neutrophi l o Bands nonocytes Eosinophil o Basophils Abnorral Lymphocytes Other YEC 7653 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophi 1s Basophi 1s Abnormal Lymphocytes Other UBC 7655 Nucleated Red Cells LyDphocyres segmented Neutrophi 1s Bands Monocytes Eosinophi 1s Basophi 1s Abnormal Lyrphocytes Other UBC RECOVERY CNT ABS e e e e e e e e e e e e e e e e e e -----_--- (--) - Data Unavailable LAECAT HE4.41c -- - e Terminal Sacrifice 03-tiQV-2ooO Page 309 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7657 7659 7661 Nucleated R e d Cells Lymphocytes Segmented Neutrophils Bands nonocytes Eosinophils Basophi 1s A b n O r M l LyllphOCytet Other UBC Nucleated Red Cells Lynphocytes Segmented Neutrophils Bands fkonocyter Eorinophi 1s Basophi 1s A b m r l l a 1 Lymphocytes Other UBC Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands monocytes Eosinophils Basophi 1s Abnormal Lymphocytes Other uec e e e e e e e e e e e e e e e e e e 0 E9 10.2 11 1.3 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 11.5 0 92 8.7 7 0.7 0 0.0 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 9.5 ----- e - Terminal Sacrifice LABCAT HE4.41c - I 03-NOV-2aoO Page 310 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7665 7667 Nucleated R e d Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosincphi 1s Basophi 1s Abnormal Lymphocytes Other UBC Nucleated Red Cells Lymphocytes Segmented Neutrophi 1s Bands Monocytes E o s i m p h i 1s Basophi 1s Abnormal Lymphocytes Other UEC 0 85 10.7 13 1.6 0 0.0 2 0.3 0 0.0 0 0.0 0 0.0 0 0.0 12.6 0 88 14.8 11 1.8 0 0.0 1 0.2 0 0.0 0 0.0 0 0.0 0 0.0 qb.0 LAECAT HE4.41c 03-NOV-2ooO Page 311 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7570 7572 7574 Nucleated R e d Cells Lymphocytes Segmented Neutrophi 1s Bands nmcytes Eosinophi 1s Barophi 1s Abnormal Lymphocytes Other UBC Nucleated R e d Cells Lymphocytes Segmented Neutrophils Bands mcytes Eosinophi 1s Basophi 1s Abnormal Lyaphocytes Other UBC Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophi 1s Basophi 1s Abnormal Lylphocytes Other YBC e e e e e e e e e e e e e e c e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e _ _ - ~ - ___-_- (-) Data Unavailable LABCAT HE4.41 c -__--- --- ___ e - Terminal Sacrifice 03-Kw-2ooO Page 312 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7570 7580 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophi 1s Basophi 1s AbnorMl Lymphocytes Other YBC Nucleated R e d Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophi 1s Aboornal Lylphocytes Other UBC e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e -(--) - Data Unavailable LABCAT HE&. 41 C -_ e - Terminal Sacrifice -- 03-NOV-2OOO Page 313 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7582 7584 7586 Nucleated Red Cells Lymphocytes segmented Neutrophi 1s Bands Monocytes Eosinophi 1s Baiophi l s Abnormal Lymphocytes Other UBC Nucleated R e d Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophi 1s Abnorwl Lynphocytes Other UBC Nucleated R e d Cells Lymphocytes Segmented Neutrophi 1s Bands Monocytes Eosinophils Basophi 1s AbnOml Lyaphocyto Other uec e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e - - (-1 Data Unavailable UBCAT HE4.41C - - e Terminal Sacrifice - 03-NOV-2ooO Page 314 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7588 755-3 7592 Nucleated Red Cells Lymphocytes Segmented Neutrophils Band$ Monocytes Eosinophi 1s Basophi 1s Abnormal Lymphocytes Other UBC Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophi 1s B a s q h i 1s Abnormal Lymphocytes Other YBC Nucleated R e d Cells Lymphocytes Segmented Neutrophils Bands Mcmcytes Eosinophi 1s Basophils Abnormal Ly.phocyte1 Other UBC e e e e e e e e e e e e e e e e e e 0 94 9.5 6 0.6 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 10.1 0 87 8.7 12 1.2 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 0 0.0 10.0 e - Terminal Sacrifice LABCAT HE4.41~ 03-NOV-2000 Page 315 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 9 Study Report for Hematology -___I----------------------------I_____-________l_____________l_-------------- ---------------- WHITE DIFFERENTIAL DA-T-A- - - - - _ I - - - I---_____ STUDY I D : 28-DAY ORAL DOSEIRAT ------------ --- STUDY NO: 132-W7 GROUP: I - F - - - I - - - - - - _ 1 - SEX: FEMALE --_I---__ Animal ID __-___----------___ -_-_- RECOVERY CNT ABS - I - - 7594 Nucleated R e d Cells Lymphocytes Segmented Neutrophi 1s Bands Monocytes Eosinophi 1s Basophi 1s Abnormal Lymphocytes Other UBC 0 91 6.5 9 0.6 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 7.1 75% Nucleated Red Cells Lymphocytes Segmented Neutrophi 1s Bands Mcimcytes Eosinophi 1s Basophi 1s Abnormal Ly-cytes Other WBC 0 92 11.8 a 1.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 12.8 7590 Nucleated Red Cells Lynphocytes Segmented Neutrophi 1s Bands Honocytes Eosinophils Basophi 1s Abnormal Lymphocytes Other UBC 0 91 7.9 9 0.8 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 8.7 (--I - Data Unavailable LABCAT HE4.41 c 03-NOV-2ooO Page 316 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7610 7642 7644 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophi 1s Basophi 1s Abnormal Lymphocytes Other uac Nucleated Red Cells Lymphocytes seganted Neutrophils Bands Monocytes Eosinophi 1s Besophi 1s Abnormal Lynphocytes Other U8t Nucleated R e d Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophi 1s Abnormal Lymphocytes Other UBC e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e c e e e e e e e e e e e e e e e e e e e e - __------(-) Data Unavailable LABCAT HE4.LlC -- --- e - Terminal sacrifice - 03-NOV-Zoo0 Page 317 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7646 7648 7650 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophi 1s Basophi 1s Abnormal Lymphocytes Other UEC Nucleated Red Cells Lynphocytes Segmented Neutrophi 1s Bands Monocytes Eosinqhilr Basophi 1s Abnormal Lymphocytes Other UEC Nucleated Red Cells Lymphocytes Segmented Neutrophi 1s Bands Monocytes Eosinophils Besophi 1s Abnormal Lymphocytes Other UEC e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e (-1 - Data Unavailable UECAT HE4.41~ e - Terminal Sacrifice 03-NOV-ZMM Page 318 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7654 7656 Nucleated Red Cells Lymphocytes Segmented Neutrophi 1s Bands Monocytes Eosinophi 1s Basophi 1s Abnormal Lymphocytes Other WEC Nucleated Red Cells Lymphocytes Segmented N e u t r o p h i 1s Bsnds Monocytes Eosinophi 1s Basophi 1s Abnorml Lymphocytes Other YBC e e e e e e e e e e e e e e e e C e e e C e e e e e e e e e e e e (--) - Data Unavailable LAECAT HE4.41~ e - Terminal Sacrifice 03-NoV-2ooO Page 319 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7660 7.562 Lymphocytes Segmented Neutrophils Bands nonocytes Eosinophils Basophi 1s Abnormal Lymphocytes Other WBC Nucleated Red Cello Lymphocytes Segmented Neutrophils Bands Monocytes Eorinophi 1s Basophi 1s AbnormaL Lymphocytes Other UBC Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands nonocytes Eosinophi 1s Basophi 1s Abnormal Lymphocytes Other UBC e e e e e e e e e e e e e e e e e 0 94 5.6 5 0.3 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 0 0.0 6.0 0 86 4.6 14 0.8 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 5.4 LABCAT HE4.41~ 03-NOV-2ooO Page 320 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 9 Study Number: 132-007 7664 7666 7668 Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophi 1s Basophi 1s Abnormal Lymphocytes Other UBC Nucleated R e d Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophi 1s Basophi 1s Abnormal iymphocytes Other UBC Nucleated Red C e l l s Lymphocytes Segmented N e u t r q h i 1s Bands Monocytes Eosinqhils Basophi 1s Abnormal Lymphocytes Other UBC 0 92 14.8 7 1.1 0 0.0 1 0.2 0 0.0 0 0.0 0 0.0 0 0.0 16.1 0 76 5.2 24 1.7 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 6.9 0 88 7.5 12 1.o 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 8.5 Page 321 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 10 INDIVIDUAL CLINICAL CHEMISTRY DATA Page 322 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 KEY TO CLINICAL CHEMISTRY TABLES AB BREVIATlON TERMINOLOGY ALP Alkaline Phosphatase AST Aspartate Aminotransferase ALT Alanine Aminotransferase CHOL Cholesterol GLU Glucose BUN Blood Urea Nitrogen CREAT Creatinine TRIG Triglycerides PHOS Phosphorus (inorganic) TP Total Protein ALB Albumin GLOB Globulin A/G Alburnin/Globulin Ratio CA Calcium CL Chloride NA Sodium K Potassium GGT Gamrna-glutamyltransferase T-BIL Total Bilirubin UNITS U/L UIL UIL mg/dL mg/dL mgldL mg/dL mg/dL mg/dL g/dL g/dL g/dL mg/dL mEq/L or mmol/L mEq/L or mmol/L mEq/L or mmol1L U/L mgldL Page 323 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 10 Study Number: 132-007 GROUP: 1-M 7569 7571 7573 7575 7577 7579 7581 7583 7585 7587 7589 7593 75% 7597 MEAN SD N 6.1 6.4 6.7 6.1 7.2 5.6 6.9 6.6 6.2 6-.1- - - - 6.4 0.47 10 GROUP: 2-n 7599 7601 7603 7605 7607 7609 7611 7613 7615 7617 MEAN SD N 6.1 6.2 6.3 6.5 5.9 6.6 6.3 6.0 6.1 6.0 6.2 0.23 10 4.2 4.2 4.7 4.1 4.0 4.0 4.9 4.6 4.2 -4.1 -- I -_ 4.4 0.33 10 133 156 192 248 138 138 214 136 116 1-37 - - 161 42.7 10 4.0 4.1 4.2 4.4 3.7 4.6 4.4 4.1 4.3 4.1 4.2 0.25 10 249 159 159 249 192 128 155 137 138 122 169 46.7 10 -- - (--I Data Unavailable LABCAT CC4.41c ----- 43 76 45 sa 50 76 63 60 67 1-0-7 --- 64 18.8 10 53 65 60 48 52 76 82 78 34 63 61 15.0 10 0.1 21 0.3 40 0.2 20 0.4 39 0.1 19 0.3 30 0.1 19 0.3 41 0.2 19 0.4 30 0.1 15 0.4 43 0.3 17 0.4 37 0.2 17 0.3 28 0.1 19 0.3 33 0-.2- -13 0-.3 2-7- --- - - - - - I - - -- 0.2 18 0.3 35 0.07 2.4 0.05 5.9 10 10 10 10 0.1 0.1 0.1 0.1 0.1 0.2 0.3 0.2 0.2 0.2 0.2 0.07 10 20 0.3 20 0.3 17 0.3 20 0.4 16 0.4 20 0.4 19 0.4 17 0.3 18 0.4 16 0.3 18 0.3 1.7 0.05 10 10 -- -- 40 40 29 47 40 51 33 26 28 32 37 8.4 70 03-NOV-2ooO Page 324 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 10 Study Number: 132-007 GROUP: 3-fl 7619 7621 7623 7625 7627 7629 7631 7633 7635 7637 MEAN SD N 6.1 6.7 6.9 6.5 6.4 6.2 6.2 6.8 6.0 5.9 6.4 0.35 10 GROUP: 4-M 7639 7641 7643 7645 7647 7649 765 1 7653 7655 7657 7659 7661 7663 7665 7667 MEAN SD N 7.0 6.2 6.3 6.2 6.1 6.4 6.4 6.1 6.1 -5.9 - - 6.3 0.30 10 4.0 4.4 4.5 4.2 4.1 4.1 4.4 4.8 4.3 4.3 4.3 0.23 10 5.0 4.1 4.1 4.3 4.3 4.6 4.6 4.2 4.5 -4.3 - - 4.4 0.28 10 163 140 168 181 171 124 117 131 135 137 147 22.1 10 44 59 57 106 64 65 74 74 32 53 63 19.9 10 170 149 153 128 123 154 104 141 124 -126 - - - 137 19.6 10 30 51 45 46 38 62 64 62 57 -48 --- 50 11.2 10 0.2 0.1 0.1 0.1 0.1 0.2 0.3 0.3 0.2 0.2 0.2 0.08 10 0.2 0.1 0.2 0.1 0.2 0.3 0.4 0.1 0.2 0-.2 - ---- 0.2 0.09 10 19 0.3 40 16 0.3 39 24 0.3 40 21 0.3 33 19 0.2 99 16 0.4 26 18 0.4 u 23 0.3 1so 17 0.3 32 19 0.3 33 19 0.3 53 2.7 0.06 10.0 10 10 10 18 0.3 40 18 0.3 42 21 0.3 86 23 0.3 41 21 0.3 38 20 0.4 28 16 0.3 48 18 0.3 56 21 0.4 36 - 2-0 0.3 -44 -- - - -- - - _- -- - - - - 20 0.3 46 2.1 0.04 16.5 10 10 10 UBCAT CC4.41 c 03-NOV-m Page 325 A 26-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 10 Study Number: 132-007 MEAN SO N 110 18.1 10 GROUP: 2-M 7599 7601 7603 7605 7607 7609 761 1 7613 7615 r6v MEAN SD N 128 110 97 119 158 97 111 89 108 95 111 20.3 10 162 41.9 10 132 122 135 162 129 180 160 117 235 148 152 35.5 10 1 11.4 10.8 32 1.6 0.53 0.66 10.2 10 10 10 10 0 11.7 7 11.6 0 11.6 0 11.9 0 11.2 0 11.0 0 10.9 0 10.6 0 10.7 0 10.7 1 11.2 2.2 0.48 10 10 10.5 11.8 11.0 11.2 10.6 9.8 10.2 8.9 9.8 8.9 10.3 0.95 10 74 45 17 23 36 29 33 47 11 27 34 18.0 10 146 7.7 2.4 1.52 10 10 145 6.3 144 9.0 146 8.4 144 7.8 144 7.2 146 6.6 145 7.6 148 5.5 147 5.6 146 5.6 146 7.0 1.4 1.24 10 10 (--) - Data Unavailable LABCAT CC4.41 C 03-NOV-ZMx) Page 326 A 26-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 10 Study Number: 132-007 GROUP: 3-M 7619 7621 7623 7625 7627 7629 7631 7633 7635 7637 MEAN SD N 126 115 123 85 219 92 100 310 105 102 138 71.3 10 GRWP:4-14 7639 128 7641 145 7643 252 7645 121 7647 114 7649 94 7651 143 7653 . 108 7655 101 7657 128 - 7659 - 7661 --- 7663 76-65 -- 7667 MEAN SD N 133 44.9 10 114 175 192 127 143 128 130 162 1.55 164 150 25.3 10 229 147 206 141 184 110 144 193 1M) 211 172 37.8 10 1 11.3 9.2 26 0 11.6 9.1 18 0 12.0 10.2 23 2 12.0 10.6 m 0 11.3 10.5 26 0 10.3 8.6 32 0 10.8 8.3 34 0 11.1 9.9 37 0 10.7 8.7 12 0 10.5 8.6 14 0 11.2 9.4 25 0.7 0.59 0.86 8.6 10 10 10 10 0 12.3 9.6 12 0 11.3 9.8 28 0 11.3 10.8 11 0 10.4 7.9 32 0 10.6 8.0 13 0 10.7 9.7 25 0 11.2 9.2 42 0 10.8 9.0 30 0 10.2 8.7 15 - - -- -- 0 10.4 8.2 21 I I 0 10.9 9.1 23 0.0 0.62 0.92 10.3 10 10 10 10 144 7.0 148 6.1 146 7.0 145 7.4 145 7.9 146 5.4 148 5.7 149 6.5 148 5.5 148 5.7 147 6.4 1.7 0.87 10 10 149 6.4 146 7.4 144 8.2 144 4.8 147 6.0 146 6.7 146 6.4 149 5.2 147 5.4 -150 5.0 -- 147 6.2 2.0 1.10 10 10 UBCAT CC4.41C 03-NOV-2aX) Page 327 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 10 Study Number: 132-007 LABCAT CC4.41C GROUP: 1-n 7569 94 7571 93 7573 93 7575 98 7577 95 7579 101 7581 97 7583 97 7585 98 7587 98 7589 7591 7593 7595 7597 MEAN w so 2.6 N 10 GROUP: 2-n 7599 94 7601 93 7603 96 7605 97 7607 99 7609 101 7611 99 7613 1w 7615 1w 7617 100 MEAN 98 SD 2.8 N 10 1.9 2.2 2.0 2.0 2.4 1.6 2.0 2.0 2.0 -2.0 - 2.0 0.20 10 2.1 2.1 2.1 2.1 2.2 2.0 1.9 1.9 1.8 1.9 2.0 0.13 10 2.2 1.9 2.3 2.0 2.0 2.5 2.5 2.3 2.1 2.0 -- 1 2.2 0.21 10 1.9 2.0 2.0 2.1 1.7 2.3 2.3 2.2 2.4 2.2 2.1 0.21 10 - 03-NOV-2WO Page 328 A 28-Day Oral Toxicity Study in Sprague-DawleyRats Study Number: 132-007 APPENDIX 10 --------- S-t--u--d--y----R--eport f--o--r----C--l--i--n--i--cal Chemistry - - - - I - -__I--__-__ INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL .................................................. ---_ STUDY I D : 28-DAY ORAL DOSE/RAT _-----_---- STUDY NO: 132-007 ----------_-------__I__ ____ -- I - - - - SEX: MALE I Animl ID CL GLOB AIG ------ ----________________----n--m--l/-L------- g/dL none GROUP: 3-M 7619 99 2.1 1.9 7621 94 2.3 1.9 7623 96 2.4 1.9 7625 96 2.3 1.8 7627 97 2.3 1.8 7629 100 2.1 2.0 7631 102 1.8 2.4 7633 99 2.0 2.4 7635 101 1.7 2.5 7637 101 1.6 2.7 - I - - HEAN SD N 98 2.1 2.1 2.6 0.28 0.33 10 10 10 p - l _ _ _ - - _ l _ GRWP: 4-H 7639 96 7641 100 7643 101 7645 103 7647 100 7649 100 7651 99 7653 101 7655 98 7657 7659 1-0-0 7661 I - 7663 - 7665 - 7667 2.0 2.1 2.2 1.9 1.8 1.8 1.8 1.9 1.6 1.6 --- - I - 2.5 2.0 1.9 2.3 2.4 2.6 2.6 2.2 2.8 2.7 1 - - - - MEAN SD N 100 1.9 2.4 1.9 0.19 0.30 10 10 10 -- ------ - (--) Data Unavailable UBCAT CC4.41C I - - - I - - - - 03-Nov-2ooo Page 329 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 10 Study Number: 132-007 STUDY I D : 28-DAY ORAL DOSE/RAT STUDY NO: 132-007 SEX: NALE Animal I D TP ALE GLU CHOL T-EIL BUN CREAT ALT g/dL g/dL wldL nsldL w/dL W/dL WdL U/L ___I_-__-_-__-__-_----------- GROUP: 1-N 7569 e e e e e e e e 7571 e e e e e e e e 7573 e e e e e e e e 7575 e e e e e e e e 7577 e e e e e e e e 7579 e e e e e e e e 7581 e . e e e e e e e 7583 e e e e e e e e 7585 e e e e e e e e 7587 e e e e e e e e 7589 6.4 4.1 177 47 0.1 19 0.3 42 7591 6.6 4.6 184 66 0.2 18 0.3 47 7593 7.1 4.5 108 68 0.2 20 0.4 47 7595 6.9 4.6 191 61 0.2 18 0.4 44 7597 6.6 4.1 146 82 0.1 16 0.3 36 NUN SD N 6.7 4.4 161 65 0.2 18 0.3 43 0.28 0.26 34.3 12.6 0.05 1.5 0.05 4.5 5 5 5 5 5 5 5 5 - ---e Terminal Sacrifice LABCAT CC4.41 c --- -- -- 03-NOV-2ooO Page 330 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 10 Study Number: 132-007 GROUP: 4-M 7639 e e e e e e e e 7641 e e e e e e e e 7643 e e e e e e e e 7645 e e e e e e e e 7647 e e e e e e e e 7649 e e e e e e c e 7651 e e e e e e e e 7653 e . e e e e e e 7655 e e e e e e e e 7657 e e e e e e e e 7659 6.5 4.5 90 65 0.1 17 0.4 51 7661 6.8 4.6 156 76 0.1 17 0.4 46 7663 7.3 5.0 217 112 0.2 18 0.3 55 7665 6.3 4.0 149 59 0.1 15 0.2 41 7667 6.7 4.5 176 63 0.1 18 0.2 42 MEAN so N 6.7 4.5 158 75 0.1 17 0.3 47 0.38 0.36 46.1 21.6 0.04 1.2 0.10 6.0 5 5 5 5 5 5 5 5 - e - Terminal Sacrifice L48CAT CC4.41C --------------- - 03-Nov-Moo Page 331 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 10 Study Number: 132-007 STUDY I D : 28-DAY ORAL DOSE/RAT STUDY NO: 132-007 SEX: MALE GROUP: 1-M 7569 7571 7573 7575 7577 7579 7581 7583 7585 7587 7589 7591 7593 7595 7597 MEAN so N e e e e e e e e e e 91 159 115 179 81 125 42.6 5 e e e e e e . e e e e 134 169 161 182 1so 159 18.3 5 e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e 5 12.0 10.1 25 2 12.7 14.3 59 0 12.3 12.5 35 2 13.0 14.9 33 0 11.9 10.6 71 2 12.4 12.5 45 2.0 0.47 2.14 19.3 5 5 5 5 e e e e e e e e e e e e e e e e e e e e 146 1.2 145 8.8 146 10.4 1 43 10.2 147 6.8 145 8.7 1.5 1.66 S 5 LABCAT CC4.41c 03-NOV-2oaO Page 332 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 10 Study Number: 132-007 GROUP: 4-M 7639 7641 7643 7645 7647 7649 7651 7653 7655 7657 7659 7661 7663 7665 7667 MEAN so N e e e e e e e e e e 101 110 186 112 % 121 36.9 5 e e e e e e e e e e 157 147 i70 115 150 149 22.7 5 e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e 1 12.3 12.2 20 3 12.7 12.7 36 6 13.5 12.9 121 1 11.6 10.0 63 1 12.4 10.2 37 2 12.5 11.a 55 2.2 0.69 1.20 39.0 5 5 5 5 e e e e e e e e e e e e e e e e e e e e 145 10.4 147 8.9 145 8.0 148 7.3 150 6.0 147 0.3 2.1 1.68 5 5 LABCAT CC4.41c 03-NOV-2oM) Page 333 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 10 Study Number: 132-007 STUDY I D : 28-OAY ORAL DOSEIRAT _-S-T-UD_Y N_O: 132-007 ~ --_____-_----- -- Animal I D tL nml/L GLOB ddL AJ= none GROUP: I - M 7569 e 7571 e 7573 e 7575 e 7577 e 7579 e 7581 e 7583 e 7585 e 7587 e 7589 96 7591 97 7593 101 7595 98 7597 99 MEAN 98 SD 1.9 N 5 e e e e e e e e e e 2.3 2.0 2.6 2.3 2.5 2.3 0.23 5 e e e e e e e e e e 1.8 2.3 1.7 2.0 1.6 1.9 0.28 5 SEX: MALE - - e - Terminal Sacrifice LABCAT CC4.41 C 03-W-MOo Page 334 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 10 Study Number: 132-007 GROUP: 4-I4 7639 e 7641 e 7643 e 7645 e 7647 e 7649 e 7651 e 7653 e 7655 c 7657 e 7659 103 7661 100 7663 94 7665 99 7667 98 MEAN 99 SO 3.3 N 5 e e e e e e e e e e 2.0 2.2 2.3 2.3 2.2 2.2 0.12 5 e e e e e e e c e e 2.2 2.1 2.2 1.7 2.0 2.0 0.21 5 -- -- e Terminal Sacrifice LABCAT CC4.41C --- - 03-NOV-2ooO Page 335 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 STUDY ID: 20-DAY ORAL M)SE/RAT STUDY No: 132-007 SEX: FEMALE - - - - - - - - - - - - - - - - - - A n i d ID ---------- GRWP: 1-F 7570 7572 7574 7576 7578 7500 7582 7584 7586 7500 7590 7592 7594 75% 7598 TP g/dL 6.0 7.2 6.7 6.0 7.2 7.1 6.1 6.5 7.1 7.0 I -- - AL0 g/dL 4.6 4.9 4.0 5.0 5.0 5.0 4.2 4.5 4.0 5-.0 -- - - - GLU w/dL CHOL T-BIL BUN CREAT ALT ----------- w/dL w/dL w/dL w/dL U/L I - - - - - - 108 53 0.2 21 0.5 37 149 75 0.2 17 0.5 36 166 79 0.2 24 0.5 40 131 70 0.2 161 97 0.1 ?46 02 0.2 20 0.5 34 w 0.4 44 16 0-4 a1 176 67 0.2 22 0.4 43 143 50 0.2 20 0.4 45 179 60 0.2 21 0.4 45 - - -- -- 195 72 0.2 14 0.4 25 I I I -- -- - - - --- - - I -- - - - - - - -- I - - - MEAN SD N 6.0 0.35 10 4.0 0.27 10 155 25.4 10 73 12.5 10 0.2 0.03 10 19 0.4 w 3.0 0.05 14.7 10 10 10 GROUP: 2-F 7600 7.2 5.2 107 66 0.2 20 0.4 44 7602 7.0 5.1 98 55 0.3 22 0.4 42 7604 6.8 4.7 128 01 0.1 23 0.5 24 7606 6.0 4.0 126 86 0.2 25 0.4 35 7608 6.6 4.7 159 67 0.2 19 0.4 39 7610 6.0 4.7 171 96 0.2 19 0.5 34 7612 7614 761 6 7610 7.0 5.3 200 71 0.2 20 0.4 33 6.9 4.0 197 sa 0.2 24 0.4 31 7.3 5.4 220 58 0.2 14 0.4 33 7.0 4.9 129 76 0.2 10 0.4 a MEAN SO N 6.9 5.0 154 71 0.2 20 0.4 35 0.21 0.27 42.2 13.4 0.05 3.2 0.04 5.7 10 10 10 10 10 10 10 10 (--I - Data Unavailable LABCAT CC4.41c 03-NoV-2ooO Page 336 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 Animal I D TP g/dL GRWP: 3-F 7620 6.9 4.7 143 66 0.2 19 0.4 36 7622 6.8 4.8 136 67 0.3 22 0.4 30 7624 6.2 3.9 117 64 0.3 20 0.4 31 7626 7.4 5.2 152 61 0.2 23 0.5 34 7628 7.0 4.8 135 88 0.2 2l 0.5 41 7630 7.0 4.5 106 79 0.2 23 0.4 37 7632 6.7 4.8 115 60 0.2 21 0.5 35 7634 6.5 4.7 200 40 0.2 24 0.4 46 7636 6.8 4.9 182 44 0.1 21 0.4 35 7638 6.4 4.5 146 4a 0.2 18 0.3 50 MEAN SD N 6.8 4.7 143 62 0.2 21 0.4 38 0.34 0.34 29.4 15.0 0.06 1.9 0.06 6.4 10 10 10 10 10 10 10 10 GRWP: 4-f 7640 6.2 4.3 151 68 0.1 23 0.4 42 76.52 6.8 4.8 127 63 0.1 21 0.4 37 7644 6.2 4.0 107 % 0.2 24 0.4 36 7646 6.2 4.4 147 77 0.1 18 0.3 37 7648 7.1 5.1 155 63 0.2 15 0.5 35 7650 6.4 4.6 134 66 0.2 23 0.4 34 7652 6.5 4.3 109 85 0.1 22 0.4 36 7654 . 6.4 4.4 95 52 0.2 21 0.4 38 7656 7.1 5.4 137 89 0.2 22 0.4 36 7658 7660 7662 7664 7- 6-.8- 4.9 126 - - I 68 0.2 18 0.4 30 7668 I MEAN SD N 6.6 4.6 129 73 0.2 21 0.4 36 0.36 0.43 20.1 13.7 0.05 2.8 0.05 3.0 10 10 10 10 10 10 10 10 (-) - Data Unavailable UBCAT CC4.41~ 03-NOV-2WO Page 337 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX I O Study Number: 132-007 NEAN SD N 124 90 1 11.8 9.9 37 144 7.8 30.6 28.3 1.o 0.34 O.% 7.7 1.8 1.21 10 10 10 10 10 10 10 10 GROUP: 2-F 7600 156 % 7602 134 82 7604 74 64 76c4 103 108 7608 105 58 7610 9s 54 7612 102 110 7614 7616 116 a5 125 77 7618 99 58 0 11.7 0 11.7 0 11.4 0 11.9 0 11.4 0 11.8 0 12.2 1 12.4 5 12.2 0 11.8 10.0 11.7 9.7 10.9 9.6 9.9 9.4 10.1 10.5 9.7 20 143 9.0 26 144 11.7 29 144 7.6 39 142 10.6 41 144 8.3 31 143 8.4 44 143 8.7 24 144 8.7 29 139 10.6 26 144 7.3 MEAN SD N 111 79 1 11.9 10.1 31 143 9.1 22.9 20.7 1.6 0.33 0.70 7.9 1.6 1.42 10 10 10 10 10 10 10 10 - ---- ---- ----- (--I Data Unavailable LABCAT CC4.41~ 03-NOV-Moo Page 338 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 10 ------------------------------------S--t--u--d--y---R---e--p--o--r-t----f--o--r Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP -----------------_________I_ P E R I O D : ------TERMINAL STUDY I D : 2&DAY ORAL DOSEIRAT STUDY NO: 132-007 ----- SEX: FEMALE Animal I D AS1 ----------~U/L---- I----- GROUP: 3-F 7620 111 7622 116 7624 113 7626 125 7628 134 7630 98 7632 132 ' 7634 91 7636 116 7638 97 ALP U/L 108 105 93 109 97 102 107 104 97 86 GGT CA PHOS TRIG NA K U/L ------w/dL. . . .W.IdL. . . .mg./dL. . . n. m.l / L. . . .mm.ol/L ----- 0 11.7 11.2 0 11.6 11.3 0 10.9 9.6 0 11.9 9.9 0 11.9 10.7 1 11.3 10.0 1 11.5 11.0 0 11.7 8.9 0 11.4 11.1 0 11.8 11.2 28 145 8.5 51 142 8.8 40 147 6.6 27 146 9.1 42 145 8.7 36 143 6.6 28 144 9.6 33 143 8.5 22 145 8.8 33 145 8.3 MEAN SD N 113 101 0 11.6 10.5 34 144 8.4 14.7 7.4 0.4 0.31 0.83 8.6 1.5 0.99 10 10 10 10 10 10 10 10 GROUP: 4-F 7640 120 7642 101 7644 110 7646 97 7648 126 7650 97 7652 110 7654 110 7656 96 7658 121 -- 7660 - 7662 7664 - -- 7666 7668 - a3 101 87 85 105 82 66 92 127 7-4- -- I 10.8 11.9 10.8 11.6 12.0 11.4 10.9 11.2 12.1 11.7 9.1 10.5 8.0 9.9 8.1 9.4 9.0 10.9 10.8 --9.8 45 148 5.7 26 145 7.7 30 146 6.2 54 144 7.3 31 147 6.5 23 143 6.8 34 146 6.7 22 144 8.3 29 145 8.1 -3-0 146 - 7-.1- - - - MEAN SD N 109 90 0 11.4 9.6 32 145 7.0 10.9 17.3 0.5 0.50 1.03 9.9 1.5 0.83 10 10 10 10 10 10 10 10 LABCAT CC4.41c 03-NOV-2WO Page 339 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 10 Study Number: 132-007 MEAN 103 SD 1.8 N 10 GROUP: 2-F 7600 102 7602 107 7604 101 7- 103 7- 1os 7610 98 7612 100 7614 101 7616 102 761 8 102 MEAN 102 SD 2.5 N 10 2.1 0.18 10 2.0 1.9 2.1 2.0 1.9 2.1 1.7 2.1 '1.9 2.1 2.0 0.13 10 2.3 0.23 10 2.6 2.7 2.2 2.4 2.5 2.2 3.1 2.3 2.8 2.3 2.5 0.29 10 (--) - Data Unavailable UBCAT CC4.41~ 03-NOV-2ooO Page 340 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 10 Study Number: 132-007 .- GROUP: 3-F 7620 102 2.2 2.1 7622 7624 1 03 2.0 2.4 1os 2.3 1.7 7626 104 2.2 2.4 7628 104 2.2 2.2 7630 1 03 2.5 1.8 7632 7634 105 1.9 2.5 1os 1.8 2.6 7636 104 1.9 2.6 7638 1M) 7.9 2.4 MEAN SD 104 2.1 2.3 1.6 0.22 0.32 N 10 10 10 -- GROUP: 4-F -- ---- 7640 7642 7644 7646 104 1.9 2.3 105 2.0 2.4 1os 2.2 1.8 104 1.8 2.4 7648 7650 103 2.0 2.5 107 1.8 2.6 7652 7654 104 2.2 2.0 10s 2.0 2.2 7656 103 1.7 3.2 7658 - 7660 - - -- 7662 -- -- 7664 7666 1-02 1.9 2-.6 - - - - - -- 7668 I NEAN SD N 104 2.0 2.4 1.4 0.16 0.38 10 10 10 LABCAT CC4.41c 03-NOV-2ooO Page 341 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 10 Study Number: 132-007 GROUP: 1-F 7570 7572 7574 7576 7578 7580 7502 7584 7586 7588 7590 7592 7594 7596 7598 MEAN SD N e e e e e e e e e e 7.9 7.2 7.1 7.6 6.8 7.3 0.43 5 e e e e e e e . e e e 5.2 5.2 5.3 5.8 4.9 5.3 0.33 5 e e e e e e e e e e 147 107 112 207 176 166 73.3 5 e e e e e e e e e e 106 62 59 92 103 84 22.5 5 e e e e e e e e e e 0.2 0.2 0.2 0.2 0.2 0.2 0. w 5 e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e 31 0.6 34 22 0.4 59 10 0.4 44 16 0.4 57 18 0.3 71 21 0.4 53 6.0 0.11 14.3 5 5 5 e - Terminal Sacrifice LABCAT CC4.41c --- 03-Nov-2ooo Page 342 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 10 Study Number: 132-007 STUDY I D : 28-DAY ORAL DOSE/RAT STUDY NO: 132-007 SEX: FEMALE GROUP: 4- F 7640 e e e e e e e e 7642 e e e e e e e e 7644 e e e e e e e e 7646 e e e e e e e e 7648 e e e e e e e e 7650 e e e e e e e e 7652 e e e e e e e e 7654 e e e e e e e e 7656 e e e e e e e e 7650 e e e e e e e e 7660 7.6 5.6 99 76 0.3 29 0.6 45 7662 7.4 5.4 119 63 0.2 16 0.3 39 7664 6.7 4.7 114 57 0.2 20 0.4 32 7666 7.0 4.8 233 82 0.1 17 0.4 35 7668 6.9 4.9 111 80 0.1 23 0.3 34 MEAN SD N 7.1 5.1 135 72 0.2 21 0.4 37 0.37 0.40 55.2 11.0 0.08 5.2 0.12 5.1 5 5 5 5 5 5 5 5 - -- e T e r m i n a l S a c r i f i c e LABCAT CC4.41~ - 03-NOV-2OW Page 343 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 10 Study Number: 132-007 GROUP: 1-F 7570 7572 7574 7576 7578 7580 7582 7584 7586 7588 7590 7592 7594 75% 7598 MEAN SD N e e e e e e e e e e 153 248 170 126 275 194 63.9 5 e e e e e C e . e e e 85 91 86 88 65 83 10.3 5 e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e 1 12.9 10.7 48 2 12.6 12.6 29 1 12.4 12.5 32 0 13.1 13.6 52 0 13.4 12.3 63 1 12.9 12.3 45 0.8 0.40 1.05 14.2 5 5 5 5 e e e e e e e e e e e e e e e e e e e e 146 8.1 142 11.7 146 9.2 144 9.0 144 7.9 144 9.2 1.7 1.52 5 5 --- - e Terminal Sacrifice UBCAT CC4.41 c _ _ _ - _ I - - - - -- 03-NOV-2ooO Page 344 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 10 Study Number: 132-007 Animal I D GROUP: 4-F 7640 7642 7644 7646 7640 7650 7652 7654 7656 7650 76.50 7662 7664 7666 7668 MEAN SD N AS1 ALP U/L U/L e e e e e e e e e e 295 236 104 lo6 124 109 70.4 5 e e e e e e e . e e e 107 74 BB 76 63 02 16.7 5 GGT U/L e e e e e e 1 1.1 5 CA mg/dL ' PMS w/dL e e e e e e e e e e 13.0 12.4 11.9 12.5 11.6 12.3 0.54 5 e e e e e e e e e e 13.3 10.1 9.1 11.6 9.4 10.7 1.74 5 TRIG mg/dL e e e e e e e e e e 24 28 36 50 23 32 11.2 5 NA rnmol/L e e e e e e e e e e 142 140 146 145 146 145 2.2 5 K rnmol/L e e e e e e e e e e 10.3 7.5 6.1 7.5 7.5 7.0 1.53 5 e - Terminal Sacrifice LABCAT CC4.41c 03-MOV-2ooO Page 345 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 10 Study Number: 132-007 GROUP: 1-F 7570 e 7572 e 7574 e 7576 e 7578 e 7580 e 7582 e 7584 e 7586 e 7588 e 7590 100 7592 106 7594 105 75% 100 7598 101 MEAN 102 SD 2.9 N 5 e e e e e e e e e e 2.7 2.0 1.8 1.8 1.9 2.0 0.38 5 e e e e e e e e e e 1.9 2.6 2.9 3.2 2.6 2.6 0.48 5 e - Terminal Sacrifice LABCAT CC4.41c 03-NOV-2Mx1 Page 346 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 10 Study Number: 132-007 GROUP: 4-F 7m e 7642 e 7644 e 7646 e 7648 e 7650 e 7652 e 7654 e 7656 e 7658 e 7660 103 7662 103 7664 102 7666 1os 7668 107 MEAN 104 SD 2.0 N 5 e e e e e e e e e e 2.0 2.0 2.0 2.2 2.0 2.0 0.09 5 e e e e e e e e e e 2.8 2.7 2.3 2.2 2.5 2.5 0.2s 5 - --------e Terminal Sacrifice LABCAT CC4.41~ - _ _ _ _ I - - - - - -- 03-NOV-2oMI Page 347 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 11 HISTORICAL CONTROL CLINICAL CHEMISTRY DATA Page 348 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 PRlMEDlCA CLINICAL CHEMISTRY HISTORICAL DATA N = 100 Sprague-Oawley Rats PARAMETER ABBREVIATION UNITS HISTORICAL RANGE N = 20 PARA METER Creatine Kinase Lactate Dehydrogenase ABBREVIATION CK LDH UNITS UIL UIL HISTORICAL RANGE 141 - 463 62 - 396 N = Number of Values Historicaldata include all animals regardlessof bloodcollection site. Hemolyzedspecimens and obvious outliers are not excluded. Page 349 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 12 INDIVIDUAL ORGAN WEIGHTS Page 350 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 12 Study Number: 132-007 ADRENAL GLANDS (C) X BWY YEIGHT X BRAIN UEIGHT BRAIN (GI X B W Y UElGHl HEART (G) X BWY UEIGHT X BRAIN YEIGHT KIDNEYS (E) X BWY UElCHT X BRAIN UElCHT LIVER (GI X BWY UEIGHT X BRAIN YEIGHT SPLEEN (GI x B a n MIGHT X BRAIN UEIGHT TESTES (GI x amy UEIGHT X BRAIN UEICHT THYMUS (GI x amy UEIGHT X BRAIN WIGHT 0.064 0.022 2.967 0.065 0.018 3.237 0.068 0.019 3.335 0.063 0.018 2.938 o.om 0.022 3.457 0.073 0.021 3.838 0.069 0.020 3.694 0.073 0.022 3.709 2.157 0.739 2.008 0.546 2.039 0.578 2.144 0.606 2.025 0.647 1.902 0.555 1.868 0.529 1.968 0.587 1.062 0.364 49.235 1.193 0.324 59.412 1.317 0.373 64.590 1.160 0.328 54.104 1.198 0.383 59.160 1.265 0.369 66.509 1.134 0.321 60.707 1.191 0.356 60.518 2.715 0.930 125.869 2.832 0.770 141.036 3.037 0.860 148.946 2.651 0.749 123.647 2.482 0.793 122.568 2.666 0.777 140.168 3.062 0.867 163.919 2.444 0.730 124.187 8.667 2.968 401.808 11.220 3.049 558.765 io.so 3.074 532.124 9.856 2.784 459.702 8.705 2.781 429.877 9.414 2.745 494.953 10.677 3.025 571.574 9.384 2.801 476.829 0.565 0.193 26.194 0.699 0.190 34.811 0.571 0.162 28.004 0.764 0.216 35.634 0.507 0.162 25.037 0.761 0.222 40.011 0.631 0.179 33.779 0.648 0.193 32.927 3.106 1.064 143.996 3.501 0.951 174.353 3.481 0.986 170.721 3.167 0.8147.715 3.066 0.980 151.407 3.~17 0.987 178.076 3.242 0.918 173.555 2.771 0.827 140.803 0.421 0.144 19.518 0.480 0.130 23.904 0.634 0.180 31.094 0.555 0.157 25.886 0.437 0.140 21.580 0.399 0.116 20.978 0.598 0.169 32.013 0.479 0.143 24.339 PRIMEOICA REOFIELD S T M Y NUWEER 132-007 Page 351 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 12 Study Number: 132-007 ADRENAL GLANDS ( 6 ) x a m y MIGHT X BRAIN WEIGHT HEART ( 6 ) x B m y EIGHT X BRAIN VEIGHT KIDNEYS ( G ) x a m y EIGHT % BRAIN WEIGHT LIVER ( 6 ) X BmY EIGHT X BRAIN MIGHT SPLEEN ( E ) x a m y EIGHT X BRAIN EIGHT TESTES ( 6 ) x BmY EIGHT X BRAIN WEIGHT THYWS ( 6 ) x a m y EIGHT X BRAIN WEIGHT 340.000 392.000 0.077 0.023 4.085 0.062 0.016 3.224 1.885 0.554 1.923 0.491 1.303 0.383 69.125 1.372 0.350 71.347 2.348 0.691 124.562 3.276 0.836 170.359 9.825 2.090 521.220 11.824 3.016 614.873 0.676 0.199 35.862 0.695 0.1n 36.141 3.031 0.891 160.7% 3.579 0.913 186.115 0.578 0.170 30.M 0.491 0.125 25.533 Page 352 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 12 Study Number: 132-007 BRAIN (G) X 8WY MlCHT HEART (G) x BrnY VEIGHT X BRAIN WElGHT KIDNEYS (G) x BWY WElGHT X BRAIN UElGHT LlVER (G) X BWY UElGHT X BRAIN WEIGHT SPLEEN (G) X BWY WEIGHT X 8RAlN E I G H T TESTES (G) X B W Y UElGHT X BRAIN WEIGHT THYWS (6) x 8WY WEIGHT X BRAIN YElGHT 2.144 0.648 2.069 0.610 1.933 0.5~ 2.069 0.619 2.039 0.579 2.112 0.556 1.964 o.5u 2.207 0.579 1.266 0.382 59.049 1.263 0.373 61 .044 1.187 0.351 61.407 1.158 0.347 55.969 1.441 0.409 70.672 1.257 0.331 59.517 1.196 0.333 60.8% 1.237 0.325 56.049 2.606 0.787 121.549 2.797 0.825 135.186 2.714 0.803 140.404 2.663 0.797 128.710 2.788 0.792 136.734 3.140 0.826 148.674 2.653 0.739 135.082 3.114 0.817 141.W7 10.553 3.188 492.21 1 10.462 3.086 505.655 9.988 2.955 516.710 10.373 3.106 501.353 10.674 3.032 523.492 11.235 2.957 531.96D 11.223 3.126 571.436 13.086 3.435 592.932 0.588 0.178 27.425 0.701 0.207 33.881 0.748 0.221 38.6% 0.537 0.161 25.955 0.911 0.259 44.679 0.674 0.l-n 31.913 0.710 0.198 36.151 0.829 0.218 37.562 3.203 0.968 149.394 2.601 0.767 125.713 2.845 0.842 147.181 3.416 1.023 165.104 2.239 0.636 109.809 2.999 0.789 141 .W8 2.894 0.806 147.352 3.089 0.811 139.964 0.447 0.135 20.849 0.480 0.142 23.200 0.436 0.129 22.556 0.451 0.135 21.798 0.821 0.233 40.265 0.644 0.169 30.492 0.484 0.135 24.644 0.434 0.114 19.665 Page 353 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 12 Study Number: 132-007 ADRENAL GLANDS ( G ) X BODY WEIGHT X BRAIN E I G H T BRAIN ( G ) X BODY E I G H T HEART (GI X BODY WEIGHT X BRAIN UEIGHT KIDNEYS ( G ) x 8wy WEIGHT X BRAIN UElGHT LIVER (GI x WEIGHT X BRAIN WEIGHT SPLEEN ( G ) X BODY YEIGHT X BRAIN WEIGHT TESTES (GI X BODY WEIGHT X BRAIN WEIGHT THYWS ( G ) X BODY UEIGHT X BRAIN WEIGH1 0.063 0.020 3.147 0.083 0.023 4.069 2.002 0.640 2.040 0.564 1.139 0.364 56.893 1.193 0.330 58.480 2.451 0.783 122.428 2.809 0.776 137.696 7.839 2.504 391.558 10.552 2.915 517.255 0.622 0.199 31.069 0.879 0.243 43.088 3.161 1.010 157.892 3.0W 0.831 147.500 0.585 0.187 29.221 0.534 0.148 26.176 Page 354 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 12 Study Number: 132-007 ADRENAL GLANDS (GI X B W Y UEIGHT X BRAIN UElGHT BRAIN (GI X BODY UEIGHT HEART ( G ) X B M Y UElGHT X BRAIN W I G H T KIDNEYS (GI X B W Y UEIGHT X BRAIN E I G H T LIVER (C) X EWY W I G H T X BRAIN UEIGHT SPLEEN ( G ) X KUY EIGHT X BRAIN E I G H T TESTES (G) X BMY WIGHT X BRAIN VEIGHT THYMUS (e, X 8WY EIGHT X BRAIN E I G H T 0.066 0.023 3.275 0.057 0.016 2.798 0.052 0.016 2.315 0.067 0.020 3.575 0.059 0.018 2.751 0.076 0.020 3.693 0.073 0.020 3.661 0.074 0.022 3.487 2.015 0.712 2.037 0.577 2.246 0.704 1.874 0.556 2.145 0.652 2.058 0.536 1.994 0.554 2.122 0.626 0.915 0.323 45.409 1.301 0.369 63.868 1.193 0.374 53.117 1.190 0.353 63.501 1.041 0.316 48.531 1.269 0.330 61.662 1.198 0.333 60.080 1.141 0.337 53.770 2.012 0.711 99.851 3.589 1.017 176.191 2.954 0.926 131.523 2.738 0.512 146.105 2.909 0.884 135.618 2.912 0.758 141.497 2.970 0.825 148.947 3.126 0.922 147.314 7.949 2.809 394.491 11.983 3.3% 588.267 9.711 3.044 432.369 12.169 3.611 649.360 11.010 3.347 513.287 12.353 3.217 600.243 12.271 3.409 615.3% 10.941 3.227 515.599 0.582 0.206 28.8115 0.758 0.215 37.212 0.643 0.202 28.629 0.698 0.207 37.247 0.655 0.199 30.536 0.878 0.229 42.663 0.725 0.201 36.359 0.674 0.199 31.762 2.721 0.961 135.037 3.104 0.879 152.381 3.179 0.997 141.541 3.297 0.978 175.934 2.955 0.898 137.762 4.054 1.056 196.987 3.716 1.032 186.359 3.380 0.997 159.284 0.456 0.161 22.630 0.488 0.138 23.957 0.504 0.158 22.440 0.371 0.110 19.797 0.505 0.153 23.543 0.511 0.133 24.830 0.506 0.141 25~476 0.552 0.163 26.013 Page 355 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 12 Study Number: 132-007 B W Y WEIGHT ( G ) ADRENAL GLANDS ( G I X BWY WEIGHT X BRAIN WIGHT BRAIN ( G ) X BWY WEIGHT HEART ( C ) X BWY WEIGHT X BRAIN UEIGHT KIDNEYS (GI x E W Y WEIGHT X BRAIN WEIGHT LIVER (G) X B W Y WEIGHT X BRAIN UEIGHT SPLEEN (t) X E W Y WEIGHT X BRAIN UElGHT TESTES ( G ) X B W Y WEIGHT X BRAIN WEIGHT THYWS ( C ) X B W Y WEIGHT X BRAIN M l G H l 290.000 378.000 0.053 0.018 2.797 0.089 0.024 4.000 1.895 0.653 2.225 0.589 1.221 0.421 64.433 1.376 0.364 61.843 2.437 0.840 128.602 3.348 0.886 150.472 9.078 3.130 479.050 10.914 2.887 490.517 0.658 0.227 34.723 0.813 0.215 36.539 2.957 1.020 156.042 3.344 0.885 150.292 0.455 0.157 24.011 0.5% 0.157 26.742 Page 356 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 12 Study Number: 132-007 ADRENAL GLANDS (6) X BWY UEIGHT X BRAIN UEIGHT BRAIN (e) x Ern7 NIGHT HEART (GI % BODY WEIGHT X BRAIN UElGHT KIDNEYS (G) X EWY E I G H T X BRAIN UEIGHT LIVER (G) X EWY UEIGHT X BRAIN UElGHT SPLEEN (GI X BODY VEIGHT X BRAIN UEIGHT TESTES (G) x Ern7 WEIGHT % B R A I N UEIGHT THYMUS (G) X EWY WEIGHT I BRAIN UEIGHT 0.056 0.020 2.857 0.056 0.017 2.888 0.066 0.022 3.720 0.056 0.018 2.969 0.050 0.015 2.591 0.093 0.025 4.443 0.070 0.019 3.271 0.073 0.021 3.566 1.960 0.695 1.939 0.577 1.?74 0.591 1.886 0.614 1.930 0.585 2.093 0.557 2.140 0.580 2.047 0.590 1.000 0.355 51.020 1.131 0.337 58.329 1.122 0.374 63.247 1.109 0.361 58.802 1.227 0.372 63.575 1.248 0.332 59.627 1.271 0.346 59.393 1.205 0.347 58.867 2.804 0.994 143.061 2.554 0.760 131.717 2.594 0.865 lU.223 2.227 0.725 118.081 2.754 0.835 142.694 3.124 0.831 149.259 3.W 0.830 143.178 3.130 0.902 152.907 12.465 4.420 635.969 10.927 3.252 563.538 10.695 3.565 602.875 11.216 3.653 594.698 11.423 3.462 591.865 15.198 4.042 726.135 14.735 3.993 688.551 13.194 3.802 6c4.553 0.620 0.220 31.633 0.662 0.197 34.141 0.459 0.153 25.874 0.580 0.189 30.753 0.678 0.205 35.130 0.810 0.215 38.700 0.5W 0.162 27.991 0.627 0.181 30.630 3.141 1.114 160.255 3.135 0.933 161.681 2.920 0.973 164.600 3.226 1.051 171.050 3.215 0.974 166.580 3.341 0.889 159.627 3.217 0.872 150.327 3.186 0.918 155.642 0.363 0.129 10.520 0.519 0.154 26.766 0.318 0.106 17.926 0.3% 0.129 20.997 0.626 0.190 32.435 0.718 0.191 34.305 0.445 0.121 20.794 0.568 0.164 27.748 ___________________-----------------------.-----------.--- PRIMEOICA REOFIELO STUDY NUMBER 132-007 Page 357 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 12 Study Number: 132-007 ADRENAL GLANDS ( G ) X Ba)Y WEIGHT X BRAlN UEICHT HEART (GI x amy W t t n T X BRAlN WEIGHT KIDNEYS ( G ) x amy EIGHT X BRAIN UEIGHT LIVER ( G ) X BODY WIGHT X BRAIN WEIGHT SPLEEN ( G I A! BODY W l G H T X BRAIN WEIGHT TESTES (GI X BODY W I G H T X BRAIN WEIGHT THYMJS (GI X BODY WIGHT X BRAIN WEIGHT 335.000 376.000 0.076 0.023 3.666 0.079 0.021 3.794 2.073 0.619 2.082 0.554 1.104 0.330 53.256 1.273 0.339 61.143 3.011 0.899 145.248 3.419 0.909 164.217 12.465 3.721 601.303 14.400 3.830 691.643 0.678 0.202 52.706 0.838 0.223 40.250 3.562 1.063 171.828 3.552 0.945 170.605 0.580 0.173 27.979 0.632 0.168 30.355 ___-______.---_----------------------------------------------- PRIMEOICA REDFIELO STUDY NWBER 132-007 Page 358 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 12 ____________-------------------------------.-------------------- ___________.---I-ND-I-V-I-D_UA_L .O_RG_AN_W_EI_GH_T_S __________-.----------.-----.- STUDY: 7-7485 SEX: FEMALE CROUP: 1 - F _________f_ATE_S: S_CHE-DU-LE-D -SA-CR-IF-IC-E __DAY_S: _29-_29 __ALL_BAL_ANC_ES ______.___------------.-- __A_NIM_AL .IO_: _._._.----7-57-0 --_75_72 __7_574__7_576___757_8 __75_80_._758_2 _-7-5-84--.--------.-----.--- 212.000 252.000 244.000 209.000 218.000 230.000 223.000 223.000 ADRENAL GLANDS (G) X BOOY UEIGHT x BRAIN uEicnT 0.071 0.033 3.606 0.082 0.033 4.084 0.101 0.041 4.858 0.089 0.043 5.159 0.078 0.036 3.879 0.095 0.041 4.781 0.067 0.030 3.510 0.080 0.036 4.171 1.969 0.929 2.008 0.797 2.079 0.852 1.725 0.825 2.011 0.922 1.987 0.864 1.909 0.856 1.918 0.860 HEART (G) X BQ)Y WEIGHT X BRAIN WEIGHT KIDNEYS (G) X BOOY WEIGHT X BRAIN UElGHT 0.800 0.377 40.630 1.585 0.747 80.396 0.943 0.374 46.962 1 .no 0.694 87.151 0.956 0.392 45.984 0.829 0.397 48.058 1.925 0.789 92.593 1.779 0.851 103.130 0.885 0.406 44.008 0.937 0.407 47.157 1.882 0.863 93.585 2.133 0.927 107.348 0.806 0.361 42.221 1.720 0.m 90.100 0.886 0.397 46.194 1.750 0.785 91.241 LIVER (G) X BODY YEIGHT X BRAIN UElCHl 6.103 2.879 309.954 7.560 3.000 376.4% 7.534 3.088 362.386 6.447 3.085 373.739 6.755 3.099 335.903 9.176 3.990 461 .802 6.316 2.832 330.854 5.970 2.67? 311.262 OVARIES (G) X E W Y WEIGHT X BRAIY UElCHT 0.114 0.054 5.790 0.112 0.044 5 .si% 0.114 0.047 5 -483 0.098 0.047 5.681 0.121 0.056 6.017 0.139 0.060 6.995 0.095 0.043 4.976 0.105 0.047 5.414 SPLEEN (G) x B m y UEIGHT X BRAIN WEIGHT 0.461 0.217 23.413 0.542 0.215 26.992 0.523 0.214 25.156 0.456 0.218 26.435 0.521 0.239 25 -908 0.57 0.251 29.039 0.507 0.227 26.550 0.478 0.214 24.922 0.528 0.249 26.816 0.461 0.183 22.958 0.604 0.248 29.052 0.415 0.199 24 .OS8 0.3% 0.181 19.6l.2 0.405 0.176 20.382 0.330 0.148 17.287 0.403 0.181 21 -01 1 Page 359 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 12 Study Number: 132-007 BRAIN (GI X BOOY WEIGHT HEART ( G I X BDOY WEIGHT X BRAIN WEIGHT KIDNEYS ( G ) X BWY M I G H T X BRAIN M I G H T LIVER (GI X BDOY WEIGHT X BRAIN K I C H T OVARIES ( G ) X BODY WEIGHT X BRAIN WEIGHT SPLEEN ( G ) X BDOY WEIGHT X BRAIN WEIGHT THYWS (GI X B a ) Y UEICHT X BRAIN WEIGHT 1.862 0.917 1.838 0.769 0.897 0.442 48.174 0.926 0.387 50.381 1.644 0.810 88.292 2.030 0.849 110.446 6.003 2.957 322.3% 7.288 3.049 396.518 0.088 0.043 4.726 0.095 0.040 5.169 0.411 0.202 22.073 0.481 0.201 26.170 0.408 0.201 21.912 0.516 0.216 28.074 Page 360 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 12 Study Number: 132-007 BODY WEIGHT (G) ADRENAL GLANDS (6) x WEIGHT X BRAIN WEIGHT BRAIN (GI X BODY WEIGHT HEART (GI X BODY UEIGHT X BRAIN WEIGHT KIDNEYS (G) X BCOY WEIGHT X BRAIN WEIGHT LIVER (G) X BODY UEIGHT X BRAIN WEIGHT OVARIES (G) X BODY UEIGHT X BRAIN UElGHT SPLEEN (6) X BODY WEIGHT X BRAIN WEIGHT X BRAIN WEIGHT 209.000 223.000 232.000 239.000 209.000 226.000 214.000 219.000 0.075 0.036 3.945 0.074 0.033 3.551 0.082 0.035 4.318 0.078 0.033 3.858 0.091 0.044 4.705 0.063 0.028 3.340 0.081 0.038 4.010 0.090 0.041 4.675 1.901 0.910 2.0w 0.935 1.899 0.819 2.022 0.846 1.934 0.925 1.886 0.835 2.020 0.944 1.925 0.879 0.856 0.410 45.029 1 .081 0.485 51.871 0.894 0.385 47.077 0.933 0.390 46.142 0.818 0.391 42.296 0.814 0.360 43.160 0.874 0.408 43.267 0.874 0.399 45.403 1.939 0.928 101.999 2.083 0.934 99.952 2.047 0.882 107.794 1.981 0.829 97.972 1.741 0.833 90.021 1 A26 0.W 96.819 1 .a0 0.860 91.089 1 A25 0.833 94.805 7.556 3.615 397.475 7.436 3.335 356.814 7.676 3.309 404.213 7.195 3.010 355.836 6.280 3.005 324.716 7.043 3.116 373.436 6.592 3.000 326.337 6.430 2.936 334.026 0.104 0.050 5.471 0.114 0.051 5.470 0.102 0.044 5.371 0.120 0.050 5.935 0.091 0.044 4.705 0.104 0.046 5.514 0.098 0.046 4.851 0.081 0.037 4.208 0.499 0.239 26.249 0.475 0.213 22.793 0.604 0.260 31.806 0.521 0.218 25.767 0.501 0.240 25 .905 0.681 0.301 36.108 0.451 0.211 22.327 0.387 0.177 20.104 0.475 0.227 24.987 0.392 0.176 18.810 0.631 0.272 33.228 0.409 0.171 20.228 0.522 0.250 26.991 0.399 0.177 21.156 0.416 0.194 20.594 0.388 0...177 20.156 Page 361 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 12 Study Number: 132-007 B a y MIGHT ( G I ADRENAL GLANDS (G) X B a y MIGHT X BRAIN M I G H T BRAIN (G) X BODY WEIGHT HEART (GI X B a Y MIGHT X BRAIN YEIGHT KIDNEYS (GI x BODY M I G H T X BRAIN WEIGHT LIVER (C) x BODY M I G H T X BRAIN aSCH1 OVARIES (GI x BQ)Y w c n i X BRAIN M I G H T SPLEEN (GI X Bu)Y MIGHT X BRAIN M I G H T THYMUS ( G I X BODY VEIGHT x BRAIW WEIGHT 206.000 229.000 0.078 0.038 4.021 0.094 0.041 4.981 1.940 0.942 1.887 0.824 0.904 0.439 46.598 0.848 0.370 44.939 1.922 0.933 99.OR 2.049 0.895 108.585 7.150 3.471 368.557 7.642 3.337 404.982 0.125 0.061 6.443 0.094 0.061 4.981 0.444 0.314 33.299 0.586 0.256 31.055 0.510 0.248 26.209 0.469 0.205 24.854 Page 362 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 12 Study Number: 132-007 ADRENAL GLANDS (GI X BCOY UEIGHT X BRAIN UEICHT BRAIN (G) X BOOY UEIGHT HEART (G) X BOOY UEICHT X BRAIN UEIGHT KIDNEYS (GI X BCOY U E I G H T X BRAIN UEIGHT LIVER (G) X BODY UElCHT X BRAIN UElGHT OVARIES (GI X BODY UEIGHT X BRAIN E I G H T SPLEEN (G) x Bmy UEIGHT X BRAIN UEIGHT THYWS (GI X BCOY E I G H T X BRAIN UEIGHT 215.000 235.000 226.000 216.000 222.000 257.000 236.000 218.000 0.078 0.036 4.176 0.076 0.032 4.038 0.079 0.035 4.173 0.085 0.039 4.422 0.079 0.036 3.758 0.062 0.024 3.234 0.078 0.033 3. a94 0.095 0.044 5.029 1.868 0.869 1.882 0.801 1 .893 0.036 1.922 0.890 2.102 0.947 1.917 0.746 2.003 0.849 1.889 0.867 0.890 0.414 47.645 0.839 0.357 44.580 0.860 0.381 45.431 0.911 0.422 47.399 0.879 0.396 41.817 1.071 0.417 55.869 0.799 0.339 39.890 0.777 0.356 41.133 1.885 0.8TI 100.910 2.090 0.889 111.052 1 A22 0.806 96.249 1.629 0.754 84.755 1.800 0.811 85.633 1.937 0.754 101.043 1 .a35 0.m 91 -613 1.769 0.811 93.647 7.304 3.397 391 .OM 7.457 3.173 396.227 7.219 3.194 381 -352 6.609 3.060 343.861 7.420 3.342 352.997 7.250 2.821 378.195 6.366 2.697 317.823 6.603 3.029 349.550 0.095 0.044 5.086 0.446 0.207 23.876 0.140 0.060 7.439 0.514 0.219 27.311 0.101 0.045 5.335 0.468 0.207 24.723 0.111 0.051 5.77s o.cm 0.218 24.454 0.113 0.051 5.376 0.392 0.177 18.649 0.115 0.045 5.999 0.546 0.212 28.482 0.103 0.044 5.142 0.560 0.237 27.958 0.116 0.053 6.141 0.364 0.167 19.269 0.446 0.207 23.876 0.492 0.209 26.142 0.320 0.142 16.904 0.432 0.200 22.477 0.403 0.182 19.1R 0.450 0.175 23.474 0.444 0.188 22.167 0.48 0.206 23.716 Page 363 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 12 Study Number: 132-007 ADRENAL GLANDS ( G ) x Bmy WEIGHT X BRAIN WEIGHT KIDNEYS (GI x BODY WEIGHT X BRAIN MIGHT LIVER (G) x KUY MIGHT X BRAIN WEIGHT OVARIES (G) x B m y WEIGHT X BRAIN WEIGHT SPLEEN (G) x B m y WEIGHT X BRAIN WEIGHT T H Y W S (GI X K U Y WEIGHT x BRAIN WEIGHT 206.000 242.000 0.099 0.048 5.132 0.083 0.034 4.373 1.929 0.936 1.898 0.784 0.768 0.373 39.813 0.816 0.337 42.W3 1.919 0.932 99.482 1.956 0.808 103.056 6.657 3.232 345.101 8.121 3.356 427.872 0.099 0.048 5.132 0.102 0.042 5.374 0.469 0.228 24.313 0.510 0.211 26.870 0.461 0.224 23.898 0.425 0.176 22.392 Page 364 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 12 Study Number: 132-007 B W Y WEIGHT ( G ) ADRENAL GLANOS (G) x BWYWEIGHT X BRAIN WEIGHT BRAIN (GI X B W Y WEIGHT HEART (G) x BWYMmT X BRAIN WEIGHT KIDNEYS (G) X BWY MIGHT x ,BRAIN M i t n i LIVER (6) x BWY MIGHT x BRAIN w m n T OVARIES (e) X BWY MIGHT x BRAIN M i c w SPLEEN (6) x a m y WEIGHT X BRAIN M I G H T THYMUS (6) X B W Y WEIGHT X BRAIN WEIGHT 200.000 247.000 241.000 238.000 228.000 225.000 239.000 241.000 0.079 0.040 4.029 0.082 0.033 3.984 0.060 0.025 3.197 0.091 0.038 4.774 0.072 0.032 3.915 0.079 0.035 4.112 0.079 0.033 3.946 0.075 0.031 3.952 1.961 0.981 2.058 0.833 1 .877 0.779 1.906 0.801 1.839 0.807 1.921 0.854 2.002 0.838 1.898 0.788 0.875 0.438 44.620 0.921 0.373 44.752 0.819 0.340 43.633 0.888 0.373 46.590 1.003 0.440 54.541 0.m 0.344 40.239 0.796 0.333 39.760 0.824 0.342 43.414 2.086 1.043 106.374 2.130 0.862 103.499 2.223 0.922 118.434 1.961 0.824 102.886 2.025 0.888 110.1 14 2.013 0.8% 104.789 1.834 0.767 91.608 2.047 0.849 107.850 6.578 3.289 335.441 7.812 3.163 379.592 8.853 3.673 471.657 7.713 3.241 404.670 7.884 3.458 428.71 1 6.970 3.098 362.832 6.368 2.664 318.082 6.986 2.899 368.072 0.098 0.049 4.997 0.106 0.043 5.151 0.110 0.046 5.860 0.159 0.067 8.342 0.105 0.046 5.710 0.135 0.060 7.028 0.103 0.043 5.145 0.099 0.041 5.216 0.547 0.274 27.894 0.590 0.239 28.669 0.592 0.246 31.540 0.498 0.209 26.128 0.447 0.196 24.307 0.491 0.218 25.560 0.560 0.234 27.972 0.565 0.226 20.714 0.316 0.158 0.536 0.217 0.339 0.141 0.516 0.217 0.482 0.211 0.315 0.140 0.474 0.198 0.541 0.226 Page 365 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 12 Study Number: 132-007 ADRENAL GLANDS ( G I X BCOY M I G H T X BRAIN WIGHT BRAIN (GI x BODY WIGHT HEART (GI X BODY WEIGHT X BRAIN WIGHT KIDNEYS (GI X BCOY UEIGHT X BRAIN WEIGHT LIVER (GI x BODY WEIGHT X BRAIN WIGHT OVARIES (t) x BODY WIGHT X BRAIN WIGHT SPLEEN CG) X BODY M I G H T X BRAIN WEIGHT THYMUS (GI x Bmy KICHT X BRAIN UEIGHT 217.000 225.000 0.092 0.042 4.930 1 .a% 0.860 0.080 0.036 3.968 2.016 0.896 0.816 0.376 43.730 0.766 0.340 37.996 1.958 0.902 104.930 1 .a77 0.834 93.105 7.283 3.356 390.300 7.176 3.189 355.952 0.070 0.032 3.751 0.108 0.048 5.357 0.448 0.206 24.009 0.480 0.213 23.810 0.380 0.175 20.364 0.441 0.196 21 . B E Page 366 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 12 Study Number: 132-007 ADRENAL GLANDS ( G ) X BODY UEIGHT X BRAIN YEIGHT BRAIN (GI X B W Y UElGHT HEART ( G I X BOOY M I G H T X BRAIN E I G H T KIDNEYS ( G ) X BWY EIGHT X BRAIN UElGHT LIVER (G) X BWY MIGHT X BRAIN MIGHT SPLEEN ( G ) X B W Y UEIGHT X BRAIN UEIGHl TESTES ( G ) X B m Y UEIGHT X BRAIN M I G H T THYWS (C) X BWI YEIGHT X BRAIN WIGHT 0.058 0.014 2.922 0.092 0.021 4.236 0.073 0.017 3.456 0.066 0.016 2.993 0.077 0.017 3.441 1.985 0.485 2.1R 0.498 2.112 0.488 2.205 0.547 2.238 0.505 1.281 0.313 64.534 1.567 0.359 R.145 1.573 0.363 74.479 1.374 0.341 62.313 1.373 0.310 61.349 3.660 3.388 0.8% 0.777 i ~ ~ 3 r 1 3i s 5 . m 3.301 0.762 156.297 3.737 0.927 169.479 3.353 0.757 149.821 13.527 3.307 681.461 14.481 3.321 666.713 16.351 3.T16 774.1% 15.507 3.848 7D3.265 15.860 3.580 708.669 0.975 0.238 49.118 0.992 0.228 45.672 0.764 0.m 37.121 0.762 0.189 34.558 0.709 0.160 31.680 2.959 0.R3 149.068 3.309 0.759 152.348 2.734 0.631 129.451 3.007 0.746 136.372 3.183 0.719 142.225 0.4R 0.115 23.m 0.592 0.136 27.256 0.559 0.129 26.- 0.588 0.146 26.667 0.491 0.111 21.939 Page 367 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 12 Study Number: 132-007 ADRENAL GLANDS ( G ) x B m y WEIGHT X BRAIN WEIGHT BRAIN (GI X B W Y WEIGHT HEART ( G I x 8mr WEIGHT X BRAIN WEIGNl KIDNEYS ( G ) X B m Y WEIGHT X BRAIN WEIGHT LIVER ( G ) X BWY EIGHT X BRAIN WEIGHT SPLEEN ( G I X B m Y WEIGHT X BRAIN WEIGHT TESTES ( C ) x B m i WEIGHT X BRAIN WEIGHT 365.000 389.000 431.000 422.000 379.000 0.054 0.015 2.439 0.067 0.017 3.057 0.091 0.021 4.365 0.OM 0.017 3.028 0.061 0.016 2.m 2.214 0.607 2.192 0.543 2.085 0.484 2.312 0.548 2.197 0.580 1.3U 0.368 60.705 1.445 0.371 65.922 1.424 0.330 68.297 1 .n6 0.421 76.817 1.306 0.345 59.445 3.415 0.936 154.246 3.315 0.852 151.232 3.555 0.825 170.504 4.209 0.997 182.050 3.4n 0.917 158.261 14.018 3.841 633.153 13.117 3.372 598.403 16.825 3.904 806.955 16.803 3.982 R6.m 12.722 3.357 579.062 0.911 0.250 41.147 0.598 0.154 27.281 0.667 0.155 31.990 0.665 0.158 28.763 0.716 0.189 32.590 3.167 0.868 143.044 3.346 0.860 152.646 3.2% 0.765 158.034 3.748 0.888 162.11 1 3.592 0.948 163.496 0.456 0.125 20.596 0.482 0.124 21.989 0.558 0.129 26.763 0.585 0.139 25 -303 0.636 0.168 28.949 Page 368 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 12 Study Number: 132-007 800Y E I G H T ( G ) ADRENAL GLANDS ( C ) X BODY UEIGHT X BRAIN WEIGHT BRAIN ( G ) X BCOY M I G H T HEART ( G ) X BWY WEIGHT X BRAIN UEIGHT KIDNEYS ( C ) X BODY M I G H T X BRAIN E I G H T LIVER ( G ) X BCOY E I G H T X BRAIN UElGHT OVARIES (GI X BWY WEIGHT % B R A I N UElGHT SPLEEN (GI X BODY E I G H T %BRAIN EIGHT THYMUS (GI X BODY E I G H T X BRAIN WEIGHT 262.000 244.000 241 .OOO 242.000 227.000 0.079 0.030 3.899 0.080 0.033 3.830 0.097 0.040 4.823 0.081 0.033 4.429 0.062 0.027 3.202 2.026 0.m 2.089 0.856 2.011 0.834 1 A29 0.756 1.936 0.853 1.044 0.398 51.530 0.986 0.404 47.200 0.987 0.410 49.080 0.931 0.385 50.WZ 0.847 0.373 43.750 2.272 0.867 112.142 2.310 0.947 110.579 2.300 0.954 114.371 1 A94 0.783 103.554 1.901 0.837 98.192 8.567 3.270 422.853 9.019 3.6% 431 .738 9.m 4.057 486.176 8.659 3.578 473.428 6.715 2.958 346.849 0.122 0.047 6.022 0.111 0.045 5.314 0.122 0.051 6.067 0.082 0.034 4.483 0.085 0.037 4.390 0.529 0.202 26.111 0.566 0.232 27.094 0.645 0.268 32.074 0.549 0.227 30.016 0.446 0.196 23.037 0.587 0.224 2a. 973 0.448 0.184 21 -446 0.532 0.221 26.L55 0.666 0.275 36.413 0.299 0.132 15.444 Page 369 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats APPENDIX 12 Study Number: 132-007 B a l l WEIGHT ( C ) ADRENAL GLANDS ( G ) x m y WEIGHT X BRAIN WEIGHT BRAIN (C) X B a l l UEIGHT HEART (6) X BWY EIGHT X BRAIN MIGHT KIDNEYS ( C ) X 8mY KIGHT X BRAIN UEIGHT LIVER (GI X 8 m Y WEIGHT X BRAIN MIGHT OVARIES (G) X B W Y WEIGHT X BRAIN UEIGHT SPLEEN (6) X 8mY MIGHT X BRAIN WEIGHT 237.000 247.000 241.000 246.000 239.000 0.097 0.041 5.157 0.105 0.043 5.250 0.080 0.033 4.022 0.076 0.031 4.011 0.089 0.037 4.302 1.881 0.794 2.000 0.810 1.989 0.825 1 .895 0.m 2.069 0.866 0.947 0.400 50.346 0.869 0.352 43.450 0.857 0.356 43.087 0.984 0.400 51.926 1.015 0.425 49.058 1.8i7 0.792 99.787 2.409 0.975 120.450 2.238 0.929 112.519 2.186 0.889 115.356 2.423 1.014 117.110 7.741 3.266 411.536 8.557 3.464 427.850 8.831 3.664 443.992 8.678 3.528 457.942 10.320 4.318 498.792 0.089 0.038 4.732 0.110 0.045 5.500 0.109 0.045 5.480 0.090 0.037 4.749 0.112 0.047 5.413 0.503 0.212 26.741 0.557 0.226 27.850 0.588 0.244 29.563 0.546 0.222 28.813 0.536 0.224 25.906 0.408 0.172 21 -691 0.328 0.133 16.400 0.513 0.213 25.792 0.354 0.144 18.681 0.499 0.209 24.118 Page 370 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 13 FORMULATED TEST MATERIAL ANALYSIS REPORT Page 371 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 DOSE FORMULATION ANALYSIS OF PERFLUOROBUTANESULFONATE IN 1% CMC BY HPLC/MS STUDY ID: A098.1 SPONSOR STUDY NO. 132-007 Southern Research Institute 2000 Ninth Avenue South P.O.Box 55537 Birmingham, AL 35255-5537 Page 372 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 SUMMARY A total of 24 formulated dose samples including blanks ranging in concentration from 4 to 40 mg/mL were analyzed by analytical method BACG 3533 to determine the concentration of perfluorobutanesulfonate (PFBS)in the formulated mixture. All dose formulations were found to be acceptable by the sponsor. Page 373 A 28-Day Oral Toxicity Study in Sprague-Oawley Rats James D.Johnson, M.S., MI3A Manager Bioanalytical Chemistry Group Gregory S. Goman, Ph.D. Staff Chemist Bioanalytical Chemistry Group KEY PERSONNEL Study Number: 132-007 Page 374 A 28-Day Oral Toxicity Study in Sprague-DawleyRats Study Number: 132-007 1. OBJECTIVE The objective of this study was to determine the dose concentration of PFBS in the supplied dosing solutions received from the study director. 2. SAFE7T All necessary procedures to ensure safety of the analysts were based on information contained in the Material Safety and Data Sheets (MSDS), provided by the study director for the test article used in this study. 3. Compliance This work was perforrhed using a validated analytical method (BACG 3533), which along with the validation report is included in the appendix of this report. While this work was not audited in compliance with GLP regulations, it was performed in the spirit of the regulations using calibrated and validated instrumentation. 4. EXPERIMENTAL 4.1 Analytical Procedures The sample preparation and analysis procedures as described in the analytical method BACG 3533 were employed for all analyses. Each sample was allowed to warm to room temperature and was then vortexed well before an aliquot was taken. Duplicated aliquots were taken from each sample and diluted a~ described in the method. Three standad curves was prepared over a concentration range of 500 to 10,000 ng/mL and analyzed along with the samples. No outliers in the calibration standards were noted and subsequently no standards were dropped from either of the calibration curves. 4.2 Results The results of the analysis are presented in the Table I at the end of the report. 5.0 Conclusion A total of 24 dose formulation samples ranging in concentration from 4 to 40 mg/mL were analyzed by BACG 3533. All samples were found to be acceptable by the sponsor. Page 375 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 Table I PFBS Dose Formulation Summary in 1 % CMC ND = not detected * Results represent average of duplicate analysis ** One of the day 14 controls (0 mg/mL) was inadvertently contaminated during preparation. Result based on single analysis. *** No sample received Page 376 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 Statement of Compliance Study A098.1 Sponsor Study 132-007 This work wa performed using validated analytical method (BACG 3533). While this work was not audited in compliance with GLP regulations, it was performed in the spirit of the regulations using calibrated and validated methods and instrumentation. Staff Chemist Bioanalytical Chemistry Group y-r-o/ Date ames D. JOIUIS~,&S, MBA Date Bioanalytical Chemistry Group Page 377 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 METHOD VALIDATION REPORT VALIDATION OF ANALYTICAL METHOD FOR DOSE FORMULATION ANALYSIS OF PEFWLUOROBUTANE SULFONATE (PFBS) IN 1% CARBOXYMETHYL CELLULOSE (CMC) STUDY ID: A098.1 Southern Research Institute 2000 Ninth Avenue South P.O. Box 55537 Birmingham,AL, 35255-5537 Page 378 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 SUMMARY Southern Research Institute has successfully validated for 3M an analytical method (BACG 3533) entitled "Dose Formulation Analysis of Perfluorobutane Sulfonate in 1% Carboxymethyl Cellulose by HPLC Mass Spectrometry". Calibration standards were prepared by spiking solvent solutions with known amounts of test article, PFBS, and internal standard, The calibration standards were prepared over a concentration range of 500 to 10,000 n g h L and the carboxymethyl cellulose (CMC) concentration was adjusted to equal that of each diluted sample in each set. Additionally, three standard curves were prepared and analyzed which contained no CMC as controls. A total of 6 calibration curves were generated during the study which produced correlation coefficients ranging from 0.9992 to 0.9999. .. Page 379 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats James D. Johnson, M.S. Manager Bioanalytical ChemistIy Group Gregory S. Gorman, Ph.D. Research Chemist III Bioanalytical Chemistry Group Lester Williams, B.S. Associate Chemist II Bioanalytical Chemistry Group KEY PERSONNEL Study Number: 132-007 Page 380 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 1. OBJECTIVE The objective of this study was to provide a validated analytical method for the determination of PFBS concentration in dose formulation samples containing 1% CMC. 2. SAFETY All necessary procedures to ensure safety of the analysts were based on information contained in the Material Safety and Data Sheets (MSDS),provided by 3M for the test article used in this study. 3. EXPERIMENTAL 3.1 Analytical Procedures The sample preparation and analysis procedures as described in the analytical method BACG 3533 were employed for all analyses. For the preparation of the calibration standards, a known volume of a solvent (e.g., 1 mi,) containing CMC was spiked with a known amount of test article and internal standard and vortexed briefly to ensure mixing. Each formulation sample was diluted to a final concentration of 3200 ng/mL and ah aliquot of this was placed into autosampler vials for analysis. 3.2 Method `Validation Validation for BACG 3533 "Dose Formulation Analysis of Perfluorobutane Sulfonate in 1% Carboxymethyl Cellulose by HPLC Mass Spectrometry" consisted of analyzing three standard curves containing CMC at the concentration present in the diluted 4 mdmL dose formulation samples (0.001%) and three curves prepared without CMC. The concentration range for both sets ranged from 500 to 10,000ng/mL. A total of 7 calibration levels in each curve containing CMC and 6 in each of the three without CMC were evaluated. The summaries are given below: Calibration Results 0% CMC A total of three standard curves each containing 6 individual standards encompassing a range of 500 to 10,000ng/mL were analyzed in duplicate. The comelation coefficient for the composite curve comprising a total of 36 data points was found to be 0.9992. No data points were dropped from the analysis. A statistical summary for the composite curve is shown below: Page 381 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 STANDARD COWOSITE CURVE PFBS (0% CMC) # of Standards Mean%Accur. Std. Deviation 6 97.71 19.47 6 102.9 55.85 6 99.73 110.6 6 99.52 187.8 6 100.1 288.2 6 100.2 356.4 calibration Results (CMC= 0.001YO) Three standards curves containing a total of 21 single standards encompassing a range of 500 to 10,000 ng/mL were analyzed. The correlation coefficient for the calibration curve was found to be 0.9997. No data points were dropped from the analysis. A statistical summary for the composite curve is shown below: STANDARD COMPOSITE CURVE PFBS (0.001% CMCJ # of Standards Mean%Accur. Std-Deviation 3 98.11 18.19 3 101.5 17.72 3 101 48.33 3 101 49.67 3 98.44 81.61 3 99.31 76.38 -3 100.7 203.4 3.3 Calculations Calculations were fdonned 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 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 determinedto be the best fit : y = a x 2 + bx + c where: y = Peak area response of test article x = Concentration of the test article in standards. a, b, c = Constants derived fiom the regression analysis. Page 382 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 4.0 Conclusion A quantitative method (BAGC 3533) has been developed and validated for the determination of PFBS in dose formulation solutions containing 1% CMC. Quantitation for this method is based on internal standard which produces standard curves with a correlation coefficients of 0.9992 or greater over a concentration range of 500 to 10,000ng/mL. 5.0 Approvals Greggry S.Gorman, PbD. Date Staff Chemist Bioanalytical Chemism Group Date W Bioan&cal Chemistry Group Page 383 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 Page 1of 8 ANALYTICAL METHOD -Method No. : BACG-3533 Title: Dose Formulation Analysis of Perfluorobutane Sulfonate in 1%Carboxymethyl Cellulose by HPLCIMass Spectrometry (HPLCIMS) 1.0 PRINCIPLE Dose formulation samples of perfluorobutane sulfonate (PFBS)kt 1 % carboxymethyl cellulose (CMC) are diluted down to 3200 ng/mL and analyzed by HPLCIMS. Quantitation is based on an internal standard using back calculated values from a calibration curve encompassing a concentration range from 500 to 10,OOO ng/mL and containing the same concentration of CMC as the dose formulations in the diluted form. 2.0 REAGENTS AND SOLUTIONS The listed reagents or their equivalents may be used. 2.1 Neat Reagents 2.1.1 Water, deionized and organic free (from in-house purification system; e.g., Ingalls 210N) 2.1.2 Methanol. HPLC grade 2.1.3 Perfluorobutanesdfonate (analyte), as provided by the client 2.1.4 (internal standard), 97% ' 2.1.5 Ammonium acetate, HPLC grade 2.2 2.2.1 Prepared Solutions Appropriate changes in the solutions may be made at the discretion of the analyst 5 mM Ammonium acetate in organic free water Page 384 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 Page 2 of 8 ANALYTICAL METHOD Method No. : BACG-3533 Title: Dose Formulation Analysis of Perfluorobutane Sulfona-3 in 1%! Carboxymethy Cellulose by HPLClMass Spectrometry (HPLC/MS) ~~ ~ 2.2.1.1 For example, to prepare 4 liters, measure out ammonium acetate (e.g., 1.542 g) and add in organic-free water (e.g., 4 L). Mix well and filter through HPLC mobile phase Ntration apparatus. 3.0 INSTRUMENTS,MATERIALS, AND APPARATUS The following or their equivalents m a y be used. 3.1 HPLC pump(s), autosampler, and single quadrupole mass spectrometer 3.2 Autosampler vials with inserts 3.3 Vortex mixers (e.g., touch mixer and IKA-Vibrax @ platform mixer) 3.4 HPLC mobile phase filtration apparatus 3.5 Filters for HPLC mobile phase filtration apparatus (e.g., Nylon-66, 0.20 pm) 3.7 Analytical balance 3.8 Volumetric flasks (e.g., 10 and 25 mL) 3.9 Disposable Pasteur pipets 3.10 Micropipettor(s) with tips 3.11 Culture tubes with teflon-lined caps 3.12 Assorted glassware and syringes Page 385 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 Page 3 of 8 ANALYTICAL METHOD Method No.: BACG-3533 Title: Dose Formulation Analysis of Perfluorobutane Sulfonate in 1 3'% Carboxymethyl Cellulose by HPLCIMass Spectrometry (HPLCIMS) 4.0 PREPARATION OF STOCKS AND WORKING STOCKS Appropriate changes in the concentrations of the solutions may be made at the discretion of the analyst. Actual dilutions will be documented on the preparation sheets. 4.1 4.1.1 4.2 4.2.1 4.3 4.3.1 Main Stock Solution of PFBS -1000 &mL - Prepare an lo00 pg/mL solution of PFBS in mobile phase (e.g., accurately weigh about 10 mg PFBS into a 10-mL volumetric flask). Add mobile phase to dissolve. Dilute to the mark. Alternatively, weigh the compound into an appropriate vessel (e.g., culture tube) and add 10 mL of mobile phase. Mix well. Transfer the solution to a clean vessel if desired. ' Spiking Stock Solution of PFBS -50 p g / d Prepare an -50 pg/mL solution of PFBS in mobile phase (e.g., measure about 500 pL of -lo00 pg/mL PFBS into a IO-mL volumetric flask). Add mobile phase to dissolve. Dilute to the mark. Alternatively. weigh the compound into an appropriate vessel (e.g.. culture tube) and add 10 mL of mobile phase. Mix well. Transfer the solution to a clean vessel if desired. Stock Solution of Internal Standard -200 p g l d Prepare an -200 p g / d solution of in deionized organic-free water (e.g., accurately weigh about 10 mg into a 50-mL volumetric flask). Add deionized organic- free water to dissolve and dilute to the mark with deionized organic-free water. Alternatively, weigh the compound into a an appropriate vessel (e.g., culture tube) and add 50 mL of deionized organic-free water. Mix well. Transfer the solution to a clean vessel if desired. Page 386 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 Page 4 of 8 ANALYTICAL METHOD Method No.: BACG-3533 Title: Dose Formulation Analysis of Perfluorobutane Sulfonate in 1 % Carboxymethyl Cellulose by HPLC/Mass Spectrometry (HPLCIMS) 4.3 4.3.1 Working Stock Solutions of PFBS To prepare. working stock solutions, make the proper dilutions as shown in the following table. Prepare in 10-mL volumetric flasks or other appropriate glassware. If desired a modiied dilution scheme can be used and documented in the study records. Working Stock Level I loo00 I 200 I 200 I 600 I Note: The mobile phase used for each standard curve should contain the same concentration of CMC as the samples. For example, the dilution factor of a 4 mg/mL sample is lo00 (prior to addition of IS). The mobile phase for a 4 m g / d sample prepared in 1 % CMC should contain 1/1OOO%CMC to account for the dilution. 5.0 PREPARATIONOF SPIKED STANDARDS AND BLANKS Appropriate changes in the concentrations of the solutions may be made at the discretion of the analyst. Page 387 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 Page 5 of 8 ANALYTICAL METHOD Method No.: BACG-3533 Title: Dose Formulation Analysis of Perfluorobutane Sulfonate in 1% Carboxymethyl Cellulose by HPLCMass Spectrometry (HPLCIMS) 5.1 Multiple (e.g.. about three) sets of standards blanks (blank + IS) are analyzed with each set of unknown samples. A double blank (blank-IS) may also be analyzed if desired. Standards may be prepared as shown in the table in 4.3.1. 6.0 PREPARATION OF SAMPLES 6.1 All samples are to be diluted to approximately the middle of the curve (e.g. 3200 ng/mL). Dilutions are to be made with mobile phase. For example, for a 4 mg/mL sample,'take 1 mL and dilute with mobile phase in a 10 mL volumetric flask. Then take 100 pL of the diluted sample and dilute that with mobile phase in a 10 mL volumetric flask. Take 800 pL of the second dilution, place in an autosampler vial, add 200 pL of IS,mix, and analyze. 7.0 ANALYSIS BY HIGH PERFORMANCE LIQUID CHROMATOGRAPHY MASS SPECTROMETRY/MASS SPECTROMETRY (HPLC/MS/MS) 7.1 Conditions are to be optimized if necessary. 7.1.1 Analytical Column: Guard Column: Elution Flow rate: Injection volume: Mobile phase: none Fluofix lZOE 10 mm x 2 mm lo00 pwmin. 5 PL A: 5mM ammonium acetate buffer B: methanol Elution Profile: Temperature: Isocratic 30%A : 70%B Ambient 7.1.2 PE Sciex API 150EX Single Quadrupole Mass Spectrometer Conditions Page 388 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 Page 6 of 8 ANALYTICAL METHOD Method No.: BACG-3533 Title: Dose Formulation Analysis of Perfluorobutane Sulfonate in 1% Carboxymethyl Cellulose by HPLC/Mass Spectrometry (HPLUMS) Software: PE Sciex TurboQuan Note: Values listed under 'MSIMS Acquisition Conditions override parameters in this table. . AuxiiiaryGas: Air (e.g., Grade 0.1) at 85 pounds per square inch Parameter Is NC TEM OR RNG Qo IQl sr RO1 DF CEM NEB CUR CAD QPE POL VCM WE yalue -5m 0 450 -25 -170 10 11 16 I1 300 2400 1s 8 0 0 0 0 0 Page 389 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 Page 7 of 8 ANALYTICAL METHOD Method No.: BACG-3533 Title: Dose Formulation Analysis of Perfluorobutane Sulfonate in 1%Carboxymethyl Cellulose by HPLC/Mass Spectrometry (HPLC/MS) Masses requested: PFRS: . . fuM=Aml 299.2 200 200 8.0 CALCULATIONS -8.1 At the end of the analytical run. review each chromatogram to ensure the retention time, peak shape, and peak height and peak area determination of the test article and the IS are acceptable. The data may be smoothed as appropriate. For quantitation, use the ion profiles at the following mass-to-charge ratios: rDnh5.k PFBS 299.2 8.2 Plot the peak area response of PFBS divided by the pcak area response of the IS fiom all standards versus the concentration of the test article in the standards. Alternatively, the peak heights may be used instead of peak areas. Obtain the best curve fit of the data (e.g., quadratic fit weighted with l/concennation of the test article or a quadratic fit). Note: The best curve fit may be dependent on the range of the standard curve and it may be necessary to have more than one standard curve for various concentration ranges using the following: y = & + bx + c where y = Peak height response of PFBS divided by peak height response of the IS in standards. x = Concentration of the PFBS in standards. Page 390 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 Page 8 of 8 ANALYTICAL METHOD Method No. : BACG-3533 Title: Dose Formulation Analysis of Perfluorobutane Sulfonate in 1%Carboxymethyl Cellulose by HPLC/Mass Spectrometry (HPLC/MS) a, b, c = Constants derived from the regression analysis. 8.3 Using the standard curve, calculate the level of PFBS in each unlcnown sample. Correct the results of samples for any dilutions. 9.0 ACCEPTANCE AND REJECTION CRITEFUA 9.1 Refer to SOP SRI 91-3 for acceptancehejection criteria except acceptable accuracy for standards is 80-12096 of theoretical. 10.0 REPORTING 10.1 Results of all analyses are tabulated, and the raw data, original chromatograms, and reports are to be fded in the appropriate study file. Authors: 747 4 6 a O Chemist III Date 7-17-2 0 0 0 Date Page 391 A 26-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 14 CERTIFICATE OF ANALYSIS Page 392 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 Certificate Of Analysis PFBS) J? Lot 2 (1999) April 17,2000 (Supercedes Certificate of Analysis dated April 11,2000) This sample was analyzed using LCIMS, ., and elemental analyses techniques. Tlic results of these tests show the samplet o contain the following weight percent composition: 0.13 % Additionally, the isomer distribution of the sample was determined using contain the following weight percent composition: techniques and found to CFJ(CF~)~-SKO' ~- 97.86 % Analytical Study Number: 60488 Page 393 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 15 PROTOCOL AND AMENDMENT Page 394 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 Primedica Redfield Protocol Roro~olNumber: 132-007 A 28-DAY ORAL (GAVAGE)TOXICITY STUDY OF T-7485 IN SPRAGUE-DAWLEY RATS PROTOCOL NO.: 132-007 OBJECTIVE: To evaluate the toxicity potential associated with oral (gavage) administration of T-7485 in Sprague-Dawley rats for a 28day repeated dose with an approximate 14day recovery period. LOCATION OF STUDY AND CONDITIONS OF TESTING: It is the intentionof 3M Corporate Toxicology. through the conduct of this study,to generate animal safety data that may be submitted to regulatory authorities. Primedica Redfield, 100 East Boone Street, Redfield, Arkansas, 72132,is accredited by W C and licensed by the United States Department of Agriculture to conduct research in laboratory animals. All the conditions of testing will conform to the Animal Wdfare Act (CFR 9) and its amendments. Primedica Redfield will follow aH requirements specified in this approved protocol as well as Primedica Redfields Standard Operating Procedures. Changes in the protocol may be made by consultation with and approval from 3M Corporate Toxicology followed by written verification of the change. 3M Corporate Toxicology reserves the right to inspect facilities and procedures used for this study by means of announced or unannounced site visits. Primedica Redfield will notify 3M Corporate Toxicology promptty by telephone prior to release of any data for review. SPONSOR: 3M Corporate Toxicology 3M Center, Building 220-2E-02 P.O. Box 33220 St Paul, MN 55133-3320 SPONSOR'S REPRESENTATIVE: Ph.D., DABT. CIH Senior Labotatorv Manaaer Telephone: FAX: TESTING FACILTTY: PERSONNEL: Primedica Redtield Mail: P.O. Box 308 Deliveries: 100 East Boone St Redfield, AR 72132 Telephone: 501-397-2540 FAX: 501497-2002 Study Director: John Seng. Ph.D. Principle Investigator: Karen Tranter, B.A, L4TG Veterinarian: Allan Manus, D.V.M., M.Sc., ACIAM Clinical Pathology: Phyllis Powell, E.S.,M.T., ASCP Head Technician: Martha Downing, B.S. PROPOSED STUDY DATES: ExperimentalStart Date: August 31, 2000 ExperimentalTermination Date: October 13,2000 Draft Report Date: December 12.2000 Page 1 of 10 Page 395 8/29/00 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 Primedica Redfield Protocol Protocol Number: 1 3 2 W 1. REGUL~TORCYOMPLIANCEA M QuAUTY ASSURANCE This study will be conducted in accordance with the following Good Laboratory Practice RegulationsStandarddGuidelines: El C(81)30 (Final) (OECD) The Quality Assurance Unit, in accordance with Primedica Redfield's Standard Operating Procedures (SOPS), will audit the protocol. study conduct, and the final report 2 lNSTlTlJ7lONALANIMALCARE AND USE cOMMl7TEE REVIEW The protocol will be reviewed and approved by Primedica Redfields InstitutionalAnimal Care and Use Committee(IACUC) for compliance with regulations prior to study initiation. In the opinion of the Sponsor, indicatedby the signature on this protocol, the study does not unnecessarily duplicate any previous work. 3. MATERIALS TESTMATERIAL T-7485 (Potassium perffuorobutane sulfonate, PFBS) l ~ w n ~ l c ~ ~ l o n r The lot number will be listed in the raw data and final report PHYSICADLfscRlpTKm White powder VEHICLE CONTROL 1% carboxyrnethyicellulose (aqueous. medium viscosity) /DENTlFlCA~ON The lot number will be listed in the raw data and final repott PHYSICADLE S C R I P ~White powder STORAGECONDITIONS The bulk test material will be stored in its original container at morn temperature. The formulated test and vehicle control material will be stored at 2" to 8'C. AMLMlCAL CHEMISTRY The Sponsor assumes responsibility for characterization (identity, purity, and stability) of the bulk test material (including under test conditions). lnfotmation on the composition and method of synthesis of the bulk test material will be held by the Sponsor. The doses, unless otherwise stated, will be calculated assuming the test material to be 100% pure. DOSE PRfPARATION AND CO-TION Doses will be formulated every ten days by Primedica Redfield. The carboxymethylcellulose will be prepared at 1% in deionizedwater and may be prepared prior to Study Day 1. Page 2 of IO Page 396 8/29/00 A 26-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 Primedica Redfield Protocol The test material container(s) will be inventoried when received at the testing laboratory, and a record of all test material use will be maintained. The technician dosing the animals will: 1) Record the weight or volume of the test material container immediately before and after dosing; 2) Compute and record the amount used and compare it to the theoretiml amount immediately after dosing; 3) Keep the formulated test material use log in the animal study books at all times; 4) Asswe the dose used is within i l O % of theoretical. A sample of each concentration of the formulated test material and vehicle will be retained pretest and after completion of treatmentwith each batch and frozen at approximately -2O'C for analysis. Prior to dosing, all pretest samples will be sent to and analyzed by the below mentioned laboratory. All end of batch samples will be sent after study termination to: Greg Gorman. Ph.D. Research Chemist 111 Southem Research Institution 2000 Ninth Avenue South Birmingham, AL 35205 Telephone: (205) 581-2725 FAX: (205) 581-2726 This laboratory. will provide their own report regarding the analysis of the vehicle and test material, validation of the test system, analyses of the data, and QAU audits or audit reports. This report will be added as an appendix to the study report RESERVE SAMPLES A reserve sample of each lot of test and vehicle control material will be retained for archiving in accordance with the selected Good Laboratory Practices. TESTMTERIAL R E T E ~ O N Unused test material may be returnedto the Sponsor or designee at the termination of the study, or retained for use on future studies. The Sponsor will be notified in advance of shipping, and a transmittal letter will accompany the shipment. The material will be packed in a suitable container to maintain the conditions specified by the Sponsor during transit plus an adequate margin of safety for any transit delays. S A F n V PRECAUTIONS General safely precautions as required by Primedica Redfield's policies and procedures will be followed. The Sponsoh Representativewill be notified of any personnel exposures requiring a physician's examination or care. Page 3 of 10 0l29lQQ Page 397 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 Primedica Redfield Protocol Promcol Number: 132-007 4. ANIMALS species: StrainlSource: Age at Initiation: Number and Sex: Identification: ANIML HUSSANDRV Rat Crl:CD@(SD)albino rats, Charles River Laboratories, Inc. Six to eight weeks 50 male and 50 fernale (female nulliparous and non pregnant) Uniquely numbered ear tag and cage card HOUSING The animals will be individually housed in stainless steel cages. The cages conform to standards set forth in the Guide for the Care and Use of Laboratow Animals,-National Academy Press. Washington, D.C.. 1996. FEED Teklad Certiied Rodent Diet a 7 2 8 will be providedad libitum. This diet is routinely analyzed by the manufacturer for nutritional components and environmentalcontaminants. Results of the manufacturets analyses are on file at Primedii Redfield. WATER COMAMIMMS Filteredtap water will be provided ad IibihJrn. Samples of the water are analyzed for total dissolved solids, hardness, specified microbiological content. and for environmental contaminants. Results of these analyses are on file at Primedica Redfield. There are no known contaminants in the feed or water that would be expected to interfere with this study. ENVIRONMENT Environmentalcontrols are set to maintain a temperature of 18" to 26C (64' to 79F)with a relative humidity of 30% to 70%. These parameten are .recorded at least once daily. A 12:12 hour lightdark cycle is maintained. Animals will be acclimated for a minimum of seven days prior to the study start An adequate number of extra animals will be purchased so that no animal in obviously poor health is placed on test At the request of the Study Director, excess animals may be used as replacement animals. Animals will be examined by the Staff Veterinarian prior to release of that shipment of animals for use on the study. ./USTlFlCATlONFOR SPECIES SELECTIONAND NUMBEROF ANIMALS Rats are an animal model for studies of this type. The number of animals assigned to this study represents the minimum required to meet the objective@)of the OECD GuidelineM07. Page 4 of 10 atmoo Page 398 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Primedica Redfield Protocol 5. EXPERIMENTAL METHODOLOGY STUDYDESIGN Study Number: 132-007 ROIOCNuOm~ber: 132-007 'Number in parenthesis indicates the number of recovery animals ASSIGNMENTTO GROUPS Animals will be randomly assigned to groups by a weightordered distribution such that individualbody weights will not exceed i20% of mean weight for each sex. FREQUENCY AND DURATION OF hMNlSTRA77ON Doseswill be administered via oral gavage for twentyeight consecutive days. The dose volume will be 25 mlfkg. The first day of dosing on the study will be Study Day 1. Individual dose volumes will be calculated using the most recently collected body weights. Rats (5/sex/group) in the vehicle control and high dose groups will be allowed an approximate fourteen-day recovery period. JUSTIFICATION FOR R O U E OF ADMNISTRAllONAND DOSE LEVEL In the assessment and evaluation of the toxic characteristics of a substance, detennination of acute oral toxicity is usually an initial step. Dose levels were chosen by the Sponsor and based on the findings reported in Primedica Redfield Study Number 132-006. ANTEMORTEM OBSERVATIONS CLINICAL OBSERVATIONS Observations will be performed and recorded twicedaily (a.m. and p.m.) for moribundity and mortality. Cageside observations will be performed approximately one to two hours postdose. according to Prirnedica Redfield's SOPS, and recorded once daily and when a change is noted. Once before the first dose (to allow for withimsubject comparisons), and at least weekly thereafter or when a change is noted, detailed clinical observations will be made in all animals. These observations will be made outside the home cage and preferably at approximately the same time of day, each time. Effort should be made to ensure that variations in the test conditions are minimal. Signs noted should include, but not be limited to, changes in skin, fur, eyes, mucous membranes, Occurrence of secretions and excretions, and autonomic activity. Changes in gait, posture, and response to handling as well as the presence of clonic or tonic movement, stereotypes, or bizarre behavior should also be recorded. Page 5 of 10 8/29/00 Page 399 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 , Primedica Redfield Protocol Protocol Number: 132-07 BODY WEIGHTS FEED CONSUMPTION HEMTOLOGY During Study Week 4, sensory reactivity to stimuli of different types (e.g. auditory, visual, and proprioceptive stimuli), assessment of grip strength, and motor activity assessment will be conducted. Body weights will be recorded pretest on Study Day 1, approximately weekly, prior to terminal fasting, and prior to necropsy. Feed consumption will be measured approximately weekly and will be reported as an average daily consumption. Blood samples will be obtained prior to necropsy while under anesthesia (CO,) via cardiac puncture. Feed will be withheld overnight prior to collection. Blood samples collected (using EDTA for hematology and sodium citrate for coagulation indices) will be evaluated for the following parameters: CLINICAL CHEMISTRY Total and relative differential leukocyte counts Erythrocyte counts Hemogbbin concentration Hemdocrit value Mean corpuscular volume Mean corpuscular hemoglobin Mean corpuscular hemoglobin concentration Platelet counts Prothrombin time Activated partial thromboplastin time Blood samples will be obtained prior to necropsy while under anesthesia (CO,) via cardiac puncture. Feedwill be withheld overnight priw to collection. Blood samples collected for clinical chemistry will be processed and evaluated for the parameters specified below: Total Protein - Albumin Glucose Triglycerides UreaNiWen Alanine Aminotransfewse Alkaline Phosphatase Calcium Sodium Potassium Globulin AlbuminlGIobulin ratio Cholesterol Total Bilirubin Creatinine Aspartate Aminotransferase Gamma-glutamyItransferase Phosphorus Chloride mSTMoR7EM OBSERVATlONS MORl8UND ANIMALS AND ANIMALS i % J N DDEAD Animals unlikely to survive until the next scheduled observation will be weighed, euthanized, and necropsied. Animals found dead will be weighed and necropsied. In either case, blood samples will not be collected and a complete necropsy will be performed as detailed below. Page 6 of IO 8/29/00 Page 400 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 Primedica Redfield Protocol Protocol Number: I32-007 EUTHANASIA NECROPSY All animals will be humanely euthanized via anesthesia with carbon dioxide to effect followed by exsanguination. Euthanasia will be performed in accordance with accepted American Veterinary Medical Association (AVMA) guidelines [J. Amw. Vet M e d . Assoc.. 202:229-249, 19931. With the exception of the recovery animals, on Study Day 29. the animals will be sacrificed rotating sequentially through groups for each sex. Recovery animals will be sacrificed rotating sequentially through the groups for each sex on approximately Study Day 44. All animals that die during the study, or are killed at study termination, will be subjected to a complete necropsy examination. A complete necropsy is defined as examination of the external surface of the body, all orifices. and the cranial, thoracic, and abdominal cavities (and their contents). The following organs will be weighed prior to fixation: adrenal glands, brain, heart, kidneys, liver, ovaries, spleen, testes, and thymus. Paired organs will be weighed together. Organ weights will not be taken from animals that die or are euthanhed prior to scheduled necropsy. Organs (or samples of organs) and tissues listed below will be examined in situ, dissected free, and fixed in 10% neutral buffered formalin or other suitable fixative for possible histopathologicalexamination. Observations noted at necrop. s.y will be recorded on the IndividualAnimal Necropsy Record. Adrenal glands Aorta Bone marrow sternum Brain brain stem cerebellum cerebrum Cervix Epididymides Esophagus Eye with optic nerve Femur with articular surface Gross lesions Harderian gland Heart Lymph nodes mandibular mesenteric Mammary gland Ovaries Oviducts Pancreas Pituitary gland Prostate gland Salivary gland mandibular Sciatic nerve Seminal vesicles Skeletal muscle Spinal cord cervical lumbar thoracic Page 7of 10 8/29/00 Page 401 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 Primedica Redfield Protocol Protocol Number: 132-007 Intestine, large cecum cdon rectum Intestine, small duodenum ileum jejunum Kidneys Lacrimalgland Liver Lungs with bronchi Spleen Stomach forestatnach glandular Testes Thymus Thyroidlparathyroid Tongue Trachea Uterus Urinary bladder Vagina Zymbal's gland HlSrOPA THOLOGY Animal identification will be saved. Histopathology will be performed on all tissues from the vehicle control, high dose group, recovery animals, all gross lesions, and all animals found dead or sacrificed in extremis. Target tissues in the intermediate groups may be examined at additional cost tu the Sponsor. Additional histopathology may be done at an additional cost to the Sponsor. Tissues will be trimmed, embedded. and sectioned. Slides will be stained with hematoxylin and eosin. Special stains may be used at the direction of the Study Pathologist, at the approval of the Sponsor, and at additional cost Slides will be read and interpreted by a qualified veterinary pathologist Data will be summarized in tabular form and will be accompanied by a narrative prepared by the Study Pathologist 6. Srnnsnca ANALYSIS Means and standard deviations will be calculated for all quantitative data. Treated groups of the same sex will be compared to Group 1 at common time points using an ANOVA with a post hoc Dunnett's t Test (Dunnett, C.W.. J. Amer. Statis. Assoc., 50:1096-1121,1955) or another appropriate test. A two-sided a of 0.05/0.01will be used to determine if statistically significant differences exist between the vehicle control and treated groups. Ifno significant differences exist at the 0.05 level, then no comparison is necessary at the 0.01 level. Statistical program names and compile dates are available in the Primedica Argus Research Laboratories Computer Operations Department. The SAS version is 6.12, from the SAS Institute. Inc.. SAS Campus Drive. Cary, North Carolina. 27513. A draft report will be sent to the Sponsor. Revisions to the initial draft report will be provided to the Sponsor by mail or fax transmission as printed copies of the corrected pages only. Additional revisions or complete copies of the revised draft reports will be provided at additional expense to the Sponsor. Page 8 of 10 0l29lQO Page 402 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 Primedica Redfield Protocol Protocol Number: 132-007 Three copies of the approved final report, two bound and one unbound. will be submitted to the Sponsor approximately two weeks after approval of the draft report. The final report will include all elements requiredlrecommended by the regulations and guidelines. The report will include, but is not limited to, those items listed below: 0 Descriptive text of the study objective Summary Test material identification (Certificate of Analysis, stability data, and analytical analysis if any are performed) Formulation reports Methods Results and conclusions Body weights and body weight changes Feed consumption Functional clinical observations report Necropsy report Histopathology report Organ weights Serum chemistry and hematology A copy of the protocol, all protocol amendments, and all protocd deviations that may affect the integrity of the study 8. MAINTENANCE OF RAw DATAAND RECORDS Original data or copies thereof, will be available at PrimedicaRedfield to facilitate auditing the study during its progress and before acceptance of the final report. When the final report is completed. all original paper data and the original final report will be retained in the archives of the laboratory for at least five years. Wet tissues, slides, and blocks (if generated) will be retained at Primedica Redfield for one year. After one year, the storage of the wet tissues, slides,and blocks will be negotiated with the Sponsor. After five years, the storage of the paper data will be negotiated with the Sponsor. The Sponsor will be notified prior to disposal of any original study data. 9. INSlllWlONAL ANIMALCARE AND USE cOMMmE (1ACUc) m E W This is to certify that this protocol has been reviewed by IACUC. This is to certify that this protocol has been reviewed by Quality Assurance. Fran Pattillo, M.S., RQAP-GLP Quality Assurance Manager Primedica Redfield a-orq-oa Date Page 9 of IO 8i29lQQ Page 403 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Primedica Redfield Protocol 11. APPROVALs Ph.D. DABT, CIH Senior Laboratory Manager 3M Corporate Toxicology Date Study Director Primedica Redfield Study Number: 132-007 Protocol Number: 132-007 Page 10 of IO Page 404 a1291oo A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 Primedica Redfield Protocol Amendment Protocol Number: 132-007 STUDY NUMBER: 132-007 AMENDMENT: S NDY TITLE: 1 A 28-DAY ORAL (GAVAGE) TOXICITY STUDY OF T-7485 IN SPRAGUE- DAWLEY RATS DATE ISSUED: September 19,2000 AMENDMENT # 1 ITEM 1: CHANGED FROM: CHANGED TO: Page 2, Section 3, Dose Preparation and Concentration Doses will be formulated every ten days by Primedica Redfield. Each batch of dosing solutions will be formulated a maximum of 14 days prior to the last day of use. The batch size will be sufficient for ten days of administration. REASON: To allow time for analysis prior to the use of each batch on study. ITEM 2: CHANGED FROM: CHANGED TO: REASON: Page 3, Section 3, Analytical Samples A sample of each concentration of the formulated test material and vehicle will be retained pretest and after completion of treatment with each batch and frozen at approximately -2O'C for analysis. Prior to dosing, all pretest samples will be sent to and analyzed by the below mentioned laboratory. All end of batch samples will be sent after study termination to: A sample of each concentration of the formulated test material and vehicle will be retained predose and after completion of treatment with each batch and frozen at approximately -2O'C for analysis. Prior to dosing, all pretest samples will be sent to and analyzed by the below mentioned laboratory. All end of batch samples will be collected on the last day of dosing for each batch prior to release of that aliquot for dosing. All samples will be sent to: Clarification. APPROVALS: Ph.D., DABT, CIH Senior Laboratory Manager 3M Corporate Toxicology Date Johh Seng, Ph.D. Study Director Primedica Redfield 9 / / 9/d Date 1 Page 405 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 16 PROTOCOL DEVIATIONS Page 406 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 PROTOCOL DEVIATIONS There were no protocol deviations that adversely affected the integrity of the study. Page 407 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 APPENDIX 17 KEY PERSONNEL Page 408 A 28-Day Oral Toxicity Study in Sprague-Dawley Rats Study Number: 132-007 KEY PERSONNEL Study Number: 132-007 Study Director ................................................ Principle Investigator ..................................... Head Technician............................................ Veterinarian ................................................... Clinical Pathology .......................................... Quality Assurance.......................................... Report Coordination ...................................... Report Preparation ........................................ John Seng, Ph.D. Karen Tranter, B.A., LATG Lance Williams, B.S. Allan Manus, D.V.M., M.Sc., ACLAM Phyllis Powell, B.S., M.T., ASCP Shevonya Noble, B.A. Amy Babb, B.S. Tammy Peckham, Ad. Asst. Dana Rose, Ad. Asst. Page 409