Document ba0YyxJEGojB546mX1jM1XKZO

AR226-3197 TRADE SECRET Study Title H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations Volume 1 of 5 Laboratory Project ID: DuPont-5386 TEST GUIDELINES: U.S. EPA Health Effects Test Guidelines OPPTS 870.3100 (1998) AUTHOR: Gregory S. Ladies, Ph.D., D.A.B.T. STUDY COMPLETED ON: December 3, 20.01 PERFORMING LABORATORY: E.I. du Font de Nemours and Company Haskell Laboratory for Toxicology and Industrial Medicine Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050 WORK REQUEST NUMBER: SERVICE CODE NUMBER^ SPONSOR STUDY NUMBER:! Page 1 of 1500 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT This study was conducted in compliance with U.S. EPA TSCA (40 CFR part 792) Good Laboratory Practice Standards except for the item documented below. The item listed does not impact the validity of the study. Test substance characterization and stability analyses were performed at Regional Analytical Services (RAS), a non-GLP laboratory. The test substance analyses performed were in compliance with regulatory guidelines. None of the aforementioned analyses were performed under Good Laboratory Practice Standards; however, the analyses were conducted in compliance with IS09002 regulations. All of the analyses are considered valid and sufficient for the purposes of this study. Applicant / Sponsor: E.I. du Font de Nemours and Company Wilmington, Delaware 19898 U.S.A. Study Director: /V^P^ ^ G<oJ^______ Gregory S. Ladies, Ph.D., D.A.B.T. Senior Research Scientist '3-^e.c.- .ZQO Date Applicant / Sponsor: _______D_u_P_on_t_R_ep_re_se_n_ta_tiv_e_______ ____D_at_e H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations QUALITY ASSURANCE STATEMENT Haskell Sample Number(s): 24516 DuPont-5386 Dates of Inspections: Protocol: Conduct: Records, Reports: December 5, 2000 January 15,30, 2001; February 13,14,28, 2001; March 1,8,13,26,29, 2001; April 25,2001 June 19,29, 2001; July 2-3,9,2001; August 8-10,13-17,20-24,27-31, 2001; September 4-9,17-21,23-28, 2001; October 15-19,22-27, 2001 Dates Findings Reported to: Study Director: January 15, 2001; March 1,14, 2001; July 5,6,13,9, 2001; August 29, 2001; September 25,27, 2001; October 23,27, 2001 Management: February 6, 2001; March 5,14, 2001; July 5,6,13, 2001; August 29, 2001; September 27, 2001; October 17,23, 2001; November 18,2001 Reported by: BrcbnerDate ----M--.--rU--)--1^--^^i^m^iie.'r^iy^^^,^__________ 3 -X>6>o^") f B. Quality Assurance Auditor H-24516: Subchronic Toxicity 90-Day Gavage Study m Rats with One-Generation Reproduction Evaluations__________DuPont-5386 CERTIFICATION We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study. d^- B.S.Date Evaluations Repo^J'S: ^- f^M^/_____ ^ Ad.-^ / Janet C. Madanka, Staff Scientist Newobehavioral Evaluations Reported by: ^y nS^^^y. -^ /%^y_________ J'-J^ - ^^/ Linda A. Malley, Ph.D., D.A.B.T. Date Senior Research Scientist Clinical Pathology Evaluations Reported by: J^^jf^s^ , ^-7- , /V^T^^ Nancy E, Everds, ^0-^______ ^V.M.Date Diplomats A.C.V.P. /\ Principal Research Scientist 3-^C -<Sf)ff/ Biochemical Evaluations Reported by: Reproductive Evaluations Reported by: {^S~v^c { ^ J o h n C. (Tl^^ O'Connor, / _ _ _ _ _ _ _ Research Scientist ^ ^ . y ^ yM^. S . D a^t^e- ^vel^ylclircest, Ph.D.Date R&earch Scientist S-\>c- 9-OQ \ W f\ Pathological CL-) i fj \ \ Evaluations Reported by: ^/\}- <Z^^ V^icVf v^*^._____ G. TiKy Mafcovec, D.V.M,Date Diplomate A.C.V.P. ^-yOj.^- ?e>c\ Senior Research Scientist Pathological Evaluations Peer Review Reported by: ^ ^--?i'--- ^/V^^ ^^-^^__________ Steven R- Frame, D.V.M., Ph.D. Diplomate A.C.V.P. Director, Anatomic Pathology -J-^fC -3c?6/ Date Approved b^^L^6^. Sul^___ Issued by Study Director: C^j^te^^______ Judith C. Stadler, Ph.D., D.A-B.T. S-b^-7-OQI Date Director, General Toxicology ->- Gregory^. Ladies, Ph.D., D.A^.T. Senior Research Scientist ?-i)gc--2oo Date - 'Swayaws anSiz@d. Dcies rot eantate T8CA CB1 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-5386 TABLE OF CONTENTS Page GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT.................................................................! QUALITY ASSURANCE STATEMENT .................................................................................................................3 CERTIFICATION......................................................................................................................................................4 LIST OF TABLES.......................................................................................................................................................? LISTOFFIGURES.....................................................................................................................................................9 LIST OF APPENDICES .............................................................................................................................................9 STUDY PERSONNEL.............................................................................................................................................. 13 SUMMARY............................................................................................................................................................... 14 INTRODUCTION .....................................................................................................................................................18 18 OBJECTIVE.............................................................................................................................................................. MATERIALS AND METHODS..............................................................................................................................18 A. Test Guidelines ............................................................................................................................................. 18 B. Test Substance............................................................................................................................................... 18 C. Test Species.................................................................................................................................................. 18 D. Animal Husbandry........................................................................................................................................ 19 E. Quarantine and Pretest Period....................................................................................................................... 20 F. Study Design................................................................................................................................................. 21 G. Assignment to Groups and Study Start..........................................................................................................22 H. Dose Suspension Preparation........................................................................................................................22 I. Test Substance Administration and Sampling...............................................................................................23 J. Analytical Methods.......................................................................................................................................24 K. BodyWeights........................................................................................................-......................................26 L. Food Consumption and Food Efficiency....................................................................................................... 26 M. Detailed Clinical Observations and Mortality............................................................................................... 26 N. Ophthalmological Evaluations......................................................................................................................27 0. Neurotoxicity Evaluations............................................................................................................................. 27 P. Clinical Pathology.........................................................................................................................................28 Q. Collection of Blood, Urine, and Feces (Three-Month Recovery) .................................................................30 R. Anatomic Pathology - Rats Designated for Subchronic Toxicity and Recovery.......................................... 30 S. Reproductive 32 Assessment.............................................................................................................................. T. Anatomical Pathology - Rats Designated for Reproductive Evaluations ...................................................... 34 U. Biochemical Measurements...........................................................................................................................35 V. Statistical Analyses........................................................................................................................................36 RECORDS AND SAMPLE STORAGE.................................................................................................................. 38 RESULTS AND DISCUSSION ................................................................................................................................39 ANALYTICAL EVALUATIONS............................................................................................................................40 A. Test Substance Stability................................................................................................................................40 B. Chromatography............................................................................................................................................ 40 C. Homogeneity, Concentration Verification and Stability Samples for Initial Mixing Procedures and Concentrations Based on Dose Volume of 10 mL/kg (Test Day 0 to Test Day 41)......................................40 D. Mixing and Stability Study for Change in Frequency of Dosing Preparation (2 times/week) and Dose Volume Change (5 mL/Kg to 7.5 mL/Kg) .................................................:..............................................-.41 E. Homogeneity and Concentration Verification Samples for Final Mixing Procedures and Concentration Change Based on Dose Volume of 7.5 mg/kg (Test Day 42)............................................................-....--...43 F. Analytical Conclusions..................................................................................................................................44 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-5386 TABLE OF CONTENTS (CONTINUED) SUBCHRONIC TOXICITY EVALUATIONS.......................................................................................................45 IN-LIFE TOXICOLOGY......................................................................................................................................... 45 A. Dosage Data..................................................................................................................................................45 B. Mean Body Weights and Body Weight Gains............................................................................................... 45 C. Food Consumption and Food Efficiency.......................................................................................................46 D. Clinical Observations, Ophthalmology Evaluations, and Survival................................................................ 47 E. In-Life Toxicology Conclusions....................................................................................................................48 NEUROBEHAVIORAL TOXICOLOGY............................................................................................................... 48 A. Sensory Function Evaluations....................................................................................................................... 48 B. Motor Activity...............................................................................................................................................48 C. Neurobehavioral Toxicity Conclusions.........................................................................................................49 CLINICAL PATHOLOGY......................................................................................................................................50 A. 50 Hematology/Coagulation............................................................................................................................... B. Clinical Chemistry.........................................................................................................................................51 C. 53 Urinalysis...................................................................................................................................................... D. Plasma and Urine Fluoride Measurements....................................................................................................54 E. Clinical Pathology Conclusions.................................................................................................................... 55 ANATOMICAL PATHOLOGY.............................................................................................................................. 56 A. Subchronic Toxicity and Recovery............................................................................................................... 56 REPRODUCTIVE TOXICOLOGY EVALUATIONS..........................................................................................61 REPRODUCTIVE FUNCTION...............................................................................................................................61 A. Pi Generation..........................................................................;..................................................................--61 B. Offspring 62 Data............................................................................................................................................... C. FI Generation................................................................................................................................................62 D. Reproductive Function Conclusions.............................................................................................................. 63 REPRODUCTIVE TOXICOLOGY EVALUATIONS ANATOMICAL PATHOLOGY .................................64 A. Organ Weight Data ....................................................................................................................................... 64 B. Gross Observations....................................................................................................................................... 64 C. Microscopic Observations............................................................................................................................. 64 D. Mortality........................................................................................................................................................65 E. Anatomical Pathology Conclusions for Reproductive Toxicity.................................................................... 65 BIOCHEMICAL MEASUREMENTS....................................................................................................................66 A. Biochemical Measurements........................................................................................................................... 66 B. Biochemical Measurements Conclusions...................................................................................................... 66 CONCLUSIONS........................................................................................................................................................ 67 REFERENCES.......................................................................................................................................................... 69 TABLES..................................................................................................................................................................... 72 FIGURES................................................................................................................................................................. 471 APPENDICES.........................................................................................................................................................482 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations____________DuPont-5386 LIST OF TABLES Page TABLE TABLE TABLE TABLE TABLE TABLE TABLE TABLE TABLE TABLE TABLE TABLE TABLE TABLE TABLE TABLE TABLE TABLE TABLE TABLE 1 SUMMARY OF DOSING ANALYSES.................................................................................................... 76 2 MEAN DAILY DOSE VOLUMES FOR MALE RATS............................................................................ 79 3 MEAN DAILY DOSE VOLUMES FOR FEMALE RATS....................................................................... 80 4 MEAN BODY WEIGHTS OF MALE RATS............................................................................................ 81 5 MEAN BODY WEIGHTS OF FEMALE RATS .......................................................................................84 6 MEAN BODY WEIGHT GAINS OF MALE RATS................................................................................. 87 7 MEAN BODY WEIGHT GAINS OF FEMALE RATS ............................................................................ 90 8 MEAN DAILY FOOD CONSUMPTION OF MALE RATS ....................................................................93 9 MEAN DAILY FOOD CONSUMPTION BY FEMALE RATS ............................................................... 96 10 MEAN DAILY FOOD EFFICIENCY OF MALE RATS........................................................................ 99 11 MEAN DAILY FOOD EFFICIENCY OF FEMALE RATS ............................................................... 102 12 SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS................................................... 105 13 SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS............................................... 114 14 SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR MALE RATS ........................... 121 15 SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR FEMALE RATS....................... 122 16 PERCENT SURVIVAL OF MALE RATS............................................................................................ 123 17 PERCENT SURVIVAL OF FEMALE RATS ...................................................................................... 124 18 MEAN FORELIMB AND HINDLIMB GRIP STRENGTH FOR MALE RATS ................................. 125 19 MEAN FORELIMB AND HINDLIMB GRIP STRENGTH FOR FEMALE RATS............................. 126 20 SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR MALE RATS....... 127 TABLE 21 SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR FEMALE RATS.. 129 TABLE 22 MOTOR ACTIVITY ASSESSMENT: DURATION OF MOVEMENTS FOR MALE RATS............ 131 TABLE 23 MOTOR ACTIVITY ASSESSMENT: DURATION OF MOVEMENTS FOR FEMALE RATS....... 132 TABLE 24 MOTOR ACTIVITY ASSESSMENT: NUMBER OF MOVEMENTS FOR MALE RATS ................ 133 TABLE 25 MOTOR ACTIVITY ASSESSMENT: NUMBER OF MOVEMENTS FOR FEMALE RATS........... 134 TABLE 26 SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS...................................................... 135 TABLE 27 SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS.................................................... 139 TABLE 28 SUMMARY OF COAGULATION VALUES FOR MALE RATS ....................................................... 143 TABLE 29 SUMMARY OF COAGULATION VALUES FOR FEMALE RATS................................................... 143 TABLE 30 SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS.................... 144 TABLE 31 SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS ............... 148 TABLE 32 SUMMARY OF URINALYSIS VALUES FOR MALE RATS............................................................. 152 TABLE 33 SUMMARY OF URINALYSIS VALUES FOR FEMALE RATS........................................................ 154 TABLE 34 SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITY IN MALE RATS..................... 156 TABLE 35 SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITY IN FEMALE RATS................. 157 TABLE 36 MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS................................................ 158 TABLE 37 MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (90-DAY EXPOSURE EVALUATION)................................................................................................ 166 ampany Saniteed. Does sal eontain TB6A BS H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-5386 LIST OF TABLES (CONTINUED) Page TABLE 38 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION)...................................................................................................... 174 TABLE 39 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION)...................................................................................................... 191 TABLE 40 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS - NEOPLASTIC AND NONNEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION)................................................................ 207 TABLE 41 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS - NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION)................................................................ 231 TABLE 42 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION)................................................................ 258 TABLE 43 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION)................................................................ 287 TABLE 44 MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED- NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION)...........................318 TABLE 45 MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED- NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION " INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION)........................... 374 TABLE 46 MEAN BODY WEIGHTS AND MEAN BODY WEIGHT GAINS OF Pi MALE RATS ...................434 TABLE 47 MEAN BODY WEIGHTS AND MEAN BODY WEIGHT GAINS OF P, FEMALE RATS DURING GESTATION......................................................................................................................-435 TABLE 48 MEAN BODY WEIGHTS AND MEAN BODY WEIGHT GAINS OF Pi FEMALE RATS DURING LACTATION .........................................................................................................................436 TABLE 49 MEAN DAILY FOOD CONSUMPTION AND MEAN FOOD EFFICIENCY OF Pi FEMALE RATS DURING GESTATION.........................................................................................................................437 TABLE 50 SUMMARY OF CLINICAL OBSERVATIONS IN P, RATS ..............................................................438 TABLE 51 MEAN ESTROUS CYCLE PARAMETERS AND PRECOITAL INTERVAL IN Pi FEMALE RATS440 TABLE 52 SUMMARY OF SPERM PARAMETERS IN Pi MALE RATS ...........................................................441 TABLE 53 SUMMARY OF REPRODUCTIVE INDICES: P, GENERATION...................................................... 442 TABLE 54 MEAN PUP NUMBERS AND SURVIVAL: Fi GENERATION ........................................................443 TABLE 55 MEAN PUP WEIGHTS: Fi GENERATION.........................................................................................444 TABLE 56 SUMMARY OF PUP CLINICAL OBSERVATIONS: Fi GENERATION........................................... 445 TABLE 57 MEAN BODY WEIGHTS AND MEAN BODY WEIGHT GAINS OF F| MALE RATS ...................446 TABLE 58 MEAN BODY WEIGHTS AND MEAN BODY WEIGHT GAINS OF Fi FEMALE RATS............... 447 TABLE 59 SUMMARY OF CLINICAL OBSERVATIONS IN Fi RATS .................:............................................448 TABLE 60 SUMMARY OF DEVELOPMENTAL LANDMARKS IN F, RATS ...................................................449 TABLE 61 MEAN FINAL BODY AND ORGAN WEIGHTS FROM MALE RATS - P) ADULTS .....................450 TABLE 62 MEAN FINAL BODY AND ORGAN WEIGHTS FROM FEMALE RATS - Pi ADULTS................. 451 TABLE 63 MEAN FINAL BODY AND ORGAN WEIGHTS FROM MALE RATS - F, ADULTS .....................452 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-5386 LIST OF TABLES (CONTINUED) Page TABLE 64 MEAN FINAL BODY AND ORGAN WEIGHTS FROM FEMALE RATS - Fi ADULTS................. 456 TABLE 65 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS - P, ADULTS .................................459 TABLE 66 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS - P, ADULTS ............................460 TABLE 67 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS - Fi PUPS........................................ 461 TABLE 68 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS - F, PUPS ...................................462 TABLE 69 INCIDENCES OF GROSS OBSERVATIONS IN RATS - Fi UNSEXABLE PUPS ...........................463 TABLE 70 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS - F, WEANLINGS .........................464 TABLE 71 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS - F, WEANLINGS..................... 465 TABLE 72 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS - Fi ADULTS................................. 466 TABLE 73 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS - Fi ADULTS ............................467 TABLE 74 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE REPRODUCTION RATS - Pi ADULTS............................................................................................... 468 TABLE 75 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE REPRODUCTION RATS - P, ADULTS............................................................................................... 469 LIST OF FIGURES Page FIGURE FIGURE FIGURE FIGURE FIGURE FIGURE FIGURE FIGURE FIGURE FIGURE 1 MEAN BODY WEIGHTS OF MALE RATS ........................................................................................472 2 MEAN BODY WEIGHTS OF FEMALE RATS.................................................................................... 473 3 MEAN FORELIMB GRIP STRENGTH FOR MALE RATS................................................................ 474 4 MEAN FORELIMB GRIP STRENGTH FOR FEMALE RATS ...........................................................475 5 MEAN HINDLIMB GRIP STRENGTH FOR MALE RATS................................................................ 476 6 MEAN HINDLIMB GRIP STRENGTH FOR FEMALE RATS............................................................ 477 7 MOTOR ACTIVITY ASSESSMENT: MEAN DURATION OF MOVEMENTS FOR MALE RATS................................................................................................................................. 478 8 MOTOR ACTIVITY ASSESSMENT: MEAN DURATION OF MOVEMENTS FOR FEMALE RATS............................................................................................................................. 479 9 MOTOR ACTIVITY ASSESSMENT: MEAN NUMBER OF MOVEMENTS FOR MALE RATS.................................................................................................................................480 10 MOTOR ACTIVITY ASSESSMENT: MEAN NUMBER OF MOVEMENTS FOR FEMALE RATS.............................................................................................................................481 LIST OF APPENDICES Page APPENDIX A ANALYTICAL DATA.....................................................................................................................483 APPENDIX B INDIVIDUAL DOSE VOLUMES (ML)..........................................................................................491 APPENDIX C INDIVIDUAL BODY WEIGHTS.................................................................................................... 569 APPENDIX D INDIVIDUAL FOOD CONSUMPTION .........................................................................................603 APPENDIX E INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA........................................................................................................... 630 APPENDIX F OPHTHALMOLOGY EXAMINATION REPORTS........................................................................ 672 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 LIST OF APPENDICES (CONTINUED) Page APPENDIX G INDIVIDUAL FORELIMB GRIP STRENGTH AND fflNDLIMB GRIP STRENGTH................675 APPENDIX H INDIVIDUAL FUNCTIONAL OBSERVATIONAL BATTERY ASSESSMENT......................... 696 APPENDDC I-INDIVIDUAL MOTOR ACTIVITY ASSESSMENT: DURATION OF MOVEMENTS............... 706 APPENDIX J INDIVIDUAL MOTOR ACTIVITY ASSESSMENT: NUMBER OF MOVEMENTS ..................717 APPENDIX K INDIVIDUAL CLINICAL PATHOLOGY DATA.......................................................................... 728 APPENDIX L INDIVIDUAL HEPATIC BETA-OXIDATION 845 ACTIVITY........................................................... APPENDDC M INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS............................................. 854 APPENDIX N INDIVIDUAL ANIMAL GROSS AND MICROSCOPIC OBSERVATIONS................................ 871 APPENDDC 0 REPRODUCTIVE TOXICOLOGY INDIVIDUAL BODY WEIGHTS OF P, MALE RATS...... 1063 APPENDIX P REPRODUCTIVE TOXICOLOGY INDIVIDUAL BODY WEIGHT GAINS OF Pi MALE RATS.................................................................................................................... 1069 APPENDIX Q REPRODUCTIVE TOXICOLOGY INDIVIDUAL BODY WEIGHTS OF Pi FEMALE RATS DURING GESTATION ....................................................................... 1075 APPENDIX R REPRODUCTIVE TOXICOLOGY INDIVIDUAL BODY WEIGHT GAINS OF Pi FEMALE RATS DURING GESTATION....................................................................... 1081 APPENDIX S REPRODUCTIVE TOXICOLOGY INDIVIDUAL BODY WEIGHTS OF Pi FEMALE RATS DURING LACTATION....................................................................... 1087 APPENDIX T REPRODUCTIVE TOXICOLOGY INDIVIDUAL BODY WEIGHT GAINS OF Pi FEMALE RATS DURING LACTATION....................................................................... 1093 APPENDIX U REPRODUCTIVE TOXICOLOGY INDIVIDUAL DAILY FOOD CONSUMPTION BY Pi FEMALE RATS DURING GESTATION...................................................................... 1099 APPENDIX V REPRODUCTIVE TOXICOLOGY INDIVIDUAL CLINICAL OBSERVATIONS IN P, MALE RATS.................................................................................................................... 1105 APPENDIX W REPRODUCTIVE TOXICOLOGY INDIVIDUAL CLINICAL OBSERVATIONS IN Pi FEMALE RATS DURING GESTATION....................................................................... 1114 APPENDIX X REPRODUCTIVE TOXICOLOGY INDIVIDUAL CLINICAL OBSERVATIONS IN Pi FEMALE RATS DURING LACTATION....................................................................... 1120 APPENDIX Y INDIVIDUAL ANIMAL ESTROUS CYCLE PARAMETERS DURING PREMATING AND COHABITATION IN P) FEMALE RATS....................................................................... 1127 APPENDIX Z INDIVIDUAL ANIMAL ESTROUS CYCLE STAGES DURING PREMATING AND COHABITATION IN Pi FEMALE RATS....................................................................... 1133 APPENDIX AA REPRODUCTIVE TOXICOLOGY INDIVIDUAL ANIMAL SPERM MOTILITY DATA IN Pi MALE RATS.................................................................................................................... 1139 APPENDIX BB INDIVIDUAL ANIMAL SPERM MORPHOLOGY DATA IN P, MALE RATS...................... 1141 APPENDIX CC INDIVIDUAL ANIMAL SPERM AND SPERMATID COUNTS IN P, MALE RATS............. 1144 APPENDIX DD REPRODUCTIVE TOXICOLOGY INDIVIDUAL MATING DATA AND GESTATION LENGTH: P, GENERATION .................................................................. 1147 APPENDIX EE REPRODUCTIVE TOXICOLOGY INDIVIDUAL IMPLANTATION SITE DATA AND IMPLANTATION EFFICIENCY..................................................................................... 1153 APPENDIX FF REPRODUCTIVE TOXICOLOGY INDIVIDUAL PUP SURVIVAL: Fi GENERATION....... 1159 APPENDDC GG REPRODUCTIVE TOXICOLOGY INDIVIDUAL PUP WEIGHTS: F, GENERATION ....... 1185 APPENDIX HH REPRODUCTIVE TOXICOLOGY INDIVIDUAL LITTER CLINICAL OBSERVATIONS: Fi GENERATION...................................................................................................................... 1235 Company BmitSzed. Daes rot ewta'" TBGA CBI 10 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations____________DuPont-5386 LIST OP APPENDICES (CONTINUED) Page APPENDIX APPENDIX APPENDIX APPENDIX APPENDIX APPENDIX APPENDIX APPENDIX APPENDIX II REPRODUCTIVE TOXICOLOGY INDIVIDUAL BODY WEIGHTS: Fi GENERATION...................................................................................................................... JJ REPRODUCTIVE TOXICOLOGY INDIVIDUAL BODY WEIGHT GAINS: Fi GENERATION...................................................................................................................... KK REPRODUCTIVE TOXICOLOGY INDIVIDUAL FOOD CONSUMPTION: Fi GENERATION................................................................................................................. LL REPRODUCTIVE TOXICOLOGY INDIVIDUAL CLINICAL OBSERVATIONS: Fi GENERATION...................................................................................................................... MM INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS - Pi ADULTS AND Fi ADULTS ...................................................................................................................... NN INDIVIDUAL ANIMAL GROSS AND MICROSCOPIC OBSERVATIONS - Pi ADULTS ... 00 INDIVIDUAL ANIMAL GROSS OBSERVATIONS - Fi PUPS............................................... PP INDIVIDUAL ANIMAL GROSS OBSERVATIONS - Fi WEANLINGS.................................. QQ INDIVIDUAL ANIMAL GROSS OBSERVATIONS - Fi ADULTS......................................... 1241 1251 1261 1271 1282 1299 1459 1465 1491 11 H-24516: Subchronic Toxicity 90-Day Gavage Stady in Rats with One-Generation Reproduction Evaluations STUDY INFORMATION Substance Tested: jl| Synonyms/Codes: H-24516 Haskell Number: 24516 Composition: DuPont-5386 Physical Characteristics^ i Sponsor: E. I. du Font de Nemours and Company Wilmington, Delaware 19898 U.S.A. Study Initiated/Completed: December 12, 2000/ (see report cover page) In-Life Initiated/Completed: December 12, 2000 / June 11, 2001 12 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations STUDY PERSONNEL Study Director: Management: Primary Technician: Gregory S. Ladies, Ph.D. Judith C. Stadler, Ph.D. Nancy C. Chromey, Ph.D. Janice L. Connell, M.S., B.A., C.I.H. Janine A. Britton, B.S. Analytical Chemist: Janet C. Maslanka, B.S. Management: S. Mark Kennedy, Ph.D. Reproductive Toxicologist: Eve Mylchreest, Ph.D. Management: Robert M. Parker, Ph.D. Clinical Pathologist: Nancy E. Everds, D.V.M. Management: Steven R. Frame, D.V.M., Ph.D. Pathologist: Management: Peer Review Pathologist: G. Tracy Makovec, D.V.M. Steven R. Frame, D.V.M., Ph.D. Steven R. Frame, D.V.M., Ph.D. Neurotoxicologist: Linda A. Malley, Ph.D. Management: Robert M. Parker, Ph.D. Biochemical Evaluation John C. O'Connor, M.S. Management: Matthew S. Bogdanffy, Ph.D. Toxicology Report Preparation: Cecilia R. Kee, B.S. Mary K-. LaRoe Ophthalmologist: Nancy M. Bromberg, V.M.D., M.S. 6119 Massachusetts Avenue Bethesda, Maryland 20816 Laboratory Veterinarians: William Singleton, D.V.M., A.C.L.A.M. Wanda L. West, D.V.M., A.C.L.A.M. DuPont-5386 ^^^i^.Does.oleontai.TBCACBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations______________DuPont-5386 SUMMARY Four groups of young adult male and female Crl:CD(SD)IGS BR rats were administered H-24516 by gavage at dosages ofO, 25,100, and 250 mg/kg/day. Selected animals from each dosage group were designated for subchronic toxicity or reproductive evaluations. m the subchronic study, body weights, food consumption, and clinical signs were evaluated weekly. Clinical pathology endpoints were evaluated on weeks 7,13, and near the end of the one-month recovery period. Neurobehavioral assessments were also performed prior to dosing, during week 13, and near the end of the one-month recovery period. Biochemical evaluations (hepatic p-oxidation) were performed on animals after 10 and approximately 90 days of dosing and following one- and three-month recovery periods. After approximately 90 days of dosing, 10 rats/sex/dose were sacrificed and given a gross and microscopic pathological examination. Approximately one month after the 90-day dosing period, 10 animals/sex in the control and high dose group were examined for recovery of toxic effects. An additional five animals/sex/dose were evaluated for recovery approximately 3 months following the end of the dosing period. The range of mean daily dose volumes of H-24516 administered to male rats was 2.5 to 4.6 ml. The range administered to female rats was 1.9 to 2.8 ml. In-Life Toxicology Parameters: No test substance-related mortality occurred in the study. A test substance-related, toxicologically significant increase in the incidence of broken (males) and absent teeth (males and females) was observed in the 250 mg/kg/day dose group. Test substancerelated, toxicologically significant decrements in body weight, body weight gain, and food efficiency occurred in males dosed with 100 and 250 mg/kg/day H-24516. Statistically significant decrements in mean body weight parameters and food consumption occurred for the female groups dosed with 100 or 250 mg/kg/day. The mean body weight and body weight gain decrements observed for the 100 and 250 mg/kg/day female groups, however, were of small magnitude. They were associated with decreased food consumption, but not with any alterations in food efficiency, and, therefore, were not considered to be toxicologically significant. Furthermore, the decrements in body weight parameters observed for both males and females appear to be related in part to test substance-induced toxicity to the teeth and subsequent decreased ability of the animals to eat the pelleted chow. Neurotoxicology Parameters: No adverse changes in neurobehavioral parameters were observed in male or female rats in any dose group. Biochemical Toxicology: The rate of hepatic p-oxidation, a measure ofperoxisome proliferation, was increased in a dose-dependent manner with statistical significance occurring in males and females administered 100 or 250 mg/kg/day H-24516. Following a one- or three-month recovery period, the rate of hepatic p-oxidation was still significantly increased in males and females administered 250 mg/kg/day. 14 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 Clinical Pathology: Samples were collected at mid-study, at the end of treatment, and after one month of recovery for hematology, clinical chemistry, urinalysis, coagulation (end of study only), and plasma and urine fluoride (end of study and end of one- and three-month recovery). Males and females dosed with 250 mg/kg/day had decreased red cell mass parameters, along with correlative changes in other hematology parameters and in red cell morphology. After one month of recovery, mean red cell mass of female rats was similar to the control group, although some changes were still present in other hematologic parameters. Male rats still had decreased red cell mass effects, and associated alterations in other hematologic parameters. Other changes in clinical pathology parameters, during treatment or after a one- or three-month recovery, were considered treatment-related but non-adverse because the magnitude of change was small, transient, and/or in a direction not associated with toxicity. The serum parameters thus affected included serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, cholesterol, triglycerides, total protein and albumin, calcium, phosphorus, sodium, chloride, and potassium. Affected plasma parameters were activated partial thromboplastin time and plasma fluoride. Affected urinalysis parameters were urine volume, osmolality, specific gravity, and fluoride. Anatomical Pathology (Subchronic Toxicity): Test substance related, toxicologically significant degeneration/disorganization of enamel organ ameloblast cells occurred in male and female rats administered 100 or 250 mg/kg/day H-24516. Test substance related, potentially adverse increases in thyroid hypertrophy were observed in the 100 and 250 mg/kg/day male and 250 mg/kg/day female dose groups. In addition, alterations in thyroid colloid were observed in male and female rats at all dose levels, but were not considered to be toxicologically significant. Test-substance related and statistically significant increases in liver weight parameters were present in males and females administered 25, 100, or 250 mg/kg/day for approximately 90 days. The increased liver weights correlated with microscopic centrilobular hepatocellular hypertrophy in the 100 and 250 mg/kg/day male and 250 mg/kg/day female groups. Test-substance related and statistically significant increases in kidney weight parameters also occurred in males and females administered 25, 100, or 250 mg/kg/day. The increased kidney weights correlated with microscopic renal tubular hypertrophy in the 100 (1 of 10 rats) and 250 mg/kg/day male groups only. The liver and kidney alterations, however, were considered to be a pharmacologically adaptive response by these organs to the test-substance and therefore, not considered toxicologically significant. After one month of recovery, rats dosed with 250 mg/kg/day showed reversibility of some effects. The ameloblastic degeneration/disorganization persisted with decreased incidence and severity in the 250 mg/kg/day male and female groups. Thyroid hypertrophy was no longer observed. Alterations in thyroid colloid persisted in both male and female rats. Increased liver weight parameters persisted in the 250 mg/kg/day male and female groups, although their magnitude was decreased relative to that observed at the end of the 90 day exposure period. Hepatocellular hypertrophy was no longer observed in female rats but persisted with decreased severity in male rats. Renal tubular hypertrophy persisted with decreased incidence and severity in males, while some kidney weight parameters remained increased in both male and female rats. @ irart eortasira TBCA I 15 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 After the three-month recovery period, ameloblastic degeneration/disorganization was still present in the 100 mg/kg/day male and 250 nig/kg/day male and female dose groups but at a lower incidence and severity relative to the one-month-recovery animals. Alterations in thyroid colloid persisted in both males and females. Liver weight parameters remained increased in both the 250 mg/kg/day male and female groups, although their magnitude was decreased relative to that observed after the 90-day period. Hepatocellular hypertrophy was observed only in the 250 mg/kg/day male group (1 of 5 rats). Alterations in kidney weight parameters or renal tubular hypertrophy were not observed at any dose level. Reproduction: Twenty male and female rats from each dose group were designated for reproductive evaluations. Parental rats (Pi generation) were dosed daily for 74 days prior to cohabitation, during the cohabitation period (mating), during gestation, and during lactation, until the weaning of the Fi offspring. The following parameters were conducted on Pi rats: body weights, food consumption, clinical signs, gross pathology, sperm parameters, estrous cyclicity and reproductive performance. The Fi offspring were evaluated during the lactation period for growth and survival and given a gross pathological examination at weaning. A subset ofFi rats (Fi generation) were retained at weaning, and the following parameters evaluated for 6 weeks: body weights, food consumption, clinical signs, and age at onset of vaginal opening and preputial separation. After 6 weeks, the Fi generation rats were given a gross pathological examination, selected reproductive organs and target organs oftoxicity were weighed. There were no toxicologically significant pathology findings in the Pi or Fi generation rats. No test substance-related mortality occurred in the study. There was a statistically significant reduction in body weight in Pi male rats during and after the cohabitation period. Although this finding was test substance-related, it was not considered toxicologically significant. There was a statistically significant increase in testicular spermatid numbers in Pi male rats administered 100 or 250 mg/kg/day. This finding was not considered test substance-related. Implantation efficiency was significantly reduced at 100 and 250 mg/kg/day and reflects a reduction in the number of pups bom. There were statistically significant reductions in the number of pups bom, the number of pups bom alive and the number of pups alive on day 4 of lactation in the 250 mg/kg/day group. Reductions of similar magnitude as in the 250 mg/kg/day group were also observed for the number of pups bom and bom alive in the 100 mg/kg/day group. Although not statistically significant, these changes were considered test substance-related and toxicologically significant, as was the significant reduction in the number of pups alive on day 4 of lactation in the 100 mg/kg/day group. There were statistically significant reductions in pup weights on lactation days 4, 7, 14 and 21 in the 250 mg/kg/day group. On the day of weaning, mean body weights were significantly lower than control in both Fi males and females in the 250 mg/kg/day group. However, mean body weights in these groups progressively returned to control values during the post-weaning period. These findings were not considered toxicologically significant. ompany Sanitoed. Doe not eortain T8CA CBS 16 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations____________DuPont-5386 NOEL for Subchronic Toxicity: The no-observed-effect level (NOEL)" for males was 25 mg/kg/day H-24516 based on adverse decrements in body weight parameters and food efficiency, increased hepatic peroxisomal p-oxidation, and the degeneration and/or disorganization of enamel organ ameloblast cells in males administered 100 mg/kg/day. The NOEL for females was 25 mg/kg/day H-24516 based on increased hepatic peroxisomal poxidation and the degeneration and/or disorganization of enamel organ ameloblast cells in females administered 100 mg/kg/day. NOEL for Reproductive Evaluations: The NOEL for the reproductive toxicity parameters evaluated under the conditions of this study was 25 mg/kg/day based on decreases in the number of pups bom, bom alive, and the number of pups alive on day 4 of lactation at the 100 mg/kg/day dose level. The NOEL for this study is defined as the highest dose at which lexicologically important effects attributable to the test substance were not detected. Thus, for this study, the NOEL is equivalent to the NOEL as defined by the United States Environmental Protection Agency (1985) and to the no-observed-adverse-effect level (NOAEL) as defined by the European Union (1994). i^ BCN Mi eortain Tl 17 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_______.______DuPont-5386 INTRODUCTION The test substance, H-24516, is kg/day dose levels for this study were selected based on the toxicity and _ pharmacokinetic analysis of plasma fluorine concentrations from a range-finding study with H-24516. In rats exposed to 200 mg/kg/day H-24516 for 35 days, toxicity (i.e., body weight effects or clinical observations) was not observed. Plasma fluorine levels approached levels previously found when animals were exposed to dosages that induced lethality. The high-dose level of 250 mg/kg/day for this 90-day study was expected to produce toxicity without excessive mortality. The low dose of 25 mg/kg/day was expected to be the no-observed-effect level, while the 100 mg/kg/day dose was expected to induce minimal or no toxicity. OBJECTIVE The objective of this study was to evaluate the potential subchronic and reproductive toxicity of H-24516 when administered by gavage to male and female rats. Recovery evaluations were included to investigate the reversibility of any observed toxicological effects. The oral route of administration was selected as the most efficient way to deliver an accurate dosage. .MATERIALS AND METHODS A. Test Guidelines The subchronic toxicity study design complies with the United States Environmental Protection Agency (EPA), Office of Prevention, Pesticides, and Toxic Substances (OPPTS) Health Effects Test Guidelines, OPPTS 870.3100 90-Day Oral Toxicity in Rodents (AUG-1998). The onegeneration reproduction study includes many endpoints of reproductive function but does not comply with a specific guideline. B. Test Substance Samples of the H-24516 were supplied near the beginning and end of the study for stability analysis and analyzed by the DuPont Regional Analytical Services (RAS), Jackson Laboratories, Deepwater, NJ. Methods and results for the stability analysis of the test substance are documented in study records. C. Test Species On November 16, 2000, 176 male and 176 female Cri:CD(SD)IGS BR rats, with an assigned birth date of October 25, 2000, were received from Charles River Laboratories, me., Raleigh, North Carolina for use on this study. 18 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations____________DuPont-5386 The rat was selected because it is the species recommended in the subchronic toxicity guidelines and is extensively used in reproduction studies. The Crl:CD(SD)IGS BR strain was chosen because extensive background information is available from the literature, the supplier, and previous studies at Haskell Laboratory. This species/strain also is considered suitable relative to longevity, hardiness, and low incidence of spontaneous diseases. D. Animal Husbandry 1. Housing With the exception of some portions of the reproductive study, all rats were housed one per cage, sexes separate, in stainless steel, wire-mesh cages suspended above cage boards. Animal rooms were maintained on a 12-hour light/dark cycle (fluorescent light) and at a temperature of 22 3C and a relative humidity of 50% 20%. Occasional excursions outside the accepted ranges were minor and did not affect the study. Rats designated for reproductive toxicity evaluations were housed as breeding pairs during the cohabitation period. During the gestation period, female rats designated for reproductive toxicity evaluations were housed individually until gestation day 20. Beginning on gestation day 20 for mated females, or at the end of the cohabitation period for females without evidence of copulation, female rats were housed individually in polycarbonate pans with bedding. During the lactation period, adult female rats were housed with their litters in polycarbonate pans. Cage racks were relocated within the animal room each week and cages were repositioned on the racks every 2 weeks for animals designated for the 90-day exposure period and one- and three-month recovery periods. during the 74-day premating period for animals designated for reproductive assessment, and the 40-day post-weaning period for FI generation rats. 2. Feed and Water Tap water was provided ad libitum. All rats were fed PMI Nutrition International, me. Certified Rodent LabDiet 5002 ad libitum. Initially, all rats were fed pelleted chow, however, beginning on test day 57, animals exhibiting effects to the teeth were placed on ground chow. On test day 74, all rats in the 250 mg/kg/day dose group that were designated for reproductive toxicity evaluations were placed on ground chow. On test day 77, all other rats in the 250 mg/kg/day dose group were placed on ground chow. 3. Identification Prior to assignment to groups, each rat was temporarily identified by either the presence or absence of a colored tail mark and cage identification. After assignment to groups, an individual identification number was tattooed on the tail of each rat. The information on the cage labels (Compaq Sanitized. Does not contain TSCA CBI ^ H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations______________DuPont-5386 included the unique 6-digit Haskell animal number and the individual identification number assigned to each rat. 4. Health Monitoring Program As specified in the Haskell Laboratory animal health and environmental monitoring program, the following procedures are performed periodically to ensure that contaminant levels are below those that would be expected to impact the scientific integrity of the study: Water samples are analyzed for total bacterial counts, and the presence ofcoliforms, lead, and other contaminants. Feed samples are analyzed for total bacterial, spore and fungal counts. Samples from freshly washed cages and cage racks are analyzed to ensure adequate sanitation by the cagewashers. Certified animal feed is used, guaranteed by the manufacturer to meet specified nutritional requirements and not to exceed stated maximum concentrations of key contaminants, including specified heavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates. The presence of these contaminants below the maximum concentration stated by the manufacturer would not be expected to impact the integrity of the study. The animal health and environmental monitoring program is administered by the attending laboratory animal veterinarian. Evaluation of these data did not indicate any conditions that affected the validity of the study. E. Quarantine and Pretest Period Upon arrival at Haskell Laboratory, the rats were quarantined for 11 days of the 26-day pretest period. The rats were observed daily for any clinically apparent signs of disease or injury, weighed 4 times, and examined by a veterinary ophthalmologist to identify animals with preexisting ocular lesions. Prior to grouping, one male rat (animal no. 643168) was accidentally killed and discarded without necropsy. One male rat (animal no.643186) and 2 female rats (animal nos. 643355 and 643469) were found dead and necropsied to check for the presence of disease. No disease was found. On the basis of acceptable body weight gains and'clinical observations, all surviving rats were released from quarantine on test day -15 by the laboratory animal veterinarian designee. 20 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 F. Study Design Gv3UpS Male Female I n ffl IV V VI vn Vffl No./ Group Male Female 45 45 35 35 35 35 45 45 Dietary Dosagea (mg/kg/day) 0 (Control) 25 100 250 Biochemical Evaluations at the 10-day Time Point I-A n-A 5 5 m-A IV-A 5 5 V-A VI-A 5 5 vn-A vm-A 5 5. Weight of test substance (adjusted fo: animal body weight. 0 (Control) 25 100 1 t 250 ive ingredient)/kg The first ten rats in each group were designated for the 90-day exposure evaluation. The next five rats in each group were initially designated as a satellite subset for serial blood collection in the event findings warranted analytical evaluations. Due to findings after the one-month recovery period, these rats were designated for evaluation of selected tissues following a threemonth recovery period; these rats are reported as the three-month recovery animals. The next 20 animals in each group were designated for reproductive evaluations. The last 10 male and female rats in the control and high dose groups were designated for recovery evaluations and are reported as the one-month recovery animals. An additional 5 rats/sex/dose were received as a separate shipment 65 days after study start for the biochemical evaluations (hepatic P-oxidation) following a 10-day exposure. Male and female rats designated for the 90-day exposure evaluation were dosed for 90 and 92 days, and necropsied on test days 91 and 93, respectively. Male and female rats designated for the one- and three-month recovery evaluations were dosed for 90 days and necropsied 36 days and 92 days postdosing, respectively. Neurobehavioral evaluations were conducted on male and female animals designated for the 90day exposure evaluation (predose and week 13) and on control and high dose animals designated for the one-month recovery (predose, week 13, one-month post dose). Biochemical evaluations (hepatic P-oxidation) were performed on animals after 10 and approximately 90 days of dosing and following one- and three-month recovery periods. Clinical pathology evaluations were conducted on animals designated for the 90-day exposure evaluation on weeks 7 and 13 and on animals designated for the one-month recovery evaluation immediately prior to necropsy. Reproductive evaluations began on test day 74 when designated male and female rats were cohoused. 21 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-5386 G. Assignment to Groups and Study Start 1. Rats Designated for the 90-Day Exposure, One-Month Recovery, and Three-Month Recovery Evaluations and Reproductive Evaluations. Rats were selected for study use on the basis of adequate body weight gain, freedom from any ophthalmological abnormalities or clinical signs of disease or injury, and a body weight within 20% of the mean within a sex. The selected rats were distributed by computerized, stratified randomization so that there were no statistically significant differences among group body weight means within a sex. Oral administration of H-24516 began on test day 0. The rats were approximately 49 days of age on test day 0. Prior to the start of the test substance administration, rats with body weights that were not within 20% of the mean within a sex, were replaced and discarded without gross or microscopic evaluations. Replacement rats were selected on the basis of freedom from any clinical signs of disease or injury and a body weight 20% of the mean within a sex. On test day 0, two male rats had clinical signs of hair loss (animal numbers 643232 (control) and 643315 (250 mg/kg/day)). Inclusion of these animals on the study does not impact the outcome of the study. 2. Rats Designated for 10-Day Biochemical Analysis The rats designated for the 10-day biochemical analysis arrived separately, 65 days after study start. They were handled the same as the other rats during the quarantine and pretest periods, except they did not receive an ophthalmological examination. They were distributed by computerized, stratified randomization into study groups (5/sex/dose), so that there were no statistically significant differences among group body weight means within a sex when this subset of rats is compared among themselves. Oral administration ofH-24768 began on test day 76. H. Dose Suspension Preparation Dose suspensions ofO, 2.5,10, or 25 mg test substance/mL were prepared with 0.5% methylcellulose. Methylcellulose was selected as the vehicle because it is the vehicle of choice for reproductive studies. Dose suspensions were prepared daily prior to dosing from test day 0 through test day 37 with a dose volume of 10 mL/kg. However, in order to administer a dose volume under 5 mL to comply with laboratory procedure, the dosing volume for male and female rats was decreased from 10 mL/kg to 7.5 mL/kg on test day 38, and the suspension concentrations were increased to 0, 3.33, 13.33, and 33.33 mg/mL. Starting on test day 42 until the end of the dosing period, these dose suspensions were prepared twice a week. The test material was melted down to approximately 90C, mixed for approximately 30 minutes, aliquoted, then mixed with methylcellulose for one minute to make the dose suspensions. When the dose suspension was prepared twice a week, the suspension was refrigerated until used. Each day the suspensions were then homogenized for one minute and then stirred for 30 minutes tSompanf SanffiteeA 0s "oS eo^ato TS6A CBI ^ H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 before the day's aliquots were removed. Remaining dose suspensions were returned to the refrigerator. The dose suspensions were stirred prior to and during dosing. I. Test Substance Administration and Sampling Animals designated for the 90-day exposure period and one- and three-month recovery periods were dosed for up to 92 days. Animals designated for reproductive evaluations, were dosed for the 74-day premating period and during the mating period. Pi male rats continued to be dosed until sacrifice. Pregnant female rats were dosed during the gestation period. Lactating females and females with no evidence of copulation were dosed until pups were weaned on day 21. The test substance was administered daily to the study animals by oral gavage to achieve dosage levels of 25,100, or 250 mg active ingredient/kg body weight/day, based on the most recently recorded body weight. All male and female control animals were treated with 0.5% aqueous methylcellulose at the same dose volume as that used for the high dose group. On test day 3, five male rats in the 25 mg/kg/day group were dosed with vehicle only. On test day 18, all male rats and the first 11 female rats in the 25 mg/kg/day groups received 37-39 mg/kg/day. There were individual rats across dose groups that were misdosed; these rats are documented in study records and reported in Appendix B. The incidences ofmisdosing described above are considered not to have affected the outcome of the study. All Pi animals in the reproduction study with the exception of pregnant females in the process or showing signs of delivery were dosed daily until sacrifice. At the initiation of the study (test day 0), samples of the dosing suspensions containing H-24516 at the concentrations ofO, 2.5, 10, and, 25 mg/mL were collected. On test day 6, to verify that the 10.0 mg/mL level was mixed homogeneously, samples of the dosing suspensions containing H-24516 at the concentrations ofO and 10 mg/mL were collected. These samples were analyzed to verify homogeneity/concentration of the test substance in the vehicle and 5- hour room temperature stability to verify the test substance stability while the animals were being dosed. Prior to the initiation of a change in frequency of dosing preparation, a long term refrigerated stability (4 days) analysis was required. Also, a need to change dose volume (10 mL/kg to 7.5 mL/kg) was identified and a subsequent change in the concentrations of the suspensions was necessary. Therefore, an additional mixing and stability study was performed. The samples collected during this additional study were not administered to the animals but addressed the mixing, range of concentrations and the stability parameters that would be needed after the frequency of mixing and dose volume changes were made in the study, m this separate study, samples of dosing suspensions containing H-24516 at the concentrations of0,5, 20, and, 50 mg/mL (based on a 5 mL/kg dose volume) were collected. These samples were analyzed to verify homogeneity, concentration and 5-hour room temperature stability. On subsequent days 2, 3, and 4 after this preparation, samples from the same preparation were collected and analyzed to verify concentration after re-dispersion of the test substance and refrigerated stability (4 days) along with 5-hour room temperature stability (day 4 samples, only). Later in the 90-day gavage study, to satisfy the dose volume change of 5 mL/kg to 7.5 mL/kg, samples of the dosing 23 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations______________DuPont-5386 suspensions containing H-24516 at the concentrations ofO and 3.33 mg/mL were collected and analyzed to verify homogeneity, concentration and 5-hour room temperature stability. Four days later, samples from the same preparation were collected and analyzed to verify concentration after re-dispersion of the test substance and refrigerated stability (4 days) along with 5-hour room temperature stability. On test day 38, after the mixing and stability was established for the storage conditions and the concentration range, the mixing frequency and dose volume change (10 mL/kg to 7.5 mL/kg) was initiated in the study. Therefore on test day 49, samples of the dosing suspensions containing H- 24516 at the concentrations ofO, 3.33,13.33, and 33.33 mg/mL were collected and analyzed to verify homogeneity and concentration. On test day 91, samples of the dosing suspensions containing H-24516 at the same concentrations were collected. The 3.33 mg/mL samples were analyzed to verify homogeneity and concentration while the remaining levels were analyzed for concentration verification. All dosing suspension samples were collected on the same day the suspensions were prepared or at the prescribed protocol time for analysis. They were analyzed when received or were frozen until analyzed. J. Analytical Methods 1. Dosing Suspension Treatment Each dosing sample was diluted to 100 mL with methanol and sonicated to dissolve the H-24516 in the suspension. The dosing samples were further diluted with the 0 mg/mL sample (initial dilution) to an expected concentration of approximately 0.05, 0.06, 0.075 or 0.09 mg/mL (a.i.) prior to analysis. An internal standard (refer to Calibration and Quantitation Section) at an equivalent amount was added to each sample before the final analysis dilution. Samples submitted for analysis were analyzed the day the suspensions were received or stored frozen until analyzed by the testing group. Company Sai^-wri o"""8 lwf cA^a'n TSCA CBI 24 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 2. Chromatographic Conditions Instmment: Column: Injector: Detector: Carrier Gas: Split vent: Injection Volume: Oven Program: Initial Temperature: Initial Time Level 1 Rate: Level 1 Temperature: Level 1 Time: Total run time: Hewlett-Packard Model J & W, DB-1701, 30 m, Split, 250C FID;250C Helium (2.1 mL/min) 22.3 mL/min 2 microliter Gradient 100C 6890 GC 0.32 mm ID, 1 um film thickness l.OOmin. 20.0C/min. 260C 0.00 min. 9.00 min. 3. Calibration and Quantitation flHBI|l|l A separate sample of H-24516 (-3) was obtained to use as the analytical reference standard A stock solution was prepared in methanol. This stock solution was sonicated to " assure that all material was in solution. Before analysis, appropriate aliquots of the stock were diluted with methanol to make calibration standards, which bracketed the target concentration of the diluted dosing samples^A stock solution of the internal staDdai(Vlfff^ffff^ffffy tfHBH^1HHHHH||vas prepared in methanol and added to each calibration standard and testsample^^iveanequivafentfinal concentration in all dilutions. The ratio of the peak heights for internal standard and H-24516 at three retention times (3.5,4.17, and 4.77 minutes) from replicate GC analysis of these suspensions were used to construct calibration curves by least squares regression (see Appendix A, Figure la, Ib, and Ic for a representative curves). Measured concentrations for the dosing samples were determined by applying the peak height ratios from replicate injections of each sample to the respective calibration curve. Test substance homogeneity in the dosing suspensions was evaluated by calculating the coefficient of variation (C.V. = standard deviation/mean x 100) of the measured concentrations in samples obtained from the top, middle, and bottom (T, M, and B) of the dosing preparation or the mean of duplicate samples for each concentration. A coefficient of variation of less than 10% is the standard criterion at Haskell Laboratory for acceptable distribution of the test substance throughout the dosing suspension. The mean result of the top, middle, and bottom homogeneity samples or duplicate concentration verification samples for each dosing level was used to determine the concentration of the test substance for the respective dosing levels. Stability was evaluated by using the mean of the top, middle, and bottom homogeneity samples or duplicate concentration verification samples (0-day room temperature) as the baseline for comparing the corresponding room temperature and refrigerated results. Company Sanitized. Does not contain TSCA CBI 25 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-5386 K. Body Weights All rats were weighed once per week during the 90-day exposure phase of the study. In addition, the rats designated for neurobehavioral evaluations, undergoing functional observational battery and motor activity assessments, were weighed on the days of those observations. During the reproduction" substudy, male rats were weighed on a weekly schedule and female rats were weighed during gestation on days 0, 7,14,18, and 21, and lactation days 0,7,14, and 21. PI female rats with no evidence of copulation or that did not deliver a litter continued to be weighed weekly. Weaned Fi rats were weighed weekly until postnatal day 56 (test day 36). L. Food Consumption and Food Efficiency The amount of food consumed by each rat over each weighing interval was determined throughout the study. Each feeder was weighed at the beginning and end of the interval and the final weight of the feeder and the amount of spillage from the feeder during the interval was subtracted from the initial feeder weight. From these measurements, mean daily food consumption over the interval was determined. From the food consumption and body weight data, the mean daily food efficiency was calculated. Mean daily food consumption was determined for all animals designated for subchronic toxicity evaluations during the 90-day exposure period. Food consumption was also determined for animals designated for one- and three-month recovery evaluations. The only exception is that food consumption was not determined for animals designated for three-month recovery during the urine and feces collection period on test days 83-89. During the reproductive assessment, food consumption was determined for rats designated for reproductive assessment as follows: Premating Dosing period - individual food consumption was determined weekly, ending test day 74. Cohabitation period, beginning test day 74 - food consumption was not determined. Following the end of cohabitation period - food consumption was not determined for males. Gestation period - individual food consumption was determined on gestation days 0, 7, 14, and 21. s Lactation period -- food consumption was not determined. Postweaning Fi rats - individual food consumption was inadvertently not collected or spillage not recorded during the postweaning period for many animals. As a result, available food consumption data are not presented in the report but are included in the study records. M. Detailed Clinical Observations and Mortality During the test period, cage-site examinations to detect moribund or dead rats and abnormal behavior and/or appearance among rats were conducted at least twice daily throughout the study. At every weighing, each rat was individually handled and examined for abnormal behavior and appearance. Detailed clinical observations in a standardized arena were also evaluated on rats designated for the 90-day exposure and one-month recovery periods. The detailed clinical 26 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-5386 observations included (but were not limited to) evaluation of fur, skin, eyes, mucous membranes, occurrence of secretions and excretions, autonomic nervous system activity (lacrimation, piloerection, and unusual respiratory pattern), changes in gait, posture, response to handling, presence of dome, tonic, stereotypical, or bizarre behavior. N. Ophthalmological Evaluations Three Ophthalmological examinations were conducted by a veterinary ophthalmologist. Both eyes were examined by focal illumination and indirect ophthalmoscopy. The examinations were conducted under subdued lighting after mydriasis had been produced with a 1% tropicamide solution. On test day -11, the initial examination was performed on all rats received for the study, prior to selection and grouping. On test day 80, all surviving rats designated for the 90-day exposure and one-month recovery were examined again. On test day 122, all surviving rats designated for the one-month recovery evaluation were given a final examination. 0. Neurotoxicity Evaluations 1. Sensory Function Evaluation Prior to test substance administration (test days -6 and--7), during week 13 (test days 86 and 87) of test substance administration, and following an approximately one-month recovery period (test day 120), assessments of responses to approach/touch, sharp auditory stimulus, and tail pinch were made while the animal was in a standard arena. These assessments were conducted on 10 animals per group for the baseline and week 13 evaluations. The recovery evaluation was conducted on the 10 animals per group designated for the one-month recovery (control and high- dose groups only). Fore- and hindlimb grip strength were measured by a strain gauge device (Chatillon Digital Force gauge). Pupillary constriction was measured immediately prior to removing the rats from the motor activity chambers because the darkened room in which the apparatus was located facilitated observing the response. Due to the technical difficulty of evaluating pupil size in albino rats under ambient light conditions, pupil size was evaluated by assessment of pupillary response. The presence or absence of pupillary constriction was assessed after a beam of light was directed into each eye. For all these assessments, the experimenter was unaware of the group designation of the animal. 2. Motor Activity Following the evaluation of grip strength and sensory function during week 13, assessment of motor activity was conducted. Rats were individually tested in 1 of 30 nominally identical, automated activity monitors (CoulboumInfrared Motor Activity System). Group and gender were counterbalanced across the monitors and time of day to the fullest extent possible. The infrared monitoring device enables measurement of 2 dependent variables: duration of movement and number of movements. A continuous movement was counted as 1 movement regardless of duration. Each test session was 60 minutes in duration, and the results were expressed for the total session as well as for 6 successive 10-minute blocks. IBbmpany ^anHteed. Does not oonlain TSCA CBI ^ H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 Presence of defecation and urination on the cageboards below the motor activity monitor were also recorded following each motor activity session. 3. Test Facility Positive Control Data Data on the effects ofacrylamide, carbaryl, d-amphetamine, and trimethyltin are described in four separate reports.0'2'3'^ These positive control studies are the basis of training certification for the individuals making judgments in the neurobehavioral and neuropathology tests. The data also document that the equipment and procedures are capable of detecting effects that may be seen in neurotoxicity studies of this type. P. Clinical Pathology A clinical pathology evaluation was conducted on the first 10 male and 10 female rats per group on test days 44 and 91 (males) or test days 45 and 93 (females). The rats were fasted overnight (approximately 16 hours) and urine was collected during this interval. Blood samples for hematology and clinical chemistry measurements were collected from the orbital sinus of each fasted rat while the rat was under light carbon dioxide anesthesia. Blood samples for coagulation parameters and plasma fluoride were collected from the abdominal vena cava while the rat was under carbon dioxide anesthesia, immediately prior to sacrifice (days 91 and 93 in males and females, respectively). All blood samples were examined visually and observations recorded. A clinical pathology evaluation (hematology, clinical chemistry, and urinalysis only) was also conducted on all one-month recovery rats from blood and urine collected on the day of necropsy (test day 125). m addition, urine samples were collected from three-month recovery rats for urine fluoride analysis only. 1. Hematology/Coagulation Complete blood counts (including reticulocytes) were determined on a Bayer Advia 120 hematology analyzer and determined from microscopic evaluation of the blood smear. Wrightstained blood smears from all rats were examined microscopically for confirmation of automated results and evaluation of cellular morphology. Coagulation times were determined on a BCS Behring Coagulation Analyzer. New methylene blue-stained blood smears were prepared from each rat undergoing hematology evaluation but were not needed for evaluation. 28 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations The following hematology and coagulation parameters were determined: Erythrocyte count (RBC) Hemoglobin concentration (HGB) Hematocrit (HCT) Mean corpuscular volume (MCV) Mean corpuscular hemoglobin (MCH) Mean corpuscular hemoglobin concentration (MCHC) Red cell distribution width (RDW) Absolute reticulocyte counts (ARET) Total leukocyte count (WBC) Differential leukocyte count Platelet count (PLT) Microscopic blood smear examination Prothrombin time (PT) Activated partial thromboplastin time (APTT) DuPont-5386 2. Clinical Chemistry Clinical chemistry parameters were measured or calculated on a Roche Diagnostics (BMC)/Hitachi 917 clinical chemistry analyzer. Plasma fluoride concentration was determined using a phi/I 2pH meter with a fluoride-selective electrode. Plasma fluorides were determined at the end of treatment and at the end of a one-month recovery period. The following serum chemistry parameters were determined: Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Sorbitol dehydrogenase (SDH) Alkaline phosphatase (ALKP) Total bilimbin (BELI) Urea nitrogen (BUN) Creatmme (CREA) Cholesterol (CHOL) Triglyceride (TRIG) Glucose (GLUC) Total protein (TP) Albumin (ALB) Globulin (GLOB) Calcium (CALC) Inorganic phosphorus (IPHS) Sodium (NA) Potassium (K) Chloride (CL) Plasma fluoride (PFLU) 3. Urinalysis The following urinalysis parameters were determined: Appearance (quality, clarity, and color) Volume (VOL) Osmolality (OSMO) Specific gravity (SG) pH Glucose (UGLU) Ketones (KET) Bilimbin (UBIL) Blood (BLD) Urobilinogen (URO) Urine, fluoride (UFLU) Protein (UMTP) Microscopic urine examination Urine volume and appearance were measured and evaluated visually, respectively. Urine constituents were semi-quantitatively measured on a Bayer Clinitek AtlasTM Automated Urine Chemistry analyzer. Urine volume and appearance were measured and evaluated visually, Swspsssf SsnWseS. Does not contain TSCA CS! 29 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations______________DuPont-5386 respectively. Urine constituents were semi-quantitatively measured on a Bayer Clinitek AtlasTM Automated Urine Chemistry analyzer. Urine protein was measured on a Roche Diagnostics (BMC)/Hitachi 717 clinical chemistry analyzer. Urine osmolality was determined using an Advanced Osmometer 3900. Sediments from all urine specimens were evaluated microscopically. Urine fluoride was determined by multiplication of measured urine volume by urine fluorideconcentration (measured using a phi/12pH meter and a fluoride selective electrode). Urine fluorides were determined at the end of treatment and at the end of the oneand three-month recovery periods. Q. Collection of Blood, Urine, and Feces (Three-Month Recovery) On test day -4 (pre-bleed) and test days 0, 3, 9, 21, 34, 55, 76, and 89 blood (approximately 0.5 - 1 mL) was collected from the orbital sinus of designated animals (5 rats/sex/dose) while the rat was under light carbon dioxide anesthesia. On the day of blood collection (except test day 4), blood was collected from the animals 2 hours ( 30 minutes) after dosing. The blood was collected in plastic tubes containing EDTA while on ice. The blood was then separated into plasma and RBCs by centrifugation and stored frozen. For each bleeding, blood was collected at approximately the same time of day. During the last week of the 90-day exposure period urine and feces were collected daily at 24-hour intervals from each animal. The animals were placed in metabolism cages for collection of feces and urine. The exact time period of collection of urine and feces was documented along with the total volume of urine obtained. Urine and feces were stored frozen. Blood was also collected for analysis at 3,7,12, 19, 26, 36, 50, 71, and 92 days postdosing for both male and female animals of each dose group and stored frozen. Animals were sacrificed at the end of the three-month recovery period. The collected blood, urine, and feces may be evaluated in the future for the test substance and/or possible metabolites. Resulting data will be reported separately. R. Anatomic Pathology - Rats Designated for Subchronic Toxicity and Recovery After approximately 90 days of exposure to the test substance (test days 91 and 93 for males and females, respectively), groups of 10 male and 10 female rats from the 0, 25, 100, and 250 mg/kg/day groups were sacrificed and necropsied. Additional groups of 10 male and 10 female rats from 0 and 250 mg/kg/day groups were sacrificed and necropsied approximately one month after the last exposure (test day 125). In addition, groups of 5 male and 5 female rats from all groups designated for the three-month recovery period were sacrificed and necropsied on test day 181. In the discussion of pathology findings, groups sacrificed after approximately 90 days are referred to as the 90-day exposure groups, and groups sacrificed on test days 125 and 181 are referred to as one-month and three-month recovery groups, respectively. Rats scheduled for sacrifice were fasted overnight on the afternoon before their scheduled sacrifice. The order of sacrifice for scheduled deaths were random among all treatment groups. Rats were euthanatized by carbon dioxide anesthesia and exsanguination. Gross examinations were performed on all male and female rats. 30 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 The following tissues were collected from 90-day exposure and one-month recovery group rats sacrificed by design, or rats that were found dead or accidentally killed. Digestive System liver esophagus stomach duodenum jejunum ileum cecum colon rectum salivary glands pancreas Urinary System kidneys urinary bladder Cardiovascular System heart aorta Hematopoietic System spleen thymus mandibular lymph node mesenteric lymph node bone marrow0 Endocrine System pituitary gland thyroid gland parathyroid glands adrenal glands Musculoskeletal System skeletal muscle femur/knee jointa sternum mandible b Reproductive System Male testes epididymides prostate seminal vesicles Female ovaries uterus mammary gland Respiratory System lungs trachea nose larynx Nervous System brain (including cerebrum, cerebellum, medulla/pons) spinal cord (3 levels: cervical, mid-thoracic, lumbar) Miscellaneous skin eyes (including optic nerve) gross observations pharynx sciatic nerve a. Both femur/knee joints were taken from 90-day exposure rats . One femur/knee joint was frozen and the other processed as described below. b. The mandible was taken from 90-day exposure and one-month recovery animals. One-half of the mandible was frozen and the other half processed as described below. c. Bone marrow was collected with the femur and sternum. The following tissues were collected from three-month recovery group rats sacrificed by design: liver, kidneys, thyroid gland, nose, testes, and fat (approximately I gram). The testes, fat and portions of the liver and kidney were placed in plastic freezer bags and stored frozen ; these tissues may be evaluated in the future for total fluorine levels to study the distribution of the test substance. Resulting data will be reported separately. The following tissues were weighed from rats sacrificed by design in the 90-day exposure group and the one-month recovery groups: liver, kidneys, adrenal glands, brain, spleen, thymus, heart, ovaries, uterus, epididymides, and testes. Organ weight/final body weight and organ weight/brain weight ratios were calculated. The thyroid gland (after fixation) was also weighed in the Pi adults. Liver, kidneys, thyroid gland (after fixation), and testes from rats sacrificed by design after three months recovery were weighed and organ weight/final body weight ratios were calculated. Organ weight/brain weight ratios were not determined for three-month sacrifice rats. Gross lesions which were diagnosed at necropsy and for which microscopic examination was not appropriate (e.g., fluid accumulation, ruffled fur, missing anatomic parts) were generally not Company Sanitized. Does not contain TSCA CB6 31 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-5386 collected. Gross lesions for which a microscopic diagnosis would not be additive (e.g., osteoarthritis, pododermatitis, chronic dermatitis of the tail, urinary calculi, and deformity of the teeth, toe, tail, or pinna) were saved but were generally not processed for microscopic evaluation. Testes, epididymides, and eyes were fixed in Bourn's solution. All other tissues were fixed in 10% neutral buffered formalin. Processed tissues were embedded in paraffin, cut at a nominal thickness of 5 micrometers, stained with hematoxylin and eosin (H&E), and examined microscopically. All collected tissues from exposure group rats sacrificed on test days 91/93 from control and 250 mg/kg/day rats, and all found dead or accidentally killed rats were processed and received a full histopathological examination. Liver, kidneys, thyroid gland, nose, and mandible were processed from 25 and 100 mg/kg/day 90-day exposure group rats and from one-month recovery rats. Liver, kidneys, thyroid gland, and nose from males and thyroid gland and nose from females sacrificed after the three-month recovery period were processed from all groups. Tissues were microscopically examined in descending order of dose until a no-effect level was reached. S. Reproductive Assessment 1. Breeding After approximately 10 weeks of exposure to the test substance, on test day 74, each female was continually housed on a 1:1 basis with a randomly selected male of the same dose concentration level in the male's cage. On the day copulation was confirmed, the female was transferred back to individual cage housing. Mating pairs were cohoused until evidence of copulation was observed (designated as day 0 of gestation), or until 2 weeks elapsed. The presence of an intravaginal or extruded copulation plug was considered evidence of copulation. 2. Estrous Cycle Evaluation Vaginal smears were collected from all Pi female rats in order to determine the stages of the estrous cycle. Vaginal smears were collected daily beginning 3 weeks prior to mating, and continuing until copulation was confirmed, or the cohabitation period ended. Vaginal smears were also collected from all Pi parental female rats at the time of sacrifice to determine the stage of estrous cycle. This data is not presented in the report but is included in the study records. 3. Gestation Procedures Female rats were transferred to polycarbonate pans (on day 20 of gestation for mated females or at the end of the cohabitation period for female rats without evidence of copulation), and were observed at least twice daily for signs of delivery and pups. 32 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations 4. Lactation Procedures ___ DuPont-5386 The day when delivery was complete was designated day 0 postpartum. At each examination period, pups were individually handled and examined for abnormal behavior and appearance; any dead, missing, or abnormal pups were recorded. a. Day 0 Postpartum Live and dead pups in each litter were counted as soon as possible after delivery was completed. Live pups in each litter were individually weighed. b. Day 4 Postpartum Litters were culled randomly to 8 (4/sex when possible). Extra pups were euthanatized (by decapitation) and discarded without pathological examination. Litters of 8 pups or less were not reduced. Litter counts were recorded prior to and after culling, and individual pup weights were recorded prior to culling. c. Days 7 and 14 Postpartum Pups in each litter were counted by sex and individually weighed. d. Day 21 Postpartum (Weaning) Pups in each litter were counted by sex and individually weighed (3 of4/sex/litter were then sacrificed and grossly examined on postnatal day 21). Randomly selected weanlings (one/sex/litter) were placed in individual cages, monitored for attainment of developmental landmarks. At each examination period, offspring were individually handled and examined for abnormal behavior and appearance; any dead, missing, or abnormal pups were recorded. 5. Post Weaning and Developmental Landmarks Developmental landmarks in the Pi generation male and female rats (one/sex/litter) were monitored on a daily basis until criterion was achieved. Once developmental landmark criterion was achieved, the animals were weighed. Body weight and food consumption were also determined weekly until postnatal day 56 (test day 36). a. Vaginal Patency Female rats were examined beginning on postpartum day 21. b. Preputial Separation Male rats were examined beginning on postpartum day 35. .Csmpany SarnVyori rune's, nn} cwWn TSCA CB8 33 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 T. Anatomical Pathology - Rats Designated for Reproductive Evaluations 1. Pi Adults All rats found dead, accidentally killed, or sacrificed in extremis prior to the cohabitation period underwent a gross and microscopic evaluation. The tissues collected are the same as those for rats designated for the 90-day exposure period. All Pi parental rats were sacrificed by carbon dioxide asphyxiation and exsanguination, and subjected to gross pathological examination, including the females that died and those for which mating did not result in a production of offspring. The uteri of all cohabited females were examined for the presence and number of implantation sites. Sperm parameters for the first 10 out of 20 Pi male animals in each treatment group were evaluated. The right cauda epididymis was weighed. Sperm was collected from the right cauda epididymis and percent motility and morphology was determined. The left epididymis and testis were frozen in liquid nitrogen and stored between -65 and -85 C for sperm and spermatid counts, respectively. The right testis and epididymis from these 10 rats were saved and placed in fixative. The following table lists tissues that were collected: Male Tissues Collected from Pi Adults Female Both Sexes Testes/Testis3 Epididymides/Epididymis" Ovaries Uterus (with oviducts) Thyroid Gland1' Gross Observations0 Prostate Vagina Pituitary Gland Seminal Vesicles Coagulating a Testes/Testis aGndleapindiddy_mi_de_s/_ep_id_id_ym_is_c_ol_lec_te_d_fr_om_m_a_le_ra_ts_w_er_e _pl_ac_ed_in_B_o_uin_'s_s_ol_ution. All other tissues (reproductive and non-reproductive) collected from male and female rats were placed in formalin. b Thyroid glands were weighed after fixation. c Gross lesions observed at necropsy for which histopathology was not appropriate or would not be additive were generally not collected. 2. Offspring Offspring that were found dead during the lactation period underwent a gross pathological evaluation. 3. FI Weanlings Three F] weanlings/sex/litter (randomly selected), litter size permitting, were sacrificed by carbon dioxide asphyxiation and underwent a gross pathological evaluation on postnatal day 21. Gross lesions were preserved. 34 H-24516: Subchronic Toxicity 90-Day Gavage Study m Rats with One-Generation Reproduction Evaluations DuPont-5386 4. FI Adults All Fi generation rats were sacrificed by carbon dioxide asphyxiation and exsanguination, and subjected to a gross pathological examination. Selected tissues and gross lesions were preserved. The following table lists tissues that were collected and/or weighed: Male Tissues Collected from Fi Adults Female Both Sexes Testes Epididymides Prostate Seminal Vesicles Coagulating Gland Ovaries Uterus (with oviducts) Vagina Thyroid Gland Gross Observations Pituitary Liver Kidney Nose Male Tissues Weighed from Fi Adults Female Both Sexes Testes Epididymides Seminal Vesicles (with coagulating glands) Prostate Uterus (with oviducts and cervix) Thyroid Gland (after fixation) Liver Brain Kidney Processed tissues for histopathological examination were embedded in paraffin, cut at a nominal thickness of 5 micrometers, and stained with hematoxylin and eosin (H&E). Histopathological examination of reproductive organs was conducted only for Pi males and females with impaired reproductive performance. Selected gross lesions were evaluated microscopically. Gross lesions observed at necropsy for which histopathology was not appropriate or would not be additive were generally not collected. U. Biochemical Measurements Following 10 or approximately 90 days of test substance administration, after 36 days on recovery, or after 92 days on recovery (control and high-dose only), five rats from each group designated for biochemical evaluation were weighed and then sacrificed by C02 anesthesia and exsanguination. Rats were fasted overnight on the afternoon before their sacrifice. The livers were removed, weighed, and then homogenized (1 gram tissue/4 mL buffer). Hepatic peroxisomes were prepared using differential centrifugation. The resulting peroxisomal pellets were resuspended in the homogenization buffer, aliquoted, and stored between -65 and -85C until analyzed for peroxisomal p-oxidation activity. The peroxisomal suspensions were diluted to a protein concentration of approximately 0.25 mg/mL. Peroxisomal p-oxidation activity was .empainy Banltized. Does not contain T8CA OBI 35 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 determined using [^Cjpalmitoyl CoA as the substrate/5) The protein content of the peroxisomes was determined before and after analysis by the Biorad method/6) V. Statistical Analyses Except for Bartlett's test (p < 0.005), significance was judged at p < 0.05. Separate analyses were performed on the data for each gender. Parameter Body Weight Body Weight Gain Food Consumption Food Efficiency Organ Weight Preliminary Test Test for lack of trend'9' Levene's test for homogeneity02'and Shapiro-Wilk test031 for normality1' Method of Statistical Analysis If preliminary test is not If preliminary test is significant significant Sequential application010 of the Jonckheere-Terpstra trend test00 Preliminary tests for pairwise comparison OR3 One-way analysis of variance04' followed with Dunnett's test'7' Kruskall-Wallistest05' followed with Dunn's test'8' Motor Activity0 Grip Strength Clinical Pathology'1 Levene's test for homogeneityTM and Shapiro-Wilk test031 for normality1' Bartlett's test081 for homogeneity of variances Levene's test for homogeneity02' and Shapiro-Wilk test03' for normality1' Repeated measures analysis of variance09 followed by contrasts07' One-way analysis of variance04' followed with Dunnett's test'7' One-way analysis of variance04' followed with Dunnett's test^ Sequential application'10' of the Jonckheere-Terpstra trend test"" Kruskall-Wallis test"5' followed with Dunn's test'8' Kruskall-Wallis test"5' followed with Dunn's test'8' Survival Incidence of Clinical Observations Incidence of FOB Descriptive Parameters Biochemical Measurements Incidence of Microscopic Lesions None None None Cochran-Armitage test for trend04'' One-way analysis of variance04' followed with Dunnett's test'7' or Dunn's test'8' None TPairwise comparisons and associated preliminary tests were only conducted if the test for lack of trend was significant. If the Shapiro-Wilk test was not significant but Levene's test was significant, a robust version of Dunnett's test was used. Test day and block (10-minute EPOCH) was used as repeated-measure factors. When an individual observation was recorded as being less than a certain value, calculations were performed on half the recorded value. For example, ifbilirubin was reported as <0.1, 0.05 was used for any calculations performed with that bilirubin data. If the incidence was not significant, but a significant lack of fit occurred, then Fisher's Exact test'19' with a Bonferroni correction was used. '^^"-"'-.-nTSCACB, 36 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 The following table lists the indices of reproductive function that were calculated for the Pi and FI adults. Parameter Body Weight Body Weight Gain Food Consumption Gestation Length Organ Weight Implantation Site Numbers Implantation Efficiency Mean Number of Pups Per Litter Percent Bom Alive Precoital Interval Estrous Cycle Length Sperm Parameters Vaginal Patency Preputial Separation Food Efficiency Preliminary Test Test for lack of tren^ Method of Statistical Analysis If preliminary test is If preliminary test is not significant significant Sequential application0^ of the Jonckheere-Terpstra Preliminary tests for pairwise comparison trend test00 OR3 Levene's test for homogeneity0^ and Shapiro-Wilk test c^for normality1' One-way analysis of variance0'0 followed with Dunnett's test^ Kruskall-Wallis test "^followed with Dunn's test'81 None One-way analysis of variance0'0 followed with Dunnett's test^ Incidence of Clinical Observations Mating Index Fertility Index Gestation mdex Viability mdex Lactation Index None Cochran-Armitage test for trend0410 Mean Pup Weights (Covariates: litter size, sex ratio) Sex Ratio None Linear contrast of least squares means0^ Dunn's test^ a Pairwise comparisons and associated preliminary tests were only conducted if the test for lack of trend was significant. b If the Shapiro-Wilk test was not significant but Levene's test was significant, a robust version ofDunnett's test was used. c If the incidence was not significant, but a significant lack of fit occurred, then Fisher's Exact test091with a Bonferroni correction was used. 37 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-5386 For each parameter analyzed with a trend test, the test was applied to the data sequentially. If a significant dose-response was detected, data from the top dose group were excluded and the test repeated until no significant trend was detected.0^ For litter parameters, the proportion of affected fetuses per litter or the litter mean was used as the experimental unit for statistical evaluation/20 Where the data are tied and the standard large sample version ofJonckheere's test is not applicable, exact p values were calculated using permutation methodology/2^ RECORDS AND SAMPLE STORAGE Laboratory-specific or site-specific raw data, such as personnel files and equipment records will be retained by the facility where the work was done. A sample of the test substance was collected for archive purposes and retained at Haskell Laboratory. Specimens (if applicable), raw data, and the final report will be retained at Haskell Laboratory, Newark, Delaware, or at Iron Mountain Records Management, Wilmington, Delaware. Clinical pathology slides and raw data will be retained at Haskell Laboratory, Newark, Delaware. Characterization data will be stored at Regional Analytical Services (RAS), Jackson Laboratories, Deepwater, New Jersey. gompany 38 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-5386 RESULTS AND DISCUSSION 39 ANALYTICAL EVALUATIONS A. Test Substance Stability Analyses of bulk samples ofH-24516 near the beginning and end of the study for stability indicated that the test substance was stable for the duration of the study. The average percent of H-24516 in thesample submitted near the beginning of the study (test day 7) and analyzed (test day 23) waaHH^JThe average percent of H-24516 in the sample submitted at the end of the study (test day 90^ and analyzed (test day 105) waa^BIB|This work can be found "w^Bf HlllRl-24516,|IHHBjThe purity was reporteTby the sponsor to be^UBphe differences ' in values between the sponsor reported purity and the experimental data represenfanalytical variability and not instability of the test substance. B. Chromatography H-24516 eluted from the GC column as resolved peaks with retention times from 2.9 minutes to approximately 6.0 minutes. For the purpose ofquantitation, resolved peaks at the retention times of approximately 3.5, 4.17, and 4.77 minutes were used. The internal standardgf[mj| mmutes^RepresentativeGCchromatogramsare shown in Appendix A, Figures 2(a - c). Test substance was not detected in the 0 mg/mL control. C. Homogeneity, Concentration Verification and Stability Samples for Initial Mixing Procedures and Concentrations Based on Dose Volume of 10 mL/kg (Test Day 0 to Test Day 41) Analytical results from dosing suspensions collected on test day 0 and test day 6 and analyzed for homogeneity/concentration verification and 5-hour room temperature stability are shown in Table 1 and Appendix A, Table I. The following table summarizes the results for homogeneity, concentration verification and stability analyses. Preparation Date Test Day 0 Nominal mg/mL 0 2.5 10 25 , W MeasuiredT nng/m] / ND 2.30, 2.47, 2.40 8.97, 10.2, 14.0 26.8, 24.8, 23.5 Mean(T,M,B) % Nominal -- 95.6 111.0 100.0 C.V. (%) -- 3 24 7 Stability1' % Nominal -- 82.4 88.9 96.4 Test Day 5 0 ND' 10 9.26, 9.58, 9.23 93.6 2 Mean results for the analysis of the top (T), middle (M) and bottom (B) samples. Samples held 5 hours at room temperature. Denotes none detected. 90.3 Pomparty Sanitized. Doss iw contain TSCA CB8 40 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-5386 The data for samples collected on test day 0 indicates that the test substance was homogeneously mixed in the vehicle except for the 10 mg/mL level (C.V. = 24). The test substance was at the targeted concentration in the samples (11% of nominal) and was stable in the vehicle when held 5 hours at room temperature. The 10 mg/mL level samples were collected again on test day 6 to show that the mixing and the room temperature stability was acceptable. The data indicated that the test substance was homogeneously mixed in the vehicle (C.V. = 2%), at the targeted concentration in the samples ( 6.4% of nominal) and stable in the vehicle when held 5 hours at room temperature. The lower than expected result for the 2.5 mg/mL (82.4% of nominal) for the 5-hour sample was within the targeted range of the study ( 20% of nominal) and is due to sampling and analytical variability of the method and not stability of the test material in the vehicle. This was concluded based on the data from the remainder of the levels in this study, which were stable for the 5-hour room temperature period. Test substance was not found in the 0 mg/mL samples. D. Mixing and Stability Study for Change in Frequency of Dosing Preparation (2 times/week) and Dose Volume Change (5 mL/Kg to 7.5 mL/Kg) This work was done prior to initiating any mixing or storage condition changes in the study. Analytical results from dosing suspensions collected for the special mixing study and analyzed to verify homogeneity and/or concentration with stability are shown in Table 1 and Appendix A, Table IL 41 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 The following table summarizes the results for homogeneity/concentration verification and stability analyses. Dose Volume Sample Type 5.0 mL/ke Homogeneity b Stability 2-Day Refrigerated'1 3-Day Refrigerated11 4-Day Refrigerated*^ Nominal mg/mL 0 5.0 20 50 5.0 5.0 5.0 Measured mg/mL ND0 4.53,4.25,4.39 19.9,17.7,18.6 53.4, 52.6, 54.0 4.77,4.76 4.74,4.48 4.81 Mean % Nominal -- 87.8 93.5 106.6 95.4 92.2 96.1 C.V. (%) Stability' % Nominal -- -- 3 92.0 6 86.0 1 96.6 0.2 -- 4 -- -- 97.1 2-Day Refrigerated'1 20 3-Day Refrigerated'1 20 4-Day Refrigerated*^ .20 2-Day Refrigerated'1 50 3-Day Refrigerated'1 50 4-Day Refrigerated'^ 50 18.7, 18.0 39.3, 19.6" 19.6 47.3, 48.4 46.5,46.9 48.9 91.5 147.0 97.8 95.8 93.4 97.8 3 47 -- -- 88.2 2 -- 1 -- -- 95.7 7.5 mL/kg b Homogeneity Stability 0 ND' 3.33 2.88, 2.54, 2.67 -- 81.1 -- -- 6 79.9 4-Day Refrigerated 3.33 2.94, 2.88 87.4 1 82.3 a Samples held 5 hours at room temperature. b Mean results for the analysis of the top (T), middle (M) and bottom (B) samples. c Denotes none detected. d Mean results of duplicate concentration verification samples. e Original analysis not reported because of apparent aliquot error. Mean result of duplicate re-analysis (n=2) of the original sample reported. f Mean result of single sample for concentration verification and a single sample for 5-hour room temperature stability. g Mean result of duplicate samples for concentration verification and a single sample for 5-hour room temperature stability. The data for samples collected initially (5.0 mL/kg dose volume change) indicate that the test substance was homogeneously mixed in the vehicle, at the targeted concentration ( 12.2% of nominal) and was stable in the vehicle when held. 4 days refrigerated followed by 5 hours at room temperature. The higher than expected result for the 3-Day refrigerated samples at the 20 mg/mL level (147.0% of nominal, C.V. = 47%) indicates that the test substance was not properly re-dispersed in the vehicle after refrigeration and before sampling. This was concluded because duplicate samples were collected and analyzed with one of the samples having a higher than expected result (39.3 mg/mL) in the analysis. The sample was reanalyzed and the results supported the duplicate reported analysis. This data along with the results from the last sampling time at this level (4-day refrigerated/97.8% of nominal) supported this conclusion. '~~~--~~~~--~~~~~~~~~~F---- Company Sanitized. Does not contain TSCACBI 42 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 The data for samples collected for the 7.5 mL/kg dose volume change indicate that the test substance was homogeneously mixed in the vehicle for the 3.33 mg/mL level (C.V. = 6) and stable in the vehicle when held 5 hours at room temperature. The concentration was lower than expected (81.1 % of nominal) but was probably due to initial sampling of the mixture before adequate mixing. The results from the 4-day refrigerated samples from the same preparation indicated the material was at the targeted level ( 12.6% of nominal) and stable when held 4 days refrigerated followed by 5 hours at room temperature. The results from this mixing and stability study indicated that the mixing time for preparation of the suspensions before use with the animals would have to be monitored for both the initial preparation and the re-dispersion of the suspensions after refrigeration. The test substance was shown to be stable in the vehicle over the concentration range needed for the dose volume change and under the storage conditions for the change in frequency of preparation (3 or 4 days/ twice a week) of the dosing suspensions. E. Homogeneity and Concentration Verification Samples for Final Mixing Procedures and Concentration Change Based on Dose Volume of 7.5 mg/kg (Test Day 42) Analytical results from dosing suspensions collected on test day 49 and test day 91 and analyzed for homogeneity and/or concentration verification are shown in Table 1 and Appendix A, Table III. The following table summarizes the results for homogeneity and concentration verification analyses. Preparation Date Test Day 49 Nominal mg/mL 0 3.33 13.33 33.33 Measured T.M.B8 mg/mL ND" 2.71,2.99,3.42 10.8, 12.7,12.8 31.0,32.4,33.4 Mean(T,M,B) % Nominal -- 91.3 90.8 96.8 C.V. (%) -- 12 9 4 Test Day 91 0 ND1' -- ---- 3.33 3.05, 3.00, 3.01 90.7 1 13.33 12.8,12.2 93.8 3 33.330 32.7, 32.3 97.5 1 a Mean results for the analysis of the top (T), middle (M) and bottom (B) samples. b Denotes none detected. c Duplicate samples submitted. C.V. for the duplicate samples used to confirm uniformity of mixture. The data for samples collected on test day 49 indicates that the test substance was homogeneously mixed in the vehicle except for the 3.33 mg/mL level (C.V. = 12). substance was at the targeted concentration in the samples ( 9.2% of nominal). The test The data for samples collected on test day 91 show that the 3.33 mg/mL level was homogeneously mixed, indicated that the test substance was properly mixed in the vehicle 43 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-5386 (C.V. = 1%) and at the targeted concentration in the samples ( 9.3% of nominal). The data for the duplicate concentration verification samples for the remaining levels indicated that the test substance was at the targeted level ( 6.2% of nominal) and mixed properly (C.V.'s = 3 and 1%, respectively). Test substance was not found in the 0 mg/mL samples. F. Analytical Conclusions Data from the analysis of the samples at the initiation of the study indicate that the test substance in the vehicle was mixed homogeneously, was at the targeted levels and was stable for 5 hours at room temperature. Data for the analysis of the samples after the mixing and dose volume changes indicated that the test substance in the vehicle was mixed homogeneously and at the targeted levels. All stability conditions were addressed in the additional stability/mixing study and the test substance in the vehicle had been shown to be stable after 4 days of refrigeration followed by 5 hours at room temperature over the concentration range. The data also indicated that controlled mixing was necessary for the initial mixing and redispersion of the test substance in the vehicle after refrigeration. Test substance was not found in the 0 mg/mL samples. Analysis of the test substance near the beginning and the end of the study indicates that the H-24516 was stable during the study. 44 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 SUBCHRONIC TOXICITY EVALUATIONS IN-LIFE TOXICOLOGY A. Dosage Data (Tables 2-3, Appendix B) Rats were dosed with suspensions of H-24516 in 0.5% aqueous methylcellulose, prepared at concentrations ofO, 2.5, 10, and 25 mg/ml, designed to deliver the targeted dose of test substance at a dosing volume of 10 ml/kg body weight. However, in order to administer a dose volume under 5 mL to comply with animal welfare guidelines, the dosing volume for male and female rats was decreased from lOmL/kg to 7.5 mL/kg and the suspension concentrations were increased to 3.33,13.33, and 33.33 mg/mL on test day 38. The quantity ofH-24516 administered to each rat was calculated, based on the most recent body weight for each rat, and subsequently rounded by a computer program. The range of mean daily dose volumes administered to male rats was 2.5-4.6 mL for the control group, 2.5-4.6 mL for the 25 mg/kg/day group, 2.5-4.6 mL for the 100 mg/kg/day group, and 2.5-4.6 mL for the 250 mg/kg/day group. The range of mean daily dose volumes administered to female rats was 1.9-2.8 mL for the control group, 1.9-2.8 mL for the 25 mg/kg/day group, 1.92.6 mL for the 100 mg/kg/day group, and 1.9-2.8 mL for the 250 mg/kg/day group. B. Mean Body Weights and Body Weight Gains (Tables 4-7, Figures 1-2, Appendices C-D) Statistically significant decrements in body weight compared to control were observed in males in the 100 mg/kg/day dose group after day 77 (7-8%) and in the 250 mg/kg/day group after test day 56 (6-14%). Statistically significant decrements in body weight in females compared to control were observed in the 100 mg/kg/day dose group after day 77 (6-7%) and in the 250 mg/kg/day group after test day 56 (6-12%). These weight gain differences appear to be directly related to test-substance induced adverse effects to the teeth (see Section C and Anatomic Pathology Report) and subsequent decreases in food consumption in the 100 mg/kg/day female and 250 mg/kg/day male and female groups (see Section C). The 250 mg/kg/day male group had significantly lower mean body weight gains compared to control over the course of the study. Significantly lower mean body weight gains were observed for the 100 mg/kg/day male group during the 35-42 and 49-56 day intervals. A significantly lower mean body weight gain also occurred for the 25 mg/kg/day male group during the 35-42 day interval. The mean body weight gain of the 250 mg/kg/day male group was significantly higher than the mean weight gain of male controls during the first week of the study and during the 77-84 and 84-90 day intervals. The increased mean body weight gains observed after test day 77 appear to be associated with an increase in food consumption and food efficiency after both the male and female rats in the 250 mg/kg/day dosage group were placed on ground chow because of adverse effects to the teeth. Overall (0-90 day interval), significantly lower mean Company Sanitised. Dee neSeartain'TSCACBS 45 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-5386 body weight gains of 13% and 16% compared to control occurred in the 100 and 250 mg/kg/day male groups. This reduction in body weight gain was considered test substance-related and lexicologically significant. The 250 mg/kg/day female group had significantly lower mean body weight gains compared to the control group over the course of the study. Significantly lower mean body weight gains also occurred for the 100 mg/kg/day female group during the 28-35 day interval and for both the 25 and 100 mg/kg/day groups during the 42-49 day interval. The mean body weight gain of the 250 g/kg/day group was significantly higher than control during the second week of the study and during the 77-84 day interval. As with males, the increased body weight gain occurring after test day 77 appears to be associated with an increase in food consumption and food efficiency (see Section B) after the animals were placed on ground chow. Overall (0-91 day interval), significantly lower mean body weight gains of 12% occurred in both the 100 and 250 mg/kg/day female groups. The mean body weight and body weight gain decrements observed for the 100 g/kg/day and 250 mg/kg/day female groups, however, were of small magnitude and were associated with decreased food consumption but not with any alterations in food efficiency (see Section B). Therefore, the statistically significant mean body weight and body weight gain decrements for the 100 mg/kg/day and 250 mg/kg/day females were considered to be test substance-related but not lexicologically significant. Furthermore, the decrements in body weight parameters observed for both males and females appear to be related to test substanceinduced adverse effects to the teeth (see Section D and Pathology Section) and subsequent decreased ability of the animals to eat the pelleted chow. Following a one-month recovery period, the mean body weight and body weight gain of both male and female rats that received 250 mg/kg/day approached control. For the overall one-month recovery period (90-119 day interval), a statistically significant decrement in mean body weight gain occurred for the 100 mg/kg/day group. The lower mean body weight gain did not occur in a dose-dependent manner and appeared to be due to test substance-induced adverse effects to the teeth and a subsequent large decrease in food consumption for one male in the 100 mg/kg/day group. Therefore, this effect was not considered toxicologically significant. Following the threemonth recovery period, the mean body weight (females only) and body weight gain of both males and females exceeded control levels. C. Food Consumption and Food Efficiency (Tables 8-11, Appendix E) Male rats in the 250 mg/kg/day group had statistically significant and lower food consumption compared to control over the course of the study. Overall (0-90 day interval), a significantly lower food consumption of 7% compared to control occurred in the 250 mg/kg/day male group. Females in the 100 and 250 mg/kg/day had statistically significant and lower food consumption compared to control over the course of the study. Overall (0-91 day interval), significantly lower food consumption of 9% and 8% occurred in the 100 and 250 mg/kg/day female groups. However, after the rats received ground chow as a result of tooth toxicity, their food consumption immediately increased and began to approach or exceed (female 77-84 day interval) control 46 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations ___ ____DuPont-5386 levels. Test-substance related and statistically significant effects on food consumption were observed in the 100 mg/kg/day female and 250 mg/kg/day male and female groups. Male rats in the 250 mg/kg/day group had significantly lower mean food efficiency compared to control over the course of the study except during the first and third week of the study and test days 77-84 and 84-91 in which significantly higher food efficiencies were observed. The 100 mg/kg/day male group had significantly lower mean food efficiency during test days 35-42 and 49-56. For the entire study interval, significantly lower food efficiencies of 8% and 9%, respectively, were observed for the 100 and 250 mg/kg/day male groups. With the exception of the first two weeks of the study and test days 77-84 in which a significantly higher mean food efficiency occurred, female rats in the 250 mg/kg/day group had significantly lower mean food efficiency compared to control over the course of the study. A significantly lower mean food efficiency was also observed for the 100 mg/kg/day female group during test days 28-35, 42-49, and 49-56, while a significant increase occurred during test days 35-42. During test days 42-49, the 25 mg/kg/day female group had significantly lower mean food efficiency. These differences were not considered to be oftoxicological significance as overall mean food efficiencies for test-substance treated female groups were similar to control. The decreased mean food efficiency in the 250 mg/kg/day male group appears to be directly related to test substance-induced toxicity of the teeth. Following the replacement of pelleted chow with ground chow on test day 77 for the 250 mg/kg/day male and female groups, a significantly higher mean food efficiency was observed for the 77-84 and 84-90 (males only) day intervals. Nevertheless, based on the parallel reduction in body weight parameters observed in the 100 and 250 mg/kg/day male groups, this reduction in food efficiency is considered to be toxicologically significant. After a one-month recovery period, mean food consumption in the 250 mg/kg/day male group was still significantly lower, while mean food efficiency was the same as that observed in control rats. For females, lower food consumption was also observed following the one-month recovery period. For the overall one-month recovery period (90-119 day interval), a statistically significant decrement in mean food efficiency occurred for the 100 mg/kg/day male and female groups. The lower mean food efficiency did not occur in a dose-dependant manner and therefore was not considered to be toxicologically significant. Following three months of recovery, mean food consumption for males and females was similar to control levels, while mean food efficiency for the 250 mg/kg/day males exceeded control levels. D. Clinical Observations, Ophthalmology Evaluations, and Survival (Tables 12-17, Appendix F) A test substance-related, toxicologically significant increase in the incidence of broken (males) and absent teeth (males and females) was observed in the 250 mg/kg/day dose group. In addition, there was an increase in tooth clipping required for both males and females in the 250 g/kg/day dose group. There was also a statistically significant increase compared to control in the incidence of stained red perineum and clear discharge from the mouth in the 250 g/kg/day male dose group. The increased incidence of stained red perineum and clear discharge from the mouth was considered to be test substance-related. 47 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 No test substance-related ophthalmological signs oftoxicity or effects on survival were observed. E. In-Life Toxicology Conclusions Under the conditions of this study, the no-observed-effect-level (NOEL) for in-life toxicology parameters (body weight, body weight gain, food consumption, food efficiency, and clinical signs oftoxicity) was 25 mg/kg/day for males and 100 nig/kg/day for females. NEUROBEHAVIORAL TOXICOLOGY A. Sensory Function Evaluations 1. Forelimb Grip Strength (Table 18-19, Figures 3-4, Appendix G) There were no test substance-related effects or statistically significant differences on forelimb grip strength in males or females administered any dosage of H-24516. Females administered 100 or 250 mg/kg/day had slightly lower (12% and 14% lower than the control value, respectively) forelimb grip strength at week 13, however, a linear dose response-relationship was not present, and the values were within the range of normal variation for this measurement, hi addition, the forelimb grip strength in the control group during the recovery evaluation was similar to the values of the 100 and 250 mg/kg/day female groups during the week 13 evaluation demonstrating the degree of variability in this type of measurement. Therefore, the slightly lower forelimb grip strength in 100 and 250 mg/kg/day females was not considered to be test substance-related. 2. Hindlimb Grip Strength (Table 18-19, Figures 5-6, Appendix G) There were no test substance-related effects or statistically significant differences in hindlimb grip strength for either males or females administered any dosage of H-24516. 3. Sensory Function Observation (Table 20-21, Appendix H) There were no test substance-related changes in neurobehavioral parameters in males or females administered any dosage of H-24516. B. Motor Activity (Tables 22-25, Figures 7-10, Appendices I-J) TT'hl- e-r,,e- _w^e_.r_e- n.-o- -tte.-s-.tt- s__u1b---stl-a_n--c-e- -r--e1l-a-1t-e--d1 e--fCfCe-c-.t*_s_ o---n d-Ju-. ration of movement or number of movements for males or females for any dosage tested. Males assigned to the 100 and 250 mg/kg/day group had significantly lower mean duration of movement during the third 10-minute interval for the baseline evaluation. In addition, mean duration of movements was significantly lower for 25, IBampany SantSfeed. Dees not contain TSCA CB8 48 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 100, and 250 mg/kg/day males compared to control during the fourth 10-minute interval of the baseline evaluation. However, test substance administration had not been initiated, and therefore, these statistical differences were not considered to be test substance related. Females in the 250 mg/kg/day group had significantly lower total duration of movement and number of movements during the recovery evaluation. The total duration of movements for both the control females and 250 mg/kg/day females was lower relative to the baseline and week 13 evaluations. However, the number of movements for both control and the 250 mg/kg/day females were within the range of baseline values for females in this study. Since there was no increase or decrease from the range of baseline values with respect to number of movements, and since there were no changes in motor activity observed at week 13 or in any other neurobehavioral parameter, the statistically significant differences compared to control were not considered to be test substance related. C. Neurobehavioral Toxicity Conclusions Under the conditions of the study, the no-observable-effect level (NOEL) for neurobehavioral parameters was 250 mg/kg/day in males and females, the highest concentration tested. 49 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 CLINICAL PATHOLOGY A. Hematology/Coagulation (Tables 26-29, Appendix K) Rats dosed with 250 mg/kg/day had minimally decreased RBC mass parameters (RBC, hemoglobin, hematocrit; variable statistical significance) (Clinical Pathology Text Table 1). These decrements were associated with minimally increased RDW in both sexes, anisocytosis, microcytes, and increased reticulocytes in males, and poikilocytosis in females. Following the approximately one-month recovery period, male rats previously dosed with 250 mg/kg/day still had minimally to mildly decreased red cell mass parameters, and decreased reticulocytes compared to control group rats. Female rats previously dosed with 250 mg/kg/day had red cell mass parameters similar to controls by day 125, although MCV, MCH, RDW and reticulocytes were decreased. The minimal red cell effects discussed above are not expected to affect red cell function or the health of the animal. Nevertheless, based on the progressive nature of the effects during treatment and the persistence of many effects into the recovery period, the red cell changes noted at 250 mg/kg/day were considered toxicologically adverse. Clinical Pathology Text Table 1: Red cell mass parameters as a percent of control group mean* Parameter Males Interval 25 100 250 Females 25 100 250 RBC Day 44/45 101% Day 91/93 97% Day 125 97% 93% 98% 90% 89% 95% 99% 96% 97% 94% 93% 101% HGB Day 44/45 101% 100% 98% Day 91/93 99% 98% 93% Day 125 92% 96% 98% 98% 97% 94% 92% 98% HCT Day 44/45 101% 100% 98% Day 91/93 97% 97% 93% Day 125 91% 96% 97% 96% 97% * Statistical significance indicated by bold italicized type 94% 92% 97% Females dosed with 250 mg/kg/day had shortened APTTs at day 93. This change was not considered to be treatment related because there was no clear dose-related response. Similar APTTs were present in all treated groups. Additionally, shortened coagulation times are not considered adverse; prolonged, rather than shortened, coagulation times are toxicologically significant. Because there were no treatment-related alterations in coagulation parameters at the end of dosing, coagulation parameters were not measured at the end of the one-month recovery (Day 125). Igompany Sa"-'*'-"6''8 ">'w "* /--*-- "^A QBI ^ H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-5386 The following minimal but statistically significant changes in hematology parameters were considered to be unrelated to treatment because they did not occur in a dose related manner: Decreased hemoglobin and hematocrit in females dosed with 25 mg/kg/day at Day 45 Increased MCH in males dosed with 100 mg/kg/day, and increased MCHC in males dosed with 25 ing/kg/day at Day 91 Increased eosinophils in males dosed with 25 mg/kg/day at Day 44, and decreased eosinophils in females dosed with 25 mg/kg/day at day 45. The following minimal but statistically significant changes in hematology parameters were considered to be unrelated to treatment because they only occurred after one month of recovery: Increased neutrophils in females dosed with 100 (day 93) or 250 mg/kg/day (day 125; recovery) Increased eosinophils in females dosed with 250 mg/kg/day (day 125 recovery) Decreased APTT in males dosed with 25 or 100 mg/kg/day at day 91 was not considered adverse because decreases in coagulation times are not associated with toxicity. Red cell counts were statistically deceased at test day 91 in males dosed with 100 mg/kg/day. This change was small, was not associated with changes in other red cell mass parameters, and did not appear to follow a dose response; and thus was considered unrelated to treatment. B. Clinical Chemistry (Tables 30-31, Appendix K) There were no lexicologically significant changes in clinical chemistry parameters in rats dosed with 25,100 or 250 mg/kg/day. All statistically significant changes in clinical chemistry parameters were considered non-adverse (not lexicologically significant) or unrelated to treatment. These changes are detailed below. Alkaline phosphatase was minimally increased in male rats dosed with 100 (day 91 only) or 250 mg/kg/day (days 44 and 91). Toxicologically important increased ALKP activity generally occurs as a result ofcholestasis, but may also be due to direct enzyme induction by a xenobiotic^. In this study, there was no evidence ofcholestasis (bilirubinemia, bilurubinuria, or histologic evidence ofcholestatisis). There was histologic evidence of enzyme induction (see Anatomic Pathology report). Therefore, the ALKP changes were most likely due to direct enzyme induction and therefore were considered non-adverse. After one month of recovery, alkaline phosphatase activity in 250 mg/kg/day males was similar to control values. 51 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 Clinical Pathology Text Table 2: Alkaline phosphatase as a percent of control group mean Males 25 100 250 Day 44 Day 91 Day 125 107% 98% 116% 143% 138% 192% 95% * Statistical significance indicated by bold italicized type Cholesterol and triglycerides were mildly decreased in males dosed with 100 or 250 mg/kg/day at days 44 and 91 (variable statistical significance), m females dosed with 100 or 250 mg/kg/day, triglycerides only were decreased at days 45 and 93 (variable statistical significance). After one month of recovery, both cholesterol and triglycerides were still statistically decreased in 250 mg/kg/day males. For females, triglycerides in most rats were still minimally decreased after one month of recovery, although there was much variability among individual rats, and values from some previously treated rats were higher than any control rat. Therefore, the relevance of the effect in recovery females is equivocal. The changes in cholesterol and triglycerides were treatment-related and indicate altered lipid metabolism, but were not considered adverse because mild decreases in cholesterol and triglycerides do not have any known adverse effects. Males and females dosed with 100 or 250 mg/kg/day had alterations in serum proteins. The primary change was mildly increased total protein in rats dosed with 100 (females only) or 250 mg/kg/day (variable statistical significance). The increased total protein was generally due to increased albumin; increased albumin also occurred in males dosed with 100 mg/kg/day (day 91), but this change did not affect total protein concentration. Globulin changes were minimal and variable between sexes; at day 91, 250 mg/kg/day males had decreased globulins, while 250 mg/kg/day females had increased globulins. After one month of recovery, protein concentrations in rats previously dosed with 250 mg/kg/day were similar to control values. The increases in serum protein noted above were primarily due to increased serum albumin. Mildly increased serum albumin is not known to have any adverse consequences, so these protein changes were considered non-adverse. Increased serum albumin in females dosed with 100 or 250 mg/kg/day caused secondary hypercalcemia. Calcium exists in serum in two forms, either bound to albumin or unbound ("ionized" calcium). Ionized calcium is the physiologically active form, and is tightly regulated. Increases in albumin are necessarily associated with physiologically appropriate increased bound calcium, with resultant increased total calcium. However, ionized calcium is unaffected. Thus, increased calcium in association with increased albumin is considered physiologically appropriate and thus non-adverse. After one month of recovery, calcium concentrations in 250 mg/kg/day females were similar to control values. Inorganic phosphorus was minimally and statistically increased in females dosed with 100 or 250 mg/kg/day at day 93 only. After one month of recovery, inorganic phosphorus values in 250 mg/kg/day females were similar to control values. Increased inorganic phosphorus was not associated with other changes that would indicate toxicity (such as increased urea nitrogen or pompany Sanitized. Does not contain TSCA CBI 52 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 creatinine, or histologic changes indicative of renal damage). In addition, rats with the highest inorganic phosphorus concentration were those dosed with 100 rather than 250 mg/kg/day. Therefore, this minimal change, although possibly related to treatment, was not considered adverse. Sodium and chloride were minimally decreased in males dosed with 250 mg/kg/day at day 91. The magnitude of change in these parameters was very small, and in individual rats there was no consistent relationship between sodium and chloride concentrations. Therefore, these changes, although possibly related to treatment, were considered non-adverse. Potassium was minimally increased in females dosed with 250 mg/kg/day at days 45 and 93. The magnitude of change was small compared to the normal variability of the parameter, and was not associated with changes that might indicate toxicity. Therefore, this change was considered nonadverse. At day 125 (one-month recovery), potassium in 250 mg/kg/day females was similar to control group values. The following minimal but statistically significant changes in clinical chemistry parameters were considered to be unrelated to treatment because they did not occur in a dose-related manner. Transiently increased phosphorus in males dosed with 100 mg/kg/day at Day 44 Decreased creatinine in females dosed with 25 or 100 mg/kg/day at Day 45 (in addition, decreases in creatinine are not toxicologically significant) Increased glucose in females dosed with 25 mg/kg/day at Day 45 Decreased sodium in males dosed with 250 mg/kg/day The following minimal but statistically significant changes in clinical chemistry parameters were considered to be unrelated to treatment because they only occurred after one month of recovery Decreased SDH in males dosed with 250 mg/kg/day (in addition, decreases in SDH are not toxicologically significant) Increased urea nitrogen in males dosed with 250 mg/kg/day Decreased calcium in males dosed with 250 mg/kg/day Decreased sodium in females dosed with 250 mg/kg/day Decreased AST and ALT in females dosed with 250 mg/kg/day at day 45 were considered to be non-adverse because decreases in transaminase activity are not considered toxicologically adverse. C. Urinalysis (Tables 32-33, Appendix K) Urine volume was increased in males and females dosed with 250 mg/kg/day at days 44 (males equivocal) and 91 (variable statistical significance). Urine osmolality and specific gravity were correspondingly decreased at these same time-points with statistical significance occurring only for males at 91 days. m addition, in males dosed with 250 mg/kg/day, urine total protein was decreased at day 91. Increased urine volume and decreased urine concentration can occur due to jSompany Sanitized. Does not contain TSCA CB8 53 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 decreased renal function or secondary to increased water consumption. Effects on urine volume and concentration in the 250 mg/kg/day groups were not associated with changes in other clinical pathology parameters (creatinine, BUN, phosphorus) indicative of primary renal toxicity. Furthermore, although renal tubular hypertrophy and increased renal weights were present in male rats, there was no evidence ofcytotoxic effects in the kidney. Therefore, these urinalysis changes were considered non-adverse. At day 125 (one-month recovery), urine volume of males previously dosed with 250 mg/kg/day was decreased, compared to control and end-of-study results. Urine concentration (measured by osmolality and specific gravity) was correspondingly increased at this time-point. These changes were not considered adverse because production of low levels of concentrated urine is considered normal for rats. The urine volume and concentration of female rats after recovery were similar to controls. D. Plasma and Urine Fluoride Measurements (Tables 30-33, Appendix K) Plasma fluoride was mildly increased in males and females dosed with 100 or 250 mg/kg/day at day 91/93. At day 125 (one-month recovery), plasma fluoride in 250 mg/kg/day rats was similar to control group values. At the end of the exposure phase of the study, urine fluoride (as determined by total fluoride excreted over the collection period) was increased in a dose-related manner in males and females dosed with 25. 100, or 250 mg/kg/day (Clinical Pathology Text Table 3). At day 125 (one-month recovery), daily urine fluoride excretion was increased in males and females previously treated with 250 mg/kg/day, although levels were markedly reduced relative to those present at the end of exposure. Thus increased urine fluoride showed evidence of reversibility, albeit incomplete, following the one-month recovery period. Additional urine was collected from males and females designated for three months of recovery, to determine whether or not further recovery had occurred. For rats previously dosed with 250 mg/kg/day, urine samples collected at day 181 still contained significant amounts of fluoride, although the total fluoride was less than at day 125, In addition, urine fluoride at Day 181 was still increased over control group values for males and females previously dosed with 100 mg/kg/day (males statistically significant). Urine fluoride was also probably increased in males and possibly females dosed with 25 mg/kg/day; but the change in females was equivocal due to the low numbers of values and the variability of the data. Increases in plasma and urine fluoride were considered to be secondary to the administration of a mixture containing fluorinated compounds and/or free fluoride. The presence of fluoride in urine three months after exposure suggests that fluoride containing compounds are slowly being released from tissue sites. 54 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 Clinical Pathology Text Table 3: Daily urine fluoride (pg)* Dose (mg/kg/day) Males Day 91 Day 125 Day 181** 0 25 100 250 20.2 14.2 12.1 213.0 ND 22.8 662.7 ND 39.1 1473.6 87.4 69.1 25 100 250 1054% 3281% 7295% ND ND 615% 188% 323% 571% Females Day 93 16.7 99.2 460.3 914.7 Day 125 8.6 ND ND 43.8 Day 181** 8.8 15.9 20.0 29.3 594% 2756% 5477% ND ND 509% 181% 227% 333% ND Group not sampled at this time point. * Data presented as absolute values (left) and as percent of control group mean (right). Bold italicized font indicates that the change was statistically significant ** Data collected from rats designated for biochemical analysis E. Clinical Pathology Conclusions Under the conditions of this study, the NOEL for males and females was 100 mg/kg/day. These were based on the findings of minimal decreased red cell mass parameters in males and females dosed with 250 mg/kg/day. After one month of recovery, red cell mass parameters were still decreased in males previously dosed with 250 mg/kg/day, and some hematologic parameters were still altered in females previously dosed with 250 mg/kg/day. There were no adverse findings for coagulation, clinical chemistry, or urinalysis parameters at any dose. company SanlteeA Does not certain TSCA CBI 55 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations______________DuPont-5386 ANATOMICAL PATHOLOGY A. Subchronic Toxicity and Recovery 1. Organ Weight Data (Tables 36-37, Appendix L) Test substance-related and/or statistically significant increases, compared to controls, in liver weight parameters were present in 25,100, and 250 mg/kg/day males and females sacrificed at the end of the approximately 90-day exposure period. At the 250 mg/kg/day dose level, liver weight parameters remained increased in the one- and three-month recovery group males and females, although the magnitude of these effects was decreased relative to that observed in the 250 mg/kg/day exposure group. No statistically significant liver weight effects were present in the three-month recovery groups previously dosed with 25 or 100 mg/kg/day (organ weights were not evaluated in these groups at one-month recovery). In 100 and 250 mg/kg/day exposure group male rats and 250 mg/kg/day one- and three-month recovery male rats and in 250 mg/kg/day exposure group females, increased liver weights correlated with microscopic hepatocellular hypertrophy (see discussion under Microscopic Findings). Test substance-related and/or statistically significant increases, compared to controls, in one or more kidney weight parameters occurred in male and female rats at all exposure concentrations. Some kidney weight parameters remained increased in males and females in the 250 mg/kg/day one-month recovery groups. However, there were no statistically significant kidney weight changes in any dosed group following three months of recovery. In male rats, increased kidney weights correlated with microscopic tubular hypertrophy in the 100 and 250 mg/kg/day groups sacrificed at the end of the exposure period and in the 250 mg/kg/day group sacrificed following a one-month recovery period (see discussion under Microscopic Findings). There were no microscopic correlates to kidney weight changes in females. There were no other test substance-related organ weight effects. All other statistically significant organ weight changes in exposure and recovery groups were secondary to decreases in body weight. In 100 and 250 mg/kg/day male rats sacrificed at the end of the exposure period, organ weight changes included: decreases in absolute organ weight and/or organ weight relative to brain weight for heart and epididymides and increased brain weights relative to body weight. There were no weight changes in heart and epididymides when adjusted to final body weight. In 250 mg/kg/day males sacrificed at the end of the exposure period, testes weight relative to body weight was increased, however, absolute testes weight was not statistically different from control testes weight, hi addition, no test substance-related microscopic changes were present. In female one-month recovery rats brain and adrenal gland weights relative to body weight were increased at 250 mg/kg/day. There were no correlative effects in other weight parameters or microscopic changes in these organs. Weights for these latter organs are generally maintained despite body weight loss, and thus this pattern of organ weight change is also consistent with effects occurring secondary to decrements in body weight. 56 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 2. Gross Observations (Tables 38-39, Appendix M) Gross observations noted were sporadic across groups and were not test substance-related. 3. Microscopic Findings . (Tables 40-45, Appendix M) Test substance-related microscopic findings were present in teeth, thyroid gland, and liver from male and female rats and in kidneys from male rats. Incidences and Average Lesion Grades of Test Substance-Related Microscopic Findings In Male and Female Rats Dose: mg/kg/day Teeth: Degeneration, ameloblasts (nose) Degeneration, ameloblasts (mandible) Thyroid gland: Hypertrophy, follicular Alteration, colloid Liver: Hypertrophy, hepatocyte, centrilobular Kidneys: Hypertrophy, tubular Teeth: Degeneration, ameloblasts (nose) Thyroid gland: Alteration, colloid Liver: Hypertrophy, hepatocyte, centrilobular Kidneys: Hypertrophy, tubular Teeth: Degeneration, ameloblasts (nose) Thyroid gland: Alteration, colloid Liver: Hypertrophy, hepatocyte, centrilobular 25 Males: Exposure 0/1081 (0.0)'' 0/10 (0.0) 0/10(0.0) 0/10 (0.0) 0/10 (0.0) 9/10 (0.9) 0/10 (0.0) 9/10(1.4) 0/10 (0.0) 0/10 (0.0) 0/10 (0.0) 0/10 (0.0) Males: One-Month Recovery 0/10(0.0) NA 10/10(1.2) NA 0/10 (0.0) NA 0/10 (0.0) NA Males: Three-Month Recovery 0/5 (0.0) 0/5 (0.0) 5/5(1.6) 0/5 (0.0) 5/5 (2.6) NE 100 250 5/10(0.5) 1/9(0.1) 2/10(0.2) 9/10 (2.3) 9/10(0.9) 1/10(0.1) 11/11(2.0) 10/10(1.8) 10/11(1.5) 11/11 (2.8) 11/11(1.9) 11/11(1.7) NA 9/10(1.3) NA 10/10 (2.7) NA 10/10(1.6) NA 2/10 (0.2) 1/5 (0.2) 5/5 (4.0) 0/5 (0.0) 2/5 (0.6) 5/5 (3.2) 1/5 (0.2) 57 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations______________DuPont-5386 Dose: mg/kg/day__________________0__________25________100_______250 Females: Exposure Teeth: Degeneration, ameloblasts (nose) Degeneration, ameloblasts (mandible) 0/10(0.0) 0/10(0.0) 0/10 (0.0) 0/9 (0.0) 6/10 (0.6) 0/10 (0.0) 11/11(2.0) 7/8 (-1.4) Thyroid gland: Hypertrophy, follicular Alteration, colloid 0/10 (0.0) 0/10 (0.0) 0/10 (0.0) 6/10(0.6) 0/10 (0.0) 4/10 (0.7) 6/11(0.5) 7/11 (0.8) Liver; Hypertrophy, hepatocyte, centrilobular 0/10(0.0) 0/10 (0.0) 0/10 (0.0) 9/11(1.3) Females: One-Month Recovery Teeth: Degeneration, ameloblasts (nose) 0/10(0.0) NA NA 7/10(1.1) Thyroid gland: Alteration, colloid 5/10(0.5) NA NA 9/10(1.1) Females: Three-Month Recovery Teeth: Degeneration, ameloblasts (nose) 0/5 (0.0) NE 0/5 (0.0) 2/5 (0.4) Thyroid gland: Alteration, colloid_______ 5/5(1.2) 4/4(1.5) 4/5(1.0) 5/5 (2.2) a Numerator indicates incidence of rats with microscopic lesion. Denominator indicates number of rats in group. b Number in parentheses indicates group average severity of lesion. NA Tissue not available. NE Tissue not examined. Test substance-related tooth lesions in male and female rats administered 100 or 250 mg/kg/day consisted of degeneration and/or disorganization of enamel organ ameloblast cells. This lesion was most evident in the upper incisors of the level 1 (anterior) nose section. A similar lesion was present in cross sections ofmandibular teeth, however, the frequency of occurrence and severity were generally less than the ameloblastic degeneration/disorganization observed in the nose sections. Following a one-month recovery, ameloblastic degeneration/disorganization was still present in male and female rats previously dosed with 250 mg/kg/day; following three months of recovery this lesion was present in males previously dosed with 100 and 250 mg/kg/day and in females previously dosed with 250 mg/kg/day. This tooth lesion is consistent with fluoride toxicosis and is considered adverse. Thyroid follicular hypertrophy was present in males administered 100 and 250 mg/kg/day and females administered 250 mg/kg/day. Follicular hypertrophy was characterized by low columnar follicular epithelium with a finely granular or vacuolated cytoplasm. Hypertrophy was reversible in both male and female rats, as this change was not present in dosed rats following the one- and three-month recovery periods. Thyroid hypertrophy was minimal and unassociated with proliferative thyroid lesions. However, this hypertrophy indicates possible disruption of thyroid homeostasis and thus was considered potentially adverse. ompany Sanitized. Does not contain TSCA CBI 58 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations______________DuPont-5386 In the thyroid gland, the relative degree (and in females, the incidence) of altered colloid was increased in males and females in all dosed groups at the end of the exposure period. Following the one- and/or three-month recovery periods, severity grades for colloid clumping were increased in males at all dose levels and in females at the 250 mg/kg/day level only. The diagnosis of "alteration, colloid" was used for colloid changes characterized by stippled, granular, clumped, and/or diffusely basophilic colloid. A 4-level grading scheme was applied based on an estimate of the percentage of follicles that contained altered colloid. A grade of 1 was applied when 1 follicle to about 25% of the follicles were involved, with grades 2,3, and 4 applied for each 25% increase in follicular involvement. The size, density, or staining intensity of stipples, granules, clumps, or diffuse basophilia within individual follicles did not impact the grading. There was no consistent association between the presence or absence of altered colloid and the presence of hypertrophy of thyroid follicular cells. Altered colloid described as clumped or granular has been reported to occur spontaneously in Sprague-Dawley rats with increasing incidence correlating to increasing age/2^ Because altered colloid occurs spontaneously in healthy Sprague-Dawley rats, and since increases in its grading score did not consistently correlate with other morphologic alterations in the thyroid gland, altered colloid was interpreted as not biologically meaningful and not adverse. Hypertrophy ofcentrilobular hepatocytes was present in 100 and 250 mg/kg/day males and 250 mg/kg/day females sacrificed at the end of the exposure period. In male rats previously dosed with 250 mg/kg/day, hepatocellular hypertrophy was present, but was less severe, after a one-month recovery period and was present in only one of 5 rats sacrificed after a three-month recovery period. Microscopic hepatocellular hypertrophy was not observed in male rats in the 100 mg/kg/day three-month recovery group or in any female rat recovery group. Taken together, these findings suggest that microscopic hepatocellular hypertrophy was mostly reversible in males following three-months recovery and in females within one month of recovery. Microscopically, hepatocellular hypertrophy was characterized by an increased amount of finely granular eosinophilic cytoplasm within hepatocytes. There was no histomorphologic evidence of hepatocellular damage, and hepatic enzyme levels were not elevated (see clinical pathology section). Thus, hepatocellular hypertrophy (and the associated increase in liver weights) was considered a test substance-related physiologic response to metabolism of a xenobiotic and not toxicologically adverse/26'27'280 Renal tubular hypertrophy was present in 250 mg/kg/day male rats sacrificed at the end of the exposure period. In addition, hypertrophy was seen in one often rats in the 100 mg/kg/day male exposure group. Following the one-month recovery period, minimal hypertrophy was present in 2 of 10 male rats, but this change was not observed in rats sacrificed after the three-month recovery period. Thus, hypertrophy decreased in incidence and severity after one-month recovery and appeared to be reversible by three-months recovery. Microscopically, tubular hypertrophy was characterized by increased eosinophilic staining of cortical tubule epithelium and a slight increase in cell height. Cortical tubule epithelial cells appeared to contain more granular cytoplasmic material then cortical tubules of control rats. Tubular lumina of hypertrophied tubules were slightly smaller then those in control rat kidneys. There was no histomorphologic evidence of renal damage, and renal clinical pathology parameters were not indicative of adverse effects (see clinical pathology section). Thus, the renal tubular hypertrophy 59 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations______________DuPont-5386 (and the associated increase in kidney weights) was considered a test substance-related physiologic response to a xenobiotic and not toxicologically adverse/250 Renal tubular hypertrophy was not observed in female rats at any dose level. All other microscopic observations noted are known to occur spontaneously in rats of this strain and age and were not present in a dose response fashion in either incidence or severity. 4. Cause of Death There were no test substance-related deaths. One 25 mg/kg/day female rat (Animal No. 643411) was accidentally killed during blood collection. One male rat in the 100 mg/kg/day group (Animal No. 643175) and one male rat and one female rat in the 250 mg/kg/day groups (Animal Nos. 643309 and 643368, respectively) died from dosing injuries. Two female rats in the control (Animal No. 643336) and 25 mg/kg/day (Animal No. 643321) groups died from urogenital inflammation/obstruction/calculi complications. A cause of death was not determined for a 250 mg/kg/day female subchronic toxicity rat (Animal No. 643340) that was found dead on test day 69. 5. Anatomical Pathology Conclusions for Subchronic Toxicity Evaluation Exposure to 100 or 250 mg/kg/day of the test substance for approximately 90 days produced degeneration/disorganization of enamel organ ameloblast cells in male and female rats. Ameloblastic degeneration/disorganization was not reversible after three-months recovery in 100 mg/kg/day males and in 250 mg/kg/day males and females. Thyroid gland hypertrophy observed in 100 and 250 mg/kg/day males and in 250 mg/kg/day females was reversible at one month and was considered to be potentially adverse. The severity of altered colloid in thyroid glands increased beyond control level as the dose increased, however, it was not consistently associated with any other morphologic alteration and was not considered biologically adverse. Increased liver weights were present in males and females at 25, 100, and 250 mg/kg/day. The increased liver weights correlated with microscopic centrilobular hepatocellular hypertrophy in males at 100 and 250 mg/kg/day and in females at 250 mg/kg/day groups. Hepatocellular hypertrophy was mostly reversible in males following three-months recovery and in females within one month of recovery. Increased kidney weights were present in 25,100 and 250 mg/kg/day males and females. In males, these kidney weight changes correlated with microscopic renal tubular hypertrophy. The increased kidney weights and male renal tubular hypertrophy appeared to be reversible by three months of recovery. These liver and kidney changes were considered to represent physiologic responses to administration of a xenobiotic and thus were not considered to be toxicologically significant. Under the conditions of this study, the NOEL for pathology for male and female rats was 25 mg/kg/day based on tooth lesions at the 100 and 250 mg/kg/day dose levels. (Company Sanded. Does not contain TSCA CB8 60 REPRODUCTIVE TOXICOLOGY EVALUATIONS REPRODUCTIVE FUNCTION A. Pi Generation 1. Mean Body Weights and Body Weight Gains (Table 44-46, Appendices 0-T) There was a statistically significant reduction (89-91% of control mean) in body weight in Pi male rats at 250 mg/kg/day during and after the cohabitation period. Although this finding was test substance-related, it was not considered toxicologically significant since there was no concomitant reduction in body weight gain in Pi males during that period. There were no test substance-related effects on body weight or body weight gain in Pi female rats during gestation or lactation. 2. Food Consumption and Food Efficiency During Gestation (Table 47, Appendix U) There were no test substance-related effects on food consumption and food efficiency in Pi female rats during gestation. 3. Clinical Observations (Tables 48, Appendices V-X) There were no toxicologically significant clinical observations in male and female rats at any dose level. There was an increase in tooth clipping required in male rats administered 250 mg/kg/day. Two females in the 250 mg/kg/day dose group also required teeth clipping (Animal No. 643429 on Day OG and 643417 on Lactation Day 7). One Pi female rat (Animal No. 643429) in the 250 mg/kg/day group and her 16 pups were found dead on Lactation Day 0. Prior to death this animal exhibited weakness, diarrhea, wet underbody, facial staining on Gestation Day 21; this animal also had teeth clipped on Gestation Day 0. The cause of death was determined to be dystocia and was not considered test substance-related due to the single occurrence of this finding and the occasional occurrence of this condition in control animals of the strain of rat used in this study. One Pi female rat (Animal No. 643454) in the 100 mg/kg/day group died on gestation day 22. The cause of death was undetermined but was not considered test substance-related due to the absence of signs oftoxicity or gross lesions in this animal. 4. Reproductive Indices (Tables 49-51, Appendices Y-EE) There were no test substance-related effects on estrous cycle parameters, sperm morphology, motility, or epididymal sperm counts in the P] generation. At 100 and 250 mg/kg/day, there was a statistically significant increase in testicular spermatid numbers (123% and 113% of control, respectively) in Pi male rats. This finding was not considered test substance-related since the 61 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 means for these groups were within the historical control range for previous studies and the increase appeared to be due to a slightly lower than usual mean in the control group. There were no test substance-related effects on mating or fertility indices, gestation length or number of implantation sites. Implantation efficiency (number of pups bom - uterine implantation sites x 100) was significantly reduced at 100 and 250 mg/kg/day (83.4% and 84.5%, respectively, compared to 96.6% in the control group), and reflects the reduction in the number of pups bom (see section B.I.). B. Offspring Data 1. Litter Size, and Pup Weights, Clinical Observations, and Survival (Table 52-54; Appendix FF-HH) At 250 mg/kg/day, there were statistically significant reductions in the number of pups bom, the number of pups bom alive and the number of pups alive on day 4 of lactation (85%, 83% and 81% of control mean, respectively). At 100 mg/kg/day, reductions of similar magnitude as in the 250 mg/kg/day group were observed for the number of pups bom and bom alive (84% and 77% of control, respectively). Although not statistically significant these changes were considered test substance-related, as was the significant reduction in the number of pups alive on Day 4 of lactation (68% of control) at 100 mg/kg/day. There were no significant reductions in gestation index, mean % bom alive, 0-4 day viability, ^\ lactation index or litter survival. At 250 mg/kg/day, there were statistically significant'reductions in pup weights on lactation days 4, 7, 14, and 21 (89%, 85%, 78%, and 75% of control mean, respectively). There were no test substance-related clinical signs in pups during lactation at any dose level. C. FI Generation Mean Body Weights and Body Weight Gains (Table 55-56, Appendices II-JJ) On the day of weaning (Lactation Day 21 = test day 1) mean body weights were significantly lower than control (74%-78% of control mean) in both Fi males and females at 250 mg/kg/day. Subsequently, weekly mean body weights in Fi males were significantly lower than control throughout the post-weaning period (81%-93% of control) in this group. For Fi females weekly mean body weights were significantly lower than control for test days 8 and 15 (85%-92% of control) and were similar to control thereafter. Thus mean body weights in these groups progressively returned to control values during the post-weaning period. Because the lower body weights in the Fi generation at 250 mg/kg/day appeared to be due to a test substance-related effect on pup weight during the lactation period (see section B.I.) and there was no concomitant reduction in body weight gain in Fi males or females during the post-weaning period these al| findings were not considered toxicologically significant. Company Sanded. Does not corta-m ,,T<S,,,C<A& /C-iBni r ___________________62 __________________ H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations______________DuPont-5386 1. Clinical Observations (Tables 57, Appendices LL) There were no test substance-related clinical signs during the post-weaning period. 2. Developmental Landmarks (Tables 58, Appendices LL) The age at onset of vaginal opening in Fi female rats was similar across groups. The age at onset ofpreputial separation in Fi male rats was similar across groups. D. Reproductive Function Conclusions For the reproductive toxicity parameters evaluated under the condition of this study, the NOEL was 25 mg/kg/day. 63 REPRODUCTIVE TOXICOLOGY EVALUATIONS ANATOMICAL PATHOLOGY A. Organ Weight Data Parental Pi Adults and Fi Adults (Tables 59-62; Appendix MM) There was a statistically significant increase in thyroid gland weight relative to body weight in Pi males at 250 mg/kg/day, however, thyroid absolute weight was not significantly different from thyroid control weights. The increased thyroid weight was secondary to decreased final body weight in the 250 mg/kg/day Pi males. m Fi males at 250 mg/kg/day there were statistically significant decreases in liver and testes absolute weights and in epididymide absolute and relative to brain weights. There were no weight changes in these organs when adjusted to final body weight. These statistically significant organ weight changes were secondary to decreased final body weight in the 250 mg/kg/day Fi males. hi Fi females there were statistically significant increases in liver weight relative to final body weight and relative to brain weight at 250 mg/kg/day and in kidney weight relative to brain weight at 100 and 250 mg/kg/day dose levels. Neither liver nor kidney absolute weights were statistically different from control weights. The kidney to brain weight changes were not dose dependent. None of the organ weight changes were considered to be lexicologically or biologically adverse. B. Gross Observations Parental Pi Adults (Tables 63-64, Appendix NN) Fi Adults and Weanlings (Tables 65-71, Appendix 00-QQ) There were no test substance-related gross observations. Observations occurred in low incidences and were randomly distributed across control and treatment groups. C. Microscopic Observations Parental P] Adults (Tables 72-73, Appendix NN) There were no test substance-related microscopic findings. Lesions occurred in low incidences without a relevant dose-response relationship and were considered incidental occurrences of spontaneous lesions in rats of this strain and age. company Sanitized. Does not contain TSGA CBi 64 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations______________DuPont-5386 D. Mortality Parental P[ Adults and Fi Adults (Appendices NN and QQ) There were no test substance-related effects on mortality. Two Pi female rats were found dead. Cause of death appeared to be dystocia for rat Animal No. 643429 (250 mg/kg/day) and was undetermined for rat Animal No. 643454 (100 mg/kg/day). One 250 mg/kg/day Pi female rat (Animal No. 643346) was sacrificed in extremis after sustaining an injury in its cage; the fate of this animal is reported as accidentally killed. E. Anatomical Pathology Conclusions for Reproductive Toxicity For pathology, the NOEL was 250 mg/kg/day (the highest dose level) for both male and female rats. 65 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_________ BIOCHEMICAL MEASUREMENTS DuPont-5386 A. Biochemical Measurements (Table 74-75, Appendix L) The rate of hepatic P-oxidation, a measure ofperoxisome proliferation, was determined in a subchronic oral toxicity study with H-24516 in rats following 10 or 90 (males) and 92 (females) days of test substance administration or following a one- or three-month recovery period. Dose-dependent increases in the rate of hepatic p-oxidation were observed at the 10-day time point with statistical significance occurring for rats administered 100 or 250 mg/kg/day (223 and 349% of control, respectively, in the males and 170 and 260% of control, respectively, in the females). Dose-dependent increases in the rate of hepatic p-oxidation were also observed at the 90-day time point with statistical significance occurring for rats administered 100 or 250 mg/kg/day (398 and 856% of control, respectively, in the males and 345 and 381% of control, respectively, in the females). At both time points, the increases in hepatic p-oxidation activity were accompanied by increases in liver weights. Following a one-month recovery period, statistically significant increases in the rate of hepatic p-oxidation persisted in rats administered 250 mg/kg/day (353 and 207% of control, respectively, in males and females). Statistically significant increases in the rate of hepatic P-oxidation also persisted after the three-month recovery period for the 250 mg/kg/day dose group (302 and 172% of control, respectively, in males and females). At the one-month recovery time point, the increase in hepatic p-oxidation activity was accompanied by increased liver weights in the males, but not the females. B. Biochemical Measurements Conclusions Under the conditions of this study, H-24516 is an inducer of hepatic peroxisomal P-oxidation. At dosages of 100 mg/kg/day and greater, changes in the rate of hepatic peroxisome proliferation were considered to be biologically significant effects. After three months of recovery, the rate of hepatic peroxisome proliferation was still increased in rats administered 250 mg/kg/day. company Sanitized. Doss mi contain TSCA CB1 66 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations______________DuPont-5386 CONCLUSIONS No test substance-related mortality or alterations in neurobehavioral parameters were observed in male or female rats. Test substance-related and toxicologically significant decrements in mean body weight, body weight gain, and food efficiency were observed in male rats administered 100 and 250 mg/kg/day compared to controls. Food consumption was also significantly lower in male rats administered 250 mg/kg/day. After a one- and/or three-month recovery period, these parameters were similar to or exceeded control. Test substance-related, toxicologically significant increases in the incidence of broken (males) and absent teeth (males and females) occurred in the 250 mg/kg/day dose group. Statistically significant decrements in mean body weight parameters and food consumption occurred for females administered 100 or 250 mg/kg/day. The decrements in female body weight parameters were not considered to be toxicologically significant. Furthermore, the decrements in body weight parameters appear to be related to test substance-induced adverse effects to the teeth and decreased ability of the animals to eat pelleted chow. Toxicologically adverse findings of minimally decreased red cell mass parameters (RBC, hemoglobin, and hematocrit), along with correlative changes in other hematology parameters and in red cell morphology were observed after the 90-day exposure period in males and females administered 250 mg/kg/day H-24516. After a one-month recovery period, the 250 mg/kg/day male dose group still had minimally to mild decreased red cell mass parameters as well as decreased reticulocytes compared to control. Red cell mass parameters for the 250 mg/kg/day female group returned to control levels, however, some hematological parameters (MCV, MCH, RDW, and reticulocytes) were still decreased. A statistically significant rate of hepatic (3-oxidation occurred in males and females administered 100 or 250 mg/kg/day H-24516. The increased rate persisted in the 250 mg/kg/day groups after one and three months. Test substance related, toxicologically significant degeneration/disorganization of enamel organ ameloblasts cells occurred in male and female rats dosed with 100 or 250 mg/kg/day H-24516. This tooth lesion is consistent with fluoride toxicosis/2^ After three months, the degeneration/disorganization of ameloblasts persisted, at a lower incidence and severity. Test substance related, potentially adverse increases in thyroid hypertrophy were observed in the 100 and 250 mg/kg/day male and 250 mg/kg/day female dose groups after the 90-day exposure period. After the one-month recovery period, thyroid hypertrophy was not observed in any dose group. Increased liver weights and/or hepatocellular hypertrophy were observed in male and female rats at all dose levels. Similarly, increased kidney weights and/or renal tubular hypertrophy were observed in male and female rats at all dose levels. These latter changes were considered to be a pharmacologically adaptive, non-adverse response. After the three-month recovery period, liver weights remained increased in the 250 mg/kg/day male and female groups, while hepatocellular 67 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations______________DuPont-5386 hypertrophy was observed only in the 250 mg/kg/day male group (1 of 5 rats). Alterations in kidneys were not observed at any dose level after the three-month recovery period. There were no toxicologically significant pathology findings in the Pi and Fi generation rats. A statistically significant increase in testicular spermatid numbers in Pi male rats was not considered test substance-related. Implantation efficiency was significantly reduced at 100 and 250 mg/kg/day and reflects the reduction in the number of pups bom. There were statistically significant reductions in the number of pups bom, the number of pups bom alive and the number of pups alive on day 4 of lactation in the 250 mg/kg/day group. Reductions of similar magnitude were also observed for the number of pups bom and bom alive in the 100 mg/kg/day group. Although not statistically significant, these changes were considered test substance-related and toxicologically significant, as was the significant reduction in the number of pups alive on day 4 of lactation in the 100 mg/kg/day group. There were statistically significant reductions in pup weights on lactation days 4,7, 14 and 21 in the 250 mg/kg/day groups. On the day of weaning mean body weights were significantly lower than control in both Fi males and females in the 250 mg/kg/day group. Fi generation body weights at 250 mg/kg/day progressively returned to control values during the post-weaning period indicating that the test substance-related effect on pup weight during the lactation period was reversed following cessation of exposure and therefore, were not considered toxicologically significant. The no-observed-effect level (NOEL)'1 for H-24516 for the 90-day exposure period was 25 mg/kg/day based on adverse decrements in body weight parameters and food efficiency, increased hepatic peroxisomal p-oxidation, and the degeneration and/or disorganization of enamel organ ameloblast cells in males administered 100 mg/kg/day. The NOEL for females was 25 mg/kg/day H-24516 based on increased hepatic peroxisomal p-oxidation and the degeneration and/or disorganization of enamel organ ameloblast cells in females administered 100 mg/kg/day. The NOEL for reproductive evaluations was 25 mg/kg/day based on decreases in the number of pups bom, bom alive, and the number of pups alive on day 4 of lactation at the 100 mg/kg/day dose level. The NOEL for this study is defined as the highest dose at which toxicologically important effects attributable to the test substance were not detected. Thus, for this study, the NOEL is equivalent to the NOEL as defined by the United States Environmental Protection Agency(30)and to the no-observed-adverse-effect level (NOAEL) as defined by the European Union(31). .Company SanBlzed. Does not- contai. n ,T--S.C,.A.. C..B.-8, 68 REFERENCES 1. DuPont(1995). Neurotoxicity Evaluation of Trimethyltin in Rats (Positive Control Study). 2. DuPont (1997). Neurotoxicity Evaluation of Amphetamine in Rats (Positive Control Study). 3. DuPont (1997). Neurotoxicity Evaluation ofCarbaryl in Rats (Positive Control Study). 4. DuPont (1996). Neurotoxicity Evaluation ofAcrylamide in Rats (Positive Control Study). 5. Lazarow, P.B. (1981). Assay ofPeroxisomal Beta-Oxidation of Fatty Acids. Methods in Enzymology 72, 315-319. 6. Bradford, M.M. (1976). A Rapid and Sensitive Method for the Quantitation ofMicrogram Quantities of Protein Utilizing the Principle of Protein-Dye Binding. Anal. Biochem. 72, 248-254. 7. Dunnett, C.W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Amer. Statist. Assoc. 50, 1096-1121.- 8. Dunn, O.J. (1964). Multiple contrasts using rank sums. Technometrics 6, 241-252. 9. Draper, N.R. and Smith, H. (1981). Applied Regression Analysis, 2nd edition, pp 266-273. Wiley, New York. 10. Selwyn, M.R. (1995). The use of trend tests to determine a no-observable-effect level in animal safety studies. Journal of the American College of Toxicology 14(2), 158-168. 11. Jonckheere, A.R. (1954). A distribution-free K-sample test against ordered alternatives. Biometrika 41, 133-145. 12. Levene, H. (1960). Robust test for equality of variances. Contributions to Probability and Statistics (J. Oikin, ed.), pp 278-292. Stanford University Press, Palo Alto. 13. Shapiro, S.S. and Wilk., M.B. (1965). An analysis of variance test for normality (complete samples). Biometrika 52, 591 -611. 14. Snedecor, G.W. and Cochran, W.G. (1967). Statistical Methods, 6th edition, pp 246-248 and 349-352. The Iowa State University Press, Ames. 15. Kruskal, W.H. and Wallis, W.A. (1952). J. Amer. Statist. Assoc. 47, 583-621. Use of ranks in one-criterion analysis of variance. "^ eenaain TS 69 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations______________DuPont-5386 16.Milliken,G.A.andJohnson,D.A.(1984). Analysis of Messy Data, Volume 1.: Designed Experiments. Lifetime Learning Publications, Belmont. 17. Hocking, R.A. (1985). The Analysis of Linear Models. Brooks/Cole, Monterey. 18. Bartlett; M.S. (1937). Some examples of statistical methods of research in agriculture and applied biology. J. Royal. Statis. Soc. Suppl. 4, 137-170. 19. Fisher, R.A. (1985). Statistical Methods for Research Workers, 13th edition. Hafiher, New York. 20. Dempster, A.P., Selwyn, M.R., Patel, C.M., and Roth, A.J. (1984). Statistical and computational aspects of mixed model analysis. The Journal of the Royal Statistical Society, Series C (Applied Statistics) 33(2), 203-214. 21. Haseman, J.K. and Hogan, M.D. (1975). Selection of the experimental unit in teratology studies. Teratology, 12, 165-171. 22. Patefield, W. (1982). Exact tests for trends in ordered contingency tables. Applied Statistics 31,32-43. 23. Hoffinan, W.E. and Solter, P.F. (1999). Clinical Enzymology. The Clinical Chemistry of Laboratory Animals (W.F. Loeb and F.W. Quimby, eds.), Taylor and Francis, Philadelphia, PA. pp399-454. 24. Reddy, C.S., and Hayes, A.W. (1089). Food Borne Toxicants. In Principles and Methods of Toxicology (A. W. Hayes, Ed.), Raven Press, New York, pp67-l 10. 25. Rao-Rupanagudi, S., Heywood, R., and Gopinah, C. (1991). "Age-related Changes in Thyroid Structures and Function in Sprague-Dawley Rats," Vet. Pathol., Vol. 29, No. 4, pp. 278-287. 26. Sipes, G. I., and Gandolfi, A. J. (1991). In Biotransformation of Toxicants, m Casearett and Doull's Toxicology: The Basic Science of Poisons (Amdur, M. 0., Doull, J., and Klaassen, C. D., Ed.), Pergamon Press, New York, pp 88-126. 27. Paynter, O.E., Harris, J.E., Burin, G.J., and Jaeger, R.B. (1985). Guidance for Analysis of Evaluation of Subchronic Exposure Studies. United States Environmental Protection Agency, EPA-540/9-85-020. 28. Greaves, P. (1990). Digestive System 2. m Histopathology ofPreclinical Toxicity Studies: Interpretation and Relevance in Drug Safety Evaluation (P. Greaves, Ed.), Elsvier, Amsterdam, pp 393-496. 29. Greaves, P. (1990). Urinary Tract. In Histopathology ofPreclinical Toxicity Studies: Interpretation and Relevance in Drug Safety Evaluation (P. Greaves, Ed.), Elsvier, Amsterdam, pp 497-583. gompany Sanitized. Does not contain TSCA CM 70 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 30. Hazard Evaluation Division, Standard Evaluation Procedure, Toxicity Potential: Guidance for Analysis and Evaluation of Subchronic and Chronic Exposure Studies Paynter, 0. E. et al.. United States Environmental Protection Agency, Office of Pesticide Programs, Washington, D.C., 20406. EPA-540/9-85-020. (June 1985). 31. Risk Assessment of Notified New Substances. Technical Guidance Document (XI/283/94EN), Chapter I, Sections 2.24 and 2.25. 1994. 71 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLES ^p^^itS.ed.Doe.n.t^^^^" 72 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLES EXPLANATORY NOTES Critical Dates DuPont-5386 Day 74 Male and female rats designated for reproduction evaluations were cohoused. Body weights and clinical observations collected during the cohabitation and post-mating periods are reported in the Reproductive Toxicology section; Dose volumes administered during the cohabitation and post-mating periods are documented in study records. Days 83-89 Rats designated for the 3-month recovery period were temporarily housed in metabolism cages for urine and feces collection. Food consumption data was not collected for these animals during this period. Day 89 Day 90 Day 91 Last day of test substance administration for male and female rats designated for one-month and 3-month recovery periods. Last day of test substance administration for male rats designated for the 90-day exposure period. Last day of non-fasted body weight and food consumption data collection for male rats designated for the 90-day exposure period. Last day of non-fasted body weight and food consumption data collection for female rats designated for the 90-day exposure period. Male rats designated for the 90-day exposure period were sacrificed. Day 92 Last day of test substance administration for female rats designated for the 90-day exposure period. Day 93 Female rats designated for 90-day exposure period were sacrificed. Day 119 Last day of non-fasted body weight and food consumption data collection for rats designated for the one-month recovery period. Day 125 Male and female rats designated for the one-month recovery were sacrificed. Day 175 Last day of non-fasted body weight and food consumption data collection for rats designated for the 3-month recovery period. Day 181 Male and female rats designated for the 3-month recovery period were sacrificed. Note On test day 18, all male rats and the first 11 female rats in the 25 mg/kg/day group received 38 mg/kg/day. 73 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLES ABBREVIATIONS: EXPLANATORY NOTES Summary ofHematology Values RBC - red blood cell count HGB - hemoglobin HCT - hematocrit MCV - mean corpuscular volume MCH - mean corpuscular hemoglobin MCHC - mean corpuscular hemoglobin concentration RDW - red cell distribution width ARET - absolute reticulocyte count WBC - white blood cell count ANEU - absolute neutrophil (all forms) ANPR - absolute neutrophil precursor ALYM - absolute lymphocyte AMON - absolute monocyte AEOS - absolute eosinophil ABAS - absolute basophil ALUC - absolute large unstained cell ABLT - absolute blast leukocyte AMSC - absolute miscellaneous leukocyte PLT - platelet count Summary of Coagulation Values PT - prothrombin time APTT - activated partial thromboplastin time DuPont-5386 Swarms Sanitized. Does not contain TSCA CB8 74 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLES DuPont-5386 ABBREVIATIONS: EXPLANATORY NOTES Summary of Serum and Plasma Chemistry Values AST - aspartate aminotransferase ALT - alanine aminotransferase SDH - sorbitol dehydrogenase ALKP - alkaline phosphatase BBLI - total bilirubin BUN CREA - urea nitrogen creatinine CHOL - cholesterol TRIG - triglycerides GLUC - glucose TP - total protein ALB - albumin GLOB - globulin CALC - calcium IPHS - inorganic phosphorous NA - sodium K - potassium CL - chloride PFLU - plasma fluoride Summary of Urinalysis Values VOL - volume UOSM - urine osmolality SG - specific gravity pH URO - the logarithm of the reciprocal of the hydrogen ion concentration urobilinogen UFLU - urine fluoride UMTP - urine protein Notes for Clinical Pathology data: When an individual observation was recorded as being less than a certain value, calculations were performed on half the recorded value. For example, ifbilirubin was reported as <0.1, 0.05 was used for any calculations performed with that bilirubin data. 75 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations______________DuPont-5386 TABLE 1 SUMMARY OF DOSING ANALYSES Nominal: Homogeneity Samples Test Day 0 Top Middle Bottom Average Measured Cone.1' Average Percent Nominal Standard Deviation b Coefficient of Variation'' Dosing Concentration of H-24516 (mg/mL) 15 25.0 2.30 (92.0) a 2.47 (98.8) 2.40 (96.0) 2.39 (95.6) 0.08 3% 8.97 (89.7) 10.2 (102.0) 14.0 (140.0) 11.1 (111.0) 2.6 24% 26.8 (107.2) 24.8 (99.2) 23.5 (94.0) 25.0 (100.0) 1.6 7% Stability Samples 5 Hour Room Temperature Homogeneity Samples Test Day 6 Top Middle Bottom Average Measured Cone.b Average Percent Nominal Standard Deviation b Coefficient of Variation b 2.06 (82.4) 8.89 (88.9) 9.26 (92.6) 9.58 (95.8) 9.23 (92.3) 9.36 (93.6) 0.19 2% 24.1 (96.4) Stability Samples 5 Hour Room Temperature 9.03 (90.3) Numbers in parentheses are the respective percent of nominal values. Statistics based on the average measured concentration (ppm) of the top, middle and bottom of each dosing level. Samples not required for study. IBempany SanKlzed, Does not contain TSCA CBI 76 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 1 (CONTINUED) SUMMARY OF DOSING ANALYSES _______Dosing Concentration of H-24516 (mg/mL)_______ Nominal: 3.33 13.33 33.33 Homogeneity Samples Test Day 49 Top 2.71 10.8 31.0 (81.4)8 (81.0) (92.9) Middle 2.99 (89.8) 12.7 (95.3) 32.4 (97.1) Bottom Average Measured Cone.b Average Percent Nominal Standard Deviation1> Coefficient of Variation" 3.42 (102.8) 3.04 (91.3) 0.4 12% 12.8 (96.3) 12.1 (90.8) 1.1 9% 33.4 (100.3) 32.3 (96.8) 1.2 4% Test Day 91 Top 3.05 (91.6) 12.8 (96.0) 32.7 (98.1) Middle 3.00 (90.1) 12.2 (91.5) 32.3 (96.6) Bottom 3.01 (90.4) Average Measured Cone.b 3.02 12.5 32.5 Average Percent Nominal (90.7) (90.8) (97.5) Standard Deviationb 0.03 0.4 0.3 Coefficient of Variation " Numbers in parentheses arebth_e r_es_pe_ct_iv_e p1er%cen_t _of_no_m_in_al_va_lu_es_. 3%__________1%_____ b Statistics based on the average measured concentration (ppm) of the top, middle and bottom of each dosing level for homogeneity samples or the average of duplicate sample for concentration verification samples (13.33 mg/mL and 33.33 mg/mL submitted test day 91). c Samples not required for study. 77 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 1 (CONTINUED) SUMMARY OF DOSING ANALYSES Stability Study _______Dosing Concentration of H-24516 (mg/mL) Nominal: 3.33s 5,0b 20.0 ' Homogeneity Samples 500" Top Middle Bottom Average Measured Cone. d Average Percent Nominal Standard Deviationd Coefficient of Variation d Stability Samples 2.88 (86.5)c 2.54 (76.3) 2.67 (80.2) 2.70 (81.1) 0.2 6% 4.53 (90.6) 4.25 (85.0) 4.39 (87.8) 4.39 (87.8) 0.14 3% 19.9 (99.5) 17.7 (88.5) 18.6 (93.0) 18.7 (93.5) 1.1 6% 53.4 (106.8) 52.6 (105.2) 54.0 (108.0) 53.3 (106.6) 0.7 1% 0-Day Room Temperature' 2.70 (81.1) 4.39 (87.8) 18.7 (93.5) 53.4 (106.8) 5 Hour Room Temperature 2.66 (79.9) 4.60 (92.0) 17.2 (86.0) 48.3 (96.6) 2-Day Refrigerated 3-Day Refrigerated f 4.77 18.3 47.9 (95.4) (91.5) (95.8) r 4.61 29.4 46.7 (92.2) (147.0) (93.4) 4-Day Refrigerated 2.91 (87.4) 4.81 (96.1) 19.6 (97.8) 48.9 (97.8) 4-Day Refrigerated/5 hr. 2.74 4.85 17.6 47.9 (82.3) (97.1) (88.2) (95.7) Samples prepared based on 7.5 mL/Kg dose volume. '' Samples prepared based on 5.0 mL/Kg dose volume. c Numbers in parentheses are the respective percent of nominal values. d Statistics based on the average measured concentration (ppm) of the top middle and bottom of each dosing level. e The mean measured values from analysis of homogeneity samples (considered fresh/0-day room temperature samples) were used as baselines for comparison with the respective stability samples. r Samples not required for study. am TCA '! 78 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 -LM (LE2 M LEA:N]DAELYDC)SEV01AJMES(mL)FOR MALERA TS DAY 0 -DAY 6 DAY 7 -DAY 13 DAY 14 -DAY 20 DAY 21 -DAY 27 DAY 28 -DAY 34 DAY 35 -DAY 41 DAY 42 -DAY 48 DAY 49 -DAY 55 DAY 56 -DAY 62 DAY 63 -DAY 69 DAY 70 -DAY 76 DAY 7-7 -DAY 83 DAY 84 -DAY 89 DAY 90 G roiup 3 0 m<3/k?/day 2 .5 0 .2 (45 ) 3 .1 0 .2 (45 ) 3 .6 0 .3 (45 ) 4 .0 0 .3 (45 ) 4 .3 0 .4 (45 ) 4 .6 0 .4 (45 ) 3 .6 0 .3 (45 ) 3 .8 0 .3 (45 ) 3 .9 0 .4 (45 ) 4 .0 0 .4 (45 ) 4 .1 0 .4 (45 ) 4 .2 0 .5 (25 ) 4 .3 0 .5 (25 ) 4 .5 0 .4 (10 ) III G ro up 2 5 1mg/kg/dtiy 2 .5 0 .2 (35 ) 3 .0 0 .2 (35 ) 3 .6 0 .3 (35 ) 3 .9 0 .3 (35 ) 4 .3 0 .4 (35 ) 4 .6 0 .4 (35 ) 3 .6 0 .3 (35 ) 3 .7 0 .3 (35 ) 3 .8 0 .4 (35 ) 3 .9 0 .4 (35 ) 4 .0 0 .4 (35 ) 4 .1 0 .4 (15 ) 4 .2 0 .4 (15 ) 4 .3 0 .5 (10 ) G:roiap v 1'00 mg/kg/da-y 2 .5 0 .2 (35 ) 3 .1 0 .2 (35 5 3 .6 0 .3 (35 ) 4 .0 0 .3 (35 ) 4 .3 0 .3 (35 ) 4 .6 0 .3 (35 ) 3 .6 0 .3 (35 ) 3 .7 0 -3 (35 ) 3 .8 0 .3 (35 ) 4 .0 0 .3 (35 ) 4 .0 0 .3 (35 ) 3 .9 0 .3 (14 ) 3 .9 0 .3 (14 ) 4 .0 0 .2 (9) Group \ ai 250 mg/'kg/day 2.5 0.2(45 ) 3.1 0.2(45 ) 3.6 0.3 (45 ) 4.0 0.3(45 ) 4.3 0.4 (45 ) 4.6 0.4(45 ) 3.6 0.3 (45 ) 3.6 0.3 (45 ) 3.6 0.3(45 ) 3.7 0.4 (45 ) 3.6 0.4 (45 ) 3.6 0.4(26 ) 3 .8 0.4(25 ) 4.0 0.3(10 ) Data summarized as: Mean Standard Deviation (n) CQmpsmySamWssed. Does not contain T8CA CBI 79 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 3 MEAN DAILY DOSE VOLUMES (mL) FOR FEMALE RATS I I G r o u p 0 mg/kg/day Group IV 25 mg/kg/day DAY 0 - DAY 6 1.9 0.2(45 ) 1.9 0.2(35 ) DAY 7 - DAY 132.01.2(45 ) 2.2 0.2(34 ) DAY 14 - DAY 20 2.3 0.2(45 ) 2.3 0.2(34 ) DAY 21 - DAY 27 2.5 0.2(45 ) 2.6 0.2(34 ) DAY 28 - DAY 34 2.6 0.2(45 ) 2.7 0.2(34 ) DAY 3 5 - DAY 4120.8.3(45 ) 2.8 0.2(33 ) DAY 42 - DAY 482.1 0.2(45 ) 2.2 0.2(33 ) DAY 49 - DAY 55 2.2 0.2(45 ) 2.2 0.2(33 ) DAY 56 - DAY 62 2.3 0.2(45 ) 2.3 0.2(33 ) DAY 63 -DAY 69 2.3 0.2(45 ) 2.3 0.2(33 ) DAY 70 - DAY 76 2.3 0.2(45 ) 2.4 0.2(33 ) DAY 77 - DAY 83 2.3 0.3(25 ) 2.3 0.2(13 ) DAY 84 - DAY 90 2.4 0.3(25 ) 2.3 0.2(13 ) DAY 90 - DAY 92 2.3 0.3(10 ) 2.4 0.2(9) Data summarized as: Mean Standard Deviation (n) Group VI 100 mg/kg/day 1.9 0.1(35 ) 2.1 0.2(35' ) 2.3 0.2(35 ) 2.5 0.2(35 ) 2.6 0.2(35 ) 2.7 0.2(35 ) 2.1 0.2(35 ) 2.1 0.2(35 ) 2.2 0.2(35 ) 2.2 0.2(35 ) 2.2 0.2(35 ) 2.2 0.2(15 ) 2.2 0.2(15 ) 2.2 0.2(10 ) Group VIII 250 mg/kg/day 1.9 0.2(45 ) 2.2 0.2(45 ) 2.4 0.2(45 ) 2.5 0.2(45 ) 2.6 0.2(45 ) 2.8 0.2(45 ) 2.1 0.2(45 ) 2.1 0.2(45 ) 2.1 0.2(44 ) 2.1 0.2(44 ) 2.1 0.2(43 ) 2.1 0.2(24 ) 2.2 0.2(24 ) 2.2 0.2(9__) 80 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations__________ DuPont-5386 TABLE 4 MEAN BODY WEIGHTS (g) OF MALE RATS Group I 0 nig/kg/day III Group 25 mg/kg/day Group V Group VII 100 mg/kg/day 250 mg/kg/day Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 DAY 7 DAY 14 DAY 21 DAY 28 DAY 35 DAY 42 DAY 49 DAY 56 DAY 63 DAY 70 DAY 74'1 250. 1 18. 5(45 ) 305. 6 23 . 2(45 ) 356. 2 29. 2(45 ) 398. 3 33 . 7(45 ) 431. 2 38. 7(45 ) 457. 5 41. 8(45 ) 483. 1 44. 2(45 ) 501. 5 45. 8(45 ) 519. 4 50. 4(45 ) 535. 4 53. 5(45 ) 551. 1 56. 7(45 ) 558. 1 60. 8 (20 ) 247 .7 20 .0(35 ) 304 .3 24 .2(35 ) 356 .6 28 .5(35 ) 392 .8 32 .2(35 ) 428 .1 35 .0(35 ) 458 .6 39 .4(35 ) 477 .1 40 .6(35 ) 490 .8 43 .2 (35 ) 507 .0 50 .1(35 ) 523 .6 51 .9(35 ) 538 .6 52 .9 (35 ) 548 .3 53 .8(20 ) 250.4 18.0(35 ) 307.8 21.8(35 ) 357.1 26.3(35 ) 398.8 28.3(35 ) 431.1 30.9(35 ) 455.1 34.3(35 ) 476.2 36.0(35 ) 493.1 37.5(35 ) 508.1 39.8(35 ) 525.3 40.5(35 ) 537.0 44.8(35 ) 558.5 39.7(20 ) 251 .6 17 .2 (45 ) 312 .9 22 .2(45 ) 360 .0 26 .1(45 ) 404 .4 30 .9(45 ) 434 .0 37 .6(45 ) 459 .3 39 .5(45 ) 475 .7 40 .9 (45 ) 483 .4 43 .7(45 ) 486 6# 46 .1(45 ) 487 7# 48 .6(45 ) 473 8# 58 .2 (45 ) 479 6# 49 .1(19 ) 81 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations _____________DuPont-5386 TABLE 4 (CONTINUED) MEAN BODY WEIGHTS (g) OF MALE RATS Group I 0 mg/kg/day I I I Group 25 mg/kg/day Group V Group VII 100 mg/kg/day 250 mg/kg/day Dosing Period for Subchronic Toxicity Evaluation (continued) DAY 77 555.5 60.4(25 ) 543.7 55.9(15 ) 513.7# 50.7(15 ) 479.2# 57.9(25 ) DAY 84 567.5 59.6(25 ) 555.7 59.2(15 ) 523.2# 38.3(14 ) 508.8# 52.2(25 ) DAY 90 573.5 60.0(25 ) 560.7 62.1(15 ) 531.1# 37.4(14 ) 522.1# 51.4(25 ) One-Month Recovery Period for Subchronic Toxicity Evaluation DAY 98 578.2 63.6(15 ) 539.6 49.3(5 ) 527.9 39.1(5 ) 526.2# 58.9(15 ) DAY 105 586.2 73.8(15 ) 549.8 52.7(5 ) 513.5# 66.0(5 ) 534.3# 62.7(15 ) DAY 112 598.5 - 70.7(15 ) 556.8 53.7(5 ) 525.4# 66.4(5 ) 540.6# 67.8(15 ) DAY 119 597.4 73.5(15 ) 552.5 60.6(5 ) 531.7 58.9(5 ) 548.6 68.4(15 ) Company^arilSased. Does not contain T8CA CBI 82 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations ___DuPont-5386 TABLE 4 (CONTINUED) MEAN BODY WEIGHTS (g) OF MALE RATS Group I 0 mg/kg/day I I I Group 25 mg/kg/day Group V Group VII 100 mg/kg/day 250 mg/kg/day Three-Month Recovery Period for Subchronic Toxicity Evaluation DAY 126 567.3 34.4(5 ) 545.3 47.9(5 ) 531.1 62.9(5 ) 530.0 109.7(5 ) DAY 133 582.3 36.1(5 ) 561.1 45.3(5 ) 545.1 54.0(5 ) 546.1 113.3(5 ) DAY 140 DAY 147 592.6 39.9(5 ) 598.3 48.2(5 ) 569.8 54.3(5 ) 581.9 56.7(5 ) 560.5 58.2(5 ) 575.0 60.7(5 ) 556.6 107.9(5 ) 573.6 110.3(5 ) DAY 154 606.9 45.6(5 ) 586.5 59.7(5 ) 587.1 63.4(5 ) 582.4 108.6(5 ) DAY 161 614.4 48.0(5 ) 592.1 61.1(5 ) 594.6 67.9(5 ) 593.9 106.0(5 ) DAY 168 DAY 175 619.1 48.8(5 ) 635.5 53.8(5 ) 602.1 61.1(5 ) 609.7 64.1(5 ) 608.0 77.7(5 ) 618.6 81.8(5 ) 607.7 113.4(5 ) 610.6 112.8(5 ) Data summarized as: Mean Standard Deviation (n) ft Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 74; subsequent data are reported as part of the reproduction evaluation. 83 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations___ _______DuPont-5386 TABLES MEAN BODY WEIGHTS (g) OF FEMALE RATS Group II 0 mg/kg/day Group IV 25 ing/kg/day Group VI 100 mg/kg/day Group VIII 250 mg/kg/day Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 DAY 7 DAY 14 DAY 21 DAY 28 DAY 35 DAY 42 DAY 49 DAY 56 DAY 63 DAY 70 DAY 74s 191.1 15.5(45 ) 214.4 19.2(45 ) 232.5 20.5(45 ) 249.2 21.8(45 ) 262.6 24.9(45 ) 276.0 26.3(45 ) 283.0 27.8(45 ) 293.0 28.9(45 ) 300.5 29.0(45 ) 304.3 29.8(45 ) 310.4 30.3(45 ) 309.2 30.2(20 ) 192.4 15.2(35 ) 215.4 19.5(34 ) 233.9 19.0(34 ) 254.8 22.1(34 ) 267.6 23.4(34 ) 280.5 24.7(33 ) 290.7 26.7(33 ) 297.7 28.3(33 ) 301.9 29.5(33 ) 307.8 27.9(33 ) 313.8 27.9(33 ) 318.2 31.5(20 ) 187.6 14.4(35 ) 211.9 15.4(35 ) 231.6 18.6(35 ) 247.8 19.1(35 ) 260.0 22.9(35 ) 268.7 2,3.7(35 ) 279.0 24.1(35 ) 286.0 22.0(35 ) 288.6 20.7(35 ) 292.7 21.2(35 ) 298.2 19.8(35 ) 302.8 16.2(20 ) 190.3 14.9(45 ) 215.5 18.6(45 ) 237.5 20.3(45 ) 251.9 22.6(45 ) 264.1 23.1(45 ) 274.9 24.4(45 ) 283.6 24.0(45 ) 287.0 28.6(45 ) 283.7# 32.3(44 ) 281.5# 29.2(44 ) 280.0# 32.6(43 ) 282.2# 37.3(19 ) ifiiefiintete Tte^ (SB 84 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 5 (CONTINUED) MEAN BODY WEIGHTS (g) OF FEMALE RATS Group II 0 mg/kg/day Group IV 25 nig/kg/day Group VI 100 mg/kg/day Group VIII 250 mg/kg/day Dosing Period for Subchronic Toxicity Evaluation (continued) DAY 77 DAY 84 DAY 91 311.8 31.9(25 ) 317.1 33.9(25 ) 318.1 40.0(25 ) 305.7 25.4(13 ) 309.4 25.5(13 ) 310.4 24.5(13 ) 292.1# 21.8(15 ) 293.6# 21.6(15 ) 295.8# 22.3(15 ) 274.5# 24.7(24 ) 296.5# 25.7(24 ) 299.4# 28.9(24 ) One-Month Recovery Period for Subchronic Toxicity Evaluation DAY 98 DAY 105 DAY 112 DAY 119 332.1 42.4(15 ) 337.1 45.0(15 ) 347.8 48.3(14 ) 348.3 50.5(14 ) 305.6 18.5(4 ) 307.7 20.8(4 ) 317.1 21.1(4 ) 320.7 22.2(4 ) 286.6 21.8(5 ) 291.6 18.3(5 ) 288.4 39.2(5 ) 282.2 46.9(5 ) 304.8 29.4(15 ) 310.4 33.2(15 ) 318.6 34.8(15 ) 322.5 38.5(15 ) . Compamr SanStoA Does not eortate TSCA CB8 85 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-5386 TABLE 5 (CONTINUED) MEAN BODY WEIGHTS (g) OF FEMALE RATS Group II 0 mg/kg/day Group IV 25 mg/kg/day Group VI 100 mg/kg/day Group VIII 250 mg/kg/day Three-Month Recovery Period for Subchronic Toxicity Evaluation DAY 126 DAY 133 DAY 140 DAY 147 DAY 154 DAY 161 DAY 168 DAY 175 292.6 17.7(5 ) 308.4 17.7(5 ) 307.8 16.8(5 ) 315.3 15.8(5 ) 316.3 22.5(5 ) 322.9 19.3(5 ) 329.6 21.1(5 ) 328.1 20.1(5 ) 317.7 23.2(4 ) 327.4 25.0(4 ) 333.5 29.6(4 ) 338.7 29.3(4 ) 344.3 23.7(4 ) 344.3 29.9(4 ) 348.6 31.4(4 ) 351.0 29.1(4 ) 293.2 34.8(5 ) 301.4 27.9(5 ) 303.1 29.2(5 ) 310.9 33.2(5 ) 316.1 30.8(5 ) 319.8 31.5(5 ) 322.0 32.2(5 ) 326.5 35.6(5 ) 325.0 51.9(5 ) 333.9 52.4(5 ) 338.0 53.5(5 ) 349.4 54.0(5 ) 356.7 54.4(5 ) 362.1 56.2(5 ) 359.2 57.2(5 ) 361.7 58.4(5 ) Data summarized as: Mean Standard Deviation (n) # Statistically significant differences at p < 0.05 by Jonckheere-Terpstra trend test. a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 74; subsequent data are reported as part of the reproduction evaluation. 86 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 6 __ DuPont-5386 MEAN BODY WEIGHT GAINS (g) OF MALE RATS Group I 0 mg/kg/day I I I Group Group V Group VII 25 mg/kg/day 100 mg/kg/day 250 mg/kg/day Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 - DAY 7 DAY 7 - DAY 14 DAY 14 - DAY 21 DAY 21 - DAY 28 DAY 28 - DAY 35 DAY 35 - DAY 42 DAY 42 - DAY 49 DAY 49 - DAY 56 DAY 56 - DAY 63 DAY 63 - DAY 70 DAY 70 - DAY 748 55.5 7.8(45 ) 50.5 8.6(45 ) 42.1 7.5(45 ) 33.0 7.7(45 ) 26.3 6.9(45 ) 25.6 5.9(45 ) 18.4 8.4(45 ) 17.9 10.3(45 ) 16.0 7.8(45 ) 15.7 6.0(45 ) 3.6 6.7(20 ) 56.6 7.0(35 ) 52.3 7.3(35 ) 36.2 6.6(35 ) 35.3 6.7(35 ) 30.5 8.0(35 ) 18. 5# 5.8(35 ) 13.7 8.0(35 ) 16.3 11.5(35 ) 16.5 9.2(35 ) 15.1 5.6(35 ) 6.8 7.6(20 ) 57.4 8.7(35 ) 49.2 8.0(35 ) 41.7 6.2(35 ) 32.3 7.4(35 ) 24.0 6.4(35 ) 21.1# 5.8(35 ) 16.9 13.3(35 ) 15. 0# 7.2(35 ) 17.2 7.5(35 ) 11.7 16.3(35 ) 2.3 5.0(20 ) 61. 3# 7.1(45 ) 47.1# 6.5(45 ) 44.5ft 6.8(45 ) 29. 6# 12.1(45 ) 25.3 6.0(45 ) 16.4# 13.9(45 ) 7. 8# 11.8(45 ) 3. 1# 22.9(45 ) 1.2# 20.0(45 ) -13.9# 39.3(45 ) 4.9 36.7(19 ) DAY 0 - DAY 743 308.8 46.8(20 ) 300.5 41.5(20 ) 307.9 32.9(20 ) 228.6# 39.3(19 ) 87 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 6 (CONTINUED) ___ ___DuPont-5386 MEAN BODY WEIGHT GAINS (g) OF MALE RATS Group I 0 mg/kg/day I I I Group Group V 25 mg/kg/day 100 mg/kg/day Dosing Period for Subchronic Toxicity Evaluation (continued) Group VII 250 mg/kg/day DAY 70 - DAY 77 DAY 77 - DAY 84 DAY 84 - DAY 90 7.1 11.5(25 ) 12.0 7.3(25 ) 6.0 6.7(25 ) 8.8 7.4(15 ) 12.0 8.3(15 ) 5.1 10.2(15 ) 2.4 17.3(15 ) 1.2 20.6(14 ) 7.9 14.2(14 ) 6.6 43.9(25 ) 29.6# 20.0(25 ) 13.3# 10.1(25 ) DAY O - DAY 90 322.7 49.9(25 ) 313.0 51.9(15 ) 281.8# 28.1(14 ) One-Month Recovery Period for Subchronic Toxicity Evaluation 271.4# 41.2(25 ) DAY 90 - DAY 98 DAY 98 - DAY 105 DAY 105 - DAY 112 DAY 112 - DAY 119 19.2 10.0(15 ) 8.0 14.1(15 ) 12.3 7.5(15 ) -1.1 14.2(15 ) 14.2 4.5(5 ) 10.2 5.0(5 ) 7.0 14.7(5 ) -4.3 12.6(5 ) 4.9# 11.4(5 ) -14.4 58.3(5 ) 11.9 17.6(5 ) 6.3 27.4(5 ) 12 . 7# 8.9(15 ) 8.0 8.7(15 ) 6.3 11.2(15 ) 8.0 7.4(15 ) DAY 90 - DAY 119 38.4 16.7(15 ) 27.2 25.2(5 ) 8.7* 19.5(5 ) 35.1 17.9(15 ) H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations __________DuPont-5386 TABLE 6 (CONTINUED) MEAN BODY WEIGHT GAINS (g) OF MALE RATS Group I 6 mg/kg/day III Group Group V 25 mg/kg/day 100 mg/kg/day Three-Month Recovery Period for Subchronic Toxicity Evaluation Group VII 250 mg/kg/day DAY 119 - DAY 126 0.6 14.2(5 ) -7.2 17.7(5 ) -0.6 26.4(5 ) 7.9 7.0(5 ) DAY 126 - DAY 133 15.0 6.0(5 ) 15.8 15.2(5 ) 14.0 18.7(5 ) 16.1 6.2(5 ) DAY 133 - DAY 140 10.2 10.7(5 ) 8.8 10.8(5 ) 15.4 9.3(5 ) 10.5 5.8(5 ) DAY 140 - DAY 147 5.7 18.4(5 ) 12.1 3.6(5 ) 14.4 3.5(5 ) 17.0 7.3(5 ) DAY 147 - DAY 154 8.6 2.9(5 ) 4.6 7.0(5 ) 12.1 7.3(5 ) 8.7 5.6(5 ) DAY 154 - DAY 161 7.5 7.0(5 ) 5.6 1.9(5 ) -7.5 7.1(5 ) 11.5 6.7(5 ) DAY 161 - DAY 168 4.7 8.3(5 ) 10.0 3.6(5 ) 13.4 10.7(5 ) 13.9 9.0(5 ) DAY 168 - DAY 175 16.4 6.1(5 ) 7.6 6.9(5 ) 10.7 6.2(5 ) 2. 9# 7.1(5 ) DAY 119- DAY 175 68.7 37.4(5 ) 57.2 13.3(5 ) 86.9 29.1(5 ) 88.6# 14.9(5 ) Data summarized as: Mean Standard Deviation (n) # Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. * Statistically significant difference at p < 0.05 by Dunnett's test. a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 74; subsequent data are reported as part of the reproduction evaluation. 89 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 7 MEAN BODY WEIGHT GAINS (g) OF FEMALE RATS I I Group Group IV 0 nig/kg/day 25 mg/kg/day Group VI Group VIII 100 mg/kg/day 250 mg/kg/day Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 - DAY 7 DAY 7 - DAY 14 DAY 14 - DAY 21 DAY 21 - DAY 28 DAY 28 - DAY 35 DAY 35 - DAY 42 DAY 42 - DAY 49 DAY 49 - DAY 56 DAY 56 - DAY 63 DAY 63 - DAY 70 DAY 70 - DAY 74 DAY O- DAY 74' 23.3 8.6(45 ) 18.0 7.1(45 ) .16.8 6.9(45 ) 13.4 7.3(45 ) 13.4 7,2(45 ) 7.1 6.3(45 ) 10.0 5.6(45 ) 7.4 7.8(45 ) 3.8 7.2(45 ) 6.1 6.1(45 ) -1.0 4.2(20 ) 115.5 20.1(20 ) 22.5 7.5(34 ) 18.4 8.1(34 ) 21.0 6.0(34 ) 12.7 7.6(34 ) 12.0 6.2(33 ) 10.2 6.6(33 ) 7. 0# 7.8(33 ) 4.1 11.6(33 ) 6.0 9.7(33 ) 5.9 6.4(33 ) -1.7 11.2(20 ) 120.3 21.5(20 ) 24.3 6.1(35 ) 19.7 6.9(35 ) 16.2 6.4(35 ) 12.2 10.9(35 ) 8 . 7# 9.2(35 ) 10.3 8.3(35 ) 7.0# 10.8(35 ) 2 . 7# 5.6(35 ) 4.0 6.5(35 ) 5.5 7.3(35 ) -1.7 10.0(20 ) 111.5 15.2(20 ) 25.3 6.5(45 ) 22 . 0# 5.8(45 ) 14.4# 6.7(45 ) 12.2 6.7(45 ) 10.8# 6.1(45 ) 8.7 5.7(45 ) 3 . 4# 14.1(45 ) -4.5# 14.5(44 ) -2.2# 22.2(44 ) -1.7# 22.4(43 ) 4.4 31.9(19 ) 85.9# 32.1(19 ) (Company Banltteed. Does not contain TSCA CBI 90 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 7 (CONTINUED) DuPont-5386 ___ MEAN BODY WEIGHT GAINS (g) OF FEMALE RATS I I G r o u p Group IV 0 nig/kg/day 25 mg/kg/day Group VI 100 ing/kg/day Dosing Period for Subchronic Toxicity Evaluation (continued) Group VIII 250 mg/kg/day DAY 70 - DAY 77 DAY 77 - DAY 84 DAY 84 - DAY 91 1.3 4.5(25 ) 5.3 5.6(25 ) 1.0 13.6(25 ) 1.4 6.2(13 ) 3.6 3.9(13 ) 1.0 5.3(13 ) 2.2 5.1(15 ) 1.4 6.0(15 ) 2.2 4.7(15 ) -7.2# 16.3(24 ) 22.0# 12.9(24 ) 2.8 8.7(24 ) DAY 0- DAY 91 129.1 32.5(25 ) 125.1 20.8(13 ) 113.1# 14.8(15 ) One-Month Recovery Period for Subchronic Toxicity Evaluation 114.1# 20.2(24 ) DAY 91 - DAY 98 DAY 98 - DAY 105 DAY 105 - DAY 112 DAY 112 - DAY 119 10.8 13.5(15 ) 5.0 11.7(15 ) 10.0 8.5(14 ) 0.5 7.6(14 ) 7.9 7.1(4 ) 2.0 6.2(4 ) 9.4 3.8(4 ) 3.6 3.2(4 ) 0.3 9.6(5 ) 5.0 4.0(5 ) -3.2 22.0(5 ) -6.2 25.3(5 ) 5.4 10.2(15 ) 5.6 5.9(15 ) 8.2 6.2(15 ) 3.9 5.8(15 ) DAY 91- DAY 119 27.6 23.4(14 ) 22.9 9.0(4 ) -4.1 24.4(5 ) 23.2 19.1(15 ) 91 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-5386 TABLE 7 (CONTINUED) MEAN BODY WEIGHT GAINS (g) OF FEMALE RATS I I Group Group IV 0 ing/kg/day 25 mg/kg/day Group VI Group VIII 100 mg/kg/day 250 mg/kg/day Three-Month Recovery Period for Subchronic Toxicity Evaluation DAY 119 - DAY 126 -5.9 7.9(5 ) -3.0 2.1(4 ) 11.0# 18.9(5 ) 3.2# 5.3(5 ) DAY 126 - DAY 133 15.8 3.5(5 ) 9.7 2.8(4 ) 8.2 12.1(5 ) 8.9 8.4(5 ) DAY 133 - DAY 140 -0.6 4.9(5 ) 6.1 7.1(4 ) 1.7 7.2(5 ) 4.1 8.8(5 ) DAY 140 - DAY 147 7.5 2.8(5 ) 5.2 7.8(4 ) 7.8 5.1(5 ) 11.4 4.2(5 ) DAY 147 - DAY 154 1.0 10.0(5 ) 5.5 7.6(4 ) 5.2 8.9(5 ) 7.3 4.7(5 ) DAY 154 - DAY 161 6.6 7.6(5 ) 0.1 7.0(4 ) 3.7 7.0(5 ) 5.4 4.6(5 ) DAY 161 - DAY 168 6.7 7.6(5 ) 4.3 2.2(4 ) 2.2# 0.9(5 ) -2 . 9# 11.4(5 ) DAY 168 - DAY 175 -1.5 3.2(5 ) 2.3 4.7(4 ) 4.5 5.3(5 ) 2.5 4.2(5 ) DAY 119- DAY 175 29.6 16.5(5 ) 30.3 8.3(4 ) 44.2 18.9(5 ) 39.9 15.1(5 ) Data summarized as: Mean Standard Deviation (n) # Statistically significant difference at; p < 0.05 by Jonckheere-Terpstra trend test. a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 74; subsequent data are reported as part of the reproduction evaluation. Company Sanitized. Does not contain TSCA CBI 92 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations ______DuPont-5386 TABLE 8 MEAN DAILY FOOD CONSUMPTION (g) OF MALE RATS Group I 0 mg/kg/day I I I Group Group V Group VII 25 nig/kg/day 100 mg/kg/day 250 mg/kg/day Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 - DAY 7 25.8 2.2(45 ) 25.8 2.5(35 ) 26.1 2.2(35 ) 26.5 2.8(45 ) DAY 7 - DAY 14 27.4 2.9(45 ) 27.7 2.8(35 ) 28.1 2.7(35 ) 28.5# 2.4(45 ) DAY 14 - DAY 21 28.3 . 2.6(45 ) 28.1 3.2(35 ) 28.1 2.3(35 ) 28.2 2.6(45 ) DAY 21 - DAY 28 28.2 2.8(45 ) 28.2 3.2(35 ) 28.9 2.6(35 ) 28.6 3.7(45 ) DAY 28 - DAY 35 28.5 2.7(45 ) 29.2 3.4(35 ) 30.0 5.6(35 ) 29.2 2.9(45 ) DAY 35 - DAY 42 28.7 2.7(45 ) 28.8 3.1(35 ) 29.1 2.6(35 ) 28.5 3.6(45 ) DAY 42 - DAY 49 29.2 2.6(45 ) 27.6 4.0(35 ) 28.6 3.6(35 ) 26.2# 3.3(45 ) DAY 49 - DAY 56 29.2 3.0(45 ) 29.1 4.1(35 ) 29.4 2.5(35 ) 26.0# 4.8(45 ) DAY 56 - DAY 63 28.9 4.2(45 ) 28.9 3.4(35 ) 29.5 2.9(35 ) 24.5ft 4.4(45 ) DAY 63 - DAY 70 28.9 3.3(45 ) 28.8 3.4(35 ) 28.8 4.5(35 ) 21.8# 7.9(45 ) DAY 70 - DAY 748 31.1 4.1(20 ) 30.1 3.4(20 ) 28.8 3.7(20 ) 25.2# 7.5(19 ) DAY O - DAY 74 28.4 2.9(20 ) 28.4 3.2(20 ) 29.5 2.0(20 ) 27.1 1.9(19 ) 93 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations______________DuPont-5386 TABLE 8 (CONTINUED) MEAN DAILY FOOD CONSUMPTION (g) BY MALE RATS III Group I Group 0 (ng/kg/day 25 mg/kg/day Group V 100 mg/kg/day Dosing Period for Subchronic Toxicity Evaluation (continued) Group VII 250 mg/kg/day DAY 70 - DAY 77 DAY 77 - DAY 84 DAY 84 - DAY 90 28.2 3.5(25 ) 28.0 3.6(25 ) 27.0 2.9(25 ) 27.4 3.5(15 ) 27.9 3.1(15 ) 26.3 3.5(15 ) 25.7 5.8(15 ) 25.0 3.5(14 ) 24.7 2.9(14 ) 24.2# 5.9(25 ) 26.8 3.5(25 ) 25.3 3.7(25 ) DAY O - DAY 90 28.2 2.4(25 ) 27.9 2.6(15 ) 27.1 2.0(14 ) 26.2# 2.4(25 ) One-Month Recovery Period for Subchronic Toxicity Evaluation DAY 90 - DAY 98 DAY 98 - DAY 105 DAY 105 - DAY 112 DAY 112 - DAY 119 28.4 2.7(15 ) 28.0 5.0(15 ) 28.7 2.8(15 ) 26.2 5.0(15 ) 26.8 2.4(5 ) 27.7 2.6(5 ) 27.7 2.2(5 ) 25.9 4.4(5 ) 25.4ft 3.6(5 ) 22.4 12.1(5 ) 25.0 5.5(5 ) 25.5 4.4(5 ) DAY 90 - DAY 119 27.8 3.1(15 ) 27.0 2.4(5 ) 24.6 4.1(5 ) 25.4# 2.9(15 ) 25.6# 3.5(15 ) 24.7# 3.8(15 ) 25.4 3.3(15 ) 25.3# 3.1(15 ) amparay ^miflzecj. Does not ortalii reCA 88 94 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 8 (CONTINUED) MEAN DAILY FOOD CONSUMPTION (g) BY MALE RATS III Group I Group 0 mg/kg/day 25 nig/kg/day Group V Group VII 100 mg/kg/day 250 mg/kg/day Three-Month Recovery Period for Subchronic Toxicity Evaluation DAY 119 - DAY 126 27.3 0.9(5 ) 26.2 0.9(5 ) 25.5 6.3(5 ) 25.1 4.1(5 ) DAY 126 - DAY 133 27.5 1.7(5 ) 26.5 6.2(5 ) 27.3 1.9(5 ) 25.8 4.1(5 ) DAY 133 - DAY 140 27.9 4.3(5 ) 28.7 2.7(5 ) 26.8 7.9(5 ) 26.9 2.5(5 ) DAY 140 - DAY 147 26.0 7.0(5 ) 29.5 2.3 (5 ) 31.7 3.0(5 ) 28.8 2.8(5 ) DAY 147 - DAY 154 30.4 2.2(5 ) 30.6 1.8(5 ) 31.2 3.2(5 ) 29.5 2.9(5 ) DAY 154 - DAY 161 32.4 2.4(5 ) 28.8. 1.8(5 ) 30.9 3.6(5 ) 30.7 3.7(5 ) DAY 161 - DAY 168 29.5 1.7(5 ) 29.2 1.9(5 ) 31.6 5.2(5 ) 30.9 3.3(5 ) DAY 168 - DAY 175 30.8 2.9(5 ) 29.0 2.0(5 ) 30.7 4.2(5 ) 28.9 3.4(5 ) DAY 119 - DAY 175 29.0 2.2(5 ) 28.6 1.7(5 ) 29.5 2.8(5 ) 28.3 3.2(5 ) Data summarized as: Mean Standard Deviation (n) # Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 74; food consumption data were not collected during the cohabitation and postulating periods. 95 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-5386 TABLE 9 MEAN DAILY FOOD CONSUMPTION (g) BY FEMALE RATS II Group 0 mg/kg/day Group IV Group VI Group VIII 25 nig/kg/day 100 mg/kg/day 250 mg/kg/day Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 - DAY 7 DAY 7 - DAY 14 DAY 14 - DAY 21 DAY 21 - DAY 28 DAY 28 - DAY 35 DAY 35 - DAY 42 DAY 42 - DAY 49 DAY 49 - DAY 56 DAY 56 - DAY 63 DAY 63 - DAY 70 DAY 70 - DAY 74" 18.7 1.9(45 ) 20.1 2.2(45 ) 19.9 2.2(45 ) 19.7 2.3(45 ) 21.0 2.3(45 ) 20.4 2.2(45 ) 20.8 2.4(45 ) 21.1 2.1(45 ) 21.1 2.0(45 ) 20.9 2.2(45 ) 21.9 2.0(20 ) 18.9 4.0(34 ) 19.7 4.0(34 5 20.9 3.9(34 ) 20.6 4.0(34 ) 21.3 3.5(33 ) 21.5 3.4(33 ) 21.0 4.3(33 ) 21.3 4.0(33 ) 20.9 1.8(33 ) 20.3 2.3(33 ) 21.3 3.7(20 ) 17.9 1.6(35 ) 18.5# 1.5(35 ) 19.9 1.6(35 ) 19.8 2.9(35 ) 19.3 2.4(35 ) 18.4# 2.8(35 ) 20.0 2.4(35 ) 20.5 1.7(35 ) 19.5# 2.1(35 ) 19.8# 1.9(35 ) 20.2 2.9(20 ) 18.0# 1.8(45 ) 19.4# 1.6(45 ) 20.8 2.3(45 ) 20.0 2.0(45 ) 20.6 2.2(45 ) 19.6# 2.2(45 ) 19.1# 3.4(45 ) 19.3# 4.4(44 ) 17.9# 4.5(44 ) 16.7# 5.2(43 ) 20. 3# 11.4(19 ) DAY O - DAY 74'1 20.5 1.9(20 ) 21.1 3.5(20 ) 20.0 1.0(20 ) 19.8 2.0(19 ) Company SasitteeA Does not contain TSCA CBS 96 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-5386 TABLE 9 (CONTINUED) MEAN DAILY FOOD CONSUMPTION (g) BY FEMALE RATS I I Group 0 mg/kg/day Group IV 25 mg/kg/day Group VI 100 mg/kg/day Dosing Period for Subchronic Toxicity Evaluation (continued) Group VIII 250 mg/kg/day DAY 70 - DAY 77 DAY 77 - DAY 84 DAY 84 - DAY 91 21.1 2.6(25 ) 21.4 3.6(25 ) 19.1 3.4(25 ) 20.9 2.7(13 ) 20.8 3.1(13 ) 19.0 2.3(13 ) 19.2# 2.1(15 ) 18.9 1.8(15 ) 17.3 2.0(15 ) 16.6# 4.3(24 ) 22.6 3.0(24 ) 18.8 3.1(24 ) DAY 0 - DAY 91 20.4 1.7(25 ) 20.1 1.7(13 ) 18.6# 1.5(15 ) One-Month Recovery Period for Subchronic Toxicity Evaluation 18.8# 1.4(24 ) DAY 91 - DAY 98 DAY 98 - DAY 105 DAY 105 - DAY 112 DAY 112 - DAY 119 ' 20.4 3.2(15 ) 21.1 4.3(15 ) 21.6 2.9(14 ) 21.4 3.3(14 ) 19.0 1.7(4 ) 20.0 1.1(4 ) 20.7 1.5(4 ) 20.4 1.4(4 ) 17.1 1.7(5 ) 18.3 1.8(5 ) 17.9 4.8(5 ) 16.9 5.8(5 ) 19.7 3.4(15 ) 20.3 3.6(15 ) 19.1# 2.6(15 ) 19.3 3.1(15 ) DAY 91 - DAY 119 21.2 2.9(14 ) 20.0 1.3(4 ) 17.5 2.9(5 ) 19.6 2.8(15 ) 97 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-5386 TABLE 9 (CONTINUED) MEAN DAILY FOOD CONSUMPTION (g) BY FEMALE RATS II Group 0 mg/kg/day Group IV Group VI 25 mg/kg/day 100 mg/kg/day Three-Month Recovery Period for Subchronic Toxi-city Evaluation Group VIII 250 mg/kg/day DAY 119 - DAY 126 DAY 126 - DAY 133 DAY 133 - DAY 140 DAY 140 - DAY 147 DAY 147 - DAY 154 DAY 154 - DAY 161 DAY 161 - DAY 168 DAY 168 - DAY 175 19.4 2.2(5 ) 21.2 1.8(5 ) 20.1 2.2(5 ) 21.9 1.7(5 ) 23.2 3.0(5 ) 24.2 2.0(5 ) 22.5 3.5(5 ) 20.9 1.6(5 ) 20.6 1.8(4 ) 20.4 1.8(4 ) 22.0 1.4(4 ) 22.3 1.3(4 ) 23.1 1.2(4 ) 21.3 1.6(4 ) 21.7 1.4(4 ) 21.1 2.6(4 ) 20.6 2.8(5 ) 20.3 2.1(5 ) 22.8 4.7(5 ) 24.5 3.4(5 ) 21.3 2.1(5 ) 22.6 2.9(5 ) 21.3 2.4(5 ) 21.0 3.1(5 ) 18.5 2.6(5 ) 18.4# 2.2(5 ) 20.4 3.2(5 ) 22.3 2.4(5 ) 22.9 2.7(5 ) 22.5 2.6(5 ) 22.2 1.8(5 ) 20.6 2.2(5 ) DAY 119 - DAY 175 21.7 2.1(5 ) 21.6 1.5(4 ) 21.8 2.0(5 ) 21.0 1.9(5 ) Data summarized as: Mean Standard Deviation (n) # Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. @ Statistically significant difference at p < 0.05 by Dunn's test. a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 74; data were not collected during the cohabitation and postmating periods. 98 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 10 MEAN DAILY FOOD EFFICIENCY OF MALE RATS (g body weight gain/g food consumed) Group I 0 mg/kg/day I I I Group 25 mg/kg/day Group V Group VII 100 mg/kg/day 250 mg/kg/day Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 - DAY 7 DAY 7 - DAY 14 DAY 14 - DAY 21 DAY 21 - DAY 28 DAY 28 - DAY 35 DAY 35 - DAY 42 DAY 42 - DAY 49 DAY 49 - DAY 56 DAY 56 - DAY 63 DAY 63 - DAY 70 DAY 70 - DAY 748 0 .307 0 .026 (45 ) 0 .262 0 .027 (45 ) 0 .211 0 .028 (45 ) 0 .166 0 .028 (45 ) 0 .131 0 .029 (45 ) 0 .127 0 .025 (45 ) 0 .089 0 .038 (45 ) 0 .086 0 .050 (45 ) 0 .075 0 .048 (45 ) 0 .076 0 .026 (45 ) 0 .028 0 .049 (20 ) 0 .314 0 .032 (35 ) 0 .270 0 .028 (35 ) 0 .184 0 .025 (35 ) 0 .178 0 .028 (35 ) 0 .148 0 .031 (35 ) 0 091# 0 .026 (35 ) 0 .068 0 .036 (35 ) 0 .072 0 .081 (35 ) 0 .081 0 .050 (35 ) 0 .074 0 .027 (35 ) 0 .053 0 .061 (20 ) 0 .314 0 .033(35 ) 0 .249 0 .025(35 ) 0 .213 0 .028(35 ) 0 .159 0 .032 (35 ) 0 .115 0 .029 (35 ) 0 .103# 0 .026(35 ) 0 .076 0 .095 (35 ) 0 .072# 0 .035 (35 ) 0 .083 0 .035(35 ) 0 .031 0 .217(35 ) 0 .017 0 .042(20 ) 0 .331# 0 .032(45 ) 0 235# 0 .024(45 ) 0 225# 0 .022(45 ) 0 135# 0 .129 (45 ) 0 .124 0 .026 (45 ) 0 .072# 0 .126(45 ) 0 .038# 0 .067(45 ) -0 019# 0 .246 (45 ) -0 .010# 0 .136(45 ) -0 .368# 0 .919(45 ) -0 .073 0 .476(19 ) DAY 0 - DAY 74 0 .146 0 .011 (20 ) 0 .143 0 .011 (20 ) 0 .141 0 .009(20 ) 0 114# 0 .015(19 ) Bompany San8feed. Does not eonfa8" "^WA. CBI 99 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 10 (CONTINUED) MEAN DAILY FOOD EFFICIENCY OF MALE RATS (g body weight gain/g food consumed) III Group I Group 0 mg/kg/day 25 mg/kg/day Group V 100 mg/kg/day Dosing Period for Subchronic Toxicity Evaluation (continued) Group VII 250 mg/kg/day DAY 70 - DAY 77 DAY 77 - DAY 84 DAY 84 - DAY 90 0 .029 0 .079 (25 ) 0 .063 0 .046 (25 ) 0 .035 0 .045 (25 ) 0. 045 0. 035(15 ) 0. 059 0. 039(15 ) 0. 028 0. 074(15 ) -0 .048 0 .320 (15 ) -0 .008 0 .159 (14 ) 0 .050 0 .089 (14 5 -0.027 0.333 (25 ) 0.158# 0.110 (25 ) 0.082# 0.064(25 ) DAY 0 - DAY 90 0 .126 0 .012 (25 ) 0. 124 0. 012(15 ) 0 .116 # 0 .009 (14 ) One-Month Recovery Pericad for Subchroni c Toxic'ity Evaluat:ion 0.115# 0.011(25 ) DAY 90 - DAY 98 DAY 98 - DAY 105 DAY 105 - DAY 112 DAY 112 - DAY 119 0 .084 0 .042 (15 ) 0 .024 0 .113 (15 ) 0 .061 0 .037 (15 ) -0 .021 0 .112 (15 ) 0. 066 0. 020(5 ) 0. 051 0. 023(5 ) 0. 034 0. 074(5 ) -0. 033 0. 080(5 ) 0 .019 # 0 .053 (5 ) -2 .355 5 .392 (5 ) 0 .075 0 .124 (5 ) 0 .024 0 .145 (5 ) 0.062# 0.043 (15 ) 0.041 0.045(15 ) 0.031 0.071j(15 ) 0.044# 0.043(15 ) DAY 90 - DAY 119 0 .047 0 .017 (15 ) 0. 034 0. 030(5 ) 0 .009 * 0 .027 (5 ) 0.047 0.022(15 ) 100 H-24516: Subchromc Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-5386 TABLE 10 (CONTINUED) MEAN DAILY FOOD EFFICIENCY OF MALE RATS (g body weight gain/g food consumed) III Group I Group 0 mg/kg/day 25 mg/kg/day Group V Group VII 100 mg/kg/day 250 mg/kg/day Three-Month Recovery Period for Subchronic Toxicity Evaluation DAY 119 - DAY 126 DAY 126 - DAY 133 DAY 133 - DAY 140 DAY 140 - DAY 147 DAY 147 - DAY 154 DAY 154 - DAY 161 DAY 161 - DAY 168 DAY 168 - DAY 175 0.002 0.072(5 ) 0.078 0.031(5 ) 0.049 0.048(5 ) -0.000 0.156(5 ) 0.041 0.014(5 ) 0.031 0.029(5 ) 0.021 0.040(5 ) 0.075 0.021(5 ) -0.039 0.096(5 ) 0.070 0.088(5 ) 0.040 0.051(5 ) 0.058 0.014(5 ) 0.021 0.032(5 ) 0.028 . 0.008(5 ) 0.049 0.018(5 ) 0.037 0.033(5 ) -0.041 0.205(5 ) 0.071 0.094(5 ) 0.092 0.071(5 ) 0.064 0.011(5 ) 0.054 0.031(5 ) 0.033 0.029(5 ) 0.056 0.034(5 ) 0.048 0.023(5 ) 0.046 0.038(5 ) 0.089 0.031(5 ) 0.058 0.034(5 ) 0.083 0.031(5 ) 0.043 0.027(5 ) 0.055 0.031(5 ) 0.062 0.036(5 ) 0.015# 0.035(5 ) DAY 119 - DAY 175 0.041 0.020(5 ) 0.036 0.007(5 ) 0.052 0.014(5 ) 0.056# 0.009(5 ) Data summarized as: Mean Standard Deviation (n) # Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. * Statistically significant difference at p < 0.05 by Dunnett's test. a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 74; data were not collected during the cohabitation and postmating periods. ISompanySanKteed.DoesnotwrtatoTSCACBS 101 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 11 MEAN DAILY FOOD EFFICIENCY OF FEMALE RATS (g body weight gain/g food consumed) I I Group 0 mg/kg/day Group IV 25 ing/kg/day Group VI Group VIII 100 mg/kg/day 250 ing/kg/day Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 - DAY 7 DAY 7 - DAY 14 DAY 14 - DAY 21 DAY 21 - DAY 28 DAY 28 - DAY 35 DAY 35 - DAY 42 DAY 42 - DAY 49 DAY 49 - DAY 56 DAY 56 - DAY 63 DAY 63 - DAY 70 DAY 70 - DAY 74s 0 .176 0 .060(45 ) 0 .128 0 .048(45 ) 0 .120 0 .045(45 ) 0 .095 0 .048(45 ) 0 .089 0 .043(45 ) 0 .048 0 .042(45 ) 0 .067 0 .034(45 ) 0 .048 0 .053(45 ) 0 .023 0 .049(45 ) 0 .041 0 .038(45 ) -0 .014 0 .050(20 ) 0. 170 0. 048 (34 ) 0. 134 0. 057 (34 ) 0. 146 0. 039(34 ) 0. 088 0. 050 (34 ) 0. 081 0. 036(33 ) 0. 067 0. 045(33 ) 0. 040# 0. 087(33 ) 0. 020 0. 096(33 ) 0. 042 0. 073(33 ) 0. 041 0. 043(33 ) -0. 062 0. 289 (20 ) 0.193 0.043(35 ) 0.150 0.047(35 ) 0.117 0.044(35 ) 0.070 0.156(35 ) 0.061# 0.069(35 ) 0.072 0.076(35 ) 0.046# 0.080(35 ) 0.018# 0.039(35 ) 0.028 0.048(35 ) 0.038 0.050(35 ) -0.048 0.234(20 ) 0.199ft 0 .037(45 ) 0.162ft 0 .042(45 ) 0.098ft 0 .044(45 ) 0.087 0 .045 (45 ) 0.074ft 0 .038(45 ) 0.063 0 .040(45 ) 0.000ft 0 .191(45 ) 0.120ft 0 .532(44 ) 0.064ft 0 .257(44 ) 0.220ft 0 .929(43 ) 0.188 0 .733(19 ) DAY 0 - DAY 74s 0 .076 0 .007(20 ) 0. 078 0. 013 (20 ) 0.076 0.010(20 ) 0.058ft 0 .020(19 ) 102 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-5386 . TABLE 11 (CONTINUED) MEAN DAILY FOOD EFFICIENCY OF FEMALE RATS (g body weight gain/g food consumed) I I G r o u p 0 nig/kg/day Group IV 25 mg/kg/day Group VI 100 mg/kg/day Dosing Period for Subchronic Toxicity Evaluation (continued) Group VIII 250 mg/kg/day DAY 70 - DAY 77 DAY 77 - DAY 84 DAY 84 - DAY 91 0.001 0.002(5 ) 0.034 0.036(25 ) -0.020 0.208(25 ) -0.002 0.001(4 ) 0.023 0.026(13 ) 0.008 0.042(13 ) 0.001 0.004(5 ) 0.009 0.045(15 ) 0.017 0.039(15 ) -0.011ft 0.009(5 ) 0.136# 0.079(24 ) 0.015 0.067(24 ) DAY 0 - DAY 91 0.069 0.013(25 ) 0.068 0.007(13 ) 0.067 0.005(15 ) 0.066 0.008(24 ) One-Month Recovery Period for Subchronic Toxicity Evaluation DAY 91 - DAY 98 DAY 98 - DAY 105 DAY 105 - DAY 112 DAY 112 - DAY 119 0.077 0.111(15 ) 0.018 0.105(15 ) 0.064 0.051(14 ) -0.000 0.060(14 ) 0.057 0.047(4 ) 0.014 0.046(4 ) 0.064 0.023(4 ) 0.024 0.021(4 ) 0.001 0.077(5 ) 0.040 0.033(5 ) -0.083 0.279(5 ) -0.159 0.452(5 ) DAY 91 - DAY 119 0.044 0.040(14 ) 0.040 0.014(4 ) -0.015* 0.055(5 ) 0.034 0.074(15 ) 0.037 0.039(15 ) 0.059 0.042(15 ) 0.026 0.039(15 ) 0.039 0.029(15 ) SBompany Sanitized. Does not contain TSCA CBI 103 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 11 (CONTINUED) MEAN DAILY FOOD EFFICIENCY OF FEMALE RATS (g body weight gain/g food consumed) I I Group 0 mg/kg/day Group IV 25 mg/kg/day Group VI 100 mg/kg/day Three-Month Recovery Period for Subchronic Toxicity Evaluation Group VIII 250 mg/kg/day DAY 119 - DAY 126 DAY 126 - DAY 133 DAY 133 - DAY 140 DAY 140 - DAY 147 DAY 147 - DAY 154 DAY 154 - DAY 161 DAY 161 - DAY 168 DAY 168 - DAY 175 -0 .048 0 .068 (5 ) 0 .107 0 .028 (5 ) -0 .007 0 .034 (5 ) 0 .050 0 .019 (5 ) 0 .001 0 .061 (5 ) 0 .041 0 .047 (5 ) 0 .040 0 .043 (5 ) -0 .009 0 .021 (5 ) -0 .022 0 .017 (4 ) 0 .068 0 .018 (4 ) 0 .038 0 .047 (4 ) 0 .032 0 .049 (4 ) 0 .035 0 .046 (4 ) -0 .001 0 .046 (4 ) 0 .028 0 .012 (4 ) 0 .014 0 .034 (4 ) 0 .069:# 0 .115 (5 ) 0 .060 0 .084 (5 ) 0 .010 0 .048 (5 ) 0 .046 0 .028 (5 ) 0 .034 0 .058 (5 ) 0 .019 0 .043 (5 ) 0 .015# 0 .005 (5 ) 0 .028 0 .029 (5 ) 0.023# 0 .042(5 ) 0.067 0 .063 (5 ) 0.023 0 .058(5 ) 0.074 0 .027(5 ) 0.045 0 .032 (5 ) 0.033 0 .027(5 ) -0.019# 0 .073 (5 ) 0.016 0 .030(5 ) DAY 119 - DAY 175 0 .024 0 .012 (5 ) 0 .025 0 .005 (4 ) 0 .036 0 .014 (5 ) 0.034 0 .012(5 S Data summarized as: Mean Standard Deviation (n) ft Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. * Statistically significant difference at p < 0.05 by Dunnett's test. @ Statistically significant difference at p < 0.05 by Dunn's test. a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 74; data were not collected during the cohabitation and postmating periods. 104 ^ey H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 12 SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS Treatment Group Dose Number Animals at Study Start I 0 mg/kg/day 45 Mass Thoracic Lateral Mass #1 Ulcerated Incidence 0 Mean onset (Days) Lateral Mass #1 Not Ulcerate-d Incidence 0 Mean onset (Days) Eye Observations Corneal Opacity Incidence 2 Mean onset (Days) 77 Exophthalmus Incidence 2 Mean onset (Days) 31 Enophthalmus Incidence 2 Mean onset (Days) 46 III 25 mg/kg/day 35 V 100 mg/kg/day 35 0 1 84 0 1 0 58 1 3 77 89 2 3 88 84 0 1 77 105 .Company Sanitized H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 12 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS Treatment Group Dose Number Animals at Study Start I 0 mg/kg/day 45 III 25 mg/kg/day 35 V 100 mg/kg/day 35 Partially Closed Incidence 2 2 Mean onset (Days) 102 126 Closed Left Incidence 1 Mean onset (Days) 181 Abnormal Gait Hindiimb Left Incidence Mean onset (Days) Muscle Tone Decreased Incidence l Mean onset (Days) 73 Pale Incidence 1 Mean onset (Days) 73 106 r / SM^: H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 12 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS Treatment Group Dose Number Animals at Study Start I 0 mg/kg/day 45 III 25 mg/kg/day 35 v 100 mg/kg/day 35 General Teeth Observations Clipped Incidence l Mean onset (Days) 58 Maloccluded Incidence 0 Mean onset (Days) Broken Incidence 0 Mean onset (Days) Absent Incidence 0 Mean onset (Days) - Loose Incidence 0 Mean onset (Days) Diarrhea Brown Incidence 0 Mean onset (Days) 2 1 89 77 0 1 119 0 0 1 1 56 84 0 0 0 0 107 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 12 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS Treatment Group Dose Number Animals at Study Start I 0 mg/kg/day 45 III 25 mg/kg/day 35 V 100 mg/kg/day 35 Breathing Observations Noise Incidence Mean onset (Days) Labored Incidence Mean onset (Days) Fast Incidence Mean onset (Days) Discharge Eye Incidence Mean onset (Days) Nose Incidence Mean onset (Days) Mouth Clear Incidence Mean onset (Days) 0 1 0 - 147 - 0 0 1 - - 77 0 0 1 - - 77 4 4 4 3 60 116 76 2 2 1 21 77 63 0 0 0 - - - 108 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 12 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS Treatment Group Dose Number Animals at Study Start I 0 mg/kg/day 45 III 25 mg/kg/day 35 V 100 mg/kg/day 35 Mouth Red Incidence Mean onset (Days) Ear left Black Incidence Mean onset.(Days) Hair Loss Incidence Mean onset (Days) Wound Superficial (nose, mouth, Incidence Mean onset (Days) Hyperreactive Incidence Mean onset (Days) Aggressive Behavior Incidence Mean onset (Days) - - 126 . 0 0 49 98 0 2 face, tail, shoulders) 21 30 5 6 116 2220 0 - 0 - 109 66 1 177 0 04 568 0 20 - 3 3Company Sanitized. Do H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 12 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS Treatment Group Dose Number Animals at Study Start I 0 mg/kg/day 45 III 25 mg/kg/day 35 V 100 mg/kg/day 35 Excessive Toe Nail Bleed Incidence 1 Mean onset (Days) 76 Stain Fur/Skin Periocular Right Brown Incidence Mean onset (Days) Periocular Bilateral Black Incidence Mean onset (Days) Pace Red Incidence Mean onset (Days) 110 'ompany SansitSz ^Q?' H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 12 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS Treatment Group Dose Number Animals at Study Start I 0 mg/kg/day 45 III 25 mg/kg/day 35 100 mg/kg/day 35 Face Black Incidence 1 Mean onset (Days) 119 Chin Red Incidence Mean onset (Days) Tail Brown Incidence Mean onset (Days) Perineum Yellow Incidence Mean onset (Days) Perineum Red Incidence Mean onset (Days) 111 Company Sanitized. Do H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 12 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS Treatment Group Dose Number Animals at Study Start I 0 mg/kg/day 45 III 25 mg/kg/day 35 V 100 mg/kg/day 35 Perineum Brown Incidence 1 Mean onset (Days) 73 Inguen Brown Incidence 1 Mean onset. (Days) 77 Forepaw Left Red Incidence Mean onset (Days) Forepaw Bilateral Red Incidence Mean onset (Days) 112 company Sanitized. Does not c H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 12 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS Treatment Group Dose Number Animals at Study Start Misshapen Observations Tail Incidence Mean onset (Days) Swollen Observations Nose Incidence Mean onset (Days) Face Incidence Mean onset (Days) Hindlimb Left Incidence Mean onset (Days) I 0 mg/kg/day 45 0 0 III 25 mg/kg/day 35 V 100 mg/kg/day 35 1 56 Incidence - The number of animals for which an observation was recorded. Mean onset (Days) - The mean of the first test day an observation was recorded for that grou # Statistically significant difference at p < 0.05 by Cochran-Armitage trend test. Company Sanitized. Does no 113 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 13 SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS Treatment Group Dose Number Animals at Study Start II 0 ing/kg/day 45 Mass Side Left Mass ftl Not Ulcerated Incidence Mean onset (Days) Mass Perineum Mass ftl Ulcerated Incidence 1 Mean onset (Days) 105 Mass Abdomen Mass #2 Incidence Mean onset (Days) Eye Observations Corneal Opacity Incidence 2 Mean onset (Days) 44 IV 25 nig/kg/day 35 VI 100 mg/kg/day 35 3 56 114 Company Sanitized. Does ^ H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 13 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS Treatment Group Dose Number Animals at Study Start II 0 mg/kg/day 45 IV 25 mg/kg/day 35 VI 100 mg/kg/day 35 Exophthalmus Incidence Mean onset (Days) Enophthalmus Incidence Mean onset (Days) Partially Closed Left Incidence Mean onset (Days) Closed Left Incidence Mean onset (Days) Wet Fur Perineum Incidence Mean onset (Days) Prostrate Incidence Mean onset (Days) 70 77 3 0 3 3 112 1 0 1 3 175 1011 - 100001000010 - - 29 115 64 49 112 - Company Sanitized. Does not ^aj.iy'^ H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 13 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS Treatment Group Dose Number Animals at Study Start II 0 mg/kg/day 45 IV 25 mg/kg/day 35 VI 100 mg/kg/day 35 General Teeth Observations Clipped Incidence Mean onset (Days) Maloccluded Incidence Mean onset (Days) Broken Incidence Mean onset (Days) Absent Incidence Mean onset (Days) Loose Incidence Mean onset (Days) Diarrhea (Brown, Black) Incidence Mean onset (Days) 1 2 58 144 1 29 116 Company Sanitized. D H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 13 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS Treatment Group Dose Number Animals at Study Start Breathing Observations Noise Fast Incidence Mean onset (Days) Incidence Mean onset (Days) Discharge Eye Incidence Mean onset (Days) Nose Incidence Mean onset (Days) Mouth Clear Incidence Mean onset (Days) Mouth Tan Incidence Mean onset (Days) II 0 mg/kg/day 45 IV 25 mg/kg/day 35 VI 100 mg/kg/day 35 140 - 2 0 115 0 1 102 3202 - 0000 - - 29 103 - 117 - 0 1 54 301 119 0 - 0 - Company Sanitized. Does not co H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 13 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS Treatment Group Dose Number Animals at Study Start II 0 mg/kg/day 45 IV 25 mg/kg/day 35 VI 100 mg/kg/day 35 Vulva Red Incidence 1 Mean onset (Days) 105 Hair Loss Incidence 4 3 2 Mean onset (Days) 78 47 39 Wound Superficial (Nose, Mouth) Incidence Mean onset (Days) 1 1 14 63 Hyperreactive Incidence Mean onset (Days) Hyperactive Incidence 0 1 0 Mean onset (Days) 56 Convulsions Clonic Incidence 0 1 0 Mean onset (Days) 29 118 company SanMzed. Do w H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 13 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS Treatment Group Dose Number Animals at Study Start II 0 nig/kg/day 45 IV 25 mg/kg/day 35 VI 100 mg/kg/day 35 Vocalization Abnormal Incidence 1 Mean onset (Days) 29 Growth on left eye Incidence Mean onset (Days) Dehydrated Incidence Mean onset (Days) Stain Fur/Skin Face Brown Incidence Mean onset (Days) Shoulder Right Brown Incidence Mean onset (Days) 119 Company Sanitized. Does H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 13 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS Treatment Group Dose Number Animals at Study Start II 0 nig/kg/day 45 IV 25 mg/kg/day 35 VI 100 mg/kg/day 35 Perineum Yellow Incidence Mean onset (Days) Inguen Yellow Incidence Mean onset, (Days) Incidence - The number of animals for which an observation was recorded. Mean onset (Days) - The mean of the first test day an observation was recorded for that grou # Statistically significant difference at p < 0.05 by Cochran-Armitage trend test. 120 Company Samftlzed. Does H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 14 SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR MALE RATS Treatment Group Dose 0 mg/kg/day III 25 mg/kg/day Examination Day : Test Day 80 Number of Rats Examined 20 10 There were no ophthaImological abnormalities detected. V 100 mg/kg/day Examination Day : Test Day 122 Number of Rats Examined 10 There were no ophfchalmological abnormalities detected. 121 Company Sanitized. Does not H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 15 SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR FEMALE RATS Treatment Group Dose II 0 mg/kg/day Examination day: Test day 80 Number of Rats Examined 20 Retina Retinal Degeneration Diffuse Left Incidence 0 ( 0%) IV 25 mg/kg/day 10 VI 100 mg/kg/day 10 0 ( 0%) 1 ( 10%) Examination day: Test day 122 Number of Rats Examined 9 There were no ophthalmological abnormalities detected. Incidence - The number of animals (percent of animals examined) for which an observation was Statistical Methods: Trend test (Cochran-Armitage). There were no statistically significant differences at p < 0.05. 122 Company Sanitized. Does no H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-53 86 TABLE 16 PERCENT SURVIVAL OF MALE RATS Treatment Group Dose (nig/kg/day) Animal Count at Study Start DAYS ON TEST 0 7 14 21 28 35 42 49 56 63 70 77 a 84 91 t:d 98 105 112 119 I III 0 25 45 35 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 V 100 35 100 100 100 100 100 100 100 100 100 100 100 100 100 b 100 100 100 100 100 VII 250 45 100 100 100 100 100 100 100 100 100 100 100 100 b 100 100 100 100 100 100 Number at study start Accidentally Killed Removed from study a Sacrificed by design d Alive on test day 119 45 35 35 45 0 0 1 1 20 20 20 19 10 10 9 10 15 5 5 15 Percent Survival = (Number of rats alive/Number of rats at risk)*100 Number of rats at risk = Number at study start - number of rats removed from study - number sacrificed by design - accidentally killed. a. Rats designated for reproduction evaluation were removed from study (cohoused) on test day 74. b. One rat was accidentally killed during the previous week. c. Recovery period began on test day 90. d. Rats designated for the 90-day exposure period were sacrificed on test day 91. There were no statistically significant decreases in survival at p < 0.05 by Cochran-Armitage trend test. Company Sanitized. Dow not contain TSCA CBI 123 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 17 PERCENT SURVIVAL OF FEMALE RATS II Treatment Group Dose (mg/kg/day) 0 Number Animals at Study Start 45 IV VI VIII 25 100 250 35 35 45 DAYS ON TEST 0 7 14 21 28 35 42 49 56 63 70 77 " 84 91 f'9 98 105 112 119 100 100 a 100 100 100 100 100 100 100 100 100 100 100 100 100 100 97 c 100 100 97 100 100 97 100 100 97 100 100 97 100 100 97 100 100 93 100 100 93 100 100 93 100 100 80 100 100 80 100 93 c 80 100 93 80 100 100 100 100 100 100 100 100 100 100 b 100 98 d 96 96 96 96 96 96 96 Number at study start Accidentally killed Found dead 45 35 35 45 0 1 0 1 0 0 0 1 Sacrificed in extremis Removed from study e Sacrificed by design g Alive on test day 119 1 1 0 0 20 20 20 19 10 9 10 9 14 4 5 15 Percent Survival = (Number of rats alive/Number of rats at risk)*l00 Number of rats at risk = Number at study start - number of rats removed from study - number sacrificed by design - accidentally killed. a. One rat was accidentally killed on test day 0 and replaced day 0. b. One rat was accidentally killed during the previous week. c. One rat was sacrificed in extremis during the previous week. d. One rat was found dead during the previous week. e. Rats designated for reproduction evaluation were removed from study (cohoused) on test day 74. f. Recovery period began on test day 90. g. Rats designated for the 90-day exposure period were sacrificed on test day 93. There were no statistically significant decreases in survival at p < 0.05 by Cochran-Armitage trend test. Swrn^my United. D@s mi eontein TSCA CB_,,i ^ H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 18 MEAN FORELIMB AND HINDLIMB GRIP STRENGTH FOR MALE RATS (MEAN OF THREE TRIALS) Assessment Period____Group Dosage (mg/kg/day) Baseline I 0 III 25 V 100 VII 250 Week 13 I 0 III 25 V 100 VII 250 Forelimb Grip Strength (kg) 0.51 (0.08) 0.52(0.10) 0.54 (0.08) 0.54 (0.09) 1.38(0.34) 1.35(0.29) 1.38(0.32) 1.31 (0.23) Hindlimb Grip Strength (kg) 0.40 (0.06) 0.38 (0.07) 0.36 (0.03) 0.40 (0.06) 0.84(0.15) 0.80 (0.07) 0.80(0.13) 0.73(0.11) Recovery I 0 VII 250 1.27(0.31) 1.03(0.32) 0.74(0.14) 0.75 (0.09) Data arranged as : Mean (Standard Deviation) Statistical Methods: Bartlett's test for homogeneity followed by analysis of variance and Dunnett's test. There were no statistically significant differences from control at p<0.05. 125 Company Sanitized. Doe. not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 19 MEAN FORELIMB AND HINDLIMB GRIP STRENGTH FOR FEMALE RATS (MEAN OF THREE TRIALS) Assessment Period____Group Dosage (mg/kg/day) Baseline n o rv 25 VI 100 VIII 250 Week 13 ii 0 IV 25 VI 100 VIII 250 Forelimb Grip Strength (kg) 0.58 (0.08) 0.54(0.12) 0.54(0.12) 0.59(0.14) 1.18(0.25) 1.22(0.21) 1.04(0.21) 1.01 (0.22) Hindlimb Grip Strength (kg) 0.37 (0.04) 0.39 (0.06) 0.36 (0.05) 0.36 (0.04) 0.73(0.10) 0.72(0.12) 0.65(0.10) 0.64(0.14) Recovery ii 0 VIII 250 1.07(0.27) 1.13(0.35) 0.69 (0.09) 0.66(0.11) Data arranged as : Mean (Standard Deviation) Statistical Methods: Bartlett's test for homogeneity followed by analysis of variance and Dunnett's test. There were no statistically significant differences from control at p<0.05. Sanitized. Do-- not contain T8CA CBI Company 126 in---r ^-.""1 '.i ^ :"-"""rf "h "i--"1 v"aaiv: H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 20 SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR MALE RATS Group: Dosage (ing/kg/day): Number Examined: Baseline I III V VII 0 25 100 250 10 10 10 10 Week:13 I III V VII 0 25 100 250 10 10 9 10 Recoivery I VII 0 250 10 10 APPROACH & TOUCH: no reaction normal increased reaction (jumps away or attacks) 0 0 0 0 10 10 10 10 0 0 0 0 0 0 9 10 1 0 1 0 8 10 0 0 0 0 10 10 0 0 AUDITORY STIMULUS: no reaction normal reaction (rat flinches or flicks ear) exaggerated reaction (rat jumps, flips) 0 0 0 0 10 10 10 10 0 0 0 0 0 0 10 10 0 0 0 0 9 10 0 0 0 0 10 10 0 0 TAIL PINCH: no response normal (turns toward site) exaggerated response 0 1 0 0 9 9 9 10 1 0 1 0 0 0 0 0 10 9 9 10 0 1 0 0 0 0 9 10 1 0 IN MOTOR ACTIVITY MONITOR: DEFECATION present absent diarrhea 7 9 8 8 3 1 2 2 0 0 0 0 3 6 5 7 7 4 4 3 0 0 0 0 8 6 2 4 0 0 URINATION: present absent 7 8 7 4 3 2 3 6 4 7 3 7 6 3 6 3 7 5 3 5 PUPILLARY RESPONSE present absent 10 10 10 10 0 0 0 0 10 10 0 0 9 10 0 0 10 10 0 0 127 Company Sanitized. Doe* not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 20 (CONTINUED) SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR MALE RATS Group: Dosage (mg/kg/day): Number Examined: Baseline I III V VII 0 25 100 250 10 10 10 10 Week 13 I III V VII 0 25 100 250 10 10 9 10 Recovery I VII 0 250 10 10 ADDITIONAL OBSERVATIONS NOTED Sore, right axilla Present Absent 0 0 0 0 10 10 10 10 0 0 10 10 1 0 8 10 0 0 10 10 Ptosis present absent 0 0 0 0 10 10 10 10 0 0 10 10 0 0 9 10 There were no statistically significant differences by Cochran-Armitage test for trend at p < 0.05. 0 1 10 9 128 .Company SainifeeeL Doea not contain TSCA CBH H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 21 SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR FEMALE RATS Group: Dosage (mg/kg/day): Number Examined: Baseline II IV VI VIII 0 25 100 250 10 10 10 10 Week:13 II IV VI VIII 0 25 100 250 10 9 10 10 Recovery II VIII 0 250 9 10 APPROACH & TOUCH: no reaction normal increased reaction (jumps away or attacks) 0 0 0 0 10 10 10 10 0 0 0 0 0 0 0 0 10 9 10 10 0 0 0 0 0 0 9 10 0 0 AUDITORY STIMULUS: no reaction normal reaction (rat flinches or flicks ear) exaggerated reaction (rat jumps, flips) TAIL PINCH: no response normal (turns toward site) exaggerated response 0 0 0 0 10 10 10 10 0 0 0 0 0 0 10 10 0 0 0 0 9 10 1 0 0 0 1 0 10 9 9 10 0 0 0 0 0 0 0 0 10 9 10 9 0 0 0 1 0 0 9 10 0 0 0 0 9 10 0 0 IN MOTOR ACTIVITY MONITOR: DEFECATION present absent diarrhea 2 4 2 6 8 6 8 4 0 0 0 0 3 0 4 5 7 9 6 5 0 0 0 0 3 6 9 0 0 URINATION: present absent 7 6 5 9 3 4 5 1 2 2 3 4 8 7 7 6 6 3 3 7 PUPILLARY RESPONSE present absent 10 10 10 10 0 0 0 0 10 9 10 10 0 0 0 0 9 10 0 0 129 Company Sanitized. Doe* not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 21 (CONTINUED) SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR FEMALE RATS Group: Dosage (ing/kg/day): Number Examined: Baseline II IV VI VIII 0 25 100 250 10 10 10 10 Week 13 II IV VI VIII 0 25 100 250 10 9 10 10 Recovery II VIII 0 250 9 10 ADDITIONAL OBSERVATIONS NOTED Ptosis present absent Scratch, right comer of eye present absent 100 010 010 010 0 0 0 0 10 10 10 10 100 09 010 0 0 0 10 10 10 Chromodacryorrhea present absent 0 0 0 0 0 10 10 10 10 10 0 0 10 10 There were no statistically significant differences by Cochran-Armitage test for trend at p < 0.05. 130 'Qoss/SMmSyamftSzed. Does fiot contain TSCA CB! H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 22 MOTOR ACTIVITY ASSESSMENT: DURATION OF MOVEMENTS (sec) FOR MALE RATS ASSESSMENT DOSAGE PERIOD GROUP (mg/kg/day) SUCCESSIVE 10-MINUTE INTERVALS BASELINE I 1 1 3 4 5 6 T 0 430(67) 313(106) 275(89) 187(127) 70(81) 34(53) 1 III 25 419(45) 329(80) 257(138) 87(88) * 11(14) 5(6) 1 V 100 403(52) 322(59) 196(110)* 96(119)* 42(78) 54(91) 1 Vll 250 392(53) 287(61) 178(114)* 73(88) * 47(80) 46(78) 1 WEEK 13 I 1 2 3 4 5 6 T 0 40^(40) 301(45) 233(49) 174(63) 116(71) 102(108) 1 III 25 392(56) 297(66) 218(71) 172(109) 99(81) 72(46) 1 V 100 368(39) 273(58) 233(99) 180(103) 171(92) 135(87) 1 VII 250 368(71) 265(98) 210(117) 147(93) 145(84) 93(95) 1 RECOVERY 1 I 0 324(58) VII 250 295(52) Data arranged as: Mean (Standard Deviation). 2 202(45) 184(42) 3 140(44) 147(48) 4 5 6 T 141(51) 12K44) 140(58) 1 131(50) 120(47) 116(61) Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Repeated measures analysis of variance with lin contrasts was used to identify which dosage groups, if any, were significantly different from the control group. These tests applied to bin data and total data. * Statistically significant difference from control at p < 0.05. 131 Company Sanitized. Doe* not H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 23 MOTOR ACTIVITY ASSESSMENT: DURATION OF MOVEMENTS (sec) FOR FEMALE RATS ASSESSMENT DOSAGE PERIOD GROUP (mg/kg/day) SUCCESSIVE 10-MINUTE INTERVALS BASELINE 11 ] ! 2 4 S 6 T 0 3?T(45) 304(84) 161(109) 166(102) 130(90) 31(58) 11 IV 25 400(27) 286(60) 249(66) 153(110) 109(113) 32(42) 12 VI 100 409(50) 327(73) 169(135) 152(157) 92(128) 79(143) 12 VIII 250 364(48) 261(80) 222(97) 164(147) 104(141) 74(121) 11 WEEK 13 II 1 2 3, 4 5 6 T 0 372(56) 263(59) 221(89) 141(86) 108(66) 116(118) 12 IV 25 432(58) 323(94) 239(87) 166(103) 101(111) 153(84) 14 VI 100 386(76) 266(85) 202(129) 144(132) 134(111) 111(76) 12 VIII 250 371(69) 268(65) 148(96) 139(80) 111(73) 91(93) 11 RECIV^F,RY Data arranged as: 1 II 0 330(55) VIII 250 297(56) Mean (Standard Deviation). 1 223(57) 153(73) 3 173(29) 105(83) 4 157(69) 86(73) 5 106(41) 41(35) 6 T 10I(64) 10 92(62) 7 Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Repeated measures analysis of variance with line contrasts was used to identify which dosage groups, if any, were significantly different from the control group. These tests applied to bin data and total data. * Statistically significant difference from control at p < 0.05. 132 iDompanySanitized. Doe H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 24 MOTOR ACTIVITY ASSESSMENT: NUMBER OF MOVEMENTS FOR MALE RATS ASSESSMENT DOSAGE PERIOD GROUP (mg/kg/day) SUCCESSIVE 10-MtNUTE INTERVALS BASELINE I 1 1 3 4 5 6 T 0 120(31) 115(22) 124(22) 81(42) 49(45) 20(26) 5 III 25 117(24) 121(25) 107(33) 50(42) 9(10) 6(4) 4 V 100 123(17) 133(21) 111(33) 55(38) 30(40) 29(38) 4 VII 250 138(12) 140(17) 102(54) 54(55) 32(50) 34(49) 5 WEEK 13 1 2 3, 4 5 6 T I 0 128(31) 125(27) 109(29) 95(32) 69(38) 55(54) 5 III 25 129(20) 115(17) 106(20) 72(37) 52(38) 44(26) 5 V 100 151(25) 136(18) 119(38) 96(50) 108(44) 84(52) 6 VII 250 135(18) 122(27) 98(41) 80(40) 86(40) 56(43) 5 RECOVERY 1 1 0 133(19) VII 250 131(19) Data arranged as: Mean (Standard Deviation). 1 106(26) 96(20) 3 80(25) 81(26) 4, 87(18) 80(33) 5 77(20) 72(25) 6 T 80(24) 5 76(35) 5 Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Repeated measures analysis of variance with lin contrasts was used to identify which dosage groups, if any, were significantly different from the control group. These test applied to bin data and total data. There were no statistically significant differences from control at p < 0.05. 133 Company SanMzed. Does H-24516; Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 25 MOTOR ACTIVITY ASSESSMENT: NUMBER OF MOVEMENTS FOR FEMALE RATS ASSESSMENT DOSAGE PERIOD GROUP (mg/kg/day) SUCCESSIVE 10-MINUTE INTERVALS BASELINE 1 2 3 4, 5 6 T II 0 134(15) 137(16) 94(49) 95(49) 93(61) 28(37) 5 IV 25 130(16) 137(19) 135(19) 100(62) 64(61) 28(34) 6 VI 100 123(28) 127(26) 80(42) 66(51) 45(33) 34(46) 4 VIII 250 136(13) 132(35) 127(33) 90(63) 59(63) 47(63) 5 WEEK 13 1 2 3 4 5 6 T 11 0 143(16) 132(16) 120(31) 88(45) 7T(41) 74(67) 6 IV 25 123(31) 121(27) 106(51) 93(50) 59(52) 81(46) 5 VI 100 132(30) 118(26) 91(42) 67(50) 77(58) 73(43) 5 VIII 250 131(24) 125(12) 91(42) 92(41) 70(40) 55(42) 5 RECOVERY Data arranged as: 1 II 0 138(11) VIII 250 140(12) Mean (Standard Deviation). 2 130(15) 101(41) 3 111(16) 74(37) 4 110(27) 62(40) 5 80(20) 41(30) 6 T 83(50) 6 75(35) 4 Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Repeated measures analysis of variance with line contrasts was used to identify which dosage groups, if any, were significantly different from the control group. These tests applied to bin data and total data. * Statistically significant difference from control at p < 0.05. 134 .Company Sanitized. D H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 FABLE 26 SUMMARY OF HEMATOLOGY VALUES FOR MALE RA TS TEST/ PERIOD Group I Omg/kg Group ffl 25mg/kg Group V lOOmg/kg Group Vn 250 mg/kg RBC (xlO^uL) DAY 44 DAY 91 DAY 125 HGB (g/dL) DAY 44 DAY 91 DAY 125 HCT (%) DAY 44 DAY 91 DAY 125 MCV (fl) DAY 44 DAY 91 DAY 125 MCH (pg) DAY 44 DAY 91 DAY 125 8.22 0.41(10) 8.88 0.56(9) 8.93 0.38(10) 15.1 0.5(10) 15.3 0.7(9) 15.6 0.5(10) 46.0 1.7(10) 48.9 2.7(9) 48.3 1.8(10) 56.0 1.8(10) 55.2 2.5(9) 54.2 1.8(10) 18.4 0.6(10) 17.3 0.6(9) 17.5 0.6(10) 8.34 0.23(10) 8.57 0.38(9) a 15.3 0.4(10) 15.1 0.8(9) a 46.6 1.5(10) 47.4 2.9(9) a 55.9 1.5(10) 55.3 1.7(9) a 18.4 0.4(10) 17.7 0.4(9) a 7.96 0.36(10) 8.27* 0.35(9) a 15.1 0.6(10) 15.0 0.5(9) a 45.8 2.1(10) 47.2 2.1(9) a 57.6 1.4(10) 57.0 1.2(9) a 19.0 0.5(10) 18.1* 0.4(9) a 8.06 0.32(10) 7.99* 0.43(10) 7.97* 0.31(10) 14.8 0.4(10) 14.3* 0.8(10) 14.3* 0.8(10) 45.2 1.4(10) 45.4* 2.5(10) 43.9* 2.7(10) 56.1 1.3(10) 56.8 2.1(10) 55.0 2.1(10) 18.3 0.5(10) 17.8 0.5(10) 17.9 0.7(10) 135 Company Sanitized. Dow nol contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-5368 TABLE 26 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I Omg/kg Group m 25mg/kg Group V 100 mg/kg Group VII 250 mg/kg MCHC (g/dL) DAY 44 DAY 91 DAY 125 RDW (%) DAY 44 DAY 91 DAY 125 ARE^xlOVuL) DAY 44 DAY 91 DAY 125 WBC(xlOV^L) DAY 44 DAY 91 DAY 125 ANEU(xlOVuL) DAY 44 DAY 91 DAY 125 32.9 0.5(10) 31.3 0.6(9) 32.2 0.5(10) 12.2 0.5(10) 13.2 0.7(9) 13.6 0.8(10) 200 40(10) 181 49(9) 188 31(10) 17.36 2.17(10) 14.37 2.08(9) 13.11 3.83(10) 2.32 1.01(10) 2.14 0.47(9) 1.79 0.97(10) 32.9 0.7(10) 31.9* 0.4(9) a 12.1 0.5(10) 12.9 0.3(9) a 185 32(10) 179 23(9) a 16.34 4.10(10) 12.15 3.14(9) a 2.31 0.76(10) 1.92 0.47(9) a 32.9 0.5(10) 31.7 0.6(9) a 11.9 0.6(10) 13.5 0.5(9) a 179 21(10) 196 36(9) a 17.97 3.83(10) 14.04 3.05(9) a 2.50 0.75(10) 1.75 0.75(9) a 32.6 0.5(10) 31.4 0.4(10) 32.6 0.4(10) 12.6 0.4(10) 15.1@ 1.3(10) 12.7 1.3(10) 177 25(10) 218 46(10) 150* 22(10) 19.29 3.11(10) 15.25 3.14(10) 13.23 3.45(10) 2.48 0.97(10) 2.34 0.66(10) 1.94 0.74(10) 136 ^Bfflp^y ^8tei D@s "oS ^i^ TSCA CBi H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TAI)LE 26 (Continued) TEST/ PERIOD SUMNIARY OF HEMA'TOLOGY VALUE,S FOR MALE RATS Group I Omg/kg Group ffl 25mg/kg Group V 100 mg/kg Group Vn 250 mg/kg ALYMCxIOVnL) DAY 44 DAY 91 DAY 125 AMOKKxIO^uL) DAY 44 DAY 91 DAY 125 AEOS (xlOVuL) DAY 44 DAY 91 DAY 125 ABASCxIO^pL) DAY 44 DAY 91 DAY 125 14.19 1.91(10) 11.54 1.59(9) 10.60 3.36(10) 0.34 0.10(10) 0.45 0.20(9) 0.34 0.19(10) 0.16 0.04(10) 0.15 0.07(9) 0.14 0.08(10) 0.11 0.03(10) 0.03 0.04(9) 0.07 0.03(10) 13.03 4.07(10) 9.57 3.16(9) a 0.40 0.10(10) 0.38 0.21(9) a 0.23* 0.05(10) 0.20 0.15(9) a 0.10 0.04(10) 0.03 0.03(9) a 14.65 3.82(10) 11.56 3.23(9) a 0.39 0.17(10) 0.37 0.21(9) a 0.15 0.05(10) 0.17 0.10(9) a 0.11 0.07(10) 0.04 0.04(9) a 15.86 2.55(10) 12.12 2.80(10) 10.62 2.98(10) 0.44 0.13(10) 0.40 0.16(10) 0.28 0.11(10) 0.15 0.07(10) 0.21 0.13(10) 0.13 0.13(10) 0.10 0.05(10) 0.04 0.04(10) 0.08 0.05(10) 137 Company Sanitized. Doe not contain TSCA CBI H-24516; Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-5368 TABLE 26 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS TEST/ Group I Group III Group V PERIOD_________Omg/kg_____25 mg/kg____IQOmg/kg ALUC (xlOVuL) DAY 44 DAY 91 DAY 125 PLT (xlO3/^) DAY 44 DAY 91 DAY 125 0.24 0.06(10) 0.07 0.09(9) 0.17 0.12(10) 1141 103(9) 1178 153(7) 110059 126(7) 0.27 0.19(10) 0.07 0.07(9) a 1077 92(9) 1055 122(9) a 0.18 0.10(10) 0.15 0.17(9) a 1069 225(8) 1092 155(8) a Group VII 250mg/kg 0.26 0.14(10) 0.13 0.13(10) 0.18 0.06(10) 1008 102(8) 1111 90(7) 1081 78(9) Data arranged as: Mean Standard deviation (Number of values included in calculation) a Group not sampled at this timepoint. * Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett). @ Statistically significant difference from control at p < 0.05 by nonparametric test (Dunn's). 138 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations ___DuPont-5368 r FABLE 27 SUMIVIARY OF HEMATOLOGY VALUES FOR FEMALE R.\TS TEST/ PERIOD Group II Omg/kg Group IV 25mg/kg Group VI lOOmg/kg Group Vm 250 mg/kg RBC^xlO^uL) DAY 45 DAY 93 DAY 125 HGB (g/dL) DAY 45 DAY 93 DAY 125 HCT (%) DAY 45 DAY 93 DAY 125 MCV (fl) DAY 45 DAY 93 DAY 125 MCH (pg) DAY 45 DAY 93 DAY 125 8.26 0.17(10) 8.41 0.27(10) 7.95 0.38(9) 15.4 0.5(10) 15.5 0.5(10) 15.1 0.7(9) 46.9 1.1(10) 47.6 1.9(10) 45.7 2.0(9) 56.8 1.2(10) 56.6 1.5(10) 57.5 1.5(9) 18.7 0.5(10) 18.5 0.4(10) 19.1 0.3(9) 7.85 0.30(9) 8.08 0.28(9) a 14.8* 0.3(9) 15.2 0.6(9) a 44.9* 1.8(9) 45.7 2.0(9) a 57.2 1.7(9) 56.6 1.9(9) a 18.9 0.6(9) 18.8 0.7(9) a 8.14 0.45(10) 8.17 0.62(10) a 15.1 0.4(10) 15.1 0.5(10) a 45.6 1.7(10) 46.2 2.4(10) a 56.0 1.6(10) 56.8 3.9(10) a 18.5 0.6(10) 18.5 0.8(10) a 7.75* 0.45(10) 7.82* 0.32(9) 8.00 0.50(9) 14.5* 0.7(10) 14.2* 0.5(9) 14.8 0.8(9) 44.3* 2.1(10) 44.0* 1.5(9) ' 44.3 2.3(9) 57.1 1.2(10) 56.3 1.1(9) 55.5* 2.1(9) 18.7 0.7(10) 18.2 0.5(9) 18.5* 0.7(9) 139 Company Sanitized. Doe* not contain TSCA CBl H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 27 (Continued) TEST/ PERIOD SUMI^IARY OF HEN1ATOLOGY VALUES F OR FEMALE RATS Group n Omg/kg Group IV 25mg/kg Group VI 100 mg/kg Group Vffl 250 mg/kg MCHC (g/dL) DAY 45 DAY 93 DAY 125 RDW (%) DAY 45 DAY 93 DAY 125 ARETCxIO^L) DAY 45 DAY 93 DAY 125 WBC (xlOV^L) DAY 45 DAY 93 DAY 125 ANEUCxIO^L) DAY 45 DAY 93 DAY 125 32.9 0.8(10) 32.7 0.5(10) 33.2 0.8(9) 11.7 0.5(10) 11.3 0.5(10) 12.4 0.7(9) 208 25(10) 151 35(10) 171 24(9) 13.67 3.13(10) 9.96 1.66(10) 7.98 1.76(9) 1.77 0.70(10) 1.15 0.32(10) 1.13 0.27(9) 33.0 0.9(9) 33.2 1.4(9) a 11.9 0.5(9) 11.3 0.4(9) a 216 35(9) 157 0.036(9) a 12.83 2.99(9) 9.86 1.76(9) a 1.62 0.48'(9) 1.46 0.49(9) a 33.1 0.5(10) 32.6 1.2(10) a 11.7 0.7(10) 12.3 2.5(10) a 201 37(10) 219 181(10) a 13.42 3.12(10) 10.36 2.27(10) a 1.69 0.54(10) 2.31 0.94(10) a 32.7 0.8(10) 32.3 0.4(9) 33.4 0.5(9) 12.2 0.4(10) 12.3 1.0(9) 11.7@ 0.3(9) 210 39(10) 172 28(9) 145@ 39(9) 13.59 1.93(10) 10.50 1.98(9) 8.12 1.47(9) 1.81 0.67(10) 1.65 0.78(9) 1.58* 0.54(9) 140 iSmpMy Sanitized. Does nol contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-5368 TAIiLE 27 (Continued) TEST/ PERIOD SUMM.ARY OF HEMATOLOGY VALUES FOR FEMALE R,VTS Group II Omg/kg Group IV 25mg/kg Group VI lOOmg/kg Group Vffl 250 mg/kg ALYM (xlOVuL) DAY 45 DAY 93 DAY 125 AMON(xlO'/uL) DAY 45 DAY 93 DAY 125 AEOS(xlO'/uL) DAY 45 DAY 93 DAY 125 ABAS(xlO'/uL) DAY 45 DAY 93 DAY 125 11.10 2.43(10) 8.22 1.50(10) 6.41 1.77(9) 0.30 0.09(10) 0.21 0.07(10) 0.21 0.07(9) 0.19 0.07(10) 0.18 0.09(10) 0.10 0.04(9) 0.10 0.07(10) 0.08 0.02(10) 0.04 0.03(9) 10.52 2.87(9) 7.83 1.70(9) a 0.25 0.08(9) 0.24 0.10(9) a 0.10* 0.05(9) 0.14 0.06(9) a 0.09 0.05(9) 0.07 0.04(9) a 10.91 2.57(10) 7.39 2.29(10) a 0.31 0.08(10) 0.26 0.08(10) a 0.18 0.09(10) 0.22 0.09(10) a 0.11 0.05(10) 0.07 0.03(10) a 10.99 1.67(10) 8.19 1.66(9) 5.94 1.51(9) 0.29 0.10(10) 0.29 0.17(9) 0.29 0.14(9) 0.18 0.04(10) 0.18 0.06(9) 0.15* 0.03(9) 0.10 0.03(10) 0.05 0.03(9) 0.04 0.02(9) "vy 141 Company SanRIzed. Ooea nol contain TSCA CBI H-24516: Subchronic Toxieity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 27 (Continue d) TEST/ PERIOD su^4ARY OF HEMA'FOLOGY VALUE S FOR FEMALE BLATS Group n Omg/kg Group IV 25mg/kg Group VI lOOmg/kg Group Vffl 250 mg/kg ALUC (xlO'/uL) DAY 45 DAY 93 DAY 125 PLT(xlO'/uL) DAY 45 DAY 93 DAY 125 0.21 0.08(10) 0.12 0.05(10) 0.09 0.03(9) 1186 110(6) 1025 144(10) 1043 217(9) 0.24 0.18(9) 0.12 0.08(9) a 1081 202(9) 1004 102(8) a 0.22 0.09(10) 0.12 0.06(10) a 1084 108(8) 1118 105(6) 0.22 0.06(10) 0.14 0.07(9) 0.11 0.04(9) 1068 106(9) 1029 143(6) 1172 159(5) Data arranged as: Mean Standard deviation (Number of values included in calculation) a Group not sampled at this timepoint. * Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett). @ Statistically significant difference from control at p < 0.05 by nonparametric test (Dunn's). 142 jEteeapanSyairalSlzeA Does not eoniiw" v^n fy H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 28 SUMMARY OF COAGULATION VALUES FOR MALE RATS TEST/ Group I Group III Group V PERIOD__________Omg/kg_____25 mg/kg____lOOmg/kg PT (seconds) DAY 91 APTT (seconds) DAY 91 15.2 0.8(10) 18.7 2.5(10) 14.7 0.4(10) 16.3* 2.2(10) 15.2 0.9(9) 15.8* 2.1(9) Group VII 250mg/kg 15.5 0.7(10) 16.8 0.8(10) Data arranged as: Mean Standard deviation (Number of values included in calculation) * Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett). TABLE 29 SUMMARY OF COAGULATION VALUES FOR FEMALE RATS TEST/ Group II Group IV Group VI Group VIII PERIOD__________Omg/kg_____25 mg/kg____100 mg/kg____250 mg/kg PT (seconds) DAY 93 APTT (seconds) DAY 93 14.5 0.8(9) 17.1 1.4(9) 14.4 0.3(9) 15.8 1.4(9) 14.5 0.5(10) 15.4 1.7(10) 14.1 0.5(9) 15.1* 1.5(9) Data arranged as: Mean Standard deviation (Number of values included in calculation) * Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett). 143 Company Sanitized. Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 30 SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group I Omg/kg Group in 25mg/kg Group V lOOmg/kg Group VII 250 mg/kg AST (U/L) DAY 44 DAY 91 DAY 125 ALT (U/L) DAY 44 DAY 91 DAY 125 SDH (U/L) DAY 44 DAY 91 DAY 125 ALKJP (U/L) DAY 44 DAY 91 DAY 125 BILI (mg/dL) DAY 44 DAY 91 DAY 125 78 10(10) 99 29(10) 78 7(10) 30 4(10) 36 8(10) 33 7(10) 18.8 4.2(10) 28.6 8.1(10) 21.5 6.5(10) 134 31(10) 97 22(10) 81 18(10) 0.09 0.03(10) 0.07 0.03(10) 0.06 0.02(10) 84 13(10) 87 18(10) a 33 5(10) 36 8(10) a 17.9 4.6(10) 23.3 6.2(10) a 144 35(10) 95 20(10) a 0.09 0.04(10) 0.06 0.02(10) a 76 7(8) 80 15(9) a 28 6(8) 33 5(9) a 18.2 2.6(10) 23.4 5.8(9) a 156 21(8) 139* 20(9) a 0.08 0.04(8) 0.05 0.00(9) a 82 14(9) 96 30(10) 79 10(10) 33 8(9) 43 22(10) 36 14(10) 17.4 6.3(10) 25.8 9.1(10) 14.0* 3.4(10) 185* 30(9) 186* 32(10) 77 14(10) 0.06 0.02(9) 0.05 0.00(10) 0.05 0.00(10) 144 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 30 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY'VALUES FOR MALE RATS TEST/ PERIOD Group I Omg/kg Group ffl 25mg/kg Group V lOOmg/kg Group VU 250 mg/kg BUN (mg/dL) DAY 44 DAY 91 DAY 125 CREA (mg/dL) DAY 44 DAY 91 DAY 125 CHOL (mg/dL) DAY 44 DAY 91 DAY 125 TRIG (mg/dL) DAY 44 DAY 91 DAY 125 GLUC (mg/dL) DAY 44 DAY 91 DAY 125 14 2(10) 15 2(10) 15 1(10) 0.34 0.05(10) 0.42 0.07(10) 0.40 0.06(10) 84 22(10) 78 27(10) 75 13(10) 97 58(10) 127 51(10) 95 37(10) 110 17(10) 125 38(10) 127 37(10) 14 2(10) 15 2(10) a 0.31 0.05(10) 0.40 0.09(10) a 65 11(10) 65 13(10) a 90 30(10) 98 39(10) a 104 12(10) 102 14(10) a 15 2(10) 16 2(9) a 0.30 0.04(10) 0.39 0.05(9) a 56* 16(10) 48@ 16(9) a 75 38(8) 49* 24(9) a 108 11(10) 112 27(9) a 14 2(10) 15 1(10) 18* 2(10) 0.34 0.07(10) 0.45 0.06(10) 0.40 0.06(10) 54* 18(10) 47@ 15(10) 56* 10(10) 53 39(9) 39* 27(10) 55@ 37(10) 112 16(10) 116 30(10) 106 16(10) 145 Company Sanitized. Dow not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 30 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group I Omg/kg Group in 25mg/kg Group V lOOmg/kg Group Vn 250 mg/kg TP (g/dL) DAY 44 DAY 91 DAY 125 ALB (g/dL) DAY 44 DAY 91 DAY 125 GLOB (g/dL) DAY 44 DAY 91 DAY 125 CALC (mg/dL) DAY 44 DAY 91 DAY 125 IPHS (mg/dL) DAY 44 DAY 91 DAY 125 6.6 0.3(10) 6.9 0.4(10) 7.0 0.3(10) 4.1 0.2(10) 4.3 0.2(10) 4.4 0.2(10) 2.4 0.2(10) 2.6 0.2(10) 2.6 0.3(10) 10.8 0.4(10) 11.0 0.7(10) 10.6 0.3(10) 8.6 0.7(10) 9.2 2.2(10) 8.1 1.5(10) 6.6 0.3(10) 6.8 0.3(10) a 4.2 0.2(10) 4.4 0.2(10) a 2.4 0.2(10) 2.4 0.2(10) a 10.9 0.4(10) 10.6 0.4(10) a 9.1 0.5(10) 8.7 1.5(10) a 6.7 0.3(8) 7.1 0.4(9) a 4.3 0.5(8) 4.7* 0.2(9) a 2.5 0.4(8) 2.4 0.3(9) a 10.8 0.5(10) 10.5 0.5(9) a 9.5* 0.8(8) 8.9 1.0(9) a 7.3* 0.4(9) 7.7* 0.4(10) 6.7 0.3(10) 5.0 0.3(9) 5.4* 0.3(10) 4.3 0.3(10) 2.3 0.2(9) 2.3* 0.1(10) 2.4 0.2(10) 11.2 0.3(10) 10.9 0.5(10) 10.2* 0.3(10) 9.4 0.9(9) 9.1 1.4(10) 7.8 0.8(10) 146 SGSSOSWWOTi6teed. Does sw confta^ TSCA CBt sEfsmavyrw ^ H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-5368 TABLE 30 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group I Omg/kg Group ffl 25mg/kg Group V lOOmg/kg Group VII 250 mg/kg NA (mmol/L) DAY 44 DAY 91 DAY 125 K (mmol/L) DAY 44 DAY 91 DAY 125 CL (mmol/L) DAY 44 DAY 91 DAY 125 PFLU (ug/mL) DAY 44 DAY 91 DAY 125 144.5 1.9(10) 147.2 2.2(10) 146.4 0.8(10) 6.02 0.40(10) 6.33 0.60(10) 6.41 0.63(10) 100.5 1.8(10) 100.7 1.7(10) 103.4 0.9(10) a 0.1 0.0(10) 0.1 0.0(10) 143.5 1.0(10) 145.9 1.4(10) a 6.05 0.23(10) 6.07 0.42(10) a 99.4 2.1(10) 100.1 1.8(10) a a 0.2 0.0(10) a 144.4 0.9(10) 146.1 1.5(9) a 6.24 0.40(8) 6.24 0.39(9) a 99.5 2.3(10) 100.5 1.3(9) a a 0.4@ 0.1(9) a 143.9 1.2(10) 145.2* 2.0(10) 146.6 1.5(10) 5.98 0.47(9) 6.25 0.56(10) 6.05 0.41(10) 99.3 1.6(10) 98.9* 1.3(10) 103.4 1.6(10) a 0.7@ 0.1(10) 0.1 0.1(9) Data arranged as: Mean Standard deviation (Number of values included in calculation) a Group not sampled at this timepoint. * Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett). @ Statistically significant difference from control at p < 0.05 by nonparametric test (Dunn's). 147 Company SanKlzed. Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 31 SUMMARY OF SERUM AND PLASMA CHEMISTR'LVALUES FOR FEMALE RATS TEST/ PERIOD Group II Omg/kg Group IV 25mg/kg Group VI lOOmg/kg Group VIII 250 mg/kg AST (U/L) DAY 45 DAY 93 DAY 125 ALT (U/L) DAY 45 DAY 93 DAY 125 SDH (U/L) DAY 45 DAY 93 DAY 125 ALKP (U/L) DAY 45 DAY 93 DAY 125 BILI (mg/dL) DAY 45 DAY 93 DAY 125 87 14(10) 90 27(10) 124 61(9) 37 6(10) 33 8(10) 65 40(9) 18.2 5.4(10) 18.9 7.5(10) 25.8 12.0(9) 66 18(10) 42 10(10) 33 13(9) 0.13 0.04(10) 0.13 0.06(10) 0.10 0.04(9) 76 15(9) 79 16(9) a 31 7(9) 33 7(9) a 18.3 4.6(9) 16.4 3.8(9) a 71 22(9) 44 17(9) a 0.11 0.05(9) 0.10 0.04(9) a 77 17(10) 89 10(10) a 31 5(10) 33 4(10) a 16.3 3.8(10) 18.3 4.2(10) a 83 18(10) 55 15(10) a 0.11 0.04(10) 0.10 0.05(10) a 69* 8(10) 87 19(9) 152 198(10) 29* 8(10) 38 16(9) 62 72(10) 15.8 4.6(10) 17.2 5.0(9) 25.0 27.6(10) 81 18(10) 52 18(9) 38 14(10) 0.09 0.04(10) 0.11 0.04(9) 0.09 0.06(10) 148 fAiBBRoiKHu i<iMIeM rtaaa aw wwitufiK Y^S^A I**- H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 31 (Continued) SUMMARY OF SERUM AND I 'LASMA CHEMISTRY ^VALUES FOR FEMALE RATS TEST/ PERIOD Group II Omg/kg Group IV 25mg/kg Group VI lOOmg/kg Group Vin 250 mg/kg BUN (mg/dL) DAY 45 DAY 93 DAY 125 CREA (mg/dL) DAY 45 DAY 93 DAY 125 CHOL (mg/dL) DAY 45 DAY 93 DAY 125 TRIG (mg/dL) DAY 45 DAY 93 DAY 125 GLUC (mg/dL) DAY 45 DAY 93 DAY 125 16 2(10) 17 2(10) 16 3(9) 0.40 0.04(10) 0.47 0.05(10) 0.48 0.06(9) 83 12(10) 79 14(10) 106 36(9) 63 26(10) 160 136(10) 136 72(9) 97 9(10) 92 8(10) 107 20(9) 15 2(9) 16 2(9) a 0.35* 0.03(9) 0.44 0.04(9) a 89 19(9) 90 19(9) a 78 41(9) 87 45(9) a 109* 13(9) 97 5(9) a 16 2(10) 16 3(10) a 0.35* 0.05(10) 0.51 0.08(10) a 82 13(10) 76 13(10) a 44 18(10) 53@ 24(10) a 98 5(10) 100 17(10) a 16 2(10) 16 1(9) 16 2(10) 0.37 0.07(10) 0.50 0.06(9) 0.48 0.04(10) 92 15(10) 95 20(9) 98 51(10) 42 13(10) 54@ 22(9) 102 96(10) 101 7(10) 94 5(9) 104 14(10) 149 Company Sanitized. Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 31 (Continued) SUMMARY OF SERUM AND I'LASMA CHEMISTRY ^/ALUES FOR F EMALE RATS TEST/ PERIOD Group II Omg/kg Group IV 25mg/kg Group VI lOOmg/kg Group Vin 250 mg/kg TP (g/dL) DAY 45 DAY 93 DAY 125 ALB (g/dL) DAY 45 DAY 93 DAY 125 GLOB (g/dL) DAY 45 DAY 93 DAY 125 CALC (mg/dL) DAY 45 DAY 93 DAY 125 IPHS (mg/dL) DAY 45 DAY 93 DAY 125 7.3 0.5(10) 7.5 0.5(10) 8.2 0.5(9) 5.0 0.5(10) 5.2 0.5(10) 5.7 0.3(9) 2.3 0.2(10) 2.3 0.2(10) 2.5 0.3(9) 11.0 0.4(10) 10.8 0.3(10) 11.1 0.5(9) 7.5 0.7(10) 5.6 0.7(10) 5.7 0.9(9) 7.4 0.4(9) 7.8 0.4(9) a 5.0 0.4(9) 5.4 0.4(9) a 2.4 0.2(9) 2.4 0.1(9) a 11.2 0.4(9) 11.0 0.5(9) a 7.6 1.2(9) 6.0 0.5(9) a 7.7 0.3(10) 8.3* 0.4(10) a 5.4 0.2(10) 6.0* 0.3(10) a 2.3 0.2(10) 2.4 0.2(10) a 11.2 0.3(10) 11.3* 0.4(10) a 7.9 0.6(10) 6.7* 1.3(10) a 8.2* 0.4(10) 8.6* 0.4(9) 8.2 0.5(10) 5.7* 0.3(10) 6.0* 0.3(9) 5.5 0.3(10) 2.4 0.2(10) 2.6* 0.2(9) 2.7 0.3(10) 11.7* 0.4(10) 11.5* 0.3(9) 10.9 0.3(10) 7.8 0.5(10) 6.6* 0.7(9) 6.4 0.9(10) 150 ' aBDffizd. Does no! eonlWn Tfifta CB H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 31 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD Group n Omg/kg Group IV 25mg/kg Group VI 100 ing/kg Group Vm 250 mg/kg DAY 45 DAY 93 DAY 125 K (mmoVL) DAY 45 DAY 93 DAY 125 CL (nunol/L) DAY 45 DAY 93 DAY 125 PFLU (ug/mL) DAY 45 DAY 93 DAY 125 143.5 2.4(10) 143.7 1.6(10) 145.5 1.3(9) 5.66 0.21(10) 5.29 0.36(10) 5.31 0.44(9) 100.8 0.9(10) 99.2 2.2(10) 102.6 1.4(9) a 0.1 0.1(10) 0.1 0.0(9) 143.5 2.7(9) 142.8 1.6(9) a 5.73 0.40(9) 5.29 0.26(9) a 99.9 1.6(9) 98.9 2.3(9) a a 0.2 0.1(9) a 142.5 1.6(10) 144.1 2.2(10) a 5.88 0.28(10) 5.62 0.40(10) a 99.7 1.2(10) 99.3 2.1(10) a a 0.4@ 0.1(10) a 143.3 1.3(10) 143.2 1.3(9) 143.9* 1.8(10) 6.32* 0.32(10) 6.05* 0.40(9) 5.45 0.48(10) 99.5 1.0(10) 97.9 1.4(9) 103.2 1.8(10) a 0.8@ 0.2(9) 0.1 0.0(10) Data arranged as: Mean Standard deviation (Number ofvalues included in calculation) a Group not sampled at this timepoint. * Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett). @ Statistically significant difference from control at p < 0.05 by nonparametric test (Dunn's). 151 'SSampsaSj[anitized. Ooe not wmimn TSCA CBS H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 32 TEST/ PERIOD SUMMARY OF URINALYSIS VALUES FOR MALE RATS Group I 6 mg/kg Group m 25mg/kg Group V 100 mg/kg Group Vn 250 mg/kg VOL (mL) DAY 44 DAY 91 DAY 125 UOSM (mOsm) DAY 44 DAY 91 DAY 125 SG DAY 44 DAY 91 DAY 125 pH DAY 44 DAY 91 DAY 125 URO (EU/dL) DAY 44 DAY 91 DAY 125 8.6 5.6(10) 7.1 5.6(10) 12.0 5.4(10) 1183 346(10) 1330 474(7) 952 364(10) 1.037 0.011(10) 1.048 0.017(9) 1.031 0.011(10) 7.2 0.6(10) 6.7 0.4(10) 6.8 0.5(10) 0.2 0.0(10) 0.2 0.0(10) 0.2 0.0(10) 10.0 5.3(10) 10.0 6.8(9) a 1019 474(10) 1158 473(10) a 1.032 0.014(10) 1.036 0.013(10) a 7.3 0.8(10) 6.9 0.7(10) a 0.3 0.3(10) 0.3 0.3(10) a 8.0 5.6(10) 10.0 9.0(9) a 1333 592(9) 1315 556(9) a 1.045 0.019(10) 1.040 0.016(9) a 7.0 0.6(10) 7.1 0.8(9) a 0.2 0.0(10) 0.2 0.0(9) a 17.1 16.7(10) 15.4@ 7.0(10) 7.2@ 6.1(10) 938 685(10) 793 297(10) 1759* 932(10) 1.029 0.019(10) 1.027* 0.009(10) 1.051* 0.023(10) 7.5 0.7(10) 6.6 0.5(10) 6.6 0.5(10) 0.2 0.0(10) 0.2 0.0(10) 0.2 0.0(10) 152 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 32 (Continuec1) TEST/ PERIOD SUIAVIARY OF UR^JALYSIS VALUES5 FOR MALE RA'rs Group I Omg/kg Group m 25mg/kg Group V 100 mg/kg Group Vn 250 mg/kg UFLU(ag) DAY 44 DAY 91 DAY 125 DAY 181 UMTP (mg/dL) DAY 44 DAY 91 DAY 125 a 20.2 5.3(7) 14.2 2.9(10) 12.1 4.8(5) 77 37(10) 119 71(10) 66 49(10) a 213.0 36.8(9) a 22.8 3.2(5) 63 47(10) 78 64(10) a a 662.7@ 188.5(9) a 39.1* 11.5(5) 103 53(10) 91 50(9) a a 1473.6 313.0(10) 87.4* 22.8(10) 69.1* 6.6(5) 66 60(10) 40* 20(10) 121 73(10) Data arranged as: Mean Standard deviation (Number of values included in calculation) a Group not sampled at this timepoint. * Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett). @ Statistically significant difference from control at p < 0.05 by nonparametric test (Dunn's). 153 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 33 TEST/ PERIOD SU1V[MARY OF URIN ALYSIS VALUES F OR FEMALE RATS Group n Omg/kg Group IV 25mg/kg Group VI lOOmg/kg Group Vffl 250 mg/kg VOL (mL) DAY 45 DAY 93 DAY 125 UOSM (mOsm) DAY 45 DAY 93 DAY 125 SG DAY 45 DAY 93 DAY 125 pH DAY 45 DAY 93 DAY 125 URO (EU/dL) DAY 45 DAY 93 DAY 125 5.8 4.2(9) 3.1 3.1(7) 5.2 4.7(9) 1271 960(8) 1178 464(3) 976 380(7) 1.035 0.021(8) 1.044 0.021(4) 1.040 0.021(9) 7.1 0.8(9) 6.5 0.9(7) 5.7 0.4(9) 0.2 0.0(9) 0.2 0.0(7) 0.2 0.0(9) 6.9 3.6(9) 4.9 2.6(8) a 1117 711(9) 1204 372(7) a 1.033 0.017(9) 1.042 0.019(8) a 6.9 0.3(9) 6.4 0.7(8) a 0.2 0,0(9) 0.2 0.0(8) a 8.2 3.6(10) 4.0 3.0(10) a 786 249(10) 1541 622(9) a 1.024 0.007(10) 1.048 0.017(10) a 7.2 0.6(10) 6.2 0.4(10) a 0.2 0.0(10) 0.2 0.0(10) a 12.6* 4.6(10) 10.7@ 7.8(9) 6.2 3.1(7) 589 197(10) 764 269(9) 983 512(7) 1.018 0.006(10) 1.024 0.008(9) 1.031 0.014(7) 7.7 0.4(10) 6.2 0.8(9) 5.8 0.5(7) 0.2 0.0(10) 0.2 0.0(9) 0.2 0.0(7) 154 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 33 (Continued) TEST/ PERIOD SUMMARY OF URINALYSIS VALUES FOR FEMALE RATS Group n Omg/kg Group IV 25mg/kg Group VI 100 mg/kg Group Vffl 250 mg/kg UFLU(ug) DAY 45 DAY 93 DAY 125 DAY 181 UMTP (mg/dL) DAY 45 DAY 93 DAY 125 a 16.7 3.8(2) 8.6 5.1(7) 8.8 3.8(5) 41 34(9) 84 56(6) 109 130(9) a 99.2 32.1(6) a 15.9 6.9(3) 24 22(9) 49 43(8) a a 460.3 127.0(4) a 20.0 5.6(5) 18 5(10) 57 31(10) a a 914.7@ 618.1(9) 43.8@ 14.9(7) 29.3* 13.1(4) 21 11(10) 54 26(9) 69 76(7) Data arranged as: Mean Standard deviation (Number of values included in calculation) a Group not sampled at this timepoint. * Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett). @ Statistically significant difference from control at p < 0.05 by nonparametric test (Dunn's). 155 jOompany SanHized. Does not contain TSCA CBS H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 34 SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITY IN MALE RATS Group'1 Dosage (mg/kg/day) Hepatic Peroxisomal Beta-Oxidation Activity (nmol/min/mg prote 10-Day Time Point 90-Day Time Point 36-Day Recovery____92 I 0 4.71.71' 5.1 1.4 8.5 2.8 III0 25 8.9 1.8 13.0 4.8 V0 100 10.5 2.6* 20.7 1.5* VII 250 16.4 4.2* 44.5 9.9* 30.0 4.1* a. Group designations for animals evaluated at the 10-day time point are I-A, III-A, V-A, and VII-A. b. Mean standard deviation. The n = 5 for each group. c. Samples were not prepared for analysis from groups III and V at the 30- and 90-day recovery time points. * Statistically significant difference from control (p < 0.05) by Dunnett's test. 156 Company Sanitized. D H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 35 SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITY IN FEMALE RATS Group3 Dosage (mg/kg/day) Hepatic Peroxisomal Beta-Oxidation Activity (nmol/min/mg protei 10-Day Timepoint 90-Day Timepoint___36-Day Recovery____92-D II 0 8.12.213 7.8 1.9 9.6 1.4 IV 25 7.7 2.3 12.3 4.2 VI0 100 13.8 2.3* 26.9 3.7* VIII 250 21.1 2.8* 29.7 7.1* 19.9 3.6* a. Group designations for animals evaluated at the 10-day time point are II-A, IV-A, VI-A, and VIII-A. b. Mean standard deviation. The n = 5 for each group. c. Samples were not prepared for analysis from groups IV and VI at the 30- and 90-day recovery timepoints. * Statistically significant difference from control (p < 0.05) by Dunnett's test. 157 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 36 MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (90-DAY EXPOSURE EVALUATION) MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) LIVER KIDNEYS HEART Group I 0 mg/kg/day 15.61430 2.40914(10) 3.87130 0.32057(10) 1.71400 0.15515(10) Group III 25 mg/kg/day 16.87710 2.21000(10) 4.16070 0.40193(10) 1.71110 0.16522(10) Group V 100 ing/kg/day 21.08367# 2.16729(9) 4.18767# 0.26834(9) 1.53744ft 0.13457(9) Group VII 250 mg/kg/day 25.53740ft 2.01802(10) 4.62600ft 0.44545(10) 1.51080ft 0.12204(10) SPLEEH 0.82560 0.10868(10) 0.73400 0.17504(10) 0.79833 0.08688(9) 0.71340 0.07769(10) BRAIN 2.11810 0.06517(10) 2.16130 0.11475(10) 2.07144 0.09339(9) 2.09800 0.08814(10) THYMUS 0.44800 0.13463(10) 0.37290 0.09756(10) 0.37211 0.09829(9) 0.35967 0.07953(9) ADRENAL GLAMDS 0.05540 0.00947(10) 0.06010 0.00881(10) 0.05167 0.00811(9) 0.05450 0.00798(10) TESTES 3.62880 0.32307(10) 3.39690 0.38948(10) 3.55367 0.14742(9) 3.54910 0.30220(10) EPIDIDYMIDES 1.60570 0.15978(10) 1.50770 0.13254(10) 1.43100# 0.09600(9) 1.46750# 0.10973(10) FINAL BODY WEIGHT 569.92000 46.42274(10) 556.23001 62.22883(10) 514.55556ft 31.85973(9) 508.24000ft 35.48981(10^- 158 'ISeWW- leeirtataTSCACtt H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 36 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (90-DAY EXPOSURE EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% of body weight) Group I 0 mg/kg/day III Group 25 ing/kg/day Group V 100 mg/kg/day Group VII 250 mg/kg/day LIVER/ FINAL BODY * 100 2.72792 0.24256(10) 3.02910# 0.10928(10) 4.09189# 0.26331(9) 5.02981# 0.30664(10) KIDNEYS/ FINAL BODY * 100 0.68187 0.06254(10) 0.75073ft 0.05504(10) 0.81464ft 0.04174(9) 0.91000ft 0.05964(10) HEART/ FINAL BODY * 100 0.30111 0.01945(10) 0.30962 0.03418(10) 0.29877 0.01816(9) 0.29751 0.01679(10) SPLEEN/ FINAL BODY * 100 0.14549 0.02010(10) 0.13149 0.02476(10) 0.15512 0.01376(9) 0.14058 0.01383(10) BRAIM/ FINAL BODY * 100 0.37366 0.02959(10) 0.39140 0.03280(10) 0.40363ft 0.02587(9) 0.41417ft 0.02660(10) THYMUS/ FIHAL BODY * 100 0.07853 0.02208(10) 0.06735 0.01762(10) 0.07197 0.01718(9) 0.07151 0.01422(9) ADRENAL GLANDS/ FINAL BODY * 100 0.00978 0.00182 (10) 0.01087 0.00169(10) 0.01001 0.00120(9) 0.01073 0.00155(10) TESTES/ FINAL BODY * 100 0.64020 0.07536(10) 0.61616 0.09099(10) 0.69236 0.04100(9) 0.69863ft 0.04115(10) EPIDIDYMIDES/ FINAL BODY * 100 0.28214 0.02174(10) 0.27346 0.03430(10) 0.27948 0.02996(9) 0.28923 0.01927(10) 159 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 36 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (90-DAY EXPOSURE EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% organ to brain weight ratio) Group I mg/kg/day Group III 25 mg/kg/day Group V 100 mg/kg/day Group VII 250 mg/kg/day LIVER/ BRAIN * 100 KIDNEYS/ BRAIK * 100 735.74333 99.37257(10) 182.68506 12.66199(10) 780.17520 85.08778(10) 192.36680 13.14320(10) 1019.5284ft 115.06490(9) 202.51532ft 15.84059(9) 1218.7006ft 103.65133(10) 220.59585# 20.88300(10) HEART/ BRAIN * 100 SPLEEN/ BRAIN * 100 80.91023 6.82263(10) 38.93490 4.57844(10) 79.30874 8.23777(10) 33.91403 7.51428(10) 74.35749 7.41525(9) 38.56439 4.15459(9) 72.04801ft 5.53580(10) 34.01722 3.46850(10) THYMOS/ BRAIN * 100 21.03669 5.97190(10) 17.30890 4.63114(10) 18.00484 4.76335(9) 17.12540 3.81584(9) ADRENAL GLANDS/ BRAIN * 100 2.62137 0.47467(10) 2.78484 0.40829(10) 2.49488 0.38735(9) 2.59483 0.34618(10) TESTES/ BRAIN * 100 171.16403 11.88715(10) 156.96718 13.69597(10) 171.72378 7.58365(9) 169.09911 11.50305(10) EPIDIDYMIDES/ BRAIN * 100 75.74999 6.44128(10) 69.76881 4.95178(10) 69.16509 4.92678(9) 70.02996 5.78874(10) 160 Sswsay Sanitized. Doe* not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 36 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) Group I 0 mg/kg/day Group VII 250 mg/kg/day LIVER 15.30650 2.06770(10) 18.99580# 2.41188 (10) KIDNEYS 3.92180 0.43359 (10) 4.52600# 0.45123(10) HEART 1.78690 0.22877(10) 1.70310 0.09352 (10) SPLEEN 0.79060 0.15057(10) 0.82750 0.12262(10) BRAIN 2.15100 0.10458 (10) 2.14830 0.06237(10) THYMUS 0.30370 0.10010(10) 0.29500 0.08028(10) ADRENAL GLANDS 0.05500 0.00939 (10) 0.05390 0.00769 (10) TESTES 3.40390 0.45855 (10) 3.35360 0.56712(10) EPIDIDYMIDES 1.51050 0.21531(10) 1.89860 1.25596(10) FINAL BODY WEIGHT 590.65000 82.53324(10) 537.98000 37.55428(10) 161 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 36 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% of body weight) Group I 0 mg/kg/day Group VII 250 mg/kg/day LIVER/ FINAL BODY * 100 2.59628 0.14348(10) 3.52278# 0.28354(10) KIDNEYS/ FINAL BODY * 100 0.67037 0.07651(10) 0.84084# 0.05450 (10) HEART/ FINAL BODY * 100 0.30689 0.05285(10) 0.31726 0.01716 (10) SPLEEN/ FINAL BODY * 100 0.13384 0.01870(10) 0.15447 0.02480 (10) BRAIN/ FINAL BODY * 100 0.37046 0.05358(10) 0.40104# 0.02998 (10) THYMUS/ FINAL BODY * 100 0.05128 0.01463(10) 0.05494 0.01501(10) ADRENAL GLANDS/ FINAL BODY * 100 0.00943 0.00187(10) 0.01005 0.00145 (10) TESTES/ FINAL BODY * 100 0.58528 0.10321(10) 0.62490 0.11357(10) EPIDIDYMIDES/ FINAL BODY * 100 0.25949 0.04537 (10) 0.35028 0.22128 (10) 162 'Company Sanitized. Does not eonlate TSCA 681 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 36 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% organ to brain weight ratio) Group I 0 mg/kg/day Group VII 250 mg/kg/day LIVER/ BRAIN * 100 KIDNEYS/ BRAIN * 100 711.34075 88.59504(10) 182.34225 18.44671(10) 884.91171* 116.18812 (10) 210.72828# 20.63654(10) HEART/ BRAIN * 100 83.23074 11.73675(10) 79.38841 5.76903(10) SPLEEN/ BRAIN * 100 36.81368 7.14802(10) 38.56659 5.91619(10) THYMUS/ BRAIN * 100 14.01786 4.23746(10) 13.72581 3.74259(10) ADRENAL GLANDS/ BRAIN * 100 2.54745 0.35256(10) 2.51,164 0.37062(10) TESTES/ BRAIN * 100 158.19880 19.42657(10) 155.98933 25.95332 (10) EPIDIDYMIDES/ BRAIN * 100 70.20005 9.34995(10) 88.28783 58.20703 (10) 163 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 36 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (THREE-MONTH RECOVERY EVALUATION) MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) Groiup I C1 mg^/kg/day LIVER 16 .86360 1 .23511(5) KIDNEYS 4 .22420 0 .38656(5) THYROID GLAMD 0 .02460 0 .00288(5) TESTES 3 .73740 0 .41919(5) FINAL BODY WEIGHT 609 .24000 49 .85251(5) I I I Groiup 25 mi3/kg/day 14 .89120 1 .29310(5) 4 .12580 0 .60763(5) 0 .02120 0 .00455(5) 3 .71440 0 .46067(5) 584.40000 60.48766(5) Gro'up V 100 ]nng/kg/day 17 .20660 1 .65902(5) 4 .20240 0 .18598(5) 0 .02480 0 .00421(5) 3 .76060 0 .66540(5) Groiup VII 250 iaig/kg/day 18 .53760 3 .89685(5) 4.49080 0 .75755(5) 0 .02360 0 .00336(5) 3 .70660 0 .38273(5 ) 597 .36000 78 .98329(5) 589 .00000 118 .00491(5) 164 'S)ompsny Sanitized. Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 36 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (THREE-MONTH RECOVERY EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% of body weight) Gro up I 0 lng/kg/day I I I Groiup 2 5 mg/ikg/day Groiup v 1 00 mg /kg/day LIVER/ FINAL BODY * 100 2 .77049 0 .08130(5) 2 .55621 0 .17311(5) 2 .89634 0 .24254(5) KIDMEYS/ FINAL BODY * 100 0 .69433 0 .05264(5) 0 .70486 0 .06776(5) 0 .71061 0 .07278(5) THYROID GLAMD/ FINAL BODY 4- 100 0.00407 0.00064(5) 0 .00360 0.00048(5) 0 .00427 0.00114(5) TESTES/ FIMAL BODY * 100 0 .61346 0 .04906(5) 0 .64182 0 .11379(5) 0 .62851 0 .06407(5) Grolip VII 250 tmg/kg/day 3 .14311# 0 .14527(5) 0 .76965 0 .07781(5) 0 .00410 0.00082(5) 0 .64002 0 .07619(5) Data summarized as: Mean Standard Deviation (n) Statistical Methods: Trend test (Jonckheere-Terpstra). # Statistically significant difference at p = 0.05. 165 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 37 MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (90-DAY EXPOSURE EVALUATION) MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) I I Gro'up c1 mg /kg/day Group IV 25 mg/kg/day Grcnup VI 100 ]mg/kg/day Groiup VIII 250 1ng/kg/day LIVER 8 .42890 0 .89310(10) 9.28989 1.29807(9) 10 .29410# 0 .93782(10) 12.58311ft 1.50915(9) KIDNEYS 2 .06880 0 .21132(10) 2.34367#. 0.28624(9) 2 .32900# 0 .22209(10) 2 .60533ft 0 .26021(9) HEART 1 .00350 0 .11037(10) 1.13856 0.23821(9) 1 .01180 0 .06157(10) 1 .02956 0 .10404(9) SPLEEN 0 .50600 0 .10310(10) 0.50611 0.05648(9) 0 .50710 0 .10450(10) 0.52567 0.07700(9) BRAIN 1 .88390 0 .07620(10) 1.98522 0.10422(9) 1 .91420 0 .08526(10) 1 .94378 0 .09538(9) THYMUS 0 .29780 0 .10562(10) 0.31222 0.08160(9) 0 .28500 0 .06451(10) 0 .28444 0 .09108(9) ADRENAL GLANDS 0 .06490 0 .01047(10) 0.06567 0.00907(9) 0 .06550 0 .00956(10) 0 .06589 0 .00819(9) OVARIES 0 .11550 0 .02923(10) 0.12211 0.01825(9) 0 .12870 0 .01818(10) 0 .11122 0 .01719(9) UTERUS 0 .57820 0 .06982(10) 0.6.6122 0.23047(9) 0 .58070 0 .10303(10) 0 .66444 0 .19643(9) FINAL BODY WEIGHT 297 .45000 35 .81503(10) 303.66667 24.73525(9) 286 .41000 22 .00290(10) 283 .48889 31 .74474(9) 166 3. Dae not contain TSCACBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 37 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (90-DAY EXPOSURE EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% of body weight) I I Group 0 mg/kg/day Group IV 25 mg/kg/day Group VI 100 mg/kg/day Group VIII 250 mg/kg/day LIVER/ FINAL BODY * 100 2.84076 0.15250(10) 3.06088 0.33230(9) 3.59318# 0.15126(10) 4.44566# 0.32538(9) KIDHEYS/ FINAL BODY * 100 0.69736 0.03459(10) 0.77374# 0.08951(9) 0.81333# 0.04616(10) 0.92685# 0.12559(9) HEART/ FINAL BODY * 100 0.33821 0.02157(10) 0.37345 0.05777(9) 0.35399 0.01733(10) 0.36475 0.03120(9) SPLEEN/ FINAL BODY * 100 0.16960 0.02557(10) 0.16691 0.01532(9) 0.17675 0.03224(10) 0.18588 0.02188(9) BRAIN/ FINAL BODY * 100 0.64099 0.07665(10) 0.65779 0.06489(9) 0.67035 0.03525(10) 0.69254 0.07652(9) THYMUS/ FINAL BODY * 100 0.09848 0.02656(10) 0.10282 0.02489(9) 0.09959 0.02191(10) 0.09983 0.02528(9) ADRENAL GLANDS/ FINAL BODY * 100 0.02185 0.00259(10) 0.02170 0.00299(9) 0.02301 0.00405(10) 0.02353 0.00419(9) OVARIES/ FINAL BODY * 100 0.03897 0.00965(10) 0.04042 0.00646(9) 0.04513 0.00682(10) 0.03964 0.00742(9) UTERUS/ FINAL BODY * 100 0.19700 0-03626(10) 0.21987 0.08249(9) 0.20335 0.03753(10) 0.23844 0.08261(9) 167 Company Sanitized. Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 37 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (90-DAY EXPOSURE EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% organ to brain weight ratio) II Group 0 mg/kg/day Group IV 25 mg/kg/day Group VI 100 mg/kg/day Group VIII 250 mg/kg/day LIVER/ BRAIM * 100 KIDNEYS/ BRAIM * 100 447.97404 49.75332(10) 109.90153 11.16263(10) 468.70612 66.48212(9) 117.94290 12.14897(9) 537.69731ft 41.01697(10) 121.67541# 10.15327(10) 647.32738ft 71.76231(9) 133.95247ft 10.39944(9) HEART/ BRAIM * 100 SPLEEN/ BRAIN * 100 53.25450 5.29987(10) 26.83701 5.20406(10) 57.72897 14.36366(9) 25.51771 2.75891(9) 52.87944 2.70601(10) 26.45901 5.11411(10) 52.91567 4.05247(9) 27.02573 3.60259(9) ADRENAL GLANDS/ BRAIN * 100 3.43808 0.47647(10) 3.31554 0.48277(9) 3.42792 0.52547(10) 3.38577 0.34751(9) THYMUS/ BRAIN * 100 15.78037 5.45880(10) 15.77146 4.41570(9) 14.89897 3.36605(10) 14.67010 4.68613(9) OVARIES/ BRAIN * 100 6.12137 1.49504(10) 6.14360 0.78541(9) 6.72625 0.90372(10) 5.72555 0.84613(9) UTERUS/ BRAIN * 100 30.74888 4.02620(10) 33.16601 10.88714(9) 30.38154 5.49538(10) 34.36785 10.75106(9) 168 -Company SanHted. Does not contain TSCA CB1 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 37 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) II Group 0 mg/kg/day LIVER 10.09844 1.67206(9) KIDNEYS 2.43678 0.24189(9) HEART 1.17433 0.10505(9) SPLEEM 0.56733 0.08403 (9) BRAIN 1.92800 0.07213(9) THYMUS 0.26833 0.07819(9) ADRENAL GLANDS 0.06656 0.01321(9) OVARIES 0.11544 0.02939(9) UTERUS 0.69278 0.15294(9) FINAL BODY WEIGHT 353.11111 37.83244(9) Group VIII 250 mg/kg/day 9.99330 1.38877 (10) 2.50730 0.40643(10) 1.08270 0.08698(10) 0.53740 0.13757(10) 1.91180 0.09510 (10) 0.22790 0.04946(10) 0.07440 0.01056 (10) 0.11770 0.01938(10) 0.68910 0.20245 (10) 308.58000# 32.73340 (10) 169 Company Sanitized. Does not contain TSCA Ctt H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 37 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% of body weight) LIVER/ FINAL BODY * 100 KIDNEYS/ FINAL BODY * 100 HEART/ FINAL BODY * 100 SPLEEN/ FINAL BODY * 100 BRAIN/ FINAL BODY * 100 THYMUS/ FINAL BODY * 100 ADRENAL GLANDS/ FINAL BODY * 100 UTERUS/ FINAL BODY * 100 OVARIES/ FINAL BODY * 100 Group 11 0 mg/kg/day 2.85512 0.29184(9) 0.69394 0.06941(9) 0.33509 0.04017(9) 0.16188 0.02643(9) 0.55117 0.05678(9) 0.07543 0.01729 (9) 0.01885 0.00301(9) 0.19783 0.04722 (9) 0.03278 0.00845(9) Group VIII 250 ing/kg/day 3.24730 0.39525(10) 0.81594# 0.12449 (10) 0.35335 0.03687(10) 0.17524 0.04700(10) 0.62527ft 0.06535(10) 0.07430 0.01715(10) 0.02445# 0.00468 (10) 0.22259 0.05160(10) 0.03839 0.00689 (10) 170 Company Sanitized. Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 37 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% of organ to brain weight ratio) Group 11 0 mg/kg/day Group VIII 250 mg/kg/day LIVER/ BRAIM * 100 KIDNEYS/ BRAIN * 100 524.83765 90.51244 (9) 126.46850 12.50757(9) 521.86193 59.78217(10) 130.75642 16.47766(10) HEART/ BRAIN * 100 SPLEEN/ BRAIN * 100 61.06879 6.79149(9) 29.51530 4.82384(9) 56.66965 4.22303(10) 28.05377 6.80548(10) THYMUS/ BRAIN * 100 ADRENAL GLANDS/ BRAIN * 100 13.96338 4.15109(9) 3.44923 0.65823 (9) 11.88806 2.39151(10) 3.89537 0.55037(10) OVARIES/ BRAIN * 100 5.95250 1.37403(9) 6.15911 0.98456(10) UTERUS/ BRAIN * 100 35.89360 7.44208(9) 36.14787 10.89853(10) 171 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations____________DuPont-5368 TABLE 37 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (THREE-MONTH RECOVERY EVALUATION) MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHT (grams) II Group 0 mg/kg/day Group IV 25 mg/kg/day Group VI 100 mg/kg/day Group VIII 250 mg/kg/day LIVER 9.09860 1.06866(5) 9.22750 0.75842(4) 9.61700 1.19121(5) 11.08840ft 1.39013(5) KIDNEYS 2.32080 0.18101(5) 2.43700 0.15436(4) 2.46780 0.29636(5) 2.70440 0.54874(5) THYROID GLAMD 0.01660 0.00114(5) 0.01825 0.00419(4) 0.01920 0.00349(5) 0.01940 0.00351(5) FINAL BODY WEIGHT 312.62000 20.92813(5) 334.42501 28.71253(4) 315.18001 32.76441(5) 347.56000 55.42101(5) 172 CmnpfHfv emitted. Does not contain TSCA CB8 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 37 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (THREE-MONTH RECOVERY EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% of body weight) II Group 0 nig/kg/day Group IV 25 ing/kg/day Group VI 100 mg/kg/day Group VIII 250 mg/kg/day LIVER/ FINAL BODY * 100 2.90754 0.24314(5) 2.76175 0.12111(4) 3.05101 0.17390(5) 3.20511# 0.17235(5) KIDNEYS/ FINAL BODY * 100 0.74382 0.06063(5) 0.73438 0.09856(4) 0.78637 0.08983(5) 0.77523 0.06208(5) THYROID GLAND/ FINAL BODY * 100 0.00532 0.00041(5) 0.00556 0.00176(4) 0.00620 0.00161(5) 0.00574 0.00163(5) Data summarized as: Mean Standard Deviation (n) Statistical Methods: Trend test (Jonckheere-Terpstra). # Statistically significant difference at p = 0.05. 173 ^'ss^ , H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 38 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESION INCIDENCE ( LESIONS LIVER NO ABNORMALITY DISCOLORATION, DISCOLORATION, DETECTED MOTTLED, TAN. TAN, LEFT. KIDNEYS NO ABNORMALITY DETECTED TREATMENT (ing/kg/day) 0 I (10) 10 (10) 10 Males 25 100 III V (10) (10) 10 9 1 (10) (10) 10 10 LUNGS NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 HEART NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 SKELETAL MUSCLE NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 SPLEEN NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 AORTA NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 174 Company Sanitized. Does H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESION INCIDENCE LESIONS BRAIN NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) 0 I (10) 10 Males 25 100 III V (10) (10) 10 10 SPINAL CORD NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 STOMACH NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 SMALL INTESTINE DISTENDED WITH GAS.. DUODENUM NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 JEJUNUM NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 ILEUM NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 PANCREAS NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 175 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESION INCIDENCE ( Males LESIONS CECUM NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) 0 I (10) 10 25 III (10) 10 100 V (10) 10 COLON NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 RECTUM NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 SALIVARY GLANDS NO ABNORMALITY DETECTED EDEMA. , (10) (10) (10) 10 10 10 MAMDIBULAR LYMPH NODE NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 THYMUS NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 ADRENAL GLANDS NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates, the finding specified was not identified 176 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESION INCIDENCE ( Males LESIONS SCIATIC NERVE NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) 0 I (10) 10 25 III (10) 10 100 V (10) 10 PITUITARY GLAND NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 THYROID GLAND NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 PARATHYROID GLANDS NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 TRACHEA NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 ESOPHAGUS NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 PHARYNX/LARYNX NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 177 \sy , H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION E LESION INCIDENCE ( Males LESIONS SKIN NO ABNORMALITY DETECTED STAIN, RED, FACE. TREATMENT (mg/kg/day) 0 I (10) 10 25 III (10) 10 100 V (10) 10 PROSTATE NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 SEMINAL VESICLES NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 URINARY BLADDER NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 TESTES NO ABNORMALITY DETECTED (10) 10 (10) 10 ' (10) 10 EPIDIDYMIDES NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 FEMUR/KNEE JOINT NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 STERNUM NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 178 paipanx Santtbed. Doenoc H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESION INCIDENCE ( Males LESIONS MOSE NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) 0 I (10) 10 25 III (10) 10 100 V (10) 10 PLEURAL CAVITY FLUID, CLEAR. MANDIBLE NO ABNORMALITY DETECTED (10) (10) (9) 10 10 9 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 179 v2.y H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (ONE-MONTH RECOVERY EVALUATION) LESIONS LIVER NO ABNORMALITY DETECTED KIDNEYS NO ABNORMALITY DETECTED LUNGS NO ABNORMALITY DETECTED HEART NO ABNORMALITY DETECTED SKELETAL MUSCLE NO ABNORMALITY DETECTED SPLEEN NO ABNORMALITY DETECTED DEFORMITY. AORTA NO ABNORMALITY DETECTED BRAIN NO ABNORMALITY DETECTED Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified TREATMENT (mg/kg/day) LESIO M 0 I (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 9 1 (10) 10 (10) 10 180 Company Sanitized. Does not ^ ^y. H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (ONE-MONTH RECOVERY EVALUATION) LESIONS SPINAL CORD NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED PANCREASNO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified TREATMENT (ing/kg/day) LESION M 0 I (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 181 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION M 0 I RECTUM NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED DISCOLORATION, RED. THYMUS NO ABNORMALITY SMALL. ' DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 9 1 (10) 9 1 (10) 10 (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 182 Oompany SanRIzed. Doe H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION M 0 I PITUITARY GLAND NO ABNORMALITY DETECTED THYROID GLAND NO ABNORMALITY DETECTED PARATHYROID GLANDS NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED SKIN NO ABNORMALITY DETECTED Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 183 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (ONE-MONTH RECOVERY EVALUATION) LESIONS PROSTATE NO ABNORMALITY DETECTED SEMINAL VESICLES NO ABNORMALITY DETECTED SMALL, LEFT. URINARY BLADDER NO ABNORMALITY DETECTED TESTES NO ABNORMALITY DETECTED SOFT, BILATERAL. DEFORMITY, RIGHT. SMALL, LEFT. EPIDIDYMIDES NO ABNORMALITY DETECTED DEFORMITY, LEFT. SMALL, LEFT. SMALL, RIGHT. FEMUR/KNEE JOINT NO ABNORMALITY DETECTED Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified TREATMENT (mg/kg/day) LESIO M 0 I (10) 10 (10) 10 (10) 10 (10) 8 1 1 (10) 8 1 1 (10) 10 184 Company SanSteed. Does not eonlat H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (ONE-MONTH RECOVERY EVALUATION) LESIONS STERNUM NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED MANDIBLE NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESIO M 0 I (10) 10 (10) 10 (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 185 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (THREE-MONTH RECOVERY EVALUATION) LESION INCIDENCE Males LESIONS LIVER NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) 0 I (5) 5 50 III (5) 5 100 V (5) 5 KIDNEYS NO ABNORMALITY DETECTED (5) (5) (5) 5 5 5 LUNGS NO ABNORMALITY DETECTED (5) (5) (5) 5 5 5 HEART NO ABNORMALITY DETECTED (5) (5) (5) 5 5 5 SKELETAL MUSCLE NO ABNORMALITY DETECTED (5) (5) (5) 5 5 5 SPLEEN NO ABNORMALITY DETECTED (5) (5) (5) 5 5 5 AORTA NO ABNORMALITY DETECTED (5) (5) (5) 5 5 5 BRAIN NO ABNORMALITY DETECTED (5) (5) (5) 5 5 5 Figures in parentheses is the number of.animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 186 'efisgwy SsmStoA Does no H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (THREE-MONTH RECOVERY EVALUATION) LESIONS SPINAL CORD NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED PANCREAS NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED COLON MO ABNORMALITY DETECTED TREATMENT. (mg/kg/day) LESION INCIDENCE 0 I (5) 5 Males 50 100 III V (5) (5) 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates, the finding specified was not identified 187 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (THREE-MONTH RECOVERY EVALUATION) LESIONS RECTUM NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED PITUITARY GLAND NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESION INCIDENCE ( Males 0 50 100 I (5) 5 III (5) 5 V (5) 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 188 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (THREE-MONTH RECOVERY EVALUATION) LESIONS THYROID GLAND NO ABNORMALITY DETECTED PARATHYROID GLANDS NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED SKIN NO ABNORMALITY DETECTED PROSTATE NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESION INCIDENCE ( Males 0 50 100 I (5) 5 III (5) 5 V (5) 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 189 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (THREE-MONTH RECOVERY EVALUATION) LESION INCIDENCE ( LESIONS SEMINAL VESICLES NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) 0 I (5) 5 Males 50 100 III V (5) (5) 5 5 URINARY BLADDER NO ABNORMALITY DETECTED (5) (5) (5) 5 5 5 TESTES NO ABNORMALITY DETECTED SMALL, SOFT, RIGHT. EPIDIDYMIDES NO ABNORMALITY DETECTED (5) (5) (5) 5 4 5 1 (5) (5) (5) 5 5 5 FEMUR/KNEE JOINT NO ABNORMALITY DETECTED (5) (5) (5) 5 5 5 STERNUM NO ABNORMALITY DETECTED (5) (5) (5) 5 5 5 NOSE NO ABNORMALITY DETECTED (5) (5) (5) 5 5 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 190 company SaniHzed. Does not con '^ , H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESION INCIDENCE Females LESIONS LIVER NO ABNORMALITY DETECTED TREATMENT (ing/kg/day) 0 II (10) 10 25 IV (10) 10 100 VI (10) 10 KIDNEYS NO ABNORMALITY DETECTED DISCOLORATION, TAN, BILATERAL. DILATATION, BILATERAL, PELVIS. LUNGS NO ABNORMALITY DETECTED DISCOLORATION, DARK. (10) 10 (10) 10 (10) 9 1 1 (10) 10 (10) 10 (10) 9 1 HEART NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 SKELETAL MUSCLE NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 SPLEEN NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 AORTA NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 N=11 in Group VIII reflects one reproduction designated animal that died on test day 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 191 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS BRAIN NO ABNORMALITY DETECTED SPINAL CORD NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED PANCREAS NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESION INCIDENCE ( Females 0 25 100 II (10) 10 IV (10) 10 VI (10) 10 (10) (10) (10) 10 10 10 (10) (10) (10) 10 10 10 (10) (10) (10) 10 10 10 (10) (10) (10) 10 10 10 (10) (10) (10) 10 10 10 (10) (10) (10) 10 10 10 (10) (10) (10) 10 10 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 192 Sompany SanHfasd. Does not contajn TS H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESION INCIDENCE ( Females LESIONS COLON NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) 0 II (10) 10 25 IV (10) 10 100 VI (10) 10 RECTUM NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 SALIVARY GLANDS NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 THYMUS NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 ADRENAL GLANDS NO ABNORMALITY DETECTED LARGE, BILATERAL. (10) (10) (10) 10 10 10 SCIATIC NERVE NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 193 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVAL LESION INCIDENCE ( Females LESIONS PITUITARY GLAND NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) 0 II (10) 10 25 IV (10) 10 100 VI (10) 10 THYROID GLAND NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 PARATHYROID GLANDS NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 TRACHEA NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 ESOPHAGUS NO ABNORMALITY DETECTED PUNCTURE, GAVAGE ERROR. (10) (10) (10) 10 10 10 PHARYNX/LARYNX NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 SKIN NO ABNORMALITY DETECTED (10) (10) (10) 10 10 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 194 Company SanRtesA Does not conta H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS SKIN STAIN. RED, PERINEUM. MAMMARY GLAND (FEMALE) NO ABNORMALITY DETECTED OVARIES NO ABNORMALITY DETECTED UTERUS NO ABNORMALITY DETECTED URINARY BLADDER NO ABNORMALITY DETECTED CALCULUS\CALCULI. DILATATION. FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESION INCIDENCE Females 0 25 100 II IV VI (10) (10) (10) (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 9 1 1 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 195 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS NOSE NO ABNORMALITY DETECTED MANDIBLE NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESION INCIDENCE ( Females 0 25 100 II (10) 10 IV (10) 10 VI (10) 10 (10) (9) (9) 10 9 9 Figures .in parentheses is the number of animals grossly examined for this tissue The absence o"f a number indicates the finding specified was not identified 196 Samoany SanHfaed. Does not eo H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) LESIO F LESIONS LIVER NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) 0 II (10) 10 KIDNEYS NO ABNORMALITY DETECTED CALCULUS\CALCULI, BILATERAL. (10) 9 1 LUNGS NO ABNORMALITY DETECTED (10) 10 HEART NO ABNORMALITY DETECTED (10) 10 SKELETAL MUSCLE NO ABNORMALITY DETECTED (10) 10 SPLEEN NO ABNORMALITY DETECTED (10) 10 AORTA NO ABNORMALITY DETECTED (10) 10 BRAIN NO ABNORMALITY DETECTED (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 197 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) LESIONS SPINAL CORD NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED PANCREAS NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESIO F 0 II (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 198 @c ifjfSt <L Dow n H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) LESIO F LESIONS RECTUM NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) 0 II (10) 10 MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED (10) 10 SALIVARY GLANDS NO ABNORMALITY DETECTED (10) 10 MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED (10) 10 THYMUS NO ABNORMALITY DETECTED (10) 10 ADRENAL GLANDS NO ABNORMALITY DETECTED (10) 10 SCIATIC NERVE NO ABNORMALITY DETECTED (10) 10 PITUITARY GLAND NO ABNORMALITY DETECTED LARGE. (10) 8 2 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 199 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) LESIONS THYROID GLAND NO ABNORMALITY DETECTED PARATHYROID GLANDS NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED SKIN NO ABNORMALITY DETECTED MAMMARY GLAND (FEMALE) NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESIO F 0 II (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 Figures in parentheses is the number of .animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 200 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OP GROSS OBSERVATIONS IN FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) LESIONS OVARIES NO ABNORMALITY DETECTED UTERUS NO ABNORMALITY DETECTED URINARY BLADDER NO ABNORMALITY DETECTED CALCULUS\CALCULI. FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED MANDIBLE NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESION F 0 II (10) 10 (10) 10 (10) 9 1 (10) 10 (10) 10 (10) 10 (9) 9 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 201 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (THREE-MONTH RECOVERY EVALUATION) LESION INCIDENCE ( Females LESIONS LIVER NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) 0 II (5) 5 25 IV (4) 4 100 VI (5) 5 KIDNEYS NO ABNORMALITY DETECTED (5) (4) (5) 5 4 5 LUNGS NO ABNORMALITY DETECTED (5) (4) (5) 5 4 5 HEART NO ABNORMALITY DETECTED (5) (4) (5) 5 4 5 SKELETAL MUSCLE NO ABNORMALITY DETECTED (5) (4) (5) 5 4 5 SPLEEN NO ABNORMALITY DETECTED (5) (4) (5) 5 4 5 AORTA NO ABNORMALITY DETECTED (5) (4) (5) 5 4 5 BRAIN NO ABNORMALITY DETECTED (5) (4) (5) 5 4 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 202 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (THREE-MONTH RECOVERY EVALUATION) LESION INCIDENCE ( Females LESIONS SPINAL CORD NO ABNORMALITY DETECTED TREATMENT (ing/kg/day) 0 II (5) 5 25 IV (4) 4 100 VI (5) 5 STOMACH NO ABNORMALITY DETECTED (5) (4) (5) 5 4 5 DUODENUM NO ABNORMALITY DETECTED (5) (4) (5) 5 4 5 JEJUNUM NO ABNORMALITY DETECTED (5) (4) (5) 5 4 5 ILEUM NO ABNORMALITY DETECTED (5) (4) (5) 5 4 5 PANCREAS NO ABNORMALITY DETECTED (5) (4) (5) 5 4 5 CECUM NO ABNORMALITY DETECTED (5) (4) (5) 5 4 5 COLON NO ABNORMALITY DETECTED (5) (4) (5) 5 4 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 203 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (THREE-MONTH RECOVERY EVALUATION) LESION INCIDENCE ( Females LESIONS RECTUM NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) 0 II (5) 5 25 IV (4) 4 100 VI (5) 5 MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED (5) (4) (5) 5 4 5 SALIVARY GLANDS NO ABNORMALITY DETECTED (5) (4) (5) 5 4 5 MANDIBULAR LYMPH MODE NO ABNORMALITY DETECTED (5) (4) (5) 5 4 5 THYMUS NO ABNORMALITY DETECTED (5) (4) (5) 5 4 5 ADRENAL GLANDS NO ABNORMALITY DETECTED (5) (4) (5) 5 4 5 SCIATIC NERVE NO ABNORMALITY DETECTED (5) (4) (5) 5 4 5 PITUITARY GLAND NO ABNORMALITY DETECTED (5) (4) (5) 5 4 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 204 Sompany Sanitized. Does not eont H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (THREE-MONTH RECOVERY EVALUATION) LESIONS THYROID GLAND NO ABNORMALITY DETECTED PARATHYROID GLANDS NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED SKIN NO ABNORMALITY DETECTED MAMMARY GLAND (FEMALE) NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESION INCIDENCE ( Females 0 25 100 II (5) 5 IV (4) 4 VI (5) 5 (5) (4) (5) 5 4 5 (5) (4) (5) 5 4 5 (5) (4) (5) 5 4 5 (5) (4) (5) 5 4 5 (5) (4) (5) 5 4 5 (5) (4) (5) 5 4 5 (5) (4) (5) 5 4 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 205 H-24516; Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (THREE-MONTH RECOVERY EVALUATION) LESIONS OVARIES NO ABNORMALITY DETECTED UTERUS NO ABNORMALITY DETECTED URINARY BLADDER NO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESION INCIDENCE ( Females 0 25 100 II (5) 5 IV (4) 4 VI (5) 5 (5) (4) (5) 5 4 5 (5) (4) (5) 5 4 5 (5) (4) (5) 5 4 5 (5) (4) (5) 5 4 5 (5) (4) (5) 5 4 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 206 Company Sanitized Dees not ^^ . H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESION INCIDEN LESIONS DIGESTIVE SYSTEM TREATMENT 0 25 (mg/kg/day) I III LIVER NO ABNORMALITY DETECTED NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC. HYPERTROPHY, HEPATOCYTE, CENTRILOBULAR. FATTY CHANGE, MEDIAN CLEFT. FATTY CHANGE, CENTRILOBULAR. (10) 10 2 1 (10) 1 9 2 2 PANCREAS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. ATROPHY. (10) 7 2 2 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 207 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVAL LESION INCIDEN LESIONS DIGESTIVE SYSTEM TREATMENT 0 25 (mg/kg/day) I III ESOPHAGUS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. EDEMA. (10) 10 STOMACH NO ABNORMALITY DETECTED (10) 10 DUODENUM NO ABNORMALITY DETECTED (10) 10 JEJUNUM NO ABNORMALITY DETECTED (10) 10 ILEUM NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 208 Company SanHized. Does not contain T H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS DIGESTIVE SYSTEM CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED RECTUM NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESION INCIDEN 0 25 I III (10) 10 (10) 10 (10) 10 (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 209 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVAL LESIONS URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. HYPERTROPHY, TUBULAR. HYDRONEPHROSIS, UNILATERAL. HYDRONE PHROSIS, BI LATERAL. URINARY BLADDER NO ABNORMALITY DETECTED | LESIOM INCIDEN TREATMENT 0 25 (mg/kg/day) I III (10) 6 4 (10) 7 3 (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 210 eempanr ^anftte*1 Do H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS PROM THE REPRODUCTION EVA LESIONS TREATMENT (mg/kg/day) RESPIRATORY SYSTEM LUNGS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. INFLAMMATION, GRANULOMATOUS. TRACHEA NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED HEMORRHAGE. NOSE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. HYPERPLASIA/HYPERTROPHY, TRANSITIONAL CELL, EPITHELIUM. DEGENERATION/NECROSIS, RESPIRATORY, EPITHELIUM. DEGENERATION, AMELOBLASTS. LESION INCIDEN 0 25 I III (10) 8 2 (10) 10 (10) 10 (10) (10) 10 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 211 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS CARDIOVASCULAR SYSTEM HEART NO ABNORMALITY DETECTED CARDIOMYOPATHY. INFLAMMATION, SUBACUTE/CHRONIC. AORTA NO ABNORMALITY DETECTED | LESION INCIDE TREATMENT 0 25 (mg/kg/day) I III (10) 5 5 (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 212 Company SanitSzed. Does not contai H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED ATROPHY. - MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED BONE MARROW NO ABNORMALITY DETECTED HYPERPLASIA, GRANULOCYTIC. TREATMENT (mg/kg/day) LESION INCIDEN 0 25 I III (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 213 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS ENDOCRINE SYSTEM PITUITARY GLAND NO ABNORMALITY DETECTED THYROID GLAND NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. HYPERTROPHY, FOLLICULAR. ALTERATION, COLLOID. PARATHYROID GLANDS . NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESION INCIDEN 0 25 I III (10) 10 (10) 1 1 9 (8) 8 (10) 10 (10) 1 9 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 214 Company Sanitized. Does not contain H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS NERVOUS SYSTEM | LESION INCIDE TREATMENT 0 25 (mg/kg/day) I III BRAIN NO ABNORMALITY DETECTED SPINAL CORD NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 215 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS MUSCULAR AND SKELETAL SYSTEM TREATMENT (mg/kg/day) LESION INCIDE 0 25 I III SKELETAL MUSCLE NO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED MANDIBLE NO ABNORMALITY DETECTED DEGENERATION, AMELOBLASTS. (10) 10 (10) 10 (10) 10 (10) (10) 10 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 216 Sompany Sanitized. Does nol contain H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS REPRODUCTIVE SYSTEM TREATMENT (mg/kg/day) LESION INCIDEN 0 25 I III TESTES NO ABNORMALITY DETECTED SPERMATID RETENTION, SEMINIFEROUS TUBULES. EPIDIDYMIDES NO ABNORMALITY DETECTED PROSTATE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. SEMINAL VESICLES NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 9 1 (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 217 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS CUTANEOUS SYSTEM SKIN NO ABNORMALITY DETECTED | LESION INCIDE TREATMENT 0 25 (mg/kg/day) I III (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 218 Qfmpes^ SwSSSssS. Does not con H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS SPECIAL SENSES SYSTEM TREATMENT (mg/kg/day) LESION INCIDE 0 25 I III EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED OPTIC NERVE NOT PRESENT. FOLD/ROSETTE, RETINAL. (10) 9 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 219 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) DIGESTIVE SYSTEM LIVER NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC. HYPERTROPHY, HEPATOCYTE, CENTRILOBULAR. FOCUS OF CELLULAR ALTERATION, BASOPHILIC. FATTY CHANGE, MEDIAN CLEFT. PATTY CHANGE, CENTRILOBULAR. Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 220 Company Santed. Dees not con H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. HYPERTROPHY, TUBULAR. HYDRONEPHROSIS, UNILATERAL. Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 221 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (ing/kg/day) RESPIRATORY SYSTEM NOSE NO ABNORMALITY DETECTED ODONTODYS PLASIA. DEGENERATION, AMELOBLASTS. Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 222 ompanif Sanfflzed. Does n H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED MANDIBULAR LYMPH NODE ERYTHROCYTOSIS/ERYTHROPHAGOCYTOSIS, SINUS. Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 223 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (nig/kg/day) ENDOCRINE SYSTEM THYROID GLAND ALTERATION, COLLOID. Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 224 CSompanySanilteed. Does not co H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS MUSCULAR AND SKELETAL SYSTEM MANDIBLE NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 225 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (ing/kg/day) REPRODUCTIVE SYSTEM TESTES DEGENERATION/ATROPHY, DEGENERATION/ATROPHY, SEMINIFEROUS TUBULES, SEMINIFEROUS TUBULES, UNILATERAL. BILATERAL. EPIDIDYMIDES NO ABNORMALITY DETECTED OLIGOSPERMIA/GERM CELL DEBRIS, UNILATERAL. SEMINAL VESICLES NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 226 Y^ .. H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESIONS DIGESTIVE SYSTEM LIVER NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC. HYPERTROPHY, HEPATOCYTE, CENTRILOBULAR. FATTY CHANGE, MEDIAN CLEFT. PATTY CHANGE, CENTRILOBULAR. TREATMENT (mg/kg/day) LESION INCIDE 0 25 I III (5) 1 5 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 227 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESIONS URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED CALCULUS\CALCULI. NEPHROPATHY, CHRONIC PROGRESSIVE. INFLAMMATION, SUBACUTE/CHRONIC. HYPERPLASIA, TRANSITIONAL CELL. TREATMENT (ing/kg/day) LESION INCIDE 0 25 I III (5) 2 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 228 Compaq SanNteed Dees not H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) RESPIRATORY SYSTEM NOSE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, NASOLACRIMAL DUCT. INFLAMMATION, SUBACUTE/CHRONIC. HYPERPLASIA/SQUAMOUS METAPLASIA, RESPIRATORY, EPITHELIUM. HYPERPLASIA/HYPERTROPHY, TRANSITIONAL CELL, EPITHELIUM. FRACTURE/CALLUS, TOOTH. DEGENERATION/NECROSIS, RESPIRATORY, EPITHELIUM. DEGENERATION, AMELOBLASTS. SCHWANNOMA [B]. LESION INCIDE 0 25 I III (5) (5) 3 1 1 2 3 2 1 3 1 [B] Benign tumour Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 229 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESIONS ENDOCRINE SYSTEM TREATMENT (mg/kg/day) LESION INCIDE 0 25 I III THYROID GLAND ALTERATION, COLLOID. (5) (5) 5 5 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 230 SBiaspstt^SwSSface&Dew mot co H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS DIGESTIVE SYSTEM TREATMENT (mg/kg/day) LESION INCIDE 0 25 II IV LIVER NO ABNORMALITY DETECTED NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC. HYPERTROPHY, HEPATOCYTE, CENTRILOBULAR. FATTY CHANGE, MEDIAN CLEFT. PANCREAS NO ABNORMALITY DETECTED ATROPHY. ESOPHAGUS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. STOMACH NO ABNORMALITY DETECTED (10) 1 1 9 2 (10) 10 (10) 10 (10) 10 (10) 1 9 1 (1) 1 (1) 1 (1) 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 231 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS DIGESTIVE SYSTEM TREATMENT (mg/kg/day) LESION INCIDE 0 25 II IV DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED AUTOLYSIS:-NECROPSY AND HISTOLOGY PERFORMED. ILEUM NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED , COLON NO ABNORMALITY DETECTED (10) (1) 10 1 (10) (1) 10 1 (10) (1) 10 1 (10) (1) 10 1 (10) (1) 10 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 232 6e ' Sanfflzed. Does not cont H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS DIGESTIVE SYSTEM TREATMENT (mg/kg/day) LESION INCIDEN 0 25 II IV RECTUM NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED (10) (1) 10 1 (10) (1) 10 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 233 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. NECROSIS, TUBULAR. INFLAMMATION, ACUTE. INPARCT. HYPERPLASIA, TRANSITIONAL CELL. HYDRONEPHROSIS, BILATERAL. CYST. AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. URINARY BLADDER NO ABNORMALITY DETECTED HYPERPLASIA, SIMPLE, TRANSITIONAL CELL. TREATMENT (mg/kg/day) LESION INCIDE 0 25 II IV (10) 6 3 1 (10) 7 2 1 1 1 1 (10) (1) 10 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 234 Campfflir Sanitized. Does Ml conta H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS RESPIRATORY SYSTEM LUNGS NO ABNORMALITY DETECTED THROMBUS. TRACHEA NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. FRACTURE/CALLUS, TOOTH. DEGENERATION, AMELOBLASTS. TREATMENT (mg/kg/day) LESION INCIDE 0 25 II IV (10) 9 1 (10) 10 (10) 10 (10) 10 (1) 1 (1) 1 (1) 1 (10) 9 1 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 235 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS CARDIOVASCULAR SYSTEM HEART NO ABNORMALITY DETECTED CARDIOMYOPATHY. AORTA NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESION INCIDE 0 25 II IV (10) (1) 7 3 1 (10) (1) 10 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 236 Compaay SanjtEzed. Does not contain H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED DEPLETION, LYMPHOID. THYMUS NO ABNORMALITY DETECTED ATROPHY. MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED BONE MARROW NO ABNORMALITY DETECTED HYPERPLASIA, GRANULOCYTIC. ATROPHY. | LESION INCIDE TREATMENT 0 25 (mg/kg/day) II IV (10) (1) 10 1 (10) (1) 10 1 (10) (1) 10 1 (9) (1) 9 1 (10) (1) 10 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 237 Company Sanitized, Does not contain H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS ENDOCRINE SYSTEM PITUITARY GLAND NO ABNORMALITY DETECTED THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. ALTERATION,- COLLOID. PARATHYROID GLANDS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESION INCIDE 0 25 II IV (10) 10 (10) 10 (6) 6 (10) 10 (1) 1 (10) 4 6 (1) 1 (1) 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 238 Gwapsttv ^aaSSfsaS.Dees w eon H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS MERVOUS SYSTEM BRAIN NO ABNORMALITY DETECTED SPINAL CORD NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESION INCIDE 0 25 II IV (10) (1) 10 1 (10) (1) 10 1 (10) (1) 10 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 239 Company SanUized. Does not conta H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS MUSCULAR AND SKELETAL SYSTEM SKELETAL MUSCLE NO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED MANDIBLE NO ABNORMALITY DETECTED DEGENERATION, AMELOBLASTS. TREATMENT (ing/kg/day) LESION INCIDE 0 25 II IV (10) (1) 10 1 (10) (1) 10 1 (10) (1) 10 1 (10) (9) 10 9 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 240 Company SanWzed. Does not cont H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS REPRODUCTIVE SYSTEM OVARIES NO ABNORMALITY DETECTED UTERUS NO ABNORMALITY DETECTED DILATATION, LUMEN. MAMMARY GLAND (FEMALE) NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESION INCIDE 0 25 II IV (10) (1) 10 1 (10) (1) 10 1 (10) (1) 1.0 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 241 I contain T H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS CUTANEOUS SYSTEM SKIN NO ABNORMALITY DETECTED TREATMENT (nig/kg/day) LESION INCIDEN 0 25 II IV (10) (1) 10 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 242 Company sanitise Does no H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS SPECIAL SENSES SYSTEM EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED OPTIC NERVE NOT PRESENT. AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. TREATMENT (mg/kg/day) LESION INCIDE 0 25 II IV (10) (1) 10 1 2 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 243 Company Sanitized. Does nofi H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC. PATTY CHANGE, MEDIAN CLEFT. PANCREAS NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 244 Company Sanitized. Does not contai H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) DIGESTIVE SYSTEM JElTOMUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED RECTUM NO ABNORMALITY DETECTED DIGESTIVE SYSTEM SALIVARY GLANDS NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 245 Company Sanitized. Does not contain T H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. NECROSIS, TUBULAR. MINERALIZATION. INFLAMMATION, ACUTE. HYPERPLASIA, TRANSITIONAL CELL. HYDRONEPHROSIS, BILATERAL. CYST. URINARY BLADDER INFLAMMATION, SUBACUTE/CHRONIC. HYPERPLASIA, SIMPLE, TRANSITIONAL HEMORRHAGE. CELL. Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 246 Company Sanitized. Does not H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS RESPIRATORY SYSTEM TREATMENT (mg/kg/day) LUNGS NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED SQUAMOUS HYPERPLASIA, NASOLACRIMAL DUCT. INFLAMMATION, SUBACUTE/CHRONIC, NASOLACRIMAL DEGENERATI ON, AMELOBLASTS. DUCT. Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 247 Company Sanitized. Does not contain TS H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS CARDIOVASCULAR SYSTEM TREATMENT (mg/kg/day) HEART NO ABNORMALITY DETECTED AORTA NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 248 Company Sanitized. Does not contain T H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED THYMUS ATROPHY. MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED BONE .MARROW HYPERPLASIA, GRANULOCYTIC. Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 249 CompanySanllteed. Does not contain T H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) ENDOCRINE SYSTEM PITUITARY GLAND NO ABNORMALITY DETECTED HYPERPLASIA, DIFFUSE. THYROID GLAND MO ABNORMALITY DETECTED ALTERATION, COLLOID. PARATHYROID GLANDS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 250 empany anttlzed. Does not contai H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS NERVOUS SYSTEM TREATMENT (mg/kg/day) BRAIN NO ABNORMALITY DETECTED SPINAL CORD NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 251 Company Sanitized. Does not co H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) MUSCULAR AMD SKELETAL SYSTEM SKELETAL MUSCLE NO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED MANDIBLE NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 252 CSompanySanitized. Does not conta H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) REPRODUCTIVE SYSTEM OVARIES NO ABNORMALITY DETECTED UTERUS NO ABNORMALITY DETECTED MAMMARY GLAMD (FEMALE) NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 253 Company Sanitized. Does not co H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (nig/kg/day) CUTANEOUS SYSTEM SKIN NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 254 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) SPECIAL SENSES SYSTEM EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 255 Company Sanitized. Does not cont H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESIONS RESPIRATORY SYSTEM NOSE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. HYPERPLASIA/SQUAMOUS METAPLASIA, DEGENERATION, AMELOBLASTS. TRANSITIONAL CELL. TREATMENT (mg/kg/day) LESION INCIDE 0 25 II IV (5) 2 3 3 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 256 Company Sanitized. Does not contain H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESIONS ENDOCRINE SYSTEM THYROID GLAND NO ABNORMALITY DETECTED ALTERATION, COLLOID. TREATMENT (mg/kg/day) LESION INCIDEN 0 25 II IV (5) (4) 5 4 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 257 Company Sanitized. Does no8 contain T8C '^ivS' H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RA NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED NECROSIS, FOCAL. minimal mild total observations per lesion INFLAMMATION, SUBACUTE/CHRONIC. minimal total observations per lesion HYPERTROPHY, HEPATOCYTE, CENTRILOBULAR. minimal mild moderate total observations per lesion FATTY CHANGE, MEDIAN CLEFT. FATTY minimal mild total observations per CHANGE, CENTRILOBULAR. lesion minimal total observations per lesion | LESION INCIDE TREATMENT 0 25 (mg/kg/day) I III (10) (10) 1 10 9 10 9 2 2 2 2 1 2 1 2 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 258 Company Sanitized. Does not con H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RA NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS DIGESTIVE SYSTEM TREATMENT (mg/kg/day) LESION INCIDE 0 25 I III PANCREAS (10) NO ABNORMALITY DETECTED 7 INFLAMMATION, SUBACUTE/CHRONIC. minimal 2 total observations per lesion 2 ATROPHY. minimal 2 total observations per lesion 2 ESOPHAGUS (10) NO ABNORMALITY DETECTED 10 INFLAMMATION, SUBACUTE/CHRONIC. minimal mild moderate total observations per lesion EDEMA. mild total observations per lesion Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 259 Company Sanitized. Does not conta H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS DIGESTIVE SYSTEM TREATMENT (mg/kg/day) LESION INCIDE 0 25 I III STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED CECUM . NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 260 Company Sanitized. Does not con H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS DIGESTIVE SYSTEM TREATMENT (mg/kg/day) LESION INCIDE 0 25 I III COLON NO ABNORMALITY DETECTED RECTUM NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 261 Company Sanitized. Does not contain H-24 516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS URINARY SYSTEM | LESION INCIDEN TREATMENT 0 25 (mg/kg/day) I III KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. minimal mild total observations per lesion HYPERTROPHY, TUBULAR. minimal mild total observations per lesion HYDRONEPHROSIS, UNILATERAL. minimal total observations per lesion HYDRONEPHROSIS, BILATERAL. minimal total observations per lesion URINARY BLADDER NO ABNORMALITY DETECTED (10) 6 4 4 (10) 7 3 3 (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 262 Company Sanitized. Does not contain H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS RESPIRATORY SYSTEM TREATMENT (mg/kg/day) LESION INCIDE 0 25 I III LUNGS (10) NO ABNORMALITY DETECTED 8 INFLAMMATION, SUBACUTE/CHRONIC. minimal 2 total observations per lesion 2 INFLAMMATI ON, GRANULOMATOUS. minimal severe total observations per lesion TRACHEA NO ABNORMALITY DETECTED (10) 10 PHARYNX/LARYNX (10) NO ABNORMALITY DETECTED 10 HEMORRHAGE. mild total observations per lesion Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 263 Company Sanitized. Does not co x^ , H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS RESPIRATORY SYSTEM TREATMENT (mg/kg/day) LESION INCIDE 0 25 I III NOSE NO ABNORMALITY DETECTED INFLAMMATI ON, SUBACUTE/CHRONIC. minimal mild total observations per lesion HYPERPLASIA/HYPERTROPHY, TRANSITIONAL CELL, EPITHELIUM. minimal mild total observations per lesion DEGENERATION/NECROSIS, RESPIRATORY, EPITHELIUM. minimal total observations per lesion DEGENERATION, AMELOBLASTS. minimal mild total observations per lesion (10) (10) 10 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 264 Company Sanitized. Does not contain H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LE SIONS CARDIOVASCULAR SYSTEM TREATMENT (mg/kg/day) LESION INCIDE 0 25 I III HEART (10) MO ABNORMALITY DETECTED 5 CARDIOMYOPATHY. minimal 5 total observations per lesion 5 INFLAMMATION, SUBACUTE/CHRONIC. moderate total observations per lesion AORTA NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 265 Company Sanitized. Does not contain %? .. H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVAL LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM TREATMENT (mg/kg/day) LESION INCIDEN 0 25 I III SPLEEN NO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED ATROPHY. mild total observations per lesion MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 266 Company Sanitized. Does not contain H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM TREATMENT (mg/kg/day) LESION INCIDEN 0 25 I III BONE MARROW (10) NO ABNORMALITY DETECTED 10 HYPERPLASIA, GRANULOCYTIC. mild moderate total observations per lesion Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 267 Company Sanitized. Does not contain '-.-&"' .. H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS ENDOCRINE SYSTEM TREATMENT (mg/kg/day) LESION INCIDE 0 25 I III PITUITARY GLAND NO ABNORMALITY DETECTED THYROID GLAND NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. minimal total observations per HYPERTROPHY, FOLLICULAR. minimal mild total observations per ALTERATION, COLLOID. minimal mild moderate severe total observations per lesion lesion lesion (10) 10 (10) 1 1 1 (10) 1 9 6 2 1 9 9 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 268 Company Sanitized. Does not cont H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS ENDOCRINE SYSTEM TREATMENT (ing/kg/day) LESION INCIDE 0 25 I III PARATHYROID GLANDS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED (8) 8 (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 269 Company Sanitized. Does not contain T8 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVAL LESIONS NERVOUS SYSTEM TREATMENT (mg/kg/day) LESION INCIDEN 0 25 I III BRAIN NO ABNORMALITY DETECTED SPINAL CORD NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 270 Company SanRfeed. Does not cont H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS MUSCULAR AND SKELETAL SYSTEM TREATMENT (mg/kg/day) LESION INCIDEN 0 25 I III SKELETAL MUSCLE NO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED MANDIBLE NO ABNORMALITY DETECTED DEGENERATION, AMELOBLASTS. minimal mild total observations per lesion (10) 10 (10) 10 (10) 10 (10) (10) 10 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 271 Company Sanitized. Does not contain H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVAL LESIONS REPRODUCTIVE SYSTEM TREATMENT (mg/kg/day) LESION INCIDEN 0 25 I III TESTES NO ABNORMALITY DETECTED SPERMATID RETENTION, SEMINIFEROUS TUBULES. minimal total observations per lesion EPIDIDYMIDES NO ABNORMALITY DETECTED PROSTATE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. minimal moderate total observations per lesion SEMINAL VESICLES NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 9 1 1 (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 272 Company Sanitized. Does not contain H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS CUTANEOUS SYSTEM TREATMENT (mg/kg/day) LESION INCIDE 0 25 I III SKIN NO ABNORMALITY DETECTED (10) 10 Figure in par'entheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 273 Company Sanitized. Does not conta H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RA NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS SPECIAL SENSES SYSTEM TREATMENT (mg/kg/day) LESION INCIDE 0 25 I III EYE(S) WITH OPTIC NERVE (10) NO ABNORMALITY DETECTED 9 OPTIC NERVE NOT PRESENT. FOLD/ROSETTE, RETINAL. mi-nimal 1 total observations per lesion 1 Figure in parentheses, is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 274 Company Sanitized. Does not c H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) DIGESTIVE SYSTEM LIVER NECROSIS, FOCAL. minimal tdtal observations per lesion INFLAMMATION, SUBACUTE/CHRONIC. minimal total observations per lesion HYPERTROPHY, HEPATOCYTE, CENTRILOBULAR. minimal mild total observations per lesion FOCUS OP CELLULAR ALTERATION, BASOPHILIC. minimal total observations per lesion PATTY CHANGE, MEDIAN CLEFT. minimal total observations per lesion FATTY CHANGE, CENTRILOBULAR. minimal total observations per lesion Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 275 Company Sanitized. Does not sontaS H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. minimal total observations per lesion HYPERTROPHY, TUBULAR. minimal total observations per lesion HYDRONEPHROSIS, UNILATERAL. minimal total observations per lesion Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 276 Company Sanitized. Does not c H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) RESPIRATORY SYSTEM NOSE NO ABNORMALITY DETECTED ODONTODYSPLASIA. moderate total observations per lesion DEGENERATION, AMELOBLASTS. minimal mild total observations per lesion Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 277 Company Sanitized. Does not contain TS H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RA NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED MANDIBULAR LYMPH NODE ERYTHROCYTOSIS/ERYTHROPHAGOCYTOSIS, SINUS, mild total observations per lesion Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 278 Company Sanitized. Does not H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) ENDOCRINE SYSTEM THYROID GLAND ALTERATION, COLLOID. minimal mi-Id moderate severe total observations per lesion Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 279 Company Sanitized. Does not con H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RA NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) MUSCULAR AND SKELETAL SYSTEM MANDIBLE NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 280 Company Sanitized. Does not conta H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) REPRODUCTIVE SYSTEM TESTES DEGENERATION/ATROPHY, SEMINIFEROUS TUBULES, mild severe total observations per lesion DEGENERATION/ATROPHY, SEMINIFEROUS TUBULES, moderate total observations per lesion UNILATERAL. BILATERAL. EPIDIDYMIDES NO ABNORMALITY DETECTED OLIGOSPERMIA/GERM CELL DEBRIS, UNILATERAL. moderate severe total observations per lesion SEMINAL VESICLES NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 281 Company Sanitized. Does not con <-/ H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESIONS DIGESTIVE SYSTEM LIVER NECROSIS, FOCAL. minimal mild total observations per lesion INFLAMMATION, SUBACUTE/CHRONIC. minimal total observations per lesion HYPERTROPHY, HEPATOCYTE, CENTRILOBULAR. minimal total observations per lesion PATTY CHANGE, MEDIAN CLEFT. mild total observations per lesion FATTY CHANGE, CENTRILOBULAR. mild total observations per lesion | LESION INCIDE TREATMENT 0 25 (mg/kg/day) I III (5) 1 1 5 5 1 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 282 Company Sanded. Does not cont H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RA NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESION INCIDE LESIONS URINARY SYSTEM TREATMENT 0 25 (mg/kg/day) I III KIDNEYS (5) NO ABNORMALITY DETECTED 2 CALCULUS\CALCULI. minimal total observations per lesion NEPHROPATHY, CHRONIC PROGRESSIVE. minimal 3 moderate total observations per lesion 3 INFLAMMATION, SUBACUTE/CHRONIC. minimal total observations per lesion HYPERPLASIA, TRANSITIONAL CELL. minimal total observations per lesion ^ Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 283 Company SanRIzed. Does not H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RA NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESION INCIDE LESIONS RESPIRATORY SYSTEM TREATMENT 0 25 (mg/kg/day) I III NOSE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, NASOLACRIMAL DUCT. mild total observations per lesion INFLAMMATION, SUBACUTE/CHRONIC. minimal mild total observations per lesion HYPERPLASIA/SQUAMOUS METAPLASIA, RESPIRATORY, EPITHELIUM. minimal mild total observations per lesion HYPERPLASIA/HYPERTROPHY, TRANSITIONAL CELL, EPITHELIUM. minimal mild total observations per lesion FRACTURE/CALLUS, TOOTH. DEGENERATION/NECROSIS, RESPIRATORY, EPITHELIUM. mild total observations per lesion DEGENERATION, AMELOBLASTS. minimal (5) (5) 3 1 1 1 1 2 1 1 2 3 1 2 2 1 2 1 3 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 284 Company Sanitized. Does not co H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESIONS RESPIRATORY SYSTEM NOSE DEGENERATION, AMELOBLASTS. mild total observations per lesion TREATMENT (mg/kg/day) LESION INCIDEN 0 25 I III (5) (5) Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 285 Company Sanitized. Does not contain TSCA H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RA NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESIONS ENDOCRINE SYSTEM THYROID GLAND ALTERATION, COLLOID. minimal mild moderate severe total observations per lesion TREATMENT (mg/kg/day) LESION INCIDE 0 25 I III (5) (5) 3 1 1 2 1 2 5 5 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 286 Company Sanitized. Dees not conta H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED NECROSIS, FOCAL. minimal total observations per lesion INFLAMMATION, SUBACUTE/CHRONIC. minimal total observations per lesion HYPERTROPHY, HEPATOCYTE, CENTRILOBULAR. minimal mild total observations per lesion FATTY CHANGE, MEDIAN CLEFT. minimal mild total observations per lesion TREATMENT (nig/kg/day) LESION INCIDE 0 25 II IV (10) 1 1 1 9 9 (10) 1 9 9 1 2 2 1 N=11 in Group VIII reflects one reproduction designated animal that died on test day 5 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 287 Company Sanitized. Does not eonSai H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE R NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS DIGESTIVE SYSTEM PANCREAS NO ABNORMALITY DETECTED ATROPHY. minimal total observations per lesion ESOPHAGUS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. severe total observations per lesion STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED TREATMENT (ing/kg/day) LESION INCIDE 0 25 II IV (10) (1) 10 1 (10) (1) 10 1 (10) (1) 10 1 (10) (1) 10 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 288 Company Sanitized. Does not contain T 'C.y .. H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE R NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS DIGESTIVE SYSTEM JEJUNUM NO ABNORMALITY DETECTED AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. moderate total observations per lesion ILEUM NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED RECTUM NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESION INCIDE 0 25 II IV (10) (1) 10 1 (10) (1) 10 1 (10) (1) 10 1 (10) (1) 10 1 (10) (1) 10 1 (10) (1) 10 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 289 Company Sanitized. Does not cont H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA | LESION INCIDE LESIONS URINARY SYSTEM TREATMENT 0 25 (mg/kg/day) II IV KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. minimal moderate total observations per lesion NECROSIS, TUBULAR. moderate total observations per lesion INFLAMMATION, ACUTE. moderate total observations per lesion INFARCT. minimal total observations per lesion HYPERPLASIA, TRANSITIONAL CELL. mild total observations per lesion HYDRONEPHROSIS, BILATERAL. mild CYST. total observations per lesion minimal (10) 6 3 3 (10) 7 2 2 1 1 1 1 1 1 1 1 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 290 Company Sanitized. Does not cont H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE R NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS URINARY SYSTEM KIDNEYS CYST. total observations per lesion AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. mild total observations per lesion URINARY BLADDER NO ABNORMALITY DETECTED HYPERPLASIA, SIMPLE, TRANSITIONAL CELL. moderate total observations per lesion TREATMENT (ing/kg/day) LESION INCIDE 0 25 II IV (10) (10) 1 (10) (1) 10 1 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 291 Company Sanitized. Does not sontain T H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESION INCIDE LESIONS RESPIRATORY SYSTEM TREATMENT 0 25 (mg/kg/day) II IV LUNGS NO ABNORMALITY DETECTED THROMBUS. minimal total observations per lesion TRACHEA NO ABNORMALITY DETECTED (10) (1) 9 1 1 1 (10) (1) 10 1 PHARYNX/LARYNX NO ABNORMALITY DETECTED (10) (1) 10 1 NOSE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. minimal mild total observations per FRACTURE/CALLUS, TOOTH. DEGENERATION, AMELOBLASTS. minimal mild total observations per lesion lesion (10) 10 (10) 9 1 1 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 292 Company Sanitized. Does not conta H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS CARDIOVASCULAR SYSTEM HEART NO ABNORMALITY DETECTED CARDIOMYOPATHY. minimal total observations per lesion AORTA NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESION INCIDE 0 25 II IV (10) (1) 7 3 1 3 1 (10) (1) 10 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 293 Company SanSflzed. Does not con H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVAL LESION INCIDEN LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM TREATMENT 0 25 (ing/kg/day) II IV SPLEEN NO ABNORMALITY DETECTED DEPLETION, LYMPHOID. mild moderate total observations per lesion THYMUS NO ABNORMALITY DETECTED ATROPHY. moderate severe total observations per lesion MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED (10) (1) 10 1 1 (10) (1) 10 1 1 (10) (1) 10 1 MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED (9) (1) 9 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 294 Company Sanitized. Does not eontain H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS BONE MARROW NO ABNORMALITY DETECTED HYPERPLASIA, GRANULOCYTIC. severe total observations per lesion ATROPHY. mild total observations per lesion TREATMENT (mg/kg/day) LESION INCIDE 0 25 II IV (10) (1) 10 1 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 295 Company Sanfflzed. Doe H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS ENDOCRINE SYSTEM PITUITARY GLAND NO ABNORMALITY DETECTED THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, POLL ICULAR. minimal total observations per lesion ALTERATION, COLLOID. minimal mild moderate total observations per lesion PARATHYROID GLANDS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESION INCIDEN 0 25 II IV (10) 10 (10) 10 (1) 1 (10) 4 6 6 (6) (1) 6 1 (10) (1) 10 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 296 CompanySanlteed. Does not e H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVAL LESIONS NERVOUS SYSTEM BRAIN NO ABNORMALITY DETECTED SPINAL CORD NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESION INCIDEN 0 25 II IV (10) (1) 10 1 (10) (1) 10 1 (10) (1) 10 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 297 eomnaw Sa-Wsred. Does no H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS MUSCULAR AND SKELETAL SYSTEM SKELETAL MUSCLE NO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED MANDIBLE NO ABNORMALITY DETECTED DEGENERATION, AMELOBLASTS. minimal mild total observations per lesion TREATMENT (nig/kg/day) LESION INCIDEN 0 25 II IV (10) (1) 10 1 (10) (1) 10 1 (10) (1) 10 1 (10) (9) 10 9 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 298 Comoany Sanitized. Does n H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS REPRODUCTIVE SYSTEM OVARIES NO ABNORMALITY DETECTED UTERUS NO ABNORMALITY DETECTED DILATATION, LUMEN. minimal mild total observations per lesion MAMMARY GLAND (FEMALE) NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESION INCIDEN 0 25 II IV (10) (1) 10 1 (10) (1) 10 1 (10) (1) 10 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 299 ^mno-w B^W-orf nno iwfl H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS CUTANEOUS SYSTEM SKIN NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESION INCIDE 0 25 II IV (10) (1) 10 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 300 Company Sanitized. Doe H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVA LESIONS SPECIAL SENSES SYSTEM EYE(S) WITH OPTIC NERVE MO ABNORMALITY DETECTED OPTIC NERVE NOT PRESENT. AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. mild total observations per lesion TREATMENT (mg/kg/day) LESION INCIDE 0 25 II IV (10) (1) 10 1 2 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 301 Company Sanitized. Does H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED NECROSIS, FOCAL. minimal total observations per INFLAMMATION, SUBACUTE/CHRONIC. minimal total observations per FATTY CHANGE, MEDIAN CLEFT. minimal total observations per lesion lesion lesion PANCREAS NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 302 Company Sanitized. Does H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS . TREATMENT (mg/kg/day) DIGESTIVE SYSTEM DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED RECTUM NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 303 Company Sanitized. Does not H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (nig/kg/day) URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. minimal total observations per lesion NECROSIS, TUBULAR. mild total observations per lesion MINERALIZATION. mild total observations per lesion INFLAMMATION, ACUTE. . mild total observations per lesion HYPERPLASIA, TRANSITIONAL CELL. moderate total observations per lesion HYDRONEPHROSIS, BILATERAL. minimal total observations per lesion Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 304 Company Santtfzed. Does n '"'s&y H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) URINARY SYSTEM KIDNEY CYST. minimal total observations per lesion URINARY BLADDER INFLAMMATION, SUBACUTE/CHRONIC. mild total observations per lesion HYPERPLASIA, SIMPLE,' TRANSITIONAL CELL. moderate total observations per lesion HEMORRHAGE. mild total observations per lesion Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 305 Company Sanitized. Does not con v_/' H-24516: Subchrondc Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS RESPIRATORY SYSTEM LUNGS NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED SQUAMOUS HYPERPLASIA, NASOLACRIMAL DUCT. ' mild total observations per lesion INFLAMMATION, SUBACUTE/CHRONIC, NASOLACRIMAL mild total observations per lesion DEGENERATION, AMELOBLASTS. minimal mild total observations per lesion DUCT. Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified TREATMENT (mg/kg/day) 306 Company Sanitized. Does not con H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) CARDIOVASCULAR SYSTEM HEART NO ABNORMALITY DETECTED AORTA NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 307 Company Sanitized. Does not co H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) INCIDENCES OP LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RA NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED THYMUS ATROPHY. mild total observations per lesion MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED BONE MARROW HYPERPLASIA, GRANULOCYTIC. mild total observations per lesion Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 308 Company Sanitized. Does not cont H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE R NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) ENDOCRINE SYSTEM PITUITARY GLAND NO ABNORMALITY DETECTED HYPERPLASIA, DIFFUSE. mild total observations per lesion THYROID GLAND NO ABNORMALITY DETECTED ALTERATION, COLLOID. minimal moderate total observations per lesion PARATHYROID GLANDS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 309 Company Sanitized. Does not c H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE R NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) NERVOUS SYSTEM BRAIN NO ABNORMALITY DETECTED SPIMAL CORD NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 310 Company Sanitized. Does not H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE R NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) MUSCULAR AND SKELETAL SYSTEM SKELETAL MUSCLE NO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED MANDIBLE NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 311 ftmmo*mv SaiWyeA Does not c H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE R NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) REPRODUCTIVE SYSTEM OVARIES NO ABNORMALITY DETECTED UTERUS NO ABNORMALITY DETECTED MAMMARY GLAND (FEMALE) NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 312 Company Sanitized. Does not contai H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE R NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) CUTANEOUS SYSTEM SKIN NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 313 CompanySanHteeA Does notco H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE R NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) SPECIAL SENSES SYSTEM EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 314 coWS^Wtee<j.Doe. n H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE R NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESION INCIDE LESIONS RESPIRATORY SYSTEM TREATMENT 0 25 (ing/kg/day) II IV NOSE (5) NO ABNORMALITY DETECTED 2 INFLAMMATION, SUBACUTE/CHRONIC. minimal 2 mild 1 total observations per lesion 3 HYPERPLASIA/SQUAMOUS METAPLASIA, TRANSITIONAL CELL. minimal mild 3 total observations per lesion 3 DEGENERATION, AMELOBLASTS. minimal total observations per lesion Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 315 Company Sanitized. Does not coifte H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE R NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESION INCIDE LESIONS ENDOCRINE SYSTEM TREATMENT 0 25 (mg/kg/day) II IV THYROID GLAND NO ABNORMALITY DETECTED ALTERATION, COLLOID. minimal mild moderate total observations per lesion (5) (4) 4 3 1 1 5 4 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 316 Company Sanfflzed. Does not conta