Document L5KGm5dLq6JovQ2M1bgJNXBq

M a t - 2/? DuPont-5990 TRADE SECRET Study Title H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations Volume 1 o f 5 Laboratory Proj ect ID : DuPont-5990 Test Guidelines: U.S. EPA Health Effects Test Guidelines OPPTS 870.3100(1998) Author: Susan A. MacKenzie, V.M.D., Ph.D., D.A.B.T. Study Completed on: January 18, 2002 Performing Laboratory: E.I. du Pont de Nemours and Company Haskell Laboratory for Health and Environmental Sciences Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050 Page 1 of 1408 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 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. None o f the items listed impact the validity o f the study. 1. 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 o f the aforementioned analyses were performed under Good Laboratory Practice Standards; however, the analyses were conducted in compliance with IS09002 regulations. All o f the analyses are considered valid and sufficient for the purposes o f this study. 2. The original necropsy sheets for 23 rats from the reproductive toxicology subset could not be located. Necropsy sheets for these rats were reprinted from the study electronic database. All information that is normally hand-entered that could be recalled or is documented elsewhere was added to these reprinted sheets. The names o f the prosector and recorder for each specific rat could not be reconstructed. Applicant / Sponsor: E.I. du Pont de Nemours and Company Wilmington, Delaware 19898 U.S.A. Study Director Susan A. MacKenzie, V.M.D., Ph.D., D.A.B.T. Senior Research Scientist ~00. Date Applicant / Sponsor:____________________________________________ __________ DuPont Representative Date -2Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations QUALITY ASSURANCE STATEMENT DuPont-5990 Haskell Sample Number(s): 24768 Dates o f Inspections: Protocol: March 1, 2001 Conduct: March 15, 2001; May 10, 2001; June 1,14, 29,2001; July 11,2001; August 8,2001; September 14,2001 Records, Reports: September 21, 24, 25, 2001; October 3-5, 8-12,14-15, 17-19, 22-26, 29-31, 2001; November 1-2, 6-9,11-12,2001; December 1 0 ,1 1 ,1 3 ,1 4 ,1 8 , 2001 Dates Findings Reported to: Study Director: October 15,22, 30,2001; November 5,9,2001; December 14,18, 2001 Management: October 22, 30,2001; November 5, 9, 20, 2001; December 14, 2001; January 11, 2002 Reported by: C- Joseph C. Hamill Sr. Quality Assurance Auditor Date -3 Company Sanitized. Does not contain TSCA C8I H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 CERTIFICATION We, the undersigned, declare that this report provides an accurate evaluation o f data obtained from this study. Analytical Assessment Reported by: Neurobehavioral Evaluations Reported by: Biochemical Evaluations Reported by: Clinical Pathology Evaluations Reported by: ' Janet C. Maslanka, B.S. Analytical Chemist Linda A. Malley, P h D , D.A.B.T. Senior Research Scientist { / John C. O'Connor, M.S. Research Scientist Date // Date n - - a-ooa. Date 1 ^ - Zoc n _ Date Reproductive Evaluations Reported by: /-? JA>1' 2.002. Date Pathological Evaluations Reported by: Pathological Evaluations Peer Review Reported by: <iZ-yx. John F. Hansen, D.V.M., Ph.D. Diplomate A.C.V.P. Principal Research Scientist Steven R. Frame, D.V.M., PhD. Diplomate A.C.V.P. Director, Anatomic Pathology Approved by: (f. / / W i t h C. Stadler.Ph.D., D.A.B.T. v Director, General Toxicology Issued by Study Director "Susan A. Mackenzie, V.M.D., Ph.D., D.A.B.T. Senior Research Scientist IS Date Date 7-TAri -ic o z. Date Date -4 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations______________________ DuPont-5990 TABLE OF CONTENTS Page GOOD LABORATORY PRACTICE COMPLIANCE STATEM ENT............................................ 2 QUALITY ASSURANCE STATEMENT............................................................................................. 3 C E R T IF IC A T IO N ..................................................................................................................................... 4 LIST OF TA B LES.................................................................................... 8 LIST OF FIGURES................................................................................................................................. 11 LIST OF APPENDICES.................................................................................................... 12 STUDY INFORMATION............................... 14 STUDY PERSO N NEL.......................................................................................................................... 15 SUM M ARY.............................................................................................................................................16 INTRODUCTION...................................................................................................................................20 OBJECTIVE............................................................................................................................................ 20 MATERIALS AND M ETHODS.......................................................................................................... 20 A. Test Guidelines........................................................................................................................... 20 B. Test Substance.,.......................................................................................................................... 21 C. Test Species............................... 21 D. Animal H usbandry.....................................................................................................................21 E. Quarantine and Pretest Period.................................................................................................. 22 F. Study D esign.............................................................................................................................. 23 G. Assignment to Groups and Study S tart................................................................................... 24 H. Dose Solution Preparation.......................................................................... 24 I. Test Substance Administration and Sam pling....................................................................... 25 J. Analytical M ethods................................................................................. 26 K. Body W eights............................................................................................................................. 27 L. Food Consumption and Food Efficiency................................................................................. 27 M. Detailed Clinical Observations and M ortality........................................................................ 27 N. Ophthalmological Evaluations................................................................................................. 28 O. Neurotoxicity Evaluations.........................................................................................................28 P . Clinical Pathology.............:...................................................................................................... 29 Q. Collection o f Blood, Urine, Feces, and Tissue (Three-Month Recovery and Fi Generation)...........................................................................31 R. Biochemical M easurem ents......................................................................................................31 S. Anatomic Pathology - Rats Designated for 90-Day Exposure and Recovery Evaluations......................................................................................................... 32 T. Reproductive A ssessm ent......................................................................................................... 33 U. Anatomical Pathology - Rats Designated for Reproductive Evaluations............ ...............36 V. Statistical Analyses.....................................................................................................................39 -5 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations______________________ DuPont-5990 RECORDS AND SAMPLE STORAGE.............................................................................................. 41 RESULTS AND DISCUSSION............................................................................................................ 42 ANALYTICAL EVALUATIONS........................................................................................................43 A. Test Substance Stability............................................................................................................ 43 B. Chromatography...........................;........................................................................................... 43 C. Uniformity o f Mixing, Concentration Verification and Stability Sam ples.........................43 D. Concentration Verification Samples During the Study.........................................................45 E. Analytical Conclusions................................................................ 45 SUBCHRONIC TOXICITY EVALUATIONS.................................................................................. 46 IN-LEFE TOXICOLOGY............................................. 46 A. Dosage D a ta ................................................................................. 46 B. Mean Body Weights and Body Weight Gains........................................................................ 46 C. Food Consumption and Food Efficiency................................................................................. 48 D. Clinical Observations and M ortality........................................................................................50 E. Ophthalmology Evaluations......................................................................................................50 F. In-Life Toxicology Conclusions............................................................................................... 50 NEUROBEHAVIORAL TOXICOLOGY........................................................................................... 51 A. Sensory Function Evaluations.................................................................................................. 51 B. Motor Activity............................................................................................................................ 52 C. Neurobehavioral Toxicity Conclusions................................................................................... 52 CLINICAL PATHOLOGY................................................................................ 53 A. Hematology/Coagulation........................................................................................................... 53 B. Clinical Chemistry......................................................................................................................56 C. Urinalysis..................................................................................................................................... 61 D. Clinical Pathology Conclusions............................................................................................... 63 BIOCHEMICAL MEASUREMENTS................................................................................................. 64 A. Biochemical M easurem ents......................................................................................................64 B. Biochemical Measurements Conclusions................................................................................ 64 ANATOMICAL PATHOLOGY SUBCHRONIC TOXICITY AND RECOVERY.....................65 A. Cause o f D eath........................................................................................................................... 65 B. Organ Weight Data.....................................................................................................................65 C. Gross Observations................................................................................................................... 66 D. Microscopic Findings................................................................................................................ 66 E. Anatomical Pathology Conclusions for Subchronic Toxicity Evaluation........................... 70 REPRODUCTIVE TOXICOLOGY EVALUATIONS..................................................................... 71 REPRODUCTIVE FUNCTION................................................................ 71 A. Pi Generation.............................................................................................................................. 71 B. Offspring D ata............................................................................................................................ 73 C. Fi Generation.............................................................................................................................. 73 D. Reproductive Function Conclusions........................................................................................74 ANATOMICAL PATHOLOGY REPRODUCTIVE TOXICOLOGY EVALUATIONS..........75 -6 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations __________________ DuPont-5990 A. Mortality...................................................................................................................................... 75 B. Organ Weight Data.....................................................................................................................75 C. Gross Observations....................................................................................................................75 D. Microscopic Observations Parental Pi A dults........................................................................75 E. Anatomical Pathology Conclusions for Reproductive Toxicity........................................... 76 CONCLUSIONS..................................................................................................................................... 77 REFERENCES........................................................................................................................................ 79 TABLES (Tables 1-44).......................................................................................................................... 81 VOLUME 2 ............................................................................................................................................337 TABLES (Tables 45-77)...................................................................................................................... 338 FIGU RES...............................................................................................................................................428 APPENDICES (Appendices A -F)........................................................... 440 VOLUME 3 ............................................................................................... 612 APPENDICES (APPENDICES G-N)................................................................................................ 613 VOLUME 4 .................. 918 APPENDICES (APPENDICES N-LL).............................................................................................. 919 VOLUME 5 ..................................................................................................................................... ...1197 APPENDICES (APPENDICES MM-QQ).............................................. 1198 -7Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 LIST OF TABLES Page TABLE 1 SUMMARY OF DOSING SOLUTION ANALYSES........................................................................................ 85 TABLE 2 MEAN DAILY DOSE VOLUMES FOR MALE RATS................................................................................... 86 TABLE 3 MEAN DAILY DOSE VOLUMES FOR FEMALE RATS..............................................................................87 TABLE 4 MEAN BODY WEIGHTS OF MALE R A TS..................................................................................................... 88 TABLE 5 MEAN BODY WEIGHTS OF FEMALE RATS.......................................................................................... ...... 91 TABLE 6 MEAN BODY WEIGHT GAINS OF MALE R A T S........................................................................................94 TABLE 7 MEAN BODY WEIGHT GAINS OF FEMALE RATS................................................................................... 97 TABLE 8 MEAN DAILY FOOD CONSUMPTION BY MALE R A TS........................................................................ 100 TABLE 9 MEAN DAILY FOOD CONSUMPTION BY FEMALE RATS....................................................................102 TABLE 10 MEAN DAILY FOOD EFFICIENCY OF MALE RATS...............................................................................104 TABLE 11 MEAN DAILY FOOD EFFICIENCY OF FEMALE RATS......................................................................... 106 TABLE 12 SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS.........................................................108 TABLE 13 SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS................................................... 114 TABLE 14 SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR MALE RATS............................... 118 TABLE 15 SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR FEMALE RATS..........................119 TABLE 16 PERCENT SURVIVAL OF MALE R A T S.....................................................................................................120 TABLE 17 PERCENT SURVIVAL OF FEMALE RATS................................................................................................ 121 TABLE 18 MEAN FORELIMB AND HINDLIMB GRIP STRENGTH FOR MALE RATS (MEAN OF THREE TRIALS).......................................... .............................................................................. 122 TABLE 19 MEAN FORELIMB AND HINDLIMB GRIP STRENGTH FOR FEMALE RATS (MEAN OF THREE TRIALS)..........................................................................................................................123 TABLE 20 SUMMARY OF FUNCTIONAL OBSERVATIONAL BATTERY FINDINGS FOR MALE R A TS..............................................................................................................................................124 TABLE 21 SUMMARY OF FUNCTIONAL OBSERVATIONAL BATTERY FINDINGS FOR FEMALE RATS......................................................................................................................................... 126 TABLE 22 MOTOR ACTIVITY ASSESSMENT: MEAN DURATION OF MOVEMENTS FOR MALE RATS................................................................... 127 TABLE 23 MOTOR ACTIVITY ASSESSMENT: MEAN DURATION OF MOVEMENTS FOR FEMALE RATS.............................................................. 128 TABLE 24 MOTOR ACTIVITY ASSESSMENT: MEAN NUMBER OF MOVEMENTS FOR MALE R A T S.......................................................................129 TABLE 25 MOTOR ACTIVITY ASSESSMENT: MEAN NUMBER OF MOVEMENTS FOR FEMALE RATS................................................................... 130 TABLE 26 SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS..............................................................131 TABLE 27 SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS........................................................ 137 -8 Company Sanitized. Does not contain TSCA CBI /'"N / --n H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 28 SUMMARY OF COAGULATION VALUES FOR MALE RATS............................................................. 143 TABLE 29 SUMMARY OF COAGULATION VALUES FOR FEMALE RATS.........................................................144 TABLE 30 SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE R A T S ...................... 145 TABLE 31 SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS..................150 TABLE 32 SUMMARY OF URINALYSIS VALUES FOR MALE RATS....................................................................155 TABLE 33 SUMMARY OF URINALYSIS VALUES FOR FEMALE R A T S.............................................................. 157 TABLE 34 SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITY IN MALE RATS........................ 159 TABLE 35 SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITY IN FEMALE RATS...................160 TABLE 36 MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE...................................................................161 TABLE 37 MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS.................................................169 TABLE 38 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS ................................................................177 TABLE 39 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS........................................................... 189 TABLE 40 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS.................................................................................200 TABLE 41 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS.................................................................................217 TABLE 42 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS....................................................................................................................... 234 TABLE 43 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NON-NEOPLASTIC LESIONS....................................................................................................................... 261 TABLE 44 MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED- NEOPLASTIC AND NON-NEOPLASTIC..................... 284 TABLE 45 MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED- NEOPLASTIC AND NON-NEOPLASTIC..................... 338 TABLE 46 MICROSCOPIC LISTING OF CAUSE OF DEATH IN MALE R A TS....................................................391 TABLE 47 MICROSCOPIC LISTING OF CAUSE OF DEATH IN FEMALE RATS FOR 90-DAY EXPOSURE AND 1-MONTH AND 3-MONTH RECOVERY ANIMALS.................................................................... 392 TABLE 48 MEAN BODY WEIGHTS AND MEAN BODY WEIGHT GAINS OF P, MALE RATS......................393 TABLE 49 MEAN BODY WEIGHTS AND MEAN BODY WEIGHT GAINS OF P, FEMALE RATS DURING GESTATION.................................................................................................................................... 394 TABLE 50 MEAN BODY WEIGHTS AND MEAN BODY WEIGHT GAINS OF P, FEMALE RATS DURING LACTATION.................................................................................................................................... 395 TABLE 51 MEAN DAILY FOOD CONSUMPTION AND MEAN FOOD EFFICIENCY OF P, FEMALE RATS DURING GESTATION.................................................................................................................................... 396 TABLE 52 SUMMARY OF CLINICAL OBSERVATIONS IN P, RATS..................................................................... 397 TABLE 53 MEAN ESTROUS CYCLE PARAMETERS AND PRECOITAL INTERVAL IN P, FEMALE RATS........................................................................................................................................399 TABLE 54 SUMMARY OF SPERM PARAMETERS IN P, MALE RATS.................................................................. 400 TABLE 55 SUMMARY OF REPRODUCTIVE INDICES: P! GENERATION........................................................ ..401 TABLE 56 MEAN PUP NUMBERS AND SURVIVAL: Ft GENERATION...............................................................402 -9 Company Sanitized. Does not contain TSCA CBI /""N H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 57 MEAN PUP WEIGHTS: F, GENERATION...................................................................................................403 TABLE 58 SUMMARY OF PUP CLINICAL OBSERVATIONS: F, GENERATION............................................. 404 TABLE 59 MEAN BODY WEIGHTS AND MEAN BODY WEIGHT GAINS OF F, MALE RATS..................... 405 TABLE 60 MEAN BODY WEIGHTS AND MEAN BODY WEIGHT GAINS OF Fj FEMALE RATS................ 406 TABLE 61 MEAN DAILY FOOD CONSUMPTION AND MEAN FOOD EFFICIENCY OF F, MALE RATS...407 TABLE 62 MEAN DAILY FOOD CONSUMPTION AND MEAN FOOD EFFICIENCY OF F, FEMALE RATS...................................................................................................................................... 408 TABLE 63 SUMMARY OF CLINICAL OBSERVATIONS IN F, RATS.....................................................................409 TABLE 64 SUMMARY OF DEVELOPMENTAL LANDMARKS IN Fi RATS........................................................ 410 TABLE 65 MEAN FINAL BODY AND ORGAN WEIGHTS FROM MALE RATS - Fj ADULTS........................411 TABLE 66 MEAN FINAL BODY AND ORGAN WEIGHTS FROM FEMALE RATS - F t ADULTS.................. 414 TABLE 67 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS - P! ADULTS..................................... 417 TABLE 68 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS - P( ADULTS................................418 TABLE 69 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS - F, PU PS............................................419 TABLE 70 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS - PUPS........................................420 TABLE 71 INCIDENCES OF GROSS OBSERVATIONS IN RATS - F, UNSEXABLE PUPS.............................. 421 TABLE 72 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS - F , WEANLINGS............................ 422 TABLE 73 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS - F, WEANLINGS.......................423 TABLE 74 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS - F, A D U LTS................. 424 TABLE 75 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS - F t ADULTS................................425 TABLE 76 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE REPRODUCTION RATS - P, ADULTS.......................................................................................... 426 TABLE 77 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE REPRODUCTION RATS - P, ADULTS................................................................................... 427 -10Company Sanitized. Does not contain TSCA CBI H-24768: Subchroriic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations____________________ DuPont-5990 LIST OF FIGURES Page FIGURE 1 MEAN BODY WEIGHTS OF MALE RATS..................................................................................................430 FIGURE 2 MEAN BODY WEIGHTS OF FEMALE RATS............................................................................................431 FIGURE 3 MEAN FORELIMB GRIP STRENGTH FOR MALE R A T S............ ......................................................... 432 FIGURE 4 MEAN FORELIMB GRIP STRENGTH FOR FEMALE RATS................................................................. 433 FIGURE 5 MEAN HINDLIMB GRIP STRENGTH FOR MALE RATS.......................................................................434 FIGURE 6 MEAN HINDLIMB GRIP STRENGTH FOR FEMALE R ATS..................................................................435 FIGURE 7 MOTOR ACTIVITY ASSESSMENT: MEAN TOTAL DURATION OF MOVEMENT FOR MALE R A T S....................................................... 436 FIGURE 8 MOTOR ACTIVITY ASSESSMENT: MEAN TOTAL DURATION OF MOVEMENT FOR FEMALE RATS.................... ...............................437 FIGURE 9 MOTOR ACTIVITY ASSESSMENT: MEAN TOTAL NUMBER OF MOVEMENTS FOR MALE RATS......................................................... 438 FIGURE 10 MOTOR ACTIVITY ASSESSMENT: MEAN TOTAL NUMBER OF MOVEMENTS FOR FEMALE RATS....................................................439 - 11 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 LIST OF APPENDICES Page APPENDIX A ANALYTICAL D A T A ................................................................................................................................. 441 APPENDIX B INDIVIDUAL DOSE VOLUMES.............................................................................................................. 449 APPENDIX C INDIVIDUAL BODY WEIGHTS........................................ 515 APPENDIX D INDIVIDUAL FOOD CONSUMPTION................................................................................................... 542 APPENDIX E INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY D A TA..........................................................................................................................560 APPENDIX F OPHTHALMOLOGICAL EXAMINATION REPORT...........................................................................610 APPENDIX G INDIVIDUAL FORELIMB AND HINDLIMB GRIP STRENGTH ASSESSMENTS......................613 APPENDIX H INDIVIDUAL FUNCTIONAL OBSERVATIONAL BATTERY ASSESSMENTS......................... 624 APPENDIX I INDIVIDUAL MOTOR ACTIVITY ASSESSMENT: DURATION OF MOVEMENT.................. 634 APPENDIX J INDIVIDUAL MOTOR ACTIVITY ASSESSMENT: NUMBER OF MOVEMENTS....................645 APPENDIX K INDIVIDUAL ANIMAL CLINICAL PATHOLOGY DATA...............................................................656 APPENDIX L INDIVIDUAL BIOCHEMICAL MEASUREMENTS.............................................................................797 APPENDIX M INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS................................................. 804 APPENDIX N INDIVIDUAL ANIMAL GROSS AND MICROSCOPIC OBSERVATIONS..................................825 APPENDIX O REPRODUCTIVE TOXICOLOGY INDIVIDUAL BODY WEIGHTS OF P, MALE RATS......1000 APPENDIX P REPRODUCTIVE TOXICOLOGY INDIVIDUAL BODY WEIGHT GAINS OF P, MALE RATS..................................................................................................................................... 1006 APPENDIX Q REPRODUCTIVE TOXICOLOGY INDIVIDUAL BODY WEIGHTS OF P, FEMALE RATS DURING GESTATION.............................................................................................................................. 1012 APPENDIX R REPRODUCTIVE TOXICOLOGY INDIVIDUAL BODY WEIGHT GAINS OF P, FEMALE RATS DURING GESTATION.................................................................................................................. 1018 APPENDIX S REPRODUCTIVE TOXICOLOGY INDIVIDUAL BODY WEIGHTS OF Pj FEMALE RATS DURING LACTATION.............................................................................................................................. 1024 APPENDIX T REPRODUCTIVE TOXICOLOGY INDIVIDUAL BODY WEIGHT GAINS OF P, FEMALE RATS DURING LACTATION.................................................................................................................. 1030 APPENDIX U REPRODUCTIVE TOXICOLOGY INDIVIDUAL DAILY FOOD CONSUMPTION BY P, FEMALE RATS DURING GESTATION................................................................................... 1036 APPENDIX V REPRODUCTIVE TOXICOLOGY INDIVIDUAL CLINICAL OBSERVATIONS IN P, MALE RATS...................................................................................................................................... 1042 APPENDIX W REPRODUCTIVE TOXICOLOGY INDIVIDUAL CLINICAL OBSERVATIONS IN P, FEMALE RATS DURING GESTATION..................................................................................... 1051 APPENDIX X REPRODUCTIVE TOXICOLOGY INDIVIDUAL CLINICAL OBSERVATIONS IN P, FEMALE RATS DURING LACTATION.................................................................................... 1059 APPENDIX Y INDIVIDUAL ANIMAL ESTROUS CYCLE PARAMETERS DURING PREMATING AND COHABITATION IN P, FEMALE RATS.................................................................................... 1067 -12Company Sanitized. Does not contain TSCA CBJ H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 APPENDIX Z INDIVIDUAL ANIMAL ESTROUS CYCLE STAGES DURING PREMATING AND COHABITATION IN P, FEMALE RATS.....................................................................................1073 APPENDIX AA REPRODUCTIVE TOXICOLOGY INDIVIDUAL ANIMAL SPERM MOTILITY DATA IN P, MALE RATS....................................................................................................................... 1079 APPENDIX BB INDIVIDUAL ANIMAL SPERM MORPHOLOGY DATA IN P, MALE RATS....................... 1081 APPENDIX CC INDIVIDUAL ANIMAL SPERM AND SPERMATID COUNTS IN P t MALE RATS............. 1084 APPENDIX DD REPRODUCTIVE TOXICOLOGY INDIVIDUAL MATING DATA AND GESTATION LENGTH: P t GENERATION..........................................................................................1087 APPENDIX EE REPRODUCTIVE TOXICOLOGY INDIVIDUAL IMPLANTATION SITE DATA AND IMPLANTATION EFFICIENCY..............................................................................................................1093 APPENDIX FF REPRODUCTIVE TOXICOLOGY INDIVIDUAL PUP SURVIVAL: F, GENERATION 1099 APPENDIX GG REPRODUCTIVE TOXICOLOGY INDIVIDUAL PUP WEIGHTS: F, GENERATION........ 1125 APPENDIX HH REPRODUCTIVE TOXICOLOGY INDIVIDUAL LITTER CLINICAL OBSERVATIONS: F, GENERATION........................................................................................................................................ 1151 APPENDIX II REPRODUCTIVE TOXICOLOGY INDIVIDUAL BODY WEIGHTS: F, GENERATION.......1157 APPENDIX JJ REPRODUCTIVE TOXICOLOGY INDIVIDUAL BODY WEIGHT GAINS: Fi GENERATION........................................................................................................................................ 1167 APPENDIX KK REPRODUCTIVE TOXICOLOGY INDIVIDUAL FOOD CONSUMPTION: F, GENERATION........................................................................................................ ;..............................1177 APPENDIX LL REPRODUCTIVE TOXICOLOGY INDIVIDUAL CLINICAL OBSERVATIONS: F, GENERATION........................................................................................................................................ 1187 APPENDIX MM INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS - F, ADULTS...................1198 APPENDIX NN INDIVIDUAL ANIMAL GROSS AND MICROSCOPIC OBSERVATIONS - P! ADULTS.... 1217 APPENDIX OO INDIVIDUAL ANIMAL GROSS OBSERVATIONS - F, P U P S.................................................... 1377 APPENDIX PP INDIVIDUAL ANIMAL GROSS OBSERVATIONS - F, WEANLINGS............. .........................1383 APPENDIX QQ INDIVIDUAL ANIMAL GROSS OBSERVATIONS - F, A D U LTS............................................. 1399 - 13Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations STUDY INFORMATION DuPont-5990 Haskell Number: 24768 Sponsor: E. I. du Pont de Nemours and Company Wilmington, Delaware 19898 . U.S.A. Study Initiated/Completed: March 14, 2001 / (see report cover page) In-Life Initiated/Completed: March 15, 2001 / September 14, 2001 - 14Company Sanitized. Does not contain TSCA CBI /" N H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations STUDY PERSONNEL Study Director: Susan A. MacKenzie, V.M.D., PhD . Management: Judith C. Stadler, Ph.D. Nancy C. Chromey, Ph.D. Janice L. Connell, M.S., B.A., C.I.H. Primary Technician: Nita B. Baker Analytical Chemist: Janet C. Maslanka, B.S. Management: S. Mark Kennedy, Ph.D. Clinical Pathologist: Nancy E. Everds, D.V.M. Management: 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. Reproductive Toxicologist: Eve Mylchreest, Ph.D. Management: Robert M. Parker, Ph.D. Pathologist: John F. Hansen, D.V.M., Ph.D. Management: Steven R. Frame, D.V.M., Ph.D. Peer Review Pathologist: Steven R. Frame, D.V.M., Ph.D. Toxicology Report Preparation: Cecilia R. Kee, B.S. Mary K. LaRoe Maryanne M. Wilford, B.A. 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-5990 - 15Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 SUMMARY Four groups o f young adult male and female Crl:CD(SD)IGS BR rats were administered H-24768 in deionized water by gavage for approximately 90 days, at dosages o f 0,25,100, or 500 mg/kg/day. Selected animals from each dosage group were designated for subchronic toxicity or reproductive evaluations. In the subchronic study, body weights, food consumption, and clinical signs were evaluated weekly. Clinical pathology endpoints were evaluated during weeks 7 and 14 o f the 90-day dosing period, and near the end of the one-month and three-month recovery periods. Neurobehavioral assessments were also performed prior to dosing, during week 13, and near the end o f the one-month recovery period. Biochemical evaluations (hepatic P-oxidation) were performed on rats after 10 and approximately 90 days o f dosing, and following one-month and three-month (males only) recovery periods. After approximately 90 days o f dosing, 10 rats/sex/dose were sacrificed and given a gross and microscopic pathological examination. One month after the 90-day dosing period, 10 rats/sex in the control and high dose group were examined for recovery o f toxic effects. An additional 5 rats/sex/dose were evaluated for recovery approximately 3 months following the end o f the dosing period. The range o f mean daily dose volumes o f H-24768 administered to male rats was 1.6 to 4.6 mL. The range administered to female rats was 1.3-2.4 mL. Analytical results demonstrated that the test substance was mixed properly, was at the targeted concentrations, and was stable in deionized water under relevant storage conditions used in this study. In-Life Toxicology Parameters: No test substance-related deaths occurred in the subchronic toxicity part o f the study. Test substance-related clinical signs o f toxicity were observed in males and/or females dosed with 100 or 500 mg/kg/day. Compared to control, statistically significant lower body weight, body weight gain, and food efficiency were observed in male and female rats dosed with 500 mg/kg/day and in male rats dosed with 100 mg/kg/day, and were considered to be adverse. Mean body weight on test day 91 was 83% and 94% o f control in male 500 and 100 mg/kg/day groups, respectively. Mean body weight on test day 91 was 94% o f control in the female 500 mg/kg/day group. The body weight effects were attributed primarily to the reduced food efficiency. Mean food efficiency over test days 0-91 was 77% and 90% o f control in male 500 and 100 mg/kg/day groups, respectively, and 88% o f control in 500 mg/kg/day females. Adverse test substance-related reductions in food consumption were observed in male rats dosed with 500 mg/kg/day. Reversal of these effects was observed in both males and females by the end of the three-month recovery period. No test substance-related ophthalmologic effects were observed in any dose group. Neurotoxicology Parameters'. No test substance-related neurological effects were observed. Test substance-related reductions in forelimb and hindlimb grip strength were observed in 500 mg/kg/day male rats at the end o f the dosing period, but were associated with reduced body weight and were partially reversible. - 16Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 Biochemical Toxicology: Reversible increases in the rate o f hepatic p-oxidation, a measure o f peroxisome proliferation, were observed in male rats dosed with 100 or 500 mg/kg/day. No biologically significant effects on hepatic P-oxidation were observed in female rats. Clinical Pathology: In males, adverse increases in liver enzyme activities (alanine aminotransferase and sorbitol dehydrogenase) were observed during treatment and following a three-month recovery period in rats dosed with 500 mg/kg/day; however, they were not associated with histological evidence o f liver cytotoxicity. In females, adverse, but reversible, findings o f decreased red cell mass (hemoglobin, hematocrit, and red cell count) were observed in rats dosed with 500 mg/kg/day. Other observed changes in clinical pathology parameters were considered treatment-related but non-adverse. The parameters thus affected were red cell mass and red cell indices in males, red cell shape, urea nitrogen, creatinine, inorganic phosphorus, cholesterol, triglycerides, alkaline phosphatase, bilirubin, albumin, globulin, calcium, sodium, chloride, potassium, urine volume, urine concentration, and urine pH. Plasma fluoride concentration was increased during the dosing period in rats dosed with 25 (males only), 100, or 500 mg/kg/day, but returned to control levels following the three-month recovery period. Urine fluoride (total fluoride excreted over the collection period) was increased in males and females dosed with 25, 100, or 500 mg/kg/day. Urine fluoride greatly decreased during the recovery period, but remained slightly above control values at the end o f the threemonth recovery period in 100 and 500 mg/kg/day males and females, thus indicating the continued presence o f fluorinated material. Anatomic Pathology (Subchronic Toxicity): Exposure to the test substance for approximately 90 days produced alterations in the liver, kidney, spleen, and thyroid. Increased liver weights and/or microscopic hepatocellular hypertrophy were present in 25,100, and 500 mg/kg/day males and females at the end o f the dosing period, and in 500 mg/kg/day males and females after the one-month recovery. These liver changes were considered to be a non-adverse, physiologic response to metabolism o f a xenobiotic. In 100 and 500 mg/kg/day male rats, the liver changes were associated with th induction o f hepatic (5-oxidation activity. Increased extramedullary hematopoiesis and increased pigment in the spleen were observed in 100 and 500 mg/kg/day males and females and, in females, were associated with increased relative spleen weight; they were considered to be non-adverse, secondary physiologic responses to changes in red cell mass. Increased chronic progressive nephropathy, sometimes accompanied by increased kidney weight in females, was present in 500 and/or 100 mg/kg/day males and females, and did not demonstrate recovery in females. These histological findings were considered to be adverse. Non-adverse increases in urine volume, associated with reduced urine osmolality and specific gravity, were observed during the dosing period in 500 mg/kg/day males and females, but were reversed by the end o f the one-month recovery period. Compound-related hypertrophy of follicular epithelium in the thyroid was present in 100 and 500 mg/kg/day males and females at the 90-day sacrifice, in 500 mg/kg/day males and females at the one-month sacrifice, and in the 500 mg/kg/day males at the three-month sacrifice, and was considered potentially adverse. Non-adverse alteration o f colloid was present in the thyroids of males and females at all dose levels at all time points. - 17Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 Reproduction: Twenty male and 20 female rats from each dose group were designated for reproductive evaluations. Parental rats (Pi generation) were dosed daily for 72 days prior to cohabitation, during the cohabitation period (mating) and during lactation, until the weaning of the Fi offspring. The following parameters were evaluated in Pi rats: body weight, food consumption, clinical signs, gross pathology, sperm parameters, estrous cyclicity, and reproductive performance. Reproductive organs o f animals with impaired reproductive performance were evaluated microscopically. The Fj offspring were evaluated during the lactation period for growth and survival and given a gross pathological examination at weaning. A subset of Fi generation rats were retained at weaning, and the following parameters were evaluated for 6 weeks: body weight, food consumption, clinical signs, and age at onset o f vaginal opening or preputial separation. After 6 weeks, the Fi generation rats were given a gross pathological examination, and selected reproductive organs and target organs o f toxicity were weighed. Test substance-related reductions in body weight gain were observed in 500 mg/kg/day Pj males during mating and in 500 mg/kg/day Pi females during gestation. The female body weight gain reduction was associated with reduced food efficiency. Clinical observations in the reproduction subset o f animals were similar to those reported for the subchronic toxicity subset. Female rats exposed to all doses had a reduced fertility index (55%, 58%, and 65% o f control in 25,100, and 500 mg/kg/day groups, respectively) and increased estrus cycle length (109%, 114%, and 112% of control in 25,100, and 500 mg/kg/day groups, respectively). For both endpoints, the magnitude of effects in the high-dose group was similar to that observed in the low-dose group. The lower fertility index was considered adverse in all groups. The toxicological significance o f the increased estrous cycle length is unclear. Females dosed with 500 mg/kg/day also had a reduction in the number o f uterine implantation sites (70% o f control). No adverse test substance-related effects on sperm parameters or other reproductive indices were observed. Groups o f male rats exposed to all doses had non-adverse reductions in epididymal sperm counts (88%, 91%, and 88% o f control in 25,100, and 500 mg/kg/day groups, respectively). There was no associated histopathology in the testis or epididymis. No test substance-related histopathology was observed in the reproductive organs o f Pi rats with impaired reproductive performance. In the 500 mg/kg/day group, the following parameters were affected (% control): number o f pups bom (72%), number o f pups bom alive (66%), number o f pups alive on day 4, 7,14, and 21 o f lactation (53, 60,14,10% o f control respectively). The viability index (day 0-4 viability) was 83% compared to 98% in the control group. Live pup weight at birth was 90% o f control and mean pup weights were 54%-71% o f the control mean during lactation (days 4-21). The lactation index (survival to day 21) was 11.4% compared to 100% in the control group. The litter survival was also reduced (25% compared to 100% in the control group). Based on these data, the number o f offspring in the 500 mg/kg/day group was already reduced at birth and death o f live offspring continued during lactation, mainly after day 14 o f lactation. Due to the high pup mortality in the 500 mg/kg/day group, there was an inadequate number to evaluate further endpoints and the remaining pups in this group were euthanized on postnatal day 33-35. - 18Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 In the 100 mg/kg/day group, there was no apparent effect on number o f pups until lactation day 14; the number o f live pups was 79% and 76% o f control at days 14 and 21, respectively. The lactation index was 76.1% compared to 100% in the control group. Pup weights were slightly reduced during lactation (86-94% o f control mean). In the 25 mg/kg/day group, there were no effects on pup viability, survival or pup weights. No test substance-related clinical observations or effects on male or female developmental landmarks were observed in 100 or 25 mg/kg/day Fj rats. NOEL fo r Subchronic Toxicity: Under the conditions o f this study, the no-observed-effect level (NOEL)3 for subchronic toxicity endpoints in male and female rats was 25 mg/kg/day. This level was based on clinical signs of toxicity, decrements in body weight parameters and food efficiency (males), thyroid follicular hypertrophy, and chronic progressive nephropathy (females), all observed in the 100 mg/kg/day groups. Other adverse, compound-related effects observed in males and/or females dosed with 500 mg/kg/day include decrements in body weight parameters and food efficiency (females), chronic progressive nephropathy (males), increased liver enzyme activity (males), reduction in red blood cell mass parameters (females), and reductions in forelimb and hindlimb grip strength (males). Most o f the effects observed during the dosing period demonstrated full or partial reversal following one or three months o f recovery. Reversal o f many effects in females was not observed until after the one-month recovery. Thyroid follicular hypertrophy (500 mg/kg/day males) and chronic progressive nephropathy (100 and 500 mg/kg/day females) were still present at the end o f the three-month recovery period. NOEL fo r Reproductive Evaluations: Under the conditions o f this study, there was no NOEL for reproductive evaluations. This was based on reductions in the fertility index in Pi rats in all dose groups. Estrous cycle length was prolonged in Pi rats in all dose groups, but the toxicological significance o f this change is unclear. Other adverse, compound-related effects observed in Pi rats dosed with 500 mg/kg/day include decrements in body weight parameters and food efficiency and reduced number o f implantation sites. In Fj generation rats, adverse, compoundrelated effects were observed in 100 and/or 500 mg/kg/day groups and included reductions in mean litter size, number o f pups bom and bom alive, pup survival during lactation, and pup weight at birth and during lactation. 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 (1985) and to the no-observed-adverse-effect level (NOAEL) as defined by the European Union (1994). -19Company Sanitized. Does not contain TSCA C8I H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 INTRODUCTION The test substance, H-24768, is a fluorinated organic ethoxylate used as a surfactant. The dose levels for this study were selected based on the toxicity and an analysis o f blood fluorine concentrations from a range-finding study in which rats were dosed by oral gavage with 50,100, 500, or 1000 mg/kg/day for approximately 62 days. In the range-finding study, rats exposed to 1000 mg/kg/day were sacrificed on test day 18, due to body weight loss and reductions in body weight gain in males. Transient, statistically significant body weight loss or reductions in body weight gain (compared to control) were observed in male and female rats exposed to 500 mg/kg/day during the first week o f exposure. In the 500 mg/kg/day male rats, mean body weights remained approximately 10-12% below control throughout the study. Weights o f female rats in this group were similar to control throughout most o f the study (no statistically signlficaht differences)/ Reduced body weight over test days 04 was also observed in rats exposed to lower doses, but body weight parameters in these groups were comparable to control over the rest o f the study. No compound-related clinical signs o f toxicity were observed in any group. Blood fluorine levels in this range-finding study appeared to have reached a plateau within approximately 2-3 weeks o f dosing. Therefore, the high-dose level for this 90-day study o f 500 mg/kg/day was selected based on the ability o f rats to tolerate this dose in the range-finding study. This dose was expected to produce toxicity without excessive mortality. The low dose o f 25 mg/kg/day was expected to be the noobserved-adverse-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 o f H-24768 when administered by gavage to male and female rats. A recovery group was 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. Blood, urine, feces, and tissues were collected for evaluation o f the pharmacokinetic profile o f H-24768, but have not been evaluated. Data from analysis o f these samples will be reported separately. MATERIALS AND METHODS A. Test Guidelines The subchronic toxicity study design complies with the United States Environmental Protection Agency (EPA), Office o f 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 o f reproductive function but does not comply with a specific guideline. - 20Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 B. Test Substance Samples o f H-24768 were supplied near the beginning, middle, and end o f the study for stability analysis and analyzed by the DuPont Regional Analytical Services (RAS). The stability analysis of H-24768 was based on the physical characterization of the test substance. Due to insufficient sample volume, the sample submitted near the beginning o f the study could not be completely analyzed. C. Test Species On March 1, 2001,176 male and 176 female Crl:CD(SD)IGS BR rats, with an assigned birth date o f January, 25,2001 were received from Charles River Laboratories, Inc., Raleigh, North Carolina for use on this study. An additional 44 rats (22 male and 22 females), with an assigned birth date o f April 8, 2001, were received in a separate shipment 63 days after study start on May 17,2001. The additional rats were designated for the 10-day hepatic biochemical analysis. 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 o f spontaneous diseases. D. Animal Husbandry 1. Housing With the exception o f some portions o f 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 o f 50% 20%. Occasional excursions outside the acceptable 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 o f the cohabitation period for females without evidence o f 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. During the entire in-life period for rats evaluated for subchronic toxicity, the 72-day premating period for Pi adults, and the 40-day postweaning period for Fi weanlings, cage racks were relocated within the animal room each week and cages were repositioned on the racks every 2 weeks. -21 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 2. Feed and Water Tap water was provided ad libitum. All rats were fed PMI Nutrition International, Inc. Certified Rodent LabDiet 5002 ad libitum. 3. Identification Prior to assignment to groups, each rat was temporarily identified by either the presence or absence o f a colored tail mark and cage identification. Subsequently, an individual identification number was tattooed on the tail o f each rat. The information on the cage labels included the unique 6-digit Haskell animal number and the individual identification number assigned to each rat. Fi generation rats retained after lactation were tattooed when they were approximately 21 days old. 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 o f the study: Water samples are analyzed for total bacterial counts, and the presence o f coliforms, 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 o f key contaminants, including specified heavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates. The presence o f these contaminants below the maximum concentration stated by the manufacturer would not be expected to impact the integrity o f the study. The animal health and environmental monitoring program is administered by the attending laboratory animal veterinarian. Evaluation o f these data did not indicate any conditions that affected the validity o f the study. E. Quarantine and Pretest Period Upon arrival at Haskell Laboratory, the rats were quarantined for 12 days o f the 14-day pretest period. The rats were observed daily for any clinically apparent signs o f disease or injury, weighed 3 times, and examined by a veterinary ophthalmologist to identify animals with preexisting ocular lesions. On the basis o f acceptable body weight gains and clinical observations, all surviving rats were released from quarantine on test day -2 by the laboratory animal veterinarian designee. - 22Compny Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 Additional male and female rats designated for the 10-day hepatic biochemical analysis were quarantined for 6 days o f the 11- and 12-day pretest period, respectively. The rats were observed daily for any clinically apparent signs o f disease or injury and weighed three times, then released from quarantine on test day 70. F. Study Design Groups No./ Group Male Female Male Female Dosage^ (mg/kg/day) In m IV V VI vn vm 45 35 35 45 45 35 35 45 0 (Control) 25 100 500 Biochemical Evaluations at the 10-day Time Point I-A m -A V-A v n -A n-A IV-A VI-A vm -A 5 5 5 5 5 5 5 5 0 (Control) 25 100 500 a Weight o f test substance / kg animal body weight. The first 10 rats in each group were designated for the 90-day exposure evaluation and are referred to in this report as the 90-day exposure animals. The next 5 rats in each group were initially designated for analysis o f fluorine in the blood. However, to assess three-month recovery from test substance-related effects, these rats were also evaluated for biochemical (males), clinical, and anatomic pathology endpoints; 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 63 days after study start for evaluation o f hepatic biochemical analysis following a 10-day exposure. Male and female rats designated for the 90-day exposure evaluation were dosed for 95 (male) and 96 (female) days, and necropsied on test days 95 and 96, respectively. One male control rat was dosed for 96 days and necropsied on test day 96. Male and female rats designated for the oneand three-month recovery evaluations were dosed for 91 days and necropsied 33 (males) or 34 (females) days and 93 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). Clinical pathology evaluations were conducted on animals designated for the 90-day exposure evaluation on weeks 7 and 14 and on animals designated for the one-month and three-month recovery evaluations immediately prior to necropsy. Biochemical evaluations were conducted on selected animals designated for the 90-day exposure evaluation, the one-month and three-month recovery -23Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 evaluations, and the 10-day exposure evaluation. Rats designated for reproduction evaluations were transferred to the reproduction group on test day 70, and reproductive evaluations began on test day 72, when designated male and female rats were cohoused. 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 o f adequate body weight gain, freedom from any ophthalmological abnormalities or clinical signs o f disease or injury, and a body weight within 20% o f the mean within a sex. One male rat with a pretest ophthalmologic observation was included in the high-dose group (rat 646365). However, it was designated for the reproductive subset, which was not evaluated for post-exposure eye effects. Therefore, this did not affect study results. 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 o f H-24768 began on test day 0, when the rats were approximately 49 days of age. Prior to the start o f test substance administration, 2 male rats with body weights that were not within 20% o f 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 o f disease or injury and a body weight 20% o f the mean within a sex. One male rat designated for the reproduction, evaluation was replaced based on a clinical observation made at the time o f dosing on test day 0. 2. Rats Designated for 10-Day Biochemical Analysis The rats designated for the 10-day biochemical analysis arrived separately, 63 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 o f rats was compared among themselves. Oral administration o f H-24768 to male and female rats began on test days 74 and 75, respectively. In-life data (body weight, food consumption, clinical observations) were collected from these animals and are in study records. However, these data will not be included in this report. H. Dose Solution Preparation Dose solutions o f 0, 3.33,13.33, or 66.67 mg test substance/mL were prepared with deionized water. The test substance, a brown paste, was melted and stirred in a 77C water bath. The appropriate amount of test substance was weighed out, then dissolved in deionized water. The dosing solutions were mixed for approximately one minute with a polytron homogenizer. Dose solutions were prepared twice a week and refrigerated until used. On the day of use, the dose solutions were removed from the refrigerator and stirred while they were brought to room - 24Company Sanitized. Does not contain TSCA CBI H-24768: Subclifonic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 temperature. A one-day aliquot was then removed and the remaining dose solutions were returned to the refrigerator. The daily aliquots were stirred prior to and during dosing. I. Test Substance Administration and Sampling Animals designated for the 90-day dosing period were dosed through test day 94 (males) or 95 (females). One control male in this subset was dosed through test day 95. Animals designated for the one- and three-month recovery evaluations were dosed through test day 90. Animals designated for reproduction evaluations were dosed through the 72-day premating period and during the mating period. Pi males continued to be dosed until sacrifice. Pregnant females were dosed during the gestation period. Lactating females and females with no evidence o f copulation were dosed until pups were weaned on postnatal day 21. All Pi animals in the reproduction study, with the exception o f pregnant females in the process or showing signs o f delivery, were dosed daily until sacrifice. The test substance was administered daily to the study animals by oral gavage to achieve dosage levels o f 25,100, or 500 mg active ingredient/kg body weight/day, based on the most recently recorded body weight. All male and female control animals were dosed with deionized water at 7.5 mL/kg, the same dose volume used in other groups. On test day 21, Group HI, rat 646458 was inadvertently dosed twice. During the course o f the study, there were individual rats across dose groups that were misdosed; these rats are documented in study records and reported in Appendix B. The incidences o f misdosing described above are considered not to have affected the outcome o f the study. All dosing solution samples were collected on the same day the solutions were prepared or as indicated by the stability analysis for the study. The solution vehicle was deionized water. Samples o f dosing solutions containing H-24768 in deionized water, at targeted concentrations of 0, 3.33,13.33, and 66.67 mg/mL were collected at the initiation o f the study (test day 0) for verification o f uniformity, concentration, and 5-hour room temperature stability. The 5-hour stability sample was analyzed to demonstrate stability o f the test substance in dosing solutions over the time the animals were being dosed. Samples o f dosing solutions prepared at the same concentrations were collected on test days 32,42, and 91 for concentration verification. Dosing solutions were prepared twice a week, then refrigerated until used (up to 4 days). Samples at the same concentrations as above, prepared on test day 39, were collected on test day 43, after 4 days o f refrigeration, to verity stability under these storage conditions. All dosing samples, except those for verification o f 4-day refrigeration stability, were collected on the same day the solutions were prepared. Samples submitted for analysis were analyzed the day the solutions were received or refrigerated until analyzed. The stability o f the test substance under 4-day refrigerated conditions was also supported prior to study start by analytical results from a developmental toxicity study previously conducted with this test substance - 25Compny Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 J. Analytical Methods 1. Dosing Solution Treatment Prior to analysis, each dosing sample was diluted with methanol and an equivalent amount o f diluted control, to an expected concentration o f 1.67 or 3.33 mg/mL (a.i.). 2. Chromatographic Conditions Instrument: Column: Injector: Detector: Carrier Gas: Split vent: Injection Volume: Oven Program: Initial Temperature: Initial Time Level 1 Rate: Level 1 Temperature: Run Time: Hewlett-Packard Model 6890 GC HP-1, 30 m x 0.32 mm ID, 0.25 ira. film thickness Split, 250C FID; 300C Helium (2.7 mL/min) 53.2 mL/min 1 microliter Gradient 50C 0.0 min. 40C/min. 300C 22.25 minutes 3. Calibration and Quantitation A stock solution of the test substance (a separate sample o f H-24768, used as analytical reference) was made in methanol. Appropriate aliquots of the stock were diluted with the methanol and an equivalent amount of the diluted control to match the samples. These solutions were used to make calibration standards that bracketed the target concentration of the diluted dosing samples. Peak heights (4 retention times) from GC analysis o f these standards were used to construct calibration curves by least square regression (see Appendix A, Figure la - Id for representative calibration curves). Measured concentrations for dosing solutions were determined by applying the peak heights from replicate injections o f the samples to each calibration curve. The mean result from the concentrations at all retention times (n = 4) is reported as the concentration for the sample. Test substance uniformity in the vehicle was evaluated by calculating the coefficient o f variation (C.V. = standard deviation/mean x 100) o f the measured concentrations in duplicate samples for each dosing level. A coefficient o f variation o f less than 10% is the standard criterion at Haskell Laboratory for acceptable distribution o f the test substance throughout the solution. The mean result o f the duplicate samples for each dosing level was used to determine the concentration o f the test substance for the respective dosing levels. Stability was evaluated by using the mean o f the duplicate samples for concentration verification as the baseline for comparing the corresponding 5-hour room temperature and 4-day refrigerated results. - 26Company Sanitized. Does not contain TSCA CSI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 K. Body Weights All rats were weighed once per week during the 90-day exposure phase o f the study. In addition, the rats designated for neurobehavioral evaluations, undergoing functional observational battery and motor activity assessments, were weighed on the days o f those observations. During the reproduction assessment, male rats were weighed on a weekly schedule and female rats were weighed during gestation on days 0, 7 ,1 4 ,1 8 , and 21, and on lactation days 0, 7, 14, and 21. Pi female rats with no evidence o f copulation, or that did not deliver a litter, continued to be weighed weekly. Weaned Fj rats were weighed weekly until postnatal day 56 (equivalent to test day 36 for the Fi generation). Gestation day 18 body weights were collected solely for the purpose o f adjusting dose volumes and are not reported. L. Food Consumption and Food Efficiency The amount o f food consumed by each rat over each weighing interval was determined throughout the study. Each feeder was weighed at the beginning and end o f the interval and the final weight o f the feeder and the amount o f 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 through test day 119, but was not determined for animals designated for the three-month recovery evaluations after test day 119. During the reproductive assessment, food consumption was determined for each female rat designated for reproductive assessment as follows: Premating Dosing period - individual food consumption was determined weekly, ending test day 70. Cohabitation period beginning test day 72 and Pi males after the end o f cohabitation - food consumption was not determined. Gestation period - individual food consumption was determined on gestation days 0, 7,14, and 21. Lactation period - food consumption was not determined. Postweaning Fi rats - individual food consumption was determined weekly, ending on postnatal day 56 (equivalent to test day 36 for the Fi generation). 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. 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- - 27Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 day exposure and one-month recovery periods. The detailed clinical observations included (but were not limited to) evaluation o f fur, skin, eyes, mucous membranes, occurrence o f secretions and excretions, autonomic nervous system activity (lacrimation, piloerection, and unusual respiratory pattern), changes in gait, posture, response to handling, presence o f clonic, tonic, stereotypical, or bizarre behavior. N. Ophthalmological Evaluations Two 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 -13, the initial examination was performed on all rats received for the study, prior to selection and grouping. On test day 85, all surviving rats designated for the 90-day exposure and one-month recovery were examined again. O. Neurotoxicity Evaluations 1. Sensory Function Evaluation Prior to test substance administration, during week 13 (test days 88 and 89) o f test substance administration, and following an approximately one-month recovery period (test day 118), assessments o f 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 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 th apparatus was located facilitated observing the response. The presence or absence o f pupillary constriction was assessed after a beam o f light was directed into each eye. For all these assessments, the experimenter was unaware o f the group designation of the animal.2 2. Motor Activity Following the evaluation o f grip strength and sensory function, assessment o f motor activity was conducted. Rats were individually tested in 1 of 30 nominally identical, automated activity monitors (Coulboum Infrared Motor Activity System). Group and gender were counterbalanced across the monitors and time o f day to the fullest extent possible. The infrared monitoring device enables measurement o f 2 dependent variables: duration of movement and number o f movements. A continuous movement was counted as 1 movement regardless o f 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. - 28Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 Presence of defecation and urination on the cageboards below the motor activity monitor was also recorded following each motor activity session. 3. Test Facility Positive Control Data Data on the effects o f acrylamide, carbaryl, d-amphetamine, and trimethyltin are described in four separate reports/1,2,3'1*4) These positive control studies are the basis o f training certification for the individuals making judgments in the neurobehavioral and neuropathology tests. The data also document that the equipment and procedures are capable o f detecting effects that may be seen in neurotoxicity studies o f this type. P. Clinical Pathology Samples for clinical pathology evaluations were collected from the first 10 male and 10 female rats per group in all groups on test days 39 and 95 (males), or 40 and 96 (females). One control group male rat had samples collected on test day 96. After one month o f recovery, samples for clinical pathology evaluations (excluding coagulation) were also collected from 10 recovery rats per group (control and 500 mg/kg/day only) on test day 123 or 124 (males or females, respectively). Additionally, after 3 months o f recovery, samples for clinical pathology evaluations (excluding coagulation and including selected urinalysis tests) were collected from up to 5 satellite recovery rats per group (all groups) on test day 184. The rats were fasted overnight (approximately 16 hours). During this interval, urine was collected from each rat into vials containing EDTA. Blood samples for hematology and serum clinical chemistry measurements were collected from the orbital sinus o f each fasted rat while the rat was under light carbon dioxide anesthesia. Blood samples for coagulation (end o f dosing only) and plasma fluoride were collected from the abdominal vena cava while the rat was under carbon dioxide anesthesia, immediately prior to sacrifice. All blood samples were examined visually and observations recorded. 1. Hematology/Coagulation Complete blood counts (including reticulocytes) were determined on a Bayer Advia 120 hematology analyzer and determined from microscopic evaluation o f the blood smear. Wrightstained blood smears from all rats were examined microscopically for confirmation o f automated results and evaluation o f 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. - 29Company Sanitized. Does not contain TSCA CBi H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations______________________ DuPont-5990 The following hematology and coagulation parameters were determined: Red blood cell count (RBC) Hemoglobin (HGB) Hematocrit (HCT) Mean corpuscular volume (MCV) Mean corpuscular hemoglobin (MCH) Mean corpuscular hemoglobin concentration (MCHC) Prothrombin time (PT) Activated partial thromboplastin time (APTT) Red cell distribution width (RDW) Absolute reticulocyte count (ARET) Platelet count (PLT) White blood cell count (WBC) Differential leukocyte count Microscopic blood smear examination 2. Clinical Chemistry All clinical chemistry parameters were measured in serum, with the exception o f fluoride, which was measured in EDTA plasma. 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/12pH meter with a fluoride-selective electrode. The following clinical chemistry parameters were determined: Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Sorbitol dehydrogenase (SDH) Alkaline phosphatase (ALKP) Total bilirubin (BILI) Urea nitrogen (BUN) Creatinine (CREA) Cholesterol (CHOL) Triglyceride (TRIG) Glucose (GLUC)3 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 (UOSM) Specific gravity (SG) pH Glucose (UGLU) Ketones (KET) Bilirubin (UBIL) Blood (BLD) Urobilinogen (URO) Urine fluoride (UFLU) Protein (UMTP) Microscopic examination of urine sediment 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 protein was measured on a Roche Diagnostics (BMC)/Hitachi 717 clinical chemistry analyzer. Urine osmolality was determined using an Advanced Osmometer 3900. Urine fluorides were determined by multiplication of measured urine volume by urine - 30Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 fluoride concentration (measured using a phi/12pH meter with a fluoride selective electrode). Sediments from all urine specimens were evaluated microscopically. Q. Collection o f Blood, Urine, Feces, and Tissue (Three-Month Recovery and Fj Generation) On test day -4 (pre-bleed) and test days 0, 3, 9,21, 3 4 ,5 5 ,7 6 , and 89, blood (approximately 0.5 -1 mL) was collected from the orbital sinus o f designated animals (5 rats/sex/dose) while the rat was under light carbon dioxide anesthesia for possible analysis o f total fluorine. On the day o f blood collection (except test day -4), blood was collected from the animals 2 hours ( 30 minutes) after dosing. Inadvertently, on test day 34, some rats were bled within 2 hours ( 50 minutes) o f 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 o f day. During the last week o f the 90-day exposure period and the last week o f the three-month recovery period, urine and feces were collected daily at 24-hour intervals from each animal. The animals were placed in metabolism cages for collection o f feces and urine. The exact time period o f collection o f urine and feces was documented along with the total volume of urine obtained. Urine and feces were stored frozen. Blood was also collected for possible analysis at 3, 7, 12, 19, 26, 36, 50, 71, and 93 days postdosing for both male and female animals o f each dose group and stored frozen. Animals were sacrificed at the end o f the three-month recovery period. The testes, fat (1 gram), and aliquots o f liver and kidney were collected and frozen for possible analysis o f total fluorine. On postnatal days 33-35 (Fi test days 13-15), all surviving Fi generation rat pups in the 500 mg/kg/day group were euthanized. At the time o f necropsy, approximately 1 mL o f blood was collected from the orbital sinus o f each rat. On the same day as the 500 mg/kg/day group sacrifice and blood collection, 5 Fi male pups and up to 5 Fi female pups (that had demonstrated vaginal patency) from the 0, 25, and 100 mg/kg/day groups had approximately 0.7 mL blood collected from the orbital sinus, while the rat was under carbon dioxide anesthesia. This blood was collected from pups in all groups for possible comparison of selected parameters among these groups. These blood samples were stored for possible comparison o f these parameters over time. The collected blood, urine, feces, and tissues may be evaluated in the future for total fluorine. Resulting data will be reported separately. R. Biochemical Measurements Following 10 or approximately 90 days o f test substance administration, or after approximately one month or three months o f recovery, five rats from each group designated for biochemical evaluation were weighed and then euthanized by carbon dioxide anesthesia and exsanguination. At each time point, the livers were removed, weighed, and then a portion was homogenized (1 gram tissue/4 mL buffer) in homogenization buffer (50 mM Tris-HCl, 50 mM Trizma-base, 0.25 M sucrose, and 5.4 mM EDTA, pH 7.4). Hepatic peroxisomes were prepared using differential -31 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 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 o f approximately 0.25 or 0.5 mg/mL. Peroxisomal p-oxidation activity was determined using [14C]palmitoyl CoA as the substrate/5) The protein content o f the peroxisomes was determined before and after analysis by the Biorad m ethod/6) Final rate calculations were made using the post-assay protein concentrations. S. Anatomic Pathology - Rats Designated for 90-Day Exposure and Recovery Evaluations After approximately 90 days o f dosing (95 for males; 96 for females and one control male), groups o f 10 male and 10 female rats from the 0, 25,100, and 500 mg/kg/day groups were sacrificed and necropsied. Following a recovery period o f approximately 30 days (one-month recovery), rats from 0 and 500 mg/kg/day groups were sacrificed and necropsied. Male and female animals from a second recovery subset were sacrificed and necropsied following a recovery period o f approximately 90 days (three-month recovery), where all exposure groups were represented. Rats were euthanatized by carbon dioxide anesthesia and exsanguination. Gross examinations were performed on all male and female rats. In rats sacrificed after three months o f recovery, the gross examination was limited to the abdominal and thoracic cavities. The following tissues were collected from rats designated for the 90-day exposure and onemonth recovery. Digestive Svstem Liver Esophagus Stomach Duodenum Jejunum Ileum Cecum Colon Rectum Salivary glands Pancreas Urinarv Svstem Kidneys Urinary bladder Cardiovascular Svstem Heart Aorta Hematopoietic Svstem Spleen Thymus Mandibular lymph node Mesenteric lymph node Bone marrow* Endocrine Svstem Pituitary gland Thyroid gland Parathyroid glands Adrenal glands Resoiratorv Svstem Nervous Svstem Lungs Brain (including cerebrum, Trachea cerebellum, medulla/pons) Nose Spinal cord (cervical, mid- Larynx thoracic, lumbar) Pharynx Sciatic nerve a Bone marrow was collected with the femur and sternum. Musculoskeletal Svstem Skeletal muscle Femur/knee joint Sternum Renroductive Svstem Male Testes Epididymides Prostate Seminal vesicles Female Ovaries Uterus Mammary glands Miscellaneous Skin Eyes (including optic nerve) Gross observations -32Company Sanitized. Does not contain TSCA C8I H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 The liver, kidneys, adrenal glands, brain, spleen, thymus, heart, ovaries, uterus, epididymides, and testes were weighed at necropsy, and organ weight/final body weight and organ weight/brain weight ratios were calculated. Thyroid glands were weighed after fixation. The following tissues were weighed from rats sacrificed after three-month recovery: liver, kidney, testes, spleen, thyroid (after fixation), and 1 gram o f fat. A sample o f liver was taken for biochemical analysis from control and 500 mg/kg/day males. A sample of liver, kidney, spleen, and thyroid was taken from all rats for histopathologic evaluation. A sample o f testes, fat, kidney, and liver was saved frozen for possible analysis o f total fluorine. 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 collected. Gross lesions for which a microscopic diagnosis would not be additive (e.g., osteoarthritis, pododermatitis, chronic dermatitis o f 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 Bouin's solution. All other tissues were fixed in 10% neutral buffered formalin. Processed tissues were embedded in paraffin, cut at a nominal thickness o f 5 micrometers, stained with hematoxylin and eosin (H&E), and examined microscopically. All collected tissues from the control and high-dose rats sacrificed on test days 95 and 96, and all found dead or accidentally killed rats were processed and received a full histopathological examination. Liver, thyroid gland, spleen, and kidneys were processed and examined microscopically from low- and intermediate-exposure groups o f 90-day rats, and from all rats sacrificed at the one-month and three-month recovery time points. The key to the Pathology Evaluation appendix describes the lesion grading system used in this study. T. Reproductive Assessment 1. Breeding After approximately 10 weeks o f exposure to the test substance, on test day 72, each female was continually housed on a 1:1 basis with a randomly selected male o f the same dose 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 o f copulation was observed (designated as day 0 o f gestation), or until 2 weeks elapsed. The presence o f an intravaginal or extruded copulation plug was considered evidence o f copulation. Two 500 mg/kg/day males in the reproduction subset died during the premating period. Two surviving males in this group were cohoused with the extra female rats after copulation was confirmed with the original female. - 33Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 2. Estrous Cycle Evaluation Vaginal smears were collected from all Pi female rats in order to determine the stages o f the estrous cycle. Vaginal smears were collected daily beginning approximately 3 weeks prior to cohabitation, 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 o f sacrifice to determine the stage o f estrous cycle. These data are not presented in the report but are included in the study records. 3. Gestation Procedures After being transferred to polycarbonate pans (on day 20 of gestation for mated females or at the end o f the cohabitation period for female rats without evidence o f copulation), female rats were observed at least twice daily for signs of delivery and pups. The day o f gestation was presumed to have been miscalculated (due to the missed first copulation plug) for one pregnant female in group VIII-0 (Animal No. 646663) since at delivery pups were much larger than expected for day 16 o f gestation and were the size expected for a litter delivered at term (day 22 o f gestation). Data from this animal were excluded from group means (gestation body weight and food consumption, gestation length, estrous cycle parameters and precoital interval). 4. Lactation Procedures 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 determined prior to and after culling, and individual pup weights were determined prior to culling. c. Days 7 and 14 Postpartum Pups in each litter were counted by sex and individually weighed. - 34Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations _________________ DuPont-5990 d. Day 21 Postpartum (Weaning) Pups in each litter were counted by sex and individually weighed (3 o f 4/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 o f developmental landmarks, and were weighed and had food consumption determined weekly until developmental landmark criteria were met. At each examination period, offspring were individually handled and examined for abnormal behavior and appearance; any dead, missing, or abnormal pups were recorded. Due to the low number of 500 mg/kg/day Fi rats still alive after weaning, post-weaning body weight, nutritional, and clinical observations data are not reported on the summary data tables. Individual animal data are included in the appendices. 5. Post Weaning and Developmental Landmarks On postnatal days 33-35 (Fi test days 13-15), all surviving Fi generation rat pups in the 500 mg/kg/day group were euthanized due to high pup mortality in this group. The method o f euthanasia and the endpoints evaluated followed procedures for Ft adults (Materials and Methods, Section U., Anatomical Pathology - Rats Designated for Reproductive Evaluations, 1. Ft Adults. At the time o f 500 mg/kg/day necropsy, blood was collected from each rat in the 500 mg/kg/day group and blood was collected from 5 Ft male pups and up to 5 Ft female pups (that had demonstrated vaginal patency) from the 0, 25, and 100 mg/kg/day groups. The methods and process are described in detail in Materials and Methods, Section Q. Collection o f Blood, Urine, Feces, and Tissue (Three-Month Recoveiy and Fi Generation). Developmental landmarks in the Fi generation male and female rats (one/sex/litter) were monitored on a daily basis until criterion was achieved. Body weight and food consumption were determined until postnatal day 56 (Fi test day 36). Animals were weighed on the day the developmental landmark was achieved. a. Vaginal Patency Female rats were examined beginning on postnatal day 21. b. Preputial Separation Male rats were examined beginning on postnatal day 35. -35Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations U. Anatomical Pathology - Rats Designated for Reproductive Evaluations Animals Adult Males Sacrifice Schedule Schedule After siring litters (at discretion of reproductive toxicologist) Pregnant Females On day o f weaning litters Nonpregnant Females With pregnant females Weanlings Fi Adults 3 of 4 rats/sex/litter will be sacrificed on postnatal day 21. At postnatal day 60 DuPont-5990 1. Pi Adults All Pi parental rats were sacrificed by carbon dioxide asphyxiation and exsanguination, and received gross pathological examination, including the females that died and those males and females for which mating did not result in a production o f offspring. The uteri of all cohabited females were examined for the presence and number o f implantation sites. Sperm parameters for the first 10 surviving Pi male animals sacrificed by design in each treatment group were evaluated. The right epididymis was removed, and 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 -65C and -85C for sperm and spermatid counts, respectively. The following table lists tissues that were collected and saved in the appropriate fixative: Male Tissues Collected from Pi Adults Female Both Sexes Testes/Testis3 Ovaries Epididymides/Epididymis3 Uterus (with oviducts) Thyroid Gland Gross Observationsb Prostate Seminal Vesicles Coagulating Gland Vagina Pituitary Gland a Testes/Testis and epididymides/epididymis collected from male rats were placed in Bourn's solution. All other tissues (reproductive and non-reproductive) collected from male and female rats were placed in formalin. b Gross lesions observed at necropsy for which histopathology was not appropriate or would not be additive were generally not collected. -36Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 2. Offspring Offspring that were found dead during the lactation period underwent a gross pathological evaluation. 3. Fi Weanlings Three Fi weanlings/sex/litter (randomly selected), litter size permitting, were sacrificed by carbon dioxide asphyxiation and underwent a gross pathological evaluation on postnatal day 21. All surviving Fi generation rats in the 500 mg/kg/day group were euthanized by carbon dioxide anesthesia and exsanguination on postnatal days 33-35 and received a gross pathological evaluation. Gross lesions were preserved. 4. Fi Adults All Fi generation rats were sacrificed by carbon dioxide asphyxiation and exsanguination, and received 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 Testes3 Ovaries Thyroid Gland Epididymides3 Prostate Uterus (with oviducts) Vagina Gross Observations'3 Pituitary Seminal Vesicles Coagulating Gland a Testes/Testis and epididymides/epididymis collected from male rats were placed in Bouin's solution. All other tissues (reproductive and non-reproductive) collected from male and female rats were placed in formalin. b Gross lesions observed at necropsy for which histopathology was not appropriate or would not be additive were generally not collected. Male Testes Epididymides Seminal Vesicles (with Coagulating glands) Prostate Tissues Weighed from Fi Adults Female Both Sexes Uterus (with oviducts and cervix) Thyroid Gland (after fixation) Liver Brain - 37Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 5. Processing o f Tissues Processed tissues (testes, epididymides, seminal vesicles, prostate, and uterus, ovaries, and vagina) for histopathological examination were embedded in paraffin, cut at a nominal thickness o f 5 micrometers, and stained with hematoxylin and eosin (H&E). Histopathological examination o f tissues was conducted only for Pi adults with impaired reproductive performance. Reproductive tissues from some male rats with impaired reproductive performance were saved but inadvertently not processed to slides, and thus not microscopically examined. As these same tissues were microscopically examined in test substance-exposed rats from the 90-day subchronic toxicity sacrifice, and found to have no test substance-related alterations, the absence o f these tissues for microscopic evaluation in the reproductive portion of the study did not impact the conclusions o f the study. Furthermore, no test substance-related alterations were observed in the male rats with impaired reproductive performance that were evaluated microscopically. Gross lesions were saved but not evaluated microscopically because they would not have been additive to the interpretations o f the study. Selected gross observations for which a microscopic diagnosis would not be additive (e.g., osteoarthritis, pododermatitis, tail chronic dermatitis, calculus, and deformities of the teeth, toe, tail, or ear pinnae) were saved, but not processed for microscopic evaluation. -38Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 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 Biochemical Measurements Motor Activity0 Grip Strength Clinical Pathologyd Survival Incidence of Clinical Observations Incidence of Ophthalmology Observations Incidence of FOB Descriptive Parameters Biochemical Measurements Incidence of Microscopic Lesions Preliminary Test Test for lack of trend*9* Levene's test for homogeneity*12*and Shapiro-Wilk test*13*for normality11 Levene's test for homogeneity*12*and Shapiro-Wilk test*13*for normality11 Bartlett's test*18*for homogeneity of variances Levene's test for homogeneity*12*and Shapiro-Wilk test*13*for normality11 Method of Statistical Analysis If preliminary test is not If preliminary test is significant significant Sequential application*10* of the Jonckheere-Terpstra trend test*11* Preliminary tests for pairwise comparison OR* One-way analysis of Rruskal-Wallis test*15* variance*14*followed with followed with Dunn's Dunnett's test*7* test*8* Repeated measures analysis of variance*16* followed by contrasts*17* Sequential application*10* of the Jonckheere-Terpstra trend test*11* One-way analysis of Kruskal-Wallis test*15* variance*14*followed with followed with Dunn's Dunnetfs test*7* test*8* One-way analysis of Kruskal-Wallis test*15* variance*14*followed with followed with Dunn's Dunnetfs test*7* test*8* None Cochran-Armitage test for trend*14*6 None None One-way analysis of variance*14*followed with Dunnetfs test*7*or Dunn's test*8* None 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 of Dunnetfs test was used. c Test day and block (10-minute EPOCH) was used as repeated-measure factors. d When an individual observation was recorded as being less than a certain value, calculations were performed on half the recorded value. For example, if bilirubin was reported as <0.1, 0.05 was used for any calculations performed with that bilirubin data. e If the incidence was not significant, but a significant lack of fit occurred, then Fisher's Exact test(l9) with a Bonferroni correction was used. -39Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations __________________ DuPont-5990 The following table lists the statistical analyses conducted on the indices o f 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 trend(9) Method of Statistical Analysis If preliminary test is If preliminary test is not significant significant Sequential application003 o f the Preliminary tests for Jonckheere-Terpstra pairwise comparison trend test013 ORa Levene's test for homogeneity(12) and Shapiro-Wilk test (13)for normality15 One-way analysis of v arian ce(14) follo w ed with Dunnett's test(7) Kruskal-Wallis test 5>followed with Dunn's test03 None One-way analysis o f variance043 followed with Dunnett's test(7) Incidence o f Clinical Observations Mating Index Fertility Index Gestation Index Viability Index Lactation Index None Cochran-Armitage test for trend04)0 Mean Pup Weights (Covariates: litter size, sex ratio) Sex Ratio None Linear contrast of least squares means003 Dunn's test(s) a Pairwise comparisons and associated preliminary tests were only conducted if the test for lack o f trend was significant. b If the Shapiro-Wilk test was not significant but Levene's test was significant, a robust version o f Dunnett's test was used. c If the incidence was not significant, but a significant lack o f fit occurred, then Fisher's Exact test(19) with a Bonferroni correction was used. - 40Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 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.(10) For litter parameters, the proportion o f affected fetuses per litter or the litter mean was used as the experimental unit for statistical evaluation.(21) Where the data were tied and the standard large sample version o f Jonckheere's test was not applicable, exact p values were calculated using permutation methodology.(22) 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 (percent purity, composition, and known impurities) will be stored at Regional Analytical Services (RAS), Jackson Laboratories, Deepwater, New Jersey. Characterization data used to support test substance stability will be retained at Haskell Laboratory, Newark, Delaware, or at Iron Mountain Records Management, Wilmington, Delaware. -41 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 RESULTS AND DISCUSSION - 42Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 ANALYTICAL EVALUATIONS A. Test Substance Stability Analyses of bulk samples o f H-24768 near the beginning, middle, and end o f the study indicated that the test substance was stable for the duration o f the study. Due to insufficient sample volume, complete analysis o f the sample submitted near the beginning of the study could not be conducted. However, analyses o f surface tension and density, reported on the certificate o f analysis, dated 29-Jan-2001, support the stability o f the test substance over the duration o f the study. The stability o f the H-24768 in the samples was based on the physical characterization o f the test substance. The analyses consisted o f the density at 65 C, the upper cloud point, the surface tension, the residual ethylene oxide (E.O.), the appearance, and the percent fluoride. This work can be found i n f l H H l H H H H i i H H H V d a s k e l l No. H-24768,]"* Analytical Text Table: Analytical Results for Test Substance Stability Sample Collection Day Test Day 3 Density @65 1.321(a,b) Upper Cloud Point (C) ___(a) Type of Analyses Surface Tension Residual (dynes/cm) Ethylene Oxide 22.0(a'b) NDC Appearance OK % Fluoride _ _ (a ) Test Day 49 1.3270 9L0 22.0 ND OK 32.5 Test Day 123 1.3210 91.5 21.0 ND OK a Sample supplied at study start for analysis was insufficient to perform entire battery o f tests, b Values listed are values reported on the sponsor's certificate o f analysis dated 29-JAN-2001. c Not detected 32.0 B. Chromatography H-24768 eluted from the GC column as resolved peaks over retention time range of approximately 5 to 20 minutes. For the purpose o f quantitation, the retention times of approximately 7.9, 8.2, 8.5, and 9.0 minutes were determined to be representative o f H-24768 in the dosing matrix. Representative GC chromatograms are shown in Appendix A, Figures 2(a - c). Test substance was not detected in the 0 mg/mL control sample. C. Uniformity of Mixing, Concentration Verification and Stability Samples Analytical results from dosing solutions prepared test day 0, and test day 39 and analyzed for uniformity of mixing, concentration verification, and stability are shown in Table 1 and Appendix A, Table I. - 43Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 Analytical Text Table: Analytical Results for Uniformity, Concentration, and Stability Nominal Measured3'15 Average15 CVb 5-Hour Stability15'3 4-Day Stability a'd mg/mL mg/mL % Nominal % % Nominal % Nominal 3.33 13.33 66.67 3.11,2.82 12.1, 11.6 60.4, 55.1 89.2 89.3 86.7 7 3 6 88.0 87.0 87.1 94.3 90.0 88.3 a Duplicate samples analyzed. b Samples taken from dose solutions prepared on test day 0. c Stability samples held for 5 hours at room temperature. d Stability samples prepared Test day 39 and held for 4 days refrigerated and sampled. Initial baseline sampling on Test day 39 was not submitted. The results for samples prepared on test day 0, show that the test substance was uniformly mixed (CV's less than 10), at the targeted levels (target = 13.3% o f nominal) and stable in the vehicle when held 5 horns at room temperature. The samples prepared on test day 39 were sampled after 4 days refrigeration. No analyses were conducted on these samples, on the day o f preparation, to establish the baseline. However, the results indicated that the test substance concentrations following this storage time were similar to those observed in other analyses conducted at the time o f dose solution preparation (i.e., test days 32,42, 91). Furthermore, stability under these storage conditions was demonstrated in a previous study (see following paragraph). Test substance was not detected in the 0 mg/mL sample. The following table summarizes results for stability samples from a developmental toxicity study H H H H ||H H f lB > r e v i o u s ly conducted with this test substance. These results indicate that the test substance inthe vehicle was stable when held 4 days refrigerated followed by 5 hours at room temperature and support the stability o f the test substance under the conditions o f this study. Thus, dosing solutions could be prepared twice a week and stored refrigerated until use, and would still provide the targeted dose. This was further confirmed by analysis o f samples collected on test day 39 o f this 90-day study, and held under the same conditions prior to analysis (see above). Analytical Text Table: Analytical Results for Stability Nominal Measured3 Average CV Stability15 Stability3 mg/mL mg/mL % Nominal % % Nominal % Nominal 5.0 4.72, 4.54 92.6 3 101.2 10.0 9.36, 8.75 90.5 5 97.0 40.0 40.2, 38.9 98.9 2 105.2 70.0 63.2,61.7 89.1 2 120.3 107.4 97.2 103.3 99.6 a Duplicate samples analyzed, b Stability samples held for 4 days refrigerated. c Stability samples held for 4 days refrigerated, then 5 hours at room temperature. 4 4- Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 D. Concentration Verification Samples During the Study Analytical results from dosing solutions prepared test day 32, test day 42 and test day 91 and analyzed for concentration verification are shown in Table 1 and Appendix A, Table H The following table summarizes the results for concentration verification analyses for the test day 32, 42, and 91 preparations. Analytical Text Table: Analytical Results for Concentration Preparation Day Nominal mg/mL Measured3 mg/mL Average % Nominal CV % Test day 32 3.33 13.33 66.67 3.05, 3.08 11.5, 11.6 59.0,61.7 92.2 1 87.0 1 90.6 3 Test day 42 3.33 13.33 66.67 3.13,3.12 12.5, 12.5 58.8, 57.6 93.7 0 93.8 0 87.3 1 Test day 91 3.33 13.33 66.67 3.17,3.18 12.4,12.6 58.7, 60.0 95.2 0 93.8 1 88.9 2 a Duplicate samples per level were analyzed. C.V. calculated to verify uniformity of mixture. The results for samples prepared on test days 32,42, and 91 indicate that the test substance was adequately mixed (CV's less than 10) and at the targeted levels (target = 13% o f nominal) for all samples. Test substance was not detected in the 0 mg/mL sample. E. Analytical Conclusions Results from the analysis o f the samples collected at study start and during the study indicate that the test substance was mixed uniformly, was at the targeted levels, and was stable under the conditions o f the study. Test substance was not found in the 0 mg/mL samples. Based on analyses o f physiochemical properties, the test substance was demonstrated to be stable over the course o f the study. - 45Company Sanitized. Does not contain TSCA C8I H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 SUBCHRONIC TOXICITY EVALUATIONS IN-LIFE TOXICOLOGY Rats designated for evaluation o f reproductive toxicity were transferred to the reproduction group on test day 70, and were co-housed for mating beginning on test day 72. All results reported in this section up to test day 70 (including day 0-70 intervals) include data from both the subchronic toxicity and reproductive toxicity subsets. All results after test day 70 (including day 0-91 intervals) are from subchronic toxicity rats alone. A. Dosage Data (Tables 2-3, Appendix B) Rats were dosed with solutions o f H-24768 in deionized water, prepared at concentrations o f 0, 3.33,13.33, and 66.67 mg/ml, designed to deliver the targeted dose o f test substance at a dosing volume o f 7.5 ml/kg body weight. The quantity o f H-24768 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 o f mean daily dose volumes administered to male rats was 1.6-4.5 ml for the control group, 1.6-4.6 ml for the 25 mg/kg/day group, 1.6-4.1 ml for the 100 mg/kg/day group, and 1.63.6 ml for the 500 mg/kg/day group. The range o f mean daily dose volumes administered to female rats was 1.3-2.4 ml for the control group, 1.3-2.3 ml for the 25 mg/kg/day group, 1.3-2.4 ml for the 100 mg/kg/day group, and 1.3-2.3 ml for the 500 mg/kg/day group. B. Mean Body Weights and Body Weight Gains (Tables 4-7, Figures 1-2, Appendices C-D) Mean body weight gain in 500 mg/kg/day male rats was lower than control over the entire dosing phase (test day 0-91). Mean body weight in this group was 83% o f control on test days 70 and 91, and mean body weight gain was 73% and 72% o f control over test days 0-70 and 0-91, respectively. All differences were statistically significant. In the 500 mg/kg/day group, mean body weight and mean body weight gain were lower than control on all test days and over all weekly intervals o f the dosing phase except test days 7-14. Differences in mean body weight were statistically significant on all test days and differences in mean body weight gain were statistically significant over all weekly intervals, except over test days 7-14, 56-63, 77-84, or 84-91. In 100 mg/kg/day males, mean body weight was lower than control over the entire dosing phase, but the differences were mild and were only statistically significant on test days 3570. Mean body weight in this group was 95% (statistically significant) and 94% (not statistically significant) o f control on test days 70 and 91, respectively. Mean body weight gain was 91% (statistically significant) and 88% (not statistically significant) o f control over test days 0-70 and 0-91, respectively. Although the body weight effects in the 100 mg/kg/day group were mild, they were considered to be compound related and adverse. No compound-related effects on body weight or body weight gain were observed in male rats dosed with 25 mg/kg/day. In this group, - 46Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 mean body weight on test day 91 and mean body weight gain over test days 0-91 were 105% and 107% of control, respectively. Neither difference was statistically significant. Mean body weight in 500 mg/kg/day female rats was lower than control over the entire dosing phase. Mean body weight was 95% and 94% o f control (both statistically significant) on test days 70 and 91, respectively. Weekly mean body weight gain in this group was significantly below control over test days 0-7,28-35, and 63-70 but was significantly higher than control over test days 7-14. Mean body weight gain over other weekly intervals was comparable to control. However, mean body weight gain over test days 0-70 and 0-91 was 87% and 85% o f control, respectively (both statistically significant). Therefore, the body weight effects in this group were considered to be mild, but adverse. No compound-related effects on body weight or body weight gain were produced in female rats dosed with 25 or 100 mg/kg/day. Mean body weight on test day 91 was 95% and 99% o f control for the 25 and 100 mg/kg/day groups, respectively. Mean body weight gain over test days 0-91 was 92% and 98% o f control for the 25 and 100 mg/kg/day groups, respectively. None o f these differences in the 25 or 100 mg/kg/day groups was statistically significant. Statistically significant lower body weight gains were observed in the 100 mg/kg/day group over test days 0-7 and 63-70. However, overall body weight gain in this group over the 0-70 and 0-91 test day intervals was 94% and 98% o f control, respectively (neither statistically significant) and there were no statistically significant differences in mean body weight on any day during the dosing phase. Therefore, the body weight effects in the 100 mg/kg/day female group were not considered to be adverse. Body weight effects were reversible in male rats. In the 500 mg/kg/day group mean body weight gain was 51% higher than control over the first month of recovery (test days 91-119), due mainly to significantly higher mean body weight gain over test days 91-98 and 98-105. Mean body weight gain was 81% higher than control over the three months o f recovery (test days 91-182). Differences in body weight gain were statistically significant over both intervals. Mean body weight in the 500 mg/kg/day group was still lower than in control on test day 119 (90% o f control) but was 8% higher than control at the end o f the three-month recovery phase (test day 182; not statistically significant). During recovery, much o f the difference in body weight gain between the control and 500 mg/kg/day male groups reflects a reduction in the control group mean body weight following the 90-day dosing and one-month recovery sacrifices. This reduction is attributed to sampling variability. Although rats were randomly assigned to subsets, and all were treated the same throughout the dosing and recovery periods, the control rats sacrificed at the end o f dosing and one-month recovery periods tended to be heavier than those retained for evaluation after three months o f recovery. In the 100 mg/kg/day group mean body weight gain was 19% higher than control over the first month o f recovery (test days 91-119) and 18% higher than control over the three-month recovery (test days 91-182; neither statistically significant). Mean body weight gain did not differ significantly from control over any weekly intervals during recovery. Mean body weight in the 100 mg/kg/day group was still lower than in control on test day 119 (96% o f control), but was 6% higher than control on test day 182. Neither difference was statistically significant. -47Company Sanitized. Does not contain TSCA CBI /'""v H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 In 500 mg/kg/day females, body weight effects did not demonstrate reversibility over the first month o f recovery. In fact, mean body weight gain was below control over 3 o f the 4 weekly intervals (variable statistical significance) and mean body weight gain over test days 91-119 was 26% o f control. Mean body weights remained significantly below control over the entire first month o f recovery. No statistically significant differences in mean body weight or weekly body weight gain were observed over any weekly intervals during these two months, nor over the test day 91-182 interval. Some o f the loss o f statistical significance is attributed to the reduced statistical power due to a reduction in the number o f rats per group. However, mean body weight gain over test days 91-182 was 90% o f control and mean body weight gain exceeded that of control over many intervals. Therefore, partial recovery was observed over the second and third months o f recovery. Overall, adverse, compound-related reductions (compared to control) in mean body weight and body weight gain were observed in male and female rats dosed with 500 mg/kg/day, and in male rats dosed with 100 mg/kg/day. The effects in 500 mg/kg/day females and in 100 mg/kg/day males were considered to be mild. Weight effects were more readily reversible in males than in females. C. Food Consumption and Food Efficiency (Tables 8-11, Appendix E) In 500 mg/kg/day male rats, mean food consumption was lower than control through test day 63. The differences were statistically significant through test day 56. No statistically significant differences in food consumption were observed over the rest of the dosing phase. However, mean food consumption over test days 0-70 and 0-91 was 90% and 93% o f control, respectively (both statistically significant). Food consumption in 100 mg/kg/day male rats was generally comparable to control. Mean food consumption in this group was 96% of control over test days 0-70 (statistically significant) and was significantly below control over test days 49-56. These differences in the 100 mg/kg/day group were not considered adverse as the differences were small and the differences in food consumption over most weekly intervals and over test days 091 (98% o f control) were not statistically significant. No compound-related effects on food consumption were observed in male rats dosed with 25 mg/kg/day. No adverse effects on food consumption were observed in female rats in any dose group. Statistically significant reductions compared to control were observed in the 500 mg/kg/day group over test days 0-7, 7-14, 21-28, and 35-42, and statistically significant increases in food consumption were observed over test days 77-84 and 84-91. However, food consumption over the 0-70 and 0-91 test day intervals was 95% and 97% o f control (neither statistically significant). No compound-related effects on food consumption were observed in female rats dosed with 25 or 100 mg/kg/day. In the 100 mg/kg/day group, mean food consumption was significantly below control over test days 0-7. However, mean food consumption over test days 0-70 and 0-91 was 100% o f control, therefore the isolated interval o f reduced food consumption was not considered to be adverse or a compound-related effect. Food consumption effects were reversible in 500 mg/kg/day male rats. Mean food consumption over the first two weeks o f recovery was significantly higher than control and overall mean food -48Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations____________ __________ DuPont-5990 consumption over test days 91-119 was 112% o f control (not statistically significant). Mean food consumption in 500 mg/kg/day female rats was also significantly higher than control over test days 91-98, but was comparable to control over the rest o f the one-month recovery phase. Mean food efficiency in 500 mg/kg/day male rats was lower than control over the entire dosing phase (test day 0-91). Mean food efficiency in this group was 79% and 77% o f control over test days 0-70 and 0-91, respectively (both statistically significant). Mean food efficiency was lower than control over all weekly intervals during the dosing phase. All differences were statistically significant through test day 56 and over test days 63-70. In the 100 mg/kg/day male group, mean food efficiency over test days 0-70 and 0-91 were 95% and 90% o f control, respectively (both statistically significant). Differences in weekly mean food efficiency were only statistically significant over test days 0-7, 14-21, 28-35, and 49-56. However, the effects in this group were considered adverse because they were associated with adverse reductions in body weight gain. No compound-related effects on food efficiency were observed in male rats dosed with 25 mg/kg/day. Compound-related adverse reductions in mean food efficiency were observed in female rats dosed with 500 mg/kg/day. Mean food efficiency was 92% and 88% o f control over test days 070 and 0-91, respectively. The differences in weekly mean food efficiency were only sporadically statistically significant but the effects on food efficiency were considered adverse based on the magnitude o f the overall effect, and because they were associated with reductions in body weight gain. Mean food efficiency in the 100 mg/kg/day female group was significantly lower than control over test days 0-7 and 63-70 and over the 0-70 test day interval (94% o f control). However, the effects on food efficiency in this group were not considered to be adverse as they were o f small magnitude, were not associated with adverse reductions in body weight gain. Furthermore, mean food efficiency over test days 0-91 was 97% o f control (not statistically significant) and weekly mean food efficiency exceeded that o f control over numerous weekly intervals (none statistically significant). The recovery in food efficiency was similar to that observed for body weight gain. In 500 mg/kg/day males, food efficiency over the first month of recovery was 27% higher than in control (statistically significant), mainly due to significantly higher food efficiency over the first 2 weeks o f recovery. In 500 mg/kg/day females, food efficiency over the first month o f recovery remained significantly below control, although weekly food efficiency was only significantly lower than control over test days 91-98. Food consumption data were not collected after test day 119; therefore, food efficiency was not calculated after that day. Mild but adverse, compound-related reductions in mean food consumption were observed in male rats dosed with 500 mg/kg/day. Adverse, compound-reductions in mean food efficiency were observed in male and female rats dosed with 500 mg/kg/day and in male rats dosed with 100 mg/kg/day. Reductions in food efficiency indicate that test substance exposure at these dosages reduced the rats' ability to convert feed into increased body mass, resulting in lower body weight gain in these groups. Although the effects on food consumption in 100 mg/kg/day males and 500 mg/kg/day females were not considered to be adverse, they were likely compound related, and may have contributed to the reduced body weight gain observed in these groups. - 49Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 D. Clinical Observations and Mortality (Tables 12,13,16,17, Appendix F) There was no compound-related effect on mortality in either male or female rats. Compoundrelated increases in clinical observations were observed in the 500 mg/kg/day male and female groups. In both sexes, there was a statistically significant increase in the incidence o f wet fur (chin/perineum), clear discharge from the mouth, hair loss, and stained fur/skin. The hair loss was observed in many sites including side, perineum, abdomen, ventral body, sacral region, and/or hindlimb. The hair loss was due to rats chewing, possibly in response to general toxicity and discomfort. Therefore, the hair loss was considered indicative o f an adverse effect. The stained fur/skin was also observed in many locations, but most notably in the perineum in both males and females. The perineum staining is likely related to staining with urine, since an increase in the volume of urine production was observed in both sexes (see Clinical Pathology section). The increased urination was considered to be a non-adverse, transient pharmacologic effect of test substance administration. Therefore, the stained perineum was considered nonadverse. Statistically significant increases in the incidence o f clear discharge from the mouth (males and females) and in hair loss over the dorsal body (females only) were also observed in rats dosed with 100 mg/kg/day, and were considered compound related because they were similar to those observed in the 500 mg/kg/day group. The clear discharge from the mouth was observed most often when rats were handled prior to dosing, and it was considered likely to be a behavioral response to dosing with the test substance. E. Ophthalmology Evaluations (Tables 14-15, Appendix F) No compound-related ophthalmological lesions were observed in male or female rats examined near the end o f the dosing phase o f the study. Three rats were observed to have unilateral, focal retinal degeneration (one each in the 25 mg/kg/day male, 500 mg/kg/day male, and 500 mg/kg/day female groups) and one rat had phthisis bulbi of the globe (one 500 mg/kg/day male). None o f these lesions was attributed to dosing with the test substance. F. In-Life Toxicology Conclusions Under the conditions o f this study, the no-observed-effect level (NOEL) for in-life parameters was 25 mg/kg/day for males and females. The NOEL was based on clinical signs o f toxicity observed in males and females dosed with 100 and 500 mg/kg/day, and reductions in body weight and nutritional parameters observed in males dosed with 100 and 500 mg/kg/day. In females, compound-related reductions in body weight and nutritional parameters were observed in rats dosed with 500 mg/kg/day. -50Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 NEUROBEHAVIORAL TOXICOLOGY A. Sensory Function Evaluations 1. Forelimb Grip Strength (Table 18-19, Figures 3-4, Appendix G) Males administered 500 mg/kg/day H-24768 had significantly lower forelimb grip strength during the week 13 evaluation (25% lower compared to control). In addition, forelimb grip strength in males administered 500 mg/kg/day was 10% lower than the control value during the recovery evaluation (not statistically significant). The decreased forelimb grip strength observed in 500 mg/kg/day males correlates with decreased hindlimb grip strength, and may be secondary to reduced body weight (17% and 10% lower than control values for week 13 and week 17, respectively). Forelimb grip strength for 500 mg/kg/day females was slightly lower (1 l% )(not statistically significant) compared to the control value for the recovery (week 17) evaluation, which correlated with a slightly lower (10%) body weight, compared to the control value. There were no test substance-related effects on forelimb grip strength in males or females administered 100 mg/kg/day or below. 2. Hindlimb Grip Strength (Table 18-19, Figures 5-6, Appendix G) Males administered 500 mg/kg/day H-24768 had significantly lower hindlimb grip strength during the week 13 evaluation (18% compared to control), and recovery evaluation (15% compared to control). The lower hindlimb grip strength for 500 mg/kg/day males correlated with the lower forelimb grip strength and may be secondary to the lower body weights. Hindlimb grip strength was also slightly lower in 500 mg/kg/day females during the recovery evaluation (13% compared to control), which may be secondary to the slightly lower body weight during recovery (week 17). There were no test substance-related effects on hindlimb grip strength in males or females administered 100 mg/kg/day or below. 3. Sensory Function Observation (Table 20-21, Appendix H) There were no test substance-related changes in sensory function parameters in males or females administered any dosage o f H-24768. However, male and female rats administered 500 mg/kg/day had higher incidences o f stained perineum (4/10 males and 5/10 females compared to 0/10 control males or females) during the week 13 evaluation. The increased incidences o f stained perineum in 500 mg/kg/day males and females were considered to be test substance-related. Male rat 646373 (100 mg/kg/day group) had abnormal gait during the week 13 evaluation. However, since this observation did not occur in any male administered 500 mg/kg/day or in any -51Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 females administered 100 or 500 mg/kg/day, it was not considered to be test substance-related. A higher incidence o f an exaggerated reaction to tail pinch (3/10) was observed in males administered 25 mg/kg/day. However, the incidences were not increased in the 100 or 500 mg/kg/day groups, and therefore, the incidence in 25 mg/kg/day males was not considered to be test substance-related. B. Motor Activity (Tables 22-25, Figures 7-10, Appendices I-J) There were no test substance-related effects on duration o f movement or number o f movements for males or females for any dosage concentration tested. Females in the 25,100, and 500 mg/kg/day groups had significantly higher mean number o f movements during the sixth 10-minute interval o f the week 13 evaluation. However, a dose-response relationship was not present, and the total number o f movements was similar to the control value. Therefore, the increased number o f movements in the sixth 10-minute interval for females administered 25, 200, or 500 mg/kg/day was not considered to be test substance-related. C. Neurobehavioral Toxicity Conclusions Under the conditions o f the study, the no-observed-effect level (NOEL) for neurobehavioral parameters was 100 mg/kg/day in males and females. The NOEL is based on the significantly decreased forelimb and hindlimb grip strength in 500 mg/kg/day males, and the increased incidences o f stained perineum in 500 mg/kg/day males and females. The reductions in grip strength were attributed to reduced body weight and were not considered evidence of neurotoxicity. Although the slightly lower forelimb and hindlimb grip strength was also observed in 500 mg/kg/day females, the minor differences were not considered to be biologically significant. -52Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 CLINICAL PATHOLOGY A. Hematology/Coagulation (Tables 26-29, Appendix K) Males and females dosed with 100 or 500 mg/kg/day had minimal to mild decreases in some or all parameters indicating red cell mass (hemoglobin, hematocrit, and/or red cell count) (Clinical Pathology Text Table 1). In males dosed with 100 or 500 mg/kg/day, minimal decreases in hemoglobin and hematocrit, but not red cell counts, were associated with small red cells. These changes were indicated by decreases in both MCV and MCH, and increased RDW. Increased incidence of microcytes and anisocytosis were also present in males dosed with 500 mg/kg/day. Male rats dosed with 500 mg/kg/day also had accelerated production o f red cells (regeneration), indicated by decreased MCHC, increased reticulocytes, and polychromasia; increased reticulocytes and polychromasia were also observed in a few rats dosed with 100 mg/kg/day. Several minor treatment-related red cell microscopic changes were observed on blood smears o f males dosed with 100 or 500 mg/kg/day only. Histologically, males dosed with 500 mg/kg/day had minimally increased splenic extramedullary hematopoiesis (see Anatomic Pathology section). Hematology changes present at the end of dosing were generally o f greater magnitude or incidence than those present at mid-study. For male rats, hematology changes were improving, albeit not completely, after one month of recovery (Day 123/124R), and were completely reversed after 3 months o f recovery (Day 183R). After one month of recovery, males previously dosed with 500 mg/kg/day still had minimally decreased hemoglobin and hematocrit, but red cell mass was recovering. However, RDW was increased to a greater magnitude compared to the end of dosing, and was consistent with the microscopic changes o f increased anisocytosis, microcytes, and macrocytes. Reticulocytes, polychromatophilic cells, and acanthocytes were increased. After 3 months o f recovery, red cell parameters in rats were similar to control values in rats previously dosed with test substance. Compared to males, females dosed with 100 or 500 mg/kg/day had similar decrements in red cell mass, however, the relative decrease in red cell mass (compared to control values) was greater, and the response o f the bone marrow (accelerated production o f red cells indicating regeneration) was more marked. Female rats dosed with 100 or 500 mg/kg/day had decreased red cell mass parameters (decreased red cell count, hemoglobin, and hematocrit), and alterations in hematologic parameters indicating accelerated production (increased reticulocytes, RDW, and polychromasia, and decreased MCHC). MCH was decreased (500 mg/kg/day only); in some animals, this decrease correlated with decreased MCV, suggesting the presence o f smaller cells with less hemoglobin. Other minor treatment-related red cell microscopic changes were observed in females dosed with 100 and 500 mg/kg/day. Histologically, females dosed with 500 mg/kg/day had minimally increased splenic extramedullary hematopoiesis (see Anatomic Pathology section). Red cell changes that were present at the end o f dosing were generally of greater magnitude or incidence than those present at mid-study. -53Company Sanitized. Does not contain TSCA C8I H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 In female rats, hematology changes were improving, albeit not completely, after one month of recovery, and were completely reversed after 3 months of recovery. After one month of recovery, females previously dosed with 500 mg/kg/day still had minimally decreased hematocrit (not statistically significant), but red cell mass was recovering. However, RDW, echinocytes, and acanthocytes were still increased compared to control values. After 3 months o f recovery, red cell parameters in rats were similar to control values in rats previously dosed with test substance. The red cell mass changes, during dosing, in female rats dosed with 500 mg/kg/day were considered adverse due to the magnitude o f the change. Similar types o f changes occurred in males during dosing, but these changes were not considered adverse because the magnitude o f change was not expected to have an adverse impact on function o f red cells. Clinical Pathology Text Table 1: Red cell mass parameters* Dose 'mg/kg/day) Males 25 100 500 Females 25 100 500 Parameter Dav RBC 39/40 95/96 123/124R 183R 98% 99% 102% 100% 98% 103% NT NT 97% 99% 98% 97% 101% 93% 93% 97% 91% 89% NT NT 98% 100% 99% 101% HGB 39/40 95/96 123/124R 183R 99% 99% 96% 99% 95% 92% NT NT 95% 101% 98% 99% 101% 97% NT 101% 94% 90% NT 94% 91% 85% 97% 97% HCT 39/40 99% 99% 96% 102% 95/96 99% 96% 94% 98% 123/124R NT NT 96% NT 183R 100% 99% 100% 104% R: recovery time-point. * Results presented as percent o f concurrent control group mean. Statistical significance is indicated by bold italicized type NT: Not taken 95% 91% NT 96% 94% 87% 97% 100% - 54Company Sanitized. Does not contain TSCA C8I H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 All other statistically significant changes in hematology or coagulation parameters were considered unrelated to treatment and/or non-adverse (not toxicologically significant). These changes are detailed below. Females dosed with 500 mg/kg/day had mildly increased platelets at Day 96. Increased platelets were likely secondary to increased erythropoietin production in response to the red cell changes. Mildly increased platelets are not associated with adverse effects. After one month of recovery, platelet counts were similar to control values in rats previously dosed with 500 mg/kg/day. Males dosed with 25,100, or 500 mg/kg/day had minimally increased monocytes at Day 39. This change is possibly related to treatment. However, because there was a relatively flat dose response, no peripheral need for increased monocytes (no inflammation observed in clinical or anatomic pathology results), and because the change was minimal and transient, this change was not considered adverse. Females dosed with 500 mg/kg/day had minimally increased white blood cells and lymphocytes at Day 40 only. This change is possibly related to treatment. However, because this change was minimal and transient, it was not considered adverse. At the end o f dosing (Day 95/96), males dosed with 100 or 500 mg/kg/day had minimally shortened activated partial thromboplastin time, and females dosed with 500 mg/kg/day had minimally shortened activated partial thromboplastin time and prothrombin time. After one month of recovery, coagulation times were similar to control values in rats previously dosed with 500 mg/kg/day. The coagulation time changes were likely related to treatment, but were not considered adverse, because shortened coagulation times are not associated with adverse effects. The following statistically significant changes in hematology or coagulation parameters were considered to be unrelated to treatment because they did not occur in a dose-related manner, or occurred only after one or three months o f recovery: Increased neutrophils in males dosed with 500 mg/kg/day after one month o f recovery Increased neutrophils and monocytes in females dosed with 25 mg/kg/day at Day 40 Increased platelets in one female previously dosed with 500 mg/kg/day, after 3 months o f recovery. This change was considered to be unrelated to treatment because subjective evaluation of platelet counts on blood smears from 2 other rats in the group did not indicate increased platelet counts. In addition, increased platelets occurred after 3 months but not one month o f recovery. -55Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 B. Clinical Chemistry (Tables 30-31, Appendix K) Liver Tests Males dosed with 500 mg/kg/day had minimally to mildly increased ALT and SDH activities during the dosing period (Clinical Pathology Text Table 2). Animals with more pronounced changes (Rat Numbers. 646346 and 646475) had similar histologic changes compared to those with less prominent enzyme changes. Changes in ALT and SDH activities were o f similar magnitude at both time-points, and persisted during one and three months o f recovery. In contrast, females dosed with 500 mg/kg/day had transiently (Day 40 only) increased ALT activity, without an associated increase in SDH. ALT activities were similar to control values at other time-points. Therefore, this change was considered to be unrelated to treatment. The minimally to mildly increased ALT and SDH activities in male rats suggest hepatocellular injury. Histologic changes (see Anatomic Pathology section) did not indicate cellular damage, only hypertrophy. In individual animals, the magnitude o f enzyme increase did not correlate with degree of hypertrophy. However, due to the consistency and persistence o f the enzyme changes, the increases in ALT and SDH in male rats were considered potentially adverse. Males and females dosed with 500 mg/kg/day had minimally increased ALKP activity and bilirubin concentration during the dosing period. (Clinical Pathology Text Table 2). Compared to control values, the change was similar at both time-points. There was only occasional correlation between ALKP activities and bilirubin concentrations, suggesting that a mechanism other than cholestasis might be involved in ALKP or bilirubin increases. Males and females dosed with 500 mg/kg/day had increased liver weights and liver hypertrophy, changes that normally are associated with enzyme induction (see Anatomic Pathology section). Enzyme induction is consistent with the ALKP changes, but would not be expected to result in increased bilirubin unless cholestasis occurred secondary to hypertrophy. Therefore, the cause for increased bilirubin is unknown. These minimal changes in ALKP and bilirubin were not present after one or three months of recovery in rats previously dosed with test substance. The changes in ALKP and bilirubin were considered non-adverse because they were minimal and were reversible on cessation of dosing. -56Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 Clinical Pathology Text Table 2: Changes in hepatic parameters for males and females Dose [mg/kg/day) Males 25 100 500 Females 25 100 500 Parameter Day ALT 39/40 95/96 123/124R 183R 92% 109% NT 156% 106% 112% NT 147% 164% 152% 129% 194% 114% 76% NT 83% 125% 61% NT 94% 164% 73% 55% 109% SDH 39/40 95/96 123/124R 183R 102% 113% NT 157% 104% 124% NT 160% 137% 130% 219% 221% 102% 89% NT 86% 90% 68% NT 120% 92% 75% 112% 131% ALKP 39/40 95/96 123/124R 183R 92% 89% NT 124% 91% 94% NT 113% 125% 142% 94% 106% 108% 102% NT 109% 101% 113% NT 82% 174% 207% 92% 133% BILI 39/40 95/96 123/124R 183R 75% 113% 250% 92% 125% 200% NT NT 100% 80% 50% 60% 100% 88% NT80% 100% 94% NT 53% 129% 124% 84% 80% R: recovery time-point. ""Results presented as percent o f concurrent control group mean. Statistical significance is indicated by bold italicized type NT: Not taken Renal and Electrolyte Changes Males dosed with 100 or 500 mg/kg/day had either no change or minimal increases in parameters that measure glomerular filtration (urea nitrogen, creatinine, and inorganic phosphorus) during the dosing period (Clinical Pathology Text Table 3). Concentrations were similar at both timepoints for urea nitrogen and creatinine. After one month o f recovery, creatinine was decreased, whereas urea nitrogen and inorganic phosphorus were increased in males previously dosed with 500 mg/kg/day. Histologically, there was no correlation between individual rats with chronic progressive nephropathy and rats with increased urea nitrogen and inorganic phosphorus. After three months o f recovery, a few rats previously dosed with 500 mg/kg/day had increased inorganic phosphorus; again, this change did not correlate with rats that had chronic progressive nephropathy. Females dosed with 500 mg/kg/day also had minimal increases in urea nitrogen, creatinine, and inorganic phosphorus during the dosing period (Clinical Pathology Text Table 3). In addition, females dosed with 25 or 100 mg/kg/day had minimally increased urea nitrogen, without changes in creatinine or inorganic phosphorus, but only at the end o f dosing. In females previously dosed with 500 mg/kg/day, these changes were not present after one month o f recovery. After three months of recovery, inorganic phosphorus was increased (not statistically significant) in females -57Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 previously dosed with 100 or 500 mg/kg/day; this change was considered to be unrelated to treatment because there was no effect observed after one month o f recovery. The minimal increases in parameters reflecting glomerular filtration (urea nitrogen, creatinine, and inorganic phosphorus) were generally considered treatment-related in males and females dosed with 100 (males only) or 500 mg/kg/day. For these parameters, changes o f the magnitude measured in this study would not be, in isolation, considered adverse. Changes o f this magnitude can be observed in the absence o f renal histologic alterations. However, in this study, histologic evidence o f renal injury was observed in males and females dosed with 500 mg/kg/day. Therefore, although the changes in urea nitrogen, creatinine, and phosphorus, by themselves, were not considered adverse, they were supportive o f adverse findings in histology. Some male rats (500 mg/kg/day) and a few female rats (100 or 500 mg/kg/day) had minimally decreased sodium and chloride during the dosing period. The effect was similar at both timepoints. Effects on chloride were still possibly present after one month o f recovery in male rats; however, the possible change in chloride at this time-point occurred in the absence o f changes in other parameters. Increased sodium after three months o f recovery was considered unrelated to treatment because this change was not present after one month o f recovery. Decreased sodium and chloride during dosing indicate loss of fluid containing these two electrolytes. Because o f the marked increase in urine volume in individual rats, loss through the urinary tract is most likely. This change was not considered adverse due to the minimal degree of change Males dosed with 100 or 500 mg/kg/day had minimally increased potassium during the dosing period. A few female rats at the same doses had similar changes. The effects were similar at both time-points. After one or three months o f recovery, potassium concentrations were similar to control values in rats previously dosed with test substance. The reason for altered potassium was not determined, but was likely related to treatment due to the consistency o f change across time-points, groups, and sexes. The magnitude o f increase in potassium was always minimal and was not considered adverse. -58Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 Clinical Pathology Text Table 3: Parameters indicating glomerular filtration rate Dose "mg/kg/day) Males 25 100 500 Females 25 100 500 Parameter Day BUN 39/40 95/96 123/124R 183R 100% 106% NT 88% 107% 119% NT 82% 143% 125% 125% 106% 100% 119% NT 107% 106% 119% NT 120% 131% 125% 106% 120% CREA 39/40 95/96 123/124R 183R 106% 108% NT 93% 113% 124% NT 88% 125% 111% 98% 109% 95% 95% 113% 98% 105% 114% NT NT 98% 92% 104% 98% DPHS 39/40 100% 106% 101% 103% 105% 122% 95/96 107% 113% 111% 107% 115% 125% 123/124R NT NT 116% NT NT 106% 183R 100% 109% 129% 104% 136% 136% R: recovery time-point. * Results presented as percent o f concurrent control group mean. Statistical significance is indicated by bold italicized type NT: Not taken Protein Male and female rats dosed with 25 (males only), 100, or 500 mg/kg/day had dose-dependant, mildly increased albumin, which generally resulted in increased total protein during the dosing period (Clinical Pathology Text Table 4). This effect was slightly more pronounced at the end o f dosing compared to mid-study. Changes in albumin were still present after one month o f recovery in male rats previously dosed with 500 mg/kg/day. In addition, after one month o f treatment, globulin concentration was mildly increased in both males and females. The albumin and globulin increases after one month o f recovery could not be definitively attributed to treatment; however, the consistency o f the result and the continued presence o f compound (as indicated by urine fluoride measurements) makes this change o f uncertain relationship to treatment. After three months o f recovery, females previously dosed with 100 or 500 mg/kg/day had minimally increased globulins (no dose response); this change may or may not be related to treatment. Increased albumin causing increased total protein indicates alterations in albumin synthesis, distribution, or metabolism. Minimally increased globulin in the presence o f increased albumin is interpreted similarly. Although the changes in albumin and globulin concentrations were considered related to treatment, they were not considered adverse because mild increases in these parameters have no known adverse effects. -59Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 Clinical Pathology Text Table 4: Protein parameters Dose 'mg/kg/day) Males 25 100 500 Females 25 100 500 Parameter TP Day 39/40 95/96 123/124R 183R 102% 101% NT 97% 108% 111% NT 101% 112% 114% 110% 101% 99% 105% NT 101% 107% 111% NT 104% 104% 111% 109% 101% ALB 39/40 95/96 123/124R 183R 105% 107% NT 93% 112% 119% NT 98% 124% 128% 115% 98% 102% 106% NT 104% 114% 115% NT 98% 110% 113% 105% 95% GLOB 39/40 100% 109% 100% 100% 96% 96% 95/96 93% 100% 93% 104% 108% 104% 123/124R NT NT 107% NT NT 115% 183R 100% 107% 103% 97% 114% 114% R: recovery time-point. * Results presented as percent o f concurrent control group mean. Statistical significance is indicated by bold italicized type NT: Not taken Calcium Males and females dosed with 100 or 500 mg/kg/day had mildly increased calcium during the dosing period. The effect was similar at both time-points. Calcium was still minimally increased in males previously dosed with 500 mg/kg/day after one month o f recovery, but had recovered in females. After three months o f recovery, calcium concentrations were similar to control values in rats previously dosed with test substance. The calcium changes paralleled the albumin changes discussed above. 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. Changes in calcium are secondary to changes in albumin, and are considered physiologically insignificant, and therefore non-adverse. Lipids Males and females dosed with 100 or 500 mg/kg/day had mildly increased cholesterol and moderately decreased triglyceride concentrations during the dosing period. The effects were similar at both time-points. In rats previously dosed with 500 mg/kg/day, cholesterol was still increased (not statistically significant in males) after one month o f recovery. After three months o f recovery, cholesterol and triglyceride concentrations were similar to control values in rats previously dosed with test substance. Increased cholesterol and decreased triglycerides indicate alterations in lipid metabolism. Changes in lipids were considered non-adverse because the magnitude was small and was not expected to result in toxicity. -60Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 The following changes in chemistry parameters were considered to be unrelated to treatment because they occurred after three months, but not one month, o f recovery. Increased sodium in males previously dosed with 500 mg/kg/day after three months of recovery Increased inorganic phosphorus in females previously dosed with 100 or 500 mg/kg/day after three months o f recovery C. Urinalysis (Tables 32-33, Appendix K) Males and females dosed with 500 mg/kg/day had mildly to markedly decreased urine specific gravity/osmolality and increased urine volume during the dosing period. This effect was similar at both time-points during dosing, but was not present after one month o f recovery. Production o f increased volumes o f dilute urine can be due to polyuria (increased loss o f water through the renal tract) or polydipsia (increased drinking o f water). In this study, the cause o f dilute urine was not determined. However, some rats dosed with 500 mg/kg/day had small volumes of concentrated urine. In addition, this change was reversible after one month o f recovery in rats previously dosed with 500 mg/kg/day. It follows that dilute urine was not caused by renal impairment, but was a transient pharmacologic effect o f test substance administration. Males and females dosed with 500 mg/kg/day had moderately decreased urine pH only at the end o f the dosing period. These changes were not present in males or females previously dosed with 500 mg/kg/day after one month o f recovery. Decreased urine pH is generally the result o f physiological renal compensation for excess acids in blood. This change was considered to be a physiologic rather than a toxicologic response. Males and females dosed with 500 mg/kg/day had mildly decreased urine protein concentration (males at the end o f the study, and females at mid-study). This change was caused by increased urine volume, which diluted the protein present in urine. Decreased urine protein concentration has no toxicologic significance. All other statistically significant changes in urinalysis parameters were considered unrelated to treatment and/or non-adverse (not toxicologically significant). These changes are detailed below. At the end o f one-month recovery, urine protein concentration was increased in female rats previously dosed with 500 mg. This increase was due to the presence o f blood in urine (incidental finding), rather than glomerular or tubular injury, and thus was not considered related to treatment. -61 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 Plasma and urine fluoride Males (25,100, or 500 mg/kg/day) and females (100 or 500 mg/kg/day) had increased plasma fluoride concentrations during the dosing period (Clinical Pathology Text Table 5-6). After one month o f recovery, plasma fluoride concentrations were decreased, relative to end of study values, in males and females previously dosed with 500 mg/kg/day. However, in females, plasma fluorides were still minimally increased compared to controls at this time-point. After three months o f recovery, plasma fluoride concentrations were similar to control values in all rats previously dosed with test substance. Males and females dosed with 25,100, or 500 mg/kg/day had increased urine fluorides (total urine fluoride excreted during urine collection period) (Clinical Pathology Text Table 5-6). Increased urine fluorides were still present after one month o f recovery in males and females previously dosed with 500 mg/kg/day, although the magnitude o f the effect had decreased substantially. After three months o f recovery, urine fluorides were further decreased relative to end-of-study and one-month recovery values in rats previously dosed with 500 mg/kg/day. However, mine fluorides were clearly increased compared to concurrent control values in both males and females previously dosed with 100 or 500 mg/kg/day. Urine fluorides in females previously dosed with 25 mg/kg/day were also slightly increased compared to control values, although this change was not statistically significant. The presence o f increased plasma and urine fluoride indicates exposure to a fluoride-containing compound. The presence o f fluoride in urine 3 months after exposure suggests that fluoridecontaining compounds are slowly being released from tissue sites. Clinical Pathology Text Table 5: Fluoride parameters (absolute values) Dose (mg/kg/day) Males Females 0 25 100 500 0 25 100 Parameter Day PFLU (gg/mL) 95/96 0.1 0.2 0.2 0.5 0.1 0.1 0.2 123/124R 0.1 NT NT 0.1 0 NT NT 183R 0.1 0.1 0.1 0.1 0.1 0.1 0.1 UFLU (m) 39/40 ND ND ND ND ND ND ND 95/96 12.1 50.6 140.8 632.6 5.5 23.7 59.4 123/124R 8.1 NT NT 98.3 4.2 NT NT 183R 10.2 13.5 21.5 46.8 5.9 8.6 9.9 R: recovery time-point. * Statistical significance is indicated by bold italicized type NT: Not taken ND: Not done 500 0.5 0.1 0.1 ND 291.2 30 15.7 -62Company Sanitized. Does not contain TSCA CBI H-24768: Subcbronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 Clinical Pathology Text Table 6: Fluoride parameters (compared to concurrent control values) 1____________ Dose (mg/kg/day) U ales Females Parameter Day/ 0 25 100 500 0 25 100 500 PFLU 95/96 123/124R 183R NA 200% NA NT NA 100% 200% NT 100% 500% 100% 100% NA NA NA 100% NT 100% 200% NT 100% 500% NA 100% UFLU 39/40 NA ND ND ND NA ND ND ND 95/96 NA 418% 1164% 5228% NA 431% 1080% 5295% 123/124R NA NT NT 1214% NA NT NT 714% 183R NA 132% 211% 459% NA 146% 168% 266% R: recovery time-point. * Results presented as percent of concurrent control group mean. Statistical significance is indicated by bold italicized type NA: Not applicable (either because the calculation would be 100%--dividing a number by itself, or because the denominator was zero) NT: Not taken ND: Not done D. Clinical Pathology Conclusions Under the conditions of this study and for the parameters measured, the no adverse effect level for males was 100 mg/kg/day, based on the presence o f increased ALT and SDH during treatment, which persisted into recovery. The no adverse effect level for female rats was 100 mg/kg/day, based on the presence o f mild decrements in red cell mass parameters (hemoglobin, hematocrit, and red cell counts), associated with regeneration. There were no adverse findings for coagulation or urinalysis parameters for either sex. -63Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 BIOCHEMICAL MEASUREMENTS A. Biochemical Measurements (Table 34-35, Appendix L) The rate o f hepatic p-oxidation, a measure of peroxisome proliferation, was determined in a subchronic oral toxicity study with H-24768 in male and female rats after 10 days or 95 days (males) or 96 days (females) o f test substance administration or following a one-month or threemonth (male only) recovery period. At the 10-day time point in male rats, the rate o f hepatic P-oxidation was increased in a dosedependent manner and was statistically significantly increased in rats dosed with 100 and 500 mg/kg/day (171 and 286% o f control, respectively). At the 90-day time point, the rate o f hepatic p-oxidation was statistically significantly increased in rats dosed with 500 mg/kg/day (181 % o f control). At the one-month recovery time point, the rate o f hepatic P-oxidation was statistically significantly increased in rats dosed with 500 mg/kg/day (195% of control). At the three-month recovery time point, the rate o f hepatic P-oxidation had returned to control levels. At the 10-day, 90-day, and one-month recovery time points, the increases in hepatic P-oxidation activity were accompanied by increases in liver weights. In female rats, the rate o f hepatic P-oxidation was reduced at the 90-day time point in rats dosed with 25 mg/kg/day. This decrease was not considered a compound-related effect due to a lack o f a dose-response and lack o f concordant changes in any o f the other dose groups at any o f the sampling time points. At the one-month recovery time point, the rate o f hepatic p-oxidation was increased in rats dosed with 500 mg/kg/day (131% o f control). Due to the small magnitude o f the increase (131% o f control), the increase at the one-month recovery time point was not considered to be biologically significant. Hepatic P-oxidation was not evaluated at the threemonth recovery time point in female rats. In-life data (body weight, nutritional and clinical observation parameters) collected for the rats evaluated for 10-day biochemical evaluations will not be included in this report but are in study records. B. Biochemical Measurements Conclusions Under the conditions o f this study, H-24768 was a mild inducer o f hepatic peroxisomal Poxidation in male rats. At dosages o f 100 mg/kg/day and greater, changes in the rate o f hepatic peroxisome proliferation were considered to be biologically significant effects. At the onemonth recovery time point, the rate of hepatic peroxisome proliferation was increased in male rats dosed with 500 mg/kg/day, but had returned to control levels by the three-month recovery time point. - 64Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 ANATOMICAL PATHOLOGY SUBCHRONIC TOXICITY AND RECOVERY A. Cause of Death (Tables 46-47, Appendix N) No unscheduled deaths occurred in any female rats in the 90-day exposure or one-month recovery groups. One male rat dosed with 100 mg/kg/day died o f trauma secondary to the bleeding procedure. One control male and 2 males dosed with 500 mg/kg/day died o f kidney inflammation and/or obstruction. None o f these deaths was considered test substance related. One control female in the three-month recovery group died o f trauma secondary to the bleeding process. There were no compound-related deaths at any dose level. B. Organ Weight Data (Tables 36-37, Appendix M) Liver: Mean liver weights (absolute and relative to body and to brain) were significantly higher in all dose groups at the 90-day sacrifice in males and females, and correlated with microscopic hepatocellular hypertrophy (see discussion under Microscopic Findings). Liver weights at the one-month recovery sacrifice were significantly higher in the 500 mg/kg/day males and females than in controls. There were no intermediate groups evaluated at the one-month recovery sacrifice. Mean absolute and relative (to body) liver weights were higher, compared to controls, in the 500 mg/kg/day males and in the 100 and 500 mg/kg/day females at the three-month recovery. Higher liver weights were considered compound-related and correlated with microscopic hepatocellular hypertrophy diagnosed in animals from the 90-day and one-month recovery sacrifices. Kidney: At the 90-day sacrifice, mean kidney weights (absolute and relative to body and to brain) were significantly higher than controls in 500 and 100 mg/kg/day females. The mean relative (to body) kidney weight was significantly higher in 500 mg/kg/day females at the one-month recovery and three-month recovery sacrifices. Higher mean kidney weights in females were considered compound-related and possibly associated with increased chronic progressive nephropathy detected microscopically. Mean relative (to body) kidney weights were significantly higher than in controls in 500 and 100 mg/kg/day males at the 90-day sacrifice and in 500 mg/kg/day males at the one-month recovery sacrifice. The increase in relative (to body) kidney weight in these groups primarily reflects the reduced body weight in these animals, but, in the 500 mg/kg/day group, was also possibly associated with increased chronic progressive nephropathy detected microscopically. -65Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 Spleen: Relative (to body and/or to brain) spleen weights were increased compared to controls in 100 and 500 mg/kg/day females at the 90-day sacrifice (relative to body at 500 mg/kg/day and relative to brain at 100 and 500 mg/kg/day). Mean spleen weights were not significantly different from controls at the one-month recovery sacrifice but relative (to body) spleen weights in the 500 mg/kg/day females were higher than controls at the three-month recovery sacrifice. The higher spleen weights were considered compound-related and correlated with increased extramedullary hematopoiesis detected microscopically. There were no other compound-related organ weight effects. All other statistically significant organ weight changes in the subchronic and recovery groups were secondary to decreases in body weight or were spurious. C. Gross Observations (Tables 38-39, Appendix N) Large livers were observed at the 90-day sacrifice in 500 and 100 mg/kg/day males and in 500 mg/kg/day females. This observation correlated with hepatocellular hypertrophy diagnosed microscopically and was considered to be compound-related. There were no compound-related gross observations in one-month or three-month recovery animals. Other gross observations noted at any time point were sporadic across groups and were not considered to be compound-related. D. Microscopic Findings (Tables 40-47, Appendix N) Liver: There was minimal to mild diffuse hepatocellular hypertrophy in 90-day males (all dose groups) and females (100 and 500 mg/kg/day), and in 500 mg/kg/day males and females at the one-month recovery time point. There was no hepatocellular hypertrophy in males or females at the threemonth recovery. Microscopically, hepatocellular hypertrophy was characterized by an increased amount of finely granular eosinophilic cytoplasm within hepatocytes. There was no histomorphologic evidence o f hepatocellular damage. The severity o f hepatocellular hypertrophy was less in one-month recovery rats than in 90-day rats and was absent in three-month recovery rats. Thus, complete reversibility of the microscopic hepatocellular hypertrophy was established, although liver weights remained elevated through the three-month recovery period. The hepatocellular hypertrophy and the associated increase in liver weights were considered a compound-related physiologic response to a xenobiotic and not toxicologically adverse.(23,24,25) -66Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 Dose (mg/kg/day) Microscopic Compound-Related Lesions in Liver Males Females 0 25 100 500 0 25 100 500 Hypertrophy 90-Day 1/11 5/10#a 10/11# 12/12# 0/10 0/10 9/10# 10/10# Hypertrophy 1-Month Recovery 0/10 NAb NA 7/10 0/10 NA NA 1/10 Hypertrophy 3-Month Recovery 0/4 0/5 0/4 0/5 0/4 0/5 0/5 0/5 a A pound sign (#) indicates an effect level, b NA indicated tissues were not available. Kidney: The incidence o f chronic progressive nephropathy, a spontaneously occurring lesion in rats, was increased (compared with controls) in 500 mg/kg/day males and in 100 and 500 mg/kg/day females at the 90-day sacrifice. The incidence o f this lesion was also increased in males and females at the one-month recovery (500 mg/kg/day) and in 100 and 500 mg/kg/day females at the three-month recovery. This lesion was considered compound related and adverse. Dose (mg/kg/day) Microscopic Compound-Related Lesions in Kidney Males Females 0 25 100 500 0 25 100 500 Nephropathy 90-Day 5/11 2/10 5/11 7/12#a 2/10 2/10 5/10# 5/10# Nephropathy 1-Month Recovery 3/10 NAb NA 8/10# 1/10 NA NA 8/10# Nephropathy 3-Month Recovery 4/4 4/5 3/4 2/5 2/4 2/5 4/5# 4/5# a A pound sign (#) indicates an effect level, b NA indicated tissues were not available. Spleen: An increased incidence of extramedullary hematopoiesis was observed in 25,100, and 500 mg/kg/day males and females at the 90-day sacrifice, in 500 mg/kg/day males and females at the one-month recovery, and was not observed in any exposure group at the three-month recovery. Thus, reversibility o f increased extramedullary hematopoiesis was established. The occurrence o f a single incidence in some groups o f extramedullary hematopoiesis (25 mg/kg/day males and females at the 90-day sacrifice and 25 and 100 mg/kg/day males at the three-month - 67Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 recovery sacrifice) was not considered a compound-related effect, as this can occur spontaneously in an occasional animal. Increased extramedullary hematopoiesis was considered a secondary physiologic response to changes in red cell mass and not a primary adverse effect. Hematological findings and interpretations are discussed within the clinical pathology portion of this report. Increased pigment in the spleen was observed in 100 and 500 mg/kg/day males and 500 mg/kg/day females at the 90-day sacrifice, in 500 mg/kg/day males at the one-month recovery and in 100 and 500 mg/kg/day females at the three-month recovery. The pigment observed was consistent with hemosiderin and could be an indication o f increased red cell turnover. As with extramedullary hematopoiesis, the presence o f increased pigment was not considered a primary adverse finding. Dose (mg/kg/day) Microscopic Compound-Related Lesions in Spleen Males Females 0 25 100 500 0 25 100 500 Hematopoiesis 90-Day 0/11 1/10 8/1l#3 10/12# Hematopoiesis 1-Month Recovery 0/10 NAb NA 8/10# Hematopoiesis 3-Month Recovery Pigment 90-Day 0/4 0/11 1/5 1/4 0/5 0/10 4/11# 6/12# Pigment 1-Month Recovery 0/10 NA NA 7/10# Pigment 3-Month Recovery 0/4 0/5 0/4 0/5 a A pound sign (#) indicates an effect level, b NA indicated tissues were not available. 0/10 0/10 0/4 1/10 0/10 0/4 1/10 6/10# 7/10# NA NA 1/10 0/5 0/5 0/5 0/10 0/10 10/10# NA NA 0/10 0/5 2/5# 2/5# Thyroid: Follicular hypertrophy was present in thyroid glands in all male dosage groups and in 100 and 500 mg/kg/day female groups at the 90-day sacrifice and in 500 mg/kg/day males and females at the one-month recovery. Follicular hypertrophy was present in 500 mg/kg/day males at the threemonth recovery, but not in females. Follicular hypertrophy was characterized by tall columnar follicular epithelium with a finely granular or vacuolated cytoplasm. The occurrence of a single incidence o f follicular hypertrophy in a 25 mg/kg/day male at the 90-day sacrifice was not considered compound related because this lesion can occasionally occur spontaneously. Hypertrophy o f thyroid follicular epithelium is, as is hypertrophy o f other endocrine organs, often an indication of a physiologic response and not necessarily adverse. However, in the absence o f -68Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 hormonal data to demonstrate maintenance o f normal hormonal levels, the thyroid hypertrophy was considered potentially adverse. Follicles containing altered colloid were found in thyroids from controls as well as in treated 90day, one-month recovery and three-month recovery rats. An increase in incidence and/or in severity grade o f this lesion was present in all exposure groups at all time points and was considered compound-related. The diagnosis "alteration, colloid" was used to diagnose stippled, granular, clumped, and/or diffusely basophilic colloid. A 4 level grading scheme was applied based on an estimate o f the percentage o f follicles that contained altered colloid. A grade o f 1 was applied when up to about 25% o f 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. Although follicular hypertrophy was usually accompanied by altered colloid, the reverse was not necessarily the case, as altered colloid was observed in the absence o f follicular hypertrophy. Altered colloid described as clumped or granular has been reported to occur spontaneously in Sprague-Dawley rats with increasing incidence correlating to increasing age.(26) Because altered colloid occurs spontaneously in healthy Sprague-Dawley rats, and since increases in its grading score occurred in some groups without morphologic alterations in the thyroid, altered colloid was interpreted in the present study as not biologically adverse. 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. Microscopic Compound-Related Lesions in Thyroid Males Females Dose (mg/kg/day) 0 25 100 500 0 25 100 500 Hypertrophy 90-Day 0/11 1/10 9/11#" 11/12# 0/10 0/10 2/10# 9/10# Hypertrophy 1-Month Recovery 0/10 NAb NA 8/10# 0/10 NA NA 6/10# Hypertrophy 3-Month Recovery 0/4 0/5 0/4 4/5# 0/4 0/5 0/4 0/4 Alteration, Colloid 90-Day 6/11 10/10# 10/11# 11/12# 3/10 6/10# 10/10# 10/10# Alteration, Colloid 1-Month Recovery 6/10 NA NA 10/10# 1/10 NA NA 10/10# Alteration, Colloid 3-Month Recovery 1/4 5/5# 4/4# 5/5# 1/4 3/5# 4/4# 3/4# a A pound sign (#) indicates an effect level, b N A indicated tissues were not available. -69Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 E. Anatomical Pathology Conclusions for Subchronic Toxicity Evaluation Exposure to the test substance for approximately 90 days produced alterations in the liver, kidney, spleen, and thyroid. Increased liver weights and/or microscopic hepatocellular hypertrophy were present in 25,100, and 500 mg/kg/day males and in 100 and 500 mg/kg/day females at 90-days, and in 500 mg/kg/day males and females at the one-month recovery. These liver changes were considered to represent a physiologic response to metabolism o f a xenobiotic and thus were not considered to be adverse. Increased chronic progressive nephropathy, sometimes accompanied by increased kidney weight in females, was present in 500 mg/kg/day males and 100 and 500 mg/kg/day females at the 90-day sacrifice, in 500 mg/kg/day males and females at the one-month recovery, and in 100 and 500 mg/kg/day females at the three-month sacrifice. This finding was considered to be adverse. Alteration o f colloid was present in the thyroids o f males and females at all exposure levels at all time points. The severity o f altered colloid in thyroid glands increased beyond control levels as the dose increased, however it was not associated with any adverse cellular morphologic alterations and was not considered biologically adverse. Compound-related hypertrophy o f follicular epithelium in the thyroid was present in 100 and 500 mg/kg/day males and females at the 90-day sacrifice, in 500 mg/kg/day males and females at the one-month recovery sacrifice, and in the 500 mg/kg/day males at the three-month recovery sacrifice. Thyroid gland follicular hypertrophy, in the absence o f hormonal data, was considered potentially adverse. The no-observed-effect level (NOEL) for this study is defined as the highest dose at which toxicologically important effects attributable to the test substance were not detected. Under the conditions o f this study, the NOEL for pathology was 25 mg/kg/day in male and female rats. These NOELs were based on microscopic chronic progressive nephropathy in males and females dosed with 500 mg/kg/day and in females dosed with 100 mg/kg/day, and on follicular hypertrophy o f the thyroid in 100 and 500 mg/kg/day males and females. - 70Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 REPRODUCTIVE TOXICOLOGY EVALUATIONS REPRODUCTIVE FUNCTION A. Pi Generation 1. Mean Body Weights and Body Weight Gains (Table 48-50, Appendices O-T) Mean body weights and body weight gains in the Pj generation rats were lower than control at 500 mg/kg/day. Mean body weight gain was significantly lower than control (68% o f control) in Pi male rats during and after the cohabitation period (test days 77-98) at 500 mg/kg/day. Weekly mean body weights were also significantly lower than control (83%-84% o f control) in this group. Weekly mean body weights were statistically significantly lower than control on test days 77-98 in Pi male rats at 100 mg/kg/day. This change was not considered toxicologically significant because it was small (93%-94% of control) and was not associated with lower body weight gain in this group. Mean body weight gain was significantly lower than control (72% o f control) in Pi females rats during gestation (days 0-21G) at 500 mg/kg/day. Weekly mean body weights were also significantly lower than control (85%-92% of control) in this group. Reductions in mean body weights and body weight gains occurred during gestation in Pi female rats at 25 and 100 mg/kg/day. These changes were not considered toxicologically significant because they were small (90%-95% of control), sporadic, and were not associated with any significant reduction in overall body weight gain in these groups. Statistically significant differences (both higher and lower than control) in mean body weight gain were observed in Pi female rats during lactation at all dose levels. These changes were not considered test substance-related due to their sporadic and inconsistent nature, and lack of effect on overall body weight gain at any dose level. Weekly mean body weights were statistically significantly lower than control in Pi female rats during lactation at 100 and 500 mg/kg/day. These changes were not considered toxicologically significant because they were small (87%97% o f control) and were not associated with lower body weight gain in these groups. 2. Food Consumption and Food Efficiency During Gestation (Table 51, Appendix U) Food consumption was not affected in Pi female rats during gestation at any dose level. Food efficiency was lower than control (73% o f control) in Pi female rats during gestation (days 021G) at 500 mg/kg/day. This change is consistent with the lower mean body weight gain observed during gestation in this group. -71 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 3. Clinical Observations (Tables 52, Appendices V-X) There was no test substance-related mortality. Salivation at the time o f daily dosing was observed in male rats at all dose levels and in female rats during gestation at > 100 mg/kg/day. Staining o f the perineal or inguinal area was observed in a few animals at 500 mg/kg/day. The toxicological significance o f salivation in Pi males at 25 mg/kg/day is uncertain due to its low incidence and sporadic occurrence. 4. Reproductive Indices (Tables 53-55, Appendices Y-EE) There were no test substance-related effects on percent days in estrus, diestrus, or proestrus. Individual animals displayed persistent or prolonged estrus or diestrus during the evaluation period. These abnormal cycling patterns were not considered test substance-related since they occurred to a similar degree in the control and treated groups. Mean cycle length was similar at 25, 100, and 500 mg/kg/day (4.7, 4.9, and 4.8 days, respectively) but was significantly greater than the control group (4.3 days), however, mean values were within the historical control range for Haskell Laboratory.3 The toxicological significance of these changes is unclear. There were no test substance-related effects on sperm motility, morphology or testicular spermatid counts. The mean number of epididymal sperm per cauda was similar at 25,100, and 500 mg/kg/day (278.8, 291.1, and 279.4 million sperm, respectively) but was significantly lower than the control group (318.4 million sperm). Although not statistically significant, a change of similar magnitude was observed in the mean number o f epididymal sperm per gram cauda at 25, 100, and 500 mg/kg/day (979.2, 969.0, and 1062.1 million sperm, respectively) compared to the control group (1180.2 million sperm). These changes were not considered toxicologically significant because they were small (82%-91% o f control), mean values were within the historical control range for Haskell Laboratory,3and were not associated with any histopathological changes in the testis or epididymis. The mean number o f testicular spermatids per testis was statistically significantly higher than control at 500 mg/kg/day (126.5 vs. 137.0 million spermatids). This change was not considered test substance-related since the mean number o f spermatids per gram testis at 500 mg/kg/day was similar to the control group. There was no test substance-related effect on the length o f the precoital interval or on the mating index (number o f females with evidence o f copulation / number o f females cohabited x 100) or gestation length. The fertility index (number o f females delivering a litter/number o f females with evidence o f copulation x 100) was similar at 25, 100, and 500 mg/kg/day (55%, 58%, and 65% at 25, 100, and 500 mg/kg/day, respectively) but was lower than the control group (85%). This change was considered test substance-related. The number of uterine implantation sites was significantly reduced at 500 mg/kg/day (10.7 vs. 15.3 for the control group). There was no effect on implantation efficiency (number o f pups bom/number o f implantation sites x 100) at any dose level, indicating no post-implantation loss (no resorptions). For seven studies conducted at Haskell Laboratory between 1999 and 2001 the mean estrous cycle length among the control groups ranged from 4.2-4.9 days; the mean epididymal sperm number among the control groups ranged from 274.3-345.5 million sperm. -72Company Sanitized. Does not contain TSCA CBi H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 B. Offspring Data 1. Litter Size, and Pup Weights, Clinical Observations, and Survival (Table 56-5 8; Appendices FF-HH) Mean litter size was lower than control at 500 mg/kg/day. Sex ratio and gestation index (percent litters having at least one live pup) were unaffected in Fi litters at any dose level. The numbers o f pups bom and bom alive were significantly lower than control at 500 mg/kg/day (72% and 66% of control, respectively). As a result, the mean percent pups bom alive was significantly lower than control at 500 mg/kg/day (86.5% compared to 100% in the control group). Pup survival during lactation was lower than control at 100 and 500 mg/kg/day. The mean number o f pups per litter on day 4 preculling, day 7, 14, and 21 o f lactation were significantly lower than control at 500 mg/kg/day (53%, 60%, 14%, 10% o f control respectively). The mean number o f pups per litter was similar to control on day 4 and 7 o f lactation at 100 mg/kg/day. The mean number o f pups alive at day 14 and 21 was significantly lower than control at 100 mg/kg/day (79% and 76% o f control, respectively). As a result, the lactation index (survival from day 4 postculling to day 21) was significantly lower than control at 100 and 500 mg/kg/day (76.1% and 11.4% compared to 100% in the control group). The litter survival index (percent litters bom with at least on live pup on day 21) was significantly lower than control at 500 mg/kg/day (25% compared to 100% in the control group). Pup weights at birth and during lactation were lower than control at 100 and 500 mg/kg/day. Mean pup weight at birth was significantly lower than control at 500 mg/kg/day (90% of control). Mean pup weights during lactation were lower than control at 100 and 500 mg/kg/day. Mean pup weights were significantly lower than control at 500 mg/kg/day on days 4, 7, 14, and 21 o f lactation (71%, 54%, 56%, 57% o f control, respectively). Mean pup weights were significantly lower than control at 100 mg/kg/day on days 4, 7,14, and 21 (94%, 86%, 94%, 94% o f control, respectively). There were no test substance-related clinical signs in pups during lactation at any dose level. C. Fi Generation Due to poor survival in 500 mg/kg/day Fi generation rats, there are insufficient data available to evaluate post-weaning in-life parameters. Therefore, results from this group will not be discussed. 1. Mean Body Weights and Body Weight Gains (Table 59-60, Appendices II-JJ) There were no test substance-related effects on body weight and body weight gain in Fi male and female rats during the post-weaning period at 25 or 100 mg/kg/day. 73- - Company Sanitized. Does not contain TSCA C8I H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 2. Food Consumption and Food Efficiency (Tables 61-62, Appendix KK) There were no test substance-related effects on food consumption and food efficiency in Fi male and female rats during the post-weaning period at 25 or 100 mg/kg/day. 3. Clinical Observations (Tables 63, Appendix LL) The few pups in the 500 mg/kg/day group that survived to weaning on postnatal day 21 either died soon after weaning or were sacrificed on postnatal day 33-35. There were no test substancerelated clinical signs in Fi male and female rats during the post-weaning period at 25 and 100 mg/kg/day. 4. Developmental Landmarks (Tables 64, Appendix LL) There were no test substance-related effects on the age at onset o f vaginal opening in Fi female rats or o f preputial separation in Fi male rats at 25 and 100 mg/kg/day. D. Reproductive Function Conclusions There was no NOEL for the reproductive toxicity parameters evaluated under the conditions of this study; this was based on effects at all dose levels on the fertility index in the Pi generation. - 74Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations ANATOMICAL PATHOLOGY REPRODUCTIVE TOXICOLOGY EVALUATIONS DuPont-5990 A. Mortality Fi Adults (Appendix NN) Due to excessive toxicity, the 500 mg/kg/day Fi animals retained after weaning were sacrificed on postnatal day 33-35. There were no compound-related effects on post-weaning mortality for the other groups. B. Organ Weight Data Fi Adults (Tables 65-66; Appendix MM) Organ weight data was not collected on the 500 mgdcg Fj animals retained after weaning because they were sacrificed early. There were no compound-related effects on the organ weights o f F t adult males or females dosed with 25 or 100 mg/kg/day. A significant decrease in mean liver weights (absolute and relative to body and to brain), and an increase in mean brain weight (relative to body) in 100 mg/kg males were considered to be secondary to lower body weight in that group. C. Gross Observations Parental Pi Adults (Tables 67-68, Appendix NN) Fi Adults and Weanlings (Tables 69-75, Appendices OO-QQ) There were no compound-related gross observations in parental or weanling rats. Observations in parental or weanling rats occurred in low incidences and were randomly distributed across control and treatment groups. Observations in pups o f lungs not expanded, and no milk spot in the stomach, are nonspecific lesions that are commonly seen in all pups that are bom dead, and thus are not considered to be compound-related. Pup viability and mortality are discussed elsewhere in this report. D. Microscopic Observations Parental Pi Adults (Tables 76-77, Appendix NN) There were no compound-related microscopic findings in any o f the Pi males or females that received microscopic evaluation. Lesions occurred in low incidences without a relevant doseresponse relationship and were considered incidental occurrences o f spontaneous lesions in rats o f this strain and age. 75- - Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 E. Anatomical Pathology Conclusions for Reproductive Toxicity The no-observed-effect level (NOEL) for this study is defined as the highest dose at which toxicologically important effects attributable to the test substance were not detected. Under the conditions o f this study, the NOEL for pathology was 100 mg/kg/day for males and females, the highest Fi adult dosage group evaluated for reproductive anatomic pathology. - 76Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 CONCLUSIONS Under the conditions o f this study, the no-observed-effect level (NOEL)3for H-24768 for the 90day exposure in male and female rats was 25 mg/kg/day. This level was based on clinical signs of toxicity, decrements in body weight parameters and food efficiency (males), thyroid follicular hypertrophy, and chronic progressive nephropathy (females), all observed in the 100 mg/kg/day groups. Other adverse, compound-related effects observed in males and/or females dosed with 500 mg/kg/day include decrements in body weight parameters and food efficiency (females), chronic progressive nephropathy (males), increased liver enzyme activities (males), reduction in red blood cell mass parameters (females), and reductions in forelimb and hindlimb grip strength (males). The reductions in grip strength were considered secondary to body weight effects and were not considered evidence o f neurotoxicity. Other compound-related effects were observed that were not considered adverse, but were either physiologic responses to exposure to the test substance or markers o f exposure. Increased liver weight and hepatocellular hypertrophy were observed in all dosed male groups and in 100 and 500 mg/kg/day female groups. These effects were considered non-adverse physiologic responses. In 100 and 500 mg/kg/day males, the liver effects were associated with reversible induction o f hepatic p-oxidation. Microscopic changes in the spleen, including extramedullary hematopoiesis and pigment, sometimes associated with increased spleen weight (in females) were considered non-adverse and secondary to effects on red cell mass. Clinical observations attributed to increased urination were observed in male and female 100 and/or 500 mg/kg/day groups, and were associated with changes in clinical chemistry and urinalysis that were attributed to a physiological effect on kidney function. An increase in altered colloid was observed in the thyroids o f all dosed male and female groups. This lesion was also observed in some control rats and was not considered adverse. Most o f the effects observed during the dosing period demonstrated full or partial reversal following one or three months o f recovery. Reversal o f many effects in females was not observed until after the one-month recovery. Thyroid follicular hypertrophy in 500 mg/kg/day males and chronic progressive nephropathy in 100 and 500 mg/kg/day females were still present at the end o f the three-month recovery period. Under the conditions o f this study, there was no NOEL for reproductive parameters. This was based on reductions in the fertility index in all dose groups. Prolongation o f estrous cycle length was also observed in Pi rats in all dose groups but the toxicological significance o f this effect is unclear. Other adverse, compound-related effects observed in Pi rats dosed with 500 mg/kg/day include decrements in body weight parameters and food efficiency and reduced number of implantation sites. A reduction in epididymal sperm counts was observed in all male groups dosed with test substance, but this effect was not considered adverse. 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 A gency(27) and to the no-observed-adverse-effect level (NOAEL) as defined by the European Union<28). - 77Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with Oae-Generation Reproduction Evaluations __________________ DuPont-5990 Adverse, compound-related effects observed in 100 and/or 500 mg/kg/day group Fi rats included reductions in mean litter size, number o f pups bom and bom alive, pup survival during lactation, and pup weight at birth and during lactation. In the 500 mg/kg/day Fi group high mortality, during lactation and post-weaning, resulting in early sacrifice of this group, precluded evaluation o f post-weaning parameters (body weight and nutritional parameters, clinical observations, developmental landmarks). No compound-related effects on any post-weaning parameters were observed in the 100 or 25 mg/kg/day Fi groups. -78Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Genration Reproduction Evaluations DuPont-5990 REFERENCES 1. DuPont (1995). Neurotoxicity Evaluation o f Trimethyltin in Rats (Positive Control Study). 2. DuPont (1997). Neurotoxicity Evaluation o f Amphetamine in Rats (Positive Control Study). 3. DuPont (1997). Neurotoxicity Evaluation o f Carbaryl in Rats (Positive Control Study). rotoxicitv Evaluation o f Acrylamide in Rats (Positive Control Study). 5. Lazarow, P.B. (1981). Assay o f Peroxisomal Beta-Oxidation o f Fatty Acids. Methods in Enzymology 72, 315-319. 6. Bradford, M.M. (1976). A Rapid and Sensitive Method for the Quantitation o f Microgram Quantities o f Protein Utilizing the Principle o f 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 o f trend tests to determine a no-observable-effect level in animal safety studies. Journal o f the American College o f 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 o f variances. Contributions to Probability and Statistics (J. Olkin, ed.), pp 278-292. Stanford University Press, Palo Alto. 13. Shapiro, S.S. and Wilk., M.B. (1965). An analysis o f 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). Use o f ranks in one-criterion analysis o f variance. J. Amer. Statist. Assoc. 47, 583-621. 16. Milliken, G.A. and Johnson, D.A. (1984). Analysis o f Messy Data, Volume 1.: Designed Experiments. Lifetime Learning Publications, Belmont. 17. Hocking, R.A. (1985). The Analysis o f Linear Models. Brooks/Cole, Monterey. 18. Bartlett, M.S. (1937). Some examples o f statistical methods o f research in agriculture and applied biology. J. Royal. Statis. Soc. Suppl. 4, 137-170. -79Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 19. Fisher, R.A. (1985). Statistical Methods for Research Workers, 13th edition. Haffner, New York. 20. Dempster, A.P., Selwyn, M.R., Patel, C.M., and Roth, A.J. (1984). Statistical and computational aspects o f mixed model analysis. The Journal o f the Royal Statistical Society, Series C (Applied Statistics) 33(2), 203-214. 21. Haseman, J.K. and Hogan, M.D. (1975). Selection o f 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. Sipes, G. I., and Gandolfi, A. J. (1991). In Biotransformation o f Toxicants. In Casarett and Doull's Toxicology: The Basic Science o f Poisons (Amdur, M. O., Doull, J., and Klaassen, C. D., Ed.), Pergamon Press, New York, pp 88-126. 24. Paynter, O.E., Harris, J.E., Burin, G.J., and Jaeger, R.B. (1985). Guidance for Analysis o f Evaluation o f Subchronic Exposure Studies. United States Environmental Protection Agency, EPA-540/9-85-020. 25. Greaves, P. (1990). Digestive System 2. In Histopathology o fPreclinical Toxicity Studies: Interpretation and Relevance in Drug Safety Evaluation (P. Greaves, Ed.), Elsvier, Amsterdam, pp 393-496. 26. 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. 27. Hazard Evaluation Division, Standard Evaluation Procedure, Toxicity Potential: Guidance for Analysis and Evaluation o f Subchronic and Chronic Exposure Studies Paynter, O. E. et al., United States Environmental Protection Agency, Office o f Pesticide Programs, Washington, D.C., 20406. EPA-540/9-85-020. (June 1985). 28. Risk Assessment o f Notified New Substances. Technical Guidance Document (XI/283/94EN), Chapter I, Sections 2.24 and 2.25. 1994. -80Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLES -81 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLES EXPLANATORY NOTES Critical Dates DuPont-5990 Day 70 Last day data from the male and female rats designated for reproduction evaluations were reported with the subchronic toxicity animals. 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. Day 90 Last day of test substance administration for male and female rats designated for one-month and three-month recovery periods. Day 91 Last day o f body weight and food consumption data collection for male and female rats designated for the 91-day exposure period. Day 94 Last day of test substance administration for male rats designated for the 91-day exposure period. Day 95 Male rats designated for the 91-day exposure period were sacrificed. Last day of test substance administration for female rats designated for the 91-day exposure period. Day 96 Female rats designated for 91-day exposure period were sacrificed. Day 119 Last day o f body weight and food consumption data collection for rats designated for the one-month recovery period. Last day of food consumption data collection for rats designated for the three-month recovery period. Day 123 Male rats designated for the one-month recovery were sacrificed. Day 124 Female rats designated for the one-month recovery were sacrificed. Day 182 Last day o f non-fasted body weight data collection for rats designated for the three-month recovery period. Day 183 Male and female rats designated for the three-month recovery period were sacrificed. Note: Group I, Male Rat No. was dosed through test day 95, and bled for clinical pathology and necropsied on test day 96. This rat's clinical and anatomical pathology data are reported with the other males from test day 95. - 82Company Sanitized. Does not contain TSCA C8I H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLES ABBREVIATIONS: EXPLANATORY NOTES Summary of Hematology 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 PLT platelet 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 AHSN absolute hypersegmented neutrophil ABAN absolute neutrophil band AMET absolute neutrophil metamyelocyte AMYE absolute neutrophil myelocyte APRO absolute neutrophil promyelocyte AMYB absolute neutrophil myeloblast ARL absolute reactive lymphocyte AAL absolute atypical lymphocyte AIL absolute immature lymphocyte ACL absolute clefted lymphocyte ABLB absolute lymphoblast AIE absolute immature eosinophil AIM absolute immature monocyte APLA absolute plasma cell count NC not calculated or not calculable Summary of Coagulation Values PT - prothrombin time APTT - activated partial thromboplastin time DuPont-5990 -83Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLES ABBREVIATIONS: EXPLANATORY NOTES Summary of Serum and Plasma Chemistry Values AST - aspartate aminotransferase ALT - alanine aminotransferase SDH - sorbitol dehydrogenase ALKP - alkaline phosphatase BELI - total bilirubin BUN - urea nitrogen CREA - creatinine CHOL - cholesterol TRIG - triglycerides GLUC - glucose TP - total protein ALB - albumin GLOB - globulin CALC - calcium EPHS - inorganic phosphorous NA - sodium K - potassium CL - chloride PFLU - plasma fluoride SOSM - serum osmolality Summary of Urinalysis Values VOL - volume UOSM - urine osmolality SG - specific gravity pH - the logarithm o f the reciprocal o f the hydrogen ion concentration URO - 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, if bilirubin was reported as <0.1, 0.05 was used for any calculations performed with that bilirubin data. When an individual observation was recorded as being greater than a certain value, calculations were performed on the recorded value. For example, if specific gravity was reported as >1.083, 1.083 was used for any calculations performed with that specific gravity data. -84- Company Sanitized. Does not contain TSCA C8I H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 1 SU M M A RY OF D O SIN G SO LU TIO N ANALYSES Sample Type Dosing Concentrations and Stability of H-24768 (mg/mL) Test Day 0 Concentration Verification Average Measured Conc.c Average Percent Nominal6 Standard Deviation6 Coefficient of Variation6 Nominal: 3.33 3.11 (93.4)a 2.82 (84.7) 2.98 (89.2) 0.21 7% 13.33 12.1 (90.8) 11.6b (87.0) 11.9 (89.3) 0.35 3% --66.6g7 (90.6) 55.l b (82.6) 57.8 (86.7) 3.7 6% Stability 2.93d (88.0) 3.14e (94.3) 11.6d (87.0) 12.0e (90.0) 58. l d (87.1) 58.9e (88.3) Concentration Verification ^ Test Day 32 3.07 (92.2) 11.6 (87.0) 60.4 (90.6) Test Day 42 3.12 (93.7) 12.5 (93.8) 58.2 (87.3) Test Day 91 Concentration Verification 8 Average Measured Cone.6 Average Percent Nominal6 Standard Deviation6 Coefficient of Variation6 3.17 (95.2) 4.72 (94.4)a 4.54 (90.8) 4.63 (92.6) 0.1 3% 9.36 (93.6) 8.75 (87.5) 9.05 (90.5) 0.4 5% 12.5 (93.8) 40.2 (100.5) 38.9 (97.3) 39.6 (98.9) 0.9 2% Stability 5.06e 9.70e 42.1e (101.2) (97.0) (105.2) 5.37h 9.72h 41.3h (107.4) (97.2) (103.3) a Numbers in parentheses are the respective percent of nominal values, b Mean result of all analyses. c Mean, S.D. and C.V. for duplicate samples calculated to verify uniformity of mixture, d Samples (Test Day 0) held at room temperature for 5 hours, e Samples (Test Day 39) held refrigerated for 4 days and sampled, f Duplicate samples submitted. MfiarugsulU^oortefr _ g Samples from previous study for h Samples held refrigerated for 4 days followed by 5 hours at room temperature. 59.3 (88.9) 63.2 (90.2) 61.7 (88.1) 62.4 (89.1) 1.1 2% 84.2e (120.3) 69.7h (99.6) -85Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 2 MEAN DAILY DOSE VOLUMES (mL) FOR MALE RATS DAY 0 - DAY 6 Group I 0 mg/kg/day 1.6 0.1(45) Group III 25 mg/kg/day 1.6 0.1(35) Group V 100 mg/kg/day 1.6 0.1(35) Group VII 500 mg/kg/day 1.6 0.1(45) DAY 7 - DAY 13 2.0 0.2(45) 2.0 0.1(35) 2.0 0.1(35) 1.8 0.1(45) DAY 14 - DAY 20 2.4 0.3(45) 2.4 0.2 (35) 2.4 0.2(35) 2.2 0.2(45) DAY 21 - DAY 27 2.8 0.3 (45) 2.9 0.5(35) 2.7 0.2(35) 2.5 0.2(45) DAY 28 - DAY 34 3.1 0.3(45) 3.1 0.3(35) 2.9 0.2(35) 2.7 0.3(45) DAY 35 - DAY 41 3.3 0.4(45) 3.4 0.3(35) 3.2 0.2(35) 2.8 0.3(43) DAY 42 - DAY 48 3.5 0.4(45) 3.6 0.3(35) 3.3 0.2(35) 3.0 0.3(43) DAY 49 - DAY 55 3.7 0.4(45) 3.8 0.4(35) 3.5 0.3(35) 3.1 0.3(43) DAY 56 - DAY 62 3.8 0.5(45) 3.9 0.4(35) 3.6 0.3(34) 3.2 0.3(43) DAY 63 - DAY 69 4.0 0.5(44) 4.1 0.4(35) 3.7 0.3(34) 3.3 0.3(43) DAY 70 4.1 0.5(44) 4.2 0.4(35) 3.9 0.3 (34) 3.4 0.4(43) DAY 71 - DAY 76 4.0 0.5(24) 4.2 0.4(15) 3.8 0.3(14) 3.3 0.3(25) DAY 77 - DAY 83 4.1 0.6(24) 4.3 0.4(15) DAY 84 - DAY 90 4.2 0.6(24) 4.4 0.4(15) DAY 91 - DAY 94 4.5 0.4(10) 4.6 0.4(10) Data summarized as : Mean Standard Deviation (n) 3.9 0.4(14) 4.0 0.4(14) 4.1 0.4(10) 3.4 0.3(25) 3.5 0.3(25) 3.6 0.4(10 -86Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 3 MEAN DAILY DOSE VOLLMES (mL) FOR FEMALE RATS Group II 0 mg/kg/day Group IV 25 mg/kg/day Group VI Group VIII 100 mg/kg/day 500 mg/kg/day DAY 0 - DAY 6 1.3 0.1(45) 1.3 0.1(35) 1.3 0.1(35) 1.3 0.1(45) DAY 7 - DAY 13 1.5 0.1(45) 1.5 0.1(35) 1.5 0.1(35) 1.4 0.1(45) DAY 14 - DAY 20 1.6 0.1(45) 1.6 0.1(35) 1.6 0.1(35) 1.6 0.1(45) DAY 21 - DAY 27 1.8 0.2(45) 1.8 0.2(35) 1.8 0.1(35) 1.7 0.1(45) DAY 28 - DAY 34 1.9 0.2(45) 1.9 0.2(35) 1.9 0.1(35) 1.8 0.2(45) DAY 35 - DAY 41 2.0 0.2(45) 2.0 0.2 (35) 1.9 0.1(35) 1.9 0.2(45) DAY 42 - DAY 48 2.1 0.2(45) 2.0 0.2(35) 2.0 0.2(35) 2.0 0.2(45) DAY 49 - DAY 55 2.2 0.2(45) 2.1 0.2(35) 2.1 0.2(35) 2.1 0.2(45) DAY 56 - DAY 62 2.2 0.2(45) 2.2 0.2(35) 2.2 0.2(35) 2.1 0.2(45) DAY 63 - DAY 69 2.2 0.2(45) 2.2 0.2(35) 2.2 0.2(35) 2.1 0.2(45) DAY 70 2.3 0.2(45) 2.2 0.2(35) 2.2 0.2(35) 2.2 0.2(45) DAY 71 - DAY 76 2.3 0.2 (25) 2.2 0.3(15) 2.3 0.2(15) 2.2 0.2(25) DAY 77 - DAY 83 2.3 0.2(25) 2.2 0.3(15) 2.3 0.2(15) 2.2 0.2(25) DAY 84 - DAY 91 2.4 0.2(25) 2.3 0.3(15) 2.4 0.2(15) 2.2 0.2(25) DAY 91 - DAY 95 2.4 0.3(10) 2.3 0.3(10) Data summarized as: Mean Standard Deviation (n) 2.4 0.2(10) 2.3 0.2(10) -87Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 4 MEAN BODY WEIGHTS (g) OF MALE RATS Group I Group III 0 mg/kg/day 25 mg/kg/day Group V Group VII 100 mg/kg/day 500 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 70a 215.7 14.3 (45) 271.8 21.1(45) 321.2 34.6(45) 370.5 38.2 (45) 409.7 42.4(45) 441.3 48.6(45) 465.0 52.1(45) 489.9 55.4(45) 511.1 60.3(45) 526.7 63.6(44) 541.6 65.6(44) 216.5 13.0(35) 273.7 18.6(35) 328.3 25.2(35) 376.7 30.5(35) 419.0 35.9(35) 451.0 42.4(35) 476.4 44.5(35) 501.2 46.4(35) 523.4 50.4(35) 540.2 52.5(35) 559.9 54.2(35) 218.3 13.1(35) 267.0 17.9(35) 314.9 19.6(35) 357.7 25.0(35) 393.7 30.2(35) 420.9# 32.4(35) 443.6# 32.4(35) 466.3# 33.7(35) 482.8# 33.9(34) 499.2# 35.0(34) 515.5# 37.2(34) 215.2 12.2(45) 237.8# 16.6(45) 287.7# 22.7(45) 328.7# 28.9(45) 359.7# 32.9(45) 376.4# 36.4(43) 392.7# 40.1(43) 410.7# 42.5(43) 427.9# 43.2 (43) 442.5# 44.9(43) 452.1# 45.5(43) -88Company Sanitized. Does not contain TSCA C8I H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 4 (Continued) MEAN BODY WEIGHTS (g) OF MALE RATS Group I 0 mg/kg/day Group III Group V Group VII 25 mg/kg/day 100 mg/kg/day 500 mg/kg/day Dosing Period for Subchronic Toxicity Evaluation (continued) DAY 77 DAY 84 DAY 91 547.8 75.4(24) 558.7 77.8(24) 568.0 77.2(24) 573.0 55.1(15) 583.5 59.6(15) 594.8 61.1(15) 520.0 51.8(14) 531.5 52.5(14) 532.1 53.0(14) 452.6# 42.0(25) 461.8# 44.0(25) 470.4# 44.9(25) One-Month Recovery Period for Subchronic Toxicity Evaluation DAY 98 551.3 83.9(14) 562.9 49.1(5) 523.7 54.2(4) 491.4# 42.8(15) DAY 105 562.0 86.3(14) 570.7 46.0(5) 543.0 57.0(4) 513.6# 40.6(15) DAY 112 572.0 86.8(14) 580.5 46.2(5) 555.8 64.8(4) 518.8# 48.6(15) DAY 119 577.3 86.5(14) 582.2 42.1(5) 556.8 67.4(4) 522.0# 56.1(15) -89Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 4 (Continued) MEAN BODY WEIGHTS (g) OF MALE RATS Group I 0 mg/kg/day Group III Group V Group VII 25 mg/kg/day 100 mg/kg/day 500 mg/kg/day Three-Month Recovery Period for Subchronic Toxicity Evaluation DAY 126 539.3 94.8(4) 593.7 42.9(5) 567.1 71.1(4) 533.2 30.7(5) DAY 133 550.2 99.1(4) 607.0 44.1(5) 572.0 67.4(4) 555.5 32.6(5) DAY 140 560.3 101.9(4) 616.3 47.2 (5) 585.9 74.2(4) 569.8 32.8(5) DAY 154 558.2 97.4(4) 625.6 45.6(5) 595.2 65.3(4) 593.6 38.9(5) DAY 147 553.4 97.1(4) 622.9 48.6(5) 585.9 67.3(4) 578.6 37.2(5) DAY 161 573.2 101.1(4) 634.1 45.8(5) 599.9 59.4(4) 60-8.7 44.9(5) DAY 168 581.6 105.2(4) 643.0 52.4(5) 611.0 63.4(4) 614.8 49.0(5) DAY 175 578.0 102.7(4) 647.2 47.5(5) 615.2 68.3(4) 622.3 39.6(5) DAY 182 588.0 104.5(4) 655.1 53.3(5) 621.3 72.4(4) 634.3 . 44.0(5) Data summarized as: Mean Standard Deviation (n) a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 70; subsequent data are reported as part of the reproduction evaluation. # Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. -90Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 5 MEAN BODY WEIGHTS (g) OF FEMALE RATS Group II 0 mg/kg/day Group IV Group VI Group VIII 25 mg/kg/day 100 mg/kg/day 500 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 70a 175.6 11.5(45) 197.0 13.5(45) 216.9 17.5(45) 236.5 20.8(45) 252.5 22.0(45) 265.3 25.8(45) 276.9 25.4(45) 287.3 28.5(45) 292.7 28.4(45) 297.1 27.9(45) 305.3 28.3(45) 177.1 12.6(35) 196.4 14.8(35) 215.1 17.6(35) 234.1 20.2(35) 252.4 22.8(35) 265.3 23.9(35) 273.4 25.4(35) 284.4 27.2 (35) 291.0 28.0(35) 293.9 30.5(35) 300.2 30.0(35) 177.3 10.8(35) 193.9 11.4(35) 214.2 14.2(35) 234.6 15.5(35) 250.0 17.5(35) 258.9 18.0(35) 270.8 20.1(35) 283.4 22.0(35) 288.2 23.5(35) 294.2 25.3(35) 299.8 24.2 (35) 176.6 12.4(45) 185.0# 15.0(45) 209.9 16.1(45) 229.5 17.6(45) 246.8 19.1(45) 255.3# 20.2(45) 265.5# 20.2(45) 275.1# 22.9(45) 280.7# 22.7(45) 285.2 22.9(45) 289.2# 23.6(45) -91 Company Sanitized. Does not contain TSCA CBI /***\ H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 5 (Continued) MEAN BODY WEIGHTS (g) OF FEMALE RATS Group II 0 mg/kg/day Group IV Group VI Group VIII 25 mg/kg/day 100 mg/kg/day 500 mg/kg/day Dosing Period for Subchronic Toxicity Evaluation (continued) DAY 77 DAY 84 DAY 91 312.0 30.1(25) 316.3 30.5(25) 320.0 31.2(24) 296.3 38.3(15) 301.4 38.6(15) 305.5 39.2(15) 307.5 30.9 (15) 316.0 32.1(15) 317.3 32.0(15) 295.1 22.8(25) 299.9 21.8(25) 300.0# 19.8(25) One-Month Recovery Period for Subchronic Toxicity Evaluation DAY 98 DAY 105 DAY 112 DAY 119 326.5 27.3(14) 328.8 27.6(14) 340.9 31.4(14) 341.2 33.0(14) 308.9 46.2(5) 309.6 61.2(5) 321.0 51.2(5) 326.4 54.5(5) 316.4 47.0(5) 323.9 47.8(5) 332.2 42.9(5) 327.2 47.6(5) 299.1# 18.7(15) 298.7# 21.0(15) 312.0# 22.4(15) 304.6# 29.1(15) -92Company Sanitized. Does not contain TSCA CBJ H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 5 (Continued) MEAN BODY WEIGHTS (g) OF FEMALE RATS Group II 0 mg/kg/day Group IV Group VI Group VIII 25 mg/kg/day 100 mg/kg/day 500 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 DAY 182 339,.3 38 .8(4) 339 .1 39 .2(4) 339,.7 43 ,.0(4) 346,.3 33..6(4) 345,.6 39..9(4) 352..6 38..4(4) 351..5 42 ,.8(4) 357..7 39,.5(4) 356..0 46,.2(4) 330..8 55..6(5) 331..3 55..9(5) 335.,4 58..9(5) 334..5 62..1(5) 335..7 60..7(5) 341..3 61..7(5) 345..8 63 .0(5) 346.,1 62 .4(5) 349..9 64..2(5) 335,.8 44 .3(5) 337 .8 46 .7(5) 344..4 50..1(5) 345,.1 46..4(5) 342..1 46..0(5) 345.,7 49..1(5) 346..2 51,.4(5) 345,.7 55..0(5) 355..3 54..8(5) 310..4 28,.4(5) 314..3 34..0(5) 320..8 39..0(5) 321..9 32..6(5) 323..0 36..0(5) 330.,0 39..1(5) 329..1 40..9(5) 328..1 42..0(5) 335..6 45..9(5) Data summarized as: Mean Standard Deviation (n) a. Rats designated for reproduction evaluation {20 rats/group) were cohoused on test day 70; subsequent data are reported as part of the reproduction evaluation. # Statistically significant differences at p < 0.05 by Jonckheere-Terpstra trend test. -93Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 6 MEAN BODY WEIGHT GAINS (g) OF MALE RATS Group I Group III Group V Group VII 0 mg/kg/day 25 mg/kg/day 100 mg/kg/day 500 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 56.1 9.2(45) 49.4 20.0(45) 49.3 12.2(45) 39.2 8.2(45) 31.6 9.2(45) 23.7 8.5(45) 24.8 6.2(45) 21.2 8.7(45) 16.8 6.4(44) 14.8 6.1(44) 57.3 7.3(35) 54.5 8.9(35) 48.4 8.7(35) 42.3 9.5(35) 32.0 8.8(35) 25.5 8.1(35) 24.7 7.1(35) 22.3 6.8(35) 16.8 9.5(35) 19.7 6.2(35) 48.7# 8.8 (35) 47.9 10.0(35) 42.8# 8.4(35) 36.0 9.8(35) 27.2# 6.7(35) 22.7 10.2(35) 22.7 5.6(35) 16.3# 5.4(34) 16.5 5.7 (34) 16.3 5.6(34) 22.5# 9.2(45) 50.0 10.6(45) 40.9# 9.7(45) 31.0# 7.6(45) 18.0# 6.5(43) 16.2# 10.4(43) 18.1# 8.6(43) 17.2# 7.4(43) 14.6 8.2(43) 9.7# 6.4(43) DAY 0 - DAY 70a 326.2 56.6(44) 343.4 47.4(35) 296.9# 32.6(34) 237.0# 40.7(43) -94Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 6 (Continued) MEAN BODY WEIGHT GAINS (g) OF MALE RATS Group I Group III Group V Group VII 0 mg/kg/day 25 mg/kg/day 100 mg/kg/day 500 mg/kg/day Dosing Period for Subchronic Toxicity Evaluation (continued) DAY 70 - DAY 77 DAY 77 - DAY 84 DAY 84 - DAY 91 12.5 6.9(24) 10.8 6.0(24) 9.3 7.7(24) 12.7 4.4(15) 10.6 9.7(15) 11.3 9.9(15) 9.8 9.2(14) 11.4 4.9(14) 0.6 6.3(14) 8.2# 10.5(25) 9.2 8.5(25) 8.6 8.3(25) DAY 0 - DAY 91 354.0 67.8(24) 377.9 54.8(15) 312.6 48.1(14) One-Month Recovery Period for Subchronic Toxicity Evaluation 255.6# 41.2(25) DAY 91 - DAY 98 DAY 98 - DAY 105 DAY 105 - DAY 112 DAY 112 - DAY 119 11.5 6.7(14) 10.7 7.1(14) 10.0 3.5(14) 5.3 5.6(14) 8.4 2.0(5) 7.8 6.7(5) 9.8 4.6(5) 1.7 5.5(5) 11.5 8.0(4) 19.3 3.2(4) 12.8 8.5(4) 1.1 3.9(4) 26.0# 8.7(15) 22.2# 12.3(15) 5.2 26.2(15) 3.3 11.1(15) DAY 91 - DAY 119 37.5 9.7(14) 27.7 7.5(5) 44.7 9.9(4) 56.6# 41.0(15) -95Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 6 (Continued) MEAN BODY WEIGHT GAINS (g) OF MALE RATS Group I Group III Group V Group VII 0 mg/kg/day 25 mg/kg/day 100 mg/kg/day 500 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 DAY 175 - DAY 182 DAY 91 - DAY 182 14.0 7.2(4) 11.0 4.9(4) 10.1 3.0(4) -7.0 17.7(4) 4.8 7.0(4) 15.0 4.2(4) 8.4 8.7(4) -3.7 5.6(4) 10.0 4.4(4) 92.3 42.0(4) 11.5 6.5(5) 13.3 8.0(5) 9.2 6.2(5) 6.7 4.9(5) 2.6 6.9(5) 8.6 1.5(5) 8.8 8.0(5) 4.2 6.7(5) 8.0 7.8(5) 100.6 19.1(5) 10.3 6.2(4) 4.8 4.1(4) 14.0 8.4(4) -0.1 10.0(4) 9.3 3.2(4) 4.7 6.5(4) 11.0 4.6(4) 4.3 5.5(4) 6.1 6.2(4) 109.2 14.1(4) 21.8 27.4(5) 22.3 7.3(5) 14.2 5.9(5) 8.9 12.1(5) 15.0# 9.9(5) 15.1 9.7(5) 6.1 11.4(5) 7.5 12.4(5) 12.0 6.0(5) 167.1# 44.4(5) Data summarized as: Mean Standard Deviation (n) a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 70; subsequent data .are reported as part of the reproduction evaluation. # Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. - 96Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 7 MEAN BODY WEIGHT GAINS (g) OF FEMALE RATS Group II Group IV Group VI Group VIII 0 mg/kg/day 25 mg/kg/day 100 mg/kg/day 500 mg/kg/day Posing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 - DAY 7 21.4 6.7(45) 19.3 6.2(35) 16.5# 5.3(35) 8.3# 10.9(45) DAY 7 - DAY 14 19.9 7.9(45) 18.7 6.5(35) 20.3 5.2 (35) 24.9# 6.9(45) DAY 14 - DAY 21 19.6 8.8(45) 19.0 6.6(35) 20.4 5.1(35) 19.6 5.6(45) DAY 21 - DAY 28 15.9 8.5(45) 18.4 6.7(35) 15.3 7.1(35) 17.3 6.7(45) DAY 28 - DAY 35 12.9 7.8(45) 12.8 5.4(35) 8.9 8.6(35) 8.6# 6.1(45) DAY 35 - DAY 42 11.6 7.1(45) 8.1 6.0(35) 11.9 8.7 (35) 10.2 5.9(45) DAY 42 - DAY 49 10.4 6.8(45) 11.0 6.7(35) 12.6 7.6(35) 9.5 7.0(45) DAY 49 - DAY 56 5.5 6.4(45) 6.6 6.0 (35) 4.8 5.4(35) 5.7 6.2(45) DAY 56 - DAY 63 4.4 5.6(45) 2.9 4.4(35) 6.1 6.0(35) 4.5 5.0(45) DAY 63 - DAY 70 8.2 5.9(45) 6.4 6.3(35) 5.5# 6.4(35) 4.0# 6.2(45) DAY 0 - DAY 70a 129.7 20.9(45) 123.1 21.7(35) 122.4 19.7(35) 112.6# 18.4(45) -97Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 7 (Continued) DuPont-5990 MEAN BODY WEIGHT GAINS (g) OF FEMALE RATS Group II Group IV Group VI Group VIII 0 mg/kg/day 25 mg/kg/day 100 mg/kg/day 500 mg/kg/day Dosing Period for Subchronic Toxicity Evaluation (continued) DAY 70 - DAY 77 DAY 77 - DAY 84 DAY 84 - DAY 91 4.1 6.9(25) 4.3 6.6(25) 2.2 5.8(24) 4.4 6.6(15) 5.2 4.8(15) 4.1 6.1(15) 2.3 6.8(15) 8.4 4.0(15) 1.4 4.5(15) 4.2 5.5(25) 4.8 5.2(25) 0.0 6.5(25) DAY 0 - DAY 91 142.9 25.0(24) 132.1 30.4(15) 140.2 26.6(15) One-Month Recovery Period for Subchronic Toxicity Evaluation 121.7# 13.8(25) DAY 91 - DAY 98 DAY 98 - DAY 105 DAY 105 - DAY 112 DAY 112 - DAY 119 7.2 8.9(14) 2.2 8.5(14) 12.2 7.4(14) 0.3 6.3(14) 2.6 3.6(5) 0.8 18.9(5) 11.4 11.2(5) 5.4 5.5(5) 3.4 6.6(5) 7.5 4.3(5) 8.4 10.7(5) -5.0 6.1(5) 0.4# 8.1(15) -0.5 15.1(15) 13.3 12.4(15) -7.4# 17.2(15) DAY 91 - DAY 119 21.9 10.7(14) 20.1 11.1(5) 14.2 17.4(5) 5.8# 23.8(15) - 98Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 7 (Continued) DuPont-5990 MEAN BODY WEIGHT GAINS (g) OF FEMALE RATS Group II Group IV Group VI Group VIII 0 mg/kg/day 25 mg/kg/day 100 mg/kg/day 500 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 154 - DAY 161 DAY 161 - DAY 168 DAY 147 - DAY 154 DAY 168 - DAY 175 DAY 175 - DAY 182 4 .3 6 .5(4) -0 .1 8,.5(4) 0 .5 12 .7(4) 6,.6 12 ,.8(4) 7,.0 3..9(4) -1..1 10,.2(4) -0,.7 9..1(4) 6,.2 5..5(4) -1..7 11..4(4) 4 .3 3 .8(5) 0,.6 4,.9(5) 4,.0 7..1(5) -0,.9 7 ,.4(5) 5,.6 9,.0(5) 4,.5 4..3(5) 1..3 6..1(5) 0,.3 1..4(5) 3,.9 2..6(5) 8 .6 7 .1(5) 2 .0 4,.3(5) 6 .6 10..7(5) 0..7 8,.1(5) 3,.5 4,.9(5) 0,.5 7,.1(5) -2..9 5,.9(5) -0..5 6..3(5) 9,.6 6..8(5) 19 .3 31 .6(5) 3 .9 7 .3(5) 6 .5 7..0(5) 1..1 7..9(5) 7..0 5..6(5) -0,.8 6,.9(5) 1..1 6,.8(5) -1..1 4..8(5) 7..6 10..5(5) DAY 91 - DAY 182 44..0 24..2(4) 43..6 20..5(5) 42..2 31..1(5) 39..8 28..4(5) Data summarized a s : Mean Standard Deviation (n) a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 70; subsequent data are reported as part of the reproduction evaluation. # Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. -99Compiny Sanitized. Does not contain TSCA C B I H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 8 MEAN DAILY FOOD CONSUMPTION (g) BY MALE RATS Group I Group III Group V Group VII 0 mg/kg/day 25 mg/kg/day 100 mg/kg/day 500 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 26.2 3.3(45) 28.0 3.2(44) 29.3 3.7(45) 30.8 3.7(45) 30.6 3.9(45) 31.1 3.8(45) 31.4* 3.7(45) 31.8 4.3(45) 31.1 4.3(44) 29.7 3.8(44) 26.4 3.8(35) 28.3 2.9(35) 30.0 3.2(35) - 31.9 3.6(35) 31.8 3.6(35) 31.7 3.6(35) 31.7 3.6(35) 32.1 3.6(35) 30.9 4.4(35) 31.4 3.9(35) 25.2 2.4(35) 26.7 2.5 (35) 28.1 2.6(35) 29.5 3.6 (35) 29.8 2.6(35) 29.8 2.8(35) 30.4 2.7(35) 29.3# 2.4(34) 29.9 2.3 (34) 29.8 2.2(34) 18.6# 2.2(45) 24.1# 2.8(45) 27.0# 3.2(45) 28.0# 3.4(45) 27.5# 3.4(43) 27.7# 3.8 (43) 28.7# 3.8(43) 29.6# 3.5(43) 30.3 4.2(43) 29.8 3.9(43) DAY 0 - DAY 70a 30.0 3.5(43) 30.6 3.2(35) 28.8# 2.1(34) 27.1# 3.0(43) - 100Company Sanitized. Does not contain TSCA CBi H-24768: Subchronic Toxicity 90-Day Gavagg Study in Rats with One-Generation Reproduction Evaluations__________________ DuPont-5990 TABLE 8 (Continued) MEAN DAILY FOOD CONSUMPTION (g) BY MALE RATS Group I Group III Group V Group VII 0 mg/kg/day 25 mg/kg/day 100 mg/kg/day 500 mg/kg/day Dosing Period for Subchronic Toxicity Evaluation (continued) Day 70 - Day 77 Day 77 - Day 84 Day 84 - Day 91 28.6 4.2(24) 28.8 4.1(24) 28.8 4.3(24) 29.1 4.4(15) 30.5 3.8(15) 30.1 4.2(15) 28.7 2.3(14) 28.8 2.5(14) 27.3 2.8(14) 28.8 3.4(25) 29.2 3.1(25) 29.6 3.2(25) DAY 0 - DAY 91 29.2 3.9(24) 30.4 3.3(15) 28.6 2.3(14) One-Month Recovery Period for Subchronic Toxicity Evaluation 27.1# 3.4(25) Day 91 - Day 98 Day 98 - Day 105 Day 105 - Day 112 Day 112 - Day 119 28.4 4.6(14) 28.1 5.1(14) 27.3 4.2(14) 27.7 4.2(14) 28.5 3.4(5) 27.7 2.6(5) 27.3 1.6(5) 26.6 1.7(5) 29.7 2.3(4) 31.6 1.3(4) 30.2 2.2(4) 28.7 2.0(4) 33.4# 4.1(15) 33.3# 3.1(15) 29.2 5.6(15) 28.8 6.3(15) DAY 91 - DAY 119 27.9 4.4(14) 27.5 2.2(5) 30.0 1.4(4) 31.2 3.6(15) Data summarized as : Mean Standard Deviation (n) a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 70; food consumption data were not collected during the cohabitation and postmating periods. # Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. - 101 Company Sanitized. Does not contain TSCA C8I H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 9 MEAN DAILY FOOD CONSUMPTION (g) BY FEMALE RATS Group II 0 mg/kg/day Group IV Group VI Group VIII 25 mg/kg/day 100 mg/kg/day 500 mg/kg/day Dosing Period for Subchronic Toxicity and Reproduction Evaluations Day 0 - Day 7 19.0 1.9(45) 18.8 1.9(35) 17.5# 1.5(35) 12.5# 3.0(45) Day 7 - Day 14 19.7 1.9(45) 20.0 2.0(35) 19.7 1.5(35) 17.4# 2.1(45) Day 14 Day 21 19.7 2.1(45) 20.7 2.4(35) 20.3 1.6(35) 19.0 2.0(45) Day 21 Day 28 20.7 2.2(45) 20.8 2.1(35) 20.5 1.7(35) 19.7# 2.4(45) Day 28 Day 35 21.8 3.0(45) 21.6 2.4(35) 21.3 2.1(35) 21.7 2.4(45) Day 35 Day 42 21.7 2.4(45) 21.5 2.5(35) 20.9 2.2(35) 2 0 . 8# 2.5(45) Day 42 Day 49 22.2 2.8(45) 22.3 2.9 (35) 22.7 2.2(35) 21.9 2.8(45) Day 49 Day 56 22.1 2.7(45) 21.8 2.5(35) 22.1 2.5(35) 22.1 2.7(45) Day 56 Day 63 21.4 2.8(45) 20.9 2.6(35) 22.3 2.7 (35) 22.3 2.6(45) Day 63 Day 70 21.2 2.8(45) 20.6 2.5(35) 21.6 2.2(35) 21.9 2.5(45) DAY 0 - DAY 70a 21.0 2.0(45) 20.9 2.1(35) 20.9 1.7(35) 19.9 2.1(45) - 102Company Sanitized. Does not contain TSCA C8I H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 9 (Continued) MEAN DAILY FOOD CONSUMPTION (g) BY FEMALE RATS Group II 0 mg/kg/day Group IV Group VI Group VIII 25 mg/kg/day 100 mg/kg/day 500 mg/kg/day Dosing Period for Subchronic Toxicity Evaluation (continued) Day 70 - Day 77 Day 77 - Day 84 Day 84 - Day 91 21.9 2.6(25) 21.0 2.2(25) 19.9 2.5(24) 20.9 3.2(15) 20.9 2.9(15) 20.2 3.2(15) 22.1 2.9(15) 22.1 3.2(15) 21.3 3.0(15) 22.7 2.4(25) 22.0# 3.0 (25) 22.1# 2.1(25) DAY 0 - DAY 91 21.1 2.0(24) 20.6 2.5(15) 21.2 2.2(15) One-Month Recovery Period for Subchronic Toxicity Evaluation 20.5 1.9(25) Day 91 - Day 98 Day 98 - Day 105 Day 105 - Day 112 Day 112 - Day 119 22.1 2.1(14) 21.6 2.0(14) 22.5 3.2(14) 21.4 2.7(14) 22.1 3.6(5) 21.2 5.6(5) 22.5 3.6(5) 21.5 3.4(5) 23.9 3.4(5) 22.9 2.4(5) 23.9 2.5(5) 22.2 2.4(5) 24.3# 2.2(15) 22.2 3.3(15) 24.1 2.4(15) 21.2 4.9(15) DAY 91 - DAY 119 Data summarized as: 21.9 2.2(14) 21.8 3.9(5) Mean Standard Deviation (n) 23.2 2.4(5) 22.9 2.7(15) a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 70; data were not collected during the cohabitation period. Food consumption data collected during gestation are reported as part of the reproduction evaluation. # Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. -103Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 10 MEAN DAILY FOOD EFFICIENCY OF MALE RATS (g body weight gain/g food consumed) Group I Group III Group V Group VII 0 mg/kg/day 25 mg/kg/day 100 mg/kg/day 500 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 0.306 0.035(45) 0.264 0.029(44) 0.240 0.053(45) 0.181 0.029(45) 0.146 0.031(45) 0.107 0.031(45) 0.112 0.021(45) 0.093 0.033 (45) 0.076 0.024(44) 0.070 0.027(44) 0.313 0.043(35) 0.274 0.027 (35) 0.230 0.029(35) 0.188 0.031(35) 0.142 0.029(35) 0.114 0.030(35) 0.111 0.027(35) 0.098 0.025(35) 0.074 0.050(35) 0.090 0.027(35) 0.275# 0.037(35) 0.256 0.048(35) 0.217# 0.034(35) 0.173 0.042(35) 0.130# 0.030(35) 0.107 0.045(35) 0.106 0.024(35) 0.079# 0.025(34) 0.079 0.027(34) 0.077 0.025(34) 0.168# 0.056 (45) 0.294# 0.042(45) 0.215# 0.037 (45) 0.157# 0.029(45) 0.092# 0.029(43) 0.081# 0.051(43) 0.089# 0.040(43) 0.083# 0.037(43) 0.068 0.036(43) 0.046# 0.030(43) DAY 0 - DAY 70a 0.154 0.012(43) 0.159 0.010(35) 0.146# 0.011(34) 0.122# 0.012(43) -104Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 10 (Continued) MEAN DAILY FOOD EFFICIENCY OF MALE RATS (g body weight gain/g food consumed) Group I Group III Group V 0 mg/kg/day 25 mg/kg/day 100 mg/kg/day Dosing Period for Subchronic Toxicity Evaluation (continued) Group VII 500 mg/kg/day DAY 70 - DAY 77 DAY 77 - DAY 84 DAY 84 - DAY 91 0.061 0.032(24) 0.052 0.027(24) 0.046 0.041(24) 0.065 0.030(15) 0.048 0.043 (15) 0.053 0.047(15) 0.047 0.043(14) 0.057 0.024(14) 0.002 0.034(14) 0.038 0.063 (25) 0.044 0.046(25) 0.040 0.040(25) DAY 0 - DAY 91 0.132 0.011(24) 0.136 0.008(15) 0.119# 0.012(14) 0.102# 0.012(25) One-Month Recovery Period for Subchronic Toxicity Evaluation DAY 91 - DAY 98 DAY 98 - DAY 105 DAY 105 - DAY 112 DAY 112 - DAY 119 0.055 0.027 (14) 0.053 0.037(14) 0.053 0.019(14) 0.028 0.030(14) 0.042 0.009(5) 0.039 0.033(5) 0.052 0.024(5) 0.010 0.032(5) 0.053 0.035(4) 0.087 0.013(4) 0.059 0.036 (4) 0.005 0.021(4) 0.111# 0.034(15) 0.094# 0.054(15) -0.008 0.215 (15) 0.005 0.067(15) DAY 91 - DAY 119 0.048 0.009(14) 0.036 0.012(5) 0.053 0.010(4) 0.061# 0.048(15) Data summarized as: Mean Standard Deviation (n) a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 70; data were not collected during the cohabitation and postmating periods. # Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. -105Company Sanitized. Does not contain TSCA C8I H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 11 MEAN DAILY FOOD EFFICIENCY OF FEMALE RATS (g body weight gain/g food consumed) Group II Group IV Group VI Group VIII 0 mg/kg/day 25 mg/kg/day 100 mg/kg/day 500 mg/kg/day Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 - DAY 7 0.160 0.048(45) 0.145 0.039(35) 0.134# 0.039(35) 0.119# 0.258(45) DAY 7 - DAY 14 0.142 0.049(45) 0.132 0.040(35) 0.146 0.033(35) 0.205# 0.054(45) DAY 14 - DAY 21 0.141 0.058(45) 0.130 0.041(35) 0.144 0.033(35) 0.148 0.041(45) DAY 21 - DAY 28 0.109 0.053(45) 0.125 0.043(35) 0.105 0.044(35) 0.125 0.047(45) DAY 28 - DAY 35 0.081 0.045(45) 0.085 0.036(35) 0.056 0.065(35) 0.056# 0.039(45) DAY 35 - DAY 42 0.076 0.045(45) 0.052 0.039(35) 0.079 0.056(35) 0.071 0.038(45) DAY 42 - DAY 49 0.065 0.040(45) 0.069 0.039(35) 0.078 0.044(35) 0.060 0.039(45) DAY 49 - DAY 56 0.035 0.041(45) 0.043 0.039(35) 0.029 0.035(35) 0.036 0.039(45) DAY 56 - DAY 63 0.028 0.036(45) 0.018 0.029(35) 0.038 0.036(35) 0.029 0.033(45) DAY 63 - DAY 70 0.055 0.039(45) 0.045 0.046(35) 0.037# 0.044(35) 0.026# 0.040(45) DAY 0 -- DAY 70a 0.088 0.009(45) 0.084 0.010(35) 0.083# 0.009(35) 0.081# 0.010(45) - 106Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 11 (Continued) MEAN DAILY FOOD EFFICIENCY OF FEMALE RATS (g body weight gain/g food consumed) Group II Group IV Group VI Group VIII 0 mg/kg/day 25 mg/kg/day 100 mg/kg/day 500 mg/kg/day Dosing Period for Subchronic Toxicity Evaluation (continued) DAY 70 - DAY 77 0.026 0.043(25) 0.027 0.042(15) 0.013 0.045(15) 0.026 0.035(25) DAY 77 - DAY 84 0.029 0.043(25) 0.037 0.037(15) 0.054 0.025(15) 0.032 0.037(25) DAY 84 - DAY 91 0.013 0.043(24) 0.028 0.045(15) 0.009 0.031(15) 0.001 0.043 (25) DAY 0 - DAY 91 0.074 0.009(24) 0.070 0.011(15) 0.072 0.008(15) 0.065# 0.005(25) One-Month Recovery Period for Subchronic Toxicity Evaluation DAY 91 - DAY 98 0.046 0.057(14) 0.017 0.023(5) 0.019 0.038(5) DAY 98 - DAY 105 0.012 0.058(14) -0.033 0.194(5) 0.046 0.023(5) DAY 105 - DAY 112 0.073 0.040(14) 0.083 0.097(5) 0.050 0.063(5) DAY 112 - DAY 119 0.000 0.044(14) 0.034 0.030(5) -0.036 0.044 (5) 0.001# 0.047 (15) -0.021 0.154(15) 0.077 0.071(15) -0.108 0.318(15) DAY 91 - DAY 119 Data summarized as: 0.035 0.016(14) 0.032 0.013(5) Mean Standard Deviation (n) 0.021 0.027 (5) 0.006# 0.043(15) a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 70; data were not collected during the cohabitation periods. Food efficiency data from the gestation period are reported as part of the reproduction evaluation. # Statistically significant difference at p < 0.05 by Jonckheere -Terpstra trend test. -107Company Sanitized. Does not contain TSCA CBI Company Sanitized. Does not contain TSCA H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 12 Treatment Group Dose Animal Count SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS i 0 mg/kg/day 45 III 25 mg/kg/day 35 V 100 mg/kg/day 35 VII 500 mg/kg/day 45 Mass Inguen Incidence 0 0 0 1 Mean onset (Days) - - - 172 Eye Observations Dark Incidence 0 3 0 0 Mean onset (Days) - 110 - - Corneal Opacity/Opaque a Incidence 0 2 2 Mean onset (Days) - 154 130 0 - Exophthalmus Incidence Mean onset (Days) 0 - 011 " 14 42 Enophthalmus Incidence Mean onset (Days) 0 - 1 154 01 - 84 Closed/Partially Closed Incidence Mean onset (Days) 0 - 1 126 01 - 63 Wet Fur (Chin, Perineum) Incidence 0 0 0 3# Mean onset (Days) - - - 46 Ruffled Fur Incidence 1 0 0 0 Mean onset (Days) 14 - - - DuPont-5990 Company Sanitized. Does not contain TSCA CBI ) H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 12 (Continued) Treatment Group Dose Animal Count SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS I 0 mg/kg/day 45 Ill 25 mg/kg/day 35 V 100 mg/kg/day 35 VII 500 mg/kg/day 45 Carriage Low Incidence Mean onset (Days) Head Tilt Incidence Mean onset (Days) Abnormal Gait Hindiimb Incidence Mean onset (Days) Scab Inguen Incidence Mean onset (Days) General Teeth Observations Clipped Incidence Mean onset (Days) Maloccluded Incidence Mean onset (Days) Absent Incidence Mean onset (Days) 0 - 1 105 0 - 0 " 0 - 0 - 0 - 001 - - 112 000 --- 001 - - 74 001 - - 183 001 - - 118 02 - 11 0 - 01 - 14 0 - -109- DuPont-5990 Company.Sanitized. Does not contain TSCA CBI ) H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 12 (Continued) Treatment Group Dose Animal Count SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS I 0 mg/kg/day 45 Ill 25 mg/kg/day 35 V 100 mg/kg/day 35 VII 500 mg/kg/day 45 Breathing Observations Labored Incidence Mean onset (Days) Discharge Eye Incidence Mean onset (Days) Nose incidence Mean onset (Days) Mouth Clear Incidence Mean onset (Days) Mouth Red Incidence Mean onset (Days) Penis Red Incidence Mean onset (Days) Hair Loss Neck Incidence Mean onset (Days) 0 2 56 0 - 0 - 0 - 0 - 0 - 00 * 23 95 56 11 42 147 1 4# 70 58 01 - 13 00 -- 00 -- 1 63 4 74 1 168 14 # 39 1 22 1 49 1 77 - 110- DuPont-5990 Company Sanitized. Does not contain TSCA CBI )) H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_______________ TABLE 12 (Continued) Treatment Group Dose Animal Count SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS I 0 mg/kg/day 45 Ill 25 mg/kg/day 35 V 100 mg/kg/day 35 VII 500 mg/kg/day 45 Face Incidence Mean onset (Days) Ventral body Incidence Mean onset (Days) Thoracic Incidence Mean onset (Days) 0 - 0 - 0 - 011 - 28 56 001 --7 001 - - 49 Side Incidence 0 0 0 3# Mean onset (Days) - - - 49 Shoulder Incidence 1 0 0 1 Mean onset (Days) 49 - - 35 Perineum Incidence 0 0 0 4# Mean onset (Days) - - - 19 Lumbar Incidence 0 0 0 1 Mean onset (Days) - - - 35 Hindpaw Incidence 0 0 0 1 Mean onset (Days) - - - 49 -111- ) DuPont-5990 Company Sanitized. Does not contain TSCA H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 12 (Continued) Treatment Group Dose Animal Count SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS I 0 mg/kg/day 45 Ill 25 mg/kg/day 35 V 100 mg/kg/day 35 VII 500 mg/kg/day 45 Hindlimb Incidence Mean onset (Days) 0 - 012 - 49 56 Forepaw Incidence 14 5 5 9 Mean onset (Days) 56 22 57 66 Forelimb Incidence 6 1 4 7 Mean onset (Days) 57 49 47 78 Base of tail Incidence Mean onset (Days) 1 77 01 - 133 1 42 Abdomen Incidence 0 0 0 Mean onset (Days) - - - Wound Superficial (mouth, face, shoulders, perineum, forelimb, forepaw. hindpaws) incidence 1 2 2 Mean onset (Days) 11 27 81 Lethargic Incidence 0 0 0 Mean onset (Days) - - - oCO 7# 34 5 64 1 22 DuPont-5990 H-24768: 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 Animal Count I 0 mg/kg/day 45 Ill 25 mg/kg/day 35 V 100 mg/kg/day 35 VII 500 mg/kg/day 45 Hyperreactive Incidence 2 0 0 Mean onset (Days) 53 - Misshapen Observations Ear Incidence Mean onset (Days! 0 - 0 - 0_ Stain Fur/Skin Incidence 2 2 3 Mean onset (Days) 46 35 81 Swollen Observations Abdomen Incidence 0 0 0 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 group. 0 - 2 18 11 # 55 1 28 a. The observation "corneal opacity/opaque'' includes "Eye observations, corneal opacity, left" "Eye observations, corneal opacity, right" and "Eye observations, opaque, left." # statistically significant difference at p < 0.05 by Cochran-Armitage trend test. DuPont-5990 Company Sanitized. Does not contain TSCA CBi -113- Company Sanitized. Does not contain TSCA H-24768: 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 Animal Count II 0 mg/kg/day 45 Mass Perineum Incidence Mean onset (Days) Eye Observations Corneal Opacity / Opaque a 0 - Incidence Mean onset (Days) 2 124 Exophthalmus Incidence Mean onset (Days) 1 102 Enophthalmus Incidence Mean onset (Days) 2 144 Wet Fur (perineum, inguen) Incidence Mean onset (Days) 0 - Abnormal Gait Hindi imb Incidence Mean onset (Days) 0 - Discharge Eye incidence Mean onset (Days) 1 147 o CD IV 25 mg/kg/day 35 0 - VI 100 mg/kg/day 35 1 63 20 119 - 10 91 - 20 105 - 01 - 56 10 35 - 22 72 172 VIII 500 mg/kg/day 45 0 - 1 105 1 105 1 147 3# 73 0 - 0 - DuPont-5990 Company Sanitized. Does not contain TSCA CBI )) H-24768: 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 Animal Count Nose Incidence Mean onset (Days) Mouth Clear Incidence Mean onset (Days) Hair Loss Neck Incidence Mean onset (Days) Head Incidence Mean onset (Days) Ventral body Incidence Mean onset (Days) Thoracic Incidence Mean onset (Days) Side Incidence Mean onset (Days) Sacral Incidence Mean onset (Days) II 0 mg/kg/day 45 1 14 0 - 1 21 0 - 0 - 0 - 0 - 0 - IV 25 mg/kg/day 35 0 - VI 100 mg/kg/day 35 0 - 0 3# - 21 00 -- 0_ 0 - 00 -- 00 -- 00 -- 00 -- VIII 500 mg/kg/day 45 0 - 6# 33 0 - 1 140 6# 46 2 35 14 # 30 9# 52 -115- ) DuPont-5990 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 13 (Continued) Treatment Group Dose Animal Count SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS II 0 mg/kg/day 45 IV 25 mg/kg/day 35 VI 100 mg/kg/day 35 VIII 500 mg/kg/day 45 Perineum Incidence Mean onset (Days) Lumbar Incidence Mean onset (Days) Hindlimb Incidence Mean onset (Days) Forepaw incidence Mean onset (Days) Forelimb Incidence Mean onset (Days) Dorsal Body Incidence Mean onset (Days) Base of tail Incidence Mean onset (Days) Abdomen Incidence Mean onset (Days) 0 - 0 - 0 - 8 49 3 51 1 49 1 49 1 56 001 - - 21 002 - - 94 0 1 10 # " 70 41 8 3 10 39 95 60 679 38 51 57 2 9* 1 49 49 49 01 - 147 3 35 0 2 9# - 35 20 -116- DuPont-5990 Company Sanitized. Does not contain TSCA CBI )) H-24768: 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 Animal Count il 0 mg/kg/day 45 IV 25 mg/kg/day 35 VI 100 mg/kg/day 35 VIII 500 mg/kg/day 45 Wound Superficial (Lumbar, Hindlimb, Forepaws) Incidence Mean onset (Days) 1 21 1 21 03 - 69 Hyperreactive Incidence Mean onset (Days) 0 011 - 14 91 Hyperactive Incidence Mean onset (Days) 0 - 1 56 02 - 98 Misshapen Observations Tail Incidence 0 1 0 0 Mean onset (Days) - 84 - - Stain Fur/Skin Incidence 2 2 3 31 # Mean onset (Days) 49 72 50 52 Swollen Observations (toe,. forepaw) Incidence 0 0 0 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 group. a. The observation "corneal opacity/opaque" includes "Eye observations, corneal opacity, left," "Eye observations, corneal opacity, right,* "Eye observations, corneal opacity, bilateral," and "Eye observations, opaque, left." # Statistically significant difference at p < 0.05 by Cochran- Armitage trend test. Statistically significant difference at p < 0.05 by Fisher 's Exact test. 2 56 -117- ) DuPont-5990 H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 14 SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR MALE RATS Treatment Group Dose I 0 mg/kg/day III 25 mg/kg/day V 100 mg/kg/day VII 500 mg/kg/day Examination Day : Test Day 85 Number of Rats Examined 20 Retina Retinal Degeneration Focal Right Globe Phthisis Bulbi Left 0 0 10 1(10%) 00 10 0 20 1(5%) 1(5%) Incidence - The number of animals (percent of animals examined) for which an observation was recorded. There were no statistically significant differences at p < 0.05 by Cochran-Armitage trend test. Company Sanitized. Does not contain TSCA C8I -118- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 15 SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR FEMALE RATS Treatment Group Dose II 0 mg/kg/day IV 25 mg/kg/day VI 100 mg/kg/day VIII 500 mg/kg/day Examination Day : Test Day 85 Number of Rats Examined 20 Retina Retinal Degeneration Focal Left 0 10 10 20 0 0 1(5%) Incidence - The number of animals (percent of animals examined) for which an observation was recorded. There were no statistically significant differences at p < 0.05 by Cochran-Armitage trend test. Company Sanitized. Does not contain TSCA CBI -119- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 16 PERCENT SURVIVAL OF MALE RATS Treatment Group Dose (mg/kg/day) Animal Count at Study Start DAYS ON TEST 0 7 14 21 28 35 42 49 56 63 70 c 77 84 91 d'e 98 105 112 119 I 0 45 100 100 100 100 100 100 100 100 100 98 a 98 96 96 96 93 93 93 93 III 25 35 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 V 100 35 100 100 100 100 100 100 100 100 97 b 97 97 93 93 93 80 80 80 80 VII 500 45 100 100 100 100 100 96 96 96 96 96 96 93 93 93 88 88 88 88 Number at study start 45 35 Sacrificed in extremis 1 0 Found Dead 00 35 45 01 11 Removed from study Sacrificed by design 20 20 10 10 20 18 10 10 Alive on test day 119 14 5 4 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. a. Rat sacrificed in extremis during the previous week. b. Rat found dead during the previous week. c . Rats designated for reproduction evaluation were removed from study (cohoused) on test day 70. d. Recovery period began on test day 91. e. Rats designated for the 91-day exposure period were sacrificed on test days 95. There were no statistically significant decreases in survival at p < 0.05 by Cochran-Armitage trend test. Note: Rats added for evaluation of 10-day hepatic biochemical evaluations not included on this table. - 120Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Pay Gavage Study ip Rats with. One-Generation Reproduction Evaluations DuPont-5990 TABLE 17 PERCENT SURVIVAL OF FEMALE RATS Treatment Group Dose (mg/kg/day) Animal Count at Study Start II 0 45 IV VI 25 100 35 35 DAYS ON TEST 0 7 14 21 28 35 42 49 56 63 70 a 77 84 91 b'c 98 105 112 119 100 100 100 100 100 100 100 100 100 100 100 100 100 100 d 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 VIII 500 45 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 Number at study start 45 35 35 45 Accidentally killed 10 00 Removed from study b Sacrificed by design c Alive on test day 119 20 20 10 10 14 5 20 20 10 10 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 - number accidentally killed. a. Rats designated for reproduction evaluation were removed from study (cohoused) on test day 70. b. Recovery period began on test day 91. c. Rats designated for the 91-day exposure period were sacrificed on test day 96. d. Rat accidentally killed during the previous week. There were no statistically significant decreases in survival at p < 0.05 by Cochran-Armitage trend test. Note: Rats added for evaluation of 10-day hepatic biochemical evaluations not included on this table. -121 Company Sanitized. Does not contain TSCA CBi H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 18 MEAN FORELIMB AND HINDLIMB GRIP STRENGTH FOR MALE RATS (MEAN OF THREE TRIALS) Assessment Dosage Period Group (mg/kg/day) Forelimb Grip Strength (kg) Hindlimb Grip Strength (kg) Baseline I m V vn 0 25 100 500 0.53 (0.09) 0.55 (0.07) 0.52 (0.10) 0.54 (0.09) 0.33 (0.06) 0.33 (0.05) 0.30 (0.06) 0.31 (0.04) W eek 13 i m V vn 0 25 100 500 1.53(0.30) 1.37 (0.24) 1.33 (0.29) 1.15(0.32)* 0.85(0.10) 0.74 (0.11) 0.74 (0.15) 0.70 (0.13)* Recovery i vn 0 500 1.42(0.33) 1.28 (0.38) 0.82 (0.13) 0.70 (0.10)* Data arranged as: Mean (Standard Deviation) Statistically significant differences from control by One-way analysis o f variance followed by Dunnetf s test; p < 0.05. - 122Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 19 MEAN FORELIMB AND HINDLIMB GRIP STRENGTH FOR FEMALE RATS (MEAN OF THREE TRIALS) Assessment Dosage Period Group (mg/kg/day) Forelimb Grip Strength (kg) Hindlimb Grip Strength (kg) Baseline n IV VI vm 0 25 100 500 0.52(0.11) 0.54(0.11) 0.56 (0.08) 0.53 (0.06) 0.33 (0.06) 0.33 (0.07) 0.32(0.06) 0.33 (0.05) W eek 13 n IV VI vm 0 25 100 500 0.98 (0.17) 0.97 (0.16) 1.16(0.24) 0.97 (0.23) 0.68 (0.14) 0.62 (0.07) 0.62 (0.13) 0.61 (0.10) Recovery n vm 0 500 1.04(0.33) 0.93 (0.21) 0.71 (0.09) 0.62(0.11) Data arranged as: Mean (Standard Deviation) a Rat 646540 was uncooperative during forelimb grip strength. Data were omitted from summary tables and statistics. There were no statistically significant differences from control by one-way analysis o f variance followed by Dunnett's test; p < 0.05. -123Company Sanitized. Does not contain TSCA C8I H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 20 SUMMARY OF FUNCTIONAL OBSERVATIONAL BATTERY FINDINGS FOR MALE RATS Group: Dosage (mg/kg/day): Number Examined: Baseline_______ Im V VII 0 25 100 500 10 10 10 10 _______ Week 13_______ I m V VII 0 25 100 500 10 10 10 10 Recovery I VII 0 500 10 10 APPROACH & TOUCH: no reaction normal increased reaction (jumps away or attacks) 0000 10 10 10 10 0000 0000 10 10 10 10 0000 00 10 10 00 AUDITORY STIMULUS: no reaction normal reaction (rat flinches or flicks ear) exaggerated reaction (rat jumps, flips) 0000 10 10 10 10 0000 0 10 1 10 9 10 9 0000 00 10 10 00 TAIL PINCH: no response normal (turns toward site) exaggerated response 00 10 10 00 00 9 10 10 0 0 0 0 10 7 9 9 03 11 00 10 10 00 IN MOTOR ACTIVITY MONITOR: DEFECATION: present absent diarrhea 5535 54 7 5 0000 8568 2 54 2 0000 45 65 00 URINATION: present absent 5 8 8 10 5 12 0 9 9 9 10 1 1 10 10 10 00 PUPILLARY RESPONSE: present absent 10 10 10 10 0000 10 10 10 10 0000 10 10 00 -124Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats witb One-Generation Reproduction Evaluations DuPont-5990 TABLE 20 (Continued) SUMMARY OF FUNCTIONAL OBSERVATIONAL BATTERY FINDINGS FOR MALE RATS Group: Dosage (mg/kg/day): Number Examined: Baseline_______ I III V VII 0 25 100 500 10 10 10 10 _______ Week 13_______ I III V VII 0 25 100 500 10 10 10 10 Recovery I VII 0 500 10 10 ADDITIONAL OBSERVATIONS NOTED Sore left forelimb: Sore forelimb toes Stained perineum Abnormal gait 0000 0000 0000 0000 000 1 002 1 0 0 0 4* 00 10 00 00 00 00 * Statistically significant differences by Cochran-Armitage test for trend; p < 0.05. a For the baseline evaluation, urination and defecation were not recorded for one animal in Group III. -125Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 21 SUMMARY OF FUNCTIONAL OBSERVATIONAL BATTERY FINDINGS FOR FEMALE RATS Group: Dosage (mg/kg/day): Number Examined: Baseline_______ II IV VI VIII 0 25 100 500 10 10 10 10 _______ Week 13_______ n IV VI VIII 0 25 100 500 10 10 10 10 Recovery II VIII 0 500 10 10 APPROACH & TOUCH: no reaction normal increased reaction (jumps away or attacks) 0000 10 10 10 10 0000 0000 10 10 10 10 0000 00 10 10 00 AUDITORY STIMULUS: no reaction normal reaction (rat flinches or flicks ear) exaggerated reaction (rat jumps, flips) 0000 10 10 10 10 0000 0000 10 10 10 10 0000 00 10 10 00 TAIL PINCH: no response normal (turns toward site) exaggerated response 000 10 10 10 000 0 9 1 0000 10 10 10 10 0000 00 10 10 00 IN MOTOR ACTIVITY MONITOR: DEFECATION: present absent diarrhea 3523 7587 0000 3677 7433 0000 45 65 00 URINATION: present absent 9 7 87 13 23 8 10 20 9 10 10 10 10 00 PUPILLARY RESPONSE: present absent 10 10 10 10 0000 10 10 10 10 0000 10 10 00 ADDITIONAL OBSERVATIONS NOTED Stained perineum 0000 0 0 0 5* * Statistically significant difference by Cochran-Amritage test for trend; p < 0.05. 00 -126Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 22 MOTOR ACTIVITY ASSESSMENT: MEAN DURATION OF MOVEMENTS (sec) FOR MALE RATS DuPont-5990 ASSESSMENT DOSAGE PERIOD GROUP (mg/kg/day)______________________ SUCCESSIVE 10-MINUTE INTERVALS BASELINE 1 2 3 4 5 6 TOTAL I 0 366(25) 270(64) 2 ll(7 2 ) 108(105) 42(81) 28(69) 1025(307) III 25 366(52) 282(47) 182(67) 85(85) 57(77) 19(21) 992(270) V 100 354(63) 257(87) 164(106) 80(98) 45(54) 7(8) 907(310) VII 500 373(38) 269(68) 173(124) 86(73) 48(65) 12(14) 959(309) WEEK 13 I 2 3 4 5 6 TOTAL I 0 405(52) 310(100) 253(96) 260(78) 22(102) 165(97) 1613(461) III 25 385(47) 299(64) 293(57) 215(76) 235(64) 193(93) 1619(304) V 100 410(52) 322(72) 272(77) 222(97) 220(90) 188(63) 1633(356) VII 500 407(55) 335(39) 270(51) 241(101) 275(66) 241(75) 1767(330) RECOVERY 1 I 0 386(34) VII 500 389(61) Data arranged as: Mean (Standard Deviation). 2 294(65) 308(46) 3 249(60) 257(46) 4 230(60) 234(60) 5 171(81) 213(58) 6 149(106) 136(122) TOTAL 1478(283) 1536(293) Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Repeated measures analysis o f variance with linear contrasts or Jonckheere's trend test were used to identify which dosage groups, if any, were significantly different from the control group. These tests were applied to bin data and total data. There were no statistically significant differences from control; p < 0.05. Company Sanitized. Does not contain TSCA CBI -127- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 23 MOTOR ACTIVITY ASSESSMENT: MEAN DURATION OF MOVEMENTS (sec) FOR FEMALE RATS DuPont-5990 ASSESSMENT DOSAGE PERIOD GROUP (mg/kg/day)_____________________ SUCCESSIVE 10-MINUTE INTERVALS BASELINE 1 2 3 4 5 6 TOTAL II 0 363(57) 272(49) 214(73) 196(138) 131(136) 67(79) 1242(367) IV 25 374(42) 254(93) 192(98) 165(124) 130(132) 41(75) 1155(413) VI 100 353(51) 257(66) 203(83) 191(134) 130(104) 58(69) 1191(399) VIII 500 354(59) 261(59) 185(93) 102(86) 72(80) 47(53) 1020(302) WEEK 13 1 2 3 4 5 6 TOTAL II 0 416(33) 288(49) 251(72) 215(95) 213(95) 154(142) 1536(292) IV 25 399(47) 281(45) 194(55) 254(44) 196(79) 203(69) 1527(200) VI 100 390(58) 315(77) 236(103) 241(76) 229(73) 220(57) 1630(367) VIII 500 406(57) 305(43) 254(57) 223(75) 241(109) 207(69) 1636(305) RECOVERY 1 II 0 413(48) VIII 500 404(53) Data arranged as: Mean (Standard Deviation). 2 323(73) 301(85) 3 269(70) 258(52) 4 225(84) 223(88) 5 167(95) 214(63) 6 186(94) 180(73) TOTAL 1582(358) 1579(266) Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Repeated measures analysis o f variance with linear contrasts was used to identify which dosage groups, if any, were significantly different from the control group. These tests were applied to bin data and total data. There were no statistically significant differences from control; p < 0.05. Company Sanitized. Does not contain TSCA CBI -128- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 24 MOTOR ACTIVITY ASSESSMENT: MEAN NUMBER OF MOVEMENTS FOR MALE RATS DuPont-5990 ASSESSMENT DOSAGE PERIOD GROUP (mg/kg/day)_______________ SUCCESSIVE 10-MINUTE INTERVALS BASELINE 1 2 3 4 5 6 TOTAL I 0 135(12) 130(15) 119(20) 64(55) 27(40) 19(43) 494(147) III 25 145(12) 145(11) 110(35) 67(56) 40(50) 16(14) 523(129) V 100 127(18) 125(17) 94(53) 51(50) 40(46) 8(4) 445(135) VII 500 127(22) 124(24) 85(50) 51(46) 28(37) 8(5) 422(124) WEEK 13 1 2 3 4 5 6 TOTAL I 0 131(12) 128(25) 118(41) 117(24) 107(38) 89(44) 690(144) III 25 137(12) 140(15) 136(17) 118(31) 126(16) 110(37) 767(65) V 100 132(16) 134(10) 122(21) 111(40) 112(44) 104(25) 714(112) VII 500 125(30) 127(23) 117(28) 105(41) 111(20) 112(32) 697(137) RECOVERY 1 I 0 137(14) VII 500 127(14) Data arranged as: Mean (Standard Deviation). 2 134(22) 129(20) 3 129(19) 116(25) 4 126(21) 115(24) 5 103(39) 109(22) 6 87(56) 70(56) TOTAL 716(122) 665(121) Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Repeated measures analysis o f variance with linear contrasts or Jonckheere's trend test were used to identity which dosage groups, if any, were significantly different from the control group. These tests were applied to bin data and total data. There were no statistically significant differences from control; p < 0.05. Company Sanitized. Does not contain TSCA CBI -129- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 25 MOTOR ACTIVITY ASSESSMENT: MEAN NUMBER OF MOVEMENTS FOR FEMALE RATS DuPont-5990 ASSESSMENT DOSAGE PERIOD_______GROUP (mg/kg/day)______________________SUCCESSIVE 10-MINUTE INTERVALS BASELINE I 2 3 4 5 6 TOTAL II 0 128(28) 122(31) 110(40) 9l(4 8 ) 65(49) 37(46) 554(175) IV 25 126(12) 121(27) 94(36) 85(51) 67(61) 32(47) 524(168) VI 100 127(14) 120(17) 114(32) 91(46) 80(51) 43(41) 575(137) VIII 500 135(14) 130(16) 105(33) 70(41) 55(54) 44(46) 539(136) WEEK 13 II IV VI vm 0 25 100 500 1 123(18) 128(14) 133(27) 131(12) 2 12?(29) 129(17) 124(33) 132(12) 3 119(31) 114(24) 117(31) 130(14) 4 112(41) 126(19) 119(33) 116(23) 5 1lT(43) 113(33) 120(35) 118(31) 6 72(53) 118(29)* 124(25)* 121(24)* TOTAL 658(145) 728(56) 737(157) 747(63) RECOVERY ii VIII 0 500 1 121(22) 130(11) Data arranged as: Mean (Standard Deviation). 2 128(25) 139(10) 3 128(29) 126(26) 4 116(33) 119(25) 5 97(46) 125(27) 6 104(39) 119(27) TOTAL 694(156) 757(49) Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Repeated measures analysis o f variance with linear contrasts was used to identify which dosage groups, if any, were significantly different from the control group. These tests were applied to bin data and total data. * Statistically significant difference from control; p < 0.05. Company Sanitized. Does not contain TSCA CBI -130- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 26 TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I 0 mg/kg/day Group HI Group V Group VH 25 mg/kg/day 100 mg/kg/day 500 mg/kg/day RBC (x106/ju.L) DAY 39 DAY 95 DAY 123 DAY 183 HGB (g/dL) DAY 39 DAY 95 DAY 123 DAY 183 HCT (%) DAY 39 DAY 95 DAY 123 DAY 183 MCV (fl) DAY 39 DAY 95 DAY 123 DAY 183 8.11 0.35(10) 8.63 0.43(10) 8.62 0.42(9) 8.79 0.62(3) 14.9 0.5(10) 15.4 0.6(10) 15.3 0.6(9) 15.4 0.4(3) 47.9 1.7(10) 47.4 2.0(10) 45.9 1.4(9) 46.7 0.4(3) 59.1 1.4(10) 54.9 1.3(10) 53.4 2.0(9) 53.2 3.4(3) 7.94 0.32(10) 8.60 0.40(10) a 8.71 0.21(5) 14.8 0.4(10) 15.3 0.6(10) a 15.5 0.7(5) 47.6 1.2(10) 46.8 1.7(10) a 46.9 1.7(5) 60.1 1.0(10) 54.5 1.4(10) a 53.9 2.6(5) 8.04 0.21(10) 8.50 0.49(10) a 8.59 0.43(4) 14.7 0.5(10) 14.7* 0.6(10) a 15.1 0.6(4) 47.2 1.4(10) 45.7 2.0(10) a 46.4 3.0(4) 58.7 2.1(10) 53.9 1.8(10) a 54.0 1.0(4) 8.25 0.33(10) 8.85 0.38(10) 8.33 0.40(10) 8.50 0.53(4) 14.3* 0.3(10) 14.2* 0.3(10) 14.5* 0.4(10) 15.2 0.7(4) 45.9* 1.2(10) 44.4* 1.1(10) 44.2* 1.8(10) 46.8 3.1(4) 55.7* 1.6(10) 50.3* 2.1(10) 53.1 2.2(10) 55.2 3.7(4) -131Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 26 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I 0 mg/kg/day Group in 25 mg/kg/day Group V Group VH 100 mg/kg/day 500 mg/kg/day MCH (pg) DAY 39 DAY 95 DAY 123 DAY 183 MCHC (g/dL) DAY 39 DAY 95 DAY 123 DAY 183 RDW (%) DAY 39 DAY 95 DAY 123 DAY 183 ARET (x l0 3//iL) DAY 39 DAY 95 DAY 123 DAY 183 18.3 0.5(10) 17.9 0.4(10) 17.8 0.7(9) 17.7 1.7(3) 31.0 0.4(10) 32.5 0.4(10) 33.4 0.4(9) 33.1 1.0(3) 11.1 0.5(10) 13.4 0.9(10) 12.7 0.4(9) 13.7 0.2(3) 200 29(10) 191 34(10) 187 38(9) 151 8(3) 18.6 0.6(10) 17.8 0.4(10) a 17.8 1.1(5) 31.0 0.6(10) 32.7 0.3(10) a 33.0 0.9(5) 11.5 0.8(10) 13.7 0.9(10) a 13.6 0.6(5) 228 96(10) 184 33(10) a 170 35(5) 18.4 0.7(10) 17.3 0.5(10) a 17.6 0.5(4) 31.3 0.4(10) 32.2 0.4(10) a 32.6 1.1(4) 11.5 0.3(10) 14.3* 0.5(10) a 14.7 0.8(4) 212 32(10) 235 48(10) a 181 42(4) 17.4* 0.6(10) 16.0* 0.7(10) 17.5 0.7(10) 17.9 1.3(4) 31.2 0.4(10) 31.9* 0.7(10) 33.0 0.6(10) 32.5 1.1(4) 12.1* 0.7(10) 15.0* 0.8(10) 16.5* 1.3(10) 13.6 0.5(4) 220 53(10) 252@ 48(10) 222* 33(10) 187 29(4) -132 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 26 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I 0 mg/kg/day Group in 25 mg/kg/day Group V Group VR 100 mg/kg/day 500 mg/kg/day PLT (xlOVjttL) DAY 39 DAY 95 DAY 123 DAY 183 WBC (xlOVjttL) DAY 39 DAY 95 DAY 123 DAY 183 ANEU (xlOVjttL) DAY 39 DAY 95 DAY 123 DAY 183 ANPR (xlOV/iL) DAY 39 DAY 95 DAY 123 1013 146(10) 1121 201(5) 1097 76(4) 1047 194(3) 13.82 2.18(10) 12.76 6.81(10) 11.46 4.47(9) 9.36 1.39(3) 1.50 0.42(10) 3.33 5.64(10) 1.99 1.80(9) 1.90 0.14(3) b b b 1084 162(8) 1099 171(8) a 1084 69(5) 16.15 3.37(10) 12.37 3.15(10) a 9.11 1.30(5) 1.88 0.56(10) 1.99 0.40(10) a 1.64 0.63(5) b b a 1024 93(8) 1163 122(9) a 1164 205(2) 15.42 1.74(10) 11.66 1.87(10) a 10.32 1.90(4) 1.79 0.50(10) 1.79 0.45(10) a 2.33 0.21(4) b b a 1028 133(9) 1246 158(8) 1209 127(7) 1105 110(4) 16.14 2.38(10) 12.31 1.89(10) 11.76 2.48(10) 11.45 3.31(4) 1.55 0.30(10) 1.93 0.43(10) 2.02@ 0.49(10) 2.01 0.53(4) b b b -133 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 26 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I 0 mg/kg/day Group IH 25 mg/kg/day Group V Group VH 100 mg/kg/day 500 mg/kg/day ALYM (x l0 3/juL) DAY 39 DAY 95 DAY 123 DAY 183 AMON (xlOV/tL) DAY 39 DAY 95 DAY 123 DAY 183 AEOS (x l0 3//iL) DAY 39 DAY 95 DAY 123 DAY 183 ABAS (x l0 3//i.L) DAY 39 DAY 95 DAY 123 DAY 183 11.61 2.30(10) 8.69 2.45(10) 8.86 3.06(9) 6.73 1.29(3) 0.30 0.08(10) 0.30 0.23(10) 0.30 0.15(9) 0.32 0.10(3) 0.12 0.06(10) 0.14 0.05(10) 0.11 0.06(9) 0.13 0.04(3) 0.16 0.04(10) 0.11 0.06(10) 0.10 0.06(9) 0.13 0.11(3) 13.38 3.12(10) 9.68 2.73(10) a 7.02 1.32(5) 0.43* 0.08(10) 0.29 0.11(10) a 0.16 0.04(5) 0.11 0.04(10) 0.15 0.08(10) a 0.11 0.04(5) 0.17 0.02(10) 0.10 0.05(10) a 0.08 0.04(5) 12.67 1.43(10) 9.18 1.74(10) a 7.49 1.93(4) 0.50* 0.12(10) 0.29 0.06(10) a 0.20 0.05(4) 0.13 0.07(10) 0.16 0.06(10) a 0.11 0.02(4) 0.16 0.05(10) 0.09 0.03(10) a 0.09 0.02(4) 13.60 2.20(10) 9.63 1.77(10) 9.14 2.21(10) 8.87 3.30(4) 0.52* 0.16(10) 0.28 0.08(10) 0.28 0.10(10) 0.30 0.14(4) 0.15 0.05(10) 0.17 0.06(10) 0.12 0.07(10) 0.09 0.06(4) 0.16 0.05(10) 0.12 0.07(10) 0.09 0.05(10) 0.10 0.10(4) -134 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations _________________ DuPont-5990 TABLE 26 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I 0 mg/kg/day Group m 25 mg/kg/day Group V Group VU 100 mg/kg/day 500 mg/kg/day ALUC (xlOVjtcL) DAY 39 DAY 95 DAY 123 DAY 183 ABLT (x KP/jkL) DAY 39 DAY 95 DAY 123 DAY 183 0.14 0.04(10) 0.20 0.14(10) 0.10 0.09(9) 0.15 0.05(3) b b b b 0.18 0.05(10) 0.17 0.05(10) a 0.11 0.02(5) b b a b 0.17 0.05(10) 0.16 0.06(10) a 0.10 0.06(4) b b a b 0.17 0.03(10) 0.18 0.05(10) 0.10 0.04(10) 0.09 0.06(4) b b b c AMSC (xlOV/iL) DAY 39 b bbb DAY 95 bbbb DAY 123 b a a b AHSN (xlOV/tL) DAY 183 b b b c ABAN (xlOVjuL) DAY 183 b b b c AMET (xlOV/rL) DAY 183 b b b c AMYE (xl03/fiL) DAY 183 b b b c APRO (xlOVgL) DAY 183 b b b c AMYB (xlOVjtL) DAY 183 b b b c -135 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 26 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I 0 mg/kg/day Group DI 25 mg/kg/day Group V Group VII 100 mg/kg/day 500 mg/kg/day ARL (xlOVjuL) DAY 183 b b b c AAL (xlOV/tL) DAY 183 b b b c AIL (x l0 3//aL) DAY 183 b b b c ACL (x l0 3//tL) DAY 183 b b b c ABLB (x l0 3/gL) DAY 183 b b b c AJOE (x l0 3//iL) DAY 183 b b b c AIM (x l0 3//iL) DAY 183 b b b c APLA (xlOV^iL) DAY 183 b b b c Data arranged as: Mean Standard deviation (Number o f values included in calculation) a Measurements for this group at this timepoint were not taken or not performed. b Measurements for these cells are determined either by instrument or microscopic examination. Microscopic slide review indicated no cells o f this type; therefore, the instrument count was accepted and no manual count was performed. Individual data are reported in the Clinical Pathology appendix, c When this analysis was performed, valid measurements were taken on only 1 animal from the group. Data from this small sample size did not add value to this summary table. Individual data are reported in the Clinical Pathology appendix. * 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). -136Company Sanitized. Does not contain TSCA C8I H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations______________________ DuPont-5990 TABLE 27 TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Group II 0 mg/kg/day Group IV 25 mg/kg/day Group VI Group VUI 100 mg/kg/day 500 mg/kg/day RBC (xlO%iL) DAY 40 DAY 96 DAY 124 DAY 183 HGB (g/dL) DAY 40 DAY 96 DAY 124 DAY 183 HCT (%) DAY 40 DAY 96 DAY 124 DAY 183 MCV (fl) DAY 40 DAY 96 DAY 124 DAY 183 7.81 0.53(10) 7.91 0.76(10) 8.17 0.45(10) 7.99 0.16(3) 14.7 0.6(10) 15.0 0.9(10) 15.1 0.7(10) 15.3 0.4(3) 45.6 2.0(10) 44.6 2.7(10) 46.0 2.8(10) 44.7 0.2(3) 58.6 2.6(10) 56.6 3.0(10) 56.3 2.3(10) 55.9 1.4(3) 7.86 0.30(10) 7.66 0.37(9) a 7.97 0.43(4) 14.8 0.6(10) 14.5 0.7(9) a 15.5 0.6(4) 46.3 1.6(10) 43.6 1.8(9) a 46.3 1.7(4) 58.9 1.5(10) 56.9 2.0(9) a 58.2 1.6(4) 7.30* 0.38(10) 7.20@ 0.49(10) a 7.89 0.38(2) 13.8* 0.6(10) 13.5* 1.0(10) a 14.4 0.1(2) 43.2* 1.9(10) 40.6* 2.7(10) a 42.7 0.8(2) 59.2 1.4(10) 56.4 2.0(10) a 54.1 1.6(2) 7.26* 0.35(9) 7.03@ 0.61(10) 8.04 0.52(10) 8.06 0.26(3) 13.3* 0.7(9) 12.7* 1.1(10) 14.7 0.9(10) 14.9 0.8(3) 42.6* 2.7(9) 38.7* 3.4(10) 44.5 2.9(10) 44.7 1.9(3) 58.6 1.9(9) 55.1 1.7(10) 55.5 1.6(10) 55.5 2.0(3) -137Compiny Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity . ,,, , ^ ,, nAA 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations______________________ DuPont-5990 TABLE 27 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Group II Omg/kg/day Group IV 25 mg/kg/day Group VI Group VIH 100 mg/kg/day 500 mg/kg/day MGH (pg) DAY 40 DAY 96 DAY 124 DAY 183 MCHC (g/dL) DAY 40 DAY 96 DAY 124 DAY 183 RDW (%) DAY 40 DAY 96 DAY 124 DAY 183 ARET (xlOV/tL) DAY 40 DAY 96 DAY 124 DAY 183 18.9 0.7(10) 19.1 1.0(10) 18.5 0.4(10) 19.1 0.8(3) 32.2 0.5(10) 33.7 0.3(10) 32.9 0.7(10) 34.2 0.6(3) 11.3 1.0(10) 11.7 1.0(10) 12.0 0.4(10) 12.5 0.8(3) 199 37(10) 168 24(10) 164 26(10) 156 26(3) 18.9 0.6(10) 19.0 0.8(9) a 19.5 0.4(4) 32.1 0.5(10) 33.3 0.3(9) a 33.5 0.3(4) 11.1 0.4(10) 11.8 0.4(9) a 12.2 0.7(4) 190 35(10) 168 25(9) a 155 15(4) 18.9 0.6(10) 18.8 0.5(10) a 18.2 0.8(2) 31.9 0.5(10) 33.3 0.7(10) a 33.7 0.5(2) 11.7 0.6(10) 12.9@ 0.9(10) a 12.1 0.2(2) 240 55(10) 187 32(10) a 152 22(2) 18.3 0.6(9) 18.0@ 0.5(10) 18.3 0.5(10) 18.5 0.9(3) 31.3* 0.8(9) 32.7* 0.4(10) 33.0 0.7(10) 33.4 0.5(3) 12.6@ 0.7(9) 14.5@ 1.2(10) 13.0* 0.8(10) 12.5 0.5(3) 252* 37(9) 225* 43(10) 148 28(10) 167 18(3) -138Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 27 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS TEST/ Group II PERIOD_____________ Omg/kg/day Group IV 25 mg/kg/day Group VI Group VIE lOOmg/kg/day 500mg/kg/day PLT (xlOVpL). DAY 40 DAY 96 DAY 124 DAY 183 WBC (xlOVjuL) DAY 40 DAY 96 DAY 124 DAY 183 ANEU (xlOVptL) DAY 40 DAY 96 DAY 124 DAY 183 ANPR (xlOVjttL) DAY 40 DAY 96 DAY 124 1119 113(9) 904 354(7) 932 188(5) 1084 130(3) 10.78 2.70(10) 8.97 1.36(10) 8.68 2.41(10) 8.14 0.60(3) 1.12 0.49(10) 0.99 0.28(10) 1.15 0.35(10) 1.58 0.43(3) b c b 1242 154(7) 1094 154(7) a 920 24(2) 13.12 3.36(10) 10.13 3.30(9) a 7.13 1.05(4) 1.76@ 0.59(10) 1.40 0.54(9) a 1.23 0.39(4) b b a 1175 126(6) 1180 179(8) a 1308 32(2) 13.74 2.52(10) 10.02 1.65(10) a 6.48 2.43(2) 1.51 0.66(10) 1.17 0.47(10) a 1.47 0.81(2) b b a 1291 160(5) 1326@ 165(6) 1025 183(6) 1708* NC(1) 14.52@ 2.16(9) 10.54 1.69(10) 7.43 1.82(10) 8.83 2.93(3) 1.35 0.26(9) 1.22 0.52(10) 1.31 0.58(10) 1.95 0.29(3) b b b -139 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 27 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Group II 0 mg/kg/day Group IV 25 mg/kg/day Group VI Group VIH 100 mg/kg/day 500 mg/kg/day ALYM (xlOVpL) DAY 40 DAY 96 DAY 124 DAY 183 AMON (xlOVfiL) DAY 40 DAY 96 DAY 124 DAY 183 AEOS (x l0 3/jtlL) DAY 40 DAY 96 DAY 124 DAY 183 ABAS (xlOVjuL) DAY 40 DAY 96 DAY 124 DAY 183 9.02 2.48(10) 7.36 1.44(10) 7.07 2.27(10) 6.01 0.23(3) 0.26 0.10(10) 0.29 0.19(10) 0.21 0.06(10) 0.22 0.02(3) 0.11 0.06(10) 0.10 0.06(10) 0.09 0.04(10) 0.16 0.06(3) 0.10 0.04(10) 0.11 0.04(10) 0.10 0.07(10) 0.08 0.06(3) 10.55 2.84(10) 7.98 2.68(9) a 5.41 1.05(4) 0.40* 0.17(10) 0.37 0.23(9) a 0.18 0.06(4) 0.13 0.08(10) 0.11 0.05(9) a 0.11 0.04(4) 0.12 0.04(10) 0.12 0.04(9) a 0.09 0.05(4) 11.41 2.06(10) 8.17 1.58(10) a 4.66 1.46(2) 0.36 0.09(10) 0.29 0.08(10) a 0.18 0.01(2) 0.13 0.06(10) 0.14 0.06(10) a 0.09 0.06(2) 0.15 0.06(10) 0.08 0.04(10) a 0.03 0.04(2) 12.35@ 2.11(9) 8.67 1.44(10) 5.65 1.42(10) 6.26 3.01(3) 0.39* 0.07(9) 0.27 0.06(10) 0.23 0.13(10) 0.26 0.09(3) 0.12 0.05(9) 0.13 0.05(10) 0.09 0.03(10) 0.14 0.02(3) 0.12 0.04(9) 0.08 0.03(10) 0.07 0.04(10) 0.10 0.08(3) -140Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 27 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS TEST/ Group II PERIOD_____________ Omg/kg/day Group IV 25mg/kg/day Group VI Group VIH lOOmg/kg/day 500 mg/kg/day ALUC (x l0 3//UL) DAY 40 DAY 96 DAY 124 DAY 183 ABLT (xlOVfiL) DAY 40 DAY 96 DAY 124 DAY 183 0.17 0.10(10) 0.13 0.05(10) 0.07 0.03(10) 0.09 0.03(3) b c b b 0.16 0.05(10) 0.15 0.05(9) a 0.10 0.03(4) b b a b 0.18 0.06(10) 0.18 0.05(10) a 0.06 0.08(2) b -b a c 0.19 0.06(9) 0.17 0.06(10) 0.07 0.03(10) 0.11 0.06(3) D b b b AMSC (xlOV/iL) DAY 40 bbD D DAY 96 cb bb DAY 124 b a a b AHSN (xlOVjtiL) DAY 183 b 0 c b ABAN (x l0 3//xL) DAY 183 b b c b AMET (x l0 3/ju.L) DAY 183 b b c b AMYE (xl03/fiL) DAY 183 b b c b APRO (x l0 3//xL) DAY 183 b b c b AMYB (xlOVjaL) DAY 183 b b c b -141 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 27 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Group II Omg/kg/day Group IV 25 mg/kg/day Group VI Group VDI 100 mg/kg/day 500mg/kg/day ARL (xlOV/tL) DAY 183 b b c b AAL (x l0 3//rL) DAY 183 b b c b AIL (xl03//tL) DAY 183 b b c b ACL (xlOVfiL) DAY 183 b b c b ABLB (x l0 3//iL) DAY 183 b b c b AIE (x 103/ptL) DAY 183 b b c b AIM (xlOVjuL) DAY 183 b b c b APLA (x l0 3//zL) DAY 183 b b c b Data arranged as: Mean Standard deviation (Number o f values included in calculation) a Measurements for this group at this timepoint were not taken or not performed. b Measurements for these cells are determined either by instrument or microscopic examination. Microscopic slide review indicated no cells o f this type; therefore, the instrument count was accepted and no manual count was performed. Individual data are reported in the Clinical Pathology appendix. c When this analysis was performed, valid measurements were taken on only 1 animal from the group. Data from this small sample size did not add value to this summary table. Individual data are reported in the Clinical Pathology appendix.* * 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 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 28 SUMMARY OF COAGULATION VALUES FOR MALE RATS TEST/ Group I PERIOD_____________ Omg/kg/day Group HI 25mg/kg/day Group V Group VH 100mg/kg/day 500mg/kg/day PT (seconds) DAY 95 DAY 123 APTT (seconds) DAY 95 DAY 123 15.7 1.2(9) 14.9 0.9(10) 20.1 2.1(9) 20.1 2.3(10) 15.3 0.5(10) a 18.6 2.2(10) a 14.8 0.8(10) a 16.5** 1.9(10) 15.2 1.2( 10) 14.8 ' 0.8( 10) 15.6* 1.8( 10) 19.7 1.7(10) Data arranged as: Mean Standard deviation (Number o f values included in calculation) a Measurements for this group at this timepoint were not taken or not performed. * Statistically significant difference from control at p < 0.05 by parametric test (Dunnetl/Tamhane-Dunnett). -143 Company Sanitized. Does not contain TSCA CB1 H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 29 SUMMARY OF COAGULATION VALUES FOR FEMALE RATS TEST/ Group II PERIOD_____________ Omg/kg/day Group IV 25mg/kg/day Group VI Group VTH lOOmg/kg/day 500mg/kg/day PT (seconds) DAY 96 DAY 124 APTT (seconds) DAY 96 DAY 124 14.6 0.7(9) 13.9 0.5(9) 18.4 1.6(9) 17.7 1.8(9) 14.5 0.6(10) a 17.8 1.6(10) a 14.2 0.4(10) a 17.2 1.9(10) a 13.7* 0.4(10) 13.8 0.3(10) 15.0@ 2.5(10) 18.1 2.7(10) Data arranged as: Mean Standard deviation (Number o f values included in calculation) a Measurements for this group at this timepoint were not taken or not performed. * 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). -144Company Sanitized. Does not contain TSCA C8I H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 30 SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group I 0 mg/kg/day Group HI 25 mg/kg/day Group V Group VH 100 mg/kg/day 500 mg/kg/day AST (U/L) DAY 39 DAY 95 DAY 123 DAY 183 ALT (U/L) DAY 39 DAY 95 DAY 123 DAY 183 SDH (U/L) DAY 39 DAY 95 DAY 123 DAY 183 ALKP (U/L) DAY 39 DAY 95 DAY 123 DAY 183 89 22(10) 84 7(10) 103 37(10) 101 18(4) 36 6(10) 33 6(10) 41 14(10) 34 6(4) 19.7 5.3(10) 22.3 6.3(10) 19.4 6.2(10) 11.5 5.2(4) 139 34(10) 90 16(10) 80 14(10) 79 18(4) 78 16(10) 90 14(10) a 100 25(5) 33 3(10) 36 13(10) a 53 31(5) 20.1 3.3(10) 25.3 7.1(10) a 18.1 4.7(5) 128 25(10) 80 13(10) a 98 21(5) 71 9(10) 80 8(10) a 94 14(4) 38 8(10) 37 4(10) a 50 20(4) 20.5 2.4(10) 27.7 5.7(10) a 18.4 2.9(4) 126 17(10) 85 15(10) a 89 18(4) 74 9(10) 79 13(10) 108 28(10) 118 43(5) 59* 14(10) 50@ 8(10) 53* 10(10) 66@ 31(5) 26.9 11.5(10) 29.1@ 4.5(10) 42.5* 9.2(10) 25.4* 6.2(5) 174 48(10) 128 46(10) 75 12(10) 84 16(5) -145Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 30 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS TEST/ Group I PERIOD_____________ Omg/kg/day Group m 25mg/kg/day Group V Group VII lOOmg/kg/day 500mg/kg/day BILI (mg/dL) DAY 39 DAY 95 DAY 123 DAY 183 BUN (mg/dL) DAY 39 DAY 95 DAY 123 DAY 183 CREA (mg/dL) DAY 39 DAY 95 DAY 123 DAY 183 CHOL (mg/dL) DAY 39 DAY 95 DAY 123 DAY 183 0.08 0.03(10) 0.12 0.03(10) 0.14 0.03(10) 0.10 0.03(4) 14 1(10) 16 3(10) 16 2(10) 17 2(4) 0.32 0.04(10) 0.38 0.06(10) 0.43 0.04(10) 0.43 0.08(4) 64 9(10) 74 12(10) 72 10(10) 91 37(4) 0.06 0.03(10) 0.11 0.05(10) a 0.08 0.04(5) 14 2(10) 17 2(10) a 15 3(5) 0.34 0.03(10) 0.41 0.04(10) a 0.40 0.06(5) 66 14(10) 85 22(10) a 80 36(5) 0.09 0.04(10) 0.15 0.06(10) a 0.05 0.00(4) 15 2(10) 19@ 3(10) a 14 1(4) 0.36 0.06(10) 0.47* 0.05(10) a 0.38 0.06(4) 100@ 12(10) 112* 29(10) a 83 22(4) 0.20@ 0.05(10) 0.24* 0.05(10) 0.14 0.02(10) 0.06 0.02(5) 20* 3(10) 20@ 2(10) 20 5(10) 18 1(5) 0.40* 0.06(10) 0.42 0.05(10) 0.42 0.04(10) 0.47 0.08(5) 102@ 36(10) 109* 30(10) 87 20(10) 80 25(5) -146Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 30 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group I 0 mg/kg/day Group III 25 mg/kg/day Group V Group VE 100 mg/kg/day 500 mg/kg/day TRIG (mg/dL) DAY 39 DAY 95 DAY 123 DAY 183 GLUC (mg/dL) DAY 39 DAY 95 DAY 123 DAY 183 TP (g/dL) DAY 39 DAY 95 DAY 123 DAY 183 ALB (g/dL) DAY 39 DAY 95 DAY 123 DAY 183 63 22(10) 85 39(10) 72 32(10) 74 37(4) 101 8(10) 98 12(10) 117 25(10) 93 7(4) 6.5 0.3(10) 7.2 0.3(10) 6.9 0.2(10) 7.4 0.4(4) 4.1 0.2(10) 4.3 0.3(10) 4.1 0.2(10) 4.5 0.2(4) 71 32(10) 90 48(10) a 115 33(5) 102 5(10) 98 8(10) a 100 23(5) 6.6 0.3(10) 7.3 0.3(10) a 7.2 0.3(5) 4.3 0.1(10) 4.6* 0.2(10) a 4.2 0.4(5) 35@ 10(10) 45 17(10) a 125 56(4) 96 8(10) 102 13(10) a 105 12(4) 7.0* 0.4(10) 8.0* 0.3(10) a 7.5 0.3(4) 4.6* 0.2(10) 5.1* 0.2(10) a 4.4 0.2(4) 28@ 6(10) 26@ 5(10) 72 35(10) 82 23(5) 97 7(10) 95 5(10) 112 24(10) 116 21(5) 7.3* 0.4(10) 8.2* 0.3(10) 7.6* 0.2(10) 7.5 0.3(5) 5.1* 0.2(10) 5.5* 0.3(10) . 4.7* 0.2(10) 4.4 0.3(5) -147Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 30 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group I 0 mg/kg/day Group El 25 mg/kg/day Group V Group VH 100 mg/kg/day 500 mg/kg/day GLOB (g/dL) DAY 39 DAY 95 DAY 123 DAY 183 CALC (mg/dL) DAY 39 DAY 95 DAY 123 DAY 183 IPHS (mg/dL) DAY 39 DAY 95 DAY 123 DAY 183 NA (mmol/L) DAY 39 DAY 95 DAY 123 DAY 183 2.3 0.2(10) 2.9 0.4(10) 2.7 0.1(10) 3.0 0.3(4) 11.1 0.4(10) 10.7 0.4(10) 10.9 0.3(10) 10.1 0.5(4) 8.9 0.7(10) 7.2 0.5(10) 8.0 0.6(10) 6.9 0.4(4) 146.4 1.1(10) 149.1 0.7(10) 146.8 1.6(10) 146.7 1.4(4) 2.3 0.2(10) 2.7 0.1(10) a 3.0 0.3(5) 11.2 0.4(10) 10.9 0.5(10) a 10.3 0.2(5) 8.9 0.3(10) 7.7 0.6(10) a 6.9 0.6(5) 146.2 1.3(10) 148.7 1.1(10) a 148.2 0.9(5) 2.5 0.3(10) 2.9 0.2(10) a 3.2 0.2(4) 11.7* 0.5(10) 11.3* 0.4(10) a 10.4 0.4(4) 9.4 0.6(10) 8.1* 0.8(10) a 7.5 0.9(4) 145.6 0.9(10) 148.5 1.3(10) a 148.1 2.4(4) 2.3 0.2(10) 2.7 0.1(10) 2.9* 0.1(10) 3.1 0.2(5) 11.7* 0.4(10) 11.5* 0.4(10) 11.3* 0.3(10) 10.6 0.3(5) 9.0 0.4(10) 8.0* 0.8(10) 9.3* 0.9(10) 8.9 2.0(5) 143.8@ 1.2(10) 146.2* 1.3(10) 146.6 1.7(10) 150.1* 2.1(5) -148 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 30 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group I 0 mg/kg/day Group in 25 mg/kg/day Group V Group VH 100 mg/kg/day 500 mg/kg/day K (mmol/L) DAY 39 DAY 95 DAY 123 DAY 183 CL (mmol/L) DAY 39 DAY 95 DAY 123 DAY 183 PFLU (jttg/mL) DAY 39 DAY 95 DAY 123 DAY 183 6.01 0.27(10) 5.88 0.18(10) 6.37 0.48(10) 6.17 0.37(4) 97.8 1.2(10) 99.0 1.7(10) 102.8 1.4(10) 99.6 1.6(4) a 0.1 0.0(10) 0.1 0.1(10) 0.1 0.0(4) 6.07 0.35(10) 6.06 0.32(10) a 6.03 0.24(5) 98.1 1.9(10) 99.9 2.0(10) a 100.8 1.5(5) a 0.2 0.1(10) a 0.1 0.0(5) 6.62* 0.51(10) 6.66@ 0.48(10) a 6.52 0.46(4) 97.0 1.8(10) 98.7 2.0(10) a 101.8 2.3(4) a 0.2@ 0.0(10) a 0.1 0.0(4) 6.75* 0.33(10) 6.57@ 0.55(10) 6.61 0.68(10) 6.47 0.44(5) 95.8* 1.5(10) 97.7 1.5(10) 101.2* 1.6(10) 103.6 3.8(5) a 0.5@ 0.1(10) 0.1 0.0(10) 0.1 0.0(5) Data arranged as: Mean Standard deviation (Number o f values included in calculation) a Measurements for this group at this timepoint were not taken or not performed. * 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). -149Company Sanitized. Does not contain TSCA CBJ H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 31 SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD Group II 0 mg/kg/day Group IV 25 mg/kg/day Group VI Group Vin 100 mg/kg/day 500 mg/kg/day AST (U/L) DAY 40 DAY 96 DAY 124 DAY 183 ALT (U/L) DAY 40 DAY 96 DAY 124 DAY 183 SDH (U/L) DAY 40 DAY 96 DAY 124 DAY 183 ALKP (U/L) DAY 40 DAY 96 DAY 124 DAY 183 84 15(10) 128 85(10) 117 56(10) 110 43(4) 36 7(10) 66 63(10) 62 37(10) 47 26(4) 20.4 2.8(10) 24.7 16.1(10) 25.1 6.2(10) 13.9 4.6(4) 85 18(10) 45 12(10) 39 10(10) 33 9(4) 93 17(10) 106 65(10) a 79 22(5) 41 11(10) 50 34(10) a 39 8(5) 20.8 5.4(10) 21.9 11.4(10) a 11.9 2.6(5) 92 20(10) 46 9(10) a 36 14(5) 73 16(10) 75 20(10) a 92 23(5) 45 11(10) 40 7(10) a 44 16(5) 18.3 1.9(10) 16.7 3.5(10) a 16.7 3.9(5) 86 21(10) 51 18(10) a 27 6(5) 75 13(10) 79 29(10) 90 18(10) 118 35(5) 59@ 13(10) 48 9(10) 34@ 8(10) 51 26(5) 18.8 2.6(10) 18.6 4.8(10) 28.1 13.5(10) 18.2 7.5(5) 148@ 62(10) 93 @ 42(10) 36 12(10) 44 14(5) -150Company Sanitized. Does not contain TSCA CBi H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations _________________ DuPont-5990 TABLE 31 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD Group II 0 mg/kg/day Group IV 25 mg/kg/day Group VI Group VIII 100 mg/kg/day 500 mg/kg/day BILI (mg/dL) DAY 40 DAY 96 DAY 124 DAY 183 BUN (mg/dL) DAY 40 DAY 96 DAY 124 DAY 183 CREA (mg/dL) DAY 40 DAY 96 DAY 124 DAY 183 CHOL (mg/dL) DAY 40 DAY 96 DAY 124 DAY 183 0.14 0.04(10) 0.17 0.03(10) 0.19 0.04(10) 0.15 0.03(4) 16 2(10) 16 2(10) 17 3(10) 15 4(4) 0.39 0.05(10) 0.44 0.06(10) 0.51 0.05(10) 0.51 0.08(4) 84 19(10) 98 23(10) 97 28(10) 103 21(4) 0.14 0.02(10) 0.15 0.03(10) a 0.12 0.06(5) 16 3(10) 19* 2(10) a 16 2(5) 0.37 0.04(10) 0.43 0.05(10) a 0.47 0.05(5) 92 11(10) 109 19(10) a 129 29(5) 0.14 0.04(10) 0.16 0.04(10) a 0.08 0.03(5) 17 3(10) 19* 2(10) a 18 4(5) 0.37 0.02(10) 0.46 0.05(10) a 0.53 0.08(5) 123* 22(10) 154* 39(10) a 142 62(5) 0.18 0.03(10) 0.21* 0.05(10) 0.16 0.03(10) 0.12 0.02(5) 21 4(10) 20* 2(10) 18 3(10) 18 2(5) 0.44* 0.03(10) 0.50* 0.05(10) 0.50 0.06(10) 0.50 0.04(5) 120* 18(10) 148* 44(10) 138* 30(10) 133 39(5) -151Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 31 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD Group II 0 mg/kg/day Group IV 25 mg/kg/day Group VI Group VIE 100 mg/kg/day 500 mg/kg/day TRIG (mg/dL) DAY 40 DAY 96 DAY 124 DAY 183 GLUC (mg/dL) DAY 40 DAY 96 DAY 124 DAY 183 TP (g/dL) DAY 40 DAY 96 DAY 124 DAY 183 ALB (g/dL) DAY 40 DAY 96 DAY 124 DAY 183 45 19(10) 74 54(10) 96 36(10) 69 39(4) 101 8(10) 103 6(10) 106 9(10) 98 9(4) 7.4 0.5(10) 7.9 0.5(10) 8.2 0.4(10) 8.4 0.3(4) 5.0 0.3(10) 5.4 0.4(10) 5.6 0.4(10) 5.5 0.3(4) 42 13(10) 46 13(10) a 132 38(5) 100 8(10) 102 6(10) a 99 10(5) 7.3 0.5(10) 8.3 0.7(10) a 8.5 0.4(5) 5.1 0.4(10) 5.7 0.4(10) a 5.7 0.3(5) 37 13(10) 39 15(10) a 148 154(5) 101 7(10) 99 12(10) a 102 2(5) 7.9 0.6(10) 8.8* 0.4(10) a 8.7 0.6(5) 5.7* 0.5(10) 6.2* 0.3(10) a 5.4 0.3(5) 25@ 4(10) 23@ 4(10) 78 26(10) 108 59(5) 104 9(10) 100 6(10) 92* 6(10) 106 10(5) 7.7 0.3(10) 8.8* 0.5(10) 8.9* 0.5(10) 8.5 0.5(5) 5.5* 0.3(10) 6.1* 0.4(10) 5.9 0.4(10) 5.2 0.5(5) -152Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 31 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS TEST/ Group II PERIOD_____________ 0 mg/kg/day Group IV Group VI Group VIE 25 mg/kg/day 100 mg/kg/day 500 mg/kg/day GLOB (g/dL) DAY 40 DAY 96 DAY 124 DAY 183 CALC (mg/dL) DAY 40 DAY 96 DAY 124 DAY 183 IPHS (mg/dL) DAY 40 DAY 96 DAY 124 DAY 183 NA (mmol/L) DAY 40 DAY 96 DAY 124 DAY 183 2.3 0.2(10) 2.5 0.2(10) 2.6 0.2(10) 2.9 0.2(4) 11.2 0.4(10) 11.3 0.5(10) 11.5 0.4(10) 10.7 0.2(4) 7.3 0.6(10) 5.5 0.5(10) 6.4 0.8(10) 5.3 0.8(4) 145.9 1.0(10) 145.8 1.0(10) 143.8 2.3(10) 144.9 2.0(4) 2.3 0.2(10) 2.6 0.3(10) a 2.8 0.1(5) 11.2 0.4(10) 11.5 0.4(10) a li.i 0.1(5) 7.5 0.5(10) 5.9 0.5(10) a 5.5 0.5(5) 145.4 1.4(10) 145.6 1.0(10) a 146.4 1.4(5) 2.2 0.2(10) 2.7 0.1(10) a 3.3* 0.3(5) 11.8 0.6(10) 12.1* 0.3(10) a 11.3 0.7(5) 7.7 1.0(10) 6.3 1.0(10) a 7.2 2.4(5) 144.6 1.4(10) 145.3 1.3(10) a 147.6 3.7(5) 2.2 0.1(10) 2.6 0.2(10) 3.0* 0.2(10) 3.3* 0.1(5) 11.8 0.5(10) 12.2* 0.3(10) 11.6 0.5(10) 11.2 0.7(5) 8.9* 1.1(10) 6.9* 0.5(10) 6.8 0.7(10) 7.2 3.3(5) 143.5* 1.4(10) 145.2 1.6(10) 144.3 1.1(10) 145.6 2.7(5) -153Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 31 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD Group II 0 mg/kg/day Group TV 25 mg/kg/day Group VI Group V m 100 mg/kg/day 500 mg/kg/day K (mmol/L) DAY 40 DAY 96 DAY 124 DAY 183 CL (mmol/L) DAY 40 DAY 96 DAY 124 DAY 183 PFLU (fig/mL) DAY 40 DAY 96 DAY 124 DAY 183 5.63 0.37(10) 5.50 0.38(10) 5.90 0.72(10) 5.36 0.30(4) 98.9 1.0(10) 101.0 1.8(10) 98.4 2.2(10) 101.4 2.4(4) a 0.1 0.0(10) 0.0 0.0(10) 0.1 0.1(4) 5.85 0.30(10) 5.47 0.39(10) a 5.57 0.35(5) 99.2 1.2(10) 99.5 1.6(10) a 100.5 0.8(5) a 0.1 0.0(10) a 0.1 0.0(5) 5.99 0.38(10) 5.53 0.56(10) a 5.87 0.89(5) 97.6 . 2.2(10) 98.5* 1.8(10) a 102.1 3.6(5) a 0.2 0.0(10) a 0.1 0.1(4) 6.34@ 0.50(10) 5.95 0.50(10) 5.84 0.76(10) 6.12 1.20(5) 96.3* 1.3(10) 97.5* 2.5(10) 98.2 2.0(10) 102.1 3.4(5) a 0.5@ 0.1(10) 0.1@ 0.1(10) 0.1 0.0(4) Data arranged as: Mean Standard deviation (Number o f values included in calculation) a Measurements for tbis group at this timepoint were not taken or not performed. * 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 (Drum's). -154 Company Sanitized. Does not c o n ta in TSCA C B H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 32 TEST/ PERIOD SUMMARY OF URINALYSIS VALUES FOR MALE RATS Group I 0 mg/kg/day Group in 25 mg/kg/day Group V Group VU 100 mg/kg/day 500 mg/kg/day VOL (mL) DAY 39 DAY 95 DAY 123 DAY 183 UOSM (mOsm) DAY 39 DAY 95 DAY 123 DAY 183 SG DAY 39 DAY 95 DAY 123 DAY 183 pH DAY 39 DAY 95 DAY 123 DAY 183 14.1 6.8(10) 10.1 6.0(10) 8.0 5.9(10) 11.4 7.4(4) 757 283(10) 1230 583(10) 1465 714(10) 1089 422(4) 1.024 0.008(10) 1.038 0.016(10) 1.045 0.020(10) 1.031 0.011(4) 7.2 0.2(10) 6.6 0.8(10) 6.5 0.3(10) a 14.8 10.0(10) 13.5 10.0(10) a 8.8 4.3(5) 843 540(10) 1046 394(10) a 1452 663(5) 1.026 0.015(10) 1.034 0.011(10) a 1.042 0.019(5) 7.1 0.3(10) 6.5 0.7(10) a a 13.0 10.8(10) 8.6 4.5(10) a 8.9 5.7(4) 1002 606(10) 1222 415(10) a 1419 396(4) 1.031 0.018(10) 1.039 0.012(10) a 1.039 0.009(4) 6.9 0.4(10) 6.2 0.5(10) a 29.6* 17.1(10) 37.2@ 17.1(10) 9.8 5.0(10) 12.7 4.6(5) 655 650(10) 506* 195(10) 1262 474(10) 955 206(5) 1.020 0.019(10) 1.018* 0.006(10) 1.040 0.014(10) 1.027 0.004(5) 7.1 0.3(10) 5.3@ 0.3(10) 6.5 0.4(10) -155 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 32 (Continued) TEST/ PERIOD SUMMARY OF URINALYSIS VALUES FOR MALE RATS Group I 0 mg/kg/day Group IH 25 mg/kg/day Group V Group VH 100 mg/kg/day 500 mg/kg/day URO (EU/dL) DAY 39 DAY 95 DAY 123 DAY 183 0.2 0.0(10) 0.2 0.0(10) 0.2 0.0(10) a 0.2 0.0(10) 0.2 0.0(10) a a 0.2 0.0(10) 0.2 0.0(10) a a 0.2 0.0(10) 0.2 0.0(10) 0.2 0.0(10) a UFLU (fig) DAY 39 DAY 95 DAY 123 DAY 183 UMTP (mg/dL) DAY 39 DAY 95 DAY 123 DAY 183 a 12.1 5.4(10) 8.1 2.5(9) 10.2 2.9(4) 60 41(10) 101 64(10) 127 73(10) 61 50(4) a 50.6 11.5(10) a 13.5 3.0(5) 59 55(10) 69 45(10) a 263 468(5) a 140.8@ 39.2(10) a 21.5* 4.3(4) 78 69(10) 91 52(10) a 123 70(4) a 632.6@ 89.0(10) 98.3@ 30.0(10) 46.8* 4.5(5) 37 56(10) 38@ 53(10) 125 84(10) 49 27(5) Data arranged as: Mean Standard deviation (Number o f values included in calculation) a Measurements for this group at this timepoint were not taken or not performed. * 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). -156Company Sanitized. Does not contain TSCA C8I H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations ____________ DuPont-5990 TABLE 33 TEST/ PERIOD SUMMARY OF URINALYSIS VALUES FOR FEMALE RATS Group II Omg/kg/day Group IV 25mg/kg/day Group VI Group VDI lOOmg/kg/day 500 mg/kg/day VOL (mL) DAY 40 DAY 96 DAY 124 DAY 183 UOSM (mOsm) DAY 40 DAY 96 DAY 124 DAY 183 SG DAY 40 DAY 96 DAY 124 DAY 183 PH DAY 40 DAY 96 DAY 124 DAY 183 7.5 4.6(9) 4.7 2.7(10) 4.1 2.4(10) 5.4 1.6(4) 7.2 3.8(10) 9.1 6.2(9) a 7.5 2.1(5) 1046 582(9) 1178 437(9) 1347 480(9) 971 102(4) 1028 493(10) 923 381(9) a 1018 266(5) 1.030 0.015(9) 1.040 0.018(10) 1.040 0.013(9) 1.027 0.002(4) 1.029 0.013(10) 1.028 0.011(9) a 1.027 0.006(5) 6.9 0.5(9) 6.0 0.7(10) 5.7 0.4(10) a 6.7 0.3(10) 5.8 0.9(9) a a 10.2 4.5(10) 7.8 7.4(10) a 7.3 3.0(5) 826 270(10) 1166 443(10) a 935 296(5) 1.025 0.008(10) 1.038 0.014(10) a 1.027 0.010(5) 6.6 0.2(10) 5.8 0.5(10) a a 23.0* 13.4(10) 16.5@ 5.6(10) 2.6 1.8(9) 7.1 3.7(5) 487@ 264(10) 595* 173(10) 1834 762(7) 934 317(5) 1.016@ 0.008(10) 1.021* 0.007(10) 1.054 0.020(9) 1.027 0.009(5) 6.7 0.3(10) 5.4@ 1.0(10) 5.5 0.5(10) a -157 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 33 (Continued) TEST/ PERIOD SUMMARY OF URINALYSIS VALUES FOR FEMALE RATS* Group II 0 mg/kg/day Group IV 25 mg/kg/day Group VI Group VIH 100 mg/kg/day 500 mg/kg/day URO (EU/dL) DAY 40 DAY 96 DAY 124 DAY 183 0.2 0.0(9) 0.2 0.0(10) 0.2 0.0(10) a 0.2 0.0(10) 0.2 0.0(9) a a 0.2 0.0(10) 0.2 0.0(10) a a 0.2 0.0(10) 0.3 0.3(10) 0.2 0.0(10) a UFLU(jttg) DAY 40 aa aa DAY 96 DAY 124 DAY 183 UMTP (mg/dL) DAY 40 DAY 96 DAY 124 DAY 183 5.5 1.8(9) 4.2 1.3(7) 5.9 1.1(4) 25 19(9) 45 42(10) 41 23(9) 45 50(4) 23.7 7.8(9) a 8.6 1.6(5) 23 18(10) 34 36(9) a 30 18(5) 59.4@ 16.0(10) a 9.9 2.0(5) 22 14(10) 278 513(10) a 333 477(5) 291.2@ 95.5(10) 30.0@ 10.6(4) 15.7@ 7.1(5) 20@ 41(10) 165 422(10) 538@ 793(8) 157 165(5) Data arranged as: Mean Standard deviation (Number o f values included in calculation) a Measurements for this group at this timepoint were not taken or not performed. * 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). -158 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 34 SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITY IN MALE RATS Group Dosage (mg/kg/day) Hepatic Peroxisomal Beta-Oxidation Activity (nmol/min/mg protein) 10-Day Timepoint 90-Day Timepoint One-Month Recovery Three-Month Recovery I0 3.5 1.2a 9.0 2.0 6.4 0.5 18.5 1.0b m 25 4.1 0.7 12.5 1 .6 Ve 100 6.0 1.7# 11.3 2.5 VII 500 10.0 4.5# 16.3 1.4# 12.5 2.1* 18.8 1.5 a Mean standard deviation. The n = 5 for each group, b n = 4. c Samples were not prepared for analysis from groups HI and V at the 30- and 90-day recovery timepoints. Statistically significant difference from control (p < 0.05) by Jonckheere Terpstra Trend test (#) or Dunnett's test (*). Company Sanitized. Does not contain TSCA o 03 H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 35 SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITY IN FEMALE RATS DuPont-5990 Group Dosage (mg/kg/day) Hepatic Peroxisomal Beta-Oxidation Activity (nmol/min/mg protein) 10-Day Timepoint 90-Day Timepoint One-Month Recovery n 0, 5.5 1.0a 12.9 3.0 9.9 1.2 IVb 25 6.9 2.6 8.0 2.1* v i 100 4.3 0.7 10.8 2 .7 VIII 500 5.0 0.9 13.4 2.1 13.0 1.9* a Mean standard deviation. The n = 5 for each group. b Samples were not prepared for analysis from groups IV and VI at the 30-day recovery time point. * Statistically significant difference from control (p < 0.05) by Dunnett's test. Company Sanitized, Does not contain TSCA CBI -160- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 36 MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (90-DAY EXPOSURE EVALUATION) M E A N FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) Group I 0 mg/kg/day Group III 25 mg/kg/day Group V Group VII 100 mg/kg/day 500 mg/kg/day LIVER 16.63310 2.80943(10) 19.02640# 2.29505(10) 21.76290# 2.91519(10) 28.54900# 4.31269(10) KIDNEYS 4.27300 0.52569(10) 4.31100 0.25110(10) 4.24910 0.52783(10) 4.00840 0.43887(10) HEART 1.82560 0.12199(10) 1.92220 0.19537(10) 1.72420 0.15012(10) 1.39460# 0.17029(10) SPLEEN 0.90380 0.19394(10) 0.87540 0.11469(10) 0.79780 0.13239(10) 0.65110# 0.09723(10) BRAIN 2.13200 0.09280(10) 2.16340 0.05560(10) 2.07150 0.08678(10) 2.07970# 0.04210(10) THYMUS 0.43440 0.13861(10) 0.45440 0.14653(10) 0.29630# 0.04005(10) 0.26950# 0.05282(10) ADRENAL GLANDS 0.05700 0.00869(10) 0.05510 0.00962(10) 0.05060 0.00765(10) 0.04870# 0.00735(10) THYROID GLAND 0.02160 0.00455(10) 0.02040 0.00295(10) 0.02170 0.00427(10) 0.02370 0.00609(10) TESTES 3.63400 0.29496(10) 3.64140 0.17140(10) 3.61030 0.29853(10) 3.58520 0.20972(10) EPIDIDYMIDES 1.55710 0.15334(10) 1.57840 0.15123(10) 1.51140 0.16395(10) 1.34760# 0.09038(10) FINAL BODY WEIGHT 586.97000 55.79240(10) 594.81000 56.63113(10) 521.24000# 49.44560(10) 455.83001# 46.70487(10) -161 Company Sanitized. Does not contain TSCA CB! H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 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 Group XIX 25 mg/kg/day Group V Group VII 100 mg/kg/day 500 mg/kg/day LIVER/ FINAL BODY * 100 2.82741 0.32735(10) 3.19494# 0.16761(10) 4.16752# 0.25124(10) 6.24277# 0.47380(10) KIDNEYS/ FINAL BODY * 100 0.72909 0.06930(10) 0.72913 0.06408(10) 0.81433# 0.04611(10) 0.88088# 0.06592(10) HEART/ FINAL BODY * 100 0.31266 0.02647(10) 0.32478 0.03760(10) 0.33309 0.04214(10) 0.30614 0.02431(10) SPLEEN/ FINAL BODY * 100 0.15358 0.02706(10) 0.14725 0.01424(10) 0.15273 0.01741(10) 0.14324 0.01740(10) BRAIN/ FINAL BODY * 100 0.36601 0.03583(10) 0.36647 0.03351(10) 0.40022 0.03778(10) 0.46035# 0.04556(10) THYMUS/ FINAL BODY * 100 0.07367 0.02055(10) 0.07549 0.01890(10) 0.05703# 0.00789(10) 0.05916# 0.01053(10) ADRENAL GLANDS/ FINAL BODY * 100 0.00977 0.00171(10) 0.00924 0.00113(10) 0.00982 0.00210(10) 0.01079 0.00203(10) THYROID GLAND/ FINAL BODY * 100 0.00367 0.00058(10) 0.00346 0.00058(10) 0.00419 0.00089(10) 0.00528# 0.00164(10) TESTES/ FINAL BODY * 100 0.62453 0.08067(10) 0.61777 0.06985 (10) 0.70006 0.10332(10) 0.79569# 0.10956(10) EPIDIDYMIDES/ FINAL BODY * 100 0.26746 0.03552(10) 0.26775 0.03808(10) 0.29268 0.04468(10) 0.29896 0.04172(10) -162Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 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 0 mg/kg Group III 25 mg/kg Group V 100 mg/kg Group VII 500 mg/kg LIVER/ BRAIN * 100 782.96063 147.78552(10) 879.89000# 107.54323(10) 1050.1984# 125.91532(10) 1371.9135# 200.20379(10) KIDNEYS/ BRAIN * 100 200.90331 27.68803(10) 199.41177 13.25286(10) 205.06197 22.60785(10) 192.60123 19.36248(10) HEART/ BRAIN * 100 85.68143 5.40052(10) 88.93735 9.68550(10) 83.36613 7.93969(10) 67.03478# 7.96076(10) SPLEEN/ BRAIN * 100 42.45121 9.35506(10) 40.45059 5.07376(10) 38.47994 5.74742(10) 31.28986# 4.44000(10) THYMUS/ BRAIN * 100 20.42288 6.61576(10) 20.96895 6.72670(10) 14.31534# 1.89127(10) 12.95050# 2.49419(10) ADRENAL GLANDS/ BRAIN * 100 2.67508 0.40284(10) 2.54529 0.42819(10) 2.43944 0.32251(10) 2.33982 0.33248(10) THYROID GLAND/ BRAIN * 100 1.01563 0.22828(10) 0.94388 0.14130(10) 1.04901 0.21199(10) 1.13830 0.27988(10) TESTES/ BRAIN * 100 170.63301 14.18460(10) 168.35760 7.63521(10) 174.61595 16.78231(10) 172.35943 8.69911(10) EPIDIDYMIDES/ BRAIN * 100 73.11609 7.48972(10) 73.09237 8.12540(10) 73.14495 9.15417(10) 64.79942# 4.12918(10) -163 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 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 500 mg/kg/day LIVER 15.91980 2.61567(10) 19.28230# 2.99843(10) KIDNEYS 4.01410 0.63080(10) 4.12190 0.56676(10) HEART 1.81180 0.26704(10) 1.71790 0.20145(10) SPLEEN 0.77380 0.12216(10) 0.75260 0.13042(10) BRAIN 2.17610 0.07422(10) 2.08670# 0.10123(10) THYMUS 0.32740 0.09491(10) 0.31770 0.06795(10) ADRENAL GLANDS 0.05270 0.01206(10) 0.04960 0.00928(10) THYROID GLAND 0.02640 0.00513 (10) 0.02610 0.00381(10) TESTES 3.47080 0.37716(10) 3.64160 0.43347(10) EPIDIDYMIDES 1.52810 0.16851(10) 1.47190 0.18300(10) FINAL BODY WEIGHT 576.09000 78.02172(10) 507.33999# 57.96794(10) -164Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 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 Group VII 500 mg/kg LIVER/ FINAL BODY * 100 2.75706 0.19397(10) 3.79193# 0.30701(10) KIDNEYS/ FINAL BODY * 100 0.69591 0.04037(10) 0.81175# 0.05428(10) HEART/ FINAL BODY * 100 0.31585 0.03450(10) 0.33906 0.02237(10) SPLEEN/ FINAL BODY * 100 0.13459 0.01570(10) 0.14853 0.02032(10) BRAIN/ FINAL BODY * 100 0.38227 0.03845(10) 0.41503 0.04063(10) THYMUS/ FINAL BODY * 100 0.05744 0.01742(10) 0.06286 0.01353(10) ADRENAL GLANDS/ FINAL BODY *100 0.00918 0.00188(10) 0.00987 0.00204(10) THYROID GLAND/ FINAL BODY * 100 0.00462 0.00092(10) 0.00518 0.00079(10) TESTES/ FINAL BODY * 100 0.60590 0.05072(10) 0.72098# 0.07942(10) EPIDIDYMIDES/ FINAL BODY * 100 0.26667 0.02168(10) 0.29132 0.03122(10) -165Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 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 Group VII 500 mg/kg LIVER/ BRAIN * 100 729.29332 100.02746(10) 921.83881# 119.30612(10) KIDNEYS/ BRAIN * 100 184.00069 24.20313(10) 197.44475 24.55331(10) HEART/ BRAIN * 100 83.11980 10.42723(10) 82.49189 10.31680(10) SPLEEN/ BRAIN * 100 35.50892 5.12558(10) 36.07912 6.01540(10) THYMUS/ BRAIN * 100 15.06621 4.37529(10) 15.29145 3.51776(10) ADRENAL GLANDS/ BRAIN * 100 2.41725 0.51509(10) 2.37473 0.41350(10) THYROID GLAND/ BRAIN * 100 1.21012 0.21265(10) 1.25315 0.18912(10) TESTES/ BRAIN * 100 159.39532 14.80609(10) 174.11728 14.55585(10) EPIDIDYMIDES/ BRAIN * 100 70.13548 6.27701(10) 70.42842 6.58358(10) -166 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with QBe-Generation Reproduction Evaluations DuPont-5990 TABLE 36 (Continued) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (THREE-MONTH RECOVERY EVALUATION) MEAN FINAlL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) Group I 0 mg/kg Group III 25 mg/kg Group V 100 mg/kg Group VII 500 mg/kg LIVER 15.18825 3.97935(4) 16.16520 2.16983(5) 17.47825 3.24147(4) 18.25980# 0.83323(5) KIDNEYS 3.57500 0.76015(4) 4.05200 0.63025(5) 4.06925 0.53882(4) 4.14060 0.29634(5) SPLEEN 0.70700 0.03459 (4) 0.85960 0.06672(5) 0.79600 0.14425(4) 0.85440 0.16217(5) THYROID GLAND 0.02450 0.00624(4) 0.02520 0.00879(5) 0.02000 0.00183(4) 0.02760 0.00573(5) TESTES 3.74800 0.21840(4) 3.82800 0.55129(5) 3.52850 0.27561(4) 3.62420 0.35247(5) FINAL BODY WEIGHT 563.70001 99.80271(4) 630.94000 47.83004(5) 597.95000 71.58256(4) 609.70000 42.75200(5) - 167 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations / TABLE 36 (Continued) DuPont-5990 MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (THREE-MONTH RECOVERY EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% of body weight) LIVER/ FINAL BODY*100 Group I 0 mg/kg/day 2.65937 0.31939(4) Group III 25 mg/kg/day Group V Group VII 100 mg/kg/day 500 mg/kg/day 2.56549 0.31336(5) 2.90979 0.28681(4) 3.00285# 0.18073(5) KIDNEYS/ FINAL BODY*100 0.63343 0.07565(4) 0.64510 0.10676(5) 0.68010 0.01923(4) 0.68060 0.05044(5) SPLEEN/ FINAL BODY*100 THYROID GLAND/ FINAL BODY*100 0.12809 0.02023 (4) 0.00432 0.00046(4) 0.13674 0.01296(5) 0.00397 0.00126(5) 0.13283 0.01340(4) 0.00340 0.00061(4) 0.13959 0.02222(5) 0.00455 0.00103(5) TESTES/ FINAL BODY*100 0.68104 0.12348(4) 0.60760 0.08141(5) 0.59534 0.07245 (4) 0.59769 0.08245(5) Data summarized a s : Mean Standard Deviation (n) Statistical Methods: Trend test (Jonckheere-Terpstra). # Statistically significant difference at p < 0.05. -168 Company Sanitized. Does not contain TSCA C B I H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 37 MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (90-DAY EXPOSURE EVALUATION) MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) Group II 0 mg/kg Group IV 25 mg/kg Group VI 100 mg/kg Group VIII 500 mg/kg LIVER 8.96410 1.17520(10) 10.49990# 1.34755(10) 14.83930# 2.41882 (10) 19.06010# 2.86309(10) KIDNEYS 2.30570 0.25369(10) 2.47140 0.38278(10) 2.74590# 0.42987(10) 2.72540# 0.54824(10) HEART 1.14650 0.11569(10) 1.13550 0.09633(10) 1.27860 0.19973(10) 1.11550 0.15138(10) SPLEEN 0.53040 0.06905(10) 0.56770 0.07731(10) 0.59510 0.06199(10) 0.57850 0.04645(10) BRAIN 1.95650 0.08639(10) 1.95530 0.11202(10) 1.95200 0.07330(10) 1.91380 0.04798(10) THYMUS 0.24630 0.05982(10) 0.27320 0.09619(10) 0.26660 0.04664(10) 0.24480 0.02340(10) ADRENAL GLANDS 0.06770 0.01800(10) 0.07100 0.01641(10) 0.06830 0.01302(10) 0.07140 0.00983(10) THYROID GLAND 0.01660 0.00386(10) 0.01790 0.00363(10) 0.01840 0.00422(10) 0.01940 0.00430(10) OVARIES 0.13390 0.01952(10) 0.10840 0.01652(10) 0.11990 0.02643(10) 0.11520 0.02006(10) UTERUS 0.88300 0.32174(10) 0.71410 0.20197(10) 0.80990 0.35177(10) 1.19680 0.72333(10) FINAL BODY WEIGHT 307.06000 35.30156(10) 296.01000 36.05821(10) 305.97000 24.82257(10) 289.03000 24.17566(10) -169 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 37 (Continued) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (90-DAY EXPOSURE EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% of body weight) Group II 0 mg/kg/day Group IV 25 mg/kg/day Group VI Group VIII 100 mg/kg/day 500 mg/kg/day LIVER/ FINAL BODY * 100 2.92243 0.26344(10) 3.55488# 0.29322(10) 4.83452# 0.55255(10) 6.57179# 0.57624(10) KIDNEYS/ FINAL BODY * 100 0.75622 0.09220(10) 0.83753 0.11222(10) 0.89393# 0.08919(10) 0.93820# 0.13*426 (10) HEART/ FINAL BODY * 100 0.37587 0.04182(10) 0.38600 0.03060(10) 0.416630 0.04293(10) 0.38467 0.02624(10) SPLEEN/ FINAL BODY * 100 0.17374 0.02282(10) 0.19331 0.02996(10) 0.19489 0.01811(10) 0.20052# 0.01128(10) BRAIN/ FINAL BODY * 100 0.64421 0.07213(10) 0.66816 0.07908(10) 0.64198 0.05953(10) 0.66609 0.05485(10) THYMUS/ FINAL BODY * 1 0 0 0.08023 0.01653(10) 0.09119 0.02354(10) 0.08687 0.01132(10) 0.08491 0.00724 (10) ADRENAL GLANDS/ FINAL BODY * 100 0.02235 0.00698(10) 0.02436 0.00658(10) 0.02225 0.00324(10) 0.02473 0.00281(10) THYROID GLAND/ FINAL BODY * 100 0.00547 0.00137(10) 0.00616 0.00161(10) 0.00609 0.00166(10) 0.00669 0.00127(10) OVARIES/ FINAL BODY * 100 0.04355 0.00328(10) 0.03720 0.00779(10) 0.03972 0.01047(10) 0.04024 0.00862(10) UTERUS/ FINAL BODY * 100 0.29584 0.12450(10) 0.24249 0.07305(10) 0.26205 0.09841(10) 0.40830 0.22284(10) - 170Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 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) Group II 0 mg/kg Group IV 25 mg/kg Group VI 100 mg/kg Group VIII 500 mg/kg LIVER/BRAIN BRAIN * 100 457.49243 52.94763(10) 537.57050# 66.19395(10) 759.94841# 117.36733(10) 994.74997# 137.46968(10) KIDNEYS/ BRAIN * 100 117.86404 12.33523(10) 125.99830 15.06599(10) 140.64122# 20.77856(10) 142.10320# 26.06927(10) HEART/ BRAIN * 100 58.69240 6.46805(10) 58.15049 4.87700(10) 65.47801 9.52060(10) 58.26306 7.55341(10) SPLEEN/ BRAIN * 100 27.17492 3.90257(10) 29.02747 3.59886(10) 30.54374# 3.55350(10) 30.24692# 2.57608(10) THYMUS/ BRAIN * 100 12.55555 2.82205(10) 13.94615 4.58716(10) 13.69236 2.58117(10) 12.78967 1.14599(10) ADRENAL GLANDS/ BRAIN * 100 3.46244 0.92313(10) 3.60811 0.67135(10) 3.49437 0.60893(10) 3.72289 0.42145(10) THYROID GLAND/ BRAIN * 100 0.85209 0.21053(10) 0.91898 0.19671(10) 0.94297 0.21733(10) 1.01498 0.23116(10) OVARIES/ BRAIN * 100 6.85126 1.04334(10) 5.54150 0.78099(10) 6.14228 1.36604(10) 6.01898 1.04377(10) UTERUS/ BRAIN * 100 45.19756 16.25939(10) 36.38737 9.19147(10) 41.32404 16.60914(10) 62.57485 38.01544(10) -171 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 37 (Continued) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) Group II 0 mg/kg/day Group VIII 500 mg/kg/day LIVER 9.67850 1.13424(10) 11.80670# 1.65066(10) KIDNEYS 2.44900 0.27689(10) 2.62610 0.25291(10) HEART 1.22860 0.12853(10) 1.24080 0.15221(10) SPLEEN 0.55070 0.10790 (10) 0.52300 0.05378(10) BRAIN 1.95200 0.06240 (10) 1.97160 0.05553(10) THYMUS 0.22570 0.02587 (10) 0.22010 0.04800(10) ADRENAL GLANDS 0.09560 0.07987(10) 0.07640 0.00866(10) THYROID GLAND 0.02070 0.00226(10) 0.01940 0.00299(10) OVARIES 0.10940 0.01580 (10) 0.11040 0.02732(10) UTERUS 0.78170 0.15328 (10) 0.91460 0.38329(10) FINAL BODY WEIGHT 330.86000 34.33764(10) 294.59000# 23.94041(10) -172 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 37 (Continued) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% of body weight) Group II 0 mg/kg/day Group VIII 500 mg/kg/day LIVER/ FINAL BODY * 100 2.92561 0.19109(10) 3.99507# 0.32765(10) KIDNEYS/ FINAL BODY * 100 0.74132 0.05681(10) 0.89161# 0.04728(10) HEART/ FINAL BODY * 100 0.37328 0.04081(10) 0.42063# 0.02988(10) SPLEEN/ FINAL BODY * 100 0.16646 0.02663(10) 0.17781 0.01594(10) BRAIN/ FINAL BODY * 100 0.59523 0.05966(10) 0.67285# 0.05154(10) THYMUS/ FINAL BODY * 100 0.06887 0.01061(10) 0.07466 0.01555(10) ADRENAL GLANDS/ FINAL BODY * 100 0.02857 0.02206(10) 0.02599 0.00275(10) THYROID GLAND/ FINAL BODY * 100 0.00628 0.00067(10) 0.00661 0.00105(10) OVARIES/ FINAL BODY * 100 0.03334 0.00565(10) 0.03765 0.00992(10) UTERUS/ FINAL BODY * 100 0.23659 0.04298(10) 0.31188 0.12397(10) -173 Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 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 II 0 mg/kg/day- Group VIII 500 mg/kg/day LIVER/ BRAIN * 100 495.94097 56.84798(10) 598.36638# 79.12881(10) KIDNEYS/ BRAIN * 100 125.38765 12.86108(10) 133.25610 13.06903(10) HEART/ BRAIN * 100 62.96376 6.57084(10) 62.94811 7.59489(10) SPLEEN/ BRAIN * 100 28.20259 5.34710(10) 26.52191 2.59702(10) THYMUS/ BRAIN * loo 11.55511 1.18346(10) 11.14676 2.35367(10) ADRENAL GLANDS/ BRAIN * 100 4.87004 3.99993 (10) 3.87639 0.44163(10) THYROID GLAND/ BRAIN * 100 1.06030 0.10863(10) 0.98505 0.15984(10) OVARIES/ BRAIN * 100 5.62234 0.92706(10) 5.58292 1.30758(10) UTERUS/ BRAIN * 100 40.05367 7.89402(10) 46.70156 20.49091(10) - 174Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 37 (Continued) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (THREE-MONTH RECOVERY EVALUATION) MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHT (grams) Group IX 0 mg/kg/day Group IV 25 mg/kg/day Group VI Group VIII 100 mg/kg/day 500 mg/kg/day LIVER 8.80150 1.11307(4) 9.37260 1.28006(5) 11.40800# 2.38708(4) 10.77225# 1.16901(4) KIDNEYS 2.32675 0.33914(4) 2.35700 0.36101(5) 2.83800 0.73122(4) 2.60075 0.23556(4) SPLEEN 0.50950 0.07548(4) 0.47540 0.04057(5) 0.54400 0.04695(4) 0.60150 0.10743(4) THYROID GLAND 0.01875 0.00250(4) 0.02050 0.00129(4) 0.01775 0.00171(4) 0.01825 0.00386(4) FINAL BODY WEIGHT 340.87500 39.19289(4) 336.88000 57.73913(5) 346.57500 55.62664(4) 309.60000 42.33793(4) -175Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 37 (Continued) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (THREE-MONTH RECOVERY EVALUATION) LIVER/ FINAL BODY*100 KIDNEYS/ FINAL BODY*100 SPLEEN/ FINAL BODY*100 THYROID GLAND/ FINAL BODY*100 MEAN RELATIVE ORGAN WEIGHTS (% of body weight) Group II 0 mg/kg/day Group IV 25 mg/kg/day Group VI Group VIII 100 mg/kg/day 500 mg/kg/day 2.58246 0.13689(4) 2.80327 0.23912(5) 3.28638# 0.33956(4) 3.49940# 0.31044(4) 0.68217 0.05267(4) 0.70360 0.06312(5) 0.81593 0.12727(4) 0.84656# 0.08237(4) 0.15176 0.03460(4) 0.14321 0.01739(5) 0.15898 0.01976(4) 0.19457# 0.02305(4) 0.00550 0.00044(4) 0.00622 0.00120(4) 0.00518 0.00060(4) 0.00589 0.00102(4) Data summarized as: Mean Standard Deviation (n) Statistical Methods: Trend test (Jonckheere-Terpstra). # Statistically significant difference at p < 0.05. - 176 Company Sanitized. Does not contain TSCA C8I H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 38 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (Numeric) Males 0 25 100 500 I III V VII LIVER NO ABNORMALITY DETECTED LARGE. KIDNEYS NO ABNORMALITY DETECTED DISCOLORATION, TAN, LEFT. DILATATION, LEFT. DILATATION, RIGHT, PELVIS. DILATATION, RIGHT. SPLEEN NO ABNORMALITY DETECTED THYROID GLAND NO ABNORMALITY DETECTED TESTES NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED (11) 11 (11) 11 (11) 11 (ID 11 (11) 11 (11) 11 (10) 10 (10) 9 1 (10) 10 (10) 10 (10) 10 (10) 10 (11) 10 1 (11) 9 1 1 (11) 11 (11) 11 (11) 11 (11) 11 (12) 7 5 (12) 10 1 1 (12) 12 (12) 12 (12) 12 (12) 12 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 Company Sanitized. Does not contain TSCA CBI - 177- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 38 (Continued) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (Numeric) Males 0 25 100 500 I III V VII AORTA NO ABNORMALITY DETECTED BRAIN NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED COAGULATING GLANDS LARGE, LEFT. COLON NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED EPIDIDYMIDES NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED (11) 11 (11) 11 (11) 11 (1) 1 (11) 11 (11) 11 (11) 11 (11) 11 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (12) 12 (12) 12 (12) 12 (12) 12 (12) 12 (12) 12 (12) 12 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 Company Sanitized. Does not contain TSCA C8I -178- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 38 (Continued) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (Numeric) Males 0 25 100 500 I III V VII FEMUR/KNEE JOINT NO ABNORMALITY DETECTED HEART NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED LUNGS NO ABNORMALITY DETECTED MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 dll) 11 (11) 11 (11) . 11 (12) 12 (12) 12 (12) 12 (12) 12 (12) 12 (12) 12 (12) 12 (12) 12 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 Company Sanitized. Does not contain TSCA CBI -179- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 38 (Continued) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (Numeric) Males 0 25 100 500 I III V VII PANCREAS NO ABNORMALITY DETECTED PARATHYROID GLANDS NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED PITUITARY GLAND NO ABNORMALITY DETECTED PROSTATE NO ABNORMALITY DETECTED RECTUM NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (12) 12 (12) 12 (12) 12 (12) 12 (12) 12 (12) 12 (12) 12 (12) 12 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 Company Sanitized. Does not contain TSCA CBI -180- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 38 (Continued) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (Numeric) Males 0 25 100 500 I III V VII SEMINAL VESICLES NO ABNORMALITY DETECTED SKELETAL MUSCLE NO ABNORMALITY DETECTED SKIN NO ABNORMALITY DETECTED ALOPECIA, PERINEUM. STAIN, RED, VENTRAL BODY. SPINAL CORD NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED ULCER/EROSION, GLANDULAR, FEW. THYMUS NO ABNORMALITY DETECTED DISCOLORATION, BILATERAL. (11) 11 (11) 11 (11) 10 1 (11) 11 (11) 11 (11) 11 (11) 11 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 9 1 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (12) 12 (12) 12 (12) 11 1 (12) 12 (12) 12 (12) 10 2 (12) 12 Figures in parentheses is the num b e r of animals grossly examined for this tissue O The absence of a number indicates the finding specified was not identified CP Company Sanitized. Does not contain TSCA H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 38 (Continued) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS . TREATMENT (mg/kg/day) LESION INCIDENCE (Numeric) Males 0 25 100 500 I III V VII TRACHEA NO ABNORMALITY DETECTED URINARY BLADDER NO ABNORMALITY DETECTED CALCULUS\CALCULI. DILATATION, RED. WHOLE BODY SITUS INVERSUS. E Y E (S ) W I T H OPTIC NERVE NO ABNORMALITY DETECTED HEMORRHAGE, RIGHT. (11) 11 (11) 9 1 1 (11) 11 (10) 10 (10) 9 1 (10) 10 (11) 11 (11) 11 (1) 1 (11) 10 1 (12) 12 (12) 11 1 (12) 12 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 Company Sanitized. Does not contain TSCA CBI -182- Company Sanitized. Does not contain TSCA H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 38 (Continued) LESIONS INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (ONE-MONTH RECOVERY EVALUATION) | LESION INCIDENCE (Numeric) | Males TREATMENT (mg/kg/day) 0 500 I VII LIVER NO ABNORMALITY DETECTED KIDNEYS NO ABNORMALITY DETECTED SPLEEN NO ABNORMALITY DETECTED THYROID GLAND NO ABNORMALITY DETECTED TESTES NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED AORTA NO ABNORMALITY DETECTED BRAIN NO ABNORMALITY DETECTED (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 O CXI DuPont-5990 H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 38 (Continued) LESIONS INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (ONE-MONTH RECOVERY EVALUATION) | LESION INCIDENCE (Numeric) | Males TREATMENT (mg/kg/day) 0 500 I VII CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED EPIDIDYMIDES NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED HEART NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED (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 DuPont-5990 Company Sanitized. Does not contain TSCA CBI -184- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 38 (Continued) LESIONS INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (ONE-MONTH RECOVERY EVALUATION) | LESION INCIDENCE (Numeric) | Males TREATMENT (mg/kg/day) 0 500 I VII JEJUNUM NO ABNORMALITY DETECTED LUNGS NO ABNORMALITY DETECTED MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED PANCREAS NO ABNORMALITY DETECTED PARATHYROID GLANDS NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED (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 DuPont-5990 Company Sanitized. Does not contain TSCA CBI -185- Company Sanitized. Does not contain TSCA H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 38 (Continued) LESIONS INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (ONE-MONTH RECOVERY EVALUATION) | LESION INCIDENCE (Numeric) | Males TREATMENT (mg/kg/day) 0 500 I VII PITUITARY GLAND NO ABNORMALITY DETECTED PROSTATE NO ABNORMALITY DETECTED RECTUM NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED SEMINAL VESICLES NO ABNORMALITY DETECTED SKELETAL MUSCLE NO ABNORMALITY DETECTED SKIN NO ABNORMALITY DETECTED (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 O CD DuPont-5990 H-24768: Subcbronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 38 (Continued) LESIONS INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (ONE-MONTH RECOVERY EVALUATION) | LESION INCIDENCE (Numeric) | Males TREATMENT (mg/kg/day) 0 500 I VII SPINAL CORD NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED URINARY BLADDER NO ABNORMALITY DETECTED E Y E (S ) WIT H OPTIC NERVE NO ABNORMALITY DETECTED (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 DuPont-5990 Company Sanitized. Does not contain TSCA CBI -187- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 38 (Continued) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (THREE-MONTH RECOVERY EVALUATION) DuPont-5990 LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (Numeric) Males 0 25 100 500 I III V VII LIVER NO ABNORMALITY DETECTED KIDNEYS NO ABNORMALITY DETECTED SPLEEN NO ABNORMALITY DETECTED THYROID GLAND NO ABNORMALITY DETECTED TESTES NO ABNORMALITY DETECTED PARATHYROID GLANDS NO ABNORMALITY DETECTED (4) (5) (4) (5) 4545 (4) (5) (4) (5) 4545 (4) (5) (4) (5) 454 5 (4) (5) (4) (5) 4545 (4) (5) (4) (5) 4545 (4) (5) (4) (5) 4545 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 Company Sanitized. Does not contain TSCA CBI - 188- H-24768: 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) LESION INCIDENCE (Numeric) Females 1 OI 1 I 1 LESIONS TREATMENT (mg/kg/day) 25 100 500 IV VI VIII 1 1H lW l 1 LIVER NO ABNORMALITY DETECTED LARGE. (10) 10 (10) 10 (10) 10 (10) 8 2 KIDNEYS NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 LUNGS NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 HEART NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 SKELETAL MUSCLE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 SPLEEN NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 AORTA NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 BRAIN NO ABNORMALITY DETECTED (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 DuPont-5990 Company Sanitized. Does not contain TSCA CBI -189- H-24768: 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) LESION INCIDENCE (Numeric) Females O\ 1 LESIONS TREATMENT (mg/kg/day) H H 25 1 0 0 500 IV VI VIII SPINAL CORD NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 STOMACH NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 DUODENUM NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 JEJUNUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED PANCREAS NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED (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 COLON NO ABNORMALITY DETECTED (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 DuPont-5990 Company Sanitized. Does not contain TSCA C8I -190- Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 39 (Continued) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION) TREATMENT (mg/kg/day) 1 1 1 1O 1 LESION INCIDENCE (Numeric) Females 25 1 0 0 500 IV VI VIII 1 1 H; Hi 1 RECTUM NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED DISCOLORATION, BILATERAL. THYMUS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED PITUITARY GLAND NO ABNORMALITY DETECTED (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) 9 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 8 (10) 10 (10) 10 (10) 10 (10) 9 1 (10) 10 (10) 10 (10) 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 -191- DuPont-5990 Company Sanitized. Does not contain TSCA CBI ) H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations ) LESIONS TABLE 39 (Continued) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION) TREATMENT (mg/kg/day) LESION INCIDENCE (Numeric) Females 0 25 100 500 II IV VI VIII PITUITARY GLAND LARGE. 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 ALOPECIA, BILATERAL, HINDLIMB. (10) (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 1 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 2 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 1 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 9 1 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- > DuPont-5990 )) H-24768: 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) !1 LESIONS TREATMENT (mg/kg/day) 1 HM O 1 1 LESION INCIDENCE (Numeric) Females 25 100 500 IV VI VIII l 1 1 MAMMARY GLAND (FEMALE) NO ABNORMALITY DETECTED LARGE, VENTRAL. OVARIES NO ABNORMALITY DETECTED UTERUS NO ABNORMALITY DETECTED LARGE. URINARY BLADDER NO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED (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) 9 1 (10) 10 (10) 9 1 (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 > DuPont-5990 Company Sanitized. Does not contain TSCA C8I -193- H-24768: 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 LESION INCIDENCE (Nxameric) Females TREATMENT (mg/kg/day) 0 II 500 VIII LIVER NO ABNORMALITY DETECTED KIDNEYS NO ABNORMALITY DETECTED DILATATION, RIGHT, PELVIS. CYST, CLEAR, LEFT. CYST, RIGHT. LUNGS NO ABNORMALITY DETECTED HEART NO ABNORMALITY DETECTED SKELETAL MUSCLE NO ABNORMALITY DETECTED SPLEEN NO ABNORMALITY DETECTED AORTA NO ABNORMALITY DETECTED (10) 10 (10) 8 1 1 1 (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 DuPont-5990 Company Sanitized. Does not contain TSCA CBI -194- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_______________________________________________________ DuPont-5990 TABLE 39 (Continued) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) LESIONS LESION INCIDENCE (Numeric) Females TREATMENT (mg/kg/day) 0 II 500 VIII BRAIN NO ABNORMALITY DETECTED SPINAL CORD NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED ULCER/EROSION, GLANDULAR. DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED PANCREAS NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 9 1 (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 Company Sanitized. Does not contain TSCA CBI -195- H-24768: 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 |LESION INCIDI3NCE (Numeric) Females TREATMENT (mg/kg/day) 0 II 500 VIII COLON NO ABNORMALITY DETECTED 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 (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 ) DuPont-5990 Company Sanitized. Does not contain TSCA CBI - 196- H-24768: 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 |LESION INCIDI3JCE (Numeric) Females TREATMENT (mg/kg/day) 0 II 500 VIII 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 E Y E (S ) WI T H OPTIC NER V E NO ABNORMALITY DETECTED SKIN NO ABNORMALITY DETECTED (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 DuPont-5990 Company Sanitized. Does not contain TSCA CBi -197- Company Sanitized. Does not contain H-24768: 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 LESION INCIDIMCE (Numeric) Females TREATMENT (mg/kg/day) 0 II 500 VIII MAMMARY GLAND (FEMALE) NO ABNORMALITY DETECTED 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 (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 DuPont-5990 )) H-24768: 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 TREATMENT (mg/kg/day) O1 1 1 LESION INCIDENCE (Numeric) Females 25 100 500 IV VI VIII H H 1 LIVER NO ABNORMALITY DETECTED KIDNEYS NO ABNORMALITY DETECTED SMALL, RIGHT, IRREGULAR SPLEEN NO ABNORMALITY DETECTED THYROID GLAND NO ABNORMALITY DETECTED PARATHYROID GLANDS NO ABNORMALITY DETECTED (4) (5) (5) (5) 4555 (4) (5) (5) (5) 4545 1 (4) (5) (5) (5) 4 5 55 (4) (5) (5) (5) 4555 (4) (5) (5) (5) 4555 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 > DuPont-5990 Company Sanitized. Does not contain TSCA CBI - 199- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 40 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) Company Sanitized. Does not contain TSCA LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, FOCAL. HYPERTROPHY, CENTRILOBULAR. FATTY CHANGE, PERIPORTAL. FATTY CHANGE, MEDIAN CLEFT. PANCREAS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, FOCAL. ESOPHAGUS NO ABNORMALITY DETECTED (11) 6 4 1 1 2 (11) 8 3 (11) 11 (10) 4 1 5 2 (11) 1 1 10 1 (1) 1 (1) 1 (12) 12 (12) 12 (12) 12 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified o CD H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (Continued) DuPont-5990 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII DIGESTIVE SYSTEM STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. ILEUM NO ABNORMALITY DETECTED AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. (11) 11 (11) 11 (11) 11 (11) 11 (1) (12) 1 12 (1) (12) 1 12 (1) (12) 1 12 1 (1) (12) 1 12 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 Company Sanitized. Does not contain TSCA CBI -201 - H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (Continued) DuPont-5990 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII DIGESTIVE SYSTEM CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED RECTUM NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED (11) 11 (11) 11 (11) 11 (11) 11 (1) (12) 1 12 (1) (12) 1 12 (1) (12) 1 12 (1) (12) 1 12 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI - 202- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (Continued) DuPont-5990 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED PYELONEPHRITIS, BILATERAL. NEPHROPATHY, CHRONIC PROGRESSIVE. INFLAMMATION, SUBACUTE/CHRONIC, FOCAL. HYDRONEPHROSIS, UNILATERAL. HYDRONEPHROSIS, BILATERAL. NO MICROSCOPIC EVIDENCE OF MACROSCOPIC FINDING. URINARY BLADDER NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. HYPERPLASIA, TRANSITIONAL CELL. HEMORRHAGE. CALCULUS/CALCULI . (11) 5 1 5 (11) 9 2 1 1 1 (10) 7 2 1 1 (1) 1 1 (11) 4 1 5 2 1 (15 1 (12) 4 1 7 1 1 1 (12) 11 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 Company Sanitized. Does not contain TSCA CBI -203- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (Continued) DuPont-5990 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII RESPIRATORY SYSTEM LUNGS NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED PHARYNX /LARYNX NO ABNORMALITY DETECTED NOSE I & II NO ABNORMALITY DETECTED NOSE III & IV NO ABNORMALITY DETECTED (11) 11 (10) 10 (11) 11 (11) 11 (11) 11 (1) (12) 1 12 (1) (12) 1 12 (1) (ID 1 11 (1) (12) 1 12 (1) (12) 1 12 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA C8I -204- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (Continued) DuPont-5990 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII CARDIOVASCULAR SYSTEM HEART NO ABNORMALITY DETECTED CARDIOMYOPATHY. AORTA NO ABNORMALITY DETECTED (11) 10 1 (11) 11 (1) (12) 1 12 (1) (12) 1 12 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA C8I -205- H-24768: Subcbronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (Continued) DuPont-5990 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED PIGMENT INCREASED. INFLAMMATION, SUBACUTE/CHRONIC, HEMATOPOIESIS, INCREASED. ATROPHY, LYMPHOID. FOCAL. THYMUS NO ABNORMALITY DETECTED NO MICROSCOPIC EVIDENCE OF MACROSCOPIC FINDING. MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED CONGESTION. (11) 10 1 (11) 11 (11) 11 (10) 9 1 (1) 1 (11) 3 4 8 (1) 1 (1) 1 (12) 1 6 10 1 (12) 12 (12) 11 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 Company Sanitized. Does not contain TSCA CBI -206- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (Continued) DuPont-5990 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII LYMPHATIC AND HEMATOPOIETIC SYSTEM MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED BONE MARROW NO ABNORMALITY DETECTED (11) 11 (11) 11 (1) (12) 1 12 (1) (12) 1 12 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA C8I -207- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (Continued) DuPont-5990 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII ENDOCRINE SYSTEM PITUITARY GLAND NO ABNORMALITY DETECTED THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. ALTERATION, COLLOID. AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. PARATHYROID GLANDS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED (11) 11 (11) 5 6 (9) 9 (11) 11 (10) 1 10 (1) 1 (11) 1 9 10 1 (1) 1 (1) 1 (12) 12 (12) 1 11 11 (12) 12 (12) 12 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified' Company Sanitized. Does not contain TSCA CBI -208- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (Continued) DuPont-5990 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS NERVOUS SYSTEM LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII BRAIN NO ABNORMALITY DETECTED SPINAL CORD NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED (11) 11 (11) 11 (11) 11 (1) (12) 1 12 (1) (12) 1 12 (1) (12) 1 12 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -209- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (Continued) DuPont-5990 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII MUSCULAR AND SKELETAL SYSTEM SKELETAL MUSCLE NO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED (11) 11 (11) 11 (11) 11 (1) (12) 1 12 (1) (12) 1 12 (1) (12) 1 12 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI - 210- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (Continued) DuPont-5990 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII REPRODUCTIVE SYSTEM TESTES NO ABNORMALITY DETECTED EPIDIDYMIDES NO ABNORMALITY DETECTED PROSTATE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. SEMINAL VESICLES NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. (11) 11 (11) 11 (11) 8 3 (11) 10 1 (1) (12) 1 12 (1) (12) 1 12 (1) (11) 10 11 (1) (12) 1 12 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -211 - H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (Continued) DuPont-5990 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII CUTANEOUS SYSTEM SKIN NO ABNORMALITY DETECTED ALOPECIA/HYPOTRICHOSIS. (11) 11 (1) (12) 1 11 1 SPECIAL SENSES SYSTEM EYE{S ) WITH OPTIC NERVE NO ABNORMALITY DETECTED OPTIC NERVE NOT PRESENT. HEMORRHAGE/INFLAMMATION (BLEEDING PROCEDURE). FOLD/ROSETTE, RETINAL. (11) 10 1 (1) (12) 8 1 12 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 Company Sanitized. Does not contain TSCA CBI - 212- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 40 (Continued) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS 1LESION INCIDI:NCE (NUMERIC) Males TREATMENT 0 500 , (mg/kg/day) I VII DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, FOCAL. HYPERTROPHY, CENTRILOBULAR. FATTY CHANGE, MEDIAN CLEFT. (10) 6 4 (10) 3 1 7 1 URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. (10) 7 3 (10) 2 8 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -213- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 40 (Continued) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS |LESION INCIDISNCE (NUMERIC) Males TREATMENT (mg/kg/day) 0 I 500 VII LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED PIGMENT INCREASED. HEMATOPOIESIS, INCREASED. (10) 10 (10) 2 7 8 ENDOCRINE SYSTEM THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. ALTERATION, COLLOID. (10) 4 6 (10) 8 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 Company Sanitized. Does not contain TSCA CBI -214- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 40 (Continued) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, FOCAL. FATTY CHANGE, PERIPORTAL. FATTY CHANGE, MEDIAN CLEFT. FATTY CHANGE, CENTRILOBULAR. (4) (5) (4) (5) 1323 211 1 121 1 URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. (4) (5) (4) (5) 113 4432 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified o CD Company Sanitized. Does not contain TSCA H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (Continued) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) DuPont-5990 LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED HEMATOPOIESIS, INCREASED. (4) (5) (4) (5) 4435 11 ENDOCRINE SYSTEM THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. ALTERATION, COLLOID. (4) (5) (4) (5) 3 4 1545 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -216- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) DuPont-5990 LESIONS DIGESTIVE SYSTEM TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 0 25 100 500 II IV VI VIII LIVER NO ABNORMALITY DETECTED NECROSIS, INDIVIDUAL CELL. INFLAMMATION, SUBACUTE/CHRONIC, FOCAL. HYPERTROPHY, CENTRILOBULAR. FATTY CHANGE, MEDIAN CLEFT. PANCREAS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, FOCAL. ESOPHAGUS NO ABNORMALITY DETECTED (10) 5 3 2 (10) 9 1 (10) 10 (10) 10 (10) 1 9 (10) 2 2 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 Company Sanitized. Does not contain TSCA CBI -217- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (Continued) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) DuPont-5990 LESIONS , LESION INCIDENCE (NUMERIC) Females TREATMENT 0 25 100 500 ! (mg/kg/day) II IV VI VIII DIGESTIVE SYSTEM STOMACH NO ABNORMALITY DETECTED EROSION/ULCER, ACUTE. DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 9 1 (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' Company Sanitized. Does not contain TSCA C8I -218- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (Continued) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) DuPont-5990 LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 0 25 100 500 II IV VI VIII DIGESTIVE SYSTEM CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED RECTUM NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (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 Company Sanitized. Does not contain TSCA CBI -219- 1H 1O H Company Sanitized. Does not contain TSCA C8I H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with Ohe-Generation Reproduction Evaluations TABLE 41 (Continued) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) DuPont-5990 LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 25 100 IV VI 500 VIII URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. INFLAMMATION, LYMPHOID, CORTICAL. URINARY BLADDER NO ABNORMALITY DETECTED (10) 8 2 (10) 10 (10) 7 2 1 (10) 5 5 (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 - 220- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (Continued) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) DuPont-5990 LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 0 25 100 500 II IV VI VIII RESPIRATORY SYSTEM LUNGS NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED NOSE I & II NO ABNORMALITY DETECTED NOSE III Sc IV NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (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 Company Sanitized. Does not contain TSCA CBI -221 - H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (Continued) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) DuPont-5990 LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 0 25 100 500 II IV VI VIII CARDIOVASCULAR SYSTEM HEART NO ABNORMALITY DETECTED AORTA 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 Company Sanitized. Does not contain TSCA CBI - 222- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (Continued) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) DuPont-5990 LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 0 25 100 500 II IV VI VIII LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED PIGMENT INCREASED. HEMATOPOIESIS, INCREASED. THYMUS NO ABNORMALITY DETECTED MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED CONGESTION. MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED (10) 9 1 (10) 10 (10) 10 (10) 10 (10) 9 1 (10) 4 6 (10) 10 7 (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 Company Sanitized. Does not contain TSCA CB! -223 - H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (Continued) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION) DuPont-5990 LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 0 25 100 500 II IV VI VIII LYMPHATIC AND HEMATOPOIETIC SYSTEM BONE MARROW NO ABNORMALITY DETECTED (10) 10 (10) 10 ENDOCRINE SYSTEM PITUITARY GLAND NO ABNORMALITY DETECTED NO MICROSCOPIC EVIDENCE OF MACROSCOPIC FINDING. THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. ALTERATION, COLLOID. (10) 10 (10) 7 3 (1) 1 1 (10) 4 6 (10) 2 10 (10) 10 (10) 9 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 Company Sanitized. Does not contain TSCA CBI -224- 1H 1O H Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (Continued) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) DuPont-5990 LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 25 100 500 IV VI VIII ENDOCRINE SYSTEM PARATHYROID GLANDS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED (8) 8 (10) 10 (9) 9 (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 -225- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (Continued) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) DuPont-5990 LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 0 25 100 500 II IV VI VIII NERVOUS SYSTEM BRAIN NO ABNORMALITY DETECTED SPINAL CORD NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED (10) 10 (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 Company Sanitized. Does not contain TSCA C8I -226- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (Continued) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION) DuPont-5990 LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 0 25 100 500 II IV VI VIII MUSCULAR AND SKELETAL SYSTEM SKELETAL MUSCLE NO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED (10) 10 (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 Company Sanitized. Does not contain TSCA CBI -227- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (Continued) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) DuPont-5990 LESIONS REPRODUCTIVE SYSTEM TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 0 25 100 500 II IV VI VIII OVARIES NO ABNORMALITY DETECTED UTERUS NO ABNORMALITY DETECTED DILATATION, LUMEN. MAMMARY GLAND (FEMALE) NO ABNORMALITY DETECTED HYPERPLASIA, LOBULAR. (10) 10 (10) 9 1 (10) 10 (10) 10 (1) (10) 7 13 (1) (10) 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 Company Sanitized. Does not contain TSCA CBI -228- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (Continued) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) DuPont-5990 LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 0 25 100 500 II IV VI VIII CUTANEOUS SYSTEM SKIN NO ABNORMALITY DETECTED ALOPECIA/HYPOTRICHOSIS. (10) 10 (10) 9 1 SPECIAL SENSES SYSTEM EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED HEMORRHAGE/INFLAMMATION (BLEEDING PROCEDURE). (10) 10 (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 Company Sanitized. Does not contain TSCA CBI -229- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 41 (Continued) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS 1LESION INCIDIINCE (NUMERIC) Females TREATMENT (mg/kg/day) 0 II 500 VIII DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, FOCAL. HYPERTROPHY, CENTRILOBULAR. STOMACH EROSION/ULCER, ACUTE. (10) 9 1 (10) 9 1 (1) 1 URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. HYDRONEPHROSIS, UNILATERAL. (10) 8 1 1 (10) 2 8 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA C8I -230- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 LESIONS TABLE 41 (Continued) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) 1LESION INCIDNCE (NUMERIC) Females TREATMENT (mg/kg/day) 0 II 500 VIII LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED HEMATOPOIESIS, INCREASED. (10) 10 (10) 9 1 ENDOCRINE SYSTEM THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. ALTERATION, COLLOID. (10) 9 1 (10) 6 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 Company Sanitized. Does not contain TSCA C8J -231 - H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 41 (Continued) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 0 25 100 500 II IV VI VIII DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, HYPERPLASIA, BILIARY. FATTY CHANGE, MEDIAN CLEFT. FOCAL. (4) (5) (5) (5) 2 553 1 1 11 URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED PYELONEPHRITIS, UNILATERAL. NEPHROPATHY, CHRONIC PROGRESSIVE. (4) (5) (5) (5) 2311 1 2244 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -232- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 41 (Continued) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED PIGMENT INCREASED. TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 0 25 100 500 II IV VI VIII (4) (5) (5) (5) 4533 22 ENDOCRINE SYSTEM THYROID GLAND NO ABNORMALITY DETECTED ALTERATION, COLLOID. (4) (5) (4) (4) 32 1-L. 1343 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CB1 -233 - H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 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) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, FOCAL. minimal total observations per lesion HYPERTROPHY, CENTRILOBULAR. minimal mild total observations per lesion FATTY CHANGE, PERIPORTAL. minimal total observations per lesion FATTY CHANGE, MEDIAN CLEFT. minimal total observations per lesion (11) 6 4 4 1 1 1 1 2 2 (10) 4 1 1 5 5 2 2 (11) 1 1 1 8 2 10 1 1 (12) 2 10 12 Figure in parentheses is number of animals microscopically examined for. this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -234- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 42 (Continued) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII DIGESTIVE SYSTEM PANCREAS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, FOCAL. minimal total observations per lesion ESOPHAGUS NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED (11) 8 3 3 (11) 11 (11) 11 (11) 11 (1) (12) 1 12 (1) (12) 1 12 (1) (12) 1 12 (1) (12) 1 12 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA C8I -235- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 42 (Continued) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII DIGESTIVE SYSTEM JEJUNUM NO ABNORMALITY DETECTED AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. ILEUM NO ABNORMALITY DETECTED AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED (11) 11 (11) 11 (11) 11 (11) 11 (1) (12) 1 12 1 (1) (12) 1 12 1 (1) (12) 1 12 (1) (12) 1 12 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -236- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 42 (Continued) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII DIGESTIVE SYSTEM RECTUM NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED (11) 11 (11) 11 (1) (12) 1 12 (1) (12) 1 12 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -237- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 42 (Continued) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED PYELONEPHRITIS, BILATERAL. minimal mild moderate total observations per lesion NEPHROPATHY, CHRONIC PROGRESSIVE. minimal mild total observations per lesion INFLAMMATION, SUBACUTE/CHRONIC, FOCAL. minimal total observations per lesion (11) 5 1 1 4 1 5 (10) 7 2 2 (11) 4 1 1 5 5 (12) 4 1 1 6 1 7 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 Company Sanitized. Does not contain TSCA CBI -238- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations____________________________________________________________ DuPont-5990 TABLE 42 (Continued) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII URINARY SYSTEM KIDNEYS (continued) HYDRONEPHROSIS, UNILATERAL. minimal mild severe total observations per lesion HYDRONEPHROSIS, BILATERAL. mild total observations per lesion NO MICROSCOPIC EVIDENCE OF MACROSCOPIC FINDING. 1 11 1 121 11 11 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 Company Sanitized. Does not contain TSCA CBI - 239- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 42 (Continued) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII URINARY SYSTEM URINARY BLADDER NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. minimal mild moderate total observations per lesion HYPERPLASIA, TRANSITIONAL CELL. minimal moderate total observations per lesion HEMORRHAGE. moderate total observations per lesion CALCULUS/CALCULI. (11) (1) (1) (12) 9 1 11 1 2 21 1 1 1 1 11 11 11 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 Company Sanitized. Does not contain TSCA CBI -240- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 42 (Continued) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII RESPIRATORY SYSTEM LUNGS NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED NOSE I & II NO ABNORMALITY DETECTED NOSE III & IV NO ABNORMALITY DETECTED (11) 11 (10) 10 (11) 11 (11) 11 (11) 11 (1) (12) 1 12 (1) (12) 1 12 (1) (11) 1 11 (1) (12) 1 12 (1) (12) 1 12 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBJ -241- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 42 (Continued) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII CARDIOVASCULAR SYSTEM HEART NO ABNORMALITY DETECTED CARDIOMYOPATHY. minimal total observations per lesion AORTA NO ABNORMALITY DETECTED (11) 10 1 1 (11) 11 (1) (12) 1 12 (1) (12) 1 12 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -242- *) H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations__________________________ ) DuPont-5990 TABLE 42 (Continued) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED PIGMENT INCREASED. minimal total observations per lesion INFLAMMATION, SUBACUTE/CHRONIC, FOCAL. minimal total observations per lesion HEMATOPOIESIS, INCREASED. minimal mild total observations per lesion ATROPHY, LYMPHOID. mild total observations per lesion (11) 10 1 1 (10) 9 1 1 (11) 3 4 4 8 8 (12) 1 6 6 9 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 Company Sanitized. Does not contain TSCA CBI - 243- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 42 (Continued) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII LYMPHATIC AND HEMATOPOIETIC SYSTEM THYMUS NO ABNORMALITY DETECTED NO MICROSCOPIC EVIDENCE OF MACROSCOPIC FINDING. MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED CONGESTION. minimal total observations per lesion MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED BONE MARROW NO ABNORMALITY DETECTED (11) (1) (1) (12) 11 1 12 1 (11) 11 (1) (12) 1 11 1 1 (11) 11 (1) (12) 1 12 (11) 11 (1) (12) 1 12 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI - 244- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 42 (Continued) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII ENDOCRINE SYSTEM PITUITARY GLAND NO ABNORMALITY DETECTED THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. minimal mild total observations per lesion ALTERATION, COLLOID. minimal mild moderate severe total observations per lesion AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. (11) 11 UU 5 4 2 6 (10) 1 1 3 2 1 4 10 (1) 1 (11) 1 9 9 1 3 2 4 10 1 (12) 12 (12) 1 3 8 11 1 1 3 6 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -245- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 42 (Continued) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII ENDOCRINE SYSTEM PARATHYROID GLANDS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED (9) 9 (11) 11 (1) (12) 1 12 (1) (12) 1 12 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -246- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 42 (Continued) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 1 25 100 500 III V VII NERVOUS SYSTEM BRAIN NO ABNORMALITY DETECTED SPINAL CORD NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED (11) 11 (11) 11 (11) 11 (1) (12) 1 12 (1) (12) 1 12 (1) (12) 1 12 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA o CD H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 42 (Continued) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII MUSCULAR AND SKELETAL SYSTEM SKELETAL MUSCLE NO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED (11) 11 (11) 11 (11) 11 (1) (12) 1 12 (1) (12) 1 12 (1) (12) 1 12 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -248- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 42 (Continued) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII REPRODUCTIVE SYSTEM TESTES NO ABNORMALITY DETECTED EPIDIDYMIDES NO ABNORMALITY DETECTED PROSTATE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. minimal mild moderate total observations per lesion (11) 11 (11) 11 (11) 8 1 1 1 3 (1) (12) 1 12 (1) (12) 1 12 (1) (11) 10 11 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -249- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 42 (Continued) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII REPRODUCTIVE SYSTEM SEMINAL VESICLES NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. mild total observations per lesion (11) 10 1 1 (1) (12) 1 12 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -250- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 42 (Continued) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII CUTANEOUS SYSTEM SKIN NO ABNORMALITY DETECTED ALOPECIA/HYPOTRICHOSIS. minimal total observations per lesion (11) 11 (1) (12) 1 11 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 Company Sanitized. Does not contain TSCA CBI -251- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 42 (Continued) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII SPECIAL SENSES SYSTEM EYE{S) WITH OPTIC NERVE NO ABNORMALITY DETECTED OPTIC NERVE NOT PRESENT. HEMORRHAGE/INFLAMMATION (BLEEDING PROCEDURE). minimal severe total observations per lesion FOLD/ROSETTE, RETINAL. minimal total observations per lesion (11) 10 1 1 (1) (12) 8 1 2 1 12 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 Company Sanitized. Does not contain TSCA CBI -252- H-24768: 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 RATS NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) DuPont-5990 LESIONS DIGESTIVE SYSTEM |LESION INCIDENCE (NUMERIC) Males TREATMENT (mg/kg/day) 0 I 500 VII LIVER NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, FOCAL. minimal total observations per lesion HYPERTROPHY, CENTRILOBULAR. minimal total observations per lesion FATTY CHANGE, MEDIAN CLEFT. minimal total observations per lesion (10) 6 4 4 (10) 3 1 1 7 7 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 Company Sanitized. Does not contain TSCA C8I -253- H-24768: 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 RATS NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) DuPont-5990 LESIONS LESION INCIDENCE (NUMERIC) Males TREATMENT (mg/kg/day) 0 I 500 VII URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. minimal total observations per lesion (10) 7 3 3 (10) 2 8 8 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -254- H-24768: 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 RATS NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) DuPont-5990 LESIONS |LESION INCIDINCE (NUMERIC) Males TREATMENT (mg/kg/day) 0 I 500 VII LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED PIGMENT INCREASED. minimal total observations per lesion HEMATOPOIESIS, INCREASED. minimal total observations per lesion (10) 10 (10) 2 7 7 8 8 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -255- H-24768: 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 RATS NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) DuPont-5990 LESIONS |LESION INCIDISNCE (NUMERIC) Males TREATMENT (mg/kg/day) 0 I 500 VII ENDOCRINE SYSTEM THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. minimal total observations per lesion ALTERATION, COLLOID. minimal mild moderate severe total observations per lesion (10) 4 6 6 (10) 8 8 2 2 3 3 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 Company Sanitized. Does not contain TSCA C8I -256- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 42 (Continued) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, FOCAL. minimal total observations per lesion FATTY CHANGE, PERIPORTAL. minimal total observations per lesion FATTY CHANGE, MEDIAN CLEFT. minimal total observations per lesion FATTY CHANGE, CENTRILOBULAR. minimal total observations per lesion (4) (5) (4) (5) 1323 211 211 1 1 121 121 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 Company Sanitized. Does not contain TSCA CBI -257- H-24768: 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 RATS NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) DuPont-5990 LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. minimal mild total observations per lesion (4) (5) (4) (5) 113 4 3 32 1 4 4 32 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -258- H-24768: 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 RATS NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) DuPont-5990 LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED HEMATOPOIESIS, INCREASED. minimal total observations per lesion (4) (5) (4) (5) 443 5 11 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -259- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 42 (Continued) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII ENDOCRINE SYSTEM THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. minimal total observations per lesion ALTERATION, COLLOID. minimal mild moderate severe total observations per lesion (4) (5) (4) (5) 3 4 4 13 2 12 31 2 1545 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -260- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 43 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 0 25 100 500 II IV VI VIII DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED NECROSIS, INDIVIDUAL CELL. minimal mild total observations per lesion INFLAMMATION, SUBACUTE/CHRONIC, FOCAL. minimal total observations per lesion HYPERTROPHY, CENTRILOBULAR. minimal mild moderate total observations per lesion FATTY CHANGE, MEDIAN CLEFT. ' minimal mild total observations per lesion (10) 5 (10) 10 3 3 1 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 (10) 1 9 9 (10) 1 1 2 2 2 1 8 1 10 Company Sanitized. Does not contain TSCA C8( - 261- H-24768: 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 RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) DuPont-5990 LESIONS DIGESTIVE SYSTEM LESION INCIDENCE (NUMERIC) Females TREATMENT o 25 100 500 (mg/kg/day) 1 II IV VI VIII PANCREAS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, FOCAL. minimal total observations per lesion ESOPHAGUS NO ABNORMALITY DETECTED . STOMACH NO ABNORMALITY DETECTED EROSION/ULCER, ACUTE. minimal total observations per lesion (10) 9 1 1 (10) 10 (10) 10 (10) 10 (10) 10 (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 Company Sanitized. Does not contain TSCA C8J -262- H-24768: 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 RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) DuPont-5990 LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 0 25 100 500 II IV VI VIII DIGESTIVE SYSTEM DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (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 Company Sanitized. Does not contain TSCA CBI -263- H-24768: 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 RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) DuPont-5990 LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 0 25 100 500 II IV VI VIII DIGESTIVE SYSTEM RECTUM NO ABNORMALITY DETECTED SALIVARY GLANDS 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 Company Sanitized. Does not contain TSCA CBI -264- H-24768: 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 RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) DuPont-5990 LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 0 25 100 500 II IV VI VIII URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. minimal mild moderate total observations per lesion INFLAMMATION, LYMPHOID, CORTICAL. minimal total observations per lesion URINARY BLADDER NO ABNORMALITY DETECTED (10) 8 2 2 GO) 10 (10) 7 2 2 1 1 GO) 5 4 1 5 GO) 5 3 1 1 5 GO) 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 Company Sanitized. Does not contain TSCA CBI -265- 1H 1O H Company Sanitized. Does not contain TSCA CBi H-24768: 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 RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) DuPont-5990 LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 25 100 500 IV VI VIII RESPIRATORY SYSTEM LUNGS NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED NOSE I & II NO ABNORMALITY DETECTED NOSE III & IV NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (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 -266- H-24768: 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 RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) DuPont-5990 LESIONS TREATMENT (mg/kg/day) HO H LESION INCIDENCE (NUMERIC) Females 25 100 500 IV VI VIII CARDIOVASCULAR SYSTEM HEART NO ABNORMALITY DETECTED AORTA 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 Company Sanitized. Does not contain TSCA CBI -267- 1H 1O H Company Sanitized. Does not contain TSCA CBI H-24768: 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 RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) DuPont-5990 LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 25 100 500 IV VI VIII LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED PIGMENT INCREASED. minimal total observations per lesion HEMATOPOIESIS, INCREASED. minimal mild total observations per lesion (10) 9 1 1 (10) 9 1 1 (10) 4 6 6 (10) 10 10 5 2 7 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- H-24768: 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 RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) DuPont-5990 LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 0 25 100 500 II IV VI VIII LYMPHATIC AND HEMATOPOIETIC SYSTEM THYMUS NO ABNORMALITY DETECTED MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED CONGESTION. mild total observations per lesion MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED BONE MARROW NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 9 1 1 (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 Company Sanitized. Does not contain TSCA CBI -269- H-24768: 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 RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) DuPont-5990 LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 0 25 100 500 II IV VI VIII ENDOCRINE SYSTEM PITUITARY GLAND NO ABNORMALITY DETECTED NO MICROSCOPIC EVIDENCE OF MACROSCOPIC FINDING. THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. minimal mild total observations per lesion ALTERATION, COLLOID. minimal mild moderate severe total observations per lesion (10) 10 (10) 7 3 3 (1) 1 1 (10) 4 6 6 (10) 2 2 4 5 1 10 (10) 10 (10) 6 3 9 2 4 3 1 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 Company Sanitized. Does not contain TSCA CBI -270- H-24768: 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 RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) DuPont-5990 LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 0 25 100 500 II IV VI VIII ENDOCRINE SYSTEM PARATHYROID GLANDS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED (8) 8 (10) 10 (9) 9 (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 Company Sanitized. Does not contain TSCA CBI -271- H-24768: 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 RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) DuPont-5990 LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 0 25 100 500 II IV VI VIII NERVOUS SYSTEM BRAIN NO ABNORMALITY DETECTED SPINAL CORD NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 GO) 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 C om p a n y S a n itiz e d . Does not contain TSCA o 00 H-24768: 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 RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) DuPont-5990 LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 0 25 100 500 II IV VI VIII MUSCULAR AND SKELETAL SYSTEM SKELETAL MUSCLE NO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED (10) 10 (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 Company Sanitized. Does not contain TSCA C8I -273- H-24768: 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 RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) DuPont-5990 LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 0 25 100 500 II IV VI VIII REPRODUCTIVE SYSTEM OVARIES NO ABNORMALITY DETECTED UTERUS NO ABNORMALITY DETECTED DILATATION, LUMEN. minimal mild total observations per lesion MAMMARY GLAND (FEMALE) NO ABNORMALITY DETECTED HYPERPLASIA, LOBULAR. ' mild total observations per lesion (10) 10 (10) 9 1 1 (10) 10 (10) 10 (1) (10) 7 3 1 13 (1) (10) 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 Company Sanitized. Does not contain TSCA CBI -274- H-24768: 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 RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) DuPont-5990 LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 0 25 100 500 II IV VI VIII CUTANEOUS SYSTEM SKIN NO ABNORMALITY DETECTED ALOPECIA/HYPOTRICHOSIS. mild total observations per lesion (10) 10 (10) 9 1 1 SPECIAL SENSES SYSTEM EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED HEMORRHAGE/INFLAMMATION (BLEEDING PROCEDURE). (10) 10 (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 Company Sanitized. Does not contain TSCA CBI -275- H-24768: 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 RATS NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) DuPont-5990 LESIONS |LESION INCIDIINCE (NUMERIC) Females TREATMENT (mg/kg/day) 0 II 500 VIII DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, FOCAL. minimal total observations per lesion HYPERTROPHY, CENTRILOBULAR. minimal total observations per lesion (10) 9 1 1 (10) 9 1 1 STOMACH EROSION/ULCER, ACUTE. minimal total observations per lesion (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 Company Sanitized. Does not contain TSCA CBI -276- H-24768: 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 RATS NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) DuPont-5990 LESIONS |LESION INCIDI3NCE (NUMERIC) Females TREATMENT (mg/kg/day) 0 II 500 VIII URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. minimal mild moderate total observations per lesion HYDRONEPHROSIS, UNILATERAL. moderate total observations per lesion (10) 8 1 1 1 1 (10) 2 6 1 1 8 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -277- H-24768: 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 RATS NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) DuPont-5990 LESIONS |LESION INCIDINCE (NUMERIC) Females TREATMENT (mg/kg/day) 0 II 500 VIII LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED HEMATOPOIESIS, INCREASED. minimal total observations per lesion (10) 10 (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 Company Sanitized. Does not contain TSCA CBI -278- H-24768: 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 RATS NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) DuPont-5990 LESIONS |LESION INCIDI3NCE (NUMERIC) Females TREATMENT (mg/kg/day) 0 II 500 VIII ENDOCRINE SYSTEM THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. minimal mild total observations per lesion ALTERATION, COLLOID. minimal mild moderate total observations per lesion (10) 9 1 1 (10) 5 1 6 1 4 5 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 Company Sanitized. Does not contain TSCA CBI -279- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 43 (Continued) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 0 25 100 500 II IV VI VIII DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, FOCAL. mild total observations per lesion HYPERPLASIA, BILIARY. minimal total observations per lesion FATTY CHANGE, MEDIAN CLEFT. minimal total observations per lesion (4) (5) (5) (5) 2553 1 1 1 1 11 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA C8I -280- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 43 (Continued) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 0 25 100 500 II IV VI VIII URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED PYELONEPHRITIS, UNILATERAL. minimal total observations per lesion NEPHROPATHY, CHRONIC PROGRESSIVE. minimal mild moderate total observations per lesion (4) (5) (5) (5) 2311 1 1 2222 12 1 2244 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -281- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 43 (Continued) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) Females 0 25 100 500 II IV VI VIII LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED PIGMENT INCREASED. minimal total observations per lesion (4) (5) (5) (5) 4 53 3 1 12 22 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was -not identified Company Sanitized. Does not contain TSCA CBI -282- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 43 (Continued) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) O1 1 LESION INCIDENCE (NUMERIC) Females 25 100 500 IV VI VIII H 'H ENDOCRINE SYSTEM THYROID GLAND NO ABNORMALITY DETECTED ALTERATION, COLLOID. minimal mild moderate total observations per lesion (4) (5) (4) (4) 32 1 133 12 1 1343 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA Oro H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 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) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, FOCAL. HYPERTROPHY, CENTRILOBULAR. (11) 646360 646367 646457 646482 646489 646492 646374 646379 646420 646485 646379 (10) 646421 646423 646426 646454 646443 646370 646399 646443 646458 646471 (11) 646477 646385 646349 646373 646385 646435 646455 646456 646463 646469 646472 646488 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -284- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LES I O N INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII DIGESTIVE SYSTEM LIVER FATTY CHANGE, PERIPORTAL. FATTY CHANGE, MEDIAN CLEFT. (11) 646420 646420 646427 (10) 646414 646458 (11) 646456 (12) Figure in parentheses is num b e r of animals m i c r oscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA C8I -285- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII DIGESTIVE SYSTEM PANCREAS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, FOCAL. (11) 646360 646367 646420 646427 646457 646482 646485 646492 646374 646379 646489 (1) 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -286- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII DIGESTIVE SYSTEM ESOPHAGUS NO ABNORMALITY DETECTED (11) 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -287- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII DIGESTIVE SYSTEM STOMACH NO ABNORMALITY DETECTED (11) 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -288- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII DIGESTIVE SYSTEM DUODENUM NO ABNORMALITY DETECTED (11) 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -289- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII DIGESTIVE SYSTEM JEJUNUM NO ABNORMALITY DETECTED AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. (ID 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) 646477 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBi -290- H-2476S: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII DIGESTIVE SYSTEM ILEUM NO ABNORMALITY DETECTED AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. (11) 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) 646477 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microsc o p i c a l l y examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -291- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII DIGESTIVE SYSTEM CECUM NO ABNORMALITY DETECTED (11) 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -292- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LES I O N INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII DIGESTIVE SYSTEM COLON NO ABNORMALITY DETECTED (ID 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA o CD H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LES I O N INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII DIGESTIVE SYSTEM RECTUM NO ABNORMALITY DETECTED (11) 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -294- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII DIGESTIVE SYSTEM SALIVARY GLANDS NO ABNORMALITY DETECTED (11) 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -295- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED PYELONEPHRITIS, BILATERAL. NEPHROPATHY, CHRONIC PROGRESSIVE. INFLAMMATION, SUBACUTE/CHRONIC, FOCAL. HYDRONEPHROSIS, UNILATERAL. HYDRONEPHROSIS, BILATERAL. NO MICROSCOPIC EVIDENCE OF MACROSCOPIC FINDING. (11) 646360 646367 646374 646379 646489 646420 646427 646457 646482 646485 646492 (10) 646399 646414 646421 646423 646454 646458 646471 646370 646426 646443 646426 (11) 646385 646455 646456 646469 646472 646349 646373 646435 646463 646477 646435 646488 646463 (12) 646343 646413 646433 646437 646380 646346 646347 646388 646407 646422 646442 646475 646442 646422 646380 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA C8I -296- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII URINARY SYSTEM URINARY BLADDER NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. HYPERPLASIA, TRANSITIONAL CELL. HEMORRHAGE. CALCULUS/CALCULI. (11) 646360 646367 646374 646379 646427 646482 646485 646489 646492 646420 646457 646420 646457 646420 (1) 646426 646426 (1) 646477 (12) 646343 646346 646347 646388 646407 646413 646422 646433 646437 646442 646475 646380 646380 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -297- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESI O N INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII RESPIRATORY SYSTEM LUNGS NO ABNORMALITY DETECTED (ID 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA C8I -298- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII RESPIRATORY SYSTEM TRACHEA NO ABNORMALITY DETECTED (10) 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -299- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII RESPIRATORY SYSTEM PHARYNX/LARYNX NO ABNORMALITY DETECTED (11) 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) 646477 (11) 646343 646346 646347 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -300- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII RESPIRATORY SYSTEM NOSE I & II NO ABNORMALITY DETECTED (11) 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. D oes not contain TSCA CBI -301- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LES I O N INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII RESPIRATORY SYSTEM NOSE III & IV NO ABNORMALITY DETECTED (ID 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA O H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII CARDIOVASCULAR SYSTEM HEART NO ABNORMALITY DETECTED CARDIOMYOPATHY. (11) 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 646360 (1} 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -303- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII CARDIOVASCULAR SYSTEM AORTA NO ABNORMALITY DETECTED (ID 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA C8I -304- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED PIGMENT INCREASED. INFLAMMATION, SUBACUTE/CHRONIC, FOCAL. HEMATOPOIESIS, INCREASED. (11) 646360 646367 646379 646420 646427 646457 646482 646485 646489 646492 646374 (10) 646370 646399 646414 646421 646423 646426 646443 646454 646458 646471 * (11) 646385 646469 646488 646435 646455 646456 646463 646349 646373 646435 646455 646456 (12) 646422 646343 646388 646407 646433 646442 646475 646343 646346 646347 646388 646407 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBi -305- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN HEMATOPOIESIS, INCREASED. ATROPHY, LYMPHOID. (11) (10) (11) 646463 646472 646477 (12) 646413 646433 646437 646442 646475 646380 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA O CD )) H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII LYMPHATIC AND HEMATOPOIETIC SYSTEM THYMUS NO ABNORMALITY DETECTED NO MICROSCOPIC EVIDENCE OF MACROSCOPIC FINDING. (11) 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) 646443 (1) 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -307- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LES I O N INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII LYMPHATIC AND HEMATOPOIETIC SYSTEM MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED CONGESTION. (11) 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) 646477 (12) 646343 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 646346 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -308- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS L E S I O N INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII LYMPHATIC AND HEMATOPOIETIC SYSTEM MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED (ID 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA C8I -309- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII LYMPHATIC AMD HEMATOPOIETIC SYSTEM BONE MARROW NO ABNORMALITY DETECTED (11) 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBJ -310- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII ENDOCRINE SYSTEM PITUITARY GLAND NO ABNORMALITY DETECTED (11) 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microsc o p i c a l l y examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA C B I -311 - " "'iv H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII ENDOCRINE SYSTEM THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. ALTERATION, COLLOID. (11) 646427 646457 646482 646489 646492 646360 646367 646374 646379 646420 646485 (10) 646423 646370 646399 646414 646421 646423 646426 (11) 646477 646349 646373 646385 646435 646455 646463 646469 646472 646488 646349 646373 646385 646435 646455 646456 (12) 646380 646343 646346 646347 646388 646407 646413 646422 646433 646437 646442 646475 646343 646346 646347 646388 646407 646413 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -312- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESI O N INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII ENDOCRINE SYSTEM THYROID GLAND ALTERATION, COLLOID. AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. (11) (10) 646443 646454 646458 646471 (11) 646463 646469 646472 646488 646477 (12) 646422 646433 646437 646442 646475 Figure in. p arentheses is number of animals m i c r oscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -313- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII ENDOCRINE SYSTEM PARATHYROID GLANDS NO ABNORMALITY DETECTED (9) 646360 646367 646374 646420 646427 646457 646485 646489 646492 (1) 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -314- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESI O N INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII ENDOCRINE SYSTEM ADRENAL GLANDS NO ABNORMALITY DETECTED (ID 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESI O N INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII NERVOUS SYSTEM BRAIN NO ABNORMALITY DETECTED (11) 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -316- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS NERVOUS SYSTEM LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII SPINAL CORD NO ABNORMALITY DETECTED (11) 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -317- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII NERVOUS SYSTEM SCIATIC NERVE NO ABNORMALITY DETECTED (11) 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) (12) 646477 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -318- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII MUSCULAR AND SKELETAL SYSTEM SKELETAL MUSCLE NO ABNORMALITY DETECTED (11) 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -319- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII MUSCULAR AND SKELETAL SYSTEM FEMUR/KNEE JOINT NO ABNORMALITY DETECTED (ID 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -320- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII MUSCULAR AMD SKELETAL SYSTEM STERNUM NO ABNORMALITY DETECTED (ID 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) 646477 12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microsc o p i c a l l y examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -321- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII REPRODUCTIVE SYSTEM TESTES NO ABNORMALITY DETECTED (ID 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -322- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII REPRODUCTIVE SYSTEM EPIDIDYMIDES NO ABNORMALITY DETECTED (11) 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Compafny Sanitized. Does not contain TSCA CBI -323- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII REPRODUCTIVE SYSTEM PROSTATE NO ABNORMALITY DETECTED INFLAMMATION, SUBA C U T E /C H R O N I C . (11) 646360 646367 646374 646379 646457 646482 646489 646492 646420 646427 646485 (1) 646477 (11) 646343 646346 646347 646388 646407 646422 646433 646437 646442 646475 646413 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBi -324- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII REPRODUCTIVE SYSTEM SEMINAL VESICLES NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. (11) 646360 646367 646374 646379 646427 646457 646482 646485 646489 646492 646420 (1) 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646437 646442 646475 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -325- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LES I O N INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII CUTANEOUS SYSTEM SKIN NO ABNORMALITY DETECTED ALOPECIA/HYPOTRICHOSIS. (11) 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) 646477 (12) 646343 646346 646347 646380 646388 646407 646413 646422 646433 646442 646475 646437 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -326- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII SPECIAL SENSES SYSTEM E Y E (S ) W I T H OPTIC NERVE NO ABNORMALITY DETECTED OPTIC NERVE NOT PRESENT. HEMORRHAGE/INFLAMMATION (BLEEDING PROCEDURE). FOLD/ROSETTE, RETINAL. (ID 646360 646367 646374 646379 646420 646427 646457 646482 646485 646489 646492 (1) (12) 646343 646347 646380 646388 646407 646422 646437 646442 646477 646475 646346 646475 646413 646433 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -327- )) H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 44 (Continued) ) DuPont-5990 MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (ONE-MONTH RECOVERY EVALUATION) LESIONS ILESION INCIDENCE (NUMERIC) Males TREATMENT (mg/kg/day) 0 I 500 VII DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, FOCAL. HYPERTROPHY, CENTRILOBULAR. FATTY CHANGE, MEDIAN CLEFT. (10) (10) 646371 646369 646411 646428 646432 646484 646460 646487 646494 646398 646384 646416 646446 646459 646337 646364 646372 646384 646397 646448 646474 646448 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA G8I -328- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 44 (Continued) DuPont-5990 MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (ONE-MONTH RECOVERY EVALUATION) LESIONS ILESI O N INCIDENCE (NUMERIC) Males TREATMENT (mg/kg/day) 0 I 500 VII URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. (10) 646371 646398 646446 646459 646460 646487 646494 646411 646416 646432 (10) 646364 646474 646337 646369 646372 646384 646397 646428 646448 646484 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -329- )) H-24768: Subcbronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 44 (Continued) ...) DuPont-5990 MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (ONE-MONTH RECOVERY EVALUATION) LESIONS ILESION INCIDENCE (NUMERIC) Males TREATMENT (mg/kg/day) 0 I 500 VII LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED PIGMENT INCREASED. HEMATOPOIESIS, INCREASED. Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) (10) 646371 646369 646398 646372 646411 646416 646432 646446 646459 646460 646487 646494 646364 646384 646397 646428 646448 646474 646484 646337 646364 646384 646397 646428 Company Sanitized. Does not contain TSCA CBI -330- ) H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 44 (Continued) > DuPont-5990 MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (ONE-MONTH RECOVERY EVALUATION) LESIONS |LESION INCIDI3NCE (NUMERIC) Males TREATMENT (mg/kg/day) 0 I 500 VII LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN HEMATOPOIESIS, INCREASED. (10) (10) 646448 646474 646484 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBi -331- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 44 (Continued) DuPont-5990 MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (ONE-MONTH RECOVERY EVALUATION) LESIONS ILESI O N INCIDENCE (NUMERIC) Males TREATMENT (mg/kg/day) 0 I 500 VII ENDOCRINE SYSTEM THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. 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 (10) (10) 646398 646411 646460 646487 646364 646369 646372 646397 646428 646448 646474 646484 646371 646337 646416 646364 646432 646369 646446 646372 646459 646384 646494 646397 646428 646448 646474 646484 Company Sanitized. Does not contain TSCA C8I -332- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (THREE-MONTH RECOVERY EVALUATION) LESIONS DIGESTIVE SYSTEM LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII LIVER NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, FOCAL. FATTY CHANGE, PERIPORTAL. FATTY CHANGE, MEDIAN CLEFT. FATTY CHANGE, CENTRILOBULAR. (4) 646468 646396 646495 646325 (5) 646368 646436 646438 646453 646449 (4) 646376 646403 646335 646327 646335 (5) 646355 646391 646466 646344 646361 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA Oro H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (THREE-MONTH RECOVERY EVALUATION) LESIONS LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. (4) 646325 646396 646468 646495 (5) 646436 646368 646438 646449 646453 (4) 646327 646335 646376 646403 (5) 646344 646361 646391 646355 646466 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -334- H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (THREE-MONTH RECOVERY EVALUATION) LESIONS LES I O N INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED HEMATOPOIESIS, INCREASED. (4) 646325 646396 646468 646495 (5) 646436 646438 646449 646453 646368 (4) 646327 646376 646403 646335 (5) 646344 646355 646361 646391 646466 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -335 - H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5990 TABLE 44 (Continued) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED NEOPLASTIC AND NON-NEOPLASTIC (THREE-MONTH RECOVERY EVALUATION) LESIONS ENDOCRINE SYSTEM LESION INCIDENCE (Animal #) Males TREATMENT (mg/kg/day) 0 I 25 100 500 III V VII THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. ALTERATION, COLLOID. (4) 646325 646396 646468 646495 (5) 646368 646436 646438 646449 646453 (4) 646327 646335 646376 646403 (5) 646344 646355 646361 646466 646344 646355 646361 646391 646466 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBI -336-