Document przL18bn547x5w6JDj8mLgXa

AR226-3184 DuPont-4739 TRADE SECRET Study Title H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations Volume 1 of 5 Laboratory Project ED: DuPont-4739 Test Guidelines: U.S. EPA Health Effects Test Guidelines OPPTS 870.3100 (1998) Author: Don A. Delker, Ph.D. Study Completed on: October 23,2001 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 Work Request Number: mService Code Number: Sponsor Study Number: t Page 1 of 1537 Company Sanitized. Does not contain TSC CB H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 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 items documented below. None of the items listed impact the validity of the study. 1. The characterization of the test substance that was conducted prior to the initiation of the study provided the percentage of solids in the test substance. This information was used to calculate the dose levels, based on percent active ingredient, for the study. Additional chemical characterization of the test substance was conducted after the completion of the study and provided analysis of the solids in the test substance. Samples of the test substance were collected on the first day of dosing, during the 90-day dosing period, and on the last day of dosing and were analyzed; these analyses provided confirmation of the percentage of solids and documented the test substance stability and uniformity over the course of the study. None of the aforementioned analyses were performed under Good Laboratory Practice Standards; however, the analyses were conducted in compliance with IS09002 regulations. All of the analyses are considered valid and sufficient for the purposes of this study. 2. Gross observations on five F| weanlings, not more than two from any treatment group, were inadvertently not documented at the time of necropsy. Due to the large number of pups that received gross observations on postnatal day 21, this lack of data will not affect the validity of the study. Submitter / Sponsor: E.I. du Pont de Nemours and Company Wilmington, Delaware 19898 U.S.A. Study Director: TW Don A. Delker, PH.D. Research Scientist 3-7 OcA- ~&e\ Date 2 Company Sanitized. Does not contain TSCA CEI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations QUALITY ASSURANCE STATEMENT DuPont-4739 Haskell Sample Number(s): 24616 Dates of Inspections: Conduct: September 6, 2000; November 13, 15, 22, 2000; December 6,14, 18,2000 Records, Reports: March 5-9, 2001; April 10-12,15,16, 27, 30, 31, 2001, May 1-4, 6 10, 13-14, 17-18,21-25,28-31,2001; June 1,4, 2001; August 6-10, 13, 30, 2001; September 11-14, 17, 2001 Dates Findings Reported to: Study Director: November 14, 2000; March 12, 2001; April 16, 2001; May 14, 2001; June 18, 2001; August 30, 31, 2001; September 17, 2001 Management: December 3, 2000; March 12, 2001; April 16, 2001; June 18, 2001, August 30, 31, 2001; September 17, 25,2001; October 18, 2001 Date 3 Company Sanitized. Does not co n tre H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 CERTIFICATION We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study. Neurological Evaluations Reported by: Reproductive Evaluations Reported by: Linda A. Malley, PlD.,T).A.B.T. Senior Research Scientist J 3 - P o d 'Date Zi- fcA ot Date Clinical Pathology Evaluations Reported by: Pathological Evaluations Reported by: Pathological Evaluations Peer Review Reported by: Diplomate A.C.V.P. Principal Research Sdentisi G. Tracy Makovec, D.V.M. Diplomate A.C.V.P. Senior Research Scientist Steven R. Frame. D.V.M., Ph.D. Diplomate A.C.V.P. Director, Anatomic Pathology 2 3 O ot2o\ Date Date Date Approved by: C . v d f c i d j ? / a. / / Judith C. StadleK Ph.D., D.A.B.T. / Director, General Toxicology Issued by Study Director: Qm k ' o3nonf iK. .DDeleklekre,rP, bP,h.D. Research Scientist H - & T -Z l Date 2-3 C^ Z**} Date 4 Company Sanitized. Does not contain T S C A CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE OF CONTENTS DuPont-4739 Page GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT...................................2 QUALITY ASSURANCE STATEMENT.................................................................................... 3 CERTIFICATION......................................................................................................................... 4 LIST OF TABLES..........................................................................................................................8 LIST OF FIGURES......................................................................................................................11 LIST OF APPENDICES............................................................................................................. 12 STUDY INFORMATION.............................................................................................................14 STUDY PERSONNEL..................................................................................................................15 SUMMARY.................................................................................................................................... 16 INTRODUCTION......................................................................................................................... 19 OBJECTIVE.................................................................................................................................. 19 MATERIALS AND METHODS.................................................................................................19 A. Test Guidelines....................................................................................................................I 9 B. Test Substance.....................................................................................................................I9 C. Test Species.........................................................................................................................I 9 D. Animal Husbandry.................................................................. . --.....................................2^ E. Quarantine and Pretest Period............................... 21 F. Study Design.......................................................................................................................22 G. Assignment to Groups and Study Start.............................................................................. 22 H. Test Substance Administration and Sampling................................................................... 23 I. Body Weights......................................................................................................................23 J. Food Consumption and Food Efficiency............................................................................ 23 K. Detailed Clinical Observations and Mortality.................................................................... 24 L. Ophthalmological Evaluations........................................................................................... 24 M. Neurotoxicity Evaluations.................................................................................................. 25 N. Clinical Pathology.............................................................................................................. 2^ O. Serial Blood Collection (Satellite Group).......................................................................... 27 P. Anatomic Pathology - Rats Designated for Subchronic Toxicity and Recovery.............. 27 Q. Reproductive Assessment.................................................................................................. 29 R. Anatomical Pathology - Rats Designated for Reproductive Evaluations.......................... 30 S. Statistical Analyses............................................................................................................. 33 RECORDS AND SAMPLE STORAGE.................................................................................... 35 5 Company Sanitized. Does not contain T S C A CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE OF CONTENTS (Continued) RESULTS AND DISCUSSION......................................................................... ANALYTICAL EVALUATIONS...................................................................... A. Test Substance Stability............................................................................ B. Test Substance Concentration Verification............................................... C. Iodine Analysis.......................................................................................... D. Analytical Conclusions.............................................................................. SUBCHRONIC TOXICITY EVALUATIONS................................................ IN-LIFE TOXICOLOGY................................................................................... A. Dosage D ata.............................................................................................. B. Mean Body Weights and Body Weight Gains........................................... C. Food Consumption and Food Efficiency................................................... D. Clinical Observations, Ophthalmology Evaluations, and Survival.......... E. In-Life Toxicology Conclusions................................................................ NEUROBEHAVIORAL TOXICOLOGY........................................................ A. Functional Observational Battery (FOB).................................................. B. Motor Activity (MA)................................................................................. C. Neurobehavioral Toxicity Conclusions..................................................... CLINICAL PATHOLOGY...... ........................................................................ A. Hematology/Coagulation........................................................................... B. Clinical Chemistry.................................................................................... C. Urinalysis.................................................................................................. D. Clinical Pathology Conclusions................................................................ ANATOMICAL PATHOLOGY....................................................................... A. Subchronic Toxicity and Recovery...................................................... B. Anatomical Pathology Conclusions for Subchronic Toxicity Evaluation REPRODUCTIVE TOXICOLOGY EVALUATIONS.................................. REPRODUCTIVE FUNCTION....................................................................... A. Pi Generation............................................................................................ B. Offspring Data.......................................................................................... C. Fi Generation............................................................................................ D. Reproductive Function Conclusions........................................................ Page ....36 ....36 ....36 ....36 ....36 ....37 ....38 ....38 ....38 ....38 ....39 ....39 ....39 ....40 ....40 ... 40 ... 41 ....42 ... 42 ... 43 ... 46 ... 47 .... 48 ....48 ....52 .... 53 .... 53 ....53 ....53 ....54 ....54 6 Company Sanitized. Does not contain T S C A CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE OF CONTENTS (Continued) ANATOMICAL PATHOLOGY......................................................... A. Organ Weight Data.................................................................... B. Gross Observations................................................................... C. Microscopic Observations......................................................... D. Mortality.................................................................................... E. Anatomical Pathology Conclusions for Reproductive Toxicity CONCLUSIONS................................................................................. REFERENCES.................................................................................... TABLES (Tables 1-41)........................................................................ VOLUME 2 TABLES (Tables 42-74)...................................................................... FIGURES............................................................................................. APPENDICES (Appendices A-E)...................................................... VOLUME 3 (Appendices F-L)................................ ......................... VOLUME 4 (Appendices L-JJ)......................................................... VOLUME 5 (Appendices KK-OO).................................................... DuPont-4739 Page ....55 ....55 ....55 ....55 ....55 ....55 ....56 .... 57 ....59 ..297 ..394 ..406 ,.607 ,.937 .1197 7 Company Sanitized. Does not contain T S C A CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 LIST OF TABLES Page TABLE 1 TABLE 2 TABLE 3 TABLE 4 TABLE 5 TABLE 6 TABLE 7 TABLE 8 TABLE 9 TABLE 10 TABLE 11 TABLE 12 TABLE 13 TABLE 14 TABLE 15 TABLE 16 TABLE 17 TABLE 18 TABLE 19 TABLE 20 TABLE 21 TABLE 22 TABLE 23 TABLE 24 TABLE 25 TABLE 26 TABLE 27 TABLE 28 MEAN DAILY DOSE VOLUMES FOR MALE RATS....................................................................63 MEAN DAILY DOSE VOLUMES FOR FEMALE RATS................................................................64 MEAN BODY WEIGHTS OF MALE RATS.....................................................................................65 MEAN BODY WEIGHTS OF FEMALE RATS................................................................................ 67 MEAN BODY WEIGHT GAINS OF MALE RATS.......................................................................... 69 MEAN BODY WEIGHT GAINS OF FEMALE RATS..................................................................... 71 MEAN DAILY FOOD CONSUMPTION BY MALE RA TS............................................................73 MEAN DAILY FOOD CONSUMPTION BY FEMALE RATS........................................................ 75 MEAN DAILY FOOD EFFICIENCY OF MALE RATS................................................................... 77 MEAN DAILY FOOD EFFICIENCY OF FEMALE RATS.............................................................. 79 SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS...............................................81 SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS......................................... 84 SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR MALE RATS......................87 SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR FEMALE RATS.................88 PERCENT SURVIVAL OF MALE RATS......................................................................................... 89 PERCENT SURVIVAL OF FEMALE RATS.................................................................................... 90 MEAN FORELIMB GRIP STRENGTH: MEAN OF THREE TRIALS..........................................91 MEAN HINDLIMB GRIP STRENGTH: MEAN OF THREE TRIALS...........,........................... 92 SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR MALE RATS.............................................................................................................................. 93 SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR FEMALE RATS......................................................................................................................... 95 MOTOR ACTIVITY ASSESSMENT: DURATION OF MOVEMENTS FOR MALE RATS.............................................................................................................................. 97 MOTOR ACTIVITY ASSESSMENT: DURATION OF MOVEMENTS FOR FEMALE RATS......................................................................................................................... 99 MOTOR ACTIVITY ASSESSMENT: NUMBER OF MOVEMENTS FOR MALE RATS.............................................................................................................................101 MOTOR ACTIVITY ASSESSMENT: NUMBER OF MOVEMENTS FOR FEMALE RATS....................................................................................................................... 103 SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS..................................................105 SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS.............................................109 SUMMARY OF COAGULATION VALUES FOR MALE RATS.................................................113 SUMMARY OF COAGULATION VALUES FOR FEMALE RATS............................................113 8 Com pany Sanitized. Does not contain T S C A CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 LIST OF TABLES (Continued) Page TABLE 29 TABLE 30 TABLE 31 TABLE 32 TABLE 33 TABLE 34 TABLE 35 TABLE 36 TABLE 37 TABLE 38 TABLE 39 TABLE 40 TABLE 41 TABLE 42 TABLE 43 TABLE 44 TABLE 45 TABLE 46 TABLE 47 TABLE 48 TABLE 49 TABLE 50 TABLE 51 TABLE 52 TABLE 53 SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS.............114 SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS....... 118 SUMMARY OF URINALYSIS VALUES FOR MALE RATS...................................................... 122 SUMMARY OF URINALYSIS VALUES FOR FEMALE RATS.................................................. 124 MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS.......................................... 126 MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS.....................................133 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS................................................... 140 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS.............................................. 155 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS....................................................................176 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS....................................................................185 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS- NON-NEOPLASTIC LESIONS.........................................................................203 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS- NON-NEOPLASTIC LESIONS................................................................... 217 MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED- NEOPLASTIC AND NON-NEOPLASTIC LESIONS........................................... 247 MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED- NEOPLASTIC AND NON-NEOPLASTIC LESIONS........................................... 297 MEAN BODY WEIGHTS AND BODY WEIGHT GAINS OF P, MALE R A TS....................... 357 MEAN BODY WEIGHTS AND BODY WEIGHT GAINS OF P, FEMALE RATS DURING GESTATION.....................................................................................................................................358 MEAN BODY WEIGHTS AND BODY WEIGHT GAINS OF P, FEMALE RATS DURING LACTATION.....................................................................................................................................359 MEAN DAILY FOOD CONSUMPTION AND FOOD EFFICIENCY BY P! FEMALE RATS DURING GESTATION.................................................................................................................... 360 SUMMARY OF CLINICAL OBSERVATIONS IN P, RATS........................................................ 361 MEAN ESTROUS CYCLE PARAMETERS AND PRECOITAL INTERVAL P, FEMALE RATS........................................................................................................................... 362 SUMMARY OF SPERM PARAMETERS IN P, MALE RATS..................................................... 363 SUMMARY OF REPRODUCTIVE INDICES: P, GENERATION..............................................364 MEAN PUP NUMBERS AND SURVIVAL: F, GENERATION.................................................. 365 MEAN PUP WEIGHTS: F, GENERATION................................................................................... 366 SUMMARY OF PUP CLINICAL OBSERVATIONS DURING LACTATION........................... 367 9 Company Sanitized. Does not contain TSCA CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 54 TABLE 55 TABLE 56 TABLE 57 TABLE 58 TABLE 59 TABLE 60 TABLE 61 TABLE 62 TABLE 63 TABLE 64 TABLE 65 TABLE 66 TABLE 67 TABLE 68 TABLE 69 TABLE 70 TABLE 71 TABLE 72 TABLE 73 TABLE 74 LIST OF TABLES (Continued) Page MEAN BODY WEIGHTS AND MEAN BODY WEIGHT GAINS OF F, MALE RATS.........368 MEAN BODY WEIGHTS AND MEAN BODY WEIGHT GAINS OF F, FEMALE RATS.....369 MEAN DAILY FOOD CONSUMPTION AND MEAN FOOD EFFICIENCY .... 370 MEAN DAILY FOOD CONSUMPTION AND MEAN FOOD EFFICIENCY DVE EEA/TATEPATQ ................................................................. .... 371 SUMMARY OF CLINICAL OBSERVATIONS IN F, RATS................................................. .... 372 SUMMARY OF DEVELOPMENTAL LANDMARKS IN F, RATS..................................... .... 373 MEAN FINAL BODY AND ORGAN WEIGHTS FROM MALE RATS - P, ADULTS...... .... 374 MEAN FINAL BODY AND ORGAN WEIGHTS FROM FEMALE RATS - P, ADULTS...... 375 MEAN FINAL BODY AND ORGAN WEIGHTS FROM MALE RATS - F, ADULTS...... .... 376 MEAN FINAL BODY AND ORGAN WEIGHTS FROM FEMALE RATS - F, ADULTS...... 378 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS - Pi ADULTS................... .... 380 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS - Pi ADULTS............. .... 381 INCIDENCES OF GROSS OBSERVATIONS IN RATS - F, PUPS..................................... .... 382 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS - F, WEANLINGS.......... .... 385 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS - F, WEANLINGS..........386 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS - F, ADULTS.................. .....387 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS - F! ADULTS............. ..... 388 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS ..... 389 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS ..... 391 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS ..... 392 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS - F, ADULTS.......................................................................................... ..... 393 Company Sanitized. Does not ennen t r o a n m 10 Company Sanitized. Does oof a^ H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 FIGURE 1 FIGURE 2 FIGURE 3 FIGURE 4 FIGURE 5 FIGURE 6 FIGURE 7 FIGURE 8 FIGURE 9 FIGURE 10 LIST OF FIGURES Page MEAN BODY WEIGHTS OF MALE RA TS................................................................... ............ 396 MEAN BODY WEIGHTS OF FEMALE RATS............................................................... ............ 397 MEAN FORELIMB GRIP STRENGTH OF MALE RATS............................................. ............ 398 MEAN FORELIMB GRIP STRENGTH OF FEMALE RATS........................................ ............ 399 MEAN HINDLIMB GRIP STRENGTH OF MALE RATS............................................. ............ 400 MEAN HINDLIMB GRIP STRENGTHOF FEMALE RATS......................................... ............ 401 MOTOR ACTIVITY ASSESSMENT: MEAN DURATION OF MOVEMENTS rn p M il E P 4 K ............................................................. .............402 MOTOR ACTIVITY ASSESSMENT: MEAN DURATION OF MOVEMENTS T7rtD T7P1MAT P R AT<5 .............................................................. .............403 MOTOR ACTIVITY ASSESSMENT: MEAN NUMBER OF MOVEMENTS PAD MATPRATQ .............................................................. .............404 MOTOR ACTIVITY ASSESSMENT: MEAN NUMBER OF MOVEMENTS FOR FEMALE RATS......................................................................................................... .............405 ll Company Sanitized. Does not contain T S C A CB ! H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 LIST OF APPENDICES Page APPENDIX A INDIVIDUAL DOSE VOLUMES................................................................................................... 407 APPENDIX B INDIVIDUAL BODY WEIGHTS................................................................................................... 497 APPENDIX C APPENDIX D INDIVIDUAL FOOD CONSUMPTION DATA............................................................................ 531 INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA.......................................................................................................................549 APPENDIX E APPENDIX F APPENDIX G APPENDIX H APPENDIX I OPHTHALMOLOGICAL EXAMINATION REPORTS............................................................... 603 INDIVIDUAL FORELIMB AND HINDLIMB GRIP STRENGTH ASSESSMENTS............... 608 INDIVIDUAL FUNCTIONAL OBSERVATIONAL BATTERY ASSESSMENTS................... 619 INDIVIDUAL MOTOR ACTIVITY ASSESSMENT: DURATION OF MOVEMENT............ 628 INDIVIDUAL MOTOR ACTIVITY ASSESSMENT: NUMBER OF MOVEMENTS............. 639 APPENDIX J INDIVIDUAL ANIMAL CLINICAL PATHOLOGY DATA........................................................650 APPENDIX K INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS........................................... 769 APPENDIX L INDIVIDUAL ANIMAL GROSS AND MICROSCOPIC OBSERVATIONS..................:.........786 APPENDIX M INDIVIDUAL BODY WEIGHTS OF P, MALE RATS................................................................969 APPENDIX N . INDIVIDUAL BODY WEIGHT GAINS OF P, MALE RATS.................................................... 975 APPENDIX O INDIVIDUAL BODY WEIGHTS OF P, FEMALE RATS DURING GESTATION.................. 981 APPENDIX P INDIVIDUAL BODY WEIGHT GAINS OF P| FEMALE RATS DURING GESTATION.......987 APPENDIX Q INDIVIDUAL BODY WEIGHTS OF P, FEMALE RATS DURING LACTATION................. 993 APPENDIX R INDIVIDUAL BODY WEIGHT GAINS OF P, FEMALE RATS DURING LACTATION.......999 APPENDIX S INDIVIDUAL DAILY FOOD CONSUMPTION BY Pi FEMALE RATS DURING GESTATION.................................................................................................................................. 1005 APPENDIX T APPENDIX U INDIVIDUAL CLINICAL OBSERVATIONS IN P, MALE RATS...........................................1011 INDIVIDUAL CLINICAL OBSERVATIONS IN P, FEMALE RATS DURING GESTATION...................................................................................................................................1020 APPENDIX V INDIVIDUAL CLINICAL OBSERVATIONS IN P, FEMALE RATS DURING LACTATION...................................................................................................................................1026 APPENDIX W INDIVIDUAL ANIMAL ESTROUS CYCLE PARAMETERS DURING PREMATING AND COHABITATION IN P, FEMALE RATS.................................................................................... 1035 APPENDIX X INDIVIDUAL ANIMAL ESTROUS CYCLE STAGES DURING PREMATING AND COHABITATION IN P, FEMALE RATS.................................................................................... 1041 APPENDIX Y INDIVIDUAL ANIMAL SPERM MOTILITY DATA IN P, MALE RATS.............................. 1047 APPENDIX Z INDIVIDUAL ANIMAL SPERM MORPHOLOGY DATA IN Pi MALE RATS......................1050 12 Company Sanitized. Does not contain T S C A CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 LIST OF APPENDICES (Continued) Page APPENDIX AA INDIVIDUAL ANIMAL SPERM AND SPERMATID COUNTS IN P, MALE RATS............ 1054 APPENDIX BB INDIVIDUAL MATING DATA AND GESTATION LENGTH: P, GENERATION............. 1057 APPENDIX CC INDIVIDUAL IMPLANTATION SITE DATA AND IMPLANTATION EFFICIENCY........ 1063 APPENDIX DD INDIVIDUAL PUP SURVIVAL: F, GENERATION................................................................. 1069 APPENDIX EE INDIVIDUAL PUP WEIGHTS: F, GENERATION................................................................... 1095 APPENDIX FF INDIVIDUAL LITTER CLINICAL OBSERVATIONS: F, GENERATION............................1145 APPENDIX GG INDIVIDUAL BODY WEIGHTS: F, GENERATION............................................................... 1151 APPENDIX HH INDIVIDUAL BODY WEIGHT GAINS: F, GENERATION....................................................1161 APPENDIX II INDIVIDUAL FOOD CONSUMPTION: F, GENERATION.....................................................1171 APPENDIX JJ INDIVIDUAL CLINICAL OBSERVATIONS: F, GENERATION.......................................... 1181 APPENDIX KK INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS......................................... 1198 APPENDIX LL INDIVIDUAL ANIMAL GROSS AND MICROSCOPIC OBSERVATIONS FOR P, ADULTS........................................................................................................................... 1215 APPENDIX MM INDIVIDUAL ANIMAL GROSS OBSERVATIONS FOR F, PUPS......................................... 1377 APPENDIX NN INDIVIDUAL ANIMAL GROSS OBSERVATIONS FOR F, WEANLINGS...........................1382 APPENDIX OO INDIVIDUAL ANIMAL GROSS AND MICROSCOPIC OBSERVATIONS FOR F, ADULTS................................................... ........... ............................................. - ............I404 13 Company Santflzed. Does not conafn T S C A CB) H-24616: Subchxonic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations STUDY INFORMATION Substance Tested: Svnonvms/Codes: Haskell Number: 24616 Composition Known Impurities: DuPont-4739 Wilmington, Delaware 19898 U.S.A. Study Initiated/Completed: September 14, 2000/ (see report cover page) In-Life Initiated/Completed: September 18, 2000 / March 19, 2001 14 Sesnpany Sanitized. Does not contain T S C A CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations STUDY PERSONNEL Study Director: Don A. Delker, Ph.D. Management: Judith C. Stadler, Ph.D., D.A.B.T. Nancy C. Chromey, Ph.D., D.A.B.T. Janice L. Connell, M.S., B.A., C.I.H. Primary Technician: Janine A. Britton, B.S. Reproductive Toxicologist: Eve Mylchreest, Ph.D. Management: Robert M. Parker, Ph.D. Clinical Pathologist: Nancy E. Everds, D.V.M. Management: Steven R. Frame, D.V.M., Ph.D. Pathologist: G. Tracy Makovec, D.V.M. Management: Steven R. Frame, D.V.M., Ph.D. Peer Review Pathologist: Steven R. Frame, D.V.M., Ph.D. Neurotoxicologist: Linda A. Malley, Ph.D. Management: Robert M. Parker, Ph.D. Toxicology Report Preparation: Mary K. LaRoe Cecilia R. Kee, B.S. . 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-4739 15 Company Sanitized. Does not contain T S C A CBJ H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 SUMMARY Four groups of young adult male and female Crl:CD(SD)IGS BR rats were administered neat H-24616 by gavage at dosages of 0, 50, 250, or 1000 mg/kg/day based on the active ingredient. Selected animals from each 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 13 of the 90-day exposure period and 1-month postdosing. Neurobehavioral assessments were also performed prior to dosing, during week 12, and near the end of the 1-month recovery period. After 90 days of dosing, ten rats/sex/dose were sacrificed and given a gross and microscopic pathological examination. One month after the 90-day dosing period, 10 animals/sex in the control and high dose group were examined for recovery of toxic effects. An additional five animals/sex/dose were evaluated for recovery 3 months following the end of the dosing period. The average daily volumes of H-24616 given to male rats over the 90-day exposure period were 0.09, 0.45, and 1.74 mL H-24616 for the 50, 250, and 1000 mg/kg/day dosage groups, respectively. The average daily volume given to female rats over the 90-day exposure period were 0.05, 0.28, and 1.08 mL H-24616 for the 50, 250, and 1000 mg/kg/day dosage groups, respectively. In-Life and Neurotoxicology Parameters: No test substance-related mortality occurred in the study. No adverse clinical signs of toxicity or changes in neurobehavioral parameters were observed in male or female rats in any dose group. Statistically significant lower body weight, body weight gain, food consumption, and food efficiency were observed in male rats administered 1000 mg/kg/day when compared to controls. There were no adverse effects on these parameters at any dose level in female rats at 90 days and no adverse effects in males and females dosed with 1000 mg/kg/day by the end of the one-month recovery period. Clinical Pathology. Potentially adverse findings of elevated liver enzymes (ALKP, AST, ALT, and/or SDH) were observed after treatment and/or a one month recovery in males and/or females dosed with 250 or 1000 mg/kg/day. Other changes in clinical pathology parameters, during treatment or after a one-month recovery, were considered treatment-related but non-adverse because the magnitude of change was small, transient, and/or in a direction not associated with toxicity. The noteworthy parameters thus affected were red cell mass, red cell shape, urea nitrogen, cholesterol, triglycerides, bilirubin, albumin, globulin, and urine fluoride. Anatomical Pathology (Subchronic Toxicity): Test-substance related and statistically significant increases in liver weight parameters occurred in male rats of all dose groups and female rats in the high-dose group after the 90-day exposure period. Histopathologically, hepatocellular hypertrophy was also observed in male rats of all dose levels but not in female rats. Nasal olfactory epithelium degeneration/necrosis was observed in male and female rats at all dose levels and inflammation of the olfactory epithelium in male rats in the 250 and 1000 mg/kg/day dose level. Thyroid hypertrophy and increased alterations in colloid were observed in male and 16 Conq>any Sanitized. Does not contain T S C A CBl H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 female rats in the 250 and 1000 mg/kg/day dose groups. No thyroid hypertrophy was observed in rats dosed with 50 mg/kg/day. After one month of recovery, rats dosed with 1000 mg/kg/day showed some reversibility of effects. Hepatocellular hypertrophy was present in male rats (less severe than at 90 days) and nasal epithelium degeneration/necrosis also persisted in male rats at a lower incidence and severity than observed at the end of the dosing period. Inflammation of the nasal epithelium was no longer seen in male rats and nasal epithelium degeneration/necrosis was not observed in female rats. Treatment-related thyroid hypertrophy and increased colloid alterations persisted in male and female rats. After the 3-month recovery period, hepatocellular hypertrophy was observed only in male rats in the 250 and 1000 mg/kg/day dose groups. Nasal epithelium degeneration/necrosis or inflammation was not observed in male or female rats at any dose level. Thyroid hypertrophy occurred in one female rat in the 1000 mg/kg/day dose group and increased colloid alterations were observed in male rats in the 250 and 1000 mg/kg/day dose groups. Reproduction: Twenty male and female rats from each dose group were designated for reproductive evaluations. Parental rats (Pi generation) were dosed daily for 70 days prior to cohabitation, during the cohabitation period (mating), during gestation, and during lactation, until the weaning of the Fi offspring. The following parameters were conducted on Pi rats: body weights, food consumption, clinical signs, gross pathology, sperm parameters, esfrous cyclicity and reproductive performance. The Fi offspring were evaluated during the lactation period for growth and survival and given a gross pathological examination at weaning. A subset of Fi rats (F, generation) were retained at weaning, and the following parameters evaluated for 6 weeks, body weights, food consumption, clinical signs, and age at onset of vaginal opening and preputial separation. After 6 weeks, the Fi generation rats were given a gross pathological examination, selected reproductive organs were weighed and histopathology evaluation of the thyroid was conducted. No test substance-related effects on reproductive parameters were observed. There were no adverse effects at any dose level on estrous cycle or sperm parameters, or reproductive indices. There were no test substance-related changes in Fi litter size, pup weights or survival during lactation. There were no test substance-related changes in body weights, food consumption, or developmental landmarks in the Fi generation. Mean thyroid organ weight was significantly lower in the 250 and 1000 mg/kg/day dose groups in the Fi generation, but not in the P, generation. However, there were no histopathological changes in the thyroid of the F, generation rats. There were no other test substance-related gross pathology findings in Pi or Fi generation rats. 17 Company Sanitized. Does not contain T S C A CB) H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 NOEL for Subchronic Toxicity and Recovery: Target organs identified in this 90-day subchronic toxicity study included liver, nose and thyroid. Based on the olfactory nasal epithelium necrosis observed after 90 days of treatment in male and female rats at all dose levels, a no-observedeffect level (NOEL)3cannot be determined for the subchronic toxicity evaluation. However, the nasal olfactory epithelium effects observed after the 90-day exposure period were completely reversible by the end of the 3-month recovery period. NOEL for Reproductive Evaluations: Although there were no test substance-related effects observed on reproductive function, a NOEL of 50 mg/kg/day was determined for reproductive evaluations based on decreased thyroid weights in both male and female Fi adults at dosages of 250 mg/kg/day and above. a 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). 18 1- Does nolrnnf.i. H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 INTRODUCTION The test substance, H-24616, contains ; ____________________ ia 2-week ifege-finding study conducted with H-24616 in rats, there was no observable systemic toxicity observed up to the limit dosage o f 1000 mg/kg/day active ingredient. Dosages of 50, 250 and 1000 mg/kg/day were selected for this 90-day subchronic toxicity with one generation reproduction study based on the ability of rats to tolerate the upper limit dosage of 1000 mg/kg/day in the range-finding study. OBJECTIVE The objective of this study was to evaluate the potential subchronic and reproductive toxicity of H-24616 when administered by gavage to male and female rats. The oral route of administration was selected as the most efficient way to deliver an accurate dosage. MATERIALS AND METHODS A. Test Guidelines The subchronic toxicity study design complies with the United States Environmental Protection Agency (EPA), Office of Prevention, Pesticides, and Toxic Substances (OPPTS) Health Effects Test Guidelines, OPPTS 870.3100 90-Day Oral Toxicity in Rodents (AUG-1998). The onegeneration reproduction study includes many endpoints of reproductive function but does not comply with a specific guideline. B. Test Substance The test substance, H-24616, was supplied by the sponsor as ' g g j r h e test substance is ^ ______ _______ ________ _ le stability analysis of the test substance before and during the study was conducted by Regional Analytical Services (RAS), Jackson Laboratories, Deepwater, New Jersey. A reserve sample of the test substance was collected and retained by Haskell Laboratory. C. Test Species On August 31, 2000, 176 male and 176 female Crl:CD(SD)IGS BR rats, with an assigned birth date of July 31, 2000, were received from Charles River Laboratories, Inc., Raleigh, North Carolina for use on this study. 19 ompany Sanitized. c i t a t o T?CA CB! H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 The rat was selected because it is the recommended species specified 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, sensitivity to the test substance, and low incidence of spontaneous diseases. ' D. Animal Husbandry 1. Housing With the exception of some portions of the reproductive study, all rats were housed one per cage, sexes separate, in stainless steel, wire-mesh cages suspended above cage boards. Animal rooms were maintained on a 12-hour light/dark cycle (fluorescent light) and at a temperature of 23 3C and a relative humidity of 50% 20%. Occasional excursions outside the accepted ranges were minor and did not affect the study. Rats designated for reproductive toxicity evaluations were housed as breeding pairs during the cohabitation period. During the gestation period, female rats designated for reproductive toxicity evaluations were housed individually until gestation day 20. Beginning on gestation day 20 for mated females, or at the end of the cohabitation period for females without evidence of copulation, female rats were housed individually in polycarbonate pans with bedding. During the lactation period, adult female rats were housed with their litters in polycarbonate pans. During the 70-day premating period for Pi adults and the 42-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. 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 of a colored tail mark and cage identification. After assignment to groups, an individual identification number was tattooed on the tail of each rat. The information on the cage labels included the unique 6-digit Haskell animal number and the individual identification number assigned to each rat. 20 Company SanHfzed. Does noi cBl H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 4. Health Monitoring Program As specified in the Haskell Laboratory animal health and environmental monitoring program, the following procedures are performed periodically to ensure that contaminant levels are below those that would be expected to impact the scientific integrity of the study: Water samples are analyzed for total bacterial counts, and the presence of 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 of key contaminants, including specified heavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates. The presence of these contaminants below the maximum concentration stated by the manufacturer would not be expected to impact the integrity of the study. The animal health and environmental monitoring program is administered by the attending laboratory animal veterinarian. Evaluation of these data did not indicate any conditions that affected the validity of the study. E. Quarantine and Pretest Period . Upon arrival at Haskell Laboratory, the rats were quarantined for 10 days of the 17-day pretest period. The rats were observed daily for any clinically apparent signs of disease or injury, weighed 4 times, and examined by a veterinary ophthalmologist to identify animals with preexisting ocular lesions. Prior to study start, one female rat (animal no. 641270) was found dead prior to grouping and was necropsied to check for the presence of disease. No disease was found; death was due to spontaneous urinary obstruction. On the basis of acceptable body weight gains and clinical observations, all surviving rats were released from quarantine on test day -7 by the laboratory animal veterinarian. 21 not contain TSCACB Company Sanitized. Does il) H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 F. Study Design Groups Male Female In m IV V VI VII vm No./ Group Dietary Dosage Male Female______ (mg/kg/day) 45 45 0 (Control) 35 35 50 35 35 250 45 45 1000 a Weight of test substance (adjusted animal body weight. ctive ingredient)/kg The first ten rats in each group were designated for the 90-day exposure evaluation. The next five rats in each group were designated as a satellite subset for serial blood collection and evaluation of selected tissues following a 3-month recovery period. 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 1-month recovery evaluations. Male and female rats designated for the 90-day exposure evaluation were dosed for 91 and 92 days, respectively, and necropsied the following day. Male and female rats designated for the one- and three- month recovery evaluations were dosed for 90 days and necropsied 33-34 days and 92 days postdosing, respectively. Neurobehavioral evaluations were conducted on control and high dose animals designated for the one-month recovery (predose, week 13, one-month post'dose) and on male and female animals designated for the 90-day exposure evaluation (predose and week 13). Clinical pathology evaluations were conducted on animals designated for the 90-day exposure evaluation on weeks 7 and 13 and on animals designated for the one-month recovery evaluation immediately prior to necropsy. G. Assignment to Groups and Study Start Rats were selected for study use on the basis of adequate body weight gain, freedom from any ophthalmological abnormalities or clinical signs o f disease or injury, and a body weight within 20% of the mean within a sex. The selected rats were distributed by computerized, stratified randomization so that there were no statistically significant differences among group body weight means within a sex. Oral administration of H-24616 began on test day 0. The rats were approximately 49 days of age on test day 0. Prior to the start of the test substance administration, rats with body weights that were not within 20% of the mean within a sex, were replaced and discarded without gross or microscopic evaluations. Replacement rats were selected on the basis of freedom from any clinical signs of disease or injury and a body weight 20% of the mean within a sex. _________________________________________ 22 Company Sanitized. Does not contain T S C A CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 H! Test Substance Administration and Sampling The test substance as received from the sponsor was administered to the study animals by oral gavage to achieve dosage levels of 50, 250, or 1000 mg active ingredient/kg body weight/day, based on the most recently recorded body weight. The neat liquid was not diluted prior to dosing but was given to the animals in varying volumes depending on the targeted dose and amount (grams) of active ingredient in the test substance preparation. Dose volumes did not exceed 20 mL/kg. Animals designated for subchronic toxicity were dosed daily by gavage for 90 days. Animals designated for reproductive evaluations were dosed daily by gavage for 70 days, and then daily during cohabitation until evidence of copulation was found or until the 14-day cohabitation period ended. Pregnant females were dosed during the 3-week gestation period. From gestation day 18 until delivery, dose volumes were based on the gestation day 18 body weights. Pregnant females in the process of delivery or showing signs of delivery were not dosed. Lactating females were dosed until pups were weaned on day 21. Pi females with no evidence of copulation continued to be dosed until sacrifice. Following the cohabitation period, Pi males were dosed until sacrifice. The test substance was supplied by the sponsor in multiple-gallon containers. To determine the stability of the test substance over the 90-day exposure period, an analytical sample was taken from gallon container # 1 on test day 0 and from gallon container # 6 on test day 91. Analytical samples for homogeneity and concentration verification were also taken. To verify proper mixing and homogeneity of the test substance over the course of the daily dosing period, an additional analytical sample was taken from the dosing container after dosing on test day 0. To verify proper mixing and homogeneity of the test substance in gallon container #1, an additional analytical sample was taken from gallon container # 1 prior to the last day of use on test day 17. All male and female control animals were treated with deionized water at the same dose volume as used in the high-dosage groups, respectively. I. Body Weights All rats were weighed once per week during the 90-day feeding phase of the study. In addition, the rats designated for neurobehavioral evaluations, undergoing functional observational battery and motor activity assessments, were weighed on the days of those observations. During the reproduction substudy, male rats were weighed on a weekly schedule and female rats were weighed during gestation on days 0, 7, 14, and 21, and 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 Fi rats were weighed weekly until postnatal day 63. J. Food Consumption and Food Efficiency The amount of food consumed by each rat over each weighing interval was determined throughout the study. Each rat's feeder was weighed at the beginning and end of the interval and the final weight of the feeder and the amount of spillage from the feeder during the interval was subtracted from the initial feeder weight. From these measurements, mean daily food 23 Company Sanitized. Does not contain T S C A CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 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 onemonth postdosing for animals designated for one- and three-month recovery evaluations. The only exception is that food consumption was not determined for animals designated for 3-month recovery during the urine and feces collection period on test days 84-91. 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 69. Cohabitation period, beginning test day 69 - food consumption was not determined. Gestation period - individual food consumption was determined on gestation days 0, 7, 14, and 21 (not reported). Lactation period - food consumption was not determined. Postweaning Fi rats - individual food consumption was determined weekly, ending on postnatal day 63. K. Detailed Clinical Observations and Mortality During the test period, cage-site examinations to detect moribund or dead rats and abnormal behavior and/or appearance among rats were conducted at least twice daily throughout the study, except for test day 36 when the rats were checked only once. One male animal in the 250 mg/kg/day dosage group was euthanized on test day 51 due to a large open wound under the neck. At every weighing, each rat was individually handled and examined for abnormal behavior and appearance. Detailed clinical observations in a standardized arena were also evaluated on rats designated for the 90-day exposure and one-month recovery periods. The detailed clinical observations included (but were not limited to) evaluation of fur, skin, eyes, mucous membranes, occurrence of secretions and excretions, autonomic nervous system activity (lacrimation, piloerection, and unusual respiratory pattern), changes in gait, posture, response to handling, presence of clonic, tonic, stereotypical, or bizarre behavior. L. Ophthalmological Evaluations Three ophthalmological examinations were conducted by a veterinary ophthalmologist. Both eyes were examined by focal illumination and indirect ophthalmoscopy. The examinations were conducted under subdued lighting after mydriasis had been produced with a 1% tropicamide solution. On test day -10, the initial examination was performed on all rats received for the study, prior to selection and grouping. On test day 88, all surviving rats designated for the 90-day exposure and one-month recovery were examined again. On test day 116, all surviving rats designated for recovery evaluation were given a final examination. 24 Company Sanitized. Does not contain T S C A CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 M. Neurotoxicity Evaluations 1. Sensory Function Evaluation Prior to test substance administration, during week 12 of test substance administration, and following an approximately one-month recovery period, assessments of responses to approach/touch, sharp auditory stimulus, and tail pinch were made while the animal was in a standard arena. These assessments were conducted on 10 animals per group for the baseline and week 12 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 (Section 2. below) because the darkened room in which the apparatus was located facilitated observing the response. The presence or absence of pupillary constriction was assessed after a beam of light was directed into each eye. For all these assessments, the experimenter was unaware of the group designation of the animal. 2. Motor Activity (MA) Following the evaluation of grip strength and sensory function, assessment of motor activity (MA) 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 of day to the fullest extent possible. The infrared monitoring device enables measurement of 2 dependent variables: duration of movement and number of movements. A continuous movement was counted as 1 movement regardless of duration. Each test session was 60 minutes in duration, and the results were expressed for the total session as well as for 6 successive 10-minute blocks. Presence of defecation and urination on the cageboards below the motor activity monitor were also recorded following each motor activity session. 3. Test Facility Positive Control Data Data on the effects of acrylamide, carbaryl, d-amphetamine, and trimethyltin are described in four separate reports/1,2,3,4) These positive control studies are the basis of training certification for the individuals making judgments in the neurobehavioral and neuropathology tests. The data also document that the equipment and procedures are capable of detecting effects that may be seen in neurotoxicity studies of this type. N. Clinical Pathology Clinical pathology evaluations were conducted on the first 10 male and 10 female rats per group in all groups on test days 45 (male) or 44 (female) and either 91 (male) or 92 (female). The rats were fasted overnight (approximately 16 hours) and urine was collected during this interval. Blood samples for hematology and clinical chemistry measurements were collected from the orbital sinus of each fasted rat while the rat was under light carbon dioxide anesthesia. Blood samples for coagulation (end of dosing only) were collected from the abdominal vena cava while 25 Company Sanitized. Does not contain T S C A CBI H-24616: Subchronic Toxicity . 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 the rat was under carbon dioxide anesthesia, immediately prior to sacrifice. All blood samples were examined visually and observations recorded. A clinical pathology evaluation (hematology, clinical chemistry, and urinalysis, but not coagulation) was also conducted on all recovery rats (control and rats dosed with 1000 mg/kg/day) from blood and urine collected after a month of recovery (test day 123, male, or 124, female). 1. Hematology/Coagulation Complete blood counts (including reticulocytes) were determined on a Bayer Advia 120 hematology analyzer and determined from microscopic evaluation of the blood smear. Wrightstained blood smears from all rats were examined microscopically for confirmation of automated results and evaluation of cellular morphology. Coagulation times were determined on a BCS Behring Coagulation Analyzer. New methylene blue-stained blood smears were prepared from each rat undergoing hematology evaluation but were not needed for evaluation. The following hematology and coagulation parameters were determined: Erythrocyte count (RBC) Hemoglobin concentration (HGB) Hematocrit (HCT) Mean corpuscular volume (MCV) Mean corpuscular hemoglobin (MCH) Mean corpuscular hemoglobin concentration (MCHC) Red cell distribution width (RDW) Absolute reticulocyte counts (ARET) Total leukocyte count (WBC) Differential leukocyte count Platelet count (PLT) Microscopic blood smear examination Prothrombin time (PT) . Activated partial thromboplastin time (APTT) 2. Clinical Chemistry Clinical chemistry parameters were measured or calculated on a Roche Diagnostics (BMC)/Hitachi 917 clinical chemistry analyzer. Plasma fluoride concentration was determined using a phi/12 pH meter with a fluoride-selective electrode. The following serum chemistry parameters were determined: Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Sorbitol dehydrogenase (SDH) Alkaline phosphatase (ALKP) Total bilirubin (BELI) Urea nitrogen (BUN) Creatinine (CREA) Cholesterol (CHOL) Triglyceride (TRIG) Glucose (GLUC) Total protein (TP) Albumin (ALB) Globulin (GLOB) Calcium (CALC) Inorganic phosphorus (IPHS) Sodium (NA) Potassium (K) Chloride (CL) Plasma fluoride (PFLU) 26 Company Sanitized. Does not contain T S C A OBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 3. Urinalysis The following urinalysis parameters were determined: Appearance (quality, clarity, and color) Volume (VOL) Osmolality (OSMO) Specific gravity (SG) pH Glucose (UGLU) Ketones (KET) Bilirubin (UBIL) Blood (BLD) Urobilinogen (URO) Urine fluoride (UFLU) Protein (UMTP) Microscopic examination of 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 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 fluoride concentration (measured using a phi/12pH meter and a fluoride selective electrode). Sediments from all urine specimens were evaluated microscopically. O. Serial Blood Collection (Satellite Group) On test day 1 (males only), and test days 4,10, 21, 36, 57, 78, and 90 (males and females) blood (approximately 0.5 - 1 mL) was collected from the orbital sinus of designated animals (5 rats/sex/dose) while the animals were under light carbon dioxide anesthesia. On the day of blood collection, blood was collected from the animals prior to dosing. The blood was collected in glass tubes containing EDTA while the tubes were on ice and then stored frozen. For each bleeding, blood was collected at approximately the same time of day. During the last week of the 90-day exposure period urine and feces were collected daily at 24-hour intervals from each animal. The animals were placed in metabolism cages for collection of feces and urine. The exact time period of collection of urine and feces was documented along with the total volume of urine obtained. Urine and feces were stored frozen. Blood was also collected 3, 9,16, 29, 43, 64, and 85 days postdosing for both male and female animals of each dose group. Animals were sacrificed at the end o f the 3-month recovery period. Blood, urine, and feces samples were not analyzed during the course of this study but may be analyzed, if needed, at a later date. Any data generated from these analyses will be archived in the study records and reported separately. P. Anatomic Pathology - Rats Designated for Subchronic Toxicity and Recovery On test days 91/92, the first 10 male/female rats from the 0, 50, 250, and 1000 mg/kg/day groups were sacrificed and necropsied. Thirty-day recovery rats from 0 and 1000 mg/kg/day were sacrificed and necropsied on test days 122 and 123 for males and females, respectively. Male and female satellite animals (90-day recovery) from each group were sacrificed and necropsied on test day 182. Rats were euthanatized by carbon dioxide anesthesia and exsanguination. Rats 27 Company Sanitized. Does not contain T S C A CBI H-24616: Subchronic Toxicity . 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations __________________ DuPont-4 scheduled for sacrifice were fasted overnight on the afternoon before their scheduled sacrifice. Gross examinations were performed on all male and female rats. The following tissues were collected from rats designated for the 90-day exposure and onemonth recovery that were found dead, accidentally killed, or sacrificed by design. Dieestive Svstem Liver Esophagus Stomach Duodenum Jejunum Ileum Cecum Colon Rectum Salivary glands Pancreas Urinarv Svstem Kidneys Urinary bladder Resoiratorv Svstem Lungs Trachea Nose Larynx Pharynx Cardiovascular Svstem Heart Aorta Hematopoietic Svstem Spleen Thymus Mandibular lymph node Mesenteric lymph node Bone Marrow3 Endocrine Svstem Pituitary gland Thyroid gland Parathyroid glands Adrenal glands Nervous Svstem Brain (including cerebrum, cerebellum, medulla/pons) Spinal Cord (3 levels: cervical, mid-thoracic, lumbar) . Sciatic Nerve Musculoskeletal Svstem Skeletal Muscle Femur/Knee Joint Sternum ReDroductive Svstem Male Testes Epididymides Prostate Seminal Vesicles Female Ovaries Uterus Mammary Gland Miscellaneous Skin Eyes (including optic nerve) gross observations a Bone marrow was collected with the femur and sternum. 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. Due to elevated liver weights observed at the one-month recovery sacrifice, liver was also collected and weighed from 3-month recovery animals designated for blood collection. 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 of the tail, urinary calculi, and deformity of the teeth, toe, tail, or pinna) were saved but were generally not processed for microscopic evaluation. Testes, epididymides, and eyes were fixed in Bouin's solution. All other tissues were fixed in 10% neutral buffered formalin. Processed tissues were embedded in paraffin, cut at a nominal thickness of 5 micrometers, stained with hematoxylin and eosin (H&E), and examined microscopically. 28 Company Sanitized. Does not contain T S C A CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 All collected tissues from rats sacrificed on test days 91/92 from control, and 1000 mg/kg/day rats and all found dead or accidentally killed rats were processed and received a full histopathological examination. Liver, thyroid gland, and nose were collected and processed from 50 and 250 mg/kg/day 90-day exposure rats and from all one-month and 3-month recovery (satellite) rats and were examined microscopically. The key to Appendix G describes the lesion grading system used in this study. Liver, kidney, testes, and approximately one gram of fat were collected from all satellite animals designated for blood collection (90-day recovery) and placed in plastic freezer bags and stored in the freezer for future analysis. Q. Reproductive Assessment 1. Breeding After approximately 10 weeks of exposure to the test substance, on test day 69, each female was continually housed on a 1:1 basis with a randomly selected male of the same dose concentration level in the male's cage. On the day copulation was confirmed, the female was transferred back to individual cage housing. Mating pairs were cohoused until evidence of copulation was observed (designated as day 0 of gestation), or until 2 weeks elapsed. The presence of an intravaginal or extruded copulation plug was considered evidence of copulation. 2. Estrous Cycle Evaluation Vaginal smears were collected from all Pi female rats in order to determine the stages of the estrous cycle. Vaginal smears were collected daily beginning 3 weeks prior to mating, and continuing until copulation was confirmed, or the cohabitation period ended. Vaginal smears were also collected from all Pi parental female rats at the time of sacrifice to determine the stage of estrous cycle. 3. Gestation Procedures Female rats were transferred to polycarbonate pans (on day 20 of gestation for mated females or at the end of the cohabitation period for female rats without evidence of copulation), and were observed at least twice daily for signs of delivery and pups. 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. 29 Company Sanitized. Does not contain TSCA CB) H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 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. d. Day 21 Postpartum (Weaning) Pups in each litter were counted by sex and individually weighed (3 of 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 of developmental landmarks, and weighed and 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. 5. Post Weaning and Developmental Landmarks 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 63. a. Vaginal Patency Female rats were examined beginning on test day 0 (postpartum day 21). b. Preputial Separation Male rats were examined beginning on test day 14 (postpartum day 35). R. Anatomical Pathology - Rats Designated for Reproductive Evaluations 1. Pi Adults All Pi parental rats were sacrificed by carbon dioxide asphyxiation and exsanguination, and subjected to gross pathological examination, including the females that died and those for which mating did not result in a production of offspring. The sacrifices were on test days 107 through 110 for male rats and on test days 113 through 118 for female rats. The uteri of all cohabited females were examined for the presence and number of implantation sites. Company Sanitized. Does not contafn H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 The testes of each male rat were weighed. Sperm parameters for the first 10 male animals sacrificed by design in each treatment group were evaluated. The right cauda epididymis was weighed. Sperm was collected from the right cauda epididymis and percent motility and morphology was determined. The left epididymis and testis were frozen in liquid nitrogen and stored between -65 and -85 C for sperm and spermatid counts, respectively. The right testis and epididymis from these 10 rats were saved and placed in fixative. The following table lists tissues that were collected: Tissues Collected from Pi Adults Male Female Both Sexes Testes/Testis3 Epididymides/Epididymis3 Prostate Seminal Vesicles Coagulating Gland Ovaries Uterus (with oviducts) Vagina Thyroid Glandb Gross Observations0 Pituitary Gland a The 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 Thyroid glands were weighed after fixation. c Gross lesions observed at necropsy for which histopathology was not appropriate or would not be additive were generally not collected. Reproductive organs from animals with impaired reproductive performance were evaluated microscopically. 2. Offspring Offspring that were found dead during the lactation period underwent a gross pathological evaluation. 3. F) 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. Gross lesions were preserved. 4. Fi Adults All Fi generation rats were sacrificed by carbon dioxide asphyxiation and exsanguination, and subjected to a gross pathological examination. Selected tissues and gross lesions were preserved. 31 Sempany Sanitized. Does not contain S C A CB'i H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 The following table lists tissues that were collected and/or weighed: Tissues Collected from Fi Adults Male Female Both Sexes Testes Epididymides Prostate Seminal Vesicles Coagulating Gland Ovaries Uterus (with oviducts) Vagina Thyroid Gland Gross Observations Pituitary Male Testes Epididymides Seminal Vesicles (with coagulating glands) Prostate Tissues Weighed from F, Adults Female Both Sexes Uterus (with oviducts and cervix) Thyroid Gland (after fixation) Liver Brain Processed tissues for histopathological examination were embedded in paraffin, cut at a nominal thickness of 5 micrometers, and stained with hematoxylin and eosin (H&E). Selected gross lesions were evaluated microscopically. 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. Thyroid glands from all Ft adults were processed for microscopic examination. Thyroid glands from F) control and 1000 mg/kg/day males and females were examined microscopically. 32 Spmpany Sanitized. Does not contain T S C A CB) H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 S. 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 Motor Activity0 Grip Strength Clinical Pathologyd Preliminary Test Test for lack of trend Levene's test for homogeneity and Shapiro-Wilk test for normalityb Levene's test for homogeneity and Shapiro-Wilk test for normality1* Bartlett's test* for homogeneity of variances Levene's test for homogeneity and Shapiro-Wilk test for normality13 Method of Statistical Analysis If preliminary test is not If preliminary test is significant significant Sequential application Preliminary tests for of the Jonckheere- pairwise comparison Terpstra trend test ORa One-way analysis of variance* followed with Dunnett's test* Kruskall-Wallis test* followed with Dunn's test* Repeated measures Sequential application analysis of variance* of the Jonckheere- followed by contrasts* Terpstra trend test One-way analysis of variance* followed with Dunnett's test* Kruskall-Wallis test' followed with Dunn's test* One-way analysis of variance* followed with Dunnett's test Kruskall-Wallis test* followed with Dunn's test* Survival Incidence of Clinical Observations None Cochran-Armitage test for trend*6 Incidence of FOB Descriptive Parameters Incidence of Microscopic Lesions None None a Pairwise comparisons and associated preliminary tests were only conducted if the test for lack of trend was b If the Shapiro-Wilk test was not significant but Levene's test was significant, a robust version of Dunnett s 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. ,17) e If the incidence was not significant, but a significant lack of fit occurred, then Fisher s Exact test with a Bonferroni correction was used. 33 Company Sanitized. Does not contain TSCA CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 The following table lists the indices of reproductive function that were calculated for the Pi and Fi adults. Parameter Mean Number of Pups Per Litter Percent Bom Alive Vaginal Patency Preputial Separation Preliminary Test Test for lack of trend(5) Levene's test for homogeneity(8) and Shapiro-Wilk test (9)for normalityb Method of Statistical Analysis If preliminary test is If preliminary test is not significant significant Sequential application of the Preliminary tests for Jonckheere-Terpstra pairwise comparison trend test(7) ORa One-way analysis of vanance(10)followed with Dunnett's test(11) Kruskall-Wallis test . (12)followed with Dunn's test(13) Body Weight Body Weight Gain Food Consumption Food Efficiency Gestation Length Implantation Site Numbers Implantation Efficiency Precoital Interval Estrous Cycle Length Sperm Parameters None None One-way analysis of variance(10) followed with Dunnett's test(11) Jonckheere-Terpstra trend test(7) Incidence of Clinical Observations Mating Index Fertility Index Gestation Index Viability Index Lactation Index None Cochran-Armitage test for trend(l0)c Sex Ratio Mean Pup Weights None (Covariates: litter size, sex ratio) Linear contrast of least squares means(18) Dunn's test(l3) 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 Dunnett's test was used. c If the incidence was not significant, but a significant lack of fit occurred, then Fisher's Exact test with a Bonferroni correction was used. 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.(6) For litter parameters, the proportion of affected fetuses per litter or the litter mean was used as the experimental unit for statistical evaluation/19) The level of significance selected was p < 0.05. 34 Company Sanitized. Does not contain TSC A CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 Where the data are tied and the standard large sample version of Jonckheerejs test is not applicable, exact p values were calculated using permutation methodology/ RECORDS AND SAMPLE STORAGE Laboratory-specific or site-specific raw data, such as personnel files and equipment records will be retained by the facility where the work was done. A sample of the test substance was collected for archive purposes and retained at Haskell Laboratory. Specimens (if applicable), raw data, and the final report will be retained at Haskell Laboratory, Newark, Delaware, or at Iron Mountain Records Management, Wilmington, Delaware. Clinical pathology slides and raw data will be retained at Haskell Laboratory, Newark, Delaware. Characterization data will be stored at Regional Analytical Services (RAS), Jackson Laboratories, Deepwater, New Jersey 35 pOflipany Sanitized. Does not contain TSCA CBI H-24616: Subchronic Toxicity . 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 RESULTS AND DISCUSSION ANALYTICAL EVALUATIONS A. Test Substance Stability To determine the stability of the test substance over the duration of the study, H-24616 (Lot # 436) was analyzed on the first and last day of dosing of the 90-day exposure period. The percent solids of the test substance on test day 0 (predose) and test day 91 wereB m | respectively. test day 0 and test day 91 analytical samples may be due to analytical variability. However, independent of analytical v a r i a b i l i t y f i H j H ^ m m m H w v o u l d not significantly impact the targeted dose given to the test animals. Therefore, under the conditions of this study, the test substance was considered stable over the course of the study. B. Test Substance Uniformity Analyses H-24616 was administered neat to the test animals. No dosing preparations were made. However, uniformity of the test substance was determined in the daily dosing container, the first gallon container used for the study, and across multiple gallon containers. 1. Daily Dosing Container On te^t day 0, percent soMsprioiUcMlosmg^predoseland after dosing (postdose) werej^ ^ H Jre sp e c tiv e ly . T h i s B ^ H J | H H f l f l H f l over the course of the daily dosing period may be due to evaporationof water from the test subslance. This__ would not significantly impact the targeted dose given to the test ahimals. Therefore, the tesf substance was considered uniform during the daily dosing period. 2. First Gallon Container On test day 0 and on test day 17 analytical samples were taken from the first gallon container used for the study. The percent solids of th ^es^u b stan cc^ccn from the first gallon container on test day 0 (predose) and test day 17 w e r e a J J ^ ^ B ( J jr e s p e c tiv e ly . Based on these results, the test substance was considered uniform in the first gallon container used for the study. 3. Across Gallon Containers Analytical samples were taken from the first and last gallon container used for the 90-day study. The percent solids of the test substance from gallon container #1 (test day 0, predose) and gallon container #6 (test day 91) w er^M B M H H R f'esp ectiv ely . Other test substance analyses of percent solids from a concurrently run developmental study with H-24616, showed percent solids from gallon container #3 to The 36 Com pany Sanitized. Does not contain T S C A GDI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 m a x im um difference in percent solids from samples from each of the three gallon containers was Based on these results, the test substance was considered uniform across containers sujfplied by the sponsor. Test Day 0 (Predose) 0 (Postdose) 17 91 Container #1 #1 #1 #6 a represents average of two analyse: % Solids 'm S f - M B J ... C. Analytical Conclusions Data from the stability and uniformity checks of the test substance, H-24616 during the study, suggest that the test substance was stable and uniform throughout me 90-day e:xposure period. 37 Company Sanitized. Does not contain T S C A CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 SUBCHRONIC TOXICITY EVALUATIONS IN-LIFE TOXICOLOGY A. Dosage Data (Tablesl-2, Appendix A) The amount of test substance administered to each animal was calculated using individual body weights, the density of the test substance and the design dosage (50, 250, and 1000 mg/kg/day). Tables 1 and 2 depict the average amount of test substance (mL) administered by gavage for a given test day. The average daily amounts given to male rats over the 90-day exposure period were 0.09,0.45, and 1.74 mL H-24616 for the 50,250, and 1000 mg/kg/day dosage groups, respectively. Based on individual body weights, these amounts equated to dose ranges of 46-55, 236-255, and 932-1036 mg/kg/day for the 50,250, and 1000 mg/kg/day dosage groups, respectively. The average daily amounts given to female rats over the 90-day exposure period were 0.05, 0.28, and 1.08 mL H-24616 for the 50,250, and 1000 mg/kg/day dosage groups, respectively. Based on individual body weights, these amounts equated to dose ranges of 43-57, 241-258, and 934-1044 mg/kg/day for the 50, 250, and 1000 mg/kg/day dosage groups, respectively. On test day 28,1.18 mL (4 times the correct amount of 0.29 mL) of test material was inadvertently administered to one female rat in the 250 mg/kg/day dosage group. On test day 45, 0.5 mL (10 times the correct amount of 0.05 mL) of test material was inadvertently administered to two female rats in the 50 mg/kg/day dosage group. These errors in dosing will not affect the validity of the study. B. Mean Body Weights and Body Weight Gains (Tables 3-6, Figures 1-2, Appendices B-C) Body weight and weight gain in male rats fed 1000 mg/kg/day were statistically lower than control rats after week 4 and throughout the remainder of the 90-day exposure period. At the end of the 90-day exposure period, mean body weights were approximately 20 % (day 90, exposure animals) and 8 % (day 91, recovery animals) lower in male rats given 1000 mg/kg/day compared to control rats. The overall weight gains were approximately 34 and 15 % lower, respectively. This reduction in body weight gain was considered toxicologically adverse. After a 30-day recovery period, the mean body weights of male rats that received 1000 mg/kg/day H-24616 were similar to controls ( 2%) indicating that the effects on body weight were reversible. There were no adverse, test substance-related effects on body weight or body weight gain in female rats. 38 Company Sanitized. Does not contain T S C A CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 C. Food Consumption and Food Efficiency (Tables 7-10, Appendix D) Compared to male control rats overall, food consumption and food efficiency was statistically lower in male rats that received 1000 mg/kg/day H-24616 after week 4 and throughout the remainder of the 90-day exposure period. At the end of the 90 day exposure period, food consumption was approximately 16 % (day 90, exposure animals) and 2 % (day 91, recovery animals) lower in male rats given 1000 mg/kg/day compared to control rats. The overall food efficiency was 21 and 20 % lower, respectively. Based on the parallel reduction in body weight gain in male rats given 1000 mg/kg/day, this reduction in food efficiency was considered toxicologically adverse. After a 30-day recovery period, food consumption and food efficiency in male rats given 1000 mg/kg/day H-24616 were similar to or greater than that observed in control rats. Therefore, the test substance-related effects on food consumption and food efficiency were reversible. There were no adverse, test substance-related effects on food consumption or food efficiency in female rats. D. Clinical Observations, Ophthalmology Evaluations, and Survival (Tables 11-16, Appendix E-F) No test substance-related clinical or ophthalmological signs o f toxicity were observed in male or female rats. Clinical signs observed were incidental, i.e., hair loss, exo/enophthalmus as the result of orbital sinus bleeding, etc. ' One male rat in the 250 mg/kg/day group was sacrificed in extremis on test day 51 due to a large, open wound under the neck of the animal. One female rat in the 1000 mg/kg/day dose group was found dead on test day 121. These deaths were considered not to be treatment related but of a spontaneous nature. E. In-Life Toxicology Conclusions Based on the decrements in body weight gain and food efficiency in males dosed with 1000 mg/kg/day H-24616 for 90 days, the NOEL for in-life parameters for male rats is 250 mg/kg/day. The NOEL for female rats is 1000 mg/kg/day since no adverse in-life effects were observed in female rats during the 90-day dosing period. 39 Company Sanitized. D oes not contain TSCA CB)| H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 NEUROBEHAVIORAL TOXICOLOGY A. Functional Observational Battery (FOB) 1. Forelimb Grip Strength (Table 17, Figures 3-4, Appendix G) There were no test substance-related effects or statistically significant differences on forelimb grip strength in males or females administered any dosage of H-24616. Males administered 250 or 1000 mg/kg/day had slightly lower (14% and 13% lower than the control value, respectively) forelimb grip strength at week 12, however, a linear dose response-relationship was not present, and the values were within the range of normal variation for this measurement. In addition, there were no effects in females for forelimb grip strength, and no effects on hindlimb gnp strength. Therefore, this slight difference was not considered to be test substance-related. 2. Hindlimb Grip Strength (Table 18, Figures 5-6, Appendix G) There were no test substance-related effects or statistically significant differences in hindlimb grip strength for either males or females administered any dosage of H-24616. 3. Sensory Function Observation (Table 19-20, Figures 7-8, Appendix H) There were no test substance-related changes in neurobehavioral parameters in males or females administered any dosage of H-24616. During the baseline evaluation, females assigned to the 1000 mg/kg/day group had a significantly lower incidence of defecation in the motor activity monitor compared to control. However, since test substance administration had not been initiated, this statistical difference was considered to be spurious. During the week 12 evaluation, females administered 50, 250 or 1000 mg/kg/day had a significantly higher incidence of defecation in the motor activity monitor compared to the control value. However, a dose response-relationship was not present, and the incidences of the females treated with 50, 250, or 1000 mg/kg/day were similar to the control incidence during the baseline evaluation. Therefore, these statistically significant differences were considered to be spurious. There were no statistically significant differences in males for any parameter. B. Motor Activity (MA) (Tables 21-24, Appendices I-J) There were no test substance-related effects on duration of movement or number of movements for males or females for any dosage concentration tested. Males assigned to the 1000 mg/kg/day group had significantly lower total duration of movement during the baseline evaluation and during the week 12 evaluation (20% and 26% lower, respectively, compared to control). In addition, mean total number of movements was significantly lower for 1000 mg/kg/day males compared to control during the week 12 evaluation. However, the values for total duration of 40 Com pany Sanitized. Does not contain CB H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 movement and total number of movements for 1000 mg/kg/day males were similar between thenbaseline, week 12, and recovery evaluations. Since there was no increase or decrease from their baseline performance with respect to either duration of movement or number of movements, the statistically significant differences compared to control were not considered to be test substance related. In addition, total duration of movement for males in the 1000 mg/kg/day group was 20% lower compared to control during the baseline evaluation and 26% lower compared to control during the week 12 evaluation. Therefore the percentage change from control between baseline and week 12 for the 1000 mg/kg/day males was not biologically relevant. Duration of movement and number of movements for males in the 1000 mg/kg/day group was also significantly lower compared to control during the third 10-minute interval for the week 12 evaluation. These statistical differences contributed to the significantly lower total duration of movement and total number of movements; however, as discussed above, they are not considered to be test substance related. There were no statistically significant differences in either duration of movement or number of movements for females administered any dosage of the test substance. C. Neurobehavioral Toxicity Conclusions Under the conditions of the study, the NOEL for neurobehavioral parameters was 1000 mg/kg/day in males and females, the highest concentration tested. 41 Company Sanitized. Does not contain T S C A C9I H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 CLINICAL PATHOLOGY A. Hematology/Coagulation (Tables 25-28, Appendix K) There were no toxicologically significant changes in hematology parameters in rats dosed with 50, 250, or 1000 mg/kg/day All statistically significant changes in hematology parameters were considered unrelated to treatment and/or non-adverse (not toxicologically significant). These changes are detailed below. Hemoglobin and hematocrit were transiently decreased in males dosed with 1000 mg/kg/day at test day 44. These decreases were considered to be non-adverse because the changes were minor (96% and 95% of control group mean, respectively) and transient. Acanthocytes were minimally increased in some males dosed with 1000 mg/kg/day at test day 44. Although this change was possibly related to treatment, acanthocytes were not considered adverse because the effect was mild, variable, transient, and in affected individual animals was not associated with any other measured changes in red blood cells. Absolute reticulocytes were mildly decreased (77% of control group mean) in males dosed with 1000 mg/kg/day at test day 91. For individual animals, there was no correlation between decreased reticulocytes and decreased RBC mass. Decreased reticulocytes were . considered to be unrelated to treatment, because mildly decreased reticulocytes in the absence of relevant alterations in red cell mass have no significance. After one month of recovery, reticulocytes of rats previously dosed with 1000 mg/kg/day were similar to control group values. Platelets were minimally decreased (82% o f control group mean) in males dosed with 1000 mg/kg/day at test day 91 only. This change was considered unrelated to treatment and non-adverse, because the change was very minor (clinically insignificant) and individual counts did not follow a dose relationship. After one month of recovery, platelet counts in rats previously dosed with 1000 mg/kg/day were statistically similar to control group values. White blood cells were transiently increased due to increased lymphocytes in male rats dosed with 1000 mg/kg/day at test day 44. This change was considered unrelated to treatment. The increases were minimal for both white blood cell counts and lymphocytes compared to the normal variability of these cell counts. Additionally, although the cell counts were increased, individual values for rats dosed with 1000 mg/kg/day were both above and below the minimum and maximum values for individual control animals. Due to the magnitude and transient nature of the responses, these changes were not considered adverse. The following statistically significant changes in hematology parameters were considered to be unrelated to treatment because they did not occur in a dose-related manner: 42 Company Sanitized. Does not contain T S C A CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 Minimally decreased red cell mass parameters (red blood cell, hemoglobin, and hematocrit) in females dosed with 50, 250, or 1000 mg/kg/day at test days 44 and 92. The decreases were variable and unrelated to dose (varying from 93-97% of control group means, variable statistical significance). Therefore, these changes were considered to be unrelated to treatment, and therefore non-adverse. After one month of recovery, red cell mass parameters in rats previously dosed with 1000 mg/kg/day were similar to control values. Increased MCHC in females dosed with 250 mg/kg/day at test day 44 Increased monocytes in males (day 44) and decreased eosinophils in females (day 92) dosed with 50 mg/kg/day At the end of treatment (test days 91/92), there were no alterations in coagulation parameters, therefore, coagulation parameters were not measured at the end of recovery (test days 123/124). B. Clinical Chemistry (Tables 29-30, Appendix K) Rats dosed with 250 (males only) or 1000 mg/kg/day (males and females) had changes in liver enzymes indicating possible adverse effects. Males dosed with 1000 mg/kg/day had increased AT.TCP (an indicator of cholestasis or enzyme induction) at mid-study, at the end of treatment, and after one month of recovery. Most males and some females previously dosed with 1000 mg/kg/day had increased enzyme activity indicating hepatocellular injury (AST, ALT, SDH) after one month of recovery. Although many of these changes, in isolation, could likely be considered non-adverse, the constellation of changes and the persistence of changes into the recovery period suggest potential adverse effects in light of continued liver weight changes even after recovery. Thus the NOEL for liver effects was conservatively determined to be 50 mg/kg/day in males and 250 mg/kg/day in females. ALT activity was minimally increased (137% of control group means) in males dosed with 1000 mg/kg/day at test day 91. The increase was consistent among all animals in the group. ALT activity was also minimally increased in males dosed with 250 mg/kg/day and possibly 50 mg/kg/day. After one month of recovery, mean ALT (males and females), and AST and SDH (females only) activities were increased in rats previously dosed with 1000 mg/kg/day. The increased mean activities were primarily due to toxicologically significant increases in the enzymes of 3 animals (Animal No. 641203 - male, Animal No. 641366 - female, and Animal No. 641399 - female). Histologically, 2 of these rats (Animal No. 641203 - male and Animal No. 641366 - female) had minimal to multiple small areas of hepatic necrosis. Excluding the outliers, the remainder of the recovery males still had minimally increased AST and ALT. The remainder of the females actually had decreased AST, ALT, and SDH activities (of no toxicologic significance). The fact that 3 of 20 rats had toxicologically significant increases in hepatocellular injury enzymes after one month of recovery suggests an ongoing process and is potentially adverse. 43 Company Sanitized. Does not contain T S C A CBS H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 ALKP activity was minimally to mildly increased (124-229% of control group mean) in male rats dosed with 1000 mg/kg/day at mid-study and at the end of dosing. The changes were more prominent at test day 91 compared to test day 44. Anatomic pathology changes included increased liver weights and hepatocellular hypertrophy; these changes might have contributed to the ALKP increase. After recovery, ALKP activity was still minimally increased. Excluding rat Animal No. 641203 (see discussion under ALT above), mean ALKP activity after one month of recovery was 126 U/L (158% of control group mean). Statistically significant increased ALKP in male rats dosed with 250 mg/kg/day was considered to be of equivocal relationship to treatment because the difference from control was very slight. The following statistically significant changes were considered unrelated to treatment and/or non-adverse (not toxicologically significant): Urea nitrogen was mildly increased in males (250 or 1000 mg/kg/day) and in females (1000 mg/kg/day) at test days 91/92. The magnitude of change was similar in both dose groups. Increased urea nitrogen was probably related to treatment. The cause of increased urea nitrogen was not determined. Generally, increased urea nitrogen indicates decreased glomerular filtration due to dehydration or renal damage. However, individual animals with increased urea nitrogen did not have indicators of dehydration (increased sodium, chloride, or albumin). Additionally, individual rats with increased serum urea nitrogen maintained urinary concentrating ability (as indicated by urine osmolality and specific gravity) indicating normal functioning kidneys. There were no changes in other markers of decreased renal function (phosphorus or creatinine) and no renal histologic lesions were observed in rats dosed with H-24616 at any dose. After one month of recovery, urea nitrogen values in treated animals were similar to controls. For the above reasons, the change in urea nitrogen was not considered to be adverse. Cholesterol and triglyceride concentrations were mildly decreased in rats dosed with 250 or 1000 mg/kg/day (variable statistical significance, variable across sexes and time-points). Cholesterol was decreased in males and females dosed with 250 or 1000 mg/kg/day (Clinical Pathology Text Table). The changes were generally similar at test days 44 and 91/92, and were more pronounced in males. After one month of recovery (test daysl23/124), cholesterol concentrations in rats previously dosed with 1000 mg/kg/day were only minimally less than those in control group rats. Triglyceride concentrations were decreased in rats dosed with 1000 mg/kg/day. Triglyceride concentrations in males were decreased at all time-points, including recovery, but were only decreased at test day 44 in females. 44 Company Sanitized. Does not contain T S 6 S81 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 The above decreases in cholesterol and triglycerides were considered to be treatment-related because they are part of a dose-response and are consistent within treatment groups. The changes in cholesterol and triglycerides indicate alteration of lipid processing. However, changes of this magnitude in cholesterol and triglycerides are not associated with adverse effects. Clinical Pathology Text Table: Cholesterol and Triglyceride changes (expressed as percent of control group mean) Males TEST_________ Dose (mg/kg/day) 50______ 250 1000 CHOL (mg/dL) Day 44 Day 91 Day 123 87% 73% 63% 87% 70% 64% ND ND 81% TRIG (mg/dL) Day 44 Day 91 Day 123 119% 127% ND 76% 88% ND 56% 54% 55% CHOL (mg/dL) Day 44 Day 92 Day 124 Females 86% 82% 74% 90% 80% 75% ND ND 94% TRIG (mg/dL) Day 44 Day 92 Day 124 85% " 93% ND 74% 102% ND 63% 82% 90% Statistical significance indicated by bold italicized font ND: Not done Decreased bilirubin concentrations in females dosed with 1000 mg/kg/day at test days 44, 92, and 124 were considered treatment-related, but were not considered adverse because decreased bilirubin is not an indicator of disease. The persistence of this change during recovery is correlated with persistence of increased liver weights. Mildly increased albumin and decreased globulins occurred in males dosed with 250 or 1000 mg/kg/day at all time-points, including recovery (except albumin at test day 44 in rats dosed with 250 mg/kg/day). The changes compared to controls were similar at all time points. These changes were probably treatment-related, but were not considered adverse because the magnitude of change was small compared to the normal variability of the parameter. Additionally, mild changes in these parameters are not associated with adverse effects. 45 Com pany Sanitized. Does not contain T S C CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 Calcium was minimally decreased in males dosed with 1000 mg/kg/day at test day 91. This change is possibly treatment-related, but was considered non-adverse because of the extremely small change in the parameter. Chloride was minimally and transiently increased in females dosed with 1000 mg/kg/day at test day 44. This change was possibly treatment-related, but was considered non-adverse because of the transient nature of the change and the extremely small magnitude of the change (103% of control group mean). The following statistically significant changes in clinical chemistry parameters were considered to be unrelated to treatment because they did not occur in a dose-related manner, or only occurred after one month of recovery: Decreased creatinine in males dosed with 50 mg/kg/day at test day 91, and in females dosed with 250 mg/kg/day at day 44 Decreased total protein in males and females dosed with 250 mg/kg/day at test day 44 Decreased globulins in females dosed with 250 mg/kg/day at test day 44 Decreased calcium in females dosed with 250 mg/kg/day at test day 44 Increased sodium in females previously dosed with 1000 mg/kg/day at test day 124 Increased inorganic phosphorus in males previously dosed with 1000 mg/kg/day at test day 123 C. Urinalysis (Tables 32-32, Appendix K) There were no toxicologically significant changes in urinalysis parameters in rats dosed with 50, 250, or 1000 mg/kg/day. All statistically significant changes were considered unrelated to treatment and/or non-adverse. These changes are detailed below. Urine volume was decreased in females dosed with 50 mg/kg/day (test day 92) or 1000 mg/kg/day (test days 44 and 92). These changes were considered to be unrelated to treatment because they did not occur in a dose-related manner. Additionally, decreased urine volume in animals with normal hydration is of no biologic or toxicologic significance. Urine fluoride was increased in males and females dosed with 250 or 1000 mg/kg/day at test days 91/92. The change occurred in a dose-related manner, and males were minimally more affected than females. After one month of recovery (test days 123/124), urine fluoride was still mildly increased in males and females previously dosed with 1000 mg/kg/day (not statistically significant in females). Although increased urine fluoride was treatment-related, it was not considered adverse because there were no adverse effects on any parameters relating to renal glomerular or tubular function. 46 eom pany Sanitized. Does no! contain T S C CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 Decreased urine protein concentration in males dosed with 1000 mg/kg/day at test day 91 is possibly treatment-related, but was not considered adverse because increased urine protein, rather than decreased urine protein, is indicative of toxicity. D. Clinical Pathology Conclusions Under the conditions of this study, the NOEL for males was 50 mg/kg/day and the NOEL for females was 250 mg/kg/day. These were based on the findings of elevated liver en2ymes at 90 days and/or recovery in males dosed with 250 or 1000 mg/kg/day and females dosed with 1000 mg/kg/day. There were no adverse findings for hematologic, coagulation or urinalysis parameters at any dose. i I\ 47 Sanitized. Does not contain TSCA CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 ANATOMICAL PATHOLOGY A. Subchronic Toxicity and Recovery 1. Organ Weight Data (Tables 33-34, Appendix L) Test substance-related and statistically significant increases, compared to controls, in liver weight parameters occurred in male rats sacrificed on test day 91. Liver weight relative to body weight was increased in 50, 250, and 1000 mg/kg/day males. Absolute and relative to body weight liver weights were increased in one-month recovery and 3-month recovery (satellite) males at 1000 mg/kg/day. At all dose levels, the increased liver weights in males correlated with microscopic hepatocellular hypertrophy (see discussion under Microscopic Findings). Liver weight relative to body weight was statistically significantly increased in 1000 mg/kg/day females on test day 92. This increased weight was most likely test substance-related, however, there were no correlative microscopic findings present in female livers. Increased absolute spleen weights (not statistically significant) and statistically significant relative to body weight and relative to brain weight spleen weights were present in 250 and 1000 mg/kg/day females on test day 92. There were no microscopic findings in spleens from 1000 mg/kg/day females, male spleen weights were not affected, and clinical pathology parameters were within normal limits. Therefore, the increased spleen weights were considered to be test substance-related but not toxicologically significant. There were no other test substance-related organ weight effects. All other statistically significant organ weight changes in subchronic and recovery groups were secondary to decreases in body weight. In 1000 mg/kg/day male rats, these included decreases in absolute organ weight and/or organ weight relative to brain weight for heart, spleen (90-day exposure and one-month recovery groups), thymus and adrenal glands. There were no weight changes in these organs when adjusted to final body weight, and no test substance-related microscopic changes were present. Also in 1000 mg/kg/day male rats, organ weights relative to body weight were increased in brain, testes (90-day exposure and one-month recovery groups), epididymides and kidney (250 and 1000 mg/kg/day exposure groups) without correlative effects in other weight parameters or microscopic changes in these organs. Weights for these latter organs are generally maintained despite body weight loss, and thus this pattern of organ weight change is also consistent with effects occurring secondary to decrements in body weight. 2. Gross Observations (Tables 35-36, Appendix M) Gross observations noted were sporadic across groups and were not test substance-related. 48 Com pany Sanitized. Does not contain T S C A CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 3. Microscopic Findings (Tables 37-42, Appendix M) Test substance-related microscopic findings were present in nose and thyroid gland from male and female rats and in liver from male rats. Summary of Test substance-Related Microscopic Findings 0 mg/kg/day 50 mg/kg/day 250 mg/kg/day Males 90-dav Exposure fDav 91) 1000 mg/kg/day Nose: Degeneration/necrosis, olfactory epithelium Inflammation, subacute/chronic 0/10a 0/10 8/10 (0.9)b 0/10 10/10(1.7) 5/10 (0.5) 10/10(2.1) 6/10 (0.6) Thyroid gland: Hypertrophy, follicular Alteration, colloid 0/10 8/10(0.8) 0/10 8/10(1.1) 5/10(0.5) 10/10(1.4) 10/10(1.8) 10/10(2.8) Liver: Hypertrophy, hepatocellular 0/10 1/10(0.1) 10/10(1.8) 10/10 (2.0) Males One-Month Recovery fDav 122) Nose: Degeneration/necrosis, olfactory 0/10 NA epithelium NA 3/10 (0.3) Thyroid gland: Hypertrophy, follicular Alteration, colloid 0/10 6/10 (0.7) Liver: Hypertrophy, hepatocellular 0/10 M ales Three-M onth Recoverv /Satellite) fDav 182) Thyroid gland: Alteration, colloid 5/5 (1.2) Liver: Hypertrophy, hepatocellular 0/5 NA . NA NA 4/5 (1.2) 0/5 NA 8/10(1.1) NA 10/10 (2.9) NA 10/10(1.0) 4/4 (2.3) 3/4 (0.8) 5/5 (2.6) 4/5 (0.8) 49 Ppm pany Sanitized. Does not contain T S C A CBt H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 Summary of Test substance-Related Microscopic Findings 0 mg/kg/day 50 mg/kg/day 250 mg/kg/day Females 90-dav Exposure (Dav 92) 1000 mg/kg/day Nose: Degeneration/necrosis, olfactory epithelium 0/10 2/10 (0.2) 4/10( 0.5) 8/10(1.0) Thyroid gland: Hypertrophy, follicular Alteration, colloid 0/10 3/10(0.3) 0/10 5/10 (0.5) 2/10 (0.2) 6/10 (0.6) 7/10(1.0) 10/10(1.1) Females One-Month Recovery (Dav 123) Thyroid gland: Hypertrophy, follicular Alteration, colloid 0/10 6/10 (0.6) Females Three-Month Recoven/ /Satellite) (Day 182) NA NA NA 5/10 (0.6) NA 7/10(1.0) Thyroid gland: Hypertrophy, follicular Alteration, colloid 0/5 3/5 (0.6) 0/5 5/5 (1.0) 0/5 4/5 (0.8) 1/5 (0.2) 3/5 (0.8) a Numerator indicates incidence of rats with microscopic lesion. Denominator indicates number of rats in group. b Number in parentheses indicates group average severity of lesion. NA Tissue not available _ Test substance-related nose lesions in 50, 250, and 1000 mg/kg/day test day 91 male and female rats consisted of degeneration and or necrosis of olfactory epithelium, which was most prominent along the endoturbinates and nasal septum of levels 3 and 4. Incidence and severity of this lesion increased in a dose dependent manner. Subacute to chronic inflammation was also present in male noses at 250 and 1000 mg/kg/day. In male one-month recovery rats the nasal degeneration/necrosis o f olfactory epithelium was still present, however, the incidence and severity were decreased. Test substance-related nose lesions were not present in female onemonth recovery rats or in male and female 3-month recovery (satellite) rats. Follicular hypertrophy was present in thyroid glands of male and female rats in the 250 and 1000 mg/kg/day 90-day exposure and one-month recovery groups, and in 1 female rat in the 1000 mg/kg/day 3-month recovery (satellite) group. Follicular hypertrophy was characterized by tall columnar follicular epithelium with a finely granular or vacuolated cytoplasm. Thyroid hypertrophy was minimal and unassociated with proliferative thyroid lesions. However, this hypertrophy indicates possible disruption of thyroid homeostasis and thus was considered potentially adverse. 50 Company Sanitized. Does not contain T S C A CBt H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 Follicles containing altered colloid were found in thyroids from controls as well as treated, one- month recovery, and 3-month recovery (satellite) rats. However, an increase in the number of affected follicles, and thus grade, was treatment related. The diagnosis of "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 of follicles that contained altered colloid. A grade of 1 was applied when 1 follicle to about 25% of the follicles were involved, with grades 2,3, and 4 applied for each 25% increase in follicular involvement. The size, density, or staining intensity of stipples, granules, clumps, or diffuse basophilia within individual follicles did not impact the grading. In this study, there was only a treatment-related increase in grade and not an appreciable increase in the overall incidence of the observation. There was no apparent association between the presence or absence of altered colloid with follicles that were lined by hypertrophic or non-hypertrophic follicular cells. . Altered colloid described as clumped or granular has been reported to occur spontaneously in Sprague-Dawley rats with increasing incidence correlating to increasing age/21^ Because altered colloid occurs spontaneously in healthy Sprague-Dawley rats, and since increases in its grading score did not consistently correlate with other morphologic alterations, altered colloid was interpreted in the present study as not biologically meaningful and not adverse. There was minimal to mild diffuse hepatocellular hypertrophy in 50, 250, and 1000 mg/kg/day male 90-day exposure rats, the male 1000 mg/kg/day one-month recovery group, and 250 and 1000 mg/kg/day male 3-month recovery (satellite) group. Microscopically, hepatocellular hypertrophy was characterized by an increased amount of finely granular eosinophilic cytoplasm within hepatocytes. There was no histomorphologic evidence of hepatocellular damage. The severity of hepatocellular hypertrophy was less in one-month recovery and three-month recovery (satellite) rats then in 90-day exposure rats, however, complete reversibility of the hypertrophy was not evident by test day 182. The hepatocellular hypertrophy (and the associated increase in liver weights) was considered a test substance-related physiologic response to a xenobiotic and not toxicologically adverse.(22'23,24) All other microscopic observations noted are known to occur spontaneously in rats of this strain and age and were not present in a dose response fashion in either incidence or severity. 4. Cause of Death (Appendix M) There were no test substance-related deaths. One male 250 mg/kg/day rat (Animal No. 641090) was sacrificed in extremis on test day 51 due to a large, open wound under the neck of the animal. One female 1000 mg/kg one-month recovery rat (Animal No. 641356) was found dead on test day 121. Cause of death was a brain tumor (mixed glioma). 51 Com pany Sanitized. Does not contain Y S C C S l H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 B. Anatomical Pathology Conclusions for Subchronic Toxicity Evaluation Exposure to 50, 250, and 1000 mg/kg/day of the test substance for up to 91/92 days produced degeneration/necrosis of olfactory epithelium in the noses of male and female rats and thyroid gland hypertrophy in 250 and 1000 mg/kg/day males and females, hicreased liver weights and microscopic hepatocellular hypertrophy were also present in males in the 50,250, and 1000 mg/kg/day groups. These liver changes were considered to represent a physiologic response to metabolism of a xenobiotic and thus were not considered to be toxicologically significant. The severity of altered colloid in thyroid glands increased beyond control level as the dose increased, however, it was not consistently correlated with any morphologic alterations and was not considered biologically adverse. Under the conditions of this study, the NOEL for pathology for male and female rats could not be determined based on nose lesions at the lowest dose tested (50 mg/kg/day). 52 Company Sanitized. Does not contain TSC H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 REPRODUCTIVE TOXICOLOGY EVALUATIONS REPRODUCTIVE FUNCTION A. Pi Generation 1. Mean Body Weights and Body Weight Gains (Table 43-45, Appendices O-T) Body weights of Pi adult male rats administered 1000 mg/kg/day H-24616 were statistically lower (10-11% of control mean) than male control body weights during and after the cohabitation period. Although this finding was test substance-related, it was not considered toxicologically significant since there was no concomitant reduction in body weight gain in Pi males during that period. There were no test substance-related effects on body weight or body weight gain in Pi female rats during gestation or lactation. 2. Food Consumption and Food Efficiency During Gestation (Table 46, Appendix U) There were no test substance-related effects on food consumption and food efficiency in Pi female rats during gestation. 3. Clinical Observations (Tables 47, Appendices V-X) There were no test substance-related clinical signs in Pi male rats during or after the cohabitation period, or in Pi female rats during cohabitation, gestation or lactation. 4. Reproductive Indices (Tables 48-50, Appendices Y-EE) There were no test substance-related effects on estrous cycle or sperm parameters, or reproductive indices in the Pi generation. B. Offspring Data 1. Litter Size, and Pup Weights, and Survival (Table 51-52; Appendix FF-HH) Mean number of pups per litter, pup weights at birth, and pup weights and survival during the lactation period were not affected by test substance administration. There were no test substance-related clinical signs in pups during lactation. 53 Company Sanitized. Does not contain TSCA CB! H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 C. Fi Generation 1. Mean Body Weights and Body Weight Gains (Table 54-55, Appendices II-JJ) There were no test substance-related effects on body weight or body weight gain during the postweaning period. 2. Food Consumption and Food Efficiency (Table 56-57, Appendix KK) There were no test substance-related effects on food consumption or food efficiency during the post-weaning period. 3. Clinical Observations (Tables 58, Appendices LL) There were no test substance-related clinical signs during the post-weaning period. 4. Developmental Landmarks (Tables 59, Appendices LL) The age at onset of vaginal opening in Fi female rats was similar across groups. The age at onset of preputial separation in Fi male rats was similar across groups. However, the mean day of preputial separation for the control group in this study (48.8) was outside the range for other studies at Haskell Laboratory.3 Thus, some of the sensitivity of the assay may have been lost because the criteria for preputial separation was more rigid in this study compared to previous studies. D. Reproductive Function Conclusions For the reproductive toxicity parameters evaluated under the condition of this study, the NOEL was 1000 mg/kg/day, the highest dose tested. The NOEL was based upon the absence of test substance-related effects on reproductive function. a Historical control data for preputial separation was collected between April and August, 1999. For these studies, the mean day of preputial separation ranged from 42.2-43.9 days. 54 Company Sanitized. Does not contain T S C A C B l H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 REPRODUCTIVE TOXICOLOGY EVALUATIONS ANATOMICAL PATHOLOGY A. Organ Weight Data Parental Pi Adults and Fi Adults (Tables 60-63; Appendix MM) There were no test substance-related weight effects on the thyroid gland of Pi adults. Thyroid gland absolute weight, relative to body weight, and relative to brain weight were decreased in Fi males and females at 250 and 1000 mg/kg/day dose levels. There were no correlating microscopic changes seen in males or females at 1000 mg/kg/day. B. Gross Observations Parental Pi Adults (Tables 64-65, Appendix NN) F, Pups, Weanlings, and Adults (Tables 66-70, Appendix OO-QQ) There were no test substance-related gross observations. Observations occurred in low incidences and were randomly distributed across control and treatment groups. C. Microscopic Observations Parental Pi Adults (Tables 71-72, Appendix NN) Fi Adults (Tables 73-74, Appendix QQ) ' There were no test substance-related microscopic findings. Lesions occurred in low incidences without a relevant dose-response relationship and were considered incidental occurrences of spontaneous lesions in rats of this strain and age. D. Mortality Parental Pi Adults and Fi Adults (Appendices NN and QQ) There were no test substance-related effects on mortality. One Pi female rat (Animal No. 641392) from the 250 mg/kg/day dose group was found dead. The cause of death was urinary calculi and obstruction. There were no test substance-related effects on mortality in Fi adults. E. Anatomical Pathology Conclusions for Reproductive Toxicity For pathology, the NOEL, based upon the decreased thyroid gland weights in F, adults, was 50 mg/kg/day for both male and female rats. 55 Company Sanitized. Does not contain TSCA f' W H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 CONCLUSIONS No test substance-related mortality or clinical signs of toxicity were observed in male or female rats. Statistically significant and toxicologically adverse lower body weights, weight gain, and food efficiency were observed in male rats administered 1000 mg/kg/day compared to controls. Food consumption was also significantly lower in male rats administered 1000 mg/kg/day. After a 30-day recovery period these parameters were similar to controls. No effects on body weight, weight gain, food consumption, or food efficiency were observed in female rats at any dose level. Potentially adverse findings of elevated liver enzymes (ALKP, AST, ALT and/or SDH) were observed after the 90-day exposure period and/or after one month of recovery in some male rats dosed with 250 and 1000 mg/kg/day and some female rats dosed with 1000 mg/kg/day. Increased liver weights and/or hepatocellular hypertrophy were observed in male rats of all dose levels and female rats administered 1000 mg/kg/day. These latter changes were considered a test substance-related physiologic response to a xenobiotic and not toxicologically adverse. After three months of recovery, hepatocellular hypertrophy was observed only in male rats administered 250 and 1000 mg/kg/day and not in female rats. Thyroid hypertrophy was observed after 90 days in male and female rats administered 250 and 1000 mg/kg/day. These changes were considered test substance-related and toxicologically adverse. After three months of recovery, thyroid hypertrophy was not observed in male rats and seen in only one female rat in the 1000 mg/kg/day dose group. Test substance-related and toxicologically adverse olfactory epithelium degeneration / necrosis was observed in male and female rats in all dose groups. Incidence and severity of the lesion occurred in a dose dependent manner. Incidence and severity of the lesions decreased after one month of recovery. Nose lesions were not observed in male or female rats at any dose level after a 3-month recovery period. There were no test substance-related effects on reproductive function. However, the Ft offspring of P, adults administered 250 and 1000 mg/kg/day had statistically significant lower thyroid weights compared to control Fi rats. These effects on FI thyroid organ weight were considered toxicologically adverse. Based on the nasal epithelium necrosis observed in male and female rats of all dose levels, a no-observed-effect-level (NOEL)3cannot be determined for the 90-day exposure period. Although there were no test-substance related effects observed on reproductive function, a NOEL of 50 mg/kg/day was determined for reproductive evaluations based on decreased thyroid weight observed in both male and female Fj adults at dosages of 250 mg/kg/day and above. a 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(25) and to the no-observed-adverse-effect level (NOAEL) as l ) defined by the European Union(26). 56 Company Sanitized. Does no! contain T S C CBl H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Genertion Reproduction Evaluations DuPont-4739 REFERENCES 1 DuPont (1995). Neurotoxicity E q u atio n of Trimethyltin in Rats (Positive Control Study). 2. DuPont (1997). Neurotoxicity EvaliMion of Amphetamine in Rats (Positive Control Study). 3. DuPont (1997). Neurotoxicity Evaluation of Carbaryl in Rats (Positive Control Study). 4. DuPont (1996). Neurotoxicity Evaluation of Acrylamide in Rats (Positive Control Study). 5. Draper, N.R. and Smith, H. (1981). Applied Regression Analysis, 2nd edition, pp 266-273. Wiley, New York. 6. Selwyn, M.R. (1995). The use of 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. 7. Jonckheere, A.R. (1954). A distribution-free K-sample test against ordered alternatives. Biometrika 41, 133-145. 8. Levene, H. (1960). Robust test for equality of variances. Contributions to Probability and Statistics (J. Olkin, ed.), pp 278-292. Stanford University Press, Palo Alto. 9. Shapiro, S.S. and Wilk., M.B. (1965). An analysis of variance test for normality (complete samples). Biometrika 52, 591-611. 10. Snedecor, G.W. and Cochran, W.G. (1967). Statistical Methods, 6th edition, pp 246-248 and 349-352. The Iowa State University Press, Ames. 11. Dunnett, C.W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Amer. Statist. Assoc. 50, 1096-1121. 12. Kruskal, W.H. and Wallis, W.A. (1952). Use of ranks in one-criterion analysis of variance. J. Amer. Statist. Assoc. 47, 583-621. 13. Dunn, O.J. (1964). Multiple contrasts using rank sums. Technometrics 6, 241-252. 14. Milliken, G.A. and Johnson, D.A. (1984). Analysis o fMessy Data, Volume J.: Designed Experiments. Lifetime Learning Publications, Belmont. 15. Hocking, R.A. (1985). The Analysis ofLinear Models. Brooks/Cole, Monterey. 57 Company Sanitized. Does not contain T S C A CB! H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 16. Bartlett, M.S. (1937). Some examples of statistical methods of research in agriculture and applied biology. J. Royal. Statis. Soc. Suppl. 4,137-170. 17. Fisher, R.A. (1985). Statistical Methodsfo r Research Workers, 13th edition. Haffiier, New York. 18. Dempster, A.P., Selwyn, M.R., Patel, C.M., and Roth, A.J. (1984). Statistical and computational aspects of mixed model analysis. The Journal o f the Royal Statistical Society, Series C (Applied Statistics) 33(2), 203-214. 19. Haseman, J.K. and Hogan, M.D. (1975). Selection of the experimental unit in teratology studies. Teratology, 12,165-171. 20. Patefield, W. (1982). Exact tests for trends in ordered contingency tables. Applied Statistics 31,32-43. 21. 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, 278-287. 22. Sipes, G. I. and Gandolfi, A. J. (1991). Biotransformation of toxicants. In Casearett and D oull's Toxicology: The Basic Science o f Poisons (M. O. Amdur, J. Doull, and C. D. Klaassen, Eds.), pp. 88-126. Pergamon Press, New York. 23. Paynter, O. E,, Harris, J. E., Burin, G. J. and Jaeger, R. B. (1985). Guidance for analysis of evaluation of subchronic exposure studies. United States Environmental Protection Agency, P/l-540/9-85-020. . 24. Greaves, P. (1990)! Digestive system 2. In Histopathology o fPreclinical Toxicity Studies: Interpretation and Relevance in Drug Safety Evaluation (P. Greaves, Ed.), pp. 393-496, Elsvier, Amsterdam. 25. Hazard Evaluation Division, Standard Evaluation Procedure, Toxicity Potential: Guidance for Analysis and Evaluation of Subchronic and Chronic Exposure Studies Paynter, O. E. et al., United States Environmental Protection Agency, Office of Pesticide Programs, Washington, D.C., 20406. EPA-540/9-85-020. (June 1985). 26. Risk Assessment of Notified New Substances. Technical Guidance Document (XI/283/94EN), Chapter I, Sections 2.24 and 2.25. 1994. 58 Company SanWzeff ennaln TSC Cflfc % H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLES 59 I. Doe I gf H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLES EXPLANATORY NOTES DuPont-4739 Critical Dates Day 69 Male and female rats designated for reproduction evaluations were co housed. Body weight and clinical observation data recorded 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 rats designated for the 90-day exposure and one-month and 3-month recovery periods, and female rats designated for one-month and 3-month recovery periods. > Last day of non-fasted body weight and food consumption data collection for male rats designated for the 90-day exposure period. Day 91 > Last day of test substance administration for female rats designated for the 90-day exposure period. > Last day of non-fasted body weight and food consumption data collection for female rats designated for the 90-day exposure period. > Male rats designated for the 90-day exposure period were sacrificed. > Recovery period begins for rats designated for the one-month and 3-month recovery periods. Days 84-91 Rats designated for the 3-month recovery period were temporarily housed in metabolism cages for urine and feces collection. Food consumption data was not collected for these animals during this period. Day 92 Female rats designated for 90-day exposure period were sacrificed. Day 119 Last day of food consumption data collection for animals designated for the one-month and 3-month recovery periods. Days 122 and 123 Male and female rats designated for the one-month recovery period were sacrificed, respectively. Days 126-182 Body weight and clinical observation data for rats designated for the 3-month recovery period are provided in the appendix. Day 182 Male and female rats designated for the 3-month recovery period were sacrificed. 60 gfempany Sanitized. Does notconfata tsr CB H-24616: 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 WBC - white blood cell count ANEU - absolute neutrophil (all forms) ANPR - absolute neutrophil precursor ALYM - absolute lymphocyte AMON - absolute monocyte AEOS - absolute eosinophil ABAS - absolute basophil ALUC - absolute large unstained cell ABLT - absolute blast leukocyte AMSC - absolute miscellaneous leukocyte PLT - platelet count Summary of Coagulation Values PT - prothrombin time APTT - activated partial thromboplastin time DuPont-4739 61 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLES DuPont-4739 ABBREVIATIONS: EXPLANATORY NOTES Summary of Serum and Plasma Chemistry Values AST - aspartate aminotransferase ALT - alanine aminotransferase SDH - sorbitol dehydrogenase ALKP - alkaline phosphatase BILI - total bilirubin BUN - urea nitrogen CREA - creatinine CHOL - cholesterol TRIG - triglycerides GLUC - glucose TP - total protein ALB - albumin GLOB - globulin CALC - calcium IPHS - inorganic phosphorous NA - sodium K - potassium CL - chloride PFLU - plasma fluoride Summary of Urinalysis Values VOL - volume UOSM - urine osmolality SG - specific gravity pH - the logarithm of the reciprocal of 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. 62 Sw npany Sanitized. Does not contain Tse** eft} H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 1 MEAN DAILY DOSE VOLUMES (mL) FOR MALE RATS Group I mg/kg/day Group III 50 mg/kg/day Group V Group VII 250 mg/kg/day 1000 mg/kg/day DAY 0 - DAY 6 1.04 0.08 (45) 0. 05 0. 00 (35) 0. 26 0. 02 (35) 1. 03 0. 08 (45) DAY 7 - DAY 13 1.26 0.10 (45) 0. 06 0. 00 (35) 0. 31 0. 02 (35) 1. 23 0. 09 (45) DAY 14 - DAY 20 1.45 0.12 (45) 0. 07 0. 01 (35) 0. 36 0. 02 (35) 1. 42 0. 12 (45) DAY 21 - DAY 27 1.62 0.14 (45) 0. 08 0. 01 (35) 0. 40 0. 03 (35) 1. 57 0. 14 (45) DAY 28 - DAY 34 1.77 0.16 (45) 0. 09 0. 01 (35) 0..43 0.,03 (35) 1. 67 0. 17 (45) DAY 35 - DAY 41 1.88 0.16 (45) 0..09 0..01 (35) 0..46 0..03 (35) 1..77 0..19 (45) j DAY 42 - DAY 48 1.97 0.,10 0..47 1.,84 0.18 (45) 0..01 (35) 0..04 (35) 0.,20 (45) DAY 49 - DAY 55 2.05 0.19 (45) 0..10 0 .01 (35) 0 .49 0 .04 (35) 1..90 0..22 (45) DAY 56 - DAY 62 2.13 0.21 (45) 0 .10 0 .01 (35) 0 .52 0 .04 (34) 1 .95 0 .22 (45) DAY 63 - DAY 69 2.18 0.22 (45) 0 .11 0 .01 (35) 0 .53 0 .04 (34) 2 .00 0 .23 (45) DAY 70 - DAY 76 2.25 0.21 (25) 0 .11 0 .01 (15) 0 .54 0 .04 (14) 2 .06 0 .27 (25) DAY 77 - DAY 83 2.32 0.22 (25) 0 .11 0 .01 (15) 0 .55 0 .04 (14) 2 .10 0 .27 (25) DAY 84 - DAY 89 2.36 0.25 (25) 0 .11 0 .02 (15) 0 .55 0 .04 (14) 2 .05 0.28 (25) DAY 90 2.37 0.24 (25) 0 .11 0 .02 (15) 0 .55 0 .04 (14) 2 .05 0.28 (25) Data summarized as: Mean Standard Deviation (n) 63 Company Sanitized. Does no! confab T S C CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 2 MEAN DAILY DOSE VOLUMES (mL) FOR FEMALE RATS 0 mg/kg/day Group IV 50 mg/kg/day DAY 0 - DAY 6 0.76 0. 04 (45) 0. 04 0. 00 (35) DAY 7 - DAY 13 0. 85 0. 05 (45) 0. 04 0. 00 (35) DAY 14 -- DAY 20 0. 92 0. 06 (45) 0. 04 0. 01 (35) DAY 21 -- DAY 27 0. 99 0. 08 (45) 0. 05 0. 00 (35) DAY 28 -- DAY 34 1. 08 0. 09 (45) 0. 05 0. 01 (35) DAY 35 -- DAY 41 1..10 0..09 (45) 0..05 0.,01 (35) DAY 42 - DAY 48 1,.14 0..10 (45) 0..06 0..01 (35) DAY 49 - DAY 55 1 .17 0 .10 (45) 0 .06 0 .01 (35) DAY 56 - DAY 62 1 .20 0 .10 (45) 0 .06 0 .01 (35) DAY 63 - DAY 69 1 .24 0 .10 (45) 0 .06 0 .01 (35) DAY 70 - DAY 76 1 .27 0 .11 (25) 0 .06 0 .00 (15) DAY 77 - DAY 83 1 .28 0 .11 (25) 0 .06 0 .01 (15) DAY 84 - DAY 90 1 .30 0 .13 (25) 0 .06 0 .01 (15) DAY 91 1 .37 0 .15 (10) 0 .06 0 .00 (10) Data summarized as : Mean Standard Deviation (n) Group VI Group VIII 250 mg/kg/day 1000 mg/kg/c 0. 19 0. 01 (35) 0. 76 0. 05 (45) 0. 21 0. 02 (35) 0. 85 0. 06 (45) 0. 23 0. 02 (35) 0. 93 0. 07 (45) 0. 25 0. 02 (35) 0. 99 0. 09 (45) 0. 27 0. 03 (35) 1. 05 0. 09 (45) 0.,28 0.,03 (35) 1. 08 0. 10 (45) 0 .29 0,.03 (35) 1. 12 0.,11 (45) 0 .30 0 .03 (35) 1,.15 0 .12 (45) 0 .30 0 .03 (35) 1 .17 0 .11 (45) 0 .31 0 .03 (35) 1 .21 0 .12 (45) 0 .30 0 .03 (15) 1 .25 0 .14 (25) 0 .32 0 .04 (15) 1 .26 0 .15 (25) 0 .33 0 .04 (15) 1 .28 0.15 (25) 0 .34 0 .04 (10) 1 .26 0.20 (10) 64 Company Sanftfeed. Does noi confato T S C A CBf H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 3 MEAN BODY WEIGHTS (g) OF MALE RATS Group I Group III Group V Group VII 0 mg/kg/day 50 mg/kg/day 250 mg/kg/day 1000 mg/kg/day Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 255.1 16.9(45 ) 254.7 15.6(35 ) 253.0 15.6(35 ) 252.9 16.9(45 ) DAY 7 308.5 22.2(45 ) 305.6 21.5(35 ) 305.9 20.3(35 ) 300.5 20.6(45 ) DAY 14 352.8 27.0(45 ) 353.2 28.2(35 ) 352.5 24.0(35 ) 344.8 26.8(45 ) DAY 21 394.2 31.9(45 ) 396.6 34.4(35 ) 392.2 28.0(35 ) 382.7 35.2(45 ) DAY 28 431.7 37.6(45 ) 427.1 39.8(35 ) 421.2 32.5(35 ) 407.1# 40.9(45 ) DAY 35 457.5 40.3(45 ) 459.9 41.4(35 ) 446.4 33.2(35 ) 431.9# 44.4(45 ) DAY 42 481.4 44.5(45 ) 482.3 43.8(35 ) 464.7 41.5(35 ) 448.5# 46.3(45 ) DAY 49 499.6 46.5(45 ) 505.0 45.1(35 ) 483.8 43.8(35 ) 465.1# 50.9(45 ) DAY 56 520.7 51.1(45 ) 520.6 47.9(35 ) 508.0 40.4(34 ) 476.5# 51.8(45 ) DAY 63 532.7 53.3(45 ) 533.0 47.9(35 ) 520.1 41.5(34 ) 487.4# 56.5(45 ) DAY 69 a 551.2 60.1(20 ) 551.7 39.6(20 ) 540.4 43.3(20 ) 498.6# 51.2(20 ) 65 Company Sanitized. Does not w n m> H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 3 (CONTINUED) MEAN BODY WEIGHTS (g) OF MALE RATS Group I Group III Group V Group VII 0 mg/kg/day 50 mg/kg/day 250 mg/kg/day 1000 mg/kg/day Dosing Period for Subchronic Toxicity Evaluation (Continued) DAY 70 548.5 542.0 524.5 503.1# 52.5(25 ) 60.5(15 ) 37.3(14 ) 63.4(25 ) DAY 77 DAY 84 DAY 90 b 565.1 55.5(25 ) 574.2 60.2(25 ) 592.9 57.3(10 ) 552.9 66.3(15 ) 562.8 68.7(15 ) 577.0 66 .1(10 ) 536.3 39.9(14 ) 538.9 42.3(14 ) 549.6 35.0(10 ) 513.0# 65.9(25 ) 500.7# 69.0(25 ) 474.7# 27.4(10 ) Recovery Period for Subchronic Toxicity Evaluation DAY 91 c 571.6 559.1 521.5 61.1(15 ) 87.7(5 ) 54.7(4 527.6 85.0(15 ) DAY 99 DAY 106 DAY 112 573.9 62.5(15 ) 580.9 64.2(15 ) 592.4 71.8(15 ) 562.5 84.2(5 570.1 89.6(5- ) 581.1 87.3(5 ) 528.6 61.0(4 ) 545.4 61.3(4 ) 561.7 67.2(4 542.9 82.6(15 ) 560.3 79.2(15 ) 572.1 85.0(15 ) DAY 119 601.5 588.9 573.8 73.4(15 ) 91.6(5 ) 64.8(4 588.2 85.9(15 ) Data summarized as: Mean Standard Deviation (n) Statistical Methods: Trend test (Jonckheere-Terpstra). # Statistically significant difference at p < 0.05. a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 69; subsequent data are reported as part of the reproduction evaluation. b. Rats designated for the 90-day sacrifice (10 rats/group) only; rats were sacrificed on test day 91. c. Rats designated for recovery evaluation. Recovery period began on test day 91. 66 C o m p ly Sanitized. Does not contain TSCA CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 4 MEAN BODY WEIGHTS (g) OF FEMALE RATS Group II Group IV Group VI Group VIII 0 mg/kg/day 50 mg/kg/day 250 mg/kg/day 1000 mg/kg/day Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 187.3 10.1(45 ) 184.7 11.8(35 ) 187.2 13.6(35 ) 186.7 11.6(45 ) DAY 7 208.4 205.5 208.7 208.5 12.0(45 ) 14.8(35 ) 16.9(35 ) 14.0(45 ) DAY 14 227.5 15.5(45 ) 227.8 15.7(35 ) 229.5 19.1(35 ) 227.0 16.4(45 ) DAY 21 244.0 244.5 249.8 241.6 18.0(45 ) 18.7(35 ) 24.4(35 ) 20.6(45 ) DAY 28 265.2 20.2(45 ) 265.2 22.5(35 ) 265.1 25.1(35 ) 258.8 21.7(45 ) DAY 35 272.3 271.7 274.2 266.3 21.8(45 ) 21.6(35 ) 25.8(35 ) 22.5(45 ) DAY 42 281.9 285.0 283.4 277.4 23.5(45 ) 23.0(35 ) 26.3(35 ) 26.0(45 ) DAY 49 289.2 22.8(45 ) 289.4 24.3(35 ) 290.5 27.5(35 ) 284.2 26,4(45.. ) DAY 56 296.4 297.8 298.7 288.9 23.6(45 ) 24.7(35 ) 28.6(35 ) 26.9(45 ) DAY 63 300.1 301.3 303.0 294.2 24.6(45 ) 26.5(35 ) 27.8(35 ) 29.1(45 ) DAY 69 a 304.2 22.9(20 ) 312.9 29.4(20 ) 306.1 27.2(20 ) 296.7 28.4(20 ) 67 ">pany Sanitized. Does not contain T S C A CBl H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 4 (CONTINUED) MEAN BODY WEIGHTS (g) OF FEMALE RATS Group II Group IV Group VI Group VIII 0 mg/kg/day 50 mg/kg/day 250 mg/kg/day 1000 mg/kg/day Dosing Period for Subchronic Toxicity Evaluation (Continued) DAY 70 307.7 299.5 309.0 303.6 27.4(25 ) 19.2(15 ) 32.9(15 ) 33.5(25 ) DAY 77 311.0 304.6 312.2 309.3 27.1(25 ) 18.9(15 ) 37.4(15 ) 36.9(25 ) DAY 84 316.6 306.2 320.0 312.7 30.1(25 ) 18.0(15 ) 40.5(15 ) 36.5(25 ) DAY 91 b 330.8 309.3 328.2 308.0 37.2(10 ) 17.5(10 ) 41.0(10 ) 45.7(10 ) Recovery Period for Subchronic Toxicity Evaluation DAY 91 c 308.6 301.7 24.9(15 ) 15.9(5 304.8 40.0(5 DAY 99 317.5 307.7 313.6 22.1(15 ) 16.7(5 ) 42.9(5 ) DAY 106 322.2 313.0 316.6 24.6(15 ) 15.7(5 ) 44.9(5 ) DAY 112 326.2 316.3 323.4 23.4(15 ) 13.2(5 ) 44.1(5 ) DAY 119 327.5 320.2 331.8 26.1(15 ) 10.1(5 ) 45.6(5 318.6 31.2(15 ) 328.1 31.9(15 ) 337.8 33.5(15 ) 337.7 34.5(15 ) 341.7 34.3(15 ) Data summarized as: Mean Standard Deviation (n) Statistical Methods: Trend test (Jonckheere-Terpstra). There were no statistically significant differences at p < 0.05. a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 69; subsequent data are reported as part of the reproduction evaluation. b. Rats designated for the 90-day sacrifice (10 rats/group) only; rats were sacrificed on test day 92. c. Rats designated for recovery evaluation. Recovery period began on test day 91. 68 eompanv SaMffeecf. Does not contain TSCA C) H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 5 MEAN BODY WEIGHT GAINS (g) OF MALE RATS Group I Group III Group V Group VII 0 mg/kg/day 50 mg/kg/day 250 mg/kg/day 1000 mg/kg/day Dosino Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 - DAY 7 '53.4 8.7(45 ) 50.9 10.0(35 ) 52.9 9.9(35 ) 47.5# 8.7(45 ) DAY 7 - DAY 14 44.3 8.3(45 ) 47.7 9.5(35 ) 46.5 6.6(35 ) 44.3 9.4(45 ) DAY 14 - DAY 21 41.4 8.9(45 ) 43.3 9.1(35 ) 39.7 10.4(35 ) 37.9 11.6(45 ) DAY 21 - DAY 28 37.5 9.0(45 ) 30.5# 10.4(35 ) 29.1# 12.3(35 ) 24.4# 11.7(45 ) DAY 28 - DAY 35 25.8 8.1(45 ) 32.8 12.6(35 ) 25.2 6.9(35 ) 24.9 9.1(45 ) DAY 35 - DAY 42 23.9 8.8(45 ) 22.4 7.9(35 ) 18.3 19.9(35 ) 16.6# 8.1(45 ) DAY 42 - DAY 49 18.2 7.6(45 ) 22.7 10.5(35 ) 19.1 13.4(35 ) 16.6 11.6(45 ) DAY 49 - DAY 56 21.1 8.9(45 ) 15.6 9.1(35 .) 20.5 11.4# 9.6(34 ) - 8.5(45 ) DAY 56 - DAY 63 12.0 11.5(45 ) 12.4 9.7(35 ) 12.0 8.7(34 ) 10.8 8.4(45 ) DAY 63 - DAY 69 a 12.8 4.9(20 ) 11.3 6.8(20 ) 10.7 8.4(20 ) 9.8 9.8(20 ) DAY 0 - DAY 69 3 294.6 46.4(20 )i 295.8 37.7(20 ) 285.0 36.2(20 ) 246.8# 41.7(20 ) 69 wnpany Sanitized. Does not contain T S C A n th j I I j | IP H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 5 (CONTINUED) MEAN BODY WEIGHT GAINS (g) OF MALE RATS Group I Group III Group V Group VII 0 mg/kg/day 50 mg/kg/day 250 mg/kg/day 1000 rag/kg/day Dosing Period for Subchronic Toxicity Evaluation (Continued) DAY 63 - DAY 70 20.4 14.1(25 ) 18.9 6.1(15 ) 18.0 6.9(14 ) DAY 70 - DAY 77 16.6 6.2(25 ) 10.9 8.5(15 ) 11.8 6.7(14 ) DAY 77 - DAY 84 9.1 9.5(25 ) 9.9 7.5(15 ) 2.7# 9.4(14 ) DAY 84 - DAY 90 b 6.9 6.1(10 ) 10.0 4.0(10 ) 5.1 6.7(10 ) DAY 84 - DAY 91 c 5.3 15.8(15 ) 4.4 8.3(5 ) -3.6 8.1(4 ) 16.9 8.1(25 ) 9.9# 10.8(25 ) -12.3# 17.0(25 ) 2.5 7.8(10 ) 7.9 10.6(15 ) DAY 0 - DAY 90 b DAY 0 - DAY 91 c 338.2 52.3(10 ) 318.2 51.6(15 ) 322.5 62.8(10 ) 308.8 76.6(5 ) 297.5 30.5(10 ) 273.1 36.8(4 ) Recovery Period for Subchronic Toxicity Evaluation DAY 91 - DAY 99 2.2 8.0(15 ) 3.4 8.6(5 ). 7.1 13.4(4 ) DAY 99 - DAY 106 7.0 7.7 (15 ) 7.6 7.0(5 ) 16.7# 2.6(4 ) DAY 106 - DAY 112 11.5 11.6(15 ) 11.0 5.0(5 ) 16.3 6.4(4 ) DAY 112 - DAY 119 9.1 6.3(15 ) 7.7 7.8(5 ) 12.2 4.3(4 ) 224.2# 28.7(10 ) 271.6# 73.7(15 ) 15.2# 14.2(15 ) 17.5# 12.3(15 ) 11.8 12.0(15 ) 16.1# 5.1(15 ) DAY 91 - DAY 119 c 29.9 20.4(15 ) 29.8 10.8(5 ) 52.3 19.9(4 ) 60.6# 22.5(15 ) Data summarized as: Mean ' Standard Deviation (n) Statistical Methods: Trend test (Jonckheere-Terpstra). # Statistically significant difference at p < 0.05. a . Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 69; subsequent data are reported as part of the reproduction evaluation. b. Rats designated for the 90-day sacrifice (10 rats/group) only; rats were sacrificed on test day 91. c. Rats designated for recovery evaluation. Recovery period began on test day 91. 70 Company Sanitized. Does no! confata T S C A CBt Company SanWzerf 'ft H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE MEAN BODY WEIGHT GAINS (g) OF FEMALE RATS Group II Group IV Group VI Group VIII 0 mg/kg/day 50 mg/kg/day 250 mg/kg/day 1000 mg/kg/day Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 - DAY 7 21.2 6.5(45 ) 20.9 9.4(35 ) 21.5 8.0(35 ) 21.7 6.6(45 DAY 7 - DAY 14 19.1 9.3(45 ) 22.3 7.6(35 ) 20.9 8.3(35 ) 18.6 6.3(45 DAY 14 - DAY 21 16.5 7.3(45 ) 16.7 6.7(35 ) 20.2 9.8(35 ) 14.6 7.9(45 DAY 21 - DAY 28 21.3 9.2(45 ) 20.6 8.7(35 ) 15.3# 8.9(35 ) 17.2# 8.2(45 DAY 28 - DAY 35 7.0 10.8(45 ) 6.5 7.8(35 ) 9.1 7.1(35 ) 7.4 7.7(45 DAY 35 - DAY 42 9.6 8.5(45 ) 13.3 7.3(35 ) 9.2 6.7(35 ) 11.2 9.4(45 fj DAY 42 - DAY 49 7.3 10.5(45 ) 4.3 6.2(35 ) 7.1 7.7(35 ) 6.8 8.1(45 DAY 49 - DAY 56 7.2 9.0(45 ) 8.4 8.8(35 ) 8.2 6.5(35 ) 4.6 7.9(45 DAY 56 - DAY 63 3.7 8.0(45 ) 3.5 8.0(35 ) 4.3 6.1(35 ) 5.3 7.0(45 DAY 63 - DAY 69 a 4.0 6.7(20 ) 4.4 5.7(20 ) 2.3 5.3(20 ) 5.6 6.8(20 DAY 0 -- DAY 69 a 116.6 20.6(20 ) 125.7 23.5(20 ) 117.8 22.3(20 ) 109.8 24.1(20 71 Company Sanitized Po"mn*o"-*'!1. H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 6 (CONTINUED) DuPont-4739 MEAN BODY WEIGHT GAINS (g) OF FEMALE RATS Group II Group IV Group VI Group VIII 0 mg/kg/day 50 mg/kg/day 250 mg/kg/day 1000 mg/kg/day Dosing Period for Subchronic Toxicity Evaluation (Continued) DAY 63 - DAY 70 7.5 5.3(25 ) 7.7 8.1(15 ) 7.0 9.9(15 ) DAY 70 - DAY 77 3.4 7.4(25 ) 5.1 10.2(15 ) 3.3 9.5(15 ) DAY 77 - DAY 84 5.6 6.6(25 ) 1.6 7.7(15 ) 7.7 10.2(15 ) DAY 84 - DAY 91 b 0.2 9.7(10 ) -0.8 6.9(10 ) 1.6 3.8(10 ) DAY 84 - DAY 91 c 1.3 5.1(15 ) 3.3 10.2(5 ) -1.9 8.4(5 ) 6.9 7.2(25 ) 5.7 8.3(25 ) 3.4 8.2(25 ) 0.7 9.4(10 ) 2.3 6.7(15 ) DAY 0 - DAY 91 130.4 28.5(25 ) 125.5 16.2(15 ) 134.7 28.4(15 ) Recovery Period for Subchronic Toxicity Evaluation DAY 91 - DAY 99 8.9 7.2(15 ) 6.0 11.7(5 ) DAY 99 - DAY 106 4.7 7.6(15 ]1 5.3 - 5.5(5 ) . DAY 106 - DAY 112 ' 4.0 5.9(15 :1 3.4 7.3(5 ) DAY 112 - DAY 119 1.3 11.9(15 ) 3.9 5.8(5 ) 8.8 7.5(5 ) 3.0 3.4(5 ) 6.8 5.5(5 ) 8.4 5.9(5 ) 127.7 28.8(25 ) 9.5 4.2(15 ) 9.7 6.8(15 ) - 0.0 21.2(15 ) 4.0 6.9(15 ) DAY 91 - DAY 119 c 18.9 11.7(15 ) 18.5 18.5(5 ) 27.0 9.2(5 ) 23.2 17.0(15 ) Data summarized as: Mean Standard Deviation (n) Statistical Methods: Trend test (Jonckheere-Terpstra). # Statistically significant difference at p < 0.05. a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 69; subsequent data are reported as part of the reproduction evaluation. b. Rats designated for the 90-day sacrifice (10 rats/group) only; rats were sacrificed on test day 92. c. Rats designated for recovery evaluation. Recovery period began on test day 91. 72 CompanySanitized. Does notcontain TSCA OBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 7 MEAN DAILY FOOD CONSUMPTION (g) BY MALE RATS Group I Group III Group V Group VII 0 mg/kg/day 50 mg/kg/day 250 mg/kg/day 1000 mg/kg/day Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 - DAY 7 28.7 3.0(44 ) 28.7 2.3(35 ) 27.6 2.5(35 ) 27.9 2.9(45 ) DAY 7 - DAY 14 30.4 3.1(45 ) 30.7 3.2(35 ) 30.5 2.7(35 ) 29.8 3.2(45 ) DAY 14 - DAY 21 32.1 3.3(45 ) 32.4 3.3(35 ) 31.6 2.6(35 ) 31.2 4.1(45 ) DAY 21 - DAY 28 32.6 3.5(45 ) 32.6 3.5(35 ) 30.5# 2.6(35 ) 29.2# 4.0(45 ) DAY 28 - DAY 35 31.2 3.4(45 ) 31.5 3.4(35 ) 30.2 2.3(35 ) 29.5# 3.9(45 ) DAY 35 - DAY 42 32.1 3.5(45 ) 31.4 3.3(35 ) 29.1# 4.6(35 ) 28.7# 3.5(45 ) DAY 42 - DAY 49 31.3 3.4(45 ) 31.1 3.3(35 ') 29.3# 3.5(35 ) 28.8# 3.9(45 ) DAY 49 - DAY 56 32.8 3.7(45 ) 31.6 2.9(35 ) 31.5 3.1(34 ) 29.5# 3.5(45 ) DAY 56 - DAY 63 32.4 4.3(45 ) 31.3 3.1(35 ) 31.2 2.9(34 ) 29.8# 3.7(45 ) DAY 63 - DAY 69 a 33.2 4.5(20 ) 33.4 3.0(20 ) 31.8 2.7(20 ) 31.1 4.2(20 ) DAY 0 -- DAY 69 a 32.03 3.651(19 ) 31.75 2.444(20 ) 30.80 2.391(20 ) 29.62# 2.788(20 73 Company Sanitized. Does not contain T S C A GBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 7 (CONTINUED) MEAN DAILY FOOD CONSUMPTION (g) BY MALE RATS Group I Group III Group V Group VII 0 mg/kg/day 50 mg/kg/day 250 mg/kg/day 1000 mg/kg/day Dosing Period for Subchronic Toxicity Evaluation (Continued) DAY 63 - DAY 70 32.5 3.6(25 ) 32.0 2.7(15 ) 30.1 2.2(14 ) DAY 70 - DAY 77 32.3 3.5(25 ) 32.0 3.4(15 ) 30.2 2.2(14 ) DAY 77 - DAY 84 b 31.7 3.4(20 ) 32.2 2 .8(10 ) 29.1# 2 .6(10 ) DAY 84 - DAY 90 32.4 4.2(10 ) 31.7 3.1(10 ) 28.3# 2.3(10 DAY 84 - DAY 91 b,d 30.9 2.3(10 ) 30.5 4.1(25 ) 30.1# 4.2(25 ) 27.6# 3.7(20 ) 25.5# 2 .1(10 ) 26.4# 6 .2(10 ) DAY 0 - DAY 90 b,c 32.43 3.296(10 ) 31.35 2.627(10 ) 29.99 1.674(10 ) DAY 0 - DAY 91 b,d 31.28 1.517(10 ) Recovery Period for Subchronic Toxicity Evaluation DAY 91 - DAY 99 29.2 2.6(15 ) 29.7 3.1(5 ) 27.6 3.6(4 ) DAY 99 - DAY 106 30.3 3.6(15 ) 30.3 4.2(5 ) 29.5 4.0(4 ) DAY 106 - DAY 112 29.6 4.0(15 ) 29.0 4.1(5 ) 30.9 3.4(4 ) DAY 112 - DAY 119 31.2 3.8(15 ) 30.4 3.7(5 ) 32.3 2.8(4 ) 27.34# 0.890(10 ) 30.70 3.117(10 ) 31.3 4.7 (15 31.9 4.5(15 31.4 4.2(15 32.5 3.8(15 DAY 91 - DAY 119 d 30.06 29.88 29.94 3.313(15 ) 3.704(5 ) 3.422(4 31.79 4.120(15 ) Data summarized as: Mean Standard Deviation (n) Statistical Methods: Trend test (Jonckheere-Terpstra). # Statistically significant difference at p < 0.05. a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 69; food consumption data were not collected during the cohabitation and postmating periods. b. Food consumption data for rats designated for the 3-month recovery (5 rats/group) were not determined for test days 84 through 91. c. Rats designated for the 90-day sacrifice (10 rats/group) only; rats were sacrificed on test day 91. d. Rats designated for recovery only. Recovery period began on test day 91. 74 e mpa">'Sar,,,fced. Does not contain TSCA CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 8 MEAN DAILY FOOD CONSUMPTION (g) BY FEMALE RATS Group II Group IV Group VI Group VIII 0 mg/kg/day 50 mg/kg/day 250 mg/kg/day 1000 mg/kg/day Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 - DAY 7 20.4 2.5(45 ) 19.9 1.7(35 ) 20.3 2.0(35 ) 20.1 1.8(45 ) DAY 7 - DAY 14 22.5 5.7(45 ) 21.8 2.0(35 ) 21.6 2.5(35 ) 21.5 2.1(45 ) DAY 14 - DAY 21 22.4 2.5(45 ) 21.9 1.9(35 ) 22.3 2.4(35 ) 21.6 2.6(45 ) DAY 21 - DAY 28 23.3 2.5(45 ) 23.9 2.4(35 ) 23.6 2.6(33 ) 22.7 2.7(44 ) DAY 28 - DAY 35 22.3 2.4(45 ) 22.5 2.0(35 ) 22.1 2.1(35 ) 21.1# 2.8(45 ) DAY 35 - DAY 42 23.1 2.5(45 ) 23.7 2.0(34 ) 23.3 2.2(35 ) 22.6 2.4(45 ) DAY 42 - DAY 49 21.2 2.4(45 ) 22.8 2.1(35 ) 21.5 2.6(35 ) 21.9 2.4(45 ) DAY' 49 - DAY 56 21.9 2.3(45 ) 21.8 3.0(35 ); 22.3 2.4(35 ) 21.2 2.7(45 ) DAY 56 - DAY 63 22.3 2.4(45 ) 23.1 2.6(35 ) 22.0 2.3(35 ) 22.0# 5.3(45 ) DAY 63 - DAY 69 a 22.65 1.717(20 ) 23.50 2.278(20 ) 22.16 2.109(20 ) 21.66 2.450(20 DAY 0 -- DAY 69 a 21.79 1.299(20 ) 22.93 1.802(20 ) 22.53 1.682(18 ) 21.46 1.742 (20 75 Com pany Sanitized. Does not contain T S C CB) H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 8 (CONTINUED) MEAN DAILY FOOD CONSUMPTION (g) BY FEMALE RATS Group II Group IV Group VI Group VIII o' mg/kg/day 50 mg/kg/day 250 mg/kg/day 1000 mg/kg/day Dosing Period for Subchronic Toxicity Evaluation (Continued) DAY 63 - DAY 70 DAY 70 - DAY 77 DAY 77 - DAY 84 b'c DAY 84 - DAY 91 b,c DAY 84 - DAY 91 b,d 22.8 2.3(25 ) 22.1 2.4(25 ) 23.0 2.1(20 ) 22.4 3.4(10 ) 21.6 1.6(10) 22.3 1.8(15 ) 22.8 1.9(15 ) 22.3 1.4(10 ) 21.2 1.2(10 ) _ - 22.6 2.6(15 ) 22.8 2.8(15 ) 22.1 3.2(10 ) 21.5 3.0(10 ) - " DAY 0 - DAY 91 b,c 22.77 2.404(20 ) 21.83 0.884(9 )1 21.94 2.386(10 ) Recovery Period for Subchronic Toxicity Evaluation DAY 91 - DAY 99 23.2 2.2(15 ) 22.2 2.6(5 ) 21.9 3.3(5 ) DAY 99 - DAY 106 DAY 106 - DAY 112 DAY 112 - DAY 119 22.9 2.0(15 ) 22.6 1.9(15 ) 22.3 2.6(15 ) 20.8 3.0(5 ) 21.5 3.7(5 ) 21.6 2.1(5 ) 23.1 1.6(5 ) 23.8 1.6(5 ) 24.4 2.0(5 ) 22.5 . b(b ) 22.8 3.2(25 ) 22.6 3.4(20 ) 22.4 2.5(10 ) 21.6 2.3(10 ) 21.62 2.146(19 ) 24.7 3.3(15 ) 24.1 3.2(15 ) 22.5 4.9(15 ) 23.3 3.8(15 ) DAY 91 - DAY 119 d 22.80 1.571(15 ) 21.55 2.364(5 ) 23.25 1.735(5 ) 23.70 2.988(15 ) Data summarized as: Mean Standard Deviation (n) Statistical Methods: Trend test (Jonckheere-Terpstra). # Statistically significant difference at p < 0.05. a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 69; data were not collected during the cohabitation and postmating periods. b. Food consumption data for rats designated for the 3-month recovery (5 rats/group) were not determined for test days 84 through 91. c. Rats designated for the 90-day sacrifice (10 rats/group) only; rats were sacrificed on test day 92. d. Rats designated for recovery only. Recovery period began on test day 91. 76 e -m p a n , Sanitized. Does net contain TSCA CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 9 MEAN DAILY FOOD EFFICIENCY OF MALE RATS (g body weight gain/g food consumed) Group I Group H I Group V Group VII 0 mg/kg/day 50 mg/kg/day 250 mg/kg/day 1000 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 69 0.265 0.029(44 0.207 0.028(45 0.184 0.029(45 0.163 0.034(45 0.118 0.034(45 0.105 0.032(45 0.082 0.032(45 0.090 0.033 (45 0.052 0.048(45 0.064 0.025(20 0.252 0.038(35 ) 0.221 0.031(35 ) 0.190 0.028(35 ) 0.133# 0.038(35 ) 0.148 0.061(35 ) 0.102 0.035(35 ) 0.104 0.047 (35 -) . 0.070 0.040(35 ) 0.055 0.042(35 ) 0.056 0.032(20 ) 0.272 0.036(35 ) 0.217 0.023(35 ) 0.179 0.041(35 ) 0.133# 0.053(35 ) 0.119 0.033(35 ) 0.054 0.276(35 ) 0.091 0,064(35 ) 0.092 0.039(34 ) 0.054 0.037(34 ) 0.056 0.041(20 ) 0.243# 0.034(45 0.211 0.029(45 0.171 0.039(45 0.116# 0.048(45 0.120 0.040(45 0.082# 0.036(45 0.079 0.050(45 0.054# 0.039(45 0.049 0.038(45 0.049 0.048(20 DAY 0 -- DAY 69 a 0.134 0.009(19 0.135 0.013(20 ) 0.134 0.013(20 ) 0.120# 0.012(20 77 Com pany Sanitized. Does not contain T S C A CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 9 (CONTINUED) 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 50 mg/kg/day 250 mg/kg/day 1000 mg/kg/day Dosing Period for Subchronic Toxicity Evaluation (Continued) DAY 63 - DAY 70 0.087 0.047(25 ) 0.084 0.025(15 ) 0.085 0.031(14 ) 0.079 0.034(25 ) DAY 70 - DAY 77 0.073 0.025(25 ) 0.047 0.036(15 ) 0.055 0.030(14 ) 0.044# 0.047(25 ) DAY 77 - DAY 84 b 0.046 0.040(20 ) 0.043 0.034(10 ) 0.011# 0.032(10 ) -0.077# 0.106(20 ) DAY 84 - DAY 90 b,c 0.035 0.032(10 ) 0.052 0.019(10 ) 0.029 0.040(10 ) 0.018 0.049(10 ) DAY 84 - DAY 91 b'd 0.043 0.039(10 ) - 0.044 0.063(10 ) DAY 0 - DAY 90 b,c 0.115 0.009(10 ) 0.114 0.016(10 ) 0.110 0.006(10 ) DAY 0 - DAY 91 b,d 0.119 0.008(10 ) - - One-Month Recovery Period for Subchronic Toxicity Evaluation DAY 91 - DAY 99 0 ;008 0.032(15 ) 0.015 0.037(5 ) 0.028 0.051(4 ) DAY 99 - DAY 106 0.032 0.037(15 ) 0.033 0.032(5 ) 0.082# 0.016(4 ) DAY 106 - DAY 112 0.060 0.050(15 ) 0.066 0.036(5 ) 0.086 0.024(4 ) DAY 112 - DAY 119 0.041 0.028(15 ) 0.034 0.035(5 ) 0.054 0.020(4 ) 0.091# 0.010(10 ) 0.095# 0.015(10 ) 0.058# 0.051(15 ) 0.080# 0.066(15 ) 0.057 0.066(15 ) 0.072# 0.023(15 ) DAY 91 -- DAY 119 d 0.034 0.021(15 ) 0.035 0.011(5 ) 0.061 0.017(4 ) 0.068# 0.021(15 ) Data summarized as: Mean Standard Deviation (n) Statistical Methods: Trend test (Jonckheere-Terpstra). # Statistically significant difference at p < 0.05. a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 69; data were not collected during the cohabitation and postmating periods. t b. Food consumption data for rats designated for the 3-month recovery (5 rats/group) were not determined for test days 84 through 91. c. Rats designated for the 90-day sacrifice (10 rats/group) only; rats were sacrificed on test day 91. d. Rats designated for recovery only. Recovery period began on test day 91. 78 Com pany Sanitized. Does not contain T S C A CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 10 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 50 mg/kg/day 250 mg/kg/day 1000 mg/kg/day Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 - DAY 7 0.148 0.042(45 ) 0.147 0.059(35 ) 0.149 0.048(35 ) DAY 7 - DAY 14 0.121 0.052(45 ) 0.145 0.046(35 ) 0.137 0.054(35 ) DAY 14 - DAY 21 0.103 0.042(45 ) 0.108 0.040(35 ) 0.127 0.056(35 ) DAY 21 - DAY 28 0.132 0.058(45 ) 0.122 0.047(35 ) 0.091# 0.052(33 ) DAY 28 - DAY 35 0.042 0.065(45 ) 0.041 0.048(35 ) 0.058 0.044(35 ) DAY 35 - DAY 42 0.058 0.050(45 ) 0.080 0.040(34 ) 0.055 0.041(35 ) DAY 42 - DAY 49 0.047 0.070(45 ) 0.026 0.038(35 ) 0.046 0.049(35 ) DAY 49 - DAY 56 0.045 0.058(45 ) 0.055 0.054(35 ) 0.052 0.040(35 ) DAY 56 - DAY 63 0.023 0.052(45 ) 0.019 0.050(35 ) 0.028 0.041(35 ) DAY 63 - DAY 69 a 0.028 0.049(20 ) 0.032 0.038(20 ) 0.015 0.038(20 ) 0.153 0.041(45 0.122 0.036(45 0.095 0.048(45 0.106# 0.050(44 0.046 0.060(45 0.068 0.057(45 0.043 0.052(45 0.029 0.051(45 0.034 0.043(45 0.041 0.052 (20 DAY 0 - DAY 69 a 0.077 0.012(20 ) 0.079 0.009(20 ) 0.077 0.010(18 ) 0.074 0.012(20 79 Com pany Sanitized. Does not contain TSCA Cl H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 10 (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 50 mg/kg/day 250 mg/kg/day 1000 mg/kg/day Dosing Period for Subchronic Toxicity Evaluation (Continued) DAY 63 - DAY 70 0.048 0.035(25 ) 0.048 0.053(15 ) 0.042 0.062(15 ) 0.042 0.043(25 ) DAY 70 - DAY 77 0.020 0.048(25 ) 0.030 0.062(15 ) 0.018 0.060(15 ) 0.033 ' 0.054(25 ) DAY 77 - DAY 84 b DAY 84 - DAY 91 b,c 0.041 0.038(20 ) -0.001 0.051(20 ) 0.006 0.038(10 ) -0.006 0.047(10 ) 0.046 0.056(10 ) 0.009 0.025(10 ) 0.025 0.043(20 ) 0.009 0.050(20 ) DAY 84 - DAY 91 b'd -0.004 0.067(10 ) -0.006 0.047(10 ) 0.009 0.025(10 ) 0.005 0.060(10 ) DAY 0 - DAY 91 b,c 0.064 0.009(20 ) 0.062 0.004(9 ) 0.069 0.007(10 ) One-Month Recovery Period for Subchronic Toxicity Evaluation DAY 91 - DAY 99 0.046 0.037(15 ) 0.029 0.071(5" ). 0.048 0.038(5 ) DAY 99 - DAY 106 0.028 0.047(15 ) 0.035 0.035(5 ) 0.017 0.021(5 ) DAY 106 - DAY 112 0.028 0.045(15 ) 0.022 0.053(5 ) 0.047 0.041(5 ) DAY 112 - DAY 119 -0.000 0.093(15 ) 0.027 0.037(5 ) 0.048 0.033(5 ) 0.062 0.011(19 ) 0.048 0.020(15 ) 0.056 0.037(15 ) -0.055 0.351(15 ) 0.026 0.050(15 ) DAY 91 - DAY 119 d 0.029 0.018(15 ) 0.029 0.031(5 ) 0.041 0.013(5 ) 0.034 0.023(15 ) Data summarized as: Mean Standard Deviation (n) Statistical Methods: Trend test (Jonckheere-Terpstra). # Statistically significant difference at p < 0.05. a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 69; data were not collected during the cohabitation and postmating periods. b. Food consumption data for rats designated for the 3-month recovery (5 rats/group) were not determined for test days 84 through 91. ^ c. Rats designated for the 90-day sacrifice (10 rats/group) only; rats were sacrificed on test day 92. d. Rats designated for recovery only. Recovery period began on test day 91. H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 11 SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS Treatment Group Dose I 0 mg/kg/day Number Animals at Study Start 45 III 50 mg/kg/day 35 V 250 mg/kg/day 35 Eye Observations Corneal Opacity Incidence 2 0 0 Mean onset (Days) 103 Exophthalmus Incidence 1 0 0 Mean onset (Days) 91 Enophthalmus Incidence 1 0 0 Mean onset (Days) 106 General Teeth Observations Absent Incidence 0 0 0 Mean onset (Days) Breathing Observations Noise Incidence 0 0 0 Mean onset (Days) V II 1000 mg/kg/day 45 1 85 1 84 $o Sompany Sanitized. Does not contain H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 11 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS Treatment Group I Dose 0 mg/kg/day Number Animals at Study Start 45 III 50 mg/kg/day 35 V 250 mg/kg/day 35 VII 1000 mg/kg/day 45 Discharge Eyes Incidence Mean onset (Days) 2 77 Nose Incidence Mean onset (Days) 1 77 Hair Loss Incidence Mean onset (Days) 5 44 Wound Deep (Neck, Tail) Incidence Mean onset (Days) 1 69 Superficial (Nose, Neck, Lumbar, Forepaw) Incidence Mean onset (Days) 3 47 O 4 35 0 O i 63 0 4 26 1 51 i 21 l 112 2 81 8 34 0 l 21 IIi ! i ong>any Sanitized. Does no! contain TSCA CB 82 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 11 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS Treatment Group I Dose 0 mg/kg/day Number Animals at :Study Start 45 III 50 mg/kg/day 35 V 250 mg/kg/day 35 # DuPont-4739 V II 1000 mg/kg/day 45 Hyperreactive Incidence Mean onset (Days) Vocalization Incidence Mean onset (Days) 1 49 1 14 001 -- 99 001 14 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. Statistical Methods: Trend test (Cochran-Armitage). : There were no statistically significant differences at p < 0.05. e mpany Sanftteed- "of cental,, tsca 83 H-24616: Subchronic Toxicity 90-Day Gavage Study inRats withOne-GenerationReproductionEvaluations TABLE 12 SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS Treatment Group II Dose 0 mg/kg/day Number Animals at Study Start 45 Mass Side Right Mass #1 Not Ulcerated Incidence Mean onset (Days) 1 63 Eye Observations Corneal Opacity Incidence Mean onset (Days) 0 Exophthalmus Incidence Mean onset (Days) 0 Enophthalmus Incidence Mean onset (Days) 0 IV 50 mg/kg/day 35 VI 250 mg/kg/day 35 00 10 106 11 99 106 10 119 DuPont-4739 VIII 1000 mg/kg/day 45 0 0 0 0 1t fS' Sanitized. Does not contain TSCA CBi 84 H-24616: Subchronic Toxicity 90-Day Gavage Study inRats withOne-GenerationReproductionEvaluations TABLE 12 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS Treatment Group II Dose 0 mg/kg/day Number Animals at Study Start 45 Abnormal Gait Hindlimb Incidence Mean onset (Days) 0 Breathing Observations Noise Incidence Mean onset (Days) 0 Discharge Eyes Incidence Mean onset (Days) 1 77 Nose Incidence Mean onset (Days) 0 IV 50 mg/kg/day 35 0 VI 250 mg/kg/day 35 0 00 41 90 14 10 84 DuPont-4739 VIII 1000 mg/kg/day 45 1 119 1 77 1 112 1 112 I Company Sanitized. Does not contain TSCA C8I 85 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 12 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS Treatment Group II Dose 0 mg/kg/day Number Animals at Study Start 45 Hair Loss Incidence Mean onset (Days) 8 51 Wound Superficial (Neck, Side, Forelimb) Incidence Mean onset (Days) 1 99 IV 50 mg/kg/day 35 7 41 0 _ VI 250 mg/kg/day 35 6 39 1 49 DuPont-4739 VIII 1000 mg/kg/day 45 11 40 2 35 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. Statistical Methods: Trend test (Cochran-Armitage). There were no statistically significant differences at p < 0.05. Company Sanitized. Does not contain TSCA CBI 86 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 13 SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR MALE RATS Treatment Group Dose I 0 mg/kg/day Examination Day: Test Day 88 Number of Rats Examined 20 Retina Retinal Degeneration Focal Incidence 0 ( 0%) III 50 mg/kg/day V 250 mg/kg/day 10 1 ( 10%) 0 ( 0 %) VII 1000 mg/kg/day 20 0( 0% ) Examination Day: Test Day 116 Number of Rats Examined 10 ,0 0 10 Retina Retinal Degeneration Focal ________ Incidence________________1 ( 10%)_______________ ______________________ I-------- -- -- 1 ( 10% ) Incidence - The number of animals (percent of animals examined) for which an observation was recorded. Statistical Methods: Trend test (Cochran-Armitage). There were no statistically significant differences at p < 0.05. H-24616'. Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 14 SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR FEMALE RATS Treatment Group Dose Number of Rats Examined II 0 mg/kg/day 25 IV 50 mg/kg/day 15 VI 250 mg/kg/day 14 VIII 1000 mg/kg/day 25 Examination Day: Test Day 88 Number of Rats Examined 20 There were no ophthalmological abnormalities detected. Examination Day: Test Day 116 Number of Rats Examined 10 There were no ophthalmological abnormalities detected. N<Q0> 3 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 15 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 70a 77 84 91b 99 106 112 119 I 0 45 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 Number at study start Sacrificed in extremis Removed from :study (test day 69)a Sacrificed by design (test day 91) Alive on test day 119 45 0 20 10 15 III V 50 250 35 35 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 35 o- 20 10 5 100 100 100 100 100 100 100 100 97 97 93 93 93 93 80 80 80 80 35 -1 20 10 4 VII 1000 AC 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 45 -- un 20 1iUr\ I1JK Percent Survival = (AE/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. Rats designated for reproduction evaluation were cohoused on test day 69 b. Recovery period began on test day 91. Statistical Method: Cochran-Armitage trend test. , There were no statistically significant decreases in survival at p < 0.0b 89 Company Sanitized. Does not contain T S C A Cfii H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 16 PERCENT SURVIVAL OF FEMALE RATS Treatment Group Dose (mg/kg/day) Number Animals at Study Start IV VI VIII 50 250 1000 35 35 35 DAYS ON TEST 0 7 14 21 28 35 42 49 56 63 70a 77 84 91b 99 106 112 119 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 Number at study start Accidentally killed a Removed from study (test day 69) Sacrificed by design (test day 92) Alive on test day 119 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 35 0 20 10 5 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 35 0 20 10 5 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 45 0 20 10 15 Percent Survival = (AE/Number of rats at risk)*100 Number of rats at risk = Number at study start - number of rats removed from study - number sacrificed by design - accidentally kille . a. Rats designated for reproduction evaluation were cohoused on test day 69. b. Recovery period began on test day 91. Statistical Method: Cochran-Armitage trend test. There were no statistically significant decreases in survival at p < 0.05. 90 Com pany Sanitized. Does not contain T S C CB <D H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 17 MEAN FORELIMB GRIP STRENGTH (kg): MEAN OF THREE TRIALS Male Rats Group: Concentration: N: I 0 mg/kg/day 10 ffl 50 mg/kg/day 10 V vn 250 mg/kg/day 1000 mg/kg/day 10 10 Baseline Week 12 Recovery 0.71 (0.14) 1.42 (0.33) 1.49 (0.43) 0.65 (0.06) 1.32 (0.36) NM 0.73 (0.10) 1.22 (0.39) NM 0.67 (0.12) 1.24 (0.34) 1.42(0.26) Female Rats Group: Concentration: N: n 0 mg/kg/day 10 IV 50 mg/kg/day 10 VI 250 mg/kg/day 10 vm 1000 mg/kg/day 10 Baseline.......... . Week 12 Recovery 0.66(0.08) 1.09(0.26) 1.01 (0.34) 0.63 (0.11) 0.94 (0.24) NM 0.70(0.16) 1.01 (0.41) NM 0.68(0.13) 1.06.(0.31) 0.93 (0.24) Data arranged as: Mean (Standard Deviation). NM = Not measured. Statistical Methods: Bartlett's test for homogeneity, followed by Analysis of Variance and Dunnett s test. There were no statistically significant differences from control at p<0.05. 91 eom panySanltteed-D oes H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 18 MEAN HINDLIMB GRIP STRENGTH (kg): MEAN OF THREE TRIALS Male Rats Group: Concentration: N: I Omg/kg/day 10 EI 50mg/kg/day 10 V VE 250mg/kg/day 1000 mg/kg/day 10 10 Baseline Week 12 Recovery 0.32 (0.07) 0.57 (0.14) 0.78 (0.15) 0.28 (0.06) 0.54 (0.13) NM 0.36 (0.05) 0.69(0.16) NM 0.32 (0.07) 0.60 (0.12) 0.66 (0.07) Female Rats Group: Concentration: N: n 0 mg/kg/day 10 IV 50 mg/kg/day 10 VI 250 mg/kg/day 10 vm 1000 mg/kg/day 10 Baseline Week 12 Recovery 0.31 (0.06) 0.51 (0.07) 0.58(0.12) 0.30 (0.05) 0.46 (0.09) NM 0.35(0.07) 0.52 (0.11) NM 0.33 (0.06) 0.47 (0.09) 0.60 (0.14) Data arranged as: Mean (Standard Deviation). NM = Not measured. Statistical Methods: Bartlett's test for homogeneity, followed by Analysis ofVariance and Dunnett's test. There were no statistically significant differences from control at p<0.05. 92 Company Sanitized. Does not contain T S C A C B l H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 Company Sanitised. Does no! contain t s c Cl TABLE 19 SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR MALE RATS BASELINE __________ WEEK 12__________ RECOVERY GROUP: CONCENTRATION (mg/kg/day): NUMBER EXAMINED: I 0 10 III V VII 50 250 1000 10 10 10 I III V VII 0 50 250 1000 10 10 10 10 I VII 0 1000 10 10 APPROACH & TOUCH: -1 no reaction 0 normal 1 increased reaction (jumps away or attacks) 0000 10 10 9 9 00 11 0000 10 10 10 10 0000 00 10 10 00 AUDITORY STIMULUS: -1 no reaction 0 normal reaction (rat flinches or flicks ear) 1 exaggerated reaction (rat jumps, flips) 0000 10 10 10 9 0 0 0 1 02 10 8 00 10 9 10 00 00 10 10 00 TAIL PINCH: -1 no response 0 normal (turns toward site) 1 exaggerated response 0000 10 10 10 9 000 1 2 12 2 898 8 0000 00 9 10 10 PUPILLARY RESPONSE: 1 absent 0 present 0000 10 10 10 10 DEFECATION IN MOTOR ACTIVITY MONITOR: 0 absent 433 1 1 present 6779 D diarrhea 0000 0000 10 10 10 10 4 6 54 64 5 6 0000 00 10 10 22 88 00 k! J H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations -- <P DuPont-4739 TABLE 19 (CONTINUED) SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR MALE RATS BASELINE WEEK 12 RECOVERY GROUP: CONCENTRATION (mg/kg/day): NUMBER EXAMINED: I 0 10 III V VII 50 250 1000 10 10 10 I III V VII 0 50 250 1000 10 10 10 10 I VII 0 1000 10 10 URINATION IN MOTOR ACTIVITY MONITOR: 0 absent 0 0 10 1 present 10 10 9 10 110 1 9 9 10 9 01 10 9 There were no statistically significant differences by Cochran-Armitage test for trend at p < 0.05. i f r Company Sanitized. Does no! contain "'''SCA r `*?l 94 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 20 SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR FEMALE RATS GROUP: CONCENTRATION (mg/kg/day): NUMBER EXAMINED: II 0 10 BASELINE IV VI 50 250 10 10 VIII 1000 10 __________ WEEK 12__________ II IV VI VIII 0 50 250 1000 10 10 10 10 RECOVERY n VI 0 1000 10 10 APPROACH & TOUCH: -1 no reaction 0 normal 1 increased reaction (jumps away or attacks) 0000 10 9 10 10 0 100 0000 10 9 10 10 0 10 0 00 10 9 00 AUDITORY STIMULUS: -1 no reaction 0 normal reaction (rat flinches or flicks ear) 1 exaggerated reaction (rat jumps, flips) 0000 10 8 10 9 020 1 00 10 9 00 10 10 0 10 0 00 10 9 00 TAIL PINCH: -1 no response 0 normal (turns toward site) 1 exaggerated response 10 10 9 9 9 10 0 10 0 1110 9 9 9 10 0000 00 10 10 00 PUPILLARY RESPONSE: 1 absent 0 present 0000 10 10 10 10 0000 10 10 10 10 00 10 10 DEFECATION IN MOTOR ACTIVITY MONITOR: 0 absent 7 7 5 3* 1 present 3357 D diarrhea 0000 1 9# 6* 7* 9 14 3 00 00 65 44 00 oiflpany Sanitized. Does not contain TSCA CBI 95 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations --0 DuPont-4739 TABLE 20 (CONTINUED) SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR FEMALE RATS GROUP: CONCENTRATION (mg/kg/day): NUMBER EXAMINED: II 0 10 BASELINE IV VI 50 250 10 10 VIII 1000 10 __________ WEEK 12__________ II IV VI VIII 0 50 250 1000 10 10 10 10 URINATION IN MOTOR ACTIVITY MONITOR: 0 absent 000 1 1 present 10 10 10 9 0 111 10 9 9 9 # Statistically significant difference by Fisher's exact test at p < 0.05. * Statistically significant difference by Cochran-Armitage test for trend at p < 0.05. RECOVERY II VIII 0 1000 10 10 00 10 9 Company Sanitized. Does O3 oo Q> 5` CO >O o 09 96 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 s? 3 ) C/ *I2 an> 3IaD J> 93 TABLE 21 MOTOR ACTIVITY ASSESSMENT: DURATION OF MOVEMENTS (sec) FOR MALE RATS DOSAGE GROUP (mg/kg/day) I0 III 50 V 250 VII 1000 1 397 (54) 408 (33) 373 (33) 378 (57) DOSAGE GROUP (mg/kg/day) I0 III 50 V 250 VII 1000 I 415 (57) 409 (37) 390 (53) 417 (58) 2 349 (87) 332 (56) 287 (50) 293 (69) 2 344 (70) 343 (67) 293 (78) 271 (93) BASELINE SUCCESSIVE 10-MINUTE INTERVALS 3 262 (95) 4 173 (115) 5 57 (99) 170(101) 77 (102) 43 (77) 166 (137) 101 (115) 74 (99) 227 (74) 65 (93) 35 (93) WEEK 12 SUCCESSIVE 10-MINUTE INTERVALS 3 288 (81) 4 220 (92) 5 152 (127) 265 (107) 208 (119) 133 (117) 243 (90) 126(106) 80 (92) 152 (139) * 135 (135) 106(138) 6 23 (37) 7(13) 40 (95) 16 (46) TOTAL 1261 (396) 1037 (202) 1041 (444) 1014 (3 27): 6 120 (83) 89 (76) 84 (87) 62 (102) TOTAL 1539 (402) 1447 (348) 1216 (347) 1143 (499) 97 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 21 (CONTINUED) MOTOR ACTIVITY ASSESSMENT: DURATION OF MOVEMENTS (sec) FOR MALE RATS DuPont-4739 RECOVERY DOSAGE GROUP (me/ke/dav) I0 VII 1000 1 393 (74) 351 (48) 2 283 (69) 233 (79) SUCCESSIVE 10-MINUTE INTERVALS 3 215 (86) 161 (59) 4 151 (76) 131 (36) 5 129 (141) 114 (77) 6 98 (107) 89 (54) TOTAL 1268 (432) 1077 (227) Data arranged as: Mean (Standard Deviation). Statistical Methods- Shapiro-Wilk's and Levene's tests were performed. Jonckheere's trend test or 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 at p < 0.05. Stpmpany Sanitized. Does no! contain ft CB! 98 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 22 MOTOR ACTIVITY ASSESSMENT: DURATION OF MOVEMENTS (sec) FOR FEMALE RATS DOSAGE GROUP fme/ke/dav) II 0 IV 50 VI 250 VIII 1000 1 379 (63) 384 (85) 391 (50) 373 (48) DOSAGE GROUP ( me/ke/dav) II 0 IV 50 VI 250 VIII 1000 1 392 (43) 391 (46) 380 (74) 378 (43) 2 284 (52) 323 (94) 258 (121) 257 (54) 2 312 (67) 322 (64) 274 (71) 266 (92) BASELINE SUCCESSIVE 10-MINUTE INTERVALS 3 146 (83) 4 91 (86) 5 77 (73) 274 (106) 167 (119) 184 (115) 193 (140) 192 (140) 105 (85) 170 (145) 141 (123) 95 (126) WEEK 12 SUCCESSIVE 10-MINUTE INTERVALS 3 207 (70) 4 138 (94) 5 132 (105) 226 (96) 184 (97) 105 (88) 158(81) 176 (124) 114 (95) 133 (99) 112(103) 115 (90) 6 46 (76) 119(140) 75 (114) 53 (78) TOTAL 1023 (249) 1464 (597) 1223 (537) 1066 (321) 6 99 (77) 63 (84) 43 (44) 86 (95) TOTAL 1280 (224) 1291 (244) 1145 (352) 1088 (319) tOa no! contain TSCA 99 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 22 (CONTINUED) MOTOR ACTIVITY ASSESSMENT: DURATION OF MOVEMENTS (sec) FOR FEMALE RATS S<QD'. RECOVERY DOSAGE GROUP (ma/kg/dav) SUCCESSIVE 10-MINUTE INTERVALS 1 2 3 4 5 6 TOTAL II 0 351 (46) 203 (56) 136 (45) 172 (70) 104 (71) 107 (54) 1073 (218) O. 5' VIII 1000 361 (61) 172 (45) 128(51) . 106 (52) 93 (61) 114 (87) 974 (206) <O>/> O19 Data arranged as: Mean (Standard Deviation). Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Jonckheere's trend test or 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 bm data and total data. There were no statistically significant differences from control at p < 0.05. 0O 35 1)I r )i4 ) i 100 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations # DuPont-4739 TABLE 23 MOTOR ACTIVITY ASSESSMENT: NUMBER OF MOVEMENTS FOR MALE RATS DOSAGE GROUP (mg/kg/day) I0 III 50 V 250 VII 1000 1 119(20) 122 (19) 128 (11) 133 (14) DOSAGE GROUP (mg/kg/day) I0 III 50 V 250 VII 1000 1 130(19) 124 (9) 133 (17) 130 (22) 2 117 (20) 125 (21) 136(10) 132 (19) 2 128 (20) 129 (14) 136 (24) 118 (24) BASELINE SUCCESSIVE 10-MINUTE INTERVALS 3 119 (27) 95 (42) 4 85 (36) 47 (59) 5 27 (37) 30 (43) 89 (56) 67 (60) 47 (54) 120 (19) 42 (36) 25 (53) WEEK 12 SUCCESSIVE 10-MINUTE INTERVALS 3 125 (17) 4 110(33) 5 78 (59) 119 (45) 94 (39) 66 (55) 118 (30) 74 (57) 59 (53) 71 (58) * 67 (54) 58 (62) 6 17 (24) 8(12) 26 (46) 16 (41) TOTAL 484 (91) 427 (136) 493 (181) 468 (134) 6 68 (41) 59 (41) 55 (44) 38 (46) TOTAL 638 (78) 591 (132) 574 (124) 482 (179) * Conywny Sanitized. Does not centa'n 101 jsw.t s . H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 23 (CONTINUED) MOTOR ACTIVITY ASSESSMENT: NUMBER OF MOVEMENTS FOR MALE RATS * DuPont-4739 DOSAGE GROUP (mg/kg/day) I0 VII 1000 1 122 (25) 136(14) 2 126 (25) 122 (33) RECOVERY SUCCESSIVE 10-MINUTE INTERVALS 3 99 (36) 4 80 (40) 5 54 (45) 100 (31) 81 (19) 72 (37) 6 49 (37) 71 (36) TOTAL 531 (118) 581 (109) Data arranged as: Mean (Standard Deviation). Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Repeated measures analysis of 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 at p < 0.05. c " pmy tanm nd Does noi connu, TSCA CB 102 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 24 MOTOR ACTIVITY ASSESSMENT: NUMBER OF MOVEMENTS FOR FEMALE RATS DOSAGE GROUP imc/ka/dav) II 0 IV 50 VI 250 VIII 1000 1 130(18) 120 (24) 129 (22) 132(18) DOSAGE GROUP Cme/ke/dav) II 0 IV 50 VI 250 VIII 1000 1 134 (14) 133 (16) 134 (19) 141 (12) 2 136(14) 124 (23) 109 (41) 129 (13) 2 140 (14) 137(16) 129 (15) 132(26) BASELINE SUCCESSIVE 10-MINUTE INTERVALS 3 91 (37) 118(25) 85 (47) 100 (53) 4 62 (49) 92 (49) 89 (60) 76 (51) 5 56 (45) 80 (60) 78 (53) 59 (67) WEEK 12 SUCCESSIVE 10-MINUTE INTERVALS 3 119(25) 119(33) 101 (40) 88 (46) 4 96 (52) 108 (42) 100(47) 73 (50) 5 89 (56) 73 (53) 79 (47) 79 (54) 6 36(51) 61 (55) 45 (49) 48 (63) > TOTAL 511(151) 595 (179) 534(191) 544(181) 6 71 (51) 48 (60) 36 (28) 57 (49) TOTAL 649(128) 618(106) 579 (107) 569 (149) Company Sanitized. Does not contain TSCA CBI 103 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 24 (CONTINUED) MOTOR ACTIVITY ASSESSMENT: NUMBER OF MOVEMENTS FOR FEMALE RATS DuPont-4739 DOSAGE GROUP fme/ke/davl II 0 VIII 1000 1 143 (15) 144 (14) 2 126(11) 121 (20) RECOVERY SUCCESSIVE 10-MINUTE INTERVALS 3 93(21) 91 (30) 4 112(30) 82 (32) 5 84 (32) 77 (41) 6 84 (30) 82 (48) TOTAL 642 (80) 596 (113) Data arranged as: Mean (Standard Deviation). Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Repeated measures analysis of 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 at p < 0.05. Company Sanitized. Does noi contain TSCA CB 104 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 25 SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS TEST/ Group I Group m Group V Group VH PERIOD______________ 0 mg/kg________ 50 mg/kg_______250 mg/kg______1000 mg/kg_ RBC (xIOV^L) DAY 45 DAY 91 DAY 123 HGB (g/dL) DAY 45 DAY 91 DAY 123 HCT (%) DAY 45 DAY 91 DAY 123 MCV (fl) DAY 45 DAY 91 DAY 123 MCH (pg) DAY 45 DAY 91 DAY 123 8.18 0.27(9) 8.74 0.23(10) 8.65 0.29(10) 15.0 0.5(9) 15.8 0.5(10) 15.0 0.5(10) 48.9 1.5(9) 49.5 1.3(10) 46.3 1.3(10) 59.8 1.2(9) 56.7 1.2(10) 53.6 1.5(10) 18.4 0.6(9) 18.1 0.6(10) 17.3 0.6(10) 8.07 0.32(10) 8.84 0.57(10) a 14.9 0.4(10) 15.8 0.9(10) a 48.0 1.6(10) 49.5 3.1(10) a 59.6 1.3(10) 56.0 1.4(10) a 18.5 0.9(10) 17.9 0.7(10) a 7.83 0.33(10) 8.73 0.37(10) a 14.7 0.6(10) 15.8 0.6(10) a 47.4 2.5(10) 49.7 2.5(10) a 60.5 2.1(10) 56.9 1.9(10) a 18.7 0.7(10) 18.1 0.6(10) a 7.86 0.31(10) 8.50 0.44(10) 8.47 0.35(10) 14.4* 0.4(10) 15.2 0.6(10) 14.6 . 0.7(10) 46.5* 1.1(10) 47.8 2.1(10) 45.5 2.3(10) 59.2 1.6(10) 56.2 1.4(10) 53.7 2.1(10) 18.3 0.6(10) 17.9 0.6(10) 17.3 0.5(10) 105 Oinpany Sanitized. Does not contain TSCA CBl H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 25 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I 0 mg/kg Group HI 50 mg/kg Group V 250 mg/kg Group VII 1000 mg/kg MCHC (g/dL) . DAY 45 DAY 91 DAY 123 RDW (%) DAY 45 DAY 91 DAY 123 ARET (xlOVaL) DAY 45 DAY 91 DAY 123 WBC (xlOVuL) DAY 45 DAY 91 DAY 123 ANEU (xl03/uL) DAY 45 DAY 91 DAY 123 30.7 0.5(9) 31.8 0.5(10) 32.3 0.5(10) 11.5 0.5(9) 12.3 0.7(10) 13.4 0.4(10) 223 33(9) 192 36(10) 183 21(10) 14.08 2.83(9) 11.26 1.97(10) 13.85 2.80(10) 1.73 0.54(9) 1.45 0.27(10) 1.84 0.55(10) 31.1 1.0(10) 31.9 0.8(10) a 11.5 0.5(10) 12.3 0.6(10) a 216 27(10) 205 27(10) a 16.84 2.73(10) 13.05 1.39(10) a 2.02 0.36(10) 1.93 0.49(10) a 31.0 0.7(10) 31.8 0.5(10) a 11.5 0.5(10) 12.1 0.5(10) a 208 33(10) 159 33(10) a 16.43 2.68(10) 12.72 2.62(10) a 1.85 0.64(10) 1.45 0.29(10) a 30.9 0.6(10) 31.8 0.5(10) 32.2 0.4(10) 12.1 0.8(10) 12.6 0.8(10) 13.7 0.8(10) 219 50(10) 147* 40(10) 177 24(10) 18.67* 5.47(10) 13.54 3.41(10) 13.35 1.52(10) 2.04 0.76(10) 1.62 0.68(10) 2.16 0.79(10) 106 eontpany Sanftfeed. Does no contain TSCA H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 25 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I 0 mg/kg Group HI 50 mg/kg Group V 250 mg/kg Group VD 1000 mg/kg ANPR (xl03//iL) bbb DAY 45 DAY 91 b bb b DAY 123 b ALYM (xl03/gL) DAY 45 DAY 91 DAY 123 AMON (xlOV/rL) DAY 45 DAY 91 DAY 123 AEOS (xlOVjiL) DAY 45 DAY 91 DAY 123 ABAS (xl03//xL) DAY 45 DAY 91 DAY 123 11.55 3.00(9) 9.18 2.00(10) 11.16 2.29(10) 0.26 0.09(9) 0.31 0.08(10) 0.32 0.11(10) 0.18 0.15(9) 0.14 0.06(10) 0.15 0.09(10) 0.12 0.04(9) 0.08 0.03(10) 0.14 0.06(10) 13.95 2.82(10) 10.36 1.48(10) a 0.38@ 0.11(10) . 0.37 _ 0.11(10) a 0.15 0.05(10) 0.17 0.05(10) a 0.10 0.05(10) 0.09 0.04(10) a 13.84 2.28(10) 10.63 2.43(10) a 0.32 0.08(10) 0.30 0.06(10) a 0.10 0.04(10) 0.15 0.09(10) a 0.12 0.04(10) 0.08 0.04(10) a 15.68* 4.78(10) 11.23 2.99(10) 10.34 1.93(10) 0.36 0.17(10) 0.32 0.08(10) 0.33 0.04(10) 0.15 0.13(10) 0.12 0.04(10) 0.15 0.08(10) 0.15 0.07(10) 0.11 0.05(10) 0.20 0.12(10) -\ ,\s^) 107 Company Sanitized. Does not contain TSCA H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 25 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I 0 mg/kg Group HI 50 mg/kg Group V 250 mg/kg Group VD 1000 mg/kg ALUC (x 10]/fiL) DAY 45 DAY 91 DAY 123 ABLT (xlOVgL) DAY 45 DAY 91 DAY 123 0.24 0.14(9) 0.11 0.05(10) 0.23 0.15(10) b b b 0.24 0.07(10) 0.12 0.03(10) a b b a 0.20 0.06(10) 0.10 0.04(10) a b b 0.31 0.27(10) 0.15 0.06(10) 0.17 0.08(10) b b b AMSC (xl03//xL) DAY 45 DAY 91 DAY 123 PLT (xlOVjiL) DAY 45 DAY 91 DAY 123 b b b 1158 76(5) 1131 117(8) 1060 128(7) b b a 1186 99(6) 1056 55(7) a b b a 1002 144(8) 972 188(9) a b b b '" 1068 116(9) 929* 122(8) 926 132(9) Data arranged as: Mean Standard deviation (Number of 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 of this type; therefore, the instrument count was accepted and no manual count was performed. 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). 108 empany Sanitized. Does not contain T S C cs ) H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 26 TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Group II 0 mg/kg Group IV 50 mg/kg Group VI 250 mg/kg Group Vin 1000 mg/kg RBC (xl06/fiL) DAY 44 DAY 92 DAY 124 8.12 0.34(10) 8.51 0.22(10) 8.12 0.37(10) 7.83 0.27(10) 8.23* 0.16(10) 7.71* 0.41(10) 8.29 0.45(10) 7.70* 0.18(10) 8.15* 0.15(10) 8.11 0.46(9) HGB (g/dL) DAY 44 DAY 92 DAY 124 15.3 0.3(10) 15.9 0.4(10) 15.0 0.4(10) 14.7* 0.7(10) 15.4 0.6(10) 14.6* 0.5(10) 15.4 0.5(10) 14.9 0.4(10) 15.7 0.5(10) 15.1 0.7(9) HCT (%) DAY 44 DAY 92 DAY 124 49.4 1.4(10) 50.0 1.4(10) 45.8 1.3(10) 47.2* 2.0(10) 48.1* 1.6(10) 45.7* ` . 1.9(10) 48.5 2.3(10) 47.0* 1.5(10) 48.4. 1.4(10) 46.0 2.4(9) MCV (fl) DAY 44 DAY 92 DAY 124 60.9 2.0(10) 58.8 1.5(10) 56.5 2.1(10) 60.4 1.5(10) 58.5 1.5(10) 59.4 1.4(10) 58.6 1.0(10) 61.1 1.5(10) 59.3 1. 1( 10) 56.8 2.0(9) MCH (pg) DAY 44 DAY 92 DAY 124 18.9 0.5(10) 18.7 0.5(10) 18.5 0.7(10) 18.8 0.6(10) 18.8 0.6(10) 18.9 0.6(10) 18.6 0.5(10) 19.3 0.5(10) 19.2 0.5(10) 18.6 0.6(9) \ 109 Sanfffeed. D oss ne! ermta'n T S C CB) H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 26 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS TEST/ PERIOD Group II 0 mg/kg Group IV 50 mg/kg Group VI 250 mg/kg Group VIE 1000 mg/kg MCHC (g/dL) DAY 44 DAY 92 DAY 124 RDW (%) DAY 44 DAY 92 DAY 124 ARET (xlOVjuL) DAY 44 DAY 92 DAY 124 WBC (xlOVptL) DAY 44 DAY 92 DAY 124 ANEU(xl07/iL) DAY 44 DAY 92 DAY 124 31.1 0.7(10) 31.8 0.4(10) 32.8 0.4(10) 11.0 0.3(10) 10.8 0.4(10) 12.0 0.5(10) 212 47(10) 153 41(10) 176 20(10) 13.87 2.94(10) 8.68 1.26(10) 11.10 2.66(10) 1.39 0.49(10) 0.93 0.36(10) 1.00 0.24(10) 31.2 0.6(10) 32.1 0.6(10) a 11.4 0.6(10) 10.6 0.4(10) a 222 43(10) 146 29(10) a . 13.20 2.48(10) 8.84 1.49(10) a 1.13 0.48(10) 0.93 0.31(10) a 31.8* 0.8(10) 31.7 0.5(10) a 11.2 0.8(10) 10.6 0.4(10) a 226 29(10) 173 13(10) a 13.32 3.68(10) 10.29 2.21(10) a 1.50 0.32(10) 1.33 1.23(10) a 31.6 0.6(10) 32.3 0.6(10) 32.7 0.3(9) 11.3 0.3(10) 10.7 0.3(10) 11.9 . 0.3(9) 241 37(10) 173 34(10) 167 31(9) 13.70 3.63(10) 10.14 3.04(10) 10.83 2.50(9) 1.58 0.63(10) 1.15 0.41(10) 1.11 0.42(9) no Company Sanitized. Does not confab H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 26 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Group II 0 mg/kg Group IV 50 mg/kg Group VI 250 mg/kg Group VIO 1000 mg/kg ANPR (xlOV/iL) bb b DAY 44 DAY 92 b CC DAY 124 c ALYM (x103//liL) DAY 44 DAY 92 DAY 124 AMON (xl0V/iL) DAY 44 DAY 92 DAY 124 AEOS (xlOV/xL) DAY 44 DAY 92 DAY 124 ABAS (xl0V/xL) DAY 44 DAY 92 DAY 124 11.68 2.71(10) 7.20 1.25(10) 9.35 2.48(10) 0.28 0.05(10) 0.23 . 0.07(10) 0.31 0.08(10) 0.17 0.06(10) 0.16 0.05(10) 0.16 0.12(10) 0.11 0.03(10) 0.08 0.03(10) 0.09 0.05(10) 11.41 2.54(10) 7.51 1.46(10) a 0.27 0.12(10) 0.19 0.04(10) a 0.12 0.06(10) 0.09* 0.04(10) a 0.09 0.05(10) 0.05 0.03(10) a 11.11 3.50(10) 8.35 2.01(10) a 0.25 0.10(10) 0.25 0.10(10) a 0.18 0.09(10) 0.13 0.04(10) a 0.09 0.05(10) 0.10 0.07(10) a 11.43 3.17(10) 8.44 2.65(10) 9.04 2.24(9) 0.22 0.09(10) 0.21 0.0800) 0.31 0.13(9) 0.19 0.23(10) 0.13 0.04(10) 0.12 0.03(9) 0.10 0.05(10) 0.08 0.05(10) 0.09 0.07(9) ill Sanitized. Does not contain T S C A CB) H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 26 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Group II 0 mg/kg Group IV 50 mg/kg Group VI 250 mg/kg Group Vm 1000 mg/kg ALUC (xIOV/iL) DAY 44 DAY 92 DAY 124 ABLT (xl07/iL) DAY 44 DAY 92 DAY 124 0.25 0.14(10) 0.09 0.03(10) 0.19 0.10(10) b c 0.18 0.09(10) 0.08 0.05(10) a b 0.19 0.12(10) 0.13 0.09(10) a b 0.20 0.08(10) 0.13 0.12(10) 0.16 0.10(9) b c c AMSC (xlO'/jtL) bbb DAY 44 DAY 92 b c c DAY 124 c PLT (x107/xL) DAY 44 DAY 92 DAY 124 1055 259(5) 1123 164(7) 954 138(7) 1084 153(8) 1050 69(6) a 1054 129(6) 1043 107(9) a 1161 218(7) 1050 152(9) 985 111(9) Data arranged as: Mean Standard deviation (Number of 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 of 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). 112 Somgxuiy SatiNhed. Doesmrte'w*)* % H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________________DuPont-4739 TABLE 27 TEST/ PERIOD SUMMARY OF COAGULATION VALUES FOR MALE RATS Group I 0 mg/kg Group HI 50 mg/kg Group V 250 mg/kg Group VU 1000 mg/kg PT (seconds) DAY 91 APTT (seconds) DAY 91 15.1 0.4(10) 20.1 3.8(10) 15.1 0.5(10) 19.9 3.0(10) 15.7 0.7(9) 19.8 1.7(9) 15.7 0.6(10) 19.5 2.6(10) Data arranged as: Mean Standard deviation (Number of values included in calculation) There were no statistically significant differences from control at p < 01.05. TEST/ PERIOD TABLE 28 SUMMARY OF COAGULATION VALUES FOR FEMALE RATS Group II 0mg/kg Group IV 50 mg/kg Group VI 250 mg/kg Group Vm 1000 mg/kg PT (seconds) DAY 92 APTT (seconds) DAY 92 15.3 0.3(9) 19.8 1.2(9) 15.2 0.7(10) 19.6 1.9(10) 15.2 0.7(10) 18.3 1.1(10) 15.2 0.5(10) 18.3 1.5(10) Data arranged as: Mean Standard deviation (Number of values included in calculation) There were no statistically significant differences from control at p < 0.05. \J 113 Company Sanitized. Does not contain TSCA CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 % TABLE 29 SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS I TEST/ PERIOD I Group I 0 mg/kg Group DI 50 mg/kg Group V 250 mg/kg Group VII 1000 mg/kg AST (U/L) DAY 45 DAY 91 DAY 123 91 17(10) 84 10(10) 79 10(10) 86 19(10) 92 22(10) a 85 14(10) 91 27(10) a 88 11(10) 94 17(10) 131 116(10) ALT (U/L) DAY 45 DAY 91 DAY 123 38 6(10) 35 5(10) 34 7(10) 39 7(10) 46 17(10) a 37 7(10) 50 26(10) a 44 10(10) 48@ 9(10) 98@ 158(9) SDH (U/L) DAY 45 DAY 91 DAY 123 20.4 3.5(10) 23.4 5.6(10) 19.4 3.8(10) 24.2 6.4(10) 27.1 8.4(10) a 23.7 5.0(10) 24.0 7.1(10) a 20.5 3.7(10) 22.4 4.4(10) 32.7 36.2(10) ALKP (U/L) DAY 45 DAY 91 DAY 123 BILI (mg/dL) DAY 45 DAY 91 DAY 123 127 17(10) 80 13(10) 80 15(10) 0.09 0.04(10) 0.14 0.01(10) 0.08 0.03(10) 130 24(10) 100 24(10) a 0.07 0.03(10) 0.14 0.04(10) a 115 20(10) 110* 26(10) a 0.06 0.02(10) 0.12 0.04(10) a 158* 31(10) 183* 28(10) 135* 37(10) 0.06 0.02(10) 0.12 0.02(10) 0.06 0.02(10) I 114 Company Sanitized. Does not eontaln T S C C H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 29 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group I 0 mg/kg Group DI 50 mg/kg Group V 250 mg/kg Group VII 1000 mg/kg BUN (mg/dL) DAY 45 DAY 91 DAY 123 15 2(10) 15 1(10) 14 1(10) 15 2(10) 16 2(10) a 15 3(10) 19* 2(10) a 16 2(10) 19* 2(10) 15 2(10) CREA (mg/dL) DAY 45 0.37 0.36 0.33 0.34 0.02(10) 0.05(10) 0.06(10) 0.06(10) DAY 91 0.42 0.37* 0.42 0.40 DAY 123 0.04(10) 0.30 0.05(10) a 0.03(10) a 0.05(10) 0.30 0.06(10) m CHOL (mg/dL) DAY 45 75 65 0.05(10) 55* 47* 16(10) 12(10) 12(10) 13(10) DAY 91 77 67 54* 49* DAY 123 19(10) 79 24(10) 19(10) a 14(10) a 15(10) 64 16(10) TRIG (mg/dL) DAY 45 DAY 91 DAY 123 75 28(10) 81 29(10) 210 62(10) 89 47(10) 103 43(10) a 57 41(10) 71 25(10) a 42@ 22(10) 44@ 11(10) 115* 53(10) GLUC (mg/dL) DAY 45 DAY 91 DAY 123 104 7(10) 113 6(10) 122 11(10) 104 6(10) 118 13(10) a 100 6(10) 117 6(10) a 109 10(10) 121 8(10) 122 8(10) jgompany S a n d e d . Does not contain T S C A CB H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 29 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group I 0 mg/kg Group HI 50 mg/kg Group V 250 mg/kg Group VH 1000 mg/kg TP (g/dL) DAY 45 DAY 91 DAY 123 ALB (g/dL) DAY 45 DAY 91 DAY 123 GLOB (g/dL) DAY 45 DAY 91 DAY 123 CALC (mg/dL) DAY 45 DAY 91 DAY 123 IPHS (mg/dL) DAY 45 DAY 91 DAY 123 6.7 0.2(10) 7.2 0.2(10) 6.9 0.2(10) 4.2 0.1(10) 4.3 0.2(10) 4.2 0.1(10) 2.5 0.2(10) ~ 3.0 0.2(10) 2.7 0.2(10) 10.7 0.3(10) 10.7 0.2(10) 11.1 0.3(10) 8.6 0.6(10) 7.4 0.2(10) 7.0 0.3(10) 6.8 0.2(10) 7.2 0.2(10) a 4.3 0.1(10) 4.3 0.2(10) a 2.5 0.2(10) 2.9 0.2(10) a 10.8 0.3(10) 10.7 0.3(10) a 8.7 0.5(10) 7.2 0.5(10) a 6.4* 0.3(10) 7.2 0.4(10) a 4.2 0.2(10) 4.5* 0.2(10) a 2.2* 0.3(10) 2.7* 0.3(10) a 10.7 0.4(10) 10.8 0.3(10) a 8.9 0.7(10) 7.7 0.5(10) a 6.8 0.3(10) 7.1 0.3(10) 7.0 0.3(10) 4.6* 0.2(10) 4.7* 0.2(10) 4.5* 0.2(10) 2.2* 0.1(10) 2.4*' 0.2(10) 2.5@ 0.2(10) 10.7 0.2(10) 10.3@ 0.2(10) 11.0 0.3(10) 9.1 0.5(10) 7.7 0.9(10) 7.5* 0.4(10) 116 Com pany Sanitized. Does not eontaln T S C OBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 29 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group I 0 mg/kg Group HI 50 mg/kg Group V 250 mg/kg Group Vil 1000 mg/kg NA (mmol/L) DAY 45 DAY 91 DAY 123 K (mmol/L) DAY 45 DAY 91 DAY 123 CL (mmol/L) DAY 45 DAY 91 DAY 123 PFLU Qig/mL) DAY 45 DAY 91 DAY 123 148.0 1.6(10) 146.5 0.9(10) 146.5 1.0(10) 6.45 0.35(10) 6.25 0.34(10) 6.05 0.24(10) 99.3 1.1(10) 101.6 1.2(10) 98.9 1.2(10) a 0.1 0.0(10) a 148.1 0.9(10) 146.6 0.9(10) a 6.29 0.18(10) 5.97 0.31(10) a 98.1 0.9(10) 100.5 1.7(10) a 0.1 0.0(9) a 148.5 0.7(10) 147.3 1.0(10) a 6.31 0.23(10) 6.07 0.30(10) a 98.9 1.0(10) 100.9 1.1(10) a 0.1 0.0(8) 147.8 0.7(10) 145.4 1.5(10) 147.0 0.9(10) 6.54 0.43(10) 6.15 0.45(10) 6.19 0.28(10) 99.7 1.9(10) 101.7 1.0(10) 99.5 1.3(10) a 0.1 0.0(10) Data arranged as: Mean Standard deviation (Number of 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 trend test (Jonckheere-Terpstra). * Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett). 117 Com pany Sanitized. Does not contain T S C A CB! H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations ? TABLE 30 DuPont-4739 SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS TEST/ Group II Group IV Group VI Group VIII PERIOD______________Omg/kg________50 mg/kg______ 250 mg/kg______1000 mg/kg A M (U /G ) DAY 44 DAY 92 DAY 124 ALT (U/L) DAY 44 DAY 92 DAY 124 SDH (U/L) DAY 44 DAY 92 DAY 124 ALKP (U/L) DAY 44 DAY 92 DAY 124 BILI (mg/dL) DAY 44 DAY 92 DAY 124 82 7(10) 88 19(9) 101 19(10) 35 3(10) 36 14(9) 64 30(10) 22.4 5.9(10) 21.8 4.8(9) 26.1 5.4(10) 81 25(10) 51 21(9) 40 13(10) 0.12 0.03(10) 0.18 0.03(9) 0.15 0.04(10) 107 47(9) 113 40(10) a 49 29(9) 62 38(10) a 24.1 12.9(10) 26.4 11.1(10) a 91 14(9) 58 22(10) a 0.09 0.04(9) 0.16 0.04(10) a 82 6(10) 87 23(10) a 36 5(10) 45 23(10) a 18.6 5.0(10) 22.0 4.5(10) a 81 17(10) 50 12(10) a 0.08 0.04(10) 0.16 0.03(10) a 91 20(10) 91 30(10) 152 176(9) 39 9(10) 39 12(10) 124 192(9) 20.3 6.1(10) ' 20.1 3.3(10) 45.4 68.7(9) 82 20(10) 58 17(10) 44 15(9) 0.06* 0.03(10) 0.10* 0.03(10) 0.09@ 0.04(9) 118 Com pany Sanitized. Does not contain T S C A CB1 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 30 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD Group II 0 mg/kg Group IV 50 mg/kg Group VI 250 mg/kg Group VIE 1000 mg/kg BUN (mg/dL) DAY 44 DAY 92 DAY 124 CREA (mg/dL) DAY 44 DAY 92 DAY 124 CHOL (mg/dL) DAY 44 DAY 92 DAY 124 TRIG (mg/dL) DAY 44 DAY 92 DAY 124 GLUC (mg/dL) DAY 44 DAY 92 DAY 124 16 2(10) 15 2(9) 15 2(10) 0.44 0.04(10) 0.46 0.08(9) 0.41 0.03(10) 102 18(10) 104 12(9) 105 29(10) 46 11(10) 57 27(9) 62 20(10) 97 12(10) 117 18(9) 107 10(10) 16 1(10) 17 3(10) a 0.39 0.04(10) 0.47 0.06(10) a 88 12(10) 94 15(10) a 39 16(9) 53 21(10) a 99 10(10) 111 13(10) a 16 2(10) 16 2(10) a 0.37* 0.05(10) 0.47 0.05(10) a 84* 18(10) 83@ 29(10) a 34 12(10) 58 47(10) a 104 9(10) 109 9(10) a 17 2(10) 18* 2(10) 15 2(9) 0.39 0.04(10) 0.46 0.05(10) 0.45 . 0.07(9) 75* 9(10) 78@ 11(10) 99 32(9) 29* 9(10) 47 15(10) 56 22(9) 103 12(10) 133 26(10) 104 11(9) 119 e " "P' "1' San," d' Doe, not conlaln TSCA CB) H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 30 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD Group II 0 mg/kg Group IV 50 mg/kg Group VI 250 mg/kg Group V in 1000 mg/kg TP (g/dL) DAY 44 DAY 92 DAY 124 ALB (g/dL) DAY 44 DAY 92 DAY 124 GLOB (g/dL) DAY 44 DAY 92 DAY 124 CALC (mg/dL) DAY 44 DAY 92 DAY 124 IPHS (mg/dL) DAY 44 DAY 92 DAY 124 7.4 0.3(10) 8.0 0.3(9) 8.3 0.6(10) 5.0 0.2(10) 5.2 0.3(9) 5.6 0.5(10) 2.4 0.1(10) 2.8 0.1(9) 2.7 0.2(10) 11.0 0.3(10) 11.1 0.4(9) 11.7 0.5(10) 8.0 0.6(10) 5.1 0.9(8) 6.3 0.6(10) 7.2 0.5(9) 8.0 0.5(10) a 4.9 0.3(9) 5.3 0.4(10) a 2.3 0.3(9) 2.6 0.2(10) a 10.7 0.3(10) 11.2 0.3(10) a 7.8 0.8(9) 5.4 0.6(10) a 7.0* 0.3(10) 7.7 0.6(10) a 4.8 0.3(10) 5.2 0.3(10) a 2.1* 0.2(10) 2.5 0.3(10) a 10.5* 0.4(10) 11.2 0.5(10) a 7.5 1.1(10) 5.7 0.7(10) a 7.5 0.4(10) 8.1 0.6(10) 8.2 0.3(9) 5.3 0.4(10) 5.5 0.4(10) 5.5 0.3(9) 2.2 0.2(10) 2.6 0.3(10) 2.6 0.3(9) 10.7 0.4(9) 11.2 0.4(10) 11.6 0.3(9) 7.9 0.5(10) 5.6 0.5(10) 6.5 0.4(9) 120 Company Sanitized. Does not contain TSC A CB) H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 30 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD Group II 0 mg/kg Group IV 50 mg/kg Group VI 250 mg/kg Group VIE 1000 mg/kg NA (mmol/L) DAY 44 DAY 92 DAY 124 K (mmol/L) DAY 44 DAY 92 DAY 124 CL (mmol/L) DAY 44 DAY 92 DAY 124 PFLU (/xg/mL) DAY 44 DAY 92 DAY 124 146.2 1.6(10) 147.7 1.2(9) 145.7 0.7(10) 6.25 0.38(10) 5.67 0.26(9) 5.67 0.56(10) 98.6 2.1(10) ' 103.1 1.7(9) 97.8 1.8(10) a 0.2 0.1(8) a 146.2 1.4(9) 147.6 1.0(10) a 6.01 0.34(9) 5.67 0.27(10) a 99.6 1.7(9) 103.8 1.2(10) a 0.2 0.0(10) a 145.9 1.4(10) 148.1 1.7(10) a 6.01 0.31(10) 5.67 0.46(10) a 100.6 1.7(10) 103.7 1.8(10) a 0.2 0.1(10) 146.2 1.4(10) 147.6 1.1(10) 146.9* 1.1(9) 6.13 0.33(10) 5.82 0.41(10) 5.41 0.24(9) 101.4@ 1.3(10) 104.2 1.9(10) 98.4 2.2(9) 0.2 0.0(10) Data arranged as: Mean Standard deviation (Number of 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). 121 Com pany Sanitized. Does not contain TSCA CBi H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 31 TEST/ PERIOD SUMMARY OF URINALYSIS VALUES FOR MALE RATS Group I 0 mg/kg Group HI 50 mg/kg Group V 250 mg/kg Group VH 1000 mg/kg VOL (mL) DAY 45 DAY 91 DAY 123 9.4 5.3(10) 8.5 7.8(10) 4.4 2.0(10) 11.9 4.6(10) 11.4 5.6(10) .a 8.5 5.4(9) 5.7 2.9(10) a 12.1 9.3(10) 9.4 5.5(10) 5.4 2.9(10) UOSM (mOsm) DAY 45 DAY 91 DAY 123 1143 380(9) 1275 384(10) 1823 723(10) 945 333(10) 990 464(10) a 1435 873(9) 1848 741(10) a 1277 882(10) 1075 472(10) 1891 795(10) SG DAY 45 DAY 91 DAY 123 1.035 0.012(10) 1.040 0.011(10) 1.054 0.018(10) 1.030 0.010(10) 1.031 0.013(10) a 1.043 . 0.024(9) 1.051 0.019(10) a 1.039 0.025(10) 1.036 0.015(10) 1.055 0.020(10) \ I. pH DAY 45 6.6 6.9 6.7 6.9 1 0.6(10) 0.2(10) 0.4(9) 0.3(10) j; DAY 91 6.7 6.4 6.6 6.6 0.3(10) 0.5(10) 0.5(10) 0.6(10) DAY 123 6.5 a a 7.1 0.9(10) 0.8(10) URO (EU/dL) DAY 45 DAY 91 DAY 123 0.2 0.0(10) 0.4 0.3(10) 0.3 0.3(10) 0.2 0.0(10) 0.3 0.3(10) a 0.4 0.4(9) 0.4 0.4(10) a U.4 0.3(10) 0.4 ' 0.3(10) 0.4 0.3(10) 122 Company Sanitized. Does not contain T S C A CBI % H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproducrionjivaluations DuPont-4739 TABLE 31 (Continued) TEST/ PERIOD SUMMARY OF URINALYSIS VALUES FOR MALE RATS Group I 0 mg/kg Group HI 50 mg/kg Group V 250 mg/kg Group VH 1000 mg/kg UFLU (/xg) DAY 45 DAY 91 DAY 123 UMTP (mg/dL) DAY 45 DAY 91 DAY 123 a 12.2 3.5(9) 10.3 4.9(10) 89 48(10) 93 36(10) 141 64(10) 14.1 3.4(10) a 60 38(10) 57 38(10) a 24.9@ 4.3(9) a 83 68(9) 86 34(9) a 42.7@ 14.1(10) 14.8* 4.4(10) 79 71(10) 45* 21(10) 129 66(10) Data arranged as: Mean Standard deviation (Number of 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). Com pany Sanitized. Does not contain T S C A C B l H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 32 TEST/ PERIOD SUMMARY OF URINALYSIS VALUES FOR FEMALE RATS Group II 0 mg/kg Group IV 50 mg/kg Group VI 250 mg/kg Group VIE 1000 mg/kg VOL(mL) DAY 44 DAY 92 DAY 124 UOSM (mOsm) DAY 44 DAY 92 DAY 124 SG DAY 44 DAY 92 DAY 124 pH DAY 44 DAY 92 DAY 124 URO (EU/dL) DAY 44 DAY 92 DAY 124 12.6 6.3(9) 8.6 3.6(10) 6.5 3.9(10) 713 265(9) 860 303(10) 1291 699(10) 1.022 0.008(9) 1.026 0.009(10) 1.040 0.019(10) 6.4 0.4(9) 6.1 0.6(10) 5.7 0.7(10) 0.2 0.0(9) 0.2 0.0(10) 0.2 0.0(10) 9.7 5.2(9) 4.3@ 1.3(10) a 763 338(8) 1255 419(10) a 1.027 0.015(9) 1.038 0.012(10) a 6.4 0.2(9) 5.9 0.2(10) a 0.2 0.0(9) 0.3 0.3(10) a 6.9 4.9(9) 5.8 3.1(10) a 1038 515(8) 1168 572(10) a 1.035 0.018(9) 1.035 0.016(10) a 6.3 0.4(9) 6.0 0.4(10) a 0.2 0.0(9) 0.3 0.3(10) a 6.8* 3.3(10) 5.8@ 5.4(9) 5.2 1.7(9) 1066 455(10) 1354 662(9) 1227 .376(9) 1.032 0.013(10) 1.041 0.019(9) 1.039 0.011(9) 6.3 0.4(10) 5.9 0.3(9) 5.8 0.3(9) U.2 0.0(10) 0.4 0.4(9) 0.2 0.0(9) 124 Com pany SanifFzed. D oes not contain H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 32 (Continued) TEST/ PERIOD SUMMARY OF URINALYSIS VALUES FOR FEMALE RATS Group II 0 mg/kg Group IV 50 mg/kg Group VI 250 mg/kg Group VIE 1000 mg/kg UFLU (Mg) DAY 44 DAY 92 DAY 124 UMTP (mg/dL) DAY 44 DAY 92 DAY 124 a 9.5 2.2(10) 9.2 3.6(9) 12 7(9) 19 10(10) 35 21(10) 8.2 2.4(10) a 18 16(9) 25 8(10) a 14.0* 4.4(9) a 22 14(9) 57 124(10) a 23.7* 8.1(7) 10.7 2.3(9) 21 12(10) 33 27(9) 30 13(9) . 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). 125 Com pany Sanitized. Does not contain T S C A C B l H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 33 MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (90-DAY EXPOSURE EVALUATION) MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (g ra m s ) LIVER KIDNEYS HEART SPLEEN BRAIN THYMUS ADRENAL GLANDS TESTES EPIDIDYMIDES Group I 0 m g/kg/day 16.29990 2.37854(10) 4.11790 0.46383(10) 1.72150 0.18011(10) 0.81060 0.13297(10) 2.11630 0.11666(10) 0.39550 0.10511(10) 0.05420 0.00819(10)' 3.55240 0.26647(10) 1.52290 0.13239(10) Group I I I 50 m g /k g /d ay 16.87220 2.61074(10) 4.07140 0.44324(10) 1.63930 0.09797(10) 0.81960 0.13467(10) 2.09420 0.05678(10) 0.35220 0.10652(10) 0.05070 0.00766(10) 3.44250 0.28401(10) 1.46590 0.10031(10) Group V Group V II 250 m g/kg/day 1000 m g/kg/day 17.17570 1.42650(10) 17.73860 1.69212(10) 4.29670 0.30710(10) 4.14600 0.50094(10) 1.60160' 0.15360(10) 1.45190# 0.15909(10) 0.75140 0.04046(10) 0.62300# 0.06573(10) 2.10710 0.07523(10) 2.08770 0.10561(10) 0.35900 0.07574(10) 0.29070# 0.08475(10) 0.05590 0.00565(10) 0.04540 0.00759(10) 3.47420 0.21284(10) 3.63750 0.46281(10) 1.44610 0.07824(10) 1.44300 0.12745 (10) FINAL BODY WEIGHT 571.20001 54.34041(10) 553.88000 64.04053(10) 525.24000 32.58446(10) 453.54000# 27.10724(10) 126 Com pany San*l!zed. D o es no! contain T S C OBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 33 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (90-DAY EXPOSURE EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% o f b o d y w e i g h t ) Group I 0 mg/kg/day Group I I I 50 m g /kg/day G roup V 250 mg/kg/day Group V II 1000 m g/kg/day LIVER/ FINAL BODY * 100 2.84282 0.18604(10) 3.03802# 0.21348(10) 3.26805# 0.13073(10) 3.90847# 0.24375(10) KIDNEYS/ FINAL BODY * 100 0.72142 0.04767(10) 0.73746 0.05458(10) 0.81838# 0.03911(10) 0.91438# 0.09585(10) HEART/ FINAL BODY * 100 0.30162 0.01735(10) 0.29831 0.02690(10) 0.30476 0.02003(10) 0.32005 0.02896(10) SPLEEN/ FINAL BODY * 100 0.14146 0.01571(10) 0.14759 0.01234(10) 0.14355 0.01190(10) 0.13746 0.01303(10) BRAIN/ FINAL BODY * 100 0.37329 0.03801(10) 0.38195 0.03860(10) 0.40251 0.02774(10) 0.46124# 0.02746(10) THYMUS/ FINAL BODY * 100 0.06894 0.01543(10) ADRENAL GLANDS/ FINAL BODY * 100 0.00952 0.00147(10) 0.06381 0.01967(10) 0.00919 0.00117(10) 0.06850 0.01460(10) 0.06376 ' 0.01674(10) 0.01066 0.00100(10) 0.01000 0.00146(10) TESTES/ FINAL BODY * 100 0.62419 0.04177(10) EPIDIDYMIDES/ FINAL BODY * 100 0 . 2 6 7 0 0 0.01067(10) 0.62763 0.07394(10) 0.26813 0.03744(10) 0.66300 0.04622(10) 0.27582 0.01536(10) 0.80306# 0.10131(10) 0.31857# 0.02711(10) 127 Gompany Sanitized. Does not contain T S C A CB H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 33 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (90-DAY EXPOSURE EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% o r g a n t o b r a i n w e i g h t r a t i o ) Group I 0 mg/kg/day Group I I I 50 m g /k g /d a y Group V 250 m g/kg/day Group V II 1000 m g/kg/day LIVER/ BRAIN * 100 770.15709 104.54656(10) 805.01169 115.90201(10) 815.55517 67.73836(10) 849.17608 61.67427(10) KIDNEYS/ BRAIN * 100 194.75542 20.46963(10) 194.18409 17.86388(10) 203.90854 12.59494(10) 198.79654 23.95776(10) HEART/ BRAIN * 100 81.49513 9.02494(10) 78.26848 3.91573(10) 76.02567 6.96468(10) 69.57323# 7.11744(10) SPLEEN/ BRAIN * 100 38.35205 6.39417(10) 39.03931 5.59356(10) 35.69114 2.14067(10) 29.85103# 2.88927(10) THYMUS/ BRAIN * 100 18.75573 5.19498(10) 16.85615 5.23759(10) 17.02594 3.49770(10) 13.92191# 3.97262(10) ADRENAL GLANDS/ BRAIN * 100 2.57297 0.43823(10) 2.41939 0.34590(10) 2.65955 0.32621(10) 2.16774# 0.29613(10) TESTES/ BRAIN * 100 168.21509 14.61825(10) 164.39229 12.67559(10) 165.02970 10.88670(10) 174.03435 18.18484(10) ! EPIDIDYMIDES/ BRAIN * 100 72.06007 6.34437(10) 70.09865 5.95636(10) 68.65294 3.39848(10) 69.12080 5.03411(10) 128 Company SanibpH noj c w ta 'n TSCA CB H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 33 (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 1000 mg/kg/day LIVER KIDNEYS 18.08270 1.47750(10) 4.45450 0.47991(10) 21.60940# 3.55199(10) 4.36820 0.56393(10) HEART SPLEEN BRAIN 1.79860 0.16518(10) 0.85170 0.09574(10) 2.21690 0.08271(10) 1.71710 0.17531(10) 0.77160# 0.07517 (10) 2.12510 0.14088(10) THYMUS ADRENAL GLANDS TESTES 0.40740 0.08460(10) 0.05500 0.00790(10) 3.50310 0.15626(10) 0.33660 0.06047(10) 0.05570 0.00983(10) 3.62410 0.34573(10) EPIDIDYMIDES 1.56120 0.11432(10) 1.53520 0.13761(10) FINAL BODY WEIGHT 614.23000 31.93733(10) 575.99000 75.57794(10) 129 Company Sanitized. -- -- CI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 33 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% of body weight) Group I 0 mg/kg/day Group VII 1000 mg/kg/day LIVER/ FINAL BODY * 100 2.94443 0.19349(10) 3.74065# 0.17971(10) KIDNEYS/ FINAL BODY * 100 0.72426 0.05939(10) 0.76003 0.06052 (10) HEART/ FINAL BODY * 100 0.29257 0.01864(10) 0.29998 0.02662(10) SPLEEN/ FINAL BODY * 100 0.13879 0.01514(10) 0.13549 0.01764(10) BRAIN/ FINAL BODY * 100 0.36188 0.02412(10) 0.37309 0.04080(10) THYMUS/ FINAL BODY * 100 0.06621 0.01259(10) 0.05842 0.00695(10) ADRENAL GLANDS/ FINAL BODY * 100 0.00896 0.00130(10) 0.00974 0.00167(10) TESTES/ FINAL BODY * 100 0.57159 0.03732(10) 0.63583# 0.07408(10) EPIDIDYMIDES/ FINAL BODY * 100 0.25424 0.01435(10) 0.26847 0.02279(10) 130 Company Sanitized. Does not eo"to'' * H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 33 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% organ to brain weight ratio) Group I 0 mg/kg/day Group VII 1000 mg/kg/day LIVER/ BRAIN*100 816.87669 76.65974(10) 1015.9066# 144.74869(10) KIDNEYS/ BRAIN*100 200.98135 205.35810 21.27432 (10) 21.95910(10) HEART/ BRAIN*100 81.24372 8.38089(10) 80.73190 5.51430(10) SPLEEN/ BRAIN*100 38.41308 3.88576(10) 36.51872 4.85835(10) THYMUS/ BRAIN*100 18.39074 3.84886(10) 15.82333 2.53299(10) ADRENAL GLANDS/ BRAIN * 100 2.47677 0.31243(10) 2.63760 0.52852(10) TESTES/ BRAIN*100 158.21602 170.75088 9.14123 (10) 14.77783(10) EPIDIDYMIDES/ BRAIN * 100 70.55650 6.38733(10) 72.33118 6.05327(10) ! 131 i Company Sanitized. Does no contain TSftA CR i H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 33 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (3-MONTH RECOVERY EVALUATION) LIVER MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) Group I 0 mg/kg/day 16.02880 3.59419(5) Group III 50 mg/kg/day 17.89020 5.71336(5) Group V Group VII 250 mg/kg/day 1000 mg/kg/day 17.80925 19.89400 2.72291(4 ) 4.91210(5) FINAL BODY WEIGHT 570.94001 115.89048(5) 613.46000 90.47218(5) 614.80000 628.34000 66.22251(4 ) 122.14361(5) MEAN RELATIVE ORGAN WEIGHT ( % organ to body weight) LIVER/ FINAL BODY * 100 2.80261 0.13585(5) 2.86633 0.46688(5) 2.88670 0.16631(4 ) 3.15405 0.33800(5) Data summarized as: Mean Standard Deviation (n) Statistical Methods: Trend test (Jonckheere-Terpstra). # Statistically significant difference at p < 0.05. 132 Company Sanitized. Does not contain T8CA CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 34 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/day Group IV 50 mg/kg/day Group VI Group VIII 250 mg/kg/day 1000 mg/kg/day LIVER KIDNEYS HEART SPLEEN BRAIN 8.84878 0.88178(9) 2.32156 0.13554(9) 1.13467 0.11533(9) 0.47933 0.06135(9) 1.95533 0.04179(9) 8.70190 0.37828(10) 2.37890 0.13760(10) 1.03470 0.09322(10) 0.51200 0.08004(10) 1.93720 0.05827(10) 9.13210 1.55337(10) 2.43270 0.32086(10) 1.08350 0.12105(10) 0.54790 0.08040(10) 1.94880 0.04951(10) 9.61140 1.45116(10) 2.41310 0.20469(10) 1.05610 0.15199(10) 0.54350 0.11346(10) 1.94110 0.11203 (10) THYMUS 0.30811 0.06008(9) 0.27820 0.05904(10) 0.32100 0.08173(10) 0.32000 0.07946(10) ADRENAL GLANDS OVARIES UTERUS 0.06756 0.01454(9) 0.13444 0.03048(9) 0.48856 0.08202(9) 0.07030 0.01046(10) 0.12380 0.02466(10) 0.62250 0.14580(10) 0.07790 0.02075(10) 0.11550 0.01848(10) 0.64920 0.10251(10) 0.07380 0.00860(10) 0.12490 0.02469(10) 0.61880 0.16651(10) FINAL BODY WEIGHT 313.86000 294.51000 33.38430(10) 17.61934(10) 311.33000 38.77024(10) 293.62000 46.15103(10) 133 Company Sanitized. Does not contain T S C A C B l H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 34 (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 50 mg/kg/day Group VI Group VIII 250 mg/kg/day 1000 mg/kg/day LIVER/ FINAL BODY * 100 2.87266 0.19054(9) 2.96392 0.21436(10) 2.92590 0.20524(10) 3.28260# 0.18650(10) KIDNEYS/ FINAL BODY * 100 0.75624 0.05892(9) 0.80964 0.05663(10) 0.78343 0.06553(10) 0.83304 0.09834(10) HEART/ FINAL BODY * 100 0.36786 0.01744(9) 0.35204 0.03400(10) 0.34870 0.01585(10) 0.36162 0.03160(10) SPLEEN/ FINAL BODY * 100 0.15582 0.01949(9) 0.17458 0.03057 (10) 0.17637# 0.01806(10) 0.18582# 0.03162(10) BRAIN/ FINAL BODY * 100 0.63885 0.06119(9) 0.66028 0.04991(10). 0.63323 0.06670(10) 0.67437 0.09883(10) THYMUS/ FINAL BODY * 100 0.10020 0.01888(9) 0.09442 0.01909(10) 0.10210 .0.01577(10) 0.10923 0.02110(10) ADRENAL GLANDS/ FINAL BODY * 100 0.02200 0.00471(9) 0.02391 0.00358(10) 0.02509 0.00590(10) 0.02573 0.00502(10) OVARIES/ FINAL BODY * 100 0.04364 0.00931(9) 0.04227 0.00945(10) 0.03746 0.00667(10) 0.04275 0.00772(10) UTERUS/ FINAL BODY * 100 0.15839 0.02151(9) 0.21128 0.04737(10) 0.21164 0.04491(10) 0.21888 0.08174(10) 134 Company Sanitized. Does not contain T S C A CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 34 (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/day Group IV 50 mg/kg/day Group VI Group VIII 250 mg/kg/day 1000 mg/kg/day LIVER/ BRAIN * 100 453.16871 51.53255(9) 449.40303 467.75182 496.43390 19.98274(10) 70.86370(10) 79.13478(10) KIDNEYS/ BRAIN * 100 118.82351 8.13654(9) 122.86286 124.72456 124.65330 7.29982(10) 14.96060(10) 12.56924(10) HEART/ BRAIN * 100 58.04840 6.01775(9) 53.39885 4.26402 (10) 55.56214 5.64538(10) 54.52115 8.21116(10) SPLEEN/ BRAIN * 100 24.52604 3.19572(9) 26.43428 4.08542(10) 28.06953# 3.72366(10) 27.90773# 4.88065(10) THYMUS/ BRAIN * 100 15.78026 3.20325(9) 14.37108 3.07053(10) 16.43012 3.95870(10) 16.50275 4.12823(10) ADRENAL GLANDS/ BRAIN * 100 3.45494 0.72733(9) 3.62641 0.50714(10) 3.98493 0.98532(10) 3.81032 0.47299(10) OVARIES/t BRAIN * 100 6.88661 1.60341(9) 6.40432 1.30463(10) 5.92383 0.91033(10) 6.41872 1.17561(10) UTERUS/ BRAIN * 100 24.99779 4.19207(9) 32.08705 7.23638(10) 33.35351 5.50293(10) 32.04322 9.03999(10) 135 Com pany Sanitized. Does no! contain T S C A OBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 34 (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 1000 mg/kg/day LIVER 9.28370 1.09118(10) 9.81700 1.02818(9) KIDNEYS 2.49660 0.13680(10) 2.49433 0.25909(9) HEART 1.18130 0.12273(10) 1.16611 0.06908(9) SPLEEN 0.53490 0.06089(10) 0.53133 0.06821(9) BRAIN 1.92700 0.06756(10) 1.90700 0.07682(9) THYMUS 0.27040 0.06344(10) 0.26578 0.08276(9) ADRENAL GLANDS 0.06720 . 0.00930(10) 0.07433 0.01158(9) . OVARIES 0.11380 0.01923(10) 0.13044 0.03080(9) UTERUS 0.69240 0.15493(10) 0.64000 0.14365(9) FINAL BODY WEIGHT 319.89000 29.45560(10) 319.46667 39.20315(9) > 136 Company Sanitized. Does no! contain T S C A CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 34 (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 1000 mg/kg/day LIVER/ FINAL BODY * 100 2.90965 0.31572(10) 3.08176 0.17865(9) KIDNEYS/ FINAL BODY * 100 0.78454 0.06459(10) 0.78462 0.07204(9) HEART/ FINAL BODY * 100 0.37077 0.04110(10) 0.36727 0.02209(9) SPLEEN/ FINAL BODY * 100 0.16798 0.02111(10) 0.16684 0.01593(9) THYMUS/ FINAL BODY * 100 0.08434 0.01769(10) 0.08194 0.01357 (9) BRAIN/ FINAL BODY * 100 0.60627 0.05176(10) 0.60309 0.06179(9) ADRENAL GLANDS/ FINAL BODY * 100 0.02115 0.00335(10) 0.02332 0.00303(9) OVARIES/ FINAL BODY * 100 0.03554 0.00488(10) 0.04080 0.00830(9) UTERUS/ FINAL BODY * 100 0.21976 0.05912(10) 0.20282 0.05408(9) 137 Com pany Sanitized. Does not contain T S C A c m H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 34 (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 1000 mg/kg/day LIVER/ BRAIN*100 481.41153 514.77685 51.16500(10) 48.35577(9) KIDNEYS/ BRAIN*100 129.58552 6.03970(10) 130.84378 12.62861(9) HEART/ BRAIN*100 61.30509 6.13495(10) 61.16895 3.06644(9) SPLEEN/ BRAIN*100 27.72580 2.69809(10) 27.85508 3.32437 (9) THYMUS/ BRAIN*100 14.02984 3.15456(10) 13.92129 4.13240(9) ADRENAL GLANDS/ BRAIN * 100 3.47982 0.39498(10) 3.90318 0.63048(9) OVARIES/ BRAIN*100 5.90446 0.97360(10) 6.83405 1.57365(9) ! UTERUS/ BRAIN*100 35.91140 33.68099 7.83175(10) 8.06631(9) 138 Company Sanitized. Does not contain T S C A CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 34 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (3-MONTH RECOVERY EVALUATION) LIVER MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHT (grams) Group II 0 mg/kg/day Group IV 50 mg/kg/day Group VI Group VIII 250 mg/kg/day 1000 mg/kg/day 9.78580 1.03445(5) 9.09420 1.03757(5) 10.15800 1.14344(5) 10.94320 1.05921(5) FINAL BODY WEIGHT 321. 19999 15 .12316(5) 329.13999 14.29032(5) 345.69999 45.08364(5) 371.77999# 33.74221(5) MEAN RELATIVE ORGAN WEIGHT ( % organ to body weight) LIVER/ FINAL BODY * 100 3.05923 0.42653(5) 2.75646 0.19747(5) 2.95270 0.25319(5) 2.95638 0.33569(5) Data summarized as: Mean Standard Deviation (n) Statistical- Methods: Trend test (Jonckheere-Terpstra). # Statistically significant difference at p < 0.05. 139 Com pany Sanitized. Does not contain T S C A CB) H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations 4 DuPont-4739 TABLE 35 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION) LESION INCIDENCE (Numeric) Males LESIONS TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII LIVER NO ABNORMALITY DETECTED KIDNEYS NO ABNORMALITY DETECTED LUNGS NO ABNORMALITY DETECTED HEART NO ABNORMALITY DETECTED SKELETAL MUSCLE NO ABNORMALITY DETECTED SPLEEN NO ABNORMALITY DETECTED 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 (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 Sanitized. Does not contain TSC CBi 140 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 35 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION) & DuPont-4739 LESION INCIDENCE (Numeric)| Males LESIONS TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII SPINAL CORD NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED PANCREAS NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED 1 |COLON 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 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 GO) 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 Company Sanitized. Does not contain TSC CBI 141 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 35 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION) DuPont-4739 LESION INCIDENCE (Numeric) Males LESIONS TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII RECTUM NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED PITUITARY GLAND NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (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 Company Sanitized. Does not cnnta'n tsca cr 142 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 35 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION) # DuPont-4739 LESIONS i LESION INCIDENCE (Numeric) 1 1 Males TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII THYROID GLAND NO ABNORMALITY DETECTED PARATHYROID GLANDS NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED SKIN NO ABNORMALITY DETECTED PROSTATE NO ABNORMALITY DETECTED (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 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified Company Sanitized. Does no! contain TSCA O CO 143 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 35 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION) " LESION INCIDENCE (Numeric) Males LESIONS TREATMENT (mg/kg/day) 0 I 50 250 III V SEMINAL VESICLES NO ABNORMALITY DETECTED URINARY BLADDER NO ABNORMALITY DETECTED TESTES NO ABNORMALITY DETECTED LARGE, RIGHT. EPIDIDYMIDES 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) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 p-j_gu;c0 i3 in parentheses is the number of animals grossly examined for this tissue The absence of a nuinbGir indicates the finding specified was not identified 1000 VII (10) 10 (10) 10 (10) 9 1 (10) 10 (10) 10 (10) 10 (10) 10 Company Sanitized. Does not contain TSCA CBI 144 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 35 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDENCE (Numeric) Males LESIONS TREATMENT (mg/kg/day) 0 I 50 250 III V LIVER NO ABNORMALITY DETECTED KIDNEYS NO ABNORMALITY DETECTED LUNGS NO ABNORMALITY DETECTED HEART NO ABNORMALITY DETECTED SKELETAL MUSCLE NO ABNORMALITY DETECTED , (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 SPLEEN NO ABNORMALITY DETECTED AORTA NO ABNORMALITY DETECTED BRAIN NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 1000 VII (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 SanRFzed. Does no! eon* ve#*a #*t 145 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 35 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (ONE-MONTH RECOVERY EVALUATION) DuPont-4739 LESION INCIDENCE (Numeric) Males LESIONS TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII SPINAL CORD NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED PANCREAS NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED (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 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 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 35 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (ONE-MONTH RECOVERY EVALUATION) DuPont-4739 LESION INCIDENCE (Numeric) Males LESIONS TREATMENT (mg/kg/day) 0 I 50 250 '1000 III V VII RECTUM NO ABNORMALITY DETECTED (10) 10 (10) 10 MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED (10) 10 (10) 10 SALIVARY GLANDS NO ABNORMALITY DETECTED (10) 10 (10) 10 |MANDIBULAR LYMPH NODE |N0 ABNORMALITY DETECTED (10) 10 (10) 10 sOsS THYMUS NO ABNORMALITY DETECTED (10) 10 (10) 10 nr ADRENAL GLANDS (10) (10) * NO ABNORMALITY DETECTED 10 10 (<oaA0 SCIATIC NERVE 3Omm NO ABNORMALITY DETECTED (10) 10 (10) 10 o PITUITARY GLAND NO ABNORMALITY DETECTED (10) 10 (10) 10 0 5f Figures in parentheses is the number of animals grossly examined for this tissue HI The absence of a number indicates the finding specified was not identified 147 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 35 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (ONE-MONTH RECOVERY EVALUATION) DuPont-4739 LESION' INCIDENCE (Numeric) Males LESIONS TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII THYROID GLAND NO ABNORMALITY DETECTED PARATHYROID GLANDS NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED SKIN NO ABNORMALITY DETECTED PROSTATE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) io (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 Company Sanitized. Does not contain TSCA CBI 148 r H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 35 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (ONE-MONTH RECOVERY EVALUATION) DuPont-4739 LESION INCIDENCE (Numeric)| Males LESIONS TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII SEMINAL VESICLES NO ABNORMALITY DETECTED URINARY BLADDER NO ABNORMALITY DETECTED TESTES NO ABNORMALITY DETECTED EPIDIDYMIDES 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 I. Does nol contain TSCA cai 149 - H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 35 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (3-MONTH RECOVERY EVALUATION) LESION INCIDENCE (Numeric) Males LESIONS TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII LIVER NO ABNORMALITY DETECTED DISCOLORATION, TAN, MANY. KIDNEYS NO ABNORMALITY DETECTED LUNGS |NO ABNORMALITY DETECTED 1 |HEART |NO ABNORMALITY DETECTED SKELETAL MUSCLE NO ABNORMALITY DETECTED SPLEEN CO NO ABNORMALITY DETECTED 3 S3 AORTA & NO ABNORMALITY DETECTED BRAIN NO ABNORMALITY DETECTED (5) (5) (4) (5) 5445 1 (5) (5) (4) (5) 554b (5) (5) (4) (5) 5545 (5) (5) (4) (5) 554 5 (5) (5) (4) (5) 554 b (5) (5) (4) (5) 554 (5) (5) (4) (5) 5545 (5) (5) (4) (5) 5545 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 ju S Q 'j V ,w w o 150 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 35 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (3-MONTH RECOVERY EVALUATION) LESION INCIDENCE (Numeric) 1 1 Males LESIONS TREATMENT (mg/kg/day) 0 I 50 250 III V SPINAL CORD NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED |DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED PANCREAS NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED (5) (5) (4) 554 (5) (5) (4) 554 (5) (5) (4) 554 (5) (5) (4) 554 (5) (5) (4) 554 (5) (5) (4) 554 (5) (5) (4) 554 (5) (5) (4) 554 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 1000 VII (5) b (5) b (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 .Cempany Sanitized. Does not contain TSCA CB 151 % H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations______________________________ 0 DuPont-4739 TABLE 35 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (3-MONTH RECOVERY EVALUATION) LESION INCIDENCE (Numeric) Males LESIONS TREATMENT | 0 (mg/kg/day) I 50 250 1000 III V VII RECTUM NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED (5) (5) 55 (5) (5) 55 SALIVARY GLANDS NO ABNORMALITY DETECTED MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED (5) (5) 55 (5) (5) 55 THYMUS NO ABNORMALITY DETECTED (5) (5) 55 ADRENAL GLANDS NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED (5) (5) 55 (5) (5) 55 PITUITARY GLAND |NO ABNORMALITY DETECTED (5) (5) 55 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 (4) 4 (4) 4 (4) 4 (4) 4 (4) 4 (4) 4 (4) 4 (4) 4 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 ompany Sanitized. Does not contain TSCA CSl 152 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 35 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (3-MONTH RECOVERY EVALUATION) LESION INCIDENCE (Numeric) Males LESIONS TREATMENT (mg/kg/day) 0 I 50 250 III V THYROID GLAND NO ABNORMALITY DETECTED PARATHYROID GLANDS |NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED PHARYNX /LARYNX NO ABNORMALITY DETECTED EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED SKIN NO ABNORMALITY DETECTED PROSTATE NO ABNORMALITY DETECTED (5) (5) (4) 554 (5) (5) (4) 554 (5) (5) (4) 554 (5) (5) (4) 554 (5) (5) (4) 554 (5) (5) (4) 554 (5) (5) (4) 554 (5) (5) (4) 554 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 1000 VII (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 Company Sanitized. Does not contain TSCA CB 153 N 2L a 3 OQ o> oa 3Da) 3 (A 3 N <aD a3 n 3 3 a3rj I > a H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 35 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (3-MONTH RECOVERY EVALUATION) LESION INCIDENCE (Numeric) Males LESIONS TREATMENT (mg/kg/day) 50 250 1000 III V VII SEMINAL VESICLES NO ABNORMALITY DETECTED (5) (5) 55 URINARY BLADDER NO ABNORMALITY DETECTED (5) (5) 55 TESTES NO ABNORMALITY DETECTED (5) (5) 55 EPIDIDYMIDES NO ABNORMALITY DETECTED (5) (5) 55 FEMUR/KNEE JOINT NO ABNORMALITY DETECTED (5) (5) 55 STERNUM NO ABNORMALITY DETECTED (5) (5) 55 NOSE NO ABNORMALITY DETECTED (5) (5) 55 ri.y u x t5 tj iii y c u c i i t u c s c s i o i-u c wo- 77 this tissue ,_ . The absence of a number indicates the finding specified was not identified (4) 4 (4) 4 (4) 4 (4) 4 (4) 4 (4) 4 (4) 4 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 154 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 I --------------- 1 11 11 11 1 H1 1O HI 11 Sanitized. Does not contain TSCA fR* TABLE 36 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION) LESION INCIDENCE (Numeric) Females LESIONS TREATMENT (mg/kg/day) 50 250 1000 IV VI VIII LIVER NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 KIDNEYS NO ABNORMALITY DETECTED LUNGS NO ABNORMALITY DETECTED DISCOLORATION, DARK, DIFFUSE. (10) 10 (10) 9 1 (10) 10 (10) 10 (10) 10 (10) 10 HEART NO ABNORMALITY DETECTED SKELETAL MUSCLE NO ABNORMALITY DETECTED SPLEEN NO ABNORMALITY DETECTED (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 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 9 155 1---------------1 i1 11 11 1 H1 1O HI 11 Company SanRIzed. Does no! contain tSC CBU H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 36 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION) LESION INCIDENCE (Numeric) Females LESIONS TREATMENT (mg/kg/day) 50 250 1000 IV VI VIII SPLEEN (10) (10) (10) DISCOLORATION, BROWN. AORTA NO ABNORMALITY DETECTED BRAIN NO ABNORMALITY DETECTED SPINAL CORD NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED DUODENUM 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 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified (10) 1 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 156 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 36 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION) LESION INCIDENCE (Numeric) Females LESIONS TREATMENT (mg/kg/day) 0 II 50 250 IV VI JEJUNUM (10) (10) (10) NO ABNORMALITY DETECTED 10 10 10 ILEUM (10) (10) (10) NO ABNORMALITY DETECTED 10 10 10 PANCREAS NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 CECUM (10) (10) (10) NO ABNORMALITY DETECTED 10 10 10 COLON NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 RECTUM NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 1000 VIII (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 I. Does not contain TSCA CB! H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 36 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION) LESION INCIDENCE (Numeric) Females LESIONS TREATMENT 0 50 250 1000 (mg/kg/day) II IV VI VIII MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 SALIVARY GLANDS NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 THYMUS NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 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 Figures in parentheses is the number of animals grossly examined for this tissue O-43 The absence of a number indicates the finding specified was not identified 5 O H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 36 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION) LESION INCIDENCE (Numeric) Females | --------- 1 11 1H lO H 1 LESIONS TREATMENT (mg/kg/day) 50 250 1000 IV VI VIII PITUITARY GLAND (10) (10) (10) (10) NO ABNORMALITY DETECTED 10 10 10 10 THYROID GLAND (10) (10) (10) (1 0 ) NO ABNORMALITY DETECTED 10 10 10 10 PARATHYROID GLANDS (10) (10) (1 0 ) (10) FT NO ABNORMALITY DETECTED & a TRACHEA 8 NO ABNORMALITY DETECTED 10 (10) 10 10 (10) 10 10 (10) 10 10 (10) 10 oo3 S' ESOPHAGUS NO ABNORMALITY DETECTED 3 to>o PHARYNX/LARYNX NO ABNORMALITY DETECTED (10) 10 (10) 10 (1 0 ) 10 (10) 10 (1 0 ) 10 (10) 10 (10) 10 (1 0 ) 10 a 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 f j ------------------------------------------------------------------------------------------- ------------- - 8 (8 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations______ _________________ _____________________________________ DuPont-4739 TABLE 36 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION) LESION INCIDENCE (Numeric) Females LESIONS TREATMENT 0 50 250 (mg/kg/day) II IV VI EYE(S ) WITH OPTIC NERVE NO ABNORMALITY DETECTED SKIN NO ABNORMALITY DETECTED MAMMARY GLAND (FEMALE) NO ABNORMALITY DETECTED OVARIES NO ABNORMALITY DETECTED UTERUS NO ABNORMALITY DETECTED URINARY BLADDER 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 (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 1000 VIII (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 Company SanRIzed. Does no? c o n fab '^ 160 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 36 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION) LESION INCIDENCE (Numeric) Females LESIONS TREATMENT 0 50 250 1000 (mg/kg/day) II IV VI VIII 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 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 Sanitized. Does no! contain TSCA CEfl 161 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 36 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) 1 1 1 LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (Numeric) Females 0 50 250 1000 II IV VI VIII LIVER NO ABNORMALITY DETECTED HERNIA. KIDNEYS NO ABNORMALITY DETECTED 1 | LUNGS NO ABNORMALITY DETECTED HEART NO ABNORMALITY DETECTED SKELETAL MUSCLE NO ABNORMALITY DETECTED SPLEEN NO ABNORMALITY DETECTED (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 Sanitized. Does not contain ^Hl 162 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 36 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDENCE (Numeric) Females LESIONS TREATMENT 0 50 250 1000 (mg/kg/day) II IV VI VIII AORTA NO ABNORMALITY DETECTED BRAIN NO ABNORMALITY DETECTED 1 SPINAL CORD NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED (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 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 163 Company Sanitized. Does not contain TSCA CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 36 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDENCE (Numeric) Females LESIONS TREATMENT 0 50 250 1000 (mg/kg/day) II IV VI VIII ILEUM (10) NO ABNORMALITY DETECTED 10 PANCREAS (10) NO ABNORMALITY DETECTED 10 CECUM NO ABNORMALITY DETECTED (10) 10 COLON NO ABNORMALITY DETECTED (10) 10 RECTUM NO ABNORMALITY DETECTED (10) 10 MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 164 Company Sanitized. Does not contain TSCA CB1 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 36 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDENCE (Numeric) Females LESIONS TREATMENT 0 50 250 1000 (mg/kg/day) II IV VI VIII SALIVARY GLANDS (10) NO ABNORMALITY DETECTED 10 MANDIBULAR LYMPH NODE (10) NO ABNORMALITY DETECTED 10 THYMUS NO ABNORMALITY DETECTED (10) 10 ADRENAL GLANDS NO ABNORMALITY DETECTED (10) 10 SCIATIC NERVE NO ABNORMALITY DETECTED (10) 10 PITUITARY GLAND NO ABNORMALITY DETECTED (10) 10 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 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 165 | ----------------- 1 1 1 1H 1O H 1 Sanitized. Does not contain TSCA CBt 5?; H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 36 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDENCE (Numeric) Females LESIONS TREATMENT (mg/kg/day) 50 250 1000 IV VI VIII THYROID GLAND (10) NO ABNORMALITY DETECTED 10 PARATHYROID GLANDS (10) NO ABNORMALITY DETECTED 10 TRACHEA NO ABNORMALITY DETECTED (10) 10 ESOPHAGUS (10) NO ABNORMALITY DETECTED 10 PHARYNX/LARYNX NO ABNORMALITY DETECTED (10) 10 EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 166 Company SanRIzed. Does not contain TSCA CB1 %9G H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations _________________________________________________________DuPont-4 /39 TABLE 36 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDENCE (Numeric) Females LESIONS TREATMENT 0 50 250 1000 (mg/kg/day) II IV VI VIII SKIN (10) NO ABNORMALITY DETECTED MAMMARY GLAND (FEMALE) 1 | NO ABNORMALITY DETECTED 10 GO) 10 OVARIES (10) NO ABNORMALITY DETECTED 10 UTERUS (10) NO ABNORMALITY DETECTED 10 URINARY BLADDER (10) NO ABNORMALITY DETECTED 10 FEMUR/KNEE JOINT (10) NO ABNORMALITY DETECTED 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 (10) 10 GO) 10 GO) 10 (10) 10 (10) 10 GO) 10 167 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 36 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDENCE (Numeric) Females LESIONS STERNUM NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED 1 TREATMENT | (mg/kg/day) 1 0 II (10) 10 (10) 10 50 IV 250 VI 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 1000 VIII (10) 10 (10) 10 a Sanitized. Does no contain TSCA 168 pom pany Sanitized). Does not contain TSCA CBI %9* H-24616: Subchronic Toxicity __ 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations________________ _________________________________ ___________UuFont-4 TABLE 36 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (3-MONTH RECOVERY EVALUATION) LESION INCIDENCE (Numeric) Females LESIONS TREATMENT 0 50 250 1000 (mg/kg/day) II IV VI VIII LIVER NO ABNORMALITY DETECTED KIDNEYS NO ABNORMALITY DETECTED LUNGS NO ABNORMALITY DETECTED HEART NO ABNORMALITY DETECTED SKELETAL MUSCLE NO ABNORMALITY DETECTED SPLEEN NO ABNORMALITY DETECTED (5) (5) (5) (5) 5555 (5) (5) (5) (5) 5555 (5) (5) (5) (5) 55 5 5 (5) (5) (5) (5) 5555 (5) (5) (5) (5) 55 55 (5) (5) (5) (5) 5555 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 169 1 -------1 l 1 lH 1O H 1 Company Sanitized. Boes not eontaln TSC CBl H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 36 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (3-MONTH RECOVERY EVALUATION) LESION INCIDENCE (Numeric) Females LESIONS TREATMENT (mg/kg/day) 50 250 IV VI AORTA NO ABNORMALITY DETECTED BRAIN NO ABNORMALITY DETECTED SPINAL CORD NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED (5) (5) 55 (5) (5) 55 (5) . (5) 55 (5) (5) 55 (5) (5) 55 (5) (5) 55 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 1000 VIII (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 170 empany Sanitized. Does not contain TSC CBl H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 36 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (3-MONTH RECOVERY EVALUATION) LESIONS -----------ILEUM NO ABNORMALITY DETECTED PANCREAS NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED RECTUM NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED LESION INCIDENCE (Numeric) I 1 1 Females TREATMENT (mg/kg/day) 0 II | (5) 50 IV (5) 250 VI (5) 1000 VIII (5) 5555 (5) (5) (5) (5) 5555 (5) (5) (5) (5) 55 55 (5) (5) (5) (5) 5555 (5) (5) (5) (5) 5555 (5) (5) (5) (5) 5555 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 171 Company SanHIzed. Does not contain T fir a H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 36 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (3-MONTH RECOVERY EVALUATION) LESION INCIDENCE (Numeric) Females LESIONS TREATMENT 0 50 250 1000 (mg/kg/day) II IV VI VIII SALIVARY GLANDS NO ABNORMALITY DETECTED MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED (5) (5) 55 (5) (5) 55 (5) (5) 55 (5) (5) 55 SCIATIC NERVE NO ABNORMALITY DETECTED (5) (5) 55 PITUITARY GLAND NO ABNORMALITY DETECTED (5) (5) 55 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 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 172 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 36 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (3-MONTH RECOVERY EVALUATION) LESION INCIDENCE (Numeric) Females LESIONS TREATMENT 0 50 250 (mg/kg/day) II IV VI 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 (5) (5) (5) 555 (5) (5) (5) 555 (5) (5) (5) 555 (5) (5) (5) 555 (5) (5) (5) 555 (5) (5) (5) 555 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 1000 VIII (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 36 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (3-MONTH RECOVERY EVALUATION) LESION INCIDENCE (Numeric) 1 Females LESIONS TREATMENT 0 50 250 (mg/kg/day) II IV VI SKIN NO ABNORMALITY DETECTED 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 (5) (5) (5) 555 (5) (5) (5) 55 5 (5) (5) (5) 555 (5) (5) (5) 555 (5) (5) (5) 55 5 (5) (5) (5) 555 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 1000 VIII (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 Sanitized. Does not contain tca CRI 174 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 36 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (3-MONTH RECOVERY EVALUATION) 1 LESION INCIDENCE (Numeric) 1 Females LESIONS STERNUM NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) 0 II (5) 5 (5) 5 50 IV (5) 5 (5) 5 250 VI (5) 5 (5) 5 1000 VIII (5) 5 (5) 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 175 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 37 LESIONS INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC. HYPERTROPHY, HEPATOCELLULAR. HYPERPLASIA, BILE DUCT. FATTY CHANGE, PERIPORTAL. FATTY CHANGE, MEDIAN CLEFT. FATTY CHANGE, CENTRILOBULAR. (10) 1 2 9 1 (10) 2 10 1 1 3 1 PANCREAS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. ATROPHY. ESOPHAGUS NO ABNORMALITY DETECTED FIBROSIS. STOMACH NO ABNORMALITY DETECTED (10) 6 4 1 (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 (10) 10 10 1 1 (10) 1 10 10 1 (10) 8 2 (10) 9 1 (10) 10 *np8ny Sanitized. Does not contain t s c a C91 176 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 37 (CONTINUED) LESIONS INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII DIGESTIVE SYSTEM DUODENUM NO ABNORMALITY DETECTED (10) 10 JEJUNUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED RECTUM NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 SALIVARY GLANDS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesibn specified was not identified (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 9 1 177 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations # DuPont-4739 TABLE 37 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS- NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS 1 LESION INCIDE NCE (NU(MERIC ) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. INFLAMMATION, SUBACUTE/CHRONIC. URINARY BLADDER NO ABNORMALITY DETECTED RESPIRATORY SYSTEM ' LUNGS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. TRACHEA NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED | INFLAMMATION, SUBACUTE/CHRONIC. | HYPERPLASIA/HYPERTROPHY, TRANSITIONAL CELL, EPITHELIUM. (10) 5 4 1 (10) 10 J (10) 5 5 (10) 10 (10) 5 5 (10) 10 (10) 10 (10) 10 (10) 2 (10) 5 (10) O 4 (10) 10 (10) 10 (10) 6 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 Sanitized. Does not contain TSCA CBI 178 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 37 (CONTINUED) DuPont-4739 LESIONS INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) I LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII RESPIRATORY SYSTEM NOSE DEGENERATION/NECROSIS, OLFACTORY, EPITHELIUM. (10) (10) 8 CARDIOVASCULAR SYSTEM HEART NO ABNORMALITY DETECTED CARDIOMYOPATHY. AORTA NO ABNORMALITY DETECTED (10) 5 5 (10) 10 LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED (10) 10 THYMUS NO ABNORMALITY DETECTED (10) 10 MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED (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 (10) 10 (10) 10 (10) 6 4 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 ompany Sanitized. Does not contain TSCA 179 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_________ DuPont-4739 TABLE 37 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 50 250 1000 I III V VII LYMPHATIC AND HEMATOPOIETIC SYSTEM BONE MARROW NO ABNORMALITY DETECTED (10) 10 ENDOCRINE SYSTEM PITUITARY GLAND NO ABNORMALITY DETECTED CYST. THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. ALTERATION, COLLOID. PARATHYROID GLANDS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED (10) 10 (10) 2 8 (6) 6 (10) 10 (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 (10) 5 10 (10) 10 (10) 9 1 (10) 10 10 (7) 7 (10) 10 Company Sanitized. Does not contain TSCA CBI 180 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 37 (CONTINUED) LESIONS INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) | LESION INCIDENCE (NUMERIC)| TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII NERVOUS SYSTEM BRAIN NO ABNORMALITY DETECTED SPINAL CORD NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 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 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 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 Company Sanitized. Does not contain TSCA CbI 181 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 37 (CONTINUED) DuPont-4739 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESION INCIDENCE (NUMERIC) LESIONS TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII REPRODUCTIVE SYSTEM TESTES NO ABNORMALITY DETECTED ! DILATATION, SEMINIFEROUS TUBULES, UNILATERAL. EPIDIDYMIDES NO ABNORMALITY DETECTED | PROSTATE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. SEMINAL VESICLES NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 9 1 (10) 10 (10) 9 1 (10) 10 (10) 9 1 (10) 10 CUTANEOUS SYSTEM SKIN NO ABNORMALITY DETECTED (10) 10 (10) 10 SPECIAL SENSES SYSTEM EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED OPTIC NERVE NOT PRESENT. FOLD/ROSETTE, RETINAL. (10) 9 1 1 Figure in parentheses is nuiriber of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 Company Sanitized. Does not contain TSCA CBI 182 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 37 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III v VII DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC. HYPERTROPHY, HEPATOCELLULAR. FATTY CHANGE, MEDIAN CLEFT. RESPIRATORY SYSTEM NOSE NO ABNORMALITY DETECTED DEGENERATION/NECROSIS, OLFACTORY, EPITHELIUM. (10) 1 9 1 (10) 10 (10) 3 10 10 (10) 7 3 ENDOCRINE SYSTEM THYROID GLAND NO ABNORMALITY DETECTED | HYPERTROPHY, FOLLICULAR. ALTERATION, COLLOID. (10) 4 6 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 1 (10) 8 10 i i i Company Sanitized. Does not contain TSCA CB! 183 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 37 (CONTINUED) LESIONS INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (3-MONTH RECOVERY EVALUATION) 1 LESION INCIDE NCE (NL(MERIC ) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII DIGESTIVE SYSTEM LIVER NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC. HYPERTROPHY, HEPATOCELLULAR. HYPERPLASIA, BILE DUCT. FATTY CHANGE, PERIPORTAL. FATTY CHANGE, MEDIAN CLEFT. FATTY CHANGE, CENTRILOBULAR. RESPIRATORY SYSTEM NOSE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. (5) (5) (4) (5) 1z 5 53 4 34 1 11 1 12 1 (5) (5) (4) (5) 5544 1 ENDOCRINE SYSTEM | THYROID GLAND | NO ABNORMALITY DETECTED I ALTERATION, COLLOID. (5) (5) (4) (5) 1 544 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Sanitized. Does not contain TSC CB! 184 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations # DuPont-4739 TABLE 38 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT 0 50 250 1000 (mg/kg/day) II IV VI VIII DIGESTIVE SYSTEM LIVER (10) (10) NO ABNORMALITY DETECTED NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC. FATTY CHANGE, MEDIAN CLEFT. 1 9 10 11 PANCREAS (10) NO ABNORMALITY DETECTED ATROPHY. 6 4 ESOPHAGUS (10) NO ABNORMALITY DETECTED FIBROSIS. 9 1 STOMACH (10) NO ABNORMALITY DETECTED CYST, KERATIN. 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 (10) 1 10 1 (10) 10 2 (10) 10 (10) 10 (10) 10 Company Sanitized. Does not contain tr c C81 185 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 38 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) 1 1 LESIONS 1 LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 II 50 250 1000 IV VI VIII DIGESTIVE SYSTEM DUODENUM NO ABNORMALITY DETECTED (10) 10 JEJUNUM (10) NO ABNORMALITY DETECTED 10 ILEUM NO ABNORMALITY DETECTED (10) 10 CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED RECTUM 1 | NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 Sanitized. Does not contain TSCA CB 186 1----- 1 11 11 11 1 H1 1O HI 11 .Company Sanitized. Does not contain TSCA CB1 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 38 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS I LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 50 250 1000 IV VI VIII DIGESTIVE SYSTEM SALIVARY GLANDS NO ABNORMALITY DETECTED 1 (10) 10 URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. INFLAMMATION, SUBACUTE/CHRONIC. HYDRONEPHROSIS, UNILATERAL. URINARY BLADDER NO ABNORMALITY DETECTED (10) 8 1 1 (10) 10 RESPIRATORY SYSTEM LUNGS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. (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 (10) 10 (10) 9 1 (10) 10 (10) 9 1 187 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 38 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT 0 50 250 1000 (mg/kg/day) II IV VI VIII RESPIRATORY SYSTEM TRACHEA NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. HYPERPLASIA/HYPERTROPHY, TRANSITIONAL CELL, EPITHELIUM. DEGENERATION/NECROSIS, OLFACTORY, EPITHELIUM. (10) 10 (10) 10 (10) 10 (10) 8 2 CARDIOVASCULAR SYSTEM HEART (10) NO ABNORMALITY DETECTED | CARDIOMYOPATHY. 8 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) 6 1 1 4 (10) 10 (10) 10 (10) 2 1 8 (10) 9 1 .Company Sanitized. Does not contain TSCA r r t 188 % H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations____________________________________________ ____________ # DuPont-4739 TABLE 38 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT 0 50 250 1000 (mg/kg/day) II IV VI VIII CARDIOVASCULAR SYSTEM AORTA NO ABNORMALITY DETECTED (10) 10 (10) 10 LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN (10) (10) NO ABNORMALITY DETECTED PIGMENT INCREASED. 9 10 1 THYMUS (10) (10) NO ABNORMALITY DETECTED 10 10 MANDIBULAR LYMPH NODE Oo NO ABNORMALITY DETECTED (WD 3O MESENTERIC LYMPH NODE (10) 10 (10) (10) 10 (10) % NO ABNORMALITY DETECTED 10 1^ 3 Figure in parentheses is number of animals microscopically examined for this tissue 4 it The absence of a number indicates the lesion specified was not identified Vt 3 10 189 Company Sanitized. H-24616: Subchronic Toxicity 90-Day Gavage Study inRats withOne-Generation Reproduction Evaluations DuPont-4739 TABLE 38 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT 0 50 250 1000 (mg/kg/day) II IV VI VIII LYMPHATIC AND HEMATOPOIETIC SYSTEM BONE MARROW NO ABNORMALITY DETECTED (10) 10 ENDOCRINE SYSTEM PITUITARY GLAND NO ABNORMALITY DETECTED THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. ALTERATION, COLLOID. PARATHYROID GLANDS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED (9) 9 (10) (10) 75 35 (8) 8 (10) 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 (10) 4 2 6 (10) 10 (10) 10 (10) 7 10 (2) 2 (10) 10 [Company Sanitized. Does not contain TSCA CB 190 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations * DuPont-4739 TABLE 38 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 II 50 250 1000 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 MUSCULAR AND SKELETAL SYSTEM SKELETAL MUSCLE NO ABNORMALITY DETECTED FEMUR/KNEE JOINT (10) 10 (10) NO ABNORMALITY DETECTED 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 (10) 10 (10) 10 (9) 9 (10) 10 (10) 10 .Company Sanitized. Does not contain TSCA cbi 191 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 38 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) O1 1 50 250 1000 IV VI VIII 1H 1H MUSCULAR AND SKELETAL SYSTEM STERNUM (10) NO ABNORMALITY DETECTED 10 REPRODUCTIVE SYSTEM OVARIES NO ABNORMALITY DETECTED (10) 10 UTERUS NO ABNORMALITY DETECTED DILATATION, LUMEN. MAMMARY GLAND (FEMALE) NO ABNORMALITY DETECTED (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 (1 0 ) 10 (1 0 ) 10 (1 0 ) 7 3 (10) 10 ompany Sanitized. Does not contain T s r* r m 192 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations D uPont-4739 TABLE 38 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) Does noi contain TSCA LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 II 50 250 1000 IV VI VIII CUTANEOUS SYSTEM SKIN NO ABNORMALITY DETECTED ( 10) 10 (10) 10 SPECIAL SENSES SYSTEM i EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED !4 OPTIC NERVE NOT PRESENT. 9I FOLD/ROSETTE, RETINAL. (10) 9 1 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 193 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 38 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS- NEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) | LESION INCIDENCE (NUMERIC) LESIONS TREATMENT 0 50 250 1000 (mg/kg/day) II IV VI VIII DIGESTIVE SYSTEM LIVER (10) NO ABNORMALITY DETECTED NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC. FATTY CHANGE, MEDIAN CLEFT. 10 3 PANCREAS | NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED DUODENUM | NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 1 (10) 1 1 3 1 (1) 1 (1) 1 (1) 1 (1) 1 ljisppp.pm g0.g "pa^isuBS XuBdjao^ 194 VU/ H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 38 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 50 250 1000 II IV VI VIII DIGESTIVE SYSTEM JEJUNUM NO ABNORMALITY DETECTED ILEUM AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. CECUM AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. COLON AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. RECTUM NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified ( 1) 1 (1 ) 1 (1 ) 1 (1 ) 1 (1 ) 1 (1 ) 1 195 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 38 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) 1 H O1 H1 1 1 ----- 11 LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 50 250 1000 IV VI VIII URINARY SYSTEM KIDNEYS 1 1 NO ABNORMALITY DETECTED URINARY BLADDER NO ABNORMALITY DETECTED RESPIRATORY SYSTEM LUNGS NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (1) 1 (1) 1 (1) 1 (1) 1 (1) 1 Sanitized. Does not c e l a t e TSC UB 196 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations # DuPont-4739 TABLE 38 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) O1 1 TREATMENT (mg/kg/day) 50 250 1000 IV VI VIII lH 1H RESPIRATORY SYSTEM NOSE NO ABNORMALITY DETECTED (10) 10 CARDIOVASCULAR SYSTEM , HEART NO ABNORMALITY DETECTED AORTA NO ABNORMALITY DETECTED LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 (1) 1 (1) 1 (1) 1 (1) 1 Sanitized. Does not contain TSCA CBI 197 % H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations <9 DuPont-4739 TABLE 38 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS 1 LESION INCIDENCE (NUMERIC) TREATMENT 0 50 250 1000 (mg/kg/day) II IV VI ' VIII LYMPHATIC AND HEMATOPOIETIC SYSTEM MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED BONE MARROW NO ABNORMALITY DETECTED ENDOCRINE SYSTEM PITUITARY GLAND NO ABNORMALITY DETECTED THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. ALTERATION, COLLOID. (10) 4 6 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (1) 1 (1) 1 (1) 1 (1) 1 (10) 2 0 7 Company Sanitized. Does not contain TSC CBS 198 .Company Sanitized. Does not contain TSCA CB) H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 38 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) | LESION INCIDENCE (NUMERIC) LESIONS TREATMENT (mg/kg/day) 0 II 50 250 1000 IV VI V I I I ENDOCRINE SYSTEM THYROID GLAND AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. PARATHYROID GLANDS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED (10) (10) 1 (1 ) 1 (1 ) 1 NERVOUS SYSTEM BRAIN MIXED GLIOMA [M]. SPINAL CORD NO ABNORMALITY DETECTED (1) 1 (1 ) 1 [M] Malignant tumor _. . Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 199 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 38 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS 1 LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 II 50 250 1000 IV VI VIII NERVOUS SYSTEM SCIATIC NERVE NO ABNORMALITY DETECTED MUSCULAR AND SKELETAL SYSTEM SKELETAL MUSCLE NO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (1) 1 (1) 1 (1) 1 (1) 1 _ ompany Sanitized. Does not contain TSCA CB) 200 j -- ----- | I1 1 1H 1O H 1 Company Sanitized. Does not contain TSCA CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 38 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 50 250 1000 IV VI VIII REPRODUCTIVE SYSTEM OVARIES NO ABNORMALITY DETECTED UTERUS NO ABNORMALITY DETECTED SPECIAL SENSES SYSTEM EYE(S ) WITH OPTIC NERVE AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (1) 1 (1) 1 (1) 1 201 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 38 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (3-MONTH RECOVERY EVALUATION) LESIONS 1 LESION INCIDE NCE (NL(MERIC) TREATMENT (mg/kg/day) 0 II 50 250 1000 IV VI . VIII DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. FATTY CHANGE, MEDIAN CLEFT. FATTY CHANGE, FOCAL. (5) (5) (5) (5) 212 3435 12 1 RESPIRATORY SYSTEM NOSE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. ATROPHY, UNILATERAL, NASAL GLANDS. (5) (5) (5) (5) 2455 21 1 ENDOCRINE SYSTEM THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. ALTERATION, COLLOID. (5) (5) (5) (5) 2 12 i 3543 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified ompany Sanitized. Does not contain TSC CBi 202 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 Company Sanitized. Does not contain TSCA CBl TABLE 39 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT 0 (mg/kg/day) I 50 250 1000 III V VII DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED NECROSIS, FOCAL. minimal Total observations per lesion INFLAMMATION, SUBACUTE/CHRONIC. minimal Total observations per lesion HYPERTROPHY, HEPATOCELLULAR. minimal mild Total observations per lesion HYPERPLASIA, BILE DUCT, minimal Total observations per lesion FATTY CHANGE, PERIPORTAL, minimal Total observations per lesion FATTY CHANGE, MEDIAN CLEFT, minimal mild Total observations per lesion (10) 1 2 2 9 9 1 1 (10) 2 2 10 10 1 1 1 1 3 3 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 (10) 10 10 2 8 10 1 1 (10) 1 1 10 10 10 10 1 1 203 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations * DuPont-4739 TABLE 39 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 50 250 1000 I III V VII DIGESTIVE SYSTEM LIVER FATTY CHANGE, CENTRILOBULAR. minimal Total observations per lesion (10) (10) PANCREAS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. minimal Total observations per lesion ATROPHY. minimal Total observations per lesion (10) 6 4 4 1 1 ESOPHAGUS NO ABNORMALITY DETECTED FIBROSIS. minimal Total observations per lesion (10) 9 1 1 STOMACH NO ABNORMALITY DETECTED (10) 10 Pignre 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 1 (10) (10) 8 2 2 (10) 9 1 1 (10) 10 Company Sanitized. Does not contain TSC CBI 204 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 39 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII DIGESTIVE SYSTEM DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED RECTUM NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. minimal Total observations per lesion (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 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 9 1 1 ompany Sanitized. Does not contain TSCA CBI 205 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 39 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 50 250 1000 I III V VII URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE, minimal Total observations per lesion INFLAMMATION, SUBACUTE/CHRONIC. minimal Total observations per lesion URINARY BLADDER NO ABNORMALITY DETECTED (10) 5 4 4 1 1 (10) 10 RESPIRATORY SYSTEM LUNGS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. minimal Total observations per lesion TRACHEA NO ABNORMALITY DETECTED (10) 5 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 (10) 5 5 5 (10) 10 (10) 6 4 4 (10) 10 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS 1 LESIOlS INCIDE NCE (NtMERIC ) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII RESPIRATORY SYSTEM PHARYNX/LARYNX NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. minimal Total observations per lesion | HYPERPLASIA/HYPERTROPHY, TRANSITIONAL CELL, EPITHELIUM. minimal Total observations per lesion DEGENERATION/NECROSIS, OLFACTORY, EPITHELIUM. minimal mild moderate Total observations per lesion (10) 10 (10) 10 (10) 2 7 1 8 CARDIOVASCULAR SYSTEM HEART NO ABNORMALITY DETECTED CARDIOMYOPATHY. minimal Total observations per lesion (10) 5 5 5 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 5 5 3 7 10 (10) 10 (10) 6 6 1 1 1 7 2 10 (10) O 4 4 Company Sanitized. Does not contain TSC CB 207 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 39 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII CARDIOVASCULAR SYSTEM AORTA NO ABNORMALITY DETECTED (10) 10 LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED BONE MARROW NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 Company Sanitized. Does not contain TSCA CBI 208 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 39 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS 1 LESION INCIDE NCE (NUIMERIC ) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII ENDOCRINE SYSTEM PITUITARY GLAND NO ABNORMALITY DETECTED CYST. minimal Total observations per lesion ! (10) 10 THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. minimal mild Total observations per lesion ALTERATION, COLLOID. minimal mild moderate severe Total observations per lesion (10) 2 (10) 2 85 3 88 PARATHYROID GLANDS NO ABNORMALITY DETECTED (6) 6 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) 5 5 6 4 10 (10) 9 1 1 (10) 2 8 10 1 3 3 3 10 (7) 7 V H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 39 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII ENDOCRINE SYSTEM ADRENAL GLANDS NO ABNORMALITY DETECTED (10) 10 (10) 10 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 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 .1 The absence of a number indicates the lesion specified was not identified (S 210 ^7 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 39 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 50 250 1000 I III V VII REPRODUCTIVE SYSTEM TESTES NO ABNORMALITY DETECTED DILATATION, SEMINIFEROUS TUBULES, UNILATERAL, mild Total observations per lesion EPIDIDYMIDES NO ABNORMALITY DETECTED PROSTATE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. minimal Total observations per lesion SEMINAL VESICLES NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 9 1 1 (10) 10 CUTANEOUS SYSTEM SKIN NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 9 1 1 (10) 10 (10) 9 1 1 (10) 10 (10) 10 Company Sanitized. Does no! confain R*si 211 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 39 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII SPECIAL SENSES SYSTEM EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED OPTIC NERVE NOT PRESENT. FOLD/ROSETTE, RETINAL, minimal Total observations per lesion (10) 9 1 1 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 ompany Sanitized. Does no! contain TSCA CBl 212 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 39 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS 1 LESIOh INCIDENCE (NUIMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED NECROSIS, FOCAL. minimal Total observations per lesion INFLAMMATION, SUBACUTE/CHRONIC. minimal Total observations per lesion HYPERTROPHY, HEPATOCELLULAR. minimal Total observations per lesion FATTY CHANGE, MEDIAN CLEFT. minimal Total observations per lesion (10) 1 9 9 1 1 (10) 3 3 10 10 10 10 RESPIRATORY SYSTEM NOSE | NO ABNORMALITY DETECTED | DEGENERATION/NECROSIS, OLFACTORY, EPITHELIUM. j minimal | Total observations per lesion (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 (10) 7 3 3 Company Santtfeed. Doss no? contain TSCA C3f 213 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 39 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII ENDOCRINE SYSTEM THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR, minimal mild Total observations per lesion ALTERATION, COLLOID, minimal mild moderate severe Total observations per lesion (10) 4 5 1 6 (10) 5 3 8 2 1 3 4 10 N Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified .a M<oaD O3 0* CO u o3 214 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations 4P DuPont-4739 TABLE 39 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (3-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 50 250 1000 III V VII DIGESTIVE SYSTEM LIVER NECROSIS, FOCAL, mild moderate Total observations per lesion INFLAMMATION, SUBACUTE/CHRONIC. minimal Total observations per lesion HYPERTROPHY, HEPATOCELLULAR. minimal Total observations per lesion HYPERPLASIA, BILE DUCT, minimal Total observations per lesion FATTY CHANGE, PERIPORTAL, minimal mild Total observations per lesion FATTY CHANGE, MEDIAN CLEFT, minimal mild Total observations per lesion (5) (5) (4) (5) 2 1 1 2 534 534 34 34 1 1 1 1 2 2 pig-nre 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 conta' TSCA 215 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 39 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (3-MONTH RECOVERY EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII DIGESTIVE SYSTEM LIVER FATTY CHANGE, CENTRILOBULAR. mild Total observations per lesion (5) (5) (4) (5) 1 1 RESPIRATORY SYSTEM NOSE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. minimal Total observations per lesion (5) (5) (4) (5) 554 4 1 1 ENDOCRINE SYSTEM THYROID GLAND NO ABNORMALITY DETECTED ALTERATION, COLLOID. minimal mild moderate severe Total observations per lesion (5) (5) (4) (5) 1 4211 12 1 1 22 54 4 5 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain CB)TSCA 216 | --------------- 1l 1 1H 1O H 1 Bempany Sanitized. Does no! contain tsc a m i V. H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 DuPont-4739 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) | LESION INCIDENCE (NUMERIC) LESIONS TREATMENT (mg/kg/day) 50 250 1000 IV VI VIII DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED NECROSIS, FOCAL. minimal Total observations per lesion INFLAMMATION, SUBACUTE/CHRONIC. minimal Total observations per lesion FATTY CHANGE, MEDIAN CLEFT. minimal Total observations per lesion (10) l (10) 9 10 9 10 11 11 PANCREAS NO ABNORMALITY DETECTED ATROPHY. minimal Total observations per lesion (10) 6 4 4 ESOPHAGUS NO ABNORMALITY DETECTED (10) 9 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 1 1 10 10 1 1 (10) 10 10 2 2 GO) 10 (10) 10 217 -1 ---- ------ 1 1H 1O H ompany Sanitized. Does not contain Ter* a o*j H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 40 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) O3 g n30m LESIONS 3 o DIGESTIVE SYSTEM ra> ESOPHAGUS | LESION INCIDENCE' (NUMERIC) TREATMENT (mg/kg/day) 50 250 1000 IV VI VIII (10) (10) FIBROSIS. minimal Total observations per lesion STOMACH NO ABNORMALITY DETECTED CYST, KERATIN. minimal Total observations per lesion l l (10) 9 1 1 GO) 10 DUODENUM GO) (10) NO ABNORMALITY DETECTED 10 10 JEJUNUM (10) (10) NO ABNORMALITY DETECTED 10 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 218 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 40 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDEJSTCE (NU(MERIC ) 0 50 250 1000 II IV VI VIII DIGESTIVE SYSTEM 1 ILEUM NO ABNORMALITY DETECTED (10) 10 CECUM NO ABNORMALITY DETECTED (10) 10 COLON NO ABNORMALITY DETECTED (10) 10 RECTUM NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED (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 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 Sanitized. Does not contain TSCA CBI 219 % H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 40 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) 1 LESIONS TREATMENT (mg/kg/day) LESIOI\ INCIDE NCE (NtIMERIC ) 0 50 250 1000 II IV VI VIII 1 URINARY SYSTEM 1 KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. minimal Total observations per lesion INFLAMMATION, SUBACUTE/CHRONIC. minimal Total observations per lesion HYDRONEPHROSIS, UNILATERAL. minimal Total observations per lesion URINARY BLADDER NO ABNORMALITY DETECTED (10) 8 1 1 1 1 (10) 10 RESPIRATORY SYSTEM LUNGS NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 9 1 1 (10) 10 (10) 9 oinpany Sanitized. Does not contain TSCA CB) 220 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 40 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS 1 LESION INCIDE NCE (NU(MERIC) TREATMENT 0 50 250 1000 (mg/kg/day) II IV VI VIII RESPIRATORY SYSTEM LUNGS (10) (10) INFLAMMATION, SUBACUTE/CHRONIC. minimal Total observations per lesion 1 1 TRACHEA (10) (10) NO ABNORMALITY DETECTED 10 10 PHARYNX/LARYNX (10) (10) NO ABNORMALITY DETECTED 10 10 NOSE (10) (10) (10) (10) NO ABNORMALITY DETECTED 10 8 6 2 INFLAMMATION, SUBACUTE/CHRONIC. minimal 1 mild 1 3 Total observations per lesion 11 HYPERPLASIA/HYPERTROPHY, TRANSITIONAL CELL, EPITHELIUM. minimal 1 * a) Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 221 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations d DuPont-4739 TABLE 40 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS TREATMENT (mg/kg/day) LESIOIS INCIDI:NCE (NX.JMERIC) 0 50 250 1000 II IV VI ' VIII RESPIRATORY SYSTEM NOSE (10) (10) HYPERPLASIA/HYPERTROPHY, TRANSITIONAL CELL, EPITHELIUM. Total observations per lesion DEGENERATION/NECROSIS, OLFACTORY, EPITHELIUM. minimal mild Total observations per lesion 2 2 CARDIOVASCULAR SYSTEM HEART NO ABNORMALITY DETECTED CARDIOMYOPATHY. minimal Total observations per lesion GO) 8 2 2 AORTA NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 1 3 1 4 GO) 6 2 8 (10) 9 1 1 (10) 10 Company Sanitized. Does not contain TSCA CBi 222 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 40 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT 0 50 250 1000 (mg/kg/day) II IV VI VIII LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN (10) NO ABNORMALITY DETECTED PIGMENT INCREASED. mild Total observations per lesion 9 1 1 THYMUS 1 1 NO ABNORMALITY DETECTED (10) 10 MANDIBULAR LYMPH NODE (10) NO ABNORMALITY DETECTED 10 MESENTERIC LYMPH NODE (10) NO ABNORMALITY DETECTED 10 BONE MARROW NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 Offlpany Sanitized. Does not contain TSCA C0) 223 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations # DuPont-4739 TABLE 40 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 50 250 1000 II IV VI VIII ENDOCRINE SYSTEM PITUITARY GLAND (9) NO ABNORMALITY DETECTED 9 THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR, minimal mild Total observations per lesion ALTERATION, COLLOID, minimal mild Total observations per lesion (10) 7 (10) 5 35 35 PARATHYROID GLANDS (8) NO ABNORMALITY DETECTED 8 ADRENAL GLANDS NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 4 2 2 6 6 (10) 10 (10) 4 3 7 9 1 10 (2) 2 (10) 10 Oompmy Sanitized. Does not contain TSCA CB) 224 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) 1 1 1 1 1O 1 TREATMENT (mg/kg/day) 50 250 1000 IV VI VIII 1 1 I H1 HI 1 NERVOUS SYSTEM BRAIN NO ABNORMALITY DETECTED SPINAL CORD NO ABNORMALITY DETECTED I 1 | SCIATIC NERVE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 1 MUSCULAR AND SKELETAL SYSTEM SKELETAL MUSCLE NO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED (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 (10) 10 (10) 10 (9) 9 GO) 10 (10) 10 Offlpanjf Sanitized. Does not contain 225 Wh TJ H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations 4 DuPont-4739 TABLE 40 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS TREATMENT (mg/kg/day) LESIOh INCIDE:n c e (NtIMERIC ) 0 50 250 1000 II IV VI VIII MUSCULAR AND SKELETAL SYSTEM STERNUM NO ABNORMALITY DETECTED (10) 10 REPRODUCTIVE SYSTEM OVARIES NO ABNORMALITY DETECTED UTERUS NO ABNORMALITY DETECTED DILATATION, LUMEN. minimal mild Total observations per lesion MAMMARY GLAND (FEMALE) NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 (10) 10 (10) 7 2 1 3 (10) 10 Company Sanitized. Does not contain TSCA CBi 226 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 40 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT 0 50 250 1000 (mg/kg/day) II IV VI VIII CUTANEOUS SYSTEM SKIN NO ABNORMALITY DETECTED (10) 10 SPECIAL SENSES SYSTEM EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED OPTIC NERVE NOT PRESENT. FOLD/ROSETTE, RETINAL, minimal Total observations per lesion (10) 9 1 1 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 (10) 10 1 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations # DuPont-4739 TABLE. 40 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) w a s i U J B P 03 gQjys LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 50 250 1000 II IV VI VIII DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED NECROSIS, FOCAL, minimal Total observations per lesion INFLAMMATION, SUBACUTE/CHRONIC. minimal Total observations per lesion FATTY CHANGE, MEDIAN CLEFT, minimal mild Total observations per lesion (10) 10 10 2 1 3 (10) 1 1 1 9 9 1 1 Figure in parentheses is number of animals microscopically examined for this tissue itBII The absence of a number indicates the lesion specified was not identified 228 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 40 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) I ----------- 1 1 1 1H 1O H 1 LESION INCIDENCE (NUMERIC) 50 250 1000 IV VI VIII | DIGESTIVE SYSTEM PANCREAS NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (1) 1 (1) 1 (1) 1 ompany Sanffhed. Does no contain TSCA OR) 229 9 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 40 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 50 250 1000 II IV VI VIII DIGESTIVE SYSTEM DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED ILEUM AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (1) 1 (1) 1 (1) 1 I. Does no! contain TSC CJ 230 1-- -- - i 1 I1 1H 1O H 1 S*nptJf Sanitized. Does not contain TSCA CBt %~ H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_________________________ # DuPont-4739 TABLE 40 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC)| TREATMENT (mg/kg/day) 50 250 1000 IV VI VIII DIGESTIVE SYSTEM CECUM AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. COLON AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED: RECTUM NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (1) 1 (1) 1 (1) 11 231 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_______________________________________________________ DuPont-4739 TABLE 40 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT 0 50 250 1000 (mg/kg/day) > II IV VI VIII DIGESTIVE SYSTEM SALIVARY GLANDS NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (1) 1 Company Sanitized. Does not contain TSCAcal 232 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations________________________________________________ DuPont-4739 TABLE 40 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) I LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 50 250 1000 II IV VI VIII URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED URINARY BLADDER NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (1) 1 (1) 1 SanHIzed Does not contain TSCA CBf 233 1- - - l 1 1 1 1H 1O H 1 no! coniato TSCACB) H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 40 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 50 250 1000 IV VI VIII RESPIRATORY SYSTEM LUNGS NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED i PHARYNX/LARYNX NO ABNORMALITY DETECTED C S Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (1) 1 (1) 1 (1) 1 o uS> 234 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations I DuPont-4739 TABLE 40 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 50 250 1000 II IV VI VIII RESPIRATORY SYSTEM NOSE NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 Company Sanitized. Does not contain TSC CBI 235 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 40 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 50 250 1000 II IV VI VIII CARDIOVASCULAR SYSTEM HEART NO ABNORMALITY DETECTED AORTA . NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (1) 1 (1) 1 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 40 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS- NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 50 250 1000 II IV VI VIII LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (1) 1 (1) 1 (1) 1 Company Sanitized. Does not contain T so a a> 237 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 40 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT 0 50 250 1000 (mg/kg/day) II IV VI VIII LYMPHATIC AND HEMATOPOIETIC SYSTEM MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED BONE MARROW NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 40 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS i LESION INC IDENCE (NL(MERIC ) 1 TREATMENT | (mg/kg/day) 1 0 II 50 250 1000 IV VI VIII 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 Total observations per lesion AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. (10) 4 6 6 (1) 1 (10) 2 4 i 5 5 1 1 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 Company Sanitized. Does not contain TSG C9H 239 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 40 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT 0 50 250 1000 (mg/kg/day) II IV VI VIII ENDOCRINE SYSTEM PARATHYROID GLANDS NO ABNORMALITY DETECTED ADRENAL GLANDS 1 NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (1) 1 (1) 1 Company SanHIzed. Does no! contain TSCA CB) 240 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 50 250 1000 II IV VI VIII NERVOUS SYSTEM SPINAL CORD NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 1 (1) 1 (1) 1 3 aI I. Does not contain TSCA CB) 241 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 40 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 50 250 1000 II IV VI VIII MUSCULAR AND SKELETAL SYSTEM SKELETAL MUSCLE . NO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (1 ) 1 (1 ) 1 (1 ) 1 Sanitized. Does not contain TSCA CBl 242 * ........ #' .. H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_______ DuPont-4739 TABLE 40 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT 0 1 50 (mg/kg/day) 1 II 1 iv 250 1000 VI VIII REPRODUCTIVE SYSTEM OVARIES NO ABNORMALITY DETECTED UTERUS NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (1) 1 (1 ) 1 Does no coirtaln TSCA CBI 243 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABL 40 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 50 250 1000 II IV V! VIII SPECIAL SENSES SYSTEM EYE(S ) WITH OPTIC NERVE AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Sanitized. Does not contain TSCA CBI 244 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations i DuPont-4739 TABLE 40 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (3-MONTH RECOVERY EVALUATION) LESIONS I LESION INCIDENCE (NUMERIC)| TREATMENT 0 50 250 1000 (mg/kg/day) II IV VI VIII DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. minimal Total observations per lesion FATTY CHANGE, MEDIAN CLEFT, minimal mild Total observations per lesion FATTY CHANGE, FOCAL. mild Total observations per lesion (5) (5) (5) (5) 2 12 3435 3435 11 1 12 1 1 RESPIRATORY SYSTEM NOSE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. minimal Total observations per lesion (5) (5) (5) (5) 55 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified ogffipany Sanitized. Does not contain TSCA CBI 245 1----- 1 1 1 1H 1O H 1 Sanitized. Does not contain TSCA CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 40 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (3-MONTH RECOVERY EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 50 250 1000 IV VI VIII RESPIRATORY SYSTEM NOSE (5) (5) (5) (5) ATROPHY, UNILATERAL, NASAL GLANDS. severe Total observations per lesion 1 1 ENDOCRINE SYSTEM THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. minimal Total observations per lesion ALTERATION, COLLOID. minimal mild Total observations per lesion (5) (5) (5) (5) 2 12 1 1 354z 1 354 3 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 246 # H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 * DuPont-4739 MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED- NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) | LESION INCIDENCE (NUMERIC) LESIONS TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC. HYPERTROPHY, HEPATOCELLULAR. 1 (10) (10) (10) (10) 641094 641149 641081 641157 641172 641198 641069 641055 641061 641067 641070 641056 641089 641077 641147 641073 641102 641086 641149 641081 641134 641095 641155 641144 641137 641097 641172 641146 641162 641132 641206 641178 641190 641157 641214 641198 641197 641166 641222 641218 641200 641201 641224 641202 641223 641081 641061 641067 641089 641077 641102 641086 641134 641095 641137 641097 641162 641132 641190 641157 641197 641166 641200 641201 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Sanitized. Does not contain TSCA CBt 247 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS DIGESTIVE SYSTEM LIVER HYPERTROPHY, HEPATOCELLULAR HYPERPLASIA, BILE DUCT. FATTY CHANGE, PERIPORTAL. FATTY CHANGE, MEDIAN CLEFT. FATTY CHANGE, CENTRILOBULAR | LESION INCIDENCE (NUMERIC)| TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII (10) 641172 ( 10) 641081 641144 641198 641224 641218 (10) 641202 641200 641200 (10) 641223 641201 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 051 248 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS DIGESTIVE SYSTEM | TREATMENT | (mg/kg/day) 1 LESION INCIDENCE (NUMERIC) 0 50 250 1000 I III V VII PANCREAS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. ATROPHY. (10) 641069 641094 641147 641155 641172 641222 641070 641149 641206 641214 641214 (10) 641067 641077 641095 641132 641157 641166 641201 641223 641086 641097 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified @mpany Sanitized. Does not contain TSCA OR) 249 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS DIGESTIVE SYSTEM ESOPHAGUS NO ABNORMALITY DETECTED FIBROSIS. TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 I 50 250 I 1 I III V 1000 VII (10) 641069 641070 641094 641147 641149 641155 641206 641214 641222 641172 ( 10) 641067 641077 641086 641095 641097 641132 641157 641201 641223 641166 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. Doss not contain T s r a m s 250 H-24616: Subchronic Toxicity DuPont-4739 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations------------------------------------------------------------------ ------------------ ------------------------- TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII DIGESTIVE SYSTEM STOMACH NO ABNORMALITY DETECTED (10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222 (10) 641067 641077 641086 641095 641097 641132 641157 641166 641201 641223 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified empany Sanitized. Does not contain ''* 251 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations * DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII DIGESTIVE SYSTEM DUODENUM NO ABNORMALITY DETECTED (10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222 (10) 641U 6 / 641077 641086 641095 641097 641132 641157 641166 641201 641223 .a a Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified S 8 252 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) DIGESTIVE SYSTEM TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 50 250 1000 I III V VII JEJUNUM NO ABNORMALITY DETECTED (10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222 (10) 641067 641077 641086 641095 641097 641132 641157 641166 641201 641223 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 253 O' H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII DIGESTIVE SYSTEM ILEUM NO ABNORMALITY DETECTED (10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222 (10) 641067 641077 641086 641095 641097 641132 641157 641166 641201 641223 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Sanitized. Dees not contain TSC CB& 254 9% ........ H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations * DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 50 250 1000 > I III V VII DIGESTIVE SYSTEM CECUM NO ABNORMALITY DETECTED (10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222 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 (10) 641067 641077 641086 641095 641097 641132 641157 641166 641201 641223 Sanitized. Does not contain TSA C6 255 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII DIGESTIVE SYSTEM COLON NO ABNORMALITY DETECTED (10) 641069 641070 641094 (10) 641067 641077 641086 641147 641095 641149 641155 641172 641097 641132 641157 641206 641166 i=s 641214 641222 641201 641223 QN(D, o Figure in parentheses is number of animals microscopically examined for this tissue g The absence of a number indicates the lesion specified was not identified OC3O Q> 3" >oCO o(9 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 50 250 1000 I III V VII DIGESTIVE SYSTEM RECTUM NO ABNORMALITY DETECTED (10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222 (10) 641067 641077 641086 641095 641097 641132 641157 641166 641201 641223 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-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII DIGESTIVE SYSTEM SALIVARY GLANDS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. (10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222 (10) 641067 641077 641086 641095 641097 641157 641166 641201 641223 641132 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 fr. H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS I LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. (10) 641069 641155 641172 641214 641222 641070 641147 641149 641206 INFLAMMATION, SUBACUTE/CHRONIC. 641094 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 (10) 641086 641132 641166 641201 641223 641067 641077 641095 641097 641157 Company Sanitized. Does not contain TSCA CBI 259 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS URINARY SYSTEM | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII URINARY BLADDER NO ABNORMALITY DETECTED (10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222 (10) 641067 641077 641086 641095 641097 641132 641157 641166 641201 641223 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 CB!TSCA 260 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS RESPIRATORY SYSTEM | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII LUNGS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. (10) 641094 641147 641149 641214 641222 641069 641070 641155 641172 641206 (10) 641077 641086 641132 641157 641166 641223 641067 641095 641097 641201 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) 261 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII RESPIRATORY SYSTEM TRACHEA NO ABNORMALITY DETECTED 1 (10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222 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) 641067 641077 641086 641095 641097 641132 641157 641166 641201 641223 Company Sanitized. Does not contain TSCA Cl1}) 262 m) ' H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII RESPIRATORY SYSTEM PHARYNX/LARYNX NO ABNORMALITY DETECTED (10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222 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 (10) 641067 641077 641086 641095 641097 641132 641157 641166 641201 641223 Company Sanitized. Does not contain TSCA CBI 263 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____ DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 50 250 1000 I III V VII RESPIRATORY SYSTEM NOSE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. HYPERPLASIA/HYPERTROPHY, TRANSITIONAL CELL, EPITHELIUM. DEGENERATION/NECROSIS, OLFACTORY, EPITHELIUM. (10) (10) (10) GO) 641069 641178 641070 641198 641094 641147 641149 641155 641172 641206 641214 641222 641089 641067 641102 641086 641162 641095 641190 641132 641202 641157 641201 641201 641055 641061 641067 641056 641089 641077 641073 641102 641086 641081 641134 641095 641144 641137 641097 Pignre 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-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 50 250 1000 I III V VII RESPIRATORY SYSTEM NOSE DEGENERATION/NECROSIS, OLFACTORY, EPITHELIUM. (10) (10) (10) (10) 641146 641162 641132 641218 641190 641157 641224 641197 641166 641200 641201 641202 641223 ______ ______ 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 eontaln TSCA C& 265 Vt H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_______________________________ # DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS CARDIOVASCULAR SYSTEM | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII HEART NO ABNORMALITY DETECTED (10) 641070 641094 641155 641172 641222 CARDIOMYOPATHY. 641069 641147 641149 641206 641214 ! 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) 641086 641097 641157 641166 641201 641223 641067 641077 641095 641132 Sanitized. Does not contain TSCA CBl 266 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations * DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 50 250 1000 I III V VII CARDIOVASCULAR SYSTEM AORTA NO ABNORMALITY DETECTED 1 (10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222 1i 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) 641067 641077 641086 641095 641097 641132 641157 641166 641201 641223 -- Does to?eonaln TSC CBI 267 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED- NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM | LESION INCIDENCE (NUMERIC) TREATMENT 0 1 50 250 1000 (mg/kg/day) 1 I 1 III V VII SPLEEN NO ABNORMALITY DETECTED (10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222 (10) 641067 641077 641086 641095 641097 641132 641157 641166 641201 641223 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified <3npany Sanitized. Does not contain TSCA c?*) 268 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V ' VII THYMUS NO ABNORMALITY DETECTED (10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222 (10) 641067 641077 641086 641095 641097 641132 641157 641166 641201 641223 Figure in. parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Sanitized. D ees nei eentaln TSCA CBI 269 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII LYMPHATIC AND HEMATOPOIETIC SYSTEM MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED (10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222 (10) 641067 641077 641086 641095 641097 641132 641157 641166 641201 641223 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 CBS 270 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED i (10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222 (10) 641067 641077 641086 641095 641097 641132 641157 641166 641201 641223 a Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified I.Does not contain TSCA O 3 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII BONE MARROW NO ABNORMALITY DETECTED (10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222 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 (10) 641067 641077 641086 641095 641097 641132 641157 641166 641201 641223 Company Sanitized. Does not contain TSCA Ci 272 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 50 250 1000 I III V VII ENDOCRINE SYSTEM PITUITARY GLAND NO ABNORMALITY DETECTED CYST. (10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222 (10) 641067 641077 641095 641097 641132 641157 641166 641201 641223 641086 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Sanitized. Dees not contain TSCA nRl 273 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS ENDOCRINE SYSTEM THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. ALTERATION, COLLOID. | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII 1 (10) (10) (10) (10) 641069 641218 641070 641224 641102 641067 641137 641077 641162 641086 641197 641095 641202 641097 641132 641157 641166 641201 641223 641094 641055 641061 641067 641147 641056 641089 641077 641149 641073 641102 641086 641155 641081 641134 641095 641172 641144 641137 641097 641206 641146 641162 641132 641214 641178 641190 641157 641222 641198 641197 641166 641200 641201 641202 641223 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified .emponjr Sanitized. Does not contain TSCA CB 274 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII ENDOCRINE SYSTEM PARATHYROID GLANDS NO ABNORMALITY DETECTED (6) 641070 641147 641172 641206 641214 641222 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 (7) 641067 641077 641095 641132 641157 641166 641201 ______ _______ Company Sanftfeed. Does not contain TSCA CBt 275 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII ENDOCRINE SYSTEM ADRENAL GLANDS NO ABNORMALITY DETECTED (10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222 (10) 6410b / 641077 641086 641095 641097 641132 641157 641166 641201 641223 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 CBl 276 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS NERVOUS SYSTEM | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII RRAIN NO ABNORMALITY DETECTED (10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222 (10) 641067 641077 641086 641095 641097 641132 641157 641166 641201 641223 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (Dompany Sanitized. Dees not contain TSCA CBI 277 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS NERVOUS SYSTEM TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 50 250 1000 I III V VII SPINAL CORD NO ABNORMALITY DETECTED (10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222 (10) 64106 / 641077 641086 641095 641097 641132 641157 641166 641201 641223 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Sanitized. Bees net contain TS S, 278 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS NERVOUS SYSTEM | LESION INCIDENCE (NUMERIC) 1 TREATMENT | (mg/kg/day) 1 0 I 50 | 250 1 III | V 1000 VII SCIATIC NERVE NO ABNORMALITY DETECTED (10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222 (10) 64106 / 641077 641086 641095 641097 641132 641157 641166 641201 641223 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-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII MUSCULAR AND SKELETAL SYSTEM SKELETAL MUSCLE NO ABNORMALITY DETECTED (10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222 (10) 641067 641077 641086 641095 641097 641132 641157 641166 641201 641223 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. Doea not contain TSCA CBI 280 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII MUSCULAR AND SKELETAL SYSTEM FEMUR/KNEE JOINT NO ABNORMALITY DETECTED (10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222 GO) 641067 641077 641086 641095 641097 641132 641157 641166 641201 641223 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-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS MUSCULAR AND SKELETAL SYSTEM TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 50 250 1000 I III V VII STERNUM NO ABNORMALITY DETECTED (10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222 (10) 641067 641077 641086 641095 641097 641132 641157 641166 641201 641223 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-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII REPRODUCTIVE SYSTEM TESTES NO ABNORMALITY DETECTED DILATATION, SEMINIFEROUS TUBULES, UNILATERAL. (10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222 (10) 641067 641077 641086 641095 641097 641132 641157 641166 641201 641223 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Sanitized. Does not contain t s o p 283 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS REPRODUCTIVE SYSTEM TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 50 250 1000 I III V ' VII EPIDIDYMIDES NO ABNORMALITY DETECTED (10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222 (10) 641067 641077 641086 641095 641097 641132 641157 641166 641201 641223 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Sanitized. Does not contain TSCA CBI 284 9 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII REPRODUCTIVE SYSTEM PROSTATE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. (10) 641069 641094 641147 641149 641155 641172 641206 641214 641222 641070 (10) 641067 641077 641086 641095 641097 641132 641166 641201 641223 641157 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Gompany Sanitized. Does not contain TSCA CB! 285 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS REPRODUCTIVE SYSTEM TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 50 250 1000 I III V VII SEMINAL VESICLES NO ABNORMALITY DETECTED (10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222 (10) 641U6/ 641077 641086 641095 641097 641132 641157 641166 641201 641223 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified . Does not contain TSCA CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII CUTANEOUS SYSTEM SKIN NO ABNORMALITY DETECTED (10) 641069 641070 641094 641147 641149 641155 641172 641206 641214 641222 (10) 641067 641077 641086 641095 641097 641132 641157 641166 641201 641223 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-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII SPECIAL SENSES SYSTEM EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED OPTIC NERVE NOT PRESENT. FOLD/ROSETTE, RETINAL. (10) 641069 641070 641094 641147 641149 641155 641206 641214 641222 641069 641172 (10) 641067 641077 641086 641095 641097 641132 641157 641166 641201 641223 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified ompany Sanitized. Does not contain TSCA CBI 288 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_________________________ DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDENCE (NUMERIC) LESIONS TREATMENT (mg/kg/day) 0 I 50 250 1000 , III V VII DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC. HYPERTROPHY, HEPATOCELLULAR. (10) 641083 641084 641085 641101 641105 641123 641154 641159 641165 641215 1 (10) 641189 641203 641213 641064 641092 641143 641153 641167 641185 641189 641203 641213 641216 641064 641092 641143 641153 641167 641185 641189 641203 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-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________________________________________________________ DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS DIGESTIVE SYSTEM TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 50 250 1000 I III V VII LIVER HYPERTROPHY, HEPATOCELLULAR. FATTY CHANGE, MEDIAN CLEFT. (10) 641159 (10) 641213 641216 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 eontatft 6rM 290 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations , DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS RESPIRATORY SYSTEM | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 HI V VII NOSE NO ABNORMALITY DETECTED DEGENERATION/NECROSIS, OLFACTORY, EPITHELIUM. GO) 641083 641084 641085 641101 641105 641123 641154 641159 641165 641215 (10) 641092 641153 641185 641189 641203 641213 641216 641064 641143 641167 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 291 t) 9 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS ENDOCRINE SYSTEM TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 50 250 1000 I III V VII THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. (10) 641083 641084 641165 641215 ALTERATION, COLLOID. 641085 641101 641105 641123 641154 641159 Figure m parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 641064 641092 641153 641167 641185 641189 641203 641216 641064 641092 641143 641153 641167 641185 641189 641203 641213 641216 Sanitized. Does not contain TSCA CBI 292 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (3-MONTH RECOVERY EVALUATION) LESIONS DIGESTIVE SYSTEM LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 1I 50 250 1000 III V VII LIVER NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC. HYPERTROPHY, HEPATOCELLULAR. HYPERPLASIA, BILE DUCT. FATTY CHANGE, PERIPORTAL. FATTY CHANGE, MEDIAN CLEFT. FATTY CHANGE, CENTRILOBULAR. (5) (5) (4) (5) 641113 641169 641196 641066 641059 641141 641057 641098 641113 641148 641130 641104 641160 641187 641169 641115 641194 641196 641220 641225 641076 641130 641141 641169 641148 641196 641205 641113 641115 641113 641205 641098 641059 641113 641205 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Oinpany Sanitized. Does not contain TSCA CBI 293 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations________________ DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED- NEOPLASTIC AND NON-NEOPLASTIC LESIONS (3-MONTH RECOVERY EVALUATION) LESIONS RESPIRATORY SYSTEM | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 * III V VII NOSE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. (5) (5) (4) (5) 641066 641059 641076 641057 641098 641113 641141 641130 641104 641160 641148 641169 641115 641194 641187 641196 641220 641225 641205 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified aSompanySanitized. Does not contain TSCA CBI 294 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________________________________________________________ DuPont-4739 TABLE 41 (CONTINUED) MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTEDNEOPLASTIC AND NON-NEOPLASTIC LESIONS (3-MONTH RECOVERY EVALUATION) LESIONS ENDOCRINE SYSTEM | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 50 250 1000 III V VII THYROID GLAND NO ABNORMALITY DETECTED ALTERATION, COLLOID. (5) (5) (4) (5) 641194 641066 641059 641076 641057 641098 641113 641141 641130 641104 641160 641148 641169 641115 641225 641187 641196 641220 641205 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Qkmpany Sanitized. Does not contain TSCA CBI 295