Document Lpk7385J7vV0DxM8w9XJozmOw

AR226-3197 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations________ ______________DuPont-5386 TRADE SECRET Study Title H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations Volume 1 of 5 Laboratory Project ID: DuPont-5386 T e s t G u id e l in e s : U.S. EPA Health Effects Test Guidelines OPPTS 870.3100(1998) A u t h o r : Gregory S. Ladies, Ph.D., D.A.B.T. S t u d y C o m p l e t e d o n : December 3, 2001 P e r f o r m in g L a b o r a t o r y : E.I. du Pont de Nemours and Company Haskell Laboratory for Toxicology and Industrial Medicine Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050 W o r k R e q u e s t N u m b e r :| M S ervice C o d e N um be Sponsor Study N um ber: wspi Samfes. D@as s t TS CS! Page 1 of 1500 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT This study was conducted in compliance with U.S. EPA TSCA (40 CFR part 792) Good Laboratory Practice Standards except for the item documented below. The item listed does not impact the validity o f the study. Test substance characterization and stability analyses were performed at Regional Analytical Services (RAS), a non-GLP laboratory. The test substance analyses performed were in compliance with regulatory guidelines. None of the aforementioned analyses were performed under Good Laboratory Practice Standards; however, the analyses were conducted in compliance with IS09002 regulations. All of the analyses are considered valid and sufficient for the purposes of this study. Applicant / Sponsor: E.I. du Pont de Nemours and Company Wilmington, Delaware 19898 U.S.A. Study Director: Gregory S. Ladies, Ph.D., D.A.B.T. Senior Research Scientist 3 ~ ) e c ~ -3o 1 Date Applicant / Sponsor:____________________________ ___________ __________ DuPont Representative Date S a u t e d . O w * not contain TSCA CS1 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations . QUALITY ASSURANCE STATEMENT Haskell Sample Number(s): 24516 DuPont-5386 Dates o f Inspections: Protocol: December 5, 2000 Conduct: January 15,30, 2001; February 13,14,28, 2001; March 1,8,13,26,29, 2001; April 25, 2001 Records, Reports: June 19,29, 2001; July 2-3,9,2001; August 8-10,13-17,20-24,27-31, 2001; September 4-9,17-21,23-28, 2001; October 15-19,22-27, 2001 Dates Findings Reported to: Study Director: January 15, 2001; March 1,14, 2001; July 5,6,13,9, 2001; August 29, 2001; September 25,27, 2001; October 23,27, 2001 Management: February 6, 2001; March 5,14, 2001; July 5,6,13, 2001; August 29, 2001; September 27, 2001; October 17,23, 2001; November 18, 2001 Reported by: frtlJM AJ^15.1dLblULS (JKimberly B. Brebner Quality Assurance Auditor Date 3 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 CERTIFICATION We, the undersigned, declare that this report provides an accurate evaluation o f data obtained from this study. Analytical Evaluations Reported by: Neurobehavioral Evaluations Reported by: Clinical Pathology Biochemical Evaluations Reported by: Reproductive Evaluations Reported by: Pathological Evaluations Reported by: Pathological Evaluations Peer Review Reported by: Approved b. * Janet C. Maslanka, B.S. Staff Scientist Linda A. Malley, Ph.D., D.AB.T. Senior Research Scientist Nancy E. Everds, tf.V.M. Diplomate A.C.V.P. .o. Principal Research Scientist U r^ ? ________ John C. O'Connor, M.S. Research Scientist Ichreest, Ph.I ^search Scientist A G. T ry Makdvec, 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 Judith C. Stadler, Ph.D., D.AB.T. Director, General Toxicology J - 2-Oe ! Date - Joe/ Date 3 - eC -fO Date 3 - - 3-l 3 - Dac - 2O oI Date o\ Date J - - e c ' O / Date 3-h& l-2c>of Date Issued by Study Director: Senior Research Scientist 3~>& c-3.o I Date Company Sanitized. Dees not contain TSCA CBS 4 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE OF CONTENTS DuPont-5386 Page GOOD LABORATORY PRACTICE COMPLIANCE STA TEM EN T.......................................................................... 2 QUALITY ASSURANCE STA TEM EN T.................................................................................................................................3 CER TIFIC A TIO N ...................................................................................................................................................................... 4 LIST OF TABLES............................................................................................................................................................................7 LIST OF FIGURES......................................................................................................................................................................... 9 LIST OF APPENDICES.................................................................................................................................................................9 STUDY PERSONNEL..................................................................................................................................................................13 S U M M A R Y ..................................................................................................................................................................................... 14 I N T R O D U C T IO N ........................................................................................................... O BJEC TIV E.................................................................................................................................................................................... 18 MATERIALS AND M E TH O D S................................................................................................................................................18 A. Test Guidelines.................................................................................................................................................................*8 B. Test Substance.................................................................................................................................................................. C. Test Species....................,................................................................................................................................................ D. Animal Husbandry........................................................................................................................................................... *9 E. Quarantine and Pretest Period....................................................................................................................................... 20 F. Study D esign..................................................................................................................................................................... 21 G. Assignment to Groups and Study Start........................................................................................................................ 22 H. Dose Suspension Preparation........................................................................................................................................ 22 I. Test Substance Administration and Sampling............................................................................................................23 J. Analytical M ethods......................................................................................................................................................... 24 K. Body Weights.................................................................................................................................................................... 26 ) ) L. Food Consumption and Food Efficiency..................................................................................................................... 26 M. Detailed Clinical Observations and Mortality............................................................................................................ 26 N. Ophthalmological Evaluations...................................................................................................................................... 27 O. Neurotoxicity Evaluations.............................................................................................................................................. 27 P. Clinical Pathology............................................................................................................................................................28 Q. Collection o f Blood, Urine, and Feces (Three-Month R ecovery)..........................................................................30 R. Anatomic Pathology - Rats Designated for Subchronic Toxicity and Recovery................................................30 S. Reproductive Assessment............................................................................................................................................. -32 T. Anatomical Pathology - Rats Designated for Reproductive Evaluations............................................................. 34 U. Biochemical Measurements............................................................................................................................................ 35 V. Statistical Analyses.......................................................................................................................................................... RECORDS AND SAM PLE STO R A G E................................................................................................................................. 38 RESULTS AND DISC U SSIO N ................................................................... 39 ANALYTICAL EV A LU A TIO N S............................................................................................................................................. 40 A. Test Substance Stability................................................................................................................................................. 4 B. Chromatography........................................................................................................... ;.............................................. 4^ C. Homogeneity, Concentration Verification and Stability Samples for Initial Mixing Procedures and Concentrations Based on Dose Volume o f 10 mL/kg (Test Day 0 to Test Day 4 1 ).......................................... 40 D. Mixing and Stability Study for Change in Frequency o f Dosing Preparation (2 times/week) and Dose Volume Change (5 mL/Kg to 7.5 m L/K g)...................................................................................................... 41 E. Homogeneity and Concentration Verification Samples for Final Mixing Procedures and Concentration Change Based on Dose Volume o f 7.5 mg/kg (Test Day 4 2 ).................................................................................. 43 F. Analytical Conclusions.................................................................................................................................................... 44 Sanitized. D@@snot @rtaim TS6A CBi 5 H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE OF CONTENTS (CONTINUED) SUBCHRONIC TOXICITY EVALUATIONS............................................. IN-LIFE TO XICO LO G Y ................................................................................... . A. Dosage Data.............................................................................................. 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........................................................... .45 .45 .45 ..45 ..46 ..47 ...48 NEUROBEHAVIORAL TOXICOLOGY...................................................... A. Sensory Function Evaluations............................................................... B. Motor Activity.......................................................................................... C. Neurobehavioral Toxicity Conclusions............................................... ..48 ..48 .48 .49 CLINICAL PA TH O L O G Y ....................................................................................................................................................... 50 A. Hematology/Coagulation.......................................................................................... ..50 B. Clinical Chemistry..................................................................................................... ..51 C. Urinalysis.................................................................................................................... ..53 D. Plasma and Urine Fluoride Measurements........................................................... ...54 E. Clinical Pathology Conclusions............................................................................. ...55 ANATOMICAL PA TH O L O G Y ......................................................................................... A. Subchronic Toxicity and Recovery........................................................................ ..56 ...56 REPRODUCTIVE TOXICOLOGY EVALUATIO NS...................................................................................................... 61 REPRODUCTIVE FUNCTION................................................................................................................................................ 61 A. P) Generation.................................................................................... 61 B. Offspring Data...................................................................................................................................................................62 C. Fi Generation....................................................................................................................................................................62 D. Reproductive Function Conclusions.......................................................... 63 REPRODUCTIVE TOXICOLOGY EVALUATIONS ANATOM ICAL PA TH O L O G Y ..................................... 64 A. Organ Weight D a ta ......................................................................................................................................................... 64 B. Gross Observations.............................................................................................. 64 C. Microscopic Observations..............................................................................................................................................64 D. Mortality.............................................................................................................................................................................65 E. Anatomical Pathology Conclusions for Reproductive T oxicity.......................................................................... 65 BIOCHEM ICAL M E A SU R EM EN TS....................................................................................................................................66 A. Biochemical Measurements............................................................................................................................................66 B. Biochemical Measurements Conclusions....................................................................................................................66 CONCLUSIONS- .67 REFERENCES ... .69 T A B L E S............... .72 FIG U R E S............. .471 A P PE N D IC E S.... .482 lei 6 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 LIST OF TABLES Page TABLE 1 SUMMARY OF DOSING ANALYSES.................................................................................................................76 TABLE 2 MEAN DAILY DOSE VOLUMES FOR MALE RATS..................................................................................... 79 TABLE 3 MEAN DAILY DOSE VOLUMES FOR FEMALE R A TS................................................................................80 TABLE 4 MEAN BODY WEIGHTS OF MALE RATS........................................................................................................81 TABLE 5 MEAN BODY WEIGHTS OF FEMALE R A TS..................................................................................................84 TABLE 6 MEAN BODY WEIGHT GAINS OF MALE R A TS...........................................................................................87 TABLE 7 MEAN BODY WEIGHT GAINS OF FEMALE R A T S..................................................................................... 90 TABLE 8 MEAN DAILY FOOD CONSUMPTION OF MALE R A T S .............................................................................93 TABLE 9 MEAN DAILY FOOD CONSUMPTION BY FEMALE R A T S .......................................................................96 TABLE 10 MEAN DAILY FOOD EFFICIENCY OF MALE R A TS.................................................................................. 99 TABLE 11 MEAN DAILY FOOD EFFICIENCY OF FEMALE R A T S .......................................................................... 102 TABLE 12 SUMMARY OF CLINICAL OBSERVATIONS FOR MALE R A T S.......................................................... 105 TABLE 13 SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS......................................................114 TABLE 14 SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR MALE R A T S ............................... 121 TABLE 15 SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR FEMALE RATS.......................... 122 TABLE 16 PERCENT SURVIVAL OF MALE RATS........................................................................................................123 TABLE 17 PERCENT SURVIVAL OF FEMALE R A T S .................................................................................................. 124 TABLE 18 MEAN FORELIMB AND HINDLIMB GRIP STRENGTH FOR MALE R A T S ......................................125 TABLE 19 MEAN FORELIMB AND HINDLIMB GRIP STRENGTH FOR FEMALE RATS................................. 126 TABLE 20 SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR MALE RATS 127 TABLE 21 SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR FEMALE R A TS.. 129 TABLE 22 MOTOR ACTIVITY ASSESSMENT: DURATION OF MOVEMENTS FOR MALE RATS..............131 TABLE 23 MOTOR ACTIVITY ASSESSMENT: DURATION OF MOVEMENTS FOR FEMALE RATS........ 132 TABLE 24 MOTOR ACTIVITY ASSESSMENT: NUMBER OF MOVEMENTS FOR MALE R A T S.................. 133 TABLE 25 MOTOR ACTIVITY ASSESSMENT: NUMBER OF MOVEMENTS FOR FEMALE RATS.............134 TABLE 26 SUMMARY OF HEMATOLOGY VALUES FOR MALE R A TS...............................................................135 TABLE 27 SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS......................................................... 139 TABLE 28 SUMMARY OF COAGULATION VALUES FOR MALE R A T S ..............................................................143 TABLE 29 SUMMARY OF COAGULATION VALUES FOR FEMALE RATS......................................................... 143 TABLE 30 SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE R A TS....................... 144 TABLE 31 SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE R A T S ................. 148 TABLE 32 SUMMARY OF URINALYSIS VALUES FOR MALE RATS.................................................................... 152 TABLE 33 SUMMARY OF URINALYSIS VALUES FOR FEMALE RATS...............................................................154 TABLE 34 SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITY IN MALE R A T S........................ 156 TABLE 35 SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITY IN FEMALE RATS....................157 TABLE 36 MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE R A TS...................................................... 158 TABLE 37 MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (90-DAY EXPOSURE EVALUATION)............................................................................................................ 166 Company Sanitised. Does 1 TSCA CBI 7 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 LIST OF TABLES (CONTINUED) Page TABLE 38 INCIDENCES OF GROSS OBSERVATIONS EN MALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION)...................................................................................................................174 TABLE 39 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION).................................................................................................................... 191 TABLE 40 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS - NEOPLASTIC AND NON NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION).......................... -............................................207 TABLE 41 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS - NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION).........................................................................231 TABLE 42 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION).........................................................................258 TABLE 43 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION).........................................................................287 TABLE 44 MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED- NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION).............................318 TABLE 45 MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED- NEOPLASTIC AND NON-NEOPLASTIC (90-DAY EXPOSURE EVALUATION ' INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION)..............................374 TABLE 46 MEAN BODY WEIGHTS AND MEAN BODY WEIGHT GAINS OF Pi MALE R A T S.....................434 TABLE 47 MEAN BODY WEIGHTS AND MEAN BODY WEIGHT GAINS OF P, FEMALE RATS DURING GESTATION.......... .............................................................................................................................. 435 TABLE 48 MEAN BODY WEIGHTS AND MEAN BODY WEIGHT GAINS OF Pi FEMALE RATS DURING LACTATION..........................................................................................................................................436 TABLE 49 MEAN DAILY FOOD CONSUMPTION AND MEAN FOOD EFFICIENCY OF Pi FEMALE RATS DURING GESTATION..........................................................................................................................................437 TABLE 50 SUMMARY OF CLINICAL OBSERVATIONS IN P, R A T S ...................................................................... 438 TABLE 51 MEAN ESTROUS CYCLE PARAMETERS AND PRECOITAL INTERVAL IN P, FEMALE RATS440 TABLE 52 SUMMARY OF SPERM PARAMETERS IN P, MALE R A T S ...................................................................441 TABLE 53 SUMMARY OF REPRODUCTIVE INDICES: P, GENERATION............................................................. 442 TABLE 54 MEAN PUP NUMBERS AND SURVIVAL: F, GENERATION............................................................... 443 TABLE 55 MEAN PUP WEIGHTS: Fi GENERATION..................................................................................................... 444 TABLE 56 SUMMARY OF PUP CLINICAL OBSERVATIONS: F, GENERATION.................................................445 TABLE 57 MEAN BODY WEIGHTS AND MEAN BODY WEIGHT GAINS OF F, MALE R A T S..................... 446 TABLE 58 MEAN BODY WEIGHTS AND MEAN BODY WEIGHT GAINS OF F, FEMALE RATS.................447 TABLE 59 SUMMARY OF CLINICAL OBSERVATIONS IN F, R A T S................. i.................................................. 448 TABLE 60 SUMMARY OF DEVELOPMENTAL LANDMARKS IN F, R A T S.........................................................449 TABLE 61 MEAN FINAL BODY AND ORGAN WEIGHTS FROM MALE RATS - P, A D U L TS........................450 TABLE 62 MEAN FINAL BODY AND ORGAN WEIGHTS FROM FEMALE RATS - Pt ADULTS................... 451 TABLE 63 MEAN FINAL BODY AND ORGAN WEIGHTS FROM MALE RATS - F, A D U L TS........................452 gWipamf SariRtnd. P n8naln T S m CBf 8 H-24516: Subchronic Toxicity LIST OF TABLES (CONTINUED) Page TABLE 64 MEAN FINAL BODY AND ORGAN WEIGHTS FROM FEMALE RATS - Fj ADULTS................. 456 TABLE 65 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS - P, ADULTS..................................... 459 TABLE 66 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS - P, A D U L T S................................460 TABLE 67 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS - F! PUPS............................................. 461 TABLE 68 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS - F, P U PS........................................462 TABLE 69 INCIDENCES OF GROSS OBSERVATIONS IN RATS - F, UNSEXABLE P U P S .............................463 TABLE 70 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS - F, WEANLINGS............................ 464 TABLE 71 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS - F, WEANLINGS........................465 TABLE 72 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS - F! A D ULTS..................................... 466 TABLE 73 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS - F, A D U L T S................................467 TABLE 74 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE REPRODUCTION RATS - P, ADULTS........................................................................................................... 468 TABLE 75 INCIDENCES A ND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE REPRODUCTION RATS - P, ADULTS........................................................................................................... 469 LIST OF FIGURES Page FIGURE 1 MEAN BODY WEIGHTS OF MALE R A T S.................................................................................................. 472 FIGURE 2 MEAN BODY WEIGHTS OF FEMALE RATS..............................................................................................473 FIGURE 3 MEAN FORELIMB GRIP STRENGTH FOR MALE R A TS....................................................................... 474 FIGURE 4 MEAN FORELIMB GRIP STRENGTH FOR FEMALE R A T S ................................................................. 475 FIGURE 5 MEAN HINDLIMB GRIP STRENGTH FOR MALE R A T S....................................................................... 476 FIGURE 6 MEAN HINDLIMB GRIP STRENGTH FOR FEMALE RATS.................................................................... 477 FIGURE 7 MOTOR ACTIVITY ASSESSMENT: MEAN DURATION OF MOVEMENTS FOR MALE R A T S...................................................................................................................................................478 FIGURE 8 MOTOR ACTIVITY ASSESSMENT: MEAN DURATION OF MOVEMENTS FOR FEMALE RATS.............................................................................................................................................. 479 FIGURE 9 MOTOR ACTIVITY ASSESSMENT: MEAN NUMBER OF MOVEMENTS FOR MALE R A T S................................................................................................................................................... 480 FIGURE 10 MOTOR ACTIVITY ASSESSMENT: MEAN NUMBER OF MOVEMENTS FOR FEMALE RATS.............................................................................................................................................. 481 LIST OF APPENDICES , Page APPENDIX A ANALYTICAL D A T A ..................................................................................................................................... 483 APPENDIX B INDIVIDUAL DOSE VOLUMES (M L).............................................. 491 APPENDIX C INDIVIDUAL BODY WEIGHTS..................................................................................................................569 APPENDIX D INDIVIDUAL FOOD CONSUMPTION..................................................................................................... 603 APPENDIX E INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY D A T A ..........................................................................................................................630 APPENDIX F OPHTHALMOLOGY EXAMINATION REPORTS.................................................................................. 672 H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 LIST OF APPENDICES (CONTINUED) . Page APPENDIX G INDIVIDUAL FORELIMB GRIP STRENGTH AND HINDLIMB GRIP STRENGTH................ 675 APPENDIX H INDIVIDUAL FUNCTIONAL OBSERVATIONAL BATTERY ASSESSMENT.......................... 696 APPENDIX I-INDIVIDUAL MOTOR ACTIVITY ASSESSMENT: DURATION OF MOVEMENTS............... 706 APPENDIX J INDIVIDUAL MOTOR ACTIVITY ASSESSMENT: NUMBER OF M OVEMENTS.................. 717 APPENDIX K INDIVIDUAL CLINICAL PATHOLOGY D A T A ..................................................................................728 APPENDIX L INDIVIDUAL HEPATIC BETA-OXIDATION ACTIVITY..................................................................845 APPENDIX M INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS.................................................. 854 APPENDIX N INDIVIDUAL ANIMAL GROSS AND MICROSCOPIC OBSERVATIONS................................... 871 APPENDIX O REPRODUCTIVE TOXICOLOGY INDIVIDUAL BODY WEIGHTS OF P, MALE RATS......1063 APPENDIX P REPRODUCTIVE TOXICOLOGY INDIVIDUAL BODY WEIGHT GAINS OF Pj MALE RATS........................................... .......................................................................................1069 APPENDIX Q REPRODUCTIVE TOXICOLOGY INDIVIDUAL BODY WEIGHTS OF Pj FEMALE RATS DURING GESTATION..............................................................................-1 0 7 5 APPENDIX R REPRODUCTIVE TOXICOLOGY INDIVIDUAL BODY WEIGHT GAINS OF P, FEMALE RATS DURING GESTATION................................................................................1081 APPENDIX S REPRODUCTIVE TOXICOLOGY INDIVIDUAL BODY WEIGHTS OF Pj FEMALE RATS DURING LACTATION................................................................................1087 APPENDIX T REPRODUCTIVE TOXICOLOGY INDIVIDUAL BODY WEIGHT GAINS OF P, FEMALE RATS DURING LACTATION................................................................................ 1093 APPENDIX U REPRODUCTIVE TOXICOLOGY INDIVIDUAL DAILY FOOD CONSUMPTION BY P, FEMALE RATS DURING GESTATION...............................................................................1099 APPENDIX V REPRODUCTIVE TOXICOLOGY INDIVIDUAL CLINICAL OBSERVATIONS IN P, MALE R A TS.................................... .............................................................................................. 1105 APPENDIX W REPRODUCTIVE TOXICOLOGY INDIVIDUAL CLINICAL OBSERVATIONS IN P, FEMALE RATS DURING GESTATION................................................................................ 1114 APPENDIX X REPRODUCTIVE TOXICOLOGY INDIVIDUAL CLINICAL OBSERVATIONS IN P! FEMALE RATS DURING LACTATION................................................................................ 1120 APPENDIX Y INDIVIDUAL ANIMAL ESTROUS CYCLE PARAMETERS DURING PREMATING AND COHABITATION IN P, FEMALE RATS................................................................................ 1127 APPENDIX Z INDIVIDUAL ANIMAL ESTROUS CYCLE STAGES DURING PREMATING AND COHABITATION IN P, FEMALE R A TS................................................................................. 1133 APPENDIX AA REPRODUCTIVE TOXICOLOGY INDIVIDUAL ANIMAL SPERM MOTILITY DATA IN P, MALE RATS.....................................................................................................................................1139 APPENDIX BB INDIVIDUAL ANIMAL SPERM MORPHOLOGY DATA IN P, MALE RATS........................ 1141 APPENDIX CC INDIVIDUAL ANIMAL SPERM AND SPERMATID COUNTS IN P, MALE RATS.............. 1144 APPENDIX DD REPRODUCTIVE TOXICOLOGY INDIVIDUAL MATING DATA AND GESTATION LENGTH: P, GENERATION............................................................................1147 APPENDIX EE REPRODUCTIVE TOXICOLOGY INDIVIDUAL IMPLANTATION SITE DATA AND IMPLANTATION EFFICIENCY........................................ ....................................................... 1153 APPENDIX FF REPRODUCTIVE TOXICOLOGY INDIVIDUAL PUP SURVIVAL: F, GENERATION....... 1159 APPENDIX GG REPRODUCTIVE TOXICOLOGY INDIVIDUAL PUP WEIGHTS: F, GENERATION....... 1185 APPENDIX HH REPRODUCTIVE TOXICOLOGY INDIVIDUAL LITTER CLINICAL OBSERVATIONS: F, GENERATION....................................................................................................................................... 1235 Company Sanitised. D oes not contain TSCA CBS 10 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 LIST OF APPENDICES (CONTINUED) Page APPENDIX II REPRODUCTIVE TOXICOLOGY INDIVIDUAL BODY WEIGHTS: ' Fi GENERATION..................................................................................................................................... 1241 APPENDIX JJ REPRODUCTIVE TOXICOLOGY INDIVIDUAL BODY WEIGHT GAINS: F, GENERATION...................................................................................................................................... 1251 APPENDIX KK REPRODUCTIVE TOXICOLOGY INDIVIDUAL FOOD CONSUMPTION: F, GENERATION..................................................................................................................................... 1261 APPENDIX LL REPRODUCTIVE TOXICOLOGY INDIVIDUAL CLINICAL OBSERVATIONS: F, GENERATION...................................................................................................................................... 1271 APPENDIX MM INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS - P, ADULTS AND F, A D U L T S................................................ 1282 APPENDIX NN INDIVIDUAL ANIMAL GROSS AND MICROSCOPIC OBSERVATIONS - Pi ADULTS ... 1299 APPENDIX OO INDIVIDUAL ANIMAL GROSS OBSERVATIONS - Fi PUPS......................................................1459 APPENDIX PP INDIVIDUAL ANIMAL GROSS OBSERVATIONS - F, WEANLINGS......................................1465 APPENDIX QQ INDIVIDUAL ANIMAL GROSS OBSERVATIONS - F, ADULTS............................................... 1491 jggsmpany Sanitised. not sertiais TSCA CBS H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations STUDY INFORMATION Substance Tested:| Svnonvms/Codes: H-24516 Haskell Number: 24516 Composition: DuPont-5386 Purity: Known Impurities Physical Characteristics* Sponsor: E. I. du Pont de Nemours and Company Wilmington, Delaware 19898 U.S.A. Study Initiated/Completed: December 12, 2000/ (see report cover page) In-Life Initiated/Comnleted: December 12, 2000 / June 11, 2001 (gsfflpnw Samfflced. 0s noi t o t a i s m 6@r 12 H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations STUDY PERSONNEL Study Director: Gregory S. Ladies, Ph.D. Management: Judith C. Stadler, Ph.D. Nancy C. Chromey, Ph.D. Janice L. Connell, M.S., B.A., C.I.H. Primary Technician: Janine A. Britton, B.S. Analytical Chemist: Janet C. Maslanka, B.S. Management: S. Mark Kennedy, Ph.D. Reproductive Toxicologist: Eve Mylchreest, Ph.D. Management: Robert M. Parker, Ph.D. Clinical Pathologist: Nancy E. Everds, D.V.M. Management: Steven R. Frame, D.V.M., Ph.D. Pathologist: 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. Biochemical Evaluation John C. O'Connor, M.S. ' Management: Matthew S. Bogdanffy, Ph.D. Toxicology Report Preparation: Cecilia R. Kee, B.S. Mary K. LaRoe Ophthalmologist: Nancy M. Bromberg, V.M.D., M.S. 6119 Massachusetts Avenue Bethesda, Maryland 20816 Laboratory Veterinarians: William Singleton, D.V.M., A.C.L.A.M. Wanda L. West, D.V.M., A.C.L.A.M. DuPont-5386 13 not contain TSC CBi Company Sanitized. Does H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 SUMMARY Four groups of young adult male and female Crl:CD(SD)IGS BR rats were administered H-24516 by gavage at dosages of 0,25,100, and 250 mg/kg/day. Selected animals from each dosage group were designated for subchronic toxicity or reproductive evaluations. In the subchronic study, body weights, food consumption, and clinical signs were evaluated weekly. Clinical pathology endpoints were evaluated on weeks 7,13, and near the end of the one-month recovery period. Neurobehavioral assessments were also performed prior to dosing, during week 13, and near the end of the one-month recovery period. Biochemical evaluations (hepatic (3-oxidation) were performed on animals after 10 and approximately 90 days o f dosing and following one- and three-month recovery periods. After approximately 90 days of dosing, 10 rats/sex/dose were sacrificed and given a gross and microscopic pathological examination. Approximately one month after the 90-day dosing period, 10 animals/sex in the control and high dose group were examined for recovery o f toxic effects. An additional five animals/sex/dose were evaluated for recovery approximately 3 months following the end of the dosing period. The range of mean daily dose volumes o f H-24516 administered to male rats was 2.5 to 4.6 ml. The range administered to female rats was 1.9 to 2.8 ml. In-Life Toxicology Parameters-. No test substance-related mortality occurred in the study. A test substance-related, toxicologically significant increase in the incidence of broken (males) and absent teeth (males and females) was observed in the 250 mg/kg/day dose group. Test substancerelated, toxicologically significant decrements in body weight, body weight gain, and food efficiency occurred in males dosed with 100 and 250 mg/kg/day H-24516. Statistically significant decrements in mean body weight parameters and food consumption occurred for the female groups dosed with 100 or 250 mg/kg/day. The mean body weight and body weight gain decrements observed for the 100 and 250 mg/kg/day female groups, however, were of small magnitude. They were associated with decreased food consumption, but not with any alterations in food efficiency, and, therefore, were not considered to be toxicologically significant. Furthermore, the decrements in body weight parameters observed for both males and females appear to be related in part to test substance-induced toxicity to the teeth and subsequent decreased ability of the animals to eat the pelleted chow. Neurotoxicology Parameters: No adverse changes in neurobehavioral parameters were observed in male or female rats in any dose group. Biochemical Toxicology: The rate of hepatic P-opdation, a measure of peroxisome proliferation, was increased in a dose-dependent manner with statistical significance occurring in males and females administered 100 or 250 mg/kg/day H-24516. Following a one- or three-month recovery period, the rate of hepatic P-oxidation was still significantly increased in males and females administered 250 mg/kg/day. gfemyamw Sanitized. 0@m@Sortaim TSCA GIB! 14 H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 Clinical Pathology: Samples were collected at mid-study, at the end o f treatment, and after one month of recovery for hematology, clinical chemistry, urinalysis, coagulation (end of study only), and plasma and urine fluoride (end of study and end of one- and three-month recovery). Males and females dosed with 250 mg/kg/day had decreased red cell mass parameters, along with correlative changes in other hematology parameters and in red cell morphology. After one month of recovery, mean red cell mass o f female rats was similar to the control group, although some changes were still present in other hematologic parameters. Male rats still had decreased red cell mass effects, and associated alterations in other hematologic parameters. Other changes in clinical pathology parameters, during treatment or after a one- or three-month recovery, were considered treatment-related but non-adverse because the magnitude of change was small, transient, and/or in a direction not associated with toxicity. The serum parameters thus affected included serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, cholesterol, triglycerides, total protein and albumin, calcium, phosphorus, sodium, chloride, and potassium. Affected plasma parameters were activated partial thromboplastin time and plasma fluoride. Affected urinalysis parameters were urine volume, osmolality, specific gravity, and fluoride. Anatomical Pathology (Subchronic Toxicity): Test substance related, toxicologically significant degeneration/disorganization of enamel organ ameloblast cells occurred in male and female rats administered 100 or 250 mg/kg/day H-24516. Test substance related, potentially adverse increases in thyroid hypertrophy were observed in the 100 and 250 mg/kg/day male and 250 mg/kg/day female dose groups. In addition, alterations in thyroid colloid were observed in male and female rats at all dose levels, but were not considered to be toxicologically significant. Test-substance related and statistically significant increases in liver weight parameters were present in males and females administered 25, 100, or 250 mg/kg/day for approximately 90 days. The increased liver weights correlated with microscopic centrilobular hepatocellular hypertrophy in the 100 and 250 mg/kg/day male and 250 mg/kg/day female groups. Test-substance related and statistically significant increases in kidney weight parameters also occurred in males and females administered 25, 100, or 250 mg/kg/day. The increased kidney weights correlated with microscopic renal tubular hypertrophy in the 100 (1 of 10 rats) and 250 mg/kg/day male groups only. The liver and kidney alterations, however, were considered to be a pharmacologically adaptive response by these organs to the test-substance and therefore, not considered toxicologically significant. After one month of recovery, rats dosed with 250 mg/kg/day showed reversibility of some effects. The ameloblastic degeneration/disorganization persisted with decreased incidence and severity in the 250 mg/kg/day male and female groups. Thyroid hypertrophy was no longer observed. Alterations in thyroid colloid persisted in both male and female rats. Increased liver weight parameters persisted in the 250 mg/kg/day male and female groups, although their magnitude was decreased relative to that observed at the end o f the 90 day exposure period. Hepatocellular hypertrophy was no longer observed in female rats but persisted with decreased severity in male rats. Renal tubular hypertrophy persisted with decreased incidence and severity in males, while some kidney weight parameters remained increased in both male and female rats. SsiifiiHagdL, @s wot esntaSira TSCA B0 15 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 After the three-month recovery period, ameloblastic degeneration/disorganization was still present in the 100 mg/kg/day male and 250 mg/kg/day male and female dose groups but at a lower incidence and severity relative to the one-month-recovery animals. Alterations in thyroid colloid persisted in both males and females. Liver weight parameters remained increased in both the 250 mg/kg/day male and female groups, although their magnitude was decreased relative to that observed after the 90-day period. Hepatocellular hypertrophy was observed only in the 250 mg/kg/day male group (1 of 5 rats). Alterations in kidney weight parameters or renal tubular hypertrophy were not observed at any dose level. Reproduction: Twenty male and female rats from each dose group were designated for reproductive evaluations. Parental rats (Pi generation) were dosed daily for 74 days prior to cohabitation, during the cohabitation period (mating), during gestation, and during lactation, until the weaning of the Fi offspring. The following parameters were conducted on Pi rats: body weights, food consumption, clinical signs, gross pathology, sperm parameters, estrous cyclicity and reproductive performance. The Fi offspring were evaluated during the lactation period for growth and survival and given a gross pathological examination at weaning. A subset of Fi rats (Fi generation) were retained at weaning, and the following parameters evaluated for 6 weeks: body weights, food consumption, clinical signs, and age at onset o f vaginal opening and preputial separation. After 6 weeks, the Fi generation rats were given a gross pathological examination, selected reproductive organs and target organs o f toxicity were weighed. There were no toxicologically significant pathology findings in the Pi or Fi generation rats. No test substance-related mortality occurred in the study. There was a statistically significant reduction in body weight in Pi male rats during and after the cohabitation period. Although this finding was test substance-related, it was not considered toxicologically significant. There was a statistically significant increase in testicular spermatid numbers in Pi male rats administered 100 or 250 mg/kg/day. This finding was not considered test substance-related. Implantation efficiency was significantly reduced at 100 and 250 mg/kg/day and reflects a reduction in the number of pups bom. There were statistically significant reductions in the number o f pups bom, the number of pups bom alive and the number of pups alive on day 4 of lactation in the 250 mg/kg/day group. Reductions of similar magnitude as in the 250 mg/kg/day group were also observed for the number of pups bom and bom alive in the 100 mg/kg/day group. Although not statistically significant, these changes were considered test substance-related and toxicologically significant, as was the significant reduction in the number o f pups alive on day 4 o f lactation in the 100 mg/kg/day group. There were statistically significant reductions in pup weights on lactation days 4, 7, 14 and 21 in the 250 mg/kg/day group. On the day of weaning, mean body weights were significantly lower than control in both Fi males and females in the 250 mg/kg/day group. However, mean body weights in these groups progressively returned to control values during the post-weaning period. These findings were not considered toxicologically significant. .Company Sanitized. D oes not contain TSCA CBI 16 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 NOEL fo r Subchronic Toxicity. The no-observed-effect level (NOEL)3for males was 25 mg/kg/day H-24516 based on adverse decrements in body weight parameters and food efficiency, increased hepatic peroxisomal p-oxidation, and the degeneration and/or disorganization of enamel organ ameloblast cells in males administered 100 mg/kg/day. The NOEL for females was 25 mg/kg/day H-24516 based on increased hepatic peroxisomal Poxidation and the degeneration and/or disorganization of enamel organ ameloblast cells in females administered 100 mg/kg/day. NOELfo r Reproductive Evaluations: The NOEL for the reproductive toxicity parameters evaluated under the conditions of this study was 25 mg/kg/day based on decreases in the number of pups bom, bom alive, and the number o f pups alive on day 4 o f lactation at the 100 mg/kg/day dose level. The NOEL for this study is defined as the highest dose at which toxicologically important effects attributable to the test substance were not detected. Thus, for this study, the NOEL is equivalent to the NOEL as defined by the United States Environmental Protection Agency (1985) and to the no-observed-adverse-effect level (NOAEL) as defined by the European Union (1994). \J "jnnullTObrrt D>$ n o l enSain TSG& <CB6 17 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations _______ DuPont-5386 INTRODUCTION The test substance, H-24516, is __ _ _____________________________ jT h e 25, 100, and 250 mg/kg/day dose levels for this study were selected based on the toxicity and pharmacokinetic analysis o f plasma fluorine concentrations from a range-finding study with H-24516. In rats exposed to 200 mg/kg/day H-24516 for 35 days, toxicity (i.e., body weight effects or clinical observations) was not observed. Plasma fluorine levels approached levels previously found when animals were exposed to dosages that induced lethality. The high-dose level of 250 mg/kg/day for this 90-day study was expected to produce toxicity without excessive mortality. The low dose of 25 mg/kg/day was expected to be the no-observed-effect level, while the 100 mg/kg/day dose was expected to induce minimal or no toxicity. OBJECTIVE The objective of this study was to evaluate the potential subchronic and reproductive toxicity of H-24516 when administered by gavage to male and female rats. Recovery evaluations were included to investigate the reversibility of any observed toxicological effects. The oral route of administration was selected as the most efficient way to deliver an accurate dosage. .MATERIALS AND METHODS A. Test Guidelines The subchronic toxicity study design complies with the United States Environmental Protection Agency (EPA), Office of Prevention, Pesticides, and Toxic Substances (OPPTS) Health Effects Test Guidelines, OPPTS 870.3100 90-Day Oral Toxicity in Rodents (AUG-1998). The onegeneration reproduction study includes many endpoints of reproductive function but does not comply with a specific guideline. B. Test Substance Samples of the H-24516 were supplied near the beginning and end of the study for stability analysis and analyzed by the DuPont Regional Analytical Services (RAS), Jackson Laboratories, Deepwater, NJ. Methods and results for the stability analysis of the test substance are documented in study records. C. Test Species On November 16, 2000, 176 male and 176 female Crl:CD(SD)IGS BR rats, with an assigned birth date of October 25, 2000, were received from Charles River Laboratories, Inc., Raleigh, North Carolina for use on this study. g*psv/ 18 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 The rat was selected because it is the species recommended in the subchronic toxicity guidelines and is extensively used in reproduction studies. The Crl:CD(SD)IGS BR strain was chosen because extensive background information is available from the literature, the supplier, and previous studies at Haskell Laboratory. This species/strain also is considered suitable relative to longevity, hardiness, and low incidence o f spontaneous diseases. D. Animal Husbandry 1. Housing With the exception o f some portions of the reproductive study, all rats were housed one per cage, sexes separate, in stainless steel, wire-mesh cages suspended above cage boards. Animal rooms were maintained on a 12-hour light/dark cycle (fluorescent light) and at a temperature of 22 3C and a relative humidity of 50% 20%. Occasional excursions outside the accepted ranges were minor and did not affect the study. Rats designated for reproductive toxicity evaluations were housed as breeding pairs during the cohabitation period. During the gestation period, female rats designated for reproductive toxicity evaluations were housed individually until gestation day 20. Beginning on gestation day 20 for mated females, or at the end of the cohabitation period for females without evidence of copulation, female rats were housed individually in polycarbonate pans with bedding. During the lactation period, adult female rats were housed with their litters in polycarbonate pans. Cage racks were relocated within the animal room each week and cages were repositioned on the racks every 2 weeks for animals designated for the 90-day exposure period and one- and three-month recovery periods. during the 74-day premating period for animals designated for reproductive assessment, and the 40-day post-weaning period for Fi generation rats. 2. Feed and Water Tap water was provided ad libitum. All rats were fed PMI Nutrition International, Inc. Certified Rodent LabDiet 5002 ad libitum. Initially, all rats were fed pelleted chow, however, beginning on test day 57, animals exhibiting effects to the teeth were placed on ground chow. On test day 74, all rats in the 250 mg/kg/day dose group that were designated for reproductive toxicity evaluations were placed on ground chow. On test day 77, all other rats in the 250 mg/kg/day dose group were placed on ground chow. 3. Identification Prior to assignment to groups, each rat was temporarily identified by either the presence or absence of a colored tail mark and cage identification. After assignment to groups, an individual identification number was tattooed on the tail o f each rat. The information on the cage labels Company Sanitized. Does not contain TSCA CBI 19 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 included the unique 6-digit Haskell animal number and the individual identification number assigned to each rat. 4. Health Monitoring Program As specified in the Haskell Laboratory animal health and environmental monitoring program, the following procedures are performed periodically to ensure that contaminant levels are below those that would be expected to impact the scientific integrity o f the study: Water samples are analyzed for total bacterial counts, and the presence o f coliforms, lead, and other contaminants. Feed samples are analyzed for total bacterial, spore and fungal counts. Samples from freshly washed cages and cage racks are analyzed to ensure adequate sanitation by the cagewashers. Certified animal feed is used, guaranteed by the manufacturer to meet specified nutritional requirements and not to exceed stated maximum concentrations o f key contaminants, including specified heavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates. The presence 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 o f these data did not indicate any conditions that affected the validity o f the study. E. Quarantine and Pretest Period Upon arrival at Haskell Laboratory, the rats were quarantined for 11 days of the 26-day pretest period. The rats were observed daily for any clinically apparent signs of disease or injury, weighed 4 times, and examined by a veterinary ophthalmologist to identify animals with preexisting ocular lesions. Prior to grouping, one male rat (animal no. 643168) was accidentally killed and discarded without necropsy. One male rat (animal no.643186) and 2 female rats (animal nos. 643355 and 643469) were found dead and necropsied to check for the presence of disease. No disease was found. On the basis of acceptable body weight gains and clinical observations, all surviving rats were released from quarantine on test day -15 by the laboratory animal veterinarian designee. P p a n f gamiteed D@ k*. IBCk CB8 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 F. Study Design Groups Male Female In m IV V VI vn vni No./ Group Male Female 45 45 35 35 35 35 45 45 Dietary Dosage^ (mg/kg/day) 0 (Control) 25 100 250 Biochemical Evaluations at thel0-day Time Point I-A ffl-A V-A v n -A n -A IV-A VI-A vrn -A 5 5 5 5 5 5 5 5_ .* 0 (Control) 25 100 250 Weight o f test substance (adjusted foi animal body weight. m ictive ingredient)/kg The first ten rats in each group were designated for the 90-day exposure evaluation. The next five rats in each group were initially designated as a satellite subset for serial blood collection in the event findings warranted analytical evaluations. Due to findings after the one-month recovery period, these rats were designated for evaluation of selected tissues following a threemonth recovery period; these rats are reported as the three-month recovery animals. The next 20 an im als in each group were designated for reproductive evaluations. The last 10 male and female rats in the control and high dose groups were designated for recovery evaluations and are reported as the one-month recovery animals. An additional 5 rats/sex/dose were received as a separate shipment 65 days after study start for the biochemical evaluations (hepatic P-oxidation) following a 10-day exposure. Male and female rats designated for the 90-day exposure evaluation were dosed for 90 and 92 days, and necropsied on test days 91 and 93, respectively. Male and female rats designated for the one- and three-month recovery evaluations were dosed for 90 days and necropsied 36 days and 92 days postdosing, respectively. Neurobehavioral evaluations were conducted on male and female animals designated for the 90day exposure evaluation (predose and week 13) and on control and high dose animals designated for the one-month recovery (predose, week 13, one-month post dose). Biochemical evaluations (hepatic P-oxidation) were performed on animals after 10 and approximately 90 days of dosing and following one- and three-month recovery periods. Clinical pathology evaluations were conducted on animals designated for the 90-day exposure evaluation on weeks 7 and 13 and on animals designated for the one-month recovery evaluation immediately prior to necropsy. Reproductive evaluations began on test day 74 when designated male and female rats were cohoused. 21 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 G. Assignment to Groups and Study Start 1. Rats Designated for the 90-Day Exposure, One-Month Recovery, and Three-Month Recovery Evaluations and Reproductive Evaluations. Rats were selected for study use on the basis o f adequate body weight gain, freedom from any ophthalmological abnormalities or clinical signs of disease or injury, and a body weight within 20% o f 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 o f H-24516 began on test day 0. The rats were approximately 49 days of age on test day 0. Prior to the start of the test substance administration, rats with body weights that were not within 20% o f the mean within a sex, were replaced and discarded without gross or microscopic evaluations. Replacement rats were selected on the basis o f freedom from any clinical signs of disease or injury and a body weight 20% o f the mean within a sex. On test day 0, two male rats had clinical signs o f hair loss (animal numbers 643232 (control) and 643315 (250 mg/kg/day)). Inclusion of these animals on the study does not impact the outcome of the study. 2. Rats Designated for 10-Day Biochemical Analysis The rats designated for the 10-day biochemical analysis arrived separately, 65 days after study start. They were handled the same as the other rats during the quarantine and pretest periods, except they did not receive an ophthalmological examination. They were distributed by computerized, stratified randomization into study groups (5/sex/dose), so that there were no statistically significant differences among group body weight means within a sex when this subset o f rats is compared among themselves. Oral administration of H-24768 began on test day 76. H. Dose Suspension Preparation Dose suspensions o f 0, 2.5,10, or 25 mg test substance/mL were prepared with 0.5% methylcellulose. Methylcellulose was selected as the vehicle because it is the vehicle of choice for reproductive studies. Dose suspensions were prepared daily prior to dosing from test day 0 through test day 37 with a dose volume o f 10 mL/kg. However, in order to administer a dose volume under 5 mL to comply with laboratory procedure, the dosing volume for male and female rats was decreased from 10 mL/kg to 7.5 mL/kg on test day 38, and the suspension concentrations were increased to 0, 3.33, 13.33, and 33.33 mg/mL. Starting on test day 42 until the end of the dosing period, these dose suspensions were prepared twice a week. The test material was melted down to approximately 90C, mixed for approximately 30 minutes, aliquoted, then mixed with methylcellulose for one minute to make the dose suspensions. When the dose suspension was prepared twice a week, the suspension was refrigerated until used. Each day the suspensions were then homogenized for one minute and then stirred for 30 minutes Company Sanitized. D oes not contain TSCA CBI 22 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 before the day's aliquots were removed. Remaining dose suspensions were returned to the refrigerator. The dose suspensions were stirred prior to and during dosing. I. Test Substance Administration and Sampling Animals designated for the 90-day exposure period and one- and three-month recovery periods were dosed for up to 92 days. Animals designated for reproductive evaluations, were dosed for the 74-day premating period and during the mating period. Pi male rats continued to be dosed until sacrifice. Pregnant female rats were dosed during the gestation period. Lactating females and females with no evidence of copulation were dosed until pups were weaned on day 21. The test substance was administered daily to the study animals by oral gavage to achieve dosage levels of 25,100, or 250 mg active ingredient/kg body weight/day, based on the most recently recorded body weight. All male and female control animals were treated with 0.5% aqueous methylcellulose at the same dose volume as that used for the high dose group. On test day 3, five male rats in the 25 mg/kg/day group were dosed with vehicle only. On test day 18, all male rats and the first 11 female rats in the 25 mg/kg/day groups received 37-39 mg/kg/day. There were individual rats across dose groups that were misdosed; these rats are documented in study records and reported in Appendix B. The incidences o f misdosing described above are considered not to have affected the outcome of the study. All Pi an im als in the reproduction study with the exception of pregnant females in the process or showing signs of delivery were dosed daily until sacrifice. At the initiation of the study (test day 0), samples o f the dosing suspensions containing H-24516 at the concentrations of 0, 2.5, 10, and, 25 mg/mL were collected. On test day 6, to verify that th 10.0 mg/mL level was mixed homogeneously, samples of the dosing suspensions containing H-24516 at the concentrations o f 0 and 10 mg/mL were collected. These samples were analyzed to verify homogeneity/concentration of the test substance in the vehicle and 5hour room temperature stability to verify the test substance stability while the animals were being dosed. Prior to the initiation o f a change in frequency o f dosing preparation, a long term refrigerated . stability (4 days) analysis was required. Also, a need to change dose volume (10 mL/kg to 7.5 mT7kg) was identified and a subsequent change in the concentrations of the suspensions was necessary. Therefore, an additional mixing and stability study was performed. The samples collected during this additional study were not administered to the animals but addressed the mixing, range o f concentrations and the stability parameters that would be needed after the frequency o f mixing and dose volume changes were made in the study. In this separate study, samples of dosing suspensions containing H-24516 at the concentrations o f 0, 5, 20, and, 50 mg/mL (based on a 5 mL/kg dose volume) were collected. These samples were analyzed to verify homogeneity, concentration and 5-hour room temperature stability. On subsequent days 2, 3, and 4 after this preparation, samples from the same preparation were collected and analyzed to verify concentration after re-dispersion of the test substance and refrigerated stability (4 days) along with 5-hour room temperature stability (day 4 samples, only). Later in the 90-day gavage study, to satisfy the dose volume change o f 5 mL/kg to 7.5 mL/kg, samples o f the dosing tasapM f S an lfesd , 0@e not eontaln TSCA li 23 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 suspensions containing H-24516 at the concentrations o f 0 and 3.33 mg/mL were collected and analyzed to verify homogeneity, concentration and 5-hour room temperature stability. Four days later, samples from the same preparation were collected and analyzed to verify concentration after re-dispersion o f the test substance and refrigerated stability (4 days) along with 5-hour room temperature stability. On test day 38, after the mixing and stability was established for the storage conditions and the concentration range, the mixing frequency and dose volume change (10 mL/kg to 7.5 mL/kg) was initiated in the study. Therefore on test day 49, samples o f the dosing suspensions containing H24516 at the concentrations of 0, 3.33,13.33, and 33.33 mg/mL were collected and analyzed to verify homogeneity and concentration. On test day 91, samples o f the dosing suspensions containing H-24516 at the same concentrations were collected. The 3.33 mg/mL samples were analyzed to verify homogeneity and concentration while the remaining levels were analyzed for concentration verification. All dosing suspension samples were collected on the same day the suspensions were prepared or at the prescribed protocol time for analysis. They were analyzed when received or were frozen until analyzed. J. Analytical Methods 1. Dosing Suspension Treatment Each dosing sample was diluted to 100 mL with methanol and sonicated to dissolve the H-24516 in the suspension. The dosing samples were further diluted with the 0 mg/mL sample (initial dilution) to an expected concentration of approximately 0.05, 0.06, 0.075 or 0.09 mg/mL (a.i.) prior to analysis. An internal standard (refer to Calibration and Quantitation Section) at an equivalent amount was added to each sample before the final analysis dilution. Samples submitted for analysis were analyzed the day the suspensions were received or stored frozen until analyzed by the testing group. Company 24 Oo< en"a*n TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 2. Chromatographic Conditions Instrument: Column: Injector: Detector: Carrier Gas: Split vent: ' Injection Volume: Oven Program: Initial Temperature: Initial Time Level 1 Rate: Level 1 Temperature: Level 1 Time: Total run time: Hewlett-Packard Model 6890 GC J & W, DB-1701, 30 m, 0.32 mm ID, 1urn film thickness Split, 250C FID;250C Helium (2.1 mL/min) 22.3 mL/min 2 microliter Gradient 100C 1.00 min. 20.0C/min. 260C 0.00 min. 9.00 min. 3. Calibration and Quantitation A separate sample o f H-24516 (-3) was obtained to use as the analytical reference standard A stock solution was prepared in methanol. This stock solution was sonicated to assux^haHm material was in solution. Before analysis, appropriate aliquots o f the stock were diluted with methanol to make calibration standards, which brackete^lK ^^ge^^jrcentratm i^^f the diluted dosing sam ples^^. stock solution of the internal s t a n d a r d ^ m ^ H H ^ H U p M H H H ^ H H fl^ H |H riH i| a s prepared in methanol and added to each calibration standard and t^ ^ arc q ^ ^ ^ g v ^ m ^ q u w a ie n t final concentration in all dilutions. The ratio o f the peak heights for internal standard and H-24516 at three retention times (3.5,4.17, and 4.77 minutes) from replicate GC analysis o f these suspensions were used to construct calibration curves by least squares regression (see Appendix A, Figure la, lb, and lc for a representative curves). Measured concentrations for the dosing samples were determined by applying the peak height ratios from replicate injections o f each sample to the respective calibration curve. Test substance homogeneity in the dosing suspensions was evaluated by calculating the coefficient of variation (C.V. = standard deviation/mean x 100) o f the measured concentrations in samples obtained from the top, middle, and bottom (T, M, and B) of the dosing preparation or the mean of duplicate samples for each concentration. A coefficient of variation of less than 10% is the standard criterion at Haskell Laboratory for acceptable distribution of the test substance throughout the dosing suspension. The mean result of the top, middle, and bottom homogeneity samples or duplicate concentration verification samples for each dosing level was used to determine the concentration of the test substance for the respective dosing levels. Stability was evaluated by using the mean o f the top, middle, and bottom homogeneity samples or duplicate concentration verification samples (0-day room temperature) as the baseline for comparing the corresponding room temperature and refrigerated results. Company Sanitized. D oes not contain TSCA CB1 25 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 K. Body Weights All rats were weighed once per week during the 90-day exposure phase o f the study. In addition, the rats designated for neurobehavioral evaluations, undergoing functional observational battery and motor activity assessments, were weighed on the days of those observations. During the reproduction substudy, male rats were weighed on a weekly schedule and female rats were weighed during gestation on days 0, 7,14,18, and 21, and lactation days 0 ,7 ,1 4 , 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 56 (test day 36). L. Food Consumption and Food Efficiency The amount of food consumed by each rat over each weighing interval was determined throughout the study. Each feeder was weighed at the beginning and end of the interval and the final weight of the feeder and the amount of spillage from the feeder during the interval was subtracted from the initial feeder weight. From these measurements, mean daily food consumption over the interval was determined. From the food consumption and body weight data, the mean daily food efficiency was calculated. Mean daily food consumption was determined for all animals designated for subchronic toxicity evaluations during the 90-day exposure period. Food consumption was also determined for animals designated for one- and three-month recovery evaluations. The only exception is that food consumption was not determined for animals designated for three-month recovery during the urine and feces collection period on test days 83-89. During the reproductive assessment, food consumption was determined for rats designated for reproductive assessment as follows: Premating Dosing period - individual food consumption was determined weekly, ending test day 74. Cohabitation period, beginning test day 74 - food consumption was not determined. Following the end of cohabitation period --food consumption was not determined for males. Gestation period --individual food consumption was determined on gestation days 0, 7, 14, and 21. Lactation period - food consumption was not determined. Postweaning Ft rats - individual food consumption was inadvertently not collected or spillage not recorded during the postweaning period for many animals. As a result, available food consumption data are not presented in the report but are included in the study records. M. Detailed Clinical Observations and Mortality During the test period, cage-site examinations to detect moribund or dead rats and abnormal behavior and/or appearance among rats were conducted at least twice daily throughout the study. At every weighing, each rat was individually handled and examined for abnormal behavior and appearance. Detailed clinical observations in a standardized arena were also evaluated on rats designated for the 90-day exposure and one-month recovery periods. The detailed clinical Ppipam if Sanitized. not eonain TSG CBS 26 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 observations included (but were not limited to) evaluation o f 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. N. Ophthalmological Evaluations Three ophthalmological examinations were conducted by a veterinary ophthalmologist. Both eyes were examined by focal illumination and indirect ophthalmoscopy. The examinations were conducted under subdued lighting after mydriasis had been produced with a 1% tropicamide solution. On test day -11, the initial examination was performed on all rats received for the study, prior to selection and grouping. On test day 80, all surviving rats designated for the 90-day exposure and one-month recovery were examined again. On test day 122, all surviving rats designated for the one-month recovery evaluation were given a final examination. O. Neurotoxicity Evaluations 1. Sensory Function Evaluation Prior to test substance administration (test days -6 and--7), during week 13 (test days 86 and 87) of test substance administration, and following an approximately one-month recovery period (test day 120), assessments o f responses to approach/touch, sharp auditory stimulus, and tail pinch were made while the animal was in a standard arena. These assessments were conducted on 10 animals per group for the baseline and week 13 evaluations. The recovery evaluation was conducted on the 10 animals per group designated for the one-month recovery (control and high dose groups only). Fore- and hindlimb grip strength were measured by a strain gauge device (Chatillon Digital Force gauge). Pupillary constriction was measured immediately prior to removing the rats from the motor activity chambers because the darkened room in which the apparatus was located facilitated observing the response. Due to the technical difficulty of evaluating pupil size in albino rats under ambient light conditions, pupil size was evaluated by assessment of pupillary response. The presence or absence o f pupillary constriction was assessed after a beam of light was directed into each eye. For all these assessments, the experimenter was unaware of the group designation of the animal. 2. Motor Activity Following the evaluation of grip strength and sensory function during week 13, assessment of motor activity was conducted. Rats were individually tested in 1 of 30 nominally identical, automated activity monitors (Coulboum Infrared Motor Activity System). Group and gender were counterbalanced across the monitors and time o f day to the fullest extent possible. The infrared monitoring device enables measurement 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. Cbmpanjr Sanitized. D oes not contain TSCA CBI 27 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 Presence of defecation and urination on the cageboards below the motor activity monitor were also recorded following each motor activity session. 3. Test Facility Positive Control Data Data on the effects o f acrylamide, carbaryl, d-amphetamine, and trimethyltin are described in four separate reports.(1,2,3,4) These positive control studies are the basis o f training certification for the individuals making judgments in the neurobehavioral and neuropathology tests. The data also document that the equipment and procedures are capable o f detecting effects that may be seen in neurotoxicity studies of this type. P. Clinical Pathology A clinical pathology evaluation was conducted on the first 10 male and 10 female rats per group on test days 44 and 91 (males) or test days 45 and 93 (females). The rats were fasted overnight (approximately 16 hours) and urine was collected during this interval. Blood samples for hematology and clinical chemistry measurements were collected from the orbital sinus o f each fasted rat while the rat was under light carbon dioxide anesthesia. Blood samples for coagulation parameters and plasma fluoride were collected from the abdominal vena cava while the rat was under carbon dioxide anesthesia, immediately prior to sacrifice (days 91 and 93 in males and females, respectively). All blood samples were examined visually and observations recorded. A clinical pathology evaluation (hematology, clinical chemistry, and urinalysis only) was also conducted on all one-month recovery rats from blood and urine collected on the day of necropsy (test day 125). In addition, urine samples were collected from three-month recovery rats for urine fluoride analysis only. 1. Hematology/Coagulation Complete blood counts (including reticulocytes) were determined on a Bayer Advia 120 hematology analyzer and determined from microscopic evaluation of the blood smear. Wrightstained blood smears from all rats were examined microscopically for confirmation of automated results and evaluation of cellular morphology. Coagulation times were determined on a BCS Behring Coagulation Analyzer. New methylene blue-stained blood smears were prepared from . each rat undergoing hematology evaluation but were not needed for evaluation. iSMfflpamf SanBfeed 0@es mt ertaim S C A CBS 28 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations The following hematology and coagulation parameters were determined: Erythrocyte count (RBC) Hemoglobin concentration (HGB) Hematocrit (HCT) Mean corpuscular volume (MCV) Mean corpuscular hemoglobin (MCH) Mean corpuscular hemoglobin concentration (MCHC) Red cell distribution width (RDW) Absolute reticulocyte counts (ARET) Total leukocyte count (WBC) Differential leukocyte count Platelet count (PLT) Microscopic blood smear examination Prothrombin time (PT) Activated partial thromboplastin time (APTT) DuPont-5386 2. Clinical Chemistry Clinical chemistry parameters were measured or calculated on a Roche Diagnostics (BMC)/Hitachi 917 clinical chemistry analyzer. Plasma fluoride concentration was determined using a phi/12pH meter with a fluoride-selective electrode. Plasma fluorides were determined at the end of treatment and at the end of a one-month recovery period. The following serum chemistry parameters were determined: Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Sorbitol dehydrogenase (SDH) Alkaline phosphatase (ALKP) Total bilirubin (BILI) 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) 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 urine examination Urine volume and appearance were measured and evaluated visually, respectively. Urine constituents were semi-quantitatively measured on a Bayer Clinitek AtlasTM Automated Urine Chemistry analyzer. Urine volume and appearance were measured and evaluated visually, Company Sanitized. D oes not contain TSCA CBI 29 H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 respectively. Urine constituents were semi-quantitatively measured on a Bayer Clinitek AtlasTM I Automated Urine Chemistry analyzer. Urine protein was measured on a Roche Diagnostics " (BMC)/Hitachi 717 clinical chemistry analyzer. Urine osmolality was determined using an Advanced Osmometer 3900. Sediments from all urine specimens were evaluated microscopically. Urine fluoride was determined by multiplication of measured urine volume by urine fluoride concentration (measured using a phi/12pH meter and a fluoride selective electrode). Urine fluorides were determined at the end o f treatment and at the end of the oneand three-month recovery periods. Q. Collection of Blood, Urine, and Feces (Three-Month Recovery) On test day -4 (pre-bleed) and test days 0, 3, 9, 21, 34, 55, 76, and 89 blood (approximately 0.5 - 1 mT.) was collected from the orbital sinus of designated animals (5 rats/sex/dose) while the rat was under light carbon dioxide anesthesia. On the day of blood collection (except test day 4), blood was collected from the animals 2 hours ( 30 minutes) after dosing. The blood was collected in plastic tubes containing EDTA while on ice. The blood was then separated into plasma and RBCs by centrifugation and stored frozen. For each bleeding, blood was collected at approximately the same time of day. During the last week of the 90-day exposure period urine and feces were collected daily at 24-hour intervals from each animal. The animals were placed in metabolism cages for collection of feces and urine. The exact time period o f collection of urine and feces was documented along with the total volume o f urine obtained. Urine and feces were stored frozen. Blood was also collected for analysis at 3,7 ,1 2 , 19, 26, 36, 50, 71, and 92 days postdosing for both male and female animals o f each dose group and stored frozen. Animals were sacrificed at the end of the three-month recovery period. The collected blood, urine, and feces may be evaluated in the future for the test substance and/or possible metabolites. Resulting data will be reported separately. R. Anatomic Pathology - Rats Designated for Subchronic Toxicity and Recovery After approximately 90 days o f exposure to the test substance (test days 91 and 93 for males and females, respectively), groups of 10 male and 10 female rats from the 0, 25, 100, and 250 mg/kg/day groups were sacrificed and necropsied. Additional groups o f 10 male and 10 female rats from 0 and 250 mg/kg/day groups were sacrificed and necropsied approximately one month after the last exposure (test day 125). In addition, groups of 5 male and 5 female rats from all groups designated for the three-month recovery period were sacrificed and necropsied on test day 181. In the discussion of pathology findings, groups sacrificed after approximately 90 days are referred to as the 90-day exposure groups, and groups sacrificed on test days 125 and 181 are referred to as one-month and three-month recovery groups, respectively. Rats scheduled for sacrifice were fasted overnight on the afternoon before their scheduled sacrifice. The order o f sacrifice for scheduled deaths were random among all treatment groups. Rats were euthanatized by carbon dioxide anesthesia and exsanguination. Gross examinations were performed on all male and female rats. 30 H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 The following tissues were collected from 90-day exposure and one-month recovery group rats sacrificed by design, or rats that were found dead or accidentally killed. Digestive System liver esophagus stomach duodenum jejunum ileum cecum colon rectum salivary glands pancreas Urinarv System kidneys urinary bladder Cardiovascular System heart aorta Hematopoietic System spleen thymus mandibular lymph node mesenteric lymph node bone marrowc Endocrine Svstem pituitary gland thyroid gland parathyroid glands adrenal glands Musculoskeletal Svstem skeletal muscle femur/knee jointa sternum mandible b Reproductive Svstem Male testes epididymides prostate seminal vesicles Female ovaries uterus mammary gland Respiratory System lungs trachea nose larynx pharynx______ Nervous System brain (including cerebrum, cerebellum, medulla/pons) spinal cord (3 levels: cervical, mid-thoracic, lumbar) sciatic nerve Miscellaneous skin eyes (including optic nerve) gross observations a. Both femur/knee joints were taken from 90-day exposure rats . One femur/knee joint was frozen and the other processed as described below. b. The mandible was taken from 90-day exposure and one-month recovery animals. One-half o f the mandible was frozen and the other half processed as described below. c. Bone marrow was collected with the femur and sternum. The following tissues were collected from three-month recovery group rats sacrificed by design: liver, kidneys, thyroid gland, nose, testes, and fat (approximately 1 gram). The testes, fat and portions of the liver and kidney were placed in plastic freezer bags and stored frozen ; these tissues may be evaluated in the future for total fluorine levels to study the distribution of the test substance. Resulting data will be reported separately. The following tissues were weighed from rats sacrificed by design in the 90-day exposure group and the one-month recovery groups: liver, kidneys, adrenal glands, brain, spleen, thymus, heart, ovaries, uterus, epididymides, and testes. Organ weight/final body weight and organ weight/brain weight ratios were calculated. The thyroid gland (after fixation) was also weighed in the Pi adults. Liver, kidneys, thyroid gland (after fixation), and testes from rats sacrificed by design after three months recovery were weighed and organ weight/final body weight ratios were calculated. Organ weight/brain weight ratios were not determined for three-month sacrifice rats. Gross lesions which were diagnosed at necropsy and for which microscopic examination was not appropriate (e.g., fluid accumulation, ruffled fur, missing anatomic parts) were generally not Company Sanitized. D oes not contain TSCA CBI 31 H-24516: Subchrome Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 collected. Gross lesions for which a microscopic diagnosis would not be additive (e.g., osteoarthritis, pododermatitis, chronic dermatitis o f the tail, urinary calculi, and deformity of the teeth, toe, tail, or pinna) were saved but were generally not processed for microscopic evaluation. Testes, epididymides, and eyes were fixed in Bouin's solution. All other tissues were fixed in 10% neutral buffered formalin. Processed tissues were embedded in paraffin, cut at a nominal thickness o f 5 micrometers, stained with hematoxylin and eosin (H&E), and examined microscopically. All collected tissues from exposure group rats sacrificed on test days 91/93 from control and 250 mg/kg/day rats, and all found dead or accidentally killed rats were processed and received a full histopathologieal examination. Liver, kidneys, thyroid gland, nose, and mandible were processed from 25 and 100 mg/kg/day 90-day exposure group rats and from one-month recovery rats. Liver, kidneys, thyroid gland, and nose from males and thyroid gland and nose from females sacrificed after the three-month recovery period were processed from all groups. Tissues were microscopically examined in descending order of dose until a no-effect level was reached. S. Reproductive Assessment 1. Breeding After approximately 10 weeks o f exposure to the test substance, on test day 74, each female was continually housed on a 1:1 basis with a randomly selected male of the same dose concentration level in the male's cage. On the day copulation was confirmed, the female was transferred back to individual cage housing. Mating pairs were cohoused until evidence o f copulation was observed (designated as day 0 o f 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 o f estrous cycle. This data is not presented in the report but is included in the : study records. 3. Gestation Procedures Female rats were transferred to polycarbonate pans (on day 20 o f 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. 0@ m py Sanitized. D ees no contain TSC C ll 32 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 4. Lactation Procedures The day when delivery was complete was designated day 0 postpartum. At each examination period, pups were individually handled and examined for abnormal behavior and appearance; any dead, missing, or abnormal pups were recorded. a. Day 0 Postpartum Live and dead pups in each litter were counted as soon as possible after delivery was completed. Live pups in each litter were individually weighed. b. Day 4 Postpartum Litters were culled randomly to 8 (4/sex when possible). Extra pups were euthanatized (by decapitation) and discarded without pathological examination. Litters of 8 pups or less were not reduced. Litter counts were recorded prior to and after culling, and individual pup weights were recorded prior to culling. c. Days 7 and 14 Postpartum Pups in each litter were counted by sex and individually weighed. d. Day 21 Postpartum (Weaning) Pups in each litter were counted by sex and individually weighed (3 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 o f developmental landmarks. At each examination period, offspring were individually handled and examined for abnormal behavior and appearance; any dead, missing, or abnormal pups were recorded. 5. Post Weaning and Developmental Landmarks Developmental landmarks in the Fi generation male and female rats (one/sex/litter) were monitored on a daily basis until criterion was achieved. Once developmental landmark criterion was achieved, the animals were weighed. Body weight and food consumption were also determined weekly until postnatal day 56 (test day 36). a. Vaginal Patency Female rats were examined beginning on postpartum day 21. b. Preputial Separation Male rats were examined beginning on postpartum day 35. Company 33 n* nnt t$CA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 T. Anatomical Pathology - Rats Designated for Reproductive Evaluations 1. Pi Adults All rats found dead, accidentally killed, or sacrificed in extremis prior to the cohabitation period underwent a gross and microscopic evaluation. The tissues collected are the same as those for rats designated for the 90-day exposure period. All Pi parental rats were sacrificed by carbon dioxide asphyxiation and exsanguination, and subjected to gross pathological examination, including the females that died and those for which mating did not result in a production of offspring. The uteri of all cohabited females were examined for the presence and number of implantation sites. Sperm parameters for the first 10 out of 20 Pi male animals in each treatment group were evaluated. The right cauda epididymis was weighed. Sperm was collected from the right cauda epididymis and percent motility and morphology was determined. The left epididymis and testis were frozen in liquid nitrogen and stored between -65 and -85 C for sperm and spermatid counts, respectively. The right testis and epididymis from these 10 rats were saved and placed in fixative. The following table lists tissues that were collected: Male Tissues Collected from Pi Adults Female Both Sexes Testes/Testis2 ` Ovaries Epididymides/Epididymis3 Uterus (with oviducts) Prostate Vagina Thyroid Glandb Gross Observations' Pituitary Gland Seminal Vesicles Coagulating Gland a Testes/Testis and epididymides/epididymis collected from male rats were placed in Bouin's solution. All other tissues (reproductive and non-reproductive) collected from male and female rats were placed in formalin. b Thyroid glands were weighed after fixation. c Gross lesions observed at necropsy for which histopathology was not appropriate or would not be additive were generally not collected. 2. Offspring Offspring that were found dead dining the lactation period underwent a gross pathological evaluation. 3. Fi Weanlings Three F] weanlings/sex/litter (randomly selected), litter size permitting, were sacrificed by carbon dioxide asphyxiation and underwent a gross pathological evaluation on postnatal day 21. Gross lesions were preserved. Sanitized. Does not eontaSn TSC CB1 34 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 4. Fi Adults All Fi generation rats were sacrificed by carbon dioxide asphyxiation and exsanguination, and subjected to a gross pathological examination. Selected tissues and gross lesions were preserved. The following table lists tissues that were collected and/or weighed: Male Tissues Collected from Fi Adults Female Both Sexes Testes Epididymides Prostate Seminal Vesicles Coagulating Gland Ovaries Uterus (with oviducts) Vagina Thyroid Gland Gross Observations Pituitary Liver Kidney Nose Male Tissues Weighed from Fi Adults Female Both Sexes Testes Epididymides Seminal Vesicles (with coagulating glands) Prostate Uterus (with oviducts and cervix) Thyroid Gland (after fixation) Liver Brain Kidney Processed tissues for histopathological examination were embedded in paraffin, cut at a nominal thickness of 5 micrometers, and stained with hematoxylin and eosin (H&E). Histopathological examination of reproductive organs was conducted only for Pi males and females with impaired reproductive performance. Selected gross lesions were evaluated microscopically. Gross lesions observed at necropsy for which histopathology was not appropriate or would not be additive were generally not collected. U. Biochemical Measurements Following 10 or approximately 90 days of test substance administration, after 36 days on recovery, or after 92 days on recovery (control and high-dose only), five rats from each group designated for biochemical evaluation were weighed and then sacrificed by CO2 anesthesia and exsanguination. Rats were fasted overnight on the afternoon before their sacrifice. The livers were removed, weighed, and then homogenized (1 gram tissue/4 mL buffer). Hepatic peroxisomes were prepared using differential centrifugation. The resulting peroxisomal pellets were resuspended in the homogenization buffer, aliquoted, and stored between -65 and -85C until analyzed for peroxisomal P-oxidation activity. The peroxisomal suspensions were diluted to a protein concentration of approximately 0.25 mg/mL. Peroxisomal P-oxidation activity was .Company Sanitized. D oes not contain TSCA CBI 35 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 determined using [14C]palmitoyl CoA as the substrate. The protein content of the peroxisomes was determined before and after analysis by the Biorad method. V. Statistical Analyses Except for Bartlett's test (p < 0.005), significance was judged at p < 0.05. Separate analyses were performed on the data for each gender. Parameter Body Weight Body Weight Gain Food Consumption Food Efficiency Organ Weight Preliminary Test Test for lack o f trend(9> Levene's test for homogeneity025 and Shapiro-Wilk test035 for normality11 Method o f Statistical Analysis If preliminary test is not If preliminary test is significant significant Sequential application0115 Preliminary tests for o f the Jonckheere-Terpstra pairwise comparison trend test0 15 ORa One-way analysis o f variance045 followed with Dunnett's test05 Kruskall-Wallis test055 followed with Dunn's test05 Motor Activity0 Grip Strength Levene's test for homogeneity025 and Shapiro-Wilk test035 for normality15 Bartlett's test085 for homogeneity o f variances Repeated measures analysis o f variance065 followed by contrasts075 One-way analysis o f variance045 followed with Dunnett's test05 Sequential application005 o f the Jonckheere-Terpstra trend test015 Kruskall-Wallis test055 followed with Dunn's test05 Clinical Pathologyd Levene's test for homogeneity025 and Shapiro-Wilk test035 for normality15 One-way analysis o f variance045 followed with Dunnett's test05 Kruskall-Wallis test055 followed with Dunn's test05 Survival Incidence o f Clinical Observations Incidence o f FOB Descriptive Parameters Biochemical Measurements None None Cochran-Armitage test for trend4)e One-way analysis o f variance045 followed with Dunnett's test05 or Dunn's test05 Incidence o f Microscopic Lesions None None a iPairwise comparisons and associated preliminary tests were only Conducted if the test for lack o f trend was significant. b If the Shapiro-Wilk test was not significant but Levene's test was significant, a robust version o f Dunnett's test was used. c Test day and block (10-minute EPOCH) was used as repeated-measure factors. d When an individual observation was recorded as being less than a certain value, calculations were performed on half the recorded value. For example, if bilirubin was reported as <0.1, 0.05 was used for any calculations performed with that bilirubin data. e If the incidence was not significant, but a significant lack o f fit occurred, then Fisher's Exact test095 with a Bonferroni correction was used. Company SanWzed. Does not contain TSCA CBI 36 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 The following table lists the indices of reproductive function that were calculated for the P1 and Fj adults. Parameter Body Weight Body Weight Gain Food Consumption Gestation Length Organ Weight Implantation Site Numbers Implantation Efficiency Mean Number of Pups Per Litter Percent Bom Alive Precoital Interval Estrous Cycle Length Sperm Parameters Vaginal Patency Preputial Separation Food Efficiency Preliminary Test Test for lack of trend01 Method of Statistical Analysis If preliminary test is If preliminary test is not significant significant Sequential application001of the Jonckheere-Terpstra Preliminary tests for pairwise comparison trend test00 ORa Levene's test for homogeneity(12) and Shapiro-Wilk test (13)for normality15 One-way analysis of variance041followed with Dunnett's test01 Kruskall-Wallis test 5)followed with Dunn's test01 None One-way analysis of variance1 followed with Dunnett's test01 Incidence of Clinical Observations Mating Index Fertility Index Gestation Index Viability Index Lactation Index None Cochran-Armitage test for trend4)c Mean Pup Weights (Covariates: litter size, sex ratio) Sex Ratio None Linear contrast of least squares means001 Dunn's test01 a Pairwise comparisons and associated preliminary tests were only conducted i f the test for lack o f trend was significant. b If the Shapiro-Wilk test was not significant but Levene's test was significant, a robust version o f Dunnett's test was used. c If the incidence was not significant, but a significant lack o f fit occurred, then Fisher's Exact test with a Bonferroni correction was used. Pompany Sanitized. not eortate TSC 11 37 H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 For each parameter analyzed with a trend test, the test was applied to the data sequentially. If a significant dose-response was detected, data from the top dose group were excluded and the test repeated until no significant trend was detected/105 For litter parameters, the proportion of affected fetuses per litter or the litter mean was used as the experimental unit for statistical evaluation/21-1 Where the data are tied and the standard large sample version o f Jonckheere's test is not applicable, exact p values were calculated using permutation methodology/225 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. Sanitized. D oes not contain TSCA CBS ompany 38 H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 RESULTS AND DISCUSSION )) gsmpMf Sanitised. B@s not amteimTSC 11 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations ANALYTICAL EVALUATIONS DuPont-5386 A. Test Substance Stability Analyses of bulk samples o f H-24516 near the beginning and end of the study for stability indicated that the test substance was stable for the duration o f the study. The average percent of H-24516 in th ^ a m p le submitted near the beginning o f the study (test day 7) and analyzed (test day 23) w a s f l ^ ^ p l T h e average percent of H-24516TiGhe sample submitted at the e ^ ^ rfttie studWtest (U^9^^mdanalyzed (test day 105) w a n ^ ^ H ^ T h i s work c&U^fomid M tf f lt i- 2 4 5 16 , p | j j | n T h e purity was reporteab^m e sponsor to b e ^ |H B " h e differences I r ^ d u l s between the sponsor reported purity and the experimental data represent analytical variability and not instability of the test substance. B. Chromatography H-24516 eluted from the GC column as resolved peaks with retention times from 2.9 minutes to approximately 6.0 minutes. For the purpose o f quantitation, resolved peaks at th e ^ te n tio ^ im e ^ of approximately 3.5, 4.17, and 4.77 minutes were used. The internal s ta n d a r d ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ """fluted as a resolved peak at approximately 3.99 minutes. Representative GC chromatograms are shown in Appendix A, Figures 2(a - c). Test substance was not detected in the 0 mg/mL control. C. Homogeneity, Concentration Verification and Stability Samples for Initial Mixing Procedures and Concentrations Based on Dose Volume of 10 mL/kg (Test Day 0 to Test Day 41) Analytical results from dosing suspensions collected on test day 0 and test day 6 and analyzed for homogeneity/concentration verification and 5-hour room temperature stability are shown in Table 1 and Appendix A, Table I. The following table summarizes the results for homogeneity, concentration verification and stability analyses. Preparation Date Test Day 0 Nominal mg/mL 0 2.5 10 25 Measured T,M,Ba mg/mL ND 2.30, 2.47, 2.40 8.97, 10.2, 14.0 26.8,24.8,23.5 Mean (T,M,B) % Nominal -- 95.6 111.0 , 100.0 C.V. (%) -- 3 24 7 Stability15 % Nominal -- 82.4 88.9 96.4 Test Day 6 0 10 NDC 9.26, 9.58, 9.23 -- 93.6 -- 2 a Mean results for the analysis o f the top (T), middle (M) and bottom (B) samples, b Samples held 5 hours at room temperature, c Denotes none detected. -- 90.3 C om p any S a n itized . D o e s not con tain TSC CBS H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 The data for samples collected on test day 0 indicates that the test substance was homogeneously mixed in the vehicle except for the 10 mg/mL level (C.V. = 24). The test substance was at the targeted concentration in the samples (+ 11% of nominal) and was stable in the vehicle when held 5 hours at room temperature. The 10 mg/mL level samples were collected again on test day 6 to show that the mixing and the room temperature stability was acceptable. The data indicated that the test substance was homogeneously mixed in the vehicle (C.V. = 2%), at the targeted concentration in the samples ( 6.4% o f nominal) and stable in the vehicle when held 5 hours at room temperature. The lower than expected result for the 2.5 mg/mL (82.4% of nominal) for the 5-hour sample was within the targeted range o f the study ( 20% of nominal) and is due to sampling and analytical variability of the method and not stability of the test material in the vehicle. This was concluded based on the data from the remainder of the levels in this study, which were stable for the 5-hour room temperature period. Test substance was not found in the 0 mg/mL samples. D. Mixing and Stability Study for Change in Frequency of Dosing Preparation (2 times/week) and Dose Volume Change (5 mL/Kg to 7.5 mL/Kg) This work was done prior to initiating any mixing or storage condition changes in the study. Analytical results from dosing suspensions collected for the special mixing study and analyzed to verify homogeneity and/or concentration with stability are shown in Table 1 and Appendix A, Table II. fBompsartf Sanitized. O ses no eontain TSCA CB1 41 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 The following table summarizes the results for homogeneity/concentration verification and stability analyses. Dose Volume Sample Type 5.0 mL/kg Homogeneity Stability 2-Day Refrigerated11 3-Day Refrigerated11 4-Day Refrigeratedf Nominal mg/mL 0 5.0 20 50 5.0 5.0 5.0 Measured mg/mL ND 4.53,4.25,4.39 19.9,17.7,18.6 53.4, 52.6, 54.0 4.77,4.76 4.74,4.48 4.81 Mean % Nominal -- 87.8 93.5 106.6 95.4 92.2 96.1 C.V. (%) -- 3 6 1 0.2 4 -- Stability3 % Nominal -- 92.0 86.0 96.6 -- -- 97.1 2-Day Refrigerated*1 3-Day Refrigerated*1 4-Day Refrigeratedf 20 20 . 20 18.7, 18.0 39.3, 19.6e 19.6 91.5 147.0 97.8 3-- 47 -- 88.2 2-Day Refrigerated*1 3-Day Refrigerated*1 4-Day Refrigeratedf 50 50 50 47.3, 48.4 46.5,46.9 48,9 95.8 2 -- 93.4 1-- 97.8 95.7 7.5 mL/kg Homogeneity Stability 4-Day Refrigerated8 0' 3.33 3.33 NDC 2.88, 2.54, 2.67 2.94, 2.88 -- 81.1 87.4 ---- 6 79.9 1 82.3 a Samples held 5 hours at room temperature. b Mean results for the analysis o f the top (T), middle (M) and bottom (B) samples, c Denotes none detected. d Mean results o f duplicate concentration verification samples. e Original analysis not reported because o f apparent aliquot error. Mean result o f duplicate re-analysis (n--2) o f the original sample reported. f Mean result o f single sample for concentration verification and a single sample for 5-hour room temperature stability. g Mean result o f duplicate samples for concentration verification and a single sample for 5-hour room temperature stability. The data for samples collected initially (5.0 mL/kg dose volume change) indicate that the test substance was homogeneously mixed in the vehicle, at the targeted concentration ( 12.2% of nominal) and was stable in the vehicle when held.4 days refrigerated followed by 5 hours at room temperature. The higher than expected result for the 3-Day refrigerated samples at the 20 mg/mL level (147.0% o f nominal, C.V. = 47%) indicates that the test substance was not properly re-dispersed in the vehicle after refrigeration and before sampling. This was concluded because duplicate samples were collected and analyzed with one o f the samples having a higher than expected result (39.3 mg/mL) in the analysis. The sample was reanalyzed and the results supported the duplicate reported analysis. This data along with the results from the last sampling time at this level (4-day reffigerated/97.8% of nominal) supported this conclusion. Company Sanitized. D oes not contain TSCACBI 42 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 The data for samples collected for the 7.5 mL/kg dose volume change indicate that the test substance was homogeneously mixed in the vehicle for the 3.33 mg/mL level (C.V. = 6) and stable in the vehicle when held 5 hours at room temperature. The concentration was lower than expected (81.1% of nominal) but was probably due to initial sampling o f the mixture before adequate mixing. The results from the 4-day refrigerated samples from the same preparation indicated the material was at the targeted level ( 12.6% o f nominal) and stable when held 4 days refrigerated followed by 5 hours at room temperature. The results from this mixing and stability study indicated that the mixing time for preparation of the suspensions before use with the animals would have to be monitored for both the initial preparation and the re-dispersion of the suspensions after refrigeration. The test substance was shown to be stable in the vehicle over the concentration range needed for the dose volume change and under the storage conditions for the change in frequency o f preparation (3 or 4 days/ twice a week) of the dosing suspensions. E. Homogeneity and Concentration Verification Samples for Final Mixing Procedures and Concentration Change Based on Dose Volume of 7.5 mg/kg (Test Day 42) Analytical results from dosing suspensions collected on test day 49 and test day 91 and analyzed for homogeneity and/or concentration verification are shown in Table 1 and Appendix A, Table III. The following table summarizes the results for homogeneity and concentration verification analyses. Preparation Date Test Day 49 Nominal mg/mL 0 3.33 13.33 33.33 Measured T,M,Ba mg/mL NDb 2.71,2.99,3.42 10.8, 12.7,12.8 31.0, 32.4, 33.4 Mean (T,M,B) % Nominal -- 91.3 90.8 96.8 C.V. (%) -- 12 9 4 Test Day 91 0 3.33 13.33 33.33c NDb 3.05, 3.00, 3.01 12.8,12.2 32.7, 32.3 -- 90.7 93.8 97.5 -- 1 3 1 a Mean results for the analysis o f the top (T), middle (M) and bottom (B) samples, b Denotes none detected. c Duplicate samples submitted. C.V. for the duplicate samples used to confirm uniformity o f mixture. The data for samples collected on test day 49 indicates that the test substance was homogeneously mixed in the vehicle except for the 3.33 mg/mL level (C.V. = 12). The test substance was at the targeted concentration in the samples ( 9.2% o f nominal). The data for samples collected on test day 91 show that the 3.33 mg/mL level was homogeneously mixed, indicated that the test substance was properly mixed in the vehicle Ssempwf Sattilfed D@snot contain TS6A CBi 43 H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 (C.V. = 1%) and at the targeted concentration in the samples ( 9.3% of nominal). The data for the duplicate concentration verification samples for the remaining levels indicated that the test substance was at the targeted level (+ 6.2% of nominal) and mixed properly (C.V. s --3 and 1/o, respectively). Test substance was not found in the 0 mg/mL samples. F. Analytical Conclusions Data from the analysis o f the samples at the initiation o f the study indicate that the test substance in the vehicle was mixed homogeneously, was at the targeted levels and was stable for 5 hours at room temperature. Data for the analysis o f the samples after the mixing and dose volume changes indicated that the test substance in the vehicle was mixed homogeneously and at the targeted levels. All stability conditions were addressed in the additional stability/mixing study and the test substance in the vehicle had been shown to be stable after 4 days of refrigeration followed by 5 hours at room temperature over the concentration range. The data also indicated that controlled mixing was necessary for the initial mixing and redispersion of the test substance in the vehicle after refrigeration. Test substance was not found in the 0 mg/mL samples. Analysis of the test substance near the beginning and the end o f the study indicates that the H-24516 was stable during the study. vI /) TSG,'SB 44 H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 SUBCHRONIC TOXICITY EVALUATIONS IN-LIFE TOXICOLOGY A. Dosage Data (Tables 2-3, Appendix B) Rats were dosed with suspensions of H-24516 in 0.5% aqueous methylcellulose, prepared at concentrations of 0, 2.5, 10, and 25 mg/ml, designed to deliver the targeted dose of test substance at a dosing volume o f 10 ml/kg body weight. However, in order to administer a dose volume under 5 mL to comply with animal welfare guidelines, the dosing volume for male and female rats was decreased from lOmL/kg to 7.5 mL/kg and the suspension concentrations were increased to 3.33,13.33, and 33.33 mg/mL on test day 38. The quantity of H-24516 administered to each rat was calculated, based on the most recent body weight for each rat, and subsequently rounded by a computer program. The range of mean daily dose volumes administered to male rats was 2.5-4.6 mL for the control group, 2.5-4.6 mL for the 25 mg/kg/day group, 2.5-4.6 mL for the 100 mg/kg/day group, and 2.5-4.6 mL for the 250 mg/kg/day group. The range of mean daily dose volumes administered to female rats was 1.9-2.8 mL for the control group, 1.9-2.8 mL for the 25 mg/kg/day group, 1.9 2.6 mL for the 100 mg/kg/day group, and 1.9-2.8 mL for the 250 mg/kg/day group. B. Mean Body Weights and Body Weight Gains (Tables 4-7, Figures 1-2, Appendices C-D) Statistically significant decrements in body weight compared to control were observed in males in the 100 mg/kg/day dose group after day 77 (7-8%) and in the 250 mg/kg/day group after test day 56 (6-14%). Statistically significant decrements in body weight in females compared to control were observed in the 100 mg/kg/day dose group after day 77 (6-7%) and in the 250 mg/kg/day group after test day 56 (6-12%). These weight gain differences appear to be directly related to test-substance induced adverse effects to the teeth (see Section C and Anatomic Pathology Report) and subsequent decreases in food consumption in the 100 mg/kg/day female and 250 mg/kg/day male and female groups (see Section C). The 250 mg/kg/day male group had significantly lower mean body weight gains compared to control over the course o f the study. Significantly lower mean body weight gains were observed for the 100 mg/kg/day male group during the 35-42 and 49-56 day intervals. A significantly lower mean body weight gain also occurred for the 25 mg/kg/day male group during the 35-42 day interval. The mean body weight gain of the 250 mg/kg/day male group was significantly higher than the mean weight gain of male controls during the first week o f the study and during the 77-84 and 84-90 day intervals. The increased mean body weight gains observed after test day 77 appear to be associated with an increase in food consumption and food efficiency after both the male and female rats in the 250 mg/kg/day dosage group were placed on ground chow because of adverse effects to the teeth. Overall (0-90 day interval), significantly lower mean Company Sanitized. D oes not contain TSCA CM 45 H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 body weight gains o f 13% and 16% compared to control occurred in the 100 and 250 mg/kg/day male groups. This reduction in body weight gain was considered test substance-related and toxicologically significant. The 250 mg/kg/day female group had significantly lower mean body weight gains compared to the control group over the course o f the study. Significantly lower mean body weight gains also occurred for the 100 mg/kg/day female group during the 28-35 day interval and for both the 25 and 100 mg/kg/day groups during the 42-49 day interval. The mean body weight gain o f the 250 g/kg/day group was significantly higher than control during the second week of the study and during the 77-84 day interval. As with males, the increased body weight gain occurring after test day 77 appears to be associated with an increase in food consumption and food efficiency (see Section B) after the animals were placed on ground chow. Overall (0-91 day interval), significantly lower mean body weight gains o f 12% occurred in both the 100 and 250 mg/kg/day female groups. The mean body weight and body weight gain decrements observed for the 100 g/kg/day and 250 mg/kg/day female groups, however, were of small magnitude and were associated with decreased food consumption but not with any alterations in food efficiency (see Section B). Therefore, the statistically significant mean body weight and body weight gain decrements for the 100 mg/kg/day and 250 mg/kg/day females were considered to be test substance-related but not toxicologically significant. Furthermore, the decrements in body weight parameters observed for both males and females appear to be related to test substanceinduced adverse effects to the teeth (see Section D and Pathology Section) and subsequent decreased ability o f the animals to eat the pelleted chow. Following a one-month recovery period, the mean body weight and body weight gain of both male and female rats that received 250 mg/kg/day approached control. For the overall one-month recovery period (90-119 day interval), a statistically significant decrement in mean body weight gain occurred for the 100 mg/kg/day group. The lower mean body weight gain did not occur in a dose-dependent manner and appeared to be due to test substance-induced adverse effects to the teeth and a subsequent large decrease in food consumption for one male in the 100 mg/kg/day group. Therefore, this effect was not considered toxicologically significant. Following the threemonth recovery period, the mean body weight (females only) and body weight gain of both males and females exceeded control levels. C. Food Consumption and Food Efficiency (Tables 8-11, Appendix E) Male rats in the 250 mg/kg/day group had statistically significant and lower food consumption compared to control over the course of the study. Overall (0-90 day interval), a significantly lower food consumption of 7% compared to control occurred in the 250 mg/kg/day male group. Females in the 100 and 250 mg/kg/day had statistically significant and lower food consumption compared to control over the course of the study. Overall (0-91 day interval), significantly lower food consumption o f 9% and 8% occurred in the 100 and 250 mg/kg/day female groups. However, after the rats received ground chow as a result o f tooth toxicity, their food consumption immediately increased and began to approach or exceed (female 77-84 day interval) control gmrnpmm Sm Mm iI. 0@s contain 1BCA CH 1 46 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 levels. Test-substance related and statistically significant effects on food consumption were observed in the 100 mg/kg/day female and 250 mg/kg/day male and female groups. Male rats in the 250 mg/kg/day group had significantly lower mean food efficiency compared to control over the course of the study except during the first and third week of the study and test days 77-84 and 84-91 in which significantly higher food efficiencies were observed. The 100 mg/kg/day male group had significantly lower mean food efficiency during test days 35-42 and 49-56. For the entire study interval, significantly lower food efficiencies o f 8% and 9%, respectively, were observed for the 100 and 250 mg/kg/day male groups. With the exception o f the first two weeks o f the study and test days 77-84 in which a significantly higher mean food efficiency occurred, female rats in the 250 mg/kg/day group had significantly lower mean food efficiency compared to control over the course o f the study. A significantly lower mean food efficiency was also observed for the 100 mg/kg/day female group during test days 28-35, 42-49, and 49-56, while a significant increase occurred during test days 35-42. During test days 42-49, the 25 mg/kg/day female group had significantly lower mean food efficiency. These differences were not considered to be o f toxicological significance as overall mean food efficiencies for test-substance treated female groups were similar to control. The decreased mean food efficiency in the 250 mg/kg/day male group appears to be directly related to test substance-induced toxicity of the teeth. Following the replacement of pelleted chow with ground chow on test day 77 for the 250 mg/kg/day male and female groups, a significantly higher mean food efficiency was observed for the 77-84 and 84-90 (males only) day intervals. Nevertheless, based on the parallel reduction in body weight parameters observed in the 100 and 250 mg/kg/day male groups, this reduction in food efficiency is considered to be toxicologically significant. After a one-month recovery period, mean food consumption in the 250 mg/kg/day male group was still significantly lower, while mean food efficiency was the same as that observed in control rats. For females, lower food consumption was also observed following the one-month recovery period. For the overall one-month recovery period (90-119 day interval), a statistically significant decrement in mean food efficiency occurred for the 100 mg/kg/day male and female groups. The lower mean food efficiency did not occur in a dose-dependant manner and therefore was not considered to be toxicologically significant. Following three months of recovery, mean food consumption for males and females was similar to control levels, while mean food efficiency for the 250 mg/kg/day males exceeded control levels. D. Clinical Observations, Ophthalmology Evaluations, and Survival (Tables 12-17, Appendix F) , A test substance-related, toxicologically significant increase in the incidence of broken (males) and absent teeth (males and females) was observed in the 250 mg/kg/day dose group. In addition, there was an increase in tooth clipping required for both males and females in the 250 g/kg/day dose group. There was also a statistically significant increase compared to control in the incidence of stained red perineum and clear discharge from the mouth in the 250 g/kg/day male dose group. The increased incidence o f stained red perineum and clear discharge from the mouth was considered to be test substance-related. 47 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 No test substance-related ophthalmological signs of toxicity or effects on survival were observed. E. In-Life Toxicology Conclusions Under the conditions o f this study, the no-observed-effect-level (NOEL) for in-life toxicology parameters (body weight, body weight gain, food consumption, food efficiency, and clinical signs of toxicity) was 25 mg/kg/day for males and 100 mg/kg/day for females. NEUROBEHAVIORAL TOXICOLOGY A. Sensory Function Evaluations 1. Forelimb Grip Strength (Table 18-19, Figures 3-4, Appendix G) There were no test substance-related effects or statistically significant differences on forelimb grip strength in males or females administered any dosage of H-24516. Females administered 100 or 250 mg/kg/day had slightly lower (12% and 14% lower than the control value, respectively) forelimb grip strength at week 13, however, a linear dose response-relationship was not present, and the values were within the range of normal variation for this measurement. In addition, the forelimb grip strength in the control group during the recovery evaluation was similar to the values o f the 100 and 250 mg/kg/day female groups during the week 13 evaluation demonstrating the degree of variability in this type of measurement. Therefore, the slightly lower forelimb grip strength in 100 and 250 mg/kg/day females was not considered to be test substance-related. 2. Hindlimb Grip Strength (Table 18-19, Figures 5-6, Appendix G) There were no test substance-related effects or statistically significant differences in hindlimb grip strength for either males or females administered any dosage o f H-24516. 3. Sensory Function Observation (Table 20-21, Appendix H) There were no test substance-related changes in neurobehavioral parameters in males or females administered any dosage of H-24516. B. Motor Activity (Tables 22-25, Figures 7-10, Appendices I-J) There were no test substance-related effects on duration o f movement or number of movements for males or females for any dosage tested. Males assigned to the 100 and 250 mg/kg/day group had significantly lower mean duration o f movement during the third 10-minute interval for the baseline evaluation. In addition, mean duration of movements was significantly lower for 25, JSompaity Sanitized. D oes not contain TSCA CBt 48 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 100, and 250 mg/kg/day males compared to control during the fourth 10-minute interval o f the baseline evaluation. However, test substance administration had not been initiated, and therefore, these statistical differences were not considered to be test substance related. Females in the 250 mg/kg/day group had significantly lower total duration o f movement and number of movements during the recovery evaluation. The total duration o f movements for both the control females and 250 mg/kg/day females was lower relative to the baseline and week 13 evaluations. However, the number o f movements for both control and the 250 mg/kg/day females were within the range o f baseline values for females in this study. Since there was no increase or decrease from the range of baseline values with respect to number of movements, and since there were no changes in motor activity observed at week 13 or in any other neurobehavioral parameter, the statistically significant differences compared to control were not considered to be test substance related. C. Neurobehavioral Toxicity Conclusions Under the conditions of the study, the no-observable-effect level (NOEL) for neurobehavioral parameters was 250 mg/kg/day in males and females, the highest concentration tested. PoMpafflf SaW*s<i. Does copain TSC CB 49 H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 CLINICAL PATHOLOGY A. Hematology/Coagulation (Tables 26-29, Appendix K) Rats dosed with 250 mg/kg/day had minimally decreased RBC mass parameters (RBC, hemoglobin, hematocrit; variable statistical significance) (Clinical Pathology Text Table 1). These decrements were associated with minimally increased RDW in both sexes, anisocytosis, microcytes, and increased reticulocytes in males, and poikiloeytosis in females. Following the approximately one-month recovery period, male rats previously dosed with 250 mg/kg/day still had minimally to mildly decreased red cell mass parameters, and decreased reticulocytes compared to control group rats. Female rats previously dosed with 250 mg/kg/day had red cell mass parameters similar to controls by day 125, although MCV, MCH, RDW and reticulocytes were decreased. The minimal red cell effects discussed above are not expected to affect red cell function or the health of the animal. Nevertheless, based on the progressive nature of the effects during treatment and the persistence of many effects into the recovery period, the red cell changes noted at 250 mg/kg/day were considered toxicologically adverse. Clinical Pathology Text Table 1: Red cell mass parameters as a percent of control group mean* Males Param eter Interval 25 100 250 Ferna es 25 100 250 RBC Day 44/45 101% 97% 98% Day 91/93 97% 93% 90% Day 125 89% 95% 99% 94% 96% 97% 93% 101% HGB Day 44/45 101% 100% 98% Day 91/93 99% 98% 93% Day 125 92% 96% 98% 94% 98% 97% 92% 98% HCT Day 44/45 101% 100% 98% Day 91/93 97% 97% 93% Day 125 91% 96% 97% 96% 97% * Statistical significance indicated by bold italicized type 94% 92% 97% Females dosed with 250 mg/kg/day had shortened APTTs at day 93. This change was not considered to be treatment related because there was no clear dose-related response. Similar APTTs were present in all treated groups. Additionally, shortened coagulation times are not considered adverse; prolonged, rather than shortened, coagulation times are toxicologically significant. Because there were no treatment-related alterations in coagulation parameters at the end of dosing, coagulation parameters were not measured at the end o f the one-month recovery (Day 125). Company Sa"'9S',<41 -- *"=~ CBI 50 H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 The following minimal but statistically significant changes in hematology parameters were considered to be unrelated to treatment because they did not occur in a dose related manner: Decreased hemoglobin and hematocrit in females dosed with 25 mg/kg/day at Day 45 Increased MCH in males dosed with 100 mg/kg/day, and increased MCHC in males dosed with 25 mg/kg/day at Day 91 Increased eosinophils in males dosed with 25 mg/kg/day at Day 44, and decreased eosinophils in females dosed with 25 mg/kg/day at day 45. The following minimal but statistically significant changes in hematology parameters were considered to be unrelated to treatment because they only occurred after one month o f recovery: Increased neutrophils in females dosed with 100 (day 93) or 250 mg/kg/day (day 125; recovery) Increased eosinophils in females dosed with 250 mg/kg/day (day 125 recovery) Decreased APTT in males dosed with 25 or 100 mg/kg/day at day 91 was not considered adverse because decreases in coagulation times are not associated with toxicity. Red cell counts were statistically deceased at test day 91 in males dosed with 100 mg/kg/day. This change was small, was not associated with changes in other red cell mass parameters, and did not appear to follow a dose response; and thus was considered unrelated to treatment. B. Clinical Chemistry (Tables 30-31, Appendix K) There were no toxicologically significant changes in clinical chemistry parameters in rats dosed with 25,100 or 250 mg/kg/day. All statistically significant changes in clinical chemistry parameters were considered non-adverse (not toxicologically significant) or unrelated to treatment. These changes are detailed below. Alkaline phosphatase was minimally increased in male rats dosed with 100 (day 91 only) or 250 mg/kg/day (days 44 and 91). Toxicologically important increased ALKP activity generally occurs as a result o f cholestasis, but may also be due to direct enzyme induction by a xenobiotic(23\ In this study, there was no evidence o f cholestasis (bilirubinemia, bilurubinuria, or histologic evidence o f cholestatisis). There was histologic evidence o f enzyme induction (see Anatomic Pathology report). Therefore, the ALKP changes were most likely due to direct enzyme induction and therefore were considered non-adverse. After one month of recovery, alkaline phosphatase activity in 250 mg/kg/day males was similar to control values. jggeapassySanliteed. Dees no1contain TSCft 51 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations Clinical Pathology Text Table 2: Alkaline phosphatase as a percent o f control group mean Day 44 Day 91 Day 125 25 107% 98% Males 100 116% 143% 250 138% 192% 95% * Statistical significance indicated by bold italicized type DuPont-5386 Cholesterol and triglycerides were mildly decreased in males dosed with 100 or 250 mg/kg/day at days 44 and 91 (variable statistical significance). In females dosed with 100 or 250 mg/kg/day, triglycerides only were decreased at days 45 and 93 (variable statistical significance). After one month of recovery, both cholesterol and triglycerides were still statistically decreased in 250 mg/kg/day males. For females, triglycerides in most rats were still minimally decreased after one month of recovery, although there was much variability among individual rats, and values from some previously treated rats were higher than any control rat. Therefore, the relevance of the effect in recovery females is equivocal. The changes in cholesterol and triglycerides were treatment-related and indicate altered lipid metabolism, but were not considered adverse because mild decreases in cholesterol and triglycerides do not have any known adverse effects. Males and females dosed with 100 or 250 mg/kg/day had alterations in serum proteins. The primary change was mildly increased total protein in rats dosed with 100 (females only) or 250 mg/kg/day (variable statistical significance). The increased total protein was generally due to increased albumin; increased albumin also occurred in males dosed with 100 mg/kg/day (day 91), but this change did not affect total protein concentration. Globulin changes were minimal and variable between sexes; at day 91, 250 mg/kg/day males had decreased globulins, while 250 mg/kg/day females had increased globulins. After one month o f recovery, protein concentrations in rats previously dosed with 250 mg/kg/day were similar to control values. The increases in serum protein noted above were primarily due to increased serum albumin. Mildly increased serum albumin is not known to have any adverse consequences, so these protein changes were considered non-adverse. Increased serum albumin in females dosed with 100 or 250 mg/kg/day caused secondary hypercalcemia. Calcium exists in serum in two forms, either bound to albumin or unbound ("ionized" calcium). Ionized calcium is the physiologically active form, and is tightly regulated. Increases in albumin are necessarily associated with physiologically appropriate increased bound calcium, with resultant increased total calcium. However, ionized calcium is unaffected. Thus, increased calcium in association with increased albumin is considered physiologically appropriate and thus non-adverse. After one month of recovery, calcium concentrations in 250 mg/kg/day females were similar to control values. Inorganic phosphorus was minimally and statistically increased in females dosed with 100 or 250 mg/kg/day at day 93 only. After one month o f recovery, inorganic phosphorus values in 250 mg/kg/day females were similar to control values. Increased inorganic phosphorus was not associated with other changes that would indicate toxicity (such as increased urea nitrogen or Som pany Sanitized. D oes not contain TSCA CBI 52 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 creatinine, or histologic changes indicative o f renal damage). In addition, rats with the highest inorganic phosphorus concentration were those dosed with 100 rather than 250 mg/kg/day. Therefore, this minimal change, although possibly related to treatment, was not considered adverse. Sodium and chloride were minimally decreased in males dosed with 250 mg/kg/day at day 91. The magnitude of change in these parameters was very small, and in individual rats there was no consistent relationship between sodium and chloride concentrations. Therefore, these changes, although possibly related to treatment, were considered non-adverse. Potassium was minimally increased in females dosed with 250 mg/kg/day at days 45 and 93. The magnitude o f change was small compared to the normal variability of the parameter, and was not associated with changes that might indicate toxicity. Therefore, this change was considered non adverse. At day 125 (one-month recovery), potassium in 250 mg/kg/day females was similar to control group values. The following minimal but statistically significant changes in clinical chemistry parameters were considered to be unrelated to treatment because they did not occur in a dose-related manner. Transiently increased phosphorus in males dosed with 100 mg/kg/day at Day 44 Decreased creatinine in females dosed with 25 or 100 mg/kg/day at Day 45 (in addition, decreases in creatinine are not toxicologically significant) Increased glucose in females dosed with 25 mg/kg/day at Day 45 Decreased sodium in males dosed with 250 mg/kg/day The following minimal but statistically significant changes in clinical chemistry parameters were considered to be unrelated to treatment because they only occurred after one month of recovery Decreased SDH in males dosed with 250 mg/kg/day (in addition, decreases in SDH are not toxicologically significant) Increased urea nitrogen in males dosed with 250 mg/kg/day Decreased calcium in males dosed with 250 mg/kg/day Decreased sodium in females dosed with 250 mg/kg/day Decreased AST and ALT in females dosed with 250 mg/kg/day at day 45 were considered to be non-adverse because decreases in transaminase activity are not considered toxicologically adverse. C. Urinalysis (Tables 32-33, Appendix K) ' Urine volume was increased in males and females dosed with 250 mg/kg/day at days 44 (males equivocal) and 91 (variable statistical significance). Urine osmolality and specific gravity were correspondingly decreased at these same time-points with statistical significance occurring only for males at 91 days. In addition, in males dosed with 250 mg/kg/day, urine total protein was decreased at day 91. Increased urine volume and decreased urine concentration can occur due to Company Sanitized. D oes not contain TSCA CBt 53 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 decreased renal function or secondary to increased water consumption. Effects on urine volume and concentration in the 250 mg/kg/day groups were not associated with changes in other clinical pathology parameters (creatinine, BUN, phosphorus) indicative o f primary renal toxicity. Furthermore, although renal tubular hypertrophy and increased renal weights were present in male rats, there was no evidence o f cytotoxic effects in the kidney. Therefore, these urinalysis changes were considered non-adverse. At day 125 (one-month recovery), urine volume o f males previously dosed with 250 mg/kg/day was decreased, compared to control and end-of-study results. Urine concentration (measured by osmolality and specific gravity) was correspondingly increased at this time-point. These changes were not considered adverse because production of low levels o f concentrated urine is considered normal for rats. The urine volume and concentration of female rats after recovery were similar to controls. D. Plasma and Urine Fluoride Measurements (Tables 30-33, Appendix K) Plasma fluoride was mildly increased in males and females dosed with 100 or 250 mg/kg/day at day 91/93. At day 125 (one-month recovery), plasma fluoride in 250 mg/kg/day rats was similar to control group values. At the end of the exposure phase of the study, urine fluoride (as determined by total fluoride excreted over the collection period) was increased in a dose-related manner in males and females dosed with 25, 100, or 250 mg/kg/day (Clinical Pathology Text Table 3). At day 125 (one-month recovery), daily urine fluoride excretion was increased in males and females previously treated with 250 mg/kg/day, although levels were markedly reduced relative to those present at the end of exposure. Thus increased urine fluoride showed evidence of reversibility, albeit incomplete, following the one-month recovery period. Additional urine was collected from males and females designated for three months of recovery, to determine whether or not further recovery had occurred. For rats previously dosed with 250 mg/kg/day, urine samples collected at day 181 still contained significant amounts o f fluoride, although the total fluoride was less than at day 125. In addition, urine fluoride at Day 181 was still increased over control group values for males and females previously dosed with 100 mg/kg/day (males statistically significant). Urine fluoride was also probably increased in males and possibly females dosed with 25 mg/kg/day; but the change in females was equivocal due to the low numbers of values and the variability of the data. Increases in plasma and urine fluoride were considered to be secondary to the administration o f a mixture containing fluorinated compounds and/or free fluoride. The presence o f fluoride in mine three months after exposure suggests that fluoride containing compounds are slowly being released from tissue sites. 54 H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 Clinical Pathology Text Table 3: Daily urine fluoride (pg)* Dose (mg/kg/day) Males Day 91 Day 125 Day 181** 0 25 100 250 20.2 213.0 662.7 1473.6 14.2 ND ND 87.4 12.1 22.8 39.1 69.1 25 250 1054% 3281% 7295% ND ND 615% 188% 323% 571% oo Females Day 93 16.7 99.2 460.3 914.7 Day 125 8.6 ND ND 43.8 Day 181** 8.8 15.9 20.0 29.3 594% 2756% 5477% ND ND 509% 181% 227% 333% ND Group not sampled at this time point. * Data presented as absolute values (left) and as percent o f control group mean (right). Bold italicized font indicates that the change was statistically significant ** Data collected from rats designated for biochemical analysis E. Clinical Pathology Conclusions Under the conditions o f this study, the NOEL for males and females was 100 mg/kg/day. These were based on the findings of minimal decreased red cell mass parameters in males and females dosed with 250 mg/kg/day. After one month of recovery, fed cell mass parameters were still decreased in males previously dosed with 250 mg/kg/day, and some hematologic parameters were still altered in females previously dosed with 250 mg/kg/day. There were no adverse findings for coagulation, clinical chemistry, or urinalysis parameters at any dose. Company Sanitized. D oes not contain TSCA CB1 55 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 ANATOMICAL PATHOLOGY A. Subehronic Toxicity and Recovery 1. Organ Weight Data (Tables 36-37, Appendix L) Test substance-related and/or statistically significant increases, compared to controls, in liver weight parameters were present in 25,100, and 250 mg/kg/day males and females sacrificed at the end of the approximately 90-day exposure period. At the 250 mg/kg/day dose level, liver weight parameters remained increased in the one- and three-month recovery group males and females, although the magnitude of these effects was decreased relative to that observed in the 250 mg/kg/day exposure group. No statistically significant liver weight effects were present in the three-month recovery groups previously dosed with 25 or 100 mg/kg/day (organ weights were not evaluated in these groups at one-month recovery). In 100 and 250 mg/kg/day exposure group male rats and 250 mg/kg/day one- and three-month recovery male rats and in 250 mg/kg/day exposure group females, increased liver weights correlated with microscopic hepatocellular hypertrophy (see discussion under Microscopic Findings). Test substance-related and/or statistically significant increases, compared to controls, in one or more kidney weight parameters occurred in male and female rats at all exposure concentrations. Some kidney weight parameters remained increased in males and females in the 250 mg/kg/day one-month recovery groups. However, there were no statistically significant kidney weight changes in any dosed group following three months of recovery. In male rats, increased kidney weights correlated with microscopic tubular hypertrophy in the 100 and 250 mg/kg/day groups sacrificed at the end o f the exposure period and in the 250 mg/kg/day group sacrificed following a one-month recovery period (see discussion under Microscopic Findings). There were no microscopic correlates to kidney weight changes in females. There were no other test substance-related organ weight effects. All other statistically significant organ weight changes in exposure and recovery groups were secondary to decreases in body weight. In 100 and 250 mg/kg/day male rats sacrificed at the end o f the exposure period, organ weight changes included: decreases in absolute organ weight and/or organ weight relative to brain weight for heart and epididymides and increased brain weights relative to body weight. There were no weight changes in heart and epididymides when adjusted to final body weight. In 250 mg/kg/day males sacrificed at the end o f the exposure period, testes weight relative to body weight was increased, however, absolute testes weight was not statistically different from control testes weight. In addition, no test substance-related microscopic changes were present. In female one-month recovery rats brain and adrenal gland weights relative to body weight were increased at 250 mg/kg/day. There were no correlative effects in other weight parameters or microscopic changes in these organs. Weights for these latter organs are generally maintained despite body weight loss, and thus this pattern of organ weight change is also consistent with effects occurring secondary to decrements in body weight. jBsimpamf Sanitized. 0@@not eerrtan TS IB! 56 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 2. Gross Observations (Tables 38-39, Appendix M) Gross observations noted were sporadic across groups and were not test substance-related. 3. . Microscopic Findings (Tables 40-45, Appendix M) Test substance-related microscopic findings were present in teeth, thyroid gland, and liver from male and female rats and in kidneys from male rats. Incidences and Average Lesion Grades of Test Substance-Related Microscopic Findings In Male and Female Rats Dose: mg/kg/day 0 25 Males: Exposure Teeth: Degeneration, ameloblasts (nose) Degeneration, ameloblasts (mandible) 0/10a (0.0)b 0/10 (0.0) 0/10(0.0) 0/10 (0.0) Thyroid gland: Hypertrophy, follicular Alteration, colloid 0/10 (0.0) 9/10 (0.9) 0/10 (0.0) 9/10(1.4) Liver: Hypertrophy, hepatocyte, centrilobular , 0/10 (0.0) 0/10 (0.0) Kidneys: Hypertrophy, tubular 0/10 (0.0) 0/10 (0.0) Males: One-Month Recovery Teeth: Degeneration, ameloblasts (nose) 0/10(0.0) NA Thyroid gland: Alteration, colloid 10/10(1.2) NA Liver: _ Hypertrophy, hepatocyte, centrilobular 0/10 (0.0) NA Kidneys: Hypertrophy, tubular 0/10 (0.0) NA Males: Three-Month Recovery Teeth: Degeneration, ameloblasts (nose) 0/5 (0.0) ' 0/5 (0.0) Thyroid gland: Alteration, colloid 5/5 (1.6) 5/5 (2.6) Liver: Hypertrophy, hepatocyte, centrilobular 0/5 (0.0) NE 100 250 5/10(0.5) 1/9 (0.1) 2/10 (0.2) 9/10 (2.3) 9/10 (0.9) 1/10(0.1) 11/11 (2.0) 10/10(1.8) 10/11 (1.5) 11/11 (2.8) 11/11 (1.9) 11/11 (1.7) NA 9/10(1.3) NA 10/10 (2.7) NA 10/10(1.6) NA 2/10 (0.2) 1/5 (0.2) 5/5 (4.0) 0/5 (0.0) 2/5 (0.6) 5/5 (3.2) 1/5 (0.2) ia s ife id L @s meScomlata TSGj 57 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 Dose: mg/kg/day 0 25 100 250 Females: Exposure Teeth: Degeneration, ameloblasts (nose) Degeneration, ameloblasts (mandible) 0/10(0.0) 0/10(0.0) 0/10 (0.0) 0/9 (0.0) 6/10 (0.6) 0/10 (0.0) 11/11 (2.0) 7/8 (1.4) Thyroid gland: Hypertrophy, follicular Alteration, colloid 0/10 (0.0) 0/10 (0.0) 0/10 (0.0) 6/10(0.6) 0/10 (0.0) 4/10 (0.7) 6/11 (0.5) 7/11 (0.8) Liver: Hypertrophy, hepatocyte, centrilobular 0/10(0.0) 0/10 (0.0) 0/10 (0.0) 9/11 (1.3) Females: One-Month Recovery Teeth: Degeneration, ameloblasts (nose) 0/10(0.0) NA NA 7/10(1.1) Thyroid gland: Alteration, colloid 5/10(0.5) NA NA 9/10(1.1) Females: Three-Month Recovery Teeth: Degeneration, ameloblasts (nose) 0/5 (0.0) NE 0/5 (0.0) 2/5 (0.4) Thyroid gland: Alteration, colloid 5/5 (1.2) 4/4 (1.5) 4/5 (1.0) 5/5 (2.2) a Numerator indicates incidence o f rats with microscopic lesion. Denominator indicates number o f rats in group. b Number in parentheses indicates group average severity o f lesion. NA Tissue not available. NE Tissue not examined. Test substance-related tooth lesions in male and female rats administered 100 or 250 mg/kg/day consisted o f degeneration and/or disorganization of enamel organ ameloblast cells. This lesion was most evident in the upper incisors of the level 1 (anterior) nose section. A similar lesion was present in cross sections o f mandibular teeth, however, the frequency of occurrence and severity were generally less than the ameloblastic degeneration/disorganization observed in the nose sections. Following a one-month recovery, ameloblastic degeneration/disorganization was still present in male and female rats previously dosed with 250 mg/kg/day; following three months of recovery this lesion was present in males previously dosed with 100 and 250 mg/kg/day and in females previously dosed with 250 mg/kg/day. This tooth lesion is consistent with fluoride toxicosis and is considered adverse.(24) Thyroid follicular hypertrophy was present in males administered 100 and 250 mg/kg/day and females administered 250 mg/kg/day. Follicular hypertrophy was characterized by low columnar follicular epithelium with a finely granular or vacuolated cytoplasm. Hypertrophy was reversible in both male and female rats, as this change was not present in dosed rats following the one- and three-month recovery periods. Thyroid hypertrophy was minimal and unassociated with proliferative thyroid lesions. However, this hypertrophy indicates possible disruption o f thyroid homeostasis and thus was considered potentially adverse. Com pany Sanitized. D oes not contain TSCA CBI 58 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 In the thyroid gland, the relative degree (and in females, the incidence) o f altered colloid was increased in males and females in all dosed groups at the end of the exposure period. Following the one- and/or three-month recovery periods, severity grades for colloid clumping were increased in males at all dose levels and in females at the 250 mg/kg/day level only. The diagnosis of "alteration, colloid" was used for colloid changes characterized by stippled, granular, clumped, and/or diffusely basophilic colloid. A 4-level grading scheme was applied based on an estimate o f the percentage of follicles that contained altered colloid. A grade o f 1 was applied when 1 follicle to about 25% o f the follicles were involved, with grades 2,3, and 4 applied for each 25% increase in follicular involvement. The size, density, or staining intensity of stipples, granules, clumps, or diffuse basophilia within individual follicles did not impact the grading. There was no consistent association between the presence or absence o f altered colloid and the presence of hypertrophy o f thyroid follicular cells. Altered colloid described as clumped or granular has been reported to occur spontaneously in Sprague-Dawley rats with increasing incidence correlating to increasing age/25'1 Because altered colloid occurs spontaneously in healthy Sprague-Dawley rats, and since increases in its grading score did not consistently correlate with other morphologic alterations in the thyroid gland, altered colloid was interpreted as not biologically meaningful and not adverse. Hypertrophy of centrilobular hepatocytes was present in 100 and 250 mg/kg/day males and 250 mg/kg/day females sacrificed at the end of the exposure period. In male rats previously dosed with 250 mg/kg/day, hepatocellular hypertrophy was present, but was less severe, after a one-month recovery period and was present in only one o f 5 rats sacrificed after a three-month recovery period. Microscopic hepatocellular hypertrophy was not observed in male rats in the 100 mg/kg/day three-month recovery group or in any female rat recovery group. Taken together, these findings suggest that microscopic hepatocellular hypertrophy was mostly reversible in males following three-months recovery and in females within one month of recovery. Microscopically, hepatocellular hypertrophy was characterized by an increased amount of finely granular eosinophilic cytoplasm within hepatocytes. There was no histomorphologic evidence of hepatocellular damage, and hepatic enzyme levels were not elevated (see clinical pathology section). Thus, hepatocellular hypertrophy (and the associated increase in liver weights) was considered a test substance-related physiologic response to metabolism of a xenobiotic and not toxicologically adverse.(26,27,28) Renal tubular hypertrophy was present in 250 mg/kg/day male rats sacrificed at the end of the exposure period. In addition, hypertrophy was seen in one of ten rats in the 100 mg/kg/day male exposure group. Following the one-month recovery period, minimal hypertrophy was present in 2 of 10 male rats, but this change was not observed in rats sacrificed after the three-month recovery period. Thus, hypertrophy decreased in incidence and severity after one-month recovery and appeared to be reversible by three-months recovery. Microscopically, tubular hypertrophy was characterized by increased eosinophilic staining of cortical tubule epithelium and a slight increase in cell height. Cortical tubule epithelial cells appeared to contain more granular cytoplasmic material then cortical tubules of control rats. Tubular lumina of hypertrophied tubules were slightly smaller then those in control rat kidneys. There was no histomorphologic evidence of renal damage, and renal clinical pathology parameters were not indicative of adverse effects (see clinical pathology section). Thus, the renal tubular hypertrophy ampamf Sanitized, not eontaSn TSCA C il 59 H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 (and the associated increase in kidney weights) was considered a test substance-related physiologic response to a xenobiotic and not toxicologically adverse/295 Renal tubular hypertrophy was not observed in female rats at any dose level. All other microscopic observations noted are known to occur spontaneously in rats of this strain and age and were not present in a dose response fashion in either incidence or severity. 4. Cause o f Death There were no test substance-related deaths. One 25 mg/kg/day female rat (Animal No. 643411) was accidentally killed during blood collection. One male rat in the 100 mg/kg/day group (Animal No. 643175) and one male rat and one female rat in the 250 mg/kg/day groups (Animal Nos. 643309 and 643368, respectively) died from dosing injuries. Two female rats in the control (Animal No. 643336) and 25 mg/kg/day (Animal No. 643321) groups died from urogenital inflammation/obstruction/calculi complications. A cause of death was not determined for a 250 mg/kg/day female subchronic toxicity rat (Animal No. 643340) that was found dead on test day 69. 5. Anatomical Pathology Conclusions for Subchronic Toxicity Evaluation Exposure to 100 or 250 mg/kg/day of the test substance for approximately 90 days produced degeneration/disorganization of enamel organ ameloblast cells in male and female rats. Ameloblastic degeneration/disorganization was not reversible after three-months recovery in 100 mg/kg/day males and in 250 mg/kg/day males and females. Thyroid gland hypertrophy observed in 100 and 250 mg/kg/day males and in 250 mg/kg/day females was reversible at one month and was considered to be potentially adverse. The severity of altered colloid in thyroid glands increased beyond control level as the dose increased, however, it was not consistently associated with any other morphologic alteration and was not considered biologically adverse. Increased liver weights were present in males and females at 25, 100, and 250 mg/kg/day. The increased liver weights correlated with microscopic centrilobular hepatocellular hypertrophy in males at 100 and 250 mg/kg/day and in females at 250 mg/kg/day groups. Hepatocellular hypertrophy was mostly reversible in males following three-months recovery and in females within one month of recovery. Increased kidney weights were present in 25,100 and 250 mg/kg/day males and females. In males, these kidney weight changes correlated with microscopic renal tubular hypertrophy. The increased kidney weights and male renal tubular hypertrophy appeared to be reversible by three months o f recovery. These liver and kidney changes were considered to represent physiologic responses to administration o f a xenobiotic and thus were not considered to be toxicologically significant. Under the conditions o f this study, the NOEL for pathology for male and female rats was 25 mg/kg/day based on tooth lesions at the 100 and 250 mg/kg/day dose levels. ' Company Sanitized. D oes not contain TSC CB1 60 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 REPRODUCTIVE TOXICOLOGY EVALUATIONS REPRODUCTIVE FUNCTION A. Pi Generation * 1. Mean Body Weights and Body Weight Gains (Table 44-46, Appendices O-T) There was a statistically significant reduction (89-91% o f control mean) in body weight in Pi male rats at 250 mg/kg/day during and after the cohabitation period. Although this finding was test substance-related, it was not considered toxicologically significant since there was no concomitant reduction in body weight gain in Pi males during that period. There were no test substance-related effects on body weight or body weight gain in Pi female rats during gestation or lactation. 2. Food Consumption and Food Efficiency During Gestation (Table 47, Appendix U) There were no test substance-related effects on food consumption and food efficiency in Pi female rats during gestation. 3. Clinical Observations (Tables 48, Appendices V-X) There were no toxicologically significant clinical observations in male and female rats at any dose level. There was an increase in tooth clipping required in male rats administered 250 mg/kg/day. Two females in the 250 mg/kg/day dose group also required teeth clipping (Animal No. 643429 on Day 0G and 643417 on Lactation Day 7). One Pi female rat (Animal No. 643429) in the 250 mg/kg/day group and her 16 pups were found dead on Lactation Day 0. Prior to death this animal exhibited weakness, diarrhea, wet underbody, facial staining on Gestation Day 21; this animal also had teeth clipped on Gestation Day 0. The cause of death was determined to be dystocia and was not considered test substance-related due to the single occurrence of this finding and the occasional occurrence o f this condition in control animals of the strain of rat used in this study. One Pi female rat (Animal No. 643454) in the 100 mg/kg/day group died on gestation day 22. The cause o f death was undetermined but was not considered test substance-related due to the absence of signs of toxicity or gross lesions in this animal. 4. Reproductive Indices (Tables 49-51, Appendices Y-EE) There were no test substance-related effects on estrous cycle parameters, sperm morphology, motility, or epididymal sperm counts in the Pi generation. At 100 and 250 mg/kg/day, there was a statistically significant increase in testicular spermatid numbers (123% and 113% of control, respectively) in Pi male rats. This finding was not considered test substance-related since the Hempafjy Sanitized. Does net ntelmTSSA GESi 61 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 means for these groups were within the historical control range for previous studies and the increase appeared to be due to a slightly lower than usual mean in the control group. There were no test substance-related effects on mating or fertility indices, gestation length or number of implantation sites. Implantation efficiency (number of pups bom uterine implantation sites x 100) was significantly reduced at 100 and 250 mg/kg/day (83.4% and 84.5%, respectively, compared to 96.6% in the control group), and reflects the reduction in the number of pups bom (see section B. 1.). B. Offspring Data 1. Litter Size, and Pup Weights, Clinical Observations, and Survival (Table 52-54; Appendix FF-HH) At 250 mg/kg/day, there were statistically significant reductions in the number o f pups bom, the number o f pups bom alive and the number of pups alive on day 4 of lactation (85%, 83% and 81% of control mean, respectively). At 100 mg/kg/day, reductions of similar magnitude as in the 250 mg/kg/day group were observed for the number of pups bom and bom alive (84% and 77% of control, respectively). Although not statistically significant these changes were considered test substance-related, as was the significant reduction in the number of pups alive on Day 4 of lactation (68% of control) at 100 mg/kg/day. There were no significant reductions in gestation index, mean % bom alive, 0-4 day viability, lactation index or litter survival. At 250 mg/kg/day, there were statistically significant reductions in pup weights on lactation days 4, 7, 14, and 21 (89%, 85%, 78%, and 75% o f control mean, respectively). There were no test substance-related clinical signs in pups during lactation at any dose level. C. Fi Generation Mean Body Weights and Body Weight Gains (Table 55-56, Appendices II-JJ) On the day of weaning (Lactation Day 21 = test day 1) mean body weights were significantly lower than control (74%-78% o f control mean) in both Fj males and females at 250 mg/kg/day. Subsequently, weekly mean body weights in Fi males were significantly lower than control throughout the post-weaning period (81%-93% o f control) in this group. For Fi females weekly mean body weights were significantly lower than control for test days 8 and 15 (85%-92% of control) and were similar to control thereafter. Thus mean body weights in these groups progressively returned to control values during the post-weaning period. Because the lower body weights in the Fi generation at 250 mg/kg/day appeared to be due to a test substance-related effect on pup weight during the lactation period (see section B. 1.) and there was no concomitant reduction in body weight gain in Fi males or females during the post-weaning period these findings were not considered toxicologically significant. . Ter. Company Sa-H-aod. Doea no. contain TSCA CB. 62 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 1. Clinical Observations (Tables 57, Appendices LL) There were no test substance-related clinical signs during the post-weaning period. 2. Developmental Landmarks (Tables 58, Appendices LL) The age at onset of vaginal opening in Fi female rats was similar across groups. The age at onset of preputial separation in Fi male rats was similar across groups. D. Reproductive Function Conclusions For the reproductive toxicity parameters evaluated under the condition o f this study, the NOEL was 25 mg/kg/day. Company Sanitized. Does not contain TSC CBt 63 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 REPRODUCTIVE TOXICOLOGY EVALUATIONS ANATOMICAL PATHOLOGY A. Organ Weight Data Parental Pi Adults and Fi Adults (Tables 59-62; Appendix MM) There was a statistically significant increase in thyroid gland weight relative to body weight in Pi males at 250 mg/kg/day, however, thyroid absolute weight was not significantly different from thyroid control weights. The increased thyroid weight was secondary to decreased final body weight in the 250 mg/kg/day Pi males. In Fi males at 250 mg/kg/day there were statistically significant decreases in liver and testes absolute weights and in epididymide absolute and relative to brain weights. There were no weight changes in these organs when adjusted to final body weight. These statistically significant organ weight changes were secondary to decreased final body weight in the 250 mg/kg/day Fi males. In Fi females there were statistically significant increases in liver weight relative to final body weight and relative to brain weight at 250 mg/kg/day and in kidney weight relative to brain weight at 100 and 250 mg/kg/day dose levels. Neither liver nor kidney absolute weights were statistically different from control weights. The kidney to brain weight changes were not dose dependent. None o f the organ weight changes were considered to be toxicologically or biologically adverse. B. Gross Observations Parental Pi Adults (Tables 63-64, Appendix NN) Fi Adults and Weanlings (Tables 65-71, 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 72-73, Appendix NN) There were no test substance-related microscopic findings. Lesions occurred in low incidences without a relevant dose-response relationship and were considered incidental occurrences of spontaneous lesions in rats of this strain and age. Company Sanitized. D oes not contain TSCA CBI 64 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 D. Mortality Parental Pi Adults and Fi Adults (Appendices NN and QQ) There were no test substance-related effects on mortality. Two Pi female rats were found dead. Cause of death appeared to be dystocia for rat Animal No. 643429 (250 mg/kg/day) and was undetermined for rat Animal No. 643454 (100 mg/kg/day). One 250 mg/kg/day Pi female rat (Animal No. 643346) was sacrificed in extremis after sustaining an injury in its cage; the fate of this animal is reported as accidentally killed. E. Anatomical Pathology Conclusions for Reproductive Toxicity For pathology, the NOEL was 250 mg/kg/day (the highest dose level) for both male and female rats. JfM^pany Sanitized. Does nodesnfi TSSA CBi 65 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 BIOCHEMICAL MEASUREMENTS A. Biochemical Measurements (Table 74-75, Appendix L) The rate o f hepatic P-oxidation, a measure o f peroxisome proliferation, was determined in a subchronic oral toxicity study with H-24516 in rats following 10 or 90 (males) and 92 (females) days of test substance administration or following a one- or three-month recovery period. Dose-dependent increases in the rate of hepatic P-oxidation were observed at the 10-day time point with statistical significance occurring for rats administered 100 or 250 mg/kg/day (223 and 349% o f control, respectively, in the males and 170 and 260% o f control, respectively, in the females). Dose-dependent increases in the rate of hepatic P-oxidation were also observed at the 90-day time point with statistical significance occurring for rats administered 100 or 250 mg/kg/day (398 and 856% of control, respectively, in the males and 345 and 381% of control, respectively, in the females). At both time points, the increases in hepatic p-oxidation activity were accompanied by increases in liver weights. Following a one-month recovery period, statistically significant increases in the rate of hepatic P-oxidation persisted in rats administered 250 mg/kg/day (353 and 207% of control, respectively, in males and females). Statistically significant increases in the rate of hepatic P-oxidation also persisted after the three-month recovery period for the 250 mg/kg/day dose group (302 and 172% of control, respectively, in males and females). At the one-month recovery time point, the increase in hepatic p-oxidation activity was accompanied by increased liver weights in the males, but not the females. B. Biochemical Measurements Conclusions Under the conditions o f this study, H-24516 is an inducer o f hepatic peroxisomal P-oxidation. At dosages of 100 mg/kg/day and greater, changes in the rate o f hepatic peroxisome proliferation were considered to be biologically significant effects. After three months o f recovery, the rate of hepatic peroxisome proliferation was still increased in rats administered 250 mg/kg/day. Company Sanitized. Does not contain TSCA CBS 66 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 CONCLUSIONS No test substance-related mortality or alterations in neurobehavioral parameters were observed in male or female rats. Test substance-related and toxicologically significant decrements in mean body weight, body weight gain, and food efficiency were observed in male rats administered 100 and 250 mg/kg/day compared to controls. Food consumption was also significantly lower in male rats administered 250 mg/kg/day. After a one- and/or three-month recovery period, these parameters were similar to or exceeded control. Test substance-related, toxicologically significant increases in the incidence o f broken (males) and absent teeth (males and females) occurred in the 250 mg/kg/day dose group. Statistically significant decrements in mean body weight parameters and food consumption occurred for females administered 100 or 250 mg/kg/day. The decrements in female body weight parameters were not considered to be toxicologically significant. Furthermore, the decrements in body weight parameters appear to be related to test substance-induced adverse effects to the teeth and decreased ability o f the animals to eat pelleted chow. Toxicologically adverse findings o f minimally decreased red cell mass parameters (RBC, hemoglobin, and hematocrit), along with correlative changes in other hematology parameters and in red cell morphology were observed after the 90-day exposure period in males and females administered 250 mg/kg/day H-24516. After a one-month recovery period, the 250 mg/kg/day male dose group still had minimally to mild decreased red cell mass parameters as well as decreased reticulocytes compared to control. Red cell mass parameters for the 250 mg/kg/day female group returned to control levels, however, some hematological parameters (MCV, MCH, RDW, and reticulocytes) were still decreased. A statistically significant rate of hepatic (3-oxidation occurred in males and females administered 100 or 250 mg/kg/day H-24516. The increased rate persisted in the 250 mg/kg/day groups after one and three months. Test substance related, toxicologically significant degeneration/disorganization o f enamel organ ameloblasts cells occurred in male and female rats dosed with 100 or 250 mg/kg/day H-24516. This tooth lesion is consistent with fluoride toxicosis/24^ After three months, the degeneration/disorganization of ameloblasts persisted, at a lower incidence and severity. Test substance related, potentially adverse increases in thyroid hypertrophy were observed in the 100 and 250 mg/kg/day male and 250 mg/kg/day female dose groups after the 90-day exposure period. After the one-month recovery period, thyroid hypertrophy was not observed in any dose group. Increased liver weights and/or hepatocellular hypertrophy were observed in male and female rats at all dose levels. Similarly, increased kidney weights and/or renal tubular hypertrophy were observed in male and female rats at all dose levels. These latter changes were considered to be a pharmacologically adaptive, non-adverse response. After the three-month recovery period, liver weights remained increased in the 250 mg/kg/day male and female groups, while hepatocellular g@npanF Sanitized. D@@s not contain TSCAB1 67 H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 hypertrophy was observed only in the 250 mg/kg/day male group (1 of 5 rats). Alterations in kidneys were not observed at any dose level after the three-month recovery period. There were no toxicologically significant pathology findings in the Pi and Fi generation rats. A statistically significant increase in testicular spermatid numbers in Pi male rats was not considered test substance-related. Implantation efficiency was significantly reduced at 100 and 250 mg/kg/day and reflects the reduction in the number o f pups bom. There were statistically significant reductions in the number o f pups bom, the number of pups bom alive and the number of pups alive on day 4 of lactation in the 250 mg/kg/day group. Reductions of similar magnitude were also observed for the number of pups bom and bom alive in the 100 mg/kg/day group. Although not statistically significant, these changes were considered test substance-related and toxicologically significant, as was the significant reduction in the number of pups alive on day 4 of lactation in the 100 mg/kg/day group. There were statistically significant reductions in pup weights on lactation days 4, 7, 14 and 21 in the 250 mg/kg/day groups. On the day of weaning mean body weights were significantly lower than control in both Fi males and females in the 250 mg/kg/day group. Fi generation body weights at 250 mg/kg/day progressively returned to control values during the post-weaning period indicating that the test substance-related effect on pup weight during the lactation period was reversed following cessation of exposure and therefore, were not considered toxicologically significant. The no-observed-effect level (NOEL)3for H-24516 for the 90-day exposure period was 25 mg/kg/day based on adverse decrements in body weight parameters and food efficiency, increased hepatic peroxisomal p-oxidation, and the degeneration and/or disorganization of enamel organ ameloblast cells in males administered 100 mg/kg/day. The NOEL for females was 25 mg/kg/day H-24516 based on increased hepatic peroxisomal P-oxidation and the degeneration and/or disorganization of enamel organ ameloblast cells in females administered 100 mg/kg/day. The NOEL for reproductive evaluations was 25 mg/kg/day based on decreases in the number of pups bom, bom alive, and the number of pups alive on day 4 of lactation at the 100 mg/kg/day dose level. The NOEL for this study is defined as the highest dose at which toxicologically important effects attributable to the test substance were not detected. Thus, for this study, the NOEL is equivalent to the NOEL as defined by the United States Environmental Protection A gency(30) and to the no-observed-adverse-effect level (NOAEL) as defined by the European Union (31>. C om pany Sanitized. Does not contain TSCA CBI 68 H -24516: Subchronic Toxicity 90-Pay Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 REFERENCES 1. DuPont (1995). Neurotoxicity Evaluation of Trimethyltin in Rats (Positive Control Study). 2. DuPont (1997). Neurotoxicity Evaluation of Amphetamine in Rats (Positive Control Study). 3^^ g ^ J ^ g g ^ f e u r o t o ^ g E v a h m t i o n o f Carbaryl in Rats (Positive Control Study). 4. _ DuPont (1996). Neurotoxicity Evaluation of Acrylamide in Rats (Positive Control Study). 5. Lazarow, P.B. (1981). Assay o f Peroxisomal Beta-Oxidation of Fatty Acids. Methods in Enzymology 72, 315-319. 6. Bradford, M.M. (1976). A Rapid and Sensitive Method for the Quantitation of Microgram Quantities of Protein Utilizing the Principle of Protein-Dye Binding. Anal. Biochem. 72, 248-254. 7. Dunnett, C.W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Amer. Statist. Assoc. 50, 1096-1121. 8. Dunn, O.J. (1964). Multiple contrasts using rank sums. Technometrics 6, 241-252. 9. Draper, N.R. and Smith, H. (1981). Applied Regression Analysis, 2nd edition, pp 266-273. Wiley, New York. 10. Selwyn, M.R. (1995). The use of trend tests to determine a no-observable-effect level in animal safety studies. Journal o f the American College o f Toxicology 14(2), 158-168. 11. Jonckheere, A.R. (1954). A distribution-free K-sample test against ordered alternatives. Biometrika 41, 133-145. 12. Levene, H. (1960). Robust test for equality o f variances. Contributions to Probability and Statistics (J. Olkin, ed.), pp 278-292. Stanford University Press, Palo Alto. ' 13. Shapiro, S.S. and Wilk., M.B. (1965). An analysis o f variance test for normality (complete samples). Biometrika 52, 591-611. , 14. Snedecor, G.W. and Cochran, W.G. (1967). Statistical Methods, 6th edition, pp 246-248 and 349-352. The Iowa State University Press, Ames. 15. Kruskal, W.H. and Wallis, W.A. (1952). Use of ranks in one-criterion analysis of variance. J. Amer. Statist. Assoc. 47, 583-621. PoBspatif SanlHnd. Does noesnSafra TSCA CB1 69 H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 16. Milliken, G.A. and Johnson, D.A, (1984). Analysis o fMessy Data, Volume 1.: Designed Experiments. Lifetime Learning Publications, Belmont. 17. Hocking, R.A. (1985). The Analysis o fLinear Models. Brooks/Cole, Monterey. 18. Bartlett; M.S. (1937). Some examples o f statistical methods of research in agriculture and applied biology. J. Royal. Statis. Soc. Suppl. 4 , 137-170. 19. Fisher, R.A. (1985). Statistical Methodsfo r Research Workers, 13th edition. Haffner, New York. 20. Dempster, A.P., Selwyn, M.R., Patel, C.M., and Roth, A.J. (1984). Statistical and computational aspects of mixed model analysis. The Journal o f the Royal Statistical Society, Series C (Applied Statistics) 33(2), 203-214. 21. Haseman, J.K. and Hogan, M.D. (1975). Selection o f the experimental unit in teratology studies. Teratology, 12, 165-171. 22. Patefield, W. (1982). Exact tests for trends in ordered contingency tables. Applied Statistics 31, 32-43. 23. Hoffman, W.E. and Solter, P.F. (1999). Clinical Enzymology. The Clinical Chemistry of Laboratory Animals (W.F. Loeb and F.W. Quimby, eds.), Taylor and Francis, Philadelphia, PA. pp399-454. 24. Reddy, C.S., and Hayes, A.W. (1089). Food Borne Toxicants. In Principles and Methods of Toxicology (A. W. Hayes, Ed.), Raven Press, New York, pp67-l 10. 25. Rao-Rupanagudi, S., Heywood, R., and Gopinah, C. (1991). "Age-related Changes in Thyroid Structures and Function in Sprague-Dawley Rats," Vet. Pathol., Vol. 29, No. 4, pp. 278-287. 26. Sipes, G. I., and Gandolfi, A. J. (1991). In Biotransformation of Toxicants. In Casearett and Doull's Toxicology: The Basic Science o f Poisons (Amdur, M. O., Doull, J., and Klaassen, C. D., Ed.), Pergamon Press, New York, pp 88-126. 27. Paynter, O.E., Harris, J.E., Burin, G.J., and Jaeger, R.B. (1985). Guidance for Analysis of Evaluation of Subchronic Exposure Studies. United States Environmental Protection Agency, EPA-540/9-85-020. 28. Greaves, P. (1990). Digestive System 2. In Histopathology of Preclinical Toxicity Studies: Interpretation and Relevance in Drug Safety Evaluation (P. Greaves, Ed.), Elsvier, Amsterdam, pp 393-496. 29. Greaves, P. (1990). Urinary Tract. In Histopathology of Preclinical Toxicity Studies: Interpretation and Relevance in Drug Safety Evaluation (P. Greaves, Ed.), Elsvier, Amsterdam, pp 497-583. Company Sanitized. D oes no! contain TSCA CM 70 H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 30. Hazard Evaluation Division, Standard Evaluation Procedure, Toxicity Potential: Guidance for Analysis and Evaluation of Subchronic and Chronic Exposure Studies Paynter, O. E. et al., United States Environmental Protection Agency, Office o f Pesticide Programs, Washington, D.C., 20406. EPA-540/9-85-020. (June 1985). 31. Risk Assessment o f Notified New Substances. Technical Guidance Document (Xl/283/94EN), Chapter I, Sections 2.24 and 2.25. 1994. gonapM f S a n lte A m m not canMtn TSC CM 71 H-24516: Subehronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLES j^ontpany Sanitized. Does not contain TSCA CB1 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLES EXPLANATORY NOTES DuPont-5386 Critical Dates Day 74 Male and female rats designated for reproduction evaluations were co housed. Body weights and clinical observations collected during the cohabitation and post-mating periods are reported in the Reproductive Toxicology section; Dose volumes administered during the cohabitation and post-mating periods are documented in study records. Days 83-89 Rats designated for the 3-month recovery period were temporarily housed in metabolism cages for urine and feces collection. Food consumption data was not collected for these animals during this period. Day 89 Last day of test substance administration for male and female rats designated for one-month and 3-month recovery periods. Day 90 Last day of test substance administration for male rats designated for the 90-day exposure period. Last day of non-fasted body weight and food consumption data collection for male rats designated for the 90-day exposure period. Day 91 Last day of non-fasted body weight and food consumption data collection for female rats designated for the 90-day exposure period. Male rats designated for the 90-day exposure period were sacrificed. Day 92 Last day of test substance administration for female rats designated for the 90-day exposure period. Day 93 Female rats designated for 90-day exposure period were sacrificed. Day 119 Last day of non-fasted body weight and food consumption data collection for rats designated for the one-month recovery period. Day 125 Male and female rats designated for the one-month recovery were sacrificed. Day 175 Last day o f non-fasted body weight and food consumption data collection for rats designated for the 3-month recovery period. Day 181 Male and female rats designated for the 3-month recovery period were sacrificed. Note On test day 18, all male rats and the first 11 female rats in the 25 mg/kg/day group received 38 mg/kg/day. P@mpMf Sanitized. 0 not eonain TSCACM H-24516: 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 HOT - hematocrit MCV - mean corpuscular volume MCH - mean corpuscular hemoglobin MCHC - mean corpuscular hemoglobin concentration RDW - red cell distribution width ARET - absolute reticulocyte count WBC - white blood cell count ANEU - absolute neutrophil (all forms) ANPR - absolute neutrophil precursor ALYM - absolute lymphocyte AMON - absolute monocyte AEOS - absolute eosinophil ABAS - absolute basophil ALUC - absolute large unstained cell ABLT - absolute blast leukocyte ` AMSC - absolute miscellaneous leukocyte PLT - platelet count Summary of Coagulation Values PT - prothrombin time APTT - activated partial thromboplastin time DuPont-5386 gompany Sanitized. Does not contain TSCACBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLES DuPont-5386 ABBREVIATIONS: EXPLANATORY NOTES Summary of Serum aud 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. ggeapap f Snfcd, 0 not ortalra TSCA CBI 75 H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 1 SUMMARY OF DOSING ANALYSES Nominal: Homogeneity Samples Test Day 0 Top Middle Bottom Average Measured Conc.b Average Percent Nominal Standard Deviation b Coefficient of Variation b Dosing Concentration o f H -24516 (mg/roL) 10.0 25.0 2.30 (92.0) a 2.47 (98.8) 2.40 (96.0) 2.39 (95.6) 0.08 3% 8.97 (89.7) 10.2 (102.0) 14.0 (140.0) 11.1 (111.0) 2 .6 24% 26.8 (107.2) 24.8 (99.2) 23.5 (94.0) 25.0 (100.0) 1 .6 7% Stability Samples 5 Hour Room Temperature Homogeneity Samples Test Day 6 Top Middle Bottom Average Measured C one.b Average Percent Nominal Standard Deviation b Coefficient of Variation b 2.06 (82.4) C C c -- -- -- -- 8.89 (88.9) 9.26 (92.6) 9.58 (95.8) 9.23 (92.3) 9.36 (93.6) 0 .1 9 2% 24.1 (96.4) C C -- -- -- -- Stability Samples 5 Hour Room Temperature c 9.03 (90.3) a Numbers in parentheses are the respective percent of nominal values. b Statistics based on the average measured concentration (ppm) of the top, middle and bottom of each dosing level. c Samples not required for study. ' jPompany Sanitized. Does not contain TSCA CBS H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 1 (CONTINUED) SUMMARY OF DOSING ANALYSES Nominal: Homogeneity Samples Test Day 49 Top Middle Bottom Average Measured C one.b Average Percent Nominal Standard Deviation b Coefficient of Variation b Dosing Concentration o f H-24516 (mg/mL) 3.33 13.33 33.33 2.71 (81.4) 8 2.99 (89.8) 3.42 (102.8) 3.04 (91.3) 0 .4 12% 10.8 (81.0) 12.7 (95.3) 12.8 (96.3) 12.1 (90.8) 1.1 9% 31.0 (92.9) 32.4 (97.1) 33.4 (100.3) 32.3 (96.8) 1 .2 4% Test Day 91 Top 3.05 (91.6) 12.8 (96.0) 32.7 (98.1) Middle 3.00 (90.1) 12.2 (91.5) 32.3 (96.6) Bottom 3.01 (90.4) C C Average Measured Cone. b Average Percent Nominal 3.02 (90.7) 12.5 (90.8) 32.5 (97.5) Standard Deviation b 0 .0 3 0 .4 0 .3 Coefficient o f Variation b 1% 3% 1% a Numbers in parentheses are the respective percent of nominal values. b Statistics based on the average measured concentration (ppm) of the top, middle and bottom of each dosing level for homogeneity samples or the average of duplicate sample for concentration verification samples (13.33 mg/mL and 33.33 mg/mL submitted test day 91). c Samples not required for study. paej/ Sanitized. Dees not contain TSCACBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 1 (CONTINUED) SUMMARY OF DOSING ANALYSES ' Stability Studv Nominal: Homogeneity Samples Dosing Concentration o f H -24516 (mg/mL) lb cr 3.33 a 20.0 b 50.0 b Top Middle Bottom Average Measured Cone. d Average Percent Nominal Standard D eviationd Coefficient of Variation d 2.88 (86.5)c 2.54 (76.3) 2.67 (80.2) 2.70 (81.1) 0 .2 6% 4.53 (90.6) 4.25 (85.0) 4.39 (87.8) 4.39 (87.8) 0.14 3% 19.9 (99.5) 17.7 (88.5) 18.6 (93.0) 18.7 (93.5) 1 .1 6% 53.4 (106.8) 52.6 (105.2) 54.0 (108.0) 53.3 (106.6) 0 .7 1% Stability Samples 0-Day Room Temperature6 2.70 (81.1) 4.39 (87.8) 18.7 (93.5) 53.4 (106.8) 5 Hour Room Temperature 2-Day Refrigerated 3-Day Refrigerated 2.66 (79.9) __f __f 4.60 (92.0) 4.77 (95.4) 4.61 (92.2) 17.2 (86.0) 18.3 (91.5) 29.4 (147.0) 48.3 (96.6) 47.9 (95.8) 46.7 (93.4) 4-Day Refrigerated 2.91 (87.4) 4.81 (96.1) 19.6 (97.8) 48.9 (97.8) 4-Day Reffigerated/5 hr. 2.74 4.85 17.6 47.9 (82.3) (97.1) (88.2) (95.7) " Samples prepared based on 7.5 mL/Kg dose volume. b Samples prepared based on 5.0 mL/Kg dose volume. c Numbers in parentheses are the respective percent of nominal values. d Statistics based on the average measured concentration (ppm) of the top middle and bottom of each dosing level. e The mean measured values from analysis of homogeneity samples (considered fresh/O-day room temperature samples) were used as baselines for comparison with the respective stability samples. r Samples not required for study. L 0 nol oraam TSCA -SB1 78 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 2 MEAN DAILY DOSE VOLUMES (mL) FOR MALE RATS Group I 0 mg/kg/day Group III 25i mg/kg/day Group V Group VII 100 mg/kg/day 250 mg/kg/day DAY 0 -DAY 6 DAY 7 -DAY 13 DAY 14 -DAY 20 DAY 21 -DAY 27 DAY 28 -DAY 34 DAY 35 -DAY 41 DAY 42 -DAY 48 DAY 49 -DAY 55 DAY 56 -DAY 62 DAY 63 -DAY 69 DAY 70 -DAY 76 DAY 77 -DAY 83 DAY 84 -DAY 89 DAY 90 2. 5 0 .2 (45 ) 3 .1 0 .2 (45 ) 3 ..6 0 .,3 (45 ) 4 ..0 0 ..3 (45 ) 4 .3 0 .4(45 ) 4..6 0 ,.4 (45 ) 3 .6 0 .3 (45 ) 3 .8 0 .3 (45 ) 3 .9 0 .4 (45 ) 4 .0 0 .4 (45 ) 4 .1 0 .4 (45 ) 4 .2 0 .5(25 ) 4 .3 0 .5 (25 ) 4 .5 0 .4 (10 ) 2. 5 0. 2(35 ) 3 .0 0 .2 (35 ) 3 .6 0 .3 (35 ) 3 .9 0. 3 (35 ) 4 .3 0. 4(35 ) 4..6 0.,4 (35 ) 3 .,6 0..3(35 ) 3 .7 0..3 (35 ) 3 .8 0,.4 (35 ) 3 .9 0 .4(35 ) 4 .0 0 .4(35 ) 4 .1 0 .4(15 ) 4 .2 0 .4(15 ) 4 .3 0 .5 (10 ) 2.5 0.2 (35 ) 3.1 0.2 (35 ) 3.6 0.3 (35 ) 4.0 0.3 (35 ) 4.3 0.3 (35 ) 4.6 0.3 (35 ) 3.6 0.3(35 ) 3.7 0.3 (35 ) 3.8 0.3 (35 ) 4.0 0.3(35 ) 4.0 0.3 (35 ) 3.9 0.3(14 ) 3.9 0.3(14 ) 4.0 0.2 (9) 2 .5 0. 2(45 ) 3 .1 0 .2 (45 ) 3 .6 0. 3 (45 ) 4. 0 0..3 (45 ) 4,.3 0..4 (45 ) 4 ,.6 0 ,.4 (45 ) 3 .6 0 .3 (45 ) 3 .6 0 .3 (45 ) 3 .6 0 .3 (45 ) 3 .7 0 .4 (45 ) 3 .6 0 .4 (45 ) 3 .6 0 .4(26 ) 3 .8 0 .4 (25 ) 4 .0 0 .3 (10 ) ' Data summarized as : Mean Standard Deviation (n) Company ISanitfzed. D oes no! contain TSCA CBl 79 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 3 MEAN DAILY DOSE VOLUMES (mL) FOR FEMALE RATS ' Group II Group IV Group VI Group VIII 0 mg/kg/day 25 mg/kg/day 100 mg/kg/day 250 mg/kg/day DAY 0 - DAY 6 DAY 7 - DAY 13 DAY 14 - DAY 20 DAY 21 - DAY 27 DAY 28 - DAY 34 DAY 35 - DAY 41 DAY 42 - DAY 48 1. 9 0. 2 (45 ) 2 .1 0 .2 (45 ) 2 ..3 0 .2 (45 ) 2 ..5 0 .,2 (45 ) 2 ..6 0..2 (45 ) 2 .8 0,.3 (45 ) 2 ,.1 0 .2 (45 ) 1.9 0.2 (35 ) 2.2 0.2 (34 ) 2.3 0.2 (34 ) 2.6 0.2 (34 ) 2.7 0.2 (34 ) 2.8 0.2 (33 ) 2.2 0.2 (33 ) 1. 9 0. 1 (35 ) 2 .1 0 .2 (35' ) 2. 3 0. 2 (35 ) 2. 5 0 .2 (35 ) 2 .6 0. 2 (35 ) 2..7 0 .,2 (35 ) 2 ..1 0 .2 (35 ) 1. 9 0. 2 (45 ) 2. 2 0 .2 (45 ) 2 .4 0. 2 (45 ) 2 .5 0. 2 (45 ) 2. 6 0..2 (45 ) 2..8 0 .2 (45 ) 2 .1 0..2 (45 ) DAY 49 - DAY 55 2 .2 0 .2 (45 ) 2.2 0.2 (33 .) DAY 56 - DAY 62 2 .3 0 .2 (45 ) 2.3 0.2(33 ) DAY 63 -DAY 69 2 .3 0 .2 (45 ) 2.3 0.2 (33 ) DAY 70 - DAY 76 2 .3 0 .2 (45 ) 2.4 0.2 (33 ) DAY 77 - DAY 83 2 .3 0 .3 (25 ) 2.3 0.2(13 ) DAY 84 - DAY 90 2 .4 0 .3 (25 ) 2.3 0.2(13 ) DAY 90 - DAY 92 2 .3 0 .3 (10 ) 2.4 0.2(9) Data summarized as: Mean Standard Deviation (n) 2 .1 0 .2 (35 ) 2 .2 0 .2 (35 ) 2 .2 0 .2 (35 ) 2 .2 0 .2 (35 ) 2 .2 0 .2(15 ) 2 .2 0 .2 (15 ) 2 .2 0 .2(10 ) 2,.1 0,.2 (45 ) 2 .1 0 .2 (44 ) 2 .1 0 .2 (44 ) 2 .1 0 .2 (43 ) 2 .1 0 .2 (24 5 2 .2 0 .2 (24 ) 2 .2 0 .2(9 ) smpiwsf Sanlfeed. Boss nrt contain TSCOil H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 4 MEAN BODY WEIGHTS (g) OF MALE RATS Group I 0 mg/kg/day Group III Group V Group VII 25 mg/kg/day 100 mg/kg/day 250 mg/kg/day Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 DAY 7 DAY 14 DAY 21 DAY 28 DAY 35 DAY 42 DAY 49 DAY 56 DAY 63 DAY 70 DAY 74a 250.1 18.5(45 ) 305.6 23.2(45 ) 356.2 29.2(45 ) 398.3 33.7(45 ) 431.2 38.7(45 ) 457.5 41.8(45 ) 483.1 44.2(45 ) 501.5 45.8(45 ) 519.4 50.4(45 ) 535.4 53.5(45 ) 551.1 56.7(45 ) 558.1 60.8(20 ) 247.7 20.0(35 ) 304.3 24.2(35 ) 356.6 28.5(35 ) 392.8 32.2 (35 ) 428.1 35.0(35 ) 458.6 39.4(35 ) 477.1 40.6(35 ) 490.8 43.2(35 ) 507.0 50.1(35 ) 523.6 51.9(35 ) 538.6 52.9(35 ) 548.3 53.8 (20 ) 250.4 18.0(35 ) 307.8 21.8(35 ) 357.1 26.3(35 ) 398.8 28.3(35 ) 431.1 30.9(35 ) 455.1 34.3(35 ) 476.2 36.0(35 ) 493.1 37.5(35 ) 508.1 39.8(35 ) 525.3 40.5(35 ) 537.0 44.8(35 ) 558.5 39.7(20 ) 251.6 17.2(45 ) 312.9 22.2(45 ) 360.0 26.1(45 ) 404.4 30.9(45 ) 434.0 37.6(45 ) 459.3 39.5(45 ) 475.7 40.9(45 ) 483.4 43.7(45 ) 486.6# 46.1(45 ) 487.7# 48.6(45 ) 473.8# 58.2(45 ) 479.6# 49.1(19 ) gariUaad.DoMnmamw' 81 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 4 (CONTINUED) MEAN BODY WEIGHTS (g) OF MALE RATS Group I 0 mg/kg/day Group III Group V Group VII 25 mg/kg/day 100 mg/kg/day 250 mg/kg/day Dosing Period for Subchronic Toxicity Evaluation (continued) DAY 77 DAY 84 555.5 60.4(25 ) 567.5 59.6(25 ) 543.7 55.9(15 ) 555.7 59.2(15 ) 513.7# 50.7(15 ) 523.2# 38.3 (14 ) 479.2# 57.9(25 ) 508.8# 52.2(25 ) DAY 90 573.5 60.0(25 ) 560.7 62.1(15 ) 531.1# 37.4(14 ) 522.1# 51.4(25 ) One-Month Recovery Period for Subchronic Toxicity Evaluation DAY 98 578.2 63.6(15 ) 539.6 49.3(5 ) 527.9 39.1(5 ) 526.2# 58.9(15 ) DAY 105 586.2 73.8(15 ) 549.8 52.7(5 ) 513.5# 66.0(5 ) 534.3# 62.7(15 ) DAY 112 598.5 ' 70.7(15 ) 556.8 53.7(5 ) 525.4# 66.4(5 ) 540.6# 67.8(15 ) DAY 119 597.4 73.5(15 ) 552.5 60.6(5 ) 531.7 58.9(5 ) 548.6 68.4(15 ) Company$an3ttzed. Dees not contain TSCA0B! H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 4 (CONTINUED) MEAN BODY WEIGHTS (g) OF MALE RATS ' Group I 0 mg/kg/day Group III Group V Group VII 25 mg/kg/day 100 mg/kg/day 250 mg/kg/day Three-Month Recovery Period for Subchronic Toxicity Evaluation DAY 126 DAY 133 DAY 140 DAY 147 DAY 154 DAY 161 DAY 168 DAY 175 567.3 34.4(5 ) 582.3 36.1(5 ) 592.6 39.9(5 } 598.3 48.2(5 ) 606.9 45.6(5 ) 614.4 48.0(5 ) 619.1 48.8(5 ) 635.5 53.8(5 ) 545.3 47.9(5 ) 561.1 45.3(5 ) 569.8 54.3(5 ) 581.9 56.7(5 ) 586.5 59.7(5 ) 592.1 61.1(5 ) 602.1 61.1(5 ) 609.7 64.1(5 ) 531.1 62.9(5 ) 545.1 54.0(5 ) 560.5 58.2(5 ) 575.0 60.7(5 ) 587.1 63.4(5 ) 594.6 67.9(5 ) 608.0 77.7(5 ) 618.6 81.8(5 ) 530.0 109.7(5 ) 546.1 113.3(5 ) 556.6 107.9(5 ) 573.6 110.3(5 ) 582.4 108.6(5 ) 593.9 106.0(5 ) 607.7 113.4(5 ) 610.6 112.8(5 ) Data summarized as: Mean Standard Deviation (n) # Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 74; subsequent data are reported as part of the reproduction evaluation. jCompany Sanitised. 0@&net affltaSmTSCAil 83 J) H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 5 MEAN BODY WEIGHTS (g) OF FEMALE RATS . Group XI 0 mg/kg/day Group IV Group VI Group VIII 25 mg/kg/day 100 mg/kg/day 250 mg/kg/day Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 DAY 7 DAY 14 DAY 21 DAY 28 DAY 35 DAY 42 DAY 49 DAY 56 DAY 63 DAY 70 DAY 74a 191.1 15.5(45 ) 214.4 19.2(45 ) 232.5 20.5(45 ) 249.2 21.8(45 ) 262.6 24.9(45 ) 276.0 26.3(45 ) 283.0 27.8(45 ) 293.0 28.9(45 ) 300.5 29.0(45 ) 304.3 29.8(45 ) 310.4 30.3 (45 ) 309.2 30.2(20 ) 192.4 15.2(35 ) 215.4 19.5(34 ) 233.9 19.0(34 254.8 22.1(34 267.6 23.4(34 280.5 24.7(33 290.7 26.7(33 297.7 28.3 (33 ) 301.9 29.5(33 ) 307.8 27.9(33 313.8 27.9(33 318.2 31.5(20 187.6 14.4(35 ) 211.9 15.4(35 ) 231.6 18.6(35 ) 247.8 19.1(35 ) 260.0 22.9(35 ) 268.7 23.7(35 ) 279.0 24.1(35 ) 286.0 22.0(35 ) 288.6 20.7(35 ) 292.7 21.2(35 ) 298.2 19.8(35 ) 302.8 16.2(20 ) 190.3 14.9(45 ) 215.5 18.6(45 ) 237.5 20.3(45 ) 251.9 22.6(45 ) 264.1 23.1(45 ) 274.9 24.4(45 ) 283.6 24.0(45 ) 287.0 28.6(45 ) 283.7# 32.3(44 ) 281.5# 29.2(44 ) 280.0# 32.6(43 ) 282.2# 37.3(19 ) :ed, Des 8 eemtaite @38 84 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 5 (CONTINUED) MEAN BODY WEIGHTS (g) OF FEMALE RATS Group II 0 mg/kg/day Group IV Group VI Group VIII 25 mg/kg/day 100 mg/kg/day 250 mg/kg/day Dosing Period for Subchronic Toxicity Evaluation (continued) DAY 77 DAY 84 DAY 91 311.8 31.9(25 ) 317.1 33.9(25 ) 318.1 40.0(25 ) 305.7 25.4(13 ) 309.4 25.5(13 ) 310.4 24.5(13 ) 292.1# 21.8(15 ) 293.6# 21.6(15 ) 295.8# 22.3(15 ) 274.5# 24.7(24 ) 296.5# 25.7(24 ) 299.4# 28.9(24 ) One-Month Recovery Period for Subchronic Toxicity Evaluation DAY 98 DAY 105 DAY 112 DAY 119 332.1 42.4(15 ) 337.1 45.0(15 ) 347.8 48.3 (14 ) 348.3 50.5(14 ) 305.6 18.5(4 ) 307.7 20.8(4 ) 317.1 21.1(4 ) 320.7 22.2(4 ) 286.6 21.8(5 ) 291.6 18.3(5 ) 288.4 39.2(5 ) 282.2 46.9(5 ) 304.8 29.4(15 ) 310.4 33.2(15 ) 318.6 34.8(15 ) 322.5 38.5(15 ) ompanySanitlzed. D oes not contain TSCA CBI 85 H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 5 (CONTINUED) MEAN BODY WEIGHTS (g) OF FEMALE RATS Group II 0 mg/kg/day Group IV Group VI Group VIII 25 mg/kg/day 100 mg/kg/day 250 mg/kg/day Three-Month Recovery Period for Subchronic Toxicity Evaluation DAY 126 DAY 133 DAY 140 DAY 147 DAY 154 DAY 161 DAY 168 DAY 175 292.6 17.7(5 ) 308.4 17.7(5 ) 307.8 16.8(5 ) 315.3 15.8(5 ) 316.3 22.5(5 ) 322.9 19.3(5 ) 329.6 21.1(5 ) 328.1 20.1(5 ) 317.7 23.2(4 ) 327.4 25.0(4 ) 333.5 29.6(4 ) 338.7 29.3(4 ) 344.3 23.7(4 ) 344.3 29.9(4 ) 348.6 31.4(4 ) 351.0 29.1(4 ) 293.2 34.8(5 ) 301.4 27.9(5 ) 303.1 29.2(5 ) 310.9 33.2(5 ) 316.1 30.8(5 ) 319.8 31.5(5 ) 322.0 32.2(5 ) 326.5 35.6(5 ) 325.0 51.9(5 ) 333.9 52.4(5 ) 338.0 53.5(5 ) 349.4 54.0(5 ) 356.7 54.4(5 ) 362.1 56.2(5 ) 359.2 57.2(5 ) 361.7 58.4(5 ) Data summarized as: Mean Standard Deviation (n) # Statistically significant differences at p < 0.05 by Jonckheere-Terpstra trend test. a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 74; subsequent data are reported as part of the reproduction evaluation. SM psiaf S a n itized . o a im TSC A CBS H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations 1 TABLE 6 DuPont-5386 MEAN BODY WEIGHT GAINS (g) OF MALE RATS Group I Group III Group V Group VII 0 mg/kg/day 25 mg/kg/day 100 mg/kg/day 250 mg/kg/day Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 - DAY 7 DAY 7 - DAY 14 DAY 14 - DAY 21 DAY 21 - DAY 28 DAY 28 - DAY 35 DAY 35 - DAY 42 DAY 42 - DAY 49 DAY 49 - DAY 56 DAY 56 - DAY 63 DAY 63 - DAY 70 DAY 70 - DAY 74a DAY 0 - DAY 74a 55.5 7.8(45 ) 50.5 8.6(45 ) 42.1 7.5(45 } 33.0 7.7(45 ) 26.3 6.9(45 ) 25.6 5.9(45 ) 18.4 8.4(45 ) 17.9 10.3(45 ) 16.0 7.8(45 ) 15.7 6.0 (45 ) 3.6 6.7(20 ) 308.8 46.8(20 ) 56.6 7.0(35 ) 52.3 7.3(35 ) 36.2 6.6(35 ) 35.3 6.7(35 ) 30.5 8.0(35 ) 18.5# 5.8(35 ) 13.7 8.0(35 ) 16.3 11.5(35 ) 16.5 9.2(35 ) 15.1 5.6(35 ) 6.8 7.6(20 ) 300.5 41.5(20 ) 57.4 8.7(35 ) 49.2 8.0(35 ) 41.7 6.2 (35 ) 32.3 7.4(35 ) 24.0 6.4(35 ) 21.1# 5.8(35 ) 16.9 13.3(35 ) 15.0# 7.2 (35 ) 17.2 7.5(35 ) 11.7 16.3(35 ) 2.3 5.0(20 ) 307.9 32.9(20 ) 61.3# 7.1(45 ) 47.1# 6.5(45 ) 44.5# 6.8(45 ) 29.6# 12.1(45 ) 25.3 6.0(45 ) 16.4# 13.9(45 ) 7.8# 11.8(45 ) 3.1# 22.9(45 ) 1.2# 20.0(45 ) -13.9# 39.3(45 ) 4.9 36.7(19 ) 228.6# 39.3(19 ) g * ? l Beactcontain TSCA 87 H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 6 (CONTINUED) MEAN BODY WEIGHT GAINS (g) OF MALE RATS Group I Group III Group V Group VII 0 mg/kg/day 25 mg/kg/day 100 mg/kg/day 250 mg/kg/day Dosing Period for Subchronic Toxicity Evaluation (continued) DAY 70 - DAY 77 DAY 77 - DAY 84 DAY 84 - DAY 90 7. 1 11. 5(25 ) 12 .,0 7 ..3(25 ) 6..0 6..7(25 ) 8. 8 7. 4 (15 ) 12 .0 8. 3 (15 ) 5 .1 10 .2 (15 ) 2. 4 17. 3 (15 ) 1. 2 20. 6(14 ) 7. 9 14. 2 (14 ) 6. 6 43 .9 (25 ) 29. 6# 20. 0 (25 ) 13 .3# 10. 1(25 ) DAY 0 - DAY 90 322 .7 49..9(25 ) 313 .0 51.,9(15 ) 281..8# 28.,1(14 ) One--Month Recovery Period for Subchronic Toxicity Evaluation 271..4# 41.,2 (25 ) DAY 90 - DAY 98 DAY 98 - DAY 105 DAY 105 - DAY 112 DAY 112 - DAY 119 19 .2 10 .0(15 ) 8 .0 14 .1(15 ) 12 .3 7 .5(15 ) -1 .1 14 .2(15 ) 14,.2 4,.5 (5 ) 4,.9# 11,.4(5 ) . 12,.7# 8,.9(15 ) 10 .2 5 .0 (5 ) -14 .4 58 .3 (5 ) 8 .0 8 .7(15 ) 7 .0 14 .7(5 ) 11 .9 17 .6(5 ) 6 .3 11 .2 (15 ) -4 .3 12 .6 (5 ) 6 .3 27 .4(5 ) 8 .0 7 .4 (15 ) DAY 90 -- DAY 119 38 .4 16 .7(15 ) 27 .2 25 .2 (5 ) 8 .7* 19 .5(5 ) 35 .1 17 .9(15 ) Connpany Sanitized. Does not contain TSCACBS 88 H -24516: Subehronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 6 (CONTINUED) MEAN BODY WEIGHT GAINS (g) OF MALE RATS Group X Group III Group V Group VII (5 mg/kg/day 25 mg/kg/day 100 mg/kg/day 250 mg/kg/day Three-Month Recovery Period for Subchronic Toxicity Evaluation DAY 119 - DAY 126 0.6 14.2(5 ) -7.2 17.7(5 ) -0.6 26.4(5 ) 7.9 7.0(5 ) DAY 126 - DAY 133 15.0 6.0(5 ) 15.8 15.2(5 ) 14.0 18.7(5 ) 16.1 6.2(5 ) DAY 133 - DAY 140 10.2 10.7(5 ) 8.8 10.8(5 ) 15.4 9.3(5 ) 10.5 5.8(5 ) DAY 140 - DAY 147 5.7 18.4(5 ) 12.1 3.6(5 ) 14.4 3.5(5 ) 17.0 7.3(5 ) DAY 147 - DAY 154 8.6 2.9(5 ) 4.6 7.0(5 ) 12.1 7.3(5 ) 8.7 5.6(5 ) DAY 154 - DAY 161 7.5 7.0(5 ) 5.6 1.9(5 ) 7.5 7.1(5 ) 11.5 6.7(5 ) DAY 161 - DAY 168 4.7 8.3(5 ) 10.0 3.6(5 ) 13 .4 10.7(5 ) 13.9 9.0(5 ) DAY 168 - DAY 175 16.4 6.1(5 ) 7.6 6.9(5 ) 10.7 6.2(5 ) 2.9# 7.1(5 ) DAY 119 - DAY 175 68.7 37.4(5 ) 57.2 13.3(5 ) 86.9 29.1(5 ) 88.6# 14.9(5 ) Data summarized as: Mean Standard Deviation (n) # Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. * Statistically significant difference at p < 0.05 by Dunnett's test. a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 74; subsequent data are reported as part of the reproduction evaluation. smpany Sanitlze& 0@ssa@8wtato TSC GW H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 7 MEAN BODY WEIGHT GAINS (g) OF FEMALE RATS Group II Group IV Group VI Group VIII 0 mg/kg/day 25 mg/kg/day 100 mg/kg/day 250 mg/kg/day Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 - DAY 7 DAY 7 - DAY 14 DAY 14 - DAY 21 DAY 21 - DAY 28 DAY 28 - DAY 35 DAY 35 - DAY 42 DAY 42 - DAY 49 DAY 49 - DAY 56 DAY 56 - DAY 63 DAY 63 - DAY 70 DAY 70 - DAY 74a DAY 0- DAY 74a 23.3 8.6(45 ) 22.5 7.5(34 ) 24.3 6.1(35 ) 18.0 7.1(45 ) 18.4 8.1(34 ) 19.7 6.9(35 ) 16.8 6.9(45 ) 21.0 6.0(34 ) 16.2 6.4(35 ) 13.4 7.3 (45 ) 12.7 7.6(34 ) 12.2 10.9(35 ) 13.4 7.2(45 ) 12.0 6.2(33 ) 8.7# 9.2(35 ) 7.1 6.3 (45 ) 10.2 6.6(33 ) 10.3 8.3(35 ) 10.0 5.6(45 ) 7.0# 7.8(33 ) 7.0# 10.8(35 ) 7.4 7.8(45 ) 4.1 11.6(33 ) 2.7# 5.6(35 ) 3.8 7.2(45 ) 6.0 9.7(33 ) 4.0 6.5(35 ) 6.1 6.1(45 ) 5.9 6.4(33 ) 5.5 7.3(35 ) -1.0 4.2(20 ) -1.7 11.2(20 ) -1.7 10.0(20 ) 115.5 20.1 (20 ) 120.3 21.5(20 ) 111.5 15.2(20 ) 25.3 6.5(45 ) 22.0# 5.8(45 ) 14.4# 6.7(45 ) 12.2 6.7(45 ) 10.8# 6.1(45 ) 8.7 5.7(45 ) 3.4# 14.1(45 ) -4.5# 14.5(44 ) -2.2# 22.2(44 ) -1.7# 22.4(43 ) 4.4 31.9(19 ) 85.9# 32.1(19 ) Company Sanitized. Does not contain TSCA GBI 90 H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 7 (CONTINUED) MEAN BODY WEIGHT GAINS (g) OF FEMALE RATS DuPont-5386 Group II Group IV Group VI Group VIII 0 mg/kg/day 25 mg/kg/day 100 mg/kg/day 250 mg/kg/day Dosino Period for Subchronic Toxicity Evaluation (continued) DAY 70 - DAY 77 DAY 77 - DAY 84 DAY 84 - DAY 91 1.3 4.5(25 ) 5.3 5.6(25 ) 1.0 13.6(25 ) 1.4 6.2(13 ) 3.6 3.9(13 ) 1.0 5.3(13 ) 2.2 5.1 (15 ) 1.4 6.0(15 ) 2.2 4.7(15 ) -7.2# 16.3(24 ) 22.0# 12.9(24 ) 2.8 8.7(24 ) DAY 0- DAY 91 129.1 32.5(25 ) 125.1 20.8(13 ) 113.1# 14.8 (15 ) 114.1# 20.2(24 ) One-Month Recovery Period for Subchronic Toxicity Evaluation DAY 91 - DAY 98 DAY 98 - DAY 105 DAY 105 - DAY 112 DAY 112 - DAY 119 10.8 13.5(15 ) 5.0 11.7(15 ) 10.0 8.5(14 ) 0.5 7.6(14 ) 7.9 7.1(4 ) 2.0 6.2(4 ) 9.4 3.8(4 ) 3.6 3.2(4 ) 0.3 9.6 (5 ) 5.0 4.0(5 ) -3.2 22.0(5 ) -6.2 25.3 (5 ) 5.4 10.2(15 ) 5.6 5.9(15 ) 8.2 6.2(15 ) 3.9 5.8(15 ) DAY 91- DAY 119 27.6 23.4(14 ) 22.9 9.0(4 ) -4.1 24.4(5 ) 23.2 19.1(15 ) pMfapan^ Sanitised. @ntaln TSS C ll H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 7 (CONTINUED) MEAN BODY WEIGHT GAINS (g) OF FEMALE RATS Group II Group IV 0 mg/kg/day 25 mg/kg/day Group VI Group VIII 100 mg/kg/day 250 mg/kg/day Three-Month Recovery Period for Subchronic Toxicity Evaluation DAY 119 - DAY 126 -5. 9 7. 9(5 ) -3 .0 2. 1(4 ) 11. 0# 18 .9(5 ) 3 .2# 5. 3 (5 ) DAY 126 - DAY 133 15. 8 3 .5(5 ) 9. 7 2 .8 (4 ) 8 .2 12 .1(5 ) 8. 9 8 .4 (5 ) DAY 133 - DAY 140 -0 .6 4..9(5 ) 6. 1 7. 1(4 ) 71 . 7..2 (5 ) 4. 1 8 .8 (5 ) DAY 140 - DAY 147 7..5 2 .8(5 ) 5.,2 7 ..8 (4 ) 7 ..8 5 .1(5 ) 11..4 4 .2(5 ) DAY 147 - DAY 154 1 ,.0 10 ,.0(5 ) 5..5 7..6(4 ) 5 ,.2 8 .9(5 ) 7 .3 4,.7(5 ) DAY 154 - DAY 161 6 .6 7 .6(5 ) 0 .1 7 .0(4 ) 3 .7 7 .0 (5 ) 5 .4 4 .6(5 ) DAY 161 - DAY 168 6 .7 7 .6(5 ) 4 .3 2 .2 (4 ) 2 .2# 0 .9(5 ) -2 .9# 11 .4(5 ) DAY 168 - DAY 175 -1 .5 3 .2 (5 ) 2 .3 4 .7 (4 ) 4 .5 5 .3 (5 ) 2 .5 4 .2 (5 ) DAY 119 - DAY 175 29 .6 16 .5(5 ) 30 .3 8 .3 (4 ) 44 .2 18 .9(5 ) 39 .9 15 .1(5 ) Data summarized as: Mean Standard Deviation (n) # Statistically significant difference af p < 0.05 by Jonckheere-Terpstra trend test. a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 74; subsequent data are reported as part of the reproduction evaluation. Company Sanitized. Does not contain TSCA CSI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 . TABLE 8 MEAN DAILY FOOD CONSUMPTION (g) OF MALE RATS Group I Group III Group V Group VII 0 mg/kg/day 25 mg/kg/day 100 mg/kg/day 250 mg/kg/day Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 - DAY 7 25.8 2.2(45 ) 25.8 2.5(35 ) 26.1 2.2(35 ) 26.5 2.8(45 ) DAY 7 - DAY 14 27.4 2.9(45 ) 27.7 2.8(35 ) 28.1 2.7(35 ) 28.5# 2.4(45 ) DAY 14 - DAY 21 DAY 21 - DAY 28 28.3 . 2.6(45 ) 28.2 2.8(45 ) 28.1 3.2(35 ) 28.2 3.2(35 ) 28.1 2.3(35 ) 28.9 2.6(35 ) 28.2 2.6(45 ) 28.6 3.7(45 ) DAY 28 - DAY 35 DAY 35 - DAY 42 DAY 42 - DAY 49 28.5 2.7(45 ) 28.7 2.7(45 ) 29.2 2.6(45 ) 29.2 3.4(35 ) 28.8 3.1 (35 ) 27.6 4.0(35 ) 30.0 5.6(35 ) 29.1 2.6(35 ) 28.6 3.6(35 ) 29.2 2.9(45 ) 28.5 3.6(45 ) 26.2# 3.3(45 ) DAY 49 - DAY 56 29.2 3.0(45 ) 29.1 4.1(35 ) 29.4 2.5(35 ) 26.0# 4.8(45 ) DAY 56 - DAY 63 DAY 63 - DAY 70 28.9 4.2(45 ) 28.9 3.3(45 ) 28.9 3.4(35 ) 28.8 3.4(35 ) 29.5 2.9(35 ) 28.8 4.5(35 ) 24.5# 4.4(45 ) 21.8# 7.9(45 ) DAY 70 - DAY 74a 31.1 4.1(20 ) 30.i 3.4(20 ) 28.8 3.7(20 ) 25.2# 7.5(19 ) DAY 0 -- DAY 74a 28.4 2.9 (20 ) 28.4 3.2(20 ) 29.5 2.0(20 ) 27.1 1.9(19 ) PwmpsMf SanMxed. P@t not contain TSGA 93 H-24516: Subehronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 8 (CONTINUED) MEAN DAILY FOOD CONSUMPTION (g) BY MALE RATS Group I Group III Group V Group VII 0 tag/kg/day 25 mg/kg/day 100 mg/kg/day 250 mg/kg/day Dosing Period for Subchronic Toxicity Evaluation (continued) DAY 70 - DAY 77 DAY 77 - DAY 84 DAY 84 - DAY 90 28.2 3.5(25 ) 28.0 3.6(25 ) 27.0 2.9(25 ) 27.4 3.5(15 ) 27.9 3.1(15 ) 26.3 3.5(15 ) 25.7 5.8(15 ) 25.0 3.5(14 ) 24.7 2.9(14 ) 24.2# 5.9(25 ) 26.8 3.5(25 ) 25.3 3.7(25 ) DAY 0 - DAY 90 28.2 2.4(25 ) 27.9 2.6(15 ) 27.1 2.0(14 ) 26.2# 2.4(25 ) One-Month Recovery Period for Subchronic Toxicity Evaluation DAY 90 - DAY 98 DAY 98 - DAY 105 DAY 105 - DAY 112 DAY 112 - DAY 119 28.4 2.7(15 ) 28.0 5.0 (15 ) 28.7 2.8(15 ) 26.2 5.0(15 ) 26.8 2.4(5 ) 27.7 2.6(5 ) 27.7 2.2(5 ) 25.9 4.4(5 ) 25.4# 3.6(5 ) 22.4 12.1(5 ) 25.0 5.5(5 ) 25.5 4.4(5 ) 25.4# 2.9(15 ) 25.6# 3.5(15 ) 24.7# 3.8(15 ) 25.4 3.3(15 ) DAY 90 - DAY 119 27.8 3.1(15 ) 27.0 2.4(5 ) 24.6 4.1(5 ) 25.3# 3.1(15 ) Company Sanitized. Does not contain TSCA C il H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 8 (CONTINUED) MEAN DAILY FOOD CONSUMPTION (g) BY MALE RATS Group I Group III Group V Group VII 0 mg/kg/day 25 mg/kg/day 100 mg/kg/day 250 mg/kg/day Three-Month Recovery Period for Subchronic Toxicity Evaluation DAY 119 - DAY 126 27.3 0.9(5 ) 26.2 0.9(5 ) 25.5 6.3(5 ) 25.1 4.1(5 ) DAY 126 - DAY 133 27.5 1.7(5 ) 26.5 6.2(5 ) 27.3 1.9(5 ) 25.8 4.1(5 ) DAY 133 - DAY 140 27.9 4.3(5 ) 28.7 2.7(5 ) 26.8 7.9(5 ) 26.9 2.5 (5 ) DAY 140 - DAY 147 26.0 7.0(5 ) 29.5 2.3(5 ) 31.7 3.0(5 ) 28.8 2.8(5 ) DAY 147 - DAY 154 30.4 2.2(5 ) 30.6 1.8(5 ) 31.2 3.2(5 ) 29.5 2.9(5 ) DAY 154 - DAY 161 32.4 2.4(5 ) 28.8. 1.8(5 ) 30.9 3.6(5 ) 30.7 3.7(5 ) DAY 161 - DAY 168 29.5 1.7(5 ) 29.2 1.9(5 ) 31.6 5.2(5 ) 30.9 -- 3.3 (5 ) DAY 168 - DAY 175 30.8 2.9(5 ) 29.0 2.0(5 ) 30.7 4.2(5 ) 28.9 3.4(5 ) DAY 119 - DAY 175 29.0 2.2(5 ) 28.6 1.7(5 ) 29.5 2.8(5 ) 28.3 3.2 (5 ) Data summarized a s : Mean Standard Deviation (n) # Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 74; food consumption data were not collected during the cohabitation and postmating periods. ) flPBfipsB!' infeiL @nSSn YSGA GB W 95 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 9 MEAN DAILY FOOD CONSUMPTION (g) BY FEMALE RATS Group II 0 mg/kg/day Group IV Group VI Group VIII 25 mg/kg/day 100 mg/kg/day 250 mg/kg/day Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 - DAY 7 DAY 7 - DAY 14 DAY 14 - DAY 21 DAY 21 - DAY 28 DAY 28 - DAY 35 DAY 35 - DAY 42 DAY 42 - DAY 49 DAY 49 - DAY 56 DAY 56 - DAY 63 DAY 63 - DAY 70 DAY 70 - DAY 74a 18.7 1.9(45 ) 20.1 2.2(45 ) 19.9 2.2(45 ) 19.7 2.3(45 ) 21.0 2.3(45 ) 20.4 2.2(45 ) 20.8 2.4(45 ) 21.1 2.1(45 ) 21.1 2.0(45 ) 20.9 2.2(45 ) 21.9 2.0(20 ) 18.9 4.0(34 ) 19.7 4.0(34 ) 20.9 3.9(34 ) 20.6 4.0(34 ) 21.3 3.5(33 ) 21.5 3.4(33 ) 21.0 4.3(33 ) 21.3 4.0(33 ) 20.9 1.8(33 ) 20.3 2.3(33 ) 21.3 3.7 (20 ) 17.9 1.6(35 ) 18.5# 1.5(35 ) 19.9 1.6(35 ) 19.8 2.9(35 ) 19.3 2.4(35 ) 18.4# 2.8(35 ) 20.0 2.4(35 ) 20.5 1.7(35 ) 19.5# 2.1(35 ) 19.8# 1.9(35 ) 20.2 2.9(20 ) 18.0# 1.8(45 ) 19.4# ' 1.6(45 ) 20.8 2.3(45 ) 20.0 2.0(45 ) 20.6 2.2(45 ) 19.6# 2.2(45 ) 19.1# 3.4(45 ) 19.3# 4.4(44 ) 17.9# 4.5(44 ) 16.7# 5.2(43 ) 20.3# 11.4(19 ) DAY 0 - DAY 74a 20.5 1.9(20 ) 21.1 3.5(20 ) 20.0 1.0(20 ) 19.8 2.0(19 ) Company Sanitized. Does not contain T S C A CBt 96 H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 9 (CONTINUED) MEAN DAILY FOOD CONSUMPTION (g) BY FEMALE RATS Group II 0 mg/kg/day Group IV Group VI Group VIII 25 mg/kg/day 100 mg/kg/day 250 mg/kg/day Dosinq Period for Subchronic Toxicity Evaluation (continued) DAY 70 - DAY 77 DAY 77 - DAY 84 DAY 84 - DAY 91 21.1 2.6(25 ) 21.4 3.6(25 ) 19.1 3.4(25 ) 20.9 2.7(13 ) 20.8 3.1(13 ) 19.0 2.3(13 ) 19.2# 2.1(15 ) 18.9@ 1.8(15 ) 17.3 2.0(15 ) 16.6# 4.3(24 ) 22.6 3.0(24 ) 18.8 3.1(24 ) DAY 0 - DAY 91 20.4 1.7(25 ) 20.1 1.7(13 ) 18.6# 1.5(15 ) One-Month Recovery Period for Subchronic Toxicity Evaluation 18.8# 1.4(24 ) DAY 91 - DAY 98 20.4 3.2(15 ) DAY 98 - DAY 105 21.1 4.3(15 ) DAY 105 - DAY 112 21.6 2.9(14 ) DAY 112 - DAY 119 21.4 3.3(14 ) 19.0 1.7(4 ) 20.0 1.1(4 ) 20.7 1.5(4 ) 20.4 1.4(4 ) 17.1 1.7(5 ) 18.3 1.8(5 ) 17.9 4.8(5 ) 16.9 5.8(5 ) 19.7 3.4(15 ) 20.3 3.6(15 ) 19.1# 2.6(15 ) 19.3 3.1(15 ) DAY 91 - DAY 119 21.2 2.9(14 ) 20.0 1.3(4 ) 17.5 2.9(5 ) 19.6 2.8(15 ) Company Sanitized. Dees n@8sortais? TSCA 11 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 9 (CONTINUED) MEAN DAILY FOOD CONSUMPTION (g) BY FEMALE RATS ' Group II Group IV Group VI Group VIII 0 mg/kg/day 25 mg/kg/day 100 mg/kg/day 250 mg/kg/day Three-Month Recovery Period for Subchronic Toxicity Evaluation DAY 119 - DAY 126 DAY 126 -- DAY 133 DAY 133 -- DAY 140 DAY 140 -- DAY 147 DAY 147 -- DAY 154 DAY 154 - DAY 161 DAY 161 - DAY 168 DAY 168 - DAY 175 19. 4 2. 2(5 ) 21.,2 1..8(5 ) 20 .1 2..2 (5 ) 21,.9 1..7 (5 ) 23 .2 3 .0(5 ) 24 .2 2 .0 (5 ) 22 .5 3 .5(5 ) 20 .9 1 .6 (5 ) 20. 6 1. 8 (4 ) 20. 4 1. 8 (4 ) 22 .0 1. 4(4 ) 22 .3 1. 3 (4 ) 23 .1 1. 2 (4 ) 21. 3 1..6 (4 ) 21..7 1..4(4 ) 21,.1 2 ,.6 (4 ) 20..6 2. 8(5 ) 20 .,3 2 .,1(5 ) 22 .,8 4..7(5 ) 24..5 3 .4(5 ) 21,.3 2,.1(5 ) 22 .6 2 .9(5 ) 21 .3 2 .4 (5 ) 21 .0 3 .1(5 ) 18. 5 2. 6(5 ) 18. 4# 2. 2(5 ) 20. 4 3 ..2(5 ) 22..3 2 .4 (5 ) 22 .9 2,.7 (5 ) 22 .5 2 .6(5 ) 22 .2 1 .8 (5 ) 20 .6 2 .2 (5 ) DAY 119 - DAY 175 21 .7 2 .1(5 ) 21,.6 1,.5 (4 ) 21 .8 2 .0 (5 ) 21 .0 1 .9 (5 ) Data summarized as: Mean Standard Deviation (n) # Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. @ Statistically significant difference at p < 0.05 by Dunn's test. a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 74; data were not collected during the cohabitation and postmating periods. iM lfe sd ra8nfiataT8S 61? H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 10 MEAN DAILY FOOD EFFICIENCY OF MALE RATS (g body weight gain/g food consumed) Group I Group III Group V Group VII 0 mg/kg/day 25 mg/kg/day 100 mg/kg/day 250 mg/kg/day Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 - DAY 7 DAY 7 - DAY 14 DAY 14 - DAY 21 DAY 21 - DAY 28 DAY 28 - DAY 35 DAY 35 - DAY 42 DAY 42 - DAY 49 DAY 49 - DAY 56 DAY 56 - DAY 63 DAY 63 - DAY 70 DAY 70 - DAY 74a 0 ..307 0.,026 (45 ) 0..262 0 .027 (45 ) 0 .211 0,.028 (45 ) 0..166 0 .028 (45 ) 0 .131 0 .029 (45 ) 0 .127 0 .025 (45 ) 0 .089 0 .038 (45 ) 0 .086 0 .050 (45 ) 0 .075 0 .048 (45 ) 0 .076 0 .026 (45 ) 0 .028 0 .049 (20 ) 0 .314 0. 032(35 ) 0 .270 0. 028(35 ) 0 .184 0. 025(35 ) 0.,178 0.,028(35 ) 0..148 0 .031(35 ) 0 ,.091# 0 ,.026(35 ) 0 .068 0 .036(35 ) 0 .072 0 .081(35 ) 0 .081 0 .050(35 ) 0 .074 0 .027(35 ) 0 .053 0 .061(20 ) 0 .314 0. 033 (35 ) 0 .249 0 .025(35 ) 0. 213 0. 028(35 ) 0 ..159 0.,032(35 ) 0 .,115 0..029 (35 ) 0..103# 0 ,.026(35 ) 0..076 0 .095(35 ) 0 .072# 0 .035(35 ) 0 .083 0 .035(35 ) 0 .031 0 .217(35 ) 0 .017 0 .042(20 ) 0. 331# 0 .032(45 ) 0. 235# 0. 024 (45 ) 0. 225# 0. 022(45 ) 0. 135# 0 .129 (45 ) 0..124 0 .,026 (45 ) 0..072# 0..126(45 ) 0 ,.038# 0 .067(45 ) -0 .019# 0 .246(45 ) -0 .010# 0 .136(45 ) -0 .368# 0 .919(45 ) -0 .073 0 .476(19 ) DAY 0 - DAY 74a 0 .146 0 .011 (20 ) 0 .143 0 .011(20 ) 0 .141 0 .009(20 ) 0 .114# 0 .015(19 ) .Company SanWzed. Does not confab Tsr:A CBI 99 Pl I 0 Sr H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 10 (CONTINUED) MEAN DAILY FOOD EFFICIENCY OF MALE RATS (g body weight gain/g food consumed) Group I Group III Group V Group VII 0 mg/kg/day 25 mg/kg/day 100 tng/kg/day 250 mg/kg/day Dosing Period for Subchronic Toxicity Evaluation (continued) DAY 70 - DAY 77 DAY 77 - DAY 84 DAY 84 - DAY 90 0.029 0.079(25 ) 0.063 0.046(25 ) 0.035 0.045(25 ) 0.045 0.035(15 ) 0.059 0.039(15 ) 0.028 0.074(15 ) -0.048 0.320(15 ) -0.008 0.159(14 ) 0.050 0.089(14 ) -0.027 0.333 (25 ) 0.158# 0.110 (25 ) 0.082# 0.064(25 ) DAY 0 - DAY 90 0.126 0.012(25 ) 0.124 0.012(15 ) 0.116# 0.009(14 ) One-Month Recovery Period for Subchronic Toxicity Evaluation DAY 90 - DAY 98 DAY 98 - DAY 105 DAY 105 - DAY 112 DAY 112 - DAY 119 0.084 0.042(15 ) 0.024 0.113(15 ) 0.061 0.037(15 ) -0.021 0.112(15 ) 0.066 0.020 (5 ) 0.051 0.023(5 ) 0.034 0.074 (5 ) -0.033 0.080(5 ) 0.019# 0.053(5 ) -2.355 5.392(5 ) 0.075 0.124(5 ) 0.024 0.145(5 ) 0.115# 0.011 (25 ) 0.062# 0.043(15 ) 0.041 0.045(15 ) 0.031 0.071/15 ) 0.044# 0.043(15 ) DAY 90 -- DAY 119 0.047 0.017(15 ) 0.034 0.030(5 ) 0.009* 0.027(5 ) 0.047 0.022(15 ) la * * not coniata TSCA S 100 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 10 (CONTINUED) MEAN DAILY FOOD EFFICIENCY OF MALE RATS (g body weight gain/g food consumed) Group I Group III Group V Group VII 0 mg/kg/day 25 mg/kg/day 100 mg/kg/day 250 mg/kg/day Three-Month Recovery Period for Subchronic Toxicity Evaluation* DAY 119 - DAY 126 DAY 126 - DAY 133 DAY 133 - DAY 140 DAY 140 - DAY 147 DAY 147 - DAY 154 DAY 154 - DAY 161 DAY 161 - DAY 168 DAY 168 - DAY 175 0.002 0.072(5 ) 0.078 0.031(5 ) 0.049 0.048(5 ) -0.000 0.156(5 ) 0.041 0.014(5 ) 0.031 0.029(5 ) 0.021 0.040(5 ) 0.075 0.021(5 ) -0.039 0.096(5 ) 0.070 0.088(5 ) 0.040 0.051(5 ) 0.058 0.014(5 ) 0.021 0.032(5 ) 0.028 . 0.008(5 ) 0.049 0.018(5 ) 0.037 0.033(5 ) -0.041 0.205(5 ) 0.071 0.094(5 ) 0.092 0.071(5 ) 0.064 0.011(5 ) 0.054 0.031(5 ) 0.033 0.029(5 ) 0.056 0.034 (5 ) 0.048 0.023(5 ) 0.046 0.038 (5 0.089 0.031(5 0.058 0.034 (5 0.083 0.031(5 0.043 0.027 (5 0.055 0.031(5 0.062 0.036 (5 0.015# 0.035 (5 DAY 119 - DAY 175 0.041 0.020(5 ) 0.036 0.007(5 ) 0.052 0.014(5 ) 0.056# 0.009(5 Data summarized a s : Mean Standard Deviation (n) # Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. * Statistically significant difference at p < 0.05 by Dunnett's test. a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 74; data were not collected during the cohabitation and postmating periods. S a n fe e d . D oes not oonlflln TSCA CBI 101 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 11 MEAN DAILY FOOD EFFICIENCY OF FEMALE RATS (g body weight gain/g food consumed) Group II 0 mg/kg/day Group IV Group VI Group VIII 25 mg/kg/day 100 mg/kg/day 250 mg/kg/day Dosinq Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 - DAY 7 DAY 7 - DAY 14 DAY 14 - DAY 21 DAY 21 - DAY 28 DAY 28 - DAY 35 DAY 35 - DAY 42 DAY 42 - DAY 49 DAY 49 - DAY 56 DAY 56 - DAY 63 DAY 63 - DAY 70 DAY 70 - DAY 74a 0.176 0.060(45 ) 0.128 0.048(45 ) 0.120 0.045(45 ) 0.095 0.048(45 ) 0.089 0.043(45 ) 0.048 0.042(45 ) 0.067 0.034(45 ) 0.048 0.053(45 ) 0.023 0.049(45 ) 0.041 0.038(45 ) -0.014 0.050(20 ) 0.170 0.048(34 ) 0.134 0.057(34 ) 0.146 0.039(34 ) 0.088 0.050(34 ) 0.081 0.036(33 ) 0.067 0.045(33 ) 0.040# 0.087(33 ) 0.020 0.096(33 ) 0.042 0.073(33 ) 0.041 0.043(33 ) -0.062 0.289(20 ) 0.193 0.043(35 ) 0.150 0.047(35 ) 0.117 0.044(35 ) 0.070 0.156(35 ) 0.061# 0.069(35 ) 0.072@ 0.076(35 ) 0.046# 0.080(35 ) 0.018# 0.039(35 ) 0.028 0.048(35 ) 0.038 0.050(35 ) -0.048 0.234(20 ) 0.199# 0.037(45 ) 0.162# 0.042(45 ) 0.098# 0.044(45 ) 0.087 0.045(45 ) 0.074# 0.038(45 ) 0.063 0.040(45 ) -0.000# 0.191(45 ) -0.120# 0.532(44 ) -0.064# 0.257(44 ) -0.220# 0.929(43 ) -0.188 0.733(19 ) DAY 0 -- DAY 74a 0.076 0.007(20 ) 0.078 0.013(20 ) 0.076 0.010(20 ) 0.058# 0.020(19 ) SSesnpany SantfadL O oes net TSC CBi H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 . TABLE 11 (CONTINUED) MEAN DAILY FOOD EFFICIENCY OF FEMALE RATS (g body weight gain/g food consumed) Group II 0 mg/kg/day Group IV Group VI Group VIII 25 mg/kg/day 100 mg/kg/day 250 mg/kg/day Dosing :Period for Subchronic Toxicity Evaluation (continued) DAY 70 - DAY 77 DAY 77 - DAY 84 DAY 84 - DAY 91 0. 001 0. 002(5 ) 0 .034 0. 036(25 ) -0 .020 0 .208(25 ) -0 .002 0. 001 (4 ) 0 .023 0. 026(13 ) 0 ..008 0 .,042(13 ) 0. 001 0 .004 (5 ) 0 .009 0. 045 (15 ) 0 .017 0. 039(15 ) -0.011# 0.009 (5 ) 0.136# 0.079(24 ) 0.015 0.067(24 ) DAY 0 - DAY 91 0 ..069 0 .,013(25 ) 0..068 0 .007(13 ) 0.,067 0 .,005(15 ) 0.066 0.008(24 ) One--Month Recovery Period for Subchronic Toxicity Evaluation DAY 91 - DAY 98 DAY 98 - DAY 105 DAY 105 - DAY 112 DAY 112 - DAY 119 0,.077 0,.111(15 ) 0 .018 0 .105(15 ) 0 .064 0 .051(14 ) -0 .000 0 .060(14 ) 0 .057 0 .047(4 ) 0 .014 0 .046 (4 ) 0 .064 0 .023 (4 ) 0 .024 0 .021 (4 ) 0..001 0 .077 (5 ) 0 .040 0 .033 (5 ) -0 .083 0 .279 (5 ) -0 .159 0 .452 (5 ) DAY 91 - DAY 119 0 .044 0 .040(14 ) 0 .040 0 .014 (4 ) -0 .015* 0 .055 (5 ) 0.034 0.074(15 ) 0.037 0.039(15 ) 0.059 0.042(15 ) 0.026 0.039(15 ) 0.039 0.029 (15 ) Company Sanitized. D oes not contain TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 11 (CONTINUED) MEAN DAILY FOOD EFFICIENCY OF FEMALE RATS (g body weight gain/g food consumed) droup II Group IV Group VI Group VIII 0 mg/kg/day 25 mg/kg/day 100 mg/kg/day 250 mg/kg/day Three-Month Recovery Period for Subchronic Toxicity Evaluation* DAY 119 - DAY 126 DAY 126 - DAY 133 DAY 133 - DAY 140 DAY 140 - DAY 147 DAY 147 - DAY 154 DAY 154 - DAY 161 DAY 161 - DAY 168 DAY 168 - DAY 175 -0.048 0.068(5 ) 0.107 0.028(5 ) -0.007 0.034(5 ) 0.050 0.019(5 ) 0.001 0.061(5 ) 0.041 0.047(5 ) 0.040 0.043(5 ) -0.009 0.021(5 ) -0.022 0.017(4 ) 0.068 0.018(4 ) 0.038 0.047(4 ) 0.032 0.049(4 ) 0.035 0.046(4 ) -0.001 0.046(4 ) 0.028 0.012(4 ) 0.014 0.034(4 ) 0.069# 0.115(5 ) 0.060 0.084(5 ) 0.010 0.048(5 ) 0.046 0.028(5 ) 0.034 0.058(5 ) 0.019 0.043(5 ) 0.015# 0.005(5 ) 0.028 0.029(5 ) 0.023# 0.042 (5 ) 0.067 0.063 (5 ) 0.023 0.058 (5 ) 0.074 0.027 (5 ) 0.045 0.032 (5 ) 0.033 0.027(5 ) -0.019# 0.073 (5 ) 0.016 0.030 (5 ) DAY 119 - DAY 175 0.024 0.012(5 ) 0.025 0.005(4 ) 0.036 0.014(5 ) 0.034 0.012(5 ) Data summarized a s : Mean Standard Deviation (n) # Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. * Statistically significant difference at p < 0.05 by Dunnett's test. @ Statistically significant difference at p < 0.05 by Dunn's test. a. Rats designated for reproduction evaluation (20 rats/group) were cohoused on test day 74; data were not collected during the cohabitation and postmating periods. Ppw pasjf Sanitized. Des not esratalsi TSGA CEI 104 H -24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 12 SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS Treatment Group I Dose 0 mg/kg/day Number Animais at Study Start 45 III 25 mg/kg/day 35 V 100 mg/kg/day 35 Mass Thoracic Lateral Mass #1 Ulcerated Incidence Mean onset (Days) Lateral Mass #1 Not Ulcerate'd Incidence Mean onset (Days) Eye Observations Corneal Opacity Incidence Mean onset (Days) Exophthalmus Incidence Mean onset (Days) Enophthalmus Incidence Mean onset (Days) 0 - 0 - 2 77 2 31 2 46 01 - 84 01 0 58 13 77 89 23 88 84 01 - 77 DuPont-4739 VII mg/kg/day 45 0 0 I 28 1 28 2 56 105 Company Sanitized. Does not contain TSCA CBI H -24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 12 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS Treatment Group I Dose 0 mg/kg/day Number Animals at Study Start 45 III 25 mg/kg/day 35 V 100 mg/kg/day 35 Partially Closed Incidence Mean onset (Days) Closed Left Incidence Mean onset (Days) Abnormal Gait Hindiimb Left Incidence Mean onset (Days) . Muscle Tone Decreased Incidence Mean onset (Days) Pale Incidence Mean onset (Days) 2 102 1 181 0 0 0 02 126 00 00 01 73 01 73 DuPont-4739 VII 250 mg/kg/day 45 1 119 0 1 63 0 0 106 jp f p a n f S a m ltta i noeonfaSn TSCA CBS H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 12 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS Treatment Group I Dose 0 mg/kg/day Number Animals at Study Start 45 III 25 mg/kg/day 35 V 100 mg/kg/day 35 General Teeth Observations Clipped Incidence Mean onset (Days) Maloccluded Incidence Mean onset (Days) Broken Incidence Mean onset (Days) Absent Incidence Mean onset (Days) Loose Incidence Mean onset (Days) Diarrhea Brown Incidence Mean onset (Days) 1 58 0 0 0 0 0 21 89 77 1 119 11 56 84 DuPont-4739 VII 250 mg/kg/day 45 32 75 1 58 10 # 72 5# 68 1 67 2 70 107 .Company Sanitized. Does not contain TSCA CB1 H -24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 12 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS Treatment Group I Dose 0 mg/kg/day Number Animals at Study Start 45 Ill 25 mg/kg/day 35 V 100 mg/kg/day 35 Breathing Observations Noise Incidence Mean onset (Days) Labored Incidence Mean onset (Days) Fast Incidence Mean onset (Days) Discharge Eye Incidence Mean onset (Days) Nose Incidence Mean onset (Days) Mouth Clear Incidence Mean onset (Days) 0 - 0 - 0 - 4 60 2 21 0 - 1 147 0 0 " 4 116 2 77 0 " 0 1 77 1 77 4 76 X 63 0 DuPont-4739 VII 250 mg/kg/day 45 1 69 1 70 0 3 65 6 77 3# 31 108 lpinpany Sanitized. Does not contain TSC CBI H -24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 12 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS Treatment Group I Dose 0 mg/kg/day Number Animals at Study Start 45 Ill 25 mg/kg/day 35 V 100 mg/kg/day 35 Mouth Red Incidence Mean onset (Days) 0 - Ear left Black Incidence Mean onset.(Days) 0 - Hair Loss Incidence Mean onset (Days) 5 49 Wound Superficial (nose, mouth, face, tail, shoulders) Incidence Mean onset (Days) 2 21 Hyperreactive Incidence Mean onset (Days) 2 116 Aggressive Behavior Incidence Mean onset (Days) 0 - 0 2 126 6 98 2 30 0 0 ~ i 66 0 4 77 0 3 68 0 DuPont-4739 VII 250 mg/kg/day 45 1 69 0 5 31 2 18 3 81 1 119 109 Company Sanitized. Does not contain TSCA CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 12 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS Treatment Group Dose I 0 mg/kg/day Number Animals at Study Start 45 III 25 mg/kg/day 35 V 100 mg/kg/day 35 Excessive Toe Nail Bleed Incidence Mean onset (Days) Stain Fur/Skin Periocular Right Brown Incidence . Mean onset (Days) Periocular Bilateral Black Incidence Mean onset (Days) Face Red Incidence Mean onset (Days) 0 0 0 0 01 76 00 00 00 DuPont-4739 VII 250 mg/kg/day 45 1 74 1 74 1 70 110 Company Sanitized. Dees net contain TSCACBS H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________________________________________________ ______ DuPont-4739 TABLE 12 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS Treatment Group I Dose 0 mg/kg/day Number Animals at Study Start 45 III 25 mg/kg/day 35 V 100 mg/kg/day 35 Face Black Incidence Mean onset (Days) Chin Red Incidence Mean onset (Days) Tail Brown Incidence Mean onset (Days) Perineum Yellow Incidence Mean onset (Days) Perineum Red Incidence Mean onset (Days) 0 0 0 0 0 1 119 0 0 0 0 0 0 0 0 0 VII 250 mg/kg/day 45 0 1 70 1 119 1 70 3# 70 111 Company Sanitized. Does not contain TSCA CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 12 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS Treatment Group I Dose 0 mg/kg/day Number Animals at Study Start 45 III 25 mg/kg/day 35 V 100 mg/kg/day 35 Perineum Brown Incidence Mean onset (Days) Inguen Brown Incidence Mean onset (Days) Forepaw Left Red Incidence Mean onset (Days) Forepaw Bilateral Red Incidence Mean onset (Days) 0 0 0 0 01 73 01 77 00 00 DuPont-4739 VII 250 mg/kg/day 45 0 0 1 70 2 70 112 Company Sanitised. Does not contain TSCA CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_______________________________________________________________ DuPont-4739 TABLE 12 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS Treatment Group I Dose 0 mg/kg/day Number Animals at Study Start 45 Misshapen Observations Tail Incidence Mean onset (Days) 0 Swollen Observations Nose Incidence Mean onset (Days) 0 Face Incidence Mean onset (Days) 0 Hindlimb Left Incidence Mean onset (Days) 0 III 25 mg/kg/day 35 0 V 100 mg/kg/day 35 0 00 01 56 0 VII 250 mg/kg/day 45 1 7 1 84 0 1 63 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. # Statistically significant difference at p < 0.05 by Cochran-Armitage trend test. Company Sanitized. Does not contain TSCA CBI 113 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 13 SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS Treatment Group II Dose 0 mg/kg/day Number Animals at Study Start 45 IV 25 mg/kg/day 35 VI 100 mg/kg/day 35 Mass Side Left Mass #1 Not Ulcerated Incidence Mean onset (Days) Mass Perineum Mass #1 Ulcerated Incidence Mean onset (Days) Mass Abdomen Mass #2 Incidence Mean onset (Days) Eye Observations Corneal Opacity Incidence Mean onset (Days) 0 1 105 0 2 44 00 00 00 03 - 56 DuPont-4739 VIII 250 mg/kg/day 45 1 64 0 1 119 3 93 114 Company Sanitized. Does not contain TSCA CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 13 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS Treatment Group II Dose 0 mg/kg/day Number Animals at Study Start 45 IV 25 mg/kg/day 35 VI 100 mg/kg/day 35 Exophthalmus Incidence Mean onset (Days) Enophthalmus Incidence Mean onset (Days) Partially Closed Left Incidence Mean onset (Days) Closed Left Incidence Mean onset (Days) Wet Fur Perineum Incidence Mean onset (Days) Prostrate Incidence Mean onset (Days) 3 70 1 77 1 112 1 175 0 " 0 - 03 - 64 01 - 49 01 " 112 00 00 10 29 4 DuPont-4739 VIII 250 mg/kg/day 45 3 109 3 84 1 112 0 1 47 0 115 Company Sanitized. Does not contain TSCA CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 13 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS Treatment Group II Dose 0 mg/kg/day Number Animals at Study Start 45 IV 25 mg/kg/day 35 VI 100 mg/kg/day 35 General Teeth Observations Clipped Incidence Mean onset (Days) Maloccluded Incidence Mean onset (Days) Broken Incidence Mean onset (Days) Absent Incidence Mean onset (Days) Loose Incidence Mean onset (Days) Diarrhea (Brown, Black) Incidence Mean onset (Days) 0 0 0 0 0 0 12 58 144 00 00 00 00 10 29 DuPont-4739 VIII 250 mg/kg/day 45 31 # 79 1 119 1 71 3# 66 1 71 1 70 116 Company Sanitized. Does not contain TSCA CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 13 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS Treatment Group II Dose 0 mg/kg/day Number Animals at Study Start 45 Breathing Observations Noise Incidence Mean onset (Days) 2 140 Fast Incidence Mean onset (Days) 0 Discharge Eye Incidence Mean onset (Days) 3 115 Nose Incidence Mean onset (Days) 2 102 Mouth Clear Incidence Mean onset (Days) 0 Mouth Tan Incidence Mean onset (Days) 0 IV 25 mg/kg/day 35 0 1 29 2 103 0 0 VI 100 mg/kg/day 35 0 0 - 3 54 1 119 0 00 DuPont-4739 VIII 250 mg/kg/day 45 1 140 0 4 108 1 70 1 63 1 47 117 Company Sanitized. Does not contain TSCA CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 13 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS Treatment Group II Dose 0 mg/kg/day Number Animals at Study Start 45 IV 25 mg/kg/day 35 VI 100 mg/kg/day 35 Vulva Red Incidence Mean onset (Days) Hair Loss Incidence Mean onset (Days) Wound Superficial (Nose , Mouth) Incidence Mean onset (Days) Hyperreactive Incidence Mean onset (Days) Hyperactive Incidence Mean onset (Days) Convulsions Clonic Incidence Mean onset (Days) 1 105 4 78 0 - 0 - 0 - 0 - 0 - 3 47 1 14 0 - 1 56 1 29 0 - 2 39 1 63 0 - 0 - 0 - DuPont-4739 VIII 250 mg/kg/day 45 0 - 5 43 0 - 1 70 1 70 0 - 118 Company Sanitized. Does not contain TSCA CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 13 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS Treatment Group II Dose 0 mg/kg/day Number Animals at Study Start 45 IV 25 mg/kg/day 35 VI 100 mg/kg/day 35 Vocalization Abnormal Incidence Mean onset (Days) Growth on left eye Incidence Mean onset (Days) Dehydrated Incidence Mean onset (Days) Stain Fur/Skin Face Brown Incidence Mean onset (Days) Shoulder Right Brown Incidence Mean onset (Days) 0 0 0 0 0 1 29 0 0 0 0 0 0 0 0 0 DuPont-4739 VIII 250 mg/kg/day 45 0 1 181 1 47 2 67 1 21 119 Company Sanitized. Does not contain TSCA CBi H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 13 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS Treatment Group II Dose 0 mg/kg/day Number Animals at Study Start 45 IV 25 mg/kg/day 35 VI 100 mg/kg/day 35 Perineum Yellow Incidence Mean onset (Days) Inguen Yellow Incidence Mean onset, (Days) 0 0 DuPont-4739 VIII 250 mg/kg/day 45 1 47 1 70 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. # Statistically significant difference at p < 0.05 by Cochran-Armitage trend test. 120 Company Sanitized. Does not contain TSCA CBf H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 14 SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR MALE RATS Treatment Group Dose I 0 mg/kg/day III 25 mg/kg/day Examination Day : Test Day 80 Number of Rats Examined 20 10 There were no ophthalmological abnormalities detected. v 100 mg/kg/day 9 DuPont-4739 VI1 250 mg/kg/day Examination Day : Test Day 122 Number of Rats Examined 10 There were no ophthalmological abnormalities detected. 0 121 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 15 SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR FEMALE RATS Treatment Group Dose II 0 mg/kg/day Examination day: Test day 80 Number of Rats Examined 20 Retina Retinal Degeneration Diffuse Left Incidence 0 ( 0 %) IV 25 mg/kg/day 10 VI 100 mg/kg/day VIII 250 mg/kg/day 20 0 ( 0 %) 1 ( 10%) 0 ( 0 %) Examination day: Test day 122 Number of Rats Examined 9 There were no ophthalmological abnormalities detected. 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. 122 Company Sanitized. Does not contain TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 16 PERCENT SURVIVAL OF MALE RATS Treatment Group Dose (mg/kg/day) Animal Count at Study Start DAYS ON TEST 0 7 14 21 28 35 42 49 56 63 70 77 a 84 91 c'd 98 105 112 119 I l11 0 25 45 35 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 V 100 35 100 100 100 100 100 100 100 100 100 100 100 100 100 b 100 100 100 100 100 VII 250 45 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 Number at study start Accidentally Killed Removed from study a Sacrificed by design d Alive on test day 119 45 35 35 45 0 0 11 20 20 20 19 10 10 9 10 15 5 5 lb Percent Survival = (Number of rats alive/Number of rats at risk)*100 Number of rats at risk = Number at study start - number of rats removed from study - number sacrificed by design - accidentally killed. a. Rats designated for reproduction evaluation were removed from study (cohoused) on test day 74. b. One rat was accidentally killed during the previous week. c. Recovery period began on test day 90. __ d. Rats designated for the 90-day exposure period were sacrificed on test day 91. There were no statistically significant decreases in survival at p < 0.05 by Cochran-Armitage trend test. Company Sanitized. Doe not contain TSCA CBI 123 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 17 PERCENT SURVIVAL OF FEMALE RATS Treatment Group Dose (mg/kg/day) Number Animals at Study Start II 0 45 IV VI VIII 25 100 250 35 35 45 DAYS ON TEST 0 7 14 21 28 35 42 49 56 63 70 77 e 84 91 '9 98 105 112 119 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 93 c 93 100 a 100 100 100 100 97 c 97 97 97 97 97 93 93 93 80 80 80 80 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 b 100 98 d 96 96 96 96 96 96 96 Number at study start Accidentally killed Found dead Sacrificed in e x t r e m i s Removed from study e Sacrificed by design 9 Alive on test day 119 45 35 35 45 01 01 00 01 11 00 20 20 20 19 10 9 10 9 14 4 5 15 Percent Survival = (Number of rats alive/Number of rats at risk)*100 Number of rats at risk = Number at study start - number of rats removed from study - number sacrificed by design - accidentally killed. a. One rat was accidentally killed on test day 0 and replaced day 0. b. One rat was accidentally killed during the previous week. c. One rat was sacrificed in e x t r e m i s during the previous week. d. One rat was found dead during the previous week. e. Rats designated for reproduction evaluation were removed from study (cohoused) on test day 74. f. Recovery period began on test day 90. g. Rats designated for the 90-day exposure period were sacrificed on test day 93. There were no statistically significant decreases in survival at p < 0.05 by Cochran-Armitage trend test. Company Sanitized. O ses not contain TSCA CB 124 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 18 MEAN FORELIMB AND HINDLIMB GRIP STRENGTH FOR MALE RATS (MEAN OF THREE TRIALS) Assessment Dosage Period Group (mg/kg/day) Forelimb Grip Strength (kg) Hindlimb Grip Strength (kg) Baseline I III V VII 0 25 100 250 0.51 (0.08) 0.52 (0.10) 0.54 (0.08) 0.54 (0.09) 0.40 (0.06) 0.38 (0.07) 0.36 (0.03) 0.40 (0.06) Week 13 I III V VII 0 25 100 250 1.38 (0.34) 1.35 (0.29) 1.38 (0.32) 1.31 (0.23) 0.84 (0.15) 0.80 (0.07) 0.80 (0.13) 0.73 (0.11) Recovery I VII 0 250 1.27 (0.31) 1.03 (0.32) 0.74 (0.14) 0.75 (0.09) Data arranged as : Mean (Standard Deviation) Statistical Methods: Bartlett's test for homogeneity followed by analysis o f variance and Dunnett's test. There were no statistically significant differences from control at p<0.05. ( W , Sanitized. Do* notcontain TSCACW H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 19 MEAN FORELIMB AND HINDLIMB GRIP STRENGTH FOR FEMALE RATS (MEAN OF THREE TRIALS) Assessment Dosage Period Group (mg/kg/day) Forelimb Grip Strength (kg) Hindlimb Grip Strength (kg) Baseline II IV VI VIII 0 25 100 250 0.58 (0.08) 0.54 (0.12) 0.54 (0.12) 0.59 (0.14) 0.37 (0.04) 0.39 (0.06) 0.36 (0.05) 0.36 (0.04) Week 13 II IV VI VIII 0 25 100 250 1.18 (0.25) 1.22 (0.21) 1.04 (0.21) 1.01 (0.22) 0.73 (0.10) 0.72 (0.12) 0.65 (0.10) 0.64 (0.14) Recovery II VIII 0 250 1.07 (0.27) 1.13(0.35) 0.69 (0.09) 0.66 (0.11) Data arranged as : Mean (Standard Deviation) Statistical Methods: Bartlett's test for homogeneity followed by analysis o f variance and Dunnett s test. There were no statistically significant differences from control at p<0.05. tscacbi ,, w tm m * .* " " * * * * * " 126 ..-v H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR MALE RATS Group: Dosage (mg/kg/day): Number Examined: Baseline I III V VII 0 25 100 250 10 10 10 10 _______ Week 13_______ I III V VII 0 25 100 250 10 10 9 10 Recovery I VII 0 250 10 10 APPROACH & TOUCH: no reaction normal increased reaction (jumps away or attacks) 0000 10 10 10 10 0000 00 9 10 10 10 8 10 00 00 10 10 00 AUDITORY STIMULUS: no reaction normal reaction (rat flinches or flicks ear) exaggerated reaction (rat jumps, flips) 0000 10 10 10 10 0000 00 10 10 00 00 9 10 00 _ 0u 10 10 00 TAIL PINCH: no response normal (turns toward site) exaggerated response 0 10 0 9 9 9 10 10 10 0000 10 9 9 10 0 10 0 _ 00 9 10 10 IN MOTOR ACTIVITY MONITOR: DEFECATION present absent diarrhea 79 88 3 12 2 0000 3657 74 4 3 0000 , 86 24 00 URINATION: present absent 7874 3236 4737 6363 . 75 35 PUPILLARY RESPONSE present absent 10 10 10 10 0000 10 10 00 9 10 00 10 10 00 ) ________________________________________________________________________________ ' 27 qgmpany Sanltiwd* Do** noicontain TSCACBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 20 (CONTINUED) SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR MALE RATS Group: Dosage (mg/kg/day): Number Examined: Baseline_______ I III V VII 0 25 100 250 10 10 10 10 _______ Week 13_______ I III V VII 0 25 100 250 10 10 9 10 Recovery I VII 0 250 10 10 ADDITIONAL OBSERVATIONS NOTED Sore, right axilla Present Absent 0000 10 10 10 10 00 10 10 10 8 10 00 10 10 Ptosis present absent 0000 10 10 10 10 00 10 10 00 9 10 There were no statistically significant differences by Cochran-Arrrutage test for trend at p < 0.05. 01 10 9 128 Company Sanitized. Doe not contain TSCA CBf H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 21 SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR FEMALE RATS Group: Dosage (mg/kg/day): Number Examined: Baseline_______ II IV VI VIII 0 25 100 250 10 10 10 10 _______ Week 13_______ II IV VI VIII 0 25 100 250 10 9 10 10 Recovery II VIII 0 250 9 10 APPROACH & TOUCH: no reaction normal increased reaction (jumps away or attacks) 0000 10 10 10 10 0000 00 0 0 10 9 10 10 00 00 00 9 10 00 AUDITORY STIMULUS: no reaction normal reaction (rat flinches or flicks ear) exaggerated reaction (rat jumps, flips) 0000 10 10 10 10 0000 0 0 10 10 9 9 10 0000 00 9 10 00 TAIL PINCH: no response normal (turns toward site) exaggerated response 00 10 10 00 00 9 10 10 0000 10 9 10 9 000 1 00 9 10 00 IN M OTOR ACTIVITY MONITOR: DEFECATION present absent diarrhea 24 26 86 84 0000 304 5 79 6 5 0000 31 69 00 URINATION: present absent 7659 34 5 1 2234 8776 63 37 PUPILLARY RESPONSE present absent 10 10 10 10 0000 10 9 10 10 0000 9 10 00 129 Company Sanitized. Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 21 (CONTINUED) SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR FEMALE RATS Group: Dosage (mg/kg/day): Number Examined: Baseline II rv VI VIII 0 25 100 250 10 10 10 10 Week 13_______ II IV VI VIII 0 25 100 250 10 9 10 10 Recovery II VIII 0 250 9 10 ADDITIONAL OBSERVATIONS NOTED Ptosis present absent 0000 10 10 10 10 000 1 10 9 10 9 Scratch, right comer o f eye present absent 0000 10 10 10 10 0000 10 9 10 10 Chromodacryorrhea present absent 0000 10 10 10 10 0000 10 9 10 10 There were no statistically significant differences by Cochran-Armitage test for trend at p < 0.05. 01 99 02 98 01 99 130 Company Sanitized. Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 22 MOTOR ACTIVITY ASSESSMENT: DURATION OF MOVEMENTS (sec) FOR MALE RATS ASSESSMENT DOSAGE PERIOD GROUP (mg/kg/day) SUCCESSIVE 10-MINUTE INTERVALS BASELINE 123 4 5 I 0 430(67) 313(106) 275(89) 187(127) 70(81) III 25 419(45) 329(80) 257(138) 87(88) * 11(14) V 100 403(52) 322(59) 196(110)* 96(119)* 42(78) VII 250 392(53) 287(61) 178(114)* 73(88) * 47(80) W EEK 13 123 4 5 I 0 407(40) 3oT(45) 233(49) 174(63) 116(71) III 25 392(56) 297(66) 218(71) 172(109) 99(81) V 100 368(39) 273(58) 233(99) 180(103) 171(92) VII 250 368(71) 265(98) 210(117) 147(93) 145(84) RECOVERY 1 I 0 324(58) VII 250 295(52) Data arranged as: Mean (Standard Deviation). 2 202(45) 184(42) 3 140(44) 147(48) 4 145(51) 131(50) 5 127(44) 120(47) 6 34(53) 5(6) 54(91) 46(78) TOTAL 1321(375) 1117(341) 1123(395) 1033(343) 6 102(108) 72(46) 135(87) 93(95) TOTAL 1332(231) 1250(298) 1360(387) 1228(477) 6 140(58) 116(61) TOTAL 1072(247) 995(213) Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Repeated measures analysis o f variance with linear contrasts was used to identify which dosage groups, if any, were significantly different from the control group. These tests were applied to bin data and total data. * Statistically significant difference from control at p < 0.05. 131 Company Sanitized. Doe* not contain TSCACBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 23 MOTOR ACTIVITY ASSESSMENT: DURATION OF MOVEMENTS (sec) FOR FEMALE RATS ASSESSMENT DOSAGE SUCCESSIVE 10-MINUTE INTERVALS BASELINE 1 II 0 37?(45) IV 25 400(27) VI 100 409(50) VIII 250 364(48) W EEK 13 1 II 0 372(56) IV 25 432(58) VI 100 386(76) VIII 250 371(69) RECOVERY II 0 330(55) VIII 250 297(56) Data arranged as: Mean (Standard Deviation). 2 304(84) 286(60) 327(73) 261(80) 2 263(59) 323(94) 266(85) 268(65) 2 223(57) 153(73) 3 163(109) 249(66) 169(135) 222(97) 4 166(102) 153(110) 152(157) 164(147) 5 130(90) 109(113) 92(128) 104(141) 6 31(58) 32(42) 79(143) 74(121) TOTAL 1176(236) 1239(215) 1240(588) 1190(478) 3 223(89) 239(87) 202(129) 148(96) 4 148(86) 166(103) 144(132) 139(80) 5 108(66) 101(111) 134(111) 111(73) 6 116(118) 153(84) 111(76) 91(93) TOTAL 1230(310) 1413(366) 1242(430) 1128(268) 3 173(29) 105(83) 4 157(69) 86(73) 5 106(41) 41(35) 6 103(64) 92(62) TOTAL 1091(191) 775(290)* Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Repeated measures analysis o f variance with linear contrasts was used to identify which dosage groups, if any, were significantly different from the control group. These tests were applied to bin data and total data. * Statistically significant difference from control at p < 0.05. 132 jpQinpanjf Sanitized. Does not contain TSCA CBS H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_______________________________________________________________ DuPont-5368 TABLE 24 MOTOR ACTIVITY ASSESSMENT: NUMBER OF MOVEMENTS FOR MALE RATS ASSESSMENT DOSAGE PERIOD_______ GROUP (mg/kg/day) SUCCESSIVE 10-MINUTE INTERVALS BASELINE 1 2 3 4 5 6 TOTAL I 0 120(31) 115(22) 124(22) 88(42) 49(45) 20(26) 527(127) III 25 117(24) 121(25) 107(33) 50(42) 9(10) 6(4) 421(78) V 100 123(17) 133(21) 111(33) 55(38) 30(40) 29(38) 491(111) VII 250 138(12) 140(17) 102(54) 54(55) 32(50) 34(49) 510(175) WEEK 13 1 2 3 4 5 6 TOTAL I 0 128(31) 125(27) 109(29) 95(32) 69(38) 55(54) 581(152) III 25 129(20) 115(17) 106(20) 72(37) 52(38) 44(26) 516(80) V 100 151(25) 136(18) 119(38) 96(50) 108(44) 84(52) 694(162) VII 250 135(18) 122(27) 98(41) 80(40) 86(40) 56(43) 575(151) RECOVERY 1 1 0 133(19) VII 250 131(19) Data arranged as: Mean (Standard Deviation). 2 106(26) 96(20) 3 80(25) 81(26) 4 8(18) 80(33) 5 77(20) 72(25) 6 80(24) 76(35) TOTAL 557(91) 537(124) Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Repeated measures analysis o f variance with linear contrasts was used to identify which dosage groups, if any, were significantly different from the control group. These tests were applied to bin data and total data. There were no statistically significant differences from control at p < 0.05. 133 Company Sanitized. Does not contain TSCA CBT H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations & DuPont-5368 TABLE 25 MOTOR ACTIVITY ASSESSMENT: NUMBER OF MOVEMENTS FOR FEMALE RATS ASSESSMENT DOSAGE PERIOD_______ GROUP (mg/kg/day) SUCCESSIVE 10-MINUTE INTERVALS BASELINE 1 2 3 4 5 6 TOTAL II 0 134(15) 137(16) 94(49) 95(49) 93(61) 28(37) 590(117) IV 25 130(16) 137(19) 135(19) 100(62) 64(61) 28(34) 605(156) VI 100 123(28) 127(26) 80(42) 66(51) 45(33) 34(46) 486(125) VIII 250 136(13) 132(35) 127(33) 90(63) 59(63) 47(63) 591(201) WEEK 13* 1 2 3 4 5 6 TOTAL 11 0 143(16) 132(16) 120(31) 88(45) 71(41) 74(67) 628(164) IV 25 123(31) 121(27) 106(51) 93(50) 59(52) 81(46) 583(198) VI 100 132(30) 118(26) 91(42) 67(50) 77(58) 73(43) 557(158) VIII 250 131(24) 125(12) 91(42) 92(41) 70(40) 55(42) 565(94) RECOVERY II VIII 0 250 1 138(11) 140(12) Data arranged as: Mean (Standard Deviation). 2 130(15) 101(41) 3 1ll(1 6 ) 74(37) 4 110(27) 62(40) 5 80(20) 41(30) 6 83(50) 75(35) TOTAL 652(55) 493(137): Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Repeated measures analysis o f variance with linear contrasts was used to identify which dosage groups, if any, were significantly different from the control group. These tests were applied to bin data and total data. * Statistically significant difference from control at p < 0.05. 134 .Company Sanitized Does not contain TSCA OB! H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 26 TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I 0 mg/kg Group HI 25 mg/kg Group V 100 mg/kg Group VII 250 mg/kg RBC (xl06/pL) DAY 44 DAY 91 DAY 125 HGB (g/dL) DAY 44 DAY 91 DAY 125 HCT (%) DAY 44 DAY 91 DAY 125 MCV (fl) DAY 44 DAY 91 DAY 125 MCH (pg) DAY 44 DAY 91 DAY 125 8.22 0.41(10) 8.88 0.56(9) 8.93 0.38(10) 15.1 0.5(10) 15.3 0.7(9) 15.6 0.5(10) 46.0 1.7(10) 48.9 2.7(9) 48.3 1.8(10) 56.0 1.8(10) 55.2 2.5(9) 54.2 1.8(10) 18.4 0.6(10) 17.3 0.6(9) 17.5 0.6(10) 8.34 0.23(10) 8.57 0.38(9) a 15.3 0.4(10) 15.1 0.8(9) a 46.6 1.5(10) 47.4 2.9(9) a 55.9 1.5(10) 55.3 1.7(9) a 18.4 0.4(10) 17.7 0.4(9) a 7.96 0.36(10) 8.27* 0.35(9) a 15.1 0.6(10) 15.0 0.5(9) a 45.8 2.1(10) 47.2 2.1(9) a 57.6 1.4(10) 57.0 1.2(9) a 19.0 0.5(10) 18.1* 0.4(9) a 8.06 0.32(10) 7.99* 0.43(10) 7.97* 0.31(10) 14.8 0.4(10) 14.3* 0.8(10) 14.3* 0.8(10) 45.2 1.4(10) 45.4* 2.5(10) 43.9* 2.7(10) 56.1 1.3(10) 56.8 2.1(10) 55.0 2.1(10) 18.3 0.5(10) 17.8 0.5(10) 17.9 0.7(10) Company Sanitized Does not contain TSCACBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 26 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I 0 mg/kg Group III 25 m g /k g__ Group V 100 mg/kg Group VII 250 mg/kg MCHC (g/dL) DAY 44 DAY 91 DAY 125 RDW (%) DAY 44 DAY 91 DAY 125 ARET (xlOVjiL) DAY 44 DAY 91 DAY 125 WBC (xlOVuL) DAY 44 DAY 91 DAY 125 ANEU (xl07pL) DAY 44 DAY 91 DAY 125 32.9 0.5(10) 31.3 0.6(9) 32.2 0.5(10) 12.2 0.5(10) 13.2 0.7(9) 13.6 0.8(10) 200 40(10) 181 49(9) 188 31(10) 17.36 2.17(10) 14.37 2.08(9) 13.11 3.83(10) 2.32 1.01(10) 2.14 0.47(9) 1.79 0.97(10) 32.9 0.7(10) 31.9* 0.4(9) a 12.1 0.5(10) 12.9 0.3(9) a 185 32(10) 179 23(9) a 16.34 4.10(10) 12.15 3.14(9) a 2.31 0.76(10) 1.92 0.47(9) a 32.9 0.5(10) 31.7 0.6(9) a 11.9 0.6(10) 13.5 0.5(9) a 179 21(10) 196 36(9) a 17.97 3.83(10) 14.04 3.05(9) a 2.50 0.75(10) 1.75 0.75(9) a 32.6 0.5(10) 31.4 0.4(10) 32.6 0.4(10) 12.6 0.4(10) 15.1 @ 1.3(10) 12.7 1.3(10) 177 25(10) 218 46(10) 150* 22(10) 19.29 3.11(10) 15.25 3.14(10) 13.23 3.45(10) 2.48 0.97(10) 2.34 0.66(10) 1.94 0.74(10) Som pw y S m lteed. m t m TCA H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 26 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I 0 mg/kg Group III 25 mg/kg Group V 100 mg/kg Group VH 250 mg/kg ALYM (xl03/pL) DAY 44 DAY 91 DAY 125 AMON (xl03/pL) DAY 44 DAY 91 DAY 125 AEOS (xlOVnL) DAY 44 DAY 91 DAY 125 ABAS (xl03/pL) DAY 44 DAY 91 DAY 125 14.19 1.91(10) 11.54 1.59(9) 10.60 3.36(10) 0.34 0.10(10) 0.45 0.20(9) 0.34 0.19(10) 0.16 0.04(10) 0.15 0.07(9) 0.14 0.08(10) 0.11 0.03(10) 0.03 0.04(9) 0.07 0.03(10) 13.03 4.07(10) 9.57 3.16(9) a 0.40 0.10(10) 0.38 0.21(9) a 0.23* 0.05(10) 0.20 0.15(9) a 0.10 0.04(10) 0.03 0.03(9) a 14.65 3.82(10) 11.56 3.23(9) a 0.39 0.17(10) 0.37 0.21(9) a 0.15 0.05(10) 0.17 0.10(9) a 0.11 0.07(10) 0.04 0.04(9) a 15.86 2.55(10) 12.12 2.80(10) 10.62 2.98(10) 0.44 0.13(10) 0.40 0.16(10) 0.28 0.11(10) 0.15 0.07(10) 0.21 0.13(10) 0.13 0.13(10) 0.10 0.05(10) 0.04 0.04(10) 0.08 0.05(10) 137 Company Sanitized. Doe not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 26 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I 0 mg/kg Group III 25 mg/kg Group V 100 mg/kg Group VII 250 mg/kg ALUC (xl07pL)* DAY 44 DAY 91 DAY 125 PLT (xl03/|iL) DAY 44 DAY 91 DAY 125 0.24 0.06(10) 0.07 0.09(9) 0.17 0.12(10) 1141 103(9) 1178 153(7) 1059 126(7) 0.27 0.19(10) 0.07 0.07(9) a 1077 92(9) 1055 122(9) a 0.18 0.10(10) 0.15 0.17(9) a 1069 225(8) 1092 155(8) a 0.26 0.14(10) 0.13 0.13(10) 0.18 0.06(10) 1008 102(8) 1111 90(7) 1081 78(9) Data arranged as: Mean Standard deviation (Number o f values included in calculation) a Group not sampled at this timepoint. * Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett). @ Statistically significant difference from control at p < 0.05 by nonparametric test (Dunn's). 138 Pewpaisy Sanitized. Does not contain TSCA CB H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 27 TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Group II 0 mg/kg Group IV 25 mg/kg Group VI 100 mg/kg Group Vm 250 mg/kg RBC (xl06/pL) DAY 45 DAY 93 DAY 125 HGB (g/dL) DAY 45 DAY 93 DAY 125 HCT (%) DAY 45 DAY 93 DAY 125 MCV (fl) DAY 45 DAY 93 DAY 125 MCH (pg) DAY 45 DAY 93 DAY 125 8.26 0.17(10) 8.41 0.27(10) 7.95 0.38(9) 15.4 0.5(10) 15.5 0.5(10) 15.1 0.7(9) 46.9 1.1(10) 47.6 1.9(10) 45.7 2.0(9) 56.8 1.2(10) 56.6 1.5(10) 57.5 1.5(9) 18.7 0.5(10) 18.5 0.4(10) 19.1 0.3(9) 7.85 0.30(9) 8.08 0.28(9) a 14.8* 0.3(9) 15.2 0.6(9) a 44.9* 1.8(9) 45.7 2.0(9) a 57.2 1.7(9) 56.6 1.9(9) a 18.9 0.6(9) 18.8 0.7(9) a 8.14 0.45(10) 8.17 0.62(10) a 15.1 0.4(10) 15.1 0.5(10) a 45.6 1.7(10) 46.2 2.4(10) a 56.0 1.6(10) 56.8 3.9(10) a 18.5 0.6(10) 18.5 0.8(10) a 7.75* 0.45(10) 7.82* 0.32(9) 8.00 0.50(9) 14.5* 0.7(10) 14.2* 0.5(9) 14.8 0.8(9) 44.3* 2.1(10) 44.0* 1.5(9) 44.3 2.3(9) 57.1 1.2(10) 56.3 1.1(9) 55.5* 2.1(9) 18.7 0.7(10) 18.2 0.5(9) 18.5* 0.7(9) 139 Company Sanitized. Does not contain TSCA CBl H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 27 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Group II 0 mg/kg Group IV 25 mg/kg Group VI 100 mg/kg Group VU! 250 mg/kg MCHC (g/dL) DAY 45 DAY 93 DAY 125 RDW (%) DAY 45 DAY 93 DAY 125 ARET (xl03/pL) DAY 45 DAY 93 DAY 125 WBC (xl03/pL) DAY 45 DAY 93 DAY 125 ANEU (xl03/pL) DAY 45 DAY 93 DAY 125 32.9 0.8(10) 32.7 0.5(10) 33.2 0.8(9) 11.7 0.5(10) 11.3 0.5(10) 12.4 0.7(9) 208 25(10) 151 35(10) 171 24(9) 13.67 3.13(10) 9.96 1.66(10) 7.98 1.76(9) 1.77 0.70(10) 1.15 0.32(10) 1.13 0.27(9) 33.0 0.9(9) 33.2 1.4(9) a 11.9 0.5(9) 11.3 0.4(9) a 216 35(9) 157 0.036(9) a 12.83 2.99(9) 9.86 1.76(9) a 1.62 0.48(9) 1.46 0.49(9) a 33.1 0.5(10) 32.6 1.2(10) a 11.7 0.7(10) 12.3 2.5(10) a 201 37(10) 219 181(10) a 13.42 3.12(10) 10.36 2.27(10) a 1.69 0.54(10) 2.31 @ 0.94(10) a 32.7 0.8(10) 32.3 0.4(9) 33.4 0.5(9) 12.2 0.4(10) 12.3@ 1.0(9) 11.7@ 0.3(9) 210 39(10) 172 28(9) 145@ 39(9) 13.59 1.93(10) 10.50 1.98(9) 8.12 1.47(9) 1.81 0.67(10) 1.65 0.78(9) 1.58* 0.54(9) 140 .Company Sanitized. Doe not contain TSCA OBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 27 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Group II 0 mg/kg Group IV 25 mg/kg Group VI 100 mg/kg Group V m 250 mg/kg ALYM (xlOVpL) DAY 45 DAY 93 DAY 125 AMON (xlO/pL) DAY 45 DAY 93 DAY 125 AEOS (xlO/pL) DAY 45 DAY 93 DAY 125 ABAS (xlO/fiL) DAY 45 DAY 93 DAY 125 11.10 2.43(10) 8.22 1.50(10) 6.41 1.77(9) 0.30 0.09(10) 0.21 0.07(10) 0.21 0.07(9) 0.19 0.07(10) 0.18 0.09(10) 0.10 0.04(9) 0.10 0.07(10) 0.08 0.02(10) 0.04 0.03(9) 10.52 2.87(9) 7.83 1.70(9) a 0.25 0.08(9) 0.24 0.10(9) a 0.10* 0.05(9) 0.14 0.06(9) a 0.09 0.05(9) 0.07 0.04(9) a 10.91 2.57(10) 7.39 2.29(10) a 0.31 0.08(10) 0.26 0.08(10) a 0.18 0.09(10) 0.22 0.09(10) a 0.11 0.05(10) 0.07 0.03(10) a 10.99 1.67(10) 8.19 1.66(9) 5.94 1.51(9) 0.29 0.10(10) 0.29 0.17(9) 0.29 0.14(9) 0.18 0.04(10) 0.18 0.06(9) 0.15* 0.03(9) 0.10 0.03(10) 0.05 0.03(9) 0.04 0.02(9) 141 Company Sanitized. Doea not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 27 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Group II 0 mg/kg Group IV 25 mg/kg Group VI 100 mg/kg Group VIII 250 mg/kg ALUC (xlO/pL) DAY 45 DAY 93 DAY 125 PLT (xlO/pL) DAY 45 DAY 93 DAY 125 0.21 0.08(10) 0.12 0.05(10) 0.09 0.03(9) 1186 110(6) 1025 144(10) 1043 217(9) 0.24 0.18(9) 0.12 0.08(9) a 1081 202(9) 1004 102(8) a 0.22 0.09(10) 0.12 0.06(10) a 1084 108(8) 1118 105(6) a 0.22 0.06(10) 0.14 0.07(9) 0.11 0.04(9) 1068 106(9) 1029 143(6) 1172 159(5) Data arranged as: Mean Standard deviation (Number o f values included in calculation) a Group not sampled at this timepoint. * Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett). @ Statistically significant difference from control at p < 0.05 by nonparametric test (Dunn's). 142 jEfmpnny Sanitized. Does no! com?TMa rqf H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 28 SUMMARY OF COAGULATION VALUES FOR MALE RATS TEST/ Group I Group III Group V Group VII PERIOD_______________mg/kg________25 mg/kg_______ 100 mg/kg______ 250 mg/kg PT (seconds) DAY 91 APTT (seconds) DAY 91 15.2 0.8(10) 18.7 2.5(10) 14.7 0.4(10) 16.3* 2.2(10) 15.2 0.9(9) 15.8* 2.1(9) 15.5 0.7(10) 16.8 0.8(10) Data arranged as: Mean Standard deviation (Number o f values included in calculation) * Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett). TABLE 29 SUMMARY OF COAGULATION VALUES FOR FEMALE RATS TEST/ Group II Group IV Group VI PERIOD______________ 0 mg/kg________25 mg/kg_______ 100 mg/kg Group VIII 250 mg/kg PT (seconds) DAY 93 APTT (seconds) DAY 93 14.5 0.8(9) 17.1 1.4(9) 14.4 0.3(9) 15.8 1.4(9) 14.5 0.5(10) 15.4 1.7(10) 14.1 0.5(9) 15.1* 1.5(9) Data arranged as: Mean Standard deviation (Number o f values included in calculation) * Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett). 143 Company Sanitized. Does not contain TSCA CSI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 30 SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group I 0 mg/kg Group III 25 mg/kg Group V 100 mg/kg Group VII 250 mg/kg AST (U/L) DAY 44 DAY 91 DAY 125 ALT (U/L) DAY 44 DAY 91 DAY 125 SDH (U/L) DAY 44 DAY 91 DAY 125 ALKP (U/L) DAY 44 DAY 91 DAY 125 BILI (mg/dL) DAY 44 DAY 91 DAY 125 78 10(10) 99 29(10) 78 7(10) 30 4(10) 36 8(10) 33 7(10) 18.8 4.2(10) 28.6 8.1(10) 21.5 6.5(10) 134 31(10) 97 22(10) 81 18(10) 0.09 0.03(10) 0.07 0.03(10) 0.06 0.02(10) 84 13(10) 87 18(10) a 33 5(10) 36 8(10) a 17.9 4.6(10) 23.3 6.2(10) a 144 35(10) 95 20(10) a 0.09 0.04(10) 0.06 0.02(10) a 76 7(8) 80 15(9) a 28 6(8) 33 5(9) a 18.2 2.6(10) 23.4 5.8(9) a 156 21(8) 139* 20(9) 0.08 0.04(8) 0.05 0.00(9) a 82 14(9) 96 30(10) 79 10(10) 33 8(9) 43 22(10) 36 14(10) 17.4 6.3(10) 25.8 9.1(10) 14.0* 3.4(10) 185* 30(9) 186* 32(10) 77 14(10) 0.06 0.02(9) 0.05 0.00(10) 0.05 0.00(10) 144 Ooos no! contain TSCA Cfll H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 30 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group I 0 mg/kg Group III 25 mg/kg Group V 100 mg/kg Group VII 250 mg/kg BUN (mg/dL) DAY 44 DAY 91 DAY 125 CREA (mg/dL) DAY 44 DAY 91 DAY 125 CHOL (mg/dL) DAY 44 DAY 91 DAY 125 TRIG (mg/dL) DAY 44 DAY 91 DAY 125 GLUC (mg/dL) DAY 44 DAY 91 DAY 125 14 2(10) 15 2(10) 15 1(10) 0.34 0.05(10) 0.42 0.07(10) 0.40 0.06(10) 84 22(10) 78 27(10) 75 13(10) 97 58(10) 127 51(10) 95 37(10) 110 17(10) 125 38(10) 127 37(10) 14 2(10) 15 2(10) a 0.31 0.05(10) 0.40 0.09(10) a 65 11(10) 65 13(10) a 90 30(10) 98 39(10) a 104 12(10) 102 14(10) a 15 2(10) 16 2(9) a 0.30 0.04(10) 0.39 0.05(9) a 56* 16(10) 48@ 16(9) a 75 38(8) 49* 24(9) a 108 11(10) 112 27(9) a 14 2(10) 15 1(10) 18* 2(10) 0.34 0.07(10) 0.45 0.06(10) 0.40 0.06(10) 54* 18(10) 47@ 15(10) 56* 10(10) 53 39(9) 39* 27(10) 55@ 37(10) 112 16(10) 116 30(10) 106 16(10) 145 Company Sanitized. Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 30 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group I 0 mg/kg Group III 25 mg/kg Group V 100 mg/kg Group VII 250 mg/kg TP (g/dL) DAY 44 DAY 91 DAY 125 ALB (g/dL) DAY 44 DAY 91 DAY 125 GLOB (g/dL) DAY 44 DAY 91 DAY 125 CALC (mg/dL) DAY 44 DAY 91 DAY 125 IPHS (mg/dL) DAY 44 DAY 91 DAY 125 6.6 0.3(10) 6.9 0.4(10) 7.0 0.3(10) 4.1 0.2(10) 4.3 0.2(10) 4.4 0.2(10) 2.4 0.2(10) 2.6 0.2(10) 2.6 0.3(10) 10.8 0.4(10) 11.0 0.7(10) 10.6 0.3(10) 8.6 0.7(10) 9.2 2.2(10) 8.1 1.5(10) 6.6 0.3(10) 6.8 0.3(10) a 4.2 0.2(10) 4.4 0.2(10) a 2.4 0.2(10) 2.4 0.2(10) a 10.9 0.4(10) 10.6 0.4(10) a 9.1 0.5(10) 8.7 1.5(10) a 6.7 0.3(8) 7.1 0.4(9) a 4.3 0.5(8) 4.7* 0.2(9) a 2.5 0.4(8) 2.4 0.3(9) a 10.8 0.5(10) 10.5 0.5(9) a 9.5* 0.8(8) 8.9 1.0(9) a 7.3* 0.4(9) 7.7* 0.4(10) 6.7 0.3(10) 5.0@ 0.3(9) 5.4* 0.3(10) 4.3 0.3(10) 2.3 0.2(9) 2.3* 0.1(10) 2.4 0.2(10) 11.2 0.3(10) 10.9 0.5(10) 10.2* 0.3(10) 9.4 0.9(9) 9.1 1.4(10) 7.8 0.8(10) 146 Campani Sanitized. Doe no coniai TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 30 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group I 0 mg/kg Group HI 25 mg/kg Group V 100 mg/kg Group VII 250 mg/kg NA (mmol/L) DAY 44 DAY 91 DAY 125 K (mmol/L) DAY 44 DAY 91 DAY 125 CL (mmol/L) DAY 44 DAY 91 DAY 125 PFLU (jig/mL) DAY 44 DAY 91 DAY 125 144.5 1.9(10) 147.2 2.2(10) 146.4 0.8(10) 6.02 0.40(10) 6.33 0.60(10) 6.41 0.63(10) 100.5 1.8(10) 100.7 1.7(10) 103.4 0.9(10) a 0.1 0.0(10) 0.1 0.0(10) 143.5 1.0(10) 145.9 1.4(10) a 6.05 0.23(10) 6.07 0.42(10) a 99.4 2.1(10) 100.1 1.8(10) a a 0.2 0.0(10) a 144.4 0.9(10) 146.1 1.5(9) a 6.24 0.40(8) 6.24 0.39(9) a 99.5 2.3(10) 100.5 1.3(9) a a 0.4@ 0.1(9) a 143.9 1.2(10) 145.2* 2.0(10) 146.6 1.5(10) 5.98 0.47(9) 6.25 0.56(10) 6.05 0.41(10) 99.3 1.6(10) 98.9* 1.3(10) 103.4 1.6(10) a 0.7@ 0.1(10) 0.1 0.1(9) Data arranged as: Mean Standard deviation (Number o f values included in calculation) a Group not sampled at this timepoint. * Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett). @ Statistically significant difference from control at p < 0.05 by nonparametric test (Dunn's). 147 Company Sanitized. Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 31 SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD Group II 0 mg/kg Group IV 25 mg/kg Group VT 100 mg/kg Group VIII 250 mg/kg AST (U/L) DAY 45 DAY 93 DAY 125 ALT (U/L) DAY 45 DAY 93 DAY 125 SDH (U/L) DAY 45 DAY 93 DAY 125 ALKP (U/L) DAY 45 DAY 93 DAY 125 BILI (mg/dL) DAY 45 DAY 93 DAY 125 87 14(10) 90 27(10) 124 61(9) 37 6(10) 33 8(10) 65 40(9) 18.2 5.4(10) 18.9 7.5(10) 25.8 12.0(9) 66 18(10) 42 10(10) 33 13(9) 0.13 0.04(10) 0.13 0.06(10) 0.10 0.04(9) 76 15(9) 79 16(9) a 31 7(9) 33 7(9) a 18.3 4.6(9) 16.4 3.8(9) a 71 22(9) 44 17(9) a 0.11 0.05(9) 0.10 0.04(9) a 77 17(10) 89 10(10) a 31 5(10) 33 4(10) a 16.3 3.8(10) 18.3 4.2(10) a 83 18(10) 55 15(10) a 0.11 0.04(10) 0.10 0.05(10) a 69* 8(10) 87 19(9) 152 198(10) 29* 8(10) 38 16(9) 62 72(10) 15.8 4.6(10) 17.2 5.0(9) 25.0 27.6(10) 81 18(10) 52 18(9) 38 14(10) 0.09 0.04(10) 0.11 0.04(9) 0.09 0.06(10) 148 Canpwiy Sanitized, P ees not contain TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 31 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD Group II Omg/kg Group IV 25 mg/kg Group VI 100 mg/kg Group Vili 250 mg/kg BUN (mg/dL) DAY 45 DAY 93 DAY 125 CREA (mg/dL) DAY 45 DAY 93 DAY 125 CHOL (mg/dL) DAY 45 DAY 93 DAY 125 TRIG (mg/dL) DAY 45 DAY 93 DAY 125 GLUC (mg/dL) DAY 45 DAY 93 DAY 125 16 2(10) 17 2(10) 16 3(9) 0.40 0.04(10) 0.47 0.05(10) 0.48 0.06(9) 83 12(10) 79 14(10) 106 36(9) 63 26(10) 160 136(10) 136 72(9) 97 9(10) 92 8(10) 107 20(9) 15 2(9) 16 2(9) a 0.35* 0.03(9) 0.44 0.04(9) a 89 19(9) 90 19(9) a 78 41(9) 87 45(9) a 109* 13(9) 97 5(9) a 16 2(10) 16 3(10) a 0.35* 0.05(10) 0.51 0.08(10) a 82 13(10) 76 13(10) a 44 18(10) 53@ 24(10) a 98 5(10) 100 17(10) a 16 2(10) 16 1(9) 16 2(10) 0.37 0.07(10) 0.50 0.06(9) 0.48 0.04(10) 92 15(10) 95 20(9) 98 51(10) 42 13(10) 54@ 22(9) 102 96(10) 101 7(10) 94 5(9) 104 14(10) to? 149 Company Sanitized. Doe* not contain TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 31 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD Group II 0 mg/kg Group IV 25 mg/kg Group VI 100 mg/kg Group Vm 250 mg/kg TP (g/dL) DAY 45 DAY 93 DAY 125 ALB (g/dL) DAY 45 DAY 93 DAY 125 GLOB (g/dL) DAY 45 DAY 93 DAY 125 CALC (mg/dL) DAY 45 DAY 93 DAY 125 IPHS (mg/dL) DAY 45 DAY 93 DAY 125 7.3 0.5(10) 7.5 0.5(10) 8.2 0.5(9) 5.0 0.5(10) 5.2 0.5(10) 5.7 0.3(9) 2.3 0.2(10) 2.3 0.2(10) 2.5 0.3(9) 11.0 0.4(10) 10.8 0.3(10) 11.1 0.5(9) 7.5 0.7(10) 5.6 0.7(10) 5.7 0.9(9) 7.4 0.4(9) 7.8 0.4(9) a 5.0 0.4(9) 5.4 0.4(9) a 2.4 0.2(9) 2.4 0.1(9) a 11.2 0.4(9) 11.0 0.5(9) a 7.6 1.2(9) 6.0 0.5(9) a OO * 7.7 0.3(10) 0.4(10) a 5.4 0.2(10) 6.0* 0.3(10) a 2.3 0.2(10) 2.4 0.2(10) a 11.2 0.3(10) 11.3* 0.4(10) a 7.9 0.6(10) 6.7* 1.3(10) a 8.2* 0.4(10) 8.6* 0.4(9) 8.2 0.5(10) 5.7* 0.3(10) 6.0* 0.3(9) 5.5 0.3(10) 2.4 0.2(10) 2.6* 0.2(9) 2.7 0.3(10) 11.7* 0.4(10) 11.5* 0.3(9) 10.9 0.3(10) 7.8 0.5(10) 6.6* 0.7(9) 6.4 0.9(10) 150 iamed,, Does mrt contain etjf H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 31 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS TEST/ ' PERIOD Group II 0 mg/kg Group IV 25 mg/kg Group VI 100 mg/kg Group V m 250 mg/kg NA (mmol/L) DAY 45 DAY 93 DAY 125 K (mmol/L) DAY 45 DAY 93 DAY 125 CL (mmol/L) DAY 45 DAY 93 DAY 125 PFLU (pg/mL) DAY 45 DAY 93 DAY 125 143.5 2.4(10) 143.7 1.6(10) 145.5 1.3(9) 5.66 0.21(10) 5.29 0.36(10) 5.31 0.44(9) 100.8 0.9(10) 99.2 2.2(10) 102.6 1.4(9) a 0.1 0.1(10) 0.1 0.0(9) 143.5 2.7(9) 142.8 1.6(9) a 5.73 0.40(9) 5.29 0.26(9) a 99.9 1.6(9) 98.9 2.3(9) a a 0.2 0.1(9) a 142.5 1.6(10) 144.1 2.2(10) a 5.88 0.28(10) 5.62 0.40(10) a 99.7 1.2(10) 99.3 2.1(10) a a 0.4@ 0.1(10) a 143.3 1.3(10) 143.2 1.3(9) 143.9* 1.8(10) 6.32* 0.32(10) 6.05* 0.40(9) 5.45 0.48(10) 99.5 1.0(10) 97.9 1.4(9) 103.2 1.8(10) 0.8@ 0.2(9) 0.1 0.0(10) Data arranged as: Mean Standard deviation (Number o fvalues included in calculation) a Group not sampled at this timepoint. * Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett). @ Statistically significant difference from control at p < 0.05 by nonparametric test (Dunn's). 151 SfiBSpany Sanitized. D oes not contain TSCA OBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 32 TEST/ ' PERIOD SUMMARY OF URINALYSIS VALUES FOR MALE RATS Group I mg/kg Group HI 25 mg/kg Group V 100 mg/kg Group VH 250 mg/kg VOL (mL) DAY 44 DAY 91 DAY 125 UOSM (mOsm) DAY 44 DAY 91 DAY 125 SG DAY 44 DAY 91 DAY 125 pH DAY 44 DAY 91 DAY 125 URO (EU/dL) DAY 44 DAY 91 DAY 125 8.6 5.6(10) 7.1 5.6(10) 12.0 5.4(10) 1183 346(10) 1330 474(7) 952 364(10) 1.037 0.011(10) 1.048 0.017(9) 1.031 0.011(10) 7.2 0.6(10) 6.7 0.4(10) 6.8 0.5(10) 0.2 0.0(10) 0.2 0.0(10) 0.2 0.0(10) 10.0 5.3(10) 10.0 6.8(9) a 1019 474(10) 1158 473(10) a 1.032 0.014(10) 1.036 0.013(10) a 7.3 0.8(10) 6.9 0.7(10) a 0.3 0.3(10) 0.3 0.3(10) a 8.0 5.6(10) 10.0 9.0(9) a 1333 592(9) 1315 556(9) a 1.045 0.019(10) 1.040 0.016(9) a 7.0 0.6(10) 7.1 0.8(9) a 0.2 0.0(10) 0.2 0.0(9) a 17.1 16.7(10) 15.4@ 7.0(10) 7.2@ 6.1(10) 938 685(10) 793 297(10) 1759* 932(10) 1.029 0.019(10) 1.027* 0.009(10) 1.051* 0.023(10) 7.5 0.7(10) 6.6 0.5(10) 6.6 0.5(10) 0.2 0.0(10) 0.2 0.0(10) 0.2 0.0(10) 152 PPW PM f Sanlfeed: 0@@ emalm TSC CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 32 (Continued) TEST/ PERIOD SUMMARY OF URINALYSIS VALUES FOR MALE RATS Group I 0 mg/kg Group HI 25 mg/kg Group V 100 mg/kg Group VH 250 mg/kg UFLUOig) DAY 44 DAY 91 DAY 125 DAY 181 UMTP (mg/dL) DAY 44 DAY 91 DAY 125 a 20.2 5.3(7) 14.2 2.9(10) 12.1 4.8(5) 77 37(10) 119 71(10) 66 49(10) a 213.0 36.8(9) a 22.8 3.2(5) 63 47(10) 78 64(10) a a 662.7@ 188.5(9) a 39.1* 11.5(5) 103 53(10) 91 50(9) a a 1473.6 313.0(10) 87.4* 22.8(10) 69.1* 6.6(5) 66 60(10) 40* 20(10) 121 73(10) Data arranged as: Mean Standard deviation (Number o f values included in calculation) a Group not sampled at this timepoint. * Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett). @ Statistically significant difference from control at p < 0.05 by nonparametric test (Dunn's). 153 Company Sanitized. Does not contain TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 33 SUMMARY OF URINALYSIS VALUES FOR FEMALE RATS TEST/ PERIOD Group II 0 mg/kg Group IV 25 mg/kg Group VI 100 mg/kg Group V in 250 mg/kg VOL (mL) DAY 45 DAY 93 DAY 125 UOSM (mOsm) DAY 45 DAY 93 DAY 125 SG DAY 45 DAY 93 DAY 125 PH DAY 45 DAY 93 DAY 125 URO (EU/dL) DAY 45 DAY 93 DAY 125 5.8 4.2(9) 3.1 3.1(7) 5.2 4.7(9) 1271 960(8) 1178 464(3) 976 380(7) 1.035 0.021(8) 1.044 0.021(4) 1.040 0.021(9) 7.1 0.8(9) 6.5 0.9(7) 5.7 0.4(9) 0.2 0.0(9) 0.2 0.0(7) 0.2 0.0(9) 6.9 3.6(9) 4.9 2.6(8) a 1117 711(9) 1204 372(7) a 1.033 0.017(9) 1.042 0.019(8) a 6.9 0.3(9) 6.4 0.7(8) a 0.2 0.0(9) 0.2 0.0(8) a 8.2 3.6(10) 4.0 3.0(10) a 786 249(10) 1541 622(9) a 1.024 0.007(10) 1.048 0.017(10) a 7.2 0.6(10) 6.2 0.4(10) a 0.2 0.0(10) 0.2 0.0(10) a 12.6* 4.6(10) 10.7@ 7.8(9) 6.2 3.1(7) 589 197(10) 764 269(9) 983 512(7) 1.018 0.006(10) 1.024 0.008(9) 1.031 0.014(7) 7.7 0.4(10) 6.2 0.8(9) 5.8 0.5(7) 0.2 0.0(10) 0.2 0.0(9) 0.2 0.0(7) 154 p a ]? SanRbed. D o notcanlah TSCA CBV H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 33 (Continued) SUMMARY OF URINALYSIS VALUES FOR FEMALE RATS TEST/ PERIOD Group II Omg/kg Group IV 25 mg/kg Group VI 100 mg/kg Group VIII 250 mg/kg UFLUGig) DAY 45 DAY 93 DAY 125 DAY 181 UMTP (mg/dL) DAY 45 DAY 93 DAY 125 a 16.7 3.8(2) 8.6 5.1(7) 8.8 3.8(5) 41 34(9) 84 56(6) 109 130(9) a 99.2 32.1(6) a 15.9 6.9(3) 24 22(9) 49 43(8) a a 460.3 127.0(4) a 20.0 5.6(5) 18 5(10) 57 31(10) a a 914.7@ 618.1(9) 43.8@ 14.9(7) 29.3* 13.1(4) 21 11(10) 54 26(9) 69 76(7) Data arranged as: Mean Standard deviation (Number o f values included in calculation) a Group not sampled at this timepoint. * Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett). @ Statistically significant difference from control at p < 0.05 by nonparametric test (Dunn's). 155 {Company Sanitized. Does not contain TSCA CBl H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 34 SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITY IN MALE RATS DuPont-5368 Dosage Groupa (mg/kg/day) Hepatic Peroxisomal Beta-Oxidation Activity (nmol/min/mg protein) 10-Day Time Point 90-Day Time Point 36-Day Recovery 92-Day Recovery I0 4.7 1.7b 5.1 1.4 8.5 2.8 8.3 1.3 IIIe 25 8.9 1.8 13.0 4.8 -- Ve 100 10.5 + 2.6* 20.7 1.5* VII 250 16.4 4.2* 44.5 9.9* 30.0 4.1* 25.1 6.0# a. Group designations for animals evaluated at the 10-day time point are I-A, III-A, V-A, and VII-A. b. Mean standard deviation. The n = 5 for each group. c. Samples were not prepared for analysis from groups III and V at the 30- and 90-day recovery time points. * Statistically significant difference from control (p < 0.05) by Dunnett's test. 156 Company Sanitized. Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 35 SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITY IN FEMALE RATS DuPont-5368 Dosage Group3 (mg/kg/day) Hepatic Peroxisomal Beta-Oxidation Activity (nmol/min/mg protein) 10-Day Timepoint 90-Day Timepoint 36-Day Recovery 92-Day Recovery II 0 8.1 2.2b 7.8 1.9 9.6 1.4 18.4 1.8 IVe 25 7.7 2.3 12.3 4.2 -- VIe 100 13.8 2.3* 26.9 3.7* -- -- VIII 250 21.1 2.8* 29.7 7.1* 19.9 3.6* 31.7 3.4* a. Group designations for animals evaluated at the 10-day time point are II-A, IV-A, VI-A, and VIII-A. b. Mean standard deviation. The n = 5 for each group. c. Samples were not prepared for analysis from groups IV and VI at the 30- and 90-day recovery timepoints. * Statistically significant difference from control (p < 0.05) by Dunnett's test. 157 swpMf iamSftoed, Sees not@nMnTSCAif H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 36 MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (90-DAY EXPOSURE EVALUATION) MEAN FIN AL BODY AND ABSOLUTE ORGAN WEIGHTS ( g r a m s ) LIVER Group I 0 mg/kg/day 15.61430 2.40914 (10) Group III 25 mg/kg/day 16.87710 2.21000(10) Group V 100 mg/kg/day 21.08367# 2.16729(9) Group VII 250 mg/kg/day 25.53740# 2.01802(10) KIDNEYS 3.87130 0.32057(10) 4.16070 0.40193(10) 4.18767# 0.26834(9) 4.62600# 0.44545(10) HEART 1.71400 0.15515(10) 1.71110 0.16522(10) 1.53744# 0.13457(9) 1.51080# 0.12204(10) SPLEEN 0.82560 0.10868(10) 0.73400 0.17504(10) 0.79833 0.08688(9) 0.71340 0.07769(10) BRAIN 2.11810 0.06517(10) 2.16130 0.11475(10) 2.07144 0.09339(9) 2.09800 0.08814(10) THYMUS 0.44800 0.13463(10) 0.37290 0.09756(10) 0.37211 0.09829(9) 0.35967 0.07953(9) ADRENAL GLANDS 0.05540 0.00947(10) 0.06010 0.00881(10) 0.05167 0.00811(9) 0.05450 0.00798(10) TESTES 3.62880 0.32307(10) 3.39690 0.38948(10) 3.55367 0.14742(9) 3.54910 0.30220(10) EPIDIDYMIDES 1.60570 0.15978(10) 1.50770 0.13254(10) 1.43100# 0.09600(9) 1.46750# 0.10973(10) FINAL BODY WEIGHT 569.92000 46.42274(10) 556.23001 62.22883(10) 514.55556# 31.85973(9) 508.24000# 35.48981(101 158 '@mpanf not contain TSCA CBS H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 36 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (90-DAY EXPOSURE EVALUATION) MEAN RELATIVE ORGAN WEIGHTS {% of body weight) LIVER/ FINAL BODY * 100 G roup I 0 m g/kg/day 2.72792 0.24256(10) G roup I I I 25 m g/kg/day G roup V 100 m g/kg/day G roup V II 250 m g/kg/day 3.02910# 0.10928(10) 4.09189# 0.26331(9) 5.02981# 0.30664(10) KIDNEYS/ FINAL BODY * 100 0.68187 0.06254 (10) 0.75073# 0.05504(10) 0.81464# 0.04174(9) 0.91000# 0.05964(10) HEART/ FINAL BODY * 100 SPLEEN/ FINAL BODY * 100 BRAIN/ FINAL BODY * 100 THYMUS/ FINAL BODY * 100 ADRENAL GLANDS/ FINAL BODY * 100 TESTES/ FINAL BODY * 100 EPIDIDYMIDES/ FINAL BODY * 100 0.30111 0.01945(10) 0.14549 0.02010(10) 0.37366 0.02959(10) 0.07853 0.02208(10) 0.00978 0.00182(10) 0.64020 0.07536(10) 0.28214 0.02174(10) 0.30962 0.03418(10) 0.13149 0.02476(10) 0.39140 0.03280(10) 0.06735 0.01762(10) 0.01087 0.00169(10) 0.61616 0.09099(10) 0.27346 0.03430(10) 0.29877 0.01816(9) 0.15512 0.01376(9) 0.40363# 0.02587(9) 0.07197 0.01718(9) 0.01001 0.00120(9) 0.69236 0.04100(9) 0.27948 0.02996(9) 0.29751 0.01679(10) 0.14058 0.01383(10) 0.41417# 0.02660(10) 0.07151 0.01422(9) 0.01073 0.00155(10) 0.69863# 0.04115(10) 0.28923 0.01927(10) 159 fip o v a v Swlfeaft, 0 e not rta fe TSCA CH H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 36 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (90-DAY EXPOSURE EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% organ to brain weight ratio) Group I 0 mg/kg/day Group III 25 mg/kg/day Group V 100 mg/kg/day Group VII 250 mg/kg/day LIVER/ BRAIN * 100 KIDNEYS/ BRAIN * 100 735.74333 99.37257(10) 182.68506 12.66199(10) 780.17520 85.08778(10) 192.36680 13.14320(10) 1019.5284# 115.06490(9) 202.51532# 15.84059(9) 1218.7006# 103.65133(10: 220.59585# 20.88300(10) HEART/ BRAIN * 100 SPLEEN/ BRAIN * 100 80.91023 6.82263(10} 38.93490 . 4.57844(10) 79.30874 8.23777(10) 33.91403 7.51428(10) 74.35749 7.41525(9) 38.56439 4.15459(9) 72.04801# 5.53580(10) 34.01722 3 .46850(10) THYM0S/ BRAIN * 100 21.03669 5.97190(10) 17.30890 4.63114(10) 18.00484 4.76335(9) 17.12540 3.81584(9) ADRENAL GLANDS/ BRAIN * 100 2.62137 0.47467(10) 2.78484 0.40829(10) 2.49488 0.38735(9) 2.59483 0.34618(10) TESTES/ BRAIN * 100 171.16403 11.88715(10) 156.96718 13.69597(10) 171.72378 7.58365(9) 169.09911 11.50305(10) EPIDIDYMIDES/ BRAIN * 100 75.74999 6.44128(10) 69.76881 4.95178(10) 69.16509 4.92678(9) 70.02996 5.78874(10) 160 gsgnpan Sanitized. Does not contain TSCA CBl H-24516: Subchrome Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 36 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) Group I 0 mg/kg/day Group VII 250 mg/kg/day LIVER 15.30650 2.06770(10) 18.99580# 2.41188 (10) KIDNEYS 3.92180 0.43359(10) 4.52600# 0.45123 (10) HEART 1.78690 0.22877 (10) 1.70310 0.09352 (10) SPLEEN 0.79060 0.15057(10) 0.82750 0.12262(10) BRAIN 2.15100 0.10458(10) 2.14830 0.06237(10) THYMUS 0.30370 0.10010(10) 0.29500 0.08028(10) ADRENAL GLANDS 0.05500 0.00939(10) 0.05390 0.00769 (10) TESTES 3.40390 0.45855 (10) 3.35360 0.56712 (10) EPIDIDYMIDES 1.51050 0.21531 (10) 1.89860 1.25596 (10) FINAL BODY WEIGHT 590.65000 82.53324(10) 537.98000 37.55428 (10) 161 jplfflpainfSanffiteed, Bow not tate TSCA CM H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 36 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% of body weight) Group I 0 mg/kg/day Group VII 250 mg/kg/day LIVER/ FINAL BODY * 100 2.59628 0.14348(10) 3.52278# 0.28354(10) KIDNEYS/ FINAL BODY * 100 0.67037 0.07651(10) 0.84084# 0.05450 (10) HEART/ FINAL BODY * 100 0.30689 0.05285 (10) 0.31726 0.01716 (10) SPLEEN/ FINAL BODY * 100 0.13384 0.01870(10) 0.15447 0.02480 (10) BRAIN/ FINAL BODY * 100 0.37046 0.05358(10) 0.40104# 0.02998 (10) THYMUS/ FINAL BODY * 100 0.05128 0.01463(10) 0.05494 0.01501(10) ADRENAL GLANDS/ FINAL BODY * 100 0.00943 0.00187(10) 0.01005 0.00145 (10) TESTES/ FINAL BODY * 100 0.58528 0.10321(10) 0.62490 0.11357(10) EPIDIDYMIDES/ FINAL BODY * 100 0.25949 0.04537(10) 0.35028 0.22128 (10) 162 Company Sanitized. Does not contain TSCA CBt H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 36 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS - (ONE-MONTH RECOVERY EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% organ to brain weight ratio) Group I 0 mg/kg/day Group VII 250 mg/kg/day LIVER/ BRAIN * 100 KIDNEYS/ BRAIN * 100 711.34075 88.59504 (10) 182.34225 18.44671(10) 884.91171# 116.18812 (10) 210.72828# 20.63654(10) HEART/ BRAIN * 100 83.23074 11.73675 (10) 79.38841 5.76903 (10) SPLEEN/ BRAIN * 100 36.81368 7.14802(10) 38.56659 5.91619 (10) THYMUS/ BRAIN * 100 14.01786 4.23746 (10) 13.72581 3.74259(10) ADRENAL GLANDS/ BRAIN * 100 2.54745 0.35256 (10) 2.51164 0.37062 (10) TESTES/ BRAIN * 100 158.19880 19.42657(10) 155.98933 25.95332 (10) EPIDIDYMIDES/ BRAIN * 100 70.20005 9.34995(10) 88.28783 58.20703(10) 163 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 36 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (THREE-MONTH RECOVERY EVALUATION) MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) Group I 0 mg/kg/day LIVER 16.86360 1.23511(5) KIDNEYS 4.22420 0.38656(5) THYROID GLAND 0.02460 0.00288(5) TESTES 3.73740 0.41919(5) FINAL BODY WEIGHT 609.24000 49.85251(5) Group III 25 mg/kg/day 14.89120 1.29310(5) 4.12580 0.60763(5) 0.02120 0.00455(5) 3.71440 0.46067(5) 584.40000 60.48766(5) Group V 100 mg/kg/day 17.20660 1.65902(5) 4.20240 0.18598(5) 0.02480 0.00421(5) 3.76060 0.66540(5) Group VII 250 mg/kg/day 18.53760 3.89685(5) 4.49080 0.75755(5) 0.02360 0.00336(5) 3.70660 0.38273(5 597.36000 78.98329(5) 589.00000 118.00491(5) 164 HompaHf Sanitized. Does notcontain TSCACBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 36 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (THREE-MONTH RECOVERY EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% of body weight) Group I 0 mg/kg/day Group III 25 mg/kg/day Group V 100 mg/kg/day LIVER/ FINAL BODY * 100 2.77049 0.08130(5) 2.55621 0.17311(5) 2.89634 0.24254(5) KIDNEYS/ FINAL BODY * 100 0.69433 0.05264(5) 0.70486 0.06776(5) 0.71061 0.07278(5) THYROID GLAND/ FINAL BODY * 100 0.00407 0.00064(5) 0.00360 0.00048(5) 0.00427 0.00114(5) TESTES/ FINAL BODY * 100 0.61346 0.04906(5) 0.64182 0.11379(5) 0.62851 0.06407(5) Group VII 250 mg/kg/day 3.14311# 0.14527(5) 0.76965 0.07781(5) 0.00410 0.00082(5) 0.64002 0.07619(5) Data summarized as: Mean Standard Deviation (n) Statistical Methods: Trend test (Jonckheere-Terpstra). # Statistically significant difference at p = 0.05. 165 Sanitized Does eenfeSrj ew H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 . TABLE 37 MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (90-DAY EXPOSURE EVALUATION) MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) Group II 0 mg/kg/day Group IV 25 mg/kg/day Group VI Group VIII 100 mg/kg/day 250 mg/kg/day LIVER 8.42890 0.89310(10) 9.28989 1.29807(9) 10.29410# 0.93782(10) 12.58311# 1.50915(9) KIDNEYS 2.06880 0.21132(10) 2.34367#. 0.28624(9) 2.32900# 0.22209(10) 2.60533# 0.26021(9) HEART 1.00350 0.11037(10) 1.13856 0.23821(9) 1.01180 0.06157(10) 1.02956 0.10404(9) SPLEEN 0.50600 0.10310(10) 0.50611 0.05648(9) 0.50710 0.10450(10) 0.52567 0.07700(9) BRAIN 1.88390 0.07620(10) 1.98522 0.10422(9) 1.91420 0.08526(10) 1.94378 0.09538(9) THYMUS 0.29780 0.10562(10) 0.31222 0.08160(9) 0.28500 0.06451(10) 0.28444 0.09108(9) ADRENAL GLANDS 0.06490 0.01047(10) 0.06567 0.00907(9) 0.06550 0.00956(10) 0.06589 0.00819(9) OVARIES 0.11550 0.02923(10) 0.12211 0.01825(9) 0.12870 0.01818(10) 0.11122 0.01719(9) UTERUS 0.57820 0.06982(10) 0.66122 0.23047(9) 0.58070 0.10303(10) 0.66444 0.19643(9) FINAL BODY WEIGHT 297.45000 35.81503(10) 303.66667 24.73525(9) 286.41000 22.00290(10) 283.48889 31.74474(9) 166 Company Sanitized. Does nt contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 37 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (90-DAY EXPOSURE EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% of body weight) Group II 0 mg/kg/day Group IV 25 mg/kg/day Group VI Group VIII 100 mg/kg/day 250 mg/kg/day LIVER/ FINAL BODY * 100 2.84076 0.15250(10) 3.06088 0.33230(9) 3.59318# 0.15126(10) 4.44566# 0.32538(9) KIDNEYS/ FINAL BODY * 100 0.69736 0.03459(10) 0.77374# 0.08951(9) 0.81333# 0.04616(10) 0.92685# 0.12559(9) HEART/ FINAL BODY * 100 0.33821 0.02157(10) 0.37345 0.05777(9) 0.35399 0.01733(10) 0.36475 0.03120(9) SPLEEN/ FINAL BODY * 100 0.16960 0.02557(10) 0.16691 0.01532(9) 0.17675 0.03224(10) 0.18588 0.02188(9) BRAIN/ FINAL BODY * 100 0.64099 0.07665(10) 0.65779 0.06489(9) 0.67035 0.03525(10) 0.69254 0.07652(9) THYMUS/ FINAL BODY * 100 0.09848 0.02656(10) 0.10282 0.02489(9) 0.09959 0.02191(10) 0.09983 0.02528(9) ADRENAL GLANDS/ FINAL BODY * 100 0.02185 0.00259(10) 0.02170 0.00299(9) 0.02301 0.00405(10) 0.02353 0.00419(9) OVARIES/ FINAL BODY * 100 0.03897 0.00965(10) 0.04042 0.00646(9) 0.04513 0.00682(10) 0.03964 0.00742(9) UTERUS/ FINAL BODY * 100 0.19700 0.03626(10) 0.21987 0.08249(9) 0.20335 0.03753(10) 0.23844 0.08261(9) 167 Company Sanitized. Does not contain TSCA CB1 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 37 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (90-DAY EXPOSURE EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% organ to brain weight ratio) Group II 0 mg/kg/day Group IV 25 mg/kg/day LIVER/ BRAIN * 100 KIDNEYS/ BRAIN * 100 447.97404 49.75332(10) 109.90153 11.16263(10) 468.70612 66.48212(9) 117.94290 12.14897(9) HEART/ BRAIN * 100 SPLEEN/ BRAIN * 100 53.25450 5.29987(10) 26.83701 5.20406(10) 57.72897 14.36366(9) 25.51771 2.75891(9) ADRENAL GLANDS/ BRAIN * 100 3.43808 0.47647(10) 3.31554 0.48277(9) THYMUS/ BRAIN * 100 OVARIES/r BRAIN * 100 15.78037 5.45880 (10) 15.77146 4.41570(9) 6.12137 1.49504(10) 6.14360 0.78541(9) UTERUS/ BRAIN * 100 30.74888 4.02620(10) 33.16601 10.88714(9) Group VI Group VIII 100 mg/kg/day 250 mg/kg/day 537.69731# 41.01697(10) 121.67541# 10.15327(10) 647.32738# 71.76231(9) 133.95247# 10.39944(9) 52.87944 2.70601(10) 26.45901 5.11411(10) 52.91567 4.05247(9) 27.02573 3.60259(9) 3.42792 0.52547(10) 3.38577 0.34751(9) 14.89897 3.36605(10) 14.67010 4.68613(9) 6.72625 0.90372(10) 5.72555 0.84613(9) 30.38154 5.49538(10) 34.36785 10.75106(9) 168 Company Sanitized. Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 37 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) Group II 0 mg/kg/day LIVER 10.09844 1.67206(9) KIDNEYS 2.43678 0.24189(9) HEART 1.17433 0.10505(9) SPLEEN 0.56733 0.08403(9) BRAIN 1.92800 0.07213 (9) THYMUS ' 0.26833 0.07819(9) ADRENAL GLANDS 0.06656 0.01321(9) OVARIES 0.11544 0.02939(9) UTERUS 0.69278 0.15294(9) FINAL BODY WEIGHT 353.11111 37.83244(9) Group VIII 250 mg/kg/day 9.99330 1.38877 (10) 2.50730 0.40643 (10) 1.08270 0.08698(10) 0.53740 0.13757(10) 1.91180 0.09510 (10) 0.22790 0.04946(10) 0.07440 0.01056 (10) 0.11770 0.01938 (10) 0.68910 0.20245 (10) 308.58000# 32.73340 (10) 169 Company Sanitized. Does not contain TSCA CBS H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 37 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% of body weight) Group II 0 mg/kg/day LIVER/ PINAL BODY * 100 2.85512 0.29184(9) KIDNEYS/ FINAL BODY * 100 0.69394 0.06941 (9) HEART/ FINAL BODY * 100 0.33509 0.04017(9) SPLEEN/ FINAL BODY * 100 0.16188 0.02643(9) BRAIN/ FINAL BODY * 100 0.55117 0.05678(9) THYMUS/ FINAL BODY * 100 0.07543 0.01729 (9) ADRENAL GLANDS/ FINAL BODY * 100 0.01885 0.00301 (9) UTERUS/ FINAL BODY * 100 0.19783 0.04722(9) OVARIES/ FINAL BODY * 100 0.03278 0.00845 (9) Group VIII 250 mg/kg/day 3.24730 0.39525(10) 0.81594# 0.12449 (10) 0.35335 0.03687(10) 0.17524 0.04700(10) 0.62527# 0.06535(10) 0.07430 0.01715 (10) 0.02445# 0.00468 (10) 0.22259 0.05160(10) 0.03839 0.00689 (10) 170 Company Sanitized. Does not contain TSCACM H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 37 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% of organ to brain weight ratio) Group II 0 mg/kg/day Group VIII 250 mg/kg/day LIVER/ BRAIN * 100 KIDNEYS/ BRAIN * 100 524.83765 90.51244(9) 126.46850 12.50757(9) 521.86193 59.78217(10) 130.75642 16.47766(10) HEART/ BRAIN * 100 SPLEEN/ BRAIN * 100 61.06879 6.79149 (9) 29.51530 4.82384(9) 56.66965 4.22303(10) 28.05377 6.80548 (10) THYMUS/ BRAIN * 100 13.96338 4.15109(9) 11.88806 2.39151 (10) ADRENAL GLANDS/ BRAIN * 100 3.44923 0.65823(9) 3.89537 0.55037 (10) OVARIES/ BRAIN * 100 5.95250 1.37403(9) 6.15911 0.98456(10) UTERUS/ BRAIN * 100 35.89360 7.44208(9) 36.14787 10.89853(10) 171 ISempMf Sanffbed. p@onten TSC C M H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 37 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (THREE-MONTH RECOVERY EVALUATION) MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHT (grams) LIVER KIDNEYS THYROID GLAND Group II 0 mg/kg/day Group IV 25 mg/kg/day Group VI 100 mg/kg/day 9.09860 1.06866(5) 9.22750 0.75842(4) 9.61700 1.19121(5) 2.32080 0.18101(5) 2.43700 0.15436(4) 2 .46780 0.29636(5) 0.01660 0.00114(5) 0.01825 0.00419(4) 0.01920 0.00349(5) Group VIII 250 mg/kg/day 11.08840# 1.39013(5) 2.70440 0.54874(5) 0.01940 0.00351(5) FINAL BODY WEIGHT 312.62000 20.92813(5) 334.42501 28.71253(4) 315.18001 32.76441(5) 347.56000 55.42101(5) ) 172 oraspmf Sanitized, Poes not eontain TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 37 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (THREE-MONTH RECOVERY EVALUATION) MEAN RELATIVE ORGAN WEIGHTS {% of body weight) Group II 0 mg/kg/day Group IV 25 mg/kg/day Group VI Group VIII 100 mg/kg/day 250 mg/kg/day LIVER/ FINAL BODY * 100 2.90754 0.24314(5) 2.76175 0.12111(4) 3.05101 0.17390(5) 3.20511# 0.17235(5) KIDNEYS/ FINAL BODY * 100 0.74382 0.06063(5) 0.73438 0.09856(4) 0.78637 0.08983(5) 0.77523 0.06208(5) THYROID GLAND/ FINAL BODY * 100 0.00532 0.00041(5) 0.00556 0.00176(4) 0.00620 0.00161(5) 0.00574 0.00163(5) Data summarized as: Mean Standard Deviation (n) Statistical Methods: Trend test (Jonckheere-Terpstra). # Statistically significant difference at p = 0.05. 173 S w it a A 0<9&not Sain T iC CHI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5368 TABLE 38 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESION INCIDENCE (Numeric) Males LESIONS TREATMENT (mg/kg/day) 0 I 25 100 250 III V VII LIVER NO ABNORMALITY DETECTED DISCOLORATION, MOTTLED, TAN. DISCOLORATION, TAN, LEFT. (10) 10 (10) 10 (10) 9 1 KIDNEYS NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 LUNGS NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 HEART NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 SKELETAL MUSCLE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 SPLEEN NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 AORTA NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified (11) 10 1 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 174 Company Sanitized. Doe not contain TSCA CB1 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESION INCIDENCE (Numeric) Males LESIONS TREATMENT (mg/kg/day) 0 I 25 100 250 III V VII BRAIN NO ABNORMALITY DETECTED SPINAL CORD NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 SMALL INTESTINE DISTENDED WITH GAS.. DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED PANCREAS NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) (10) 10 I 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 (11) 11 (11) 11 (11) 11 (1) 1 (11) 11 (11) 11 (11) 11 (11) 11 175 p m p ! Sanitized. Benet eonfaim TSCA CBf H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESION INCIDENCE (Numeric) Males LESIONS TREATMENT (mg/kg/day) 0 I 25 100 250 III V VII CECUM NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 COLON NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 RECTUM NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED EDEMA. , MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED ADRENAL GLANDS 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 (11) 11 (11) 11 (11) 11 (11) 11 (11) 10 1 (11) 11 (11) 11 (11) 11 176 nnpani' Sanitized. D ost not contain TSCA CBf H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) DuPont-5386 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESION INCIDENCE (Numeric) Males LESIONS TREATMENT (mg/kg/day) 0 I 25 100 250 III V VII SCIATIC NERVE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (11) 11 PITUITARY GLAND NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (11) 11 THYROID GLAND NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (11) 11 PARATHYROID GLANDS NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (11) 11 TRACHEA NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (11) 11 ESOPHAGUS NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED E Y E (S) WITH OPTIC NERVE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (11) 11 (11) 11 (11) 11 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 177 Psmpany gifa d 0@s9gcontain t s c o b i H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESION INCIDENCE (Numeric) Males LESIONS TREATMENT (mg/kg/day) 0 I 25 100 250 III V VII SKIN NO ABNORMALITY DETECTED STAIN, RED, FACE. (10) 10 (10) 10 (10) 10 PROSTATE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 SEMINAL VESICLES NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 URINARY BLADDER NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 TESTES NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 EPIDIDYMIDES NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 FEMUR/KNEE JOINT NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 STERNUM NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates,the finding specified was not identified (11) 10 1 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 QpBupanjSafttUzad. Doe* no*contain TSCACB1 H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESION INCIDENCE (Numeric) Males LESIONS TREATMENT (mg/kg/day) 0 I 25 100 250 III V VII NOSE NO ABNORMALITY DETECTED PLEURAL CAVITY FLUID, CLEAR. MANDIBLE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (9) 9 (11) 11 (1) 1 (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 179 P@npMf Sanfttaed. B@@notmtaln TSC CB H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDE Males LESIONS TREATMENT (mg/kg/day) 0 I 250 % 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 DEFORMITY. AORTA NO ABNORMALITY DETECTED BRAIN NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 9 1 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 F i g u r e s i n p a r e n t h e s e s i s t h e num ber o f a n im a ls g r o s s l y e x a m in e d _f o r t h i s t i s s u e The absence o f a number in d ic a te s th e fin d in g s p e c ifie d was n o t id e n tif ie d 180 Company Sanitized. Does not contain TSCA CB! H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDE Males LESIONS TREATMENT (mg/kg/day) 0 I 250 VII SPINAL CORD NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED PANCREASNO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 F ig u re s in p a re n th e se s i s th e number o f anim als g ro s s ly exam ined fo r t h is tis s u e The absence o f a number in d ic a te s th e fin d in g s p e c if ie d was n o t id e n tif ie d 181 'Cosmpansr Sanitized. D@@snot oontaln TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (ONE-MONTH RECOVERY EVALUATION) LESIONS RECTUM NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED DISCOLORATION, RED. THYMUS NO ABNORMALITY DETECTED SMALL. ' ADRENAL GLANDS NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED LESION INCIDE Males TREATMENT (mg/kg/day) 0 I 250 VII (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 9 1 (10) 10 (10) 9 1 (10) 9 1 (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 182 DompanySanitized. Doesnotcontain TSCACB1 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDE Males LESIONS TREATMENT (mg/kg/day) 0 I 250 VII PITUITARY GLAND NO ABNORMALITY DETECTED THYROID GLAND NO ABNORMALITY DETECTED PARATHYROID GLANDS NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED E Y E (S) WITH OPTIC NERVE NO ABNORMALITY DETECTED SKIN NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 183 parsf Sanifesd, P@awlasfaimTSCCBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) DuPont-5386 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDE Males LESIONS TREATMENT (mg/kg/day) 0 I 250 VII PROSTATE NO ABNORMALITY DETECTED SEMINAL VESICLES NO ABNORMALITY DETECTED SMALL, LEFT. URINARY BLADDER NO ABNORMALITY DETECTED TESTES NO ABNORMALITY DETECTED SOFT, BILATERAL. DEFORMITY, RIGHT. SMALL, LEFT. EPIDIDYMIDES NO ABNORMALITY DETECTED DEFORMITY, LEFT. SMALL, LEFT. SMALL, RIGHT. FEMUR/KNEE JOINT NO ABNORMALITY DETECTED F ig u re s in p a re n th e se s i s th e number o f anim als g ro s s ly exam ined f o r t h is tis s u e The absence o f a number in d ic a te s th e fin d in g s p e c if ie d was n o t id e n tif ie d (10) 10 (10) 10 (10) 10 (10) 8 1 1 (10) 8 1 1 (10) 10 (10) 10 (10) 9 1 (10) 10 (10) 9 1 (10) 9 1 (10) 10 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDE Males LESIONS TREATMENT (mg/kg/day) 0 I 250 VII STERNUM NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED MANDIBLE NO ABNORMALITY DETECTED (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 185 IPinapanf SanltesdL Does not mtaln TS6 CHI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (THREE-MONTH RECOVERY EVALUATION) LESION INCIDENCE (Numeric) Males LESIONS TREATMENT (mg/kg/day) 0 I 50 100 III V LIVER NO ABNORMALITY DETECTED (5) (5) (5) 555 KIDNEYS NO ABNORMALITY DETECTED (5) (5) (5) 555 LUNGS NO ABNORMALITY DETECTED (5) (5) (5) 555 HEART NO ABNORMALITY DETECTED (5) (5) (5) 555 SKELETAL MUSCLE NO ABNORMALITY DETECTED SPLEEN NO ABNORMALITY DETECTED AORTA NO ABNORMALITY DETECTED BRAIN NO ABNORMALITY DETECTED (5) (5) (5) 555 (5) (5) (5) 555 (5) (5) (5) 555 (5) (5) (5) 555 Figures in parentheses is the number of tanimals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 250 VII (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (THREE-MONTH RECOVERY EVALUATION) LESIONS SPINAL CORD NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED PANCREAS NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESION INCIDENCE (Numeric) Males 0 I (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 50 III (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 100 V (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 250 VII (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 187 0 sontalm H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation. Reproduction Evaluations TABLE 39 (CONTINUED) DuPont-5386 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (THREE-MONTH RECOVERY EVALUATION) LESION INCIDENCE (Numeric) LESIONS RECTUM NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED PITUITARY GLAND NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) 0 I (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 Males 50 100 III V (5) (5) 55 (5) (5) 55 (5) (5) 55 (5) (5) 55 (5) (5) 55 (5) (5) 55 (5) (5) 55 (5) (5) 55 250 VII (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 188 CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) DuPont-5386 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (THREE-MONTH RECOVERY EVALUATION) LESIONS THYROID GLAND NO ABNORMALITY DETECTED PARATHYROID GLANDS NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED E Y E (S) WITH OPTIC NERVE NO ABNORMALITY DETECTED SKIN NO ABNORMALITY DETECTED PROSTATE NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESION INCIDENCE (Numeric Males 0 50 100 250 I III V VII (5) (5) (5) (5) 5 55 5 (5) (5) (5) 555 (5) 5 (5) (5) (5) (5) 5555 (5) (5) (5) (5) 5555 (5) (5) 55 (5) (5) 55 (5) (5) 55 (5) (5) 55 (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 189 ppHipsmg m m M l eemtalss TSG CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) DuPont-5386 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (THREE-MONTH RECOVERY EVALUATION) LESION INCIDENCE (Numeric) Males LESIONS TREATMENT (mg/kg/day) 0 I 50 100 III V SEMINAL VESICLES NO ABNORMALITY DETECTED URINARY BLADDER NO ABNORMALITY DETECTED TESTES NO ABNORMALITY DETECTED SMALL, SOFT, RIGHT. EPIDIDYMIDES NO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED (5) (5) (5) 555 (5) (5) (5) 555 (5) (5) (5) 54 5 1 (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 250 yn (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 190 Company Sanft&eed, Does not contain TSCA CBl H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 DuPont-5386 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESION INCIDENCE (Numeric) Females LESIONS TREATMENT 0 25 100 250 (mg/kg/day) II IV VI VIII LIVER NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (11) 11 KIDNEYS NO ABNORMALITY DETECTED DISCOLORATION, TAN, BILATERAL. DILATATION, BILATERAL, PELVIS. (10) 10 (10) 9 1 1 (10) 10 (11) 11 LUNGS NO ABNORMALITY DETECTED DISCOLORATION, DARK. (10) 10 (10) 10 (10) 9 1 (11) 11 HEART NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (11) 11 SKELETAL MUSCLE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (11) 11 SPLEEN NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (11) 11 AORTA NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (11) 11 N=ll in Group VIII reflects one reproduction designated animal that died on test day 53. Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 191 B*4Mqr8anlltndL @smeteewMn T tS A CW H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) DuPont-5386 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESION INCIDENCE (Numeric) Females LESIONS TREATMENT 0 25 100 250 (mg/kg/day) II IV VI VIII BRAIN NO ABNORMALITY DETECTED SPINAL CORD NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED PANCREAS NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 192 Sompany Sanitized. Does not contain TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) DuPont-5386 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESION INCIDENCE (Numeric) Females 1 Oi 1 I 1 1 LESIONS TREATMENT (mg/kg/day) 25 1 0 0 250 IV VI VIII 1 1H 1H 1 1 i COLON NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 RECTUM NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 SALIVARY GLANDS NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 THYMUS NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 ADRENAL GLANDS NO ABNORMALITY DETECTED LARGE, BILATERAL. (10) 10 (10) 10 (10) 10 SCIATIC NERVE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 10 1 (11) 11 193 fSwnpasaf SanfftzedL Does not certain TSCA CB H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) DuPont-5386 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESION INCIDENCE (Numeric) Females LESIONS TREATMENT 0 25 100 250 (mg/kg/day) II IV VI VIII PITUITARY GLAND NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (11) 11 THYROID GLAND NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (11) 11 PARATHYROID GLANDS NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (11) 11 TRACHEA NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (11) 11 ESOPHAGUS NO ABNORMALITY DETECTED PUNCTURE, GAVAGE ERROR. (10) 10 (10) 10 (10) 10 (11) 10 1 PHARYNX/LARYNX NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (11) 11 EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (11) 11 SKIN NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (11) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 194 Company Sanitized. Does notcontain TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) DuPont-5386 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESION INCIDENCE (Numeric) Females LESIONS TREATMENT 0 25 100 250 (mg/kg/day) II IV VI VIII SKIN STAIN. RED, PERINEUM. MAMMARY GLAND (FEMALE) NO ABNORMALITY DETECTED OVARIES NO ABNORMALITY DETECTED UTERUS NO ABNORMALITY DETECTED URINARY BLADDER NO ABNORMALITY DETECTED CALCULUS\CALCULI. DILATATION. FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED (10) (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) (10) 10 (10) 10 (10) 10 (10) 9 1 1 (10) 10 (10) 10 (10) (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (11) 1 1 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 195 Company S&nfilzed. D@snef coniai TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) DuPont-5386 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS TREATMENT (mg/kg/day) 1 l I 1H 1O M 1 LESION INCIDENCE (Numeric) Females 25 1 0 0 250 IV VI VIII NOSE NO ABNORMALITY DETECTED MANDIBLE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (9) 9 (10) 10 (9) 9 (11) 11 (8) 8 Figures in parentheses is the number of animals grossly examined for this tissue The absence o'f a number indicates the finding specified was not identified 196 Dempany SanHfeed. Does not confate TSCA Cfif H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) DuPont-5386 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDE Female LESIONS TREATMENT (mg/kg/day) 0 II 250 Vili LIVER NO ABNORMALITY DETECTED KIDNEYS NO ABNORMALITY DETECTED CALCULUS\CALCULI, BILATERAL. LUNGS NO ABNORMALITY DETECTED HEART NO ABNORMALITY DETECTED SKELETAL MUSCLE NO ABNORMALITY DETECTED (10) 10 (10) 9 1 (10) 10 (10) 10 (10) 10 SPLEEN NO ABNORMALITY DETECTED (10) 10 AORTA NO ABNORMALITY DETECTED (10) 10 BRAIN NO ABNORMALITY DETECTED (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 197 tanpasqr SanKbedL 0@net smtato YSA C1E H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) DuPont-5386 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDE Female LESIONS TREATMENT (mg/kg/day) 0 II 250 Vili 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 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 198 @ompanjf Sanitized. D oes not contain TSCA CB! H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) DuPont-5386 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDE Female LESIONS TREATMENT (mg/kg/day) 0 II 250 Vili RECTUM NO ABNORMALITY DETECTED (10) 10 MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED (10) 10 SALIVARY GLANDS NO ABNORMALITY DETECTED (10) 10 MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED (10) 10 THYMUS NO ABNORMALITY DETECTED (10) 10 ADRENAL GLANDS NO ABNORMALITY DETECTED (10) 10 SCIATIC NERVE NO ABNORMALITY DETECTED (10) 10 PITUITARY GLAND NO ABNORMALITY DETECTED LARGE. (10) 8 2 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 199 'estpanf S a n ite d D@mai eenain TSC CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) DuPont-5386 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDE Female LESIONS TREATMENT (mg/kg/day) 0 II 250 Vili THYROID GLAND NO ABNORMALITY DETECTED PARATHYROID GLANDS NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED E Y E (S ) WITH OPTIC NERVE NO ABNORMALITY DETECTED SKIN NO ABNORMALITY DETECTED MAMMARY GLAND (FEMALE) NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 200 Company Sanitized. Does not contain TSCA CHI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) DuPont-5386 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDE Female LESIONS OVARIES NO ABNORMALITY DETECTED UTERUS NO ABNORMALITY DETECTED URINARY BLADDER NO ABNORMALITY DETECTED CALCULUS\CALCULI. FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED MANDIBLE NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) 0 II (10) 10 (10) 10 (10) 9 1 (10) 10 (10) 10 (10) 10 (9) 9 250 Vili (10) io (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 201 Company SanRbied. Dees net contain TSCCSS H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (THREE-MONTH RECOVERY EVALUATION) DuPont-5386 LESION INCIDENCE (Numeric) Females LESIONS TREATMENT 0 25 100 250 (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 AORTA NO ABNORMALITY DETECTED BRAIN NO ABNORMALITY DETECTED (5) (4) (5) (5) 54 55 (5) (4) (5) (5) 54 5 5 (5) (4) (5) (5) 54 5 5 (5) (4) (5) (5) 5455 (5) (4) (5) (5) 5455 (5) (4) (5) (5) 54 5 5 (5) (4) (5) (5) 54 5 5 (5) (4) (5) (5) 54 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 202 Company Sanitized. Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) DuPont-5386 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (THREE-MONTH RECOVERY EVALUATION) LESION INCIDENCE (Numeric) Females LESIONS TREATMENT 0 25 100 250 (mg/kg/day) II IV VI VIII 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) (4) (5) (5) 54 5 5 (5) (4) (5) (5) 545 5 (5) (4) (5) (5) 54 5 5 (5) (4) (5) (5) 5455 (5) (4) (5) 54 5 (5) 5 (5) (4) (5) (5) 54 5 5 (5) (4) (5) (5) 54 5 5 (5) (4) (5) (5) 54 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 203 Compaqr Sanllbed. 0os not eemtsfa TSCA GB! H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) DuPont-5386 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (THREE-MONTH RECOVERY EVALUATION) LESION INCIDENCE (Numeric) Females LESIONS TREATMENT 0 25 100 (mg/kg/day) II IV VI RECTUM NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED (5) (4) (5) 54 5 (5) (4) (5) 54 5 (5) (4) (5) 54 5 (5) (4) (5) 54 5 THYMUS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED PITUITARY GLAND NO ABNORMALITY DETECTED (5) (4) (5) 54 5 (5) (4) (5) 54 5 (5) (4) (5) 54 5 (5) (4) (5) 545 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 250 VIII (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 204 ompany Sanitized. Does not confate TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) DuPont-5386 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (THREE-MONTH RECOVERY EVALUATION) LESION INCIDENCE (Numeric) Females LESIONS THYROID GLAND NO ABNORMALITY DETECTED PARATHYROID GLANDS NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED E Y E (S) WITH OPTIC NERVE NO ABNORMALITY DETECTED SKIN NO ABNORMALITY DETECTED MAMMARY GLAND (FEMALE) NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) 0 II (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 25 IV (4) 4 (4) 4 (4) 4 (4) 4 (4) 4 (4) 4 (4) 4 (4) 4 100 VI (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 250 VIII (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 205 ompany Sanitized. Bee motsmfaSmTSCA cm H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) DuPont-5386 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (THREE-MONTH RECOVERY EVALUATION) LESION INCIDENCE (Numeric) Females LESIONS OVARIES NO ABNORMALITY DETECTED UTERUS NO ABNORMALITY DETECTED URINARY BLADDER NO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) 0 II (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 25 IV (4) 4 (4) 4 (4) 4 (4) 4 (4) 4 (4) 4 100 VI (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 250 VIII (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 206 Company Sanifized Dees not contain TSCA CBS H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 DuPont-5386 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESION INCIDENCE (NUMERIC) LESIONS TREATMENT (mg/kg/day) 0 I 25 100 250 III V VII DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC. HYPERTROPHY, HEPATOCYTE, CENTRILOBULAR. FATTY CHANGE, MEDIAN CLEFT. FATTY CHANGE, CENTRILOBULAR. PANCREAS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. ATROPHY. (10) 10 2 1 (10) 7 2 2 (10) 1 9 2 2 (10) 1 9 9 2 6 (1) 1 (11) 3 10 11 3 (11) 9 1 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 207 g@mpa8if Sanitised. D@@not mtafnTSC C il H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) DuPont-5386 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESION INCIDENCE (NUMERIC) LESIONS TREATMENT (mg/kg/day) 0 I 25 100 250 III V VII DIGESTIVE SYSTEM ESOPHAGUS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. EDEMA. STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (1) (11) 9 12 1 (1) (11) 1 11 (1) (11) 1 11 JEJUNUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED (10) 10 (10) 10 (1) (11) 1 11 (1) (11) 1 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 208 Company Sanitised Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) DuPont-5386 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS DIGESTIVE SYSTEM CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED RECTUM NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 25 100 250 III V ' VII (10) 10 (10) 10 (10) 10 (10) 10 (1) (11) 1 11 (1) (11) 1 11 (1) (11) 1 11 (1) (11) 1 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 209 Ktgfflyswiy SanSttes4 0@not contain CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) DuPont-5386 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. HYPERTROPHY, TUBULAR. HYDRONEPHROSIS, UNILATERAL. HYDRONE PHROSIS, BILATERAL. URINARY BLADDER NO ABNORMALITY DETECTED 1 LESION INCIDENCE (NUMERIC) TREATMENT (m g/k g/day) 0 I 25 100 250 III V VII (10) 6 4 (10) 10 (10) 7 3 (10) 5 4 1 (1) 1 (11) 6 il 1 1 (i d 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 210 Company Sanitized. Doe# not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) DuPont-5386 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS TREATMENT (mg/kg/day) RESPIRATORY SYSTEM LUNGS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. INFLAMMATION, GRANULOMATOUS. TRACHEA NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED HEMORRHAGE. NOSE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. HYPERPLASIA/HYPERTROPHY, TRANSITIONAL CELL, EPITHELIUM. DEGENERATION/NECROSIS, RESPIRATORY, EPITHELIUM. DEGENERATION, AMELOBLASTS. LESIOlI INCIDI3NCE (NtJMERIC) 0 25 100 250 I III V VII (10) 8 2 (10) 10 (10) 10 (10) 10 (10) 10 (1) 1 (1) 1 (1) 1 (10) 4 1 1 5 (11) 8 2 1 (11) 11 (11) 10 1 (11) 2 2 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 211 fgM pasf SamSfeed- B@M l contain TSC CB1 H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) DuPont-5386 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS CARDIOVASCULAR SYSTEM HEART NO ABNORMALITY DETECTED CARDIOMYOPATHY. INFLAMMATION, SUBACUTE/CHRONIC. AORTA NO ABNORMALITY DETECTED | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 25 100 250 III V VII (10) 5 5 (10) 10 (1) (11) 8 3 1 (1) (11) 1 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 212 CompanySanitized. Does notcontain TSCCBS H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) DuPont-5386 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED ATROPHY, - MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED BONE MARROW NO ABNORMALITY DETECTED HYPERPLASIA, GRANULOCYTIC. | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 25 100 250 III V VII (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (1) (11) 1 11 (11) 10 1 (1) (11) 1 11 (1) (11) 1 11 (1) (11) 10 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 213 B w panf Sanilbed. 0@snel artaimTSCA CB1 H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) DuPont-5386 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS ENDOCRINE SYSTEM PITUITARY GLAND NO ABNORMALITY DETECTED THYROID GLAND NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. HYPERTROPHY, FOLLICULAR. ALTERATION, COLLOID. PARATHYROID GLANDS . NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 25 100 250 I III V VII (10) 10 (10) 1 1 9 (8) 8 (10) 10 (10) 1 9 (1) 1 (10) 1 2 9 (1) 1 (11) 11 (11) 10 11 (10) 10 (11) 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 214 Campant Sanitized. Does not contain TSCACB! H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) DuPont-5386 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS NERVOUS SYSTEM TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 25 100 250 I III V VII BRAIN NO ABNORMALITY DETECTED SPINAL CORD NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (1) (ID 1 11 (1) (11) 1 11 (11) 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 215 Pw ipSiF Isnftteed B@@snot solata TS6 CSt H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) DuPont-5386 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS MUSCULAR AND SKELETAL SYSTEM TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 25 100 250 I III V VII SKELETAL MUSCLE NO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED MANDIBLE NO ABNORMALITY DETECTED DEGENERATION, AMELOBLASTS. (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (1) (11) 1 11 (1) (11) 1 11 (1) (11) 1 11 (9) (10) 8 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 216 empsmy Sanitized. Does no! contain YSCA cm H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) DuPont-5386 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS REPRODUCTIVE SYSTEM TESTES NO ABNORMALITY DETECTED SPERMATID RETENTION, SEMINIFEROUS TUBULES. EPIDIDYMIDES NO ABNORMALITY DETECTED PROSTATE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. SEMINAL VESICLES NO ABNORMALITY DETECTED i LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 25 100 250 III V VII (10) 10 (10) 10 (10) 9 1 (10) 10 (1) (11) 11 1 (1) (11) 1 11 (1) (11) 10 11 (1) (11) 1 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 217 SsrftitescL Beo not oomtafa TSCA CBl H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) DuPont-5386 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS CUTANEOUS SYSTEM SKIN NO ABNORMALITY DETECTED | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 25 100 250 III V VII (10) 10 (1) (11) 1 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 218 1 fes? H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) IP DuPont-5386 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS SPECIAL SENSES SYSTEM TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 25 100 250 I III V ' VII EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED OPTIC NERVE NOT PRESENT. FOLD/ROSETTE, RETINAL. (10) 9 1 (1) (11) 19 2 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 219 Panpamf S u it e d 0 m no! ontalmTSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) DuPont-5386 LESIONS DIGESTIVE SYSTEM LIVER NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC. HYPERTROPHY, HEPATOCYTE, CENTRILOBULAR. FOCUS OF CELLULAR ALTERATION, BASOPHILIC. FATTY CHANGE, MEDIAN CLEFT. FATTY CHANGE, CENTRILOBULAR. LESION INCIDE Males TREATMENT (mg/kg/day) 0 I 250 VII (10) 10 1 1 (10) 1 9 10 1 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 220 Company Sanitized Does not contain TSCA CBt H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) DuPont-5386 LESIONS URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. HYPERTROPHY, TUBULAR. HYDRONEPHROSIS, UNILATERAL. LESION INCIDE Males TREATMENT (mg/kg/day) 0 I 250 VII (10) 5 5 (10) 5 4 2 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 221 S m p m f Sanftked 0@@n t a t o T iC CB! H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS LESION INCIDE Males TREATMENT (mg/kg/day) 0 I 250 VII RESPIRATORY SYSTEM NOSE NO ABNORMALITY DETECTED ODONTODYS PLASIA. DEGENERATION, AMELOBLASTS. (10) 9 1 (10) 1 9 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 222 ompamjf Sanitized Does Biotcontain TSCACB8 H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 40 (CONTINUED) LESIONS INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDE Males TREATMENT (mg/kg/day) 0 I 250 VII LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED MANDIBULAR LYMPH NODE ERYTHROCYTOSIS/ERYTHROPHAGOCYTOSIS, SINUS. (1) X (1) (1) 11 (1) 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 223 gMfpiMf SanlUsed B e no! Mtei TSC CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 40 (CONTINUED) LESIONS INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDE Males TREATMENT (mg/kg/day) 0' I 250 VII ENDOCRINE SYSTEM THYROID GLAND ALTERATION, COLLOID. (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 224 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDE LESIONS TREATMENT (mg/kg/day) Males 0 250 I VII MUSCULAR AND SKELETAL SYSTEM MANDIBLE 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 225 Bonpaqr SanH nd m l awsfalm TSCA CHI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDE LESIONS TREATMENT (mg/kg/day) Males 0 250 I VII REPRODUCTIVE SYSTEM TESTES DEGENERATION/ATROPHY, SEMINIFEROUS TUBULES, UNILATERAL. DEGENERATION/ATROPHY, SEMINIFEROUS TUBULES, BILATERAL. EPIDIDYMIDES NO ABNORMALITY DETECTED OLIGOSPERMIA/GERM CELL DEBRIS, UNILATERAL. SEMINAL VESICLES NO ABNORMALITY DETECTED (2) (1) 2 1 (2) (1) 1 11 (1) 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 25 100 250 III V VII DIGESTIVE SYSTEM LIVER NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC. HYPERTROPHY, HEPATOCYTE, CENTRILOBULAR. FATTY CHANGE, MEDIAN CLEFT. FATTY CHANGE, CENTRILOBULAR. (5) (5) (5) 1 21 5 55 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 227 net m tsfe TSC CBt H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations w* 0 DuPont-5386 TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS- NEOPLASTIC AND NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESION INCIDENCE (NUMERIC) LESIONS TREATMENT (mg/kg/day) 0 I 25 100 250 III V VII URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED CALCULUS\CALCULI. NEPHROPATHY, CHRONIC PROGRESSIVE. INFLAMMATION, SUBACUTE/CHRONIC. HYPERPLASIA, TRANSITIONAL CELL. (5) (5) 2 1 34 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 228 &. H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations w DuPont-5386 TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESION INCIDENCE (NUMERIC) LESIONS TREATMENT (mg/kg/day) 0 I 25 100 250 III V VII RESPIRATORY SYSTEM NOSE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, NASOLACRIMAL DUCT. INFLAMMATION, SUBACUTE/CHRONIC. HYPERPLASIA/SQUAMOUS METAPLASIA, RESPIRATORY, EPITHELIUM. HYPERPLASIA/HYPERTROPHY, TRANSITIONAL CELL, EPITHELIUM. FRACTURE/CALLUS, TOOTH. DEGENERATION/NECROSIS, RESPIRATORY, EPITHELIUM. DEGENERATION, AMELOBLASTS. SCHWANNOMA [B]. (5) (5) (5) (5) 313 11 2324 2 12 1 32 1 1 12 1 [B] Benign tumour Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 229 fionpanf mm m@ lata T8CA CSS H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS- NEOPLASTIC AND NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESION INCIDENCE (NUMERIC) LESIONS TREATMENT (mg/kg/day) 0 I 25 100 250 III V VII ENDOCRINE SYSTEM THYROID GLAND ALTERATION, COLLOID. (5) (5) (5) (5) 5555 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 230 Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 41 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC. HYPERTROPHY, HEPATOCYTE, CENTRILOBULAR. FATTY CHANGE, MEDIAN CLEFT. PANCREAS NO ABNORMALITY DETECTED ATROPHY. ESOPHAGUS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. STOMACH NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESIOI INCIDI1NCE (NlJMERIC) 0 25 100 250 II IV VI VIII (10) 1 1 9 2 (10) 10 (10) 10 (10) 10 (10) 1 9 1 (1) 1 (1) 1 (1) 1 (10) 1 1 9 (11) 2 7 9 (11) 9 2 (ID 10 1 (11) 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 231 sipf S ite 4 0@noi eonlaSmTSCACBS H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) DuPont-5386 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS DIGESTIVE SYSTEM | LESION INCIDENCE (NUMERIC) TREATMENT 0 25 100 250 (mg/kg/day) II IV VI VIII DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED AUTOLYSIS:-NECROPSY AND HISTOLOGY PERFORMED. ILEUM NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (1) 1 (1) 1 (1) 1 (1) 1 (1) 1 (11) 11 (11) 11 2 (11) 11 (11) 11 (11) 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 232 Company S a n f a d . Does not contain 7SCA CBS H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) DuPont-5386 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS DIGESTIVE SYSTEM | LESION INCIDENCE (NUMERIC) TREATMENT 0 25 100 250 (mg/kg/day) II IV VI VIII RECTUM NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED (10) 10 (10) 10 (1) 1 (1) 1 (11) 11 (ID 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 233 ipffspnf t o i M L B@sm l wtata T8GA CIS H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) DuPont-5386 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. NECROSIS, TUBULAR. INFLAMMATION, ACUTE. INFARCT. HYPERPLASIA, TRANSITIONAL CELL. HYDRONEPHROSIS, BILATERAL. CYST. AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. URINARY BLADDER NO ABNORMALITY DETECTED HYPERPLASIA, SIMPLE, TRANSITIONAL CELL. TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 25 100 250 II IV VI VIII (10) 6 3 1 (10) 10 (10) 7 2 1 1 1 1 (1) 1 (10) 7 3 (11) 7 4 1 1 (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 234 CksmpanySanitized. Does not contain TSCACBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) DuPont-5386 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS RESPIRATORY SYSTEM LUNGS NO ABNORMALITY DETECTED THROMBUS. TRACHEA NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. FRACTURE/CALLUS, TOOTH. DEGENERATION, AMELOBLASTS. I LESION INCIDENCE (NUMERIC) TREATMENT 0 25 100 250 (mg/kg/day) II IV VI Vili (10) 9 1 (10) 10 (10) 10 (10) 10 (1) 1 (1) 1 (1) 1 (10) 9 1 1 (1) 1 (10) 4 6 (11) 11 (11) 11 (11) 11 (11) 1 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 235 wnparaf S a sfe 4 B@s m i rti TSG GBl H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) DuPont-5386 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS CARDIOVASCULAR SYSTEM HEART NO ABNORMALITY DETECTED CARDIOMYOPATHY. AORTA NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 25 100 250 II IV VI VIII (10) 7 3 (10) 10 (1) 1 (1) 1 (11) 11 (11) 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 236 GoHspaay Sanitized. Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) DuPont-5386 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED DEPLETION, LYMPHOID. THYMUS NO ABNORMALITY DETECTED ATROPHY. MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED BONE MARROW NO ABNORMALITY DETECTED HYPERPLASIA, GRANULOCYTIC. ATROPHY. I LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 II 25 100 250 IV VI VIII (10) 10 (10) 10 (10) 10 (9) 9 (10) 10 (1) 1 (1) 1 (1) 1 (1) 1 (1) 1 (10) 8 2 (11) 9 2 (11) 11 (9) 9 (11) 10 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 237 Dompanjf Sanitized. Does not contain TSCA CBl H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) DuPont-5386 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS ENDOCRINE SYSTEM PITUITARY GLAND NO ABNORMALITY DETECTED THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. ALTERATION,- COLLOID. PARATHYROID GLANDS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED | LESION INCIDENCE (NUMERIC) 1 1 1 1H 1O H 1 TREATMENT (mg/kg/day) 25 100 250 IV VI VIII (10) 10 (10) 10 (6) 6 (10) 10 (1) 1 (10) 4 6 tu i (U i (10) 6 4 (11) 11 (11) 3 6 7 (7) 7 (11) 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 238 gampm&g H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) DuPont-5386 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS NERVOUS SYSTEM BRAIN NO ABNORMALITY DETECTED SPINAL CORD NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 25 100 250 II IV VI VIII (10) 10 (10) 10 (10) 10 (1) 1 (1) 1 (1) 1 (11) 11 (11) 11 (11) 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 239 Company Sanded. Does not contain TSCA CBi H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) DuPont-5386 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS- NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUAION) LESIONS MUSCULAR AND SKELETAL SYSTEM SKELETAL MUSCLE NO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED MANDIBLE NO ABNORMALITY DETECTED DEGENERATION, AMELOBLASTS. TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 25 100 250 II IV VI VIII (10) 10 (10) 10 (10) 10 (10) 10 (1) (11) 1 11 (1) (11) 1 11 (1) (11) 1 11 (9) (10) 9 10 (8) 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 240 Company Sanitised. Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) DuPont-5386 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS REPRODUCTIVE SYSTEM OVARIES NO ABNORMALITY DETECTED UTERUS NO ABNORMALITY DETECTED DILATATION, LUMEN. MAMMARY GLAND (FEMALE) NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 25 100 250 II IV VI VIII (10) 10 (10) 10 (10) 10 (1) 1 (1) 1 (1) 1 (11) 11 (11) 8 3 (11) 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 241 net contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) DuPont-5386 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS CUTANEOUS SYSTEM SKIN NO ABNORMALITY DETECTED | LESION INCIDENCE (NUMERIC) TREATMENT 0 25 100 250 (mg/kg/day) II IV VI VIII (10) 10 (1) 1 (11) 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 242 jMwy Sanitized. Does not contain TSCACBi H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) DuPont-5386 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS SPECIAL SENSES SYSTEM EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED OPTIC NERVE NOT PRESENT. AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. | LESION INCIDENCE (NUMERIC) TREATMENT 0 25 100 250 (mg/kg/day) II IV VI VIII (10) 10 2 (1) 1 (11) 11 3 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 243 Company Sanitized Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS- NEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC. FATTY CHANGE, MEDIAN CLEFT. PANCREAS NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED LESION INCIDE Female TREATMENT (mg/kg/day) 0 II 250 VIII (10) 1 1 8 1 (1) 1 (1) 1 (1) 1 (1) 1 (10) 1 1 9 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 244 Company Sanitized. Does not contain TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS DIGESTIVE SYSTEM JEJUNUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED RECTUM NO ABNORMALITY DETECTED DIGESTIVE SYSTEM SALIVARY GLANDS NO ABNORMALITY DETECTED LESION INCIDE Female TREATMENT (mg/kg/day) 0 II 250 VIII (1) 1 (1) 1 (1) 1 (1) 1 (1) 1 (1) 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 245 Company Sanitized. Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS LESION INCIDE Female TREATMENT (mg/kg/day) 0 II 250 VIII URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. NECROSIS, TUBULAR. MINERALIZATION. INFLAMMATION, ACUTE. HYPERPLASIA, TRANSITIONAL CELL. HYDRONEPHROSIS, BILATERAL. CYST. URINARY BLADDER INFLAMMATION, SUBACUTE/CHRONIC. HYPERPLASIA, SIMPLE, TRANSITIONAL CELL. HEMORRHAGE. (10) 3 5 1 1 1 1 1 1 (1) 1 1 1 (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 246 Company Sanitized. Does not contain TSC CBi H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS LESION INCIDE Female TREATMENT (mg/kg/day) 0' II 250 VIII RESPIRATORY SYSTEM LUNGS NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED SQUAMOUS HYPERPLASIA, NASOLACRIMAL DUCT. INFLAMMATION, SUBACUTE/CHRONIC, NASOLACRIMAL DUCT. DEGENERATION, AMELOBLASTS. (1) 1 (1) 1 (1) 1 (10) 9 X (10) 3 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 247 Company Sanitized. Does not contain TSCA CSi H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS- NEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS CARDIOVASCULAR SYSTEM LESION INCIDE Female TREATMENT (mg/kg/day) 0 II 250 VIII HEART NO ABNORMALITY DETECTED AORTA NO ABNORMALITY DETECTED (I) 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 248 Company Sanitized. Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 41 (CONTINUED) LESIONS INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDE Female TREATMENT (mg/kg/day) 0 II 250 VIII LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED THYMUS ATROPHY. MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED BONE MARROW HYPERPLASIA, GRANULOCYTIC. (1) 1 (1) 1 (1) 1 (1) 1 (1) 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 249 ompary Sanitized. Does not contain TSCA CBl H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS- NEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS LESION INCIDE Female TREATMENT (mg/kg/day) 0 II 250 VIII ENDOCRINE SYSTEM PITUITARY GLAND NO ABNORMALITY DETECTED HYPERPLASIA, DIFFUSE. THYROID GLAND NO ABNORMALITY DETECTED ALTERATION, COLLOID. PARATHYROID GLANDS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED (2) 1 1 (10) 5 5 tu i (U 1 (10) 1 9 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 250 Company SanftteeA Does not contain TSCA CBf H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS NERVOUS SYSTEM LESION INCIDE Female TREATMENT (mg/kg/day) 0 II 250 VIII BRAIN NO ABNORMALITY DETECTED SPINAL CORD NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED (1) 1 (1) 1 (1) 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 251 Company Sanitized. Does not contain TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS MUSCULAR AND SKELETAL SYSTEM SKELETAL MUSCLE NO ABNORMALITY DETECTED FEMUR/KNEE J.OINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED MANDIBLE NO ABNORMALITY DETECTED LESION INCIDE Female TREATMENT (mg/kg/day) 0 II 250 VIII (1) 1 (1) 1 (1) 1 (10) 10 (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 252 Company Sanitized. Does not contain TSCA CBf H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS LESION INCIDE Female TREATMENT (mg/kg/day) 250 VIII 1 1H O 1H 1 1 1 REPRODUCTIVE SYSTEM OVARIES NO ABNORMALITY DETECTED UTERUS NO ABNORMALITY DETECTED MAMMARY GLAND (FEMALE) NO ABNORMALITY DETECTED (l) i (l) i (l) i Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 253 Company Sanitized. Does not contain TSCA CB H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS LESION INCIDE Female TREATMENT (mg/kg/day) 0 II 250 VIII CUTANEOUS SYSTEM SKIN NO ABNORMALITY DETECTED (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 254 Sanitized. Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS- NEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS LESION INCIDE Female TREATMENT (mg/kg/day) 0 II 250 Vili SPECIAL SENSES SYSTEM EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED (1) I Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 255 Company Sanitized. Does not contain TSCA CBl H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS- NEOPLASTIC AND NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESIONS RESPIRATORY SYSTEM NOSE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. HYPERPLASIA/SQUAMOUS METAPLASIA, DEGENERATION, AMELOBLASTS. TRANSITIONAL CELL. TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 25 100 250 II IV VI VIII (5) (5) (5) 2 31 3 22 3 23 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 256 Company Sanitized. Does not contain TSCA CB1 H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS- NEOPLASTIC AND NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESIONS ENDOCRINE SYSTEM THYROID GLAND NO ABNORMALITY DETECTED ALTERATION, COLLOID. TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 25 100 250 ' II IV VI VIII (5) (4) (5) (5) 1 544 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 257 Company Sanitized. Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 42 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED NECROSIS, FOCAL. minimal mild total observations per lesion INFLAMMATION, SUBACUTE/CHRONIC. minimal total observations per lesion HYPERTROPHY, HEPATOCYTE, CENTRILOBULAR. minimal mild moderate total observations per lesion FATTY CHANGE, MEDIAN CLEFT. minimal mild total observations per lesion FATTY CHANGE, CENTRILOBULAR. minimal total observations per lesion TREATMENT (mg/kg/day) LES101I INCIDIINCE (NtJMERIC) 0 25 100 250 I III V VII (10) 10 10 2 2 1 1 (10) 1 9 9 2 2 2 2 (10) 1 1 9 9 9 9 1 1 2 6 6 (11) 2 i 3 10 10 2 8 1 11 3 3 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 258 Company Sanitized. Does not contain TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS DIGESTIVE SYSTEM | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 25 100 250 III V VII PANCREAS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. minimal total observations per lesion ATROPHY. minimal total observations per lesion ESOPHAGUS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. minimal mild moderate total observations per lesion EDEMA. mild total observations per lesion (10) 7 2 2 2 2 (10) 10 (1) (11) 19 1 1 1 1 (1) (11) 9 1 1 1 12 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 259 Company Sanitized. Does not contain TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS DIGESTIVE SYSTEM TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 25 100 250 I III V VII STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED CECUM . NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (1) (11) 1 11 (1) (11) 1 11 (1) (11) 1 11 (1) (11) 1 11 (1) (11) 1 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 260 Company Sanitized. Does not contain TSCA CBi H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 25 100 250 I III V VII DIGESTIVE SYSTEM COLON NO ABNORMALITY DETECTED RECTUM NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED (1 0 ) 10 (10 ) 10 (10 ) 10 (1 ) (1 1 ) 1 11 (1 ) ( 11) 1 11 (1 ) (11) 1 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 261 Company Sanitized. Does not contain TSCACBt H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 25 100 250 I III V VII URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE, minimal mild total observations per lesion HYPERTROPHY, TUBULAR, minimal mild total observations per lesion HYDRONEPHROSIS, UNILATERAL. minimal total observations per lesion HYDRONEPHROSIS, BILATERAL, minimal total observations per lesion URINARY BLADDER NO ABNORMALITY DETECTED (10) 6 4 4 (10) 10 (10) 7 3 3 (10) 5 4 4 1 1 (1) 1 (11) 5 1 6 3 8 11 1 1 1 1 (11) 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 262 Company Sanitized. Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS- NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS RESPIRATORY SYSTEM | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 25 100 250 III V VII LUNGS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. minimal total observations per lesion INFLAMMATION, GRANULOMATOUS, minimal severe total observations per lesion TRACHEA NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED HEMORRHAGE. mild total observations per lesion (10) 8 2 2 (10) 10 (10) 10 (1) (11) 8 2 2 1 1 11 (1) (11) 1 11 (1) (11) 1 10 1 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 263 Company Sanitized Does not contain TSCA CBf H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS RESPIRATORY SYSTEM TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 25 100 250 I III V VII NOSE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. minimal mild total observations per lesion HYPERPLASIA/HYPERTROPHY, TRANSITIONAL CELL, EPITHELIUM. minimal mild total observations per lesion DEGENERATION/NECROSIS, RESPIRATORY, EPITHELIUM. minimal total observations per lesion DEGENERATION, AMELOBLASTS. minimal mild total observations per lesion (10) 10 (10) 10 (10) 4 1 1 1 1 5 5 (11) 1 1 2 1 1 2 il XX Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 264 Company Sanitized. Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS CARDIOVASCULAR SYSTEM TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 25 100 250 I III V VII HEART NO ABNORMALITY DETECTED CARDIOMYOPATHY. minimal total observations j lesion INFLAMMATION, SUBACUTE/CHRONIC. moderate lesion AORTA NO ABNORMALITY DETECTED (10) 5 5 5 (10) 10 (1) (11) 8 3 3 1 1 (1) (11) 1 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 265 Company Sanitized. Does not contain TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS- NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 25 100 250 > I III V VII SPLEEN NO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED ATROPHY. mild total observations per lesion MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (1) (11) 1 11 (11) 10 1 1 (1) (11) 1 11 (1) (11) 1 11 plgure in parentheses is number of animals microscopically1 examinee! for this tissue The absence of a number indicates the lesion specified was not identified 266 Company Sanitized. Does not contain TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 25 100 250 III V VII BONE MARROW NO ABNORMALITY DETECTED HYPERPLASIA, GRANULOCYTIC. mild moderate total observations per lesion (10) 10 (1) (11) 10 1 1 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 267 Company Sanitized. Does not contain TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 25 100 250 I III V VII ENDOCRINE SYSTEM PITUITARY GLAND NO ABNORMALITY DETECTED THYROID GLAND NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. minimal total observations per lesion HYPERTROPHY, FOLLICULAR. minimal mild total observations per lesion ALTERATION, COLLOID, minimal mild moderate severe total observations per lesion (10) 10 (10) 1 1 1 9 9 (10) 1 6 2 1 9 (1) 1 (10) 1 2 2 3 2 4 9 (11) 11 (11) 3 7 10 4 5 2 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 268 Company Sanitized. Does not contain TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 25 100 250 I III V VII ENDOCRINE SYSTEM PARATHYROID GLANDS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED (8) 8 (10) 10 (10) 10 (1) (11) 1 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 269 Company Sanitized. Does not contain TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS NERVOUS SYSTEM | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 25 100 250 III V VII BRAIN NO ABNORMALITY DETECTED SPINAL CORD NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (1) (11) 1 11 (1) (11) 1 11 (11) 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 270 Company Sanitized. Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 25 100 250 > III V VII MUSCULAR AND SKELETAL SYSTEM SKELETAL MUSCLE NO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED MANDIBLE NO ABNORMALITY DETECTED DEGENERATION, AMELOBLASTS. minimal mild total observations per lesion (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (1) (11) 1 11 (1) (11) 1 11 (1) (11) 1 11 (9) (10) 8 12 8 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 271 Company Sanitized. Does not contain TSCA CBf H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 25 100 250 III V VII REPRODUCTIVE SYSTEM TESTES NO ABNORMALITY DETECTED SPERMATID RETENTION, SEMINIFEROUS TUBULES, minimal total observations per lesion EPIDIDYMIDES NO ABNORMALITY DETECTED PROSTATE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. minimal moderate total observations per lesion SEMINAL VESICLES NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 9 1 1 (10) 10 (1) (11) 11 1 1 (1) (11) 1 11 (1) ( I D 10 1 1 11 (1) (11) 1 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 272 Company Sanitized. Does not contain TSCA CBl H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS CUTANEOUS SYSTEM | LESION INCIDENCE (NUMERIC) TREATMENT (mg/kg/day) 0 I 25 100 250 III V VII SKIN NO ABNORMALITY DETECTED (10) 10 (1) (11) 1 11 Figure in par'entheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 273 Company Sanitized. Does not contain TSCA Cd! H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS SPECIAL SENSES SYSTEM TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 25 100 250 I III V VII E Y E (S) WITH OPTIC NERVE NO ABNORMALITY DETECTED OPTIC NERVE NOT PRESENT. FOLD/ROSETTE, RETINAL, minimal total observations per lesion (10) 9 1 1 (1) ( I D 19 2 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 274 Company Sanitized. Does not contain TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS LESION INCIDE Males TREATMENT (mg/kg/day) 0 I 250 VII DIGESTIVE SYSTEM LIVER NECROSIS, FOCAL. minimal tdtal observations per lesion INFLAMMATION, SUBACUTE/CHRONIC. minimal total observations per lesion HYPERTROPHY, HEPATOCYTE, CENTRILOBULAR. minimal mild total observations per lesion FOCUS OF CELLULAR ALTERATION, BASOPHILIC. minimal total observations per lesion FATTY CHANGE, MEDIAN CLEFT. minimal total observations per lesion FATTY CHANGE, CENTRILOBULAR. minimal total observations per lesion Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 10 1 1 1 1 (10) 1 1 9 9 4 6 10 1 1 1 1 275 Company Sanitized. Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS LESION INCIDE Males TREATMENT (mg/kg/day) 0 I 250 VII URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE, mi'nimal total observations per lesion HYPERTROPHY, TUBULAR, minimal total observations per lesion HYDRONEPHROSIS, UNILATERAL, minimal total observations per lesion (10) 5 5 5 (10) 5 4 4 2 2 1 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBi H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS- NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS RESPIRATORY SYSTEM NOSE NO ABNORMALITY DETECTED ODONTODYSPLASIA. moderate total observations per lesion DEGENERATION, AMELOBLASTS. minimal mild total observations per lesion LESION INCIDE Males TREATMENT (mg/kg/day) 0 I 250 VII (10) 9 1 1 (10) 1 5 4 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 277 Company Sanitized. Does not contain TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS LESION INCIDE Males TREATMENT (mg/kg/day) 0 I 250 VII LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED MANDIBULAR LYMPH NODE ERYTHROCYTOSIS/ERYTHROPHAGOCYTOSIS, SINUS. mild total observations per lesion (1) 1 (1) (1) 11 (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 278 Company Sanitized. Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations m DuPont-5386 TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS- NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS ENDOCRINE SYSTEM THYROID GLAND ALTERATION, COLLOID. minimal mi'ld moderate severe total observations per lesion LESION INCIDE Males TREATMENT (mg/kg/day) 0 I 250 VII (10) 8 2 10 (10) 1 3 4 2 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 279 Company Sanitized. Does not contain TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS LESION INCIDE Males TREATMENT (mg/kg/day) 0 I 250 VII MUSCULAR AND SKELETAL SYSTEM MANDIBLE NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 (10) 10 280 Company Sanitized. Does not contain TSCA CBI ^ H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS REPRODUCTIVE SYSTEM TESTES DEGENERATION/ATROPHY, SEMINIFEROUS TUBULES, UNILATERAL. mild severe total observations per lesion DEGENERATION/ATROPHY, SEMINIFEROUS TUBULES, BILATERAL. moderate total observations per lesion EPIDIDYMIDES NO ABNORMALITY DETECTED OLIGOSPERMIA/GERM CELL DEBRIS, UNILATERAL. moderate severe total observations per lesion SEMINAL VESICLES NO ABNORMALITY DETECTED LESION INCIDE Males TREATMENT (mg/kg/day) 0 I 250 VII (2) (1) 1 1 2 1 1 (2) (1) 1 1 1 11 (1) 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 281 Company Sanitized. Does not contain TSCA CBi H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) DuPont-5386 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESIONS DIGESTIVE SYSTEM LIVER NECROSIS, FOCAL. minimal mild total observations per lesion INFLAMMATION, SUBACUTE/CHRONIC. minimal total observations per lesion HYPERTROPHY, HEPATOCYTE, CENTRILOBULAR. minimal total observations per lesion FATTY CHANGE, MEDIAN CLEFT. mild total observations per lesion FATTY CHANGE, CENTRILOBULAR. mild total observations per lesion TREATMENT (mg/kg/day) LESIOII INCIDI:n c e (niJMERIC) 0 25 100 250 I III v . VII (5) (5) (5) 12 1 1 21 5 55 5 55 1 1 1 1 I 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 282 Company Sanitized. Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESIONS URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED CALCULUS\CALCULI. minimal total observations per lesion NEPHROPATHY, CHRONIC PROGRESSIVE. minimal moderate total observations per lesion INFLAMMATION, SUBACUTE/CHRONIC. minimal total observations per lesion HYPERPLASIA, TRANSITIONAL CELL. minimal total observations per lesion TREATMENT (mg/kg/day) LESIOII INCIDI]NCE (NXJMERIC) 0 25 100 250 I III V VII (5) (5) 2 1 1 33 1 34 1 1 1 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 283 Company Sanitized. Does not contain TSCA CBi H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) DuPont-5386 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT (mg/kg/day) LESI01 INCIDI3NCE (NIJMERIC) 0 25 100 250 I III V VII RESPIRATORY SYSTEM NOSE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, NASOLACRIMAL DUCT. mild total observations per lesion INFLAMMATION, SUBACUTE/CHRONIC. minimal mild total observations per lesion HYPERPLASIA/SQUAMOUS METAPLASIA, RESPIRATORY, EPITHELIUM. minimal mild total observations per lesion HYPERPLASIA/HYPERTROPHY, TRANSITIONAL CELL, EPITHELIUM. minimal mild total observations per lesion FRACTURE/CALLUS, TOOTH. DEGENERATION/NECROSIS, RESPIRATORY, EPITHELIUM. mild total observations per lesion DEGENERATION, AMELOBLASTS. minimal (5) (5) (5) (5) 3I3 11 11 12 3 1121 2324 111 21 2 12 1 22 1 32 1 X 1 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 284 Company Sanitized. Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS- NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESIONS RESPIRATORY SYSTEM NOSE DEGENERATION, AMELOBLASTS. mild total observations per lesion TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 25 100 250 I III V VII (5) (5) (5) (5) 1 2 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 285 Company Sanitized. Does not contain TSCACBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 42 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESIONS ENDOCRINE SYSTEM THYROID GLAND ALTERATION, COLLOID, minimal mild moderate severe total observations per lesion TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 25 100 250 I III V VII (5) (5) (5) (5) 31 1 12 11 253 5555 Figure in parentheses-is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 286 Company Sanitized. Does not contain TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 43 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED NECROSIS, FOCAL. minimal total observations per lesion INFLAMMATION, SUBACUTE/CHRONIC. minimal total observations per lesion HYPERTROPHY, HEPATOCYTE, CENTRILOBULAR. minimal mild total observations per lesion FATTY CHANGE, MEDIAN CLEFT. minimal mild total observations per lesion TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 25 100 250 II IV VI VIII (10) 1 1 1 9 9 2 2 (10) 1 9 9 1 1 (10) 1 1 1 9 9 (11) 2 7 7 4 5 9 N=ll in Group VIII reflects one reproduction designated animal that died on test day 53. Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 287 Company Sanitized. Does not contain TSCA CBi H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) DuPont-5386 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS TREATMENT (m g/kg/day) LESION INCIDENCE (NUMERIC) 0 25 100 250 II IV VI VIII DIGESTIVE SYSTEM PANCREAS NO ABNORMALITY DETECTED ATROPHY. m in im al to ta l observations per le sio n ESOPHAGUS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. severe to ta l observations per le sio n STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED (10) (1) 10 1 (10) (1) 10 1 (10) (1) 10 1 (10) (1) 10 1 (11) 9 2 2 (i d 10 1 1 (i d 11 du 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 288 Company Sanitized. Does not contain TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) DuPont-5386 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS DIGESTIVE SYSTEM JEJUNUM NO ABNORMALITY DETECTED AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED, moderate total observations per lesion ILEUM NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED RECTUM NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 25 100 250 II IV VI VIII (10) 10 (1) 1 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (1) 1 (1) 1 (1) 1 (1) 1 (1) 1 (11) 11 2 2 (11) 11 (11) 11 (ID 11 (11) 11 (11) 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 289 Company Sanitized. D oes not contain SCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS I LESION INCIDENCE (NUMERIC) TREATMENT 0 25 100 250 (mg/kg/day) II IV VI VIII URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE, minimal moderate total observations per lesion NECROSIS, TUBULAR. moderate total observations per lesion INFLAMMATION, ACUTE. moderate total observations per lesion INFARCT. minimal total observations per lesion HYPERPLASIA, TRANSITIONAL CELL, mild total observations per lesion HYDRONEPHROSIS, BILATERAL. mild total observations per lesion CYST. minimal (10) 6 3 3 (10) 7 2 2 1 1 1 1 1 1 1 1 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 7 3 3 (11) 7 3 1 4 1 1 290 Company Sanitized. Does not contain TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) DuPont-5386 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT 0 25 100 250 (mg/kg/day) II IV VI VIII URINARY SYSTEM KIDNEYS CYST. total observations per lesion AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED, mild total observations per lesion URINARY BLADDER NO ABNORMALITY DETECTED HYPERPLASIA, SIMPLE, TRANSITIONAL CELL, moderate total observations per lesion (10) 1 (10) 10 (10) (1) 1 1 (10) (11) 1 1 (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 291 not contain TSCACB1 Company Sanitized. Does H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) DuPont-5386 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT 0 25 100 250 (mg/kg/day) II IV VI VIII RESPIRATORY SYSTEM LUNGS NO ABNORMALITY DETECTED THROMBUS. minimal total observations per lesion (10) 9 1 1 (1) 1 TRACHEA NO ABNORMALITY DETECTED (10) 10 (1) 1 PHARYNX/LARYNX NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. minimal mild total observations per lesion FRACTURE/CALLUS, TOOTH. DEGENERATION, AMELOBLASTS. minimal mild total observations per lesion (10) 10 (10) 10 (1) 1 (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 (1) 1 (10) 4 6 6 (11) 11 (11) 11 (11) 11 (11) 1 1 11 11 292 Company Sanitized. Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) DuPont-5386 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS CARDIOVASCULAR SYSTEM HEART NO ABNORMALITY DETECTED CARDIOMYOPATHY. minimal total observations per lesion AORTA NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) H H 1 O1 1 1 1 LESION INCIDENCE (NUMERIC) 25 100 250 IV VI VIII (10) 7 3 3 (10) 10 (1) 1 1 (1) 1 (11) 11 (11) 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) DuPont-5386 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESION INCIDENCE (NUMERIC) LESIONS TREATMENT 0 25 100 250 (mg/kg/day) II IV VI VIII LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED DEPLETION, LYMPHOID, mild moderate total observations per lesion (10) 10 (1) 1 1 THYMUS NO ABNORMALITY DETECTED ATROPHY. moderate severe total observations per lesion (10) 10 (1) 1 1 MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED (10) 10 (1) 1 MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED (9) (1) 91 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) 8 2 2 (11) 9 2 2 (11) 11 (9) 9 294 Company Sanitized. Does not contain TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) DuPont-5386 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS BONE MARROW NO ABNORMALITY DETECTED HYPERPLASIA, GRANULOCYTIC, severe total observations per lesion ATROPHY. mild total observations per lesion | LESION INCIDENCE (NUMERIC) TREATMENT 0 25 100 250 (mg/kg/day) II IV VI VIII (10) 10 (1) (11) 10 1 1 1 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 295 Company SanHked. Does no* contain TSCA CBf H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) DuPont-5386 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS ENDOCRINE SYSTEM PITUITARY GLAND NO ABNORMALITY DETECTED THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. minimal total observations per lesion ALTERATION, COLLOID. minimal mild moderate total observations per lesion PARATHYROID GLANDS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) 1 1 1 1H 1O M 1 LESION INCIDENCE (NUMERIC) 25 100 250 IV VIII V I. (10) 10 (10) 10 (6) 6 (10) 10 (1) 1 (10) 4 (10) 6 63 1 64 (1) 1 (1) 1 (11) 11 (11) 3 6 6 5 2 7 (7) 7 du 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 296 Company Sanitized. Does not contain TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) DuPont-5386 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS NERVOUS SYSTEM BRAIN NO ABNORMALITY DETECTED SPINAL CORD NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED | LESION INCIDENCE (NUMERIC) t O1 1 t 1 1 TREATMENT (mg/kg/day) 25 100 250 IV VI VIII 1 H H (10) 10 (10) 10 (10) 10 (1) 1 (1) 1 (1) 1 (11) 11 (11) 11 (11) 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 297 Comoany SanWyed. D oes not confato TSCA CB H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) DuPont-5386 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS I LESION INCIDENCE (NUMERIC) TREATMENT 0 25 100 250 (mg/kg/day) II IV VI VIII MUSCULAR AND SKELETAL SYSTEM SKELETAL MUSCLE NO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED MANDIBLE NO ABNORMALITY DETECTED DEGENERATION, AMELOBLASTS. minimal mild total observations per lesion (10) 10 (10) 10 (10) 10 (10) 10 (1) (ID 1 11 (1) (11) 1 11 (1) (11) 1 11 (9) (10) 9 10 (8) 1 3 4 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 298 Company SanWzed. Does not contain TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) DuPont-5386 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS | LESION INCIDENCE (NUMERIC) TREATMENT 0 25 100 250 (mg/kg/day) II IV VI VIII REPRODUCTIVE SYSTEM OVARIES NO ABNORMALITY DETECTED UTERUS NO ABNORMALITY DETECTED DILATATION, LUMEN, minimal mild total observations per lesion MAMMARY GLAND (FEMALE) NO ABNORMALITY DETECTED (10) 10 (10) 10 (1) 1 (1) 1 (10) 10 (1) 1 (11) 11 (11) 8 2 1 3 (11) 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 299 R w w f ftae * Mnfennhjln T S fij ftm H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) DuPont-5386 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS CUTANEOUS SYSTEM SKIN NO ABNORMALITY DETECTED TREATMENT (mg/kg/day) LESION INCIDENCE (NUMERIC) 0 25 100 250 II IV VI VIII (10) 10 (1) 1 (11) 11- Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 300 Company Sanitized. Does not contain TSCACB! H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) DuPont-5386 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION INCLUDING EARLY DEATHS FROM THE REPRODUCTION EVALUATION) LESIONS SPECIAL SENSES SYSTEM E Y E (S) WITH OPTIC NERVE NO ABNORMALITY DETECTED OPTIC NERVE NOT PRESENT. AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED, mild total observations per lesion | LESION INCIDENCE (NUMERIC) TREATMENT 0 25 100 250 (mg/kg/day) II IV V I . VIII (10) 10 2 (1) 1 (11) 11 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 301 Company Sanitized. Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) DuPont-5386 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS 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 PANCREAS NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED LESION INCIDE Female TREATMENT (mg/kg/day) 0 II 250 VIII (1 0 ) 1 1 1 8 8 1 1 (1 ) 1 (1 ) 1 (1 ) 1 (1 0 ) 1 1 1 9 9 1 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 302 Company Sanitized. Does not contain TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) DuPont-5386 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS LESION INCIDE Female TREATMENT (mg/kg/day) 0 II 250 VIII 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 (1) 1 (1) 1 (1) X (1) 1 (1) 1 {1) 1 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) 1 303 Company Sanitized. Does not contain TSCA CBi H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDE LESIONS TREATMENT (mg/kg/day) Female 0 250 II VIII URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. minimal total observations per lesion NECROSIS, TUBULAR. mild total observations per lesion MINERALIZATION. mild total observations per lesion INFLAMMATION, ACUTE. mild total observations per lesion HYPERPLASIA, TRANSITIONAL CELL. moderate total observations per lesion HYDRONEPHROSIS, BILATERAL. minimal total observations per lesion Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 3 5 5 1 1 1 1 1 1 1 1 1 1 (10) 4 6 6 304 Company Sanitized. Does not contain TSCA CB H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDE Female LESIONS TREATMENT (mg/kg/day) 0 II 250 VIII URINARY SYSTEM KIDNEY CYST. minimal total observations per lesion URINARY BLADDER INFLAMMATION, SUBACUTE/CHRONIC. mild total observations per lesion HYPERPLASIA, SIMPLE,' TRANSITIONAL CELL. moderate total observations per lesion HEMORRHAGE. mild total observations per lesion 1 1 (1) 1 X 1 1 1 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 305 Company Sanitized. Does not contain TSCA CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) DuPont-5386 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS LESION INCIDE Female TREATMENT (mg/kg/day) 0 II 250 VIII RESPIRATORY SYSTEM LUNGS NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED SQUAMOUS HYPERPLASIA, NASOLACRIMAL DUCT. mild total observations per lesion INFLAMMATION, SUBACUTE/CHRONIC, NASOLACRIMAL DUCT. mild total observations per lesion DEGENERATION, AMELOBLASTS. minimal mild total observations per lesion Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (1) 1 (1) 1 (1) 1 (10) 9 1 1 (10) 3 1 1 3 4 7 306 Company Sanitized. Does not contain TSCA CBf H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDE Female LESIONS TREATMENT (mg/kg/day) 0 II 250 VIII CARDIOVASCULAR SYSTEM HEART NO ABNORMALITY DETECTED AORTA NO ABNORMALITY DETECTED (1) 1 (1) 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 307 Company Sanitized. Does not contain TSCA CBf H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_________________ TABLE 43 (CONTINUED) m DuPont-5386 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS LESION INCIDE Female TREATMENT (mg/kg/day) 0 II 250 VIII LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED THYMUS ATROPHY. mild total observations per lesion MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED BONE MARROW HYPERPLASIA, GRANULOCYTIC. mild total observations per lesion (1) 1 (1) 1 1 (1) 1 (1) 1 (1) 1 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 308 Company Sanitized. Does not contain TSCA CBH H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 43 (CONTINUED) DuPont-5386 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS ENDOCRINE SYSTEM PITUITARY GLAND NO ABNORMALITY DETECTED HYPERPLASIA, DIFFUSE. mild total observations per lesion THYROID GLAND NO ABNORMALITY DETECTED ALTERATION, COLLOID. minimal moderate total observations per lesion PARATHYROID GLANDS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED LESION INCIDE Female TREATMENT (mg/kg/day) 250 VIII 1 1H O 1H 1 1 (2) 1 1 1 (10) 5 5 5 (1) 1 (1) 1 (10) 1 8 1 9 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 309 Company Sanitized. Does not contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDE Female LESIONS TREATMENT (mg/kg/day) 0 II 250 VIII ' NERVOUS SYSTEM BRAIN NO ABNORMALITY DETECTED SPINAL CORD NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED (1) 1 (1) 1 (1) 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 310 Company Sanitized. D ow not contain TSC CBI H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDE Female LESIONS TREATMENT (mg/kg/day) 0. II 250 Vili MUSCULAR AND SKELETAL SYSTEM SKELETAL MUSCLE NO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED MANDIBLE NO ABNORMALITY DETECTED (1) 1 (1) 1 (1) 1 (10) 10 (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 311 Sawed. Does not contain TSCA CB H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDE Female LESIONS TREATMENT (mg/kg/day) 0 II 250 VIII REPRODUCTIVE SYSTEM OVARIES NO ABNORMALITY DETECTED UTERUS NO ABNORMALITY DETECTED MAMMARY GLAND (FEMALE) NO ABNORMALITY DETECTED (1) 1 (1) 1 (1) 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 312 Company Sanitized. Does not contain TSCA CBf H -24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDE Female LESIONS TREATMENT (mg/kg/day) 0 II 250 VIII CUTANEOUS SYSTEM SKIN NO ABNORMALITY DETECTED (1) 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCA CBl H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDE Female LESIONS TREATMENT (mg/kg/day) 0 II 250 VIII SPECIAL SENSES SYSTEM E Y E (S ) WITH OPTIC NERVE NO ABNORMALITY DETECTED (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 314 Does nolGontafn TSCA CBi H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESIOII INCIDI3NCE (NIIMERIC) LESIONS TREATMENT 0 25 100 250 (mg/kg/day) II IV VI Vili RESPIRATORY SYSTEM NOSE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. minimal mild total observations per lesion HYPERPLASIA/SQUAMOUS METAPLASIA, TRANSITIONAL CELL. minimal mild total observations per lesion DEGENERATION, AMELOBLASTS. minimal total observations per lesion (5) (5) (5) 2 31 2 21 11 3 22 1 3 ii 3 23 2 2 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 315 Company SanfHzed. Does noi contain TSCA CBI H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABLE 43 (CONTINUED) INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) | LESION INCIDENCE (NUMERIC) LESIONS TREATMENT 0 25 100 250 (mg/kg/day) II IV v i VIII ENDOCRINE SYSTEM THYROID GLAND NO ABNORMALITY DETECTED ALTERATION, COLLOID. minimal mild moderate total observations per lesion (5) (4) (5) (5) X 433 11 11 544 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 316 Company Sanitized. Does not contain TSCA CBf