Document d6GyprzkjB2Z529y00MOarB5

firK&k) -- 468 DuPont-11418 ftM U b -} * * 6 TRADE SECRET Study Title H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations Volume 1 of 5 Laboratory Project ID: DuPont-11418 Test Guidelines: U.S. EPA Health Effects Test Guidelines OPPTS 870.3100 (AUG-1998) AUTHOR: Susan A. MacKenzie, V.M.D., Ph D., D.A.B.T. Study Completed on: August 1,2003 PERFORMING Laboratory: E.I. du Pont de Nemours and Company Haskell Laboratory for Health and Environmental Sciences Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050 W ork Request Number: Service Code Number: Page 1 of 1602 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT This study was conducted in compliance with U.S. EPA TSCA (40 CFR part 792) Good Laboratory Practice Standards, which are consistent with the OECD Principles of Good Laboratory Practice (as revised in 1997) published in ENV/MC/CHEM(98)17 and MAFF Japan Good Laboratory Practice Standards (59 NohSan Number 3850) except for the item documented below. The item listed does not impact the validity of the study. Test substance characterization and stability analyses were performed at Regional Analytical Services (RAS), a non-GLP laboratory. The test substance analyses performed were in compliance with regulatory guidelines. None of the aforementioned analyses were performed under Good Laboratory Practice Standards; however, the analyses were conducted in compliance with IS09002 regulations. All of the analyses are considered valid and sufficient for the purposes of this study. Applicant / Sponsor: E.I. du Pont de Nemours and Company Wilmington, Delaware 19898 U.S.A. Study Director: o_ Susan A. MacKenzie, V.M.D., Ph.D,, D.A.B.T. Senior Research Toxicologist PL - 0 G - - l.# 3 Date Applicant / Sponsor:____________ _____________________________ ___ DuPont Representative Date -2 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations QUALITY ASSURANCE STATEMENT DuPont-11418 Haskell Sample Number(s): 25425 Dates of Inspections: Protocol: June 28,2002; July 2, 2002 Conduct: August 6,29,2002; September 10,20,2002; October 7,21,30, 2002; November 14,21,22,29, 2002 Records, Reports: February 27-28, 2003; March 2-5,11-14,17, 2003; April 7-8,1011,14-15; 2003; May 6-9,12-16,19-20,2003; July 14-17, 2003 Dates Findings Reported to: Study Director: July 2, 2002; September 23, 2002; October 8,21,31, 2002; November 22, 2002; March 3,6,28, 2003; April 11,15, 2003; May 20, 2003; July 17, 2003 Management: September 23, 2002; October 18,21,31, 2003; December 3, 2003; March 6,14,27, 2003; April 30, 2003; July 18, 2003 Reported by: Matthew Frentzel Quality Assurance Auditor 0l~ A U C - 2 Date -3Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 CERTIFICATION We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study. Analytical Evaluation by: Neurobehavioral and Reproductive Evaluations Reported by: Janet C. Maslanka, B.S. Analytical Chemist Linda A. Malley, Ph.D^, D.A.B.T. Senior Research Toxicologist Clinical Pathology Evaluation by: 'fancy E. Everds, D.V.M. Diplomate A.C.V.P. Principal Research Clinical Pathologist and Manager Anatomic Pathology Evaluation by: Diplomate A.C.V.P., A.C.L.A.M., A.B.T. Veterinary Pathologist Anatomic Pathology Evaluation Peer Review by: Peter Mann, D.V.M. Diplomate A.C.V.P. Veterinary Pathologist Date Date Date o l- &)- Date Mechanistic Evaluation by: X. John C. O'Connor, M.S. Biochemical Toxicologist . 3 I - Tt.y - 2jX>> Date Approved by: Scott E. Loveless, Ph.D. Management 31 - Date Issued by Study Director: Susan A. MacKenzie, V.M.D., rn.D., D.A.B.T. Senior Research Toxicologist /W -.4i/- 1&0 Date -4 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 TABLE OF CONTENTS Page GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT.....................................2 QUALITY ASSURANCE STATEMENT........................................................................................3 CERTIFICATION................................................................................. 4 LIST OF TABLES................................................................. 9 LIST OF FIGURES....................... 12 LIST OF APPENDICES.................................................................................................................. 12 STUDY INFORMATION................................................................ 14 STUDY PERSONNEL........................................................................... 15 S U M M A R Y ............................................................................................. 16 INTRODUCTION.................................................................................. 19 OBJECTIVE....................................................................................................................................... 19 STUDY DESIGN................................................................................................................................. 19 MATERIALS AND METHODS................................................................................................. ....20 A. Test Guidelines.........................................................................................................................20 B. Test Substance............................................................ .....20 C. Test Species............................................................................................................................. 21 D. Animal Husbandry......................................................... 21 1. Housing.............................................................................................................................. 21 2. Feed and W ater..................................................................................................................21 3. Identification......................................................................................................................22 4. Animal Health and Environmental Monitoring Program .............................................. 22 E. Quarantine and Pretest Period.................................................................................................22 F. Assignment to Groups and Study Start.................................................................................. 23 1. Rats Designated for the Subchronic Toxicity, One-Month Recovery, Total Fluorine Level Analysis, and Reproductive Evaluations..............................................................23 2. Rats Designated for 10-Day Biochemical Analysis....................................................... 23 G. Dosing Suspension Preparation............................................................................................. 23 H. Test Substance Administration..................................................... 23 I. Test Substance Sampling...... ................................................................................................. 24 J. Analytical M ethods................................................................................................................. 24 1. Recovery Sample Analysis.............................................................................................. 24 2. Dosing Suspension Treatment......................................................................................... 25 3. Chromatographic Conditions........................................................................................... 25 4. Calibration and Quantitation............................................................................................ 25 K. Body Weights............................................................................ 26 -5 Company Sanitized. Does not contain TSCA C8I H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations _______________ DuPont-11418 L. Food Consumption and Food Efficiency............................................................................... 26 M. Detailed Clinical Observations and M ortality...................................................................... 26 N. Ophthalmology Evaluation..................................................................................................... 27 O. Neurobehavioral Evaluations..................................................................................................27 1. Sensory Motor Function Evaluation................................................................................27 2. Motor Activity Evaluation..... ..........................................................................................27 P. Clinical Pathology Evaluation.................................................,............................................. 28 1. Hematology and Coagulation........................................................................................... 28 2. Clinical Chemistry................................................................ 29 3. Urinalysis........................................................................................................................... 29 Q. Total Fluorine and Perfluorooctanoic Acid Level Evaluations................................................... 30 1. Total Fluorine Evaluations............................................................................................... 30 2. Perfluorooctanoic Acid Level Evaluations........................................................... 30 R. Biochemical Measurements............................................................................ S. Anatomic Pathology Evaluation for Rats Designated for Subchronic Toxicity and Recovery Evaluations..............................................................................................................31 T. Reproductive Evaluations....................................................................................................... 33 1. Observations and Mortality for Parental R ats................................................................. 33 2. Body Weights for Parental Rats....................................................................................... 33 3. Food Consumption and Food Efficiency for Parental R a ts........................................... 33 4. Estrous Cycle Evaluation................................................. 34 5. Breeding.... .........................................................................................................................34 6. Gestation Procedures........................................................................................................ 34 7. Lactation Procedures................................................... r.................................................... 34 8. Fi Generation Post W eaning.............................................................................................35 9. Fi Generation Developmental Landmarks.......................................................................35 10. Sperm Number, Morphology, and M otility.................................................................... 36 U. Anatomic Pathology Evaluation for Rats Designated for Reproductive Evaluations....... 36 1. Pi Adults..............................................................................................................................36 2. Offspring.............................................................................................................................36 3. Fi W eanlings...................................................................................................................... 37 4. Fj A dults.............................................................................................................................37 V. Statistical Analyses.................................................................................................................. 38 RECORDS AND SAMPLE STORAGE........................................................................................ 41 RESULTS AND DISCUSSION........................................................... 42 Analytical Evaluation............................................................................ 42 A. Test Substance Stability A nalyses......................................................................................... 42 B. Chromatography....................................................................................................................... 42 C. Recovery Samples....................................................................................................................42 D. Homogeneity and Stability Samples....................................... 42 E. Concentration Verification Samples...................................................................................... 43 F. Analytical Conclusion........................ 44 ...30 -6Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 In-Life Toxicology.............................................................................................................................. 44 A. Dosage D ata............................................................................................................................. 44 B. Mean Body Weights and Body Weight Gains ..................................................................... 45 C. Food Consumption and Food Efficiency...............................................................................45 D. Clinical Observations and Mortality...................................................................................... 46 E. Ophthalmology Evaluations....................................................................................................47 F. In-Life Toxicology Conclusions.................................... 47 Neurobehavioral Evaluation......................................... .................................................................. 47 A. Forelimb Grip Strength......................................................................................................... ..47 B. Hindlimb Grip Strength....................................................... 47 C. Sensory Motor Function Observations.................................................................................. 47 D. Motor Activity.......................................................................................................................... 48 E. Neurobehavioral Conclusions.................................................................................................48 Clinical Pathology Evaluation............................................................ ............................................ 48 A. Hematology.............................................................................................................................. 48 B. Coagulation.............................................................................................................................. 49 C. Clinical Chemistry...................................................................................................................50 D. Urinalysis..................................................................................................................................52 E. Urine and Plasma Fluoride...................................................................................................... 52 F. Clinical Pathology Conclusions..............................................................................................52 Biochemical Evaluation.................................................................................................................... 53 A. Biochemical Evaluation.......................................................................................................... 53 B. Biochemical Evaluation Conclusions.................................................................................... 53 Anatomic Pathology Evaluation - Rats Designated for Subchronic Toxicity and Recovery Evaluations......................................................................................................................................... 54 A. Mortality...................................................................................................................................54 B. Organ Weight D ata..................................................................................................................54 C. Gross Observations..................................................................................................................55 D. Microscopic Observations..................................................................................................... 55 E. Anatomic Pathology Conclusions for the Subchronic Toxicity and Recovery Evaluations................................................... ;.......................................................................... 57 Reproductive Toxicity Evaluations................................................................................................ 57 A. Pi Rats - Clinical Observations and Mortality......................................................................57 1. P, M ales................................................................ 57 2. Pi Females During Gestation........................................................................................... 57 3. Pi Females During Lactation........................................................................................... 57 B. Pi Rats - Mean Body Weights and Body Weight G ains...................................................... 58 1. Pi M ales..............................................................................................................................58 2. Pi Females During Gestation........................................................................................... 58 3. Pi Females During Lactation.............................................................. 58 -7 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 C. Pi Rats - Food Consumption and Food Efficiency...............................................................58 Pi Females During Gestation.................................................................................................. 58 D. Reproductive Indices....................................................... 58 E. Sperm Count, Morphology, and Motility.............................................................................. 59 F. Estrous C ycle........................................................................................................................... 59 G. Fi Offspring D ata..................................................................................................................... 59 1. Litter Size, Sex Ratio and Pup Survival.......................................................................... 59 2. Clinical Observations in Fi Pups....................................... ............................................. 59 3. Pup W eights....................................................................................................................... 59 H. Fi Rats - Clinical Observations and Mortality...................................................................... 59 I. Fi Rats - Mean Body Weights and Body Weight G ains.......................................................60 J. Fi Rats - Food Consumption and Food Efficiency............................................................... 60 K. Fi Rats - Developmental Landmarks..................................................................................... 60 L. Reproductive Toxicity Conclusions....................................................................................... 60 Anatomic Pathology Evaluation - Rats Designated for Reproductive Evaluations............. 60 A. Organ Weight D ata..................................................................................................................60 B. Gross Observations..................................................................................................................61 C. Microscopic Observations...................................................................................................... 61 1. Parental Pi A dults................. 61 2. Fi A dults......................................... 61 D. Mortality....................................................................................................................................61 E. Anatomical Pathology Conclusions for Reproductive Toxicity............................... 61 CONCLUSIONS.................................................................................................................................62 R E FE R EN C E S.................................................................................................................................... 63 TABLES............................................................................................................................................... 65 FIGURES.......................................................................................................................... 472 APPENDICES...................................................................................................................................484 -8Company Sanitized. Does not contain TSCA C8I /"-N ^ H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 LIST OF TABLES Page TABLE 1 SUMMARY OF DOSING SUSPENSION ANALYSIS.............................................................................. 70 TABLE 2 MEAN DAILY DOSE VOLUMES FOR MALE RATS............................................................................. 71 TABLE 3 MEAN DAILY DOSE VOLUMES FOR FEMALE RATS.......................................................................... 73 TABLE 4 MEAN BODY WEIGHTS OF MALE RATS (G).........................................................................................75 TABLE 5 MEAN BODY WEIGHTS OF FEMALE RATS (G ).................................................................................. 78 TABLE 6 MEAN BODY WEIGHT GAINS OF MALE RATS (G)............................................................................. 81 TABLE 7 MEAN BODY WEIGHT GAINS OF FEMALE RATS (G )........................................................................85 TABLE 8 MEAN DAILY FOOD CONSUMPTION BY MALE (G/DAY)................................................................89 TABLE 9 MEAN DAILY FOOD CONSUMPTION BY FEMALE (G/DAY)............................................................92 TABLE 10 MEAN DAILY FOOD EFFICIENCY OF M ALE......................................................................................95 TABLE 11 MEAN DAILY FOOD EFFICIENCY OF FEM ALE................................................................................ 98 TABLE 12 SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS..................................................... 101 TABLE 13 SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS................................................ 104 TABLE 14 SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR MALE RATS............................ 106 TABLE 15 SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR FEMALE RATS....................... 107 TABLE 16 PERCENT SURVIVAL OF MALE RATS................................................................................................. 108 TABLE 17 PERCENT SURVIVAL OF FEMALE RATS............................................................................................109 TABLE 18 MEAN FORELIMB AND HINDLIMB GRIP STRENGTH FOR MALE RATS (MEAN OF THREE TRIALS).......................................................................................................................................................................... 110 TABLE 19 MEAN FORELIMB AND HINDLIMB GRIP STRENGTH FOR FEMALE RATS (MEAN OF THREE TRIALS)............................................................................................................................................................I l l TABLE 20 SUMMARY OF SENSORY MOTOR FUNCTION PARAMETERS FOR MALE RATS.....................112 TABLE 21 SUMMARY OF SENSORY MOTOR FUNCTION PARAMETERS FOR FEMALE RATS............... 113 TABLE 22 MOTOR ACTIVITY ASSESSMENT: MEAN DURATION OF MOVEMENT FOR MALE RATS (SEC).................................................................................................................................................................... 114 TABLE 23 MOTOR ACTIVITY ASSESSMENT: MEAN DURATION OF MOVEMENT FOR FEMALE RATS (SEC).................................................................................................................................................................... 115 TABLE 24 MOTOR ACTIVITY ASSESSMENT: MEAN NUMBER OF MOVEMENTS FOR MALE RATS.... 116 TABLE 25 MOTOR ACTIVITY ASSESSMENT: MEAN NUMBER OF MOVEMENTS FOR FEMALE RATS......................................... 117 TABLE 26 SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS.......................................................... 118 TABLE 27 SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS...................................................... 122 TABLE 28 SUMMARY OF COAGULATION VALUES FOR MALE RATS...... ...................................................126 TABLE 29 SUMMARY OF COAGULATION VALUES FOR FEMALE RATS..................................................... 127 TABLE 30 SUMMARY OF CLINICAL CHEMISTRY VALUES FOR MALE R A TS............................................128 TABLE 31 SUMMARY OF CLINICAL CHEMISTRY VALUES FOR FEMALE RATS....................................... 132 TABLE 32 SUMMARY OF URINALYSIS VALUES FOR MALE RATS................................................................136 -9Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 TABLE 33 SUMMARY OF URINALYSIS VALUES FOR FEMALE RA TS.........................................................138 TABLE 34 SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITY IN MALE RATS..................... 140 TABLE 35 SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITY IN FEMALE RATS................ 141 TABLE 36 MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION..............................................................................................................142 TABLE 37 MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS DESIGNATED FOR RECOVERY EVALUATION...................................................................................................................... ................ 145 TABLE 38 MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION............................................................................................................... 148 TABLE 39 MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS DESIGNATED FOR RECOVERY EVALUATION............................................. 151 TABLE 40 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION...........................................................................................................................................154 TABLE 41 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS DESIGNATED FOR RECOVERY EVALUATION............................................................................................................................................................... 161 TABLE 42 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION..................................... 168 TABLE 43 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS DESIGNATED FOR RECOVERY EVALUATION...................................................................................... 175 TABLE 44 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NONNEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION............................... 182 TABLE 45 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NONNEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION........................................................222 TABLE 46 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION................... .261 TABLE 47 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION..............................................301 VOLUME 2 .................................................................................................................................................................304 TABLE 48 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION....................305 TABLE 49 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION............................................. 345 TABLE 50 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION.................... 384 TABLE 51 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION............. .............................:.424 TABLE 52 SUMMARY OF CLINICAL OBSERVATIONS IN Pi MALE RATS............................ v..................... 427 TABLE 53 SUMMARY OF CLINICAL OBSERVATIONS IN P, FEMALE RATS DURING GESTATION..... 428 TABLE 54 SUMMARY OF CLINICAL OBSERVATIONS IN P, FEMALE RATS DURING LACTATION..... 429 TABLE 55 MEAN BODY WEIGHTS (GRAMS) OF Pi*MALE RATS...................................................................430 TABLE 56 MEAN BODY WEIGHT GAINS (GRAMS) OF P, MALE RATS ................................................ 431 TABLE 57 MEAN BODY WEIGHTS (GRAMS) OFP! FEMALE RATS DURING GESTATION......................432 TABLE 58 MEAN BODY WEIGHT GAINS (GRAMS) OF P, FEMALE RATS DURING GESTATION.......... 433 TABLE 59 MEAN BODY WEIGHTS (GRAMS) OF Pi FEMALE RATS DURING LACTATION..................... 434 - 10Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with Qne-Generation Reproduction Evaluations___________________ DuPont-11418 TABLE 60 MEAN BODY WEIGHT GAINS (GRAMS) OF P, FEMALE RATS DURING LACTATION..........435 TABLE 61 MEAN DAILY FOOD CONSUMPTION (GRAMS) OF P, FEMALE RATS DURING GESTATION................................................................................................................................................................... 436 TABLE 62 MEAN FOOD EFFICIENCY (GRAMS WEIGHT GAIN/GRAMS FOOD CONSUMED) OF Pj FEMALE RATS DURING GESTATION..................................................................................................................... 437 TABLE 63 SUMMARY OF REPRODUCTIVE INDICES: Pi GENERATION....................................................... 438 TABLE 64 SUMMARY OF SPERM PARAMETERS IN Pi MALE RATS..............................................................439 TABLE 65 MEAN ESTROUS CYCLE PARAMETERS AND PRECOITAL INTERVAL IN P, FEMALE RATS..............................................................................................................................................................440 TABLE 66 MEAN PUP NUMBERS AND SURVIVAL: F, GENERATION.......................................................... .441 TABLE 67 SUMMARY OF PUP CLINICAL OBSERVATIONS: F, GENERATION........................................... 442 TABLE 68 MEAN PUP WEIGHTS: Fj GENERATION........................................................................................... 443 TABLE 69 SUMMARY OF CLINICAL OBSERVATIONS IN F, MALE RATS.....................................................444 TABLE 70 SUMMARY OF CLINICAL OBSERVATIONS IN F, FEMALE RATS................................................445 TABLE 71 MEAN BODY WEIGHTS (GRAMS) OF F, MALE RATS.................................................................... 446 TABLE 72 MEAN BODY WEIGHTS GAINS (GRAMS) OF F, MALE RATS.......................................................447 TABLE 73 MEAN BODY WEIGHTS (GRAMS) OF F t FEMALE RATS...............................................................448 TABLE 74 MEAN BODY WEIGHTS GAINS (GRAMS) OF F, FEMALE RATS.................................................. 449 TABLE 75 MEAN DAILY FOOD CONSUMPTION (GRAMS) OF F, MALE RATS........................................... 450 TABLE 76 MEAN DAILY FOOD EFFICIENCY (GRAMS WEIGHT GAIN/GRAMS FOOD CONSUMED) OF Fi MALE RATS..............................................................................................................................................................451 TABLE 77 MEAN DAILY FOOD CONSUMPTION (GRAMS) OF F, FEMALE RATS...................................... 452 TABLE 78 MEAN FOOD EFFICIENCY (GRAMS WEIGHT GAIN/GRAMS FOOD CONSUMED) OF Fi FEMALE RATS................................................................................................,............................................................ 453 TABLE 79 SUMMARY OF DEVELOPMENTAL LANDMARKS IN Fj RATS......................................................454 TABLE 80 MEAN FINAL BODY AND ORGAN WEIGHTS FROM MALE RATS - Fj ADULT.........................455 TABLE 81 MEAN FINAL BODY AND ORGAN WEIGHTS FROM FEMALE RATS - F, ADULT................... 458 TABLE 82 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS - Pi ADULTS...................................461 TABLE 83 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS - P, ADULTS...............................462 TABLE 84 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS - F, ADULTS................................... 463 TABLE 85 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS - Fj ADULTS...............................464 TABLE 86 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS Pi ADULTS.....................................................................................................................................................................465 TABLE 87 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS PI ADULTS....................................................................................................................................................................466 TABLE 88 INCIDENCES OF GROSS OBSERVATIONS IN GENERATION F, MALE WEANLINGS............. 467 TABLE 89 INCIDENCES OF GROSS OBSERVATIONS IN GENERATION Fj FEMALE WEANLINGS.........468 TABLE 90 INCIDENCES OF GROSS OBSERVATIONS IN GENERATION F, MALE PUPS............................469 TABLE 91 INCIDENCES OF GROSS OBSERVATIONS IN GENERATION Fj FEMALE PU PS...................... 470 TABLE 92 INCIDENCES OF GROSS OBSERVATIONS IN GENERATION F, UNSEXABLE PUPS............... 471 -11 - Company Sanitized. Does not contain TSCA C8I H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 LIST OF FIGURES Page FIGURE 1 MEAN BODY WEIGHTS OF MALE RATS............................................................................................474 FIGURE 2 MEAN BODY WEIGHTS OF FEMALE RATS.......................................................................................475 FIGURE 3 MEAN FORELIMB GRIP STRENGTH FOR MALE RATS...................................................................476 FIGURE 4 MEAN FORELIMB GRIP STRENGTH FOR FEMALE RATS..............................................................477 FIGURE 5 MEAN HINDLIMB GRIP STRENGTH FOR MALE RATS................................................................... 478 FIGURE 6 MEAN HINDLIMB GRIP STRENGTH FOR FEMALE RATS..............................................................479 FIGURE 7 MOTOR ACTIVITY ASSESSMENT: MEAN TOTAL DURATION OF MOVEMENT FOR MALE RATS............................................................................................................................................................................... 480 FIGURE 8 MOTOR ACTIVITY ASSESSMENT: MEAN TOTAL DURATION OF MOVEMENT FOR FEMALE RATS............................................................................................................................................................. 481 FIGURE 9 MOTOR ACTIVITY ASSESSMENT: MEAN TOTAL NUMBER OF MOVEMENTS FOR MALE RATS............................................................................................................................................................................... 482 FIGURE 10 MOTOR ACTIVITY ASSESSMENT: MEAN TOTAL NUMBER OF MOVEMENTS FOR FEMALE RATS............................................................................................................................................................. 483 ^ LIST OF APPENDICES Page APPENDIX A ANALYTICAL DATA......................................................................................................................... 486 APPENDIX B INDIVIDUAL DOSE VOLUMES....................................................................................................... 493 APPENDIX C INDIVIDUAL BODY WEIGHTS....................................................................................................... 591 VOLUME 3 ....................................................................................................................................................................629 APPENDIX D INDIVIDUAL FOOD CONSUMPTION.............................................................................................630 APPENDIX E INDIVIDUAL CLINICAL OBSERVATIONS AND MORTALITY RECORDS............................ 656 APPENDIX F INDIVIDUAL OPHTHALMOLOGY OBSERVATIONS..................................................................717 APPENDIX G INDIVIDUAL FORELIMB AND HINDLIMB GRIP STRENGTH................................................. 727 APPENDIX H INDIVIDUAL SENSORY MOTOR FUNCTION OBSERVATIONS.............................................. 738 APPENDIX I INDIVIDUAL MOTOR ACTIVITY: DURATION OF MOVEMENT............................................. 760 APPENDIX J INDIVIDUAL MOTOR ACTIVITY: NUMBER OF MOVEMENTS.............................................. 767 APPENDIX K INDIVIDUAL ANIMAL CLINICAL PATHOLOGY DATA............................................................774 APPENDIX L INDIVIDUAL ANIMAL BIOCHEMICAL DATA.................... 880 APPENDIX M INDIVIDUAL ANIMAL BODY AND ORGAN WEIGHTS............................................................887 , - 12Company Sanitized. Does not contain TSCA C8I H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 VOLUME 4 ....................................................................................................................................................................908 APPENDIX N INDIVIDUAL ANIMAL GROSS AND MICROSCOPIC OBSERVATIONS................................. 909 APPENDIX O INDIVIDUAL ANIMAL MICROSCOPIC OBSERVATIONS LISTING INDIVIDUAL ANIMALS AFFECTED............................................................................................................................................................ 1053 APPENDIX P INDIVIDUAL CLINICAL OBSERVATIONS AND MORTALITY DATA IN Pj MALE RATS..........................................................................................................................................................1178 APPENDIX Q INDIVIDUAL CLINICAL OBSERVATIONS AND MORTALITY DATA IN P, FEMALE RATS DURING GESTATION........................................................................................................................................1188 APPENDIX R INDIVIDUAL CLINICAL OBSERVATIONS AND MORTALITY DATA IN P, FEMALE RATS DURING LACTATION........................................................................................................................................1198 APPENDIX S INDIVIDUAL BODY WEIGHTS OF Pi MALE RATS....................................................................1208 APPENDIX T INDIVIDUAL BODY WEIGHT GAINS OF P, MALE RATS........................................................1214 APPENDIX U INDIVIDUAL BODY WEIGHTS OF P, FEMALE RATS DURING GESTATION.................... 1220 APPENDIX V INDIVIDUAL BODY WEIGHT GAINS OF Pi FEMALE RATS DURING GESTATION....... 1226 APPENDIX W INDIVIDUAL BODY WEIGHTS OF Pi FEMALE RATS DURING LACTATION..................1232 APPENDIX X INDIVIDUAL BODY WEIGHT GAINS OF P, FEMALE RATS DURING LACTATION........1238 APPENDIX Y INDIVIDUAL FOOD CONSUMPTION OF P, FEMALE RATS DURING GESTATION......... 1244 APPENDIX Z INDIVIDUAL ANIMAL SPERM MOTILITY DATA IN P, MALE RATS.................................. 1250 APPENDIX AA INDIVIDUAL ANIMAL SPERM MORPHOLOGY DATA IN P, MALE RATS..................... 1252 VOLUME 5 .................................................................................................................................................................. 1255 APPENDIX BB INDIVIDUAL ANIMAL SPERM AND SPERMATID COUNTS IN P, MALE RATS............. 1256 APPENDIX CC INDIVIDUAL ANIMAL ESTROUS CYCLE PARAMETERS IN P, FEMALE RATS.... .........1259 APPENDIX DD INDIVIDUAL ANIMAL ESTROUS CYCLE STAGES IN P, FEMALE RATS......................... 1265 APPENDIX EE INDIVIDUAL MATING DATA AND GESTATION LENGTH: Pi GENERATION.................1271 APPENDIX FF INDIVIDUAL IMPLANTATION SITE DATA AND IMPLANTATION EFFICIENCY: P, GENERATION......................................................................................................................................................1277 APPENDIX GG INDIVIDUAL PUP SURVIVAL: F, GENERATION..................................................................1283 APPENDIX HH INDIVIDUAL LITTER CLINICAL OBSERVATIONS: F, GENERATION.............................1309 APPENDIX II INDIVIDUAL PUP WEIGHTS: F, GENERATION........................................................................1314 APPENDIX JJ INDIVIDUAL CLINICAL OBSERVATIONS, DEVELOPMENTAL LANDMARKS, AND MORTALITY DATA IN F, MALE AND FEMALE RATS...............................................................................1340 APPENDIX KK INDIVIDUAL BODY WEIGHTS OF Fi MALE AND FEMALE RATS.................................... 1358 APPENDIX LL INDIVIDUAL BODY WEIGHT GAINS OF Fj MALE AND FEMALE RATS..........................1368 APPENDIX MM INDIVIDUAL FOOD CONSUMPTION OF Fj MALE AND FEMALE RATS........................ 1378 APPENDIX NN INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS - F, ADULTS.................1387 APPENDIX OO INDIVIDUAL ANIMAL PATHOLOGY DATA - P, ADULTS.................................................1413 APPENDIX PP INDIVIDUAL ANIMAL GROSS OBSERVATIONS - FI ADULTS..........................................1575 APPENDIX QQ INDIVIDUAL GROSS OBSERVATIONS IN GENERATION FI PUPS AND WEANLINGS.........................................................................................................................................................1585 -13 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations STUDY INFORMATION Svnonvms/Codes: Haskell Number: 25425 DuPont-11418 Physical Characteristics: Amber-yellow-brown solid Stability: The test substance appeared to be stable under the conditions of the study; no evidence of instability was observed. Sponsor: E.I. du Pont de Nemours and Company Wilmington, Delaware 19898 U.S.A. Study Initiated/Completed: October 3, 2002 / (see report cover page) In-Life Initiated/Completed: October 15, 2002 / April 15, 2003 - 14Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 STUDY PERSONNEL Study Director: Susan A. MacKenzie, V.M.D., Ph.D. Management: Scott E. Loveless, Ph.D. Primary Technician: Robert E. Walker, Jr. Analytical Chemist: Janet C. Maslanka, B.S. Management: S. Mark Kennedy, Ph.D. Neurobehavioral and Reproductive Toxicologist: Linda A. Malley, Ph.D. Robert M. Parker, Ph.D. Management: Scott E. Loveless, Ph.D. Clinical Pathologist: Nancy E. Everds, D.V.M. Management: Steven R. Frame, D.V.M., Ph.D. Anatomic Pathologist: Greg P. Sykes, V.M.D. John F. Hansen, D.V.M., Ph.D. Management: Steven R. Frame, D.V.M., Ph.D. Peer Review Anatomic Pathologist: Peter Mann, D.V.M. Biochemical Toxicologist: John C. O'Connor, M.S. Management: Gary W. Jepson, Ph.D. Statistical Analysis: John W. Green, Ph.D., Ph.D. Management: Janice L. Connell, M.S., B.A., C.I.H. Toxicology Report Preparation: Cecilia Rowe Kee, B.S. Brenda Tiffin Management: Nancy S. Selzer, M.S. Ophthalmologist: Nancy M. Bromberg, V.M.D., M.S. 6119 Massachusetts Avenue Bethesda, MD 20816 Laboratory Veterinarian: Thomas W. Mayer, D.V.M., A.C.L.A.M. - 15 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations__________________ DuPont-11418 SUMMARY Four groups of young adult male and female Crl:CD(SD)IGS BR rats were administered H-25425 in 0.5% methylcellulose in deionized water by gavage for approximately 90 days (92 days in males and 93 days in females), at dosages of 0,10,100, or 1000 mg/kg/day. Selected animals from each dosage group were designated for evaluation of subchronic toxicity, recovery from subchronic toxicity, or reproductive toxicity. In the subchronic study, body weights, food consumption, and clinical signs were evaluated weekly. Clinical pathology endpoints were evaluated during weeks 6 and 14 of the dosing period, and near the end of the one-month recovery period. Neurobehavioral assessments were performed prior to dosing, during week 13 of dosing, and near the end of the one-month recovery period. Biochemical evaluations (hepatic (3-oxidation) were performed on rats after 10 days (male and female), during week 14 of the dosing period, and following a one-month recovery period. At the end of the dosing period, 10 rats/sex/dose were sacrificed and given a gross and microscopic pathological examination. One month after the end of the dosing period, 10 rats/sex in the control and high dose groups were examined for recovery of toxic effects. An additional 5 rats/sex/dose were held without dosing for approximately 3 months following the end of the dosing period. These rats had blood collected periodically throughout the dosing and recovery periods and selected tissues collected at the end of recovery for possible analysis of fluorine levels. These tissues have not been analyzed to date. Blood was also collected from subchronic toxicity and recovery rats at the end of the dosing and recovery periods for evaluation of perfluorooctanoic acid levels. These levels will be reported in a separate report. The range of mean daily dose volumes administered to male rats was 1.2-3.0 mL for the control group, and 1.2-2.9 mL for the 10,100, and 1000 mg/kg/day groups. The range of mean daily dose volumes administered to female rats was 0.9-1.6 mL for the control group, and 0.9-1.5 for the 10, 100, and 1000 mg/kg/day groups. Analytical results demonstrated that the test substance was mixed properly, was at the targeted concentrations, and was stable in the vehicle under relevant storage conditions used in this study. In-Life Toxicology Parameters: No test substance-related deaths, clinical signs, or ophthalmologic signs occurred in rats in either the subchronic toxicity or recovery periods of the study. No adverse, test substance-related effects on body weight, body weight gain, food consumption, or food efficiency were observed in any male or female dose group. Neurobehavioral Parameters: No test substance-related effects on forelimb or hindlimb grip strength, sensory motor function, or motor activity were observed in any male or female dose group. Biochemical Toxicology: Exposure to 1000 mg/kg/day of H-25425 for 10 days (females only) or approximately 90 days (males and females) produced mild elevations in hepatic 6-oxidation activity. This elevation was associated with elevated liver weight in males at the 90-day time point. Activity had returned to control levels in females but remained elevated in males after a -16- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 one-month recovery period. These effects were considered test substance-related but not adverse. Clinical Pathology: No adverse effects were observed on hematology, coagulation, clinical chemistry, or urinalysis parameters in any male or female dose group. In male and/or female rats dosed with 1000 mg/kg/day, minimal to mild reductions in red cell mass parameters, bilirubin, triglycerides (all male dose groups), total protein, and albumin were observed but were not considered adverse based on the very slight level of effect. All effects except the minimal red cell mass effects in males were reversed by the end of the one-month recovery period. No effects on plasma fluoride concentration were observed in any male or female dose group. Urine fluoride (total fluoride excreted over the collection period) was increased at the end of the dosing period in males and females dosed with 1000 mg/kg/day and in a few males and females dosed with 100 mg/kg/day. Urine fluoride greatly decreased during the one-month recovery period, but remained slightly above control values in 1000 mg/kg/day males, thus indicating the continued presence of fluorinated material. The increased urine fluoride was considered a marker of exposure to a fluorinated material, and was not considered adverse. Anatomic Pathology (Subchronic Toxicity): Mild increases in absolute and relative liver and kidney weights were observed in male rats dosed with 1000 mg/kg/day at the end of the dosing period. The increased liver weights were associated with minimal hepatocellular hypertrophy and elevated 8-oxidation activity, but no histological correlate to the increased kidney weight was observed. The increased liver weights and histopathology were reversed after a one-month recovery period. These liver and kidney changes were considered to be non-adverse, pharmacological responses to exposure to a xenobiotic. Minimal to mild hypertrophy of thyroid follicular epithelium was present in 1000 mg/kg/day males and females at the end of the dosing period. This effect is indicative of altered thyroid gland homeostasis and, although the follicular cell response observed in this study was within the range of normal physiological response, the effect is potentially adverse. The hypertrophy was still present in both males and females at the end of the one-month recovery period but the incidence and severity were reduced in males and were very low at both time points in females. Therefore, this lesion is considered reversible, even though full reversal had not occurred after one month. Reproduction: Twenty male and 20 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) and during lactation, until the weaning of the Fi offspring. The following parameters were evaluated in Pj rats: body weight, food consumption, clinical signs, gross pathology, sperm parameters, estrous cyclicity, and reproductive performance. Reproductive organs from animals that did not produce litters were evaluated microscopically. The Fj offspring were evaluated during the lactation period for growth and survival and given a gross pathological examination at weaning. A subset of Fi generation rats was retained at weaning, and the following parameters were evaluated for 6 weeks: body weight, food consumption, clinical signs, and age at onset of vaginal opening or - 17Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 preputial separation. After 6 weeks, the Fi generation rats were given a gross pathological examination, and selected reproductive organs and target organs of toxicity were weighed. No systemic toxicity was observed in any dose group in the Pi or Fi generation in the reproduction subset. No test substance-related, adverse effects on any reproductive, sperm, estrus, or pathology endpoint were observed in any dose group in the Pi generation. No effects were observed on litter size, sex ratio, pup survival, or developmental landmark acquisition, nor were any signs of systemic toxicity observed in any dose group in the F] generation. NOEL fo r Subchronic Toxicity: Under the conditions of this study, the no-observed-effect level (NOEL)3for subchronic toxicity endpoints in male and female rats was 100 mg/kg/day. This level was based on reversible, minimal to mild thyroid follicular hypertrophy observed in the 1000 mg/kg/day male and female groups. Other test substance-related effects observed in males and/or females dosed with 1000 mg/kg/day include mild alterations in clinical pathology parameters, increased liver and kidney weights, increased hepatic 8-oxidation activity and minimal hepatocellular hypertrophy; however, these were not considered to be adverse. Most of the effects observed during the dosing period demonstrated full or partial reversal following one month of recovery. Thyroid follicular hypertrophy was still present at the end of the one-month recovery period; however, the incidence and mean severity level in maids had decreased by this time and were very low in females at both time points. NOEL fo r Reproductive Evaluations: Under the conditions of this study, the NOEL for reproductive evaluations was 1000 mg/kg/day, the highest dose tested. This NOEL was based on a lack of test substance-related effects on any reproductive parameter in Pi or Fi generation animals dosed up to 1000 mg/kg/day. The NOEL for this study is defined as the highest dose at which toxicologically important effects attributable to the test substance were not detected. Thus, for this study, the NOEL is equivalent to the NOEL as defined by the United States Environmental Protection Agency (1985) and to the no-observed-adverse-effect level (NOAEL) as defined by the European Union (1994). - 18- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 INTRODUCTION The test substance, H-25425 is as a fabric protector. The dose levels for this study were selected based on the toxicityand an analysis of blood fluorine concentrations from a range-finding study in which rats were dosed by oral gavage with 1,10,100, or 1000 mg/kg/day for approximately 45 days.(1) No compound-related effects on body weight, clinical signs of toxicity, organ weights, or gross pathology lesions were observed in rats in any dose group. Blood fluorine levels appeared to have reached a plateau within 1-2 weeks of dosing with 1000 mg/kg/day, and levels remained very low throughout the entire exposure period. Dose levels of 0,10,100, and 1000 mg/kg/day were selected for this study, based on the results of the rangefinder study. OBJECTIVE The objective of this study was to evaluate the potential subchronic and reproductive toxicity of H-25425 when administered by gavage to male and female rats. A recovery group was included to investigate the reversibility of any observed toxicological effects. The oral route of administration was selected as the most efficient way to deliver an accurate dosage. Blood, urine, feces, and tissues were collected for evaluation of total fluorine and/or perfluorooctanoic acid (PFOA), but have not been evaluated. Data from analysis of these samples will be reported separately. STUDY DESIGN Group Number/Group Male Female Male Female Daily Dosage* (mg/kg) Concentration15(mg/mL) I n 50 50 in IV 40 40 .V VI 40 40 v n v m 50 50 0 (Control) 10 100 1000 0 2 20 200 a Weight of test substance/kg animal bod v w eig h ^ b Suspensions will be adjusted for p u r ity H H j|^ R The first 10 rats/sex/dose were designated for evaluation of subchronic toxicity; the next 5 rats/sex/dose were designated for collection of blood for analysis of fluorine; the next 20 rats/sex/dose were designated for reproductive assessment; the remaining 10 rats/sex/dose (control and high-dose groups only) were designated for one-month recovery assessment. An additional subgroup (5 rats/sex/dose) was received as a separate shipment and was added to each dose group approximately 84 days after study start, for evaluation of hepatic beta-oxidation -19Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 activity following a 10-day exposure. The rats designated for collection of blood for fluorine analysis are also referred to as the three-month recovery subset. Study Parameters________________________ Frequency Body Weight Food Consumption Detailed Clinical Observations Mortality/Moribundity Checks Clinical Pathology Ophthalmoscopic Evaluations Neurobehavioral Evaluations Biochemical Analysis Subchronic Recovery Satellite (day 10) Reproductive Assessments Pi adults Fi weanlings Vaginal Smears (Pi Females) Developmental Landmarks (Fi adults) Necropsy Subchronic Pi adults Weanlings Recovery Fi adults Blood fluorine animals Day 0 and weekly thereafter Weekly Day 0 and weekly thereafter Twice daily Week 6, Week 14, and W eek 19 Pretest and Week 13 Pretest, Week 13, and Week 18 Week 14 Week 17 After 10 days of dosing Week 11-18 Week 13-18 Week 7-9 Week 19-23 Week 14 Week 12-18 Week 17-18 Week 18 Week 23-25 Week 26 MATERIALS AND METHODS A. Test Guidelines The study design complies with the following test guideline: * 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). B. Test Substance The test substance, H-25425, was supplied by th e ^ ponsor as an amber-yellow-brown solid. The sponsor reported purity of the sample w a M p i ^ K t a b i l i t y of the test substance was confirmed by analysis near the beginning and end of the study -20Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations__________________ DuPont-11418 C. Test Species On October 1, 2002,176 male and 176 female Crl:CD(SD)IGS BR rats, with an assigned birth date of August 26,2002 were received from Charles River Laboratories, Inc., Raleigh, North Carolina. An additional 45 rats (23 male and 22 females), with an assigned birth date of November 24, 2002, were received in a separate shipment 84 days after study start on January 7,2003. The additional rats were designated for the 10-day hepatic biochemical analysis. The rat was selected because it is the species recommended in the subchronic toxicity guidelines and is extensively used in reproduction studies. The Crl:CD(SD)IGS BR rat was selected based on consistently acceptable health status and on extensive experience with this strain at Haskell Laboratory. D. Animal Husbandry 1. Housing With the exception of some portions of the reproductive study, all rats were housed one per cage, sexes separate, in stainless steel, wire-mesh cages suspended above cage boards. Animal rooms were maintained on a 12-hour light/dark cycle (fluorescent light) and at a temperature of 22 3C and a relative humidity of 50 20%. Rats designated for reproductive toxicity evaluations were housed as breeding pairs during the cohabitation period. During the gestation period, female rats designated for reproductive toxicity evaluations were housed individually until gestation day 20. Beginning on gestation day 20 for mated females, or at the end of the cohabitation period for females without evidence of copulation, female rats were housed individually in polycarbonate pans with bedding. During the lactation period, adult female rats were housed with their litters in polycarbonate pans. During the entire in-life period for rats evaluated for subchronic toxicity, the 74-day premating period for Pi adults, and the postweaning period for Fi weanlings, cage racks were relocated within the animal room each week and cages were repositioned on the racks every 2 weeks. 2. Feed and Water Tap water was provided ad libitum. All rats were fed PMI Nutrition International, Inc. Certified Rodent LabDiet 5002 ad libitum. One animal in group V (animal number 665150) was inadvertently without food for approximately 24 hours. This fasting was not considered to have impacted the study as the rat lost approximately 3% body weight, but regained this same amount of weight and more by the next weigh day. Furthermore, no clinical signs were noted after the fasting. -21 - Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 3. Identification Each rat was assigned a unique 6-digit Haskell number, the last 3 digits of which were tattooed on the tail of each rat. The information on the cage labels included the unique 6-digit Haskell animal number and the cage identification number assigned to each rat. Fj generation rats retained after lactation were identified by a temporary tail number on postnatal day 21 (weaning), and were tattooed after all litters were weaned. 4. Animal Health and Environmental Monitoring Program As specified in the Haskell Laboratory animal health and environmental monitoring program, the following procedures are performed periodically to ensure that contaminant levels are below those that would be expected to impact the scientific integrity of the study: Water samples are analyzed for total bacterial counts, and the presence of coliforms, lead, and other contaminants. Feed samples are analyzed for total bacterial, spore, and fungal counts. Samples from freshly washed cages and cage racks are analyzed to ensure adequate sanitation by the cagewashers. Certified animal feed is used, guaranteed by the manufacturer to meet specified nutritional requirements and not to exceed stated maximum concentrations of key contaminants, including specified heavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates. The presence of these contaminants below the maximum concentration stated by the manufacturer would not be expected to impact the integrity of the study. The animal health and environmental monitoring program is administered by the attending laboratory animal veterinarian. Evaluation of these data did not indicate any conditions that affected the validity of the study. E. Quarantine and Pretest Period Upon arrival at Haskell Laboratory, the rats were quarantined for 6 days of the 14-day pretest period. The rats were observed daily for any clinically apparent signs of disease or injury, weighed 3 times, and examined by a veterinary ophthalmologist to identify animals with preexisting ocular lesions. On the bases of acceptable body weight gains and no clinical observations, all rats were released from quarantine on test day -8 by the laboratory animal veterinarian. Additional male and female rats designated for the 10-day hepatic biochemical analysis were quarantined for 6 days of the 6- and 7-day pretest period, respectively. The rats were observed daily for any clinically apparent signs of disease or injury and weighed three times, then released from quarantine on test day 90 by the laboratory animal veterinarian. - 22Company Sanitized. Does not contain TSCA CBt H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 F. Assignment to Groups and Study Start 1. Rats Designated for the Subchronic Toxicity, One-Month Recovery, Total Fluorine Level Analysis, and Reproductive Evaluations Rats were selected for study use on the bases of adequate body weight gain, freedom from any ophthalmology abnormalities or clinical signs of disease or injury, and a body weight within 20% of the mean within a sex. The selected rats were distributed by computerized, stratified randomization so that there were no statistically significant differences among group body weight means within a sex. Oral administration of H-25425 began on test day 0 when the rats were approximately 51 days of age. Prior to the start of the test substance administration, 3 female rats were replaced to attain desired body weight mean for each group. One female rat with a body weight that was not within 20% of the mean within a sex was replaced. One female rat was replaced based on a clinical observation observed on test day 0. Replacement rats were selected on the bases of freedom from any clinical signs of disease or injury and a body weight 20% of the mean within a sex. 2. Rats Designated for 10-Day Biochemical Analysis The rats designated for the 10-day biochemical analysis arrived separately, 84 days after study start. They were handled the same as the other rats during the quarantine and pretest periods, except they did not receive an ophthalmological examination. They were distributed by computerized, stratified randomization into study groups (5/sex/dose), so that there were no statistically significant differences among group body weight means within a sex when this subset of rats was compared among themselves. Oral administration of H-25425 to male and female rats began on test days 90 and 91, respectively. The rats were approximately 50 (males) and 51 (females) days of age. In-life data (body weight, food consumption, clinical observations) were collected from these animals and are in study records. However, these data will not be included in this report. G. Dosing Suspension Preparation Dose suspensions of 0, 2,20, or 200 mg test substance/mL were prepared in 0.5% methylcellulose (in deionized water). The dosing suspensions were mixed for approximately one minute with a polytron homogenizer. Then the dosing suspensions were placed on a magnetic stirrer and stirred for 30 minutes prior to dosing and during dosing. Dosing suspensions of the test substance were prepared daily and stored at room temperature until used. H. Test Substance Administration Animals designated for evaluation of subchronic toxicity, recovery, and analysis of blood for fluorine were dosed daily by gavage for 92 (males) and 93 (females) days. Animals designated for recovery or blood fluorine analysis were dosed for 91 days. Animals designated for 10-day biochemical evaluation were dosed daily by gavage for 10 days, starting 90 days after study start. -23Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 Animals designated for reproductive evaluations were dosed daily by gavage for approximately 74 days, and then daily during the 14-day mating period. The Pi male rats continued to be dosed following the cohabitation period until sacrifice. Pregnant females were dosed during the threeweek gestation period. Pregnant females in the process of delivery or showing signs of delivery were not dosed. From gestation day 18 until delivery, dose volumes were based on the gestation day 18 body weights. Lactating females and females with no evidence of copulation were dosed until pups were weaned on postpartum day 21. The volume of H-25425 given to each rat (5 mL/kg) was based on the most recently recorded body weight. Male and female control animals were similarly treated with 0.5% methylcellulose at the same dose volume as used in the other groups. On test day 22, one animal in group VII (animal number 665118) struggled during dosing and only received a partial dose. On test day 69, one animal in group VI (animal number 665262) was observed with dose suspension on the lips following dosing. Therefore, a full dose was not delivered. These partial doses were not considered to have impacted the study as they were isolated incidents, the rats were not in the same group, and they received most of the intended dose. On test day 89, one animal in group VII (animal number 665084) received 0.4 mL over his targeted dose volume (2.5 mL). This single incident of a misdose was not considered to have impacted the study as the rat received the targeted dose thereafter and no adverse clinical signs were observed in this rat subsequent to this misdosing. I. Test Substance Sampling Dosing suspensions at concentrations of 2,20, and 200 mg/mL of H-25425 were prepared and collected for homogeneity/concentration verification and stability analysis (5-hour room temperature) on test day 2 (October 17, 2002). Because of an unexpected high coefficient of variation (C.V.) on the low level for test day 2 samples, samples were collected for the low level from test day 8 dose preparation (October 23, 2002) for the homogeneity/concentration verification. On test day 42 (November 26,2002) and test day 86 (January 9, 2003), dosing suspensions at all levels were collected for uniformity/concentration verification analysis. In addition, 0 mg/mL (control) samples were submitted for analysis with the each set of samples. All dosing samples were collected and analyzed on the same day the suspensions were prepared. The suspension vehicle was 0.5% methylcellulose. J. Analytical Methods 1. Recovery Sample Analysis Concurrent with dosing suspensions analyses, recovery of H-25425 from spiked 0.5 % methylcellulose was tested at the low level (2 mg/mL), at the mid level (20 mg/mL) and at the high level (200 mg/mL) to confirm the analytical method. For the low level, H-25425 was weighed (approximately 12 mg) and diluted with 6 mL of 0.5% methylcellulose. For the mid and -24Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations____________________ DuPont-11418 high level, H-25425 was weighed (approximately 60 and 600 mg, respectively) and diluted with 3 mL of 0.5% methylcellulose. All recovery samples were then vortexed for dispersion of the H-25425 in the methylcellulose. The samples were then processed and analyzed in the same manner as the dosing samples at similar concentrations. 2. Dosing Suspension Treatment Each dosing sample was collected in a 15 mL centrifuge tube (6 mL for 2 mg/mL level and 3 mL for 20 and 200 mg/mL levels). Methanol (3 mL) was added to each tube, followed by vortexing for mixing, centrifuging and removal of the supernatant. After the supernatant was removed, the test substance, remaining as solids, was washed with 3 replicate washes (3 mL) of methanol with vortexing, centrifuging and removal of the supernatant after each wash. The test substance, remaining as solids, was dried under nitrogen. These solids were then reconstituted in tetrahydrofuran (THF) using sonication to assure all material was dissolved. The 2 mg/mL samples were reconstituted to 3 mL with THF, the 20 mg/mL samples were reconstituted to 10 mL with THF and the 200 mg/mL Samples were reconstituted to 100 mL with THF. The following target concentrations were then analyzed: 4.0 mg/mL, 6.0 mg/mL and 6.0 mg/mL, respectively. 3. Chromatographic Conditions Instrument: Column: Mobile Phase Flow Rate: Injection Volume: Column Temperature Detection: Hewlett-Packard Model 1100 HPLC Styragel HR 4; 7.8 mm x 300 mm (GPC column) 100% tetrahydrofuran (THF) l.OmL/min 50 pi 35C Refractive Index 4. Calibration and Quantitation i A separate sanmle of H-25425 test substance was designated as the analytical reference standard stock solution of H-25425 in tetrahydrofuran (THF) was used to make ^calibration solutions that bracketed the test solutions. Peak heights from replicate HPLC/GPC/RI analysis of each calibration solution were used to construct a calibration curve by least-squares regression. Measured concentrations for each test solution were determined by applying respective peak heights to the calibration curve. Test substance homogeneity/uniformity in the vehicle was evaluated by calculating the coefficient of variation (C.V. = standard deviation/mean x 100) of the measured concentrations in the top, middle, and bottom samples (homogeneity) or duplicate samples (concentration verification) for each dosing level. A coefficient of variation of less than or equal to 10% is the standard criterion at Haskell Laboratory for acceptable distribution of the test substance throughout the solution. However, if the test substance has been shown to be difficult to disperse in the vehicle or the analysis has shown variability, a coefficient greater than 10 may be acceptable. - 25Company Sanitized. Does not contain TSCA C8I H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations____________________DuPont-11418 The mean result of the homogeneity samples (n = 3) or concentration verification samples (n = 2) 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 result of the homogeneity samples as the baseline for comparing the corresponding stability results. Because of the procedure used to isolate the test substance in the method for analysis, spiked recovery samples at each level were monitored. A correction based on these recovery samples was applied to the sample results, if the spiked recovery sample analysis was less than 90% of nominal for the level. K. Body Weights All rats were weighed once per week during the subchronic toxicity and recovery periods of the study. In addition, the rats designated for neurobehavioral evaluations, undergoing functional observational battery and motor activity assessments, were weighed on the days of those observations. 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. Food consumption for the rats that were sampled for blood fluorine was only collected during the exposure period. 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. On five occasions, due to inclement weather or technician error, cage-site examinations were only done once a day. These missed cage-site examinations did not affect the validity of the study as there were no animals found dead or sacrificed in extremis at the next cage-site examination. 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 subchronic toxicity exposure and one-month recovery periods. The detailed clinical observations included (but were not limited to) evaluation of fur, skin, eyes, mucous membranes, occurrence of secretions and excretions, autonomic nervous system activity (lacrimation, piloerection, and unusual respiratory pattern), changes in gait, posture, response to handling, presence of clonic, tonic, stereotypical, or bizarre behavior. - 26- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 N. Ophthalmology Evaluation Two ophthalmology 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 87, all surviving rats designated for the 90-day exposure and one-month recovery were examined again. O. Neurobehavioral Evaluations 1. Sensory Motor Function Evaluation Prior to test substance administration, during week 13 of test substance administration, and near the end of the recovery period, assessments of responses to approach/touch, sharp auditory stimulus, and tail pinch were made while the animal was in a standard arena. For the 0 mg/kg/day and 1000 mg/kg/day groups, the baseline, week 13, and recovery assessments were conducted on the 10 animals per sex per group designated for recovery. For the 10 mg/kg/day and 100 mg/kg/day groups, the baseline and week 13 assessments were conducted on the 10 animals per sex per group designated for subchronic toxicity. Recovery assessments were not conducted on the 10 or 100 mg/kg/day groups. 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 ehambers (Section 2. below) because the darkened room in which the apparatus was located facilitated observing the response. The presence or absence of pupillary constriction was assessed after a beam of light was directed into each eye. For all these assessments, the experimenter was unaware of the group designation of the animal. 2. Motor Activity Evaluation Following the evaluation of grip strength and sensory function, assessment of motor activity (MA) was conducted. Rats were individually tested in 1 of 30 nominally identical, automated activity monitors (Coulboum Infrared Motor Activity System). Group and gender were counterbalanced across the monitors and time of day to the fullest extent possible. The infrared monitoring device enables measurement of 2 dependent variables: duration of movement and number of movements. A continuous movement was counted as 1 movement regardless of duration. Each test session was 60 minutes in duration, and the results were expressed for the total session, as well as for 6 successive 10-minute blocks. Presence of defecation and urination on the cage boards below the motor activity monitor were also recorded following each motor activity session. - 27Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 P. Clinical Pathology Evaluation Clinical pathology evaluations were conducted on the rats designated for subchronic toxicity approximately 6 and 14 weeks after initiation of the study, and on rats designated for recovery (control and high dose only) after approximately 5 weeks of recovery. The day before collection of samples for the clinical pathology evaluations, the animals were placed in metabolism cages. These animals were fasted after 3 p.m. (at least 15 hours) and urine was collected from each animal. On the morning after the fast, blood samples for hematology and clinical chemistry measurements were collected from the orbital sinus of each animal while the animal was under carbon dioxide anesthesia. Blood samples for plasma fluoride and coagulation parameters were collected at sacrifice only from the abdominal vena cava of each animal while the animal was under carbon dioxide anesthesia. Additional blood collected from the vena cava was placed in a serum tube, processed to serum, and frozen at -80C. Serum collected from the vena cava was discarded without analysis because further tests were not required to support experimental findings. Bone marrow smears were prepared at scheduled sacrifice from all animals. Bone marrow smears were stained with Wright's stain, but analysis was not necessary to support experimental findings. 1. Hematology and Coagulation Blood samples were evaluated for quality by visual examination prior to analysis. Complete blood counts, including reticulocytes, were determined on a Bayer Advia 120 hematology analyzer or determined from microscopic evaluation of the blood smear. Wright-stained blood smears from all animals were examined microscopically for confirmation of automated results and evaluation of cellular morphology. Blood smears, stained with new methylene blue, were prepared from each animal undergoing a hematology evaluation, but were not needed for examination. Coagulation times were determined on a Sysmex CA-1000 Coagulation Analyzer. The following hematology and coagulation parameters were determined: red blood cell count hemoglobin hematocrit mean corpuscular volume mean corpuscular hemoglobin mean corpuscular hemoglobin concentration red cell distribution width absolute reticulocyte count platelet count white blood cell count differential white blood cell count microscopic blood smear examination prothrombin time activated partial thromboplastin time -28Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 2. Clinical Chemistry Serum clinical chemistry parameters were determined on a Roche Diagnostics (BMC)/Hitachi 717 clinical chemistry analyzer. Plasma fluoride concentrations were determined using a Beckman model 012 digital pH/ISE meter and a fluoride-selective electrode. The following clinical chemistry parameters were determined: aspartate aminotransferase alanine aminotransferase sorbitol dehydrogenase alkaline phosphatase total bilirubin urea nitrogen creatinine cholesterol triglycerides glucose total protein albumin globulin calcium inorganic phosphorus sodium potassium chloride fluoride (sacrifice only)a 3. Urinalysis Urine volume and appearance (quality, color, and clarity) were measured and evaluated visually, respectively. Urine constituents were semi-quantitatively measured on a Bayer Clinitek AtlasTM Automated Urine Chemistry analyzer. Urine protein was measured on a Roche Diagnostics (BMC)/Hitachi 717 clinical chemistry analyzer. Urine osmolality was determined using an Advanced Osmometer 3900. Urine fluoride concentrations were determined using a Beckman model 012 digital pH/ISE meter and a fluoride-selective electrode, and total urine fluorides were calculated (volume x concentration). Sediments from all urine specimens were evaluated microscopically. The following urinalysis parameters were determined: quality color clarity volume 'osmolality pH glucose ketone bilirubin blood urobilinogen fluoride (sacrifice only)b protein microscopic urine sediment examination a Fluoride determination was analyzed on EDTA plasma, b Fluoride determination was analyzed from urine with EDTA added. -29 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 Q. Total Fluorine and Perfluorooctanoic Acid Level Evaluations 1. Total Fluorine Evaluations On test day -4 (pre-bleed), and test days 3,9, 22,34, 55,76, and 89, blood (approximately 0.6 mL) was collected from the orbital sinus of designated animals (5 rats/sex/dose), while the animals were under light carbon dioxide anesthesia, for possible total blood fluorine analysis. On the day of blood collection (except test day -4), blood was collected from the animals 2 hours (+30 minutes) after dosing. Blood was also collected for possible total blood fluorine analysis at 3 ,7 ,1 1 ,1 8 , 25,36, 50,71, and 92 days postdosing (after the last dose) for both male and female animals of each dose group. Animals were sacrificed after the 3-month recovery period (test day 182). The blood was collected in plastic tubes containing EDTA while on ice and stored frozen. During the last week of the approximately 90-day exposure period animals were placed in metabolism cages for daily collection of feces and urine. Urine and feces were collected at 24hour intervals from each animal. Urine and feces were frozen and stored. Blood fluorine analysis has not yet been performed but may be analyzed at a later date. 2. Perfluorooctanoic Acid Level Evaluations Blood was collected in EDTA from the vena cava at necropsy from all rats designated for subchronic toxicity evaluation and from all rats designated for recovery evaluation. Plasma was prepared and stored frozen at -8 0 to -20C until analyzed for concentration of perfluorooctanoic acid (PFOA). Plasma has not yet been analyzed. Plasma will be analyzed from control and high-dose rats, and data will be reported in a supplementary report. The decision to evaluate low- and intermediatedose groups will be based on results in the high-dose group. Plasma samples will be extracted by organic solvent protein precipitation using a protein precipitation column and then analyzed for PFOA byLC-MS-MS. R. Biochemical Measurements Following 10 days (males and females) or 92 days (males) or 93 days (females) of test substance administration or after one-month of recovery (test day 127 for males and females), five rats from each group designated for biochemical evaluation were weighed and then euthanized by CO2 anesthesia and exsanguination. At each time point, the livers were removed, weighed, and then a portion was homogenized (1 gram tissue/4 mL buffer) in homogenization buffer (50 mM TrisHC1, 50 mM Trizma-base, 0.25 M sucrose, and 5.4 mM EDTA, pH 7.4). 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 |3-oxidation activity. The peroxisomal suspensions were diluted to a protein concentration of approximately 0.5 mg/mL. Peroxisomal (3-oxidation activity was determined using [,4C]palmitoyl CoA as the substrate. The protein content of the peroxisomes - 30Company Sanitized. Does not contain TSCA C8I H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations _______________ DuPont-11418 was determined before and after analysis by the Biorad method/3) Final rate calculations were made using the post-assay protein concentrations. S. Anatomic Pathology Evaluation for Rats Designated for Subchronic Toxicity and OneMonth Recovery Evaluations After approximately 90 days of exposure to the test substance (test days 92 and 93 for males and females, respectively), groups of 10 male and 10 female rats from the 0,10,100, and 1000 mg/kg/day groups were sacrificed and necropsied. Additional groups of 10 male and 10 female rats from the 0 and 1000 mg/kg/day groups were sacrificed and necropsied approximately one month after the last exposure (test day 127). In the discussion of pathology findings, groups sacrificed after approximately 90 days are referred to as the subchronic toxicity groups, and groups sacrificed on test day 127 are referred to as the one-month recovery groups, respectively. Rats designated for possible evaluation of blood fluorine levels did not receive a gross or microscopic pathology evaluation. Rats scheduled for sacrifice were fasted overnight on the afternoon before their scheduled sacrifice. The order of sacrifice for scheduled deaths was random among all treatment groups. Rats were euthanized by carbon dioxide anesthesia and exsanguination. Gross examinations were performed on all male and female rats. -31 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 The following tissues were collected from subchronic toxicity and one-month recovery group rats sacrificed by design, and from one rat that was accidentally killed. Digestive Svstem liver esophagus stomach duodenum jejunum ileum cecum colon rectum salivary glands pancreas Urinarv Svstem kidneys urinary bladder Cardiovascular Svstem heart aorta Hematopoietic Svstem spleen thymus mandibular lymph node mesenteric lymph node bone marrowa Endocrine Svstem pituitary gland thyroid gland parathyroid glands adrenal glands Musculoskeletal Svstem skeletal muscle femur/knee joint sternum Reproductive Svstem Male testes epididymides prostate seminal vesicles Female ovaries uterus mammary glands gross observations Respiratory Svstem Nervous Svstem lungs brain (including cerebrum, trachea nose larynx cerebellum, medulla/pons) spinal cord (3 levels: cervical, mid-thoracic, lumbar) pharynx sciatic nerve a. Bone marrow was collected with the femur and sternum. Miscellaneous skin eyes (including retina optic nerve) gross observations b b. Gross observations made at necropsy for which histopathology was not appropriate (e.g., fluid, ruffled fur, and missing anatomic parts) were generally not collected. The following tissues were weighed from rats sacrificed by design in the subchronic toxicity group and the one-month recovery groups: liver, kidneys, adrenal glands, thymus, brain, spleen, heart, thyroid (weighed after fixation), ovaries, uterus, epididymides, and testes. Organ weight/final body weight and organ weight/brain weight ratios were calculated. Gross lesions which were diagnosed at necropsy and for which microscopic examination was not appropriate (e.g., fluid accumulation, ruffled fur, missing anatomic parts) were generally not collected. Gross lesions for which a microscopic diagnosis would not be additive (e.g., osteoarthritis, pododermatitis, chronic dermatitis of the tail, urinary calculi, and deformity of the teeth, toe, tail, or pinna) were saved but were generally not processed for microscopic evaluation. Testes, epididymides, and eyes were fixed in Bouin's solution. All other tissues were fixed in 10% neutral buffered formalin. Processed tissues were embedded in paraffin, cut at a nominal thickness of 5 micrometers, stained with hematoxylin and eosin (H&E), and examined microscopically. -32Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 All collected tissues from subchronic toxicity group rats sacrificed on test days 92/93 were evaluated microscopically from control and 1000 mg/kg/day rats. Liver and thyroid gland were processed and evaluated microscopically from 1 0 and 1 0 0 mg/kg/day subchronic toxicity group rats and from one-month recovery rats. All collected tissues were processed and received a full histopathological examination from one control male rat in the recovery subset that was accidentally killed. T. Reproductive Evaluations 1. Observations and Mortality for Parental Rats Cage-site examinations were conducted twice daily throughout the study. At least once weekly throughout the premating, cohabitation, gestation, and lactation periods, each of the Pi parental rats were individually handled and carefully examined for abnormal behavior and/or appearance. 2. Body Weights for Parental Rats a. Cohabitation Period All Pi males and females were weighed on the first day of the cohabitation period, and weekly thereafter. Female rats without evidence of copulation were weighed weekly until delivery or until sacrifice. b. Gestation and Lactation Periods Pi female rats were weighed on days 0, 7,14, and 21 of each period. In addition, body weight on gestation day 18 was collected in order to adjust the dosage during this period of rapid weight gain. However, these weights are not included in the final report. 3. Food Consumption and Food Efficiency for Parental Rats a. Cohabitation Food consumption was not determined during cohabitation. b. Gestation Period Individual food consumption of pregnant Pi females was recorded on gestation days 0 ,7 , 14, and 21. 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 the food consumption and body weight data, the mean daily food efficiency was calculated. Food consumption was not measured for females without evidence of copulation or for males following the cohabitation period. - 33Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 c. Lactation Period Food consumption was not measured during lactation. 4. Estrous Cycle Evaluation Vaginal smears were collected daily from all Pi female rats in order to determine the stages of the estrous cycle. Vaginal smears were collected beginning 3 weeks prior to cohabitation, and continuing until copulation was confirmed or until the cohabitation period ended. Vaginal smears were also collected from all Pi parental female fats at the time of sacrifice to determine the stage of estrous cycle. However, these data were not needed for data interpretation, and will not be included in the final report. These data are maintained with the study records. 5. Breeding a. Start of Cohabitation Each female was continually housed on a 1:1 basis with a randomly selected, nonsibling male of the same dosage level, in the male's cage. Cohabitation was initiated on test day 74. b. Duration of Cohabitation Period Cohabitation continued until evidence of copulation was observed (designated as day 0 of gestation), or 2 weeks had elapsed. On the day copulation was confirmed, the female was transferred back to individual cage housing. c. Evidence of Copulation Each female was examined once daily for the presence of an intravaginal copulation plug or sperm in the vaginal lavage sample. 6 . Gestation Procedures After being transferred into polycarbonate pans (on day 20 of gestation for mated females, or at the end of the cohabitation period for females without evidence of copulation), female rats were observed at least twice daily for signs of delivery and offspring. 7. Lactation Procedures The day when delivery was complete was designated day 0 postpartum. At each examination period, offspring were individually handled and examined for abnormal behavior and appearance; any dead, missing, or abnormal pups were recorded. - 34Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 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 offspring were euthanized by decapitation and discarded without pathological examination. Litters of 8 offspring or fewer were not reduced. Litter counts were determined prior to and after culling. Individual pup weights were determined prior to culling. c. Days 7 and 14 Postpartum Pups in each litter were counted by sex and individually weighed. d. Day 21 Postpartum (Weaning) Pups in each litter were counted by sex and individually weighed. Randomly selected weanlings (one/sex/litter) were placed in individual cages and monitored for attainment of developmental landmarks. Three of 4 pups/sex/litter were then sacrificed and subjected to a gross pathological examination. 8 . Fi Generation Post Weaning a. Clinical Observations Cage-site examinations were conducted at least once daily. At least once weekly each rat was individually handled and carefully examined for abnormal behavior and/or appearance. b. Body Weight Measurements All rats were weighed weekly until termination (approximately postnatal day 60). Rats were also weighed on the day of preputial separation or vaginal opening. c. Food Consumption and Food Efficiency Individual food consumption was determined weekly until termination (approximately postnatal day 60). 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 determinations and body weight data, individual daily food consumption and food efficiency were calculated. 9. Fi Generation Developmental Landmarks a. Vaginal Patency Female rats were examined once daily beginning on postnatal day 21 until achievement, or postnatal day 43, which ever came first. Body weight was recorded on the day of achievement. - 35Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 b. Preputial Separation Male rats were examined beginning on postnatal day 35 until achievement, or postnatal day 55, which ever came first. Body weight was recorded on the day of achievement. 10. Sperm Number, Morphology, and Motility Sperm parameters were evaluated for the first 10 surviving Pi males in each dosage group. The right epididymis was removed from each designated rat, and the right cauda epididymis was weighed. Sperm was collected from the right cauda epididymis, and the percent motility and morphology were determined. The left epididymis and testis were frozen in liquid nitrogen and stored between -65 and -85 C until sperm and spermatid counts were determined. U. Anatomic Pathology Evaluation for Rats Designated for Reproductive Evaluations 1. Pi Adults All Pi parental rats received a gross pathological examination, including rats sacrificed by design or found dead. Rats were sacrificed by carbon dioxide anesthesia and exsanguination. The uteri of all cohabited females were examined for the presence and number of implantation sites. Sperm parameters for the first 10 Pi males per group were evaluated as described above. Following collection of samples for sperm parameter evaluation, the right testis and epididymis from these 1 0 rats were saved and placed in fixative for histopathological evaluation. The following table lists tissues that were collected from all Pi adults (including those that died anytime prior to the scheduled sacrifice) and preserved in appropriate fixative for possible future histopathological examination: Male Tissues Collected from Pi Adults Female Both Sexes Testes/Testis3 Ovaries Thyroid Glandb Epididymides/Epididymis3 Uterus (with oviducts) Gross Observations* Prostate Vagina Pituitary Seminal Vesicles Coagulating Gland a Testes/Testis and epididymides/epididymis collected from male rats were placed in Bourn's solution. All other tissues (reproductive and non-reproductive) collected from male and female rats were placed in formalin, b Thyroid glands were weighed after fixation. c Gross lesions observed at necropsy for which histopathology was not appropriate or would not be additive were generally not collected. 2. Offspring Offspring that were found dead during the lactation period underwent a gross pathological evaluation. - 36Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 3. Fi Weanlings Three Fi weanlings/sex/litter (randomly selected), litter size permitting, were sacrificed by carbon dioxide anesthesia and underwent a gross pathological evaluation on postnatal day 2 1 . Gross lesions were preserved. 4. Fi Adults All Fi generation rats were sacrificed by carbon dioxide anesthesia 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 Testes3 Ovaries Thyroidb Epididymides3 Uterus (with oviducts) Gross Observationsc Prostate Vagina Pituitary Seminal Vesicles Coagulating Gland a Testes/Testis and epididymides/epididymis collected from male rats were placed in Bouin's solution. All other tissues (reproductive and non-reproductive) collected from male and female rats were placed in formalin. b 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. Male Organs Weighed from Fi Adults Female Both Sexes Testes Epididymides Seminal Vesicles (with coagulating glands) Prostate Uterus (with oviducts and cervix) Thyroid (after fixation) Liver Brain Processed tissues for histopathological examination were embedded in paraffin, cut at a nominal thickness of 5 micrometers, and stained with hematoxylin and eosin (H&E). Histopathological examination of reproductive organs was conducted only for Pi males and females with impaired reproductive performance (3 pairs of Pi rats). Gross lesions were not evaluated microscopically. - 37Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 V. Statistical Analyses Except for Bartlett's test (p < 0.005), significance was judged at p < 0.05. Separate analyses was performed on the data collected for each sex. Statistical Methods for Subchronic Toxicity Parameters Parameter Preliminary Test Body Weight Test for lack of trend(4) Body Weight Gain Food Consumption Food Efficiency Levene's test for Organ Weight homogeneity(7) and 6-Oxidation Shapiro-Wilk test for normality8 Survival Incidence of Clinical Observations Incidence of Ophthalmology None Observations Incidence of FOB Descriptive Parameters Levene's test for Motor Activity8 homogeneity and Shapiro-Wilk test for normality8 Grip Strength Bartlett's test(17) for homogeneity of variances Clinical Pathology6 Incidence of Microscopic Lesions Levene's test for homogeneity and Shapiro-Wilk test for normality8 None Method of Statistical Analysis If preliminary test is not If preliminary test is significant significant Sequential application of the Jonckheere-Terpstra trend test Preliminary tests for pairwise comparison ORa One-way analysis of variance followed with Dunnett's test00'11' Kruskal-Wallis test031 followed with Dunn's test041 Cochran-Armitage test for trend6 Repeated measures analysis of variance051 followed by contrasts061 One-way analysis of variance followed with Dunnett's test001 One-way analysis of variance followed with Dunnett's test001 Sequential application151of the Jonckheere-Terpstra trend test Kruskal-Wallis test031 followed with Dunn's test041 Kruskal-Wallis test031 followed with Dunn's test041 none a Pairwise comparisons and associated preliminary tests were only conducted if the test for lack of trend was significant. b If the Shapiro-Wilk test was not significant but Levene's test was significant, a robust version of Dunnett's test was used. If the Shapiro-Wilk test was significant, Kruskal-Wallis test was followed by Dunn's test. c If the incidence was not significant, but a significant lack of fit occurred, then Fisher's Exact test081 with a Bonferroni correction was used. d Test day and block (10-minute intervals) were used as repeated-measure factors. e When an individual observation was recorded as being less than a certain value, calculations were performed on one-half of the recorded value. For example, if bilirubin was reported as <0.1,0.05 was used for any calculations performed with that bilirubin data. When an individual observation was recorded as being greater than a certain value, calculations were performed on the recorded value. For example, if specific gravity was reported as >1.083, 1.083 was used for any calculations performed with that data. - 38Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 The follow ing table lists the indices o f reproductive function that were calculated for the Pj and Fi adults. Mating Index (%) = Number CoDulateda Number Cohabited x 100 Fertility Index (%) = Number Pregnant^ Number Copulateda x 100 Gestation Index (%) Number o f Litters with = at Least One Live Pud N umber o f Litters x 100 Implantation Efficiency (%)c = Number o f Puds Bom Number o f Implantation Sites x 100 Pups Bom Alive (%)c = Number o f Pups Bom Alive Number o f Pups Bom x 100 Viability Index (%)c >d = Number o f Puds A live Dav 4 Preculling Number o f pups bom alive x 100 Lactation Index (%)c>d Number o f pups alive = at weaning (Dav 21 Dostoartum) Number o f pups alive Day 4 Postculling x 100 Litter Survival (%)d = Number o f litters weaned Number of viable litters delivered x 100 a Evidence of copulation = intravaginal copulatory plug, sperm in vaginal lavage sample, found dead pregnant, or delivery of a litter. b Including pregnant animals that were found dead during gestation. c Determined for each litter. Mean and standard deviation for each dose level were calculated, d Excluding litters sacrificed due to death of dam during lactation. -39Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 Statistical Methods for Reproductive Toxicity Parameters Parameter Body Weight Body Weight Gain Food Consumption Food Efficiency Gestation Length Organ Weight Implantation Site Numbers Implantation Efficiency Mean Number of Pups Per Litter Percent Bom Alive Sex Ratio 0-4 Day Viability Lactation Index Vaginal Patency Preputial Separation Estrous Cycle Parameters Sperm Parameters Incidence of Clinical Mating Index Fertility Index Gestation Index Litter Survival Mean Pup Weights (Covariates: litter size, sex ratio) Preliminary Test . Test for lack of trend(4) Method of Statistical Analysis If preliminary test is not If preliminary test is significant significant Sequential application of the JonckheereTerpstra trend test Preliminary tests for pairwise comparison ORa Levene's test for homogeneity(7) and Shapiro-Wilk test(8) for normality8 One-way analysis of variance and Dunnett's test(,0) Kruskal-Wallis test(!3) and Dunn's test<14> None None Cochran-Armitage test for trendc Linear contrast of least squares means<19) Dunn's test(14) Incidence of Microscopic Lesions None None J a Pairwise comparisons and associated preliminary tests were only conducted if the test for lack of trend was significant. b If the Shapiro-Wilk test was not significant but Levene's test was significant, a robust version of Dunnett's test was used. c If the incidence was not significant, but a significant lack of fit occurred, then Fisher's Exact test(18) with a Bonferroni correction was used. For each parameter analyzed with a trend test, the test was applied to the data sequentially. If a significant dose-response was detected, data from the top dose group were excluded and the test repeated until no significant trend was detected/ For litter parameters, the proportion of affected fetuses per litter or the litter mean were used as the experimental unit for statistical evaluation/2 The level of significance selected was p < 0.05. - 40Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations _______________DuPont-11418 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. Characterization data (percent purity, composition, and known impurities) will be stored at Regional Analytical Services (RAS), Jackson Laboratories, Deepwater, New Jersey. Characterization data used to support test substance stability will be retained at Haskell Laboratory, Newark, Delaware, or at Iron Mountain Records Management, Wilmington, Delaware. -41 Company Sanitized. Does not contain TSCA CBI H-2342D: Subchromc Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 RESULTS AND DISCUSSION Analytical Evaluation A. Test Substance Stability Analyses Samples of the test substance were analyzed near the beginning and end of the study. These analyses indicated that the H-25425 was stable over the course of the study. The average of the active ingredient w a s H H H H B M H H H H H n f r samples analyzed lOctober 15,2002 and February 2 7 ,2003. This work is reported in analytical repor Iand can be found in Haskell Laboratory Record "The H-25425 was reported by the sponsor to The difference between the sponsor reported purity and the experimental data represent analytical variability. B. Chromatography H-25425 eluted from the HPLC/GPC column as a resolved peak over an average retention time of 8.5 to 9.0 minutes. Representative HPLC/GPC/IR chromatograms are shown in Appendix A, Figures 2 (a - d). Test substance was not detected in the 0 mg/mL control. C. Recovery Samples Detailed analytical results of recovery samples are summarized in Appendix A, Table I. The variability of the analytical method was demonstrated by the coefficients of variation of the recovery results at each targeted dosing concentration (approximately 2, 20,200 mg/mL) over the course of the study. The measured concentrations of H-25425 for the 2 mg/mL level were 68.5% to 78.4% of nominal (mean percent recovery = 74.2% 4.2, C.V. = 6 %). The measured concentrations of H-25425 for the 20 mg/mL level were 84.1% to 88.1% of nominal (mean percent recovery = 86.0% 2.0, C.V. = 2%). The measured concentrations of H-25425 for the 200 mg/mL level were 89.1% to 96.5% of nominal (mean percent recovery = 92.8% 3.7, C.V. = 4%). Based on this data, a correction was applied to all sample results when the spiked recovery for the concentration analyzed below 90% of nominal. D. Homogeneity and Stability Samples Analytical results from dosing suspensions collected on test day 2 (October 17, 2002) and analyzed for homogeneity/concentration verification and 5-hour room temperature stability and test day 8 (October 23, 2002) and analyzed for homogeneity/concentration verification are shown in Appendix A, Table II and Summary Table 1. - 42Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 The following table summarizes the results for homogeneity/concentration verification and stability analyses for these sampling days of the H-25425 sample preparation. Sample Day Sample Type Nominal Measured T,M,Ba Mean (T,M,B) C.V. Stability11 mg/mL mg/mL % Nominal (%) % Nominal Test day 2 Homogeneity Test day 8 Homogeneity 0 NDC 2d 1.36, 1.87, 2.00 2 0 d 19.0,20.8, 21.3 2 0 0 187,188, 191 0 NDC 2d 1.87,1.97,1.91 -- 87.0 1 0 2 .0 94.5 -- 96.0 ---- 19 91.5 6 108.5 1 98.0 --- -- 2-- a Mean results for the analysis of the top (T), middle (M) and bottom (B) samples, b Samples held 5 hours at room temperature, c Denotes none detected. d Reported results corrected for recovery of the spiked sample at the level (refer to Table I). The results for H-25425 samples prepared and collected on test day 2 show that the test substance was at the targeted concentrations for all levels ( 13.0% of nominal), adequately mixed except for the 2.0 mg/mL level (CV = 19) and stable in the vehicle when held 5 hours at room temperature for all levels. Test substance was not detected in the 0 mg/mL samples. The results for H-25425 samples (2.0 mg/mL level) prepared and collected on test day 8 show that the test substance was at the targeted concentration ( 4.0% of nominal), and adequately mixed (CV = 2). Test substance was not detected in the 0 mg/mL samples. E. Concentration Verification Samples Analytical results from dosing suspensions collected on test day 42 (November 26,2002) and test day 8 6 (January 9, 2003) and analyzed for concentration verification (uniformity) are shown in Appendix A, Table III and Summary Table 1. The following table summarizes the results for concentration verification analyses for both sampling days of the H-25425 sample preparation. Preparation Day Nominal mg/mL Measured3 mg/mL Average % Nominal CV % Test day 42 Test day 8 6 2b 20b 200 2b 20b 200b 2.35, 2.36 20.5,20.8 190,193 2.03, 2.04 19.6,21.8 209, 203 118.0 103.5 96.0 1 0 2 .0 103.5 103.0 0.4 1 1 0.5 7 2 a Duplicate samples per level were analyzed. C.V. calculated to verify uniformity of mixture, b Reported results corrected for recovery of the spiked sample at the level (refer to Table I). -43Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 The results for samples prepared and collected on test day 42 indicate that the test substance was at the targeted levels ( 4.0% of nominal) except for the 2.0 mg/mL level that was marginally higher than expected ( 18.0% of nominal) and adequately mixed (CY's less than 10) for all H-25425 samples. Test substance was not detected in the 0 mg/mL samples. The results for samples prepared and collected on test day 8 6 indicate that the test substance was at the targeted levels (target = 3.5% of nominal) and adequately mixed (CV's less than 10) for all H-25425 samples. Test substance was not detected in the 0 mg/mL samples. F. Analytical Conclusion Results from the analysis of the test substance dosing suspensions during the study indicate that the test substance was mixed properly except for the initial sampling of the 2 mg/mL level, at the targeted levels and stable under the conditions of the study. Test substance was not found in the 0 mg/mL samples. In-Life Toxicology Rats designated for evaluation of reproductive toxicity were transferred to the reproduction group on test day 72, and were co-housed for mating beginning on test day 74. All results reported in this section up to test day 72 (including day 0-70 intervals) include data from both the subchronic toxicity and reproductive toxicity subsets. All results after test day 72 (including day 0-91 intervals) are from subchronic toxicity rats alone. A. Dosage Data (Tables 2-3, Appendix B) Rats were dosed with solutions of H-25425 in 0.5% methylcellulose, prepared at concentrations of 0, 2, 20, or 200 mg H-25425/mL, designed to deliver the targeted dose of test substance at a dosing volume of 5.0 mL/kg body weight. The quantity of H-25425 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 1.2-3.0 mL for the control group, and 1.2-2.9 mL for the 10, 100, and 1000 mg/kg/day groups. The range of mean daily dose volumes administered to female rats was 0.9-1.6 mL for the control group, and 0.9-1.5 for the 1 0 , 1 0 0 , and 1 0 0 0 mg/kg/day groups. - 44Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 B. Mean Body Weights and Body Weight Gains (Tables 4-7, Figures 1-2, Appendices C) No adverse, test substance-related effects on body weight or body weight gain were observed in any male or female dose group. No statistically significant differences in mean body weight, compared to control, were observed in male rats on any test day. Mean body weight in the 1000 mg/kg/day group was 97% of control on test days 70 and 91, 96% of control at the end of the one-month recovery (test day 126), and 90% of control at the end of the three-month recovery (test day 182; fluorine analysis subgroup). None of the differences was statistically significant. Statistically significant reductions in mean body weight gain were observed in the male 1000 mg/kg/day group over test days 0-7,7-14, 2128,49-56, 70-77, and 105-112. Although these reductions may have been test substance-related, they were not considered adverse effects as mean body weight gain in this group was comparable to control over most weekly intervals; there was no statistically significant difference in overall mean body weight gain over test days 0-70 or 0-91 (94% of control); and mean body weight gain exceeded control (not statistically significant) over numerous weekly intervals. Furthermore, the latter two weekly intervals occurred during the recovery period. Statistically significant reductions in mean body weight gain were also observed over test days 7-14 and 70-77 in the 100 mg/kg/day group and over test days 7-14 in the 10 mg/kg/day group. These differences were not considered test substance-related as they were isolated intervals, rats were not dosed on test days 70-77, and no statistically significant differences in overall mean body weight gain were observed in these groups over the test day 0-70 or 0-91 dosing periods or the one- or three-month recovery periods. No statistically significant differences in mean body weight or mean body weight gain were observed in any female dose group on any test day or over any weekly interval of the study. Mean body weight in the female 1000 mg/kg/day group was 99% and 96% of control on test days 70 and 91, respectively. Mean body weight gain in this group was 100% and 93% of control over test days 0-70 and 0-91, respectively. Mean body weight gain in this group was comparable to control (95%) over the one-month recovery and exceeded control (131% of control) over the three-month recovery. None of these interval differences was statistically significant. Mean body weight and body weight gain in other female dose groups were also comparable to control throughout the dosing and recovery periods. C. Food Consumption and Food Efficiency (Tables 8-11, Appendix D) No adverse, test substance-related effects on food consumption or food efficiency were observed in any male or female dose group. In male rats, no statistically significant differences in weekly or overall food consumption were observed in any dose group throughout the dosing or recovery periods of the study. Mean food consumption in the male 1000 mg/kg/day group was 99% and 97% of control over the test day 0- - 45Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations____________________DuPont-11418 70 and 0-91 intervals, respectively (neither statistically significant). Mean food consumption in this group was 101% of control during recovery (test days 91-126). In female rats, no adverse effects on food consumption were observed in any dose group throughout the dosing or recovery periods. Statistically significant reductions in mean food consumption were observed in the 1000 mg/kg/day group over test days 21-28,28-35, 84-91, and 112-119. Statistically significant reductions in mean food consumption were observed in the 100 mg/kg/day group over test days 84-91. These differences were not considered adverse as mean food consumption in these groups was comparable to control over most weekly intervals, there was no statistically significant difference in overall mean food consumption, and rats were not dosed during the test day 112-119 interval. Mean food consumption in the 1000 mg/kg/day female group was 99% and 97% of control over test days 0-70 and 0-91, respectively and 94% of control during recovery (test days 91-126). In 1000 mg/kg/day male rats, statistically significant reductions in mean food efficiency were observed over test days 0-7, 7-14, 21-28,49-56, and 70-77, and statistically significant increases in mean food efficiency were observed over test days 28-35 and 119-126. A few statistically significant decreases and increases in mean food efficiency, compared to control, were also observed in the 10 and 100 mg/kg/day groups over one or more intervals. It is questionable whether these effects were test substance related, and they were not considered adverse as the differences included increases and decreases, a dose-response was not always evident, and overall mean food efficiency in all male dose groups did not differ from control during dosing or recovery periods. Mean overall food efficiency in 1000 mg/kg/day males was 96%, 97%, and 95% of control over test days 0-70, 0-91, and 91-126, respectively (none statistically significant). No statistically significant differences from control in mean food efficiency were observed in any female dose group throughout the study, except for a single weekly interval (test day 91-98), in which mean food efficiency in the 1 0 0 0 mg/kg/day group was significantly higher than in control. Mean overall food efficiency in 1000 mg/kg/day females was 102%, 97%, and 97% of control over test days 0-70,0-91, and 91-126, respectively (none statistically significant). D. Clinical Observations and Mortality (Tables 12-13,16-17, Appendix E) There was no test substance-related effect on mortality in either male or female rats. A male control rat was accidentally killed during the bleeding procedure on test day 127. One male rat in the 100 mg/kg/day group was found dead on test day 108. This rat was part of the subset bled for possible fluorine evaluation and did not receive a pathological evaluation. Therefore, the cause of death is unknown. No early deaths occurred in any female dose group. No increases in any clinical observations occurred that were attributed to test substance exposure. -46- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 E. Ophthalmology Evaluations (Tables 14-15, Appendix F) No compound-related ophthalmological lesions were observed in male or female rats examined near the end of the dosing phase of the study. Unilateral focal retinal degeneration was observed in one male and one female rat. This observation was not test substance related as these rats were in the control group. F. In-Life Toxicology Conclusions Under the conditions of this study, the no-observed-effect level (NOEL) for in-life parameters was 1000 mg/kg/day for males and females. The NOEL was based on a lack of adverse effects on any in-life parameters in rats dosed up to 1 0 0 0 mg/kg/day, the highest dose tested. Neurobehavioral Evaluation A. Forelimb Grip Strength (Tables 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 the test substance. Mean values for all groups were similar to the control values for both males and females. B. Hindlimb Grip Strength (Tables 18-19, Figures 5-6, Appendix G) There were no test substance-related effects or statistically significant differences for hindlimb grip strength in males or females administered any dosage of the test substance. Mean values for all groups were similar to the control values for both males and females. C. Sensory Motor Function Observations (Tables 20-21, Appendix H) There were no test substance-related effects or statistically significant differences for the sensory motor function parameters in either males or females administered any dosage of the test substance. One female in the 1000 mg/kg/day group was observed to be circling during the week 13 and recovery evaluations. Although this observation is suggestive of neurotoxicity, since only one animal administered 1 0 0 0 mg/kg/day was observed with this behavior, and since no other clinical signs or changes in grip strength or motor activity were evident in any dosage group, the circling behavior was not considered to be test substance-related. The incidences for all groups were similar to the values for the control values for both males and females. -47Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 D. Motor Activity (Tables 22-25, Figures 7-9, Appendices I-J) There were no test substance-related effects on duration of movement or number of movements for males or females administered any dosage of the test substance. During the week 13 evaluation, males administered 1 0 0 0 mg/kg/day had significantly increased duration of movement and number of movements during the 6 th 1 0 -minute interval compared to the control value. The statistical differences may be suggestive of a delayed habituation in the males administered 1000 mg/kg/day compared to control. However, the range of individual duration of movement values during the 6 th 1 0 -minute interval for the 13-week evaluation were similar for all 3 treatment groups (45-366, 70-370,41-320 seconds for the 10,100, and 1000 mg/kg/day males, respectively), and were higher compared to the range of individual control values during the 6 th 10-minute interval (10-207 sec). In addition, the range of individual number of movements for the 6 th 1 0 -minute interval during the 13-week evaluation was similar for all groups (14-155, 36-151, 59-152, 37-160 for the 0,10,100, and 1000 mg/kg/day males, respectively). Therefore, these statistical differences were not considered to be test substancerelated for the following reasons: 1) a dose-response relationship is not evident for the range of individual duration of movement values; 2 ) a dose-response-relationship is not evident for the mean and range of number of movement values; and 3) the mean duration of movement and number of movement values for 1 0 0 0 mg/kg/day females were similar to control values. Therefore, these statistical differences were not considered to be treatment-related. Mean values for all other groups and time intervals were similar to the values for the control groups for both males and females. E. Neurobehavioral Conclusions Under the conditions of the study, the NOEL for grip strength, sensory motor function observations, and motor activity, was 1 0 0 0 mg/kg/day, the highest dosage tested. Clinical Pathology Evaluation A. Hematology (Tables 26-27, Appendix K) There were no adverse changes in hematologic parameters in male or female rats. The following statistically significant changes in mean hematologic parameters were not adverse or not related to exposure to compound: Red cell mass parameters (red cell count, hemoglobin, and hematocrit) were minimally decreased in males dosed with 1000 mg/kg/day at test days 37 and 92, and after one month of recovery (variable statistical significance). At these three time-points, mean values for red cell mass parameters were 95-97% of respective concurrent control group means. There were no correlative changes in other numeric or microscopic red cell parameters. -48Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 Red cell mass parameters (hemoglobin and hematocrit) were minimally but statistically decreased in females dosed with 1000 mg/kg/day at test day 93 (97 and 95% of control group means, respectively). There were no correlative changes in other numeric or microscopic red cell parameters. After one month of recovery, red cell mass parameters in females previously dosed with 1 0 0 0 mg/kg/day were similar to control values. The above changes in red cell mass parameters in male and female rats dosed with 1 0 0 0 mg/kg/day were probably due to treatment due to the consistency of change between sexes and across time-points. However, because the changes were so minimal (all within 95% of control group means, whereas control group means can vary by 1 0 percentage points between studies), they were considered to be non-adverse. Although the changes in males persisted into the recovery period, the very minimal nature of the effects suggested that the changes were non-adverse. Platelets were transiently and minimally decreased in males dosed with 1000 mg/kg/day at test day 37 (91% of control group mean). At the end of the study (test day 92) and after one month of recovery (test day 127), platelets were similar to control group counts. The decrease in platelets at test day 37 was possibly due to treatment. However, the range of individual counts in males dosed with 1000 mg/kg/day was similar to that of other groups. In addition, all values were well within the historical reference range for individual animal values for this parameter (729-1415 x l0 3/uL for males approximately 19 weeks old). Therefore, although this change was possibly due to treatment, it was considered to be nonadverse. The following statistically significant changes in mean hematology parameters were considered to be unrelated to treatment and non-adverse because they did not occur in a dose-related pattern, or occurred only after one month of recovery: Increased red cell distribution width in males dosed with 100 mg/kg/day at test day 37 Increased neutrophils and monocytes in males dosed with 100 mg/kg/day at test day 37 Increased neutrophils in females dosed with 10 mg/kg/day at test day 93 Increased white blood cells, lymphocytes, monocytes, and large unstained cells in males previously dosed with 1000 mg/kg/day after one month of recovery (test day 127) Decreased red cell distribution width in females previously dosed with 1000 mg/kg/day after one month of recovery (test day 127) B. Coagulation (Tables 28-29, Appendix K) There were no adverse changes in coagulation parameters in male or female rats. The following statistically significant changes in mean coagulation parameters were considered to be unrelated to treatment and non-adverse because they did not occur in a dose-related pattern: - 49Company Sanitized. Does not contain TSCA C8I H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 Activated partial thromboplastin time was minimally decreased in males dosed with 100 mg/kg/day at test day 92. This change was considered to be unrelated to treatment because there was no dose-relationship in the response; activated partial thromboplastin times were similar in groups dosed with 10,100, or 1000 mg/kg/day. In addition, minimally decreased activated partial thromboplastin time has no toxicologic significance. Activated partial thromboplastin times were similar to control group times in males previously dosed with 1 0 0 0 mg/kg/day after one month of recovery. C. Clinical Chemistry (Tables 30-31, Appendix K) There were no adverse changes in clinical chemistry parameters in male or female rats. The following statistically significant changes in mean clinical chemistry parameters were not adverse or not related to exposure to compound: Alanine aminotransferase activity was decreased in female rats dosed with 100 or 1000 mg/kg/day at test day 93 (not statistically significant). At this time point, there were unusually high activities of both aspartate and alanine aminotransferase in one female (#665221) dosed with 0 (vehicle) and in one female (#665332) dosed with 10 mg/kg/day. These two rats had alanine aminotransferase activities of 223 and 165 U/L, respectively (individual age-matched historical control activities range from 25-122 U/L). These changes were considered to be due to spontaneous lesions unrelated to treatment. Therefore, the apparent decrease in mean alanine aminotransferase resulted from spontaneous lesions in control and low dose females, rather than from treatment-related changes in females dosed with 1000 mg/kg/day. After one month of recovery, alanine aminotransferase activities in females previously dosed with 1 0 0 0 mg/kg/day were similar to control values. Bilirubin was minimally decreased in males and females dosed with 1000 mg/kg/day at test day 92 and 93, respectively (variable statistical significance). In males, there was histologic evidence of enzyme induction (centrilobular hypertrophy), and liver weights were increased. Decreased bilirubin was likely to be secondary to enzyme induction, as a result of a physiologic response to dosing of a xenobiotic. Therefore, these changes were considered to be non-adverse. After one month of recovery (test day 127), bilirubin concentrations in rats previously dosed with 1 0 0 0 mg/kg/day were similar to control group values. Triglyceride was mildly decreased in males dosed with 10,100, or 1000 mg/kg/day at test day 92 (70, 76, and 58% of control group means; statistically significant at 10 and 1000 mg/kg/day only). These changes were likely related to treatment. However, mildly decreased triglycerides have no adverse effects; therefore, this change was considered to be non-adverse. After one month of recovery (test day 127), triglyceride concentrations in males previously dosed with 1 0 0 0 mg/kg/day were similar to control group values. Total protein was mildly decreased due to decreased globulin in males dosed with 1000 mg/kg/day at test day 92. Means were 96 and 83% of control group means, respectively. These changes were considered to be due to treatment. However, the group means of 7.1 and 2.4 mg/dL for total protein and globulin, respectively, were within the historical range of means for age-matched control animals (6 .8-7.5 and 1.9-2.6 mg/dL, - 50Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations___________________ DuPont-11418 respectively). In addition, individual animal concentrations of .8-7.4 mg/dL for total protein and 1.9-2.7 mg/dL for globulin were within their respective historical reference ranges (6.28.2 mg/dL for total protein and 1.5-3.3 mg/dL for globulin). Therefore, this change, although treatment-related, was considered to be non-adverse. After one month of recovery (test day 127), total protein and globulin concentrations in males previously dosed with 1 0 0 0 mg/kg/day were similar to control group values. Calcium was minimally increased in females dosed with 1000 mg/kg/day at test day 38 (104% of control group mean). The change in calcium was due to the minimal increase in albumin (not statistically significant). 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, which results in increased total calcium. However, ionized calcium is unaffected. Therefore, this change was considered to be non-adverse. After one month of recovery (test day 127), calcium concentrations in females previously dosed with 1 0 0 0 mg/kg/day were similar to control group values. Inorganic phosphorus was minimally and transiently increased in females dosed with 10,100, and 1000 mg/kg/day at test day 38 (108,107, and 114% of control group mean, not statistically significant at 100 mg/kg/day). Individual phosphorus values were similar across all three groups dosed with the test substance despite the 100-fold difference in dose. In addition, there were no changes in correlative clinical chemistry parameters (urea nitrogen, creatinine) or in histopathology that suggest that these phosphorus changes are treatmentrelated. Therefore, these changes were considered to be unrelated to treatment and nonadverse. Chloride was minimally increased in females dosed with 1000 mg/kg/day at test day 93 (102% of control group mean). This change is possibly related to treatment. However, the mean concentration (100.5 mmol/L) and individual animal concentrations (97.9103.4 mmol/L) were well within the historical range for age-matched historical data (historical range of means is 95-102 mmol/L and historical range of individual animal values is 91-105. Therefore, although this change is possibly related to treatment, it was considered to be non-adverse. After one month of recovery (test day 127), chloride concentrations were similar to control group values in females previously dosed with 1 0 0 0 mg/kg/day. The following statistically significant changes in mean clinical chemistry parameters were considered to be unrelated to treatment and non-adverse because they did not occur in a doserelated pattern, or occurred only after one month o'f recovery: Increased alanine aminotransferase in males dosed with 100 mg/kg/day at test day 37 Decreased alanine aminotransferase in females dosed with 100 mg/kg/day at test day 38 Increased aspartate aminotransferase, alanine aminotransferase, and albumin in males previously dosed with 1000 mg/kg/day after one month of recovery (test day 127) Decreased triglycerides in females dosed with 10 mg/kg/day at test day 93. -51 - Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 D. Urinalysis (Tables 32-33, Appendix K) The following statistically significant changes in mean urinalysis parameters were considered to be unrelated to treatment and non-adverse because they occurred only after one month of recovery: Decreased urine protein and osmolality, and increased urine volume in males previously dosed with 1000 mg/kg/day after one month of recovery (test day 127) Decreased urine volume and pH, and increased urine protein and urobilinogen in females previously dosed with 1000 mg/kg/day after one month of recovery (test day 127) E. Urine and Plasma Fluoride (Tables 30-33, Appendix K) There were no treatment-related or statistically significant changes in plasma fluoride in males or females dosed with up to 1 0 0 0 mg/kg/day. Urine fluoride was increased (statistically significant) in males and females dosed with 1000 mg/kg/day (see text table below). Urine fluoride was also increased in most males and a few females dosed with 100 mg/kg/day at test day 92/93 (statistically significant in males only). After one month of recovery, urine fluoride was statistically increased in males previously dosed with 1 0 0 0 mg/kg/day; this change was probably related to treatment based on the individual animal data. Increased urine fluoride indicates exposure to and metabolism of a fluoride-containing compound. Plasma and Urine Fluoride Measurements* Dose (mg/kg/day) 0 10 100 1000 10 m i III/IV V/VI VI1/VIII m /iv Plasma Males Day 92 0.1 0.1 0.1 0.1 100% (ug/mL) Day 127 0.1 - - 0.1 Females Day 93 0.1 0.1 0.1 0.1 100% Day 127 0.1 - - 0.1 Urine Males Day 92 9.5 9.2 17.5 5 3 .4 97% (ug) Day 127 7.7 - - 10.8 Females Day 93 6.5 5.5 9.8 2 8 .6 85% Day 127 6.3 - - 4.8 100 V/VI 100% 100% 184% 151% 1000 v n /v iii 100% 100% 100% 100% 562% 140% 440% 76% *Results expressed as actual values or as percent of control group mean. Statistical significance is indicated by b o ld ita lic iz e d f o n t F. Clinical Pathology Conclusions In conclusion, males and females dosed with 1000 mg/kg/day had minimally decreased red cell mass parameters (red cell count, hemoglobin, and hematocrit) and minimally decreased serum - 52Company Sanitized. Does not contain TSCA GBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 bilirubin. In addition, male rats dosed for 90 days with the test substance had mildly decreased triglycerides (1 0 , 1 0 0 , and 1 0 0 0 mg/kg/day), and mildly decreased total protein due to decreased globulin (1000 mg/kg/day males only). Urine fluoride was increased in males and females dosed with 100 or 1000 mg/kg/day. After one month of recovery, red cell mass parameters were still minimally decreased and urine fluoride was still increased in males previously dosed with 1000 mg/kg/day. None of these effects were considered to be adverse. Therefore, under the conditions of this study and for the clinical pathology parameters measured, the NOEL was 1000 mg/kg/day for males and females, based on the lack of adverse effects at any dose. Biochemical Evaluation A. Biochemical Evaluation (Tables 34-35, Appendix L) In male rats at the 10-day time point, the rate of hepatic P-oxidation was statistically significantly decreased at a dosage of 1000 mg/kg/day (91% of control). This decrease was considered a spurious finding and was not considered to be test substance-related due to a lack of concordance with the effects observed at the 92-day and one-month recovery time points. At the 92-day and one-month recovery time points in male rats, the rate of hepatic P-oxidation was statistically significantly increased at a dosage of 1000 mg/kg/day (159% and 149% of control, respectively). At the 92-day time point, the increase in hepatic P-oxidation activity at a dosage of 1 0 0 0 mg/kg/day was accompanied by an increase in absolute and relative liver weight in all subchronic toxicity male rats. Liver weights were not affected at the one-month recovery time point in male rats. At the 10-day and 93-day time points in female rats, the rate of hepatic P-oxidation was statistically significantly increased at a dosage of 1000 mg/kg/day (120 and 125% of control, respectively). At the one-month recovery time point, hepatic P-oxidation activity had returned to control levels in female rats. B. Biochemical Evaluation Conclusions Under the conditions of this study, H-25425 is a mild inducer of hepatic peroxisomal P-oxidation in male and female rats. At a concentration of 1000 mg/kg/day, changes in the rate of hepatic peroxisome proliferation are considered to be test substance-related effects. However, the effects were not considered adverse. At the one-month recovery time point, the rate of hepatic peroxisome proliferation was still increased at a dosage of 1 0 0 0 mg/kg/day in males, but had returned to control levels in female rats. -53 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 Anatomic Pathology Evaluation Rats Designated for Subchronic Toxicity and Recovery Evaluations A. Mortality (Tables 16-17, Appendix N) There were no test substance-related deaths. One control male rat (Animal No. 665042) was accidentally killed during blood collection on the last day of the one-month recovery period. The gross and microscopic pathology data for this rat were included in the incidence tables; organ weights were not taken. B. Organ Weight Data (Tables 36-39, Appendix M) In the subchronic toxicity groups, the only test substance-related organ weight effects were increases in mean liver and kidney weights in male rats given 1 0 0 0 mg/kg/day, as compared to controls. Male liver weight parameters remained increased, to a lesser extent, in the high-dose males following the one-month recovery period. Mean absolute, relative (liver/body weight), and relative (liver/brain weight) liver weights were increased 19%, 23%, and 22%, respectively, in the 1000 mg/kg/day male rats as compared to the controls. All three increases were statistically significant by the trend test. The increase in liver weights correlated with the microscopic observation of minimal hepatocellular hypertrophy in all ten male rats following the subchronic toxicity exposure period (see discussion under Microscopic Observations). In the one-month recovery 1000 mg/kg/day male rats, mean absolute, relative (liver/body weight), and relative (liver/brain weight) liver weights were still increased 1 0 %, 1 1 %, and 1 1 %, respectively, although only the mean relative (liver/body weight) was statistically significant. Microscopic hepatocellular hypertrophy was not evident in these recovery males. In female rats, increases in absolute and relative (to brain) liver weight parameters that were observed in the subchronic toxicity exposure and one-month recovery groups were considered to be biologically insignificant. Mean absolute, relative (kidney/body weight), and relative (kidney/brain weight) kidney weights were increased 12%, 16%, and 14%, respectively, in the 1000 mg/kg/day male rats as compared to the control rats. All three increases w.ere statistically significant by the trend test. There was . no microscopic morphological correlate to the increase in kidney weights in this study (see discussion under Microscopic Observations). In the one-month recovery 1000 mg/kg/day male rats, kidney weight parameters were similar to control rat values. Test substance-related kidney weight effects were not observed in female rats at any dose level in the subchronic toxicity or one-month recovery groups. All other individual and mean organ weight differences were considered to be spurious and unrelated to test substance administration. Although some female thyroid weight parameters in the subchronic study were increased in all treated groups (variable statistical significance), there - 54Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 was no dose response. These increases were attributed to a spuriously low control group mean, and not to a test substance related effect. C. Gross Observations (Tables 40-43, Appendix N) There were no test substance-related gross observations. All gross observations at necropsy were interpreted to be naturally occurring background lesions that are typical of rats of this age and strain. D. Microscopic Observations (Tables 44-51, Appendices N and O) Test substance-related microscopic findings were present in the liver of male rats and the thyroid gland of male and female rats. Incidences and Average Lesion Grades of Test Substance-Related Microscopic Findings In Male and Female Rats Dose: mg/kg/day 0 10 100 1000 Males: Subchronic Toxicity Liver: Hypertrophy, hepatocyte, centrilobular 0/10 (0.0) 0/10 (0.0) 0/10 (0.0) 9/10 (0.9) Thyroid gland: Hypertrophy, follicular cell 1/10(0.2) 1/10(0.1) 1/10(0.1) 10/10(1.6) Males: One-Month Recovery Thyroid gland: Hypertrophy, follicular cell 1/10(0.1) NA NA 6/10 (0.9) Females: Subchronic Toxicity Thyroid gland: Hypertrophy, follicular cell 0/10(0.0) 0/10(0.0) 0/10 (0.0) 2/10 (0.2) Females: One-Month Recovery Thyroid gland: Hypertrophy, follicular cell . 0/10 (0.0) NA NA 2/10 (0.2) a Numerator indicates number of rats with microscopic lesion. Denominator indicates number of rats in group. b Number in parentheses indicates group average severity of lesion. NA Tissue not available. Hypertrophy of centrilobular hepatocytes was observed in most (9/10) high-dose (1000 mg/kg/day) males and was graded minimal in all cases. Since hepatocellular hypertrophy was not observed in any of the one-month recovery males, this effect was clearly reversible. Hepatocellular hypertrophy was not observed in any female rats following the 93-day exposure - 55Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 period. Microscopically, hepatocellular hypertrophy was characterized by an increased amount of finely granular eosinophilic cytoplasm within centrilobular 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 pharmacological response to the metabolism of a xenobiotic and not adverse. An increased incidence of thyroid follicular cell hypertrophy was present in males and females administered 1000 mg/kg/day for approximately 90 days. Follicular cell hypertrophy was characterized by low columnar follicular epithelium with a finely granular or vacuolated cytoplasm. Follicles were decreased in size, irregular in shape, and contained decreased amounts of normal pink colloid. Following the one-month recovery period, both the incidence and severity of follicular hypertrophy was decreased in the male rats. In female rats, the incidence (2/20) and severity (minimal) was the same in both the exposure and recovery groups. Despite the persistence of the effect following the one-month recovery, the overall decrease in the incidence and severity demonstrates the reversibility of follicular cell hypertrophy in this study. An increase in the incidence and severity of thyroid follicular cell hypertrophy is indicative of altered thyroid gland homeostasis. Although the follicular cell response observed in this study (minimal to mild hypertrophy) was within the range of normal physiological response, the effect is potentially proliferative and adverse, especially in the rat. Since follicular cell hypertrophy is consistent with several different mechanisms of altered thyroid gland homeostasis, the specific cause of the hypertrophic response in this study is not clear. In rats, a common cause of thyroid follicular cell hypertrophy is an increase in the rate of hepatic thyroxine (T4) glucuronidation and subsequent biliary excretion.(21) An increased rate of T4 excretion results in lower T4 blood levels which triggers an increase in the release of pituitary-derived thyroid stimulating hormone (TSH), resulting in thyroid follicular cell hypertrophy. Many inducers of hepatic cytochrome P450 isoenzymes in the rat are known to secondarily cause thyroid follicular cell hypertrophy by this mechanism. In this study, the presence of test substance-related hepatocellular hypertrophy in the high-dose males demonstrates that hepatocellular enzyme systems have been induced and that T4 excretion may have been secondarily increased. DUe to differences in T4 half-life, thyroglobulin binding, and the ease of UDP-glucuronyl-transferase induction, rats are much more susceptible than humans to secondary thyroid follicular cell hypertrophy.(21) Male and female kidneys did not demonstrate any morphological change despite a 14% increase in mean relative (kidney/brain) kidney weights in the 1 0 0 0 mg/kg/day male rats, as compared to the controls. Although tubular cell hypertrophy was not apparent, it is likely that the increase in kidney weight parameters in the high-dose males is indicative of a non-adverse, slight, pharmacological response by the kidney to xenobiotic exposure. Since an organ weight increase was not present following the one-month recovery period, the effect was reversible. All other microscopic observations in this study are known to occur naturally in rats of this strain and age and were not present in a dose response fashion in either incidence or severity. -56Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 E. Anatomic Pathology Conclusions for the Subchronic Toxicity and Recovery Evaluations Exposure to 1000 mg/kg/day of the test substance for approximately 90 days produced minimal to mild thyroid follicular cell hypertrophy in male and female rats, minimal centrilobular hepatocellular hypertrophy in male rats, and increased liver and kidney weights in male rats. Following a one-month recovery period, thyroid follicular cell hypertrophy and organ weight effects were decreased and hepatocellular hypertrophy was not present. Liver and kidney effects were indicative of a pharmacological response to a xenobiotic and were not considered to be biologically adverse. The thyroid effect, although mild and reversible, was regarded to be potentially adverse. Under the conditions of this study, the NOEL for pathology for male and female rats was 1 0 0 mg/kg/day based on thyroid effects at the 1 0 0 0 mg/kg/day dose level. Reproductive Toxicity Evaluations A. Pi Rats - Clinical Observations and Mortality 1. Pi Males (Table 52, Appendix P) No test substance-related effects or statistically significant differences in the incidences of clinical observations were observed in males administered any dosage of the test substance. One male rat in the 1000 mg/kg/day group was found dead on test day 89. The death may be due to a gavage error, and was not considered to be test substance-related. 2. Pi Females During Gestation (Tables 53, Appendices Q) No test substance-related effects or statistically significant differences in the incidences of clinical observations were observed in females administered any dosage of the test substance during gestation. Mortality did not occur in female rats during gestation. 3. Pj Females During Lactation (Tables 54, Appendices R) No test substance-related effects or statistically significant differences in the incidences of clinical observations were observed in females administered any dosage of the test substance during lactation. One female in the 10 mg/kg/day group was found dead on lactation day 10. / ( ' 'N - 57Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 B. Pi Rats - Mean Body Weights and Body Weight Gains 1. Pi Males (Tables 55 and 56, Appendices S and T) No test substance-related effects or statistically significant differences on body weight or weight gain were observed in males administered any dosage of the test substance during the reproductive portion of the study. 2. Pi Females During Gestation (Tables 57 and 58, Appendices U and V) No test substance-related effects or statistically significant differences in body weight or weight gain were observed in females administered any dosage of the test substance during gestation. 3. Pi Females During Lactation (Tables 59 and 60, Appendices W and X) No adverse test substance-related effects on body weight or weight gain were observed in females administered any dosage of the test substance during lactation. Females administered 1000 mg/kg/day had significantly increased weight gain during lactation days 0-7 and 0-21 compared to the control values. Variability in weight gain during lactation is common, and the increased weight gain was not considered to be test substance-related or adverse. C. Pi Rats - Food Consumption and Food Efficiency Pi Females During Gestation (Tables 61 and 62, Appendix Y) No test substance-related effects or statistically significant differences in food consumption or food efficiency were observed in females administered any dosage of the test substance during gestation. D. Reproductive Indices (Table 63, Appendices EE and FF) No test substance-related effects or statistically significant differences in mating index, fertility index, gestation index, or gestation length were observed in Pi males and females administered any dosage of the test substance. -58Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 E. Sperm Count, Morphology, and Motility (Table 64, Appendices Z-BB) No test substance-related effects or statistically significant differences in sperm motility, morphology, or number were observed in parental males administered any dosage of the test substance. F. Estrous Cycle (Table 65, Appendices CC and DD) No test substance-related effects or statistically significant differences were observed on the percent of days in estrus, percent of days in diestrus, percent of days in proestrus, mean cycle length, or the mean number of days in the precoital interval in females administered any dosage of the test substance. G. Fi Offspring Data 1. Litter Size, Sex Ratio and Pup Survival (Table 6 6 , Appendix GG) No test substance-related effects or statistically significant differences were observed on the number of pups bom, number of pups bom alive, sex ratio, lactation index, or litter survival in offspring from any dosage group. 2. Clinical Observations in Fi Pups (Table 67, Appendix HH) No test substance-related effects or statistically significant differences in the incidence of clinical observations were observed in offspring from any dosage group. 3. Pup Weights (Table 6 8 , Appendix H) No test substance-related effects or statistically significant differences in body weight of pups during the lactation period were observed in offspring from any dosage group. H. Fi Rats - Clinical Observations and Mortality (Tables 69 and 70, Appendix JJ) No test substance-related effects or statistically significant differences in the incidence of clinical observations were observed in Fi male or female rats from any dosage group. Test substancerelated mortality did not occur in Fi male or female rats from any dosage group. -59Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 I. Fi Rats - Mean Body Weights and Body Weight Gains (Tables 71-74, Appendices KK and LL) No test substance-related effects or statistically significant differences in body weights or weight gain were observed in Fi male or female rats from any dosage group. J. Fi Rats - Food Consumption and Food Efficiency (Tables 75-78, Appendix MM) No test substance-related effects or statistically significant differences in food consumption or food efficiency were observed in Fi male or female rats from any dosage group. K. Fi Rats - Developmental Landmarks (Table 79, Appendix JJ) No test substance-related effects or statistically significant differences in the development of preputial separation or vaginal patency were observed in Fj male or female rats from any dosage group. L. Reproductive Toxicity Conclusions The no-observed-effect-level (NOEL) for reproductive parameters was 1000 mg/kg/day in parental males and females. In addition, no systemic toxicity was observed in parental males, parental females, or offspring from any dosage group. Anatomic Pathology Evaluation Rats Designated for Reproductive Evaluations A. Organ Weight Data Fi Adults (Tables 80 and 81, Appendix NN) There were no test substance-related effects on organ weights in the Fi adults. Minimal differences in some weight parameter means in the high-dose (1 0 0 0 mg/kg/day) male testes (increased relative to brain weight) and female livers (decreased absolute and relative to body weight and to brain weight) were statistically significant by the trend test. These differences were considered to be spurious and not test substance related. - 60Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 B. Gross Observations Parental Pi Adults (Tables 82 and 83, Appendix OO) Fi Adults, Weanlings, and Pups (Tables 84 and 85, Appendices PP and QQ) In Pi adults, Fi adults, Fi weanlings, and Fi pups, 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 1. Parental Pi Adults (Tables 8 6 and 87, Appendix OO) In the Pi adult generation, there were no test substance-related microscopic findings. Microscopic examination of Pi adults was limited to the reproductive tissues of the two found dead rats (see Mortality) and the three pairs of rats that did not produce litters (i.e., reproductive failures). The male and female rats that did not produce litters were in the 0 mg/kg/day group (Animal Nos. 665069 and 665289, respectively), 100 mg/kg/day group (Animal Nos. 665114 and 665298, respectively), and the 1000 mg/kg/day group (Animal Nos. 665133 and 665224, respectively). 2. Fi Adults In the Fi adult generation, there was no histopathology conducted since there was no mortality. D. Mortality Parental Pi Adults and Fi Adults (Appendices OO and PP) In the Pi adult generation, there were no test substance-related effects on mortality. O f 160 adult Pi rats, one 1000 mg/kg/day male (Animal No. 665050) and one 10 mg/kg/day female (Animal No. 665248) were found dead. The causes of death were undetermined. In the Fi adult generation, there were no test substance-related effects on mortality. There were no deaths among the 152 adult Fi rats. E. Anatomical Pathology Conclusions for Reproductive Toxicity For pathology, the NOEL was 1000 mg/kg/day (the highest dose level) for both male and female rats. -61 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 CONCLUSIONS NOEL fo r Subchronic Toxicity: Under the conditions of this study, the no-observed-effect level (NOEL)a for subchronic toxicity endpoints in male and female rats was 100 mg/kg/day. This level was based on reversible, minimal to mild thyroid follicular hypertrophy, observed in the 1000 mg/kg/day male and female groups. Other test substance-related effects observed in males and/or females dosed with 1 0 0 0 mg/kg/day include mild alterations in clinical pathology parameters and in hepatic 6 -oxidation activity; however, these were not considered to be adverse. Most of the effects observed during the dosing period demonstrated full or partial reversal following one month of recovery. Thyroid follicular hypertrophy was still present at the end of the one-month recovery period; however, the incidence and mean severity level in males had decreased by this time. NOELfo r Reproductive Evaluations: Under the conditions of this study, the NOEL for reproductive evaluations was 1000 mg/kg/day, the highest dose tested. This was based on a lack of test substance-related effects on any reproductive parameter in Pi or Fi generation animals dosed up to 1 0 0 0 mg/kg/day. a The NOEL for this study is defined as the highest dose at which toxicologically important effects attributable to the test substance were not detected. Thus, for this study, the NOEL is equivalent to the NOEL as defined by the United States Environmental Protection Agency(22>and to the no-observed-adverse-effect level (NOAEL) as defined by the European Union.(23> - 62- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 REFERENCES 1. DuPont Haskell Laboratory. H-25^54: Repeated-jPose Oral Toxicity Gavage Range-Finding Study in Rats. Unpublished r e p o r p | | | | f l A 2. Lazarow, P.B. (1981). Assay of Peroxisomal Beta-Oxidation of Fatty Acids. Methods in Enzymology 72, 315-319. 3. 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. 4. Draper, N.R. and Smith, H. (1981). Applied Regression Analysis, 2nd edition, pp 266-273. Wiley, New York. 5. 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. 6. Jonckheere, A.R. (1954). A distribution-free K-sample test against ordered alternatives. Biometrika 41, 133-145. 7. Levene, H. (1960). Robust test for equality of variances. Contributions to Probability and Statistics (J. Olkin, ed.), pp 278-292. Stanford University Press, Palo Alto. 8. Shapiro, S.S. and Wilk., M.B. (1965). An analysis of variance test for normality (complete samples). Biometrika 52, 591-611. 9. Snedecor, G.W. and Cochran, W.G. (1967). Statistical Methods, 6th edition, pp 246-248 and 349-352. The Iowa State University Press, Ames. 10. Dunnett, C.W. (1964). New tables for multiple comparisons with a control. Biometrics 20, 482-491. 11. Dunnett, C.W. (1980). Pairwise multiple comparisons in the unequal variance case. J. Amer. Statist. Assoc. 75, 796-800. 12. Tamhane, A.C. (1979). A comparison of procedures for multiple comparison of means with unequal variances. J. Amer. Statist. Assoc. 74, 471-480. 13. Kruskal, W.H. and Wallis, W.A. (1952). Use of ranks in one-criterion analysis of variance. J. Amer. Statist. Assoc. 47, 583-621. 14. Dunn, OJ . (1964). Multiple contrasts using rank sums. Technometrics 6, 241-252. 15. Milliken, G.A. and Johnson, D.A. (1984). Analysis of Messy Data, Volume 1.: Designed Experiments. Lifetime Learning Publications, Belmont. 16. Hocking, R.A. (1985). The Analysis of Linear Models. Brooks/Cole, Monterey. 17. Bartlett, M.S. (1937). Some examples of statistical methods of research in agriculture and applied biology. J. Royal. Statis. Soc. Suppl. 4, 137-170. -63 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations _______________ DuPont-11418 /v 18. Fisher, R.A. (1985). Statistical Methods fo r Research Workers, 13th edition. Haffner, New York. 19. 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. 20. Haseman, J.K. and Hogan, M.D. (1975). Selection of the experimental unit in teratology studies. Teratology, 12,165-171. 21. Capen, C.C., DeLellis, R.A., Yarrington, J.T. (2002). Endocrine system. Handbook o f Toxicologic Pathology, 2ndedition. (W.M. Haschek, C.G. Rousseaux, and M.A. Wallig, eds), pp. 737-740. Academic Press, New York. 22. Hazard Evaluation Division, Standard Evaluation Procedure, Toxicity Potential: Guidance for Analysis and Evaluation of Subchronic and Chronic Exposure Studies Paynter, O. E. et al., United States Environmental Protection Agency, Office of Pesticide Programs, Washington, D.C., 20406. EPA-540/9-85-020. (June 1985). 23. Risk Assessment of Notified New Substances. Technical Guidance Document (XI/283/94EN), Chapter I, Sections 2.24 and 2.25. 1994. -64Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 TABLES - 65Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 TABLES EXPLANATORY NOTES Critical Dates Day 72 Last day data from the male and female rats designated for reproduction evaluations were reported with the subchronic toxicity animals. Body weights and clinical observations collected during the cohabitation and post-mating periods are reported in the Reproductive Toxicology section; Dose volumes administered during the cohabitation and post-mating periods are documented in study records. Day 90 Last day of test substance administration for male and female rats designated for one-month and three-month recovery periods. Day 91 Last day of body weight and food consumption data collection for male and female rats designated for the subchronic toxicity evaluation. Last day of test substance administration for male rats designated for the subchronic toxicity evaluation. Day 92 Male rats designated for the subchronic toxicity evaluation were sacrificed. Last day of test substance administration for female rats designated for the subchronic toxicity evaluation. Day 93 Female rats designated for the subchronic toxicity evaluation were sacrificed. Day 126 Last day of body weight and food consumption data collection for rats designated for the one-month recovery period. Last day of food consumption data collection for rats designated for the three-month recovery period. Day 127 Male and female rats designated for the one-month recovery were sacrificed. Day 182 Male and female rats designated for blood fluorine level evaluation were sacrificed. - 66Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLES Abbreviations mg/kg = mg/kg/day g/anm/day = grams/animal/day EXPLANATORY NOTES incide = incidence Summary of Hematology Values RBC - red blood cell count HGB - hemoglobin HCT - hematocrit MCV - mean corpuscular volume MCH - mean corpuscular hemoglobin MCHC - mean corpuscular hemoglobin concentration RDW - red cell distribution width ARET - absolute reticulocyte count PLT - platelet count WBC - white blood cell count ANEU - absolute neutrophil (all forms) ALYM - absolute lymphocyte AMON - absolute monocyte AEOS - absolute eosinophil ABAS - absolute basophil ALUC - absolute large unstained cell - - _ no data Summary of Coagulation Values PT - prothrombin time APTT - activated partial thromboplastin time -- - no data DuPont-11418 - 67Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 TABLES EXPLANATORY NOTES Abbreviations: (Continued) Summary of Clinical Chemistry Values AST - aspartate aminotransferase ALT - alanine aminotransferase SDH - sorbitol dehydrogenase ALKP - alkaline phosphatase B E I - total bilirubin BUN - urea nitrogen CREA - creatinine CHOL - cholesterol TRIG - triglycerides GLUC - glucose TP - total protein ALB - albumin GLOB - globulin CALC - calcium EPHS - inorganic phosphorous NA - sodium K - potassium CL - chloride PFLU - plasma fluoride -- - no data Summary of Urinalysis Values VOL - volume UOSM - urine osmolality pH - the logarithm of the reciprocal of the hydrogen ion concentration URO - urobilinogen UFLU - urine fluoride UMTP - urine protein -- - no data - 68Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations___________________ DuPont-11418 TABLES EXPLANATORY NOTES Notes: Summary of Hematology Values Summary of Coagulation Values Summary of Clinical Chemistry Values Summary of Urinalysis Values 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. Reproduction Tables Test Day 1 for F I males and females = Postnatal Day 21 - 69Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 TABLE 1 SUMMARY OF DOSING SUSPENSION ANALYSIS Sample Type Dosing Concentrations and Stability of H-25425 (mg/mL) Homoeeneitv Test day 2 Top Nominal: Middle Bottom Average Measured Conc.c Average Percent Nominalc Standard Deviation0 Coefficient of Variation0 2.00 1.36a (68.0)b 1.87a (93.5) 2.00a (100.0) 1.74 (87.0) 0.34 19% 20.0 19.0a (95.0) 20.8a (104.0) 21.3a (106.5) 20.4 (102.0) 1.2 6% 200 187 (93.5) 188 (94.0) 191 (95.5) 189 (94.5) 2.1 1% Stability 5-hour Room Temperature Homoeeneitv Test day 8 Top Middle Bottom Average Measured Cone.0 Average Percent Nominal0 Standard Deviation0 Coefficient of Variation0 1.83a (91.5) 1.87a (93.5) 1.97a (98.5) 1.91a (95.5) 1.92 (96.0) 0.05 2% 21.7a (108.5) ...d ...d ...d 196 (98.0) ...d ...d ...d Concentration Verification6 Test day 42 2.36a (118.0) 20.7a (103.5) 192 (96.0) Test day 86 2.04a 20.7a 206a (102.0) (103.5) (103.0) a All reported results corrected based on recovery o f the spiked sample (refer to Table I). b Numbers in parentheses are the respective percent o f nominal values. c The average measured concentration, average percent o f nominal (in parentheses), standard deviation, and coefficient of variation of top, middle, and bottom. d Denotes samples not submitted (--) e Duplicate samples submitted. Mean result reported. - 70Company Sanitized. Does not contain TSCA CBI Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Group : Dosage(mg/kg/day) DAY0-DAY6 DAY7-DAY13 DAY14-DAY20 DAY21-DAY2 7 DAY2 8-DAY3 4 DAY3 5-DAY41 DAY42-DAY48 DAY49-DAY5 5 ' DAY56-DAY62 DAY 63-DAY69 DAY7 0-DAY7 2 TABLE 2 MEAN DAILY DOSE VOLLMES FOR MALE RATS I 0 1.2 0.1(45) 1.5 0.1(45) 1.7 0.1(45) 1.9 0.1(45) 2.1 0.1(45) 2.2 0.2(45) 2.3 0.2(45) 2.5 0.2(45) 2.6 0.2(45) 2.6 0.2(45) 2.7 0.2(45) III 10 1.2 0.1(35) 1.5 0.1(35) 1.7 0.1(35) 1.9 0.2(35) 2.0 0.2(35) 2.1 0.2 (35) 2.3 0.2(35) 2.4 0.2(35) 2.5 0.2(35) 2.6 0.2(35) 2.6 0.2(35) V 100 1.2 0.1(35) 1.5 0.1(35) 1.7 0.1(35) 1.9 0.2(35) 2.1 0.2(35) 2.2 0.2(35) 2.3 0.2(35) 2.4 0.2 (35) 2.5 0.2(35) 2.6 0.2(35) 2.6 0.3(35) -71 - DuPont-11418 VII 1000 1.2 0.1(45) 1.4 0.1(45) 1.7 0.1(45) 1.9 0.1(45) 2.0 0.1(45) 2.2 0.1(45) 2.3 0.2(45) 2.4 0.2(45) 2.5 0.2(45) 2.6 0.2(45) 2.6 0.2(45) H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-11418 TABLE 2 (CONTINUED) MEAN DAILY DOSE VOLUMES FOR MALE RATS Group: Dosage(mg/kg/day) I 0 DAY73a -DAY7 6 2.8 0.2(25) DAY77-DAY83 2.8 0.3(25) DAY84-DAY88 2.9 0.3(25) DAY 89 2.9 0.3(25) DAY90 2.9 0.3 (25) DAY91 3.0 0.3(10) Dataarrangedas: Mean Standarddeviation(Number ofanimalsincludedincalculation) III 10 2.7 0.3(15) 2.7 0.3(15) 2.7 0.3(15) 2.7 0.3 (15) 2.7 0.3(15) 2.9 0.2(10) V 100 2.8 0.3(15) 2.8 0.3(15) 2.9 0.3(15) 2.9 0.3(15) 2.9 0.3(15) 2.9 0.3(10) VII 1000 2.6 0.2(25) 2.7 0.2(25) 2.7 0.2(25) 2.8 b 0.2(25) 2.7 0.2(25) 2.9 0.2(10) a Ratsdesignatedforreproductionevaluation(20rats/group)were transferredforreproductiveassessmenton testday72;subsequentdataarereportedaspartofthe reproduction evaluation. b Includesratinadvertentlygivenan additional0.4mL dose. Company Sanitized. Does not contain TSCA O CD )) H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 3 Group : Dosage(mg/kg/day) DAY0-DAY6 * DAY7-DAY13 DAY14-DAY20 DAY21-DAY27 DAY28-DAY34 DAY3 5-DAY41 DAY42-DAY48 DAY49-DAY5 5 DAY56-DAY62 DAY63-DAY69 ` DAY7 0-DAY7 2 MEAN DAILY DOSE VOLUMES FOR FEMALE RATS II IV VI 0 10 100 0.9 0.1(45) 0.9 0.1(35) 0.9 0.1(35) 1.0 0.1(45) 1.0 0.1(35) 1.0 0.1(35) 1.1 0.1(45) 1.1 0.1(35) 1.1 0.1(35) 1.2 0.1(45) 1.2 0.1(35) 1.2 0.1(35) 1.3 0.1(45) 1.3 0.1(35) 1.3 0.1(35) 1.3 0.1(45) 1.3 0.1(35) 1.3 0.1 (35) 1.4 0.1(45) 1.4 0.1(35) 1.3 0.1(35) 1.4 0.1(45) 1.4 0.1(35) 1.4 0.1(35) 1.4 0.1(45) 1.4 0.1(35) 1.4 0.1(35) 1.5 0.1(45) 1.5 0.1(35) 1.5 0.1(35) 1.5 0.1(45) 1.5 0.1(35) 1.5 0.1(35) ') DuPont-11418 VIII 1000 0.9 0.1(45) 1.0 0.1(45) 1.1 0.1(45) 1.2 0.1(45) 1.2 0.1(45) 1.3 0.1(45) 1.3 0.1(45) 1.4 0.1(45) 1.4 0.1(45) 1.4 0.1(45) 1.5 0.1(45) Company Sanitized. Does not contain TSCA CBI - 73- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-11418 TABLE 3 (CONTINUED) Group : Dosage(mg/kg/day) DAY7 3a-DAY7 6 DAY77-DAY83 DAY84-DAY90 DAY91-DAY92 MEAN DAILY DOSE VOLUMES FOR FEMALE RATS II IV VI 0 10 100 1.5 0.2 (25) 1.5 0.1(15) 1.5 0.1(15) 1.5 0.2(25) 1.5 0.1(15) 1.5 0.1(15) 1.5 0.2(25) 1.6 0.2(10) 1.5 0.1(15) 1.5 0.1(10) 1.5 0.1(15) 1.5 0.1(10) VIII 1000 1.4 0.1(25) 1.5 0.1(25) 1.5 0.1(25) 1.5 0.1(10) Data arrangedas: Mean Standarddeviation(Number ofanimalsincludedincalculation) a Ratsdesignatedforreproductionevaluation(20rats/group)were transferredforreproductiveassessmenton testday 72;subsequentdataarereportedaspartofthe reproductionevaluation. Company Sanitized. Does not contain TSCA CBI - 74- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE4 Group : Dosage(mg/kg/day) MEAN BODY WEIGHTS OF MALE RATS (G) III V 10 100 Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAYO DAY7 DAY14 DAY21 DAY28 DAY35 DAY42 DAY 49 DAY56 DAY 63 240.1 14.3(45) 295.2 19.0(45) 342.8 23.0(45) 387.0 27.6(45) 421.0 31.6(45) 448.4 35.0(45) 469.5 36.3(45) 492.1 40.8(45) 511.7 43.4(45) 529.4 46.1(45) 238.3 12.6(35) 289.7 16.9(35) 330.8 22.9(35) 371.7 27.9 (35) 407.5 32.0(35) 430.7 34.7(35) 452.2 35.3(35) 476.8 39.5(35) 491.8 39.5(35) 509.6 42.5(35) 239.6 13.1(35) 295.6 18.8 (35) 335.6 23.6(35) 377.1 29.7(35) 412.2 33.6(35) 442.9 38.4(35) 461.0 39.7(35) 480.9 42.5(35) 498.3 44.6(35) 515.6 48.9(35) DuPont-11418 VII 1000 241.2 13.1(45) 291.2 16.4(45) 334.5 20.6(45) 378.0 23.6(45) 407.1 27.1(45) 435.2 28.8(45) 456.6 30.6(45) 481.7 35.1(45) 495.5 37.2(45) 512.4 40.7(45) Company Sanitized. Does not contain TSCA CBI - 75- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 4 (CONTINUED) Group: Dosage(mg/kg/day) DAY70 a MEAN BODY WEIGHTS OF MALE RATS (g) I III V 0 10 100 544.5 48.5(45) 526.1 44.7(35) 527.1 54.7 (35) Dosing Period for Subchronic Toxicity Evaluation (continued) DAY 77 563.0 52.2(25) 538.7 57.9(15) DAY 84 572.5 54.1(25) 549.2 60.7(15) DAY 91 578.9 56.7(25) 553.8 61.8(15) One-Month Recovery Period for Subchronic Toxicity Evaluation DAY 98 576.2 47.4(15) 512.7 63.5(5) DAY105 587.9 47.0(15) 523.6 60.0(5) DAY112 594.4 49.0(15) 530.0 61.6(5) DAY119 610.0 48.8(15) 541.1 66.3 (5) DAY126 607.8 48.9(15) 542.9 68.5(5) 560.0 58.8(15) 572.5 58.9(15) 578.0 62.1(15) 602.2 73.8(5) 613.1 75.1(5) 617.3 89.8(4) 636.2 96.5(4) 639.6 99.0(4) DuPont-11418 VII 1000 527. 4 43. 1(45) 537 .,8 42 ..3(25) 549.,7 45..5(25) 559,.0 47,.3(25) 555 .2 52 .1(15) 567 .1 52 .2(15) 568 .8 52 3(15) 583 .3 53 .8(15) 584 .3 56 .8(15) Company Sanitized. Does not contain TSCA CBI - 76- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-11418 TABLE 4 (CONTINUED) MEAN BODY WEIGHTS OF MALE RATS (g) Group : Dosage(mg/kg/day) I 0 III V 10 100 Three-Month Recovery Period for Subchronic Toxicity Evaluation VII 1000 DAY133 DAY140 DAY147 DAY154 DAY161 639.4 33.6(5) 643.7 38.0(5) 649.2 37.4(5) 658.2 43.6(5) 670.3 44.6(5) 562.8 73.9(5) 568.2 77.3(5) 571.7 78.3(5) 576.1 80.6(5) 585.1 82.9(5) 663.2 100.2 (4) 672.7 110.2 (4) 676.5 111.4(4) 683.7 110.8(4) 696.7 117.2(4) 568.0 46.5(5) 578.2 48.9(5) 581.9 52.0(5) 589.8 51.2(5) 602.8 53.2(5) DAY168 672.2 49.2(5) 587.1 86.0(5) 697.9 114.2(4) 604.1 57.9(5) DAY175 685.0 50.4(5) 597.1 89.8(5) 713.6 115.6(4) 617.2 59.8(5) DAY182 691.6 51.0(5) 605.5 93.0(5) 723.8 117.7(4) 621.8 61.1(5) Data arranged as: Mean Standard deviation (Number o f animals included in calculation) a Rats designated for reproduction evaluation (20 rats/group) were transferred for reproductive assessment on test day 72; subsequent data are reported as part o f the reproduction evaluation. There were no statistically significant differences from control at p < 0.05. Company Sanitized. Does not contain TSCA CBI - 77- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 5 MEAN BODY WEIGHTS OF FEMALE RATS (g) Group : Dosage(mg/kg/day) II 0 IV VI 10 100 Period for Subchronic Toxicity and Reproduction Evaluations DAYO DAY7 DAY 14 DAY21 DAY28 DAY35 DAY42 DAY49 DAY56 DAY 63 173.6 10.7(45) 194.3 14.0(45) 214.5 20.0(45) 236.6 19.6(45) 252.5 21.7(45) 260.9 22.7(45) 271.0 23.3(45) 281.7 25.6(45) 286.3 26.2(45) 291.2 26.4(45) 172.7 14.3(35) 194.9 17.6(35) 213.0 18.2(35) 236.4 21.4(35) 252.4 24.8(35) 260.7 26.1(35) 272.2 25.3(35) 279.9 27.6(35) 286.5 29.3 (35) 291.4 28.1(35) 174.4 12.2(35) 195.6 14.3 (35) 213.7 16.0(35) 234.2 18.1(35) 251.0 20.2 (35) 259.5 20.7(35) 268.8 24.2(35) 279.1 24.3(35) 285.9 25.3(35) 291.0 26.0(35) DuPont-11418 VIII 1000 170.8 11.8(45) 193.4 14.4(45) 209.8 18.4(45) 232.0 20.0(45) 246.4 21.9(45) 256.3 25.0(45) 266.1 25.0(45) 275.9 27.6(45) 281.3 27.6(45) 286.8 28.2(45) Company Sanitized. Does not contain TSCA CBI - 78- )) H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 5 (CONTINUED) MEAN BODY WEIGHTS OF FEMALE RATS (g) Group : Dosage(mg/kg/day) IX 0 IV 10 DAY70 295.3 27.6(45) 294.8 27.2(35) Dosing Period for Subchronic Toxicity Evaluation (continued) DAY77 301.2 31.9(25) 296.6 24.3(15) DAY84 306.4 32.5(25) 303.0 22.0(15) DAY 91 311.4 33.4(25) 305.4 22.8(15) One-Month Recovery Perio'd for Subchronic Toxicity Evaluation DAY 98 306.3 35.3 (15) 308.1 9.6(5) DAY105 317.1 39.8(15) 317.5 15.4(5) DAY112 322.8 39.2(15) 322.8 15.7(5) DAY119 327.9 44.1(15) 325.2 16.5(5) DAY126 330.2 44.1(15) 329.5 19.5(5) VI 100 294.3 26.5(35) 296.9 18.6(15) 303.3 20.0(15) 306.4 19.3(15) 310.1 24.1(5) 322.6 19.6(5) 328.6 23.3(5) 330.2 24.6(5) 330.9 26.5(5) ) DuPont-11418 VIII 1000 292.7 28.9(45) 293.8 19.8(25) 297.0 21.5(25) 299.2 23.4(25) 296.8 18.1(15) 307.4 19.4(15) 313.8 21.5(15) 314.1 20.7(15) 315.7 20.9(15) Company Sanitized. Does not contain TSCA CBI - 79- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-11418 TABLE 5 (CONTINUED) MEAN BODY WEIGHTS OF FEMALE RATS (g) Group: Dosage(mg/kg/day) II 0 IV VI 10 100 Three-Month Recovery Period for Subchronic Toxicity Evaluation VIII 1000 DAY133 308.7 54.0(5) 334.3 20.4(5) 341.1 24.7(5) 323.7 8.6(5) DAY140 316.0 55.0(5) 339.9 16.5(5) 350.8 29.0(5) 330.0 8.6(5) DAY147 316.2 60.7(5) 337.8 20.4(5) 348.3 25.2(5) 333.2 7.0(5) DAY154 316.8 61.8(5) 342.3 19.6(5) 352.4 25.2(5) 335.7 5.9(5) DAY161 327.0 70.5(5) 353.7 24.7 (5) 361.3 27.8(5) 347.7 8.3(5) DAY168 323.2 65.5(5) 350.1 24.9(5) 357.9 25.4(5) 349.3 7.6(5) DAY175 327.4 69.8(5) 354.0 22.7(5) 363.9 32.0(5) 356.4 9.9(5) DAY182 331.4 67.0(5) 360.1 23.1(5) 368.1 27.7(5) 360.7 11.0(5) Data arranged as: Mean Standard deviation (Number o f animals included in calculation) a Rats designated for reproduction evaluation (20 rats/group) were transferred for reproductive assessment on test day 72; subsequent data are reported as part o f the reproduction evaluation. t There were no statistically significant differences from control at p < 0.05. Company Sanitized. Does not contain TSCA CBI -80- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE Group : Dosage(mg/kg/day) MEAN BODY WEIGHT GAINS OF MALE RATS (g) I III V 0 10 100 Period for Subchronic Toxicity and Reproduction Evaluations DAY0-DAY7 DAY7-DAY14 DAY14-DAY21 DAY21-DAY2 8 DAY28-DAY35 DAY35-DAY42 DAY42-DAY49 DAY49-DAY56 DAY56-DAY63 55.0 7.8(45) 47.6 7.2(45) 44.2 7.5(45) 34.0 6.7(45) 27.5 7.0(45) 21.0 7.3 (45) 22.6 6.9(45) 19.7 6.7(45) 17.7 7.4(45) 51.4 7.2(35) 41.1# 7.7(35) 40.8 6.6(35) 35.8 6.6(35) 23.3 5.5(35) 21.5 6.9(35) 24.5 6.9(35) 15.0 10.2(35) 17.8 9.6(35) 56.0 8.0(35) 39.9# 7.5(35) 41.5 7.7(35) 35.1 7.2(35) 30.6 7.6(35) 18.1 6.4(35) 20.0 6.7(35) 17.3 7.5(35) 17.3 7.4(35) DuPont-11418 VII 1000 50.0# 6.1(45) 43.3# 6.6(45) 43.5 6.9(45) 29.1# 6.1(45) 28.1 5.5(45) 21.4 6.8(45) 25.1 7.7(45) 13.8# 5.4(45) 16.9 6.1(45) Company Sanitized. Does not contain TSCA CBI -81- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 6 (CONTINUED) Group: Dosage(mg/kg/day) DAY63-DAY70 a DAY0-DAY70 MEAN BODY WEIGHT GAINS OF MALE RATS (g) I III V 0 10 100 15.1 6.6(45) 16.4 5.4(35) 11.5 13.1(35) 304.4 41.5(45) 287.8 37.0(35) 287.5 46.8(35) Period for Subchronic Toxicity Evaluation (continued) DAY7 0-DAY77 DAY77-DAY84 DAY84-DAY91 12.7 6.5(25) 9.4 6.0(25) 6.4 6.2(25) 8.3 20.5(15) 10.6 12.3(15) 4.5 9.8(15) 6.7# 7.5(15) 12.5 6.3(15) 5.5 6.8(15) DAY0-DAY91 335.6 48.1(25) 314.3 52.7(15) 335.7 52.5(15) DuPont-11418 VII 1000 15.1 6.1(45) 286.2 35.7 (45) 7.8# 5.6(25) 11.9 7.4(25) 9.3 7.7(25) 316.2 39.5(25) Company Sanitized. Does not contain TSCA C8I - 82- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 6 (CONTINUED) MEAN BODY WEIGHT GAINS OF MALE RATS (g) Group : Dosage(mg/kg/day) I 0 III V 10 100 One-Month Recovery Perio'd for Subchronic Toxicity Evaluation DAY91-DAY98 11.5 5.5(15) 6.0 5.2(5) 1.4 11.5(5) DAY9 8-DAY105 11.6 7.2(15) 10.9 8.9(5) 10.9 4.1(5) DAY105-DAY112 6.6 7.1(15) 6.5 5.8(5) 5.7 6.6(4) DAY112-DAY119 15.6 5.6(15) 11.1 6.3(5) 18.9 7.2(4) DAY119-DAY126 -2.2 4.1(15) 1.7 6.2(5) 3.3 2.6(4) DAY 91-DAY126 43.0 8.4(15) 36.2 16.8(5) Three-Month Recovery Period for Subchronic Toxicity Evaluation 43.6 20.4(4) DAY126-DAY133 DAY133-DAY140 14.9 8.1(5) 4.4 6.2(5) 20.0 9.0(5) 5.3 4.7(5) 23.7 4.0(4) 9.4 10.9(4) DuPont-11418 VII 1000 8.3 7.0(15) 12.0 6.5(15) 1.6# 3.7(15) 14.5 5.0(15) 1.0 5.5(15) 37.5 13.9(15) 18.1 5.0(5) 10.2 6.7(5) Company Sanitized. Does not contain TSCA CBI - 83- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-11418 TABLE 6 (CONTINUED) MEAN BODY WEIGHT GAINS OF MALE RATS (g) Group : Dosage(mg/kg/day) I 0 III V 10 100 Three-Month Recovery Period for Subchronic Toxicity Evaluation VII 1000 DAY140-DAY147 DAY147-DAY154 D A Y 1 54 - D A Y 1 61 DAY161-DAY168 DAY168-DAY175, DAY175-DAY182 5.5 3.0(5) 9.0 6.3(5) 12.1 5.1(5) 1.9 7.1(5) 12.8 3.6(5) 6.6 3.5(5) 3.6 5.3(5) 4.3 4.7(5) 9.1 6.4(5) 1.9 4.6(5) 10.1 5.0(5) 8.4 5.9(5) 3.8 4.3(4) 7.3 1-0(4) 13.0 9.2(4) 1.2 4.9(4) 15.8 6.5(4) 10.2 2.2(4) 3.7 6.1(5) 7.9 4.4(5) 13.0 4.3(5) 1.3 5.2(5) 13.1 5.3(5) 4.6 3.2(5) DAY91-DAY182 106.6 35.2(5) 98.8 33.7(5) 127.8 . 40.2(4) 98.4 31.1(5) Data arrangedas: Mean Standarddeviation(Number ofanimalsincludedincalculation) a Ratsdesignatedforreproductionevaluation(20rats/group)were transferredforreproductiveassessmenton testday72;subsequentdataarereportedaspartofthe reproductionevaluation. # Statisticallysignificantdifferencefromcontrolatp < 0.05by Jonckheere-Terpstratrendtest. Company Sanitized. Does not contain TSCA CBI -84- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 7 MEAN BODY WEIGHT GAINS OF FEMALE RATS (g) Group: II IV VI Dosage(mg/kg/day) 0 10 100 Period for Subchronic Toxicity and Reproduction Evaluations DAY0-DAY7 > DAY7-DAY14 ' DAY14-DAY21 DAY21-DAY28 DAY28-DAY35 DAY35-DAY42 DAY42-DAY49 DAY49-DAY56 DAY56-DAY63 20.6 8.0(45) 20.2 10.2(45) 22.1 9.4(45) 15.9 6.4(45) 8.3 7.1(45) 10.1 8.4(45) 10.7 6.8(45) 4.6 5.5(45) 4.9 6.6(45) 22.2 7.3(35) 18.1 6.6(35) 23.4 8.2(35) 16.0 6.9(35) 8.3 6.4(35) 11.6 7.4(35) 7.6 7.5(35) 6.6 5.4(35) 4.9 6.5(35) 21.2 5.3 (35) 18.2 7.3 (35) 20.5 7.1(35) 16.8 6.2(35) 8.6 5.7(35) 9.3 7.7(35) 10.3 8.8(35) 6.8 6.7(35) 5.1 7.0(35) DuPont-11418 VIII 1000 22.6 6.0(45) 16.4 7.9(45) 22.3 6.8(45) 14.4 6.1(45) 9.9 6.7(45) 9.8 6.9(45) 9.8 7.5(45) 5.4 7.0(45) 5.5 8.0(45) Company Sanitized. Does not contain TSCA CBI -85- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 7 (CONTINUED) MEAN BODY WEIGHT GAINS OF FEMALE RATS (g) Group: Dosage(mg/kg/day) DAY63-DAY70 a II 0 4.2 7.4(45) IV 10 3.4 7.5(35) DAY0-DAY70 121.7 21.6(45) 122.1 18.5 (35) Dosing Period for Subchronic Toxicity Evaluation (continued) DAY70-DAY77 DAY7 7 -DAY84 DAY84-DAY91 5.0 7.6(25) 5.1 6.3(25) 5.1 5.9(25) 0.4 9.0(15) 6.4 8.6(15) 2.4 8.0(15) DAYQ-DAY91 139.4 27.1(25) 132.8 17.0(15) One-Month Recovery Period for Subchronic Toxicity Evaluation DAY91-DAY98 1.9 7.9(15) 5.7 5.7(5) DAY 98-DAY105 10.8 10.0(15) 9.4 8.0(5) DAY105-DAY112 5.7 5.1(15) 5.4 1.8(5) VI 100 3.4 6.5(35) 120.0 18.8(35) 3.2 5.7(15) 6.4 5.8(15) 3.1 5.8(15) 132.2 14.1(15) 1.7 4.4(5) 12.4 8.8(5) 6.0 9.3(5) - 86- DuPont-11418 VIII 1000 5.9 7.8(45) 121.9 20.4(45) 5.6 6.9(25) 3.2 5.5 (25) 2.2 6.0(25) 130.2 16.9(25) 5.7 6.6(15) 10.6 6.5(15) 6.3 8.4(15) H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 7 (CONTINUED) MEAN BODY WEIGHT GAINS OF FEMALE RATS (g) Group : Dosage(mg/kg/day) DAYl 12-DAYl19 DAY119-DAY126 11 0 5.1 11.0(15) 2.3 5.8(15) IV 10 2.4 10.0(5) 4.3 8.0(5) DAY91-DAY12 6 25.8 14.3(15) 27.1 15.3(5) Three-Month Recovery Period for Subchronic Toxicity Evaluation DAY126-DAY133 DAY133-DAY140 DAY140-DAY147 DAY147-DAYl54 DAYl54 -DAYl61 DAYl61 -DAYl68 4.9 5.8(5) 7.4 7.8(5) 0.2 6.1(5) 0.6 7.1(5) 10.2 10.5(5) -3.8 8.9(5) 4.8 4.9(5) 5.5 8.0(5) -2.1 6.1(5) 4.5 7.8(5) 11.4 8.3(5) -3.6 2.2(5) VI 100 1.6 3.5(5) 0.7 3.9(5) 22.4 8.2(5) 10.2 5.7(5) 9.7 6.9(5) -2.6 5.3(5) 4.1 4.9(5) 8.9 3.6(5) -3.4 5.9(5) DuPont-11418 VIII 1000 0.3 8.7(15) 1.6 8.2(15) 24.6 6.8(15) 4.1 8.7(5) 6.2 3.2(5) 3.2 9-9(5) 2.5 5.0(5) 12.0 5.0(5) 1.6 4.6(5) Company Sanitized. Does not contain TSCA CBI -87- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-11418 TABLE 7 (CONTINUED) MEAN BODY WEIGHT GAINS OF FEMALE RATS (g) Group : Dosage(mg/kg/day) DAY168 -DAY175 DAY175 -DAY182 II 0 4.2 6.6(5) 4.0 4.2(5) IV 10 3.9 2.4(5) 6.1 6.3(5) VI 100 6.0 8.4(5) 4.2 6.2(5) VIII 1000 7.1 5.0(5) 4.3 5.5(5) DAY91-DAYl82 50.3 29.9(5) 57.7 19.6(5) 59.6 11.1(5) 66.1 9.8(5) Data arranged as: Mean Standard deviation (Number o f animals included in calculation) a Rats designated for reproduction evaluation (20 rats/group) were transferred for reproductive assessment on test day 72; subsequent data are reported as part o f the reproduction evaluation. There were no statistically significant differences from control at p < 0.05. Company Sanitized. Does not contain TSCA CBI -88- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with Qne-Generation Reproductive Evaluations TABLE 8 MEAN DAILY FOOD CONSUMPTION BY MALE RATS (g/day) Group : Dosage(mg/kg/day) III V 10 100 Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY0-DAY7 DAY7-DAY14' DAY14-DAY21 DAY21-DAY28 DAY2 8-DAY3 5 DAY35-DAY42 DAY42-DAY49 DAY49 -DAY5 6 DAY 56-DAY63 DAY63-DAY7 0 26.9 2.0(45) 28.2 2.0(45) 29.5 2.3(45) 29.5 2.4(45) 29.6 2.4(45) 28.6 2.5(45)' 29.5 2.8(45) 29.6 2.6(45) 29.9 2.7(45) 28.9 2.9(45) 26.8 1.9(35) 27.3 2.5(35) 28.8 2.4(35) 29.6 2.6 (35) 29.1 2.6(35) 28.1 2.2(35) 29.5 3.2(35) 28.9 3.0(35) 29.8 2.7(35) 29.3 2.9(35) 27.0 2.3(35) 27.3 2.7(35) 28.7 2.8(35) 29.2 2.9(35) 29.3 3.1(35) 28.2 2.7(35) 28.5 3.1(35) 28.4 3.2(35) 28.7 3.0(35) 28.3 4.0 (35) DuPont-11418 VII 1000 26.1 1.9(45) 27.3 2.1(45) 28.7 2.4(45) 28.7 2.1(45) 28.6 2.2(45) 28.5 2.3(45) 29.8 2.8(45) 28.5 2.5(45) 29.0 2.7(45) 29.0 2.8(45) Company Sanitized. Does not contain TSCA CBI -89- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 8 (CONTINUED) MEAN DAILY FOOD CONSUMPTION BY MALE RATS (g/day) Group: Dosage(mg/kg/day) I 0 III 10 DAYO-DAY70 , 20.5 1.6(45) 20.4 1.7(35) Dosing Period for Subchronic Toxicity Evaluation (continued) DAY70-DAY77 DAY77-DAY84 DAY84-DAY91 29.4 2.9(25) 28.1 2.9(25) 27.4 3.1(25) 28.2 5.7(15) 29.0 3.5(15) 27.6 4.2(15) DAY0-DAY91 29.0 2.1(25) 28.8 3.0(15) One-Month Recovery Period for Subchronic Toxicity Evaluation DAY91 -DAYS8 28.0 2.5(10) . (0) DAY98 -DAY105 28.4 3.0(10) . (0) DAY105-DAY112 DAY112-DAY119 29.7 3.0(10) 29.9 2.6(10) . (0) . (0) V 100 20.4 1.9(35) 28.4 3.4(14) 28.5 2.9(15) 27.0 2.9(15) 28.7 2.7(14) . (0) . (0) . CO) - (0) DuPont-11418 VII 1000 20.2 1.7(45) 27.8 3.0(25) 27.6 2.9(25) 27.4 2.8(25) 28.2 2.1(25) 28.6 2.6(10) 29.3 1.1(10) 29.4 2.9(10) 29.4 2.9(10) H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-11418 TABLE 8 (CONTINUED) MEAN DAILY FOOD CONSUMPTION BY MALE RATS (g/day) Group : D o sa g e(m g /k g /d a y ) D A Y 119-D A Y 126 D A Y 91-D A Y 126 I 0 29.3 2.9(10) 29.0 2.6(10) III 10 (0) (0) V 100 . (0) (0) V II 1000 29.9 2.9(10) 29.3 2.4(10) Data arranged as: Mean Standard deviation (Number o f animals included in calculation) a Rats designated for reproduction evaluation (20 rats/group) were transferred for reproductive assessment on test day 72; food consum ption data w ere not collected during the cohabitation and postmating periods. # Statistically significant difference from control at p < 0.05 by Jonckheere-Terpstra trend test. Company Sanitized. Does not contain TSCA CBI -91- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 9 MEAN DAILY FOOD CONSUMPTION BY FEMALE RATS (g/day) Group : Dosage(mg/kg/day) II 0 IV VI 10 100 Period for Subchronic Toxicity and Reproduction Evaluations DAY0-DAY7 DAY7-DAY14' DAY14-DAY21 DAY21-DAY28 DAY28-DAY35 DAY35-DAY42 DAY 42 -DAY4 9 DAY49-DAY56 DAY56-DAY63 DAY63-DAY7 0 a 18.8 1.7(45) 20.1 1.8(45) 21.1 2.1(45) 21.6 2.3(45) 21.2 2.0(45) 20.5 1.8(45) 21.2 2.1(45) 20.2 2.1(45) 20.7 1.8(45) 20.0 1.8(45) 18.5 1.6 (35) 20.3 1.8(35) 20.4 2.2(35) 21.4 2.0(35) 21.1 2.9(35) 20.9 2.0(35) 20.9 2.3(35) 20.3 1.9(35) 20.4 2.2 (35) 19.8 1.7(35) 19.2 1.6(35) 20.2 2.1(35) 20.8 3.2(35) 20.7 2.1(35) 20.7 1.9(35) 20.5 2.4(35) 21.4 2.1(35) 19.8 2.4(35) 20.1 2.0(35) 20.6 3.6(35) DuPont-11418 VIII 1000 19.1 1.5(45) 19.7 1.7(45) 20.3 2.0(45) 20.4# 1.9(45) 20.4# 2.1(45) 20.4 2.1(45) 20.7 2.3(45) 20.0 1.9(45) 20.2 1.9(45) 20.5 2.0(45) Company Sanitized. Does not contain TSCA CBI -92- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with Qne-Generation Reproductive Evaluations TABLE 9 (CONTINUED) MEAN DAILY FOOD CONSUMPTION BY FEMALE RATS (g/day) Group: Dosage(mg/kg/day) II 0 IV 10 DAYO-DAY70 20.5 1.6(45) 20.4 1.7(35) Dosing Period for Subchronic Toxicity Evaluation (continued) DAY70-DAY77 DAY77-DAY84 DAY84-DAY91 20.5 2.1(25) 19.7 2.0(25) 19.7 2.1(25) 20.7 1.5(15) 20.4 1.5(15) 19.4 1.6(15) DAY0-DAY91 20.5 1.7(25) 20.2 1.0(15) One-Month Recovery Period for Subchronic Toxicity Evaluation DAY91-DAY98 20.5 1.8(10) . (0) DAY98-DAY105 21.9 2.9(10) . (0) DAY105-BAY112 21.9 2.6(10) . (0) DAYl12-DAYl19 22.1 3.0(10) . (0) VI 100 20.4 1.9(35) 20.4 1.6(15) 20.1 2.0(15) 18.1# 1.1(15) 20.2 1.4(15) . (0) . (0) . (0) . (0) DuPont-11418 VIII 1000 20.2 1.7(45) 19.9 1.3(25) 20.2 1.7(25) 18.7# ' 1.6(25) 19.9 1.1(25) 19.7 1.5(10) 20.6 1.7(10) 21.2 2.3(10) 19.4# 2.2(10) Company Sanitized. Does not contain TSCA CBI - 93- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-11418 TABLE 9 (CONTINUED) MEAN DAILY FOOD CONSUMPTION BY FEMALE RATS (g/day) Group : Dosage(mg/kg/day) DAY119-DAY126 DAY91-DAY12 6 II 0 22.2 2.5(10) 21.7 2.3(10) IV 10 . (0) (0) VI 100 . (0) (0) VIII 1000 20.8 2.2(10) 20.3 1.6(10) Data arranged as: Mean Standard deviation (Number of animals included in calculation) a Rats designated for reproduction evaluation (20 rats/group) were transferred for reproductive assessment on test day 72; data were not collected during the cohabitation period. F ood consum ption data collected during gestation are reported as part o f the reproduction evaluation. # Statistically significant difference from control at p < 0.05 by Jonckheere-Terpstra trend test. Company Sanitized. Does not contain TSCA C8I -94- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations___________________________ ______________________________DuPont-11418 TABLE 10 Group : Dosage(mg/kg/day) MEAN DAILY FOOD EFFICIENCY OF MALE RATS 1 III V 0 10 100 Period for Subchronic Toxicity and Reproduction Evaluations DAY0-DAY7 DAY7-DAY14 DAY14-DAY21 DAY21-DAY28 DAY28-DAY35 DAY35-DAY42 DAY42-DAY49 DAY49-DAY56 DAY 56-DAY 63 DAY 63-DAY7 0 a 0.292 0.028(45) 0.241 0.028(45) 0.213 0.026(45) 0.164 0.025(45) 0.132 0.029(45) 0.104 0.032(45) 0.108 0.026(45) 0.094 0.030(45) 0.084 0.031(45) 0.074 0.032(45) 0.274 0.031(35) 0.214# 0.029(35) 0.202 0.025(35) 0.173 0.026(35) 0.114 0.023(35) 0.109 0.032(35) 0.118 0.026(35) 0.073 0.049(35) 0.084 0.038(35) 0.079 0.023(35) 0.2 9 6 0.030(35) 0.208# 0.029(35) 0.207 0.028(35) 0.171 0.026(35) 0.148# 0.026(35) 0.091 0.029(35) 0.099 0.029 (35) 0.086 0.034(35) 0.084 0.034(35) 0.050 0.100(35) VII 1000 0.273# 0.024(45) 0.226# 0.024(45) 0.216 0.027(45) 0.144# 0.024(45) 0.140# 0.025(45) 0.106 0.029(45) 0.119 0.031(45) 0.069# 0.025(45) 0.082 0.026(45) 0.073 0.029(45) Company Sanitized. Does not contain TSCA CBI -95- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 10 (CONTINUED) Group: Dosage(mg/kg/day) MEAN DAILY FOOD EFFICIENCY OF MALE RATS X III V 0 10 100 DAY0-DAY70 0.149 0.012(45) 0.143 0.010(35) Dosing Period for Subchronic Toxicity Evaluation (continued) 0.144 0.014(35) DAY70-DAY77 DAY7 7-DAY84 ' DAY84-DAY91 0.060 0.029(25) 0.047 0.029(25) 0.032 0.030(25) 0.012 0.201(15) 0.050 0.057(15) 0.020 0.060(15) 0.032# 0.046(14) 0.063 0.031(15) 0.028 0.032 (15) DAY0-DAY91 0.127 0.011(25) 0.119 0.011(15) One-Month Recovery Period for Subchronic Toxicity Evaluation DAY91-DAY9 8 0.060 0.026(10) (0) DAY9 8-DAY105 0.062 0.038(10) (0) DAY105-DAY112 0.029 0.040(10) (0) DAY112-DAY119 0.079 0.019(10) (0) 0.125 0.009(14) (0) (0) (0) (0) DuPont-11418 VII 1000 0.143 0.011(45) 0.039# 0.027(25) 0.060 0.036(25) 0.046 0.040 (25) 0.123 0.008(25) 0.057 0.026(10) 0.065 0.025(10) 0.008 0.020(10) 0.071 0.024(10) Company Sanitized. Does not contain TSCA CBI -96- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-11418 Group : Dosage(mg/kg/day) DAY119-DAY126 DAY91-DAY12 6 TABLE 10 (CONTINUED) MEAN DAILY FOOD EFFICIENCY OF MALE RATS I III V 0 10 100 -0.012 0.016(10) (0) (0) 0.044 0.004(10) . (0) . (0) VII 1000 0.007# 0.029(10) 0.042 0.010(10) Data arranged as: Mean Standard deviation (Number of animals included in calculation) a Rats designated for reproduction evaluation (20 rats/group) were transferred for reproductive assessment on test day 72; food consumption data were not collected during the cohabitation and postmating periods. # Statistically significant difference from control at p < 0.05 by Jonckheere-Terpstra trend test. Company Sanitized. Does not contain TSCA CBI -97- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 11 Group : Dosage(mg/kg/day) MEAN DAILY FOOD EFFICIENCY OF FEMALE RATS II IV VI 0 10 100 Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY0-DAY7 DAY7-DAY14 DAY14-DAY21 DAY21-DAY28 DAY28-DAY35 ' DAY35-DAY42 DAY42-DAY49 DAY49-DAY56 DAY5 6-DAY63 DAY63-DAY7 0 a 0. 155 0. 053(45) 0. 143 0. 075(45) 0. 150 0 .059(45) 0..105 0..042(45) 0..055 0..046(45) 0 .069 0 .057(45) 0 .071 0 .044(45) 0 .032 0 .036(45) 0 .032 0 .044(45) 0 .028 0 .051(45) 0. 169 0. 052(35) 0. 127 0. 044 (35) 0. 162 0. 048(35) 0..105 0.,042(35) 0..055 0..042(35) 0..078 0,.049(35) 0 .050 0 .047 (35) 0 .046 0 .038(35) 0 .035 0 .048(35) 0 .023 0 .053(35) 0. 158 0. 036(35) 0. 127 0. 045(35) 0..140 0..047(35) 0..115 0..038(35) 0..058 0..037(35) 0 .061 0 .048(35) 0 .068 0 .057(35) 0 .048 0 .046(35) 0 .034 0 .054(35) 0 .023 0 .047(35) DuPont-11418 VIII 1000 0. 168 0. 041(45) 0. 116 0. 053(45) 0. 156 0. 041(45) 0..099 0.,038(45) 0..068 0..043(45) 0 .068 0 .046(45) 0 .065 0 .049(45) 0 .038 0 .049(45) 0 .038 0 .055(45) 0 .039 0 .052(45) Company Sanitized. Does not contain TSCA CBI -98- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 11 (CONTINUED) MEAN DAILY FOOD EFFICIENCY OF FEMALE RATS Group: Dosage(mg/kg/day) XI 0 IV VI 10 100 DAY0-DAY70 0.084 0.011(45) 0.085 0.009(35) Dosing Period for Subchronic Toxicity Evaluation (continued) 0.084 0.009(35) DAY7 0-DAY7 7' DAY7 7-DAY84 DAY84-DAY91 0.034 0.052(25) 0.037 0.045(25) 0.036 0.041(25) 0.002 0.060(15) 0.043 0.058(15) 0.018 0.061(15) 0.023 0.039(15) 0.044 0.038(15) 0.024 0.047(15) DAY0-DAY91 0.074 0.010(25) 0.072 0.007(15) One-Month Recovery Period for Subchronic Toxicity Evaluation DAY91-DAY98 0.014 0.057(10) (0) DAY98-DAY105 0.068 0.054(10) (0) DAY105-DAY112 0.026 0.032(10) (0) DAY112-DAY119 0.046 0.069(10) (0) 0.072 0.006(15) (0) (0) (0) (0) DuPont-11418 VIII 1000 0.086 0.009(45) 0.039 0.049(25) 0.021 0.038(25) 0.016 0.047(25) 0.072 0.007(25) 0.064# 0.031(10) 0.059 0.028(10) 0.036 0.057(10) 0.001 0.079(10) Company Sanitized. Does not contain TSCA C8I -99- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-11418 TABLE 11 (CONTINUED) MEAN DAILY FOOD EFFICIENCY OF FEMALE RATS Group : Dosage(mg/kg/day) DAY119-DAY126 II o 0.014 0.034(10) IV 10 (0) VI 100 (0) VIII 1000 -0.000 0.058(10) DAY91-DAY126 0.035 0.015(10) (0) 0.034 (0) 0.009(10) Data arranged as: Mean Standard deviation (Number of animals included in calculation) a Rats designated for reproduction evaluation (20 rats/group) were transferred for reproductive assessment on test day 72; data were not collected during the cohabitation period. Food consumption data collected during gestation are reported as part of the reproduction evaluation. # Statistically significant difference from control at p < 0.05 by Jonckheere-Terpstra trend test. Company Sanitized. Does not contain TSCA CBI - 100- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Treatment Group Dosage (mg/kg/day) Animal Count Eye Observations Corneal Opacity Right Incidence Mean onset (Days) Enophthalmus Left Incidence Mean onset (Days) Wet Fur Incidence Mean onset (Days) General Teeth Observations Clipped Incidence Mean onset (Days) Diarrhea Brown Incidence Mean onset (Days) Discharge Eye Incidence Mean onset (Days) Nose Incidence Mean onset (Days) TABLE 12 SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS I III V. o 10 100 45 35 35 VII 1000 45 1 168 1 56 1 77 1 77 12 140 102 3 75 1 63 3 137 - 101 - DuPont-11418 H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Treatment Group Dosage (mg/kg/day) Animal Count Mouth Red Incidence Mean onset (Days) Hair Loss Incidence Mean onset (Days) Wound Superficial Incidence Mean onset (Days) Hyperreactive Incidence Mean onset (Days) Aggressive Behavior Incidence Mean onset (Days) Misshapen Observations Tail Incidence Mean onset (Days) TABLE 12 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS I III V ' 0 10 100 45 35 35 VII 1000 45 0010 63 5 11 4 8 61 26 24 44 0 1 77 0 > 1 7 1 42 1 84 0 0 01 28 01 105 01 105 00 DuPont-11418 Company Sanitized. Does not contain TSCA CBI - 102- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations_________________________________________________________DuPont-11418 TABLE 12 (CONTINUED) Treatment Group Dosage (mg/kg/day) Animal Count Stain Fur/Skin Incidence Mean onset (Days) Swollen Observations Face Incidence Mean onset (Days) SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS I III V 0 10 100 45 35 35 VII 1000 45 02 112 21 56 105 0100 8 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. There were no statistically significant differences at p < 0.05. Company Sanitized. Does not contain TSCA CBI -103- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Treatment Group Dosage (mg/kg/day) Animal Count Mass Side Left Mass #1 Not Ulcerated Incidence Mean onset (Days) Eye Observations Dark Right Incidence Mean onset (Days) Corneal Opacity Right Incidence Mean onset (Days) Enophthalmus Right Incidence Mean onset (Days) Discharge Eye Incidence Mean onset (Days) Hair Loss Incidence Mean onset (Days) TABLE 13 SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS II IV VI VIII 0 10 100 1000 45 35 35 45 0001 91 0001 77 0011 147 119 0011 147 154 4111 105 21 126 126 6 12 9 9 63 32 44 68 -104- DuPont-11418 Company Sanitized. Does not contain TSCA C8I H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 13 (CONTINUED) Treatment Group Dosage (mg/kg/day) Animal Count Wound Superficial Incidence Mean onset (Days) Arches back during handling Incidence Mean onset (Days) Ear twitch Bilateral Incidence Mean onset (Days) Hyperreactive Incidence Mean onset (Days) Hyperactive Incidence Mean onset (Days) Stain Fur/Skin Incidence Mean onset (Days) SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS II IV VI VIII 0 10 100 1000 45 35 35 45 0020 21 4212 70 70 49 56 23 105 49 11 77 63 12 14 84 33 107 102 14 49 39 00 02 49 45 99 108 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. There were no statistically significant differences at p < 0.05. - 105- DuPont-11418 H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-11418 TABUE 14 SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR MALE RATS Treatment Group Dosage (mg/kg/day) I 0 III V 10 100 VII 1000 Examination D a y : Test D a y 87 Number of Rats Examined 20 10 10 20 Retina Retinal Degeneration, Focal Right Incidence 1 ( 5%) 0 0 0 Incidence - The number of animals (percent of animals examined) for which an observation was recorded. There were no statistically significant differences at p < 0.05 by Cochran-Armitage trend test. Company Sanitized. Does not contain TSCA CBI - 106- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 15 SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR FEMALE RATS DuPont-11418 Treatment Group Dosage (mg/kg/day) * II 0 Examination D a y : Test D a y 87 Number of Rats Examined Retina Retinal Degeneration. Focal Left 20 Incidence 1 ( 5%) IV 10 10 0 VI VIII 100 1000 10 20 00 Incidence - The number of animals (percent of animals examined) for which an observation was recorded. There were no statistically significant differences at p < 0.05 by Cochran-Armitage trend test. Company Sanitized. Does not contain TSCA CBI -107 - H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 TABLE 16 DAYS ON TEST 0 PERCENT SURVIVAL OF MALE RATS Group I 0 mg/kg/day 100 Group HI 10 mg/kg/day 100 Group V 100 mg/kg/day 100 Group V 1000 mg/kg/day 100 7 14 21 28 35 42 49 56 63 70 77 a 84 9 1 b .c 98 105 112 119 126 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 80d 100 100 100 80 100 100 100 80 100 Number at study start 45 35 35 45 Found dead 00 10 Removed from study3 20 20 20 20 Sacrificed by design0 10 10 10 10 Alive on test day 126 15 5 4 15 Percent Survival = (Number of Rats Alive/Number of Rats at Risk)* 100 Number of rats at risk = Number at study start - number removed from study - number sacrificed by design a Rats designated for reproduction evaluation (20 rats/group) were transferred for reproductive assessment on test day 72. b Recovery period began on test day 91. c Rats designated for the subchronic toxicity evaluation were sacrificed on test day 92. d Rat found dead during previous week. There were no statistically significant decreases in survival at p < 0.05 by Cochran-Armitage trend test. Note: Rats designated for evaluation of 10-day hepatic biochemical evaluations are not included in this table. - 108Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 TABLE 17 DAYS ON TEST 0 PERCENT SURVIVAL OF FEMALE RATS Group II 0 mg/kg/day 100 Group IV 10 mg/kg/day 100 Group VI 100 mg/kg/day 100 Group Vm 1000 mg/kg/day 100 7 14 21 28 35 42 49 56 63 70 77a 84 9 1 b,c 98 105 112 119 126 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 Number at study start 45 35 35 45 Removed from study3 20 20 20 20 Sacrificed by design' 10 10 10 10 Alive on test day 126 15 5 5 15 Percent Survival = (Number of Rats Alive/Number of Rats at Risk)* 100 Number of rats at risk = Number at study start -number removed from study - number sacrificed by design a Rats designated for reproduction evaluation (20 rats/group) were transferred for reproductive assessment on test day 72. b Recovery period began on test day 91. c Rats designated for the subchronic toxicity evaluation were sacrificed on test day 93. There were no statistically significant decreases in survival at p < 0.05 by Cochran-Armitage frend test. Note: Rats designated for evaluation of 10-day hepatic biochemical evaluations are not included in this table. - 109Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-11418 TABLE 18 MEAN FORELIMB AND HINDLIMB GRIP STRENGTH FOR MALE RATS (MEAN OF THREE TRIALS) Assessment Dosage Period Group (mg/kg/day) Forelimb Grip Strength (kg) Hindlimb Grip Strength (kg) Baseline I m V vn 0 10 100 1000 0.61 (0.07) 0.62 (0.07) 0.64 (0.09) 0.56 (0.08) 0.38 (0.07) 0.38 (0.05) 0.33 (0.07) 0.37 (0.06) Week 13 i m V vn 0 10 100 1000 1.54(0.33) 1.64(0.36) 1.54 (0.40) 1.49 (0.14) 0.74 (0.08) 0.81 (0.15) 0.75 (0.17) 0.71 (0.09) Recovery i vn 0 1000 1.64 (0.35) 1.40(0.40) 0.68 (0.14) 0.62 (0.09) Data arranged as : Mean (Standard Deviation) Statistical Methods: Bartlett's test for homogeneity followed by analysis of variance and Dunnett's test. There were no statistically significant differences from control at p<0.05. - 110Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-11418 TABLE 19 MEAN FORELIMB AND HINDLIMB GRIP STRENGTH FOR FEMALE RATS (MEAN OF THREE TRIALS) Assessment Dosage Period_______Group (mg/kg/day) Forelimb Hindlimb Grip Strength (kg)_______ Grip Strength (kg) Baseline n IV VI vm 0 10 100 1000 0.46 (0.08) 0.47 (0.05) 0.47(0.15) 0.49 (0.07) 0.35 (0.03) 0.34 (0.06) 0.32 (0.06) 0.34 (0.08) Week 13 n IV VI vm 0 10 100 1000 1.18 (0.28) 0.99 (0.21) 1.24(0.31) 1.16(0.31) 0.65 (0.08) 0.65 (0.10) 0.61 (0.09) 0.63(0.10) Recovery n vm 0 1000 0.97 (0.29) 1.06 (0.37) 0.63 (0.09) 0.61 (0.14) Data arranged as : Mean (Standard Deviation) Statistical Methods: Bartlett's test for homogeneity followed by analysis of variance and Dunnett's test. There were no statistically significant differences from control at p<0.05 by Dunnett's test. - Ill Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-11418 TABLE 20 SUMMARY OF SENSORY MOTOR FUNCTION PARAMETERS FOR MALE RATS BASELINE 13-WEEK Group: Dosage (mg/kg/day): Number examined: I III V VII 0 10 100 1000 10 10 10 10 I III V VII 0 10 100 1000 10 10 10 10 MANIPULATIONS: APPROACH & TOUCH: no reaction normal increased reaction (jumps away or attacks) 00 0 0 10 10 10 10 00 0 0 000 0 10 10 10 10 0000 AUDITORY STIMULUS: no reaction normal reaction (rat flinches or flicks ear) exaggerated reaction (rat jumps, flips) 00 0 0 10 10 10 10 0000 0000 10 10 10 10 0000 TAIL PINCH: no response normal (turns toward site) exaggerated response (vocalizations, rapid turning) 0000 10 10 10 10 0000 0000 10 9 10 10 0 10 0 Recovery I VII 0 1000 10 10 00 10 10 00 00 10 10 00 12 98 00 IN MOTOR ACTIVITY MONITOR: PUPILLARY RESPONSE present absent 10 10 10 10 00 0 0 10 10 10 10 0000 DEFECATION absent present diarrhea 5642 54 68 0000 65 3 6 4574 0000 URINATION: absent present 42 15 6895 10 1 1 9 10 9 9 ADDITIONAL OBSERVATIONS NOTED VOCALIZATION WHEN HANDLED absent present 10 10 00 10 10 00 10 10 10 10 0000 There were no statistically significant differences by Cochran-Armitage test for trend at p < 0.05. 10 10 00 54 56 00 32 78 9 10 10 - 112Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-11418 TABLE 21 SUMMARY OF SENSORY MOTOR FUNCTION PARAMETERS FOR FEMALE RATS BASELINE 13-WEEK Recovery Group: Dosage (mg/kg/day): Number examined: II IV VI VIII 0 10 100 1000 10 10 10 10 II IV VI v m 0 10 100 1000 10 10 10 10 II VIII 0 1000 10 10 MANIPULATIONS: APPROACH & TOUCH: no reaction normal increased reaction (jumps away or attacks) 0000 10 10 10 10 0000 0000 10 10 10 10 000 0 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 9 10 10 00 9 10 10 00 10 9 01 TAIL PINCH: no response normal (turns toward site) exaggerated response (vocalizations, rapid turning) 0000 10 10 10 10 0000 0000 10 10 10 10 0000 00 10 9 01 IN MOTOR ACTIVITY MONITOR: PUPILLARY RESPONSE present absent 10 10 10 10 0000 10 10 10 10 0000 DEFECATION absent present diarrhea 2543 8567 0000 542 2 5688 000 0 URINATION: absent present 2425 8 6 8- 5 10 1 1 9 10 9 9 ADDITIONAL OBSERVATIONS NOTED CIRCLING - CLOCKWISE absent present 10 10 10 10 00 0 0 10 10 10 9 000 1 MASS - SUBCUTANEOUS, LEFT SIDE absent present 10 10 10 10 0000 10 10 10 10 0000 There were no statistically significant differences by Cochran-Armitage test for trend at p < 0.05. 10 10 00 44 66 00 43 67 10 9 01 10 9 01 - 113 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 22 MOTOR ACTIVITY ASSESSMENT: MEAN DURATION OF MOVEMENT FOR MALE RATS (sec) DuPont-11418 Company Sanitized. Does not contain TSCA ASSESSMENT DOSAGE PERIOD GROUP (mg/kg/davl______________________________ SUCCESSIVE 10-MINUTE INTERVALS BASELINE 13-WEEK I III V VII I III V VII 0 10 100 1000 0 10 100 1000 I 391(30) 426(40) 404(49) 420(18) 387(36) 417(45) 387(59) 420(41) 2 257(48) 301(87) 296(91) 312(58) 313(54) 346(52) 284(71) 359(69) 3 137(97) 168(114) 197(120) 194(114) 4 36(51) 109(116) 95(112) 100(99) 5 10(14) 39(69) 52(112) 41(84) 6 5(7) 27(71) 8(7) 17(40) TOTAL 836(144) 1070(363) 1053(410) 1084(283) 235(56) 292(65) 272(68) 321(55) 266(65) 272(72) 249(83) 296(43) 212(72) 186(62) 235(68) 245(33) 114(78) 173(91) 202(104) 215(88) * 1526(223) 1685(299) 1630(362) 1854(233) RECOVERY I VII 0 1000 377(73) 415(77) Data arranged as: Mean (Standard Deviation). N=10 262(68) 321(68) 226(48) 259(70) 233(66) 236(87) 170(65) 175(124) 174(49) 139(95) 1442(275) 1545(366) Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Repeated measures analysis of variance with linear contrasts was used to identify which dosage groups, if any, were significantly different from the control group. These tests were applied to Interval data and Total data. * Statistically significant difference from control at p < 0.05. O CD H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-11418 TABLE 23 MOTOR ACTIVITY ASSESSMENT: MEAN DURATION OF MOVEMENT FOR FEMALE RATS (sec) ASSESSMENT DOSAGE PERIOD GROUP (mg/kg/day)_______________________ SUCCESSIVE 10-MINUTE INTERVALS BASELINE II IV VI VIII 13-WEEK II IV VI VIII 0 10 100 1000 0 10 100 1000 1 392(30) 405(37) 404(37) 380(52) 436(41) 430(41) 438(41) 434(43) 2 283(82) 239(102) 279(66) 307(63) 3 216(116) 158(122) 196(88) 203(85) 4 191(146) 125(106) 169(125) 232(107) 5 133(88) 130(109) 102(107) 133(102) 6 129(137) 79(82) 69(97) 106(101) TOTAL 1343(442) 1137(446) 1218(302) 1361(336) 353(51) 350(53) 364(42) 372(74) 265(95) 237(128) 283(44) 274(104) 247(86) 249(112) 280(65) 263(112) 220(98) 254(80) 238(88) 264(94) 211(114) 234(133) 234(46) 208(103) 1733(341) 1755(446) 1836(249) 1815(418) RECOVERY II VHI 0 1000 346(72) 354(62) Data arranged as: Mean (Standard Deviation). N=10 259(67) 235(77) 218(72) 213(65) 228(80) 214(93) 207(55) 164(72) 136(91) 156(78) 1395(377) 1337(344) Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Repeated measures analysis of variance with linear contrasts was used to identify which dosage groups, if any, were significantly different from the control group. These tests were applied to Interval data and Total data. There were no statistically significant differences from control at p < 0.05. Company Sanitized. Does not contain TSCA CBI 115 H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-11418 TABLE 24 MOTOR ACTIVITY ASSESSMENT: MEAN NUMBER OF MOVEMENTS FOR MALE RATS ASSESSMENT DOSAGE PERIOD GROUP (mg/kg/dav)______________________________ SUCCESSIVE 10-MINUTE INTERVALS BASELINE 13-WEEK I III V VII I III V VII 0 10 100 1000 0 10 100 1000 1 134(11) 127(19) 130(15) 126(10) 141(17) 130(17) 132(20) 133(13) 2 138(14) 134(25) 134(15) 139(26) 143(16) 147(8) 134(12) 144(18) 3 89(54) 98(54) 106(55) 107(58) 126(36) 138(21) 134(19) 141(16) 4 34(45) 71(66) 64(60) 62(54) 133(30) 135(12) 134(20) 134(18) 5 13(17) 35(47) 30(49) 26(45) 122(32) 107(22) 126(20) 125(20) 6 4(3) 20(42) 10(9) 17(35) TOTAL 413(93) 485(189) 473(140) 477(162) 79(47) 99(35) 111(27) 115(35) * 744(136) 756(73) 772(48) 792(92) RECOVERY I VII 0 1000 134(25) 130(23) Data arranged as: Mean (Standard Deviation). N=10 129(27) 137(17) 120(28) 117(18) 122(31) 110(31) 100(45) 92(54) 103(26) 81(46) 709(146) 667(118) Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Repeated measures analysis of variance with linear contrasts and Jonckheere s trend test were used to identify which dosage groups, if any, were significantly different from the control group. These tests were applied to Interval data and Total data. * Statistically significant differences from control at p < 0.05. Company Sanitized. Does not contain TSCA CBI 116 H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-11418 TABLE 25 MOTOR ACTIVITY ASSESSMENT: MEAN NUMBER OF MOVEMENTS FOR FEMALE RATS Company Sanitized. Does not contain TSCA ASSESSMENT DOSAGE PERIOD GROUP (mg/kg/day) SUCCESSIVE 10-MINUTE INTERVALS BASELINE II IV VI VIII 13-WEEK II IV VI VIII 0 10 100 1000 0 10 100 1000 1 135(22) 128(14) 133(20) 136(17) 127(18) 134(19) 129(23) 130(21) 2 141(31) 121(35) 134(29) 143(13) 140(20) 151(20) 146(21) 145(14) 3 111(50) 101(67) 119(51) 122(40) 129(34) 115(38) 139(18) 136(21) 4 100(63) 91(69) 98(63) 118(45) 127(35) 121(46) 135(26) 130(27) 5 89(55) 78(65) 66(61) 78(53) 128(41) 129(31) 123(37) 135(33) 6 76(64) 61(53) 45(48) 69(59) TOTAL 652(210) 580(231) 595(195) 666(144) 122(42) 118(46) 126(18) 119(37) 773(152) 768(140) 799(109) 794(77) RECOVERY II 0 VIII 1000 151(18) 146(16) Data arranged as: Mean (Standard Deviation). N=10 141(14) 137(18) 132(21) 130(27) 140(25) 125(42) 131(16) 115(36) 87(45) 106(40) 782(73) 759(108) Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Repeated measures analysis of variance with linear contrasts and Jonckheere's trend test were used to identify which dosage groups, if any, were significantly different from the control group. These tests were applied to Interval data and Total data. There were no statistically significant differences from control at p < 0.05. o 03 H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 TABLE 26 SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I 0 mg/kg Group in 10 mg/kg Group V 100 mg/kg Group VH 1000 mg/kg RBC (xlOfytL) DAY 37 DAY 92 DAY 127 HGB (g/dL) DAY 37 DAY 92 DAY 127 HCT (%) DAY 37 DAY 92 DAY 127 MCV (fl) DAY 37 DAY 92 DAY 127 ' MCH(pg) DAY 37 DAY 92 DAY 127 7.82 0.18(10) 8.58 0.31(10) 8.56 0.39(10) 15.8 0.3(10) 15.8 0.5(10) 15.1 0.7(10) 46.3 0.6(10) 47.6 2.0(10) 48.6 2.4(10) 59.2 1.3(10) 55.4 1.4(10) 56.8 1.7(10) 20.1 0.5(10) 18.5 0.5(10) 17.7 0.5(10) 7.70 0.40(10) 8.53 0.42(9) "" 15.5 0.6(10) 15.7 0.6(9) -- 45.4 2.4(10) 47.6 2.5(9) -- 59.0 1.8(10) 55.8 1.8(9) 20.1 0.8(10) 18.4 0.8(9) -- 7.66 0.39(10) 8.51 0.29(10) 15.3 0.6(10) 15.5 0.5(10) -- 44.8 2.1(10) 47.2 1.6(10) -- 58.5 1.6(10) 55.5 1.7(10) 20.0 0.7(10) 18.3 0.6(10) -- 7.51 0.21(10) 8.22 0.32(10) 8.24 0.30(9) 15.0* 0.5(10) 15.2 0.8(10) 14.4* 0.5(9) 44.6* 1.3(10) 46.0 2.4(10) 46.7 2.0(9) 59.4 1.6(10) 56.0 2.0(10) 56.7 1.7(9) 20.0 0.8(10) 18.5 0.8(10) 17.4 0.6(9) - 118Company Sanitized. Does not contain TSCA C8I H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations____________________DuPont-11418 TABLE 26 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I 0 mg/kg Group in 10 mg/kg Group V 100 mg/kg Group VII 1000 mg/kg MCHC (g/dL) DAY 37 DAY 92 DAY 127 RDW (%) DAY 37 DAY 92 DAY 127 ARET (xl03//iL) DAY 37 DAY 92 DAY 127 PLT (xl03//iL) DAY 37 DAY 92 DAY 127 WBC (xl03//tL) DAY 37 DAY 92 DAY 127 34.0 0.4(10) 33.3 0.7(10) 31.1 0.2(10) 11.2 0.2(10) 12.6 0.5(10) 13.0 0.9(10) 177.4 19.8(10) 155.6 34.2(10) 184.4 26.7(10) 1207 99(9) 1063 166(6) 1135 123(6) 13.87 1.97(10) 12.28 2.34(10) 10.28 1.82(10) 34.1 0.8(10) 32.9 0.8(9) __ 11.3 0.4(10) 12.8 0.7(9) __ 162.8 21.3(10) 173.7 29.3(9) 1237 54(8) 1192 174(3) __ 16.01 4.18(10) 13.99 3.39(9) ~ 34.2 0.5(10) 32.9 0.8(10) -- 11.6* 0.3(10) 12.7 0.5(10) -- 179.0 22.9(10) 161.7 30.7(10) ... 1189 116(10) 1109 127(7) -- 15.68 3.36(10) 13.18 3.71(10) -- 33.7 0.4(10) 33.0 0.7(10) 30.8 0.5(9) 11.2 0.2(10) 12.4 0.8(10) 13.6 0.6(9) 169.9 21.7(10) 177.1 30.0(10) 190.8 32.7(9) 1101* 84(10) 1137 35(3) 1277 135(5) 16.08 4.03(10) 13.32 4.96(10) 14.16* 3.64(9) - 119Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 TABLE 26 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I 0 mg/kg Group HI 10 mg/kg Group V 100 mg/kg Group VII 1000 mg/kg ANEU (xl03//iL) DAY 37 DAY 92 DAY 127 ALYM (xl03//xL) DAY 37 DAY 92 DAY 127 AMON (xl03/jtiL) DAY 37 DAY 92 DAY 127 AEOS (xl03//iL) DAY 37 DAY 92 DAY 127 ABAS (xl03/jttL) DAY 37 DAY 92 DAY 127 1.43 0.33(10) 1.66 0.35(10) 1.87 0.62(10) 11.79 1.76(10) 9.99 1.91(10) 7.91 1.75(10) 0.27 0.05(10) 0.35 0.08(10) 0.26 0.09(10) 0.13 0.05(10) 0.12 0.05(10) 0.12 0.03(10) 0.10 0.05(10) 0.07 0.04(10) 0.08 0.05(10) 1.93 0.81(10) 2.75 2.31(9) -- 13.39 3.47(10) 10.60 2.03(9) -- 0.28 0.06(10) 0.31 0.13(9) -** 0.15 0.08(10) 0,14 0.04(9) --* 0.10 0.04(10) 0.07 0.05(9) " "' 2.01 @ 0.37(10) 2.03 0.54(10) -- 12.79 3.07(10) 10.41 3.31(10) """ 0.42* 0.12(10) 0.40 0.19(10) -- 0.12 0.03(10) 0.14 0.05(10) . 0.12 0.05(10) 0.08 0.04(10) 2.08 1.09(10) 1.87 0.73(10) 2.26 0.69(9) 13.28 3.16(10) 10.88 4.53(10) 11.21* 3.10(9) 0.29 0.10(10) 0.29 0.12(10) 0.37* 0.10(9) 0.12 0.04(10) 0.13 0.07(10) 0.16 0.07(9) 0.12 0.06(10) 0.05 0.02(10) 0.09 0.03(9) - 120Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 TABLE 26 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I 0 mg/kg Group HI 10 mg/kg Group V 100 mg/kg Group VH 1000 mg/kg ALUC (xl03//xL) DAY 37 DAY 92 DAY 127 0.15 0.06(10) 0.10 0.04(10) 0.05 0.02(10) 0.15 0.05(10) 0.13 0.07(9) -- 0.22 0.20(10) 0.13 0.07(10) -- 0.19 0.15(10) 0.11 0.07(10) 0.07* 0.03(9) Data arranged as: Mean Standard deviation (Number of values included in calculation) * Statistically significant difference from control at p < 0.05 by Dunnett/Tamhane-Dunnett test. @ Statistically significant difference from control at p < 0.05 by Dunn's test. - 121 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 TABLE 27 SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Group II 0 mg/kg Group IV 10 mg/kg Group VI 100 mg/kg Group VIII 1000 mg/kg RBC (xl0%tL) DAY 38 DAY 93 DAY 127 HGB (g/dL) DAY 38 DAY 93 DAY 127 HCT (%) DAY 38 DAY 93 DAY 127 MCV (fl) DAY 38 DAY 93 DAY 127 MCH(pg) DAY 38 DAY 93 DAY 127 7.95 0.33(10) 8.21 0.23(10) 8.14 0.22(10) 15.9 0.7(10) 15.8 0.6(10) 15.3 0.5(10) 45.1 1.9(10) 46.5 1.6(10) 48.3 1.3(10) 56.7 0.9(10) 56.6 1.6(10) 59.4 1.6(10) 20.1 0.5(10) 19.3 0.6(10) 18.7 0.5(10) 7.94 0.48(10) 8.19 0.38(10) -- 15.9 0.8(10) 15.7 0.4(10) *-- 45.4 2.5(10) 46.1 1.5(10) -- 57.2 1.3(10) 56.3 1.4(10) 20.0 0.5(10) 19.2 0.6(10) 7.87 0.29(10) 8.17 0.21(10) -- 15.8 0.4(10) 15.8 0.4(10) -- 44.9 1.0(10) 46.4 1.2(10) -- 57.1 1.4(10) 56.9 2.0(10) 20.1 0.6(10) 19.3 0.7(10) 7.87 0.34(10) 7.96 0.42(10) 8.12 0.36(10) 15.7 0.4(10) 15.3 @ 0.5(10) 15.1 0.7(10) 44.5 1.3(10) 44.4* 1.8(10) 48.5 3.1(10) 56.6 1.9(10) 55.9 2.2(10) 59.7 2.1(10) 20.0 0.6(10) 19.3 0.7(10) 18.7 0.5(10) - 122Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 TABLE 27 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Group II 0 mg/kg Group IV 10 mg/kg Group VI 100 mg/kg Group VIH 1000 mg/kg MCHC (g/dL) DAY 38 DAY 93 DAY 127 RDW (%) DAY 38 DAY 93 DAY 127 ARET (x l0 3//xL) DAY 38 DAY 93 DAY 127 PLT (xlOVL) DAY 38 DAY 93 DAY 127 WBC (x l0 3//xL) DAY 38 DAY 93 DAY 127 35.4 0.6(10) 34.1 0.5(10) 31.6 0.5(10) 10.6 0.3(10) 11.0 0.4(10) 11.7 0.3(10) 134.6 33.3(10) 122.7 31.2(10) 180.9 35.2(10) 1183 144(9) 1044 174(4) 1148 ' 134(5) 13.75 2.34(10) 9.89 2.22(10) 7.96 2.73(10) 35.0 0.5(10) 34.0 0.5(10) -- 10.8 0.4(10) 11.3 0.3(10) -- 154.7 28.6(10) 154.2 48.7(10) -- 1366 157(6) 1165 51(2) -- 12.29 2.20(10) 9.47 1.50(10) -- 35.2 0.5(10) 34.0 0.4(10) "** 10.6 0.5(10) 11.0 0.4(10) -- 150.0 38.4(10) 146.4 32.1(10) -- 1178 94(9) 1120 57(4) -- 14.46 3.31(10) 9.36 2.59(10) -- 35.3 0.4(10) 34.5 0.5(10) 31.3 0.8(10) 10.7 0.4(10) 11.0 0.4(10) 11.5 0.5(10) 168.3 26.7(10) 146.7 44.7(10) 185.1 43.6(10) 1254 171(9) 991 221(4) 1008 82(3) 14.36 2.60(10) 8.96 2.63(10) 8.23 1.50(10) - 123 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 TABLE 27 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Group II Group IV Group VI Group VDI 0 mg/kg_______ 10 mg/kg_______ 100 mg/kg______ 1000 mg/kg ANEU (xl03//tiL) DAY 38 DAY 93 DAY 127 ALYM (xl03//xL) DAY 38 DAY 93 DAY 127 AMON (xlOVjaL) DAY 38 DAY 93 DAY 127 AEOS (xl03/jtiL) DAY 38 DAY 93 DAY 127 ABAS (xl03//L) DAY 38 DAY 93 DAY 127 1.16 0.38(10) 1.15 0.58(10) 1.17 0.44(10) 11.89 1.99(10) 8.14 1.81(10) 6.43 2.34(10) 0.32 0.13(10) 0.28 0.18(10) 0.16 0.09(10) 0.11 0.03(10) 0.11 0.02(10) 0.10 0.03(10) 0.12 0.03(10) 0.08 0.03(10) 0.05 0.03(10) 1.20 0.55(10) 1.61 0.37(10) -- 10.42 1.75(10) 7.27 1.55(10) -- 0.29 0.09(10) 0.27 0.12(10) -- 0.13 0.05(10) 0.11 0.05(10) 0.12 0.05(10) 0.10 0.06(10) -- 1.28 0.51(10) 1.26 0.55(10) -- 12.51 2.80(10) 7.61 2.09(10) -- 0.29 0.18(10) 0.21 0.09(10) -- 0.12 0.04(10) 0.11 0.06(10) 0.12 0.03(10) 0.08 0.04(10) -- 1.56 0.94(10) 1.56 1.00(10) 1.33 0.47(10) 12.10 2.05(10) 6.96 1.91(10) 6.50 1.37(10) 0.34 0.15(10) 0.19 0.13(10) 0.19 0.07(10) 0.10 0.03(10) 0.10 0.06(10) 0.13 0.08(10) 0.11 0.06(10) 0.06 0.04(10) 0.05 0.02(10) - 124Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 TABLE 27 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS* Group II 0 mg/kg Group IV 10 mg/kg Group VI 100 mg/kg Group VUI 1000 mg/kg ALUC (xl03/jaL) DAY 38 DAY 93 DAY 127 0.15 0.02(10) 0.13 0.07(10) 0.05 0.03(10) 0.14 0.04(10) 0.11 0.04(10) ~ 0.16 0.09(10) 0.09 0.04(10) -- 0.15 0.06(10) 0.08 0.05(10) 0.04 0.01(10) Data arranged as: Mean Standard deviation (Number of values included in calculation) * Statistically significant difference from control at p < 0.05 by Dunnett/Tamhane-Dunnett test. @ Statistically significant difference from control at p < 0.05 by Dunn's test. - 125 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 TABLE 28 SUMMARY OF COAGULATION VALUES FOR MALE RATS Group I Group HI Group V Group VII __________ Omg/kg________ 10 mg/kg_______ 100 mg/kg______ 1000 mg/kg PT (seconds) DAY 92 DAY 127 APTT (seconds) DAY 92 DAY 127 16.0 0.9(10) 16.0 0.9(9) 20.6 1.4(10) 20.7 1.6(9) 15.9 1.0(10) 19.4 1.4(10) 15.4 0.3(10) 18.9** 2.0(10) 15.7 0.6(10) 15.5 0.5(10) 19.0 1.6(10) 21.1 1.8( 10) Data arranged as: Mean Standard deviation (Number of values included in calculation) * Statistically significant difference from control at p < 0.05 by Dunnett/Tamhane-Dunnett test. - 126 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 TABLE 29 SUMMARY OF COAGULATION VALUES FOR FEMALE RATS Group II Group IV Group VI Group VIII __________ Omg/kg________10 mg/kg_______ 100 mg/kg______ 1000 mg/kg PT (seconds) DAY 93 DAY 127 APTT (seconds) DAY 93 DAY 127 15.0 0.4(9) 14.9 0.7(10) 18.0 1.6(9) 17.5 1.9(10) 15.5 0.5(10) 18.7 0.8( 10) 15.5 0.4(10) 17.6 2.0(10) 15.1 0.8(9) 15.3 0.6(10) 19.2 1.8(9) 17.7 2.5(10) Data arranged as: Mean Standard deviation (Number of values included in calculation) There were no statistically significant differences from control at p < 0.05. - 127Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations____________________DuPont-11418 TABLE 30 SUMMARY OF CLINICAL CHEMISTRY VALUES FOR MALE RATS Group I 0 mg/kg Group m 10 mg/kg Group V 100 mg/kg Group VII 1000 mg/kg AST (U7L) DAY 37 DAY 92 DAY 127 ALT (U/L) DAY 37 DAY 92 DAY 127 SDH (U/L) DAY 37 DAY 92 DAY 127 ALKP (U/L) DAY 37 DAY 92 DAY 127 BILI (mg/dL) DAY 37 DAY 92 DAY 127 73 7(10) 80 11(10) 79 13(10) 29 2(10) 33 4(10) 37 9(10) 12.6 1.3(10) 19.2 1.9(10) 17.2 5.4(10) 156 44(10) 96 26(10) 82 15(10) * 0.08 0.03(10) 0.11 0.03(10) 0.12 0.04(10) 74 6(10) 92 27(10) -- 31 4(10) 48 30(10) -- 11.6 2.0(10) 20.8 10.6(10) -- 164 45(10) 103 28(10) -- 0.07 0.03(10) 0.10 0.03(10) -- 75 9(10) 78 8(10) -- 34* 4(10) 38 6(10) -- 11.5 1.2(10) 16.3 3.4(10) -- 159 25(10) 97 15(10) -- 0.06 0.03(10) 0.09 0.04(10) -- 70 6(10) 76 9(10) 93 @ 22(10) 31 5(10) 35 7(10) 45 @ 11(10) 12.5 2.3(10) 17.5 4.7(10) 18.6 9.4(10) 150 31(10) 111 17(10) 79 9(10) 0.06 0.02(10) 0.07 @ 0.03(10) 0.10 0.03(10) -128 Company Sanitized. Does not contain TSCA C8I H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations____________________DuPont-11418 TABLE 30 (Continued) SUMMARY OF CLINICAL CHEMISTRY VALUES FOR MALE RATS Group I 0 mg/kg Group IH 10 mg/kg Group V 100 mg/kg Group VII 1000 mg/kg BUN (mg/dL) DAY 37 DAY 92 DAY 127 CREA (mg/dL) DAY 37 DAY 92 DAY 127 CHOL (mg/dL) DAY 37 DAY 92 DAY 127 TRIG (mg/dL) DAY 37 DAY 92 DAY 127 GLUC (mg/dL) DAY 37 DAY 92 DAY 127 14 1(10) 15 2(10) 14 2(10) 0.36 0.05(10) 0.47 0.07(10) 0.35 0.05(10) 64 11(10) 68 14(10) 70 15(10) 48 22(10) 79 20(10) 71 29(10) 99 10(10) 107 25(10) 113 20(10) 14 1(10) 15 2(10) -- 0.33 0.03(10) 0.45 0.07(10) -- 65 18(10) 69' 23(10) -- 37 12(10) 55* 23(10) -- 105 7(10) 135 34(10) -- 14 1(10) 16 2(10) -- 0.33 0.04(10) 0.41 0.05(10) -- 55 8(10) 52 8(10) -- 59 27(10) 60 23(10) -- 98 8(10) 128 48(10) ~ 14 1(10) 16 2(10) 15 2(10) 0.31 0.05(10) 0.44 0.06(10) 0.34 0.04(10) 53 11(10) 51 13(10) 60 12(10) 45 27(10) 46* 19(10) 69 32(10) 99 7(10) 127 41(10) 144 45(10) -129Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations _______________ DuPont-11418 TABLE 30 (Continued) SUMMARY OF CLINICAL CHEMISTRY VALUES FOR MALE RATS Group I 0 mg/kg Group HI 10 mg/kg Group V 100 mg/kg Group VII 1000 mg/kg TP (g/dL) DAY 37 DAY 92 DAY 127 ALB (g/dL) DAY 37 DAY 92 DAY 127 GLOB (g/dL) DAY 37 DAY 92 DAY 127 CALC (mg/dL) DAY 37 DAY 92 DAY 127 DPHS (mg/dL) DAY 37 DAY 92 DAY 127 6.8 0.3(10) 7.4 0.3(10) 7.1 0.3(10) 4.4 0.2(10) 4.5 0.2(10) 4.5 0.2(10) 2.5 0.1(10) 2.9 0.2(10) 2.7 0.2(10) 10.9 0.3(10) 11.3 0.6(10) 11.1 0.4(10) 8.4 0.5(10) 9.6 0.9(10) 8.0 0.8(10) 6.7 0.3(10) 7.3 0.3(10) 4.3 0.2(10) 4.4 0.2(10) -- 2.4 0.3(10) 2.8 0.3(10) 11.1 0.5(10) 11.7 0.5(10) ""' 8.5 0.7(10) 9.9 1.1(10) 6.7 0.4(10) 7.2 0.3(10) 4.3 0.3(10) 4.5 0.2(10) 2.4 0.2(10) 2.7 0.2(10) 10.9 0.3(10) 11.4 0.7(10) 8.8 0.3(10) 9.8 1.5(10) 6.6 0.4(10) 7.1* 0.2(10) 7.2 0.4(10) 4.4 0.2(10) 4.7 0.1(10) 4.7* 0.2(10) 2.2 0.3(10) 2.4 @ 0.2(10) 2.5 0.3(10) 11.1 0.3(10) 11.0 0.5(10) 11.4 0.4(10) 8.9 0.5(10) 10.4 1.6(10) 9.0@ 0.9(10) -130Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 TABLE 30 (Continued) SUMMARY OF CLINICAL CHEMISTRY VALUES FOR MALE RATS* Group I 0 mg/kg Group HI 10 mg/kg Group V 100 mg/kg Group VH 1000 mg/kg NA (mmol/L) DAY 37 DAY 92 DAY 127 K (mmol/L) DAY 37 DAY 92 DAY 127 CL (mmol/L) DAY 37 DAY 92 DAY 127 * PFLU (/ig/mL) DAY 92 DAY 127 151.6 3.2(10) 150.5 2.9(10) 149.5 2.0(10) 6.04 0.28(10) 6.47 0.52(10) 6.35 0.22(10) 102.6 3.0(10) 106.9 3.9(10) 103.6 1.8(10) 0.1 0.0(10) 0.1 0.0(9) 150.8 3.2(10) 151.6 3.0(10) -- 6.09 0.67(10) 6.69 0.77(10) 102.9 2.0(10) 107.2 3.5(10) --- 0.1 0.0(10) 151.2 2.6(10) 151.3 3.5(10) -- 6.02 0.26(10) 6.46 0.63(10) 102.2 2.8(10) 107.3 2.9(10) -- 0.1 0.0(10) 151.6 2.8(10) 150.9 2.5(10) 149.9 1.8(10) 6.14 0.39(10) 6.76 1.10(10) 6.39 0.63(10) 103.5 2.7(10) 109.0 3.4(10) 104.3 1.3(10) 0.1 0.0(10) 0.1 0.0(10) Data arranged as: Mean Standard deviation (Number of values included in calculation) * Statistically significant difference from control at p < 0.05 by Dunnett/Tamhane-Dunnett test. @ Statistically significant difference from control at p < 0.05 by Dunn's test. - 131 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 TABLE 31 SUMMARY OF CLINICAL CHEMISTRY VALUES FOR FEMALE RATS Group II Group IV Group VI _______________Omg/kg_______ 10 mg/kg_______ 100 mg/kg Group VDI 1000 mg/kg AST (U/L) DAY 38 DAY 93 DAY 127 ALT (U/L) DAY 38 DAY 93 DAY 127 SDH (U/L) DAY 38 DAY 93 DAY 127 ALKP (U/L) DAY 38 DAY 93 DAY 127 BILI (mg/dL) DAY 38 DAY 93 DAY 127 75 11(10) 102 64(10) 101 16(10) 34 5(10) 60 58(10) 58 13(10) 14.4 2.6(10) 23.2 13.8(10) 22.0 6.7(10) 120 28(10) 58 9(10) 51 25(10) 0.10 0.03(10) 0.09 0.04(10) 0.15 0.03(10) 75 10(10) 101 40(10) -- 32 6(10) 57 40(10) -- 13.9 3.8(10) 22.3 12.1(10) -- Ill 32(10) 60 18(10) ~ 0.12 0.01(10) 0.11 0.04(10) -- 71 10(10) 84 18(10) 28* 4(10) 41 20(10) -- 13.8 3.2(10) 19.8 6.5(10) ~ 122 24(10) 60 8(10) -- 0.10 0.03(10) 0.09 0.04(10) -- . 77 11(10) 84 19(10) 105 31(10) 33 6(10) 37 10(10) 57 35(10) 14.8 3.2(10) 14.1 3.8(10) 20.9 12.2(10) 118 33(10) 67 19(10) 49 14(10) 0.10 0.04(10) 0.05 0.00(10) 0.13 0.02(10) - 132 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 TABLE 31 (Continued) SUMMARY OF CLINICAL CHEMISTRY VALUES FOR FEMALE RATS Group II Group IV Group VI Group Vm _______________Omg/kg_______ 10 mg/kg_______ 100 mg/kg______ 1000 mg/kg BUN (mg/dL) DAY 38 DAY 93 DAY 127 CREA (mg/dL) DAY 38 DAY 93 DAY 127 CHOL (mg/dL) DAY 38 DAY 93 DAY 127 TRIG (mg/dL) . DAY 38 DAY 93 DAY 127 GLUC (mg/dL) DAY 38 DAY 93 DAY 127 17 3(10) 17 2(10) 16 2(10) 0.47 0.06(10) 0.54 0.05(10) 0.49 0.06(10) 69 13(10) 76 10(10) 80 16(10) 40 11(10) 53 12(10) 45 16(10) 100 8(10) 102 26(10) 115 17(10) 16 2(10) 16 1(10) 0.45 0.05(10) 0.49 0.05(10) -- 65 13(10) 73 18(10) -- 34 15(10) 34 @ 11(10) -- 100 9(10) 94 8(10) *--* 16 2(10) 17 2(10) 0.45 0.05(10) 0.52 0.03(10) -- 67 10(10) 71 15(10) -- 39 14(10) 42 11(10) -- 100 7(10) 95 4(10) -- 16 2(10) 18 2(10) 18 2(10) 0.44 0.04(10) 0.50 0.04(10) 0.46 0.05(10) 70 14(10) 71 9(10) 78 9(10) 37 22(10) 42 19(10) 39 11(10) 100 10(10) 106 20(10) 114 25(10) -133Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 TABLE 31 (Continued) SUMMARY OF CLINICAL CHEMISTRY VALUES FOR FEMALE RATS Group H Group TV Group VI _______________Omg/kg_______ 10 mg/kg_______ 100 mg/kg Group VIE 1000 mg/kg TP (g/dL) DAY 38 DAY 93 DAY 127 ALB (g/dL) DAY 38 DAY 93 DAY 127 GLOB (g/dL) DAY 38 DAY 93 DAY 127 CALC (mg/dL) DAY 38 DAY 93 DAY 127 IPHS (mg/dL) DAY 38 DAY 93 DAY 127 7.2 0.4(10) 7.7 0.5(10) 8.3 0.5(10) 4.9 0.3(10) 5.2 0.3(10) 5.6 0.3(10) 2.3 0.2(10) 2.4 0.2(10) 2.6 0.4(10) 11.2 0.3(10) 11.2 0.4(10) 11.7 0.4(10) 7.3 0.6(10) 6.6 1.5(10) 6.2 0.9(10) 7.4 0.3(10) 7.8 0.4(10) -- 5.0 0.3(10) 5.2 0.4(10) -- 2.4 0.2(10) 2.5 0.2(10) -- 11.5 0.3(10) 11.1 0.3(10) -- 7.9* 0.5(10) 6.5 1.0(10) -- 7.4 0.3(10) 7.6 0.4(10) " 5.0 0.3(10) 5.2 0.5(10) " 2.4 0.3(10) 2.5 0.2(10) 11.5 0.3(10) 11.1 0.4(10) 7.8 0.3(10) 6.3 0.9(10) -- 7.6 0.2(10) 7.5 0.2(10) 8.3 0.4(10) 5.2 0.2(10) 5.2 0.3(10) 5.6 0.5(10) 2.4 0.3(10) 2.3 0.2(10) 2.7 0.2(10) 11.6* 0.4(10) 11.0 0.4(10) 11.7 0.4(10) 8.3* 0.6(10) 7.0 1.0(10) 7.4 1.9(10) - 134 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations____________________DuPont-11418 TABLE 31 (Continued) SUMMARY OF CLINICAL CHEMISTRY VALUES FOR FEMALE RATS Group II 0 mg/kg Group IV 10 mg/kg Group VI 100 mg/kg Group VIE 1000 mg/kg NA (mmol/L) DAY 38 DAY 93 DAY 127 K (mmol/L) DAY 38 DAY 93 DAY 127 CL (mmol/L) DAY 38 DAY 93 DAY 127 PFLU (/xg/mL) DAY 93 DAY 127 145.7 2.0(10) 144.9 1.2(10) 151.9 1.4(10) 5.75 0.36(10) 5.30 0.48(10) 5.74 0.49(10) 100.6 1.7(10) 98.5 1.6(10) 105.6 2.6(10) 0.1 0.0(9) 0.1 0.0(10) 147.2 2.4(10) 145.6 1.5(10) -- 6.04 0.39(10) 5.54 0.52(10) -- 101.8 1.8(10) 99.7 1.9(10) -- 0.1 0.0(10) 146.8 1.7(10) 145.8 2.0(10) -- 5.89 0.23(10) 5.65 0.38(10) "*** 101.3 1.3(10) 99.9 1.7(10) 0.1 0.0(10) 146.4 1.4(10) 144.5 1.5(10) 152.2 2.0(10) 5.97 0.34(10) 5.75 0.37(10) 5.95 0.39(10) 101.4 1.8(10) 100.5* 1.9(10) 106.9 1.9(10) 0.1 0.0(10) 0.1 0.1(10) Data arranged as: Mean Standard deviation (Number of values included in calculation) * Statistically significant difference from control at p < 0.05 by Dunnett/Tamhane-Dunnett test. @ Statistically significant difference from control at p < 0.05 by Dunn's test. - 135 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 TABLE 32 SUMMARY OF URINALYSIS VALUES FOR MALE RATS Group I 0 mg/kg Group m 10 mg/kg Group V 100 mg/kg Group VH 1000 mg/kg VOL (mL) DAY 37 DAY 92 DAY 127 UOSM (mOsm) DAY 37 DAY 92 DAY 127 pH DAY 37 DAY 92 DAY 127 ' URO (EU/dL) DAY 37 DAY 92 DAY 127 UFLU (Mg) DAY 92 DAY 127 8.6 4.1(10) 8.7 6.2(10) 4.8 1.7(10) 1043 316(10) 1194 383(10) 2092 669(10) 6.8 0.3(10) 6.7 0.5(10) 6.4 0.5(10) 0.2 0.0(10) 0.2 0.0(10) 0.5 0.4(10) 9.5 3.9(10) 7.7 1.8(10) 11.6 12.1(10) 8.5 5.1(10) *" 896 425(9) 1070 342(10) 6.7 0.3(9) 6.6 0.3(10) -- * 0.2 0.0(9) 0.2 0.0(10) 9.2 2.6(10) "" 9.5 3.5(10) 6.7 2.5(10) 1014 353(10) 1534 655(10) 6.9 0.2(10) 6.8 0.4(10) 0.2 0.0(10) 0.4 0.4(10) 17.5* 3.5(10) 10.2 5.7(10) 9.0 3.8(10) 8.9* 3.5(9) 1279 537(10) 1155 407(10) 1228 @ 464(9) 6.9 0.3(10) 6.6 0.3(10) 6.7 0.6(9) 0.2 0.0(10) 0.3 0.3(10) 0.3 0.3(9) 53.4* 9.0(10) 10.8* 1.5(9) - 136Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 TABLE 32 (Continued) SUMMARY OF URINALYSIS VALUES FOR MALE RATS* Group I 0 mg/kg Group in 10 mg/kg Group V 100 mg/kg Group VH 1000 mg/kg UMTP (mg/dL) DAY 37 DAY 92 DAY 127 76 34(10) 111 50(10) 143 36(10) 73 49(9) 75 40(10) -- 58 41(10) 92 55(10) -- 51 35(10) 61 41(10) 75@ 59(9) Data arranged as: Mean Standard deviation (Number of values included in calculation) * Statistically significant difference from control at p < 0.05 by Dunnett/Tamhane-Dunnett test. @ Statistically significant difference from control at p < 0.05 by Dunn's test. - 137 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 TABLE 33 SUMMARY OF URINALYSIS VALUES FOR FEMALE RATS Group II 0 mg/kg Group TV 10mg/kg Group VI 100 mg/kg Group V m 1000 mg/kg VOL (mL) DAY 38 DAY 93 DAY 127 UOSM (mOsm) DAY 38 DAY 93 DAY 127 pH DAY 38 DAY 93 DAY 127 URO (EU/dL) DAY 38 DAY 93 DAY 127 UFLU (fig) DAY 93 DAY 127 10.4 6.6(10) 6.1 5.6(10) 8.6 4.7(10) 839 486(10) 1120 538(10) 1035 342(10) 7.3 0.7(10) 6.0 0.5(10) 6.2 0.3(10) 0.2 0.0(10) 0.3 0.3(10) 0.2 0.0(10) 6.5 3.3(10) 6.3 2.5(10) 7.7 3.6(10) 4.1 2.5(10) ~ 952 497(10) 1339 549(10) -- 7.1 0.4(10) 6.1 0.6(10) -- 0.2 0.0(10) 0.3 0.3(10) -- 5.5 1.8(9) -- 7.5 3.2(10) 4.5 3.5(10) -- 7.1 8.1(10) 5.8 4.7(9) 3.4@ 1.9(10) 868 340(10) 1324 552(10) -- 1279 659(10) 1744 1341(9) 1388 443(6) 6.9 0.4(10) 5.9 0.4(10) ~ 7.0 0.2(10) 6.0 0.3(9) 5.7@ 0.5(10) 0.2 0.0(10) 0.2 0.0(10) ~ 9.8 3.2(8) -- * 0.2 0.0(10) 0.2 0.0(9) 0.5@ 0.4(10) 28.6* 9.1(7) 4.8 1.2(9) - 138 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 TABLE 33 (Continued) SUMMARY OF URINALYSIS VALUES FOR FEMALE RATS Group II 0 mg/kg Group IV 10 mg/kg Group VI 100 mg/kg Group Vm 1000 mg/kg UMTP (mg/dL) DAY 38 DAY 93 DAY 127 22 13(10) 32 21(10) 19 9(10) 28 21(10) 38 23(10) -- 19 7(10) 32 22(10) -- 32 19(10) 44 43(9) 35* 19(10) Data arranged as: Mean Standard deviation (Number of values included in calculation) * Statistically significant difference from control at p < 0.05 by Dunnett/Tamhane-Dunnett test. @ Statistically significant difference from control at p < 0.05 by Dunn's test. - 139Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 TABLE 34 SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITY IN MALE RATS Group I Dosage (m g/kg/day) 0 m 10 V 100 Hepatic Peroxisomal Beta-Oxidation Activity (nmol/min/mg protein) 10-Day Time Point 92-Day Time Point One-Month Recovery Time Point 17.4 1.3a 18.6+1.8 15.0 0.9 18.7 1.0 18.1 2.0 20.1 2.0 16.6 1.4 ___b b v n 1000 15.9 2.1#c 29.7 2.0# 24.8 5.6* a Mean standard deviation. The n = 5 for each group unless otherwise noted. b Samples were not prepared for analysis from groups HI and V at the one-month recovery time points. c The n = 4. # Statistically significant difference at p < 0.05 by Jonckheere's Tend test. * Statistically significant difference at p < 0.05 by Dunnett's test. Company Sanitized. Does not contain TSCA C8I - 140- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-11418 TA BLE35 SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITY IN FEMALE RATS Group Dosage (m g/kg/day) Hepatic Peroxisomal Beta-Oxidation Activity __________ (nmol/min/mg protein)__________ 10-Day Time Point 93-Day Time Point One-Month Recovery Time Point n0 IV 10 VI 100 15.9 3.1a 17.0 3.1 19.2 2.3 19.2 1.5 19.4 3.0 21.0 2.2 21.2 1.8 b b Vffl 1000 19.1 3.1# 24.0 2.7# 23.4 2.5 a Mean standard deviation. The n = 5 for each group. b Samples were not prepared for analysis from groups TV and VI at the one-month recovery time point. # Statistically significant difference at p < 0.05 by Jonckheere's Tend test. Company Sanitized. Does not contain TSCA CBI - 141- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 36 Group: Dosage(mg/kg) Test LIVER KIDNEYS HEART SPLEEN BRAIN THYMUS ADRENAL GLANDS THYROID GLAND TESTES EPIDIDYMIDES FINAL BODY WEIGHT MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION MEAN FINAL, BODY AND ABSOLUTE ORGAN WEIGHTS (grams) I III V VII 0 10 100 1000 15.189 1.815(10) 3.922 0.498(10) 1.705 0.160(10) 0.803 0.098(10) 2.175 0.110(10) 0.421 0.079(10) 0.051 0.008(10) 0.025 0.006(9) 3.513 0.430(10) 1.469 0.170(10) 15.092 1.512(10) 4.045 0.341(10) 1.729 0.195(10) 0.887 0.139(10) 2.170 0.106(10) 0.458 0.097(10) 0.060 0.011(10) 0.021 0.006(10) 3.637 0.276(10) 1.564 0.100(10) 14.964 2.027(10) 3.995 0.437(10) 1.695 0.164(10) 0.813 0.154(10) 2.128 0.081(10) 0.428 0.094(10) 0.057 0.012(10) 0.023 0.005(10) 3.523 0.316(10) 1.480 0.189(10) 18.135# 1.646(10) 4.389# 0.273(10) 1.780 0.106(10) 0.809 0.091(10) 2.135 0.109(10) 0.437 0.088(10) 0.051 0.008(10) 0.023 0.005(10) 3.702 0.319(10) 1.500 0.086(10) 570.380 61.904(10) 552.870 50.408(10) 544.040 54.651(10) 551.070 37.294(10) - 142- DuPont-11418 H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_________________________________________________________DuPont-11418 TABLE 36 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION MEAN RELATIVE ORGAN WEIGHTS (% of body weight) Group: Dosage(mg/kg) I 0 III V VII 10 100 1000 Test LIVER/ FINAL BODY * 100 2.665 0.185(10) 2.731 0.138(10) 2.744 0.146(10) 3.289# 0.158(10) KIDNEYS/ FINAL BODY * 100 0.688 0.061(10) 0.734 0.052(10) 0.735 0.051(10) 0.799# 0.072(10) HEART/ FINAL BODY * 100 0.300 0.023(10) 0.313 0.022(10) 0.312 0.022 (10) 0.324# 0.019(10) SPLEEN/ FINAL BODY * 100 0.141 0.012(10) 0.160 0.021(10) 0.150 0.026(10) 0.147 0.011(10) BRAIN/ FINAL BODY * 100 0.384 0.032(10) 0.395 0.029(10) 0.394 0.036(10) 0.389 0.028(10) THYMUS/ FINAL BODY * 100 ADRENAL GLANDS/ FINAL BODY * 100 THYROID GLAND/ FINAL BODY * 100 TESTES/ FINAL BODY * 100 EPIDIDYMIDES/ FINAL BODY * 100 0.074 0.012(10) 0.009 0.002(10) 0.004 0.001(9) 0.617 0.051(10) 0.259 0.029(10) 0.083 0.018(10) 0.011 0.002(10) 0.004 0.001(10) 0.662 0.077(10) 0.285 0.029(10) 0.078 0.014(10) 0.011 0.002(10) 0.004 0.001(10) 0.650 0.044(10) 0.273 0.027(10) 0.079 0.013(10) 0.009 0.002(10) 0.004 0.001(10) 0.676 0.090(10) 0.274 0.029(10) Company Sanitized. Does not contain TSCA CBI -143 - Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 36 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION Group: Dosage (mg/kg) MEAN RELATIVE ORGAN WEIGHTS (% organ to brain weight ratio) I III V VII 0 10 100 1000 Test LIVER/ BRAIN * 100 KIDNEYS/ BRAIN * 100 HEART/ BRAIN * 100 SPLEEN/ BRAIN * 100 THYMUS/ BRAIN * 100 ADRENAL GLANDS/ BRAIN * 100 THYROID GLAND/ BRAIN * 100 697.326 65.322(10) 180.200 20.354(10) .78.304 4.845(10) 36.949 4.390(10) 19.362 3.587(10) 2.339 0.390(10) 1.148 0.267(9) 695.197 60.585(10) 186.673 17.166(10) 79.635 7.729(10) 40.819 5.911(10) 21.105 4.463(10) 2.742 0.489(10) 0.980 0.275(10) 702.743 89.168(10) 187.660 18.934(10) 79.557 6.428(10) 38.084 6.458(10) 20.062 3.914(10) 2.690 0.534(10) 1.070 0.246(10) 850.523# 78.915(10) 206.158# 18.086(10) 83.552 6.374(10) 37.916 3.933(10) 20.438 3.898(10) 2.405 0.420(10) 1.080 0.219(10) TESTES/ BRAIN * 100 EPIDIDYMIDES/ BRAIN * 100 161.197 15.013(10) 67.507 6.869(10) 167.743 12.660(10) 72.206 5.336(10) 165.607 14.772(10) 69.672 9.604(10) 173.979 19.138(10) 70.352 4.315(10) Data summarized as: Mean Standard Deviation (n) # Statistically significant difference from control at p < 0.05 by Jonckheere-Terpstra trend test. - 144- DuPont-11418 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 37 MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS DESIGNATED FOR RECOVERY EVALUATION MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) Group: Dosage(mg/kg) i VII 0 1000 Test LIVER 15.754 * 2.172(9) 17.296 2.051(10) KIDNEYS 4.105 0.200(9) 4.081 0.420(10) HEART 1.792 0.174(9) 1.753 0.113(10) SPLEEN 0.797 0.175(9) 0.840 0.072(10) BRAIN 2.172 0.157(9) 2.129 0.067(10) THYMUS 0.378 0.113(9) 0.382 0.104(10) ADRENAL GLANDS 0.051 0.008(9) 0.051 0.005(10) THYROID GLAND 0.029 0.006(9) 0.029 0.005(10) TESTES 3.668 0.307(9) 3.575 0.307(10) EPIDIDYMIDES 1.583 0.195(9) 1.545 0.131(10) FINAL BODY WEIGHT 589.344 49.966(9) 583.300 52.368(10) -145- DuPont-11418 ) ') H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations__________________________________________ _________ TABLE 37 (CONTINUED) ` MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS DESIGNATED FOR RECOVERY EVALUATION MEAN RELATIVE ORGAN WEIGHTS (% of body weight) Group: Dosage(mg/kg) I VII 0 -1000 Test LIVER/ FINAL BODY * 100 2.670 0.259(9) 2.962# 0.178(10) KIDNEYS/ FINAL BODY * 100 0.701 0.066(9) 0.702 0.068(10) HEART/ FINAL BODY * 100 0.304 0.07(9) 0.302 0.028(10) SPLEEN/ FINAL BODY * 100 0.135 0.025(9) 0.144 0.011(10) BRAIN/ FINAL BODY * 100 0.370 0.033(9) 0.368 0.037(10) THYMUS/ FINAL BODY * 100 ADRENAL GLANDS/ FINAL BODY * 100 THYROID GLAND/ FINAL BODY * 100 TESTES/ FINAL BODY * 100 EPIDIDYMIDES/ FINAL BODY * 100 0.064 0.018(9) 0.009 0.001(9) 0.005 0.001(9) 0.624 0.056(9) 0.269 0.026(9) 0.065 0.014(10) 0.009 0.001(10) 0.005 0.001(10) 0.617 0.074(10) 0.266 0.030(10) ) DuPont-11418 Company Sanitized. Does not contain TSCA CBI -146- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 37 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS DESIGNATED FOR RECOVERY EVALUATION MEAN RELATIVE ORGAN WEIGHTS (% organ to brain weight ratio) Group: Dosage(mg/kg) I VII 0 1000 Test LIVER/ BRAIN * 100 730.212 128.329(9) 813.590 105.495(10) KIDNEYS/ BRAIN * 100 189.802 15.475(9) 191.896 22.036(10) HEART/ BRAIN * 100 82.627 7.037(9) 82.463 6.930(10) SPLEEN/ BRAIN * 100 36.680 7.454(9) 39.454 3.454(10) THYMUS/ BRAIN * 100 17.499 5.505(9) 17.923 4.866(10) ADRENAL GLANDS/ BRAIN * 100 2.367 0.489(9) 2.394 0.287(10) THYROID GLAND/ BRAIN * 100 1.348 0.264(9) 1.344 0.232(10) TESTES/ BRAIN * 100 170.012 22.044(9) 167.937 14.182(10) EPIDIDYMIDES/ BRAIN * 100 73.331 11.109(9) 72.653 7.088(10) Data summarized as: Mean Standard Deviation (n) # Statistically significant difference from control at p < 0.05 by Jonckheere-Terpstra trend test. -147- DuPont-11418 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 38 MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) Group : Dosage(mg/kg) II IV VI VIII 0 10 100 1000 Test LIVER 8.053 1.128(10) 7.992 0.992(10) 7.990 0.746(10) 8.512 0.581(10) KIDNEYS 2.220 0.248(10) 2.265 0.210(10) 2.208 0.224(10) 2.282 0.217(10) HEART 1.098 0.110(10) 1.067 0.117(10) 1.079 0.072(10) 1.092 0.119(10) SPLEEN 0.498 0.066(10) 0.566 0.082(10) 0.531 0.069(10) 0.547 0.095(10) BRAIN 1.896 0.086(10) 1.908 0.115(10) 1.960 0.084(10) 1.981 0.119(10) THYMUS 0.276 0.079(10) 0.292 0-058(10) 0.345 0.073(10) 0.314 0.062(10) ADRENAL GLANDS 0.068 0.011(10) 0.072 0.009(10) 0.070 0.013 (10) 0.071 0.009(10) THYROID GLAND 0.015 0.004(10) 0.018 0.003(10) 0.018 0.003(10) 0.019# 0.004(10) OVARIES 0.117 0.019(10) 0.140 0.022(10) 0.137 0.022(10) 0.137 0.023(10) UTERUS 0.735 0.215(10) 0.761 0.275(10) 0.851 0.325(10) 0.838 0.387(10) FINAL BODY WEIGHT 303.050 29.058(10) 288.340 26.761(10) 290.080 16.350(10) 294.990 23.672(10) - 148- DuPont-11418 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 38 (CONTINUED) Group: Dosage (mg/kg) Test LIVER/ FINAL BODY * 100 KIDNEYS/ FINAL BODY * 100 HEART/ FINAL BODY * 100 SPLEEN/ FINAL BODY * 100 BRAIN/ FINAL BODY * 100 THYMUS/ FINAL BODY * 100 ADRENAL GLANDS/ FINAL BODY * 100 THYROID GLAND/ FINAL BODY * 100 OVARIES/ FINAL BODY * 100 UTERUS/ FINAL BODY * 100 MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION MEAN RELATIVE ORGAN WEIGHTS (% of body weight) II IV VI VIII 0 10 100 1000 2.654 0.235(10) 0.733 0.052(10) 0.363 0.024(10) 0.164 0.019(10) 0.630 0.054(10) 0.092 0.028(10) 0.022 0.003(10) 0.005 0.001(10) 0.039 0.006(10) 0.244 0.075(10) 2.768 0.170(10) 0.787 0.048(10) 0.370 0.028(10) 0.196* 0.016(10) 0.665 0.056(10) 0.102 0.021(10) 0.025 0.003(10) 0.006# 0.001(10) 0.049 0.007(10) 0.261 0.082(10) 2.756 0.229(10) 0.761 0.058(10) 0.373 0.032(10) 0.183 0.020(10) 0.677 0.037(10) 0.118# 0.020(10) 0.024 0.004(10) 0.006# 0.001(10) 0.047 0.008(10) 0.289 0.092 (10) 2.891# 0.135(10) 0.775 0.064(10) 0.371 0.036(10) 0.184 0.022(10) 0.674 0.046(10) 0.106# 0.018(10) 0.024 0.004(10) 0.006# 0.002(10) 0.047 0.009(10) 0.283 0.122(10) - 149- DuPont-11418 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 38 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION Group : Dosage(mg/kg) MEAN RELATIVE ORGAN WEIGHTS (% organ to brain weight ratio) II IV VI VIII 0 10 100 1000 Test LIVER/ BRAIN * 100 KIDNEYS/ BRAIN * 100 HEART/ BRAIN * 100 SPLEEN/ BRAIN * 100 THYMUS/ BRAIN * 100 ADRENAL GLANDS/ BRAIN * 100 THYROID GLAND/ BRAIN * 100 OVARIES/ BRAIN * 100 UTERUS/ BRAIN * 100 423.933 49.157(10) 117.072 11.741(10) 57.901 4.680(10) 26.241 3.181(10) 14.685 4.718(10) 3.571 0.526(10) 0.801 0.185(10) 6.199 1.068(10) 38.681 10.903(10) 419.320 50.890(10) 118.977 11.451(10) 55.937 5.197(10) 29.656 3.927(10) 15.466 3.597(10) 3.775 0.354(10) 0.944 0.175(10) 7.336 1.135(10) 39.692 13.456(10) 408.327 41.392(10) 112.671 10.372(10) 55.164 4.690(10) 27.122 3.392(10) 17.553 3.264(10) 3.569 0.625(10) 0.915 0.154(10) 6.990 1.077(10) 43.155 14.879(10) 429.945 20.218(10) 115.414 11.117(10) 55.095 5.002(10) 27.576 4.484(10) 15.857 3.253(10) 3.581 0.391(10) 0.935 0.226(10) 6.896 1.011(10) 41.946 18.021(10) Data summarized as: Mean Standard Deviation (n) # Statistically significant difference from control at p < 0.05 by Jonckheere-Terpstra trend test. * Statistically significant difference from control at p < 0.05 by Dunnett/Tamhane-Dunnett test. -150- DuPont-11418 H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS DESIGNATED FOR RECOVERY EVALUATION MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) Group : Dosage(mg/kg) II VIII 0 1000 Test LIVER 8.705 1.550(10) 8.722 1.093(10) KIDNEYS 2.309 0.254(10) 2.367 0.230(10) HEART 1.135 0.067(10) 1.114 0.138(10) SPLEEN 0.564 0.073(10) 0.526 0.106(10) BRAIN 1.903 0.069(10) 1.891 0.046(10) THYMUS 0.277 0.075(10) 0.300 0.071(10) ADRENAL GLANDS 0.066 0.008(10) 0.069 0.010(10) THYROID GLAND 0.021 0.002(10) 0.026# 0.006(10) OVARIES 0.119 0.013(10) 0.122 0.029(10) UTERUS 0.844 0.242(10) 0.772 0.334(10) FINAL BODY WEIGHT 325.260 34.988(10) 298.620 22.864(10) -151 - DuPont-11418 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS DESIGNATED FOR RECOVERY EVALUATION MEAN RELATIVE ORGAN WEIGHTS (% of body weight) Group : Dosage(mg/kg) II VIII 0 1000 Test LIVER/ FINAL BODY * 100 2.669 0.273(10) 2.915# 0.204(10) KIDNEYS/ FINAL BODY * 100 0.711 0.046(10) 0.793# 0.043(10) HEART/ FINAL BODY * 100 0.351 0.025(10) 0.373 0.033(10) SPLEEN/ FINAL BODY * 100 0.174 0.016(10) 0.176 0.036(10) BRAIN/ FINAL BODY * 100 0.590 0.059(10) 0.637 0.051(10) THYMUS/ FINAL BODY * 100 ADRENAL GLANDS/ FINAL BODY * 100 THYROID GLAND/ FINAL BODY * 100 OVARIES/ FINAL BODY * 100 UTERUS/ FINAL BODY * 100 0.085 0.017(10) 0.020 0.003(10) 0.006 0.001(10) 0.037 0.005(10) 0.258 0.067(10) 0.101 0.024(10) 0.023# 0.003(10) 0.009# 0.002(10) 0.041 0.010(10) 0.260 0.117(10) - 152- (( DuPont-11418 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 39 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS DESIGNATED FOR RECOVERY EVALUATION MEAN RELATIVE ORGAN WEIGHTS (% organ to brain weight ratio) Group : Dosage(mg/kg) II VIII . 0 1000 Test LIVER/ BRAIN * 100 456.513 71.989(10) 461.664 60.058(10) KIDNEYS/ BRAIN * 100 121.292 12.325(10! 125.275 12.836(10) HEART/ BRAIN * 100 59.727 4.623(10) 58.991 7.676(10) SPLEEN/ BRAIN * 100 29.694 4.143(10) 27.739 5.218(10) THYMUS/ BRAIN * 100 14.546 3.724(10) 15.900 3.899(10) ADRENAL GLANDS/ BRAIN * 100 3.463 0.455(10) 3.652 0.556(10) THYROID GLAND/ BRAIN * 100 OVARIES/ BRAIN * 100 UTERUS/ BRAIN * 100 1.099 0.135(10) 1.369# 0.300(10) 6.286 0.763(10) 6.453 1.448(10) 44.402 40.999 13.049(10)_______ 18.445(10) Data summarized as: Mean Standard Deviation (n) # Statistically significant difference from control at p < 0.05 by Jonckheere-Terpstra trend test. -153- DuPont-11418 ( Company Sanitized. Does not contain TSCA CBI Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations T A B L E 40 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION LESIONS TREATMENT LESION INCIDENCE (Numeric) Males ; 10 m0g/kg|! mg/kg I 1 III 1 100 mg/kg V 1000 mg/kg VII LIVER NO ABNORMALITY D E T E C T E D KIDNEYS NO ABNORMALITY DETECTED DILATATION, BILATERAL, PELVIS, LEFT MODERATE RIGHT SEVERE. LUNGS NO ABNORMALITY DETECTED HEART NO ABNORMALITY DETECTED SKELETAL MUSCLE NO ABNORMALITY DETECTED (1.0) 10 (10) 10 (10) 10 (10) 10 (10) 10 GO) 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 (10) 10 (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified DuPont-11418 -154- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 40 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (Numeric)| --------------------------- | Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII SPLEEN NO ABNORMALITY DETECTED AORTA NO ABNORMALITY DETECTED BRAIN NO ABNORMALITY DETECTED SPINAL CORD NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (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 - 155 - DuPont-11418 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 40 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (Numeric) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII JEJUNUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED PANCREAS NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED RECTUM NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (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 his tissue The absence of a number indicates the finding specified was not identified -156- DuPont-11418 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 40 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (Numeric) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (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 - 157- DuPont-11418 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 40 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (Numeric) Males 0 10 100 1000 mg /kg mg/kg mg/kg mg/kg I III V 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 (10) 10 (10) 10 ` (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (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 - 158- ( DuPont-11418 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 40 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION LESION INCIDENCE (Numeric) Males TREATMENT 0 10 100 1000 mg/kg mg/kg mg/kg rag/kg I III V VII E YE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED SKIN . NO ABNORMALITY DETECTED PROSTATE NO ABNORMALITY DETECTED SEMINAL VESICLES NO ABNORMALITY DETECTED URINARY BLADDER NO ABNORMALITY DETECTED TESTES 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 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 - 159- DuPont-11418 Company Sanitized. Does not contain TSCA CBI Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with Qne-Generation Reproduction Evaluations LESIONS TABLE 40 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (Numeric) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII EPIDIDYMIDES NO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified DuPont-11418 - 160- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TA BLE41 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDE Males 0 1000 mg/kg mg/kg I VII LIVER (10) NO ABNORMALITY DETECTED 10 KIDNEYS (10) NO ABNORMALITY DETECTED 10 LUNGS (10) NO ABNORMALITY DETECTED 10 HEART (10) NO ABNORMALITY DETECTED 10 SKELETAL MUSCLE (10) NO ABNORMALITY DETECTED 10 SPLEEN (10) NO ABNORMALITY DETECTED * Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 1 -161 - DuPont-11418 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 41 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDE Males 0 1000 mg/kg mg/kg I VII AORTA NO ABNORMALITY DETECTED BRAIN NO ABNORMALITY DETECTED SPINAL CORD NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified DuPont-11418 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 41 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDE Males 0 1000 mg/kg mg/kg I VII ILEUM NO ABNORMALITY DETECTED PANCREAS NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED RECTUM NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 GO) 10 GO) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified - 163- DuPont-11418 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 41 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS DESIGNATED FOR RECOVERY EVALUATION LESION INCIDE . Males TREATMENT 0 1000 mg/kg mg/kg I VII SALIVARY GLANDS NO ABNORMALITY DETECTED MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED PITUITARY GLAND NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 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 -164- DuPont-11418 Company Sanitized. Does not contain TSCA C8I H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 41 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS DESIGNATED FOR RECOVERY EVALUATION 1LESION INCIDE 11 1 Males TREATMENT 0 1000 mg/kg mg/kg I VII THYROID GLAND NO ABNORMALITY DETECTED PARATHYROID GLANDS NO ABNORMALITY DETECTED TRACHEA | NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED PHARYNX/ LARYNX NO ABNORMALITY DETECTED E YE(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 (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 -165- DuPont-11418 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 41 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDE Males 0 1000 mg/kg mg/kg I VII SKIN NO ABNORMALITY DETECTED PROSTATE NO ABNORMALITY DETECTED SEMINAL VESICLES NO ABNORMALITY DETECTED URINARY BLADDER NO ABNORMALITY DETECTED TESTES NO ABNORMALITY DETECTED EPIDIDYMIDES NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 Figures in parentheses is the number of animals grossly examined for Chis tissue The absence of a number indicates the finding specified was not identified - 166- DuPont-11418 Company Sanitized. Does not contain TSCA CBI Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 41 (CONTINUED) . LESIONS INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDE Males 0 1000 mg/kg mg/kg I VTI FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified DuPont-11418 - 167- ( H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS T A B L E 42 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (Animal No Females 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg II IV VI VIII LIVER NO ABNORMALITY DETECTED DEFORMITY, RIGHT, LOBE. KIDNEYS NO ABNORMALITY DETECTED LUNGS NO ABNORMALITY DETECTED HEART NO ABNORMALITY DETECTED SKELETAL MUSCLE NO ABNORMALITY DETECTED SPLEEN NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 9 1 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified -168- DuPont-11418 ( Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 42 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (Animal No Females 0 10 100 1000 mg /kg mg/kg mg/kg mg/kg II IV VI VIII AORTA (10) (10) (10) NO ABNORMALITY DETECTED 10 10 10 BRAIN (10) (10) (10) NO ABNORMALITY DETECTED 10 10 10 SPINAL CORD (10) (10) (10) NO ABNORMALITY DETECTED 10 10 10 STOMACH (10) (10) (10) NO ABNORMALITY DETECTED 10 10 10 DUODENUM (10) (10) (10) NO ABNORMALITY DETECTED 10 10 10 JEJUNUM (10) (10) (10) 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 -169- DuPont-11418 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 42 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (Animal No Females 0 10 100 1000 mg /kg mg/kg mg/kg mg/kg II IV VI VIII ILEUM NO ABNORMALITY DETECTED PANCREAS NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED RECTUM NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified DuPont-11418 Company Sanitized. Does not contain TSCA C8I H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 42 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION LESIONS TREATMENT LESION INCIDENCE (Animal No Females 0 10 , 100 1000 mg/kg mg/.kg mg/kg mg/kg II IV VI VIII SALIVARY GLANDS i (10) (10) (10) NO ABNORMALITY DETECTED 10 10 10 MANDIBULAR LYMPH NODE (10) (10) (10) NO ABNORMALITY DETECTED 10 10 10 THYMUS (10) (10) (10) NO ABNORMALITY DETECTED 10 10 10 ADRENAL GLANDS (10) (10) (10) NO ABNORMALITY DETECTED 10 10 10 SCIATIC NERVE (10) (10) (10) NO ABNORMALITY DETECTED 10 10 10 PITUITARY GLAND (10) (10) (10) NO ABNORMALITY DETECTED LARGE. 9 10 1 *> Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 - 171 - DuPont-11418 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 42 (CONTINUED) . INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (Animal No Females 0 10 100 1000 mg /kg mg/kg mg/kg mg/kg II IV VI VIII THYROID GLAND (10) (10) (10) NO ABNORMALITY DETECTED 10 10 10 PARATHYROID GLANDS (10) (10) (10) NO ABNORMALITY DETECTED 10 10 10 TRACHEA NO ABNORMALITY DETECTED GO) (10) (10) 10 10 10 ESOPHAGUS (10) (10) (10) NO ABNORMALITY DETECTED 10 10 10 PHARYNX/ LARYNX (10) (10) (10) NO ABNORMALITY DETECTED 10 10 10 EY E (S ) WITH OPTIC NERVE (10) (10) (10) NO ABNORMALITY DETECTED 10 10 1 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 - 172- ( DuPont-11418 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 42 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (Animal No Females 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg II IV VI VIII SKIN NO ABNORMALITY DETECTED MAMMARY GLAND (FEMALE) NO ABNORMALITY DETECTED OVARIES NO ABNORMALITY DETECTED UTERUS NO ABNORMALITY DETECTED VAGINA NO ABNORMALITY DETECTED URINARY BLADDER NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10! 10 (10) 10 (10) 10 (10) 10 (10) 10 (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 - 173- DuPont-11418 Company Sanitized. Does not contain TSCA CBI Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 42 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION LESION INCIDENCE (Animal No . Females TREATMENT 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg II IV VI VIII FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 Figures in parentheses is the nuiriber of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified DuPont-11418 - 174- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with Qne-Generation Reproduction Evaluations 1 LESIONS TABLE 43 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDE Females 0 1000 mg/kg mg/kg II 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 (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 -175- ( DuPont-11418 ( Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 43 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDE Females 0 1000 mg/kg mg/kg II VIII AORTA (10) NO ABNORMALITY DETECTED 10 BRAIN (10) NO ABNORMALITY DETECTED 10 SPINAL CORD (10) NO ABNORMALITY DETECTED 10 STOMACH (10) NO ABNORMALITY DETECTED 10 DUODENUM (10) NO ABNORMALITY DETECTED 10 JEJUNUM (10) | NO ABNORMALITY DETECTED 1 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 - 176- DuPont-11418 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 43 (CONTINUED) ' INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDE Females 0 1000 mg/kg mg/kg II VIII ILEUM NO ABNORMALITY DETECTED PANCREAS NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED RECTUM NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED (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 - 177- DuPont-11418 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 43 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDE Females 0 1000 mg/kg mg/kg II VIII SALIVARY GLANDS NO ABNORMALITY DETECTED MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED PITUITARY GLAND NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified -178- DuPont-11418 Company Sanitized. Does not contain TSCA C8I H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 43 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS DESIGNATED FOR RECOVERY EVALUATION LESION INCIDE Females TREATMENT 0 1000 mg/kg mg/kg II VIII THYROID GLAND NO ABNORMALITY DETECTED PARATHYROID GLANDS NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED EYE (S) WITH OPTIC NERVE NO ABNORMALITY DETECTED (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 - 179- DuPont-11418 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 43 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDE Females 0 1000 mg/kg mg/kg II VIII SKIN NO ABNORMALITY DETECTED MAMMARY GLAND (FEMALE) NO ABNORMALITY DETECTED OVARIES NO ABNORMALITY DETECTED UTERUS NO ABNORMALITY DETECTED DILATATION, HORNS. VAGINA NO ABNORMALITY DETECTED URINARY BLADDER NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 9 1 (10) 10 (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified - 180- DuPont-11418 Company Sanitized. Does not contain TSCA CBI Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 43 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDE Females 0 1000 mg/kg mg/kg II VIII FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 GO) 10 (10) 10 (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified DuPont-11418 -181 - Company Sanitized. Does not contain TSCA C8I H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE44 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC! Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC. HYPERTROPHY, HEPATOCELLULAR, CENTRILOBULAR. FATTY CHANGE, PERIPORTAL. FATTY CHANGE, MEDIAN CLEFT. DEGENERATION, HEPATOCELLULAR, FOCAL. (10) 10 7 2 (10) 1 9 1 3 (10) 10 3 5 (10) 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 DuPont-11418 - 182- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII DIGESTIVE SYSTEM PANCREAS NO ABNORMALITY DETECTED INFLAMMATION, FOCAL. (10) 9 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 - 183 - Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII DIGESTIVE SYSTEM ESOPHAGUS NO ABNORMALITY DETECTED (9) 9 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -184- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION LESION INCIDENCE (NUMERIC) > Males TREATMENT 0 10 100 1000 mg/kg mg /kg mg/kg mg/kg I III V VII DIGESTIVE SYSTEM STOMACH NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 - 185- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg /kg I III V VII DIGESTIVE SYSTEM DUODENUM NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 - 186- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg /kg mg/kg mg/kg mg /kg I III V VII DIGESTIVE SYSTEM JEJUNUM NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 - 187- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII DIGESTIVE SYSTEM ILEUM NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 - 188- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII DIGESTIVE SYSTEM CECUM * NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -189- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg /kg I III V VII DIGESTIVE SYSTEM COLON NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -190- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII DIGESTIVE SYSTEM RECTUM NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 Company Sanitized. Does not contain TSCA CBI Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII DIGESTIVE SYSTEM SALIVARY GLANDS NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -192- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED CHRONIC PROGRESSIVE NEPHROPATHY. HYDRONEPHROSIS, UNILATERAL. CYST, TUBULAR. AGGREGATES, LYMPHOID. (10) 2 7 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 (9) 1 5 1 1 4 DuPont-11418 -193- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII URINARY SYSTEM URINARY BLADDER NO ABNORMALITY DETECTED AGGREGATES, LYMPHOID. (10) 8 2 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 7 3 DuPont-11418 - 194- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 44 (CONTINUED) LESIONS INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION LESION INCIDENCE (NUMERIC) Males TREATMENT . 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII RESPIRATORY SYSTEM LUNGS NO ABNORMALITY DETECTED MACROPHAGES, ALVEOLAR, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC, PERIVASCULAR. HEMORRHAGE, ALVEOLAR. (10) 4 2 1 3 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 4 1 3 3 DuPont-11418 -195- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg /kg mg /kg mg/kg mg/kg 1 III V VII RESPIRATORY SYSTEM TRACHEA NO ABNORMALITY DETECTED INFLAMMATION, FOCAL. (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 9 1 DuPont-11418 -196- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII RESPIRATORY SYSTEM PHARYNX /LARYNX NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -197- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg /kg mg/kg mg/kg I III V VII RESPIRATORY SYSTEM NOSE NO ABNORMALITY DETECTED INFLAMMATION, TURBINATES. INFLAMMATION, VOMERONASAL ORGAN. INFLAMMATION, ORAL MUCOSA. INFLAMMATION, NASOLACRIMAL DUCT. (10) 7 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) 6 2 1 1 1 DuPont-11418 - 198- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII CARDIOVASCULAR SYSTEM HEART NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. (10) 9 '1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 9 1 DuPont-11418 - 199- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII CARDIOVASCULAR SYSTEM AORTA NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 - 200- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -201 - Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII LYMPHATIC AND HEMATOPOIETIC SYSTEM THYMUS NO ABNORMALITY DETECTED HEMORRHAGE. (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 (10) 2 8 DuPont-11418 - 202- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) * INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII LYMPHATIC AND HEMATOPOIETIC SYSTEM MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED NECROSIS, LYMPHOID. LEUKOCYTOSIS, PLASMA CELL, MEDULLARY. ERYTHROCYTOSIS/ERYTHROPHAGOCYTOSIS, SINUS. (10) 8 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) 6 1 1 3 DuPont-11418 -203- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII LYMPHATIC AND HEMATOPOIETIC SYSTEM MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -204- ( Company Sanitized. Does not contain TSCA C8I H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII LYMPHATIC AND HEMATOPOIETIC SYSTEM BONE MARROW NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -205- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 44 (CONTINUED) LESIONS ENDOCRINE SYSTEM INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION J TREATMENT 1 1 LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII PITUITARY GLAND NO ABNORMALITY DETECTED CYST. (10) 9 1 (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified DuPont-11418 - 206- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MATE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION LESION INCIDENCE (NUMERIC) Males TREATMENT 0 10 100 1000 mg /kg mg/kg mg/kg mg/kg I III V VII ' ENDOCRINE SYSTEM THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR CELL. (10) 9 1 (10) 9 1 (10) 9 1 (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified DuPont-11418 -207- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII ENDOCRINE SYSTEM PARATHYROID GLANDS NO ABNORMALITY DETECTED (9) 9 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -208- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII ENDOCRINE SYSTEM ADRENAL GLANDS NO ABNORMALITY DETECTED ADRENAL MEDULLA MISSING. (10) 9 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -209- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII NERVOUS SYSTEM BRAIN NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 - 210- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg /kg mg/kg mg/kg mg/kg I III V VII NERVOUS SYSTEM SPINAL CORD NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -211 - ( Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII NERVOUS SYSTEM SCIATIC NERVE NO ABNORMALITY DETECTED (9) 9 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 - 212- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION LESIONS MUSCULAR AND SKELETAL SYSTEM LESION INCIDENCE (NUMERIC) Males TREATMENT 0 mg/kg 1I 1 10 mg/kg III 100 mg/kq V 1000 mq/kq VII SKELETAL MUSCLE NO ABNORMALITY DETECTED (9) (10) 9 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified DuPont-11418 -213- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg /kg mg/kg mg/kg I III V VII MUSCULAR AND SKELETAL SYSTEM FEMUR/KNEE JOINT NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -214- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC! Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII MUSCULAR AND SKELETAL SYSTEM STERNUM NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -215- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION LESION INCIDENCE (NUMERIC) > Males TREATMENT 0 10 100 1000 mg /kg mg /kg mg/kg mg/kg I III V VII REPRODUCTIVE SYSTEM TESTES NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -216- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg /kg mg/kg mg/kg mg/kg I III V VII REPRODUCTIVE SYSTEM EPIDIDYMIDES NO ABNORMALITY DETECTED AGGREGATES, LYMPHOID. (10) 6 4 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 5 5 DuPont-11418 -217- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 44 (CONTINUED) LESIONS REPRODUCTIVE SYSTEM INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 mg /kg I 10 mg/kg III 100 1 1000 mg/kg| mg/kg V i VII 1 PROSTATE NO ABNORMALITY DETECTED AGGREGATES, LYMPHOID. (10) 3 7 (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 DuPont-11418 -218- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII REPRODUCTIVE SYSTEM SEMINAL VESICLES NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -219- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII CUTANEOUS SYSTEM SKIN , NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -220- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 44 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION . LESION INCIDENCE (NUMERIC) Males TREATMENT 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII SPECIAL SENSES SYSTEM E Y E (S ) WITH OPTIC NERVE NO ABNORMALITY DETECTED OPTIC NERVE NOT PRESENT, UNILATERAL. INFLAMMATION, PERIOCULAR, UNILATERAL. ATROPHY, RETINAL, UNILATERAL. (10) 5 4 4 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) 8 1 2 DuPont-11418 -221 - Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII DIGESTIVE SYSTEM LIVER NECROSIS, FOCAL. INFLAMMATION, SUBACUTE /CHRONIC. FATTY CHANGE, PERIPORTAL. FATTY CHANGE, MEDIAN CLEFT. (10) 10 5 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 (10) 2 10 2 5 DuPont-11418 - 222- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII DIGESTIVE SYSTEM PANCREAS FOCUS OF CELLULAR ALTERATION, BASOPHILIC. (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 DuPont-11418 - 223- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) 'INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII DIGESTIVE SYSTEM ESOPHAGUS . 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 DuPont-11418 -224- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 45 (CONTINUED) LESIONS INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION | TREATMENT 1 1 1 LESION INCIDENCE (NUMERIC! Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII DIGESTIVE SYSTEM STOMACH 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 DuPont-11418 -225- :;spany Sanitized. Does not contain tbA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII DIGESTIVE SYSTEM DUODENUM 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 DuPont-11418 -226- ((( H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII DIGESTIVE SYSTEM JEJUNUM 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 DuPont-11418 Company Sanitized. Does not contain TSCA C8I -227- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION LESION INCIDENCE (NUMERIC) Males TREATMENT 0 10 100 1000 mg /kg mg/kg mg/kg mg/kg I III V VII DIGESTIVE SYSTEM ILEUM 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 DuPont-11418 -228- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_______ _____________________ ___________________________ DuPont-11418 LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII DIGESTIVE SYSTEM CECUM 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 -229- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION LESIONS TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg /kg mg/kg mg/kg mg/kg I III V VII DIGESTIVE SYSTEM COLON 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 DuPont-11418 - 230- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII DIGESTIVE SYSTEM RECTUM 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 DuPont-11418 -231- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII DIGESTIVE SYSTEM SALIVARY GLANDS 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 DuPont-11418 -232- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII URINARY SYSTEM KIDNEYS (1) 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 DuPont-11418 -233- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII URINARY SYSTEM URINARY BLADDER . 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 DuPont-11418 -234- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII RESPIRATORY SYSTEM LUNGS MACROPHAGES, ALVEOLAR, FOCAL. HEMORRHAGE, ALVEOLAR. (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 DuPont-11418 -235- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 45 (CONTINUED) LESIONS INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg /kg mg/kg mg/kg mg/kg I III V VII RESPIRATORY SYSTEM TRACHEA 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 DuPont-11418 - 236- ( Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg /kg mg/kg I III V VII RESPIRATORY SYSTEM PHARYNX/LARYNX 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 DuPont-11418 -237- Company Sanitized. Does not contain TSCA C8I H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII RESPIRATORY SYSTEM NOSE (1) NO ABNORMALITY DETECTED 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 DuPont-11418 - 238- ( x,. Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII CARDIOVASCULAR SYSTEM HEART 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 DuPont-11418 -239- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg /kg mg/kg mg/kg mg /kg I III V VII CARDIOVASCULAR SYSTEM AORTA 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 DuPont-11418 -240- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN 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 DuPont-11418 i, -241 - Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MATE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII LYMPHATIC AND HEMATOPOIETIC SYSTEM THYMUS HEMORRHAGE. (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 DuPont-11418 -242- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII LYMPHATIC AND HEMATOPOIETIC SYSTEM MANDIBULAR LYMPH NODE 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 DuPont-11418 -243- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII LYMPHATIC AND HEMATOPOIETIC SYSTEM MESENTERIC LYMPH NODE 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 DuPont-11418 - 244- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII LYMPHATIC AND HEMATOPOIETIC SYSTEM BONE MARROW 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 DuPont-11418 -245- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Pay Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg /kg mg/kg mg/kg mg/kg I III V VII ENDOCRINE SYSTEM PITUITARY GLAND 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 DuPont-11418 -246- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg /kg mg/kg mg/kg mg /kg I III V VII ENDOCRINE SYSTEM THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR CELL. (10) 9 1 Figure in parentheses is number of animals microscopically examined' for this tissue The absence of a number indicates the lesion specified was not identified (10) 4 6 DuPont-11418 -247- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII ENDOCRINE SYSTEM ADRENAL GLANDS 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 DuPont-11418 -248- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 45 (CONTINUED) LESIONS INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION 1 TREATMENT 1 1 1 LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII NERVOUS SYSTEM BRAIN NO ABNORMALITY DETECTED d 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 DuPont-11418 -249- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Dy Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION LESION INCIDENCE (NUMERIC) Males TREATMENT 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII NERVOUS SYSTEM SPINAL CORD 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 DuPont-11418 -250- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 45 (CONTINUED) LESIONS NERVOUS SYSTEM INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION j TREATMENT 1 LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII SCIATIC 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 DuPont-11418 -251 - Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION LESIONS TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII 4 MUSCULAR AND SKELETAL SYSTEM SKELETAL MUSCLE 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 DuPont-11418 -252- ( Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg /kg mg /kg I III V VII MUSCULAR AND SKELETAL SYSTEM FEMUR/KNEE JOINT 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 DuPont-11418 -253- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg /kg mg/kg mg/kg mg/kg I III V VII MUSCULAR AND SKELETAL SYSTEM STERNUM 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 DuPont-11418 -254- H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII REPRODUCTIVE SYSTEM TESTES 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 DuPont-11418 Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg /kg I III V VII REPRODUCTIVE SYSTEM EPIDIDYMIDES 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 DuPont-11418 Company Sanitized. Does not contain TSCA C8I Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII REPRODUCTIVE SYSTEM PROSTATE 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 DuPont-11418 -257- Company Sanitized. Does not contain TSCA C8I H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg /kg mg/kg mg/kg mg/kg I III V VII REPRODUCTIVE SYSTEM SEMINAL VESICLES 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 DuPont-11418 -258- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Males 0 10 100 1000 mg/kg mg /kg mg/kg mg/kg I III V VII 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 DuPont-11418 -259- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 45 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION LESION INCIDENCE (NUMERIC) Males TREATMENT 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg I III V VII SPECIAL SENSES SYSTEM EY E (S ) WITH OPTIC NERVE OPTIC NERVE NOT PRESENT, UNILATERAL. (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 DuPont-11418 - 260- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS T A B L E 46 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION LESION INCIDENCE (NUMERIC) Females TREATMENT 0 10 100 1000 * mg/kg mg/kg mg/kg mg/kg II IV VI VIII DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED NECROSIS, FOCAL. INFLAMMATION, SUBACUTE /CHRONIC. FATTY CHANGE, PERIPORTAL. FATTY CHANGE, MEDIAN CLEFT. (10) 1 8 6 3 (10) 2 8 1 (10) 1 10 1 (10) 3 7 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 DuPont-11418 -261 - Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) In c id e n c e s o f m ic r o s c o p ic o b s e r v a t io n s in f e m a l e r a t s NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg II IV VI VIII DIGESTIVE SYSTEM PANCREAS NO ABNORMALITY DETECTED AGGREGATES, LYMPHOID. (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 8 2 DuPont-11418 -262- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg II IV VI VIII DIGESTIVE SYSTEM ESOPHAGUS NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -263- Company Sanitized. Does not contain TSCA CBI H-25425 : Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg II IV VI VIII DIGESTIVE SYSTEM STOMACH NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -264- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/kg mg /kg mg/kg mg/kg II IV VI VIII DIGESTIVE SYSTEM DUODENUM NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is .number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (9) 9 DuPont-11418 -265- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg /kg mg/kg mg/kg mg/kg II IV VI VIII DIGESTIVE SYSTEM JEJUNUM NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -266- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg II IV VI VIII DIGESTIVE SYSTEM ILEUM NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 - 267- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg /kg mg/kg mg/kg mg/kg II IV VI VIII DIGESTIVE SYSTEM CECUM NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -268- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg II IV VI VIII DIGESTIVE SYSTEM COLON NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 - 269- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg II IV VI VIII DIGESTIVE SYSTEM RECTUM NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is fiumber of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -270- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg II IV VI VIII DIGESTIVE SYSTEM SALIVARY GLANDS NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -271 - Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg II IV VI VIII URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED CHRONIC PROGRESSIVE NEPHROPATHY. AGGREGATES, LYMPHOID. (10) 6 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 (10) 6 1 3 DuPont-11418 -272- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/kg mg /kg mg/kg mg/kg II IV VI VIII URINARY SYSTEM URINARY BLADDER * NO ABNORMALITY DETECTED (9) 9 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -273- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg II IV VI VIII RESPIRATORY SYSTEM LUNGS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, PERIVASCULAR. HEMORRHAGE, ALVEOLAR. (10) 2 2 7 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 6 1 3 DuPont-11418 -274- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with Qne-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASHC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/'kg mg/kg mg/kg mg/kg II IV VI VIII RESPIRATORY SYSTEM TRACHEA (10) NO ABNORMALITY DETECTED INFLAMMATION. AGGREGATES, LYMPHOID. 9 1 ( Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 9 1 DuPont-11418 -275 - Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION LESION INCIDENCE (NUMERIC) Females TREATMENT 0 10 100 1000 mg /kg mg/kg mg/kg mg/kg * II IV VI VIII RESPIRATORY SYSTEM PHARYNX/LARYNX NO ABNORMALITY DETECTED DEGENERATION, MYOFIBER. (10) 9 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -276- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg II IV VI VIII RESPIRATORY SYSTEM NOSE NO ABNORMALITY DETECTED INFLAMMATION, TURBINATES. INFLAMMATION, SINUS. INFLAMMATION, ORAL MUCOSA. (10) 9 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 7 3 1 DuPont-11418 -277- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASHC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION LESIONS LESION INCIDENCE (NUMERIC) Females TREATMENT 0 | mg/kg ! 11 10 mg/kg IV 100 mg/kg VI 1000 mg/kg VIII CARDIOVASCULAR SYSTEM HEART * NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. (10) 10 (10) 9 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified DuPont-11418 -278- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 46 (CONTINUED) LESIONS INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION % LESION INCIDENCE (NUMERIC) Females | TREATMENT 1 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg II IV VI VIII CARDIOVASCULAR SYSTEM AORTA 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 DuPont-11418 -279- ( Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg /kg mg/kg mg/kg mg/kg II IV VI VIII LYMPHATIC AMD HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -280- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/kg mg /kg mg/kg mg/kg II IV VI VIII LYMPHATIC AND HEMATOPOIETIC SYSTEM THYMUS NO ABNORMALITY DETECTED HEMORRHAGE. CYST, EPITHELIAL. (10) 5 5 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 2 8 1 DuPont-11418 -281 - Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/kq mg/kg mg/kg mg /kg II IV VI VIII LYMPHATIC AND HEMATOPOIETIC SYSTEM MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED LEUKOCYTOSIS/ PLASMA CELL, MEDULLARY. HYPERPLASIA, LYMPHOID. ERYTHROCYTOSIS/ERYTHROPHAGOCYTOSIS, SINUS. (10) 8 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) 9 1 1 DuPont-11418 -282- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS . DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg II IV VI VIII LYMPHATIC AND HEMATOPOIETIC SYSTEM MESENTERIC DYMPH NODE NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -283- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg II IV VI VIII LYMPHATIC AND HEMATOPOIETIC SYSTEM BONE MARROW NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 - 284- ( Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXKTTY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg II IV VI VIII ENDOCRINE SYSTEM PITUITARY GLAND NO ABNORMALITY DETECTED CYST. (10) 8 2 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 - 285- ( Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg /kg mg/kg mg/kg mg/kg II IV VI VIII ENDOCRINE SYSTEM THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR CELL. (10) 10 (10) 10 (10) 10 (10) 8 2 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified DuPont-11418 -286- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg II IV VI VIII ENDOCRINE SYSTEM PARATHYROID GLANDS . NO ABNORMALITY DETECTED (8) 8 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (9) 9 DuPont-11418 - 287- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS ' DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg II IV VI VIII ENDOCRINE SYSTEM ADRENAL GLANDS NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -288- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg II IV VI VIII NERVOUS SYSTEM BRAIN NO ABNORMALITY DETECTED AGGREGATES, LYMPHOID*, CHOROID PLEXUS. (10) 9 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -289- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg /kg mg/kg mg/kg mg/kg II IV VI VIII NERVOUS SYSTEM SPINAL CORD NO ABNORMALITY DETECTED (9) 9 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -290- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg II IV VI VIII NERVOUS SYSTEM SCIATIC NERVE NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is nuinber of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -291 - Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg II IV VI VIII MUSCULAR AND SKELETAL SYSTEM SKELETAL MUSCLE NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -292- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg II IV VI VIII MUSCULAR AND SKELETAL SYSTEM FEMUR/KNEE JOINT NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -293- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg II IV VI VIII MUSCULAR AND SKELETAL SYSTEM STERNUM NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -294- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg II IV VI VIII REPRODUCTIVE SYSTEM OVARIES NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -295- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/kg mg/kg mg /kg mg/kg II IV VI VIII REPRODUCTIVE SYSTEM UTERUS NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -296- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXKTTY EVALUATION LESIONS REPRODUCTIVE SYSTEM LESION INCIDENCE (NUMERIC) Females TREATMENT 0 1 mg/kg 1 II 1 10 mg/kg IV 100 mg/kg VI 1000 mg/kg VIII VAGINA ESTRUS STAGE: METESTRUS. ESTRS STAGE: ESTRUS. ESTRUS STAGE: PROESTRUS. (10) 4 2 4 (10) 2 3 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 DuPont-11418 -297- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS ` DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg /kg mg/kg mg/kg mg/kg II IV VI VIII REPRODUCTIVE SYSTEM MAMMARY GLAND (FEMALE) NO ABNORMALITY DETECTED (10) 10 Figure -in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 DuPont-11418 -298- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations TABLE 46 (CONTINUED) LESIONS INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg /kg mg/kg mg/kg mg/kg II IV VI VIII CUTANEOUS SYSTEM SKIN . NO ABNORMALITY DETECTED DERMATITIS, FOCAL. (10) 9 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 9 1 DuPont-11418 -299- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 46 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR SUBCHRONIC TOXICITY EVALUATION LESION INCIDENCE (NUMERIC) . Females TREATMENT 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg II IV VI VIII SPECIAL SENSES SYSTEM EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED OPTIC NERVE NOT PRESENT, UNILATERAL. OPTIC NERVE NOT PRESENT, BILATERAL. INFLAMMATION, PERIOCULAR, UNILATERAL. FOLD/ROSETTE, RETINAL. (10) 8 5 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 (10) 5 4 1 4 1 DuPont-11418 -300- Company Sanitized. Does not contain TSCA C8I H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABUE 47 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg II IV VI VIII ENDOCRINE SYSTEM THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR CELL. ECTOPIC THYMUS TISSUE. (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 7 2 1 DuPont-11418 -301 - ( Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 47 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg II IV VI VIII REPRODUCTIVE SYSTEM UTERUS NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (1) 1 DuPont-11418 - 302- Company Sanitized. Does not contain TSCA CBI H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations LESIONS TABLE 47 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS DESIGNATED FOR RECOVERY EVALUATION TREATMENT LESION INCIDENCE (NUMERIC) Females 0 10 100 1000 mg/kg mg/kg mg/kg mg/kg II IV VI VIII REPRODUCTIVE SYSTEM VAGINA ESTRUS STAGE: PROESTRUS- 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 DuPont-11418 - 303- Company Sanitized. Does not contain TSCA CBI Company Sanitized. Does not contain TSCA CBI Company Sanitized. Does not contain TSCA CBI Company Sanitized. Does not contain TSCA C8I