Document gbO9g0L0vp223v30XgJJbxnrN

H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats AR226-3243 DuPont-6554 TRADE SECRET Study Title H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats Volume 1 of 4 Laboratory Project ID: DuPont-6554 TEST GUIDELINES: U.S. EPA Health Effects Test Guidelines OPPTS 870.3100 (1998) AUTHOR: Don A. Delker, Ph.D STUDY COMPLETED ON: April 22, 2002 PERFORMING LABORATORY: E.L du Font de Nemours and Company Haskell Laboratory for Health and Environmental Sciences Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050 WORK REQUEST NUMBER:|U| J SERVICE CODE NUMBER:^mj HHB CLINICSATLUDPYANTUHMOBLERO:G! Y/^^^^^^I Page 1 of 1022 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT This study was conducted in compliance with U.S. EPA TSCA (40 CFR part 792) Good Laboratory Practice Standards except for the item documented below. None of the items listed impact the validity of the study. Test substance characterization and stability analyses were performed at Regional Analytical Services (RAS), Deepwater, NJ. 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 Djiecton RrA. /^ [)^^I. Don A. Delker, Ph.D Research Scientist 73, ^! TaoZ^ Applicant / Sponsor: ________Du_P_o_nt_R_ep_re_se_n_ta_tiv_e _______ ____D_at_e Comp^ ^^^ ,,.,,,, _. _,^ ^^ ^ H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats QUALITY ASSURANCE STATEMENT Haskell Sample Number(s): 24678;24894 DuPont-6554 Dates of Inspections: Protocol: April 11,2002 Conduct: May 25,2001; June 22,25, 2001; August 6,13,14,2001 Records, Reports: January 11,14-18,21,22-25,28-31,2002; February 1,2,4,11-15, 2002; March 26,27,2002; April 1,11,2002 Dates Findings Reported to: Study Director: August 24,2001; January 21,29,2001; February 4,15,2002; April 1.2002 Management: August 24, 2001; January 21,29, 2002; February 4,20, 2002; April 11,18, 2002 Reported by: JLCl^J^ Joseph C. Hamill Sr- Quality Assurance Auditor 2 2. - ^Date 2wz. Company Sanitized. Does not contain TSCA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 CERTIFICATION We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study. Analytical Assessment Reported by: C^ja, fr^c <.- , Q-- ff{f^*it^^______ Janet C. Maslanka, B.S. Analytical Chemist ^ /8'rtfi*^-' swsu Date Neurobchavioral Evaluations Reported by: f) ^^^i i fj \fwAr\\uJL^ -fai. Una* A. /Mff{/t Linda A. Malfey,BU?., D.A.B.T.'3Date Senior Research Scientist 16-Mut^tcm Biochsmical Evaluations Reported by: .V^'^ (/ John C. ^--^___ O'Connor, M.S. _ _ _ ^ . A y f A .a^ Date a . Research Scientist Evaluations Repotted by: - ^ ^ ^ C ^ Nancy B. Eve^is,D.V.M-, Diplomate A.C.VJP. Principal Research Scientist ^-^-goo^ Date ^ \ A J Pathological <u~^^ Evaluations Reported by: 0^0-------5 _^-/^-^i^fp^ Vl/^fya.JJfkci ^ ^ G. Tiacy mSsovec,D.V.M., Diplomate A.C.V.P. Senior Research Scientist ^e-Afi?- a^a Date Pathological Evaluations Peer Reviewed by: %^ // jy /Af ,, i ,, ,, i^fc^L^___________it-AarU-lfS'L /tohnF.Hansen, D.V.M., Ph-D., Diplomate A.C.V.P. Date Principal ReseaTeh Scientist Approved by: D.A.B.T.Date /y C~^'/-^jOL C. ^^Q^UjUt^_____ff.9, -/? PIS-2WSL (/ Judith C. Stadler, PhS)., Prindpal Research Toxicologist Issued by Study Director: Q<AA 4- Q<fi^^----__________Z&jfe^2982' nrm s n<*Tfc-Af ph n 'rDiflafrtfet Research Scientist Company Sanitized. Does not contain TSCA CB^ H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE OF CONTENTS Page GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT.........................................^ QUALITY ASSURANCE STATEMENT......................................................................................3 CERTIFICATION.......................................................-..................................................................^ LIST OFTABLES...........................................................................................................................7 LISTOFnGURES..........................................................................................................................8 LIST OF APPENDICES..................................................................................................................9 STUDY INFORMATION............................................................................................................. 10 STUDY PERSONNEL..................................................................................................................12 SUMMARY...................................................................................................................................13 INTRODUCTION..........................................................................................................................15 OBJECTIVE..................................................................................................................................15 MATERIALS AND METHODS...................................................................................................^ A. Test Guidelines..................................................................................................................16 B. Test Substance ...................................................................................................................16 C. Test Species .......................................................................................................................16 D. Animal Husbandry.............................................................................................................16 E. Quarantine and Pretest Period............................................................................................17 F. Study Design......................................................................................................................l8 G. Assignment to Groups and Study Start..............................................................................19 H. Dose Solution Preparation.................................................................................................19 I. Test Substance Administration ..........................................................................................19 J. Test Substance Sampling.............,,.....................--............................................................20 K. Analytical Methods............................................................................................................20 L. Body Weights....................................................................................................................^ M. Food Consumption and Food Efficiency ...................................,........--............................22 N. Detailed Clinical Observations and Mortality ...................................................................23 0. Ophthalmological Evaluations...........................................................................................23 P. Neurotoxicity Evaluations..................................................................................................23 Q. Clinical Pathology..............................................................................................................24 R. Collection of Blood, Urine, Feces, and Tissue (Three-Month Recovery ) ........................26 S. Biochemical Measurements...............................................................................................27 T. Anatomic Pathology............................--............................................................................27 U. Statistical Analyses............................................--.............................................................30 RECORDS AND SAMPLE STORAGE.......................................................................................31 RESULTS AND DISCUSSION...................................................................................................^ ANALYTICAL EVALUATIONS .................................................................................................33 A. Chromatography................................................................................--.............................33 B. Uniformity of Mixing, Concentration Verification and Stability Samples........................33 Company 8gmSlte@d. Does not an8an TCGACffl H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 C. Concentration Verification Samples During the Study......................................................34 D. Analytical Conclusions......................................................................................................35 IN-UFETOXICOLOGY...............................................................................................................36 A. Dosage Data.......................................................................................................................36 B. Mean Body Weights and Body Weight Gains ...................................................................36 C. Food Consumption and Food Efficiency ...........................................................................37 D. Clinical Observations and Mortality ..................................................................................37 E. In-Life Toxicology Conclusions ........................................................................................38 NEUROBEHAVIORAL TOXICOLOGY .....................................................................................39 A. Sensory Function Evaluations............................................................................................39 B. Motor Activity.......................................................................-.................................-......39 C. Neurobehavioral Toxicity Conclusions .............................................................................39 CLINICALPATHOLOGY............................................................................................................40 A. Hematology/Coagulation...................................................................................................40 B. Clinical Chemistry.............................................................................................................41 C. Urinalysis...........................................................................................................................44 D. Plasma and urine fluoride..................................................................................................44 E. Clinical Pathology Conclusions.........................................................................................44 BIOCHEMICAL MEASUREMENTS..........................................................................................45 A. Biochemical Measurements...............................................................................................45 B. Biochemical Measurements Conclusions ..........................................................................46 ANATOMICALPATHOLOGY....................................................................................................47 A. Mortality............................................................................................................................^? B. Organ Weight Data............................................................................................................47 C. Gross Observations............................................................................................................48 D. Microscopic Findings.........................................................................................................49 E. Anatomical Pathology Conclusions ...................................................................................52 CONCLUSIONS.....................................................-...-........-......................................-........,..53 REFERENCES.........................................................................................................................-.^ TABLES...........................................................................................................................-..........^ VOLUME 2..................................................................................................................................216 VOLUME 3............................................................................-..........-..-..............--..-...-..485 VOLUME 4........................................................................................--...............................-...763 6 Company Sanifeed. Does naS eonSain' H-24678: Subchronic Toxicity 90-Day OralGavage Study in Rats DuPont-6554 UST OF TABLES Page TABLE 1 SUMMARY OF DOSING SOLUTION ANALYSES................................................................................61 TABLE 2 MEAN DAILY DOSE VOLUMES FOR MALE RATS ............................................................................63 TABLE 3 MEAN DAILY DOSE VOLUMES FOR FEMALE RATS........................................................................64 TABLE 4 MEAN BODY WEIGHTS OP MALE RATS ............................................................................................65 TABLE 5 MEAN BODY WEIGHTS OF FEMALE RATS........................................................................................67 TABLE 6 MEAN BODY WEIGHT GAINS OF MALE RATS .................................................................................69 TABLE 7 MEAN BODY WEIGHT GAINS OF FEMALE RATS.............................................................................71 TABLE 8 MEAN DAILY FOOD CONSUMPTION BY MALE RATS ....................................................................73 TABLE 9 MEAN DAILY POOD CONSUMPTION BY FEMALE RATS................................................................75 TABLE 10 MEAN DAILY FOOD EFFICIENCY OP MALE RATS.........................................................................77 TABLE 11 MEAN DAILY POOD EFFICIENCY OF FEMALE RATS ....................................................................79 TABLE 12 SUMMARY OF CLINICAL OBSERVATIONS OF MALE RATS ........................................................81 TABLE 13 SUMMARY OF CLINICAL OBSERVATIONS OF FEMALE RATS....................................................85 TABLE 14 SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR MALE RATS..............................90 TABLE 15 SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR FEMALE RATS .........................91 TABLE 16 PERCENT SURVIVAL OP MALE RATS...............................................................................................92 TABLE 17 PERCENT SURVIVAL OF FEMALE RATS ..........................................................................................93 TABLE 18 MEAN FORELIMB AND fflNDLIMB GRIP STRENGTH FOR MALE RATS (MEAN OF THREE TRIALS) .............................................................................................................................94 TABLE 19 MEAN FORELIMB AND fflNDLIMB GRIP STRENGTH FOR FEMALE RATS (MEAN OF THREE TRIALS) .............................................................................................................................95 TABLE 20 SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR MALE RATS ..........96 TABLE 21 SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR FEMALE RATS .....97 TABLE 22 MOTOR ACTIVITY ASSESSMENT: MEAN DURATION OF MOVEMENTS FOR MALE RATS...............................................................................................................................................98 TABLE 23 MOTOR ACTIVITY ASSESSMENT: MEAN DURATION OF MOVEMENTS FOR FEMALE RATS ..........................................................................................................................................99 TABLE 24 MOTOR ACTIVITY ASSESSMENT: MEAN NUMBER OP MOVEMENTS FOR MALE RATS.............................................................................................................................................100 TABLE 25 MOTOR ACTIVITY ASSESSMENT: MEAN NUMBER OF MOVEMENTS FOR FEMALE RATS ........................................................................................................................................101 TABLE 26 SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS......................................................... 102 TABLE 27 SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS................................................... 107 TABLE 28 SUMMARY OF COAGULATION VALUES FOR MALE RATS........................................................112 TABLE 29 SUMMARY OF COAGULATION VALUES FOR FEMALE RATS................................................... 112 SanaW..^"0"50'*"1""'1001 CompaW H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats____________________________________DuPont-6554 TABLE 30 SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS..................... 113 TABLE 31 SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS................ 118 TABLE 32 SUMMARY OF URINALYSIS VALUES FOR MALE RATS .............................................................123 TABLE 33 SUMMARY OF URINALYSIS VALUES FOR FEMALE RATS ........................................................125 TABLE 34 SUMMARY OF HEPATIC BETA-OXIDATION ACTIVITY IN MALE RATS .................................127 TABLE 35 SUMMARY OF HEPATIC BETA-OXIDATION ACTIVITY IN FEMALE RATS ............................128 TABLE 36 MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS.................................................129 TABLE 37 MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS ............................................136 TABLE 38 INCIDENCES OP GROSS OBSERVATIONS IN MALE RATS.......................................................... 143 TABLE 39 INCIDENCES OP GROSS OBSERVATIONS IN FEMALE RATS..................................................... 158 TABLE 40 INCIDENCES OP MICROSCOPIC OBSERVATIONS IN MALE RATS- NEOPLASTIC AND NON-NEOPLASTIC LESIONS...................................................................................... 173 TABLE 41 INCIDENCES OP MICROSCOPIC OBSERVATIONS IN FEMALE RATS- NEOPLASTIC AND NON-NEOPLASTIC LESIONS...................................................................................... 192 TABLE 42 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS- NON-NEOPLASTICLESIONS.....................................................................................................-...........--217 TABLE 43 INCIDENCES OP LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS- NON-NEOPLASTICLESIONS............................................................................-............................--........240 TABLE 44 MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED-NEOPLASTIC AND NON-NEOPLASTIC................................................-..............................270 TABLE 45 MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFECTED-NEOPLASTIC AND NON-NEOPLASTIC.................................................................................319 LIST OF FIGURES Page FIGURE 1 MEAN BODY WEIGHTS OF MALE RATS.........................................................................................373 FIGURE 2 MEAN BODY WEIGHTS OF FEMALE RATS ....................................................................................374 FIGURE 3 MEAN FORELIMB GRIP STRENGTH FOR MALE RATS.................................................................375 FIGURE 4 MEAN FORELIMB GRIP STRENGTH FOR FEMALE RATS ............................................................376 FIGURE 5 MEAN HINDLIMB GRIP STRENGTH FOR MALE RATS.................................................................377 FIGURE 6 MEAN HINDLIMB GRIP STRENGTH FOR FEMALE RATS ............................................................378 FIGURE 7 MEAN TOTAL DURATION OP MOVEMENT FOR MALE RATS....................................................379 FIGURE 8 MEAN TOTAL DURATION OP MOVEMENT FOR FEMALE RATS ...............................................380 FIGURE 9 MEAN TOTAL NUMBER OF MOVEMENTS FOR MALE RATS .....................................................381 FIGURE 10 MEAN TOTAL NUMBER OF MOVEMENTS FOR FEMALE RATS...............................................382 -i----g^pany Sanitted. &o^ W oMA TBGA H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 UST OF APPENDICES Page APPENDIX A ANALYTICAL DATA.....................................................................................................................384 APPENDIX B INDIVIDUAL DOSE VOLUMES ....................................................................................................397 APPENDIX C INDIVIDUAL BODY WEIGHTS ..................................................................................................486 APPENDIX D INDIVIUAL FOOD CONSUMPTION........................................................................................... 516 APPENDIX E INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY RECORDS ......................................................................................................................538 APPENDIX F INDIVIDUAL OPHTHALMOLOGY EXAMINATION REPORT................................................ 590 APPENDIX G INDIVIDUAL FORELIMB AND HINDLIMB GRIP STRENGTH ASSESSMENTS.................. 592 APPENDIX H INDIVIDUAL FUNCTIONAL OBSERVATIONAL BATTERY ASSESSMENTS .....................602 APPENDIX I INDIVIDUAL MOTOR ACTIVITY ASSESSMENT: DURATION OF MOVEMENT................ 612 APPENDIX J INDIVIDUAL MOTOR ACTIVITY ASSESSMENT: NUMBER OF MOVEMENTS.................622 APPENDIX K INDIVIDUAL ANIMAL CLINICAL PATHOLOGY DATA........................................................632 APPENDIX L INDIVIDUAL ANIMAL BIOCHEMICAL MEASUREMENTS IN MALE AND FEMALE RATS .................................................................................................................................................764 APPENDIX M INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS..............................................773 APPENDIX N INDIVIDUAL ANIMAL GROSS AND MICROSCOPIC OBSERVATIONS ................................802 Company Sanmva^ p "^^^^tainTSCAeBt H-24678: Subchronic Toxicity 90-DayOralGavage Study in Rats STUDY INFORMATION SubstanceTested: Synonyms/Codes? . H-24678 Haskell Number: 24678 Composition Known Impurities: ^ Physical Characteristics:!^ DuPont-6554 y SBBi8?!tea9 roffl i* ftawftBti 10 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats STUDY INFORMATION (CONTINUED) 9th Collective Nomenclature: 2-Propanol Synonyms/Codes: . Isopropanol Isopropyi alcohol IPA H-24894 Haskell Number: 24894 CAS Registry Number: 76-63-0 Composition: Isopropyi alcohol Purity: 99.98% Known Impurities: Not supplied by the sponsor Physical Characteristics: Clear, colorless liquid Sponsor: E. I. du Pont de Nemours and Company Wilmington, Delaware 19898 U.S.A. Study Initiated/Completed: 11-May-2001 / (see report cover page) In-Life Initiated/Completed: 14-May-2001 / 13-Nov-2001 DuPont-6554 eompaw SanHteed. Qeos net eontehs TCA CBI ll H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats STUDY PERSONNEL Study Director: Management: Primary Technician: Don A. Delker, Ph.D. Judith C. Stadler, Ph.D. Janice L. Connell, M.S-, B.A., C.I.H. Robert E. Walker, Jr. Analydcal Chemist: Janet C. Maslanka, B.S. Management: S. Mark Kennedy, Ph.D. Clinical Pathologist: Nancy E. Everds, D.V.M. Management: Steven R. Frame, D.V.M., Ph.D. Neurotoxicologist: Linda A. Malley, Ph.D. Management: Robert M. Parker, Ph.D. Biochemical Evaluation: John C. O'Connor, M.S. Management: Matthew S. Bogdanffy, Ph.D. Pathologist: Management: Peer Review Pathologist: G. Tracy Makovec, D.V.M. Steven R. Frame, D.V.M., Ph.D. Steven R. Frame, D.V.M., Ph.D. Toxicology Report Preparation: Cecilia R. Kee, B.S. Mary K. LaRoe Brenda Tiffin Ophthalmologist: Nancy M. Bromberg, V.M.D., M.S. 6119 Massachusetts Avenue Bethesda, Maryland 20816 Laboratory Veterinarians: William Singleton, D.V.M., A.C.L.A.M. WandaL. West, D.V.M., A.C.L.A.M. DuPont-6554 pjRlpffl^ Batted. Does not ear 12 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 SUMMARY Four groups of young adult male and female Cri:CD(SDS)BR rats were administered H-24678 by gavage at dosages of 0,10,60, or 300 mg/kg/day. An additional control group of male and female rats was administered 60 mg/kg/day isopropanol. Selected animals from each group were designated for subchronic toxicity, recovery, and/or biochemical evaluations. Body weights, food consumption, and clinical signs were evaluated weekly. Clinical pathology endpoints were evaluated during the dosing period on weeks 7 and 13 and then after one and three months recovery. Neurobehavioral assessments were performed prior to dosing and during week 12 of the dosing period. After 10 days of dosing, five animals/sex/dose were sacrificed and evaluated for biochemical endpoints. After 90 days of dosing, ten rats/sex/dose were sacrificed and given a gross and microscopic pathological examination. One month after the 90-day dosing period, 10 animals/sex in the control and high-dose group were examined for recovery from effects. An additional five animals/sex/dose were evaluated for recovery three months following the end of the dosing period. No compound-related mortality occurred in the study. No adverse clinical signs of toxicity or changes in neurobehavior parameters were observed in male or female rats in any dose group. Statistically significant lower body weight gain, food consumption, and food efficiency were observed in male rats administered 300 mg/kg/day when compared to controls. There were no adverse effects on these parameters at any dose level in female rats after 90 days of dosing and no adverse effects in males and females dosed with 300 mg/kg/day by the end of the one month recovery period. During the 90-day exposure period, hepatic p-oxidation activity was statistically higher (50100%) in male and female rats administered 60 and 300 mg/kg/day H-24678 compared to controls. The rate of hepatic peroxisome proliferation remained elevated in male and female rats throughout the recovery period. Due to the small magnitude of change in hepatic P-oxidation activity, these effects were not considered lexicologically adverse. Test substance-related minimal to mild decreases in red cell mass parameters (red cell count, hemoglobin, and hematocrit) were observed in male rats administered 60 or 300 mg/kg/day during the dosing period. Due to the magnitude of the change in male rats dosed with 300 mg/kg/day, these decreases were considered toxicologically adverse. These changes persisted into the one and three month recovery periods, but showed evidence of partial recovery. Test substance-related and toxicologically adverse elevated liver enzymes (aspartate aminotransferase, alanine aminotransferase, and sorbitol dehydrogenase) were observed in male rats of all dose levels and female rats dosed with 300 mg/kg/day during the 90-day exposure period. After three months of recovery, increased enzyme activities were still evident in males of all dose groups and were more severe in male rats previously dosed with 300 mg/kg/day. After three months of recovery, enzyme activities for female rats previously dosed with H-24678 were similar to control group values. ampany Sanitized. Doss not ecmtain TSCA CBI 13 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 Elevated liver weights and hepatocellular hypertrophy were observed in male rats administered 60 and 300 mg/kg/day after the 90-day exposure period. Increased liver weights were also observed in female rats administered 300 mg/kg/day. Increased kidney weights and renal tubular hypertrophy were observed in male rats administered 60 and 300 mg/kg/day after the 90-day exposure period. Elevated kidney weights were also observed in female rats administered 300 mg/kg/day. These changes were considered a test substance-related physiologic response to a xenobiotic and not lexicologically adverse. After three months of recovery, liver and kidney weights and microscopic observations were similar to controls in both male and female rats. Test substance-related thyroid hypertrophy was observed in male and female rats administered 300 mg/kg/day and in male rats administered 60 mg/kg/day. Increased colloid alterations were also observed in male rats administered 300 mg/kg/day. Thyroid hypertrophy in male and female rats was considered test substance-related and potentially adverse. After three months of recovery, thyroid hypertrophy was reversible in male and female rats. Increases in colloid alterations were not considered lexicologically significant. Minimal focal hepatocellular necrosis was observed in male rats administered 10 and 60 mg/kg/day after 90 days of exposure and in male rats given 60 mg/kg/day after three months recovery. Focal hepatocellular necrosis was not observed in male rats administered 300 mg/kg/day after the 90-day exposure period. Minimal to moderate focal hepatocellular necrosis was observed in male rats administered 300 mg/kg/day after three months recovery. Focal hepatocellular necrosis observed in male rats of all dose levels was considered testsubstance-related and lexicologically adverse. Target organs identified as having adverse effects in this 90-day subchronic toxicity study included liver, thyroid, and red blood cells. Based on the hepatocellular necrosis observed after the 90-day exposure period and/or after one and three months of recovery in male rats of all dose levels, a no-observed-effect level (NOEL)" cannot be determined for male rats. A NOEL for female rats was 60 mg/kg/day, based on elevated liver enzymes and thyroid gland hypertrophy observed in female rats administered 300 mg/kg/day. Company Sanitized. Does not contain TSCA CBI 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). ^ H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 INTRODUCTION The test substance, H-24678, is, ^^^^^^^^^^^^^^^jThedose levels for this study were^dected based on toxicity^ obse^e^n^ran^^idinyitudy in which male rats were dosed by oral gavage with 10,100, 1000, or 3000 mg/kg/day for 45 days. Male rats exposed to 3000 mg/kg/day in the range-finding study exhibited statistically significant lower body weights (16% lower than controls) and reduced body weight gain (36% lower than controls) after 4 weeks of dosing. Due to this excessive loss in body weight gain the high dose was lowered to 2000 mg/kg/day for the remaining two weeks of study. Reductions in body weight gain (15% - 20% lower than controls) were also observed in rats exposed to 100 and 1000 mg/kg/day after 45 days of treatment. No treatment-related effects on body weight were observed in the low dose group of 10 mg/kg/day. No compound-related clinical signs of toxicity were observed in any group. Compared to control rats, absolute and relative liver organ weights were significantly higher (40%-45%) in rats administered 1000 and 3000/2000 mg/kg/day H-24678. No compoundrelated effects on organ weight were observed in rats administered 10 or 100 mg/kg/day. Therefore, 300 mg/kg/day was selected as the high-dose level for this 90-day study. This dose was expected to produce toxicity without excessive mortality. The low dose of 10 mg/kg/day was expected to be the no-observed-adverse-effect level, while the 60 mg/kg/day dose was expected to induce minimal or no toxicity. The test substance, H-24678, i|IHk isopropyi alcohol. Therefore, a concurrent control group of 10 male and 10 female rats was dosed with isopropyi alcohol in deionized water, at a dose equivalent to that received by the high-dose animals. This control group provided important information regarding the contribution of isopropanol in the overall toxicity of H-24678. OBJECTIVE The objective of this study was to evaluate me potential subchronic loxicity of H-24678 when administered by gavage to male and female rats. A recovery group was also included to investigate the reversibility of any observed toxicological effects. The oral route of administration was selected because it is a potential route of exposure. CompanySain-fee^ ^ ^^"TaCACBI 15 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats MATERIALS AND METHODS DuPont-6554 A. Test Guidelines The subchronic toxicity study design complies with the United States Environmental Protection Agency (EPA), Office of Prevention, Pesticides, and Toxic Substances (OPPTS) Health Effects Test Guidelines, OPPTS 870.3100 90-Day Oral Toxicity in Rodents (AUG-1998). B. Test Substance ^IHBHBHHI^1^ The test substance, H-24678, was supplied by the sponsor as known composition. The test substance is a suspensioif----|in isopFdpanol and water'n'he stability analysis of the test substance before and during tRestudywas conducted at DuPont Regional Analytical-SeFvices^RAS). A reserve sample^sfAetesfrsubstane&was eelleeted-and retained by Haskell Laboratory. The isopropyi alcohol (isopropanol) was supplied by ExxonMobil Chemical and assigned Haskell Number 24894. C. Test Species On April 26, 2001,129 male and 127 female Crl:CD(SD)IGS BR rats, with an assigned birth date of March 25, 2001 were received from Charles River Laboratories, Inc., Raleigh, North Carolina for use on this study. The rat was selected because it is the species recommended in the subchronic toxicity guidelines. The Crl:CD(SD)IGS BR strain was chosen because extensive background information is available from the literature, me supplier, and previous studies at Haskell Laboratory. This species/strain is considered suitable relative to longevity, hardiness, and low incidence of spontaneous diseases. D. Animal Husbandry 1. Housing All rats were housed one per cage, sexes separate, in stainless steel, wire-mesh cages suspended above cage boards. Cage racks were relocated within the animal room each week and cages were repositioned on the racks every 2 weeks. Animal rooms were maintained on a 12-hour light/dark cycle (fluorescent light) and at a temperature of 22 3C and a relative humidity of 50% 20%. Occasional excursions outside the acceptable ranges were minor and did not affect the study. 2. Feed and Water Tap water was provided ad libitum. All rats were fed PMI Nutrition International, me. Certified Rodent LabDiet 5002 ad libitum. ^S^ea.Ooesno.c^SC.CB. ^ H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 3. Identification Prior to assignment to groups, each rat was temporarily identified by either the presence or absence of a colored tail mark and cage identification. Subsequently, an individual identification number was tattooed on the tail of each rat. The information on the cage labels included the unique 6-digit Haskell animal number and the individual identification number assigned to each rat. 4. Health Monitoring Program As specified in the Haskell Laboratory animal health and environmental monitoring program, the following procedures are performed periodically to ensure that contaminant levels are below those that would be expected to impact the scientific integrity of the study: Water samples are analyzed for total bacterial counts, and the presence of coliforms, lead, and other contaminants. Feed samples are analyzed for total bacterial, spore and fungal counts. Samples from freshly washed cages and cage racks are analyzed to ensure adequate sanitation by the cagewashers. Certified animal feed is used, guaranteed by the manufacturer to meet specified nutritional requirements and not to exceed stated maximum concentrations of key contaminants, including specified heavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates. The presence of these contaminants below the maximum concentration stated by the manufacturer would not be expected to impact the integrity of the study. The animal health and environmental monitoring program is administered by the attending laboratory animal veterinarian. Evaluation of these data did not indicate any conditions that affected the validity of the study. E. Quarantine and Pretest Period Upon arrival at Haskell Laboratory, the rats were quarantined for 7 days of the 17-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 basis of acceptable body weight gains and clinical observations, all surviving rats were released from quarantine on test day -11 by the laboratory animal veterinarian designee. Company BaniSized. Does not ontain TSCA CB8 17 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 P. Study Design Group Male I Female n ffl IV Dosage 0 mg/kg/day v f'&f jy ^^\J 60 mg/kg/day Test Substance Vehicle ' W&JLI.VJLW cWo-.nH.MtrL ^o>/l* --^ _ IsopropanoLconti-ol J^y|w/w active ingredien V VI 10 mg/kg/day H-24678 vn vm 60 mg/kg/day H-24678 IX x 300 mg/kg/day H-24678 v/w active ingredient) v/w active ingredient) v/w active ingredient) Each group of study animals, except the isopropanol groups, consisted of the following subgroups: The first 10 rats in each group were designated for the evaluation of subchronic toxicity and are referred to in this report as the 90-day exposure animals. The next 5 rats in each group were initially designated as a subset for blood sampling and potential analysis of fluorine. However, to assess three-month recovery from test substance-related effects, these rats were also evaluated for biochemical, clinical, and anatomic pathology endpoints; these rats are reported as the three-month recovery animals. The next 10 rats in the control and high-dose groups were designated for recovery evaluations and are reported as the one-month recovery animals. The last 5 rats in each group were designated for evaluation of hepatic biochemical analysis following a 10-day exposure. In the isopropanol groups, the first 10 rats in each group were included in the 90-day exposure subgroup and the last 5 rats were included in the hepatic biochemical analysis subgroup. Male and female rats designated for the 90-day exposure evaluation were dosed through test days 91 (male) and 92 (female), and necropsied on test days 92 and 93, respectively. Male and female rats designated for the one- and three-month recovery evaluations were dosed for 91 days and necropsied 32 and 94 days postdosing, respectively. Neurobehavioral evaluations were conducted on male and female animals designated for the 90day exposure evaluation (predose and week 13) and on control and high-dose animals designated for the one-month recovery (predose, week 13). Clinical pathology evaluations were conducted on animals designated for the 90-day exposure evaluation on weeks 6 and 14 and on animals designated for the one-month and three-month recovery evaluations immediately prior to necropsy. Biochemical evaluations were conducted on selected animals designated for the 90day exposure evaluation, the one-month and three-month recovery evaluations, and the 10-day exposure evaluation. ifiampafly SanffizeA Dee eentain TBCA CB! 18 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 G. Assignment to Groups and Study Start 1. Rats Designated for the 90-Day Exposure, One-Month Recovery, and Three-Month Recovery Evaluations Rats were selected for study use on the basis of adequate body weight gain, freedom from any ophthalmological abnormalities or clinical signs of disease or injury, and a body weight within 20% of the mean within a sex. The selected rats were distributed by computerized, stratified randomization so that there were no statistically significant differences among group body weight means within a sex. Oral administration of H-24678 began on test day 0, when the rats were approximately 50 days of age. Prior to the start of test substance administration, 5 male rats and 3 female rats with out-ofrange body weights, clinical signs, or neurobehavioral findings during pretest were replaced. Replacement rats were selected on the basis of freedom from any clinical signs of disease or injury and a body weight 20% of the mean within a sex. 2. Rats Designated for 10-Day Biochemical Analysis Oral administration of H-24678 to male and female rats designated for the 10-day biochemical analysis began on test days 0 and 1, respectively. In-life data (body weight, food consumption, clinical observations) were collected from these animals and are in study records. However, these data are not included in this report. H. Dose Solution Preparation H-24678 and isopropanol were dissolved in deionized water. Dosing solutions of the test substance were prepared every day for the first week of study and then twice a week thereafter. Dosing solutions were stored refrigerated in closed glass containers to minimize evaporation of the isopropanol. I. Test Substance Administration Animals designated for the 90-day dosing period were dosed through test day 91 (males) or 92 (females). Animals designated for the one- and three-month recovery evaluations were dosed through test day 90. Animals designated for the 10-day biochemical evaluation were dosed through test day 10. The test substance was administered daily to the study animals by oral gavage to achieve dosage levels of 10, 60, or 300 mg/kg body weight/day, based on the most recently recorded body weight. Deionized water was administered to control groups I and n and isopropanol (dissolved in deionized water) was administered to groups in and IV. Dose volumes for all groups were 7.5 mL/kg. PMHIXMySBBHtotfDc <^ neteortain rsCA CM 19 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 J. Test Substance Sampling Samples containing H-24678 at the concentrations of 0,1.33,8.0 and 40.0 mg/mL and isopropyi alcohol control at the concentration of 8.0 mg/mL were collected on test day 1 for uniformity/concentration verification and 5-hour room temperature stability. Samples from the same preparation were collected after being stored refrigerated for 7 days to determine if the test substance could be mixed twice a week with refrigerated storage. They were analyzed for 7-day refrigerated stability and for 7-day refrigerated followed by 5-hour room temperature stability. Samples at the same concentrations were collected on test day 42 and test day 91 for concentration verification analysis. All dosing solution samples were collected on the same day the solutions were prepared or as indicated by the stability analysis for the study. K. Analytical Methods 1. Dosing Solution Treatment Prior to analysis on the GC, the dosing samples were diluted with HPLC grade water to an expected concentration of 2.4 mg/mL isopropyi alcohol. Prior to analysis on the LC/MS, each dosing sample was diluted with HPLC grade water and an equivalent amount of diluted isopropyi positive control to an expected concentration of 0.156, 0.160 or 0.168 mg/mL H-24678. Samples submitted for analysis were analyzed the day the solutions were received or refrigerated until analyzed by the testing group. Company Santeeci. Does no, contain TSCACBI 20 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 2. Chromatographic Conditions GC Method Instalment: Column: Injector: Detector: Carrier Gas: Split vent: Injection Volume: Oven Program: Initial Temperature: Initial Time Level 1 Rate: Level 1 Temperature: Level 2 Rate: Level 2 Temperature: Final Time Run Time: Hewlett-Packard Model 6890 GC Restex RTX-5,30 m x 0.25 mm ID, 0.25 iim film thickness Split, 250C HD;250C Helium (2.8 mL/min) 58.3 mL/min 1 microliter Gradient 40C 0.50 min. 5C/mm. 60C 25C/min. 300C 1.00 min. 15.10 minutes LC/MS Method HPLC Instrument: MS Instrument Hewlett-Packard Model 1100 HPLC Micromass Quattro LC MS with "Z-spray" electrospray LC parameters: Column: Zorbax SB-C8,2.1mm x 15mm Mobile Phase (Time Table): 0.00 minutes: 50% methanol/50% 10 mM Ammonium Acetate-Triethylamine 10.00 minutes: 100% methanol/0% 10 mM Ammonium Acetate-Triethylamine 16.01 minutes: 50% methanol/50% 10 mM Ammonium Acetate-Triethylamine Run Time: 23.0 minutes Flow Rate: Injection Volume: Oven Temperature: 0.20 mL/min. 20 microliter 30C MS parameters: lonization mode: Capillary voltage: Cone Voltage: Source Temperature: Desolvation Temperature: Scan function: Electrospray (ESI), negative ions 3.0 kV 20V 120 300 SIR: 443, 543, and 643 m/z 485, 585, and 685 m/z time: 0-16 minutesCompany Sanifeed. Does not eortain TSCA GBS 21 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 3. Calibration and Quantitation A stock solution of the isopropyi alcohol (SPA) test material (a separate sample of H-24894, used as analytical reference) was made in HPLC grade water. Appropriate aliquots of the stock were diluted with the HPLC grade water. These solutions were used to make calibration standards that bracketed the target concentration of the diluted dosing samples. Peak areas from GC analysis of these standards were used to construct a calibration curve by least square regression (see Appendix A, Figure la for a representative calibration curve). Measured concentrations for dosing solutions were determined by applying the peak areas from replicate injections of the samples to the calibration curve. A stock solution of the H-24678 test material (a separate sample of H-24678, used as analytical reference) was made in HPLC grade water. Appropriate aliquots of the stock were diluted with a solution of the initial diluted IPA positive control sample so that an amount of the IPA similar to the dosing samples would be maintained in each diluted standard. These solutions were used as calibration standards that bracketed the target concentration of the diluted dosing samples. Mass to charge ratio (m/z) from LC/MS analysis using negative ion electrospray ionization and selective ion monitoring of these standards over the mass range of 443 to 685 were used to construct calibration curves by the appropriate regression (see Appendix A, Figure Ib - Ig for representative calibration curves). Measured concentrations for dosing solutions were determined by applying the peak area or height from replicate injections of the samples to each calibration curve. The mean result from the concentrations at all selected m/z (n = 6) is reported as the concentration for the sample. Test substance uniformity in the vehicle was evaluated by calculating the coefficient of variation (C.V. = standard deviation/mean x 100) of the measured concentrations in duplicate samples 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. The mean result of the duplicate samples for each dosing level was used to determine the concentration of the test substance for the respective dosing levels. Stability was evaluated by using the mean result of the duplicate samples from the concentration verification as the baseline for comparing the corresponding stability results. L. Body Weights All rats were weighed once per week during the 90-day exposure phase of the study. In addition, the rats designated for neurobehavioral evaluations, undergoing functional observational battery and motor activity assessments, were weighed on the days of those observations. M. 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 22 Company Sanity. Doe. .0, . ^ ,-SCA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 subtracted from the initial feeder weight. From these measurements, mean daily food consumption over the interval was determined. From the food consumption and body weight data, the mean daily food efficiency was calculated. Mean daily food consumption was determined for all animals designated for subchronic toxicity evaluations during the 90-day exposure period. Pood consumption was also determined for animals designated for one- and three-month recovery evaluations through test day 119, but was not determined for animals designated for the three-month recovery evaluations after test day 119. Food consumption for the three-month recovery animals was inadvertently not collected on test day 84 prior to placement of rats in metabolism racks. N. 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. Moribund rats were sacrificed. At every weighing, each rat was individually handled and examined for abnormal behavior and appearance. Detailed clinical observations in a standardized arena were also evaluated on rats designated for the 90-day exposure and one-month recovery periods. The detailed clinical observations included (but were not limited to) evaluation of fur, skin, eyes, mucous membranes, occurrence of secretions and excretions, autonomic nervous system activity (lacrimation, piloerection, and unusual respiratory pattern), changes in gait, posture, response to handling, presence of clonic, tonic, stereotypical, or unusual behavior. 0. Ophthalmological Evaluations Two Ophthalmological examinations were conducted by a veterinary ophthalmologist. Both eyes were examined by focal illumination and indirect ophthalmoscopy. The examinations were conducted under subdued lighting after mydriasis had been produced with a 1% tropicamide solution. On test day -17, the initial examination was performed on all rats received for the study, prior to selection and grouping. On test day 81, all surviving rats designated for the 90-day exposure and one-month recovery were examined again. P. Neurotoxicity Evaluations 1. Sensory Function Evaluation Prior to test substance administration and during week 13 of test substance administration, assessments of responses to approach/touch, sharp auditory stimulus, and tail pinch were made while the animal was in a standard arena. These assessments were conducted on the 10 animals per group designated for recovery from the control and high-dose groups, and on the 10 animals per group designated for subchronic toxicity for the isopropanol, low-dose, and mid-dose 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 23 Company Sanitized. Does not contain TSCAC11 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats____________________________________DuPont-6554 the motor activity channibers (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 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 (CoulboumInfrared Motor Activity System). Group and gender were counterbalanced across the monitors and time of day to the fullest extent possible. The infrared monitoring device enables measurement of 2 dependent variables: duration of movement and number of movements. A continuous movement was counted as 1 movement regardless of duration. Each test session was 60 minutes in duration, and the results were expressed for the total session as well as for 6 successive 10-minute blocks. Presence of defecation and urination on the cageboards below the motor activity monitor were also recorded following each motor activity session. 3. Test Facility Positive Control Data Data on the effects of acrylamide, carbaryl, d-amphetamine, and trimethyltin are described in four separate reports.0'2'3'^ These positive control studies are the basis of training certification for the individuals making judgments in the neurobehavioral and neuropathology tests. The data also document that the equipment and procedures are capable of detecting effects that may be seen in neurotoxicity studies of this type. Q. Clinical Pathology Samples for clinical pathology evaluations were collected from the first 10 male and 10 female rats per group in all groups on test days 38 and 92 (males), or 39 and 93 (females). After one month of recovery, samples for clinical pathology evaluations (excluding coagulation) were also collected from 10 recovery rats per group (control and 300 ing/kg/day only) on test day 122. Additionally, after 3 months of recovery, samples for clinical pathology evaluations (excluding coagulation and plasma fluoride), and including selected urinalysis tests) were collected from 4 (groups n and Vffl) or 5 (all other groups) satellite recovery rats on test day 183. The rats were fasted overnight (approximately 16 hours). During this interval, urine was collected from each rat into vials containing EDTA (except for test days 38/39). Blood samples for hematology and serum clinical chemistry measurements were collected from the orbital sinus of each fasted rat while the rat was under light carbon dioxide anesthesia. Blood samples for coagulation (end of dosing only) and plasma fluoride were collected from the abdominal vena cava while the rat was under carbon dioxide anesthesia, immediately prior to sacrifice. All blood samples were examined visually and observations recorded. 24 Company Sanitized, De@s not eontelm T8CA CBl H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 1. Hematology/Coagulatipn Complete blood counts (including reticulocytes) were detennined on a BayerAdvia 120 hematology analyzer and determined from microscopic evaluation of the blood smear. Wrightstained blood smears from all rats were examined microscopically for confirmation of automated results and evaluation of cellular morphology. Coagulation times were determined on a BCS Bearing Coagulation Analyzer. New methylene blue-stained blood smears were prepared from each rat undergoing hematology evaluation but were not needed for evaluation. The following hematology and coagulation parameters were detennined: Red blood cell count (RBC) Hemoglobin (HGB) Hematocrit (HCT) Mean corpuscular volume (MCV) Mean corpuscular hemoglobin (MCH) Mean corpuscular hemoglobin concentration (MCHC) Red cell distribution width (RDW) Absolute reticulocyte count (ARET) Platelet count (PLT) White blood cell count (WBC) Differential leukocyte count Microscopic blood smear examination Prothrombin time (PT) Activated partial thromboplastin time (APTT) 2. Clinical Chemistry All clinical chemistry parameters were measured in serum, with the exception of fluoride, which was measured in EDTA plasma. Clinical chemistry parameters were measured or calculated on a Roche Diagnostics (BMC)/Hitachi 917 clinical chemistry analyzer. Plasma fluoride concentration was determined using a phi/12pH meter with a fluoride-selective electrode. The following clinical chemistry parameters were determined: Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Sorbitol dehydrogenase (SDH) Alkaline phosphatase (ALKP) Total bilirubin (BIU) Urea nitrogen (BUN) Creatinine (CREA) Cholesterol (CHOL) Triglyceride (TRIG) Glucose (GLUC) Total protein (TP) Albumin (ALB) Globulin (GLOB) Calcium (CALC) Inorganic phosphorus (IPHS) Sodium (NA) Potassium (K) Chloride (CL) Plasma fluoride (PFLU) 25 TOf gaiR.tp'i'rayi H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 3. Urinalysis The following urinalysis parameters were determined: Appearance (quality, clarity, and color) Volume (VOL) Osmolality (UOSM) Specific gravity (SG) pH Glucose (UGLU) Ketones (KET) Bilirubin (UBIL) Blood (BLD) Urobilinogen (URO) Urine fluoride (UFLU) Protein (UMTP) Microscopic urine examination Urine volume and appearance were measured and evaluated visually, respectively. Urine constituents were semi-quantitatively measured on a Bayer Clinitek AtlasTM Automated Urine Chemistry analyzer. Urine protein was measured on a Roche Diagnostics (BMQ/Hitachi 717 clinical chemistry analyzer. Urine osmolality was determined using an Advanced Osmometer 3900. Urine fluorides were determined by multiplication of measured urine volume by urine fluoride concentration (measured using a phi/12pH meter with a fluoride selective electrode). Sediments from all urine specimens were evaluated microscopically. R. Collection of Blood, Urine, Feces, and Tissue (Three-Month Recovery) On test day -4 (pre-bleed) and test days 0,3,9,21, 35, 56,77, and 88, blood (approximately 0.5 - 1 mL) was collected from the orbital sinus of designated animals (5 rats/sex/dose) while the rat was under light carbon dioxide anesthesia for possible analysis of total fluorine. On test day 35 blood was not collected from two animals in group V because they were misdosed with isopropanol dose solution. On the day of blood collection (except test day -4), blood was collected from the animals 2 hours ( 30 minutes) after dosing. The blood was collected in plastic tubes containing EDTA while on ice. The blood was then separated into plasma and RBCs by centrifugation and stored frozen. For each bleeding, blood was collected at approximately the same time of day. During the last week of the 90-day exposure period, urine and feces were collected daily at 24-hour intervals from each animal. The animals were placed in metabolism cages for collection of feces and urine. The exact time period of collection of urine and feces was documented along with the total volume of urine obtained. Urine and feces were stored frozen. Blood was also collected for possible analysis at 3, 7,12,19, 26, 37, 51, 72, and 93 days postdosing for both male and female animals of each dose group and stored frozen. Animals were sacrificed at the end of the three-month recovery period. The testes, liver, kidney and fat samples were collected and frozen for possible analysis of total fluorine. The collected blood, urine, feces, and tissues may be evaluated in the future for total fluorine. Resulting data will be reported separately. 26 Company Santed. Do@g not eonSain T6CA C89 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 S. Biochemical Measurements Following 10 days or 91 and 92 days for males and females, respectively, of compound administration, or after a one-month or three-month recovery period, 4 or 5 rats from each group designated for biochemical evaluation were weighed and then euthanized by C02 anesthesia and exsanguination. At each time point, the livers were removed, weighed, and then a portion was homogenized (1 gram tissue/4 mL buffer) in homogenization buffer (50 mM Tris-HCl, 50 mM Trizma-base, 0.25 M sucrose, and 5.4 mM EDTA, pH 7.4). Hepatic peroxisomes were prepared using differential centrifugation. The resulting peroxisomal pellets were resuspended in the homogenization buffer, aliquoted, and stored between -65 and -85C until analyzed for peroxisomal P-oxidation activity. The peroxisomal suspensions were diluted to a protein concentration of approximately 0.25 or 0.5 mg/mL. Peroxisomal P-oxidation activity was determined using [14C]palmitoyl CoA as the substrate.^ The protein content of the peroxisomes was determined before and after analysis by the Biorad method.^ Final rate calculations were made using the post-assay protein concentrations. T. Anatomic Pathology After approximately 90 days (test days 92 and 93 for males and females, respectively), groups of 10 male and 10 female rats from the 0,10,60, and 300 mg/kg/day H-24678 groups (and the 60 mg/kg/day isopropanol group) were sacrificed and necropsied. Additional groups of 10 male and 10 female rats from 0 and 300 mg/kg/day groups were sacrificed and necropsied approximately 1 month after the last exposure (test day 122). In addition, groups of 5 male and 4 or 5 female rats from all groups (except the isopropanol group), designated for analysis of blood for parent compound and metabolites were sacrificed and necropsied approximately 3 months after the last exposure (test day 183). In the discussion of pathology findings, groups sacrificed after approximately 90 days of exposure are referred to as exposure groups, and groups sacrificed on test days 122 and 183 are referred to as one-month and three-month recovery groups, respectively. 27 Company Sanitized. Doss no?; H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 Rats were euthanatized by carbon dioxide anesthesia and exsanguination. Gross examinations were performed on all male and female rats. The following tissues were collected from exposure and one-month recovery group rats sacrificed by design, or rats that were found dead, sacrificed in extremis, or accidentally killed. Digestive System liver esophagus stomach duodenum jejunum ileum cecum colon rectum salivary glands pancreas Urinary System kidneys urinary bladder Cardiovascular System heart aorta Hematopoietic System spleen thymus mandibular lymph node mesenteric lymph node bone marrow' Endocrine System pituitary gland thyroid gland parathyroid glands adrenal glands Respiratory System Nervous System lungs brain (including cerebrum, trachea cerebellum, medulla/pons) nose spinal cord (3 levels: cervical, larynx mid-thoracic, lumbar) pharynx____ sciatic nerve a Bone marrow was collected with the femur and sternum. Musculoskeletal System skeletal muscle femur/knee joint sternum Reproductive System Male testes epididymides prostate seminal vesicles Female ovaries uterus mammary gland Miscellaneous skin eyes (including optic nerve) gross observations Liver, kidneys, testes, thyroid gland, and fat were collected from three-month recovery group rats sacrificed by design. Small portions of liver and kidneys and the entire thyroid gland were fixed in 10% neutral buffered formalin. The remaining fresh liver and kidney tissue, testes, and fat (approximately 1 gram) were frozen. The following tissues were weighed from rats sacrificed by design in all 90-day exposure groups and one-month recovery groups: liver, kidneys, adrenal glands, brain, spleen, thymus, heart, ovaries, uterus, epididymides, and testes. Organ weight/final body weight and organ weight/brain weight ratios were calculated. Liver, kidneys, thyroid gland, and testes (males) from rats sacrificed by design after 3 months recovery were weighed and organ weight/final body weight ratios were calculated. Organ weight/brain weight ratios were not determined for three-month sacrifice rats. Gross lesions which were diagnosed at necropsy and for which microscopic examination was not appropriate (e.g., fluid accumulation, ruffled fur, missing anatomic parts) were generally not 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. 28 Company an(}Iz@d. Does not centaSn TCA CBS H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 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. All collected tissues from the control and 300 mg/kg/day exposure group rats, and all found dead, sacrificed in extremis, or accidentally killed rats were processed and received a full histopathological examination. liver (males only), kidneys (males only), and thyroid gland were processed to slides and microscopically examined from the 60 mg/kg/day isopropanol treated group. Liver, kidneys (males only), and thyroid gland were processed to slides from 10 and 60 mg/kg/day exposure group rats and from all one-month recovery rats. Liver and kidneys from males and thyroid gland from males and females were microscopically examined from 10 and 60 mg/kg/day exposure rats and from one-month recovery rats in descending order of dose until a no effect level was reached. Liver, kidneys, and thyroid gland from males and females from all groups sacrificed after the three-month recovery period were processed to slides. Liver (males only) and thyroid gland were microscopically examined from three-month recovery rats in descending order of dose until a no effect level was reached. The key to Appendix G describes the lesion grading system used in this study. 29 Company Sanitized. Does not contain T8CA Cl H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 U. Statistical Analyses Except for Bartlett's test (p < 0.005), significance was judged at p < 0.05. Separate analyses were performed on the data for each gender. Parameter Body Weight Body Weight Gain Food Consumption Food Efficiency Organ Weight Biochemical Measurements Preliminary Test Test for lack of trend'9' Levene's test for homogeneity02a' nd Shapiro-Wilk test03'for normality1' Method of Statistical Analysis If preliminary test is not significant If preliminary test is significant Sequential application00' of the Jonckheere-Terpstra trend test01' Preliminary tests for pairwise comparison OR" One-way analysis of variance04' followed with Dunnett's test" Kruskal-Wallis test05' followed with Dunn's test Motor Activity0 Grip Strength Clinical Pathology4 Levene's test for homogeneity02a' nd Shapiro-Wilk test03' for normality1' Bartlett's test08' for homogeneity of variances Levene's test for homogeneity02'and Shapiro-Wilk test03'for normality1' Repeated measures analysis of variance06' followed by contrasts07' One-way analysis of variance04' followed with Dunnett's test" One-way analysis of variance04' followed with Dunnett's test" Sequential application00' of the Jonckheere-Terpstra trend test0" Kruskal-Wallis test05' followed with Dunn's test<8' Kruskal-Wallis test05' followed with Dunn's test Survival Incidence of Clinical Observations Incidence of Ophthalmology Observations Incidence of FOB Descriptive Parameters Incidence of Microscopic Lesions None None Cochran-Armitage test for trend04'6 None Pairwise comparisons and associated preliminary tests were only conducted if the test for lack of trend was significant. If the Shapiro-Wilk test was not significant but Levene's test was significant, a robust version of Dunnett's test was used. Test day and block (10-minute EPOCH) was used as repeated-measure factors. When an individual observation was recorded as being less than a certain value, calculations were performed on half the recorded value. For example, ifbilirubin was reported as <0.1,0.05 was used for any calculations performed with that bilirubin data. If the incidence was not significant, but a significant lack of fit occurred, then Fisher's Exact test09' with a Bonferroni correction was used. 30 Company SaniSlzed. Dees ^ cwWn TSCA CB8 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 RECORDS AND SAMPLE STORAGE Laboratory-specific or site-specific raw data, such as personnel files and equipment records will be retained by the facility where the work was done. A sample of the test substance was collected for archive purposes and retained at Haskell Laboratory. Specimens (if applicable), raw data, and the final report will be retained at Haskell Laboratory, Newark, Delaware, or at Iron Mountain Records Management, Wilmington, Delaware. Clinical pathology slides and raw data will be retained at Haskell Laboratory, Newark, Delaware. Test Substance characterization data 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. 3 [ Compapy 8a'?'fsd, Ooes oof confate TSCA CBj H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 RESULTS AND DISCUSSION 32 Company Sanitized. DOBS not contain T8CA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 ANALYTICAL EVALUATIONS A. Chromatography Isopropyi alcohol (H-24894) eluted from the GC column as a resolved peak with retention time of approximately 1.0 minute. Representative GC chromatograms are shown in Appendix A, Figures 2(a - c). H-24678 eluted from the HPLC column as resolved peaks over mass to charge (m/z) range of approximately 443 to 685. For the purpose of quantitation, the m/z of 443,543,643 for the "mono" substituted componentsjHBMBHBlWd 485,585,685 for the "mixed bis" substituted components llHHIIlBlHHBlHB^01'0 ^'Bte^Dlnedto be representative of the H-24678 in the dosing matrix. Representative LC/MS chromatograms are shown in Appendix A, Figures 2(d - f). Test substance was not detected in the 0 mg/mL control. B. Uniformity of Mixing, Concentration Verification and Stability Samples Analytical results from dosing solutions prepared test day 1 and analyzed for uniformity/concentration verification and stability are shown in Appendix A, Table I and Summary Table 1. The following table summarizes the results for uniformity/concentration verification and stability analyses for the H-24678 sample preparation on test day 1 along with the refrigerated stability needed to change mixing to twice a week. Preparation Nominaf Measured"AverageCVStability0 Stability''d Stability6 Day mg/mL mg/mL % Nominal % % Nominal % Nominal % Nominal TestDayl 1.33 1.51,1.48 112.8 1 106.0 8.00 7.32,7.99 95.8 6 97.5 40.0 40.4,36.8 96.5 6 95.5 a Dosing solution concentration mg H-24678/mL based on 7.5 naL dose volume. 112.0 108.9 112.0 H-24678 is | 119.5 107.9 108.5 c Stability samples held for 5 hours at room temperature. % Nominal based on measured. d Stability samples held for 7 days refrigerated and sampled. Average % Nominal based on measured. Solutions not administered to the animals. e Stability samples held for 7 days refrigerated followed by 5 hours at room temperature. % Nominal based on measured. Solutions not administered to the animals. The results for H-24678 samples prepared on test day 1, show that the test substance was adequately mixed (CV's less than 10), at the targeted levels (target = 12.8% of nominal) and stable in the vehicle when held 5 hours at room temperature. Samples from the same preparation collected after 7 days refrigeration and analyzed for refrigerated stability followed by 5 hours room temperature indicated that the test substance was stable for the required storage time in the 33 Company SanHized. Does not contain TSCA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 and resulted in a mixing time interval of twice a week. Test substance was not detected in the 0 mg/mL sample. The following table summarizes the results for uniformity/concentration verification and stability analyses for the test day 1 of the isopropyi alcohol positive control and the 40 mg/mL dosing sample along with the refrigerated stability information needed to change the mixing to twice a week. Preparation Nominal Measured'AverageCVStability"Stability^ Stability" Day mg/mL mg/mL % Nominal % % Nominal % Nominal % Nominal TestDayl 8.00/IPA 8.71,8.68 108.8 0 108.3 40.0 7.80,7.97 98.6 2 100.4 110.0 99.9 113.0 97.9 a Duplicate samples per level were analyzed. C.V. calculated to verify uniformity of mixture. b Stability samples held for 5 hours at room temperature. % Nominal based on measured. c Stability samples held for 7 days refrigerated and sampled. Average % Nominal based on measured. Solutions not administered to the animals. d Stability samples held for 7 days refrigerated followed by 5 hours at room temperature. % Nominal based on measured. Solutions not administered to the animals. e 40 mg/mL H-24678 sample was analyzed to show that it contained 20% or 8 mg/mL of isopropyi alcohol. The results for positive control sample and the 40 mg/mL dosing sample prepared on test day 1, show that the isopropyi alcohol was adequately mixed (CV's less than 10), at the targeted levels (target == 8.8% of nominal) and stable in the vehicle when held 5 hours at room temperature. Samples from the same preparation collected after 7 days refrigeration and analyzed for refrigerated stability followed by 5 hours at room temperature indicated that the isopropyi alcohol was stable for the required storage time in the study to change the mixing time interval to twice a week. C. Concentration Verification Samples During the Study Analytical results from dosing solutions prepared test day 42 and test day 91 and analyzed for concentration verification are shown in Appendix A, Table n and Summary Table 1. The following table summarizes the results for concentration verification analyses for the test days 42 and 91 of the H-24678 sample preparation. Preparation Nominal' Measured1' Average CV Day mg/mL mg/mL % Nominal % Test Day 42 1.33 1.22,1.20 91.0 2 8.00 7.56,7.62 94.9 1 40.0 41.6, 36.3 97.5 10 Test Day 91 1.33 1.39,1.33 102.3 3 8.00 8.49,7.96 102.9 5 40.0 37.9, 38.3 95.3 1 a.Dosing solution concentration mg H-24678/mL based on 7.5 mL dose volume. H-24678 i bDupIicatesamplesperleva were analyzed. C.V. calculated to verify uniformity of mixture. 34 Company Sanitized. Does not contain TSCA CBl H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 The results for samples prepared on test day 42 and 91 indicate that the test substance was adequately mixed (CV > 10) and at the targeted levels (target = 9.0% of nominal) for all H-24678 samples. Test substance was not detected in the 0 mg/mL sample. The following table summarizes the results for concentration verification analyses for the test days 42 and 91 of the isopropyi alcohol sample preparation. Preparation Day Nominal mg/mL Measured" mg/mL Average CV % Nominal % Test Day 42 8.00/IPA b 40.0 9.20, 9.02 7.59,7.41 113.9 1 93.8 2 Test Day 91 8.00/IPA 40.0 9.31,9.64 7.27,7.35 118.5 2 91.4 1 a Duplicate samples per level were analyzed. C.V. calculated to verify uniformity of mixture. b 40 mg/mL H-24678 sample was analyzed to show that it contained 20% or 8 mg/mL of isopropyi alcohol. The results for the isopropanol control sample and the 40 mg/mL dosing solution prepared on test day 42 and 91 indicate that the isopropyi alcohol was adequately mixed (CV less than 10) and at the targeted levels ( 18.5% of nominal) for these samples. D. Analytical Conclusions Results from the analysis of the test substance dosing solutions during the study indicate that the test substance was mixed properly, at the targeted levels and stable under the conditions of the study. Test substance was not found in the 0 mg/mL samples. Results from the analysis of the isopropyi alcohol in the 40 mg/mL samples and the isopropyi alcohol control samples during the study indicate that the isopropyi alcohol was mixed properly, at the targeted levels and stable under the conditions of the study. 35 Company Sanitized. Does not contain TSCA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats IN-LIFE TOXICOLOGY DuPont-6554 A. Dosage Data (Tables 2-3, Appendix B) The amount of test substance and isopropanol (IPA) administered to each animal was calculated using individual body weights and the design dosage_(Q, 10,60, and 300 mg H-24678/kg/day or administered at the same dosage (oD mg IPA/kg/day) as that received in the high dose group (300 mg H-24678/kg/day). Animals were dosed with the test substance and IPA diluted to varying concentrations in water. The test substance concentrations in water were 0,1.33,8, and 40 mg/mL for the 0,10,60, and 300 mg/kg/day dosage groups, respectively. The IPA concentration in water was 8 mg/mL. Tables 2 and 3 depict the average amount of diluted test substance and IPA administered to each group during the 90-day exposure period. On test day 35, seven male rats in Group V (5 designated for 90-day exposure period, 2 designated for three-month recovery) were dosed with IPA (60 mg/kg/day) instead of the test substance (10 mg/kg/day). On test day 87, one male rat in Group VII (60 mg/kg/day) inadvertently received 5 ml instead of the desired 3.8 mL of test substance. These errors in dosing did not affect the validity of the study. B. Mean Body Weights and Body Weight Gains (Tables 4-7, Figures 1-2, Appendix C) Mean body weight in male rats administered 300 mg/kg/day H-24678 was statistically lower than control rats beginning on test day 42 and throughout the remainder of the 90-day exposure period. Mean body weight gain in this dose group was also lower than controls during the majority of the exposure period. At the end of the 90-day exposure period, mean body weights were approximately 6% lower in male rats given 300 mg/kg/day compared to control rats. The overall weight gain in male rats administered 300 mg/kg/day was approximately 11% lower than controls. This reduction in body weight gain was considered test substance-related and toxicologically adverse due to parallel reductions in food efficiency (See Section C). After a one-month recovery period, mean body weights of male rats that received 300 mg/kg/day H-24678 were similar to male control rats. Mean body weight gain in the male 300 mg/kg/day dose group was statistically higher (T67%) than in the male control group after recovery, indicating that the test substance-related adverse effects on body weight were reversible. There were no adverse, test substance-related effects on body weight or body weight gain in female rats. 36 Company Sanitized. Does not contain TSCA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 C. Food Consumption and Food Efficiency (Tables 8-11, Appendix D) Mean daily food consumption in male rats administered 300 mg/kg/day H-24678 was statistically lower than control rats beginning on test day 42 and through most of the remainder of the 90-day exposure period. Mean daily food efficiency in this dose group was also lower than controls during the majority of the exposure period. At the end of the 90-day exposure period, food consumption was approximately 6% lower in male rats given 300 mg/kg/day than in control rats. The overall food efficiency in this dose group was 8% lower than controls. This reduction in food efficiency was considered test substance-related and toxicologically adverse. During the one-month recovery period, food consumption in male rats given 300 mg/kg/day H-24678 was similar to that observed in control rats. Food efficiency was statistically higher after one and three weeks of recovery and for the overall recovery period (t64%). Therefore, the test substance-related effects on food consumption and food efficiency were reversible. There were no adverse, test substance-related effects on food consumption or food efficiency in female rats. D. Clinical Observations and Mortality (Tables 12-17, Appendix E-P) There were no adverse test substance-related clinical or ophthalmological signs oftoxicity in male or female rats. A statistically significant increase in the number of animals with hair loss in male rats administered 60 and 300 mg/kg/day H-24678 compared to controls (5/10 vs 0/10) was observed. This observation was considered a spurious finding since a similar number of female control animals demonstrated hair loss (5/10). A higher incidence in hyperactivity and/or hyperreactivity was observed in male and female rats administered 300 mg/kg/day H-24678 compared to controls. This activity was not considered test-substance related due to the hyperactivity and/or hyperreactivity also observed in control animals (water and isopropanol) and the lack of test substance-related motor activity findings in the neurobehavioral assessment. No test substance-related effects on survival were observed in male or female rats. During the 90-day exposure period, one male Group I rat was accidentally killed and one male Group DC rat was found dead due to misdosing. One Group n female rat was accidentally killed at the end of the one-month recovery period during orbital sinus blood collection. One Group X female rat was found dead on test day 5 with cause of death undetermined. One Group VI female rat was sacrificed in extremis due to a mammary tumor during the three-month recovery period. 37 Company Sanitized. Does not contain TSCACBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 E. In-Life Toxicology Conclusions Based on the decrements in body weight gain and food efficiency in males dosed with 300 mg/kg/day H-24678 for 90-days, the NOEL for in-life parameters for male rats is 60 mg/kg/day. The NOEL for female rats is 300 mg/kg/day since no adverse in-life effects were observed in female rats during the 90-day dosing period. 38 ---Oo--Bipany Sanitized. Does not contaiR TSCA CBt H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats NEUROBEHAVIORAL TOXICOLOGY DuPont-6554 A. Sensory Function Evaluations 1. Forclimb Grip Strength (Table 18-19, Figures 3-4, Appendix G) There were no test substance-related effects or statistically significant differences on forelimb grip strength in males or females administered any dosage of H-24678 or isopropanol. 2. Hindlimb Grip Strength (Table 18-19, Figures 5-6, Appendix G) There were no test substance-related effects or statistically significant differences in hindlimb grip strength for either males or females administered any dosage of H-24678 or isopropanol. 3. Sensory Function Observation (Table 20-21, Appendix H) There were no test substance-related changes or statistically significant differences in neurobehavioral parameters in males or females administered any dosage of H-24678 or isopropanol. B. Motor Activity (Tables 22-25, Figures 7-10, Appendices I-J) There were no test substance-related or statistically significant differences on duration of movement or number of movements for males or females for any dosage of H-24678 or isopropanol. C. Neurobehavioral Toxicity Conclusions Under the conditions of the study, the no-observed-effect level (NOEL) for neurobehavioral parameters was 300 mg/kg/day of H-24678 in males and females, the highest concentration tested. 39 Company SaniSlzad. Does not contain TSCA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 CLINICAL PATHOLOGY Rats dosed with isopropanol had no significant changes in hematology, coagulation, clinical chemistry, or urinalysis parameters, compared to controls. All references in this report refer only to rats dosed with H-24678, except where indicated otherwise. A. Hematology/Coagulation (Tables 26-29, Appendix K) Males dosed with 60 or 300 mg/kg/day had minimal to mild dose-related decreases in some or all parameters indicating red cell mass (hemoglobin, hematocrit, and/or red cell count) (Clinical Pathology Text Table). The red cell mass decrements occurred without associated clinical or anatomic evidence of accelerated red cell production during the study. These changes persisted into the recovery period (variable statistical significance), but showed evidence of partial recovery after one and three months of recovery, m addition, during recovery, there was a minimal (not statistically significant) tendency towards increased reticulocytes in males previously dosed with 60 or 300 mg/kg/day. Clinical Pathology Text Table: Changes in red cell mass parameters for male rats* Parameter RBC Day/Dose Test Day 38 Test Day 92 Test Day 122R Test Day 183R Group V 10 mg/kg/day 101% 99% ND 97% Group VTI 60 mg/kg/day 99% 97% ND 94% Group DC 300 mg/kg/day 96% 94% 90% 97% HGB Test Day 38 Test Day 92 Test Day 122R Test Day 183R 99% 95% ND 97% 97% 95% ND 94% 93% 92% 94% 92% HCT Test Day 38 100% 98% 94% Test Day 92 96% 95% 91% Test Day 122R ND ND 93% Test Day 183R 98% 94% 93% R: recovery time point. ND: not done *Results presented as percent of concurrent control group mean. Statistical significance is indicated by bold italicized type The red cell mass changes in male rats dosed with 300 mg/kg/day were considered adverse due to the magnitude of the change during dosing and the persistence of the change into recovery. 40 Company Sanded. Does H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 All other statistically significant changes in hematology or coagulation parameters were considered unrelated to treatment and/or non-adverse (not lexicologically significant). These changes are detailed below. In the 300 mg/kg/day males, minimal changes in MCV (decreased at test day 92, increased at test day 122) and MCH (increased at test day 122, decreased at test day 183) were of uncertain relationship to treatment. These parameters changed without relationship to other red cell parameters. At test day 92, MCV in rats dosed with 300 mg/kg/day was similar to that of isopropyi alcohol rats. Therefore, these changes were minimal and had no relationship to other changes in red cell parameters, and thus were considered non-adverse. Neutrophils were transiently and minimally increased in females dosed with 300 mg/kg/day at test day 39. This change is possibly related to treatment; however, a change of this magnitude is not expected to have adverse effects. The following statistically significant changes in hematology or coagulation parameters were considered to be unrelated to treatment because they did not occur in a dose-related manner, or occurred only after one or three months of recovery: Minimally decreased basophils in males dosed with 60 mg/kg/day at test day 92. Minimally decreased hemoglobin and hematocrit in females previously dosed with 10 mg/kg/day after 3 months of recovery. Increased lymphocytes and eosinophils (test day 122) in females dosed with 300 mg/kg/day. B. Clinical Chemistry (Tables 30-31, Appendix K) Liver Tests Males dosed with 10, 60, or 300 mg/kg/day had mild to markedly increased activities of AST and ALT during dosing. Some rats also had less prominent increased SDH activities as well. Changes in activities of these three enzymes were of similar magnitude at both the 38- and 92day time points during dosing, but became more severe during three months of recovery in rats previously dosed with 60 or 300 mg/kg/day. In addition, after three months of recovery, one of five males previously dosed with 10 mg/kg/day also had increased AST, ALT, and SDH activities. Increased serum activities of AST, ALT, and SDH indicate hepatocellular injury. In all groups of males dosed with test compound, serum enzyme changes that occurred during dosing and persisted into recovery were considered adverse. Some females dosed with 300 mg/kg/day had increased AST and ALT activities during the dosing period (not statistically significant). After one month of recovery, one of ten females previously dosed with 300 mg/kg/day still had increased AST and ALT, along with increased SDH; this change was of uncertain relationship to treatment. After three months of recovery, females previously dosed with test compound had transaminase activities that were similar to 41 Gampa^ Sa"'?'-4 "-- --' ^"W" TCflA e8< H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 control values. In females dosed with 300 mg/kg/day, serum enzyme changes that occurred during dosing were considered adverse. All other statistically significant changes in clinical chemistry parameters were considered unrelated to treatment and/or non-adverse (not lexicologically significant). These changes are detailed below. Males dosed with 60 or 300 mg/kg/day had mildly increased ALKP activities during dosing. The mild changes in ALKP were not present after one or three months of recovery in rats previously dosed with test substance. Increased ALKP is generally caused by enzyme induction, either by increased biliary pressure (cholestasis) or by direct action of a xenobiotic compound. The cause of ALKP activity increase in these rats is not known. However, mildly increased ALKP activity is not, by itself, associated with adverse effects. Bilirubin was minimally decreased in females dosed with 60 or 300 mg/kg/day during dosing. After one and three months of recovery, females previously dosed with test compound had bilirubin concentrations that were similar to control values. This change was considered to be non-adverse because mildly decreased bilirubin has no known toxicologic significance. Urea nitrogen was decreased in females dosed with 60 mg/kg/day (test day 93), and increased in females previously dosed with 300 mg/kg/day after one month, but not three months, of recovery. These changes were considered unrelated to treatment because there was generally a lack of dose response and no consistency in the change during the course of the study. Creatinine was minimally decreased (no dose relationship) during dosing in all groups of males, and in females dosed with 300 mg/kg/day. Creatinine was also decreased after one month but not three months of recovery in males dosed with 300 mg/kg/day. The decreases in creatinine may be related to treatment, but were not considered adverse because minimally decreased creatinine has no known toxicologic significance. Males dosed with 10,60, or 300 mg/kg/day had minimally decreased protein during dosing. The decreased protein was due primarily to decreased globulin; globulin was minimally decreased in rats dosed with 60 or 300 mg/kg/day. After one month of recovery, protein, along with globulin, was still decreased in males previously dosed with 300 mg/kg/day. After three months of recovery, both total protein and globulins were similar to control values in rats previously dosed with 10,60, or 300 mg/kg/day. After one month of recovery, females previously dosed with 300 mg/kg/day had minimally decreased total protein, due to decreased globulin. The decreased total protein was considered possibly related to treatment, due to the similarity of the effect with that in males. However, because the changes in proteins were mild and not expected to have adverse effects, this change was considered non-adverse. Cholesterol was minimally decreased in males dosed with 60 or 300 mg/kg/day at test day 92. The change resolved by one month of recovery (measured for 300 mg/kg/day only). This change was considered related to treatment, but non-adverse, because this magnitude of the 42 Company Sanitized. Does not contain TSCA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 effect was not expected to have adverse effects. Cholesterol was also transiently and minimally decreased in females dosed with 10 mg/kg/day at test day 39; this change was considered to be unrelated to treatment due to the lack of dose-response relationship. Triglycerides were minimally decreased in females dosed with 300 mg/kg/day. This change was considered unrelated to treatment because the effect was due to increased triglycerides in some control females rather than a true decrease in treated females. Additionally, this change occurred only after one month of recovery, and is therefore unlikely to be related to dosing. Glucose was minimally increased in males dosed with 300 mg/kg/day at test day 92, and in females dosed with 60 mg/kg/day at test day 183. Although the change at test day 92 may have been related to dosing, increased glucose of this magnitude was not expected to have adverse effects. Calcium was variably and minimally decreased in males dosed with 10,60, or 300 mg/kg/day at test days 38 and 92; there was no dose-relationship at 300 mg/kg/day. 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. Decreases in albumin are necessarily associated with physiologically appropriate decreased bound calcium, with resultant decreased total calcium. However, ionized calcium is unaffected. Therefore, due to the lack of dose-response and the correlation with albumin changes, this change was considered non-adverse. Calcium was minimally decreased in females previously dosed with 300 mg/kg/day after one month of recovery. The mean calcium concentration was within the range of means for other groups on this study. In addition, albumin was minimally decreased at this time point as well (not statistically significant); minimally decreased albumin could have contributed to the change in calcium. However, the change in calcium was very small, and the change only occurred after one month of recovery. Therefore, this change was considered unrelated to treatment. The following statistically significant changes in chemistry parameters were considered to be unrelated to treatment because there was no dose-relationship or they occurred only during recovery. Albumin was minimally decreased in males dosed with 10 or 60 mg/kg/day at test day 92. At test day 183, albumin was decreased only in rats dosed with 60 mg/kg/day. Due to the lack of a dose response, this change was not considered to be treatment-related. Cholesterol was minimally increased in males previously dosed with 10 mg/kg/day after 3 months of recovery. This was considered unrelated to treatment because of the lack of doseresponse relationship, and because the change only occurred after three months of recovery. Sodium was transiently increased in males dosed with 10 mg/kg/day at test day 38. This was considered unrelated to treatment because of the lack of dose-response relationship 43 Company Sanitised. Does not contain TSCA CBS H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 Chloride was increased in males dosed with 60 or 300 mg/kg/day at test day 92; however, there was no dose relationship to the response. This change was considered unrelated to treatment because of the lack of relationship to dose. C. Urinalysis (Tables 32-33, Appendix K) Urine pH was minimally decreased in male rats previously dosed with 300 mg/kg/day at day 122. Urine protein (UMTP) was mildly decreased in female rats previously dosed with 300 mg/kg/day at day 122. These two statistically significant changes were considered to be unrelated to treatment because they occurred only during recovery. D. Plasma and urine fluoride (Tables 30-33, Appendix K) Plasma fluoride was minimally increased only in males dosed with 300 mg/kg/day at test day 92. After one month of recovery, plasma fluoride was similar to control values. Plasma fluoride in females was not affected by dosing. There was a dose-dependent increase in urine fluoride. Urine fluoride was increased in males dosed with 10,60, or 300 mg/kg/day at test day 92, and in males dosed with 300 mg/kg/day after one month of recovery. After three months of recovery, urine fluoride was minimally increased in males previously dosed with 60 or 300 mg/kg/day; the relationship of this change to dosing is equivocal, because the values overlapped with historical results. Urine fluoride was increased in females dosed with 60 or 300 mg/kg/day at test day 93. For rats dosed with 10 mg/kg/day, the number of samples available for analysis was too few to make a conclusion. After one month of recovery, urine fluoride was still minimally above controls in females previously dosed with 300 mg/kg/day. The relationship of this change to dosing is equivocal, because the values overlapped with historical results. After three months of recovery, urine fluoride was similar to control amounts in females previously dosed with test substance. The presence of increased plasma and/or urine fluoride indicates exposure to a fluoride- containing compound, but was not considered adverse. E. Clinical Pathology Conclusions Under the conditions of this study and for the parameters measured, the no adverse effect level for males was not determined due to increased serum activities for AST, ALT, and SDH during the dosing and/or recovery periods in all dose groups, m addition, at the end of dosing, males dosed with 300 mg/kg/day had decreases in parameters indicating red cell mass (hemoglobin, hematocrit, and red cell counts). The no adverse effect level for female rats was 60 mg/kg/day, based on the presence of increased serum activities for AST and ALT in some rats dosed with 300 mg/kg/day during the dosing period. There were no adverse findings for coagulation or urinalysis parameters for either sex. 44 Company Sanitized. Does not eontam TSCACBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats BIOCHEMICAL MEASUREMENTS DuPont-6554 F. Biochemical Measurements (Table 34-35, Appendix L) The rate of hepatic p-oxidation, a measure of peroxisome proliferation, was determined in male and female rats after 10 days or 91 days (males) or 92 days (females) of test substance administration or following a one-month or three-month recovery period. There were no statistically significant differences in the rate of hepatic P-oxidation between the untreated control and the isopropanol control group after 10 days or 91 days (males) or 92 days (females) of test substance administration. As a result, all statistical analyses for male rats were compared to the untreated control group. At the 10-day time point in male rats, the rate of hepatic P-oxidation was increased in rats dosed with 300 mg/kg/day H-24678 (181% of untreated control), although the increase was not statistically significant. At the 90-day time point, the rate of hepatic P-oxidation was increased in a dose-dependant manner and was statistically significantly increased in rats dosed with 60 and 300 mg/kg/day H-24678 (144% and 206% of untreated controls, respectively). At the one-month recovery time point, the rate of hepatic Poxidation was statistically significantly increased in rats dosed with 300 mg/kg/day H-24678 (167% of untreated control). At the three-month recovery time point, the rate of hepatic Poxidation was statistically significantly increased in rats dosed with 300 mg/kg/day H-24678 (153% of untreated control). At the 90-day and one-month recovery time points, the increases in hepatic P-oxidation activity were accompanied by slight increases in relative liver weights. In female rats, there was a statistically significant difference between the untreated control group and the isopropanol control group at the 10-day time point (isopropanol control was 67% of the untreated control). This finding was considered spurious since it was not replicated at the 90-day time point in female rats or at either time point in male rats. In addition, no other parameters of the study showed statistically significant differences between the two control groups. As a result, all statistical analyses for female rats were compared to the untreated control group. At the 10day time point in female rats, the rate of hepatic P-oxidation was increased in a dose-dependant manner and was statistically significantly increased in rats dosed with 60 and 300 mg/kg/day H-24678 (129% and 154% of untreated control, respectively). At the 90-day time point, the rate of hepatic P-oxidation was statistically significantly increased in rats dosed with 300 mg/kg/day H-24678 (130% of untreated control). At the one-month recovery time point, the rate of hepatic P-oxidation was statistically significantly increased in rats dosed with 300 mg/kg/day H-24678 (122% of untreated control). At the three-month recovery time point, the rate of hepatic P-oxidation was statistically significantly increased in rats dosed with 60 and 300 mg/kg/day H-24678 (130% and 133% of untreated control, respectively). At the 90-day time point, the increases in hepatic P-oxidation activity were accompanied by slight increases in relative liver weights. In-life data (body weight, nutritional and clinical observations parameters) and liver weights collected for the rats evaluated for 10-day biochemical evaluations are not included in this report but are in study records. 45 Company SanStSzed. Does no8 cantam TSCA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 G. Biochemical Measurements Conclusions Under the conditions of this study, H-24678 was a mild inducer of hepatic peroxisomal Poxidation in male and female rats. At dosages of 60 mg/kg/day and greater, changes in the rate of hepatic peroxisome proliferation were considered to be biologically significant but not lexicologically adverse effects. The rate of hepatic peroxisome proliferation remained elevated in male and female rats dosed with 60 mg/kg/day (females only) or 300 mg/kg/day H-24678 throughout the recovery period. Due to the small magnitude of test substance-related changes in hepatic biochemical measurements, the no-observed-effect level (NOEL) was the highest dose tested (300 mg/kg/day) for both male and female rats. 46 Company Sanitized. Does nog cwta'n TSCA CBS H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 ANATOMICAL PATHOLOGY A. Mortality (Appendix N) There were no compound-related deaths. Two control rats (male animal no. 648294 and female animal no. 648439) were accidentally killed. One female rat dosed with 10 mg/kg/day in the three-month recovery group (animal no. 648352) was sacrificed in extremis due to a mammary tumor. One male rat dosed with 300 mg/kg/day in the one-month recovery group (animal no. 648231) was found dead with foreign material in its nose and lungs which is consistent with a misdose into the lungs. A cause of death was not determined for a 300 mg/kg/day female onemonth recovery rat (animal no. 648375) that was found dead on test day 5. B. Organ Weight Data (Tables 36-37, Appendix M) Compound-related and/or statistically significant increases, compared to controls, in liver weight parameters were present in 300 mg/kg/day males and females and 60 mg/kg/day males (liver weight relative to body weight) sacrificed at the end of the exposure period. At the 300 mg/kg/day dose level, liver weight parameters remained increased above controls in the one-month recovery group males, although the magnitude of this effect was decreased relative to that observed at the end of the exposure period. No statistically significant liver weight effects were present in one-month recovery group females or in three-month recovery groups previously dosed with 300,60, or 10 mg/kg/day (there were no intermediate dose groups at the one-month recovery timeline). In 60 and 300 mg/kg/day exposure group male rats and 300 mg/kg/day onemonth recovery male rats increased liver weights correlated with microscopic hepatocellular hypertrophy (see discussion under Microscopic Findings). Compound-related and/or statistically significant increases, compared to controls, in one or more kidney weight parameters occurred in male and female rats dosed with 300 mg/kg/day and in male rats given 60 mg/kg/day and sacrificed at the end of the exposure period. Some kidney weight parameters remained increased in males in the 300 mg/kg/day one-month recovery group. However, there were no statistically significant kidney weight changes in female one-month recovery rats at 300 mg/kg/day or in any dosed group following a 3 month recovery. In male rats, increased kidney weight correlated with microscopic tubular hypertrophy in the 300 mg/kg/day group sacrificed at the end of the exposure period (see discussion under Microscopic Findings). There were no microscopic correlates to kidney weight changes in females. Compound-related and/or statistically significant increases, compared to controls, in one or more thyroid gland weight parameters occurred in female rats dosed with 300 mg/kg/day and sacrificed at the end of the exposure period and at the one-month and three-month recovery periods. However, there were no statistically significant thyroid gland weight changes in male rats sacrificed at any time period. In female rats, increased thyroid gland weight correlated with 47 Company Sanitized. Doss not caniain TSCA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 follicular hypertrophy in the 300 mg/kg/day group that was sacrificed at the end of the exposure period (see discussion under Microscopic Findings). There were no other compound-related organ weight effects. All other statistically significant organ weight changes in exposure and recovery groups were either secondary to changes in body weight, did not exhibit a dose related response, did not have compound-related microscopic findings, and/or the degree of weight change was biologically inconsequential. The following is a list of statistically significant organ weights that were considered not compound-related and not biologically meaningful: Adrenal gland - decreased absolute and relative to brain weights in male 60 and 300 mg/kg/day exposure groups. Adrenal gland - decreased relative to brain weight in male 60 mg/kg/day isopropanol exposure group. Heart - increased relative to body weight in male 60 and 300 mg/kg/day exposure groups. Heart - increased absolute weight in male 60 mg/kg/day isopropanol exposure group. Testes - increased absolute weight in male 60 and 300 mg/kg/day exposure groups and increased relative to body weight in male 300 mg/kg/day exposure group. Brain - increased relative to body weight in male 300 mg/kg/day exposure group. Testes - increased relative to body weight in male 300 mg/kg/day one-month recovery group. Epididymides - decreased absolute weight in male 300 mg/kg/day one-month recovery group. Thymus - increased relative to body weight in male 300 mg/kg/day one-month recovery group. Brain - increased absolute weight in female 300 mg/kg/day exposure group. C. Gross Observations (Tables 38-39, Appendix N) Gross observations noted were sporadic across groups and were not compound-related. 48 Company Sanitized. Does not eonSaEn TSCA CBi H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 D. Microscopic Findings (Tables 40-45, Appendix N) Compound-related microscopic findings were present in liver, kidneys, and thyroid gland from male rats and thyroid gland from female rats. Anatomical Pathology Text Table: Incidences and Average Lesion Grades of Compound-Related Microscopic Findings In Male and Female Rats Dose: mg/kg/day 60 0 Control 10 60 300 Isopropanol Males; 90-Day Exposure Group Liver: Hypertrophy, hepatocyte, centrilobular O/IO^O-O)" 0/10(0.0) 0/10(0.0) Necrosis, focal 0/10(0.0) 0/10(0.0) 4/10(0.4) 1/10(0.1) 3/10(0.3) 10/11(1.9) 0/11(0.0) Kidneys: Hypertrophy, tubular 0/10(0.0) 0/10(0.0) 0/10(0.0) 0/10(0.0) 11/11(1.0) Thyroid gland: Hypertrophy, follicular Alteration, colloid " 0/10 (0.0) 8/10(1.2) 0/10 (0.0) 5/10(0.9) 0/10(0.0) 8/10(0.8) 2/10(0.2) 4/10(0.4) 7/11(0.7) 10/11(2.4) Males: One-Month Recovery Liver: Hypertrophy, hepatocyte, centrilobular NA 0/10 (0.0) NA Necrosis, focal NA 0/10 (0.0) NA Thyroid gland: Hypertrophy, follicular Alteration, colloid NA 0/10 (0.0) NA NA 5/10 (0.8) NA NA 6/9 (0.7) NA 1/9(0.1) NA 6/9 (0.7) NA 9/9 (2.7) Liver: Necrosis, focal Thyroid gland: Alteration, colloid Males: Three-Month Recovery NA 0/5(0.0) 0/5(0.0) 1/5(0.2) 3/5(0.8) NA 5/5(1.2) 5/5(1.0) 5/5(1.2) 5/5(2.0) 49 Company San?S%ed, Dees no't! esntein TSCA CB5 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 Anatomical Pathology Text Table (Continued): Incidences and Average Lesion Grades of Compound-Related Microscopic Findings Male and Female _D_os_e_: _m_g/k_g_/d_ay___________In 60 0 ConRtroalts___1_0 ______6_0______3_00_ ______________________Isopropanot_________________________ Females; 90-Day Exposure Group Thyroid gland: Hypertrophy, follicular Alteration, colloid 0/10(0.0) 2/10(0.2) 0/10(0.0) 5/10(0.5) 0/10(0.0) 3/10(0.3) 0/10(0.0) 4/10(0.4) 1/11(0.1) 3/11(0.3) Thyroid gland: Alteration, colloid Females; One-Month Recovery NA 2/10(0.2) NA NA 9/9(1.1) Females; Three-Month Recovery Thyroid gland: Alteration, colloid_____________NA 5/5(1.0) 5/5(1.2) 4/5(1.2) 4/5(1.0) a. Numerator indicates incidence of rats with microscopic lesion. Denominator indicates number of rats in group. b. Number in parentheses indicates group average severity of lesion. NA Tissue not available since no animals were dosed at these levels. Focal hepatocellular necrosis accompanied by a minimal inflammatory response was present in 10 and 60 mg/kg/day male exposure groups, in 300 mg/kg/day one-month recovery males, and in 60 and 300 mg/kg/day three-month recovery males. In addition, liver enzymes were increased in all test compound dosed male groups at all time points (see Clinical Pathology results). There was correlation (not 100%) between rats with liver necrosis and elevated liver enzymes. Focal liver necrosis was considered to be a compound-related adverse finding in 10, 60, and 300 mg/kg/day male rats. Hypertrophy of centrilobular hepatocytes was present in 60 and 300 mg/kg/day males sacrificed at the end of the exposure period. In male rats previously dosed with 300 mg/kg/day, hepatocellular hypertrophy was present, but showed partial reversibility, after a one-month recovery period and was not present after a three-month recovery period. Taken together, these findings suggest that microscopic hepatocellular hypertrophy was reversible in males following a three-month recovery. Microscopically, hepatocellular hypertrophy was characterized by an increased amount of finely granular eosinophilic cytoplasm within hepatocytes. Hepatocellular hypertrophy (and the associated increase in liver weights) was considered a test substance-related physiologic response to metabolism of a xenobiotic and not lexicologically adverse. (232425) Renal tubular hypertrophy was present in 300 mg/kg/day male rats sacrificed at the end of the exposure period. This change was not observed in rats sacrificed at the one-month recovery 50 'Cempany Sanitized. DOP^ wt r'.^Wn TSCA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 period. Thus, kidney tubular hypertrophy appeared to be reversible during the one-month recovery period. Microscopically, tubular hypertrophy was characterized by increased eosinophilic staining of cortical tubule epithelium and a slight increase in cell height. Cortical tubule epithelial cells appeared to contain more granular cytoplasmic material then cortical tubules of control rats. There was no histomorphologic evidence of renal damage, and no changes indicative of adverse effects were present in renal clinical pathology parameters (see clinical pathology section). Thus, the renal tubular hypertrophy (and the associated increase in kidney weights) was considered a test substance-related physiologic response to a xenobiotic and not lexicologically adverse.0^ Thyroid follicular hypertrophy was present in males administered 60 and 300 mg/kg/day and females administered 300 mg/kg/day. Follicular hypertrophy was characterized by short columnar follicular epithelium with a finely granular or vacuolated cytoplasm. Hypertrophy was reversible in both male and female rats, as this change was not present in dosed male rats following the three-month recovery period or in female rats following the 1- month and threemonth recovery periods. Thyroid hypertrophy was minimal and unassociated with proliferative thyroid lesions. However, this hypertrophy indicates possible disruption of thyroid homeostasis and thus was considered potentially adverse. In the thyroid gland, the relative degree of altered colloid was increased in the 300 mg/kg/day males at the end of the exposure and at the 1- and three-month recovery periods. Incidence of altered colloid was also increased in 300 mg/kg/day males at the end of exposure and at onemonth recovery, m 300 mg/kg/day females the relative degree of altered colloid and incidence was increased only at the one-month recovery period. The diagnosis of "alteration, colloid" was used for colloid changes characterized by stippled, granular, clumped, and/or diffusely basophilic colloid. A 4-level grading scheme was applied based on an estimate of the percentage of follicles that contained altered colloid. A grade of 1 was applied when'l follicle to about 25% of the follicles were involved, with grades 2, 3, and 4 applied for each 25% increase in follicular involvement. The size, density, or staining intensity of stipples, granules, clumps, or diffuse basophilia within individual follicles did not impact the grading. There was no consistent association between the presence or absence of altered colloid and the presence of hypertrophy of thyroid follicular cells. Altered colloid described as clumped or granular has been reported to occur spontaneously in Sprague-Dawley rats with increasing incidence correlating to increasing age/271Because altered colloid occurs spontaneously in healthy Sprague-Dawley rats, and since increases in its grading score did not consistently correlate with other morphologic alterations in the thyroid gland, altered colloid was interpreted as not biologically meaningful and not adverse. All other microscopic observations noted are known to occur spontaneously in rats of this strain and age and were not present in a dose response fashion in either incidence or severity. 51 Pompany SanEHzed. Does no6 contain TSCA CB! H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 E. Anatomical Pathology Conclusions Exposure of the test compound for approximately 90 days produced focal hepatocellular necrosis in male rats at 10,60, and 300 mg/kg/day dose groups and was considered to be lexicologically adverse. Increased liver weights were present in males at 60 and 300 mg/kg/day and in females at 300 mg/kg/day groups. The increased liver weights correlated with microscopic centrilobular hepatocellular hypertrophy in males at 60 and 300 mg/kg/ groups. Hepatocellular hypertrophy was reversible in males following a three-month recovery. Increased kidney weights were present in 60 and 300 mg/kg/day males and 300 mg/kg/day female groups. In males, these kidney weight changes correlated with microscopic renal tubular hypertrophy. The increased kidney weights and male renal tubular hypertrophy appeared to be reversible by the three-month recovery period. These liver and kidney changes were considered to represent a physiologic response to metabolism of a xenobiotic and thus were not considered to be lexicologically significant. Thyroid gland hypertrophy in 60 and 300 mg/kg/day males and in 300 mg/kg/day females, was reversible at three-months recovery in males and at one-month recovery in females, and was considered to be potentially adverse. The severity of altered colloid in thyroid glands increased beyond control level at the male 300 mg/kg/day dose level, however, it was not consistently associated with any other morphologic alteration and was not considered biologically adverse. Under the conditions of this study, there was no NOEL for pathology for male rats based on liver necrosis at all dose levels. The NOEL for female rats was 60 mg/kg/day based onthyroid gland hypertrophy at 300 mg/kg/day. 52 Company San?t?zB<i Ow% (vfe<^fam tSCA i H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 CONCLUSIONS No test substance-related mortality or clinical signs of toxicity were observed in male or female rats. Statistically significant and lexicologically adverse lower body weights, weight gain, and food efficiency were observed in male rats administered 300 mg/kg/day compared to controls. Food consumption was also significantly lower in male rats administered 300 mg/kg/day. After a one-month recovery period these parameters were similar to controls. No effects on body weight, weight gain, food consumption, or food efficiency were observed in female rats at any dose level. Test substance-related and lexicologically adverse decreases in red cell mass parameters (red cell count, hemoglobin, and hematocrit) were observed in male rats administered 300 mg/kg/day during the dosing period and after one and three months of recovery. Adverse findings of elevated liver enzymes (AST, ALT and SDH) were observed in male rats of all dose levels and female rats dosed with 300 mg/kg/day after the 90-day exposure period. The enzyme changes in males were still present after three months of recovery and were more severe in high-dose males, while female rats recovered. Increased liver and kidney weights were observed in male rats administered 60 and 300 mg/kg/day and in female rats administered 300 mg/kg/day after the 90-day exposure period. m male rats these organ weight changes correlated with microscopic observations of hepatocellular hypertrophy and renal tubular hypertrophy, respectively. These changes were considered a test substance-related physiologic response to a xenobiotic and not lexicologically adverse. After three months of recovery, liver and kidney weights and microscopic observations were similar to controls in both male and female rats. Thyroid hypertrophy was observed in male rats administered 60 and 300 mg/kg/day and in female rats administered 300 mg/kg/day after the 90-day exposure period. These changes were considered test substance-related and lexicologically adverse. After three months of recovery, thyroid hypertrophy was not observed in male or female rats of any dose group. Test substance-related and lexicologically adverse focal hepatocellular necrosis was observed in male rats of all dose groups after the 90-day exposure and/or one and three month recovery periods. Focal liver necrosis was considered to be a test substance-related adverse finding. 53 Company Sanifeed. Oagg rte-feanfafn' H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 Based on focal liver necrosis observed in male rats of all dose groups, a no-observed-effect-level (NOEL)" cannot be determined for male rats. A NOEL of 60 mg/kg/day was determined for female rats based on elevated liver enzymes and thyroid hypertrophy observed in females administered 300 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(28)and to the no-observed-adverse-effect level (NOAEL) as defined by the European Union(29). 54 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 REFERENCES 1. DuPont (1995). Neurotoxicity Evaluation of Trimemyltin in Rats (Positive Control Study). 2. DuPont (1997). Neurotoxicity Evaluation of Amphetamine in Rats (Positive Control Study). 3. DuPont (1997). Neurotoxicity Evaluation of Carbaryl in Rats (Positive Control Study). 4. DuPont (1996). Neurotoxicity Evaluation of Acrylamide in Rats (Positive Control Study). 5. Lazarow, P.B. (1981). Assay of Peroxisomal Beta-Oxidation of Fatty Acids. Methods in Enzymology 72, 315-319. 6. Bradford, M.M. (1976). A Rapid and Sensitive Method for the Quantitation of Microgram Quantities of Protein Utilizing the Principle of Protein-Dye Binding. Anal. Biochem. 72, 248-254. 7. Dunnett, C.W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Amer. Statist. Assoc. 50,1096-1121. 8. Dunn, O.J. (1964). Multiple contrasts using rank sums. Technometrics 6,241-252. 9. Draper, N.R. and Smith, H. (1981). Applied Regression Analysis, 2nd edition, pp 266-273. Wiley, New York. 10. Selwyn, M.R. (1995). The use of trend tests to determine a no-observable-effect level in animal safety studies. Journal of the American College of Toxicology 14(2), 158-168. 11. Jonckheere, A.R. (1954). A distribution-free K-sample test against ordered alternatives. Biometrika 41, 133-145. 12. Levene, H. (1960). Robust test for equality of variances. Contributions to Probability and Statistics (J. Oikin, ed.), pp 278-292. Stanford University Press, Palo Alto. 13. Shapiro, S.S. and Wilk., M.B. (1965). An analysis of variance test for normality (complete samples). Biometrika 52, 591-611. 14. Snedecor, G.W. and Cochran, W.G. (1967). Statistical Methods, 6th edition, pp 246-248 and 349-352. The Iowa State University Press, Ames. 15. Kruskal, W.H. and Wallis, W.A. (1952). Use of ranks in one-criterion analysis of variance. J. Amer. Statist. Assoc. 47, 583-621. 16. Milliken, G.A. and Johnson, D.A. (1984). Analysis of Messy Data, Volume 1.: Designed Experiments. Lifetime Learning Publications, Belmont. 17. Hocking, R.A. (1985). The Analysis of Linear Models. Brooks/Cole, Monterey. 18. Bartlett, M.S. (1937). Some examples of statistical methods of research in agriculture and applied biology. J. Royal. Statis. Soc. Suppl. 4,137-170. 55 Company Sanitized. Does not contain TSCA CBI H-24678: SubchronicToxicity 90-Day Oral Gavage Study in Rats___________________________________DuPont-6554 19. Fisher, R.A. (1985). Statistical Methods for Research Workers, 13th edition. Haffner, New York. 20. Dempster, A.P., Selwyn, M.R., Patel, C.M., and Roth, A.J. (1984). Statistical and computational aspects of mixed model analysis. The Journal of the Royal Statistical Society, Series C (Applied Statistics) 33(2), 203-214. 21. Haseman, J.K. and Hogan, M.D. (1975). Selection of the experimental unit in teratology studies. Teratology, 12,165-171. 22. Patefield, W. (1982). Exact tests for trends in ordered contingency tables. Applied Statistics 31, 32-43. 23. Sipes, G. I., and Gandolfi, A. J. (1991). In Biotransformation of Toxicants. In Casarett and Doull's Toxicology: The Basic Science of Poisons (Amdur, M. 0., Doull, J., and Klaassen, C. D., Ed.), Pergamon Press, New York, pp 88-126. 24. Paynter, O.E., Harris, J.E., Burin, G.J., and Jaeger, R.B. (1985). Guidance for Analysis of Evaluation of Subchronic Exposure Studies. United States Environmental Protection Agency, EPA-540/9-85-020. 25. Greaves, P. (1990). Digestive System 2. In Histopathology of Preclinical Toxicity Studies: Interpretation and Relevance in Drug Safety Evaluation (P. Greaves, Ed.), Elsvier, Amsterdam, pp 393-496. 26. Greaves, P. (1990). Urinary Tract. In Histopathology of Preclinical Toxicity Studies: Interpretation and Relevance in Drug Safety Evaluation (P. Greaves, Ed.), Elsvier, Amsterdam, pp 497-583. 27. Rao-Rupanagudi, S., Heywood, R., and Gopinah, C. (1991). "Age-related Changes in Thyroid Structures and Function in Sprague-Dawley Rats," Vet. Pathol., Vol. 29, No. 4, pp. 278-287. 28. Hazard Evaluation Division, Standard Evaluation Procedure, Toxicity Potential: Guidance for Analysis and Evaluation of Subchronic and Chronic Exposure Studies Paynter, 0. E. et al.. United States Environmental Protection Agency, Office of Pesticide Programs, Washington, D.C., 20406. EPA-540/9-85-020. (June 1985). 29. Risk Assessment of Notified New Substances. Technical Guidance Document (X3/283/94EN), Chapter I, Sections 2.24 and 2.25. 1994. 56 Company Sanitized. Does no? co^'ta'n TSCA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLES 57 Company Sanitized. Does not canfain TSCA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLES DuPont-6554 EXPLANATORY NOTES Study Design Group Male Female I n m IV V VI vn vm DC x Dosage 0 mg/kg/day 60 mg/kg/day 10 mg/kg/day 60 mg/kg/day 300 mg/kg/day Test Substance Vehicle control Isopropanol control H-24678 H-24678 H-24678 Critical Dates Day 90 > Last day of test substance administration for male and female rats designated for the one-month and 3-month recovery periods. Day 91 > Last day of test substance administration for male rats designated for the 90-day exposure period. > Recovery period begins for rats designated for the one-month and 3-month recovery periods. Day 92 > Last day of test substance administration for female rats designated for the 90-day exposure period. > Male rats designated for the 90-day exposure period were sacrificed. Day 93 > Female rats designated for the 90-day exposure period were sacrificed. Day 122 > Male and female rats designated for the one-month recovery period were sacrificed. 58 Company Sanitized. Does not contain TSCA CBl H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLES ABBREVIATIONS: EXPLANATORY NOTES Summary of Hematology Values RBC - red blood cell count HGB - hemoglobin HCT - hematocrit MCV - mean corpuscular volume MCH - mean corpuscular hemoglobin MCHC - mean corpuscular hemoglobin concentration RDW - red cell distribution width ARET - absolute reticulocyte count PLT - platelet count WBC - white blood cell count ANEU - absolute neutrophil (all forms) ANPR - absolute neutrophil precursor ALYM - absolute lymphocyte AMON - absolute monocyte AEOS - absolute eosinophil ABAS - absolute basophil ALUC - absolute large unstained cell ABLT - absolute blast leukocyte AMSC - absolute miscellaneous leukocyte AHSN - absolute hypersegmented neutrophil ABAN - absolute neutrophil band AMET - absolute neutrophil metamyelocyte AMYE - absolute neutrophil myelocyte APRO - absolute neutrophil promyelocyte AMYB - absolute neutrophil myeloblast ARL - absolute reactive lymphocyte AAL - absolute atypical lymphocyte AIL - absolute immature lymphocyte ACL - absolute clefted lymphocyte ABLB - absolute lymphoblast ABE - absolute immature eosinophil AIM - absolute immature monocyte APIA - absolute plasma cell count NC - not calculated or not calculable Summary of Coagulation Values PT - prothrombin time APTT - activated partial thromboplastin time DuPont-6554 59 Company Sanitized. Does not contain TSCA CBS H-24678: Subchronic Toxicity 90-Day Oral Gavage Study m Rats DuPont-6554 TABLES ABBREVIATIONS: EXPLANATORY NOTES Summary of Serum and Plasma Chemistry Values AST - aspartate aminotransferase ALT - alanine aminotransferase SDH - sorbitol dehydrogenase ALKP - alkaline phosphatase BIU BUN - total bilimbin urea nitrogen CREA - creatinine CHOL - cholesterol TRIG - triglycerides GLUC - glucose TP - total protein ALB - albumin GLOB - globulin CALC - calcium IPHS - inorganic phosphorous NA - sodium K - potassium CL - chloride PPLU - plasma fluoride Summary ofUrinalysis Values VOL - volume UOSM - urine osmolality SG - specific gravity pH - the logarithm of the reciprocal of the hydrogen ion concentration URO - urobilinogen UFLU - urine fluoride UMTP - urine protein Notes for Clinical Pathology data: When an individual observation was recorded as being less than a certain value, calculations were performed on half the recorded value. For example, if bilirubin was reported as <0.1,0.05 was used for any calculations performed with that bilirubin data. When an individual observation was recorded as being greater than a certain value, calculations were performed on the recorded value. For example, if specific gravity was reported as >1.083, 1.083 was used for any calculations performed with that specific gravity data. 60 Cempany SaniHzed. Does nat contain TSCA CN3.1 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 1 SUMMARY OF DOSING SOLUTION ANALYSES Sample Type Test Day 1 Concentration Verification Average Measured Cone.' Average Percent Nominal' Standard Deviation*1 Coefficient of Variation' ___ ____Dosing Concentrations and Stability of H-24678 (ingtal^ Nominal: 1.33 8.00 40.0 1.51 (m.S)1' 7.32 (91.5) 40.4 (101.0) 1.48 (111.3) 7.99 (99.9) 36.8 (92.0) 1.50 (112.8) 7.66 (95.8) 38.6 (96.5) 0.02 047 2.5 Stability 0-Day Room TemperatureS-hour Room Temperature 7-Day Refrigerated 7-Day Refrigerated/5 hr. 1.50 (112.8) 1.41 (106.0) 1.49 (112.0) 1.59 (119.5) 7.66 (95.8) 7.80 (97.5) 8.71 (108.9) 8.63 (107.9) 38.6 (96.5) 38.2 (95.5) 44.8 (112.0) 43.4 (108.5) Concentration Verification1 Test Day 42 1.21 (91.0) 7.59 (94.9) 39.0 (97.5) Test Day 91 1.36 (102.3) 8.23 (102.9) 38.1 (95.3) ; solution concentration '8/mL based on 7.5 mL dose volume. H-24678 isj Numbers in parentheses are the respectivepercent of nominal values. Mean, S.D., and C.V. for duplicate samples calculated to verify uniformity of mixture. Mean result for Test Day 1 concentration verification samples used for baseline for stability samples. Samples (Test Day 1) held at room temperature for 5 hours. Duplicate samples submitted. Mean result reported. 61 Company Sanitrod.. Ows ro? r.wv'i'w. "?;''. CB! H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 Sample Type Test Day 1 Concentration Verification Average Measured Cone.' Average Percent Nominal' Standard Deviation' Coefficient of Variation' Table 1 (continued) Summary of Dosing Solution Analyses Dosing Concentrations and Stability oflsopropyi Alcohol (mg/mL) Nominal: 8.00 40.0 a 8.71 (108.9) b 7.80 (97.5) 8.68 (108.5) 7.97 (99.6) 8.70 (108.8) 7.89 (98.6) 0.02 0.12 Stability 0-Day Room Temperature^ 5-hour Room Temperature 7-Day Refrigerated 7-Day Refrigerated/5 hr. 8.70 (108.8) 8.66 (108.3) 8.80 (110.0) 9.04 (113.0) 7.89 (98.6) 8.03 (100.4) 7.99 (99.9) 7.83 (97.9) Concentration Verification' Test Day 42 9.11 (113.9) 7.50 (93.8) Test Day 91 9.48 (118.5) 7.31 (91.4) 40 mg/mL H-24678 sample was analyzed to show that it contained 20% or 8 mg/mL ofisopropyi alcohol. Numbers in parentheses are the respective percent of nominal values. Mean, S.D. and C.V. for duplicate samples calculated to verify uniformity of mixture. Mean result for Test Day 1 concentration verification samples used for baseline for stability samples. Samples (Test Day 1) held at room temperature for 5 hours. Duplicate samples submitted. Mean result reported. 62 Company Sanitized. Does not eontam TSCA CBS H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TAI?LE2 MEAND.MLY DOSEV01LUMES(mL):FORM[ALE RAT;3 Group :[ 0 mg/ktj/dai{ III G roup 6 0 ing/kg/day I sopropanol Group ^T 10 nig/Icg/ciay'1 DAYO-DAY6 1.9 0.1(25 ) 2 .0 0 .1(10 ) 1.9 0.2(15 ) DAY7-DAY14 2.3 0.2(25 ) 2 .4 0 .1(10 ) 2.3 0.2(15 ) DAY15-DAY20 2.7 0.2(25 ) 2 .8 0 .1(10 ) 2.7 0.2(15 ) DAY21-DAY27 2.9 0.2(25 ) 3 .1 0 .2(10 ) 3.0 0.3(15 ) DAY28-DAY34 3.2 0.2(25 ) 3 .3 0 .2(10 ) 3.3 0.3(15 ) DAY35-DAY41 3.4 0.3(25 ) 3 .6 0 .3(10 ) 3.5 0.3(15 ) DAY42-DAY48 3.5 0.3(24 ) 3 .6 0 .2(10 ) 3.6 0.3(15 ) DAY49-DAY55 3.7 0.3(24 ) 3 .8 0 .3(10 ) 3.7 0.3(15 ) DAY56-DAY62 3.8 0.3(24 ) 4 .0 0 .3(10 ) 3.9 0.3(15 ) DAY63-DAY69 3.9 0.4(24 ) 4 .1 0 .3(10 ) 4.0 0.4(15 ) DAY70-DAY76 4.0 0.4(24 ) 4 .2 0 .3(10 ) 4.1 0.4(15 ) DAY77-DAY83 4.1 0.4(24 ) 4 .3 0 .3(10 ) 4.2 0.4(15 ) DAY84-DAY90 4.2 0.4(24 ) 4 .4 . 0 .3(10 ) 4.3 0.4(15 ) DAYS1 4.4 0.2(9 ) 4 .4 0 .3(10 ) 4.5 0.4(10 ) Data summarized as: Mean Standard Deviation (n) Group VII 6 0 mg/kg/day" 1 .9 0 .2(15 ) 2 .3 0 .2(15 ) 2 .7 0 .2(15 ) 2 .9 0 .3(15 ) 3 .2 0 .3(15 ) 3 .4 0 .4(15 ) 3 .5 0 .4(15 ) 3 .6 0 .4(15 ) 3 .8 0 .4(15 ) 3 .9 0 .5(15 ) 4 .0 0 .5(15 ) 4 .1 0 .5(15 ) 4 .1 0 .5(15 ) 4 .4 0 .5(10 ) Group :rx 300 mg,^kg/day" 1.9 0.1(25 ) 2.3 0.2(25 ) 2.6 0.2(25 ) 2.9 0.2(25 ) 3.1 0.3(25 ) 3.3 0.3(25 ) 3.4 0.3(25 ) 3.5 0.3(25 ) 3.6 0.3(25 ) 3.7 0.3(24 ) 3.9 0.4(24 ) 3.9 0.4(24 ) 4.0 0.4(24 ) 4.2 0.5(10 ) a. H-24678 is 63 Company Sanitized. Does r,oi contain TSCA CB! H-24678: Subchrcinic Toxicity 90-Day Oral Gavajge Study in Rats DuPont-6554 TAB LE3 MEAN DAD-,YD(3SEVOLIJMES (mL) PC>RFE^IALERAT'S II Group 0 ing/kg/day Group rv 60 mg/kg/dai' Islopropanol Group VI 10 mg/kg/disy" DAYO-DAY6 1.4 0.1(25 ) 1. 5 0. 2(10 ) 1.4 0.1(15 ) DAY7-DAY14 1.6 0.2(25 ) 1. 6 0. 1(10 ) 1.6 0.1(15 ) DAY15-DAY20 1.8 0.2(25 ) 1. 8 0. 1(10 ) 1.7 0.1(15 ) DAY21-DAY27 1.9 0.2(25 ) 1..9 0..2(10 ) 1.8 0.1(15 ) DAY28-DAY34 2.0 0.2(25 ) 2..0 0,.1(10 ) 1.9 0.1(15 ) DAY35-DAY41 2.1 0.2(25 ) 2,.1 0 .1(10 ) 2.0 0.1(15 ) DAY42-DAY48 2.2 0.2(25 ) 2 .1 0 .1(10 ) 2.1 0.2(15 ) DAY49-DAY55 2.2 0.2(25 ) 2 .2 0 .1(10 ) 2.1 0.2(15 ) DAY56-DAY62 2.3 0.3(25 ) 2 .2 0 .1(10 ) 2.2 0.2(15 ) DAY63-DAY69 2.3 0-3(25 ) 2 .2 0 .1(10 ) 2.2 0.2(15 ) DAY70-DAY76 2.4 0.3(25 ) 2 .3 0 .1(10 ) 2.2 0.2(15 ) DAY77-DAY83 2.4 0.3(25 ) 2 .4 0 .1(10 ) 2.3 0.2(15 ) DAY84-DAY90 2.5 0.3(25 ) 2 .4 0 .1(10 ) 2.3 0.2(15 ) DAY91-DAY92 2.5 0.2(10 ) 2 .4 0 .1(10 ) 2.3 0.2(10 ) Data summarized as: MSetaanndard Deviation (n) a. H-24678 is Group VIII 60 mg/kg/dai'" 1. 5 0. 1(15 ) 1. 6 0. 1(15 ) 1. 8 0. 1(15 ) 1. 9 0. 1(15 ) 2.0 0.2(15 ) 2..1 0.,2(15 ) 2,.2 0,.2(15 ) 2 .2 0 .2(15 ) 2 .3 0 -2(15 ) 2 .3 0 .2(15 ) 2 .3 0 .2(15 ) 2 .4 0 .2(15 ) 2 .4 0 .2(15 ) 2 .5 0 .4(10 ) Group X 3010 ing/kg/day" 1. 5 0. 1(25 ) 1..6 0..1(24 ) 1..8 0..1(24 ) 1,.9 0 .1(24 ) 2 .0 0 .1(24 ) 2 .1 0 .1(24 ) 2 .1 0 .2(24 ) 2 .2 0 .2(24 ) 2 .3 0 .2(24 ) 2 .3 0 .2(24 ) 2 .4 0 .2(24 ) 2 .4 0 .2(24 ) 2 .4 0 .2(24 ) 2.6 0.2(10 ) 64 Company Sanitized. Does not contain TSCA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE4 MEAl^JBODY WEIGHrrs(g)OFMAUERATS Dosing Pe;riod Group I 0 mg/kg/day DAYO DAY7 DAY15 DAY21 DAYS 8 DAY35 DAY42 DAY49 DAYS 6 DAY63 DAY70 DAY7 7 DAYS 4 DAY91 254.7 18.4(25 ) 308.5 23.2(25 ) 359.3 26.6(25 ) 393.5 29.2(25 ) 424.8 31.6(25 ) 450.9 35.0(25 ) 468.4 38.0(24 ) 490.8 39.7(24 ) 511.1 42.6(24 ) 519.9 58.8(24 ) 537.3 54.7(24 ) 550.4 50.9(24 ) 557.7 55.3(24 ) 567.7 54.4(24 ) III Group 60 ing/kg/day Isopropanol 262.9 13.9(10 ) 322.6 16.8(10 ) 377.7 20.2(10 ) 413.6 22.9(10 ) 444.0 27.4(10 ) 473.2 33.2(10 ) 481.8 33.5(10 ) 507.0 34.3(10 ) 528.5 36.0(10 ) 544.7 38.2(10 ) 563.6 38.9(10 ) 570.8 41.3(10 ) 581.0 43.0(10 ) 589.2 44.0(10 ) Group V Group VII Group IX 10 mg/kg/day" 60 nig/kg/day* 300 mg/kg/day' 256.1 19.7(15 ) 311.5 24.9(15 ) 363.3 28.5(15 ) 402.0 33.7(15 ) 434.2 37.6(15 ) 464.5 41.2(15 ) 480.0 37.3(15 ) 497.6 38.0(15 ) 520.2 41.3(15 ) 536.8 44.9(15 ) 548.1 45.2(15 ) 562.1 48.0(15 ) 567.2 58.9(15 ) 574.6 57.0(15 ) 257.1 20.0(15 ) 308.5 26.5(15 ) 360.4 31.7(15 ) 393.7 35.2(15 ) 424.5 44.1(15 ) 453.7 49.3(15 ) 462.6 48.3(15 ) 483.0 50.9(15 ) 503.7 52.7(15 ) 520.3 60.1(15 ) 531.7 62.8(15 ) 543.2 64.8(15 ) 547.4 70.7(15 ) 552.5 68.9(15 ) 255.0 17.4(25 ) 305.8 22.5(25 ) 351.9 25.8(25 ) 383.3 31.5(25 ) 415.1 35.8(25 ) 441.1 38.4(25 ) 449.5# 38.4(25 ) 467.0# 38.6(25 ) 486.2# 42.2(25 ) 497.0# 45.2(24 ). 512.5ft 47.9(24 ) 522.5# 48.2(24 ) 529.7# 51.3(24 ) 535.9# 52.3(24 ) 65 Company Sanitized. Does noS contain TSCA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 4 (CONTINUED) MEAN BODY WEIGHTS (g) OF MALE RATS One-Month Recovery Period Group I 0 nig/kg/day Group V 10 mg/kg/day" Group VII 60 mg/kg/day Group IX 300 nig/kg/day' DAY98 DAY105 DAY113 DAY119 562.0 69.2(15 ) 575.2 67.4(15 ) 581.5 79.9(15 ) 590.9 74.9(15 ) 531.1 40.5(5 ) 544.1 37.4(5 ) 558.9 35.0(5 ) 565.5 37.6(5 ) 505.8 53.7(5 ) 517.2 54.9(5 ) 523.5 63.8(5 ) 529.7 65.0(5 ) Data summarized as: Mean Standard Deviation (n) 535.9 45.0(14 ) 553.2 48.3(14 ) 572.0 46.9(14 ) 579.5 48.4(14 ) III # Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. Group (isopropanol control) was excluded from trend comparisons. III There were no statistically significant differences between Groups I and at p < 0.05 by pairwise comparisons. 66 Conwxww SanffiteeA Oo8' H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TAB1LE5 MEAN BODYWEIGIrrs(g)lOFFEMy\LERATS Dosing Period I I Gro'up 0 m g/kg/day DAYO DAY7 DAY15 DAY21 DAY28 DAYS 5 DAY42 DAY49 DAYS 6 DAY63 DAY70 DAY7 7 DAY84 DAY91 193 .5 14 .9(25 ) 216 .2 19 .9(25 ) 239 .6 23 .6(25 ) 254 .1 25 .1(25 ) 267 .4 29 .6(25 ) 279 .1 30 .6(25 ) 287 .1 31 .9(25 ) 297 .1 33 .0(25 ) 306 .3 35 .4(25 ) 308 .8 39 .0(25 ) 316 .8 38 .2(25 ) 321 .3 38 .8(25 ) 326 .9 40 .6(25 ) 326 .1 41 .0(25 ) Group IV 60 mg/kg/dai/ Isopropanol 193.9 17.2(11 ) 211.7 16.2(10 ) 236.3 17.9(10 ) 249.9 19.5(10 ) 265.7 16.4(10 ) 273.6 17.6(10 ) 280.0 14.0(10 ) 289.0 15.8(10 ) 297.8 15.7(10 ) 297.2 14.1(10 ) 308.7 11.9(10 ) 313.0 10.9(10 ) 319.9 15.7(10 ) 318.8 13.8(10 ) Group VI 10 :nig/kg/day'1 Group VIII 60 nig/kg/day'* Group X 300 mg/kg/day" 193 .0 10 .5(15 ) 210 .9 10 .4(15 ) 230 .1 16 .3(15 ) 243 .7 16 .8(15 ) 255 .1 16 .7(15 ) 269 .2 16 .3(15 ) 273 .3 19 .4(15 ) 279 .5 21 .0(15 ) 288 .2 22 .2(15 ) 291 .0 20 .0(15 ) 296 .7 23 .2(15 ) 300 .4 22 .3(15 ) 306 .8 23 .1(15 ) 310 .3 22 .1(15 ) 195.5 12.0(15 ) 216.1 13.3(15 ) 237.9 18.2(15 ) 251.2 16.0(15 ) 267.5 20.3(15 ) 280.2 24.4(15 ) 287.1 27.4(15 ) 295.3 25.6(15 ) 306.8 26.7(15 ) 310.9 32.6(15 ) 313.8 30.3(15 ) 319.1 34.3(15 ) 326.4 34.7(15 ) 328.6 38.9(15 ) 197.3 13.4(25 ) 215.6 14.5(24 ) 237.9 17.4(24 ) 249.0 19.7(24 ) 264.5 18.0(24 ) 277.5 20.2(24 ) 284.9 19.7(24 ) 291.8 20.6(24 ) 307.1 26.3(24 ) 307.9 23.1(24 ) 317.1 26.3(24 ) 317.9 26.3(24 ) 322.2 27.0(24 ) 325.6 30.0(24 ) 67 Company SanttesA D@@snaS eontain TSCA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 5 (CONTINUED) MEAN BODY WEIGHTS (g) OF FEMALE RATS One-Month Recovery Period I I G r o u p 0 ing/kg/day Group VI 10 mg/kg/day^ Group VIII 60 nig/kg/day'1 Group X 300 nig/kg/day" DAY98 DAY105 DAY113 DAY119 337.5 56.4(15 ) 344.8 59.6(15 ) 349.0 59.3(15 ) 353.2 61.8(15 ) 314.3 30.6(5 ) 332.4 26.9(5 ) 339.3 29.7(5 ) 339.7 30.8(5 ) Data summarized as: Mean 322.5 17.6(5 ) 334.8 20.9(5 ) 341.1 22.8(5 ) 340.8 24.0(5 ) 321.3 27.9(14 ) 327.2 27.9(14 ) 334.4 30.4(14 ) 340.0 32.6(14 ) There were no statistically significant differences at p < 0.05 by JonckheereTerpstra trend test. Group IV (isopropanol control) was excluded from trend comparisons. There were no statistically significant differences between Groups II and IV at p < 0.05 by pairwise comparisons. 68 Company Sanitized. Doss not eontain TSCA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TAISUE 6 MEANB ODY1WEIGHI'GAINSi(G) OF]^IALEiRATS Dosing Pericid Gro up I 0 HI'g/kg/clay DAYO-DAY7 DAY7-DAY15 DAY15-DAY21 DAY21-DAY28 DAY28-DAY35 DAY35-DAY42 DAY42-DAY49 DAY49-DAY56 DAY56-DAY63 DAY63-DAY70 DAY70-DAY77 DAY77-DAY84 DAY84-DAY91 53 .8 8 .3(25 ) 50 .9 8 .4(25 > 34 .1 7 .1(25 ) 31 .3 5 .6(25 ) 26 .1 8 .6(25 ) 18 .1 6 .3(24 ) 22 .4 6 .5(24 ) 20 .3 6 .3(24 ) 8 .7 24 .4(24 ) 17 .5 12 .6(24 ) 13 .0 8 .1(24 ) 7 .4 9 .4(24 ) 10 .0 7 .3(24 ) I I I Groiup 60 nig/kg/da.y ISO:propanol 59. 7 6. 6(10 ) 55. 1 9. 0(10 ) 36. 0 4. 2(10 ) 30. 4 6. 8(10 ) 29. 1 8. 0(10 ) 8. 6 * 6. 9(10 ) 25. 2 5. 6(10 ) 21. 5 3. 8(10 ) 16. 2 5. 4(10 ) 18. 9 3. 4(10 ) 7. 3 8 4. 4(10 ) 10. 2 5. 9(10 ) 8. 1 12. 6(10 ) GrouLP V 10 n ig/kg,/day'a 55. 4 8. 5(15 ) 51. 8 7. 3(15 ) 38. 7 9. 2(15 ) 32. 2 7. 4(15 ) 30. 3 6. 5(15 ) 15. 5 9. 5(15 ) 17. 6 5. 8(15 ) 22. 5 6. 4(15 ) 16. 6 10. 2(15 ) 11. 3 2. 7(15 ) 14. 0 5. 2(15 ) 5. 1 18. 9(15 ) 7. 5 5. 4(15 ) Gro up VI:1: 60 :nig/kg;/day'a 51 .4 8 .7(15 ) 51 .9 8 .3(15 ) 33 .3 7 .4(15 ) 30 .8 10 .8(15 ) 29 .2 6 .5(15 ) 8 9ft 6 .4(15 ) 20 .4 9 .9(15 ) 20 .6 6 .2(15 ) 16 .6 8 .8(15 ) 11 .4 7 .5(15 ) 11 .5 5 .6(15 ) 4 .2 8 .9(15 ) 5 .Itt 7 .9(15 ) Group IX 300 mg/kcJ/day' 50 .8 9 .1(25 ) 46 1# 9 .8(25 ) 31 -3# 10 .0(25 ) 31 .8 8 .3(25 ) 26 .0 8 .1(25 ) 8 .4# 8 .9(25 ) 17 .5# 7 .0(25 ) 19 .3 6 .6(25 ) 9 .8 11 .3(24 ) 15 .5 6 .8(24 ) 10 .0 5 .8(24 ) 7 .2 7 .9(24 ) 6 .2# 8 .0(24 ) DAYO-DAY91 314 .2 46 .9(24 ) 326 .2 41 .8(10 ) 318. 5 47. 0(15 ) 295 .5 55 .6(15 ) 281 .2ft 39 .8(24 ) 69 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 6 (CONTINUED) MEAN BODY WEIGHT GAINS (g) OF MALE RATS One-Month Recovery Period Group I 0 mg/kg/day Group V 10 ing/kg/day' Group VII 60 mg/kg/day" Group IX 300 nig/kg/day' DAY91-DAY98 DAY98-DAY105 DAY105-DAY113 DAY113-DAY119 4 .6 11 .6(15 ) 13 .1 3 .8(15 ) 6 .4 19 .4(15 ) 9 .4 11 .3(15 ) 1 .3 8 .1(5 ) 13 .0 7 .2(5 ) 14 .8 3 .4(5 ) 6 .6 8 .1(5 ) 5 .0 7 .8(5 ) 11 .4 4 .1(5 ) 6 .4 11 .2(5 ) 6 .2 6 .1(5 ) 12. 1# 11. 4(14 ) 17. 3 7. 5(14 ) 18. 8# 7. 2(14 ) 7. 5 4. 3(14 ) DAY91-DAY119 33 .4 19 .5(15 ) 35 .7 22 .9(5 ) 28 .9 22 .3(5 ) 55. 8# 17. 0(14 ) Data summarized as: ^ a. H-24678 is Mean Standard Deviation (n) III # Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. Group (isopropanol control) was excluded from trend comparisons. * Statistically significant difference from control (Group I) at p < 0.05 by Dunnett's test. @ Statistically significant difference from control (Group I) at p < 0.05 by Dunn's test. 70 Company Sanitized. D6@S not eorrtain TSCA CBl H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABL3E7 MEAN BO:DY WEIGHT G^\INS(g)OFFE]\AALERATS Dosing Peric3d I I Group 0 nig/kg/day DAYO-DAY7 DAY7-DAY15 DAY15-DAY21 DAY21-DAY28 DAY28-DAY35 DAY35-DAY42 DAY42-DAY49 DAY49-DAY56 DAY56-DAY63 DAY63-DAY70 DAY70-DAY77 DAY77-DAY84 DAY84-DAY91 22.6 8.8(25 ) 23.4 7.2(25 ) 14.5 8.0(25 ) 13.3 7.5(25 ) 11.7 8.4(25 ) 8.1 7.4(25 ) 9.9 6.0(25 ) 9.2 6.7(25 ) 2.5 8.2(25 ) 7.9 6.5(25 ) 4.5 5.9(25 ) 5.6 7.3(25 ) -0.9 7.6(25 ) Group IV 60 nig/kg/day Isopropanol 18.2 11.8(10 ) 24.5 5.8(10 ) 13.6 9.2(10 ) 15.9 4.6(10 ) 7.8 7.4(10 ) 6.4 7.8(10 ) 9.0 6.7(10 ) 8.8 3.0(10 ) -0.6 9.1(10 ) 11.5 5.0(10 ) 4.3 5.3(10 ) 6.9 5.7(10 ) -1.1 5.4(10 ) Group VI Group VIII Group X 10 rng/kg/day3 60 nig/kg/day" 300 mg/kg/day' 18.0 5.7(15 ) 19.2 8.7(15 ) 13.6 7.4(15 ) 11.4 6.9(15 ) 14.0 5.4(15 ) 4.1 7.7(15 ) 6.2 6.8(15 ) 8.7 5.7(15 ) 2.7 7.6(15 ) 5.7 5.7(15 ) 3.8 6.9(15 ) 6.4 6.3(15 ) 3.5 7.3(15 ) 20.6 6.5(15 ) 21.7 9.3(15 ) 13.3 9.2(15 ) 16.3 8.4(15 ) 12.7 6.2(15 ) 6.9 8.1(15 ) 8.1 7.9(15 ) 11.5 9.2(15 ) 4.2 9.4(15 ) 2.9 9.7(15 ) 5.2 6.9(15 ) 7.3 7.3(15 ) 2.2 7.2(15 ) 18.3 7.1(24 ) 22.3 6.0(24 ) 11.1 7.5(24 ) 15.5 8.9(24 ) 13.0 7.0(24 ) 7.4 6.1(24 ) 7.0 5.7(24 ) 15.2 20.7(24 ) 0.8 22.0(24 ) 9.3 6.3(24 ) 0.8# 4.6(24 ) 4.3 6.7(24 ) 3.4# 8.4(24 ) DAYO-DAY91 132.5 29.9(25 ) 125.3 17.0(10 ) 117.3 16.3(15 ) 133.1 31.6(15 ) 128.3 21.7(24 ) 71 Company Sanitized. Des not contain TSCA CBS H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 7 (CONTINUED) MEAN BODY WEIGHT GAINS (g) OP FEMALE RATS One-Month Recovery Period I I Group 0 mg/ kg/day Group VI 10 ing/kg/day' Group VIII 60 nig/kg/day" Group X 300 mg/kg/day" DAY91-DAY98 DAY98-DAY105 DAY105-DAY113 DAY113-DAY119 11 .0 9 .3 (15 ) 7 .4 6 .3 (15 ) 4 .1 4 .4(15 ) 4 .2 8 .9(15 ) 2.7 11.9(5 ) 18.1 11.4(5 ) 6.9 5.7(5 ) 0.4 3.9(5 ) 0.8 12.0(5 ) 12.3 7.2(5 ) 6.3 10.6(5 ) -0.3 9.4(5 ) 6.5 7.7(14 ) 5.9 7.4(14 ) 7.2 6.9(14 ) 5.6 9.3(14 ) DAY91-DAY119 26 .7 16 .0 (15 ) 28.1 10.9(5 ) 19.0 20.3(5 ) Data summarized as Mean Standard Deviation (n) 25.2 15.9(14 ) a. H-24678 is # Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. Group IV (isopropanol control) was excluded from trend comparisons. There were no statistically significant differences between Groups II and IV at p < 0.05 by pairwise comparisons. 72 Company Sanitized. Does not eorrtain TSCA CBl H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABUE8 MEANDAIL'Y FOOD CONSIJMPTION (g) B''f MALE RATS Dosing Pericid Group I 0 ing/kg/day DAY7 DAY15 DAY21 DAY28 DAY35 DAY42 DAY49 DAYS 6 DAY63 DAY70 DAY7 7 DAY84 b DAY91 26.6 2.4(25 ) 27.7 2.1(25 ) 28.7 2.5(25 ) 29.6 2.5(25 ) 29.0 2.9(25 ) 27.5 2.6(24 ) 30.2 2.8(24 ) 29.7 2.9(24 ) 28.3 4.7(24 ) 28.7 3.7(24 ) 29.0 2.9(24 ) 30.1 3.1(19 ) 28.0 3.6(24 ) III Group 60 mg/kg/day Isopropanol 28.5 * 1.6(10 ) 28.9 1.8(10 ) 30.0 2.5(10 ) 29.7 2.0(10 ) 29.3 2.8(10 ) 25.6 2.2(10 ) 30.3 2.3(10 ) 30.5 2.6(10 ) 29.4 2.8(10 ) 30.4 2.5(10 ) 29.8 3.0(10 ) 29.9 2.6(10 ) 28.2 2.3(10 ) Group V Group VII Group IX 10 nig/kg/day' 60 mg/kg/day* 300 lag/kg/day' 27.4 2.6(15 ) 28.1 2.3(15 ) 30.2 2.9(15 ) 30. 0 3.0(14 ) 30.0 2.6(15 ) 27.2 1.7(15 ) 29.8 2.7(15 ) 30.1 2.5(15 ) 28.3 2.8(15 ) 28.9 2.1(15 29.9 2.2(15 ) 30.0 2.1(10 ) 26.4 3.3(15 ) 27.6 2.5(15 ) 28.3 2.8(15 ) 29.1 3.0(15 ) 28.9 3.1(15 ) 28.8 3.2(15 ) 25.9 2.6(15 ) 28.9 3.2(15 ) 29.5 3.6(15 ) 27.8 3.7(15 ) 28.2 3.7(15 ) 28.8 3.1(15 ) 28.7 2.9(10 ) 25.3 2.8(15 ) 26.9 2.6(25 ) 27.3 2.7(25 ) 28.2 3.1(25 ) 28.2 3.0(25 ) 27.4 3.2(25 ) 25.2# 2.4(25 ) 27.2# 2.7(25 ) 28.2# 2.7(25 ) 27.2 3.1(24 ) 27. U 2.9(24 ). 28.0 3.0(24 ) 28.0ft 2.9(19 ) 26.8 3.5(24 ) DAYO-DAY91b 29.5 1.8(19 ) 29.3 2.0(10 ) 29.9 1.4(9 ) 29.2 2.3(10 ) 27. 7# 2.2(19 ) 73 Company Sanitized. Does not contain TSCA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats___________________________________DuPont-6554 TABLE 8 (CONTINUED) MEAN DAILY POOD CONSUMPTION (g) BY MALE RATS One-Month Recovery Period Group I 0 mg/kg/day Group V 10 nig/kg/day" Group VII 60 ing/kg/day' Group IX 300 nig/kg/day' DAY98 DAY105 DAY113 DAY119 25.7 4.6(15 ) 27.6 3.0(15 ) 28.1 4.1(15 ) 28.0 3.2(15 ) 23.8 0.7(5 ) 25.6 2.1(5 ) 27.2 2.1(5 ) 26.6 3.0(5 ) 24.3 3.4(5 ) 24.9 2.7(5 ) 25.4 4.6(5 ) 24.7 4.3(5 ) 27.3 3.3(14 ) 28.6 3.1(14 ) 29.1 2.6(14 ) 28.5 2.4(14 ) DAY91-DAY119 27.4 3.5(15 ) 25.8 1.8(5 ) 24.9 3.6(5 ) 28.4 2.7(14 ) Data summarized as: Mean ^. Standard Deviation (n) ^ a. H-24678 is HIHIJHBIIHHJIHHIH^^^HIBBg^Bi^BHHBi b.On test day 84, food consumption data were^iadvertently not collected for 5 rats/group designated for 3-month recovery. III # Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. Group (isopropanol control) was excluded from trend comparisons. * Statistically significant difference from control (Group I) at p < 0.05 by Dunnett's test. 74 Company Sanitized. Does not eontaEn TSCA CB1 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABUE9 MEAN DAILY POOD CONSU1OPTION (g) BY FEMALE RAT; Dosing Pericid I I Group 0 mg/kg/day DAY? DAY15 DAY21 DAY28 DAY35 DAY42 DAY49 DAYS 6 DAY63 DAY70 DAY77 DAY84 b DAY91 20.0 2.3(25 ) 20.8 2.6(25 ) 21.5 2.7(25 ) 22.1 3.3(25 ) 21.3 2.9(25 ) 19.9 2.8(25 ) 21.6 2.4(25 ) 21.5 2.8(25 ) 20.3 2.5(25 ) 21.1 2.9(25 ) 20.7 2.6(25 ) 21.7 3.5(20 ) 19.3 2.6(25 ) Group IV 60 ing/kg/day Isopropanol 20.2 0.9(10 ) 20.6 1.2(10 ) 21.6 1.3(10 ) 21.0 0.9(10 ) 20.8 0.8(10 ) 19.2 1.2(10 ) 21.5 1.2(10 ) 21.3 1.1(10 ) 19.8 2.3(10 ) 21.4 1.4(10 ) 20.9 1.7(10 ) 21.1 2.1(10 ) 20.1 1.3(10 ) Group VI Group VIII Group X 10 mg/kg/day3 60 nig/kg/day'* 300 ing/kg/day3 19.6 1.7(15 ) 19.9 2.1(15 ) 21.0 2.3(15 ) 20.9 1.6(15 ) 20.9 1.5(15 ) 18.9 1.8(15 ) 20.8 2.2(15 ) 21.1 2.0(15 ) 19.6 1.6(15 ) 20.3 2.1(15 ) 20.6 2.1(15 ) 21.0 2.1(10 ) 20.0 2.2(15 ) 19.4 1.5(15 ) 20.6 1.8(15 ) 20.8 2.3(15 ) 21.1 2.2(15 ) 20.7 2.1(15 ) 20.2 2.4(15 ) 21.9 2.0(15 ) 22.0 2.4(15 ) 20.9 2.2(15 ) ... 21.0 2.3(15 ) 21.0 2.5(15 ) 21.9 3.1(10 ) 20.5 2.8(15 ) 19.4 1.6(24 ) 20.1 2.2(24 ) 20.6 2.2(24 ) 21.2 1.8(24 ) 21.2 1.9(24 ) 19.5 2.0(24 ) 21.7 1.7(24 ) 21.5 1.9(24 ) 20.4 2.0(24 ) 21.2 1.9(24 ) 20.6 1.9(24 ) 20.5 1.8(19 ) 19.8 2.2(24 ) DAYO-DAY91ll 21.4 2.4(20 ) 20.7 0.5(10 ) 20.4 1.7(10 ) 21.2 2.3(10 ) 20.8 1.5(19 ) 75 Sanitized. Does no'i contain TSCA CBi comply H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 9 (CONTINUED) MEAN DAILY FOOD CONSUMPTION (g) BY FEMALE RATS One-Month Recovery Period II Group 0 mg/ kg/day Group VI 10 mg/kg/day" Group VTII 60 Big/kg/day" Grovip x 300 nig/kg/day" DAYS 8 DAY105 DAY113 DAY119 20 .2 3 .3 (15 ) 20 .7 3 .8(15 ) 21 .0 2 .9(15 ) 20 .5 2 .9 (15 ) 20.3 4.5(5 ) 21.8 2.3(5 ) 23.2 2.2(5 ) 21.4 1.7(5 ) 19.9 2.7(5 ) 21.2 3.0(5 ) 22.8 3.6(5 ) 21.1 2.0(5 ) 19. 9 2. 2(14 ) 21. 0 2. 0(14 ) 21. 5 2. 0(14 ) 21. 2 2. 3(14 ) DAY91-DAY119 20 .6 2 .9(15 ) 21.7 2.4(5 ) 21.3 2.5(5 ) Data summarized as: Mean Standard Deviation (n) 20. 9 1. 9(14 ) b. On test day--84, food consumption data were inadvertently not collected for 5 rats/group designated for 3-month recovery. There were no statistically significant differences at p < 0.05 by JonckheereTerpstra trend test. Group IV (isopropanol control) was excluded from trend comparisons. II There were no statistically significant differences between Groups at p < 0.05 by pairwise comparisons. and IV 76 Comoany Sanitized. Does not c^a'n TSCA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE?10 MEA^ID^ULYFOOD EFI^ICIENCY ( )FIvIALERATS1 (; body weightgaim/g food coi1SUIned) Dosing PeriocI Group I 0 mg/kg/dciy DAYO-DAY7 DAY7-DAY15 DAY15-DAY21 DAY21-DAY28 DAYS 8-DAYS 5 DAY35-DAY42 DAY42-DAY49 DAY49-DAY56 DAY56-DAY63 DAY63-DAY70 DAY70-DAY77 DAY77-DAY84 b DAY84-DAY91 0.288 0.031(25 ) 0.229 0.029(25 ) 0.197 0.029(25 ) 0.151 0.021(25 ) 0.127 0.036(25 ) 0.093 0.029(24 ) 0.105 0.027(24 ) 0.097 0.025(24 ) 0.004 0.294(24 ) 0.093 0.098(24 ) 0.064 0.040(24 ) 0.043 0.032(19 ) 0.051 0.042(24 ) III Group 60 mg/kg/clay Isopropanc?1 0.299 0.025(10 ) 0.237 0.031(10 ) 0.200 0.018(10 ) 0.145 0.029(10 ) 0.141 0.029(10 ) 0.048 * 0.037(10 ) 0.118 0.023(10 ) 0.101 0.016(10 ) 0.079 0.025(10 ) 0.089 0.017(10 ) 0.034 @ 0.019(10 ) 0.049 0.029(10 ) 0.039 0.061(10 ) Group V Group VII Group IX 10 mg/kg/cisy"[ 60 mg/kg/clay3 300 mg/kgj'day8 0.288 0.029(15 ) 0.232 0.035(15 ) 0.212 0.037(15 ) 0.152 0.028(14 ) 0.144 0.027(15 ) 0.081 0.049(15 ) 0.085 0.028(15 ) 0.107 0.028(15 ) 0.081 0.043(15 ) 0.056 0.013(15 ) 0.066 0.022(15 ) 0.048 0.033(10 ) 0.042 0.031(15 ) 0.265# 0.031(15 ) 0.229 0.029(15 ) 0.190 0.035(15 ) 0.149 0.041(15 ) 0.144 0.023(15 ) 0.049# 0.035(15 ) 0.099 0.042(15 ) 0.100 0.029(15 ) 0.082 0.040(15 ) 0.056 0.040(15 ) 0.057 0.026(15 ) 0.042 0.029(10 ) 0.029 0.044(15 ) 0.269# 0.037(25 ) . 0.212 0.040(25 ) 0.183# 0.041(25 ) 0.159 0.032(25 ) 0.136 0.037(25 ) 0.046# 0.049(25 ) 0.091 0.035(25 ) 0.097 0.029(25 ) 0.048 0.066(24 ) 0.081 0.035(24 ) 0.050 0.026(24 ) 0.047 0.029(19 ) 0.031# 0.041(24 ) DAYO-DAY91b 0.123 0.008(19 ) 0.122 0.011(10 ) 0.124 0.011(9 ) 0.118 0.011(10 ) 0.113# 0.010(19 ) Company Sanitised. Does not contain TSCA GBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 10 (CONTINUED) MEAN DAILY FOOD EFFICIENCY OF MALE RATS (g body weight gain/g food consumed) One-Month Recovery Period Group I 0 mg/kg/day Group V 10 mg/kg/day" Group VII 60 nig/kg/day'1 Group IX 300 mg/kg/day" DAY91--DAY98 DAY98-DAY105 DAY105-DAYH3 DAY113-DAY119 0 .018 0 .074(15 ) 0 .069 0 .024(15 ) 0 .016 0 .123(15 ) 0 .058 0 .076(15 ) 0 .008 0 .049(5 ) 0 .072 0 .038(5 ) 0 .068 0 .016(5 ) 0 .038 0 .049(5 ) 0. 027 0. 049(5 ) 0. 065 0. 021(5 ) 0. 024 0. 054(5 ) 0. 040 0. 046(5 ) 0 .057# 0 .070(14 ) 0 .085 0 .032(14 ) 0 .081ft 0 .032(14 ) 0 .043 0 .023(14 ) DAY91- -DAY119 0 .042 0 .026(15 ) 0 .048 0 .030(5 ) 0. 039 0. 030(5 ) Data summarized as: Mean Standard Deviation (n) 0 069# 0 .018(14 ) b. On test day4, food consumption data were inadvertently not collected for 5 rats/group designated for 3-month recovery. III # Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. Group (isopropanol control) was excluded from trend comparisons. * Statistically significant difference from control (Group I) at p < 0.05 by Dunnett's test. @ Statistically significant difference from control (Group I) at p < 0.05 by Dunn's test. 78 Company Sanitized. Caasi i.J. s...ia;ii '^-A Mi H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLEill MEAN DAlLYFOODEFPHCIENCY OF FE1^ALERATS (&; body weight gain/g food consumed) Dosing Periodl I I G r o u p 0 mg/kg/day DAYO-DAY7 DAY7-DAY15 DAY15-DAY21 DAY21-DAY28 DAY28-DAY35 DAY35-DAY42 DAY42-DAY49 DAY49-DAY56 DAY56-DAY63 DAY63-DAY70 DAY70-DAY77 DAY77-DAY84 b DAY84-DAY91 0.159 0.049(25 ) 0.139 0.033(25 ) 0.110 0.054(25 ) 0.083 0.039(25 ) 0.077 0.053(25 ) 0.057 0.053(25 ) 0.065 0.038(25 ) 0.060 0.041(25 ) 0.015 0.056(25 ) 0.054 0.043(25 ) 0.030 0.038(25 ) 0.038 0.052(20 ) -0.010 0.053(25 ) DAYO-DAY91 b 0.070 0.009(20 ) Group IV 60 nig/kg/day Isopropanol 0.129 0.083(10 ) 0.149 0.035(10 ) 0.104 0.070(10 ) 0.108 0.034(10 ) 0.054 0.052(10 ) 0.045 0.058(10 ) 0.060 0.044(10 ) 0.059 0.021(10 ) -0.011 0.075(10 ) 0.077 0.033(10 ) 0.028 0.034(10 ) 0.047 0.040(10 ) -0.007 0.039(10 ) Group VI 10 mg/kg/day8 0.131 0.040(15 ) 0.118 0.043(15 ) 0.109 0.059(15 ) 0.078 0.046(15 ) 0.097 0.038(15 ) 0.029 0.056(15 ) 0.041 0.045(15 ) 0.058 0.036(15 ) 0.020 0.055(15 ) 0.038 0.038(15 ) 0.025 0.045(15 ) 0.036 0.033(10 ) 0.022 0.051(15 ) Group VIII 60 mg/kg/day 0.149 0.040(15 ) 0.129 0.045(15 ) 0.109 0.079(15 ) 0.107 0.048(15 ) 0.086 0.038(15 ) 0.046 0.056(15 ) 0.053 0.051(15 ) 0.072 0.054(15 ) 0.024 0.061(15 ) 0.018 0.076(15 ) 0.033 0.044(15 ) 0.054 0.048(10 ) 0.012 0.047(15 ) Group X 300 nig/kg/ day3 0.135 0.049(24 ) 0.138 0.034(24 ) 0.090 0.060(24 ) 0.104 0.058(24 ) 0.086 0.046(24 ) 0.053 0.045(24 ) 0.045 0.037(24 ) 0.103 0.156(24 ) 0.001 0.178(24 ) 0.061 0.038(24 ) 0.005# 0.032(24 ) 0.033 0.043(19 ) 0.020# 0.065(24 ) 0.066 0.009(10 ) 0.063 0.006(10 ) 0.069 0.012(10 ) 0.069 0.008(19 ) 79 Company SainWzed, Paes no? eontatn TSCA CBl H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 11 (CONTINUED) MEAN DAILY FOOD EFFICIENCY OF FEMALE RATS (g body weight gain/g food consumed) One-Month Recovery Period Group IX 0 lag/kg/day Group VI 10 ing/kg/day' Group VIII 60 ing/kg/day" Group X 300 rag/kg/day" DAY91-DAY98 DAY98-DAY105 DAY105-DAY113 DAY113-DAY119 0 .070 0 .066(15 ) 0 .048 0 .039(15 ) 0 .023 0 .024(15 ) 0 .030 0 .069(15 ) 0 .004 0 .084(5 ) 0 .119 0 .075(5 ) 0 .036 0 .030(5 0 .002 0 .030(5 ) -0. 003 0. 096(5 ) 0. 079 0. 040(5 ) 0. 029 0. 058(5 ) -0. 005 0. 076(5 ) 0 .046 0 .052(14 ) 0 .039 0 .048(14 ) 0 .041 0 .037(14 ) 0 .040 0 .078(14 ) DAY91-DAY119 0 .044 0 .023(15 ) 0 .045 0 .013(5 ) 0. 029 0. 032(5 ) 0 .043 0 .027(14 ) Data summarized as: Mean ^ Standard Deviation (n) a. H-24678 -i-sJ|UUBHBH||BU^1^^H^^^^W| b. On test day 84, food consumption data were inadvertently noc collected for 5 rats/group designated for 3-month recovery. # Statistically significant difference at p < 0.05-by Jonckheere-Terpstra trend test. Group IV (isopropanol control) was excluded from trend comparisons. II There were no statistically significant differences between Groups at p < 0.05 by pair-wise comparisons. and IV 80 Company Sanitized. Does not contain TSCA CBi- H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 12 SUMMARY OF CLINICAL OBSERVATIONS OP MALE RATS Treatment Group Dose Animal Count I 0 nig/kg/day 25 III 60 mg/kg/day V 10 ing/kg/day VII 60 mg/kg/day'1 300 Isopropanol 10 15 15 Mass Inguen Left Mass #1 Not Ulcerated Incidence Mean onset (Days) Eye Observations Corneal Opacity Incidence Mean onset (Days) Exophthalmus Incidence Mean onset (Days) Enophthalmus/'Partially Closed Scab Head Incidence Mean onset (Days) Incidence Mean onset (Days) - 88 - - 0100 _ - - 105 0 0002 - 0- .0- 1 81 - - - 74 0001 - - 84 - 0 0 1 0 81 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 12 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS OF MALE RATS Treatment Group Dose Animal Count General Teeth Observations Broken Incidence Mean onset (Days) I 0 mg/kg/day 25 0 III 60 ing/kg/day V 10 mg/kg/day51 VII 60 ing/kg/day3 300 Isopropanol 10 15 15 Discharge Eye Black Incidence Mean onset (Days) Nose Incidence 1 Mean onset (Days) 49 Mouth 1 2 147 58 1 98 Penis Red Incidence Mean onset (Days) Incidence 1 Mean onset (Days) 98 82 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 12 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS OF MALE RATS Hair Loss Treatment Group Dose Animal Count I 0 mg/kg/day 25 60 III mg/kg/day V 10 mg/kg/day8 VII 60 mg/kg/day'1 300 Isopropanol 10 15 15 Incidence 0 2 2 5 # Mean onset (Days) - 58 70 41 Wound Superficial Incidence Mean onset (Days) - - 72 67 Hyperreactive Incidence 0022 Mean onset (Days) 38 56 53 - 3 Aggressive Behavior 3 2 2 0 7 1B ^ Incidence W Mean onset (Days) 56 ' - RT Misshapen Observations & Ear a Left 1000 Q 0 1 ^ Incidence 0 0 Q Mean onset (Days) - - - 56 s 0 a S 3T W-i ^ 0 83 Of H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TAB>LE 12 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS OP MAJLERATS Treatment Group Dose Animal Count I 0 mg/kg/day 25 III 60 mg/kg/day Isopropanol 10 V 10 mg/kg/day8 15 VII 60 mg/kg/day3 15 300 m Protrusion Umbilical Hernia Incidence 1 0 0 0 Mean onset (Days) 49 Stain Fur/S.kin Incidence 0 Mean onset (Days) 1 1 1 84 175 35 Swollen Obs ervations Nose 1 0 Incidence 0 0 0 1 o Mean onset (Days) 66 Incidence - The number of animals for which an observation was recorded. (a3ft Mean onset (Days) - The mean of the first test day an observation was rec;ord<3d for that grovip ^. -T a. a. H-24678 ? # Statistic ally significant difference'at p < 0.05 by Cochran-Armitage ti-end test. GrouP 13:I A control) wa s excluded from trend comparisons. III 1 There were no statistically significant differences between. Groups I and at p < 0.05 by F a. test. s ^ea. a 3' s 0 > 0 s 84 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 13 SUMMARY OF CLINICAL OBSERVATIONS OF FEMALE RATS Treatment Group Dose Animal Count II 0 mg/kg/day 25 IV VI VIII 60 mg/kg/day 10 mg/kg/day81 60 mg/kg/day" 300 Isopropanol 10 15 15 Mass Perineum Mass #1 Not Ulcerated Incidence Mean onset (Days) Eye Observations Dark Right Incidence Mean onset (Days) Pale Right Incidence Mean onset (Days) Corneal Opacity Incidence Mean onset (Days) - - 154 0010 98-98 - 3 0 1 0 63 - - - 15000130 81 - 126 98 85 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 13 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS OF FEMALE RATS Treatment Group Dose Animal Count II 0 mg/kg/day 25 IV VI VIII 60 mg/kg/day 10 mg/kg/day'1 60 ing/kg/day" 300 Isopropanol 10 15 15 Exophthalmus Incidence Mean onset (Days) Enophthalmus/Partially closed Closed Incidence Mean onset (Days) Incidence Mean onset (Days) Scab Head Incidence Mean onset (Days) General Teeth Observations Clipped Incidence Mean onset (Days) 93 - 3 0 1 3 140 - 2012 - - 0011 - _ 01000000 34 - 98 113 147 - 100 97 35 - 86 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 13 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS OF FEMALE RATS Treatment Group Dose Animal Count II 0 mg/kg/day 25 IV VI VIII 60 mg/kg/day 10 mg/kg/day'1 60 mg/kg/day'' 300 Isopropanol 10 15 15 Discharge Eye Nose Black Incidence Mean onset (Days) Incidence Mean onset (Days) 2 1 1 3 119 49 98 86 0 0 0 0 - - - - . Hair Loss Incidence Mean onset (Days) 73 46 58 60 3 Q Wound < Superficial W) S 5231 Incidence K Mean onset (Days) 70 - - 62 as & c Hyperreactive SB Incidence 1001 | Mean onset (Days) - 84 - - 0 c ta8-. 3 0 1 0 0 ^aj 0 > 0 C3 87 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 13 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS OF FEMALE RATS Treatment Group Dose Animal Count II 0 mg/kg/day 25 IV VI VIII 60 mg/kg/day 10 mg/kg/day 60 nig/kg/day'1 300 Isopropanol 10 15 15 Hyperactive Incidence Mean onset (Days) 56 63 - 77 Misshapen Observations Ear Right 1 3 0 1 Incidence Mean onset (Days) - - 28 Stain Pur/Skin Head Brown 0010 0 Incidence 1 0 0 0 "g Mean onset (Days) 182 < w ta s: N" & 0 vs 3 0 =g< 3, SB 5" $en 8 ______________________________________8_8 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 13 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS OF FEMALE RATS Treatment Group Dose Animal Count Swollen Observations Pace II . 0 nig/kg/day 25 IV 60 mg/kg/day Isopropanol 10 VI 10 mg/kg/day" 15 VIII 60 mg/kg/day'1 300 15 Incidence 2 1 Mean onset (Pays) 106 105 incidence - The number of animals for which an observation was recorded. Mean onset (Days) - The mean of the first test day an observation was recorded for that grou III There were no statistically significant differences at p < 0.03 by Cochran-Armitage trend te Group (isopropanol control) was excluded from trend comparisons. There were no statistically significant differences from control (Group II) at p < 0.05 by F test. 89 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 14 SUMMARY OP OPHTHALMOLOGICAL OBSERVATIONS FOR MALE RATS Treatment Group Dose Number of Rats Examined 0 mg/kg/day 19 Examination Day : Test Day 81 Retina Retinal Degeneration Focal Left Incidence 1 ( 5%) 60 III mg/kg/day 10 V VII 10 mg/kg/day' 60 mg/kg/day' 30 10 10 1 ( 10%) 0 ( 0%) Incidence - The number of animals (percent of animals examined) for which an observation was There were no statistically significant (isopropanol control) was excluded from There were no statistically significant test. differences at p < 0.05 by trend comparisons. differences between. Groups Cochran-Armitage I and III at p < trend tes 0.05 by F 90 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 15 SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR FEMALE RATS Treatment Group Dose Mumber of Rats Examined II 0 nig/kg/day 20 Examination Day : Test Day 81 Retina Retinal Degeneration Focal Right Incidence 0(0%) III 60 mg/kg/day 10 0(0%) VI VIII 10 mg/kg/day" 60 mg/kg/day'1 30 10 10 0 ( 0%) 0(0%) Incidence - The number of animals (percent of animals examined) for which an observation was There were no statistically significant (isopropanol control) was excluded from There were no statistically significant test. differences at p < 0.05 by trend comparisons. differences between Groups Cochran-Armitage II and IV at p < trend tes 0.05 by F 91 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 Days on Test 0 7 15 21 28 35 42 49 56 63 70 77 84 91" 98 c 105 113 119 TABLE 16 PERCENT SURVIVAL OF MALE RATS III Group I CSroup Group V Group VII Group IX 0 mg/kg /day 60 nig/kg/day 10 mg/ kg/day" 60 rng/k:g/day*1 300 m g/kg/day" Is<)propanol 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 96 100 100 100 100 96 100 100 100 100 96 100 100 100 100 96 100 100 100 100 96 100 c 100 100 93 100 100 100 93 100 100 100 93 100 100 100 93 Number at study start 25 10 15 15 25 Accidentally Killed 1 0 0 0 0 Found Dead 0 0 0 0 1 Sacrificed by design 9 10 10 10 10 Alive on test day 119 15 0 5 5 14 . Percent Survival = (AE/Number of rats at risk)*100 Number of rats at risk = Number at study start - number of rats accidentally killed - number sacrificed by design^____ c. Rats designated for the 90-day exposure period were sacrificed on test days 92. There were no rats designated for recovery in Group III. III There were no statistically significant decreases in survival at p < 0.05 by Cochran-Annitage trend test. Group (isopropanol control) was excluded from trend comparisons. There were no statistically significant differences between Groups I and III at p < 0.05 by Fisher's Exact test. 92 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 Days on Test 0 7 . 15 21 28 35 42 49 56 63 70 77 84 91 b 98 c 105 113 119 TABLE 17 PERCENT SURVIVAL OF FEMALE RATS I I Groul3 0 mg/kg/'day Group IV 60 i ng/kg/day 10 Is<ipropanol Group VI mer/kg/day8 60 G!roup VIII mer/kg/day8 300 Group X me^/kg/day" 100 100 100 100 100 100 100 100 100 96 100 100 100 100 96 100 100 100 100 96 100 100 100 100 96 100 100 100 100 96 100 100 100 100 96 100 100 100 100 96 100 100 100 100 96 100 100 100 100 96 100 100 100 100 96 100 100 100 100 96 100 100 100 100 96 100 100 100 100 96 100 c 100 100 93 100 100 100 93 100 100 100 93 100 100 100 93 Number at study start 25 10 15 Pound Dead 0 0 0 Sacrificed by design 10 10 10 Alive on test day 119 15 0 5 Percent Survival = (AE/Mumber of rats at risk)*100 Number of rats at risk = Number at study start 15 25 0 1 10 10 5 14 number sacrificed by b. Recovery period began on test day9^^ c. Rats designated for the 90-day exposure period were sacrificed on test days 93. There were no statistically significant decreases in survival at p < 0.05 Cochran-Annitage trend test. Group IV (isopropanol control) was excluded trend comparisons. There were no statistically significant differences between Groups II and at p < 0.05 by Fisher's Exact test. by from IV 93 Company Sanltl^-D0681 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 18 MEAN FOREUMB AND HINDUMB GRIP STRENGTH FOR MALE RATS (MEAN OF THREE TRIALS) Assessment Period Group Dosage (mg/kg/day) Forelimb Grip Strength (kg) Hindlimb Grip Strength (kg) Baseline I 0 (control) m 60 (Isopropanol) v 103 vn 60a K 300s1 0.64 (0.09) 0.62 (0.11) 0.65 (0.13) 0.65 (0.13) 0.66 (0.07) 0.28 (0.05) 0.31 (0.06) 0.28 (0.09) 0.29 (0.09) 0.31 (0.08) Week 13 I 0 (control) ffl 60 (Isopropanol) V Iff vn 60a DC 300' 1.31 (0.36) 1.43 (0.38) 1.47 (0.17) 1.18 (0.18) 1.31 (0.33) 0.43 (0.08) 0.50 (0.15) 0.48 (0.09) 0.46 (0.10) 0.38 (0.09) Data arranged as: Mean (Standard Deviation) H-24678isBH^H------------------^B^H^^^B/ a. j^^^^^^^^^^^^^^^^^^^^^^B^------^--------------^^^1------^^^^^^^^^rB There were no statistically significant differences from control by one-way analysis of variance followed by Dunnett's test; p < 0.05. 94 Company Sanitized. Does not contain TSCA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 19 MEAN PORELIMB AND fflNDUMB GRIP STRENGTH FOR FEMALE RATS (MEAN OP THREE TRIALS) Assessment Period Group Dosage (mg^kg/day) Forelimb Grip Strength (kg) Hindlimb Grip Strength (kg) Baseline H IV VI Vffl X 0 (control) 60 (Isopropanol) 10" 60'' 30tf 0.59 (0.16) 0.50 (0.15) 0.49(0.11) 0.64 (0.15) 0.60 (0.11) 0.29 (0.08) 0.26 (0.08) 0.30 (0.06) 0.28 (0.07) 0.29 (0.08) Week 13 n IV VI Vin O (control) 60 (Isopropanol) lO" 60a 1.15(0.42) 1.06 (0.21) 1.07 (0.22) 1.10 (0.27) 0.46 (0.14) 0.39 (0.06) 0.43 (0.04) 0.47 (0.13) _X______300"_______1.01 (0.29) Data arranged as: .Mean (StandardDgyjation). 0.35 (0.06) a. H-24678 is There were no statistically significant differences from control by one-way analysis of variance followed by Dunnett's test; p < 0.05. 95 Company Sanitized. Does noi contain TSCA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 20 SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR MALE RATS Baseline ' Group: I ffl V VD IX Dosage (mg/kg/day): 0 60 10s 60 300s Number Examined: 10 10 10 10 10 Week 13 i m v vn x 0 60 10 60 300 10 10 10 10 91' APPROACH & TOUCH: no reaction normal increased reaction (jumps away or attacks) AUDITORY STIMULUS: no reaction normal reaction (rat flinches or flicks ear) exaggerated reaction (rat jumps, flips) TAIL PINCH: no response normal (turns toward site) exaggerated response 0000000000 10 10 10 10 10 00001 10 10 10 10 9 OOOOO 0 0 0 0 0 10 10 10 10 10 0 0 0 0 0 0000000000 10 10 10 10 9 0000000000 10 10 10 10 9 0 1 0 10 9 10 0 0 0 IN MOTOR ACTIVITY MONITOR: DEFECATION; present absent diarrhea URINATION: present absent 2O82O83O72O828O 10 0 PUPILLARY RESPONSE: present 10 10 10 10 10 absent 0 000 0 a. b H-24678 One rat dieiodp_ri_o_r t_o_th_e w_e_ek_1_3 _ev_al_ua_tio_n_. 7O38O24O62O83O6 10 10 10 000 10 10 10 10 0 0 0 0 There were no statistically significant differences by Cochran-Annitage test for trend; p < 0.05. 96 Sanitized. Dees not eanla'sn T8CA CBS Company H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 21 SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR FEMALE RATS Group: Dosage (mg/kg/day): Number Examined: Baseline n iv vi vm x 0 60 10 60' 300" 10 10 10 10 10 Week 13 n rv vi vm x 0 60 10 60' 300' 10 10 10 10 9" APPROACH & TOUCH: no reaction normal increased reaction (jumps away or attacks) AUDITORY STIMULUS: no reaction normal reaction (rat flinches or flicks ear) exaggerated reaction (rat jumps, flips) TAIL PINCH: no response normal (turns toward site) exaggerated response IN MOTOR ACTIVITY MONITOR; DEFECATION: present absent diarrhea URINATION: present absent 0 0 0 0 0 10 10 10 10 10 OOOOO 00010 10 10 10 9 10 OOOOO 0 0 0 0 0 10 10 10 10 10 0 0 0 0 0 46O2O83O74O64O6 0000000000 10 10 10 10 9 OOOOO 10 10 10 10 9 OOOOO 0 0 0 1 0 10 10 10 9 9 0 0 000 7O38O23O76O44O5 10 10 10 0 0 0 PUPILLARY RESPONSE: present absent 10 10 10 10 10 OOOOO 10 10 10 10 0000 a. H-24678 isl b One rat died prior to the w_ee_k_13 evaluation. There were no statistically significant differences by Cochran-Armitage test for trend; p < 0.05. 97 Company Sanitized. Does noi contain TSCA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 22 MOTOR ACTIVITY ASSESSMENT: MEAN DURATION OF MOVEMENTS (sec) FOR MALE RATS ASSESSME1W PERIOD GROUP N DOSAGE (mg/kg/day) BASELINE I 10 0 (control) III 10 60 (Isopropanol) V 10 10s VII 10 60' IX 10 300' WEEK 13 I 10 0 (control) III 10 60 (Isopropanol) V 10 10' VII 10 IX 9" 60' 300 Data arranged as: Mean (Standard Deviation). ]. 399(61) 407(43) 397(78) 408(62) 395(28) 1 419(55) 408(36) 385(36) 415(36) 395(44) SUCCESSIVE 10-MINUTE INTERVALS 2 347(50) 326(49) 294(82) 353(53) 306(53) 3 262(69) 258(86) 210(110) 255(89) 268(109) 4 151(117) 135(133) 124(106) 130(145) 135(121) 5 124(134) 51(85) 91(104) 102(93) 55(63) 6 27(4 28(6 42(6 32(5 31(5 2 . 323(111) 334(55) 304(40) 337(37) 331(49) 3 322(80) 295(52) 261(104) 314(50) 318(53) 4 271(97) 259(61) 200(69) 251(112) 239(91) 5 190(116) 215(92) 207(74) 217(113) 192(120) 6 158(1 177(1 175(1 149(9 129(1 Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Repeated measures analysis of variance with linear contr used to identify which dosage groups, if any, were significantly different from the control group. These tests were applied to bin d total data. There were no statistically significant differences from control; p < 0.05. 98 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 23 MOTOR ACTIVITY ASSESSMENT: MEAN DURATION OF MOVEMENTS (sec) FOR FEMALE RATS ASSESSMENT PERIOD GROUP N DOSAGE (mg/kg/day) BASELINE II 10 0 (control) IV 10 60 (Isopropanol) VI 10 10 VIII 10 60" X 10 300 WEEK 13 II IV VI VIII X 10 0 (control) 10 60 (Isopropanol) 10 10s 10 60 9" 300" Data arranged as: Mean (Standard Deviation). SUfCCESSIVE 10-MINUTIiINTERVAlLS 1 386(34) 363(64) 384(42) 377(69) 376(73) 2 262(68) 291(92) 293(71) 280(111) 307(77) 3 232<76) 270(100) 249(81) 257(141) 229(93) 4 197(59) 229(112) 233(85) 239(84) 242(91) 5 153(97) 228(119) 184(82) 180(94) 177(80) 6 142(12 216(12 150(10 131(10 131(90 1 402(38) 431(74) 411(43) 394(64) 389(75) 2 307(61) 356(113) 338(54) 320(93) 302(109) 3 244"(55) 273(148) 271(62) 279(103) 250(126) 4 226(31) 239(140) 220(98) 262(129) 190(128) 5 210(97) 245(163) 164(101) 218(127) 165(151) 6 157^( 219(99 139(13 170(11 124(15 Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Repeated measures analysis of variance with linear con used to identify which dosage groups, if any, were significantly different from the control group. These tests were applied to bin total data. There were no statistically significant differences from control; p < 0.05. 99 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 24 MOTOR ACTIVITY ASSESSMENT: MEAN NUMBER OP MOVEMENTS FOR MALE RATS ASSESSMENT PERIOD GROUP N DOSAGE (mg/kg/day) BASELINE I 10 0 (control) III 10 60 (Isopropanol) V 10 10 VII 10 IX 10 60 300 WEEK 13 I 10 0 (control) III 10 60 (Isopropanol) V 10 10 VII 10 IX 9" 60" 300' Data arranged as: Mean (Standard Deviation). SUCCESSIVE 10-MINUTI1 INTERVALS 1 121(18) 135(12) 118(31) 127(20) 138(13) 2 136(10) 141(16) 120(28) 139(12) 138(20) 3 134(30) 133(32) 100(49) 130(18) 127(26) 4 91(53) 79(66) 76(61) 67(68) 84(63) 5 74(55) 38(51) 49(50) 65(54) 44(49) 6 21(25) 20(40) 31(44) 23(24) 26(40) 1 133(25) 140(11) 132(6) 131(16) 134(16) 2 130(22) 137(17) 127(17) 137(19) 135(19) 3 139(21) 136(19) 120(43) 139(18) 136(20) 4 126(17) 127(28) 106(30) 125(40) 115(44) 5, 100(51) 112(42) 110(33) 115(52) 88(56) 6 80(54) 105(46) 99(57) 89(57) 82(58) Statistical Methods; Shapiro-Wilk's and Levene's tests were performed. Repeated measures analysis of variance with linear contra used to identify which dosage groups, ifiiny, were significantly different from the control group. These tests were applied to bin da total data. There were no statistically significant differences from control; p < 0.05. 100 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 25 MOTOR ACTIVITY ASSESSMENT: MEAN NUMBER OF MOVEMENTS FOR FEMALE RATS ASSESSMEN'r PERIOD GROUP' N BASELINE II 10 IV 10 VI 10 VIII 10 x 10 DOSAGE (mg/kg/day) 0 (control) 60 (Isopropanol) 10" GO' 300" WEEK 13 II IV VI VIII x 10 0 (control) 10 60 (Isopropanol) 10 10" 10 60 9" 300 Data arranged as: Mean (Standard Deviation). |||BHtfBHl|IIL a. H-24678 is b One rat diedprior to the week 13 evaluation. 1 135(16) 128(16) 135(18) 133(17) 119(21) 1 132(10) 127(23) 132(9) 136(14) 130(32) <SUCCESSIVIi 10-MINin'EINTERV^\LS 2 132(20) 123(19) 131(19) 131(32) 117(27) 3 123(26) 125(33) 122(26) 109(44) 105(27) 4 125(37) 118(15) 121(36) 135(19) 111(24) . 93(50) 111(39) 111(34) 114(51) 103(30) & 82(52 112(43) 101(51) 84(49) 80(52) 2 133(15) 129(27) 138(9) 123(17) 131(34) 2 131(18) 122(38) 136(21) 127(39) 127(30) 4 133(14) 111(46) 126(45) 113(41) 116(25) . 122(37) 114(50) 100(41) 103(44) 101(50) 6 99(26) 119(27) 87(62) 108(42) 80(48) Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Repeated measures analysis of variance with linear contra Juw/oeftnrepckanhpnenpellriioee/'d1s +tt/or*elbn^idin^ td/e4a/s>tt*a"wa^e--nr-dea Atuo--stea^dlI dt3oa-t'iad. entify which dosage groups, if any, were significantly different from the controlI group. Thes There were no statistically significant differences from control; p < 0.05. 101 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 26 SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS TEST/ PERIOD Group I 0 mg/kg/day Group ffl 60 mg/kg/day Isopropanol Group V 10 mg/kg/day' Group Vn 60 nig/kg/day" Group DC 300 ing/kg/day' RBC (x!0%lL) DAY 38 DAY 92 DAY 122 DAY 183 HGB (g/dL) DAY 38 DAY 92 DAY 122 DAY 183 HCT (%) DAY 38 DAY 92 DAY 122 DAY 183 MCV (fl) DAY 38 DAY 92 DAY 122 DAY 183 8.07 0.46(7) 8.41 0.38(9) 8.94 0.31(10) 8.87 0.32(4) 15.2 0.7(7) 15.2 0.4(9) 15.5 0.6(10) 15.6 0.3(4) 47.6 2.4(7) 47.4 1.8(9) 47.6 1.6(10) 48.4 1.0(4) 59.0 1.5(7) 56.4 1.1(9) 53.2 0.7(10) 54.6 1.0(4) 8.39 0.35(8) 8.51 0.70(10) b b 15.3 0.4(8) 15.0 1.1(10) b b 48.5 2.1(8) 47.1 2.9(10) b b 57.8 0.7(8) 55.5 2.0(10) b b 8.14 0.37(10) 8.29 0.43(10) b 8.61 0.29(5) 15.0 0.5(10) 14.5 0.5(10) b 15.1 0.5(5) 47.4 1.9(10) 45.7 1.8(10) b 47.6 1.3(5) 58.4 2.0(10) 55.2 1.6(10) b 55.3 1.4(5) 7.97 0.18(10) 8.18 0.34(10) b 8.34 0.49(5) 14.8 0.4(10) 14.4@ 0.4(10) b 14.7 0.7(5) 46.6 0.9(10) 45.0* 1.3(10) b 45.5* 2.2(5) 58.4 0.8(10) 55.1 1.3(10) b 54.6 0.9(5) 7.75 0.47(9) 7.90 0.43(10) 8.09* 0.46(8) 8.64 0.21(4) 14.2* 0.6(9) 13.8 0.5(10) 14.5* 0.7(8) 14.4* 0.7(4) 44.7* 1.8(9) 43.0* 2.0(10) 44.5* 1.9(8) 45.1* 1.3(4) 57.7 2.1(9) 54.4* 1.8(10) 55.1* 1.7(8) 52.2 1.3(4) 102 Conwany SanVrod. Dow f^ eft-'ta1" ^CA CW H-24678: Subchromc Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 26 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I 0 mg/kg/day Group ffl 60 mg/kg/day Isopropanol Group V 10 nag/kg/day' Group Vn 60 nig/kg/day' Group IX 300 ing/kg/day' MCH(pg) DAY 38 DAY 92 DAY 122 DAY 183 MCHC (g/dL) DAY 38 DAY 92 DAY 122 DAY 183 RDW (%) DAY 38 DAY 92 DAY 122 DAY 183 ARET (xKP/fiL) DAY 38 DAY 92 DAY 122 DAY 183 18.8 0.4(7) 18.1 0.5(9) 17.3 0.5(10) 17.6 0.5(4) 31.8 0.5(7) 32.1 0.5(9) 32.5 0.7(10) 32.3 0.6(4) 11.3 0.4(7) 13.0 0.8(9) 13.5 0.8(10) 12.9 0.8(4) 186 13(7) 189 23(9) 183 28(10) 156 52(4) 18.2 0.3(8) 17.7 0.4(10) b b 31.5 0.6(8) 31.9 0.6(10) b b 11.4 0.8(8) 13.0 1.3(10) b b 189 41(8) 194 44(10) b b 18.4 0.6(10) 17.6 0.7(10) b 17.6 0.4(5) 31.6 0.6(10) 31.8 0.6(10) b 31.8 0.6(5) 11.5 0.3(10) 12.9 0.5(10) b 13.5 0.5(5) 198 37(10) 180 34(10) b 186 14(5) 18.5 0.4(10) 17.6 0.5(10) b 17.6 0.4(5) 31.7 0.5(10) 32.0 0.4(10) b 32.2 0.5(5) 11.5 0.6(10) 12.5 0.8(10) b 13.8 1.0(5) 182 31(10) 169 14(10) b 201 31(5) 18.3 0.6(9) 17.4 0.7(10) 17.9* 0.5(8) 16.7* 0.6(4) 31.8 0.4(9) 32.0 0.7(10) 32.6 0.6(8) 32.0 0.5(4) 11.6 0.5(9) 13.5 0.8(10) 13.4 0.4(8) 13.9 0.4(4) 196 27(9) 175 27(10) 190 26(8) 193 38(4) 103 comply Sanifeed- H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 26 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I 0 ing/kg/day Group ffl 60 mg/kg/day Isopropanol Group V 10 ing/kg/day' GroupVn 60 nig/kg/day' Group IX 300 nig/kg/day3 PLT (xlO^L) DAY 38 DAY 92 DAY 122 DAY 183 WBC (xKPy/xL) DAY 38 DAY 92 DAY 1-22 DAY 183 ANEU (xlO^L) DAY 38 DAY 92 DAY 122 DAY 183 ALYM (xlO^L) DAY 38 DAY 92 DAY 122 DAY 183 1173 69(7) 1155 62(9) 1048 134(10) 1001 169(3) 15.86 3.41(7) 12.76 2.71(9) 10.75 2.73(10) 11.63 3.15(4) 1.42 0.27(7) 1.63 0.46(9) 2.08 0.43(10) 1.63 0.45(4) 13.60 3.35(7) 10.48 2.47(9) 8.05 2.36(10) 9.42 2.83(4) 1184 149(6) 1110 141(9) b b 15.04 3.79(8) 13.11 3.54(10) b b 1.65 0.48(8) 2.18 1.42(10) b b 12.58 3.32(8) 10.11 2.43(10) b b 1122 100(9) 1092 117(10) b 1085 219(5) 16.37 2.84(10) 12.90 2.41(10) b 11.36 2.29(5) 1.81 0.70(10) 2.37 1.03(10) b 1.79 1.16(5) 13.61 2.33(10) 9.93 2.21(10) b 9.04 1.63(5) 1209 102(10) 1186 106(10) b 1011 126(4) 14.24 2.84(10) 12.23 2.69(10) b 11.75 2.78(5) 1.78 0.40(10) 2.23 0.82(10) b 2.43 1.14(5) 11.57 2.47(10) 9.36 2.10(10) b 8.65 1.68(5) 1313 127(7) 1242 138(9) 1101 140(8) 933 148(3) 16.98 1.39(9) 13.77 1.57(10) 11.50 2.80(8) 11.25 2.65(4) 1.97 0.45(9) 2.17 0.56(10) 2.11 0.56(8) 2.23 1.08(4) 13.96 1.66(9) 10.89 1.30(10) 8.80 2.25(8) 8.42 3.03(4) "eonnpany SanStIzad. 104 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 26 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I 0 nag/kg/day Group DI 60mg/kg/day Isopropanol Group V 10 nig/kg/day" Group VH 60 ing/kg/day' Group IX 300 mg/kg/day" AMON (xl(P//xL) DAY 38 DAY 92 DAY 122 DAY 183 AEOS (xKP/^L) DAY 38 DAY 92 DAY 122 DAY 183 ABAS (xlO^L) DAY 38 DAY 92 DAY 122 DAY 183 0.47 0.11(7) 0.23 0.08(9) 0.30 0.11(10) 0.29 0.16(4) 0.15 0.06(7) 0.14 0.07(9) 0.13 0.04(10) 0.13 0.06(4) 0.12 0.03(7) 0.16 0.07(9) 0.11 0.07(10) 0.09 0.04(4) 0.53 0.18(8) 0.37 0.20(10) b b 0.13 0.08(8) 0.14 0.06(10) b b 0.08 0.04(8) 0.16 0.08(10) b b 0.54 0.13(10) 0.26 0.11(10) b 0.21 0.07(5) 0.18 0.13(10) 0.11 0.06(10) b 0.16 0.07(5) 0.13 0.05(10) 0.10 0.06(10) b 0.07 0.03(5) 0.50 0.18(10) 0.29 0.10(10) b 0.31 0.13(5) 0.19 0.08(10) 0.16 0.06(10) b 0.18 0.15(5) 0.09 0.05(10) 0.08* 0.04(10) b 0.09 0.02(5) 0.63 0.21(9) 0.33 0.08(10) 0.28 0.08(8) 0.33 0.12(4) 0.22 0.13(9) 0.17 0.13(10) 0.12 0.06(8) 0.10 0.01(4) 0.11 0.05(9) 0.09 0.04(10) 0.09 0.04(8) 0.07 0.04(4) 105 CoWpsW Sanded. Po-^60"^' H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 26 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS TEST/ PERIOD ALUC (xKP/^L) DAY 38 DAY 92 DAY 122 DAY 183 Group I Omg/kg/day 0.09 0.02(7) 0.13 0.06(9) 0.08 0.03(10) 0.08 0.04(4) Group m 60 nig/kg/day Isopropanol Group V lOing/kg/day" Group Vn 60 mg/kg/day" 0.08 0.05(8) 0.16 0.09(10) b 0.10 0.04(10) 0.12 0.06(10) b 0.12 0.11(10) 0.10 0.04(10) b b 0.09 0.08 0.02(5) 0.02(5) Data arranged as: Mean Standard deviation (Number of values included in calculation) Group IX 300^lg/kg/daya 0.10 0.02(9) 0.12 0.05(10) 0.09 0.03(8) 0.09 0.02(4) b. Measurements for this group at this tfmepoint were not taken or not performed. * Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett). @ Statistically significant difference from control at p < 0.05 by nonparametric test (Dunn's). 106 Company Sanrth'ed """" ""fiwiain TSCA CR1 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 27 TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Group n 0 mg/kg/day Group IV 60 mg/kg/day Isopropanol Group VI 10 mg/kg/day" Group Vffl 60 mg/kg/day3 Group X 300 mg/kg/day3 RBC (xlO%iL) DAY 39 DAY 93 DAY 122 DAY 183 HGB (g/dL) DAY 39 DAY 93 DAY 122 DAY 183 HCT (%) DAY 39 DAY 93 DAY 122 DAY 183 MCV (fl) DAY 39 DAY 93 DAY 122 DAY 183 8.29 0.28(10) 8.24 0.45(10) 7.94 0.49(8) 8.48 0.28(4) 15.4 0.5(10) 15.4 0.8(10) 15.1 0.7(8) 15.8 0.4(4) 48.1 2.3(10) 46.9 2.5(10) 45.3 2.4(8) 48.6 1.5(4) 58.0 1.4(10) 57.0 1.6(10) 57.1 1.5(8) 57.3 1.5(4) 8.23 0.29(10) 8.20 0.49(10) b b 15.3 0.4(10) 15.2 0.8(10) b b 47.3 1.5(10) 46.4 2.7(10) b b 57.6 1.0(10) 56.6 0.9(10) b b 8.10 0.34(9) 8.14 0.36(10) b 7.96 0.22(3) 15.0 0.4(9) 15.1 0.5(10) b 14.7* 0.6(3) 47.0 1.3(9) 46.3 1.9(10) b 45.4* 1.4(3) 58.0 1.1(9) 56.9 0.7(10) b 57.0 0.2(3) 7.95 0.31(10) 8.06 0.30(10) b 8.11 0.36(4) 15.0 0.6(10) 15.2 0.5(10) b 15.7 0.2(4) 46.5 2.0(10) 46.2 1.4(10) b 47.9 1.8(4) 58.5 1.2(10) 57.4 1.5(10) b 59.2 1.4(4) 8.09 0.61(10) 7.84 0.52(10) 8.01 0.29(9) 8.38 0.46(5) 15.2 0.9(10) 14.8 0.7(10) 15.2 0.5(9) 15.4 0.6(5) 47.1 2.9(10) 45.0 2.6(10) 45.7 1.7(9) 47.3 1.4(5) 58.2 1.3(10) 57.5 1.2(10) 57.1 1.3(9) 56.5 1.8(5) 107 Company Sanitized. P""*-; ""< contain TSCA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 27 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Groupn 0 mg/kg/day Group IV 60 mg/kg/day Isopropanol Group VI 10 mg/kg/day3 Group Vffl 60 mg/kg/day2 Group X 300 nog/kg/day" MCH(pg) DAY 39 DAY 93 DAY 122 DAY 183 MCHC (g/dL) DAY 39 DAY 93 DAY 122 DAY 183 RDW (%) DAY 39 DAY 93 DAY 122 DAY 183 ARET (xKW/tL) DAY 39 DAY 93 DAY 122 DAY 183 18.6 0.4(10) 18.7 0.5(10) 19.0 0.6(8) 18.7 0.4(4) 32.1 0.5(10) 32.8 0.5(10) 33.2 0.8(8) 32.6 0.7(4) 11.1 0.5(10) 11.4 0.6(10) 12.1 0.6(8) 11.6 0.3(4) 192 36(10) 163 42(10) 151 22(8) 144 23(4) 18.6 0.4(10) 18.5 0.5(10) b b 32.3 0.3(10) 32.7 0.5(10) b b 10.9 0.3(10) 11.2 0.4(10) b b 188 20(10) 138 17(10) b b 18.5 0.4(9) 18.6 0.4(10) b 18.5 0.3(3) 31.9 0.4(9) 32.7 0.4(10) b 32.5 0.4(3) 11.2 0.2(9) 11.3 0.4(10) b 11.9 0.4(3) 183 21(9) 145 24(10) b 154 30(3) 18.8 0.5(10) 18.8 0.6(10) b 19.4 0.7(4) 32.2 0.4(10) 32.8 0.5(10) b 32.7 0.9(4) 11.2 0.3(10) 11.4 0.3(10) b 11.9 1.0(4) 193 32(10) 160 40(10) b 162 8(4) 18.9 0.7(10) 18.9 0.5(10) 18.9 0.5(9) 18.5 0.8(5) 32.4 0.5(10) 32.8 0.4(10) 33.2 0.6(9) 32.6 0.6(5) 11.0 0.3(10) 11.2 0.3(10) 11.9 0.6(9) 11.6 0.2(5) 198 27(10) 177 30(10) 171 22(9) 150 22(5) 108 Company Sanitized. Does not eonsain TSCA CBf H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 27 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Groupn 0 mg/kg/day Group IV 60 mg/kg/day Isopropanol Group VI 10 Dag/kg/day8 GroupVin 60 mg/kg/day' Group X 300 mg/kg/day" PLT (xlO^L) DAY 39 DAY 93 DAY 122 DAY 183 WBC (xlOV/riL) DAY 39 DAY 93 DAY 122 DAY 183 ANEmxIO^L) DAY 39 DAY 93 DAY 122 DAY 183 ALYM (xW/iiL) DAY 39 DAY 93 DAY 122 DAY 183 1122 102(8) 1100 67(8) 958 94(8) 815 160(4) 10.80 2.67(10) 8.90 1.50(10) 8.15 1.96(8) 7.35 0.99(4) 0.80 0.31(10) 1.22 0.49(10) 1.33 0.73(8) 1.32 0.52(4) 9.51 2.49(10) 7.16 1.09(10) 6.29 1.46(8) 5.55 0.69(4) 1156 151(9) 1047 126(8) b b 11.84 2.60(10) 8.89 1.34(10) b b 1.41* 0.55(10) 0.97 0.37(10) b b 9.81 2.08(10) 7.37 1.37(10) b b 1135 167(9) 1065 176(9) b 879 281(3) 11.08 1.77(9) 9.32 2.20(10) b 9.26 3.70(3) 1.21 0.51(9) 1.04 0.43(10) b 2.37 1.86(3) 9.12 1.64(9) 7.65 2.05(10) b 5.88 1.25(3) 1145 135(8) 1102 89(9) b 807 237(4) 12.66 4.24(10) 9.14 2.62(10) b 7.17 2.35(4) 1.35 0.57(10) 1.20 0.47(10) b 1.41 0.83(4) 10.64 3.78(10) 7.32 2.55(10) b 5.28 1.56(4) 1030 149(8) 960 105(8) 1061 126(9) 984 119(4) 13.00 1.99(10) 9.64 1.98(10) 9.83 1.52(9) 8.28 1.70(5) 1.52* 0.49(10) 1.53 0.64(10) 1.47 0.34(9) 1.33 0.48(5) 10.76 1.98(10) 7.64 1.38(10) 7.77* 1.18(9) 6.44 1.24(5) 109 Company Sanitized. Does not contain TSf: H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 27 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Group n 0 ing/kg/day Group IV 60 nig/kg/day Isopropanol Group VI 10 mg/kg/day" Group Vffl 60 ing/kg/day" Group X 300 mg/kg/day" AMON (xlO^L) DAY 39 DAY 93 DAY 122 DAY 183 AEOS (xKP/^iL) DAY 39 DAY 93 DAY 122 DAY 183 ABAS (xW/liL) DAY 39 DAY 93 DAY 122 DAY 183 0.22 0.09(10) 0.18 0.05(10) 0.26 0.12(8) 0.24 0.08(4) 0.12 0.10(10) 0.13 0.07(10) 0.11 0.03(8) 0.13 0.03(4) 0.07 0.06(10) 0.11 0.05(10) 0.09 0.07(8) 0.07 0.03(4) 0.29 0.07(10) 0.19 0.04(10) b b 0.13 0.04(10) 0.13 0.03(10) b b 0.09 0.05(10) 0.11 0.04(10) b b 0.39 0.34(9) 0.23 0.07(10) b 0.66 0.60(3) 0.12 0.05(9) 0.15 0.08(10) b 0.15 0.08(3) 0.10 0.04(9) 0.13 0.06(10) b 0.09 0.04(3) 0.28 0.10(10) 0.18 0.05(10) b 0.24 0.13(4) 0.17 0.07(10) 0.15 0.04(10) b 0.14 0.08(4) 0.10' 0.04(10) 0.15 0.06(10) b 0.05 0.01(4) 0.30 0.07(10) 0.18 0.10(10) 0.28 0.06(9) 0.25 0.10(5) 0.18 0.13(10) 0.12 0.06(10) 0.16* 0.04(9) 0.14 0.06(5) 0.11 0.06(10) 0.09 0.06(10) 0.08 0.03(9) 0.06 0.03(5) 110 Company Sanitized. DW.S ""t c^tam TSCA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 27 (Continued) SUMMARY OP HEMATOLOGY VALUES FOR FEMALE RATS TEST/ PERIOD ALUC (xKP/FiL) DAY 39 DAY 93 DAY 122 DAY 183 Group n Omg/kg/day 0.09 0.06(10) 0.09 0.03(10) 0.07 0.02(8) 0.05 0.01(4) Group IV 60 ing/kg/day Isopropanol 0.12 0.05(10) 0.12 0.09(10) b 1) Group VI 10 ing/kg/day" Group Vffl Group X 60 nag/kg/day0 300 mg/kg/day0 0.13 0.06(9) 0.12 0.02(10) b 0.11 0.07(3) 0.12 0.04(10) 0.14 0.08(10) b 0.06 0.02(4) 0.13 0.06(10) 0.09 0.06(10) 0.07 0.03(9) 0.05 0.02(5) Data arranged as: Mean Standard deviation (Number of values included in calculation) b. Measurements for this group at this timepoint were not taken or not performed. * Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett). Ill Company Sanitized. Does not contain TSCA CB8 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 28 TEST/ PERIOD SUMMARY OF COAGULATION VALUES FOR MALE RATS Group I 0 mg/kg/day Group ffl 60 mg/kg/day Isopropanol Group V Group Vn Group IX 10 ing/kg/day3 60 mg/kg/day' 300 mg/kg/day' PT (seconds) DAY 92 APTT (seconds) DAY 92 15.1 0.6(9) 19.0 1.2(9) 15.0 0.8(10) 19.4 1.7(10) 15.1 0.4(10) 19.0 2.1(10) 14.9 0.5(10) 18.2 1.7(10) 15.1 1.0(10) 17.6 2.7(10) Data arranged as: Mean Standard deviation (Number of values included in calculation) a. H-24678 is' There were no statistically significant differences from control at p < 0.05 by parametric (Dunnett/TamhaneDunnett) and non-parametric (Dunn's) tests. TABLE 29 TEST/ PERIOD SUMMARY OF COAGULATION VALUES FOR FEMALE RATS Group n 0 mg/kg/day Group IV 60 mg/kg/day Isopropanol Group VI Group vrn Group X 10 mg/kg/day' 60 mg/kg/day" 300 mg/kg/day3 PT (seconds) DAY 93 APTT (seconds) DAY 93 14.3 0.5(10) 16.8 1.6(10) 14.0 0.5(10) 17.2 1.4(10) 14.2 0.6(10) 17.3 1.6(10) 14.6 0.7(10) 16.3 1.5(10) 13.8 0.5(10) 16.3 2.1(10) Data arranged as: Mean Standard deviation (Number of values included in calculation) a. H-24678 is There were no statistically significant differences from control at p < 0.05 by parametric (Dunnett/TamhaneDunnett) and non-parametric (Dunn's) tests. 112 c.^s^."--""""13"061 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 30 SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group I 0 mg/kg/day Group ffl 60 mg/kg/day Isopropanol Group V Group VII Group IX 10 ing/kg/day' 60 mg/kg/day3 300 mg/kg/da/ AST (U/L) DAY 38 DAY 92 DAY 122 DAY 183 ALT (U/L) DAY 38 DAY 92 DAY 122 DAY 183 SDH (U/L) DAY 38 DAY 92 DAY 122 DAY 183 ALKP (U/L) DAY 38 DAY 92 DAY 122 DAY 183 86 18(9) 74 9(9) 89 13(10) 95 23(5) 31 5(9) 29 5(9) 37 9(10) 38 6(5) 20.8 7.3(9) 21.8 5.5(9) 14.8 2.0(10) 12.7 5.2(5) 134 31(9) 85 19(9) 87 35(10) 81 14(5) 90 21(10) 75 7(10) b b 34 4(10) 31 6(10) b b 19.2 5.3(10) 19.2 3.2(10) b b 144 31(10) 98 28(10) b b 90 15(10) 128@ 82(10) b 110 60(5) 34 8(10) 88@ 93(10) b 57 38(5) 20.7 9.9(10) 32.1 30.4(10) b 16.2 10.3(5) 139 25(10) 100 22(10) b 101 24(5) 138@ 50(10) 327@ 164(10) b 137 12(5) 94@ 44(10) 291 @ 166(10) b 76 25(5) 26.4 6.9(10) 58.7 30.5(10) b 17.8 4.8(5) 174* 35(10) 178* 48(10) b 99 15(5) 142@ 35(10) 148 @ 50(10) 178 @ 142(9) 416 414(5) 109 34(10) 133 60(10) 121 123(9) 312 371(5) 29.5 7.6(10) 34.3 13.6(10) 20.1 12.9(9) 55.5 58.8(5) 222* 36(10) 228* 44(10) 105 27(9) 105 21(5) 113 Company Sanitized. Does noS contain TSCA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 30 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group I Omg/kg/day Group ffl 60 nig/kg/day Isopropanol Group V Group Vn Group IX 10 mg/kg/day3 60 mg/kg/day" 300 mg/kg/day" BILI(mg/dL) DAY 38 DAY 92 DAY 122 DAY 183 BUN (mg/dL) DAY 38 DAY 92 DAY 122 DAY 183 CREA (mg/dL) DAY 38 DAY 92 DAY 122 DAY 183 CHOL (mg/dL) DAY 38 DAY 92 DAY 122 DAY 183 0.10 0.04(9) 0.11 0.04(9) 0.10 0.04(10) 0.14 0.05(5) 15 1(9) 15 2(9) 16 2(10) 15 1(5) 0.42 0.05(9) 0.42 0.05(9) 0.49 0.03(10) 0.44 0.06(5) 70 10(9) 86 18(9) 76 16(10) 67 14(5) 0.09 0.03(10) 0.11 0.02(10) b b 15 2(10) 16 2(10) b b 0.41 0.05(10) 0.35* 0.05(10) b b 59 8(10) 71 12(10) b b 0.10 0.04(10) 0.12 0.03(10) b 0.09 0.04(10) 0.11 0.04(10) b 0.11 0.06(5) 14 2(10) 14 2(10) b 0.11 0.04(5) 13 1(10) 15 2(10) b 15 0(5) 0.38 0.08(10) 0.32* 0.05(10) b 21 15(5) 0.37 0.04(10) 0.32* 0.04(10) b 0.43 0.03(5) 65 11(10) 69 16(10) b 0.49 0.19(5) 58 12(10) 60* 11(10) b 95* 15(5) 117 51(5) 0.10 0.03(10) 0.11 0.04(10) 0.08 0.04(9) 0.10 0.03(5) 16 3(10) 16 2(10) 15 1(9) 15 3(5) 0.40 0.05(10) 0.32* 0.06(10) 0.43* 0.05(9) 0.38 0.05(5) 61 14(10) 59* 17(10) 63 12(9) 63 13(5) 114 Company Sanitized. Does not c'-^-s'-n TSCA CBS H-24678: Subchronic Toxicity 90-Day Oral Gavage Study inRats^ DuPont-6554 TABLE 30 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group I Omg/kg/day Group ffl 60 mg/kg/day Isopropanol Group V Group VH Group IX 10 mg/kg/day0 60 mg/kg/day" 300 mg/kg/day2 TRIG(mg/dL) DAY 38 DAY 92 DAY 122 DAY 183 GLUC (mg/dL) DAY 38 DAY 92 DAY 122 DAY 183 TP(g/dL) DAY 38 DAY 92 DAY 122 DAY 183 ALB (g/dL) DAY 38 DAY 92 DAY 122 DAY 183 66 24(9) 79 27(9) 82 36(10) 60 14(5) 104 18(9) 102 15(9) 101 4(10) 105 12(5) 6.6 0.4(9) 7.1 0.3(9) 7.3 0.2(10) 7.3 0.3(5) 4.1 0.3(9) 4.3 0.1(9) 4.3 0.1(10) 4.4 0.2(5) 62 26(10) 73 27(10) b b 109 23(10) 99 6(10) b b 6.7 0.4(10) 7.1 0.3(10) b b 4.3 0.2(10) 4.3 0.2(10) b b 76 41(10) 79 30(10) b 86 32(5) 100 19(10) 109 17(10) b 109 11(5) 6.5 0.2(10) 6.6* 0.2(10) b 7.0 0.3(5) 4.0 0.1(10) 3.9* 0.2(10) b 4.3 0.3(5) 77 39(10) 68 30(10) b 100 70(5) 101 10(10) 102 7(10) b 110 18(5) 6.2' 0.3(10) 6.6* 0.3(10) b 6.9 0.4(5) 3.9* 0.2(10) 4.1* 0.2(10) b 4.0* 0.3(5) 58 29(10) 63 33(10) 62 28(9) 69 30(5) 107 10(10) 109@ 7(10) 107 17(9) 110 13(5) 6.4 0.3(10) 6.7* 0.3(10) 7.0* 0.2(9) 7.1 0.2(5) 4.1 0.2(10) 4.3 0.1(10) 4.3 0.1(9) 4.2 0.2(5) 115 , i^ D@@@ f-mf^n TSCACB8 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 30 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group I 0 mg/kg/day Group ffl 60 mg/kg/day Isopropanol Group V 10 mg/kg/day'' Group VII Group K 60 mg/kg/day3 300 mg/kg/day2 GLOB (g/dL) DAY 38 DAY 92 DAY 122 DAY 183 CALC (mg/dL) DAY 38 DAY 92 DAY 122 DAY 183 IPHS (mg/dL) DAY 38 DAY 92 DAY 122 DAY 183 NA (mmol/L) DAY 38 DAY 92 DAY 122 DAY 183 2.4 0.2(9) 2.8 0.3(9) 3.0 0.2(10) 2.9 0.2(5) 10.7 0.4(9) 10.8 0.2(9) 10.5 0.3(10) 1L1 0.4(5) 9.3 1.1(9) 7.5 0.8(9) 7.9 0.8(10) 7.1 1.1(5) 144.7 1.7(9) 148.7 1.5(9) 147.2 1.1(10) 145.9 1.4(5) 2.5 0.3(10) 2.8 0.3(10) b b 10.8 0.3(10) 10.7 0.1(10) b b 9.2 1.0(10) 7.2 0.3(10) b b 144.9 1.7(10) 148.2 1.7(10) b b 2.4 0.2(10) 2.7 0.1(10) b 2.7 0.2(5) 10.6 0.3(10) 10.4* 0.2(10) b 11.0 0.2(5) 8.6 1.1(10) 7.3 0.4(10) b 6.8 0.5(5) 146.4* 0.7(10) 147.8 1.2(10) b 145.7 0.5(5) 2.3 0.2(10) 2.5* 0.2(10) b 2.9 0.3(5) 10.3 @ 0.3(10) 10.3* 0.2(10) b 10.8 0.5(5) 9.2 1.1(10) 7.7 0.5(10) b 6.9 0.4(5) 144.9 1.5(10) 147.8 1.3(10) b 146.0 0.8(5) 2.3 0.2(10) 2.4* 0.2(10) 2.7* 0.2(9) 2.9 0.3(5) 10.5 0.3(10) 10.5* 0.3(10) 10.3 0.2(9) 10.9 0.4(5) 10.0 1.0(10) 8.3 0.2(10) 8.3 0.7(9) 7.8 1.2(5) 145.1 1.4(10) 147.4 0.7(10) 147.3 1.3(9) 144.1 1.7(5) 116 Company Sanitized. Does not eontain T8CA CIM H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 30 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group I Omg/kg/day Group DI 60 mg/kg/day Isopropanol Group V Group Vn Group IX 10 mg/kg/day3 60 mg/kg/day' 300 mg/kg/day3 K (mmol/L) DAY 38 DAY 92 DAY 122 DAY 183 CL (mmol/L) DAY 38 DAY 92 DAY 122 DAY 183 PPLU Qng/mL) DAY 92 DAY 122 5.99 0.41(9) 6.25 0.47(9) 6.19 0.38(10) 6.13 0.16(5) 101.0 1.1(9) 100.7 1.5(9) 101.3 1.9(10) 100.3 1.4(5) 0.1 0.0(9) 0.1 0.0(10) 5.97 0.50(10) 5.96 0.28(10) b b 100.5 2.0(10) 101.2 1.6(10) b b 0.1 0.0(10) b 5.85 0.35(10) 5.86 0.34(10) b 6.08 0.20(5) 101.8 1.5(10) 102.6 1.3(10) b 99.9 1.3(5) 0.1 0.0(10) b 6.05 0.43(10) 6.05 0.27(10) b 5.86 0.31(5) 102.0 1.1(10) 103.90 1.4(10) b 100.3 2.2(5) 0.1 0.0(10) b 6.58 0.72(10) 6.07 0.43(10) 6.14 0.33(9) 6.36 0.77(5) 102.1 1.4(10) 102.9 1.3(10) 102.8 1.4(9) 98.8 1.8(5) 0.2@ 0.1(10) 0.1 0.0(9) Data arranged as: Mean Standard deviation (Number of values included in calculation) H-24678 is) Measurement for this group at this timepoint were not taken or not performed. Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Durmett). Statistically significant difference from control at p < 0.05 by nonparametric test (Dunn's). -m------^^^taeAD'"o'"s^srWe^g,..^ TSCA CB! H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 31 SUMMARY OP SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD Group n 0 mg/kg/day Group IV 60 mg/kg/day Isopropanol Group VI GroupVffl Group X 10 mg/kg/day" 60 mg/kg/day' 300 mg/kg/day3 AST (U/L) DAY 39 DAY 93 DAY 122 DAY 183 ALT (U/L) DAY 39 DAY 93 DAY-122 DAY 183 SDH(U/L) DAY 39 DAY 93 DAY 122 DAY 183 ALKP(U/L) DAY 39 DAY 93 DAY 122 DAY 183 89 13(10) 81 9(10) 80 29(9) 215 166(4) 34 5(10) 33 5(10) 36 15(9) 78 24(4) 19.1 3.6(10) 14.8 2.9(10) 14.1 3.9(9) 28.4 11.0(4) 92 23(10) 56 14(10) 33 4(9) 58 16(4) 82 9(10) 81 12(10) b b 29 3(10) 37 8(10) b b 17.1 3.4(10) 15.5 3.9(10) b b 88 18(10) 47 13(10) b b 95 41(10) 95 17(10) b 315 343(4) 37 19(10) 42 18(10) b 205 272(4) 19.3 8.1(10) 17.3 5.9(10) b 65.6 84.3(4) 83 15(10) 46 10(10) b 35 19(4) 81 17(10) 78 8(10) b 130 41(4) 30 5(10) 34 7(10) b 70 28(4) 15.2 3.1(10) 13.9 2.8(10) b 23.9 9.7(4) 78 13(10) 43 7(10) b 38 6(4) 123 132(10) 114 57(10) 123 80(9) 92 19(5) 45 36(10) 55 32(10) 68@ 58(9) 45 7(5) 26.8 35.0(10) 21.5 10.1(10) 19.7 11.2(9) 13.8 2.6(5) 72 22(10) 45 15(10) 46 18(9) 34 13(5) 118 Company Sanitized. Does not contain T<W^ Qyj H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 31 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD Group n 0 mg/kg/day Group TV 60 mg/kg/day Isopropanol Group VI Group Vffl Group X 10 mg/kg/day" 60 mg/kg/day' 300 mg/kg/day" BILI(mg/dL) DAY 39 DAY 93 DAY 122 DAY 183 BUN (mg/dL) DAY 39 DAY 93 DAY 122 DAY 183 CREA (mg/dL) DAY 39 DAY 93 DAY 122 DAY 183 CHOL (mg/dL) DAY 39 DAY 93 DAY 122 DAY 183 0.16 0.03(10) 0.15 0.05(10) 0.12 0.03(9) 0.14 0.02(4) 18 2(10) 19 1(10) 16 3(9) 17 1(4) 0.49 0.04(10) 0.51 0.04(10) 0.56 0.05(9) 0.49 0.06(4) 87 26(10) 95 29(10) 100 22(9) 109 24(4) 0.16 0.04(10) 0.15 0.04(10) b b 16 2(10) 17 2(10) b b 0.46 0.06(10) 0.51 0.04(10) b b 75 14(10) 88 21(10) b b 0.14 0.03(10) 0.12 0.03(10) b 0.18 0.02(4) 17 3(10) 19 2(10) b 20 6(4) 0.45 0.04(10) 0.50 0.05(10) b 0.59 0.06(4) 65* 10(10) 73 15(10) b 127 19(4) 0.11@ 0.06(10) 0.13 0.03(10) b 0.12 0.07(4) 16 1(10) 16@ 2(10) b 15 3(4) 0.45 0.06(10) 0.50 0.04(10) b 0.50 0.09(4) 72 11(10) 80 14(10) b 111 10(4) 0.10@ 0.05(10) 0.11@ 0.03(10) 0.10 0.04(9) 0.12 0.04(5) 16 3(10) 17 4(10) 19@ 4(9) 16 2(5) 0.43* 0.05(10) 0.50 0.05(10) 0.56 0.06(9) 0.53 0.08(5) 77 16(10) 86 21(10) 88 23(9) 106 27(5) 119 Company Sanilized. i H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 31 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD Group n 0 ing/kg/day Group IV 60 mg/kg/day bopropanol Group VI Group Vffl Group X 10 mg/kg/day3 60 mg/kg/day3 300 mg/kg/day3 TRIG (mg/dL) DAY 39 DAY 93 DAY 122 DAY 183 GLUC (mg/dL) DAY 39 DAY 93 DAY 122 DAY 183 TP(g/dL) DAY 39 DAY 93 DAY 122 DAY 183 ALB (g/dL) DAY 39 DAY 93 DAY 122 DAY 183 45 16(10) 72 57(10) 142 86(9) 59 15(4) 98 8(10) 97 6(10) 109 10(9) 101 7(4) 7.4 0.5(10) 7.8 0.6(10) 8.6 0.5(9) 8.2 0.3(4) 5.0 0.3(10) 5.3 0.4(10) 5.7 0.3(9) 5.5 0.5(4) 38 9(10) 42 13(10) b b 102 9(10) 102 5(10) b b 7.4 0.5(10) 7.9 0.4(10) b b 5.1 0.4(10) 5.5 0.4(10) b b 38 10(10) 39 11(10) b 93 38(4) 105 12(10) 98 9(10) b 107 8(4) 7.2 0.3(10) 7.6 0.4(10) b 8.6 0.1(4) 4.8 0.2(10) 5.1 0.3(10) b 5.8 0.2(4) 42 13(10) 53 30(10) b 89 38(4) 101 6(10) 98 9(10) b 117* 3(4) 7.2 0.3(10) 7.8 0.5(10) b 8.5 0.5(4) 4.9 0.3(10) 5.3 0.5(10) b 5.4 0.7(4) 40 12(10) 55 28(10) 65* 29(9) 122 92(5) 102 12(10) 102 6(10) 101 6(9) 109 6(5) 7.2 0.3(10) 7.8 0.4(10) 8.0* 0.5(9) 8.5 0.7(5) 5.0 0.2(10) 5.5 0.3(10) 5.4 0.4(9) 5.6 0.5(5) 120 Company SanitWi Does i H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 31 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD Group n 0 nig/kg/day Group IV 60 ing/kg/day Isopropanol Group VI Group Vffl Group X 10 mg/kg/day" 60 mg/kg/day" 300 mg/kg/day" GLOB (g/dL) DAY 39 DAY 93 DAY 122 DAY 183 CALC (mg/dL) DAY 39 DAY 93 DAY 122 DAY 183 IPHS (mg/dL) DAY 39 DAY 93 DAY 122 DAY 183 NA (mmol/L) DAY 39 DAY 93 DAY 122 DAY 183 2.4 0.2(10) 2.5 0.3(10) 2.9 0.2(9) 2.8 0.3(4) 11.2 0.4(10) 11.0 0.4(10) 11.2 0.3(9) 11.6 0.4(4) 8.0 0.7(10) 6.2 1.1(10) 6.2 0.7(9) 4.8 0.5(4) 142.9 1.7(10) 143.5 1.4(10) 144.8 1.4(9) 144.2 1.5(4) 2.3 0.3(10) 2.4 0.2(10) b b 1L1 0.4(10) 11.0 0.4(10) b b 7.4 0.9(10) 6.1 1.0(10) b b 142.5 1.6(10) 143.4 1.1(10) b b 2.4 0.3(10) 2.5 0.2(10) b 2.8 0.3(4) 11.0 0.3(10) 10.8 0.4(10) b 11.7 0.3(4) 7.5 1.1(10) 6.2 0.7(10) b 5.1 1.5(4) 143.6 1.0(10) 143.7 1.8(10) b 143.7 1.0(4) 2.4 0.2(10) 2.5 0.2(10) b 3.1 0.3(4) 11.0 0.3(10) 10.9 0.4(10) b 11.6 0.4(4) 7.7 1.0(10) 5.8 0.3(10) b 5.2 0.3(4) 142.5 1.3(10) 143.8 1.1(10) b 145.5 2.0(4) 2.3 0.1(10) 2.4 0.2(10) 2.6* 0.2(9) 2.9 0.3(5) 11.2 0.3(10) 11.0 0.3(10) 10.8* 0.3(9) 11.6 0.4(5) 7.7 0.8(10) 6.0 0.8(10) 6.5 0.7(9) 4.9 0.6(5) 142.7 1.2(10) 143.7 2.1(10) 145.9 1.3(9) 144.3 0.9(5) 121 Company Sanitized. Dos8' H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 31 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD Group II 0 mg/kg/day Group IV 60 mg/kg/day Isopropanol Group VI Group VIH Group X 10 mg/kg/day" 60 mg/kg/day" 300 mg/kg/day3 K (mmol/L) DAY 39 DAY 93 DAY 122 DAY 183 CL (mmol/L) DAY 39 DAY 93 DAY 122 DAY 183 PFLUOig/mL) DAY 93 DAY 122 5.81 0.55(10) 5.38 0.47(10) 5.31 0.54(9) 5.45 0.12(4) 99.8 2.6(10) 100.2 1.9(10) 100.1 2.7(9) 99.3 1.7(4) 0.1 0.0(10) 0.1 0.0(9) 5.41 0.47(10) 5.28 0.50(10) b b 99.6 1.9(10) 99.7 2.0(10) b 1 0.1 0.0(10) b 5.52 0.35(10) 5.24 0.26(10) b 5.21 0.52(4) 99.7 1.6(10) 100.8 2.1(10) b 100.2 1.7(4) 0.1 0.0(10) b 5.35 0.20(10) 5.23 0.28(10) b 5.62 0.52(4) 99.7 1.4(10) 100.6 1.7(10) b 99.6 2.7(4) 0.1 0.0(10) b 5.56 0.43(10) 5.11 0.25(10) 5.39 0.32(9) 5.39 0.25(5) 100.5 1.9(10) 100.6 2.0(10) 101.3 1-8(9) 99.3 1-7(5) 0.1 0.0(10) 0.1 0.0(9) Data arranged as: Mean Standard deviation (Number of values included in calculation) b. Measurements for this group at this timepoint were not taken or not performed. * Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett). @ Statistically significant difference from control at p < 0.05 by nonparametric test (Duim's). 122 Company Sanitized. Does not eontain TSCA CBl H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 32 TEST/ PERIOD SUMMARY OF URINALYSIS VALUES FOR MALE RATS Group I 0 mg/kg/day Group ffl 60 mg/kg/day Isopropanol Group V Group VH Group IX 10 nig/kg/day3 60 mg/kg/da/ 300 mg/kg/day8 VOL (mL) DAY 38 DAY 92 DAY 122 DAY 183 UOSM (mOsm) DAY 38 DAY 92 DAY-122 DAY 183 SG DAY 38 DAY 92 DAY 122 DAY 183 pH DAY 38 DAY 92 DAY 122 12.5 6.7(10) 7.1 3.6(9) 8.3 6.7(10) 7.7 7.0(5) 764 324(9) 1031 333(8) 1183 457(8) 1404 956(4) 13.5 7.8(10) 6.0 4.4(10) b b 697 262(10) 1324 485(9) b b 10.3 2.7(10) 8.7 4.8(10) b 9.8 6.8(5) 816 180(10) 1102 429(9) b 1319 739(5) 10.8 5.0(10) 7.0 3.5(10) b 8.1 4.9(5) 795 279(10) 1116 329(10) b 1539 989(5) 16.0 9.7(10) 13.6 8.8(10) 11.6 10.5(9) 11.7 4.9(5) 664 372(10) 830 344(10) 952 447(7) 820 264(5) 1.028 0.015(10) 1.036 0.014(9) 1.045 0.020(10) 1.047 0.028(5) 1.023 0.009(10) 1.046 0.018(10) b b 1.026 0.006(10) 1.039 0.018(10) b 1.039 0.022(5) 1.026 0.009(10) 1.036 0.011(10) b 1.044 0.023(5) 1.022 0.012(10) 1.026 0.011(10) 1.040 0.022(9) 1.025 0.007(5) 7.2 0.2(10) 6.7 0.4(9) 6.7 0.5(10) 7.1 0.4(10) 6.5 0.3(10) b 7.1 0.3(10) 6.4 0.3(10) b 7.2 0.6(10) 6.8 0.4(10) b 7.3 0.4(10) 6.4 0.5(10) 6.2@ 0.4(9) 123 Company Sanifced. Does not contain TSCA CBB H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 32 (Continued) TEST/ PERIOD SUMMARY OF URINALYSIS VALUES FOR MALE RATS Group I 0 mg/kg/day Group ffl 60 mg/kg/day Isopropanol Group V Group VH Group IX 10 mg/kg/day2 60mg/kg/day'1 300 mg/kg/day3 URO (EU/dL) DAY 38 DAY 92 DAY 122 UFLU(^g) DAY 92 DAY 122 DAY 183 UMTP(mg/dL) DAY 38 DAY 92 DAY 122 DAY 183 0.2 0.0(10) 0.2 0.0(9) 0.2 0.0(10) 7.8 2.8(8) 12.0 7.2(9) 12.8 3.7(4) 64 43(9) 105 83(9) 132 78(10) 117 69(5) 0.2 0.0(10) 0.2 0.0(10) b 8.7 2.9(7) i b 57 37(10) 122 52(9) b b 0.2 0.0(10) 0.2 0.0(10) b 19.1 5.9(9) b 14.0 2.9(5) 49 30(10) 77 72(9) b 83 46(5) 0.2 0.0(10) 0.2 0.0(10) b 50.1 11.4(10) b 16.0 5.2(4) 46 18(10) 89 47(10) b 255 225(5) 0.2 0.0(10) 0.2 0.0(10) 0.2 0.0(9) 159.2 56.8(10) 26.1* 8.9(7) 19.4 3.6(5) 49 58(10) 48 40(10) 77 72(9) 35 24(5) Data arranged as: Mean Standard deviation (Number of values included in calculation) a. H-24678 i b. Measure: for this group at this timepoint were not taken or not performed. Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett). @ Statistically significant difference from control at p < 0.05 by nonparametric test (Dunn's). H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 33 TEST/ PERIOD SUMMARY OF URINALYSIS VALUES FOR FEMALE RATS Group n 0 mg/kg/day Group IV 60 mg/kg/day Isopropanol Group VI Group Vffl Group X 10 mg/kg/day0 60 mg/kg/day2 300 mg/kg/day' VOL (mL) DAY 39 DAY 93 DAY 122 DAY 183 UOSM (mOsm) DAY 39 DAY 93 DAY 122 DAY 183 SG DAY 39 DAY 93 DAY 122 DAY 183 pH DAY 39 DAY 93 DAY 122 9.4 5.1(10) 4.3 3.2(9) 5.8 3.4(10) 4.4 4.6(5) 897 518(10) 1241 579(6) 1046 415(9) 1257 561(4) 5.8 2.8(10) 4.0 2.0(9) b b 1198 562(10) 1160 301(7) b b 4.6 2.4(10) 4.3 5.3(9) b 6.4 3.2(4) 1276 461(10) 1147 490(5) b 937 318(4) 1.027 0.015(10) 1.043 0.015(9) 1.036 0.017(10) 1.044 0.025(5) 1.036 0.016(10) 1.043 0.016(9) b b 1.039 0.013(10) 1.046 0.020(9) b 1.027 0.007(4) 7.3 0.7(10) 5.8 0.4(9) 6.0 0.5(10) 6.8 0.4(10) 5.6 0.4(9) b 6.8 0.4(10) 5.7 0.5(9) b 8.0 5.5(10) 7.6 7.4(10) b 6.8 3.8(5) 925 432(10) 890 390(7) b 861 138(4) 12.3 6.7(10) 5.1 2.1(10) 7.1 3.3(9) 6.2 1.7(5) 796 484(10) 1298 485(9) 890 317(9) 956 230(5) 1.028 0.013(10) 1.037 0.018(10) b 1.036 0.027(5) 1.025 0.014(10) 1.040 0.012(10) 1.028 0.010(9) 1.027 0.006(5) 7.0 0.3(10) 5.8 0.4(10) b 6.8 0.3(10) 5.9 0.3(9) 5.9 0.5(9) 125 Company Sanitized. Does not eontain TSCA CBS H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 33 (Continued) SUMMARY OP URINALYSIS VALUES FOR FEMALE RATS TEST/ PERIOD Group n 0 mg/kg/day Group IV (50 nag/kg/day Isopropanol Group VI 10 mg/kg/day' Group Vm Group X 60 mg/kg/day0 300 mg/kg/day3 URO (EU/dL) DAY 39 DAY 93 DAY 122 UFLUQig) DAY 93 DAY 122 DAY 183 UMTP(mg/dL) DAY 39 DAY 93 DAY 122 DAY 183 0.2 0.0(10) 0.2 0.0(9) 0.2 0.0(10) 8.1 2.5(3) 8.8 1.6(9) 9.1 3.1(3) 21 16(10) 50 47(6) 90 113(10) 47 22(4) 0.2 0.0(10) 0.2 0.0(9) b 0.2 0.0(10) 0.2 0.0(9) b 6.6 1.3(6) b b 31 18(10) 41 23(7) b b 9.3 1.9(3) b 7.8 1.1(4) 30 20(10) 29 17(5) b 108 165(4) 0.2 0.0(10) 0.2 0.0(10) b 30.4 8.3(7) b 11.1 1.5(4) 21 10(10) 22 14(7) b 29 33(4) 0.2 0.0(10) 0.2 0.0(9) 0.2 0.0(9) 87.0@ 16.2(8) 11.7 4.5(9) 10.9 2.4(5) 22 13(10) 63 92(10) 20 11(9) 40 39(5) Data arranged as: Mean Standard deviation (Number of values included in calculation) b. Measurements for (Bis grouj^nnis timepomtwerenot taken or not performed. @ Statistically significant difference from control at p < 0.05 by nonparametric test (Dunn's). 126 Company Sanitized. Does not eontain TSCA CBl H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 34 SUMMARY OF HEPATIC BETA-OXIDATION ACTIVITY IN MALE RATS Group Dosage (mg/kg/day) Hepatic Peroxisomal Beta-Oxidation Activity (nmol/min/mg protein) 10-Day Time Point 90-Day Time Point 1-Month Recovery 3-Mo I 0 7.711.7' mb (isopr^anol) 8032 V^ 10 7.2 1.1 VIT4 60 5.3 0.9 a IX 300 13.9 4.4 9.6 0.5 84l4 10.0 1.8 13.8 1.6* 19.8 3.4* 13.512.0 --- --- 22.6 1.8* "< a. Mean standard deviation. The n = 5 for each group. b. Samples were not prepared for analysis fromigroup III at the 1- and 3-month recovery time points p. d. Samples were not prepared for analysis from groups V and VII at 1-month recovery time point. 0 a * Statistically significant difference from control (p < 0.05) by Dunnett's test. fWs S3' a 0 127 .-,::,.. , ^--..,..---------------------- H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 35 SUMMARY OF HEPATIC BETA-OXTOATION ACTIVITY IN FEMALE RATS Group Dosage (mg/kg/day) Hepatic Peroxisomal Beta-Oxidation Activity (nmol/min/mg prote 10-Day Time Point 90-Day Time Point 1-Month Recovery 3-M n IV1' VI^ 0 60 (,i. sopropano,,l) 10 12.912.1' 8.6 2.2* 14.3 1.1 18.3 2.5 17.4 2.8 17.8 1.0 Vm^ 60 16.6 2.8* 17.7 2.1 ^ X 300 19.9 2.5* 23.8 3.1* 17.8 2.2 --- --- 21.8 2.0* a> "3 a. Mean standard deviation. The n = 5 for each group unless otherwise noted. b. Samples were not prepared for analysis from group IV at the 1- and 3-month recovery time points a d. Samples were not prepared for analysis from groups VJ[and VIII at 1-month recovery time point. 1 g * Statistically significant difference from untreated control (*) by Dunnett's test (p < 0.05). ? 53 S i ^ .. -........... >> 128 0- or H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats^ DuPont-6554 TABLE 36 MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS LIVER KIDNEYS HEART SPLEEN BRAIN THYMUS ADRENAL GLANDS THYROID GLAND TESTES EPIDIDYMIDES FINAL BODY WEIGHT (90-DAY EXPOSURE EVALUATION) MEAN FINAL BODY AMD ABSOLUTE ORGAN WEIGHTS (grams) Group I 0 mg/kg/day 15.08189 0.83853(9) 3.81011 0.25835(9) 1.64289 0.07568(9) III Group 60 ing/kg/day Isopropanol 15.26610 1.25088(10) 3.97040 0.30793(10) 1.80590B 0.21061(10) Group V Group VH 10 mg/kg/day3 60 ing/kg/daY" 15.65400 1.72811(10) 4.01810 0.42819(10) 1.82460 0.33901(10) 16.10800 2.54757(10) 4.27590* 0.31916(10) 1.76490 0.16277(10) 0.84122 0.05199(9) 0.87600 0.14426(10) 0.84790 0.09991(10) 0.83750 0.12432(10) 2.10433 0.06112(9) 2.15380 0.08665(10) 2.15320 0.04886(10) 2.13610 0.09297(10) 0.37367 0.10616(9) 0.05933 0.00630(9) 0.02422 0.00441(9) 0.36980 0.04806(10) 0.05420 0.00625(10) 0.02300 0.00753(10) 0.33350 0.09733(10) 0.05510 0.00840(10) 0.02660 0.00636(10) 0.40390 0.08918(10) 0.05000ft 0.00794(10) 0.02670 0.00683(10) 3.41756 0.38267(9) 3.58280 0.20377(10) 3.48710 0.25185(10) 3.77130* 0.35601(10) 1.43944 0.12571(9) 557.28889 29.74413(9) 1.50580 0.09056(10) 562.01999 41.82330(10) 1.50700 0.14321(10) 573.62000 50.99172(10) 1.57190 0.12840(10) 553.52000 63.77206(10) Group IX 300 mg/kg/day" 19.33890* 2.66904(10) 4.61410* 0.48195(10) 1.78100 0.24031(10) 0.82690 0.11316(10) 2.25230 0.28855(10) 0.40350 0.11397(10) 0.05290* 0.01042(10) 0.02210 0.00722(10) 3.62650* 0.38068(10) 1.41580 0.12522(10) 526.30000 63.47923(10) 129 Company Sanitized. Does not contain TSCA CBS H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 36(CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (90-DAY EXPOSURE EVALUATION) LIVER/ FINAL BODY*100 MEAN RELATIVE ORGAN WEIGHTS (% of body weight) Group I 0 nig/kg/day I I I Group 60 mg/kg/day Isopropanol Group V 10 ng/kg/day Group VII 60 ing/kg/day'1 Group IX 300 ing/kg/day3 2.71144 0.18792(9) 2.71625 0.09724(10) 2.73278 0.23034(10) 2.90036# 0.18283(10) 3.67045* 0.14199(10) KIDNEYS/ FINAL BODY*100 0.68483 0.05169(9) 0.70699 0.03181(10) 0.70318 0.07445(10) 0.78006# 0.09026(10) 0.88232* 0.08555(10) HEART/ FINAL BODY*100 SPLEEN/ FINAL BODY* 100 0.29529 0.01657(9) 0.15134 0.01216(9) 0.32196 0.03472(10) 0.15584 0.02296(10) 0.31851 0.05249(10) 0.14838 0.01741(10) 0.32100* 0.03164(10) 0.15225 0.02226(10) 0.33937ft 0.03477(10) 0.15838 0.02229(10) BRAIM/ FINAL BODY*100 0.37840 0.01980(9) 0.38518 0.03262(10) 0.37764 0.02908(10) 0.39016 0.04291(10) 0.43344# 0.07621(10) THYMUS/ FINAL BODY*100 0.06730 0.01992(9) 0.06599 0.00864(10) 0.05847 0.01812(10) 0.07312 0.01440(10) 0.07698 0.02196(10) ADRENAL GLANDS/ FINAL BODY* 100 0.01067 0.00124(9) - 0.00970 0.00138(10) 0.00974 0.00215(10) 0.00905 0.00115(10) 0.01011 0.00195(10) THYROID GLAND/ FINAL BODY*100 0.00437 0.00091(9) 0.00414 0.00144(10) 0.00468 0.00120(10) 0.00483 0.00116(10) 0.00419 0.00129(10) TESTES/ FINAL BODY*100 0.61558 0.08312(9) 0.64118 0.06476(10) 0.61069 0.05318(10) 0.69070 0.11565(10) 0.69381# 0.07389(10) EPIDIDYMIDES/ FINAL BODY*100 0.25905 0.02773(9) 0.26886 0.01973(10) 0.26447 0.03486(10) 0.28735 0.04058(10) 0.27110 0.02702(10) 130 Company Sanitized. Does not contain TSCA CE H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 36(CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (90-DAY EXPOSURE EVALUATION) LIVER/ BRAIM*100 MEAN RELATIVE ORGAN WEIGHTS (% organ to brain weight ratio) Group I 0 ing/kg/day III Group 60 ing/kg/day Isopropanol Group V 10 mg/kg/day1 Group VII 60 nig/kg/day'1 717.64202 51.69105(9) 709.42857 60.31705(10) 726.64682 74.71493(10) 754.49609 119.56178(10) Group IX 300 ing/kg/day3 868.64363# 148.28634(10) KIDNEYS/ BRAIN* 100 181.04111 10.71936(9) 184.40956 13.49349(10) 186.67962 20.24034(10) 200.32932* 14.41936(10) 207.38365* 30.76367(10) HEART/ BRAIN*100 78.15965 4.80593(9) 83.93581 10.16850(10) 84.80677 16.37083(10) 82.64902 7.07642(10) 80.09919 13.94435(10) SPLEEN/ BRAIN* 100 39.97797 2.20162(9) 40.74231 6.80788(10) 39.39784 4.75126(10) 39.23224 5.89183(10) 37.26524 7.26970(10) THYMUS/ BRAIN*100 17.73973 4.98509(9) 17.22085 2.52732(10) 15.51057 . 4.66942(10) 18.83530 3.75089(10) 18.11717 5.68768(10) ADRENAL GLANDS/ BRAIN* 100 2.81686 0.26250(9) 2.51585* 0.27170(10) 2.56454 0.42604(10) 2.33989* 0.35437(10) 2.37171* 0.54223(10) THYROID GLAND/ BRAIN*100 1.15187 0.20968(9) 1.07123 0.35467(10) 1.23482 0.28919(10) 1.25019 0.31721(10) 0.97974 0.30882(10) TESTES/ BRAIN*100 162.64373 19.82149(9) 166.54741 10.80923(10) 162.02295 12.29517(10) 177.27617 22.50748(10) 163.01471 23.89849(10) EPIDIDYMIDES/ BRAIN* 100 68.51800 6.94988(9) 69.99758 4.82806(10) 70.03002 6.94203(10) 73.82834 7.98932(10) 63.73639 9.43188(10) 131 Company Sanitized, boes nm cow H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 36(CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAN FINAL BODY AMD ABSOLUTE ORGAN WEIGHTS (grams) Group I 0 mg/kg/day Group IX 300 mg/kg/day' LIVER 15.81280 1.89401(10) 17.71611 2.77443(9) KIDNEYS 4.10070 0.51303(10) 4.53367 0.56052(9) HEART 1.93330 0.23361(10) 1.80000 0.15538(9) SPLEEN 0.83820 0.08562(10) 0.77667 0.11221(9) BRAIN 2.14400 0.09869(10) 2.18933 0.10357(9) THYMUS 0.33390 0.06640(10) 0.42211 0.12042(9) ADRENAL GLANDS 0.04800 0.00812(10) 0.04522 0.00766(9) THYROID GLAND 0.02160 0.00597(10) 0.02222 0.00429(9) TESTES 3.51750 0.17968(10) 3.66511 0.26334(9) EPIDIDYMIDES 1.54360 0.05685(10) 1.50078 0.16784(9) FINAL BODY WEIGHT 595.10000 51.11742(10) 568.42222 39.71186(9) 132 Company Sanitized. Does not contain TSCA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 36(CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% of body weight) Group I 0 mg/kg/day Group IX 300 nig/kg/day" LIVER/ FINAL BODY*100 2.65213 0.14226(10) 3.10558* 0.32569(9) KIDNEYS/ FINAL BODY*100 0.68817 0.04775(10) 0.79659* 0.06928(9) HEART/ FINAL BODY*100 0.32582 0.03845(10) 0.31789 0.03445(9) SPLEEN/ FINAL BODY*100 0.14132 0.01403(10) 0.13674 0.01864(9) BRAIN/ FINAL BODY*100 0.36293 0.03916(10) 0.38643 0.02669(9) ADRENAL GLANDS/ FINAL BODY*100 0.00808 0.00135(10) 0.00799 0.00145(9) THYMUS/ FINAL BODY*100 0.05636 0.01155(10) 0.07358* 0.01695(9) THYROID GLAND/ FINAL BODY*100 0.00363 0.00101(10) 0.00394 0.00087(9) TESTES/ FINAL BODY*100 0.59385 0.04398(10) 0.64663* 0.05279(9) EPIDIDYMIDES/ FINAL BODY*100 0.26109 0.02384(10) 0.26508 0.03403(9) 133 Company Sanitized. Does not GOTta'n TSCA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 36(CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% organ to brain weight ratio) Group I 0 mg/kg/day Group IX 300 ing/kg/day" LIVER/ BRAIN*100 739.01373 94.03186(10) 808.12266 113.30466(9) KIDNEYS/ BRAIN*100 191.47131 24.00495(10) 207.09056 23.83624(9) HEART/ BRAIN*100 90.25849 82.25375 10.98188(10) 6.57906(9) SPLEEN/ BRAIN*100 39.12067 3.81317(10) 35.50236 5.01238(9) ADRENAL GLANDS/ BRAIN*100 2.23668 0.35142(10) 2.06323 0.31688(9) THYMUS/ BRAIN*100 15.55432 2.84614(10) 19.23278 5.27550(9) THYROID GLAND/ BRAIN*100 1.01216 0.28837(10) 1.01566 0.19728(9) TESTES/ BRAIN*100 164.34666 10.80786(10) 167.56032 11.78020(9) EPIDIDYMIDES/ BRAIN*100 72.17039 4.90211(10) 68.63487 7.71067(9) 134 Company Sai't^ed Pses "wt contain TSCA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 36(CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (THREE-MONTH RECOVERY EVALUATION) MEM? FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) Group I 0 nig/kg/day Group V 10 mg/kg/day'1 Group VII 60 ing/kg/day'* Group IX 300 mg/kg/day LIVER 14.14780 2.06533(5) 15.20120 0.88601(5) 17.57700 4.50755(5) 16.89200 2.68111(5) KIDNEYS 3.68740 0.36504(5) 3.98560 0.38329(5) 5.63980 4.24687(5) 4.55400 0.86744(5) THYROID GLAND TESTES 0.02240 0.00288(5) 3.72720 0.25474(5) 0.02460 0.00251(5) 3.42680 0.30835(5) 0.02420 0.00789(5) 3.37320 0.28733(5) 0.02140 0.00422(5) 3.66560 0.19962(5) FINAL BODY WEIGHT 562.24000 62.85940(5) 596.67999 49.44883(5) 588.96001 86.66663(5) 610.57999 65.35249(5) LIVER/ FINAL BODY*100 KIDNEYS/ FINAL BODY*100 THYROID GLAND/ FINAL BODY*100 TESTES/ FINAL BODY*100 MEAN RELATIVE ORGAM WEIGHTS (% of body weight) Group I 0 mg/kg/day Group V 10 ing/kg/day'1 Group VII 60 mg/kg/day Group IX 300 nig/kg/day3 2.50898 0.09046(5) 2.73184 0.29663(5) 3.00723 0.83617(5) 2.75690 0.19853(5) 0.65875 0.06087(5) 0.67421 0.11256(5) 1.02047 0.91632(5) . 0.74167 0.07355(5) 0.00399 0.00040(5) 0.00413 0.00043(5) 0.00409 0.00105(5) 0.00349 0.00052(5) 0.66898 0.08212(5) 0.57994 0.09309(5) 0.57830 0.05782(5) 0.60532 0.06755(5) Data summarized as: Mean Standard Deviation (n) a. H-24678 isl III # Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. Group (isopropanol control) was excluded from trend comparisons. * Statistically significant difference from control (Group I) at p < 0.05 by Dunnett's test. @ Statistically significant difference from control (Group I) at p < 0.05 by Dunn's test. 135 Company Sanitized. Does no2 ftonlain T8CA CBl H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 37 MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (90-DAY EXPOSURE EVALUATION) LIVER KIDNEYS HEART SPLEEN BRAIN THYMOS ADRENAL GLANDS THYROID GLAND OVARIES UTERUS FINAL BODY WEIGHT KtEMI FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) I I Group 0 mg/kg/day Group IV 60 mg/kg/day Isopropanol Group VI 10 nig/kg/day3 Group VIII 60 nig/kg/day'1 8.67870 1.09243(10) 8.73520 0.70672(10) 8.05260 0.82624(10) 9.25420 1.14428(10) 2.21880 0.19422(10) 2.23970 0.17790(10) 2.24860 0.09961(10) 2.35160 0.22373(10) 1.21850 0.17648(10) 1.14930 0.08638(10) 1.056208 0.07636(10) 1.15300 0.15320(10) 0.53030 0.05220(10) 0.51640 0.06933(10) 0.50260 0.07997(10) 0.56440 0.07812(10) 1.92630 0.11686(10) 1.93330 0.07293(10) 1.88920 0.08708(10) 1.97520 0.06380(10) 0.30630 0.04060(10) 0.27560 0.04608(10) 0.29080 0.05258(10) 0.32300 0.10464(10) 0.06530 0.01117(10) 0.06580 0.00873(10) 0.06770 0.01065(10) 0.06950 0.01126(10) 0.01790 0.00303(10) 0.01730 0.00245(10) 0.01730 0.00380(10) 0.01880 0.00336(10) 0.11690 0.01969(10) 0.13130 0.03323(10) 0.13120 0.03156(10) 0.13950 0.03332(10) 0.79250 0.30595(10) 0.64090 0.17783(10) 0.71740 0.24541(10) 0.77330 0.16970(10) 309.18000 22.67685(10) 305.93000 15.19658(10) 293.97000 25.01995(10) 316.11000 42.21386(10) Group X 300 mg/kg/day'1 9.83900# 1.04012(10) 2.46620# 0.15020(10) 1.18580 0.17369(10) 0.53740 0.10276(10) 1.99550# 0.07710(10) 0.33710 0.07626(10) 0.07290 0.01343(10) 0.02020 0.00518(10) 0.12300 0.01913(10) 0.76020 0.21547(10) 322.79000 . 28.80534(10) 136 Company a"^<^-pee<5 n^ eonsas"ITSCA CB! H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 37(CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (90-DAY EXPOSURE EVALUATION) LIVER/ FINAL BODY*100 MEMI REIATIVE ORGAN WEIGHTS (% of body weight) I I G r o u p 0 Big/kg/day Group IV 60 ing/kg/day Isopropanol Group VI 3.0 nig/kg/day" Group VIII 60 ing/kg/day'1 Group X 300 nig/kg/day 2.80290 0.22742(10) 2.85766 0.22340(10) 2.74618 0.25686(10) 2 .93782 0.21812(10) 3.04854 0.16311(10) KIDNEYS/ FINAL BODY*100 0.72035 0.07489(10) 0.76919 0.05935(10) 0.73299 0.06493(10) 0.74948 0 .07153(10) 0.76636 0.03813(10) HEART/ FINAL BODY*100 0.39486 0.05513(10) 0.36064 0.02409(10) 0.37584 0.02933(10) 0 .36563 0.02579(10) 0.36836 0.05197(10) SPLEEN/ FINAL BODY*100 0.17174 0.01463(10) 0.16826 0.01561(10) 0.17107 0.02278(10) 0 .17944 0 .02011(10) 0.16566 0.02256(10) BRAIN/ FINAL BODY*100 0.62456 0.03881(10) 0.63299 0.03219(10) 0.64733 0.06918(10) 0 .63381 0 .07811(10) 0.62202 0.05301(10) THYMUS/ FINAL BODY*100 0.09911 0.01138(10) 0.09022 0.01493(10) 0.09944 0.01938(10) 0 .10177 0 .03006(10) 0.10384 0.01859(10) ADRENAL GLANDS/ FINAL BODY*100 0.02112 0.00342(10) 0.02159 0.00331(10) 0.02314 0.00392(10) 0 .02220 0 .00402(10) 0.02253 0.00323(10) THYROID GLAND/ FINAL BODY*100 0.00581 0.00105(10) 0.00566 0.00082(10) 0.00587 0.00104(10) 0 .00601 0 .00122(10) 0.00631 0.00182(10) OVARIES/ FINAL BODY*100 UTERUS/ FINAL BODY*100 0.03802 0.00693(10) 0.25572 0.09172(10) 0.04290 0.01064(10) 0.20960 0.05628(10) 0.04453 0.00980(10) 0.24650 0.08894(10) 0 .04463 0 .01054(10) 0 .24753 0 .06125(10) 0.03824 0.00590(10) 0.24161 0.09408(10) 137 Company SanSt^sri ^sas ""t c^ta'i TSC.A CB1 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 37(CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (90-DAY EXPOSURE EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% organ to brain weight ratio) I I Group 0 ing/kg/day Group IV 60 ing/kg/day Isopropanol Group VI 10 mg/kg/day" Group VIII 60 nig/kg/day" Group X 300 ing/kg/day' LIVER/ BRAIN*100 450.97784 53.57531(10) 452.29062 38.89301(10) 426.50556 41.38126(10) 468.17896 52.62215(10) 493.15457# 49.08503(10) KIDNEYS/ BRAIN* 100 115.52074 11.85912(10) 116.09064 11.41802(10) 119.32911 8.73265(10) 119.14585 11.59916(10) 123.56578 5.28399(10) HEART/ BRAIN* 100 63.28631 8.38153(10) 59.51655 4.82343(10) 56.03737 4.94241(10) 58.40968 7.72237(10) 59.31338 7.27454(10) SPLEEN/ BRAIN*100 27.57986 2.76124(10) 26.72732 3.61594(10) 26.70644 4.67721(10) 28.57337 3.83565(10) 26.88685 4.78189(10) THYMUS/ BRAIN* 100 15.90487 1.91689(10) 14.31295 2.68467(10) 15.38581 2.61279(10) 16.46200 5.62151(10) 16.84635 3.51737(10) ADRENAL GLANDS/ BRAIN* 100 * 3.38997 0.55983(10) 3.40764 0.46746(10) 3.58773 0.57406(10) 3.51049 0.51452(10) 3.65099 0.62860(10) THYROID GLAND/ BRAIN* 100 0.93019 0.15195(10) 0.89548 0.12478(10) 0.92130 0.23195(10) 0.95325 0.17695(10 1.01745 0.28439(10) UTERUS/ BRAIN* 100 41.05732 15.22120(10) 33.23672 9.22236(10) 38.15598 13.70562(10) 39.32106 9.46924(10) 38.22284 11.32543(10) OVARIES/ BRAIN*100 6.10926 1.18806(10) 6.80055 1.70454(10) 6.96446 1.70819(10) 7.05801 1.65752(10) 6.17057 0.97247(10) 138 Company Sanitized. Does not capitam TSCA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 37(CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAM FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) II Group 0 mg/kg/day Group X 300 mg/kg/day1 LIVER 9.56067 1.85565(9) 9.24544 1.16496(9) KIDNEYS 2.37811 0.29487(9) 2.30067 0.30399(9) HEART 1.22056 0.12026(9) 1.19378 0.13361(9) SPLEEN 0.53100 0.06307(9) 0.54144 0.06944(9) BRAIN 1.98367 0.07833(9) 1.93756 0.08583(9) THYMUS 0.32078 0.06797(9) 0.30778 0.07416(9) ADRENAL GLANDS 0.06422 0.01278(9) 0.06011 0.01574(9) THYROID GLAND 0.01811 0.00203(9) 0.02089 0.00434(9) OVARIES 0.12333 0.02183(9) 0.11756 0.01663(9) UTERUS 0.72178 0.23775(9) 0.70022 0.28483(9) FINAL BODY WEIGHT 356.77778 62.97787(9) 325.14444 31.49080(9) 139 Company SawYred ^"s p-t c-'-'t,'-''"! ^SCA GBl H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 37(CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAN RELATIVE ORGAN WEIGHTS I I Group 0 mg/kg/day Group X 300 ing/kg/day LIVER/ FINAL BODY*100 2.67851 0.18233(9) 2.84290 0.20658(9) KIDNEYS/ FINAL BODY*100 0.67295 0.05276(9) 0.70699 0.05197(9) HEART/ FINAL BODY*100 0.34703 0.03754(9) 0.36817 0.03426(9) SPLEEN/ FINAL BODY*100 0.15137 0.02313(9) 0.16828 0.02967(9) BRAIN/ FINAL BODY*100 0.56997 0.09306(9) 0.59971 0.04942(9) THYMUS/ FINAL BODY*100 0.09040 0.01484(9) 0.09493 0.02238(9) ADRENAL GLANDS/ FINAL BODY*100 0.01866 0.00604(9) 0.01842 0.00372(9) THYROID GLAND/ FINAL BODY*100 0.00515 0.00063(9) 0.00644* 0.00123(9) OVARIES/ FINAL BODY*100 0.03550 0.00850(9) 0.03636 0.00569(9) UTERUS/ FINAL BODY*100 0.20693 0.07187(9) 0.21760 -0.09061(9) 140 Company SanfSteed. Doss not conSaEn TSCA CBI H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 37(CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% organ to brain weight ratio) I I Group 0 mg/kg/day Group X 300 mg/kg/day LIVER/ BRAIN*100 481.85190 90.04451(9) 476.69219 50.80728(9) KIDNEYS/ BRAIN*100 119.93033 14.50344(9) 118.44874 11.51039(9) HEART/ BRAIN*100 61.57367 6.04114(9) 61.56573 5.83283(9) SPLEEN/ BRAIN*100 26.73712 2.67330(9) 28.01959 4.05704(9) THYMUS/ BRAIN*100 16.14120 3.23004(9) 15.94323 4.06477(9) ADRENAL GLANDS/ BRAIN*100 3.22922 0.59413(9) 3.08901 0.69960(9) THYROID GLAND/ BRAIN*100 0.91335 0.09895(9) 1.07557* 0.20505(9) OVARIES/ BRAIN*100 6.22973 1.12355(9) 6.06376 0.79569(9) UTERUS/ BRAIN*100 36.20586 11.14940(9) 36.25603 15.19679(9) 141 Company Sanitized. Does not contain TSCA CBI i.j.-^tti / o; auocnromc Toxicity 90-Day Oral Gavage Study in Rats DuPont-6554 TABLE 37(CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (THREE-MONTH RECOVERY EVALUATION) LIVER KIDNEYS THYROID GLAMD FINAL BODY WEIGHT MEAN FXMaL BODY I I Group 0 ing/kg/day 8.71380 0.93073(5) 2.30900 0.18728(5) 0.01540 0.00434(5) AMD ABSOLUTE ORGAN WEIGHTS (grams) Group VI 10 nig/kg/day* Group VTII 60 nig/kg/day'1 Group X 300 mg/kg/day' 9.73575 1.11897(4) 9.42960 1.66419(5) 10.41600 2.13378(5) 2.42400 0.43082(4) 2.43420 0.39420(5) 2.44660 0.28291(5) 0.01925 0.00350(4) 0.01660 0.00288(5) 0.02040 0.00467(5) 317.02000 32.07768(5) 356.72499 19.20909(4) 359-40000 32.90624(5) 353.60001 40.09009(5) LIVER/ FINAL BODY*100 KIDNEYS/ FINAL BODY*100 THYROID GLAND/ FINAL BODY*100 MEAN RELATIVE II Group 0 mg/kg/day ORGAN WEIGHTS (% Group VI 10 mg/kg/day8 of body weight) Group VIII 60 mg/kg/day'1 Group X 300 mg/kg/day3 2.76925 0.36928(5) 2.73048 0.2860.5(4) 2.61172 0.27937(5) 2.92797 0.34079(5) 0.73735 0.12031(5) 0.67915 0.10778(4) 0.67461 0.06254(5) 0.69425 0.06904(5) 0-00486 0.00122(5) 0.00541 0.00103(4) Mean Standard Deviation (n) 0.00461 0.00057(5) 0.00574 0.00092(5) # Statistically significant difference at p test. Group IV (isopropanol < 0.05 by Jonckheere-Terpstra trend * Statistically Dunnett's significant control) was difference from excluded from control (Group trend comparisons. II) at p < 0.05 by @ SDutannti'sstitceaslttle.ysts. ignificant difference from control (Group II) at p < 0.05 by 142 Company ganil'aed. -24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 38 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION) LESIONS LIVER NO ABNORMALITY DETECTED KIDNEYS MO ABNORMALITY DETECTED LUNGS NO ABNORMALITY DETECTED FLUID, CLEAR, DIFFUSE. HEART NO ABNORMALITY DETECTED SKELETAL MUSCLE NO ABNORMALITY DETECTED SPLEEN NO ABNORMALITY DETECTED AORTA NO ABNORMALITY DETECTED BRAIN NO ABNORMALITY DETECTED TREATMENT LESION INCIDENCE (Numeric) Males 0 ing/kg /day I 60 ing/kg /day9 III 10 ing/kg /day" v 60 ing/kg /day0 VII 300 nig/kg /day8 IX (10) (10) (10) (10) (11) 10 10 10 10 11 (10) (10) (10) (10) (11) 10 10 10 10 11 (10) (10) (10) (10) (11) 10 10 10 10 10 1 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) . 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 60 mg/kg/da b H-24678 id propanol 143 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 38(CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION) LESIONS SPINAL CORD NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTE3 ILEUM NO ABNORMALITY DETECTED PANCREAS NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED TREATMENT LESION INCIDENCE (Numeric) Males 0 nig/kg /day I 60 ing/kg /day' III 10 ing/kg /day" V 60 ing/kg /day13 VII 300 nig/kg /day6 IX (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified " 60 mg/kg/dj " H-24678 a panol 144 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 38(CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION) LESIONS RECTUM NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED SALIVARY GLANDS MO ABNORMALITY DETECTED MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED PITUITARY GLAND NO ABNORMALITY DETECTED TREATMENT LESION INCIDENCE (Numeric) Males 0 nig/kg /day I 60 nig/kg /day a III 10 mg/kg /day" V 60 ing/ kg /day" VII 300 ing/kg /day" IX (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not Identified 60n)g/kg/d nol b H-24678 145 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 38(CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION) LESIONS THYROID GLAND NO ABNORMALITY DETECTED PARATHYROID GLANDS NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED SKIN NO ABNORMALITY DETECTED PROSTATE NO ABNORMALITY DETECTED TREATMENT LESION INCIDENCE (Numeric) Males 0 ing/kg /day I 60 mg/kg /day" III 10 ing/kg /day" V 60 mg/kg /day" VII 300 nig/kg /day6 IX (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified % ' 60 mg/kg/i y b H-24678 is| 0 w 146 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 38(CONTINUED) INCIDENCES OP GROSS OBSERVATIONS IN MALE RATS (90-DAY EXPOSURE EVALUATION) LESIONS SEMINAL VESICLES NO ABNORMALITY DETECTED URINARY BLADDER NO ABNORMALITY DETECTED TESTES NO ABNORMALITY DETECTED EPIDIDYMIDES NO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED POPLITEAL LYMPH NODE MASS, LEFT. TREATMENT LESION INCIDENCE (Numeric) Males 0 mg/kg /day I 60 ing/kg /day8 III 10 mg/kg /day" V 60 mg/kg /day" VII 300 mg/kg /day6 IX (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (1) 1 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (,11) 11 (11) 11 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 60 mg/kg/da' 11 H-24678 147 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 38(CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (ONE-MONTH RECOVERY EVALUATION) LESIONS LIVER NO ABNORMALITY DETECTED HERNIA. KIDNEYS NO ABNORMALITY DETECTED LUNGS NO ABNORMALITY DETECTED HEART NO ABNORMALITY DETECTED SKELETAL MUSCLE NO ABNORMALITY DETECTED SPLEEN NO ABNORMALITY DETECTED AORTA NO ABNORMALITY DETECTED BRAIN MO ABNORMALITY DETECTED LESION INCIDENCE (Numeric) TREATMENT Males 0 nig/kg /day I 300 ing/kg /day8 IX (10) (9) 9 9 1 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified OS 148 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 38(CONTINUED) INCIDENCES OP GROSS OBSERVATIONS IN MALE RATS (ONE-MONTH RECOVERY EVALUATION) LESIONS SPINAL CORD NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED PANCREAS NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED LESION INCIDENCE (Numeric) Males TREATMENT 0 mg/kg /day I 300 nig/kg /day IX (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 Figures in parentheses is the number o animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 149 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 38(CONTINUED) INCIDENCES OP GROSS OBSERVATIONS IN MALE RATS (ONE-MONTH RECOVERY EVALUATION) LESIONS RECTUM NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED PITUITARY GLAND NO ABNORMALITY DETECTED LESION INCIDENCE (Numeric) Males TREATMENT 0 ing/kg /day I 300 ing/kg /day' IX (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 150 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 38(CONT1NUED) INCIDENCES OP GROSS OBSERVATIONS IN MALE RATS (ONE-MONTH RECOVERY EVALUATION) LESIONS THYROID GLAND NO ABNORMALITY DETECTED PARATHYROID GLANDS NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED SKIN NO ABNORMALITY DETECTED PROSTATE NO ABNORMALITY DETECTED LESION INCIDENCE (Numeric) Males TREATMENT 0 ing/kg /day I 300 mg/kg /day8 IX (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 151 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 38(CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (ONE-MONTH RECOVERY EVALUATION) LESIONS SEMINAL VESICLES NO ABNORMALITY DETECTED URINARY BLADDER NO ABNORMALITY DETECTED TESTES NO ABNORMALITY DETECTED EPIDIDYMIDES MO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED LESION INCIDENCE (Numeric) Males TREATMENT 0 mg/kg /day I 300 Mg/kg /day' IX (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 Figures in parentheses is the nuniber of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 152 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 38(CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (THREE-MONTH RECOVERY EVALUATION) LESIONS LIVER NO ABNORMALITY DETECTED DISCOLORATION, PALE. KIDNEYS NO ABNORMALITY DETECTED DISCOLORATION, MOTTLED, BILATERAL. CHRONIC PROGRESSIVE NEPHROPATHY, BILATERAL. LUNGS NO ABNORMALITY DETECTED HEART NO ABNORMALITY DETECTED SKELETAL MUSCLE NO ABNORMALITY DETECTED SPLEEN NO ABNORMALITY DETECTED AORTA NO ABNORMALITY DETECTED TREATMENT LESION INCIDENCE (Numeric) Males 0 ing/kg /day I 10 nig/kg /day' V 60 xng/kg /day' VII 2JOO n?g/kg /day' ix (5) (5) (5) (5) 5 5 4 5 1 (5) (5) (5) (5) 5 4 4 5 1 1 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence^ of a number indicates the finding specified was not identified 153 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 38(CONT]NUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (THREE-MONTH RECOVERY EVALUATION) LESIOMS BRAIN NO ABNORMALITY DETECTED SPINAL CORD NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED ILEUM MO ABNORMALITY DETECTED PANCREAS NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED TREATMENT LESION INCIDENCE (Numeric) Males 0 ing/kg /day 10 mg/kg /day-1 V 60 ing/kg /day8 VII 300 mg/kg /day8 IX (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5. 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 154 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 38(CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (THREE-MONTH RECOVERY EVALUATION) LESIONS COLON MO ABNORMALITY DETECTED RECTUM NO ABNORMALITY DETECTED MESENTERXC LYMPH NODE NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED THYMOS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED TREATMENT LESION INCIDENCE (Numeric) Males 0 nig/kg /day I 10 nig/kg /day3 V 60 nig/kg /day a VII 3;00 ing/kg /day1 IX (5) 15) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5)' (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 155 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 38(CONTINUED) INCIDENCES OP GROSS OBSERVATIONS IN MALE RATS (THREE-MONTH RECOVERY EVALUATION) LESIONS TREATMENT LESIOM INCIDENCE (Numeric) Males 0 ing/kg /day I 10 nig/kg /day' V 60 ing/kg /day' VII 300 nig/kg /day8 IX PITUITARY GLAND MO ABNORMALITY DETECTED (5) (5) (5) (5) 5 5 5 5 THYROID BLAMD NO ABNORMALITY DETECTED (5) (5) (5) (5) 5 5 5 5 PARATHYROID GLANDS ' NO ABNORMALITY DETECTED (5) (5) (5) (5) 5 5 5 5 TRACHEA NO ABNORMALITY DETECTED (5) (5) (5) (5) 5 5 5 5 ESOPHAGUS NO ABNORMALITY DETECTED (5) (5) (5) (5) 5 5 5 5 PHARYMX/LARYMX NO ABNORMALITY DETECTED (5) (5) (5) (5) 5 5 5 5 EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED (5) (5) (5) (5) 5 5 5 5 % SKIN NO ABNORMALITY DETECTED a. 15) (5) (5) (5) 5 5 5 5 0 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 S5". -4 w a > 0 S3 156 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 38(CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS (THREE-MONTH RECOVERY EVALUATION) LESIONS PROSTATE NO ABNORMALITY DETECTED SEMINAL VESICLES MO ABNORMALITY DETECTED URINARY BLADDER HO ABNORMALITY DETECTED TESTES NO ABNORMALITY DETECTED DISCOLORATION, OPAQUE, LEFT. EPIDIDYMIDES NO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED TREATMENT LESION INCIDENCE (Numeric) Males 0 mg/kg /day I 10 ing/kg /day" V 60 ing/kg /day2 VII 300 ing/kg /day" IX (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 4 5 5 5 1 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 157 H-24678: Subchronic Toxicity 90-Day Oral Oavage Study in Rats TABLE 39 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION) LESIONS TREATMENT LIVER MO ABNORMALITY HERMIA. DISCOLORATION, DETECTED DARK, RAISED, LEFT, MIDDLE. KIDNEYS NO ABNORMALITY DETECTED CYST, RIGHT. LUNGS NO ABNORMALITY DETECTED HEART NO ABNORMALITY DETECTED SKELETAL MUSCLE NO ABNORMALITY DETECTED SPLEEN MO ABNORMALITY DETECTED AORTA NO ABNORMALITY DETECTED LESION INCIDENCE (Numeric) Females 0 nig/kg /day II 60 nig/kg /day' IV 10 nig/kg /day" VI 60 300 mg/kg nig/kg /day1' |/day VIII X (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 (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 (10) 10 (11) 10 1 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 Figures in parentheses is the number o animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified " 60 nig/kg/I " H-24678 ' 158 H-24678; Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 39(CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION) LESIONS BRAIN NO ABNORMALITY DETECTED SPINAL CORD NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED PANCREAS NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED TREATMENT ' LESION INCIDENCE (Numeric) Females 0 ing/kg /day II 60 ing/kg /day a IV 10 rng/kg /day1' VI 60 300 1 / y mg/kg /day" VIII X (10) 10 (10) 10 (10) 10 (10) 10 , (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified " 60 mg/kg/dg " H-24678 i:" 159 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION) LESIONS COLON MO ABNORMALITY DETECTED RECTUM NO ABNORMALITY DETECTED MESEMTERIC LYMPH NODE NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED MANDIBULAR LYMPH NODE MO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED ADRENAL GLAMDS NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED TREATMENT LESION INCIDENCE (Numeric) Females 0 ing/kg /day II 60 ing/kg /day" IV 10 nig/kg /day" VI 60 ing/kg /day" VIII 300 nig/kg /day6 X (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) (10) 10 10 (10) (10) 10 10 (10) (10) 10 10 (10) (10) 10 10 (10) 10 (10) 10 (10) (10) 10 10 (10) (10) 10 10 (10) (10) 10 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 (11) 11 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 60 mg/kg/da: b H-24678i; 160 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALEiRATS (90-DAY EXPOSURE EVALUATION) LESIONS PITUITARY GLAMD NO ABNORMALITY DETECTED THYROID GLAND NO ABNORMALITY DETECTED PARATHYROID GLANDS NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED SKIN NO ABNORMALITY DETECTED TREATMENT LESION INCIDENCE (Numeric): Females 0 ing/kg /day II 60 nig/kg /day' IV 10 ing/kg /day1' VI 60 nig/kg /day1' VIII 300 ing/kg /flay" X (10) 10 (10) 10 (10) 10 110) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (11) 11 (11) 11 (11) 11 (11) 11 (.11) 11 (11) 11 (!ll) 11 1:11) 11 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 60 mg/kg/d b H-24678 il panol 161 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 39 (CONTINUED) INCIDENCES OP GROSS OBSERVATIONS IN FEMALE RATS (90-DAY EXPOSURE EVALUATION) LESIONS MAMMARY GLAND (FEMALE) NO ABNORMALITY DETECTED OVARIES NO ABNORMALITY DETECTED UTERUS NO ABNORMALITY DETECTED VAGINA MO ABNORMALITY DETECTED URINARY BLADDER MO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED TREATMENT LESION INCIDENCE (Numeric) Females 0 ing/kg /day II 60 ing/kg /day3 IV 10 ing/kg /day" VI 60 mg/kg /day" VIII 3]00 mg/kg /day6 X (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (3.1) 11 (11) 11 (.11) 11 (11) 11 (11) 11 (;11) 11 (.11) 11 I'll) 11 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 60 mg/kg/dj^ I^opropanol 11 H - 2 4 6 7 8 i 162 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) LESIONS LIVER NO ABNORMALITY DETECTED KIDNEYS NO ABNORMALITY DETECTED LUNGS NO ABNORMALITY DETECTED HEART NO ABNORMALITY DETECTED SKELETAL MUSCLE NO ABNORMALITY DETECTED SPLEEN MO ABNORMALITY DETECTED AORTA NO ABNORMALITY DETECTED BRAIN NO ABNORMALITY DETECTED LESION INCIDENCE (Numeric) | Females TREATMENT 0 mg/kg /day II 3|00 irig/kg /day a X (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 Figures in parentheses is the number o animals grossly examined for this tissue The absence of a number indicates the finding specified, was not identified 163 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) LESIONS SPINAL CORD NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED PANCREAS NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED LESXON INCIDENCE (Numeric) Females TREATMENT 0 ing/kg /day II 3p0 ing/kg /day" Xi (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 164 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) LESIONS RECTUM NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED MAMDIBULAR LYMPH NODE NO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED PITUITARY GLAND NO ABNORMALITY DETECTED LESION INCIDENCE (Numeric) Females TREATMENT 0 ing/kg /day II 300 ing/kg /day8 X (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 165 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) LESIONS THYROID GLAND NO ABNORMALITY DETECTED PARATHYROID GLANDS NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED PHARYNX/ LARYNX NO ABNORMALITY DETECTED EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED DISCOLORATION, WHITE, LEFT. SKIN NO ABNORMALITY DETECTED MAMMARY GLAND (FEMALE) NO ABNORMALITY DETECTED LESION INCIDENCE (Numeric )| Females TREATMENT 0 ing/kg /day II 300 nfg/kg /day2 X (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 9 9 1 (10) (9) 10 9 (10) (9) 10 9 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 166 ^y,; H-24678: Subchronic Toxicity 90-Day Oral Oavage Study in Rats TABLE 39 (CONTINUED) INCIDENCES OP GROSS OBSERVATIONS IN FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) LESION INCIDENCE (Numeric) LESIONS OVARIES NO ABNORMALITY DETECTED UTERUS NO ABNORMALITY DETECTED VAGINA NO ABNORMALITY DETECTED URINARY BLADDER NO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED . NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED TREATMENT Females 0 nig/kg /day II 300 , nig/kg /day " X (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 (10) (9) 10 9 Fig The u res abs e in nc e par of e n a t heses numbe r i s in the dica num tes ber the o f i anima nding l s s grossly pecified examined for this tissue was not identified 167 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (THREE-MONTH RECOVERY EVALUATION) LESIONS LIVER MO ABNORMALITY DETECTED KIDNEYS NO ABNORMALITY DETECTED DILATATION, LEFT. LUNGS NO ABNORMALITY DETECTED HEART NO ABNORMALITY DETECTED SKELETAL MUSCLE MO ABNORMALITY DETECTED SPLEEN NO ABNORMALITY DETECTED AORTA NO ABNORMALITY DETECTED BRAIN NO ABNORMALITY DETECTED TREATMENT LESION INCIDENCE (Numeric) females 0 ing/kg /day II 10 ing/kg /day" VI 60 mg/kg /day8 VIII 3:00 mg/kg /day a | (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 4 5 5 1 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) 15) (5) (5) 5 5 5 5 15) (5) (5) (5) 5 5 5 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 168 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (THREE-MONTH RECOVERY EVALUATION) LESIONS SPINAL CORD NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED PANCREAS NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED TREATMENT , LESION INCIDENCE (Numeric) Females 0 nig /kg /day II 10 mg/kg /day8 VI 60 ing/kg /day3 VIII 300 mg/kg /day a | X (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 t5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 Figures in parentheses is the number of animals grossly examined tor this tissue The absence of a number indicates the finding specified was not identified 169 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (THREE-MONTH RECOVERY EVALUATION) LESIONS RECTUM NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED SCIATIC NERVE MO ABNORMALITY DETECTED PITUITARY GLAND NO ABNORMALITY DETECTED TREATMENT LESION INCIDENCE (Numeric) Females 0 ing/kg /day II 10 mg/kg /day* VI 60 | 300 ing/kg| mg/kg /day ' |/day a VIII | X (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 Figures in parentheses is the number o animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 170 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (THREE-MONTH RECOVERY EVALUATION) LESIONS THYROID GLAND NO ABNORMALITY DETECTED PARATHYROID GLANDS MO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED SKIN NO ABNORMALITY DETECTED MASS, PINK, FIRM, INGUEM, RIGHT. MAMMARY GLAND (FEMALE) NO ABNORMALITY DETECTED TREATMENT LESION INCIDENCE (Numeric) Females 0 mg/kg /day II 10 mg/kg /day3 VI 60 ing/kg /day" VIII 300 ing/kg /day8 X (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 15) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 4 5 5 1 (5) (5) (5) (5) 5 5 5 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 171 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS (THREE-MONTH RECOVERY EVALUATION) LESIONS OVARIES NO ABNORMALITY DETECTED UTERUS MO ABNORMALITY DETECTED URINARY BLADDER NO ABNORMALITY DETECTED CALCULUS\CALCULI. FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED TREATMENT LESION INCIDENCE (Numeric) Females 0 nig/kg /day II 10 mg/kg /day* VI 60 ing/kg /day' VIII 300 rog/kg /day3 X (5) (5) (5) (5) 5 5 5 5 (5) (5) 15) (5) 5 5 5 5 (5) (5) (5) (5) 5 4 5 5 1 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 (5) (5) (5) (5) 5 5 5 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified 172 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 40 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS- NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS TREATMENT LESION INCIDENCE (NUMERIC) 0 ing/kg /day I 60 ing/kg /day' III Males 10 | 60; ing/kg ( nig/kg /day" | /day11 V 1 VI It 300 ing/kg /day ] IX DIGESTIVE SYSTEM TLIT.LiVn&roK NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC. HYPERTROPHY, HEPATOCYTE, CENTRILOBULAR. HYPERPLASIA, BILE DUCT. FATTY CHANGE, MEDIAN CLEFT. FATTY CHANGE, CENTRILOBULAR. 110) 10 (10) 10 3 (10) 4 10 1 3 (10) 3 10 1 2 3 (11) 9 10 1 2 FThigeuraebseinncpe aroefntahensuemsbeirs inndumicbaetresof thaenimleaslsionmiscproesccifoiepdicawlalys nexoatmiidneedntfiofiredthis tissue 173 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS DIGESTIVE SYSTEM TREATMENT LESION INCIDENCE (NUMERIC) Males 0 mg/kg /day I 60 mg/kg /day8 III 10 60i 300 mg/kg mg/kg mg/kg /day" |/day1) |/day V VII IX PANCREAS MO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. HYPERPLASIA, FOCAL, ACINAR CELL. ATROPHY. ALTERATION, BASOPHILIC, FOCAL. (10) 6 1 4 (11) 7 3 1 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 "60mg/kg/d b H-24678 panol 174 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS' (90-DAY EXPOSURE EVALUATION) LESIONS DIGESTIVE SYSTEM TREATMENT LESION INCIDENCE (NUMERIC) Males 0 ing/kg /day I 60 mg/kg /day3 III 10 ing/kg /day" V 60 , mg/kg /day1' vi ni 300 ing/kg /day6 IX ESOPHAGUS NO ABNORMALITY DETECTED (10) (10) 10 10 STOMACH NO ABNORMALITY DETECTED (10) (11) 10 11 DUODENUM NO ABNORMALITY DETECTED (10) (11) 10 11 JEJUNUM NO ABNORMALITY DETECTED (10) (11) 10 11 ILEUM NO ABNORMALITY DETECTED (10) (11) 10 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified n 60 mg/kg/i " H-24678 i: 175 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS DIGESTIVE SYSTEM TREATMENT LESION INCIDENCE (NUMERIC) Males 0 mg/kg /day I 60 mg/kg /day a III 10 mg/kg /day" V 60 300 mg/kg mg/kg /day" |/day VII IX CECUM NO ABNORMALITY DETECTED (10) (11) 10 11 COLON NO ABNORMALITY DETECTED (10) (11) 10 11 RECTUM NO ABNORMALITY DETECTED (10) (11) 10 11 SALIVARY GLANDS NO ABNORMALITY DETECTED (10) (11) 10 11 Figure in parentheses is number of animals microscopically examined tor this tissue The absence of a number indicates the lesion specified was not identified " 60 mg/kg/d^ b H-24678 is, propanol 176 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS URINARY SYSTEM TREATMENT LESION INCIDENCE (NUMERIC) Males 0 mg/kg /day I 60 mg/kg /day8 III 10 | 60 ing/kg] ing/kg /day" I/day" V VII 300 nig/kg /day6 IX KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. HYPERTROPHY, TUBULAR. HYDRONEPHROSIS, UNILATERAL. CYST. (10) 5 5 (10) 8 2 (10) 5 4 1 (10) 5 4 1 (11) 8 11 URINARY BLADDER NO ABNORMALITY DETECTED (10) (11) 10 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified ' 60 mg/kg/dMjsop b H-24678 isl 177 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS RESPIRATORY SYSTEM TREATMENT LESION INCIDENCE (NUMERIC) Males 0 xng/kg /day I 60 ing/kg /day" III 10 ing/kg /day13 V 60 ing/kg /day" VII 300 ing/kg /day0 IX LUNGS NO ABNORMALITY DETECTED FOREIGN MATERIAL. EDEMA. (10) 10 (11) 10 1 1 TRACHEA NO ABNORMALITY DETECTED (10) (11) 10 11 PHARYMX/LARYNX NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. (10) 9 1 (11) 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 60 mg/kg/^ b H-24678 i| panol 178 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS RESPIRATORY SYSTEM TREATMENT LESION INCIDENCE (NUMERIC) Males 0 mg/kg /day I 60 ing/kg /day3 III 10 ing/kg /day" V 60 mg/kg /day" VII 300 ing/kg /day" IX NOSE NO ABNORMALITY DETECTED ODONTODYSPLASIA. INFLAMMATION, SUBACUTE/CHRONIC. FOREIGN MATERIAL. DEGENERATION/NECROSIS, OLFACTORY, EPITHELIUM. (10) 9 1 (11) 7 2 1 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified " 60 mg/kg/d b H-24678 id panol 179 H-24678: Snbchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS CARDIOVASCULAR SYSTEM TREATMENT LESION INCIDENCE (NUMERIC) Males 0 ing/kg /day I 60 ing/kg /day a III 10 ing/kg /day'3 V 60 ing/kg /day" VII 300 ing/kg /day11 IX HEART NO ABNORMALITY DETECTED CARDIOMYOPATHY. (10) 9 1 (11) 7 4 AORTA N"3 ABNORMALITY DETECTED (10) (11) 10 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 60 mg/kg/d b H-24678 i| panel 180 H-24678; Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM TREATMENT LESION INCIDENCE (NUMERIC) Males 0 ing/kg /day I 60 ing/kg /day' III 10 mg/kg /day" V 60 ing/kg /day" VII 300 rog/kg /day | IX SPLEEN NO ABNORMALITY DETECTED (10) (11) 10 11 THYMUS NO ABNORMALITY DETECTED (10) (11) 10 11 MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED (10) (11) 10 11 MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED (10) (11) 10 11 POPLITEAL LYMPH NODE (1) HEMANGIOSARCOMA [M] . 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 60 mg/kg/d b H-24678 ij panol 181 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESXONS LYMPHATIC AND HEMATOPOIETIC SYSTEM TREATMENT LESION INCIDENCE (HOMERIC) Males 0 ing/kg /day I 60 ing/kg /day8 III 10 ing/kg /day" V 60 300 mg/kg mg/kg /day" I/day6 VII IX BONE MARROW NO ABNORMALITY DETECTED (10) (11) 10 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified " 60 mg/kg/da;; Isi " H-24678 i; 182 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 40 (CONTINUED) LESIONS ENDOCRINE SYSTEM INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESION INCIDENCE (NUMERIC) Males TREATMENT 0 nig/kg /day I 60 mg/kg /day' III 10 mg/kg /day" y 60 mg/kg /day" VII 300 ing/kg /day6 IX PITUITARY GLAND NO ABNORMALITY DETECTED (10) (11) 10 11 THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. ALTERATION, COLLOID. AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. (10) 5 5 (10) 2 8 (10) 2 8 (10) 5 2 4 (11) 1 7 10 1 PARATHYROID GLANDS NO ABNORMALITY DETECTED (9) (9) 9 9 ADRENAL GLANDS NO ABNORMALITY DETECTED (10) (11) 10 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 1160 mg/kg/d^ " H-24678 i;"" 183 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS; (90-DAY EXPOSURE EVALUATION) LESIONS NERVOUS SYSTEM TREATMENT LESION INCIDENCE (NUMERIC) Males 0 nig/kg /day I 60 mg/kg /day' III 10 mg/kg /day" V 60 mg/ikg /day" VIE 300 ing/kg /day6 IX BRAIN NO ABNORMALITY DETECTED (10) (11) 10 11 SPINAL CORD NO ABNORMALITY DETECTED (10) (11) 10 11 SCIATIC NERVE NO ABNORMALITY DETECTED (10) (11) 10 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 60 mg/kg/i " H-24678 i! 184 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS MUSCULAR AND SKELETAL SYSTEM TREATMENT LESION INCIDENCE (NUMERIC) Males 0 mg/kg /day I 60 nig/kg /day" III 10 ing/kg /day b v 60 300 nig/kg mg/kg /day " I/day5 vn IX SKELETAL MUSCLE NO ABNORMALITY DETECTED FEMUR/KMEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (11) 11 (11) 11 (11) 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified " 60 mg/kg/d " H-24678 isj panol 185 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS REPRODUCTIVE SYSTEM THEATMENT LESION INCIDENCE (NUMERIC) Males 0 nig/kg /day I 60 ing/kg /day' III 10 ing/kg /day13 V 60 300 mg/kg nig/kg /day" I/day VII IX TESTES MO ABNORMALITY DETECTED DEGENERATION/ATROPHY, SEMINIFEROUS TUBULES, BILATERAL.' (10) 10 (11) 10 1 EPIDIDYMIDES NO ABNORMALITY DETECTED (10) (11) 10 11 PROSTATE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. (10) 7 3 (11) 9 2 SEMINAL VESICLES NO ABNORMALITY DETECTED (10) (11) 10 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified a 60 mg/kg/di b H-2467S i!' 186 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MA1E RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS CUTANEOUS SYSTEM TREATMENT LESION INCIDENCE (NUMERIC) Males 0 ing/kg /day I 60 mg/kg /day" III 10 mg/kg /day1' V 60 300 ing/kg mg/kg /day" |/day VI I IX SKIN NO ABNORMALITY DETECTED (10) (11) 10 11 SPECIAL SENSES SYSTEM EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED FOLD/ROSETTE, RETINAL. ATROPHY, RETINAL. (10) 8 1 1 (11) 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified " 60 mg/kg/^gjfcl^opropanol b H-24678i 187 '^-^/ H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS DIGESTIVE SYSTEM LESION INCIDENCE (NUMERIC) TREATMENT Males 0 ing/kg /day I 300 mg/kg /day' IX LIVER MO ABNORMALITY DETECTED NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC. HYPERTROPHY, HEPATOCYTE, CENTRILOBULAR. FATTY CHANGE, MEDIAN CLEFT. FATTY CHANGE, CENTRILOfiULAR. (10) (9) 1 1 9 9 6 3 1 1 Figure in parentheses is number o animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 188 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MAT .P. RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS URINARY SYSTEM LESION INCIDENCE (NUMERIC) TREATMENT Males 0 nig/kg /day I 300 mg/kg /day' IX KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. HYDRONEPHROSIS, UNILATERAL. (10) (9) 3 4 7 4 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 189 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS LESION IMCIDENCE (MUMERIC) TREATMENT Males 0 nig/kg /day I 300 nig/kg /day3 IX ENDOCRINE SYSTEM THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. ALTERATION, COLLOID. AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. (10) (9) 5 6 5 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 190 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 40 (CONTINUED) LESIONS INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESION INCIDENCE (NUMERIC) TREATMENT Males 0 ing/kg /day I 10 ing/kg /day8 V 60 ing/kg /day a VII 300 ing/kg /day IX DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED NECROSIS, FOCAL. INFLAMMATION, SUBACUTE / CHRONIC. HYPERPLASIA, BILE DUCT. FIBROSIS, BILE DUCT. FATTY CHANGE, MEDIAN CLEFT. FATTY CHANGE, CENTRILOBULAR. ECTASIA, BILE DUCT. (5) (5) (5) (5) 1 1 1 3 3 4 5 5 1 1 1 2 1 1 1 ENDOCRINE SYSTEM THYROID GLAND (5) (5) (5) (5) ALTERATION, COLLOID. 5 5 5 5 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 191 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 41 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS DIGESTIVE SYSTEM TREATMENT LESION INCIDENCE (NUMERIC) Females 0 ing/kg /day II 60 ing/kg /day' IV 10 ing/kg /day" VI 60 ing/kg /day" VIII 300 ing/kg /day6 X LIVER NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/'CHRONIC. FATTY CHANGE, MEDIAN CLEFT. AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. (10) 9 3 (11) 4 7 1 1 PANCREAS NO ABNORMALITY DETECTED HYPERPLASIA, FOCAL, ACIMAR CELL. DEGENERATION/MECROSIS, ACINAR CELL. ATROPHY. (10) 7 1 1 2 (11) 9 2 1 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 60 mg/kg/da' ''?246781;" 192 'VsW I v3/ H-24678: Subctu-onic Toxicity 90-Day Oral Gavage Study in Rats TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS DIGESTIVE SYSTEM TREATMENT LESION INCIDENCE (NUMERIC) Females 0 ing/kg /day II 60 ing/kg /day8 IV 10 nig/kg /day1' VI 60 300 ing/kg ing/kg /day" I/day6 | VIII x ESOPHAGUS NO ABNORMALITY DETECTED INFLAMMATION, SUBACOTE/ CHRONIC. (10) 9 1 (11) 9 2 STOMACH NO ABNORMALITY DETECTED (10) (11) 10 11 DUODENUM MO ABNORMALITY DETECTED AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. (10) 10 (11) 11 1 JEJUNUM (10) (11) NO ABNORMALITY DETECTED 10 11 AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. 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 p 60 mg/kg/dg b H-24678 i| panol 193 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 41 (CONTINUED) INCIDENCES OP MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS DIGESTIVE SYSTEM ILEUM NO ABNORMALITY DETECTED AUTOLYSIS: NECROPSY AMD HISTOLOGY PERFORMED. TREATMENT LESION INCIDENCE (NUMERIC) Females 0 mg/kg /day II 60 nig/kg /day' IV 10 nig/kg /day1' VI 60 nig/kg /day" VIII 300 mg/kg /day6 x (10) (11) 10 11 1 CECUM NO ABNORMALITY DETECTED (10) (11) 10 11 COLON NO ABNORMALITY DETECTED (10) (11) 10 11 RECTUM NO ABNORMALITY DETECTED (10) (11) 10 11 Figure in parentheses is number o animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified " 60 mg/kg/d 11 H-24678 i| 194 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS DIGESTIVE SYSTEM TREATMENT LESION INCIDENCE (NUMERIC) Females 0 mg/kg /day II 60 mg/kg /day8 IV 10 ing/kg /day" VI 60 mg/kg /day" VIII 300 mg/kg /day5 X SALIVARY GLANDS NO ABNORMALITY DETECTED (10) (11) 10 11 URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. INFARCT. AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. (10) 6 4 1 (11) 8 3 1 URINARY BLADDER NO ABNORMALITY DETECTED (10) (11) 10 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified " 60 mg/kg/d; b H-24678 ij paiiol 195 H-24678; Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 41 (CONTINUED) LESIONS RESPIRATORY SYSTEM INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) TREATMENT LESION INCIDENCE (NUMERIC) Females 0 ing/kg /day II 60 ing/kg /day' IV 10 mg/kg /day" VI 60 ing/kg /day" VIII 300 nig/kg /day b | X LUNGS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE,'CHRONIC. (10) 9 1 (11) 11 TRACHEA NO ABNORMALITY DETECTED (10) (11) 10 11 PHARYNX/LARYNX (10) NO ABNORMALITY DETECTED 9 INFLAMMATION, SUBACUTE/CHRONIC. 1 NOSE (10) NO ABNORMALITY DETECTED 10 REGENERATION, OLFACTORY, EPITHELIUM. AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified ' ' 60 mg/kg/d nol " H-24678 i (10) 10 (11) 10 1 1 196 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 41 (CONTINUED) INCIDENCES OP MICROSCOPIC OBSERVATIONS IN FEMALE RATS(90-DAY EXPOSURE EVALUATION) LESIONS CARDIOVASCULAR SYSTEM TREATMENT LESION INCIDENCE (NUMERIC) Females 0 ing/kg /day II 60 nig/kg /day8' IV 10 ing/kg /day" VI 60 300 ing/kg ing/kg /day" |/day VIII HEART MO ABNORMALITY DETECTED CARDIOMYOPATHY. (10) 9 1 (11) 9 2 AORTA NO ABNORMALITY DETECTED (10) (11) 10 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified " 60 mg/kg/d b H-24678 id panol 197 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM TREATMENT LESION INCIDENCE (NUMERIC) Females 0 ing/kg /day II 60 ing/kg /day* IV 10 nig/kg /day" VI 60 mg/kg /day" VII;I 300 ing/kg /day" X SPLEEN NO ABNORMALITY DETECTED (10) (11) 10 11 THYMUS NO ABNORMALITY DETECTED (10) (11) 10 11 MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED (10) (11) 10 11 MESEMTERIC LYMPH NODE NO ABNORMALITY DETECTED (10) (11) 10 11 BONE MARROW (10) (11) NO ABNORMALITY DETECTED 10 11 AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. 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 " 60 mg/kg/d " H-24678 ifi panol 198 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats ^ /iv^vy TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS ENDOCRINE SYSTEM PITUITARY GLAND NO ABNORMALITY DETECTED CYST. THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. ALTERATION, COLLOID. AUTOLYSIS: NECROPSY AMD HISTOLOGY PERFORMED. TREATMENT LESION INCIDENCE (NUMERIC) Females 0 mg/kg /day II 60 mg/kg /day' IV 10 mg/kg /day b VI 60 mg/kg /day" VIII 300 mg/kg /day6 X (10) 10 (10) 5 5 (10) 8 2 (10) 7 3 (10) 6 4 (11) 10 1 (11) 8 1 3 1 PARATHYROID GLANDS NO ABNORMALITY DETECTED (8) (7) S 7 ADRENAL GLANDS (10) (11) NO ABNORMALITY DETECTED 10 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified we.s not identified 60 mg/kg/day Isppropanol " H-24678 199 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS NERVOUS SYSTEM TREATMENT LESION INCIDENCE (NUMERIC) Females 0 ing/kg /day II 60 nig/kg /day8 IV 10 mg/kg /day" VI 60 300 nig/kg rog/kg /day" |/day 6 VIII x BKAIN NO ABNORMALITY DETECTED (10) (11) 10 11 SPINAL CORD NO ABNORMALITY DETECTED (10) (11) 10 11 SCIATIC NERVE NO ABNORMALITY DETECTED (10) (11) 10 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 60 mg/kg/day Ig " H-246781 200 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS MUSCULAR AND SKELETAL SYSTEM TREATMENT LESION INCIDENCE (NUMERIC) Females 0 nig/kg /day II 60 nig/kg /day2 IV 10 1 60 300 ing/kg | Big/kg ing/kg /day" [/day" |/day s VI VIII x SKELETAL MUSCLE NO ABNORMALITY DETECTED (10) (11) 10 11 FEMUR/KNEE JOINT NO ABNORMALITY DETECTED (10) (11) 10 11 STERNUM NO ABNORMALITY DETECTED (10) (11) 10 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence o a number indicates the lesion specified was not identified 60 rngflkg/dj^Isj b H-24678 ii 201 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS REPRODUCTIVE SYSTEM TREATMENT LESION INCIDENCE (NUMERIC! Females 0 nig/kg /day II 60 nig/kg /day" IV 10 nig/kg /day" VI 60 mg/kg /day" VIII 300 mg/kg /day5 OVARIES NO ABNORMALITY DETECTED (10) (11) 10 11 UTERUS NO ABNORMALITY DETECTED DILATATION, BLAND/LUMEN. (10) 6 4 (11) 9 2 MAMMARY GLAMD (FEMALE) MO ABNORMALITY DETECTED (8) (11) 8 11 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 60 mg/kg/day Ispprg " H-24678 id 202 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS CUTANEOUS SYSTEM TREATMENT LESION INCIDENCE (NUMERIC) Females 0 mg/kg /day II 60 ing/kg /day" IV 10 ing/kg /day" VT 60 300 ing/kg ing/kg /day13 |/day b VIII X SKIN NO ABNORMALITY DETECTED (10) (11) 10 11 SPECIAL SENSES SYSTEM EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED OPTIC NERVE NOT PRESENT. AUTOLYSIS-: NECROPSY AND HISTOLOGY PERFORMED. (10) 10 1 (11) 11 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 60 mg/kg/dOT b H-24678 isj anol 203 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS DIGESTIVE SYSTEM LESIOM INCIDENCE (NUMERIC) | Females TREATMENT 0 ing/kg /day II 300 nig/kg /day a X LIVER (1) FATTY CHANGE, MEDIAN CLEFT. 1 PANCREAS (1) NO ABNORMALITY DETECTED 1 ESOPHAGUS (1) NO ABNORMALITY DETECTED 1 STOMACH (1) MO ABNORMALITY DETECTED 1 DUODENUM (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 204 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS DIGESTIVE SYSTEM LESION INCIDENCE (NUMERIC) I Females TREATMENT 0 300 mg/kg ag/kg /day /day' II x JEJUNUM (1) NO ABNORMALITY DETECTED AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. ILEUM (1) NO ABNORMALITY DETECTED AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. CECUM (1) NO ABNORMALITY DETECTED 1 COLON (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 205 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats spy ^./ TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS; (ONE-MONTH RECOVERY EVALUATION) LESIONS DIGESTIVE SYSTEM LESION INCIDEMCE (NUMERIC) TREATMENT females 0 mg/.kg /day II 300 mg/kg /day" X RECTUM (1) NO ABNORMALITY DETECTED I SALIVARY GLANDS (1) NO ABNORMALITY DETECTED 1 URINARY SYSTEM KIDNEYS (1) NO ABNORMALITY DETECTED 1 URINARY BLADDER (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 206 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS' (ONE-MONTH RECOVERY EVALUATION) LESIONS RESPIRATORY SYSTEM LESION INCIDENCE (NUMERIC) | Females TREATMENT 0 300 ing/peg mg/kg /dayi II /day" X LUNGS (1) NO ABNORMALITY DETECTED 1 TRACHEA (li) NO ABNORMALITY DETECTED 1 PHARYNX / LARYNX (1) NO ABNORMALITY DETECTED 1 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 207 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS i (ONE-MONTH RECOVERY EVALUATION) LESIONS CARDIOVASCULAR SYSTEM LESION INCIDENCE (NUMERIC) I Eemales TREATMENT 0 nig/kg /day ' II 300 mg/kg /day8 X HEART (1) NO ABNORMALITY DETECTED 3. AORTA (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 208 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM LESION INCIDENCE (NUMERIC) TREATMENT Females 0 ing/kg /day II 300 ing/kg /day' X SPLEEN (1) NO ABNORMALITY DETECTED 1 THYMUS (1) NO ABNORMALITY DETECTED 1 MANDIBULAR LYMPH NODE (1) NO ABNORMALITY DETECTED 1 MESEMTERIC LYMPH NODE (1) NO ABNORMALITY DETECTED 1 BONE MARROW (1) NO ABNORMALITY DETECTED 1 Figure in parentheses is number o animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 209 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS ENDOCRINE SYSTEM LESION INCIDENCE (NUMERIC) TREATMENT Females 0 ing/kg /day II 300 mg/kg /day* X PITUITARY GLAND (1) NO ABNORMALITY DETECTED 1 THYROID GLAND NO ABNORMALITY DETECTED ALTERATION, COLLOID. (10) (9) 8 2 9 ADRENAL GLANDS (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 210 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS NERVOUS SYSTEM LESION INCIDENCE (NUMERIC) I Females TREATMENT 0 nig/kg /day II 300 ing/kg /day8 x BRAIN (1) NO ABNORMALITY DETECTED 1 SPINAL CORD (1) NO ABNORMALITY DETECTED 1 SCIATIC NERVE (1) NO ABNORMALITY DETECTED 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence o a number indicates the lesion specified was not identified 211 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS MUSCULAR AND SKELETAL SYSTEM LESIOM INCIDENCE (NUMERIC) I Females TREATMENT 0 ing/kg /day II 300 ing/kg /day* X SKELETAL MUSCLE (1) NO ABNORMALITY DETECTED 1 FEMUR/KNEE JOINT (1) NO ABNORMALITY DETECTED 1 STERNUM (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 212 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS REPRODUCTIVE SYSTEM LESION INCIDENCE (NUMERIC) | Females TREATMENT 0 nig/kg /day II 300 ing/kg /day' X OVARIES (1) NO ABNORMALITY DETECTED 1 UTERUS (1) NO ABNORMALITY DETECTED 1 MAMMARY GLAND (FEMALE) (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 213 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLAST1C AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS CUTANEOUS SYSTEM LESION INCIDENCE (NUMERIC) TREATMENT Females 0 ing/kg /day II 300 nig/kg /day8 X SKIN (1) NO ABNORMALITY DETECTED 1 SPECIAL SENSES SYSTEM EYE(S) WITH OPTIC NERVE (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 214 H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATSNEOPLASTIC AND NON-NEOPLASTIC LESIONS (THREE-MONTH RECOVERY EVALUATION) LESIONS ENDOCRINE SYSTEM TREATMENT LESION INCIDENCE (NUMERIC) Females 0 ing/kg /day II 10 ing/kg /day " VI 60 300 ing/kg nig/kg /day a |/day a VIII | X THYROID GLAND NO ABNORMALITY DETECTED ALTERATION, COLLOID. (5) (5) (5) (5) 1 1 5 5 4 4 REPRODUCTIVE SYSTEM MAMMARY GLAND (FEMALE) (1) FIBROADENOMA [B] . 1 [B] Benign tumour Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 215