Document MJGQ1bgmbnx03bM8NL5GM6Vma

TRADE SECRET Study Title ISubchronic Toxicity 90-Day Oral Gavage Study in Rats Volume 1 of 3 Laboratory Project ID: DuPont-9478 DuPont-9478 Test Guidelines: U.S. EPA Health Effects Test Guidelines OPPTS 870.3100 (1998) Author: Gregory S. Ladies, Ph.D Study Completed on: April 1,2003 Performing Laboratory: E.I. du Pont de Nemours and Company Haskell Laboratory for Health and Environmental Sciences Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050 Work Request Number: Service Code Number: P I Page 1 o f 967 Company Sanitized. Does not contain TSCA CSi Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT This study was conducted in compliance with U.S. EPA TSCA (40 CER 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 was 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. Study Director: Gregory S. Ladies, PhD . Senior Research Scientist ] ~ - A P r - 3 Q03 Date -2Company Sanitized. Does not contain TSC CBI Subchronic Toxicity 90-Day Oral Gavage Study in Rats QUALITY ASSURANCE STATEMENT DuPont-9478 Haskell Sample Number(s): 24691 Dates of Inspections: Protocol: February 1,7, 2002 Conduct: February 12, 2002; March 26, 2002; April 1,2,25, 2002; May 14,23, 2002 Records, Reports: October 1-4,7-9,14-15,22-23,25,28, 2002; November 11-13,24-27 2002; December 16-19,22, 2002; January 12-15, 2003 Dates Findings Reported to: Study Director: October 9,15,28, 2002; November 13,27; January 14,15, 2003 Management: October 9,18, 2002; November 5,27, 2002; December 10, 2002; January 14,29, 2003 Reported by: J S m Jjju jsl E$nberly B . Brebner Staff Quality Assurance Auditor l- A P - 3 D ate Company Sanitized. Does not contain TSCA CBI t [kubdhronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 CERTIFICATION We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study. Analytical Evaluations by:______ ( f . * fJna--nmem4t^G. ^Mit jatslnaan& tk"na, QB.OS. Senior Staff Chemist Neurobehaviorali TiooxxriccDoliogy Evaluations by: / C/ Linda A. Mailey, Ph-D., D.AB.T. Senk: Research Toxicologist Clinical Pathology Evaluations by; Wfaanrcy E. Everds, D.V.M. Diplomate AC.V P. Principal Research Clinical Pathologist and Manager Anatomic Pathology Evaluationssby; G. Tracy M1 akovec, D .V $k Diplomate A.C.V.P. Senior Research Pathologist Anatomic Pathology Evaluations Peer Review by: John F Hansen, D.V.M., Diplomate A.C.V.P: Principal Research Pathologist Date Date Date iY '/p /o '/ t '&Q Date P> Date Biochemical Evaluations by: John C. O'Connor, M.S. Research Toxicologist SI - A|o>Tc^ ` P-aoS Date Approved by: L jr f Scott E. Loveless, PnhJD. Research Manager and Director ST- ~ Date Issued by Study Director: 5- 4 ) ^ Gregory si. Ladies, Ph.D., D.A.B.T Senior Research Toxicologist 1 - j fr-^0 0 3 Date -4 Company Sanitized. Does not contain TSCA CBI Toxicity 90-Day Oral Gavage Study in Rats _______ DuPont-9478 TABLE OF CONTENTS Page GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT............................................ 2 QUALITY ASSURANCE STATEMENT............................................................................................ 3 CERTIFICATION........................................................... 4 LIST OF TABLES............................................................................................ ..............:..................... 7 LIST OF FIGURES................................................................................... 7 LIST OF APPENDICES....... .................................................................................................................9 STUDY INFORMATION............................................ 10 STUDY PERSONNEL.......................................................................................................................... 11 SUM M ARY........................................................................................................................................... 12 INTRODUCTION..................................................................................................................................15 OBJECTIVE......................... 15 MATERIALS AND METHODS......................................................................................................... 15 A. Test Guidelines.......................................................................................................................... 15 B. Test Substance........................................................... 15 C. Test Species................................................. 16 D. Animal Husbandry.............................................................................................. 16 E. Quarantine and Pretest Period.................................................. 17 F. Study D esign............................................... 17 G. Assignment to Groups...............................................................................................................18 H. Dose Suspension Preparation.............................. 18 I. Test Substance Administration.................... 19 J. Test Substance Sampling.................................................. 19 K. Analytical M ethods.................................................................................................... 20 L. Body W eights............................ 21 M. Food Consumption and Food Efficiency.......................................................... 21 N. Detailed Clinical Observations and M ortality....................................................................... 22 O. Ophthalmological Evaluations.............................................................................. 22 P. Neurotoxicity Evaluations.........................................................................................................22 Q. Clinical Pathology..........!......... .................................................................... .......................... 23 R. Collection of Blood, Urine, Feces, and Tissue (Three-Month Recovery ) ...... 25 S . . Biochemical M easurem ents.............................. ...25 T. Anatomic Pathology.................................... :........................................ ..................................26 RESULTS AND DISCUSSION.................................................................................. 29 ANALYTICAL EVALUATIONS................................................... ,................................................ 29 A. Test Substance Stability....................................................................................................... ... 29 B. Chromatography............................. 30 C. Homogeneity and Stability Samples........................................................................................30 D. Concentration Verification Sam ples................................................. 32 -5 Company Sanitized. Does not contain TSCA CBI 9(LDa^Qra^5va^^t!iay in Rats________ DuPont-9478 E. Discussion of R esults............................................................................................................... 36 F. Analytical Conclusion............................ 36 IN-LIFE TOXICOLOGY..................................................................................................................... 37 A. Dosage D a ta .............................. .......:......................................................................................37 B. Mean Body Weights and Body Weight Gains....................................................................... 37 C. Food Consumption and Food Efficiency................................................................................ 38 D. Clinical Observations and M ortality.......................................................................................38 E. In-Life Toxicology Conclusions.................................................................. 39 NEUROBEHAVIORAL TOXICOLOGY.......................................................... 39 A. Sensory Function Evaluations...................................................................... .39 B. Motor Activity................................................................... 39 C. Neurobehavioral Toxicity Conclusions...................................................................................40 CLINICAL PATHOLOGY.................................................................................................................. 40 A. .HematologyTCoagulaiion,.,,.,.,.;............................... 40 B. Clinical Chemistry.....................................................................................................................42 C. Urinalysis.... ............. 44 D. Plasma and Urine Fluoride.......................................................................................................45 E. Clinical Pathology Conclusions.............................................................. 45 BIOCHEMICAL MEASUREMENTS........................................................................................... 46 A. Biochemical M easurements.................................................................................................... 46 B . Biochemical Measurements Conclusions................................. 47 ANATOMICAL PATHOLOGY........................................................... A. Mortality......... .................................... B. Organ Weight Data.................................................. C. Gross Observations................................. D . Microscopic Findings................................................ E. Anatomical Pathology Conclusions............................. ......47 47 47 48 48 50 CONCLUSIONS...................................................... 51 RECORDS AND SAMPLE STORAGE............................... 52 REFERENCES....................................................................................................................................... 53 TABLES.....:....................................................................................................... 56 FIGU RES............... ......................:..................................................................................................... 268 APPENDICES...................................................................... ..280 -6Company Sanitized. Does not contain TSCA CBi LSubchromc Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 LIST OF TABLES Page TABLE 1 SUMMARY OF DOSING MIXING AND STABILITY ANALYSES...........................................................60 TABLE 2 MEAN DAILY DOSE VOLUMES FOR MALE RATS ................................................................................ 64 TABLE 3 MEAN DAILY DOSE VOLUMES FOR FEMALE R A T S......... !.................................................................. 66 TABLE 4 MEAN BODY WEIGHTS OF MALE RATS ..................................................................................................68 TABLE 5 MEAN BODY WEIGHTS OF FEMALE R A T S............................................A.................. ............................. 71 TABLE 6 MEAN BODY WEIGHT GAINS OF MALE RATS ....................... ............................................................. 74 TABLE 7 MEAN BODY WEIGHT GAINS OF FEMALE R A T S..........................................!................................... ....77 TABLE 8 MEAN DAILY FOOD CONSUMPTION BY MALE RATS ........................................................................ 80 TABLE 9 MEAN DAILY FOOD CONSUMPTION BY FEMALE R A T S....................................................................83 TABLE 10 MEAN DAILY FOOD EFFICIENCY OF MALE RATS.......................................................... .................... 86 TABLE 11 MEAN DAILY FOOD EFFICIENCY OF FEMALE RATS............ ...................................... .......................89 TABLE 12 SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS..........................................................92 TABLE 13 SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS.................................................... 97 TABLE 14 SUMMARY OF OPHTHALMOLOGY OBSERVATIONS FOR MALE R A TS.....................................103 TABLE 15 SUMMARY OF OPHTHALMOLOGY OBSERVATIONS FOR FEMALE RATS................................104 TABLE 16 PERCENT SURVIVAL OF MALE RATS..................................................................................................... 105 TABLE 17 PERCENT SURVIVAL OF FEMALE RATS................................................ ............................................... 106 TABLE 18 MEAN FORELIMB AND HINDLIMB GRIP STRENGTH FOR MALE RATS (MEAN OF THREE TRIALS)........................................................................................................................ 107 TABLE 19 MEAN FORELIMB AND HINDLIMB GRIP STRENGTH FOR FEMALE RATS (MEAN OF THREE TRIALS)........................... ............................................................................................108 TABLE 20 SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR MALE R A TS 109 TABLE 21 SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR FEMALE RATS ..110 TABLE 22 MOTOR ACTIVITY ASSESSEMENT: DURATION OF MOVEMENTS FOR MALE R A TS'.........I l l TABLE 23 MOTOR ACTIVITY ASSESSEMENT: DURATION OF MOVEMENTS FOR FEMALE RATS ... 112 TABLE 24 MOTOR ACTIVITY ASSESSEMENT: NUMBER OF MOVEMENTS FOR MALE R A T S............. 113 TABLE 25 MOTOR ACTIVITY ASSESSEMENT: NUMBER OF M OVEMENTSJOR FEMALE RATS.......114 TABLE 26 SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS.............. ............................................... 115 TABLE 27 SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RA TS............. .......................................... 119 TABLE 28 SUMMARY OF COAGULATION VALUES FOR MALE RATS............................................................ 123 TABLE 29 SUMMARY OF COAGULATION VALUES FOR FEMALE R A TS.......................................... .............123 TABLE 30 SUMMARY OF CLINICAL CHEMISTRY VALUES FOR MALE R A TS............................................. 124 TABLE 31 SUMMARY OF CLINICAL CHEMISTRY VALUES FOR FEMALE RATS......................................... 128 -7 Company Sanitized. Does not contain TSCA C8I Subchronic Toxicity 90-Day Oral Gavage Study in Rats.______ _________________________________________ ___________DuPont-9478 LIST OF TABLES (CONTINUED) Page TABLE 32 SUMMARY OF URINALYSIS VALUES FOR MALE R A TS.............................. ...................................132 TABLE 33 SUMMARY OF URINALYSIS VALUES FOR FEMALE RATS............................................................. 134 TABLE 34 SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITY IN MALE RATS........................ 136 TABLE 35 SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITY IN FEMALE R A T S.................. 137 TABLE 36 MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS..................................................... 138 TABLE 37 MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS........................... 145 TABLE 38 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS.............................................................. 154 TABLE 39 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS.................................... ....... ,............175 TABLE 40 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS.......................... 197 TABLE 41 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS............................................................................... 215 TABLE 42 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS............................................................................... 231 TABLE 43 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS . NON-NEOPLASTIC LESIONS..................................................................................................................... 251 LIST OF FIGURES Page FIGURE 1 MEAN BODY WEIGHTS OF MALE RATS....................................................................... .........................270 FIGURE 2 MEAN BODY WEIGHTS OF FEMALE RATS.................................................................................. ........ 271 FIGURE 3 MEAN FORELIMB GRIP STRENGTH FOR MALE RATS....................... ......................................... .....272 FIGURE 4 MEAN FORELIMB GRIP STRENGTH FOR FEMALE RATS............................................................... 273 FIGURE 5 MEAN HINDLIMB GRIP STRENGTH FOR MALE RATS..................................................................... 274 FIGURE 6 MEAN HINDLIMB GRIP STRENGTH FOR FEMALE R A TS............................................................... 275 FIGURE 7 MEAN TOTAL DURATION OF MOVEMENT FOR MALE RATS................ :............ .......................... 276 FIGURE 8 MEAN TOTAL DURATION OF MOVEMENT FOR FEMALE RATS.............................................. ....277 FIGURE 9 MEAN TOTAL NUMBER OF MOVEMENTS FOR MALE R A TS.........................................................278 FIGURE 10 MEAN TOTAL NUMBER OF MOVEMENTS FOR FEMALE RATS..................................................279 -8Company Sanitized. Does not contain TSCA C8I _ __________|Subchronic Toxicity 90-Day Oral Gavage Stuay in Rats_________ DuPont-9478 LIST OF APPENDICES Page APPENDIX A ANALYTICAL D A TA ............................................................................................................................... 282 VOLUME 2 .............................................................................................................................................................................. 294 APPENDIX B INDIVIDUAL DOSE VOLUMES....................................................................... . ............................295 APPENDIX C INDIVIDUAL BODY WEIGHTS ................................:..........................................................................376 APPENDIX D INDIVIDUAL FOOD CONSUMPTION.......................................................................... ................ ......411 APPENDIX E INDIVIDUAL CLINICAL OBSERVATIONS AND MORTALITY D A TA .....................................436 APPENDIX F INDIVIDUAL OPHTHALMOLOGICAL OBSERVATIONS............................................................... 478 .APPENDIX GINDDTDUAL FORELIMB GRIP STRENGTH AND HLNDLIMB GRIP STRENGTH................490 APPENDIX H INDIVIDUAL FUNCTIONAL OBSERVATIONAL BATTERY ASSESSM ENT..........................511 APPENDIX I INDIVIDUAL MOTOR ACTIVITY: DURATION OF MOVEMENTS.............................................522 APPENDIX J INDIVIDUAL MOTOR ACTIVITY: NUMBER OF MOVEMENTS................................................ 535 APPENDIX K INDIVIDUAL ANIMAL CLINICAL PATHOLOGY DATA................................................................548 VOLUME 3 .............................................................................................................................................................................. 622 APPENDIX L INDIVIDUAL ANIMAL BIOCHEMICAL DATA.................................................................................. 651 APPENDIX M INDIVIDUAL ANIMAL BODY AND ORGAN W EIGHTS.............................................................. 658 APPENDIX N INDIVIDUAL ANIMAL GROSS AND MICROSCOPIC OBSERVATIONS ............................ 695 APPENDIX O INDIVIDUAL ANIMAL MICROSCOPIC OBSERVATIONS LISTING INDIVIDUAL ANIMALS AFFECTED.......................... ........................................................ .............:................................................. 881 . 9. Company Sanitized. Does not contain TSCA CB! m H U m H H n Subchronic Toxicity HO-Day Oral Gavage Study in Rats_____ . STUDY INFORMATION, DuPont-9478 Haskell Number: 24691 CAS Registry Number: Purity: Known Impurities: Physical Characteristics: Stability: The test substance appeared to be stable under the conditions of the study; no evidence of instability was observed. Sponsor: Telomer Research Program 1200 South Hayes Street Arlington, Virginia 22202-5050 U.S.A. Study Initiated/Completed: February 7, 2002 / (see report cover page) In-Life Mtiated/Comnleted: February 12, 2002 / August 22, 2002 - 10Company Sanitized. Does not contain TSCA CBI [Subchronic Toxicity 30-Day Oral Gavage Study in Rats STUDY PERSONNEL Study Director: Gregory S. Ladies, Ph.D. Management: Scott E. Loveless, Ph.D. Janice L. Connell, M.S., B.A., C.I.H. Primary Technician: Deborah A. Vick, B.S. Analytical Chemist: Janet C. Maslanka, B.S. Management: S. Mark Kennedy, Ph.D. Clinical Pathologist: Nancy E. Everds, D.V.M. Management: Steven R. Frame, D.V.M., Ph.D. Neurobehavioral Toxicologist: Linda A. Mailey, Ph.D. Management: Robert M. Parker, Ph.D. Biochemical Toxicologist: John C. O 'Connor, M.S. Management: Matthew S. Bogdanffy, Ph.D. Pathologist: G. Tracy Makovec, D.V.M. Management: Steven R. Frame, D.V.M., Ph.D. Peer Review Pathologist: Steven R. Frame, D.V.M., Ph.D. Toxicology Report Preparation: Cecilia R. Kee, B .S. Brenda Tiffin Ophthalmologist: Nancy M. Bromberg, V.M.D., M.S. 6119 Massachusetts Avenue Bethesda, Maryland 20816 Statistical Analysis: John W. Green, Ph.D. Management: Janice L. Connell, M.S., B.A., C.I.H. Laboratory Veterinarian: Thomas W. Mayer, D.V.M., A.C.L.A.M. DuPont-9478 -11 Company Sanitized. Does not contain TSCA CBI 1Subchronic Toxicity 90-Day Oral Gavage Study in Rats__________ DuPont-9478 SUMMARY R v ^ ro u p sp T y o u n g adult male and female Crl:GD(SD)IGS BR rats were a d m in is te r e d ^ ^ by gavage at dosages of 0,1, 5,25, and 125 mg/kg/day for approximately 90 days. Body weights, food consumption, and clinical signs were evaluated weekly. Clinical pathology endpoints were evaluated on weeks 7,13, and near the end of the three-month recovery period. Neurobehavioral assessments were also performed prior to dosing and during week 13. Biochemical evaluations (hepatic (3-oxidation) were performed on animals after 10 and approximately 90 days of dosing and following the three-month recovery period. After approximately 90 days of dosing, 10 rats/sex/dose were sacrificed and given a gross and microscopic pathological examination. Approximately three months after the 90-day dosing period, 10 animals/sex in the control and high dose group were examined for recovery of toxic effects. A subgroup of 5 rats/sex/dose were designated as satellite bleed animals. An additional five animals/sex/dose were designated for hepatic biochemical analysis following a 10-day exposure to the test substance. The range of mean daily dose volumes o i | | m | |m i m m H H ( d m i n i s t e r e d to male rats was 1.2 to 3.0 ml. The range administered to female rats was 0.9 to 1.6 ml. In-Life Toxicology Parameters: No test substance-related mortality occurred in the study. A test substance-related, toxicologically significant increase in the incidence of striated teeth was observed in the 125 mg/kg/day male and female dose groups. On test day 77, all male and female high dose animals were placed on ground chow due to test substance-induced alterations to the teeth. There were no test substance-related, toxicologically significant alterations in body weight, body weight gain, food consumption, or food efficiency observed in any of the male or female dose groups. Neurotoxicology Parameters: No adverse changes in neurobehavioral parameters were observed in male or female rats in any dose group. Biochemical Toxicology: The rate o f hepatic (3-oxidation, a measure of peroxisome proliferation, was significantly increased in females administered 25 m g / k g / d a y ^ m m a n d in males and females administered 125 m g / k g / d a y J | ^ | | H H H H p [ Following a threemonth recovery period, the rate of hepatic [3-oxidation was lower but still significantly increased in males administered 125 m / k g / ^ y ) H H B H H H f l r i h n d had returned to control levels in female rats. Clinical Pathology: Samples were collected at mid-study, at the end of treatment, and after three months of recovery for hematology, clinical chemistry, urinalysis, coagulation (end of study only), and plasma and urine fluoride (end of study and three-month recovery period). Hiere were no toxicologically sigm fican^hangeyi^linicalpathology parameters observed in rats dosed with up to 125 m g / k g / d a y [ p J H H H H H H | | Other changes during treatment or after a three-month recovery were considered treatment-related but non-adverse because the magnitude of change was small, transient, and/or in a direction not associated with toxicity. - 12Company Sanitized. Does not contain TSCA CBI P H I H H H H H H V p u b c h r o n ic Toxicity 90-Day Oral Gavage Stuay in Rats__________ DuPont-9478 Treatment-related changes observed in rats administered > 25 mg/kg/day included decreases in some red cell mass parameters along with reticulocytosis and increased serum cholesterol (females only). Test substance-related changes in clinical pathology of rats dosed with 125 mg/kg/day included transiently increased alkaline phosphatase (males only), increased phosphorus (males only), decreased triglycerides (males only), increased total protein and albumin, increased calcium (females only), increased urine volume (males only), and decreased urine ketone concentrations (males only). Plasma fluoride levels were significantly increased in males and females dosed with 125 mg/kg/day, but returned to control levels following three months of recovery. Urine fluoride excretion was increased in males and females dosed with > 5 mg/kg/day. After three months of recovery, urine fluoride levels in females returned to control levels, while levels in males were significantly reduced compared to those at the end of the exposure period. Anatomical Pathology: Test substance-related, toxicologically significant degeneration/disorganization of enamel organ ameloblast cells occurred in male rats administered 125 mg/kg/d a y p B H H H H f | 0 ^ Q A test substance-related, adverse increase in the incidence and severity of focal hepatic necrosis was observed in males administered 25 and 125 mg/kg/day. An increased incidence and severity of chronic progressive nephropathy occurred in the 125 mg/kg/day female group and was considered adverse. Test-substance related and statistically significant increases in liver weight parameters were present in males and females administered 25 or 125 mg/kg/day for approximately 90 days. The increased liver weights correlated with microscopic hepatocellular hypertrophy in the 125 mg/kg/day male dose group. Liver weight changes and microscopic hypertrophy were considered to be a physiological adaptive response to metabolism of the test substance and not adverse. Test-substance related and statistically significant increases in kidney weight parameters occurred in males and females administered 25 or 125 mg/kg/day. The increased kidney weights correlated with microscopic renal tubular hypertrophy in the 25 and 125 mg/kg/day male groups only. However, no correlative microscopic or clinical pathological evidence of renal toxicity were present. Therefore, kidney weight changes and microscopic tubular .hypertrophy were not considered adverse findings. Altered colloid, a common spontaneous finding in rats, was increased in incidence and/or severity in treated male groups. This change was not associated with other findings in the thyroid gland and was also not considered an adverse finding. After three months of recovery, rats dosed with 125 mg/kg/day showed-reversibility of some effects. The ameloblastic degeneration/disorganization persisted with decreased incidence and severity in the 125 mg/kg/day male group. Alterations in thyroid colloid persisted in male rats. Increased liver weight parameters and hepatocellular hypertrophy (males only) were no longer observed in the 125 mg/kg/day male and female groups. However, the incidence of hepatocellular necrosis in the 125 mg/kg/day male group increased after three months of recovery. Increased kidney weight parameters and renal tubular hypertrophy (males only) were not observed in rats sacrificed after three months of recovery. In contrast, the incidence and - 13Company Sanitized. Does not contain TSCA CBI [Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 severity of chronic progressive nephropathy were increased in the 125 mg/kg/day female group following three months of recovery. In conclusion, the no-observed-effect level (NOEL)3for males was 5 mg/kg/dayI m ^ b a s e d on the increased incidence of hepatic necrosis observed in males administered > 25 mg/kg/day. The NOEL for females was 25 m g T g / d a y ^ H M |B H |M f |p a s e d on the increased incidence and severity of chronic progressive nephropathy observed in females administered 125 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 (1985) and to the no-observed-adverse-effect level (NOAEL) as defined by the European Union (1994). - 14- Company Sanitized. Does not contain TSCA CBI Subchronic Toxicity 9^D a^Q ra^ avageStady in Rats____________________________________________________________ DuPont-9478 INTRODUCTION The test s u b s t a n c e , T h e 1, 5, 25, and 125 mg/kg/day dose levels for this study were selected based on the toxicity observed in an 84- day range finding study with 5, 25, and 125 mg/kj^ d a y f l | J [ [ [ [ [ J J [ J ^ n d subchronic studies with s i m i l a r f l ^ | | | H | B B I f l H R a n d perfluorooctanoic acid (PFOA). In the _______ [ange finder study, significantly lower mean body weights compared to control were observed in male rats administered 125 mg/kg/day. Similarly, significantly lower mean body weights compared to control were also observed in rats administered 100 mg/kg/day or greater of similar fluorotelomer-based alcohols. Significantly increased liver weights occurred in males dosed with 125 mg/kg/d Liver weights were also significantly increased compared to control in rats administered dose levels o f| f l H H H H H a s low as 100 mg/kg/day. Furthermore, data suggest that the PFOA metabolite may^ccumuM e in animals dosed with repeat dose studies, PFOA at doses of 10 mg/kg/day or lower produced the following effects: increased liver weights, increased hepatic cell proliferation and beta oxidation, and altered serum hormone levels.(1,2,3,4) The high-dose level of 125 mg/kg/day for this study was selected based on the reductions in body w e ig h te d increased liver weights observed in males dosed with 125 m g / k g / d a y f f ^ f f ^ p J ^ a s well as the ability of rats to tolerate a 100 mg/kg/day dose level in subchronic studies with s i m i l a r J |||B H B I i H i H H I H t f i T i i e 125 mg/kg/day dose was expected to produce toxicity without excessive mortality. The low dose of 1 mg/kg/day was expected to be the no observed-effect level (NOEL), while the 5 and 25 mg/kg/day dose levels were expected to induce minimal to ho toxicity. OBJECTIVE The objective of this study is to evaluate the potential subchronic toxicity and reversibility o: j m H p f l H ^ h e n administered by gavage to male and female rats. The oral route of administration was selected as the most efficient way to deliver an accurate dosage. MATERIALS AND METHODS A. Test Guidelines The subchronic toxicity study design complies with the United States Environmental Protection Agency (EPA), Office of Prevention, Pesticides, and Toxic Substances (OPPTS) Health Effects Test Guidelines, OPPTS 870.3100 90-Day Oral Toxicity in Rodents (Aug-1998). B. Test Substance Hie test s u b s t a n c A M H H B H g l ^ a s supplied by the sponsor as ith known purityf lH H p a n d composition. A reserve sample of the test substance was collected and retained by Haskell Laboratory. - 15Company Sanitized. Does not contain TSCA CBI ^ J Subchronic Toxicity 90-Day Oral Gavage Study La Rats_________ DuPont-9478 C. Test Species On 29-Jan-2002, Crl:CD(SD)IGS BR rats with an assigned birth date of 31-Dec-2001 were received from Charles River Laboratories, Inc., Raleigh, North Carolina. One hundred five male and 105 female rats were received for the main study and 28 male and 28 female rats were received for the 10-day biochemical evaluation. 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, the supplier, and previous studies at Haskell Laboratory. This species/strain is considered suitable relative to longevity 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 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 pelleted PMI Nutrition International, Inc. Certified Rodent LabDiet 5002 ad libitum. On test day 77, all rats in the male and female 125 mg/kg/day groups were placed on ground chow because of test substance-induced alterations to the teeth. 3. Identification 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. i 4. Health Monitoring Program As specified in the Haskell Laboratory animal health and environmentaTmonitoring program, the following procedures are performed periodically to ensure that contaminant levels are below i 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. -16- Company Sanitized. Does not contain TSCA CBi JSubchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 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, all rats were quarantined for 7 days, observed daily for any clinically apparent signs of disease or injury, and weighed 4 times. Rats designated for the subchronic toxicity and three-month recovery evaluations, and satellite bleeds were also examined by a veterinary ophthalmologist to identify animals with preexisting ocular lesions. Rats designated for the subchronic toxicity and three-month recovery evaluations were given a baseline neurobehavioral evaluation. On the basis of acceptable body weight gains and clinical observations, all surviving main study rats were released from quarantine by the laboratory animal veterinarian designee on test day -11; rats designated for the 10-day biochemical analysis were released on test day -4. F. Study Design Group Male Female In m IV V VI vn vm IX X Number/Group Male Female 30 30 20O A A3 20 20 20 20 30 30 Dosagea 0 mg/kg/day (Control) i mg/kg/day 5 mg/kg/day 25 mg/kg/day 125 mg/kg/day a W eight/weight of test substance (adjusted for sponsor-supplied purity o f active ingredient). Each group of study animals, except those designated for the 10-day biochemical analysis, consisted of three subgroups: the first 10 rats/sex/dose were designated for evaluation of subchronic toxicity; the next 5 rats/sex/dose were designated as satellite bleed animals; and the last 10 rats/sex/dose (control and high-dose groups only) were designated as three-month recovery animals. An additional subgroup of 5 rats/sex/dose were designated for hepatic biochemical analysis following a 10-day exposure to the test substance. -17- Company Sanitized. Does not contain TSCA CBI ISubchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 Male and female rats designated for the subchronic toxicity evaluation were dosed through test days 92 (male) and 93 (female), and necropsied on test days 93 and 94, respectively. Male and female rats designated for the satellite bleeds were dosed through test day 90 and necropsied on test day 175 (85 days post dosing). Male and female rats designated for the three-month recovery evaluations were dosed through test day 90 and necropsied on test day 183 (93 days post dosing). Neurobehavioral evaluations were conducted on male and female animals designated for the subchronic toxicity evaluation and three-month recovery evaluation (predose and week 13). A clinical pathology evaluation was conducted on rats designated for the subchronic toxicity evaluation during week 7 and week 13 (prior to necropsy). Coagulation parameters and plasma and urine fluoride were not determined on week 7. Plasma and urine fluoride were determined for the three-month recovery animals on week 26. Biochemical evaluations were conducted on selected animals designated for the subchronic toxicity evaluation, the three-month recovery evaluations, and the 10-day exposure evaluation. In-life data (body weight, food consumption, clinical observations) for rats designated for the 10-day biochemical analysis were collected from these animals and are in study records. However, these data are not included in this report. G. Assignment to Groups 1. Rats Designated for the Subchronic Toxicity and Three-Month Recovery Evaluations, and Satellite Bleeds 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. On test day 0, prior to the start of test substance administration, 3 male rats and 3 female rats with out-of-range 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. Due to technician error, one male control rat with an out-of-range body weight was used on study. H. Dose Suspension Preparation /as suspended in 0.5% aqueous methylcellulose. Dosing suspensions of the test substance were prepared twice per week up to day 48, then prepared daily through the remainder of the dosing period. -18- Company Sanitized. Does not contain TSCA CBI J Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 I. Test Substance Administration The test substance was administered daily to the study animals by oral gavage to achieve dosage levels of 1, 5, 25, or 125 mg/kg body weight/day, based on the most recently recorded body weight. Dose volumes for all groups were 5 mL/kg. Male and female control rats were similarly treated with 0.5% aqueous methylcellulose at the same dose volume as used in their respective high-dosage group. Based on the results of analytical analysis of a 4-day dose preparation obtained on test day 45, rats at all dose levels may not have received a full dose of test substance on test days 45, 46, 47, and 48. Subsequent analytical analysis on additional dose preparations (not administered to rats) indicated that the test day 45 results were due to a sampling error. 1. Rats Designated for the Subchronic Toxicity and Three-Month Recovery Evaluations, and Satellite Bleeds Oral administration o ijp H H H H H iiiH I H h e g a n on test day 0, when the rats were approximately 50 days o f age. Rats designated for the subchronic toxicity evaluation were dosed through test day 92 (males) or 93 (females). Rats designated for the three-month recovery evaluation and satellite bleeds were dosed through test day 90. Rats designated for recovery and satellite bleeds did not receive test substance during the recovery period. 2. Rats Designated for 10-Day Biochemical Analysis Oral administration o f ^ H H H H f l f l H f l ^ S ^ 7 days prior to study start when the rats were approximately 42 days of age and ended on test day 2. J. Test Substance Sampling Dosing suspensions for this study were prepared at the beginning of the study as a large volume mix to be used either for 3 or 4 days of dosing. Subsequently, on day 49 of the study, the dosing suspension preparation was changed to a small volume mix to be used for 1 day of dosing. Samples c o n t a i n i n ^ H H H H H H M ^ t the concentrations of G, 0.2,1.0, 5.0, and 25.0 mg/mL were collected on test day - 6 (large volume/3-4 day mix). These samples were analyzed to determine homogeneity/concentration verification and 5-hour room temperature stability. Samples from the same preparation at the 0,2 mg/mL level only, were collected on test day 0, after 7 days of refrigeration. These samples were analyzed to determine redispersion/cortcentration verification and refrigerated stability along with 5-hour room temperature stability. The refrigerated re-dispersion/concentration verification and stability for the other levels had been established during the mixing/stability study for a previous study.(5) On test days 48, 52, 56, 58, 65, and 91 (small volume/1 day mix), concentration verification samples for all levels were collected. The test day 48 preparation was not dosed to animals. On test days 42,45, 63, and 73 (3-4 day mix), concentration verification samples for all levels were collected. Test day 63 and 73 preparations were not used for dosing the animals but for evaluation of the large volume mix (3-4 day). % - 19- Company Sanitized. Does not contain TSCA CBI ] Subchronic Toxicity -90-Day Oral Gavage Study in Ruts_________ DuPont-9478 All dosing suspension samples were collected on the day the suspensions were dosed to the animals or at the established stability time for analysis. They were analyzed when received or frozen until analyzed. K. Analytical Methods 1. Dosing Solution Treatment Each dosing sample (10 mL for 0.2 mg/mL; 3 mL for other levels) was diluted to 100 mL with methanol and mixed to dissolve t h e ^ ^ H H H | f | | | g L n the suspension. The dosing samples were analyzed without further dilution or were further diluted with the 0 mg/mL sample (initial dilution) to an expected concentration of approximately 0.03mg/mL (a.i.) prior to analysis. Before all final dilutions, the internal standard diluted solution (refer to Calibration and Quantitation Section) was added to each test sample to give a final concentration of approximately 0.04 mg/mL. Each sample (final dilution) had an equivalent amount matrix (3%) when analyzed, except the 0.2 mg/mL (10%). Samples submitted for analysis were analyzed the day the suspensions were received by the testing group or frozen until analyzed. 2. Chromatographic Conditions Instrument: Hewlett-Packard Model 6890 GC Column: J & W, DB-1701,30 m, 0.32 mm ID, 1 urn film thickness Injector: Split, 250C Detector: F ID ;250C Carrier Gas: Helium (2.1 mL/min) Split vent: 22.3 mL/min Injection Volume: 2 microliter Oven Program: Gradient Initial Temperature; 100C Initial Time: 1.00 min. Level 1 Rate: 20.0C/min. Level 1 Temperature: 260C Level 1 Time: 0.00 min. Total run time: 9.00 min . 3. Calibration and Quantitation A separate sample o f ( ^ H H H H H H H ^ as obtained for use as the analytical reference standard. A stock solution was prepared in methanol. This stock solution was sonicated to assure that all material was in solution. Before analysis, appropriate aliquots of the stock were diluted with the 0 mg/mL sample (initial dilution) to make calibration standards, which bracketed die target concentration of the diluted dosing samples. A stock solution of internal standard prepared in methanol and added to each calibration standard and test sample to give a final concentration of approximately 0.04 mg/mL. - 20- Company Sanitized. Does not contain TSCA C8I [Subchronic Toxicity 90-Day Oral Gavage Study in Rats _____ DuPont-9478 The ratio of the internal standard an(^ H I I I H I H H H H V ea'k ^e^ ts from replicate GC analysis of these solutions was used to construct a calibration curve by least squares regression (see Appendix A, Figure 1 for a representative curve). Measured concentrations for the dosing samples were determined by applying the peak height ratios from replicate injections of each sample to the calibration curve. Test substance homogeneity/uniformity in the vehicle was evaluated by calculating the coefficient of variation (C.V. = standard deviation/mean x 100) of the measured concentrations in the top, middle, and bottom samples (homogeneity) or duplicate samples (concentration verification) for each dosing level. A coefficient of variation of less than or equal to 10% is the standard criterion at Haskell Laboratory for acceptable distribution of the test substance throughout the solution. However, if the test substance has been shown to be difficult to disperse in the vehicle or the analysis has shown variability, a coefficient greater than 10 may be acceptable. The mean result of the homogeneity samples or concentration verification 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 homogeneity samples or the duplicate samples from the concentration verification as the baseline for comparing the corresponding stability results. L. Body Weights 1. Rats Designated for the Subchronic Toxicity and Three-Month Recovery Evaluations, and Satellite Bleeds Rats were weighed once per week during the approximately 90-day exposure phase of the study, hi addition, the rats designated for neurobehavioral evaluations (functional observational battery and motor activity assessments) were weighed on the days of those observations. 2. Rats Designated for 10-Day Biochemical Analysis Rats were weighed on the first, eighth, and tenth day of test substance administration. 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 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. -21 Company Sanitized. Does not contain TSCA CBI ,Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 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, except on test day 46 only one cage-site examination was conducted. 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 subchronic toxicity and three-month recovery periods. Detailed clinical observations were not evaluated on rats designated for satellite bleeds. 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. O. 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 -11, prior to selection and grouping, the initial examination was performed on all main study rats received for the study. On test day 87, all surviving rats designated for the subchronic toxicity and three-month recovery evaluations were examined again. P. Neurotoxicity Evaluations 1. Sensory Motor 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 o n 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 from the 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 the motor activity chambers (Section 2. below) because the darkened room in which the apparatus was located facilitated observing the response. The presence or absence of pupillary constriction was assessed after a beam of light was directed into each eye. For all these assessments, the experimenter was unaware of the group designation of the animal. 2. Motor Activity 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 - 22Company Sanitized. Does not contain TSCA CBI _________________l Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 activity monitors (Coulbourn Infrared Motor Activity System). Group and sex 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.(6'7,8,9) 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 A clinical pathology evaluation was conducted on all rats designated for subchronic toxicity on test days 48/49 and 93/94 in males and females, respectively. The day before collection of samples for the clinical pathology evaluation the animals were placed in metabolism cages. These animals were fasted overnight (approximately 15-17 hours) and urine was collected from each animal. Blood samples for hematology and clinical chemistry measurements were collected from the orbital sinus of each animal while the animal was under light carbon dioxide anesthesia. Blood samples for coagulation parameters and fluoride analysis were collected at sacrifice from the abdominal vena cava of each animal while the animal was under carbon dioxide anesthesia. Additional blood collected from the vena cava was placed in a serum tube, processed to serum, and frozen at -80C. Seram was discarded without analysis, however, because further tests were not required to support experimental findings. Bone marrow smears were prepared at the final sacrifice from all surviving animals. Bone marrow smears were stained with W right's stain and coverslipped, but analysis was not necessary to support experimental findings. At the end of a 3-month recovery period, samples for hematology, clinical chemistry, urinalysis, and plasma and urine fluoride were collected and analyzed from rats designated for recovery.1 1. Hematology and Coagulation Blood samples were evaluated for quality by visual examination prior to analysis. Complete blood counts, including reticulocytes, were determined on a Bayer Advia 120 hematology analyzer or determined from microscopic evaluation of the blood smear. Wright-stained blood smears from all animals were examined microscopically for confirmation of automated results and evaluation of cellular morphology. Blood smears, stained with new methylene blue, were prepared from each animal undergoing a hematology evaluation but were not needed for examination. Coagulation times were determined on a Sysmex CA-1000 Coagulation Analyzer. - 23Company Sanitized. Does not contain TSCA CBI Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 The following hematology and coagulation parameters were determined: red blood cell count hemoglobin hematocrit mean corpuscular volume mean corpuscular hemoglobin mean corpuscular hemoglobin concentration red cell distribution width absolute reticulocyte count platelet count white blood cell count differential white blood cell count microscopic blood smear examination prothrombin time activated partial thromboplastin time 2. Clinical Chemistry Serum clinical chemistry parameters were determined on a Roche Diagnostics (BMC)/Hitachi 717 clinical chemistry analyzer. Plasma fluorides were determined using a phi 12 pH meter and a fluoride-selective electrode. The following clinical chemistry parameters were determined: aspartate aminotransferase alanine aminotransferase sorbitol dehydrogenase alkaline phosphatase total bilirubin urea nitrogen creatinine cholesterol triglycerides glucose total protein albumin globulin calcium inorganic phosphorus sodium potassium chloride fluoride2 3. Urinalysis Urine volume and appearance (quality, color, and clarity) were measured and evaluated visually, respectively. Urine constituents were semi-quantitatively measured on a Bayer Clinitek AtlasTM Automated Urine Chemistry analyzer. Urine protein was measured on a Roche Diagnostics (BMC)/Hitachi 717 clinical chemistry analyzer. Urine osmolality was determined using an Advanced Osmometer 3900. Urine fluorides were determined using a phil2 pH meter and a fluoride-selective electrode. Sediments from all urine specimens were evaluated microscopically. Huoride determination was analyzed on EDTA plasma. -24Company Sanitized. Does not contain TSCA C3I Subchronic Toxicity "90-Day Oral Gavage Study in Rats _______ The following urinalysis parameters were determined: quality color clarity volume osmolality PH glucose ketone bilirubin blood urobilinogen fluoride2 protein microscopic urine sediment examination DuPont-9478 R. Collection of Blood and Tissue (Three-Month Recovery) Blood was collected from animals (5 animals/sex/group) designated as satellite bleeds during the 90-day dosing period and recovery period and stored for possible analysis of parent compound andlriefaboTifes. Blood collection time points were: prior to dosing (test day -7), and days 0, 4,10, 21, 35, 56,77, 90, 94,98 ,1 0 5 ,1 1 9 ,1 3 3 ,1 5 4 , and 175. Blood (approximately 0.6 mL) was collected from the orbital sinus of designated animals while under light carbon dioxide anesthesia. On the day of blood collection, blood was collected from the animals approximately 2 hours ( 30 minutes) after dosing. For each bleeding, blood was collected at approximately the same time of day. The blood was collected in plastic tubes containing EDTA while on ice. The blood from each anim al was then separated into plasma and red blood cells. The separated plasma samples were stored frozen at -80C and red blood cells were discarded. After the final bleeding (day 175), all animals were euthanatized by carbon dioxide asphyxiation and exsanguination and liver and fat were collected, weighed, and stored at -80C. The pliamiacokinetic profile of lay be evaluated in the future and resulting data reported separately. S. Biochemical Measurements Following 10, 93 (males) or 94 (females) days of test substance administration or after threemonths (test day 183 for males and females) of recovery, five rats from each group designated for biochemical evaluation were weighed and then euthanized by CO2 anesthesia and exsanguination. At each time point, the livers were removed, weighed, and then a portion was homogenized (1 gram tissue/4 mL buffer) in homogenization buffer (50 mM 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 (3-oxidation activity. The peroxisomal suspensions were diluted to a protein concentration of approximately 0.5 mg/mL. Peroxisomal P-oxidation activity was determined using [14C]paimitoyi CoA as the substrate.*10) The protein content of the peroxisomes was determined before and after analysis by the Biorad method.*1.9 Final rate calculations were made using the post-assay protein concentrations. Fluoride determination was analyzed from urine with EDTA added. -25Company Sanitized. Does not contain TSCA GBI 1Subchronic Toxicity '90-Day Oral Gavage Study in Rats DuPont-9478 T. Anatomic Pathology After approximately 90 days of exposure to the test substance (test days 93 and 94 for males and females, respectively), groups of 10 male and 10 female rats from the 0, 1, 5, 25, and 125 mg/kg/day groups were sacrificed and necropsied. Additional groups of 10 male and 10 female rats from the 0 and 125 mg/kg/day groups were sacrificed and necropsied approximately three months after the last exposure (test day 183) to evaluate recovery of toxic effects. In addition, groups of 5 male and 5 female rats from all groups designated for hepatic biochemical analysis were sacrificed and necropsied approximately three months after the last exposure (test day 183). 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 subchronic exposure and 3-month recovery group rats sacrificed by design, or rats that were accidentally killed. Digestive Svstem liver esophagus stomach duodenum jejunum ileum cecum colon rectum salivary glands pancreas Urinarv Svstem kidneys urinary bladder Cardiovascular Svstem heart aorta Hematopoietic Svstem spleen thymus mandibular lymph node mesenteric lymph node bone marrow2 Endocrine Svstem pituitary gland thyroid gland parathyroid glands adrenal glands Respiratory Svstem Nervous Svstem 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 Svstem skeletal muscle femnr/knee joint sternum Reproductive Svstem Male testes epididymides prostate seminal vesicles Female ovaries uterus mammary gland Miscellaneous skin eyes (including optic nerve) gross observations The following tissues were weighed from rats sacrificed by design in the subchronic exposure group and the 3-month recovery groups: liver, kidneys, adrenal glands, thyroid (weighed after fixation), brain, spleen, thymus, heart, ovaries, uterus, epididymides, and testes. Organ weight/final body weight and organ weight/brain weight ratios were calculated. Gross lesions which were diagnosed at necropsy and for which microscopic examination was not appropriate (e.g., fluid accumulation, ruffled fur, missing anatomic parts) were generally not collected. Gross lesions for which a microscopic diagnosis would not be additive - 26Company Sanitized. Does not contain TSCA CBI Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 (e.g., osteoarthritis, pododermatitis, chronic dermatitis of the tail, urinary calculi, and deformity of the teeth, toe, tail, or pinna) were saved but were generally not processed for microscopic evaluation. Testes, epididymides, and eyes were fixed in Bouin's solution. All other tissues were fixed in 10% neutral buffered formalin. Processed tissues were embedded in paraffin, cut at a nominal thickness of 5 micrometers, stained with hematoxylin and eosin (H&E), and examined microscopically. All collected tissues from 90-day exposure group control and 125 mg/kg/day rats, and all accidentally killed rats were processed and received a full histopathological examination. Liver and kidneys were processed from 1, 5, and 25 mg/kg/day 90-day exposure group and from all 3month recovery group male and female rats. In addition, thymus, thyroid gland, and nose frdm 1, 5, and 25 mg/kg/day subchronic exposure group and all 3-month recovery group male rats were processed and examined microscopically. - 27Company Sanitized. Does not contain TSCA CBI Subchronic Toxicity 90-Day Oral Gavage Study in Rats_________ DuPont-9478 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 sex. Parameter Body W eight Body W eight Gain Food Consumption Food Efficiency B-Oxidation Organ W eight Motor Activityc Grip Strength Foot Splay Clinical Pathology4 Survival Incidence o f Clinical Observations Incidence of Ophthalmological Observations Incidence o f FOB Descriptive Parameters Incidences o f Gross and M icroscopic Lesioris Preliminary Test Test for lack o f trend02* Levene's test for hom ogeneity05* and Shapiro-Wilk test06*for normality1* Levene's test for hom ogeneity05*and Shapiro-Wilk test0 for normalityb Bartlett's test03*for homogeneity of variances Levene's test for hom ogeneity05*and Shapiro-Wilk test06*for normality6 Method o f Statistical Analysis If preliminary test is not If preliminary test is significant significant Sequential application03* of the Jonckheere-Terpstra trend test04* Preliminary tests for pairwise comparison ORa One-way analysis o f variance07*followed with Dunnett's test08* Kruskal-W allis test09* follow ed with Dunn's test00* Repeated measures analysis o f variance01* followed by contrasts02* One-way analysis o f variance07*followed with Dunnett's test08* One-way analysis of variance07*followed with Dunnett's test08* Sequential application03* o f the Jonckheere-Terpstra trend test04* Kruskal-W allis test09* follow ed with Dunn's test00* Kruskal-W allis test09* follow ed with Dunn's test00* None Cochran-Armitage test for trend07*" None None a Pairwise comparisons and associated preliminary tests were only conducted if the test for lack o f trend was significant. b If the Shapiro-Wilk test was hot significant but Levene's test was significant, a robust version o f Dunnett's test was used (Durmett/Tamhane-Dunnett). c Test day and block (10-minute EPOCH) was used as repeated-measure factors. d When an individual observation was recorded as being less than a certain value,^calculations were performed on half the recorded value. For example, if bilirubin was reported as <0.1, 0.05 was used for any calculations performed with that bilirubin data. e If the incidence was not significant, but a significant lack of fit occurred, then Fisher's Exact test04*with a Bonferroni correction was used. - 28Company Sanitized. Does not contain TSCA CBI ISubchronic Toxicity '90-Day Oral Gavage Study in Rats DuPont-9478 RESULTS AND DISCUSSION ANALYTICAL EVALUATIONS Dosing suspensions for this study were prepared at the beginning of the study as large volume mixes to be used either for 3 or 4 days of dosing. Samples c o n t a i n i n g f l ^ H H H H ^ ^ H K a t the concentrations of 0, 0.2, 1.0, 5.0, and 25.0 mg/mL were collected at the initiation of the 90day study (test day - 6 for large volume/3-4 day mix). These samples were analyzed to determine homogeneity/concentration verification and 5-hour room temperature stability. Samples from the same preparation at the 0.2 mg/mL level only were collected on test day 0, after 7 days of refrigeration. These samples were analyzed to determine re-dispersion/concentration verification and refrigerated stability along with 5-hour room temperature stability. The refrigerated redispersion/concentration verification and stability for the other levels had been established during the mixing/stability study for a previous study. These data indicated that the test substance was homogeneously mixed, could be re-dispersed after refrigeration to the expected concentration, and was stable in the vehicle for 5 hours after refrigeration. On test days 42 and 45 (3-4 day mix), concentration verification samples for all levels were collected. Results from analysis of the dosing suspensions collected near the mid-point of the study (test day 42) for concentration verification indicated that test substance was marginally at the targeted concentration ( 20% of nominal). In order to investigate these results, a new large volume preparation of the dosing suspensions was made and sampled on test day 45. The results for these samples were lower than expected (range: -33.4% to -66.0% of nominal) indicating a sampling problem. Investigation of the study records showed that the correct amount of test material was contained in the preparations but that a possible technician error had occurred with the re-dispersing and sampling of the test material to the analytical group. Due to the length of time needed for evaluation of the samples, the preparations had already been dosed to the animals and further sampling could not be done to define the problem with the sampling of this mix. Therefore, due to the unexpected analytical results observed on test day 45, the following study changes were implemented: 1) on test day 49 of the study, the dosing suspension preparation was changed to small volume mix to be used for 1 day of dosing and concentration verification samples for all levels were collected on test days 48 (not dosed to animals), 52, 56, 58, 65, and 91 (small volume/1 day mix); and 2) on test day 63 and 73 large volume mixes (3-4 day) were prepared and samples were collected from all levels for evaluation of the mixing and sampling for the study before test day 45. These preparations were not used for dosing the animals. A. Test Substance Stability Samples of test substance were analyzed near the beginning and the end of the study. These analyses indicated that the test substance was stable over the course of the study. The average percent of active ingredient was 99.1% 0.81 and 101.8% 2.9 for the samples analyzed on February 15, 2002, and May 30, 2002, respectively. ' report ed by - 29Company Sanitized. Does not contain TSCA CBI Subchronic Toxicity 90-Day Oral Gavage Study in Rats__________ DuPont-9478 the sponsor to have 99.2% active ingredient The differences in values between the sponsor reported purity and the experimental data represent analytical variability. B. Chromatography luted from the GC column as resolved peak with a retention time of approximately 3.5 minutes. The internal standard eluted from the GC column as a resolved peak with a retention time of approximately 3.9 minutes.' Representative GC chromatograms are shown in Appendix A, Figures 2(a - c). Test substance was not detected in the 0 mg/mL control. C. Homogeneity and Stability Samples Analytical results from dosing suspensions collected on test day -6 and test day 0 and analyzed for homogeneity and/or concentration verification and stability are shown in Appendix A, Table I and Summary Table 1. The following table summarizes the results for all homogeneity and/or concentration verification and stability analyses. Test Day Sample Type Test Day -6 Homogeneity Test Day 0 Nominal Measured T,M,Ba Mean (T,M,B) C.V.b mg/mL mg/mL % Nominal (%) 0 ND 0.2 0.163,0.164,0.161 1.0 0.803, 0.857,0.890 5.0 4.55, 4.80, 4.61 25 19.9d, 21.9, 22.9 -- 81.5 85.0 93.0 86.4 -- 1 5 3 7 Stability 7 Day Refrigerated 0 0.2f ND 0.161,0.173 ---- 83.5 5 a. Mean results for the analysis of the top (T), middle (M), and bottom (B) samples. b. C.V. = Coefficient of Variation c. Samples held 5 hours at room temperature. d. Denotes none detected. e. Duplicate re-analysis of the original sample supports the original result and are not reported. Mean results foi tile analysis of duplicate concentration verification samples. Stability12 % Nominal -- 83.5 81.8 82.8 87.2 -- 79.0e The data for samples collected on test day -6 indicates that the test substance was homogeneously mixed in the vehicle at all levels (C.V.'s = 1, 5, 3 and 7, respectively). The test substance was at the targeted concentration in the samples ( 18.5% of nominal) and was stable in the vehicle when held 5 hours at room temperature. The data for 0.2 mg/mL sample collected on test day 0 after 7 days of refrigeration indicates that the test substance was homogeneously re-suspended in the vehicle (C.V. = 5). The test substance was at the targeted concentration ( 16.5% of nominal) and stable in the vehicle when held refrigerated for 7 days followed by 5 hours at room temperature. The 5-hour sample analyzed at - 30Company Sanitized. Does not contain TSCA CBI [ Subchronic Toxicity ~90-Day Oral Gavage Study in Rats DuPont-9478 79.0% of nominal appeared to be lower than expected but this can be attributed to sampling and analytical variability and not stability of the test material in the vehicle. All other concentrations in the study had been shown to be homogeneously mixed and stable in the vehicle after 7 days of refrigeration followed by 5 hours at room temperature in the mixing/stability study.(5) The following table from this study is included. Test Day Nominal Sample Type mg/mL Test Day 4 Homogeneity 0 1.0 5.0 25 Test Day 11 Stability 7 Day Refrigerated1 0 1.0 5.0 25 Measured T,M,Ba mg/mL NDC 0.944, 0.884, 0.836d 4.43, 4.37, 4.72d 22.2, 22.7, 24.2 NDC 0.900, 0.864, 0.859 4.46, 4.44 24.2, 23.9 Mean (T,M,B) % Nominal -- 88.8 90.2 92.0 -- 87.4 89.0 96.4 C.V. Stability15 (%) % Nominal ---- 6 85.4e 4 95.0 5 96.0 ---- 3 90.4g 0 84.2g 1 84.8g a Mean results for the analysis of the top (T), middle (M) and bottom (B) samples. b Samples held 5 hours at room temperature. c Denotes none detected. d Mean result of all analyses reported. e Mean result o f all analyses reported except for one duplicate repeat sample which was iow due to aliquot error. f Duplicate concentration verification samples analyzed except for the 1.0 mg/mL level (homogeneity). Mean result o f duplicate re-sampling from the original diluted sample. Original analysis was lower than expected due to aliquot error and not reported. -31 Company Sanitized. Does not contain TSCA CBI LSubchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 D. Concentration Verification Samples Analytical results from dosing suspensions prepared test days 42, 45, 48, 52, 56, 58, 65, and 91 and analyzed for concentration verification are shown in Appendix A, Table II and Summary Table 1. The following table summarizes the results for concentration verification analyses of the m m H a m p l e preparations for the above test days 42 and 45 (3/4-day mix), that were dosed to the animals. Preparation Day Test Day 42 Nominal mg/mL 0.2b 1.0b 5.0 25.0C Measured" mg/mL 0.156, 0.169 0.749, 0.776 3.87b, 3.91 19.4, 19.1 Average % Nominal 81.5 76.3 77.8 77.2 CV % 6 3 1 1 Test Day 45 0.2b 1.0b 5.0b 25.0b 0.066, 0.083 0.676, 0.656 2.20, 2.32 8.34,8.64 37.5 13 66.6 2 45.2 4 34.0 3 a Duplicate samples per level were analyzed. C.V. calculated to verify uniformity of mixture, b Mean result o f the original analysis and duplicate reanalysis of the original sample. c Mean result o f duplicate re-sampling from the original diluted sample. Original analysis was lower than expected due to aliquot error and not reported. Results from analysis of the dosing suspensions collected on test day 42 for concentration verification indicated that test substance was marginally acceptable (-23.7% of nominal). Therefore, to investigate these results, a new large volume preparation (3/4-day mix) of the dosing suspensions was made and sampled on test day 45. The results for these samples were lower than expected (range: -33.4% to -66.0% of nominal) based on previously analyzed samples for the study. Additional work was then done to investigate whether the results for test day 45 were unique to the sampling for the analytical group. This involved the preparation of two large volume dose suspensions (3-4 day mixes) on test days 63 and 73 to be used only for analysis to verify the mixing and sampling procedures of the large volume dose preparations. These suspensions were not dosed to the animals. On test day 49 the dose suspensions were prepared daily for the remainder of the study. - 32- Company Sanitized. Does not contain TSCA CBI Subchronic Toxicity 90-Day Oral Gavage tudy in Rats DuPont-9478 The following table summarizes the results for concentration verification analyses of the ample preparations for the test days 48 (not dosed to animals), and 52, 56, 58,65, and 91 (1-day mixes) that were dosed to the animals. Preparation Day Test Day 48b Nominal mg/mL 0.2 1.0 5.0 25.0 Measured3 mg/mL 0.197, 0.219 0.865, 0.948 3.93, 3.90 21.9, 22.5 Average % Nominal 104.0 90.7 78.3 88.8 CV % 7 6 1 2 Test Day 52 0.2 1.0 5.0 25.0 0.174, 0.184 0.845, 0.895 4.22,4.16 23.5, 22.3 89.5 4 87.0 4 83.8 1 91.6 4 Test Day 56 0.2 1.0 5.0 25.0 0.167, 0.189 0.964, 0.950 4.41,4.31 22.8, 21.4 89.0 9 95.7 1 87.2 2 88.4 4 Test Day 58 0.2 1.0 5.0 25.0 0.174, 0.150 0.945, 0.937 4.48,4.17 22.5,22.1 81.0 10 94.1 1 86.5 5 89.2 1 Test Day 65 0.2 1.0 5.0 25.0 0.159, 0.150 0.832,0.898 4.32,4.40 20.8, 20.5 77.5 4 86.5 5 87.2 1 82.6 1 Test Day 91 0.2 0.162, 0.165 82.0 1 1.0 0.760, 0.863 81.2 9 5.0C 3.96, 3.90 78.6 1 25.0 19.9, 18.7 77.2 4 a Duplicate samples per level were analyzed. C.V. calculated to verify uniformity o f mixture, b Suspensions not dosed to animals. c Mean result of the original analysis and duplicate reanalysis of the original sample. Because of the results from test day 45, samples were collected from the daily mixes to verify concentration on test day 48 (not dosed to animals), 52, 56, 58, 65, arid 91. W ith the exception of four samples, results from these analyses indicated that the dosing suspensions were at the targeted concentrations ( 20% of nominal). On test day 48, the result for the 5.0 mg/mL level was marginally acceptable at 78.3% of nominal. On test day 65, the result for the 0.20 mg/mL level was marginally acceptable at 77.5% of nominal. On test day 91, the result for the 5.0 mg/mL and the 25.0 mg/mL levels were marginally acceptable at 78.6% and 77.2% of nominal, respectively. - 33- Company Sanitized. Does not contain TSCA CBI LSubchromc Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 Based on the statistics (mean % of nominal) for all samples analyzed for the daily mixing, it can be concluded that the dosing suspensions contained the targeted amount o i p [ m [ luring the period from test day 48 (not dosed to animals) until the end for the study. The following table shows the mean % of nominal for all analyzed samples at each concentration for the daily preparations and the average of the mean % of nominal, with the SD, and the CV based on this average for all the levels analyzed. Statistics for all Samples Analyzed for Small Volume Mix (1-day) Nominal Mean mg/mL % Nominal 0-- 0.20 87.2 1.0 89.2 5.0 83.6 25 86.3 Mean: 86.6 SD 2.3 CV 3% On test day 63 and 73, dose preparations (3-4 day/large volume) were prepared but used only for verification of mixing and sampling procedures on the large volume dose preparation. These suspensions were not dosed to the animals. The following table summarizes the results for concentration verification analysis for these preparations. Preparation Day Test Day 63 Nominal mg/mL 0.2 1.0 5.0 25,0 Measured2 mg/mL 0.190,0.192 0.784, 0.792 4.12,4.08 23.0, 21.4 Average % Nominal 95.5 78.8 82.0 88.8 CV % 1 1 1 5 Test Day 73 . 0.2 0.176,0.155 82.8 9 1.0 0.980,1.03 101.0 4 5.0 4.57, 4.60 91.8 0.4 25.0 23.3, 24.4 95.6 3 a. Duplicate samples per level were analyzed. ' C.V. calculated to verify uniformity o f mixture. With the exception of one sample, results from these analyses indicated that the dosing suspensions were at the targeted concentrations ( 20% of nominal). On test day 63, the result for the 1.0 mg/mL level was marginally acceptable at 78.8% of nominal. Neither of these preparations were dosed to the animals but the results were used as statistical data along with the results from the previously dosed large volume preparations (test days -6 , 42, and 45) to show that the dosing suspensions contained the targeted amount of test substance before test day 45 - 34Company Sanitized. Does not contain TSCA CBI _ . Subchromc Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 and that the results for that day were due to technician error while sampling for the Analytical group. Based on the statistics (mean % of nominal) for all samples analyzed for a 3-4-day preparation (large volume), it can be concluded that the dosing suspensions contained the targeted amount of luring the period from the initial sampling (test day -6 ) for the study until test day 45. TheTollowing table shows the mean % of nominal for all analyzed samples at each concentration and the average of the mean % of nominal, with the SD, and the CV based on this average for all the levels analyzed. Included are the two preparations (test day 63 and 73) that were not dosed to animals but prepared only to evaluate the mixing and sampling process. The table includes results (a) with test day 45 and (b) excluding test day 45. Statistics for all Samples Analyzed for Large Volume Mix (3-4-day) Nominal Mean mg/mL % Nominal (a) 0-- 0.20 75.8 1.0 81.5 5.0 78.0 25 76.4 M ean: 77.9 - SD 2.6 CV 3% (b) 0-- 0.20 85.3 1.0 85.3 5.0 86.2 25 87.0 M ean: 85.9 SD 0.8 CV 1% The statistics for the large volume dose preparations with the exclusion of the test day 45 indicate that the samples were at the targeted concentrations having a mean % of.nominal 85.9% 0.8, and a CV of 1%. Although the statistics based on all large volume preparations are marginally acceptable with the inclusion of test day 45 (77.9% of nominal), the test day 45 sample analysis should not be considered as part of the dose verification samples for the study and should be excluded from these statistics because: 1) previous analysis on large volume mixes indicated no problem; 2) the study notebook dose preparation sheet shows that the correct amount of test substance was present at each dosing level for the preparation, and 3) subsequently, that in sampling and analyzing the two large volume preparations after test day 45 (test days 63 and 73), the test material was dispersed properly and at the targeted concentrations. - 35- Company Sanitized. Does not contain TSCA CBI Subchronic Toxicity 90-Day Oral Gavage Study in Rats________ DuPont-9478 Test substance was not found in the 0 mg/mL samples. E. Discussion of Results Based on the statistics (mean % of nominal) for all sample sets analyzed for the study and dosed to the animals, it can be concluded that the dosing suspensions contained marginally the targeted amount ( 20% of nominal) o i H H H |H H B H H M v ith test day 45 included and the targeted amount ( 20% of nominal) o f g [ | | B | | | J ^ v i t h test day 45 excluded. The following table shows the mean % of nominal for all analyzed samples at each concentration and the average of the mean % of nominal, with the SD, and the CV based on this average for all the levels analyzed (a) including test day 45 and (b) excluding test day 45. Statistics for all Samples Analyzed and Dosed to Animals Nominal Mean mg/mL % Nominal (a) 0-- 0.20 77.4 1.0 84.1 5.0 79.9 25 78.3 Mean: 79.9 SD 2.9 CY 4% (b> 0-- 0.20 83.1 1.0 86.5 5.0 84.9 25 84.9 M ean: 84.8 SD 1.4 CV 2% F. Analytical Conclusion Results from the analysis of the] using suspensions prior to the study start, at the initiation of the study, for the daily dose preparations after test day 45, and including the additional large volume dose preparation on test days 63 and 73 (not dosed to the animals) indicated that the test substance was homogeneously mixed, at the targeted concentrations and stable in the vehicle under the conditions of the study. Furthermore, the study records indicate that the correct amount of test substance was contained in the test day 45 dosing suspensions. Taken together, these data point to a problem unique to the analytical samples that were collected on test day 45. - 36Company Sanitized. Does not contain TSCA CBI ISubchronic Toxicity 90-Day Oral Gavage Study in Rats_________ DuPont-9478 IN-LIFE TOXICOLOGY A. Dosage Data (Tables 2-3, Appendix B) Rats were dosed with suspensions 0-5% aqueous methylcellulose, prepared at concentrations of 0, 0.2,1, 5, and 25 mg/mL, designed to deliver the targeted dose of test substance at a dosing volume of 5 ml/kg body weight. The quantity o f| m ^ ^ d m i n i s t e r e d to each rat was calculated, based on the most recent body weight for each rat, and subsequently rounded by a computer program. The range of mean daily dose volumes administered to male rats was 1.2-2.9 mL for the control group, 1.2-2.8 mL for the 1 mg/kg/day group, 1.2-3.0 mL for the 5 mg/kg/day group, 1.2-3,0 mL for the 25mg/kg/day groupVand_Ii2-278*nLfdr die 125 mg/kg/day group. The range of mean daily dose volumes administered to female rats was 0.9-1.5 mL for the control group, 0.9-1.5 mL for the 1 mg/kg/day group, 0.9-1.5 mL for the 5 mg/kg/day group, 0.9-1.6 mL for the 25 mg/kg/day group, and 0.9-1.6 mL for the 125 mg/kg/day group. B. Mean Body Weights and Body Weight Gains (Tables 4-7, Figures 1-2, Appendix C) There were no test substance-related, toxicologically significant alterations in mean body weight or body weight gain observed in any of the male or female dose groups. Significant decrements of 40 and 51%, respectively, occurred in the mean body weight gain of the 25 and 125 mg/kg/day male groups during the 63-70 test day interval, while a significant increase occurred for the 125 mg/kg/day male group during the 7-14 day interval. For the 49-56 day interval, significant increases in mean body weight gain were observed for the 5 and 25 mg/kg/day male groups. On test day 77, all animals in the high-dose male and female dose groups were placed on ground chow because of test substance-induced alterations to the teeth. Once placed on ground chow, males in the 125 mg/kg/day group had a significant increase in mean body weight gain for the 84-91 test day interval. The overall (0-91 day interval) mean body weight gain of male rats, however, was similar to control across all dose levels. Over the course of the three-month recovery period, statistically significant increases in mean body weight gain occurred for the 125 mg/kg/day male group. Overall mean body weight gain for the three-month recovery period for the 125 mg/kg/day male group was significantly increased 36% compared to control. During the 77-84 test day interval, females in the 125 mg/kg/day dose group had a significant increase in mean body weight gain following their placement on ground chow. For the overall interval (0-91 days), the mean body weight gain for females was similar to control across all dose levels. A significant increase in mean body weight gain occurred for the 25 mg/kg/day female group during the 154-161 test day interval. Statistically significant increases and decreases in mean body weight gain also occasionally occurred over the three-month recovery period for the 125 mg/kg/day female group; however, the mean body weight gain for all female dose groups was similar to control for the overall recovery interval. - 37- Company Sanitized. Does not contain TSGA CB1 JSubchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 C. Food Consumption and Food Efficiency (Tables 8-11, Appendix D) There were no test substance-related, toxicologically significant alterations in food consumption observed in any of the male or female dose groups. For the 98-105 and 105-112 test day intervals, males in the 125 mg/kg/day three month recovery group had statistically significant and lower food consumption of 9 and 10%, respectively. Overall (91-182 day interval), however, food consumption for the 125 mg/kg/day male three-month recovery group was similar to control. There were no test substance-related, toxicologically significant alterations in mean daily food efficiency observed in any of the male or female dose groups. Male rats in the 125 mg/kg/day group had several incidences of significantly higher mean daily food efficiency compared to control over the course of the study except during the 63-70 day interval in which significantly lower (59% compared to control) mean daily food efficiency was observed. Males in the 25 mg/kg/day dose group also had a. significantly lower mean daily food efficiency of 42% during the 63-70 test day interval. Following the replacement of pelleted chow with ground chow on test day 77 for the 125 mg/kg/day male group, a significantly higher mean daily food efficiency was observed for the 84-91 day interval. For the 0-91 day study interval, however, mean daily food efficiency for male rats was similar to control, while for the overall three-month recovery interval, mean daily food efficiency was significantly increased 26% compared to control for the 125 mg/kg/day male group. Female rats in the 125 mg/kg/day group had significantly lower (60%) mean daily food efficiency during the 63-70 day interval. Following the replacement of pelleted chow with ground chow on test day 77 for the 125 mg/kg/day female group, a significantly higher mean daily food efficiency was observed for the 77-84 day interval. Overall mean daily food efficiencies for test-substance treated female groups, however, were similar to control. During the three-month recovery (test days 154-161), females in the 125 mg/kg/day group had a significant increase in mean daily food efficiency; however, for the overall three month recovery interval, mean daily food efficiency was similar to control. D. Clinical Observations and Mortality (Tables 12-17, Appendix E-F) A test substance-related, toxicologically significant increase in the incidence of striated teeth was observed in the 125 mg/kg/day male and female dose groups. In addition, there was an increase in tooth clipping required for both males and females in the 125 mg/kg/day dose group. No test substance-related ophthalmological signs of toxicity or effects on survival were observed. - 38Company Sanitized. Does not contain TSCA CBI  R s u b c h r o m c Toxicity 90-Day Oral Gavage Study in Rats_______ DuPont-9478 E. In-Life Toxicology Conclusions Under the conditions of this study, the NOEL for in-life toxicology parameters (body weight, body weight gain, food consumption, food efficiency, and clinical signs of toxicity) was 25 mg/kg/day for both males and females based on the increased incidence of striated teeth observed in male and female rats administered 125 mg/kg/day. NEUROBEHAVIORAL TOXICOLOGY A. Sensory Function Evaluations 1. Forelimb Grip Strength (Table 18-19, Figures 3-4, Appendix G) There were no test substance-relatedeffects on forelimb grip strength in males or females administered any dosage During the baseline evaluation, females in the 5 mg/kg/day group had significantl^ncreased forelimb grip strength. However, since administration of the test material had not been initiated, this statistical difference was not test substance related. There were no statistically significant differences for males administered any dosage of the test material. 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 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 o: B. Motor Activity (Tables 22-25, Figures 7-10, Appendices I-J) There were no test substance-related effects on duration of movement or number of movements for males or females for any dosage During the third 10-minute interval for the baseline evaluation, males in the 1 mg/kg/day group had significantly higher duration of movement compared to the control value. During the fourth 10-minute interval of the baseline evaluation, males in the 1, 5, 25, and 125 mg/kg/day groups had significantly higher duration of movement compared to the control value. During the fifth 10-minute interval of the baseline evaluation, males in the 5 mg/kg/day group had significantly higher duration of - 39Company Sanitized. Does not contain TSCA CB) ,Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 movement compared to the control value. However, since administration of the test material had not been initiated, these statistical differences were not test substance related. During the fifth 10-minute interval for the 13-week evaluation, duration of movement for 25 mg/kg/day males was significantly lower compared to the control value. However, since duration of movement was similar to control for 125 mg/kg/males, the statistically lower value for the 25 mg/kg/day males was not considered to be test substance-related. During the fourth 10-minute interval for the baseline evaluation, number of movements for 1, 5, and 25 mg/kg/day males was significantly higher than the control value. In addition, during the fifth 10-minute interval for the baseline evaluation, number of movements for 5 mg/kg/day males was significantly higher than the control value. However, since administration of the test material had not been initiated, these statistical differences were not test substance related. Total number of movements and the- number of movements during the fifth 10-minute interval of the 13-week evaluation were significantly lower for 25 mg/kg/day males compared to the control value. However, since number of movements for 125 mg/kg/day males was similar to control, these statistical differences were not considered to be test substance related. Number of movements for 125 mg/kg/day males during the fourth 10-minute interval for the 13-week evaluation was significantly lower compared to the control value. However, since the total number of movements was similar to the control value, the statistically lower value for 125 mg/kg/day males was not considered to be test substance related. There were no statistically significant differences for females administered any dosage of the test material. C. Neurobehavioral Toxicity Conclusions Under the conditions of the study, the NOEL for neurobehavioral parameters was 125 mg/kg/day o n males and females, the highest concentration tested. CLINICAL PATHOLOGY A. Hematology/Coagulation (Tables 26-29, Appendix K) There were no adverse changes in hematologic parameters in male or female rats at either time point during treatment. The following statistically significant changes in mean hematologic parameters were considered to be non-adverse. Red cell mass (red cell count, hemoglobin, hematocrit) was minimally decreased in males and females dosed with 125 mg/kg/day (at both time points during treatment, variable statistical significance for males) (Clinical Pathology Text Table 1). Decreased red cell mass was associated with regeneration of red cells (increased reticulocytes) in males (statistically significant only at 125 mg/kg/day, test days 48 and 93) and females (statistically significant at - 40- Gompany Sanitized. Does not contain TSCA CBI Subchronic Toxicity 90-Pay Oral Gavage Study in Rats DuPont-9478 test day 94 only). Increased reticulocytes resulted in increased red cell distribution width and mean cell volume (variable statistical significance). However, histologically, there was no increase in extramedullary hematopoiesis. Red cell counts (males) and hematocrits (females) were minimally but statistically decreased in rats dosed with 25 mg/kg/day. These changes were sometimes associated with minimal -increases in red cell distribution width and mean cell volume (variable statistical significance). In addition, minimally increased changes in red cell morphology (acanthocytes) were present in males dosed with 25 or 125 mg/kg/day at both time-points during treatment. The above changes in red cell parameters were considered to be related to treatment, and indicate minimally increased red cell turnover. However, due to the minimal nature of the changes, they were considered to be non-adverse. After approximately 90 days of recovery, red cell mass parameters, reticulocytes, red cell distribution width, and mean cell volume were similar to control group values of rats previously dosed with 125 mg/kg/day. Minimally increased mean corpuscular hemoglobin in males dosed with 125 mg/kg/day at test day 93 was considered to be possibly related to treatment, but was considered to be nonadverse-because minimal increases in mean corpuscular hemoglobin are not associated with adverse effects. After approximately 90 days of recovery, mean corpuscular hemoglobin concentrations were similar to control group values of rats previously dosed with 125 mg/kg/day. The following statistically significant changes in mean clinical chemistry parameters were considered to be non-adverse because they were unrelated to dose and/or occurred only at three months post dosing: Minimally and transiently decreased reticulocytes in females dosed with 25 mg/kg/day at test day 49. Minimally increased basophils in females previously dosed with 125 mg/kg/day after approximately 90 days of recovery. -41 Company Sanitized. Does not contain TSCA CBI iSubchronic Toxicity '90-Day Oral Gavage Study in Rats DuPont-9478 Clinical Pathology Text Table 1: Red cell mass parameters and reticulocytes (expressed as a percent of control group mean)* Males Females Dosage (mg/kg/day): 1 5 25 125 1 5 25 125 TestDav RBC 48/49 99% 98% 95% 93% 93/94 100% 97% 95% 91% 183 -- - - 96% HGB 48/49 101% 100% 98% 96% 93/94 100% 98% 98% 94% 183 -- - - 98% HCT 48/49 100% 100.% 97% 96% 93/94 roi% 99% 98% 95% 183 -- - - 97% ARET 48/49 97% 111% 113% 123% 93/94 92% 108% 112% 126% 183 -- - - 105% * Statistical significance indicated by bold italicized type 98% 100% 99% 102% 98% 101% -88% 98% - 98% 102% 99% 102% 99% 102% -97% 110% _ 97% 91% 98% 93% -- 100% 96% 91% 98% 94% ~ 103% 96% 91% 97% 94% - 103% 85% 94% 99% 125% - 107% B. Clinical-Chemistry . (Tables 30-31, Appendix K) There were no adverse changes in clinical chemistry parameters in male or female rats. The following statistically significant changes in mean clinical chemistry parameters were not toxicologically significant (i.e., not adverse) or not related to exposure to test substance: Alkaline phosphatase activity was minimally and transiently increased in males dosed with 125 mg/kg/day at test day 48. At the end of dosing (test day 93), alkaline phosphtase activity was more similar to controls, although it was still minimally increased (not statistically significant). Increased alkaline phosphatase can be due to induction by a xenobiotic compound or can be due to increased biliary pressure. In this study, males dosed with 125 mg/kg/day had both increased liver weights and histologic evidence of hypertrophy, but no evidence, of cholestasis. Therefore, in this study, increased alkaline phosphatase activity was probably due to induction by the test substance. Increased alkaline phosphatase activity was considered to be non-adverse because minimally increased alkaline phosphatase is not associated with adverse effects. After approximately 90 days of recovery, alkaline phosphatase activities were similar to control group values in rats previously dosed with 125 mg/kg/day. -42- Company Sanitized. Does not contain TSCA CBI Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 Cholesterol was mildly increased in females dosed with 25 or 125 mg/kg/day (variable statistical significance) at test days 49 and 94 (group means were 136% to 139% of control group means). Although this change was likely due to treatment, mildly increased cholesterol does not result in adverse events. Therefore, this change was considered to be non-adverse. ' After approximately 90 days of recovery, cholesterol concentrations were similar to control group values in females previously dosed with 125 mg/kg/day. Triglycerides were mildly decreased in males dosed with 125 mg/kg/day at test days 48 and 93 (49 and 48% of control group means, respectively). Mildly decreased triglycerides were : considered to be related to treatment; however, mildly decreased triglycerides are not associated with adverse effects, and therefore were considered non-adverse. After approximately 90 days of recovery, triglyceride concentrations were similar to control group values in males previously dosed with 125 mg/kg/day. Total protein was mildly increased due to increased albumin in males and females dosed with 125 mg/kg/day at days 48/49 and 93/94. Mildly increased total protein and albumin concentrations were likely due to treatment, but were considered to be non-adverse because mild increases in these parameters are not associated with adverse effects. After approximately 90 days of recovery, protein concentrations were similar to control group values in rats previously dosed with 125 mg/kg/day. Calcium was increased in females dosed with 125 mg/kg/day at test day 94. The increased calcium was considered to be secondary to increased albumin. Calcium exists in semm in two forms, either bound to albumin or unbound ("ionized" calcium). Ionized calcium is the physiologically active form and is tightly regulated. Increases in albumin are necessarily associated with physiologically appropriate increased bound calcium, with resultant increased total calcium. However, ionized calcium is unaffected. Therefore, this change was considered to be non-adverse. After approximately 90 days of recovery, calcium concentrations were similar to control group values in rats previously dosed with 125 mg/kg/day. Phosphorus was minimally increased in males dosed with 125 mg/kg/day at test day 48 and 93, and at the end of recovery (test day 183). Increased phosphorus was possibly due to treatment at test day 48 and 93, but was likely to be unrelated to treatment at test day 183 (after three months of recovery). Increased phosphorus is of toxicologic significance when it is associated with evidence of decreased glomerular filtration rate, but may also be affected by extrarenal factors. In this study, other indicators of glomerular filtration rate (urea nitrogen and creatinine) were unaffected by treatment. Anatomic pathology changes included increased kidney weights associated with renal .tubular hypertrophy; these changes were not present after three months of recovery. However, these anatomic pathology changes are not expected to result in decreased glomerular filtration rates. Therefore, the minimally increased phosphorus was considered to be non-adverse. - 43Company Sanitized. Does not contain TSCA CBI Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 The following statistically significant changes in mean clinical chemistry parameters were considered to be non-adverse because they were unrelated to dose and/or occurred only at three months post-dosing: Decreased bilirubin in males dosed with 1 mg/kg/day at test days 48 and 93 Decreased cholesterol in males dosed with 25 mg/kg/day at test day 48 Increased urea nitrogen in males dosed, with 25 mg/kg/day at test day 93 Decreased urea nitrogen and creatinine in males previously dosed with 125 mg/kg/day at recovery test day 183 Decreased cholesterol in males dosed with 1 mg/kg/day at test day 93 C. Urinalysis (Tables 32-33, Appendix K) Microscopic ne evaluation had lower priority than other urine tests. After other tests were completed on day 94, some females had insufficient urine for microscopic observation. Although no treatment-related changes were present in the samples evaluated, there were too few specimens to make unequivocal determinations. For other time-points and for males at test day 93, there were no adverse changes in urinalysis parameters. The following statistically significant changes in mean or individual urinalysis parameters were considered to be nonadverse. < Urine volume was increased in males dosed with 125 mg/kg/dy at test day 93. Increased urine volume can be due to primary increased urine production, or can be secondary to increased water consumption. The cause of increased urine production in this study was not determined. These changes correlated with anatomic pathology findings of increased kidney weights and renal tubular hypertrophy which were considered to be non-adverse (see discussion under Microscopic Findings). Increased urine production in the absence of alterations in other renal parameters (serum urea nitrogen, serum creatinine, or adverse histologic changes in the kidney) is considered to be non-adverse. After approximately 90 days of recovery, urine volumes were similar to control group values in rats previously dosed with 125 mg/kg/day. Decreased urine ketone concentrations were present in males dosed with 125 mg/kg/day at test day 93. These decreases were likely secondary to increased urine volumes, and were considered to be- non-adverse. After approximately 90 days of recovery, urine ketone concentrations were similar to control group values in rats previously dosed with 125 mg/kg/day. -44- Company Sanitized. Does not contain TSCA CBI ' y i m m i m j ^ l s u b c h r o n i c Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 D. Plasma and Urine Fluoride (Tables 30-33, Appendix K) Plasma fluoride was increased in males dosed with 125 mg/kg/day, and in females dosed with 25 or 125 mg/kg/day at test day 93/94 (not statistically significant in females dosed with 25 mg/kg/day). After approximately 90 days of recovery, plasma fluoride concentrations were similar to control concentrations for males and females previously dosed with 125 mg/kg/day. Urine fluoride was increased in males and females dosed with 5, 25, and 125 mg/kg/day at test day 93/94 (not statistically significant in females dosed with 5 mg/kg/day). After approximately 90 days of recovery, total urine fluoride amounts were approximately 3 times greater than controls in males previously dosed with 125 mg/kg/day, but only minimally greater than controls in females. Increased plasma and urine fluoride indicates exposure to and metabolism of a fluoridecontaining compound. The presence of fluoride after 90 days of recovery indicates continued metabolism of the test substance. Clinical Pathology Text Table 2: Plasma fluoride (expressed as mean and as percent of control group mean)* Parameter Sex Test Dav im II/IV V/V v n /v iii 0 1 5 25 me/ke/dav me/ke/dav me/ke/dav me/ke/dav PFLU (ug/mL) Males 93 0.1 PFLU (ug/mL) Females 183 94 0.1 - 0.1 183 0.1 UFLU (ug) Males 93 -- 10.7 -- 183 9.9 UFLU (ug) Females 94 -- 6 -- 183 11.9 - * Statistical significance indicated by bold italicized type. 0.1 100% - -- 0.1 100% -- -- 13 121% - -- 5.7 95% - 0.1 100% -- -- 0.1 100% -- -- 38.8 363% -- 14.1 235% -- -- 0.1 100% -- - 0.2 200% - -- 202.4 1892% - -- 88 1467% -- -- DUX' 125 me/ke/dav 0.4 400% 0.1 100% 0.5 500% 0.1 100% 997.2 9320% 27.6 279% 702.6 11710% 15.7 132% E. Clinical Pathology Conclusions In conclusion, there were no adverse effects, measured by clinical pathology parameters, in rats dosed w i t h p U H H H H m ^ t doses up to 125 mg/kg/day. Treatment related changes in rats dosed with > 25 mg/kg/day included decreases in some red cell mass parameters along with - 45- Company Sanitized. Does not contain TSCA GBI ISubchronic Toxicity r90-Day Oral Gavage Study in Rats DuPont-9478 regeneration (increased reticulocytes), increased serum cholesterol (females only) and increased serum phosphorus (males only). Additional treatment-related changes in clinical chemistry observed in rats dosed with 125 mg/kg/day included transiently increased alkaline phosphatase (males only), decreased triglycerides, increased total protein and albumin, and increased calcium (females only). For urinalysis parameters, males dosed with 125 mg/kg/day had increased urine volume and decreased urine ketone concentration. Treatment-related changes in fluoride measurements included increased plasma fluoride in males dosed with 125 mg/kg/day, and in females dosed with > 25 mg/kg/day (variable statistical significance). Urine fluoride excretion was increased in males and females dosed with > 5 mg/kg/day (variable statistical significance). None of the above changes are expected to be adverse. Therefore, under the conditions of this study and for the clinical pathology parameters measured, the NOEL was 125 mg/kg/day for males and females, based on the lack of adverse effects at any dose. BIOCHEMICAL MEASUREMENTS A. Biochemical Measurements (Table 34-35, Appendix L) The rate of hepatic (3-oxidation, a measure of peroxisome proliferation, was determined in a subchronic oral toxicity study w i t h p [ | | ^ j | | ^ | H p n male and female rats after approximately 10 or 90 days of test substance administration or following a three-month recovery period. At the 10-day, 90-day, and 3-month recovery time points in male rats, the rate of hepatic 13oxidation was statistically significantly increased at 125 mg/kg/day (163, 166 and 133% of control, respectively). At the 10-day and 90-day time points, the increases in hepatic (3-oxidation activity at 125 mg/kg/day in male rats were accompanied by increases in relative liver weights (133 and 152% of control, respectively). A t the three-month recovery time point, the relative liver weights had returned to control levels. At the 10-day time point in female rats, the rate of hepatic (3-oxidation was statistically significantly increased at 125 mg/kg/day (131% of control). At the 90-day time, point, the rate of hepatic ^-oxidation was statistically significantly increased at 25 and 125 mg/kg/day (116 and 152% of control, respectively). Hepatic (3-oxidation returned to control levels at the three-month recovery time point. A t the 10-day time point, the increase in hepatic (3-oxidation activity at 125 mg/kg/day was accompanied by an increase in relative liver weight (132% o f control). At the 90-day time point, the increases in hepatic 3-oxidation activity at 25 and 125 mg/kg/day were accompanied by increases in relative liver weights (112 and 145% of control, respectively). At the three-month recovery time point, the relative liver weights had returned to control levels. - 46- Company Sanitized. Does not contain TSCA CBI SubcRronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 B. Biochemical Measurements Conclusions Under the conditions of this study, s a mild inducer of hepatic peroxisomal 3-oxidation in male and female rats. At concentrations of 125 mg/kg/day in males and 25 mg/kg/day in females, changes in the rate of hepatic peroxisome proliferation were considered to be test substance-related effects. At the three-month recovery time point, the rate of hepatic peroxisome proliferation was still slightly increased at 125 mg/kg/day in males, but had returned to control levels in female rats. ANATOMICAL PATHOLOGY A. Mortality (Appendix N) There were no test substance-relatecLdeaths. One male rat- (animal- number- 654949)- and-one female rat (animal number 655071) from the control group were accidentally killed on study days 183 and 19, respectively. B. Organ Weight Data (Tables 36-37, Appendix M) Test substance-related and/or statistically significant increases, compared to controls, in liver weight parameters were present in 25 and 125 mg/kg/day males and females sacrificed at the end of the exposure period. Liver weight parameters were not significantly increased in males or females in the 125 mg/kg/day three-month recovery group (there were no recovery' groups in intermediate dosed groups). In 125 mg/kg/day exposure group male rats, increased liver weight correlated with microscopic hepatocellular hypertrophy (see discussion under Microscopic Findings). Test substance-related and/or statistically significant increases, compared to controls, in one or more kidney weight parameters were present in 25 and 125 mg/kg/day males and females sacrificed at the end of the exposure period. Kidney weight parameters were not significantly increased in males or females in the 125 mg/kg/day three-month recovery group (there were no recovery groups in intermediate dosed groups). In male rats, increased kidney weights correlated with microscopic tubular hypertrophy in the 25 and 125 mg/kg/day groups sacrificed at the end of the exposure period (see discussion under Microscopic Findings), There were no other test substance-related organ weight effects. All. other statistically significant organ weight changes in exposure and recovery groups were considered spurious and not biologically significant. These changes included decreased adrenal gland weight relative to body weight in 1 mg/kg/day female rats sacrificed at the end of the exposure period and decreased heart weight relative to body weight in the 125 mg/kg/day three-month recovery group females. In 125 mg/kg/day three-month recovery males, absolute, relative to body weight, and relative to brain weight thymus weights were increased; however, no test substance-related microscopic changes were present. - 47- Company Sanitized. Does not contain TSCA CBI Subchronic Toxicity 90-Day Oral Gavage iudy in Rats DuPont-9478 C. Gross Observations (Tables 38-39, Appendix N) Gross observations noted were sporadic across groups and were not test substance related. D. Microscopic Findings (Tables 40-45, Appendix N) Test substance-related microscopic findings were present in liver, kidneys, thyroid gland, and teeth from male rats and in kidneys from female rats. Anatomical Pathology Text Table: Incidences and Average Lesion Grades of Test substance-Related Microscopic Findings In Male and Female Rats Dose (mg/kg/day): 0 1 5 25 125 Liver: Hypertrophy, hepatocellular Necrosis, focal Males: 90-Day Exposure 0/10a (0.0)b 0/10 (0.0) 0/10 (0.0) 0/10 (0.0) 0/10 (0.0) 1/10(1.0) 0/10 (0.0) 5/10 (1.0) 10/10(1.6) 3/10 (1.0) Kidneys: Hypertrophy, tubular 0/10 (0.0) 0/10 (0.0) 0/10 (0.0) 9/10 (1.0) 10/10(1.0) Thyroid gland: Alteration, colloid 3/10 (1.0) 8/10 (1.1) 9/10 (1.0) 10/10 (1.0) 8/10 (2.3) Teeth: Degeneration, ameloblasts (nose) 0/10 (0.0) 0/10 (0.0) 0/10 (0.0) 0/10 (0.0) 5/10 (1.6) Liver: Necrosis, focal 3/10(1.3) Males: Three-Month Recovery NA NA NA 7/10(1.1) Thyroid gland: Alteration, colloid 7/10 (1.4) NA NA NA 10/10 (1.6) Teeth: Degeneration, ameloblasts (nose) 0/10 (0.0) NA NA NA 2/10(1.0) Kidneys: Chronic progressive nephropathy 2/11 (1.0) Females: 90-Day Exposure 2/10 (1.0) 3/10(1.0) - 3/10(1.0) 7/10 (1.0) Kidneys: Chronic progressive nephropathy 5/9 (1.0) Females: Three-Month Recovery NA NA NA 8/10 (1.4) a. Numerator indicates incidence of rats with microscopic lesion. Denominator indicates number of rats in group. b. Number in parentheses indicates average severity o f lesion. NA Tissue not available because there were no intermediate recovery groups. -48- Company Sanitized. Does not contain TSCA CBl ______ Subchxonic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 Focal hepatocellular necrosis accompanied by a minimal inflammatory response was present in 25 and 125 mg/kg/day male 90-day exposure groups. In addition, the incidence of hepatocellular necrosis in 125 mg/kg/day three-month recovery males was increased when compared to the control group. The single occurrence of hepatocellular necrosis in males at 5 mg/kg/day was most likely not test substance-related since this lesion can occur spontaneously in control animals/26'1 Focal liver necrosis was considered to be a test substance-related adverse finding in 25 and 125 mg/kg/day male rats. Hepatocellular hypertrophy was present in 125 mg/kg/day males sacrificed at the end of the exposure period. In three-month recovery male rats previously dosed with 125 mg/kg/day, hepatocellular hypertrophy was not present and appears to be reversible. Microscopically, hepatocellular hypertrophy was characterized by an increased amount of finely granular eosinophilic cytoplasm within hepatocytes. Thus, hepatocellular hypertrophy (and the associated increase in liver weights) was considered a test substance-related physiologic response to metabolism of a xenobiotic and not biologically adverse/27'28,29' Test substance-related tooth lesions in 125 mg/kg/day exposure group male rats consisted of degeneration and/or disorganization of enamel organ ameloblast cells. This lesion was most evident in the upper incisors of the level 1 (anterior) nose section. Following a three-month recovery, ameloblastic degeneration/disorganization was still present in male rats previously dosed with 125 mg/kg/day. This tooth lesion is similar to lesions seen with fluoride toxicosis and is considered adverse/30^ in the thyroid gland, the incidence and/or relative degree of altered colloid was increased in males in all dosed groups at the end of the 90-day exposure period. Following the three-month recovery period, severity and incidence of altered colloid were increased in males at 125 mg/kg/day when compared to controls. 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 1 follicle to about 25% of the follicles were involved, with grades 2, 3, and 4 applied for each 25% increase in follicular involvement. The size, density, or staining intensity of stipples, granules, clumps, or diffuse basophilia within individual follicles did not impact the grading. Altered colloid described as clumped or granular has been reported to occur spontaneously in Sprague-Dawley rats with increasing incidence correlating to increasing age/31) Because altered colloid occurs spontaneously in healthy Sprague-Dawley rats, and since there were no other microscopic alterations in the thyroid gland, altered colloid, although likely test substancerelated, was not considered adverse. The incidence of chronic progressive nephropathy was increased in 125 mg/kg/day 90-day exposure females when compared to controls. Incidence and severity of this lesion were increased in 125 mg/kg/day females at three months recovery when compared to controls. This lesion appears to progress after cessation of test material exposure and is considered adverse. - 49- Company Sanitized. Does not contain TSCA CBI jSubchronic Toxicity 90-Day Oral Gavage tody in Rats DuPont-9478 Renal tubular hypertrophy was present in 25 and 125 mg/kg/day male rats sacrificed at the end of the exposure period. This change was not observed in male rats sacrificed after the three-month recovery period and appears to be reversible. Microscopically, tubular hypertrophy was characterized by increased eosinophilic staining of cortical tubule epithelium and a slight increase in cell height. Cortical tubule epithelial cells appeared to contain more granular cytoplasmic material then cortical tubules of control rats. Tubular lumina of hypertrophied tubules were slightly smaller then those in control rat kidneys. Tubular hypertrophy was not associated with other histomorphologic evidence of renal damage, and renal clinical pathology parameters indicative of renal toxicity were not present (see clinical pathology section). Increased kidney weights occurring absent correlative evidence of renal toxicity commonly occur in toxicology studies and may represent a physiological response to high doses of a test material.(32) Thus, increased kidney weights and the associated renal tubular hypertrophy were likely test substance-related; however, these changes were not considered adverse but most likely represent a test substance-related physiologic response. 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. E. Anatomical Pathology Conclusions Exposure to 125 mg/kg/day of the test substance for approximately 90 days produced degeneration/disorganization of enamel organ ameloblast cells in male rats. Ameloblastic degeneration/disorganization was not reversible after three months recovery. Increased incidence and severity o f chronic progressive nephropathy in 125 mg/kg/day female recovery rats was considered test substance related and biologically adverse. Focal hepatic necrosis was present in 90-day males at 25 and 125 mg/kg/day and in three-month recovery males at 125 mg/kg/day. This lesion was considered test substance related and adverse. The incidence and/or severity of altered colloid in thyroid glands of male rats increased beyond control level as the dose increased; however, since there were no other microscopic alterations present this finding was not considered adverse. Increased liver weights were present in males and females at 25 and 125 mg/kg/day. The irxreased liver weights correlated with microscopic hepatocellular hypertrophy in males at 125 mg/kg/day. Hepatocellular hypertrophy was reversible in males following three-months recovery. These liver changes were considered to represent a physiologic response to metabolism of a xenobiotic and thus were not considered to be adverse. Increased kidney weights were present in 25 and 125 mg/kg/day males and females. In males, these kidney weight changes correlated with microscopic renal tubular hypertrophy. The increased kidney weights and renal tubular hypertrophy appeared to be reversible by three-months recovery. Increased kidney weights and microscopic tubular hypertrophy were not associated with correlative morphologic or clinical pathological changes and thus were not considered to be adverse findings. Under the conditions of this study, the NOEL for pathology for male rats was 5 mg/kg/day based on hepatic necrosis at the 25 and 125 mg/kg/day dose levels and for female rats was 25 mg/kg/day based on an increased incidence and severity of nephropathy at 125 mg/kg/day. -50- Company Sanitized. Does not contain TSCA CBI ______ _ JSubchronic Toxicity *90-Day Oral Gavage Study in Rats DuPont-9478 CONCLUSIONS No test substance-related mortality or alterations in neurobehavioral parameters were observed in male or female rats. No test substance-related decrements in mean body weight, body weight gain, food consumption, or food efficiency were observed in male or female rats administered up to 125 m g / k g / d a ^ y ^ l ^ ^ l l ^ H n T e s t substance-related, toxicologically significant increases in the incidence of striated teeth occurred in the 125 mg/kg/day male and female dose groups. There were no toxicologically significant changes observed in clinical pathology parameters in rats dosed with up to 125 statistically significant increase in the rate of hepatic (3-oxidation occurred in the 25 mg/kg/day female and 125 mg/kg/day male and female groups. After the recovery period, the increased rate of (3-oxidation persisted, albeit at a reduced level compared to the 90-day time point, in the 125 mg/kg/day male group. Test substance-related, toxicologically significant degeneration/disorganization of enamel organ ameloblasts cells occurred in male rats dosed with 125 mg/kg/ This tooth lesion, along with the increased incidence of striated teeth, is consistent with fluonae toxicosis/30-1 After three months, the degeneration/disorganization of ameloblasts persisted, at a lower incidence and severity. A test substance-related, adverse increase in the incidence and severity of focal hepatic necrosis was observed in males administered 25 and 125 mg/kg/day. An increased incidence and severity of chronic progressive nephropathy occurred in the 125 mg/kg/day female group that was considered adverse. After three months of recovery, both the incidence of hepatocellular necrosis in the 125 mg/kg/day male group and the incidence and severity of chronic progressive nephropathy in the 125 mg/kg/day female group were increased compared to control. Test-substance related and statistically significant increases in liver weight parameters were present in males and females administered 25 or 125 mg/kg/day for approximately 90 days. The increased liver weights correlated with microscopic hepatocellular hypertrophy in the 125 mg/kg/day male dose group. liv e r weight changes and microscopic hypertrophy were considered to be a physiological adaptive response to metabolism of the test substance and not adverse. Test-substance related and statistically significant increases in kidney weight parameters occurred in males and females administered 25 or 125 mg/kg/day. The increased ki dney weights correlated with microscopic renal tubular hypertrophy in the 25 and 125 mg/kg/day male groups only. However, no correlative microscopic or clinical pathological evidence of renal toxicity were present. Therefore, kidney weight changes and microscopic tubular hypertrophy were not considered adverse findings. Altered colloid, a common spontaneous finding in rats, was increased in incidence and/or severity in treated male groups. This change was not associated with other findings in the thyroid gland and was also not considered an adverse finding. After the three-month recovery period, increased liver weight parameters and hepatocellular hypertrophy (males only) were no longer observed in the 125 mg/kg/day male and female groups. Similarly, increased kidney weight parameters and renal tubular hypertrophy (males only) were not observed in rats sacrificed after three months of recovery. - 51 Company Sanitized. Does not contain TSCA CBI H H H V H B H H H P j Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 The no-observed-effectjevel (NOEL)3 the 90-day exposure period was 5-mg/kg/day on the increased incidence of hepatic necrosis ^observed in males administered > 25 mg/kg/day. The NOEL for females was 25 mg/kg/day [ H ^ I B H H i H v a s e d on the increased incidence and severity of chronic progressive nephropathy observed in females administered 125 mg/kg/day. 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. Test Substance characterization data will be retained at Haskell Laboratory, Newark, Delaware, or at Iron Mountain Records Management, Wilmington, Delaware. 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 c3) and to the no-observed-adverse-effect level (NOAEL) as defined by the European Union.(34> -52- Company Sanitized. Does not contain TSCA CBI JSubchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 REFERENCES 1. Covance study No. 6329-183 (1998). "104-week dietary carcinogenicity study with perfluorooctane sulfonic acid potassium salt ( P F O S r a t s . " 2. Ikeda, T., Fukuda, K., Mori, I., Enomoto, M., Komai, T., Suga, T. (1987). Induction of cytochrome P-450 and peroxisome proliferation in rat liver by perfluorinated octanesulfonic acid. In: Fahixni HD, Sies H, eds. Peroxisomes in Biology and Medicine. Springer Verlag, New York, pp 304-308. 3. Sohlenius, A.K., Eriksson, A.M., Hogstrom, C., Kimland, M., Depierre, J.W. (1993). Perfluorooctane sulfonic acid is a potent inducer of peroxisomal fatty acid beta-oxidation and other activities known to be affected by peroxisome proliferators in mouse liver. Pharmacol. Toxicol., 72: 90-93. 4. Haughom, B., Spydevold, O. (1992). The mechanism underlying the hypolipemic effect of perfluorooctanoic acid (PFOA), perfluorooctane sulphonic acid (PFOSA) and clofibric acid. Biochem. Biophys. Acta., 1128: 65-72. 5. DuPont Haskell Analytical Repo 6. DuPont (1995). Neurotoxicity Evaluation of Trimethyltin in Rats (Positive Control Study). 7. DuPont (1997). Neurotoxicity Evaluation of Amphetamine in Rats (Positive Control Study). fHL-1997-00686. (MRID 44628703)] J8. DuPont (1997). Neurotoxicity Evaluation of Carbaryl in Rats (Positive Control Study). j*HL-1997-00361. (MRID 44628702) 9. DuPont (1996). Neurotoxicity Evaluation of Acrylamide in Rats (Positive Control Study). [HLR 293-95. (MRID 44660601).] 10. Lazarow, P.B. (1981). Assay of Peroxisomal Beta-Oxidation of Fatty Acids. Methods in Enzymology 72, 315-319. 11. 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. 12. Draper, N.R. and Smith, H. (1981). Applied Regression Analysis, 2nd edition, pp 266-273. Wiley, New York. 13. Selwyn, M.R. (i995). The use of trend tests to determine a no-observable-effect level in animal safety studies. Journal o f the American College o f Toxicology 14(2), 158-168. 14. Jonckheere, A.R. (1954). A distribution-free K-sample test against ordered alternatives. Biometrika 41, 133-145. 15. Levene, H. (1960). Robust test for equality of variances. Contributions to Probability and Statistics (J. Olkin, ed.), pp 278-292. Stanford University Press, Palo Alto. - 53- Company Sanitized. Does not contain TSCA CBI flSubchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 16. Shapiro, S.S. and Wilk., M.B. (1965). An analysis of variance test for normality (complete samples). Biometrika 52, 591-611. 17. Snedecor, G.W. and Cochran, W.G. (1967). Statistical Methods, 6th edition, pp 246-248 and 349-352. The Iowa State University Press, Ames. 18. Dunnett, C.W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Amer. Statist. Assoc. 50, 1096-1121. 19. Kruskal, W.H. and Wallis, W.A. (1952). Use of ranks in one-criterion analysis of variance. J. Amer. Statist. Assoc. 47, 583-621. 20. Dunn, O.J. (1964). Multiple contrasts using rank sums. Technometrics 6, 241-252. 21. Milliken, G.A. and Johnson, D.A. (1984). Analysis of Messy Data, Volume 1.: Designed Experiments. Lifetime Learning Publications, Belmont. 22. Hocking, R.A, (1985). The Analysis of Linear Models. Brooks/Cole, Monterey. 23. Bartlett, M.S. (1937). Some examples of statistical methods of research in agriculture and applied biology. J. Royal. Statis. Soc. Suppl. 4, 137-170. 24. Fisher, R.A. (1985). Statistical Methods for Research Workers, 13th edition. Haffner, New York. 25. DuPont Haskell Laboratory! [Analytical Reports 26. Greaves, P. (2000). In Histopathology o f Preclinical Drug Safety Evaluation, Elsvier, Amsterdam, pp 453. 27. Sipes, G. I., and Gandolfi, A. J. (1991). In Biotransformation of Toxicants. In Casarett and DoulTs Toxicology: The Basic Science of Poisons (Amdur, M. O., Doull, J., and Klaassen, C. D., Ed.), Pergamon Press, New York, pp 88-126. 28. 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. 29. Greaves, P. (1990). Digestive System 2. In Histopathology o f Preclinical Toxicity Studies: Interpretation and Relevance in Drug Safety Evaluation (P. Greaves, Ed.), Elsvier, Amsterdam, pp 393-496. 30. Reddy, C.S., and Hayes, A.W. (1989). Food Borne Toxicants. In Principles and Methods o f Toxicology (A.W. Hayes, Ed.), Raven Press, New York, pp 67-110. 31. Rao-Rupanagudi, S., Heywood, R., and Gopinah, C. (1991). "Age-related Changes in Thyroid Structures and Function in Sprague-Dawley Rats," Vet. P athol, Vol. 29, No. 4, pp. 278-287. 32. 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. -54Company Sanitized. Does not contain TSCA CBI Subchronic Toxicity 90-Day Oral Gavage Study in Rats________ DuPont-9478 33. Hazard Evaluation Division, Standard Evaluation Procedure, Toxicity Potential: Guidance for.Analysis and Evaluation of Subchronic and Chronic Exposure Studies Paynter, O. E. et al., United States Environmental Protection Agency, Office of Pesticide Programs, Washington, D.C., 20406. EPA-540/9-85-020. (June 1985). 34. Risk Assessment of Notified New Substances. Technical Guidance Document (XI/283/94EN), Chapter I, Sections 2.24 and 2.25. 1994. -55Company Sanitized. Does not contain TSCA CBI Subchronic Toxicity 90-Day Oral Gavage Study in Rats________ DuPont-9478 TABLES -56Company Sanitized. Does not contain TSCA CBI ubchronic Toxicity 90-Day Oral Gavage Stflffy in Rats_________ DuPont-9478 TABLES EXPLANATORY NOTES Critical Dates Day 91 Last day of test substance administration for rats designated for satellite bleeds and 3-month recovery. Last day of non-fasted body weight and food consumption data collection for rats designated for the 90-day exposure period. Last day of food consumption data collection for rats designated for satellite bleeds in the 1, 5, and 25 mg/kg/day dose groups. Day 92 Last day of test substance administration for male rats designated for the 90-day exposure period. Day 93 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 94 Female rats designated for 90-day exposure period were sacrificed. Day 175 Rats designated for satellite bleeds were sacrificed Day 182 Last day of non-fasted body weight and food consumption data collection for rats designated for the 3-month recovery period. Day 183 Male and female rats designated for the 3-month recovery period were sacrificed. Note mg/kg = mg/kg/day 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. -57Company Sanitized. Does not contain TSCA CBI lubchronic Toxicity 90-Day Oral Gavage Si !y in Rats_________ TABLES EXPLANATORY NOTES (CONTINUED) ABBREVIATIONS: Summary of Hematology Values RBC - red blood cell count HGB - hemoglobin HCT - hematocrit MCV - mean corpuscular volume MCH - mean corpuscular hemoglobin MCHC - mean corpuscular hemoglobin concentration RDW - red cell distribution width ARET - absolute reticulocyte count PLT - platelet count WBC - white blood cell count ANEU - absolute neutrophil (all forms) ALYM - absolute lymphocyte AMON - absolute monocyte AEOS - absolute eosinophil ABAS - absolute basophil ALUC - absolute large unstained cell -- - no data Summary o f Coagulation Values PT - prothrombin time APTT - activated partial thromboplastin time -- - no data DuPont-9478 -58Company Sanitized. Does not contain TSCA CBI c ubchronic Toxicity 90-Day Oral Gavage Study in Rats TABLES EXPLANATORY NOTES (CONTINUED) ABBREVIATIONS: (Continued) Summary o f Clinical Chemistry Values AST - aspartate aminotransferase ALT - alanine aminotransferase SDH - sorbitol dehydrogenase ALKP - alkaline phosphatase BILI - total bilirubin BUN - urea nitrogen CREA - creatinine CHOL - cholesterol TRIG - triglycerides GLUC - glucose TP - total protein ALB - albumin GLOB - globulin CALC - calcium IPHS - inorganic phosphorous NA - sodium K - potassium CL - chloride PFLU - plasma fluoride - - no data Summary o f Urinalysis Values VOL - volume UOSM - urine osmolality pH - the logarithm of the reciprocal of the hydrogen ion concentration URO - urobilinogen UFLU - urine fluoride UMTP - urine protein -- - no data DuPont-9478 -59Company Sanitized. Does not contain TSCA CBI ISubchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 TABLE 1 SUMMARY OF DOSING MIXING AND STABILITY ANALYSES Nominal: Homogeneity Samples Test Day 1/-6 Top Middle Bottom Average Measured Cone.c Average Percent Nominal Standard Deviationc Coefficient of Variationc Stability Samples 5 Hour Room Temperature Test Day 1/-6 and Test Day 4 d (baseline for stability) 7-Day Refrigerated #1 #2 #3 Average Measured Cone. Average Percent Nominal Standard Deviation Coefficient of Variation Dosing Concentration 0.20 L0 0.163 (81.5)b 0.164 (82.0) 0.161 (80.5) 0.163 (81.5) 0.002 1% 0.167 (83.5) 0.163 (81.5) 0.161 (80.5) 0.173 (86.5) -- 0.167e (83.5) 0.01e 5%e 0.803 (80.3) 0.857 (85.7) 0.890 (89.0) 0.850 (85.0) 0.04 5% 0.818 (81.8) 0.888 (88.8) 0.900 (90.0) 0.864 (86.4) 0.859 (85.9) 0.874e (87.4) 0.02e 3%e 54) * 254) 4.55 (91.0) 4.80 (96.0) 4.61 (92.2) 4.65 (93.0) 0.13 3% 4.14 (82.8) 4.51 (90.2) 4.46 (89.2) 4.44 (88.8) -- 4.45e (89.0) 0.01e 0.2 %e 19.9 a (79.6) 21.9 (87.6) 22.9 (91.6) 21.6 (86.4) 1.5 7% 21.8 (87.2) 23.0 (92.0) 24.2 (96.8) 23.9 (95.6) -- 24.1" (96.4) 0.21e l% e 5 Hour Room Temperature 0.158a 0.904f 4.21f 21.2f (79.0) (90.4) (84.2) (84.8) a Result of the original aliquot. Duplicate reanalysis of original sample support original analysis and not reported. b Numbers in parentheses are the respective percent o f nominal values. c Statistics based on the average measured concentration Of the top, middlejjpd bottom o f each dosing level. d Samples analyzed in previous study e Statistics based on the average measured concentration of duplicate samples for the dosing level. f Mean results o f duplicate re-analysis of the original sample. Original results were low due to aliquot error -60Company Sanitized. Does not contain TSCA CBi ubchronic Toxicity 90-Day Oral Gavage Study in Rats________ DuPont-9478 TABLE 1 (CONTINUED) SUMMARY OF DOSING MIXING AND STABILITY ANALYSES Nominal: Concentration Verification Test Day 42 #1 Dosing Concentration 0.20 1 .0 " * 0.156c (78.0)b 0.749c (74.9) 5.0 ^ 25.0 3.87e (77.3) 19.4 ` (77.6) #2 0.169c 0.776 e 3.91f 19.1f (84.5) (77.6) (78.2) (76.2) Average M easured C one.e Average Percent Nominal Standard D eviatione Coefficient of V ariatione 0.163 (81.5) 0 .0 1 6% 0.763 (76.3) 0 .0 2 3% 3.89 (77.8) 0 .0 3 1% 19.3 (77.2) 0 .2 1 1% Test Day 45 #1 0.066c (33.0) 0.676 e (67.6) 2.20 e (44.0) 8.34r (33.4) #2 0.083c 0.656e 2.32 e 8.64r (41.5) (65.6) (46.4) (34.6) Average M easured C one.e A verage Percent Nomina] Standard Deviation * Coefficient of V ariatione 0.075 (37.5) 0 .0 1 13% 0.666 (66.6) 0.01 2% 2.26 (45.2) 0 .0 9 4% 8.49 (34.0) 0 .2 1 3% T est D ay 48 #1 0.197 (98.5) 0.865 (86.5) 3.93 (78.6) 21.9 (87.6) #2 . eA verage M easured Cone Average Percent Nominal Standard D eviatione Coefficient of Variation * 0.219 (109.5) 0.208 (104.0) 0 .0 2 7% 0.948 (94.8) 0.907 (90.7) 0 .0 6 6% 3.90 (78.0) 3.92 (783) 0 .0 2 1% 22.5 (90.0) 22.2 (88.8) 0 .4 2 3% Test Day 52 #1 0.174 (87.0) 0.845 (84.5) 4.22 (84.4) 23.5 (94.0) #2 0.184 0.895 4.16 22.3 (92.0) (89.5) ~ (83.2) (89.2) Average Measured Cone. * 0.179 0.870 4.19 22.9 Average Percent Nominal (89.5) (87.0) (83.8) (91.6) Standard D eviatione 0.01 0 .0 4 0 .0 4 0 .8 5 Coefficient of V ariatione 4% 4% 1% 4% b Numbers in parentheses are the respective percent of nominal values. c Mean result of the original analysis and duplicate reanalysis of the original sample reported. c Statistics based on the average measured concentration of duplicate samples for the dosing level. 1 Mean results of duplicate re-analysis of the original sample. Original results were low due to aliquot error g Suspension not dosed to animals. -61 Company Sanitized. Does not contain TSCA CBI ubchronic Toxicity 90-Day Oral Gavage Study in Rats________ DuPont-9478 TABLE 1 (CONTINUED) SUMMARY OF DOSING MIXING AND STABILITY ANALYSES Nominal: Concentration Verification Test Day 56 . #1 Dosing Concentration ofj 0.20 L 1 ' ' 0.167 (83.5)b 0.964 (96.4) 54) 4.41 (88.2) |mg/mL) 254) 22.8 (91.2) #2 0.189 0.950 4.31 21.4 (94.5) (95.0) (86.2) (85.6) Average Measured Cone. ` Average Percent Nominal Standard Deviatione Coefficient of V ariatione 0.178 (89.0) 0 .0 2 9% 0.957 (95.7) 0.01 1% 4.36 (87.2) 0.07 2% 22.1 (88.4) 0.99 4% Test Day 58 #1 0.174 (87.0) 0.945 (94.5) 4.48 (89.6) 22.5 (90.0) #2 0.150 0.937 4:17 22.1 (75.0) (93.7) (83.4) (88.4) Average Measured C one.e Average Percent Nominal Standard Deviatione Coefficient of Variation * 0.162 (81.0) 0.02 10% 0.941 (94.1) 0.01 1% 4.33 (86.5) 0.22 5% 22.3 (89.2) 0.28 1% Test Day 65 #1 0.159c (79.5) 0.832 (83.2) 4.32 (86.4) 20.8 (83.2) #2 0.150c 0.898 4.40 20.5 (75.0) (89.8) (88.0) (82.0) Average Measured Cone. * Average Percent Nominal 0.155 (77.5) 0.865 (86.5) 4.36 (87.2) Standard Deviatione 0.01 0.05 0.06 Coefficient of V ariatione 4% 5% 1% b Numbers in parentheses are the respective percent o f nominal values. c Mean result of the original analysis and duplicate reanalysis of the original sample reported. * Statistics based on the average measured concentration o f duplicate samples for the dosing level. 20.7 (82.6) 0.21 1% - 62Company Sanitized. Does not contain TSCA CBI ubchronic Toxicity 90-Day Oral Gavage Study in Rats________ DuPont-9478 TABLE 1 (CONTINUED) SUMMARY OF DOSING MIXING AND STABILITY ANALYSES Nominal: Concentration Verification Test Day 91 #1 Dosing Concentration 0.20 L O ** 0.162 (81.0)b 0.760 e (76.0) 54) 3.96 e (79.2) #2 0.165 0.863 3.90 e (82.5) (86.3) (78.0) Average Measured Cone. * Average Percent Nominal Standard Deviation ` Coefficient of Variatione 0.164 (82.0) 0.002 1%C 0.812 (81.2) 0.07 9% 3.93 (78.6) 0.04 1% Test Day 63 #1 0.190 (95.0)* 0.784 (78.4) 4.12 (82.4) #2 0.192 0.792 4.08 (96.0) (79.2) (81.8) Average Measured Cone. * Average Percent Nominal Standard Deviatione Coefficient of Variatione 0.191 (95.5) 0.001 1% 0.788 (78.8) 0.01 1% 4.10 (82.0) 0.03 1% Test Day 73 #1 0.176 (88.0) 0.980 (98.0) 4.57 (91.4) #2 0.155 1.03 4.60 (77.5) (103.0) (92.0) Average Measured C one.e Average Percent Nominal Standard Deviatione Coefficient of Variation * 0.166 (82.8) 0.01 9% 1.01 (101.0) 0.04 4% 4.59 (91.8) 0 .0 2 0.4% b Numbers in parentheses are the respective percent o f nominal values. e Mean result of the original analysis and duplicate reanalysis of the original sample reported. e Statistics based on the average measured concentration of duplicate samples for the dosing level. 254) 19.9e (76.4) 18.7e (74.8) 19.3 (77.2) 0.85 4% 23.0 (92.0) 21.4 (85.6) 22.2 (88.8) 1 .1 5% 23.3 (93.2) 24.4 (97.6) 23.9 (95.6) 0.78 3% -63Company Sanitized. Does not contain TSCA CBI 'X Subchronic Toxicity 90-Day Oral Gavage Study in Rats ) Group: Dosage(mg/kg/day) DAYO -DAY7 DAY7 -DAY14 DAY14 -DAY21 DAY21 -DAY28 DAY28 -DAY35 DAY35 -DAY42 DAY42 -DAY49 DAY49 -DAY56 DAY56 -DAY,63 DAY63 -DAY70 DAY70 -DAY77 TABLE2 MEAN DAILY DOSE VOLUMES FOR MALE RATS (mL) X 0 1.2 0.2(25) 1.4 0.2(25) 1.7 0.2(25) 1.9 0.2(25) 2.1 0.2(25) 2.2 0.2(25) 2,3 0.3(25) 2.4 0.3 (25) 2.5 0.3(25) 2.7 0.3 (25) 2.7 0.3(25) III 1 1.2 0.1(15) 1.5 0.1(15) 1.8 0.1(15) 2.0 0.1(15) 2.1 0.1(15) 2.3 0.1(15) 2.4 0.2(15) 2.4 0.2(15) 2.5 0.2(15) 2.7 0.2(15) 2.7 0.2(15) V 5 1.2 0.1(15) 1.5 0.1(15) 1.7 0.2(15) 2.0 0.2(15) 2.2 0.2(15) 2.3 0.2(15) 2.4 0.3(15) 2.5 0.2(15) 2.6 0.3(15) 2.8 0.3(15) 2.9 0.3(15) VII 25 1.2 0.1(15) 1.5 0.1(15) 1.7 0.1(15) 2.0 0.1(15) 2.1 '0.2(15) 2.3 0.2(15) 2.4 0.2(15) 2.5 0.2(15) 2.6 0.2(15) 2.8 0.2(15) 2.9 0.2(15) ) DuPont-9478 IX 125 1.2 0.1(25) 1.5 0.1(25) 1.7 0.1(25) 1.9 0.2(25) 2.1 0.2(25) 2.2 0.2(25) 2.4 0.2(25) 2.4 0.2(25) 2.5 0.2(25) 2.6 0.2(25) 2.6 0.3 (25) Company Sanitized. Does not contain TSCA CBI -64- 90-Day Oral Gavage Study in Rats Group : Dosage(mg/kg/day) DAY84 -DAY91 DAY91 DAY92 TABLE 2 (CONTINUED) MEAN DAILY DOSE VOLUMES FOR MALE RATS (mL) I 0 2.8 0.3(25) 2.8 0.3(25) 2.9 0.2(10) III 1 2.7 0.2(15) 2.8 0.2(15) 2.8 0.2(10) V 5 2.9 0.3(15) 2.9 0.3(15) 3.0 0.3(10) VII 25 2.9 0.2(15) 3.0 0.2(15) 2.9 0.2(10) ) DuPont-9478 IX 125 2.7 0.3(25) 2.8 0.3 (25) 2.8 0.1(10) i Company Sanitized. Does not contain TSCA CBI -65- [subchronic Toxicity 90-Day Orai Gavage Study in Rats TABLE3 MEAN DAILY DOSE VOLUMES FOR FEMALE RATS (xnL) Group: Dosage(mg/kg/day) DAYO DAY7 -DAY7 -DAY14 `V DAY14 -DY21 DAY21 -DAY28 DAY28 -DAY35 DAY35 -DAY42 DAY42 -DAY49 DAY49 -DAY5 6 DAY56 -DAY63 DAY63 -DAY70 DAY70 -DAY77 II 0 0,9 0.1(25) 1.0 0.1(25) 1.1 0.1(25) 1.2 0.1(24) 1.3 0.1(24) 1.3 0.1(24) 1:4 0.1(24) 1.4 0.2(24) 1.4 0.2(24) 1.4 0.2(24) 1.5 0.2(24) IV 1 0.9 0.1(15) 1.0 0.1(15) 1.1 0.1(15) 1.2 0.1(15) 1.2 0.1(15) 1.3 0.1(15) 1.4 0.1(15) 1.3 0.1(15) 1.4 0.1(15) 1.5 0.1(15) 1.5 0.1(15) VI 5 0.9 0.1(15) 1.0 0.1(15) 1.1 0.1(15) 1.2 0.1(15) 1.3 0.1(15) 1.3 0.1(15) 1.4 0.1(15) 1.4 0.1(15) 1.4 0.1(15) 1.5 0.1(15) 1.5 0.1(15) VIII 25 0.9 0.1(15) 1.0 0.1(15) 1.1 0.1(15) 1.2 0.1(15) 1.2 0.1(15) 1.3 0.1(15) 1.4 0.1(15) 1-4 0.1(15) 1.5 0.1(15) 1.5 0.1(15) 1.5 0.1(15) DuPont-9478 X 125 0.9 0.1(25) 1.0 0.1(25) 1.1 0.1(25) 1.3 0.1 (25) 1.3 0.1(25) 1.3 0.1(25) 1.4 0.1(25) 1.4 0.2(25) 1.5 0.2(25) 1.5 0.2(25) 1.5 0.1(25) Company Sanitized. Does not contain TSCA CBI -66- Subchronic Toxicity 90-Day Oral uavage stS ly in Rats_________ TABLE 3 (CONTINUED) MEAN DAILY DOSE VOLUMES FOR FEMALE RATS (mL) Group : Dosage(mg/kg/day) DAY77 -DAY84 DAY84 -DAY91 DAY91 DAY92 -DAY93 IX 0 1.5 0.2 (24) 1.5 0.2(24) 1.5 0.2(24) 1.5 0.1(10) IV 1 1.5 0.1(15) 1.5 0.1(15) 1.5 0.1(15) 1.5 0.1(10) VI 5 1.5 0.1(15) 1.5 0.1(15) 1.5 0.1(15) 1.5 0.1(10) VIII 25 1.6 0.1(15) 1.6 0.1(15) 1.6 0.1(15) 1.6 0.1(10) ) DuPont-9478 X 125 1.5 0.2(25) 1.6 0.2 (25) 1.6 0.1(25) 1.5 0.1(10) I Company Sanitized. Does not contain TSCA CBI -67- m Subchronic Toxicity 90-Day Oral Gavage Kly in Rats TABLE4 MEAN BODY WEIGHTS OF MALE RATS (g) Group: Dosage(mg/kg/day) I 0 Period for Subchronic Toxicity Evaluation DAYO 234.5 23.9(25) DAY7 288.7 29.3(25) DAYX4 DAY21 337.2 33.0(25) 383.6 37.5(25) DAY28 415.5 40.3(25) DAY35 445.1 48.4(25) DAY42 467.2 56.5(25) DAY 49 * 483.2 52.4(25) DAY56 503.8 56.9(25) DAY63 520.5 58.6(25) DAY70 537.8 57.4(25) III 1 245.6 19.7(15) 299.2 24.9(15) 352.6 20.2(15) 394.9 23.2(15) 426.0 24.9(15) 455.1 27.2(15) 475.8 30.0(15) 485.0 30.8(15) 508.4 32.1(15) 523.2 34.3(15) 539.2 39.7(15) V 5 240.8 21.0(15) 295.8 26.6(15) 348.4 31.7(15) 396.1 36.4(15) 432.2 42.8(15) 464.0 47.0(15) 487.4 50.4(15) 498.4 48.7(15) 525.8 53.1(15) 545.1, 56.7(15) 559.1 56.4(15) VII 25 239.4 16.0(15) 294.9 18.3(15) 345.6 22.7(15) 393.1 27.4(15) 427.1 32.0(15) 460.8 36.5(15) 489.2 37.8(15) 501.1 39.8(15) 528.5 43.0(15) 548.0 44.2(15) 558.4 45.5(15) DuPont-9478 IX 125 235.1 22.1(25) 289.2 25.7(25) 343.3 28.4(25) 387.9 32.3 (25) 422.0 36.4(25) 448.9 40..7 (25) 473.8 42.2(25) 486.8 45.5(25) 507.2 49.1(25) 516.0 51.9 (25) 524.5 50.8(25) Company Sanitized. Does not contain TSCA CBI -68- Subchronic Toxicity 90-Day Oral Gavage St5y in Rats TABLE 4 (CONTINUED) MEAN BODY WEIGHTS OF MALE RATS (g) Group: Dosage(mg/kg/day) I 0 m 1 Dosing Period for Subchronic Toxicity Evaluation (continued) DAY77 547.7 57.5(25) 544.8 36.4(15) DAY 84 554.6 58.2(25) 549.5 39.1(15) DAY 91 562.0 54.0(25) 561.0 42.2(15) Three-Month Recovery Period for Subchronic Toxicity Evaluation DAY98 568.1 55.2(15) 567.9 58.8(5) DAY105 573.3 64.3 (15) 582.8 59.0(5) DAY112 581.6 63.4(15) 584.4 60.6(5) DAY119 590.9 62.8(15) 595.0 58.6(5) DAY126 605.5 62.7(15) 604.5 65.8(5) DAY133 613.7 61.8(15) 615.2 62.5(5) DAY14Q 612.0 64.0(15) 615.8 65.5(5) V 5 571.1 55.9(15) 582.5 58.0(15) 589.1 60.9(15) 567.0 69.6(5) 575.6 70.3(5) 579.2 72.9(5) 590.6 74.8(5) 600.6 74.0(5) 610.0 75.9(5) 608.0 87.4(5) VII 25 571.2 45.9(15) 581.2 45.7(15) 591.2 47.6(15) 606.8 59.8(5) 614.6 59.8(5) 619.3 67.0(5) 630.7 69.4(5) 646.4 70.5(5) 654.8 74.0(5) 656.8 76.7(5) DuPont-9478 IX 125 518.5 61.7(25) 531.5 53.6(25) 551.9 53.9(25) 556.0 65.4(15) 567.8 68.6(15) 573.5 67.4(15) 583.3 71.3(15) 599.3 76.1(15) 610.3 80.7(15) 612.9 81.7(15) Company Sanitized. Does not contain TSCA CBI -69- Subchronic Toxicity 90-Day Oral Gavage Study in Rats I TABLE 4 (CONTINUED) MEAN BODY WEIGHTS OF MATE RATS (g) Group: I III V Dosage(mg/kg/day) 0 1 5 Three-Month Recovery Period for Subchronic Toxicity Evaluation (continued) DAY147 617.2 65.6(15} 626.4 68.2(5) 618.3 86.9(5) DAY154 625.0 68.2(15) 635.2 65.9(5} 627.1 82.4(5) DAY161 623.7 71.9(15) 637.2 68.2(5) 629.5 85.5(5) DAY168 629.8 71.5(15) 642.3 65.9(5) 631.0 88.6(5) DAY175 631.4 79.3(15) 646.3 66.8(5) 632.5 85.8(5) DAY182 647.6 66.5(10) . (0) (0) VII 25 665.6 79,9(5) 681.5 82.6(5) 678.9 83.7(5) 690.7 85.1(5) 693.8 81.8(5) . (0) Data summarized as: Mean Standard Deviation (n) There were no statistically significant differences at p < 0.05 by Jonckheere-Terpstra trend test. DuPont-9478 IX 125 621.5 83.0(15) 635.7 81.2(15) 636.5 82.0(15) 649.1 85.3(15) 648.1 84.3(15) 634.7' 86.3(10) Company Sanitized. Does not contain TSCA CBI -70- Company Sanitized. Does not contain TSCA _____ ^JSubchronic Toxicity 90-Day Oral Gavage Study in R ats________ TABLE 5 MEAN BODY WEIGHTS OF FEMALE RATS (g) Group: Dosage(mg/kg/day) XI 0 Period for Subchronic Toxicity Evaluation DAYO . 186.6 15.1(25) DAY7 204.8 18.0(25) DAY14 223.5 21.1(25) DAY21 241.1 24.2(24) DAY28 251.8 26.5(24) DAY35 263.5 27.3(24) DAY42 273.0 27.6(24) DAY49 fc: 272.8 30.2(24) DAY56 284.4 30.2(24) DAY 63 288.7 31.7(24) DAY70 296.1 31.0(24) IV 1 183.8 17.0(15) 205.7 15.0(15) 224.8 15.4(15) 238.7 15.9(15) 250.1 15.9(15) 264.3 17.3(15) 274.1 17.2(15) 267.2 16.9(15) 286.4 18.9(15) 291.4 21.0(15) 298.5 23.2(15) VI 5 182.2 17.0(15) 204.5 15.3(15) 223.7 17.1(15) 239.0 20.8(15) 250.9 20.0(15) 264.0 24.3(15) 274.9 24.1(15) 271.6 22.6(15) 286.8 26.2(15) 292.7 27.3(15) 297.4 26.2(15) VIII 25 182.6 14.7(15) 202.8 18.6(15) 225.7 16.7(15) 239.9 17.8(15) 252.7 21.9(15) 266.3 20.9(15) 278.5 22.0(15) 272.0 25.6(15) 292.1 27.0(15) 294.4 25.0(15) 305.1 27.4(15) ) DuPont-9478 X 125 188.5 16.5(25) 209.0 18.1(25) 230.4 18.6(25) 247.7 21.8(25) 259.9 24.1(25) 270.3 24.5(25) 278.2 25.4(25) 280.4 30.1(25) 292.1 29.8(25) 297.1 31.1(25) 300.0 28.6(25) J ______ Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 5 (CONTINUED) MEAN BODY WEIGHTS OF FEMALE RATS (g) Group: Dosage(mg/kg/day) II 0 IV 1 Dosing Period for Subchronic Toxicity Evaluation (continued) DAY77 DAY 84 299.7 31.5(24) 302.5 31.9(24) 302.1 22.2(15) 305.8 25.0(15) DAY 91 303.7 31.5(24) 304.9 25.4(15) Three-Month Recovery Period for Subchronic Toxicity Evaluation DAY98 310.9 38.7(14) 306.6 26.3(5) DAY105 315 .'8 39.9(14) 311.0 24.4(5) DAY112 318 0 37.7(14) 312.5 25.8(5) DAY119 320.2 36.9(14) 313.7 26.9(5) DAY!26 327.9 38.0(14) 319.1 27.7(5) DAY133 328.9 38.6(14) 324.4 28.7(5) DAY140 331.6 36.5(14) 325.6 29.6(5) DAY147 337.0 39.2(14) 327.6 32.0(5) VI 5 301.7 27.1(15) 300.8 26.8(15) 302.5 26.5(15) 299.9 30.8(5) 299.8 34.1(5) 305.7 34.2(5) 309.2 32.0(5) 314.5 35.7(5) 319.8 38.7(5) 320.3 34.9(5) 324.5 42.0(5) VIII 25 310.5 28.9(15) 311.3 29.7(15) 310.6 29.0(15) 322.9 26.3(5) 326.9 30.0(5) 329.6 32.7(5) 340.5 32.2(5) 346.2 39.0(5) 351.3 37.4(5) 351.6 39.7 (5) 354.8 39.5(5) DuPont-9478 X 125 303.0 29.5(25) 311.3 30.8(25) 310.2 29.3 (25) 317.6 36.4(15) 317.8 35.1(15) 319.1 39.8(15) 324.9 40.8(15) 340.1 45.6(15) 343.9 ' 46.4(15) 343.3 48.3(15) 349.5 50.8(15) Company Sanitized. Does not contain TSCA CBI - 72- ) .ubchromc Toxicity 90-Day Oral Gavage Study in Rats TABLE 5 (CONTINUED) MEAN BODY WEIGHTS OF FEMALE RATS (g) Group: II IV VI Dosage(mg/kg/day) 0 1 5 -Month Recovery Period for Subchronic Toxicity Evaluation (continued) DAY154 339.3 39.8(14) 331.3 32.0(5) 331.3 45.1(5) DAY161 333.4 36.8(14) 330.4 28.7(5) 327.9 41.2 (5) DAY168 340.3 37.0(14) 336.0 28.3(5) 333.9 44.3(5) DAY175 342.3 38.6(14) 336.2 29.3(5) 335.9 44.6(5) DAY182 354.1 33.0(9) - (0) - (0) VIII 25 359.1 42.6(5) 361.6 47.5(5) 368.3 48.0(5) 366.8 53.8(5) (0) Data summarized as: Mean Standard Deviation(n) There were no statistically significant differences at p < 0.05 by Jonckheere-Terpstra trend test. ) DuPont-9478 X 125 355.1 52.2(15) 353.9 54.0(15) 360.4 58.2(15) 363.6 60.0(15) 368.7 67.8(10) Company Sanitized. Does not contain TSCA O DO c lubchronic Toxicity 90-Day Oral Gavage !u5y in Rats ') TABLE MEAN BODY WEIGHT GAINS OF MALE RATS (g) Group : Dosage(mg/kg/day) I 0 Period for Subchronic Toxicity Evaluation DAYO -DAY7 DAY7 -DAY14 54.3 7.9(25) 48.5 7.2(25) DAY14 -DAY21 DAY21 -DAY28 46.4 7.8(25) 31.9 8.8(25) DAY28 -DAY3 5 29.5 19.4(25) DAY35 -DAY42 22.2 12 ;4(25) DAY42 -DAY49 16.0 13.0(25) DAY49 -DAY56 20.5 9.2(25) DAYS 6 -DAY63 16.8 6.8(25) DAY63 -DAY70 17.2 7.8(25) DAY70 -DAY77 9.9 5.7(25) III 1 53.6 12.0(15) 53.5 8.7(15) 42.3 4.2(15) 31.1 6.7(15) 29.0 5.3(15) 20.8 6.6(15) 9.2 6.1(15) 23.5 5.4(15) 14.8 4.5(15) 16.0 7.9(15) 5.5 11.4(15) V 5 55.0 9.3(15) 52.6 8.7(15) 47.8 7.8(15) 36.0 8.2(15) 31.8 6.0(15) 23.4 8.8(15) 11.0 8.8(15) 27.4* 8.1(15) 19.3 7.1(15) 14.0 6.6(15) 12.0 8.2(15) VII 25 55.5 6.4(15) 50.7 7.8(15) 47.6 9.2(15) 34.0 8.9(15) 33.7 7.1(15) 28.3 4.8(15) 11.9 8.7(15) 27.4* 7.5(15) 19.5 4.3(15) 10.4# 5.3(15) 12.8 5.5(15) DuPont-9478 IX 125 54.1 10.0(25) 54.1# 6.5(25) 44.6 8.1(25) 34.1 6.4(25) 26.9 6.6(25) 24.9 6.9(25) 13.0 8.5(25) 20.5 6.9(25) 8.7 15.5(25) 8.5# 16.7(25) -6.0 28.0(25) Company Sanitized. Does not contain TSCA CBI -74- C _______ Subchronic Toxicity 90-Day Oral Gavage Study in R ats___ TABLE 6 (CONTINUED) MEAN BODY WEIGHT GAINS OF MALE RATS (g) Group: Dosage(mg/kg/day) I 0 III 1 Dosing Period for Subchronic Toxicity Evaluation (continued) DAY77 -DAY84 6.9 6.6(25) 4.8 13.7(15) DAY84 -DAY91 7.5 11.0(25) 11.5 8.0(15) V 5 11.5 5.6(15) 6.6 9.9(15) VII 25 10.0 6.8(15) 10.1 6.4(15) DAYO -DAY91 327.6 43.5(25) 315.4 35.9(15) Three-Month Recovery Period for Subchronic Toxicity Evaluation DAY91 -DAY98 13.3 6.5(15) 9.1 3.9(5) DAY98 -DAY105 5.3 19.1(15) 14.9 2.8(5) DAY105 -DAY112 8.3 7.1(15) 1.5 4.2(5) DAY112 -DAY19 9.3 6.9(15) 10.7 3.7(5) DAY119 -DAY126 14.6 6.7(15) 9.4 8.6(5) DAY126 -DAY133 8.2 5.7(15) 10.7 7.1(5) 348.2 50.8(15) 12.2 5.1(5) 8.6 5.1(5) 3.6 7.5(5) 11.4 5.9(5) 10.0 5.1(5) 9.4 5.4(5) 351.9 47.2(15) 9.3 3.8(5) 7.9 2.2(5) 4.6 8.6(5) 11.5 7.5(5) 15.7 5.3(5) 8.3 4.2(5) ) DuPont-9478 IX 125 13.1 22.4(25) 20.3# 14.2(25) 316.8 43.9(25) 11.9 6.9(15) 11.9 6.9(15) 5.6 7.2(15) 9.8 6.4(15) 16.0 7.6(15) 11.0 6.7(15) Company Sanitized. Does not contain TSCA CBI - 75- Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 6 (CONTINUED) MEAN BODY WEIGHT GAINS OF MALE RATS (g) Group : I 1X1 V Dosage(mg/kg/day) 0 1 5 Three-Month Recovery Period for Subchronic Toxicity Evaluation (continued) DAY133 -DAY140 DAY140 -DAY147 DAY147 -DAYl'54 DAY154 -DAY161 DAY161 DAY168 -DAY168 - -DAY175 DAY175 -DAY182 -1.7 6.4(15) 5.2 6.3(15) 7.8 8.6(15) -1.3 11.9(15) 6.1 5.4(15) 1.5 12.3(15) 2.1 5.0(10) 0.6 6.7(5) 10.6 3.0(5) 8.8 2.7(5) 2.0 2.5(5) 5.1 2.8(5) 4.0 5.7(5) . (0) -1.9 16.5(5) 10.3 8.0(5) 8.8 6.0(5) 2.4 4.5(5) 1.6 4.4(5) 1.4 6.8(5) . (0) DAY91 DAY91 -DAY175 i -DAY182 76.6 32.2(15) 89.2 21.4(10) 87.5 26.9(5) (0) 77.7 18.0(5) . (0) Data summarized as : Mean Standard Deviation (n) # Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. * Statistically significant difference at p < 0.05 by Dunnett/Tamhane-Dunnett test. VII 25 2.0 6.0(5) 8.9 4.9(5) 15.9 4.5(5) -2.6 5.6(5) 11.8 8.8(5) 3.1 5.0(5) (0) 96.4 24.1(5) (0) DuPont-9478 IX 125 2.6 7.4(15) 8.6 4.9(15) 14.2# 6.7(15) 0.8 5.6(15) 12.6# 8.5(15) -1.0 7.6(15) 11.4# 4.6(10) 104.1# 28.8(15) 108.2 31.3(10) Company Sanitized. Does not contain TSCA CBI - 76- 90-Day Oral Gavage Study in Rats TABLE 7 MEAN BODY WEIGHT GAINS OF FEMALE RATS (g) Group: Dosage(mg/kg) II 0 Period for Subchronic Toxicity Evaluation DAYO -DAY7 18.2 5.6(25) DAY7 -DAY14 18.7 7.9(25) DAY14 -DAY21 16.4 5.7(24) . DAY21 -DAY28 10.7 5.7(24) DAY28 -DAY3 5 11.8 5.7(24) DAY35 -DAY42 9.5 5:3(24) DAY42 -DAY49 -0.2 6.2(24) DAY49 DAYS 6 -DAY56 -t -DAY63 11.6 6.0(24) 4.3 5.4(24) DAY63 -DAY70 7.4 5.7(24) DAY70 -DAY77 3.5 4.2(24) IV 1 21.9 10.0(15) 19.1 4.1(15) 13.9 3.3(15) 11.4 5.4(15) 14.2 4.2(15) 9.8 5.6(15) -6.9 7.1(15) 19.3 7.1(15) 4.9 6.9(15) 7.2 4.3(15) 3.6 5.0(15) VI 5 22.3 9.0(15) 19.2 4.0(15) 15.2 7.6(15) 11.9 4.4(15) 13.1 6.7(15) 10.9 8.9(15) -3.3 7.2(15) 15.2 7.7(15) 5.9 7.4(15) 4.7 5.8(15) 4.3 4.5(15) VIII 25 20.2 6.9(15) 22.9 7.5(15) 14.1 7.4(15) 12.8 6.9(15) 13.6 5.9(15) 12.3 7.7(15) -6.5 9.6(15) 20.0 8.2(15) 2.3 6.4(15) 10.6 6.2(15) 5.5 4.8(15) ) DuPont-9478 X 125 20.5 4.8(25) 21.4 4.2(25) 17.3 6.5(25) 12.2 4.9(25) 10.4 5.9(25) 7.9 7.2(25) 2.2 9.2 (25) 11.7 12.4(25) 5.0 7.6(25) 2.9 6.3(25) 3.0 5.3(25) Company Sanitized. Does not contain TSCA CBI -11- Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 7 (CONTINUED) MEAN BODY WEIGHT GAINS OF FEMALE RATS (g) Group: Dosage(mg/kg) XX IV 01 Dosing Period for Subchronic Toxicity Evaluation (continued) DAY77 -DAY84 2.8 5.4(24) 3.7 5.2(15) DAY84 -DAY91 1.3 6.5(24) -0.9 5.9(15) VI 5 -0.8 3.3(15) 1.6 .6.3(15) Vili 25 0.7 5.4(15) -0.7 5.8(15) DAYO -DAY91 116.9 21.6(24) 121.1 24.6(15) Three-Month Recovery Period for Subchronic Toxicity Evaluation DAY91 -DAY98 - 4.5 7.4(14) 8.0 3.4(5) DAY98 -DAY105 4.9 6.8(14) 4.4 5.6(5) DAY105 -DAY112 2.2 5.3(14) 1.5 4.5(5) DAY112 DAY119 -DAY119 f -DAY126 2.2 6.5(14) 7 .1 6.0(14) 1.1 2.3(5) 5.4 1.4(5) DAY126 -DAY133 1.0 6.3(14) 5.3 1.6(5)' DAY133 -DAY140 2.7 6.2(14) 1.1 6.1(5) 120.2 20.5(15) 8.8 4.4(5) -0.1 6.3(5) 5.9 1.3(5) 3.5 5.3(5) 5.2 3.7(5) 5.3 6.3(5) 0.6 5.3(5) 128.0 18.2(15) 9.7 7.5(5) 3.9 6.3(5) 2.8 4.1(5) 10.9 3.3(5) 5.7 7.2(5) 5.1 4.8(5) 0.3 5.1(5) > DuPont-9478 X 125 8.3# 6.2(25) -1.1 6.7 (25) 121.7 19.9(25) 5.0 9.3(15) 0.2 5.3(15) 1.3 11.7(15) 5.8 10.5(15) 15.2# 7.1(15) 3.8 6.4(15) . -0.6# 5.4(15) Company Sanitized. Does not contain TSCA CBI - 78- ubchronic Toxicity TABLE 7 (CONTINUED) MEAN BODY WEIGHT GAINS OF FEMALE RATS (g) ,Group : Dosage(mg/kg) il IV VI 015 Three-Month Recovery Period for Subchronic Toxicity Evaluation (continued) DAY140 -DAY147 5.4 5.9(14) 2.0 4.5(5) 4.2 7.1(5) DAY147 -DAY154 2.4 6.2(14) 3.7 6.2(5) 6.8 7.5(5) DAY154 -DAY161 -6.0 5.2(14) -0.9 5.2(5) 3.5 5.0(5) DAY161 -DAY168 7.0 5.7(14) 5.6 4.8(5) 6.1 4.0(5) DAY168 -DAY175 2.0 3.9(14) 0.2 5.3(5) 2.0 4.2(5) DAY175 -DAY182 2.7 6.2(9) . (0) . (0) VIII 25 3.2 11.2(5) 4.4 11.0(5) 2.5# 8.3(5) 6.7 3.4(5) -1.5 7.5(5) . (0) DY91 -DAY175 DAY91 -DAY182 36.0 13.8(14) 42.1 15.5(9) 37.5 10.7 (5) . (0) 44.9 20.1(5) . (0) 53.6 24.3(5) (0) Data summarized as : Mean Standard Deviation (n) # Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. DuPont-9478 X 125 6.1 6.8(15) 5.6 8.6(15) -1.2#. 4.6(15) 6.5 6.9(15) 3.2 5.8(15) 2.9 7.6(10) 51.0 33.1(15) 56.3 38.4(10) Company Sanitized. Does not contain TSCA CBI - 79 - I^Jl'ubchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 8 MEAN DAILY FOOD CONSUMPTION BY MALE RATS (g/day) Group: Dosage(mg/kg/day) I 0 Dosing Period for Subchronic Toxicity Evaluation DAYO -DAY7 27.0 3.0(25) DAY7 -DAY14 28.3 4.1(25) DAY14 -DAY21 29.8 3.3(25) DAY21 -DAY28 30.5 3.3(25) DAY28 -DAY35 30.4 5.9(25) DAY35 -DAY42 29.5 5.2(25) DAY42 -DAY49 28.8 3.6(25) DAY49 -DAY56 s 29.4 3.2(25) DAY56 -DAY63 28.3 3.9(25) DAY63 -DAY70 29.2 3.3(25) DAY70 -DAY77 28.8 3.1(25) III 1 28.7 2.6(15) 30.1 2.1(15) 31.2 2.1(15) 29.8 1.9(15) 30.4 2.4(15) 30.0 1.7(15) 27.1 2.2(15) 29.2 1.4(15) 29.1 1.9(15) 29.6 2.5(15) 30.0 2.9(15) V 5 27.2 3.3(15) 29.6 3.6(15) 30.7 4.0(15) 31.3 3.9(15) 31.8 4.1(15) 30.9 4.2(15) 28.6 3.3(15) 30.2 3.4(15) 30.1 3.8(15) 30.2 2.8(15) 30.1 2.8(15) VII 25 27.9 2.5(15) 30.2 . 2.7(15) 31.2 3.4(15) 30.9 4.1(15) . 32.2 4.1(15) 31.5 3.7(15) 29.1 3.7(15). 31.5 3.3(15) 31.6 3.2(15) 30.2 3.1(15) 30.3 2.8(15) ) DuPont-9478 IX 125 26.6 2.5(25) 29.0 2.3(25) 30.0 3.0(25) 29.1 2.9(25) 30.4 3.2(25) 29.8 3.2(25) 28.6 3.4(25) 29.1 3.3 (25) 27.2 4.5(25) 26.6 4.3 (25) 25.3 6.2(25) Company Sanitized. Does not contain TSCA CBi - 80- Subchronic Toxicity 90-Day Oral Gavage By in Rats ) TABLE 8 (CONTINUED) MEAN DAILY FOOD CONSUMPTION BY MALE RATS (g/day) Group: Dosage(mg/kg/day) X 0 III 1 Dosing Period for Subchronic Toxicity EvaXuation (continued) DAY77 -DAY84 28.3 3.0(25) 28.0 1.5(15) DAY84 -DAY91 27.8 3.2(25) 28.9 1.9(15) V 5 29.7 2.6(15) 28.9 3.1(15) VII 25 29.2 2.2(15) 30.3 3.0(15) DAYO -DAY91 28.9 3.0(25) 29.4 1.5(15) Three-Month Recovery Period for Subchronic Toxicity Evaluation DAY9X -DAY98 27.2 1.9(10) . (0) DAY98 -DAY105 28.4 2.3(10) . (0) DAY105 -DAY112 28.8 2.0(10) - (0) DAY112 -DAYX19 k 27.6 2.9(10) . (0) DAYXX9 -DAYX26 27.7 2.3(10) . (0) DAYX26 -DAYX33 28.1 2.3(10) . (0) DAYX33 -DAYX40 28.1 2.8(10) . (0) 30.0 3.2(15) . (0) . (0) . (0) - (0) . (0) . (0) . (0) 30.5 2.9(15) . (0) . (0) . (0) . (0). (0) . (0) . (0) ) DuPont-9478 IX 125 26.6 4.6(25) 29.4 3.5(25) 28.3 2.5(25) 25.5 3.8(10) 25.9# 3.5(10) 26.0# 2.6(10) 26.6 3.3(10) 26.2 4.6(10) 27.1 3.4(10) 28.1 3.3(10) Company Sanitized. Does not contain TSCA CBI -81- c BSubchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 8 (CONTINUED) MEAN DAILY FOOD CONSUMPTION BY MALE RATS (g/day) Group: X III V Dosage(mg/kg/day) 0 1 5 Three-Month Recovery Period for Subchronic Toxicity Evaluation (continued) DAY140 -DAY147 26.8 2.9(10) . (0) (0) DAY147 -DAY154 27.5 2.4(10) . (0) (0) DAY154 -DAY161 28.3 2.3(10) . (0) (0) DAY161 -DAY168 28.5 2.4(10) . (0) (0) DAY168 -DAY175 - DAY175 -DAY182 28.2 3.0(10) 27.9 2.2(10) . (0) . (0) (0) (0) VII 25 . (0) . (0) (0) . (0) - (0) . (0) DAY91 -DAY175 DAY91 -DAY182 27.9 2.2(10) 27.9 2.2(10) . (0) . (0) (0) . (0) (0) . (0) Data summarized as : Mean Standard Deviation (n) # Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. ) DuPont-9478 IX 125 26.4 3.9(10) 26.8 2.4(10) 26.1 2.9(10) 27.5 3.0(10) 26.4 3.1(10) 27.0 3.7(10) 26.6 3.1(10) 26.6 3.1(10) Company Sanitized. Does not contain TSCA CBI -82- ISubchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 9 MEAN DAILY FOOD CONSUMPTION BY FEMALE RATS (g/day) Group: Dosage(mg/kg/day) II 0 Dosing Period for Subchronic Toxicity Evaluation DAYO -DAY7 19.4 1.9(25) DAY7 -DAY14 . 19.5 2.2(25) DAY14 -DAY21 21.1 2.2(24) DAY21 -DAY28 20.3 2.1(24) DAY28 -DAY35 21.0 2.3(24) DAY35 -DAY42 21.3 2:1(24) DAY42 -DAY49 19.7 2.6(24) DAY49 -DAY56 21.2 2.2(24) DAY56 -DAY63 20.9 2.3(24) DAY63 -DAY70 20.5 2.0(24) DAY70 -DAY77 20.7 2.2(24) IV 1 19.9 1.9(15) 19.6 1.4(15) 21.0 1.9(15) 20.1 1.8(15) 20.8 1.8(14) 21.2 1.6(15) 18.9 1.4(15) 21.5 2.3(15) 20.9 2.1(15) 20.6 2.8(15) 20.6 2.1(15) VI 5 19.8 1.8(15) 19.6 2.0(15) 21.2 2.1(15) 21.0 1.7(15) 21.5 2.2(15) 21.2 2.3(15) 20.2 2.0(15) 22.1 2.0(15) 21.6 2.2(15) 20.8 1.6(15) 20.9 2.0(15) VIII 25 19.5 1.9(15) 19.5 1.6(15) 21.8 2.8(15) 20.8 2.1(15) 21.7 2.3(15) 22.0 2.7(15) 20.4 2.7(15) 23.0 1.6(15) 21.8 1.8(15) 22.1 2.2(15) 21.9 2.2(15) ) DuPont-9478 X 125 19.1 1.8(25) 20.2 1.8(25) 21.5 2.1(25) 21.0 2.0(25) 21.4 2.2 (25) 20.7 2.2(24) 20.7 3.4(25) 21.7 2.6(25) 20.7 2.4(25) 20.5 2.2(25) 20.2. 2.4(25) Company Sanitized. Does not contain TSCA CBI -83- _____ Subchronic Toxicity 90-Day Oral Gavage Study in Rats _______ ) TABLE 9 (CONTINUED) MEAN DAILY FOOD CONSUMPTION BY FEMALE RATS (g/day) Group: Dosage(mg/kg/day) II 0 IV 1 Dosing Period for Subchronic Toxicity Evaluation (continued) DAY77 -DAY84 20.4 2.6(24) 20.2 2.0(15) DAY84 -DAY91 19.7 2.3 (24) 19.7 . 1.5(15) DAYO -DAY91 20.5 2.0(24) 20.4 1.7(14) Three-Month Recovery Period for Subchronic Toxicity Evaluation DAY91 -DAY98 19.6 2.5(9) (0) DAY98 -DAY105 21.1 3.2(9) . (0) DAY105 -DAY112 21.9 2.2(9) . (0) 5 ' DAY112 -DAY119 20.6 2.0(9) (0) DAY119 -DAY126 22.0 2.4(9) . (0) DAY126 -DAYX33 21.8 2.4(9) . (0) DAY133 -DAY140 22.5 2.0(9) . (0) VI 5 20.3 1.5(15) 20.2 1.2(15) 20.8 1.6(15) 1 . (0) . (0) . (0) . (0) . (0) . (0) . (0) VIII 25 21.3 1.9(15) 20.3 1.9(15) 21.2 1.7(15) . . (0) . (0) . (0) . (0) . (0) . (0) . (0) DuPont-9478 X 125 20.4 4.0(25) 20.1 3.1(25) 20.6 2.1(24) 19.4 2.5(10) 20.2 2.9(10) 20.0 3.0(10) 21.1 3.8(10) 22.4 4.5(10) 22.4 4.6(10) 23.5 3.3(10) Company Sanitized. Does not contain TSCA CB1 -84- ) t rlSubchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 9 (CONTINUED) MEAN DAILY FOOD CONSUMPTION BY FEMALE RATS (g/day) Group: II IV VI Dosage(mg/kg/day) 0 1 5 Three-Month Recovery Period for Subchronic Toxicity Evaluation (continued) DAY140 -DAY147 19.9 4.9(9) (0) (0) DAY147 -DAY154 20.8 2.8(9) . (0) (0) DAY154 -DAY161 20.6 2.9(9) . (0) (0) DAY161 -DAY168 22.2 2.3(9) (0) (0) DAY168 -DAY175 - DAY175 -DAY182 22.4 1.9(9) 22.4 2.4(9) (0) . (0) (0) (0) VIII 25 . (0) (0) . (0) . (0) - (0) . (0) DAY91 -DAY175 DAY91 -DAY182 1 21.3 2.1(9) 21.4 2,0(9) - (0) . (0) (0) (0) . (0) . (0) Data summarized as: Mean Standard Deviation (n) There were no statistically, significant differences at p < 0.05 by Jonckheere-Terpstra trend test. DuPont-9478 X 125 21.9 3.9(10) 22.2 4.4(10) 21.7 4.2(10) 24.5 4.8(10) 21.1 3.8(10) 20.6 2.7(10) 21.7 3.5(10) 21.6 3.4(10) Company Sanitized. Does not contain TSCA CBI -85- jubchronic Toxicity 90-Day Oral Gavage Sti ly in Rats TABLE 10 MEAN DAILY FOOD EFFICIENCY OF MALE RATS (g body weight gain/g food consumed) Group: Dosage(mg/kg/day) I 0 Period for Subchronic Toxicity Evaluation III 1 V 5 DAYO -DAY7 DAY7 -DAY14 DAY14 -DAY21 DAY21 -DAY28 DAY28 -DY35 DAY35 -DAY42 DAY42 -DAY49 DAY49 -DAY5i6 DAY56 -DAY63 0.288 0.026(25) 0.248 0.040(25) 0.222 0.027(25) 0.149 0.036(25) 0.104 0.235(25) 0.094 0.i04(25) 0.079 0.067(25) 0.098 0.046(25) 0.083 0.037(25) 0.265 0.050(15) 0.256 0.055(15) 0.193 0.016(15) 0.149 0.027(15) 0.136 0.023(15) 0.099 0.030(15) 0.047 0.031(15) 0.114 0.024(15) 0.072 0.019(15) 0.288 0.027(15) 0.253 0.028(15) 0.223 0.026(15) 0.163 0.022 (15) 0.142 0.018(15) 0.107 0.034(15) 0.055 0.042(15) 0.129 0.032(15) 0.090 0.027(15) DAY63 -DAY70 DAY70 -DAY77 0.085 0.044(25) 0.048 0.031(25) 0.075 0.034(15) 0.029 0.048(15) 0.067 0.034(15) 0.057 0.038(15) VII 25 0.284 0.025(15) 0.239 0.023(15) 0.217 0.024(15) 0.156 0.027(15) 0.149 0.021(15) 0.129 0.022(15) 0.056 0.035(15) 0.124 0.027(15) 0.088 0.020.(15) 0.049# 0.024(15) 0.061 0.026(15) DuPont-9478 IX 125 0.290 0.041(25) 0.266# 0.025(25) 0.211 0.026(25) 0.166# 0.022(25) 0.125# 0.023(25) 0.119 0.030(25) 0.063 0.037(25) 0.099 0.028(25) 0.039 0.099(25) 0.035# 0.107(25) -0.106 . 0.339(25) Company Sanitized. Does not contain TSCA C8I -86- 90-Day ubchronic Toxicity avage Study in Rats TABLE 10 (CONTINUED) MEAN DAILY FOOD EFFICIENCY OF MALE RATS (g body weight gain/g food consumed) Group: Dosage(mg/kg/day) i 0 III 1 Dosing Period for Subchronic Toxicity Evaluation (continued) DAY77 -DAY84 0.034 0.034(25) 0.023 0.067(15) DAY84 -DAY91 0.034 0.073(25) 0.055 0.037(15) V 5 0.054 0.025(15) 0.029 0.046(15) DAYO -DAY91 0.124 0.012(25) 0.118 0.010(15) Three-Month Recovery Period for Subchronic Toxicity Evaluation DAY91 -DAY98 0.074 0.029(10) (0) DAY98 -DAY105 0.070 0.024(10) (0) DAY105 -DAY112 0.030 0.022(10) (0) DAY112 -DAY1.19 0.035 0.019(10) (0) DAY119 -DAY126 0.068 0.024(10) (0) DAY126 -DAY133 0.038 0.028(10) (0) DAY133 -DAY140 ; -0.008 0.020(10) (0) 0.128 0.010(15) (0) (0) (0) (0) (0) (0) (0) VII 25 0.049 0.032(15) 0.046 0.029(15) 0.127 0.010(15) (0) (0) (0) (0) (0) (0) (0) DuPont-9478 IX 125 0.059 0.133(25) 0.096# 0.060(25) 0.123 0.010(25) 0.064 0.033(10) 0.050 0.027(10) 0.026 0.034(10) 0.051 0.028(10) 0.079 0.044(10) 0.055 0.034(10) 0.009 0.036(10) Company Sanitized. Does not contain TSCA CBI -87- j>ubchronic Toxicity 90-Day Oral Gavage Study in Rats ) TABLE 10 (CONTINUED) MEAN DAILY FOOD EFFICIENCY OF MALE RATS (g body weight gain/g food consumed) Group: I III V Dosage(mg/kg/day) 0 1 5 Three-Month Recovery Period for Subchronic Toxicity Evaluation (continued) DAY140 -DAY147 0.037 0.015(10) (0) (0) DAY147 -DAY154 0.037 0.024(10) (0) (0) DAY154 -DAY161 0.007 0.030(10) (o) ! (0) DAY161 -DAY168 0.027 0.026(10) (0) (0) DAY168 -DAY175 0.025 0.027(10) (o) ! (0) DAY175 -DAY182 0.012 0.026(10) (0) (0) VII 25 (0) (0) (0) (0) (0) (0) DAY91 DAY91 -DAY175 | -DAY!82 0.037 0.007(10) 0.035 0.007(10) (o) (0) ! (0) (0) (0) (0) Data summarized as: Mean Standard Deviation (n) # Statistically significant differences at p < 0.05 by Jonckheere-Terpstra trend test. DuPont-9478 IX 125 0.044 0.025(10) 0.078 0.036(10) -0.006 0.029 CIO) 0.049 0.033(10) 0.006 0.025(10) 0.060 0.020(10) 0.043 0.009(10) 0.044# 0.009(10) Company Sanitized. Does not contain TSCA CBI -88- lubchronic Toxicity 90-Day Oral Gavage Study in Rats________ > TABLE 11 MEAN DAILY FOOD EFFICIENCY OF FEMALE RATS (g body weight gain/g food consumed) Group: Dosage(mg/kg/day) XI 0 Lod for Subchronic Toxicity Evaluation DAYO -DAY7 0.133 0.036(25) DAY7 -DAY14- 0.134 0.053(25) DAY14 -DAY21 0.109 0.031(24) DAY21 DAY28 -DAY28 - -DAY3 5 0.074 0.040(24) 0.080 0.036(24) DAY35 -DAY42 0.064 0.034(24) DAY42 -DAY49 0.004 0.044(24) DAY49 -DAY5I 0.078 0.040(24) DAY56 -DAY63 0.028 0.034(24) DAY63 -DAY70 0.052 0.040(24) DAY70 -DAY77 0.024 0.028(24) IV 1 0.157 0.071(15) 0.138 0.025(15) 0.095 0.023(15) 0.081 0.038(15) 0.100 0.022(14) 0.065 0.034(15) -0.054 0.057(15) 0.125 0.040(15) 0.032 0.045(15) 0.048 0.029(15) 0.025 0.037(15) VI 5 0.161 0.066(15) 0.140 0.023(15) 0.101 0.049(15) 0.082 0.032(15) 0.085 0.038(15) 0.070 0.063 (15) -0.023 0.051(15) 0.097 0.045(15) 0.037 0.044(15) 0.033 0.039(15) 0.028 0.029(15) VIII 25 .0.146 0.044(15) 0.168 0.056(15) 0.092 0.047 (.15) 0.086 0.043 (15) 0.089 0.040(15) 0.078 0.044(15) -0.052 0.069(15) 0.124 0.051(15) 0.015 0.041(15) 0.068 0.034(15) 0.035 0.030(15) DuPont-9478 X 125 o'.153 0.033(25) 0.152 0.028(25) 0.114 0.039(25) 0.082 0.030(25) 0.069 0.036(25) 0.053 0.047(24) 0.008 0.062 (25) 0.077 0.074(25) 0.032 0.045(25) 0.021# 0.045(25) 0.020 0.038(25) Company Sanitized. Does not contain TSCA CBI -89- Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 11 (CONTINUED) MEAN DAILY FOOD EFFICIENCY OF FEMALE RATS (g body weight gain/g food consumed) Group: Dosage(mg/kg/day) II 0 IV 1 Dosing Period for Subchronic Toxicity Evaluation (continued) DAY?7 -DAY84 0.019 0.038(24) 0.024 0.035(15) DAY84 -DAY91 0.008 0.045(24) -0.007 0.044(15) VI 5 -0.006 0.023(15) 0.010 0.043(15) VIII 25 0.004 0.037(15) -0.006 0.041(15) DAYO -DAY91 0.062 0.008(24) 0.066 0.010(14) Three-Month Recovery Period for Subchronic Toxicity Evaluation DAY9X -DAY98 0.031 0.064(9) (0) DAY98 -DAY105 0.026 0.042(9) (0) DAY105 -DAY112 0.019 0.041(9) (0) DAY112 -DAYli9 0.013 0.047(9) (0) DAY119 -DAY126 0.067 0.029(9) (0) DAY126 -DAY133 0.008 0.047(9) (0) DAY133 -DAY140 0.010 0.048(9) (0) 0.063 0.008(15) (0) (0) (0) (0) (0) (0) (0) 0.066 0.006(15) (0) (0) (0) 1 (0) (0) (0) (0) ) DuPont-9478 X 125 0.056# 0.041(25) -0.009 0.047 (25) 0.065 0.007(24) 0.024 0.078(10) 0.008 0.032(10) -0.011 0.097(10) 0.046 0.081(10) 0.095 0.039(10) 0.032 0.041(10) -0.013 0.028(10) Company Sanitized. Does not contain TSCA CBI -90- mbchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 11 (CONTINUED) MEAN DAILY FOOD EFFICIENCY OF FEMALE RATS (g body weight gain/g food consumed) Group : IX IV VI Dosage(mg/kg/day) 0 1 5 Three-Month Recovery Period for Subchronic Toxicity Evaluation (continued) DAY140 -DAY147 0.041 0.043(9) (0) (0) DAY147 -DAY154 DAY154 -DAY161 DAY161 -DAY168 DAY168 -DAY175 0.007 . 0.063(9) -0.044 0.027(9) 0.053 0.034(9) 0.013 0.023(9) . ' (0) ! (0) (0) ! (0) (0) ! (0) ' (0) ! (0) DAY175 -DAY182 0.015 0.039(9) (0) ! (0) DAY91 -DAY175 0.022 1 0.008(9) (0) (0) DAY91 -DAY182 0.021 0.007(9) (0) (0) VIII 25 (0) (0) ! (o) (0) (0) (0) (0) ! (0) Data summarized as : Mean Standard Deviation (n) # Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. DuPont-9478 X 125 0.054 0.036(10) 0.032 0.029(10) -0.011# 0.030(10) 0.037 0.039(10) 0.026 0.035 (10) 0.024 0.054(10) 0.028 0.018(10) 0.028 0.016(10) Company Sanitized. Does not contain TSCA CBI - 91 - Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 12 SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS Treatment Group Dosage (mg/kg/day) Animal Count I III V VII 0 1 5 25 25 15 15 15 Absent Toe Forepaw Right Incidence Mean onset (Days) Eye Observation Corneal Opacity Right 0 ( 0%) 0 ( 0%) 0 ( 0%) 1 ( 7%) 35 Incidence Mean onset. (Days) 1 ( 4%) 91 2 ( 13%) 14 0 ( 0%) 0 ( 0%) Exophthalmus Right Incidence Mean onset (Days) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Exophthalmus Bilateral Incidence Mean onset (Days) 0 ( 0%) 1 ( 7%) 21 0 ( 0%) 0 ( 0%) Enophthalmus Right Incidence Mean onset (Days) 2 ( 8%) 88 2 ,( 13%) 77 1 ( 7%) 35 0 ( 0%) IX 125 25 0 ( 0%) 1 ( 4%) 63 1 ( 4%) 56 0 ( 0%) 1 ( 4%) 63 ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI -92- J* H I H H B ^ ^ ^ ^ B ^ j p u b c h r o n ic Toxicity 90-Day Oral Gavage Study in Rats ) TABLE 12 (CONTINUED) ) DuPont-9478 Treatment Group Dosage (mg/kg/day) Animal Count SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS I III V VII 0 1 5 25 25 15 15 15 Wet Fur Ventral body Ventral Incidence Mean onset (Days) 0 ( 0%) 0 ( 0%) 1 ( 7%) 70 0 ( 0%) General Teeth Observations Striated Incidence Mean onset (Days) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Clipped Incidence Mean onset (Days) 0 ( 0%) 0 ( 0%) 0 ( 0%) 1 ( 7%) 86 Absent Incidence Mean onset (Days) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) IX 125 25 0 ( 0%) 24 ( 96%) # 58 16 ( 64%) # 84 1 ( 4%) 91 Company Sanitized. Does not contain TSCA CBI -93- __________ _________ Subchronic Toxicity 90-Day Oral Gavage/Study- in Rats TABLE 12 (CONTINUED) Treatment Group Dosage (mg/kg/day) Animal Count SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS I III V VII 0 1 5 25 25 15 15 15 IX 125 25 Discharge Eye right Black Incidence Mean onset (Days) 4 ( 16%) 98 0 ( 0%) 1 ( 7%) 91 0 ( 0%) 2 ( 8%) 63 Nose Incidence Mean onset (Days) 1 ( 4%) 98 0 ( 0%) 1 ( 7%) 42 0 ( 0%) 3 ( 12%) 98 Hair Loss Incidence Mean onset (Days) 4 ( 16%) 65 5 ( 33%) 83 1 ( 7%) 25 1 ( 7%) 18 4 ( 16%) 62 Wound Superficial Incidence Mean onset (Days) t;. Hyperreactive 1 ( 4%) 112 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 ( 8%) 42 Incidence Mean onset (Days) 2 ( 8%) 98 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 ( 8%) 116 ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI -94- 90-Day Oral Gavage Study in Rats TABLE 12 (CONTINUED) Treatment Group Dosage (nig/kg/day) Animal Count SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS I III V VII 0 1 5 25 25 15 15 15 IX 125 25 Hyperactive Incidence Mean onset (Days) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 1 ( 4%) 42 Aggressive Behavior Incidence Mean onset (Days) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 ( 8%) 77 Vocalization No Abnormality Detected Incidence . Mean onset (Days) 0 ( 0%) 0 ( 0%) 0 ( 0%) 1 ( 7%) 21 0 ( 0%) Protrusion Umbilical Hernia Incidence Mean onset (Days) 1 ( 4%) 21 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 { 0%) Stain Fur/Skin 1 Incidence Mean onset (Days) 5 ( 20%) 130 2 ( 13%) 131 2 ( 13%) 112 1 ( 7%) 154 6 ( 24%) 150 ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI -95- pubchronic Toxicity 90-Day Oral Gavage Study in Rats_________ DuPont-9478 TABLE 12 (CONTINUED) Treatment Group Dosage (mg/kg/day) Animal Count SUMMARY OF CLINICAL OBSERVATIONS FOR MALE RATS I III V VII 0 1 5 25 25 15 15 15 Swollen Observations Face Incidence Mean onset (Days) 1 ( 4%) 91 0 ( 0%) 0 ( 0%) 0 ( 0%) Forepaw Right Incidence Mean onset (Days) 0 ( 0%) 0 ( 0%) 0 ( 0%) 1 ( 7%) 35 IX 125 25 0{ 0( Incidence - The number of. animals for which an observation was recorded. Mean onset (Days) - The mean of the first test day an observation was recorded for that group. # Statistically significant difference at p < 0.05 by Cochran-Armitage trend test. Company Sanitized. Does not contain TSCA C8I -96- ubchronic Toxicity 90-Day Oral Gavage Study in Rats_________ TABLE 13 SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS Treatment Group Dosage (mg/kg/day) Animal Count II IV VI VIII X 0 1 5 25 125 25 15 15 15 25 Eye Observations Dark Right Incidence Mean onset (Days) 1 ( 4%) 49 1 ( 7%) 1 ( 7%) 91 105 1 ( 7%). 91 0 ( 0%) Dark Lef t Incidence Mean onset (Days) 0 ( 0%) 1 ( 7%) 49 0 ( 0%) 0 ( 0%) 0 ( 0%) Corneal Opacity Right Incidence Mean onset (Days) 1 ( 4%) 1 ( 7%) 1 ( 7%) 7 140 119 0 ( 0%) 0 ( 0%) Corneal Opacity Bilateral Incidence Mean onset (Days) 1 ( 4%) 35 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Exophthalmus Right Incidence Mean onset (Days) 1 ( 4%) 1 ( 7%) 7 147 0 ( 0%) 0 ( 0%) 0 ( 0%) DuPont-9478 Company Sanitized. Does not contain TSCA CBI -97- __ Bubchronic Toxicity 90-Day Oral Gavage Study in Rats__________ TABLE 13 (CONTINUED) Treatment Group Dosage (mg/kg/day) Animal Count SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS II IV VI VIII 0 1 5 25 25 15 15 15 X 125 25 Exophthalmus Lef t Incidence Mean onset (Days) 1 ( 4%) 28 0 ( 0%) 0 ( 0%) 0 { 0%) 0 ( 0%) Enophthalmus Right Incidence Mean onset (Days) 1 ( 4%) 21 0 ( 0%) 1 ( 7%) 112 0 ( 0%) 0 ( 0%) Enophthalmus Bilateral Incidence Mean onset (Days) 1 ( 4%) 42 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Closed Bilateral Incidence Mean onset (Days) Wet Fr I' 1 ( 4%) 119 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) Incidence Mean onset (Days) 0 ( 0%) 1 ( 7%) 14 0 ( 0%) 0 (' 0%) 0 ( 0%) ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI -98-  M H B H l i u b c l i r o n i c Toxicity 90-Day Oral Gavage Stuay in Rats DuPont-9478 TABLE 13 (CONTINUED) Treatment Group Dosage (mg/kg/day) Animal Count SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS II IV VI VIII X 0 1 5 25 25 15 15 15 X 125 25 Scab Face Incidence Mean onset (Days) 1 ( 4%) 21 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) General Teeth Observations Striated Incidence Mean onset (Days) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 24 ( 96%) # 53 Clipped Incidence Mean onset (Days) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 9 ( 36%) # 108 Breathing Observations Noise Incidence Mean onset (Days) 0 ( 0%) 0 ( 0%) 0 ( 0%) 1 ( 7%) 63 0 ( 0%) Discharge Bye Incidence Mean onset (Days) 2 ( 8%) 74 1 ( 7%) 91 1 ( 7%) 91 0 ( 0%) 2 ( 8%) 137 Company Sanitized. Does not contain TSCA CBI -99- ubchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 13 (CONTINUED) Treatment Group Dosage (mg/kg/day) Animal Count Nose Black SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS II IV VI VIII 0 1 5 25 25 15 15 15 X 125 25 Incidence Mean onset (Days) Mouth Clear 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 1 ( 4%) 112 Incidence Mean onset (Days) 0 ( 0%) 1 ( 7%) 14 0 ( 0%) 0 ( 0%) 0 ( 0%) Hair Loss Incidence Mean onset (Days) Wound Deep Mouth Incidence Mean onset (Days) Superficial Incidence Mean onset (Days) 5 ( 20%) 32 3 ( 20%) 53 1 ( 7%) 21 4 ( 27%) 64 2 ( 8%) 35 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 1 ( 4%) 112 2 ( 8%) 11 0 ( 0%) 0 ( 0%) 1 ( 7%) 1 ( 4%) 42 119 DuPont-9478 C* H M B H M ( 0 H H f l ^ u b c h r o n i c Toxicity 90-Day Oral Gavage Study in Rats______ TABLE 13 (CONTINUED) Treatment Group Dosage (mg/kg/day) Animal Count SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS II IV VI VIII 0 1 5 25 25 15 15 15 X 125 25 Arches back during handling Incidence Mean onset (Days) 2 ( 8%) 35 2 ( 13%) 25 4 ( 27%) 32 3 ( 20%) 49 6 ( 24%) 42 Ear twitch Incidence Mean onset (Days) 3 ( 12%) 39 2 ( 13%) 25 3 ( 20%) 33 3 ( 20%) 54 4 ( 16%) 39 Hyperreactive Incidence Mean onset- (Days) 1 ( 4%) 42 0 ( 0%) 0 ( 0%) 0 ( 0%) 1 ( 4%) 63 Hyperactive Incidence Mean onset (Days) 1 ( 4%) 77 1 ( 7%) 35 1 ( 7%) 28 3 ( 20%) 49 2 ( 8%) 74 Vocalization No Abnormality Detected h Incidence Mean onset (Days) 0 ( 0%) 1 ( 7%) 35 0 ( 0%) 0 ( 0%) 0 ( 0%) Comments Excessive Salivation Incidence Mean onset (Days) 0 ( 0%) 0 ( 0%) 1 ( 7%) 40 0 ( 0%) 0 ( 0%) DuPont-9478 Company Sanitized. Does not contain TSCA CBI - 101- __ ubchronic Toxicity 90-Day Oral Gavage Study in Rats } DuPont-9478 TABLE 13 (CONTINUED) Treatment Group Dosage (mg/kg/day) Animal Count Comments Teeth Stuck in Cage SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS II IV VI VIII 0 1 5 25 25 15 15 15 X 125 25 Incidence Mean onset (Days) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 ( 8%) 108 Misshapen Observations. Ear ' Incidence Mean onset (Days) 0 ( 0%) 1 ( 7%) 21 0 ( 0%) 0 ( 0%) 0 ( 0%) Stain Fur/Skin Incidence Mean onset (Days) Swollen Observations Nose 2 ( 8%) 147 0 ( 0%) 1 ( 7%) 1 ( 7%) 2 ( 8%) 42 154 110 Face Incidence Mean onset (Days) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 1 ( 4%) 105 Incidence Mean onset (Days) 0 ( 0%) 0 < 0%) 0 ( 0%) 0 ( 0%) 2 ( 8%) 109 Incidence - The number of animals for which an observation was recorded. Mean onset (Days) - The mean of the first test day an observation was recorded for that group. # Statistically significant difference at p < 0.05 by Cochran-Armitage trend test. Company Sanitized. Does not contain TSCA C8I l 90-Day Oral Gavage ubchronic Toxicity j in Rats_______ ) DuPont-9478 TABLE 14 SUMMARY OF OPHTHALMOLOGY OBSERVATIONS FOR MALE RATS (Test Day 87) Treatment Group Dosage (mg/kg/day) Number Examined " Retina Retinal Degeneration Focal Incidence Globe Phthisis bulbi Right Incidence . I 0 20 1 ( 5%) 0 ( 0%) III 1 10 1 ( 10%) 0(0%) V 5 10 1 ( 10%) 0(0%) VII 25 10 0 ( 0%) 0 ( 0%) IX 125 20 0( 1 ( 5%) Incidence - The number of animals (percent of animals examined) for which an observation was recorded. There were no statistically significant differences at p < 0.05 by Cochran-Armitage trend test. Company Sanitized. Does not contain TSCA CBI - 103- Subchronic Toxicity ?D^Pay Oral Gavage Study in Rats ) DuPont-9478 TABLE 15 SUMMARY OF OPHTHALMOLOGY OBSERVATIONS FOR FEMALE RATS (Test Day 87) Treatment Group Dosage (mg/kg/day) Number Examined Retina Retinal Degeneration Focal Right Incidence II 0 20 1(5%) IV 1 10 0(0%) VI VIII X 5 25 125 10 10 20 0 ( 0%) 0 ( 0%) 0 ( 0%) Incidence - The number of animals (percent of animals examined) for which an observation was recorded. There were no statistically significant differences at p < 0.05 by Cochran-Armitage trend test. Company Sanitized. Does not contain TSCA CBI - 104- ubchronic Toxicity 90-Day Oral Gavage Study in Rats_________ DuPont-9478 TABLE 16 PERCENT SURVIVAL OF MALE RATS Treatment Group Dose (mg/kg/day) I III 01 V VII IX 5 25 125 DAYS ON TEST 0 100 100 100- 100 100 7 100 100 100 100 100 14 100 100 100 100 100 21 100 100 100 100 100 28 100 100 100 100 100 35 100 100 100 100 100 42 100 100 100 100 100 49 100 100 100 100 100 56 100 100 100 100 100 63 100 100 100 100 100 70 100 100 100 100 100 77 100 100 100 100 100 84 100 100 100 100 100 91 100 100 100 ; 100 100 93 a.b 100 100 100 100 100 105 100 100 100 100 100 112 100 100 100 100 100 119 100 100 100 100 100 126 100 100 100 100 100 133 100 100 100 100 100 140 100 100 100 100 100 147 100 100 100 100 100 154 100 100 100 100 100 161 100 100 100 100 100 168 100 100 100 100 100 175 100 100 100 100 100 182 100 - - - 100 Number at study start 25 15 15 15 25 Sacrificed by design b,c 15 15 15 15 15 Alive on test day 182 10 0 0 0 10 Percent Survival = (Number of rats alive/Number of rats at risk)*100 Number of rats at risk = Number at study start - number sacrificed by design. a. Rats designated for the 90-day recovery period and satellite bleeds began recovery on test day 92. b. Rats designated for the 90-day exposure: period were sacrificed on test day 93. c. Rats designated for satellite bleeds were sacrificed on test day 175. There were no statistically significant decreases in survival at p < 0.05 by Cochran-Armitage trend test. -105Company Sanitized. Does not contain TSCA CBI IIH H IlH H H H H K JS ubchrom c Toxicity 90-Day Oral Gavage Study in Rats _____________________________________________________ DuPont-9478 TABLE 17 PERCENT SURVIVAL OF FEMALE RATS Treatment Group Dose (mg/kg/day) II IV VI VIII X 0 1 5 25 125 DAYS ON TEST 0 100 100 100 100 100 7 100 100 100 100 100 14 100 100 100 100 100 21 100 100 100 100 100 28 100 100 100 100 100 35 100 100 100 100 . 100 42 100 100 100 100 100 49 100 100 100 100 100 56 100 100 100 100 100 63 100 100 100 100 100 70 100 100 100 100 100 77 100 100 100 100 100 84 100 100 100 100 100 91 100 100 100 100 100 98 a'b 100 100 100 100 100 105 100 100 100 100 100 112 100 100 100 100 100 119 100 100 100 100 100 126 100 100 100 100 100 133 100 100 100 100 100 140 100 100 100 100 100 147 100 100 100 100 100 154 100 100 100 100 100 161 100 100 100 100 100 168 100 100 100 100 100 175 100 100 100 100 100 182 100 -- - 100 Number at study start 25 15 15 15 25 Accidentally killed a 1 0 0 0 0 Sacrificed by design b'c 15 15 15 15 15 Alive on test day 182 9 0 .0 0 10 Percent Survival = (Number of rats alive/Number of rats at risk) *100 Number of rats at risk = Number at study start - number accidentally killed - number sacrificed by design . S'' a. Rats designated for the 90--day recovery period and satellite bleeds began recovery on test days 92. b. Rats designated for the 90--day exposure period were :sacrificed on test day 94. c. Rats designated for satellite bleeds were sacrificed on test day 175. There were no statistically significant decreases in survival at p < 0.05 by Cochran-Armitage trend test. - 106Company Sanitized. Does not contain TSCA CBI !Subchronic Toxicity 90-Day Oral Gavage Sfl y in Rats_________ DuPont-9478 TABLE 18 MEAN FORELIMB AND HINDLIMB GRIP STRENGTH FOR MALE RATS (MEAN OF THREE TRIALS) Assessment Dosage Period ~ Group (mg/kg/day) Forelimb Hindlimb Grip Strength (kg)_______ Grip Strength (kg) Baseline I in V V IX 0 i 5 25 125 0.53 (0.08) 0 .5 8 (0 .1 1 ) 0.57(0.11) 0.60(0.11) 0 .5 8 (0 .1 1 ) 0.30 (0.06) 0.31 (0.06) 0.28 (0.05) 0.29(0.06) 0.27 (0.07) Week 13 I m V vn IX 0 l 5 25 125 1.13 (0.31) 1.17(0.17) 1.22(0.21) 1.27(0.18) 1.14(0.29) 0.53 (0.15) 0.58 (0.12) 0.53 (0.10) 0.58 (0.16) 0.49 (0.14) Data arranged as : Mean (Standard Deviation) Statistical Methods: Bartlett's test for homogeneity followed by analysis of variance and Dunnett's test. There were no statistically significant differences from control at p<0.05. - 107Company Sanitized. Does not contain TSCA CBI ubchronic Toxicity 90-Day Oral Gavage Study in Rats_________ DuPont-9478 TABLE 19 MEAN FORELIMB AND HINDLIMB GRIP STRENGTH FOR FEMALE RATS (MEAN OF THREE TRIALS) Assessment Dosage Period Group (mg/kg/day) Forelimb Grip Strength (kg) Hindlimb Grip Strength (kg) Baseline n IV VI vnr X 0 1 5 25 125 0.56 (0.08) 0.63 (0.09) 0.65 (0.09) * 0.60 (0.09) 0.60(0.10) 0.37 (0.07) 0.35 (0.05) 0.36 (0.03) 0.35 (0.09) 0.33 (0.06) Week 13 na IV VI vm X 0 1 5 25 125 0.88 (0.21) 1.03 (0.19) 1.05 (0.15) 0.99 (0.19) 0.97 (0.13) 0.50 (0.10) 0.40 (0.09) 0.49 (0.09) 0.47 (0.13) 0.46 (0.07) Data arranged as : Mean (Standard Deviation) an=9 due to unscheduled death. Statistical Methods: Bartlett's test for homogeneity followed by analysis o f variance and Dunnett's test. * Statistically significant difference from control at p<0.05 by Dunnett's test. - 108Company Sanitized. Does not contain TSCA CBi Subchronic Toxicity 90-Day Oral Gavage Study in Rats_______________ ___________________ _______________________ DuPont-9478 TABLE 20 SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR MALE RATS BASELINE __________13-WEEK Group I m V VII IX Dosage (:mg/kg/day) 0 l 5 25 125 Number examined: 10 10 10 ' 10 10 I m V VII IX 0 l 5 25 125 10 10 10 10 10 MANUPULATIONS: .APPROACH & TOUCH: no reaction normal Increased reaction (jumps away or attacks) 0 10 0 0000 9 10 10 10 10 0 0 00000 10 10 10 10 10 0 0 0 .0 0 AUDITORY STIMULUS: no reaction 00000 normal reaction (rat flinches or flicks ear) 10 10 10 10 10 exaggerated reaction (rat jumps, flips) 00000 00000 10 10 10 10 10 00000 TAIL PINCH: no response normal (turns toward site) exaggerated response 00000 9 9 10 10 10 110 0 0 00000 10 10 10 10 10 00000 IN MOTOR ACTIVITY MONITOR: PUPILLARY RESPONSE present absent DEFECATION present absent diarrhea URINATION: present absent 10 10 10 10 10 00000 63 834 47276 00000 10 9 10 10 9 0 100 1 10 10 10 10 10 00000 47 334 63776 00000 89979 2 113 1 There were no statistically significant differences by Cochran-Armitage test for trend"at p < 0.05. -109Company Sanitized. Does not contain TSCA CBI ubchronic Toxicity DuPont-9478 TABLE 21 SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR FEMALE RATS BASELINE Group n rv VI v m X Dosage (:mg/kg/day) 0 1 5 25 :125 Number examined: 10 10 10 10 10 13-WEEK IT IV VI vin X 0 1 5 25 125 10 10 10 10 10 MANUPULATIONS: APPROACH & TOUCH: no reaction 00000 normal 10 10 10 10 10 increased reaction (jumps away or attacks) 0 0 0 0 0 00000 9 10 10 10 10 00000 AUDITORY STIMULUS: no reaction 00 000 normal reaction (rat flinches or flicks ear) 10 10 10 10 10 exaggerated reaction (rat jumps, flips) 00 0 0 0 00000 9 10 10 10 10 00000 TAIL PINCH: no response normal (turns toward site) exaggerated response 0 0 0 0! 0 10 10 10 10 10 00000 00 000 9 10 10 10 10 00000 IN MOTOR ACTIVITY MONITOR: PUPILLARY RESPONSE present absent 10 10 10 10 10 00000 9 10 10 10 10 00000 DEFECATION present absent diarrhea 43 7 6 8 67 342 00 0 0 0 37 755 63355 00000 URINATION: present absent 7 9 10 10 9 3 100 1 7 10 9 9 10 2 0 1 10 il n=9 due to unscheduled death. There were no statistically significant differences by Cochran-Armitage test for trend at p < 0.05. 110 Company Sanitized. Does not contain TSCA CBI _______________ _jiubchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 22 MOTOR ACTIVITY ASSESSEMENT: DURATION OF MOVEMENTS FOR MALE RATS (sec) DuPont-9478 ASSESSMENT DOSAGE PERIOD GROUP ( m g / k g / d a y ) ____________________ SUCCESSIVE 10-MINUTE INTERVALS BASELINE I Iff V VII Di 0 1 5 25 125 1 383(34) 402(60) 401(39) 398(33) 402(49) 13-WEEK I IIIa V VII DC 0 1 5 25 125 383(42) 395(39) 390(42) 413(27) 405(69) Data arranged as: Mean (Standard Deviation). % n=9 due to sensor malfunction. 2 318(50) 344(56) 334(44) 292(71) 343(74) 327(36) 345(27) 333(40) 308(64) 327(69) 3 216(90) 312(78)* 254(74) 200(108) 281(121) 4 60(67) 163(120)* 172(130) * 146(135)* 164(149)* 5' 35(87) 83(138) 112(139)* 68(99) 90(123) 6 27(67) 34(52) 72(113) 60(105) 51(75) TOTAL 1039(202) 1338(354) 1346(466) 1163(430) 1331(488) 288(52) 295(46) 244(46) 228(107) 275(115) 270(55) 277(54) 209(91) 210(93) 220(133) 226(64) 205(108) 163(96) 129(85)* 202(128) 158(96) 127(98) 105(111) 158(77) 168(108) 1652(280) 1645(310) 1443(253) 1446(364) 1596(556) Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Repeated measures analysis of variance with linear contrasts was used to identify which dosage groups, if any, were significantly different from the control group. These tests were applied to bin data and total data: * Statistically significant difference from control at p < 0.05. Company Sanitized. Does not contain TSCA CBI - Ill - m ______________ Subchronic Toxicity 90-Day Oral Gavage Study in Rats_______ TABLE 23 MOTOR ACTIVITY ASSESSEMENT: DURATION OF MOVEMENTS FOR FEMALE RATS (sec) ) DuPont-9478 ASSESSMENT DOSAGE PERIOD GROUP (mg/kg/dav)_______________________________ SUCCESSIVE 10-MINUTE INTERVALS BASELINE II IV VI VIII X 0 1 5 25 125 1 370(53) 389(61) 364(29) 373(45) 367(68) 2 265(101) 302(75) 283(94) 259(96) 321(64) 3 243(120) 244(90) 234(80) 234(75) 272(88) 4 241(83) 207(135) 256(107) 200(69) 236(112) 5 189(118) 183(163) 154(121) 153(128) 181(113) 13-WEEK IIa IV VI VIII xb 0 1 5 25 125 383(47) 408(48) 408(40) 407(64) 403(47) 289(44) 294(69) 311(58) 298(72) 302(62) 237(46) 246(65) 211(78) 234(58) 241(71) 226(59) 249(70) 166(88) 193(95) 226(71) 203(39) 182(61) 151(77) 142(78) 206(89) 6 112(92) 145(158) 140(124) 73(64) 145(116) TOTAL 1419(381) 1471(599) 1430(372) 1292(322) 1522(442) 202(85) 150(114) 170(88) 176(66) 153(114) 1540(215) 1529(288) 1418(230) ' 1451(321) 1531(335) Data arranged as: Mean (Standard Deviation). an=9 due to unscheduled death. n=9 due to sensor malfunction. Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Jonckheere's trend test was used to identify which dosage groups, if any, were significantly different from the control group. These tests Were applied to bin data and total data. There were no statistically significant differences from control at p < 0.05. Company Sanitized. Does not contain TSCA CBI -112- ubchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 24 MOTOR ACTIVITY ASSESSEMENT: NUMBER OF MOVEMENTS FOR MALE RATS ) DuPont-9478 ASSESSMENT DOSAGE PERIOD GROUP ( m g / k g / d a y ) ______________________ SUCCESSIVE 10-MINUTE INTERVALS BASELINE I III V VII IX 0 T 5 25 125 1 135(19) 129(26) 132(14) 138(13) 127(26) 2 139(13) 129(26) 140(17) 137(7) 136(27) 3 124(36) 128(25) 131(17) 108(47) 126(34) 4 51(50) 91(65) * 100(50) * 87(68) * 73(50) 5 21(47) 39(51) 61(61)* 46(59) 44(56) 13-WEEK I IIIa V vn IX 0 1 5 25 125 141(16) 142(10) 139(12) 130(16) 133(22) . Data arranged as: Mean (Standard Deviation). 144(10) 148(10) 138(17) 129(14) 134(16) 134(13) 138(16) 124(19) 108(45) 116(33) 137(17) 133(16) 109(32) 109(43) 96(45) * 123(22) 108(47) 89(43) 73(44) * 101(57) an=9 due to sensor malfunction. 6 21(41) 23(36) 44(57) 40(53) 28(40) TOTAL 491(141) 539(160) 609(156) 556(201) 534(162) 95(50) 76(54) 66(60) 87(47) 88(55) 773(79) 745(112) 665(78) 637(179)* 668(168) Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Repeated measures analysis of variance with linear contrasts was used to identify which dosage groups, if any, were significantly different from the control group. These tests were applied to bin data and total data. * Statistically significant difference from control at p < 0.05. Company Sanitized. Does not contain TSCA CBI -113- ________ Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 25 MOTOR ACTIVITY ASSESSEMENT: NUMBER OF MOVEMENTS FOR FEMALE RATS ) DuPont-9478 ASSESSMENT DOSAGE PERIOD GROUP ( m g / k g / d a y ) __________________________ SUCCESSIVE IQ-MINUTE INTERVALS BASELINE II IV VI VHI X 0 ,1 5 25 125 1___ 138(17) 131(28) 137(13) 138(17) 131(26) 13-WEEK IT IV VI VIII Xb 0 1 5 25 125 132(25) 135(24) 125(16) . 135(17) 136(11) Data arranged as: Mean (Standard Deviation). an=9 due to unscheduled death. bn=9 due to sensor malfunction. 2 132(32) 127(27) 125(27) 127(24) 138(32) 133(14) 136(12) 138(15) 133(16) 134(19) 3 120(48) 124(27) 130(32) 132(20) 131(29) 128(21) 128(24) 115(29) 132(20) 130(27) 4 130(20) 97(48) 122(43) 127(30) 124(49) 126(27) 130(20) 100(36) 108(37) 126(27) 5 115(54) 85(58) 95(60) 86(66) 94(56) 127(21) 117(22) 96(38) 96(46) 111(35) 6 82(58) 71(55) 84(67) 62(52) 83(68) TOTAL 7.17(146) 635(162) 692(160) 673(148) 702(195) 121(35) 86(50) 101(41) 111(29) 87(55) 767(101) 732(82) 675(104) 716(78) 725(103) Statistical Methods: Shapiro-Wilk's and Levene's tests were performed. Jonckheere's trend test was used to identify which dosage groups, if any, were significantly different from the control group. These tests were applied to bin data and total data. There were no statistically significant differences from control at p < 0.05. Company Sanitized. Does not contain TSCA CBI -114- ubchronic Toxicity 90-Day Oral Gavage St3y in Rats_________ DuPont-9478 . TABLE 26 TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I 0 mg/kg/day Group HI 1 mg/kg/day Group V 5 mg/kg/day Group VH 25 mg/kg/day Group IX 125 mg/kg/day RBC (x l0 6/pL) DAY 48 DAY 93 DAY 183 HGB (g/dL) DAY 48 DAY 93 DAY 183 HOT (%) DAY 48 DAY 93 DAY 183 MCV (fl) DAY 48 DAY 93 DAY 183 MCH(pg) DAY 48 DAY 93 DAY 183 8.33 0.38(10) 8.57 0.32(10) 8.71 0.42(10) 15.1 0.6(10) 15.9 0.6(10) 15.4 0.6(10) 48.3 1.7(10) 47.7 1.7(10) 47.8 1.8(10) 58.0 1.4(10) 55.7 0.9(10) 54.9 1.6(10) 18.2 0.5(10) 18.6 0.5(10) 17.7 0.7(10) 8.26 0.35(10) 8.55 0.37(10) -- 15.2 0.7(10) 15.9 0.6(10) -- 48.3 2.2(10) 48.0 1.6(10) -- 58.5 1.8(10) 56.2 1.8(10) 18.4 0.7(10) 18.6 0.7(10) "" 8.18 0.13(9) 8.32 0.22(10) "" 15.1 0.4(9) 15.6 0.5(10) -- 48.4 1.2(9) 47.0 1.5(10) -- 59.1 1.2(9) 56.5 1.0(10) -- 18.5 0.4(9) 18.7 0.5(10) -- 7.90* 0.20(10) 8.12* 0.22(10) -- 14.8 0.5(10) 15.6 0.7(10) 47.0 1.4(10) 46.8 1.9(10) 59.5 1.7(10) 57.5* 1.4(10) --* 18.7 0.6(10) 19.1 0.5(10) 7.78* 0.42(10) 7.76* 0.44(10) 8.39 0.47(7) 14.5 0.7(10) 15.0* 0.7(10) 15.1 0.3(7) 46.4 2.4(10) 45.5* 2.5(10) 46.6 1.6(7) 59.7 2.0(10) 58.7* 2.4(10) 55.6 1.4(7) 18.7 0.5(10) 19.4* 0.6(10) 18.1 0.8(7) -115 Company Sanitized. Does not contain TSCA CBi Bubchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 TABLE 26 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS TEST/ PERIOD Group I 0 mg/kg/day Group EH Group V 15 mg/kg/day mg/kg/day Group VII 25 mg/kg/day Group IX 125 mg/kg/day MCHC (g/dL) DAY 48 DAY 93 DAY 183 RDW (%) DAY 48 DAY 93 DAY 183 ARET (xl03//iL) DAY 48 DAY 93 DAY 183 PLT (xl03//iL) DAY 48 DAY 93 DAY 183 WBC (xl03/jttL) DAY 48 DAY 93 DAY 183 31.3 0.5(10) 33.3 0.6(10) 32.3 0.7(10) 31.5 0.5(10) 33.1 0.5(10) 31.3 0.4(9) 33.1 0.8(10) 31.5 0.7(10) 33.3 0.6(10) 31.3 0.5(10) 33.0 0.7(10) 32.5 0.6(7) 11.9 0.4(10) 12.8 0.6(10) 13.5 0.5(10) 11.5 0.5(10) 12.2 0.5(10) -- 11.9 0.6(9) 12.6 0.7(10) 12.2 0.8(10) 12.7 0.5(10) ~~ 12.9* 0.9(10) 13.6 1.8(10) 13.3 0.6(7) 212.6 16.7(10) 172.4 22.7(10) 179.0 24.2(10) 206.0 25.6(10) 159.2 21.2(10) -- 235.8 44.5(9) 187.0 30.8(10) -- 239.6 43.2(10) 192.6 31.2(10) -- 262.0* 26.0(10) 216.8* 53.6(10) 188.4 22.9(7) 1010 151(6) 1221 132(9) 1145 188(6) 1098 20(4) 1227 109(7) 1054 104(7) 1199 128(8) 1012 48(5) 1252 126(8) / 950 178(5) 1275 209(9) 1074 165(7) 14.18 2.18(10) 12.19 3.55(10) 13.47 3.28(10) 15.67 3.75(10) 12.45 1.99(10) 15.12 3.70(9) 11.77 2.58(10) 15.46 3.13(10) 13.36 3.59(10) 16.29 4.01(10) 13.89 3.97(10) 13.97 2.30(7) -116Company Sanitized. Does not contain TSCA CBI ubchronic Toxicity 90-Day Oral Gavage St3y in Rats_________ DuPont-9478 TABLE 26 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I 0 mg/kg/day Group IH 1 mg/kg/day Group V 5 mg/kg/day Group VII 25 mg/kg/day Group IX 125 mg/kg/day ANEU (xlOVpL) DAY 48 DAY 93 DAY 183 ALYM (xlOVfiL) DAY 48 DAY 93 DAY 183 AMON (xlOVpL) DAY 48 DAY 93 DAY 183 AEOS (xl03//xL) DAY 48 DAY 93 DAY 183 ABAS (xl03//tL) DAY 48 DAY 93 DAY 183 1.63 0.55(10) 1.86 0.68(10) 2.75 1.37(10) 11.97 1.60(10) 9.89 3.01(10) 9.99 2.56(10) 0.30 0.13(10) 0.21 0.06(10) 0.40 0.14(10) 0.12 0.08(10) 0.14 0.07(10) 0.17 0.06(10) 0.09 0.05(10) 0.04 0.03(10) 0.11 0.05(10) 1.61 0.79(10) 1.45 0.33(10) -- 13.50 3.21(10) 10.55 1.99(10) -- 0.24 0.10(10) 0.24 0.14(10) -- 0.11 0.05(10) 0.13 0.06(10) 0.14 0.09(10) 0.04 0.03(10) -- 1.96 0.66(9) 1.81 1.04(10) -- 12.50 3.11(9) 9.49 1.45(10) -- 0.38 0.15(9) 0.24 0.12(10) -- 0.10 0.05(9) 0.14 0.12(10) 0.10 0.05(9) 0.04 0.01(10) 2.00 0.68(10) 2.48 1.13(10) "" 12.84 2.95(10) 10.34 2.79(10) -- 0.29 0.10(10) 0.26 0.10(10) 0.11 0.04(10) 0.17 0.14(10) 0.14 0.05(10) 0.04 0.02(10) -- . 2.04 0.90(10) 2.17 0.79(10) 2.49 0.56(7) 13.69 3.35(10) 11.26 3.21(10) 10.67 1.74(7) 0.27 0.11(10) 0.21 0.06(10) 0.43 0.13(7) 0.12 0.04(10) 0.14 0.04(10) 0.18 0.05(7) 0.11 0.07(10) 0.04 0.01(10) 0.14 0.08(7) -117Company Sanitized. Does not contain TSCA CBI ubchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 TABLE 26 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I 0 mg/kg/day Group IH 1 mg/kg/day Group V 5 mg/kg/day Group VII 25 mg/kg/day Group LX 125 mg/kg/day ALUC (x l0 3//iL) DAY 48 DAY 93 DAY 183 0.08 0.03(10) 0.06 0.03(10) 0.05 0.02(10) 0.07 0.04(10) 0.05 0.04(10) -- 0.08 0.02(9) 0.05 0.01(10) -- 0.09 0.02(10) 0.06 0.03(10) -- 0.07 0.04(10) 0.06 0.02(10) 0.07 0.02(7) Data arranged as: Mean Standard deviation (Number of values included in calculation) * Statistically significant difference from control at p < 0.05 by Dunnett/Tamhane-Dunnett test. -118Company Sanitized. Does not contain TSCA CBI ubchronic Toxicity 90-Day Oral Gavage dflfly in Rats ________________________________________ _______________DuPont-9478 TABLE 27 TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Group II 0 mg/kg/day Group IV 1 mg/kg/day Group VI 5 mg/kg/day Group V m 25 mg/kg/day Group X 125 mg/kg/day RBC (xl06//tL) DAY 49 DAY 94 DAY 183 HGB (g/dL) DAY 49 DAY 94 DAY 183 HCT (%) DAY 49 DAY 94 DAY 183 MCV (fl) DAY 49 DAY 94 DAY 183 MCH (pg) DAY 49 DAY 94 DAY 183 8.28 0.29(10) 8.24 0.26(10) 7.76 0.36(9) 15.6 0.5(10) 16.1 0.5(10) 14.7 0.6(9) 49.0 1.7(10) 47.2 1.5(10) 44.0 1.7(9) 59.2 0.9(10) 57.2 0.9(10) 56.8 1.8(9) 18.8 0.4(10) 19.6 0.3(10) 19.0 0.7(9) 8.09 0.29(9) 8.28 0.25(10) -- 15.4 0.5(9) 16.4 0.4(10) -- 48.1 1-7(9) 47.9 1.4(10) -- 59.5 1.1(9) 57.8 0.9(10) -- 19.1 0.3(9) 19.8 0.3(10) -- 8.14 0.36(10) 8.38 0.31(10) -- 15.5 0.6(10) 16.5 0.4(10) 48.3 1.7(10) 48.3 1.8(10) -- 59.4 1.6(10) 57.7 1.3(10) -- 19.0 0.4(10) 19.7 0.5(10) -- 8.00 0.41(10) 8.07 0.46(10) -- 14.9 0.6(10) 15.7 0.7(10) -- 46.8* 2.2(10) 45.8 2.4(10) -- 58.5 1.2(10) 56.8 0.8(10) -- 18.7 0.4(10) 19.5 0.5(10) ~ 7.50* 0.43(10) 7.66* 0.34(10) 7.75 0.30(10) 14.2* 0.7(10) 15.1* 0.7(10) 15.1 0.5(10) 44.5* 2.5(10) 44.6* 2.1(10) 45.1 1.9(10) 59.4 1.4(10) 58.3 1.6(10) 58.2 1.1(10) 19.0 0.6(10) 19.8 0.6(10) 19.4 0.3(10) - 119Company Sanitized. Does not contain TSCA CBI Subchronic Toxicity 90-Day Oral Gavage StuHy in Rats DuPont-9478 TABLE 27 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS TEST/ PERIOD Group II 0 mg/kg/day Group IV 1 mg/kg/day Group VI 5 mg/kg/day Group VUI 25 mg/kg/day Group X 125 mg/kg/day MCHC (g/dL) DAY 49 DAY 94 DAY 183 RDW (%) DAY 49 DAY 94 DAY 183 ARET (xl03//xL) DAY 49 DAY 94 DAY 183 PLT (x l0 3//zL) DAY 49 DAY 94 DAY 183 WBC (x l0 3//xL) DAY 49 DAY 94 DAY 183 31.8 0.4(10) 34.3 0.4(10) 33.4 0.3(9) 32.1 0.3(9) 34.3 0.4(10) -- 32.0 0.4(10) 34.2 0.5(10) -- 32.0 0.5(10) 34.4 0.8(10) -- 32.0 0.5(10) 34.0 0.3(10) 33.4 0.6(10) 11.7 0.6(10) 10.9 0.5(10) 11.8 0.5(9) 11.6 0.4(9) 11.0 0.4(10) 11.8 0.5(10) 11.0 0.4(10) 11.8 0.4(10) 10.8 0.3(10) 12.0 0.4(10) 11.6* 0.5(10) 12.1 0.8(10) 256.6 44.7(10) 141.4 31.4(10) 153.5 33.4(9) 225.4 26.9(9) 139.0 16.0(10) -- 249.0 51.4(10) 155.1 28.4(10) -- 217.1 31.2(10) 140.6 19.8(10) -- 240.6 18.0(10) 176.6* 39.0(10) 164.4 27.0(10) 973 835 46(7) 175(7) 1083 1025 130(10) 174(9) 1059 194(7) 1095 185(8) 1158 88(7) 952 181(8) 1026 190(7) 978 160(5) 1068 88(9) 957 231(6) 13.02 4.11(10) 10.84 3.92(10) 7.29 1.97(9) 11.83 2.63(9) 9.59 2.57(10) 13.25 3.38(10) 10.57 2.47(10) 12.56 2.78(10) 9.86 2.61(10) 11.10 3.04(10) 10.26 1.38(10) 8.19 1.73(10) -120Company Sanitized. Does not contain TSCA CBI Subchronic Toxicity 90-Day Oral Gavage Study in Rats_________ DuPont-9478 TABLE 27 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Group II 0 mg/kg/day Group IV 1 mg/kg/day Group VI 5 mg/kg/day Group V m 25 mg/kg/day Group X 125 mg/kg/day ANEU (xl03//xL) DAY 49 DAY 94 DAY 183 ALYM (xl03///L) DAY 49 DAY 94 DAY 183 AMON (xl03/jtiL) DAY 49 DAY 94 DAY 183 AEOS (xl03//xL) DAY 49 DAY 94 DAY 183 ABAS (xl03//iL) DAY 49 DAY 94 DAY 183 1.36 0.66(10) 1.28 0.47(10) 1.33 0.49(9) 11.18 3.47(10) 9.07 3.39(10) 5.55 1.65(9) 0.22 0.15(10) 0.18 0.07(10) 0.25 0.11(9) 0.11 0.06(10) 0.18 0.07(10) 0.09 0.03(9) 0.09 0.05(10) 0.06 0.02(10) 0.04 0.04(9) 0.94 0.36(9) 1.32 0.81(10) -- 10.50 2.40(9) 7.85 2.27(10) 0.20 0.07(9) 0.18 0.09(10) -- 0.09 0.03(9) 0.13 0.03(10) 0.05 0.02(9) 0.06 0.03(10) 1.50 0.56(10) 1.45 0.51(10) -- 1.43 0.82(10) . 1.76 1.22(10) -- 11.23 3.25(10) 8.70 2.48(10) 10.60 2.79(10) 7.61 2.12(10) 0.23 0.10(10) 0.15 0.08(10) -- ' 0.25 0.13(10) 0.23 0.21(10) -- 0.12 0.04(10) 0.17 0.06(10) 0.11 0.05(10) 0.15 0.06(10) 0.10 0.08(10) 0.05 0.05(10) 0.08 0.05(10) 0.06 0.04(10) 1.40 0.56(10) 1.74 0.68(10) 1.43 0.47(10) 9.25 2.67(10) 8.01 1.14(10) 6.27 1.67(10) 0.22 0.08(10) 0.26 0.09(10) 0.29 0.13(10) 0.10 0.05(10) 0.13 0.05(10) 0.11 0.05(10) 0.06 0.04(10) 0.06 0.02(10) 0.06 @ 0.01(10) -121 Company Sanitized. Does not contain TSCA CBI 90-Day Oral ubchronic Toxicity f in Rats DuPont-9478 TABLE 27 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS* Group II 0 mg/kg/day Group IV Group VI 15 mg/kg/day mg/kg/day Group VTH 25 mg/kg/day Group X 125 mg/kg/day ALUC (xl03//tL) DAY 49 DAY 94 DAY 183 0.07 0.03(10) 0.06 0.04(10) 0.03 0.01(9) 0.05 0.02(9) 0.05 0.03(10) -- 0.07 0.03(10) 0.04 0.03(10) -- 0.08 0.03(10) 0.05 0.04(10) -- 0.07 0.04(10) 0.05 0.02(10) 0.03 0.01(10) Data arranged as: Mean Standard deviation (Number o f values included in calculation) * Statistically significant difference from control at p < 0.05 by Dunnett/Tamhane-Dunnett test. @ Statistically significant difference from control at p < 0.05 by Dunn's test. -122Company Sanitized. Does not contain TSCA CBI pubchranic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 TABLE 28 TEST/ PERIOD SUMMARY OF COAGULATION VALUES FOR MALE RATS Group I 0 mg/kg/day Group HI 1 mg/kg/day Group V 5 mg/kg/day Group VH 25 mg/kg/day Group IX 125 mg/kg/day PT (seconds) DAY 93 APTT (seconds) DAY 93 15.9 0.8(9) 18.2 2.5(9) 16.1 0.6(10) 20.2 2.1(10) 15.9 1.1(9) 19.1 1.6(9) 15.5 0.5(10) 17.7 1.7(10) 15.9 1-7(9) 19.3 2-1(9) Data arranged as: Mean Standard deviation (Number of values included in calculation) There were no statistically significant differences from control at p < 0.05. TABLE 29 TEST/ PERIOD SUMMARY OF COAGULATION VALUES FOR FEMALE RATS Group II 0 mg/kg/day Group IV 1 mg/kg/day Group VI 5 mg/kg/day Group V m 25 mg/kg/day Group X 125 mg/kg/day PT (seconds) DAY 94 APTT (seconds) DAY 94 15.3 0.5(10) 15.8 1.8(10) 14.9 0.6(10) 16.2 2.0(10) 15.3 0.6(10) 15.0 1.6(10) 15.2 0.6(10) 15.4 1.7(10) 14.9 1.0(10) 14.1 2.0(10) Data arranged as: , Mean Standard deviation (Number of Values included in calculation) There were no statistically significant differences from control at p < 0.05. -123Company Sanitized. Does not contain TSCA CBI c ubchronic Toxicity 90-Day Oral Gavage StSSy in Rats DuPont-9478 TABLE 30 SUMMARY OF CLINICAL CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group I 0 mg/kg/day Group IE 1 mg/kg/day Group V 5 mg/kg/day Group VII 25 mg/kg/day Group IX 125 mg/kg/day AST (U/L) DAY 48 DAY 93 DAY 183 ALT (U/L) DAY 48 DAY 93 DAY 183 SDH (U/L) DAY 48 DAY 93 DAY 183 ALKP (U/L) - DAY 48 DAY 93 DAY 183 BILI (mg/dL) DAY 48 DAY 93 DAY 183 69 10(10) 85 12(10) 147 134(10) 33 4(10) 36 5(10) 77 91(10) 14.1 3.5(10) 18.7 3.1(10) 24.7 18.0(10) 131 18(9) 109 25(10) 86 20(10) 0.11 0.04(10) 0.10 . 0.03(10) 0.14 0.05(10) 69 5(10) 88 13(9) -- 33 5(10) 42 8(9) -- 13.2 2.8(10) 16.9 4.8(10) -- 114 21(10) 97 18(9) -- 0.07* ' 0.03(10) 0.06 @ 0.02(9) -- 70 6(10) 114 69(10) -- 72 9(10) 186 152(10) -- 32 5(10) 49 44(10) -- 33 5(10) 89 71(10) -- 12.6 2.4(10) 17.5 16.3(10) -- 13.2 3.0(10) 41.5 38.2(10) -- 126 17(9) 91 18(10) -- 135 33(10) 110 25(10) -- 0.10 0.03(10) 0.10 0.04(10) -- '*i' 0.10 0.04(10) 0.09 0.05(10) -- 69 6(10) 81 17(10) 134 51(10) 34 7(10) 44 16(10) 67 26(10) 13.3 3.5(10) 18.4 6.6(10) 21.0 6.8(10) 165* 39(10) 136 35(10) 86 23(10) ' 0.07 0.03(10) 0.09 0.03(10) 0.12 0.04(10) -124Company Sanitized. Does not contain TSCA CBI ISubchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 TABLE 30 (Continued) SUMMARY OF CLINICAL CHEMISTRY VALUES FOR MALE RATS TEST/ Group I PERIOD 0 ____________________ mg/kg/day Group III 1 mg/kg/day Group V 5 mg/kg/day Group VH 25 mg/kg/day Group IX 125 mg/kg/day BUN (mg/dL) DAY 48 DAY 93 DAY 183 CREA (mg/dL) DAY 48 DAY 93 DAY 183 CHOL (mg/dL) DAY 48 DAY 93 DAY 183 TRIG (mg/dL) DAY 48 DAY 93 DAY 183 GLUC (mg/dL) DAY 48 DAY 93 DAY 183 14 2(10) 13 2(10) 18 2(10) 14 1(10) 14 2(10) --. 14 2(10) 13 2(10) -- 14 1(10) 15* 2(10) -- 13 1(10) 13 2(10) 16* 2(10) 0.25 0.06(10) 0.42 0.06(10) 0.46 0.03(10) 0.27 0.04(10) 0.39 0.08(10) -- 0.28 0.04(10) 0.36 0.04(10) -- 0.26 0.02(10) 0.37 0.06(10) -- 0.26 0.04(10) 0.37 0.04(10) 0.41* 0.04(10) 66 9(10) 80 16(10) 76 28(10) 53 11(10) 57* 9(10) -- 62 12(10) 74 19(10) -- 52* 15(10) 66 17(10) -- 57 11(10) 65 15(10) 79 17(10) 87 24(10) 77 32(10) 81 33(10) 119 7(10) 109 28(10) 129 40(10) 74 27(10) 67 23(9) -- 95 50(10) 77 28(10) -- 115 9(10) 117 32(10) , -- 122 10(10) 114 24(10) -- 83 42(10) 64 26(10) -- 118 9(10) 110 29(10) -- 43* 21(10) 37* 18(10) 95 59(10) 122 20(10) 105 22(10) 127 31(10) -125Company Sanitized. Does not contain TSCA CBI Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 TABLE 30 (Continued) SUMMARY OF CLINICAL CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group I 0 mg/kg/day Group III 1 mg/kg/day Group V 5 mg/kg/day Group VII '2 5 mg/kg/day Group IX 125 mg/kg/day TP (g/dL) DAY 48 DAY 93 DAY 183 ALB (g/dL) DAY 48 DAY 93 DAY 183 / " N GLOB (g/dL) DAY 48 DAY 93 DAY 183 CALC (mg/dL) DAY 48 DAY 93 DAY 183 IPHS (mg/dL) DAY 48 DAY 93 DAY 183 6.5 0.3(10) 7.2 0.4(10) 6.9 0.2(10) 4.2 0.2(10) 4.4 0.2(10) 4.2 0.2(10) 2.4 0.3(10) 2.8 0.3(10) 2.7 0.2(10) 10.8 0.4(10) 11.3 0.4(10) 11.4 0.5(10) 8.3 0.6(10) 8.1 0.6(10) 8.5 0.8(10) 6.6 0.4(10) 7.0 0.3(9) ~" 4.1 0.3(10) 4.3 0.2(9) -- 2.4 0.2(10) 2.6 0.2(9) "" 10.8 0.2(10) 11.3 0.6(10) 7.9 0.5(10) 8.9 1.4(9) -- 6.6 0.4(10) 7.0 0.5(10) -- 4.2 0.2(10) 4.3 0.2(10) 2.5 0.3(10) 2.7 0.3(10) -- 10.8 0.5(10) 11.2 0.6(10) 8.4 0.7(10) 8.7 0.9(10) 6.5 0.3(10) 7.0 0.4(10) 4.2 0.2(10) 4.4 0.3(10) *" ** 2.3 0.2(10) 2.6 0.2(10) 10.5 0.4(10) 11.1 0.2(10) 8.4 1.0(10) 9.2 1.3(10) - 7.0* 0.4(10) 7.6* 0.1(10) 6.8 0.1(10) 4.7* 0.2(10) 5.0 @ 0.2(10) 4.2 0.1(10) 2.3 0.3(10) 2.6 0.2(10) 2.7 0.1(10) 10.8 0.4(10) 11.4 0.4(10) 11.5 0.3(10) 9.2* 0.9(10) 9.5* 1.2(10) 9.2 1.0(10) - 126Company Sanitized. Does not contain TSCA CBI ubchronic Toxicity 90-Day Oral Gavage Study in Rats_____________________________________ DuPont-9478 TABLE 30 (Continued) SUMMARY OF CLINICAL CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group I 0 mg/kg/day Group III 1 mg/kg/day Group V 5 mg/kg/day Group VII 25 mg/kg/day Group IX 125 mg/kg/day NA (mmol/L) DAY 48 DAY 93 DAY 183 K (mmol/L) DAY 48 DAY 93 DAY 183 CL (mmol/L) DAY 48 DAY 93 DAY 183 PFLU (/xg/mL) DAY 93 DAY 183 148.2 1.3(10) 148.4 1.3(10) 147.9 1.4(10) 149.5 4.7(10) 149.4 2.2(10) -- 148.2 2.3(10) 148.3 3.0(10) 148.3 1.2(10) 148.3 2.5(10) 147.7 1.6(10) 148.1 2.4(10) 148.4 2.2(10) 5.87 0.53(10) 6.15 0.51(10) 6.17 0.45(10) 5.68 0.47(10) 6.16 0.47(9) --* 5.76 0.62(10) 6.31 0.52(10) 5.52 0.43(10) 6.32 0.71(10) "" 5.74 0.34(10) 6.31 0.59(10) 6.29 0.54(10) 102.2 2.1(10) 100.7 1.9(10) 102.3 2.2(10) 103.2 3.7(10) 101.8 1.8(10) -- 101.5 2.2(10) 101.1 1.5(10) -- 101.0 2.1(10) 101.2 1.7(10) -- 101.1 2.0(10) 100.1 1.5(10) 104.1 1.9(10) 0.1 0.0(10) 0.1 0.1(9) 0.1 0.0(10) -- 0.1 0.0(10) ***" 0.1 0.0(10) *** 0.4 @ 0.0(10) 0.1 0.0(10) Data arranged as: Mean Standard deviation (Number of values included in calculation) * Statistically significant difference from control at p < 0.05 by Dunnett/Tamhane-Dunnett test. @ Statistically significant difference from control at p < 0.05 by Dunn's test. -127 Company Sanitized. Does not contain TSCA CBI |Subchromc Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 TABLE 31 SUMMARY OF CLINICAL CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD Group II 0 mg/kg/day Group IV 1 mg/kg/day Group VI 5 mg/kg/day Group VIH 25 mg/kg/day Group X 125 mg/kg/day AST (U/L) DAY 49 DAY 94 DAY 183 ALT (U/L) DAY 49 DAY 94 DAY 183 SDH (U/L) DAY 49 DAY 94 DAY 183 ALKP (U/L) DAY 49 DAY 94 DAY 183 BELI (mg/dL) DAY 49 DAY 94 DAY 183 72 11(10) 85 17(10) 177 176(9) 34 8(10) 40 17(10) 96 90(9) 10.5 2.7(10) 16.7 4.4(10) 29.2 27.5(9) 83 16(10) 51 11(10) 34 8(9) - 0.15 0.04(10) 0.15 0.01(10) 0.17 0.07(9) 77 15(10) 119 51(10) 35 7(10) 64 46(10) -- 10.5 4.0(10) 21.5 8.2(10) 79 19(10) 52 13(10) 0.15 0.03(10) 0.15 0.03(10) -- 65 6(10) 82 18(10) "" 91 89(10) 176 285(10) -- * 29 4(10) 37 10(10) -- 44 41(10) 75 106(10) 7.9 . 0.9(10) 13.6 2.7(10) 21.8 41.2(10) 44.4 84.1(10) -- 79 24(10) 54 19(10) 73 28(10) 49 19(10) 0.13 0.03(10) 0.12 0.03(10) -- Si,.- 0.14 0.04(10) 0.14 0.04(10) 61 9(10) 93 40(10) 103 54(10) 32 5(10) 45 16(10) 58 41(10) 10.0 2.2(10) 19.0 10.4(10) 17.5 10.4(10) 75 14(10) 53 10(10) 38 10(10) 0.16 0.03(10) 0.17 0.04(10) 0.15 0.04(10) - 128Company Sanitized. Does not contain TSCA CBI ^ u b ch ro n ic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 TABLE 31 (Continued) SUMMARY OF CLINICAL CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD Group II 0 mg/kg/day Group IV 1 mg/kg/day Group VI 5 mg/kg/day Group VIE 25 mg/kg/day Group X 125 mg/kg/day BUN (mg/dL) DAY 49 DAY 94 DAY 183 CREA (mg/dL) DAY 49 DAY 94 DAY 183 CHOL (mg/dL) DAY 49 DAY 94 DAY 183 TRIG (mg/dL) DAY 49 DAY 94 DAY 183 GLUC (mg/dL) DAY 49 DAY 94 DAY 183 15 2(10) 17 2(10) 17 2(9) 16 2(10) 17 2(10) -- 16 2(10) 17 1(10) -- 15 2(10) 17 4(10) 15 2(10) 17 2(10) 16 3(10) 0.33 0.05(10) 0.47 0.06(10) 0.52 0.05(9) 0.35 0.06(10) 0.49 0.03(10) --- 0.34 0.06(10) 0.44 0.06(10) 0.33 0.07(10) 0.48 0.10(10) -- 0.31 0.03(10) 0.46 0.06(10) 0.48 0.06(10) 77 19(10) 85 19(10) 134 26(9) 86 16(10) 97 15(10) **"* 73 14(10) 79 18(10) 105 28(10) 125 45(10) --* 107 @ 21(10) 123 39(10) 147 67(10) 44 20(10) 51 26(10) 78 14(9) 115 10(10) 101 9(10) 121 32(9) 50 20(10) 66 53(10) 112 13(10) 104 12(10) -- 37 12(10) 39 11(10) .43 22(10) 41 13(10) 116 13(10) 104 9(10) H- 113 5(10) 106 16(10) "** 55 46(10) 42 47(10) 89 63(10) 111 5(10) 100 5(10) 104 6(10) -129Company Sanitized. Does not contain TSCA CBI ubchronic Toxicity 90-Day Oral Gavage Study in Rats ___ DuPont-9478 TABLE 31 (Continued) SUMMARY OF CLINICAL CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD Group II 0 mg/kg/day Group IV 1 mg/kg/day Group VI 5 mg/kg/day Group VTH 25 mg/kg/day Group X 125 mg/kg/day TP (g/dL) DAY 49 DAY 94 DAY 183 ALB (g/dL) DAY 49 DAY 94 DAY 183 GLOB (g/dL) DAY 49 DAY 94 DAY 183 CALC (mg/dL) DAY 49 DAY 94 DAY 183 IPHS (mg/dL) DAY 49 DAY 94 DAY 183 7.3 0.3(10) 7.8 0.3(10) 8.5 0.3(9) 4.9 0.2(10) 5.2 0.3(10) 5.7 0.3(9) 2.4 0.2(10) 2.6 0.2(10) 2.8 0.1(9) 11.3 0.2(10) 11.7 0.4(10) 12.4 0.3(9) 7.0 L3(10) 6.8 1.7(10) 7.1 1-3(9) 7.3 0.3(10) 8.0 0.3(10) 4.9 0.2(10) 5.4 0.3(10) 2.4 0.2(10) 2.6 0.1(10) -- 11.3 0.4(10) 11.5 0.2(10) 7.4 1.2(10) 5.9 0.8(10) -- 7.0 0.5(10) 7.6 0.5(10) 4.6 0.4(10) 5.0 0.3(10) 2.5 0.3(10) 2.7 0.3(10) **" 11.0 0.3(10) 11.3 0.4(10) 6.8 0.7(10) 6.8 0.9(10) 7.6 0.5(10) 8.3 0.7(10) -- 5.0 0.4(10) 5.5 0.5(10) 2.6 0.3(10) 2.7 0.4(10) "" 11.4 0.4(10) 11.8 0.5(10) 6.9 0.5(10) 6.7 0.9(10) -- 7.9* 0.4(10) 8.6* 0.6(10) 8.4 0.4(10) 5.5@ 0.3(10) 5.8* 0.3(10) 5.4 0.4(10) 2.4 0.2(10) 2.8 0.3(10) 2.9 0.4(10) 11.6 0.5(10) 12.2* 0.4(10) 12.2 0.3(10) 7.6 1.0(10) 7.3 0.5(10) 7.4 1.0(10) - 130Company Sanitized. Does not contain TSCA CBI ubchronic Toxicity DuPont-9478 TABLE 31 (Continued) SUMMARY OF CLINICAL CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD Group 13 0 mg/kg/day Group IV 1 mg/kg/day Group VI 5 mg/kg/day Group VIE 25 mg/kg/day Group X 125 mg/kg/day NA (mmol/L) DAY 49 - DAY 94 DAY 183 K (mmol/L) DAY 49 DAY 94 DAY 183 CL (mmol/L) DAY 49 DAY 94 DAY 183 PFLU Qtg/mL) DAY 94 DAY 183 145.2 1.4(10) 145.6 2.1(10) 148.7 1.5(9) 145.1 1.7(10) 145.7 1.3(10) -- 145.1 1.6(10) 145.9 1.6(10) -- 144.1 2.4(10) 145.5 1.2(10) -- 144.5 1.8(10) 146.3 2.5(10) 149.6 1.5(10) 5.74 0.70(10) 5.74 0.67(10) 5.80 0.55(9) 5.59 0.48(10) 5.54 0.39(10) -- 5.50 0.38(10) 5.96 0.36(10) -- 5.36 0.27(10) 5.40 0.31(10) -- 5.55 0.38(10) 5.95 0.31(10) 5.94 0.53(10) 101.2 1.6(10) 101.1 3.0(10) 104.1 1.6(9) 101.6 1.3(10) 101.1 1.8(10) -- 101.9 1.1(10) 102.4 1.5(10) -- 100.7 2.0(10) 100.5 2.0(10) -- 100.9 1.0(10) 100.5 1.9(10) 103.9 2.3(10) 0.1 0.0(10) 0.1 0.0(9) 0.1 0.1(10) -- 0.1 0.0(10) -- 0.2 0.0(10) -- 0.5 @ 0.1(10) 0.1 0.0(9) Data arranged as: Mean Standard deviation (Number o f values included in calculation) * Statistically significant difference from control at p < 0.05 by Dunnett/Tamhane-Dunnett test @ Statistically significant difference from control at p < 0.05 by Dunn's test. -131 Company Sanitized. Does not contain TSCA CBI Subchromc Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 TABLE 32 TEST/ PERIOD. SUMMARY OF URINALYSIS VALUES FOR MALE RATS Group I 0 mg/kg/day Group III 1 mg/kg/day Group V Group VH 5 25 mg/kg/day . mg/kg/day. Group IX 125 mg/kg/day VOL (mL) DAY 48 DAY 93 DAY 183 UOSM (mOsm) DAY 48 DAY 93 DAY 183 pH DAY 48 DAY 93 DAY 183 URO (EU/dL) DAY 48 DAY 93 DAY 183 UFLUOxg) DAY 93 DAY 183 14.4 10.5(10) 6.8 2.5(10) 7.5 6.5(10) 10.9 5.6(10) 6.3 1.8(10) -- 11.7 6.0(10) 7.6 4.2(10) 13.0 7.9(10) 7.8 5.6(10) 17.2 5.6(10) 21.1@ 13.4(10) 7.7 4.1(10) 790 429(10) 1321 457(10) 1400 808(9) 841 341(10) 1324 323(10) -- 913 313(10) 1293 593(10) 840 365(10) 1549 854(10) 605 162(10) 703 452(10) 1322 590(10) 7.3 0.3(10) 6.8 0.7(10) 6.6 0.6(10) 7.1 0.2(10) 6.8 0.4(10) -- 7.1 0.2(10) 6.8 0.4(10) 7.1 0.4(10) 6.8 0.3(10) .-- 7.4 0.3(10) 7.0 0.4(10) 6.6 0.4(10) 0.2 0.0(10) 0.2 0.0(9) 0.4 0.3(10) 0.2 0.0(10) 0.2 0.0(10) -- 0.2 0.0(10) 0.2 0.0(10) 0.2 0.0(10) 0.30.3(10) -- 0.2 0.0(10) 0.2 0.0(10) 0.3 0.3(10) 10.7 4.4(10) 9.9 3.1(9) 13.0 1.9(10) -- 38.8@ 10.1(9) -- 202.4@ 57.9(9) -- 997.2@ 246.3(10) 27.6* 5.1(10) -132 Company Sanitized. Does not contain TSCA CBI 90-Day Oral Gavage Iubchronic Toxicity y in Rats ________ DuPont-9478 TABLE 32 (Continued) TEST/ PERIOD SUMMARY OF URINALYSIS VALUES FOR MALE RATS* Group I 0 mg/kg/day Group IH 1 mg/kg/day Group V 5 mg/kg/day Group VII 25 mg/kg/day Group IX 125 mg/kg/day UMTP (mg/dL) DAY 48 DAY 93 DAY 183 49 34(10) 108 87(10) 161 164(10) 48 26(10) 98 47(10) -- 55 34(10) 81. 49(10) -- 47 33(10) 89 53(10) -- 43 34(10) 67 91(10) 95 91(10) Data arranged as: Mean Standard deviation (Number o f values included in calculation) * Statistically significant difference from control at p < 0.05 by Dunnett/Tamhane-Dunnett test. @ Statistically significant difference from control at p < 0.05 by Dunn's test. -133Company Sanitized. Does not contain TSCA CBI C iubchronic Toxicity 90-Day Oral Gavage Study in Rats___________________________________________________________DuPont-9478 TABLE 33 TEST/ PERIOD SUMMARY OF URINALYSIS VALUES FOR FEMALE RATS Group n 0 mg/kg/day Group IV 1 mg/kg/day Group VI 5 mg/kg/day Group v m 25 mg/kg/day Group X 125 mg/kg/day VOL (mL) DAY 49 DAY 94 DAY 183 UOSM (mOsm) DAY 49 DAY 94 DAY 183 pH DAY 49 DAY 94 DAY 183 URO (EU/dL) DAY 49 DAY 94 DAY 183 LJFLU Qxg) DAY 94 DAY 183 7.2 3.3(10) 5.0 4.5(10) 8.2 14.1(7) 7.5 5.8(10) 2.8 1.8(9) -- 8.2 6.2(10) 4.2 2.5(10) . 14.4 13.3(10) 4.8 3.1(10) __ 8.2 5.2(10) 7.7 4.3(10) 4.9 4.4(10) 882 281(10) 1336 615(10) 1477 1104(7) 985 499(10) 1519 598(8) 1050 509(9) 1317 528(10) 623 257(10) 1231 493(10) -- 954 569(10) 1051 714(10) 1445 868(10) 7.1 0.2(10) 6.0 0.3(10) 5.7 0.5(7) 7.0 0.6(10) 6.1 0.4(9) -- 6.8 0.3(10) 5.9 0.4(10) 7.0 0.3(10) 6.4 0.3(10) ___ 6.9 0.4(10) 6.2 0.3(10) 6.1 0.5(10) 0.2 0.0(10) 0.2 0.0(10) 0.2 0.0(7) - 0.2 0.0(10) 0.2 0.0(9) 0.2 0.0(10) 0.2 0.0(10) 0.2 0.0(10) 0.2 0.0(10) 0.2 0.0(10) 0.2 0.0(10) 0.3 0.3(10) 6.0 2.3(8) 11.9 12.4(5) 5.7 1.4(6) 14.1 3.3(8) 88.0@ 29.0(8) 702.6@ 255.8(9) 15.7 3.2(7) -134Company Sanitized. Does not contain TSGA CBI ISubchronic Toxicity 90-Day Oral Gavage tdy in Rats DuPont-9478 TABLE 33 (Continued) TEST/ PERIOD SUMMARY OF URINALYSIS VALUES FOR FEMALE RATS Group II 0 mg/kg/day Group IV 1 mg/kg/day Group VI 5 mg/kg/day Group VEOE 25 mg/kg/day Group X 125 mg/kg/day UMTP (mg/dL) DAY 49 DAY 94 DAY 183 22 7(10) 33 23(10) 172 278(7) 34 24(10) 48 37(9) -- 26 18(10) 30 15(10) -- 13 6(10) 88 147(10) -- 46 35(10) 230 313(10) 588 1031(10) Data arranged as: Mean Standard deviation (Number o f values included in calculation) @ Statistically significant difference from control at p < 0.05 by Dunn's test. I ---- Company Sanitized. Does not contain TSCA CB1 Subchronic Toxicity 90-Day Oral Gavage Si ly in Rats_________ DuPont-9478 TABLE 34 SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITY IN MALE RATS Group I Dosage (mg/kg/day) 0 Hepatic Peroxisomal Beta-Oxidation Activity _________ (nmol/min/mg protein)_________ 10-Day Time point 90-Day Time point 3-Month Recovery Time point 14.8 1.0a 12.4 1.2 11.2 1.8 fflb 1 14.0 1.7 13.6 1.5 Vb 5 15.9 2.1 13.6 3 .0 vnb 25 14.7 1.1 13.4 2.1 -- r x 125 24.1 3.7# 20.6 2.8# 14.9 2.0* " Mean standard deviation. The n = 5 for each group. b Samples were not prepared for analysis from groups HI, V and VH at the 90-day recovery time points. # Statistically significant difference from control (p < 0.05) by Jonckheere's Tend test * Statistically significant difference from control (p < 0.05) by Dunnett's test. - 136Company Sanitized. Does not contain TSCA CBI ubchronic Toxicity 90-Day Oral Gavage Study in Rats_________ DuPont-9478 TABLE 35 SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITY IN FEMALE RATS Group n Dosage (mg/kg/day) 0 Hepatic Peroxisomal Beta-Oxidation Activity _________ (nmol/min/mg protein)_________ 10-Day Time point 90-Day Time point 3-Month Recovery Time point 22.5 2.2a 25.6 3.3 23.811.3 rvb 1 22.2+1.5 25.411.4 vi 5 23.8 4.5 27.312.1 vm b 25 23.2 2.2 29.7 13.3# X 125 29.5 4.4# 39.114.7# 2 7 .0 1 5.6 1 Mean standard deviation. The n = 5 for each group. b Samples were not prepared for analysis from groups IV, VI and VHI at the 90-day recovery time point. # Statistically significant difference from control (p < 0.05) by Jonckheere's Tend test. - 137Company Sanitized. Does not contain TSCA CBI iSubchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 36 G ro u p : D o s a g e (m g /k g /d a y ) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS RATS DESIGNATRD FOR SUBCHRONIC TOXICITY M EAN F IN A L BO DY AND A B S O LU T E ORGAN W E IG H T S (g ra in s ) I III 01 V V II 5 25 IX 125 L IV E R K ID N E Y S HEART SPLEEN B R A IN THYMUS ADRENAL GLANDS T H Y R O ID G LAN D TESTES E P ID ID Y M ID E S F IN A L BODY W E IG H T 1 4 .8 7 6 1 .7 7 0 (1 0 ) 3 .9 2 4 0 .4 6 3 (1 0 ) 1 .7 6 1 0 .1 8 4 (1 0 ) 0 .9 1 3 0 .1 3 7 (1 0 ) 2 .1 8 6 0 .0 8 4 (1 0 ) 0 .4 5 0 0 .1 3 4 (1 0 ) 0 .0 6 1 0 .0 0 9 (1 0 ) 0 .0 2 4 ,0 .0 0 4 (1 0 ) 3 .5 8 8 0 .2 2 8 (1 0 ) 1 .5 2 8 0 .2 8 9 (1 0 ) 5 5 2 .9 4 0 4 9 .1 4 5 (1 0 ) 1 4 .1 0 9 1 .2 5 4 (1 0 ) 3 .8 0 4 0 .2 6 3 (1 0 ) 1 .8 3 2 0 .0 9 5 (1 0 ) 0 .8 4 2 0 .1 2 6 (1 0 ) 2 .1 6 7 0 .1 0 5 (1 0 ) 0 .3 7 5 0 .0 7 2 (1 0 ) 0 .0 4 8 0 .0 1 3 (1 0 ) 0 .0 2 3 0 .0 0 4 (1 0 ) 3 .5 0 0 0 .2 5 5 (1 0 ) 1 .5 4 9 0 .1 3 3 (1 0 ) 5 4 0 .7 9 0 3 7 .4 0 0 (1 0 ) 1 5 .5 7 5 1 .7 4 4 (1 0 ) 4 .0 8 7 0 .5 0 1 (1 0 ) 1 .7 9 7 0 .1 8 7 (1 0 ) 0 .8 7 4 0 .1 7 1 (1 0 ) 2 .2 3 4 0 .0 8 9 (1 0 ) 0 .4 8 0 0 .1 1 7 (1 0 ) 0 .0 6 5 0 .0 1 1 (1 0 ) 0 .0 2 6 0 .0 0 3 (1 0 ) 3 .7 0 0 0 .4 4 2 (1 0 ) 1 .6 2 3 0 .1 6 0 (1 0 ) 5 8 2 .6 5 0 4 6 .1 8 6 (1 0 ) 1 7 .2 1 9 # 1 .6 9 3 (10) 4 .3 5 1 # 0 .4 1 7 (1 0 ) 1 .8 6 6 0 .1 3 3 (1 0 ) 0 .9 1 9 0 .1 0 2 (1 0 ) 2 .1 7 5 0 .0 9 4 (1 0 ) 0 .4 5 7 0 .1 3 1 (1 0 ) 0 .0 5 7 0 .0 1 2 (1 0 ) 0 .0 2 6 0 .0 0 3 (1 0 ) 3 .6 9 7 0 .3 3 0 (1 0 ) 1 .6 3 6 0 .2 2 1 (1 0 ) 5 6 4 .1 4 0 4 3 .1 1 9 (1 0 ) 2 1 .9 7 6 # 1 .9 2 8 (1 0 ) 4 .6 3 6 # 0 .3 4 6 (1 0 ) 1 .9 1 6 0 .3 0 3 (10). 0 .9 6 3 0 .1 8 6 (1 0 ) 2 .1 7 5 0 .0 6 9 (1 0 ) 0 .4 5 5 0 .1 3 8 (1 0 ) 0 .0 6 2 0 .0 1 4 (1 0 ) 0 .0 2 3 0 .0 0 3 (1 0 ) 3 .5 5 2 0 .5 5 2 (1 0 ) 1 .4 5 6 0 .2 4 8 (1 0 ) 5 3 6 .9 8 0 3 1 .7 3 4 (1 0 ) ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI - 138 - ISubchronic Toxicity. 90-Day Oral Gavage tdy in Rats__________ TABLE 36 (CONTINUED) G ro u p : D o s a g e (m g /k g /d a y ) L IV E R / F IN A L BODY * 100 K ID N E Y S / F IN A L BODY * 1 0 0 HEART/ F IN A L BODY * 100 SPLEEN/ F IN A L BODY * 100 B R A IN /' F IN A L BODY * 100 TH YM U S/ F IN A L BODY * 1 00 ADRENAL G LANDS/ F IN A L BODY * 1 00 1 T H Y R O ID G L A N D / F IN A L BODY * 10 0 TESTES/ F IN A L BODY * 100 E P ID ID Y M ID E S / F IN A L BODY * 1 00 MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS RATS DESIGNATED FOR SUBCHRONIC TOXICITY M E A N R E L A T I V E O R G A N W E IG H T S (% o f b o d y w e i g h t ) I III 01 V V II 5 25 2 .6 9 0 0 .2 2 5 (1 0 ) 0 .7 1 2 0 .0 9 1 (1 0 ) 2 .6 0 9 0 .1 4 0 (1 0 ) 0 .7 0 7 0 .0 7 6 (1 0 ) 2 .6 6 9 0 .1 4 8 (1 0 ) 0 .7 0 2 0 .0 6 9 (1 0 ) 3 .0 5 0 # 0 .1 2 4 (1 0 ) 0 .7 7 1 0 .0 3 5 (1 0 ) 0 .3 2 0 0 .0 3 5 (1 0 ) 0 .1 6 5 0 .0 2 1 (1 0 ) 0 .3 9 8 0 .0 3 8 (1 0 ) 0 .0 8 1 0 .0 2 1 (1 0 ) 0 .0 1 1 0 .0 0 2 (1 0 ) 0 .0 0 4 0 .0 0 1 (1 0 ) 0 .3 3 9 0 .0 1 6 (1 0 ) 0 .1 5 6 0 .0 2 3 (1 0 ) 0 .4 0 2 0 .0 3 1 (1 0 ) 0 .0 6 9 0 .0 1 0 (1 0 ) 0 .0 0 9 0 .0 0 2 (1 0 ) 0 .0 0 4 0 .0 0 1 (1 0 ) 0 .3 0 8 0 .0 2 0 (1 0 ) 0 .1 4 9 0 .0 2 2 (1 0 ) 0 .3 8 5 0 .0 3 0 (1 0 ) 0 .0 8 2 0 .0 1 8 (1 0 ) 0 .0 1 1 0 .0 0 2 (1 0 ) 0 .0 0 4 0 .0 0 1 (1 0 ) 0 .3 3 1 . 0 .0 1 3 (1 0 ) 0 .1 6 4 0 .0 2 0 (1 0 ) 0 .3 8 7 0 .0 3 0 (1 0 ) 0 .0 8 1 0 .0 2 0 (1 0 ) 0 .0 1 0 0 . 0 0 2 (10). 0 .0 0 5 0 .0 0 1 (1 0 ) 0 .6 5 1 0 .0 4 8 (1 0 ) 0 .6 4 9 0 .0 5 7 (1 0 ) 0 .6 3 5 0 .0 5 3 (1 0 ) 0 .6 5 7 0 .0 5 4 (1 0 ) 0 .2 7 9 0 .0 6 0 (1 0 ) 0 .2 8 7 0 .0 2 5 (1 0 ) 0 .2 8 0 0 .0 3 2 (1 0 ) . 0 .2 9 0 0 .0 3 5 (1 0 ) IX 125 4 .1 0 2 # 0 .4 1 0 (1 0 ) 0 .8 6 7 # 0 .0 9 6 (1 0 ) 0 .3 5 7 0 .0 5 9 (1 0 ) 0 .1 8 0 0 .0 3 7 (1 0 ) 0 .4 0 6 0 .0 2 8 (1 0 ) 0 .0 8 5 0 .0 2 5 (1 0 ) 0 .0 1 2 0 .0 0 3 (1 0 ) 0 .0 0 4 0 .0 0 1 (1 0 ) 0 .6 6 4 0 .1 1 0 (1 0 ) 0 .2 7 3 0 .0 5 4 (1 0 ) } D u P on t-9478 Company Sanitized. Does not contain TSCA CBI -139- 90-Day Oral Gavage Study in Rats ) DuPont-9478 G ro u p : D o s a g e (m g /k g /d a y ) L IV E R / B R A IN * 1 0 0 K ID N E Y S / B R A IN * 1 0 0 HEART/ B R A IN * 1 0 0 SPLEEN/ B R A IN * 1 0 0 TH YM U S/ B R A IN * 1 0 0 ADRENAL G LANDS/ B R A IN * 1 0 0 T H Y R O ID G L A N D / B R A IN * 1 0 0 TESTES/ B R A IN * 1 0 0 E P ID ID Y M ID E S / B R A IN * 1 0 0 TABLE 36 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS RATS DESIGNATED FOR SUBCHRONIC TOXICITY M E A N R E L A T I V E O R G A N W E IG H T (% o r g a n t o b r a i n w e i g h t r a t i o ) I III V 0, 1. 5 V II 25 IX 125 6 8 0 .7 9 4 8 0 .3 5 6 (1 0 ) 1 7 9 .3 5 0 1 9 .0 3 4 (1 0 ) 8 0 .5 4 5 7 .7 3 0 (1 0 ) 4 1 .7 3 5 5 .6 8 0 (1 0 ) 2 0 .5 1 1 5 .8 5 4 (1 0 ) 2 .7 9 4 0 .3 6 0 (1 0 ) 1 .0 9 2 0 .1 6 4 (1 0 ) 1 6 4 .2 4 7 1 0 .7 1 6 (1 0 ) 6 9 .8 4 8 1 2 .7 9 1 (1 0 ) 6 5 2 .3 8 6 6 4 .4 4 9 (1 0 ) 1 7 5 .8 0 2 1 3 .1 1 7 (1 0 ) 8 4 .7 1 9 5 .8 1 3 (1 0 ) 3 8 .8 1 7 5 .2 7 3 (1 0 ) 1 7 .2 9 5 3 .1 7 0 (1 0 ) 2 .2 3 0 0 .6 2 2 (1 0 ) 1 .0 6 5 0 .1 6 8 (1 0 ) 1 6 1 .9 9 9 1 5 .7 2 6 (1 0 ) 7 1 .5 5 2 5 .8 8 6 (1 0 ) 6 9 7 .5 1 3 7 6 .8 4 6 (1 0 ) 1 8 2 .5 9 3 1 7 .3 5 9 (1 0 ) 8 0 .4 1 5 7 .3 6 4 (1 0 ) 3 9 .0 6 3 7 .2 7 9 (1 0 ) 2 1 .4 9 6 5 .3 0 3 (1 0 ) 2 .9 0 1 0 .4 5 6 (1 0 ) 1 .1 6 3 0 .1 0 1 (1 0 ) 1 6 5 .6 2 8 1 8 .8 2 7 (1 0 ) 7 2 .7 1 9 7 .2 9 9 (1 0 ) 7 9 2 .3 3 0 # 7 8 .2 1 5 (1 0 ) 2 0 0 .1 3 7 # 1 8 .9 0 9 (1 0 ) 8 5 .8 8 8 6 .2 8 9 (1 0 ) 4 2 .3 0 2 4 .6 1 4 (1 0 ) 2 1 .0 8 7 6 .1 6 8 (1 0 ) 2 .6 4 2 0 .5 5 3 (1 0 ) 1 .1 8 8 0 .1 6 1 (1 0 ) 1 7 0 .0 7 1 1 4 .4 7 7 (1 0 ) 7 5 .1 0 2 8 .7 4 1 (1 0 ) 1 0 1 1 .4 4 8 # 9 3 .8 5 3 (1 0 ) 2 1 3 .3 7 1 # 1 6 .8 6 8 (1 0 ) 8 8 .1 3 9 1 3 .9 3 4 (1 0 ) 4 4 .2 8 3 8 .1 6 8 (1 0 ) 2 0 .8 2 9 5 .8 5 8 (1 0 ) 2 .8 4 9 0 .5 8 5 (1 0 ) 1 .0 7 1 0 .1 2 4 (1 0 ) 1 6 3 .4 7 9 2 6 .0 4 2 (1 0 ) 6 6 .8 8 5 1 0 .8 7 0 (1 0 ) Company Sanitized. Does not contain TSCA CBI - 140- Company Sanitized. Does not contain TSCA CBI 90-Day Oral Gavage Study in Rats TABLE 36 (CONTINUED) G ro u p : D o s a g e (m g /k g /d a y ) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS RATS DESIGNATED FOR RECOVERY I IX 0 125 L IV E R K ID N E Y S HEART SPLEEN B R A IN THYMUS ADRENAL GLANDS T H Y R O ID G LAND TESTES E P ID ID Y M ID E S F IN A L BODY W E IG H T 1 5 .7 7 9 2 .4 8 1 (9 ) 3 .9 1 1 0 .4 2 8 (9 ) 1 .7 9 9 0 .1 6 1 (9 ) 0 .8 6 3 0 .1 1 5 (9 ) 2 .1 6 1 0 .1 0 0 (9 ) 0 .2 2 2 0 .0 8 8 (9 ) 0 .0 5 5 0 .0 0 9 (9 ) 0 .0 3 1 0 .0 0 5 (9 ) 3 .6 5 5 0 .2 7 0 (9 ) 1 .5 1 3 0 .1 4 4 (9 ) 6 2 6 .3 1 1 6 7 .7 8 3 (9 ) 1 5 .0 6 7 2 .7 2 7 (1 0 ) 3 .9 4 0 0 .5 2 0 (1 0 ). 1 .8 4 1 0 .2 7 6 (1 0 ) 0 .8 4 0 0 .1 0 6 (1 0 ) 2 .1 1 1 0 .0 6 7 (1 0 ) 0 .3 3 8 # 0 .0 5 6 (1 0 ) 0 .0 4 9 0 .0 1 0 (1 0 ) 0 .0 2 9 0 .0 0 5 (1 0 ) 3 .4 6 0 0 .1 2 5 (1 0 ) 1 .4 8 0 0 .1 1 4 (1 0 ) 6 0 9 .8 6 0 8 5 .8 6 4 (1 0 ) -141- > DuPont-9478 Company Sanitized. Does not contain TSCA CBI ____________ JSubchronic Toxicity 90-Day Oral Gavage Study in Rats__________ TABLE 36 (CONTINUED) G ro u p : D o s a g e (m g /k g /d a y ) L IV E R / F IN A L BODY * 100 K ID N E Y S / F IN A L BODY * 1 00 HEART/ F IN A L BODY * 100 SPLEEN/ F IN A L BODY * 1 00 B R A IN / F IN A L BODY * 1 00 TH YM U S/ F IN A L BODY * 100 ADRENAL G LANDS/ F IN A L BODY * 1 00 | T H Y R O ID G L A N D / F IN A L BODY * 100 TESTES/ F IN A L BODY * 1 00 E P ID ID Y M ID E S / F IN A L BODY * 1 00 MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS RATS DESIGNATED FOR RECOVERY M E A N R E L A T IV E ORGAN W E IG H T S ( % o f b o d y w e i g h t ) I IX 0 125 2 .5 1 0 0 .1 5 9 (9 ) 2 .4 6 2 0 .1 8 4 (1 0 ) 0 .6 2 5 : 0 .0 2 7 (9 ) 0 .6 4 8 0 .0 4 6 (1 0 ) 0 .2 8 9 0 .0 2 4 (9 ) 0 .3 0 2 0 .0 1 4 (1 0 ) 0 .1 3 8 0 .0 1 8 (9 ) 0 .1 3 9 0 .0 1 5 (1 0 ) 0 .3 4 8 0 .0 3 0 (9 ) 0 .3 5 2 0 .0 5 1 (1 0 ) 0 .0 3 6 0 .0 1 5 (9 ) 0 .0 5 6 # 0 .0 0 7 (1 0 ) 0 .0 0 9 0 .0 0 2 (9 ) 0 .0 0 8 0 .0 0 1 (1 0 ) 0 .0 0 5 0 .0 0 1 (9 ) 0 .0 0 5 0 .0 0 1 (1 0 ) 0 .5 8 9 0 .0 6 4 (9 ) 0 .5 7 7 0 .0 8 0 (1 0 ) 0 .2 4 4 0 .0 3 2 (9 ) 0 .2 4 8 0 .0 4 5 (1 0 ) -142- ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI Bubchronic Toxicity 90-Day Oral Gavage Study in Rats_____ TABLE 36 (CONTINUED) G ro u p : D o s a g e (m g /k g /d a y ) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS RATS DESIGNATED FOR RECOVERY M E A N R E L A T I V E O R G A N W E I G H T S . (% o r g a n t o b r a i n w e i g h t r a t i o ) I IX 0 125 L IV E R / B R A IN * 1 0 0 K ID N E Y S / B R A IN * 10 0 HEART/ B R A IN * 1 0 0 SPLEEN/ B R A IN * 1 0 0 TH YM U S/ B R A IN * 1 0 0 ADRENAL GLANDS/ B R A IN * 1 0 0 T H Y R O ID G L A N D / B R A IN * 1 0 0 ' TESTES/ B R A IN * 10 0 E P ID ID Y M ID E S / B R A IN * 1 0 0 7 2 8 .2 4 3 9 4 .6 1 4 (9 ) 1 8 0 .8 5 5 1 7 .1 8 2 (9 ) 8 3 .1 8 0 5 .4 5 0 (9 ) 3 9 .8 5 2 4 .3 7 9 (9 ) 1 0 .3 6 1 4 .2 8 0 (9 ) 2 .5 5 4 0 .4 2 1 (9 ) 1 .4 2 8 0 .2 6 7 (9 ) 1 6 9 .4 2 1 1 4 .4 9 2 (9 ) 7 0 .0 2 2 6 .3 6 5 (9 ) 7 1 4 .9 4 2 1 3 3 .7 3 0 (1 0 ) 1 8 6 .7 6 6 2 4 .8 4 8 (1 0 ) 8 7 .3 3 4 1 3 .5 4 9 (1 0 ) 3 9 .8 5 6 5 .4 7 8 (1 0 ) 1 6 .0 4 4 # 2 .6 5 0 (1 0 ) 2 .3 0 6 0 .4 6 8 (1 0 ) 1 .3 7 1 0 .2 6 0 (1 0 ) 1 6 3 .9 3 6 4 .5 2 7 (1 0 ) 7 0 .1 7 1 5 .9 8 2 (1 0 ) -143- DuPont-9478 c Subchronic Toxicity TABLE 36 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS RATS DESIGNATED FOR SATELLITE EV AT.HATTONS (TO-DAY SACRIFICE') G ro u p : D o s a g e (m g /k g /d a y ) L IV E R F IN A L BODY W E IG H T L IV E R / F IN A L BODY * 1 00 I 0 1 0 .4 1 9 0 .9 4 0 (5 ) 2 4 8 .3 8 1 6 .9 5 3 (5 ) 4 .1 9 3 0 .2 0 6 (5 ) hi l 1 0 .2 1 6 0 .7 3 3 (5 ) 2 4 4 .6 6 1 1 .9 6 4 (5 ) 4 .1 7 4 0 .1 6 4 (5 ) V 5 1 0 .4 1 9 1 .4 4 4 (5 ) 2 4 5 .6 6 2 3 .0 2 3 (5 ) 4 .2 3 2 0 .2 9 0 (5 ) V II 25 1 0 .7 0 3 1 .0 0 4 (5 ) 2 4 1 .3 6 1 7 .0 8 5 (5 ) 4 .4 3 3 0 .2 4 2 (5 ) IX 125 1 4 .1 8 2 1 .6 8 4 (5 ) 2 5 2 .9 4 1 7 .8 1 9 (5 ) 5 .5 9 3 0 .2 9 7 (5 ) RATS DESIGNATED FOR SATELLITE EVALUATIONS (FINAL SACRIFICE! G ro u p : D o s a g e (m g /k g /d a y ) L IV E R F IN A L BO DY W E IG H T L IV E R / F IN A L BODY * 100 I 0 1 9 .6 2 8 ' 4 .4 0 5 (5 ) 6 0 3 .0 4 0 9 8 .4 3 6 (5 ) 3 .2 3 2 0 .3 5 6 (5 ) III 1 2 0 .5 2 1 3 .7 6 8 (5 ) 6 4 6 .3 4 0 6 6 .8 1 4 (5 ) 3 .1 5 7 0 .2 9 6 (5 ) V 5 1 9 .9 6 3 3 .8 3 3 (5 ) 6 3 2 .4 8 0 8 5 .8 3 8 (5 ) 3 .1 3 9 0 .2 3 6 (5 ) D a ta s u m m a riz e d a s : M ean S ta n d a rd D e v ia tio n (n ) # S t a t i s t i c a l l y s ig n if ic a n t d iffe r e n c e a t p < 0 .0 5 b y J o n c k h e e re -T e rp s tra tr e n d t e s t . V II 25 2 2 .6 0 1 3 .9 7 6 (5 ) 6 9 3 .8 4 0 8 1 .7 7 8 (5 ) 3 .2 4 1 0 .2 0 3 (5 ) IX 125 2 2 .5 5 9 3 .6 8 6 (5 ) 6 9 7 .9 4 0 # 6 5 .7 1 9 (5 ) 3 .2 2 0 0 .2 6 7 (5 ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI - 144- j iubchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 37 MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS G ro u p : D o s a g e (m g /k g /d a y ) L IV E R K ID N E Y S HEART SPLEEN B R A IN THYMUS ADRENAL GLANDS T H Y R O ID G LAN D O V A R IE S * UTERUS F IN A L BO DY W E IG H T 1 RATS DESIGNATED FOR SUBCHRONIC TOXICITY M E A N F IN A L BO DY A N D A B S O LU T E ORG AN W E IG H T S ( g r a m s ) II 0 7 .9 0 4 0 .8 4 9 (1 0 ) 2 .2 3 9 0 .1 8 8 (1 0 ) 1 .2 2 3 0 .2 9 4 (1 0 ) 0 .5 7 9 0 .0 9 0 (1 0 ) 1 .9 6 7 0 .0 6 8 (1 0 ) 0 .3 5 1 0 .0 7 4 (1 0 ) 0 .0 7 6 0 .0 1 2 (1 0 ) 0 .0 2 0 0 .0 0 3 (1 0 ) 0 .1 4 1 0 .0 1 8 (1 0 ) 0 .7 0 4 0 .1 6 8 (1 0 ) IV 1 8 .2 2 4 0 .9 8 2 (1 0 ) 2 .1 4 7 0 .2 3 9 (1 0 ) 1 .1 0 8 0 .0 6 7 (1 0 ) 0 .5 4 9 0 .0 9 5 (1 0 ) 1 .9 7 8 0 .0 7 7 (1 0 ) 0 .2 6 7 0 .0 6 8 (1 0 ! 0 .0 6 3 0 .0 1 9 (1 0 ) 0 .0 2 0 0 .0 0 6 (1 0 ) 0 .1 3 2 0 .0 2 5 (1 0 ) 0 .7 7 9 0 .1 7 0 (1 0 ) VI 5 8 .1 8 5 0 .8 4 5 (1 0 ) 2 .1 5 5 0 .1 7 3 (1 0 ) 1 .1 3 0 0 .1 2 0 (1 0 ) 0 .6 2 2 0 .1 0 5 (1 0 ) 1 .9 3 1 0 .0 8 5 (1 0 ) 0 .3 2 4 0 .0 8 2 (1 0 ) 0 .0 7 0 0 .0 1 0 (1 0 ) 0 .0 2 0 0 .0 0 3 (1 0 ) 0 .1 4 1 0 .0 3 3 (1 0 ) 0 .7 3 8 0 .3 0 0 (1 0 ) V III 25 9 .2 3 0 # 1 .0 7 6 (1 0 ) 2 .4 5 3 0 .2 6 7 (1 0 ) 1 .1 6 1 0 .1 2 5 (1 0 ) 0 .5 7 4 0 .0 7 3 (1 0 ) 2 .0 0 3 0 .0 8 5 (1 0 ) 0 .3 2 8 0 .0 6 0 (1 0 ) 0 .0 6 5 0 .0 0 6 (1 0 ) 0 .0 2 1 0 .0 0 4 (1 0 ) 0 .1 3 4 0 .0 2 4 (1 0 ) 0 .7 8 0 0 .1 6 6 (1 0 ) 2 8 6 .8 3 0 2 5 .3 0 4 (1 0 ) 2 9 4 .6 0 0 2 5 .1 0 7 (1 0 ) 2 9 4 .0 9 0 2 5 .8 2 0 (1 0 ) 2 9 7 .5 2 0 2 6 .0 4 5 (1 0 ) X 125 1 1 .5 1 3 # 0 .9 7 2 (1 0 ) 2 .4 6 2 # 0 .2 6 5 (1 0 ) 1 .1 5 0 0 .0 7 5 (1 0 ) 0 .6 0 9 0 .0 6 5 (1 0 ) 2 .0 0 9 0 .1 2 6 (1 0 ) 0 .3 2 3 0 .0 7 4 (1 0 ) 0 .0 7 3 0 .0 1 3 (1 0 ) 0 .0 2 2 0 .0 0 4 (1 0 ) 0 .1 4 0 0 .0 2 5 (1 0 ) 0 .8 0 8 0 .3 5 4 (1 0 ) 2 8 8 .9 6 0 1 7 .9 1 1 (1 0 ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI -145- ubchromc Toxicity 90-Day Oral Gavage 55y in Rats TABLE 37 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS RATS DESIGNATED FOR SIIBCHRONIC TOXICITY G ro u p : D o s a g e (m g /k g /d a y ) L IV E R / F IN A L BODY * 100 K ID N E Y S / F IN A L B O D Y * 100.- HEART/ F IN A L BODY * 1 0 0 SPLEEN/ F IN A L BODY * 1 0 0 B R A IN / F IN A L BODY * 1 0 0 TH YM U S/ F IN A L BODY * 100 A D R EN AL G L A N D S /, 6F I N A L B O D Y * 1 0 T H Y R O ID G L A N D / F IN A L BODY * 100 O V A R IE S / F IN A L BODY * 100 II 0 2 .7 5 5 0 .1 5 8 (1 0 ) 0 .7 8 2 0 .0 4 3 (1 0 ) 0 .4 2 6 0 .0 9 4 (1 0 ) 0 .2 0 1 0 .0 2 3 (1 0 ) 0 .6 8 9 0 .0 4 9 (1 0 ) 0 .1 2 2 0 .0 2 2 (1 0 ) 0 .0 2 7 0 .0 0 4 (1 0 ) 0 .0 0 7 0 .0 0 1 (1 0 ) 0 .0 4 9 0 .0 0 5 (1 0 ) M E A N R E L A T I V E O R G A N W E IG H T S (% o f b o d y w e i g h t ) IV V I V I I I 1 5 25 2 .7 9 0 0 .2 1 2 (1 0 ) 0 .7 3 2 0 .0 8 7 (1 0 ) 2 .7 8 4 0 .1 6 1 (1 0 ) 0 .7 3 4 0 .0 4 3 (1 0 ) 3 .0 9 8 # 0 .1 7 1 (1 0 ) 0 .8 2 5 0 .0 5 6 (1 0 ) 0 .3 7 8 0 .0 3 2 (1 0 ) 0 .3 8 5 0 .0 3 4 (1 0 ) 0 .3 9 0 0 .0 2 0 (1 0 ) 0 .1 8 6 0 .0 2 5 (1 0 ) 0 .2 1 2 0 .0 3 0 (1 0 ) 0 .1 9 4 0 .0 2 8 (1 0 ) 0 .6 7 6 0 .0 6 6 (1 0 ) 0 .6 6 0 0 .0 5 0 (1 0 ) 0 .6 7 8 0 ,0 6 4 (1 0 ) 0 .0 9 1 0 .0 2 2 (1 0 ) 0 .1 1 0 0 .0 2 5 (1 0 ) 0 .1 1 1 0 .0 2 3 (1 0 ) 0 .0 2 2 * 0 .0 0 7 (1 0 ) 0 .0 2 4 . 0 .0 0 3 (1 0 ) 0 .0 2 2 0 .0 0 3 (1 0 ) 0 .0 0 7 0 .0 0 2 (1 0 ) 0 .0 0 7 0 .0 0 1 (1 0 ) 0 .0 0 7 0 .0 0 1 (1 0 ) 0 .0 4 5 0 .0 0 9 (1 0 ) 0 .0 4 8 0 .0 1 2 (1 0 ) 0 .0 4 5 0 .0 0 8 (1 0 ) X 125 3 .9 8 8 # 0 .2 8 7 (1 0 ) 0 .8 5 2 # 0 .0 6 4 (1 0 ) 0 .3 9 8 0 .0 1 8 (1 0 ) 0 .2 1 2 0 .0 2 8 (1 0 ) 0 .6 9 6 0 .0 3 9 (1 0 ) 0 .1 1 2 0 .0 2 6 (1 0 ) 0 .0 2 5 0 .0 0 4 (1 0 ) 0 .0 0 8 0 .0 0 2 (1 0 ) 0 .0 4 9 0 .0 1 0 (1 0 ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI -146 - Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 37 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS RATS DESIGNATED FOR SUBCHRONIC TOXICITY G ro u p : D o s a g e (m g /k g /d a y ) UTERUS/ F IN A L BODY * 1 0 0 II 0 0 .2 4 8 0 .0 6 4 (1 0 ) M E A N R E L A T I V E O R G A N W E IG H T S (% o f b o d y w e i g h t ) IV V I V I I I 1 5 25 0 .2 6 9 0 .0 7 9 (1 0 ) 0 .2 5 5 0 .1 2 3 (1 0 ) 0 .2 6 2 0 .0 4 9 (1 0 ) X 125 0 .2 7 7 0 .1 1 1 (1 0 ) G ro u p : D o s a g e (m g /k g /d a y ) L IV E R / B R A IN * 10 0 K ID N E Y S / B R A IN * 1 0 0 HEART/ B R A IN * 1 0 0 SPLEEN/ B R A IN * 1 0 0 TH YM U S/ B R A IN * 100 5 ADRENAL G LANDS/ B R A IN * 10 0 II 0 4 0 1 .3 4 8 3 4 .7 2 7 (1 0 ) 1 1 3 .7 9 8 8 .3 0 6 (1 0 ) 6 2 .1 0 5 1 4 .5 9 8 (1 0 ) 2 9 .3 5 3 3 .9 4 3 (1 0 ) 1 7 .8 7 0 3 .6 4 5 (1 0 ) 3 .8 6 2 0 .5 4 8 (1 0 ) M E A N R E L A T I V E O R G A N W E IG H T S (% o r g a n t o b r a i n w e i g h t r a t i o ) IV V I V I I I X 1 5 25 125 4 1 7 .0 4 3 5 8 .8 2 4 (1 0 ) 4 2 3 .3 4 2 3 3 .4 8 1 (1 0 ) 4 6 1 .6 1 8 # 5 7 .2 0 4 (10) 5 7 3 .6 1 7 # 4 1 .7 6 6 (1 0 ) 1 0 8 .8 3 1 1 3 .7 9 0 (1 0 ) 5 6 .1 6 3 4 .7 0 3 (1 0 ) 1 1 1 .4 9 2 5 .9 3 1 (1 0 ) 5 8 .4 6 3 5 .0 7 4 (1 0 ) 1 2 2 .5 4 7 1 2 .6 7 0 (1 0 ) 5 8 .0 3 7 6 .5 9 2 (1 0 ) 1 2 2 .3 8 4 # 7 .8 3 1 (1 0 ) 5 7 .3 7 7 4 .2 0 8 (1 0 ) 2 7 .7 5 9 4 .4 6 8 (1 0 ) 3 2 .2 4 3 5 .2 8 0 (1 0 ) 2 8 .6 7 0 3 .6 4 5 (1 0 ) 3 0 .4 1 0 3 .4 4 2 (1 0 ) 1 3 .4 6 6 3 .2 6 7 (1 0 ) 1 6 .8 2 2 4 .3 2 5 (1 0 ) 1 6 .5 2 1 3 .6 9 9 (1 0 ) 1 6 .0 0 6 3 .1 8 7 (1 0 ) 3 .1 8 8 0 .9 0 5 (1 0 ) 3 .6 3 1 0 .4 5 3 (1 0 ) 3 .2 6 0 0 .2 7 8 (1 0 ) 3 .6 1 3 0 .5 2 2 (1 0 ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI -147- pubchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 TABLE 37 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS RATS DESIGNATED FOR SIJBCHRONIC TOXICITY G ro u p : D o s a g e (m g /k g /d a y ) XX 0 M E A N R E L A T I V E O R G A N W E IG H T S (% o r g a n t o b r a i n w e i g h t r a t i o ) XV V I V I I I X 1 5 25 125 T H Y R O ID G L A N D / B R A IN * 1 0 0 O V A R IE S / B R A IN * 1 0 0 UTERUS/ B R A IN * 10 0 1 .0 1 8 0 .1 5 9 (1 0 ) 7 .1 7 6 0 .8 5 7 (1 0 ) 3 5 .8 3 9 8 .6 1 5 (1 0 ) 1 .0 1 9 0 .2 9 0 (1 0 ) 6 .6 7 2 1 .1 6 2 (1 0 ) 3 9 .4 4 2 8 .4 7 7 (1 0 ) 1 .0 4 5 0 .1 4 4 (1 0 ) 7 .2 7 4 1 .5 6 9 (1 0 ) 3 8 .0 0 3 1 4 .9 2 6 (1 0 ) 1 .0 6 8 0 .2 3 5 (1 0 ) 6 .6 5 8 1 .1 1 2 (1 0 ) 3 9 .1 4 4 9 .1 1 5 (1 0 ) 1 .0 8 1 0 .2 1 1 (1 0 ) 6 .9 9 4 1 .3 0 1 (1 0 ) 3 9 .8 7 8 1 6 .3 4 8 (1 0 ) Company Sanitized. Does not contain TSCA CBI -148- Company Sanitized. Does not contain TSCA CBI Eubchronic Toxicity 90-Day Oral Gavage Study in Rats_________ ) TABLE 37 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS RATS DESIGNATED FOR RECOVERY M EAN F IN A L BODY AN D AB S O LU TE ORGAN W E IG H TS (g ra m s ) G ro u p : D o s a g e (m g /k g /d a y ) II 0 X 125 L IV E R K ID N E Y S HEART SPLEEN B R A IN THYMUS ADRENAL GLANDS T H Y R O ID G LAN D O V A R IE S t UTERUS F IN A L BO DY W E IG H T 1 0 .3 0 9 1 .0 4 0 (9 ) 2 .6 0 5 0 :2 7 7 (9 ) 1 .3 3 2 0 .1 5 8 (9 ) 0 .6 3 7 0 .1 0 1 (9 ) 2 .0 5 5 0 .1 0 2 (9 ) 0 .2 3 9 0 .0 7 2 (9 ) 0 .0 8 5 0 .0 2 0 (9 ) 0 .0 2 6 0 .0 0 7 (9 ) 0 .1 3 1 0 .0 4 0 (9 ) 0 .8 8 6 0 .3 6 4 (9 ) 3 3 4 .0 3 3 3 2 .8 4 7 (9 ) 1 0 .3 3 9 1 .9 6 1 (1 0 ) 2 .7 3 8 0 .5 4 1 (1 0 ) 1 .2 3 4 0 .1 7 5 (1 0 ) 0 .5 9 2 0 .0 9 0 (1 0 ) 1 .9 3 6 0 .0 8 6 (1 0 ) 0 :2 6 9 0 .1 0 2 (1 0 ) 0 .0 7 5 0 .0 1 3 (1 0 ) 0 .0 2 6 0 .0 0 4 (1 0 ) 0 .1 2 3 0 .0 3 5 (1 0 ) 0 .9 1 4 0 .3 0 5 (1 0 ) 3 4 8 .9 2 0 6 5 .8 1 8 (1 0 ) -149- ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI | Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 37 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS RATS DESIGNATED FOR RECOVERY G ro u p : D o s a g e (m g /k g /d a y ) L IV E R / F IN A L BODY * 10 0 K ID N E Y S / F IN A L BODY * 100 HEART/ F IN A L BODY * 100 SPLEEN/ F IN A L BODY * 100 B R A IN / F IN A L BODY * 100 TH YM U S/ F IN A L BODY * 1 00 ADRENAL GLANDS/ F IN A L BODY * 100 4 T H Y R O ID G L A N D / F IN A L BODY * 100 O V A R IE S / F IN A L BODY * 100 M E A N R E L A T I V E O R G A N W E IG H T S (% o f b o d y w e i g h t ) II X 0 125 3 .0 9 4 0 .2 4 8 (9 ) 2 .9 7 7 0 .3 4 0 (1 0 ) 0 .7 8 3 0 .0 7 9 (9 ) 0 .3 9 9 0 .0 4 0 (9 ) 0 .7 9 3 0 .1 3 7 (1 0 ) 0 .3 5 7 # 0 .0 3 1 (1 0 ) 0 .1 9 2 0 .0 3 1 (9 ) 0 .6 1 9 0 .0 5 2 (9 ) 0 .0 7 2 0 .0 2 3 (9 ) 0 .0 2 6 0 .0 0 6 (9 ) 0 .0 0 8 0 .0 0 2 (9 ) 0 .1 7 4 0 .0 3 7 (1 0 ) 0 .5 7 0 0 .0 9 6 (1 0 ) 0 .0 7 6 0 .0 1 8 (1 0 ) 0 .0 2 2 0 .0 0 5 (1 0 ) 0 .0 0 8 0 .0 0 2 (1 0 ) 0 .0 3 9 0 .0 1 0 (9 ) 0 .0 3 7 0 .0 1 3 (1 0 ) -150- DuPont-9478 Company Sanitized. Does not contain TSCA CBI ) Subchronic Toxicity 90-Day Oral Gavage Study in Rats ) TABLE 37 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS G ro u p : D o s a g e (m g /k g /d a y ) UTERUS/ F IN A L BODY * 1 00 M E A N R E L A T I V E O R G A N W E IG H T S (% O f b o II X 0 125 0 .2 6 8 0 .1 0 7 (9 ) 0 .2 7 8 0 .1 3 0 (1 0 ) G ro u p : D o s a g e (m g /k g /d a y ) M E A N R E L A T I V E O R G A N W E IG H T S (% o r g a n II X 0 125 L IV E R / B R A IN * 1 0 0 K ID N E Y S / B R A IN * 100 HEART/ B R A IN * 1 0 0 SPLEEN/ B R A IN * 1 0 0 1 THYM US/ B R A IN * 10 0 ADRENAL GLANDS/ B R A IN * 1 0 0 5 0 1 .3 1 1 3 9 .2 5 3 (9 ) 1 2 6 .7 6 5 1 1 .6 1 4 (9 ) 6 4 .8 4 8 7 .4 2 0 (9 ) 3 0 .9 4 4 4 .1 8 4 (9 ) 1 1 .5 4 9 3 .1 1 1 (9 ) 4 .1 1 8 0 .8 6 2 (9 ) 5 3 3 .7 3 7 9 6 .9 1 4 (1 0 ) 1 4 1 .5 9 1 2 8 .3 8 1 (1 0 ) 6 3 .6 7 5 8 .0 7 9 (1 0 ) 3 0 .6 4 2 4 .7 7 7 (1 0 ) 1 3 .8 3 5 4 .9 5 5 (1 0 ) 3 .8 8 2 0 .6 8 9 (1 0 ) - 151- ) DuPont-9478 Subchronic Toxicity 90-Day Oral Gavage si udy in Rats ) TABLE 37 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS RATS DESIGNATED FOR RECOVERY G ro u p : D o s a g e (m g /k g /d a y ) T H Y R O ID G L A N D / B R A IN * 1 0 0 O V A R IE S / B R A IN * 1 0 0 UTERUS/ B R A IN * 1 0 0 M E A N R E L A T I V E O R G A N W E IG H T S (% o r g a n t o b r a i n w e i g h t r a t i o ) II X 0 125 1 .2 6 1 0 .2 9 7 (9 ) 1 .3 4 5 0 . 220( 10). 6 .3 3 0 1 .8 1 3 (9 ) 6 .3 5 5 1 .6 5 0 (1 0 ) 4 2 .8 1 9 1 5 .7 9 4 (9 ) 4 7 .5 0 2 1 6 .3 7 8 (1 0 ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI - 152- ubchronic Toxicity TABLE 37 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS RATS DESIGNATED FOR SATELLITE EVALUATIONS (10-DAY SACRIFICE) G ro u p : D o s a g e (m g /k g /d a y ) L IV E R F IN A L BO DY W E IG H T L IV E R / F IN A L BODY * 100 ii 0 7 .1 8 5 0 .7 8 5 (5 ) 1 7 0 .5 4 1 7 .8 2 5 (5 ) 4 .2 1 3 0 .1 1 8 (5 ) IV 1 7 .1 7 4 0 .9 2 3 (5 ) 1 6 0 .4 4 1 5 .7 0 9 (5 ) 4 .4 7 3 0 .3 5 5 (5 ) VI 5 7 .8 1 4 0 .5 8 2 (5 ) 1 7 0 .7 4 1 6 .1 2 9 (5 ) 4 .5 8 9 0 .2 8 2 (5 ) V III 25 8 .3 6 4 1 .2 4 3 (5 ) 1 7 5 .5 8 1 4 .3 1 5 (5 ) 4 .7 4 8 0 .4 2 4 (5 ) X 125 1 0 .1 3 4 1 .1 2 9 (5 ) 1 8 2 .5 2 1 8 .0 6 0 (5 ) 5 .5 5 7 0 .3 4 4 (5 ) RATS DESIGNATED FOR SATELLITE EVALUATIONS (FINAL SACRIFICE) G r o u p - X I IV V I D o s a g e (m g /k g /d a y ) 0 1 5 L IV E R F IN A L BO DY W E IG H T | L IV E R / F IN A L BODY * 100 1 2 .4 4 4 2 .9 2 2 (5 ) 3 2 5 .9 0 0 4 6 .6 0 2 (5 ) 3 .7 8 4 0 .4 4 5 (5 ) 1 1 .8 9 7 1 .6 3 7 (5 ) 3 3 6 .1 6 0 2 9 .2 7 8 (5 ) 3 .5 3 7 0 .3 4 0 (5 ) 1 2 .7 1 1 0 .5 5 3 (5 ) 3 3 5 .9 2 0 4 4 .5 7 6 (5 ) 3 .8 2 8 0 .4 4 9 (5 ) D a ta s u m m a riz e d a s : M ean S ta n d a rd D e v ia tio n (n ) # S t a t i s t i c a l l y s i g n i f i c a n t -d i f f e r e n c e a t p < 0 . 0 5 b y J o n c k h e e r e - T e r p s t r a t r e n d t e s t . V III 25 1 3 .5 2 7 3 .3 0 1 (5 ) 3 6 6 .8 4 0 5 3 .7 7 1 (5 ) 3 .6 5 1 0 .4 3 4 (5 ) X 125 1 2 .7 2 9 1 .3 0 5 (5 ) 3 5 9 -3 2 0 4 4 .2 8 7 (5 ) 3 .5 6 7 0 .4 0 2 (5 ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI - 153- Company Sanitized. Does n o t c o n ta in TSCA C B i ______________ Subchronic Toxicity )-Day Oral Gavage Study in Rats TABLE 38 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS RATS DESIGNATED FOR SUBCHRONIC TOXICITY LE S IO N S TREATMENT L E S IO N IN C ID E N C E ( N u m e r ic ) M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX L IV E R NO A B N O R M A LIT Y D E TE C TE D K ID N E Y S NO A B N O R M A L IT Y D E TE C TE D D IL A T A T IO N , R IG H T . LUNGS NO A B N O R M A LIT Y D E TE C TE D HEART NO A B N O R M A L IT Y D E TEC TED SKELETAL MUSCLE f NO A B N O R M A L IT Y D E TE C TE D SPLEEN NO A B N O R M A L IT Y D ETEC TED (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 9 1 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 F ig u r e s i n p a r e n th e s e s i s th e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e The absence o f a num ber in d ic a te s th e fin d in g s p e c ifie d w as n o t id e n t if ie d - 154- DuPont-9478 Company Sanitized. Does not contain TSCA CBI 90-Day Oral Gavage ubchronic Toxicity y in Rats TABLE 38 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS RATS DESIGNATED FOR SIJBCHRONIC TOXICITY LE S IO N S TREATMENT L E S IO N IN C ID E N C E ( N u m e r ic ) M a le s 0 mg /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX AORTA NO A B N O R M A LIT Y D E TE C TE D B R A IN NO A B N O R M A LIT Y D E TE C TE D S P IN A L CORD NO A B N O R M A L IT Y D E TE C TE D STOMACH NO A B N O R M A L IT Y D E TE C TE D DUODENUM NO A B N O R M A LIT Y D E TE C TE D JEJUNUM ' NO A B N O R M A LIT Y D E TE C TE D (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 F ig u r e s i n p a r e n th e s e s i s th e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e The absence o f a num ber in d ic a te s th e fin d in g s p e c ifie d w as n o t id e n t if ie d - 155- ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI ubchronic Toxicity 90-Day Oral Gavage i mly in Rats LE S IO N S TABLE 38 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN M ATE RATS RATS DESIGNATED FOR SUBCHRONIC TOXICITY TREATMENT L E S IO N IN C ID E N C E (N u m e ric ) M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX IL E U M NO A B N O R M A LIT Y D E TE C TE D PANCREAS NO A B N O R M A LIT Y D E TEC TED CECUM NO A B N O R M A LIT Y D E TEC TED COLON NO A B N O R M A LIT Y D E TEC TED RECTUM NO A B N O R M A LIT Y D E TE C TE D M E S E N TE R IC LYM PH NODE NO A B N O R M A LIT Y D E TEC TED (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10. (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 F ig u r e s i n p a r e n th e s e s i s th e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e The absence o f a num ber in d ic a te s th e fin d in g s p e c ifie d w as n o t id e n t if ie d -156- DuPont-9478 Company Sanitized. Does not contain TSCA CBI 90-Day Oral Gavage ubchronic Toxicity y in Rats LE S IO N S TABLE 38 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS RATS DESIGNATED FOR SUBCHRONIC TOXICITY TREATMENT L E S IO N IN C ID E N C E (N u m e ric ) M a le s 0 m g /k g I 1 m g /k g III 5 mg /k g V 25 m g /k g V II 125 m g /k g IX S A L IV A R Y G LANDS NO A B N O R M A L IT Y D E TE C TE D M A N D IB U LA R LYM PH NODE NO A B N O R M A L IT Y D E TEC TED THYMUS NO A B N O R M A L IT Y D E TE C TE D ADRENAL GLANDS NO A B N O R M A L IT Y D E TE C TE D S C IA T IC NERVE NO A B N O R M A LIT Y D E TEC TED P IT U IT A R Y GLAND NO A B N O R M A L IT Y D E TE C TE D (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 GO) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 F ig u r e s i n p a r e n th e s e s i s th e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e The a b se n ce o f a n u m b e r in d ic a te s th e fin d in g s p e c ifie d w as n o t id e n t if ie d -157- DuPont-9478 Company Sanitized. Does not contain TSCA CBI ubchronic Toxicity ?0-Day Oral Gavage ! iBy in Rats LE S IO N S TABLE 38 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS RATS DESIGNATED FOR SUBCHRONIC TOXICITY TREATMENT L E S IO N IN C ID E N C E (N u m e r ic ) M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX T H Y R O ID G LAN D NO A B N O R M A LIT Y D E TE C TE D P A R A T H Y R O ID G LA N D S NO A B N O R M A LIT Y D E TE C TE D TRACHEA NO A B N O R M A L IT Y D E TE C TE D ESOPHAGUS NO A B N O R M A L IT Y D E TE C TE D P H A R Y N X /LA R Y N X NO A B N O R M A LIT Y D E FE C TE D E Y E (S ) W IT H O P T IC NERVE NO A B N O R M A LIT Y D E TE C TE D GO) 10 (10) 10 (10) 10 (10) 10 (10) io (10) "10 GO) 10 (10) 10 GO) 10 (10) 10 (10) 10 GO) 10 GO) 10 GO) 10 GO) 10 GO) 10 GO) 10 GO) 10 GO) GO) 10 10 GO) GO) 10 10 GO) GO) 10 10 GO) GO) 10 10 GO) GO) 10 10 GO) (9.) 10 9 F ig u r e s i n p a r e n th e s e s i s th e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T he a bsence o f, a n u m b e r in d ic a te s th e f in d in g s p e c ifie d w as n o t id e n t if ie d - 158- ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI 'ubchronic Toxicity 90-Day Oral Gavage 53y in Rats_________ LE S IO N S TABLE 38 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS RATS DESIGNATED FOR SUBCHRONIC TOXICITY TREATMENT L E S IO N IN C ID E N C E (N u m e ric ) M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX S K IN NO A B N O R M A LIT Y D E TE C TE D A L O P E C IA , R IG H T . PROSTATE NO A B N O R M A L IT Y -D E T E C T E D S E M IN A L V E S IC L E S NO A B N O R M A LIT Y D E TE C TE D U R IN A R Y BLA D D E R NO A B N O R M A LIT Y D E TE C TE D D IL A T A T IO N . TESTES s NO A B N O R M A LIT Y D E TE C TE D SM ALL, U N IL A T E R A L . D IS C O L O R A T IO N , OPAQ UE. (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 91 (1 0 ) 9 1 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 9 1 (1 0 ) 9 1 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (10.) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 9 1 F ig u r e s i n p a r e n th e s e s i s th e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e The absence o f a num ber in d ic a te s th e fin d in g s p e c ifie d w as n o t id e n t if ie d -159- ) DuPont-9478 1 '^ ^ ^ ^ ^ ^ ^ ^ i ^ S u b c h r o n i c Toxicity 90-Day Oral Gavage Study in Rats L E S IO N S TABLE 38 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS RATS DESIGNATED FOR StJBCHRONTC TOXICITY TREATM ENT L E S IO N IN C ID E N C E ( N u m e r ic ) M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX E P ID ID Y M ID E S N O A B N O R M A L IT Y D E T E C T E D S M A L L , U N IL A T E R A L . F E M U R /K N E E J O IN T N O A B N O R M A L IT Y D E T E C T E D STERNUM N O A B N O R M A L IT Y D E T E C T E D NOSE N O A B N O R M A L IT Y D E T E C T E D (1 0 ) 1 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 3 1 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 F ig u r e s i n p a r e n th e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c if ie d w a s n o t id e n t if ie d ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI -160- Company Sanitized. Does not contain TSCA CBI ubchronie Toxicity 90-Day Oral Gavage Si i3y in Rats ) L E S IO N S TABLE 38 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS RATS DESIGNATED FOR RECOVERY TREATM ENT L E S IO N IN C ID E M a le s 0 m g /k g I 125 m g /k g IX L IV E R N O A B N O R M A L IT Y D E T E C T E D K ID N E Y S N O A B N O R M A L IT Y D E T E C T E D C A L C U L U S \C A L C U L I, R IG H T . LUNG S N O A B N O R M A L IT Y D E T E C T E D HEART N O A B N O R M A L IT Y D E T E C T E D S K E LE T A L M USCLE N O A B N O R M A L IT Y D E T E C T E D SPLEEN N O A B N O R M A L IT Y D E T E C T E D (1 0 ) (1 0 ) 10 10 (1 0 ) . (1 0 ) 10 9 1 (1 0 ) (1 0 ) 10 10 (1 0 ) . (1 0 ) 10 10 (1 0 ) (1 0 ) 10 10 (1 0 ) (1 0 ) 10 . 10 F ig u r e s i n p a r e n t h e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e fin d in g s p e c ifie d w as n o t id e n t if ie d -161- DuPont-9478 Company Sanitized. Does not contain TSCA CBI |>ubchronic Toxicity 90-Day Oral Gavage i 5y in Rats L E S IO N S TABLE 38 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS RATS DESIGNATED FOR RECOVERY TREATM ENT L E S IO N IN C ID E M a le s 0 m g /k g I 125. m g /k g IX AO R TA N O A B N O R M A L IT Y D E T E C T E D B R A IN N O A B N O R M A L IT Y D E T E C T E D S P IN A L CO RD N O A B N O R M A L IT Y D E T E C T E D STOM ACH N O A B N O R M A L IT Y D E T E C T E D DUODENUM N O A B N O R M A L IT Y D E T E C T E D JEJU N U M N O A B N O R M A L IT Y D E T E C T E D (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 F ig u r e s i n p a r e n t h e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c if ie d w a s n o t id e n t if ie d - 162- ) DuPont-9478 90-Day Oral Gavage lubchronic Toxicity iy in Rats ; L E S IO N S TABLE 38 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS RATS DESIGNATED FOR RECOVERY TREATM ENT L E S IO N IN C ID E M a le s 0 m g /k g I 125 m g /k g IX IL E U M N O A B N O R M A L IT Y D E T E C T E D PANCREAS N O A B N O R M A L IT Y D E T E C T E D CECUM N O A B N O R M A L IT Y D E T E C T E D CO LO N N O A B N O R M A L IT Y D E T E C T E D RECTUM N O A B N O R M A L IT Y D E F E C T E D M E S E N T E R IC L Y M P H N O D E N O A B N O R M A L IT Y D E T E C T E D (1 0 ! (1 0 ) 10 10 (1 0 ) (1 0 ) 10 10 (1 0 ) 10 (1 0 ) To (1 0 ) (1 0 ) 10 10 (1 0 ) (1 0 ) 10 10 (1 0 ) (1 0 ) 110 10 F ig u r e s i n p a r e n t h e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c ifie d w a s n o t id e n t if ie d Company Sanitized. Does not contain TSCA CBI -163- Company Sanitized. Does not contain TSCA CBI ^ H B H M m H i H t t i u b c h r o n i c Toxicity 90-Day Oral Gavage Study in Rats_________ L E S IO N S TABLE 38 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS RATS DESIGNATED FOR RECOVERY TREATM ENT L E S IO N IN C ID E M a le s 0 m g /k g I 125 m g /k g IX S A L IV A R Y G LA N D S N O A B N O R M A L IT Y D E T E C T E D m a n d ib u l a r LY M P H NO D E N O A B N O R M A L IT Y D E T E C T E D THYM US N O A B N O R M A L IT Y D E T E C T E D ADRENAL G LANDS N O A B N O R M A L IT Y D E T E C T E D S C IA T IC N E R V E N O A B N O R M A L IT Y D E T E C T E D P IT U IT A R Y G LA N D N O A B N O R M A L IT Y D E T E C T E D (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) .1 0 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 F ig u r e s i n p a r e n th e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e fin d in g s p e c ifie d w a s n o t id e n t if ie d -164 - ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI c Upubchronic Toxicity 90-Day Oral Gavage iudy in Rats ___ ) L E S IO N S TABLE 38 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS RATS DESIGNATED FOR RECOVERY TREATM ENT L E S IO N IN C ID E M a le s 0 m g /k g I 125 m g /k g IX T H Y R O ID G L A N D (1 0 ) N O A B N O R M A L IT Y D E T E C T E D 10 P A R A T H Y R O ID G L A N D S (1 0 ) N O A B N O R M A L IT Y D E T E C T E D 10 TRACHEA (1 0 ) N O A B N O R M A L IT Y D E T E C T E D 10 ESOPHAGUS (1 0 ) N O A B N O R M A L IT Y D E T E C T E D 10 P H A R Y N X /L A R Y N X (1 0 ) N O A B N O R M A L IT Y D E T E C T E D 10 E Y E (S ) W IT H O P T IC N E R V E (1 0 ) N O A B N O R M A L IT Y D E T E C T E D . 10 F ig u r e s i n p a r e n t h e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e fin d in g s p e c ifie d w a s n o t id e n t if ie d (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 -165- ) DuPont-9478 Company Sanitized. Does not contain TSCA MSubchronic Toxicity 90-Day Oral Gavage :udy in Rats_______ ) L E S IO N S TABLE 38 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS RATS DESIGNATED FOR RECOVERY TREATM ENT L E S IO N IN C ID E M a le s 0 m g /k g I 125 m g /k g IX S K IN N O A B N O R M A L IT Y D E T E C T E D PR O STATE N O A B N O R M A L IT Y D E T E C T E D S E M IN A L V E S IC L E S N O A B N O R M A L IT Y D E T E C T E D U R IN A R Y B L A D D E R N O A B N O R M A L IT Y D E T E C T E D TESTES N O A B N O R M A L IT Y D E T E C T E D E P ID ID Y M ID E S N O A B N O R M A L IT Y D E T E C T E D (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 F ig u r e s i n p a r e n th e s e s is " t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c if ie d w a s n o t id e n t if ie d O CD ) DuPont-9478 90-Day Oral Gavage Subchronic Toxicity ly in Rats L E S IO N S TABLE 38 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS RATS DESIGNATED FOR RECOVERY TREATM ENT L E S IO N IN C ID E M a le s 0 m g /k g I 125 m g /k g IX F E M U R /K N E E . J O IN T N O A B N O R M A L IT Y D E T E C T E D STERNUM N O A B N O R M A L IT Y D E T E C T E D NOSE N O A B N O R M A L IT Y D E T E C T E D (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 GO) 10 (1 0 ) 10 (1 0 ) 10 F ig u r e s i n p a r e n t h e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c ifie d w a s n o t id e n t if ie d ) DuPont-9478 Company Sanitized. Does not contain TSCA C8I -167- Company S a n itiz e d . D o e s not contain TSCA C B I Subchronic Toxicity 90-Day Oral Gavage ! 3y in Rats TABLE 38 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS RATS DESIGNATED FOR SATELLITE EVALUATIONS L E S IO N S TREATM ENT L E S IO N IN C ID E N C E ( N u m e r ic ) 0 ra g / k g I 1 m g /k g III M a le s 5 m g /k g V 25 m g /k g V II 125 m g /k g IX L IV E R N O A B N O R M A L IT Y D E T E C T E D K ID N E Y S N O A B N O R M A L IT Y D E T E C T E D LUNG S N O A B N O R M A L IT Y D E T E C T E D HEART N O A B N O R M A L IT Y D E T E C T E D S K E LE T A L M USCLE N O A B N O R M A L IT Y D E F E C T E D SPLEEN N O A B N O R M A L IT Y D E T E C T E D (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 F ig u r e s i n p a r e n t h e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c ifie d w a s n o t id e n t if ie d (5 ) 5 (5 ) 5 (5 ) 5 (5 ) 5 (5 ) 5 (5 ) 5 -168- DuPont-9478 Company Sanitized. Does not contain TSCA CBI 90-Day Oral Gavage ubchronic Toxicity y in Rats TABLE 38 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN M ATE RATS RATS DESIGNATED FOR SATELLITE EVALUATIONS L E S IO N S TREATM ENT L E S IO N IN C ID E N C E ( N u m e r ic ) M a le s 0 mg/kg I 1 mg/kg III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX AO R TA N O A B N O R M A L IT Y D E T E C T E D B R A IN N O A B N O R M A L IT Y D E T E C T E D S P IN A L CORD N O A B N O R M A L IT Y D E T E C T E D STOM ACH N O A B N O R M A L IT Y D E T E C T E D DUODENUM N O A B N O R M A L IT Y D E T E C T E D JEJU N U M N O A B N O R M A L IT Y D E T E C T E D ; (5 ) 5 (5 ) 5 (5 ) 5 (5 ) 5 (5 ) 5 (5 ) 5 (5 ) (5 ) 55 (5 ) (5 ) 55 (5 ) (5 ) 55 (5 ) (5 ) 55 (5 ) (5 ) 55 (5 ) (5 ) 55 F ig u r e s i n p a r e n t h e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c ifie d w a s n o t id e n t if ie d (5) 5 (5) 5 (5 ) 5 (5 ) 5 (5 ) 5 (5) 5 (5 ) 5 (5) 5 (5) 5 (5 ) 5 15! 5 (5 ) 5 -169- DuPont-9478 Company Sanitized. Does not contain TSCA CBI 90-Day Oral Gavage , iSubchronic Toxicity lay in Rats ) ' L E S IO N S TABLE 38 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS RATS DESIGNATED FOR SATELLITE EVALUATIONS TREATM ENT L E S IO N IN C ID E N C E ( N u m e r ic ) M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX IL E U M N O A B N O R M A L IT Y D E T E C T E D PANCREAS N O A B N O R M A L IT Y D E T E C T E D CECUM N O A B N O R M A L IT Y D E T E C T E D C O LO N N O A B N O R M A L IT Y D E T E C T E D RECTUM NO. A B N O R M A L IT Y D E T E C T E D M E S E N T E R IC L Y M P H N O D E N O A B N O R M A L IT Y D E T E C T E D (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 ) 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 F ig u r e s i n p a r e n t h e s e s i s t h e n u m b e r o a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c ifie d w a s n o t id e n t if ie d -170- ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI Subchronic Toxicity 90-Day Oral Gavage :Tuay in Rats L E S IO N S TABLE 38 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS RATS DESIGNATED FOR SATELLITE EVALUATIONS TREATM ENT L E S IO N IN C ID E N C E ( N u m e r ic ) M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX S A L IV A R Y G LA N D S N O A B N O R M A L IT Y D E T E C T E D M A N D IB U L A R L Y M P H N O D E N O A B N O R M A L IT Y D E T E C T E D THYM US N O A B N O R M A L IT Y D E T E C T E D AD R EN AL G LANDS N O A B N O R M A L IT Y D E T E C T E D S C IA T IC N E R V E N O A B N O R M A L IT Y D E T E C T E D 1 P IT U IT A R Y G LA N D N O A B N O R M A L IT Y D E T E C T E D (5)( 5 ) ( 5 ) (5 ) (5 ) 5 5 5 55 (5 ) (5 ) (5 ) (5 ) (5 ) 55555 ( 5 ) ( 5 ) (5) ( 5 ) (5) 55 5 5 5 (5)( 5 ) ( 5 ) (5 ) (5 ) 5 5 5' 5 5 ( 5 ) ( 5 ) (5) (5) ( 5 ) 5 555 5 5)1 5 ) ( 5 ) ( 5 ) ( 5 ) 55555 F ig u r e s i n p a r e n t h e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c ifie d w a s n o t id e n t if ie d -171- ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI ubchronic Toxicity 90-Day Oral Gavage E3y in Rats L E S IO N S TABLE 38 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS RATS DESIGNATED FOR SATELLITE EVALUATIONS TREATM ENT L E S IO N IN C ID E N C E ( N u m e r ic ) M a le s 0 m g /k g I 1 m g /k g III 5 ra g /k g V 25 m g /k g V II 125 m g /k g IX T H Y R O ID G LA N D N O A B N O R M A L IT Y D E T E C T E D P A R A T H Y R O ID G L A N D S N O A B N O R M A L IT Y D E T E C T E D TRACHEA N O A B N O R M A L IT Y D E T E C T E D ESOPHAGUS N O A B N O R M A L IT Y D E T E C T E D P H A R Y N X /L A R Y N X N O A B N O R M A L IT Y D E T E C T E D E Y E ( S ) W IT H O P T IC N E R V E N O A B N O R M A L IT Y D E T E C T E D (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 ) 55 (5 ) (5 ) 55 (5 ) ,5 (5 ) 5 (5 ) (5 ) 55 (5 ) (5 ) 55 (5 ) . (5 ) 55 F ig u r e s i n p a r e n th e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e fin d in g s p e c ifie d w a s n o t id e n t if ie d - 172- ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI 90-Day Oral Gavage pubchronic Toxicity ly in Rats l e s io n s TABLE 38 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS RATS DESIGNATED FOR SATELLITE EVALUATIONS TREATM ENT L E S IO N IN C ID E N C E ( N u m e r ic ) M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX S K IN N O A B N O R M A L IT Y D E T E C T E D PR O STATE N O A B N O R M A L IT Y D E T E C T E D S E M IN A L V E S IC L E S ' N O A B N O R M A L IT Y D E T E C T E D U R IN A R Y B L A D D E R N O A B N O R M A L IT Y D E T E C T E D TESTES N O A B N O R M A L IT Y D E T E C T E D E P ID ID Y M ID E S N O A B N O R M A L IT Y D E T E C T E D (5 ) (5 ) (5 ) (5 ) 5555 (5 ) (5 ) (5 ) (5 ) 555 5 (5 ) (5 ) (5 ) (5 ) 5555 (5 ) !5 ) (5 ) (5 ) ,5 5 5 5 ( 5 ) ( 5 ) ( 5 ) 15) 55 5 5 (5 ) (5 ) (5 ) (5 ) 55 5 5 F ) 9 u r s i n p a r e n th e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c if ie d w a s n o t id e n t if ie d (5 ) 5 (5 ) 5 (5 ) 5 (5 ) 5 (5 ) 5 (5) 5 - 173- DuPont-9478 Day Oral Gavage Subchronic Toxicity y in Rats_______ ) TABLE 38 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS RATS DESIGNATED FOR SATELLITE EVALUATIONS L E S IO N S TREATM ENT L E S IO N IN C ID E N C E ( N u m e r ic ) M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX F E M U R /K N E E J O IN T N O A B N O R M A L IT Y D E T E C T E D STERNUM N O A B N O R M A L IT Y D E T E C T E D NOSE N O A B N O R M A L IT Y D E T E C T E D (5 ) (5 ) (5 ) (5 ) (5 ) 55 5 5 5 ( 5 ) (5) ( 5 ) ( 5 ) (5) 55 5 5 5 ( 5 ) (5) (5) ( 5 ) (5) 55555 F ig u r e s i n p a r e n th e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c if ie d w a s n o t id e n t if ie d I ) DuPont-9478 Company Sanitized. Does not contain TSCA CBJ -174- Company Sanitized. Does not contain TSCA C B I 90-Day Oral Gavage iiubchronic Toxicity y in Rats ) L E S IO N S TABLE 39 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS RATS DESIGNATED FOR SUBCHRONIC TOXTC.TTY TREATM ENT L E S IO N IN C ID E N C E ( N u m e r ic ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V IZ I 125 m g /k g X L IV E R N O A B N O R M A L IT Y D E T E C T E D K ID N E Y S N O A B N O R M A L IT Y 'D E T E C T E D . LUNG S N O A B N O R M A L IT Y D E T E C T E D HEART N O A B N O R M A L IT Y D E T E C T E D LARG E. S K E LE TA L M USCLE $ N O A B N O R M A L IT Y D E T E C T E D ( ID 11 (1 1 ) 11 (U ) 11 (1 1 ) 10 1 (1 1 ) 11 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) . 10 (1 0 ) 10 (IQ ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10, (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 F ig u r e s i n p a r e n th e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c if ie d w a s n o t id e n t if ie d N = ll in G ro u p I I r e f le c t s 1 e a r ly d e a th 9 0 d a y tim e p e r io d -175- ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI ubchronic Toxicity 90-Day Oral Gavage tudy in Rats L E S IO N S TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS RATS DESIGNATED FOR SUBCHRONIC TOXICITY TREATM ENT L E S IO N IN C ID E N C E ( N u m e r ic ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 m g /k g X SPLEEN , N O A B N O R M A L IT Y D E T E C T E D AO R TA N O A B N O R M A L IT Y D E T E C T E D B R A IN N O A B N O R M A L IT Y D E T E C T E D S P IN A L CO RD NO a b n o r m a l it y d e t e c t e d STO M AC H N O A B N O R M A L IT Y D E T E C T E D F L U ID , R E D . (1 1 ) 11 (1 1 ) 11 (1 1 ) 11 (1 1 ) 11 (1 1 ) 10 1 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ); 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 F ig u r e s i n p a r e n t h e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e fin d in g s p e c ifie d w as n o t id e n t if ie d N = ll in G ro u p X I r e f le c t s 1 e a r ly d e a th 9 0 d a y tim e p e r io d -176- ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI Bubchronic Toxicity 90-Day Oral Gavage St ly in Rats L E S IO N S TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS RATS DESIGNATED FOR SUBCHRONIC TOXICITY TREATM ENT L E S IO N IN C ID E N C E ( N u m e r ic ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 . m g /k g X DUODENUM N O A B N O R M A L IT Y D E T E C T E D JEJU N U M N O A B N O R M A L IT Y D E T E C T E D IL E U M N O A B N O R M A L IT Y D E T E C T E D PANCREAS N O A B N O R M A L IT Y D E T E C T E D CECUM N O A B N O R M A L IT Y D E T E C T E D C O LO N N O A B N O R M A L IT Y D E T E C T E D (1 1 ) 11 (1 1 ) 11 (1 1 ) 11 (1 1 ) 11 (1 1 ) 11 (ID 11 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 GO) (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 10 (1 0 ) (1 0 ) 10 10 (1 0 ) (1 0 ) 10 10 (1 0 ) - (1 0 ) 10 10 (1 0 ) (1 0 ) 10 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 F ig u r e s i n p a r e n t h e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c ifie d w a s n o t id e n t if ie d N = ll in G ro u p I I r e f le c t s 1 e a r ly d e a th 9 0 d a y tim e p e r io d - 177 - ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI ___________ __Subchronic Toxicity 90-Day Oral Gavage Study in Rats_________ L E S IO N S TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS RATS DESIGNATED FOR SUBCHRONIC TOXICITY TREATM ENT L E S IO N IN C ID E N C E ( N u m e r ic ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 m g /k g X RECTUM N O A B N O R M A L IT Y D E T E C T E D M E S E N T E R IC L Y M P H N O D E , N O A B N O R M A L IT Y D E T E C T E D S A L IV A R Y G LA N D S N O A B N O R M A L IT Y D E T E C T E D M A N D IB U L A R L Y M P H N O D E N O A B N O R M A L IT Y D E T E C T E D THYM US N O A B N O R M A L IT Y D E T E C T E D AD R EN AL GLANDS N O A B N O R M A L IT Y D E T E C T E D ill) 11 (1 1 ) 11 (1 1 ) 11 (1 1 ) 11 (1 1 ) 11 (1 1 ) 11 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 ' (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 F ig u r e s i n p a r e n th e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c if ie d w a s n o t id e n t if ie d N = ll in G ro u p I I r e f le c t s 1 e a r ly d e a th 9 0 d a y tim e p e r io d -178- ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI ___ Subchronic Toxicity *90-Day Oral Gavage StuSy in Rats_________ L E S IO N S TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS RATS DESIGNATED FOR SIJBC.HRONTC TOXICITY TREATM ENT L E S IO N IN C ID E N C E ( N u m e r ic ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 m g /k g X S C IA T IC N E R V E N O A B N O R M A L IT Y D E T E C T E D P IT U IT A R Y G LA N D N O A B N O R M A L IT Y D E T E C T E D T H Y R O ID G LA N D N O A B N O R M A L IT Y D E T E C T E D P A R A T H Y R O ID G L A N D S N O A B N O R M A L IT Y D E T E C T E D TRACHEA N O A B N O R M A L IT Y D E F E C T E D ESOPHAGUS N O A B N O R M A L IT Y D E T E C T E D ( ID 11 (1 1 ) 11 (1 1 ) 11 (1 1 ) 11 (1 1 ) 11 (1 1 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) (1 0 ) 10 10 (1 0 ) (1 0 ) 10 10 (1 0 ) (1 0 ) 10 10 (1 0 ) ' (1 0 ) 10 10 (1 0 ) (1 0 ) 10 (1 0 ) . 10 (1 0 ) 10 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) , 10 (1 0 ) 10 F ig u r e s in . p a r e n th e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c ifie d w a s n o t id e n t if ie d N = ll in G ro u p I I r e f le c t s 1 e a r ly d e a th 9 0 d a y tim e p e r io d -179- ) DuPont-9478 Company Sanitized. Does not contain TSCA C B I 90-Day Oral Gavage Subchronic Toxicity [yin Rats TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS RATS DESIGNATED FOR SUBCHRONIC TOXICITY L E S IO N S TREATM ENT L E S IO N IN C ID E N C E ( N u m e r ic ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 m g /k g X ESOPHAGUS P E R F O R A T IO N . P H A R Y N X /L A R Y N X N O A B N O R M A L IT Y D E T E C T E D E Y E (S ) W IT H O P T IC N E R V E N O A B N O R M A L IT Y D E T E C T E D S K IN N O A B N O R M A L IT Y D E T E C T E D S T A IN , R E D , N O S E . M AM M ARY G LA N D (F E M A L E ) N O A B N O R M A L IT Y D E T E C T E D (U ) 1 (1 0 ) (1 0 ) (1 0 ) (1 0 ) (1 1 ) 11 (1 1 ) 11 (1 1 ) 10 1 (1 0 ) (1 0 ) 10 10 (1 0 ) (1 0 ) 10 10 (1 0 ) (1 0 ) 10 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 1 ) (1 0 ) (1 0 ) (1 0 ) 1 0 ) k 11 10 10 10 10 F ig u r e s i n p a r e n th e s e s i s th e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c ifie d w a s n o t id e n t if ie d N = ll i n G ro u p I I r e f le c t s 1 e a r ly d e a th 9 0 d a y tim e p e r io d - 180- DuPont-9478 Company Sanitized. Does not contain TSCA CBI [Subchronic Toxicity 90-Day Oral Gavage fudy in Rats L E S IO N S TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS RATS DESIGNATED FOR SUBCHRONIC TOXTCITY TREATM ENT L E S IO N IN C ID E N C E ( N u m e r ic ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 m g /k g X O V A R IE S N O A B N O R M A L IT Y D E T E C T E D UTERUS N O A B N O R M A L IT Y D E T E C T E D V A G IN A N O A B N O R M A L IT Y D E T E C T E D U R IN A R Y B L A D D E R N O A B N O R M A L IT Y D E T E C T E D F E M U R /K N E E J O IN T N O A B N O R M A L IT Y p E T E C T E D STERNUM N O A B N O R M A L IT Y D E T E C T E D (ID 11 (ID 11 (1 1 ) 11 (1 1 ) 11 .(1 1 ) 11 (1 1 ) 'll (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ). 10 (1 0 ) To (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 GO) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 F ig u r e s i n p a r e n th e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c if ie d w a s n o t id e n t if ie d N = ll in G ro u p I I r e f le c t s 1 e a r ly d e a th 9 0 d a y tim e p e r io d -181- DuPont-9478 L E S IO N S TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS RATS DESIGNATED FOR SUBCHRONIC TOXICITY TREATM ENT L E S IO N IN C ID E N C E ( N u m e r ic ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 m g /k g X NOSE N O A B N O R M A L IT Y D E T E C T E D (1 1 ) 11 (1 0 ) (1 0 ) 10 10 (1 0 ) 10 (1 0 ) 10 F ig u r e s i n p a r e n t h e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c ifie d w as n o t id e n t if ie d N = ll in G ro u p I I r e f le c t s 1 e a r ly d e a th 9 0 d a y tim e p e r io d ) DuPont-9478 Company Sanitized. Does not contain TSCA CBi -182- Company Sanitized. Does not contain TSCA ubchronic Toxicity 90-Day Oral Gavage ! y in Rats L E S IO N S TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS RATS DESIGNATED FOR RECOVERY TREATM ENT L E S IO N IN C ID E F e m a le s 0 m g /k g II 125 m g /k g X L IV E R N O A B N O R M A L IT Y D E T E C T E D K ID N E Y S N O A B N O R M A L IT Y D E T E C T E D LUNG S N O A B N O R M A L IT Y D E T E C T E D HEART N O A B N O R M A L IT Y D E T E C T E D - S K E LE T A L M USCLE N O A B N O R M A L IT Y D E F E C T E D SPLEEN N O A B N O R M A L IT Y D E T E C T E D (9 ) 9 (9 ) 9 (9 ) 9 (9 ) 9 (9 ) 9 (9 ) 9 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 F ig u r e s i n p a r e n t h e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c ifie d w a s n o t id e n t if ie d N = 9 i n G ro u p IX r e f le c t s 1 e a r ly d e a th in 9 0 d a y tim e p e r io d O 03 ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI 90-Day Oral Gavage ubchronic Toxicity y in Rats ) L E S IO N S TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS RATS DESIGNATED FOR RECOVERY TREATM ENT L E S IO N IN C ID E F e m a le s 0 m g /k g II 125 m g /k g X AO R TA N O A B N O R M A L IT Y D E T E C T E D B R A IN N O A B N O R M A L IT Y D E T E C T E D S P IN A L CO RD N O A B N O R M A L IT Y D E T E C T E D STO M ACH N O A B N O R M A L IT Y D E T E C T E D DUODENUM NO A B N O R M A L IT Y D E T E C T E D JEJU N U M ' N O A B N O R M A L IT Y D E T E C T E D (9 ) 9 (9 ) 9 (9 ) 9 (9 ) 9 (9 ) 9 (9 ) g (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 F ig u r e s i n p a r e n th e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c if ie d w a s n o t id e n t if ie d N = 9 in G ro u p I I r e f le c t s 1 e a r ly d e a th in 9 0 d a y tim e p e r io d - 184 - ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI lubchronic Toxicity 90-Day Oral Gavage S Sy in Rats L E S IO N S TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS RATS DESIGNATED FOR RECOVERY TREATM ENT L E S IO N IN C ID E F e m a le s 0 m g /k g II 125 m g /k g X IL E U M (9 ) N O A B N O R M A L IT Y D E T E C T E D 9 PANCREAS N O A B N O R M A L IT Y D E T E C T E D (9 ) 9 CECUM N O A B N O R M A L IT Y D E T E C T E D (9 ) 9 C O LO N (9 ) N O A B N O R M A L IT Y D E T E C T E D 9 RECTUM N O A B N O R M A L IT Y D E T E C T E D M E S E N T E R IC L Y M P H N O D E N O A B N O R M A L IT Y D E T E C T E D (9 ) 9 I (9) 9 F ig u r e s i n p a r e n th e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c if ie d w a s n o t id e n t if ie d N = 9 in G ro u p I I r e f le c t s 1 e a r ly d e a th in 9 0 d a y tim e p e r io d GO) 10 GO) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 GO) 10 -185- ) DuPont-9478 Company Sanitized. Does not contain TSCA C8I Subchronic Toxicity 90-Day Oral Gavage lay in Rats L E S IO N S TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS RATS DESIGNATED FOR RECOVERY TREATM ENT L E S IO N IN C ID E F e m a le s 0 m g /k g II 125 m g /k g X S A L IV A R Y G LA N D S N O A B N O R M A L IT Y D E T E C T E D M A N D IB U L A R L Y M P H N O D E n o A b n o r m a l it y d e t e c t e d THYM US N O A B N O R M A L IT Y D E T E C T E D ADRENAL G LANDS N O A B N O R M A L IT Y D E T E C T E D S C IA T IC N E R V E fcN O A B N O R M A L I T Y D E T E C T E D P IT U IT A R Y G LA N D N O A B N O R M A L IT Y D E T E C T E D F ig u r e s i n p a r e n th e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e fin d in g s p e c ifie d w a s n o t id e n t if ie d N = 9 in G ro u p I I r e f le c t s 1 e a r ly d e a th in 90 d a y tim e p e r io d !9 ) (1 0 ) 9 10 (9 ) (1 0 ) 9 10 (9 ) (1 0 ) 9 10 (9 ) (1 0 ) 9 10 (9 ) 9 (1 0 ) 10 (9 ) (1 0 ) 8 10 1 - 186- DuPont-9478 Company Sanitized. Does not contain TSCA CBI ISubchronic Toxicity 90-Day Oral Gavage ! ay in Rats ) L E S IO N S l TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS RATS DESIGNATED FOR RECOVERY TREATM ENT L E S IO N IN C ID E F e m a le s 0 m g /k g II 125 m g /k g X P IT U IT A R Y G LA N D LARG E. T H Y R O ID G LA N D N O A B N O R M A L IT Y D E T E C T E D P A R A T H Y R O ID G L A N D S N O A B N O R M A L IT Y D E T E C T E D TRACHEA N O A B N O R M A L IT Y D E T E C T E D ESOPHAGUS N O A B N O R M A L IT Y D E T E C T E D P H A R Y N X /L A R Y N X N O A B N O R M A L IT Y D E T E C T E D (9 ) 1 (9 ) 9 (9 ) 9 (9 ) 9 (9 ) 9 , (9 9 (1 0 ). (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 F ig u r e s i n p a r e n th e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e fin d in g s p e c ifie d w a s n o t id e n t if ie d N -9 in G ro u p I I r e f le c t s 1 e a r ly d e a th in 9 0 d a y tim e p e r io d - 187- DuPont-9478 Company Sanitized. Does not contain TSCA CBI JSubchronic Toxicity 90-Day Oral Gavage St1 ay in Rats L E S IO N S TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS RATS DESIGNATED FOR RECOVERY . TREATM ENT L E S IO N IN C ID E F e m a le s 0 m g /k g II 125 m g /k g X E Y E (S ) W IT H O P T IC N E R V E N O A B N O R M A L IT Y D E T E C T E D S K IN N O A B N O R M A L IT Y D E T E C T E D . M AM M ARY G LA N D (F E M A L E ) N O A B N O R M A L IT Y D E T E C T E D O V A R IE S N O A B N O R M A L IT Y D E T E C T E D UTERUS N O A B N O R M A L IT Y D E T E C T E D D IL A T A T IO N . .$ F ig u r e s i n p a r e n th e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c ifie d w a s n o t id e n t if ie d N = 9 in G ro u p I I r e f le c t s 1 e a r ly d e a th in 90 d a y tim e p e r io d (9 ) (1 0 ) 9 10 (9 ) 9. (1 0 ) 10 (9 ) 9 (1 0 ) 10 (9 ) (1 0 ) 9 10 (9 ) (1 0 ) 8 10 1 ' -188- ) DuPont-9478 SSubchronic Toxicity 90-Day Oral Gavage S y in Rats_________ TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS RATS DESIGNATED FOR RECOVERY L E S IO N S . TREATM ENT L E S IO N IN C ID E F e m a le s 0 m g /k g II 125 m g /k g X V A G IN A N O A B N O R M A L IT Y D E T E C T E D U R IN A R Y B L A D D E R N O A B N O R M A L IT Y D E T E C T E D F E M U R /K N E E J O IN T '' N O A B N O R M A L IT Y D E T E C T E D STERNUM N O A B N O R M A L IT Y D E T E C T E D NOSE N O A B N O R M A L IT Y D E T E C T E D 1 F ig u r e s i n p a r e n th e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c if ie d w a s n o t id e n t if ie d N = 9 in G ro u p I I r e f le c t s 1 e a r ly d e a th i n 9 0 d a y tim e p e r io d (9 ) (1 0 ) 9 10 (9 ) (1 0 ) 9 10 (9 ) (1 0 ) 9 10 (9 ) ' (1 0 ) 9 10 (9 ) (1 0 ) 9 10 DuPont-9478 Company Sanitized. Does not contain TSCA CBI - 189- Company Sanitized. Does not contain TSCA CBI 90-Day Oral Gavage , Subchronic Toxicity iy in Rats ) TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS RATS DESIGNATED FOR SATF.T.T.TTF, F.VALUATIONS L E S IO N S TREATM ENT L E S IO N IN C ID E N C E ( N u m e r ic ) 0 m g /k g II F e m a le s 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III. 125 m g /k g X L IV E R N O A B N O R M A L IT Y D E T E C T E D K ID N E Y S N O A B N O R M A L IT Y D E T E C T E D LUNG S N O A B N O R M A L IT Y D E T E C T E D HEART N O A B N O R M A L IT Y D E T E C T E D S K E LE T A L M USCLE N O A B N O R M A L IT Y D E T E C T E D e SPLEEN N O A B N O R M A L IT Y D E T E C T E D (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 F f g u r e s i n p a r e n th e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d , f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c if ie d w a s n o t id e n t if ie d (5 ) 5 (5 ) 5 (5 ) 5 (5 ) 5 (5 ) 5 (5 ) 5 -190- ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI Subchronic Toxicity 90-Day Oral Gavage ! 5y in Rats L E S IO N S TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS RATS DESIGNATED FOR. SATELLITE EVALUATIONS TREATM ENT L E S IO N IN C ID E N C E ( N u m e r ic ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 m g /k g X AO R TA N O A B N O R M A L IT Y D E T E C T E D B R A IN N O A B N O R M A L IT Y D E T E C T E D S P IN A L CORD N O A B N O R M A L IT Y D E T E C T E D STOM ACH N O A B N O R M A L IT Y D E T E C T E D DUODENUM N O A B N O R M A L IT Y D E T E C T E D JEJU N U M N O A B N O R M A L IT Y D E T E C T E D (5 ) 5 (5 ) 5 (5 ) 5 (S ) 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 F ig u r e s i n p a r e n t h e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c ifie d w a s n o t id e n t if ie d -191- DuPont-9478 Company Sanitized. Does not contain TSCA CBI Subchronic Toxicity 90-Day Oral Gavage y in Rats L E S IO N S TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS RATS DESIGNATED FOR SATELLITE EVALUATIONS TREATM ENT L E S IO N IN C ID E N C E ( N u m e r ic ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 m g /k g X IL E U M N O A B N O R M A L IT Y D E T E C T E D PANCREAS N O A B N O R M A L IT Y D E T E C T E D CECUM N O A B N O R M A L IT Y D E T E C T E D C O LO N N O A B N O R M A L IT Y D E T E C T E D RECTUM N O A B N O R M A L IT Y D E T E C T E D M E S E N T E R IC L Y M P H N O D E N O A B N O R M A L IT Y D E T E C T E D (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 F ig u r e s i n p a r e n th e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c ifie d w a s n o t id e n t if ie d -192 - DuPont-9478 Company Sanitized. Does not contain TSCA CBI ffiubchronic Toxicity 90-Day Oral Gavage !udy in Rats L E S IO N S TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS RATS DESIGNATED FOR SATELLITE EVALUATIONS TREATM ENT L E S IO N IN C ID E N C E ( N u m e r ic ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 m g /k g X S A L IV A R Y G LA N D S N O A B N O R M A L IT Y D E T E C T E D M A N D IB U L A R L Y M P H N O D E N O A B N O R M A L IT Y D E T E C T E D THYM US N O A B N O R M A L IT Y D E T E C T E D ADRENAL GLANDS N O A B N O R M A L IT Y D E T E C T E D S C IA T IC N E R V E N O A B N O R M A L IT Y D E T E C T E D P IT U IT A R Y G LA N D N O A B N O R M A L IT Y D E T E C T E D (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 F ig u r e s i n p a r e n th e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c ifie d w a s n o t id e n t if ie d -193- DuPont-9478 Company Sanitized. Does not contain TSCA ________ LSubchronic Toxicity yO-Day Ora avage Study in Rats L E S IO N S TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS RATS DESIGNATED FOR SATELLITE EVALUATIONS TREATM ENT L E S IO N IN C ID E N C E ( N u m e r ic ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 m g /k g X T H Y R O ID G LA N D N O A B N O R M A L IT Y D E T E C T E D P A R A T H Y R O ID G L A N D S N O A B N O R M A L IT Y D E T E C T E D TRACHEA N O A B N O R M A L IT Y D E T E C T E D ESOPHAGUS N O A B N O R M A L IT Y D E T E C T E D P H A R Y N X /L A R Y N X N O A B N O R M A L IT Y I|E T E C T E D E Y E (S ) W IT H O P T IC N E R V E N O A B N O R M A L IT Y D E T E C T E D (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 (S ) 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 F ig u r e s i n p a r e n t h e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c if ie d w a s n o t id e n t if ie d O CO ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI ubchronic Toxicity y in Rats ) TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS RATS DESIGNATED FOR SATELLITE EVALUATIONS L E S IO N S TREATM ENT L E S IO N IN C ID E N C E ( N u m e r ic ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 . m g /k g V III 125 m g /k g X S K IN N O A B N O R M A L IT Y D E T E C T E D MAMMARY G LA N D (F E M A L E ) N O A B N O R M A L IT Y D E T E C T E D O V A R IE S N O A B N O R M A L IT Y D E T E C T E D UTERUS N O A B N O R M A L IT Y D E T E C T E D V A G IN A N O A B N O R M A L IT Y D E T E C T E D U R IN A R Y B L A D D E R ' N O A B N O R M A L IT Y D E T E C T E D (5 ) 5 (5 ) S (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 F ig u r e s in . p a r e n t h e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c ifie d w a s n o t id e n t if ie d -195- ) DuPont-9478 ____________Subchronic Toxicity 90-Day Oral Gavage Study in Rats_________ L E S IO N S TABLE 39 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS RATS DESIGNATED FOR SATELLITE EVALUATIONS TREATM ENT L E S IO N IN C ID E N C E ( N u m e r ic ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g . V III 125 m g /k g X F E M U R /K N E E J O IN T N O A B N O R M A L IT Y D E T E C T E D STERNUM N O A B N O R M A L IT Y D E T E C T E D NOSE N O A B N O R M A L IT Y D E T E C T E D (5 ) 5 (5 ) . 5 (5 ) 5 (5 ) 5 (5 ) 5 (5 ) 5 (5 ) 5 (5 ) 5 (5 ) 5 (5 ) 5 (5 ) 5 (5 ) 5 F ig u r e s i n p a r e n t h e s e s i s t h e n u m b e r o f a n im a ls g r o s s ly e x a m in e d f o r t h i s t is s u e T h e a b s e n c e o f a n u m b e r in d ic a te s th e f in d in g s p e c ifie d w a s n o t id e n t if ie d (5 ) 5 (5 ) 5 (5 ) 5 DuPont-9478 Company Sanitized. Does not contain TSCA CBI -196- Company Sanitized. Does not contain TSCA CBI iibchronic Toxicity 90-Day Oral Gavage 'dy in Rats ) L E S IO N S TABLE 40 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY 1 L E S IO N IN C ID E N C E (N U M E R IC ) M a le s TREATM ENT 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX D IG E S T IV E S Y S T E M L IV E R N E C R O S IS , F O C A L . IN F L A M M A T IO N , S U B A C U T E /C H R O N IC . HYPERTROPHY, H EPATO C ELLU LAR. F A T T Y C H A N G E , M E D IA N C L E F T . F A T T Y C H A N G E , C E N T R IL O B U L A R . (1 0 ) 10 2 (1 0 ) 9 2 (1 0 ) '1 10 2 PANCREAS (1 0 ) N O A B N O R M A L IT Y D E T E C T E D ATR O PH Y. 8 2 ESOPHAGUS . (1 0 ) N O A B N O R M A L IT Y D E T E C T E D 10 STO M ACH (1 0 ) N O A B N O R M A L IT Y D E T E C T E D 10 1 F ig u r e i n p a r e n t h e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s n o t id e n t if ie d tis s u e (1 0 ) 5 9 1 (1 0 ) 3 8 10 1 1 (1 0 ) 8 2 (1 0 ) 10 (1 0 ) 10 -197- ) DuPont-9478 Company Sanitized. Does not contain TSCA CBi Subchronic Toxicity 90-Day Oral Gavage SlE3y in Rats L E S IO N S TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX D IG E S T IV E S Y S T E M DUODENUM N O A B N O R M A L IT Y D E T E C T E D JEJU N U M N O A B N O R M A L IT Y D E T E C T E D IL E U M N O A B N O R M A L IT Y D E T E C T E D CECUM N O A B N O R M A L IT Y D E T E C T E D C O LO N N O A B N O R M A L IT Y D E T E C T E D (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 F ig u r e i n p a r e n t h e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c if ie d w a s n o t id e n t if ie d tis s u e (1 0 ) 10 . O) 9 (9 ) 9 (9 ) 9 (1 0 ) 10 -198- ) DuPont-9478 ) C 90-Day Oral Gavage Subchronic Toxicity Hy in Rats ) L E S IO N S TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) M a le s 0 m g /k g I 1 ra g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX D IG E S T IV E S Y S TE M RECTUM N O A B N O R M A L IT Y D E T E C T E D S A L IV A R Y G LA N D S N O A B N O R M A L IT Y D E T E C T E D (1 0 ) 10 (1 0 ) 10 F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c if ie d w a s n o t id e n t if ie d tis s u e O) 9 (1 0 ) 10 DuPont-9478 Company Sanitized. Does not contain TSCA CBI -199- ubchronic Toxicity 90-Day Oral Gavage itu3y in Rats L E S IO N S TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX U R IN A R Y S Y S T E M K ID N E Y S N O A B N O R M A L IT Y D E T E C T E D C H R O N IC P R O G R E S S IV E N E P H R O P A T H Y . P IG M E N T , T U B U L A R . HYPERTROPHY, TU BU LAR . H Y D R O N E P H R O S IS , U N IL A T E R A L . CYST. U R IN A R Y B L A D D E R N O A B N O R M A L IT Y D E T E C T E D (1 0 ) 5 5 (1 0 ) 10 (1 0 ) 4 6 (1 0 ) 3 7 (1 ) 1 (1 0 ) 1 4 9 1 (1 0 ) 8 1 10 1 (1 0 ) 10 F i g u r e i n p a r e n t h e s e s '5 i s n u m b e r o f a n i m a l s m i c r o s c o p i c a l l y e x a m i n e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s n o t id e n t if ie d tis s u e DuPont-9478 Company Sanitized. Does not contain TSCA CBI -200- 90-Day Oral Gavage ubchronic Toxicity [y in Rats L E S IO N S TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ). M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX R E S P IR A T O R Y S Y S T E M LUNG S N O A B N O R M A L IT Y D E T E C T E D IN F L A M M A T IO N , S U B A C U T E /C H R O N IC . TRACHEA N O A B N O R M A L IT Y D E T E C T E D P H A R Y N X /L A R Y N X N O A B N O R M A L IT Y D E T E C T E D NOSE N O A B N O R M A L IT Y D E T E C T E D D E G E N E R A T IO N , A M E L O B L A S T S . (1 0 ) 9 1 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 9 1 (IP ) 10 (1 0 ) 10 (1 0 ) 5 5 F ig u r e i n p a r e n t h e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c if ie d w a s n o t id e n t if ie d tis s u e ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI -201- Subchronic Toxicity 90-Day Oral Gavage ay in Rats_________ L E S IO N S TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX C A R D IO V A S C U L A R S Y S T E M HEART N O A B N O R M A L IT Y D E T E C T E D C A R D IO M Y O P A T H Y . AO R TA N O A B N O R M A L IT Y D E T E C T E D . (1 0 ) 5 5 GO) 10 F ig u r e i n p a r e n t h e s e s i s n u m b e r o f a n im a ls m i c r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s n o t id e n t if ie d tis s u e (1 0 ) 5 5 (1 0 ) 10 DuPont-9478 Company Sanitized. Does not contain TSCA CBI -202- Company Sanitized. Does not contain TSCA CBI ubchronic Toxicity 90-Day Oral Gavage Sdy in Rats L E S IO N S TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX L Y M P H A T IC A N D H E M A T O P O IE T IC S Y S T E M SPLEEN N O A B N O R M A L IT Y D E T E C T E D THYM US N O A B N O R M A L IT Y D E T E C T E D M A N D IB U L A R L Y M P H N O D E N O A B N O R M A L IT Y D E T E C T E D M E S E N T E R IC L Y M P H N O D E N O A B N O R M A L IT Y 'D E T E C T E D BO NE MARROW NO A B N O R M A L IT Y D E T E C T E D (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ). 10 F ig u r e i n p a r e n t h e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s n o t id e n t if ie d tis s u e (1 0 ) 10 (1 .0 ) 10 (1 0 ) 10 (9 ) 9 (1 0 ) 10 -203- DuPont-9478 ubchronic Toxicity 90-Day Oral Gavage !53y in Rats ) L E S IO N S TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MATE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX E N D O C R IN E S Y S T E M . P IT U IT A R Y G LA N D N O A B N O R M A L IT Y D E T E C T E D CYST. T H Y R O ID G LA N D N O A B N O R M A L IT Y D E T E C T E D A L T E R A T IO N , C O L L O ID . P A R A T H Y R O ID G L A N D S N O A B N O R M A L IT Y D E T E C T E D ADRENAL G LANDS ^ N O A B N O R M A L IT Y D E T E C T E D (9 ) 8 1 (1 0 ) 7 3 (9 ) 9 (1 0 ) 10 (1 0 ) 2 8 (1 0 ) 1 9 (1 0 ) 10 (1 .0 ) 10 (1 0 ) 2 8 (9 ) 9 (1 0 ) 10 F ig u r e i n p a r e n t h e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th le s io n s p e c ifie d w a s .n o t id e n t if ie d tis s u e ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI - 204 - ubchronic Toxicity 90-Day Oral Gavage STdy in Rats_________ L E S IO N S TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX NERVOUS SYSTEM B R A IN N O A B N O R M A L IT Y D E T E C T E D S P IN A L CORD N O A B N O R M A L IT Y D E T E C T E D S C IA T IC N E R V E N O A B N O R M A L IT Y D E T E C T E D (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m tfe r in d ic a t e s th e le s io n s p e c if ie d w a s n o t i d e n t i f i e d tis s u e (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 DuPont-9478 Company Sanitized. Does not contain TSCA CBI -205- ubchronic Toxicity 90-Day Oral Gavage S 'dy in Rats L E S IO N S TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SI IBCHRONIC TOXTCITY TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX M USCULAR AND S K E LE T A L SYSTEM S K E LE T A L M USCLE N O A B N O R M A L IT Y D E T E C T E D F E M U R /K N E E J O IN T N O A B N O R M A L IT Y D E T E C T E D STERNUM N O A B N O R M A L IT Y D E T E C T E D (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m i c r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b fe r in d ic a t e s t h e l e s i o n s p e c i f i e d w a s n o t i d e n t i f i e d tis s u e (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 DuPont-9478 Company Sanitized. Does not contain TSCA CBI -206- Company Sanitized. Does not contain TSCA CBI ) ubchronic Toxicity 90-Day Oral Gavage ludy in Rats L E S IO N S TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g/kg IX R E P R O D U C T IV E S Y S T E M TESTES N O A B N O R M A L IT Y D E T E C T E D D IL A T A T IO N , S E M IN IF E R O U S T U B U L E S , U N IL A T E R A L . D E G E N E R A T IO N /A T R O P H Y , S E M IN IF E R O U S T U B U L E S , U N IL A T E R A L . D E G E N E R A T IO N /A T R O P H Y , S E M IN IF E R O U S T U B U L E S , B IL A T E R A L . E P ID ID Y M ID E S N O A B N O R M A L IT Y D E T E C T E D O L IG O S P E R M IA /G E R M C E L L D E B R IS , O L IG O S P E R M IA /G E R M C E L L D E B R IS , U N IL A T E R A L . B IL A T E R A L . PR O STATE | N O A B N O R M A L IT Y D E T E C T E D IN F L A M M A T IO N , S U B A C U T E /C H R O N IC . S E M IN A L V E S IC L E S N O A B N O R M A L IT Y D E T E C T E D (1 0 ) 8 2 !1 0 ) 9 1 (1 0 ) 7 3 (1 0 ) 10 (1 ) 1 i F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s n o t id e n t if ie d tis s u e (1 0 ) 9 1 (1 0 ) 9. 1 (1 0 ) 10 (1 0 ) 10 -207- DuPont-9478 ^ubchronic Toxicity 90-Day Oral Gavage Study in Rats_________ L E S IO N S TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX CUTANEOUS SYSTEM S K IN N O A B N O R M A L IT Y D E T E C T E D (1 0 ) 10 di 1 F ig u r e i n p a r e n t h e s e s i s n u m b e r o f a n im a ls m i c r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s n o t id e n t if ie d tis s u e (1 0 ) 10 I DuPont-9478 Company Sanitized. Does not contain TSCA CBI -208- c 90-Day Oral Gavage Subchronic Toxicity ly in Rats ) L E S IO N S TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) M a le s 0 m g /k g 'I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX S P E C IA L S E N S E S S Y S TE M E Y E (S ) W IT H O P T IC N E R V E N O A B N O R M A L IT Y D E T E C T E D O P T IC N E R V E N O T P R E S E N T . F O L D /R O S E T T E , R E T IN A L . A D H E S IO N , R E T IN A L . (1 0 ) 8 3 1 1 F ig u r e i n p a r e n t h e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r, in d ic a t e s th e le s io n s p e c if ie d w a s n o t id e n t i f i e d tis s u e (1 0 ) 10 1 1 I > DuPont-9478 Company Sanitized. Does not contain TSCA CBI -209- 90-Day Oral Gavage Bubchronic Toxicity ly in Rats L E S IO N S TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR RECOVERY L E S IO N IN C ID E N C E M a le s TREATM ENT 0 m g /k g I 125 m g /k g IX D IG E S T IV E S Y S TE M L IV E R N E C R O S IS , F O C A L . IN F L A M M A T IO N , S U B A C U T E /C H R O N IC . H Y P E R P L A S IA , B IL E D U C T . F A T T Y C H A N G E , M E D IA N C L E F T . F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s n o t id e n t if ie d tis s u e (1 0 ) 3 9 5 2 (1 0 ) 7 9 6 DuPont-9478 Company Sanitized. Does not contain TSCA CBI -210- J Subchronic Toxicity 90-Day Oral Gavage l ady in Rats L E S IO N S TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR RECOVERY L E S IO N IN C ID E N C E M a le s TREATM ENT 0 m g /k g I 125 m g /k g X U R IN A R Y S Y S T E M K ID N E Y S N O A B N O R M A L IT Y D E T E C T E D C H R O N IC P R O G R E S S IV E N E P H R O P A T H Y . H Y P E R P L A S IA , T R A N S IT IO N A L C E L L . H Y D R O N E P H R O S IS , U N IL A T E R A L . H Y D R O N E P H R O S IS , B IL A T E R A L . CYST. F ig u r e i n p a r e n t h e s e s i s n u m b e r o f a n im a ls m i c r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s n o t id e n t if ie d tis s u e (1 0 ) 4 6 (1 0 ) 3 5 1 1 1 1 ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI -211 - Bubchronic Toxicity 90-Day Oral Gavage Stcty in Rats L E S IO N S TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR RECOVERY L E S IO N IN C ID E N C E M a le s TREATM ENT 0 m g /k g I 125 m g /k g IX R E S P IR A T O R Y S Y S T E M NOSE N O A B N O R M A L IT Y D E T E C T E D O D O N T O D Y S P L A S IA . IN F L A M M A T IO N , S U B A C U T E /C H R O N IC . D E G E N E R A T IO N , A M E L O B L A S T S . F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s n o t id e n t if ie d tis s u e (1 0 ) 10 (1 0 ) 7 1 1 2 DuPont-9478 Company Sanitized. Does not contain TSC CBI -212- Jubchronic Toxicity Jay Oral Gavage Study in Rats________ L E S IO N S TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR RECOVERY L E S IO N IN C ID E N C E M a le s TREATM ENT 0 m g /k g I 125 m g /k g IX L Y M P H A T IC A N D H E M A T O P O IE T IC S Y S T E M THYM US N O A B N O R M A L IT Y D E T E C T E D F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s n o t id e n t if ie d tis s u e (1 0 ) 10 (1 0 ) 10 1 ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI -213- ubchronie Toxicity 90-Day Oral Gavage icly in Rats ) L E S IO N S TABLE 40 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR RECOVERY L E S IO N IN C ID E N C E M a le s TREATM ENT 0 m g /k g I 125 m g /k g IX E N D O C R IN E S Y S T E M T H Y R O ID G LA N D N O A B N O R M A L IT Y D E T E C T E D A L T E R A T IO N , C O L L O ID . F ig u r e i n p a r e n t h e s e s i s n u m b e r o f a n im a ls m i c r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s n o t id e n t if ie d tis s u e (1 0 ) 3 7 (1 0 ) 10 ) DuPont-9478 Company Sanitized. Does not contain TSCA C8I -214- Company Sanitized. Does not contain TSCA CBI ) fSubchronic Toxicity 90-Day Oral Gavage uay in Rats_________ TABLE 41 INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY L E S IO N IN C ID E N C E (N U M E R IC ) F e m a le s L E S IO N S TREATM ENT 0 m g /k g XI 1 m g /k g IV 5' m g /k g VI 25 m g /k g V III 125 m g /k g X D iG E S T IV E S Y S T E M L IV E R N O A B N O R M A L IT Y D E T E C T E D IN F L A M M A T IO N , S U B A C U T E /C H R O N IC . H Y P E R P L A S IA , B IL E D U C T . F A T T Y C H A N G E , M E D IA N C L E F T . . (1 1 ). 1 10 2 2 (1 0 ) 1 6 3 1 PANCREAS N O A B N O R M A L IT Y D E T E C T E D IN F L A M M A T IO N , S U B A C U T E /C H R O N IC . (1 1 ) 11 (1 0 ) 9 1 ESOPHAGUS N O A B N O R M A L IT Y D E T E C T E D IN F L A M M A T IO N , L A C E R A T IO N . S U B A C U T E /C H R O N IC . . STO M ACH N O A B N O R M A L IT Y D E T E C T E D (1 1 ) 10 1 1 (1 1 ) 11 (1 0 ) 10 (1 0 ). 10 DUODENUM N O A B N O R M A L IT Y D E T E C T E D (1 1 ) 11 (1 0 ) 10 F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s N = ll IN GROUP I I DUE TO EA R LY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e -215 ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI iubchronic Toxicity 90-Day Oral Gavage I5y in Rats L E S IO N S TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUB CHRONIC TOXICITY TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 m g /k g X D IG E S T IV E S Y S T E M JEJU N U M N O A B N O R M A L IT Y D E T E C T E D (1 1 ) 11 IL E U M N O A B N O R M A L IT Y D E T E C T E D (1 1 ) 11 CECUM N O A B N O R M A L IT Y D E T E C T E D (1 1 ) 11 CO LO N (1 1 ) N O A B N O R M A L IT Y D E T E C T E D 11 RECTUM (1 1 ) N O A B N O R M A L IT Y D E T E C T E D 11 S A L IV A R Y G L A N D S N O A B N O R M A L IT Y D E T E C T E D (1 1 ) 1 11 F ig u r e in p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s N = ll IN GROUP I I DUE TO EAR LY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 -216- ) DuPont-9478 rjsubchronic Toxicity ay Oral Gavage Sittudy in Rats L E S IO N S TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ! F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k q VI 25 m g /k g V III 125 m g /k g X U R IN A R Y S Y S T E M K ID N E Y S NO A B N O R M A L IT Y D E T E C T E D C H R O N IC P R O G R E S S IV E N E P H R O P A T H Y . IN F L A M M A T IO N , S U B A C U T E / C H R O N IC . H Y D R O N E P H R O S IS , U N I L A T E R A L . H Y D R O N E P H R O S IS , B IL A T E R A L . U R IN A R Y B L A D D E R N O A B N O R M A L IT Y D E T E C T E D IN F L A M M A T IO N , S U B A C U T E /C H R O N IC . (1 1 ) 7 2 2 1 (1 1 ) 10 1 (1 0 ) 8 2 I (1 0 ) 7 3 (1 0 ) 7 3 (1 0 ) 1 7 1 1 (1 0 ) 10 F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c if ie d w a s N = ll IN GROUP I I DUE TO EA R LY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI -217- 90-Day Oral Gavage Study in Rats L E S IO N S TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ). F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 m g /k g X R E S P IR A T O R Y S Y S T E M LUNG S N O A B N O R M A L IT Y D E T E C T E D TRACHEA N O A B N O R M A L IT Y D E T E C T E D P H A R Y N X /L A R Y N X N O A B N O R M A L IT Y D E T E C T E D NOSE N O A B N O R M A L IT Y D E F E C T E D (1 1 ) 11 (1 1 ) 11 (1 1 ) 11 (1 1 ) 11 F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s N = ll IN GROUP I I DUE TO EAR LY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI -218- ubchronic Toxicity 90-Day Oral Gavage dy in Rats ) L E S IO N S TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 m g /k g X C A R D IO V A S C U L A R S Y S T E M HEART N O A B N O R M A L IT Y D E T E C T E D C A R D IO M Y O P A T H Y : AO R TA N O A B N O R M A L IT Y D E T E C T E D (1 1 ) 6 5 (1 1 ) 11 F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c if ie d w a s N = ll IN GROUP I I DUE TO EAR LY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e (1 0 ) 8 2 (1 0 ) 10 ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI -219- Company Sanitized. Does not contain TSCA CBJ Subchronic Toxicity 90-Day Oral Gavage Study in Rats L E S IO N S TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 m g /k g X L Y M P H A T IC A N D H E M A T O P O IE T IC S Y S T E M SPLEEN N O A B N O R M A L IT Y D E T E C T E D THYM US N O A B N O R M A L IT Y D E T E C T E D M A N D IB U L A R L Y M P H N O D E N O A B N O R M A L IT Y D E T E C T E D M E S E N T E R IC L Y M P H N O D E N O A B N O R M A L IT Y D E T E C T E D BO NE MARROW N O A B N O R M A L IT Y D E T E C T E D . H Y P E R P L A S IA , G R A N U L O C Y T IC . ( ID 11 ill) 11 (1 1 ) 11 (1 1 ) 11 (1 1 ! 10 1 F ig u r e i n p a r e n th e s e s is n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s N = ll IN GROUP I I DUE TO EAR LY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 -220- ) DuPont-9478 ubchronic Toxicity 90-Day Oral Gavage !udy in Rats ) L E S IO N S TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 m g /k g X E N D O C R IN E S Y S T E M P IT U IT A R Y G LA N D N O A B N O R M A L IT Y D E T E C T E D T H Y R O ID G LA N D N O A B N O R M A L IT Y D E T E C T E D P A R A T H Y R O ID G L A N D S N O A B N O R M A L IT Y D E T E C T E D AD R EN AL GLANDS N O A B N O R M A L IT Y D E F E C T E D M IN E R A L IZ A T IO N . (1 1 ) 11 (1 1 ) 11 (9 ) 9 (1 1 )' 11 F ig u r e in p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s N = ll IN GROUP I I DUE TO EAR LY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e (1 0 ) 10 l (1 0 ) 10 (9 ) 9 (1 0 ) 9 1 DuPont-9478 Company Sanitized. Does not contain TSCA CBI -221- ______ _____________ Subchronic Toxicity 90-Day Oral Gavage Study in Rats L E S IO N S TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 m g /k g X NERVOUS SYSTEM B R A IN N O A B N O R M A L IT Y D E T E C T E D S P IN A L CORD N O A B N O R M A L IT Y D E T E C T E D S C IA T IC N E R V E N O A B N O R M A L IT Y D E T E C T E D !U ) 11 (1 1 ! 11 (1 1 ) 11 F ig u r e in p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e p in d ic a te s th e le s io n s p e c ifie d w a s N = ll IN GROUP' I I D U E T O E A R LY D E A TH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI -222- _________ __ Subchronic Toxicity 90-Day Oral Gavage Study in Rats L E S IO N S TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 m g /k g X M USCULAR AND S K E LE T A L SYSTEM S K E LE T A L M USCLE N O A B N O R M A L IT Y D E T E C T E D IN F L A M M A T IO N ,. S U B A C U T E /C H R O N IC . F E M U R /K N E E J O IN T N O A B N O R M A L IT Y D E T E C T E D STERNUM N O A B N O R M A L IT Y D E T E C T E D (1 1 ) 11 (1 1 ) 11 (1 1 ) 11 F ig u r e i n p a re n th e s e s , is n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s N = ll IN GROUP I I DUE TO EA R LY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e (1 0 ) 9 1 (1 0 ) 10 (1 0 ) 10 ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI -223- ubchronic Toxicity avage Stu5y in Rats ) L E S IO N S TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III ' 125 m g /k g X R E P R O D U C T IV E S Y S T E M O V A R IE S N O A B N O R M A L IT Y D E T E C T E D UTERUS N O A B N O R M A L IT Y D E T E C T E D M AM M ARY G L A N D (F E M A L E ) N O A B N O R M A L IT Y D E T E C T E D (1 1 ) 11 (1 1 ) 11 (1 1 ) 11 F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s N = ll IN GROUP I I DUE TO EAR LY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e MO) 10 (1 0 ) 10 (8 ) 8 ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI -224- L E S IO N S TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 m g /k g X CUTANEOUS SYSTEM S K IN N O A B N O R M A L IT Y D E T E C T E D ( ID 11 F ig u r e in p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s N = ll IN GROUP I I DUE TO EARLY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e (1 0 ) 10 % ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI -225- 0 ISubchronic Toxicity 90-Day Oral Gavage tdy in Rats_________ L E S IO N S TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 m g /k g X S P E C IA L S E N S E S S Y S T E M E Y E (S ) W IT H O P T IC N E R V E N O A B N O R M A L IT Y ' D E T E C T E D O P T IC N E R V E N O T P R E S E N T . F O L D /R O S E T T E , R E T IN A L . (1 1 ) 11 F ig u r e i n p a r e n t h e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c if ie d w a s n o t id e n t if ie d N = ll IN GROUP I I DUE TO EAR LY DEATH tis s u e (1 0 ) 9 1 1 ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI -226- l _________ Subchronic Toxicity 90-Day Oral Gavage Smay in Rats_________ L E S IO N S TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR RECOVERY L E S IO N IN C ID E N C E '1 F e m a le s TREATM ENT O' m g /k g II 125 m g /k g X D IG E S T IV E S Y S T E M L IV E R N O A B N O R M A L IT Y D E T E C T E D N E C R O S IS , F O C A L . IN F L A M M A T IO N , S U B A C U T E /C H R O N IC H Y P E R P L A S IA , B IL E D U C T . F A T T Y C H A N G E , M E D IA N C L E F T . A N G IE C T A S IS . F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c if ie d w a s N = 9 IN GROUP I I DUE TO E A R LY D EATH t e x a m in e d f o r t h i s n o t id e n tifie d tis s u e 19) 3 1 3 1 2 (1 0 ) 2 6 1 1 2 DuPont-9478 Company Sanitized. Does not contain TSCA CBI -227- I Subchronic Toxicity 90-Day Oral Gavage idy in Rats L E S IO N S TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR RECOVERY L E S IO N IN C ID E N C E 1 F e m a le s TREATM ENT 0 m g /k g II 125 m g /k g X U R IN A R Y S Y S T E M K ID N E Y S N O A B N O R M A L IT Y D E T E C T E D C H R O N IC P R O G R E S S IV E N E P H R O P A T H Y . H Y D R O N E P H R O S IS , B IL A T E R A L . F ig u r e in p a r e n th e s e s is n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s N = 9 IN GROUP I I DUE TO EAR LY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e (9 ) (1 0 ) 42 58 1 ) DuPont-9478 Company Sanitized. Does not contain TSCA C8I -228- ubchronic Toxicity 90-Day Oral Gavage S! icly in Rats__________ L E S IO N S TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR RECOVERY L E S IO N IN C ID E N C E F e m a le s TREATM ENT 0 m g /k g II 125 mg/kg X E N D O C R IN E S Y S T E M P IT U IT A R Y G LA N D N O A B N O R M A L IT Y D E T E C T E D F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c if ie d w a s N =9 IN GROUP I I DUE TO EAR LY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e (1 ) 1 DuPont-9478 Company Sanitized. Does not contain TSCA CBI -229- 90-Day Oral Gavage Subchronic Toxicity [yin Rats_________ L E S IO N S TABLE 41 (CONTINUED) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NEOPLASTIC AND NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR RECOVERY L E S IO N IN C ID E N C E F e m a le s TREATM ENT 0 m g /k g II 125 m g /k g X R E P R O D U C T IV E S Y S T E M UTERUS D IL A T A T IO N . F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s N =9 IN GROUP I I DUE TO E A R LY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e (1 ) 1 D u P on t-9478 Company Sanitized. Does not contain TSCA CBI -230- [Subchronic Toxicity 90-Day Oral Gavage ay in Rats _______ TABLE 42 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY L E S IO N S TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX DuPont-9478 D IG E S T IV E S Y S TE M L IV E R N E C R O S IS , F O C A L . m in im a l t o t a l o b s e r v a tio n s p e r le s io n IN F L A M M A T IO N , S U B A C U T E / C H R O N IC . m in im a l t o t a l o b s e r v a tio n s p e r le s io n HYPERTROPHY, H EPATO C ELLU LAR . m in im a l m ild t o t a l o b s e r v a tio n s p e r le s io n F A T T Y C H A N G E , M E D IA N C L E F T . m in im a l m ild t o t a l o b s e r v a tio n s p e r le s io n F A T T Y C H A N G E , C E N T R IL O B U L A R . m in im a l t o t a l o b s e r v a tio n s p e r le s io n (1 0 ) (1 0 ) (1 0 ) (1 0 ) (1 0 ) 153 153 10 9 10. 9 8. 1 0 9 3.0 9 8 4 6 10 22111 1 22211 1 1 F ig u r e i n p a r e n t h e s e s i s n u m b e r o f a n im a ls m i c r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s n o t id e n t if ie d tis s u e Company Sanitized. Does not contain TSCA CBI -231 - Subchronic Toxicity 90-Day Oral Gavage !uay in Rats_______ ) DuPont-9478 TABLE 42 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY L E S IO N S TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) M a le s 0 m g/kg I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX D IG E S T IV E S Y S TE M PANCREAS N O A B N O R M A L IT Y D E T E C T E D ATR O PH Y. m in im a l t o t a l o b s e r v a tio n s per le s io n ESOPHAGUS N O A B N O R M A L IT Y D E T E C T E D STO M ACH N O A B N O R M A L IT Y D E T E C T E D DUODENUM N O A B N O R M A L IT Y D E T E C T E D JEJU N U M N O A B N O R M A L IT Y D E T E C T E D (1 0 ) 8 2 2 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m i c r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s n o t id e n t if ie d tis s u e (1 0 ) 8 2 2 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 O) 9 Company Sanitized. Does not c o n ta in T S C A C B I -232- ubchronic Toxicity 90-Day Oral Gavage fdy in Rats DuPont-9478 TABLE 42 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY L E S IO N S TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) M a le s 0 m g /k g . I 1 m g /k g III 5 mg /k g V 25 m g /k g V II 125 m g /k g ' IX D IG E S T IV E S Y S TE M IL E U M N O A B N O R M A L IT -Y D E T E C T E D CECUM N O A B N O R M A L IT Y D E T E C T E D C O LO N N O A B N O R M A L IT Y D E T E C T E D RECTUM tf N O A B N O R M A L IT Y D E T E C T E D S A L IV A R Y G LA N D S N O A B N O R M A L IT Y D E T E C T E D (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w as n o t id e n t if ie d tis s u e (9 ) 9 (9 ) 9 (1 0 ) 10 (9 ) 9 (1 0 ) 10 Company Sanitized. Does not contain TSCA CBI -233- Subchronic Toxicity 90-Day Oral Gavage StuSy in Rats TABLE 42 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY L E S IO N S TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX U R IN A R Y S Y S T E M K ID N E Y S N O A B N O R M A L IT Y -D E T E C T E D C H R O N IC P R O G R E S S IV E N E P H R O P A T H Y . m in im a l t o t a l o b s e r v a tio n s p e r le s io n P IG M E N T , T U B U L A R . m in im a l t o t a l o b s e r v a tio n s p e r le s io n HYPERTROPHY, TU B U LAR . m in im a l t o t a l o b s e r v a tio n s p e r le s io n H Y D R O N E P H R O S IS , U N IL A T E R A L . m in im a l S t o t a l o b s e r v a tio n s p e r le s io n CYST. m in im a l t o t a l o b s e r v a tio n s p e r le s io n U R IN A R Y B L A D D E R N O A B N O R M A L IT Y D E T E C T E D (1 0 ) 5 5 5 (1 0 ) 4 6 6 (1 0 ) 10 (1 0 ) 3 7 7 (1 0 ) 1 4 4 9 9 1 1 (1 ) 1 (1 0 ) 8 8 1 1 10 10 1 1 (1 0 ) 10 F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m i c r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s n o t id e n t if ie d tis s u e DuPont-9478 Company Sanitized. Does not contain TSCA CBI -234- 90-Day Oral Gavage ubchronic Toxicity iy in Rats______ TABLE 42 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY L E S IO N S TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) M a le s 0 m g /k g I 1 m g /k g III 5' m g /k g V 25 m g /k g V II 125 m g /k g IX R E S P IR A T O R Y S Y S T E M LUNG S N O A B N O R M A L IT Y D E T E C T E D IN F L A M M A T IO N , S U B A C U T E /C H R O N IC . m in im a l t o t a l o b s e r v a tio n s p e r le s io n TRACHEA N O A B N O R M A L IT Y D E T E C T E D P H A R Y N X /L A R Y N X N O A B N O R M A L IT Y D E T E C T E D & NOSE N O A B N O R M A L IT Y D E T E C T E D D E G E N E R A T IO N , A M E L O B L A S T S . m in im a l m ild t o t a l o b s e r v a tio n s p e r le s io n (1 0 ) 9 1 1 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 GO) 9 1 1 (1 0 ) 10 (1 0 ) 10 (1 0 ) 5 2 3 5 F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m i c r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s n o t id e n t if ie d tis s u e ) DuPont-9478 Company Sanitized. Does not contain TSCA C8I -235- Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 42 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS ' RATS DESIGNATED FOR SUBCHRONIC TOXICITY L E S IO N S TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX C A R D IO V A S C U L A R S Y S T E M HEART N O A B N O R M A L IT Y D E T E C T E D C A R D IO M Y O P A T H Y . m in im a l t o t a l o b s e r v a tio n s p e r le s io n AO R TA N O A B N O R M A L IT Y D E T E C T E D (1 0 ) 5' 5 5 (1 0 ) 10 F ig u r e i n p a r e n t h e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s n o t id e n t if ie d tis s u e (1 0 ) 5 5 5 (1 0 ) 10 ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI -236- ubchronic Toxicity 90-Day Oral Gavage 3y in Rats TABLE 42 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY L E S IO N S TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX L Y M P H A T IC A N D H E M A T O P O IE T IC S Y S T E M SPLEEN N O A B N O R M A L IT Y D E T E C T E D THYM US N O A B N O R M A L IT Y D E T E C T E D M A N D IB U L A R L Y M P H N O D E N O A B N O R M A L IT Y D E T E C T E D M E S E N T E R IC L Y M P H N O D E N O A B N O R M A L IT Y D E F E C T E D BO NE MARROW N O A B N O R M A L IT Y D E T E C T E D (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s n o t id e n t if ie d tis s u e GO) 10 (1 0 ) 10 (1 0 ) 10 (9 ) 9 GO) 10 ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI - 237- ) 90-Day Oral Gavage ubchronic Toxicity y in Rats TABLE 42 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY L E S IO N S TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) M a le s 0 m g /k g I 1 m g /k g III 5 m g i/k g V 25 m g /k g V II 125 m g /k g IX E N D O C R IN E S Y S T E M P IT U IT A R Y G LA N D N O A B N O R M A L IT Y D E T E C T E D CYST. m in im a l t o t a l o b s e r v a tio n s per le s io n T H Y R O ID G L A N D N O A B N O R M A L IT Y D E T E C T E D A L T E R A T IO N , C O L L O ID . m in im a l m ild m o d e ra te t s e v e re t o t a l o b s e r v a tio n s per le s io n (9 ) 8 1 1 (1 0 ) 7 3 3 (1 0 ) 2 7 1 8 (1 0 ) 1 9 9 (1 0 ) 10 (1 0 ) 10 10 (1 0 ) 2 3 2 1 2 8 F ig u r e i n p a r e n t h e s e s i s n u m b e r o f a n im a ls m i c r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s n o t id e n t if ie d tis s u e ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI - 238- BSubchronic Toxicity 90-Day Oral Gavage i cly in Rats TABLE 42 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY L E S IO N S TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX E N D O C R IN E S Y S T E M P A R A T H Y R O ID G L A N D S N O A B N O R M A L IT Y D E T E C T E D ADRENAL GLANDS N O A B N O R M A L IT Y D E T E C T E D (9 ) 9 (1 0 ) 10 F ig u r e i n p a r e n t h e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w as n o t id e n t if ie d tis s u e (9 ) 9 (1 0 ) 10 ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI -239- t MSubchronic Toxicity 90-Day Oral Gavage Bay in Rats TABLE 42 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY L E S IO N S TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g , IX NERVOUS SYSTEM B R A IN N O A B N O R M A L IT Y D E T E C T E D S P IN A L CORD N O A B N O R M A L IT Y D E T E C T E D S C IA T IC N E R V E N O A B N O R M A L IT Y D E T E C T E D (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w as n o t id e n t if ie d tis s u e (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI -240- c 90-Day Oral Gavage Subchronic Toxicity idy in Rats ) TABLE 42 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTiC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY L E S IO N S TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 mg/kg V II 125 m g /k g IX M USCULAR AND S K E LE T A L SYSTEM S K E LE T A L M USCLE N O A B N O R M A L IT Y D E T E C T E D F E M U R /K N E E J O IN T N O A B N O R M A L IT Y D E T E C T E D STERNUM N O A B N O R M A L IT Y D E T E C T E D (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 F ig u r e i n p a r e n t h e s e s i s n u ir ib e r o f a n im a ls m ic r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s n o t id e n t if ie d tis s u e (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 DuPont-9478 Company Sanitized. Does not contain TSCA CBI -241- Subchronic Toxicity 90-Day Oral Gavage Study in Rats TABLE 42 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY I L E S IO N S TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX R E P R O D U C T IV E S Y S T E M TESTES N O A B N O R M A L IT Y D E T E C T E D D IL A T A T IO N , S E M IN IF E R O U S T U B U L E S , U N IL A T E R A L . m o d e ra te t o t a l o b s e r v a tio n s p e r le s io n D E G E N E R A T IO N /A T R O P H Y , S E M IN IF E R O U S T U B U L E S , U N IL A T E R A L . m ild m o d e ra te t o t a l o b s e r v a tio n s p e r le s io n D E G E N E R A T IO N /A T R O P H Y , S E M IN IF E R O U S T U B U L E S , B IL A T E R A L . m in im a l s e v e re * t o t a l o b s e r v a tio n s p e r le s io n (1 0 ) 8 1 1 2 (1 ) 1 1 1 1 F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s n o t id e n t if ie d tis s u e (1 0 ) 9 1 1 DuPont-9478 Company Sanitized. Does not contain TSCA CBi -242- TABLE 42 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY L E S IO N S TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX R E P R O D U C T IV E S Y S T E M E P ID ID Y M ID E S N O A B N O R M A L IT Y D E T E C T E D O L IG O S P E R M IA /.G E R M C E L L D E B R IS , U N IL A T E R A L . s e v e re t o t a l o b s e r v a tio n s p e r le s io n O L IG O S P E R M IA /G E R M C E L L D E B R IS , B IL A T E R A L . s e v e re t o t a l o b s e r v a tio n s p e r le s io n PR O STATE N O A B N O R M A L IT Y D E T E C T E D IN F L A M M A T IO N , S U B A C U T E /C H R O N IC . m in im a l * t o t a l o b s e r v a tio n s p e r le s io n S E M IN A L V E S IC L E S N O A B N O R M A L IT Y D E T E C T E D (1 0 ) 9 1 1 (1 0 ) 7 3 3 (1 0 ) 10 F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m i c r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s n o t id e n t if ie d tis s u e (1 0 ) 9 1 1 (1 0 ) 10 (1 0 ) 10 ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI -243- ubchronic Toxicity 90-Day Oral Gavage Study in Rats_________ TABLE 42 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY L E S IO N S TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX CUTANEOUS SYSTEM S K IN N O A B N O R M A L IT Y D E T E C T E D (1 0 ) 10 (1 ) 1 F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s n o t id e n t if ie d tis s u e (1 0 ) 10 DuPont-9478 Company Sanitized. Does not contain TSCA CBI -244- ubchronic Toxicity 90-Day Oral Gavage Sy in R ats________ ) DuPont-9478 TABLE 42 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTlC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY L E S IO N S TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) M a le s 0 m g /k g I 1 m g /k g III 5 m g /k g V 25 m g /k g V II 125 m g /k g IX S P E C IA L S E N S E S S Y S T E M E Y E (S ) W IT H O P T IC N E R V E N O A B N O R M A L IT Y D E T E C T E D O P T IC N E R V E N O T P R E S E N T . F O L D /R O S E T T E , R E T IN A L . m in im a l t o t a l o b s e r v a tio n s A D H E S IO N , R E T IN A L . m in im a l t o t a l o b s e r v a tio n s per per le s io n le s io n (1 0 ) 8 3 1 1 1 1 F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r ^ in d ic a te s t h e le s io n s p e c if ie d w a s n o t i d e n t i f i e d tis s u e (1 0 ) 10 1 Company Sanitized. Does not contain TSCA CBI -245- Subchronic Toxicity 0-Day Oral Gavage idy in Rats > DuPont-9478 TABLE 42 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTlC LESIONS RATS DESIGNATED FOR RECOVERY L E S IO N S L E S IO N IN C ID E N C E 1 M a le s TREATM ENT 0 m g /k g I 125 m g /k g IX D IG E S T IV E S Y S T E M L IV E R N E C R O S IS , F O C A L . m in im a l m ild t o t a l o b s e r v a tio n s p e r le s io n IN F L A M M A T IO N , S U B A C U T E /C H R O N IC . m in im a l m ild t o t a l o b s e r v a tio n s p e r le s io n H Y P E R P L A S IA , B IL E D U C T . m in im a l t o t a l o b s e r v a tio n s p e r le s io n F A T T Y C H A N G E , M E D IA N C L E F T . m in im a l ' t o t a l o b s e r v a tio n s p e r le s io n F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s n o t id e n t if ie d tis s u e (1 0 ) (1 0 ) 26 11 37 a9 l 99 56 56 2 2 Company Sanitized. Does not contain TSCA CBI -246- t Subchronic Toxicity 90-Day Oral Gavage Si iy in Rats_________ DuPont-9478 TABLE 42 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTlC LESIONS RATS DESIGNATED FOR RECOVERY L E S IO N S L E S IO N IN C ID E N C E 1 1 M a le s TREATM ENT 0 m g /k g I 125 m g /k g IX U R IN A R Y S Y S T E M K ID N E Y S N O A B N O R M A L IT Y D E T E C T E D C H R O N IC P R O G R E S S IV E N E P H R O P A T H Y . m in im a l t o t a l o b s e r v a tio n s p e r le s io n H Y P E R P L A S IA , T R A N S IT IO N A L C E L L . m in im a l t o t a l o b s e r v a tio n s p e r le s io n H Y D R O N E P H R O S IS , U N IL A T E R A L . m in im a l t o t a l o b s e r v a tio n s p e r le s io n H Y D R O N E P H R O S IS , B IL A T E R A L . m in im a l t o t a l o b s e r v a tio n s p e r le s io n CYST. m in im a l t o t a l o b s e r v a tio n s p e r le s io n (1 0 ) 4 6 6 (1 0 ) 3 5 5 1 1 1 1 1 1 1 1 F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c if ie d w a s n o t id e n t if ie d tis s u e Company Sanitized. Does not contain TSCA C8I -247- f i H H m i m i ^ ^ u b c h r o n i c Toxicity 90^ayQ ral Gavage Study in Rats_________ ) DuPont-9478 TABLE 42 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR RECOVERY L E S IO N S L E S IO N 1 IN C ID E N C E M a le s TREATM ENT 0 m g /k g I 125 m g /k g IX R E S P IR A T O R Y S Y S T E M NOSE N O A B N O R M A L IT Y D E T E C T E D O D O N T O D Y S P L A S IA . m o d e ra te t o t a l o b s e r v a tio n s per le s io n IN F L A M M A T IO N , S U B A C U T E /C H R O N IC . m ild t o t a l o b s e r v a tio n s p e r le s io n D E G E N E R A T IO N , A M E L O B L A S T S . m in im a l t o t a l o b s e r v a tio n s p e r le s io n F ig u r e i n p a r e n th e s e s * ' i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s n o t id e n t if ie d tis s u e (1 0 ). 10 (1 0 ) 7 1 1 1 1 2 2 Company Sanitized. Does not contain TSCA CBI -248- ubchronic Toxicity 90-Day Oral Gavage !u3y in Rats ) DuPont-9478 TABLE 42 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR RECOVERY L E S IO N S L E S IO N IN C ID E N C E M a le s TREATM ENT 0 m g /k g I 125 m g /k g IX L Y M P H A T IC A N D H E M A T O P O IE T IC S Y S T E M THYM US N O A B N O R M A L IT Y D E T E C T E D F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s n o t id e n t if ie d tis s u e (1 0 ) 10 (1 0 ) 10 Company Sanitized. D oes not contain TSCA CBI \ -249- __________________Subchronic Toxicity 90-Day Oral Gavage Stu5y in Rats DuPont-9478 TABLE 42 (CONTENDED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR RECOVERY L E S IO N S L E S IO N IN C ID E N C E M a le s TREATM ENT 0 m g /k g I 125 m g /k g IX E N D O C R IN E S Y S T E M T H Y R O ID G LA N D N O A B N O R M A L IT Y D E T E C T E D A L T E R A T IO N , C O L L O ID . m in im a l m ild m o d e ra te t o t a l o b s e r v a tio n s per le s io n F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly e x a m in e d f o r t h i s T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w as n o t id e n t if ie d tis s u e 6 (1 0 ) 3 5 1 1 7 (1 0 ). 6 2 2 10 Company Sanitized. Does not contain TSCA CB! -250- c 90-Day Oral Gavage Subchronic Toxicity ay in Rats ) DuPont-9478 TABLE 43 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY L E S IO N S TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) F e m a le s 0 m g /k g II 1 m q /k g IV 5 m q /k q VI 25 m g /k g V III 125 m g /k g X D IG E S T IV E S Y S T E M L IV E R N O A B N O R M A L IT Y -D E T E C T E D IN F L A M M A T IO N , S U B A C U T E /C H R O N IC . m in im a l t o t a l o b s e r v a tio n s p e r le s io n H Y P E R P L A S IA , B IL E D U C T . m in im a l t o t a l o b s e r v a tio n s p e r le s io n F A T T Y C H A N G E , M E D IA N C L E F T . m in im a l t o t a l o b s e r v a tio n s p e r le s io n PANCREAS tj N O A B N O R M A L IT Y D E T E C T E D IN F L A M M A T IO N , S U B A C U T E /C H R O N IC . m in im a l t o t a l o b s e r v a tio n s p e r le s io n (1 1 ) 1 10 10 2 2 * 2 2 (1 1 ) 11 F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s N = ll IN GROUP I I DUE TO EAR LY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e (1 0 ) 1 6 6 3 3 1 1 (1 0 ) 9 1 1 Company Sanitized. Does not contain TSCA CBI -251 - 90-Day Oral Gavage ubchronic Toxicity y in Rats ) DuPont-9478 TABLE 43 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY L E S IO N S TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 m g /k g X D IG E S T IV E S Y S TE M ESOPHAGUS N O A B N O R M A L IT Y D E T E C T E D IN F L A M M A T IO N , S U B A C U T E /C H R O N IC . severe total observations per lesion L A C E R A T IO N . STOM ACH N O A B N O R M A L IT Y D E T E C T E D DUODENUM N O A B N O R M A L IT Y D E fE C T E D JEJU N U M N O A B N O R M A L IT Y D E T E C T E D (ID 10 1 1 1 (1 1 ) 11 (1 1 1 11 (1 1 ) 11 F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s N = ll IN GROUP I I DUE TO EARLY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e GO) 10 (1 0 ) 10 GO) TO (1 0 ) 10 Company Sanitized. Does not contain TSCA CBI -252- 1 _ p H H H H H H H H y p u b c h r o n ic Toxicity 90-Day Oral Gavage Study in Rats ) DuPont-9478 TABLE 43 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY L E S IO N S TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ), F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 m g /k g X D IG E S T IV E S Y S TE M IL E U M N O A B N O R M A L IT Y D E T E C T E D CECUM N O A B N O R M A L IT Y D E T E C T E D CO LO N N O A B N O R M A L IT Y D E T E C T E D RECTUM N O A B N O R M A L IT Y D E T E C T E D S A L IV A R Y G LA N D S N O A B N O R M A L IT Y D E T E C T E D (1 1 ) 11 (1 1 ) 11 (1 1 ) 11 (1 1 ) 11 ( ID 11 F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s N = ll IN GROUP I I DUE TO EAR LY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 Company Sanitized. Does not contain TSCA CBI -253- 90-Day Oral Gavage ubchronic Toxicity y in Rats DuPont-9478 TABLE 43 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY L E S IO N S TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 m g /k g X U R IN A R Y S Y S T E M K ID N E Y S N O A B N O R M A L IT Y D E T E C T E D C H R O N IC P R O G R E S S IV E N E P H R O P A T H Y . m in im a l t o t a l o b s e r v a tio n s p e r le s io n IN F L A M M A T IO N , S U B A C U T E /C H R O N IC . m in im a l t o t a l o b s e r v a tio n s p e r le s io n H Y D R O N E P H R O S IS , U N IL A T E R A L . m in im a l t o t a l o b s e r v a tio n s p e r le s io n H Y D R O N E P H R O S IS , B IL A T E R A L . m in im a l t o t a l o b s e r v a tio n s p e r le s io n t U R IN A R Y B L A D D E R N O A B N O R M A L IT Y D E T E C T E D IN F L A M M A T IO N , S U B A C U T E /C H R O N IC . m in im a l t o t a l o b s e r v a tio n s p e r le s io n (1 1 ) 7 2 2 2 2 (1 0 ) 8 2 2 1 1 1 1 (1 1 ) 10 1 1 (1 0 ) 7 3 3 (1 0 ) 7 3 3 (1 0 ) 1 7 7 1 1 1 1 (1 0 ) 10 F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s N = ll IN GROUP I I DUE TO EAR LY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e Company Sanitized. Does not contain TSCA CBI -254- __ ____ Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 TABLE 43 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY L E S IO N S TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 m g /k g X R E S P IR A T O R Y S Y S T E M LUNG S N O A B N O R M A L IT Y D E T E C T E D TRACHEA N O A B N O R M A L IT Y D E T E C T E D P H A R Y N X /L A R Y N X N O A B N O R M A L IT Y D E T E C T E D NOSE N O A B N O R M A L IT Y D E T E C T E D (1 1 ) 11 (1 1 ) 11 (ID 11 (1 1 ) 11 F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s N = ll IN GROUP I I DUE TO EAR LY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e . (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 Company Sanitized. Does not contain TSCA CBI -255- lubchronic Toxicity 90-Day Oral Gavage !u3y in Rats DuPont-9478 TABLE 43 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NON-NEOPLASTlC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY L E S IO N S TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /.k g V III 125 m g /k g X C A R D IO V A S C U L A R S Y S T E M HEART N O A B N O R M A L IT Y D E T E C T E D C A R D IO M Y O P A T H Y . ' m in im a l t o t a l o b s e r v a tio n s per le s io n AO R TA N O A B N O R M A L IT Y D E T E C T E D (1 1 ) 6 5 5 (1 1 ) 11 F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s N = ll IN GROUP I I DUE TO Sa R LY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e (1 0 ) 8 2 2 (1 0 ) 10 Company Sanitized. Does not contain TSCA CBI -256. t Subchronic Toxicity 0-Day Oral Gavage Si ly in Rats DuPont-9478 TABLE 43 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NON-NEOPLASTiC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY L E S IO N S TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) F e m a le s 0 m g/kg II 1 mg/ k g IV 5 m g /k g VI 25 m g /k g V III 125 m g /k g X L Y M P H A T IC A N D H E M A T O P O IE T IC S Y S T E M SPLEEN N O A B N O R M A L IT Y D E T E C T E D ill) 11 THYM US (1 1 ) N O A B N O R M A L IT Y D E T E C T E D 11 M A N D IB U L A R L Y M P H N O D E N O A B N O R M A L IT Y D E T E C T E D M E S E N T E R IC L Y M P H N O D f (1 1 ) 11 (1 1 ) N O A B N O R M A L IT Y D E T E C T E D 11 BO NE MARROW (1 1 ) N O A B N O R M A L IT Y D E T E C T E D H Y P E R P L A S IA , G R A N U L O C Y T IC , m ild t o t a l o b s e r v a tio n s p e r le s io n 10 1 1 F ig u r e - i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s N = ll IN GROUP I I DUE TO E A R LY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 Company Sanitized. Does not contain TSCA CBI -257- Subchronic Toxicity ' 90-Day Oral Gavage Stu5y in Rats DuPont-9478 TABLE 43 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR StJBCHRONIC TOXICITY L E S IO N S TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 . m g /k g X oo 3o <303 3fCi)O N 0 a E N D O C R IN E S Y S T E M P IT U IT A R Y G LA N D N O A B N O R M A L IT Y D E T E C T E D T H Y R O ID G LA N D N O A B N O R M A L IT Y D E T E C T E D P A R A T H Y R O ID G L A N D S N O A B N O R M A L IT Y D E T E C T E D AD R EN AL GLANDS N O A B N O R M A L IT Y D E T E C T E D M IN E R A L IZ A T IO N , m in im a l t o t a l o b s e r v a tio n s per le s io n (1 1 ) 11 (1 1 ) 11 (9 ) 9 (1 1 ) 11 F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s N - ll IN GROUP I I DUE TO E A R LY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e (1 0 ) 10 (1 0 ) 10 (9 ) 9 (1 0 ) 9 1 1 ' Does not contain TSCA CBI -258- Subchronie Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 TABLE 43 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY L E S IO N S TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 m g /k g X NERVOUS SYSTEM B R A IN N O A B N O R M A L IT Y D E T E C T E D S P IN A L CORD N O A B N O R M A L IT Y D E T E C T E D S C IA T IC N ER VE N O A B N O R M A L IT Y D E T E C T E D (1 1 ) 11 (1 1 ) 11 (1 1 ) 11 I sF i g u r e I n p a r e n t h e s e s n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u itib e r in d ic a t e s t h e l e s i o n s p e c i f i e d w a s N = ll IN GROUP I I DUE TO E A R LY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e (1 0 ) 10 (1 0 ) 10 (1 0 ) 10 Company Sanitized. Does not contain TSCA CBI -259- 90-Day Oral Gavage Subchronic Toxicity [y in Rats ) DuPont-9478 TABLE 43 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY L E S IO N S TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 m g /k g X M USCULAR AND S K E LE T A L SYSTEM S K E LE T A L M USCLE N O A B N O R M A L IT Y -D E T E C T E D IN F L A M M A T IO N , S U B A C U T E /C H R O N IC . m in im a l t o t a l o b s e r v a tio n s p e r le s io n F E M U R /K N E E J O IN T N O A B N O R M A L IT Y D E T E C T E D STERNUM N O A B N O R M A L IT Y D E T E C T E D (1 1 ) 11 (1 1 ) 11 (1 1 ) 11 F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c if ie d w a s N = ll IN GROUP I I DUE TO EA R LY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e (1 0 ) 9 1 T (1 0 ) 10 (1 0 ) 10 Company Sanitized. Does not contain TSCA CBI -260- _________ _________ Bubchronic Toxicity 90-Day Oral Gavage Study in Rats__________ DuPont-9478 TABLE 43 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY L E S IO N S TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 m g /k g X R E P R O D U C T IV E S Y S T E M O V A R IE S N O A B N O R M A L IT Y D E T E C T E D UTERUS N O A B N O R M A L IT Y D E T E C T E D M AM M ARY G LA N D (F E M A L E ) N O A B N O R M A L IT Y D E T E C T E D (1 1 ) 11 (U ) 11 (1 1 ) 11 F i g u r e i n p a r e n t h e s e s i 's n u m b e r o f a n im a ls m i c r o s c o p i c a l l y T h e a b s e n c e o f a n u ir b e r in d ic a t e s th e le s io n s p e c if ie d w a s N = ll IN GROUP I I DUE TO EAR LY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e (1 0 ) 10 (1 0 ) 10 (8 ) 8 Company Sanitized. Does not contain TSCA CB! -261 - c ubchronic Toxicity 90-Day Oral Gavage Stu5y in Rats_________ DuPont-9478 TABLE 43 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY L E S IO N S TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 m g /k g X CUTANEOUS SYSTEM S K IN N O A B N O R M A L IT Y D E T E C T E D (1 1 ) 11 F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s N = ll IN GROUP I I DUE TO EAR LY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e (1 0 ) 10 Company Sanitized. Does not contain TSCA CBI -262- subchronic Toxicity i-Day Oral Gavage ITucly in Rats DuPont-9478 TABLE 43 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR SUBCHRONIC TOXICITY L E S IO N S TREATM ENT L E S IO N IN C ID E N C E (N U M E R IC ) F e m a le s 0 m g /k g II 1 m g /k g IV 5 m g /k g VI 25 m g /k g V III 125 m g /k g X S P E C IA L S E N S E S S Y S T E M E Y E (S ) W IT H O P T IC N E R V E N O A B N O R M A L IT Y .D E T E C T E D O P T IC N E R V E N O T P R E S E N T . F O L D /R O S E T T E , R E T IN A L , m in im a l t o t a l o b s e r v a tio n s per le s io n (1 1 ) 11 F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s N = ll IN GROUP I I DUE TO EAR LY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e I (1 0 ) 9 1 1 1 Company Sanitized. Does not contain TSCA CBI -263- ubchronic Toxicity 90-Day Oral Gavage dy in Rats__________ DuPont-9478 TABLE 43 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR RECOVERY L E S IO N S L E S IO N IN C ID E N C E TREATM ENT I F e m a le s 0 m g /k g II 125 m g /k g X D IG E S T IV E S Y S TE M L IV E R N O A B N O R M A L IT Y D E T E C T E D N E C R O S IS , F O C A L . m in im a l t o t a l o b s e r v a tio n s p e r le s io n IN F L A M M A T IO N , S U B A C U T E /C H R O N IC . m in im a l t o t a l o b s e r v a tio n s p e r le s io n H Y P E R P L A S IA , B IL E D U C T . m in im a l t o t a l o b s e r v a tio n s p e r le s io n F A T T Y C H A N G E , M E D IA N C L E F T . m in im a l < m ild t o t a l o b s e r v a tio n s p e r le s io n A N G IE C T A S IS . m in im a l t o t a l o b s e r v a tio n s p e r le s io n F ig u r e in p a r e n th e s e s is n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s N =9 IN GROUP I I DUE TO EA R LY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e (9 ) (1 0 ) 32 1 1 36 36 11 11 1 11 21 2 2 Company Sanitized. Does not contain TSCA CBI -264- Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 TABLE 43 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR RECOVERY L E S IO N S L E S IO N IN C ID E N C E 1 F e m a le s TREATMENT 0 m g /k g XI 125 m g /k g X U R IN A R Y S Y S T E M K ID N E Y S N O A B N O R M A L IT Y D E T E C T E D C H R O N IC P R O G R E S S IV E N E P H R O P A T H Y . m in im a l m ild t o t a l o b s e r v a tio n s p e r le s io n H Y D R O N E P H R O S IS , B IL A T E R A L . m in im a l t o t a l o b s e r v a tio n s p e r le s io n F ig u r e in p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e r^ in d ic a t e s th e le s io n s p e c if ie d w a s N =9 IN GROUP I I DUE TO EAR LY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e (9 ) 4 (1 0 ) 2 55 .3 58 1 1 Company Sanitized. Does not contain TSCA CBI -265- lubchronic Toxicity ' 90-Day Oral Gavage tu3y in Rats DuPont-9478 TABLE 43 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR RECOVERY L E S IO N S L E S IO N IN C ID E N C E F e m a le s TREATMENT 0. m g /k g II 125 mg /k g X E N D O C R IN E S Y S T E M P IT U IT A R Y G LA N D N O A B N O R M A L I T Y 'D E T E C T E D F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s N =9 IN GROUP I I DUE TO EAR LY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e ( l 1 Company Sanitized. Does not contain TSCA CBI -266- _____________Subchronic Toxicity 90-Day Oral Gavage Sway in Rats________ DuPont-9478 TABLE 43 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS NON-NEOPLASTIC LESIONS RATS DESIGNATED FOR RECOVERY L E S IO N S L E S IO N IN C ID E N C E F e m a le s TREATM ENT 0 m g /k g IX 125 m g /k q X R E P R O D U C T IV E S Y S T E M UTERUS D IL A T A T IO N . m ild to ta l o b s e r v a tio n s per le s io n F ig u r e i n p a r e n th e s e s i s n u m b e r o f a n im a ls m ic r o s c o p ic a lly T h e a b s e n c e o f a n u m b e r in d ic a te s th e le s io n s p e c ifie d w a s N =9 IN GROUP I I DUE TO EAR LY DEATH e x a m in e d f o r t h i s n o t id e n tifie d tis s u e il) 1 1 Company Sanitized. Does not contain TSCA CBI -267- C fig u res Company Sanitized. Does not contain TSCA CBI /"N ubchronic Toxicity 90-Day Oral Gavage 3 y in Rats__________ FIGURES EXPLANATORY NOTES DuPont-9478 Critical Dates Day 91 . Last day of test substance administration for rats designated for satellite bleeds and 3-month recovery. Last day of non-fasted body weight and food consumption data collection for rats designated for the 90-day exposure period. Last day of food consumption data collection for rats designated for satellite bleeds in the 1, 5, and 25 mg/kg/day dose groups. Day 92 Last day of test substance administration for male rats designated for the 90-day exposure period. Day 93 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 94 Female rats designated for 90-day exposure period were sacrificed. Day 175 Rats designated for satellite bleeds were sacrificed Day 182 Last day of non-fasted body weight and food consumption data collection for rats designated for the 3-month recovery period. Day 183 Male and female rats designated for the 3-month recovery period were sacrificed. -269Company Sanitized. Does not contain TSCA CBi ISubchronic Toxicity 90-Day Oral Gavage Sfudy in Rats__________ FIGURE 1 MEAN BODY WEIGHTS OF MALE RATS 800 Exposure Period (test days 0-92) Recovery Period (test days 92-182) DuPont-9478 0 mg/kg/day - B - -1 mg/kg/day - r -5 mg/kg/day -25 mg/kg/day -125 mg/kg/day Company Sanitized. Does not contain TSCA C8I 0 7 14 21 28 35 42 49 56 63 70 77 84 91 98 105 112 119 126 133 140 147 154 161 168 175 182 Days on Test -270- FIGURE 2 MEAN BODY WEIGHTS OF FEMALE RATS DuPont-9478 Company Sanitized. Does not contain TSCA CBI 271 - ) ubchronic Toxicity ! in Rats DuPont-9478 1.6 -, 1.4 - 1.2 - 60 t1 1 CO u 0.8 1 0.6 Ifr * 0.4 0.2 FIGURE 3 MEAN FORELIMB GRIP STRENGTH FOR MALE RATS Baseline Error bars represent standard deviation Assessment Period Week 13 0 mg/kg/day H I mg/kg/day H 5 mg/kg/day 25 mg/kg/day 125 mg/kg/day *1 Company Sanitized. Does not contain TSCA CBI -272- ubchronic Toxicity 90-Day Oral Gavage By in Rats FIGURE 4 MEAN FORELIMB GRIP STRENGTH FOR FEMALE RATS DuPont-9478 Company Sanitized. Does not contain TSCA CBI 1.4 ! 1.2 - a 1 % 010 08 O 0.6 1 1* 0.4 - I * 0.2 - 0 Baseline Assessment Period Error bars represent standard deviation * Statistically significant difference from control at p<0.05. - 273 - Week 13 0 mg/kg/day D 1 mg/kg/day B 5 mg/kg/day 1125 mg/kg/day 125 mg/kg/day ISubchronic Toxicity 90-Day Oral Gavage lay in Rats FIGURE 5 MEAN HDNDLIMB GRIP STRENGTH FOR MALE RATS ) DuPont-9478 0.8 -I 0.7 0.6 - 0 mg/kg/day oo B 1 mg/kg/day T3J Rl 5 mg/kg/day >B3<) 1125 mg/kg/day CO 125 mg/kg/day Q> 3 N(B a oa In o3 ft* ao 3 Sr-?+- Baseline Week 13 5' H Assessment Period >COO o Error bars represent standard deviation CO - 274 - 'ubchronic Toxicity 90-Day Oral Gavage By in Rats FIGURE 6 MEAN HINDLIMB GRIP STRENGTH FOR FEMALE RATS DuPont-9478 0.7 -, 0.6 - 0 mg/kg/day U 1 mg/kg/day 115 mg/kg/day 1125 mg/kg/day 125 mg/kg/day Company Sanitized. Does not contain TSCA C8J Baseline Error bars represent standard deviation Assessment Period Week 13 -275 - subchronic Toxicity 90-Day Oral Gavage ! 3y in Rats FIGURE 7 MEAN TOTAL DURATION OF MOVEMENT FOR MALE RATS ) DuPont-9478 2500 -1 2000 - 0 mg/kg/day U 1 mg/kg/day 5 mg/kg/day. B 25 mg/kg/day 125 mg/kg/day Company Sanitized. Does not c o n t a in TSCA C B I Baseline Error bars represent standard deviation Assessment Period Week 13 -276- c fcubchronic Toxicity 90-Day Oral Gavage 3Wroy in Rats FIGURE 8 MEAN TOTAL DURATION OF MOVEMENT FOR FEMALE RATS DuPont-9478 2500 2000 - i5o> 1500 s !o ao 1000 Q 500 - ,;;iW 0 mg/kg/day 131 mg/kg/day D 5 mg/kg/day 25 mg/kg/day 125 mg/kg/day Company Sanitized. D oes not contain TSCA CBI Baseline Error bars represent standard deviation Assessment Period Week 13 -277- ISubchronic Toxicity 90-Day Oral Gavage : Tuny in Rats FIGURE 9 MEAN TOTAL NUMBER OF MOVEMENTS FOR MALE RATS ) DuPont-9478 Company Sanitized. Does not contain TSCA CBI 900 -i 800 - 700 - a 600 - 1 S 500 - S s 400- ! 2 300- 200 - 100 - 0- Baseline Assessment Period Error bars represent standard deviation. * Statistically significant difference from control at p<0.05. -278 - Week 13 O 0 mg/kg/day i l 1 mg/kg/day 5 mg/kg/day H 25 mg/kg/day 125 mg/kg/day 1 ___ Subchronic Toxicity 90-Day Oral Gavage Study in Rats FIGURE 10 MEAN TOTAL NUMBER OF MOVEMENTS FOR FEMALE RATS DuPont-9478 Omg/kg/day i l 1 mg/kg/day o 5 mg/kg/day O 3u) H 25 mg/kg/day . <3 B 125 mg/kg/day CSO/> 3rV, <a& wooo 3 O r4* oo3 Baseline Week 13 sr 5' Assessment Period H O>C/> Error bars represent standard deviation OOd -279- ;ubchronic Toxicity 90-Day Oral Gavage Ely in Rats__________ DuPont-9478 APPENDICES - 280 Company Sanitized. Does not contain TSCA CBI lubchronic Toxicity 90-Day Oral Gavage Sy in Rats_________ DuPont-9478 Critical Dates APPENDICES EXPLANATORY NOTES Day 91 Last day of test substance administration for rats designated for satellite bleeds and 3-month recovery. Last day of non-fasted body weight and food consumption data collection for rats designated for the 90-day exposure period. Last day of food consumption data collection for rats designated for satellite bleeds in the 1, 5, and 25 mg/kg/day dose groups. Day 92 Last day of test substance administration for male rats designated for the 90-day exposure period. Day 93 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 94 Female rats designated for 90-day exposure period were sacrificed. Day 175 Rats designated for satellite bleeds were-sacrificed Day 182 Last day of non-fasted body weight and food consumption data collection for rats designated for the 3-month recovery period. Day 183 Male and female rats designated for the 3-month recovery period were sacrificed. Note mg/kg = mg/kg/day -281Company Sanitized. Does not contain TSCA CBI _ubchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 APPENDIX A ANALYTICAL DATA I /*J**l|***iv - 282Company Sanitized. Does not contain TSCA CBI ubchronic Toxicity 90-Day Oral Gavage !3y in Rats DuPont-9478 w H nTable I. Homogeneity and Stability Sample mg/m lV lo sin g Suspensions Percent Type Nominal Measured Nominal Test Day 1/-6 Homogeneity C ontrol T op M eddle B ottom 0.00 0.20 0.20 0.20 n d (A ) 0.163 0.164 0.161 -- 81.5 82.0 80.5 M ea ii& l- 0.1630.002 C.V. 1% (81.5% ) TOP M iddle B ottom 1.0 0.803 1.0 0.857 1.0 0.890 M ean : 0.8500.04 C.V. 5% 80.3 85.7 89.0 (85.0% ) Top M iddle B ottom 5.0 4.55 5.0 4.80 5.0 4.61 M ean : 4.650.13 C.V. 3% 91.0 96.0 92.2 (93.0% ) T o p .. middle B ottom 25.0 19.9 25.0 21.9 25.0 22.9 M ea n ; 21.61.5 ,, C.V. 7% 79.6 87.6 91.6 (86.4%) Stability 5Hour 0.20 1.0 5.0 25.0 0.167 0.818 4.14 21.8 83.5 81.8 82.8 87.2 7-Da y Refrigerated 0.2 0.161 0.2 0.173 Mean: 0.1670.01 a v .5 % 80.5 86.5 (83.5%) 5 H o u r 0.2 0.158 79.0 (A) D enotes not detected. (B) The average m easured concentration, average percent of nom inal (in parentheses), standard deviation, and coefficient o f variation o f top, m iddle, and bottom. (C) D uplicate reanalysis of original sam ple support original analysis and are not reported. (D) Stability sam ples held 5 hours a room temperature. (E) The average measured concentration, average percent o f nom inal (in parentheses), standard deviation, and coefficient of variation of duplicate samples. -283 Company Sanitized. Does not contain TSCA CBI Jsubchronic Toxicity 90-Day Oral Gavage Study in Rats_________ DuPont-9478 Table I. Homogeneity and Stability o1 Dosing Suspensions (continued) Sample __________ ____________________________________ Type________ Nominal * * Measured Test Day 4(F) Homogeneity Control 0.00 ND(A) Top 1.0 0.944 M iddle Bottom 1.0 1.0 0.884 0.836 (C) Percent Nominal -- 94.4 88.4 83.6 TOP M iddle Bottom Mean(B): 0.888+0.05 C.V. 6% 5.0 4.43 5.0 4.37 5.0 4.72 (O (88.8% ) 88.6 87.4 94.4 Top M iddle B ottom 25.0 25.0 25.0 M e a n iB); 4.51 0.19 C.V. 4% 22.2 22.7 24.2 (90.2% ) 88.8 90.8 96.8 Stability 5 H o u r (D) 1.0 5.0 25.0 M ean(B): 23.0+1.0 C.V. 5% 0.854(G) 4.75 24.0 (92.0% ) 85.4 95.0 96.0 7-Da y R efrigerated Top M iddle Bottom 1.0 1.0 1.0 0.900 0.864 0.859 90.0 86.4 85.9 M e a n iB); 0.8740.02 (87.4% ) C.V. 3% #1 5.0 4.46 89.2 #2 5.0 4.44 88.8 M ean(): 4.45+0.01 (89.0% ) C.V. 0.2% #1 25.0 24,2 96.8 #2 25.0 23.9 95.6 M ea n iE); 24.1+ 0.21 (96.4% ) C.V. 1% 5 H o u r (D) 1.0 5.0 25.0 0.904(H) 4.21(H) 21.2(H) 90.4 84.2 84.8 (A) Denotes not detected. (B) The average m easured concentration, average percent o f nom inal (in parentheses), standard deviation, and coefficient o f variation o f top, m iddle, and bottom. (C) D uplicate reanalysis o f original sam ple support original analysis and are not reported.. (D) Stability sam ples held 5 hours a room tem perature. (E) T he average m easured concentration, average percent o f nom inal (in parentheses), standard deviation, and coefficient o f variation for duplicate sam ples. (F) Sam ples analyzed in a previous s t u d y B H H H H H H H H H H H W ^ P (G) M e an resu lt o f a ll reported analyses except fo r o n e d uplicate repeat sam ple. A liq u o t error c a u sed re su lt to b e low. (H) M ean result o f duplicate re-sam pling from the original diluted sample. O riginal result was low er than expected due to aliquot error. - 284Company Sanitized. Does not contain TSCA CBI Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 Table II. Concentration Verification o Preparation Day ________Sam ple Type_______________ Test Day 42 Concentration Verification^ ) Control 0.0 ND(b ) Percent Nominal 0.2-1(0) 0.2-l(l) 0.2-1(2) 0.2-2(O) 0.2-2(l) 0.2-2(2) m ean^-h 0.153 0.158 0.158 0.156 0.167 0.170 0.169 76.5 79.0 79.0 78.0 83.5 85.0 84.5 m ea n ^ X - 0.169 84.5 l.O-l(O) 1.0-1(1) 1.0-1(2) M ean(D h 0.163 0 .0 1 C.V. 6% 0.718 0.757 0.773 (81.5) 71.8 75.7 77.3 1.0-2(0) 1.0-2(1) 1.0-2(2) m ean^X ' 0.749 0.764 0.779 0.784 74.9 76.4 77.9 78.4 meanXX-X 0.776 77.6 5.0-1(0) 5.0-l(l) 5.0-1(2) M e a n tD X- 0.763 0 .0 2 C.V. 3% 3.89 3.82 3.89 (76.3) 77.8 76.4 77.8 5.0-2(l) 5.0-2(2) m eaner 3.87 3.89 3.93 77.3 77.8 78.6 r n e a n & X 3.91 78.2 25.0-1(1) 25.0-1(2) M ean(D h 3.89 0 .0 3 C.V. 1% 19.4 19.4 (77.8) 77.6 77.6 25.0-2(1) 25.0-2(2) meant^X- 19.4 19.3 ' IO m eanX E ): 19.1 77.6 77.2 75.2 76.2 M ean < D X- 1 9 .3 0 . 2 1 (77.2) C .V .1% (A) Duplicate sam ples (-1, -2) per level were analyzed. M ean, S.D. and C.V. calculated to verify uniform ity o f mixture. (B) Denotes not detected. (C) M ean result o f the original analysis [(O)], and duplicate reanalysis o f the original sam ple [(1), (2)]. (D) The average m easured concentration, average percent o f nom inal (in parentheses), standard deviation, and coefficient o f variation for duplicate samples (E) M ean result o f duplicate reanalysis on the original subm itted sam ple [(1), (2)]. O riginal analysis not reported due to aliquot error. -285Company Sanitized. Does not contain TSCA CBI ubchronic Toxicity 90-Day Oral Gavage dy in Rats DuPont-9478 Table II. Concentration Verification o: in Dosing Solutions (continued) Preparation Day Sample Type Test D ay 45 Nominal Measured Percent Nominal Concentration V erification^) Control 0.0 0.24(0) 0.24(1) 0.2-1(2) n d (b ) 0.065 0.067 0.065 -- 32.5 33.5 32.5 m eantP): 0.2-2(O) 0.2-2(l) 0.2-2(2) 0.066 0.081 0.083 0.084 33.0 40.5 41.5 42.0 mea(Q: 0.083 41.5 M e a n tP ): 1.04(0)' 1.04(1) 1.0-1(2) 0.075 0.01 C.V. 13% 0.662 0.678 0.687 (37.5) 66.2 67.8 68.7 mean(C): 1.0-2(0) 1.0-2(1) 1.0-2(2) 0.676 0.646 0.657 0.665 67.6 64.6 65.7 66.5 m e a n iQ : 0.656 65.6 M eanP ): 5.04(0) 5.04(1) 5.04(2) 0.666 0.01 C.V. 2% 2.13 2.27 2.21 (66.6) 42.6 45.4 44.2 m eariiQ : 5.0-2(O) 5.0-2(l) 5.0-2(2) 2.20 2.26 2.36 2.33 44.0 45.2 47.2 46.6 m e a n t Q: 2.32 46.4 M eanP): 25.0-1(1) 25.0-1(2) 2.26 0.09 C .V .4% 8.31 8.36 (45.2) 33.2 - 33.4 m eanP): ' 25.0-2(1) 25.0-2(2) 8.34 8.76 8.52 33.4 35.0 34.1 m ea n (P ); 8.64 34.6 M ean(P): 8.49 0 .2 1 C.V. 3% (34.0) (A) D uplicate samples (-1, -2) per level were analyzed. M ean, S.D. and C.V. calculated to verity uniform ity o f m ixture. (B) Denotes not detected. (C) M ean result o f the original analysis 1(0)1, and duplicate reanalysis o f the original sam ple [(1), (2)]. (D) The average m easured concentration, average percent o f nom inal (in parentheses), standard deviation, and coefficient o f variation for duplicate samples. (E) M ean result of duplicate reanalysis on the original subm itted sam ple [(1), (2)J. Original analysis n o t reported due to aliquot error. -286Company Sanitized. Does not contain TSCA CBI ^!?BSb\ Subchronic Toxicity 90-Day Oral Gavage Study in Rats_________ DuPont-9478 T able II. Concentration V erification o: Preparation Day ms/m Sample Type N om in al Test Day 4 8 ^ Concentration Verification(A) Control 0.0 n D osing Solutions (continued) Percent Measured N o m in a l n d (b ) -- 0.2-1 0.2-2 1.0-1 1.0-2 5.0-1 5.0-2 25.0-1 25.0-2 Test Day 52 Concentration Verification^) Control 0.0 0.197 0.219 M eant); 0.208 0.02 C.V. 7% 0.865 0.948 M eanfh 0.907 0 .0 6 C.V. 6% 3.93 3.90 M eant ); 3.92 0.02 C.V. 1% 21.9 22.5 M eant ); 22. 2 0.42 C.V. 2% n d (b ) 98.5 109.5 (104.0) 86.5 94.8 (90.7) 78.6 78.0 (78.3) 87.6 90.0 (88.8) -- 0.2-1 0.2-2 1.0-1 1.0-2 5.0-1 5.0-2 25.0-1 25.0-2 0.174 0.184 M eant ); 0.179 0 .0 1 C.V. 4% 0.845 0.895 M eant ); 0.870 0 .0 4 C.V. 4% 4.22 4.16 M eant); 4.19 0 .0 4 C.V. 1% 23.5 22.3 M eant); 22.9 0.85 C.V. 4% 87.0 92.0 (89.5) 84.5 89.5 (87.0) 84.4 83.2 (83.8)- 94.0 89.2 (91.6) (A ) D u p licate sam ples (-1, -2) p e r level w ere analyzed. M ean, S.D . a n d C .V . calculated to verify uniform ity of m ixture. (B) Denotes not detected. (D) The average m easured concentration, average percent o f nom inal (in parentheses), standard deviation, and coefficient o f variation for duplicate sam ples. (F) Suspension not dosed to animals. -287 Company Sanitized. Does not contain TSCA CBI ubchronic Toxicity 90-Day Oral Gavage 3y in Rats DuPont-9478 Table II. Concentration Verification o Preparation Day _______ Sam ple T ype_______________ Test Day 56 Concentration Verification^ ) Control 0.0 0.2-1 0.2-2 Mean!): 1.0-1 1.0-2 Mean!'): 5.0-1 5.0-2 Mean!): 25.0-1 25.0-2 Mean!): n d (b ) 0.167 0.189 0.178 0.02 C.V. 9% 0.964 0.950 0.957 0.01 C.V. 1% 4.41 4.31 4.36 0.07 C.V. 2% 22.8 21.4 22.1 0.99 C.V. 4% -- 83.5 94.5 (89.0) 96.4 95.0 (95.7) 88.2 86.2 (87.2) 91.2 85.6 (88.4) Test Day 58 Concentration Verification^ ) Control 0.0 n d (B) -- 0.2-1 0.174 87.0 0.2-2 0.150 75.0 Mead): 0.162 0.02 C.V. 10% (81.0) 1.0-1 1.0-2 0.945 0.937 94.5 93.7 Meat!): 0.941 0.01 C.V. 1% (94.1) 5.0-1 5.-2 4.48 4.17 89.6 *" 8 3 .4 Mead): 4.33 0.22 C.V. 5% (86.5) 25.0-1 25.0-2 22.5 22.1 90.0 88.4 Mead); 22. 3 0.28 (89.2) C.V. 1% (A) Duplicate samples (-1, -2) per level were analyzed. Mean, S.D. and C.V. calculated to verify uniformity of mixture. (B) Denotes not detected. (D) The average measured concentration, average percent of nominal (in parentheses), standard deviation, and coefficient of variation for duplicate samples. -288Comparty Sanitized. Does not contain TSCA CBI Subchronic Toxicity 90-Day Oral Gavage Study in Rats DuPont-9478 Table II. Concentration V erification o: Preparation Day ________ Sam ple Type________ ' Test D ay 65 ma/rri Nominal Concentration Verification^ ) Control 0.0 in D osing Solutions (continued) Percent Measured N om in al n d (B) -- 0.2-1(0) 0.2-K l) 0.2-1(2) 0.158 0.158 0.162 79.0 79.0 81.0 mean(C\- 0.2 -2 (O ) 0.2-2 ) 0.2-2(2) 0.159 0.148 0.149 0.153 79.5 74.0 74.5 76.5 mean(P\- 0.150 75.0 M ean^h 0.155 0.01 C.V. 4% (77.5) 1.0-1 1.0-2 0.832 0.898 83.2 89.8 Mean(D); 0.865 0.05 C.V. 5% (86.5) 5.0-1 5.0-2 4.32 4.40 86.4 88.0 M ean(h 25.0-1 25.0-2 4.36 0 .0 6 C.V. 1% 20.8 20.5 (87.2) 83.2 82.0 M ean(h 20.7 0.21 (82.6) C.V. 1% (A) Duplicate samples (-1, -2) per level were analyzed. Mean, S.D. and C.V. calculated to verify uniformity of mixture. (B) Denotes not detected. (G) Mean result of the original analysis [(O)], and duplicate reanalysis of the original sample [(1), (2)]. (D) The average measured concentration, average percent of nominal (in parentheses), standard deviation, and coefficient of variation for duplicate samples. -289Company Sanitized. Does not contain TSCA CB1 ISubchronic Toxicity 90-Day Oral Gavage Study in Rats_________ DuPont-9478 Table II. Concentration Verification o f Preparation Day Sample Type Test Day 91 m g/m Lj N om in a l Concentration V erification^) Control 0.0 jin D osin g Solutions (continued) Measured Percent Nominal n d (b > --- 0.2-1 0.162 81.0 0.2-2 0.165 82.5 M ean(Dh 0.164 0.002 C.V. 1% (82.0) 1.0-1(0) 1.0-1(1) 1.0-1(2) 0.781 0.744 0.754 78.1 74.4 75.4 1.0-2 m ean (C); 0.760 0.863 76.0 86.3 M e a n (D ): 0 .8 1 2 0 .0 7 C.V. 9% (81.2) 5.0-1(0) 5 .0 -l(l) 5.0-1(2) 3.90 4.07 3.91 78.0 81.4 78.2 m ean(^); 3.96 79.2 - 5.0-2(0) 3.81 76.2 5.0-2(1) 3.98 79.6 5.0-2(2) 3.90 78.0 mean(Q: 3 .9 0 78.0 M eant ); 3.93 0.04 C.V. 1% (78.6) 25.0-1(0) 25.0-1(1) 25.0-1(2) 19.1 20.3 20.2 76.4 81.2 80.8 2 5 .0 -2 (0 ) 25.0-2(1) 25.0-2(2) m ean (C); 19.9 18.8 18.9 18.4 76.4 75.2 75.6 73.6 mean(Q: 18.7 74.8 Meant); 19.3 0.85 C .V .4% ^ (77.2) (A) Duplicate samples (-1,-2) per level were analyzed. Mean, S.D. and C.V. calculated to verify uniformity of mixture. (B) Denotes not detected. (C) Mean result of the original analysis [(O)], and duplicate reanalysis of the original sample [(1), (2)]. (D) The average measured concentration, average percent of nominal (in parentheses), standard deviation, and coefficient of variation for duplicate samples. ' _ 29Q _ Company Sanitized. Does not contain TSCA CBi Subchronic Toxicity 50-Day Oral Gavage Study in Rats DuPont-9478 Table II. Concentration Verification o Preparation Day _____ ______ Sample Type_____________ Nominal Test D ay 63 Concentration Verification^ ) Control 0.0 fin D osin g Solutions (continued) Measured Percent Nominal n d (b ) -- 0.2-1 0.2-2 1.0-1 1.0-2 5.0-1 5.0-2 25.0-1 25.0-2 M eant M ead^h M ean(Ch M ean(C ): 0.190 0.192 0.191 0 .0 0 1 C.V. 1% 0.784 0.792 0.788 0 .0 1 C.V. 1% 4.12 4.08 4.10 0.03 C.V. 1% 23.0 21.4 22.2 1 .1 C.V. 5% 95.0 96.0 (95.5) 78.4 79.2 (78.8) 82.4 81.8 (82.0) 92.0 85.6 (88.8) Test Day 73 Concentration Verification^ ) Control 0.0 n d (c ) -- 0.2-1 0.2-2 0.176 0.155 88.0 77.5 M eant 0.166 0.01 C.V. 9% (82.8) 1.0-1 1.0-2 0.980 1.03 98.0 103.0 M ean(C): L 0 1 0 .0 4 C.V. 4% (101.0) 5.0-1 5.-2 4.57 4.60 91.4 92.0 M ecm W : 4.59 0.02 C.V. 0.4% (91.8) 25.0-1 25.0-2 23.3 24.4 93.2 97.6 M ean(Ch 23.9 0.78 (95.6) C.V. 3% (A) Duplicate samples (-1, -2) per level were analyzed. Mean, S.D. and C.V. calculated to verify uniformity of mixture. (B) Denotes not detected. (D) The average measured concentration, average percent of nominal (in parentheses), standard deviation, and coefficient of variation for duplicate samples. -291 Company Sanitized. Does not contain TSCA CB1 | Subchronic Toxicity 90-Day Oral Gavage Study in Rats Figure 1 Representative Analytical Calibration Curve DuPont-9478 Figure 1: Calibration curve showing linear fit Gine) to replicate peak^eight ratio measurements (squares) for calibration solutions of^0IM BBflH BH H (pdiluted over a concentration range of 0.0050 to 0.0453 mg/rhL with the 0 mg/mL control diluted sample was used as the zero. - 292Company Sanitized. Does not contain TSCA CBI 90-Day Oral Gavage Subchronic Toxicity ly in Rats DuPont-9478 Figure 2 Representative High Performance Liquid Chromatography Chromatograms Figure 2a: Rggresentative HPLC chromatogran^f 0 mg/mL (control) s a m ^ with internal standa^ approximately 3.5 minutest Retention time fSr nternal standard is approximately 3.9 minutes. ^ Figure 2b: Representative HPLC chromatogram of 5.0 m g /in l^ B H H H H H H H iH lo s in g solution diluted to a nominalconcentration of 0.03 mg/mL. The measured concentration of me representative solution is 4.85 mg/mL Figure 2c: Representative HPLC chromatogram of 0.0302 mg/mL reference solution. .nalytical -293Company Sanitized. Does not contain TSCA CBI