Document ppzZoYYVK1K2ddb7XyMyjxmQw

m 478 TRADE SECRET Study Title H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 Test Guidelines: U.S. EPA Health Effects Test Guidelines OPPTS 870.3200 (1998) OECD Guidelines for Testing of Chemicals Section 4: Health Effects, Number 410 (1981) Author: Carol Finlay, B.A. Study Completed on: September 3,2003 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 Laboratory Project ID: DuPont-11574 Work Request Number: mService Code Number: Comoanv Sanitized. Does not contain TSCA CBI Page 1 o f 154 H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT This study was conducted in compliance with U.S. EPA TSCA (40 CFR part 792) Good Laboratory Practice Standards, which are consistent with the OECD Principles of Good Laboratory Practice (as revised in 1997) published in ENV/MC/CHEM(98) except for the item documented below. The item listed does not impact the validity of the study. Test substance characterization and stability analyses were performed at Regional Analytical Services (RAS), Deepwater, New Jersey. None of the aforementioned analyses were performed under Good Laboratory Practice Standards; however, the analyses were conducted in compliance with IS09002 regulations. All of the analyses are considered valid and sufficient for the purposes of this study. Applicant / Sponsor: E.I. du Pont de Nemours and Company Wilmington, Delaware 19898 U.S.A. Study Director:__________ ? M & t f a l l u Carol Finlay, B.A. ( Staff Toxicologist Date Applicant / Sponsor:______________________________________ _ _________ DuPont Representative Date Company Sanitized. Does not contain TSCACB1 -2- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ QUALITY ASSURANCE STATEMENT DuPont-11574 Haskell Sample Number(s): 25435 Dates of Inspections: Protocol: October 21,2002 Conduct: November 12, 2003 November 19,2002 November 27,2002 March 5,2003 Records, Reports: February 26,2003 February 28, 2003 March 3, 2003 March 17-18, 2003 July 16, 17, 18,21,2003 Dates Findings Reported to: Study Director: October 21,2002 February 26, 2003 March 3, 2003 March 5,2003 March 18,2003 July 31,2003 Management: October 21,2002 February 26,2003 March 3, 2003 March 5, 2003 March 20, 2003 August 25, 2003 Reported by: Denise Mijjmney Q Quality Assurance Auditor '2 ^ 3 ale Company Sanitized. Doss not contain TSCACB -3 - H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11574 CERTIFICATION We, the undersigned, declare that this report provides an accurate evaluation of the data obtained from this study. C lin ical P athology E valuation by: .O -, J N aniy E . Evente, D.V.M . D iplom ate A .C .V .P. Principal R esearch Scientist A natom ic P athology E valuation by: T ju c - P eter C. M ann, D.V .M . D iplom ate A.C.V P . V eterinary Pathologist A pproved by: %u*& Scott E . L oveless, Ph.D . M anagement D ate X '& P-ZW D ate 2-S efT D ate Issued by S tudy D irector: fi /ltL 'ichiiUfr C afol Finlay, B A . S taff T oxicologist ... D ate Company Sanitized. Dcas not contain TSCA CBI H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male R ats_____ _______ DuPont-11574 TABLE OF CONTENTS Page GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT..................................2 QUALITY ASSURANCE STATEMENT................................................................................... 3 CERTIFICATION....................... .................................................................................................4 LIST OF TABLES.......................................................................................... ..............................7 LIST OF FIGURES .......................................................................... 8 LIST OF APPENDICES...............................................................................................................8 STUDY INFORMATION.............................................................................................................9 STUDY PERSONNEL......................................................... 10 SUMMARY.................................................................................................................................. 11 INTRODUCTION....................................................................................... 12 STUDY DESIGN..........................................................................................................................12 MATERIALS AND METHODS................................................................................................12 A. Test Guidelines..................................................................................................................12 B. Test Substance.......................... 13 C. Test Species.......................................................................................................................13 D. Animal Husbandry.............. 13 1. Housing............................................................................................................................................................. 13 2. Environmental Conditions............................................................................................................................... 13 3. Feed and W ater..........i..................................................................................................................................... 13 4. Identification.................................................................................................................................................... 13 5. Health Monitoring Program............................................................................................................................14 E. Pretest Period...................................... 14 F. Assignment to Groups and Study Start.............................................................................. 14 G. Test Substance Preparation and Administration................................................................14 H. Body Weights.....................................................................................................................15 I . . Food Consumption and Food Efficiency.....................,,............................................ .......15 J. Mortality and Clinical Observations.................................................................................. 15 K. Total Fluorine and Perfluorooctanoic Acid Level Evaluations..........................................16 L. Clinical Pathology Evaluation........................................................................................... 16 1. Hematology...................................................................................................................................................... 16 2. Clinical Chemistry............................................................................................................................................17 3. Urinalysis..........................................................................................................................................................17 M. Anatomic Pathology Evaluations.......................................................................................18 N. Statistical Analyses............................................................................................................19 Company Sanifed. Boos ncl ooma,,, TSCACH H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats _________ DuPont-11574 TABLE OF CONTENTS (Continued) Page RESULTS AND DISCUSSION..................................................................................................20 In-Life Toxicology........................................................................................................................ 20 A. Mean Body Weights and Body Weight Gains...................................................................20 B. Food Consumption and Food Efficiency...........................................................................20 C. Clinical Observations, Dermal Evaluations, and Survival.................................................20 D. Blood Fluorine Analysis............................................................ E. In-Life Conclusions......................................................................................... 21 Clinical Pathology Evaluations...................................................................................................21 A. Hematology.................................................... 21 B. Clinical Chemistry.............................................................................................................21 C. Urinalyses...........................................................................................................................23 D. Urine and Plasma Fluoride........................................................................................... 23 E. Clinical Pathology Conclusions.........................................................................................23 Anatomic Pathology Evaluations............................................................................... ..24 A. Mortality.................................................................................................... /"--n B. Organ Weights.................................................................................................................. 24 C. Gross Observations........................................................................................................... 24 D. Microscopic Findings........................................................................................................ 24 E. Anatomic Pathology Conclusions.................................................................................. 24 CONCLUSIONS..........................................................................................................................25 RECORDS AND SAMPLE STORAGE....................................................................................25 R E F E R E N C E S ............................................................................................................................. 25 TABLES.......................................................................................................... FIGURES......................................................................................................................................51 APPENDICES..............................................................................................................................53 Company Sanitized. Does not contain TSCA CBl H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11574 LIST OF TABLES Page 1. MEAN DAILY APPLIED DOSE VOLUMES FOR MALE R A TS......................................................................... 30 2. MEAN BODY WEIGHTS OF MALE RATS..............................................................................................................33 3. MEAN BODY WEIGHT GAINS OF MALE RATS....... .......................................................................................... 34 4. MEAN DAILY FOOD CONSUMPTION BY MALE RATS.................................................................................... 35 5. MEAN DAILY FOOD EFFICIENCY OF MALE RATS...........................................................................................36 6. SUMMARY OF CLINICAL OBSERVATIONS IN MALE R A TS......................................................................... 37 7. SUMMARY OF CLINICAL OBSERVATIONS - POST DOSING IN MALE RATS..........................................38 8. PERCENT SURVIVAL OF MALE RATS..................................................................................................................40 9. SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS................................................. 41 10. SUMMARY OF CLINICAL CHEMISTRY VALUES FOR MALE R A TS...........................................................43 11. SUMMARY OF URINALYSIS VALUES FOR MALE R A TS............................................................................... 45 12. MEAN FINAL BODY AND ORGAN WEIGHTS FROM MALE R A TS.............................................................. 46 13. INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS................................................................... 47 14. INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE R A TS................48 Company Sanitized. Does not contain TSCACBl -7 - H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats __________ DuPont-11574 LIST OF FIGURES Page 1. MEAN BODY WEIGHTS OF MALE RATS.............................................................................................................52 LIST OF APPENDICES Page A. INDIVIDUAL DAILY APPLIED DOSE VOLUMES............................................................................................. 54 B. INDIVIDUAL BODY WEIGHTS.............................................................................................................................. 63 C. INDIVIDUAL FOOD CONSUMPTION................................................................................................................. 66 D. INDIVIDUAL CLINICAL OBSERVATIONS AND MORTALITY RECORDS.............................................. . 68 E. INDIVIDUAL CLINICAL OBSERVATIONS - POST-DOSING........................................ !.................................78 F. INDIVIDUAL EDEMA AND ERYTHEMA SCORES.............................................................................................88 G. INDIVIDUAL BLOOD FLUORINE LEVELS.......................................................................................................102 __ H. INDIVIDUAL ANIMAL CLINICAL PATHOLOGY DATA................................................................................104 I. INDIVIDUAL ANIMAL FINAL BODY AND ORGAN W EIGHTS.................................................................. 128 J. INDIVIDUAL ANIMAL PATHOLOGY DATA ............................................................... .................................... 133 /*******-, Company Sanitized. Doss not contain TSCACBI -8- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats STUDY INFORMATION Substance Tested: Svnonvms/Codes: Haskell Number: 25435 Composition: DuPont-11574 Known Impurities: Sponsor: E. I. du Pont de Nemours and Company Wilmington, Delaware 19898 U.S.A. Study Initiated/Completed: October 25, 2002 / (see report cover page) Company Sanitized. Does not contain TSCA GB! H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11574 STUDY PERSONNEL Study Director: Carol Finlay, B.A. Management: Scott E. Loveless, Ph.D. Primary Technician: Sherman J. Gude Clinical Pathologist: Nancy E. Everds, D.V.M. Management: Steven R. Frame, D.V.M., Ph.D. Anatomic Pathologist: Peter C. Marni, D.V.M. Management: Steven R. Frame, D.V.M., Ph.D. Peer Review Anatomic Pathologist: John F. Hansen, D.V.M., Ph.D. Statistical Analysis: John W. Green, Ph.D. Management: Janice L. Connell, M.S., B.A., C.I.H. Toxicology Report Preparation: Brenda Tiffin Cecilia Rowe Kee, B.S. Management: Nancy S. Selzer, M.S. Laboratory Veterinarian: Thomas W. Mayer, D.V.M., A.C.L.A.M. Management: Janice L. Connell, M.S., B.A., C.I.H. Company Sanitized. Does not contain TSC CB H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11574 SUMMARY The objective of this study was to determine the potential toxicity of H-25435 following repeated dermal exposure. The test substance was applied to the shaved, intact skin of male Crl:CD(SD)IGS BR rats for 6 hours/day for 28 consecutive days. Three groups of 10 male rats were treated dermally with 10, 100, and 1000 mg/kg/day H-25435. A control group of 10 male rats was similarly treated with deionized water. The rats were observed for mortality, clinical signs, dermal effects, and body weight effects during the study. Food consumption was determined weekly during the study. Blood samples for total fluorine were collected on test days -4, 3, 9, and 21. Blood and urine samples were collected for clinical pathology prior to sacrifice on day 29. All rats underwent necropsy for gross and microscopic pathological evaluation. There were no effects on body weight, food consumption, food efficiency, or mortality at any dosage. No clinical signs attributable to systemic toxicity occurred. No dermal irritation was observed during the study. Some fluorine was present in the day 21 blood from rats dosed with the test substance, indicating exposure to a fluoride-containing compound. This finding was considered to be treatmentrelated but not adverse. Organ weights were not different in a dose response fashion in either incidence or severity. Gross observations and microscopic findings occur spontaneously in rats of this strain and age and were not present in a dose response fashion in either incidence or severity. There were no adverse changes in hematology parameters. Aspartate and alanine aminotransferase activities were increased along with increased sorbitol dehydrogenase activities in rats treated at 1000 mg/kg/day. These increases were considered to be potentially adverse. Urine fluoride was increased in rats treated at 1000 mg/kg/day, indicating exposure to and metabolism of a fluoride-containing compound. This urine fluoride increase was considered to be treatment-related but not adverse. Based on the presence of mildly increased liver enzymes at 1000 mg/kg/day, the no-observed effect level (NOEL)a for the dermal exposure of H-25435 under the conditions of this study was 100 mg/kg/day for male rats. 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 U.S. EPA (1985) and to the no-observable-adverse-effect level (NOAEL) as defined by the European Union (1994). Company Sanitized. Does not contain TSCA CB1 H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 INTRODUCTION The purpose of this study was to evaluate the toxicity of H-25435 in rats when administered dermally for 28 days. This study was intended to provide insight to the possible human health hazards associated with repeated dermal exposures to the test substance over a limited period of time. A range-finding study was conducted to aid in dosage selection for the 28-day dermal study. Groups of 2 male rats received dermal applications of H-25435 at dosages of 10, 60, 500, or 1000 mg/kg for 6 hours for 4 consecutive days. No dermal irritation was observed, and no test substance-related clinical signs or body weight losses occurred. Based on the lack of toxicity observed in the range finding study, dosages of 0,10,100, and 1000 mg/kg/day were selected for the 28-day study. Group I m V vn STUDY DESIGN Number/Group 10 10 10 10 Dosage (mg/kg) 0 10 100 1000 MATERIALS AND METHODS A. Test Guidelines Except as noted below, the study design complies with the following test guidleines: Office of Prevention, Pesticides and Toxic Substances (OPPTS) U.S. Environmental Protection Agency (EPA) (1998). OPPTS 870.3200 21/28-Day Dermal Toxicity. Health Effects Test Guidelines. Organisation for Economic Co-Operation and Development (OECD) (1981). 410 Repeated Dose Dermal Toxicity: 21/28-Day Study. Guidelinefo r Testing o f Chemicals. Only male rats were treated. This exception did not affect the objectives or validity of the study because males are the more sensitive sex to the toxicological effects of fluorinated test substances such as H-25435. Company Sanitized. Does not contain TSCA CB1 H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11574 _ B. Test Substance The test substance, H-25435, was supplied by the sponsor as an amber brown liquid. The test substance appeared to be stable under the conditions of the study. No evidence of instability, such as a change in color or physical state, was observed. All of the test substance administered was assumed to be available for absorption. For the purposes of this study, all toxic effects were reported as a function of the administered dosage. C. Test Species On October 15, 2002,44 male Crl:CD(SD)IGS BR rats, with an assigned birth date of September 2, 2002, were received from Charles River Laboratories, Inc., Raleigh, North Carolina. The Crl:CD(SD)IGS BR rat was selected because extensive background information is available from the literature, the supplier, and previous studies conducted at Haskell Laboratory. This strain is also considered suitable relative to hardiness and low incidence of spontaneous disease. D. Animal Husbandry 1. Housing Rats were housed singly in stainless steel, wire-mesh cages suspended above cage boards. 2. Environmental Conditions Animal rooms were maintained at a temperature of 19-25C and a relative humidity of 30-70%. Animal rooms were artificially illuminated (fluorescent light) on an approximate 12-hour light/dark cycle. Excursions outside of these ranges were of insufficient magnitude and/or duration to have adversely affected the validity of the study. 3. Feed and Water Tap water was provided ad libitum. PMI Nutrition International, LLC Certified Rodent LabDiet 5002 meal was available ad libitum except when the rats were fasted. 4. Identification Prior to assignment to groups, each rat was temporarily identified by a cage card affixed to the outside of its cage. After assignment to groups, each rat was assigned a unique 6-digit Haskell animal number and an individual cage identification number. The last 3 digits of the Haskell animal number were tattooed on the tail of each rat. The information on the cage labels included the Haskell animal number and th individual identification number assigned to each rat. Company Sanitized. Does not contain TSCA CB1 - 13 - H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 5. Health Monitoring Program As specified in the Haskell Laboratory animal health and environmental monitoring program, the following procedures are performed periodically to ensure that contaminant levels are below those that would be expected to impact the scientific integrity of the study: Water samples are analyzed for total bacterial counts, and the presence of coliforms, lead, and other contaminants. Feed samples are analyzed for total bacterial, spore, and fungal counts. Samples from freshly washed cages and cage racks are analyzed to ensure adequate sanitation by the cagewashers. Certified animal feed is used, guaranteed by the manufacturer to meet specified nutritional requirements and not to exceed stated maximum concentrations of key contaminants, including specified heavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates. The presence of these contaminants below the maximum concentration stated by the manufacturer would not be expected to impact the integrity of the study. The animal health and environmental monitoring program is administered by the attending laboratory animal veterinarian. Evaluation of these data did not indicate any conditions that affected the validity of the study. E. Pretest Period Upon arrival at Haskell Laboratory, the rats were quarantined for 6 days. The rats were weighed 3 times and examined daily for any clinically apparent signs of disease or injury. On the bases of acceptable body weight gains and clinical signs, the rats were released from quarantine on test day -8 by the laboratory animal veterinarian's designee. F. Assignment to Groups and Study Start Forty rats were selected for study use on the bases of adequate body weight gain, freedom from clinical signs of disease or injury, and a body weight within 20% of the mean. The selected rats were divided by computerized, stratified randomization into 4 groups of 10 rats, so that there were no statistically significant differences among group body weight means. Dose administration with H-25435 began on test day 0 when the rats were approximately 8 weeks of age. G. Test Substance Preparation and Administration Gn the day prior to the first treatment, the fur of each rat was closely shaved to expose the skin from the back and trunk. On each day of treatment, the rats wore plastic collars during the Company Sanitized. Doss not contain TSCA CB1 - 14- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____ DuPont-11574 exposure period to prevent ingestion of the test substance and disruption of the wrappings. The area to be treated was marked on the back of each rat with a water-insoluble marker. The approximate total body surface area covered for the 0,10, 100, and 1000 mg/kg/day groups was 1.2%, 0.1%, 0.3%, and 1.5%, respectively. The volume of neat test substance or vehicle was not sufficient to cover 10% of the total body surface area. The test substance was applied evenly and as thinly as possible to the test site. The test substance was covered with a 2-ply porous gauze dressing followed by successive layers of stretch gauze (no more than 8 layers) and self-adhesive bandage. Each day of dosing, the control rats received the same volume of deionized water as the high-dose treatment group. The rats were treated at approximately the same time each day. Groups of 10 male rats were treated at dosages of 0,10,100, or 1000 mg of test substance per kg body weight. The rats were treated for 28 consecutive days. The amount of neat test substance needed to treat each rat was based on the most recently determined body weight measurement and the test substance density of 1150 mg/mL. The exposure period was approximately 6 hours. After the exposure period, the collars and wrappings were removed and the test site was wiped with a wet paper towel and washed with warm tap water. The test site of each rat was then gently patted dry and the rat was returned to its cage. Control animals received the same washing technique as the treated animals. The animals were reshaved as needed during the study to facilitate the evaluation of dermal effects. The entire area that was originally shaved (including the untreated control skin) was reshaved. The animals were shaved only after an evaluation. H. Body Weights All rats were weighed at 3-4 day intervals during the study. L Food Consumption and Food Efficiency The amount of food consumed by each rat was determined once per week throughout the study. Individual food consumption was determined by weighing the amount of diet in each feeder at the beginning and end of the week and subtracting the final weight and the amount of spillage from the feeder during the week from the initial weight. From these measurements, mean daily food consumption was determined. From the food consumption and body weight data, mean daily food efficiency was calculated. J. Mortality and Clinical Observations The rats were checked twice daily for mortality and for signs of illness, injury, or abnormal behavior. Comoany Sanitized. Does not contain TSCA CBT - 15- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 The rats were observed for clinical signs of toxicity and dermal effects after removal of the test substance. The Draize Scale was used to score skin irritation. Adjacent areas of untreated skin were used for comparison. The rats were also observed for clinical signs at each weighing. K. Total Fluorine and Perfluorooctanoic Acid Level Evaluations Blood was collected into EDTA tubes from the orbital sinus of the first 5 rats in each group on test days -4, 3, 9, and 21 approximately one hour after removal of the test substance. The blood was refrigerated. The total fluorine content of the day 21 blood samples was determined by using a Wickbold torch combustion method followed by analysis with a fluoride ion selective electrode. The remaining samples were not analyzed. Fluorine blood analysis was performed at Jackson Laboratory, Deepwater, New Jersey. Additional blood was collected from the vena cava of all rats at necropsy into a tube containing EDTA. Plasma was prepared and stored frozen at -80C to -20C. Concentration of perfluorooctanoic acid (PFOA) will be determined. The results of the analysis will be presented in a supplemental report. L. Clinical Pathology Evaluation A clinical pathology evaluation was conducted on all rats 29 days after initiation of the study. The day before collection of samples for the clinical pathology evaluation, the animals were placed in metabolism cages. These animals were fasted overnight (approximately 16 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 carbon dioxide anesthesia. Blood was collected from the vena cava and was placed in a serum tube, processed to serum, and frozen at -80C. Bone marrow smears were prepared at sacrifice from all surviving animals. Bone marrow smears were stained with Wright's stain, but analysis was not necessary to support experimental findings. 1. Hematology 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. The following hematology parameters were determined: red blood cell count hemoglobin hematocrit red cell distribution width absolute reticulocyte count platelet count Company Sanitized. Does not contain TSCACB1 -16- /"""N /""n H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats________ DuPont-11574 mean corpuscular volume white blood cell count mean corpuscular hemoglobin differential white blood cell count mean corpuscular hemoglobin concentration microscopic blood smear examination 2. Clinical Chemistry Serum clinical chemistry parameters were determined on a Roche Diagnostics (BMC)/Hitachi 717 clinical chemistry analyzer. Plasma fluoride concentrations were determined using a 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 fluoride3 3. Urinalysis Urine volume and appearance (quality, color, and clarity) were measured and evaluated visually, respectively. Urine constituents were semi-quantitatively measured on a Bayer Clinitek AtlasTM Automated Urine Chemistry analyzer. Urine protein was measured on a Roche Diagnostics (BMC)/Hitachi 717 clinical chemistry analyzer. Urine osmolality was determined using an Advanced Osmometer 3900. Urine fluoride concentrations were determined using a phi 12 pH meter and a fluoride-selective electrode, and total urine fluorides were calculated (volume x concentration). Sediments from all urine specimens were evaluated microscopically. The following urinalysis parameters were determined: quality color clarity volume osmolality pH glucose ketone bilirubin blood urobilinogen fluorideb protein microscopic urine sediment examination a Fluoride determination was analyzed on EDTA plasma. b Fluoride determination was analyzed from urine with EDTA added. Company Sanitized. Does not contain TSCA CBi -17- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11574 M. Anatomic Pathology Evaluations Rats were fasted after 3 p.m. on the afternoon before their scheduled sacrifice. A final sacrifice was performed on the rats following the final clinical pathology evaluation. All rats sacrificed by design underwent a gross and microscopic evaluation. Rats were euthanatized by carbon dioxide anesthesia and exsanguination. The order of sacrifice was random among all treatment groups. The following tissues were collected from the rats: gross observations1 liverb kidneys15 thyroid gland (after fixation)15 skin (treated and untreated) teeth a Gross observations made at necropsy for which histopathology was not appropriate (e.g., fluid, ruffled fur, and missing anatomic parts) was generally not collected, b Organs weighed All tissues were placed in an appropriate fixative. The rats had the following organs weighed: liver, kidneys, and thyroid. Relative organ weights (percent of final body weight) were calculated. Final body weights determined just prior to necropsy were used in the assessment of organ weight changes. Tissues collected from rats in the high-dose and control group were further processed to slides, stained with hematoxylin and eosin, and examined microscopically. Most gross lesions and any additional target organs from rats in the low- and intermediate-dosage groups were evaluated microscopically. Selected gross observations for which a microscopic diagnosis would not be additive (e.g., osteoarthritis, pododermatitis, chronic tail dermatitis, calculus, and deformities of the teeth, toe, tail, or ear pinna) were saved, but were not processed for microscopic evaluation. Company Sanitized. Does not contain TSCA CBT -18- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11574 N. Statistical Analyses Significance was judged at p < 0.05. Parameter Preliminary Test Body Weight Body Weight Gain Food Consumption Food Efficiency Organ Weight Clinical Pathologyd Survival Incidence o f Clinical Observations Incidence o f Dermal Effects Test for lack of trend Levene's test for homogeneity and Shapiro-Wilk test for normality15 Levene's test for homogeneity and Shapiro-Wilk test for normality15 None Method of Statistical Analysis If preliminary test is not If preliminary test is significant significant Sequential application of the Jonckheere-Terpstra trend test Preliminary tests for pairwise comparison ORa One-way analysis of variance followed with Dunnett's test9' Kruskal-Wallis test(H) followed with Dunn's test< One-way analysis of variance followed with Dunnett's test9' Kruskal-Wallis test(11) followed with Dunn's test< Cochran-Armitage test for trend0 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 not significant but Levene's test was significant, a robust version o f Dunnett's test was used. If the Shapiro-Wilk test was significant, Kruskal-Wallis test was followed by Dunn's test, c If the incidence was not significant, but a significant lack o f fit occurred, then Fisher's Exact test(13) with a Bonferroni correction was used. 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. Company Sanitized. Does not contain TSCA CBf /<***'\ H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_________ RESULTS AND DISCUSSION DuPont-11574 In-Life Toxicology A. Mean Body Weights and Body Weight Gains (Tables 2-3, Figure 1, Appendix B) No effects on body weights or body weight gains occurred in any group of rats dosed with the test substance, H-25435. B. Food Consumption and Food Efficiency (Tables 4-5, Appendix C) No effects on food consumption or food efficiency occurred in any group of rats dosed with the test substance. C. Clinical Observations, Dermal Evaluations, and Survival (Tables 6-8, Appendices D-F) No clinical signs resulting in systemic toxicity occurred. Red ocular discharge was observed in all rats during the study. Red nasal discharge and swollen face were observed in rats in all dose groups. These clinical signs are considered to be due to the wrapping/collar application procedure. Superficial wounds and hair loss were present in both treated and control animals and were not considered test substance-related. The observation of dark eye in one rat treated at 100 mg/kg was short in duration, was not observed in any other rats, and therefore is not considered to be test substance-related. No dermal irritation was observed during the study. No deaths occurred. D. Blood Fluorine Analysis (Appendix G) There was some fluorine present in the day 21 blood from rats dosed with the test substance. This indicated exposure to a fluoride-containing compound and is considered to be treatment related but not adverse. Two rats treated at 10 mg/kg/day had fluorine levels below the limit of quantification (LOQ). The remaining 3 rats had levels ranging from 0.52 to 5.96 ppm. The rats treated at 100 mg/kg had levels of fluorine ranging from 0.54 to 0.78 ppm. Two rats treated at Company Sanitized. Does not contain TSCA CBS -20- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_________ DuPont-11574 1000 mg/kg/day had fluorine levels below the LOQ. The remaining 3 rats had levels ranging from 1.22 to 1.38 ppm. All values for the control rats were below the LOQ. E. In-Life Conclusions Under the conditions of this study, the no-observed-effect level for inlife parameters was 1000 mg/kg/day for male rats based on the absence of adverse effects. Clinical Pathology Evaluations A. Hematology (Table 9, Appendix H) There were no adverse changes in hematologic parameters in males. The following statistically significant changes in mean hematologic parameters were considered to be non-adverse or not related to exposure to the test substance: Mean red cell parameters (red cell count, hemoglobin, and hematocrit) were similarly decreased in males dosed with 10,100, or 1000 mg/kg/day (statistically significant for red cell count at 10 mg/kg/day, and for hemoglobin and hematocrit at 100 and 1000 mg/kg/day). There was no dose-relationship to the changes, despite the 100-fold range of doses. There were no correlative changes in other red cell parameters (reticulocytes, indices, or morphology) that would be expected with processes that alter red cell mass. In addition, red . cell mass parameters for the three dosed groups were similar to that of the control groups on a recent dermal study/'14'1 It is likely that the apparent decrements in red cell mass were due to higher than usual red cell mass in the control group, rather than a direct effect of the compound. Therefore, these changes were considered to be unrelated to treatment. Eosinophils were minimally increased in males dosed with 1000 mg/kg/day (147% of control group mean). Due to the consistency of change, this increase was likely to be due to treatment. There were no other alterations in leukocyte counts, and no correlative histologic changes. In addition, eosinophils counts of all individual rats dosed with 1000 mg/kg/day were within the range of the control group counts. Therefore, although this change was possibly related to treatment, it was considered to be non-adverse. B. Clinical Chemistry (Table 10, Appendix H) Aspartate and alanine aminotransferase activities were minimally (aspartate aminotransferase) to mildly (alanine aminotransferase) increased in some males dosed with 100 or 1000 mg/kg/day. In these groups, mean activities were statistically significant, and were 133-144% of control for aspartate aminotransferase, and 200-222% of control for alanine aminotransferase. In individual Does not TSCA Cr -21 - H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11574 affected rats, generally activities of both enzymes were elevated. Sorbitol dehydrogenase was also increased in affected rats in both groups, although mean activities were not statistically different from the control mean. The presence of increased transaminases and sorbitol dehydrogenase indicates hepatocellular injury. Histologically, there were no alterations in the liver. Due to the magnitude of the change, this effect was considered to be potentially adverse. There were no other adverse changes in clinical chemistry parameters. The following statistically significant changes in mean clinical chemistry parameters were considered to be non-adverse or not related to exposure to the test substance: Alkaline phosphatase was minimally increased in males dosed with 1000 mg/kg/day (mean was 136% of control group mean). This change was possibly related to treatment. However, the magnitude of change was very small. In addition, there were no alterations in correlative clinical or anatomic pathology parameters. Increased alkaline phosphatase activity did not occur in the same rats that had increased transaminase and sorbitol dehydrogenase activities. Therefore, although this change was possibly related to treatment, it was considered to be non-adverse. Bilirubin was statistically and minimally increased in males dosed with 1000 mg/kg/day (133% of control group mean). Mean and individual bilirubin concentrations for this group (mean: 0.12 mg/dL, individual values: <0.10 to 0.16 mg/dL) were well within the historical age-matched control range (control mean range: 0.09-0.29 mg/dL; range of individual animals: 0.07-0.33 mg/dL). Based on individual rat data compared to the control and other treated groups, this change was unlikely to be related to treatment. Regardless, the magnitude of change was very small, and non-adverse. Cholesterol was minimally increased in males dosed with 10,100, or 1000 mg/kg/day. Although this change may have been related to treatment, the magnitude of change was very small, and was not expected to result in adverse events. Therefore, this change was considered to be non-adverse. Triglycerides were minimally increased in males dosed with 10,100, or 1000 mg/kg/day (147%, 150%, and 187% of control group means; statistically significant only at 1000 mg/kg/day). Increased triglycerides were likely to be treatment-related. However, the magnitude of change was very small, and was not expected to result in adverse events. Therefore, this change was considered to be non-adverse. The following statistically significant change in mean clinical chemistry parameters was considered to be non-adverse because it was unrelated to dose: Minimally decreased albumin in males dosed with 100 mg/kg/day Company Sanitized. Does not contain TSCA CBi H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______ DuPont-11574 C. Urinalyses (Table 11, Appendix H) There were no adverse changes in urinalysis parameters. The following statistically significant changes in mean urinalysis parameters were considered to be non-adverse: Urine osmolality was mildly decreased (62% of control group means) in males dosed with 1000 mg/kg/day. This was associated with an appropriate tendency (not statistically significant) towards minimally higher urine volumes in this group. There were no alterations in other renal parameters on this study. The presence of decreased osmolality with increased urine volume, in the absence of other changes in renal parameters, has no toxicologic significance. Therefore, this change was considered to be non-adverse. Urine protein concentration was decreased in males dosed with 1000 mg/kg/day. Decreases in urine protein concentration were secondary to increased urine volume. In addition, decreases in urine protein have no toxicologic significance. Therefore, this change was considered to be non-adverse. D. Urine and Plasma Fluoride There was no effect of treatment on plasma fluoride concentration. Urine fluoride (total fluoride excreted overnight) was increased in males dosed with 1000 mg/kg/day (Text Table I). Increased urine fluoride indicates exposure to and metabolism of a fluoride-containing compound. Text Table I: Mean urine fluoride for males Dose (mg/kg/day) Parameter (units) 0 10 100 UFLU(pg) 14.8 17.4 19.2 % of control mean NA 118% 130% 1000 33.9 229% Statistical significance is indicated by bold italicized type E. Clinical Pathology Conclusions In conclusion, dermal dosing of male rats with 1000 mg/kg/day resulted in increased aspartate and alanine aminotransferase activities, along with increased sorbitol dehydrogenase activities, in some rats. This change was considered to be potentially adverse. Urine fluoride was increased in males dosed with 1000 mg/kg/day; this change indicated exposure to and metabolism of a fluoride-containing compound, and was considered to be treatment-related but non-adverse. Therefore, under the conditions of this study and for the clinical pathology parameters measured, the no-observed-effect level was 100 mg/kg/day for male rats, based on the presence of mildly increased liver enzymes at 1000 mg/kg/day. Company Sanitized. Does not contain TSCA CBI H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Anatomic Pathology Evaluations D u P o n t-1 1574 A. Mortality There were no early deaths. B. Organ Weights (Table 12, Appendix I) Organ weights were not different in a dose response fashion in either incidence or severity. C. Gross Observations (Table 13, Appendix J) All gross 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. D. Microscopic Findings (Table 14, Appendix J) All 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. Anatomic Pathology Conclusions Under the conditions of this study, the no-observed-effect level for pathology was 1000 mg/kg/day. Comoany Sanitized. Does not contain TSCA CB1 - 24- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______ DuPont-11574 CONCLUSIONS No deaths occurred during the study. No adverse test substance-related effects on body weight, food consumption, food efficiency, clinical signs, or dermal irritation were seen in male rats that received 28 applications of H-25435 applied daily to the shaved skin. Organ weight differences, gross observations, and microscopic findings were considered to occur spontaneously in rats and/or were not present in a dose response fashion. There were no adverse changes in hematology or urinalysis parameters. Dermal administration of H-25435 resulted in increased aspartate and alanine aminotransferase activities along with increased sorbitol dehydrogenase activities at 1000 mg/kg/day. The no-observed-effect level (NOEL)awas 100 mg/kg/day based on the presence of mildly increased liver enzymes at 1000 mg/kg/day. RECORDS AND SAMPLE STORAGE All data and records for analytical characterizations conducted by the sponsor will be retained by the sponsor. 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 will be collected for archive purposes and retained at Haskell Laboratory, Newark, Delaware. 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. REFERENCES 1. DuPont Haskell Laboratory (2002). H-24678: Subchronic Toxicity 90-Day Oral Gavage Study in Rats. Unpublished report! 2.- Draper, N.R. and Smith, H. (1981). Applied Regression Analysis, 2nd edition, pp 266-273. Wiley, New York. 3. Selwyn, M.R. (1995). The use of trend tests to determine a no-observable-effect level in animal safety studies. Journal o f the American College o f Toxicology 14(2), 158-168. 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(I5) and to the no-observed-adverse-effect level (NOAEL) as defined by the European Union.(16) Company Sanitized. Does not contain TSCA CB\ - 25- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11574 4. Jonckheere, A.R. (1954). A distribution-free K-sample test against ordered alternatives. Biometrika 41, 133-145. 5. Levene, H. (1960). Robust test for equality of variances. Contributions to Probability and Statistics (J. Olldn, ed.), pp 278-292. Stanford University Press, Palo Alto. 6. Shapiro, S.S. and Wilk., M.B. (1965). An analysis of variance test for normality (complete samples). Biometrika 52, 591-611. 7. Snedecor, G.W. and Cochran, W.G. (1967). Statistical Methods, 6thedition, pp 246-248 and 349-352. The Iowa State University Press, Ames. 8. Dunnett, C.W. (1964). New tables for multiple comparisons with a control. Biometrics 20, 482-491. 9. Dunnett, C.W. (1980). Pairwise multiple comparisons in the unequal variance case. J. Amer. Statist. Assoc. 75, 796-800. 10. Tamhane, A.C. (1979). A comparison of procedures for multiple comparison o f means with unequal variances. J Amer. Statist. Assoc. 74, 471-480. 11. Kruskal, W.H. and Wallis, W.A. (1952). Use of ranks in one-criterion analysis o f variance. J. Amer. Statist. Assoc. 47, 583-621. 12. Dunn, O.J. (1964). Multiple contrasts using rank sums. Technometrics 6, 241-252. 13. Fisher, R.A. (1985). Statistical Methodsfo r Research Workers, 13th edition. Haffher, New York. 14. DuPont Haskell Laboratory (2003). H-25509: 28-Day Study in Male Rats. Unpublished repo 15. Hazard Evaluation Division, Standard Evaluation Procedure, Toxicity Potential: Guidance for Analysis and Evaluation of Subchronic and Chronic Exposure Studies Paynier, O. E. et al., United States Environmental Protection Agency, Office of Pesticide Programs, Washington, D.C., 20406. EPA-540/9-85-020. (June 1985). 16. Risk Assessment of Notified New Substances. Technical Guidance Document (XI/283/94EN), Chapter I, Sections 2.24 and 2.25. 1994. Company Sanitized. Does not contain TSCA CB1 H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11574 TABLES Company Sanitized. Does not contain TSCA CBl H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11574 TABLES EXPLANATORY NOTES 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 Summary of Clinical Chemistry Values AST - aspartate aminotransferase ALT - alanine aminotransferase SDH - sorbitol dehydrogenase ALKP - alkaline phosphatase BILI - total bilirubin BLN - 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 Company Sanitized. Does not contain TSCA CB1 - 28- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11574 TABLES EXPLANATORY NOTES (Continued) ABBREVIATIONS: (Continued) Summary of Urinalysis Values VOL - volume UOSM - urine osmolality pH - the logarithm of the reciprocal of the hydrogen ion concentration URO - urobilinogen UFLU - urine fluoride UMTP - urine protein NOTES: Summary of Hematology Values Summary of Clinical Chemistry Values Summary of Urinalysis Values When an individual observation was recorded as being less than a certain value, calculations were performed on half the recorded value. For example, if bilirubin was reported as <0.1, 0.05 was used for any calculations performed with that bilirubin data. Company Sanitized. Does not contain TSCA CB1 H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 TABLE 1 MEAN DAILY APPLIED DOSE VOLUMES FOR MATE RATS (jiL) Group: Dosage(mg/kg) DAYO DAY1 DAY 2 DAY3 DAY4 DAY 5 DAY 6 DAY7 DAY 8 DAY 9 DA Y 10 I 0 242.2 1 6 . 6 (10) 242.2 1 6 . 6 (10) 242.2 16.6(10) 256.1 19.9(10) 256.1 19.9(10) 256.1 19.9(10) 256.1 1 9 . 9 (10) 267.5 2 2 . 4 (10) 267.5 22.4(10) 267.5 2 2 . 4 (10) 280.9 2 3 . 8 (10) III 10 2.5 0.1(10) 2.5 0. 1 (10) 2.5 0. 1 (10) 2.6 0. 1 (10) 2.6 0.1(10) 2.6 0. 1 (10) 2.6 0. 1 (10) 2.7 0.2(10) 2.7 0.2(10) 2.7 0.2(10) 2.9 0.2(10) V 100 24.4 1.0(10) 24.4 1. 0 (10) 24.4 1.0 (10) 25.7 1. 0 (10) 25.7 1.0(10) 25.7 1. 0 (10) 25.7 1.0(10) 26.5 1.0(10) 26.5 1.0 (10) 26.5 1.0(10) 27.4 1. 1 (10) VII 1000 247.6 10.6(10) 247.6 10.6(10) 247.6 10.6(10) 260.3 13.2(10) 260.3 13.2(10) 260.3 13.2(10) 260.3 1 3 . 2 (10) 270.5 14.1(10) 270.5 14.1(10) 270.5 1 4 . 1 (10) 283.2 1 4 . 8 (10) CompanySanitized. Does not contain TSCACB) -30- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 TABLE 1 (CONTINUED) MEAN DAILY APPLIED DOSE VOLUMES FOR MALE RATS (jiL) Group: Dosage(mg/kg) DA Y 11 D A Y 12 D A Y 13 DAY14 DAY15 D A Y 16 DAY17 D A Y 18 DAY19 DAY20 DAY21 I 0 280.9 2 3 . 8 (10) 280.9 2 3 . 8 (10) 280.9 23.8(10) 290.8 2 3 . 6 (10) 290.8 2 3 . 6 (10) 290,8 23.6(10) 300.5 2 4 . 8 (10) 300.5 2 4 . 8 (10) 300.5 24.8(10) 300.5 2 4 . 8 (10) 309.2 23.1(10) III 10 2.9 0.2(10) 2.9 0 .2 (10) 2.9 0.2 (10) 3.0 0.2(10) 3.0 0.2(10) 3.0 0. 2 (10) 3.1 0. 2 (10) 3.1 0.2(10) 3.1 0.2(10) 3.1 0.2(10) 3.2 0.2(10) V 100 27.4 1.1(10) 27.4 1. 1 (10) 27.4 1.1(10) 28.1 1.3(10) 28.1 1.3(10) 28.1 1.3(10) 29.0 1. 4 (10) 29.0 1.4(10) 29.0 1.4(10) 29.0 1.4(10) 30.0 1.4(10) VII 1000 283.2 14.8(10) 283.2 14.8(10) 283.2 14.8(10) 293.4 15.2(10) 293.4 15.2(10) 293.4 15.2(10) 302.1 1 8 . 9 (10) 302.1 18.9(10) 302.1 1 8 . 9 (10) 302.1 1 8 . 9 (10) 314.1 2 0 . 3 (10) ______________________ Company Sanitized, D oes not contain TSCA CSi -31 - H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 TABLE 1 (CONTINUED) MEAN DAILY APPLIED DOSE VOLUMES FOR MALE RATS (jiL) Group : Dosage(mg/kg) DAY22 DAY23 DAY24 DAY25 DAY26 DAY27 DAY28 I 0 309.2 2 3 . 1 (10) 309.2 2 3 . 1 (10) 313.1 2 6 . 4 (10) 313.1 26.4(10) 313.1 2 6 . 4 (10) 313.1 26.4(10) 320.4 26.2(10) Data summarized as: Mean Standard Deviation (n) III 10 3.2 0.2(10) 3.2 0.2(10) 3.3 0.2 (10) 3.3 0.2(10) 3.3 0.2(10) 3.3 0.2(10) 3.3 0.3 (10) V 100 30.0 1. 4 (10) 30.0 1.4(10) 30.7 1. 6 (10) 30.7 1.6 (10) 30.7 1.6(10) 30.7 1.6(10) . 31.4 1.8(10) VII 1000 314.1 2 0 . 3 (10) 314.1 2 0 . 3 (10) 321.3 21.5(10) 321.3 21.5(10) 321.3 21.5(10) 321.3 21.5(10) 331.4 2 0 . 7 (10) Company Sanitized, Does no! contain TSCA CUT H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 TABLE 2 MEAN BODY WEIGHTS OF MALE RATS (g) Group : Dosage(mg/kg) DAYO DAY3 DAY 7 DA Y 10 DAY14 D A Y 17 DAY21 DAY24 DAY28 I 0 278.6 1 9 . 1 (10) 294.5 22.9(10) 307.7 25.8(10) 323.0 2 7 . 3 (10) 334.4 27.1(10) 345.6 2 8 . 6 (10) 355.6 26.6(10) 360.1 3 0 . 4 (10) 368.4 3 0 . 1 (10) 111 10 283.3 15.4(10) 297.6 1 7 . 0 (10) 313.3 1 9 . 8 (10) 331.3 20.6(10) 345.5 22.9(10) 356.8 2 5 . 5 (10) 370.6 2 8 . 4 (10) 378.4 28.1(10) 384.8 30.3(10) V 100 280.4 1 1 . 0 (10) 295.1 11.3(10) 304.6 1 1 . 7 (10) 315.4 1 3 . 2 (10) 323.6 15.4(10) 333.1 16.4(10) 345.1 16.3(10) 352.8 18.3(10) 360.7 2 0 . 3 (10) VII 1000 284.7 12.2(10) 299.4 1 5 . 2 (10) 311.1 16.2(10) 325.7 1 7 . 0 (10) 337.4 1 7 . 4 (10) 347.4 2 1 . 7 (10) 361.2 23.3(10) 369.5 24.8(10) 381.1 23.8(10) Data summarized as: Mean Standard Deviation (n) There were no statistically significant differences at p < 0.05 by Jonckheere-Terpstra trend test. Company Sanitized. "Does notcontain TSCAUBl -33- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 Group : Dosage(mg/kg) DAY0-DAY3 DAY3-DAY7 DAY7-DAY10 DAY10-DAY14 DAY14-DAY17 DAY17-DAY21 DAY21-DAY24 DAY24-DAY2 8 TABLE 3 MEAN BODY WEIGHT GAINS OF MALE RATS (g) I III V 0 10 100 15.9 7. 2 (10) 14.3 5. 6 (10) 14.6 6.5(10) 13.2 5. 2 (10) 15.8 5.5 (10) 9.6 5. 4 (10) 15.3 4. 2 (10) 11.4 5.8(10) 11.2 5.5(10) 10.0 7. 1 (10) 17.9 5 . 9 (10) 14.3 4 . 9 (10) 11.2 3.7(10) 13.9 5. 8 (10) 10.7 6. 1 (10) 8.3 4.4(10) 9.5 6. 6 (10) 12.0 6. 9 (10) 4.5 6.5(10) 8.3 7.5(10) 7.8 5.2(10) 6.5 9.4(10) 7.6 7.6(10) 7.9 9. 6 (10) VII 1000 14.7 9.0(10) 11.7 4.5(10) 14.6 4.7(10) 11.7 7.0(10) 10.0 9. 9 (10) 13.8 6 . 6 (10) 8.3 7.3(10) 11.6 6.7(10) D A Y O - D A Y 28 89.9 1 5 . 5 (10) 101.6 23.1(10) 80.3 17.5(10) 96.5 21.1(10) Data summarized as: Mean Standard Deviation (n) There were no statistically significant differences at p < 0.05 by Jonckheere-Terpstra trend test. ___________________ ' Company Sanitized. Does no! csnfaln TSCACBI H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats____________________ ) DuPont-11574 TABLE 4 MEAN DAILY FOOD CONSUMPTION BY MALE RATS (g/day) Group: Dosage(mg/kg) DAY0-DAY7 DAY7-DAY14 DAY14-DAY21 DAY21-DAY28 I 0 26.7 2.1(10) 26.6 1.7(10) 26.4 1 . 4 (10) 27.3 0 .9 (10) III 10 26.2 1.6 (10) 26.9 1.8(10) 26.9 1 . 6 (10) 27.5 1.3 (10) V 100 25.6 1.6(10) 25.6 1.1(10) 26.1 1.0(10) 27.2 1.3(10) VII 1000. 26.1 2.1(10) 27.1 1. 6 (10) 27.2 1.9(10) 27.5 1. 1 (10) DAY0-DAY28 26.7 1.3 (10) 26.9 1.3(10) 26.1 0.9(10) 27.0 1.5(10) Data summarized as: Mean Standard Deviation (n) There were no statistically significant differences at p < 0.05 by Jonckheere-Terpstra trend test. Company Sanitized, does no! contain TSCA CBf -35- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 Group: Dosage(mg/kg) DAY0-DAY7 DAY7-DAY14 DAY14-DAY21 DAY21-DAY28 TABLE 5 MEAN DAILY FOOD EFFICIENCY OF MALE RATS (g body weight gain/g food consumed) I III V 0 10 100 .152 0 . 0 5 5 (10) 0.143 0 . 0 2 7 (10) 0.115 0 . 0 4 0 (10) 0.163 0 . 0 3 4 (10) 0.169 0 . 0 4 1 (10) 0.132 0 . 0 3 4 (10) 0.135 0 . 0 3 4 (10) 0.106 0.056(10) 0.117 0.047(10) 0.067 0 . 0 3 9 (10) 0.073 0.064(10) 0.081 0 . 0 4 8 (10) VII 1000 0.141 0.050(10) 0.139 0.039(10) 0.123 0.053(10) 0.103 0.036(10) DAY0-DAY28 0.120 0.017(10) 0.134 0.027(10) 0.109 0 . 0 2 2 (10) 0.127 0 . 0 2 3 (10) Data summarized a s : Mean Standard Deviation (n) There were no statistically significant differences at p < 0.05 by Jonckheere-Terpstra trend test. Company Sanitized. Does net contain TSCA CBI H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 TABLE 6 SUMMARY OF CLINICAL OBSERVATIONS IN MALE RATS Group Dosage(mg/kg) Animal Count I III V VII 0 10 100 1000 10 10 10 10 Discharge Eye right Incidence M e a n o n set (Days) Nose Incidence M e a n o nset (Days) Hair Loss Incidence M e a n o n s e t (Days) Wound Superficial Incidence M e a n o n set (Days) 0 0 1 ( 10%) 21 2 ( 20%) 19 0 2 ( 20%) 3 1 ( 10%) 28 1 ( 10%) 18 0 0 1 ( 10%) 22 1 ( 10%) 18 1 29 0 2 9 2 9 Incidence - The number of animals for which an observation was recorded. M e a n onset (Days) - The m e a n of the first test d a y a n o b s e r v a t i o n was r e c o r d e d for that group. T h e r e w e r e n o statistica'lly s i g n i f i c a n t d i f f e r e n c e s at p < 0.05 by Cochran-Armitage trend test. Company Sanitized. Boss net contain TSCA CB1 H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats TABLE 7 SUMMARY OF CLINICAL OBSERVATIONS - POST DOSING IN MALE RATS Group Dosage(mg/kg) Animal Count Eye Observations Dark Incidence M e a n onset (Days) Discharge Eye Incidence ' M e a n onset (Days) Nose Incidence M e a n onset (Days) I 0 10 0 10 (100%) 5 1 ( 10%) 3 III 10 10 0 10 (100%) 5 2 ( 20%) 2 V 100 10 1 ( 10%) 4 10 (100%) 7 1 ( 10%) 3 Hair Loss Incidence M e a n onset (Days) Wound Superficial Incidence M e a n onset (Days) 1 ( 10%) 21 2 ( 20%) 19 1 ( 10%) 27 1 ( 10%) 15 1 ( 10%) 13 1 ( 10%) 17 DuPont-11574 VII 1000 10 0 ( 0%) 10 (100%) 8 1 ( 10%) 6 2 ( 20%) 9 2 ( 20%) 10 Company SanTfizeci. "D oss no! conialnTSCA CBI H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____ DuPont-11574 TABLE 7 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS - POST DOSING IN MALE RATS Group Dosage(mg/kg) Animal Count Swollen Observations Face Incidence M e a n onset (Days) I 0 10 4 ( 40%) 1 III 10 10 1 ( 10%) 14 V 100 10 2 ( 20%) 2 VII 1000 10 2 0 Incidence - The number of animals for which an observation was recorded. M e a n onset (Days) - The m e a n of the first test day an o b s e r v a t i o n wa s r e c o r d e d for that group. T h ere w ere n o 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 s at p < 0.05 by Cochran-Armitage trend test. -39- C o m p a n y Sanitized. B o s s no? c o n f a b T S C A CB! H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_________ . DuPont-11574 TABLE 8 PERCENT SURVIVAL OF MALE RATS Group: I m V VII Dosage (mg/kg) 0 10 100 1000 Davs on Test 0 7 14 21 28 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 Number at study start 10 10 10 10 Alive on test day 28 10 10 10 10 Percent Survival = (Number of rats alive/Number of rats at risk)* 100 Number of rats at risk = Number at study start. There were no statistically significant decreases in survival. CSmoany -40- n* TRrtA CRH H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11574 TABLE 9 SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I Group III Group V Group VII _________ Omg/kg_______ lOmg/kg______ 100 mg/kg_____ 1000 mg/kg RBC (xl06/pL) DAY 29 8.32 7.95*a 7.95a 8.01 0.34(10) 0.36(10) 0.36(10) 0.27(10) HGB (g/dL) DAY 29 16.3 15.9 15.6* 15.6* 0.6(10) 0.6(10) 0.6(10) 0.3(10) HCT (%) DAY 29 48.2 46.6 46.0* 45.8* 1.8(10) 1.1(10) 1.8(10) 0.9(10) MCV (fl) DAY 29 58.0 58.7 57.8 57.1 1.8(10) 1.8(10) 1.4(10) 1.8(10) MCH (pg) j9 DAY 29 19.6 20.0 19.6 19.4 0.5(10) 0.6(10) 0.6(10) 0.5(10) MCHC (g/dL) DAY 29 33.8 34.0 34.0 34.0 0.3(10) 0.6(10) 0.6(10) 0.4(10) RDW (%) DAY 29 11.0 11.1 10.9 11.1 0.5(10) 0.4(10) 0.3(10) 0.5(10) ARET (xlOVpL) DAY 29 177.4 190.5 172.6 185.1 49.9(10) 42.2(10) 54.5(10) 35.5(10) PLT (xl03/pL) DAY 29 1186 1277 1326 1265 00 T"* 115(9) 157(10) 175(8) WBC (xlOVpL) DAY 29 12.05 12.17 12.85 14.66 3.27(10) 3.04(10) 2.15(10) 2.42(10) ANEU (xl03/pL) DAY 29 1.70 1.59 1.37 2.00 0.91(10) 0.57(10) 0.21(10) 0.72(10) ALYM (xl03/pL) DAY 29 9.61 9.85 10.72 11.69 2.32(10)- 2.77(10) 2.14(10) 1.82(10) Company Sanitized. Doss not contain TSCA CB1 -41 - H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11574 TABLE 9 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I 0 mg/kg Group III 10 mg/kg Group V 100 mg/kg Group VE 1000 mg/kg AMON (xl03/pL) DAY 29 AEOS (xl03/pL) DAY 29 ABAS (xl03/|j.L) DAY 29 ALUC (xl03/pL) DAY 29 0.31 0.12(10) 0.17 0.07(10) 0.12 0.04(10) 0.14 0.06(10) 0.27 0.06(10) 0.21 0.09(10) 0.11 0.03(10) 0.14 0.08(10) 0.31 0.07(10) 0.19 0.06(10) 0.09 0.04(10) 0.17 0.06(10) 0.41 0.13(10) 0.25@ 0.05(10) 0.14 0.06(10) 0.17 0.08(10) Data arranged as: Mean Standard deviation (Number of values included in calculation) a Groups with identical values may vary in statistical significance, because tabulated statistics are rounded to fewer decimal places than the values used for statistical determination. * 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. Company Sanitized. Does not containTSCACBI - 42- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_________ DuPont-11574 TABLE 10 SUMMARY OF CLINICAL CHEMISTRY VALUES FOR MALE RATS Group I Omg/kg Group in lOmg/kg Group V lOOmg/kg Group VII lOOOmg/kg AST (U/L) DAY 29 ALT (U/L) DAY 29 SDH (U/L) DAY 29 ALKP (U/L) DAY 29 BILI (mg/dL) DAY 29 BUN (mg/dL) DAY 29 CREA (mg/dL) DAY 29 CHOL (mg/dL) DAY 29 TRIG (mg/dL) DAY 29 GLUC (mg/dL) DAY 29 TP (g/dL) DAY 29 ALB (g/dL) DAY 29 109 14(10) 50 8(10) 12.8 2.9(10) 201 37(10) 0.09 0.03(10) 15 2(10) 0.38 0.04(10) 43 6(10) 30 10(10) 91 8(10) 6.7 0.2(10) 4.3 0.2(10) 112 8(10) 60 15(10) 13.5 3.8(10) 214 37(10) 0.12 0.02(10) 15 2(10) 0.39 0.03(10) 51* 5(10) 44 15(10) 97 13(10) 6.7 0.3(10) 4.2 0.1(10) 145@ 41(10) 100@ 37(10) 20.6 10.5(10) 225 46(10) 0.12 0.01(10) 15 2(10) 0.42 0.05(10) 51* 7(10) 45 15(10) 97 9(10) 6.5 0.2(10) 4.1* 0.2(10) 157@ 79(10) 111@ 66(10) 13.9 5.0(10) 274* 52(10) 0.12@ 0.04(10) 15 2(10) 0.41 0.04(10) 57* 6(10) 56@ 19(10) 101 10(10) 6.7 0.2(10) 4.1 0.1(10) Company Sanitized. Does no*contain TSCACEfl -43 - H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11574 TABLE 10 (Continued) SUMMARY OF CLINICAL CHEMISTRY VALUES FOR MALE RATS Group I 0 mg/kg Group III 10 mg/kg Group V 100 mg/kg Group VII 1000 mg/kg GLOB (g/dL) DAY 29 CALC (mg/dL) DAY 29 IPHS (mg/dL) DAY 29 NA (mmol/L) DAY 29 K (mmol/L) DAY 29 CL (mmol/L) DAY 29 PFLU (pg/mL) DAY 29 2.4 0.2(10) 10.8 0.4(10) 8.1 0.5(10) 150.0 1.5(10) 6.19 0.22(10) 102.4 1.6(10) 0.1 0.0(10) 2.5 0.3(10) 10.8 0.4(10) 8.0 0.5(10) 149.8 1.6(10) 6.05 0.40(10) 102.5 1.9(10) 0.1 0.0(10) 2.4 0.1(10) 10.5 0.3(10) 7.9 0.5(10) 149.7 1.2(10) 6.22 0.39(10) 103.9 1.5(10) 0.1 0.0(10) 2.5 0.1(10) 10.5 0.2(10) 8.0 0.4(10) 149.0 1.4(10) 5.99 0.32(10) 102.5 1.4(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 cqntrol at p < 0.05 by Dunn's test. Company Sanitized. Does not contain TSCACB1 - 44- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11574 TABLE 11 SUMMARY OF URINALYSIS VALUES FOR MALE RATS Group I 0 mg/kg Group III 10 mg/kg Group V 100 mg/kg Group VII 1000 mg/kg VOL (mL) DAY 29 UOSM (mOsm) DAY 29 pH DAY 29 URO (EU/dL) DAY 29 UFLU(pg) DAY 29 UMTP (mg/dL) DAY 29 8.6 7.6(10) 1551 903(10) 6.8 0.3(10) 0.3 0.3(10) 14.8 4.0(9) 111 67(10) 10.2 6.3(10) 1235 511(10) 6.9 0.6(10) 0.2 0.0(10) 17.4 4.3(10) 60 28(10) 7.7 3.9(10) 1283 328(10) 7.2 0.7(9) 0.2 0.0(9) 19.2 5.3(10) 61 38(10) 10.8 3.3(10) 962@ 284(10) 6.8 0.5(10) 0.2 0.0(10) 33.9@ 12.1(10) 34* 11(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. Company SanBbed. Do ,,o c0,,ls,, tsca CB, -45- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats _____________________________________________________________________________ .____________DuPont-11574 TABLE 12 MEAN FINAL BODY AND ORGAN WEIGHTS FROM MALE RATS M EAN FINAL BODY A N D ABSOLUTE O R G A N WEIGHTS (GRAMS) Group: Dosage(mg/kg) I III V VII 0 10 100 1000 LIVER 10.794 1 . 2 6 6 (10) 11.105 1.372(10) 10.252 1 . 0 0 4 (10) 11.574 1 . 2 2 3 (10) KIDNEYS 3.014 0 . 4 1 3 (10) 3.137 0 . 3 3 0 (10) 2.915 0 . 3 0 2 (10) 3.105 0.316(10) THYROID GLAND 0.017 0 . 0 0 3 (9) 0.020 0.004(10) 0.017 0.002(10) 0.018 0.002(10) FINAL BODY WEIGHT 347.622 24.048(9) 367.770 3 3 . 5 6 3 (10) 342.030 20.450(10) 357.880 24.679(10) 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 F B O D Y W E I G H T ) LIVER/ FINAL BODY * 100 3.081 0 . 2 7 7 (9) 3.016 0 . 1 9 2 (10) 2.992 0.158(10) 3.234 0.254(10) KIDNEYS/ FINAL BODY * 100 0.865 0.078(9) 0.853 0 . 0 4 3 (10) 0.851 0 . 0 6 2 (10) 0.869 0 . 0 7 8 (10) THYROID GLAND/ FINAL BODY * 100 0.005 0.001(8) 0.005 0.001(10) 0.005 0.001(10) 0.005 0.001(10) Data summarized a s : Mean S t a n d a r d D e v i a t i o n (n); n. < 10 r e f l e c t s w e i g h i n g error. There were no statistically significant differences at p < 0.05 by Jonckheere-Terpstra trend test. CompanySanitized. Dos not contain TSCACBI -46- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 TABLE 13 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS LESIONS | LESION INCIDENCE (Numeric) TREATMENT 0 mg/kg I 10 mg/kg III 100 mg/kg V 1000 mg/kg VII LIVER NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 KIDNEYS NO ABNORMALITY DETECTED DILATATION, UNILATERAL. (10) 10 (10) 10 (10) 9 1 THYROID GLAND NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 SKIN NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 TESTES LARGE, BILATERAL. (1) 1 TEETH NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 ^emoany Sanitized. Does net contain TSC CB1 -47- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 TABLE 14 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS LESIONS TREATMENT LESION INCIDENCE (NUMERIC) 0 mg/kg I 10 mg/kg III 100 mg/kg V 1000 mg/kg VII DIGESTIVE SYSTEM LIVER NECROSIS, HEPATOCELLULAR, FOCAL. minimal total observations per lesion MACROPHAGES, PIGMENTED, FOCAL. minimal total observations per lesion INFLAMMATION, S U B ACUTE/C H R O N I C , FOCAL. minimal total observations per lesion HEMATOPOIESIS, EXTRAMEDULLARY. minimal total observations per lesion (10) 1 1 5 5 10 10 (10) 1 1 8 8 10 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Comoany Sanitized. Doss contain TSCACBi H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 TABLE 14 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS LESIONS TREATMENT LESION INCIDENCE (NUMERIC) 0 mg/kg I 10 mg/kg III 100 mg/kg V 1000 mg/kg VII URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. minimal total observations per lesion DILATATION, PELVIS, UNILATERAL. mild total observations per lesion ENDOCRINE SYSTEM THYROID GLAND NO ABNORMALITY DETECTED REPRODUCTIVE SYSTEM TESTES NO ABNORMALITY DETECTED NO MICROSCOPIC EVIDENCE OF MACROSCOPIC FINDING. (10) 5 5 5 (10) 10 (1) (10) 4 6 6 l 1 (10) 10 (1) 1 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCACBI -49- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 TABLE 14 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS LESIONS CUTANEOUS SYSTEM SKIN NO ABNORMALITY DETECTED TISSUES NOT INCLUDED WITHIN BODY SYSTEMS TEETH NO ABNORMALITY DETECTED INFLAMMATION, ACUTE. mild total observations HEMORRHAGE. mild total observations per per lesion lesion TREATMENT LESION INCIDENCE (NUMERIC) 0 mg/kg I 10 mg/kg III 100 mg/kg V 1000 mg/kg VII (10) 10 (10) 10 (10) 10 (10) 9 1 1 1 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified Company Sanitized. Does not contain TSCACB1 -50- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11574 FIGURES Company Sanitized. Does not contain TSCA C6I H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats FIGURE 1 MEAN BODY WEIGHTS OF MALE RATS DuPont-11574 -- 0 mg/kg --S --10 mg/kg A 100 mg/kg X 1000 mg/kg Comoanv Sanitized. Does notcontainTSCACB1 - 52- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11574 APPENDICES Company Sanitized. Does not contain TSCA CBI H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11574 APPENDIX A Individual Daily Applied Dose Volumes Company Sanitized. Does no! contain TSCA CBI H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 dermal Pi Day 0 Male, I 0 mg/kg 665732 665733 665734 665735 665736 665737 665738 665739 665740 665741 248.0 253.0 261.7 239.7 237.6 237.7 207.7 260.8 251.2 225.0 Male, III 10 mg/kg 665742 665743 665744 665745 665746 665747 665748 665749 665750 665751 2.2 2.3 2.5 2.5 2.4 2.5 2.4 2.5 2.6 2.7 Male, V 100 rag/kg 665752 665753 665754 665755 665756 665757 665758 665759 665760 665761 24.2 24.1 25.3 24.1 24.8 23.6 24.0 25.2 26.0 22.6 dermal Ul Day 1 248.0 253.0 261.7 239.7 237.6 237.7 207.7 260.8 251.2 225.0 2.2 2.3 2.5 2.5 2.4 2.5 2.4 2.5 2.6 2.7 24.2 24.1 25.3 24.1 24. a 23.6 24.0 25.2 26.0 22.6 dermal Pi Day 2 248.0 253.0 261.7 239.7 237.6 237.7 207.7 260.8 251.2 225.0 2.2 2.3 2.5 2.5 2.4 2.5 2.4 2.5 2.6 2.7 24.2 24.1 25.3 24.1 24.8 23.6 24.0 25.2 26.0 22.6 Individual Daily Applied Dose Volumes dermal Pi Day 3 dermal Pi Day 4 dermal Ul Day 5 dermal Ul Day 6 264.8 270.1 271.9 240.8 259.2 250.7 215.4 280.1 270.3 237.7 264.8 270.1 271.9 240.8 259.2 250.7 215.4 280.1 270.3 237.7 264.8 270.1 271.9 240.8 259.2 250.7 215.4 280.1 270.3 237.7 264.8 270.1 271.9 240.8 259.2 250.7 215.4 280.1 270.3 237.7 2.4 2.4 2.4 2.4 2.4 2.4 2.4 2.4 2.7 2.7 2.7 2.7 2.6 2.6 2.6 2.6 2.6 2.6 2.6 2.6 2.6 2.6 2.6 2.6 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.8 2.8 2.8 2.8 2.9 2.9 2.9 2.9 25.9 26.2 27.2 25.3 25.6 24.7 24.4 26.4 26.7 24.4 25.9 26.2 27.2 25.3 25.6 24.7 24.4 26.4 26.7 24.4 25.9 26.2 27.2 25.3 25.6 24.7 24.4 26.4 26.7 24.4 25.9 26.2 27.2 25.3 25.6 24.7 24.4 26.4 26.7 24.4 dermal Ul Day 7 278.2 290.0 279.7 244.4 270.6 260.4 225.7 296.7 281.2 248.4 2.5 2.5 2.8 2.7 2.7 2.8 2.6 2.7 2.9 3.0 27.2 26.4 28.0 25.8 26.1 25.4 26.1 27.7 27.2 24.9 dermal Pi Day 8 278.2 290.0 279.7 244.4 270.6 260.4 225.7 296.7 281.2 248.4 2.5 2.5 2.8 2.7 2.7 2.8 2.6 2.7 2.9 3.0 27.2 26.4 28.0 25.8 26.1 25.4 26.1 27.7 27.2 24.9 ^TomoanySamffeetf.* (jgy -55 H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 dermal Hi Day 0 Male, VII 1000 mg/kg 665762 665763 665764 665765 665766 665767 665768 665769 665770 665771 241.7 245.0 262.3 241.7 238.2 236.6 251.8 261.4 260.8 236.3 dermal Hi Day 1 241.7 245.0 262.3 241.7 238.2 236.6 251.8 261.4 260.8 236.3 dermal Ul Day 2 241.7 245.0 262.3 241.7 238.2 236.6 251.8 261.4 260.8 236.3 Individual Daily Applied Dose Volumes dermal Ul Day 3 dermal Hi Day 4 dermal Hi Day 5 dermal Hi Day 6 251.1 265.2 263.1 254.3 261.6 246.7 264.6 273.7 284.3 238.7 251.1 265.2 263.1 254.3 261.6 246.7 264.6 273.7 284.3 238.7 251.1 265.2 263.1 254.3 261.6 246.7 264.6 273.7 284.3 238.7 251.1 265.2 263.1 254.3 261.6 246.7 264.6 273.7 284.3 238.7 dermal ill Day 7 258.8 273.7 275.4 271.0 277.0 255.6 275.5 284.8 289.8 243.3 dermal ill Day 8 258.8 273.7 275.4 271.0 277.0 255.6 275.5 284.8 289.8 243.3 Company Sanitized. Does not contain TSCA CBI H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats dermal Pi Day 9 Male, I 0 mg/kg 665732 665733 665734 665735 665736 665737 665738 665739 665740 665741 278.2 290.0 279.7 244.4 270.6 260.4 225.7 296.7 281.2 248.4 Male, III 10 mg/kg 665742 665743 665744 665745 665746 665747 665748 665749 665750 665751 2.5 2.5 2.8 2.7 2.7 2.8 2.6 2.7 2.9 3.0 Male, V 100 mg/kg 665752 665753 665754 665755 665756 665757 665758 665759 665760 665761 27.2 26.4 28.0 25.8 26.1 25.4 26.1 27.7 27.2 24.9 dermal Pi Day 10 293.8 302.4 290.3 254.0 287.0 270.0* 234.7 310.6 298.1 267.7 2.7 2.6 2.9 2.9 2.9 3.0 2.7 2.8 3.1 3.2 28.8 27.3 29.0 26.5 27.4 26.1 27.9 27.7 28.0 25.3 dermal Pi Day 11 293.8 302.4 290.3 254.0 287.0 270.0 234.7 310.6 298.1 267.7 2.7 2.6 2.9 2.9 2.9 3.0 2.7 2.8 3.1 3.2 28.8 27.3 29.0 26.5 27.4 26.1 27.9 27.7 28.0 25.3 Individual dermal pl Day 12 293.8 302.4 290.3 254.0 287.0 270.0 234.7 310.6 298.1 267.7 2.7 2.6 2.9 2.9 2.9 3.0 2.7 2.8 3.1 3 .2 28.8 27.3 29.0 26.5 27.4 26.1 27.9 27.7 28.0 25.3 DuPont-11574 Daily Applied Dose Volumes dermal Ul Day 13 dermal Hi Day 14 dermal Hi Day 15 dermal Hi Day 16 dermal Hi Day 17 293.8 302.4 290.3 254.0 287.0 270.0 234.7 310.6 298.1 267.7 306.9 313.0 293.7 260.0 291.7 290.3 248.3 321.7 307.5 274.5 306.9 313.0 293.7 260.0 291.7 290.3 248.3 321.7 307.5 274.5 306.9 313.0 293.7 260.0 291.7 290.3 248.3 321.7 307.5 274.5 309.7 328.3 302.9 268.5 308.0 295.9 260.0 332.0 321.8 278.0 2.7 2.9 2.9 2.9 2.9 2.6 2.7 2.7 2.7 2.8 2.9 3.0 3.0 3.0 3.1 2.9 3.1 3.1 3.1 3.2 2.9 3.0 3.0 3.0 3.1 3.0 3.1 3.1 3.1 3.2 2.7 2.8 2.8 2.8 2.8 2.8 2.9 2.9 2.9 3.1 3.1 3.3 3.3 3.3 3.4 3.2 3.3 3.3 3.3 3.4 28.8 27.3 29.0 26.5 27.4 26.1 27.9 27.7 28.0 25.3 29.6 28.2 29.8 27.3 28.7 26.7 28.8 27.7 29.0 25.5 29.6 28.2 29.8 27.3 28.7 26.7 28.8 27.7 29.0 25.5 29.6 28.2 29.8 27.3 28.7 26.7 28.8 27.7 29.0 25.5 29.7 28.6 31.9 28.5 29.4 27.7 29.1 28.2 30.0 26.6 Company Sanitized. Does not contain TSCACBf H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 dermal Ul Day 9 Male, VII 1000 mg/kg 665762 665763 665764 665765 665766 665767 665768 665769 665770 665771 258.8 273.7 275.4 271.0 277.0 255.6 275.5 284.8 289.8 243.3 dermal Ul Dy 10 268.4 280.4 291.7 283.8 291.1 263.4 289.4 294.4 307.5 261.6 dermal Ul Day 11 268.4 280.4 291.7 283.8 291.1 263.4 289.4 294.4 307.5 261.6 Individual Daily Applied Dose Volumes dermal Ul Day 12 dermal Ul Day 13 dermal Ul Day 14 dermal ul Day 15 268.4 280.4 291.7 283.8 291.1 263.4 289.4 294.4 307.5 261.6 268.4 280.4 291.7 283.8 291.1 263.4 289.4 294.4 307.5 261.6 275.0 297.9 296.4 299.3 300.9 273.4 310.5 296.4 313.3 270.8 275.0 297.9 296.4 299.3 300.9 273.4 310.5 296.4 313.3 270.8 dermal Ul Day 16 275.0 297.9 296.4 299.3 300.9 273.4 310.5 296.4 313.3 270.8 dermal Ul Day 17 269.8 310.8 306.3 306.7 323.2 278.3 315.5 317.7 313.1 279.7 Company Sanitized. Does not contain TSCA CB1 H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats dermal Ul Day 18 Male, I 0 mg/kg 665732 665733 665734 66573.5 665736 665737 665738 665739 665740 665741 309.7 328.3 302.9 268.5 308.0 295.9 260.0 332.0 321.8 278.0 Male, III 10 mg/kg 665742 665743 665744 665745 665746 665747 665748 665749 665750 665751 2.9 2.8 3.1 3.2 3.1 3.2 2.8 3.1 3.4 3.4 Male, V 100 mg/kg 665752 665753 665754 665755 665756 665757 665758 665759 665760 665761 29.7 28.6 31.9 28.5 29.4 27.7 29.1 28.2 30.0 26.6 dermal Ul Day 19 309.7 328.3 302.9 268.5 308.0 295.9 260.0 332.0 321.8 278.0 * 2.9 2.8 3.1 3.2 3.1 3.2 2.8 3.1 3.4 3.4 29.7 28.6 31.9 28.5 29.4 27.7 29.1 28.2 30.0 26.6 dermal Ul Day 20 309.7 328.3 302.9 268.5 308.0 295.9 260.0 332.0 321.8 278.0 2.9 2.8 3.1 3.2 3.1 3.2 2.8 3.1 3.4 3.4 29.7 28.6 31.9 28.5 29.4 27.7 29.1 28.2 30.0 26.6 Individual Daily Applied dermal Hi Day 21 dermal ul Day 22 328.0 331.9 310.9 286.8 318.3 295.1 269.0 338.5 325.0 288.9 328.0 331.9 310.9 286.8 318.3 295.1 269.0 338.5 325.0 288.9 3.1 3.1 2.8 2.8 3.3 3.3 3.3 3.3 3.2 3.2 3.4 3.4 2.9 2.9 3.2 3.2 3.6 3.6 3.5 3.5 30.9 28.8 32.4 30.6 30.2 29.1 30.1 30.0 30.9 27.1 30.9 28.8 32.4 30.6 30.2 29.1 30.1 30.0 30.9 27.1 DuPont-11574 Dose Volumes dermal pi Day 23 dermal Pi Day 24 dermal Pi Day 25 dermal Pi Day 26 328.0 331.9 310.9 286.8 318.3 295.1 269.0 338.5 325.0 288.9 342.4 341.7 316.4 290.3 322.3 294.6 265.5 335.4 332.1 290.4 342.4 341.7 316.4 290.3 322.3 294.6 265.5 335.4 332.1 290.4 342.4 341.7 316.4 290.3 322.3 294.6 265.5 335.4 332.1 290.4 3.1 3.2 3.2 3.2 2.8 2.9 2.9 2.9 3.3 3.3 3.3 3.3 3.3 3.5 3.5 3.5 3.2 3.3 3.3 3.3 3.4 3.4 3.4 3.4 2.9 3.0 3.0 3.0 3.2 3.2 3.2 3.2 3.6 3.6 3.6 3.6 3.5 3.6 3.6 3.6 30.9 28,8 32.4 30.6 30.2 29.1 30.1 30.0 30.9 27.1 31.5 30.4 33.7 31.6 30.4 28.7 30.7 31.1 30.7 27.9 31.5 30.4 33.7 31.6 30.4 28.7 30.7 31.1 30.7 27.9 31.5 30.4 33.7 31.6 30.4 28.7 30.7 31.1 30.7 27.9 Comoany Sanitized. Does not contain TSCA CBI H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 dermal pi Day 18 Male, VII 1000 mg/kg 665762 665763 665764 665765 665766 665767 665768 665769 665770 665771 269.8 310.8 306.3 306.7 323.2 278.3 315.5 317.7 313.1 279.7 dermal Pi Day 19 * 269.8 310.8 306.3 306.7 323.2 278.3 315.5 317.7 313.1 279.7 dermal Pi Day 20 269.8 310.8 306.3 306.7 323.2 278.3 315.5 317.7 313.1 279.7 Individual Daily Applied Dose Volumes dermal Pi Day 21 dermal Pi Day 22 dermal Pi Day 23 dermal Pi Day 24 284.5 318.3 318.3 317.9 348.7 292.4 324.9 323.1 326.3 286.4 284.5 318.3 318.3 317.9 348.7 292.4 324.9 323.1 326.3 286.4 284.5 318.3 318.3 317.9 348.7 292.4 324.9 323.1 326.3 286.4 295.4 336.6 320.4 329.1 353.7 300.1 330.4 321.7 340.1 285.7 dermal Pi Day 25 295.4 336.6 320.4 329.1 353.7 300.1 330.4 321.7 340.1 285.7 dermal Pi Day 26 295.4 336.6 320.4 329.1 353.7 300.1 330.4 321.7 340.1 285.7 Company S an in e. Dms ^ H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats dermal pl Day 27 Male, I 0 mg/kg 665732 665733 665734 665735 665736 665737 665738 665739 665740 665741 342.4 341.7 316.4 290.3 322.3 294.6 265.5 335.4 332.1 290.4 Male, III 10 m g / k g 665742 665743 665744 665745 665746 665747 665748 665749 665750 665751 3.2 2.9 3.3 3.5 3.3 3.4 3.0 3.2 3.6 3.6 Male., V 100 mg/kg 665752 665753 665754 665755 665756 665757 665758 665759 665760 665761 31.5 30.4 33.7 31.6 30.4 28.7 30.7 31.1 30.7 27.9 dermal Pi Day 28 337.7 348.0 329.8 304.8 324.3 298.2 275.0 349.8 343.7 292.3 3.3 2.9 3.2 3.6 3.3 3.6 3.0 3.2 3.5 3.7 32.5 30.9 34.4 31.7 31.1 30.5 33. p 31.1 30.8 27.7 Individual Daily Applied Dose Volumes DuPont-11574 Company Sanitized. Does no! containTSCACB! -61- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats dermal m Day 27 Male, VII 1000 mg/kg 665762 665763 665764 665765 665766 665767 665768 665769 665770 665771 295.4 336.6 320.4 329.1 353.7 300.1 330.4 321.7 340.1 285.7 dermal pi Day 28 303.5 339.2 334.1 337.5 356.0 305.9 351.0 333.1 352.4 301.6 Individual Daily Applied Dose Volumes DuPont-11574 Company Sanitized. Does not contain TSCACffl H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats____________ DuPont-11574 APPENDIX B , Individual Body Weights company Sanitized. Does not contain TSCACBI -63 - ) H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) ) DuPont-11574 Individual Body Weights Body Weight y Day 0 Male, I 0 rag/kg Body Weight 9' Day 3 Body Weight g Day 7 Body Weight g Day 10 Body Weight g Day 14 Body Weight g Day 17 Body Weight g Day 21 Body Weight g Day 24 Body Weight 9 Day 28 665732 665733 665734 665735 665736 665737 665738 665739 665740 665741 285.2 291.0 300.9 275.6 273.2 273.3 238.9 299.9 288.9 258.8 Male, III 10 mg/kg 304.5 310.6 312.7 276.9 298.1 288.3 247.7 322.1 310.8 273.4 319.9 333.5 321.7 281.1 311.2 299.5 259.5 341.2 323.4 285.7 337.9 347.8 333.9 292.1 330.1 310.5 269.9 357.2 342.8 307.9 352.9 360.0 337.8 299.0 335.4 333.8 285.6 369.9 353.6 315.7 356.2 377.5 348.3 308.8 354.2 340.3 299.0 381.8 370.1 319.7 377.2 381.7 357.5 329.8 366.1 339.4 309.3 389.3 373.8 332.2 393.8 393.0 363.9 333.9 370.7 338.8 305.3 385.7 381.9 334.0 388.4 400.2 379.3 350.5 372.9 342.9 316.2 402.3 ' 395.3 336.2 665742 665743 665744 665745 665746 665747 665748 665749 665750 665751 257.6 263.3 291.6 285.0 277.4 285.6 277.3 285.2 304.2 305.3 Male, V 100 mg/kg 275.1 280.9 307.4 297.4 295.4 294.9 284.1 291.3 319.8 329.2 283.8 289.9 320.8 315.4 314.4 322.6 298.5 305.1 335.3 347.6 310.8 300.8 328.7 335.7 333.0 344.5 310.9 325.8 358.0 364.4 330.9 311.9 346.0 351.0 347.3 361.6 316.3 334.3 378.3 377.6 337.8 320.5 357.8 362.4 360.7 373.2 320.4 350.7 391.9 392.1 356.7 326.0 374.6 382.7 365.0 387.0 331.1 364.6 412.9 405.4 368.7 328.3 382.0 396.8 374.9 395.1 339.8 373.3 408.8 415.8 377.2 338.6 373.3 416.7 380.1 410 ;8 345.3 371.3 404.0 430.7 665752 665753 665754 665755 665756 665757 665758 665759 665760 665761 278.4 277.7 290.5 277.1 285.2 271.3 275.7 289.8 298.6 260.0 298.4 300.8* 312.7 290.4 294.2 283.9 280.1 303.7 306.5 280.1 312.6 303.5 322.2 296.3 300.4 292.1 300.7 318.5 313.3 286.7 331.7 314.5 333.0 305.2 315.4 300.4 320.7 318.7 322.5 291.4 340.7 324.6 343.0 313.8 330.5 307.6 331.1 318.6 333.0 293.5 341.7 329.3 366.7 328.2 338.1 318.1 334.3 324.2 344.5 306.1 355.3 331.0 372.7 351.5 347.0 335.1 346.5 345.3 354.8 312.0 362.6 349.4 387.6 363.8 349.8 329.5 352.9 358.0 352.7 321.4 373.2 355.6 396.1 364.5 357.6 351.1 379.2 357.3 353.8 318.7 Comoanv SanHbad. 0Sf?no*contain TSCACBI -64- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 Individual Body Weights Body Weight Body Weight gg Day 0 Day 3 Male, VII 1000 mg/kg Body Weight 9 Day 7 Body Weight g Day 10 Body Weight g Day 14 Body Weight 9 Day 17 Body Weight g Day 21 Body Weight 9 Day 24 Body Weight 9 Day 28 665762 665763 665764 665765 665766 665767 665768 665769 665770 665771 277.9 281.7 301.6 277.9 273.9 272.1 289.6 300.6 299.9 271.7 288.8 305.0 302.6 292.4 300.8 283.7 304.3 314.8 326.9 274.5 297.6 314.7 316.7 311.7 318.6 293.9 316.8 327.5 333.3 279.8 308.7 322.5 335.5 326.4 334.8 302.9 332.8 338.6 353.6 300.8 316.3 342.6 340.9 344.2 346.0 314.4 357.1 340.9 360.3 311.4 310.3 357.4 352.2 352.7 371.7 320.1 362.8 365.4 360.1 321.6 327.2 366.1 366.1 365.6 401.0 336.3 373.6 371.6 375.3 329.4 339.7 387.1 368.5 378.5 406.8 345.1 380.0 370.0 391.1 328.5 349.0 390.1 384.2 388.1 409.4 351.8 403.6 383.1 405.3 346.8 Company Sanitized. Does no! confalo TSC CBS H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11574 APPENDIX C Individual Food Consumption Company Sanitized. Doss net contain TSCA CB1 H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Individual Food Consumption Food Cons. g/anm/day Day 7 Food Cons. g/anm/day Day 14 Food Cons. g/anm/day Day 21 Food Cons. g/anm/day Day 28 0 1 1 Male, I 665732 665733 665734 665735 665736 665737 665738 665739 665740 665741 27.1 27.4 26.1 21.5 28.5 27.3 25.2 28.3 28.1 27.4 27.8 27.4 25.6 22.2 27.6 27.6 26.4 26.7 27.4 27.2 28.3 28.2 25.4 24.3 27.1 26.1 25.9 27.3 26.7 24.5 28.2 28.4 26.7 26.5 27.4 27.1 26.2 28.5 27.2 26.4 Male, III 10 mg/kg 665742 665743 665744 665745 665746 665747 665748 665749 665750 665751 27.8 24.9 26.8 25.0 26.0 26.6 25.7 23.1 27.6 28.4 27.8 24.5 25.8 26.9 27.9 28.6 25.1 24.9 29.8 27.7 27.1 24.5 27.0 27.9 27.1 27.0 24.9 25.5 29.8 27.8 28.4 26.8 27.1 29.9 27.8 27.0 25.2 26.4 28.2 28.3 Male, V 100 mg/kg 665752 665753 665754 665755 665756 665757 665758 665759 665760 665761 26.9 25.8 27.1 27.2 23.3 24.5 22.9 25.2 26.0 27.1 26.6 24.6 27.4 26.5 24.0 26.0 24.7 25.3 26.2 24.7 27.1 25.4 27.7 27.7 25.5 25.6 25.7 25.9 25.7 25.0 28.7 28.0 28.0 28.1 27.3 26.9 28.3 24.3 26.3 26.4 Male, VII 1000 mg/kg 665762 665763 665764 665765 665766 665767 665768 665769 665770 665771 25.7 29.0 24.4 25.6 28.2 24.4 27.0 26.6 28.2 22.2 26.7 29.5 25.5 26.6 28.3 24.5 28.5 27.4 28.4 25.2 26.8 28.2 26.1 25.9 31.0 26.0 26.9 29.6 26.5 24.9 27.8 28.9 25.7 27.1 28.7 26.5 27.5 27.2 28.8 26.9 DuPont-11574 Company SanFfeed. Doss no*contain TSCAcm - 67- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11574 APPENDIX D Individual Clinical Observations and Mortality Records (/^B***\ Company Sanitized. Does not containTSCA CBI - 68- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_______ _____ DuPont-11574 INDIVIDUAL CLINICAL OBSERVATIONS AND MORTALITY RECORDS EXPLANATORY NOTES Clinical observations reported in this appendix were recorded during body weight collection. Clinical observations recorded post-dosing are not included. Company Sanitized. Does net containTBCCBI H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Sex Group Animal 665732 665733 665734 665735 665736 665737 Individual Clinical Observations and Mortality Records Observation Days General observation, Mo Abnormality Detected 0, 3 , 7 , 10, 14, 17, 21,24,28,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 Eye Observations, Bled via Orbital for Clin Path, Right 3 . 9.21 Sacrificed by design 29 General observation, No Abnormality Detected 0 , 3 ,7 , 10, 14, 17,21,24,28,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 Eye Observations, Bled via Orbital for Clin Path, Right 3 . 9.21 Sacrificed by design 29 General observation. No Abnormality Detected 0, 3 , 7, 10, 14, 17, 21, 24,28,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 Eye Observations, Bled via Orbital for Clin Path, Right 3 . 9.21 Sacrificed by design 29 General observation, No Abnormality Detected 0 ,3 , 7 , 10, 14, 17, 21, 24,28,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 Eye Observations, Bled via Orbital for Clin Path, Right 3 . 9.21 Sacrificed by design 29 General observation, No Abnormality Detected 0 , 3 ,7 , 10, 14, 17, 21, 24, 28,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 Eye Observations, Bled via Orbital for Clin Path, Right 3 . 9.21 Sacrificed by design 29 General observation, No Abnormality Detected 0, 3 , 7 , 10, 14, 17, 21, 24, 28,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 Sacrificed by design 29 DuPont- 1574 Company Sanitized. Does no?contain TSCACBI -70- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Sex Group Animal M 665738 M 665739 M 665740 M 665741 Individual Clinical Observations and Mortality Records Observation Days General observation, No Abnormality Detected 0,3,7,10,14,17,28,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 Wound, Superficial, Abdomen 21.24 Sacrificed by design 29 General observation. No Abnormality Detected 0,3,7,10,14,28,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 Hair Loss, Neck, Right 21.24 Wound, Superficial, Shoulder, Left 17 Sacrificed by design 29 General observation, No Abnormality Detected 0,3,7,10,14,17,21,24,28,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 Sacrificed by design 29 General observation, No Abnormality Detected 0,3,7,10,14,17,21,24,28,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 Sacrificed by design 29 DuPont-11574 Company Sanitized. Does no! contain TSCA CB1 H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats . Individual Clinical Observations and Mortality Records Sex Group Animal Observation Days M III 665742 General observation, No Abnormality Detected 0,7,10,14,17,21,24,28,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 Eye Observations, Bled via Orbital for Clin Path, Right 3.9.21 Discharge, Nose, Red 3 Sacrificed by design 29 III 665743 General observation, No Abnormality Detected 0,3,7,10,14,17,21,24,28,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 Eye Observations, Bled via Orbital for Clin Path, Right 3.9.21 Sacrificed by design 29 665744 General observation. No Abnormality Detected 0,3,7,10,14 Eye Observations, Bled via Orbital for Clin Path, Left 29 Eye Observations, Bled via Orbital for Clin Path, Right 3.9.21 Wound, Superficial, Dorsal Body, outside of test area 17 Wound, Superficial, Dorsal Body, out of the test area 24.28.29 Wound, Superficial, Shoulder, Bilateral 21.24.28.29 Wound, Superficial, Shoulder, Right 17 Sacrificed by design 29 III 665745 General observation, No Abnormality Detected 0,3,7,10,14,17,21,24,28,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 Eye Observations, Bled via Orbital for Clin Path, Right 3.9.21 Sacrificed by design 29 DuPont-11574 Company Sanitized. Does not contain TSCACB! -72- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Individual Clinical Observations and Mortality Records Sex Group Animal Observation Days M III 665746 General observation. No Abnormality Detected 0,3,7,10,14,17,21,24 Eye Observations, Bled via Orbital for Clin Path, Left 29 Eye Observations, Bled via Orbital for Clin Path, Right 3,9,21 Hair Loss, Forepaw, Left 28,29 M III 665747 Sacrificed by design General observation, No Abnormality Detected 29 0,7,10,14,17,21,24,28,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 Discharge, Nose, Red 3 M III 665748 Sacrificed by design General observation, No Abnormality Detected 29 0,3,7,10,14,17,21,24,28,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 M III 665749 Sacrificed by design General observation. No Abnormality Detected 29 0,3,7,10,14,17,21,24,28,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 Sacrificed by design 29 M III 665750 General observation, No Abnormality Detected 0,3,7,10,14,17,21,24,28,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 Sacrificed by design 29 M III 665751 General observation, No Abnormality Detected 0,3,7,10,14,17,21,24,28,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 Sacrificed by design 29 DuPont-11574 Company Sanitized. Does no! contain TSCA CBI H-25435; Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Sex Group Animal 665752 665753 665754 665755 Individual Clinical Observations and Mortality Records Observation Days General observation, No Abnormality Detected 0,3,7,10,14,17,21,24,28,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 Eye Observations, Bled via Orbital for Clin Path, Right 3.9.21 Sacrificed by design 29 General observation. No Abnormality Detected 0,3,7,10,14,17,21,24,28,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 Eye Observations, Bled via Orbital for Clin Path, Right 3.9.21 Sacrificed by design General observation. No Abnormality Detected 29 0,3,7,10,14,17,21,24,28,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 Eye Observations, Bled via Orbital for Clin Path, Right 3.9.21 Sacrificed by design 29 General observation. No Abnormality Detected 0,3,7,10,14,17,21,24,28,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 Eye Observations, Bled via Orbital for Clin Path, Right 3.9.21 Sacrificed by design 29 ) DuPont-11574 Company Sanitized. Does not contain TSCACBI -74- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 Sex Group Animal 665756 MV 665757 MV 665758 665759 665761 Individual Clinical Observations and Mortality Records Observation Days General observation, No Abnormality Detected 0, 3,7 Eye Observations, Bled via Orbital for Clin Path, Left 29 Eye Observations, Bled via Orbital for Clin Path, Right 3 , 9,21 Hair Loss, Forepaw, Left 14, 17,21, 24, 28,29 Hair Loss, Shoulder, Bilateral 29 Wound, Superficial, Dorsal Body, outside test area 28 Wound, Superficial, Forepaw, Left 10 Wound, Superficial, Shoulder, Bilateral 21, 24,28 Wound, Superficial, Shoulder, Left 14,17 Sacrificed by design 29 General observation, No Abnormality Detected 0 , 3 , 7 , 10, 14, 17,21,24, 28,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 Sacrificed by design 29 General observation, No Abnormality Detected 0 ,3 , 7 , 10, 14, 17, 21,24,28,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 Sacrificed by design 29 General observation, No Abnormality Detected 0 , 3 , 7 , 10, 14, 17,21, 24,28,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 Sacrificed by design 29 General observation, No Abnormality Detected 0, 3 , 7 , 10, 14, 17,21, 24, 28,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 Sacrificed by design 29 General observation, No Abnormality Detected 0 , 3, 7 , 10, 14, 17, 21,24,28,29 Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design 29 29 Company Sanitized Does not contain TSCACBI ) H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 Individual Clinical Observations and Mortality Records Sex Group Animal Observation Days M VII 665762 General observation, No Abnormality Detected 0,3 Eye Observations, Bled via Orbital for Clin Path, Left 29 Eye Observations, Bled via Orbital for Clin Path, Right 3.9.21 Hair Loss, Forepaw, Bilateral 7,10,14,17,21,24,28,29 Wound, Superficial, Forelimb, Right 7.10 Wound, Superficial, Forepaw, Left 7.10 Sacrificed by design 29 665763 General observation, No Abnormality Detected 0,3,7,10,14,17,21,24,28,29 Eye Observations, Bledvia Orbital for Clin Path, Left 29 Eye Observations, Bledvia Orbital for Clin Path, Right 3.9.21 Sacrificed by design 29 665764 General observation, No Abnormality Detected 0,3,7,10,14,17,21,24,28,29 Eye Observations, Bledvia Orbital for Clin Path, Left 29 Eye Observations, Bledvia Orbital for Clin Path, Right 3.9.21 Sacrificed by design 29 VII 665765 General observation, No Abnormality Detected 0,3,7,10,14,17,21,24,28,29 Eye Observations, Bledvia Orbital for Clin Path, Left 29 Eye Observations, Bledvia Orbital for Clin Path, Right 3.9.21 Sacrificed by design 29 VII 665766 General observation. No Abnormality Detected 0,3,7,28,29 Eye Observations, Bledvia Orbital for Clin Path, Left 29 Eye Observations, Bledvia Orbital for Clin Path, Right 3.9.21 Hair Loss, Forepaw, Bilateral 10,14,17,21,24 Sacrificed by design 29 Company Sanitized, Does not contain TSCA CB1 -76- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ' Sex Group Animal M VII 665767 M VII 665768 M VII 665769 M VII 665770 M VII 665771 Individual Clinical Observations and Mortality Records Observation Days General observation, No Abnormality Detected 0,3,7,10,14,17,21,24,28 Eye Observations, Bled via Orbital for Clin Path, Left 29 Discharge, Eye right, Red 29 Sacrificed by design 29 General observation, No Abnormality Detected 0,3,7,10,14,17,21,24,28,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 Sacrificed by design 29 General observation, No Abnormality Detected 0,3,7,10,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 Wound, Superficial, Dorsal Body, outside the test area 14,17,21,24,28 Sacrificed by design 29 General observation, No Abnormality Detected 0,3,7,10,14,17,21,24,28,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 Sacrificed by design 29 General observation, No Abnormality Detected 0,3,7,10,14,17,21,24,28,29 Eye Observations, Bled via Orbital for Clin Path, Left 29 Sacrificed by design 29 DuPont-11574 Company Sanitized, Doss not contain TSCACBf -77- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11574 APPENDIX E Individual Clinical Observations - Post-Dosing Company Sanitized. Does not contain TSCACBI - 78- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11574 INDIVIDUAL CLINICAL OBSERVATIONS- POST-DOSING EXPLANATORY NOTES Clinical observations reported in this appendix were recorded daily after removal of the test substance. Clinical observations recorded during body weight collection are not included. Company Sanitized. Does no! contain TSCACBI - 79- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 Sex Group Animal MI 665732 MI 665733 MI 665734 MX 665735 MI 665736 MI 665737 Individual Clinical Observations Observation General observation, No Abnormality Detected Discharge, Eye bilateral, Red Discharge, Eye right, Red Swollen Observations, Face General observation, No Abnormality Detected Discharge, Eye bilateral, Red Discharge, Eye right, Red General observation, No Abnormality Detected Discharge^ Eye bilateral. Red Discharge, Nose, Red Discharge, Eye right, Red Swollen Observations, Face General observation. No Abnormality Detected Discharge, Eye bilateral, Red Discharge, Eye left, Red Discharge, Eye right, Red General observation, No Abnormality Detected Discharge, Eye bilateral, Red General observation, No Abnormality Detected Discharge, Eye bilateral, Red Discharge, Eye right, Red Post-Dosing Days 5,10-13,14,16,17,19-20,21-23,24-27 1-2,3-4,6,7-8,9,28 0,15,18 1 0,2,4-5,7-8,11-13,14,16,18-20,21-23,24-27,28 1,3,6,9,17 10,15 0,4-5,7,14-15,22,24-27,28 1-2,3,6,8,9,12-13,17-19,21,23 3 10-11,16,20 1.23 2,3-6,7,9,11-13,14-15,17-19,21,24-27,28 0-1,10,16,22-23 8 20 4,7-8,9,10,13,14-16,17-20,23,24-26,28 0-2,3,5-6,11-12,21-22,27 11,13,14-15,17-20,25-26,28 0-2,3-6,7-9,12,16,21-22,24,27 10.23 Company Sanitized. Does no! contain TSCA CBI H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 Sex Group Animal MI 665738 MI 665739 MI 665740 MI 665741 Individual Clinical Observations Observation General observation, No Abnormality Detected Discharge, Eye bilateral. Red Discharge, Eye right, Red Wound, Superficial, Abdomen General observation, No Abnormality Detected Discharge, Eye bilateral, Red Hair Loss, Neck, Right Wound, Superficial, Shoulder, Left Swollen Observations, Face General observation, No Abnormality Detected Discharge, Eye bilateral, Red Swollen Observations, Face General observation. No Abnormality Detected Discharge, Eye bilateral. Red Discharge, Eye right, Red Post-Dosing Days 10-13,15,17 3-4,6,7,9,14,16,18-20,21-23,24-27,28 0- 2,5,8 21-23,24-26 0,2,3,5-6,7,9,10-11,16,19 4,8,12-13,14-15,18,20,27,28 21-23,24-26 17-18 1,4 1- 2,4-6,7,10-13,14-16,17-20,21,23,24-27,28 8-9,22 0,3 1-2,4,10,12-13,16,19,21-22,24,26,28 0,3,5-6,7-9,11,15,17-18,20,23,25,27 14 Comoany Sanitized. Does not contain TSCA CB1 H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 Sex Group Animal Observation Individual Clinical Observations M III 665742 General observation, No Abnormality Detected Discharge, Eye bilateral, Red Discharge, Nose, Red M III 665743 General observation, No Abnormality Detected Discharge, Eye bilateral, Red Discharge, Nose, Red Discharge, Eye right, Red M III 665744 General observation. No Abnormality Detected Discharge, Eye bilateral, Red Discharge, Eye right, Red Wound, Superficial, Dorsal Body, out of the test area Wound, Superficial, Shoulder, Bilateral Wound, Superficial, Shoulder, Right Wound, Superficial, Neck M III 665745 General observation, No Abnormality Detected Discharge, Eye bilateral, Red Discharge, Eye right, Red Swollen Observations, Face M III 665746 General observation, No Abnormality Detected Discharge, Eye bilateral. Red Discharge, Eye right, Red Hair Loss, Forepaw, Left Post-Dosing Days 1-2,3-6,7-8,9,10-13,14-16,17-20,21,23,26-27,28 22,24-25 0 1-2,6,7-8,9,10-13,14-16,17,19-20,21-23,24-27,28 3-5,18 3 0 0,9,10-13,14-16 2,3-4,7-8,19,23,24-25 1,5-6 21-23,24-27,28 20,21-23,24-27,28 17-19 3 1-2,5,7,10,13,15,19,27,28 4,6,8,11-12,14,16,17-18,21-23 0,3,9,20,24-26 14 1,5,7,9,10-13,14-16,17-20,22-23,24-26 3-4,8,21 0 , 2,6 27,28 Company Sanitized. Doss not contain TSCA CBI H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) DuPont-11574 Sex Group Animal M III 665747 M III 665748 M III 665749 M III 665750 M III 665751 Individual Clinical Observations - Po -Dosing Observation Days General observation, No Abnormality Detected 13,14-15,17,22-23,24-27 Discharge, Eye bilateral, Red 0-2,3-6,7-9,10,16,18,20,28 Discharge, Eye right. Red 11-12,19,21 General observation, No Abnormality Detected 3-6,7,9,10,13,17,19-20,22,26-27 Discharge, Eye bilateral. Red 0-2,8,11-12,14,16,18,21,23,24-25,28 Discharge, Eye right, Red 15 General observation, No Abnormality Detected 9,10,12-13,14-16,17,19-20,21-22,26-27,28 Discharge, Eye bilateral, Red 0-2,3-6,7-8,11,23,24-25 Discharge, Eye right, Red 18 General observation, No Abnormality Detected 0-2,3-5,7,9,10-11,14,16,17,20,23,28 Discharge, Eye bilateral, Red 6,8,12,15,18-19,21-22,24-27 Discharge, Eye left, Red 13 General observation, No Abnormality Detected 2,4-6,9,10-13,14,16,17-19,23,24-27,28 Discharge, Eye bilateral. Red 3,7-8,15,21-22 Discharge, Eye right, Red 0 - 1,20 Company Sanitized. Doss not contain TSCACB1 -83- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 Sex Group Animal MV 665752 MV 665753 MV 665754 MV 665755 MV 665756 Individual Clinical Observations Observation General observation, No Abnormality Detected Discharge, Eye bilateral, Red Discharge, Eye right. Red General observation, No Abnormality Detected Discharge, Eye bilateral, Red Discharge, Eye left, Red General observation, No Abnormality Detected Discharge, Eye bilateral. Red Discharge, Eye left, Red Discharge, Eye right. Red Swollen Observations, Face General observation. No Abnormality Detected Discharge, Eye bilateral, Red Discharge, Eye right, Red General observation, No Abnormality Detected Eye Observations, Dark, Right Discharge, Eye bilateral. Red Discharge, Eye left. Red Hair Loss, Forepaw, Left Wound, Superficial, Dorsal Body, outside test area Wound, Superficial, Forepaw, Left Wound, Superficial, Shoulder, Bilateral Wound, Superficial, Shoulder, Left Post-Dosing Days 0,5-6,9,10-11,14,16,17,19-20,21-22,25 3- 4,8,12-13,15,18,23,24,26-27,28 1-2,7 2.7.9.10- 11,13,14-16,17,20,21,28 1.3- 6,8,12,18-19,22-23,24-27 0 2.8.10- 12,14,16,19,22,25-27 1.3- 6,7,9,13,15,18,20,23,24,28 21 17 0 3,10 0-2,6,7-8,9,11-13,14-16,17-20,21-23,24-27,28 4- 5 0,2,3,7 4-6 16,21-22,26 1 13,14-16,17-20,21-23,24-27,28 25-27,28 8.9.10- 12 20,21-23,24-27,28 14-16 Company Sanitized. Does no! containTSCACB1 -84- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 Sex Group Animal MV 665757 MV 665758 MV 665759 MV 665760 MV 665761 Individual Clinical observations Observation General observation. No Abnormality Detected Discharge, Bye bilateral, Red Discharge, Eye right, Red Swollen Observations, Face General observation, No Abnormality Detected Discharge, Eye bilateral, Red Discharge, Eye right, Red General observation, No Abnormality Detected Discharge', Eye bilateral, Red Discharge, Nose, Red General observation. No Abnormality Detected Discharge, Eye bilateral, Red General observation, No Abnormality Detected Discharge, Eye bilateral, Red Post-Dosing Days 1-2,3,7-8,10,13,14,20,23,24-26,28 0,5-6,11-12,15-16,17,19,21-22,27 9,18 4 2,8,11-12,14-16,17,19-20,22-23,27,28 3-6,7,9,10,13,18,21,24-26 0-1 0-2,4-6,7-9,10-13,14-16,17-18,20,21,24-27,28 19,22-23 3 0-2,3-6,7-9,10-13,14-16,17-20,21,23,24-27,28 22 2,3-4,7-9,10-13,14-16,18-20,21-23,24-27,28 0-1,5-6,17 Sani}?7f>ri. Ras aawffraTSCACBT H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 Sex Group Animal Observation Individual Clinical Observations M VII 665762 General observation. No Abnormality Detected Discharge, Eye bilateral, Red Discharge, Eye right, Red Hair Loss, Forepaw, Bilateral Wound, Superficial, Forelimb, Right Wound, Superficial, Forepaw, Left M VII 665763 General observation, No Abnormality Detected Discharge, Eye bilateral, Red Discharge, Eye right. Red M VII 665764 General observation, No Abnormality Detected Discharge, Eye bilateral, Red Discharge, Eye left, Red Discharge, Eye right. Red M VII 665765 General observation, No Abnormality Detected Discharge, Eye bilateral, Red M VII 665766 General observation, No Abnormality Detected Discharge, Eye bilateral, Red Discharge( Nose, Red Discharge, Eye left, Red Discharge, Eye right, Red Hair Loss, Forepaw, Bilateral Post-Dosing Days 1-2,3-6 0,13,18,22 20 7-8,9,10-13,14-16,17-20,21-23,24-27,28 7-8,9,10 7-8,9,10 1,5-6,7-8,9,11,14-16,17-18,20,21-22,24-27,28 0,3-4,12-13,19 2,10,23 9,10,14-15,17-20,21,23,24,27,28 0-2,3-6,7-8,11-12,16,22,26 13 25 2,3-6,9,10-11,13,14,16,17-20,21-23,24-25,27,28 0-1,7-8,12,15,26 7,9,24 0-2,3-6,8,13,14,17-20,25-27,28 6 12 11 10-13,14-16,17-20,21-23 Company Sanitized. Does not contain TSCA CB1 H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 Sex Group Animal M VII 665767 M VII 665768 M VII 665769 M VII 665770 M VII 665771 Individual Clinical Observations Observation General observation, No Abnormality Detected Discharge, Eye bilateral, Red Discharge, Eye right, Red General observation. No Abnormality Detected Discharge, Eye bilateral, Red Discharge, Eye right, Red General observation. No Abnormality Detected Discharge, Eye bilateral, Red Discharge, Eye left, Red Discharge, Eye right, Red Wound, Superficial, Dorsal Body, outside the test area Wound, Superficial, Shoulder, Left Wound, Superficial, Neck Swollen Observations, Face General observation, No Abnormality Detected Discharge, Eye bilateral, Red Discharge, Eye left. Red Discharge, Eye right, Red Swollen Observations, Face General observation, No Abnormality Detected Discharge, Eye bilateral. Red Discharge, Eye left. Red Discharge, Eye right. Red Post-Dosing Days 7,10-13,14-15,17-20,21-22,24-26 0-2,3-6,8-9,16,23,27 28 0- 2,3-5,7,10,14-15,17-18,20,21,23 6,8-9,11-13,19,22,26-27,28 16,24-25 3-4,7-8,11 0,5-6,9,12 1 10,13,14 14-16,17-20,21-23,24-27,28 19 1- 2 0-1 13,14-15,17,20,21-23,24,26-27,28 0-2,5-6,7,9,11-12,18-19 25 3-4,8,10,16 0-1 0,3,8-9,12,14,16,17-20,21-23,24,26-27,28 1-2,5-6,10-11,13,15,25 4 7 Company S anitized. D oes n o t co n ta in TSCA CBI ^!**"*\ H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 APPENDIX F Individual Edema and Erythema Scores t Comoany Sanitized. Does not contain TSCACBI -88- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11574 INDIVIDUAL EDEMA AND ERYTHEMA SCORES EXPLANATORY NOTES DRAIZEa SCALE FOR SCORING SKIN IRRITATION Evaluation of Skin Reactions Score Erythema and eschar formation: No erythema....................................................................................................... 0 Very slight erythema (barely perceptible)............................................................... 1 (Slight) Well-defined erythema........................................................................................... 2 (Mild) Moderate to severe erythema.................................................................................. 3 (Moderate) Severe erythema (beet redness) to slight eschar formation (injuries in depth).......... 4 (Severe) Edema formation: No edema............... Very slight edema (barely perceptible).......... ..................................................... Slight edema (edges of area well defined by definite raising)............................... Moderate edema (raised approximately 1.0 mm)................................................. Severe edema (raised more than 1.0 mm extending beyond the area of exposure). 0 1 (Slight) 2 (Mild) 3 (Moderate) 4 (Severe) a Draize, J. H., "Dermal Toxicity." Appraisal of the Safety of Chemicals in Foods. Drugs and Cosmetics. The Editorial Committee o f the Association of Food and Drug Officials o f the United States, Austin, Texas, 1959, pp. 46-59. Company Sanitized. Does not contain TSCACB - 89- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 Edema Edema Day 0 Day 1 Male. I 0 mg/kg 665732 665733 665734 665735 665736 665737 665738 665739 665740 665741 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Male, III 10 rag/kg 665742 665743 665744 665745 665746 665747 665748 665749 665750 665751 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Male, V 100 mg/kg 665752 665753 665754 665755 665756 665757 665758 665759 665760 665761 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Edema Day 2 0 0 0 0 0 0 0 0 0 0 * 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Edema Day 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Individual Edema and Erythema Scores Edema Edema Edema Edema Day 4 Day 5 Day 6 Day 7 Edema Day 8 0 0 0 0 0 0 00 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 00 0 0 0 0 0 0 00 0 0 0000 0 0 00 0 0 00 00 0 0 0 0 0 0 0 0 0 00 0 0 0 00 0 0 00 00 0 0 0 00 00 0 0 0 0 0 0 0 0 00 0 0 0000 0 0 0 0 0 0 0 0 0 00 0 0 00 0 0 0 00 0 0 0 0 00 0 0 00 0 0 0 0 00 0 0 0 00 0 00 0 Edema Day 9 00 0 00 00 0 0 0 0 0 00 0 0 0 00 0 0 00 0 0 0 00 0 0 Edema Day 10 0 00 0 00 00 0 0 00 0 00 0 0 0 0 0 0 0 00 0 0 0 00 0 Edema Day 11 0 0 00 0 0 0 00 0 00 0 0 00 0 00 0 0 0 0 00 0 0 0 00 Company Sanitized. Does not contain TSCA CB! H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 Edema Edema Day 0 Day 1 Male, VII; 1000 mg/kg 665762 665763 665764 665765 665766 665767 665768 665769 665770 665771 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Edema Day 2 0 0 0 0 0 0 0 0 0 0 Edema Day 3 0 0 0 0 0 0 0 0 0 0 Individual Edema and Erythema Scores Edema Edema Edema Edema Day 4 Day 5 Day 6 Day 7 Edema Day 8 0 0 000 0 0 000 0 0 000 0 0 000 0 0 000 0 0 000 0 0 000 0 0 000 0 0 000 0 0 000 Edema Day 9 Edema Day 10 Edema Day 11 00 0 0 0 0 00 00 0 0 000 0 00 0 00 00 0 000 000 -91 - Company Sanitized. Does not oontainTSCAtM H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 ' Edema Day 12 Edema Day 13 Male, I 0 mg/kg 665732 665733 665734 665735 665736 665737 665738 665739 665740 665741 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Male, III 10 mg/kg 665742 665743 665744 665745 665746 665747 665748 665749 665750 665751 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Male, V 100 mg/kg 665752 665753 665754 665755 665756 665757 665758 665759 665760 665761 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Edema Day 14 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 *0 0 Edema Day 15 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Individual Edema and Erythema Scores Edema Edema Edema Edema Day 16 Day 17 Day 18 Day 19 Edema Day 20 Edema Day 21 Edema Day 22 Edema Day 23 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 00 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 000000 0 0 0 0 0 0 0 00 00 0 0 00 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 000000 0 0 000000 0 0 0 0 0 0 0 0 0 0 0 0 00 00 0 0 0 0 0 0 0 0 00 00 0 00 0 0 00 0 000 0 0 0 00 0 0 00 0 0 0 0 00 00 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 00 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 00 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 Company Sanitized. Does not containTSCACBI -92- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 Edema Edema Day 12 Day 13 Male, VII 1000 mg/kg 665762 665763 665764 665765 665766 665767 665768 665769 665770 665771 0 0 0 0 0 0 0 0 0 0 0 0 0 Q 0 0 0 0 0 0 Edema Day 14 0 0 0 0 0 0 0 0 0 0 Edema Day 15 0 0 0 0 0 0 0 0 0 0 Individual Edema and Erythema Scores Edema Edema Edema Edema Day 16 Day 17 Day 18 Day 19 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 Edema Day 20 0 0 0 0 0 0 0 0 0 0 Edema Day 21 0 0 0 0 0 0 0 0 0 0 Edema Day 22 0 0 0 0 0 0 0 0 0 0 Edema Day 23 0 0 0 0 0 0 0 0 0 0 Company Sanitized. Does no! contain TSCA CB1 H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Edema Edema Day 24 Day 25 Male, I 0 mg/kg 665732 665733 665734 665735 665736 665737 665738 665739 665740 665741 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Male, XII 10 mg/kg 665742 665743 665744 665745 665746 665747 665748 665749 665750 665751 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Male, V 100 mg/kg 665752 665753. 665754 665755 665756 665757 665758 665759 665760 665761 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Edema Day 26 0 0 0 0 0 0 0 0 0 ,0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Edema Day 27 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Individual Edema and Erythema Scores Edema Day 28 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 DuPont-11574 Company Sanitized. Does no! contain TSCA CB1 H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Edema Day 24 Edema Day 25 Edema Day 26 Edema Day 27 Individual Edema and Erythema Scores Edema Day 28 Male, VII 1000 mg/kg 665762 0 0 0 0 0 665763 0 0 0 0 0 665764 0 0 0 0 0 665765 0 0 0 0 0 665766 0 0 0 0 0 665767 0 0 0 0 0 665768 0 0 0 0 0 665769 0 0 0 0 0 665770 0 0 0 0 0 665771 0 0 0 0 0 * DuPont-11574 Company Sanitized. Does noi cohiainTSCADTSS I H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ____________________ __________________________________ DuPont-11574 Erythema Day 0 Male, I 0 mg/kg Erythema Day 1 Erythema Day 2 Erythema Day 3 Individual Edema and Erythema Scores Erythema Erythema Erythema Erythema Day 4 Day 5 Day 6 Day 7 Erythema Day 8 Erythema Day 9 Erythema Day 10 Erythema Day 11 665732 665733 665734 665735 665736 665737 665738 665739 665740 665741 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 o 0 0 Q o 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Male, III io mg/kg 665742 665743 665744 665745 665746 665747 665748 665749 665750 665751 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 o 0 0 o o 0 o 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Male, V 100 mg/kg 665752 665753 665754 665755 665756 665757 665758 665759 665760 665761 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 o 0 o o o o o 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Comoany Sanitized. Doesnot containTSCACBI -96- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 Individual Edema and Erythema Scores Erythema Erythema Erythema Erythema Erythema Erythema Erythema Erythema Erythema Erythema Erythema Erythema Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Day 11 Male, VII 1000 mg/kg 665762 0 0 0 0 0 0 0 0 0 0 0 0 665763 0 0 .0 0 0 0 0 0 0 0 0! 0 665764 0 0 0 0 0 0 0 0 0 0 0 0 665765 0 0 0 0 0 0 0 0 0 0 0 0 665766 0 0 0 0 0 0 0 0 0 0 0 0 665767 0 0 0 0 0 0 0 0 0 0 0 0 665768 0 0 0 0 0 0 0 0 0 0 0 0 665769 0 0 0 0 0 0 0 0 0 0 0 0 665770 0 0 0 0 0 0 0 0 0 0 0 0 665771 0 0 0 0 0 0 0 0 .0 0 0 0 Comoany Sanitized. Doe?not contain TSCACBI -97- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 Individual Edema and Erythema Scores Erythema Erythema Erythema Erythema Erythema Erythema Erythema Erythema Erythema Erythema Erythema Erythema Day 12 Male, I 0 mg/kg Day 13 14 Day 15 Day 16 Day 17 Day 18 Day 19 Day 20 Day 21 Day 22 Day 23 665732 0 0 0 0 0 000 665733 665734 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 665735 665736 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0665737 0 0 0 0 0 0665738 , 0 0 0 0 0 0665739 0 0 0 0 0 0665740 0 0 0 0 0 0665741 0 0 0 0 0 00 00 00 00 00 Male, III 10 mg/kg 0 0 00 0 0 0 0 00 00 00 00 00 00 665742 0 0 0 0 0 0 00 665743 665744 0 0 0 0 0 0 0 0 0 0 0 0 10 00 665745 0 0 0 0 0 00 0 665746 0 0 0 0 0 00 0 0665747 0 0 0 0 0 0 0665748 0 0 0 0 0 0 0 0 0665749 0 0 0 0 0 0 0 0665750 0 0 0 0 0 0 0665751 0 0 0 0 0 0 0 0 Male, V 100 mg/kg 00 00 0 0 00 00 00 00 00 00 00 665752 665753 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 665754 665755 665756 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 00 0 0 0 0 0 0 0 665757 0 0 0 0 0 0 0 0 665758 0 0 0 0 0 0 0 0 665759 0 0 0 0 0 0 0 0 0665760 0 0 0 0 0 00 665761 0 0 0 0 0 0 0 0 00 0 0 00 0 0 0 0 00 00 00 00 00 Company Sanitized. Doss not contain TSCA CBI H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 Individual Edema and Erythema Scores Erythema Erythema Erythema Erythema Erythema Erythema Erythema Erythema Erythema Erythema Erythema Erythema Day 12 Day 13 Day 14 Day 15 Day 16 Day 17 Day 18 Day 19 Day 20 Day 21 Day 22 Day 23 Male, VII 1000 mg/kg 665762' 0 0 0 0 0 0 0 0 0 0 0 0 665763 0 0 0 0 0 0 0 0 0 0 0 0 665764 0 0 0 0 0 0 0 0 0 0 0 0 665765 0 0 0 0 0 0 0 0 0 0 0 0 665766 0 0 0 0 0 0 0 0 0 0 0 0 665767 0 0 0 0 0 0 0 0 0 0 0 0 665768 0 0 0 0 0 0 0 0 0 0 0 0 665769 0 0 0 0 0 0 0 0 0 0 0 0 665770 0 0 0 0 0 0 0 0 0 0 0 0 665771 0 0 0 0 0 0 0 0 0 0 0 0 Cofttpany Sanitized. Does not contain TSCA CB1 1 H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Individual Edema and Erythema Scores Erythema Erythema Erythema Erythema Erythema Day 24 Day 25 Day 26 'Day 27 Day 28 Male, I 0 mg/kg 0665732 0 0 0 0 0665733 0 0 0 0 0665734 0 0 0 0 0665735 0 0 0 0 0665736 0 0 0 0 665737 0 0 0 0 0 665738 0 0 0 0 0 665739 0 0 0 0 0 665740 0 0 0 0 0 665741 0 0 0 0 0 Male, III 10 mg/kg 0665742 0 0 0 0 0665743 0 0 0 0 0665744 0 0 0 0 0665745 0 0 0 0 0665746 0 0 0 0 665747 0 0 0 0 0 665748 0 0 0 0 0 665749 0 0 0 0 0 665750 0 0 0 0 0 665751 0 0 0 0 0 Male, V 100 mg/kg 0665752 0 0 0 0 0665753 0 0 40 0 0665754 0 0 0 0 0665755 0 0 0 0 0665756 0 0 -0 0 0665757 0 0 0 0 0665758 0 0 0 0 0665759 0 0 0 0 0665760 0 0 0 0 0665761 0 0 0 0 DuPont-11574 - 100- Company SanMzed. Does not contain TSCACW H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Individual Edema and Erythema Scores Erythema Erythema Erythema Erythema Erythema Day 24 Day 25 Day 26 Day 27 Day 28 Male, VII 1000 mg/kg 665762 0 0 0 0 0 665763 0 0 0 0 0 665764 0 0 0 0 0 665765 0 0 0 0 0 665766 0 0 0 0 0 665767 0 0 0 1 0 665768' 0 0 0 0 0 665769 0 0 0 0 0 665770 0 0 0 0 0 665771 0 0 0 0 0 DuPont-11574 - 101- Company Sanitized. Does not contain TSCACB1 H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male R ats_____________ DuPont-11574 APPENDIX G Individual Blood Fluorine Levels / ''""'N - 102- C n m m m Sanitized. D oes^ n contain TSCA CB1 H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ BLOOD FLUORINE LEVELS TEST DAY 21 Animal Number Group Dosage (mg/ke/dav) 665732 665733 665734 665735 665736 I I I I I 0 0 0 0 0 665742 665743 665744 665745 665746 m in m m in 10 10 10 10 10 665752 665753 665754 665755 665756 V V V V V 100 100 100 100 100 665762 665763 665764 665765 665766 VII vn vn vn vn 1000 1000 1000 1000 1000 * a. <0.5 is below the limit o f quantification Fluorine (ppm) <0.5a <0.5 <0.5 <0.5 <0.5 5.96 <0.5 0.97 0.52 <0.5 0.78 0.57 0.54 0.66 0.6 1.24 <0.5 <0.5 1.22 1.38 DuPont-11574 Company Sanitized. Does not contain TSCA CBI - 103- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______ DuPont-11574 APPENDIX H Individual Animal Clinical Pathology Data Company Sanitized. Does not contain tsca obi - 104- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11574 INDIVIDUAL ANIMAL CLINICAL PATHOLOGY DATA EXPLANATORY NOTES ABBREVIATIONS : General: ADEQ NT OK QNS RNV < - adequate - not taken or not performed - sample condition OK for testing - quantity not sufficient for testing ~ result not valid - less than Individual Hematology Values : COND - sample condition RBC - red blood cell count HGB - hemoglobin HOT - hematocrit MCV - mean corpuscular volume MCH - mean corpuscular hemoglobin MCHC - mean corpuscular hemoglobin concentration RDW - red cell distribution width ARET - absolute reticulocyte count 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 Individual Red Blood Cell Morphology Values: NORM - Normal ANIS - anisocytosis MIC ~ microcytes MAC macrocytes POLY - polychromasia HYPO - hypochromasia ECHI - echinocytes ACAN - acanthocytes TARG - Target cells RX - rouleaux HJB - Howell-Jolly body - not observed or not examined; see whole blood sample condition Individual White Blood Cell / Platelet Morphology Values: NORM - Normal SM - Smudge white blood cells TOX - toxic neutrophils DB - Dohle bodies VC - vacuolated cytoplasm BC - basophilic cytoplasm PCE - platelet clumps / estimate GP - giant platelets BP - bizarre platelets - - not observed or not examined; see whole blood sample condition Company Sanitized. Does not contain TSCACBI -105 - H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_________ DuPont-11574 INDIVIDUAL ANIMAL CLINICAL PATHOLOGY DATA EXPLANATORY NOTES (Continued) ABBREVIATIONS : (Continued) Individual Clinical Chemistry Values: SHEM serum hemolysis SLIP - serum lipemia SICT - serum icterus 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 PHEM - plasma hemolysis from blood sample for fluoride determination PLIP - plasma lipemia from blood sample for fluoride determination PICT - plasma icterus from blood sample for fluoride determination PFLU - plasma fluoride Individual Urinalysis Values: QUAL - quality (modifies color) COL - color CLAR - clarity VOL UOSM - volume urine osmolality PH - the logarithm of the reciprocal of the hydrogen ion concentration UGLU KET UBIL - urine glucose - ketone - urine bilirubin BLD - blood URO - urobilinogen UFLU - urine fluoride UMTP - urine protein Individual Urine Microscopic Examination Values: EPIT - epithelial cells UWBC - urine white blood cells URBC - urine red blood cells NCRY normal crystals MICR " mi croorgani sms SPER - sperm Company Sanitized. Does noi contain TSCA CBS - 106- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11574 i. INDIVIDUAL ANIMAL CLINICAL PATHOLOGY DATA EXPLANATORY NOTES (Continued) NOTES: When individual animal data are not reported, it may be due to one of the following reasons or other reasons, all of which are explained in the study records: the sample was clotted (CLOT) there was insufficient sample for testing (QNS) a valid result could not be obtained (RNV) the sample was not suitable for testing the animal died prior to* sample collection no sample was available for testing (NSR) 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. Company Sanitized. Does not contain TSCACB1 - 107- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Animal Number COND RBC x IOVuL HGB g/dL Male, Group I - 0 mg/kg - Day 29 665732 665733 665734 665735 665736 665737 665738 665739 665740 665741 OK OK OK OK OK OK OK OK OK OK 8.15 7.86 8.00 7.92 8.38 8.88 8.34 8.63 8.35 8.69 16.2 16.1 15.4 15.7 17.0 16.8 15.7 17.2 16.1 16.8 Male, .Group III - 10 mg/kg - Day 29 665742 665743 665744 665745 665746 665747 665748 665749 665750 665751 OK OK OK OK OK OK OK OK OK OK 7.79 7.62 8.07 7.42 7.97 7.93 8.45 8.44 8.26 7.56 15.4 15.0 16.4 15.0 16.2 16.0 '16.3 16.0 16.5 15.8 HCT % 47.7 47.7 46.0 46.7 50.4 49.7 46.6 51.3 47.0 49.0 45.7 45.3 46.9 44.9 48.0 46.3 47.5 47.1 48.1 46.5 Individual Hematology Values MCV MCH MCHC RDW fL pg g/dL % ARET PLT WBC xloVpL XloVpL xl03/pXi 58.5 60.7 57.5 59.0 60.2 56.0 55.8 59.4 56.3 56.4 19.9 20.4 19.3 19.8 20.3 19.0 18.8 19.9 19.3 19.3 34.0 33.7 33.5 33.5 33.7 33.8 33.7 33.6 34.2 34.2 11.4 10.7 10.9 12.0 11.1 10.7 11.4 10.1 10.8 10.6 209.3 154.7 221.5 242.3 258.3 143.9 131.4 149.2 130.3 133.1 1222 1344 1292 RNV 1039 1264 1141 991 1212 1172 9.62 8.99 15.60 12.97 11.79 19.56 9.73 10.46 11.06 10.68 58.6 59.4 58.2 60.5 60.2 58.4 56.2 55.8 58.3 61.5 19.8 19.7 20.4 20.2 20.3 20.2 19.3 19.0 19.9 20.9 33.8 33.2 35.0 33.4 33.7 34.7 34.3 34.0 34.2 34.0 11.7 11.2 10.7 11.3 10.9 11.7 11.0 10.5 11.2 10.8 208.6 196.1 209.1 263.1 181.2 215.2 144.4 127.2 141.4 218.6 1104 1338 1183 1284 RNV RNV 1266 1445 1436 1162 15.71 10.20 10.55 10.11 8.37 14.84 7.96 15.66 14.76 13.55 DuPont-11574 Company Sanitized. Does not contain TSCA CBI H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Animal Number COND RBC xloVuL HGB g/dL Male, Group V - 100 mg/kg - Day 29 665752 665753 665754 665755 665756 665757 665758 665759 665760 665761 OK OK OK OK OK OK OK OK OK OK 8.19 7.79 7.66 7.95 7.42 7.84 7.57 8.28 8.49 8.35 16.0 14.9 15.1 16.4 15.1 15.3 15.2 *15.4 16.5 16.2 Male, Group VII - 1000 mg/kg - Day 29 665762 665763 665764 665765 665766 665767 665768 665769 665770 665771 OK OK OK OK OK OK OK OK OK OK 7.97 8.37 8.23 7.80 7.66 8.23 7.57 7.98 8.08 8.24 15.6 16.2 15.3 15.6 15.3 15.3 15.1 15.7 15.9 15.7 HOT % 48.2 45.2 43.5 47.8 44.2 45.6 43.7 46.1 48.2 47.2 46.5 47.2 44.7 46.2 45.8 45.4 44.0 46.1 45.9 45.7 Individual Hematology Values MCV MCH MCHC RDW fit pg g/dL % ARET PLT WBC xl03/pL xloVpL x I O V u L 58.8 58.1 56.8 60.1 59.6 58.2 57.8 55.7 56.8 56.5 19.6 19.1 19.7 20.6 20.3 19.5 20.0 18.7 19.4 19.5 33.3 32.9 34.6 34.3 34.1 33.6 34.7 33.5 34.2 34.4 11.2 11.5 11.0 11.1 11.0 10.6 11.0 10.3 10.7 10.9 183.5 199.4 253.9 190.6 240.4 152.8 145.5 79.4 175.8 105.0 1253 1369 1709 1306 1197 1181 1429 1191 1284 1342 14.64 11.19 15.06 15.60 11.86 12.56 8.94 14.99 11.49 12.19 58.3 56.5 54.3 59.2 59.8 55.2 58.2 57.7 56.8 55.4 19.6 19.3 18.6 20.0 19.9 18.6 19.9 19.7 19.7 19.0 33.7 34.2 34.3 33.7 33.3 33.7 34.2 34.1 34.7 34.4 10.7 10.5 11.7 11.6 11.2 11.8 10.8 10.5 11.0 11.3 191.0 189.4 169.5 262.3 215.1 180.0 161.9 165.6 128.1 188.1 942 1085 1355 1295 1426 1213 RNV 1436 RNV 1364 12.13 12.39 10.35 17.14 16.53 17.21 16.68 13.65 15.88 14.65 DuPont-11574 -109- Company Sanitized. Does not containTSCACBf H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Animal Number ANEU ALYM AMON xlCr/uL x I O V u L x I O V u L Male, Group - 0 mg/kg - Day 29 665732 665733 665734 665735 665736 665737 665738 665739 665740 665741 0.83 1.00 1.93 1.65 1.44 4.02 2.09 0.98 1.51 1.51 8.32 7.42 12.60 10.35 9.84 14.48 7.16 8.66 8.79 8.52 0.18 0.27 0.46 0.45 0.19 0.44 0.17 0.22 0.39 0.31 Male, Group III - 10 mg/kg - Day 29 665742 665743 665744 665745 665746 665747 665748 665749 665750 665751 1.57 1.82 2.59 0.88 1.38 2.19 0.74 1.26 1.95 1.55 13.24 7.61 7.35 8.59 6.59 11.76 6.59 13.43 12.06 11.24 0.37 0.30 0.33 0.21 0.17 0.21 0.24 0.28 0.27 0.29 AEOS xloVpL 0.15 0.13 0.22 0.19 0.14 0.19 0.12 0.34 0.15 0.08 0.23 0.25 0.10 0.27 0.12 0.43 0.16 0.19 0.22 0.17 Individual Hematology Values ABAS ALUC xloVpL XloVpL 0.06 0.06 0.17 0.16 0.10 0.18 0.09 0.09 0.12 0.15 0.08 0.11 0.23 0.17 0.07 0.24 0.11 0.17 0.10 0.10 0.15 0.07 0.11 0.08 0.05 0.12 0.09 0.14 0.12 0.12 0.16 0.13 0.07 0.09 0.06 0.14 0.13 0.34 0.14 0.18 DuPont-11574 Comoanv S a n e a d Or*rr>fe*fain TSCA CBf H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Animal Number ANEU ALYM xl03/|iL XioVpL AMON xioVuij Male, Group V - 100 mg/kg - Day 29 AEOS xl03/pL Individual Hematology Values ABAS ALUC xloVpL xloVpb 665752 665753 665754 665755 665756 665757 66575B 665759 665760 665761 1.24 1.44 1.36 1.21 1.89 1-39 1.46 1.21 1.13 1.38 12.54 8.93 12.93 13.47 9.27 10.51 6.92 12.79 9.63 10.17 0.33 0.37 0.39 0.27 0.29 0.27 0.30 0.43 0.24 0.24 0.18 0.25 0.16 0.17 0.22 0.16 0.09 0.27 0.28 0.15 0.12 0.05 0.07 0.15 0.08 0.09 0.03 0.13 0.09 0.09 0.23 0.14 0.15 0.32 0.11 0.12 0.14 0.15 0.13 0.16 Male, Group VII - 1000 mg/kg - Day 29 665762 665763 665764 665765 665766 665767 665768 665769 665770 665771 1.41 1.05 1.13 2.04 2.95 2.68 2.91 2.47 1.69 1.66 9.73 10.42 8.52 14.12 12.44 13.55 12.33 10.42 13.12 12.28 0.35 0.48 0.32 0.45 0.51 0.44 0.68 0.26 0.42 0.23 0.23 0.21 0.20 0.20 0.25 0.26 0.29 0.28 0.33 0.20 0.30 0.07 0.12 0.13 0.12 0.11 0.14 0.13 0.11 0.17 0.10 0.15 0.06 0.19 0.26 0.17 0.32 0.10 0.21 0.11 DuPont-11574 Company Sanitized. Doss not contain TSCA CBI H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Animal Number NORM ANIS MIC Male, Group I - 0 mg/kg - Day 29 665732 665733 665734 665735 665736 665737 665738 665739 665740 665741 NO NO NO NO NO NO NO NO NO NO t_ - - - - - Male, Group III - 10 mg/kg - Day 29 665742 665743 665744 665745 665746 665747 665748 665749 665750 665751 NO NO NO NO NO NO NO NO NO NO _ - - Individual Red Blood Cell Morphology Values MAC POLY HYPO ECHI ACAN TARG _ TRACE - TRACE - TRACE - TRACE - TRACE - TRACE - TRACE - TRACE _ TRACE - TRACE _ TRACE - TRACE - TRACE - TRACE - TRACE TRACE - TRACE - TRACE - TRACE - TRACE _ MODERATE FEW - MODERATE TRACE - TRACE - - MANY TRACE - _- - FEW - - - FEW --- - - TRACE - MANY TRACE - _ FEW - - FEW -- - - MODERATE TRACE _ TRACE TRACE --- - FEW - - FEW FEW - MODERATE FEW --- - - - - - - - - - ~ - - RX - - - - - - HJB ) DuPont-11574 - 112- Company Sanitized. Does not contain TSCACB1 H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Animal Number NORM ANIS MIC Male, Group V - 100 mg/kg - Day 29 665752 NO _ _ 665753 NO - - 665754 NO - - 665755 NO - - 665756 NO - - 665757 NO - - 665758 NO - - 665759 NO - - 665760 NO - - 665761 NO - - Male, Group VII - 1000 mg/kg - Day 29 665762 665763 665764 665765 665766 665767 665768 665769 665770 665771 NO NO NO NO NO NO NO NO NO NO -_ ---- *_ --- _ -- Individual Red Blood Cell Morphology Values MAC POLY HYPO ECHI ACAN TARG _ TRACE - TRACE - TRACE - TRACE - TRACE - TRACE - TRACE - TRACE - TRACE - TRACE -- - - FEW FEW - FEW TRACE - FEW - - FEW - - FEW FEW - MODERATE TRACE - TRACE - FEW TRACE --- - - - _ TRACE _ FEW TRACE - - TRACE - MODERATE FEW - - TRACE - MODERATE MODERATE - - TRACE - MODERATE TRACE - - TRACE - MODERATE FEW - - TRACE - MANY MODERATE - - TRACE - TRACE TRACE - - TRACE - - - - - TRACE - TRACE TRACE - _ TRACE - TRACE FEW - RX - - - - - - HJB - - - - - - - - DuPont-11574 Company Sanitized, Does not contain TSCA CB1 H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Animal Number NORM SM TOX Male, Group I - 0 mg/kg - Day 29 665732 665733 665734 665735 665736 665737 665738 665739 665740 665741 YES YES YES NO YES YES YES YES YES YES - - - - - - Male, Group III - 10 mg/kg - Day 29 665742 665743 665744 665745 665746 665747 665748 665749 665750 665751 YES YES YES YES NO NO YES YES YES YES _ - - - - - - _ - - Individual White Blood Cell / Platelet Morphology Values DB VC BC PCE GP BP -----_- -- ------- - - - YES/ADEQ - ------ _____- ---_ - ------ ------ - - -- -- ___ _ ------ - -- -__ ----__ -- - YES/ADEQ - - - - - YES/ADEQ - - - --- __ ---___ - -- _-_ -_--__ DuPont-11574 Company Sanitized. Does not contain TSCA CBI H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Animal Number NORM SM Individual White Blood Cell / Platelet Morphology Values TOX DB VC BC PCE GP BP Male, Group V - 100 mg/kg - Day 29 .665752 665753 665754 665755 665756 665757 665758 665759 665760 665761 YES YES YES YES YES YES YES YES YES YES Male, Group VII - 1000 mg/kg - Day 29 665762 665763 665764 665765 665766 665767 665768 665769 665770 665771 YES YES YES NO YES YES NO YES NO YES TRACE YES/ADEQ YES/ADEQ DuPont-11574 Company Sanitized. Does not contain TSCA CB! H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Animal Number SHEM SLIP SICT Male, Group I - 0 mg/kg - Day 29 665732 665733 665734 665735 665736 665737 665738 665739 665740 665741 TRACE TRACE TRACE NONE TRACE TRACE NONE TRACE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE Male, Group III - 10 mg/kg - Day 29 665742 665743 665744 665745 665746 665747 665748 665749 665750 665751 TRACE TRACE TRACE NONE NONE NONE NONE TRACE SMALL TRACE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE Individual Clinical Chemistry Values AST ALT SDH ALKP BILI BUN CREA CHOL U/L U/L U/L U/L mg/dL mg/dL mg/dL mg/dL 113 42 15.5 126 <0.10 16 0.34 39 106 49 14.0 187 0.12 14 0.40 36 117 52 11.8 197 <0.10 14 0.35 39 112 59 12.2 176 0.10 13 0.39 49 130 63 14.2 232 0.11 16 0.46 51 95 55 7.2 213 0.10 13 0.35 42 107 50 11.6 190 0.12 16 0.42 49 126 49 11.6 245 0.11 19 0.38 33 89 35 11.7 197 <0.10 13 0.30 49 94 50 18.0 251 0.11 17 0.38 43 117 73 12.8 176 0.11 12 0.40 53 118 65 H O 205 0.10 14 0.37 58 110 50 15.4 187 0.16 19 0.39 47 99 45 14.7 210 0.11 16 0.43 55 119 57 16.8 237 0.12 18 0.40 45 115 57 10.1 184 0.10 15 0.37 46 99 42 13.6 171 0.12 17 0.44 50 124 91 12.5 234 0.11 14 0.39 58 108 51 5.6 288 0.12 13 0.33 53 109 65 19.8 244 0.12 13 0.37 48 DuPont-11574 Company Sanitized. Does not contain TSCA CB! H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Animal Number SHEM SLIP SICT Male, Group V - 100 mg/kg - Day 29 665752 665753 665754 665755 665756 665757 665758 665759 665760 665761 TRACE TRACE TRACE TRACE TRACE TRACE NONE TRACE TRACE TRACE NONE NONE NONE NONE NONE NONE NONE NONE NONE TRACE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE Male, Group VII - 1000 mg/kg - Day 2 665762 665763 665764 665765 665766 665767 665768 665769 665770 665771 SMALL TRACE TRACE TRACE TRACE TRACE TRACE SMALL NONE TRACE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE Individual Clinical Chemistry Values AST ALT SDH ALKP BILI BUN CREA CHOL U/L U/L U/L U/L mg/dL mg/dL mg/dL mg/dL 234 165 39.8 313 0.14 16 0.49 51 108 75 15.0 252 0.10 16 0.40 47 119 70 12.8 225 0.11 14 0.49 52 120 63 11.6 195 0.12 14 0.42 41 130 66 14.8 168 0.11 13 0.42 61 134 96 22.3 263 0.12 15 0.40 53 155 132 38.1 198 0.12 17 0.36 51 144 103 15.5 164 0.13 15 0.35 40 198 147 24.1 227 0.14 12 0.45 56 111 78 11.9 245 0.12 13 0.39 58 185 90 7.2 257 0.14 14 0.36 53 123 82 10.3 248 0.12 14 0.43 57 107 80 12.2 244 <0.10 15 0.42 66 135 98 15.6 338 0.15 16 0.44 55 150 112 19.2 338 0.15 13 0.38 67 123 88 16.5 206 <0.10 16 0.39 56 121 80 7.7 248 0.15 12 0.40 54 372 297 20.4 258 0.16 18 0.50 52 139 99 19.2 363 0.14 17 0.40 46 111 87 10.2 244 0.10 13 0.36 60 DuPont-11574 Company Sanitized. Does no"contain TSCA CBI H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Animal Number TRIG mg/dL GLUC mg/dL TP g/dL Male, Group I - 0 mg/kg - Day 29 665732 665733 665734 665735 66573.6 665737 665738 665739 665740 665741 23 27 25 23 52 25 20 26 36 39 85 6.6 94 6.6 85 6.7 83 6.8 96 6.9 106 6.7 91 6.2 81 6.6 98 6.6 95 7.1 Male, Group III - 10 mg/kg - Day 29 665742 665743 665744 665745 665746 665747 665748 665749 665750 665751 54 41 50 25 44 66 28 28 33 66 100 6.6 91 6.2 111 6.7 93 6.6 86 *6.4 80 6.5 89 6.8 101 7.1 97 7.0 125 6.8 ALB g/dL Individual Clinical Chemistry Values GLOB g/dL CALC mg/dL IPHS mg/dL NA mmol/L K mmol/L CL mmol/L 4.3 2.3 10.8 8.2 148.3 6.29 103.2 4.5 2.1 10.9 8.8 149.8 6.47 102.4 4.1 2.6 10.9 8.5 150.4 6.08 103.0 4.3 2.5 11.1 7.8 151.3 6.14 103.3 4.6 2.3 11.3 8.5 151.8 6.13 102.8 4.2 2.5 10.6 8.2 147.1 6.37 98.1 4.0 2.2 9.9 7.4 148.4 5.84 101.9 4.2 2.4 10.8 7.9 150.3 6.27 103.5 4.1 2.5 10.9 8.1 150.9 5.86 101.9 4.5 2.6 11.0 7.3 151.3 6.42 103.7 4.1 2.5 10.5 7.5 149.4 5.91 102.1 4.0 2.2 10.6 7.7 150.5 6.05 104.0 4.2 2.5 10.8 7.4 148.7 5.31 99.4 o CO 4.2 2.4 10.8 151.8 5.96 105.0 4.3 2.1 11.3 8.4 152.9 6.06 105.4 4.1 2.4 10.1 7.8 147.7 5.74 100.8 4.5 2.3 10.7 7.4 149.4 5.93 101.8 4.2 2.9 10.7 8.1 148.3 6.37 102.5 4.2 2.8 11.3 8.0 149.4 6.80 101.6 4.1 2.7 11.4 9.2 149.7 6.35 101.9 DuPont-11574 Company Sanitized. Does not contain TSCA CB1 H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Animal Number TRIG mg/dL GLUC mg/dL TP g/dL Male, Group V - 100 mg/kg - Day 29 665752 665753 665754 665755 665756 665757 665758 665759 665760 665761 74 42 26 38 46 65 42 38 49 32 96 7.1 88 6.4 91 6.4 98 6.5 86 6.5 114 *6.6 88 6.4 101 6.2 109 6.6 103 6.4 Male, Group VII - 1000 mg/kg - Day 29 665762 40 85 6.7 665763 72 100 6.5 665764 46 106 6.4 665765 50 88 6.5 665766 103 105 6.8 665767 50 101 6.6 665768 44 100 6.8 665769 53 117 6.7 665770 54 95 6.9 665771 43 111 6.6 ALB g/dL 4.5 4.0 3.8 4.3 4.0 4.1 4.0 4.0 4.2 4.0 4.2 4.1 3.9 4.1 4.1 4.0 4.0 4.2 4.3 4.2 Individual Clinical Chemistry Values GLOB g/dL CALC mg/dL IPHS mg/dL NA mmol/L K mmol/L CL mmol/L 2.6 10.9 8.8 150.7 6.55 102.7 2.4 10.7 7.9 150.1 6.23 104.6 2.6 10.6 8.5 147.7 6.31 104.2 2.2 10.9 7.8 149.3 6.64 105.4 2.5 10.2 7.4 151.3 5.71 104.9 2.5 10.1 7.7 147.5 5.82 100.4 2.4 10.4 7.8 14 9.5 5.65 102.5 2.2 10.4 7.2 150.0 6.11 104.6 2.4 10.7 7.8 150.7 6.44 104.6 2.4 10.2 7.8 150.1 6.75 104.6 2.5 10.0 8.1 149.2 6.66 102.4 2.4 10.7 8.2 147.1 5.96 101.2 2.5 10.6 8.0 147.8 5.75 101.8 2.4 10.6 8.1 150.9 6.05 104.9 2.7 10.6 8.6 150.8 5.84 103.3 2.6 10.4 8.1 148.0 6.12 101.1 2.8 10.6 7.8 148.7 5.41 101.9 2.5 10.4 7.6 147.4 6.21 101.0 2.6 10.9 8.3 149.7 5.92 102.8 2.4 10.6 7.1 150.2 5.93 104.6 DuPont-11574 Company Sanitized. Does no! contain TSCA CBI H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Animal Number PHEM PLXP PICT Male, Group I - 0 mg/kg - Day 29 .665732 665733 665734 665735 665736 665737 665738 665739 665740 665741 NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE Male, Group III - 10 mg/kg - Day 29 665742 665743 665744 665745 665746 665747 665748 665749 665750 665751 NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE .NONE PFLU Vig/mL Individual Clinical Chemistry Values 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 DuPont-11574 -120- Company Sanitized. Does not contain TSCACBI H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Animal Number PHEM PLIP PICT Male, Group V - 100 mg/kg - Day 29 ,665752 665753 665754 665755 665756 665757 665758 665759 665760 665761 NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE Male, Group VII - 1000 mg/kg - Day 29 665762 665763 665764 665765 665766 665767 665768 665769 665770 665771 NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE ,NONE NONE NONE NONE NONE NONE NONE PFLU pg/mL 0.1 0.1 0.1 0.1 0.1 0.0 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Individual Clinical Chemistry Values DuPont-11574 Company Sanitized, Does not contain TSCA CB1 H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Animal QUAL COL CLR Number Male, Group X - 0 mg/kg - Day 29 665732 665733 665734 665735 665736 665737 665738 665739 665740 665741 MEDIUM MEDIUM LIGHT LIGHT LIGHT LIGHT MEDIUM LIGHT LIGHT LIGHT YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW CLEAR CLEAR CLEAR CLEAR .HAZY HAZY CLEAR HAZY HAZY CLEAR Male, Group III - 10 mg/kg - Day 29 665742 665743 665744 665745 665746 665747 665748 665749 665750 665751 MEDIUM LIGHT LIGHT LIGHT LIGHT LIGHT LIGHT LIGHT LIGHT LIGHT YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW HAZY CLEAR HAZY HAZY HAZY CLEAR HAZY HAZY CLEAR HAZY Individual VOL UOSM mL mOsm/kg PH 3.8 5.0 7.0 10.4 5.4 13.6 2.2 28.0 6.4 3.8 2055 1784 1189 937 1590 828 3706 412 1347 1663 6.0 7.0 7.0 6.5 6.5 7.0 7.0 7.0 7.0 7.0 5.4 10.4 5.2 10.8 6.0 27.0 8.0 10.4 10.6 8.0 1653 761 1949 861 1364 443 991 1112 1218 1999 6.5 6.5 6.5 7.0 7.0 6.5 7.0 7.0 6.5 8.5 ) Urinalysis Values UGLU mg/dL KET mg/dL UBIL BLD URO EU/dL NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE 5 5 5 NEGATIVE 5 NEGATIVE 5 NEGATIVE 15 5 NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE SMALL NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE TRACE NEGATIVE NEGATIVE TRACE NEGATIVE NEGATIVE 0.2 0.2 0.2 0.2 0.2 0.2 1.0 0.2 0.2 0.2 NEGATIVE 15 NEGATIVE TRACE 0.2 NEGATIVE 5 NEGATIVE NEGATIVE 0.2 NEGATIVE 15 NEGATIVE TRACE 0.2 NEGATIVE 15 NEGATIVE SMALL 0.2 NEGATIVE 5 NEGATIVE NEGATIVE 0.2 NEGATIVE 5 NEGATIVE NEGATIVE 0.2 NEGATIVE 5 NEGATIVE NEGATIVE 0.2 NEGATIVE 5 NEGATIVE NEGATIVE 0.2 NEGATIVE 5 NEGATIVE NEGATIVE NEGATIVE 15 NEGATIVE NEGATIVE 0.2 o to DuPont-11574 -122- Company Sanitized, Does not contain TSCACBl H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Animal QUAL COL CLAR Number Male, Group V - 100 mg/kg - ]Day 29 665752 665753 665754 665755 665756 665757 665758 665759 665760 665761 LIGHT LIGHT LIGHT LIGHT LIGHT MEDIUM MEDIUM LIGHT LIGHT LIGHT YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW CLEAR CLOUDY CLEAR HAZY CLEAR CLEAR CLEAR HAZY HAZY HAZY Male, Group VII - 1000 mg/kg - Day 29 665762 665763 665764 665765 665766 665767 665768 665769 665770 665771 LIGHT LIGHT LIGHT LIGHT LIGHT LIGHT LIGHT LIGHT LIGHT LIGHT YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW CLEAR CLEAR CLEAR HAZY CLEAR CLEAR CLEAR HAZY CLEAR `HAZY VOL mL 12.0 4.6 5.8 6.8 6.8 5.8 3.0 7.0 16.4 9.0 12.8 11.0 8.8 11.4 16.4 6.6 15.8 8.0 9.2 8.2 individual Urinalysis Values UOSM mOsm/kg pH UGLU mg/dL KET mg/dL UBIL BLD URO EU/dL 758 1509 1550 1589 1176 1307 1802 1101 912 1123 7.0 NEGATIVE 5 NEGATIVE NEGATIVE 0.2 7.0 NEGATIVE 5 NEGATIVE SMALL 0.2 7.0 NEGATIVE 15 NEGATIVE NEGATIVE 0.2 7.0 NEGATIVE 5 NEGATIVE NEGATIVE 0.2 6.5 NEGATIVE 5 NEGATIVE NEGATIVE 0.2 6.5 NEGATIVE 5 NEGATIVE NEGATIVE 0.2 7.0 NEGATIVE 15 NEGATIVE NEGATIVE 0.2 NT NT NT NT NT NT 8.0 NEGATIVE NEGATIVE NEGATIVE NEGATIVE 0.2 8.5 NEGATIVE 5 NEGATIVE NEGATIVE 0.2 779 1107 888 739 722 1080 743 1640 821 1096 6.5 NEGATIVE 6.5 NEGATIVE 6.5 NEGATIVE 6.0 NEGATIVE 6.5 NEGATIVE 6.5 NEGATIVE 7.0 NEGATIVE 7.5 NEGATIVE 7.0 NEGATIVE 7.5 NEGATIVE 5 NEGATIVE NEGATIVE 0.2 5 NEGATIVE NEGATIVE 0.2 5 NEGATIVE TRACE 0.2 5 NEGATIVE NEGATIVE 0.2 5 NEGATIVE NEGATIVE 0.2 5 NEGATIVE MODERATE 0.2 5 NEGATIVE NEGATIVE 0.2 5 NEGATIVE NEGATIVE 0.2 5 NEGATIVE NEGATIVE 0.2 5 NEGATIVE NEGATIVE 0.2 DuPont-11574 -123- Company Sanitized. Does not contain TSCACBI H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Animal Number UFLTJ ug UMTP mg/dL Male, Group I - 0 mg/kg - Day 665732 665733 665734 665735 665736 665737 665738 665739 665740 665741 11.4 15.3 12.3 15.2 13.3 20.7 QNS 21.7 13.5 10.2 40 159 13 69 165 190 192 84 51 151 Male, Group III - 10 mg/kg - ] 665742 665743 665744 665745 665746 665747 665748 665749 665750 665751 15.7 18.2 14.7 14.4 13.5 23.2 12.6 15.5 20.5 25.4 12 48 49 60 86 95 40 81 34 94 Individual Urinalysis Values DuPont-11574 finmpanv Sanitized. Does not contain TSC CBI -124 H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Animal Number UFLU pg UMTP mg/dL Male, Group V - 100 mg/kg - Day, 29 665752 665753 665754 665755 665756 665757 665758 665759 665760 665761 19.1 16.2 23.5 21.7 21.0 15.0 11.0 15.1 29.7 19.7 110 132 29 24 29 28 84 70 64 40 Male, Group VII 1000 mg/kg - Day 29 665762 665763 665764 665765 665766 665767 665768 665769 665770 665771 35.8 32.8 27.5 31.4 44.9 26.9 61.8 17.3 27.6 32.8 52 28 34 31 47 39 32 37 20 16 Individual Urinalysis Values DuPont-11574 Company Sanitized. Does no! contain TSCA CBf H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Animal Number SPIT UWBC URBC Male, Group I - 0 mg/kg - Day 29 665732 665733 665734 665735 665736 665737 665738 665739 665740 665741 FEW NONE NONE FEW NONE NONE QNS NONE NONE NONE NONE NONE NONE NONE NONE NONE NT NONE NONE NONE NONE NONE NONE NONE FEW NONE NT NONE NONE NONE Male, Group III - 10 rag/kg - Day 29 665742 665743 665744 665745 665746 665747 665748 665749 665750 665751 FEW NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE tNONE `n o n e NONE NONE NONE NONE NONE NONE NCRY Individual Urine Microscopic Values MICR SPER FEW FEW FEW FEW FEW MODERATE FEW FEW FEW FEW FEW MANY FEW FEW FEW FEW FEW MANY NT NT NT FEW FEW FEW MODERATE FEW MANY FEW FEW FEW FEW FEW FEW FEW FEW FEW FEW FEW FEW MODERATE FEW FEW FEW MODERATE FEW FEW FEW FEW FEW FEW FEW MODERATE FEW FEW MODERATE FEW FEW MODERATE MODERATE MANY DuPont-11574 -126- CompanySanitized. Does net contain TSCACB1 H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Animal Number EPIT UWBC URBC NCRY Individual Urine Microscopic Values M1CR SPER Male, Group V - 100 mg/kg - Day 29 665752 665753 665754 665755 665756 665757 665758 665759 665760 665761 NONE NONE NONE NONE NONE NONE QNS NONE NONE NONE NONE NONE NONE NONE NONE NONE NT NONE NONE NONE NONE NONE NONE NONE 'NONE NONE NT NONE NONE NONE FEW FEW FEW FEW FEW FEW NT MODERATE FEW FEW FEW FEW FEW FEW FEW FEW NT FEW MODERATE MANY FEW FEW FEW MODERATE MODERATE FEW NT MODERATE MANY MANY Male, Group VII - 1000 mg/kg - Day 29 665762 665763 665764 665765 665766 665767 665768 665769 665770 665771 NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE FEW FEW MANY FEW FEW FEW FEW FEW MANY FEW FEW MODERATE FEW FEW FEW FEW FEW FEW FEW MODERATE MODERATE FEW FEW MANY FEW FEW MODERATE FEW FEW MANY DuPont-11574 Company Sanitized. Does not contain TSCA CB| H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11574 APPENDIX I Individual Animal Final Body and Organ Weights Company Sanitized. Doss not contain TSCACB1 -128- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Group : I 0 mg/kg Sex :MALES J ANIMAL FBW KIDNEYS (Gms) (Gms) %FBW 665732 665733 665734 665735 665736 665737 665738 665739 665740 665741 367.10 374.40 344.90 325.60 349.80 NW 308.50 369.40 366.90 322.00 3.603 0.9815 3.391 0.9057 3.056 0.8861 2.757 0.8467 2.764 0.7902 2.972 2.499 0.8100 3.079 0.8335 3.577 0.9749 2.443 0.7587 Mean S.D. 347.62 24.048 3.014 0.8633 0.413 0.0783 INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS LIVER (Gms) %FBW 13.370 3.6421 11.858 3.1672 11.177 3.2406 9.469 2.9082 10.941 3.1278 11.468 9.907 3.2113 10.394 2.8138 10.330 2.8155 9.029 2.8040 10.794 3.0812 1.266 0.2774 THYROID GLAND (Gms) %FBW 0.022 0.0060 0.014 0.0037 0.017 0.0049 0.015 0.0046 0.018 0.0051 0.014 0.021 0.0068 0.013 0.0035 0.019 0.0052 NW 0.017 0.0050 0.003 0.0011 I 1 NW = Not weighed due to technician error FBW - Final Body Weight DuPont-11574 Company Sanitized. Does not contain TSCA CB1 H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Group : III 10 mg/kg Sex :MALES 1 ANIMAL FBW KIDNEYS (Gms) (Gms) %FBW 665742 665743 665744 665745 665746 665747 665748 665749 665750 665751 357.60 323.20 358.50 379.60 365.60 379.80 321.70 357.50 400.10 434.10 3.220 0.9004 2.747 0.8499 3.332 0.9294 3.207 0.8448 3.055 0.8356 3.138 0.8262 2.769 0.8607 2.811 0.7863 3.238 0.8093 3.857 0.8885 Mean S.D. 367.77 33.563 3.137 0.8531 0.330 0.0433 INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS LIVER (Gras) %FBW 11.866 3.3182 9.521 2.9459 10.955 3.0558 10.301 2.7136 10.983 3.0041 10.959 2.8855 9.960 3.0961 9.900 2.7692 12.686 3.1707 13.914 3.2053 11.105 3.0164 1.372 0.1925 THYROID GLAND (Gms) %FBW 0.012 0.0034 0.022 0.0068 0.014 0.0039 0.024 0.0063 0.021 0.0057 0.026 0.0068 0.019 0.0059 0.020 0.0056 0.017 0.0042 0.021 0.0048 0.020 0.0054 0.004 0.0012 1 1 FBW - Final Body Weight DuPont-11574 Company Sanitized. Doss not contain TSC CB1 H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Group : V 100 mg/kg Sex -.MALES ! ANIMAL 1 665752 665753 665754 665755 665756 665757 665758 665759 665760 665761 FBW (Gras) 349.00 333.10 386.20 352.10 336.40 331.00 347.10 330.00 348.30 307.10 KIDNEYS (Gras) %FBW 3.050 0.8739 2.641 0.7929 3.271 0.8470 2.845 0.8080 2.565 0.7625 2.764 0.8350 3.260 0.9392 2.966 0.8988 3.298 0.9469 2.487 0.8098 Mean S.D. 342.03 20.450 2.915 0.8514 0.302 0.0622 INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS LIVER (Gms) %FBW 10.923 3.1298 10.373 3.1141 11.874 3.0746 10.946 3.1088 9.508 2.8264 9.854 2.9770 10.333 2.9770 10.224 3.0982 10.415 2.9902 8.072 2.6285 10.252 2.9925 1.004 0.1583 THYROID GLAND (Gms) %FBW 0.020 0.0057 0.015 0.0045 0.016 0.0041 0.017 0.0048 0.015 0.0045 0.017 0.0051 0.019 0.0055 0.016 0.0048 0.017 0.0049 0.018 0.0059 0.017 0.0050 0.002 0.0006 i 1 FBW - Final Body Weight DuPont-11574 tympany Sanitized. Does not contain TSCA CB1 H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Group : VII 1000 mg/kg Sex :MALES J MIHAL FBW KIDNEYS (Gms) (Gras) %FBW 665762 665763 665764 665765 665766 665767 665768 665769 665770 665771 321.80 377.80 355.20 362.00 388.90 324.90 385.40 357.70 373.70 331.40 3.036 0.9434 2.988 0.7909 2.878 0.8102 2.911 0.8041 3.516 0.9041 2.918 0.8981 3.143 0.8155 2.831 0.7914 3.813 1.0203 3.018 0.9107 Mean S .D . 357.88 24.679 3.105 0.8689 0.316 0.0781 INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS LIVER (Gms) %FBW 10.006 3.1094 11.661 3.0866 11.442 3.2213 10.613 2.9318 14.101 3.6259 10.549 3.2468 11.865 3.0786 10.642 2.9751 12.746 3.4108 12.111 3.6545 11.574 3.2341 1.223 0.2542 THYROID GLAND (Gms) %FBW 0.020 0.0062 0.019 0.0050 0.016 0.0045 0.015 0.0041 0.022 0.0057 0.014 0.0043 0.017 0.0044 0.018 0.0050 0.019 0.0051 0.017 0.0051 0.018 0.0050 0.002 0.0006 I I FBW - Final Body Weight DuPont-11574 - ^npanySanitized. Does no! contain TSCACBI H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11574 APPENDIX J Individual Animal Pathology Data - 133 - Company Sanitized. Does not contain TSCA CBI /"n H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____ DuPont-11574 INDIVIDUAL ANIMAL PATHOLOGY DATA KEY TO APPENDIX LESION GRADING: Histopathology changes are described according to their morphologic character, distribution and severity. The distribution {extent of tissue involvement) is indicated, where appropriate, by modifiers such as focal, multifocal, diffuse, unilateral, bilateral, etc. A severity score, if appropriate, is also assigned as follows: MINIMAL: MILD: MODERATE : SEVERE : The amount of change present barely exceeds that which is considered to be within normal limits. In general, the lesion is easily identified but of limited severity. The lesion probably does not produce any functional impairment. The lesion is prominent but there is significant potential for increased severity. Limited tissue or organ dysfunction is possible. The degree of change is either as complete as considered possible or great enough in intensity or extent to expect significant tissue or organ dysfunction. COMMENT : Grades minimal through severe represent progressive involvement/severity along a continuum with minimal lesions being the least severe and severe lesions being the most severe. While the grades refer to the morphologic characteristics of lesions, they also indicate their relative biologic significance. Gross observations listing multiple masses for a tissue are distinguished with letters (i.e., A, b, c, d, et c .) . Company Sanitised. Does net contain TSCA CB? -134- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ Individual Animal Pathology Data Dose Group : I 0 mg/kg Sex: Males .Animal Ref Microscopic & Macroscopic Findings 665732 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH Histopathology : LIVER : HEMATOPOIESIS, EXTRAMEDULLARY, minimal. No Microscopic Abnormality Observed : KIDNEYS, THYROID GLAND, SKIN, TEETH 665733 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH Histopathology : LIVER : HEMATOPOIESIS, EXTRAMEDULLARY, minimal. KIDNEYS : NEPHROPATHY, CHRONIC PROGRESSIVE, minimal. 665733 Continued on the next page .... D u P o n t-11574 Company Sanitised. Does not contain TSCA CB1 - 135- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ Individual Animal Pathology Data Dose Group : I 0 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 665733 Continued from previous page Histopathology No Microscopic Abnormality Observed : THYROID GLAND, SKIN, TEETH 665734 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH Histopathology : LIVER : INFLAMMATION, SUBACOTE/CHRONIC, FOCAL, minimal. HEMATOPOIESIS, EXTRAMEDULLARY, minimal. KIDNEYS : NEPHROPATHY, CHRONIC PROGRESSIVE, minimal. No Microscopic Abnormality Observed : THYROID GLAND, SKIN, TEETH 665735 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH 665735 Continued on the next page .... DuPont-11574 Company Sanitized. Does not contain TSCA CBI H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats____________ Individual Animal Pathology Data Dose Group : I 0 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 665735 Continued from previous page Histopathology : LIVER : HEMATOPOIESIS, EXTRAMEDULLARY, minimal. INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. No Microscopic Abnormality Observed : KIDNEYS, THYROID GLAND, SKIN, TEETH 665736 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH Histopathology : LIVER : HEMATOPOIESIS, EXTRAMEDULLARY, minimal. KIDNEYS : NEPHROPATHY, CHRONIC PROGRESSIVE, minimal. No Microscopic Abnormality Observed : THYROID GLAND, SKIN, TEETH DuPont-11574 Comoanv Sanfffyed. floes not c o n fn T$CA CBI -137- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Individual Animal Pathology Data Dose Group : I 0 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 665737 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH Histopathology : LIVER : HEMATOPOIESIS, EXTRAMEDULLARY, minimal. No Microscopic Abnormality Observed : KIDNEYS, THYROID GLAND, SKIN, TEETH 665738 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH Histopathology : LIVER : HEMATOPOIESIS, EXTRAMEDULLARY, minimal. INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. 665738 Continued on the next page .... DuPont-11574 Company Sanitized. Doss not contain TSCA CBI - 138- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ Individual Animal Pathology Data Dose Group : I 0 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 665738 Continued from previous page Histopathology : No Microscopic Abnormality Observed : KIDNEYS, THYROID GLAND, SKIN, TEETH 665739 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH Histopathology : LIVER : MACROPHAGES, PIGMENTED, FOCAL, minimal. HEMATOPOIESIS, EXTRAMEDULLARY, minimal. INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. KIDNEYS : NEPHROPATHY, CHRONIC PROGRESSIVE, minimal. No Microscopic Abnormality Observed : THYROID GLAND, SKIN, TEETH 665740 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH 665740 Continued on the next page .... DuPont-11574 Company Sanitized. Does not contain TSCACBI - 139- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________________________________________________________ DuPont-11574 Individual Animal Pathology Data Dose Group : I 0 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 665740 Continued from previous page Hi stopathology LIVER : HEMATOPOIESIS, EXTRAMEDULLARY, minimal. KIDNEYS : NEPHROPATHY, CHRONIC PROGRESSIVE, minimal. No Microscopic Abnormality Observed : THYROID GLAND, SKIN, TEETH 665741 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH Histopathology : LIVER : HEMATOPOIESIS, EXTRAMEDULLARY, minimal. INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. No Microscopic Abnormality Observed : KIDNEYS, THYROID GLAND, SKIN, TEETH Company Sanitized. Does not contain TSCACBI -140- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ Individual Animal Pathology Data Dose Group : III 10 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 665742 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH 665743 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH 665744 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH 665745 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH DuPont-11574 Company Sanitized. Does no? contain TSCA CB1 -141 - H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_________ _ Individual Animal Pathology Data Dose Group : III 10 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 665746 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH 665747 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH 665748 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH 665749 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH DuPont-11574 Company Sanitized. Does nof contain TSCA CBI H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ Individual Animal Pathology Data Dose Group : III 10 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 665750 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology- No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH 665751 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH DuPont-11574 Company Sanitized. Does not contain TSCA CB1 - 143- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ Individual Animal Pathology Data Dose Group : V 100 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 665752 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH 665753 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH 665754 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology : TESTES : LARGE, BILATERAL, mild. No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH 665754 Continued on the next page .... DuPont-11574 Company Sanitized. Doss not contain TSCA CB1 - 144- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats__________ ; Individual Animal Pathology Data Dose Group : V 100 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 665754 Continued from previous page Histopathology TESTES : NO MICROSCOPIC EVIDENCE OF MACROSCOPIC FINDING. No Microscopic Abnormality Observed : TESTES 665755 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH 665756 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH 665757 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH DuPont-11574 Company Sanitized Does not contain TSCA CB1 - 145- H-25435; Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Individual Animal Pathology Data Dose Group : V 100 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 665758 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH 665759 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH 665760 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology KIDNEYS : DILATATION, UNILATERAL. No Macroscopic Abnormality Observed : LIVER, THYROID GLAND, SKIN, TEETH 665760 Continued on the next page .... DuPont-11574 Company Sanitized. Does not contain TSCA CB1 -146- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ Individual Animal Pathology Data Dose Group : V 100 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 665760 Continued from previouspage Histopathology : KIDNEYS : DILATATION, PELVIS, UNILATERAL, mild. 665761 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH DuPont-11574 Company Sanitized. Does not contain TSCA CB1 - 147- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ Individual Animal Pathology Data Dose Group : VII 1000 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 665762 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH Histopathology : LIVER : HEMATOPOIESIS, EXTRAMEDULLARY, minimal. INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. Np Microscopic Abnormality Observed : KIDNEYS, THYROID GLAND, SKIN, TEETH 665763 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH Histopathology : LIVER : HEMATOPOIESIS, EXTRAMEDULLARY, minimal. INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. 665763 Continued on the next page .... DuPont-11574 Company Sanitized. Does not contain TSCCB1 - 148 - H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ f Individual Animal Pathology Data Dose Group : VII 1000 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 665763 Continued from previous page Histopathology KIDNEYS : NEPHROPATHY, CHRONIC PROGRESSIVE, minimal. No Microscopic Abnormality Observed : THYROID GLAND, SKIN, TEETH 665764 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH Histopathology : LIVER : HEMATOPOIESIS, EXTRAMEDULLARY, minimal. INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. KIDNEYS : tNEPHROPATHY, CHRONIC PROGRESSIVE, minimal. No Microscopic Abnormality Observed : THYROID GLAND, SKIN, TEETH DuPont-11574 Company Sanitized. Does not contain TSCACB! - 149- H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ Individual Animal Pathology Data Dose Group : VII 1000 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 665765 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology : Ho Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH Histopathology : LIVER : HEMATOPOIESIS, EXTRAMEDULLARY, minimal. No Microscopic-Abnormality Observed : KIDNEYS, THYROID GLAND, SKIN, TEETH 665766 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH Histopathology : LIVER : HEMATOPOIESIS, EXTRAMEDULLARY, minimal. KIDNEYS : NEPHROPATHY, CHRONIC PROGRESSIVE, minimal 665766 Continued on the next page .... DuPont-11574 Company Sanitized. Does not contain TSCA CB! H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats__________________ _____________________________________ Individual Animal Pathology Data Dose Group : VII 1000 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 665766 Continued from previous page Histopathology No Microscopic Abnormality Observed : THYROID GLAND, SKIN, TEETH 665767 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH Histopathology : LIVER : HEMATOPOIESIS, EXTRAMEDULLARY, minimal. INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. TEETH : HEMORRHAGE, mild, peridontal . INFLAMMATION, ACUTE, mild, peridontal . No Microscopic Abnormality Observed : KIDNEYS, THYROID GLAND, SKIN 665768 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH 665768 Continued on the next page .... DuPont-11574 Company Sanitized. Doss not contain TSCA CBi -151 - H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ Individual Animal Pathology Data Dose Group : VII 1000 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 665768 Continued from previous page Histopathology LIVER : HEMATOPOIESIS, EXTRAMEDULLARY, minimal. INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal No Microscopic Abnormality Observed : KIDNEYS, THYROID GLAND, SKIN, TEETH 665769 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH Histopathology LIVER : HEMATOPOIESIS, EXTRAMEDULLARY, minimal. INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal NECROSIS, HEPATOCELLULAR, FOCAL, minimal. KIDNEYS : NEPHROPATHY, CHRONIC PROGRESSIVE, minimal. No Microscopic Abnormality Observed : THYROID GLAND, SKIN, TEETH DuPont-11574 Company Sanitized. Does not contain TSCA CBS /^\ H-25435: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ Individual Animal Pathology Data Dose Group : VII 1000 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 665770 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH Histopathology : LIVER : HEMATOPOIESIS, EXTRAMEDULLARY, minimal. INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. KIDNEYS : NEPHROPATHY, CHRONIC PROGRESSIVE, minimal. No Microscopic Abnormality Observed : THYROID GLAND, SKIN, TEETH 665771 Terminal Sacrifice Killed on Day : 29 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, THYROID GLAND, SKIN, TEETH Histopathology : LIVER : HEMATOPOIESIS, EXTRAMEDULLARY, minimal. S65771 Continued on the next page .... DuPont-11574 Company Sanitized. Does not contain TSCACBl - 153 - H-25435: Repeated-Dose Demial Toxicity 28-Day Study in Male Rats______________ Individual Animal Pathology Data Dose Group : VII 1000 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 665771 Continued from previous page Histopathology : LIVER : INFLAMMATION, SUBACUTE /CHRONIC, FOCAL, minimal. KIDNEYS : NEPHROPATHY, CHRONIC PROGRESSIVE, minimal. No Microscopic Abnormality Observed : THYROID GLAND, SKIN, TEETH DuPont-11574 Company Sanitized. Does not contain TSCACB1 - 154-