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M aa6 - }* * * M A26- 3^72 DuPont-11763 TRADE SECRET Study Title H-25509: Repeated Dose Dermal Toxicity 28-Day Study in Male Rats 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: August 4,2003 Performing Laboratory: E.I. du Pont ae Nemours and Company Haskell Laboratory for Health and Environmental Sciences Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050 Laboratory Project ID: DuPont-11763 $a pd.O06 CoiflP Page 1 o f 196 C# H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 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 did not impact the validity of the study. The sponsor characterized the test substance. Although the characterization was not performed under Good Laboratory Practice Standards, both the validity and accuracy of the analysis was considered acceptable and therefore sufficient for the purpose of this study. Applicant / Sponsor: E.I. du Pont de Nemours and Company Wilmington, Delaware 19898 U.S.A. Staff Toxicologist Applicant / Sponsor: DuPont Representative Date noi contai SanW\xedoeS Company -2 - H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats QUALITY ASSURANCE STATEMENT DuPont-11763 Haskell Sample Number(s): 25509 Dates of Inspections: Protocol: November 22,2002 Conduct: December 10,12,16,23,2002; March 5, 2003 Records, Reports: March 3-7,12-13,28, 2003; July 14-16, 2003 Dates Findings Reported to: Study Director: March 5,10,13,28, 2003; July 16, 2003 Management: March 5,13,20, 2003; July 16,22, 2003 Reported by: K_- d\ L_j L] pu i y Quality Assurance Auditor y-fiuA-lOCB Date Company Sanitized. Does not contain TSCA CBt H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 CERTIFICATION We, the undersigned, declare that this report provides an accurate evaluation of the data obtained from this study. Clinical Pathology Evaluation bv: ' '2 / f (2 r Nancy. Evcrds, D.V.M. Diplomate A.C.V.P. Principal Research Clinical Pathologist andManager Date Anatomic Pathology Evaluation by: f i C [\j\ l(M Peter C. Mann, D.V.M. Diplomate A.C.V.P. Veterinary Pathologist h Aufc-^3 Date Annroved bv: / p j & ~ T i* ^ V ScottE. Loveless, Ph.D. Management Date Issued by Study Director:________ j t h i / U * _____________________ Carol lnlay, B.A. ^ StaffToxicologist H duck Dak {Company Sanitized. Does not contain TSCA CB1 H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 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. H ousing................................................................................................................................................................... 13 2. Environmental Conditions....................................................................................................................................13 3. Feed and Water.......................................................................................................................................................13 4. Identification.......................................................................................................................................................... 14 5. Health Monitoring Program..................................................................................................................................14 E. Pretest Period..................................................................................................................... 14 F. Assignment to Groups and Study Start............................................................................. 14 G. Test Substance Preparation and Administration..................................... 15 H. Body Weights.................................................................................................................... 15 I. Food Consumption and Food Efficiency........................................................................... 16 J. Mortality and Clinical Observations................................................................................. 16 K. Total Fluorine and Perfluorooctanoic Acid Level Evaluations..........................................16 L. Clinical Pathology Evaluation........................................................................................... 16 1. Hematology and Coagulation.............................................................................................................................. 17 2. Clinical Chemistry................................................................................................................................................. 17 3. Urinalysis.................................................................................................................................................................18 M. Anatomic Pathology Evaluations...................................................................................... 18 N. Statistical Analyses............................................................................................................20 Company Sanitized. Does not contain t s c a CB1 H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ RESULTS AND DISCUSSION................................................ In-Life Toxicology...................................................................... A. Mean Body Weights and Body Weight Gains.................. B. Food Consumption and Food Efficiency.......................... C. Clinical Observations, Dermal Evaluations, and Survival D. Blood Fluorine Analysis................................................... E. In-Life Conclusions.......................................................... Clinical Pathology Evaluations................................................. A. Hematology........... .......................................................... B. Coagulation...................................................................... C. Clinical Chemistry........................................................... D. Urinalysis.......................................................................... E. Urine and Plasma Fluoride............................................... F. Clinical Pathology Conclusions....................................... Anatomic Pathology Evaluations.............................................. A. Mortality........................................................................... B. Organ Weights.................................................................. C. Gross Observations.......................................................... D. Microscopic Findings....................................................... E. Anatomic Pathology Conclusions.................................... CONCLUSIONS........................................................................ RECORDS AND SAMPLE STORAGE.................................. REFERENCES........................................................................... TABLES...................................................................................... FIGURES.................................................................................... APPENDICES............................................................................ 21 21 21 21 21 22 22 22 22 22 22 23 23 23 24 24 24 24 24 24 24 25 25 27 73 75' Sanm* -6 - H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 LIST OF TABLES Page 1. MEAN BODY WEIGHTS OF MALE RATS................................................... ............................................................. 31 2. MEAN BODY WEIGHT GAINS OF MALE RATS..................................................................................................... 32 3. MEAN DAILY FOOD CONSUMPTION BY MALE RATS......................................................................................33 4. MEAN DAILY FOOD EFFICIENCY OF MALE R A TS.............................................................................................34 5. SUMMARY OF CLINICAL OBSERVATIONS IN MALE RATS............................................................................. 35 6. SUMMARY OF CLINICAL OBSERVATIONS IN MALE RATS - POST DOSING........................................... 37 7. PERCENT SURVIVAL OF MALE RATS..................................................................................................................... 38 8. SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS.............................................................................. 39 9. SUMMARY OF COAGULATION VALUES FOR MALE R A T S.............................................................................41 10. SUMMARY OF CLINICAL CHEMISTRY VALUES FOR MALE R ATS............................................................. 42 11. SUMMARY OF URINALYSIS VALUES FOR MALE RATS................................................................................... 44 12. MEAN FINAL BODY AND ORGAN WEIGHTS FROM MALE RATS.................................................................45 13. INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS...............................................................................48 14. INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS................. 55 ,,ot contain TSCA OBI Company Santtizad*Doea -7 / '"'N H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 LIST OF FIGURES Page 1. MEAN BODY WEIGHTS OF MALE RATS................................................................................................................. 74 N LIST OF APPENDICES Page A. INDIVIDUAL BODY WEIGHTS.................................................................................................................................... 76 B. INDIVIDUAL FOOD CONSUMPTION..........................................................................................................................81 C. INDIVIDUAL CLINICAL OBSERVATIONS AND MORTALITY RECORDS.................................................... 83 D. INDIVIDUAL CLINICAL OBSERVATIONS - POST-DOSING.............................................................................. 95 E. INDIVIDUAL EDEMA AND ERYTHEMA SCORES............................................................................................... 105 F. INDIVIDUAL BLOOD FLUORINE LEVELS............................................................................................................. 119 G. INDIVIDUAL ANIMAL CLINICAL PATHOLOGY D A T A ....................................................................................121 H. INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS.......................................................................147 I. INDIVIDUAL ANIMAL PATHOLOGY DATA.........................................................................................................154 Company Sanitized. Does not confo'" TC;ca CBI -8 - H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ STUDY INFORMATION Substance Tested:1 Svnonvms/Codes: DuPont-11763 Submitter's Notebook NumbertsV. Haskell Number: 25509 CAS Registry NumberKnown Impurities: Sponsor: E.L du Pont de Nemours and Company Wilmington, Delaware 19898 U.S.A. Study Initiated/Completed: 22-Nov-2002 / (see report cover page) Company Sanitized. Does not car H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 STUDY PERSONNEL Study Director: Carol Finlay, B.A. Management: Scott E. Loveless, Ph.D. Primary Technician: Janine A. Britton, B.S. Clinical Pathologist: Nancy E. Everds, D.V.M. Management: Steven R. Frame, D.V.M., Ph.D. Anatomic Pathologist: John F. Hansen, D.V.M., Ph.D. Peter C. Mann, 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 Prparation: 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. Company Sanitized. Does not contain TSCA CB -10- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 SUMMARY The objective of this study was to determine the potential toxicity of H-25509 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 approximately 28 consecutive days. Three groups of 10 male rats were treated dermally with 5, 50, and 500 mg/kg/day H-25509. A control group of 10 male rats was similarly treated with mineral oil. Food consumption was determined weekly during the study. Blood samples for blood fluorine were collected on test days 0, 7,14,21, and 27. Blood and urine samples were collected for clinical pathology prior to sacrifice on test day 28. 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. Erythema (score of 1 or 2) observed sporadically was considered not test substance-related. Some fluorine was present in the day 27 blood, indicating exposure to a fluoride-containing compound. This finding was considered treatment-related but not adverse. Differences in organ weights were not present in a dose response fashion and there were no correlative gross or microscopic lesions. 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 treatment-related changes in hematologic or coagulation parameters in the rats. Treatment-related mild decreases in serum cholesterol in rats treated at 500 mg/kg/day were considered to be potentially adverse. Treatment-related mild decreases in triglycerides in rats treated at 500 mg/kg/day were considered to be non-adverse. There were no statistically significant or treatment-related changes in urinalysis parameters. Urine fluoride was increased in rats dosed at 50 or 500 mg/kg/day; this change indicated exposure to and metabolism of a fluoride-containing compound. Urine fluoride changes were considered to be treatment-related but non-adverse. Based on the presence of decreased cholesterol in some rats treated at 500 mg/kg/day, the no observed effect level (NOEL)8for the dermal exposure of H-25509 under the conditions of this study was 50 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). - 11 - ICpmpany Sanitized. Does not contain TSCA CM H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats____________ DuPont-11763 INTRODUCTION The purpose of this study was to evaluate the toxicity of H-25509 in male rats when administered dermally for approximately 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 rangefinding study was conducted to aid in dosage selection. Groups of 2 male rats received dermal applications of H-25509 at dosages of 0,10,100, or 1000 mg/kg for 6 hours for 5 consecutive days. No adverse clinical signs or body weight losses occurred. Dosages of 0, 5, 50, and 500 mg/kg/day were selected for the 28-day study. The high dose level of 500 mg/kg/day was selected because it is greater than the level to which humans may be potentially exposed to the test substance. STUDY DESIGN Group mI vVn Number/Group 10 10 10 10 Dosage (mg/kg) 0 5 50 500 MATERIALS AND METHODS A. Test Guidelines Except as noted below, the study design complies with the following test guidelines: 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. Guidelinefor 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-25509. jPompany Sanitized Does not contain TSCACBI -12- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11763 ^ I9^ \ The laboratory closed on test day 10 because of inclement weather. The rats were exposed for approximately 1.5 hours on that day. This exception did not affect the objectives or validity of the study because the test guidelines say the exposure period can be 21 days. B. Test Substance The test substance, H-25509, was supplied by the sponsor as a dark brown ground solid. 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. The test substance was moistened with mineral oil to form a thick paste before application to the skin. These pastes were not analyzed for stability or homogeneity. The procedures used were believed to result in a paste that was homogeneous and stable between preparation and application. 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 November 19,2002, 45 male Crl:CD(SD)IGS BR rats, with an assigned birth date of October 3,2002 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. - 13jPpinpany Sanitized. Does not contain TSCA CBI H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 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 the individual identification number assigned to each rat. 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 0 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 within a sex. 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. -14Jj&mpany Sanitized. Does not contain TSCA CBF H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 Dose administration with H-25509 began on test day 0 when the rats were approximately 8 weeks of age. G. Test Substance Preparation and Administration The dosing pastes were prepared just prior to treatment by mixing the test substance with just enough mineral oil to form a paste. Water was not used because it did not sufficiently moisten the test substance. On 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 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 rats dosed at 0 or 500 mg/kg/day had a treatment area of 37 cm2. The 37 cm2treatment area is approximately equal to 10% of the total body surface area for rats in the 200 to 300 g range of body weights. The volume of test substance for the rats dosed at 5 or 50 mg/kg/day was too small to cover 37 cm2. The treatment area for these rats was 12.25 cm2, or 3.3% of the total body surface. The aliquot of test substance designated for an animal was moistened with mineral oil to form a paste and 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 mineral oil 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, 5, 50, or 500 mg of test substance per kg body weight. The rats were treated for approximately 28 consecutive days. The amount of test substance needed to treat each rat was based on the most recently determined body weight measurement. The exposure period was approximately 6 hours. After the exposure period, the collars and wrappings were removed and the test site wiped with a wet paper towel and washed with soap and 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. On test day 10, the laboratory closed due to inclement weather. The test substance was removed from the rats after approximately 1.5 hours of exposure. 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. - 15- ppmpany Sanitized. Does not contain CBl H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats _____ DuPont-11763 I. Food Consumption and Food Efficiency The amount of food consumed by each rat was determined weekly by weighing 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 over the week was determined. From the food consumption and body weight data, mean daily food efficiency for each group was calculated. J. Mortality and Clinical Observations The rats were checked once for mortality and for signs of illness, injury, or abnormal behavior on the day the laboratory closed because of inclement weather. They were checked twice daily all other days. 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 0,7,14,21, and 27 approximately one hour after removal of the test substance. The blood was refrigerated. The total fluorine content of the day 27 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 will be stored frozen at -80C to -20C until analyzed for concentration of perfluorooctanoic acid (PFOA). 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 28 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 samples for coagulation parameters were collected at sacrifice from the abdominal vena cava of each animal while the animal was under carbon dioxide anesthesia. Additional blood collected from the vena cava was placed in a serum tube, processed to serum, and frozen at -80C. Bone marrow smears were prepared at sacrifice from all -16- jgggipany Sanitized Does no! eonfafn TSCA C6V H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11763 surviving animals. Bone marrow smears were stained with Wright's stain, but analysis was not necessary to support experimental findings. 1. Hematology and Coagulation Blood samples were evaluated for quality by visual examination prior to analysis. Complete blood counts, including reticulocytes, were determined on a Bayer Advia 120 hematology analyzer or determined from microscopic evaluation of the blood smear. Wright-stained blood smears from all animals were examined microscopically for confirmation of automated results and evaluation of cellular morphology. Blood smears, stained with new methylene blue, were prepared from each animal undergoing a hematology evaluation but were not needed for examination. Coagulation times were determined on a Sysmex CA-1000 Coagulation Analyzer. The following hematology and coagulation parameters were determined: red blood cell count platelet count hemoglobin white blood cell count hematocrit differential white blood cell count mean corpuscular volume microscopic blood smear examination mean corpuscular hemoglobin mean corpuscular hemoglobin concentration red cell distribution width absolute reticulocyte count prothrombin time activated partial thromboplastin time 2. Clinical Chemistry Serum clinical chemistry parameters were determined on a Roche Diagnostics (BMC)ZHitachi 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 a Fluoride determination was analyzed on EDTA plasma. -17jP&mpany Sanitized. Does not contain TSCA GBf H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______ DuPont-11763 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 fluoride3 protein microscopic urine sediment examination a Fluoride determination was analyzed from urine with EDTA added. 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. Digestive Svstem liver esophagus stomach duodenum jejunum ileum cecum colon rectum salivary glands pancreas Urinary Svstem kidneys urinary bladder Cardiovascular Svstem heart aorta Hematopoietic Svstem spleen thymus mandibular lymph node mesenteric lymph node bone marrow3 Endocrine System pituitary gland thyroid gland parathyroid glands adrenal glands Musculoskeletal Svstem skeletal muscle femur/knee joint sternum Reproductive Svstem testes epididymides prostate seminal vesicles Miscellaneous skin eyes (including optic nerve) gross observationsb -18fiSW pany .Sanitized. Does not contain t s c a CBI H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11763 Respiratory System Nervous System lungs brain (cerebral cortex, cerebellar cortex, trachea medulla/pons) nasal tissue spinal cord (cervical, mid-thoracic, larynx lumbar) pharynx sciatic nerve a Bone marrow was collected with the femur and sternum, b Gross observations made at necropsy for which histopathology is not appropriate (e.g., fluid, ruffled fur, and missing anatomic parts) were generally not collected. All tissues were placed in an appropriate fixative. The rats sacrificed by design had the following organs weighed: liver, kidneys, adrenal glands, thymus, brain, spleen, heart, testes, and epididymides. Relative organ weights (percent of final body weight; ratio to brain weight) were calculated. Final body weights determined just prior to necropsy were used in the assessment of organ weight changes. All tissues collected from rats in the high-dosage and control groups 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 t s c a CBl H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ N. Statistical Analyses Significance was judged at p < 0.05. DuPont-11763 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 o f trend Levene's test for homogeneity and Shapiro-Wilk test for normalityb Levene's test for homogeneity and Shapiro-Wilk test for normalityb None Method o f Statistical Analysis If preliminary test is not If preliminary test is significant significant Sequential application o f the Jonckheere-Terpstra Preliminary tests for trend test pairwise comparison ORa One-way analysis o f variance followed with Dunnett's test8 Kruskal-Wallis test(10) followed with Dunn's test(lI> One-way analysis o f variance followed with Dunnett's test*7'8 Kruskal-Wallis test(l0) followed with Dunn's test<n) 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(I2) 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. Sawittteed Doeno'ltcontaint! -20- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11763 RESULTS AND DISCUSSION In-Life Toxicology A. Mean Body Weights and Body Weight Gains (Tables 1-2, Figure 1, Appendix A) No effects on body weights occurred in any group of rats dosed with the test substance, H-25509. Mean body weight gain was significantly decreased compared to control in the 500 mg/kg/day group during the interval day 24-27. However, this decrease was considered non-adverse because it only occurred at one timepoint and weight gain was not significantly decreased over the course of the study. B. Food Consumption and Food Efficiency (Tables 3-4, Appendix B) 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 5-7, Appendices C-E) No clinical signs attributable to systemic toxicity occurred. Ocular or nasal discharge and swollen face observed in both control rats and rats treated with the test substance were considered to be due to the wrapping/collar application procedure. Superficial wounds or hair loss was present in single rats in the 50 mg/kg/day group and were considered incidental and not a direct effect of the test substance. Red oral discharge was observed in 1 rat in the 50 mg/kg/day group was not observed in any rats in treated at 500 mg/kg/day and, therefore, was not considered to be treatment-related. The observation of dark eye in 2 rats in the 50 mg/kg/day group and 1 rat in the 500 mg/kg/day group was considered to be a result of orbital sinus bleeding. Erythema (score of 1 or 2) was observed in some rats in the 50 mg/kg/day group and is considered not to be test substance-related because it was also observed in control rats. No deaths occurred. Qew,OiCO(1t\ia'n TS< Sawk\tl*ed -21 - H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 D. Blood Fluorine Analysis (Appendix F) Some fluorine was present in the day 27 blood from rats dosed with the test substance, indicating exposure to a fluoride-containing compound. This finding was considered to be treatment related but not adverse. All rats treated at 5 mg/kg/day had fluorine levels below the limit of quantification (LOQ). The rats treated at 50 mg/kg had levels of fluorine ranging from 1.14 to 1.83 ppm. The rats treated at 500 mg/kg/day had fluorine levels ranging from 5.07 to 19.35 ppm. Fluorine levels of 0.58 or 1.57 ppm in 2 control rats cannot be explained. All values for the remaining control rats were below the LOQ. E. In-Life Conclusions Under the conditions of this study, the no-observed-adverse-effect level for inlife parameters was 500 mg/kg/day for male rats based on the absence of adverse or test substance-related effects. Clinical Pathology Evaluations A. Hematology (Table 8, Appendix G) There were no treatment-related changes in hematologic parameters in male rats. The following statistically significant changes in mean hematology parameters were considered to be unrelated to treatment and non-adverse because they did not occur in a dose-related pattern: Minimally decreased red blood cell counts in males treated at 50 mg/kg/day. Minimally increased mean cell hemoglobin concentration in males dosed with 5 mg/kg/day. B. Coagulation (Table 9, Appendix G) There were no treatment-related or statistically significant changes in coagulation parameters in male rats. C. Clinical Chemistry (Table 10, Appendix G) Cholesterol was mildly decreased in some male rats treated at 500 mg/kg/day (mean cholesterol was 71% of control group mean). Individual concentrations of rats treated at 500 mg/kg/day ranged from 27-69 mg/dL, while cholesterol concentrations in control rats varied over a smaller -22- gfeynpang .Sanitized. Does m i contain TSCA CBI H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats___________ DuPont-11763 range (47-65 mg/dL). This change was considered to be treatment-related, and potentially adverse. Triglycerides were mildly decreased in male rats treated at 500 mg/kg/day. This change was considered to be treatment-related. However, mildly decreased triglycerides are not associated with toxic events, so this change was considered to be non-adverse. There were no other treatment-related changes in clinical chemistry parameters in male rats. The following statistically significant change in mean clinical chemistry parameters was considered to be unrelated to treatment and non-adverse because it did not occur in a dose-related pattern: Increased glucose in male rats treated at 50 mg/kg/day D. Urinalysis (Table 11, Appendix G) There were no statistically significant or treatment-related changes in urinalysis parameters in male rats. E. Urine and Plasma Fluoride Urine fluoride (total fluoride excreted during overnight fast) was increased in males treated at 50 or 500 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) Parameter (units) 0 5 50 500 UFLU (g) 9.5 13.3 23.0 147.2 % of control mean NA 242% 1549% Statistical significance is indicated by bold italicized type. F. Clinical Pathology Conclusions In conclusion, dermal dosing of 500 mg/kg/day caused mild decreases in serum cholesterol and triglycerides; decreased cholesterol was considered to be potentially adverse. Urine fluoride was increased in males treated at 50 or 500 mg/kg/day; this change indicated exposure to and metabolism of a fluoride-containing compound. Urine fluoride changes were 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-adverse-effect level was 50 mg/kg/day for male rats, based on presence of decreased cholesterol in some rats treated at 500 mg/kg/day. -23JPpntpany Sanitized. Does no! eo* **'* rqy H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ Anatomic Pathology Evaluations DuPont-11763 A. Mortality There were no early deaths. B. Organ Weights (Table 12, Appendix H) The mean absolute and relative weights of the liver and kidneys were statistically significantly higher than the control. There were no correlative gross or microscopic lesions in either the liver or kidney, and the organ weight changes were not present in a dose response fashion across the groups. Thus, higher mean weights of the liver and kidney were considered to be spurious and not adverse. C. Gross Observations (Table 13, Appendix I) 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 I) 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 500 mg/kg. 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 approximately 28 applications of H-25509 applied daily to the shaved skin. Organ weight differences, gross observations, and microscopic findings were considered to be nonadverse, occur spontaneously in rats, and/or were not present in a dose response fashion. There were no adverse changes in hematology, coagulation, or urinalysis parameters. Mildly decreased cholesterol in some rats dosed at 500 mg/kg/day was considered treatment-related and potentially adverse. Mildly decreased triglycerides in rats dosed at 500 mg/kg/day were considered -24lQMnpan]f Sanitized. D oes not contain TSCA OBI H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_________ DuPont-11763 treatment-related but non-adverse. Increased urine fluoride at 50 or 500 mg/kg/day and the presence of fluorine in the day 27 blood indicated exposure to and metabolism of a fluoridecontaining test substance and was considered treatment-related but not adverse. Based on the presence of decreased cholesterol in some rats dosed with 500 mg/kg/day, the no observed-effect level (NOEL)3for the dermal exposure of H-25509 under the conditions of this study was 50 mg/kg/day for male rats. 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. Draper, N.R. and Smith, H. (1981). Applied Regression Analysis, 2nd edition, pp 266-273. Wiley, New York. 2. Selwyn, M.R. (1995). The use of trend tests to determine a no-observable-effect level in animal safety studies. Journal of the American College o f Toxicology 14(2), 158-168. 3. Jonckheere, A.R. (1954). A distribution-free K-sample test against ordered alternatives. Biometrika 41,133-145. 4. Levene, H. (1960). Robust test for equality of variances. Contributions to Probability and Statistics (J. Olkin, ed.), pp 278-292. Stanford University Press, Palo Alto. 5. Shapiro, S.S. and Wilk., M.B. (1965). An analysis of variance test for normality (complete samples). Biometrika 52, 591-611. 6. Snedecor, G.W. and Cochran, W.G. (1967). Statistical Methods, 6th edition, pp 246-248 and 349-352. The Iowa State University Press, Ames. 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). -25- JRgflapapy Sanitized. Does not contain TSCA CBI H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 7. Dunnett, C.W. (1964). New tables for multiple comparisons with a control. Biometrics 20, 482-491. 8. Dunnett, C.W. (1980). Pairwise multiple comparisons in the unequal variance case. J.Amer. Statist. Assoc. 75,796-800. 9. Tamhane, A.C. (1979). A comparison of procedures for multiple comparison of means with unequal variances. J. Amer. Statist. Assoc. 74, 471-480. 10. Kruskal, W.H. and Wallis, W.A. (1952). Use of ranks in one-criterion analysis of variance. J. Amer. Statist. Assoc. 47, 583-621. 11. Dunn, O.J. (1964). Multiple contrasts using rank sums. Technometrics 6, 241-252. 12. Fisher, R.A. (1985). Statistical Methodsfor Research Workers, 13th edition. Hafiner, New York. g&mpany Santtteed. 0098 not contain TSCACfc - 26- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats _________ DuPont-11763 TABLES Company8* " 0, c,,-i '"tscivCB' - 27- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ ABBREVIATIONS: TABLES EXPLANATORY NOTES Summary of Hematology Values RBC - red blood cell count HGB - hemoglobin HCT - hematocrit MCV - mean corpuscular volume MCH - mean corpuscular hemoglobin MCHC - mean corpuscular hemoglobin concentration RDW - red cell distribution width ARET - absolute reticulocyte count PLT - platelet count WBC - white blood cell count ANEU - absolute neutrophil (all forms) ALYM - absolute lymphocyte AMON - absolute monocyte AEOS - absolute eosinophil ABAS - absolute basophil ALUC - absolute large unstained cell Summary of Coagulation Values PT - prothrombin time APTT - activated partial thromboplastin time DuPont-11763 ^ p a n y g a n f f lz e d . Does not contain TSCACBi -28 - H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 TABLES EXPLANATORY NOTES (Continued) ABBREVIATIONS: (Continued) Summary of Clinical Chemistry Values AST - aspartate aminotransferase ALT - alanine aminotransferase SDH - sorbitol dehydrogenase ALKP - alkaline phosphatase BILI - total bilirubin BUN - urea nitrogen CREA - creatinine CHOL - cholesterol TRIG - triglycerides GLUC - glucose TP - total protein ALB - albumin GLOB - globulin CALC - calcium EPHS - inorganic phosphorous NA - sodium K - potassium CL - chloride PFLU - plasma fluoride 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 jCempany Sanitized, Does not contain TSCA CBt -29- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 TABLES NOTES: EXPLANATORY NOTES (Continued) Summary of Hematology Values Summary of Coagulation Values Summary of Clinical Chemistry Values Summary of Urinalysis Values When an individual observation was recorded as being less than a certain value, calculations were performed on half the recorded value. For example, if bilirubin was reported as <0.1, 0.05 was used for any calculations performed with that bilirubin data. jppmpany Sanitized. Does not contain TSCA CBI jPompany Sanitized. Does not contain TSCA CBI ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) ) DuPont-11763 Group : D osage(m g/kg) DAYO DAY3 DAY7 DAY10 DAY14 DAY17 DAY21 DAY24 DAY27 TABLE 1 MEAN BODY WEIGHTS OF MALE RATS (g) I hi V 0 5 50 240.3 7.6(10) 259.0 12.7(10) 288.1 11.3 (10) 303.1 11.8(10) 320.1 14.5(10) 329.8 15.8(10) 345.9 17.0(10) 356.7 16.4(10) 364.3 16.7(10) 238.0 8.2(10) 257.4 13.7(10) 287.7 16.8(10) 303.5 17.9(10) 324.5 21.5(10) 335.3 18.9(10) 345.4 24.0(10) 357.9 22.3(10) 363.0 22.1(10) 241.7 6.9(10) 257.5 7.4(10) 287.1 11.5(10) 301.8 14.5(10) 321.2 18.9(10) 332.3 17.6(10) 342.0 18.4(10) 354.2 16.6(10) 361.5 18.3(10) V II 500 241.3 8.8(10) 260.2 10.1(10) 285.4 14.7(10) 303.8 17.3(10) 321.8 27.5(10) 328.5 32.0(10) 342.8 32.6(10) 351.7 34.8(10) 352.2 38.1(10) Data summarized a s: Mean Standard D e v ia tio n (n) There were no s t a t i s t i c a l l y s ig n if ic a n t d iffe r e n c e s a t p < 0.05 by Jonckheere--T erpstra trend t e s t . -31- Company Sanitized. Does not contain tr^ c bi ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) TABLE2 MEAN BODY WEIGHT GAINS OF MALE RATS (g) Group : Dosage(mg/kg) DAY0-DAY3 DAY3-DAY7 DAY7-DAY10 DAY10-DAY14 DAY14-DAY17 DAYl7-DAY21 DAY21-DAY2 4 DAY2 4-DAY2 7 I 0 18.7 7.1(10) 29.1 5.7(10) 15.0 4.3(10) 17.0 5.7(10) 9.7 5.3(10) 16.2 8.6(10) 10.8 4.3(10) 7.6 5.4(10) hi 5 19.3 7.2(10) 30.4 6.0(10) 15.8 3.0(10) 21.0 7.0(10) 10.8 6.8(10) 10.2 7.9(10) 12.5 5.9(10) 5.1 4.7(10) V 50 15.8 3.9(10) 29.6 6.1(10) 14.7 7.8(10) 19.4 5.4(10) 11.2 6.2(10) 9.6 7.4(10) 12.3 3.3(10) 7.3 4.5(10) DAY0-DAY27 124.0 14.2(10) 125.0 19.1(10) 119.8 17.1(10) Data summarized as : Mean Standard Deviation (n) # Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. -32- ) ___________ DuPont-11763 VII 500 18.9 5.3(10) 25.3 15.9(10) 18.4 8.5(10) 17.9 11.7(10) 6.8 6.0(10) 14.3 7.3(10) 8.9 6.0(10) 0.5# 6.7(10) 110.9 37.8(10) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11763 TABLE 3 MEAN DAILY FOOD CONSUMI TION BY MALE RATS (g/day) Group : Dosage(mg/kg) DAY0-DAY7 DAY7-DAY14 DAY14-DAY21 DAY21-DAY27 I 0 24.5 1.0(10) 25.7 1.8(10) 26.2 1.7 (10) 27.1 1.2(10) hi 5 24.8 2.2(10) 26.1 1.3(10) 25.9 1.4(10) 27.5 1.6(10) V 50 25.7 1.4(10) 26.3 1.4(10) 26.1 0.8(10) 27.7 1.6(10) VII 500 24.8 1.9(10) 25.9 2.3(10) 25.6 2.2(10) 26.5 3.3(10) DAY0-DAY27 25.8 1.3(10) 26.0 1.4(10) 26.4 0.9(10) 25.7 2.0(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 not TCA CBf -33- ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) ) DuPont-11763 TABLE 4 MEAN DAILY FOOD EFFICIENCY OF MALE RATS (g body weight gain/g food consumed) Group: Dosage(mg/kg) DAY0-DAY7 DAY7-DAY14 DAY14-DAY21 DAY21-DAY2 7 I 0 0.278 0.025(10) 0.177 0.035(10) 0.141 0.025(10) 0.113 0.025(10) III 5 0.284 0.053(10) 0.202 0.044(10) 0.115 0.042(10) 0.107 0.043(10) V 50 0.252 0.037(10) 0.184 0.063 (10) 0.114 0.039(10) 0.118 0.023(10) VII 500 0.252 0.095(10) 0.194 0.101 (10) 0.116 0.040(10) 0.053 0.079(10) DAY0-DAY27 0.178 0.015(10) 0.178 0.024(10) 0.168 0.022(10) 0.157 0.050(10) Data summarized as: Mean Standard Deviation (n) There were no statistically significant differences at p < 0.05 by Jonckheere-Terpstra trend test. Sanitized. D oes not contain TSCA CBI -34- ;> H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats___________________________ ) Treatment Group Dose Animal Count Eye Observations Dark Incidence Mean onset (Days) Opaque Incidence Mean onset (Days) Discharge Eye Incidence Mean onset (Days) Nose Incidence Mean onset (Days) Mouth Incidence Mean onset (Days) Hair Loss Incidence Mean onset (Days) TABLE 5 SUMMARY OF CLINICAL OBSERVATIONS IN MALE RATS I 0 mg/kg 10 III 5 mg/kg 10 V 50 mg/kg 10 0 1 ( 10%) 28 0 0 2 ( 20%) 19 0 8 ( 80%) 6 0 7 ( 70%) 3 0 8 ( 80%) 3 0 0 0 1 ( 10%) 28 0 0 1 ( 10%) 7 ) DuPont-11763 VII 500 mg/kg 10 1 ( 10%) 28 0 7 ( 70%) 0 1 ( 10%) 0 0 0 Company Sanitized. Does not contain TSCA CBl -35- ') H-25509: Repeated-Dose Deimal Toxicity 28-Day Study in Male Rats ) ) DuPont-11763 TABLE 5 (CONTINUED) SUMMARY OF CLINICAL OBSERVATIONS IN MALE RATS Treatment Group Dose Animal Count Wound Superficial Incidence Mean onset (Days) Swollen Observations Face Incidence Mean onset (Days) I 0 mg/kg 10 0 1 ( 10%) 0 III 5 mg/kg 10 0 0 V 50 mg/kg 10 1 ( 10%) 24 0 VII 500 mg/kg 10 0 1 ( 10' 0 Incidence - The number of animals for which an observation was recorded. Mean onset (Days) - The mean of the first test day an observation was recorded for that group. There were no statistically significant differences at p < 0.05 by Cochran-Armitage trend test. pazffiuegtoAfioit ao oo>> oas -36- ) H-25509: Repeated-Dose Dennal Toxicity 28-Day Study in Male Rats ) DuPont-11763 TABLE 6 SUMMARY OF CLINICAL OBSERVATIONS IN MALE RATS - POST DOSING Treatment Group Dose Animal Count I 0 mg/kg 10 hi 5 mg/kg 10 V 50 mg/kg 10 VII 500 mg/kg 10 Eye Observations Dark Incidence 0 0 1 ( 10%) 0 Mean onset (Days) 8 Discharge Eye Incidence Mean onset (Days) 10 (100%) 8 10 (100%) 3 10 (100%) 4 10 (100%) 3 Nose Incidence 1 10%) 0 0 0 Mean onset (Days) 2 Hair Loss Incidence 0 0 1 ( 10%) 0 Mean onset (Days) 7 Wound Superficial Incidence Mean onset (Days) 0 0 1 ( 10%) 0 24 Swollen Observations Face Incidence Mean onset (Days) 1 ( 10%) 4 0 0 Incidence - The number of animals for which an observation was recorded. Mean onset (Days) - The mean. of the first test day an observation was recorded for that group. There were no statistically significant differences at p < 0.05 by Cochran -Armitage trend test. 0 ggmpaiiy Sanitized. Does not contain TSCACBI -37- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 TABLE 7 PERCENT SURVIVAL OF MALE RATS Group: Dosage (mg/kg) Davs on Test 0 7 14 21 28 I 0 100 100 100 100 100 m 5 100 100 100 100 100 V vn 50 500 100 100 100 100 100 100 100 100 100 100 Number at study start Alive on test day 27 10 10 10 10 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. pmpoty -38- TSCACBI H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 TABLE 8 SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I 0 mg/kg Group III 5 mg/kg Group V 50 mg/kg Group VII 500 mg/kg RBC (xl06//tL) DAY 28 HGB (g/dL) DAY 28 HCT (%) DAY 28 MCV (fl) DAY 28 MCH (pg) DAY 28 MCHC (g/dL) DAY 28 RDW (%) DAY 28 ARET (xlOVjiiL) DAY 28 PLT (xl03/juL) DAY 28 WBC (xl03/jU,L) DAY 28 ANEU (xlOVjtiL) DAY 28 ALYM (xlOV/tL) DAY 28 7.55 0.37(10) 15.2 0.6(10) 46.3 1.9(10) 61.3 1.4(10) 20.1 0.6(10) 32.7 0.5(10) 11.8 0.8(10) 268.2 53.4(10) 1214 97(4) 18.28 2.90(10) 2.32 0.41(10) 14.81 2.79(10) 7.36 0.41(10) 15.2 0.5(10) 45.5 1.4(10) 62.0 2.3(10) 20.7 0.8(10) 33.5* 0.4(10) 11.7 0.5(10) 235.4 36.0(10) 1170 105(6) 17.19 3.70(10) 2.48 0.46(10) 13.65 3.31(10) 7.11* 0.42(9) 14.5 0.8(9) 44,2 2.5(9) 62.3 1.8(9) 20.5 0.7(9) 32.9 0.8(9) 11.7 0.4(9) 230.6 52.0(9) 1139 67(3) 18.42 5.28(9) 2.45 0.99(9) 15.07 4.27(9) 7.38 0.34(9) 15.0 0.4(9) 45.4 1.0(9) 61.5 2.3(9) 20.3 0.8(9) 33.0 0.3(9) 11.4 0.3(9) 219.1 45.3(9) 1095 108(3) 14.84 1.93(9) 2.18 0.57(9) 11.77 1.40(9) -39- pmpany Sanitized. Dees not contain TSCACBi H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 TABLE 8 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I Omg/kg Group in 5 mg/kg Group V 50 mg/kg Group VH 500 mg/kg AMON (xl03//tL) DAY 28 AEOS (xlOV/iL) DAY 28 ABAS (xl03//tL) DAY 28 ALUC (xl03//xL) DAY 28 0.52 0.13(10) 0.21 0.13(10) 0.21 0.07(10) 0.21 0.07(10) 0.47 0.21(10) 0.25 0.17(10) 0.15 0.04(10) 0.19 0.08(10) 0.43 0.24(9) 0.13 0.06(9) 0.16 0.09(9) 0.18 0.11(9) 0.40 0.09(9) 0.17 0.12(9) 0.17 0.09(9) 0.15 0.06(9) Data arranged as: Mean Standard deviation (Number o f values included in calculation) * Statistically significant difference from control at p < 0.05 by Dunnett/Tamhane-Dunnett test. Sonpany Sanitized. Does not contain TSCACBl -40- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11763 TABLE 9 SUMMARY OF COAGULATION VALUES FOR MALE RATS Group I Group HI Group V Group VH _________ Omg/kg_______ 5 mg/kg________ 50 mg/kg_______ 500 mg/kg PT (seconds) DAY 28 APTT (seconds) DAY 28 15.7 0.8(9) 20.0 1.5(9) 15.2 0.6( 10) 18.8 1.7(10) 15.2 0.3(10) 18.9 2 .0( 10) 15.3 0.7(10) 18.4 1.9(10) Data arranged as: Mean Standard deviation (Number o f values included in calculation) There were no statistically significant differences from control at p < 0.05. pmpany SanRizod. D oes not contain TSCA CBI -41 - H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11763 TABLE 10 SUMMARY OF CLINICAL CHEMISTRY VALUES FOR MALE RATS Group I 0 mg/kg Group HI 5 mg/kg Group V 50 mg/kg Group VII 500 mg/kg AST (U/L) DAY 28 ALT (U/L) DAY 28 SDH (U/L) DAY 28 ALKP (U/L) DAY 28 BILI (mg/dL) DAY 28 BUN (mg/dL) DAY 28 CREA (mg/dL) DAY 28 CHOL (mg/dL) DAY 28 TRIG (mg/dL) DAY 28 GLUC (mg/dL) DAY 28 TP (g/dL) DAY 28 ALB (g/dL) DAY 28 114 18(10) 49 7(10) 14.6 3.5(10) 193 33(10) 0.10 0.03(10) 15 2(10) 0.29 0.03(10) 56 5(10) 44 14(10) 87 10(10) 6.4 0.3(10) 4.1 0.2(10) 124 27(10) 53 12(10) 13.0 4.8(10) 204 33(10) 0.09 0.03(10) 15 2(10) 0.33 0.05(10) 56 8(10) 49 15(10) 95 24(10) 6.5 0.3(10) 4.2 0.1(10) 116 18(10) 48 11(10) 11.1 6.6(10) 170 37(10) 0.07 0.03(10) 14 1(10) 0.29 0.06(10) 48 10(10) 39 10(10) 104@ 20(10) 6.3 0.4(10) 4.1 0.2(10) 118 52(9) 53 27(9) 13.6 8.6(10) 207 53(9) 0.07 0.03(9) 15 1(10) 0.28 0.05(10) 40* 14(10) 26* 6(9) 98 15(10) 6.4 0.4(9) 4.3 0.2(9) - 4 2 - contain TSCACW S_aniillzed.De H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 TABLE 10 (Continued) SUMMARY OF CLINICAL CHEMISTRY VALUES FOR MALE RATS Group I 0 mg/kg Group HI 5 mg/kg Group V 50 mg/kg Group VII 500 mg/kg GLOB (g/dL) DAY 28 CALC (mg/dL) DAY 28 IPHS (mg/dL) DAY 28 NA (mmol/L) DAY 28 K (mmol/L) DAY 28 o- CL (mmol/L) DAY 28 PFLU (/xg/mL) DAY 28 2.3 0.3(10) 11.1 0.5(10) 9.7 0.7(10) 148.5 2.1(10) 6.40 0.28(10) 100.4 2.1(10) 0.1 0.1(10) 2.3 0.2(10) 11.1 0.5(10) 9.4 1.0(10) 148.4 2.0(10) 6.31 0.46(10) 100.4 1.8(10) 0.0 0.0(10) 2.2 0.3(10) 10,9 0.3(10) 10.1 0.8(10) 148.0 1.7(10) 6.63 0.59(10) 101.3 3.3(10) 0.0 0.0(10) 2.2 0.3(9) 10.8 0.4(10) 9.4 0.6(9) 148.8 2.6(10) 6.29 0.34(9) 101.5 3.0(10) 0.1 0.0(10) Data arranged as: Mean Standard deviation (Number o f values included in calculation) * Statistically significant difference from control at p < 0.05 by Durmett/Tamhane-Dunnett test. @ Statistically significant difference from control at p < 0.05 by Dunn's test. Does not contain T5CACBI l^ppany. Sanitized. -43 - H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11763 TABLE 11 SUMMARY OF URINALYSIS VALUES FOR MALE RATS Group I 0 mg/kg Group HI 5 mg/kg Group V 50 mg/kg Group VH 500 mg/kg VOL (mL) DAY 28 UOSM (mOsm) DAY 28 pH DAY 28 URO (EU/dL) DAY 28 UFLU (ng) DAY 28 UMTP (mg/dL) DAY 28 9.1 5.7(10) 1161 771(10) 7.0 0.3(10) 0.4 0.3(10) 9.5 2.8(10) 72 58(10) 12.8 5.5(10) 704 390(10) 7.1 0.2(10) 0.3 0.3(10) 13.3 4.1(10) 36 32(10) 6.7 2.9(10) 1291 699(10) 6.9 0.3(10) 0.4 0.3(10) 23.0@ 3.9(10) 62 35(10) 10.1 7.6(10) 1235 1099(10) 7.0 0.6(10) 0.2 0.0(10) 147.2@ 40.3(9) 70 88(10) Data arranged as: Mean Standard deviation (Number o f values included in calculation) @ Statistically significant difference from control at p < 0.05 by Dunn's test. sm...panx"Sanitized. Des not contain TSCACBl -44- /) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) TABLE 12 MEAN FINAL BODY AND ORGAN WEIGHTS FROM MALE RATS Group: Dosage(mg/kg) LIVER KIDNEYS HEART SPLEEN BRAIN THYMUS ADRENAL GLANDS TESTES EPIDIDYMIDES FINAL BODY WEIGHT I 0 10.105 0.938(10) 2.946 0.251(10) 1.295 0.113(10) 0.711 0.107(10) 2.053 0.127(10) 0.490 0.129(10) 0.058 0.013(10) 3.223 0.271(10) 1.035 0.104(10) 331.200 17.305(10) III 5 10.318 0.933(10) 2.948 0.296(10) 1.267 0.108(10) 0.672 0.083 (10) 2.021 0.129(10) 0.487 0.129(10) 0.066 0.021(10) 3.226 0.171(10) 1.114 0.124(10) 332.660 23.298(10) V 50 10.612 1.090(10) 3.119 0.385(10) 1.290 0.085(10) 0.681 0.100(10) 2.010 0.067(10) 0.502 0.134(10) 0.066 0.013(10) 3.231 0.147(10) 1.079 0.131(10) 334.530 15.817(10) VII 500 12.440# 1.439(10) 3.165# 0.239(10) 1.291 0.191(10) 0.641 0.082(10) 1.994 0.097(10) 0.470 0.144(10) 0.064 0.015(10) 3.319 0.199(10) 1.110 0.115(10) 330.400 27.176 (10) ) DuPont-11763 not contain tsca CBS -45- ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) TABLE 12 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FROM MALE RATS Group: Dosage(mg/kg) LIVER/ FINAL BODY * 100 KIDNEYS/ FINAL BODY * 100 HEART/ FINAL BODY * 100 SPLEEN/ FINAL BODY * 100 BRAIN/ FINAL BODY * 100 THYMUS/ FINAL BODY * 100 ADRENAL GLANDS/ FINAL BODY * 100 TESTES/ FINAL BODY * 100 EPIDIDYMIDES/ FINAL BODY * 100 MEAN RELATIVE ORGAN WEIGHTS (% of body weights)) I III V 0 5 50 VII 500 3.049 0.200(10) 3.100 0.145(10) 3.169 0.244(10) 3.762# 0.247 (10) 0.889 0.056(10) 0.887 0.069(10) 0.932 0.102(10) 0.960# 0.053(10) 0.391 0.026(10) 0.383 0.041(10) 0.386 0.018(10) 0.390 0.037(10) 0.215 0.031(10) 0.202 0.021(10) 0.203 0.028(10) 0.194 0.020(10) 0.621 0.050(10) 0.610 0.051(10) 0.602 0.027(10) 0.607 0.051(10) 0.148 0.042(10) 0.146 0.035(10) 0.150 0.036(10) 0.141 0.038(10) 0.017 0.003(10) 0.020 0.005(10) 0.020 0.003(10) 0.019 0.004(10) 0.977 0.107 (10) 0.973 0.066(10) 0.968 0.067 (10) 1.008 0.058(10) 0.313 0.035(10) 0.337 0.045 (10) 0.323 0.044(10) 0.336 0.022 (10) ) DuPont-11763 tym p an y Sanitized. D oes not contain TSCA CBt -46- CBI ggppanjr Sanitized. Does not contain ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) TABLE 12 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FROM MALE RATS MEAN RELATIVE ORGAN WEIGHTS (% organ to brain weight ratio) Group: Dosage(mg/kg) I III V VII 0 5 50 500 LIVER/ BRAIN * 100 493.449 47.874(10) 511.669 47.093(10) 527.149 40.362(10) 624.487# 72.011(10) KIDNEYS/ BRAIN * 100 143.797 12.163(10) 145.990 12.343(10) 154.858 15.237(10) 158.852# 11.286(10) HEART/ BRAIN * 100 63.230 6.054(10) 62.870 5.687(10) 64.207 4.258(10) 64.917 10.429(10) SPLEEN/ BRAIN * 100 34.590 4.275(10) 33.295 4.078(10) 33.803 4.305(10) 32.179 4.005(10) THYMUS/ BRAIN * 100 23.964 6.732(10) 24.019 5.716(10) 24.924 6.219(10) 23.573 7.383(10) ADRENAL GLANDS/ BRAIN * 100 2.806 0.538(10) 3.244 0.916(10) 3.261 0.546(10) 3.203 0.656(10) TESTES/ BRAIN * 100 157.323 13.681(10) 160.200 12.794(10) 160.726 5.677(10) 166.692 10.991(10) EPIDIDYMIDES/ BRAIN * 100 Data summarized as: 50.505 5.123(10) Mean Standard Deviation (n). 55.246 6.092(10) 53.622 5.625(10) # Statistically significant difference at p < 0.05 by Jonckheere-Terpstra trend test. 55.773 6.045(10) -47- ') DuPont-11763 Smpanf Sanitized, Poes not contain TSC CB ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) TABLE 13 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS DuPont-11763 LESIONS | LESION INCIDENCE (Numeric) TREATMENT 0 5 50 500 mg/kg mg/kg mg/kg mg/kg I III V VII LIVER NO ABNORMALITY DETECTED FOCI, DARK, FEW. KIDNEYS NO ABNORMALITY DETECTED DILATATION, PELVIS, RIGHT. DILATATION, RIGHT, PELVIS. LUNGS NO ABNORMALITY DETECTED HEART NO ABNORMALITY DETECTED SKELETAL MUSCLE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 GO) 10 (10) 10 GO) 10 (10) 9 1 (10) 8 1 1 (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 -48- > H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) > DuPont-11763 LESIONS TABLE 13 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS TREATMENT LESIOIi INCIDI3NCE (Nimeric) 0 5 50 500 mg/kg mg/kg mg/kg mg/kg I III V VII SPLEEN NO ABNORMALITY DETECTED AORTA NO ABNORMALITY DETECTED BRAIN NO ABNORMALITY DETECTED SPINAL CORD NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified Company Sanitized. D oes not contain TSGA CBI -49- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats TABLE 13 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS DuPont-11763 LESIONS TREATMENT LESIOlJ INCIDIINCE (Nirmeric) 0 5 50 500 mg/kg mg/kg mg/kg mg /kg I III V VII IBOM'JV* JEJUNUM is, NO ABNORMALITY DETECTED *< ILEUM s$39i. NO ABNORMALITY DETECTED PANCREAS NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED RECTUM NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 GO) 10 (10) 10 GO) 10 (10) 10 GO) 10 (10) 10 (10) 10 (10) 10 GO) 10 (10) 10 (10) 10 GO) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified -50- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats TABLE 13 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS DuPont-11763 LESIONS | LESION INCIDENCE (Numeric) TREATMENT 0 5 50 500 mg /kg mg /kg mg/kg mg/kg I III V VII MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED SALIVARY GLANDS NO ABNORMALITY DETECTED MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 GO) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified SanR&ced. Does notcontain TSCA CBf -51 - ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________________________ ) ___________________________________________________ TABLE 13 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS ) DuPont-11763 LESIONS | LESION INCIDENCE (Numeric) TREATMENT 0 5 50 500 mg/kg mg/kg mg/kg mg/kg I III V VII PITUITARY GLAND (10) (10) (10) (10) NO ABNORMALITY DETECTED 10 10 10 10 THYROID GLAND (10) (10) (10) (10) NO ABNORMALITY DETECTED 10 10 10 10 PARATHYROID GLANDS (10) (10) (10) (10) NO ABNORMALITY DETECTED 10 10 10 10 TRACHEA (10) (10) (10) (10) NO ABNORMALITY DETECTED 10 10 10 10 ESOPHAGUS (10) (10) (10) (10) NO ABNORMALITY DETECTED 10 10 10 10 o> ow PHARYNX/LARYNX NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified -52- ))) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ___________________________________________________________________ ___________ ___________________ DuPont-11763 TABLE 13 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS pees noi contain TSCA CBI LESIONS TREATMENT LESIO1 INCIDI3NCE (Nrimeric) 0 5 50 500 mg/kg mg/kg mg/kg mg/kg I III V VII EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED SKIN NO ABNORMALITY DETECTED PROSTATE NO ABNORMALITY DETECTED SEMINAL VESICLES NO ABNORMALITY DETECTED URINARY BLADDER NO ABNORMALITY DETECTED TESTES NO ABNORMALITY DETECTED (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified -53- ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) TABLE 13 (CONTINUED) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS ) DuPont-11763 LESIONS | LESION INCIDENCE (Numeric) TREATMENT 0 5 50 500 mg/ kg mg/kg mg /kg mg/kg I III V VII EPIDIDYMIDES NO ABNORMALITY DETECTED FEMUR/KNEE JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED POPLITEAL LYMPH NODE LARGE, DARK. DISCOLORATION, DARK,. RIGHT. (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) (10) 10 10 (10) (10) 10 10 (10) (10) 10 10 (10) (10) 10 , 10 (1) (1) 1 1 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified jjC&fflpany Sanitized. D oes not contain TSCA CBf -54- ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats )) ________________________________________________________DuPont-11763 TABLE 14 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS LESIONS TREATMENT LESION INCIDENCE (NUMERIC) Males 0 5 50 500 mg /kg mg/kg mg/kg mg/kg I III V VII DIGESTIVE SYSTEM LIVER NO ABNORMALITY DETECTED NECROSIS, HEPATOCELLULAR, FOCAL. minimal total observations per lesion INFLAMMATION, SUBACUTE/CHRONIC, FOCAL. minimal total observations per lesion HEMORRHAGE, FOCAL. minimal total observations per lesion (10) 1 9 9 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 1 1 10 10 1 1 jgOffipang; Sanitised. Does not contain TSCACBf -55- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11763 TABLE 14 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS LESIONS TREATMENT LESION INCIDENCE (NUMERIC) Males 0 5 50 500 mg/kg mg/kg mg/kg mg/kg I III V VII a,* o. m 3. CT O % 3 DIGESTIVE SYSTEM PANCREAS NO ABNORMALITY DETECTED (10) 10 ESOPHAGUS NO ABNORMALITY DETECTED (10) 10 STOMACH NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 (10) 10 (10) 10 H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11763 TABLE 14 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS LESIONS TREATMENT LESION INCIDENCE (NUMERIC) Males 0 5 50 500 mg /kg mg/kg mg/kg mg/kg I III V VII DIGESTIVE SYSTEM DUODENUM NO ABNORMALITY DETECTED (10) 10 JEJUNUM NO ABNORMALITY DETECTED (10) 10 ILEUM NO ABNORMALITY DETECTED (10) 10 to>o Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified o (10) 10 (10) 10 (10) 10 Does not contain ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) > DuPont-11763 TABLE 14 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS jPgmpany Sanitized. Des noi contain TSC CBf LESIONS TREATMENT LESION INCIDENCE (NUMERIC) Males 0 5 50 500 mg /kg mg/kg mg/kg mg/kg I III V VII DIGESTIVE SYSTEM CECUM NO ABNORMALITY DETECTED (10) 10 COLON NO ABNORMALITY DETECTED (10) 10 RECTUM NO ABNORMALITY DETECTED (10) 10 SALIVARY GLANDS NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 (10) 10 (9) 9 (10) 10 -58- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11763 TABLE 14 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS LESIONS TREATMENT LESION INCIDENCE (NUMERIC) Males 0 5 50 500 mg/kg mg/kg mg /kg mg/kg I III V VII if a. s%ooa 3 Oa i.S URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED CHRONIC PROGRESSIVE NEPHROPATHY. minimal total observations per lesion DILATATION, PELVIS, UNILATERAL. mild total observations per lesion (10) 4 6 6 URINARY BLADDER NO ABNORMALITY DETECTED GO) 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 -59- (10) 5 5 5 2 2 (10) 10 H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11763 TABLE 14 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS LESIONS TREATMENT LESION INCIDENCE (NUMERIC) Males 0 5 50 500 mg/kg mg /kg mg/kg mg/kg I III V VII afit o % 9 %Oo SL . 3 o4 > o RESPIRATORY SYSTEM LUNGS NO ABNORMALITY DETECTED PNEUMONITIS, ACUTE, FOCAL. minimal total observations per lesion HEMORRHAGE, ALVEOLAR, FOCAL. minimal total observations per lesion (10) 8 1 1 1 1 TRACHEA NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified -60- GO) 9 1 1 (10) 10 ') H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) ) DuPont-11763 TABLE 14 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS LESIONS TREATMENT LESION INCIDENCE (NUMERIC) Males 0 5 50 500 mg/kg mg /kg mg/kg mg /kg I III V VII RESPIRATORY SYSTEM PHARYNX/LARYNX NO ABNORMALITY DETECTED (10) 10 NOSE NO ABNORMALITY DETECTED METAPLASIA, SQUAMOUS, EPITHELIUM. mild total observations per lesion INFLAMMATION, ACUTE, EPITHELIAL. minimal total observations per lesion (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 mo> o S -61- (10) 10 (10) 10 S90Q H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11763 TABLE 14 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS LESIONS TREATMENT LESION INCIDENCE (NUMERIC) Males 0 5 50 500 mg /kg mg/kg mg/kg mg/kg I III V VII gpmpany Sanitized. Does not contain CARDIOVASCULAR SYSTEM HEART NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, FOCAL. minimal total observations per lesion DEGENERATION, MYOFIBER, FOCAL. minimal total observations per lesion (10) 7 1 1 3 3 AORTA NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 0* o> oOS -62- (10) 7 3 3 (10) 10 H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11763 TABLE 14 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS LESIONS TREATMENT LESION INCIDENCE (NUMERIC) Males 0 5 50 500 mg /kg mg /kg mg/kg mg/kg I III V VII LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED (10) 10 THYMUS NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 GO) 10 i a o J S x ^ . 6 a e oe W W a i -63- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11763 TABLE 14 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS LESIONS TREATMENT LESION INCIDENCE (NUMERIC) Males 0 5 50 500 mg/kg mg/kg mg/kg mg /kg I III V VII LYMPHATIC AND HEMATOPOIETIC SYSTEM MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED HYPERPLASIA, LYMPHOCYTE/PLASMACYTE. minimal mild total observations per lesion ERYTHROCYTOSIS/ERYTHROPHAGOCYTOSIS. minimal mild total observations per lesion (10) 1 2 1 3 7 1 8 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 2 5 5 3 2 5 gompang Sanitized. Does not contain TSCACBi - 64- ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats )) ________________________ DuPont-11763 TABLE 14 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS LESIONS TREATMENT LESION INCIDENCE (NUMERIC) Males 0 5 50 500 mg/kg mg/kg mg/kg mg/kg I III V VII LYMPHATIC AND HEMATOPOIETIC SYSTEM MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED ERYTHROCYTOSIS/ERYTHROPHAGOCYTOSIS. minimal total observations per lesion (10) 10 POPLITEAL LYMPH NODE HYPERPLASIA, LYMPHOCYTE/PLASMACYTE. mild total observations per lesion BONE MARROW NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 9 1 1 (1) 1 1 (10) 10 Sanitized. D oes not contain TSC CBI -65- ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) ) DuPont-11763 TABLE 14 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS LESIONS TREATMENT LESION INCIDENCE (NUMERIC) Males 0 5 50 500 mg /kg mg/kg mg/kg mg/kg I III V VII ENDOCRINE SYSTEM PITUITARY GLAND m NO ABNORMALITY DETECTED I THYROID GLAND NO ABNORMALITY DETECTED (10) 10 (10) 10 contain TSCA CBI PARATHYROID GLANDS NO ABNORMALITY DETECTED (7) 7 ADRENAL GLANDS NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 (10) 10 (10) 10 (10) 10 -66- > H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) ) DuPont-11763 TABLE 14 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS LESIONS TREATMENT LESION INCIDENCE (NUMERIC) Males 0 5 50 500 mg /kg mg/kg mg /kg mg /kg I III V VII NERVOUS SYSTEM BRAIN NO ABNORMALITY DETECTED (10) 10 SPINAL CORD NO ABNORMALITY DETECTED (10) 10 SCIATIC NERVE NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 (10) 10 (10) 10 Company Sanitized. Does not contain TSCA CBf - 6 7- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11763 TABLE 14 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS LESIONS TREATMENT LESION INCIDENCE (NUMERIC) Males 0 5 50 500 mg/kg mg /kg mg/kg mg/kg I III V VII not contain TSCA CBI MUSCULAR AND SKELETAL SYSTEM SKELETAL MUSCLE NO ABNORMALITY DETECTED GO) 10 FEMUR/KNEE JOINT NO ABNORMALITY DETECTED (10) 10 STERNUM NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 (10) 10 (10) 10 'ftaji|Saijitged, Does not contain TSCA CBf ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) ) DuPont-11763 TABLE 14 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS LESIONS TREATMENT LESION INCIDENCE (NUMERIC) Males 0 5 50 500 mg /kg mg/kg mg /kg mg/kg I III V VII REPRODUCTIVE SYSTEM TESTES NO ABNORMALITY DETECTED (10) 10 EPIDIDYMIDES NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal total observations per lesion (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 (10) 9 1 1 - 69- Gottlpatty Sanitized. Does not contain TsnA CB )) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_________________________________________________________________________________________________________ DuPont-11763 TABLE 14 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS LESIONS TREATMENT LESION INCIDENCE (NUMERIC) Males 0 5 50 500 mg /kg mg/kg mg/kg mg/kg I III V VII REPRODUCTIVE SYSTEM PROSTATE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal total observations per lesion (10) 8 2 2 SEMINAL VESICLES NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified GO) 10 (10) 10 -70- Company Sanitized. Does not contain TSCA CBI H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11763 TABLE 14 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS LESIONS TREATMENT LESION INCIDENCE (NUMERIC) M ales 0 m g/kg I 5 m g/kg III 50 m g/kg V 500 m g/kg V II CUTANEOUS SYSTEM SKIN NO ABNORMALITY DETECTED (10) 10 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 -71 - Company Sanitized. Does not contain TSCA CBI ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) ____ _____ ___ > DuPont-11763 TABLE 14 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS LESIONS TREATMENT LESION INCIDENCE (NUMERIC) Males 0 5 50 500 mg/kg mg/ kg mg /kg mg /kg I III V VII SPECIAL SENSES SYSTEM EYE(S ) WITH OPTIC NERVE NO ABNORMALITY DETECTED OPTIC NERVE NOT PRESENT. (10) 10 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified (10) 10 - 72- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 FIGURES ponpany Sanitized. Does notco** `rer^CBI -73 - H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ FIGURE 1 MEAN BODY WEIGHTS OF MALE RATS DuPont-11763 Omg/kg --B --5 mg/kg A 50 mg/kg - X - 500 mg/kg Company Sanitized. Does not coot* Te5r`A H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 APPENDICES jpmpany Sanitized. Does not contain t s o a CBl H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 APPENDIX A Individual Body Weights .D o es not contain TSCACBt Company Saniti*1 -76- s o jPgpipany Sanitized. Does not conta* T<5rA OBI ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______ ) ) DuPont-11763 Individual Body Weights Body Weight Body Weight Body Weight Body Weight Body Weight Body Weight Body Weight Body Weight Body Weight ggggggggg Day 0 Day 3 Day 7 Day 10 Day 14 Day 17 Day 21 Day 24 Day 27 Male, I 667165 667166 667167 667168 667169 667170 667171 667172 667173 667174 232.1 244.6 234.2 239.3 238.9 245.2 231.3 244.1 237.2 256.5 235.0 263.4 254.3 261.0 257.1 271.6 251.4 270.4 248.1 278.0 273.0 292.5 281.7 284.8 294.6 299.5 271.5 297.0 281.7 304.7 289.1 296.6 297.5 302.2 308.2 318.8 286.4 315.9 298.0 318.5 305.9 309.2 317.3 313.6 334.8 337.2 300.6 325.4 313.0 343.9 307.1 321.4 330.4 319.8 337.7 350.4 313.5 343.7 320.7 353.1 336.3 329.9 346.4 335.7 367.0 366.8 327.7 345.0 331.6 372.9 347.3 343.1 353.0 350.4 372.3 383.8 341.3 359.2 337.8 379.2 355.8 351.0 363.6 349.0 390.6 385.4 349.1 368.3 347.3 383.0 Body Weight g Day 28 Male, I 0 mg/kg 667165 667166 667167 667168 667169 667170 667171 667172 667173 667174 313.9 328.5 327.9 319.2 352.3 354.1 313.8 335.5 311.8 355.0 -77- ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats /) J) DuPont-11763 Individual Body Weights Body Weight Body Weight Body Weight Body Weight Body Weight Body Weight Body Weight Body Weight Body Weight gggg ggggg Day 0 Day 3 Day 7 Day 10 Day 14 Day 17 Day 21 Day 24 Day 27 Male, III 5 mg/kg 667175 667176 667177 667178 667179 667180 667181 667182 667183 667184 228.1 247.3 226.7 243.3 235.8 242.0 250.7 228.8 237.6 240.1 242.7 279.1 240.7 266.2 260.0 253.8 277.7 247.4 246.8 259.2 269.9 309.9 276.2 297.2 296.9 278.1 315.1 280.5 264.9 288.7 283.4 328.3 293.2 318.1 315.2 294.4 326.9 296.0 276.7 303.0 291.9 347.5 316.2 347.0 338.0 310.9 353.4 307.3 303.0 329.9 317.5 356.0 330.2 355.2 351.2 315.9 354.2 317.4 310.1 344.9 316.1 366.8 344.1 376.5 367.1 327.6 366.0 312.1 323.3 354.5 340.5 379.5 361.2 377.9 377.4 337.3 380.0 322.0 334.1 369.4 348.5 380.9 366.6 389.2 379.9 342.0 376.5 323.7 342.7 380.0 Body Weight g Day 28 Male, III 5 mg/kg 667175 667176 667177 667178 667179 667180 667181 667182 667183 667184 306.8 351.4 339.2 353.7 347.4 308.1 363.3 303.8 307.6 345.3 3O 8 aSi 5" O> o S Company Sanitized. Does -78- ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_______ ) ) DuPont-11763 Individual Body Weights Body Weight Body Weight Body Weight Body Weight Body Weight Body Weight Body Weight Body Weight Body Weight ggggggg gg Day 0 Day 3 Day 7 Day 10 Day 14 Day 17 Day 21 Day 24 Day 27 Male, V 50 mg/kg 667185 667186 667187 667188 667189 667190 667191 667192 667193 667194 228.9 247.1 235.8 250.3 239.6 244.0 234.6 242.0 246.9 248.1 248.3 262.9 243.8 266.6 261.7 261.8 251.3 255.9 259.3 263.4 267.0 287.3 270.1 304.0 289.5 298.0 288.9 282.6 289.6 294.3 278.0 299.8 281.4 321.3 318.2 311.3 306.4 299.7 309.5 292.3 296.7 313.8 293.8 347.2 342.3 333.9 329.6 321.4 330.7 302.4 303.8 319.3 309.3 357.1 351.6 340.5 336.5 330.9 346.2 328.2 316.5 320.5 324.4 361.8 359.5 352.2 353.7 348.7 359.2 323.1 331.2 332.8 342.0 370.3 367.6 364.8 361.2 364.2 372.0 336.0 335.1 337.4 344.0 379.6 380.4 366.6 370.5 368.5 383.0 349.9 Body Weight 9 Day 28 Male, V 50 mg/kg 667185 667186 667187 667188 667189 667190 667191 667192 667193 667194 308.4 315.7 330.0 350.5 351.1 335.2 352.8 330.6 348.0 323.0 fenpanx Sanitized. Does not contain TSCACBf - 79 - H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11763 Individual Body Weights Body Weight g Day 0 Male, VII 500 mg/kg Body Weight g 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 g Day 27 667195 667196 667197 667198 667199 667200 667201 667202 667203 667204 230.2 250.3 237.6 239.8 233.5 244.8 238.7 244.3 234.0 259.6 246.4 265.7 266.8 259.3 248.7 260.7 250.1 269.1 256.7 278.3 273.8 300.7 295.6 303.2 277.6 276.2 267.7 300.2 294.0 265.4 286.9 314.7 318.4 318.4 300.9 289.9 270.4 323.5 315.8 299.5 299.7 331.1 344.0 347.3 319.6 305.5 258.7 344.8 338.9 328.0 305.9 331.1 356.1 351.4 330.8 309.8 253.5 356.8 351.6 338.3 319.0 352.6 353.3 372.5 342.7 324.1 266.8 367.8 374.2 355.3 332.3 364.8 367.5 378.4 350.0 342.2 264.1 373.4 385.1 359.2 330.9 368.7 366.1 379.2 362.8 349.0 252.1 374.8 379.6 359.0 Body Weight g Day 28 Male, VII 500 mg/ 667195 667196 667197 667198 667199 667200 667201 667202 667203 667204 304.7 334.0 353.0 356.1 334.1 317.2 269.4 347.1 355.0 333.4 H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 APPENDIX B Individual Food Consumption Company Sanitized. Coes not con** Tort&CBI -81 - H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 Individual Food Consumption Food Cons. Food Cons. Food Cons. Food Cons g/anm/day g/anm/day g/anm/day g/anm/day Day 7 Day 14 Day 21 Day 27 Male, I 0 mg/kg 667165 667166 667167 667168 667169 667170 667171 667172 667173 667174 23.4 23.2 24.2 25.2 24.8 26.1 24.2 26.0 23.7 24.3 25.5 22.8 24.5 26.6 27.1 28.1 23.3 27.9 26.1 25.5 26.0 23.1 25.3 25.7 28.3 28.4 26.4 28.1 24.9 25.4 26.5 25.5 27.4 27.6 28.5 28.8 28.1 27.6 25.5 25.7 Male, III 5 mg/kg 667175 23.6 26.7 25.9 27.4 667176 27.3 26.0 24.3 27.2 667177 23.0 26.5 27.3 28.9 667178 26.5 26.3 26.6 25.9 667179 24.4 26.8 26.6 27.9 667180 23.0 24.4 24.1 26.0 667181 27.3 27.7 27.0 29.8 ! 667182 26.9 26.8 26.2 28.1 667183 20.9 23.1 23.3 24.6 667184 24.6 26.5 27.2 29.0 Male, V 50 mg/kg 667185 667186 667187 667188 667189 667190 667191 667192 667193 667194 22.7 25.9 26.2 26.5 25.6 26.6 25.6 24.2 27.3 26.6 24.2 24.7 26.9 27.3 28.8 26.9 25.6 25.9 27.0 25.7 24.8 25.7 26.1 26.1 26.9 25.5 27.4 26.9 25.8 25.6 25.5 28.7 28.9 29.4 28.5 26.1 29.3 26.2 25.8 28.4 Male, VII 500 mg/kg 667195 667196 667197 667198 667199 667200 667201 667202 667203 667204 23.8 26.3 26.9 25.3 23.4 21.3 25.1 27.4 25.1 23.0 24.1 26.0 28.3 27.5 25.9 22.5 22.2 28.4 27.2 27.3 24.9 24.4 27.2 27.8 25.8 23.7 20.9 27.8 27.7 25.8 25.0 26.1 29.5 29.2 27.8 26.5 18.0 27.4 28.6 27.3 Sanitized. D oes not contain TSCA CB1 -82- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 APPENDIX C Individual Clinical Observations and Mortality Records | ^ mpany Sanitized. Doe*notcontain TSCA CW -83- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 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. /"N Sanitized. Does not contain TSCA CBI - 84- SanStzeS. Does ftof contain TS^A CBf ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) Sex Group Animal MI 667165 MI 667166 MI 667167 MI 667168 INDIVIDUAL CLINICAL OBSERVATIONS AND MORTALITY RECORDS Observation Days General observation, No Abnormality Detected 3,7,10,14,17,21,27 Eye Observations, Opaque, Right 28 Eye Observations, Bled via Orbital for Clin Path, Right 0,7,14,21,27,28 Discharge, Eye bilateral, Red 0,28 Discharge, Eye right. Red Swollen Observations, Face 24 0 Sacrificed by design 28 General observation, No Abnormality Detected 3,7,10,14,17,21,24,27 Eye Observations, Bled via Orbital for Clin Path, Bilateral 21 Eye Observations, Bled via Orbital for Clin Path, Left 27 Eye Observations, Bled via Orbital for Clin Path, Right 0,7,14,28 Discharge, Eye bilateral, Red 0,28 Sacrificed by design 28 General observation. No Abnormality Detected 3,7,10,14,17,21,24,27,28 Eye Observations, Bled via Orbital for Clin Path, Left 21,27 Eye Observations, Bled via Orbital for Clin Path, Right Discharge, Eye bilateral, Red 0,7,14,28 0 Sacrificed by design 28 General observation, No Abnormality Detected 0,3,7,10,14,17,21,24,27 Eye Observations, Bled via Orbital for Clin Path, Bilateral 14 Eye Observations, Bled via Orbital for Clin Path, Left 21,27 Eye Observations, Bled via Orbital for Clin Path, Right 0,7,28 Discharge, Eye bilateral, Red 28 Sacrificed by design 28 - 85- ) DuPont-11763 J*flPpa*jf.Sanitized Does notcontain TSCA CB! ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) Sex Group Animal MI 667169 MI 667170 MI 667171 MI 667172 MI 667173 INDIVIDUAL CLINICAL OBSERVATIONS AND Observation General observation. No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Left Eye Observations, Bledvia Orbital for Clin Path, Right Discharge, Eye bilateral. Red Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Left Eye Observations, Bledvia Orbital for Clin Path, Right Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Left Eye Observations, Bledvia Orbital for Clin Path, Right Discharge, Eye bilateral. Red Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Left Eye Observations, Bledvia Orbital for Clin Path, Right Discharge, Eye bilateral, Red Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Left Eye Observations, Bledvia Orbital for Clin Path, Right Discharge, Eye right, Red Sacrificed by design -86- MORTALITY RECORDS Days 3,7,10,14,17,21,24,27 21,27 0,7,14,28 0,28 28 0,3,7,10,14,17,21,24,27,28 21,27 0,7,14,28 28 3,7,10,14,17,21,24,27 21,27 0,7,14,28 0,28 28 3,7,14,17,21,24,27,28 21,27 0,7,14,28 0,10 28 3,7,10,14,17,21,24,27,28 21,27 0,7,14,28 0 28 DuPont-11763 ') H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) Sex Group Animal MI 667174 INDIVIDUAL CLINICAL OBSERVATIONS AND MORTALITY RECORDS Observation Days General observation. No Abnormality Detected 0,3,7,10,14,17,21,24,27,28 Eye Observations, Bled via Orbital for Clin Path, Left 21,27 Eye Observations, Bled via Orbital for Clin Path, Right 0,7,14,28 Sacrificed by design 28 ) DuPont-11763 'Company Sanitized. Does not contain TSCA CBI -87- ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) Sex Group Animal M III 667175 M III 667176 M III 667177 M III 667178 M III 667179 INDIVIDUAL CLINICAL OBSERVATIONS AND Observation General observation. No Abnormality Detected ,* Eye Observations, Bled via Orbital for Clin Path, Left Eye Observations, Bled via Orbital for Clin Path, Right Discharge, Eye bilateral, Red Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Left Eye Observations, Bledvia Orbital for Clin Path, Right Discharge, Eye bilateral. Black Discharge, Eye bilateral, Red Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Left Eye Observations, Bledvia Orbital for Clin Path, Right Discharge, Eye bilateral, Red Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Left Eye Observations, Bledvia Orbital for Clin Path, Right Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Left Eye Observations, Bledvia Orbital for Clin Path, Right Discharge, Eye bilateral, Red Sacrificed by design .Company Sanitized. Does not contain TSCA CBf -88- MORTALITY RECORDS Days 3,7,10,14,17,21,24,27,28 21,27 0,7,14,28 0 28 3,7,10,14,17,24,27,28 21,27 0,7,14,28 21 0 28 3,7,14,17,21,24,27,28 14,21,27 0,7,28 0,10 28 0,3,7,10,14,17,21,24,27,28 14,21,27 0,7,28 28 3,7,10,14,17,21,24,27,28 14,21,27 0,7,28 0 28 DuPont-11763 ?to p a n y SanHteetf. D oes no! contain TSCA CBf ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats _____ ) Sex Group Animal M III 667180 M III 667181 M III 667182 M III 667183 M III 667184 INDIVIDUAL CLINICAL OBSERVATIONS AND Observation General observation. No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Left Eye Observations, Bledvia Orbital for Clin Path, Right Discharge, Eye bilateral, Red Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Left Eye Observations, Bledvia Orbital for Clin Path, Right Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Left Eye Observations, Bledvia Orbital for Clin Path, Right Discharge, Eye bilateral, Red Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Left Eye Observations, Bledvia Orbital for Clin Path, Right Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Left Eye Observations, Bledvia Orbital for Clin Path, Right Discharge, Eye bilateral, Red Sacrificed by design - 89- MORTALITY RECORDS Days 3,7,10,14,17,21,24,27,28 14,21,27 0,7,28 0 28 0,3,7,10,14,17,21,24,27,28 14,21,27 0,7,28 28 3,7,10,14,17,21,24,27,28 14,21,27 0,7,28 0 28 0,3,7,10,14,17,21,24,27,28 14,21,27 0,7,28 28 3,7,10,14,17,21,24,27,28 14,21,27 0,7,28 0 28 DuPont-11763 jfSpmpany Sanitized. Does not contain TSCA CB ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) Sex Group Animal MV 667185 MV 667186 MV 667187 MV 667188 INDIVIDUAL CLINICAL OBSERVATIONS AND MORTALITY RECORDS Observation Days General observation, No Abnormality Detected 3,7,14,17,21,24,27 Eye Observations, Bled via Orbital for Clin Path, Left 14,21,27 Eye Observations, Bled via Orbital for Clin Path, Right 0,7,28 Eye Observations, Dark, Right 10 Discharge, Mouth, Red Discharge, Eye right. Red 28 0 Sacrificed by design 28 General observation, No Abnormality Detected 3,7,10,14,17,21,24,27,28 Eye Observations, Bled via Orbital for Clin Path, Left 14,21,27 Eye Observations, Bled via Orbital for Clin Path, Right Discharge, Eye bilateral, Red 0,7,28 0 Sacrificed by design 28 General observation, No Abnormality Detected 3,7,10,14,17,21,24 Eye Observations, Bled via Orbital for Clin Path, Bilateral 27 Eye Observations, Bled via Orbital for Clin Path, Left 14,21 Eye Observations, Bled via Orbital for Clin Path, Right 0,7,28 Discharge, Eye bilateral. Red 0,27,28 Sacrificed by design 28 General observation, No Abnormality Detected 0,3,7,10,14,17,21,24,27,28 Eye Observations, Bled via Orbital for Clin Path, Left 14,21,27 Eye Observations, Bled via Orbital for Clin Path, Right 0,7,28 Sacrificed by design 28 ) DuPont-11763 -90- fPsMipanjr Sanitized. Does not contain TSCA CBi ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) Sex Group Animal MV 667189 MV 667190 MV 667191 MV 667192 INDIVIDUAL CLINICAL OBSERVATIONS AND Observation General observation, No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Eye Observations, Bled via Orbital for Clin Path, Right Discharge, Eye bilateral. Red Wound, Superficial, Shoulder, Left Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Left Eye Observations, Bledvia Orbital for Clin Path, Right Discharge, Eye bilateral, Red Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Left Eye Observations, Bledvia Orbital for Clin Path, Right Discharge, Eye bilateral, Red Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Left Eye Observations, Bledvia Orbital for Clin Path, Right Discharge, Eye bilateral. Red Discharge, Eye right. Red Sacrificed by design -91. MORTALITY RECORDS Days 3,7,10,17,21,28 14.21.27 0,7,28 0,14 24.27 28 3,7,10,14,17,21,24,27,28 14,21,27 0,7,28 0 28 3,7,10,14,17,21,24,27,28 14,21,27 0,7,28 0 28 3.7.10.14.17.21.24.27 14.21.27 0,7,28 0 28 28 DuPont-11763 ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ') Sex Group Animal MV 667193 MV 667194 INDIVIDUAL CLINICAL OBSERVATIONS AND MORTALITY RECORDS Observation Days General observation, No Abnormality Detected 0,3 Eye Observations, Bled via Orbital for Clin Path, Left 14,21,27 Eye Observations, Bled via Orbital for Clin Path, Right 0,7,28 Hair Loss, Forelimb, Bilateral 7,10,14,17,21,24,27,28 Sacrificed by design 28 General observation, No Abnormality Detected 3,7,10,14,17,21,24,27 Eye Observations, Bled via Orbital for Clin Path, Left 14,21,27 Eye Observations, Bled via Orbital for Clin Path, Right 0,7,28 Eye Observations, Dark, Left Discharge, Eye bilateral, Red 28 0 Sacrificed by design 28 MmS 1. fs. ho<m0 ) DuPont-11763 not contata TSCA tD -92- ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) Sex Group Animal M VII 667195 M VII 667196 M VII 667197 M VII 667198 M VII 667199 INDIVIDUAL CLINICAL OBSERVATIONS AND Observation General observation, No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Left Eye Observations, Bledvia Orbital for Clin Path, Right Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Left Eye Observations, Bledvia Orbital for Clin Path, Right Discharge, Eye bilateral. Red Discharge, Nose, Red Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Left Eye Observations, Bledvia Orbital for Clin Path, Right Discharge, Eye bilateral. Red Swollen Observations, Face Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Left Eye Observations, Bledvia Orbital for Clin Path, Right Discharge, Eye bilateral. Red Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Left Eye Observations, Bledvia Orbital for Clin Path, Right Sacrificed by design gkmpany Sanitized. Does not contain TSCACB -93- MORTALITY RECORDS Days 0,3,7,10,14,17,21,24,27,28 21.27 0,7,14,28 28 3.7.10.14.17.21.24.27.28 14.21.27 0,7,28 0 0 28 3.7.10.17.21.24.27.28 14.21.27 0,7,28 0,14 0 28 3,7,10,14,17,21,24,27,28 14,21,27 0,7,28 0 28 0,3,7,10,14,17,21,24,27,28 14,21,27 0,7,28 28 DuPont-11763 ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) Sex Group Animal M VII 667200 M VII 667201 M VII 667202 M VII 667203 M VII 667204 INDIVIDUAL CLINICAL OBSERVATIONS AND MORTALITY RECORDS Observation Days General observation, No Abnormality Detected 3,7,10,14,17,21,24,28 Eye Observations, Bled via Orbital forClinPath, Left 14,21,27 Eye Observations, Bled via Orbital forClinPath, Right 0,7,28 Discharge, Eye bilateral. Red Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bled via Orbital forClinPath, Left Eye Observations, Bled via Orbital forClinPath, Right Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bled via Orbital forClinPath, Bilateral Eye Observations, Bled via Orbital forClinPath, Left Eye Observations, Bled via Orbital forClinPath, Right Discharge, Eye bilateral. Red 0,27 28 0,3,7,10,14,17,21,24,27,28 14,21,27 0,7,28 28 3,7,10,14,17,21,24,27,28 7 14,21,27 0,28 0 Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Eye Observations, Bled via Orbital for Clin Path, Right Discharge, Eye bilateral. Red Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital forClinPath, Left Eye Observations, Bled via Orbital forClinPath, Right Eye Observations, Dark, Right Discharge, Eye bilateral, Red Sacrificed by design 28 3,7,10,14,17,21,27,28 14,21,27 0,7,28 0,24 28 3,7,10,14,17,21,27 14,21,27 0,7,28 28 0,24 28 ) DuPont-11763 Sjrpmpany Sanitized. Does not contain TSCA CBI -94- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11763 APPENDIX D Individual Clinical Observations - Post-Dosing SPpmpany Sanitized. Does not contain TSCA CBf -95- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 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. D oes not contain TSCA CBi -96- Company Sanitized. Does not contain TSCACBI ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ ) INDIVIDUAL CLINICAL OBSERVATIONS - POST-DOSING Sex Group Animal Observation Days MI 667X65 General observation, No Abnormality Detected 0,3,5-6,7-8, 10,12,16,17-20, 21 Discharge, Eye bilateral. Red 1-2,9,11,13, 14-15,24-26,27 Discharge, Eye right, Red 22-23 Swollen Observations, Face 4,27 MI 667166 General observation, No Abnormality Detected 0,3-6,7-9, 10-13,14-15, 17-20,21,24,27 Discharge, Eye bilateral. Red 16,22-23,25-26 Discharge, Eye right, Red 1-2 MI 667167 General observation, No Abnormality Detected 0,3-6,7-9, 10-13,14-16, 18-20,21-23, 24-26,27 Discharge, Eye bilateral. Red 1-2,17 MI 667168 General observation, No Abnormality Detected 0-2,3-6, 7-9,10-13, 14-16,18-20, 21-23,24-26,27 Discharge, Eye bilateral. Red 17 MI 667169 General observation, No Abnormality Detected 0,3,5-6,8,10, 12-13,14,17-20 Discharge, Eye bilateral, Black 27 Discharge, Eye bilateral, Red 1-2,4,7,9,11, 15-16,21-23, 24-26 MI 667170 General observation, No Abnormality Detected 0-2,3-6, 8-9,10-13, 14-16,17-20, 21-22,24-25,27 Discharge, Eye bilateral. Red 7,23,26 -97- DuPont-11763 ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats __________ ) INDIVIDUAL CLINICAL OBSERVATIONS - POST-DOSING Sex Group Animal Observation Days MI 667171 General observation, No Abnormality Detected 0,3-6,10-12, 17-20 Discharge, Eye bilateral, Red 1-2,7-9,13, 14-16,21-23, 24-26,27 Discharge, Nose, Red 2 MI 667172 General observation. No Abnormality Detected 0,3,5-6,10, 12-13,14-16,17, 19-20,21-23, 24-26,27 Discharge, Eye bilateral, Red 1-2,4,7-9, 11,18 MI 667173 General observation, No Abnormality Detected 0,3,5-6,10-13, 15-16,17-20, 24-25 Discharge, Eye bilateral, Red 1-2,4,7-9, 21-23,26,27 Discharge, Eye right, Red 14 MI 667174 General observation, No Abnormality Detected 0,2,3-6,7-9, 10-13,14,16,17, 19-20,21-23, 24-26,27 Discharge, Eye bilateral. Red 1,15,18 > DuPont-11763 Sanitized. Does notcontain TSCA CBI -98- ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) Sex Group Animal M III 667175 M III 667176 M III 667177 M III 667178 M III 667179 M III 667180 INDIVIDUAL CLINICAL OBSERVATIONS -- POST-DOSING Observation Days General observation, No Abnormality Detected 0,3-6,8-9, 10,13,17,19-20 Discharge, Eye bilateral, Red 1-2,7,11-12, 14-16,18,21-23, 24-26,27 General observation, No Abnormality Detected 0-2,3,5-6, 7-8,10-13, 14,16,19-20 Discharge, Eye bilateral. Red 4,9,15,17-18, 21-23,24-26, 27 General observation. No Abnormality Detected 0,3,5-6,10, 12-13,14,17-20, 21-23,24-25, 27 Discharge, Eye bilateral, Red 1-2,4,7-9, 11,15-16,26 General observation, No Abnormality Detected 0,3,5-6,8-9, 10-13,14-16, 17-20,21-23, 24-26,27 Discharge, Eye bilateral, Red 4,7 Discharge, Eye right, Red 1-2 General observation, No Abnormality Detected 0,3,5-6,7-8, 10-11,13,14-16, 18-20,21,23,24 Discharge, Eye bilateral. Red 1-2,4,9,12,17, 22,25-26,27 General observation, No Abnormality Detected 0,3,5-6,10,13, 14,16,20,21-23, 24 Discharge, Eye bilateral, Red I- 2,4,7-9, II-12,15,17-19, 25-26,27 -99- ) DuPont-11763 ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats )) ____________________________________________________________________ DuPont-11763 INDIVIDUAL CLINICAL OBSERVATIONS - POST-DOSING Sex Group Animal Observation Days M III 667181 General observation, No Abnormality Detected 0,3-6,7,10, 12-13,14-16, 17-20,24-26,27 Discharge, Eye bilateral. Red 1-2,8-9,11, 21-23 M III 667182 General observation, No Abnormality Detected 0,3-6,7-8, 10,12-13,16,17, 19-20,21-23, 24-26,27 Discharge, Eye bilateral, Red 1-2,9,14,18 Discharge, Eye left. Red 15 Discharge, Eye right. Red 11 M III 667183 General observation, No Abnormality Detected 0,3-6,8,10-13, 15-16,19-20, 21-23,24,27 Discharge, Eye bilateral. Red 1-2,7,9,14, 17-18,25-26 M III 667184 General observation, No Abnormality Detected 0,3-6,9,10-13, 14-16,17-20, 21-23,24-25, 27 Discharge, Eye bilateral, Red 1-2,7-8,26 UgBspany Sanitized. Does notcontain TSCA C8 I -100- ) H-25509: Repeated-Dose Dennal Toxicity 28-Day Study in Male Rats ) INDIVIDUAL CLINICAL OBSERVATIONS - POST-DOSING Sex Group Animal Observation Days MV 667185 General observation, No Abnormality Detected 0,2,3-6,7, 12-13,14-16, 19-20,21-23, 25-26,27 Eye Observations, Dark, Right 8-9,10 Discharge, Eye bilateral. Red 1,11,17-18,24 MV 667186 General observation, No Abnormality Detected 0,3,5-6,10, 19-20,21,26 Discharge, Eye bilateral, Red I- 2,4,7-9, II- 13,14-16, 17-18,22-23, 24-25,27 MV 667187 General observation, No Abnormality Detected 0,3,5-6,7,9, 10-13,14,17-20 Discharge, Eye bilateral, Red 1-2,4,8,15-16, 21-23,24-26, 27 MV 667188 General observation, No Abnormality Detected 0,3,5-6,7-8, 10,12-13,14-15, 17,19-20,21-22, 24,27 Discharge, Eye bilateral, Red 1-2,4,11,16,18, 23,25-26 Discharge, Eye right, Red 9 MV 667189 General observation, No Abnormality Detected 0,3,5-6,7-9, 10-11,14-16, 17-20,21-23, 27 Discharge, Eye bilateral, Red 1-2,4,12-13, 26 Wound, Superficial, Shoulder, Left 24-26 > ______DuPont-11763 Pompany Sanitized. Does notcontain tsc a raw -101- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) " 'jg m ifjj 5* 1 Sf'X * H 2 a a3 4 W > OCD g g g g a g g Sanitized. Does not contain TSCACBi Sex Group Animal MV 667190 MV 667191 MV 667192 MV 667193 MV 667194 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 General observation. No Abnormality Detected Discharge, Eye bilateral, Red Discharge, Eye right, Red General observation, No Abnormality Detected Discharge, Eye bilateral, Red Hair Loss, Forelimb, Bilateral General observation, No Abnormality Detected Discharge, Eye bilateral. Red POST-DOSING Days 0,3-6,10,17-20, 21,23,24-26,27 1-2,7-9,13, 14-16,22 11-12 0,3,5-6,10-11, 14,16,19-20,27 1-2,4,7-9, 12-13,15,17-18, 21-23,24-26 0,3-6,10,14-16, 18-20,21-23, 24,27 1-2,7-9, 12-13,17,25-26 11 0-2,3-6 8 7-9,10-13, 14-16,17-20, 21-23,24-26, 27 0,3,5-6,10-11, 14,19-20,21,23, 24-25,27 1-2,4,7-9, 12-13,15-16, 17-18,22,26 DuPont-11763 -102- jCj^ganj' Sanitized. P o e s not contain TSCA CBS ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats > INDIVIDUAL CLINICAL OBSERVATIONS Sex Group Animal Observation M VII 667195 General observation, No Abnormality Detected Discharge, Eye bilateral, Red M VII 667196 General observation, No Abnormality Detected Discharge, Eye bilateral, Red M VII 667197 General observation, No Abnormality Detected Discharge, Eye bilateral, Red M VII 667198 General observation. No Abnormality Detected Discharge, Eye bilateral, Red M VII 667199 General observation. No Abnormality Detected Discharge, Eye bilateral, Red M VII 667200 General observation, No Abnormality Detected Discharge, Eye bilateral, Red POST-DOSING Days 0-1,3,5-6, 7-8,10,13,15-16, 17-20,21-23, 27 2,4,9,11-12,14, 24-26 0-1,3,5-6, 9,10,14-15, 19-20,21-23 2,4,7-8,11-13, 16,17-18,24-26, 27 0,3,5-6,10,16, 17-20,21,24-25, 27 I- 2,4,7-9, II-13,14-15, 22-23,26 0,3,5-6,8-9, 10-13,14,19-20, 21-22,24-26, 27 1-2,4,7,15-16, 17-18,23 0,3-6,10-13, 14,19-20,21-23, 24-26,27 1-2,7-9, 15-16,17-18 0,3-6,10,19-20 I- 2,7-9, II-13,14-16, 17-18,21-23, 24-26,27 > _________ DuPont-11763 - 103- ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) Sex Group Animal M VII 667201 M VII 667202 M VII 667203 M VII 667204 INDIVIDUAL CLINICAL OBSERVATIONS - POST-DOSING Observation Days General observation, No Abnormality Detected 0-2,3-6, 7-9,10-13,14, 16,17-20,27 Discharge, Eye bilateral, Red 15,21-23,24-26 General observation, No Abnormality Detected 0-1,3-6,10, 13,19-20 Discharge, Eye bilateral. Red 2,7-9,11-12, 14-16,17-18, 21-23,24-26, 27 General observation. No Abnormality Detected 0,3,5-6,10-11, 19-20 Discharge, Eye bilateral, Red 1-2,4,7-9, 12-13,14-16, 17-18,21-23, 24-26,27 General observation. No Abnormality Detected 0,3,5-6,10-11, 19-20,27 Discharge, Eye bilateral, Red 1-2,4,7-9, 12-13,14-16, 17-18,21-23, 24-26 ) DuPont-11763 jggmpany Sanitized. D oes not contain t s <?a r -104- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats____________ _ DuPont-11763 APPENDIX E Individual Edema and Erythema Scores Company Sanitized. D oes not contain - 105 - /"'""`N H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL EDEMA AND ERYTHEMA SCORES EXPLANATORY NOTES DRAIZE3SCALE 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 o f the Safety o f Chemicals in Foods. Drugs and Cosmetics. The Editorial Committee o f the Association o f Food and Drug Officials o f the United States, Austin, Texas, 1959, pp. 46-59. jgfippaiy Sanzed. Does not contain TSCACBI - 106- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11763 Edema Edema Edema Day 0 Day 1 Day 2 Male, I 0 mg/kg 667165 0 0 0 667166 0 0 0 667167 0 0 0 667168 0 0 0 667169 0 0 0 667170 0 0 0 667171 0 0 0 667172 0 0 0 667173 0 0 0 667174 0 0 0 Male, III 5 mg/kg 667175 0 0 0 667176 0 0 0 667177 0 0 0 667178 0 0 0 667179 0 0 0 667180 0 0 0 667181 0 0 0 667182 0 0 0 667183 0 0 0 667184 0 0 0 Male, V 50 mg/kg 667185 667186 667187 667188 667189 667190 667191 667192 667193 667194 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 00000 00 000 0 0 00 0 0 0 00 0 00000 00000 0 0000 00000 0 0 00 0 00000 0000 0 00000 0 000 0 0 000 0 00000 0 0 00 0 00000 00000 00000 00000 00000 00000 00000 00000 00000 0 0000 0000 0 00000 00000 00000 Edema Day 9 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 D a y 10 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 D ay 11 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 ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) ) DuPont-11763 Edema Edema Day 0 Day 1 Male, VII: 500 mg/kg 667195 667196 667197 667198 667199 667200 667201 667202 667203 667204 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 00000 00000 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00000 00000 0 0 0 0 0 0 0 0 0 0 00000 Edema Day 9 0 0 0 0 0 0 0 0 0 0 Edema Day 10 0 0 0 0 0 0 0 0 0 0 Edema Day 11 0 0 0 0 0 0 0 0 0 0 Psmpany Sanitized. Does noi conialo t s r * o * | -108- ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) ) DuPont-11763 INDIVIDUAL EDEMA AND ERYTHEMA SCORES Edema Edema Edema Edema Edema Edema Edema Edema Edema Edema Edema Edema 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, I 0 mg/kg 667165 0 0 0 0 0 0 0 0 0 0 0 0 667166 0 0 0 0 0 0 0 0 0 0 0 0 667167 0 0 0 0 0 0 0 0 0 0 0 0 667168 0 0 0 0 0 0 0 0 0 0 0 0 667169 0 0 0 0 0 0 0 0 0 0 0 0 667170 0 0 0 0 0 0 0 0 0 0 0 0 667171 0 0 0 0 0 0 0 0 0 0 0 0 667172 0 0 0 0 0 0 0 0 0 0 0 0 667173 0 0 0 0 0 0 0 0 0 0 0 0 667174 0 0 0 0 0 0 0 0 0 0 0 0 Male, III 5 mg/kg 667175 0 0 0 0 0 0 0 0 0 0 0 0 667176 0 0 0 0 0 0 0 0 0 0 0 0 667177 0 0 0 0 0 0 0 0 0 0 0 0 667178 0 0 0 0 0 0 0 0 0 0 0 0 1 667179 0 0 0 0 0 0 0 0 0 0 0 0 u 667180 0 0 0 0 0 0 0 0 0 0 0 0 ar 667181 667182 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 s 667183 0 0 0 0 0 0 0 0 0 0 0 0 667184 0 0 0 0 0 0 0 0 0 0 0 0 Male, V 50 mg/kg 667185 0 0 0 0 0 0 0 0 0 0 0 0 667186 0 0 0 0 0 0 0 0 0 0 0 0 667187 0 0 0 0 0 0 0 0 0 0 0 0 667188 0 0 0 0 0 0 0 0 0 0 0 0 667189 0 0 0 0 0 0 0 0 0 0 0 0 667190 0 0 0 0 0 0 0 0 0 0 0 0 667191 0 0 0 0 0 0 0 0 0 0 0 0 667192 0 0 0 0 0 0 0 0 0 0 0 0 667193 0 0 0 0 0 0 0 0 0 0 0 0 667194 0 0 0 0 0 0 0 0 0 0 0 0 -109- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11763 Edema Edema Day 12 Day 13 Male, VII: 500 mg/kg 667195 667196 667197 66719S 667199 667200 667201 667202 667203 667204 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 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 Edema Day 20 00000 00000 00000 00000 00000 00000 00000 00000 00000 00000 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 lay v a s i UJ81U03ioti ssoq *p0ZHluBgXub!uS53 ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_________________ ) Edema Edema Day 24 Day 25 Male, I 0 mg/kg 667165 667166 667167 667168 667169 667170 667171 667172 667173 667174 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Male, III 5 mg/kg 667175 667176 667177 667178 667179 667180 667181 667182 667183 667184 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Male, V 50 mg/kg 667185 667186 667187 667188 667189 667190 667191 667192 667193 667194 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 -111 - DuPont-11763 ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) Edema Edema Day 24 Day 25 Male, VII 500 mg/kg 667195 667196 667197 667198 667199 667200 667201 667202 667203 667204 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 Edema Day 27 0 0 0 0 0 0 0 0 0 0 INDIVIDUAL EDEMA AND ERYTHEMA SCORES DuPont-11763 ( p a n i S a n i t t e d . Does no. c o n t a i TSCACBI -112- ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) ) DuPont-11763 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, I 0 mg/kg 667165 0 0 0 0 0 0 0 0 0 0 0 0 667166 0 0 0 0 0 0 0 0 0 0 0 0 667167 0 0 0 0 0 0 0 0 0 0 0 0 667168 0 0 0 0 0 0 0 0 0 0 0 1 667169 0 0 0 0 0 0 0 0 0 0 0 0 667170 0 0 0 0 0 0 0 0 0 0 0 0 667171 0 0 0 0 0 0 0 0 0 0 0 0 667172 0 0 0 0 0 0 0 0 0 0 0 0 667173 0 0 0 0 0 0 0 0 0 0 0 0 667174 0 0 0 0 0 0 0 0 0 0 0 0 Male, III 5 mg/kg 667175 0 0 0 0 0 0 0 0 0 0 0 0 667176 0 0 0 0 0 0 0 0 0 0 0 0 667177 0 0 0 0 0 0 0 0 0 0 0 0 667178 0 0 0 0 0 0 0 0 0 0 0 0 667179 0 0 0 0 0 0 0 0 0 0 0 0 667180 0 0 0 0 0 0 0 0 0 0 0 0 667181 0 0 0 0 0 0 0 1 0 0 0 0 667182 0 0 0 0 0 0 0 0 0 0 0 0 667183 0 0 0 0 0 0 0 0 0 0 0 0 667184 0 0 0 0 0 0 0 0 0 0 0 0 Male, V 50 mg/kg 667185 0 0 0 0 0 0 0 0 0 0 0 0 667186 0 0 0 0 0 0 0 0 0 0 0 0 667187 0 0 0 0 0 0 0 0 0 0 0 0 667188 0 0 0 0 0 0 0 0 0 0 0 0 667189 0 0 0 0 0 0 0 0 0 0 0 1 667190 0 0 0 2 0 0 0 0 0 0 0 0 667191 0 0 0 0 0 0 0 0 0 0 0 0 667192 0 0 0 0 0 0 0 0 0 0 0 0 667193 0 0 0 0 0 0 0 0 0 0 0 0 667194 0 0 0 0 0 0 0 0 0 0 0 0 Sanitized. Does not contain r s c a 5 - 113 - H-25509: Repeated-Dose Dermal Toxicity 28 -D a y Study in M ale Rats_______________ D u P on t-11763 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 500 mg/kg 667195 0 0 0 0 0 0 0 0 0 0 0 0 667196 0 0 0 0 0 0 0 0 0 0 0 0 667197 0 0 0 0 0 0 0 0 0 0 0 0 667198 0 0 0 0 0 0 0 0 0 0 0 0 667199 0 0 0 0 0 0 0 0 0 0 0 0 667200 0 0 0 0 0 0 0 0 0 0 0 0 667201 0 0 0 0 0 0 0 0 0 0 0 0 667202 0 0 0 0 0 0 0 0 0 0 0 0 667203 0 0 0 0 0 0 0 0 0 0 0 0 667204 0 0 0 0 0 0 0 0 0 0 0 0 uieiuooiOttS9 Hto>l otr - 114- > H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) ) DuPont-11763 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, I 0 mg/kg 667165 0 0 0 0 0 0 0 0 0 0 0 0 667166 0 0 0 0 0 0 0 0 0 0 0 0 667167 0 0 0 0 0 0 0 0 0 0 0 0 667168 0 0 0 0 0 0 0 0 0 0 0 0 667169 0 0 0 0 0 0 0 0 0 0 0 0 667170 0 0 0 0 0 0 0 0 0 0 0 0 667171 0 0 0 0 0 0 0 0 0 0 0 0 667172 0 0 0 0 0 0 0 0 0 0 0 0 667173 0 0 0 0 0 0 0 0 0 0 0 0 667174 0 0 0 0 0 0 0 0 0 0 0 1 Male, III 5 mg/kg 667175 0 0 0 0 0 0 0 0 0 0 0 0 667176 0 0 0 0 0 0 0 0 0 0 0 0 667177 0 0 0 0 0 0 0 0 0 0 0 0 667178 0 0 0 0 0 0 0 0 0 0 0 0 667179 0 0 0 0 0 0 0 0 0 0 0 0 667180 0 0 0 0 0 0 0 0 0 0 0 0 667181 0 0 0 0 0 0 0 0 0 0 0 0 667182 0 0 0 0 0 0 0 0 0 0 0 0 667183 0 0 0 0 0 0 0 0 0 0 0 0 667184 0 0 0 0 0 0 0 0 0 0 0 0 Male, V 50 mg/kg 667185 0 0 0 0 0 0 0 0 0 0 0 0 667186 0 0 0 0 0 0 0 0 0 0 0 0 667187 0 0 0 0 0 0 0 0 0 0 0 0 667188 0 0 0 0 0 0 0 0 0 0 0 0 667189 1 0 0 0 0 0 0 0 0 0 0 0 667190 0 0 0 0 0 0 0 0 0 0 0 0 667191 0 0 0 0 0 0 0 0 0 0 0 0 667192 0 0 0 0 0 0 0 0 0 0 0 0 667193 0 0 0 0 0 0 0 0 0 0 0 0 667194 0 0 1 0 0 0 0 0 0 0 0 0 pompany Sanitized. Does notconialo tw *a r* , - 115- ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) ) DuPont-11763 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 500 mg/kg 667195 0 0 0 0 0 0 0 0 0 0 0 0 667196 0 0 0 0 0 0 0 0 0 0 0 0 667197 0 0 0 0 0 0 0 0 0 0 0 0 667198 0 0 0 0 0 0 0 0 0 0 0 0 667199 0 0 0 0 0 0 0 0 0 0 0 0 667200 0 0 0 0 0 0 0 0 0 0 0 0 667201 0 0 0 0 0 0 0 0 0 0 0 0 667202 0 0 0 0 0 0 0 0 0 0 0 0 667203 0 0 0 0 0 0 0 0 0 0 0 0 667204 0 0 0 0 0 0 0 0 0 0 0 0 & <m pan% S anitized. Does not contain TSCA CBf -116- .Company Sanitized. Does not contain TSCA CBI ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) Erythema Erythema Erythema Erythema Day 24 Day 25 Day 26 Male, I 0 mg/kg oooooooooo oooooooooo oooooooooo 667165 0 0 0 667166 0 0 0 667167 0 0 0 667168 0 0 0 667169 0 0 0 667170 0 0 0 667171 0 0 0 667172 0 0 0 667173 0 0 0 667174 1 0 0 Male, III 5 mg/kg 667175 0 0 0 667176 0 0 0 667177 0 0 0 667178 0 0 0 667179 0 0 0 667180 0 0 0 667181 0 0 0 667182 0 0 0 667183 0 0 0 667184 0 0 0 Male, V 50 mg/kg 667185 0 0 0 667186 0 0 0 667187 0 0 0 667188 0 0 0 667189 0 0 0 667190 0 0 0 667191 0 0 0 667192 0 0 0 667193 0 0 0 667194 0 0 0 INDIVIDUAL EDEMA AND ERYTHEMA SCORES - 117- DuPont-11763 ") H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male R a ts ) ') _________________________________________________________ DuPont-11763 Erythema Erythema Erythema Erythema D a y 24 D a y 25 Day 26 Day 27 Male, VII 500 mg/kg 667195 0 0 0 0 667196 0 0 0 0 667197 0 0 0 0 667198 0 0 0 0 667199 0 0 0 0 667200 0 0 0 0 667201 0 0 0 0 667202 0 0 0 0 667203 0 0 0 0 667204 0 0 0 0 INDIVIDUAL EDEMA AMD ERYTHEMA SCORES gpjtngany Sanitized. D oes no! .contain TSCA CBi - 118- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 APPENDIX F Individual Blood Fluorine Levels Company Sanitized. Does no! contain tso a csf - 119- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ BLOOD FLUORINE LEVELS TEST DAY 27 Animal Number Group Dosage (mg/kg/day) 667165 667166 667167 667168 667169 667175 667176 667177 667178 667179 I I I I I mmmmin 0 0 0 0 0 5 5 5 5 5 667185 667186 667187 667188 667189 V V V V V 50 50 50 50 50 667195 667196 667197 667198 667199 VII VII VvvunII 500 500 500 500 500 a <0.5 is below the limit o f quantification F(lPuPormin)e 1.57 <0.5a <0.5 0.58 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 1.83 1.16 1.67 1.14 1.55 19.35 7.15 6.52 5.07 8.49 DuPont-11763 jS&mpany Sanitized. D oes no! contain TSCA CBi H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 APPENDIX G Individual Animal Clinical Pathology Data Company Sanitized. D oes not contain TSCA CBf - 121 - H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL CLINICAL PATHOLOGY DATA EXPLANATORY NOTES ABBREVIATIONS: General: ADEQ CLOT DECR NT NT-HEMOL OK QNS KNV UTD adequate sample clotted decreased not taken or not performed not taken due to hemolysis sample condition OK for testing quantity not sufficient for testing result not valid unable to determine less than Individual Hematology Values: COND - sample condition RBC - red blood cell count HGB - hemoglobin HCT MCV - hematocrit mean corpuscular volume MCH MCHC RDW ARET PLT WBC - mean corpuscular hemoglobin - mean corpuscular hemoglobin concentration - red cell distribution width - absolute reticulocyte count - platelet count - white blood cell count ANEU ALYM AMON AEOS ABAS ALUC - absolute neutrophil (all forms) - absolute lymphocyte - absolute monocyte - absolute eosinophil ~ absolute basophil - absolute large unstained cell SPEC special observations Individual Red Blood Cell Morphology Values: NORM - Normal ANIS MIC -_ anisocytosis microcytes MAC - macrocytes POLY - polychromasia HYPO - hypochromas ia 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 SM - Normal Smudge white blood cells TOX - toxic neutrophils DB VC - Dohle bodies 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 ffem pany Sanitized. D oes not contain TSCA CBf -122- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIM AL CLINICAL PATHOLOGY D A TA EXPLANATORY NOTES (Continued) ABBREVIATIONS: (Continued) Individual Coagulation Values: PHEM - plasma hemolysis PLIP - plasma lipemia PICT - plasma icterus PT - prothrombin time APTT - activated partial thromboplastin time 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 sarrple 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 - volume UOSM - urine osmolality PH - the logarithm of the reciprocal of the hydrogen ion concentration UGLU - urine glucose KET - ketone UBIL - 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 - microorganisms SPER - sperm SPEC - special observations &pmpan Sanitized, Does not contain TSCA OBI -123- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____ DuPont-11763 IND IVID UA L ANIM AL CLINICAL PATHOLOGY D A T A 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. j&ompany Sanitized. D oes not contain TSCA C8I ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) Animal Number COND RBC x I O V aiL HGB g/dL Male, Group i - 0 mg/kg - Day 28 667165 667166 667167 667168 667169 667170 667171 667172 667173 667174 OK OK OK OK OK OK OK OK OK OK 7.62 7.52 7.59 7.41 7.60 8.33 7.54 6.96 7.12 7.85 15.3 14.5 15.5 15.2 15.3 16.5 14.6 14.7 14.8 15.4 Male, Group III - 5 mg/kg - Day 28 667175 667176 667177 667178 667179 667180 667181 667182 667183 667184 OK OK OK OK OK OK OK OK OK OK 7.59 6.91 6.72 7.18 7.62 7.76 7.80 7.79 7.25 6.93 15.5 15.3 14.7 14.9 16.0 15.3 15.9 15.3 14.7 14.7 HCT % 46.6 44.5 46.3 45.8 46.4 50.8 45.6 43.9 45.7 47.5 46.1 45.0 43.6 44.6 48.1 46.9 46.8 45.4 44.4 44.4 Individual Hematology Values MCV MCH MCHC RDW fL pg g/dL % ARET PLT WBC x 103/m L x 103/m L xl03//iL 61.1 59.1 60.9 61.9 61.1 60.9 60.4 63.1 64.1 60.5 20.1 19.2 20.4 20.5 20.1 19.8 19.4 21.1 20.7 19.6 32.9 32.6 33.5 33.1 32.9 32.4 32.0 33.4 32.3 32.3 11.6 11.9 11.4 11.3 11.9 11.1 13.9 11.0 11.7 11.7 355.7 241.1 263.2 210.9 266.8 337.9 327.5 213.2 234.3 231.0 KNV RNV 1100 RNV RNV RNV RNV 1175 1324 1256 16.63 20.03 14.92 20.97 19.51 18.96 23.26 14.27 18.84 15.38 60.7 65.2 64.9 62.1 63.2 60.4 59.9 58.3 61.3 64.1 20.4 22.1 21.9 20.7 21.0 19.7 20.3 19.7 20.3 21.2 33.6 34.0 33.7 33.4 33.3 32.6 33.9 33.8 33.1 33.1 10.9 12.0 11.3 12.6 11.4 12.3 11.3 11.5 12.3 11.8 231.1 318.0 233.8 246.0 267.5 193.8 199.8 221.8 214.1 228.2 RNV 1074 1105 RNV RNV 1309 RNV 1142 1096 1295 17.43 14.33 15.65 21.67 14.56 10.45 17.41 22.34 17.24 20.85 ) DuPont-11763 Sanitized, D oes not contain TSCA CBt -125- ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) Animal Number COND RBC x 1 0 6/ L HGB g/dL Male, Group V - 50 mg/kg - Day 28 667185 667186 667187 667188 667189 667190 667191 667192 667193 667194 OK OK OK OK CLOT OK OK OK OK OK 7.63 6.91 7.11 7.49 NT 7.31 6.82 7.20 7.27 6.23 14.8 14.3 15.0 15.2 NT 14.5 14.9 14.9 14.7 12.6 Male, Group VII - 500 mg/kg - Day 28 667195 667196 667197 667198 667199 667200 667201 667202 667203 667204 OK OK OK OK OK OK OK OK OK CLOT 7.81 7.56 6.89 7.32 7.44 7.26 7.88 7.33 6.94 NT 15.5 15.0 15.2 14.5 15.4 14.6 15.2 14.8 14.6 NT HCT % 45.2 44.4 43.3 47.2 NT 44.9 44.4 45.1 45.4 38.2 47.4 45.4 45.2 44.6 46.4 44.0 45.8 44.8 44.8 NT Individual Hematology Values MCV MCH MCHC RDW fL pg g/dL % ARET x 1 0 3/ m L PLT x 1 0 3/ m L WBC x 103/L 59.2 64.3 61.0 63.0 NT 61.4 65.2 62.6 62.5 61.2 19.5 20.8 21.1 20.3 NT 19.9 21.9 20.7 20.2 20.1 32.9 32.3 34.6 32.1 NT 32.4 33.6 33.2 32.3 32.9 11.1 12.1 11.5 11.2 NT 11.2 12.2 12.1 11.6 11.9 160.4 241.1 292.7 180.4 NT 177.3 233.1 243.0 315.6 231.4 RNV 1149 RNV 1201 NT RNV RNV RNV RNV 1068 14.42 17.58 23.74 16.75 NT 13.58 17.99 14.50 17.19 30.01 60.7 60.0 65.7 60.9 62.4 60.5 58.1 61.1 64.5 NT 19.8 19.8 22.0 19.8 20.7 20.1 19.2 20.2 21.0 NT 32.7 33.1 33.5 32.5 33.2 33.2 33.1 33.0 32.6 NT 11.4 11.5 11.4 11.8 11.6 11.5 10.8 11.3 11.3 NT 198.5 237.2 217.9 200.3 279.6 130.7 191.9 249.8 265.8 NT RNV RNV RNV 1136 RNV RNV 972 RNV 1177 NT 14.27 16.52 17.96 14.39 14.46 14.28 11.95 16.86 12.90 NT ) DuPont-11763 jPgmpap Sanitized. Does not contain TSCA rtu -126- ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats /) Individual Hematology Values Animal Number ANEU ALYM AMON AEOS ABAS ALUC xl03/nL x 103/m L x 103/m L x I O V m L xloV/rL xl03//xL Male, Group I - 0 ing/kg - Day 28 667165 667166 667167 667168 667169 667170 667171 667172 667173 667174 3.08 2.12 1.72 2.57 2.69 2.45 1.81 2.36 2.28 2.15 12.32 16.60 12.43 16.92 15.56 15.27 20.29 11.22 15.31 12.22 0.52 0.54 0.36 0.77 0.61 0.48 0.40 0.36 0.66 0.50 0.34 0.27 0.12 0.26 0.10 0.48 0.16 0.12 0.11 0.10 0.15 0.30 0.15 0.24 0.27 0.16 0.32 0.13 0.21 0.12 0.21 0.22 0.14 0.22 0.28 0.13 0.28 0.08 0.27 0.28 Male, Group III - 5 mg/kg - Day 28 667175 667176 667177 667178 667179 667180 667101 667182 667183 667184 2.17 2.62 1.85 2.40 2.67 1.88 2.87 2.45 2.49 3.41 14.39 10.88 12.83 17.70 10.73 7.86 13.16 18.42 14.05 16.47 0.38 0.34 0.39 0.91 0.36 0.38 0.43 0.81 0.26 0.46 0.17 0.16 0.24 0.26 0.57 0.18 0.55 0.18 0.13 0.08 0.18 0.19 0.18 0.17 0.10 0.08 0.10 0.16 0.15 0.20 0.14 0.14 0.15 0.22 0.12 0.07 0.30 0.31 0.17 0.23 ) DuPont-11763 Company .Sanitized. Does not contain TSCA CBS - 127- ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats )) _________________________________________________________________________ DuPont-11763 Individual Hematology Values Animal Number ANEU xloViiL ALYM xlOViiL AMON x 103/L AEOS x 103/m L ABAS xIOVmD ALUC SPEC xloVfiL Male, Group V - 50 mg/kg - Day 28 667185 667186 667187 667188 667189 667190 667191 667192 667193 667194 1.65 2.07 2.85 3.34 NT 1.09 2.59 1.57 2.58 4.29 12.09 14.41 20.41 12.34 NT 11.80 14.38 12.38 13.78 24.06 0.28 0.37 0.24 0.58 NT 0.20 0.51 0.27 0.49 0.95 0.09 0.13 0.24 0.19 NT 0.08 0.15 0.06 0.08 0.15 0.20 0.30 0.00 0.13 NT 0.23 0.22 0.07 0.10 0.16 0.12 0.29 0-00 0.15 NT 0.18 0.14 0.14 0.18 0.40 1 NUCLEATED RED BLODD CELL/100 WBC Male, Group VII - 500 mg/kg - Day 28 667195 667196 667197 667198 667199 667200 667201 667202 667203 667204 2.26 2.25 2.63 2.22 2.78 1.41 1.31 2.91 1.86 NT 10.99 13.25 14.24 11.40 10.77 11.99 10.05 12.73 10.49 NT 0.40 0.55 0.45 0.37 0.47 0.32 0.29 0.45 0.28 NT 0.09 0.24 0.17 0.07 0.15 0.13 0.05 0.45 0.14 NT 0.34 0.10 0.31 0.15 0.16 0.18 0.12 0.14 0.07 NT 0.20 0.13 0.16 0.17 0.12 0.25 0.13 0.18 0.05 NT .Sanitized. Poes notcontain TSCA CB 128- o H Company Sanitized. Does not contain TSCA CB )> H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_________________________________________________ Animal Number NORM ANIS MIC Male, Group mg/kg - Day 28 667165 667166 667167 667168 667169 667170 667171 667172 667173 667174 NO NO NO NO NO NO NO NO NO NO - - - - _ - - - - - - Male, Group III - 5 mg/kg - Day 28 667175 667176 667177 667178 667179 667180 667181 667182 667183 667184 NO NO NO NO NO NO NO NO NO NO _ - - - - _ - - _ - Individual Red Blood Cell Morphology Values MAC POLY HYPO ECHI ACAN TARG _ FEW - FEW - TRACE - TRACE - FEW - FEW - FEW - TRACE - TRACE - TRACE _ FEW - FEW - FEW - TRACE - FEW - TRACE - TRACE - TRACE - TRACE - TRACE MODERATE MODERATE - - TRACE - TRACE TRACE - TRACE TRACE - - TRACE - FEW TRACE - - FEW - - TRACE -- --- _ - - - - _ MODERATE FEW - TRACE TRACE - - TRACE - TRACE TRACE - TRACE TRACE - - TRACE - TRACE TRACE - TRACE - --- - TRACE TRACE _ - - - _ - RX _ - - - - _ - - - HJB - - - - - _ ~ - ) DuPont-11763 -129- Company Sanitized. Woes not contain TSCA CBI ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study inMale Rats_________ ) Animal Number NORM ANIS MIC Male, Group V - 50 mg/kg - Day 28 667185 667186 667187 667188 667189 667190 667191 667192 667193 667194 NO NO NO NO CLOT NO NO NO NO NO NT - - - - NT - - - Male, Group VII - 500 mg/kg - Day 28 667195 667196 667197 667198 667199 667200 667201 667202 667203 667204 NO NO NO NO NO NO NO NO NO CLOT _ - NT _ - NT Individual Red Blood Cell Morphology Values MAC POLY HYPO ECHI ACAN TARG - TRACE - FEW TRACE - ~ TRACE - - TRACE - - FEW - TRACE TRACE - - TRACE - - - - NT NT NT NT NT NT - TRACE - - - - - FEW - - - - - FEW - TRACE TRACE - TRACE - - - - - FEW - - TRACE - TRACE _ TRACE _ _ - TRACE - TRACE TRACE - - TRACE - - - - TRACE - TRACE TRACE - - FEW - - - * - FEW - - TRACE - - TRACE - - - - - TRACE _ - - - - FEW - TRACE TRACE N T NT NT N T NT NT RX HJB --- -_ -- NT NT --- -- _-- __ -------- - TRACE NT NT ) DuPont-11763 -130- j ^ p a n y Sanitized. Does not contain TSCA CSI ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) ' Animal Number NORM SM TOX Male, Group I - 0 mg/kg - Day 28 667165 667166 667167 667168 667169 667170 667171 667172 667173 667174 NO NO YES NO NO NO NO YES YES YES _ - - - - - - - - - - Male, Group III - 5 mg/kg - Day 28 667175 667176 667177 667178 667179 667180 667181 667182 667183 667184 NO YES YES NO NO YES NO YES YES YES - - - _ - - - Individual White Blood Cell / Platelet Morphology Values DB VC BC PCE GP BP _ _ _ YES/UTD _ _ - - - YES/ADEQ - - --- -- - - - - YES/UTD TRACE - - - - YES/UTD - - -- YES/UTD - - - - - YES/UTD - - - ~--- - --_ --_ ------ _ _ _ YES/UTD _ _ - --- _ _ ---- -_ - - _ YES/ADEQ - - - - - YES/UTD - _ - _---_ - _ - YES/UTD _ _ '- - - - _ _ - --_ _ _ -_ __ __ ) DuPont-11763 -131- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats___________ Animal Number NORM SM TOX Male, Group V - 50 mg/kg - Day 28 667185 667186 667187 667188 667189 667190 667191 667192 667193 667194 NO YES NO NO CLOT NO NO NO NO YES _ - - NT - - _ - - NT - - - Male, Group VII - 500 mg/kg - Day 28 667195 667196 667197 667198 667199 667200 667201 667202 667203 667204 NO NO NO YES NO NO YES NO YES CLOT _ - - - - - NT _ - - - NT Individual White Blood Cell / Platelet Morphology Values DB VC BC PCE GP BP _ - - YES/UTD TRACE - -- -- -- - - - YES/UTD - - - - - - TRACE - NT NT NT NT NT NT - - - YES/UTD - - - - YES/DECR - - -- - YES/UTD - - - - - YES/DECR TRACE - - - -- -- _ - _ YES/UTD _ - - - YES/ADEQ - - - - - YES/UTD - - - -- - - - - - - YES/UTD - - - - - YES/DECR - - - --- - - - - - YES/UTD _ - - -- - - NT NT NT NT NT NT DuPont-11763 -132- 'Company Sanitized D oes not contad tsc cr .') H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) Animal Number PHEM PLIP PICT Male, Group I - 0 mg/kg - Day 28 667165 667166 667167 667168 667169 667170 667171 667172 667173 667174 NONE NONE NONE NONE NONE NONE NONE NONE CLOT NONE NONE NONE NONE NONE NONE NONE NONE NONE NT NONE NONE NONE NONE NONE NONE NONE NONE NONE NT NONE Male, Group III - 5 mg/kg - Day 28 667175 667176 667177 667178 667179 667180 667181 667182 667183 667184 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 PT sec 15.9 15.9 17.3 15.1 15.0 15.5 14.8 15.7 NT 16.1 15.9 15.1 15.4 15.5 14.2 15.9 14.8 15.5 14.5 15.2 Individual Coagulation Values APTT sec 19.3 20.6 21.2 19.9 21.0 17.9 19.7 22.3 NT 17.8 18.1 20.2 17.2 19.2 19.0 19.9 21.1 17.5 15.7 20.2 ) DuPont-11763 -133 - ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) Animal Number PHEM PLIP PICT Male, Group V - 50 mg/kg - Day 28 667185 667186 667187 667188 667189 667190 667191 667192 667193 667194 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 - 500 mg/kg - Day 28 667195 667196 667197 667198 667199 667200 667201 667202 667203 667204 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 PT sec 15.5 15.6 15.1 15.4 14.6 15.1 15.6 14.9 15.1 14.9 16.7 15.1 15.8 15.8 14.8 14.7 15.8 14.7 15.0 14.5 Individual Coagulation Values APTT sec 21.0 21.5 16.3 18.3 18.1 20.3 21.5 18.3 18.0 15.9 20.4 19.4 17.3 19.7 21.0 18.5 14.3 17.3 17.7 18.3 ) DuPont-11763 Company Sanitized. Owes not contain TSCA CBf -134- ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_______ ) Animal Number SHEM SLIP SICT Male, Group I - 0 mg/kg - Day 28 667165 667166 667167 667168 667169 667170 667171 667172 667173 667174 NONE NONE TRACE NONE TRACE TRACE 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 - 5 mg/kg - Day 28 667175 667176 667177 667178 667179 667180 667181 667182 667183 667184 TRACE NONE NONE NONE TRACE NONE TRACE NONE TRACE NONE 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 aU/L U/L U/L u/L mg/dL mg/dL mg/dL mg/dL 147 63 19.8 216 0.11 14 0.32 62 109 41 16.3 199 0.13 18 0.26 57 124 47 7.8 174 <0.10 12 0.31 57 101 50 16.3 145 <0.10 16 0.24 57 118 55 14.5 236 0.13 14 0.28 50 113 48 18.3 169 <0.10 16 0.33 55 99 50 13.2 156 0.11 16 0.31 56 136 48 15.5 209 0.11 15 0.27 47 106 48 11.2 243 0.12 14 0.27 52 88 35 13.4 181 0.13 16 0.32 65 143 76 7.5 188 0.10 15 0.26 65 116 53 16.2 154 <0.10 12 0.35 43 115 50 18.0 190 0.11 14 0.38 49 98 37 12.6 262 0.14 14 0.30 59 176 52 11.8 252 <0.10 16 0.39 67 106 42 10.8 206 <0.10 15 0.33 50 155 61 22.9 207 0.10 17 0.41 62 118 50 10.6 196 0.11 16 0.29 54 89 40 7.6 208 0.11 15 0.29 63 125 66 11.6 173 0.10 19 0.30 47 ) DuPont-11763 ! 8 i/ v ^ x u je ju o o jo u S 0O 0 "p a z fifu e s fttecfiiiisgg - 135- .Company Sanitized. Does not contain t sc a r*t ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) Animal Number SHEM SLIP SICT Male, Group V - 50 mg/kg - Day 28 667185 667186 667187 667188 667189 667190 667191 667192 667193 667194 TRACE TRACE TRACE NONE TRACE NONE NONE TRACE TRACE TRACE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE Male, Group VII - 500 mg/kg - Day 28 667195 667196 667197 667198 667199 667200 667201 667202 667203 667204 TRACE TRACE TRACE TRACE TRACE TRACE NONE NONE TRACE MODERATE 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 U/L U/L U/L U/L mg/dL 124 67 19.5 200 <0.10 102 33 12.8 131 <0.10 149 50 5.7 96 0.12 126 64 20.2 164 <0.10 133 43 0.8 178 <0.10 90 49 11.6 157 <0.10 113 43 15.5 186 0.11 120 52 13.5 230 <0.10 95 32 7.7 185 0.10 103 47 3.5 174 <0.10 113 99 117 95 103 100 255 86 91 NT-HEMOL 47 38 60 39 44 52 120 31 44 NT-HEMOL 7.6 11.6 19.8 17.2 13.9 8.4 34.3 9.0 6.5 7.2 238 276 161 127 243 141 249 204 228 NT-HEMOL 0.10 0-10 0.10 <0.10 <0.10 0.12 <0.10 <0.10 <0.10 NT-HEMOL BUN mg/dL 16 13 13 16 14 13 12 13 14 14 15 17 14 13 16 16 13 15 14 17 CREA mg/dL 0.36 0.23 0.31 0.31 0.31 0.18 0.23 0.37 0.31 0.28 0.26 0.25 0.38 0.28 0.33 0.26 0.29 0.24 0.19 0.33 CHOL mg/dL 38 49 45 40 59 37 40 64 45 60 27 39 36 56 28 45 38 69 27 33 ) DuPont-11763 -136- ) H-25509: 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 28 667165 667166 667167 667168 667169 667170 667171 667172 667173 667174 42 40 41 67 49 19 31 61 45 49 79 6.4 82 6.5 83 6.4 88 6.1 92 6.8 111 6.8 86 6.2 85 5.9 78 6.3 82 6.2 Male, Group III - 5 mg/kg - Day 28 667175 667176 667177 667178 667179 667180 667181 667182 667183 667184 56 54 55 77 33 49 28 43 33 64 76 6.0 78 6.5 86 6.4 90 6.5 151 6.7 75 6.5 120 6.9 87 6.4 103 6.9 84 6.3 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 4.1 2.3 10.8 9.1 144.4 5.94 96.2 4.3 2.2 11.0 9.5 150.0 6.70 99.2 4.0 2.4 10.3 9.5 148.2 6.63 103.0 3.7 2.4 11.3 9.9 150.2 6.41 100.9 4.4 2.4 10.8 9.6 151.7 6.38 102.2 3.9 2.9 12.1 11.5 146.0 6.68 98.6 4.2 2.0 10.8 9.2 147.8 6.63 99.2 3.9 2.0 10.8 9.1 148.3 6.27 101.1 4.1 2.2 11.1 9.2 149.8 5.93 102.0 4.3 1.9 11.7 9.9 148.9 6.41 101.5 4.2 1.8 10.3 9.2 145.8 5.86 98.7 4.1 2.4 11.0 8.1 149.0 6.41 100.2 4.1 2.3 10.5 8.4 148.3 6.35 99.7 4.3 2.2 11.4 9.8 149.1 6.48 101.3 4.4 2.3 11.8 11.2 152.2 7.03 104.3 4.1 2.4 10.9 8.6 146.8 5.95 99.2 4.3 2.6 11.5 10.5 149.1 6.97 99.1 4.0 2.4 11.4 9.4 146.1 5.69 98.1 4.3 2.6 11.4 9.5 147.5 6.47 101.5 4.1 2.2 10.8 8.9 150.5 5.92 101.6 ) DuPont-11763 .Company Sanitized. D oes noi conta T<?#- * ' ,r*1 -137- ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) sr 3 5" * $ mHi 3 * g o 3 I Of Company Sanitized. Do m not ** Animal Number TRIG mg/dL GLUC mg/dL TP g/dL 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 Male, Group V - 50 mg/kg - Day 28 667185 667186 667187 667188 667189 667190 667191 667192 667193 667194 24 44 43 28 52 32 35 35 54 41 97 6.3 4.3 2.0 10.7 10.8 146.0 7.62 98.8 88 5.9 3.9 2.0 10.3 9.5 147.9 6.18 99.7 136 6.0 4.0 2.0 10.8 10.8 147.5 6.65 102.4 89 6.7 4.1 2.6 10.6 9.4 150.4 6.22 103.0 97 6.2 4.1 2.1 11.1 10.5 149.2 7.05 105.5 81 6.2 4.1 2.1 10.9 9.2 145.7 6.35 97.6 104 6.6 4.1 2.5 10.9 9.0 146.2 5.97 96.4 144 7.0 4.3 2.7 11.5 11.3 150.1 6.95 101.6 99 6.1 4.1 2.0 10.7 9.5 148.1 5.97 101.7 105 5.8 3.5 2.3 11.0 10.8 148.7 7.37 106.7 Male, Group VII - 500 mg/kg - Day 28 667195 21 70 6.6 4.3 2.3 10.3 8.7 146.1 6.19 96.9 667196 23 97 5.8 4.1 1.7 10.4 10.6 146.4 6.22 98.7 667197 28 101 6.3 4.1 2.2 10.9 9.4 151.1 6.05 100.8 667198 24 112 6.5 4.2 2.3 10.4 9.7 151.1 6.52 103.6 667199 25 96 7.1 4.7 2.4 11.0 10.1 153.8 6.99 105.6 667200 27 84 6.0 4.0 2.0 10.7 9.3 146.9 5.95 98.0 667201 39 109 6.2 4.2 2.0 10.6 8.8 147.5 6.47 102.8 667202 28 93 7.1 4.6 2.5 11.4 9.1 146.4 6.29 100.4 667203 17 92 6.3 4.3 2.0 11.1 9.3 149.1 5.92 102.7 667204 NT-HEMOL 122 NT-HEMOL NT-HEMOL NT-HEMOL 11.5 NT-HEMOL 149.9 NT-HEMOL 105.5 ) DuPont-11763 -138- ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats _____ ') Animal Number PHEM PLIP PICT Male, Group I - 0 mg/kg - Day 28 667165 NONE NONE NONE 667166 NONE NONE NONE 667167 NONE NONE NONE 667168 NONE NONE NONE I.W 667169 NONE NONE NONE lj 667170 NONE NONE NONE Lap 667171 NONE NONE NONE !|g 667172 NONE NONE NONE S 667173 NONE NONE NONE 667174 NONE NONE NONE Male, Group III - 5 mg/kg - Day 28 667175 667176 667177 667178 667179 667180 667181 667182 667183 667184 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 Mg/mL Individual Clinical Chemistry Values OO oo 0.1 0.0 0.0 0.0 0.1 0.1 0.1 0.1 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 ) DuPont-11763 o o Does not contain TSCACBf -139- J H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) Animal Number PHEM PLIP PICT Male, Group V - 50 mg/kg - Day 28 667185 667186 667187 667188 667189 667190 667191 667192 667193 667194 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 - 500 mg/kg - Day 28 667195 667196 667197 667198 667199 667200 667201 667202 667203 667204 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 Mg/mL Individual Clinical Chemistry Values Oo o o oo o o 0.1 0.0 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 ) DuPont-11763 1 8 0 VO S! ujbiooqoii sa o a 'p a z j f C m X ^ ^ f o o -140- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Animal QUAL COL CLAR Number [ale, Group I - 0 mg/kg - Day 28 667165 667166 667167 667168 667169 667170 667171 667172 667173 667174 LIGHT LIGHT LIGHT MEDIUM LIGHT LIGHT LIGHT LIGHT LIGHT LIGHT YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW CLEAR HAZY CLEAR CLEAR HAZY HAZY HAZY HAZY HAZY HAZY [ale, Group III - 5 mg/kg - Day 28 667175 667176 667177 667178 667179 667180 667181 667182 667183 667184 LIGHT LIGHT LIGHT LIGHT LIGHT LIGHT LIGHT LIGHT LIGHT LIGHT YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW CLEAR CLEAR CLEAR CLEAR HAZY CLEAR HAZY CLEAR HAZY CLEAR Individual VOL UOSM mL mOsm/kg pH 18.0 9.0 3.9 2.3 12.8 10.8 17.2 2.3 7.0 7.5 358 958 1457 2867 718 719 527 2050 896 1055 7.0 7.5 7.0 6.5 7.0 7.0 7.0 6.5 7.0 7.0 2.2 20.4 7.2 17.0 11.0 12.8 9.6 15.0 19.0 13.4 1714 446 840 500 771 546 809 567 360 489 7.0 7.0 7.0 7.0 7.0 7.0 7.5 7.0 7.5 7.0 Urinalysis Values UGLU mg/dL KET mg/dL UBIL BLD URO EU/dL oo o to to to NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE 5 15 5 5 NEGATIVE NEGATIVE 15 5 5 NEGATIVE NEGATIVE NEGATIVE SMALL NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE SMALL NEGATIVE NEGATIVE NEGATIVE SMALL NEGATIVE NEGATIVE TRACE SMALL NEGATIVE 0.2 0.2 0.2 1.0 0.2 0.2 1.0 0.2 0.2 NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE 15 5 5 NEGATIVE 5 5 NEGATIVE 5 NEGATIVE 5 NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE TRACE NEGATIVE MODERATE SMALL NEGATIVE NEGATIVE NEGATIVE SMALL SMALL 1.0 0.2 0.2 0.2 0.2 0.2 0.2 DuPont-11763 CN O -141 ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats fjSPfmnjf Sanitized. Does not contain tso Animal QUAL COL CLAR Number Male, Group V - 50 mg/kg - Day 28 667185 667186 667187 667188 667189 667190 667191 667192 667193 667194 LIGHT LIGHT LIGHT MEDIUM LIGHT LIGHT LIGHT LIGHT LIGHT LIGHT YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW HAZY CLEAR CLEAR CLEAR CLEAR HAZY CLEAR HAZY HAZY HAZY Male, Group VII - 500 mg/kg - Day 28 667195 667196 667197 667198 667199 667200 667201 667202 667203 667204 MEDIUM LIGHT LIGHT LIGHT LIGHT LIGHT MEDIUM LIGHT LIGHT LIGHT YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW CLEAR CLEAR CLEAR HAZY CLEAR CLEAR CLOUDY HAZY CLEAR HAZY Individual VOL UOSM mL mOsm/kg pH 5.9 6.3 3.5 2.0 11.0 7.0 4.0 10.0 9.0 8.2 1167 1072 2021 2826 644 1021 1761 747 773 882 7.0 7.0 6.5 6.5 6.5 7.0 6.5 7.5 7.0 7.0 1.2 22.0 9.8 10.8 23.0 9.3 1.0 3.4 11.0 9.8 2718 380 954 806 381 552 3602 1669 622 668 7.5 7.0 7.0 7.0 6.5 7.0 8.0 6.5 6.0 7.0 ) Urinalysis Values UGLU mg/dL KET mg/dL UBIL BLD URO EU/dL oo o o oO o CO CO CO CO CO CO CO NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE 5 NEGATIVE NEGATIVE 0.2 5 NEGATIVE NEGATIVE 0.2 5 SMALL NEGATIVE 1.0 5 NEGATIVE NEGATIVE 1.0 5 NEGATIVE NEGATIVE 5 NEGATIVE NEGATIVE 0.2 5 NEGATIVE NEGATIVE 5 NEGATIVE TRACE 5 NEGATIVE TRACE 0.2 5 NEGATIVE MODERATE CN O NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE 5 5 NEGATIVE NEGATIVE 5 NEGATIVE 5 NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE SMALL NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE SMALL NEGATIVE MODERATE MODERATE NEGATIVE 0.2 0.2 0.2 0.2 0.2 0.2 DuPont-11763 -142- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats Animal Number UFLU mu UMTP mg/dL Male, Group I - 0 mg/kg - Day 667165 667166 667167 667168 667169 667170 667171 667172 667173 667174 7.2 12.3 7.6 6.7 11.0 12.4 13.0 4.9 10.0 9.6 10 37 81 160 40 53 18 186 73 59 Male, Group III - 5 mg/kg - D< 667175 667176 667177 667178 667179 667180 667181 667182 667183 667184 5.8 20.0 9.8 12.4 14.0 11.6 13.0 15.1 12.3 19.0 116 16 60 17 28 35 38 15 14 16 _____________________________________________ _____ DuPont-11763 Individual Urinalysis Values Does ro tonan TSCA -143- ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ______________________________________ ) Animal Number UFLU m UMTP mg/dL ale, Group V - 50 mg/kg - 667185 667186 667187 667188 667189 667190 667191 667192 667193 667194 24.4 29.8 22.0 17.8 25.5 25.6 17.0 24.7 23.6 19.6 68 49 98 129 19 60 95 32 47 27 Male, Group VII - 500 mg/kg - Day 28 667195 667196 667197 667198 667199 667200 667201 667202 667203 667204 75.1 198.7 136.8 172.6 187.7 97.4 QNS 141.2 153.6 161.3 288 11 30 34 15 21 160 72 35 33 Individual Urinalysis Values ) DuPont-11763 Company Sanitized. D oes not contain TSCA CBI - 144- Company Sanitized. Does ) H-25509: Repeated-Dose Dernial Toxicity 28-Day Study in Male Rats ________________ ) Animal Number EPIT UWBC URBC Male, Group I - 0 mg/kg - :Day 28 667165 667166 667167 667168 667169 667170 667171 667172 667173 667174 NONE NONE NONE QNS NONE FEW NONE QNS NONE NONE NONE NONE NONE NT NONE NONE NONE NT NONE NONE NONE NONE NONE NT NONE NONE NONE NT NONE NONE Male, Group III - 5 mg/kg - Day 28 667175 QNS NT NT 667176 NONE NONE NONE 667177 NONE NONE NONE 667178 NONE NONE NONE 667179 NONE NONE NONE 667180 FEW NONE NONE 667181 NONE NONE NONE 667182 NONE NONE NONE 667183 NONE NONE NONE 667184 NONE NONE NONE I I NCRY Individual Urine Microscopic Values MICR SPER SPEC FEW FEW FEW FEW FEW MODERATE FEW FEW MODERATE NT NT NT FEW MODERATE MODERATE FEW MODERATE FEW FEW FEW FEW NT NT NT FEW MODERATE MANY FEW FEW MODERATE NT NT NT FEW FEW FEW FEW FEW FEW FEW FEW FEW FEW FEW FEW FEW MODERATE MODERATE FEW FEW MANY FEW MUCUS STRANDS FEW FEW FEW FEW FEW FEW FEW MODERATE FEW B'S - 145- ) DuPont-11763 Company Sanitized. Does not contain ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) Animal Number EPIT UWBC URBC ale, Group V - 50 mg/kg - Day 28 667185 667186 667187 667188 667189 667190 667191 667192 667193 667194 NONE NONE NONE QNS NONE NONE NONE NONE NONE NONE NONE NONE NONE NT NONE NONE FEW NONE NONE NONE NONE NONE NONE NT NONE NONE FEW NONE NONE NONE ale. Group VII - 500 mg/kg - Day 28 667195 667196 667197 667198 667199 667200 667201 667202 667203 667204 QNS NONE NONE NONE NONE NONE QNS FEW NONE NONE NT NONE NONE NONE NONE NONE NT NONE NONE NONE NT NONE NONE NONE NONE NONE NT FEW NONE NONE NCRY Individual Urine Microscopic Values MICR SPER SPEC FEW FEW FEW FEW FEW FEW FEW FEW MODERATE FEW MUCUS STRANDS NT NT NT FEW MODERATE NONE FEW FEW FEW FEW FEW FEW FEW MODERATE MODERATE FEW MODERATE MODERATE FEW FEW MODERATE NT NT NT FEW FEW FEW FEW FEW FEW FEW FEW FEW FEW MODERATE MODERATE FEW FEW MODERATE NT NT NT FEW FEW FEW FEW MUCUS STRANDS FEW FEW MODERATE FEW MUCUS STRANDS FEW MODERATE FEW ) DuPont-11763 - 146- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 APPENDIX H Individual Animal Final Body and Organ Weights { Company Sanitised- Does not contain TSCACI -147- V r n u m Sanitized. B oas W! contain TSCA CB ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS ) DuPont-11763 Group : I 0 mg/kg Sex :MALES | ANIMAL 1 667165 667166 667167 667168 667169 667170 667171 667172 667173 667174 FBW (Gms) 313.90 328.50 327.90 319.20 352.30 354.10 313.80 335.50 311.80 355.00 BRAIN (Gmsi %FBW 2.208 0.7034 2.199 0.6694 1.964 0.5990 2.142 0.6711 2.211 0.6276 2.016 0.5693 1.981 0.6313 2.021 0.6024 1.881 0.6033 1.902 0.5358 Mean S.D. 331.20 2.053 0.6212 17.305 0.127 0.0504 ADRENAL GLANDS (Gms) %FBW %BRAIN 0.053 0.0169 2.4004 0.057 0.0174 2.5921 0.053 0.0162 2.6986 0.050 0.0157 2.3343 0.088 0.0250 3.9801 0.062 0.0175 3.0754 0.067 0.0214 3.3821 0.050 0.0149 2.4740 0.043 0.0138 2.2860 0.054 0.0152 2.8391 0.058 0.0174 2.8062 0.013 0.0034 0.5384 EPIDIDYMIDES (Gms) %FBW %BRAIN 0.974 0.3103 44.112 1.154 0.3513 52.478 0.960 0.2928 48.880 0.893 0.2798 41.690 1.189 0.3375 53.777 1.010 0.2852 50.099 1.178 0.3754 59.465 1.019 0.3037 50.421 1.031 0.3307 54.811 0.938 0.2642 49.317 1.035 0.3131 50.505 0.104 0.0350 5.1231 HEART (Gms) %FBW %BRAIN 1.312 0.4180 59.420 1.269 0.3863 57.708 1.162 0.3544 59.165 1.241 0.3888 57.937 1.429 0.4056 64.631 1.480 0.4180 73.413 1.336 0.4257 67.441 1.172 0.3493 57.991 1.166 0.3740 61.988 1.381 0.3890 72.608 1.295 0.3909 63.230 0.113 0.0264 6.0540 KIDNEYS | (Gms) %FBW %BRAIN | 2.776 0.8844 125.72 3.054 0.9297 138.88 2.649 0.8079 134.88 2.806 0.8791 131.00 3.546 1.0065 160.38 3.017 0.8520 149.65 2.856 0.9101 144.17 2.811 0.8379 139.09 2.859 0.9169 151.99 3.085 0.8690 162.20 2.946 0.8893 143.80 0.251 0.0556 12.163 Group : III 5 mg/kg Sex :MALES j ANIMAL FBW (Gms) BRAIN (Gms) % F B W 667175 667176 667177 667178 667179 667180 667181 667182 306.80 351.40 339.20 353.70 347.40 308.10 363.30 303.80 2.002 2.216 1.951 2.077 2.087 2.094 1.866 2.040 0.6525 0.6306 0.5752 0.5872 0.6007 0.6796 0.5136 0.6715 ADRENAL GLANDS (Gms) % F B W % B R A I N 0.047 0.083 0.051 0.114 0.073 0.057 0.051 0.053 0.0153 0.0236 0.0150 0.0322 0.0210 0.0185 0.0140 0.0174 2.3477 3.7455 2.6140 5.4887 3.4978 2.7221 2.7331 2.5980 EPIDIDYMIDES (Gms) % F B W % B R A I N 1.233 1.174 1.125 1.223 1.220 1.219 0.935 0.911 0.4019 0.3341 0.3317 0.3458 0.3512 0.3957 0.2574 0.2999 61.588 52.978 57.663 58.883 58.457 58.214 50.107 44.657 (Gms) HEART %FBW %BRAIN 1.365 1.235 1.133 1.409 1.415 1.328 1.184 1.118 0.4449 0.3515 0.3340 0.3984 0.4073 0.4310 0.3259 0.3680 68.182 55.731 58.073 67.838 67.801 63.419 63.451 54.804 KIDNEYS | (Gms) % F B W % B R A I N j 2.853 3.434 2.701 3.337 3.327 2.698 2.857 2.703 0.9299 0.9772 0.7963 0.9435 0.9577 0.8757 0.7864 0.8897 142.51 154.96 138.44 160.66 159.42 128.84 153.11 132.50 FBW - Final Body Weight -148- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS ) DuPont-11763 Group : III 5 mg/kg Sex :MALES 1 ANIMAL 1 FBW (Gins) ! 667183 307.60 I 667184 345.30 BRAIN (Gms) %FBW 1.770 0.5754 2.104 0.6093 1 Mean 1 S.D. 332.66 2.021 0.6096 23.298 0.129 0.0507 ADRENAL GLANDS (Gms) %FBW %BRAIN 0.057 0.0185 3.2203 0.073 0.0211 3.4696 0.066 0.0197 3.2437 0.021 0.0053 0.9163 EPIDIDYMIDES (Gms) %FBW %BRAIN 1.105 0.3592 62.429 0.999 0.2893 47.481 1.114 0.3366 55.246 0.124 0.0453 6.0918 (Gms) HEART %FBW %BRAIN 1.248 0.4057 70.508 1.239 0.3588 58.888 1.267 0.3826 62.870 0.108 0.0408 5.6872 KIDNEYS | (Gms) %FBW %BRAIN | 2.777 0.9028 156.89 2.789 0.8077 132.56 2.948 0.8867 145.99 0.296 0.0693 12.343 Group : V 50 mg/kg Sex :MALES I ANIMAL 1 FBW (Gms) 667185 667186 667187 667188 667189 667190 667191 667192 667193 667194 308.40 315.70 330.00 350.50 351.10 335.20 352.80 330.60 348.00 323.00 BRAIN (Gms) %FBW 1.982 0.6427 2.021 0.6402 1.910 0.5788 2.094 0.5974 1.988 0.5662 2.051 0.6119 2.138 0.6060 1.969 0.5956 1.976 0.5678 1.973 0.6108 Mean S.D. 334.53 2.010 0.6017 15.817 0.067 0.0266 ADRENAL GLANDS (Gms) %FBW %BRAIN 0.058 0.0188 2.9263 0.060 0.0190 2.9688 0.062 0.0188 3.2461 0.054 0.0154 2.5788 0.071 0.0202 3.5714 0.077 0.0230 3.7543 0.096 0.0272 4.4902 0.060 0.0181 3.0472 0.060 0.0172 3.0364 0.059 0.0183 2.9904 0.066 0.0196 3.2610 0.013 0.0033 0.5460 EPIDIDYMIDES (Gms) %FBW %BRAIN 0.977 0.3168 49.294 1.296 0.4105 64.127 0.911 0.2761 47.696 1.145 0.3267 54.680 0.958 0.2729 48.189 1.152 0.3437 56.168 1.191 0.3376 55.706 1.159 0.3506 58.862 0.920 0.2644 46.559 1.084 0.3356 54.942 1.079 0.3235 53.622 0.131 0.0440 5.6248 (Gms) HEART %FBW %BRAIN 1.187 0.3849 59.889 1.206 0.3820 59.673 1.258 0.3812 65.864 1.243 0.3546 59.360 1.295 0.3688 65.141 1.374 0.4099 66.992 1.374 0.3895 64.266 1.310 0.3962 66.531 1.441 0.4141 72.925 1.212 0.3752 61.429 1.290 0.3857 64.207 0.085 0.0180 4.2582 KIDNEYS | (Gms) %FBW %BRAIN | 2.738 0.8878 138.14 3.140 0.9946 155.37 3.003 0.9100 157.23 3.471 0.9903 165.76 3.039 0.8656 152.87 3.384 1.0095 164.99 3.837 1.0876 179.47 3.201 0.9682 162.57 2.487 0.7147 125.86 2.887 0.8938 146.33 3.119 0.9322 154.86 0.385 0.1024 15.237 o 31 FBW - Final Body Weight ,,D oes not contain TSC -149- ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ") INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS ) DuPont-11763 Group : VII 500 mg/kg Sex MALES 1 ANIMAL FBW BRAIN (Gms) (Gms) %FBW ADRENAL GLANDS (Gms) %FBW %BRAIN 667195 667196 667197 667198 667199 667200 667201 667202 667203 667204 304.70 334.00 353.00 356.10 334.10 317.20 269.40 347.10 355.00 333.40 1.914 0.6282 2.160 0.6467 2.153 0.6099 1.979 0.5557 2.019 0.6043 1.918 0.6047 1.948 0.7231 1.981 0.5707 2.002 0.5639 1.864 0.5591 0.046 0.0151 2.4033 0.092 0.0275 4.2593 0.080 0.0227 3.7157 0.055 0.0154 2.7792 0.057 0.0171 2.8232 0.062 0.0195 3.2325 0.052 0.0193 2.6694 0.084 0.0242 4.2403 0.056 0.0158 2.7972 0.058 0.0174 3.1116 Mean S.D. 330.40 27.176 1.994 0.6066 0.097 0.0512 0.064 0.0194 3.2032 0.015 0.0042 0.6563 EPIDIDYMIDES (Girts) %FBW %BRAIN 1.115 0.3659 58.255 1.110 0.3323 51.389 1.140 0.3229 52.949 1.069 0.3002 54.017 1.073 0.3212 53.145 1.097 0.3458 57.195 0.860 0.3192 44.148 1.184 0.3411 59.768 1.325 0.3732 66.184 1.131 0.3392 60.676 1.110 0.3361 55.773 0.115 0.0221 6.0451 (Gms) HEART %FBW %BRAIN 1.168 0.3833 61.024 1.169 0.3500 54.120 1.419 0.4020 65.908 1.554 0.4364 78.525 1.176 0.3520 58.247 1.277 0.4026 66.580 0.921 0.3419 47.279 1.338 0.3855 67.542 1.364 0.3842 68.132 1.525 0.4574 81.813 1.291 0.3895 64.917 0.191 0.0372 10.429 KIDNEYS 1 (Gms) %FBW %BRAIN | 2.782 0.9130 145.35 3.043 0.9111 140.88 3.424 0.9700 159.03 3.162 0.8880 159.78 3.296 0.9865 163.25 3.061 0.9650 159.59 2.886 1.0713 148.15 3.313 0.9545 167.24 3.562 1.0034 177.92 3.119 0.9355 167.33 3.165 0.9598 158.85 0.239 0.0532 11.286 Sanitized. D oes not contain TSCA C8I FBW - Final Body Weight - 150- i ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS Group : I 0 mg/kg Sex MALES 1 ANIMAL 1 667165 667166 667167 667168 667169 667170 667171 667172 667173 667174 LIVER (Gms) %FBW %BRAIN 9.845 3.1363 445.88 9.614 2.9266 437.20 9.638 2.9393 490.73 9.243 2.8957 431.51 12.007 3.4082 543.06 11.460 3.2364 568.45 10.283 3.2769 519.08 9.480 2.8256 469.07 9.239 2.9631 491.17 10.239 2.8842 538.33 SPLEEN (Gms) %FBW %BRAIN 0.651 0.2074 29.484 0.877 0.2670 39.882 0.612 0.1866 31.161 0.699 0.2190 32.633 0.832 0.2362 37.630 0.823 0.2324 40.823 0.775 0.2470 39.122 0.643 0.1917 31.816 0.612 0.1963 32.536 0.586 0.1651 30.810 TESTES (Gms) %FBW %BRAIN 3.279 1.0446 148.51 3.147 0.9580 143.11 3.429 1.0457 174.59 3.309 1.0367 154.48 3.710 1.0531 167.80 2.858 0.8071 141.77 3.224 1.0274 162.75 3.042 0.9067 150.52 3.415 1.0953 181.55 2.818 0.7938 148.16 THYMUS 1 (Gms) %FBW %BRAIN | 0.392 0.1249 17.754 0.508 0.1546 23.101 0.568 0.1732 28.921 0.511 0.1601 23.856 0.430 0.1221 19.448 0.585 0.1652 29.018 0.766 0.2441 38.667 0.327 0.0975 16.180 0.365 0.1171 19.405 0.443 0.1248 23.291 Mean S.D. 10.105 3.0492 493.45 0.938 0.1996 47.874 0.711 0.2149 34.590 0.107 0.0312 4.2753 3.223 0.9768 157.32 0.271 0.1069 13.681 0.490 0.1484 23.964 0.129 0.0417 6.7317 Group : III 5 mg/kg Sex MALES 1 ANIMAL 1 667175 667176 667177 667178 667179 667180 667181 667182 (Gms) LIVER %FBW %BRAIN 9.359 3.0505 467.48 11.073 3.1511 499.68 11.090 3.2695 568.43 11.814 3.3401 568.80 10.541 3.0343 505.08 9.491 3.0805 453.25 10.330 2.8434 553.59 8.962 2.9500 439.31 SPLEEN (Gms) %FBW %BRAIN 0.639 0.2083 31.918 0.639 0.1818 28.836 0.583 0.1719 29.882 0.832 0.2352 40.058 0.726 0.2090 34.787 0.612 0.1986 29.226 0.748 0.2059 40.086 0.702 0.2311 34.412 TESTES (Gms) %FBW %BRAIN 3.197 1.0420 159.69 3.531 1.0048 159.34 3.350 0.9876 171.71 3.324 0.9398 160.04 3.103 0.8932 148.68 3.008 0.9763 143.65 3.103 0.8541 166.29 3.004 0.9888 147.25 THYMUS J (Gms) %FBW %BRAIN | 0.456 0.1486 22.777 0.598 0.1702 26.986 0.397 0.1170 20.349 0.651 0.1841 31.343 0.714 0.2055 34.212 0.366 0.1188 17.479 0.423 0.1164 22.669 0.522 0.1718 25.588 FBW - Final Body Weight ) DuPont-11763 j&wnpanySatteed Odes no! conin w * * ^ -151 - Company .Sanitized. Does not contain TSCA ) H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats ) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS Group : III 5 mg/kg Sex :MALES 1 ANIMAL 1 667183 667184 (Gms) LIVER %FBW %BRAIN 9.575 3.1128 540.96 10.943 3.1691 520.10 SPLEEN (Gms) %FBW %BRAIN 0.557 0.1811 31.469 0.679 0.1966 32.272 TESTES (Gms) %FBW %BRAIN 3.312 1.0767 187.12 3.329 0.9641 158.22 THYMUS 1 (Gms) %FBW %BRAIN | 0.403 0.1310 22.768 0.337 0.0976 16.017 Mean S.D. 10.318 3.1001 511.67 0.933 0.1451 47.093 0.672 0.2020 33.295 0.083 0.0207 4.0782 3.226 0.9728 160.20 0.171 0.0656 12.794 0.487 0.1461 24.019 0.129 0.0354 5.7156 Group : V 50 mg/kg Sex :MALES 1 ANIMAL 1 667185 667186 667187 667188 667189 667190 667191 667192 667193 667194 (Gms) LIVER %FBW %BRAIN 9.633 3.1235 486.02 10.483 3.3206 518.70 10.115 3.0652 529.58 11.263 3.2134 537.87 10.639 3.0302 535.16 10.650 3.1772 519.26 13.201 3.7418 617.45 10.556 3.1930 536.11 10.484 3.0126 530.57 9.091 2.8146 460.77 SPLEEN (Gms) %FBW %BRAIN 0.602 0.1952 30.373 0.661 0.2094 32.707 0.632 0.1915 33.089 0.617 0.1760 29.465 0.576 0.1641 28.974 0.720 0.2148 35.105 0.920 0.2608 43.031 0.629 0.1903 31.945 0.695 0.1997 35.172 0.753 0.2331 38.165 TESTES (Gms) %FBW %BRAIN 3.238 1.0499 163.37 3.361 1.0646 166.30 3.120 0.9455 163.35 3.304 0.9427 157.78 3.215 0.9157 161.72 3.206 0.9564 156.31 3.460 0.9807 161.83 3.137 0.9489 159.32 2.935 0.8434 148.53 3.329 1.0307 168.73 THYMUS 1 (Gms) %FBW %BRAIN | 0.356 0.1154 17.962 0.547 0.1733 27.066 0.449 0.1361 23.508 0.461 0.1315 22.015 0.700 0.1994 35.211 0.382 0.1140 18.625 0.771 0.2185 36.062 0.477 0.1443 24.225 0.430 0.1236 21.761 0.450 0.1393 22.808 Mean S.D. 10.612 3.1692 527.15 1.090 0.2440 40.362 0.681 0.2035 33.803 0.100 0.0280 4.3052 3.231 0.9678 160.73 0.147 0.0667 5.6767 0.502 0.1495 24.924 0.134 0.0358 6.2187 FBW - Final Body Weight DuPont-11763 -152- Company Sanitized. Does not contain TSCA CB H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS Group : VII 500 mg/kg Sex :MALES 1 ANIMAL (Gms) LIVER %FBW %BRAIN SPLEEN (Gms) %FBW %BRAIN TESTES (Gms) %FBW %BRAIN THYMUS 1 (Gms) %FBW %BRAIN | 667195 667196 667197 667198 667199 667200 667201 667202 667203 667204 10.450 3.4296 545.98 12.014 3.5970 556.20 12.749 3.6116 592.15 13.656 3.8349 690.05 12.530 3.7504 620.60 10.993 3.4656 573.15 10.689 3.9677 548.72 14.623 4.2129 738.16 14.165 3.9901 707.54 12.532 3.7588 672.32 0.566 0.1858 29.572 0.680 0.2036 31.481 0.673 0.1907 31.259 0.692 0.1943 34.967 0.505 0.1512 25.012 0.695 0.2191 36.236 0.556 0.2064 28.542 0.666 0.1919 33.619 0.779 0.2194 38.911 0.600 0.1800 32.189 3.028 0.9938 158.20 3.273 0.9799 151.53 3.484 0.9870 161.82 3.475 0.9758 175.59 3.443 1.0305 170.53 3.508 1.1059 182.90 2.974 1.1039 152.67 3.199 0.9216 161.48 3.497 0.9851 174.68 3.309 0.9925 177.52 0.210 0.0689 10.972 0.394 0.1180 18.241 0.522 0.1479 24.245 0.502 0.1410 25.366 0.518 0.1550 25.656 0.542 0.1709 28.259 0.287 0.1065 14.733 0.726 0.2092 36.648 0.463 0.1304 23.127 0.531 0.1593 28.487 Mean S.D. 12.440 3.7619 624.49 1.439 0.2475 72.011 0.641 0.1942 32.179 0.082 0.0201 4.0048 3.319 1.0076 166.69 0.199 0.0577 10.991 0.470 0.1407 23.573 0.144 0.0382 7.3835 DuPont-11763 FBW - Final Body Weight H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11763 APPENDIX I Individual Animal Microscopic and Macroscopic Observations PpmpanySanitized. Does not contain TSCA CBI - 154- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS EXPLANATORY NOTES Lesion Grading Histopathological 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: the amount of change present barely exceeds that which is considered to be within normal limits. Mild: in general, the lesion is easily identified but of limited severity. The lesion probably does not produce any functional impairment. Moderate: the lesion is prominent but there is significant potential for increased severity. Limited tissue or organ dysfunction is possible. Severe: 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 morphological characteristics of lesions, they also indicate their relative biological significance. Gross observations listing multiple masses for a tissue are distinguished with letters (i.e., ,a, b, c, d, etc.) pompany Sanitized. Does not cor'ln,'> -155- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : I 0 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667165 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. HEART : DEGENERATION, MYOFIBER, FOCAL, minimal. MANDIBULAR LYMPH NODE : ERYTHROCYTOSIS/ERYTHROPHAGOCYTOSIS, minimal. PARATHYROID GLANDS : ONE OF A PAIR PRESENT. 667165 Continued on the next page .... Sanitized, Dees not contain T8CCB1 H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats D u P on t-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : X 0 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667165 Continued from previous page Histopathology : No Microscopic Abnormality Observed : KIDNEYS, LUNGS, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E YE(S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, BONE MARROW, NOSE, SKIN, TREATED, SKIN, UNTREATED 667166 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE 667166 Continued on the next page .... pgmpanyjSapltKzedDoes not contain TSCCBl - 157- / " ''N H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : I 0 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667166 Continued from previous page Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. KIDNEYS : CHRONIC PROGRESSIVE NEPHROPATHY, minimal. MANDIBULAR LYMPH NODE : ERYTHROCYTOSIS/ERYTHROPHAGOCYTOSIS, minimal. PARATHYROID GLANDS : ONE OF A PAIR PRESENT. No Microscopic Abnormality Observed : LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, BONE MARROW, NOSE, SKIN, TREATED, SKIN, UNTREATED 667167 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, 667167 Continued on the next page .... TSCA - 158- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : I 0 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667167 Continued from previous page Gross Pathology No Macroscopic Abnormality Observed : THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE Histopathology LIVER : INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. MANDIBULAR LYMPH NODE : ERYTHROCYTOSIS/ERYTHROPHAGOCYTOSIS, minimal. PARATHYROID GLANDS : ONE OF A PAIR PRESENT. No Microscopic Abnormality Observed : KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, BONE MARROW, NOSE, SKIN, TREATED, SKIN, UNTREATED Bfifilffapy.Sanitized. D oes not contain TS6A 11 - 159- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : I 0 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667168 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. KIDNEYS : CHRONIC PROGRESSIVE NEPHROPATHY, minimal. PARATHYROID GLANDS : MISSING. NOSE : METAPLASIA, SQUAMOUS, EPITHELIUM, mild. INFLAMMATION, ACUTE, EPITHELIAL, minimal. 667168 Continued on the next page .... Does not contain TSCA CBI -160- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : I 0 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667168 Continued from previous page Histopathology : No Microscopic Abnormality Observed : LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, BONE MARROW, SKIN, TREATED, SKIN, UNTREATED ORGANS NOT EXAMINED: PARATHYROID GLANDS 667169 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, 667169 Continued on the next page .... not coniai TSCAClft gjjgjljHzed*08 - 161 - /""N H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : I 0 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667169 Continued from previous page Gross Pathology No Macroscopic Abnormality Observed : THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EY E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE Histopathology LUNGS : HEMORRHAGE, ALVEOLAR, FOCAL, minimal. MANDIBULAR LYMPH NODE : ERYTHROCYTOSIS/ERYTHROPHAGOCYTOSIS, minimal. PARATHYROID GLANDS : MISSING. EYE(S ) WITH OPTIC NERVE : OPTIC NERVE NOT PRESENT. PROSTATE : INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. No Microscopic Abnormality Observed : LIVER, KIDNEYS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E YE(S ) WITH OPTIC NERVE, SKIN, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, BONE MARROW, NOSE, SKIN, TREATED, SKIN, UNTREATED 667169 Continued on the next page jQpmpany Sanitized. D oes not contain TSCA CBi - 162- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : I 0 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667169 Continued from previous page Histopathology : ORGANS NOT EXAMINED: PARATHYROID GLANDS 667170 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE Histopathology : 667170 LIVER : INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. KIDNEYS : CHRONIC PROGRESSIVE NEPHROPATHY, minimal. HEART : DEGENERATION, MYOFIBER, FOCAL, minimal. Continued on the next page .... m rnpm t Sanitized. Does net contain TSCA CBl -163 - H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : I 0 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667170 Continued from previous page Histopathology MANDIBULAR LYMPH NODE : ERYTHROCYTOSIS/ERYTHROPHAGOCYTOSIS, minimal. PARATHYROID GLANDS : MISSING. No Microscopic Abnormality Observed : LUNGS, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, BONE MARROW, NOSE, SKIN, TREATED, SKIN, UNTREATED ORGANS NOT EXAMINED: PARATHYROID GLANDS 667171 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND 667171 Continued on the next page .... Does notcontain TSC* < H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : I 0 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667171 Continued from previous page Gross Pathology : No Macroscopic Abnormality Observed : THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. KIDNEYS : CHRONIC PROGRESSIVE NEPHROPATHY, minimal. MANDIBULAR LYMPH NODE : ERYTHROCYTOSIS/ERYTHROPHAGOCYTOSIS, min ima1. PROSTATE : INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. No Microscopic Abnormality Observed : LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E YE(S ) WITH OPTIC NERVE, SKIN, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, BONE MARROW, NOSE, SKIN, TREATED, SKIN, UNTREATED Sanitized Does not contain TSCA CBf -165- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPICAND MACROSCOPIC OBSERVATIONS Dose Group : I 0 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667172 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. MANDIBULAR LYMPH NODE : HYPERPLASIA, LYMPHOCYTE/PLASMACYTE, mild. ERYTHROCYTOSIS/ERYTHROPHAGOCYTOSIS, mild. PARATHYROID GLANDS : ONE OF A PAIR PRESENT. 667172 Continued on the next page .... Pompan^ Sanitized. D oes notcontain TSCA C8I -166- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPICAND MACROSCOPIC OBSERVATIONS Dose Group : I 0 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667172 Continued from previous page Histopathology : No Microscopic Abnormality Observed : KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, BONE MARROW, NOSE, SKIN, TREATED, SKIN, UNTREATED 667173 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE 667173 Continued on the next page .... not contain TSCA CE Company Sanitized. Does - 167- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPICAND MACROSCOPIC OBSERVATIONS Dose Group : I 0 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667173 Continued from previous page Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. KIDNEYS : CHRONIC PROGRESSIVE NEPHROPATHY, minimal. MANDIBULAR LYMPH NODE : HYPERPLASIA, LYMPHOCYTE/PLASMACYTE, minimal. PARATHYROID GLANDS : ONE OF A PAIR PRESENT. No Microscopic Abnormality Observed : LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, BONE MARROW, NOSE, SKIN, TREATED, SKIN, UNTREATED 667174 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, 667174 Continued on the next page .... Sejnp^TixSanitized. Sees notcontain TSCACB - 168- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : I 0 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667174 Continued from previous page Gross Pathology : No Macroscopic Abnormality Observed : THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. KIDNEYS : CHRONIC PROGRESSIVE NEPHROPATHY, minimal. LUNGS : PNEUMONITIS, ACUTE, FOCAL, minimal. HEART : DEGENERATION, MYOFIBER, FOCAL, minimal. INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. MANDIBULAR LYMPH NODE : ERYTHROCYTOSIS/ERYTHROPHAGOCYTOSIS, minimal. HYPERPLASIA, LYMPHOCYTE/PLASMACYTE, minimal. No Microscopic Abnormality Observed : SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, 667174 Continued on the next page .... jggBBapy ganfttred, D oes not contain TSCA CB -169- /"S H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : I 0 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667174 Continued from previous page Histopathology : No Microscopic Abnormality Observed : PHARYNX/LARYNX, EYE(S> WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, BONE MARROW, NOSE, SKIN, TREATED, SKIN, UNTREATED ISBfi! Ilagitlzed. D oes no! contain TSCA CB* - 170- ,/ , H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : III 5 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667175 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology- No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE 667176 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, :a' AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE SfflWzed. Bees M l contain TSCRCBI - 171 - H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPICAND MACROSCOPIC OBSERVATIONS Dose Group : III 5 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667177 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE 667178 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE iSgpgaaw Sanitized. D oes not contain TSCA t H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : III 5 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667179 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE 667180 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E YE(S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE jCompany Sanitized. Does not contain TSCA CBI - 173 - H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPICAND MACROSCOPIC OBSERVATIONS Dose Group : III 5 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667181 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE 667182 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E YE(S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE not contain TSCACBl Pompany Sanltlzasi 0 * -174- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : III 5 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667183 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE 667184 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E {S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE pottpany Sanitized. Doe not contain tsca cm - 175- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : V 50 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667185 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE 667186 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE* THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E YE(S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE toM W Smlteed. Does notconi.li. tsc* CB! - 176 - H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : V 50 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667187 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE 667188 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : POPLITEAL LYMPH NODE : DISCOLORATION, DARK, RIGHT. No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE,. THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, 667188 Continued on the next page .... S g g P iH D pes not eonlain TSCA CBt - 177- /"'"'N, H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : V 50 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667188 Continued from previous page Gross Pathology No Macroscopic Abnormality Observed : THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E YE{S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE 667189 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E {S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE TSC* CBI - 178- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : V 50 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667190 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE 667191 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EY E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE Sanitized. Does not contain TSCA CBI - 179- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : V 50 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667192 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S> WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE 667193 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE not contain TSCA COT Pompan* Sanitized. Does H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : V 50 m g / k g Sex: Males Animal Ref Microscopic & Macroscopic Findings 667194 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E YE(S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE Company -181 - D oes not contain TSCA CB1 r^ - H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : VII 500 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667195 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE Histopathology : LIVER : NECROSIS, HEPATOCELLULAR, FOCAL, minimal. INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. HEART : DEGENERATION, MYOFIBER, FOCAL, minimal. MANDIBULAR LYMPH NODE : HYPERPLASIA, LYMPHOCYTE/PLASMACYTE, minimal. PARATHYROID GLANDS : ONE OF A PAIR PRESENT. 667195 Continued on the next page .... -182- A\ H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats_____________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : VII 500 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667195 Continued from previous page Histopathology No Microscopic Abnormality Observed : KIDNEYS, LUNGS, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, BONE MARROW, NOSE SKIN, TREATED, SKIN, UNTREATED 667196 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE 667196 Continued on the next page /""N .Company Sanitized. Poes noi contain TSCACBf -183- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : VII 500 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667196 Continued from previous page Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. MANDIBULAR LYMPH NODE : ERYTHROCYTOSIS/ERYTHROPHAGOCYTOSIS, minimal. PARATHYROID GLANDS : ONE OF A PAIR PRESENT. No Microscopic Abnormality Observed : KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, BONE MARROW, NOSE, SKIN, TREATED, SKIN, UNTREATED 667197 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : KIDNEYS : DILATATION, RIGHT, PELVIS, moderate. 667197 Continued on the next page .... JSflfflPanyjlinlEfoed. Does not contain TSCAC'i - 184- H-25509: Repeated-Dose Dermal Toxicity 2.8-Day Study in Male Rats DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : VII 500 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667197 Continued from previous page Gross Pathology : No Macroscopic Abnormality Observed : LIVER, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. KIDNEYS : DILATATION, PELVIS, UNILATERAL, mild. CHRONIC PROGRESSIVE NEPHROPATHY, minimal. No Microscopic Abnormality Observed : LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, BONE MARROW, NOSE, SKIN, TREATED, SKIN, UNTREATED ysw naiiw gtajjltized. Does not contain TSCA OBI - 185- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : VII 500 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667198 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E {S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. KIDNEYS : CHRONIC PROGRESSIVE NEPHROPATHY, minimal. No Microscopic Abnormality Observed : LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, 667198 Continued on the next page .... yjflfnpany Sanitized. Does not contain TRCA CBt - 186- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : VII 500 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667198 Continued from previous page Histopathology : No Microscopic Abnormality Observed : TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, BONE MARROW, NOSE, SKIN, TREATED, SKIN, UNTREATED 667199 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E YE(S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE Histopathology : 667199 LIVER : INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. KIDNEYS : CHRONIC PROGRESSIVE NEPHROPATHY, minimal. Continued on the next page .... Company .Sanitized. Does not contain T9":*n ' - 187- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : VII 500 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667199 Continued from previous page Histopathology MANDIBULAR LYMPH NODE : ERYTHROCYTOSIS/ERYTHROPHAGOCYTOSIS, mild. PARATHYROID GLANDS : ONE OF A PAIR PRESENT. EPIDIDYMIDES : INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. No Microscopic Abnormality Observed : LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, FEMUR/KNEE JOINT, STERNUM, BONE MARROW, NOSE, SKIN, TREATED, SKIN, UNTREATED 667200 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : KIDNEYS : DILATATION, PELVIS, RIGHT, moderate 667200 Continued on the next page .... Company.Sanitized, Does notcontain TSCACBi H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : VII 500 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667200 Continued from previous page Gross Pathology : No Macroscopic Abnormality Observed : LIVER, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. KIDNEYS : CHRONIC PROGRESSIVE NEPHROPATHY, minimal. DILATATION, PELVIS, UNILATERAL, mild. MANDIBULAR LYMPH NODE : HYPERPLASIA, LYMPHOCYTE/PLASMACYTE, minimal. PARATHYROID GLANDS : ONE OF A PAIR PRESENT. No Microscopic Abnormality Observed : LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, 667200 Continued on the next page .... * Company Sanitized. Dees not contain TSCA CB1 H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : VII 500 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667200 Continued from previous page Histopathology : No Microscopic Abnormality Observed : PHARYNX/LARYNX, E YE(S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, BONE MARROW, NOSE, SKIN, TREATED, SKIN, UNTREATED 667201 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : LIVER : FOCI, DARK, FEW. POPLITEAL LYMPH NODE : LARGE, DARK. No Macroscopic Abnormality Observed : KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E {S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE 667201 Continued on the next page .... jCgmpanx Sanitized. D oes not contain TSCA CBI -190- /""N H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : VII 500 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667201 Continued from previous page Histopathology LIVER : HEMORRHAGE, FOCAL, minimal. INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. HEART : DEGENERATION, MYOFIBER, FOCAL, minimal. MANDIBULAR LYMPH NODE : ERYTHROCYTOSIS/ERYTHROPHAGOCYTOSIS, minimal. HYPERPLASIA, LYMPHOCYTE/PLASMACYTE, minimal. POPLITEAL LYMPH NODE : HYPERPLASIA, LYMPHOCYTE/PLASMACYTE, mild. No Microscopic Abnormality Observed : KIDNEYS, LUNGS, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, BONE MARROW, NOSE, SKIN, TREATED, SKIN, UNTREATED /"V {Company S an itizes. W w 0* e o n , TSCA cm -191- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : VII 500 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667202 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. LUNGS : HEMORRHAGE, ALVEOLAR, FOCAL, minimal. MANDIBULAR LYMPH NODE : HYPERPLASIA, LYMPHOCYTE/PLASMACYTE, minimal. 667202 Continued on the next page .... Company Sanitized. Does not contain TSCA CBI - 192- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : VII 500 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667202 Continued from previous page Histopathology : Mo Microscopic Abnormality Observed : KIDNEYS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, BONE MARROW, NOSE, SKIN, TREATED, SKIN, UNTREATED 667203 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE 667203 Continued on the next page .... Company Sanitized. Does not contain TSCA CBI -193- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : VII 500 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667203 Continued from previous page Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. KIDNEYS : CHRONIC PROGRESSIVE NEPHROPATHY, minimal. MESENTERIC LYMPH NODE : ERYTHROCYTOSIS/ERYTHROPHAGOCYTOSIS, minimal. MANDIBULAR LYMPH NODE : ERYTHROCYTOSIS/ERYTHROPHAGOCYTOSIS, minimal. HYPERPLASIA, LYMPHOCYTE/PLASMACYTE, minimal. PARATHYROID GLANDS : ONE OF A PAIR PRESENT. No Microscopic Abnormality Observed : LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, SALIVARY GLANDS, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, BONE MARROW, NOSE, SKIN, TREATED, SKIN, UNTREATED g fflffr'a -Santtfe*11' Does not contain TSCACBt - 194- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : VII 500 mg/kg Sex: Males Animal Ref Microscopic St Macroscopic Findings 667204 Terminal Sacrifice Killed on Day : 28 Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, SALIVARY GLANDS, MANDIBULAR LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. HEART : DEGENERATION, MYOFIBER, FOCAL, minimal. RECTUM : MISSING. MANDIBULAR LYMPH NODE : ERYTHROCYTOSIS/ERYTHROPHAGOCYTOSIS, mild. PARATHYROID GLANDS : ONE OF A PAIR PRESENT. 667204 Continued on the next page .... Pom pane Sanitized. D oes not contain TSCA CBS -195- H-25509: Repeated-Dose Dermal Toxicity 28-Day Study in Male Rats______________ DuPont-11763 INDIVIDUAL ANIMAL MICROSCOPIC AND MACROSCOPIC OBSERVATIONS Dose Group : VII 500 mg/kg Sex: Males Animal Ref Microscopic & Macroscopic Findings 667204 Continued from previous page Histopathology No Microscopic Abnormality Observed : KIDNEYS, LUNGS, SKELETAL MUSCLE, SPLEEN, AORTA, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, MESENTERIC LYMPH NODE, SALIVARY GLANDS, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, PITUITARY GLAND, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, E Y E (S ) WITH OPTIC NERVE, SKIN, PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, FEMUR/KNEE JOINT, STERNUM, BONE MARROW, NOSE, SKIN, TREATED, SKIN, UNTREATED ORGANS NOT EXAMINED: RECTUM .Company Sanitized. Does not contain TSCA CBi - 196-