Document omQpxZwDKkb5DNLwD65BDMXME

AR226-3168 TRADE SECRET Study Title H-24267: Two-Week Inhalation Toxicity Study in Male Rats Laboratory Project ID: DuPont-4292 AUTHOR: David P. Kelly, B.S. STUDY COMPLETED ON: October 6, 2000 PERFORMING LABORATORY: E.I. du Pont de Nemours and Company Haskell Laboratory for Toxicology and Industrial Medicine Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050 ^^^| WORK REQUEST NUMBER:|--------J v^ SERVICE CODE NUMBER:yB^j CLINICAL PATHOLOGY^* t Page 1 of 181 MBpany SanBSzed. Doos not conSaSiraTSCA GBI H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT This study was conducted in compliance with U.S. EPA TSCA (40 CPR part 792) Good Laboratory Practice Standards except for the items documented below. None of the items listed impact the validity of the study. 1. The test substance was characterized by the sponsor prior to the initiation of this study and a report was supplied, however, records of the characterization are not available. Although the characterization was not performed under Good Laboratory Practice Standards, based on the familiarity with the laboratory and the techniques used, the data is considered sufficient for the purposes of this study. 2. Prior to the daily experiments, samples of the test compound were transferred to holding containers. These intermediate containers were used for convenience in transferring the test compound into syringes that were used in metering the test chemical into the atmosphere generation system. The intermediate containers were not labeled in compliance with Good Laboratory Practice Standards. In addition, the weights of the test substance were recorded on sample containers and later transferred to the study notebook and labels were discarded. Submitter / Sponsor: E. I. du Font de Nemours and Company Wilmington, Delaware 19898 U.S.A. DuPont Registration Representative: Date H-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 QUALITY ASSURANCE STATEMENT Haskell Sample Number(s): 24267 Dates of Inspections: Conduct: May 2,4,17,2000 Records, Reports: September 13-15,18-21,2000 Dates Findings Reported to: Study Director: September 21,2000 Management: October 6,2000 Reported by: ^r<te^\ i^^^W L-- ^ Joseph C/.TH-T^a_m_"i1l1l \1T^^^_1- Senior Quality Assurance Auditor ^&> O^f- ^g^ Date -3 CERTIFICATION We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study. ' / ^ Clinical Pa&ology . ______/_/^__^ ^ ^ Y Evaluations Reported by; ^ C^J^'^- Nancy B. Bverds, D.V.M. Diplomate A.C.V.P- Principal Research Scientist ^a^y^ Date Anatomic Pathology Evaluatiam Reported by: ~ '/f ^ ''^f^^' ^ft/^^AjLA^ /<' ^^u^^ Steven R- Frame, D.V.M., Ph.D. Diplomate A.C.Vi1. Director ^ /^V-&sw>~ Date Ac'mnsastwowmwai^c. a P^R^S! j ^^_^W^^^h &*^ _^tOW^^ ff^- LG^-_T_M___ G. Tracy Makovec'D.V.M. Diplomate A.C.V.P. Senior Research Scientist ^Z&Z^J^t? _____D_ate_ Approved by:: 4^ 'J*^^_____ ' (r SccootfCfE. Loveless. Ph.D. Director (-oot >&0 Date -4- ___ H-24267: Two-Week Inhalation Toxicity Study in Male Rats___ DuPont-4292 TABLE OF CONTENTS Page GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT ...................................2 QUALITY ASSURANCE STATEMENT ...................................................................................3 CERTIFICATION........................................................................................................................^ LIST OF TABLES .........................................................................................................................7 LIST OF FIGURES .......................................................................................................................7 LIST OF APPENDICES...............................................................................................................8 STUDY INFORMATION .............................................................................................................9 STUDY PERSONNEL.................................................................................................................10 SUMMARY ..................................................................................................................................11 INTRODUCTION........................................................................................................................12 MATERIALS AND METHODS ................................................................................................12 A. Test Substance ...................................................................................................................12 B. Animals..............................................................................................................................12 C. Animal Husbandry.............................................................................................................12 1. Temporary Animal Identification and Quarantine.................................................................................. 12 2. 13 Housing.................................................................................................................................................. 3. Animal Room Environment.................................................................................................................... 13 4. Animal Selection and Permanent Identification..................................................................................... 13 5. Feed and Water.......................................................................................................................................l3 6. Health Monitoring Program..............................................................................................................,.....13 D. Study Design......................................................................................................................l4 E. Inhalation Exposure System...............................................................................................14 1. Atmosphere Generation..........................................................................................................................14 2. Chamber Construction and Design.........................................................................................................l4 3. Exposure Mode......................................................................................................................................15 F. Characterization of Chamber Atmosphere......................................................................... 15 1. Test Substance Sampling and Analysis ..................................................................................................15 2. Environmental Monitoring.....................................................................................................................15 G. Body Weights and Clinical Observations ..........................................................................15 H. Clinical Pathology Evaluations...........................................................................................16 1. Hematology.........................................................--................................................................................16 2. Coagulation Parameters.......................................................................................................................... 16 3. Serum Chemistry.................................................................................................................................... 16 4. 17 Urinalysis................................................................................................................................................ I. Anatomic Pathology Evaluations.......................................................................................17 J. Statistical Analyses............................................................................................................ 18 -5- TABLE OF CONTENTS (Continued) Page RESULTS AND DISCUSSION ..................................................................................................20 In-Life Animal Measuremente ....................................................................................................20 A. Chamber Atmosphere Analysis of H-24267 ......................................................................20 B. Body Weights and Clinical Observations ..........................................................................20 Clinical Pathology Evaluations..................................................................................................^! A. Hematology/Coagulation...................................................................................................21 B. Serum Chemistry................................................................................................................21 C. Urinalysis...........................................................................................................................22 D. Conclusions........................................................................................................................23 Anatonnc Pathology Evaluations................................................................................................23 A. Organ Weights...................................................................................................................23 B. Gross Observations............................................................................................................23 C. Microscopic Findings.........................................................................................................24 D. Conclusions.......................................................................................................................^ CONCLUSIONS ..........................................................................................................................25 RECORDS AND SAMPLE STORAGE ....................................................................................25 REFERENCES............................................................................................................................^ Jrlb'lJRllio.......................................................................................................................73 APPENDICES.............................................................................................................................^ -6- CiWtpwsi BanEtteeA LIST OF TABLES Page 1. CHAMBER CONCENTRATIONS OF H-24267 ................................................................................................31 2. PARTICLE SIZE DISTRIBUTION OF H-24267................................................................................................31 3. CHAMBER ENVIRONMENTAL CONDITIONS..............................................................................................31 4. MEAN BODY WEIGHTS OF MALE RATS ......................................................................................................32 5. MEAN BODY WEIGHT GAINS OP MALE RATS ...........................................................................................34 6. SUMMARY OP CLINICAL OBSERVATIONS IN MALE RATS AT WEIGHING.........................................36 7. SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS ......................................................................37 8. SUMMARY OF COAGULATION VALUES FOR MALE RATS .....................................................................42 9. SUMMARY OF SERUM CHEMISTRY VALUES FOR MALE RATS.............................................................43 10. SUMMARY OF URINALYSIS VALUES FOR MALE RATS..........................................................................46 11. MEAN FINAL BODY AND ORGAN WEIGHTS FROM MALE RATS DAY 11 SACRIFICE ......................47 12. MEAN FINAL BODY AND ORGAN WEIGHTS FROM MALE RATS DAY 25 SACRIFICE ......................49 13. INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS DAY 11 SACRIFICE ..................................51 14. INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS DAY 25 SACRIFICE ..................................56 15. INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS DAY 11 SACRIFICE........................................................................................................................................... 60 16. INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS DAY25SACRIHCE.-.........................................................................................................................................70 LIST OF FIGURES Page 1. SCHEMATIC OFEXPOSURE SYSTEM....................................................................--................................^ 2. MEAN BODY WEIGHTS OF MALE RATS ......................................................................................................75 -7. LIST OF APPENDICES Page A. DAILY ATMOSPHERIC ANALYSES...............................................................................................................77 B. DAILY ENVIRONMENTAL CONDITIONS..................................................................................................... 81 C. INDIVIDUAL BODY WEIGHTS....................................................................................................................... 85 D. INDIVIDUAL CLINICAL OBSERVATIONS AND MORTALITY RECORDS ...............................................90 E. INDIVIDUAL ANIMAL CLINICAL PATHOLOGY DATA .............................................................................95 P. INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS................................................................ 135 G. INDIVIDUAL ANIMAL PATHOLOGY DATA............................................................................................... 140 -8- Ctosnpany SaR*tfe@d. Doe not eontain TSCA CBI H-24267: Two-Week Inhalation Toxicity Study in Male Rats STUDY INFORMATION Substance Tested: |f|i||i^^J^^^M^^.J1| Synonyms/Codes: H-24267 Haskell Number: 24267 MSDS Reference NumbeJ| DuPont-4292 Stability: The test substance appeared to be stable under the conditions of the study; no evidence of instability was observed. Sponsor: E. I. du Pont de Nemours and Company Wilmington, Delaware 19898 U.S.A. Study Initiated/Completed: May 4, 2000 / (see report cover page) In-life Initiated/Completed: May 8, 2000 / June 2,2000 9- H-24267: Two-Week Inhalation Toxicity Study in Male Rats STUDY PERSONNEL Study Director: Management: Primary Technician: David P. Kelly, B.S. Scott E. Loveless, Ph.D. Nancy C. Chromey, Ph.D. Thomas A. Kegelman, A.A. Clinical Pathologist: Nancy E. Everds, D.V.M. Management: Steven R. Frame, D.V.M., Ph.D. Pathologist: Management: Peer Review Pathologist: Steven R. Frame, D.V.M., Ph.D. Steven R. Frame, D.V.M., Ph.D. Robert W. Rickard, Ph.D., D.A.B.T. G. Tracy Makovec, D.V.M. Toxicology Report Preparation: Maryanne M. Wilford, B.A. Laboratory Veterinarian: Wanda L. West, D.V.M., A.C.L.A.M. DuPont-4292 -10- 'Cmpww SSwwWwxi ftfltws (M)# iewm(!fi) TOGA CBI SUMMARY Groups of 10 male Cri:CD(SD)IGS BR rats were exposed for 6 hours/day, for a total of 9 exposures over a 2-week period to design concentrations of 25,125, or 600 mg/m3 (actual mean concentrations were 23,110, and 600 mg/m3) of H-24267 aerosol. The mass median aerodynamic equivalent diameter of the aerosols ranged from 2.6 to 4.2 fim. A control group of 10 male rats was exposed simultaneously to houseline air. At the end of the exposure period, blood and urine samples were collected for clinical analyses, and 5 rats per group were sacrificed for pathologic examination. After a 2-week recovery period, the surviving rats were also given clinical and pathologic examinations. During the exposure period a dose-related body weight depression occurred primarily in the 125 and 600 mg/m3 groups and all 3 test groups gained less weight than the controls. The H-24267 exposed rats resumed a normal weight gain rate during the recovery period. Clinical pathology evaluations at both evaluation times showed no lexicologically significant changes in hematology, clinical chemistry, or urinalysis parameters, including urinary fluoride. Weight analysis of the major organs showed no effects attributable to the test compound. Histological findings were confined to the respiratory tract; there were no significant findings in any other evaluated organs. Minimal, dose-related histologic effects attributable to the test compound were detected in the respiratory tract of all treated groups at the end of the 2-week exposure period. The effects were consistent with minimal irritation and were slightly more apparent with increasing dose. These effects occurred throughout the respiratory tract, including the nose, larynx, and lung. In the lung, inflammation was characterized by mild thickening of alveolar duct bifurcations and adjacent alveolar septa due to mononuclear inflammatory cell infiltration. Slight hypertrophy of terminal bronchiolar epithelium was also present in association with the centriacinar inflammatory response. In the larynx, minimal squamous metaplasia was present in all treated groups. Necrosis of cartilage overlying the laryngeal saccule was present in 1 rat in the 600 mg/m group. In the nose, hypertrophy of goblet cells was present in all treated groups and was most apparent in the mucosa of the pharyngeal duct. Following an approximate 2-week recovery period, respiratory tract lesions were essentially reversible. Single occurrences of focal, very slight thickening of alveolar duct septa occurred in the 125 and 600 mg/m3 recovery groups. In addition, focal residual cartilage necrosis in the larynx occurred in 2/5 rats in the 600 mg/m3 recovery group. Based on the finding of minimal respiratory tract inflammation observed in all exposed groups, including the lowest concentration tested, 25 mg/m3, a no-observed-adverse- effect-level (NOAEL) was not determined for repeated aerosol exposures to H-24267 in rats. -11 Id-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 INTRODUCTION The purpose of this 2-week inhalation study was to investigate the effects of repeated inhalation exposure in rats to high concentrations ofH-24267. exposure. The data will Inhalation is an expected route of human be used to provide information for safe handling of the test substance. The 4-hour rats died approximate lethal concentration (ALC) in rats for this compound was 3.9 mg/L; after exposure to 2.3 mg/L (DuPont HL-1997-00273). rangefinding Prior to the present study, a no for 3 days to experiment was conducted in groups of rats exposed for approximately 6 hours/day a mean concentration of approximately 790 mg/m3 of the test compound. During 1 exposure there was a reduced response to an alerting stimulus observed. noise and weight After exposure, lung loss were observed. These effects were reversible within 2 days. In another 3e1xpmergi/mme3nwt iwtheiegxhctulorssisonwsasasohbisgehrved6i9n mragts/me3x;posed for 3 days to a mean concentration of after the last exposure. A group ofarsats exposed tfhoer r1atdsaryetsoum25edmag/nmo3rmshalowweedignhot geaffienctosn. the day MATERIALS AND METHODS A. Test Substance 4H The test substance, H-24267, was supplied by the sponsor as batch analysis was provided by the sponsor. throughout The test substancewas assumed to be st the exposure phase of the study; no evidence of instability was observed. B. Animals Male Crl:CD(SD)IGSBR rats were received from Charles River Laboratories, North Carolina. The rats were approximately 7 weeks old on the day of arrival. me., Raleigh, Rats have historically Crl:CD(SD)IGS been used in safety evaluation studies for inhalation toxicity testing. The extensive experienBceR wraitthwtahse ssetrleacinteadt bHaassekdeollnLcaobnosriasttoernyt.ly acceptable health status and on C. Animal Husbandry 1. Temporary Animal Identification and Quarantine Upon arrival, each rat was assigned a temporary, 1- to 2-digit identification recorded on a card affixed to the cage. During number, which was Rats were quarantined for 6 days prior to test initiation. the quarantine period rats were weighed and observed 3 times for clinical signs of disease. -12- dompan^ Hmfflteed. Bess not contain T8CA CBI H-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 2. Housing Rats were housed either singly or in pairs in suspended, stainless steel, wire-mesh cages. 3. Animal Room Environment Animal rooms were maintained on a timer-controlled, 12-hour light/12-hour dark cycle. Environmental conditions of the rooms were targeted to be within a temperature range of 23 2C and a relative humidity range of 50 10%. Excursions outside of these ranges were of insufficient magnitude and/or duration to have adversely affected the validity of the study. 4. Animal Selection and Permanent Identification Prior to the end of the quarantine period, rats were assigned to 4 groups of 10 male rats each. Rats were divided into groups with the aid of a computerized, stratified, randomization program, so that mean body weights for each group were similar. Rats were approximately 8 weeks old and weighed between 257 and 333 grams at the start of the exposures. Upon grouping, each rat was assigned a unique 6-digit animal number. Following grouping, a 1to 2-digit identification number was tattooed onto the tail of each rat. Both numbers were recorded on a card affixed to the cage. 5. Feed and Water Except during exposure, tap water was available ad libitum. PMI Nutrition International, me. Certified Rodent LabDiet 5002 was available ad libitum except during exposure and fasting periods prior to necropsy. 6. Health Monitoring Program As specified in the Haskell Laboratory animal health and environmental monitoring program, the following procedures are performed periodically to assure 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. _^_ H-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 The animal health and environmental monitoring program is administered by the attending laboratory animal veterinarian. D. Study Design Four groups of 10 male rats each were exposed to concentrations of H-24267 targeted to 0,25, 125, or 600 mg/m3. Rats were exposed nose-only for 6 hours per day for a total of 9 exposures. On the day of the last exposure, collection of an overnight urine specimen was initiated for each rat. On the day following the last exposure, blood samples were collected for clinical analyses, and 5 rats per group were sacrificed for anatomic pathology examination. All remaining rats were allowed to recover for a 14-day period. At the end of the recovery period, blood and urine samples were collected for clinical analyses, and all surviving rats were sacrificed for anatomic pathology examination. All rats were weighed and individually observed for clinical signs of toxicity throughout the exposure period. Group clinical signs were observed during each exposure. In addition, the alerting response to an auditory stimulus was checked during each exposure. After each exposure, rats were checked for the alerting response to an auditory stimulus prior to removal from chambers and were observed for clinical signs immediately after they were returned to their cages. Surviving rats were weighed and individually observed for clinical signs of toxicity throughout the recovery period. E. Inhalation Exposure System (Figure 1) 1. Atmosphere Generation Chamber atmospheres were generated by nebulization of H-24267 in air with a Spraying Systems nebulizer. The test substance was metered into the nebulizer with a Harvard Model 22 syringe drive. The syringe containing the test substance was heated (as high as 60C) to facilitate liquid spraying. Filtered houseline air, introduced at the nebulizer, atomized the test substance and carried the aerosol into the exposure chamber. Dilution air was added to the chamber turret so that the total airflow to each chamber was 30 liters per minute. A baffle placed at the bottom of the chamber turret was used to promote uniform aerosol distribution throughout the chamber. Varying the test substance feed rate to the aerosol generator controlled chamber concentrations of H-24267. Test atmospheres were exhausted through a dry-ice cold trap and an MSA filter prior to discharge into the fume hood. 2. Chamber Construction and Design The exposure chamber was constructed of stainless steel and glass (NYU style) with a nominal internal of 150 liters. A tangential air feed on the chamber promoted uniform chamber distribution of the test atmosphere. -14- H-24267: Two-Week Inhalation Toxicity Study in Male Rats____________________ 3. Exposure Mode DuPont-4292 During exposure, rats were individually restrained in stainless steel cylinders with conical nose pieces. The restrainers were inserted into the polymethylmethacrylate faceplate of the exposure chamber so that only the nose of each rat extended into the chamber. F. Characterization of Chamber Atmosphere 1. Test Substance Sampling and Analysis The atmospheric concentration of H-24267 was determined at approximately 60-minute intervals by gravimetric analysis of the test chambers. The control chamber was sampled once daily. Known volumes of chamber atmosphere were drawn from the breathing zone of the rats through 25 mm filter cassettes that contained preweighed Gelman glass fiber (Type A/E) filters. The filters were weighed on a Cahn Model C-26 Electrobalance. The atmospheric concentrations of H-24267 were calculated from the difference in the pre- and post-sampling filter weights. An air sample was taken from each exposure chamber1 once per week to determine the particle size distribution (mass median aerodynamic diameter and geometric standard deviation) using a Sierra Series 210 cyclone preseparator/cascade impactor and Sierra Series 110 Constant How Air Sampler.^ 2. Environmental Monitoring Chamber airflow was set at the beginning of each exposure to achieve at least 12 air changes per hour. The airflow was monitored continually with a calibrated Brooks model 1355 Sho-Rate Rotometer and recorded initially and whenever changes were made. Chamber temperature was targeted at 22 2C. The temperature was monitored continually with an Omega model DP41TC Thermocouple Thermometer and recorded 3 times during each exposure. Chamber relative humidity was targeted at 50 10%. The relative humidity was measured with an Omega model RH5100C Digital Psychrometer and recorded twice during each exposure. Chamber oxygen concentration was targeted to at least 19%. The oxygen concentration was measured with a Biosystems model 3100R Oxygen Analyzer and recorded twice during each exposure. G. Body Weights and Clinical Observations During the exposure phase of the study, all rats were weighed daily and individually observed for clinical signs oftoxicity before and after each exposure. Group clinical observations were made during exposures. In addition, rats were checked for an alerting response to an auditory stimulus 3 times during each exposure and after each exposure. During the recovery period, all remaining rats were weighed and individually observed daily. a Particle size samples were not taken from the control chamber. -15- H-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 H. Clinical Pathology Evaluations A clinical pathology evaluation was conducted on all rats after the last exposure and from all remaining rats on the last day of recovery. The day before collection of blood samples for the clinical pathology evaluation, the rats were placed in metabolism cages. These rats were fasted overnight and urine was collected from each rat. Blood samples for hematology and clinical chemistry measurements were collected from the orbital sinus of each rat while the rat was under light carbon dioxide anesthesia. Blood samples for coagulation parameters and fluoride analysis were collected under carbon dioxide immobilization from the abdominal vena cava at sacrifice. Blood samples were evaluated for quality by visual examination prior to analysis. 1. Hematology The following hematology parameters were determined: red blood cell count hemoglobin hematocrit mean corpuscular volume mean corpuscular hemoglobin mean corpuscular hemoglobin concentration red cell distribution width absolute reticulocyte count white blood cell count absolute differential white blood cell count percent differential white blood cell count platelet count microscopic blood smear examination Complete blood counts were determined on a Bayer(Technicon) H-1E hematology analyzer, calculated within the Xybion data collection system using the hematology analyzer's results, or determined from microscopic evaluation of the blood smear. Wright-stained blood smears from all rats were examined microscopically for confirmation of automated results and evaluation of cellular morphology. Reticulocyte counts were determined on a SysmexR-3000. New methylene blue-stained blood smears were prepared from all hematology samples but were not needed for evaluation. 2. Coagulation Parameters The following coagulation parameters were determined: prothrombin time activated partial thromboplastin time Coagulation times were determined on a SysmexCA-1000. 3. Serum Chemistry The following serum chemistry parameters were determined: aspartate aminotransferase alanine aminotransferase sorbitol dehydrogenase total protein albumin globulin 16- Censpan^ Banlttej. Does not eontain TCCA CBI H-24267: Two-Week Inhalation Toxicity Study in Male Rats alkaline phosphatase total bilirubin urea nitrogen creatinine cholesterol triglycerides glucose calcium inorganic phosphorus sodium potassium chloride fluoride1' DuPont-4292 Clinical chemistry parameters were measured on a Roche Diagnostics (BMC)/Hitachi 717 clinical chemistry analyzer or calculated using results of chemistry tests within the Xybion data collection system. 4. Urinalysis The following urinalysis parameters were determined: quality color transparency volume osmolality specific gravity pH protein glucose ketone bilirubin blood urobilinogen fluoride0 microscopic urine examination Urine volume, color and transparency were evaluated visually. All other urine parameters were semi-quantitatively measured on a Bayer Clinitek AtlasTM Automated Urine Chemistry, utilizing Ames Multistix chemistry dipsticks. Sediments from all urine specimens were evaluated microscopically. I. Anatomic Pathology Evaluations After the last exposure, 5 rats per group were euthanized by carbon dioxide anesthesia and exsanguination ad given gross and histopathology evaluations. On the last day of the recovery period, the remaining rats of each group were similarly sacrificed and evaluated. All rats on study were given a complete gross examination and representative samples of the following tissues were saved at necropsy: Hematopoietic System Circulatory System Respiratory System - bone marrow (femur and sternum), mesenteric lymph nodes, spleen, thymus - heart - trachea, lungs, nose, larynx, pharynx b Fluoride determination was analyzed from plasma with EDTA added. c Fluoride determination was analyzed from urine with EDTA added. -17- H-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 Digestive System Urinary System Endocrine System Reproductive System Nervous System Other - esophagus, stomach, liver, pancreas (exocrine and islets), small intestine (duodenum, jejunum, and ileum), large intestine (cecum, colon, and rectum) - kidneys, urinary bladder - thyroid gland (cortex and medulla), parathyroid glands, adrenal glands, - prostate, testes, epididymides, seminal vesicles - brain (cerebrum, midbrain, cerebellum, medulla/pons), spinal cord (cervical, thoracic, lumbar), sciatic nerve - eyes and selected gross lesions Liver, kidneys, lungs, brain, and testes from rats sacrificed by design at the end of the exposure and recovery periods were weighed wet at necropsy. Gross lesions which were diagnosed at necropsy and for which microscopic examination was not appropriate (e.g., missing anatomic parts) were not collected. Selected gross lesions for which a microscopic diagnosis would not be additive (e.g., deformity of tail) were saved but were not processed for microscopic evaluation. All tissues were fixed in 10% neutral buffered formalin except testes, epididymides, and eyes which were fixed in Bouin's solution. The lungs were inflated with 10% neutral buffered formalin after weighing. All tissues were processed, embedded in paraffin, cut at a nominal thickness of 5 micrometers, stained with hematoxylin and eosin (H&E) and examined microscopically. J. Statistical Analyses Descriptive statistics including mean, standard deviation, and standard error of the mean were used to summarize experimental data. Significance was judged at p < 0.05. -18- 'tanpiM^ SmWesS. Does not en8a5n TSCA CBI H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 Parameter Exposure Concentration Data Particle Size Data Body Weight Body Weight Gain Organ Weight Clinical Pathology0 Incidence of Clinical Observations Preliminary Test None None Test for lack of trend^ Levene's test for homogeneity and Shapiro-Wilktest^ for normality1' Levene's test for homogeneity and Shapiro-Wilktest^ for normality1' None Method of Statistical Analysis If preliminary test is If preliminary test is not significant significant Descriptive statistics (e.g., mean, standard deviation) Regression analysis or probit analysis^ Sequential application^ of the Preliminary tests for Jonckheere-Terpstra pairwise comparison trend test^ OR2 One-way analysis of variance^ followed with Dunnett's test^ Kmskall-Wallistest^ followed with Dunn's test00) One-way analysis of variance^ followed with Dunnett's test^ Kruskall-Wallis test^ followed with Dunn's test00) Cochran-Armitage test for trend^ a Pairwise comparisons and associated preliminary tests were only conducted if the test for lack of trend was significant. b If the Shapiro-Wilk test was not significant but Levene's test was significant, a robust version of Dunnett's test was used. c When an individual observation was recorded as being less than a certain value, calculations were performed on half the recorded value. For example, ifbilirubin was reported as <0.1,0.05 was used for any calculations performed with that bilirubin data. d If the incidence was not significant, but a significant lack of fit occurred, then Fisher's Exact test00 with a Bonferroni correction was used. -19%aHw^anfcd.Des^ RESULTS AND DISCUSSION In-Life Animal Measurements A. Chamber Atmosphere Analysis of H-24267 (Tables 1-3, Appendices A-B) Mean aerosol concentrations, particle size measurements, and chamber environmental conditions results are in tables 1,2, and 3, respectively. Mean analytically determined aerosol concentrations of H-24267 for the 3 test chambers were 23,110 and 600 mg/m3 (2 significant figures) for design concentrations of 25,125, and 600 mg/m3, respectively. Based on 2 measurements per test concentration, the mass median aerodynamic equivalent diameter of the H-24267 aerosol ranged from 2.6 to 4.2 ^m. The chamber oxygen concentration measurements were 21%, The relative humidity for the chambers was between 35 and 84% and the chamber temperatures were between 21 and 26C. The temperature and humidity in the chambers were close to that targeted with the exception of the %RH in the 600 mg/m3 chamber, and this was appreciably higher than targeted due to the presence of a high percentage of water (60 to 85%) in the test sample. Although the chamber humidity was high, these conditions are frequently encountered in inhalation studies with water- based aerosols and this was not expected to affect the study outcome. B. Body Weights and Clinical Observations (Tables 4-6, Figure 2, Appendices C-D) During the exposure period, there was a dose-related body weight depression that occurred especially in the 125 and 600 mg/m3 groups and all 3 groups gained less weight than controls. The H-24267 exposed rats appeared to resume a normal weight gain rate during the recovery period. After the third exposure, slight lung noise occurred in 2 rats in the 600 mg/m3 group. These effects were not observed in the other test groups. Sporadic incidences of alopecia were observed in some rats during the study. These findings were not dose-related and are frequently seen in inhalation studies where the animals are exposed in body restrainers. - 20 - bmpwy Smteeci Doe. wt ew TSCA CB H-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 Clinical Pathology Evaluations A. Hematology/CoaguIation (Tables 7-8, Appendix E) There were no lexicologically significant changes in male rats for hematologic or coagulation parameters. All statistically significant changes were considered not lexicologically significant (non-adverse) or not related to compound administration. These changes are detailed below. The statistically significant minimal decreases in reticulocytes at day 11 in rats exposed to 125 or 600 mg/m3 were not correlated with any other supportive changes in erythrocyte parameters. Therefore, these changes were considered lexicologically insignificant and not compound related. Reticulocyte counts in H-24267-exposed rats at recovery were similar to control group values. Statistically significant changes in the following parameters were minimal, did not occur in a concentration-dependent manner, and therefore were lexicologically insignificant: Decreased absolute neutrophils in rats exposed to 25 or 125 mg/m3 at day 11 Decreased platelets in rats exposed to 25 mg/m3 at day 11 Increased relative lymphocytes in rats exposed to 25 (day 11 only) or 125 (days 11 and 25) mg/m3 Decreased relative neutrophils in rats exposed to 25 (day 11 only) or 125 (days 11 and 25) mg/m3. B. Serum Chemistry (Table 9, Appendix E) There were no lexicologically significant changes in male rats for clinical chemistry parameters. All statistically significant changes were considered not lexicologically significant (non-adverse) or not related to compound. These changes are detailed below. Statistically significant minimally decreased sodium, with minimally increased urea nitrogen and creatinine, occurred in rats exposed to 600 mg/m3 at day 11. These changes were mostly due to 1 animal (637830) who had moderate alterations in these 3 parameters. This rat also had dilute urine and nephropathy on histologic examination (grade mild), a background lesion that is commonly seen in CD-CRL IGS rats. The histologic lesion in this rat was not considered treatment related; therefore, the clinical pathology changes were also not considered related to treatment. Two other rats in the 600 mg/mg3 group had minimally increased urea nitrogen and creatinine (637835 and 637837) at day 11. These rats also had mildly increased albumin (with resulting -21- H-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 increased total protein and calcium,'1 and decreased chloride at this same time-point. The renal concentrating ability of these rats was intact, and they had no histologic evidence of nephropathy. Therefore, although the changes discussed above were possibly related to treatment, they were not considered lexicologically significant in this group because there were no treatment related alterations in renal function (as measured by concentrating ability) or renal histology at either time-point. Minimally increased albumin in rats exposed to 25 or 125 mg/m3 (or 600 mg/m3, see burger dot 2 above) at day 11 was possibly related to treatment, but was not considered lexicologically significant because the changes were very slight (approximately 0.2 g/dl greater than the control group mean). At recovery (day 25), albumin concentrations in H-24267-exposed rats were similar to control group values, and within the reference range for the parameter (reference range: 4.3-4.9 g/dl). Minimally increased cholesterol in rats exposed to 125 or 600 mg/m3 at day 11, although possibly related to treatment, was not considered lexicologically significant because the change was slight and individual values generally were within the reference range for this parameter (reference range: 46-102 mg/dl). At recovery (day 25), cholesterol concentrations in H-24267-exposed rats were similar to control group values. Statistically significant changes in the following parameters were minimal and did not occur in a concentration-dependant manner, or only occurred during the recovery phase, and therefore were lexicologically insignificant: Increased urea nitrogen and creatinine in rats exposed to 25 mg/m3 at day 11 Decreased triglycerides in rats exposed to 25 mg/m3 at day 11 Decreased globulins in rats exposed to 125 mg/m3 at day 25 Increased chloride in rats exposed to 25 mg/m3 at day 11. C. Urinalysis (Table 10, Appendix E) There were no lexicologically significant changes in male rats for urinalysis parameters. All statistically significant changes were considered not lexicologically significant (non-adverse) or not related to compound. These changes are detailed below. Urine pH was moderately decreased (statistically significant) in rats exposed to 125 or 600 mg/m3 at day 11. Although decreased urine pH was possibly related to treatment, there were no correlative changes in other parameters (chloride, sodium, potassium) to suggest d Calcium exists in serum in 2 forms, either bound to albumin or unbound ("ionized" calcium). Ionized calcium is the physiologically active form, and is tightly regulated. Increased albumin is necessarily associated with physiologically appropriate increased bound calcium, with resultant increased total calcium. However, ionized calcium is unaffected; therefore this change is not toxicologically significant. -22- H-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 alterations in systemic acid/base homeostasis. Therefore, this change was considered toxicologically insignificant. Urine pH was similar in all groups at the end of recovery (day 25). Total urinary fluoride was minimally increased in rats exposed to 125 mg/m3 at day 11. This statistically significant change did not occur in a concentration-dependant manner, and therefore was toxicologically insignificant: D. Conclusions There were no toxicologically significant changes in hematology, clinical chemistry, or urinalysis parameters. Therefore, under the conditions of this study and for the clinical pathology parameters measured, the no-observed-effect level (NOEL) was greater than 600 mg/m3, the highest exposure tested. Anatomic Pathology Evaluations A. Organ Weights (Tables 11-12, Appendix F) There were no compound-related changes in organ weights. At the end of the exposure period, statistically significant increases in all organ weights relative to body weight were present in the 125 and/or 600 mg/m3 groups. These changes were secondary to decreases in final body weights and thus were not indicative of direct target organ toxicity. All other statistically significant organ weight changes in the exposure groups were neither concentration-related nor associated with correlative microscopic changes and were thus considered spurious findings. In the recovery groups, a statistically significant increase in lung weight relative to body weight was present in the 600 mg/m3 group. This change was not associated with changes in other lung weight parameters in this group or with correlative microscopic changes. The minimal findings in some rats in this group would not be expected to produce lung weight changes. Therefore, this finding was not considered to be compound-related. B. Gross Observations (Tables 13-14, Appendix G) There were no compound-related gross findings. Only a few gross lesions were noted in the study. These occurred as single instances in treated and control groups and were lesions common to rats of this strain and age. -23- H-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 C. Microscopic Findings (Tables 15-16, Appendix G) Compound-related microscopic changes consistent with slight irritation were present in the respiratory tract of rats in all treated groups. In the lungs, minimal inflammation confined to the centriacinar regions was present in all treated groups. Inflammation was characterized by mild thickening of alveolar duct bifurcations and adjacent alveolar septa due to mononuclear inflammatory cell infiltration. Slight hypertrophy of terminal bronchiolar epithelium was also present in association with the centriacinar inflammatory response. Lesions in the lungs were minimal at all exposure concentrations; however, changes were slightly more apparent with increasing concentration, m the larynx, minimal squamous metaplasia was present in all treated groups. Metaplasia occurred most consistently in the ventral laryngeal mucosa at the base of the epiglottis. Necrosis of cartilage overlying the laryngeal saccule was present in 1 rat in the 600 mg/m3 group. In the nose, hypertrophy of goblet cells was present in all treated groups and was most apparent in the mucosa of the pharyngeal duct. Following an approximately 2-week recovery period, respiratory tract lesions were essentially reversible. Single occurrences of focal, very slight thickening of alveolar duct septa occurred in the 125 and 600 mg/m3 recovery groups. In addition, focal residual cartilage necrosis in the larynx occurred in 2/5 rats in the 600 mg/m3 recovery group. All other microscopic changes observed occurred in low incidences across treated and control groups and/or are spontaneous lesions common to rats of this strain and age. D. Conclusions Under the conditions of this study, a no-observed-adverse effect level for pathology was not determined based on the presence of irritant lesions in the respiratory tract at all exposure concentrations tested. These changes were minimal and mostly reversible following a 2-week recovery period. -24. H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 CONCLUSIONS During the exposure period there was a dose-related body weight depression occurred primarily in the 125 and 600 mg/m3 groups and all 3 test groups gained less weight than the controls. The H-24267 exposed rats resumed a normal weight gain rate during the recovery period. Clinical pathology evaluations at both evaluation times showed no lexicologically significant changes in hematology, clinical chemistry, or urinalysis parameters, including urinary fluoride. Weight analysis of major organs showed no effects attributable to the test compound. Histological findings were confined to the respiratory tract; no significant findings were observed in any other evaluated organs. Minimal, dose-related histologic effects attributable to the test compound were found in the respiratory tract of all treated groups at the end of the 2-week exposure period. The effects were consistent with minimal irritation and were slightly more apparent with increasing dose. These effects occurred throughout the respiratory tract, including the nose, larynx, and lung. In the lungs, inflammation was characterized by mild thickening of alveolar duct bifurcations and adjacent alveolar septa due to mononuclear inflammatory cell infiltration. Slight hypertrophy of terminal bronchiolar epithelium was also present in association with the centriacinar inflammatory response. In the larynx, minimal squamous metaplasia was present in all treated groups. Necrosis of cartilage overlying the laryngeal saccule was present in 1 rat in the 600 mg/m group. In the nose, hypertrophy of goblet cells was present in all treated groups and was most apparent in the mucosa of the pharyngeal duct. Following an approximately 2-week recovery period, respiratory tract lesions were essentially reversible. Single occurrences of focal, very slight thickening of alveolar duct septa occurred in the 125 and 600 mg/m3 recovery groups. In addition, focal residual cartilage necrosis in the larynx occurred in 2/5 rats in the 600 mg/m3 recovery group. Based on the finding of minimal respiratory tract inflammation observed in all exposed groups including the lowest concentration tested, 25 mg/m3, a no-observed-adverse- effect-level (NOAEL) was not determined for repeated aerosol exposures to H-24267 in rats. RECORDS AND SAMPLE STORAGE 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 (formerly known as the E. I. du Font de Nemours and Company Records Management Center). Clinical pathology slides and raw data will be retained at Haskell Laboratory, Newark, Delaware. Wet specimens and records related to clinical pathology analyses were retained by DuPont Pharmaceuticals Company. -25 H-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 REFERENCES 1. Calculation described in Sierra Instruments, Inc., Bulletin 7-79-219IM, Instruction Manual: Series 210 Ambient Cascade hnpactors and Cyclone Preseparators. 2. Draper, N.R. and Smith, H. (1981). Applied Regression Analysis, 2nd edition, pp 266-273. Wiley, New York. 3. Selwyn, M.R. (1995). The use of trend tests to determine a no-observable-effect level in animal safety studies. Journal of the American College of Toxicology 14(2), 158-168. 4. Jonckheere, A.R. (1954). A distribution-free K-sample test against ordered alternatives. Biometrika 41,133-145. 5. Levene, H. (1960). Robust test for equality of variances. Contributions to Probability and Statistics (J. Oikin, ed.), pp 278-292. Stanford University Press, Palo Alto. 6. Shapiro, S.S. and Wilk., M.B. (1965). An analysis of variance test for normality (complete samples). Biometrika 52, 591-611. 7. Snedecor, G.W. and Cochran, W.G. (1967). Statistical Methods, 6th edition, pp 246-248 and 349-352. The Iowa State University Press, Iowa. 8. Dunnett, C.W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Amer. Statist. Assoc. 50,1096-1121.' 9. Kruskal, W.H. and Wallis, W.A. (1952). Use of ranks in one-criterion analysis of variance. J. Amer. Statist. Assoc. 47, 583-621. 10. Dunn, O.J. (1964). Multiple contrasts using rank sums. Technometrics 6, 241-252. 11. Fisher, R.A. (1985). Statistical Methods for Research Workers, 13th edition. Haffner, New York. -26- Cfsmpany Sanitized. Does not contain TSCA CB! TABLES -27 H-24267: Two-Week Inhalation Toxicity Study in Male Rats TABLES ABBREVIATIONS: EXPLANATORY NOTES Tables 1 and 3 S.D. - standard deviation S.E.M. mg/m3 - standard error of the mean milligrams per cubic meter n - number of samples Table? RBC HGB HCT MCV MCH - MCHC RDW ARET NRBC WBC ANEU ANPR - ALYM AMON - AEOS ABAS ALUC ABLT AMSC - PLT BASO BLST - EOS - LUC LYMP MISC MONO NEUT NPRE - red blood cell count hemoglobin hematocrit mean corpuscular volume mean corpuscular hemoglobin mean corpuscular hemoglobin concentration red cell distribution width absolute reticulocyte count nucleated red blood cell count white blood cell count absolute neutrophil (all forms) absolute neutrophil precursor absolute lymphocyte absolute monocyte absolute eosinophil absolute basophil absolute large unstained cell absolute blast leukocyte absolute miscellaneous leukocyte platelet count percent basophil percent blast leukocyte percent eosinophil percent large unstained cell percent lymphocyte percent miscellaneous leukocyte percent monocyte percent neutrophil percent neutrophil precursor DuPont-4292 28CSompanySanRteed-rl""-- --1 '" ompany Ssralted. Does not eonfaSsi TSCA CB' H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 TABLES EXPLANATORY NOTES (Continued) ABBREVIATIONS: (Continued) Table 8 PT - APTT - prothrombin time activated partial thromboplastin time Table 9 AST ALT SDH ALKP BDJ BUN CREA CHOL TRIG GLUC TP ALB GLOB CALC IPHS NA K CL PFLU aspartate aminotransferase alanine aminotransferase sorbitol dehydrogenase alkaline phosphatase total bilirubin urea nitrogen creatinine cholesterol triglycerides glucose total protein albumin globulin calcium inorganic phosphorous sodium potassium chloride plasma fluoride Table 10 VOL UOSM SG pH URO UFLU volume urine osmolality specific gravity the logarithm of the reciprocal of the hydrogen ion concentration urobilinogen urine fluoride .29- Company SanWzed. Dees nS OTtaSn TSCA CB! TABLES EXPLANATORY NOTES (Continued) NOTES: Tables 1 3 Values are reported to 2 significant figures. Means and standard errors of the mean were calculated prior to rounding values to 2 significant figures. Tables 7 -10 When an individual observation is recorded as being less than a certain value, calculations are performed on half the recorded value. For example, if bilirubin is reported as <0.1,0.05 is used for any calculations performed with that bilirubin data. -30- TABLE 1 CHAMBER CONCENTRATIONS OF H-24267 DESIGN CONCENTRATION MEASURED CONCENTRATION8 (mg/m3) (mg/m3)_____MEAN 0 0 25 23 125 110 600 600 S.E.M._____RANGE_____n_ 0 0 54 2.0 4.0 - 70 54 4.6 18-200 54 25 85 - 960 54 Values represent the mean, standard error of the mean (S.E.M.), and range for all samples obtained from n exposures. TABLE 2 PARTICLE SIZE DISTRIBUTION OF H-24267 DESIGN CONCENTRATION (mg/m3) 25 125 600 TEST DAY 4 11 3 10 2 9 MASS MEDIAN AERODYNAMIC DIAMETER Qmi) 3.2 2.6 4.0 2.6 3.9 4.2 GEOMETRIC STANDARD DEVIATION 2.5 2.2 3.1 2.2 3.0 2.2 % PARTICLES BY MASS <1 itm 13 12 <3 iim 48 58 <10 fim 86 96 11 40 84 14 62 96 11 42 82 3.0 33 88 TABLE 3 CHAMBER ENVIRONMENTAL CONDITIONS DESIGN RELATIVE CONCENTRATION TEMPERATURE HUMIDITY AIRFLOW (mg/m3)8 (C) (%) (L/min) n 0 22-26 35-50 30 9 25 22-26 38-54 30 9 125 22-25 37-61 30 9 600 21-24 65-84 30 9 a Values represent the range for all samples obtained from n exposures. -31- H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 DAYS ON TEST EXPOSURE DAYO DAY1 DAY 2 DAYS DAY 4 DAY 7 DAYS DAY 9 DAY 10 TABLE 4 MEAN BODY WEIGHTS OF MALE RATS Group I Omg/m3 MEANBOD^' WEIGHTS (g) Group ni Group V 25 mg/m3 125 mg/m3 291.8 23.4(10) 294.4 23.3(10) 301.6 25.0(10) 306.9 24.7(10) 309.8 25.1(10) 328.4 28.6(10) 332.6 28.0(10) 332.6 29.7(10) 338.7 29.0(10) 288.9 16.3(10) 284.6 16.3(10) 287.2 15.2(10) 289.3 15.4(10) 293.7 16.7(10) 315.8 18.0(10) 316.7# 18.2(10) 317.9 19.5(10) 320.5 21.3(10) 295.5 10.2(10) 288.0 9.7(10) 291.1 10.7(10) 296.7 9.2(10) 299.2 10.6(10) 322.9 11.6(10) 319.1# 10.2(10) 315.8# 11.6(10) 318.7# 13.1(10) Group VH 600 mg/m3 298.5 17.4(10) 286.1 18.1(10) 287.1 19.3(10) 285.9# 21.0(10) 287.4# 22.1(10) 313.2 22.5(10) 309.1# 24.5(10) 309.7# 24.5(10) 309.0# 25.6(10) -32. H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 DAYS ON TEST RECOVERY DAY 11 DAY 14 DAY 18 DAY 22 DAY 25 TABLE 4 (Continued) MEAN BODY WEIGHTS OF MALE RATS Group I Omg/m3 MEANBOD^r WEIGHTS (g) Group ffl Group V 25 mg/m3 125 mg/m3 306.4 25.7(10) 338.6 38.9(5) 367.3 44.0(5) 391.7 45.0(5) 375.8 47.2(5) 286.8# 17.7(10) 313.8 25.9(5) 340.9 29.3(5) 360.6 32.5(5) 348.9 35.8(5) 287.1# 14.7(10) 337.2 16.4(5) 366.9 21.1(5) 391.8 23.8(5) 379.3 22.2(5) Group VH 600 mg/m3 272.2# 22.6(10) 310.6 37.3(5) 343.0 44.2(5) 363.5 47.2(5) 354.0 47.2(5) Data arranged as: Mean Standard deviation (Number of values included in calculation) # Statistically significant difference from control at p < 0.05 by trend test (Jonckheere-Terpstra). 33Company BsnWsssd. Does not contaSni TSCA CB8 H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 TABLES MEAN BODY WEIGHT GAINS OF MALE RATS DAYS ON TEST Group I Omg/m3 MEAN BODY W]EIGHT GAINS (g)1 Group HI Group V 25 mg/m3 125 mg/m3 Group VH 600 mg/m3 EXPOSURE DAY 0 - DAY 1 2.6 6.1(10) -4.3# 3.8(10) -7.6# 3.9(10) -12.4# 6.1(10) DAY 1 - DAY 2 7.2 2.8(10) 2.6# 2.5(10) 3.1# 2.8(10) 1.0# 4.9(10) DAY 2 - DAY 3 5.3 2.7(10) 2.1 2.5(10) 5.7 4.5(10) -1.1# 3.5(10) DAY 3-DAY 4 2.9 3.7(10) 4.4 1.8(10) 2.4 2.9(10) 1.4 6.5(10) DAY 4-DAY 7 18.6 5.3(10) 22.1 5.1(10) 23.7# 4.3(10) 25.9# 6.1(10) DAY 7 - DAY 8 4.2 3.2(10) 0.9# 2.0(10) -3.8# 5.0(10) -4.1# 3.6(10) DAY 8 - DAY 9 -0.1 10.5(10) 1.2 2.9(10) -3.2# 3.7(10) 0.6# 4.0(10) DAY 9 - DAY 10 6.1 7.5(10) 2.6 2.8(10) 2.9 3.3(10) -0.7 6.1(10) DAY 10-DAY 11s -32.3 8.6(10) -33.7 7.5(10) -31.6 5.0(10) -36.8 5.8(10) -34- H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 TABLE 5 (Continued) MEAN BODY WEIGHT GAINS OF MALE RATS DAYS ON TEST Group I Omg/m3 MEAN BODY W EIGHT GAINS (g) Group DI Group V 25 mg/m3 125 mg/m3 Group VTI 600 mg/m3 RECOVERY DAY 11-DAY 14 37.6 11.3(5) 34.6 5.7(5) 43.2 8.6(5) 42.6 7.7(5) DAY 14 - DAY 18 DAY 18 - DAY 22 DAY 22 - DAY 25s1 28.7 7.6(5) 24.4 3.3(5) -15.9 2.9(5) 27.1 5.1(5) 19.7 5.6(5) -11.7 4.9(5) 29.7 6.8(5) 24.9 5.2(5) -12.4# 1.9(5) 32.4 7.4(5) 20.5 5.5(5) -9.5# 2.1(5) OVERALL DAY 0-DAY 10 46.9 14.7(10) 31.6# 13.1(10) 23.2# 9.1(10) 10.5# 10.8(10) DAY 11-DAY 25 74.5 17.1(5) 69.7 16.2(5) 85.3 11.6(5) 86.0 16.6(5) DAY 0-DAY 25 89.8 23.6(5) 67.9 30.3(5) 84.1 13.0(5) 59.6 23.7(5) Data arranged as: Mean Standard deviation (Number of values included in calculation) # Statistically significant difference from control at p < 0.05 by trend test (Jonckheere-Terpstra). a Weight losses due to fasting of rats prior to clinical pathology evaluations. -35- Canroww Ba"8^^. Does awt sontain TCCA CB1 H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 TABLE 6 SUMMARY OF CLINICAL OBSERVATIONS IN MALE RATS AT WEIGHING GROUP: I DESIGN CONCENTRATION (mg/m3): 0 ffl V vn 25 125 600 ANIMAL COUNT: 10 10 10 10 Hair Loss Face, Right Incidence Observed Mean onset (Days) Forepaw, Left Incidence Observed Mean onset (Days) Forepaw, Bilateral Incidence Observed Mean onset (Days) 0 (0%) 1 (10%) 0 (0%) 0 (0%) 0 3 0 0 0 (0%) 8 0 (0%) 1 (10%) 0 (0%) 00107 0 (0%) 0 (0%) 2 (20%) 0 (0%) 0 0 10 0 5 - Forelimb, Bilateral Incidence Observed Mean onset (Days) Hair Loss Totals Incidence Observed Mean onset (Days) 0 (0%) 0 (0%) 1 (10%) 0 (0%) 0 0 5 0 0 (0%) 4 1 (10%) 2 (20%) 0 (0%) 0 3 16 0 8 5 Wound, Superficial, Face 0 5 0 0 Incidence Observed Mean onset (Days) 0 (0%) 1 (10%) 0 (0%) 0 1 Incidence - The number of animals (percent of group) for which an observation was recorded. Observed - The total number of test days the observation was recorded for animals in the group. Mean onset (Days) - The mean of the test days each observation was first recorded for that group. A dash indicates a clinical observation was not observed, therefore, there is no mean onset day. (0%) There were no statistically significant differences from control at p < 0.05. -36- H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 TABLE 7 TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I Omg/m3 Group ID: 25 mg/m3 Group V 125 mg/m3 Group Vn 600 mg/m3 RBC (xlO%tL) DAY 11 DAY 25 HGB (g/dL) DAY 11 DAY 25 HCT (%) DAY 11 DAY 25 MCV (fl) DAY 11 DAY 25 MCH(pg) DAY 11 DAY 25 MCHC (g/dL) DAY 11 DAY 25 RDW (%) DAY 11 DAY 25 ,^-, 7.57 0.32(10) 8.12 0.42(5) 15.2 0.7(10) 15.8 0.4(5) 47.3 2.0(10) 48.2 1.8(5) 62.4 1.6(10) 59.4 1.2(5) 20.1 0.5(10) 19.4 0.6(5) 32.1 0.6(10) 32.8 0.5(5) 13.0 0.6(10) 13.3 0.5(5) 7.74 0.64(10) 8.51 0.31(5) 15.2 0.9(10) 15.9 0.6(5) 47.4 3.2(10) 49.5 1.7(5) 61.3 2.1(10) 58.2 0.3(5) 19.7 0.7(10) 18.7 0.3(5) 32.1 0.5(10) 32.1 0.5(5) 13.1 0.6(10) 13.3 0.2(5) 7.60 0.35(10) 7.67 0.30(5) 15.3 0.4(10) 15.4 0.4(5) 47.1 1.3(10) 47.2 1.3(5) 62.0 1.8(10) 61.6 1.8(5) 20.2 0.8(10) 20.1 0.6(5) 32.5 0.6(10) 32.7 0.4(5) 13.4 0.7(10) 13.2 0.3(5) 8.05 0.49(10) 8.05 0.38(5) 15.9 0.7(10) 15.5 0.2(5) 49.2 2.0(10) 47.7 0.6(5) 61.2 1.7(10) 59.3 2.2(5) 19.8 0.5(10) 19.3 0.8(5) 32.3 0.5(10) 32.5 0.4(5) 13.5 0.5(10) 13.6 0.4(5) -37- eemwmy Santt-ed- pfflcw ^ ew^ TSCA CBI H-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 TABLE 7 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS TEST/ Group I Group m Group V Group VH PERIOD_________Omg/m3_____25 mg/m3____125 mg/m3____600 mg/m3 ARET (xlO-V/iL) DAY 11 DAY 25 NRBC (/100 WBC) DAY 11 DAY 25" 234.9 30.6(10) 261.4 28.6(5) 203.7 29.0(10) 266.2 11.2(5) 174.1* 31.3(10) 258.2 31.6(5) 159.6* 35.1(10) 253.2 35.5(5) WBC (xlO3/^) DAY 11 DAY 25 ANEU (xlO3/^) DAY 11 DAY 25 ANPR (xlO3/^) DAY 11" DAY 25" 13.11 2.63(10) 14.68 5.23(5) 2.09 0.84(10) 2.65 1.30(5) 12.77 2.93(10) 14.91 4.15(5) 1.38@ 0.49(10) 2.47 0.67(5) 12.32 1.56(10) 14.38 3.25(5) 1.27 0.26(10) 1.77 0.63(5) 13.05 4.43(10) 14.47 2.68(5) 1.66 0.75(10) 2.00 0.29(5) ALYM (xlO^L) DAY 11 DAY 25 AMON (xlO3/^) DAY 11 DAY 25 10.24 2.04(10) 11.23 3.75(5) 0.37 0.10(10) 0.35 0.16(5) 10.65 2.59(10) 11.48 3.37(5) 0.29 0.16(10) 0.43 0.08(5) 10.23 1.37(10) 11.75 2.58(5) 0.35 0.15(10) 0.37 0.10(5) 10.53 3.66(10) 11.59 2.39(5) 0.35 0.25(10) 0.38 0.03(5) -38- eempary tMiiltaeed. Ooss not eontain TCCA CBS H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 TABLE 7 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I Omg/m3 Group in 25 mg/m3 Group V 125 mg/m3 Group VII 600 mg/m3 AEOS (xlO^L) DAY 11 DAY 25 ABAS (xlO^/xL) DAY 11 DAY 25 ALUC (xlO3/^) DAY 11 DAY 25 A-DT T' /\,m3/,,T \ 0.12 0.04(10) 0.14 0.04(5) 0.08 0.03(10) 0.09 0.04(5) 0.22 0.06(10) 0.23 0.07(5) 0.11 0.04(10) 0.15 0.07(5) 0.09 0.06(10) 0.09 0.06(5) 0.24 0.13(10) 0.29 0.18(5) 0.20 0.23(10) 0.10 0.03(5) 0.04 0.03(10) 0.09 0.03(5) 0.17 0.10(10) 0.29 0.06(5) 0.15 0.08(10) 0.10 0.04(5) 0.07 0.05(10) 0.09 0.02(5) 0.24 0.21(10) 0.31 0.13(5) DAY 25" AMSC (xlO3/^) DAY 11' DAY 25b PLT (xlO^L) DAY 11 DAY 25 BASO (%) DAY 11 DAY 25 1082 145(7) 1088 99(4) 0.6 0.2(10) 0.6 0.3(5) 919* 148(9) 946 109(3) 0.7 0.5(10) 0.6 0.2(5) 946 120(9) 1004 113(5) 0.4 0.3(10) 0.6 0.2(5) 926 95(9) 943 88(5) 0.5 0.3(10) 0.6 0.1(5) -39- TABLE 7 (Continued) TEST/ PERIOD SUMMARY OP HEMATOLOGY VALUES FOR MALE RATS Group I Omg/m3 Groupffl 25 mg/m3 Group V 125 mg/m3 Group VII 600 mg/m3 BLST (%) DAY 11s DAY 25" EOS (%) DAY 11 DAY 25 LUC (%) DAY 11 DAY 25 LYMP (%) DAY 11 DAY 25 MISC (%) DAY 11s DAY 25b 0.9 0.3(10) 1.0 0.3(5) 1.7 0.5(10) 1.6 0.4(5) 78.2 5.0(10) 76.9 3.0(5) 0.9 0.3(10) 1.0 0.5(5) 1.9 1.0(10) 1.8 0.6(5) 83.2* 3.6(10) 76.7 3.1(5) 1.6 1.9(10) 0.7 0.1(5) 1.4 0.8(10) 2.0 0.3(5) 83.0* 3.2(10) 81.9* 1.4(5) 1.2 0.7(10) 0.7 0.3(5) 1.8 1.2(10) 2.1 0.7(5) 80.5 4.1(10) 79.9 2.1(5) MONO (%) DAY 11 DAY 25 NEUT (%) DAY 11 DAY 25 2.9 0.7(10) 2.4 0.6(5) 15.7 4.5(10) 17.6 2.9(5) 2.2 0.9(10) 2.9 0.5(5) 11.0* 3.7(10) 16.9 3.1(5) 2.9 1.3(10) 2.7 0.9(5) 10.3* 1.6(10) 12.1* 2.2(5) 2.6 1.6(10) 2.7 0.4(5) 13.0 3.6(10) 14.1 2.2(5) -40- ComparasfSwW^ Doe MS eontain rSQA CBI TABLE 7 (Continued) TEST/ PERIOD SUMMARY OP HEMATOLOGY VALUES FOR MALE RATS Group I Omg/m3 Group HI 25 mg/m3 GroupV 125 mg/m3 Group Vn 600 mg/m3 NPRE (%) DAYll" DAY 25*' Data arranged as: Mean Standard deviation (Number of values included in calculation) a When this analysis was performed, valid measurements were taken on only a few animals from the group. Data from this small sample size did not add value to this summary table. Individual data are reported in the Clinical Pathology appendix. b Measurements for all animals were not taken or not performed. Data of this type did not add value to this summary table. Individual data are reported in the Clinical Pathology appendix. * Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett). @ Statistically significant difference from control at p < 0.05 by nonparametric test (Dunn's). .41 TABLES TEST/ PERIOD SUMMARY OF COAGULATION VALUES FOR MALE RATS Group I Omg/m3 Group m 25 mg/m3 Group V 125 mg/m3 Group Vn 600 mg/m3 PT (seconds) DAY 11 DAY 25 APTT (seconds) DAY 11 DAY 25 15.8 1.5(5) 14.8 0.6(5) 19.9 6.1(5) 19.0 2.8(5) 15.2 0.3(5) 15.4 0.8(5) 21.0 3.6(5) 19.1 4.0(5) 15.5 1.0(4) 14.5 0.3(5) 17.2 1.8(4) 16.7 1.4(5) 15.1 0.4(5) 14.7 0.9(5) 20.1 3.6(5) 17.1 2.4(5) Data arranged as: Mean Standard deviation (Number of values included in calculation) There were no statistically significant differences from control at p < 0.05. -42- G^mpsmj Sanitized. Does not eontain TSCA CB! TABLE 9 TEST/ PERIOD SUMMARY OF SERUM CHEMISTRY VALUES FOR MALE RATS Group I Omg/m3 Group ffl 25 mg/m3 Group V 125 mg/m3 Group Vn 600 mg/m3 AST (U/L) DAY 11 DAY 25 ALT (U/L) DAY 11 DAY 25 SDH (U/L) DAY 11 DAY 25 ALKP (U/L) DAY 11 DAY 25 BILI (mg/dL) DAY 11 DAY 25 BUN (mg/dL) DAY 11 DAY 25 CREA (mg/dL) DAY 11 DAY 25 95 16(10) 95 13(5) 38 6(10) 45 4(5) 17.6 3.1(10) 21.5 2.3(5) 219 38(10) 200 39(5) 0.08 0.03(10) 0.11 0.04(5) 13 2(10) 14 2(5) 0.33 0.05(10) 0.42 0.05(5) 98 19(10) 104 13(5) 43 5(10) 44 4(5) 16.3 2.7(10) 22.5 4.1(5) 193 27(10) 185 17(5) 0.08 0.04(10) 0.13 0.05(5) 17@ 2(10) 16 1(5) 0.40 0.05(10) 0.48 0.06(5) 83 12(10) 92 16(5) 35 5(10) 40 3(5) 15.5 2.8(10) 20.2 3.0(5) 199 51(10) 192 38(5) 0.07 0.03(10) 0.10 0.03(5) 15 2(10) 14 1(5) 0.38 0.05(10) 0.42 0.03(5) 89 15(10) 97 19(5) 45 11(10) 43 6(5) 16.2 3.6(10) 19.7 6.1(5) 181 33(10) 169 36(5) 0.10 0.05(10) 0.13 0.02(5) 21@ 6(10) 16 2(5) 0.45 0.10(10) 0.37 0.05(5) -43- Bimpans? Sanifiteed. twifi nitaiira JSCA CE TABLE 9 (Continued) TEST/ PERIOD SUMMARY OF SERUM CHEMISTRY VALUES FOR MALE RATS Group I Omg/m3 Group m 25 mg/m3 Group V 125 mg/m3 GroupVn 600 mg/m3 CHOL (mg/dL) DAY 11 DAY 25 TRIG (mg/dL) DAY 11 DAY 25 GLUC (mg/dL) DAY 11 DAY 25 TP(g/dL) DAY 11 DAY 25 ALB (g/dL) DAY 11 DAY 25 GLOB (g/dL) DAY 11 DAY 25 CALC (mg/dL) DAY 11 DAY 25 65 20(10) 68 12(5) 45 14(10) 60 28(5) 90 7(10) 95 11(5) 6.1 0.2(10) 6.9 0.4(5) 4.2 0.1(10) 4.6 0.2(5) 1.9 0.2(10) 2.2 0.3(5) 10.9 0.4(10) 10.9 0.2(5) 65 12(10) 75 16(5) 32* 12(10) 61 16(5) 85 6(10) 89 10(5) 6.3 0.3(10) 7.0 0.2(5) 4.4* 0.2(10) 4.8 0.1(5) 1.9 0.2(10) 2.2 0.1(5) 10.9 0.3(10) 10.9 0.2(5) 83* 18(10) 76 18(5) 40 10(10) 72 24(5) 89 10(10) 95 11(5) 6.2 0.2(10) 6.6 0.2(5) 4.4* 0.1(10) 4.7 0.2(5) 1.8 0.1(10) 1.9* 0.0(5) 11.0 0.2(10) 10.8 0.3(5) 85* 15(10) 76 13(5) 38 9(10) 43 7(5) 89 5(10) 92 9(5) 6.5* 0.3(10) 6.8 0.2(5) 4.5* 0.2(10) 4.7 0.2(5) 2.0 0.2(10) 2.1 0.2(5) 11.3 0.3(10) 10.9 0.3(5) -44- oiBpany8nte@d. TABLE 9 (Continued) SUMMARY OF SERUM CHEMISTRY VALUES FOR MALE RATS TEST/ Group I Group ffl Group V PERIOD_________Omg/m3_____25 mg/m3____125 mg/m3 Group VH 600 mg/m3 DAY 11 DAY 25 NA (mmol/L) DAY 11 DAY 25 K (mmol/L) DAY 11 DAY 25 CL (mmol/L) DAY 11 DAY 25 PFLU (^g/mL) DAY 11 DAY 25 10.0 1.0(10) 8.8 0.7(5) 149.1 1.4(10) 150.5 1.1(5) 6.21 0.33(10) 5.98 0.41(5) 95.4 1.0(10) 95.9 1.7(5) 0.1 0.0(5) 0.1 0.0(5) 9.7 0.4(10) 8.7 0.7(5) 149.0 1.4(10) 150.5 0.9(5) 6.18 0.30(10) 6.27 0.07(5) 97.8* 1.3(10) 97.0 2.0(5) 0.1 0.0(5) 0.1 0.0(5) 9.7 0.4(10) 8.6 0.5(5) 148.6 1.0(10) 150.9 1.4(5) 6.04 0.24(10) 5.96 0.36(5) 96.4 2.1(10) 96.8 1.0(5) 0.1 0.0(5) 0.1 0.0(5) 9.6 0.7(10) 9.2 0.6(5) 147.2* 2.2(10) 150.1 1.4(5) 5.93 0.31(10) 6.00 0.20(5) 93.4 2.4(10) 97.0 1.2(5) 0.1 0.0(5) 0.1 0.0(5) Data arranged as: Mean Standard deviation (Number of values included in calculation) * Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett). @ Statistically significant difference from control at p < 0.05 by nonparametric test (Dunn's). -45. TABLE 10 TEST/ PERIOD SUMMARY OF URINALYSIS VALUES FOR MALE RATS Group I Omg/m3 Groupffl 25 mg/m3 Group V 125 mg/m3 Group Vn 600 mg/m3 VOL(mL) DAY 11 DAY 25 UOSM (mOsm) DAY 11 DAY 25 SG DAY 11 DAY 25 pH DAY 11 DAY 25 URO (EU/dL) DAY 11 DAY 25 UELUQtg) DAY 11 DAY 25 9.6 6.7(9) 12.5 7.6(5) 914 342(9) 868 444(5) 1.029 0.011(9) 1.028 0.014(5) 6.4 0.6(9) 6.5 0.4(5) 0.3 0.3(9) 0.2 0.0(5) 9.4 3.3(9) 11.5 4.1(5) 9.0 3.5(10) 12.7 5.7(5) 830 223(10) 705 248(5) 1.026 0.006(10) 1.022 0.007(5) 6.2 0.4(10) 6.3 0.3(5) 0.2 0.0(10) 0.2 0.0(5) 10.8 3.1(10) 12.1 2.6(5) 9.3 5.4(10) 13.8 4.4(5) 854 461(10) 661 209(5) 1.029 0.015(10) 1.021 0.005(5) 5.5* 0.5(10) 6.1 0.5(5) 0.2 0.0(10) 0.2 0.0(5) 14.8* 4.9(10) 15.3 2.7(5) 10.6 3.7(10) 10.6 8.3(5) 732 270(10) 957 425(5) 1.024 0.008(10) 1.030 0.013(5) 5.4* 0.3(10) 6.0 0.4(5) 0.2 0.0(10) 0.2 0.0(5) 12.9 2.8(10) 12.5 4.4(5) Data arranged as: Mean Standard deviation (Number of values included in calculation) * Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett). -46- 'Cem^By Sanitized. Des w^ wn^n JSCA CBI H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 TABLE11 MEANTTNAL BODY AND 0 RGANWEKSHTSFROMMAUERATS DAY 11 SACRIFK^E TEST/ PERIOD Group I Omg/m3 Groupm 25 mg/m3 Group V 125 mg/m3 GroupVn 600 mg/m3 MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) UVER 10.54880 0.55032(5) 9.50840 0.56907(5) 9.85100 1.02333(5) 10.03180 0.67382(5) KIDNEYS 2.83220 0.31214(5) 2.76240 0.25635(5) 2.66800 0.19941(5) 2.76800 0.10556(5) LUNGS 1.80220 0.12323(5) 1.49680 0.08472(5) 2.01000 0.33803(5) 1.80380 0.20042(5) BRAIN 1.93720 0.05766(5) 1.86640 0.08421(5) 1.92360 0.09308(5) 1.90600 0.07562(5) TESTES 2.84160 0.38756(5) 3.33860* 0.19602(5) 3.28120 0.09154(5) 2.97040 0.30940(5) FINAL BODY WEIGHT (grams) 311.80000 11.18928(5) 2<54.40000*# 6.22896(5) 280.20000*# 10.40192(5) 276.40000*# 10.31019(5) MEAN RELATIVE ORGAN WEIGHTS ( % of body weight) UVER/ FINAL BODY*100 3.38205 0.08260(5) 3.22938 0.17369(5) 3.50953 0.24956(5) 3.62979# 0.20580(5) KIDNEYS/ FINAL BODY* 100 0.90831 0.09411(5) 0.93744 0.07309(5) 0.95157 0.04758(5) 1.00204# 0.03924(5) LUNGS/ FINAL BODY* 100 0.57810 0.03517(5) 0.50818 0.01956(5) 0.71656* 0.11089(5) 0.65263# 0.06705(5) -47- Gsmpsny Sanitized. Boos not GOiitain TC^ CBB H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 TABLE 11 (Continued) MEAN FINAL BODY AND ORGAN WEIGHTS FROM MALE RATS DAY 11 SACRIFICE TEST/ PERIOD Group I Omg/m3 Group m 25 mg/m3 Group V 125 mg/m3 Group Vn 600 mg/m3 MEAN RELATIVE ORGAN WEIGHTS ( % of body weight) BRAIN/ FINAL BODY* 100 0.62189 0.02732(5) 0.63389 0.02293(5) 0.68680*# 0.03039(5) 0.68962*# 0.01266(5) TESTES/ FINAL BODY* 100 0.91322 0.13523(5) 1.13395*# 0.05970(5) 1.17268*# 0.06463(5) 1.07356*# 0.08925(5) MEAN RELATIVE ORGAN WEIGHTS (organ to brain weight ratio) LIVER/BRAIN 5.44863 0.31536(5) 5.09267 0.12069(5) 5.11662 0.40345(5) 5.26273 0.26177(5) KIDNEYS/BRAIN 1.46104 0.14027(5) 1.47861 0.10078(5) 1.38671 0.07224(5) 1.45356 0.06636(5) . LUNGS/BRAIN 0.93029 0.05627(5) 0.80245* 0.04060(5) 1.04812 0.18989(5) 0.94588 0.08873(5) TESTES/BRAIN 1.46377 0.16187(5) 1.79131* 0.12406(5) 1.70816* 0.07573(5) 1.55774 0.14152(5) Data arranged as: Mean Standard deviation (Number of values included in calculation) There were no statistically significant differences from control at p < 0.05. # Statistically significant difference from control at p < 0.05 by trend test (Jonckheere-Terpstra). * Statistically significant difference from control at p < 0.05 by parametric test (Dunnett/Tamhane-Dunnett). -48- TABLE 12 MEAN FINAL BODY AND ORGAN WEIGHTS FROM MALE RATS DAY 25 SACRIFICE TEST/ PERIOD Group I Omg/m3 Groupffl 25 mg/m3 Group V 125 mg/m3 Group Vn 600 mg/m3 MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) LIVER 11.81520 1.54485(5) 10.82700 1.99882(5) 12.56100 0.95760(5) 11.87300 2.05716(5) KIDNEYS 3.18140 0.42244(5) 2.87560 0.34528(5) 3.32220 0.24865(5) 3.18700 0.42985(5) LUNGS 1.78640 0.25665(5) 1.69700 0.19552(4) 1.87220 0.14939(5) 1.91360 0.29441(5) BRAIN 1.94560 0.16046(5) 2.00780 0.11708(5) 2.06580 0.10822(5) 1.99020 0.10492(5) TESTES 3.17320 0.31452(5) 3.29320 0.34343(5) 2.82860 0.52816(5) 3.27060 0.28905(5) FINAL BODY WEIGHT (grams) 375.80000 47.17112(5) 348.90000 35.83001(5) 379.32000 22.24718(5) 354.00000 47.17536(5) MEAN RELATIVE ORGAN WEIGHTS ( % of body weight) UVER/ FINAL BODY*100 3.14308 0.11223(5) 3.08887 0.32592(5) 3.30980 0.11230(5) 3.34305 0.25029(5) KIDNEYS/ FINAL BODY* 100 0.84605 0.02050(5) 0.82327 0.02397(5) 0.87592 0.04028(5) 0.90275 0.07877(5) LUNGS/ FINAL BODY* 100 0.47483 0.01857(5) 0.48396 0.06297(4) 0.49457 0.04540(5) 0.53948# 0.02622(5) .49. TABLE 12 (Continued) MEAN FINAL BODY AND ORGAN WEIGHTS FROM MALE RATS DAY 25 SACRIFICE TEST/ PERIOD Group I Omg/m3 Groupm 25 mg/m3 Group V 125 mg/m3 Group Vn 600 mg/m3 BRAIN/ FINAL BODY* 100 0.52227 0.06124(5) 0.57859 0.04583(5) 0.54580 0.03818(5) 0.56807 0.05830(5) TESTES/ FINAL BODY* 100 0.85014 0.09459(5) 0.94481 0.04910(5) 0.74234 0.10856(5) 0.93325 0.11274(5) MEAN RELATIVE ORGAN WEIGHTS ( organ to brain weight ratio) LIVER/BRAIN 6.07890 0.66519(5) 5.36315 0.69015(5) 6.09520 0.56827(5) 5.94192 0.80947(5) KIDNEYS/BRAIN 1.63796 0.19474(5) 1.42971 0.11537(5) 1.61037 0.12665(5) 1.59608 0.14198(5) LUNGS/BRAIN 0.91981 0.12105(5) 0.83631 0.11746(4) 0.91065 0.11247(5) 0.95879 0.11860(5) TESTES/BRAIN 1.64389 0.25262(5) 1.64009 0.14469(5) 1.37226 0.26123(5) 1.64189 0.08712(5) Data arranged as: Mean Standard deviation (Number of values included in calculation) # Statistically significant difference from control at p < 0.05 by trend test (Jonckheere-Terpstra). -50- H-24267: Two-Week Inhalation Toxicity Study in Male Rats TABLE 13 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS DAY 11 SACRIFICE LESIONS LIVER NO ABNORMALITY DETECTED DEFORMITY, IRREGULAR, MIDDLE. DISCOLORATION, YELLOW. LEFT. KIDNEYS NO ABNORMALITY DETECTED DILATATION, UNILATERAL, PELVIS. LUNGS NO ABNORMALITY DETECTED HEART NO ABNORMALITY DETECTED SPLEEN NO ABNORMALITY DETECTED DEFORMITY, IRREGULAR. BRAIN NO ABNORMALITY DETECTED TREATMENT LESION INCIDENCE (Num 0 mg/m3 I 25 mg/m3 III 125 mg/m3 V (5) (5) (5) 4 5 5 1 1 (5) (5) (5) 5 4 5 1 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 4 5 1 (5) (5) (5) 5 5 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified -51- Coswpany Sanitized. Does not contain H-24267: Two-Week Inhalation Toxicity Study in Male Rats TABLE 13 (Continued) INCIDENCES OP GROSS OBSERVATIONS IN MALE RATS DAY 11 SACRIFICE LESIONS SPINAL CORD NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY-DETECTED ILEUM NO ABNORMALITY DETECTED PANCREAS NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED TREATMENT LESION INCIDENCE (Num 0 ing/m3 I 25 mg/m3 III 125 mg/m3 V (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified -52- H-24267: Two-Week Inhalation Toxicity Study in Male Rats TABLE 13 (Continued) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS DAY 11 SACRIFICE LESIONS COLON NO ABNORMALITY DETECTED RECTUM NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED THYROID GLAND NO ABNORMALITY DETECTED TREATMENT LESION INCIDENCE (Num 0 mg/m3 25 mg/m3 III 125 mg/m3 V (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified -53- Company Sanitized. Does no6 cont H-24267: Two-Week Inhalation Toxicity Study in Male Rats TABLE 13 (Continued) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS DAY 11 SACRIFICE LESIONS PARATHYROID GLANDS NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED PHARYNX/LARYNX MO ABNORMALITY-DETECTED EYE(S) NO ABNORMALITY DETECTED PROSTATE 'NO ABNORMALITY DETECTED SEMINAL VESICLES NO ABNORMALITY DETECTED TREATMENT LESION INCIDENCE (Num 0 25 125 ing/m3 mg/m3 mg/m3 m I III V V (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified -54- H-24267: Two-Week Inhalation Toxicity Study in Male Rats TABLE 13 (Continued) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS DAY 11 SACRIFICE LESIONS URINARY BLADDER NO ABNORMALITY DETECTED TESTES NO ABNORMALITY DETECTED EPIDIDYMIDES NO ABNORMALITY DISCOLORATION, DISCOLORATION, DETECTED MOTTLED, TAIL, RIGHT. TAN, FIRM, TAIL. STERNUM NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED TREATMENT LESION INCIDENCE (Num 0 mg/m3 25 mg/m3 III 125 mg/m3 V (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 4 5 5 1 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified -55- eampany Sanitized. Does not con H-24267: Two-Week Inhalation Toxicity Study in Male Rats TABLE 14 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS DAY 25 SACRIFICE LESIONS LIVER NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED COLON NO ABNORMALITY DETECTED TREATMENT LESION INCIDENCE (Nu 0 mg/iti3 I 25 mg/m3 III 125 mg/m3 V (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates, the finding specified was not identified -56- H-24267: Two-Week Inhalation Toxicity Study in Male Rats TABLE 14 (Continued) INCIDENCES OP GROSS OBSERVATIONS IN MALE RATS DAY 25 SACRIFICE LESIONS RECTUM NO ABNORMALITY DETECTED PANCREAS NO ABNORMALITY DETECTED URINARY BLADDER NO ABNORMALITY DETECTED KIDNEYS NO ABNORMALITY- DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED LUNGS NO ABNORMALITY DETECTED NOSE NO ABNORMALITY DETECTED LESION INCIDENCE (Num TREATMENT ' 0 ing/m3 T 25 mg/m3 III 125 mg/m3 V (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified -57- ompany Sanitised. Does n H-24267: Two-Week Inhalation Toxicity Study in Male Rats TABLE 14 (Continued) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS DAY 25 SACRIFICE LESIONS HEART NO ABNORMALITY DETECTED MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED SPLEEN NO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED PARATHYROID GLANDS NO ABNORMALITY DETECTED THYROID GLAND NO ABNORMALITY DETECTED BRAIN NO ABNORMALITY DETECTED TREATMENT LESION INCIDENCE (Num 0 mg/m3 I 25 mg/m3 III 125 mg/m3 V (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified -58- Company Sanitized. Does not contain H-24267: Two-Week Inhalation Toxicity Study in Male Rats TABLE 14 (Continued) INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS DAY 25 SACRIFICE LESIONS SPINAL CORD NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED EPIDIDYMIDES NO ABNORMALITY- DETECTED PROSTATE NO ABNORMALITY DETECTED SEMINAL VESICLES 'NO ABNORMALITY DETECTED TESTES NO ABNORMALITY DETECTED EYE(S) NO ABNORMALITY DETECTED TREATMENT LESION INCIDENCE (Num 0 mg/iti3 I 25 mg/m3 III 125 mg/m3 V (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 (5) (5) (5) 5 5 5 Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified -59- H-24267: Two-Week Inhalation Toxicity Study in Male Rats TABLE 15 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS DAY 11 SACRIFICE LESIONS DIGESTIVE SYSTEM LIVER INFLAMMATION, SUBACUTE/CHRONIC. minimal -total observations per lesion INFLAMMATION, GRANULOMATOUS, with mineralization. minimal total observations per lesion FATTY CHANGE, MEDIAN CLEFT. minimal total observations per lesion PANCREAS NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED TREATMENT LESION INCIDENCE 0 25 12 ing/in3 mg/m3 mg I III V (5) (5) ( 5 5 5 5 1 1 (5) 5 (5) 5 (5) 5 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified -60- eompany SanRfzed. Does not contain H-24267: Two-Week Inhalation Toxicity Study in Male Rats TABLE 15 (Continued) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS DAY 11 SACRIFICE LESIONS DIGESTIVE SYSTEM DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED ILEUM NO ABNORMALITY DETECTED CECUM NO ABNORMALITY DETECTED COLON. NO ABNORMALITY DETECTED RECTUM NO ABNORMALITY DETECTED TREATMENT LESION INCIDENCE 0 25 12 mg/m3 mg/m3 mg T III V (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 (5) 5 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified -61- H-24267: Two-Week Inhalation Toxicity Study in Male Rats TABLE 15 (Continued) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS DAY 11 SACRIFICE LESIONS URINARY SYSTEM KIDNEYS NO ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. .minimal mild total observations per lesion HYDRONEPHROSIS. UNILATERAL. minimal total observations per lesion URINARY BLADDER NO ABNORMALITY DETECTED RESPIRATORY SYSTEM LUNGS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, CENTRIACINAR. minimal total observations per lesion TREATMENT LESION INCIDENCE 0 25 125 mg/m3 mg/m3 mg I III V (5) (5) (5 3 4 2 2 1 1 (5) 5 (5) (5) ( 4 2 3 3 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified -62- Goeapwy Sanitized. Does not con H-24267: Two-Week Inhalation Toxicity Study in Male Rats TABLE 15 (Continued) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS DAY 11 SACRIFICE LESIONS RESPIRATORY SYSTEM LUNGS INFLAMMATION, SUBACUTE/CHRONIC, FOCAL. minimal total observations per lesion INFLAMMATION, ACUTE, PERIVASCULAR. minimal total observations per lesion HYPERTROPHY, BRONCHIOLAR EPITHELIAL CELL. minimal total observations per lesion TRACHEA NO .ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED NECROSIS, CARTILAGE. minimal total observations per lesion METAPLASIA, SQUAMOUS. minimal TREATMENT LESION INCIDENCE 0 25 125 mg/m3 mg/m3 mg III V (5) (5) (5 1 2 1 2 2 2 (5) 5 (5) (5) ( 5 3 2 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified -63- H-24267: Two-Week Inhalation Toxicity Study in Male Rats TABLE 15 (Continued) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS DAY 11 SACRIFICE LESIONS RESPIRATORY SYSTEM PHARYNX/LARYNX METAPLASIA, SQUAMOUS. total observations per lesion II NOSE I & NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. minimal total observations per lesion HYPERTROPHY, GOBLET CELL. minimal total observations per lesion HYPERPLASIA/HYPERTROPHY, RESPIRATORY. minimal total observations per lesion DEGENERATION/NECROSIS, OLFACTORY. minimal total observations per lesion I I I NOSE & IV NO ABNORMALITY DETECTED TREATMENT LESION INCIDENCE 0 25 12 mg/m3 mg/m3 mg III V (5) (5) ( 2 (5) (5) ( 5 5 (5) (5) ( 5 1 Figure in parentheses is number of animals microsbopically examined for this tissue The absence of a number indicates the lesion specified was not identified -64. oalpany Sanitized. Does not c H-24267: Two-Week Inhalation Toxicity Study in Male Rats TABLE 15 (Continued) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS DAY 11 SACRIFICE LESIONS RESPIRATORY SYSTEM I I I NOSE & IV HYPERTROPHY, GOBLET CELL. minimal -total observations per lesion CARDIOVASCULAR SYSTEM HEART NO ABNORMALITY' DETECTED LYMPHATIC AND HEMATOPOIETIC SYSTEM SPLEEN NO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED TREATMENT LESION INCIDENCE 0 25 125 mg/m3 mg/m3 mg/ I III V (5) (5) (5 4 4 4 4 (5) 5 (5) (1) 5 1 (5) 5 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified -65- Company SasElteed. Does not contain H-24267: Two-Week Inhalation Toxicity Study in Male Rats TABLE 15 (Continued) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS DAY 11 SACRIFICE LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED BONE MARROW NO ABNORMALITY DETECTED ENDOCRINE SYSTEM THYROID GLAND NO ABNORMALITY DETECTED PARATHYROID GLANDS NO ABNORMALITY DETECTED NOT PRESENT. ADRENAL GLANDS NO ABNORMALITY DETECTED NOT PRESENT, MEDULLA. TREATMENT LESION INCIDENCE 0 25 12 ing/in3 mg/m3 m III V (5) 5 (5) 5 (5) 5 (5) 4 1 (5) 3 2 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified -66- H-24267: Two-Week Inhalation Toxicity Study in Male Rats TABLE 15 (Continued) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS DAY 11 SACRIFICE LESIONS NERVOUS SYSTEM BRAIN NO ABNORMALITY DETECTED SPINAL CORD NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED MUSCULAR AND SKELETAL SYSTEM STERNUM NO -ABNORMALITY DETECTED REPRODUCTIVE SYSTEM TESTES NO ABNORMALITY DETECTED TREATMENT LESION INCIDENCE 0 25 125 mg/m3 mg/m3 mg I III V (5) 5 (5) 5 (5) 5 (5) 5 (5) (5) (5 3 5 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified -67- OBipany Sanitized. Does mat conta H-24267: Two-Week Inhalation Toxicity Study in Male Rats TABLE 15 (Continued) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS DAY 11 SACRIFICE LESIONS TREATMENT REPRODUCTIVE SYSTEM TESTES DEGENERATION/ATROPHY, SEMINIFEROUS TUBULES, minimal -mild total observations per lesion BILATERAL. PROSTATE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. minimal total observations per lesion EPIDIDYMIDES NO ABNORMALITY DETECTED OLIGOSPERMIA/GERM CELL DEBRIS, UNILATERAL. minimal total observations per lesion OLIGOSPERMIA/GERM CELL DEBRIS, BILATERAL. minimal mild total observations per lesion LESION INCIDENCE 0 25 12 mg/m3 mg/m3 mg I III V (5) (5) ( 2 2 (5) 4 1 1 (5) 2 1 1 2 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified -68- H-24267: Two-Week Inhalation Toxicity Study in Male Rats TABLE 15 (Continued) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS DAY 11 SACRIFICE LESIONS REPRODUCTIVE SYSTEM EPIDIDYMIDES GRANULOMA, SPERM. SEMINAL VESICLES NO ABNORMALITY DETECTED SPECIAL SENSES SYSTEM EYE(S) NO ABNORMALITY DETECTED TREATMENT | LESION INCIDENCE 25 12 mg/m3 mg/m3 mg III V (5) 1 (5) 5 (5) 5 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified -69- Gompany Sanitized. Does not co H-24267: Two-Week Inhalation Toxicity Study in Male Rats TABLE 16 INCIDENCES AND LESION GRADES OP MICROSCOPIC OBSERVATIONS IN MALE RATS DAY 25 SACRIFICE LESIONS DIGESTIVE SYSTEM LIVER INFLAMMATION, SUBACUTE/CHRONIC. minimal - total observations per lesion FATTY CHANGE, MEDIAN CLEFT. minimal mild total observations per lesion URINARY SYSTEM KIDNEYS NO-ABNORMALITY DETECTED NEPHROPATHY, CHRONIC PROGRESSIVE. minimal total observations per lesion HYDRONEPHROSIS, UNILATERAL. minimal total observations per lesion TREATMENT LESION INCIDENCE 0 25 12 mg/m3 mg/m3 mg I III V (5) 5 5 1 1 2 (5) 1 4 4 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified -70- H-24267: Two-Week Inhalation Toxicity Study in Male Rats TABLE 16 (Continued) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS DAY 25 SACRIFICE LESIONS RESPIRATORY SYSTEM LUNGS NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC, CENTRIACINAR. - minimal total observations per lesion INFLAMMATION, SUBACUTE/CHRONIC, FOCAL. minimal total observations per lesion PHARYNX/LARYNX NO ABNORMALITY DETECTED NECROSIS, CARTILAGE. minimal total observations per lesion II NOSE I & NO ABNORMALITY DETECTED I I I NOSE & IV NO ABNORMALITY DETECTED TREATMENT LESION INCIDENCE 0 25 12 mg/m3 mg/m3 m III V (5) (5) 4 5 1 1 (5) (5) 5 5 (5) 5 (5) 5 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified -Pi- Company Sanitized. Does n H-24267: Two-Week Inhalation Toxicity Study in Male Rats TABLE 16 (Continued) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS DAY 25 SACRIFICE LESIONS TREATMENT REPRODUCTIVE SYSTEM TESTES NO ABNORMALITY DETECTED DEGENERATION/ATROPHY, SEMINIFEROUS TUBULES, - minimal total observations per lesion UNILATERAL. LESION INCIDENCE 0 25 12 mg/m3 mg/m3 mg I III V (5) 4 1 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified -72- H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 FIGURES -73- CoaBpal^' (rorasffia*"-^^08 H-24267: Two-Week Inhalation Toxicity Study in Male Rats FIGURE 1 SCHEMATIC OF EXPOSURE SYSTEM Spraying Systems nebulizer syringe drive 1 ex posure ch amber -74- ^ ------^ MSA filter cold trap fume hood Qowpaasy Sanitized. Does no sg^.fe ....^S-.Q-^^S^ H-24267: Two-Week Inhalation Toxicity Study in Male Rats FIGURE 2 MEAN BODY WEIGHTS OF MALE RATS 390-^ 370-^ 3' 31(H 2901 10 15 Days on Test * Weight losses due to fasting of rats prior to clinical pathology evaluations. -75- APPENDICES -76- ampa8W ta'"!*!A08 "8 ew^^" TCCA CB8 APPENDIX A Daily Atmospheric Analyses .77 DAILY ATMOSPHERIC ANALYSES ABBREVIATIONS: EXPLANATORY NOTES S.D. - n - mg/m3 - standard deviation number of samples milligrams per cubic meter NOTES: Values are reported to 2 significant figures. -78 H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 DAILY ATMOSPHER][CANA]LYSES GROUP : I DESIGN CON(CENTRAiTION: Omg/m3 EXPOSURE NUMBER 1 2 3 4 5 6 7 8 9 TEST DAY 0 1 2 3 4 7 8 9 10 MEASURED CONCE,NTRATION(mg/rn3) MEAN S.D. RANGE n 0 0 0 1 0 0 0 1 0 0 0 1 0 0 0 1 0 0 0 1 0 0 0 1 0 0 0 1 0 0 0 1 0 0 0 1 GROUP: m DESIGN CONCENTRATION: 25 mg/m3 EXPOSURE NUMBER 1 2 3 4 5 6 7 8 9 TEST DAY 0 1 2 3 4 7 8 9 10 MEASURED CONCENTRATION (mg/m3) MEAN S.D. RANGE n 15 9.8 4.0 - 27 6 26 8.7 13-36 6 34 26 8.4 - 70 6 17 7.7 5.0 - 27 6 24 6.7 18-36 6 31 17 7.9 - 58 6 19 14 6.4 - 45 6 19 10 8.4 - 39 6 24 18 8.4 - 55 6 -79- H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 DAILY ATMOSPHERIC ANALYSES GROUP: V DESIGN CONCENTRATION: 125 mg/m3 EXPOSURE NUMBER 1 2 3 4 5 6 7 8 9 TEST DAY 0 1 2 3 4 7 8 9 10 MEASURED CONCEiNTRATION (mg/m3) MEAN S.D. RANGE n 120 22 110-170 6 99 41 50 -160 6 140 46 62 - 200 6 110 25 94 -160 6 120 34 73 -160 6 120 37 80 -170 6 110 17 94 - 140 6 79 36 18 -120 6 96 12 84-110 6 GROUP: vn DESIGN CONCENTRATION: 600 mg/m3 EXPOSURE NUMBER 1 2 3 4 5 6 7 8 9 TEST DAY 0 1 2 3 4 7 8 9 10 MEASURED CONCENTRATION (mg/m3) MEAN S.D. RANGE n 720 150 460 - 840 6 650 70 560 - 720 6 460 250 85 - 840 6 460 160 280 - 720 6 520 180 380 - 860 6 720 260 290 - 960 6 620 150 440 - 850 6 600 120 470 - 780 6 620 100 490 - 740 6 -80- Qempwf Sanitized. APPENDIX B Daily Environmental Conditions -81 H-24267: Two-Week Inhalation Toxicity Study in Male Rats DAILY ENVIRONMENTAL CONDITIONS ABBREVIATIONS: EXPLANATORY NOTES n - number of observations NOTES: Values are reported to 2 significant figures. DuPont-4292 -82- eempany SanStteed. Does not contain TSCA CBB H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 DAILY ENVIRONMENTAL CONDITIONS GROUP': I I )ESIGN CONCI3NTRATION: Onig/m3 RELATIVE TOTAL EXPOSURE TEST TEMPE]RATUR]5 HUMIDITY AIRFLOW NUMBER DAY ( C) n (%) n (L/MIN) n 1 1 24 -26 3 37-50 2 30 1 2 2 23 -25 3 46-47 2 30 1 3 3 23 -25 3 43-49 2 30 1 4 4 23 -24 3 40-44 2 30 1 5 5 23 -25 3 38-42 2 30 1 6 8 24 -24 3 43-46 2 30 1 7 9 23 -24 3 35-39 2 30 1 8 10 23 -24 3 43-45 2 30 1 9 11 22 -23 3 37-39 2 30 1 GROUP: m DESIGN CONCENTRATION: 25 mg/m3 RELATIVE TOTAL EXPOSURE TEST TEMPERATURE HUMIDITY AIRFLOW NUMBER DAY (C) n (%) n (L/MIN) n 1 1 24 -26 3 42-54 2 30 1 2 2 23 -24 3 46-51 2 30 2 3 3 22 -24 3 51-54 2 30 1 4 4 22 -23 3 40-41 2 30 1 5 5 24 -24 3 41-51 2 30 2 6 8 24 -24 3 40-50 2 30 1 7 9 23 -24 3 40-42 2 30 1 8 10 23 -24 3 39-43 2 30 1 9 11 22 -24 3 38-42 2 30 1 83 H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 DAILY ENVIRONMENTAL CONDITIONS G ROUP: V D ESIGNCO:NCENTRATION: 125]mg/m3 RELATIVE TOTAL EXPOSURE TEST TEMPE]RATURE HUMIDITY AIRFLOW NUMBER 1 DAY 1 (c'0 23 -25 n (%) n (L/MIN) n 3 50-61 2 30 1 2 2 22 -24 3 54-56 2 30 1 3 3 22 -23 3 56-58 2 30 1 4 4 22 -23 3 50-54 2 30 1 5 5 23 -23 3 53-57 2 30 1 6 8 23 -24 3 48-57 2 30 1 7 9 22 -23 3 48-58 2 30 1 8 10 22 -24 3 37-43 2 30 1 9 11 22 -23 3 39-41 2 30 1 GROUP: Vn DESIGN CONC:ENTRATION: 600 mg/m3 RELATIVE TOTAL EXPOSURE TEST TEMPERATURE HUMIDITY AIRFLOW NUMBER DAY (C) n (%) n (L/MIN) n 1 1 23 -24 3 69-81 2 30 1 2 2 21 -23 3 71-73 2 30 1 3 3 21 -22 3 72-78 2 30 1 4 4 21 -22 3 65-70 2 30 1 5 5 21 -22 3 75-78 2 30 1 6 8 21 -22 3 70-72 2 30 1 7 9 21 -22 3 72-76 2 30 1 8 10 21 -22 3 77-82 2 30 1 9 11 22 -22 3 82-84 2 30 1 -84- Company Sanitoed. Does not contain TCCA CB6 H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 APPENDIX C Individual Body Weights -85 ^32teA^3SS8:Sai H-24267: Two-Week Inhalation Toxicity Study in Male Rats Body Weight g Day 0 Body Weight g Day 1 Body Weight g Day 2 Ind ividual Body Weights Body Weight g Day 3 Body Weight g Day 4 B ody We ight g Day 7 Body Weight g Day 8 Body Weight g Day 9 Body W g Day Male, I - 0 mg/rn3 637800 291.0 305.1 309.4 316.1 325.8 346 .3 355.1 360.1 36 637801 305.0 300.3 305.1 313.2 310.0 330 .9 337.8 308.2 33 637802 302.0 308.8 317.9 322.1 323.3 341 .4 348.0 350.6 35 637803 292.0 292.0 300.2 310.6 314.8 332 .3 335.0 340.1 34 637804 298.0 306.2 312.7 313.7 314.2 332 .8 334.4 338.2 34 637805 267.0 273.3 282.0 287.8 295.1 322 .0 326.0 329.1 32 637806 309.0 310.0 318.7 324.7 327.1 343.1 346.5 350.2 35 637807 257.0 254.9 260.4 264.8 268.0 279 .5 281.0 284.2 28 637808 333.0 329.0 341.9 344.4 348.2 373 .7 372.3 374.5 38 637809 264.0 264.0 267.8 271.9 271.9 282 .4 290.1 290.5 30 Body Weight g Day 11 Body Weight g Day 14 Body Weight g Day 18 Body Weight g Day 22 Body Weight g Day 25 Male, I - 0 mg/m3 637800 637801 637802 637803 637804 637805 637806 637807 637808 637809 327.0 303.0 317.0 313.0 299.0 304.0 332.0 264.0 340.0 265.0 340.0 355.0 298.0 394.0 306.0 378.0 388.4 319.0 424.0 327.0 406.1 409.7 339.5 449.8 353.2 388-5 393.6 320.6 438.5 337.8 -86- Company Sanitized. Does not contain T H-24267: Two-Week Inhalation Toxicity Study in Male Rats B ody Weight g Day 0 Body Weight g Day 1 Body Weight g Day 2 Individual Body Weights Body Weight g Day 3 Body Weight g Day 4 Body Weight g Day 7 Body Weight g Day 8 Body We ight g Day 9 Body W g Day 1 Male, III - 25 mg/m3 637810 296.0 296.8 298.0 297.1 301.9 329.1 326.8 331 .5 335 637811 298.0 296.7 300.3 302.5 308.4 331.3 330.8 330 .9 339 637812 303.0 299.7 300.8 303.0 308.8 335.0 337.2 339 .7 345 637813 292.0 290.9 294.0 296.9 302.8 326.3 .325.4 326 .8 327 637814 295.0 285.3 283.9 288.7 292.0 309.0 308.6 312 .0 314 637815 270.0 267.5 272.2 273.0 274.4 294.7 295.4 299 .6 299 637816 305.0 298.9 299.6 298.4 301.4 321.5 325.1 324 .1 323 637817 259.0 253.6 256.0 255.6 258.4 277.3 277.2 272.4 272 637818 301.0 290.0 293.0 298.0 305.0 319.2 322.0 321 .0 322 637819 270.0 266.5 274.1 279.4 283.6 314.7 318.1 320 .8 324 Body Weight g Day 11 Body Weight g Day 14 Body Weight g Day 18 Body Weight g Day 22 Body Weight g Day 25 Male, III - 637810 637811 637812 637813 637814 637815 637816 637817 637818 637819 25 ing/m3 293.0 298.0 303.0 291.0 287.0 273.0 302.0 243.0. 285.0 293.0 299.0 337.0 276.0 323.0 334.0 328.4 368.7 297.4 344.8 365.3 346.3 384.1 311.3 369.7 391.6 332.4 370.0 296.2 357.4 388.5 -87. H-24267: Two-Week Inhalation Toxicity Study in Male Rats Individual Body Weights Male, V 637820 637821 637822 637823 637824 637825 637826 637827 637828 637829 3 Body Weight Day 0 Body Weight Day 1 - 125 mg/rn3 301.0 288.2 294.0 281.9 302.0 289.8 290.0 287.7 292.0 287.7 294.0 286.6 316.0 307.3 277.0 271.0 300.0 297.7 289.0 281.6 ( s g g Body Weight Day 2 Body Weight Day 3 Body Weight Day 4 286.8 300.9 308.3 283.3 288.4 291.9 296.3 296.1 298.4 291.2 294.3 295.7 292.1 293.4 290.9 288.1 296.4 295.3 310.2 311.8 316.6 271.0 281.6 282.8 302.7 310.8 313.4 289.0 293.7 298.2 gBody Weight Day 7 330.1 315.4 319.4 321.7 310.9 323.1 346.1 304.8 330.0 327.4 g g s Body Weight Day 8 Body Weight Day 9 Body W Day 328.4 320.2 32 304.6 303.1 29 320.4 314.0 31 322.6 317.4 32 312.4 307.0 31 317.0 311.1 31 332.7 336.8 34 301.4 298.4 29 326.0 326.1 32 325.1 324.0 32 Body Weight g Day 11 Body Weight g Day 14 Body Weight g Day 18 Body Weight g Day 22 Body Weight g Day 25 Male, V - 637820 637821 637822 637823 637824 637825 637826 637827 637828 637829 125 mg/m3 288.0 264.0 282.0 290.0 277.0 290.0 320.0 276.0 293.0 291.0 326.0 356.0 315.0 344.0 345.0 360.0 394.1 336.5 368.6 375.1 377.1 419.7 359.4 397.0 405.6 364.9 405.4 349.2 385.9 391.2 -88- affipasy Sanitised. Does not contai H-24267: Two-Week Inhalation Toxicity Study in Male Rats i3ody Weight g Day 0 Iiody Weight g Day 1 Body Weight g Day 2 IndiLvidual Body Weights Body Weight g Day 3 Body Weight g Day 4 Body We ight g Day 7 Body Weight g Day 8 Body Weight g Day 9 Body W g Day Male, VI][ - 600 mg/m3 637830 295.0 284.7 289.7 285.0 276.7 306 .1 306.0 302.5 30 637831 293.0 280.6 285.1 291.3 282.6 310 .1 305.8 308.1 3 637832 315.0 290.0 298.9 295.9 294.2 328 .8 322.5 330.2 31 637833 308.0 294.2 293.9 294.8 296.9 332 .7 327.3 329.9 3 637834 302.0 286.2 278.7 278.1 287.8 314 .0 307.1 302.2 30 637835 292.0 276.3 271.0 266.7 275.1 293 .8 293.0 291.0 29 637836 311.0 300.9 305.1 304.2 309.4 329 .9 328.9 325.3 3 637837 261.0 247.8 248.6 242.7 243.4 267 .9 257.3 260.9 2 637838 322.0 318.3 318.4 319.0 326.5 345.9 346.3 347.0 3 637839 286.0 281.6 281.3 281.6 281.2 303.1 296.8 299.7 2 Body Weight g Day 11 Body Weight g Day 14 Body Weight g Day 18 Body Weight g Day 22 Body Weight g Day 25 Male, VII - 637830 637831 637832 637833 637834 637835 637836 637837 637838 637839 600 mg/m3 264.0 270.0 283.0 290.0 275.0 257.0 295.0 226.0 304.0 258.0 296 .0 334 .0 263 .0 360.0 300 .0 330 .9 370 .6 285 .3 400 .7 327 .5 358. 7 393. 6 299. 7 422. 6 343.1 345.5 384.6 291.1 413.8 335.0 .89- H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 APPENDIX D Individual Clinical Observations and Mortality Records -90- Company 8aisItteA Does not contain TSCA CBI Sex Group Animal M I 637800 M I 637801 M I 637802 M I 637803 M I 637804 M I 637805 M I 637806 M I 637807 M I 637808 M I 637809 Individual Clinical Observations and Mortality Records Observation General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation, Mo Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Bilateral Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation, Mo Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design -91 H-24267: Two-Week Inhalation Toxicity Study in Male Rats Sex Group Animal M III 637810 M III 637811 M III 637812 M III 637813 M III 637814 M III 637815 M III 637816 M III 637817 M III 637818 M III 637819 Individual Clinical Observations and Mortality Records Observation General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Hair Loss, Face, Right Wound, Superficial, Face Sacrificed by design Left General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation. Wo Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design DuPont-4292 Days 0-11 11 11 0-11 11 11 0-11 11 11. 0-11 11 11 0-11 11 11 0,11-25 11,25 8-10 1-7 25 0-25 11,25 25 0-25 11,25 25 ' 0-25 11,25 25 0-25 11,25 25 -92 H-24267: Two-Week Inhalation Toxicity Study in Male Rats Sex Group Animal M V 637820 M V 637821 M V 637822 M V 637823 M V M V M V M V M V M V 637824 637825 637826 637827 637828 637829 Individual Clinical Observations and Mortality Records Observation General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Hair Loss, Forepaw, Bilateral Hair Loss, Forepaw, Left Sacrificed by design Left General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Hair Loss, Forelimb, Bilateral Hair Loss, Forepaw, Bilateral Sacrificed by design Left General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design DuPont-4292 Days 0-11 11 11 0-11 11 11 0-4,11 11 8-10 7 11 0-1,11 11 4-10 2-10 11 0-11 11 11 0-25 11,25 25 0-25 11,25 25 0-25 11,25 25 0-25 11,25 25 0-25 11,25 25 -93 H-24267: Two-Week Inhalation Toxicity Study in Male Rats Sex Group Animal M VII 637830 M VII 637831 M VII 637832 M VII 637833 M VII 637834 M VII 637835 M VII 637836 M VII 637837 M VII 637838 M VTI 637839 Individual Clinical Observations and Mortality Records Observation General observation. Ho Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General .observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Sacrificed by design DuPont-4292 Days 0-11 11 11 0-11 11 11 0-11 11 11. 0-11 11 11 0-11 11 11 0-25 11,25 25 0-25 11,25 25 0-25 11,25 25 0-25 11,25 25 0-25 11,25 25 -94- eompany D@@s awt cwWm TSCA CBi H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 APPENDIX E Individual Animal Clinical Pathology Data -95 H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 INDIVIDUAL ANIMAL CLINICAL PATHOLOGY DATA EXPLANATORY NOTES ABBREVIATIONS: General: ADEQ DECK NSR NT OK RNV UTD < adequate decreased no sample received for testing not taken or not performed sample condition OK for testing result not valid unable to determine less than Individual COND RBC HGB HCT MCV MCH MCHC RDW ARET MRBC WBC ANEU ANPR ALYM AMON AEOS ABAS ALUC ABLT AMSC PLT BASO BLST EOS LUC LYMP MISC MOMO NEUT MPRE Hematology Values: - sample condition - red blood cell count - hemoglobin - hematocrit - mean corpuscular volume - mean corpuscular hemoglobin - mean corpuscular hemoglobin concentration - red cell distribution width - absolute reticulocyte count - nucleated red blood cell count - white blood cell count - absolute neutrophil (all forms) - absolute neutrophil precursor - absolute lymphocyte - absolute monocyte - absolute eosinophil - absolute basophil - absolute large unstained cell - absolute blast leukocyte - absolute miscellaneous leukocyte - platelet count - percent basophil - percent blast leukocyte - percent eosinophil - percent large unstained cell - percent lymphocyte - percent miscellaneous leukocyte - percent monocyte - percent neutrophil - percent neutrophil precursor Individual Red Blood Cell Morphology Values: NORM - normal ANIS - anisocytosis MICR - microcytes MACR - macrocytes POLY - polychromasia HYPO - hypochromasia ECHI - echinocytes ACAN - acanfchocytes TARG RX - HJB - target cells rouleaux HHoowwee1111--JJoolllly body not observed or not examined; see whole blood sample condition -96- H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 INDIVIDUAL ANIMAL CLINICAL PATHOLOGY DATA EXPLANATORY NOTES (Continued) ABBREVIATIONS: (Continued) Individual NORM SM TG DB VN PC GP BP White Blood Cell / Platelet Morphology Values: - normal - smudge white blood cells - toxic granulation (white blood cells) - Dohle bodies - vacuolated neutrophils - platelet clumps - giant platelets - bizarre platelets - not observed or not examined; see whole blood sample condition Individual PHEM FLIP PICT PT APTT Coagulation Values: plasma hemolysis plasma lipemia plasma icterus prothrombin time activated partial thromboplastin time Individual SHEM SLIP SICT AST ALT SDH ALKP BILI BUN CREA CHOL TRIG GLUC TP ALB GLOB CALC IPHS NA K CL PFLU FHEM FLIP FICT Serum Chemistry Values: - serum hemolysis - serum lipemia - serum icterus - aspartate aminotransferase - alanine aminotransferase - sorbifcol dehydrogenase - alkaline phosphatase - total bilirubin - urea nitrogen - creatinine - 'cholesterol - triglycerides - glucose - total protein - albumin - globulin - calcium - inorganic phosphorous - sodium - potassium - chloride - plasma fluoride - plasma hemolysis from blood sample for fluoride determination - plasma lipemia from blood sample for fluoride determination - plasma icterus from blood sample for fluoride determination -97. H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 INDIVIDUAL ANIMAL CLINICAL PATHOLOGY DATA EXPLANATORY NOTES (Continued) ABBREVIATIONS: (Continued) Individual Urinalysis Values: QUAL - quality (modifies COL - color CLAR - clarity VOL - volume color) UOSM SG - pH UPRO UGLU - KET - urine osmolality specific gravity the logarithm of the reciprocal of the hydrogen ion concentration urine protein urine glucose ketone UBIL - BLD - urine bilirubin blood URO - urobilinogen UFLU - urine fluoride Individual EPIT UWBC URBC NCRY MICR Urine Microscopic Examination - epithelial cells - urine white blood cells - urine red blood cells - normal crystals - microorganisms Values: -98- Csmpwss?SanSSSmS. Does not eonlalst TSCA CB8 H-24267: Two-Week Inhalation Toxicity Study in Male Rats _______ DuPont-4292 INDIVIDUAL ANIMAL CLINICAL PATHOLOGY DATA EXPLANATORY NOTES (Continued) KEY: Red Blood Cell Morphology Values, White Blood Cell / Platelet Morphology Values, and Special Observations: 1 - few 2 - moderate 3 - many 4 - all 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 (for hematology or coagulation data) (CLOT) there was insufficient sample for analysis a valid result could not be obtained (RMV) the sample was not suitable for evaluation the animal died prior to sample collection no sample was available for analysis (NSR) When an individual observation is recorded as being less than a certain value, calculations are performed on half the recorded value. For example, if bilirubin is reported as <0.1, 0.05 is used for any calculations performed with that bilirubin data. -99 H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL HEMATOLOGY VALUES FOR MALE RATS Animal Number COND RBC xlO"6/nL HBB g/dL Male, Group: I - 0 mg/m3 - Day 11 637800 637801 637802 637803 637804 637805 637806 637807 637808 637809 OK 7.40 OK 7.34 OK 7.70 OK 7.51 OK 7.91 OK 7.51 OK 7.51 OK 7.81 OK 6.96 OK 8.08 Male, Group: III 25 mg/m3 - Day 11 637810 637811 637812 637813 637814 637815 637816 637817 637818 637819 OK 7.44 OK 7.47 .OK 7.08 OK 7.21 OK 7.14 OK 8.74 OK 7.89 OK 8.68 OK 8.33 OK 7.37 14.5 14.3 15.9 14.8 16.1 15.2 15.0 15.4 14.6 16.0 15.6 14.7 14.5 14.5 14.3 16.6 14.9 16.5 16.0 14.3 HCT % 46.6 44.6 50.1 46.6 50.5 47.2 46.5 47.5 44.4 48.5 49.3 45.9 44.0 45.1 43.6 51.5 46.8 52.5 50.0 45.0 MCV L 63.0 60.8 65.1 62.0 63.8 62.8 61.9 60.8 63.8 60.0 66.3 61.5 62.1 62.6 61.0 58.9 59.3 60.5 60.0 61.1 MCH pg 19.6 19.5 20.6 19.7 20.4 20.2 20.0 19.7 21.0 19.8 21.0 19.7 20.5 20.1 20.0 19.0 18.9 19.0 19.2 19.4 MCHC g/dL 31.1 32.0 31.7 31.8 31.9 32.2 32.3 32.4 32.9 33.0 31.6 32.0 33.0 32.1 32.8 32.2 31.8 31.4 32.0 31.8 RDW ARET % xlO"3/tlL N /100 13.0 13.2 12.3 12.7 12.5 13.4 14.2 12.6 13.6 12.6 13.3 13.3 13.1 13.4 13.7 11.8 13.4 12.7 12.8 13.7 262.5 199.1 231.6 239.0 212.0 298.4 216.2 204.9 257.0 228.2 193.4 176.7 217.5 189.4 194.0 250.7 213.6 178.5 171.8 251.3 100- Company SanBizeeS. Does not co \ ^ ^ -l^y^SWyV H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL HEM&TOLOGY VALUES FOR MALE RATS Animal Number COND RBC xlO"6/iL HGB g/dL Male, Group: V - 125 mg/m3 - Day 11 637820 637821 637822 637823 637824 637825 637826 637827 637828 637829 OK 7.46 15.1 OK 7.86 14.7 OK 7.70 15.4 OK 7.57 15.1 OK 8.31 15.8 OK 7.73 15.8 OK 6.96 14.6 OK 7.57 15.5 OK 7.33 15.6 OK 7.55 15.5 Male, Group: VII - 600 ing/in3 - Day 11 637830 637831 637832 637833 637834 637835 637836 637837 637838 637839 OK 8.72 17.0 OK 8.01 16.2 OK 8.23 16.0 OK 7.67 15.2 OK 8.26 16.0 OK 7.91 15.5 OK 7.68 15.4 OK 8.83 16.9 OK 7.-18 15.0 OK 8.05 15.8 HCT % 47.0 46.1 47.3 46.8 50.1 48.2 45.2 47.0 47.2 46.5 51.4 49.5 50.9 47.0 50.3 47.4 48.1 52.0 46.2 49.2 MCV fL 63.0 58.6 61.4 61.8 60.3 62.3 64.9 62.1 64.4 61.6 58.9 61.8 61.8 61.3 60.9 59.9 62.6 58.9 64.4 61.1 MCH PSf 20.2 18.7 20.0 19.9 19.0 20.4 21.0 20.5 21.3 20.5 19.5 20.2 19.4 19.8 19.4 19.6 20.1 19.1 20.9 19.6 MCHC g/dL 32.1 31.9 32.6 32.3 31.5 32.8 32.3 33.0 33.0 33.3 33.1 32.7 31.5 32.3 31.8 32.7 32.0 32.5 32.4 32.1 RDW ARET NR x!0''3/f;L /100 W 14.5 14.0 13.5 12.8 12.1 12.8 13.4 13.3 13.5 14.0 14.0 13.7 12.8 12.6 13.2 13.7 14.3 13.5 13.1 13.9 207.0 132.6 187.7 161.5 119.8 189.5 167.6 203.6 160.4 211.2 202.4 132.5 171.2 157.2 206.9 153.6 168.6 82.6 167.3 154.0 -101- H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL HEMATOLOGY VALUES FOR MALE RATS Animal Number ANEU xlO"3/;xL ANPR xl0^3/A ALYM xlO-^/^L AMOM xlOA3/^tL AEOS xl0"3/l.it, ABAS xlO"3/tlL ALUC xlO"3/fiL ABLT xlO"3/(A AMSC xlO''3/fiL xlO"3 Male, Group: I - 0 aig/in3 - Day 11 637800 2.15 NT 12.92 0.50 0.18 0.08 0.26 NT NT 637801 2.01 NT 9.17 0.46 0.14 0.05 0.19 NT NT 637802 1.24 NT 9.21 0.41 0.07 0.07 0.18 NT NT 637803 3.32 NT 9.00 0.40 0.08 0.09 0.30 NT NT 637804 1.85 NT 12.47 0.36 0.07 0.04 0.13 NT NT 637805 3.80 NT 13.00 0.45 0.12 0.14 0.30 NT MT 637806 1.18 NT 8.32 0.16 0.07 0.11 0.22 NT MT 637807 1.68 NT 9.62 0.25 0.17 0.05 0.12 NT MT 1 637808 1.97 NT 11.35 0.38 0.16 0.06 0.23 MT NT 1 637809 1.69 NT 7.30 0.36 0.12 0.07 0.22 NT NT 1 Male, Group: III - 25 mg/m3 - Day 11 637810 0.98 MT 10.79 0.26 0.12 0.06 0.20 NT NT 1 637811 1.01 NT 7.90 0.24 0.06 0.10 0.20 NT NT 637812 1-40 NT 8.63 0.16 0.10 0.04 0.14 NT NT 637813 0.93 NT 10.14 0.22 0.07 0.12 0.26 NT NT 637814 1.82 NT 9.02 0.31 0.16 0.09 0.33 NT NT 637815 1.39 MT 9.34 0.37 0.09 0.20 0.43 NT NT 637816 2.05 NT 17.04 0.59 0.10 0.12 0.39 NT NT 637817 1.01 NT 11.76 0.36 0.08 0.05 0.19 NT NT 637818 0.94 NT 11.95 0.37 0.19 0.12 0.29 NT NT 637819 2.23 0.00 9.92 0.00 0.12 0.00 0.00 0.00 0.12 102- H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL HEMATOLOGY VALUES FOR MALE RATS Animal Number AMEU xl0''3/fiL AMPR xlO"3/flL ALYM xlO"3/(tL AMON xlO"3/p.L AEOS xl0^3/flL ABAS x.lO"3/ltL ALUC xl0"31 p.L ABLT xlO^/fiL AMSC xlO"3/(iL xlO"3 Male, Group: V - 125 ing/in3 - Day 11 637820 637821 637822 637823 637824 637825 637826 637827 637828 637829 1.12 1.13 1.74 1.23 1.09 0.83 1.41 1.59 1.36 1.19 NT 0.00 NT 0.00 NT NT NT NT NT NT 10.77 10.76 12.02 9.58 8.69 10.17 12.26 10.86 9.04 8.11 Male, Group: VII - 600 mg/m3 - Day 11 637830 637831 637832 637833 637834 637835 637836 637837 637838 637839 1.58 1.50 1.47 1.40 1.93 1.16 3.66 1.54 0.91 1.49 0.00 NT MT NT NT 0.00 NT NT NT NT 9.05 7.91 13.95 5.66 12.29 9.10 14.62 16.67 6.64 9.42 0.47 0.25 0.39 0.00 0.41 0.35 0.46 0.26 0.49 0.41 0.00 0.31 0.31 0.25 0.55 0.00 0.54 0.74 0.20 0.57 0.18 0.00 0.20 0.11 0.14 0.06 0.19 0.17 0.83 0.09 0.11 0.10 0.13 0.11 0.20 0.32 0.12 0.18 0.02 0.17 0.03 0.00 0.04 0.00 0.04 0.09 0.10 0.05 0.04 0.05 0.00 0.07 0.08 0.05 0.06 0.00 0.14 0.14 0.07 0.04 0.19 0.00 0.20 0.00 0.21 0.23 0.29 0.21 0.18 0.20 0.00 0.20 0.18 0.16 0.31 0.00 0.29 0.76 0.23 0.25 NT 0.00 MT 0.00 NT MT MT NT MT NT 0.00 NT NT NT MT 0.00 MT MT MT MT MT 0.38 MT 0.22 MT MT MT NT MT NT 0.57 NT MT NT MT 0.00 NT NT NT NT 103. H-24267: Two-Week Inhaladon Toxicity Study in Male Rats INDIVIDUAL HEM&TOLOGY VALUES FOR MALE RATS Animal Number BLST EOS % LUC % Male, Group: I - 0 mg/m3 - Day 11 637800 637801 637802 637803 637804 637805 637806 637807 637808 637809 NT 1.1 1.6 NT 1.2 1.6 NT 0.6 1.6 NT 0.6 2.3 NT 0.5 0.9 NT 0.7 1.7 NT 0.7 2.2 NT 1.4 1.0 NT 1.1 1.6 NT 1.2 2.3 Male, Group: III - 25 mg/m3 - Day 11 637810 637811 637812 637813 637814 637815 637816 637817 637818 637819 NT 1.0 1.6 NT 0.6 2.1 -NT 1.0 1.3 NT 0.6 2.2 NT 1.4 2.8- NT 0.8 3.6 NT 0.5 1.9 NT 0.6 1.4 NT 1.4 2.1 0 1.0 0.0 LYMP % 80.4 76.3 82.3 68.2 83.5 72.9 82.7 80.9 80.3 74.7 86.8 83.1 82.3 86.4 76.9 79.0 84.0 87.4 86.1 80.0 MISC NT NT NT NT NT NT NT NT NT NT NT NT NT NT NT NT NT NT NT 1 MONO % 3.1 3.8 3.7 3.0 2.4 2.5 1.6 2.1 2.7 3.7 2.1 2.5 1.5 1.9 2.6 3.1 2.9 2.7 2.7 0.0 NEOT % 13.4 16.7 11.1 25.2 12.4 21.3 11.7 14.1 13.9 17.3 7.9 10.6 13.4 7.9 15.5 11.8 10.1 7.5 6.8 18.0 NPRE % SPECIAL OBSERVATIONS NT NT NT NT NT NT NT KT NT NT NT NT NT NT NT NT NT NT NT 0 1%-ATYPICAL LY 104- ompany Sanitized. Does no H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL HEMATOLOGY VALUES FOR MALE RATS Animal BLST EOS LUC Number % Male, Group: V - 125 mg/m3 - Day 11 637820 637821 637822 637823 637824 637825 637826 637827 637828 637829 MT 1.4 1.5 0 0.0 0.0 NT 1.4 1.4 0 1.0 0.0 MT 1.3 2.0 NT 0.5 2.0 NT 1.3 2.0 NT 1.3 1.6 NT 7.0 1.5 NT 0.9 2.0 Male, Group: VII - 600 ing/in' - Day 11 637830 0 1.0 0.0 637831 NT 1.0 2.0 637832 -NT 0.8 1.1 637833 NT 1.4 2.1 637834 NT 1.3 2.0 637835 0 3.0 0.0 637836 NT 0.6 1.5 637837 NT 0.9 3.8 637838 NT 0.3 2.9 637839 NT 1.4 2.1 LYMP % 84.4 86.0 82.3 86.0 82.1 86.6 83.4 82.5 75.8 80.7 80.0 78.3 86.6 74.2 80.2 86.0 75.4 83.2 82.1 78.9 MISC NT 3 NT 2 NT NT NT NT NT NT 5 NT NT NT NT 0 NT NT NT NT MONO % 3.7 2.0 2.7 0.0 3.9 3.0 3.1 2.0 4.1 4.1 0.0 3.1 1.9 3.3 3.6 0.0 2.8 3.7 2.5 4.8 NEUT % 8.8 9.0 11.9 11.0 10.3 7.1 9.6 12.1 11.4 11.8 14.0 14.9 9.1 18.4 12.6 11.0 18.9 7.7 11.3 12.5 NPRE % SPECIAL OBSERVATIONS NT 0 3%- ATYPICAL L NT 0 2%- ATYPICAL L NT NT NT NT NT NT 0 5%-HYPERSEGIIEN NT NT NT NT 0 NT NT NT NT -105- H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL HEMATOLOGY VALUES FOR MALE RATS Animal Number COMD RBC xlO-'6/nL HGB g/dL Male, Group: I - 0 mg/m3 - Day 25 637805 637806 637807 637808 637809 OK 8.09 16.0 OK 8.22 15.6 OK 8.51 16.2 OK 7.43 15.1 OK 8.37 16.0 Male, Group: III - 25 nig/in3 - Day 25 637815 637816 637817 637818 637819 OK 8.79 OK 8.54 OK 8.65 OK 8.58 OK 7.97 16.5 15.7 16.4 15.6 15.1 Male, Group: V - 125 mg/m3 - Day 25 637825 637826 637827 637828 637829 OK 7.91 15.7 OK 7.34 14.8 OK 7.97 15.6 OK 7.35 15.5 OK 7.77 15.5 Male, Group: VII - 600 ing/in' - Day 25 637835 637836 637837 637838 637839 OK 8.19 15.5 OK 8.10 15.7 OK 8.41 15.5 OK 7.41 15.2 OK 8.13 15.5 HCT % 48.8 48.7 49.8 45.2 48.5 51.2 49.4 50.4 49.7 46.8 47.3 45.1 48.1 47.3 48.3 48.2 47.5 48.4 46.8 47.6 MCV L 60.3 59.2 58.5 60.9 57.9 58.2 57.9 58.3 57.9 58.7 59.8 61.5 60.3 64.3 62.1 58.8 58.6 57.6 63.1 58.6 MCH pg 19.8 19.0 19.0 20.3 19.1 18.8 18.4 19.0 18.2 18.9 19.8 20.2 19.6 21.1 19.9 18.9 19.4 18.4 20.5 19.1 MCHC g/dL 32.8 32.1 32.5 33.4 33.0 32.3 31.8 32.5 31.4 32.3 33.2 32.8 32.5 32.8 32.1 32.2 33.1 32.0 32.5 32.5 KDW AKET % xlO^/fxL N /100 13.9 13.7 13.3 12.6 12.9 13.1 13.4 13.1 13.2 13.6 13.0 13.0 13.4 13.1 13.6 13.7 14.2 13.8 13.0 13.4 308.5 235.4 242.0 258.8 262.2 279.5 249.1 266.4 271.7 264.4 219.8 238.8 267.8 261.1 303.3 267.3 300.8 209.9 260.3 227.7 106- Company Sanitized. Does not conta H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL HEMATOLOGY VALUES FOR MALE RATS Animal Number ANEU xl0''3/p.L AMPR xlO"3/ftL ALYM xlO^/fiL AMON xlO"3/^L AEOS xlO"3/ttL ABAS xlO"3/(iL ALUC xlO-^/tiL ABLT xlO^/fiL AMSC xl0^3/^L xlO"3 Male, Group: 0 mg/m3 - Day 25 637805 4.81 MT 16.94 0.62 0.21 0.12 0.32 NT NT 1 637806 1.62 NT 9.93 0.33 0.11 0.10 0.27 NT NT 637807 1.72 NT 7.70 0.19 0.13 0.03 0.14 NT NT 1 637808 2.84 NT 12.92 0.26 0.11 0.08 0.20 NT NT 1 637809 2.24 NT 8.68 0.34 0.16 0.12 0.20 NT NT Male, Group: III 25 ag/rn3 - Day 25 637815 2.14 NT 8.07 0.35 0.07 0.04 0.20 NT NT 637816 3.65 NT 15.99 0.53 0.17 0.19 0.59 NT NT 1 637817 2.31 NT 8.91 0.35 0.13 0.07 0.17 NT NT 637818 2.05 NT 13.92 0.41 0.14 0.12 0.34 NT NT 637819 2.20 NT 10.51 0.49 0.25 0.05 0.16 NT NT Male, Group: V - 125 ing/a3 - Day 25 637825 1.37 NT 10.84 0.40 0.09 0.07 0.25 NT NT 1 637826 2.55 NT 13.52 0.23 0.10 0.08 0.29 NT NT 637827 2.21 NT 15.09 0.42 0.13 0.15 0.39 NT NT 1 637828 1.74 NT 10.83 0.49 0.11 0.07 0.26 NT NT 637829 0.99 NT 8.49 0.32 0.06 0.08 0.24 MT NT 1 Male, Group: VII - 600 mg/m3 - Day 25 637835 1.85 MT 10.32 0.35 0.16 0.08 0.19 NT NT 637836 2.50 MT 14.49 0.43 0.11 0.11 0.32 NT NT 637837 1.75 MT 13.86 0.35 0.10 0.12 0.52 NT NT 637838 1.95 MT 9.93 0.39 0.05 0.06 0.21 NT NT 1 637839 1.95 MT 9.36 0.36 0.06 0.10 0.29 NT NT -107- H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL HEMATOLOGY VALUES FOR MALE RATS Animal Number BLST % EOS % LUC % Male, Group: 0 mg/m3 - Day 25 637805 637806 637807 637808 637809 NT 0.9 1.4 NT 0.9 2.2 NT 1.3 1.4 NT 0.7 1.2 NT 1.4 1.7 Male, Group: III - 25 mg/m3 - Day 25 637815 637816 637817 637818 637819 NT 0.6 1.8 NT 0.8 2.8 NT 1.1 1.4 NT 0.8 2.0 NT 1.8 1.2 Male, Group: V - 125 mg/m3 - Day 25 637825 637826 637827 637828 637829 NT 0.7 1.9 NT 0.6 1.7 NT 0.7 2.1 NT 0.8 1.9 NT 0.6 2.4 Male, Group: VII - 600 mg/m3 - Day 25 637835 637836 637837 637838 637839 NT 1.2 1.5 NT 0.6 1.8 NT 0.6 3.1 NT 0.4 1.7 NT 0.5 2.4 LYMP % 73.6 80.3 77.7 78.8 74.0 74.2 75.8 74.6 82.0 77.0 83.3 80.6 81.9 80.3 83.3 79.7 80.6 83.0 78.8 77.3 M1SC % NT NT NT NT NT NT NT NT NT NT NT NT NT NT NT NT NT NT NT NT MONO % 2.7 2.7 1.9 1.6 2.9 3.2 2.5 2.9 2.4 3.6 3.1 1.4 2.3 3.6 3.1 2.7 2.4 2.1 3.1 3.0 NEUT % 20.9 13.1 17.4 17.3 19.1 19.7 17.3 19.3 12.1 16.1 10.5 15.2 12.0 12.9 9.7 14.3 13.9 10.5 15.5 16.1 NPKE % SPECIAL OBSERVATIONS NT NT NT NT NT NT NT NT NT NT NT NT NT NT NT NT NT NT NT NT 108- CoBsspany Sanitized. Does not  ! ''W--'--.-:-,-:'ysif 'te.^g^ H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL RED BLOOD CELL MORPHOLOGY VALUES FOR MALE RATS Animal Nuaiber NORM AMIS MICR Male, Group: I - 0 ing/m3 - Day 11 637800 637801 637802 637803 NORMAL 663377880045 -- 1 i 637806 637807 637808 NORMAL 637809 Male, Group: III - 25 mg/m3 - Day 11 637810 637811 -- 1 i 637812 637813 637814 -- 1 l 637815 NORMAL 637816 637817 NORMAL 637818 NORMAL 637819 HACK POLY -- -- -- , -- HYPO ECHI ACAN 2 1 2 1 1 . 2 1 2 1 1 1 1 - 1 1 4 2 --1 1 -- 2 1 2 1 1 -- 2 1 TARG -- 109- ------------------------------------------------ H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL RED BLOOD CELL MORPHOLOGY VALUES FOR MALE RATS Animal Number NORM AMIS MICR Male, Group: V - 125 mg/m3 - Day 11 637820 637821 637822 -- 1 1 637823 637824 637825 637826 637827 -- 637828 637829 -- 1 l 1 1 Male, Group: VII - 600 mg/m3 - Day 11 637830 637831 637832 637833 637834 637835 637836 637837 637838 637839 NORMAL NORMAL NORMAL NORMAL MACR --- -- POLY -- - HYPO -- ECHI 2 1 1 1 2 2 1 3 1 1 2 1 2 2 1 ACAN 2 ] 1 1 ] 1 1 1 - -- 2 --1 1 1 -- TARG -- -- -- 110- Con(pany SanKized. Does not H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL RED BLOOD CELL MORPHOLOGY VALUES FOR MALE RATS Animal Muniber NORM AMIS MICR Male, Group: I - 0 mg/m3 - Day 25 637805 637806 637807 637808 637809 2 1 1 i Male, Group: III - 637815 637816 637817 637818 637819 25 mg/m3 - Day 25 Male, Group: V - 125 mg/m3 - Day 25 637825 637826 637827 637828 637829 Male, Group: VII - 637835 637836 637837 637838 637839 600 mg/m3' - Day 25 MACR 1 -- POLY -- -- 1 1 HYPO -- -- -- -- ECHI ACAM 2 1 2 1 1 2 1 3 1 2 1 ] 2 1 1 1 3 1 2 1 2 2 4 2 2 1 2 1 2 1 2 1 2 1 1 2 1 TARG --- -111- H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL WHITE BLOOD CELL / PLATELET MORPHOLOGY VALUES FOR MALE RATS Animal NORM SM TG DB VN PC GP BP SPECIAL Number OBSERVATIONS Male, Group: I - 0 mg/m3 - Day 11 637800 637801 637802 637803 637804 637805 637806 637807 637808 637809 NORMAL NORMAL NORMAL NORMAL NORMAL NORMAL NORMAL Male, Group: III - 25 mg/m3 - 637810 637811 637812 637813 637814 637815 637816 637817 637818 637819 NORMAL NORMAL NORMAL NORMAL NORMAL NORMAL NORMAL NORMAL NORMAL Day 11 DECR PLATELET DECR PLATELET DECR PLATELET DECR PLATELET 112- eompany Sanitized. Does no H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL WHITE BLOOD CELL / PLATELET MORPHOLOGY VALUES FOR MALE RATS Animal NORM SM TG DB VN PC GP BP SPECIAL Number OBSERVATIONS Male, Group: V - 125 mg/m3 - Day 11 637820 637821 637822 637823 637824 637825 637826 637827 637828 637829 NORMAL NORMAL NORMAL NORMAL NORMAL NORMAL NORMAL NORMAL NORMAL Male, Group: VII - 600 nig/in3 - Day 11 637830 637831 637832 637833 637834 637835 637836 637837 637838 637839 NORMAL NORMAL NORMAL NORMAL NORMAL NORMAL NORMAL NORMAL NORMAL OTD DECR PLATELET US- Company Sanitised. Does not cont H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL WHITE BLOOD CELL / PLATELET MORPHOLOGY VALUES FOR MALE RATS Animal NORM SM TG DB VN PC GP BP SPECIAL Number OBSERVATIONS Male, Group: 637805 637806 637807 637808 637809 1-0 mg/m3 - NORMAL NORMAL NORMAL NORMAL Day 25 Male, Group: 637815 637816 637817 637818 637819 III - 25 mg/m3 - NORMAL NORMAL NORMAL Day 25 Male, Group: V - 125 mg/m3 - 637825 637826 637827 637828 637829 NORMAL NORMAL NORMAL NORMAL NORMAL Day 25 Male, Group: VII - 600 mg/m3 - 637835 637836 637837 637838 637839 NORMAL NORMAL NORMAL NORMAL NORMAL Day 25 DECR PLATELET DECK PLATELET ADEQ PLATELET -114- H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL COAGULATION VALUES FOR MALE RATS Animal Number PHEM FLIP PICT Male, Group: 637800 637801 637802 637803 637804 0 mg/m3 - Day 11 NOME NONE TRACE TRACE NONE NONE NONE NONE NONE NONE NOME NONE NONE NONE NONE Male, Group: 637810 637811 637812 637813 637814 III - 25 mg/m3 - Day 11 NOME NOME NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE Male, Group: 125 ing/in3 - Day 11 637820 637821 637822 637823 637824 MODERATE NONE NONE NONE NONE NONE NOME NOME NONE NONE NONE NONE NONE NOME NONE Male, Group: VII - 600 nig/a3 - Day 11 637830 637831 637832 637833 637834- NONE NONE TRACE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE PT sec 14.3 15.3 18.0 16.5 14.7 15.5 14.9 15.0 15.5 15.0 15.2 14.6 16.9 15.1 15.2 14.8 15.0 15.8 14.7 APTT sec 20.0 14.5 28.8 22.1 13.9 25.9 22.5 21.5 17.1 18.0 17.8 17.2 19.0 14.8 25.8 17.7 19.5 20.8 16.5 US- Company Sanitized. Does not H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL COAGULATION VALUES FOR MALE RATS Animal Number PHEM PLIP PICT Male, Group: I - 0 ing/in3 - Day 25 637805 637806 637807 637808 637809 NOME NOME TRACE MOME MONE MOME MOME MOME MOME MOME MOME MOME MOME MOME MOME Male, Group: 637815 637816 637817 637818 637819 III - 25 mg/m3 - Day 25 MOME TRACE MOME MOME MOME MOME MOME MOME MOME MOME MOME MOME MOME MOME MOME Male, Group: V - 125 mg/m3 - Day 25 637825 637826 637827 637828 637829 NOME MOME TRACE TRACE MOME MOME MOME MOME MOME MOME MOME MOME MOME MOME MOME Male, Group: VII - 600 mg/m3 - Day 25 637835 637836 637837 637838 637839 TRACE MOME MOME MOME MOME MOME MOME MOME MONE MOME MOME MOME NONE MOME MOME PT sec 14.2 15.2 15.7 14.3 14.8 14.9 15.8 16.4 15.5 14.2 14.6 14.1 14.3 14.7 14.8 14.1 14.5 16.2 13.9 14.6 APTT sec 18.0 19.0 23.5 18.6 15.9 18.0 23.0 23.3 17.3 13.8 17.3 15.4 15.9 16.1 19.0 14.9 17.7 21.0 15.7 16.1 -116- H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL SERUM CHEMISTRY VALUES FOR MALE RATS Animal Number SHEM SLIP SICT Male, Group: 637800 637801 637802 637803 637804 637805 637806 637807 637808 637809 0 mg/m3 - Day 11 NOME NOME 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: 637810 637811 637812 637813 637814 637815 637816 637817 637818 637819 III - 25 mg/m3 - Day 11 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 AST IU/L 88 86 90 81 135 85 105 84 100 100 122 86 76 83 100 87 131 113 83 98 ALT IU/L 35 32 39 27 44 34 48 35 41 42 40 44 44 36 51 40 51 40 37 43 SDH IU/L 18.1 20.5 20.7 16.2 23.4 14.1 17.6 14.0 16.2 15.2 12.7 15.7 14.8 14.0 19.9 17.4 20.7 15.0 14.3 18.3 ALKP BILI BUN C IU/L mg/dL mg/dL mg 241 <0.10 236 0.11 172 <0.10 209 <0.10 186 <0.10 165 0.13 275 0.10 239 0.10 263 <0.10 208 0.12 155 <0.10 174 <0.10 256 <0.10 200 0.14 196 0.10 176 0.10 190 0.11 187 <0.10 211 0.14 183 <0.10 15 0 12 0 17 0 10 0 14 0 15 0 11 0 12 0 13 0 12 0 14 0 15 0 17 0 16 0 18 0 17 0 16 0 17 0 21 0 14 0 117- Company Sanitized. Does no H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL SERUM CHEMISTRY VALUES FOR MALE RATS Animal Number SHEM SLIP SICT Male, Group: V - 125 mg/m3 - Day 11 637820 637821 637822 637823 637824 637825 637826 637827 637828 637829 NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NOME NONE NONE NONE NONE NONE NONE NOME NOME NOME NOME NONE NONE NONE Male, Group: VII 600 mg/m3 - Day 11 637830 637831 637832 637833 637834 637835 637836 637837 637838 637839 NOME NONE NONE NOME NONE NOME NOME NONE NONE NONE NOME NOME NONE NONE NOME MOME NONE NONE NOME NONE NONE NONE NONE NONE NONE NONE MONE NOME NONE MONE AST IU/L 66 79 81 105 74 79 78 87 104 81 81 108 75 74 93 75 114 78 98 98 ALT IU/L 29 39 37 42 40 27 39 34 31 36 36 38 43 36 72 44 37 38 51 52 SDH IU/L 16.6 15.9 18.2 21.1 11.0 14.6 15.3 14.2 14.6 13.3 17.6 11.4 14.2 11.7 17.0 15.0 21.4 14.3 16.6 22.3 ALKP BILX BUN C IU/L ing/dL mg/dL mg 125 <0.10 273 0.11 186 <0.10 218 <0.10 193 0.12 232 <0.10 273 <0.10 130 <0.10 185 <0.10 174 0.11 171 <0.10 184 0.11 184 <0.10 178 0.14 207 0.19 127 0.10 199 <0.10 243 0.10 176 <0.10 141 0.11 11 0 16 0 16 0 16 0 17 0 14 0 17 0 12 0 15 0 12 0 37 0 20 0 16 0 22 0 19 0 19 0 15 0 21 0 16 0 21 0 -118- H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL SERUM CHEMISTRY VALUES FOR MALE RATS Animal number TRIG mg/dL GLUC mg/dL TP g/dL Male, Group: 0 mg/m3 - Day 11 637800 637801 637802 637803 637804 637805 637806 637807 637808 637809 73 94 5.7 46 93 5.8 36 78 6.0 38 84 6.0 44 104 6.4 38 87 6.3 50 94 6.2 22 91 5.9 44 82 5.9 63 90 6.3 Male, Group: III 25 mg/m3 - Day 11 637810 56 637811 26 637812 -49 637813 19 637814 24 637815 29 637816 34 637817 24 637818 22 637819 41 69 6.3 88 5.8 87 6.1 91 6.1 90 6.3 85 6.8 86 5.8 85 6.6 87 6.7 83 6.2 ALB g/dL 4.0 4.2 4.0 4.1 4.3 4.2 4.3 4.1 4.0 4.3 4.3 4.2 4.3 4.2 4.1 4.7 4.2 4.5 4.6 4.4 GLOB g/dL CALC mg/dL IPHS NA K mg/dL inmol/L mmol/L inm 1.7 10.8 10.3 147.6 6.33 9 1.6 10.6 9.4 149.0 5.68 9 2.0 10.7 10.0 148.9 6.12 9 1.9 10.5 8.6 150.3 6.17 9 2.1 11.9 12.0 150.0 6.91 9 2.1 11.0 10.3 148.2 6.30 9 1.9 10.8 8.9 149.9 5.96 9 1.8 10.8 9.7 151.0 6.07 9 1.9 11.0 10.0 149.7 6.46 9 2.0 10.7 10.7 146.5 6.09 9 2.0 10.8 10.3 146.3 6.46 9 1.6 10.6 10.0 148.8 5.74 9 1.8 11.3 9.7 150.5 5.95 9 1.9 11.0 9.5 149.7 6.04 9 2.2 10.5 9.4 148.0 5.72 9 2.1 11.2 9.0 149.5 6.50 9 1.6 10.8 10.1 148.1 6.50 9 2.1 10.7 9.5 148.6 6.30 9 2.1 11.2 9.8 150.0 6.19 9 1.8 11.1 9.3 150.8 6.37 9 119- Company SanKteed. Does no H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL SERUM CHEMISTRY VALUES FOR MALE RATS Animal Number TRIG mg/dL GLUC mg/dL TP g/dL Male, Group: V - 125 mg/in3 - Day 11 637820 637821 637822 637823 637824 637825 637826 637827 637828 637829 40 81 6.3 34 82 6.3 31 93 6.4 47 81 6.0 35 77 6.4 23 97 6.1 54 109 5.9 34 90 5.9 49 85 6.0 51 92 6.2 Male, Group: VII - 600 mg/m3 - Day 11 637830 54 83 6.7 637831 38 81 6.2 637832 53 93 6.2 637833 -30 92 6.4 637834 38 89 6.6 637835 27 95 6.8 637836 35 94 5.9 637837 32 91 7.0 637838 36 88 6.7 637839 40 '88 6.8 ALB g/dL 4.5 4.3 4.6 4.3 4.4 4.4 4.3 4.3 4.2 4.4 4.7 4.4 4.2 4.5 4.7 4.8 4.3 4.8 4.5 4.3 GLOB g/dL CALC mg/dL IPHS NA K mg/dL mmol/L nmol/L nni 1.8 10.9 9.4 149.0 6.18 9 2.0 11.0 9.6 149.2 6.09 9 1.8 11.1 9.6 148.3 5.82 9 1.7 11.0 10.0 148.7 6.18 9 2.0 11.5 9.1 149.4 5.94 9 1.7 10.7 9.8 147.9 6.43 9 1.6 11.0 10.3 146.5 5.72 9 1.6 10.8 9.3 147.9 5.67 9 1.8 11.1 10.3 149.9 6.23 10 1.8 11.1 9.7 149.1 6.12 9 2.0 11.0 11.2 143.1 6.21 8 1.8 11.1 9.2 145.2 5.50 9 2.0 11.2 9.1 149.0 6.04 9 1.9 11.2 8.6 146.4 5.35 9 1.9 11.8 9.8 147.8 6.11 9 2.0 11.4 9.4 146.3 5.70 9 1.6 10.9 10.0 149.3 5.93 9 2.2 11.5 9.9 150.7 6.11 9 2.2 11.3 9.3 148.0 6.02 9 2.5 11.2 9.5 146.6 6.28 9 -120- H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL SERUM CHEMISTRY VALUES FOR MALE RATS Animal Number PFLU FHEM FLIP Male, Group: 637800 637801 637802 637803 637804 1-0 nig/m3 0.1 0.1 0.1 0.1 0.1 - Day 11 NONE NONE TRACE NONE NONE NONE NONE NONE NONE NONE Male, Group: 637810 637811 637812 637813 637814 III - 25 mg/m3 - Day 11 0.1 NONE 0.1 NONE 0.1 NONE 0.1 NONE 0.1 NONE NONE NONE NONE NONE NONE Male, Group: V - 125 mg/m3 - Day 11 637820 0.1 TRACE NONE 637821 0.1 NONE NOME 637822 0.1 NONE NONE 637823 0.1 NONE NONE 637824 0.1 NONE NONE Male, Group: VII - 600 mg/m3 - Day 11 637830 637831 637832 637833 637834 0.1 0.1 . 0.1 0.1 0.1 NONE NONE NONE NONE NONE NONE NONE NOME NOME NOME FICT NONE NONE NOME NOME NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE .121- comTO 9m^- Oo^ n H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL SERUM CHEMISTRY VALUES FOR MALE RATS Animal Number SHEM SLIP SICT Male, Group: 0 mg/m3 - Day 25 637805 637806 637807 637808 637809 NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE Male, Group: 637815 637816 637817 637818 637819 III - 25 ing/in3 - Day 25 NONE TRACE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE Male, Group: V - 125 mg/m3 - Day 25 637825 637826 637827 637828 637829 TRACE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE Male, Group: VII - 600 mg/m3 - Day 25 637835 637836 637837 637838 637839 NONE TRACE NONE MONE NONE NONE NOME NONE NONE NONE NONE NONE NONE NONE NONE AST IU/L 87 107 77 94 109 102 94 126 98 100 119 90 87 88 77 110 125 83 85 82 ALT IU/L 44 44 40 48 51 37 46 47 43 47 38 39 44 42 37 51 35 45 46 38 SDH IU/L 24.3 21.7 18.0 21.5 21.9 24.2 22.5 15.4 24.8 25.7 24.8 19.7 16.7 20.9 18.9 24.4 10.0 19.2 19.7 25.2 ALKP BILI BUN C IU/L mg/dL mg/dL mg 148 0.12 239 0.15 210 0.12 230 <0.10 173 0.11 155 0.12 189 <0.10 188 0.13 195 0.16 199 0.17 215 0.12 238 0.13 138 0.10 186 0.12 181 <0.10 126 0.14 184 0.14 212 0.11 186 0.15 138 0.10 18 0 13 0 12 0 14 0 13 0 16 0 15 0 17 0 15 0 16 0 13 0 14 0 14 0 15 0 13 0 15 0 19 0 17 0 15 0 16 0 -122- H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL SERUM CHEMISTRY VALUES FOR MALE RATS Animal Number TRIG mg/dL GLUC mg/dL TP g/dL Male, Group: I - 0 mg/m3 - Day 25 637805 637806 637807 637808 637809 49 83 7.5 61 100 6.9 22 95 6.8 71 109 6.3 99 86 6.9 Male, Group: III 25 mg/m3 - Day 25 637815 55 76 7.0 637816 83 97 6.9 637817 53 82 7.2 637818 42 91 7.2 637819 73 99 6.8 Male, Group: V - 125 ing/in3 - Day 25 637825 637826 637827 637828 637829 32 80 6.8 76 110 6.3 78 98 6.6 78 93 6.5 95 94 6.7 Male, Group: VII - 600 mg/m3 - Day 25 637835 637836 637837 637838 637839 45 95 7.1 54 104 6.5 37 90 6.8 38 93 6.8 43 78 6.6 ALB g/dL 4.8 4.7 4.8 4.3 4.6 4.7 4.8 4.8 5.0 4.7 4.9 4.5 4.7 4.6 4.8 4.9 4.7 4.6 4.7 4.4 GLOB g/dL CALC mg/dL IPHS NA K mg/dL imnol/L inmol/L mm 2.7 11.3 2.2 10.9 2.0 10.8 2.0 10.7 2.3 10.8 9.0 151.5 5.99 9 8.6 149.3 5.61 9 8.7 151.9 5.73 9 9.7 150.1 6.66 9 7.9 149.8 5.92 9 2.3 10.7 2.1 10.8 2.4 10.7 2.2 11.2 2.1 10.9 8.2 151.8 6.15 9 9.4 150.1 6.30 9 7.8 149.7 6.25 9 9.3 151.0 6.30 9 8.9 150.1 6.34 9 1.9 10.6 1.8 10.4 1.9 10.9 1.9 10.9 1.9 11.2 8.0 150.0 5.88 9 8.9 149.1 5.64 9 8.5 152.6 5.61 9 8.5 151.0 6.26 9 9.2 151.6 6.41 9 2.2 10.7 8.4 149.3 5.73 9 1.8 10.6 9.1 148.0 6.03 9 2.2 11.2 9.1 151.2 6.11 9 2.1 11.1 10.0 151.3 5.88 9 2.2 11.0 9.3 150.7 6.23 9 123- Company Sanitized. Do H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL SERUM CHEMISTRY VALUES FOR MALE RATS Animal Number PFLU FHEM FLIP Male, Group: I 0 ing/in3 - Day 25 637805 0.1 TRACE NONE 637806 0.1 NONE NONE 637807 0.1 NONE NONE 637808 0.1 NOME NONE 637809 0.1 NONE TRACE Male, Group: III - 25 ing/in' - Day 25 637815 0.1 637816 0.1 637817 0.1 637818 0.1 637819 0.1 NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE Male, Group: V - 125 ing/in3 - Day 25 637825 0.1 NONE NONE 637826 0-.1 TRACE NONE 637827 0.1 637828 0.1 637829 0.1 NONE NONE NONE NONE NONE NONE Male, Group: VII - 600 ing/in3 - Day 25 637835 0.1 TRACE NONE 637836 0.1 TRACE NONE 637837 0.1 NONE NONE 637838 0.1 NONE NONE 637839 0.1 NONE NONE FICT NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE NONE 124- osapsay SanBized. Does not H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL URIHALYSIS VALUES FOR MALE RATS Animal Number QUAL COL CLAR Male, Group: 637800 637801 637802 637803 637804 637805 637806 637807 637808 637809 0 mg/m3 - Day 11 DARK LIGHT LIGHT LIGHT LIGHT LIGHT LIGHT LIGHT LIGHT NSR BROWN YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW NT CLOUDY HAZY HAZY CLEAR CLEAR CLEAR CLEAR CLEAR HAZY NT Male, Group: 637810 637811 637812 637813 637814 637815 637816 637817 637818 637819 III - 25 mg/m3 - Day 11 LIGHT LIGHT LIGHT LIGHT LIGHT LIGHT LIGHT MEDIUM LIGHT LIGHT YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW CLEAR CLEAR CLEAR HAZY CLEAR CLEAR CLEAR CLEAR CLEAR CLEAR VOL UOSM SG mL m()sm/kg 6.3 9.4 5.2 5.5 26.0 3.2 12.2 9.1 9.2 KIT 6.0 8.2 11.0 8.3 9.8 12.8 3.9 4.0 12.0 13.6 1475 808 999 1233 330 1149 688 696 851 NT 1003 852 685 849 826 555 1006 1278 672 578 1.046 1.025 1.030 1.039 1.012 1.037 1.022 1.021 1.025 NT 1.031 1.026 1.023 1.026 1.025 1.019 1.031 1.040 1.022 1.019 pH UPRO UGLU mg/dL mg/dL m 7. 5 6. 5 6. 06. 5 6. 0 6. 0 5. 5 6. 5 7.0 NT 30 TRACE 30 30 NEGATIVE 30 TRACE TRACE 30 NT NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NT NEGA NEGA 6.0 30 NEGATIVE 7.0 TRACE NEGATIVE 6.0 TRACE NEGATIVE 6.5 TRACE NEGATIVE NEGA 6.5 TRACE NEGATIVE 6.0 NEGATIVE NEGATIVE NEGA 5.5 30 NEGATIVE NEGA 6.0 30 NEGATIVE 6.5 TRACE NEGATIVE NEGA 6.0 NEGATIVE NEGATIVE NEGA 125- Company Sanitized. Does n H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL URINALYSIS VALUES FOR MALE RATS Animal Number QUAL COL CLAR Male, Group: V - 125 nig/in3 - Day 11 637820 637821 637822 637823 637824 637825 637826 637827 637828 637829 MEDIUM LIGHT LIGHT MEDIUM LIGHT LIGHT MEDIUM LIGHT MEDIUM LIGHT YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW CLEAR CLEAR CLEAR CLEAR HAZY HAZY CLEAR CLEAR CLEAR CLEAR Male, Group: VII - 600 nig/in3 - Day 11 637830 637831 637832 637833 637834 637835 637836 637837 637838 637839 LIGHT LIGHT LIGHT LIGHT LIGHT MEDIUM LIGHT LIGHT LIGHT LIGHT YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW HAZY CLEAR CLEAR CLEAR HAZY HAZY CLEAR CLEAR HAZY CLEAR VOL UOSM SG niL mOsm/kg 1.7 15.8 13.4 4.5 9.7 13.0 6.7 8.0 3.0 17.2 9.3 11.8 7.9 12.6 7.3 5.3 10.0 10.0 18.0 14.0 1023 365 499 1416 779 617 1179 522 1717 427 699 621 766 500 1227 1166 791 602 460 486 1.036 1.012 1.018 1.047 1.025 1.021 1.038 1.018 1.055 1.015 1.022 1.021 1.025 1.018 1.039 1.038 1.025 1.019 1.017 1.017 pH UPRO UBLU ag/dL mg/dL in 5 .0 5 .5 5 .0 5 .56.0 6 .5 6 .0 5 .0 5 .5 5.0 TRACE NEGATIVE NEGATIVE 30 NEGATIVE NEGATIVE 30 NEGATIVE 30 NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGA NEGA NEGA NEGA NEGA NEGA NEGA 6 .0 TRACE NEGATIVE NEGA 5 .0 NEGATIVE NEGATIVE NEGA 5 .5 NEGATIVE NEGATIVE NEGA 5 .0 NEGATIVE NEGATIVE NEGA 5.5 TRACE NEGATIVE 5 .5 TRACE NEGATIVE NEGA 5 .5 NEGATIVE NEGATIVE NEGA 5 .5 NEGATIVE NEGATIVE NEGA 5 .0 NEGATIVE NEGATIVE NEGA 5 .0 NEGATIVE NEGATIVE NEGA -126- H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL URINALYSIS VALUES FOR MALE RATS Animal Number BLD URO EU/dL UFLU W Male, Group: I - 0 mg/m3 - Day 11 637800 MODERATE 1 .0 637801 NEGATIVE 0 .2 637802 NEGATIVE 0.2 637803 NEGATIVE 0 .2 637804 NEGATIVE 0 .2 637805 NEGATIVE 0 .2 637806 NEGATIVE 0 .2 637807 NEGATIVE 0 .2 637808 NEGATIVE 0.2 637809 NT NT Male, Group: III - 25 637810 637811 637812 637813 637814 637815 637816 637817 637818 637819 NEGATIVE NEGATIVE NEGATIVE TRACE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE mg/ni3 - Day 11 0 .2 0 .2 0 .2 0 .2 0 .2 0 .2 0 .2 0 .2 0 .2 0 .2 6 .6 9 .2 6 .7 8 .6 13 .2 4 .9 15 .1 10 .4 10 .2 NSR 7 .3 10 .1 10 .9 13 .0 14 .8 11.7 5 .7 7.4 12 .6 14.2 SPECIAL OBSERVATIONS FECAL CONTAMINATION OBSERVED FECAL CONTAMINATION OBSERVED FECAL CONTAMINATION OBSERVED 127- cawwfsws H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL URINALYSIS VALUES FOR MALE RATS Animal Number BLD URO EO/dL DFLU 111 Male, Group: V - 125 mg/m3 - Day 11 637820 637821 637822 637823 637824 637825 637826 637827 637828 637829 NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE 0.2 4.1 0.2 15.7 0.2 17.6 0.2 13.3 0.2 18.4 0.2 21.8 0.2 17.8 0.2 12.5 0.2 11.6 0.2 15.3 .e. Group : VII - 66100 mg/in3 - Day 11 637830 637831 637832 637833 637834 637835 637836 637837 637838 637839 NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE TRACE NEGATIVE NEGATIVE 0.2 8.1 0.2 13.9 0.2 11.2 0.2 10.9 0.2 12.9 0.2 11.7 0.2 14.7 0.2 13.2 0.2 18.9 0.2 13.6 SPECIAL OBSERVATIONS -128- H-24267: Two-Week Inhalation Toxicity Study in Male Rats -129- Comparay Sanitized. Does not e H-24267: Two-\Veeklnhalation Toxicity Study in Male Rats INDIVIDUAL URINALYSIS VALUES FOR MALE RATS Animal Number QUAL COL CLAR Male, Group: 637805 637806 637807 637808 637809 1-0 mg/m3 MEDIUM MEDIUM LIGHT LIGHT LIGHT - Day 25 YELLOW YELLOW YELLOW YELLOW YELLOW HAZY CLEAR CLEAR CLOUDY CLEAR Male, Group: 637815 637816 637817 637818 637819 III - 25 LIGHT LIGHT MEDIUM LIGHT LIGHT mg/m3 - Day YELLOW YELLOW YELLOW YELLOW YELLOW 25 CLEAR CLEAR CLEAR CLOUDY HAZY Male, Group: V - 125 mg/m3 - Day 25 637825 637826 637827 637828 637829 LIGHT LIGHT LIGHT LIGHT LIGHT YELLOW YELLOW YELLOW YELLOW YELLOW HAZY CLEAR CLOUDY CLOUDY CLEAR Male, Group: VII - 600 mg/m3 - Day 25 637835 637836 637837 637838 637839 LIGHT MEDIUM MEDIUM LIGHT MEDIUM YELLOW YELLOW YELLOW YELLOW YELLOW CLEAR HAZY CLEAR CLEAR CLEAR VOL UOSM SG mL mOsm/kg 6.4 4.3 15.4 13.4 23.2 14.2 9.7 5.4 20.8 13.2 20.6 9.2 10.8 13.4 15.2 24.0 6.7 2.5 12.4 7.3 1274 1394 551 729 390 483 882 1030 462 670 470 1016 567 648 605 355 1386 1329 760 956 1.041 1.044 1.018 1.023 1.014 1.015 1.026 1.031 1.015 1.022 1.015 1.030 1.020 1.022 1.020 1.012 1.044 1.042 1.024 1.029 pH UPRO UGLU mg/dL mg/dL m 6.5 30 NEGATIVE 6.5 30 NEGATIVE 6.5 TRACE NEGATIVE 7.0 TRACE NEGATIVE 6.0 TRACE NEGATIVE 6.0 NEGATIVE NEGATIVE 6.5 30 NEGATIVE 6.5 30 NEGATIVE 6.5 TRACE NEGATIVE NEGA 6.0 TRACE NEGATIVE NEGA 6.0 NEGATIVE NEGATIVE NEGA 7.0 30 NEGATIVE 6.0 TRACE NEGATIVE NEGA 6.0 TRACE NEGATIVE 5.5 NEGATIVE NEGATIVE 6.0 NEGATIVE NEGATIVE NEGA 6.0 30 NEGATIVE 5.5 30 NEGATIVE 6.0 TRACE NEGATIVE 6.5 TRACE NEGATIVE 130- H-24267: Two-Week Inhalation Toxicity Stody in Male Rats INDIVIDUAL URINALYSIS VALUES FOR MALE RATS Animal Number BLD ORO EU/dL UFLU M Male, Group: 1-0 mg/m3 - Day 25 637805 NEGATIVE 0.2 637806 NEGATIVE 0.2 637807 NEGATIVE 0.2 637808 NEGATIVE 0.2 637809 NEGATIVE 0.2 Male, Group: III - 25 mg/m3 - Day 25 637815 NEGATIVE 0.2 637816 TRACE 0.2 637817 NEGATIVE 0.2 637818 TRACE 0.2 637819 NEGATIVE 0.2 7.7 7.1 12.1 14.5 16.3 12.2 1-0.9 8.5 15.4 13.5 Male, Group: V - 125 nig/in' - Day 25 637825 637826 637827 637828 637829 NEGATIVE NEGATIVE SMALL TRACE NEGATIVE 0.2 16.2 0.2 15.1 0.2 11.0 0.2 18.3 0.2 16.1 Male, Group: VII - 600 mg/m3 - Day 25 637835 637836 637837 637838 637839 NEGATIVE NEGATIVE NEGATIVE NEGATIVE NEGATIVE 0.2 16.8 0.2 13.4 0.2 5.3 0.2 15.0 0.2 12.0 SPECIAL OBSERVATIONS FECAL CONTAMINATION OBSERVED FECAL CONTAMINATION OBSERVED FECAL CONTAMINATION OBSERVED 131- opanySanitized. Does nog H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL URIME MICROSCOPIC VALUES FOR MALE RATS Animal Number EPIT UWBC URBC Male, Group: I-O mg/m3 - Day 11 637800 NT NT NT 637801 FEW 0 0 637802 FEW 1-10 0 637803 FEW 0 0 637804 FEW 0 0 637805 FEW 0 0 637806 PEW 0 0 637807 FEW 0 0 637808 PEW 0 0 637809 NSR NT NT Male, Group: 637810 637811 637812 637813 637814 637815 637816 637817 637818 637819 III 25 mg/m3 - Day 11 FEW HEW NONE FEW MONE NOME HONE NONE PEW FEW 0 0 0 0 0 1-10 1-10 0 0 0 NCRY MICR SPECIAL OBSERVATIONS MT NONE NONE NONE NONE NONE NONE NONE KONE NT NT PEW FEW FEW FEW PEW FEW FEW FEW MT GROSSLY CONTAMINATED CELLULAR MATERIAL. 1-SPERM 1-SPERM WITH FECAL MATERIAL, UNABL 1-SPERM 1-SPEHM NONE NONE NONE NONE NOME NONE NONE NONE NONE NONE FEW FEW PEW MODERATE FEW FEW FEW PEW NONE NOME 1-SPERM 1-SPERM 1-SPERM 1-SPERM 1-SPERM -132- H-24267: Two-Week Inhalation Toxicity Smdy in Male Rats INDIVIDUAL URIME MICROSCOPIC VALUES FOR MALE RATS Animal Number EPIT UWBC URBC Male, Group: V - 637820 637821 637822 637823 637824 637825 637826 637827 637828 637829 125 mg/m3 - Day 11 FEW FEW FEW FEW FEW FEW FEW FEW FEW FEW 0 0 1-10 0 1-10 0 0 0 0 0 Male, Group: VII - 600 mg/m3 - Day 11 637830 637831 637832 637833 637834 637835 637836 637837 637838 637839 FEW FEW NONE FEW FEW NONE NONE NONE FEW PEW 0 0 0 1-10 1-10 0 0 0 0 0 NCRY FEW NONE NOME NONE NOME NONE NONE NONE NONE NOME FEW NOME NOME NONE NONE NOME NONE NONE NONE MONE MICR SPECIAL OBSERVATIONS FEW FEW FEW FEW FEW FEW FEW NOME FEW FEW Sample status: 1-SPERM 1-SPERM 1-SPERM 1-SPERM 1-SPERM BELOW RECOMMENDED VOLUME 1-SPERM FEW FEW FEW FEW FEW FEW FEW FEW FEW FEW 1-SPERM 1-SPERM 1-SPERM -133- Company Sanitized. Does no H-24267: Two-Week Inhalation Toxicity Study in Male Rats INDIVIDUAL URINE MICROSCOPIC VALUES FOR MALE RATS Animal Number EPIT U WBC U RBC Male, Group: 1-0 mg/m3 - D ay 25 637805 NOME 0 0 637806 NONE 0 0 637807 NONE 0 0 637808 NONE 0 0 637809 NONE 0 0 Male, Group: III - 25 mg/m' - Day 25 637815 NONE 0 0 637816 NONE 1-10 0 637817 NONE 0 0 637818 FEW 0 0 637819 PEW 0 0 Male, Group: V - 125 mg/m3 - Day 25 637825 FEW 0 0 637826 NONE 0 0 637827 FEW 0 0 637828 NONE 0 0 637829 NONE 0 0 Male, Group: VXI - 600 nig/in3 - Day 25 637835 FEW 0 0 637836 FEW 0 0 637837 NONE 0 0 . 637838 NOME 0 0 637839 . NOME 0 0 MCRY MICR SPECIAL OBSERVATIONS NONE NONE NOME PEW NONE MODERATE MODERATE FEW FEW FEW 2-SPERM 2-SPERM; 1-MUCUS 1-SPERM; 1-MUCUS . 1-SPERM 1-SPERM MOME NONE NOME NONE NONE FEW MODERATE MODERATE MANY PEW 2-SPERM; 1-MUCUS 1-MUCUS 2-SPERM 1-SPERM; 1-MUCUS 1-MUCUS NONE FEW NONE NONE NONE FEW FEW MODERATE MANY FEW 1-SPERM 1-SPERM 1-MUCUS NONE NOME NONE NONE NONE FEW MODERATE FEW FEW MODERATE 1-SPERM; 2-SPERM; 2-SPERM; 1-MUCUS 2-SPERM; 1-MUCUS 1-MUCUS 1-MUCUS 1-MUCUS -134- H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 APPENDIX F Individual Animal Final Body and Organ Weights -135- ompany Sanitized. Does not contain TSCA CBI H-24267: Two-Week Inhalation Toxicity Study in Male Rats Group : I ANIMAL - 0 mg/m3 Treatment : FINA (Gins) BRAIN (Gms) %FIMA 637800 637801 637802 637803 637804 327.00 303.00 317.00 313.00 299.00 1.887 1.954 1.963 2.011 1.871 0.5771 0.6449 0.6192 0.6425 0.6258 Mean S.D. 311.80 11.19 1.937 0.6219 0.058 0.0273 Individual Animal Final Body and Organ Weights 0 mg/m3 I Sex :MALES (Gms) KIDNEYS %FINA %BHAIN (Gms) LIVER %PINA %BRAIM (Gms) LUNGS %FINA %BRAIN 2.932 2.734 2.566 3.328 2.601 0.8966 0.9023 0.8095 1.0633 0.8699 155.38 139.92 130.72 165.49 139.02 2.832 0.9083 146.10 0.312 0.0941 14.027 11.066 10.028 11.165 10.472 10.013 3.3841 3.3096 3.5221 3.3457 3.3488 586.43 513.20 568.77 520.74 535.17 10.549 3.3821 544.86 0.550 0.0826 31.536 1.760 1.727 2.013 1.803 1.708 0.5382 0.5700 0.6350 0.5760 0.5712 93.270 88.383 102.55 89.657 91.288 1.802 0.5781 93.029 0.123 0.0352 5.6268 Group : III - 25 mg/m3 Treatment ANIMAL FINA (Gms) BRAIN (Gms) %FINA 637810 637811 637812 637813 637814 293.00 298.00 303.00 291.00 287.00 1.964 1.868 1.918 1.840 1.742 0.6703 0.6268 0.6330 0.6323 0.6070 Mean S.D. 294.40 6.23 1.866 0.6339 0.084 0.0229 25 mg/m3 III Sex -.MALES (Bms) KIDNEYS %FINA %BRAIN (Gms) LIVER %FINA %BRAIN 2.780 2.931 2.948 2.832 2.321 0.9488 0.9836 0.9729 0.9732 0.8087 141.55 156.91 153.70 153.91 133.24 10.326 9.305 9.844 9.138 8.929 3.5242 3.1225 3.2488 3.1402 3.1111 525.76 498.13 513.24 496.63 512.57 2.762 0.9374 147.86 0.256 0.0731 10.078 9.508 3.2294 509.27 0.569 0.1737 12.069 (Gms) LUNGS %FINA %BRAIN 1.488 1.510 1.631 1.407 1.448 0.5078 0.5067 0.5383 0.4835 0.5045 75.764 80.835 85.036 76.467 83.123 1.497 0.5082 80.245 0.085 0.0196 4.0602 (Gms) TESTES %PINA % 2.449 0.7489 1 3.093 1.0208 1 2.701 0.8521 1 3.385 1.0815 1 2.580 0.8629 1 2.842 0.9132 1 0.388 0.1352 1 (Gms) TESTES %FINA % 3.226 1.1010 1 3.677 1.2339 1 3.282 1.0832 1 3.321 1.1412 1 3.187 1.1105 1 3.339 1.1340 1 0.196 0.0597 1 136- i not c H-24267: Two-Week Inhalation Toxicity Study in Male Rats Group : V - 125 ing/in3 Treatment ANIMAL FINA (Gms) BRAIN (Gms) %FINA 637820 637821 637822 637823 637824 288.00 264.00 282.00 290.00 277.00 1.932 1.902 1.834 2.077 1.873 0.6708 0.7205 0.6504 0.7162 0.6762 Mean S.D. 280.20 10.40 1.924 0.6868 0.093 0.0304 Individual Animal Final Body and Organ Weights 125 mg/m3 V Sex :MALES (Gms) KIDNEYS %FINA %BRAIN (Gms) LIVER %FINA %BRAIN (Gas) LUNGS %PINA %BRAIN 2.667 2.489 2.722 2.972 2.490 0.9260 0.9428 0.9652 1.0248 0.8989 138.04 130.86 148.42 143.09 132.94 10.901 8.605 9.355 10.921 9.473 3.7851 3.2595 3.3174 3.7659 3.4199 564.23 452.42 510.09 525.81 505.77 2.478 1.666 1.903 1.769 2.234 0.8604 0.6311 0.6748 0.6100 0.8065 128.26 87.592 103.76 85.171 119.27 2.668 0.9516 138.67 0.199 0.0476 7.2241 9.851 3.5095 511.66 1.023 0.2496 40.345 2.010 0.7166 104.81 0.338 0.1109 18.989 Group : VII - 600 mg/m3 Treatment : 600 mg/m3 VII Sex :MALES ANIMAL FINA (Gms) BRAIN (Gms) %FINA (Gms) KIDNEYS %FINA %BRAIN (Gms) LIVER %FINA %BRAIM 637830 637831 637832 637833 637834 Mean S.D. 264.00 270.00 283.00 290.00 275.00 276.40 10.31 1.793 1.868 1.980 1.955 1.934 0.6792 0.6919 0.6996 0.6741 0.7033 1.906 0.6896 0.076 0.0127 2.750 2.642 2.697 2.886 2.865 1.0417 0.9785 0.9530 0.9952 1.0418 153.37 141.43 136.21 147.62 148.14 2.768 1.0020 145.36 0.106 0.0392 6.6362 9.650 9.616 11.220 9.905 9.768 3.6553 3.5615 3.9647 3.4155 3.5520 538.20 514.78 566.67 506.65 505.07 10.032 3.6298 526.27 0.674 0.2058 26.177 (Gms) LONGS %PINA %BRAIN 1.695 1.775 2.157 1.698 1.694 0.6420 0.6574 0.7622 0.5855 0.6160 94.534 95.021 108.94 86.854 87.590 1.804 0.6526 94.588 0.200 0.0671 8.8731 (Gms) TESTES %FINA % 3.334 1.1576 1 3.398 1.2871 1 3.202 1.1355 1 3.294 1.1359 1 3.178 1.1473 1 3.281 1.1727 1 0.092 0.0646 7 (Gms) TESTES %FINA % 2.584 0.9788 1 3.165 1.1722 1 2.901 1.0251 1 3.381 1.1659 1 2.821 1.0258 1 2.970 1.0736 1 0.309 0.0893 1 137- Company Sanitized. Does not conta H-24267: Two-Week Inhalation Toxicity Study in Male Rats Group : I - 0 mg/m3 Treatment : ANIMAL FINA (Gms) BRAIN (Sms) %FINA 637805 637806 637807 637808 637809 388.50 393.60 320.60 438.50 337.80 2.007 2.087 1.982 1.983 1.669 0.5166 0.5302 0.6182 0.4522 0.4941 Mean S.D. 375.80 47.17 1.946 0.5223 0.160 0.0612 Individual Animal Final Body and Organ Weights 0 ing/in3 I Sex :MALES (Gms) KIDNEYS %PIMA %BRAIN (Gms) LIVER %PINA %BRAIM (Gms) LUNGS %FINA %BRAIN 3.224 3.452 2.649 3.698 2.884 0.8299 0.8770 0.8263 0.8433 0.8538 160.64 165.40 133.65 186.49 172.80 3.181 0.8460 163.80 0.422 0.0205 19.474 12.558 12.921 9.789 13.255 10.553 3.2324 3.2828 3.0533 3.0228 3.1240 625.71 619.12 493.90 668.43 632.29 11.815 3.1431 607.89 1.545 0.1122 66.519 1.906 1.759 1.526 2.159 1.582 0.4906 0.4469 0.4760 0.4924 0.4683 94.968 84.284 76.993 108.88 94.787 1.786 0.4748 91.981 0.257 0.0186 12.105 Group : III - 25 mg/m3 Treatment | ANIMAL PINA (Gms) BRAIN (Gms) %FINA : 25 mg/m3 III Sex :MALES (Gms) KIDNEYS %FINA %BRAIN (Gms) LIVER %FINA %BRAIN 637815 637816 637817 637818 637819 332.40 370.00 296.20 357.40 388.50 Mean S.D. 348.90 35.83 NW = NOT WEIGHED 1.894 2.115 1.947 1.931 2.152 0.5698 0.5716 0.6573 0.5403 0.5539 2.008 0.5786 0.117 0.0458 2.749 3.052 2.410 2.832 3.335 0.8270 0.8249 0.8136 0.7924 0.8584 145.14 144.30 123.78 146.66 154.97 2.876 0.8233 142.97 0.345 0.0240 11.537 9.229 13.003 8.944 10.014 12.945 2.7765 3.5143 3.0196 2.8019 3.3320 487.28 614.80 459.37 518.59 601.53 10.827 3.0889 536.31 1.999 0.3259 69.015 (Gms) LUNGS %FINA %BRAIN NW 1.490 1.579 1.910 1.809 0.4027 0.5331 0.5344 0.4656 70.449 81.099 98.912 84.061 1.697 0.4840 83.631 0.196 0.0630 11.746 (Gms) TESTES %PINA % 3.177 0.8178 1 3.378 0.8582 1 2.632 0.8210 1 3.287 0.7496 1 3.392 1.0041 2 3.173 0.8501 1 0.315 0.0946 2 (Gms) TESTES %FINA % 2.998 0.9019 1 3.596 0.9719 1 2.856 0.9642 1 3.577 1.0008 1 3.439 0.8852 1 3.293 0.9448 1 0.343 0.0491 1 -138- H-24267: Two-Week Inhalation Toxicity Study in Male Rats Group : V - 125 ing/in3 Treatment ANIMAL FINA (Gms) BRAIN (Gms) %FINA 637825 637826 637827 637828 637829 364.90 405.40 349.20 385.90 391.20 2.215 2.058 1.916 2.102 2.038 0.6070 0.5076 0.5487 0.5447 0.5210 Mean S.D. 379.32 22.25 2.066 0.5458 0.108 0.0382 Individual Animal Final Body and Organ Weights 125 mg/m3 V Sex :MALES (Gms) KIDNEYS %FINA %BRAIN (Gms) LIVER %FINA %BRAIN (Gms) LUNGS %FIMA %BRAIN 3.246 3.726 3.094 3.376 3.169 0.8896 0.9191 0.8860 0.8748 0.8101 146.55 181.05 161.48 160.61 155.50 11.459 13.358 11.643 12.835 13.510 3.1403 3.2950 3.3342 3.3260 3.4535 517.34 649.08 607.67 610.61 662.90 1.682 2.040 1.986 1.764 1.889 0.4609 0.5032 0.5687 0.4571 0.4829 75.937 99.125 103.65 83.920 92.689 3.322 0.8759 161.04 0.249 0.0403 12.665 12.561 3.3098 609.52 0.958 0.1123 56.827 1.872 0.4946 91.065 0.149 0.0454 11.247 Group : VII - 600 mg/m3 Treatment I ANIMAL FINA (Gms) BRAIN (Gms) %PINA : 600 mg/m3 VII Sex (Gms) KIDNEYS %FINA %BRAIN :MALES (Gms) LIVER %FINA %BRAIN 637835 637836 637837 637838 637839 Mean S.D. 345.50 384.60 291.10 413.80 335.00 354.00 47.18 2.042 1.968 1.816 2.068 2-.057 0.5910 0.5117 0.6238 0.4998 0.6140 1.990 0.5681 0.105 0.0583 3.318 3.029 2.555 3.717 3.316 0.9603 0.7876 0.8777 0.8983 0.9899 162.49 153.91 140.69 179.74 161.21 3.187 0.9027 159.61 0.430 0.0788 14.198 12.712 12.175 8.896 14.462 11.120 3.6793 3.1656 3.0560 3.4949 3.3194 622.53 618.65 489.87 699.32 540.59 11.873 3.3431 594.19 2.057 0.2503 80.947 (Gms) LUNGS tFINA %BRAIN 1.834 2.142 1.466 2.210 1.916 0.5308 0.5569 0.5036 0.5341 0.5719 89.814 108.84 80.727 106.87 93.145 1.914 0.5395 95.879 0.294 0.0262 11.860 (Gms) TESTES %FINA % 2.216 0.6073 1 3.025 0.7462 1 2.312 0.6621 1 3.298 0.8546 1 3.292 0.8415 1 2.829 0.7423 1 0.528 0.1086 2 (Gms) TESTES %FINA % 3.649 1.0562 1 3.080 0.8008 1 2.908 0.9990 1 3.421 0.8267 1 3.295 0.9836 1 3.271 0.9333 1 0.289 0.1127 8 139- Company Sanitized. Does not contain H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 APPENDIX G Individual Animal Pathology Data -140- Compan^ SanWzeS. Does not contain TSCA CBS H-24267: Two-Week Inhalation Toxicity Study in Male Rats KEY TO APPENDIX INDIVIDUAL ANIMAL PATHOLOGY DATA DuPont-4292 LESION GRADING: Histopatho-logical changes are described according to their morphologic character, distribution and severity. The distribution (extent of tissue involvement) is indicated, where appropriate, by modifiers such as focal, multifocal, diffuse, unilateral, bilateral, etc. A severity score, if appropriate, is also assigned as follows: MINIMAL: MILD: MODERATE: SEVERE: the amount of change present barely exceeds that which is considered to be within normal limits. in general, the lesion is easily identified but of limited severity, the lesion probably does not produce any functional impairment. the lesion is prominent but there is significant potential for increased severity, limited tissue or organ dysfunction is possible. the degree of change is either as complete as considered possible or great enough in intensity or extent to expect significant tissue or organ dysfunction. COMMENT: Grades minimal through severe represent progressive involvement/severity along a continuum with minimal lesions being the least severe and severe lesions being the most severe. While the grades refer to the 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.). -141- Individual Animal Listing Dose Group : I - 0 nig/in3 Treatment: 0 ing/m3 I Sex: Males Animal Ref Microscopic & Macroscopic Findings 637800 Terminal Sacrifice Killed on Day : 11 Exposure Group : MAIN Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES. STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, KIDNEYS : SUBACUTE/CHRONIC, minimal. NEPHROPATHY, CHRONIC PROGRESSIVE, minimal. ADRENAL GLANDS : NOT PRESENT, MEDULLA. TESTES : DEGENERATION/ATROPHY, SEMINIFEROUS TUBULES, BILATERAL, mild. EPIDIDYMIDES : OLIGOSPERMIA/GERM CELL DEBRIS, BILATERAL, mild. No Microscopic Abnormality Observed : LUNGS. HEART, SPLEEN. BRAIN, SPINAL CORD, STOMACH, DUODENUM. JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, STERNUM, BONE MARROW, NOSE I & III II, & IV NOSE -142- H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 Individual Animal Listing Dose Group : I - 0 nig/in3 Treatment: 0 ing/in3 I Sex: Males Animal Ref Microscopic & Macroscopic Findings 637801 Terminal Sacrifice Killed on Day : 11 Exposure Group : MAIN Animal is signed off from necropsy Gross Pathology No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN. SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Histopathology LIVER : INFLAMMATION, PROSTATE : INFLAMMATION, SUBACUTE / CHRONIC, SUBACUTE/CHRONIC, minimal. minimal. No Microscopic Abnormality Observed : KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH. DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, BONE MARROW, NOSE I & II, NOSE III & IV -143. H-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 Individual Animal Listing Dose Group : I - 0 ing/in3 Treatment: 0 mg/m3 I Sex: Males Animal Ref Microscopic & Macroscopic Findings 637802 . Terminal Sacrifice Killed on Day : 11 Exposure Group : MAIN Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES. EPIDIDYMIDES, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, minimal. No Microscopic Abnormality Observed : KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, BONE MARROW, NOSE I & II, NOSE III & IV -144- ompany SanBbed. Does not nSan TSCA QW H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 Individual Animal Listing Dose Group : I - 0 mg/m3 Treatment: 0 mg/m3 I Sex: Males Animal Ref Microscopic & Macroscopic Findings 637803 . Terminal Sacrifice Killed on Day : 11 Exposure Group : MAIN Animal is signed off from necropsy Gross Pathology : EPIDIDYMIDES : DISCOLORATION, MOTTLED, TAIL, RIGHT, 3MM dia. No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAMD, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES. STERNUM, NOSE Histopathology : LIVER : INFLAMMATION. SUBACUTE/CHRONIC, LUNGS : INFLAMMATION, SUBACUTE/CHRONIC, PARATHYROID GLANDS : NOT PRESENT. EPIDIDYMIDES : GRANULOMA, SPERM. minimal. FOCAL, minimal. No Microscopic Abnormality Observed : KIDNEYS. HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES. STERNUM, BONE MARROW, NOSE I & II, NOSE III & IV 145 Individual Animal Listing Dose Group : I - 0 mg/m3 Treatment: 0 mg/m3 I Sex: Males Animal Ref Microscopic & Macroscopic Findings 637804 Terminal Sacrifice Killed on Day : 11 Exposure Group : MAIM Animal is signed off from necropsy Gross Pathology : LIVER : DISCOLORATION, YELLOW, LEFT, 4 MM dia. DEFORMITY, IRREGULAR, MIDDLE, only one lobe evident. No Macroscopic Abnormality Observed : KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, minimal. INFLAMMATION, GRANULOMATOUS, minimal, with mineralization. KIDNEYS : NEPHROPATHY, CHRONIC PROGRESSIVE, minimal. ADRENAL GLANDS : NOT PRESENT, MEDULLA. TESTES : DEGENERATION/ATROPHY, SEMINIFEROUS TUBULES, BILATERAL, mild. EPIDIDYMIDES : OLIGOSPERMIA/GERM CELL DEBRIS, BILATERAL, minimal. No Microscopic Abnormality Observed : LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM. MESENTERIC LYMPH NODE, THYMUS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, STERNUM, BONE MARROW, NOSE I & III II, & IV NOSE -146- 'Companif Sanitized. Does not eortain TSCA CBI H-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 Individual Animal Listing Dose Group : I - 0 ing/in3 Treatment: 0 mg/m3 I Sex: Males Animal Ref Microscopic & Macroscopic Findings 637805 . Terminal Sacrifice Killed on Day : 25 Exposure Group : RECOVERY Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER. TESTES, EPIDIDYMIDES, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, minimal. PATTY CHANGE, MEDIAN CLEFT, minimal. KIDNEYS : NEPHROPATHY, CHRONIC PROGRESSIVE, minimal. II, III No Microscopic Abnormality Observed : LUNGS, PHARYNX/LARYNX, TESTES, NOSE I & NOSE & IV -147- Company Sanited. Does not eontabi TCCA CBi H-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 Individual Animal Listing Dose Group : I - 0 mg/m3 Treatment: 0 mg/m3 I Sex: Males Animal Ref Microscopic & Macroscopic Findings 637806 . Terminal Sacrifice Killed on Day : 25 Exposure Group : RECOVERY Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, minimal. KIDNEYS : NEPHROPATHY, CHRONIC PROGRESSIVE, minimal. II, III No Microscopic Abnormality Observed : LUNGS, PHARYNX/LARYNX, TESTES, NOSE I & NOSE & IV -148- H-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 Individual Animal Listing Dose Group : I - 0 lag/in3 Treatment: 0 mg/m3 I Sex: Males Animal Ref Microscopic & Macroscopic Findings 637807 Terminal Sacrifice Killed on Day : 25 Exposure Group : RECOVERY Animal is signed.off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYMX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, minimal. TESTES : DEGENERATION/ATROPHY, SEMINIFEROUS TUBULES, minimal. UNILATERAL, II, III No Microscopic Abnormality Observed : KIDNEYS, LUNGS, PHARYNX/LARYNX, NOSE I & NOSE & IV -149- ompany Sanitized. Does rog contain TSCA C@i H-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 Individual Animal Listing Dose Group : I - 0 mg/m3 Treatment: 0 mg/m3 I Sex: Males Animal Ref Microscopic & Macroscopic Findings 637808 . Terminal Sacrifice Killed on Day : 25 Exposure Group : RECOVERY Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS. ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, FATTY CHANGE, KIDNEYS : SUBACUTE/CHRONIC, minimal. MEDIAN CLEFT, mild. NEPHROPATHY, CHRONIC PROGRESSIVE, minimal. LUNGS : INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. II, III No Microscopic Abnormality Observed : PHARYNX/LARYNX, TESTES, NOSE I & NOSE & IV -150- Dose Group : I - 0 mg/ni3 Individual Animal Listing Treatment: 0 mg/m3 I Sex: Males Animal Ref Microscopic & Macroscopic Findings 637809 Terminal Sacrifice Killed on Day : 25 Exposure Group : RECOVERY Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS. SCIATIC NERVE, THYROID GLAMD, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, minimal. KIDNEYS : NEPHROPATHY, CHRONIC PROGRESSIVE, minimal. No Microscopic Abnormality Observed : LUNGS, PHARYNX/LARYNX, TESTES, NOSE I & II, NOSE III & IV -151- Company Sanftfeed. Does not ewtaSn TSCA CW H-24267: Two-Week Inhalation Toxicity Study in Male Rats_____________________DuPont-4292 Individual Animal Listing Dose Group : Animal Ref III - 25 nig/in3 Treatment: 25 mg/m3 III Microscopic & Macroscopic Findings Sex: Males 637810 . Terminal Sacrifice Killed on Day : 11 Exposure Group : MAIN Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON. RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS. TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, minimal. LUNGS : NOSE INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. INFLAMMATION, SUBACUTE/CHRONIC, CENTRIACINAR, minimal. IIIINFLAMMATION, ACUTE, PERIVASCULAR, & IV : HYPERTROPHY, GOBLET CELL, minimal. minimal. II No Microscopic Abnormality Observed : KIDNEYS, PHARYNX/LARYNX, TESTES, NOSE I & -152. H-24267: Two-Week Inhalation Toxicity Study in Male Rats_____________________DuPont-4292 Individual Animal Listing Dose Group : Animal Ref III - 25 rog/m3 Treatment: 25 mg/rn3 III Microscopic & Macroscopic Findings Sex: Males 637811 - Terminal Sacrifice Killed on Day : 11 Exposure Group : MAIN Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, minimal. LUNGS : INFLAMMATION, SUBACUTE/CHRONIC, CENTRIACINAR, I I I NOSE INFLAMMATION, ACUTE, PERIVASCULAR, & IV : HYPERTROPHY, GOBLET CELL, minimal. minimal. minimal. II No Microscopic Abnormality Observed : KIDNEYS, PHARYNX/LARYNX, TESTES, NOSE I & -153- CompanySaniSfeed. Dose Group : Animal Ref III - Individual Animal Listing 25 mg/m3 Treatment: 25 mg/m3 III Microscopic & Macroscopic Findings Sex: Males 637812 Terminal Sacrifice Killed on Day : 11 Exposure Group : MAIM Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, LUNGS : INFLAMMATION, INFLAMMATION, SUBACUTE/CHRONIC, SUBACUTE/CHRONIC, SUBACUTE/CHRONIC, minimal. FOCAL, minimal. CENTRIACINAR, minimal. II, III No Microscopic Abnormality Observed : KIDNEYS, PHARYNX/LARYMX, TESTES, NOSE I & MOSE & IV -154- CQMBpanySanHBzeA Does nrt eontain TSGA OBI Individual Animal Listing Dose Group : Animal Ref III - 25 mg/m3 Treatment: 25 mg/m3 III Microscopic & Macroscopic Findings Sex: Males 637813 . Terminal Sacrifice Killed on Day : 11 Exposure Group : MAIN Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, minimal. PHARYNX/LARYNX : III METAPLASIA, SQUAMOUS, minimal. NOSE & IV : HYPERTROPHY, GOBLET CELL, minimal. II No Microscopic Abnormality Observed : KIDNEYS, LUNGS, TESTES, NOSE I & -155 H-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 Individual Animal Listing Dose Group : Animal Re III - 25 ing/in3 Treatment: 25 ing/in3 III Microscopic S: Macroscopic Findings Sex: Males 637814 . Terminal Sacrifice Killed on Day : 11 Exposure Group : MAIN Animal is signed off from necropsy Gross Pathology : KIDNEYS : DILATATION, UNILATERAL, SPLEEN : DEFORMITY, IRREGULAR. PELVIS, mild. No Macroscopic Abnormality Observed : LIVER, LUNGS, HEART, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC MERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S). PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, minimal. KIDNEYS : HYDRONEPHROSIS, UNILATERAL, minimal. PHARYNX/LARYHX : METAPLASIA, SQUAMOUS, minimal. NOSE III & IV : HYPERTROPHY, GOBLET CELL, minimal. II No Microscopic Abnormality Observed : LUNGS, SPLEEN, TESTES. NOSE I & -156- Compainy Sanitized. Does not contain TSCA CBI H-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 Individual Animal Listing Dose Group : Animal Ref III - 25 ing/in3 Treatment: 25 mg/m3 III Microscopic & Macroscopic Findings Sex: Males 637815 Terminal Sacrifice Killed on Day : 25 Exposure Group : RECOVERY Animal is signed off from necropsy Gross Pathology : LUNGS : Inflated, not weighed, protocol deviation. No Macroscopic Abnormality Observed : LIVER, KIDNEYS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS. ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Hisfcopathology : No Microscopic Abnormality Observed : LUNGS, PHARYNX/LARYNX 157- Individual Animal Listing Dose Group : Animal Ref III - 25 ing/m3 Treatment: 25 ing/in3 III Microscopic & Macroscopic Findings Sex: Males 637816 Terminal Sacrifice Killed on Day : 25 Exposure Group : RECOVERY Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIM, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Histopathology : No Microscopic Abnormality Observed : LUNGS, PHARYNX/LARYNX 158- Compansf Sanitized. Does not contain TSCA CB Individual Animal Listing Dose Group : Animal Ref III - 25 rag/in3 Treatment: 25 mg/m3 III Microscopic & Macroscopic Findings Sex: Males 637817 Terminal Sacrifice Killed on Day : 25 Exposure Group : RECOVERY Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX. EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Histopathology : No Microscopic Abnormality Observed : LUNGS, PHARYNX/LARYNX 159- Individual Animal Listing Dose Group : Animal Ref III - 25 ing/in3 Treatment: 25 mg/m3 III Microscopic & Macroscopic Findings Sex: Males 637818 Terminal Sacrifice Killed on Day : 25 Exposure Group : RECOVERY Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES. EPIDIDYMIDES. STERNUM, NOSE Hisfcopathology : No Microscopic Abnormality Observed : LUNGS, PHARYNX/LARYNX 160- Cornpany SanWteecS. Does not sontaimi TCCA CBt H-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 Individual Animal Listing Dose Group : Animal Ref III - 25 mg/m3 Treatment: 25 ing/in3 III Microscopic & Macroscopic Findings Sex: Males 637819 Terminal Sacrifice Killed on Day : 25 Exposure Group : RECOVERY Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Histopathology : No Microscopic Abnormality Observed : LUNGS, PHARYNX/LARYNX -161 H-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 Individual Animal Listing Dose Group : V - 125 ing/in3 Treatment: 125 mg/m3 V Sex: Males Animal Re Microscopic & Macroscopic Findings 637820 . Terminal Sacrifice Killed on Day : 11 Exposure Group : MAIN Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENDM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, minimal. KIDNEYS : NEPHROPATHY, CHRONIC PROGRESSIVE, minimal. LUNGS : HYPERTROPHY, BRONCHIOLAR EPITHELIAL CELL, minimal. INFLAMMATION, SUBACUTE/CHRONIC, CENTRIACINAR, minimal. PHARYNX/LARYNX : III METAPLASIA, SQUAMOUS, minimal. NOSE & IV : HYPERTROPHY, GOBLET CELL, minimal. II No Microscopic Abnormality Observed : TESTES, NOSE I & -162- Qwmpwsy Sanitized. Does not eotfa8n TtCA CB8 Individual Animal Listing Dose Group : V - 125 mg/m3 Treatment: 125 ing/in3 V Sex: Males Animal Ref Microscopic & Macroscopic Findings 637821 Terminal Sacrifice Killed on Day : 11 Exposure Group : MAIN Animal is signed off from necropsy Gross Pathology : Mo Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN. BRAIN. SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, minimal. KIDNEYS : NEPHROPATHY, CHRONIC PROGRESSIVE, minimal. LUNGS : HYPERTROPHY, BRONCHIOLAR EPITHELIAL CELL, minimal. INFLAMMATION, SUBACUTE/CHRONIC, CENTRIACINAR, minimal. PHARYNX/LARYNX : IIIMETAPLASIA, SQUAMOUS, minimal. NOSE & IV : HYPERTROPHY, GOBLET CELL, minimal. II No Microscopic Abnormality Observed : TESTES, NOSE I & -163 H-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 Individual Animal Listing Dose Group : V - 125 mg/m3 Treatment: 125 Big/m3 V Sex: Males Animal Ref Microscopic & Macroscopic Findings 637822 . Terminal Sacrifice Killed on Day : 11 Exposure Group : MAIN Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, minimal. KIDNEYS : NEPHROPATHY, CHRONIC PROGRESSIVE, minimal. LUNGS : HYPERTROPHY, BRONCHIOLAR EPITHELIAL CELL, minimal. INFLAMMATION, SUBACUTE/CHRONIC, CENTRIACINAR, minimal. PHARYNX/LARYNX : METAPLASIA, SQUAMOUS, minimal. III II, No Microscopic Abnormality Observed : TESTES, NOSE I & NOSE & IV -164- Cwnpany Sanitized. Doe not contain TSCA CB8 H-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 Individual Animal Listing Dose Group : V - 125 ing/in3 Treatment: 125 mg/m3 V Sex: Males Animal Ref Microscopic & Macroscopic Findings 637823 . Terminal Sacrifice Killed on Day : 11 Exposure Group : MAIN Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS. LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE. THYROID GLAND. PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, minimal. FATTY CHANGE, MEDIAN CLEFT, minimal. LUNGS : HYPERTROPHY, BRONCHIOLAR EPITHELIAL CELL, minimal. INFLAMMATION, SUBACUTE/CHRONIC, CENTRIACINAR, minimal. PHARYNX/LARYNX : IIIMETAPLASIA, SQUAMOUS, minimal. NOSE & IV : HYPERTROPHY, GOBLET CELL, minimal. II No Microscopic Abnormality Observed : KIDNEYS, TESTES, NOSE I & -165 H-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 Individual Animal Listing Dose Group : V - 125 ing/in3 Treatment: 125 ing/in3 V Sex: Males Animal Ref Microscopic & Macroscopic Findings 637824 Terminal Sacrifice Killed on Day : 11 Exposure Group ; MAIM Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTOM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, minimal. KIDNEYS : NEPHROPATHY, CHRONIC PROGRESSIVE, minimal. LUNGS : HYPERTROPHY, BRONCHIOLAR EPITHELIAL CELL, minimal. INFLAMMATION, SUBACUTE/CHRONIC, CENTRIACINAR, minimal. I I I NOSE & IV : HYPERTROPHY, GOBLET CELL, minimal. II No Microscopic Abnormality Observed : PHARYNX/LARYNX, TESTES, NOSE I & -166- Company Sanitized. Does no8 eontain TSCA CBI H-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 Individual Animal Listing Dose Group : V - 125 mg/m3 Treatment: 125 nig/in3 V Sex: Males Animal Ref Microscopic & Macroscopic Findings 637825 . Terminal Sacrifice Killed on Day : 25 Exposure Group : RECOVERY Animal is signed off from necropsy Gross Pathology : Mo Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON. RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC MERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Hisfcopathology : No Microscopic Abnormality Observed : LUNGS, PHARYNX/LARYNX -167. Individual Animal Listing Dose Group : V - 125 mg/m3 Treatment: 125 mg/ai3 V Sex: Males Animal Ref Microscopic & Macroscopic Findings 637826 Terminal Sacrifice Killed on Day : 25 Exposure Group : RECOVERY Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS. SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Histopathology : LUNGS : INFLAMMATION, SUBACUTE/CHRONIC, CENTRIACINAR, minimal. No Microscopic Abnormality Observed : PHARYNX/LARYNX -168- Compan^ SanfflzeA Does not conlaBn T8CA CBI H-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 Individual Animal Listing Dose Group : V - 125 mg/m3 Treatment: 125 mg/m3 V Sex: Males Animal Ref Microscopic & Macroscopic Findings 637827 . Terminal Sacrifice Killed on Day : 25 Exposure Group : RECOVERY Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART. SPLEEN, BRAIM, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS. SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Histopathology : No Microscopic Abnormality Observed : LUNGS, PHARYNX/LARYNX -169- Cmnpssy ^anHIzed. I H-24267: Two-Week Inhalation Toxicity Study in Male Rats_____________________DuPont-4292 Individual Animal Listing Dose Group : V - 125 ing/in3 Treatment: 125 ing/in3 V Sex: Males Animal Re Microscopic & Macroscopic Findings 637828 . Terminal Sacrifice Killed on Day : 25 Exposure Group : RECOVERY Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM. JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS. PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES. STERNUM, NOSE Histopathology : LUNGS : INFLAMMATION, SUBACUTE/CHRONIC, FOCAL, minimal. No Microscopic Abnormality Observed : PHARYNX/LARYNX -170. H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 Individual Animal Listing Dose Group : V - 125 ing/in3 Treatment: 125 lug/in3 V Sex: Males Animal Ref Microscopic & Macroscopic Findings 637829 - Terminal Sacrifice Killed on Day : 25 Exposure Group : RECOVERY Animal is signed off from necropsy Gross Pathology : Ho Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS. PHARYNX/LARYNX. EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Histopathology : No Microscopic Abnormality Observed : LUNGS, PHARYNX/LARYNX -171- Company SanStteed. Does not contain TSCA CBI H-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 Individual Animal Listing Dose Group : VII - 600 mg/ni3 Treatment: 600 Big/Hi3 VII Sex: Males Animal Ref Microscopic & Macroscopic Findings 637830 Terminal Sacrifice Killed on Day : 11 Exposure Group : MAIN Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS. HEART, SPLEEN. BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM. PANCREAS, CECUM, COLON, RECTUM. MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS. PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM. NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, minimal. KIDNEYS : NEPHROPATHY, CHRONIC PROGRESSIVE, mild. LUNGS : HYPERTROPHY, BRONCHIOLAR EPITHELIAL CELL, minimal. INFLAMMATION, SUBACUTE/CHRONIC, CENTRIACINAR, minimal. PHARYNX/LARYNX : METAPLASIA, SQUAMOUS, minimal. TESTES : DEGENERATION/ATROPHY, SEMINIFEROUS TUBULES, BILATERAL, mild. EPIDIDYMIDES : III NOSE OLIGOSPERMIA/GERM CELL DEBRIS, BILATERAL, & IV : HYPERTROPHY, GOBLET CELL, minimal. minimal. No Microscopic Abnormality Observed : HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, STERNUM, BONE MARROW, NOSE I & II ,!fSU\ -172- H-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 Individual Animal Listing Dose Group : VII - Animal Ref 600 ing/in3 Treatment: 600 mg/m3 VII Microscopic & Macroscopic Findings Sex: Males 637831 . Terminal Sacrifice Killed on Day : 11 Exposure Group : MAIN Animal is signed off from necropsy Gross Pathology : Mo Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX. EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, minimal. LUNGS : HYPERTROPHY, BRONCHIOLAR EPITHELIAL CELL, minimal. INFLAMMATION, SUBACUTE/CHRONIC, CENTRIACINAR, minimal. PHARYNX/LARYNX : NOSE NOSE METAPLASIA, SQUAMOUS, minimal. II I & : HYPERTROPHY, III & IV : HYPERTROPHY, GOBLET CELL, GOBLET CELL, minimal. minimal. No Microscopic Abnormality Observed : KIDNEYS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMOS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, BONE MARROW -173- Ccmmm^ Ban'tteed. Ooe not emrtafts) TSCA CBI Individual Animal Listing Dose Group : VII - 600 lug/in3 Treatment: 600 ing/in3 VII Animal Ref Microscopic & Macroscopic Findings 637832 . Terminal Sacrifice Killed on Day : 11 Exposure Group : MAIN Animal is signed off from necropsy Gross Pathology : EPIDIDYMIDES : DISCOLORATION, TAN, FIRM, TAIL. Sex: Males No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAMD, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, minimal. KIDNEYS : NEPHROPATHY, CHRONIC PROGRESSIVE, minimal. LUNGS : HYPERTROPHY, BRONCHIOLAR EPITHELIAL CELL, minimal. INFLAMMATION, SUBACUTE/CHRONIC, CENTRIACINAR, minimal. PHARYNX/LARYNX : NECROSIS, CARTILAGE, minimal. EPIDIDYMIDES : OLIGOSPERMIA/GERM CELL DEBRIS, UNILATERAL, minimal. II NOSE I & : INFLAMMATION, SUBACUTE/CHRONIC, minimal. HYPERPLASIA/HYPERTROPHY, RESPIRATORY, minimal. I I I NOSE & IV : HYPERTROPHY, GOBLET CELL, minimal. No Microscopic Abnormality Observed : HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, STERNUM, BONE MARROW -174. H-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 Dose Group : VII - Animal Ref Individual Animal Listing 600 Big/in3 Treatment: 600 mg/in3 VII Microscopic & Macroscopic Findings Sex: Males 637833 Terminal Sacrifice Killed on Day : 11 Exposure Group : MAIM Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA. ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, KIDNEYS : SUBACUTE/CHRONIC, minimal. NEPHROPATHY, CHRONIC PROGRESSIVE, minimal. LUNGS : HYPERTROPHY, BRONCHIOLAR EPITHELIAL CELL, minimal. INFLAMMATION. SUBACUTE/CHRONIC, CENTRIACINAR, minimal. PARATHYROID GLANDS : NOT PRESENT. PHARYNX/LARYNX : METAPLASIA, SQUAMOUS, minimal. TESTES : DEGENERATION/ATROPHY, SEMINIFEROUS TUBULES, BILATERAL, minimal. EPIDIDYMIDES : II OLIGOSPERMIA/GERM CELL DEBRIS, BILATERAL, minimal. NOSE I & : DEGENERATION/NECROSIS, OLFACTORY, minimal. HYPERPLASIA/HYPERTROPHY, RESPIRATORY, minimal. HYPERTROPHY, I I I NOSE & IV : HYPERTROPHY, GOBLET CELL, GOBLET CELL, minimal. minimal. No Microscopic Abnormality Observed : HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, .COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS. SCIATIC NERVE, THYROID GLAND, TRACHEA, ESOPHAGUS, EYE(S), PROSTATE, SEMINAL VESICLES, -URINARY BLADDER, STERNUM, BONE MARROW -175- Campany Sanitized. Dees not eorrtain TCCA W H-24267: Two-Week Inhalation Toxicity Study in Male Rats______________________DuPont-4292 Individual Animal Listing Dose Group : VII - Animal Ref 600 Big/in3 Treatment: 600 mg/m3 VII Microscopic & Macroscopic Findings Sex: Males 637834 . Terminal Sacrifice Killed on Day : 11 Exposure Group : MAIN Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, minimal. KIDNEYS : NEPHROPATHY, CHRONIC PROGRESSIVE, minimal. LUNGS : HYPERTROPHY, BRONCHIOLAR EPITHELIAL CELL, minimal. INFLAMMATION, SUBACUTE/CHRONIC, CENTRIACINAR, minimal. PARATHYROID GLANDS : NOT PRESENT. PHARYNX/LARYNX : METAPLASIA, SQUAMOUS. minimal. TESTES : DEGENERATION/ATROPHY, SEMINIFEROUS TUBULES, BILATERAL, minimal. EPIDIDYMIDES : I I I NOSE OLIGOSPERMIA/GERM CELL DEBRIS, BILATERAL, & IV : HYPERTROPHY, GOBLET CELL, minimal. minimal. No Microscopic Abnormality Observed : HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM. COLON, RECTUM, MESENTERIC LYMPH NODE, THYMOS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, TRACHEA, ESOPHAGUS, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, STERNUM, BONE MARROW, NOSE I & II -176- amBairay sfc@i Does ng cimtain TSCA CBI H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 Individual Animal Listing Dose Group : VII - Animal Ref 600 ing/m3 Treatment: 600 mg/m3 VII Microscopic & Macroscopic Findings Sex: Males 637835 Terminal Sacrifice Killed on Day : 25 Exposure Group : RECOVERY Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTBS, EPIDIDYMIDES, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, minimal. KIDNEYS : NEPHROPATHY, CHRONIC PROGRESSIVE, minimal. II, III No Microscopic Abnormality Observed : LUHGS, PHARYNX/LARYNX, TESTES, NOSE I & NOSE & IV -177- Individual Animal Listing Dose Group : VII - Animal Ref 600 ing/Hi3 Treatment: 600 mg/m3 VII Microscopic & Macroscopic Findings Sex: Males 637836 Terminal Sacrifice Killed on Day : 25 Exposure Group : RECOVERY Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, minimal. KIDNEYS : MEPHROPATHY, CHRONIC PROGRESSIVE, minimal. PHARYNX/LARYNX : NECROSIS, CARTILAGE, minimal. II, III No Microscopic Abnormality Observed : LUNGS, TESTES, NOSE I & NOSE & IV -178- Campany Sanitized. Does not contain TSCA CBI H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 Individual Animal Listing Dose Group : VII - 600 ing/Hi3 Treatment: 600 mg/m3 VII Sex: Males Animal Ref Microscopic & Macroscopic Findings 637837 Terminal Sacrifice Killed on Day : 25 Exposure Group : RECOVERY Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, minimal. FATTY CHANGE, MEDIAN CLEFT, minimal. KIDNEYS : NEPHROPATHY, CHRONIC PROGRESSIVE, minimal. PHARYNX/LARYNX : NECROSIS, CARTILAGE, minimal. II, III No Microscopic Abnormality Observed : LUNGS, TESTES, NOSE I & NOSE & IV -179- H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 Individual Animal Listing Dose Group : VII - 600 ing/in3 Treatment: 600 ing/in3 VII Sex: Males Animal Ref Microscopic & Macroscopic Findings 637838 Terminal Sacrifice Killed on Day : 25 Exposure Group : RECOVERY Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LONGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES. STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE / CHRONIC, minimal. KIDNEYS : HYDRONEPHROSIS, UNILATERAL, minimal. LUNGS : INFLAMMATION, SUBACUTE/CHRONIC, CENTRIACINAR, minimal. III II, No Microscopic Abnormality Observed : PHARYNX/LARYNX, TESTES, NOSE I & NOSE & IV -180- eempany Saailted. Does not eertaSn TSfiA CBi H-24267: Two-Week Inhalation Toxicity Study in Male Rats DuPont-4292 Individual Animal Listing Dose Group : VII - 600 mg/m3 Treatment: 600 ing/in3 VII Sex: Males Animal Ref Microscopic & Macroscopic Findings 637839 Terminal Sacrifice Killed on Day : 25 Exposure Group : RECOVERY Animal is signed off from necropsy Gross Pathology : No Macroscopic Abnormality Observed : LIVER, KIDNEYS, LUNGS, HEART, SPLEEN, BRAIN, SPINAL CORD, STOMACH, DUODENUM, JEJUNUM, ILEUM, PANCREAS, CECUM, COLON, RECTUM, MESENTERIC LYMPH NODE, THYMUS, ADRENAL GLANDS, SCIATIC NERVE, THYROID GLAND, PARATHYROID GLANDS, TRACHEA, ESOPHAGUS, PHARYNX/LARYNX, EYE(S), PROSTATE, SEMINAL VESICLES, URINARY BLADDER, TESTES, EPIDIDYMIDES, STERNUM, NOSE Histopathology : LIVER : INFLAMMATION, SUBACUTE/CHRONIC, minimal. No Microscopic Abnormality Observed : KIDNEYS, LUNGS, PHARYNX/LARYNX, TESTES, NOSE I & III II, & IV NOSE -181