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AR226-3007 DuPont HLR 696-92 Study Title Subchronic Inhalation Toxicity Study with in Rats Laboratory Project ID Haskell Laboratory Report No. 696-92 Author Hanan N. Ghantous, Ph.D. Study Completed On December 21, 1994 Performing Laboratory E. I. du Pont de Nemours and Company Haskell Laboratory for Toxicology and Industrial Medicine Elkton Road, P.0. Box 50 Newark, Delaware 19714 . Medical Research No. C o m p a n y SanHize. 0 o e s nof contain T S C A C B Page 1 of 156 (includes Page 36a) DuPont HLR 696-92 GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT This study was conducted in compliance with EPA TSCA (40 CFR 792) Good Laboratory Practice Standards except for the deviation documented and explained below. 1. A characterization of the test substance was not performed prior to the initiation of the study. The deviation did not affect the integrity of the study. Submitter: E. I. du Pont de Nemours and Company Sponsor: DuPont Specialty Chemicals E. I. du Pont de Nemours and Company Wilmington, Delaware Study Director: _____ l/j ' ^ ------ ___________ !%/ % \/ Q[Lj Eanan N. Ghantous, Ph.D. Research Toxicologist Biochemical Toxicology -- 'Sem p a n y Sanitised. not contain t SGA CB1 - 2- GENERAL INFORMATION DuPont HLR 696-92 Haskell No.: Physical Form: Puri ty: Composition : 17375 -3- Company Sanitized. Does ne? contain TSC CBt Synonyms : GENERAL INFORMATION (continued) DuPont HLR 696-92 Other Codes: Stability: Sponsor: In-Life Phase Initiated - Completed: Study Initiated - Completed: The test material was assumed to be stable throughout the exposure phase of the test. DuPont Specialty Chemicals E. I. du Pont de Nemours and Company, Inc. Wilmington, Delaware 10/17/88 - 11/11/88 10/7/88 - 12/21/94 ORpssw Sant/te'dL -sas no? -4 - c^F DuPont HLR 696-92 TABLE OF CONTENTS Page GOOD LABORATORY PRACTICE COMPLIANCE GENERAL INFORMATION ............. TABLE OF CONTENTS .... S U M M A R Y ..................... STATEMENT ........... 9 1 3 5 SIGNATURE P A G E .... ! .................................. ................ 6 QUALITY ASSURANCE DOCUMENTATION 7 I N T R O D U C T I O N ..................... ' .................................... 8 MATERIAL AND M E T H O D S .... ............................................ 9 RESULTS AND DISCUSSION .. 9 CONCLUSIONS ............... '........................................... 13 REFERENCES ....... ................................................ : 1* .................................................... 14 TABLES Table 1 Table 2 Table 3 Table 4 Table 5 Atmospheric Concentrations ofJj| Particle Size Characterization < Mean Body Weights of Male Rats .... Mean Body Weight Gains of Male Rats ......... !s o l ....... 16 Atmospheres 17 Summary of Clinical Observations in Male Rats ........... 19 ................... 20 APPENDICES Appendix A Protocol and Protocol Amendments ............ Appendix B - Daily Atmospheric Analyses ................... Appendix C - Individual Body Weights of Male Rats ........ Appendix D - Individual Clinical Observations of Male Rats Appendix E - Clinical Pathology Report No. 10-89 ......... Appendix F - Pathology Report No. 6-89 ......... .... 21 37 40 49 51 87 -5 - I D o e s hof contain T S C A CBi Subchronic Inhalation Toxicity Study with SUMMARY DuPont HLR 696-92 in Rats This study was carried out to determine the toxic e fferi-g 0 f repeated inhalation of sublethal concentrations o f M H H H V k e r o s o l . Three groups of ten male CrlrCD'BR rats were exposed six hours/day, five days a week for two weeks, ( e x c ^ ^ ^ ^ ^ j ^ m - d a y s and Sundays) to design concentrations of 1, 5, or mg m in air. A control group of ten male rats was exposed simultaneously to air only. At the end of the exposure period, blood and urine samples were collected for clinical analyses, and five rats per group were sacrificed for pathological examinations. The remaining rats were retained for a 14-day post-exposure observation period and then subjected to the same clinical and pathologic examinations. During as well as immediately following each exposure most rats including control animals exhibited nasal and/or ocular discharges. One control animal and one rat in the low-dose group exhibited ocular discharge and/or ocular opacity during the post-exposure observation period. No other clinical signs were observed in any animals during this time. At the end of the exposure period a statistically significant decrease in J H j y | ^ ^ y w l u m e and increase in mean urine osmolality were noted in all exposed rats compared to the control rats. During this period there was also a significant decrease in the absolute lung weight of rats in the low-dose level. The c ^ m ^ a ^ ^ h e m i s t r y and organ weight differences were not dependent o w l H ^ e r o s o l exposure concentration. Under the conditions of this test the no-observed effect level (NOEL), based on clinia^signs. body weight, clinical pathology, and histopatholgy, was 10 m g / m ^ J J ^ H H f l e r o s o l . o m p & n y a ftf? ? ze ' f? e s g * n ? co n fe T n f S C A e g ? Subchronic Inhalation Toxicity Study with SIGNATURE PAGE DuPont HLR 696-92 iin Rats Approved by: /JM t y d (UUnK Nanc/`C. C h r o m e y , Ph.D ., D.A.B.T. Oral Toxicology Authored, Reviewed, and Approved for Issue by Study Director: >2/2i, f H m a n N. Ghantous, Ph.D. Study Director C o m p a n y Sanitized. D o e s not contain T S C A CB -7- DuPont HLR 696-92 QUALITY ASSURANCE DOCUMENTATION (H-17375) Dates of Inspection: Conduct - 10/24,27/88, 11/3,11/88 Records, Report(s) - 5/4,8/89, 8/30/89, 9/6-8,11/89 11/17,18/92, 12/20/94 ' Date Findings Reported to: Study Director - 5/5,9/89, 11/18/92, 12/21/94 Management - 5/5,9/92, 12/11/92, 12/21/94 Reported by: (J James Hackay Quality Assurance Auditor -8- C o m p a n y Sanitized. D o s s not contain T S C CBI INTRODUCTION DuPont HLR 696-92 -- halation- In an acute four-hour inhalation study clinical signs observed in ijexpose rats included nasal, ocular, and respiratory irritation d ) '* lethal concentration (ALC) o t M m M m M s 21 /m i' Durdone ofPth"re ll,lts this test "riaWB^^^Ktablished. The S'tpoL^Mjly^0 the toxicity associated vith erosol in male rats. MATERIALS AND METHODS A- General Experimental Design male/ f ts were used to assess the toxic effects of . CL ^ B I H B x erosol inhalation exposures on body weights, clinical and h i s toPathologic parameters. T^ 'test Rroups were exposed to design concentrations of 1, 5, or 10 m g / m 3 o f l B B H ^ t / contr1 S rouP of rats matched for age, s e x , ^ ^ ^ M g h t M L | g ^ lniU taneously to air only. The highest exposure concentration of ^ ^ R i e r o s o l was selected based on the results of two rangefinding " !. e g ^0UP s of male rats were exposed for several days to mean 3 -nS aPProximately 7 13 m g / m 3 without signs of toxicity, and In the'iren t0 f i-aS establlshed approximate lethal concentration of 2iymg / m 3. ieeki f f ? ra? Vere exPsed six hours/day, five days a week for two trrnnn' (eXcludlI?g Saturdays and Sundays) and five animals from each exposure g oup were retained for a 14-day post-exposure recovery period. All rats were siudy 7 Veight Changes and clinical signs of toxicity throughout the f r n r A M 116 f V f SXp?SUre Period> blod and urine samples were collected for n a ^ ^ CliniCal analyses' a"d v e rats per group were sacrificed for pathologic examination. After 14 days of recovery, the remaining rats were g ven similar clinical and pathologic examinations. The complete protocol and amendments to the protocol for this study are attached as A p p e n d i x T B. Animal Husbandry R i v e f B r e ^ n ^ T ^ Crl :CD@BR Trats <b TM 8-22-88) were received from Charles ver* hn s Laboratories, Inc., Raleigh, North Carolina on 10/10/88. Rats were housed one per cage m 5 x 11" x 7" stainless steel, wire mesh cages suspended above cageboards. Each rat was assigned a six-digit identification number which was recorded on a card that was affixed to the cage. Rats were t i m e ^ H 111^ f?h S1X dayS Pri r t0 testing; and were weighed and observed three four treaimenfthe qUaranJlne P" 01- DurinS this time, rats were assigned to our treatment groups of ten male rats each. The rats were grouped using a computer randomization program such that there were no statistically significant differences in the groups' mean body weights prior to the start of Company Sanitized. Does of contain TSCA CS! 9 DuPont HLR 696-92 the first exposure. After grouping, each rat was assigned a one- to two-digit identification number that was tattooed on the rat's tail and recorded on a card affixed to their respective cages. Upon grouping, rats were housed in pairs in 8" x 14" x 8" cages. Rats were approximately eight weeks old and weighed between 217 and 247 grams at the start of the exposures. Except during the exposures, Purina Certified Rodent Chow #5002 and water were available ad libitum. C- Exposure Protocol, Atmosphere Generation, and Analysis 1. Exposure Protocol Four groups of ten male rats were individually restrained in perforated, stainless steel cylinders with nonperforated conical nose pieces." Each restrainer was inserted into a face plate on the exposure chambers such that only the nose of each rat protruded into the chamber. The exposures were conducted six hours/day, five days/week for two weeks, (excluding Saturdays and Sundays) and were followed by a 14-day recovery period. Three test groups were exposed nose-only to design concentrations of 1, 5, or 10 m g / m 3 o f j j H l H V aerosol in air (groups III, V and VII, respectively). A control group was exposed to air only (group I). 2. Atmosphere Generation Mixed aerosol/vapor atmospheres were generated with a Spraying Systems air atomizing nozzle usin^E^^^gh pressure air stream. The test material was metered into the spray nozzle with a Harvard model 975 compact infusion pump and atomized with high pressure air. The aerosol was passed through a one-liter glass cyclone to assist in the removal of larger non-respirable particles before being introduced to a cylindrical, glass 38-liter exposure chamber. Each chamber was fitted with a baffle to enhance aerosol dispersion. Atmospheric concentrations o f l f l H I H B l L e r e controlled by regulating, (1) the delivery rate of the test m a t e ^ a ^ ^ h e syringe drive (approximate range 20-200 pl/min), (2) the generation air (approximate range 5-21 L/min), and (3) the dilution air (approximate range 21-43 L/min). Exposure chamber atmospheres were exhausted through a dry ice cold trap and a MSA cartridge filter prior to discharge into a fume hood. The control group was exposed to air only (approximately 30 L/min) in an exposure system of similar design. 3- Analysis of the Test Atmospheres Generation off ^ ^ ^ ^ B ^ K a t m o s p h e r e s by the method described above produces both an aerosol vapors of acetone and ethylene glycol. Based on a previous inhalation study w i t h f l | H H H B j t h e design aerosol concentrations of 1, 5, or 10 m g / m 3 would not produce toxicologically significant concentrations of vapor.(*) In the present study, no analysis of vapor was made. Atmospheric aerosol concentrations o f A ^ H f e i B H V j t e r e determined by gravimetric analysis at approximately 3 0 ? n i n u t ^ n t e r v a l s . At the high and intermediate design exposure levels (10 or 5 m g / m 3) known volumes of chamber atmospheres were drawn through preweighed Gelman glass fiber filters. Filters were w e i g h e ^ o r ^ ^ C a h i ^ M o d e l 26 automatic Electrobalance. Atmospheric concentrations o f f l H H ^ H H V K r e r e calculated from the filter 10 - DuPont HLR 696-92 weight gain, determined from the pre- and post-sampling filter weights, Model 8510 Piezobalance was used to monitor the low-design exposure concentration (1 mg/m3). A TSI During each exposure, chamber temperatures were measured with mercury thermometers, relative humidities were measured with a Belfort Instrument chamber oxyg en i n t e n t s were measured with a Biosystems, Inc., Model 3100R oxygen monitor. ' Body Weights and Clinical Observations During the exposure_period, rats were weighed and individually observed for clinical signs of^ toxicity before each exposure. Groups of animals were observed for clinical signs of toxicity during and immediately following each exposure. An evaluation of group acoustical response was also made during the exposures During the recovery period, all rats were weighed and observed daily, Saturdays and Sundays excluded except when warranted by the rats' condition. J E. Clinical Pathology . .Jrine samPles ver collected overnight from all surviving rats after the ninth exposure, and from the remaining rats on the.13th day of recovery. analyzed for volume' osmolality, urobilinogen, pH, hemoglobin or occult blood, glucose, protein, bilirubin and ketone by personnel from the Clinical Pathology Section of Haskell Laboratory. The color and transparency of each sample was noted, and the sediment from each sample was examined microscopically. A blood sample was taken from the orbital sinus of each rat after the tenth exposure, and from each remaining rat on the 14th day of recovery. Blood samples were analyzed for hemoglobin concentration, hematocrit, erythrocyte count, platelet count, leukocyte count, and relative numbers of neutrophils ' lymPh cytes' atypical lymphocytes, eosinophils, m o n ocytes'and basophils by personnel from the Clinical Pathology Section of Haskell Laboratory. Mean corpuscular volume, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration were calculated (Vintrobe erythrocyte indices) from the erythrocyte data. Serum activities of alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase, and serum concentrations of urea nitrogen, creatinine, total protein and cholesterol were F. Pathology The ten rats per exposure group were each subdivided into groups of five based on computer generated random number tables. The five rats per group were sacrificed after the tenth exposure by sodium pentobarbital anesthesia and exsanguination for gross and histopathologic evaluations. On the 14th day of the post-exposure recovery period the remaining rats of each group were similarly sacrificed and evaluated. The lungs, liver, kidneys, spleen and testes were weighed at necropsy, and representative samples of the following 11 C o m p a n y Sanitized. D o e s not contain T S C A CB1 DuPont HLR 696-92 tissues were obtained for microscopic examination: heart, lungs, mesenteric lymph nodes, nasal cavities (nose), trachea, liver, pancreas, esophagus stomach, duodenum, jejunum, ileum, cecum, colon, rectum, Sidneys, urina y bladder, sternum (bone and marrow), spleen, thymus, thyroid 8 lan* jdrena glands, brain, eyes, testes, epididymides, and any other organ or tissue with gross lesions. G. Statistical Analysis Mean body weights and body weight gains for test rats were compared to controls during the exposure and recovery periods. Data were statistically analyzed by a one-way analysis of variance. Exposure group values were compared to c o n t r o l s ^ the least significant difference test when the ratio of variance (F) indicated a significant a m o n g - t o - w i t h m group variation. Significant differences were declared at the 0.05 probability level. T statistical analyses' used to evaluate the clinical pathology data, mean organ weights ("absolute" weights) and mean organ-to-body weight ratios ( rela weights) are described in Appendices E and F, respective y. H. Records Retention All raw data (including slides and paraffin-blocked tissues) and final reports will be stored in the archives of Haskell Laboratory for Toxicology and Industrial Medicine, Newark, Delaware, or in the DuPont Records Management Center, E. I. du Pont Nemours and Company, Inc., Wilmington, Delaware. Gsstipapiy Ssrsitfeed. Doi m l eer:?a?n T S C A C'S! 12 DuPont HLR 696-92 RESULTS AND DISCUSSION A. Exposure Conditions In the test chambers, chamber temperature ranged from approximately 20 to 2 4 C, relative humidity ranged from approximately 53 to 71%, and chamber oxygen content was approximately 21%. In the control chamber, chamber temperature ranged from approximately 19 to 24C, relative humidity ranged from approximately 60 to 73%, and chamber oxygen content was approximately 21%. The mean atmospheric concentrations measured in the chambers as well as particle size characterization for each exposure concentration are presented m Tables 1 and 2, respectively. Daily atmospheric characterization data are presented m Appendix B. B. Body Weights The mean body weights of rats exposed to 1, 5, or 10 mg / m 3 aerosol were indistinguishable from control group values during the exposure and post-exposure recovery periods. One or two mean body weight gain values m the low- and high-exposure groups during the study were significantly different from control values. These dif f e r e n c e s ^ j e r ^ s o l a t e d and did not represent a toxicological response dependent o r J | j ^ d ^ K ^ e r o s o l concentration. Dal y mean body weights and mean body weight gains are presented m Tables 3 an respectively. Individual body weights are presented in Appendix C. C. Mortality and Clinical Signs ` During the first exposure to 10 m g / m 3 aerosol rats were observed with clear nasal discharge. Most other study animals (including controls) exhibited red nasal discharge during exposures. No animals had a decreased acoustical response at any time evaluated. Immediately following each exposure, most animals studied (including controls) exhibited red nasal and/or red ocular discharges. These responses were not related to the concentration of the test compound. In the post-exposure period Con median t&st day 16) a control animal and one rat exposed to 1 m g / m 3 o f f l H | H e r o s o l had left ocular discharge, and left ocular discharge and coraea^opacity, respectively. The post-exposure responses were likely to be related to the orbital sinus technique used for blood sampling. A summary of observed clinical signs is presented m Table 5. Clinical signs of individual animals are in Appendix D. D. Clinical Pathology Clinical pathologic examination revealed several statistically significant findings, however, these physiologic changes were not dependent on exposure concentration of test material. Following the exposure period a statistically significant d e c r e a s e - i n m e a n u r i n e volume and increase in mean urine osmolality were observed in a l l i B H H H f e e r o s o l - exposed groups compared to the control mean. Such Changes in clinical chemistry are normally associated with C o m p a n y Sanitized. D o s s no! contain T S C A CBE 13 DuPont HLR 696-92 dehydration, however, other indices of dehydration such as coincident significant increases in blood total protein, urea nitrogen, and hematocrit concentrations were not present. Significant findings were observed in mean serum cholesterol at the end of the exposure period in the high-dose group, as well as in mean blood lymphocyte and serum creatinine at the end of recovery m the intermediate- and low-dose groups, respectively. Clinical Pathology Report No. 10-89 is attached as Appendix E. E. Pathology No compound related effects were observed at any f l | ^ | ^ m P J e x p o s u r e concentration tested. Absolute mean lung weight was"Significantly decreased at the end of the exposure period in the low-dose group compared to mean value in the control group. This finding was isolated and was probably a reflection of the lower mean body weight within the group. The decrease in lung weights did not""exhibit" a relevant do'se-response relationship. In addition, no histopathological changes were found in the lungs. Thus, these effects were ,u n r e l a t e d ! ! exposure and there was no evidence of a toxic effect of lung tissue. Pathology Report No. 6-89 is attached as "Appendix F. CONCLUSIONS The results indicated that repeated inhalation exposure to 1, 5, or 10 mg/m3/ U B B B H ^ e r o s o l had no toxicological effects in male rats. the condiltions of this test the no-observed effect level was 10 mg/m3 ^maerosol. Under 1. Haskell Laboral Concentration o REFERENCES | Inhalation Approximate Lethal i s s s n f a f n T S C .4 C S U 14 Subchronic Inhalation Toxicity Study wit DuPont HLR 696-92 TABLES Note: Data are reported to two significant figures. Company Sanitized. 0 0 5 3 nf contain T S C A CBf 15 Subchronic Inhalation Toxicity Study with DuPont HLR 696-92 3 TABLE 1 ATMOSPHERIC CONCENTRATIONS ROSOL (mg/m3) Group No. I III V VII Design . Concentration 0 1 5 10 n 720 120 120 Mean - 1.3a 4.8b llb S.D. - 0.87 1.5 4.0 Range - 0.0 - 5.0 0.10 - 8.3 2.2 - 33 - Refers to values that were not determined. Values shown represent the mean, standard deviation (S.D.), range, and number of measurements (n) for ten exposures at each exposure concentration. a Values based on Piezobalance analyses. b Values based on filter weights obtained immediately after sampling and assumed to represent the amount of polymer present as .an ae r osol.. This assumption is consistent with t h e * ^ ^ ^ ^ ^ L j exposure concentration in HLR N o . | ^ U ^ P j w^ _ aerosol concentration is expressed on a weight/volume basis (mg/m ). fop'aftjrenK!re& Dss h o !esnfan TSCA CBI 16 - DuPont HLR 696-92 Subchronic Inhalation Toxicity Study with TABLE 2 PARTICLE SIZE CHARACTERIZATION OF ATMOSPHERES Design Concentration % Particles*5 (mg/m3) n a < 3 pmi < 10 pm 0 -- - 1 2 73 . 97 5 2 80 96 10 2 86 99 MMD(pm) - 1.6 1.1 1.0 - Refers to values that were not determined. a Number of measurements that were made during the entire course of ten exposures for each concentration of aerosol. b Percent by weight of particles with aerodynamic diameters (AD) less than 3 pm and less than 10 pm. Represents the mean value from two exposures. c Mass median aerodynamic diameter. Represents the mean value from two exposures. C o m p a n y Sanitized. D o e s not contain T S C A CBI 17 DuPont HLR 696-92 Subchronic Inhalation Toxicity Study vi TABLE 3 MEAN BODY WEIGHTS OF MALE RATS Group: I III V Design Concentration (mg/m3): 0 15 Days On Test Body Weight (g) Exposure Period 1 2 3 4 5 8 9 10 11 12 233.,4( 8..0)* 238..3(11.9) 243..5(12.9) 250.,7(13.1) 256..6(12.7) 286..2(11.9) 291.,0(12.3) 297.,4(12.6) 305..4(14.6) 306..1(10.5) 232. 4( 9,.5) 235. 2( 9..9) 242. 9( 9,5) 247. 9(11.7) 256. 1(11..8) 283. 2(13..4) 286. 7(12.7) 292. 5(15..4) 295. 8(14,.8) 290. 5(22,.3) 232,,2( 7.7) 235,,1(12..1) 240..3(12..3) 246..1(12..2) 253..2(13.4) 277..0(18.1) 284..7(18..1) 289..4(18..7) 294..8(18.4) 295..4(20.6) VII 10 233.0( 9 0) 235.5(14..0) 243.4(13,8) 250.0(13,3) 253.7(13,3) 282.5(16..3) 286.8(17,6) 291.5(17,1) 295.8(17,1) 299.1(17,2) Recovery Period 15 319.3( 6.9) 16 323.6( 5.8) 17 334.1( 8.7) 18 340.3( 7.4) 19 347.7( 6.3) 22 369.8( 7.4) 23 378.4(10.0) 24 385.3(12.0) 25 392.0(12.4) 26 388.5( 9.4) 319.2(29.8) 325.5(25.8) 335.1(29.1) 339.3(32.3) 350.9(30.5) 370.7(31.9) 381.4(32.6) 388.5(35.4) 399.0(37.3) 388.7(28.6) 303.3(18.8) 304.1(20.2) 314.6(19.1) 316.9(18.8) 322.1(21.5) 345.5(22.0) 355.0(22.6) 360.1(20.9) 365.6(19.4) 364.3(21.8) 317.8(23.0) 320.8(21.6) 331.0(23.4) 337.3(25.6) 345.1(23.4) 363.9(26.8) 374.9(28.9) 381.9(30.1) 385.1(28.6) 375.1(26.0) a Values in parentheses are standard deviations. C o m p a n y Sanitised. D o s s noi contain Y S C A CBl 18 Subchronic Inhalation Toxicity Study with DuPont HLR 696-92 TABLE 4 MEAN BODY WEIGHT GAINS OF MALE RATS Group: I Design Concentration (mg/m3): 0 Days On Test Exposure Period 1- 2 2-3 3-4 4-5 5-8 8-9 9-10 10 - 11 11 - 12 4.9( 7.3)a 5.2( 7.0) 7.2 ( 3.8) 5.9( 5.3) 29.6( 2.4) 4.8( 3.3) 6.3( 4.0) 8 . 1( 3.9) 0 . 7( 6.8) III V 1 _5 Body Weight Gain (g) 2.8( 3.1) 77( 3.7) 5.0( 4.4) 8.2( 5.7) 27.1( 6.0) 3.5( 2.8) 5.8( 4.3) 3.3( 3.4)b -5.3(12.9) 2.9 ( 7-2) 5.2 ( 3.6) 5.7( 2.6) 7 2( 3.5) 23.8( 7.1) 7 7( 4.8) 4.7( 2.5) 5.4( 2.3) 0.6( 4.8) VII 10 2.4( 6.9) 7.9( 2.8) 6 7( 3.6) 3 6( 2.4) 28.9( 4.9) 4.2( 2.9) 4.8 ( 1.9) 4.2( 2.6)b 3.3( 6.6) Recovery Period 12 - 15 15 - 16 16 - 17 17 - 18 18 - 19 19 - 22 22 - 23 23 - 24 24 - 25 25 - 26 17.0( 5.5) 4.3( 3.0) 10.4( 3.8) 6.2( 3.1) 7.5( 2.2) 22.0( 4.6) 8.7 ( 4.5) 6.9( 3.6) 6.7 ( 3.7) -3.5( 4.9) 26.4( 4.8)b 6 3 ( 4.9) 9.6( 4.5) 4 -2 ( 4.4) 11.6( 2.8) 19.8( 3.7) 10.7( 1.9) 7- 1C 3.6) 10.5( 2.4) -10.3(11.4) 17.1( 3.8) 0.8( 7.7) 10.5( 3-4) 2.3 ( 2.3) 5.3( 4.8) 23.3( 7.6) 9.5( 5.6) 5 . 1( 2.9) 5.4( 2.6) -1.3( 4.0) 20.6( 6.3) 3.0( 1.8) 10.2( 2.0) 6.3( 4.2) 7.8( 3.0) 18.8( 3.8) 11.0( 2.9) 7.1( 2.5) 3.2( 2.6) -10.0(10.8) a Values in parentheses are standard deviations. b Significant statistical differences from control, alpha = 0.05. C o m p a n y Sanitized. D o e s not contain T S C A CBi 19 DuPont HLR 696-92 Subchronic Inhalation Toxicity Study with TABLE 5 SUMMARY OF CLINICAL OBSERVATIONS IN MALE RATS3 Groupb : Design Concentration (mg/m3): Observation Colored Discharge, Left Eye Corneal Opacity, Left Eye I III V VII 0 1 5 10 Number of Rats :Exhibiting Sign 1 (16)= 0 1 (16-)1 (16) 0 0 0 0 a Excluding clinical signs observed during or immediately following exposure. b Ten rats per group at study start c The number in parentheses is the median day on test the sign was first observed. ' C o m p a n y Sanfifzetf. P a s s no! contain 7 S C DBF - 20 - Subchronic Inhalation Toxicity Study with( DuPont HLR 696-92 APPENDIX A Protocol and Protocol Amendments C o m p a n y Sanitized. D o e s noi contain T S C A CBT 21 DuPont HLR 696-92 PROTOCOL SUBCHRONIC INHALATION 'OXICITY STUDY WITH IlN RATS STUDY Subchronic Inhalation Toxicity Study Medical Research N o . ^ | ^ ^ m 3 Proposed In-Life Starting Date: Proposed In-Life Completion Date: 10/17/88 11/117 88 3 Haskell No. 17,375 PURPOSE _____ [is considered to be extremelvt^^^ ^ j ^ ^ i h a l a t i o n with a 4-hr 3apjp^rroximate lethal concentration of 21 mg/m3 T^e PurPose this study is to determine the effects of r e p e ^ e ^ e x p o s re to sublethal concentrations o by inhalation in male rats. STUDY CONDUCT This standard protocol and the Acute and Developmental Toxicology Division's SOP's constitute the protocol for this study. Except as documented in the Acute and Developmental Toxicology Division's SOP's and study records, this study will be conducted according to the U.S. Environmental Protection Agency Good Laboratory Practice Standards (40 CFR Part 792). TEST FACILITY This study will be conducted at Haskell Laboratory for Toxicology and Industrial Medicine, E. I. du Pont de Nemours and Company, Inc., P. 0. Box 50, Elkton Road, Newark, Delaware 19714. -22- DuPont HLR 696-92 SPONSOR The sponsor of this test is the Chemicals and Pigments Department of the Du Pont Company. The address of the sponsor is the corporate headquarters of E. I. du Pont de Nemours and Company, Inc., Wilmington, Delaware. The sponsor's approval of the test protocol is indicated by the sponsor's signature on the Medical Research Project proposal which authorizes the conduct of the test: The date of the sponsor's approval is the date the sponsor authorized the test. ROUTE OF ADMINISTRATION Animals will be exposed to the test material by inhalation. The inhalation route is specified by the sponsor of the test. Generally, the inhalation route is chosen based on the potential for human exposure to the test material by inhalation, or because inhalation testing is specified by the appropriate regulatory agency(s). DURATION OF THE STUDY The starting date of the study will be defined as the day that study animals are first exposed to the test material. The-, completion date of the in-life portion of the study will be defined as the last day of the recovery period. The completion date of the entire study will be defined as the date .the final report is issued. TEST MATERIAL Identification The test material is Information on the purity, composition, contaminants, .Tonyms, ^^artmental codes, CAS registry number, basic physical properties, unusual hazards, and hazardous material classification(s) are provided by the sponsor on the Haskell Laboratory Sample Evaluation form; The original form will be retained in the official Medical Research file for the study in Haskell's Information Section. A copy of the form will be included in the study records. -2 C o m p a n y Sanitized. D o e s not contain T S C CBt -23- DuPont HLR 696-92 Stability Unless otherwise indicated on the Sample Evaluation form and m the absence of visible or analytical evidence to the contrary, the test material will be assumed to be stable under the conditions of this test. Degree of Absorption For the purpose of this test, it will be assumed that all of the test material that is inhaled will be absorbed. No attempt will be made to establish the actual dose each rat received. All toxic effects will be reported as a function of the exposure concentrations rather than as a function of dose. TEST SYSTEM AND HUSBANDRY Species/Strain Sex Source Age Weight Range Number per Group Crl:CDBR rats Male . . Charles River Breeding Laboratories, Raleigh, North Carolina Approximately 8 weeks old at the start of exposures Approximately 210 to 250 grams 10 Justification of Test System Rats have historically been used in safety evaluation studies, and their use is specified by the appropriate regulatory agency(s). This strain of rats has been well characterized in this laboratory. Quarantine and Stock Rats will be quarantined for a minimum of 6 days prior to testing. Rats will be weighed and observed at least twice during the quarantine period. In the absence of clinical signs to the contrary, rats are assumed to be free of any disease or condition that may interfere with the purpose of this study. Selection of Animals To group the rats, the total number of rats to be used on the test plus a few extra rats will be arbitrarily assigned to a pretest group. Any rat that 3- -24- S a m p a n sanfte*. Does *>! contain T S C A C B DuPont HLR 696-92 has been gaining weight at a normal rate and has no overt signs of disease is acceptabi^fobtesting. The rat(s) with the lowest anc[ highest body weights will be culled from the sample. The remaining rats will be divided into boiJgroups by computer randomization such that the pretest mean th e i f all groups are similar (p>0.05). Rats will be grouped based on their body weights days prior to the first exposure, Rats will be selected for sacrifice based on random number tables. Control of Bias To control bias, rats will be randomly assigned to groups. No significant differences between test groups that may affect the o u t c l e of thiS study are oxpoctod. In the absence of evidence to he contrary, toxic effects following inhalation of the test material will b interpreted as being the result of exposure to the test material. Identification Each rat will be assigned a unique 6-digit identification number which is recorded on a card affixed to the cage. Upon grouping, each rat wiil be assigned a 1-3 digit identification number that will be tattooed on the rat s. tail and recorded on the cage card. Tattoo numbers and cor^sponciing 6-digit numbers will be recorded in the study records. Prior to exposure, tail and cage cards may be color-coded with water-insoluble markers to identify the exposure group to which each rat belongs. Housing Environment Except as restricted by facility design, animal rooms wil\ 5 \ maia*aii ^ r at approximately 50 10% Relative humidity and 23 2C on a 12 hour/12 hour light/dark cycle. Unless judged by the study director or the site veterinarian to have significantly affected the results of a " Jual relative humidity and temperature ranges incurred will be recorded thornot be included in the final report. Except during exposurest housed in suspended, stainless steel, wire-mesh cages. Rats will be housed^ -ino-iv in 5" x 11" x 7" cages, or singly or in pairs in 8 x 14 x a cages. Except during exposures, Purina Certified.RodJJgW^ J * 1J5Jg available water from the Wilmington Suburban Water Corporation (WSWC) will be available ad libitum. Food Contaminants The potential effects of dietary contaminants have been considered and, on the basis of the manufacturer's data, contaminant levels are S i e v e d to be within acceptable ranges. To supplement these data, feed is periodica y analyzed for selected heavy metals, pesticides, and nitrosamines- Records the results of these analyses are maintained by the site veter other contaminants reasonably anticipated to be present m the fee a expected to interfere with the results of this study. -4- ss Iff? -25- DuPont HLR 696-92 Water Contaminants The potential effects of water contaminants reported by WSWC have been considered and appear to be within acceptable ranges. To supplement these data, laboratory water is periodically monitored for selected microorganisms, pesticides, heavy metals and halogens reasonably anticipated to be present in the water supply. Records of the results of these analyses are maintained by the site veterinarian and the Quality Assurance Section. STUDY, DESIGN General Study Design Four groups of 10 male rats will be exposed to the test material by inhalation 6 hours/day, 5 days/veek for 2 weeks. The exposure period will be followed by a 14-day recovery period. Three t e s ^ r o u ^ W i l l be exposed o design concentrations of 0.5, 1.5 or 5 m g / m S M H B H P ^ " . 3?;^ control group will be exposed to air only. Rats will oe weighed and observed throughout the exposure and recovery periods. At the end of the exposure period, blood and urine samples will be collected from 10 rats per group for clinical analysis, and 5 rats per group will be killed for pathologic examination. After the 14-day recovery period, the remaining rats will be . subjected to the same clinical and pathological examinations. Any variations in this study design will be documented in the study records ana m a protocol amendment. Exposure Concentrations Three exposure concentrations (targeted at 0.5, 1.5 or 5 mg/m3J . and an air control will be tested during this study. Ideally, "exposure concentration will cause no adverse effects, 1 concentration will cause marginal effects, and 1 concentration will severely stress the rats without causing death. However, the preliminary design concentrations may be refined after observing the effects of repeated-dose rangefinding. Control Group(s) An air-exposed control group will be subjected to the same experimental conditions and evaluation(s) as the test groups. Rangefinding Preliminary rangefinding exposures will be conducted before the initiation of the study. Rangefinding trials at the planned exposure concentrations will be conducted without rats to establish the generation parameters needed o -5C o m p a n y Sanitized. D o e s no? contain T S C A CBI -26- DuPont HLR 696-92 achieve the desired atmospheric concentrations. In addition, rangefinding^ exposures may be conducted with rats at the high-level exposure concentration to help predict whether 10 exposures to the design concentration will cause adverse effects without killing the rats. The estimates of potential effects will be based mainly on body weights changes. Based on the results of the rangefinding exposures, the selected exposure concentrations may be adjusted accordingly. The results of the rangefinding exposures will be included m the study records, but will ordinarily not be included in the final report. Exposure Mode Rats will be individually restrained in a perforated, stainless steel cylinders with conical, nonperforated nose pieces and exposed nose-only. Each restrainer will be inserted into a face plate attached to a 38 liter glass cylindrical exposure chamber such that only the nose of each rat protrudes into the chamber. Duration of Exposure Each group of rats will be exposed 6 hours/day, 5 days/week for 2 weeks to an atmosphere of the test material in air. The starting time of each exposure will be defined as the time when the generation system is turned on. The ending time of each exposure will be defined as the time when the generator is turned off. Rats will be exposed to the test material during both the time it takes for the chamber to reach concentration, and the time it takes for the chamber to blow down. After each exposure, the rats will be returned to their cages. The exposure period will be defined as the period between initiation of the first exposure and completion of the 10th exposure. The recovery period will be defined as the period between completion of the 10th exposure and. euthanasia of the last rat. Viability Checks Each rat will be weighed and observed daily prior to exposures. Unless restricted by the physical characteristics of the test atmospheres or exposure systems, observations of group clinical signs will be taken during each exposure. After each exposure, rats will be observed for clinical signs before they are returned to their cages. During the recovery period, remaining rats will be weighed and observed daily, weekends and holidays excluded unless warranted by the rats' condition. Endpoints The primary end points in this study include body weights, clinical observations, organ weights, gross and microscopic pathological changes, and 6- - -27- Com pany Sanitize#. Doss not contain r S c DuPont HLR 696-92 changes in clinical chemical, hematologic, and urinalysis parameters in the test rats as compared to controls. Additional endpoints may be added at the request of the sponsor or at the discretion of the study director, and will be documented in the study records. Collection of Specimens Urine samples wiil be collected overnight from 10 rats per group after the 9th exposure, and from 5 rats per group on the 13th day of recovery. Each urine sample will be labeled with the rat number from which the specimen was collected. Each sample will be analyzed by personnel of the Clinical Pathology Section of Haskell Laboratory for volume, osmolality, urobilinogen, pH, blood, sugar, protein, bilirubin and ketone. The color and transparency of each specimen will be noted, and the sediment from each sample will be examined microscopically. Additional analyses may be performed at the discretion of the study director or the Clinical Pathology staff, and will be documented in the Clinical Pathology report or in the study records. Carbon dioxide will be used to lightly anesthetize each rat prior to blood sampling. Blood samples will be collected from the orbital sinus of 10 rats per group after the 10th exposure and from 5 rats per group on the 14th day of recovery. Samples will be analyzed by the Clinical Pathology staff for erythrocyte count, hemoglobin concentration, hematocrit, platelet count, . leukocyte count, and relative numbers of neutrophils, band neutrophils, lymphocytes, atypical lymphocytes, eosinophils, monocytes and basophils. Mean corpuscular volume, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration will be calculated from the erythrocyte data. Serum activities of alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase, and serum concentrations of urea nitrogen, creatinine, tota protein and cholesterol will be measured. Additional analyses may be performed at the discretion of the study director or the Clinical Pathology staff, and will be documented in the Clinical Pathology report or in the study records. The procedures and methods for analyzing samples are documented m the Clinical Pathology Section's SOP's. Post Mortem Observations Five rats per group will be killed after the 10th exposure, and 5 rats per group will be killed on the 14th day of recovery for gross and histopathologic examination. Rats will be killed by pentobarbital anesthesia and exsanguination by the Pathology staff of Haskell Laboratory. The lungs, liver, kidneys, spleen and testes will be weighed at necropsy. Each rat will be given a complete gross examination, and the following organs and tissues will be examined microscopically: liver, kidneys, urinary bladder, heart, lungs, nasal cavities, pancreas, thymus, spleen, adrenal glands, thyroid gland, mesenteric lymph nodes, trachea, esophagus, stomach, duodenum, jejunum, -7- C o m p a n y Sanitized. D o e s not contain T S C A CBf -28- DuPont HLR 696-92 ileum, cecum, colon, rectum, sternum, bone marrow, testes, epididymides, brain and eyes. Additional organs and tissues may be examined at the discretion of the study director or the Pathology staff, and will be documented in the Pathology report or in the study records. All remaining organs and tissues will be incinerated. The procedures and methods for analyzing organs and tissues are documented in the Pathology Section's SOP's. Statistical Analyses Mean body weights for test rats will be compared to controls during the exposure and recovery periods. Data will be statistically analyzed by one-way analysis of variance. Test rats will be compared with controls by least significant difference test when the ratio of variance (F) indicates a significant among-to-within group variation. Significance will be judged at the 0.05 probability level. Any additional statistical comparisons will be documented in the study records. Statistical analyses of clinical pathology and organ weight data will be conducted by the appropriate personnel; the methods used will be documented in the Clinical Pathology and Pathology supplementary reports, respectively. ADMINISTRATION OF THE TEST MATERIAL Atmosphere Generation Attempts will be made to generate respirable atmospheres of the test material which approximate the physical form of the test material expected to be encountered in human exposure situations. Test atmospheres will be generated dynamically using airflows needed to achieve at least 10 air changes per hour. Attempts will also be made to evenly distribute the test material throughout the exposure chamber. F o r \ H H i i | H attempts will be made to generate particles of respirable size. I d e a l l y T a t i e a s t 90% of the test atmosphere will be composed of particles smaller than 10 urn aerodynamic diameter, with a mass median aerodynamic diameter of less than 3 urn. If the ideal particle size cannot be attained, the most respirable atmosphere practically attainable will be tested. The general principles of generation and safety procedures are documented in the Acute and Developmental Toxicology Division's SOP's. Actual generation equipment and conditions will be documented in the study records. Chamber Conditions Ideally, the chamber conditions will be similar to housing conditions (i.e., temperature of 23 + 2C, relative humidity of 40-60%). However, temperature and humidity variations outside of these ranges are commonly encountered due to the generation procedures used and the characteristics of 8- - -29- SaififesL contais 'C CB DuPont HLR 696-92 the test material itself. These variations are not expected to significantly affect the results of this type of study. The minimum acceptable chamber oxygen concentration will be 19%. Analyses of the Test Atmosphere A suitable analytical method will be approved by the study director to monitor the atmospheric concentrations of the test material in the breathing zone of the animals within the exposure chambei^Thyy^fliary method for determining the atmospheric concentration o n j H ^ ^ ^ J ^ g f r i l l be gravimetric analysis. Unless prohibited by the nature or the test material, the chamber temperatures, relative humidities and chamber oxygen contents will be monitored. The general principles of monitoring chamber atmospheres are documented in the Acute and Developmental Toxicology Division's SOP'S. Details of the analytical method(s) used will be documented in the study records. Frequency of Measurements The atmospheric concentration of the test material in the breathing zone of the animals will be determined daily by gravimetric analysis at approximately 30-minute intervals for each exposure chamber, when possible. More or less frequent samples may be taken at the discretion of the study director. The chamber airflow will be recorded at the start of exposure and any time an adjustment in airflow is made. When possible, chamber ^ temperatures, relative humidities and oxygen.concentrations will be monitored at least once per exposure per chamber. Samples for particle size analysis will be collected at least once during the study for each exposure chamber. The actual frequency of measurements will be recorded in the study records. DISPOSAL OF WASTE MATERIALS Unless otherwise indicated in the study records, waste materials will be packaged with absorbent material in polyethylene-lined fiberpacs and incinerated. RECORDS RETENTION All raw data (including slides and paraffin-blocked tissues) and final reports will be stored in the archives of Haskell Laboratory for Toxicology and Industrial Medicine, Newark, Delaware, or in the Du Pont Records Management Center, E. I. du Pont de Nemours and Company, Inc., Wilmington, Delaware. -9- CompanySanitizes*. oas no? eonfan T S C A CBf -30- DuPont HLR 696-92 FINAL REPORT A final report will be written which includes, but is not limited to, the items cited in CFR 40, Part 792, Subpart J, Section 792.185. CHANGES IN PROTOCOL Changes in protocol will be documented in protocol amendments signed by the Study Director. Prepared by: Dolores E. Malek, Ph.D. Study Director / 8g> Approved by: fj,,,, nxj. (L^4*. iff! ? fT* Nancy' C . Chromey ,i/Ph.D . Manager . Acute and Developmental Toxicology Division - 10 psny -31- j-o &s not contain T s C CE CENTRAL RESEARCH AND DEVELOPMENT DEPARTMENT HASKELL LABORATORY FOR TOXICOLOGY AND INDUSTRIAL MEDICINE DuPont HLR 696-92 cc: Qual i t y A s s u r a n c e May 19, 1989 TO: MEDICAL RESEARCH PROJECT NO FROM: DOLORES E. MALEK PROTOCOL AMENDMENT #1 TWO WEEK SUBCHRONIC INHALATION TOXICITY STUDY 0 Haskell Laboratory No. 17375 Medical Research No. 3 1. Design Concentration o Protocol - 0.5, 1.5 and 5 mg/m3 Study - 1, 5, 10 rag/m3 [has been changed: 2. Time when the test animals were grouped has been changed: Protocol - states that rats will be "grouped" based on their body weights days prior to the first exposure. Study - rats were "grouped" based on their body weights the morning of (within a few hours) the first exposure. Prepared by: jkXK S' /tvs'? Dolores E. Malek, Ph.D. Study Director Research Toxicologist Acute and Developmental Toxicology Division fete -32- CENTRAL RESEARCH AND DEVELOPMENT DEPARTMENT HASKELL LABORATORY FOR TOXICOLOGY AND INDUSTRIAL MEDICINE DuPont HLR 696-92 cc: Quality Assurance June 12, 1989 TO: MEDICAL RESEARCH PROJECT NO. FROM: DOLORES E. MALEK PROTOCOL AMENDMENT #2 TWO-WEEK INHALATION TOXICITY STUDY WIT Haskell Laboratory No. 17375 IMedical Research No. N RATS The title has been changed from "Subchronic Inhalation Toxicity H H H V Y i n Rats" to "Two-Week Inhalation Toxicity Study with tin Rats". Prepared by: 0<-> /IZ./ 8 9 Dolores E. Malek, Ph.D. Study Director Research Toxicologist Acute and Developmental Toxicology Division > -33- no contain T S C A C B * C 0tnpanYSanif,2ed'D0ES DuPont HLR 696-92 PROTOCOL AMENDMENT #3 MR N u m b e r S t u d y Code: t o Haskell Number: 17,37s. Descriptive Title of Study: Two-Week Inhalation Toxicity Study wittj| in Rats ^ Compound Name: As of 02/05/91, Judith C. Stadler will replace Dolores E. Malek as study director for the purpose of completion and issuance of the final report. - l ^ Jx j^ X / S ' /?/ //Judith C. Stadler, Ph'.D. (Senior Research Toxicologist Acute Toxicology < Z/ 5/ Dolores E. Malek, Ph.D. Research Toxicologist Acute Toxicology -34- Company Sasilfteed. Be Siin?a!n T SG A CB CENTRAL RESEARCH AND DEVELOPMENT DEPARTMENT HASKELL LABORATORY FOR TOXICOLOGY AND INDUSTRIAL MEDICINE TO: MEDICAL RESEARCH PROJECT NO. PROTOCOL AMENDMENT #3 DuPont HLR 696-92 cc: Quality Assurance November 11, 1992 The Study Protocol, issued 10-07-88, is amended as follows: Prepared By : Presently Reads: "Dolores E. Malek, Ph.D. Study Director" Amend to Read: "Hanan N. Ghantous, Ph.D Study Director" Prepared by: Maryanne Ml Wilford Toxicology Associate Approved by: : Hanan Ghantous V Study Director Il / I! / fX Sanitized. Does not soman TSC CBi -35 CENTRAL RESEARCH AND DEVELOPMENT DEPARTMENT HASKELL LABORATORY FOR TOXICOLOGY AND INDUSTRIAL MEDICINE TO: MEDICAL RESEARCH PROJECT NO PROTOCOL AMENDMENT #5 DuPont HLR 696-92 cc: Quality Assurance December 11, 1992 The Study Protocol Ammendment, issued 11-11-92, is amended as follows: Title: Presently Reads: "PROTOCOL AMENDMENT #3" Amend to Read: "PROTOCOL AMENDMENT #4" Amendment: Presently Reads: "Prepared B y : Presently Reads: Dolores E. Malek, Ph.D. Study Director Amend to Read: Hanan N. Ghantous, Ph.D Study Director" Amend to Read: "As of June 1, 1992, Hanan N. Ghantous will replace Judith C. Stadler as study director for this study." Prepared by: Vk ( ___________________ (X Maryanne.M. Uilford ^ Toxicology Associate Approved by: Hanan Ghantous Study Director it / II / ?x -36- CENTRAL RESEARCH AND DEVELOPMENT DEPARTMENT HASKELL LABORATORY FOR TOXICOLOGY AND INDUSTRIAL MEDICINE TO MEDICAL RESEARCH PROJECT 1 PROTOCOL AMENDMENT #6 1. Protocol Amendment #2 is amended as follows: The title o ^ t h ^ s t u d ^ :is changed from "Two-Week Inhalation Toxicology Study wit in Rats" to "Subchronic Inhalation Toxicology Study wit in Rats". The titles on all study protocol amendments are amended to reflect this change. 2. The study protocol is amended as follows: Page 5, Water Contaminants, sentence 3 is amended to read "Records of the results of these analyses are maintained by the site veterinarian. Approved by: (J, U (jHanan Ghantous ^Study Director Date nh'lw - 36a - C o m p a n y Sanitized. D o e s not contain T S C CB Subchronic Inhalation Toxicity Study with DuPont HLR 696-92 APPENDIX B Daily Atmospheric Analyses Note: ` Data are reported to two significant figures. S c p s a w Ssnfffer??. E'f'ipq no! 37 fB! Subchronic Inhalation Toxicity Study with DuPont H LR 696-92 3 Appendix B Daily Atmospheric Analyses (Control: 0 mg/m*3 ^ ) Exposure No. Concentration (mg/m3) Mean S.D. Range 1 2 3 4 5 6 7 8 9 10 Chamber3 Temp. CC) R e l a t i v e 13 Humidity (X) 20 - 24 20 - 23 20 - 24 19 - 23 20 - 23 20 - 24 19 - 23 19 - 23 19 - 22 20 - 22 63 60 68 73 63 64 69 65 67 68 Oxygen*3 Content (X) 21 21 21 21 21 21 21 21 21 21 Design Concentration: 1 mg/m3 Exposure No. 1 2 3 4 5 6 7 8 9 10 Concentration (mg/m3) Mean S.D. Range 0.92 1.3 1.3 0.69 0.96 1.7 1.4 1.3 1.5 1.5 0.46 0.93 1.3 0.27 0.19 1.0 1.1 0.84 0.39 0.95 0.25 - 3.6 0.05 - 4.2 0.0 - 4.6 0.25 - 1.6 0.50 - 1.5 0.15 - 3.8 0.0 - 5.0 0.0 - 3.7 0.65 - 2.2 0.10 - 3.8 Chamber3 Temp. ( CC) 22 - 23 22 - 24 22 - 23 20 - 23 21 - 24 22 - 24 21 - 22 21 - 22 20 - 22 20 - 22 R e l a t i v e 13 Humidity (*) 61 62 61 64 55 58 61 58 62 58 0xygenc Content (*) 21 21 21 21 21 21 21 21 21 21 - Refers to values that were not determined. 3 Range of two measurements per exposure. b One measurement per exposure. c One measurement per exposure. d Mean of 72 measurements per exposure. - 38 - C o m p a n y Sanitized. D o e s not contain T S C A CBi Subchronic Inhalation Toxicity Study vith DuPont HLR 696-92 ] Appendix B (continued) Daily Atmospheric Analyses Design Concentration: 5 m g / m 2l Exposure No. 1 Concentration (mg/m3) Mean S.D. Range 1 4.6 0.67 3.3 - 5.4 2 5.6 1.6 2.6 - 7.8 3 3.7 ' 2.5 0.10 - 8.1 4 4.1 1.3 1.5 - 5.7 5 5.2 1.7 2.6 - 8.3 6 4.6 1.0 3.1 - 7.3 7 4.7 0.97 2.3 - 5.9 8 6.2 1.2 4.0 - 8.0 9 4.8 1.5 3.1 - 7.6 10 4.5 1.0 3.0 - 6.6 C h a m b e r 13 Temp. (C) 22 - 23 21 - 23 21 - 23 20 - 22 20 - 22 20 - 24 20 - 22 20 - 22 20 - 22 20 - 22 Relative0 Humidity (%) 63 61 56 69 53 56 65 58 62 60 0xygend Content C/o) 21 21 21 21 21 21 21 21 21 21 im am 3Design Concentration:: 10 mg/m 3 Exposure Concentration (mg/m3) No. Mean S.D. Range 1 9.5 1.5 6.0 - 11 2 8.7 2.9 2.2 - 14 3 11 3.2 5.2 - 16 4 11 2.1 7.8 - 15 5 13 5.7 8.7 - 27 6 9.3 0.84 8.4 - 11 7 12 1.0 10 - 13 8 13 1.4 11 - 16 9 17 6.9 6.2 - 33 10 9.1 1.7 4.4 - 11 Chamberb Temp. ( C) 22 - 24 22 - 24 22 - 24 21 - 23 22 - 23 22 - 24 21 - 24 21 - 23 20 - 23 20 - 23 Relative0 Humidi ty C/o) 69 71 54 62 53 58 61 58 62 58 Oxygend Content C/o) 21 21 21 21 21 21 21 21 21 21 a Mean of 12 measurements per exposure. b Range of two measurements per exposure. c One measurement per exposure. d One measurement per exposure. 39 'Company S s m & e Sees ao! conte? TSC CBi Subchronic Inhalation Toxicity Study with DuPont HLR 696-92 APPENDIX C Individual Body Weights of Male Rats Note: All weights are reported in grams. SD = Rats sacrificed after the tenth exposure for pathological examination. Cprmsrv f3n>f'7d. R o p " unf eonfgiri T S C OB - 40 - Subchronic Inhalation Toxicity Study with DuPont HLR 696-92 Appendix C Individual Body Weights of Control Male Rats Group I Rat No. 1 447112 447113 447114 447115 447116 447117 447118 447119 447120 447121 231.9 237.2 245.3 226.9 228.2 235.9 244.1 218.9 229.8 236.2 Days on Test 2 3 4 5 8 9 10 235.1 234.3 259.8 220.9 233.6 244.0 256.6 231.9 234.3 232.5 222.2 242.2 268.0 232.2 239.4 248.1 259.0 239.9 239.6 244.4 228.2 241.0 277.0 244.2 248.7 257.0 262.8 246.1 249.7 252.5 245.1 247.1 284.4 248.4 254.1 259.9 273.5 251.0 253.6 249.2 276.9 275.8 311.3 277.5 283.3 292.2 301.4 284.7 280.1 279.0 278.0 276.9 314.1 287.8 284.7 297.6 308.2 292.4 288.0 282.6 281.7 284.9 324.9 293.9 292.5 303.2 309.9 291.4 297.1 294.1 Rat No. 11 447112 447113 447114 447115 447116 447117 447118 447119 447120 447121 289.4 294.0 337.2 296.4 293.0 313.0 319.4 303.3 308.2 300.2 Pay3 on Test 12 15 16 . 17 18 19 22 299.4 307.6 314.0 304.9 322.7 325.3 329.3 SD (day 12) 303.3 324.8 324.8 296.6 SD (day 12) 312.5 SD (day 12) 315.1 SD (day 12) 297.1 318.7 324.2 306.6 322.7 329.9 296.2 SD (day 12) 319.1 338.1 339.8 333.7 339.6 329.5 342.8 345.8 336.0 347.3 337.4 348.9 351.8 347.1 353.5 357.8 371.1 376.9 374.2 368.8 C o m p a n y Sanitized. D o e s not contain T S C A CB\ - 41 - m Subchronic Inhalation Toxicity Study with DuPont HLR 696-92 Appendix C (continued) Individual Body Weights of Control Male Rats Group I (continued) Rat No. 447112 447113 447114 447115 447116 447117 447118 447119 447120 447121 23 364.1 376.3 392.1 379.3 380.4 24 369.0 377.9 399.8 Days on Test 25 26 373.7 386.1 378.1 382.2 403.7 400.0 389.3 390.5 401.9 394.7 396.7 385.6 C o m p a n y Ssnliilgsd. B o s s no? contain T S C A CBi - 42 Subchronic Inhalation Toxicity Study wit DuPont HLR 696-92 Appendix C (continued) Individual Body Weights of Male R a ts Exposed to 1 m g / m ^ p Group III Rat No. 447122 447123 44/124 447125 44/126 447127 447128 447129 447130 447131 1 240.6 221.1 229.4 236.6 241.2 217.0 232.7 233.8 247.1 224.7 2 243.4 228.3 234.9 237.8 242.0 221.0 231.8 236.1 253.9 223.1 Days on Test 345 249.8 239.0 243.7 241.2 248.5 230.6 232.0 247.2 261.8 235.1 250.6 245.0 250.6 248.2 251.5 235.0 234.5 245.5 276.2 241.9 260.3 248.6 250.4 254.2 269.1 245.0 247.7 259.4 281.3 244.6 8 285.3 279.4 284.2 282.5 286.4 265.6 278.0 280.3 316.8 273.2 9 290.9 281.5 288.3 284.4 283.5 272.5 284.0 283.9 319.9 277.7 10 289.9 284.4 294.2 286.2 288.6 278.7 291.5 294.1 334.0 283.0 Rat No. 447122 447123 447124 447125 447126 447127 447128 447129 447130 447131 11 296.8 288.8 302.5 291.2 292.2 282.1 289.3 292.6 335.0 287.3 Days on Test 12 15 16 270.3 SD (day 12) 280.7 SD (day 12) 305.8 325.4 328.4 295.9 SD (day 12) 292.3 315.6 321.5 265.7 294.5 308.0 297.9 SD (day 12) 296.6 SD (day 12) 337.4 366.6 367.6 262.5 293.7 301.8 17 340.4 330.3 310.5 382.0 312.3 18 340.4 336.5 314.5 392.5 312.5 19 354.2 349.3 328.5 400.0 322.6 22 373.0 363.3 349.1 423.9 344.1 a Design concentration. - 43 - C o m p a n y Sanitized. D o e s not contain T S C A CB! Subchronic Inhalation Toxicity Study with DuPont HLR 696-92 J Appendix C (continued) Individual Body Weights of Male Rat: Exposed to 1 mg / m J' Group III (continued) Rat No. 447122 447123 447124 447125 447126 447127 447128 447129 447130 447131 23 383.3 376.7 357.3 435.3 354.4 Days on Test 24 25 26 388.6 382.9 366.0 401.3 391.6 373.9 398.7 384.3 360.8 447.8 357.4 461.2 367.2 432.5 367.3 * Design concentration. Company Sanitized. Does not contain TSC CsS 44 - Subchronic Inhalation Toxicity Study with DuPont HLR 696-92 Group V Rat No. 447132 447133 447134 447135 447136 447137 447138 447139 447140 447141 Appendix C (continued) Individual Body Weigh of Male Rats Exposed to 5 mg / m 3 Days on Test 1 229.1 235.9 240.5 218.1 232.9 235.3 242.1 221.3 231.2 235.5 2 242.1 247.2 249.7 215.6 237.8 230.8 244.9 220.9 221.6 240.5 3 248.2 251.0 259.4 219.0 235.2 238.3 248.4 226.9 231.6 245.2 4 253.8 253.1 264.5 227.1 237.3 245.7 254.3 231.3 237.4 256.0 5 263.2 264.5 274.1 230.7 243.9 256.3 255.1 237.2 246.9 260.3 8 289.8 280.7 312.4 251.7 262.8 283.0 287.0 259.1 262.8 281.1 9 302.3 291.0 314.7 259.9 268.9 290.2 288.1 261.0 274.5 296.3 10 303.0 296.3 319.4 263.8 270.1 296.0 294.1 265.8 279.4 306.0 Rat No. 11 447132 447133 447134 447135 447136 447137 447138 447139 447140 447141 307.7 302.0 327.6 270.0 277.1 300.3 299.4 274.6 281.4 308.1 Days on Test 12 15 16 17 18 19 22 310.5 SD (day 12) 305.0 316.6 320.9 326.3 SD (day 12) 267.9 288.1 277.3 282.8 300.5 302.0 306.9 327.9 326.8 299.8 SD (day 12) 268.3 283.5 293.5 274.1 SD (day 12) 312.8 SD (day 12) 328.0 292.3 309.6 339.7 303.2 331.4 297.7 311.5 341.3 302.4 341.4 303.9 309.1 349.5 306.8 353.1 326.4 338.8 380.1 328.9 a Design concentration. C o m p a n y Sanitized. D o e s not contain T S C A CB! - 45 - Subchronic Inhalation Toxicity Study with DuPont HLR 696-92 Appendix C (continued) Individual Body Weights of Male Rats Exposed to 5 mg/m^j| Group V (continued) Rat No. 23 447132 447133 447134 447135 447136 447137 447138 447139 447140 447141 366.7 330.7 343.5 388.1 346.0 Days on Test 24 25 26 367.1 370.6 370.0 337.3 351.3 392.5 344.1 360.6 395.8 343.7 353.1 399.4 352.5 356.7 355.2 Design concentration. 'Sompsny SarmfeecL Oos: ornain T S C CB? - 46 - Subchronic Inhalation Toxicity Study with DuPont HLR 696-92 3 Group VII Appendix C (continued) Individual Body Weights of Male Rats Exposed to 10 m g / m ^ | Rat No. 1 447142 447143 447144 447145 447146 447147 447148 447149 447150 447151 243.5 224.5 230.1 238.9 240.9 224.7 231.7 236.2 243.0 216.9 2 256.1 214.0 233.7 248.4 241.2 227.3 230.3 232.8 252.4 218.5 Days on Test 345 262.9 226.3 238.4 253.0 250.3 234.5 240.5 242.7 262.4 222.6 265.7 231.1 251.2 265.3 255.7 242.3 247.4 249.4 263.8 228.5 270.1 237.3 252.7 265.7 263.7 247.3 250.5 253.3 266.7 229.2 8 303.6 255.5 287.8 296.2 296.4 272.7 277.7 283.7 293.2 258.5 9 313.0 260.5 295.1 301.6 298.5 274.7 277.9 285.1 299.0 262.1 10 314.5 265.6 297.6 306.3 305.1 282.5 283.1 291.0 304.4 265.3 Rat No. 447142 447143 447144 447145 447146 447147 447148 447149 447150 447151 11 321.3 273.8 302.2 307.6 311.6 289.3 285.3 292.6 306.4 267.5 Days on Test 12 15 16 17 319.4 345.0 273.6 287.8 295.7 SD (DAY 318.6 SD (DAY 307.7 336.3 294.8 SD (DAY 291.5 310.5 293.8 309.2 320.5 SD (DAY 274.9 SD (DAY 347.2 293.5 12) 12) 338.0 12) 312.1 313.1 12) 12) 359.1 302.5 350.7 320.0 322.6 18 366.0 308.6 362.7 326.4 322.8 19 370.8 316.3 367.5 337.5 333.3 22 391.6 330.9 391.0 357.3 348.7 a Design concentration. C o m p a n y Sanitized. D o e s not contain T S C A CB 47 Subchronic Inhalation Toxici ty Study with DuPont HLR 696-92 J Appendix C (continued) Individual Body Weights of Male Rats Exposed to 10 mg / m 3| Group VII (continued) Rat No. 23 447142 447143 447144 447145 447146 447147 447148 447149 447150 447151 407.1 341.0 402.9 365.1 358.3 Days on Test 24 25 26 412.9 345.5 412.2 348.6 397.8 333.2 412.8 374.6 363.9 415.3 380.7 368.8 392.6 383.9 368.1 Design concentration. Company Sanitized. Doss not eonfeln TSCa CBf 48 S u b c hronic In h a l a t i o n T o x i c i t y S t udy with. DuPont HLR 696-92 APPENDIX D Individual Clinical Observations of Male Rats Note: NR = Not Recovered. Rat exhibited given sign at last weighing. . Clinical observations do not include signs observed during or immediately following exposure. C o m p a n y Sanitized. D o e s not contain T S C A CBi - 49 Subchronic Inhalation Toxicity Study with/ DuPont HLR 696-92 3 Appendix D Individual Clinical Observations of Male Rats Rat No. Control 447112 Observation Slight red discharge, left eye Day First Observed 16 Day Last Observed 23 Design concentration: 1 mg/m3 447131 Slight black discharge, left eye Corneal opacity, left Eye 16 16 22 16 WJ C o m p a n y Sanitized. Oses not contain T 3 C C 3 - 50 - Subchronic Inhalation Toxicity Study wi DuPont HLR 696-92 APPENDIX E Clinical Pathology Report No. 10-89 C o m p a n y SanFfFzed. D e s s no* contain T S C c r j DuPont HLR 696-92 CLINICAL PATHOLOGY REPORT NO. 10-89 SUBCHRONIC INHALATION TOXICITY STUDY ifHni^BMHRfs MEDICAL RESEARCH PROJECT NO HASKELL LABORATORY NO. 17375 Sponsor: DuPont Specialty Chemicals -52- itognpan? Sanitized, c c a s not contain T S C C 8 / DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WITH N RATS Summary Male Crl:CD\BR rats were exposed by inhalation t o l ^ m i H V ^ t design concentrations of 0 (control) 1, 5, or 10 mg/m3 six hours per day for ten days. There were no biologically significant clinical laboratory findings which were attributable to exposure to the test material. Under the conditions of this study the no-observable-effect level in male rats was considered to be 10 mg/m3 for the hematologic, clinicalchemical, and urinalysis parameters measured. Prepared by: CuJf i x, -For Donna R. Holt Technician Report by: Michael C. Carakostas,/.V.M., Ph.D. Diplomate, A.C.V.P. . Coordinator, Clinical Pathology Approved by: William 'C. Krauss, D.V.M. Manager, Pathology Division Company Sanitized. Does ns! contain TSCA CBi -53- DuPont HLR 696-92 Procedure Four groups of ten male C r l : C D B R r a t ^ w e r ^ x p o s e d , by inhalation, for six hours per day for .ten days design concentrations of 0 (control), 1 (low), 5 (intermediate), or 10 (high) mg/m . After the tenth,exposure (12 DAYS ON TEST) blood was taken from the orbital sinus of each rat for enumeration of erythrocytes (RBC), leukocytes (WBC), and platelets (PLAT); analysis of hemoglobin concentration (Hb) and hematocrit (Ht); and determination of relative numbers of neutrophils (Neut), band neutrophils (Band), lymphocytes (Lymph), atypical lymphocytes (Alym), monocytes (Mono), eosinophils (Eosin), and basophils (Baso). Absolute values for the various types of leukocytes were calculated from the leukocytic data. Mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) were calculated from the erythrocytic data. Blood cell counts, hemoglobin concentration, and Wintrobe indices were determined on an Ortho model ELT-8ds hematology analyzer. Differential cell counts were determined on a Hematrak Automated Differential System cell counter. Serum activities of alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) and serum concentrations of urea nitrogen (BUN), creatinine (CREAT), total protein (TPROT), and cholesterol (CHOL) were measured on an Coulter DACOS clinical chemistry analyzer using Coulter DART reagents. One day prior to the 12--day bleeding time, an overnight (approximately 16--hour) urine specimen was collected from each rat to measure volume, (VOL), osmolality (OSMOL), urobilinogen (UROBL), and pH; and to determine the presence of hemoglobin or occult blood (BLOOD), glucose, protein, bilirubin, and ketone (acetoacetic acid). Osmolality was determined on a Micro Diagnostics model AO-- 10 osmometer. Urine biochemical constituents were measured manually using Ames Multistix urine chemistry dipsticks. Urine appearance (color and transparency) was recorded and the sediment from each specimen was microscopically examined. After the 12-day sampling time, five rats from each group were killed for pathologic evaluation. Following a 14-day recovery period (26 DAYS ON TEST), the hematologic and clinical chemical (serum and urine) measurements were repeated on the remaining five rats from each group. Statistical Analyses A one-way analysis of variance (ANOVA) and Bartlett's test were calculated for each sampling time. When the F-test from ANOVA was Cosn$s>ny Sanfffe Dee nf? confata TSCA CBI -54- DuPont HLR 696-92 significant, the Dunnett test was used t o c o m p a r ^ n e a n s from the control group and each of the groups exposed W 11611 the results of the Bartlett test were significant (p <^D.005), the Kruskal-Wallis test was employed and the Mann-Whitney U test was used t o c o m p a r ^ g a n s from the control group and each of the groups exposed Significance was judged at the 5% probability level. Results Statistically significant results are summarized in Table 1. Group means and standard deviations for hematologic (Table 2), clinical chemical (Table 3), and urinalysis (Table 4) data are presented after the Discussion and Conclusions. Data for individual animals are listed in Appendix A. -55- C o m p a n y Sanitized. D o e s not contain T S C A CBE DuPont HLR 696-92 Discussion and Conclusions A statistically significant decrease in mean urine volume and increase in mean urine osmolality were observed in all treatment groups. Biologically, the differences from the control group were small to moderate and of questionable biological significance. Additionally, they did not occur in a dose-related manner. These urinalysis findings suggest dehydration, but other indicators of hemoconcentration/dehydration (such as an increase in protein, urea nitrogen, and Ht) were not significantly different.from the control group. Therefore, the statistically significant urinalysis findings were considered unrelated to exposure to the test material and of equivocal significance biologically. After the 14-day recovery period there were no biologically significant clinical laboratory findings observed. Statistically significant clinical laboratory results listed in Clinical Pathology Text Table 1 and not specifically addressed above were considered within the range of expected biologic variation and unrelated to exposure to the test material. . Under the conditions of this stud^ the no-observable-effect level in male rats was considered to be 10 mg/m for the hematologic, clinical chemical and urinalysis parameters measured. DRH:bl CP 13.26 -56- Sanitized. Does not eonie'n TSCA OBI DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY WITH CLINICAL PATHOLOGY TEXT TABLE 1 SUMMARY OF STATISTICALLY SIGNIFICANT HEMATOLOGIC AND CLINICAL CHEMICAL FINDINGS FOR MALE RATS Sampling Time________________ 12 DAYS ON TEST______________ 26 DAYS ON TEST Measurement Hematology Lymph - 4- V Clinical Chemistry (Serum) CREAT TPROT CHOL - 4- VII 4- VII+ 4- III - -- Clinical Chemistry (Urine) VOL OSMOL 4- III,V,VII + III,V,VII - t = Significantly higher than controls by Dunnett or Mann-Whitney U (+) criteria 4- = Significantly lower than controls by Dunnett or Mann-Whitney U (+) criteria - = Not statistically significant 2 Group Designation and Concentration (mg/m ) III - Low (1) V - Intermediate (5) VII - High (10) Due to analytical and inter-animal variability, the number of animals per group, and other experimental design factors, statistical significance should not be interpreted as inferring biological or toxicological significance. See the discussion section for an interpretation of biologically significant results. -57- Imrf Barms, 2. 36S %cm DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WITH TABLE 2 SUMMARY OF HEMATOLOGIC FINDINGS FOR MALE RATS TESTS CONCENTRATION (m g / m ) SAMPLING TIME 12 DAYS 26 DAYS ON TEST ON TEST RBC, xlO/ul 0 7.03( 0.35)a 7.41 ( 0.34) 1 7.09 ( 0.38) 7.16( 0.30) 5 6.84( 0.32) 7.25( 0.32) 10 6.75( 0.19) 7.38 ( 0.34) Hb g/dl 0 14.6( 0.8) 1 15.1( 0.8) 5 14.7( 0.7) 10 14.4( 0.7) 15.0( 14.4( 15.0( 15.2( 0.9) 0.4) 0.7) 0.8) 0 4 9.( 2.) 50. ( 2.) Ht o. 1 4 9.( 2.) 4 9.( 1.) 5 4 8.( 2.) 50. ( 2.) 10 47 . ( 1.) 51. ( 2.) MCV fl 0 6 9 . ( 1.) 6 8 . ( 1.) 1 7 0 . ( 1.) 6 8 . ( 1.) 5 7 0 . ( 1.) 6 9 . ( 1,) 10 7 0 . ( 1.) 6 9 . ( 1.) 0 21. ( 1.) 20.( 1.) MCH 1 21.( 1.) 20. ( 1.) p g 5 22. ( 1.) 21.( 0.) 10 21.( 1.) 21.( 1.) MCHC g/dl 0 30.( 1.) 30.( 1.) 1 31.( 1.) 29.( 0.) 5 31.( 0.) 30. ( 0.) 10 31. ( 1.) 30.( 1.) PLAT XlO/ul 0 1144.( 326.) 1151.( 363. ) 1 1127.( 221.) 1028.( 258. ) 5 1115.( 261. ) 983. ( 161. ) 10 1146.( 246.) 843.( 74.) a Group means and standard deviations (SD) No statistically significant differences found at 5% level by Dunnett or Mann-Whitney U criteria -58- C o m p a n y Sanitized. D o e s not contain T S C A CSf DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WITH TABLE 2 (continued) SUMMARY OF HEMATOLOGIC FINDINGS FOR MALE RATS TESTS CONCENTRATION (mg/rn ) SAMPLING TIME 12 DAYS 26 DAYS ON TEST ON TEST WBC, xlO /ul 0 14.6( 1.6)a 15.0( 2.4) 1 14.3( 2.5) 14.3( 0.8) 5 14.4( 1.8) 12.8( 1.6) 10 12.7( 2.0) 12.3( 1.5) Neut WBCx% 0 2250.( 1004.) 2793.( 1431.) 1 2806.( 1404.) 3448.( 1390.) 5 2423.( 1085.) 3089.( 1186.) 10 2578.( 1000.) 2452.( 1017.) Band WBCx% 0 0.( o.) 0.( 0.) 1 0.( o.) 0.( 0.) 5 0.( 0.) o.< 0.) 10 0.( 0.) 0.( 0.) Lymph WBCx% 0 11499.( 1892.) 1 10856.( 1827.) 5 11081. ( 1769.) 10 9453. ( 1649.) 10753.( 1824.) 9943. ( 772. ) 8721.( 820.)* 8979.( 872. ) a Group means and standard deviations (SD) * Significantly different from control at 5% level by Dunnett criteria -59 ' C o m p a n y Sanitized. S e e s net contain T S C C S DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WITH TABLE 2 (continued) SUMMARY OF HEMATOLOGIC FINDINGS FOR MALE RATS TESTS Alym WBCx% Mono WBCx% Eosin WBCx% Baso WBCx% CONCENTRATION (mg/m ) SAMPLING TIME 12 :DAYS 26 !DAYS O N 'TEST ON 'TEST 0 147. ( 203.)a 38.( 85.) 1 103.( 229.) 0-( 0.) 5 136. ( 199.) 29. ( 65.) 10 172. ( 161.) 95.( 130.) 0 626. ( 409.) 1362.( 393.) 1 481. ( 301.) 889. ( 252.) 5 767. ( 383. ) 916. ( 311.) 10 432. ( 267.) 728. ( 526.) 0 58. ( 77.) 1 15.( 47.) 5 25.( 78.) 10 65.( 86.) 54. ( 0.( 66. ( 26. ( 73.) o.) 96.) 58.) 0 0.( 0.) 1 0.( 0.) 5 0.( 0.) 10 0.( 0.) 0.( 0.) 0.( 0.) 0.( 0.) 0.( 0.) a Group means and standard deviations(SD) No statistically significant differences found at 5% level by Dunnett or Mann-Whitney U criteria -60- Sanitized- D o e s not contain T S C A CBi Company H-17375 S DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WITH TABLE 3 SUMMARY OF CLINICAL CHEMICAL FINDINGS FOR MALE RATS TESTS ALP U/L ALT U/L AST U/L BUN mg/dl CREAT mg/dl TPROT g./dl CHOL mg/dl CONCENTRATION (mg/rti ) SAMPLING TIME 12 iDAYS 26 iDAYS ON 'TEST ON 1TEST 0 468. ( 9 7 . )a 466. ( 92.) 1 394. ( 85.) 391. ( 65.) 5 454. ( 18.) 494. ( 119. ) 10 428. ( 47.) 464. ( 101.) 0 45.( 6.) 41.( 5.) 1 53.( 23.) 38.( 7.) 5 56. ( 33.) 39. ( 6.) 10 51. ( 10.) 41.( 5.) 0 75.( 13.) 1 82. ( 29.) 5 77.( 41.) 10 72.( 9.) 66.( 66.( 61.( 70. ( 4.) 4.) 8.) 5.) 0 16. ( 2.) 17.( 2.) 1 19-( 4.) 15.( 3.) 5 16.( 2.) 19. ( 2.) 10 16.( 2.) 17.( 3.) 0 0.6( 0.1) 0.6 ( 0.0) 1 0.5( 0.1) 0.5( 0.1)* 5 0.5( 0.1) 0.6 ( 0.0) 10 0.5 ( 0.0) 0.6( 0.0) 0 6.0( 0.3) 6.5( 0.3) 1 6.2 ( 0.4) 6.2 ( 0.2) 5 5.8 ( 0.2) 6.3( 0.1) 10 5.6( 0.3)* 6.0( 0.2) 0 67.( 15.) 76. ( 16.) 1 55. ( 9.) 63.( 7.) 5 60.( 6.) 63.( 10.) 10 55.( 5.)# 62.( 14.) a Group means and standard deviations(SD) __ * Significantly different from control at 5% level by Dunnett criteria # Significantly different from control at 5% level by Mann-Whitney U criteria -61- H-17375 DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WI TABLE 4 SUMMARY OF CLINICAL URINALYSIS FINDINGS FOR MALE RATS TESTS CONCENTRATION (mg/nT) SAMPLING TIME 12 DAYS 26 DAYS ON TEST ON TEST 0 12.7( 3.0)a 13.9( 4.1) VOL 1 7.5( 2.2)* 18.4( 10.1) ml 5 8.7( 1.3)* 13.0( 3.2) 10 8.4( 2.0)* 14.3( 3.3) OSMOL mOs 0 1368.( 208.) 1506.( 407.) 1 1916.( 304.)* 1296.( 627.) 5 1783.( 198.)* 1558.( 316.) 10 1797.( 337.)* 1323.( 473. ) 0 7.4( 0.3) 7.4{ 0.4) PH 1 7.3( 0.4) 7.7( 0.3) 5 7.2( 0.4) 7.6( 0.2) 10 7.3( 0.4) 7.9( 0.2) UROBL mg/dl 0 0.1( 0.0) 1 0.1( 0.0) 5' 0.1( 0.0) 10 0.1( 0.0) 0.1( 0.0) 0.1( 0.0) o.i( 0.0) 0.1( 0.0) a Group means and standard deviations(SD) * Significantly different from control at 5% level by Dunnett criteria IX to -62- C o m p a n y Sanitized. D o e s not contain T S C A CBi DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WITH TABLE 4 (continued) SUMMARY OF CLINICAL URINALYSIS FINDINGS FOR MALE RATS Measurement Concentration (mg/in ) Blood Number Positive 0 1 5 10 Glucose Number Positive 0 1 5 10 Protein Number Abnormal >+ 3 0 1 5 10 Bilirubin Number Positive 0 1 5 10 Ketone Number Positive 0 1 5 10 Appearance (Color and Transparency) 0 1 5 10 Microscopic Number Abnormal 0 1 5 10 ___________ Sampling Time 12 DAYS ON TEST 26 DAYS ON TEST 1/10++ 2/10 1/10 2/10 3/5 1/5 0/5 1/5 0/10 0/10 0/10 0/10 0/5 0/5 0/5 1/5 0/10 0/10 0/10 0/10 0/5 0/5 0/5 0/5 0/10 .0/10 0/10 0/10 0/5 0/5 0/5 0/5 10/10 10/10 10/10 10/10 0/10 0/10 0/10 0/10 5/5 5/5 5/5 5/5 0/5 0/5 0/5 0/5 6/10 7/10 5/10 7/10 5/5 5/5 5/5 5/5 ++ Number of abnormal or positive findings/number of individual specimens examined V Company Sanitized. Sees no?containTSC Bl -63- I DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX A H-17375, -64- C o m p a n y Sanitized. D e e s no! contain T S C CBI DuPont HLR 696-92 APPENDIX A ~ EXPLANATORY NOTES TERMS AND CRITERIA USED IN URINALYSES Abbreviations for Descriptive Terms Normally Used for Gross Evaluation of Urine (other Abbreviations and Descriptive Terms may be used if they are more applicable) Y = Yellow LY = Light Yellow DY = Dark Yellow A = Amber DA = Dark Amber G = Green BL = Bloody R = Red" C = Clear CL = Cloudy P/PPT = Precipitate F = Feed FEC = Feces QNS = Quantity not sufficient Abbreviations for Descriptive Terms Used for Microscopic Evaluation of Urine TNTC Epith hpf lpf RBC WBC (99-99) = Epithelial Cells : = high power field = low power field = Red Blood Cells = White Blood Cells = Too Numerous to Count Definition of "Normal" and "Abnormal" Designations Used for Gross and Microscopic Appearance of Urine Appearance Color Microscopic Red Blood Cells Casts Normal Light to dark yellow or amber Average of 0 to 4 red blood cells per high power field None observed Abnormal Color other than yellow or amber Average of more than 4 red blood cells per high power field Average of more than 0 per low power field Epithelial Cells White Blood Cells Average of 0 to 9 per high power field Average of 0 to 9 per high power field Average of more than 9 per high power field Average of more than 9 per high power field -65- g o a p g n y Sanitizad. Does Pat contain fc GB DuPont BLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX A ANIMALS WITH MISSING CLINICAL DATA Animal Number 447150 Group Sampling Test(s) Designation_____ Time________ Omitted VII 12 DAYS Serum TPROT ON TEST Reason for Omission Invalid results-data not used -66- no! contain T S C CBi G o m p a n y Sanitized. D o e s SUBCHRONIC INHALATION TOXICITY STUDY WT DuPont HLR 696-92 0 APPENDIX A INDIVIDUAL HEMATOLOGIC FINDINGS FOR MALE RATS A T 12 DAYS ON TEST GROUP: I SAMPLE DATE: 10/28/88 RBC Hb ANIMAL#: 447112 447113 447114 447115 447116 447117 447118 447119 447120 447121 x l 0 6/ u l 7.13 6.84 6.29 6.97 6.93 6.86 7.23 7.12 7.50 7.45 g/dl 14.5 14.7 12.8 14.3 15.3 14.2 14.9 14.5 15.0 15.7 AVG. S. D. S. E. 7.03 0.35 0.11 14.6 0.8 0.2 Ht % 49. 48. 43. 48. 49. 47. 50. 49. 52. 52. 49. 2. 1. CONCENTRATION: 0 mg/m3 BIRTH DATE: 08/22/88 MCV MCH MCHC PLAT fl 68. 70. 69. 69. 70. 69. 69. 68. 69. 69. P9 20. 22. 20. 21. 22. 21. 21. 20. 20. 21. g/dl 30. 31. 30. 30. 31. 30. 30. 30. 29. 31. x l03/ul 680. 1102. 1031. 1300. 1484. 1599. 1500. 1026. 665. 1051. 69. 21. 30. 1144. 1. 1. 1. 326. 0. 0. 0. 103. GROUP: III SAMPLE DATE: 10/28/88 RBC Hb ANIMAL#: 447122 447123 447124 447125 447126 447127 447128 447129 447130 447131 x l 0 6/ u l 7.55 6.83 6.89 6.79 6.74 7.12 7.04 7.21 6.86 7.92 g/dl 16.7 14.6 15.0 15.2 14.4 14.9 14.8 15.4 14.0 16.3 AVG. S. D. S. E. 7.09 0.38 0.12 15.1 0.8 0.3 Ht % 53. 48. 49. 48. 47. 49. 49. 50. 47. 54. 49. 2. 1. CONCENTRATION: 1 mg/m BIRTH DATE: 08/22/88 MCV MCH MCHC PLAT fl 70. 70. 71. 71. 70. 69. 69. 70. 69. 68. pg 22. 21. 22. 22. 21. 21. 21. 21. 20. 21. g/dl 32. 31. 31. 32. 31. 30. 31. 31. 30. 30. x l03/ul 1020. 1547. 858. 1079. 971. 1295. 1389. 1154. 903. 1056. 70. 21. 31. 1127. 1. 1. 1. 221. 0. 0. 0. 70. -67- Gompany Sanitized. Does not contain T S C A CBI DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WI APPENDIX A (continued) INDIVIDUAL HEMATOLOGIC FINDINGS FOR MALE RATS AT 12 DAYS ON TEST GROUP: V SAMPLE DATE: 10/28/88 RBC Hb ANIMAL#: 447132 447133 447134 447135 447136 447137 447138 447139 447140 447141 x l06/ul 6.39 7.03 6.77 6.89 7.29 6.76 6.72 6.97 7.23 6.33 g/dl 13.7 15.0 14.7 14.7 15.9 14.9 13.8 15.3 15.1 14.0 AVG. S. D. S. E. 6.84 0.32 0.10 14.7 0.7 0.2 Ht % 45. 49. 47. 48. 51. 48. 45. 49. 50. 45. 48. 2. 1. CONCENTRATION: 5 mg/m3 BIRTH DATE: 08/22/88 MCV MCH MCHC PLAT fl 71. 70. 70. 70. 70. 70. 67. 70. 69. 72. pg 21. 21. 22. 21. 22. 22. 21. 22. 21. 22. g/dl 30. 31. 31. 31. 31. 31. 31. 31. 30. 31. x l 0 3/ul 1622. 1280. 941. 1351. 804. 1113. 797. 1036. 964. 1246. 70. 22. 31. 1115. 1. 1. 0. 261. 0. 0. 0. 83. GROUP: VII SAMPLE DATE: 10/28/88 RBC Hb ANIMAL#: 447142 447143 447144 447145 447146 447147 447148 447149 447150 447151 x l 0 6/ u l 6.88 6.63 6.73 7.12 6.75 6.62 6.63 6.86 6.83 6.43 g/dl 14.6 15.1 13.9 15.5 15.1 13.6 13.5 14.5 14.1 14.1 AVG. S. D. S. E. 6.75 0.19 0.06 14.4 0.7 0.2 CONCENTRATION: 10 mg/m3 BIRTH DATE: 08/22/88 Ht g*,6 48. 48. 46. 50. 48. 46. 46. 48. 47. 46. MCV fl 70. 72. 68. 70. 71. 69. 70. 69. 69. 71. MCH MCHC PLAT pg 21. 23. 21. 22. 22. 21. 20. 21. 21. 22. g/dl 30. 32. 30. 31. 32. 30. 29. 31. 30. 31. xl 0 3/ul 1422. 822. 1050. 920. 1138. 1359. 758. 1377. 1272. 1340. 47. 70. 21. 31. 1146. 1. 1. 1. 1. 246. 0. 0. 0. 0. 78. C o m p a n y Sanitized. D o e s no! contain T S C A CBF DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX A (continued) INDIVIDUAL HEMATOLOGIC FINDINGS FOR MALE RATS AT 12 DAYS ON TEST GROUP: I SAMPLE DATE: 10/28/88 CONCENTRATION: 0 mg/m3 BIRTH DATE: 08/22/88 me ANIMAL#: 447112 447113 447114 447115 447116 447117 447118 447119 447120 447121 x l 0 3/ul 17.1 14.8 11.5 15.6 12.9 13.8 15.7 14.1 15.5 14.8 AVG. S. D. S. E. 14.6 1.6 0.5 Neut Band WBCx% 2907. 2220. 3105. 3120. 1032. 2622. 1727. 3666. 620. 1480. WBCx% 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 2250. 1004. 317. 0. 0. 0. Lymph Alym Mono Eosin Baso WBCxI 12654. 11100. 7935. 12012. 11481. 10212. 12560. 9588. 14570. 12876. WBCxI 0. 296. 0. 312. 0. 552. 314. 0. 0. 0. WBCxI 1368. 1184. 345. 156. 387. 414. 942. 705. 310. 444. WBCxI 171. 0. 115. 0. 0. 0. 157. 141. 0. 0. WBCxI 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 11499. 1892. 598. 147. 203. 64. 626. 409. 129. 58. 77. 24. 0. 0. 0. GROUP: III SAMPLE DATE: 10/28/88 CONCENTRATION: 1 mq/m3 BIRTH DATE: 08/22/88 WBC ANIMAL#: 447122 447123 447124 447125 447126 447127 447128 447129 447130 447131 x l03/ul 16.3 14.2 15.5 11.8 10.6 16.8 16.7 10.4 15.4 14.9 AVG. S. D. S. E. 14.3 2.5 0.8 Neut Band WBCx% 2934. 2414. 2015. 1652. 530. 3192. 3507. 1976. 4620. 5215. WBCxI 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 2806. 1404. 444. 0. 0. 0. Lymph Alym Mono Eosin Baso WBCx% 12388. 11218. 12710. 9440. 9964. 12768. 12859. 7800. 10626. 8791. WBCxI 0. 0. 0. 354. 0. 672. 0. 0. 0. 0. WBCxI 978. 568. 775. 354. 106. 168. 334. 624. 154. 745. WBCxI 0. 0. 0. 0. 0. 0. 0. 0. 0. 149. WBCxI 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 10856. 1827. 578. 103. 229. 72. 481. 301. 95. 15. 47. 15. 0. 0. 0. -69- f H-17375 DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX A (continued) INDIVIDUAL HEMATOLOGIC FINDINGS FOR MALE RATS A T 12 DAYS ON TEST GROUP: V SAMPLE DATE: 10/28/88 CONCENTRATION: 5 mg/m3 BIRTH DATE: 08/22/88 WBC ANIMAL#: 447132 447133 447134 447135 447136 447137 447138 447139 447140 447141 xl03/ul 13.3 14.1 . 15.4 12.0 12.3 16.3 17.0 12.8 16.7 14.4 AVG. S. D. S. E. 14.4 1.8 0.6 Neut Band WBCx% 798. 2538. 2464. 1800. 1968. 3260. 4590. 2816. 2839. 1152. WBCxI 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 2423. 1085. 343. 0. 0. 0. Lymph Alym Mono Eosin Baso WBCxI 11704. 10716. 12012. 8640. 8856. 12388. 11730. 8704. 13527. 12528. WBCxI 133. 423. 0. 0. 0. 0. 0. 512. 0. 288. WBCxI 665. 423. 924. 1560. 1230. 652. 680. 768. 334. 432. WBCxI 0. 0. 0. 0. 246. 0. 0. 0. 0. 0. WBCxI 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 11081. 1769. 559. 136. 199. 63. 767. 383. 121. 25. 78. 25. 0. 0. 0. GROUP: VII SAMPLE DATE : 10/28/88 CONCENTRATION : 10 mg/m3 BIRTH DATE: 08/22/88 WBC Neut Band Lymph Alym Mono Eosin Baso ANIMAL#: 447142 447143 447144 447145 447146 447147 447148 447149 447150 447151 x l03/ul 10.7 13.9 11.9 16.1 9.8 13.2 10.6 12.3 15.0 13.5 WBCxI 2461. 3475. 1190. 4347. 1470. 3564. 2014. 2337. 1950. 2970. WBCxI 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. WBCxI 7490. 10008. 10353. 11109. 7742. 8712. 7950. 9102. 12750. 9315. WBCxI 214. 0. 238. 0. 196. 0. 0. 369. 300. 405. WBCx! 321. 278. 119. 483. 392. 792. 636. 492. 0. 810. WBCxI 214. 139. 0. 161. 0. 132. 0. 0. 0. 0. WBCxI 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. AVG. S. D. S. E. 12.7 2.0 0.6 2578. 1000. 316. 0. 0. 0. 9453. 1649. 521. 172. 161. 51. 432. 267. 84. 65. 86. 27. 0. 0. 0. 70 Company SanfzeS. Doss m i confaFn TSCA CQf DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX A (continued) INDIVIDUAL CLINICAL CHEMICAL FINDINGS FOR MALE RATS AT 12 DAYS ON TEST GROUP: I SAMPLE DATE: 10/28/88 ALP ALT ANIMAL# : 447112 447113 447114 447115 447116 447117 447118 447119 447120 447121 U/L 457. 539. 425. 539. 630. 353. 526. 410. 492. 307. AVG. 468. S. D. . 97. S. E. 31. U/L 51. 43. 48. 43. 48. 53. 51. 39. 37. 40. 45. 6. 2. CONCENTRATION: 0 mg/m3 BIRTH DATE: 08/22/88 AST BUN CREAT TPROT CHOL U/L 69. 67. 72. 68. 75. 100. 74. 67. 95. 60. mg/dl 21. 16. 15. 15. 14. 15. 17. 15. 16. 14. mg/dl 0.5 0.5 0.6 0.5 0.5 0.6 0.6 0.5 0.6 0.6 g/dl 6.1 5.8 6.4 5.7 5.4 5.8 6.3 6.0 6.1 6.1 mg/dl 72. 61. 56. 64. 50. 79. 73. 61. 101. 56. 75. 16. 0.6 6.0 67. 13. 2. 0.1 0.3 15. 4. 1. 0.0 0.1 5. GROUP: III SAMPLE DATE: 10/28/88 ALP ANIMAL#: 447122 447123 447124 447125 447126 447127 447128 447129 447130 447131 U/L 307. 413. 396. 457. 536. 326. 394. 471. 395. 242. ALT U/L 28. 37. 66. 42. 41. 30. 48. 68. 106. 61. AVG. S. D. S. E. 394. 85. 27. 53. 23. 7. CONCENTRATION: 1 mg/m3 BIRTH DATE: 08/22/88 AST BUN CREAT TPROT CHOL U/L 57. 56. 97. 64. 68. 65. 65. 100. 149. 96. mg/dl 21. 16. 15. 20. 13. 24. 15. 19. 16. 27. mg/dl 0.6 0.6 0.4 0.5 0.5 0.5 0.5 0.5 0.5 0.6 g/di 6.4 5.9 6.0 6.3 5.8 6.1 6.3 6.1 5.7 7.0 mg/dl 37. 64. 58. 61. 44. 66. 55. 53. 60. 52. 82. 19. 0.5 6.2 55. 29. 4. 0.1 0.4 9. 9. 1. 0.0 0.1 3. C o m p a n y Sanitized. D o e s not contain T S C A CBS DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WI APPENDIX A (continued) INDIVIDUAL CLINICAL CHEMICAL FINDINGS FOR MALE RATS A T 12 DAYS ON TEST GROUP: V SAMPLE DATE: 10/28/88 CONCENTRATION: 5 mg/m3 BIRTH DATE: 08/22/88 ALP ALT AST BUN CREAT TPROT CHOL ANIMAL#: 447132 447133 447134 447135 447136 447137 447138 447139 447140 447141 U/L 641. 498. 607. 495. 460. 317. 357. 409. 374. 377. U/L 40. 37. 147. 55. 40. 57. 53. 34. 41. 51. U/L 55. 67. 193. 60. 58. 67. 72. 56. 65. 75. mg/d-1 13. 15. 17. 18. 17. 17. 14. 15. 16. 16. mg/dl 0.5 0.6 0.6 0.5 0.6 0.6 0.5 0.5 0.5 0.5-. g/dl 5.8 5.8 5.7 5.9 6.2 5.7 5.9 6.0 5.7 5.8 mg/dl 63. 55. 59. 51. 52. 67. 60. 69. 62. 60. AVG. S. D. S. E. 454. 108. 34. 56. 77. 16. 0.5 5.8 60. 33. 41. 2. 0.1 0.2 6. 10. 13-, 0. 0.0 0.1 2. GROUP: VII SAMPLE DATE: 10/28/88 ALP ALT ANIMAL#: 447142 447143 447144 447145 447146 447147 447148 447149 447150 447151 U/L 434. 506. 418. 386. 466. 457. 417. 439. 330. 427. U/L 46. 66. 48. 48. 46. 48. 47. 61. 34. 63. AVG. S. D. S. E. 428. 47. 15. 51. 10. 3. CONCENTRATION: 10 mg/m3 BIRTH DATE: 08/22/88 AST BUN CREAT TPROT CHOL U/L 69. 82. 84. 67. 72. 64. 72. 79. 55. 73. mg/dl 17. 17. 15. 16. 17. 15. 12. 16. 17. 16. mg/dl 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.4 0.6 0.5 g/dl 5.8 5.7 5.3 6.1 5.7 5.2 5.5 5.8 5.7 mg/dl 61. 60. 50. 50. 49. 57. 55. 58. 58. 50. 72. 16. 0.5 5.6 55. q. 2. 0.0 0.3 5. 3. 0. 0.0 0.1 1. -72- ompany oaiimz&sg. Soea m i contai?. est H-17375 DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX A (continued) INDIVIDUAL CLINICAL URINALYSIS FINDINGS FOR MALE RATS . AT 12 DAYS ON TEST GROUP: I SAMPLE DATE: 10/28/88 CONCENTRATION: 0 mg/m3 BIRTH DATE: 08/22/88 ANIMAL#: 447112 447113 447114 447115 447116 447117 447118 447119 447120 447121 VOL ml 15.0 10.0 16.0 10.0 18.0 15.0 11.0 11.0 11.0 10.0 OSMOL mOs 1280. 1553. 1220. 1554. 969. 1159. 1579. 1358. 1445. 1558. BLOOD + -- -- -- -- -- - - GLUCOSE -- -- _ -- -- -- -- -- - PROTEIN +1 +2 + +i +i + +i +2 +1 +2 AVG. S. D. S. E. 12.7 3.0 0.9 1368. 208. 66. pH 7.5 7.5 7.5 7.5 8.0 7.5 7.0 7.0 7.0 7.5 BILI-- RUBIN __ __ _ _ _ _ _ _ - UROBL mg/dl Q;1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Ketone + + + +1 + + -f + + + 7.4 0.1 0.3 0.0 0.1 0.0 GROUP: III SAMPLE DATE: 10/28/88 CONCENTRATION: 1 mg/m3 BIRTH DATE: 08/22/88 ANIMAL#: 447122 447123 447124 447125 447126 447127 447128 447129 447130 447131 VOL ml 6.0 5.2 8.0 6.5 11.0 5.2 8.0 10.0 10.0 5.0 OSMOL mOs 2035. 2278. 1889. 2017. 1475. 2094. 1775. 1419. 1844. 2338. BLOOD - + -- _ + - - GLUCOSE -- - PRO TEIN +2 +2 +2 +2 +1 +2 +2 +2 +2 +2 AVG. S. D. S. E. 7.5 2.2 0.7 1916. 304. 96. pH 7.0 6.5 8.0 7.5 7.5 7.5 7.5 7.0 7.0 7.0 BILI RUBIN _ _ _ _ _ _ _ - UROBL mg/dl 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Ke tone + + + + 4* + + + +1 + 7.3 0.1 0.4 0.0 0.1 0.0 -73- C o m p a n y Sanitized. D o e s not contain T S C A CB? H-17375 DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WI APPENDIX A (continued) INDIVIDUAL CLINICAL URINALYSIS FINDINGS FOR MALE RATS . A T 12 DAYS ON TEST GROUP: V SAMPLE DATE: 10/28/88 CONCENTRATION: 5 mg/ra3 BIRTH DATE: 08/22/88 ANIMAL#: 447132 447133 447134 447135 447136 447137 447138 447139 447140 447141 VOL ml 11.0 7.0 10.0 9.0 8.0 8.0 10.0 7.0 9.0 8.0 OSMOL mOs 1464. 1778. 1523. 1743. 1971. 2001. 1865. 2057. 1784. 1646. BLOOD - -- -' -- -- + -- - GLUCOSE -- -- -- - - - - PRO TEIN +1 +1 +1 +2 +2 +2 +2 +2 +1 +1 pH 7.5 7.0 8.0 7.0 7.5 7.0 7.0 7.5 6.5 7.0 BILI RUBIN - -- -- _ - - - - - - UROBL mg/dl 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Ke tone + + + + +1 + + + + +1 AVG. S. D. S. E. 8.7 1783. 1.3 198. 0.4 63. 7.2 0.1 0.4 0.0 0.1 0.0 GROUP: VII SAMPLE DATE: 10/28/88 CONCENTRATION : 10 mg/m BIRTH DATE: 08/22/88 ANIMAL#: 447142 447143 447144 447145 447146 447147 447148 447149 447150 447151 VOL ml 5.0 6.0 10.0 9.0 9.0 11.0 6.6 7.8 10.0 10.0 OSMOL mOs 2403. 2261. 1484. 1641. 1639. 1303. 2025. 1871. 1705. 1561. BLOOD -- -- -- - + - + GLUCOSE -- -- -- -- -- -- - - PRO TEIN +2 +2 +1 +2 +2 +2 +2 +2 +1 +2 pH 6.5 7.0 7.5 7.0 7.5 7.5 7.5 8.0 7.0 7.5 BILI RUBIN - - - UROBL mg/dl 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Ketone + + + + + + + + + + AVG. S. D. S. E. 8.4 1797. 2.0 337. 0.6 107. 7.3 0.1 0.4 0.0 0.1 0.0 -74- C o m p a n y San i z e d D e s s contain iSCtk c \ SUBCHRONIC INHALATION TOXICITY STUDY WITH DuPont HLR 696-92 APPENDIX A (continued) INDIVIDUAL CLINICAL URINALYSIS FINDINGS FOR MALE RATS A T 12 DAYS ON TEST GROUP: I SAMPLE DATE: 10/28/88 CONCENTRATION: 0 mg/m3 BIRTH DATE: 08/22/88 ANIMAL#: 447112 447113 447114 447115 447116 447117 447118 447119 447120 447121 RBC /hpf 0-2 15-20 1-2 2-3 8-10 6-8 5-6 2-3 5-6 6-8 WBC /hpf 1-2 0-2 0-1 0-1 0-1 0-1 1-2 0-1 2-3 1-2 Epith /hpf 2-3 3-4 1-2 1-2 4-5 3-4 2-3 1-2 1-2 1-2 Cast /lpf 0-0 0-0 0-0 0-0 0-0 0-0 0-1 0-0 0-0 0-0 APPEARANCE DY CL PPT FEED FECES LY CL PPT FEED LY CL PPT FEED Y CL PPT LY CL PPT FEED Y CL PPT Y CL PPT Y CL PPT FECES Y CL PPT Y CL PPT FEED GROUP: III SAMPLE DATE: 10/28/88 CONCENTRATION: 1 mg/m BIRTH DATE: 08/22/88 ANIMAL#: 447122 447123 447124 447125 447126 447127 447128 447129 447130 447131 RBC /hpf 6-8 3-4 1-2 6-8 2-3 4-5 5-6 3-4 5-6 8-10 WBC /hpf 0-2 0-0 0-1 0-2 0-0 0-2 0-1 0-0 1-2 1-2 Epith /hpf 1-2 0-2 2-3 3-4 0-1 1-2 4-5 4-5 3-4 4-5 Cast /lpf 0-0 0-0 0-0 0-0 0-1 0-0 0-0 0-0 0-0 0-0 APPEARANCE LY CL PPT FEED Y CL PPT FEED DY CL PPT FEED Y CL PPT Y CL PPT Y CL PPT Y CL PPT FEED LY CL PPT FEED Y CL PPT FEED FECES Y CL PPT -75- Gorr m a n v S a n d e d . 0 ^ nsi T S C A C.nf DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WITH, APPENDIX A (continued) INDIVIDUAL CLINICAL URINALYSIS FINDINGS FOR MALE RATS . AT 12 DAYS ON TEST GROUP: V SAMPLE DATE: 10/28/88 CONCENTRATION: 5 mg/m3 BIRTH DATE: 08/22/88 ANIMAL#: 447132 447133 447134 447135 447136 447137 447138 447139 447140 447141 RBC /hpf 4-5 3-4 1-2 6-8 8-10 3-4 4-6 4-6 2-3 3-4 WBC /hpf 8-10 3-4 4-6 4-6 8-10 4-6 4-6 6-8 2-3 4-6 Epith /hpf 0-1 0-0 0-0 0-0 0-1 0-0 0-0 0-1 0-0 0-0 Cast /lpf 0-0 0-0 0-0 0-0 0-0 0-0 0-0 0-0 0-0 0-0 APPEARANCE Y CL PPT Y CL PPT Y CL PPT Y CL PPT Y CL PPT Y CL PPT Y CL PPT DY CL PPT FEED Y CL PPT Y CL PPT GROUP: VII SAMPLE DATE: 10/28/88 CONCENTRATION: 10 mg/m3 BIRTH DATE: 08/22/88 ANIMAL#: 447142 447143 447144 447145 447146 447147 447148 447149 447150 447151 RBC /hpf 3-4 3-4 10-15 8-10 8-10 4-6 3-4 6-8 3-4 5-6 me /hpf 4-6 4-6 8-10 12-14 8-10 16-18 6-8 6-8 3-4 6-8 Epith /hpf 0-1 0-0 1-2 2-3 0-0 2-3 1-2 0-0 0-0 0-1 Cast /lpf 0-0 0-0 0-0 0-0 0-0 0-0 0-0 0-0 0-1 0-0 APPEARANCE Y CL PPT Y CL PPT LY CL PPT Y CL PPT Y CL PPT Y CL PPT FEED Y CL PPT FEED DY CL PPT FEED FECES Y CL PPT Y CL PPT FEED 4 'Gompsny SaizedL B e ss neS eenfaFn TS CBF DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY APPENDIX A INDIVIDUAL HEMATOLOGIC FINDINGS FOR MALE RATS AT 26 DAYS ON TEST GROUP: I SAMPLE DATE: 11/11/88 RBC Hb ANIMAL#-: 447112 447113 447115 447119 447120 x l 0 6/ u l 7.08 7.37 7.09 7.69 7.81 g/dl 14.4 15.2 13.9 15.1 16.3 AVG. S. D. S. E. 7.41 0.34 0.15 15.0 0.9 0.4 Ht Q*.5 48. 51. 49. 51. 54. 50. 2. 1. CONCENTRATION: 0 mg/m3 BIRTH DATE: 08/22/88 MCV MCH MCHC PLAT fl 67. 69. 68. 67. 69. P9 20. 21. 20. 20. 21. g/dl 30. 30. 29. 29. 30. x l03/l 1089. 1385. 1645. 869. 769. 68. 20. 30. 1151. 1. 1. 1. 363. 0. 0. 0. 162. GROUP: III SAMPLE DATE : 11/11/88 RBC .Hb ANIMAL#: 447124 447126 447127 447130 447131 x l 0 6/ u l 6.96 6.84 7.12 7.28 7.61 g/dl 14.4 14.1 13.9 14.6 15.0 AVG. S. D. S. E. 7.16 0.30 0.13 14.4 0.4 0.2 CONCENTRATION: 1 mg/rn BIRTH DATE: 08/22/88 Ht O'.O 49. 47. 48. 49. 51. MCV fl 70. 69. 68. 67. 67. MCH MCHC PLAT pg 21. 21. 20. 20. 20. g/dl 29. 30. 29. 30. 29. x l03/ul 872. 910. 1412. 1166. 782. 49. 68. 20. 29. 1028. 1. 1. 1. 0. 258. 1. 1. 0. 0. 115. -77- Comsany San^sc. Boas nnf ennSafr TSf?& SUBCHRONIC INHALATION TOXICITY STUDY WITH DuPont HLR 696-92 APPENDIX A (continued) INDIVIDUAL HEMATOLOGIC FINDINGS FOR MALE RATS AT 26 DAYS ON TEST GROUP: V SAMPLE DATE: 11/11/88 RBC Hb ANIMAL#: 447133 447135 447136 447137 447139 x l06/ul 7.55 6.83 7.44 7.44 6.97 AVG. S. D. S. E. 7.25 0.32 0.14 g/di 15.6 14.2 15.4 15.6 14.3 15.0 0.7 0.3 Ht oo. 52. 48. 52. 52. 49. 50. 2. 1. CONCENTRATION: 5 mg/m3 BIRTH DATE: 08/22/88 MCV MCH MCHC PLAT fl 68. 70. 69. 69. 70. pg 21. 21. 21. 21. 21. g/di 30. 30. 30. 30. 29. x l 0 3/ul 830. 1105. 793. 1143. 1042. 69. 21. 30. 1. 0. 0. 0. 0. 0. 983. 161. 72. GROUP: VII SAMPLE DATE: 11/11/88 RBC Hb ANIMAL#: 447142 447143 447146 447148 447149 x l 0 6/ u l 7.59 7.26 7.25 6.96 7.84 g/di 15.3 16.0 15.2 13.9 15.7 AVG. S. D. S. E. 7.38 0.34 0.15 15.2 0.8 0.4 Ht o',o 52. 52. 51. 48. 54. 51. 2. 1. CONCENTRATION: 10 mg/in BIRTH DATE: 08/22/88 MCV MCH MCHC PLAT fl 68. 71. 70. 69. 68. pg 20. 22. 21. 20. 20. g/di 30. 31. 30. 29. 29. x l03/ul 723. 817. 889. 896. 888. 69. 21. 30. 1. 1. 1. 1. 0. 0. 843. 74. 33. # mny SsriMssd. Pees r eenian t SC CBli -78- H-17375 DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY APPENDIX A (continued) INDIVIDUAL HEMATOLOGIC FINDINGS FOR MALE RATS AT 26 DAYS ON TEST GROUP: I SAMPLE DATE: 11/11/88 WBC ANIMAL#: 447112 447113 447115 447119 447120 xl 0 3/ul 13.3 13.5 13.8 15.4 19.0 AVG. S. D. S. E. 15.0 2.4 1.1 ,3 CONCENTRATION: 0 mg/m BIRTH DATE: 08/22/88 Neut Band Lymph Alym Mono Eosin Baso WBCx% 3857. 1080. 1380. 3850. 3800. WBCx% 0. 0. 0. 0. 0. WBCx% 8379. 10935. 10488. 10472. 13490. WBCx% 0. 0. 0. 0. 190. WBCx% 931. 1350. 1932. 1078. 1520. WBCx% 133. 135. 0. 0. 0. WBCx% 0. 0. 0. 0. 0. 2793. 1431. 640. 0. 0. 0. 10753. 1824. 816. 38. 1362. 85. 393. 38. 176. 54. 73. 33. 0. 0. 0. GROUP: III SAMPLE DATE: 11/11/88 WBC ANIMAL#: 447124 447126 447127 447130 447131 x l 0 3/ul 13.8 13.6 14.3 14.1 15.6 AVG. S. D. S. E. 14.3 0.8 0.4 3 CONCENTRATION : 1 mg/m BIRTH DATE: 08/22/88 Neut Band Lymph Alym Mono Eosin Baso WBCx% 2898. 2176. 3575. 2820. 5772. WBCx% 0. 0. 0. 0. 0. WBCx% 9936. 10880. 10010. 10152. 8736. WBCx% 0. 0. 0. 0. 0. WBCx% 966. 544. 715. 1128. 1092. WBCx% 0. 0. 0. 0. 0. WBCx% 0. 0. 0. 0. 0. 3448. 1390. 622. 0. 0. 0. 9943. 0. 889. 0. 0. 772. 0. 252. 0. 0. 345. 0. 113. 0. 0. 79- DuPont H LR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX A (continued) INDIVIDUAL HEMATOLOGIC FINDINGS FOR MALE RATS A T 26 DAYS ON TEST GROUP: V SAMPLE DATE: 11/11/88 CONCENTRATION: 5 mg/m3 BIRTH DATE: 08/22/88 WBC Neut Band Lymph Alym Mono Eos in Baso ANIMAL#: 447133 447135 447136 447137 447139 x l 0 3/ u l 10.6 11.6 13.6 14.5 13.8 WBCx% 1590. 2320. 4488. 3045. 4002. WBCx% 0. 0. 0. 0. 0. WBCx% 8056. 8004. 8568. 10005. 8970. WBCx% 0. 0. 0. 145. 0. WBCx% 742. 1160. 544. 1305. 828. WBCx% 212. 116. 0. 0. 0. WBCx% 0. 0. 0. 0. 0. AVG. S. D. S. E. 12.8 1.6 0.7 3089. 1186. 531. 0. 0. 0. 8721. 820. 367. 29. 916. 65. 311. 29. 139. 66. 96. 43. 0. 0. 0. GROUP: VII SAMPLE DATE: 11/11/88 CONCENTRATION : 10 mg/m3 BIRTH DATE: 08/22/88 WBC Neut Band Lymph Alym Mono Eos in Baso ANIMAL#: 447142 447143 447146 447148 447149 x l 0 3/ u l 12.9 14.5 11.9 11.8 10.3 WBCx% 2838. 3770. 2618. 2006. 1030. WBCx% 0. 0. 0. 0. 0. WBCx% 9159. 10005. 8568. 9440. 7725. WBCx% 0. 0. 238. 236. 0. WBCx% 774. 725. 476. 118. 1545. WBCx% 129. 0. 0. 0. 0. WBCx% 0. 0. 0. 0. 0. AVG. S. D. S. E. 12.3 1.5 0.7 2452. 1017. 455. 0. 0. 0. 8979. 872. 390. 95. 130. 58. 728. 526. 235. 26. 58. 26. 0. 0. 0. -80- Camp'aWy Sanitized. Does not contain (SC CBS ]H - 1 7 3 7 5 DuPont H LR 696-92 !S U B C H R O N I C I N H A L A T I O N T O X I C I T Y S T U D Y W I T H APPENDIX A (continued) INDIVIDUAL CLINICAL CHEMICAL FINDINGS FOR MALE RATS . A T 26 DAYS ON TEST GROUP: I SAMPLE DATE: 11/11/88 ALP ALT ANIMAL#: 447112 447113 447115 447119 447120 U/L 384. 530. 590. 446. 382. U/L 46. 41. 42. 42. 33. AVG. S. D. S. E. 466. 92. 41. 41. 5. 2. CONCENTRATION: 0 mg/m3 BIRTH DATE: 08/22/88 AST BUN CREAT TPROT CHOL U/L 63. 68. 62. 66. 71. mg/dl 18. 16. 17. 20. 16. mg/dl 0.7 0.6 0.6 0.6 0.6 g/dl 6.4 6.6 6.3 6.9 6.1 mg/dl 69. 59. 72. 79. 102. 66. 17. 0.6 6.5 76. 4. 2. 0.0 0.3 16. 2. 1. 0.0 0.1 7. GROUP: III SAMPLE DATE: 11/11/88 ALP ALT ANIMAL#: 447124 447126 447127 447130 447131 U/L 414. 490. 360. 319. 371. U/L 35. 35. 31. 41. 48. AVG. S. D. S. E. 391. 65. 29. 38. 7. 3. CONCENTRATION: 1 mg/m3 BIRTH DATE: 08/22/88 AST BUN CREAT TPROT CHOL U/L mg/dl mg/dl 65. 16. 0.6 70. 13. 0.5 65. 15. 0.5 70. 13. 0.5 62. 20. 0.6 g/dl 6.4 6.0 6.0 6.3 6.5 mg/dl 63. 53. 70. 69. 62. 66. 15. 0.5 6.2 63. 4. 3. 0.1 0.2 7. 2. 1. 0.0 0.1 3. %/^npai^f s a n fe s i. pass rsf contain VSC CBS -81- DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY APPENDIX A (continued) INDIVIDUAL CLINICAL CHEMICAL FINDINGS FOR MALE RATS . AT 26 DAYS ON TEST GROUP: V SAMPLE DATE: 11/11/88 ALP ALT ANIMAL#: 447133 447135 447136 447137 447139 U/L 583. 617. 404. 337. 528. U/L 37. 48. 34. 44. 34. AVG. S. D. S. E. 494. 119. 53. 39. 6. 3. CONCENTRATION: 5 mg/m3 BIRTH DATE: 08/22/88 AST BUN CREAT TPROT CHOL U/L 75. 61. 56. 58. 54. mg/dl 16. 22. 17. 20. 19. mg/dl 0.6 0.6 0.6 0.6 0.6 g/dl 6.4 6.3 6.1 6.4 6.2 mg/dl 59. 61. 50. 78. 66. 61. 19. 0.6 6.3 63. 8. 2. 0.0 0.1 10. 4. 1. 0.0 0.1 5.' GROUP: VII SAMPLE DATE: 11/11/88 CONCENTRATION: 10 mg/m3 BIRTH DATE: 08/22/88 ALP ALT AST BUN CREAT TPROT CHOL ANIMAL#: 447142 447143 447146 447148 447149 U/L 371. 526. 360. 466. 595. U/L 36. 43. 38. 39. 49. U/L 67. 76. 72. 63. 71. mg/dl 15. 21. 15. 18. 16. mg/dl 0.6 0.6 0.6 0.6 0.6 g/di 6.0 6.0 6.0 5.9 6.3 mg/dl 68. 67. 41. 57. 78. AVG. S. D. S. E. 464. 101. 45. 41. 70. 17. 0.6 6.0 62. 5. 5. 3. 0.0 0.2 14. 2. 2. 1. 0.0 0.1 6. Company Sanitized. D o e s not contain T S C CB1 -82 H-17375 DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WI APPENDIX A (continued) INDIVIDUAL CLINICAL URINALYSIS FINDINGS FOR MALE RATS . AT 26 DAYS ON TEST GROUP: I SAMPLE DATE: 11/11/88 CONCENTRATION: 0 mg/m3 BIRTH DATE: 08/22/88 ANIMAL#: 447112 447113 447115 447119 447120 VOL ml 19.0 12.4 8.0 16.0 14.2 OSMOL mOs 1021. 1792. 1923. 1669. 1125. BLOOD - + +3 +1 GLUCOSE _ _ - PRO TEIN +1 +2 +2 +2 +1 pH 8.0 7.0 7.0 7.5 7.5 BILI RUBIN _ * -- -- - UROBL mg/dl 0.1 0.1 0.1 0.1 0.1 Ke tone + +1 +1 + +1 AVG. S. D. S. E. 13.9 4.1 1.8 1506. 407. 182. 7.4 0.1 0.4 0.0 0.2 0.0 GROUP: III SAMPLE DATE: 11/11/88 CONCENTRATION: 1 mg/m3 BIRTH DATE: 08/22/88 ANIMAL#: 447124 447126 447127 447130 447131 VOL ml 9.2 35.0 17.0 18.8 11.8 OSMOL mOs 2075. 526. 993. 1101. 1787. BLOOD -- + GLUCOSE PRO TEIN -- ' +2 - +1 - +1 - +2 - +2 pH BILI UROBL Ke RUBIN mg/dl tone 8.0 -- 0.1 + r 8.0 -- 0.1 + 7.5 -- 0.1 + 7.5 -- 0.1 +1 7.5 - 0.1 + AVG. S. D. S. E. 18.4 10.1 4.5 1296. 627. 280. 7.7 0.1 0.3 0.0 0.1 0.0 -83- Company Sanfsed, o -e s no? soitfaln H-17375 DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WITH! 0 APPENDIX A (continued) INDIVIDUAL CLINICAL URINALYSIS FINDINGS FOR MALE RATS . AT 26 DAYS ON TEST GROUP: V SAMPLE DATE: 11/11/88 CONCENTRATION: 5 mg/nt* BIRTH DATE: 08/22/88 ANIMAL#: 447133 447135 447136 447137 447139 VOL ml 9.0 16.6 16.0 11.2 12.4 OSMOL mOs 1828. 1290. 1225. 1934. 1513. BLOOD -- - - - - GLUCOSE - - PRO TEIN +2 +2 +2 +2 +2 PH BILI UROBL Ke RUBIN mg/dl tone 7.5 - 0.1 +1 7.5 - 0.1 +1 8.0 - 0.1 +1 7.5 - 0.1 +1 7.5 -- 0.1 + AVG. S. D. S. E. 13.0 3.2 1.4 1558. 316. 141. 7.6 0.1 0.2 0.0 0.1 0.0 GROUP: VII SAMPLE DATE: 11/11/88 CONCENTRATION: 10 mg/m^ BIRTH DATE: 08/22/88 ANIMAL#: 447142 447143 447146 447148 447149 AVG. S. D. S. E. VOL ml 16.4 11.2 19.0 12.0 12.8 OSMOL mOs 863. 1316. 857. 1911. 1668. BLOOD - + GLUCOSE - + 14.3 3.3 1.5 1323. 473. 211. PRO TEIN +1 +1 +2 +2 +2 PH BILI UROBL Ke RUBIN mg/dl tone 7.5 - 0.1 +1 8.0 8.0 8.0 8.0 - - -- 0.1 +1 0.1 +1 0.1 +1 0.1 +1 7.9 0.1 0.2 0.0 0.1 0.0 -84- C o m p a n y Sanitized. D o e s net contain T S C A CBi DuPont HLR 696-92 H-17375 SUBCHRONIC INHALATION TOXICITY STUDY APPENDIX A (continued) INDIVIDUAL CLINICAL URINALYSIS FINDINGS FOR MALE RATS . A T 26 DAYS ON TEST GROUP: I SAMPLE DATE: 11/11/88 CONCENTRATION: 0 mg/m3 BIRTH DATE: 08/22/88 ANIMAL#: 447112 447113 447115 447119 447120 RBC /hpf 25-30 50-60 8-10 TNTC 8-10 WBC /hpf TNTC 20-25 8-10 20-25 10-15 Epith /hpf 4-5 2-3 2-3 2-3 1-2 Cast /Ipf 0-0 0-0 0-0 0-0 0-0 APPEARANCE Y CL PPT FEED FECES Y CL PPT FEED DY CL PPT FEED FECES DY CL PPT FEED FECES DY CL PPT FEED FECES GROUP: III SAMPLE DATE: 11/11/88 CONCENTRATION: 1 mg/m3 BIRTH DATE: 08/22/88 ANIMAL#: 447124 447126 447127 447130 447131 RBC /hpf 15-20 6-8 8-10 15-20 TNTC WBC /hpf 10-15 6-8 4-6 8-10 50-60 Epith /hpf 3-4 0-1 1-2 2-3 4-5 Cast /lpf 0-0 0-0 0-0 0-0 0-0 . APPEARANCE Y CL PPT LY CL PPT Y CL PPT Y CL PPT DY CL PPT FEED FECES -85- Company Santlzsd. Pass nofoontafnTSC CBf DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WITH/ APPENDIX A (continued) INDIVIDUAL CLINICAL URINALYSIS FINDINGS FOR MALE RATS . AT 26 DAYS ON TEST GROUP: V SAMPLE DATE: 11/11/88 CONCENTRATION: 5 mg/m3 BIRTH DATE: 08/22/88 ANIMAL#: 447133 447135 447136 447137 447139 RBC /hpf 25-30 TNTC 10-15 25-30 15-20 WBC /hpf 10-15 25-30 8-10 15-20 10-15 Epith /hpf 2-3 6-8 3-4 2-3 2-3 Cast /lpf 0-0 0-0 0-0 0-0 0-0 APPEARANCE Y CL PPT Y CL PPT FEED Y CL PPT Y CL PPT Y CL PPT GROUP: VII SAMPLE DATE: 11/11/88 CONCENTRATION: 10 mg/m3 BIRTH DATE: 08/22/88 ANIMAL#: 447142 447143 447146 447148 447149 RBC /hpf 6-10 10-15 20-25 50-60 TNTC WBC /hpf 4-6 4-6 8-10 50-60 45-50 Epith /hpf 0-1 1-2 1-2 2-3 1-2 Cast /lpf 0-0 2-3 0-1 4-5 0-0 APPEARANCE Y CL PPT Y CL PPT LY CL PPT Y CL PPT DY CL PPT FEED FECES -86- C o m p a n y Sanitized. D o e s not contain T S C A CB5 Subchronic Inhalation Toxicity Study with DuPont HLR 696-92 APPENDIX F Pathology Report No. 6-89 Company Sanitized. Does not contain TSCA CB\ - 87 - DuPont HLR 696-92 PATHOLOGY REPORT NO. 6-89 SUBCHRONIC INHALATION TOXICITY STUDY WITH N RATS -88- ' RoS esrs?a?R TSC.M SSI DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WITH :n RATS SUMMARY Groups of 10 male Crl:CDBR rats were exposed by inhalation t o t B ^ H ^ ^ j a t concentrations of 0, 1, 5, and 10 mg/m3 for 6 hours/day, Mondafr through Friday for 2 weeks. At study termination, all animals were necropsied, examined grossly, and.selected tissues were weighed and/or examined microscopically. There were no compound-related effects detected. There was a statistically significant difference in absolute lung weights between the control group and a treated group that was considered to be a spurious occurrence without biological significance. Under the conditions of this study the no observable-effect level, based upon final body and organ weights and gross and microscopic pathology, was the high-dose level (10 mg/m ) for male tats- Report by: Approved by: GTM/PER/wfd VPSP/MAKOVEC G-.^-SoPf2f'ac--y. Makovec, D.V.M. Diplomate, A.C.V.P. Staff Pathologist TU Paul E. Ross, D.V.M. Diplomate, A.C.V.P. Pathology Mw -89- ganifeed. Boss rto! contain TSC CB1 DuPont HLR 696-92 INTRODUCTION AND METHODS Body and organ weight data and gross and indings from male Crl:CDBR rats exposed via inhalation t o ( j ^ | ^ H H v a p o r or air alone are summarized in this report. Exposure groups were as follows: GROUP I III V VII RATS/GROUP 10 10 10 10 CONCENTRATION OF (mg/m 0 (air-exposed control) 1 (low) 5 (intermediate) 10 (high) Animals were exposed to their respective concentrations o f y j ^ ^ M ^ ^ H v a p o r for 6 hours/day, Monday through Friday for two weeks. At the end of the exposure period, 5 rats/group were sacrificed for pathologic evaluation and the remaining 5 rats/group were sacrificed following a 14-day recovery period. Following euthanasia by sodium pentobarbital anesthesia and exsangumation, all animals were examined for gross alterations. The following organs were collected for weighing: spleen, lungs, liver, kidneys, and testes. Representative samples of the following organs and tissues were collected from all rats for microscopic evaluation: liver, kidneys, urinary bladder, lungs, heart, spleen, thymus, pancreas, adrenals, thyroid, trachea, esophagus, brain, stomach, duodenum, jejunum, ileum, cecum, colon, rectum, mesenteric lymp . node, testes, epididymides, sternum (bone and marrow), eyes, nose, and any gross lesions. Testes, epididymides, sternum, and eyes were fixed in Bourn s solution. Remaining tissues were fixed in 10% neutral buffered formalin. Processed tissues were embedded in paraffin, sectioned at a nominal thickness of 5 micrometers, and stained with hematoxylin and eosin. Moan body weights, mean absolute organ weights, and mean relative organ weights (organ-to-body weight ratios) were analyzed using a one-way analysis of variance (AN0VA). When the F-test from the AN0VA was significant, the Least Significant Difference (LSD) test and Dunnett's test were used to compare means from the control group with the test group. Significance was judged at the 0.05 probability level. resu lts and d iscu ssio n Table 1 summarizes mean final body and organ weights. Incidences of gross observations are listed in Table 2. Table 3 contains incidences o microscopic observations. Appendix A lists body weights and absolute and -90- Comoanv Saniiired. no! coniato T S C A C W DuPont HLR 696-92 relative organ weights for individual animals. Appendix B contains individual animal gross and microscopic pathology data. There were no compound-related effects detected. Lung weights were statistically significantly decreased in the 1 rag/m3 zero-day recovery group when compared to the control group. This finding was considered to be a spurious occurrence without biological significance. There were no compound-related changes grossly or microscopically. The gross observations and microscopic diagnoses noted in these animals were incidental occurrences of spontaneous lesions common to rats of this strain and age. CONCLUSION Under the conditions of this study the no-observable-effect level, based upon final body and organ weights and gross and microscopic pathology, was the high-dose level (10 mg/m3) for male rats. Company Sanitized. Goes notcontain 'SCCBt -91- SUBCHRONIC INHALATION TOXICITY STUDY WITI TABLE 1 MEAN FINAL BODY AND ORGAN WEIGHTS FROM MALE RAT ( A N I M A L S N E C R O P S I E D O N D A Y 12) MEAN FINAL BODY WEIGHTS (grams) GROUP I 111 V VII CONC. (M G / M 3 ) 0.0 1 .0 5.0 10.0 FINAL BODY 309.9 2BB.3 304.7 300.9 ( 13.9) ( 12.3) ( 19.5) ( 19.0) M E A N ,A B S O L U T E O R G A N W E I G H T S ( g r a m s ) GROUP I 111 V VII CONC. (MG/M3) 0.0 1.0 5.0 10.0 LUNGS 1.443 1.304 1.403 1.385 (0.044) (0.071)# (0.066) (0.096) LIVER 11.168 10.531 10.792 1 1 . OBI (1.347) (1.265) (1.471) (1.214) KIDNEYS 2.527 2.399 2.481 2.324 (0.101 ) (0.146) (0.291) (0.167) SPLEEN 0.632 0.575 0.632 0.701 (0.062) (0.064) (0.072) (0.144) TESTES 3.147 3.116 3.052 3.245 (0.174) (0.230) (0.230) (0.437) M E A N R E L A T I V E O R G A N W E I G H T S (% of b o d y weight) GROUP I III V VII CONC. (MG/M3) 0.0 1 .0 5.0 10.0 LUNGS 0.4667 0.4526 0.4618 0.4604 (.0314) (.0183) (.0321) (.0139) LIVER 3.5997 3.6531 3.5308 3.6753 (.3655) (.3983) (.2984) (.2156) KIDNEYS 0.8172 0.8332 0.8135 0.7724 (.0592) (.0568) (.0725) (.0265) SPLEEN 0.2036 0.1998 0.2078 0.2332 (.0130) (.0230) (.0219) (.0450) STANDARD DEVIATION IN PARENTHESES + - SIGNIFICANTLY DIFFERENT (P<0.05) FROM CONTROL GROUP BY LSD ft - SIGNIFICANTLY DIFFERENT (P<0.05) FROM CONTROL GROUP BY LSD AND DUNNETT'S TEST TESTES 1.0170 1.0836 1.0045 1.0794 (.0713) (.1071) (.0915) (.1410) DuPont HLR 696-92 Company Sanitized. Does not contain TSCA CBi H# 17,375 U SUBCHRONIC INHALATION TOXICITY STUDY WITI TABLE 1 (continued) MEAN FINAL BODY AND ORGAN WEIGHTS FROM MALE RAT (ANIMALS N E C R O P S I E D ON DAY 26) fl MEAN FINAL BODY WEIGHTS (grams) GROUP I III V VI I CONC . (M G / M 3 ) 0.0 1.0 5.0 10.0 FINAL BODY 3BB.5 388.7 364.3 375.1 ( 9.4) ( 28.6) ( 21.8) ( 26.0) MEAN ABSOLUTE ORGAN WEIGHTS (grams) GROUP I III V VII CONC. (M G / M 3 ) 0.0 1.0 5.0 10.0 LUNGS 1.719 1.843 1 .608 1.609 (0.125) (0.220) (0.195) (0.144) LIVER 14.277 14.501 13.841 13.763 (2.226) (1.562) ( 1 .01B) (1.112) KIDNEYS 2.995 3.154 2.9B4 3.111 (0.307) (0.361) (0.115) (0.451) SPLEEN 0.794 0.845 0.789 0.732 (0.087): (0.077) (0.149) (0.058) TESTES 3.355 3.480 3.203 3.535 (0.260) (0.249) (0.399) (0.230) MEA N R E L A T I V E OR G A N W E I G H T S (% of body weight) GROUP I 11 I V VI I CONC. (MG/M3) 0.0 1.0 5.0 10.0 LUNGS 0.4430 0.4731 0.4420 0.4297 (.0398) (.0262) (.0236) (.0356) LIVER 3.6719 3.7364 3.7983 3.6690 (.5443) (.3709) (.1097) (.1625) KIDNEYS 0.7709 0.8108 0.8211 0.8276 ( .0762) (.0603) ( .0503) ( .0938) SPLEEN 0.2042 0.2179 0.2168 0.1956 (.0187) (.0209) (.0410) (.0148) S T A N D A R D D E V I A T I O N IN PAREN T H E S E S + - SIGNIFICANTLY DIFFERENT (P<0.05) FROM CONTROL GROUP BY LSD D - SIGNIFICANTLY DIFFERENT (P<0.05) FROM CONTROL GROUP BY LSD AND DUNNETT'S TEST TESTES 0.B632 0.B961 0.8780 0.9444 (.0567) (.0458) ( . 0 B 2 1) (.0654) -9 3 - &mpmy S a n fls DuPont HLR 696-92 5 t? Ior-IC o o ='"* O'i o> O: m SITE/LESION LUNGS FOCI DISCOLORATION RENAL PELVIS DILATATION EPIDIDYMIDES SMALL ADRENALS DEFORMITY 4S I SUBCHRONIC INHALATION TOXICITY STUDY WIT TABLE 2 INCIDENCES OF GROSS O B S ERVATIONS IN MALE RAT ( A N I M A L S N E C R O P S I ED O N D A Y 12) GROUP DESIGNATION: DOSE (UNITS): NUMBER IN GROUP: I 0 MG/M3 5 111 1.0 MG/M3 5 V 5.0 MG/M3 5 VII 10.0 MG/M3 5 01 0 1 0 0 00 00 1 00 0 00 0 DuPont HLR 696-92 ompany Sanitized. Does not contain TSCA oDB H N - 17375 SI T E / L E S I O N LUNGS FOCI RENAL PELVIS DILATATION EPIDIDYMIDES NODULE Ln I SUBCHRONIC INHALATION TOXICITY STUDY WIT TABLE 2 (continued) I N C I D E N C E S OF G R O S S O B S E R V A T I O N S IN M A L E RAT (ANIMALS N E C R O P S I E D ON DAY 26) GROUP DESIGNATION: DOSE (UNITS): NUMBER IN GROUP: I O MG/M3 5 III v 1.0 MG/M3 5.0 MG/M3 555 VII 10.0 MG/M3 0 10 0 1100 0 00 s:xS30C -pssUUSS -iuBdua: DuPont HLR 696-92 O S o-85L -} ti.v Q S* O 03' H N - 17375 I vCO\ I O 0 x1> Q) S3 W 0) 3. N (P a, a o (WD 3 O oO 3 *O)*,> 3 OHT O > o 00 TISSUE/LESI0N LIVER INFLAMMATION, SUBACUTE KIDNEYS DILATATION, RENAL PELVIS URINARY BLADDER LUNGS HEMORRHAGE, ACUTE HEART SPLEEN THYMUS PANCREAS ADRENALS THYROID TRACHEA ESOPHAGUS BRAIN STOMACH DUODENUM JEJUNUM ILEUM CECUM SUBCHRONIC INHALATION TOXICITY STUDY WITh TABLE 3 I N C I D E N C E S OF M I C R O S C O P I C O B S E R V A T I O N S IN M A L E RATS ( A N I M A L S N E C R O P S I ED ON DAY 12) GROUP DESIGNATION: D O S E (M G / M 3 ): NU M B E R IN GROUP: I 0.0 5 111 1.0 5 5 5 ! 5 2 5 5 1 5 5 5 5 5 5 5 5 2 5 " 5 5 " 5 5 5 5 5 5 5 V 5.0 5 5 3 5 " 5 5 " 5 5 5 5 5 5 5 ,5 VII 10.0 5 5 3 5 1 5 5 " 5 5 5 5 5 5 5 DuPont HLR 696-92 DuPont HLR 696-92 97_ Comoanv Sanitised. Does oof eanfaSo Tna r w H N - 17375 TISSUE/LESION COLON RECTUM MESENTERIC LYMPH NODE TESTES EPIDIDYMIDES SPERM GRANULOMA STERNUM EYES NOSE OTHER S U B C H R O N I C I N H A L A T I O N T O X I C I T Y S T U D Y WIT! TABLE 3 (continued) I N C I D E N C E S OF M I C R O S C O P I C O B S E R V A T I O N S IN M A L E RATS ( A N I M A L S N E C R O P S I E D ON D A Y 12) GROUP DESIGNATION: DOSE (MG/M3): NUMBER IN GROUP: I 0.0 5. 111 1.0 5 NOTES: o THE NUM B E R OF O R G A N S E X A M I N E D FOR EACH G R O U P IS UNDERLINED. V 5.0 5 V1I0I. 0 5 aM pssTf S'gRffze'd. 0 se na eenaln T S C e s t - 98- v.;/' H N - 17375 TISSUE/LESION LIVER INFLAMMATION, SUBACUTE KIDNEYS DILATATION, RENAL PELVIS URINARY BLADDER LUNGS HEART SPLEEN THYMUS PANCREAS ACINAR CELL ATROPHY ADRENALS THYROIO TRACHEA ESOPHAGUS BRAIN STOMACH DUODENUM JEJUNUM ILEUM CECUM SUBCHRONIC INCIDENCES INHALATION TOXICITY STUDY WITH1 TABLE 3 (continued) OF M I C R O S C O P I C O B S E R V A T I O N S IN MALE RATS ( A N I M A L S N E C R O P S I E D ON DAY 26) GROUP DESIGNATION: DOSE (MG/M3): N U M B E R IN GROUP: I 0.0 5 III 1.0 5. V 5.0 5 555 24 2 555 1" ~ 55 5 555 5 55 555 55 5 55 5 55 55 555 555 555 555 555 55 5 45 5 45 5 VII 10. 5 5 1 6 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 DuPont HLR 696-92 DuPont HLR 696-92 -99- C o m p a n y Sanitized, Does not contain T S C A C TISSUE/LESION SUBCHRONIC INHALATION TOXICITY STUDY WITI TABLE 3 (continued) INCIDENCES OF M I C R O S C O P I C O B S E R V A T I O N S IN MAL E RATS (ANIMALS NE C R O P S I E D ON DAY 26) GROUP DESIGNATION: D O S E (M G / M 3 ): N U M B E R IN GROUP: I 0.0 5 111 1.0 ,5 COLON RECTUM MESENTERIC LYMPH NODE TESTES EPIDIDYMIDES SPERM GRANULOMA STERNUM EYES INFLAMMATION, CHRONIC, CORNEA NOSE OTHER 55 55 55 55 55 "1 55 55 ~1 55 00 NOTES: O T H E N U M B E R OF O R G A N S E X A M I N E D FOR EACH G R O U P IS UNDERLINED. V 5.0 5 5 5 5 5 5 " 5 5 " 5 0 VI I 10. 0 5 5 5 5 5 5 " 5 5 " 5 0 t SUBCHRONIC INHALATION TOXICITY STUDY WITH] APPENDIX A INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS ( A N I M A L S N E C R O P S I E D O N D A Y 12) F I N A L B O D Y `A N D A B S O L U T E O R G A N W E I G H T S (g r a m s ) F R O M M A L E R A T GROUP : I - 0 MG/M3 ANIMAL NUMBER FINAL BODY LUNGS LIVER KIDNEYS SPLEEN TESTES 447114 447116 447117 447118 447121 329.3 296.6 312.5 315.1 296.2 1.442 1.491 1 .377 1.431 1 .4 75 11.637 10.580 13.116 11.033 9.468 2.450 2.605 2.649 2.408 2.523 0.720 0.547 0.621 0.645 0.626 3.292 3.366 2.961 3.091 3.027 Gr o u p m e a n STD., DEV. 309.9 13.9 1.443 0.044 11.168 1.347 ; 2.527 0.101 0.632 0.062 3.147 0.174 DuPont HLR 696-92 O 0 1 C8 a m& *1 0 C5 r*F N (B . o fmt* a? <7* O S35 3 o C1' H# 17.375 SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS ( A N I M A L S N E C R O P S I E D ON D A Y 12) FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) FROM MALE RAT GROUP : III - 1.0 M G / M 3 ANIMAL NUMBER 447122 447123 447125 447128 447129 GROUP MEAN STD. DEV. FINAL BODY 270.3 280.7 295.9 297.9 296.6 288.3 12.3 LUNGS 1.241 1 .273 1.315 1 .423 1 .270 1.304 0.071 LIVER 9.947 10.109 12.096 11.532 8.972 '10.531 1.265 KIDNEYS 2.439 2.256 2.285 2.393 2.624 2.399' 0.146 SPLEEN 0.594 0.542 0.481 0.635 0.624 0.575 0.064 TESTES 3.308 3.0B4 3.076 3.344 2.769 3.116 0.230 DuPont HLR 696-92 ompany Sanitized. Dees not contain T S C A o B3 SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS ( A N I M A L S N E C R O P S I E D ON D A Y 12) FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) FROM MALE RAt GROUP- il V - 5.0 MG/M3 ANIMAL NUMBER 447132 447134 447138 447140 447141 GROUP MEAN STD. DEV. FINAL BODY 310.5 326.3 299.8 274.1 312.8 304.7 19.5 LUNGS 1 .3 4 2 1.511 1 .362 1,413 1 .389 1 .403 0.066 LIVER 12.050 .12.439 `l0 . 25B 8.811 10.400 10.792 1.471 KIDNEYS 2.900 2.461 2.337 2.118 2.587 2.481 0.291 SPLEEN 0.710 0.688 0.638 0.592 0.534 0.632 0.072 TESTES 2.841 3.419 2.936 3.128 2.938 3.052 0.230 DuPont HLR 696-92 0 N5 1 1 d>! 3V ft?)! m 9 :-a *mmQ3 iQ'-3U .^10 3 m o > o m H# 17.375 SUBCHRONIC INHALATION TOXICITY STUDY WIT APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS ( A N I M A L S N E C R O P S I E D ON D A Y 12) FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) FROM MALE RAT GROUP : VII - 10.0 MG/M3 ANIMAL NUMBER 447144 447145 447147 447150 4471 5 1 GROUP MEAN STD. DEV. FINAL BODY 295.7 318.6 294.8 320.5 274.9 300.9 19.0 LUNGS 1.419 1.467 1 .299 1.474 1 .268 1 .385 0.096 LIVER 10.945 11.502 11.206 12.550 9.203 11.081 1.214 KIDNEYS 2.384 2.396 2.331 2.471 2.040 2.324 0.167 SPLEEN 0.526 0.640 0.6BB 0.917 0.736 0.701 0.144 TESTES 3.624 2.859 3.535 3.518 2.687 3.245 0.437 DuPont HLR 696-92 103- C o m p a n y Sanifeed. oas not contain T S C A CBi H* 17.375 SUBCHRONIC INHALATION TOXICITY STUDY APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS ( A N I M A L S N E C R O P S I E D ON D A Y 12) RELATIVE ORGAN WEIGHTS (% of body weight) FROM MALE RAT GROUP : I - 0 MG/M3 ANIMAL NMBER 447114 447116 447117 447118 447121 GROUP'MEAN STD. DEV. LUNGS 0.4379 0.5027 0.4406 0.4541 0.4980 0.4667 0.0314 LIVER 3.5339 3.5698 4.1971 3.5014 3.1965 3 .E'9 9 ;7 0.3655 KIDNEYS 0.7440 0.87B3 0.8477 0.7642 0.B51B 0.8172 0.0592 SPLEEN 0.2186 0.1844 0.1987 0.2047 0.2113 0.2036 0.0130 TESTES 0.9997 1.1349 0.9475 0.9810 1.0219 1.0170 0.0713 I -- 0 I 1 m si Sal S o 1 5 1' O o 'As' DuPont HLR 696-92 ~ SUBCHRONIC INHALATION TOXICITY STUDY WITH c APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS ( A N I M A L S N E C R O P S I E D O N D A Y 12) RELATIVE ORGAN WEIGHTS (% of body weight) FROM MALE RAT GROUP : Ill - 1.0 M G / M 3 ANIMAL NUMBER 447122 447123 447125 447128 447129 GROUP MEAN STD. DEV. LUNGS 0.4591 0.4535 0.4444 0.4777 0.4282 0.4526 0.0183 LIVER 3.6800 3.6014 4.0879 3.8711 3.0249 3.6531 0.3983 KIDNEYS 0.9023 0.8037 0.7722 0.B033 0.8847 0.8332 0.0568 SPLEEN 0.2198 0.1931 0.1626 0.2132 0.2104 0.1998 0.0230 TESTES 1.2238 1.0987 1.0395 1.1225 0.9336 1.0836 0.1071 DuPont HLR 696-92 _105- prpfjosfiv Satifeed. Boas not contain T S C CBf WJ S U B C H R O N I C I N H A L A T I O N T O X I C I T Y S T U D Y WITI APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS ( A N I M A L S N E C R O P S I E D ON D A Y 12) RELATIVE ORGAN WEIGHTS (% of body weight) FROM MALE RAT GROUP : V - 5.0 MG/M3 ANIMAL NUMBER' 447132 447134 447138 447140 447141 GROUP.MEAN STD. DEV. LUNGS 0.4322 0.4631 0.4543 0.5155 0.4441 0.4618 0.0321 LIVER 3.BB08 3.8121 3.4216 3.2145 3.324B 3.530B 0.2984 KIDNEYS 0.9340 0.7542 0.7795 0.7727 0.8270 0.8135 0.0725 SPLEEN 0.2287 0.2108 0.2128 0.2160 0.1707 0.2078 0.0219 TESTES 0.9150 1.0478 0.9793 1.1412 0.9393 1.0045 0.0915 O ON yssQ 'peiiiuBS AgQsy DuPont HLR 696-92 0> 5up) ! HI O 6 o 5 H * 17.375 SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS ( A N I M A L S N E C R O P S I E D O N D A Y 12) RELATIVE ORGAN WEIGHTS (% of body weight) FROM MALE RAT GROUP : VII - 10.0 MG/M3 ANIMAL NUMBER 447144 4 4 7 145. ' 447147 447150 4 4 7 1'5 1 GROUP MEAN STD. DEV. LUNGS 0.4799 0.4605 0.4406 0.4599 0.4613 0.4604 0.0139 LIVER 3.7014 3.6102 3.8012 3.9158 3.3478 3.6753 0.2156 KIDNEYS 0.8062 0.7520 0.7907 0.7710 0.7421 0.7724 0.0265 SPLEEN O'. 1779 0.2009 0.2334 0.2861 0.2677 0.2332 0.0450 TESTES 1.2256 0.0974 1.1991 : 1.0977 0.9774 1.0794 0.1410 0 I I 0 '-J 1 DuPont HLR 696-92 Company Sanitized. Does not contain TSC CBf SUBCHRONIC INHALATION TOXICITY STUDY WIT APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS (ANIMALS N E C R O P S I E D ON DAY 26) FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (gCams) FROM MALE RAT GROUP : I - 0 MG/M3 ' ANIMAL NUMBER I ' ' 447112 4471 13 447115 4471 19 447120 GROUP MEAN STD. DEV. finL BODY 378.1 382.2 400.0 396.7 385.6 388.5 9.4 LUNGS 1.684 1.843 1.559 1.658 1.849 1.719 0.125 LIVER 12.978 16.033 14.725 16.512 11.139 14.277 2.226 KIDNEYS 2 .'750 3.250 2.807 3.400 2.768 2.995 0.307 SPLEEN 0.763 0.733 0.948 0.777 0.751 0.794 0.087 TESTES 3.215 2.988 3.397 3.636 3.541 3.355 0.260 I 09 3 03 S3 N o OS3 HI o o O-i'i w S U B C H R O N I C I N H A L A T I O N T O X I C I T Y S T U D Y WITI APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS (ANIMALS N E C R O P S I E D ON DAY 26) FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) FROM MALE RAT GROUP : ANIMAL NUMBER III - 1.0 1 FINAL BODY MG/M3 ' .' LUNGS LIVER ' KIDNEYS SPLEEN ' TESTES 447124 447126 447127 447130 447131 398.7 384.3 360.8 432.5 367.3 1.811 1.800 1 .7 43 2.218 1.641 17.036 12.907 13.S20 14.754 13.989 3.324 2.B48 3.174 3.656 2 .770 0.874 0.751 0.777 0.899 0.924 3.689 3.319 3.136 3.719 3.536 GROUP MEAN STD. DEV'. 388.7 28.6 1 .B 4 3 0.220 14.501 1.562 3.1^4 0.361 0.845 . 077 3.480 .249 0 I I 0 VO 1 DuPont HLR 696-92 CompanySanzed.Doesno!eonfanTSC CB1 H# 17,375 SUBCHRONXC INHALATION TOXICITY STUDY WITH APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS (ANIMALS N E C R O P S I E D ON DAY 26) FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) FROM MALE RAT GROUP V - 5 . 0 MG/M3 ANIMAL NUMBER 447133 447135 447136 447137 447139 FINAL BODY 370.0 343.7 353 .1 399.4 355.2 , LUNGS Aw 1.496 1.475 1.894 1.566 LIVER 14.114 13.419 13.315 15.481 12.878 "i ; KIDNEYS 2.994 2.995 3.090 3.051 2.791 SPLEEN 0.693 0.954 0.742 0.937 0.620 TESTES 3.613 2.598 3.261 3.482 3.062 GROUP MEAN STD. DEV. 364.3 21.8 1.608 0. 195 13.841 1.018 2.984 0.115 0.789 0.149 3.203 0.399 NW = NOT WEIGHED pezijiUGg Aueauio; DuPont HLR 696-92 a Q O > nos SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS (ANIMALS' N E C R O P S I E D ON DAY 26) FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) FROM MALE RAT GROUP.':;; ' ANIMAL NUMBER 447142 447143 447146 447148 447149 i GROUP MEAN STD. DEV. V I I - 1:0.0 M G / M 3 FINAL BODY 397.0 333.2 392.6 383.9 368.1 375.1 26.0 LUNGS 1.743 1.558 1.779 1.450 1.516 1.609 0.144 I LIVER 13.870 11 .909 14.177 14.896 13.962 13.763 1.112 KIDNE,YS 3.124 2.407 3.472 3.019 3.532 3.1 11 0.451 SPLEEN 0.782 0.668 0.736 0.679 0.797 0.732 0.058 TESTES 3.450 3.221 3.648 3.517 3.838 3,. 535 0.230 DuPont HLR 696-92 Q 3 c C3 y If Q(fat SI CmmD CD C%OD S3 Hm] o a c H# 17,375 SUBCHRONIC INHALATION TOXICITY STUDY WIThI APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AMD ORGAN WEIGHTS (ANIMALS N E C R O P S I E D ON DAY 26) RELATIVE' O R G A N W E I G H T S (% of body weight) FROM M A L E RAT G R O U P ': j I - 0.MG/M3 ANIMAL NUMBER 447112 447113 447115 447119 447120 GROUP MEAN STD. DEV. LUNGS 0.4454 0.4022 .3B98 0.4179 0.4795 0.4430 0.0398 LIVER 3.4324 4.1949 3.68' 12 4.1623 2.8887 3.6719 0.5443 KIDNEYS :1 0.7273 0.8503 0.7017 0.8571 0.7178 0 .,7709 0.0762 SPLEEN 0.2018 0.1918 0 . 237 0.1959 0.1948 0.2042 0.0187 TESTES 0.8503 0.7810 0.8493 0.9166, 0.9183 0.8632 0.0567 I N3 I DuPont HLR 696-92 Company Sanitized. Does not contain TSCA CSM H# 17,375 V SUBCHRONIC INHALATION TOXICITY STUDY WIT APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS (ANIMALS N E C R O P S I E D ON DAY 26) R E L A T I V E O R G A N W E I G H T S (% of b<?dy w e i g h t ) F R O M M A L E R A T GROUP : Ill - 1.0 M G / M 3 ANIMAL NUMBER 447124 447126 447127 447130 447131 GROUP MEAN STD'. DEV. LUNGS 0.4542 0.46B4 0.4831 0.5128 0.4468 0.4731 0.0262 LIVER 4.272 3.3586 3.8304 3.4113 3.8086 3.7364 P .3 7 9 KIDNEYS 0 .B 3 7 0.7411 0.8797 0.8453 0.7542 0.8108 0.0603 SPLEEN 0.2192 0.1954 0.2154 0.2079 0.2516 0.2179 0.0209 TESTES 0.9253 0.8636 0.8692 0.8599 0.9627 0.8961 0.0458 H# 17,375 SUBCHRONIC INHALATION TOXICITY STUDY WITI APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS (ANI M A L S N E C R O P S I E D ON DAY 26) R E L A T I V E O R G A N W E I G H T S (% of body weight) FROM M A L E RAT GROUP : V - 5.0 MG/M3 1 ''A N I M A L NUMBER ; ! '1 447133 447135 447136 447137 447139 " I- ' LUNGS NW 0.4353 0.4177 0.4742 0.4409 ,t LIVER 3.8146 3.9043 3.7709 3.8761 3.6256 KIDNEYS 0.8092 ;8 7 1 4 0.8751 0 ;7 6 3 9 0.7858 SPLEEN 0.1873 0.2776 0.2101 0.2346 0.1745 TESTES 0.9765 0.7559 0.9235 0.8718 0.8620 GROUP MEAN STD. DEV. 0.4420 0.0236 3.7983 0.1097 0.8211 0.0503 0.2168 0.0410 0.8780 0.0821 NW = NOT WEI GHED DuPont HLR 696-92 -114- CompanySanitized.DoesmeteentainTSC CBS SUBCHRONIC INHALATION TOXICITY STUDY WITH! APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS (ANI M A L S N E C R O P S I E D ON DAY 26) RELATIVE ORGAN WEIGHTS (% of body weight) FROM MALE RAT GROUP VII -, 10.0 M / M 3 ;1 ANIMAL : NUMBER 447 1.42 447143 447146 447148 447149 . V'. 1 LUNGS 0.4382 0.4676 0.4531 0.3777 0.4118 L IVER 3.4867 3.5741 3.6P11 3,.8802 3.7930 KIDNEYS 0.7853 0.7224 0.8844 0.7864 0.9595 spleen 0.1966 0.2005 0.1875 0.1769 0.2165 TESTES 0.8673 0.9667 0.9292 0.9161 T. 0 4 2 7 G'ROUP M E A N STD. DEV. 0.4297 0.0356 3.6690 0.1625 0.8276 0.0938 0.1956 0.0148 0.9444 0.0654 Ln I # DuPont HLR 696-92 Company Sanitized. Dees not contain TSC o H N - 17375 SUBCHRONIC INHALATION TOXICITY STUDY WITH Key to Appendix B M ode of Death SD = Sacrificed by Design Lesion Codes H 1 s t o p a t h o 1o g 1cal c h a n g e s a re d e s c r i b e d a c c o r d i n g i t o t h e i r m o r p h o l o g i c a l c h a r a c t e r , d i s t r i b u t i o n and s e v e r i t y . T h e d i s t r i b u t i o n ( e x t e n t of t i s s u e I n v o l v e m e n t ) 1s I n d i c a t e d , w h e r e a p p r o p r H a t e , by m o d i f i e r s s u c h as focal, m u l t i f o c a l , d i f f u s e , u n i l a t e r a l , .bilateral, etc.; a s e v e r i t y score, 1f a p p r o p r i a t e , 1s a l s o a s s i g n e d as f o i l o w s : : Minimal - the a m o u n t of c h a n g e p r e s e n t b a r e l y e x c e e d s that w h i c h 1s c o n s i d e r e d to be w i t h i n norma I limits , Ml Id - the a m o u n t of c h a n g e p r e s e n t is e a s i l y d e t e c t e d M o d e r a t e - a large a m o u n t of c h a n g e 1s p r e s e p t Severe !! the d e g r e e of c h a n g e w i t h i n the a f f e c t e d a r e a ( s ) 1s e s s e n t i a l l y as s e v e r e a n d c o m p l e t e as 1s t h o u g h t p o s s i b l e In t e r m s :of q u a n t i f i c a t i o n , t h e ^ e r m s . m l l d ' a n d m o d e r a t e r e p r e s e n t p r o g r e s s i v e 1 n v o l v e m e n t / s e v e r i t y a l o n g a contin u u m . Thus, "mild" r e p r e s e n t s a ch a n g e felt to be a p p r o x i m a t e l y o n e - t h 1 r d of the way along the c o n t i n u u m b e t w e e n m i n i m a l a n d m a r k e d , a n d " m o d e r a t e " 1s a p p r o x i m a t e l y t w o - t h 1 r d s of the w a y a l o n g t h i s s a m e c o n t i n u u m . DuPont HLR 696-92 -116- CompanySanitized.DoesnotcontainTSCACBS SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX B INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: I DOSE: 0.0 MG/M3 A N I M A L #: 4 4 7 1 1 2 1: ! ^ DAYS ON TEST: 26 , ,,f GROSS OBSERVATIONS: NO ABNORMALITIES DETECTED, MODE OF DEATH: 'i SD MICROSCOPIC OBSERVATIONS: NONE THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS. BRAIN, CECUM, COLON, DUODENUM, EPIDIDYMIDES ESOPHAGUS, EYES, HEART, ILEUM, JEJUNUM, KIDNEYS, LIVER, LUNGS, MESENTERIC LYMPH NODE, NOSE, PANCREAS. RECTUm ' SPLEEN STERNUM, STOMACH, TESTES, THYMUS, THYROID, TRACHEA, URINARY BLADDER THE FOLLOWING TISSUES WERE A U T O L Y Z E D ; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROS C O P I C DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INCIDENCE TABLESNONE SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE -J S E C T I O N S OF T H E F O L L O W I N G T I S S U E S W E R E I N S U F F I C I E N T 'FOR M I C R O S C O P I C E X A M I N A T I O N : O R G A N N O T C O U N T E D IN I N C I D E N C E T A B L E S : I NONE DuPont HLR 696-92 Cmoany Sanitized.DoesnotcontainTSCA OBI SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: I DOSE: 0.0 MG/M3 ANIMAL ' 4 47 1 13 !' : * :l 1 DAYS pN TEST: , 26 ; J. !1 'I GROSS OBSERVATIONS: : NO A B N O R M A L I T ES DETECTED , M OO^ OF D E A T H : : SD I MICROSCOPIC OBSERVATIONS: PANCREAS : - ACINAR CELL ATROPHY, MINIMAL THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN, CECUM, COLON, DUODENUM, EPIDIDYMIDES, E S O P H A G U S , E Y E S , H E A R T , ILEUld, J E J U N U M , K I D N E Y S , L I V E R , L U N G S , M E S E N T E R I C L Y M P H N O D E . N O S E , R E C T U M , S P L E E N , S T E R N U M , STOMACH, TESTES, THYMUS, THYROID, TRACHEA, URINARY BLADDER THE FOLLOWING TISSUES WERE AUTOLYZED: DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE THE F O LLOWING T I S S U E S WER E SEVERELY AUTOLYZED; MICROS C O P I C DIAGNOSES NOT MADE, ORGAN NOT C O U N T E D IN INCIDENCE TABLES: NONE SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE SECTIONS OF THE FOLLOWING TISSUES WERE INSUFFICIENT FOR MICROSCOPIC EXAMINATION; ORGAN NOT COUNTED IN INCIDENCE TABLES: NONE DuPont HLR 696-92 -118- C o m o a n y Sanitized. Does not contain T S C C**6 SUBCHRONIC INHALATION TOXICITY STUDY WIT APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: I DOSE: 0.0 MG/M3 ANIMAL # : 447114 DAYS O N TEST:! , i- "i '! GROSS OBSERVATIONS: I .i 1' N O : A B N O R M A L I T I E S D E T E C T E D '. '. i 12 !M O D E OF D E A T H : SD MICROSCOPIC OBSERVATIONS: LIVER - INFLAMMATION, SUBACUTE, MINIMAL THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN, CECUM, COLON DUODENUM, EPIDIDYMIDES, ESOPHA G U S , EYES, HEART, ILEUM, JEJUNUM, KIDNEYS, liUNGS,.M E S E N T E R I C L Y M P H NODE, NOSE, PANCREAS, RECTUM, SPLEEN, STERNUM, STOMACH, TESTES, THYMUS, THYROID, TRACHEA, URINARY BLADDER T H E F O L L O W I N G T I S S U E S W E R E A U T O L Y Z E D ; D E C R E E OF. A U T O L Y S I S D I D N O T P R E C L U D E M I C R O S C O P I C E X A M I N A T I O N : N O N E THE F O L L O W I N G T I S S U E S W E R E S E V E R E L Y AUTOLYZED; M I C R O S C O P I C D I A G N O S E S NOT MADE, O R G AN NOT C O U N T E D IN INCI D E N C E TABLESNONE SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE SECTIONS- OF THE FOLLOWING TISSUES WERE INSUFFICIENT FOR MICROSCOPIC EXAMINATION; ORGAN NOT COUNTED IN INCIDENCE TABLES: NONE DuPont HLR 696-92 -1 1 9 - e e n isa n y SanRIzs. OJ 0 tfll S3 0 e 3 5" -SI Iff a > o 03 V SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA lyiALE R A T GROUP: I DOSE: 0.0 MG/M3 ANIMAL,/: 4471 15 ... DAYS ON TEST:; 26 : MODE OF DEATH:. SD GRQSS OBSERVATIONS: NO ABNORMALITIES DETECTED ' i !f MICROSCOPIC OBSERVATIONS: NONE THEc C c c L u c a o t T I ^ UES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS. BRAIN, COLON. DUODENUM EPIDIDYMIDES ESOPHAGUS testes^ thymus^ thyroid^ traGhea^ urinary^bladder^1^ 1C LYMPH N0DE- N0SE' PAn6rEAS- rTM ' - TM ^ r ^ A C H , THE 1FOLL.OWING TISSUES WERE, AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE THENONELWING TISSUES WERE severelV AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INCIDENCE TABLES: SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: CECUM. ILEUM SECTIONS OF THE FOLLOWING TISSUES WERE INSUFFICIENT FOR MICROSCOPIC EXAMINATION ORGAN NOT COUNTED IN INCIDENCE TABLES: DuPont HLR 696-92 - 120- m' ip l >: Vl'n i*) '/,T p{ xf 0# SUBCHRONIC INHALATION T O X I C I T Y S T U D Y WITH1 APPENDIX.B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: I DOSE: 0.0 MG/M3 A N I M A L A: 4 4 7 1 1 6 i 1|' ' GROSS OBSERVATIONS: LUNGS 1 D A Y S O N T E S T : 12 MODE OF DEATH: SD ,1:: , . * - DISCOLORATION, DARK RED PATCHY AREAS, DIFFUSE, (< 1 C M ) ! MICROSCOPIC OBSERVATIONS: LIVER LUNGS - INFLAMMATION, SUBACUTE, MINIMAL - HEMORRHAGE. ACUTE, MINIMAL THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN, CECUM, COLON, DUODENUM, EPIDIDYMIDES ESOPHAGUS, Ey e s , HEART, ILEUM, JEJUNUM, KIDNEYS,. MESENTERIC LYMPH NODE, NOSE, PANCREAS. RECTUM. SPLEEN STERNUM STOMACH, TESTES, THYMUS, THYROID, TRACHEA, URINARY BLADDER THE FOLLOWING TISSUES WERE AUTOLYZED: DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE , T^IE F O L L O W I N G T I S S U E S W E R E S E V E R E L Y A U T O L Y Z E D ; M I C R O S C O P I C D I A G N O S E S N O T M A D E , O R G A N N O T C O U N T E D IN I N C I D E N C E T A B L E S - H* N O N E fo 1 7 " S E C T I O N S OF. T H E F O L L O W I N G T I S S U E S W E R E N O T P R E S E N T F O R M I C R O S C O P I C E X A M I N A T I O N : N O N E SECTIONS OF THE F OLLOWING TISSUES WE R E INSUFFICIENT FOR MICROSCOPIC EXAMINATION; ORGAN NOT COUNTED IN INCIDENCE TABLESNONE DuPont HLR 696-92 Company Sanitized.DoesnotcontainTSC DBF I H N - 17375 ANIMAR 0 : 447117 SUBCHRONIC INHALATION TOXICITY STUDY WITI APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: I DOSE: 0.0 MG/M3 D A Y S O N T E S T : 12 MODE OF DEATH:; SD GROSSI OBSERVATIONS: RENAL PELVIS DIL'ATATlbN, RIGHT. MODERATE MICROSCOPIC OBSERVATIONS: KIDNEYS LIVER - DILATATION, RENAL PELVIS, MILD -INFLAMMATION, SUBACUTE, MINIMAL THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN, CECUM, COLON, DUODENUM, EPIDIDYMIDES ESOPHAGUS, EYES, HEART, ILEUM, JEJUNUM, LUNGS, MESENTERIC LYMPH NODE, NOSE, PANCREAS, RECTUM, SPLEEN, STERNUM STOMACH, TESTES, THYMUS, THYROID, 'TRACHEA, URINARY BLADDER THE FOLLOWING TISSUES WERE A U T O L Y Z E D ; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE THE F O L L O W I N G T I S S U E S W E R E S E V E R E L Y A U T O L Y Z E D ; M I C R O S C O P I C D I A G N O S E S NOT MADE, O R G A N NOT C O U N T E D IN I N C I D E N C E TABLES: NONE ro S E C T I O N S OF T H E F O L L O W I N G T I S S U E S W E R E N O T P R E S E N T F O R M I C R O S C O P I C E X A M I N A T I O N : - N O N E M' ' SECTIONS OF THE FOLLOWING TISSUES WER E INSUFFICIENT FOR M ICROSCOPIC EXAMINATION; ORGAN NOT COUNTED IN INCIDENCE TABLES: NONE DuPont HLR 696-92 CHOI O > o Ctt <9 M M - 1717K A N I M A L A: 4 4 7 1 1 8 SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: I DOSE: 0.0 MG/M3 AYS ON TEST: i 12 MODE OF DEATH: SD MACROSCOPIC OBSERVATIONS: LIVER INFLAMMATION, SUBACUTE, MINIMAL THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY': ADRENALS, BRAIN, CECUM, COLON, DUODENUM, EPIDIDYMIDES, ESOPHAGUS, EYES, HEART, ILEUM, JEJUNUM, KIDNEYS, LUNGS, MESENTERIC LYMPH NODE, NOSE, PANCREAS, RECTUM, SPLEEN STERNUM, STOMACH, TESTES, THYMUS, THYROID, TRACHEA,' URINARY BLADDER THE FOLLOWING TISSUES WERE A U T O L Y Z E D D E G R E E OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE THE F O L L O W I N G T I S S U E S W E R E S E V E R E L Y AU T O L Y Z E D ; M I C R O S C O P I C D I A G N O S E S NOT MADE, O R G A N NOT C O U N T E D IN I N C I D E N C E TABLES: NONE SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE SECTIONS OF THE FOLLOWING TISSUES WERE INSUFFICIENT FOR MICROSCOPIC EXAMINATION: ORGAN NOT COUNTED IN INCIDENCE TABLES: NONE AueuUiog 21 ay y y S i uvjuua jwu sau DuPont HLR 696-92 !?H N - 17375 S U B C H R O N I C I N H A L A T I O N 'T O X I C I T Y S T U D Y WITI APPENDIX B (continued) individual animal pathology data MALE RAT GROUP: DOSE: 0.0 MG/M3 A N I M A L #: 4 4 7 1 1 9 1 GROSS OBSERVATIONS: . R E N A L ,P E L V I S 1 1 DAYS ON TEST: 26 MODE OF DEATH: V ;M :. ;;i i ;- D I L A T A T I O N , S E V E R E , R I G H T SD. 1 MICROSCOPIC OBSERVATIONS; SIDNEYS 1 LIVER - DILATATION, RENAL PELVIS, MILD - INFLAMMATION, SUBACUTE, MINIMAL THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN, CECUM, COLON, DUODENUM, EPIDIDYMIDES ESOPHAGUS, EYES, HEART, ILEUM, JEJUNUM, LUNGS, MESENTERIC LYMPH NODE, NOSE, PANCREAS, RECTUM SPLEEN STERNUM STOMACH, TESTES, THYMUS, THYROID, TRACHEA, URINARY1 BLADDER THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUJOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE THE F O LLOWING TISSUES WER E SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT C O U NTED IN INCIDENCE TABLES- I NONE I ' N3 4N S E C T I O N S OF T H E F O L L O W I N G T I S S U E S W E R E N O T P R E S E N T F O R M I C R O S C O P I C E X A M I N A T I O N : N O N E Ii SECTIONS OF THE F OLLOWING TISSUES WERE INSUFFICIENT FOR M I C R O SCOPIC EXAMINATION; ORGAN NOT COUNTED IN INCIDENCE TABLES: NONE DuPont HLR 696-92 3 <ND Qc D O OT 3 O O3 3&> C/> o > o 09 0B SUBCHRONIC INHALATION TOXICITY STUDY WIT APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: I DOSE: 0.0 MG/M3 ANIMAL # : 447120 DAY.S O N T EST: 26 ' ; " GROSS OBSERVATIONS: NO ABNORMALITIES DETECTED !J' MODE OF DEATH: SD : i ! MICROSCOPIC OBSERVATIONS: LIVER - INFLAMMATION, SUBACUTE, MINIMAL T H E F O L L O W I N G T I S S U E S W E R E U N R E M A R K A B L E ,M I C R O S C O P I C A L L Y : A D R E N A L S , B R A I N , C E C U M , C O L O N , D U O D E N U M , E P I D I D Y M I D E S , ESOPHAGUS, EYES, HEART, ILEUM, JEJUNUM, KIDNEYS!, LUNGS, M E S E N T E R I C L Y M P H NODE, NOSE, PANCREAS, RECTUM, SPLEEN, STERNUM, STOMACH, TESTES, THYMUS, THYROID, TRACHEA, URINARY BLADDER THE FOLLOWING TISSUES WERE AUTOLVZED'DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE T H E ;F O L L O W I N G T I S S U E S W E R E S E V E R E L Y A U T O L Y Z E D ; M I C R O S C O P I C D I A G N O S E S N O T MADE, O R G A N N O T C O U N T E D IN I N C I D E N C E T A B L E S : NONE ' I SECTIONS OF JHE FOLLOWING TISSUES W E R E NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE ro Ln I S E C T I O N S OF T H E F O L L O W I N G T I S S U E S W E R E I N S U F F I C I E N T FOR M I C R O S C O P I C E X A M INATION! OR G A N NOT C O U N T E D IN I N C I D E N C E TABLES: NONE I DuPont HLR 696-92 'C o n i p a r s j ? SsiISifd. D ass nst contain s C CB 1I c........... ANIMAL.#: 447121' GROSS OBSERVATIONS: RENAL PELVIS SUBCHRONIC INHALATION TOXICITY STUDY WIT APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP DOSE: 0.0 MG/M3 DAYS DN TEST:. 12 I M O D E OF DEATfi: SD DILATATION, RIGHT ; MODERATE MICROSCOPIC OBSERVATIONS: KIDNEYS LIVER DILATATION, RENAL PELVIS, MILD INFLAMMATION, SUBACUTE, MINIMAL THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN, CECUM, COLON, DUODENUM, EPIDIDYMIDES, ESOPHAGUS, EYES, HEART, ILEUM, JEJUNUM, LUNGS, MESENTERIC LYMPH NODE, NOSE, PANCREAS, RECTUM, SPLEEN, STERNUM, STOMACH, TESTES, THYMUS, THYROID, TRACHEA, URINAR'i' BLADDER THE FOLLOWING TISSUES WERE A U T O L Y Z E D : DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INCIDENCE TABLES: NONE. ro SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE SECTIONS OF THE FOLLOWING TISSUES WERE INSUFFICIENT FOR MICROSCOPIC EXAMINATION; ORGAN NOT COUNTED IN INCIDENCE TABLES: NONE . I, DuPont HLR 696-92 Company Sanitized.Dess notcontainTSC o 00 H N - 17375 SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: III DOSE: 1.0 MG/M3 fl ANIMAL 4 4 7 1 2 2 '' D A Y S O N T E S T : 12 MODE OF D A T H : SD . G R O S S O B S E R V A T I O N ^ : .. i NO ABNORMALITIES DETECTED MICROSCOPIC OBSERVATIONS: LIVER - INFLAMMATION, SUBACUTE, MINIMAL THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY:, ADRENALS, BRAIN; CECUM, COLON, DUODENUM, EPIDIDYMIDES, ESOPHAGUS, EYES, HEART, JLEUM, JEJUNUM, KIDNEYS, LUNGS, MESENTERIC LYMPH NODE, NOSE, PANCREAS, RECTUM, SPLEEN, STERNUM, STOMACH, TESTES, THYMUS, THYROID, TRACHEA, URINARY BLADDER THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE THE FOL L O W I N G T I S SUES WERE SEVERELY AUTOLYZED; MICROS C O P I C DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INCIDENCE TABLES: NONE SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE ro -u S E C T I O N S OF T H E F O L L O W I N G T I S S U E S W E R E I N S U F F I C I E N T F O R M I C R O S C O P I C E X A M I N A T I O N ; O R G A N N O T C O U N T E D IN I N C I D E N C E T A B L E S : i NONE DuPont HLR 696-92 O' G B U V3 vs ro M w & a k 0q 3(Fin V3 o > oro w A N I M A L It : 4 4 7 1 2 3 S U B C H R O N I C I N H A L A T I O N T O X I C I T Y S T U D Y WI APPENDIX 0 (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: III DOSE- 1 .0 M G / M 3 D A Y S ON T E S T : 12 MODE OF DEATH: SO GROSS OBSERVATIONS: NO ABNORMALITIES DETECTED 'J MICROSCOPIC OBSERVATIONS: NONE T H E E S O P H A g s G I ^ U " ; dE ? E U N R E M A R K A B L E M I C R O S C O P I C A L L Y : ADRENALS BRAIN CECUM, COLON C LYMPH NODE DUODENUM, EPIDIDYMIDES NOSE, PANCREAS, RECTUM SPLEEN, THE FOLLOWING TISSUES WERE AUTOLYZED: DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE T H E N o e L W I N G T I S S U E S W E R E S E V E R E L Y AUTOLY Z E D : M I C R O S C O P I C D I A G N O S E S NOT MADE, O R G A N NOT C O U N T E D IN I N C I D E N C E TAB L E S : I fr--o* SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE 00 1 SECTIONS OF THE FOLLOWING TISSUES WERE NONE INSUFFICIENT FOR MICROSCOPIC EXAMINATION; ORGAN NOT COUNTED IN INCIDENCE TABLES: DuPont HLR 696-92 I M 0 1 a& 1 a S3 3 m H N - 17375 A N I M A L #: 4 4 7 1 2 4 GROSS OBSERVATIONS LUNGS EPIDIDYMIDES SUBCHRONIC INHALATION TOXICITY STUDY WITh | A P P E N D I X B (c o n t 1 n u e d ) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: III DOSE: 1 . 0 MG/M3 DAYS ON TEST: 26 MODE OF DEATH: SD F O C I , (< 2 M M), FEW, S C A T T E R E D - NODULE, (5 MM IN DIAMETER), RIGHT TAIL, TAN MICROSCOPIC OBSERVATIONS EPIDIDYMIDES LIVER SPERM GRANULOMA, MILD INFLAMMATION, SUBACUTE, MINIMAL COLON DUODENUM, ESOPHAGUS, EYES, RECTUM SPLEEN, STERNUM, STOMACH,' THE FOLLOWING THE FOLLOWING NONE TISSUES TISSUES WERE WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: SEVERELY AUTOLYZED. * M I C R O S C O P I C D I A G N O S E S NOT MADE, O R G A N NOT C O U N T E D IN NONE INCIDENCE TABLES: SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: SECNONES F TM E FOLLOWING t S U E S WERE INSUFFICIENT FOR MICROSCOPIC EXAMINATION NONE ORGAN NOT COUNTED IN INCIDENCE TABLES: DuPont HLR 696-92 Q pa oo 3 '3 -,') 2 .fia i" Q > A N I M A L Ht : 4 4 7 126 SBCHRONIC IN H A L A T I O N T O X I C I T Y STUDY WIT APPENDIX B (continued) IN D I V I D U A L ANIM A L PATHOLOGY DATA MALE RAT GROUP: III DOSE : 1.0 MG/M3 DAYS ON TEST: 26 MODE OF DEATH: SD GROSS OBSERVATIONS: .NO A B N O R M A L I T I E S D E T E C T E D '] MICROSCOPIC OBSERVATIONS LIVER INFLAMMATION, SUBACUTE, MINIMAL T H E F O L L O W i N G T I S S U E S W E R E U N R E M A R K A B L E M I C R O S C O P I C A L L Y - A D R E N A L S B R A I N CFrilM ESOPHAGUS. EYES. HEART. ILEUM, JEJUNUM, KIDNEYS, LUNGS MESENTERIC^LYMPH^NODF' COLON, DUODENUM, EPIDIDYMIDES, STERNUM, STOMACH. TESTES, THYMUS. THYRilD. TRACHEA S E N A R Y B L A Z E R ' NOSE, PANCREAS, RECTUM, SPLEEN, THE FOLLOWING TISSUES WERE A U T O L Y Z E D ; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE THE-FOLLOWING TISSUES WERE SEVERELY AUTOLYZED- NONE MICROS C O P I C DIAGNOSES NOT MADE, ORGAN NOT C O U NTED IN INCIDENCE TABLES to S E C T I O N S OF T H E F O L L O W I N G T I S S U E S W E R E N O T P R E S E N T F OR M I C R O S C O P I C E X A M I N A T I O N : N O N E 0 1 SE C N 0 N E S F TM E F0LL0WING TISSUES WERE INSUFFICIENT FOR MICROSCOPIC EXAMINATION; ORGAN NOT COUNTED IN INCIDENCE TABLES DuPont HLR 696-92 Company Sanitized. Dees not contain t s o . fins I A N I M A L A: 4 4 7 1 2 5 GROSS OBSERVATIONS LUNGS SUB C H R O N I C IN H A L A T I O N T O X I C I T Y STUDY WITH APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: III DOSE: 1.0 MG/M3 D A Y S ON T E S T : 12 MODE OF DEATH: SD - F O C I . ( 1 M M IN D I A M E T E R ) , RED,' L E F T MICROSCOPIC OBSERVATIONS: NONE Tns|!5SisG u *k ls STERNUM, STOMACH. TESTES. THYMUS. T H Yr i d , T r a c i a ! U r n A R Y ^ ^ A D d r CECUM, COLON IC L Y M P H NODE DUODENUM, EPIOIDYMIDES, NOSE, PANCREAS, RECTUM, SPLEEN, THE FOLLOWING THE FOLLOWING NONE TISSUES TISSUES WERE WERE AUTOLYZED i DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: SEVERELY A U T O LYZED: M I C R O S C O P I C D I A G N O S E S NOT MADE, O R G A N NOT C O U N T E D IN NONE INCIDENCE TABLES: SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE SECTIONS OF THE FOLLOWING TISSUES WERE NONE INSUFFICIENT FOR M ICROSCOPIC EXAMINATION; ORGAN NOT COUNTED IN INCIDENCE TABLES: DuPont HLR 696-92 -131- Company Sanitized.Doesno?confaloTSCA CBf I : I. vyy .H N - 17375 A N I M A L #: 4 4 7 1 2 7 SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP! Ill DOSE: 1.0 MG/M3 DAYS ON TEST: 26 MODE OF DEATH: SD GROSS.OBSERVATIONS: NO ABNORMALITIES DETECTED MICROSCOPIC OBSERVATIONS: NONE SS!fTWi8:*asS: _ THE FOLLOWING TISSUES WERE A U T O L Y Z E D ; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE T H E N O N E LOWING TI S S U E S W ERE s e v e r e l y AUTOLYZED: M I C R O S C O P I C D IAGNOSES NOT MADE, ORGAN NOT C O U N T E D IN I NCIDENCE TABLES: SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE U> N5 S E C N O N E S F TM E F 0 L L 0 W I N G T I S S U E S W E R E I N S U F F I C I E N T FOR M I C R O S C O P I C E X A M I N A T I O N : O R G A N NOT C O U N T E D IN I N C I D E N C E TABLES: I &mdUJ1 03 DuPont HLR 696-92 iO auuao 3 *(n/la o i ouuurmuiNic INHALATION TOXICITY STUDV A N I M A L #: 4 4 7 1 2 8 APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: III DOSE: 1.0 MG/M3 D A Y S O N T E S T : 12 M ODE OF DEATH: SD GROSS|OBSERVATIONS: NO"ABNORMALI TIES DETECTED MICROSCOPIC OBSERVATIONS LIVER INFLAMMATION, SUBACUTE, MINIMAL T H E ES OP H A G S G y ESS U E H E A R ? E r E U M ^ U E U U N U r ^ K ? ^ ^ ^ ^ 1- ^ A D R E N A L S ' B R A I N . . , C O L O N , D U O D E N U M , E P I D I D Y M I D E S STERNUM. STOMACH. TESTs, THYMUS. THYr i D ^ r I c A e A ^ n L T S r TM ^ NOSE, PANCREAS, RECTUM, SPLEEN, THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE T H E N O N E L O W I N G T I S S U E S W E R E s e v e r e l y AUTOLY Z E D : M I C R O S C O P I C D I A G N O S E S NOT MADE, O R G A N NOT C O U N T E D IN I N C I D E N C E TABLES: I H- U> SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE OJ I SECTIONS OF THE FOLLOWING TISSUES WERE NONE I N S U F F I C I E N T FOR M I C R O S C O P I C EXAMINATION: O R GAN NOT C O U N T E D IN I N C I D E N C E TABLES: DuPont BLR 696-92 CompanySanitized.DoesnotcontainTSC CBI I .1` l)H N - 17375 ANIMAL # : . 447129 SUBCHRONIC INHALATION TOXICITY STUDY WIT APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: III D O S E : 1 .0 M G / M 3 D A Y S O N T E S T : 12 M ODE OF DEATH: SD GROSS OBSERVATIONS: NO ABNORMALITIES DETECTED MICROSCOPIC OBSERVATIONS: NONE THEE 5 3 ? V E S ^ rT LEUMARu u h N U r CK ? ^ ^ CAL^ Y! A * ENALS' BRAI N' CECUM. COLON, D U O D E N U M , E P I D I D Y M I D E S STERNUM, STOMACH. TESTES , THYMUS. THYR I d ! Tr I cAe A! NARYG^ A D D E R NTERI ' ^ N D E ' N O S E , P A N C R E A S , R E C T U M S P L E E N , THE FOLLOWING THE FOLLOWING NONE TISSUES TISSUES WERE WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN NONE INCIDENCE TABLES I >-- SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE to -fs SECTM F THE F0LL0W1NG I S S U E S WERE INSUFFICIENT FOR MICROSCOPIC EXAMINATION ORGAN NOT C O U NTED IN INCIDENCE TABLES: DuPont HLR 696-92 Comoany Sanitized.DoasnotcontainTSCA CB! ! tesit-- H N - 17375. ANIMAL # : 447130 GROSS OBSERVATIONS: RENAL PELVIS SUBCHRONIC INHALATION +OXICTY STUDY WITH APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: III DOSE : 1 . 0 MG/M3 DAYS ON TEST: 26 MOD E OF DEATH: SD DILATATION, LEFT, MILD MICROSCOPIC OBSERVATIONSLIVER - INFLAMMATION, SUBACUTE, MINIMAL U3 Ln I O' S<3 m Mm 9* a o STERNUM, STOMACH, TESTES, THYMUS, THYROlS!TRACHEA^ URINARY^BLADDER ND E ' N S E ' PANCREAS- RECTUM. SPLEEN, THE FOLLOWING TISSUES WERE A U T O L Y Z E D : DEGREE OF AUTOLYSIS. DID NOT PRECLUDE MICROSCOPIC EXAMINATION- NONE t H E n F O L L w i n g t i s s u e s W E R E SEVERELY AUTOLYZED; M I C R O S C O P I C DIAGNOSES NOT MADE. ORGAN NOT C O U N T E D IN I N CIDENCE TABLES: SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE SECTIONS OF THE FOLLOWING TISSUES WER E INSUFFICIENT FOR MICROS C O P I C EXAMINATION: ORGAN NOT COUNTED IN INCIDENCE TABLES: oo 3 o DuPont HLR 696-92 WM y. | /\ ANIMAL tt : 447131 APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROU P : III DOSE: 1 . 0 MG/M3 DAYS ON TEST: 26 MODE OF DEATH: SD GROSS OBSERVATIONS: NO ABNORMALITIES DETECTED MICROSCOPIC OBSERVATIONS EYES LIVER I N F L A M M A T I O N CHRONIC, CORNEA,' M I N I M A L INFLAMMATION SUBACUTE, MINIMAL "mmmmnmmiwTM**CECUM, NOSE, COLON, DUODENUM, EPIDIDYMIDES PANCREAS. RECTUM, SPLEEN, STERNUM, THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE THE FOLLOWING TISSUES I NONE W E R E S E V E R E L Y A U T O L Y Z E D ; M I C R O S C O P I C D I A G N O S E S N O T MADE, O R G A N N OT C O U N T E D IN INCIDENCE TABLES: U) o\ I SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE SECTIONS OF THE FOLLOWING TISSUES WERE NONE INSUFFICIENT FOR MICROSCOPIC EXAMINATION; ORGAN NOT COUNTED IN INCIDENCE TABLES: DuPont HLR 696-92 ComoanySanitized.Doesno?containTSC CBS I It SUBCHRONIC INHALA+1N TOXICITYiSTUDY WITH ANIMAL #: 4 4 7 1 3 2 APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: V DOSE: 5 . 0 MG/M3 DAYS ON TEST: 12 MODE OF DEATH: SD GROSS OBSERVATIONS: NO ABNORMALITIES DETECTED MICROSCOPIC OBSERVATIONS: NONE THE FOLLOWING TI SSUES WERE ESOPHAGUS, EYES, HEART, STERNUM, STOMACH, TESTES UNREMARKABLE MICROSCOPICALLY: ADRENALS BRAIN ILEUM, JEJUNUM, KIDNEYS, LI VER, LUNGS, MESENTERI , THYMUS. THYROID, TRACHEA, URNARY BLADDER CECUM, COLON, C LYMPH NODE, DUODENUM, EPIDIDYMIDES NOSE, PANCREAS, RECTUM SPLEEN, THE FOLLOWING TI SSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE THE FOLLOWING TI SSUES NONE WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE. ORGAN NOT COUNTED IN INCIDENCE TABLES: I SECTIONS OF THE FOLLOWING TI SSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE LJ -~J I SEC^ N f F ^ F0LL0WING I S S U E S WERE I NSUFFI CI ENT FOR MICROSCOPIC EXAMINATION; ORGAN NOT COUNTED IN INCIDENCE TABLES: DuPont HLR 696-92 Company Sanitized.DoesnetcontainT S C CSS I f HN- 1 7375 ANIMAL ft: 447133 SUBCHRONIC .INHALATION TOXICITY STUDY WITH APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: V DOSE: 5.0 MG/M3 DAYS ON TEST: 26 MOD E OF DEATH: SD GROSS OBSERVATIONS: NO ABNORMALITIES DETECTED 1 MICROSCOPIC OBSERVATIONS: NONE EESOPHAGUSG EYESGEHEARTE I L E U r RJEJUNUMICKIDNE^ ^ U N G S ^ M E S E N T E R CELv L h C LN ' D U 0 D E N U M - EPIDIDYMIDES. STERNUM, STOMACH, TESTES, THYMUS, THYROIO. TRACHEA, U R I N AR^BLADDER ? ^ ^ PH N D E ' N 0 S E > P A N C R EAS, RECTUM. SPLEEN, THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF .AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE T H E N o S k L 0 W I N G T I S S U ^ S W B ? E S E V E R E L V A U T O L Y Z E D : M I C R O S C O P I C D I A G N O S E S NOT. MADE, O R G A N N OT C O U N T E D IN I N C I D E N C E T A B L E S : I SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE h"* CO CO S E C J o E S F T H E F O L L O W I N G T I S S U E S W E R E I N S U F F I C I E N T F O R M I C R O S C O P I C E X A M I N A T I O N ; O R G A N N O T C O U N T E D IN I N C I D E N C E T A B L E S l DuPont HLR 696-92 Company Sanitized. Does not contain TSCA CBt SUBCHRONIC INHALATION'TOXICITY STUDY WITI APPENDIX B Cc o n t 1 n u e d ) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: V DOSE: 5 . 0 MG/M3 ANIMAL A: 4 4 7 1 3 4 DAYS ON TEST: 12 MODE OF DEATH: SD GROSS OBSERVATIONS: NO ABNORMALITIES DETECTED MICROSCOPIC OBSERVATIONS LIVER INFLAMMATION, SUBACUTE, MINIMAL THEEESSOOPPHHAAGr[IUJSSG, iEiYFERSU, EHHEPA4 RBT? E, nILE? U"MA, RKJEAJBULNEUMM,ICRKOIDSNCEOYPISC, ALLLUYN:GS, AMDREESNENATLES,RICBRLAYINM,PHCENCOUDME , STERNUM, STOMACH. TESTES. THYMUS, THYROID. TRACHEA. URINARY BLADDER COLON, OUODENUM, EPI DI DYMI DES, NOSE, PANCREAS, RECTUM, SPLEEN, THE FOLLOWING TI SSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE THENONELOWING TI SSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INCIDENCE TABLES: u\D> I SECTIONS OF THE FOLLOWING TI SSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: SECTIONS NONE OF THE FOLLOWING TI SSUES WERE INSUFFICIENT FOR MICROSCOPIC EXAMINATION; NONE ORGAN NOT COUNTED IN INCIDENCE TABLES: 1 a S'jSA wjt&Sj4)>4 '&@ZgU3g|WJSUiOQ DuPont HLR 696-92 I. <9 HN-17375 ANIMAL 447135 SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA .MALE RAT GROUP: V DOSE: 5.0 MG/M3 DAYS ON TEST: 26 MODE OF DEATH: SD GROSS OBSERVATIONS: NO ABNORMALITIES DETECTED MICROSCOPIC OBSERVATIONS: NONE 0 e s o p h a g u s '? e y e s E h e a r t ! I L E U ^ J E J U ^ ^UNGS^MESENTER C ^ Y M P H ^ O D F ' DU0DENUM- EPIDIDYMIDES, STERNUM, STOMACH. TESTES. THYMUS, THYROID. TRACHEa ! URINARY BLADDER ' NSE ' PANCREAS- RECTUM, SPLEEN, THE FOLLOWING TISSUES WERE AUT0LY2ED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE THENONELOWING TISSUES WERE SEVERELY AUTOLYZED: MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INCIDENCE TABLES: SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE -t' 0 1 SECNONES F THE F0LL0WING TISSUES WERE INSUFFICIENT FOR MICROSCOPIC EXAMINATION i ORGAN NOT COUNTED IN INCIDENCE TABLES: : DuPont HLR 696-92 Company Sanitized. Dees to o > o DO c HN-17375 SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: V DOSE: 5.0 MG/M3 ANIMAL.' #i: ,1447136 1i ;D A Y S O N f E S T : 26 i ' GROSS OBSERVATIONS: i NO ABNORMALITIES DETECTED' M O D E OR D E A TIH:: SD s MICROSCOPIC OBSERVATIONS LIVER INFLAMMATION, SUBACUTE, MINIMAL T H E ESOPHAGIJSG y ! s UEH F A p ? E n " TM RKABLE MICROSCOPICALLY; ADRENALS, BRAIN, CECUM COLON, DUODENUM, EPIDIDYMIDES NOSE, PANCREAS, RECTUM, SPLEEN, THE FOLLOWING TISSUES WERE AUTC'LYZED ; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE T H E u n S c LW I N G T I S S U E S W E R E S E V E R E L Y A U T O L Y Z E D ; M I C R O S C O P I C D I A G N O S E S NOT MADE, O R G A N NOT C O U N T E D IN I N C I D E N C E TABLES: SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: SECNONFS F THE F LL0WING I S S U E S WERE INSUFFICIENT FOR MICROSCOPIC EXAMINATION NONE ORGAN NOT C O U NTED IN INCIDENCE TABLES: DuPont HLR 696-92 -ompanySanitized.Does not <n o> o JO SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: V DOSE: 5.0 MG/M3 A N I M A L # . 4 4 7 137 I DAYS ON TEST: . GROSS OBSERVAT IONS: NO'ABNORMALITIES DETECTED 26 MOD E OF DEATH: SD MICROSCOPIC OBSERVATIONS: ' NONE TM EESOPHAg J s G i f S ARKi BLE MICROSCOPICALLY: A D R E N A L S B R A I N . CECUM, COLON, D U O D E N U M , E P I D I D Y M I D E S , STPRNMM^ tTHMArw HE RI ' ILEUM> JEJUNUM- KIDNEYS, LIVER, LUNGS, MESENTERIC STERNUM, STOMACH, TESTES, THYMUS, THYROID, T R A C H E A ,;UR INARY BLADDER LYMPH NODE, NOSE, PANCREAS, RECTUM, SPLEEN, THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE THEN O N E LOWING T I S SUES WE R E SEVERELY AUTOLYZED; M I C R O SCOPIC DIAGNOSES NOT MADE, ORGAN NOT C O U NTED IN INCIDENCE TABLES ^ SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE NJ S E C N O N E S F TM E F 0 L L 0 W I N G t i s s u ? s W E R E I N S U F F I C I E N T F O R M I C R O S C O P I C E X A M I N A T I O N : O R G A N N O T C O U N T E D IN I N C I D E N C E T A B L E S DuPont HLR 696-92 CompanySanitized.DoesnotcontainTSC CBi ANIMAL A: '447138 GROSS OBSERVATIONS EPIDIDYMIDES ADRENALS SUBCHRONIC INHALATION TOXICITY STUDY WITH] APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: V DOSE: 5. MG/M3 DAYS ON TEST: 12 MODE OF DEATH: SD - SMALL, POSTERIOR END - DEFORMITY, LEFT, MISSING MICROSCOPIC OBSERVATIONS LIVER INFLAMMATION, SUBACUTE, MINIMAL THEF^ D M n K G IiccUEL WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS. BRAIN. CECUM, ESOPHAGUS, EYES, HEART, ILEUM, JEJUNUM, KIDNEYS, LUNGS, MESENTERIC LYMPH NODE STERNUM, STOMACH, TESTES, THYMUS. THYROID, TRACHEA, URINARY BLADDER COLON. DUODENUM, EPIDIDYMIDES NOSE, PANCREAS, RECTUM, SPLEEN, THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE TM ENONELOWING TISSUES WERE SEVEREL.Y AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INCIDENCE TABLES -14 3- C o m n a v Si!Na r w e SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE SECNONES F TM E F0LL0WI^G TISSUES WERE INSUFFICIENT FOR. MICROSCOPIC EXAMINATION; ORGAN NOT COUNTED IN INCIDENCE TABLES DuPont HLR 696-92 T<Sf*,, rBT SUBCHRONIC INHALATION TOXICITY STUDY WITH A P P E N D I X B' ( c o n t i n u e d ) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: V DOSE: 5.0 MG/M3 A N I M A L #: 4 4 7 1 3I9'1 . D A Y S ON. T E S T : 26 ' ' : ,' GROSS OBSERVATIONS: NO ABNORMALITIES DETECTED i *MODE OF DEATH- : ' , , > SD ' 0 MICROSCOPIC OBSERVATIONS: LIVER - INFLAMMATION, SUBACUTE, MINIMAL THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN, CECUM ESOPHAGUS, EYES, HEART, ILEUM, JEJUNUM, KIDNEYS, LUNG?, MESENTERIC LYMPH NODE STERNUM, STOMACH, TESTES, THYMUS, THYROID, TRACHEA, URINARY BLADDER COLON, DUODENUM, EPIDIDYMIDES, NOSE, PANCREAS, RECTUM. SPLEEN, THE FOLLOWING TISSUES WERE AUTOLY2ED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE THE FOLLOWING T I S SUES WER E SEVERELY AUTOLYZED; MICROS C O P I C DIAGNOSES NOT MADE, ORGAN NOT C O U NTED IN INCIDENCE TABLES: ^ SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE .pf" S E C T I O N S OF T H E F O L L O W I N G T I S S U E S W E R E I N S U F F I Cl E N T ;F OR M I C R O S C O P I C E X A M I N A T I O N ; O R G A N N O T C O U N T E D IN I N C I D E N C E T A B L E S : < NONE DuPont HLR 696-92 0 3 T&S 3 m 03 3 Nm p, o OE(id 3 {'i e c 3 0? 5l "m*? o > am SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX 0 (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: V DOSE: 5.0 MG/M3 ANIMAL' tt : ; 4 4 7 1 4 0 ' D A Y S O N T E S T : 1 2 1. MODE OF DEAH: SD ' ' 1 GROSS' OBSERVATIONS: NO ABNORMALITIES DETECTED 1* rj MICROSCOPIC OBSERVATIONS: NONE THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN, CECUM, COLON, DUODENUM EPIDIDYMIDES ESOPHAGUS, EYES, HEART, ILEUM, JEJUNUM, KIDNEYS, LIVER, LUNGS, MESENTERIC LYMPH NODE, NOSE. PANCREAS RECTUm ' SPLEEN S T E R N U M , S T O M A C H , T E S T E S , T H Y M U S , :T H Y R O I D , T R A C H E A , U R I N A R Y B L A D D E R ' ' THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NQT PRECLUDE MICROSCOPIC EXAMINATION: NONE THE FOLLOWING T I S SUES WE R E SEVERELY AUTOLYZED: M I C R O SCOPIC DIAGNOSES NOT MADE. ORGAN NOT C O U NTED IN INCIDENCE TABLES: NONE SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE I SECTIONS OF THE FOLLOWING TISSUES WERE INSUFFICIENT FOR MICROSCOPIC EXAMINATION; ORGAN NOT COUNTED IN INCIDENCE TABLES: S NONE I DuPont HLR 696-92 CompanySanitized.DoesnotcontainTSCA CBi if H N - 17375. A N I M A L A: 4 4 7 1 4 1 SUBCHRONIC INHALATION TOXICITY STUOY WITH APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: V DOSE: 5.0 MG/M3 D A Y S O N T E S T : 12 MODE OF DEATH: SD GROSS OBSERVATIONS: NO ABNORMALITIES DETECTED if MICROSCOPIC OBSERVATIONS: LIVER INFLAMMATION, SUBACUTE, MINIMAL THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN CECUM ESOPHAGUS, EYES, HEART, ILEUM, JEJUNUM, KIDNEYS, LUNGS, COLON, MESENTERIC LYMPH NODe ' DUODENUM, EPIDIDYMIDES, STERNUM, STOMACH, TESTES . THYMUS, THYROID, TRACHEA, URINARY BLADDER NOSE, PANCREAS, RECTUM, SPLEEN, THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE T H E N O N E L O W I N G T I S S U E S W E R E S E V E R E L Y AU T O L Y Z E D , M I C R O S C O P I C D I A G N O S E S NOT MADE, O R G A N NOT C O U N T E D IN I N C I D E N C E TABLES: I H-* S E C T I O N S OF T H E F O L L O W I N G T I S S U E S W E R E N O T P R E S E N T FOR M I C R O S C O P I C E X A M I N A T I O N : N O N E JN OS \ SECTM S F T H E F 0 L L 0 W I N G TIS S U E S W E R E INS U F F I C I E N T FOR M I C R O S C O P I C EXAMINATION: ORGAN NOT C O U N T E D IN I N C I D E N C E T A B L E S 3 $ 'U SSI <& w <1 Qo 89 S'1 Mnj? (tt o > a DuPont HLR 696-92 ANIMAL # 4 4 7 1 4 2 SUBCHRONIC INHALATION TOXICITY STUDY WIT APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: VII DOSE: 10.0 MG/M3 0 DAYS ON TEST: 26 MODE OF DEATH: SD GROSS OBSERVATIONS: NO ABNORMALITIES DETECTED MICROSCOPIC OBSERVATIONS: NONE THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN, CECUM, COLON ESOPHAGUS, EYES, HEART, ILEUM, JEJUNUM, KIDNEYS, LIVER, LUNGS, MESENTERIC LYMPH NODE STERNUM, STOMACH, TESTES , THYMUS, THYROID, TRACHEA, URINARY BLADDER DUODENUM, EPIDIDYMIDES NOSE, PANCREAS, RECTUM SPLEEN, THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUT0LYS3S DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE T H E N o S e L O W I N G TIS S U E S W E R E S E V ERELV AUTOLYZED: M I C R O S C O P I C D I A G N O S E S NOT MADE, OR G A N NOT C O U N T E D IN INCI D E N C E T A B L E S SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE S E C N O N E S F THE F 0 L L 0 W I N G TIS S U E S w e r e I N S U F F I C I E N T FOR M I C R O S C O P I C EXAMINATION; O R G A N NOT C O U N T E D IN I N C I D E N C E T A BLES DuPont HLR 696-92 Oa! Oil 3! < CIS. 330 (ND 0 WCD 1 lD"0 O 3 3 4<)wa 3 Hn a H N - 17375 ANIMAL # : 447143 SUBCHRONIC INHALATION TOXICITY STUDY WITHl APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: VII DOSE: 10.0 MG/M3 3 DAYS ON TEST: 26 MODE OF DEATH: SD GROSS OBSERVATIONS: NO ABNORMALITIES DETECTED MICROSCOPIC OBSERVATIONS: NONE THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS. BRAIN CECUM COLON, DUODENUM, EPIDIDYMIDES, ESOPHAGUS, EYES, HEART, ILEUM, JEJUNUM, KIDNEYS, LIVER, LUNGS, MESENTERIC LYMPH NODE, STERNUM, STOMACH, TESTES, THYMUS, THYROID, TRACHEA, URINARY BLADDER NOSE, PANCREAS, RECTUM, SPLEEN, T H E F O L L O W I N G T I S S U E S W E R E A U T O L Y Z E D ; D E G R E E O F A U T O L Y ;S I S D I D N O T P R E C L U D E M I C R O S C O P I C E X A M I N A T I O N : N O N E ^ OLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INCIDENCE TABLES SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE 03 I SECTI O N S OF THE FOL L O W I N G T I S SUES WERE I N SUFFICIENT FOR M I C R O S C O P I C EXAMINATION; ORGAN NOT C O U NTED IN INC I D E N C E TABLES: NONE DuPont HLR 696-92 Company Sanitized.Does notcontainTSCA ora H N - 17375 i SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: VII DOSE: 10.0 MG/M3 ANIMAL # : 447144 D A Y S O N T E S T : 12 MODE OF DEATH: SD GROSS OBSERVATIONS: NO ABNORMALITIES DETECTED I PvO I i ) 3 MICROSCOPIC OBSERVATIONS LIVER INFLAMMATION, SUBACUTE, MINIMAL THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN, CECUM COLON, DUODENUM, EPIDIDYMIDES, ESOPHAGUS, EVES, HEART, ILEUM, JEJUNUM, KIDNEYS, LUNGS, MESENTERIC LYMPH N O D E ! NOSE, PANCREAS, RECTUM, SPLEEN, STERNUM, STOMACH, TESTES, THYMUS, THYROID, TRACHEA, URINARY BLADDER THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLVSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE T H E N O N F L0WING T I S SUES WE R E SEVERELY AUTOLYZED; M I C R O S C O P I C D I AGNOSES NOT MADE, OR G A N NOT C O U N T E D IN INCIDENCE T ABLES SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE SECTIONS OF THE F O LLOWING TISSUES WE R E I N S UFFICIENT FOR MI C R O S C O P I C EXAMINATION; ORGAN NOT C O U NTED IN I N CIDENCE TABLES: DuPont HLR 696-92 Sanitized. Does not contain T S C A CRs V .HN-17375 ANIMAL # : 447145 GROSS OBSERVATIONS: RENAL PELVIS SUBCHRONIC INHALATION TOXICITV STUDY WITH APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: VII DOSE: 10.0 MG/M3 D A Y S O N T E S T : 12 MODE OF DEATH: SD DILATATION, MILD, RIGHT MICROSCOPIC OBSERVATIONS: KIDNEYS LIVER - DILATATION, RENAL PELVIS. MILD " INFLAMMATION, SUBACUTE, MINIMAL THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN, CECUM, COLON DUODENUM, EPIDIDYMIDES. ESOPHAGUS, EYES, HEART, ILEUM, JEJUNUM, LUNGS, MESENTERIC LYMPH NODE, NOSE, PANCREAS' RECTUM, SPLEEN. STERNUM. STOMACH, TESTES, THYMUS, THYROID, TRACHEA, URINARY ' THE FOLLOWING TISSUES WERE AUTOLVZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE I THE FOLLOWING TISSUES WERE NONE SEVERELY AUTOLVZED: MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INCIDENCE TABLES: SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE SECT I O N S OF THE F O LLOWING TISSUES WERE I N SUFFICIENT FOR MI C R O S C O P I C EXAMINATION: ORGAN NOT C O U NTED IN INCI D E N C E TABLES: NONE 150- DuPont HLR 696-92 SaMfzeeL 0e ns! esnian TSCA CBi / \ H N - 17375 ANIMAL # : 447146 SUBCHRONIC INHALATION TOXICITY STUDY WIT APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: VII r DOSE: 10.0 MG/M3 DAYS ON TEST: 26 MODE OF DEATH: SD GROSS OBSERVATIONS: NO ABNORMALITIES DETECTED MICROSCOPIC OBSERVATIONS: LIVER INFLAMMATION, SUBACUTE, MINIMAL THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN, CECUM, COLON, DUODENUM, EPIDIDYMIDES, ESOPHAGUS, EYES. HEART, ILEUM, JEJUNUM, KIDNEYS, LUNGS, MESENTERIC LYMPH NODE, NOSE, PANCREAS, RECTUM, SPLEEN, STERNUM, STOMACH, TESTES, THYMUS, THYROID, TRACHEA, URINARY BLADDER THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE THE FOLLOWING TISSUES WE R E SEVERELY AUTOLYZED: MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INCIDENCE TABLES: NONE SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE SECTIONS OF THE F O L L O W I N G T I S SUES W E R E I N S U F F I C I E N T FOR MI C R O S C O P I C EXAMINATION; ORGAN NOT C O U N T E D IN INCI D E N C E TABLES: NONE DuPont HLR 696-92 _151- "Company SanSMif. Does not contain TSC HR! A N I M A L #: 4 4 7 1 4 7 SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: VII DOSE: 10.0 MG/M3 D A Y S ON T E S T : 12 MODE OF DEATH: SD GROSS OBSERVATIONS: NO ABNORMALITIES DETECTED MICROSCOPIC OBSERVATIONS: EPIDIDYMIDES - SPERM GRANULOMA, MILD THE FOLLOWING TISSUES WERE HEART, ILEUM, JEJUNUM, STOMACH, TESTES, THYMUS UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN CECUM COLON KIDNEYS, LIVER, LUNGS, MESENTERIC LYMPH NODE, NOSE. PANCREAS , THYROID, TRACHEA, URINARY BLADDER ' DUODENUM, ESOPHAGUS, EYES, 'R E C T U M , S P L E E N , S T E R N U M , THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE T H E N O N E LOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE. ORGAN NOT COUNTED IN INCIDENCE TABLES I M Ln SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE M I S E C N O N E S F TM E F 0 L L 0 W I N G t * U E S W E R E I N S U F F I C I E N T FOR M I C R O S C O P I C E X AMINATION; O R G A N NO T C O U N T E D IN I N C I D E N C E T A B L E S DuPont HLR 696-92 gflpanySanitized.Does 3 o o Q 3 0# 3* CO o > o CD H N - 17375 A N I M A L *: 4 4 7 1 4 8 SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: VII DOSE: 10.0 MG/M3 DAYS ON TEST: 26 MODE OF DEATH: SD GROSS OBSERVATIONS: NO ABNORMALITIES DETECTED MICROSCOPIC OBSERVATIONS: NONE THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN, CECUM COLON DUODENUM, EPIDIDYMIDES ESOPHAGUS, EYES, HEART, ILEUM, JEJUNUM, KIDNEYS, LIVER, LUNGS, MESENTERIC LYMPH N O D E ' NOSE, PANCREAS, RECTUM STERNUM, STOMACH, TESTES, THYMUS, THYROID, TRACHEA, URINARY BLADDER SPLEEN, THE FOLLOWING TISSUES WERE AUTOLYZEDj DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE NONE ORGAN NOT C O U NTED IN INCI D E N C E TABLES: SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE Ln LO S E C T I O N S O F T H E F O L L O W I N G T I S S U E S W E R E I N S U F F I C I E N T F O R M I C R O S C O P I C E X A M I N A T I O N ; O R G A N N O T C O U N T E D IN I N C I D E N C E T A B L E S : I NONE DuPont HLR 696-92 Company Sanitized.Does notcontainTSC o DO 0H N - 17375 A N I M A L *: 4 4 7 1 4 9 S U B C H R O N I C I N H A L A T I O N T O X I C I T Y S T U D Y WITI A P P E N D I X B (c ont in u e d ) IN D I V I D U A L A N I M A L P A T H O L O G Y D A T A MALE RAT GROUP: VII DOSE: 10.0 MG/M3 DAYS ON TEST: 26 MODE OF DEATH: SD: GROSS OBSERVATIONS: NO ABNORMALITIES DETECTED MICROSCOPIC OBSERVATIONS: NONE THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS BRAIN CECUM, COLON ESOPHAGUS, EYES, HEART, ILEUM, JEJUNUM, KIDNEYS, LIVER, LUNGS, MESENTERI C LYMPH NODE STERNUM, STOMACH, TESTES, THYMUS, THYROID, TRACHEA, URINARY BLADDER DUODENUM, EPIDIDYMIDES, NOSE, PANCREAS, RECTUM, SPLEEN, THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE T H E N O N E LOWING TISSUES WERE s e v ERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INCIDENCE TABLES SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE SECNnNF5 F THE F0LL0WING I S S U E S WERE INSUFFICIENT FOR MICROSCOPIC EXAMINATION; ORGAN NOT COUNTED IN INCIDENCE TABLES DuPont HLR 696-92 Sanitized.Does notcontainTSCA o SUBCHRONIC INHALATION TOXICITY STUDY WIT APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: VII DOSE: 10.0 MG/M3 A N I M A L A: 4 4 7 1 5 0 D A Y S ON TEST: 12 MODE OF DEATH: SD GROSS OBSERVATIONS: NO ABNORMALITIES DETECTED MICROSCOPIC OBSERVATIONS: LIVER INFLAMMATION. SUBACUTE, MINIMAL THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN, CECUM, COLON, DUODENUM, EPIDIDYMIDES, ESOPHAGUS, EYES, HEART, ILEUM, JEJUNUM, KIDNEYS, LUNGS, MESENTERIC LYMPH NODE, NOSE, PANCREAS, RECTUM, SPLEEN, STERNUM, STOMACH, TESTES, THYMUS, THYROID, TRACHEA, URINARY BLADDER THE FOLLOWING TISSUES WERE AUTOLYZED: DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INCIDENCE TABLES: NONE SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE SECTIONS OF THE F O LLOWING TISSUES WERE INSUF F I C I E N T FOR MI C R O S C O P I C E XAMINATION ORGAN NOT C O U NTED IN I N CIDENCE TABLES: NONE DuPont HLR 696-92 - 1 5 5 - avspsR Sgfiized. Deeg sus! eenfars T S C A CB A N I M A L # . 4 4 7 1 5 1 SUBCHRONIC INHALATION TOXICITY STUDY WIT APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: VII DOSE: 10.0 MG/M3 D A Y S O N T E S T : 12 MODE OF DEATH: SD GROSS OBSERVATIONS: NO ABNORMALITIES DETECTED MICROSCOPIC OBSERVATIONS: NONE THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN, CECUM, COLON, DUODENUM, EPIDIDYMIDES, ESOPHAGUS, EYES, HEART, ILEUM, JEJUNUM, KIDNEYS, LIVER, LUNGS, MESENTERIC LYMPH NODE, NOSE, PANCREAS, RECTUM, STERNUM, STOMACH, TESTES, THYMUS, THYROID, TRACHEA, URINARY BLADDER SPLEEN, THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NONE THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INCIDENCE TABLES: NONE SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE I u! S E C T I O N S OF T H E F O L L O W I N G T I S S U E S W E R E I N S U F F I C I E N T F O R M I C R O S C O P I C E X A M I N A T I O N ; O R G A N N O T C O U N T E D IN I N C I D E N C E T A B L E S : O' N O N E DuPont HLR 696-92 aa -o3as 3 m us 3 N IS a a o n> (A 3 O o o 3 57 cn o > oS3