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AR226-3007 DuPont HLR 696-92 Study Title Subchronic Inhalation Toxicity Study vith|U||^--------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 Haskell E. I. du Font de Nemours and Company Laboratory for Toxicology and Industrial Elkton Road, P.O. Box 50 Newark, Delaware 19714 Medicine Medical Research No. Gbmoany Sanitized. Poeg not contain TSCA CBr 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 Font de Nemours and Company Sponsor: DuPont Specialty Chemicals E. I. du Font de Nemours and Company Vilmington, Delaware Study Director: man N. Ghantous, Ph.D. Research Toxicologist Biochemical Toxicology l^/^/^H CBW.W W"* t">s 1""""" Ts t) Material Tested: GENERAL INFORMATION DuPont HLR 696-92 Medical Research No.: Haskell No.: Physical Form: Purity: Composition: 17375 3 - Campany SgniHzed. Does ne? eoriiain TSCA 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 Vilmington, Delaware Company, Inc. 10/17/88 - 11/11/88 10/7/88 - 12/21/94 iSoR?BS!T 'Ss^S'se'S. Tw.s """.s ^Q-.t'a!?! 7Sj3 RR? 4 - TABLE OF CONTENTS DuPont HLR 696-92 GOOD LABORATORY PRACTICE GENERAL INFORMATION COMPLIANCE STATEMENT ..................... 2 3 TABLE OF CONTENTS ............................................... 5 SUMMARY ................................................. 6 SIGNATURE..P.A.G.E...................................................... 7 QUALITY ASSURANC.E..D.O.C..U.M.E.N.T.A.T.IO.N..................................... 8 INTRODUCTION ................................... 9 MATERIAL AND M.E.T.H.O.D.S................................................ 9 RESULTS AND DISCUSSION.............................................. 13 CONCLUSIONS ............................................ 14 REFERENCES ....................................................... 14 ......................................................;. TABLES Table 1 Table 2 Table 3 Table 4 Table 5 - r^^^H'1 APtamrotiscplheerSicizeCoCnhceanratrcatteiorinzsatioilniJoBq^^^^^^^^BBBBvB\\ |i^utn1i1o1s.p.h.e.r.e.s. 16 17 Mean Body Weights of Male Rats . .'-^^^^^--l........... 18 Mean Body Weight Gains of Male Rats Summary of Clinical Observations in M..a.le..R..a.ts............. 19 20 ........... APPENDICES Appendix A Appendix B Protocol and Protocol Amendments Daily Atmospheric Analyses ..................... 21 37 - Appendix C - Individual Body Weights of M..a.le..R..a.ts................... ................. 40 Appendix D Appendix E Individual Clinical Observations of Male Rats Clinical Pathology Report No. 10-89 ........ 49 51 - Appendix F - Pathology Report No. 6-89 .................. ............................ 87 Company SanHhe'fS. Ooes hot contain TSCA CBI DuPont HLR 696-92 Subchronic Inhalation Toxicity Study with^H^^HBfJin Rats SUMMARY This study was carried out to determinethe^ox^^effects of repeated inhalation of sublethal concentrations ofgHBH^U^erosol. Three groups of ten male Crl:CDBR rats were exposed six hours/day, five days a week for two weeks, (exc^id^i^Saturdays and Sundays) to design concentrations of 1, 5, or 10 nig/in3 of[UHHBI|faerosoI in air. A control group of ten male rats was exposed simultaneous^ 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 meanuiymevolume and increase in mean urine osmolality were noted in all flUH^H^erosol 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^uuca^^hemistry and organ weight differences were not dependent oruHH|HI^H[|aerosol exposure concentration. Under the conditions of this test the no-observed effect level (NOEL), based on clinical signs,_body weight, clinical pathology, and histopathology, was 10 mg/m1'^fllfHllHH^^HI^H^^H^BI'IB^ferosol. n ny gaiRRPze^ g-^ag Rn.6 goppg^ ygg^i. Subchronic Inhalation Toxicity Study with SIGNATURE PAGE DuPont HLR 696-92 in Rats Approved by: U^m^tM^_____ /J^L^d NancWC. Chromey, ffh.D., D.A.B.T Oral Tnoyxipcnoilroxgryv Authored, Reviewed, and Approved for Issue I /^/^/ by Study Director: ^ 5anan N. Ghantous, Ph.D. Study Director Company Sanitized. Does not contain TSCA CBt 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: CL^. ^^JL^ ^ /y James Hackay ^S. Quality Assurance Auditor p/^/yy Date Qwipss'^ SaniHzsd. Dc?9 noi coritain TSCA CBe INTRODUCTION DuPont HLR 696-92 iHuman exposure to this compound is possiblethrouga _ _ _nha_^tion_ In an acute four-hour inhalation study clinical signs observed in IBIHHIRexposed rats included nasal, ocular, and respiratory irritation.<: I TheapproxTmate lethal concentration (ALC) offllHBHIHf^s 21 nig/in3.'1) To date no exposure limLUXitLs_> fJ-oUJr. tLh11Ji.sO tLeC st materian?aveoeenestablished. The purpose of the preseSnT^j^ssytjuudd^^vwaassJ-^tco evaluate the toxicity associated with repeated exposure tov^^^^^^^ffa.erosol in male rats. MATERIALS AND METHODS A. General Experimental Design Four.groups of ten male rats were used to assess the toxic effects of repeatedJIUBHUfjerosol inhalation exposures on body weights, clinical iBHBI^ml signs, clinicaTpathologic and histopathologic parameters. Tlyee test groups were exposed to design concentrations of 1, 5, or 10 mg/m3 0^ aerosol in air. A control group of rats matched for age, sex^anffSod^weight was exposed^simultaneously to air only. The highest exposure concentration of HBHHH|reerosol was selected based on the results of two rangefinding i^id^s^mffl-e groups of male rats were exposed for several days to mean concentrations of approximately 7 or 13 mg/m3 without signs of toxicity, and consideration of an established approximate lethal concentration of 21 mg/m3. In the present study rats were exposed six hours/day, five days a week for two weeks, (excluding Saturdays and Sundays) and five animals from each exposure group were retained for a 14-day post-exposure recovery period. All rats were monitored for body weight changes and clinical signs of toxicity throughout the study. At the end of the exposure period, blood and urine samples were collected from all rats for clinical analyses, and five rats per group were sacrificed for pathologic examination. After 14 days of recovery, the remaining rats were given similar clinical and pathologic examinations. The complete protocol and amendments to the protocol for this study are attached as Appendix A. B. Animal Husbandry Seven-week-old Crl:CDBR rats (born 8-22-88) were received from Charles River Breeding Laboratories, Inc., Raleigh, North Carolina on 10/10/88. Rats were housed one per cage in 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 quarantined for six days prior to testing, and were weighed and observed three times during the quarantine period. During this time, rats were assigned to four 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 not contain TSCA CS1 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 grains 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 res trainer 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 tvo weeks, (excluding Saturdays and III, 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 mg/m3 of(l|H^BU| aerosol in air (groups V and VII, respectively). A control group was exposed to air only (group I). 2. Atmosphere Generation Mixed aerosol/vapor atmospheres oq|IU^UH|j were generated with a Spraying Systems air atomizing nozzle using ah^h 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 fittedw^l^^baffle to enhance aerosol dispersion. Atmospheric concentrations of|IIB|UH|jrere controlled by regulating, (1) the delivery rate of the test material at the syringe drive (approximate range 20-200 ul/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 ofU^B^B^BLatmospheres by the method described above produces both an aerosc^^^|mU|||B----Jand vaoor^o^acetone and ethylene glycol. Based on a previous inhalation study ^thflBHmi^jthe design aerosol concentrations of 1, 5, or 10 mg/m3 would not produce toxicologically significant concentrations of vapor.(1* In the present study, no analysis of vapor was made. Atmospheric aerosol concentrations ofA^HHHHI^ere determined by gravimetric analysis at approximately 30-^ii^ii^e^Tntervals. At the high and intermediate design exposure levels (10 or 5 mg/m3) known volumes of chamber atmospheres were drawn through preweighed Gelman glass fiber D filters. Filters were weighed on a Cahn Model 26 automatic Electrobalance. Atmospheric concentrations of^^^^^^^^^Bfwere calculated from the filter 10 sr?y Sanded. Saes ^ extern TSC.A e^e 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 Psychron, and chamber oxygen contents were measured with a Biosystems, Inc., Model 3100R oxygen monitor. D. 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. E. Clinical Pathology Urine samples were collected overnight from all surviving rats after the ninth exposure, and from the remaining rats on the.13th day of recovery. Samples were 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, band neutrophils, lymphocytes, atypical lymphocytes, eosinophils, monocytes 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 (Wintrobe 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 also measured. P. 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 - Company Sanitized. Does not contain TSCA CBl 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, kidneys, urinary bladder, sternum (bone and marrow), spleen, thymus, thyroid gland, adrenal 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 controls by the least significant difference test when the ratio of variance (F) indicated a significant among-to-within group variation. Significant differences were declared at the 0.05 probability level. The statistical analyses used to evaluate the clinical pathology da-ta; mean organ weights ("absolute" weights) and mean organ-to-body weight ratios ("relative" weights) are described in Appendices E and F, respectively. 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., Vilmington, Delaware. comw s5Rlsized- ^ no? ec^ah TSCA Ci 12 DuPont HLR 696-92 RESULTS AND DISCUSSION A. Exposure Conditions In the test chambers, chamber temperature ranged from approximately 20 to 24C, relative humidity ranged from approximately 53 to 71%, and chamber oxygen content vas 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 veil as particle size characterization for each exposure concentration are presented in Tables 1 and 2, respectively. Daily atmospheric characterization data are presented in Appendix B. B. Body Weights [im||^J|J The mean body weights of rats exposed to 1, 5, or 10 mg/m3 aerosol were indistinguishable from control group values during the exposure and post-exposure recovery periods. One or two mean body weight gain values in the low- and high-exposure groups during the study were significantly different from control values. These differences were isolated and did not represent a toxicological response dependent orill^llHBH|Jaerosol concentration. Daily mean body weights and mean body weight gains are presented in Tables 3 and 4, respectively. Individual body weights are presented in Appendix C. C. Mortality and Clinical Signs During the first exposure to 10 mg/m3 aerosol rats were observed with nasal discharge. Most other study animals (including controls) exhibited nasal discharge during exposures. No animals had a decreased acoustical response at any time evaluated. clear red 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 Conmediantes t day 16) a control animal and one rat exposed to 1 mg/m3 ofMHIBIHI|H^erosol had left ocular discharge, and left ocular discharge and cornea^opaci ty, 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 in 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 decrease^^.yneanunne volume and increase in mean urine osmolality were observed in all^H^|^HH|aerosol- exposed groups compared to the ^^i control mean. Such changes^^^Tinical chemistry are normally associated with P _ 13 _ Company Sanitized. Doa not contain TSCA CBE 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 in the intermediate- and low-dose groups, respectively. Clinical Pathology Report Mo. 10-89 is attached as Appendix E. E. Pathology No compound related effects were observed at any H^UUHJexposure concentration tested. Absolute mean lung weight was"Significan'tly 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 exHi'BTt' a relevant dose-resrponsre rela'tioTishrp. In ad^iti-on, no histopathological changes were found in the lungs. Thus, these effects were exposure and there was no evidence of a toxic effect of in lung tissue. Pathology Report No. 6-89 is attached as CONCLUSIONS The resu^s^^idicated that repeated inhalation exposure to 1, 5, or 10 mg/n^AUIUlJaerosol had no toxicological effects in male rats. the conditions of this test the no-observed effect level was 10 mg/m3 aerosol. Under REFERENCES 1. Haskell Laboratory Report No.|J|^B^{ Inhalation Approximate Lethal Compaq Sartoa,. Q^ ^ ^^ ^^ ^ 14 - DuPont HLR 696-92 Subchronic Inhalation Toxicity Study vitnU|^^Bi9J TABLES Note: Data are reported to two significant figures. eompany^^Oo.=nofoo^TSCACBf 15 - DuPont HLR 696-92 Subchronic Inhalation Toxicity Study with TABLE 1 ATMOSPHERIC CONCENTRATIONS OF ;OSOL (mg/m3) Design Group No. . Concentration n I 0- III 1 720 V 5 120 VII 10 120 Mean - 1.33 4.8b lib S.D. - 0.87 1.5 4.0 Ran;?e - 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^nae^so^. This assumption is consistent with the^inethod^f^eport^gI^BHimaerosol exposure concentration in HLR No.[IJU^j(IBU^HlBperosol concentration is expressed on a weight/volume basis (mg/m^^^^^^^ Sempg'Ry aiiis?2^ s^ss Ht eSi^afc TSCA CBt 16 DuPont HLR 696-92 Subchronic Inhalation Toxicity Study with TABLE 2 PARTICLE SIZE C-BARACTERIZATION OF .TMOSPHERES Design Concentration ____(mg/m3)_____ na 0 1 2 5 2 10 2 % Particles1' < 3 urn < 10 urn 73 97 80 96 86 99 MMD(um)' 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 urn and less than 10 urn. Represents the mean value from two exposures. c Mass median aerodynamic diameter. exposures. Represents the mean value from two Company Sanitized. Does not contain TSCA CBf 17 - DuPont HLR 696-92 Subchronic Inhalation Toxicity Study withig TABLE 3 MEAN BODY WEIGHTS OF MALE RATS Group: Design Concentration (mg/m3): Days On Test Exposure Period 1 233.4( 8.0)a 2 238.3(11.9) 3 243.5(12.9) 4 250.7(13.1) 5 256.6(12.7) 8 286.2(11.9) 9 291.0(12.3) 10 297.4(12.6) 11 305.4(14.6) 12 306.1(10.5) III Body WejLght (g) 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.!( 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. Car/ipss-iy Sanitised, Ssss rtai contain TSCA CBS 18 - DuPont HLR 696-92 Subchronic Inhalation Toxicity Study with TABLE 4 MEAN BODY WEIGHT GAINS OF MALE RATS Group: Design Concentration (mg/m3): I )ays On Test Exposurei Period 1- 2 2- 3 3 - 4 4- 5 5 - 8 8- 9 9 - 10 10 - 11 11 - 12 4.9( 5.2( 7.2( 5.9( 29.6( 4.8( 6.3( 8.1( 0.7( 7.3)3 7.0) 3.8) 5.3) 2.4) 3.3) 4.0) 3.9) 6.8) III Etody Veighl: Gain (g:) 2 8( 3.1) 7 7( 3.7) 5 0( 8 2( 27 1( 3 5( 5 .8( 3 3( 4.4) 5.7) 6.0) 2.8) 4.3) 3.4)b -5 .3(12.9) 2.9( 5.2( 5.7( 7.2( 23.8( 7.7( 4.7( 5.4( 0.6( 7 .2) 3 .6) 2 .6) 3 .5) 7 .1) 4 .8) 2 .5) 2 .3) 4 .8) VII 10 2 .4( 7 9( 6 7( 3 6( 28 9( 4 2( 4 .8( 4 .2( 3 3( 6 .9) 2 .8) 3 .6) 2 .4) 4 .9) 2 .9) i j. .9) 2 .6)" 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 1( 3.6) 10 5( 2.4) -10.3(11.4) 17.1( 0.8( 10.5( 2.3( 5.3( 23.3( 9.5( 5.1( 5.4( -1.3( 3 .8) 7 .7) 3 ^) 2 .3) 4 .8) 7 .6) 5 .6) 2 .9) 2 .6) 4.0) 20 6(. 3 0( 10 2( 6 3( 7 8( 18 8( 6 .3) 1 .8) 2 .0) 4 .2) 3 .0) 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. Company Sanitized. Doss nol contain TSCA CBi 19 DuPont HLR 696-92 Subchronic Inhalation Toxicity Study vithj^B^^^^^H^ TABLE 5 SUMMARY OF CLINICAL OBSERVATIONS IN MALE RATS-1 Group1': Design Concentration (mg/m3): I III V VII 0 1 5 10 Observation Colored Discharge, Left Eye Corneal Opacity, Left Eye Number of Rats Exhibiting Sign 1 (16)<= 1 (16') 0 0 0 l.(16) O 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. 'eemp@??yan?tis@G. Doss n'st esntate TSCA CBi 20 - Subchronic Inhalation Toxicity Study with, DuPont HLR 696-92 APPENDIX A Protocol and Protocol Amendments Company Sanitized. Does not confam TSCA CBT 21 - DuPont HLR 696-92 PROTOCOL '(I------) SUBCHRONICC.-JNHALATIONT1I.0XICITY WIT] CN RATS STUDY STUDY Subchronic Inhalation Toxicity Study Medical Research No.\j|^^BfJ Proposed In-Life Starting Date: Proposed In-Life Coiiipretion Date; 10/17/88 11/11788 Haskell No. 17,375 PURPOSE I^IH^UHis approximate letnal considered to concentration be of ex 21 tmreg/nmi3eflyB^^o^x^--by--in h^ a l atio The n with purpose a 4 of - h r this study is to determine the effects of repeatedexposure to sublethal concentrations ofJj^HB^^IBR|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 Font de Nemours and Company, Inc., P. 0. Box 50, Elkton Road, Newark, Delaware 19714. ^WSar^d. ^ ^ ^ ^ ^ -22- DuPont HLR 696-92 SPONSOR The sponsor of this test is the Chemicals and Pigments Department of the Du Font Company. The address of the sponsor is the corporate headquarters of E. I. du Font 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 animals are first exposed to in-life portion of the study period. The completion date , the final report is issued. study will be defined as the day that study the test material. The-, completion date of the will be defined as the last day of the recovery of the entire study will be defined as the date TEST MATERIAL Identification The test material is Information on the purity, composition, contaminants, ^5n^y^m^s7^"^"d^epartmental 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 fo':m. 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. -23- Company Sanitized. Does not contain TSCA CBl ,,iS\ DuPont HLR 696-92 Stability Unless otherwise indicated on the Sample Evaluation form and in 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 - ^^ps^ Sands'~- -t "^^^^^ntefnTSeAC^ -24- DuPont HLR 696-92 has been gaining, weight at a normal rate and has no overt signs of disease is acceptable for testing. The rat(s) with the lowest and highest body weights will be culled from the sample. The remaining rats will be divided into groups by computer randomization such that the pretest mean body weights of 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 control and treatment groups. No significant differences between test groups that may affect the outcome of this study are expected. In the absence of evidence to the contrary, toxic effects following inhalation of the test material will be 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 will 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 corresponding 6-digit numbers will be recorded in the study records. Prior to exposure, rats' tails 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 will be maintained 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 study, the actual relative humidity and temperature ranges incurred will be recorded but will not be included in the final report. Except during exposures, rats will be housed in suspended, stainless steel, wire-mesh cages. Rats will be housed either singly in 5" x 11" x 7" cages, or singly or in pairs in 8" x 14" x 8" cages. Except during exposures, Purina Certified Rodent Chow #5002 and tap 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 believed to be within acceptable ranges. To supplement these data, f'sed is periodically analyzed for selected heavy metals, pesticides, and ni^rosamines. Records of the results of these analyses are maintained by the site veterinarian. No other contaminants reasonably anticipated to be present in the feed are expected to interfere with the results of this study. 4 - ^g"-^^,^_^ -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 ^ w e i g h e d Four groups of 10 male rats will be exposed to the test material by inhalation 6 hours/day, 5 days/week for 2 weeks. The exposure period will be followed by a 14-day recovery period. Three tes^fi.rouos.wi11 be exposed to design concentrations of 0.5, 1.5 or 5 mg/.m3 ffllHHHBP.n air. A procedural control group will be exposed to air only. 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 and in a protocol amendment. Exposure Concentrations __JTThree exposure concentrations (targeted at 0.5, 1.5 or 5 mg/m3j_ and an air control will be tested during this study. Ideally, expoissure 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 rarigefinding exposures will be conduct:"d before the initiation of the study. Rangefinding trials at the planned exposure concentrations will be conducted without rats to establish the generation parameters needed to D Company Sanitized. Doss no? contain TSCA CB( -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 in 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 te 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 - WRy SsRlfesa. Soss n^ ^^ TSCA.^ DuPont HLR 696-92 changes in clinical chemical, hematologic, and test rats as compared to controls. Additional request of the sponsor or at the discretion of documented in the study records. urinalysis parameters in the endpoints may be added at the the study director, and will be Collection of Specimens Urine samples will 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 iii 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, total 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 in 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, Company anK?zed. Does not contain TSCA CBi -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. For^JBHUm attempts will be made to generate particles of respirable size. Ideally, at Teast 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 W-6W). However, temperature and humidity variations outside of these ranges are commonly encountered due to the generation procedures used and the characteristics of - 8 - -29- GWpa^S,n^ _ ^ "-'"^^^rscACBS 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 o^lHH^UQrill zone of the animals within the exposure chamber^TheDryiary method for determining the atmospheric concentration be gravimetric analysis. Unless prohibited by the nature otthetestmaterial, 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 Di.i Font Records Management Center, E. I. du Font de Nemours and Company, Inc., Wilmington, Delaware. ^'""^--"""^rsc^B, -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: ^^^A. JH^^ Jn^V^ C^>. ^tEr-. lto / ^-f- / 88 Dolores E. Maiek, Ph.D. Study Director Approved by: Acute fjg ^_/^ d CLj^.yyx^> ffft ? / f^ Nan^ C. Chromey,0fh.D, Manager and Developmental Toxicology Division 10 - eesipssrH? Sarimzes, &sss no? fcontain TSCA CB6 -31- CENTRAL HASKELL RESEARCH AND DEVELOPMENT DEPARTMENT LABORATORY FOR TOXICOLOGY AND INDUSTRIAL MEDICINE DuPont HLR 696-92 cc: Quality Assurance TO: MEDICAL RESEARCH PROJECT NO FROM: DOLORES E. MALEK PROTOCOL AMENDMENT #1 May 19, 1989 TWO WEEK SUBCHRONIC INHALATION TOXICITY STUDY 0 Haskell Laboratory No. Medical Research No. 17375 1. Design Concentration oaflUUJyihas been changed: Protocol - 0.5, 1.5 and 5 mg/m3 Study - 1, 5, 10 mg/m3 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 ^-^^.V^ by: ,/v\^t-\ S Dolores E. Maiek, Ph.D. Study Director Research Toxicologist Acute and Developmental Toxicology / U / V> Division _r?P\ -32- CENTRAL HASKELL RESEARCH AND DEVELOPMENT DEPARTMENT LABORATORY FOR TOXICOLOGY AND INDUSTRIAL MEDICINE DuPont HLR 696-92 cc: Quality Assurance TO: MEDICAL RESEARCH PROJECT N0.1 FROM: DOLORES E. MALEK PROTOCOL AMENDMENT #2 June 12, 1989 TVO-VEEK INHALATION TOXICITY STUDY WIT ;N RATS Haskell Laboratory No. 17375 Medical Research No. )| 0 The title .Study with has been changed from "Subchronic Inhalation Toxicity iin Rats" to "Two-Week Inhalation Toxicity Study with Prepared by: ^J^L^^ JUX 0'' /'^./ 8^ Dolores E. Malek., Ph.D. Study Director Research Toxicologist Acute and Developmental Toxicology Division h .33. company Sanded. Doss- DuPont HLR 696-92 PROTOCOL AMENDMENT #3 Jf__\ MR Number:! |^ Study Code::t|jJHfj Haskell Number: 17,375. Descriptive Title of Study: Two-Week Inhalation Toxicity Study wit in Rats Compound Name: As of 02/05/91, Judith C. Stadler will replace Dolores E. Maiek as study director for the purpose of completion and issuance of the final report. d^^^^/7/ ^.^Jflf. /-/Judith C. Stadler, Ph.D. (Senior Research Toxicologist Acute Toxicology <^P^^.A^^ ^/s/-fi Dolores E. Maiek, Ph.D. Research Toxicologist Acute Toxicology -34- C9ESpa ^s'Hfeed!. iSa^s EK-I eontein TSGA GE DuPont HLR 696-92 CENTRAL RESEARCH AND DEVELOPMENT DEPARTMENT HASKELL LABORATORY FOR TOXICOLOGY AND INDUSTRIAL MEDICINE TO: MEDICAL RESEARCH PROJECT NO. cc: Quality Assurance November 11, 1992 PROTOCOL AMENDMENT #3 Descriptive Title of Study; Two-Week Inhalation Toxicity Study vithffl L in Rats The Study Protocol, issued 10-07-88, is amended as follows: Prepared By: Presently Reads: "Dolores E. Maiek, Ph.D. Study Director" Amend to Read: "Hanan N. Ghantous, Study Director" Ph.D ^v^^vsL^- Prepared by: ttW^P (JMaryanne MJ. Wilford Toxicology Associate Approved by: ' ^I' ^ Hanan Ghantous Study Director /'/ /'/^ -35- Company Sanitized. Does not se^ain TSCA CBl CENTRAL RESEARCH AND DEVELOPMENT DEPARTMENT HASKELL LABORATORY FOR TOXICOLOGY AND INDUSTRIAL MEDICINE TO: MEDICAL RESEARCH PROJECT ^-IflBBU 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 By: Presently Reads: Dolores E. Maiek, Ph.D. Study Director Amend to Read: Hanan N. Ghantous, Study Director" Ph.D Amend to Read: "As of June 1, 1992, Hanan N. Ghantous will replace Judith C. Stadler as study director for this study." Prepared by: Y\\lL^U(i'^v.'6\Y- \. I .II-I.JT-I^______ !\Maryanne y. Wilford Toxicology Associate Approved by: r Hanan Ghantous Study Director /^ / // / ?z. ^^ ^^ ^ ,,,^^ ,^ ^ CENTRAL RESEARCH AND DEVELOPMENT DEPARTMENT HASKELL LABORATORY FOR TOXICOLOGY AND INDUSTRIAL MEDICINE TO: MEDICAL RESEARCH PROJECT NOd PROTOCOL AMENDMENT #6 1. Protocol Amendment #2 is amended as follows: ^^fHIUj111 The title ofthestudvis changed from "Two-Week Inhalation Toxicology Study vitlfflllHHHiin Rats" to "Subchronic Inhalation Toxicology Study 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: THanan Ghantous ^Study Director Date l^l^l^ 36a - Company Sanitized. Does not contain TSCA CBI Subchronic Inhalation Toxicity Study with, DuPont HLR 696-92 APPENDIX B Daily Atmospheric Analyses Note: 'Data are reported to two significant figures. 37 - ?Oi?S19@SgygnSHsr"?. E''?P^ "i^ ^wir-^ TR^fi f*RB Subchronic Inhalation Toxicity Study vithi DuPont HLR 696-92 Appendix B Daily Atmospheric Analyses Control: 0 mg/m3 Exposure No. [ } Conceritration (mg/m3) Mean S.D. Range 1 2 -- -- -- 3 -- -- -- 4 -- -- 5 -- 6 -- -- 7 - -- 8 -- -- -- 9 -- -- -- 10 -- -- -- Chamber3 Temp. (C) Relative13 Humidity m 20 - 24 63 20 - 23 60 20 - 24 68 19 - 23 73 20 - 23 63 20 - 24 64 19 - 23 69 19 - 23 65 19 - 22 67 20 - 22 68 Oxygen0 Content W 21 21 21 21 21 21 21 21 21 21 Design Concentration ; 1 mg/m3 Exposure [--------t l Concentration (mg/m3) No. Mean S.D. Range 1 0.92 0.46 0.25 - 3.6 2 1.3 0.93 0.05 - 4.2 3 1.3 1.3 0.0 - 4.6 4 0.69 0.27 0.25 - 1.6 5 0.96 0.19 0.50 - 1.5 6 1.7 1.0 0.15 - 3.8 7 1.4 1.1 0.0 - 5.0 8 1.3 0.84 0.0 - 3.7 9 1.5 0.39 0.65 - 2.2 10 1.5 0.95 0.10 - 3.8 Chamber'1 Temp. (C) 22 - 23 22 - 24 22 - 23 20 - 23 21 - 24 22 - 24 21 - 22 21 - 22 20 - 22 20 - 22 Relative13 Humidity (%) 61 62 61 64 55 58 61 58 62 58 Oxygen Content m 21 21 21 21 21 21 21 21 21 21 - Refers to values that were not determined. a Range of two measurements per exposure. b One measurement per exposure. c One measurement per exposure. d Mean of 72 measurements per exposure. Company Sanitized. Doas not contain TSCA CBl 38 Subchronic Inhalation Toxicity Study with DuPont HLR 696-92 Append!:K. B ( continilied) Dclily Atmiosphe ric An.alyses Design Coiicentratior1: 5 rng/ni3 1) Exposure Mo. Conce'ntratiori (mg/m3.) Mean S.D. Rangfa 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 Cham]aer1' r Cemp. lCc) 22 - 23 21 - 23 21 - 23 20 - 22 20 - 22 20 - 24 20 - 22 20 - 22 20 - 22 20 - 22 Relativec Humidity W 63 61 56 69 53 56 65 58 62 60 Oxygen'1 Content (%) 21 21 21 21 21 21 21 21 21 21 Design Concentration : 10 mg/m3 Exposure No. [ lUlllO Concentration (mg/m3) 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 Chamber1' Temp. ( C) 22 - 24 22 - 24 22 - 24 21 - 23 22 - 23 22 - 24 21 - 24 21 - 23 20 - 23 20 - 23 Relative0 Humidity W 69 71 54 62 53 58 61 58 62 58 Oxygen'3 Content m 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. w Genfpsny S^,^. 5oeg ^ esm^ TSCA egs 39 DuPont HLR 696-92 Subchronic Inhalation Toxicity Study vl ^lUBIHHtf ) 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. - 40 - Cwnnairav ganWyad. Rnpss ""? contain TSCA CRT Subchronic Inhalation Toxicity Study withi DuPont HLR 696-92 Appendix C Individual Body Weights of Control Male Rats Group I Rat No. 447112 447113 447114 447115 447116 447117 447118 447119 447120 447121 1 231 .9 237 .2 245 .3 226 .9 228 .2 235 .9 244 .1 218 .9 229 .8 236 .2 2 235.1 234.3 259.8 220.9 233.6 244.0 256.6 231.9 234.3 232.5 D ays on. Te st 3 4 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 8 276 .9 275 .8 311 .3 277 .5 283 .3 292 .2 301 .4 284 .7 280 .1 279 .0 9 278 .0 276 .9 314 .1 287 .8 284 .7 297 .6 308 .2 292 .4 288 .0 282 .6 10 281.7 284.9 324.9 293.9 292.5 303.2 309.9 291.4 297.1 294.1 Rat No. 447112 447113 447114 447115 447116 447117 447118 447119 447120 447121 11 289.4 294.0 337. 2 296. 4 293. 0 313. 0 319. 4 303. 3 308. 2 300. 2 Days on Test 12 15 16 . 17 299.4 304.9 329.3 303.3 296.6 312.5 315.1 297.1 306.6 296.2 307.6 322.7 SD (day 324.8 SD (day SD (day SD (day 318.7 322.7 SD (day 314.0 325.3 12) 324.8 12) 12) 12) 324. 2 329. 9 12) 319.1 338.1 339.8 333. 7 339. 6 18 329.5 342.8 345.8 336. 0 347. 3 19 337.4 348.9 351.8 347. 1 353. 5 22 357.8 371.1 376.9 374.2 368.8 Company Sanitized. Does not contain TSCA CB\ 41 - 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 42 - y Ss?iiS?2@d. Pass no? eaniain TSCA CBf Subchronic Inhalation Toxicity Study witnl DuPont HLR 696-92 Appendix C (continued) Individual Body Weights of Male Rats Exposed to 1 mg/m^ Group III Rat No. 447122 447123 447124 447125 447126 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 3 4 5 249.8 239.0 243.7 241.2 248.5 230.6 232.0 247.2 261.8 235.1 250.6 245.0 250.6 248.2 251.5 235.0 234.5 245.5 276.2 241.9 260.,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 17 270.3 280.7 305.8 295.9 292.3 265.7 297.9 296.6 337.4 262.5 SD (day SD (day 325.4 SD (day 315.6 294.5 SD (day SD (day 366.6 293.7 12) 12) 328.4 12) 321.5 308.0 12) 12) 367.6 301.8 340. 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. Sonroany Sanitized. Does nof contain TSCA CBI 43 Subchronic Inhalation Toxicity Study with DuPont HLR 696-92 Appendix C (continued) Individual Body Weights of Male Rats Exposed to 1 mg/m3] 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 24 388.6 382.9 366.0 447.8 357.4 Days on Test 25 26 401.3 391.6 373.9 398.7 384.3 360.8 461.2 367.2 432.5 367.3 d Design concentration. 'Sampany SartiEEsses. Dae^ ROE eaEHain TSCA CBE 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 Exposed to 5 mg/m3 of Male Rats 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 D,ays on T<ast 3 4 5 248.2 251.0 259.4 219.0 235.2 238.3 248.4 226.9 231.6 245.2 253.8 253.1 264.5 227.1 237.3 245.7 254.3 231.3 237.4 256.0 263.2 264.5 274.1 230.7 243.9 256.3 255.1 237.2 246.9 260.3 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. 447132 447133 447134 447135 447136 447137 447138 447139 447140 447141 1 1 307 .7 302 .0 327 .6 270 .0 277 .1 300 .3 299 .4 274 .6 281 .4 308 .1 D,iys on Te;3t 12 15 1 6 1 7 310.5 305.0 326.3 267.9 282.8 306.9 299.8 268.3 274.1 312.8 SD (day 316.6 SD (day 288.1 300.5 327.9 SD (day 283.5 SD (day SD (day 12) 320 .9 12) 277 .3 302 .0 326 .8 12) 293 .5 12) 12) 328 .0 292 .3 309 .6 339 .7 303 .2 1 8 331 .4 297 .7 311 .5 341 .3 302 .4 1 9 341 .4 303 .9 309 .1 349 .5 306 .8 22 353.1 326.4 338.8 380.1 328.9 a Design concentration. y Company Sanitized. Does not contain TSCA CBI 45 - Subchronic Inhalation Toxicity Study with DuPont HLR 696-92 Appendix C (continued) Individual Body Weights of Male Rats Exposed to 5 mg/n Group V (continued) Da:ys on Test Rat No. 23 r !4 2'5 26 447132 447133 447134 447135 447136 447137 447138 447139 447140 447141 366.7 330.7 343.5 388.1 346.0 367. 1 337. 3 351. 3 392. 5 352. 5 370. 6 344. 1 360. 6 395. 8 356. 7 370.0 343.7 353.1 399.4 355.2 a Design concentration. 'SampaRy Satirised. OGS 'WE sorEta'-s TSCA CB? 46 - DuPont HLR 696-92 Subchronic Inhalation Toxicity Study withj|| Group VII Rat No. 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 Appendix C (continued) Individual Body Weights of Male Rats Exposed to 10 sig/m\ 2 256.1 214.0 233.7 248.4 241.2 227.3 230.3 232.8 252.4 218.5 D,ays on T est 3 4 5 262.9 226.3 238.4 253.0 250.3 234.5 240.5 242.7 262.4 222.6 265.7 231.1 251.2 265.3 255.7 242.3 247.4 249.4 263.8 228.5 270.1 237.3 252.7 265.7 263.7 247.3 250.5 253.3 266.7 229.2 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 Mo. 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. 4 273. 6 295. 7 318. 6 307. 7 294. 8 291. 5 293. 8 320. 5 274. 9 345.0 287.8 SD (DAY SD (DAY 336.3 SD (DAY 310.5 309.2 SD (DAY 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 34R. 7 a Design concentration. Company Sanit?zed. Does noi contain TSCA CBi 47 Subchronic Inhalation Toxicity Study with/ DuPont HLR 696-92 Appendix C (continued) Individual Body Weights of Male .Rats Exposed to 10 mgTFJIB Group VII (continued) Days on Test Rat No. 23 24 25 26 447142 447143 447144 447145 447146 447147 447148 447149 447150 447151 407.1 341.0 402.9 365.1 358.3 412.9 345.5 412.2 348.6 397.8 333.2 412.8 374.6 363.9 415.3 380.7 368.8 392.6 383.9 368.1 a Design concentration. Qompsny SafiiSiz&d. Soes not coniEJn TSCA ( 48 - Subchronic Inhalation Toxicity Study with| DuPont HLR 696-92 APPENDIX D Individual Clinical Observations of Male Rats Note: NR = Not Recovered. Rat Clinical observations do following exposure. exhibited given sign at last weighing. . not include signs observed during or immediately Company Sanitized. Does not contain TSCA CBi 49 - Subchronic Inhalation Toxicity Study wit DuPont HLR 696-92 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 16 22 Corneal opacity, left Eye 16 16 50 - OBRpsny -Ss'r'fSiaed. Does ~c? cwiain T3C.& CSE Subchronic Inhalation Toxicity Study with] DuPont HLR 696-92 APPENDIX E Clinical Pathology Report Mo. 10-89 Company SanFtfzed. D"as n^t contain TSCA (*R? 51 DuPont HLR 696-92 CLINICAL PATHOLOGY REPORT NO. 10-89 SUBCHRONIC.INHALATION TOXICITY STUDY MEDICAL RESEARCH PROJECT N01 --------I HASKELL LABORATORY NO. 17375 Sponsor: DuPont Specialty Chemicals & G&snpani? SaniSIzecS. c-css nw contain TSCA C@i -52- SUBCHRONIC INHALATION TOXICITY STUDY WITH DuPont HLR 696-92 Summary tolHUUR^t Male Crl:CD\BR rats were exposed by inhalation 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: Cn^t-ilr ^e^yTT^f-yT-^ 'o l~ Donna R. Holt Technician UK H Report by: .^^^^^^^^C ^C- Michael C. Carakostas,^D.V.M., Ph.D. Diplomate, A.C.V.P. . . Coordinator, Clinical Pathology Approved by: D.V.M.^ William 'C. Krauss, Manager, Pathology Division ^>Cb- Company Sanitized. Does nat contain TSCA CBt -53- DuPont HLR 696-92 Procedure Four groups of ten male Crl:CDBRratswere^xposed, by inhalation, for six hours per day for ten days &ou|||||UHat 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 leukoeytes 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 (GREAT), 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 tima. When the F-test from ANOVA was -54- ny 3an??ted. 0oe^ r;-?? con'a^ T8CA CE DuPont HLR 696-92 significant, the Dunnett test was usedi tocompareemmeeaans from the control to1U--IB--H--H--U --------^ group and each of the groups exposed When the results of the Bartlett test were significant (p ^<o-D..000055)),^hthee KK ruskal-Wallis test was employed and the Mann-Whitney U test was used to, compare means from the ^UUil^^^fj 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- Gemoany Sanitized. Qoes not contain TSCA 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 studs 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 CoffloqitV SanHis'st?. Does nf\1. conWn TSC& RBi -56- DuPont HLR 696-92 H-17375 SUBCHRONIC INHALATION TOXICITY WITH CLINICAL PATHOLOGY TEXT TABLE 1 SUMMARY OF STATISTICALLY SIGNIFICANT HEMATOLOGIC AND CLINICAL CHEMICAL FINDINGS FOR MALE RATS Sampling Time Measurement Hematology Lymph Clinical CREAT TPROT CHOL Chemistry (Serum) Clinical Chemistry (Urine) VOL OSMOL 12 DAYS ON TEST - -I- VII 4- VII+ + III,V,VII + III,V. VII 26 DAYS ON TEST ^ v 'I' III + == Significantly higher than controls by Dunnett or Mann-Whitney U (+) criteria + = Significantly lower than controls by Dunnett or Mann-Whitney U (+) criteria - = Not statistically significant 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. ws--------^^ -57- H-17375 DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WITH, TABLE 2 SUMMARY OF HEMATOLOGIC FINDINGS FOR MALE RATS TESTS CONCENTRATION (mg/m ) SAMPLING TIME 12 DAYS 26 DAYS ON TEST ON TEST RBC,- xlOVul Hb g/di Ht % MCV fl MCH pg MCHC g/di PIAT xlO /ul 0 7.03( 0.35)'' 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) 0 14.6( 0.8) 15.0( 0.9) 1 15.1( 0.8) 14.4( 0.4) 5 14.7( 0.7) 15.0( 0.7) 10 14.4( 0.7) 15.2( 0.8) 0 49.( 2.) 50. ( 2.) 1 49.( 2.) 49.( 1.) 5 48.( 2.) 50. ( 2.) 10 47.( 1.) 51. ( 2.) 0 69.( 1.) 68.( 1.) 1 70.( 1.) 68.( 1.) 5 70.( 1.) 69.( 1.) 10 70.( 1.) 69.( 1.) 0 21.( 1.) 20.( 1.) 1 21.( 1.) 20. ( 1.) 5 22.( 1.) 21.( 0.) 10 21.( 1.) 21. ( 1.) 0 30.( 1.) 30.( 1.) 1 31.( 1.) 29.( 0.) 5 31.( 0.) 30. ( 0.) 10 31.( 1.) 30.( 1.) 0 1144.( 326.) 1151.( 363.) 1 1127.( 221.) 1028.( 258.) 5 1115.( 261.) 983.( 161.) 10 1146.( 246.) 843.( 74.) Group means and standard deviations(SD) No statistically significant differences found at 5% level by Dunnett or Mann-Whitney U criteria ^ -58- Company Sanitized. Does not contain TSCA CBf H-17375 DuPont HLR 696-92 SUBCHROMIC INHALATION TOXICITY STUDY WITH TABLE 2 (continued) SUMMARY OF HEMATOLOGIC FINDINGS FOR MALE RATS TESTS CONCENTRATION (mg/m ) SAMPLING TIME 12 DAYS 26 DAYS OM TEST ON TEST WBC, xl0-/ul Neut WBCx% 0 14.6( 1.6)' 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) 0 2250, ( 1004.) 2793.( 1431.) 1 2806, ( 1404.) 3448.( 1390.) 5 2423. ( 1085.) 3089.( 1186.) 10 2578, ( 1000.) 2452.( 1017.) Band WBCxo Lymph WBCx% 0 0.( 0.) 0.( 0.) 1 0.( 0.) 0.( 0.) 5 0.( 0.) 0.{ 0.) 10 0.( 0.) 0.( 0.) 0 11499. ( 1892.) 10753.( 1824.) 1 10856.( 1827.) 5 11081.( 1769.) 9943.( 772.) 8721.( 820.)* 10 9453. ( 1649.) 8979.( 872.) Group means and standard deviations(SD) * Significantly different from control at 5% level by Dunnett criteria -59- eampaRy Sanitized. Does ns? csniain TSCA C? H-17375 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 (nig/in ) 0 1 5 10 0 1 5 10 0 1 5 10 0 1 5 10 SAMPLING TIME 12 DAYS 26 DAYS ON TEST ON TEST 147. ( 103.( 136. ( 172. ( 203.)a 229.) 199.) 161.) 38. ( o.( 29. ( 95.( 85.) 0.) 65.) 130.) 626. ( 481. ( 767. ( 432. ( 409.) 301.) 383.) 267.) 1362.( 889. ( 916. ( 728. ( 393.) 252.) 311.) 526.) 58. ( 77.) 15.( 47.) 25.( 78.) 65.( 86.) 54.( 73.) 0.( 0.) 66. ( 96.) 26. ( 58.) o.( 0.) o.( 0.) 0.( 0.) 0.( 0.) 0.( 0.) 0.( 0.) 0.( 0.) 0.( 0.) Group means and standard deviations(SD) No statistically significant differences found at 5% level by Dunnett or Mann-Whitney U criteria -60- ^pany Sa^zeti. OOCB nc. contain TSCA CB( 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/m ) 0 1 5 10 0 1 5 10 0 1 5 10 0 1 5 10 0 1 5 10 0 1 5 10 0 1 5 10 SAMPLING TIME 12 DAYS 26 DAYS ON TEST ON TEST 468. ( 394. ( 454. ( 428. ( 97.)3 85.) 108.) 47.) 466. ( 391. ( 494.( 464. ( 92.) 65.) 119.) 101.) 45.( 6.) 53.( 23.) 56. ( 33.) 51. ( 10.) 75.( 13.) 82. ( 29.) 77.( 41.) 72.( 9.) 16. ( 2.) 19.( 4.) 16.( 2.) 16.( 2.) 0.6( 0.1) 0.5( 0.1) 0.5( 0.1) 0.5( 0.0) 41.( 5.) 38.( 7.) 39. ( 6.) 41.( 5.) 65.( 4.) 66. ( 4.) 61.( 8.) 70. ( 5.) 17.( 2.) 15.( 3.) 19.( 2.) 17.( 3.) 0.6( 0.0) 0.5( 0.1)* 0.6( 0.0) 0.6( 0.0) 6.0( 0.3) 6.2( 0.4) 5.8( 0.2) 5.6( 0.3)* 6.5( 0.3) 6.2( 0.2) 6.3( 0.1) 6.0( 0.2) 67.( 55. ( 60.( 55.( 15.) 9.) 6.) 5.)# 76.( 16.) 63.( 7.) 63.( 10.) 62.( 14.) 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 iSemaSi'"? ^an^igia^. "os6; "r? F;s"?aSn Ti^fe CBf -61- H-17375 DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WI TABLE SUMMARY OF CLINICAL URINALYSIS FINDINGS FOR MALE RATS TESTS VOL ml OSMOL nOs pH UROBL ing/dl CONCENTRATION (ing/m ) SAMPLING TIME 12 DAYS 26 DAYS ON TEST ON TEST 0 12.7( 3.a)3 13.9( 4. 1) 1 7.5( 2.2)* 18.4( 10. 1) 5 8.7( 1.3)* 13.0( 3. 2) 10 8.4( 2.0)* 14.3( 3. 3) 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) 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) 0 0.1( 0.0) 1 0.1( 0.0) 5' 0.1( 0.0) 10 0.1( 0.0) 0.1( 0.1( 0.1( 0.1( 0. 0) 0. 0) 0. 0) 0. 0) Group means and standard deviations(SD) * Significantly different from control at 5^ level by Dunnett criteria -62- ;ompany Sanitized. Does not contain TSCA CBi DuPont HLR 696-92 H-17375 SUBCHRONIC INHALATION TOXICITY STUDY WITHj TABLE 4 (continued) SUMMARY OF CLINICAL URINALYSIS FINDINGS FOR MALE RATS Measurement Con<:entration lCrng/m ) Blood 0 Number Positive 1 5 10 Glucose 0 Number Positive 1 5 10 Protein 0 Number Abnormal 1 >+ 3 5 10 Bilirubin 0 Number Positive 1 5 10 Ketone 0 Number Positive 1 5 10 Appearance (Color 0 and Transparency) 1 5 10 Microscopic 0 Number Abnormal 1 5 10 Sampling; Time 12 DAYS ON TEST 26 DAYS ON TEST 1/10++ 3/5 2/10 1/5 1/10 0/5 2/10 1/5 0/10 0/5 0/10 0/5 0/10 0/5 0/10 1/5 0/10 0/5 0/10 0/5 0/10 0/5 0/10 0/5 0/10 0/5 .0/10 0/5 0/10 0/5 0/10 0/5 10/10 5/5 10/10 5/5 10/10 5/5 10/10 5/5 0/10 0/5 0/10 0/5 0/10 0/5 0/10 0/5 6/10 5/5 7/10 5/5 5/10 5/5 7/10 5/5 ++ Number of abnormal or positive findings/number of individual specimens examined -63- company SanitlEeeL Saes ns? cRriisiR TSGA GBS DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WITH' APPENDIX A H-17375 -64- Company Sanitized. Dess Rot eoriia!n TSCA CB( 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 = CL = P/PPT = P = Clear Cloudy Precipitate Feed FEC = Feces QNS = Quantity not sufficient Abbreviations for Descriptive Terms Used for Microscopic Evaluation of Urine TNTC Epith hpf Ipf RFC 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 tu 4 red blood cells per high power field None observed Epithelial Cells White Blood Cells Average of 0 to 9 per high power field Average of 0 to 9 per high power field 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 Average of more than 9 per high power field Average of more than 9 per high power field -65- ('e?spsny SarEJfi2@Q. oaes not contain T'sGA C3S- DuPont HLR 696-92 5-17375 SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX A ANIMALS WITH MISSING CLINICAL DATA Animal Number 447150 Group Sampling Test(s) Designation___Time______Omitted_____Reason for Omission VII 12 DAYS Serum TPROT Invalid results-data ON TEST not used B) i/ -66- eoww Seized. Do.., no, contain TSCACB, H-17375 DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WI APPENDIX A INDIVIDUAL HEMATOLOGIC FINDINGS FOR MALE RATS AT 12 DAYS ON TEST GROUP: I SAMPLE DATE: 10/28/88 RB iC Hb ANIMAL#: 447112 447113 447114 447115 447116 447117 447118 447119 447120 447121 AVG. S. D. S. E. ;<106/ul 7 .13 6 .84 6 .29 6 .97 6 .93 6 .86 7 .23 7 .12 7 .50 7 .45 7 .03 0 .35 0 .11 9/dl 14 .5 14 .7 12 .8 14 .3 15 .3 14 .2 14 .9 14 .5 15 .0 15 .7 14 .6 0 .8 0 .2 Ht % 49. 48. 43. 48. 49. 47. 50. 49. 52. 52. 49. 2. 1. CONCENTRATION: 0 mg/m BIRTH DATE: 08/22/88 MCV MCH MCHC PLAT fl pg g/di xlO^ul 68. 20. 30. 680. 70. 22. 31. 1102. 69. 20. 30. 1031. 69. 21. 30. 1300. 70. 22. 31. 1484. 69. 21. 30. 1599. 69. 21. 30. 1500. 68. 20. 30. 1026. 69. 20. 29. 665. 69. 21. 31. 1051. 69. 21. 30. 1144. 1. 1. 1. 326. 0. 0. 0. 103. I I I GROUP: SAMPLE DATE: 10/28/88 RBC Hb ANIMALft: 447122 447123 447124 447125 447126 447127 447128 447129 447130 447131 AVG. S. D. S. E. :il06/ul 7 .55 6 .83 6 .89 6 .79 6 .74 7 .12 7 .04 7 .21 6 .86 7 .92 7 .09 0 .38 0 .12 g/'dl 16 .7 14 .6 15 .0 15 .2 14 .4 14 .9 14 .8 15 .4 14 .0 16 .3 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 Pg g/di xlO^ul 70. 22. 32. 1020. 70. 21. 31. 1547. 71. 22. 31. 858. 71. 22. 32. 1079. 70. 21. 31. 971. 69. 21. 30. 1295. 69. 21. 31. 1389. 70. 21. 31. 1154. 69. 20. 30. 903. 68. 21. 30. 1056. 70. 21. 31. 1127. 1. 1. 1. 221. 0. 0. 0. 70. -67- Company Sanded. Does not conta-.n- H-17375 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 RB1C Hb ANIMAL#: 447132 447133 447134 447135 447136 447137 447138 447139 447140 447141 AVG. S. D. S. E. ;tl06/ul 6 .39 7 .03 6 .77 6 .89 7 .29 6 .76 6 .72 6 .97 7 .23 6 .33 6 .84 0 .32 0 .10 9/dl 13 .7 15 .0 14 .7 14 .7 15 .9 14 .9 13 .8 15 .3 15 .1 14 .0 14 .7 0 .7 0 .2 Ht % 45. 49. 47. 48. 51. 48. 45. 49. 50. 45. 48. 2. 1. CONCENTRATION: 5 mg/m BIRTH DATE: 08/22/88 MCV MCH MCHC PLAT fl P9 g/dl xlO3/^ 71. 21. 30. 1622. 70. 21. 31. 1280. 70. 22. 31. 941. 70. 21. 31. 1351. 70. 22. 31. 804. 70. 22. 31. 1113. 67. 21. 31. 797. 70. 22. 31. 1036. 69. 21. 30. 964. 72. 22. 31. 1246. 70. 22. 31. 1115. 1. 1. 0. 261. 0. 0. 0. 83. GROUP: VII SAMPLE DATE: 10/28/88 RBC 1Ib ANIMALft: 447142 447143 447144 447145 447146 447147 447148 447149 447150 447151 x]LO^ul 6.88 6.63 6.73 7.12 6.75 6.62 6.63 6.86 6.83 6.43 g/c11 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 Ht % 48. 48. 46. 50. 48. 46. 46. 48. 47. 46. 47. 1. 0. CONCENTRATION: 10 mg/m BIRTH DATE: 08/22/88 MCV MCH MCHC PLAT fl pg g/dl xlO^ul 70. 21. 30. 1422. 72. 23. 32. 822. 68. 21. 30. 1050. 70. 22. 31. 920. 71. 22. 32. 1138. 69. 21. 30. 1359. 70. 20. 29. 758. 69. 21. 31. 1377. 69. 21. 30. 1272. 71. 22. 31. 1340. 70. 21. 31. 1146. 1. 1. 1. 246. 0. 0. 0. 78. -68- Company Sanitized. Does not contain TSCA CBI 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 WBCi ANIMAL#: 447112 447113 447114 447115 447116 447117 447118 447119 447120 447121 AVG. S. D. S. E. :tl03/'ul 17 .1 14 .8 11 .5 15 .6 12 .9 13 .8 15 .7 14 .1 15 .5 14 .8 14 .6 1 .6 0 .5 CONCENTRATION: 0 nig/in" BIRTH DATE: 08/22/88 Neut Band Lymph Alym Mono Eosin Baso WBCx% 2907. 2220. 3105. 3120. 1032. 2622. 1727. 3666. 620. 1480. 1/Cx% 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 2250. 0. 1004. 0. 317. 0. WBCx% 12654. 11100. 7935. 12012. 11481. 10212. 12560. 9588. 14570. 12876. 11499. 1892. 598. WBCx% 0. 296. 0. 312. 0. 552. 314. 0. 0. 0. 147. 203. 64. WBCx% 1368. 1184. 345. 156. 387. 414. 942. 705. 310. 444. 626. 409. 129. WBCx% 171. 0. 115. 0. 0. 0. 157. 141. 0. 0. 58. 77. 24. 1fCx% 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. I I I GROUP: SAMPLE DATE: 10/28/88 WBC ANIMALft: 447122 447123 447124 447125 447126 447127 447128 447129 447130 447131 xlO3/^ 16.3 14.2 15.5 11-R 10.6 16.8 16.7 10.4 15.4 14.9 AVG. S. D. S. E. 14.3 2.5 0.8 CONCENTRATION: 1 nig/in BIRTH DATE: 08/22/88 Neut Band Lymph Alym Mono Eosin Baso WBCx% 2934. 2414. 2015. 1652. 530. 3192. 3507. 1976. 4620. 5215. WBCx% 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. WBCx% 12388. 11218. 12710. 9440. 9964. 12768. 12859. 7800. 10626. 8791. WBCx% 0. 0. 0. 354. 0. 672. 0. 0. 0. 0. WBCx% 978. 568. 775. 354. 106. 168. 334. 624. 154. 745. WBCx% 0. 0. 0. 0. 0. 0. 0. 0. 0. 149. WBCx% 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 2806. 0. 1404. 0. 444. 0. 10856. 103. 481. 15. 0. 1827. 229. 301. 47. 0. 578. 72. 95. 15. 0. -69- 'QQmps^j SaRJSESod. Bess n"6 serifem TCA C? H-17375 DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WITHJ APPENDIX A (continued) INDIVIDUAL HEMATOLOGIC FINDINGS FOR MALE RATS AT 12 DAYS ON TEST GROUP: V SAMPLE DATE: 10/28/88 WBC ANIMALft: 447132 447133 447134 447135 447136 447137 447138 447139 447140 447141 AVG. S. D. S. E. :xl03/'ul 13 .3 14 .1 . 15 .4 12 .0 12 .3 16 .3 17 .0 12 .8 16 .7 14 .4 14 .4 1 .8 0 .6 CONCENTRATION: 5 mg/m BIRTH DATE: 08/22/88 Neut Band Lymph Alyro Mono Eosin Baso WBCx% 798. 2538. 2464. 1800. 1968. 3260. 4590. 2816. 2839. 1152. 2423. 1085. 343. 1WBCx% 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. WBCx% 11704. 10716. 12012. 8640. 8856. 12388. 11730. 8704. 13527. 12528. 11081. 1769. 559. WBCx% 133. 423. 0. 0. 0. 0. 0. 512. 0. 288. 136. 199. 63. WBCx% 665. 423. 924. 1560. 1230. 652. 680. 768. 334. 432. 767. 383. 121. WBCx% 0. 0. 0. 0. 246. 0. 0. 0. 0. 0. 25. 78. 25. \ /TOCx% 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. GROUP: VII SAMPLE DATE: 10/28/88 WBCi ANIMALft: 447142 447143 447144 447145 447146 447147 447148 447149 447150 447151 AVGS. D. S. E. :<103/ul 10 .7 13 .9 11 .9 16 .1 9 .8 13 .2 10 .6 12 .3 15 .0 13 .5 12 .7 2 .0 0 .6 CONCENTRATION: 10 mg/m- BIRTH DATE: 08/22/88 Neut Band Lymph Alym Mono Eosin Baso WBCx% 2461. 3475. 1190. 4347. 1470. 3564. 2014. 2337. 1950. 2970. 1WBCx% 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. WBCx% 7490. 10008. 10353. 11109. 7742. 8712. 7950. 9102. 12750. 9315. WBCx% 214. 0. 238. 0. 196. 0. 0. 369. 300. 405. WBCx% 321. 278. 119. 483. 392. 792. 636. 492. 0. 810. WBCx% 214. 139. 0. 161. 0. 132. 0. 0. 0. 0. 1WBCx% 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 2578. 0. 1000. 0. 316. 0. 9453. 172. 432. 65. 0. 1649. 161. 267. 86. 0. 521. 51. 84. 27. 0. -70- eempany an?feetf. Q^ ^ , ^ ^ ^ H-17375 DuPont HLR 696-92 SUBCHROMIC INHALATION TOXICITY STUDY WITH1 APPENDIX A (continued) INDIVIDUAL CLINICAL CHEMICAL FINDINGS FOR MALE RATS AT 12 DAYS ON TEST GROUP; I SAMPLE DATE: 10/28/88 ALP ALT ANIMALft : U/L U/L 447112 457. 51. 447113 539. 43. 447114 425. 48. 447115 539. 43. 447116 630. 48. 447117 353. 53. 447118 526. 51. 447119 410. 39. 447120 492. 37. 447121 307. 40. AVG. 468. 45. S. D. . 97. 6. S. E. 31. 2. CONCENTRATION: 0 mg/m BIRTH DATE: 08/22/88 AST BUN CHEAT 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 75. 16. 0.6 13. 2. 0.1 4. 1. 0.0 g/dl 6 .1 5 .8 6 .4 5 .7 5 .4 5 .8 6 .3 6 .0 6 .1 6 .1 6 .0 0 .3 0 .1 mg/dl 72. 61. 56. 64. 50. 79. 73. 61. 101. 56. 67. 15. 5. I I I GROUP: SAMPLE DATE: 10/28/88 ALP ALT ANIMALft: 447122 447123 447124 447125 447126 447127 447128 447129 447130 447131 U/L 307. 413. 396. 457. 536. 326. 394. 471. 395. 242. U/L 28. 37. 66. 42. 41. 30. 48. 68. 106. 61. AVG. 394. 53. S. D. 85. 23. S. E. 27. 7. CONCENTRATION: 1 mg/m 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 82. 19. 0.5 29. 4. 0.1 9. 1. 0.0 g/ dl 6 .4 5 .9 6 .0 6 .3 5 .8 6 .1 6 .3 6 .1 5 .7 7 .0 6 .2 0 .4 0 .1 mg/dl 37. 64. 58. 61. 44. 66. 55. 53. 60. 52. 55. 9. 3. Sani^d.Doesnotoonla.nTSCACBS Company -71- H-17375 DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WI APPENDIX A (continued) INDIVIDUAL CLINICAL CHEMICAL FINDINGS FOR MALE RATS AT 12 DAYS ON TEST GROUP: V SAMPLE DATE; 10/28/88 CONCENTRATION: 5 mg/m 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/dl 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/d11- 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. B 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#: U/L U/L 447 142 434. 46. 447 143 506. 66. 447 144 418. 48. 447 145 386. 48. 447 146 466. 46. 447 147 457. 48. 447 148 417. 47. 447.149 439. 61. 447:150 330. 34. 447:151 427. 63. N /G. 428. 51. 5. D. 47. 10. S. E. 15. 3. CONCENTRATION: 10 mg/m BIRTH DATE: 08/22/88 AST BUN CREAT TPROT CHOL U/L mg/dl mg/c11 g/c11 mg/dl 69. 17. 0.,5 5.,8 61. 82. 17. 0. 5 5.,7 60. 84. 15. 0. 5 5.,3 50. 67. 16. 0. 5 6. 1 50. 72. 17. 0. 5 5. 7 49. 64. 15. 0. 5 5. 2 57. 72. 12. 0. 5 5. 5 55. 79. 16. 0. 4 5. 8 58. 55. 17. 0. 6 58. 73. 16. 0. 5 5. 7 50. 72. 16. 0. 5 5. 6 55. 9. 2. 0. 0 0. 3 5. 3. 0. 0. 0 0. 1 1. Qsm^&ny Sa?iEtl2&d. BSHS& Fi&s. SorttaSri. c aCA CBt 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/m BIRTH DATE: 08/22/88 ANIMALft: 447112 "447113 447114 447115 447116 447117 447118 447119 447120 447121 AVG. S. D. S. E. VOL ml 15 .0 10 .0 16 .0 10 .0 18 .0 15 .0 11 .0 11 .0 11 .0 10 .0 12 .7 3 .0 0 .9 OSMOL m0s 1280. 1553. 1220. 1554. 969. 1159. 1579. 1358. 1445. 1558. 1368. 208. 66. BLOOD GLUCOSE PRO TEIN +1 +2 + +1 +1 + +1 +2 +1 +2 pH BILI- UROBL Ke- RUBIN mg/dl tone 7.5 - 0.1 + 7.5 - 0.1 + 7.5 7.5 - 0.1 + 0.1 +1 8.0 - 0.1 + 7.5 - 0.1 + 7.0 - 0.1 + 7.0 - 0.1 + 7.0 - 0.1 + 7.5 - 0.1 + 7.4 0.1 0.3 0.0 0.1 0.0 I I I GROUP: 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 VOL ml 6.0 5.2 8.0 6.5 11.0 5.2 8.0 10.0 10.0 5.0 OSMOL m0s 2035. 2278. 1889. 2017. 1475. 2094. 1775. 1419. 1844. 2338. BLOOD + GLUCOSE PRO TEIN +2 +2 +2 +2 +1 +2 +2 +2 +2 +2 pH BILI- UROBL Ke- RUBIN mg/dl tone 7.0 - 0.1 + 6.5 - 0.1 + 8.0 - 0.1 + 7.5 - 0.1 + 7.5 - 0.1 + 7.5 -- 0.1 + 7.5 -- 0.1 + 7.0 - 0.1 + 7.0 - 0.1 +1 7.0 - 0.1 + AVG. S. D. S. E. 7.5 1916. 2.2 304. 0.7 96. 7.3 0.1 0.4 0.0 0.1 0.0 -73- Company Sanitized. Doss not contain TSCA CB!! H-17375 DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDy WT 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/m BIRTH DATE: 08/22/88 ANIMALft: 447132 447133 447134 447135 447136 447137 447138 447139 447140 447141 AVG. S. D. S. E. 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 8.7 1783. 1.3 198. 0.4 63. PRO TEIN +1 +1 +1 +2 +2 +2 +2 +2 +1 +1 pH BILI- UROBL Ke- RUBIN mg/dl tone 7.5 - 0.1 + 7.0 - 0.1 + 8.0 - 0.1 + 7.0 - 0.1 + 7.5 - 0.1 +1 7.0 - 0.1 + 7.0 - 0.1 + 7.5 - 0.1 + 6.5 7.0 - 0.1 + 0.1 +1 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 ANIMALft: 447142 447143 447144 447145 447146 447147 447148 447149 447150 447151 VOL OSMOL ml m0s 5.0 2403. 6.0 2261. 10.0 . 1484. 9.0 9.0 11.0 6.6 7.8 10.0 10.0 1641. 1639. 1303. 2025. 1871. 1705. 1561. BLOOD + GLUCOSE PRO TEIN +2 +2 +1 +2 +2 +2 +2 +2 +1 +2 P H 6 .5 7 .0 7 .5 7 .0 7 .5 7 .5 7 .5 8 .0 7 .0 7 .5 BILI- RUBINf - 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- Qovapsnj San'Sizsdi. Dc-as.;',;. eonfairs ''SCA CS H-17375 SUBCHRONIC INHALATION TOXICITY STUDY WITH DuPont HLR 696-92 APPENDIX A (continued) INDIVIDUAL CLINICAL URINALYSIS FINDINGS FOR MALE RATS AT 12 DAYS ON TEST GROUP: I SAMPLE DATE: 10/28/88 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 CONCENTRATION: O mg/m BIRTH DATE: 08/22/88 Epith /hpf 2-3 3-4 1-2 1-2 4-5 3-4 2-3 1-2 1-2 1-2 Cast /Ipf 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 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 FECES I I I G R O U P : SAMPLE DATE: 10/28/88 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 CONCENTRATION: 1 mg/m BIRTH DATE: 08/22/88 Epith /hpf 1-2 0-2 2-3 3-4 0-1 1-2 4-5 4-5 3-4 4-5 Cast /Ipf 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 0^ Comoanv Sa^ed. -75- -^ eo"ain TSCA CRI W 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 D!VTE: 10//28/88 ANIMALft: 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 (:ON(:EKn^RATION: 5 mg/m3 13IR'm E(ATE: 08/22/88 Epifch /hpf 0-1 0-0 0-0 0-0 0-1 0-0 0-0 0-1 0-0 0-0 Cast /Ipf 0-0 0-0 0-0 0-0 0-0 0-0 0-0 0-0 0-0 0-0 A]?PEfl>RANCE Y CL P-P-T Y CL PPT Y CL PPT Y CL PPT Y CL PPT Y CL PPT .Y CL PPT DY CL PPT Y CL PPT Y CL PPT FEED GROUP: VII SAMPLE DATE: 10/28/88 CONCENTRATION: 10 mg/m"' BIRTH DATE: 08/22/88 ANIMALft: 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 .^-4 5-6 WBC /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 /Ipf 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 Y CL PPT Y CL PPT FEED FECES -76- 'e&Ripany SasiStesdL Bess nsi eerifain TCA E H-17375 DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WI APPENDIX A INDIVIDUAL HEMATOLOGIC FINDINGS FOR MALE RATS AT 26 DAYS ON TEST GROUP: I SAMPLE DATE: 11/11/88 RB C I:tb ANIMAL#-: 447112 447113 447115 447119 447120 AVG. S. D. S. E. ;cl-06/U.1 7 .08 7 .37 7 .09 7 .69 7 .81 7 .41 0 .34 0 .15 g/d1114. 4 15. 2 13. 9 15. 1 16. 3 15. 0 0. 9 0. 4 Ht % 48. 51. 49. 51. 54. 50. 2. 1. CONCENTRATION: 0 mg/m BIRTH DATE: 08/22/88 MCV MCH MCHC PLAT fl pg g/di xlO3/!!! 67. 20. 30. 1089. 69. 21. 30. 1385. 68. 20. 29. 1645. 67. 20. 29. 869. 69. 21. 30. 769. 68. 20. 30. 1151. 1. 1. 1. 363. 0. 0. 0. 162. I I I GROUP: SAMPLE DATE: 11/11/88 RBC Hb ANIMAL#: 447124 447126 447127 447130 447131 AVG. S. D. S. E. ;t l 0 6 / u l 6 .96 6 .84 7 .12 7 .28 7 .61 7 .16 0 .30 0 .13 g/dl 14 .4 14 .1 13 .9 14 .6 15 .0 14 .4 0 .4 0 .2 Ht % 49. 47. 48. 49. 51. 49. 1. 1. CONCENTRATION: 1 mg/m BIRTH DATE: 08/22/88 MCV MCH MCHC PLAT fl pg g/di xlO^ul 70. 21. 29. 872. 69. 21. 30. 910. 68. 20. 29. 1412. 67. 20. 30. 1166. 67. 20. 29. 782. 68. 20. 29. 1028. 1. 1. 0. 258. 1. 0. 0. 115. -77- CoiTlQanv Sani^ad. BBSS n"? ennWn T<3f?& fef H-17375 DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WITH 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 xlO6/^ 7.55 6.83 7.44 7.44 6.97 g/di 15.6 14.2 15.4 15.6 14.3 AVG- S. D. S. E. 7.25 0.32 0.14 15.0 0.7 0.3 Ht % 52. 48. 52. 52. 49. 50. 2. 1. CONCENTRATION: 5 mg/m BIRTH DATE: 08/22/88 MCV MCH MCHC PLAT fl pg g/di xlO3/^ 68. 21. 30. 830. 70. 21. 30. 1105. 69. 21. 30. 793. 69. 21. 30. 1143. 70. 21. 29. 1042. 69. 21. 30. 1. 0. 0- 0. 0. 0. 983. 161. 72. GROUP: VII SAMPLE DATE: 11/11/88 RB C Hb ANIMAL#: 447142 447143 447146 447148 447149 xl06 /ul 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 CONCENTRATION: 10 ing/in BIRTH DATE: 08/22/88 Ht MCV MCH MCHC PLAT % fl 52. 68. 52. 71. 51. 70. 48. 69. 54. 68. P9 g/di xl03/Ml 20. 30. 723. 22. 31. 817. 21. 30. 889. 20. 29. 896. 20. 29. 888. 51. 69. 21. 30. 2. 1. 1. 1. 1. 1. 0. 0. 843. 74. 33. -78- "eeRiparsy arsiSizsd. o'ses RSi eantefn TCA CBi H-17375 DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WI 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 AVG. S. D. S. E. xlO3/^il 13. 3 13. 5 13. 8 15. 4 19. 0 15. 0 2. 4 1. 1 CONCENTRATION: 0 mg/m BIRTH DATE: 08/22/88 Neut Band Lymph Alym Mono Eosin Baso WBCx% 3857. 1080. 1380. 3850. 3800. 2793. 1431. 640. WBCx% 0. 0. 0. 0. 0. 0. 0. 0. WBCx% 8379. 10935. 10488. 10472. 13490. 10753. 1824. 816. WBCx% 0. 0. 0. 0. 190. 38. 85. 38. WBCx% 931. 1350. 1932. 1078. 1520. 1362. 393. 176. WBCx% 133. 135. 0. 0. 0. 54. 73. 33. WBCx% 0. 0. 0. 0. 0. 0. 0. 0. I I I GROUP: SAMPLE DATE: 11/11/88 ANIMAL#: 447124 447126 447127 447130 447131 WBC ;(10 ^Ail 13. 8 13. 6 14. 3 14. 1 15. 6 AVG. S. D. S. E. 14. 3 0. 8 0. 4 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. 0. 1390. 0. 622. 0. 9943. 0. 889. 0. 0. 772. 0. 252. 0. 0. 345. 0. 113. 0. 0. -79- r-wioaw Ssr^pd. Goes ^ c<-.n?a?n TS^ ^ H-17375 DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WITH' APPENDIX A (continued) INDIVIDUAL HEMATOLOGIC FINDINGS FOR MALE RATS AT 26 DAYS ON TEST GROUP: V SAMPLE DATE: 11/11/88 WBC ANIMALft: 447133 447135 447136 447137 447139 AVG. S. D. S. E. :(lO3/!;il 10. 6 11. 6 13. 6 14. 5 13. 8 12. 8 1. 6 0. 7 CONCENTRATION: 5 mg/m BIRTH DATE: 08/22/88 Neut Band Lymph Alym Mono Eos in Baso WBCx% 1590. 2320. 4488. 3045. 4002. I flBCx% 0. 0. 0. 0. 0. 3089. 0. 1186. 0. 531. 0. WBCx% 8056. 8004. 8568. 10005. 8970. 8721. 820. 367. WBCx% 0. 0. 0. 145. 0- 29. 65. 29. WBCx% 742. 1160. 544. 1305. 828. 916. 311. 139. WBCx% 212. 116. 0. 0. 0. 66. 96. 43. \ i?BCx% 0. 0. 0. 0. 0. 0. 0. 0. GROUP: VII SAMPLE DATE: 11/11/88 WBCi ANIMALft: 447142 447143 447146 447148 447149 AVG. S. D. S. E. xl03/ ul 12 .9 14 .5 11 .9 11 .8 10 .3 12 .3 1 .5 0 .7 CONCENTRATION: 10 mg/m BIRTH DATE: 08/22/88 Neut Band Lymph Alym Mono Eos in Baso 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. 2452. 0. 1017. 0. 455. 0. 8979. 95. 728. 26. 0. 872. 130. 526. 58. 0. 390. 58. 235. 26. 0. -80- Campany Sanitized. Does P.ot contain TSCA CBE H-17375 DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY WITH! APPENDIX A (continued) INDIVIDUAL CLINICAL CHEMICAL FINDINGS FOR MALE RATS AT 26 DAYS ON TEST GROUP: I SAMPLE DATE: 11/11/88 ALP ALT ANIMAL#: U/L U/L 447112 384. 46. 447113 530. 41. 447115 590. 42. 447119 446. 42. 447120 382. 33. AVG. 466. 41. S. D. 92. 5. S. E. 41. 2. CONCENTRATION: 0 mg/m BIRTH DATE: 08/22/88 AST BUN CREAT TPROT CHOL U/L mg/dl mg/dl 63. 18. 0.7 68. 16. 0.6 62. 17. 0.6 66. 20. 0.6 71. 16. 0.6 66. 17. 0.6 4. 2. 0.0 2. 1. 0.0 g/dl 6.4 6.6 6.3 6.9 6.1 mg/dl 69. 59. 72. 79. 102. 6.5 76. 0.3 16. 0.1 7. I I I G R O U P ; SAMPLE DATE: 11/11/88 ALP ALT ANIMALft : U/L U/L 447124 414. 35. 447126 490. 35. 447127 360. 31- 447130 319. 41. 447131 371. 48. AVG. 391. 38. S. D. 65. 7. S. E. 29. 3. CONCENTRATION: 1 mg/m BIRTH DATE: 08/22/88 AST BUN CREAT TPROT CHOL U/L mg/dl mg/c11 65. 16. 0. 6 70. 13. 0. 5 65. 15. 0. 5 70. 13. 0. 5 62. 20. 0. 6 66. 15. 0. 5 4. 3. 0. 1 2. 1. 0. 0 g/dl 6.4 6.0 6.0 6.3 6.5 mg/dl 63. 53. 70. 69. 62. 6.2 63. 0.2 7. 0.1 3. -81- .Jiriparsy SanKIssd. DOSS ^&i Gomain TaC-a CB8 H-17375 DuPont HLR 696-92 SUBCHROMIC INHALATION TOXICITY STUDY WI 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#: U/L U/L 447133 583. 37. 447135 617. 48. 447136 404. 34. 447137 337. 44. 447139 528. 34. AVG. 494. 39. S. D. 119. 6. S. E. 53. 3. CONCENTRATION: 5 mg/m BIRTH DATE: 08/22/88 AST BUN CREAT TPROT CHOL U/L mg/dl mg/dl 75. 16. 0.6 61. 22. 0.6 56. 17. 0.6 58. 20. 0.6 54. 19. 0.6 61. 19. 0.6 8. 2. 0.0 4. 1. 0.0 g/dl 6.4 6.3 6.1 6.4 6.2 mg/dl 59. 61. 50. 78. 66. 6.3 63. 0.1 10. 0.1 5.' GROUP: VII SAMPLE DATE: 11/11/88 ALP ALT ANIMALft: 447142 447143 447146 447148 447149 U/L 371. 526. 360. 466. 595. . U/L 36. 43. 38. 39. 49. . AVG. 464. 41. S. D. 101. 5. S. E. 45. 2. CONCENTRATION: 10 mg/m BIRTH DATE: 08/22/88 AST BUN CREAT TPROT CHOL U/L mg/dl mg/dl 67. 15. 0-6 76. 21. 0.6 72. 15. 0.6 63. 18. 0.6 71. 16. 0.6 g/dl 6.0 6.0 6.0 5.9 6.3 mg/dl 68. 67. 41. 57. 78. 70. 17. 0.6 6.0 62. 5. 3. 0.0 0.2 14. 2. 1. 0.0 0.1 6. -82- Company Sanitized. Does not contain TSCA CSl 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/m" BIRTH DATE: 08/22/88 ANIMALft: 447112 447113 447115 447119 447120 AVG. S. D. S. E. VOL ml 19.0 12.4 8.0 16.0 14.2 OSMOL m0s 1021. 1792. 1923. 1669. 1125. BLOOD -- -- + +3 +1 GLUCOSE 13.9 4.1 1.8 1506. 407. 182. PRO TEIN +1 +2 +2 +2 +1 pH BILI- UROBL Ke- RUBIN mg/dl tone 8.0 0.1 + 7.0 0.1 +1 7.0 0.1 +1 7.5 0.1 + 7.5 0.1 +1 7.4 0.1 0.4 0.0 0.2 0.0 I I I GROUP: SAMPLE DATE: 11/11/88 CONCENTRATION: 1 mg/m BIRTH DATE: 08/22/88 ANIMALft: 447124 447126 447127 447130 447131 VOL ml 9.2 35.0 17.0 18.8 11.8 OSMOL m0s 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 +1- 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 -S) -83- CoETspalnii'i? Oc Br^egntaiRTgeAeBS H-17375 DuPont HLR 696-92 SLBCHROMIC INHALATION TOXICITY STUDY WI 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/m BIRTH DATE: 08/22/88 ANIMAL#: 447133 447135 447136 447137 447139 VOL ml 9.0 16.6 16.0 11.2 12.4 OSMOL BOS 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 ANIMALft: 447142 447143 447146 447148 447149 VOL ml 16.4 11.2 19.0 12.0 12.8 OSMOL m0s 863. 1316. 857. 1911. 1668. BLOOD -- - + GLUCOSE -- -- - + PRO TEIN +1 +1 +2 +2 +2 pH BrLI- UROBL Ke- RUBIN mg/dl tone 7.5 -- 8.0 -- 8.0 - 0.1 +1 0.1 +1 0.1 +1 8.0 -- 8.0 - 0.1 +1 0.1 +1 AVG. S. D. S. E. 14.3 3.3 1.5 1323. 473. 211. 7.9 0.1 0.2 0.0 0.1 0.0 1 Company Sanitized. Does not contain TSCA CBt -84- WH-17375 DuPont HLR 696-92 SUBCHRONIC INHAIATION TOXICITY STUDY Wn APPENDIX A (continued) INDIVIDUAL CLINICAL URINALYSIS FINDINGS FOR MALE RATS AT 26 DAYS ON TEST GROUP: I SAMPLE DATE: 11/11/88 CONCENTRATION: O mg/m BIRTH DATE: 08/22/88 ANIMALft: 447112 447113 447115 447119 447120 RBC /hpf 25-30 50-60 8-10 TNTC 8-10 MBC /hpf TNTC 20-25 8-10 20-25 10-15 Epith /hpf 4-5 2-3 2-3 2-3 1-2 Cast Apt 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 PECES I I I GROUP: SAMPLE DATE: 11/11/88 CONCENTRATION: I mg/m BIRTH DATE: 08/22/88 ANIMALft: 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 /Ipf 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 Ir>v GoE^parsy SasiSizsA, Dass no.^ ssntaiR TSCA C^ -85- DuPont HLR 696-92 f} 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/m" BIRTH DATE: 08/22/88 ANIMALft: 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 /Ipf 0-0 0-0 0-0 0-0 0-0 A]?PEARAN( 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/m BIRTH DATE: 08/22/88 ANIMALft: 447142 RBC /hpf 6-10 WBC /hpf 4-6 Epith /hpf 0-1 Cast /Ipf 0-0 APPEARANCE Y CL PPT 447143 10-15 4-6 1-2 2-3 Y CL PPT 447146 20-25 8-10 1-2 0-1 LY CL PPT 447148 50-60 50-60 2-3 4-5 Y CL PPT 447149 TNTC 45-50 1-2 0-0 DY CL PPT FEED FECES -86- Company Sanitized. Does no8 contain TSCA CBS Subchronic Inhalation Toxicity Study with DuPont HLR 696-92 APPENDIX F Pathology Report No. 6-89 Company Sanitized. Doss no^ eontaSn TSCA CBl - 87 - DuPont HLR 696-92 PATHOLOGY REPORT NO. 6-89 SUBCHRONIC INHALATION TOXICITY STUDY WITH -88- empsny 'SQn'SSzsiS. Os.es Roi?eanga?R TSCA Q8\' DuPont HLR 696-92 SUBCHRONIC INHALATION TOXICITY STUDY VITH SUMMARY (I Groups of 10 male Crl:CDBR rats were exposed by inhalation concentrations of 0, 1, 5, and 10 mg/m3 for 6 hours/day, Monidaay7' 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 noobservable-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- ^ ^ D.V.M.'' Report by: _J^. ^Jl-------- G.^acy Makovec, Diplomate, A.C.V.P. Staff Pathologist 1^1^ Approved by: UoMJj ^L (j^r^ Paul E. Ross, D.V.M. Diplomate, A.C.V.P. Pathology l^kol^ GTM/PER/wfd WPSP/MAKOVEC -89- ^wwanv ganlfeed. Boss iw8 cwSain TSCA CB1 DuPont HLR 696-92 INTRODUCTION AND METHODS Body and organ weight data and gross and m^roscoo^^ findings from male Crl:CDBR rats exposed via inhalation tc{IBHBlBvaPor or alr ^Q"6 are summarized in this report. Exposure groupsvereasTollows: GROUP I III V VII RATS/GROUP 10 10 10 10 CONCENTRATION OF (ing/in 0 (air-exposed control) 1 (low) 5 (intermediate) 10 (high) oflHHm^vapor Animals were exposed to their respective concentrations 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 exsanguination, 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 lymph node, testes, epididymides, sternum (bone and marrow), eyes, nose, and any gross lesions. Testes, epididymides, sternum, and eyes were fixed in Bouin'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. Mean 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 (ANOVA). Vhen the F-test from the ANOVA 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. RESULTS AND DISCUSSION Table 1 summarizes mean final body and organ weights. Incidences of gross observations are listed in Table 2. Table 3 contains incidences of microscopic observations. Appendix A lists body weights and absolute and -90- Comoanv SanWyari- Does "^ contain TSRA CCT DuPont HLR 696-92 relative organ weights for individual animals. animal gross and microscopic pathology data. Appendix B contains individual There were no compound-related effects detected. Lung weights were statistically significantly decreased in the 1 mg/m3 zero-day recovery when compared to the control group. This finding was considered to be spurious occurrence without biological significance. group a 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. -91- GeiRRpan^ Sanitized. Ooes ESQSesniisirt TSCA CBi -w a SUBCHRONIC INHALATION TOXICITY STUDY WITI MEAN TABLE 1 FINAL BODY AND ORGAN WEIGHTS FROM (ANIMALS NECROPSIED ON DAY 12) MALE RAT MEAN FINAL BODY WEIGHTS GROUP I III V VII CONC. (MG/M3) 0.0 1 .0 5.0 10.0 (grams) FINAL BODY 309.9 ( 13.9) 288.3 ( 12.3) 304.7 ( 19.5) 300.9 ( 19.0) MEAN il\B;iOLUT E ORG,AN WE IGHTS (g rams) GROUP I VIII VII CO NC. (M G/M3) 0. 0 1. 0 5. 0 10 .0 LU NGS 1 .443 I .304 1 .403 1 .385 (0. 044) (0. 07) ), (0. 066) (0. 096) L];VER 1 1 . 168 10 .531 10 .792 1 1 .081 (1. 347) (1. 265) (1 . 471 ) (1. 214) KIDN EYS 2. 527 2. 399 2. 481 2. 324 (0. 101 ) (0. 146) (0. 291 ) (0. 167) SPL-EEN 0 .632 0 .575 0 .632 0 .701 (0. 062) (0. 064) (0. 072) (0. 144) MEAN I=iEl-ATIVE ORGAN WlEIGHTS (% of body weigh t) GROUP I III V VII CON C. (MG /M3) 0.0 1 .0 5.0 10. 0 LUN GS 0 .4667 0 .4526 0 .4618 0 .4604 ( .0314) ( .0183) ( .0321) ( .0139) LI VE R 3 .5997 3 .6531 3 .5308 3 .6753 ( . 3655) (. 3983) (. 2984) (. 2156) KID^IEY S 0 .8172 0 .8332 0 .8135 0 .7724 (. 0592) (. 0568) (. 0725) (. 0265) SPI.E EN 0. 2036 0. 1998 0. 2078 0. 2332 ( .0130) ( .0230) ( .0219) ( .0450) STANDARD DEVIATION IN PARENTHESES + - SIGNIFICANTLY DIFFERENT CP<0.05) It - SIGNIFICANTLY DIFFERENT (P<0.05) FROM CONTROL GROUP BY FROM CONTROL GROUP BY LSD LSD AND DUNNETT'S TEST TES.TES 3. 147 3. 1 16 3. 052 3. 245 (0. 174) (0. 230) (0. 230) (0. 437) TE;>TE S 1.0170 1.0836 1.0045 1.0794 (. 0713) (. 1071) (. 0915) (. 1410) SUBCHRONIC INHALATION TOXICITY STUDY WITI TABLE 1 (continued) MEAN FINAL BODY AND ORGAN WEIGHTS FROM MALE RAT (ANIMALS NECROPSIED ON DAY 26) MEAN FINAL BODY WEIGHTS (grams) GROUP I III V VII COI1C. (M(3/M3) O.ID 1 .1D 5.1D 10 .0 FINAI BOD'f 3138 .5 ( 9.4) 3138 .7 ( :28.6) 3154 .3 ( :21 .8) 3'75 .1 ( :26.0) MEAN ,1\BSOLUT E ORGAN WE IGHTS ( grams ) GROUP I VIII VII CO NC. (M G/M3) 0. 0 1. 0 5. 0 10 .0 LU.N3 S 1 .719 1 .843 1 .608 1 .609 (0 .125) (0 .220) (0 . 195) (0 . 144) LI VEiR 14 .277 14 .501 13 .841 13 .763 (2 .226) (1 .562) (1 .018) (1 .112) KIDNIEY S 2.995 3. 154 2.984 3.111 (0 .307) (0 .361) (0 .115) (0 .451 ) SPL EEN 0. 794 0. 845 0. 789 0. 732 (O.OB7): (0.077) (0.149) (0.058). MEAN RELATIVE ORGAN WEIGHTS ( % Of body weight) GROUP I III V VII CONC. (MG/M3) 0. 0 1. 0 5. 0 10.0 LUNGS 0. 4430 0. 4731 0. 4420 0. 4297 (. 039B) (. 0262) (. 0236) (. 0356) STANDARD DEVIATION IN PARENTHESES + - SIGNIFICANTLY DIFFERENT (P<0.05) It - SIGNIFICANTLY DIFFERENT (P<0.05) LIVER 3. 6719 3. 7364 3. 7983 3. 6690 (. 5443) (. 3709) (. 1097) C. 1625) KIDNEYS 0.7709 0.8108 0.8211 0.8276 (. 0762) (. 0603) (. 0503) (. 0938) SPLEEN 0.2042 (.0187) 0.2179 (.0209) 0.216B (.0410) 0.1956 (.0148) FROM CONTROL GROUP BY LSD FROM CONTROL GROUP BY LSD AND DUNNETT'S TEST TES;TE S 3. 355 3. 480 3. 203 3. 535 (0 .260) (0 .249) (0 .399 (0 .230 TESTES 0.8632 0.8961 0.8780 0.9444 (. 0567 (. 0458 (. OB21 (. 0654 SITE/LESION: LUNGS FOCI DISCOLORATION RENAL PELVIS DILATATION EPIDIDYMIDES SMALL ADRENALS DEFORMITY SUBCHRONIC INHALATION TOXICITY STUDY WIT TABLE 2 INCIDENCES OF GROSS OBSERVATIONS IN MALE RAT (ANIMALS NECROPSIED ON DAY 12) GROUP DESIGNATION: DOSE (UNITS): NUMBER IN GROUP; I 0 MG/M3 5 III 1.0 MG/M3 5 V 5.0 MG/M3 5 VII 10.0 MG/M3 5 020101000000111000 HN-17375 SITE/LESION: =========:===:===:= LUNGS FOCI RENAL PELVIS DILATATION EPIDIDVMIDES 'NODULE SUBCHRONIC INHALATION TOXICITY STUDY WIT TABLE 2 (continued) INCIDENCES OF GROSS OBSERVATIONS IN MALE RAT (ANIMALS NECROPSIED ON DAY 26) GROUP DESIGNATION: DOSE (UNITS): NUMBER IN GROUP: I 0 MG/M3 5 1.0IIIMG/M3 5 V 5.0 MG/M3 5 VII 10.0 MG/M3 5 001111000000 SUBCMRONIC INHALATION TOXICITY STUDY WITh TISSUE/LESION 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 (ANIMALS NECROPSIED ON DAY 12) GROUP DESIGNATION: DOSE (MG/M3): NUMBER IN GROUP: ' ' 55552553 I 0.0 5 2 5 . 1_5_ 5 III 1.0 5 - 5 _5_ 5 V 5.0 5 - 5 _5_ S 5 5 5 _5_ __5_ 5 ' 5 __5_ __5_ _5_ __5_ _5_ 5 __5_ 5 __5_ __5_ 5 5 __5_ __5_ __5_ __5_ _L- 5 ----5- 5 _5_ __5_ __5_ __5_ ----5_ __5_ --5_ ----5_ ----5----5- --5- ----5- _HN-17375 ^ TISSUE/LESION SUBCMRONIC INHALATION TOXICITY STUDY WITI TABLE 3 (continued) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS (ANIMALS NECROPSIED ON DAY 12) III GROUP DESIGNATION; I V DOSE (MG/M3): 0.0 1.0 5.0 NUMBER IN GROUP: 5 5 5 COLON RECTUM MESENTERIC LYMPH NODE TESTES EPIOIDYMIDES SPERM GRANULOMA STERNUM EYES NOSE OTHER __5_ __5_ __5_ 5 5 5 __5_ __5_ __5_ _ 5 __5_ __5_ __5_ - 5 __5_ __5_ __5_ - __5_ __5_ __5_ __5_ __5_ __5_ __5_ __0 __0_ __0_ NOTES: o THE NUMBER OF ORGANS EXAMINED FOR EACH GROUP IS UNDERLINED. HN-17375 TISSUE/LESION SUBCHRONIC INHALATION TOXICITV STUDY WITH TABLE 3 (continued) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS (ANIMALS NECROPSIED ON DAY 26) GROUP DES1:GNATION: I DOSE (MG/f.1\3): . NUMBER IN GROUP: 0.0 5 III 1 .0 5 . LIVER INFLAMMATION, SUBACUTE KIDNEYS DILATATION, RENAL PELVIS URINARY BLADDER LUNGS HEART SPLEEN THYMUS 1 \0 00 PANCREAS 1 ACINAR CELL ATROPHY ADRENALS THYROID TRACHEA ^ ESOPHAGUS oa 1 BRAIN N STOMACH (B a; DUODENUM 01 0 JEJUNUM (it Kil 3) ILEUM 0 M 1 CECUM CO M 5 -i OT 0 > 33 5 5 2 4 5 5 1 5 5 5 5 5 5 5 5 5 5 5 5 1 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 4 5 4 5 V 5.0 5 5 2 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 SUBCHRONIC INHALATION TOXICITY STUDY WIT ,HN-17375 TISSUE/LESION TABLE 3 (continued) INCIDENCES OF MICROSCOPIC OBSERVATIONS IN MALE RATS (ANIMALS NECROPSIED ON DAY 26) GROUP DESIGNATION; I DOSE (MG/M3): 0.0 NUMBER IN GROUP: 5 III 1.0 ,5 V 5.0 . 5 COLON RECTUM MESENTERIC LYMPH NODE TESTES EPIOIOYMIDES SPERM GRANULOMA STERNUM EYES INFLAMMATION, CHRONIC, CORNEA 5 5 5. 5 5555 5 55 - 5 5 5 - 1 - 5 5 5 5555 5 5 5 - 1 - 50505050 y3 NOSE OTHER ^ NOTES: 3 0 THE NUMBER OF ORGANS EXAMINED FOR EACH GROUP IS UNDERLINED. O (U '< w 0) 3: ?3 (D p. a a (D ai 3 a, r a 3 pi M 5' ^ 0 > 0 a H 17.375 SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX A INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS (ANIMALS NECROPSIED ON DAY 12) FINAL BODY'AND ABSOLUTE ORGAN WEIGHTS (grams) FROM MALE RAT GROUP : I - 0 MG/M3 ANIMAL NUMBER FINAL BODY LUNGS LIVER KIDNEYS SPLEEN TESTES 447114 447116 447117 447118 447121 GROUP MEAN STO., DEV. 329.3 296.6 312.5 315.1 296.2 309.9 13.9 1 .442 1 .491 1 .377 1 .431 1 .475 1 .443 0.044 1 1.637 10.588 13. 116 11.033 9.468 11.168 1.347 . 2.450 2.605 2.649 2.408 2.523 2.527 0.101 0.720 0.547 0.621 0.645 0.626 0.632 0.062 3.292 3.366 2.961 3.091 3.027 3. 147 0. 174 ^ (0' (8 3 . S3 M (0 a 0 (U W 3 0 9S. 3" jiijl W R ^ 0 cHO 17.375 SUBCHRONIC INHALATION TOXICITY STUDY WITH' APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS (ANIMALS NECROPSIED ON DAY 12) FINAL BODY AND ABSOLUTE ORGAN WEIGHTS GROUP : ANIMAL NUMBER II I - 1.0 MG/M3 FINAL BODY LUNGS (grams) LIVER FROM MALE RAT KIDNEYS SPLEEN TESTES 447122 447123 447125 447128 447129 GROUP MEAN STD. DEV. 270.3 280.7 295.9 297.9 296.6 288.3 12.3 1 .241 1 .273 1.315 1 .423 1 .270 1 .304 0.071 9.947 10.109 12.096 11.532 8.972 10.531 1 .265 2.439 2.256 2. 285 2.393 2.624 2.399' 0. 146 0.594 0.542 0.481 0.635 0.624 0.575 0.064 3.308 3.084 3.076 3.344 2.769 3.116 0.230 0 0 0 3. 0) 3" W 0 > 0 ei SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS (ANIMALS NECROPSIED ON DAY 12) FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) FROM MALE RAT GROUP- L. I ANIMAL NUMBER V - 5.0 MG/M3 FINAL BODY LUNGS LIVER KIDNEYS SPLEEN TESTES 447132 447134 447138 447140 447141 GROUP MEAN STD. DEV. 310.5 326.3 299.8 274. 1 312.8 304.7 19.5 1 .342 1.511 1 .362 1,413 1 .389 1 .403 0.066 12.050 .12.439 '10.258 8.811 10.400 10.792 1 .471 2.900 2.461 2.337 2.118 2.587 2.481 0.291 0.710 0.688 0.638 0.592 0.534 0.632 0.072 2.841 3.419 2.936 3. 128 2.938 3.052 0.230 H) 17,375 SUBCHRONIC INHALATION TOXICITY STUDY WITI APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS (ANIMALS NECROPSIED ON DAY 12) FINAL BODY AND ABSOLUTE ORGAN WEIGHTS GROUP : ANIMAL NUMBER VII - 10.0 MG/M3 FINAL BODY LUNGS (grams) LIVER FROM MALE KIDNEYS RAT SPLEEN TESTES 447144 447145 447147 447150 447'151 GROUP MEAN STD. DEV. 295.7 318.6 294.8 320.5 274.9 300.9 19.0 1 .419 1 .467 1 . 299 1 .474 1 . 268 1 .385 0.096 10.945 11.502 11.206 12.550 9.203 11.081 1 .214 2.384 2.396 2. 331 2.471 2.040 2.324 0.167 0.526 0.640 0.688 0.917 0.736 0.701 0.144 3.624 2.859 3.535 3.518 2.687 3.245 0.437 Hi? 17,375 SUBCHRONIC INHALATION TOXICITY STUDY WITI APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS (ANIMALS NECROPSIED ON DAY 12) RELATIVE GROUP : ORGAN WEIGHTS (% of I - 0 MG/M3 body weight) FROM MALE RAT ANIMAL NUMBER LUNGS LIVER KIDNEYS SPLEEN TESTES 447114 447116 447117 447118 447121 GROUP'MEAN STD. DEV. 0.4379 0.5027 0.4406 0.4541 0.4980 0.4667 0.0314 3.5339 3.5698 4..1971 3.5014 3.1965 3 . E.997 0.3655 0.7440 0.8783 0.8477 0.7642 0.8518 0.8172 0.0592 0.2186 0.1844 0.1987 0.2047 0.2113 0.2036 0.0130 0.9997 1.1349 0.9475 0.9810 1.0219 1.0170 0.0713 MC 17,375 SUBCHRONIC INHALATION TOXICITY STUDY WITI C----J APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS (ANIMALS NECROPSIED ON DAY 12) RELATIVE ORGAN WEIGHTS (% of body weight) FROM MALE RAT GROUP : ANIMAL NUMBER III - 1.0 MG/M3 LUNGS LIVER KIDNEYS SPLEEN TESTES 447122 447123 447125 447128 447129 GROUP MEAN STD. DEV. 0.4591 0.4535 0.4444 0.4777 0.4282 0.4526 0.0183 3.6800 3.6014 4.0879 3.8711 3.0249 3.6531 0.3983 0.9023 0.8037 0.7722 0.8033 0.8847 0.8332 0.0568 0.2198 0.1931 0.1626 0.2132 0.2104 0.1998 0.0230 1.2238 1.0987 1.0395 1.1225 0.9336 1.0836 0.1071 H# 17,375 SUBCHRONIC INHALATION TOXICITY STUDY WITI APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS (ANIMALS NECROPSIED ON DAY 12) RELATIVE ORGAN WEIGHTS (% of body weight) FROM MALE RAT GROUP ; ANIMAL NUMBER' V - 5.0 MG/M3 LUNGS LIVER KIDNEYS SPLEEN TESTES 447132 447134 447138 447140 447141 GROUP MEAN STD. DEV. 0.4322 0.4631 0.4543 0.5155 0.4441 0.4618 0.0321 3.8808 3.8121 3.4216 3.2145 3.3248 3.5308 0.2984 0.9340 0.7542 0.7795 0.7727 0.8270 0.8135 0.0725 0.2287 0.2108 0.2128 0.2160 0.1707 0.2078 0.0219 0.9150 1.0478 0.9793 1.1412 0.9393 1.0045 0.0915 " ^ j SUBCHRONIC INHALATION TOXICITY STUDY WITI APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS (ANIMALS NECROPSIED ON DAY 12) RELATIVE ORGAN WEIGHTS (% of body weight) FROM MALE RAT GROUP ; VII - 10.0 MG/M3 ANIMAL NUMBER LUNGS LIVER KIDNEYS SPLEEN TESTES 447144 447145. ' 447147 447150 ..4471'51 GROUP MEAN STD. DV . 0.4799 0.4605 0.4406 0.4599 0.4613 0.4604 0.0139 3.7014 3.6102 3.6012 3.9(58 3.3478 3.6753 0.2156 O.B062 0.7520 0.7907 0.7710 0.7421 0.7724 0.0265 0.1779 0.2009 0.2334 0.2861 0.2677 0.2332 0.0450 1.2256 0.8974 1.1991 1.0977 0.9774 1.0794 0.1410 SUBCHRONIC INHALATION TOXICITY STUDY WITI APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS (ANIMALS NECROPSIED ON DAY 26) FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (gCams) FROM MALE RAT GROUP : 0 MG/M3 '. ANIMAL NUMBER ' ' 447112 447113 447115 447119 447120 GROUP MEAN STD. DEV. ' FINlML BOI3Y 378 . 1 382 .2 400 .0 396 .7 385 .6 388 .5 9 .4 LU NGS 1 . 684 1 . 843 1 . 559 1 . 658 1 . 849 1 . 719 0. 125 L IVER 12 .978 16 .033 14 .725 16 .512 1 1 . 139 14 .277 2 .226 KIDNEYS 2.'750 3.250 2.B07 3.400 2. 768 .2.. 995 0.307 SPL EEN 0. 763 0. 733 0. 948 0. 777 0. 751 0. 794 0- 087 ' TE:STES 3 .215 2 .988 3 .397 3 .636 3 .541 3 .355 0 .260 SUBCHRONIC INHALATION TOXICITY STUDY WITI APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS (ANIMALS NECROPSIED ON DAY 26) FINAL BODY AND ABSOLUTE ORGAN WEIGHTS GROUP : ANIMAL NUMBER III - 1.0 FINAL BODY MG/M3 LUNGS (grams) LIVER FROM MALE RAT KIDNEYS SPLEEN TESTES 447124 447126 447)27 447130 447131 GROUP MEAN STD. DEV. 398.7 384.3 360.8 432.5 367.3 388.7 2B.6 1.811 1 .800 1 .743 2.218 1 .641 1 .843 0.220 17.036 12.907 13.820 14.754 13.989 14.501 1 .562 3.324 2.848 3. 174 3.656 2.770 3. 154 0.361 0.874 0.751 0.777 0. 899 0.924 0.845 0.077 3.6B9 3.319 3. 136 3.719 3.536 3.480 0.249 HC 17,375 SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS (ANIMALS NECROPSIED ON DAY 26) FINAL BODY AND ABSOLUTE ORGAN WEIGHTS GROUP : ANIMAL NUMBER V - 5.0 MG/M3 FINAL BODY LUNGS (grams) LIVER FROM MALE RAT KIDNEYS SPLEEN TESTES 447133 447135 447136 447)37 447139 370.0 343.7 353. 1 399.4 355.2 GROUP MEAN STD. DEV. 364.3 21.8 NW NOT WEIGHED NW 1 .496 1 .475 1 .894 1 .566 1 .608 0. 195 14.114 13.419 13.315 15.481 12.878 13.841 1.0)8 2.994 2.995 3.090 3.051 2.791 2.984 0.115 0.693 0.954 0. 742 0.937 0.620 0.789 0. 149 3.613 2.598 3, 261 3.482 3.062 3.203 0.399 MC 17,375 ^ f 3 SUBCHRONIC INHALATION TOXICITV STUDY WITH APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS (ANIMALS'NECROPSIED ON DAY 26) FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) FROM MALE RAT GROUP. ;; VII - 1:0.0 MG/M3 ; , -ANIMAL NUMBER FINA L BOD Y LUNGS L IVER KID NE.YS SPL EEN TES TES 447142 447143 447146 447)48 447149 GROUR MEAN STD. DEV. 397. 8 333. 2 392. 6 383. 9 368. 1 375. 1 26. 0 .743 .558 .779 .450 .516 1.609 0.144 13 .870 1 1 .909 14 . 177 14 .896 13 .962 13 .763 1 .112 3 . 124 2 .407 3 .472 3 .019 3.532 3 .111 0 .451 0. 782 0; 668 0. 736 0. 679 0. 797 0. 732 0. 058 3. 450 3. 221 3. 648 3. 517 3. 838 3,. 535 0. 230 H<> 17,375 SUBCHRONIC INHALATION TOXICITY STUDY WITI APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AMD ORGAN WEIGHTS (ANIMALS NECROPSIED ON DAY 26) RELATIVE ORGAN WEIGHTS (% of body weight) FROM MALE RAT GROUP ; i I - 0.MG/M3 ANIMAL NUMBER i 447)12 447113 447115 447119 447120 LUNGS 0.4454 0.4822 0.3898 0.4179 0.4795 LIVER 3.4324 4.1949 3 . 68' 1 2 4.1623 2.8887 KIDNEYS 0.7273 O.B503 0.7017 0.8571 0.7178 SPLEEN 0.2018 0.1918 0.2370 0.1959 0.1948 TESTES 0.8503 0.7818 0.8493 0.9166, 0.9183 GROUP MEAN STD. DEV. 0.4430 0.0398 3.6719 0.5443 0..7709 0.0762 0.2042 0.0187 0.8632 0.0567 H 17,375 SUBCHRONIC INHALATION TOXICITY STUDY WITI APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS (ANIMALS NECROPSIED ON DAY 26) RELATIVE ORGAN WEIGHTS (% of body weight) PROM MALE RAT GROUP : ' AN-IMAL NUMBER III - 1.0 MG/M3 LUNGS LIVER KIDNEYS SPLEEN TESTES 447124 447126 447127 447130 447131 GROUP MEAN STD-. DEV. 0.4542 0.4684 0.4831 0.5128 0.4468 0.4731 0.0262 4.2725 3.3586 3.S304 3.4113 3.8086 3.7364 0.3709 0.8337 0.7411 0.8797 0.8453 0.7542 0.8108 0.0603 0.2192 0.1954 0.2154 0.2079 0.2516 0.2179 0.0209 0.9253 0.8636 0.8692 0.8599 0.9627 0.8961 0.0458 SUBCHRONIC INHALATION TOXICITY STUDY WIT APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS (ANIMALS NECROPSIED ON DAY 26) RELATIVE GROU.P':''' : . ORGAN V WEIGHTS (7. of ' - 5.0 MG/M3 body weight) FROM MALE RAT ' ' ' ' AN'IMAL NUMBER '! ' . 447133 447)35 447136 447137 447139 " I'- ' LUNGS NW 0 .4353 0 .4)77 0 .4742 0 .4409 .''.' r 1LIVER 3 .8146 3 .9043 3 .7709 3 .8761 3 .6256 I , ' KIIONEYS 0 .8092 0 .8714 0 .87S1 0 .7639 0 .7858 ' . SP LEEN 0. 1873 0. 2776 0. 2101 0. 2346 0. 1745 GROUP MEAN STD. DEV. 0 .4420 0 .0236 3 .7983 0 . 1097 0 .8211 0 .0503 0. 2168 0. 0410 T ESTES 0 .9765 0 .7559 0 .9235 0 .8718 0 .8620 0 .8780 0 .0821 NW = NOT WEIGHED Hff 17.375 SUBCHRONIC INHALATION TOXICITY STUDY WITI APPENDIX A (continued) INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS (ANIMALS NECROPSIED ON DAY 26) RELATIVE ORGAN WEIGHTS (% of body weight) FROM MALE RAT GROUP :' VII -. 10.0 MGi/M3 : ; i ANIMAL : : NUMBER LUNGS LIVER KIDNEYS SPLEEN TESTES :4471,42 4471'43 447)46 447148 447149 G'ROUP MEAN STD. DEV. 0.43B2 0.4676 0.453) 0.3777 0.4118 0.4297 0.0356 3.4867 3.5741 3. en 1 3,.8B02 '3.7930 3.6690 0.1625 0.7853 0.7224 0.8844 0.7864 0.9595 0.8276 0.0938 0.1966 0.2005 0.1875 0.1769 0.2V65 0.1956 0.01'4B O.B673 0.9667 0.9292 0.9161 1'. 0.4 2 7 0.9444 0.0654 0 y 0 001. HN-17375 SUBCMRONIC INHALATION TOXICITY STUDY WITH Key to Appendix B Mode of Death SD = Sacrificed by Design : . . . 'i Lesion Codes ': 1-Hstopathologlcal changes are described according :to their morphological character, distribution severity. The distribution (extent of tissue Involvement) Is Indicated, where approprliate, by modifiers as focal, multlfocal, diffuse, unilateral, .bilateral, etc.; a severity score, If appropriate. Is also a as foilows: : '.Minimal . - the amount of change present barely exceeds that which Is considered to be within normal 11m1ts Mild - the amount of change present 1s easily detected Moderate - a large amount of chanqe Is presept Severe ' I! - the degree of change within the affected area(s) Is essentially as severe and compl as Is thought possible, 1: f In terms'of quantification, the,terms ml 1d and moderate represent progressive Involvement/severity alon continuum. Thus, "mild" represents a change felt to be approximately one-third of the ,way along the co between minimal and marked, and "moderate" Is approximately two-thirds of the way along this same contin SUBCHRONIC INHALATION TOXICITY STUDY WITH MALE RAT ANIMAL tt: 447112 ' ' ; ' ' '' DAYS ON TEST: 26 ; : !' ' GROSS OBSERVATIONS: NO ABNORMALITIES DETECTED, GROUP: I DOSE; 0,0 MG/M3 MODE OF DEATH: SD :..' I . : ; ; . ' . 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, TMYMUS, THYROID. TRACHEA, URINARY BLADDER DUODENUM, EPIDI NOSE, PANCREAS, THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NON THE FOLLOWING TISSUES WERE SEVERELY AUTOLVZEO; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INCI NONE SECTIONS .OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE SECTIONS OF THE FOLLOWING TISSUES WERE INSUFFICIENTFOR MICROSCOPIC EXAMINATION; ORGAN NOT COUNTED IN IN NONE HN-17375 . ANIMAL ,f|:' 4471)3 , SUBCHRONIC t e ^ J INHALATION TOXICITY STUDY WIT APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: I DOSE; 0.0 MG/M3 DAYS ?N TEST: , 26 MODE OF DEATH:; SD GROSS OBSERVATIONS: : : NO ABNORMALITIES DETECTED , '[' . I MICROSCOPIC OBSERVATIONS; PANCREAS - ; ACINAR CELL ATROPHY/MINIMAL THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN, CECUM. COLON, ESOPHAGUS, EYES, HEART, ILEUM, JEJUNUM, KIDNEYS, LIVER, LUNGS, MESENTERIC LYMPH NODE, STOMACH, TESTES, THYMUS, THYROID, TRACHEA, URINARY BLADDER DUODENUM, EPIDI NOSE, RECTUM, THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION; NON THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INCI NONE , ^ SECTIONS OF THE .FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE S SECTIONS OF THE FOLLOWING TISSUES WERE INSUFFICIENT FOR MICROSCOPIC EXAMINATION; ORGAN NOT COUNTED IN IN ' NONE | , ' '. :. < US 1 . , vtf N" <0 a, a o <0 w o UN-17375 ANIMAL If: 447114 SUBCHRONIC INHALATION TOXICITY STUDY WIT APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: I DOSE: 0.0 MG/M3 DAYS ON TEST:' 12 ; ; MODE OF DEATH: SD ' ' GROSS OBSERVATIONS: NOrAB.NORMALITIES DETECTED.. i ; : '; . MICROSCOPIC OBSERVATIONS; LIVER- : .,- INFLAMMATION, SUBACUTE, MINIMAL THE FOLLOWING TISSUES 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, EPID NOSE, PANCREAS, RECTU THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF. AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NO THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE. ORGAN NOT COUNTED IN INC NONE . I SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE S SECTIONS-OF THE FOLLOWING TISSUES WERE INSUFFICIENT FOR MICROSCOPIC EXAMINATION; ORGAN NOT COUNTED IN I ' NONE R) o, 3! vi <; w B ai S s& ra Q (B 0 -3 Cf \'t 0 3 vrc?. 5' -51 W0 > 0 ro ' ' ., , . ' . , : . HN-17375 ^ ANIMAL .it: 447115 'SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA ;MALE RAT GROUP: I DOSE: 0.0 MG/M3 , :. DAYS ON TEST:; 26 MODE OF DEATH:. SD GROSS OBSERVATIONS: ' . NO ABNORMALITIES DETECTED ' i . . ' MICROSCOPIC OBSERVATIONS: NONE THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN, COLON, DUODENUM, EPIDIDYMIDE EYES, HEART, JEJUNUM, KIDNEYS, LIVER, LUNGS, MESENTERIC LYMPH NODE, NOSE, PANCREAS, RECTUM, SPLEEN, TESTES, THVMUS, THYROID. TRACHEA, URINARY BLADDER THE'FOLLOWING TISSUES WERE. AUTOLVZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION; N THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INC NON,E : SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: CECUM, ILEUM i^ SECTIONS OF THE FOLLOWING TISSUES WERE INSUFFICIENT FOR MICROSCOPIC EXAMINATION; ORGAN NOT COUNTED IN 0 NONE I a "?.' vil w ss i^r rg ';') "i i) ':".: w ^aiir HN-17375 ANIMAL If : 447116 SUBCHRONIC INHALATION TOXICITY STUDY WITI APPENDIX.B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: I DOSE: 0.0 MG/M3 DAYS ON TEST: 12 MODE OF DEATH; SD GROSS OBSERVATIONS: LUNGS - DISCOLORATION, DARK RED PATCHY AREAS, DIFFUSE, C< 1 CM') ' MICROSCOPIC OBSERVATIONS: LIVER LUNGS - INFLAMMATION, SUBACUTE, MINIMAL - HEMORRHAGE, ACUTE, MINIMAL THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN, ESOPHAGUS, EYES, HEART, ILEUM, JEJUNUM, KIDNEYS,. MESENTERIC LYMPH NODE, STOMACH, TESTES, THYMUS, THYROID, TRACHEA, URINARY BLADDER CECUM. COLON. DUODENUM, NOSE, PANCREAS. RECTUM, EPID SPLE THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NO THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INC 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 I NONE HN-17375 _ ANIMAL #.: 447117 : SUBCHRONIC INHALATION TOXICITY STUDY WIT APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT .GROUP: I DOSE; 0.0 MG/M3 DAYS ON TEST: 12 MODE OF DEATH:: SO GROSS)OBSERVATIONS: RENAL PELVIS . ,- DILATATION, RIGHT, MODERATE MICROSCOPIC OBSERVATIONS: KIDNEYS , LIVER - DILATATION, RENAL PELVIS, MILD --INFLAMMATION, SUBACUTE, MINIMAL THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN, CECUM, COLON, ESOPHAGUS, EYES, HEART, ILEUM, JEJUNUM, LUNGS, MESENTERIC LYMPH NODE, NOSE, PANCREAS, STOMACH, TESTES, THYMUS, THYROID, 'TRACHEA. URINARY BLADDER DUODENUM, EPIDID RECTUM, SPLEEN, THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NON i . THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INCID NONE ; K SECTIONS OF THE FOLLOWlNG'TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION:. NONE ro ' , ' SECTIONS OF THE FOLLOWING TISSUES WERE INSUFFICIENT FOR MICROSCOPIC EXAMINATION; ORGAN NOT COUNTED IN IN NONE w M N (D Q. a a CD CO 0 fi> 3 0? 0 0 CO [W ANIMAL .: 4471 18 SUBCHRONIC INHALATION TOXICITY STUDY WITH' APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: I DOSE; 0.0 MG/M3 DAYS ON TEST; 12 MODE OF DEATH: SD GROSS,OBSERVATIONS; : , NO'ABNORMALITIES. DETECTED MACROSCOPIC OBSERVATIONS; LIVER - INFLAMMATION, SUBACUTE, MINIMAL THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN, CECUM, ESOPHAGUS, EYES, HEART, ILEUM, JEJUNUM, KIDNEYS, LUNGS, MESENTERIC LYMPH NODE, STERNUM, STOMACH, TESTES, THYMUS, THYROID, TRACHEA,' URI'NARY BLADDER COLON, DUODENUM. EPIDID NOSE, PANCREAS, RECTUM THE FOLLOWING TISSUES WERE AUTOLYZED;.DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NON THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INCID 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 IN NONE HN-17375 ANIMAL tt: 4471 19 SUBCHRONIC INHALATION'TOXICITY STUDY WIT APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: I DOSE: 0.0 MG/M3 DAYS ON TEST: 26 MODE OF DEATH: 3D GROSS OBSERVATIONS: . RENAL .PELVIS ,'-; DILATATION, SEVERE,'RIGHT MICROSCOPIC OBSERVATIONS: SIDNEYS ' LIVER - DILATATION, RENAL PELVIS. MILD - INFLAMMATION, SUBACUTE, MINIMAL THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN, CECUM, COLON, ESOPHAGUS, EYES, HEART, ILEUM, JEJUNUM, LUNGS, MESENTERIC LYMPH NODE, NOSE, PANCREAS, STOMACH. TESTES, THYMUS, THYROID, TRACHEA, URINA'RY BLADDER DUODENUM, EPID RECTUM, SPLEEN THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NO THE FOLLOWING TISSUES WERE SEVERELY AL1TOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INC ' ' 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 I NONE . . ANIMAL .: 447120 SUBCHRONIC INHALATION TOXICITY STUDY WITI APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP; I. DOSE: 0.0 MG/M3 DAY.S 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. ESOPHAGUS, EYES. HEART, ILEUM, JEJUNUM, KIDNEYS', LUNGS, MESENTERIC LYMPH NODE, STERNUM, STOMACH, TESTES, THYMUS, THYROID, TRACHEA, URINARY BLADDER COLON, DUODENUM, EPID NOSE, PANCREAS, RECTU THE FOLLOWING TISSUES WERE AUTOLVZED;'DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: N THE:FOLLOWING TISSUES WERE SEVERELY AUTOLVZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INC NONE ' ! ' ^ SECTIONS OF 7HE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION; NONE M ' ' : . ^ SECTIONS OF THE FOLLOWING TISSUES WERE INSUFFICIENT FOR MICROSCOPIC EXAMINATION; ORGAN NOT COUNTED IN NONE S w IR <K a ffil^ 5' w 0 3?' 0 CC! ANIMAL, tf: 447121' SUBCHRONIC INHALATION TOXICITY STUDY WIT APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: I DOSE: 0.0 MG/M3 DAYS ON TEST:. 12 MODE OF DEATH: SD GROSS OBSERVATIONS: RENAL PELVIS - DILATATION, RIGHT; 'MODERATE MICROSCOPIC OBSERVATIONS: KIDNEYS LIVER - DILATATION, RENAL PELVIS, MILD - INFLAMMATION. SUBACUTE, MINIMAL THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN, CECUM, COLON, ESOPHAGUS. EYES, HEART, ILEUM. JEJUNUM. LUNGS, MESENTERIC LYMPH NODE, NOSE, PANCREAS, STOMACH, TESTES, THYMUS, THYROID, TRACHEA, URINARY BLADDER DUODENUM, EPIDI RECTUM, SPLEEN, THE FOLLOWING TISSUES WERE THE FOLLOWING TISSUES WERE NONE. AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION; SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN ' . NON INCI 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 IN NONE . , i..y HN-17375 ANIMAL tf: '4471 22 SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: III DOSE; 1.0 MG/M3 DAYS ON TEST: 12 MODE OF DEATH: SD GROSS OBSERVATIONS:: i NO ABNORMALITIES DETECTED MICROSCOPIC OBSERVATIONS: LIVER - INFLAMMATION, SUBACUTE, MINIMAL THE FOLLOWING TISSUES 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, EPIDID NOSE, PANCREAS, RECTUM THE FOLLOWING THE FOLLOWING NONE TISSUES TISSUES WERE WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION; SEV'ERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN ' ' NONE INCID 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 INC NONE th ANIMAL if: 447123 SUBCHRONIC INHALATION TOXICITY STUDY WIT APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: III DOSE: 1.0 MG/M3 DAYS ON TEST: 12 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. EP NOSE, PANCREA THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION; N THE FOLLOWING TISSUES WERE SEVERELY AUTOLY2ED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN IN NONE SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION; NONE ^ SECTIONS OF THE FOLLOWING TISSUES WERE INSUFFICIENT FOR MICROSCOPIC EXAMINATION; ORGAhN NOT COUNTED IN NONE I CO B) I 0 p. a 0 fS> M 3 0 I 01 0 SB 0 SB HN-17375 ANIMAL : 447124 SUBCHRONIC INHALATION TOXICITY STUDY WITMl APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: III DOSE: 1.0 MG/M3 DAYS ON TEST: 26 MODE OF DEATH: SD GROSS OBSERVATIONS: LUNGS EPIDIDYMIDES - FOCI, (< 2 MM), FEW, SCATTERED - NODULE, (5 MM IN DIAMETER), RIGHT, TAIL, TAN MICROSCOPIC OBSERVATIONS: EPIDIDYMIDES LIVER - SPERM GRANULOMA, MILD - INFLAMMATION, SUBACUTE, MINIMAL THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN, CECUM, COLON, HEART, ILEUM, JEJUNUM, KIDNEYS, LUNGS. MESENTERIC LYMPH NODE, NOSE, PANCREAS, RECTUM, TESTES, THVMUS, THYROID, TRACHEA, URINARY BLADDER DUODENUM, ESO SPLEEN, STERN THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION; N THE FOLLOWING TISSUES WERE SEVERELY AUTOLVZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN IN 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 NONE HN-17375 ANIMAL If: 447126 SUBCHRONIC INHALATION TOXICITV STUDY WIT! APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: III DOSE: 1.0 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. ESOPHAGUS, EYES,'HEART, ILEUM, JEJUNUM, KIDNEYS, LUNGS, MESENTERIC LYMPH NODE, STERNUM, STOMACH, TESTES, THYMUS, THYROID, TRACHEA, URINARY BLADDER COLON, DUODENUM. EPI NOSE, PANCREAS, RECT THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: N THE'F&LLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN IN 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 NONE ^ OS ^ w u S! P0 o (t> m 3 0 S 3 ^ 3 > a HN-17375 ANIMAL : 447125 GROSS OBSERVATIONS; LUNGS SUBCHRONIC INHALATION TOXICITY STUDY WITI APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: III DOSE: 1.0 MG/M3 DAYS ON TEST: 12 MODE OF DEATH: SD - FOCI, (1 MM IN DIAMETER), RED, LEFT LOBE , 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, EPI NOSE, PANCREA THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: N THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN IN 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 NONE , H.N-1 7375 ANIMAL If: 447127 SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP; III DOSE: 1.0 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, MESENTERIC LYMPH NODE, STERNUM, STOMACH. TESTES, THYMUS, THYROID, TRACHEA, URINARY BLADDER DUODENUM, EP101 NOSE, PANCREAS THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NON THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INCI 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 IN NONE : 0UN-17375 . ANIMAL #: 447128 ; . , SUBCHRONIC INHALATION TOXICITY STUDY WITI APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: III DOSE; 1.0 MG/M3 DAYS 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, ESOPHAGUS, EYES. HEART, ILEUM, JEJUNUM. KIDNEYS, LUNGS. MESENTERIC LYMPH NODE, STERNUM, STOMACH, TESTES, THYMUS, THYROID, TRACHEA, URINARY BLADDER COLON, DUODENUM, EPID NOSE, PANCREAS, RECTU THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLVSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NO THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INC NONE SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE i^ SECTIONS OF THE FOLLOWING TISSUES WERE INSUFFICIENT FOR MICROSCOPIC EXAMINATION; ORGAhN NOT COUNTED IN IN NONE i TS Uf ^B) . -OiT 0 > s ANIMAL : 447129 SUBCHRONIC INHALATION TOXICITY STUDY WIT APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP; III DOSE: 1.0 MG/M3 DAYS ON TEST: 12 MODE OF DEATH: SO 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, EPIDI NOSE, PANCREAS THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSI.S DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NON THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE. ORGAN NOT COUNTED IN INCI 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 IN -(>- NONE ' 0 0 ^ a s a j I - y 0 > 0 oa gp1 , Ln ' o- a R9 ^ (f9 a? a, wao; N <i9 , 1-3 0 (1;1 [.til ANIMAL if: 447130 SUBCHRONIC ( H ^ ^ INHALATION TOXIClfTY STUDY WIT APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: III DOSE: 1.0 MG/M3 DAYS ON TEST: 26 MODE OF DEATH: SD GROSS OBSERVATIONS: RENAL PELVIS - DILATATION, LEFT, MILD MICROSCOPIC OBSERVATIONS: LIVER - INFLAMMATION, SUBACUTE, MINIMAL THE FOLLOWING TISSUES 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, EPID NOSE, PANCREAS, RECTU THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS. DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NO THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INC 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 NONE -.^1 <0 0 s" HN-17375 _ ANIMAL if: 447131 SUBCHRONIC;INHALATION TOXICITY STUDY WIT APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: III DOSE; 1.0 MG/M3 DAYS ON TEST: 26 MODE OF DEATH: SD GROSS OBSERVATIONS:' NO ABNORMALITIES DETECTED : i . MICROSCOPIC OBSERVATIONS: EYES LIVER ' j . - INFLAMMATION, CHRONIC, CORNEA, MINIMAL - INFLAMMATION, SUBACUTE, MINIMAL THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN, CECUM, ESOPHAGUS, HEART, ILEUM, JEJUNUM, KIDNEYS, LUNGS, MESENTERIC LYMPH NODE, NOSE, STOMACH, TESTES, THYMUS, THYROID, TRACHEA, URINARY BLADDER COLON, DUODENUM, EPID PANCREAS, RECTUM, SPL THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NO THE FOLLOWING TISSUES WERE SEVERELY AUTOLVZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INC NONE S SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE CT. ' SECTIONS OF THE FOLLOWING TISSUES WERE INSUFFICIENT FOR MICROSCOPIC EXAMINATION; ORGAN NOT COUNTED IN NONE ^ us B ss 00 0 o (K ia 3 0 fl>. 5 -6 w 0 3 0 HN-17375 .. ANIMAL if: 447132 SUBCHRONIC INHALATION TOXI C.ITY i STUDY WITH 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 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, EPID NOSE, PANCREAS THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION; NO THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INC NONE SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION; NONE {^ SECTIONS OF THE FOLLOWING TISSUES WERE INSUFFICIENT FOR MICROSCO'PIC EXAMINATION; ORGAN NOT COUNTED IN I -'-I NONE Ia w I N" (9 P 0 S5; W 0 > 0 ill ^ HN-17375 ,, ANIMAL : 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 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, EPID NOSE, PANCREAS THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NO THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT.MADE, ORGAN NOT COUNTED IN INC NONE SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE I C SECTIONS OF THE FOLLOWING TISSUES WERE INSUFFICIENT FOR MICROSCOPIC EXAMINATION; ORGAN NOT COUNTED IN IN CO NONE OS cu R ro 0. 0 0 (D w 3 0 0 0 I- 3 0) 9 0 S .HN-17375 ANIMAL ff: 447134 SUBCHRONIC INHALATION'TOXICITY STUDY WITI 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: LIVER INFLAMMATION, SUBACUTE, MINIMAL THE FOLLOWING TISSUES 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, EPIDI NOSE, PANCREAS, RECTUM THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION; NON THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INCI 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 IN NONE .HN-17375 ^ SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA .MALE RAT GROUP: V : , DOSE; 5.0 MG/M3 ANIMAL //,: 447135 . ' DAYS ON TEST; 26 i '. . GROSS OBSERVATIONS: NO ABNORMALITIES DETECTED MODE OF DEATH: SD . , ' '' ' ' ' MICROSCOPIC OBSERVATIONS: NONE THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN, CECUM, COLON, ESOPHAGUS, EYES, HEART, ILUM, JEJUNUM, KIDNEYS. LIVER, LUNGS, MESENTERIC LYMPH NODE, STERNUM, STOMACH. TESTES, THYMUS, THYROID, TRACHEA, URINARY BLADDER DUODENUM, EPIDI NOSE, PANCREAS THE FOLLOWING TISSUES WERE AUTOLVZED; DEGREE OP AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NO THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INCI 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 IN 0 NONE w S'.s' IB) P. 0 o (C in 3 s o 0 I ^ ? 0 CO HN-17375 ANIMAL.. if';: .1.447136 SUBCHRONIC INHALATION TOXICITY STUDY WIT APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: V DOSE: 5.0 MG/M3 ;DAYS ON TEST:; 26 MODE OR DEATH; SD GROSS OBSERVATIONS: NO ABNORMALITIES DETECTED' MICROSCOPIC OBSERVATIONS; LIVER - INFLAMMATION, SUBACUTE, MINIMAL THE FOLLOWING TISSUES 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, EPIDI NOSE. PANCREAS, RECTUM THE FOLLOWING TISSUES WERE AUTC'LYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NON THE FOLLOWING TISSUES WERE SEVERELY AUTOLY2ED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INCI 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 IN NONE .HN-17375,, ANIMAL #: 447)37 . SUBCHRONIC INHALATION TOXICITY STUDY WIT 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 OB'SER VAT IONS; NO-ABNORMALITIES DETECTED MICROSCOPIC OBSERVATIONS:' NONE , THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS,"BRAIN. CECUM, COLON, ESOPHAGUS, EYES, HEA|RT, ILEUM, JEJUNUM, KIDNEYS,'LIVER, LUNGS, MESENTERIC LYMPH NODE, STERNUM, STOMACH, TESTES, THYMUS, THYROID, TRACHEA,;URINARY BLADDER ' ' ' I !. DUODENUM, EPID NOSE, PANCREAS THE :FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NO THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INC NONE I 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 I Nl NONE . I '^ OS ffl I3. . v^f 0 0 <B in 3 2. I 5" w 0 > 0 03 ' ,HN-17375 ANIMAL If: ' 447138 SUBCHRONIC INHALATION TOXICITY STUDY WITI 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: EPIDIDYMIDES ADRENALS - SMALL, POSTERIOR END - DEFORMITY, LEFT, MISSING MICROSCOPIC OBSERVATIONS: LIVER INFLAMMATION, SUBACUTE, MINIMAL THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS. BRAIN, CECUM, ESOPHAGUS, EYES, HEART, ILEUM, JEJUNUM, KIDNEYS, LUNGS, MESENTERIC LYMPH NODE, STERNUM, STOMACH, TESTES, THVMUS, THYROID, TRACHEA, URINARY BLADDER COLON, DUODENUM, EPID NOSE, PANCREAS, RECTU THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NDT PRECLUDE MICROSCOPIC EXAMINATION; NO THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INC 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 I . NONE HN-17375 _ SUBCMRONIC INHALATION TOXICITY STUDY WITH APPENDIX B' (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA . MALE RAT GROUP: V DOSE: 5.0 MG/M3 ANIMAL If: . 447139 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, ESOPHAGUS, EYES, HEART, ILEUM, JEJUNUM, KIDNEYS, LUNGS, MESENTERIC LYMPH NODE, STERNUM, STOMACH, TESTES, THYMUS, THYROID, TRACHEA, URINARY BLADDER COLON, DUODENUM, EPID NOSE, PANCREAS, RECTU THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: NO THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN INC NONE SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE ^ SECTIONS OF THE FOLLOWING TISSUES WERE INSUFPICIENT:FOR MICROSCOPIC EXAMINATION; ORRGGAANf NOT COUNTED IN IN I NONE c? I I (ftl as . 3 i ivc-tJ ' p-, 0 0 (ft us ' , ' ' ' ' . : , ' " 3 ^ 0 I a OS ANIMAL #: .447140 ' SUBCHRONIC INHALATION TOXICITV STUDY WITH' APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: V DOSE: 5.0 MG/M3 DAYS .ON TEST: 12 MODE OP DEATH: SD .' ' GROSS-OBSERVATIONS: NO ABNORMALITIES DETECTED ' ' ' ' ' , ! . >- n 0 o I I w 0) N <B a o 10 w 31 a FIB B 33" -4 US 0 > 0 t MICROSCOPIC OBSERVATIONS: NONE ' : ' ' ; . THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN, CECUM, COLON, ESOPHAGUS, EYES, HEART, ILEUM, JEJUNUM, KIDNEYS.'LlVER. LUNGS, MESENTERIC LYMPH NODE, STERNUM, STOMACH, TESTES, THYMUS,;THYROID, TRACHEA, URINARY BLADDER DUODENUM, EPIDI NOSE, PANCREAS THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NQT PRECLUDE MICROSCOPIC EXAMINATION: NON THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE. ORGAN NOT COUNTED IN INCI . . . 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 IN NONE , ' . ' . . ' ..,I..;I HN-17375. _ ANIMAL #: 447141 SUBCHRONIC INHALATION TOXICITY STUDY WITH| 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: LIVER - INFLAMMATION, SUBACUTE, MINIMAL THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN, CECUM, ESOPHAGUS, EVES, HEART, ILEUM, JEJUNUM, KIDNEYS, LUNGS, MESENTERIC LYMPH NODE, STERNUM, STOMACH. TESTES, THYMUS, THYROID, TRACHEA, URINARY BLADDER COLON, DUODENUM, EPI NOSE, PANCREAS, RECT THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: N THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN IN 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 NONE ANIMAL If: 447142 SUBCHRONIC INHALATION TOXICITV STUDY WITI APPENCIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROU.P: 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, MESENTERIC LYMPH NODE, STERNUM, STOMACH, TESTES. THYMUS, THYROID, TRACHEA, URINARY BLADDER DUODENUM, EP NOSE, PANCREA THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYS3S DID NOT PRECLUDE MICROSCOPIC EXAMINATION: N THE FOLLOWING TISSUES WERE SEVERELY AUTOLVZED; MICROSCOPIC DIAGNOSES NOT MADE. ORGAN NOT COUNTED IN IN 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 'J NONE 1 us. 3 (0. a 3 HN-17375 SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: VII DOSE: 10.0 MG/M3 ANIMAL : 447143 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, EP NOSE, PANCRE THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLY.SIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: THE FOLLOWING TISSUES WERE SEVERELY AUTOLVZED; MICROSCOPIC DIAGNOSES NOT MADE,' ORGAN NOT COUNTED IN IN 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 NONE K.V HN-17375 ANIMAL ff: 447144 SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: VII DOSE: 10.0 MG/M3 DAYS 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, ESOPHAGUS, EVES, HEART, ILEUM, JEJUNUM, KIDNEYS, LUNGS, MESENTERIC LYMPH NODE, STERNUM, STOMACH. TESTES, THYMUS, THYROID, TRACHEA, URINARY BLADDER COLON, DUODENUM, EP NOSE, PANCREAS, RECT THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: N THE FOLLOWING TISSUES WERE SEVERELY AUTOLVZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN IN NONE |L SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION; NONE .0- ^ SECTIONS OF THE FOLLOWING TISSUES WERE INSUFFICIENT FOR MICROSCOPIC EXAMINATION; ORGAN NOT COUNTED IN ' NONE I < US i a s a, a OT 3 0 W 0 > ) a ANIMAL ; 447145 SUBCHRONIC INHALATION TOXICITY STUDY WITH APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: VII DOSE: 10.0 MG/M3 DAYS ON TEST; 12 MODE OF DEATH: SD GROSS OBSERVATIONS: RENAL PELVIS - DILATATION, MILD, RIGHT MICROSCOPIC OBSERVATIONS; KIDNEYS LIVER - DILATATION, RENAL PELVIS, MILD - INFLAMMATION. SUBACUTE. MINIMAL THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY: ADRENALS, BRAIN, CECUM. COLpN, ESOPHAGUS, EYES, HEART, ILEUM, JEJUNUM, LUNGS, MESENTERIC LYMPH NODE, NOSE, PANCREAS, STOMACH, TESTES, THYMUS, THYROID, TRACHEA, URINARY BLADDER DUODENUM, EP RECTUM, SPLE THE FOLLOWING TISSUES WERE AUTOLVZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: THE FOLLOWING TISSUES WERE SEVERELY AUTOLVZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN I 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 NONE UN-17375 , ANIMAL if: 447)46 SUBCMRONIC INHALATION TOXICITY STUDY WIT 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: LIVER - INFLAMMATION, SUBACUTE, MINIMAL THE FOLLOWING TISSUES 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, EPI NOSE, PANCREAS, RECT THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: N THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN IN 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 NONE HN-17375 SUBCHRONIC INHALATION TOXICITV STUDY WITH APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: VII DOSE: 10.0 MG/M3 ANIMAL #: 447147 DAYS ON TEST: 12 MODE OF DEATH: SD GROSS OBSERVATIONS: NO ABNORMALITIES DETECTED MICROSCOPIC OBSERVATIONS; EPIDIDYMIDES - SPERM GRANULOMA, MILD THE FOLLOWING TISSUES WERE UNREMARKABLE MICROSCOPICALLY; ADRENALS, BRAIN, CECUM, COLON, DUODENUM, ESO HEART, ILEUM, JEJUNUM, KIDNEYS, LIVER, LUNGS, MESENTERIC LYMPH NODE, NOSE, PANCREAS, RECTUM, SPLEEN STOMACH, TESTES, THYMUS, THYROID. TRACHEA, URINARY BLADDER THE FOLLOWING TISSUES WERE AUTOLVZED; DEGREE OF AUTOLYSIS DID NOT PREC.LUDE MICROSCOPIC EXAMINATION: THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN IN 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 NONE Y^ HN-17375 ANIMAL It: 447)48 SUBCHRONIC INHALATION TOXICITV STUDY WIT 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, ESOPHAGUS, EYES, HEART, ILEUM, JEJUNUM, KIDNEYS, LIVER, LUNGS, MESENTERIC LYMPH NODE, STERNUM, STOMACH, TESTES, THYMUS. THYROID, TRACHEA, URINARY BLADDER DUODENUM, EPI NOSE, PANCREA THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: N THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE. ORGAN NOT COUNTED IN IN NONE , SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION; NONE I-' L" SECTIONS OF THE FOLLOWING TISSUES WERE INSUFFICIENT FOR MICROSCOPIC EXAMINATION; ORGAN NOT COUNTED IN " NONE 0 I w i nV M fl P a 0 (0 w I 0 0 3. Si. 3 W 0 > 0 00 ANIMAL *; 447149 SUBCHRONIC INHALATION TOXICITY STUDY WIT 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, ESOPHAGUS, EVES, HEART, ILEUM, JEJUNUM, KIDNEYS, LIVER. LUNGS, MESENTERIC LYMPH NODE, STERNUM, STOMACH, TESTES, THVMUS, THYROID, TRACHEA, URINARY BLADDER DUODENUM, EPI NOSE, PANCREA THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: N THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN IN NONE SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE i3^ SECTIONS OF THE FOLLOWING TISSUES WERE INSUFFICIENT FOR MICROSCOPIC EXAMINATION; ORGAN NOT COUNTED IN <~ NONE 0 3 ^ 3 SS s a. 0 Q <0 w 0 s(ft 0 CO HN-17375. ^ ANIMAL tf: 447150 SUBCHRONIC INHALATION TOXICITY STUDY WIT. APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: VII DOSE: 10.0 MG/M3 DAYS 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, ESOPHAGUS, EYES, HEART, ILEUM, JEJUNUM, KIDNEYS, LUNGS, MESENTERIC LYMPH NODE, STERNUM, STOMACH, TESTES, THYMUS, THYROID, TRACHEA, URINARY BLADDER COLON, DUODENUM, EPI NOSE, PANCREAS, RECT THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: N THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN IN NONE (L SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION; NONE Ul U1 SECTIONS OF THE FOLLOWING TISSUES WERE INSUFFICIENT FOR MICROSCOPIC EXAMINATION; ORGAN NOT COUNTED IN NONE i^i Q I i >,?.; (IS iii) 3 N IB a a a? 5 -s Cfi 0 > 0 ANIMAL : 447151 SUBCHRONIC INHALATION TOXICITV STUDY WIT APPENDIX B (continued) INDIVIDUAL ANIMAL PATHOLOGY DATA MALE RAT GROUP: VII DOSE: 10.0 MG/M3 DAYS ON TEST: 12 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, EP NOSE, PANCRE THE FOLLOWING TISSUES WERE AUTOLYZED; DEGREE OF AUTOLYSIS DID NOT PRECLUDE MICROSCOPIC EXAMINATION: THE FOLLOWING TISSUES WERE SEVERELY AUTOLYZED; MICROSCOPIC DIAGNOSES NOT MADE, ORGAN NOT COUNTED IN IN NONE SECTIONS OF THE FOLLOWING TISSUES WERE NOT PRESENT FOR MICROSCOPIC EXAMINATION: NONE ^n SECTIONS OF THE FOLLOWING TISSUES WERE INSUFFICIENT FOR MICROSCOPIC EXAMINATION; ORGAN NOT COUNTED IN <^ NONE CH 9 U .3 w ui 3 S5 N' TO a a 0 (It w 3 0 w 0 > 0 S3