Document 9Jm3xa29dDBgMMxqJq7yxQvv3

INTERDEPARTMENTAL PATHOLOGY REPORT TITLE: SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS AUTHORS: J. D. Burek, T. J. Bell, J. E. Beyer, R. R. Albee, J. E. Battjes FILE NUMBER: HET K-6117-(10) CHARGE NUMBER: 998-0170200 DATE OF REPORT: August 8, 1980 DISTRIBUTION: R. J, Kociba, B. A. Schwetz, K. S. Rao, J. A. John, J. S. Murray, J. E. Betso, W. E. Hoover, M. J. McKenna, G, C. Jersey, Tox Files, Path Files Toxicology Research Laboratory Health and Environmental Sciences, USA 1803 Building Dow Chemical U.S.A. Midland, Michigan 48640 DOW CONFIDENTIAL HO i;-r]4]o CONF TOFImt J4,( TABLE OF CONTENTS Page LIST OF FIGURES....................................................................................................... LIST OF TABLES............................................................................................................. INTRODUCTION .................................................................................................................. MATERIALS AND METHODS ............................................................................................... Gross Necropsy Examination .................................................................... Histopathologic Examination ....................... . ..................................... Ultrastructural Examination of Testicular Tissue from Male Rabbits...................................................................................... RESULTS, PART I - RATS........................................................................................... Gross and Histopathologic Evaluation.................................... 4-Week Interim Kill...................................................................................... 14-Week Interim Kill.................................................................................. Animals Dying or Killed Moribund During the Recovery Period and the Terminal Kill at the End of the Recovery Period ........................................................................................... RESULTS, PART II - RABBITS.................................................................................. Gross and Histopathologic Evaluation .............................................. Electron Microscopic Evaluation of Testicles from Male Rabbits...................................................................................... SUMMARY............................................................................................................................... REFERENCES.................................................................................................................. LEGENDS TO FIGURES.................................................................................................... FIGURES 1-9...................................................................................................................... TABLES 1-16...................................................................................................................... 1 3 5 6 7 9 9 12 12 12 13 15 20 20 23 27 29 30 32 38 no 1314 11 CONFTOFNTTAl LIST OF FIGURES FIGURE 1 Schematic Illustration of the cells within a normal seminiferous tubule. FIGURE 2 Normal seminiferous tubule showing Sertoli cells (SC) and spermatogonia (SG) on the basal lamella (BL) and the relation ship of these structures to the primary (PR) and secondary (SEC) spermatocytes. Original magnification 2,600X. FIGURE 3 Normal seminiferous tubule near the luminal surface illustrating cap-phase spermatide (CP) and spermatozoa (S). Original magnification 2,070X. FIGURE 4 Seminiferous tubule from a rabbit exposed to 10 ppm of DBCP for 8 weeks. Note the absence of spermatozoa on the luminal surface and the absence of spermatogonia, primary and secondary spermato cytes, and the lack of cap-phase spermatids. Original magnifi cation 2,600X. FIGURE 5 A. Interstitial cell from a control rabbit. B. Interstitial cell from a rabbit exposed to 10 ppm of DBCP and containing increased lysosomes (LY) in the cytoplasm. Original magnification 4,100X. FIGURE 6 Normal-appearing seminiferous tubule from a rabbit that had been exposed to 10 ppm of DBCP for 8 weeks followed by 38 weeks of recovery. BL = basal lamella; SG - spermatogonia; SC = Sertoli cell; and PR = primary spermatocyte. Original magnification 8,300X. FIGURE 7 Seminiferous tubule from a rabbit exposed to 10 ppm DBCP for 8 weeks followed by 38 weeks of recovery. Note the absence of spermatogenesis. BL = basal lamella and SC * Sertoli cell. Original magnification 8,300X. ROW CONFIDENTIAL f)0 131417 CONFTOFNTTAi -2- LIST OF FIGURES (Con't) FIGURE 8 Abnormal spermatozoa seen in rabbits exposed to 1 or 10 ppm of DBCP. A-C are from control rabbits and D-F are from treated rabbits. FIGURE 9 Seminiferous tubule from a rabbit exposed to 1 ppm or DBCP for 14 weeks followed by 32 weeks of recovery. Note the degenerative spermatozoa (f) within Sertoli cells (SC). BL = basal lamella and PR primary spermatocyte. Original magnifica tion 8,300X. DOW CONFIDENTIAL DU 131413 CONFTDFNTTAi -3- ' LIST OF TABLES TABLE 1 Tissues routinely collected at necropsy and preserved in 10% formalin TABLE 2 Number of rabbits examined by electron microscopy TABLE 3 Gross pathologic observations on rats from the 4-week interim kill TABLE 4 Histopathologic observations and number of tissues examined on rats from the 4-week interim kill TABLE 5 Gross pathologic observations on rats from the 14-week interim kill TABLE 6 Histopathologic observations and number of tissues examined on rats from the 14-week interim kill TABLE 7 Gross pathological observations on male rats exposed for 14 weeks and then held for up to 32 weeks of recovery TABLE 8 Gross pathological observations on female rats exposed for 14 weeks and then held for up to 26 weeks of recovery TABLE 9 Histopathologic observations and number of tissues examined on male rats exposed for 14 weeks and then held for up to 32 weeks of recovery TABLE 10 Histopathologic observations and number of tissues examined on female rats exposed for 14 weeks and then held for up to 26 weeks of recovery DOW CONFIDENTIAL DO 101414 CONFTDFNT TA1 -4- LIST OF TABLES (Con't) TABLE 11 Cause of death or moribund condition of rats dying or killed moribund during the recovery period TABLE 12 Gross pathologic observations on male rabbits exposed for up to 14 weeks and then held for up to 32 weeks of recovery TABLE 13 Histopathologic observations and number of tissues examined on male rabbits exposed for up to 14 weeks and then held for 32 weeks of recovery TABLE 14 Cause of death or moribund condition of rats dying or killed moribund during the recovery period TABLE 15 Number of ultrastructurally abnormal spermatozoa in rabbits immediately after exposure period TABLE 16 Number of ultrastructurally abnormal spermatozoa in rabbits after recovery period no 1 31 0 c.onft OF NT T A1. -5- SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS INTRODUCTION The compound 1,2-dibromo-3-chloropropane (DBCP) has been used as a [soil fumigant and nematocide. Recent reports have associated exposure to DBCP with low sperm counts in male workers (Whorton et al., 1977) and studies in laboratory animals have indicated that DBCP has an adverse effect on spermatogenesis and leads to testicular atrophy (Torkelson et jil., 1961). Torkelson e al., (1961) showed that the liver, kidney, digestive tract, and testicles of several species were affected by DBCP. However, the most sensitive organ was the testicle in all species. The changes were associated with degenerative changes of the seminiferous tubules, a reduction or absence of sperm cells, and the presence of abnormal sperm cells. A probe study was recently conducted and reported from thisj laboratory (Burek ejt al, 1980). Groups of 5 male Sprague-Dawley rats, 2 male New Zealand white rabbits, and 2 male beagle dogs each were exposed to 30 ppm of DBCP for 6 hours per day, 5 days per week for 2 weeks (rats and rabbits) or for A weeks (dogs) with degenerative testicular changes observed in all three species. The rabbit was considered to be the most sensitive species for the testicular alterations. Furthermore, semen samples were easily obtained and breeding studies could be conducted. Therefore, the rabbit was recommended for longer studies. A study was conducted to further assess the effects of inhaled DBCP. It was designed: 1) to assess the effects of inhaled DBCP on spermatogenesis and fertility in laboratory animals, 2) to determine the maximum level of exposure of DBCP that does not have an effect on reproduction, and 3) to evaluate the potential for reversibility of these effects. The purpose of this report is to summarize the pathology results of that study. DOW CONFIDENTIAL 131416 CONF J Of NT TAi -6- MATERIALS AND METHODS Groups of 10 male rabbits, 35 male rats, and 35 female rats each were exposed by inhalation to 0, 0.1, 1.0 or 10 ppm of DBCP vapor. Exposures continued for 6 hours/day, 5 days/week for 14 consecutive weeks, with the exception of the 10 ppm rabbits which were exposed for only 8 weeks due to a high incidence of mortality. Five rats per sex per dose were killed after 14 weeks for cytogenetic studies. The semen of rabbits was evaluated on a weekly basis during the 14-week exposure period and at periodic intervals during the recovery period. The fertility of male rats was evaluated by mating trials with unexposed females. The exposed female rats were mated to unexposed male rats at the end of the 14-week exposure period and were allowed to deliver a litter. In order to assess the fertility of the exposed rabbits, each male was allowed to mate with an unexposed female rabbit during the 14th week of the s tudy. At the end of the respective exposure period, animals were held for various periods to determine whether any of the observed effects were reversible. Male and female Sprague-Dawley rats (Spartan substrain from Spartan Animals, Haslett, MI) were exposed to 0, 0.1, 1.0 or 10 ppm of DBCP. Five/sex/exposure level were killed after 4 weeks and after 14 weeks of exposure. None died spontaneously during the exposure period leaving 20/sex/exposure level for the recovery portion of the study. During the recovery period, a few male and female rats died spontaneously or were killed moribund. However, most survived until the end of the recovery period (26 and 32 weeks for females and males, respectively). The groups of 10 male New Zealand White rabbits (Longshaw Farms, Augusta, MI) were exposed to 0, 0.1 or 1.0 ppm of DBCP for 14 weeks or to 10 ppm for 8 weeks. Some died or were killed moribund during the exposure periods and included 1 control, 1 in the 1 ppm group and 3 in the 10 ppm group. D(hV CONFiDFNTiil DO 131417 C ONFTDFNT TAt -7- Because of the increased mortality in the 10 ppm group, exposure was discontinued after 8 weeks and 1 additional rabbit from this group was sacrificed after 8 weeks of exposure. The remaining 6 rabbits were placed on recovery for 32 weeks before the final kill at the end of the recovery period. Likewise, some rabbits in the groups exposed to 0, 0.1 or 1.0 ppm for 14 weeks were killed after the 14-week exposure period leaving 6 rabbits in the 0 and 0.1 ppm exposure groups and 5 in the 1 ppm exposure group for the recovery portion of the study. Only 1 rabbit in the 10 ppm group died during the recovery period. The purpose of the pathologic evaluation of the rats and rabbits was to evaluate the onset and possible reversibility of the morphological repro ductive changes produced by inhalation exposure to DBCP. As a result, a complete gross pathology examination was conducted on each animal, but only selected tissues were examined histopathologically. As a minimum, the reproductive organs were examined by light microscopy. In addition, electron microscopy was conducted on testicular tissue from some of the rabbits. The selection of additional tissues for light microscopy was based on the judgment of the pathologist after evaluating data generated from the various portions of this study. Gross Necropsy Examination. A gross necropsy examination was performed on all male and female rats and male rabbits and including those animals that were part of the exposure period, those that were part of the recovery portion of the study, and those that died or were killed moribund during the study. The first interim kill was after 4 weeks of exposure (rats only), the second was at the termination of the exposure period (8 weeks for the 10 ppm rabbits and 14 weeks for all other groups). The final kill took place at the termination of the recovery period and occurred after 26 weeks of recovery (40th week of the study) for the female rats, after 32 weeks of recovery (46th week of the study) for the male rats and after 32 weeks of recovery (38 weeks for the 10 ppm group) for the rabbits. In addition, all animals that were found dead or were killed moribund were also submitted for a complete necropsy examination. The rats that were submitted alive were killed DOW CONFIDENTIAL on in Mi8 GONF TDFNTTAl -8- by decapitation following clamping of the trachea under methoxyflurane anesthesia, while the rabbits that were submitted alive were killed by decapitation following CC^ anesthesia. Those animals that were submitted as part of the interim or terminal kills had been deprived of food over night prior to necropsy. The eyes from all animals were examined by gently pressing a glass slide against the cornea and examining the eye under bright fluorescent illumi nation. A complete gross pathologic examination was performed by a veterinary pathologist. Prior to fixation of the tissues, the weights of the liver, kidneys, brain, heart, testes, and epididymides were recorded from all rats at all dose levels from the 4-week, 14-week and recovery terminal kill groups and from rabbits at the 8-week, 14-week and terminal kill groups. Adrenal gland weights were also taken from rabbits at the terminal kill. In addition, the lungs and trachea from all animals were removed as a unit and expanded with phosphate-buffered 10% formalin using a syringe. Representative sections of all the major organs and tissues were collected and preserved in neutral prosphatebuffered 10% formalin and those tissues routinely collected are listed in Table 1. Exceptions to the formalin fixation included the fixing of one ovary from each female rat and one testicle and epididymis from each male rat and rabbit in Bouin's fixative. The other testicle and epididymis and the other ovary from each rat were fixed in 10% buffered formalin. Furthermore, the eyes from all rats and rabbits from the interim and terminal kills were fixed in Zenker's fixative while the eyes from the animals that were killed moribund or died spontaneously during the study were fixed in phosphate-buffered 10% formalin. In addition to the tissues routinely collected for light microscopy, there were tissues collected and fixed in glutaraldehyde for possible electron microscopy. Tissue for this purpose was collected from 5 male rats per dose level at the 14-week kill and from 3 male rats per dose level from the terminal kill of the recovery animals. Tissue was col lected in glutaraldehyde from the one rabbit in the 10 ppm group that HOW nflNFIDENTIfll OO 131410 c ONF TDFNT I At -9- was killed after 8 weeks of exposure and from all of the control and treated rabbits after 14 weeks exposure as well as all at the terminal kill of the recovery period. These tissues were collected from the testicles for possible future electron microscopy; however, tissues from rats were not processed because of difficulties in handling the tissue and the fact that the rabbit was the most sensitive species for the testicular effects of DBCP. The rabbits provided better material for electron microscopic evaluation and they were, therefore, the only animals used for this portion of the study. Serum was collected and saved from all animals that were killed as part of the interim and terminal kills. The serum was collected immediately following the decapitation procedure by exsanguinating the animals into a glass test tube. Histopathologic Examination of Tissues. Tissues were processed using conventional methods, embedded in paraffin, sectioned (5-6 y) and stained with hematoxylin and eosin. A complete list of the organs and tissues examined microscopically from the rats and rabbits is presented in the tables summarizing the histopathologic findings for the various time periods during the study. In general, complete sets of tissues were run on the rats and rabbits that were killed in the control and top dose groups at the end of the recovery period. From the other groups, various selected tissues were examined as deemed appropriate by the pathologist. Ultrastructural Examination of Testicular Tissue From Male Rabbits. Testicular tissue was collected and examined ultrastructurally from most of the male rabbits on this study as summarized in Table 2. These included 3 animals from the control group which were killed after 14 weeks of exposure, 4 animals from the 0.1 ppm group which were killed after 14 weeks, 4 animals in the 1.0 ppm group which were also killed after 14 weeks, and 1 animal from the 10 ppm group which was killed nnw nnNFiDFNTiA! (HI 131430 CONFTDFNT TAl -10- af ter 8 weeks of exposure. Following the exposure period, rabbits in each of the different dose groups were allowed to go on for recovery for up to 38 weeks. These included 6 control animals and 3 animals each in the 0.1 ppm, 1.0 ppm, and 10 ppm groups. At the time of necropsy, the testicles were quickly removed from the animals following the decapitation procedure. They were then weighed and a slice approximately 2 mm in thickness was taken for electron microscopy. In order to increase the firmness of the tissue before cutting into 1 mm blocks, the slice was fixed for 1-6 hours in 2.5% phosphate-buffered glutaraldehyde. The blocks were then cut and held overnight in glutaraldehyde fixative, washed in phosphate buffer, and post-fixed in 1% phosphate-buffered osmium tetroxlde. Dehydration was accomplished through a series of ethanol washes. After immersion in propylene oxide, the blocks were infiltrated with Epon 812 and embedded in polyethylene capsules. Testicular sections of about 1 y in thickness were cut with a glass knife on a Sorvall MT-2B ultramicrotome, stained with toluidine blue, and examined by light microscopy. The sections were used to select the more desirable blocks for thin sectioning. Three blocks were selected and examined per animal. Thin sections, approximately 600-700 % were cut from the 3 selected blocks per rabbit. Selected tissues were cut with a diamond knife on the Sorvall MT-2B ultramicrotome, floated on a 200-mesh grid, and stained with uranyl acetate and lead citrate. The individual grids were examined and electron photomicrographs were made using a Zeiss EM-10 electron microscope. Development of negative sheets and printing was performed within this laboratory using standard techniques for Kodak 4489 film and Kodak Kodachrome RC// paper. The grids were first examined by the electron microscopist in conjunc tion with the pathologist, and initial comments recorded on individual animal observation sheets. There were two types of parameters that were evaluated and these included a qualitative descriptive portion and an attempt to quantify the results. Mature spermatids were counted and DOW CONFIDENTIAL DO 131401 OONF T OF NT T Al -11- graded as either abnormal or normal. Cap phase spermatids were also evaluated for the presence or absence of nuclear breaks in the nuclear membrane and were counted as having 0, 1, or >1 nuclear break per c^ll. For both the mature spermatids and the cap phase spermatids, approxi mately 25 cells were counted per grid. Interstitial cells were also evaluated and graded as having numerous or few lysosomes, and the fat content was also evaluated on a semi-qualitative basis. ! I no 1014?? CONF TDFNTTA! h -12- RESULTS PART I - RATS GROSS AND HISTOPATHOLOGIC EVALUATION OF MALE AND FEMALE RATS The gross pathology observations are tabulated in Table 3 for the interim kills after 4 weeks of exposure. Table 5 for the interim kills after 14 weeks of exposure, and Tables 7 and 8 for the terminal kill at the end of the recovery period which followed the 14 weeks of exposure. In addition, animals that died during the recovery period are also tabu lated in Tables 7 and 8. The histopathologic observations are listed in Table 4 for the interim kill after 4 weeks of exposure, Table 6 for the interim kill after 14 weeks of exposure, and the terminal kill at the end of the recovery period which followed the 14 weeks of exposure in Tables 9 and 10. Furthermore, rats that died during the recovery period are also sum marized in Tables 9 and 10. 4-ufeek Interim Kill. Five male and five female rats were killed after 4 weeks of exposure to DBCP. There were no grossly observed treatmentrelated alterations in either the male or the female rats after the 4 weeks of exposure. A few tissue alterations were observed, but these were typical of spontaneous changes commonly seen in rats of this age and strain. Histopathologic evaluation of tissues was limited to the male repro ductive system which included the testicles, epididymides, prostate, seminal vesicles, and coagulating glands; the female reproductive system which included the ovaries, oviducts, uterus, and cervix; the brain; and the adrenal glands. Histopathologic alterations that were considered to be treatment-related were confined to the testicles of male rats. The changes consisted of focal or multifocal atrophy of individual semini ferous tubules within the testicles. The atrophy consisted of decreased r>0 13 14P3 r.ONFTOFNT TAI -13- spermatogenesis and loss of spermatogenic elements in individual semini ferous tubules. A few tubules had lost most of the germinal elements and contained predominately Sertoli cells. Such changes were observed in 1 of 5 rats from the 10 ppm group, 2 of 5 rats from the 1 ppm group, but in 0 of 5 and 0 of 5 rats from the 0.1 ppm and control groups respectively. Although these changes were slight and were not seen in all 10 ppm or 1 ppm rats, they were consistent with induced changes. There were a few other tissue alterations observed, but these were typical of the spectrum of spontaneous lesions seen in rats of this age and strain. 14-Week Interim Kill. Five male and 5 female rats were killed at the termination of the 14-week exposure period. Grossly observed alterations that were considered to be treatment-related were confined to the testicles; they were bilaterally decreased in size and often had a dark or tan colored appearance in 5 of the 5 male rats from the 10 ppm group. Similar changes were not observed in any of the male rats from the 1 ppm, 0.1 ppm or control groups, although 2 controls did have testicular alterations. One control rat had one testicle that was severely decreased in size. Another control had two small testicles. The etiology of the testicular changes in the controls was undetermined and could either be congenital or acquired. In either case, the changes were different from the alterations seen in the rats from the 10 ppm groups. The changes in these control rat testicles were considered to be incidental spontaneously-occurring alterations. In addition, there were a few other observations In both male and female rats that were typical of the spectrum of spontaneous lesions seen in rats of this age and strain. Histopathologic evaluation of tissues was limited to the male reproductive system which included the testicles, epididymides, prostate, coagulating glands, and seminal vesicles; the female reproductive system which in cluded the ovaries, oviducts, uterus, and cervix; the liver; the kidneys; the urinary bladder; the brain; and the adrenal glands. Histopathologic changes that appeared to be treatment-related were observed in the testi cles and in the adrenal glands. DM CONFIDENTIAL no 1314?4 CONFTDFNTTAl -14- The changes in the testicles consisted of individual seminiferous tubules with decreased spermatogenesis. Some lacked germinal cells and contained only or predominantly Sertoli cells. Other tubules had some germinal cells, but they were decreased in amount. Approximately 50% or more of the tubules appeared normal with active sperm production and normal-appearing spermatogenesis. Despite the testicular alterations, there were no recognized changes in the epididymides or the accessory male genitalia of these rats. Furthermore, similar changes were not observed in any of the rats in the 1, or 0.1, or 0 ppm groups. However, there were control rats with testicles that were severely decreased in size as noted on gross examination. One was unilateral, the other bilateral. Both of these control rats with the testicular changes also had mineral deposits in seminiferous tubules, interstitial edema, and multinucleated spermatids. Such changes are suggestive for an acquired lesion possibly due to circulatory disturbances. The alterations seen in these 2 control animals were clearly different than those seen in the testicles of the rats from the 10 ppm group. Furthermore, the epididymides in these 2 rats also were decreased in size and had decreased sperm in the tubular lumina. These alterations were perhaps congenital (i.e. hypoplasia), or more likely, were acquired (i.e. atrophy). In any case, the etiology is unknown, but they were considered to be spontaneous lesions unrelated to the experimental procedure. Alterations in the adrenal glands were observed in both male and female rats in the 10 ppm groups. The alterations were classified as foci of altered cells in the adrenal cortex. The foci consisted of collections or focal aggregates of cells that differed in tinctorial and textural appearance from the surrounding normal tissue. The foci were usually multiple, were composed of only a few cells and were present in the cortex, especially the zona fasciculata. These foci were composed of cells that were usually larger than normal, their cytoplasm was either vacuolated, granular, or homogeneous, and the color of the cells was either pale or more eosinophilic. In any case, they were morphologically DOW COrtFiDENHAI no conftofnttai -15- distinct from the surrounding normal cortical cells. Similar foci occur spontaneously in aging rats. They begin to be seen after 12 months of age and are very common in rats older than 18 months of age, especially in females. They increase in size, frequency and incidence with age. One control male had a small unilateral focus of altered cells. On the other hand, the male and female rats from the 10 ppm groups had more of these foci and they tended to be larger and bilateral. Three of the five males and three of the five females had such foci. Normally, so few numbers would make a correlation with the treatment difficult. However, based on background historical experience for animals of this age and strain, and since similar but larger foci as well as nodular hyperplasias, were observed in the adrenal glands of the recovery rats, and since it is very unusual to see so many foci (3 of 5 males and 3 of 5 females) in rats of this age, these adrenal gland changes in rats from the 10 ppm groups are considered to be treatmentrelated alterations. There were a few other histopathologic observations made in the male and female rats, but these were typical of spontaneous naturally-occurring changes commonly seen in rats of this age and strain and are not con sidered to be treatment-related. Animals Dying or Killed Moribund During the Recovery Period and the Terminal Kill at the End of the Recovery Period. Twenty male and twenty female rats were exposed to DBCP by inhalation for 14 weeks. Following the exposure period, they were removed from the inhalation chambers and allowed to go untreated to evaluate possible reversibility of the in duced tissue changes. During this recovery period, a few rats died or were killed moribund. These included two males and three females in the 10 ppm groups, one female in the 1 ppm group, one male in the 0.1 ppm group, and 3 males and 1 female in the control groups. DO 101406 CONF TDFNT TA1 -16- The cause of death of these rats Is summarized in Table 11. Although a few tumors were observed, all could be expected in this strain of rat, and the small numbers of animals makes any correlation with the exposure levels inconclusive. Grossly observed alterations which appeared to be treatment-related were observed in the rats that died spontaneously or were killed moribund as well as in those that were killed at the end of the recovery period. These grossly observed alterations included changes in the adrenal glands in both males and females, and in the ovaries of females. The changes in the adrenal glands were a variation in color which lead to a mottled appearance and/or the presence of pinpoint dark foci. These changes were present in 16 of the 20 males in the 10 ppm group, 2 of the 20 males in the 1 ppm group, 0 of 20 in the males from the control and 0.1 ppm groups. Ten of 20 females in the 10 ppm group, 4 of 20 females in the 1 ppm group, and 1 of 20 and 1 of 20 females from the control and 0.1 ppm groups. Ovarian cysts were observed in 6 of the 20 (6 of 17 females at the terminal kill) females from the 10 ppm experimental group, and only 0 of 20, 2 of 20, and 1 of 20 in the females from the 1 ppm, 0.1 ppm, and control experimental groups, respectively. All of the male rats exposed to 10 ppm and sacrificed after 14 weeks of exposure had testicles that were grossly decreased in size. Grossly, at terminal sacrifice, only 2 of 20 rats from the 10 ppm group had testicles that were slightly decreased in size while 0 of 20, 1 of 20, and 0 of 20 of the rats in the 1, 0.1, and control groups had changes. It is possible that the two top dose males still had residual treatmentrelated changes. However, it is also possible that the changes occurring are age-associated. Therefore, the grossly observed testicular changes in the two male rats at the 10 ppm group may or may not be treatmentrelated. In any case, 18 of the 20 male rats from the 10 ppm group had grossly normal-appearing testicles suggesting a reversibility of the gross alterations that were seen after 14 weeks of exposure. DOW CONFIDENTIAL ^ 0 13]4 py CONFTDFNTTA -17- Histopathologic evaluation of tissues was conducted on all the major organs and tissues of male and female rats that died or were killed moribund during the recovery period and on all rats from the control and 10 ppm exposure levels at the termination of the recovery period. Evaluation of tissues was limited for the rats from the 1 ppm and 0.1 ppm exposure levels. The tissues examined in these groups included the male reproductive system which included the testicles, epididymides, prostate, coagulating glands, and seminal vesicles; the female repro ductive system which included the ovaries, oviducts, uterus, and cervix; the liver; the kidneys; the urinary bladder; the brain; and the adrenal glands. Treatment-related changes were observed in the testicles of males, the ovaries of females, the adrenal glands of both males and females, and the brains of both males and females. Testicular changes consisted of either bilateral or unilateral atrophy (decreased spermatogenesis) of individual seminiferous tubules. These I changes were slight and were less extensive than those observed at the 14-week interim kill. Age-associated, spontaneous testicular changes begin to be seen in male rats after approximately 12 months of age. Therefore, it is not surprising to see some control and low-dose rats with testicular changes. For example, 7 of 20, 5 of 20, and 5 of 20 rats from the 0, 1, and 0.1 ppm exposure levels had unilateral or bi lateral testicular alterations. Such alterations were slight and are very likely age-associated. In contrast, 14 of the 20 rats from the 10 ppm group had some type of testicular alterations. Therefore, some treatment-related testicular changes were present in the rats from the 10 ppm exposure levels, but not in the 1 or 0.1 ppm exposure groups. Female rats also had alterations in the reproductive system. Ovarian cysts were seen in 7 (6 unilateral and 1 bilateral) of the 20 females in the 10 ppm exposure group. This is in contrast to ovarian cysts present in only 1 of 20 rats in the control, 1 of 20 rats in the 0.1 ppm, and 0 of 20 rats in the 1 ppm exposure groups. The cysts were thin-walled, appeared to be follicular in origin, and varied from 2 to 7 mm in size. rmiy nnynnrHT'M OO 1314 3 8 CONFTDrNTTAl -18- A spectrum of lesions were observed in the adrenal cortex of both male and female rats. This spectrum of changes ranged from foci of altered cortical cells, to nodular hyperplasias, to dilated or ectatic cortical sinusoids, and even hematocyst formation. The foci were similar to, but larger than, those foci described in rats hilled after 14 weeks of exposure. The hyperplastic nodules were much larger than the foci, often caused compression of normal-appearing cortical cells, and varied in textural and tinctorial appearance from the surrounding normal cells. The hyper plastic nodules were usually bilateral and usually multifocal. One or more hyperplastic nodules were seen in the adrenal cortex in 19 of 20 males and in 18 of 20 female rats from the 10 ppm recovery groups. In 1 of 20 males and 7 of 20 females from the 1 ppm recovery groups, but in 0 of 20 rats from each of the male and female groups from the 0.1 or control recovery groups. Although similar lesions are occasionally seen in aging rats of this strain, those observed in the present study are clearly more extensive than would be expected for this age, or even from older rats of this strain. Therefore, the nodular hyperplasias in the cortex of the rats from the 10 ppm and 1 ppm exposure groups (both males and females) are considered treatment-related alterations. Ectasia (dilatation) of adrenal cortical sinusoids and cortical hematocyst formation are both age-associated, spontaneously-occurring lesions in aging rats of this strain. However, the number found in the treated groups clearly exceeded the expected incidence and severity for rats of this strain and age. In the males, 4 of 20, and in the females, 3 of 20, in the 10 ppm recovery groups had ectatic cortical sinusoids. In contrast, similar changes were found in 0 or 1 of 20 males or females from the 1, 0.1, or 0 ppm recovery groups. Hematocyst formation was similar to the dilated cortical sinusoids except that the hematocyst represented cystic dilatation to the extent that normal architecture was altered. Present within the cortex were large areas filled with blood and generally lined by sinusoidal lining cells. The presence of these hematocysts in the adrenal glands was even more clearly treatment-related than the focal areas of ectatic sinusoids. For example, 4 of 20 males from the 10 ppm group had hemato cysts while none of the 20 rats from each of the 1, 0.1, or 0 ppm recovery w WMonr?.irm DO 131479 CONFTDFNTIAI -19- groups had these changes. In females this lesion was observed In 17 of 20 rats from the 10 ppm exposure group, and in 4 of 20 rats in the 1 ppm group. None of the 20 rats from each of the 0.1 or 0 ppm exposure groups had similar changes. Therefore, adrenal cortical alterations were considered to be treatment-related in both males and females from the 10 ppm exposure groups and in females from the 1 ppm exposure group, but not in the rats from the 0.1 ppm or control groups. The brains in both males and females had mineralized deposits in the cerebrum occurring as unilateral or bilateral multifocal basophilic deposits. Here, again, these changes are similar to those seen in aging rats, but they occurred earlier and at a much higher incidence than would be expected in rats of this age and strain. Fifteen of 20 males and 6 of 20 females from the 10 ppm groups had mineral deposits in the brain. The etiology of the mineral deposits in unknown. The brains from the animals from the 4 and 14-week interim kills were reexamined for possible early alterations, but no changes were detected. DOW CONFIDENTIAL no 131430 CONF T DFN1 TAL -20- RESULTS PART XI - RABBITS GROSS AND HISTOPATHOLOGIC EVALUATION OF MALE RABBITS The gross pathologic observations for the rabbits are tabulated in Table 12 for the 10 rabbits at each dose level. The table summarizes the findings in the rabbits that died or were killed moribund during the exposure period (one control, one in the 1 ppm group, and three from the 10 ppm groups); the number killed after 8 weeks of exposure (one rabbit in the 10 ppm group); the number that died or were killed moribund during the recovery period (one in the 10 ppm group ); the number killed at the 14-week interim kill (three controls and four rabbits in the 0,1 ppm and 1 ppm groups); and finally, the number terminated at the end of the recovery period (six control and 0.1 ppm rabbits and five rabbits exposed to 1 and 10 ppm of DBCP). Com plete sets of tissues were evaluated from the control and top dose rabbits killed at the end of the recovery period. Selected tissues were examined on the remaining animals with emphasis placed on the reproductive system to evaluate the onset, severity and reversibility of the morphological changes induced by DBCP. The actual tissues examined in each of the rabbits at each dose level are given in Table 13 along with the diagnoses made on each of the tissues. Six rabbits died or were killed moribund during this study (Table 14). Five of the six had pneumonia, rhinitis, pleuritis or other lesions that were con sistent with a severe bacterial infection. Although cultures were not made on these rabbits, the most likely agent is Fasteurella multocida which is a common bacterial organism in rabbits. This agent often leads to the types of lesions that were seen in these animals. It is possible that all of the deaths associated with a bacterial infection were spon taneous in nature. However, since more animals died in the top dose group, it is possible the exposure to 10 ppm of DBCP made the animals more sus ceptible to bacterial infection. Therefore, the increased deaths due to bacterial infection in the rabbits exposed to 10 ppm of DBCP may or may not be treatment-related. now nnNFIDFNT!*! DO 131431 CONFTDFNTTAl -21- Despite the early mortality due to the bacterial infections, an adequate evaluation of the testicles could be made on the animals that died or were killed moribund, as well as those from the interim and terminal kills. The testicles could be adequately evaluated from these rabbits and the onset and progression of the testicular alterations could be assessed. Treatment-related changes were confined to the reproductive system and included atrophy of the testicles, atrophy of the epididymis, atrophy of the prostate, and atrophy of the accessory genitalia. In the 10 ppm rabbits, diffuse severe testicular atrophy was present based on both the gross and histopathologic examination of these animals. Testicular alter ations consisted of complete or nearly complete loss of spermatogenic elements in nearly all of the seminiferous tubules. Most tubules were lined by predominately or only by Sertoli cells. In addition, the tubules that still contained some evidence of germinal cells usually had necrotic debris. The cellular debris and degenerative changes appeared to be confined to the germinal elements of the seminiferous tubules with the Sertoli cells appear ing normal. One rabbit in the 10 ppm group died after approximately 4 weeks of exposure. This animal had a few tubules with germinal elements still present, as well as necrotic debris. The next two rabbits in the 10 ppm group chat died after 4-8 weeks of exposure had even fewer tubules with germinal elements and still had some necrotic debris present in the tubules. The fourth rabbit from the 10 ppm group was killed after 8 weeks of exposure. Tliis represented the interim kill at the end of the exposure period for the 10 ppm rabbits. At this time, the atrophy was virtually complete and bi lateral with no germinal cells identified in the seminiferous tubules of either testicle. The seminiferous tubules appeared to be lined only by Sertoli cells. Furthermore, there appeared to be a relative increase in the number of interstitial cells present within these testicles. This change is interpreted as a relative increase in interstitial cells due to the fact that the testicle, which once occupied a larger area, was now much smaller and the same number of cells which were present in the larger area are now confined to a smaller area due to the atrophy of the DOW CONFIDENTI*! DO 131 A3? CONFTDFNTTAl -22- seminiferous tubules. In summary, the major changes occurred within the germinal cells of the individual seminiferous tubules, were diffuse and were nearly complete with no effects visible in Sertoli or interstitial cells. The epididymides were also atrophic with decreased sperm in the tubular lumina. In addition, the prostate and accessory genitalia showed some decrease in size. Following the recovery period, there were clear signs of tubular regenera tion in the testicles from the rabbits that had been exposed to 10 ppm of DBCP. Some tubules appeared normal, while other tubules appeared to lack any evidence of spermatogenesis. Of the five rabbits in the 10 ppm group, three had regeneration to the extent that approximately 25% of the tubules appeared normal. Two of the five animals had between 25-50% of the tubules with normal-appearing spermatogenesis. Therefore, even though atrophy was still present, all rabbits in the 10 ppm group showed definite signs of partial recovery or reversibility of the severe atrophy that was present after 8 weeks of exposure. At the 14-week interim kill, rabbits exposed to 1 ppm of DBCP had moderate testicular atrophy (approximately 50% reduction in size and weight). After the recovery period, the testicles of two of the five rabbins at the terminal kill, which followed the 32-week recovery period, were grossly and histologically normal. Three of the rabbits did have gross and/or histologic alterations in the testicles, but the alterations were much less severe in degree than that seen after the 14-week exposure period. Thus, at 1 ppm, recovery was nearly complete, and would very likely have been completely reversible had the animals been allowed to live even longer. There were other gross and histopathologic alterations seen in the control and top dose rabbits as well as in the tissues examined from the 0.1 and 1 ppm rabbits. These changes were not considered to be treatment-related, however, but rather spontaneous in nature. now nnNFinFNTim OO 1^1433 OONFTDFNTTA! -23- ELECTRON MICROSCOPIC EVALUATION OF TESTICLES FROM MALE RABBITS An electron microscopic (ultrastructural) evaluation was conducted pn the testicles from the rabbits killed at the 8, 14 and 46 week sacrifices as summarized in Table 2. There was considerable variability in the ultrastructural features of seminiferous tubules from individual rabbits and within different tubules of the same rabbit. This variation was true for both the exposed and control rabbits. Such variability was expected because I individual tubules normally differ in the stages of spermatogenesis that are present at any one time. Some tubules are active while others are inactive and, therefore, some variability in the appearance of seminiferous tubules was expected. This variability did, however, make it difficult to quantify and interpret subtle or slight ultrastructural changes. The normal rabbit testicle contains many seminiferous tubules. The relationship of the different cells within individual tubules is I illustrated in Figure 1. This can be compared to Figures 2 and 3 which are electron micrographs from a control rabbit. Note the presence and relationship of the spermatogonia, primary spermatocytes, secondary spermatocytes, cap-phase spermatocytes and spermatozoa. The rabbit exposed to 10 ppm of DBCP for 8 weeks and sacrificed at the interim kill had nearly complete testicular atrophy. The individual tubules had small lumina, lacked spermatogonia or spermatocytes, were lined by Sertoli cells and were surrounded by a thickened and convoluted basement lamella (Figure 4). The Sertoli cells were normal except for an apparent increase in the number of lysosomes present in the cytoplasm. The interstitial cells between the seminiferous tubules appeared normal, but some did have an increased number of lysosomes in the cytoplasm (Figure 5). Following the 38-week recovery period, the rabbits that had been exposed to 10 ppm for 8 weeks showed incomplete recovery. Some tubules were normal (Figure 6), others were still severely atrophic (Figure 7) and others had stages in between. The normal-appearing tubules had all stages of spermatogenesis including spermatogonia, primary, secondary and cap-phase spermatocytes, and spermatozoa. In the tubules with active 131434 CONFTOFNTTAl 24- spermatogenesis, there was an apparent increase in the number of abnormal spermatozoa present compared to the controls. When the abnormal spermatozoa were formed is unknown because the rate of movement of abnormal spermatozoa into the epididymis may be different than that for normal spermatozoa. The rabbits exposed to 1 ppm of DBCP for 14 weeks had less severe testicular alterations. Approximately 50% of the tubules appeared normal. The remain ing tubules were atrophic and varied from severe (complete or nearly com plete) to slight atrophy. The types of changes present consisted of loss of spermatogonia, spermatocytes and spermatozoa with normal-appearing Sertoli cells. There were abnormal spermatozoa present in the tubules of control and treated rabbits and they had many forms as illustrated in Figure 8. Some were multinucleated, others had multiple tails, others had abnormal head and acrosomal shapes and still others appeared degenerative or necrotic. Abnormal sperm were found in the controls of this study, but the relative numbers appeared to be increased in the rabbits exposed to 1 ppm of DBCP for 14 weeks. As a result, they were considered-treatment related. After 32 weeks of recovery, the rabbits that had been exposed to 1 ppm of DBCP for 14 weeks now appeared to have undergone nearly complete recovery. The tubules were similar to those in the controls and had normal-appearing active spermatogenesis. However, some tubules still had an apparent increase in the numbers of abnormal spermatozoa. Again, the alterations were also seen in controls, but the relative number appeared greater in the 1 ppm recovery group. Some tubules also had debris from spermatozoa within Sertoli cells (Figure 9). Rabbits exposed to 0.1 ppm of DBCP for 14 weeks and submitted to an interim sacrifice had normal-appearing testicles. Their seminiferous tubules were similar to those seen in the controls with normal-appearing active spermatogenesis. A few abnormal spermatozoa were observed in the tubules, but the relative number was similar to the control animals. After the 32-week recovery period, there were no treatment-related alterations observed in the rabbits that had been exposed to 0.1 ppm of DBCP for 14 weeks. nnw nn&iFiriFNTisf DO 1314OF CONFTDFNTTAl -25- In order to quantify the ultrastructural finding of an apparently increased number of normal spermatozoa in certain exposure groups, spermatozoa within the seminiferous tubules were counted and the number (percentage) of abnormal spermatozoa were evaluated. The results are summarized in Table 15 for the rabbits examined at the end of the exposure periods (interim kills) and Table 16 for those evaluated at the end of the recovery period. The tables summarize the total number of spermatozoa counted from each rabbit and the number that appeared abnormal (see Figure 8). One control rabbit (78-792) had one testicle that was severely decreased in size. Tissue for electron microscopy was taken from the normal-appearing testicle, but 51% of the spermatozoa were morphologically abnormal. This was in contrast to an average of 5% (range of 0 to 10%) in the other 8 control rabbits in this study. Therefore, the data from this rabbit were shown in Table 15, but the data was not used to determine the average percentage of abnormal spermatozoa for the control rabbits. The 10 ppm rabbit that was examined at the interim kill after the 8-week exposure period did not have spermatozoa in the seminiferous tubules that were examined. Therefore, no counts were obtained. However, following the 38-week recovery period, 20% of the spermatozoa were morphologically abnormal, indicating increased abnormal spermatozoa compared to the controls. Similarly, the rabbits exposed to 1 ppm of DBCP for 14 weeks and evaluated and those exposed to 1 ppm of DBCP for 14 weeks followed by 32 weeks of recovery had average values of 18% and 24%, respectively. Therefore, both the rabbits exposed to 10 ppm or 1 ppm of DBCP had increased numbers of abnormal spermatozoa within the seminiferous tubules and this increase appeared to be related to exposure to the test material. The 0.1 ppm group was more difficult to evaluate because the 4 rabbits examined after 14 weeks of exposure had 10% (range of 7-14%) abnormal spermatozoa. Since the average percentage of abnormal sperm in the controls was 5% (range from 0 to 10%, excluding animal 78-792, which had 51%), there was an apparent increase in the 0.1 ppm group after 14 weeks. Because -26- the variability of such counts is so great, the 10% figure may represent normal biological variation and be unrelated to the exposure to DBCP. On the other hand, it could represent a slight effect at the 0.1 ppm exposure level and also with a dose response compared to the 18% seen in the 1 ppm exposed rabbits. This can not be resolved with the data obtained from this study. In any case, if an effect was present after 14 weeks, it was not present after the 32-week recovery period (average was 6% with a range of 5-8%). DOW vr ( UL 00 131437 OONFTOFNTTA1 -27- SUMMARY Rats (males and females) and rabbits (males) were exposed by inhalation to 0, 0.1, 1.0 or 10 ppm of DBCP. The rabbits in the 10 ppm exposure group were exposed for 8 weeks followed by 38 weeks of recovery. All other groups of rats and rabbits were exposed for 14 weeks followed by recovery periods of up to 32 weeks. Treatment-related alterations were observed in male and female rats exposed to 10 ppm for 14 weeks, but not in those exposed to 1.0 or 0.1 ppm. The effects in the rats exposed to 10 ppm for 14 weeks included moderate testicular atrophy (males) and focal aggregates of altered cells in the adrenal cortex (males and females). Pathologic evaluation of the rats from the recovery portion of the study showed treatment-related alterations in males and females in the 10 and 1.0 ppm exposure groups, but not in the groups exposed to 0.1 ppm. The testicular alterations that were present in the 10 ppm males immediately after the 14-week exposure period had nearly completely reversed by the end of the recovery period. On the other hand, the changes in the adrenal cortex of males and females from the 10 ppm exposure level progressed so some rats had cortical hematocyst formation, dilated cortical sinusoids, foci of altered cortical cells and nodular hyperplastic lesions of the cortex. They were more extensive in rats from the 10 ppm exposure level, but some were also present in rats from the 1.0 ppm groups. In addition, increased numbers of ovarian cysts were present in females from the 10 ppm exposure level. Finally, brain effects consisting of focal or multifocal mineralized deposits were present in males and females in the 10 ppm exposure level. No treatment-related alterations were recognized in any of the rats from the 0.1 ppm recovery groups. Treatment-related pathologic alterations in rabbits were confined to the male reproductive system. Rabbits exposed to 10 ppm had testicular DOW CONFIDENTIAL DO 131 4 VO OONF T DFNT T Al -28- alterations as early as 4 weeks into the study and had nearly complete testicular atrophy by 8 weeks. Those exposed to 1 ppm for 14 weeks developed moderate testicular atrophy (approximately 50% reduction in size). Following the recovery period, both the rabbits in the 10 and 1 ppm groups had evidence of partial reversibility of the testicular atrophy. Electron microscopic evaluation of testicular tissue confirmed the light microscopic effects and also indicated increased numbers of abnormal sperm within the seminiferous tubules of rabbits at both the 10 and 1 ppm exposure levels. Those exposed to 0.1 ppm had an equivocal increase in abnormal sperm after the 14-week exposure period which may or may not have been treatment-related. This equivocal effect was not present after the recovery period. Therefore, exposure to 1 or 10 ppm of DBCP for 14 weeks produced treatmentrelated alterations in both rats and rabbits. There were no effects in either rats or rabbits exposed to 0.1 ppm by conventional methods of evaluation. However, electron microscopy did show equivocal effects in the rabbits exposed to 0.1 ppm immediately following the 14-week exposure period, but not after the recovery period. CONFIDENTIAL no 1 4 3'-<; C.ONF TDFNTTAl -29- REFERENCES Burek, J. D., Potts, W. J., Crawford, A. A., Murray, J. S., John, J.; A., Bell, T. J., and Murray, F. J.: Results of Two Inhalation Probe Studies in Rabbits, Rats and Dogs that were Exposed to 1, 2-Dibromo - 3-Chloro- propane (DBCP). Toxicology Research Laboratory, Midland, MX. j February 7, 1980. Torkelson, T. R., Sadek, S. E., and Rowe, V. K.: Toxicologic Investigations of 1, 2-Dibromo - 3-Chloropropane. Tox. Appl. Pharm. 3:545-559, 1961. Whorton, D., Krauss, R. M., Marshall, S., and Milby, T. H.: in Male Pesticide Workers. Lancet 2:1259-1261, 1977. Infertility DO 131440 GONFTDFNTTAl -30- LEGEND TO FIGURES FIGURE 1 Schematic Illustration of the cells within a normal seminiferous tubule. FIGURE 2 Normal seminiferous tubule showing Sertoli cells (SC) and spermatogonia (SG) on the basal lamella (BL) and the relation ship of these structures to the primary (PR) and secondary (SEC) spermatocytes. Original magnification 2.600X. FIGURE 3 Normal seminiferous tubule near the luminal surface illustrating cap-phase spermatids (CP) and spermatozoa (S). Original magnification 2.070X. FIGURE 4 Seminiferous tubule from a rabbit exposed to 10 ppm of DBCP for 8 weeks. Note the absence of spermatozoa on the luminal surface and the absence of spermatogonia, primary and secondary spermato cytes, and the lack of cap-phase spermatids. Original magnifi cation 2,600X. FIGURE 5 A. Interstitial cell from a control rabbit. B. Interstitial cell from a rabbit exposed to 10 ppm of DBCP and containing increased lysosomes (LY) in the cytoplasm. Original magnification 4.100X. FIGURE 6 Normal-appearing seminiferous tubule from a rabbit that had been exposed to 10 ppm of DBCP for 8 weeks followed by 38 weeks of recovery. BL basal lamella; SG ** spermatogonia; SC = Sertoli cell; and PR * primary spermatocyte. Original magnification 8.300X. DOW CONFIDENTIAL 00 131441 CONF T OF NT T Al -31- LEGENDS TO FIGURES (Con't) FIGURE 7 Seminiferous tubule from a rabbit exposed to 10 ppm DBCP for 8 weeks followed by 38 weeks of recovery. Note the absence of spermatogenesis. BL " basal lamella and SC - Sertoli cell. Original magnification 8,300X. FIGURE 8 Abnormal spermatozoa seen in rabbits exposed to 1 or 10 ppm of DBCP. A-C are from control rabbits and D-F are from treated rabbits. FIGURE 9 Seminiferous tubule from a rabbit exposed to 1 ppm of DBCP for 14 weeks followed by 32 weeks of recovery. Note the degenerative spermatozoa (+) within Sertoli cells (SC) . BL = basal lamella and PR = primary spermatocyte. Original magnification 8,300X. DOW CONFIDENTIAL 13144> CDMr t DFNTT Al i }* >; ' ;) 1; t -If Tl "On _U) -f **i . ` i:.ffi ^ ~f \lv\1 SPERMATOZOA SPERMATID (CAP-PHASE) ** SERTOLI 'J. r v :f >;f m J. o DOW C0NFIDFNTI4I 00 131444 OONFTDFNT TA1 00 13144S - r DOW CONFIDENT!/!! MNFTDTMTTfll ^144^ T0F^TTA| 36 DOW CONFIDENTIAL I31447 CONF TDFNT TA( 37- DOW CONFIDENTIAL ^0 13144ft C.ONF TOFNTTAI -38- TABLE 1 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS TISSUES ROUTINELY COLLECTED AT NECROPSY AND PRESERVED IN 10% FORMALIN esophagus salivary gland stomach small intestine large intestine (cecum and colon) pancreas liver gallbladder (rabbits) kidneys urinary bladder prostate seminal vesicle coagulating gland testes epididymis ovaries oviduc ts uterus mammary gland brain (cerebellum, cerebrum, brain stem) spinal cord and vertebral column pituitary gland peripheral nerve (sciatic) trachea larynx lungs (bronchi) spleen thymus lymph nodes (thoracic, mesenteric) heart anterior mediastinal blood vessels (aorta) skeletal muscle adrenal glands thyroid gland parathyroid glands mesenteric adipose tissue skin eyes lower jaw, including tongue any gross lesion of mass DOW CONFIDENTIAL OO 131449 r.ONF T DFNTT A1 CONF I DENT TAl TABLE 2 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP RATS AND RABBITS NUMBER OF RABBITS EXAMINED BY ELECTRON MICROSCOPY Exposure Level (ppm) 0 0.1 1 10 Number Examined After 8 Weeks Exposure 0 0 0 1 Number Examined After 14 Weeks Exposure 3 4 4 0 Number Examined After Recovery Period c E_f, o o ^/ Diagnosis Code E-l P-3 LL-8 Q-7 -40- TABLE 3 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS GROSS PATHOLOGIC OBSERVATIONS ON RATS FROM THE 4-WEEK INTERIM KILL ________________Observations Number of rats per group GENERAL No visible lesions URINARY SYSTEM Mineraliiation of renal cortex or pelvis FEMALE REPRODUCTIVE SYSTEM Clear fluid distending uterine horn(s) INTEGUMENT AND SUBCUTANEOUS Abscess or inflammation of preputial gland Exposure Level _____ (ppm) Male Female 0 55 0.1 5 5 1.0 5 5 10.055__________________ 0 0.1 1.0 10.0 35 33 5A 55 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 2 0 0 -0 -2 -1 -0 02 0.1 1 1.0 0 10.0 0 - Indicates none examined or not applicable. i no-' DO 13]4 S1 CONF TDFNT TA1 Diagnosis Code T-l T-3s E-l E-7 Pr-1 Pr-2. Pr-2n SV-1 CG-1 41- TABLE 4 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON RATS FROM THE 4-WEEK INTERIM KILL Observations Number of rats per group Exposure Level (ppm)_______ 0 0.1 1.0 10.0 MALE REPRODUCTIVE SYSTEM Testes - Number of tissues examined No visible lesions Atrophy (decreased spermatogenesis of individual seminiferous tubules. Includes Individual semi niferous tubules containing predominantly sertoll cells) - focal or multifocal, slight 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0,1 1.0 10.0 Male Female Epididymides - Number of tissues examined No visible lesions Aggregate of mononuclear lymphoid cells, peri vascular - focal Prostate - Number of tissues examined No visible lesions Aggregate of mononuclear lymphoid cells - focal or multifocal, interstitial Seminal Vesicles - Number of tissues examined No visible lesions Coagulating Gland - Number of tissues examined No visible lesions - Indicates none examined or not applicable. 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 5 5 5 5 5 5 4 5 0 0 1 0 s 5 5 5 4 3 4 4 1 2 1 1 vnr?!TP,1 no 13140? OONF TDFNTTAl Diagnosis Coda Ov-1 OD-1 U-l C-l B-l A-l -42- TABLE 4 (Continud) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON RATS FROM THE 4-WEEK INTERIM KILL __________________ Observations Number of rats per group FEMALE REPRODUCTIVE SYSTEM Ovaries - Number of tissues examined No visible lesions Oviducts - Number of tissues examined No visible lesions Uterus - Number of tissues examined No visible lesions Cervix - Number of tissues examined No visible lesions Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Male Female 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 NERVOUS SYSTEM Brain - Number of tissues examined No visible lesions 0 0.1 1.0 10.0 0 0.1 1.0 10.0 55 55 55 55 55 55 55 55 ENDOCRINE SYSTEM Adrenal Glands - Number of tissues examined No visible lesions 0 0.1 1.0 10.0 0 0.1 1.0 10.0 55 55 55 55 55 45 45 55 - Indicates none examined or not applicable. nni'i r'.mTHr.riJTIM DO 131453 CONF TDFNT TAl Diagnosis Code A-2us A-14bs -43- TABLE 4 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON RATS FROM THE 4-WEEK. INTERIM KILL Observations Number of rats per group ENDOCRINE SYSTEM (cont'd) Adrenal Glands (cont'd) Focu*(i) of altered cells, cortex - unilateral, slight Increasedvacuolization, cortex - bilateral, slight Exposure Level (ppm) 0 0.1 1.0 10.0 Male 5 5 5 5 Female 5 5 5 5 0 0.1 1.0 10.0 0 0.1 1.0 10.0 - Indicates none examined or not applicable. no 1.11454 nrv'J OONF TDFNTTA Diagnosis Code A-4 D-l D-2 D-3 E-l E-2 L-l L-2 L-19 H-l -44- TABLE 5 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS CROSS PATHOLOGIC OBSERVATIONS ON RATS FROM THE 14-WEEK INTERIM KILL Observations Number of rats per group ADRENAL GLANDS Unilateral absence of adrenal EYES Exophchalaus Intraocular cloudiness Cloudiness of cornea(s) GENERAL No visible lesions Nodule of necrotic omental or mesometrial fat * MALE REPRODUCTIVE SYSTEM Decreased size of testicle(s) with or without mineral-like lesions Dark or tan appearance of testes Irregular pale area on testicle RESPIRATORY SYSTEM Dark or red focus(i) in lungs - Indicates none examined or not applicable. Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.1 Male 5 5 5 5 Female 5 5 5 5 -0 -0 -1 0 -1 -0 -0 -0 -1 -0 -0 -0 00 11 00 60 23 34 54 04 -2 -0 -0 "0 20 05- 00 * 03" 1000" 0101- wr.v* DO 101405 CONF TDFNTT Al Diagnosis Code P-7 Q-l-(l) Q-4 0-7 -45- TABLE 5 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS CROSS PATHOLOGIC OBSERVATIONS ON RATS FROM THE 14-WEEK INTERIM KILL Observations Number of rats per group URINARY SYSTEM Focal dark, depressed foci or area(s) in kidney Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Male 5 5 5 5 Female 5 5 5 5 1- 00- 0- INTEGUMENT AND SUBCUTANEOUS Subcutaneous mass - inguinal, mammary or midcervical region Abscess of clitoral gland Abscess or inflammation of preputial gland 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 - Indicates none examined or not applicable. -0 -0 -0 -1 -1 -0 -0 -0 10* 00- WRDBITItt DO 131456 CONFTDFNTTAt Diagnosis Code 1^1 L-2, L-2s L-7s L-10 L-13m K-l K-2, K-2s K-3 K-4 K-S -46- TABLE 6 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED OX RATS FROM THE 14-WEEK INTERIM KILL Observations Number of rats per group Exposure Level (ppm) 0 0.1 1.0 10.0 LIVER Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Aggregates of mononuclear, lymphoid or retieuloendothelial cells - focal or multifocal 0 0.1 1.0 10.0 Biliary hyperplasia - focal or multifocal, slight 0 0.1 1.0 10.0 Coagulation necrosis and inflammation - focal 0 0.1 1.0 10.0 Chronic active inflammation, portal triads - moderate 0 0.1 1.0 10.0 Male 5 5 5 5 5 5 5 5 3 4 3 3 2 0 1 2 0 1 0 0 0 0 1 1 0 1 0 0 URINARY SYSTEM Kidnevs - Number of tissues examined No visible lesions Dilated renal tubules with eosinophilic cast forma- tion - focal or multifocal Basophilic staining renal tubules, cortex - focal or multifocal Mineral deposits, cortex, medulla or corticomedullary junction - focal or multifocal Mineral deposits, renal pelvis - focal or multifocal - Indicates none examined or not applicable. 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.1 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 5 5 5 5 1 1 1 0 2 2 3 2 1 1 0 1 1 1 0 0 1 1 0 0 Female 5 5 5 5___ 5 5 5 5 4 3 5 4 1 2 0 1 0 0 0 0 0 0 0 0 0 0 0 0 5 5 5 5 2 2 1 3 3 3 1 2 0 1 0 0 1 3 1 0 0 1 2 0 PipMf f'nvnnFNTifli 00 131457 rONF 1 Of NT T Al Diagnosis Code K-6vs K-6s K-10 K-lls K-12 UB-1 T-l T-3s T-2u, sev -47- TABLE 6 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITV AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON RATS FROM THE 14-WEEK INTERIM KILL Exposure Level ____________________ Observations _____________________________ (ppm)_____________ Male Number of rats per group 0 0.1 5 5 1.0 5 _____________________________________________________________ 10.0________________ 5 URINARY SYSTEM (coat'd) Kldnev (cont'd) Chronic progressive glomerulonephropathy - very slight 0 0,1 1.0 10.0 0 2 1 0 Chronic progressive glomerulonephropathy - slight 0 0.1 1.0 10.1 0 O 0 3 Inflammation, subacute, interstitium 0 0.1 1.0 10.0 0 0 0 0 Aggregates of mononuclearlymphoid cells, pelvis - focal ormultifocal, slight 0 0.1 1.0 10.0 0 0 0 0 Aggregates of mononuclear lymphoid cells, peri- vascular - focal or multifocal 0 0.1 1.0 10.0 0 0 0 0 Urinarv Bladder - Number of tissues examined ` No visible lesions 0 0.1 1.0 10.0 0 0.1 1.0 10.0 4 5 5 5 4 5 5 5 MALE REPRODUCTIVE SYSTEM Testes - Number of tissues examined No visible lesions Atrophy (decreased spermatogenesis of individual seminiferous tubules - includes individualsemini- ferous tubules containing predominantlysertoli cells) - focal or multifocal, slight Atrophy (generalized) - unilateral, severe 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 5 5 5 5 3 5 5 0 0 0 0 5 1 0 0 0 Female m i* va 0 0 1 0 0 0 0 0 0 0 1 0 0 1I 0 0 I 0 0 1 0 5 4 4 5 5 4 4 5 - Indicates none examined or not applicable. 131453 CONFTOFNTTA1 Diagnosis Code T-2bsev T-4u T-4b T-6u T-6b T-7u T-7b E-l E-2u E-2b "48- TABLE 6 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON RATS FROM THE 14-WEEK INTERIM KILL ____________________ Observations Number of rats per group MALE REPRODUCTIVE SYSTEM (cont'd) Testes (cont'd) Atrophy (generalized) - bilateral, severe Mineralization (intratubular calcification) - multifocal, unilateral Mineralization (intratubular calcification) - multifocal, bilateral Edema, interstitial - unilateral Edema, Interstitial - bilateral Locally increased multinucleated spermatids - unilateral Locally increased multinucleated spermatids - bilateral Exposure Level (ppm)____________ Male Female 0 55 0.1 5 5 1.0 5 5 .. -ip-q_______________ 5-----------------5-- 0 0.1 1.0 10.0 0 0.1 1.0 10.1 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 1 0 0 0 1 0 0 o 1 0 0 0 1 0 0 0 1 0 0 0 1 0 0 0 1 0 0 0 Epididvmides - Number of tissues examined No visible lesions Atrophy Atrophy - unilateral - bilateral 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 5 5 5 5 3 5 5 5 1 0 0 0 1 0 0 0 - Indicates none examined or not applicable. rn"' cnetinrcTijl ~ DO -'1459 C0NFTDFHTrai Diagnosis Code__ E-3u E-3b SV-1 CC-1 Pr-1 Pr-2 Pr-4s 49- TABLE 6 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCF IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON RATS FROM THE 14-Vi*EEK INTERIM KILL Exposure Level ____________________ Observations____________________________________ (ppm)_______ Number of rats per group 0 0.1 1.0 __________ ____________________________________ 10.0_____ MALE REPRODUCTIVE SYSTEM (cont'd) Bpldidvnldes (cont'd) Decreased sperm content, tubular lumlna - unilateral 0 0.1 1.0 10.0 Decreased sperm content, tubular lumlna - bilateral 0 0.1 1.0 10.0 Male 5 5 5 5 X 0 0 0 1 0 0 0 Female 5 5 5 5 Seminal Vesicles - Number of tissues examined No visible lesions 0 0.1 1.0 10.0 0 0.1 1.0 10.0 5 5 5 5 5 5 5 5 Coagulating Gland - Number of tissues examined No visible lesions 0 0.1 1.0 10.0 0 0.1 1.0 10.0 5 5 4 5 5 5 4 5 Prostate - Number of tissues examined No visible lesions Aggregates of mononuclear lymphoidcells - focal or multifocal,interstitial Suppurativeinflammation - focal, slight 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 5 5 5 5 5 5 5 2 0 0 0 2 0 0 0 1 FEMALE REPRODUCTIVE SYSTEM Ovaries - Number of tissues examined 0 0.1 1.0 10.0 5 5 5 5 - Indicates none examined or not applicable. nrv-i/ prmnFNTis.1. DO 131460 CONF TDFNTlAl Diagnosis Code Ov-1 OD-1 U-l C-l B-l A-l 50- TABLE 6 (Continued) SUBCHROMIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON RATS FROM THE 14-WEEK INTERIM KILL Observations Number of rats per group FEMALE REPRODUCTIVE SYSTEM (cont'd) Ovaries (cont'd) No visible lesions Exposure Level (ppm) 0 0.1 1.0 10.0 Male 5 5 5 5 Female 5 5 5 5 0 0.1 1.0 10.0 -5 -5 -5 -5 Oviducts - Number of tissues examined No visible lesions 0 0.1 1.0 10.0 0 0.1 1.0 10.0 -A -5 -5 -5 -A -5 -5 -5 Uterus - Number of tissues examined No visible lesions 0 0.1 1.0 10.0 0 0.1 1.0 10.0 .5 -5 -5 -5 .5 -5 -5 -5 Cervix - Number of tissues examined No visible lesions 0 0.1 1.0 10.0 0 0.1 1.0 10.0 5 -5 -A -A -5 -5 -A -A NERVOUS SYSTEM Brain - Number of tissues examined No visible lesions ENDOCRINE SYSTEM Adrenal Glands - Number of tissues examined No visible lesions 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 55 55 55 55 55 55 55 55 55 55 A5 55 A5 55 AA 22 - Indicates none examined or not applicable. r.r"l `JTSfil 00 131461 conftdfntial Diagnosis Code A-2us A-2bs A-5us -51 TABLE 6 (Continued) SUBCHRQNIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCF IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON RATS FROM THE 14-WEEK INTERIM KILL Observations Number of rats per group Exposure Level (ppm) 0 0.1 1.0 10.0 ENDOCRINE SYSTEM (cont'd) Adrenal Glands (cont'd) Focus(i) of altered cells, cortex - unilateral, slight Focus(i) of altered cells, cortex - bilateral, slight Ectatic sinusoids - multifocal, unilateral, slight 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Male 5 5 5 5 Female 5 5 5 5 - Indicates none examined or not applicable. DO 13146? CONFTDFNT TA! Diagnosis Code A-2 5-1 B-2 B-3 C-l 3 D-4 D-5 D-6 E-l -52- TABLE 7 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS CROSS PATHOLOGICAL OBSERVATIONS ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rats per group Exposure Level (ppm) 0 0.1 1.0 10.0 ADRENAL GLANDS Mottled adrenal(s) and/or pinpoint focus(i) 0 0.1 1.0 10.0 CARDIOVASCULAR SYSTEM Pale screaks, foci or area(s) in myocardium Dilatation and inelasticity of aorta and large vessels of heart Mesenteric or testicular periarteritis with or without thrombosis 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 CENTRAL NERVOUS SYSTEM Darkened, discolored or distorted area in brain 0 0.1 1.0 10.0 EYES Cloudiness of cornea(s) Cloudiness of lens Pale focal area on Iris Inflammatory lesion on eyelid 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 GENERAL No visible lesions (NVL) 0 0.1 1.0 10.0 - Indicates none examined or not applicable. Died or Killed Moribund During Recovery Period 3 1 0 2 0 0 * 0 0 0 1 0 0 - 1 0 0 - 0 0 0 - 1 0 0 - 0 0 0 - 0 0 0 0 0 0 - 0 0 0 - 0 Terminal Kill 17 19 20 18 0 0 2 16 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 1 1 2 3 2 1 4 0 0 0 0 1 0 0 1 0 5 10 0 0 Cumulative Results 20 20 20 20 0 0 2 16 0 0 0 1 0 0 0 1 0 0 1 0 0 0 0 1 1 1 2 3 2 1 4 0 0 0 0 1 0 0 1 0 5 10 0 0 nn''! en>ir!nr>i',iM 00 1 3 1 4 ti 3 conftdfnttai Diagnosis Code E-2 E-3 E-7 E-9 E-10 E-ll E-12 F-5 F-6 F-8 F-9 -53- TABLE 7 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS GROSS PATHOLOGICAL OBSERVATIONS ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rats per group GENERAL (cont'd) Nodule of necrotic omental or mesometrial fat Postmortem autolysis Exudate or porphyrin-like pigment accumulotion lateral to external nares or around eyes Perineal soiling Depletion of adipose tissue, including serous atrophy of fat Loss of body condition and/or roughened and dirty hair Excess adipose tissue Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 GASTROINTESTINAL SYSTEM Thickened area in nonglandular gastric nucosa suggestive of hyperkeratosis Absence or decreased normal ingesta in gastrointestinal tract Snail intestinal mass(es) or nodule(s) Mineralization of gastric vail 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 - Indicates none examined or not applicable. Died or Killed Moribund During Recovery Period 3 1 0 2 Terminal Kill 17 19 20 18 Cumulative Results i 20 20 ! 20 20 0 00 0 11 11 0 00 1 01 0 00 * 00 I 01 0 00 1 01 - 11 2 13 0 0 i0 0 00 - 1 11 0 11 1 12 0 00 22 0 11 1 01 1 01 - 00 0 00 2 02 1 01 - 00 0 00 0 00 0 00 - 00 0 11 1 01 0 00 - 00 I 01 1 01 0 00 - 00 0 00 I 01 0 00 - 00 1 01 da'1! n/vinpvHmM !~U : I A 1 4 64 CONF T DFNT T A[ Diagnosis Code F-10 F-ll G-l G-2 G-5 G-7 G-8 G-9 0-10 H-3 H-5 -54- TABLE 7 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS CROSS PATHOLOGICAL OBSERVATIONS ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rats per group GASTROINTESTINAL SYSTEM (cont'd) Caseous distention of stomach and/or intestinal tract Enlarged Payer's Patch in small intestine LIVER Diaphragmatic hernia Solitary to several red or darkened focus (1) or area(s) in liver Few small pale foci or focus in liver Enlarged liver Darkened or congested liver Firm liver Linear streak(s) or areas in liver LYMP1IORETICULAR SYSTEM Enlarged axillary lymph node(s) Enlarged renal lymph node(s), color variable and/or firm Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 . 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 - Indicates none examined or not applicable. Died or Killed Moribund During Recovery Period 3 1 0 2 Terminal Kill 17 19 20 18 Cumulative Results 20 20 20 20 0 00 0 00 - 00 1 01 0 00 1 01 - 00 0 00 0 11 0 00 - 11 0 00 0 00 0 00 _ 22 0 11 0 00 0 00 0 11 0 00 2 02 1 01 - 00 0 00 2 02 0 00 - 00 0 00 2 02 0 00 - 00 0 00 0 00 0 11 - 11 0 00 0 00 0 00 - 00 0 11 0 11 0 00 - 00 0 00 DO 131465 OONFIDFNTTAt rt ***** f AfMirmrMTJM Diagnosis Code H-6 H-7 1-1 J-l J-2 K-l K-2 K-3 K-4 L-l -55- TABLE 7 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCF IN RATS AND RABBITS CROSS PATHOLOGICAL OBSERVATIONS ON MALE RATS EXPOSED FOR It WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rats per group LYMPHORCTICl'LAR SYSTEM (cont'd) Cyst replacing renal lymph node(s) Mottled renal lvmph node(s) Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 MUSCULOSKELETAL SYSTEM Demineralization of bones 0 0.1 1.0 10.0 PANCREAS Nodule(s) in region of pancreas Slight thickening(s) within pancreas, color pale or dark, but not clearly nodule 0 0.1 1.0 10.0 0 0.1 1.0 10.0 PITUITARY GLAND Dark, red or hemorrhagic focus(i) on pituitary Enlarged pituitary Mottled pituitary Cvst on pituitary 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 TESTES Decreased size of testicle(s) with or without mineral-like lesions 0 0.1 1.0 10.0 - Indicates none examined or not applicable. Died or Killed Moribund During Recovery Period 3 1 0 2 Terminal Kill 17 19 20 18 01 00 -0 00 00 01 _0 00 10 00 -0 00 00 00 -1 00 00 00 -1 00 00 00 -0 10 00 00 -1 01 00 00 -1 00 00 01 -0 00 00 01 -0 02 Cumulative Results 20 20 20 20 1 0 0 0 0 1 0 0 1 0 0 0 0 0 1 0 0 0 1 0 0 0 0 1 0 0 1 1 0 0 1 0 0 1 0 0 0 1 0 2 n*-i pn'.'tnrM'nM no 131460 OONF IDFNT TAI Diagnosis Code L-2 L-5 L-6 L-4 L-7 L-3 L-S L-9 M-l v_2 -56TABLE 7 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCF IN RATS AND RABBITS CROSS PATHOLOGICAL OBSERVATIONS ON MALE RATS EXPOSED FOR 16 WEEKS AND THEN' HELD FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rats per group TESTES (cont'd) Dark or tan appearance of testes Increased sire of testes Edematous appearance of testes EPIDIDYMIDES Nodule of necrosis in epididymal fat pad Abscess or inflammation of epididymides accessory SEX GLANDS Decreased sire of accessory sex glands Dark focus on prostate Enlarged prostate RESPIRATORY SYSTEM Dark or red focus(i) in lungs Few pale foci in lungs Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 - Indicates none examined or not applicable. Died or Killed Moribund During Recovery Period 3 1 0 2 Terminal Kill 17 19 20 18 O0 01 -0 00 00 00 -0 01 00 01 -0 01 00 00 -0 01 00 00 -0 01 00 00 -0 01 00 00 -1 00 00 10 -0 00 05 01 - 10 01 11 00 -0 00 Cumulative Results 20 20 20 20 0 1 0 0 0 0 0 1 0 1 0 1 0 0 0 1 0 0 0 1 0 0 0 1 0 0 1 0 0 1 0 0 5 1 10 1 2 0 0 0 n-,., ovrinruTiM HO 131467 OONFTDFNTIAl Diagnosis Code M-3 >t-4 M-5 N-l 0-1 P-1 P-2 P-3 P-7 -57- TABLE 7 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS GROSS PATHOLOGICAL OBSERVATIONS ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rats per group RESPIRATORY SYSTEM (cont'd) Pulnonarv congestion or dark color Pulmonary edema Mottled appearance of lungs Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 SPLEEN Ectopic splenic tissue Enlarged spleen 0 0.1 1.0 10.0 0 0.1 1.0 10.0 PARATHYROID GLANDS Enlarged parathyroids 0 0.1 1.0 10.0 KIDNEYS Moderate to severe chronic renal disease (moderately to severely enlarged, pale. roughened, etc.) Slight to moderate chronic renal disease (slightly pale, enlarged, roughened. etc.) Mineralization of renal cortex or pelvis Focal dark depressed foci or area(s) in kidney 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 3 1 0 2 1 0 - 0 1 1 - 0 0 1 - 0 0 0 - 0 0 0 _ 0 1 0 - 1 1 0 - 1 I 0 - 1 0 0 - 0 0 0 - 0 Terminal Kill 17 19 20 18 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 1 0 0 0 1 0 0 0 0 0 0 0 0 A 2 5 5 1 0 0 1 0 1 1 0 Cumulative Results 20 20 20 20 1 0 0 0 1 1 0 0 0 1 0 1 0 0 0 1 0 0 0 1 1 0 0 1 1 0 0 1 5 2 5 6 1 0 0 1 0 1 1 0 - Indicates none examined or not applicable, DO 1314^8 CONFTDFNTTAl Diagnosis Code P-8 P-9 P-10 P-19 P-6 0-1(1) f)-3(l) 0-6(1) Q-S(2) Q-7 58- TABLE 7 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY and RECOVERY1 STUDY OF DBCP IN RATS AND RABBITS CROSS PATHOLOCICAL OBSERVATIONS ON MALE RATS EXPOSED FOR 14 weeks AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Observations Number o rats per group Exposure Level (ppm) 0 0.1 1.0 10.0 KIDNEYS (cont'd) Dilated renal pelvis(es) (hydronephrosis) 0 0.1 1.0 10.0 Mottled appearance of kidney(s) Cvst(s) in kidney Pale depressed area on kidney 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 URINARY BLADDER Organized plug within urinary bladder 0 0.1 1.0 10.0 INTFCl'MENT AND SUBCUTANEOUS Subcutaneous mass - inguinal, mammary or midcervical region - Number per rat: 1 0 0.1 1.0 10.0 Subcutaneous mass - bodv or limb region - Number per rat: 1 0 0.1 1.0 10.0 Cutaneous nodule or mass; body, head or limb region - Number per rat: 1 0 0.1 1.0 10.0 Cutaneous nodule or mass; body, head or limb region - Number per rat: 2 0 0.1 1.0 10.0 Abscess or inflammation of preputial gland 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 3 1 0 2 Terminal Kill 17 19 20 18 10 00 -1 00 00 00 -0 01 00 00 a- 1 -1 00 00 -1 00 03 01 -3 01 00 00 -0 02 00 00 -0 01 01 00 -0 01 00 00 -0 01 01 01 -1 02 Cumulative Results 20 20 20 20 1 0 1 0 0 0 0 1 0 0 1 1 0 0 1 0 3 1 3 1 0 0 0 2 0 0 0 1 1 0 0 1 0 0 0 1 1 1 1 2 - Indicates none examined or not applicable. DO 131 A#-. 9 C ONF I DFNT T Al Diagnosis Code ^8 s-i -59TABLE 7 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS GROSS PATHOLOGICAL OBSERVATIONS ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rats per group INTEGUMENT AND SUBCUTANEOUS (cont'd) Subcutaneous edema Abscess of eyelid THORACIC CAVITY Blood in thoracic cavity Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 3 1 0 2 1 0 - 0 1 0 - 1 Terminal Kill 17 19 20 18 Cumulative Results 20 20 [ 20 20 1 01 00 00 00 01 00 00 01 0 0.1 1.0 10.0 0 0 - 0 00 00 11 11 - Indicates none examined or not applicable. DO 131470 C0NFTDFNTTA1 Diagnosis Code A-2 A-3 C-l C-2 D-3 E-l E-3 E-4 E-3 E-6 TABLE 8 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS CROSS PATHOLOGICAL OBSERVATIONS ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 26 WEEKS OF RECOVERY Observations Number ot rats per group Exposure Level (ppm) 0 0.1 1.0 10.0 ADRENAL GLANDS Mottled adrenal(s) and/or pinpoint focus(i) Enlarged adrenal(s) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 CENTRAL NERVOUS SYSTEM Darkened, discolored or distorted area in brain Focal hemorrhage lesions on the meninges 0 0.1 1.0 10.0 0 0.1 1.0 10.0 EYES Cloudiness of cornea(s) 0 0.1 1.0 10.0 CENTRAL No visible lesions (NIT) Postmortem autolysis Vaginal discharge Ascites - cloudy, dark or hemorrhage Multiple nodules within abdominal cavity (possible pancreatic or mesothellal involvement) 0 0.1 . 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 1 0 1 3 Terminal Kill 19 20 19 17 01 -1 O4 19 00 -0 00 03 00 -0 00 10 00 -1 00 00 00 -1 00 00 05 -1 01 02 10 -0 00 00 00 -0 10 10 00 -0 00 10 00 -0 00 10 Cumulative Results 20 20 20 20 1 1 4 10 0 0 0 3 0 0 0 1 0 1 0 0 0 1 0 0 5 1 1 2 1 0 0 0 0 0 1 1 0 0 0 1 0 0 0 1 - Indicates none examined or not applicable. f-'O 131471 CONFTDFNTTAi Diagnosis Code E-7 E-8 E-9 E-10 E-ll F-l F-2 F-3 F-i F-5 F-6 -61TABLE 8 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS GROSS PATHOLOGICAL OBSERVATIONS ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 26 WEEKS OF RECOVERY Observations Number ot rats per group Exposure Level (ppm) 0 0.1 1.0 10.0 GENERAL (cont'd) Exudate or porphyrin-like pigment accumula- tlon lateral to external nares or around eyes Diffuse paleness of tissues (anemia) Perineal soiling Depletion of adipose tissue, including serious atrophy of fat Loss of body condition and/or roughened and dirty hair 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 GASTROINTESTINAL SYSTEM Hyperplastic ileitis Dark (or hemolyred blood) material in gastrointestinal tract Ulceration or erosion of gastric mucosa Edematous gastric vail Thickened area in nonglandular gastric mucosa, suggestive of hyperkeratosis Absence or decreased normal ingesta in gastrointestinal tract 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 1 0 1 3 Terminal Kill 19 20 19 17 00 -0 12 00 00 -0 10 00 00 -0 02 00 00 -0 02 00 00 -0 02 00 00 -0 00 01 00 -1 11 00 00 -1 02 00 00 -0 01 00 00 -0 01 00 00 -0 01 00 Cumulative Results 20 20 20 20 0 0 3 0 0 0 1 0 0 0 2 0 0 0 2 0 0 0 2 0 0 0 0 1 0 1 2 0 0 1 2 0 0 0 1 0 0 0 1 0 0 0 1 0 - Indicates none examined or not applicable! nn'JJ cwfhfntim no 13147? CONF TDFNT TAl Diagnosis Code F-7 C-l G-: G-3 G--i G-5 C-6 H-l H-2 H-3 H-i -62- TABLE 8 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS GROSS PATHOLOGICAL OBSERVATIONS ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR U? TO 26 WEEKS OF RECOVERY Observations Number of rats per group Exposure Level (ppm) 0 0.1 1.0 10.0 GASTROINTESTINAL SYSTEM (cont'd) Dry and firm contents of colon - suggestive of dehydration 0 0.1 1.0 10.0 LIVER Diaphragmatic hernia Solitary to several red or darkened focus(l) or area(s) in liver Diffuse paleness of liver Accentuated lobular pattern of liver Fcv snail pale foci or focus in liver Pale area(s) in liver (>5mm in diameter) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 1.YVPH0RETICULAR SYSTEM Dark and congested thoracic lymph nodes Atrophy of thymus Enlarged axillary lymph node(s) Mottled thymus 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 - Indicates none examined or not applicable. Died or Killed Moribund During Recovery Period 1 0 1 3 Terminal Kill 19 20 19 17 00 0 01 00 01 0 00 00 00 1 01 02 00 0 10 00 00 0 10 00 00 0 01 00 00 0 01 00 00 0 00 10 00 0 00 10 00 0 00 01 00 0 00 01 Cumulative Results 20 20 20 20 0 0 1 0 1 0 0 0 0 1 1 2 0 0 1 0 0 0 1 0 0 0 1 0 0 0 1 0 0 0 0 1 0 0 0 1 0 0 0 1 0 0 0 1 P'V'f DO 131470 CONF TDFNT T At. Diagnosis Code J-l K-l LL-1 ll-: LL-3 LL-4 LL-5 LL-6 LL-7 LL-8 63TABLE 8 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS GROSS PATHOLOGICAL OBSERVATIONS ON FEMALE RATS EXPOSED FOR It WEEKS AND THEN HELD FOR UP TO 26 WEEKS OF RECOVERY Observations Number of rats per group PANCREAS Nodule(s) In region of pancreas PITUITARY GLAND Dark, red or hemorrhagic focus(i) on pituitary FEMALE REPRODUCTIVE SYSTEM Cvst in ovary Endometrial polyp(s) Dark or hyperemia appearance to uterus or mesometrlal blood vessels Mass involving uterus Cvst(s) in uterus Cravid uterus Implantation (fetal reabsorbtion) sites within gravid uterus Clear fluid distending uterine horn(s) Exposure Level (ppm) 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 1 0 1 3 Terminal Kill 19 20 19 17 Cumulative Results 20 20 20 20 0 0.1 1.0 10.0 0 00 - 00 0 00 1 01 0 0.1 1.0 10.0 0 00 - 11 0 00 0 00 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 11 - 22 0 00 0 66 0 11 - 11 0 11 0 00 0 AA *- 16 16 0 13 13 0 13 13 0 00 - 00 0 00 0 11 0 11 - 00 0 00 0 00 0 00 - 00 1 01 1 01 0 00 - 00 0 00 1 01 0 00 - 00 0 00 0 11 - Indicates none examined or not applicable. H- * V DO 131474 CONFTDFNT T At Diagnosis Code____ LL-9 LL-10 LL-11 M-l M-2 S-l N-2 p-: P-3 P-4 P-5 -64- TABLE 8 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS CROSS PATHOLOCICAL OBSERVATIONS ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 26 WEEKS OF RECOVERY ___________________Observations Number ot rats per group FgiALE REPRODUCTIVE SYSTEM (cont'd) Distention of and congestion of uterine horns due to endometrial polyps Endometrial hyperplasia Portion of placenta within vagina RESPIRATORY SYSTEM Dark or red focus(i) in lungs Fcv pale foci in lungs SPLEEN Ectopic splenic tissue Enlarged spleen KIDNEY Slight to moderate chronic renal disease (slightly pale, enlarged, roughened, etc.) Mineralization of renal cortex or pelvis Pale appearance of kidneys Right kidney enlarged containing hemorrhage Exposure Died or Killed Level Moribund During Terminal Pbm) 0 0.1 1.0 -------R--e--c--o--v- -e--r-y----P---e---r-i-o--d------- 0 1 Kill 19 20 19 10.0 3 17 0 00 0.1 - 0 1.0 0 1 10.0 0 0 0 00 0.1 - 1 1.0 0 1 10.0 0 0 0 00 0.1 - 0 1.0 1 0 10.0 0 0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 03 -0 02 00 00 -1 10 00 01 _0 01 01 00 -0 10 10 0 00 0.1 - 0 1.0 0 0 10.0 0 1 0 01 0.1 - 0 1.0 0 0 10.0 0 0 0 00 0.1 - 0 1.0 0 1 10.0 0 1 0 10 0.1 - 0 1.0 0 0 10.0 0 0 Cumulative Results 20 20 20 20 0 0 1 0 0 1 1 0 0 0 1 0 3 0 2 0 0 1 1 0 1 0 1 1 0 0 1 1 0 0 0 1 1 0 0 0 0 0 1 1 1 0 0 0 - Indicates none examined or not applicable. r.ft'l PfV.^T^rtfTI* f DO 131470 CONFTDFNTTAl Diagnosis Code '-6 1-KD 1-1(2) 1-4 1-5 i-6 >1 ;-i -65TABLE 8 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS CROSS PATHOLOGICAL OBSERVATIONS ON FEMALE RATS EXPOSED FOR 14 WEEKS and then held FOR UP TO 26 WEEKS OF RECOVERY 1 Observations Number of rats per group urinary bladder Organized plug within urinary bladder INTEGUMENT AND SUBCUTANEOUS Subcutaneous mass - inguinal, mammary or nidcervical region - number per rat: 1 Subcutaneous mass - inguinal, mammary or roidcervical region - number per rat: 2 Abscess of clltoral gland Galactocele formation Cutaneous nodule or mass - body, head or limb region - number per rat: 1 salivary gland Enlarged salivary glands with or without purulent material or hemorrhage THORACIC CAVITY Hydrothorax TONGUE Mass involving tongue Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 1 0 1 3 Terminal Kill 19 20 19 17 Cumulative i Results ( 20 I 20 1 20 20 0 00 11 0 00 0 00 0 55 - 4A 0 33 3 25 0 00 - 00 0 0 ,0 0 3 13 0 00 - 00 0 11 0 00 0 11 - 00 0 00 0 11 0 00 - 11 0 00 0 00 0 00 - 00 0 11 0 00 0 00 * 00 1 01 0 00 0 00 - 00 0 11 0 00 - Indicates none examined or not applicable * 5f*s *^r\vrt * \ DO 131476 CONF TDFNTTAI Diagnosis Code A-l A-2u, A-2us, A-s A-2b, A-2bs A-3 A-4u A-4b, A-Abm, A-8b A-5uf A-5us A-5b A-6, A-6u A-6b A-llb 66- TABLE 9 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED OK MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rats per group Exposure Level (ppm) 0 0.1 1.0 10.0 ENDOCRINE SYSTEM Adrenal Glands - Number of tissues examined No visible lesions 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Focus(i) of altered cells, cortex - unilateral 0 0.1 1. 10.0 Focus(i) of altered cells, cortex - bilateral Thrombus, adrenal blood vessel Nodular hyperplasia, cortex - multifocal, unilateral 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Nodular hvperplasia, cortex - multifocal, bilateral 0 0.1 1.0 10.0 Ectatic sinusoids - mulcifocal, unilateral 0 0.1 1.0 10.0 Ectatic sinusoids - multifocal, bilateral 0 0.1 1.0 10.0 Hematocvst , cortex - unilateral Heoatocyst, cortex - bilateral 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 3 1 0 2 Terminal Kill 17 19 20 18 3 17 1 19 0 19 2 18 32 03 -1 00 0 11 18 -9 04 04 08 -9 0 11 01 00 -0 00 00 00 -0 01 00 00 -1 2 16 00 00 -0 03 00 00 -0 10 00 00 .0 02 00 00 -0 02 Cumulative Results 20 20 20 20 20 20 20 20 5 3 1 0 11 9 9 4 4 8 9 11 1 0 0 0 0 0 0 1 0 0 1 18 0 0 0 3 0 0 0 1 0 0 0 2 0 0 0 2 - Indicates none examined or not applicable. ITI _D ^31477 CC)NFt OEN TTAl Diagnosis Code A-7u A-9s, A-9u A-9us A-lOs P-1 P-2 P-3, P-3s P-4 P-5s PI-1 67' TABLE 9 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rats per group ENDOCRINE SYSTEM (cont'd) Adrenal Glands (cont'd) Pheochrotnocytoma - unilateral Nodular hyperplasia, medulla - focal, unilateral Aggregate of mononuclear lymphoid cells, cortex - slight Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Pituitary - Number of tissues examined No visible lesions Cyst Focus(i) of altered cells anterior portion Adenoma, anterior portion * Pigmented (golden brown) macrophages, pars intermedia - focal, slight Pineal Gland - Number of tissues examined No visible lesions 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Died or tailed Moribund During Recovery Period 3 1 0 2 Terminal Kill 17 19 20 18 00 00 -1 01 00 01 -1 02 00 00 -1 00 2 15 10 01 2 18 29 1-0 1 14 02 0-0 01 04 0-0 02 00 0-1 11 00 0-0 01 01 00 00 00 _1 .. -.- Cumulative Results 20 20 20 20 0 0 1 1 0 1 1 2 0 0 1 0 17 1 1 20 11 1 0 15 2 0 0 1 4 0 0 2 0 0 1 2 0 0 0 1 1 0 0 0 1 . - Indicates none examined or not applicable. r** 9^ V no 1 3 1 4 7 R OONF TOFNT I Al Diagnosis Code Th-l Th-2s Th-3 Th-4m Th-5 PG-1 PG-2, PG-2b PG~3n TG-l -68- TABLE 9 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rats per group ENDOCRINE SYSTEM (cont'd) Thvroid Gland - Number of tissues examined No visible lesions Hyperplasia, parafollicular cells (C-cell) - focal, slight Medullary thyroid carcinoma - solitary Cervical blood vessels near thyroid. periarteritis - multifocal, moderate I'ltinobranchial cyst Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 o.l 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Parathyroid Glands Number of tissues examined No visible lesions Hyperplasia - bilateral Atrophy - moderate 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 GASTROINTESTINAL SYSTEM Tongue - Number of tissues examined No visible lesions 0 0.1 1.0 10.0 0 0.1 1.0 10.0 - Indicates none examined or not applicable. Died or Killed Moribund During Recovery Period 3 1 0 2 3 1 0 2 3 0 2 0 0 0 0 0 - 0 0 0 - 0 0 1 - 0 3 1 0 2 2 1 1 1 0 1 0 0 0 3 1 0 2 1 0 - 1 ?>!) n ry tp'M'i rr|| Terminal Kill 17 19 20 18 Cumulative Results 20 20 20 20 16 19 01 00 18 20 14 17 -0 -- 14 16 22 -0 -33 11 -0 -- 11 00 -0 -11 00 -1 -11 1A 17 01 00 1A 16 13 15 -1 -- 14 15 01 -0 -. 01 11 -0 - s. 00 17 20 01 00 18 20 12 13 .0 -. 15 16 DO 131479 CONF TOFNT J A! Diagnosis Code TG-2, TG-2s TG-3 TG-4s TG-5s TG-6s TG-7, TG-7s SG-1 Es-1 TABLE 9 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCF IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rats per group Exposure Level (ppm) 0 0.1 1.0 10.0 GASTROINTESTINAL SYSTEM (cont'd) Tongue (cont'd) Periarteritis - focal or multifocal 0 0.1 1.0 10.0 Medial calcification, small arterioles. secondary to severe chronic renal disease 0 0.1 1.0 10.0 Aggregate of mononuclear lymphoid cells - focal, slight 0 0.1 1.0 10.0 Chronic active inflammation, submucosa - multifocal, slight 0 0.1 1.0 10.0 Subacute inflammation, submucosa - focal or multifocal, slight 0 0.1 1.1 10.0 Foreign body granuloma or subacute inflammation, submucosa - focal 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 3 1 0 2 Terminal Kill 17 19 20 18 11 1-02 10 010 01 0-00 01 0-00 02 0-00 00 1-01 Cumulative Results 20 20 20 20 2 1 2 1 0 1 1 0 0 1 0 0 2 0 * 0 0 1 1 Salivarv Glands - Number of tissues examined 0 3 16 19 0.1 1 01 1.0 0 00 10.0 2 17 19 No visible lesions 0 3 16 19 0.1 1 -1 1.0 - -- 10.0 2 17 19 Esochaeus - Number of tissues examined 0 3 15 18 0.1 1 01 1.0 0 00 10.0 2 16 18 No visible lesions 0 3 15 18 0.1 1 -1 1.0 - ** 10.0 2 16 18 - Indicates none examined or not applicable. r: r> 'i!i (I'.< >t-i DO 131480 rONFTOFNT TAl Diagnosis Code S-l S-2, S-2s S-3 S-4 5-5 s-2 SI-1 SI-2 -70' TABLE 9 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rats per group GASTROINTESTINAL SYSTEM (cont'd) Stomach - Number of tissues examined Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Cystic dilatation, base of crypts, glandular portion 0 0.1 1.0 10.0 Transmural calcification, glandular portion, secondary to severe chronic renal disease 0 0.1 1.0 10.0 Submucosal edema, nonglandular portion 0 0.1 1.0 10.0 Diffuse acanthosis and hyperkeratosis, mucosa 0 0.1 1.0 10.0 Aggregate of mononuclear lymphoid cells, submucosa, glandular portion - focal, slight 0 0.1 1.0 10.0 Small Intestine - Number of tissues examined No visible lesions Mucinous adenocarcinoma 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Cecum - Number of tissues examined 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 3 1 0 2 Terminal Kill 17 19 20 18 3 16 10 00 2 18 1 15 1" - 1 16 11 0- - 00 10 0 -" 10 00 0-01 00 0--1 00 0* -01 3 16 10 00 2 17 3 16 0- -- 2 17 00 1-00 1 17 00 00 0 17 Cumulative Results 20 20 20 20 19 1 0 20 16 1 - 17 2 0 " 0 1 0 1 0 0 1 0 0 1 0 0 1 19 1 0 19 19 0 - 19 0 1 0 18 0 0 17 - Indicates none examined or not applicable. - _-.t r -.i-tnrtiTl*! no 13)48) r.ONFTDFNTTAl Diagnosis Code Ce-1 Ce-2 LI-1 LI-2 LI-3 L-l L-2, L-2vs, L-2s L-3 L-4vs -71TABLE 9 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS | HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR IT TO 32 WEEKS OF RECOVERY Observations Number of rats per group Exposure Level (ppm) 0 0.1 1.0 10.0 GASTROINTESTINAL SYSTEM (cont'd) Cecum (cont'd) No visible lesions 0 0.1 1.0 10.0 Intraluminal nematode parasites consistent with pinworms 0 0.1 1.0 10.0 Laree Intestine - Number of tissues examined No visible lesions Intraluminal nematode parasites consistent with pinworms Medial calcification of small arterioles. secondary to severe chronic renal disease 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Liver - Number of tissues examined No visible lesions Aggregates of mononuclear lymphoid cells or reticuloendothelial cells - focal or multifocal Congestion Vacuoliiation consistent with fatty change - focal or multifocal, very slight 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 3 1 0 2 Terminal Cumulative Kill 1 Results 17 j 20 19 20 20 20 18 _i_____20______ 1 14 13 - -" - "" - 17 17 0 33 * -" -" 00 3 16 19 1 01 0 0 io 2 18 1 20 3 10 13 11 - -" 1 11 12 0 66 0 -0 -0 77 0 00 0 -0 -1 01 3 17 20 1 19 20 0 20 20 2 18 20 1 12 1 01 - 11 0 00 1 34 0 00 - 22 1 23 2 02 0 00 - 00 0 00 0 22 0 11 - 66 0 66 - Indicates none examined or not applicable. DO 1314ft? OONFIDFNT1AL Diagnosis Code L-4s L-4m L-5vs L-5s L-6, L-6s, L-6n L-19s L-7s L-8 L-9vs L-9s L-12s -72- TABLE 9 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Exposure Died or Killed Level Moribund During Terminal Cumulative _________________ Observations________________________(ppm)_______ Recovery Period______ Kill________ Results Number of rats per group 0 0.1 1.0 10.0 3 17 20 1 19 20 0 20 20 2 18 20 GASTROINTESTINAL SYSTEM (cont'd) Liver (cond't) Vacuolization consistent with fatty change 0 1 89 - focal or multifocal, slight 0.1 0 12 12 1.0 - 99 10.0 1 B9 Vacuolization consistent with fatty change - focal or multifocal, moderate 0 0.1 1.0 10.0 0 0 - 0 00 11 00 11 Extramedullary hematopoiesis - focal or multifocal, very slight 0 0.1 1.0 10.0 0 0 - 0 11 00 00 00 Extramedullary hematopoiesis - focal or multifocal, slight 0 0.1 1.0 10.0 0 0 - 0 44 99 99 99 Focus(i) of altered hepatocytes 0 0 66 0.1 0 77 1.0 - 88 10.0 0 14 14 Area of altered hepatocytes - slight 0 0.1 1.0 10.0 0 0 - 0 00 00 11 00 Biliary hyperplasia - focal or multifocal, slight 0 0.1 1.0 10.0 0 0 - 0 22 22 22 22 Herniated portion of liver, nodular 0 0.1 1.0 10.0 0 0 - 0 11 00 00 00 Subacute Inflammation - focal, very slight 0 0.1 1.0 10.0 0 0 - 0 11 00 00 00 Subacute inflammation - focal, slight 0 0.1 1.0 10.0 0 0 - 0 00 33 11 11 Atrophy, hepatic cords, eentrilobular region - slight 0 0.1 1.0 10.0 0 0 - 1 00 00 00 01 - Indicates none examined or not applicable. DO 131483 rONFTOFNT TAI Diagnosis Code L-13s L-lis L-15s L-18s Pa-1 Pa-2vs, Fa-2s Pa-3 Pa-5, Pa-5sev Pa-6s -73- TABLE 9 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rats per group GASTROINTESTINAL SYSTEM (cont'd) Liver (cont'd) Chronic active inflammation, portal triads - slight Dilated (telangiectatic) sinusoids - slight Sclerosis, portal triad - slight Periarteritis, portal triads - focal, slight Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Pancreas - Number of tissues examined No visible lesions Atrophy, with or without inflammation, acinar cells - focal or multifocal Medial calcification, pancreatic arteries, secondary to severe chronic renal disease - multifocal Periarteritie - focal or multifocal Fibrosis, interstitial - focal, slight 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 RESPIRATORY SYSTEM Nasal Turbinates - Number of tissues examined 0 0.1 1.0 10.0 - Indicates none examined or not applicable. Died or Killed Moribund During Recovery Period 3 1 0 2 Terminal Kill 17 19 20 18 00 02 -0 00 00 00 -1 00 00 01 -1 0O 00 00 -01 3 17 10 01 2 18 1 11 1-0 2 12 26 0-0 04 10 0-0 10 00 0-1 01 00 0-0 01 3 17 10 00 2 18 Cumulative Results 20 20 20 20 0 2 0 0 0 0 1 0 0 1 1 0 0 0 1 20 1 1 20 12 1 0 14 8 0 0 4 1 0 0 1 0 0 1 1 0 0 0 1 20 1 0 20 r* --'M DO 131484 OONFTDFNTTAl Diagnosis Code NT-1 NT-2vs, NT-2 s NT-3, NT-3 s NT-3sev NT-4 s NT-5 NT-6 NT-7 s NT-8 Tr-1 Tr-2 s -74- TABLE 9 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rats per group Exposure Level (ppm) 0 0.1 1.0 10.0 RESPIRATORY SYSTEM (cont'd) Nasal Turbinates (cont'd) No visible lesions 0 0.1 1.0 10.0 Aggregates of mononuclear lymphoid cells. submucosa - focal or multifocal 0 0.1 1.0 10.0 Suppurative (acute) rhinitis - focal or multifocal, slight 0 0.1 1.0 10.0 Suppurative (acute) rhinitis - focal or multifocal, slight 0 0.1 1.0 10.0 Chronic active inflammation - focal, slight 0 0.1 1.0 10.0 Malignant schwannoma * primary Fibrous osteodystrophy, probably secondary to severe chronic renal disease 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Acute inflammation with or without necrosis , mucosa and subnucosa of olfactory portion of the dorsal medial turbinates 0 0.1 1.0 10.0 Adenocarcinoma 0 0.1 1.0 10.0 Trachea - Number of tissues examined NO visible lesions Subacute inflammation, submucosa - multifocal, slight 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 -Indicates none examined or not applicable. Died or Killed Moribund During Recovery Period 3 1 0 2 Terminal Kill 17 19 20 18 Cumulative Results 20 20 20 20 1 23 0 *0 - -w 0 00 1 14 15 01 - -1 17 18 1 01 11 - -0 11 0 00 0 "0 - -1 01 0 11 0 -0 - -0 11 0 00 0 -0 - -1 01 0 00 0 -0 - -1 01 0 00 0 -0 - -0 22 0 00 0 -0 - -0 22 3 16 19 1 01 0 00 2 18 20 3 14 17 1 -1 - -- 2 16 18 0 22 0 -0 - -- 0 00 DO 131485. CONF TDFNTTAl Diagnosis Code Tr-3s Tr-4 Lu-2, Lu-2s Lu-3s Lu-7s Lu-lOs Lu-4 Lu-5 Lu-6s Lu-8s 75- TABLE 9 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rats per group RESPIRATORY SYSTEM (cont'd) Trachea (cont'd) Periarteritis, submucosa - focal, slight Aggregate of mononuclear lymphoid cells, submucosa - focal Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Lungs - Number of tissues examined Aggregates of mononuclear lymphoid cells, peribronchial - focal or multifocal Aggregates of mononuclear lymphoid cells. perivascular - focal or multifocal Aggregates of mononuclear lymphoid cells. subpleural - focal or multifocal Aggregates of mononuclear lymphoid cells, interstitial - focal or multifocal Generalized congestion Edema, perivascular - focal or multifocal Alveolar histiocytosis - focal or multifocal, slight Subacute inflammation. Interstitial - focal or multifocal, slight 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1,0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 3 1 0 2 Terminal Kill 17 19 20 18 00 0 -- 01 00 0-01 3 17 11 0 19 2 18 3 17 11 - 19 0 IB 18 01 -2 05 11 10 -3 00 00 00 -0 01 30 00 -0 10 20 00 -0 10 17 01 -3 03 02 00 -4 00 Cumulative Results 20 20 20 20 0 0 1 0 0 1 20 2 19 20 20 2 19 18 9 1 2 5 2 i 3 0 0 0 0 1 3 0 0 1 2 0 0 1 8 1 3 3 2 0 4 0 - Indicates none examined or not applicable. DO 131486 OONF T DFN7 TAi Diagnosis Code Lu-9s Lu-lls Lu-12s Lu-13s Lu-14 Lu-15 Lu-16 Lu-17 Lu-16s PS-1 -76- TABLE 9 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rats per group Exposure Level (ppm) 0 0.1 1.0 10.0 RESPIRATORY SYSTEM (cont'd) Lungs (cont'd) Granulomatous inflammation - focal, slight 0 0.1 1.0 10.0 Chronic inflammation, bronchiole - slight 0 0.1 1.0 10.0 Cholesterol clefts - focal, slight 0 0.1 1.0 10.0 Microgranuloma - focal, slight 0 0.1 1.0 10.0 Mineralization, alveolar septae, secondary to severe chronic renal disease 0 0.1 1.0 10.0 Mineralization, pleura - multifocal, secondary to severe chronic renal disease 0 0.1 1.0 10.0 Chronic inflammation, pleura - multifocal, secondary to severe chronic renal disease 0 0.1 1.0 10.0 Hemorrhage - multifocal, secondary to severe chronic renal disease 0 0.1 1.0 10.0 Chronic active inf lamination - multifocal 0 0,1 1.0 10.0 NERVOUS SYSTEM Peripheral Nerve - Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 - Indicates none examined or not applicable. Died or Killed Moribund During Recovery Period 3 1 0 2 0 0 - 0 0 0 - 0 0 0 . 0 0 0 - 0 0 0 - 1 0 0 - 1 0 0 - 1 0 0 - 1 0 0 - 0 3 1 0 2 3 1 - 2 Terminal Kill 17 19 20 18 1 0 1 0 0 0 0 1 0 0 0 1 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 16 0 0 18 10 . - 9 Cumulative Results 20 20 20 20 1 0 1 0 0 0 0 1 0 0 0 1 0 0 1 0 0 0 0 1 0 0 0 1 0 0 0 1 0 0 0 1 0 0 0 1 19 1 0 20 13 1 - 11 r ^ ^ Jiri f*i it* * y ^ 0 1 F 1 4 ft 7 OONF T DFNT TAI Diagnosis Code PS-2vs PS-2 s SC-1 B-l B-2 B-3s. B-3b, B-3bs B-A B-5m -77TABLE 9 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 1A WEEKS ASP THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Exposure Level _________________ Observations________________________(ppm) Number of rats per group 0 0.1 1.0 ____________________________________________ _____ NERVOUS SYSTEM (cont'd) Peripheral Serve (cont'd) Peripheral neuropathy - very slight 0 0.1 1.0 10.0 Peripheral neuropathy - slight 0 0.1 1.0 10.0 Spinal Cord - Number oftissues examined No visible lesions 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Brain - Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Malignant schwannoma, infiltrating from primary site in nasal turbinates. (Do not include as a tumor in tumor tally) 0 0.1 1.0 10.0 Mineralization, cerebrum - focal or multifocal 0 0.1 1.0 10.0 Granular cell tumor located in meninges, cerebrum, dorsal surface 0 0.1 1.0 10.0 Vacuolization and degeneration of the cerebellum, midbrain, and cerebrum - multifocal, moderate 0 0.1 1.0 10.0 MUSCULOSKELETAL SYSTEM Skeletal Muscle - Number of tissues examined 0 0.1 1.0 10.0 - Indicates none examined or not applicable. Died or Killed Moribund During Recovery Period 3 1 0 2 Terminal Cumulative Kill Results 17 1 20 19 20 20 20 18 - J___ ?o ... 0 AA 00 0 AA 0 33 00 0 55 3 17 20 1 01 0 00 2 18 | 20 3 17 ! 20 1 -1 2 18 20 3 17 20 1 18 19 0 20 20 2 18 20 3 17 20 1 18 19 19 19 1 3A 0 00 0 00 00 1 01 0 00 0 00 00 0 15 15 0 00 0 00 00 0 11 0 00 0 00 11 0 00 3 17 20 1 01 0 00 2 17 19 r* IT! I OO 131488 CONFTDFNTT Al Diagnosis Code SM-1 VB-1 VB-2, VB- 2 s VBM-1 K-4us, K-4s K-4b K-5us -78- TABLE 9 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rats per group MUSCULOSKELETAL SYSTEM (eont'dl Skeletal Muscle (cont'dl No visible lesions Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Vertebral Bone - Number of tissues examined No visible lesions Fibrous osteodystrophy, secondary to severe chronic renal disease 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Vertebral Bone Marrow Number of tissues examined No visible lesions 0 0.1 1.0 10.0 0 0.1 l.d 10.0 URINARY SYSTEM Kidneys - Number of tissues examined Mineral deposits, cortex, medulla or corticomedullary junction - focal or multifocal, unilateral Mineral deposits, cortex, medulla or corticomedullary junction - focal or multifocal, bilateral Mineral deposits, renal pelvis - focal or multifocal, unilateral 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 - Indicates none examined or not applicable. Died or Killed Moribund During Recovery Period 3 1 0 2 Terminal Kill 17 19 20 18 3 17 1-2 17 3 17 10 00 2 18 2 17 1-1 18 10 0-10 3 17 10 00 2 18 3 17 1-2 18 3 17 1 19 0 20 2 18 01 00 _1 01 10 00 -0 10 05 02 -4 02 Cumulative Results 20 20 20 20 20 1 - 19 20 1 0 20 19 1 - 19 1 0 1 20 1 0 20 20 1 - 20 20 20 20 20 1 0 1 1 1 0 0 1 5 2 4 2 n"-,i O'!'-<-r*iTI 11 DO 131489 OONF TOFNT TAl Diagnosis Code K-Sb, K-5bs K-6s, K-6bs K-6m, K-6bm K-6sev, K-6b,sev K-llus K-13us K-14us K-16 K-17us K-18 K-24 -79- TABLE 9 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCF IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON HALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rats per group Exposure Level (ppm) 0 0.1 1.0 10.0 URINARY SYSTEM (cont'd) Kidneys (cont'd) Mineral deposits, renal pelvis - focal of multifocal, bilateral 0 0.1 1.0 10.0 Chronic progressive glomerulonephropathy - slight 0 0.1 1.0 10.0 Chronic progressive glomerulonephropathy - moderate 0 0.1 1.0 10.0 Chronic progressive glomerulonephropathy - severe 0 0.1 1.0 10.0 Aggregates of mononuclear lymphoid cells, pelvis - focal or multifocal, unilateral, slight 0 0.1 1.0 10.0 Vacuolization, pelvic epithelium - unilateral, slight 0 0.1 1.0 10.0 Hyperplasia, pelvic epithelium - unilateral, slight 0 0.1 1.0 10.0 Cyst, cortex Hydrohephrosis - unilateral, slight 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Adenoma, cortex 0 0.1 1.0 10.0 Focus or (pleomorphic) basophilic cells 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 3 1 0 2 Terminal Kill 17 19 20 18 00 00 -0 I1 19 0 11 - 11 16 06 18 -8 0 10 22 00 -1 12 01 00 -0 00 00 00 -0 01 01 00 -2 02 00 00 -2 00 01 00 -0 00 00 00 -0 01 00 00 -0 01 Cumulative Results 20 20 20 20 0 0 0 2 10 11 11 7 6 9 8 10 4 0 1 3 1 0 0 0 0 0 0 1 1 0 2 2 0 0 2 0 1 0 0 0 0 0 0 1 0 0 0 1 - Indicates none examined or not applicable. I - ^ *t*-?r* ^T.tn 11 DO 13 i 490 rONFTDFNTTAl Diagnosis Code UB-1 H-l H-2s, H-5s, H-6s H-3 H-4vs H-4s ABV-1 ABV-2, ABV-2s, ABV-2m -80- TABLE 9 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON HALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rats per group Exposure Level (ppm) 0 0.1 1.0 10.0 URINARY SYSTEM (cont'd) Urinary Bladder - Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 CARDIOVASCULAR SYSTEM Heart - Number of tissues examined No visible lesions Myocardial degeneration with or without inflammation - focal or multifocal, slight Medial calcification, coronary arteries, secondary to severe chronic renal disease - multifocal Aggregate of mononuclear lymphoid cells - focal or multifocal, very slight Aggregate of mononuclear lymphoid cells - focal or multifocal, slight Anterior Mediastinal Blood Vessels Number of tissues examined No visible lesions Periarteritis - focal or multifocal 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 -Indicates none examined or not applicable. Died or Killed Moribund During Recovery Period 3 1 0 2 Terminal Kill 17 19 20 18 3 17 1 19 0 20 2 17 3 17 1 19 - 20 2 17 3 17 10 00 2 18 1 14 1-1 14 21 0- -- 14 10 0- -- 10 01 000 01 0- -- 00 3 17 10 01 2 17 1 16 1-0 1 15 11 0-1 02 Cumulative Results 20 20 20 20 20 20 20 19 20 20 20 19 20 1 0 20 15 1 - 15 3 0 5 1 0 1 1 0 0 1 0 * 0 20 1 1 19 17 1 0 16 2 0 1 2 r-' 1 i 4 9 ] CNfr T OFN 7 TA1 Diagnosis Code ABV-3 CBV-2 MBY-1 MBY-2 MBV-3 MF-1 MF-2 0-2 -81- TABLE 9 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Exposure Level _________________ Observetlons________________________(ppm) Number of rats per group 0 0.1 1.0 _____________________________________________________ 10.0 CARDIOVASCULAR SYSTEM (cont'd) Anterior Mediastinal Blood Vessels (cont'd) Medial calcification, secondary to severe chronic renal disease - multifocal 0 0.1 1.0 10.0 Cervical Blood Vessels Number of tissues examined Periarteritis - multifocal 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Mesenteric Blood Vessels Number of tissues examined No visible lesions Periarteritis - focal or multifocal Subintimal mineralization, secondary to severe chronic renal disease - focal or multifocal 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1,0 10.0 ABDOMINAL CAVITY Mesenteric Fat - Number oftissues examined No visible lesions Atrophy Strangulated (necrotic) fat 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 - Indicates none examined or not applicable. Died or Killed Moribund During Terminal Cumulative Recovery Period______ Kill______ Results 17 20 19 20 20 20 18 20 10 0 0 10 00 10 00 00 1 3 17 10 00 2 18 1 17 1 1 18 10 0 10 20 0 10 3 17 11 01 2 18 3 17 10 0 1 18 00 00 0 10 00 00 1 00 1 0 0 1 0 1 0 0 1 20 1 0 20 IB 1 19 1 0 1 2 0 1 20 2 1 20 20 1 0 19 0 0 0 1 0 0 1 0 +>* k i r> f, 11 on 13149? CONF TDFN'T T Al 333 Diagnosis Code 0-3 EA-2 EY-1 EY-2b, EY-2bs, EY-2bm EY-4ur EY-3us, EY-3um T-l -82- TABLE 9 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OP DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rats per group ABDOMINAL CAVITY (cont'd) Mesenteric Fat (cont'd) Necrosis and chronic Inflammation of fat Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 HEAD REGION Ear - Number of tissues examined Squamous cell carcinoma, probably zymbal gland origin Eves - Number of tissues examined No visible lesions Keratitis with increased corneal vasculari- ration - bilateral Corneal vascularization and chronic inflam- nation - unilateral, moderate Retinal atrophy and degeneration - unilateral 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 MALE REPRODUCTION SYSTEM Testes - Number of tissues examined No visible lesions 0 0.1 1.0 10.0 0.1 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 3 1 0 2 Terminal Kill 17 19 20 18 00 01 -0 00 00 00 00 01 --*-1 3 17 12 06 2 17 2 IS 02 -5 0 16 10 10 -0 10 00 00 -1 00 02 00 -0 01 3 17 1 19 0 20 2 18 1 12 1 14 - 15 15 Cumulative Re suits 20 20 20 20 0 1 0 0 0 0 0 1 1 20 3 6 19 17 2 5 16 1 1 0 1 0 0 1 0 2 0 0 1 20 20 20 20 13 15 15 6 - Indicates none examined or not applicable. `I t J DO 131493 conftdfnttai Diagnosis Code T-2um T-2bm T-2u,sev T-3u,vs T-3us T-3bs T-3utn T-4us T-4um T-Ab, T-4bs -83- TABLE 9 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY ! Observations Number of rats per group Exposure Level (com) 0 0.1 1.0 10.0 MALE REPRODUCTIVE SYSTEM (cont'd) Testes (cont'd) Atrophy (generalized) - unilateral, moderate 0 0.1 1.0 10.0 Atrophy (generalized) - bilateral, moderate 0 0.1 1.0 10.0 Atrophy (generalized) - unilateral, severe 0 0.1 1.0 10.0 Atrophy (decreased spermatogenesis of individual seminiferous tubules - includes individual seminiferous tubules containing predominantly sertoli cells) - unilateral, very slight 0 0.1 1.0 10.0 Atrophy (decreased spermatogenesis of individual seminiferous tubules - includes individual seminiferous tubules containing predominantly sertoli cells) - unilateral, slight 0 0.1 1.0 10.0 Atrophy (decreased spermatogenesis of individual seminiferous tubules - includes individual seminiferous tubules containing predominantly sertoli cells) - bilateral, slight 0 0.1 1.0 10.0 Atrophy (decreased spermatogenesis of indi- 0 vidual seminiferous tubules - includes 0.1 individual seminiferous tubules containing 1.0 predominantly sertoli cells) 10.0 - focal or multifocal, unilateral, moderate Mineralization (intratubular calcification) - unilateral, slight 0 0.1 1.0 10.0 Mineralization (intratubular calcification) - unilateral, moderate 0 0.1 1.0 10.0 Mineralization (intratubular calcificatlon) - multifocal, bilateral 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 3 1 0 2 0 0 0 0 0 1 0 0 0 0 0 * 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 Terminal Kill 17 19 20 18 1 0 0 1 0 0 0 1 0 1 0 0 1 0 0 0 1 2 5 8 1 1 0 6 0 1 0 0 2 0 0 1 0 1 0 0 0 0 0 1 Cumulative J Results 20 I 20 20 , 20 1 0 0 1 0' 0 0 2 0 1 0 0 11 0 0 0 1 2 5 8 1 1 0 U 0 1 0 0 2 0 0 1 0 1 0 0 0 0 0 2 -Indicates none examined or not applicable. p'*! *riO 131494 C.ONF TDFNTTAt Diagnosis Code T-5b T-5bn T-6un T-6u,sev T-8u E-l E-3u^( E-3u,sev E-3b E-4s TABLE 9 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 32 KEEKS OF RECOVERY Observations Number of rats per group MALE REPRODUCTIVE SYSTEM (cont'd) Testes (cont'd) Periarteritis - focal or multifocal, bilateral Periarteritis - focal or multifocal, moderate Edema, interstitial - unilateral, moderate Edema, interstitial Interstitial cell tumor - unilateral Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Epididvmides - Number of tissues examined No visible lesions Decreased sperm content in tubular lumina - unilateral, moderate Decreased sperm content in tubular lunina - unilateral, severe Decreased sperm content in tubular lumina - bilateral Sperm granuloma - slight 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Died or Killed Moribund During Recoverv Period 3 1 0 2 Terminal Kill 17 19 20 18 20 00 -0 11 00 00 -0 01 00 01 -0 00 00 01 s- 0 01 01 00 -0 00 3 17 1 19 0 20 2 18 3 16 1 17 - 19 1 14 00 00 -0 01 01 01 -0 00 00 00 -0 11 01 00 -0 00 Cumulative Results 20 20 20 20 2 0 0 2 0 0 0 1 0 1 0 0 0 1 0 1 1 0 0 0 20 20 20 20 19 18 19 15 0 0 0 1 1 1 0 0 0 0 0 2 1 0 0 0 -Indicates none examined or not applicable. "ri'innrKTMi no 131495 CONF T DFNT T At Diagnosis Code E-5u E-5b E-6, E-6u E-?us FR-l PR-3, PR-3s, PR- 3r. PR-5s FR-6s CC-1 -85- TABLE 9 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rats per group Exposure Level (ppm) 0 0.1 1.0 10.0 MALE REPRODUCTIVE SYSTEM (cont'd) Epididvmides (cont'd) Increased cellular debris in tubular lumina - unilateral 0 0.1 1.0 10.0 Increased cellular debris in tubular lumina - bilateral 0 0.1 1.0 10.0 Periarteritis - focal Aggregate of mononuclear lymphoid cells, perivascular - focal, unilateral, slight 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Prostate Gland - Number of tissues examined No visible lesions Corpora amylacea-like bodies - focal or multifocal Papillary hyperplasia, glands - focal, slight Hyperplasia, glands - focal, slight 0 0.1 1.0 10.0 0 0.1 1.0 10. 0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Coagulating Gland Number of tissues examined No visible lesions 0 0.1 1.0 10.0 0 0.1 1.0 10.0 - Indicates none examined or not applicable. Died or Killed Moribund During Recovery Period 3 1 0 2 Terminal Kill 17 19 20 18 00 01 -0 01 00 00 -0 11 00 01 -0 01 00 00 -1 01 3 17 1 19 0 20 1 17 13 03 -5 02 2 14 1 16 - 15 1 15 00 00 -0 01 00 01 -0 00 3 17 1 18 0 20 2 16 3 17 1 18 20 1 15 Cumulative Results 20 20 20 20 0 1 0 1 0 0 0 2 0 1 0 1 0 0 1 1 20 20 20 18 4 3 5 2 16 17 15 16 0 0 0 1 0 1 0 0 20 19 20 18 20 19 20 16 r^n 13149^ CONFTDFNTTA! Diagnosis Code CG-2 SV-1 SV-2 SV-3 PPG-2s, PPG-2n, PPG-2sev PPG-3m, PPG-3sev PPG-4 TY-2m 86- TABLE 9 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON HALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rats per group MALE REPRODUCTIVE SYSTEM (cont'd) Coagulating Gland (cont'd) Atrophy Seminal Vesicles Number of tissues examined No visible lesions Atrophy Corpora amylacea-like bodies - focal or multifocal Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Preputial Gland - Number of tissues examined Chronic inflammation - multifocal Cystic dilatation, ducts Abscess 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 LYMPHORETICULAR SYSTEM Thymus - Number of tissues examined Atrophy - moderate 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 3 1 0 2 Terminal Kill 17 19 20 18 00 00 0 11 3 17 1 18 0 20 2 17 3 17 1 18 - 20 1 16 00 00 -0 11 00 00 -0 10 01 01 01 02 -1 -1 -0 -1 -1 -1 -0 -1 -0 -0 -1 -1 2 15 10 01 2 17 2 15 1-1 1 17 Cumulative Results 20 20 20 20 0 0 0 2 20 19 20 19 20 19 20 17 0 0 0 2 0 0 0 1 1 1 1 2 1 1 0 1 1 1 0 1 0 0 1 1 17 1 1 19 17 1 1 18 - Indicates none examined or not applicable. ' T nrMTiM DO 101497 CONF TDFNTTAl Diagnosis Code TY-2sev Sp-1 Sp*2m Sp-3 Sp-4s Sp-5s MLN-1 ml:;-2 ml:;-3s -87TABLE 9 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rats per group LYMPHORETICULAR SYSTEM (cont'd) Thvmus (cont'd) Atrophy - severe Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Spleen - Number of tissues examined No visible lesions Hemosiderosis - moderate Ectopic spleen, near adrenal or in omentum Periarteritis - focal, slight Increased extramedullary hematopoiesis, red pulp - slight 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Mesenteric Lvmph nodes Number of tissues examined No visible lesions Free and phagocytized red cells in the sinusoids Sinus histiocytosis 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 3 1 0 2 Terminal Kill 17 19 20 18 00 0" -0 10 3 17 10 00 2 18 Z 17 1- -- 2 15 10 0-00 00 0-01 00 0-01 00 0- -- 01 3 16 10 01 2 16 2 12 1-0 1 16 03 0" -0 10 01 0-0 00 Cumulative Results 20 20 20 20 0 0 0 1 20 1 0 20 19 1 17 1 0 0 0 0 1 0 0 1 0 0 1 19 1 1 18 14 1 0 17 3 0 0 1 1 0 0 0 - Indicates none examined or not applicable, DO 10 14 98 OONFTDFNT TAI rt Diagnosis Code MLN-4 MLN-5 Pa-4 Pa-7 K-20sev K-21 K-22 K-23 -88- TABLE 9 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 32 MEEKS OF RECOVERY Observations Number of rats per group LYMFHORETICULAR SYSTEM (cont'd) Mesenteric Lvmph Nodes (cont'd) Reactive hyperplasia Plasmacytosis of the medullary cords Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Pancreatic Lvmph Nodes Number of tissues examined No visible lesions Free and phagocytiied red cells, medullary sinuses 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Renal Lvmoh Nodes NunDer of tissues examined Cystic dilatation, sinusoids - severe Free and phagocytieed red cells, medullary sinuses Histiocytosis, medullary sinuses Accumulations of hematogenous pigment (hemosiderin) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Anterior Mediastinal Lvmph Nodes Number of tissues examined 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 3 1 0 2 Terminal Kill 17 19 20 18 00 0-1 00 00 0.1 00 02 00 00 01 -2 -* --0 -0 - --1 02 01 00 00 .2 *0 -- -0 -1 --- -0 -1 --- -0 -1 --- 2 17 10 01 2 18 Cumulative Results 20 20 20 20 0 0 1 0 0 0 1 0 2 0 0 1 2 * 0 0 1 2 1 0 0 2 0 - 0 1 - 0 1 - 0 1 - 19 1 1 20 - Indicates none examined or not applicable. r-rr'T'r-tMTtr'l DO 131499 CONFTDFNTTA1 Diagnosis Code AL.N-l ALN-2 ALN-3, ALN-3s ALN-4 AX-2 SLN-1 LN-1 LN-2 -89TABLE 9 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS 1 m so O *1 histopathologic observations TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rats per group LYMPHORETICULAR SYSTEM (cont'd) Anterior Mediastinal Lymph Nodes (cont'd) No visible lesions Free and phagocytized red cells in the medullary sinuses Hematogenous pigment (hemosiderin). medullary sinuses Sinus histiocytosis Axillarv Lvmph Nodes Number of tissues examined Reactive hyperplasia Subcutaneous Lvmph Nodes Numper of tissues examined No visible lesions Lvr.oh Nodes - (origin undetermined) Number of tissues examined No visible lesions Free and phagocytized red cells in the medullary sinuses Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10,0 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 3 1 0 2 Terminal Kill 17 19 20 18 2 10 1 -0 2 16 06 0" -0 02 04 0 -0 00 00 0- 1' 00 00 00 00 01 --- -- -1 05 00 00 18 -5 -- -- 18 00 10 00 01 -_ 0- -- -1 -- 1- -- -0 Cumulative Results 20 20 20 20 12 1 0 18 6 0 0 2 4 0 0 0 0 0 1 0 0 0 0 1 1 5 0 0 9 5 - 9 0 1 0 1 _ 0 1 - 1 - 0 - Indicates none examined or not applicable. rr"i ftfiyinnrMTJ no KiU>oo C.ONF TOFNT 1 A1 Diagnosis Code LN-3 Sk-1 Sk-2 Sk-3 Sk-4 Sk-3 Sk-6 Sq-1 Sq-2 -90- TABLE 9 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR IT TO 32 WEEKS OF RECOVERY Observations Number of rats per group Exposure Level (ppm) 0 0.1 1.0 10.0 LYMFHORETICULAR SYSTEM (cont'd) Lvmph Nodes - (orig.undeterm.) (cont'd) Hematogenous pigment accumulations, medullary 0 sinuses 0.1 1.0 10.0 SKIN AND SUBCUTANEOUS Skin - Number of tissues examined No visible lesions Granulomatous inflammation, eyelid - focal Squamous papilloma Chronic active inflammation and fibrosis. eyelid Epidermal inclusion cyst Squamous cell carcinoma with secondary cutaneous metastasis 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Subcutaneous - Number of tissues examined Subcutaneous arteries, medial calciflca- tion, secondary to severe chronic renal disease - multifocal Fibroma 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 - Indicates none examined or not applicable. Died or Killed Moribund During Recovery Period 3 1 0 2 Terminal Kill 17 19 20 18 -1" -- 0 3 16 10 00 2 18 2 15 1- ,1 17 10 0-00 01 0-00 00 0-10 00 0-01 00 0-01 3 16 10 00 2 18 10 0-10 00 0-02 Cumulative Results 20 20 20 20 1 0 19 1 0 20 17 1 - 18 1 0 0 1 0 0 0 0 1 0 0 1 0 0 1 19 1 0 20 1 0 1 0 0 2 DO 101001 C ONF T DFNT T Al Diagnosis Code Sq-3 MG-1 MG-Zs MG-3s -91TABLE 9 (Continued) SUBCHROMIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 32 '..'ZENS OF RECOVERY , ___________________ Observations Number of rats per group LYMPHORETICULAR SYSTEM (cont'd) Subcutaneous (cont'd) Lipoma Exposure Died or Killed Level Moribund During Terminal (ppm)_______ Recovery Period______ Kill 0 3 17 0.1 1 19 1.0 0 20 10.0________________ _2______________ 18 0 0.1 1.0 10.1 0 0 0 0 1 Marnnarv Gland - Number of tissues examined No visible lesions Acinar hyperplasia - slight Ductal hyperplasia - slight C 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 3 12 00 00 1 15 00 01 3 11 1 14 01 00 Cumulative Results 20 20 20 20____ 0 0 1 15 0 0 16 0 1 14 15 1 0 - Indicates none examined or not applicable. r\ } ('"VCinTMTH! DO 131 SOD CONS IDF NTT Al -92- TABLE 10 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 26 WEEKS OF RECOVERY Diagnosis Code A-1 A-2s, A-2u, A-2us A-2b, A-2bs A-4u, A-4us A-4b A-5u A-5b A-6ut A-llu, A-11U5 A-6b, A-lib Observations Number of rats per group ENDOCRINE SYSTEM Adrenals - Number of tissues examined No visible lesions Focus(i) of altered cells, cortex - unilateral Focus(i) of altered cells, cortex - bilateral Nodular hyperplasia, cortex - multifocal, unilateral Nodular hyperplasia, cortex - multifocal, bilateral Ectatic sinusoids - multifocal, unilateral Ectatic sinusoids - multifocal, bilateral Hematocyst, cortex - unilateral Hematocyst, cortex - bilateral Exposure Level (ppm) 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 1 0 1 3 Terminal Kill 19 20 19 17 Cumulative Results 20 20 20 20 0 0.1 1.0 10.0 0 0.1 1.0 10.0 1 0 1 3 1 _ 0 Q 19 20 20 20 19 20 17 20 45 66 44 00 0 0.1 1.0 10.0 0 - 0 1 88 10 10 66 12 0 0.1 1.0 10.0 0 - 0 0 66 33 66 33 0 0.1 1,0 10,0 0 - 0 0 11 00 44 11 0 0.1 1.0 10.0 0 - 0 3 00 00 33 14 17 0 0.1 1.0 10.0 0 - 0 0 11 00 00 11 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0 1 0 0 0 0 0 1 00 00 00 12 00 11 33 44 00 00 11 12 13 * Indicates none examined or not applicable. DO 101 DO3 CONF tofntia; -93- TABLE 10 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 26 WEEKS OF RECOVERY Diagnosis Code A-12bs A-13bs P-I P-3 P-4 TH-1 TH-5. TH-5s TH-6, TH-6s Observations Number of rats per group ENDOCRINE SYSTEM (eont'd) Necrosis, cortex - bilateral, slight Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Extramedullary hematopoiesis, cortex - bilateral, slight 0 0.1 1.0 10.0 Pituitary - Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 o.l 1.0 10.0 Focus or foci of altered cells, anterior portion 0 0.1 1.0 10.0 Adenoma, anterior portion 0 o.l 1.0 10.0 Thvroid Gland - Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 I'ltimobranchial cyst 0 0.1 1.0 10.0 Parafollicular cell (C-cell) hyperplasia - focal 0 0.1 1.0 10.0 Parathvroid Glands Number of tissues examined 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 1 0 1 3 Terminal Kill 19 20 19 17 00 -0 10 00 00 -0 01 00 1 19 01 10 3 16 1 17 -1 13 16 01 -0 000 01 -0 000 1 19 00 10 3 17 1 17 -12 13 01 -0. 03 01 -0 V12 1 18 00 10 3 13 Cumulative Results 20 20 20 20 0 0 1 0 0 0 1 0 20 1 1 19 18 1 1 19 1 0 0 0 1 0 0 0 20 0 1 20 18 1 15 1 0 3 1 0 3 *19 0 1 16 - Indicates none examined o? not applicable. nnv.l nr'Tl'TrilTIM DO 1 31 BOA CONF TDENT TAL TABLE 10 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 26 WEEKS OF RECOVERY Diagnosis Code PG-1 PG-4 TG-1 TG-2 TG-4s TG-6s TG-7, TG-7s TG-8-s TG-9 TG-10 Observations Number of rats per group Parathvroid Glands (cont'd) No visible lesions Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Altered cells - focal 0 0.1 1.0 10.0 GASTROINTESTINAL SYSTEM Toncue - Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 o.l 1.0 10.0 Periarteritis - focal or multifocal 0 0.1 1.0 10.0 Aggregate of mononuclear lymphoid cells - focal, slight 0 0.1 1.0 10.0 Subacute inflammation, subnucosa - focal or multifocal, slight 0 0.1 1.0 10.0 Foreign body granuloma or subacute inflamnation, submucosa - focal 0 o.l 1.0 10.0 Fibrosis and suppurative inflammation, lacrimal ducts of tongue - focal, slight 0 0.1 1.0 10.0 Increased number of mast cells, musculature 0 0.1 1.0 10.0 Squamous cell carcinoma 0 o.l 1.0 10.0 Died or Killed Moribund During Recoverv Period 1 0 1 3 Terminal Kill 19 20 19 17 1 17 -13 13 01 -000 1 19 00 11 3 17 1 11 * 10 1 14 00 -- 00 01 00 -00 01 07 -00 10 01 -00 10 01 -00 00 00 -00 01 00 -01 00 Cumulative Results 20 20 20 20 18 1 16 1 0 0 20 0 2 20 12 1 15 0 0 1 0 - 0 1 7 0 1 1 * 0 1 1 " 0 0 0 0 1 0 - 1 0 - Indicates none examined or not applicable, rrvt DO 131^- CONMHFNTT -95- TABLE 10 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 26 WEEKS OF RECOVERY Diagnosis Code SG-1 ES-1 S-l S-2s S-4 S-7 S-8 S-9 Observations Number of rats per group GASTROINTESTINAL SYSTEM (cont'd) . Exposure Level (ppm) 0 Died or Killed Moribund During Recovery Period 1 0.1 0 1.0 1 _____________ UM1____ __________2____________ Terminal Kill 19 20 19 17 Sallvarv Glands - Number of tissues examined 0 0.1 1.0 10.0 1 0 0 3 18 0 0 17 No visible lesions 0 0.1 1.0 10.0 1 - 3 18 - - 17 Esophagus - Number of tissues examined 0 0.1 1.0 10.0 1 0 1 3 18 0 0 14 No visible lesions 0 0.1 1.0 10.0 1 - 1 3 18 - - 14 Stomach - Number of tissues examined 0 0.1 1.0 10.0 1 0 1 3 19 1 2 17 No visible lesions 0 0.1 1.0 10.0 1 - 1 3 18 1 0 13 Cystic dilatation, base of crypts, glandular portion - slight 0 0.1 1.0 10.0 0 - 0 0 1 0 0 4 Submucosal edema, nonglandular mucosa 0 0.1 1.0 10.0 0 - 0 0 0 0 1 0 Hyperkeratosis, nonglandular portion 0 0.1 1.0 10.0 0 - 0 0 0 0 2 0 Ulcer, nonglandular portion 0 0.1 1.0 10.0 0 - 0 0 0 0 1 0 Subacute inflammation, nonglandular portion 0 0.1 1.0 10.0 0 - 0 0 0 0 1 0 Cumulative Results 20 20 20 20 19 0 0 20 19 - - 20 19 0 1 17 19 - 1 17 20 1 3 20 19 1 1 16 1 0 0 4 0 0 1 0 0 0 2 0 0 0 1 0 0 0 1 0 - Indicates none examined or not applicable. r>0 1 31 306 r ONF T OFNTTAl -96- TABLE 10 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCF IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 26 WEEKS OF RECOVERY Diagnosis Code SI-1 SI-3 CE-1 CE-2 LI-1 LI-2 L-l Observations Number of rats per group Exposure Level (ppm) 0 0.1 1.0 10.0 GASTROINTESTINAL SYSTEM (cont'd) Small Intestine - Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Acute inflammation, serosal surface 0 0.1 1.0 10.0 Cecum - Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Intraluminal nematode parasites consistent with pinworms 0 0.1 1.0 10.0 Large Intestine - Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Intraluminal nematode parasite consistent with a pinuorm 0 0.1 1.0 10.0 LIVER - Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Died or Killed Moribund During Recoverv Period 1 0 1 3 Terminal Kill 19 20 19 17 1 19 00 10 3 17 1 19 -13 16 00 -- 001 0 17 00 00 2 12 _ 11 --- 2 11 .6 -- -- 01 1 19 00 10 3 17 1 16 -- 13 16 03 -- 001 1 19 0 20 1 19 3 17 07 -9 07 06 Cumulative Results 20 20 20 20 20 0 1 20 20 - 1 19 0 - 0 1 17 0 0 14 11 - 13 6 . 1 20 0 1 20 17 . 1 19 3 - 0 1 20 20 20 20 7 9 7 6 - Indicates none examined or not applicable. nnvu rnwinFNTIAl DO 131507 OONFTDFNT TAl -97 TABLE 10 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON FEMALE RA:rs EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 26 WEEKS OF RECOVERY Diagnosis Code L-2s L-4s L-4m L-5s 1-6, L-6s L-19 L-7s L-9s L-lCs L-17 L-20s Observations Number of rats per group LIVER (cont'd) Aggregates of mononuclear lymphoid or reticuloendothelial cells focal or multifocal Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Vacuolization consistent with fatty change - focal or multifocal, slight 0 0.1 1.0 10.0 Vacuolization consistent with fatty change - focal or multifocal. moderate 0 0.1 1.0 10.0 Extramedullary hematopoiesis - focal or multifocal, slight 0 0.1 1.0 10.0 Focus or foci of altered hepatocytes 0 0.1 1.0 10.0 Area of altered hepatocytes - focal 0 0.1 1.0 10.0 Biliary hyperplasia - focal or multifocal, slight 0 0.1 1.0 10.0 Subacute inflammation - focal, slight 0 0.1 1.0 10.0 Coagulation necrosis and inflammation - focal, slight 0 0.1 1.0 10.0 Altered tinctorial properties to various portions of the liver lobules 0 0.1 1.0 10.0 Individual hepatocellular necrosis, centri- lobular - multifocal 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 1 0 1 3 1 0 0 0 0 2 1 0 0 0 0 2 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 2 Terminal Kill 19 20 19 17 Cumulative Results 20 20 1 20 20 1 3A 00 11 11 66 77 44 8 10 01 00 22 00 1 51 5 4i4 66 46 11 11 33 11 00 00 00 11 00 00 11 00 00 00 00 11 01 00 00 00 11 00 00 00 0 .0 00 00 02 - Indicates none examined or not applicable. no OONF T of NTT Al -98- TABLE 10 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 26 WEEKS OF RECOVERY Diagnosis Code Observations Number of rats per group L-21sev LIVER (cont'd) Coagulation necrosis and atrophy, sinusoids - severe PANCREAS - Number of tissues examined PA-1 No visible lesions PA-2, PA-2 s PA-9 PA-lOs PA-12s Atrophy, with or without inflammation, acinar cells - focal or multifocal Cystic duct with associated fibrosis and chronic-active inflammation Increased cytoplasmic secretory material - focal, slight Subacute inflammation - focal, slight PA-13 NT-1 Aggregates of mononuclear lymphoid cells, interstitium RESPIRATORY SYSTEM Nasal Turbinates Number of tissues examined No visible lesions NT-2 s Aggregates of mononuclear lymphoid cells, submucosa - focal or multifocal - Indicates none examined or not applicable. Exposure Level (ppm) 0 0.1 1.0 10.0 Died or Killed Moribund During Recoverv Period 1 0 1 3 Terminal Kill 19 20 19 17 Cumulative Results 20 20 20 20 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 1 0 1 0 1 3 1 1 1 0 - 0 2 0 - 0 1 0 - 0 0 0 - 0 0 0 0 0 00 00 01 00 19 20 00 01 17 20 16 17 -* -1 13 14 33 --0 13 00 .* .0 01 00 -- -0 11 00 .-0 11 00 * -0 11 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 1 0 1 3 1 0 0 0 1 3 19 20 00 01 17 20 01 - -0 0 .0 13 13 .* .1 15 18 FIIVl ^ 1 DO 101509 OONF TDFNTTAl Diagnosis Code NT-7, NT-7 s NT- 9 NT-10s NT-11, NT-11s NT-12 NT-13 NT-14s TR-1 TR-2s -99TABLE 10 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOFATHOLOCIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 26 KEEKS OF RECOVERY Observations Number of rats per group Exposure Level (ppm) 0 0.1 1.0 10.0 RESPIRATORY SYSTEM (cont'd) Nasal Turbinates (cont'd) Acute inflammation, with or without necrosis, mucosa and submucosa. olfactory portion, dorsal medial turbinates 0 0.1 1.0 10.0 Ulceration, olfactory epithelium with or without adherent exudative material, dorsal medial turbinates 0 0.1 1.0 10.0 Subacute inflammation, respiratory epithelium 0 0.1 1.0 10.0 Subacute inflammation, olfactory epithelium, dorsal medial turbinates 0 0.1 1.0 10.0 Chronic active inflammation, with squamous metaplasia, olfactory epithelium. dorsal medial turbinates 0 0.1 1.0 10.0 Acute (suppurative) or subacute metaplasia and cuboidalization, olfactory epithelium. dorsal medial turbinates 0 0.1 1.0 10.0 Suppurative inflammation associated with a foreign body - focal, slight 0 0.1 1.0 10.0 Trachea - Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Subacute inflammation, submucosa - multifocal, slight 0 0.1 1.0 10.0 Died or Killed Moribund During Recoverv Period 1 0 1 3 Terminal Kill 19 20 19 17 04 -004 01 -001 02 -000 09 -009 00 -010 00 -- 004 00 -001 1 19 00 10 3 16 1 18 -13 13 01 -- 001 Cumulative Results 20 20 20 20 4 0 4 1 0 1 2 " 0 0 9 - 0 9 0 0 1 0 0 4 0 0 1 20 0 1 19 19 1 16 1 0 `1 - Indicates none examined or not applicable, m'M nnMrinrviTiii DO 131510 C ONF T DFN'T T Al -100- TABLE 10 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 26 WEEKS OF RECOVERY Diagnosis Code TR-2m TR-4s LL'-2s LU-3, LL'-3s LU-7s Ll'-4 LU-5n LU-6s LU-Ss Ll-19 Observations Number of rats per group RESPIRATORY SYSTEM (cont'd) Trachea (cont'd) Subacute inflammation, submucosa - multifocal, moderate Expoaure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Aggregate of mononuclear lymphoid cells. submucosa - focal, slight 0 0.1 1.0 10.0 Lungs - Number of tissues examined 0 0.1 1.0 10.0 Aggregates of mononuclear lymphoid cells. peribronchial - focal or multifocal, slight 0 0.1 1.0 10.0 Aggregates of mononuclear lymphoid cells. perivascular - focal or multifocal 0 0.1 1.0 10.0 Aggregates of mononuclear lymphoid cells. subpleural - focal or multifocal 0 0.1 1.0 10.0 Generalized congestion 0 0.1 1.0 10.0 Edema, perivascular - focal or multifocal 0 0.1 1.0 10.0 Alveolar histiocytosis - slight 0 0.1 1.0 10.0 Subacute inflammation, interstitial - focal or multifocal, slight 0 0.1 1.0 10.0 Mineralization - focal 0 0.1 1.0 10.0 - Indicates none examined or not applicable. Died or Killed Moribund During Recoverv Period 1 0 1 3 Terminal Kill 19 20 19 17 Cumulative Results 20 20 20 20 0 00 - -0 -0 0 11 0 00 - -0 -0 0 22 1 19 20 0 22 1 23 3 17 20 1 19 20 - 11 1 23 3 17 20 0 10 10 - 11 0 00 1 67 0 00 - 00 0 00 0 11 0 00 - 00 0 00 1 01 0 00 - 00 0 00 1 01 0 88 - 11 0 11 0 33 0 11 - 00 0 11 0 2 ,2 0 11 - 00 0 00 0 00 DO 131 Ml CONFTDFNTTAl -101- TABLE 10 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE; TOXICITY AND RECOVERY STUDY OF DBCF IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 26 WEEKS OF RECOVERY Diagnosis Code Observations Number of rats per group Lf-20s RESPIRATORY SYSTEM (cont'd) Lungs (cont'd) Granuloma - focal, slight LL'-21 PN'-l Medial hypertrophy, pulmonary artery focal NERVOUS SYSTEM Peripheral Nerve Number of tissues examined No visible lesions Spiral Cord - Number of tissues examined SC-1 No visible lesions Brain - Number of tissues examined B-l No visible lesions B-3, B-3b B-6 Mineralization, cerebrum - focal or multifocal Clial cell tumor - Indicates none examined or not applicable. Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 1 0 1 3 Terminal Kill 19 20 19 17 01 -0 00 01 00 -0 00 10 1 15 00 10 3 16 1 15 -13 16 1 18 00 10 3 17 1 18 -13 17 1 19 0 20 1 18 3 17 1 19 - 20 1 17 1 12 00 -0 00 15 0O -0 01 10 Cuinu lative Results 20 20 20 20 1 0 0 1 0 0 0 1 16 0 1 19 16 - 1 19 19 0 1 20 19 - 1 20 20 20 19 20 20 20 18 13 0 0 0 6 0 0 >1 1 DO 131510 C.ONF TnFNTTAL -102- TABLE 10 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 26 WEEKS OF RECOVERY Diagnosis Code SM-1 VB-1 VBM-1 VBM-2 K-l K-2us K-2bs Observations Number of rats per group MUSCULOSKELETAL SYSTEM Skeletal Muscle Number of tissues examined Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10,0 No visible lesions 0 0.1 1.0 10.0 Vertebral Bone - Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Vertebral Bone Marrow Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Myeloid hyperplasia 0 0.1 1.0 10.0 URINARY SYSTEM Kidnevs - Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Dilated renal tubules with eosinophilic cast formation - focal or multifocal. unilateral, slight 0 0.1 1.0 10.0 Dilated renal tubules with eosinophilic cast formation - focal or multifocal. bilateral, slight 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 1 0 1 3 1 0 1 3 1 - 1 3 1 0 1 3 1 - 1 3 1 0 1 3 1 - 1 2 0 - 0 1 1 0 1 3 0 - 0 0 0 - 1 1 0 - 0 0 * Indicates none examined or not applicable. T'f ' Terminal Kill 19 20 19 17 Cumulative Results 20 20 20 20 19 20 00 01 17 20 19 20 -- -1 17 20 18 19 00 01 17 20 18 19 .* -1 17 20 18 19 00 01 17 20 18 19 . *1 17 19 00 -- -0 01 19 20 20 20 19 20 17 20 11 11 11 00 11 22 1 '2 01 33 11 11 11 on 1 31513 f.ONF TDFNT TAl, -103- table 10 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 26 WEEKS OF RECOVERY Diagnosis Code K-3us N-3bs y K*-us, K- -bs Observations Number of rats per group URINARY SYSTEM (cont'd) Kidneys (cont'd) Basophilic staining renal tubules - unilateral, slight Basophilic staining renal tubules - bilateral, slight Mineral deposits, cortex, medulla, or cortlconedullary junction - focal or multifocal, unilateral Mineral deposits, cortex, medulla, or cortlconedullary junction - focal or multifocal, bilateral Exposure Level (ppm) 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 1 0 1 3 Terminal Kill ! 19 l! 20 1 19 l 17 Cumulative Results 20 20 20 20 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0 0 0 0 0 1 - 0 2 0 - 0 1 1 1 0 0 0 1 0 0 1 3 2 3i 41 6 3 4 4 1 0 0 0 1 0 0 1 4 2 3 6 6 3 4 5 K- 5 s * 'k- 5us Mineral deposits, renal pelvis - focal or multifocal 0 0.1 1.0 10.0 0 * 0 0 44 22 22 22 K-;b Mineral deposits, renal pelvis - focal or multifocal. bilateral 0 0.1 1.0 10.0 0 0 0 00 11 00 00 K-6vk, K-obvs Chronic progressive glonerulonephropathy - very slight 0 0.1 1.0 10.0 0 - 0 0 00 22 44 11 K-6st K-bbs K-^hn K-Bus Chronic progressive glonerulonephropathy - slight Chronic progressive glonerulonephropathy - moderate Inflammation, subacute, renal pelvis - unilateral, slight 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 - 0 2 0 - 0 0 0 - 0 0 99 11 11 88 13 IS 00 00 22 00 11 00 00 00 K-9us Inflammation, subacute, cortex - unilateral, slight - Indicates none examined or not applicable* 0 0.1 1.0 10.0 0 - 0 0 11 00 00 00 no 131514 CONF 1 DFNT T Al now. r^'Tir.rNTlM -104- TABLE 10 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 26 WEEKS OF RECOVERY Diagnosis Code K-lOus K-lObs K-llus N-15s K-19u l 3-1 H-l It-- 2 a, H-6s Observations Number of rats per group URINARY SYSTEM (cont'd) Kidnevs (cont'd) Inflammation, subacute, interstitium - unilateral, slight Exposure Level (ppm) 0 0,1 1.0 10.0 0 0.1 1.0 10.0 Inflammation, subacute, interstitium - bilateral, slight 0 0.1 1.0 10.0 Aggregates of mononuclear lymphoid cells, pelvis - focal or multifocal. unilateral, slight 0 0.1 1.0 10.0 Lipomatosis, cortex - slight 0 0.1 1.0 10.0 Transitional cell carcinoma - unilateral 0 0.1 1.0 10.0 Urinarv Bladder - Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 CARDIOVASCULAR SYSTEM Heart - Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Myocardial degeneration, with or without inflanmiation - focal or multifocal. slight 0 0.1 1.0 10.0 - Indicates none examined or not applicable. Died or Killed Moribund During Recovery Period 1 0 1 3 Terminal Kill 19 20 19 17 00 -0 01 00 00 -1 01 01 01 -0 00 01 00 -0 00 01 10 -0 00 00 1 19 00 1 19 3 15 1 19 -1 19 3 15 1 19 00 10 3 17 0 18 .- 02 14 11 -- 011 Cumulative Results 20 20 20 20 0 0 1 0 0 1 1 1 1 0 0 1 0 0 0 1 1 0 0 0 20 0 20 18 20 - 20 18 20 0 1 20 18 0 16 2 - 0 2 nmi f'nvrnnrrim no I 31 5.1 s CONF TDFNTTA Diagnosis Code 11- 7 s li-8s A3V-1 .\bv-: W V- -* MBV- 1 AC-1 -105- TABLE 10 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 26 WEEKS OF RECOVERY Observation* Number of rats per group CARDIOVASCULAR SYSTEM (cont'd) Heart (cont'd) Mineralization, myocardium - multifocal, slight Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Endomyocardial disease, left ventricle - slight 0 0.1 1.0 10.0 Anterior Mediastinal Blood Vessels Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Periarteritis, small arterioles - focal or multifocal 0 0.1 1.0 10.0 Medial calcification, aorta - multifocal 0 0.1 1.0 10.0 Mesenteric Blood Vessels Nir-.oer of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 ABDOMINAL cavity Abdominal Cavity Lymphosarcoma, abdominal cavity, mesentery and serosal surface of numerous organs 0 0.1 1.0 10.0 Mesenteric Fat - Number of tissues examined 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 1 0 1 3 Terminal Kill 19 20 19 17 00 -100 00 -001 1 19 00 10 3 16 0 19 -12 15 00 -00 01 10 -000 1 19 00 10 3 17 1 19 -13 17 00 00 00 10 1 19 00 10 3 17 Cumulative Results 20 20 20 20 0 1 0 0 0 1 20 0 1 19 19 1 17 0 * 0 1 1 0 0 20 0 1 20 20 1 20 0 0 0 1 20 0 1 20 Indicates none examined or not applicable. oo 131516 00NFTDFNTTA1 -106- TABLE 10 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 26 WEEKS OF RECOVERY Diagnosis Code Observations Number of rats per group >!F-1 ABDOMINAL CAVITY (cont'd) Mesenteric Fat (cont'd) No visible lesions MF-2 Atrophy MF-3 Diffuse atrophy with mononuclear cell inf lamation HEAD RECION Eves - Nunber of tissues examined Li-1 No visible lesions FC-ALE REPRODUCTIVE SYSTEM Uterus - Number of tissues examined U-l L-3, L- 3f. U-3bs l`-3bs i-- r--is U-ibrn No visible lesions Cvstic endometrial hyperplasia - slight Cvstic endometrial hyperplasia - moderate Squamous metaplasia Squamous metaplasia * bilateral Indicates none examined or not applicable. Exposure Level (ppm) 0 0.1 1.0 10.0 Died or Killed Moribund During Reeoverv Period 1 0 1 3 Terminal Kill 19 20 19 17 Cumulative Results 20 20 20 20 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 1 I 2 0 - 0 0 0 0 1 1 0 1 3 1 1 3 1 0 1 3 0 0 2 0 0 0 0 0 0 0 0 0 0 0 0 19 20 --1 16 18 00 "-0 11 00 --0 01 19 20 00 01 17 20 19 20 -" -1 17 20 19 20 19 19 19 20 17 20 4A 22 55 57 88 66 33 AA 11 00 00 00 4A 66 33 00 11 00 00 00 DO 131517 CONFTDFNTTAI -107- TABLE 10 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS ,AND NUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 26 WEEKS OF RECOVERY Diagnosis Code U-5 1-7. U-7u L'-6, v*C3 I'-Sscv U-9 l'* 13* L'-ilsev u-i: U-13sev C-l Observations Number of rats per group FEMALE REPRODUCTIVE SYSTEM (cont'd) Uterus (cont'd) Endometrial stromal polyp with focal necrosis and inflammation Endometrial stromal polyp Hematogenous pigment Granulomatous and necrotic placentitis - severe Hemorrhage, nesometrial fat - multifocal Suppurative endometritis - focal, slight Suppurative inflammation and necrosis - transmural, severe Placenta with severe coagulation necrosis Transmural endometritis - focal, severe Cervix - Number of tissues examined No visible lesions Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 1 0 1 3 Terminal Kill 19 20 19 17 01 -0 00 00 01 -0 02 00 09 * 11 0 10 0e 00 -0 00 10 10 -0 00 00 00 -0 00 01 00 -0 10 00 00 -0 10 00 00 -0 00 10 1 16 0 19 1 17 3 15 1 16 - 18 1 17 3 15 Cumulative Results 20 20 20 20 1 0 0 0 1 0 2 0 9 11 10 8 0 0 0 1 1 0 0 0 0 0 0 1 0 0 1 0 0 0 1 0 0 0 0 1 17 19 18 18 17 18 18 18 - Indicates none examined or not applicable. r"'-v rrVJfinFNTiSI DO 131 STB CONF TOFNTTAI 108TABLE 10 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 26 WEEKS OF RECOVERY Diagnosis Code C-2 OV-1 OV-2u Oi-2b OY- 3 QV-i 0>1 or>-Ju Observations Number of rats per group FEMALE REPRODUCTIVE SYSTEM (cont'd) Cervix (cont'd) Well-differentiated stromal cell sarcoma, subnucosa of cervix Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Ovaries - Number of tissues examined 0 0.1 1.0 10 0 No visible lesions 0 0.1 1.0 10.0 Cvst - unilateral 0 0.1 1.0 10.0 Cvst - bilateral 0 0.1 1.0 10.0 Prominent corpora lutea - multifocal 0 0.1 1.0 10.0 Hemorrhage, mesovarial fat - focal 0 0.1 1.0 10.0 Oviducts - Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Cavernous hemangiosarcoma of the Oviduct and uterine horn - unilateral 0 0.1 1.0 10.0 Clitoral Gland - Number of tissues examined 0 0.1 1.0 10.0 - Indicates none examined or not applicable. Died or Killed Moribund During Recoverv Period 1 0 1 3 Terminal Kill 19 20 19 17 Cumulative Results 20 20 20 20 0 00 - 11 0 00 0 00 1 19 20 0 20 20 1 18 19 3 17 20 0 18 18 - 19 19 0 18 18 2 10 12 0 11 - 11 0 0 0 0 66 0 00 - 00 0 00 0 11 0 00 - 00 1 01 1 01 1 01 - 00 0 00 0 00 1 18 19 0 17 17 1 16 17 3 1A 17 1 18 19 - 17 17 1 16 17 3 13 16 0 00 - 00 0 00 0 11 0 00 0 00 o' 1 1 0 00 no 1 31519 rONFTDFN'T TAI -109- TABLE 10 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 26 WEEKS OF RECOVERY j Diagnosis Code CL-lu Cl-2u TY-l T~:'-3s SP-l SP-3 SP-5s Observations Number of rats per group FEMALE REPRODUCTIVE SYSTEM (cont'd) Clitor.il Gland (tout'd) Abscess - unilateral Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Dilated duct, filled with keratinous debris - unilateral 0 0.1 1.0 10.0 LYV.PHORETICULAR SYSTEM Thvmus - Number of tissues examined No visible lesions 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Atropbv - moderate Epithelial hyperplasia - focal, slight 0 0.1 1.0 10.0 0 0.1 1.0 10.0 fplcen - Number of tissues examined 0 1.0 1.0 10.0 No visible lesions 0 0.1 1.0 10.1 Ectopic spleen, near adrenal or in omentum 0 0.1 1.0 10.0 Increased extramedullary hematopoiesis - slight 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 1 0 1 3 Terminal Kill 19 20 19 17 Cumulative Results 20 20 20 20 - -- -- 11 - -- -- -- 11 - -" 1 19 20 0 0i0 1 011 2 16 ! 18 0 00 - -0 -0 0 11 1 19 20 - -1 -1 2 15 17 0 11 -0 -0 0 11 1 19 20 0 00 1 12 3 17 20 0 19 19 - -0 11 0 88 0 11 - -0 11 0 22 0 00 - -0 00 0 11 - Indicates none examined or not applicable. no ! 3 1 50 OONF TOFNT T Al Diagnosis Code SP-5n SP-5sev SP-6, SP-6s SP-7sev 1 mln-2 ml:;-3 PA-7 -110- TABLE 10 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE: TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 16 WEEKS OF RECOVERY Observations Number of rats per group LYMPHORETICllAR SYSTEM (cont'd) Snleen (cont'd) Increased extramedullary hematopoiesis - moderate Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Increased extramedullary hematopoiesis - severe 0 0.1 1.0 10.0 Increased hematogenous pigment, red pulp 0 0.1 1.0 10.0 Lymphoid depletion, splenic follicles - severe 0 0.1 1.0 10.0 Mesenteric Lvr.ph Nodes '.a-ber of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Free and phagocytized red cells, sinusoids 0 0.1 1.0 10.0 Sinus histiocytosis 0 0.1 1.0 10.0 Pancreatic Lymph Nodes Number of tissues examined 0 0.1 1.0 10.0 Free and phagocytized red cells, medullary sinuses of pancreatic lymph nodes 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 1 0 1 3 Terminal Kill 19 20 19 17 10 - 00 20 00 -10 00 00 -00 17 00 -10 00 1 18 00 10 3 16 1 15 -13 14 01 -000 02 -001 00 00 00 02 -*" --2 Cumulative Results 20 20 20 20 1 " 0 2 0 " 1 0 0 0 8 0 1 0 19 0 1 19 16 1 17 1 0 0 2 0 1 0 0 0 2 2 - Indicates rone examined or not applicable. rn'.'! Miynsmu HO 101571 no NT 7 DFNT TAl 111TABLE 10 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 26 WEEKS OF RECOVERY Diagnosis Code PA-11 ALN-l ALN .Lrf .t"*2 ALN-3. AL>- 3 s * ALN-3- -* CLN-1 sln-i Observations Number of rats per group LYMPHORETICULAR SYSTEM (cont'd) Pancreatic Lvraph Nodes (cont'd) Hematogenous pigment, medullary sinuses of pancreatic lymph nodes Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Anterior Mediastinal Lymph Nodes Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Free and phagocytized red cells in the medullary sinuses 0 0.1 1.0 10.0 Hematogenous pigment sinuses (hemosiderin), medullary 0 0.1 1.0 10.0 Sinus histiocytosis 0 0.1 1.0 10.0 Cervical Lymph Nodes Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.1 Subcutaneous Lymph Nodes Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 SKIN AND SUBCUTANEOUS Skin - Number of tissues examined 0 0.1 1.0 10.0 - Indicates none examined or not applicable. Died or Killed Moribund During Recovery Period 1 0 1 3 Terminal Kill 19 20 19 17 Cumulative Results 20 20 20 20 - -- -- - " - 22 1 17 18 0 00 1 01 3 14 17 0 12 12 -1 -1 1 10 11 1 45 -0 -0 1 23 0 44 0 -0 1 23 1 01 - -0 -0 0 00 0 00 0 00 0 00 1 01 - .- -- -1 -1 1 67 0 00 0 00 2 9 11 1 67 _- - .2 9 11 1 19 20 0 11 1 01 2 17 19 no 131533 coNr TDFN7 TAl -112- TABLE 10 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OP TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 26 WEEKS OF RECOVERY Diagnosis Code SK-1 SK-5 SO-6 mg-: s >!G-3s MC-5 MG-6 SQ-4 SQ-4(2) Observations Number of rats per group SKIN AND SUBCUTANEOUS (cont'd) Skin (cont'd) No visible lesions Exposure Level (ppm) 0 0.1 1.0 10,0 . _ Died or Killed Moribund During Recovery Period 1 0 1 3 0 0.1 1.0 10.0 1 - 1 2 Epidermal inclusion cyst 0 0.1 1.0 10.0 0 - 0 0 Subcutaneous - Number of tissues examined 0 0.1 1.0 10.0 1 0 1 2 Undifferentiated sarcoma 0 0.1 1.0 10.0 0 - 0 0 Nvrnrv Gland Number of tissues examined 0 0.1 1.0 10.0 1 0 1 3 Acinar hyperplasia - slight 0 0.1 1.0 10.0 1 - 0 0 Ductal hyperplasia - slight 0 0.1 1.0 10.0 0 - 0 2 Diffuse acinar hyperplasia associated with a latter stage of pregnancy 0 0.1 1.0 10.0 0 * 1 1 Intraductal nodular hyperplasia with assoelated periductal connective tissue - focal 0 0.1 1.0 10.0 0 - 0 0 Fibroadenoma, mammary gland origin 0 0.1 1.0 10.0 0 - 0 2 Fibroadenoma, mammary gland origin, 2 in number 0 0.1 1.0 10.0 0 0 0 Terminal Kill 19 20 19 17 19 0 - 17 0 1 " 0 19 1 0 17 1 0 0 19 4 4 16 4 0 0 5 17 0 0 11 0 0 0 0 0 0 0 1 4 4 4 4 0 0 0 1 Cumulative Results 20 20 20 20 20 0 1 19 0 1 0 0 20 1 1 19 1 0 0 0 20 4 5 19 5 0 0 5 17 0 0 13 0 0 1 1 0 0 0 1 4 4 4 6 0 0 0 1 - Indicates none examined or not applicable. nrw rnMFinFMTIjil ,, , ,__ DO 1315?.-! C.ONF T OF NT T Al Diagnosis Code SQ-5 SQ-7 SQ-S -113- TABLE 10 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 26 WEEKS OF RECOVERY Exposure Level _________________ Observations________________________(ppm) Number of rats per group 0 0.1 1.0 _____________________________________________________ 10.0 SKIN AND SUBCUTANEOUS (cont'd) Mjmatv Gland (cont'd) Calactocele formation, mammary gland origin 0 0.1 1.0 10.0 Papillary adenocarcinoma, mammary gland origin 0 0.1 1.0 10.0 Adenocarcinoma, mammary gland origin 0 0.1 1.0 10.0 Died or Killed Moribund During Terminal Recovery Period______ Kill 1 19 0 20 1 19 3_________________ IL_ Cumulative Results 20 20 20 20 1 0 0 1 0 0 0 2 0 0 0 1 - Indicates none examined or not applicable. p-H<i on i b."'4 CONFIDENT! A! P.itholocv No. 77-7471 77-7477 77-7487 77-7557 77-7680 77-7683 TABLE 11 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS CAUSE OF DEATH OR MORIBUND CONDITION OF RATS DYING OR KILLED MORIBUND DURING THE RECOVERY PERIOD Exposure Cone, Sex (ppm) Weeks After Last Exposure Possible or Probable Cause of Death or Illness M0 >1 0 >! 0 M 0.1 M 10 M 10 28 Obesity and sudden death 27 Obesity and sudden death 23 Renal failure from severe chronic progressive renal disease. 31 Obesity and sudden death. Also had a small mucinous adenocarcinoma of the small Intestine. 23 Malignant schwannoma in the nasal turbinates with local invasion to brain. 32 Renal failure from severe chronic progressive renal disease. 77-7423 77-7566 77-7629 77-7633 77-7634 F0 r1 F 10 r 10 r 10 2 Nonmetastatic transitional cell carcinoma of kidney. 23 Focal severe, suppurative transmural inflammation and necrosis of the uterus. Focal severe coagu lation necrosis of the placenta. 22 Malignant glial cell tumor of the brain. 18 Lymphosarcoma in the abdominal cavity. 24 Unknown, possibly secondary to a fibroadenoma of the mammary gland which was ulcerated. BOW CGOTIM wv,,<r i w NTT At -115- TABLE 12 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS CROSS PATHOLOGIC OBSERVATIONS ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKS* AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY j Diagnosis Code A-6 A-7 3-A L" 5 D-7 ;>-8 E-l r-3 E-5 Number of rabbits per group ADRENAL GLANDS Slightly raised pale focus(i) on adrenal Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Raised dark focus(i) on adrenal 0 0.1 1.0 10.0 CARDIOVASCULAR SYSTEM Serosangulneous fluid within the pericardial sac 0 0.1 1.0 10.0 Fibrinous or fibrous pericarditis (adhesions to epicardium) 0 0.1 1.0 10.0 lie-art involved in a suppurative infla=;atory response with abscess formation 0 0.1 1.0 10.0 :.ves Focal scar on eyelid 0 0.1 1.0 10.0 Purulent or nueoid exudate adhering to conjunctiva GENERAL No visible lesions 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Postmortem autolysis 0 0.1 1.0 10.0 Ascites - cloudy, dark or hemorrhagjc 0 0.1 1.0 10.0 0-8 Weeks 1 0 0 3 8-Week Interim Kill 0 0 0 1 8-14 Weeks 0 0 1 1 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill i Results 10 f 10 5 10 5 10 0.-01 1 ---02 2 .-001 1 000-00 0 _ 000 s- - - 0 0 0 --001 1 000 * 0 0 0-_ 000 --_ 000 --01Q1 000-Q0 0--01 1 ---00 0 --0000 000 -0 0 0-- 0 0 0 --- 101 --0000 0 01 - 0 1 0--000 --. 101 .-0 00 0 0 00 * 0 0 0 00 0 --- 000 .-000 0 001 - 01 0--01 1 ---02 2 --0 00 0 000- 0 0 0--000 --- 00 0 --0000 001- 01 0 -000 . --1 0 1 --0 00 0 0 00* 0 0 JTop dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none examined or not applicable. "TV TTriFiBENM DO 101500 OONF TDFNT T Al 116- TABLE 12 (Continued) Diagnosis Code t>7 F.-9 E-10 F.-ll E-13 r-ii E-1S l- 16 E-17 E- IS SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS CROSS PATHOLOGIC OBSERVATIONS ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKS* AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Number of rabbits per group CENERAL (cant'd) Exudate or porphyrin-like pig- ment accumulation lateral to external nares or around eyes Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Perineal soiling 0 0.1 1.0 10.0 Depletion of adipose tissue. including serous atrophy of fat 0 0.1 1.0 10.0 Loss of body condition and/or roughened and dirty hair 0 0.1 1.0 10.0 Exudate within external ear canals 0 0.1 1.0 10.0 Aoscess at base of incisor or -olar tooth 0 0.1 1.0 10.0 DeeuBitus ulceration and scab formation of feet 0 0.1 1.0 10.0 Second set of incisors posterior to the normal set 0 0.1 1.0 10.0 Tapeworm cysts scattered throughuut peritoneum and omentum 0 0.1 1.0 10.0 Vellowlsn, purulent inflammatory material occluding ear canal 0 0.1 1.0 10.0 0-8 Weeks 1 0 0 3 8-Week Interim Kill 0 0 0 1 8-14 Weeks 0 0 1 1 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill Results 6 10 6 10 5 10 5 10 0--1 01 ---4 04 -- 1 3 04 1 00" 0 1 0-- 1 1 2 _ -202 --0134 000"1 1 0_ 01 1 --- 10 1 --112 4 000 00 0_ .1 1 2 ---000 -- 102 3 000-00 1--05 6 ---04 4 --03 2 5 000 33 0--01 1 ---000 - -0000 000-00 0_-01 1 -- -1 01 -- 01 2 3 01 0-01 0--000 -- -0 0 0 -- 00 1 1 0 O' 0 - 0 0 0- - 0 0 0 ---000 --0000 000-1 1 1--0 0 1 --- 0 00 --0000 000--0 0 '"17op dose rabbits (10 ppm) were -only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none examined or not applicable. 00 1 c'-0 NF Op7 -117- TABLE 12 (Continued) Jin gnosis Code F-6 F-8 f-i: F-13 F-li G- 3 0-i G-5 Is- 8 l>9 subchronic inhalation reproductive toxicity and recovery study OF DBCP IN RATS AND RABBITS CROSS PATHOLOGIC OBSERVATIONS ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKS8 AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Number of rabbits per group Exposure Level (ppm) 0 0.1 1.0 10.0 GASTROINTESTINAL SYSTEM Absence or decreased normal lngesta In gastrointestinal tract 0 0.1 1.0 10.0 Small intestinal nass(es) or nodule(s) 0 0.1 1.0 10.0 MassCes) or nodule(s) in stomach 0 0.1 1.0 10.0 Dark area or focus on gastric mucosa, suggestive of henolyzed blood ^dsixed with bile 0 0.1 1.0 10.0 Pinpoint dark foci on stomach r.ucosa 0 0.1 1.0 10.0 i_v:zr Diffuse paleness of liver 0 0.1 1.0 10.0 Accentuated lobular pattern of 1 Ivl'T 0 0.1 1.0 10.0 Few small pale foci or focus in liver 0 0.1 1.0 10.0 Darkened or congested liver 0 0.1 1.0 10.0 Firm, liver 0 0.1 1.0 10.0 0-8 Weeks 1 0 0 3 8-Week Interim Kill 0 0 0 1 8-14 Weeks 0 0 1 1 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill Results 6 10 6 10 5 10 5 10 0--00 0 ---00 0 --1001 100"0 1 0--00 0 .--1 01 -- 000 0 000-00 0_-01 1 .- -0 0 0 --0000 00 0-0 0 0--00 0 ---00 0 -- 100 1 00 0"0 0 0- - 00 0 ---00 0 -- 0 00 0 0 0 1-0 1 0-- 000 --00 0 *- 0000 001-01 0- -000 ---000 --001 1 000-00 0-- 00 0 -- - 00 0 --001 1 000- 00 0-- 00 0 --- 1 0 1 --1 01 2 010-- 1 0.-000 ---101 --101 2 00 0- 0 0 aTop dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none examined or not applicable. r-M-inoJTI?!! no CONFTDFN1 T Al -118- TABLE 12 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS CROSS PATHOLOGIC OBSERVATIONS ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKS3 AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Diagnosis Code G-ll C-12 013 OH 015 C-lh H-- 3 H-8 H-9 I'-IO Number of rabbits per group Exposure Level (ppm) 0 0.1 1.0 10.0 LIVER (cont'd) Adhesions and/or Inflammation of liver capsule 0 0.1 1.0 10.0 White focus (i) in subcapsular region 0 of liver, suggestive of parasitic 0.1 lesion(s) 1.0 10.0 White focus(i) on liver capsule, suggestive of fibrous connective tissue 0 0.1 1.0 10.0 Friable liver 0 0.1 1.0 10.0 Finely nebular surface of liver 0 0.1 1.0 10.0 \trcphied liver (decreased size) 0 0.1 1.0 10.0 I'lO'.PHORniC.'IaVR SYSTEM i.nlarged axillary lymph node(s) 0 0.1 1.0 10.0 Tan appearance of axillary lymph node (s) 0 0.1 1.0 10.0 Fnlarged thoracic lymph node(s) 0 0.1 1.0 10.0 Fder-.a of thoracic lymph node(s) 0 0.1 1.0 10.0 0-8 Weeks 1 0 0 3 8-Week Interim Kill 0 0 0 1 8-14 Weeks 0 0 1 1 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill Results 6 10 6 10 5 10 5 10 0 01 1 000 0000 0 0 00 0 000 01 1 00 0 0 000 11 0 000 000 0000 0 0 11 0 000 000 000 0 01 0 01 0 000 101 0000 000 00 0 000 10 1 1 001 000 00 0 101 000 01 0 1 000 00 0 101 000 0000 0 0 00 0 000 000 01 01 0 0 00 0 000 000 0101 0 0 00 aTop dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none examined or not applicable. pt-i rr'fCinq'rw on C ONF TOFNT T Al -119- TABLE 12 (Continued) 0 1 Ji gnosis Code 1-3 2 *" i :-5 i-i L-6 L-9 L-11 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY 0? DBCP IN RATS AND RABBITS CROSS PATHOLOGIC OBSERVATIONS ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Number of rabbits per group MUSCULOSKELETAL SYSTEM Nodule on mandible consistent with an abscess Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0-8 Weeks 1 0 0 3 8-Week Interim Kill 0 0 0 1 8-14 Weeks 0 0 1 1 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill Results 6 10 6 10 5 10 5 10 0 -01 1 ---00 0 --011 2 0 00"0 0 Hock joint swollen and arthritic due to an inflammatory reaction 0 0.1 1.0 10.0 0-01 1 ---000 -- 000 0 000-0 0 Ceneralired atrophy of muscle Edema of bind limb muscles 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 _01 1 ---00 0 --001 1 000-0 0 0*_ 000 .--101 -*0 00 0 000-00 MALE REPRODUCTIVE SYSTEM Decreased site of testicle(s) with or without minerallike lesions 0 0.1 1.0 10.0 0-_11 2 -- 101 --04 2 6 111 58 Dark ton appearance of testes 0 0.1 1.0 10.0 0.000 -- - 00 0 - -0 3 1 4 000 " 5 5 Ed&satous appearance of testes 0 0.1 1.0 10.0 0 _011 ---000 -- 000 0 000-0 0 Enlarged prostate 0 0.1 1.0 10.0 0*-01 1 - *-00 0 --000 0 0 0 0 ** 0 0 Edematous appearance of prostate 0 0.1 1.0 10,0 0--01 1 ---00 0 -* 001 1 000- 1 1 Absence or severe atrophy of One t S t iS 0 0.1 1.0 10.0 0.00 0 - - - 0 0 0 -*001 1 000-00 JTop dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none examined or not applicable. 'r^WNTlM. no CONFTDFNTTAt -120- TABLE 12 (Continued) diagnosis Code L-12 L-13 L-14 L-15 L-lb I * 17 L-13 M-l M-2 M-5 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS CROSS PATHOLOGIC OBSERVATIONS ON MALE RABBITS EXPOSED FOR UP TO 14 KEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Number of rabbits per group MALE REPRODUCTIVE SYSTEM (cont'd) Flaccid tcsticle(s) Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Decreased size of prostate 0 0.1 1.0 10.0 Prostate - flaccid 0 0.1 1.0 10.0 Dark appearance of prostate 0 0.1 1.0 10.0 Prostate - filled with a .cilovlsh fluid 0 0.1 1.0 10.0 Decreased size of epididymis(ides) 0 0.1 1.0 10.0 Testicle - mottled in color with vollow to tan colored streaks 0 0.1 1.0 10.0 0-8 Weeks 1 0 0 3 8-Week Interim Kill 0 0 0 1 8-14 Weeks 0 0 1 1 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill Results 6 10 6 10 5 10 5 10 0 -. 01 1 ---10 1 --1 22 5 000"5 5 0 _000 --- 10 1 * _021 3 001-3 4 0 _000 * -*00 0 --011 2 0 00 44 0 _- 00 0 .--00 0 --0000 000-1 1 0-. 00 0 _ -- 00 0 - *0 00 0 000-1 1 0--00 0 _ --00 0 - -000 0 011 -0 2 0-.101 - *- 00 0 --000 0 000-0 0 RESPIRATORY SYSTEM Dark or red focus(i) in lungs Few pale foci in lungs "at tied appearance of lungs 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0--31 4 ---2 4 6 --033 6 000-4 4 0-*00 0 ---01 1 -. 000 0 000-0 0 0-.000 -*-01 1 -002 2 011-02 ''lop dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none examined or not applicable. r-T.v f?NnnFNTW no 131031 CONFIDFNl TAl  -121- TABLE 12 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS CROSS PATHOLOGIC OBSERVATIONS ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY i Diagnosis Code M-6 M-7 :'-8 V-9 M-10 - 1 1 m-i: N-14 N-15 N-lb Number of rabbits per group RESPIRATORY SYSTEM (cont'd) Mucopurulent or caseopurulent exudate in turbinates Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Erosion or necrosis of nasal turbinates 0 0.1 1.0 10.0 Lung nodule(s) consistent with abscess(es) 0 0.1 1.0 10.0 Fibrinous or fibrous pleural aches ions 0 0.1 1.0 10.0 Pulmonary atelectasis 0 0.1 1.0 10.0 iiypercmic and/or congested appear.mce of nasal turbinates 0 0.1 1.0 10.0 Darkened, congested, consolidated. and/or edematous appearance of lungs due to pneumonia 0 0.1 1.0 10.0 Severe absecssation of thoracic cavitv <ind lung 0 0.1 1.0 10.0 Red and hemorrhagic appearance of tracnoa 0 0.1 1.0 10.0 Suppurative exudate in bronchi 0 0.1 1.0 10.0 0-8 Weeks 1 0 0 3 0 1 0 - - 0 0 - - 0 0 1 0 1 0 1 0 1 0 - 0 0 - 0 0 - 0 8-Week Interim Kill 0 0 0 1 8-14 Weeks 0 0 1 1 ---1 10 _--1 00 - a--0 11 .--0 00 __ --0 01 ---0 01 -- --1 00 _- --0 01 -- --1 00 _ -- -1 00 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill Results 10 6 10 p 10 5 10 1 3l 4 12 3 438 13 21 3 02 2 22 5 1 1 0I 1 000 01 1 *02 0\ 1 000 000 -61 1 01 000 123 -02 101 303 202 -02 00 0 000 00 1 -01 00 0 101 01 1 -01 000 000 00 1 -0 0 000 000 001 -00 ,1Top dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none examined or not applicable. 03V/ CONFIDENTIAL DO 13KS3? CONFtOFNTTAl -122- TABLE 12 (Continued) Jiajnosis Code ?-7 ?-8 ?-9 r-io ?-n P-12 r-13 P-14 P-13 P- lb SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS CROSS PATHOLOGIC OBSERVATIONS ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKS0 AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Number of rabbits per group URINARY SYSTEM Focal dark depressed foci or area(s) in kidnev Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Dilated renal pelvis(es) (hydronephrosis) 0 0.1 1.0 10.0 Mottled appearance of kidney(s) 0 0.1 1.0 10.0 Cvst(s) in kidney 0 0.1 1.0 10.0 Hvpert'nic appearance of blood vessels oi urinary bladder 0 0.1 1.0 10.0 Polvpoid mass in bladder 0 0.1 1.0 10.0 Focal henorrnagic areas on urinary bladder mucosa 0 0.1 1.0 10.0 Subcapsular white focus(i) in kidney 0 0.1 1.0 10.0 livdroureter 0 0.1 1.0 10.0 Firm kidneys 0 0.1 1.0 10.0 0-8 Weeks 1 0 0 3 8-Week Interim Kill 0 0 0 1 8-14 Weeks 0 0 1 1 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill Results 6 10 6 10 5 10 5 10 0.-01 1 --- 00 0 - 0123 000-0 0 0 _.00 0 - --00 0 --0000 000-1 1 0 a. - 0 0 0 ---0 0 0 --000 0 000-2 2 0--00 0 ---00 0 -- 000 0 000-1 1 0-_00 0 ---01 1 --000 0 000-00 0_ 00 0 ___01 1 --000 0 0 00-0 0 0 -. 0 0 0 ---00 0 --001 1 000-0 0 0 000 ---00 0 - a- 001 1 000-0 0 0_ 00 0 ---00 0 --000 0 000-1 1 0. 000 -*-00 0 --000 0 000-1 1 '"'lop dose rabbits (10 ppr.) were only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none examined or not applicable. rvf wirigriffiai on T0FN'f^1 OONF -123- TABLE 12 (Continued) Diagnosis Code P-17 r-is r-:o r-:i i>8 1-11 1: 'M3 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCF IN RATS AND RABBITS CROSS PATHOLOGIC OBSERVATIONS OS MALE RABBITS EXPOSED FOR UP TO 14 WEEKS* AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Number of rabbits per group Exposure Level (ppm) 0 0.1 1.0 10.0 URINARY SYSTEM (cont'd) Kidneys - Irregular surface pitted with white fibrous connective tissue extending from capsule into cortex 0 0.1 1.0 10.0 Pitted kidney cortex suggestive of nosenatosis 0 0.1 1.0 10.0 Roughened or irregular appearance of kidnevs 0 0.1 1.0 10.0 Mass or nodule involving kidney 0 0.1 1.0 10.0 INTEGUMENT AND SUBCUTANEOUS Subcutaneous edena 0 0.1 1.0 10.0 Supcutaneous abscess 0 0.1 1.0 10.0 Subcutaneous region containing -uppuratlve necrotic debris and fluid suggestive for suppurative Inf lactaation 0 0.1 1.0 10.0 Edema and fluid of the scrotal sac 0 0.1 1.0 10.0 0-8 Weeks 1 0 0 3 8-Week Interim Kill 0 0 0 1 8-14 Weeks 0 0 1 1 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill Results 6 10 6 10 5 10 5 10 0--00 0 - - - 0 0 0 - -000 0 0 0 0 *- 1 1 0-- 00 0 - --0 0 0 --0000 1 00-01 0.- 000 ---000 - - 0 00 0 000-11 0-. 000 --00 0 - .1 001 0 00"0 0 0--00 0 _-101 --0000 0 00 - 0 0 0_ 000 ---000 -- 100 1 000"00 0-- 000 *--000 --0000 001 01 0*-00 0 --- 101 - - 000 0 0 00-00 'lap dose rabbits (10 ppm) were only exposed for 8 weeks end held for 38 weeks of recovery. - Indicates none examined or not applicable. V/r,r. Lr _ CONFIDENTIAL DO 131534 CONFTDFNT TAl 124- TABLE 13 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND number of TISSUES EXAMINED ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKS'* AND THEN HELD FOR 32 WEEKS OF RECOVERY Diagnosis Code A-l A-2 r-i 711-1 711-2 Til-3 PC-1 Number of rabbits per group ENDOCRINE SYSTEM Adrenals Number of tissues examined No visible lesions Malignant lsrr.phona, secondary site - bilateral Pi cuicarv Clnnd Number c: tissues examined \o visible lesions TV'-toU eland Nu-.oet of tissues examined No visible lesions Colloid cyst - focal, slight Atrophv with decreased secretory contents - bilateral, moderate Parathyroid Glands .'.ur.her of tissues examined No visible lesions Exposure Level (pph) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0-8 Weeks 1 0 0 3 8-Week Interim Kill 0 0 0 1 8-14 Weeks 0 0 1 1 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill Results 6 10 6 10 5 10 5 10 10006 7 00 001 1 00 100 1 30104 8 1 _67 -- --1 1 -- 0-. 0 3- 1 48 0 _00 -__.0 0 a- - 1 .-1 0- 0 00 100067 000000 00 1 0 0 1 30 104 8 1__.6 7 - - . -- _ -- 1-_ 1 3- 1-4 8 10006 7 000000 0 0 1 00 1 300058 1-_ .5 6 - - - - -- 1 -- 1 3---4 7 0._ 11 -- - w - * 0 * a- 0 0- --0 0 0__ *_ 00 _ -- 0 -. 0 0---1 1 00001 1 00000 0 000000 10002 3 -___1 1 -- -*.. --. _ _ 1- -- 1 2 ^Top dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none examined or not applicable. 00 131.B35 OONF TDFNT T A; 'Tuim -125- TABLE 13 (Continued) Diagnosis Code PC-2 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCF IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKS" AND THEN HELD FOR 32 WEEKS OF RECOVERY Number of rabbits per group Exposure Level . (pp") 0 0.1 1.0 10.0 ENDOCRINE SYSTEM (cont'd) Parathvroid Glands (cont'd) Ectopic parathyroid tissue, thymus region, otherwise no visible lesions 0 0.1 1.0 10.0 0-8 Weeks 1 0 0 3 8-Week Interim Kill 0 0 0 1 8-1* Weeks 0 0 1 1 14-Week Interim Kill 3 * 4 0 Terminal Cumulative Kill Results 6 10 6 10 5 10 5 10 _ 00 -- . --. -- - -- - 0* --11 5G-1 rs-i LS - 5-1 s-: GASTROINTESTINAL SYSTEM Salivnrv Glands N'um.oer of tissues examined 0 10006 0.1 0 0 0 0 0 1.0 0 0 1 0 0 10.0 3 0 1 0 5 So visible lesions 0 1--- 6 0.1 - - - . 1.0 - - 1 . 10.0 3 - 1 - 5 Fsonh.icus Number o: tissues examined No visible lesions 0 10 005 0.1 0 0 0 0 0 1.0 0 0 0 0 0 10.0 2 0 1 0 5 a0 1- ._4 0.1 - - - - - 10.0 2 - 1 - 5 Suoocu to inf lama cion, muscular is 0 0 1 - multifocal, slight 0.1 - - - - - 1.0 - - a- - - 10.0 0 - 0 - 0 Stn-.ich - Number of tissues examined 0 10005 0.1 0 0 0 0 0 1.0 0 0 1 0 0 10.0 2 0 0 0 5 No visible lesions 0 1_ 4 a0.1 - _ ._ 1.0 - - 1 _ _ 10.0 2 - - - 5 Reactive hyperplasia with associated 0 0_ acute Inflammation, edema and multi- 0.1 - _ _ 1 _ focal necrosis, submucosal and 1.0 . 0 mucosal edema, severe. Erosions, 10.0 0 - -0 gastric mucosa, multifocal moderate. Fibrin thrombi in blood vessels, - multifocal nTop dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none examined or not applicable. 7 0 1 9 7 . 1 9 6 0 0 8 5 - 8 1 * 0 6 0 1 7 5 _ 1 7 1 0 0 nn"/ mqnnFNTW r)0 131536 OONFTDFNTTAi -126 TABLE 13 (Continued) Diagnosis Code SI-1 LI-1 SR-i SR-2 CB-1 GB-2m SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS H~~ISTOP-E-AX--TP-H-O-OSEWLDOGVFICOWROrUBrPvSELTRTOVAW1T4IONrWS.E^EAKaNSD NUMBER OF TISSUES AND >TrHuE--Ne uHEnLrD. rFnOnR EXAMINED a3n2 tW.TEEriK/cS ON nOFr MALE RABBITS uRErmCOuVrEuRvY Number of rabbits per group GASTROINTESTINAL SYSTEM (cont'd) Small Intestine Number of tissues examined Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Larne Intestine Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 ficculus Kotur.dus '.umoer of tissues examined 0 0.1 1.0 10.0 'o visible lesions 0 0.1 1.0 10.0 Cranulomata and histiocytosis, submucosa - multifocal 0 0.1 1.0 10.0 Gallbladder Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Subacute inflammation, submucosa - diffuse, moderate 0 0.1 1.0 10.0 LIVER - Number of tissues examined 0 0.1 1.0 10.0 0-8 Weeks 1 0 0 3 8-Week Interim Kill 0 0 0 1 8-14 Weeks 0 0 1 1 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill Results 6 10 6 10 5 10 5 10 1 00056 00 00 0 0 001 001 301 05 9 1 --- 5 6 --*- --1-"1 3- 1 -5 9 1 0 005 6 00 00 0 0 00 1 00 1 301 048 1* -56 -- -- - - -- 1 - - 1 3*1-48 1 0005 6 000000 00 00 00 000055 0--- 5 5 -- -------" *- -- 5 5 1--- 01 -- - - - --- - --- 0 0 000044 00000 0 000000 30005 B ----3 3 ---" " *----- 3---5 8 _ *- - 1 1 - -- - -- -- - 0---0 0 1 0 0 3 6 10 0 0 0 4 6 10 0 0 1 4 5 10 3 1 1 0 5 10 Top dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none examined or not applicable. DO 13153? P'v'! prr.'rinruTjm CONFIDFNTTA! -127- TABLE 13 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RABBITS I EXPOSED FOR UP TO 14 WEEKSa~AND THEN HELD FOR 32 WEEKS OF RECOVERY Diagnosis Code L-l L-lvs L-2s L-'!5 L-3"> L-3-- L*-Vs L-is L-5s Number of rabbits per group LIVER (cont'd) No visible lesions Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0--8 Weeks 1 0 0 3 8-Week Interim Kill 0 0 0 _L. 8-14 Weeks 0 0 1 1 14-Week Interim Terminal Cumulative Kill 3 fill ... Results 1 6 10 4 !6 45 10 10 0 ______________ 10 0.-0 00 ---02 2 --0000 100T 1 2 Vacuolization of hepatocytes, con- 0 0- - 0 0 0 sistent with fatty change 0.1 - - - 1 0 1 - very slight 1.0 - - 0 0 0 0 10.0 0 0 0 - 0 0 Vacuolization of hepatocytes, con- 0 1 * - 001 sistent with fatty change 0.1 - - - 0 2 2 - slight 1.0 - - 0 0 1 1 10.0 0 1 0 - 0 1 Vacuolization of hepatocytes, con- 0 0 - . 3 I0 3 sistent with fatty change 0.1 - - - 3 0 3 - moderate 1.0 - - 1 4 0 5 10.0 1 0 0 " 0 1 Aggregates of mononuclear predora- 0 1__102 inanely lymphoid cells 0.1 - - - 2 0 2 - slight 1.0 - - 0 1 0 1 10.0 0 0 0 00 Aggregates of mononuclear predom- 0 0 202 inantly lynphoid cells 0.1 - - - 0 0 0 - moderate 1.0 - - 1 1 0 2 10.0 0 0 0 - 0 0 Subacute inflammation, periportal 0 0- 000 - multifocal, very 0.1 - - * 0 1 1 slight 1.0 - - 0 0 1 1 10.0 0 0 0 - 0 0 Subacute inflammation, periportal 0 0-_02 2 - multifocal, slight 0.1 - - - 0 1 1 1.0 - - 0 0 0 0 10.0 0 0 0 - 1 1 Subacute inflammation, periportal 0 0__ 04 4 - multifocal, moderate 0.1 - * - 0 0 0 1.0 - - 0 0 3 3 10.0 0 0 0 - 3 3 Subacute inflammation within lobule 0 0__01 1 - multifocal, slight 0.1 - - - 0 0 0 1.0 - - 0 0 1 1 10.0 0 0 0 - 0 0 nTop dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none examined or not applicable. ' n'vrvrriiTim . fj U)NF f OF NT T A! -128- TABLE 13 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKS AND THEN HELD FOR 32 WEEKS OF RECOVERY Diagnosis Code L-15 L-9s L-6s L-12 L-13 L-7i L-8 L-lOs L-14 Number or rabbits per group LIVER (cont'd) Subacute inflammation, centrl lobular - multifocal, slight Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Subacute inf lamination with focal fibrosis - slight 0 0.1 1.0 10.0 Centrilobular congestion with or 0 without hepatocellular degenera- 0.1 tion, multifocal coagulation 1.0 necrosis and slight mononuclear and 10.0 polymorphonuclear inflammation Diffuse congestion 0 0.1 1.0 10.0 Consolation necrosis - focal 0 0.1 1.0 10.0 3illary hyperplasia - focal, slight Cranulomata with mineralization, probably parasitic in origin - slight 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Dilated (telangiectatic) sinusoids , subcnpsular region 0 0.1 1.0 10.0 Fibrinous adhesions, capsular surface - focal, slight 0 0.1 1.0 10.0 PANCREAS - Number of tissues examined 0 0.1 1.0 10.0 0-8 Ueeks 1 0 0 3 8-Week Interim Kill 0 0 0 1 8-14 Weeks 0 0 1 1 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill Results 6 10 6 10 5 10 5 10 0_ 000 -* . 000 * 001 1 00 0*00 0 _000 ---000 -- 001 1 000-00 0__000 --- 1 01 --001 1 000-00 0__000 -- -0 00 -- 0000 101-02 0_ _ 0 00 -- -000 -- 0000 10 0-01 0_ 000 -- -101 -- 0000 00 0-00 0__000 - *- . 0 1 1 -- 0000 000-1 1 0_ 000 -- - 00 0 --001 1 00 0-0 0 0_ 000 -- -00 0 --0000 000-1 1 10006 7 00 000 0 00 1 00 1 301059 aTop dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none examined or not applicable. Dn 131539 f.ONF TDFNT T A! -129TABLE 13 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKS** AND THEN HELD FOR 32 WEEKS OF RECOVERY Diagnosis Code PA-1 TR-1 T"5- 2 s TR-3 7K-* TRo NT-1 NT-2 s Number of rabbits per group PANCREAS (cont'd) No visible lesions Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 RESPIRATORY SYSTEM Trachea - Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Aggro cates of mononuclear predominantiv 1\--phoid cells, submucosa - multifocal, slight 0 0.1 1.0 10.0 Chronic active tracheitis 0 0.1 1.0 10.0 Suppurative necrotizing tracheitis 0 0.1 1.0 10.0 Mild acute tracheitis 0 0.1 1.0 10.0 Nasal Turbinates Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Aggregates of mononuclear predominantly lvnphoid cells, submucosa - multifocal, slight 0 0.1 1.0 10.0 0-8 Weeks 1 0 0 3 8-Week Interim Kill 0 0 0 1 8-14 Weeks 0 0 1 1 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill Results 6 10 6 10 5 10 5 10 1---6 7 -- - - " " -- 1-" 1 3" 1- 5 9 10006 7 00 0000 00 1 0 0 1 30105 9 1---5 6 -----" -- 0-w 0 1 1-46 0---1 1 - - -- - --0-- 0 0- 0-1 1 0- --0 0 -"-- * --1-- 1 0- 0-0 0 0- - - 0 0 ----- -- 0-- 0 1- 0-0 1 0- --0 0 ----- -- 0-- 0 1- 0-01 10006 7 00000 0 00000 0 2000 S 7 0- - - 0 0 0---1 1 1_ 67 -- - *- - ----- - 0--- 4 4 LlTop dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none examined or not applicable. rm-M 00 131540 OONFtnFNTTAl -130- TABLE 13 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKSa AND THEN HELD FOR 32 WEEKS OF RECOVERY Diagnosis Code NT-3s XT-As NT-5 s NT- 5m NT-5scv `.T'-'ira NT-fixuv Ll-1 LI-2 s Number of rabbits per group Exposure Level (ppm) 0 0.1 1.0 10.0 RESPIRATORY SYSTDI (eont'd) Nasal Turbinates (eont'd) Acute inf lamation with associated foreign body - focal, slight 0 0.1 1.0 10.0 Focal ulcer with chronic active infIntimation, mucosa and submucosa - slight Suppurative inflammation - slight Suppurative inflammation - moderate 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 Suppurative inflammation - severe 10.0 0 0.1 10.0 Suppurative necrotizing rhinitis - moderate Suppurative necrotizing rhinitis - severe !unes - Number of tissues examined No visible lesions 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Aiy^rc^aies of tnononuclear predom*inanely lymphoid cells, peribronchial - multifocal, slight 0 0.1 1.0 10.0 0-8 Weeks 1 0 0 3 8-Week Interim Kill 0 0 0 1 8-14 Weeks 0 0 1 1 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill Results 6 10 6 10 5 10 5 10 0 _1 1 -._ _ - _ r - -- 0-"-00 0 11 -. - - - - - --- - - 0-- - 0 0 0 11 ------- --- - 0---0 0 0 11 ----- - 0---00 0__ 00 -- - --- 0---1 1 0___0 0 -- --- -----1---01 0_ __0 0 - - -- - _ - _ - 1---0 1 1001 68 00010 1 00102 3 3 1 1 0 5 10 0 _000 ---0- 0 --0*0 0 100-01 1 067 ---0 0 --0*00 00 0- 5 5 Top dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none examined or not applicable. I ft AM DO 131541 CONFTDFN7 T Al -131- TABLE 13 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKS AND THEN HELD FOR 32 WEEKS OF RECOVERY Diagnosis Code LU-3 Ll*-6 LI-9 LL'-*4 s I I.`J-5scv 7 L'.'-d LC-10s r:;-i Number of rabbits per group Exposure Level (ppm) 0 0.1 1.0 10.0 RESPIRATORY SYSTEM (cont'd) Luncs (cont'd) Bronchopneumonia and/or bronchio- litis - focal or multifocal 0 0.1 1.0 10.0 Suppurative necrotizing bronchopneumonia - multifocal, severe 0 0.1 1.0 10.0 Interstitial pneumonia 0 0.1 1.0 10.0 Subacute inflammation - multifocal, slight 0 0.1 1.0 10.0 Abscess iotttjLion 0 0.1 1.0 10.0 Atelectasis - multifocal 0 0.1 1.0 10.0 Suppurative necrotizing pleuritis 0 o.l 1.0 10.0 Microzranulonata - multifocal, slight 0 0.1 1.0 10.0 NTRVOUS SYSTEM Peripheral Nerve Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 1.0 10.0 0-8 Weeks 1 0 0 3 8-Week Interim Kill O 0 0 1 8-14 Weeks 0 0 1 1 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill Results 6 10 6 10 5 10 5 10 0..101 ---0 0 --0-00 00 0" 2 2 0 000 ---1- 1 -- 1-01 100-01 0--00 0 -* - 0 - 0 -- 0- 0 0 1 0 0-0 1 0--03 3 ---0- 0 -- 0-0 0 000-2 2 0-.0 1 1 ---1-1 --0-2 2 010-12 0_ 000 ---0-0 .- 0- 0 0 1 0 0 - 0 .1 0--000 ---0- 0 -- 0-0 0 101-0 2 0_ _00 0 ---0- 0 --0-0 0 000-1 1 10004 5 000000 001001 101035 1---45 * 1II1 1-1-35 aTop dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none examined or not applicable. no 13154? OONFTDFNTTAl nn\f/ r'VJrinrMTp? 132- TABLE 13 (Continued) subchronic inhalation reproductive toxicity and recovery study OF DBCF IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKSJ~~AND THEN HELD FOR 32 WEEKS OF RECOVERY Diagnosis Code SC-1 3-1 > 2- 3s V-s S"-l SM-2s Number of rabbits per group NERVOUS SYSTEM (cont'd) SDinal Cord Number of tissues examined Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 No visibl e lesions 0 0.1 1.0 10.0 Brain - Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 1.0 10.0 Chronic active meningitis and enceph- 0 alitis, secondary to middle ear 0.1 infection 1.0 10.0 Subacute inf lamination, perivascular - nultifocal, slight 0 0.1 1.0 10.0 'llal nod u les - multifocal, slight 0 0.1 1.0 10.0 vY5CYLO.SKELETAL SYSTEM k t* 1 L't *11 Nuscle NumDcr of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Atrophy - slight 0 0.1 1.0 10.0 0-8 Weeks 1 0 0 3 8-Week Interim Kill 0 0 0 1 8-14 Weeks 0 0 1 1 14-week Interim Kill 3 4 4 .0 Terminal Cumulative Kill Results 6 10 6 10 5 10 5 10 100056 0000 00 000000 2000 35 1 ---5 6 " 2 - 35 100067 0 000 0 0 001001 30105 9 0--- 2 2 1_1 3-1- 3 7 1 -_ 01 -- -- - - --0-- 0 0- 0-0 0 0.- 44 -*-- - - -0-- 0 0*0- 2 2 0_ 00 ---- - - - -0.- 0 0-0-2 2 1 0005 6 0000 00 00100 1 3000 5 8 1---4 5 _1 _1 3--- 5 8 0---1 1 *---- --0-- 0 0 - - e- 0 0 ''Toji dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none examined or not applicable. DO 131540 CONF T DFN7 TAI -133- TABLE 13 (Continued) Diagnosis Code VB-1 Y3M-1 7F,M-2 M-l KK-lsev SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RABBIT! EXPOSED FOR UP TO 14 WEEKS'* AND THEN HELD FOR 32 WEEKS OF RECOVERY Number of rabbits per group MUSCULOSKELETAL SYSTEM (cont'd) Vertebral Bono Number of tissues examined Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 No visible lesions 0 0.1 Vertebral Bone Marrow Number of tissues examined 10.0 0 0.1 1.0 10.0 No visible lesions 0 0.1 Vveloid hyperplasia 10.0 0 0.1 1.0 10.0 Mandible - Number of tissues examined 0 0.1 1.0 10.0 Abscess 0 0.1 10.0 Hock - Number of tissues examined 0 0.1 1.0 10.0 Chronic active inflammation with a ns cess formation - diffuse, severe 0 0.1 1.0 10.0 URINARY SYSTEM Kidneys - Number of tissues examined 0 0.1 1.0 10.0 0-8 Weeks 1 0 0 3 0 0 0 0 - - 0 0 0 0 " - - 0 0 0 0 " - 0 0 0 0 . * " 8-Week Interim Kill 0 0 0 1 8-14 Weeks 0 0 1 1 00 00 00 00 -"- -- 00 00 00 00 --- -- ---"- 00 00 00 00 --- -- 00 00 00 00 -_ --- - 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill Results 6 6 i5 10 10 10 5 10 ' 055 000 000 044 -55 ---" -44 05 5 000 000 04 4 -4 - !" 4 -- -44 -11 -" --00 01 1 000 000 000 -1 1 -"- --- 01 1 000 00 0 000 _1 1 -- --- --- 1 0 0 3 6 10 0 0 0 4 6 10 0 0 1 4 5 10 3 1 1 0 5 10 'top dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none examined or not applicable, no 101544 C'ONFTDFNTTAl -m 11 a ^ 1 * -134- TABLE 13 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RABBITS EXPOSED FOR UP TO 14 MEEKS AND THEN HELD FOR 32 WEEKS OF RECOVERY Diagnosis Code K-l K-5. K-5m K-3s f.-3a K- A s K-?s K-6 Exposure Level ______ ___________________________________ (PPiQ___ Number of rabbits per group 0 0.1 1.0 10.0 URINARY SYSTEM (cont'd) Kidnevs (cont'd) No visible lesions 0 0.1 1.0 10.0 Mineral deposits, renal pelvis 0 - unilateral or bilateral , 0.1 focal or multifocal, 1.0 slight 10.0 Mineral deposits, corticomedullary 0 iunction - unilateral or bilateral , 0.1 multifocal 1.0 10.0 Subacute Inflammation, interstitium, with or without fibrosis - multifocal, slight 0 0.1 1.0 10.0 Subacute Inflammation, intersititum. with or without fibrosis - multifocal, moderate 0 0.1 1.0 10.0 i-vdronephrosls - unilateral, severe 0 0.1 1.0 10.0 Dilated renal tubules with eosinopill 1 icast formation - multifocal, slight 0 0.1 1.0 10.0 Cyst, cortex - multifocal, slight bilateral. 0 0.1 1.0 10.0 Malignant lymphoma, secondary site 0 0.1 1.0 10.0 Urlnarv Bladder Number of tissues 0 0.1 1.0 10.0 0-8 Weeks 1 0 0 3 8-Week Interim Kill 0 0 0 1 8-14 Weeks 0 0 1 1 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill Results 6 10 6 10 5 10 5 10 0--2 1 3 ---2 13 --0202 301-04 1- -00 1 ---02 2 --0000 010"2 3 0--00 0 ---02 2 --013 4 000-1 1 0-_15 6 ---24 6 -- 02 5 7 01 0-3 4 0 _000 -- -00 0 -- 000 0 000-1 1 0__000 ---000 -- 000 0 000-1 1 0 _ a. 1 0 1 -*-000 --0000 000-00 0__000 -- -0 0 0 --0000 000-1 1 0- - 0 0 0 ---000 *-100 1 0 00- 0 0 1 0 005 6 00 00 1 1 00102 3 11 1 058 ^Top dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none examined or not applicable. T-H) 1 .'11845 rONFTOFNTTAi -135- TABLE 13 (Continued) Diagnosis Code UB-1 UB-:s 15-3s 13* 3m l 5-4 sev I/B-oti Vb-3sov VB-*n L 5* Sl*v U b- 7 k SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKS*" AND THEN HELD FOR 32 WEEKS OF RECOVERY Xumoer of rabbits per group URINARY SYSTEM (cont'd) Urlnarv Bladder (cont'd) No visible lesions Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Aggregates of mononuclear predominantly lymphoid cells - multifocal, slight 0 0.1 1.0 10.0 Subacute inflamnation, mucosa and submucosa - multifocal, slight 0 0.1 1.0 10.0 Subacute Inflaraation, mucosa and Durnucosa - multifocal, moderate 0 0.1 1.0 10.0 Cnronic active Inflammation, mucosa And submucosa - severe 0 0.1 1.0 10.0 '4ema, mucosa and submucosa - moderate 0 0.1 1.0 10.0 Fdcr-a* tiucoms and submucosa - severe 0 0.1 1.0 10.0 Increased vascularity, submucosa - moderate 0 0.1 1.0 10.0 Increased vascularity, submucosa - severe 0 0.1 1.0 10.0 llvperplasla, nucosa - multifocal, slight 0 0.1 1.0 10.0 0-8 Ueeks 1 0 0 3 8-Week Interim Kill 0 0 0 1 8-14 Weeks 0 0 1 1 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill Results 6 10 6 10 5 10 5 10 1---34 - .. - - 0 0 - 1-01 111*2 5 0.* - 1 1 ---*00 --0-00 00 0* 00 0 --11 ----00 --0-00 000"00 0..-00 - e- - - 0 0 -- 0- 0 0 000" 1 1 0_..00 ----1 1 *-0-22 000* 2 2 0. - - 0 0 ---* 00 -- 0- 00 000" 1 1 0_ -00 ---- 1 1 --0- 2 2 000"2 2 0_*-0 0 ---- 0 0 --0-00 000-1 1 0---00 --- -1 1 --0- 2 2 000* 1 1 0_*-00 ----00 --0-00 000"11 ^Tnp dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. * Indicates none examined or not a ppllcable. no 131540 CONFTDFNTTAl TABLE 13 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RABBITS EXPOSED FOR UP TO 14 MEEKS'1 AND THEN HELD FOR 32 MEEKS OF RECOVERY Diagnosis Code LB-7m l'3-7scv LB-Sscv LA-1 'LA' LA-7 s L'A-2m i'A M'V LA- 3-1 Number of rabbits per group URINARY SYSTEM (eont'd) Exposure Level (ppm) 0 0.1 1.0 ______ 1S*S_____ Lrlnarv Bladder (cont'd) Hyperplasia, mucosa - multifocal, moderate 0 0.1 1.0 10.0 Hyperplasia, mucosa - multifocal, severe 0 0.1 1.0 10.0 0-8 Weeks 1 0 0 3 8-Week InterIn Kill 0 0 0 1 8-14 Weeks 0 0 1 1 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill Results 6 10 6 10 5 10 5 10 0 0 0 1 0 1 2 0 Ulceration - multifocal, severe 0 0.1 1.0 10.0 Urethra - Number of tissues examined 0 0.1 1.0 10.0 0 1 2 0 5 6 5 5 No visible lesions 0 0.1 1.0 10.0 3 3 4 2 Susaeutc lnilamation, mucosa and suomucosa - diffuse, very slight 0 0.1 1.0 10.0 0 1 0 0 Subacute inflarrniation, mucosa and sub-.ucosa - diffuse, slight 0 0.1 1.0 10.0 0 1 0 1 cute inflammation, mucosa and bmucosa - diffuse, moderate 0 0.1 1.0 10.0 1 0 0 1 Sue,Acute Inflammation, mucosa and ,ubmucosa - diffuse, severe 0 0.1 1.0 10.0 0 0 0 1 Chronic active inf lamination, rucosa and submucosa - diffuse, moderate 0 0.1 1.0 10.0 1 1 1 0 Top dose rabbits (10 ppm) were only exposed for 8 weeks and held for 3B weeks of recovery. - Indicates none examined or not applicable. 00 13104 7 OONFTDFNT T At -137- TABLE 13 (Continued) Diagnosis Code UA-4m H-l H-3 AO-1 A0-2s < SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCF IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKS AND THEN HELD FOR 32 WEEKS OF RECOVERY Number of rabbits per group URINARY SYSTEM (cont'd) Urethra (cont'd) Epithelial hyperplasia - diffuse, moderate Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 CARDIOVASCULAR SYSTEM Heart - Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Subacute inflammation, myocardium - focal, slight 0 0.1 1.0 10.0 Severe necrotizing epicarditis 0 0.1 1.0 10.0 Aorta - Number of tissues examined No visible lesions 0 0.1 1.0 10.0 0 Subacute inf lamination, subintlmal - focal, slight Vt-eenterlc Blood Vessels Number of tissues examined 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0--8 Weeks 1 0 0 3 8-Week Interim Kill 0 0 0 1 8-14 Weeks 0 0 1 1 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill Results 6 10 6 10 5 10 5 10 ----1 1 ---- 0 0 ---- 00 -"-"00 1 0 006 7 0000 0 0 001001 30105 9 1--- 5 6 - - - -- - .,1-- 1 3- 0-5 8 0-.-1 1 -- - -- -- 0--0 0- 0- 00 0- -- 0 0 ---- - -- 0--0 0- 1-01 10005 6 000000 001001 300058 1---4 5 __1_. 1 3--* 5 8 0-.-1 1 ----- --0-- 0 0---00 00000 0 00000 0 000000 30000 3 ` T.ip dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none examined or not applicable. rr'-.'i 00 131548 CONFTDFNTTAi -138- TABLE 13 (Continued) SUBCHRONIC INHALATION REPRODL'CTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKSJ AND THEN HELD FOR 32 MEEKS OF RECOVERY Diagnosis Code I3V-1 NF-1 Li'--1 EY-1 EY-2s Number of rabbits per group Exposure Level 0-8 (ppm)________ Weeks 01 0.1 0 1.0 0 10.0 3 CARDIOVASCULAR SYSTEM (cont'd) Mesenteric Blood Vessels (cont'd) No visible lesions 0 0.1 1.0 10.0 3 ABDOMINAL CAVITY Mesenteric Fat Number of tissues examined No visible lesions 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0 0 3 _ 3 iv-.encum - Number of tissues examined 0 0.1 1.0 10.0 0 0 0 0 Parasitic granulomas with calcification - r-.uitifocal 0 0.1 1.0 10.0 - - ..FAD PEGION ;..icrl-al Gland Num.oer of tissues examined Subacute inflammation Fves - Number of tissues examined 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0 0 0 - 1 0 0 3 `o visible lesions 0 0.1 1.0 10.0 1 - 3 Aggregates of mononuclear predominantJy lymphoid cells, corneal scleral junction - focal, unilateral. slight 0 0.1 1.0 10.0 0 0 8-Week Interim Kill 0 0 0 1 - 0 0 0 0 _ - 0 0 0 0 _ - 0 0 0 0 - 0 0 0 0 > - - 8-14 Weeks 0 0 1 1 * 0 0 1 0 1 - 0 0 0 0 . - 0 0 0 0 - 0 0 1 1 1 1 0 0 14-Week Interim Terminal Cumulative Kill_______ Kill Results 3 6 10 4 6 10 4 5 10 0 5 10 "* *- " " -"" 3 000 000 001 00 3 ----- 1 --3 000 000 000 011 *.-- -- -1 1 01 1 00 0 000 000 -11 -- -- --- 06 7 00 0 00 1 05 9 -5 6 ----- 1 -4 8 -1 1 -- -- 0 -1 1 aTop dose rabbits (10 ppm) were Only exposed for 8 weeks and held for 38 weeks of recovery. Indicates none examined or not applicable. DO 131549 CONFTDFNTTA1 ^'I -139- TABLE 13 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCF IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKS AND THEN HELD FOR 32 WEEKS OF RECOVERY Diagnosis Code ME-1 Number of rabbits per group HEAD REGION (cont'd) Middle Ear Number of tissues examined Severe suppurative otitis media with necrotizing inflammation of the bone Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0-8 Weeks 1 0 0 3 1 0 0 0 1 - 8-Week Interim Kill 0 0 0 1 0 0 0 0 - 8-14 Weeks 0 0 1 1 0 0 0 0 " * -- 14-Week Interim Terminal Cumulative Kill 3 Kill l Results 10 4 10 4 is 10 0 ______ 5____ 1 10 001 000 000 000 -- 1 ---- " THORACIC CAVITY' Anterior Mediastinum Nu"&er of tissues examined 0 0.1 1.0 10.0 000000 00 01 0 1 00 101 2 2000p2 AM- l->ev Abscess formation - severe, multifocal 0 0.1 1.0 10.0 _ ---- --- 1-1 --0-l 1 0 -"--0 AM-2 Localized suppurative anterior 0 a. - - - - - reaiastinltis 0.1 - - - 0 - 0 1.0 - - 1 - 0 1 10.0 0 - " "0 AM-3 No visible lesions 0 0.1 1.0 10.0 _ _.-- ---0-0 --0-00 1-"-"1 Suppurative necrotizing medlastlnltls 0 0.1 1.0 10.0 -- --- - ---0- 0 --0-00 1 --"- 1 Anterior wediastinal Fat Nur.ocr o: tissues examined 0 0.1 1.0 10.0 100001 00000 0 0 0000 0 000000 A.MF- 1 ".o visible lesions 0 0.1 1.0 10.0 1_---1 - -- -- ------ ------ JTop dose rabbits (10 ppm) were only exposed for 8 weeks end held for 38 weeks of recovery. - Indicates none examined or not applicable. '-liriifi I no loinno CONFTDFNTTAl -140- TABLE 13 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKS AND THEN HELD FOR 32 WEEKS OF RECOVERY Diagnosis Code T-1 7-2bs 7-:b,sev >3 T-4us T-ibs T-4bm Exposure Level 0-8 _________________________________ ________ ____ CeeeJ_____ Number of rabbits per group 0 Weeks 1 0.1 0 1.0 0 10.0 ______ 3____ 8-Week Interim Kill 0 0 0 1 8-14 Weeks 0 0 1 ____ 1_____ 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill Results 6 10 6 10 5 10 -3____ 10 MALE REPRODUCTIVE SYSTEM Testes - Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 1 0 O 3 6 10 0 0 0 4 6 10 0 0 1 4 5 10 3 1 1 0 5 10 1_-157 .--15 6 _-0033 000-00 Atrophy (decreased spermatogenesis) - unilateral, moderate 0 0.1 1.0 10.0 0 s- - 1 0 1 -- -0 00 .- 001 1 00 0- 00 Atrophy (decreased spermatogenesis) - bilateral, slight 0 0.1 1.0 10.0 0- -0 00 ---000 -* 100 1 00 0-00 Atrophy (decreased spermatogenesis) - bilateral, moderate 0 0.1 1.0 10.0 0- -0 0 0 -- -0 00 -- 03 1 4 00 0-00 Atrophy (decreased spermatogenesis) - bilateral, severe 0 0.1 1.0 10.0 0- -0 0 0 -- -0 00 -- 0101 3 1 1 - 5 10 Hvpoplastlc seminiferous tubules - focal 0 0.1 1.0 10.0 0--1 01 -- -0 00 -- 0000 000-00 Multinucleated spermatids - unilateral, slight Multlnucleated spermatids - bilateral, slight 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0--1 0 1 *--01 1 -- 00 00 100-01 0-.10 1 ---3 0 3 -- 1 2 03 00 0- 3 3 Multlnucleated spermatids - bilateral, moderate 0 0.1 1.0 10.0 0-- 0 0 0 ---000 -- 01 01 00 0-00 ^Top dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none examined or not applicable. r*"? vimniTui DO 131551 (' ONFTDFNTTAl -141- TABLE 13 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKSa~AND THEN HELD FOR 32 WEEKS OF RECOVERY Diagnosis Code Exposure Level (ppm) Number of rabbits per group 0 0.1 1.0 ________________________________________________ 10*0______ T-5n MALE REPRODUCTIVE SYSTEM (cont'd) Testes (cont'd) Atrophy, primarily subcapsular, probably secondary to severe stress and cachexia - bilateral, moderate 0 0.1 1.0 10.0 T-6u Necrotic debris in the lumen of the seminiferous tubules - unilateral 0 0.1 1.0 10.0 T-fib. *7* s, 7-6bn Necrotic debris in the lumen of the seminiferous tubules - bilateral 0 0.1 1.0 10.0 7-7b Increased prominence of Sertoli cells, secondary to decreased spermatogenesis - bilateral 0 0.1 1.0 10.0 T-Ss Mononuclear predominately lymphoid cell inflammation - focal, slight 0 0.1 1.0 10.0 *>9a Normal-appearing seminiferous tubules occupying less than 252 of total sections * multifocal 0 0.1 1.0 10.0 >9b Normal-appearing seminiferous tubules occupying between 25% and 507 of total sections - nultifocal 0 0.1 1.0 10.0 T-1Oui Dilated seminiferous tubules with decreased spermatic elements - unilateral, slight 0 0.1 1.0 10.0 7- Dilated seminiferous tubules with 0 J.creased spermatic elements 0.1 - bilateral, moderate 1.0 10.0 K p i d i d \t i d l- s Number of tissues examined 0 0.1 1.0 10.0 0-8 Weeks i 0 0 3 8-Week Interim Kill 0 0 0 1 8-14 Ueeks 0 0 1 1 0 0 0 00 0 0 0 00 0 1 2 00 0 1 3 11 0 00 0 0 0 00 0 0 0 00 0 0 0 00 0- 0 0 - 00 0 0 10 0 00 0 00 1 3 11 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill Results 6 10 6 10 5 10 5 10 oil 0 00 0 00 00 10 00 00 0 1 0 0 0 0 00 0 00 3 04 02 0 00 0 00 20 3 05 00 00 10 0 0 0 1 0 0 00 0 00 0 0o 33 0 00 0 00 0 00 22 0 00 0 00 Oil 00 0 00 Oil 0 00 00 3 6 10 4 6 10 4 5 10 0 5 10 `'top dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none examined or not applicable. ' M rnrMTtsi DO 13155? CONFTDFNT7A! -i4:- TABLE 13 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HI5TOPATHOLOCIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKS AND THEN HELD FOR 32 WEEKS OF RECOVERY Diagnosis Code E-l E-2 t-3u E-3"i F_-3b,sev E--us F-jus F.-6b E-7b E-8b Number of rabbits per group Exposure Level (ppm) O 0.1 1.0 10.0 MALE REPRODUCTIVE SYSTEM (cont'd) Enldidvnides (cont'd) No visible lesions 0 0.1 1.0 10.0 Sperm granuloma - focal 0 0.1 1.0 10.0 Decreased sperm in tubular lunina - unilateral 0 0.1 1.0 10.0 Decreased sperm in tubular lumina - bilateral 0 0.1 1.0 10.0 Decreased sperm in tubular lumina - bilateral, severe 0 0.1 1.0 10.0 Epithelial hyperplasia - unilateral, slight 0 0.1 1.0 10.0 Vacuolization, mucosa - multifocal, unilateral, slight 0 0.1 1.0 10.0 Decreased in site (atrophy) - bilateral 0 0.1 1.0 10.0 Increased intratubular, cellular, and/or proteinaceous debris - bilateral 0 0.1 1.0 10.0 Quest1 enable (equivocal) decrease in sperm, tubular lumina - bilateral 0 0.1 1.0 10.0 0-8 Weeks 1 0 0 3 8-Week Interim Kill 0 0 0 _____ 1_____ 6-14 Weeks 0 0 1 1 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill Results 6 10 6 10 5 10 5 10 000 0-- 0 0 00 0-- 0 000 0 0 2 11 0 0 000 0 0 0 00 0 0 0 00 0 0 110 0 -- 0 0 00 0 0 0 00 2 69 4 6 10 03 4 -00 10 00 00 0 1 0 0 0 101 0 00 0 00 00 0 00 0 00 2 02 04 0 00 0 00 0 00 55 0 00 0 00 Oil 00 0 00 0 00 0 22 00 0 00 0 00 0 00 -57 0 00 0 00 0 00 55 0 00 0 00 2 02 00 aTop dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none examined or not applicable. '>"/ prv.icinrwTm 131553 CONFTDFNTl A! -143- TABLE 13 (Continued) Diagnosis Code AS-1 ?R-1 ? X- 2 s pa-3 s ?R-4s PR- 3s PS-bs PR-7 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RABBITS EXPOSED FOR UP TO 14 KEEKS AND THEN HELD FOR 32 WEEKS OF RECOVERY .Number of rabbits per group Exposure Level (ppm) 0 0.1 1.0 10,0 MALE REPRODUCTIVE SYSTEM (cont'd) Accessory Sex Glands Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Prostate - Number of tissues examined 0 0.1 1.0 10.0 !!o visible lesions 0 0.1 1.0 10.0 Acgrogates of mononuclear predominantlv lymphoid cells, submucosa - multifocal, slight 0 0.1 1.0 10.0 squamous metaplasia, with or without kcratlnization - focal or multifocal 0 0.1 1.0 10.0 Epithelial hyperplasia - focal or multifocal, slight 0 0.1 1.0 10.0 Subacute inflammation - multifocal, slight 0 0.1 1.0 10.0 Interstitial fibrosis - slight 0 0.1 1.0 10.0 Dilated acini 0 0.1 1.0 10.0 0-8 Weeks 1 0 0 3 8-Week Interim Kill 0 0 0 1 8-14 Weeks 0 0 1 I 14-Week Interim J5iU3 4 4 0 Terminal Cumulative Kill Results 6 10 6 10 5 10 5 10 1 0 0 3 6 10 0 0 0 4 6 10 0 0 1 4 5 10 3 1 1 0 5 10 1 _ 3 6 10 _ . - 4 6 10 - . I 4 5 10 311 5 10 1 0 0 3 6 10 0 0 0 4 6 10 0 0 1 4 5 10 31005 9 1 _168 ---1 3 4 -. I33 7 3 1--5 9 0--20 2 -- -00 0 -- 0000 00-*00 0- -000 -- -3 1 4 -- 0101 0 0-- 0 0 0.-00 0 - - - 0 2 2-- 001 1 00--00 0 -000 ---01 1 - 0000 00--00 0. -00 0 -- -01 1 -- 001 1 00-"00 0_ _00 0 -- -00 0 -- 010 1 0 0 -- 0 0 aTop dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none examined or not applicable. no 1 3) fj c CQNF j 0fNT TAl w --144- TABLE 13 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKS*1 AND THEN HELD FOR 32 WEEKS OF~~RECOVERY Dl.-i^nosls Code LS-1 TY-1 TY-Z^cv SP-l s?-: SP-3 SP-4 SP-5 Number of rabbits per group LYMPHORETICULAR SYSTEM :'j1 lgnar.t lymphoma, primary site Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Thvrus - Number of tissues examined 0 0.1 1.0 10.0 ::o visible lesions 0 0.1 1.0 10.0 Atrophy - severe 0 1.0 10.0 Srleen - .'-amber of tissues examined 0 0.1 1.0 10.0 ,',o visible lesions 0 Acute splenitis 1.0 10.0 0 Severe ccntestion Hemosiderin within histiocytes 1.0 10.0 0 0.1 1.0 10.0 0 H.ilitnant lymphoma, secondary site 1.0 10.0 0 1.0 10.0 0-8 Weeks 1 0 0 3 8-Week Interim Kill 0 0 0 1 8-14 Weeks 0 0 1 1 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill Results 6 10 6 10 5 10 J 10 00000 0 00000 0 001001 00000 0 00006 6 00000 0 001 00 1 30004 7 -- --5 5 _ 0 .0 0-- -4 4 ----1 1 _ 1_.1 3-- 03 1 0006 7 000000 0 0 1 00 1 3 0105 9 0- --6 6 __0__0 3- 1-5 9 1 ---0 1 _ _ 0 _ 0 0-0-00 0---00 - ---- -- 1-- 1 0*0-00 0---0 0 -_1*.1 0-0-00 0---00 __1 1 0-000 aTop dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 we eks of recovery. - Indicates none examined or not applicable. r- DfrlFlDEHTIM. no 131S55 OONF TDFNT TAI -145- TABLE 13 (Continued) Diagnosis Code MLN-1 MLN- 2 MLN- 3 \ LJt- i aln- 2 SK-1 SK-2 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS u0, 1 HISTOPATHOLOGIC OBSERVATIONS AND TISSUES EXAMINED ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKS" AND THEN HELD FOR 32 WEEKS OF RECOVERY Nunber of rabbits per group Exposure Level (ppm) 0 0.1 1.0 10.0 LYMPHORETI Cl'LAR SYSTEM (cont'd) Mesenteric Lvr.ph Nodes Number of tissues examined 0 0.1 1.0 10.0 No visible lesions Reactive lymphoid hyperplasia, paracortical zones and medullary cords 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Free and phaeocytized red blood ceil, medullary sinuses 0 0.1 1.0 10.0 Anterior Mediastinal Lvmnh Nodes Number of tissues examined 0 0.1 1.0 10.0 o visible lesions 0 0.1 1.0 10.0 Suppurative lymphadenitis 0 0.1 1.0 10.0 SKIS AND SUBCUTANEOUS Skin - Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 1.0 10.0 Subcutaneous abscess formation 0 0.1 1.0 10.0 0-8 Weeks 1 0 0 3 8-Week Interim Kill 0 0 0 1 8-14 Weeks 0 0 1 1 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill 6 Results 10 10 10 10 10003 6 0 000 0 0 00 100 1 300025 0---5 5 ----- - - - 0-- 0 3 ---2 5 1---01 -- - -" - - 0--0 0---00 0. -*00 -- --1- -- 1- 1 0---00 10002 3 000000 00 1001 10003 4 1---2 3 *- ---- _- 0-- 0 1 - -- 3 4 0---00 -- -----1--1 0--- 0 0 1 0006 7 000000 001 10 2 20005 7 1- --6 7 1 0 1 2---5 7 0---0 0 - - - -- " --- 1-1 0" ---00 `"'Top dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery - Indicates none examined or not applicable. r> ! '"'.nr'EHTim no 131536 OONFTDFNTTA1 ir.-J era CO Vi CO rri IZZ u no 131557 CONF TD FN TI Al TABLE 14 SUBCHBONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF UUCr IN RATS AND RABBITS CAUSE OF DEATH OR MORIBUND CONDITION OF RABBITS DYING OR KILLED MORIBUND DURING THE RECOVERY PERIOD Pathology Number 78-186 78-867 78-154 78-155 78-192 78-880 Exposure Concentrate (ppm) 0 1.0 10 10 10 10 Weeks of Exposure or Recovery 7 weeks of exposure 10 weeks of exposure 7 weeks of exposure 7 weeks of exposure 8 weeks of exposure 8 weeks of exposure plus 3 weeks of recovery Possible or Probable Cause of Death or Illness Severe suppurative otitis media with secondary bone and brain inflammation. Severe rhinitis and bronchopneumonia. Not determined. Severe rhinitis and bronchopneumonia Suppurative pleuritls and pneumonia. Severe pleuritis and epicarditis. i i/iIh jLlDi'ib J :3 :> P Oz Vo TJ Z "_n --i Ln -t CO T> TABLE 15 Duration of Exposure 14 weeks 14 weeks 14 weeks 8 weeks SUBCNRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY 01' DBCl* IN RATS AND RABBITS NUMBER OF Ul.TRASTRUCTURAU.Y ABNORMAL SPERMATOZOA IN RABBITS I MM ED I ATEl X ARTE R EXPOS UR E P ERIOD Dose Level Pathology Number Number of Abnormal Spermatozoa Number of Normal Spermatozoa Total Number of Spermatozoa Counted Percent of Abnormal Spermatozoa 0 ppm 78-791 78-792 78-793 18 222 240 3% 103 100 203 51% 4 55 59 7% overall 0.1 ppm 78-799 78-800 78-801 78-802 15 93 108 14% 10 124 134 7% 19 176 195 10% 13 112 125 10% overall 1.0 ppm 78-795 78-796 78-797 78-798 17 178 195 9% 52 97 149 35% 44 210 254 17% 19 146 165 12% overall 10 ppm 78-226 none present none present - - Average Percentage Abnormal Spermatozoa 5Z3 10% 18% - Mean Percent S.D. 53%c 10 3% 18+12% - N| I Without rabbit number 78-792 which had a spontaneous unilateral testicular abnormality. TABLE 16 Duration of Exposure 14 weeks exposure plus 32 weeks recovery Dose Level 0 ppm 14 weeks exposure plus 32 weeks exposure 0.1 ppm 14 weeks exposure plus 32 weeks recovery 1.0 ppm 8 weeks 10 ppm exposure plus z q 38 weeks " I recovery Z7 ; hj-------------- ---------------------- ~n -- Z Ln --f Ln -f sO 3> - SUJU:ilKUNIC INIIALATtON REPRODUC'llVE TOXICITY AND RECOVERY STUDY OE IHiCP IN RATS AND RABBITS NllMltEK OE [ILTRASTKUOTURAl.LY ABNORMAL SPERMATOZOA IN RABBITS AFITIK RECOVERY PERIOD Pathology Number Number of Abnormal Spermatozoa Number of Normal Spermatozoa Total Number of Spermatozoa Counted Percent of Abnormal Spermatozoa 78-1732 78-1733 78-1734 78-1735 78-1736 78-1737 6 107 113 5% 9 163 172 5% 8 72 80 10% 4 72 76 5% 0 67 67 0% 6 83 89 7% overall 78-1738 11 200 211 5% 78-1739 *9 109 118 8% 78-1740 6 102 108 6% Average Percentage Abnormal Spermatozoa 5% Mean Percent S.D. 53% overall 78-1744 29 160 189 15% 78-1745 28 52 80 35% 78-1746 11 39 50 22% 6% 62% overall 78-1749 78-1750 78-1751 overall -- 24% 5 19 24 21% 11 25 36 31% 10 110 120 8% _______________________________________________________ 20% -- ---------- ---------------- ----------------------------------------------- 1 1 -------- 24+10% 2012% * 00 1 i jji.