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1,2-DIBROMO-3-CHLOROPROPANE: INHALATION FERTILITY STUDY IN RATS AND RABBITS* BY: K. S. RAO, J. D. BUREK, J. S. MURRAY, J. A. JOHN, B. A. SCHWETZ F. J. MURRAY, A. A. CRAWFORD, M. M. DEACON, W. J. POTTS, B. N. SUTTER D. A. DITTENBER, T. J. BELL, J. E. BEYER, R. R. ALBEE J. E. BATTJES AND C. M. PARKER** REVIEWED BY: J. F. QUAST TOXICOLOGY RESEARCH LABORATORY HEALTH AND ENVIRONMENTAL SCIENCES, U.S.A. DOW CHEMICAL, U.S.A. MIDLAND, MICHIGAN 48640 DECEMBER 19, 1980 *CO-SPONSORED BY SHELL DEVELOPMENT COMPANY, HOUSTON, TEXAS AND DOW CHEMICAL, U.S.A., MIDLAND, MICHIGAN **TOXICOLOGY RESEARCH, WESTHOLLOW RESEARCH CENTER, SHELL DEVELOPMENT COMPANY, HOUSTON, TEXAS 77082 DO 101003 O.ONF TDFNTTA TABLE OF CONTENTS SUMMARY ....................................................................................................................................... 1 INTRODUCTION ........................................................................................................................ 5 MATERIALS AND METHODS.................................................................................................... 8 Test Material......................................................................................................... 8 Test Animals.............................................................................................................. 8 Experimental Design .......................................................................................... 9 Vapor Generation.................................................................................................... II Chambers...................................................... 12 Chamber Analysis .................................................................................................... 12 Observations ................................................. 13 Semen Evaluation...................................................................................................... 14 Fertility in Rats................................................................................................ 16 Male Rats.............................................................................................................. 16 Female Rats......................................................................................................... 17 Fertility in Rabbits ........................................................................................... 18 Clinical Observations ...................................................................................... 19 Cytogenetics ............................................................................................................... 19 Serum Hormone Determinations....................................................................... 20 Heritable Translocation Test ....................................................................... 20 Gross Necropsy Examination............................................................................ 21 Histopathologic Examination of Tissues .............................................. 23 Ultrastructural Examination of Testicular Tissues from Male Rabbits ............................................. 24 Statistical Evaluation.................................. 26 00 l.'-i 1004 OONF TDF N1 TA1 TABLE OF CONTENTS (Continued) RESULTS . . ................................................................................................................... Page 27 SPRAGUE-DAWLEY RATS.................................................................................................... 27 Mortality, General Health and Demeanor ......................................... 27 Body Weights......................................................................................................... 27 Reproductive Parameters - Male Rats.............................................. 28 Reproductive Parameters - Female Rats ......................................... 31 Heritable Translocation Study in Rats ......................................... 33 Clinical Laboratory Findings ................................................................. 34 Hematology.................................................................................................... Clinical Chemistry ................................................................................. Urinalysis.................................................................................................... Organ Weights............................................................................................... 34 35 35 35 Gross and Histopathologic Evaluation of Male and Female Rats................................................................................ 37 4-Week Interim Kill................................................................................. 37 14-Week Interim Kill.......................................................................................38 Animals Dying or Killed Moribund During the Recovery Period and the Terminal Kill at the End of the Recovery Period........................................................ 42 NEW ZEALAND WHITE RABBITS..................................................................................... 47 Mortality, General Health and Demeanor ......................................... 47 Body Weights......................................................................................................... 47 Semen Evaluation - Male Rabbits........................................................ 48 Reproductive Parameters - Male Rabbits ......................................... 51 Hematology and Clinical Chemistry Determinations ............................................................................................... 53 1-310 ? s f-ONF TDFNT T Ai TABLE OF CONTENTS (Continued) Organ Weights......................................................................................................... Page 54 Gross and Histopathologic Evaluation of Hale Rabbits............................................................................................... 56 Electron Microscopic Evaluation of Testicles from Male Rabbits................................................................. 60 Qualitative Evaluation ........................................................................... 60 Quantitative Evaluation ........................................................................... 63 DISCUSSION............................................................................................................................. 65 SIGNATURE PAGE................................................................................................................... 71 QUALITY ASSURANCE STATEMENT ................................................................................ 72 REFERENCES............................................................................................................................. 73 APPENDIX.................................................................................................................................. 77 GENERAL TABLES...................................................... 78 TEXT RAT TABLES.............................................................................................................. 82a TEXT RABBIT TABLES............................................................................................................... 183 TEXT FIGURES..............................................................................................................................236 INDIVIDUAL ANIMAL DATA TABLES ........................................................................... 245 DO 131 ODD CONF TDFNT T Al SUMMARY Groups of 10 male New Zealand white rabbits, 35 male and 35 female Sprague-Dawley rats were exposed by inhalation to 0, 0.1, 1.0 or 10 ppm of l,2-dibromo-3-chloropropane (DBCP) vapor for 6 hours/day, 5 days/week. The rabbits in the 10 ppm exposure group were exposed for 8 weeks followed by 38 weeks of recovery. All other groups were exposed for 14 weeks followed by recovery periods of up to 32 weeks. The semen of rahbits was evaluated on a weekly basis during the 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 again during recovery 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 during the 14th and 41st week of the study. Five rats/sex/exposure level were killed after 4 weeks and after 14 weeks of exposure. None died spontaneously during the exposure period. 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). One rabbit each in the control and 1 ppm groups and three rabbits in the 10 ppm group died or were killed moribund during the exposure period. 00 1010 P7 r.ONF TDFNT TAt Exposure of rabbits to 1 and 10 ppm of DBCP by inhalation produced reductions in fertility as well as decreases in sperm count, motility and viability. Rabbits had decreased sperm.counts at 1 and 10 ppm between the 8th and 14th weeks of the study. All of the 10 ppm rabbits were infertile when mated during the 14th week. In rats, no effect on fertility was observed, but a dominant lethal effect was evident at 10 ppm which tended to reverse by 5 weeks after termination of exposure. The effects of DBCP on spermatogenesis were shown to be reversible in both species exposed to 1 ppm; however, at 10 ppm, recovery was not complete under the conditions of the test. Treatment-related pathologic alterations were observed In male and female rats sacrificed immediately after exposure 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 after the 14-week exposure period were tending to reverse by the end of the recovery period. Lesions in the adrenal cortex of males and females from the 10 ppm exposure level were progressive. Some rats had cortical hematocyst formation, dilated cortical sinusoids, foci DO 131078 00NF1DFNTTA1 -3-- of altered cortical cells and nodular hyperplastic lesions of the cortex. i Also, females exposed to 1 ppm had slight adrenal cortical lesions at the end of the recovery period. In addition, increased numbers of ovarian cysts were present in females from the 10 ppm exposure lev^l. ii Finally, brain effects consisting of focal or multifocal mineralized I 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. Rabbits exposed to 10 ppm had severe testicular alterations as early as 4 weeks into the study and these progressed to severe testicular atrophy I by 8 weeks. Those exposed to 1 ppm for 14 weeks developed moderate testicular atrophy (approximately 50% reduction in size). Following the recovery period, the rabbits in both 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 semini ferous 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. This equivocal effect was not present after the recovery period. In conclusion, exposure to 1 or 10 ppm of DBCP for 14 weeks produced treatment-related pathologic alterations and effects on reproductive capacity in both rats and rabbits. No adverse effects were observed in either rats or rabbits exposed to 0.1 ppm following conventional DO 131 or 9 OONF T DF NT T A( -4methods of evaluation. However, electron microscopy did show equivocal effects in the rabbits exposed to 0.1 ppm immediately following the 14week exposure period, but not after the recovery period. It is signi ficant to note that male rats and rabbits displaying moderate testicular atrophy and other DBCP-induced alterations were still fertile and upon breeding with unexposed females were able to sire normal appearing pups. Based upon these results, it was concluded that the no adverse effect level of DBCP was determined to be 0.1 ppm in both species except for an equivocal effect on sperm morphology in rabbits detected only by elec tron microscopy, which did not appear to affect fertility. DO 101030 CONF IDF NT T At tS.- 1,2-DIBROHO-3-CHLOROPROPANE: INHALATION FERTILITY STUDY IN RATS AND RABBITS BY: K. S. RAO, J. D. BUREK, J. S. MURRAY, J. A. JOHN, B. A. SCHWETZ F. J. MURRAY, A. A. CRAWFORD, M. M. DEACON, W. J. POTTS, B. N. SUTTER, D. A. DITTENBER, T. J. BELL, J. E. BEYER R. R. ALBEE, J. E. BATTJES AND C. M. PARKER INTRODUCTION The compound l,2-dibrorao-3-chloropropane (DBCP) has been used as a soil fumigant and nematocide since 1953. Recent reports have associated exposure to DBCP with low sperm counts among male workers in several chemical companies (Whorton et al., 1977; Federal Register, September 9, 1977). Studies in laboratory animals Indicate some potential for DBCP to adversely affect spermatogenesis. Prior to this observation in male workers, toxic effects of DBCP were reported in experimental animals by several investigators. Torkelson et al. (1961) exposed rats, guinea pigs, rabbits and monkeys for 50-66 ex posures (7 hrs/day) at 10-12 ppm DBCP over 70-92 days. Histologic examination of the testes of rats exposed to DBCP revealed degenera tive changes in the seminiferous tubules, an increase in the number of Sertoli cells, and a reduction in the number of sperm cells. In male rats exposed to 5 ppm DBCP (50 exposures in 70 days), focal histologic changes were noted in the epithelium of the testes. no CONF1 OFNil A -6- Faydysh et al., (1970) reported necrosis in the testes of rats given 70. mg/kg/day of DROP orally for 45 days. Administration of 5 mg/kg/day of DBCP orally to male rats for 8 months resulted in decreased sperm motility (Rakhmatullaev, 1971). Reznik and Sprinchan (1975) found marked effects on spermatogenesis in male rats and on the estrous cycle in female rats given a single oral dose of 100 mg/kg of DBCP or multiple doses of 10 mg/kg. Ruddick and Newsome (1979) administered DBCP orally at dosage levels of 12.5, 25 or 50 mg/kg/day to pregnant rats on days 615 of gestation. No teratogenic effects were observed; however, fetotoxic effects were apparent at maternally toxic doses of 25 and 50 mg/kg DBCP. DBCP was found to be directly mutagenic to Salmonella typhimurium TA 1530 and Escherichia coli pol. A (Rosenkranz, 1975). Prival et al., (1977) reported DBCP to be a direct weak mutagen in Salmonella TA 1535. Blum and Ames (1977) presented data which shows that DBCP was mutagenic with metabolic activation in Salmonella typhimurium TA 100. Biles at al., (1978) reported DBCP to be a potent mutagen after metabolic acti vation in microbial studies using Salmonella typhimurium TA 1535. Kapp (1979) reported DBCP to be a clastogenic agent in the rat. DBCP also induced unscheduled DNA synthesis in premeiotic germ cells of male mice (Lee and Suzuki, 1979). Teramoto at al., (1980) showed that DBCP induced dominant lethal mutations in rats but did not cause dominant lethals in mice. 00 13103? CONF T OF NTT Al Two inhalation probe toxicity studies were recently conducted with DBCP and reported from this laboratory (Burek et al., 1980). In the first probe study, groups of 5 male Sprague-Dawley rats, 2 male New Zealand white rabbits, and 2 male beagle dogs were exposed to 50 ppm of DBCP for 6 hours per day, 5 days per week for 2 weeks (rats and rabbits) or for 4 weeks (dogs). Degenerative testicular changes were observed in all three species. In the second probe study, 4 male New Zealand white rabbits were exposed to 10 ppm for 2 weeks. All 4 rabbits had slight treatment-related histologic alterations in the testicles. The rabbit was considered to be the most sensitive species for the testicular al terations. Furthermore, semen samples were easily obtained and breeding studies could be conducted. Therefore, the rabbit was selected for use in the study described in this report. The rat was selected because DBCP-induced testicular effects had already been studied in earlier work CTorkelson, et al., 1961). The purpose of the study reported herein was: 1) to assess the effects of inhaled DBCP on spermatogenesis and fertility in laboratory animals, 2) to determine the maximum level of exposure to DBCP that does not have an effect on reproduction and 3) to evaluate the reversibility of these effects. To assess the effects of DBCP on the fertility of rats and rabbits, test animals were exposed for a period of 14 weeks (slight excess of one spermatogenic cycle) and animals were held for recovery for several weeks. -8- Peribdic analysis of a semen sample from each rabbit was performed during the exposure and recovery periods. The male rabbits were mated to unexposed female rabbits at the termination of the exposure period and again prior to sacrifice at the end of the recovery period to determine their ability to sire normal litters. To assess fertility in male rats, animals were mated periodically to unexposed female rats both during and after the exposure period. The exposed female rats were mated with unexposed males at the end of the 14-week exposure period and again during the recovery period. MATERIALS AND METHODS Test Material. Production grade purity of l,2-dibromo-3-chloropropane (Lot No. M03196) was supplied by the Dow Chemical Company, Magnolia, Arkansas. Results of gas chromatographic analysis of the test material before and after exposure are presented in Table 1. Test Animals. Male New Zealand white rabbits (Langshaw Farms, Augusta, Michigan) and male and female Spartan Sprague-Dawley rats (Spartan Research Animals, Haslett, Michigan) were used for this study. Adults of both species were used with the male rabbits being approxi mately 6 months old and the male and female rats weighing 350 to 450 and 225 to 300 grams, respectively. They were housed individually in wirebottom cages during the intervals between exposures in rooms designed to maintain a temperature of 73F, relative humidity of 45%, and light cycle of 12 hours light and dark. DO 131034 OONFTDFNTTAl -9- Anlmals were maintained in facilities fully accredited by the American Association for Accreditation of Laboratory Animal Care. They were supplied with commercial laboratory chow (Ralston Purina Company, St. Louis, Missouri) and tap water free choice during the intervals! between exposures. I \ During the exposure period, food and water were not I available. During exposures, rabbits and rats were placed 2 per cage and 5-7 per cage, respectively, in wire-mesh exposure cages. During periods of breeding, rats were held 2 to 3 per cage in wire-bottom cages in rooms designed to maintain parameters similar to those listed above. Following breeding, the bred female rats were maintained singly in i plastic shoe box reproduction cages provided with nesting material (BEDO-COBS, Paxton, Indiana). During the recovery period, all animals were housed individually in wire-bottom cages. All animals were uniquely identified by a metal ear tag (rats) or ear tattoo (rabbits). The rabbits and rats were allowed to acclimate to the laboratory for a period of at least one month prior to use. Animals were assigned randomly to cages before being placed on test by a series of random numbers which were computer-generated. Experimental Design. The experimental design of the study is summarized in Table 2. 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 were for 6 hours/day, 5 days/week (Monday through Friday) for 14 consecutive weeks, with the exception of the 10 ppm rabbits which D0 131035 OONF TDFNTTAl -lo were exposed for only 8 weeks due to a high Incidence of mortality. The exposure length was designed to encompass the length of the spermato genesis cycle in the rat and rabbit (Swierstra and Foote, 1965). The semen of rabbits was evaluated on a weekly basis during the 14 week exposure period and at periodic intervals during the recovery period. Semen evaluation consisted of color, volume, sperm concentration, sperm motility and viability. All male rats employed in this study were of proven fertility (able to sire at least one litter during a pre-exposure mating), The fertility of male rats during the study was evaluated by mating trials with unexposed females as indicated in Table 2. The exposed female rats were mated to unexposed male rats at the end of the 14-week exposure period and during the 33rd and 34th week of the study and were allowed a normal delivery of the 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 and 41st week of the study. Hematology, clinical chemistry and urinalysis determinations (rats only) were performed at various intervals during the study (Table 2). At the end of the exposure period, animals were held for various periods to determine whether any of the observed effects were reversible. The various parameters which were monitored during the post-exposure period are summarized in Table 2. During the exposure period, an interim sacrifice of 5 rats/sex/group was performed at 4 weeks; a second sacri fice was performed at the termination of the exposure period (8 weeks for the 10 ppm rabbits and 14 weeks for all other groups). The final DO 101006 CONFTDFNTTAl -11- sacrifice 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 moribund were also submitted for a complete necropsy examination. Additional details of the study design are presented in the respective section under methods. Vapor Generation. DBCP was generated using a perforated-plate dis tillation column. The column was ~18" long, ~1" ID, and had fifteen plates. The column was connected to one neck of a 3-neck 500 ml flask. Liquid DBCP (~300 ml) was placed in the flask, and continuously pumped from the flask to the top of the column using a FMI (3/8") ceramic piston pump, having a pumping rate of ~3 ml/mln. Teflon tubing, 1/4" OD, was dipped into the liquid DBCP in the flask and passed through a tight fitting on the inlet side of the pump. Another 1/4" Teflon tube was similarly fitted to the outlet side of the pump and was heat-sealed to a glass fitting at the top of the column which provided a tube through which liquid DBCP could drip onto the top plate of the column. This arrangement ensured that the system was airtight. Compressed air was passed through a charcoal filter, a needle valve, a rotameter, and into the third neck of the flask, exiting through a side-arm on the glass fitting at the top of the column. A measurement of DBCP con centration in the air exiting from the column showed that it was roughly i 3A 0'^ -12- at the calculated saturation level at room temperature (0.5 mm Hg -700 ppm). In order to achieve target concentrations for the exposures, appropriate dilutions with air were made. Chambers. The study consisted of exposure of animals to concentrations of 0.1, 1.0 and 10 ppm of DBCP. Three Rochester-type chambers, each 3 having a volume of A.5 m , and located in adjacent rooms, were employed. All chambers were operated at a main airflow rate of -900 liters/min, equivalent to ~12 air changes/hour and a negative pressure of ~0.1" H2O. With this system, nominal (10%) target concentrations were reached within about 20 minutes from start-up, and target concentrations were usually easily maintained to within 5% throughout the 6 hours of exposure. Chamber Analysis. The vapor generation methods were such that the ultimate control of the level of DBCP in each exposure was the analy tical concentration of DBCP in the chamber, thereby requiring frequent analysis of chamber air, especially during daily start-up procedures. The method chosen was gas chromatography, employing two sample loops and arranging for short retention times, so that analyses could be made as frequently as once each 2 minutes or as necessary. A separate gas chromatograph was used to analyze each chamber. The basic gas chromatography arrangement employed a Varian Model 1A00 instrument, using a 6' x 1/8" stainless steel column packed with a 10% UCW-98 on 80/100 mesh Chromosorb-W. The column was operated isothermally r>0 131038 CONFTDFNTTAI -13- at 160C using prepurified nitrogen carrier gas at a flow rate of 50 ml/min. Under these conditions, the DBCP peak had a retention time of "'40 seconds, was sharp, and was well-resolved from background (air) signal. For analysis at the levels of 1 ppm and 10 ppm, the sample loops had a volume of 1 ml. The detector was flame ionization, using 30 ml/min H2, 200 ml/min air, and thermostated at 200C. Response and signal/noise were entirely satisfactory for concentrations in the range 1-50 ppm DBCF. Sensitivity was well below 1 ppm, and repeatability was within 2% of the measured amount. Response was linear in all ranges. For analysis at the level of 0.1 ppm, an electron capture detector was employed, thermostated at 240C. The sensitivity was so high that the sample loops consisted simply of "shorting" together the leads of the miltiport valve used to switch sample loops. Repeatability was +15 to -3% of the measured amount. The results of the chamber air analyses are summarized in Table 3. Observations. The body weights of all rabbits and rats were generally recorded weekly throughout the study. The animals were generally observed daily for overt signs of toxicity or changes in demeanor. Any animals which appeared moribund or died spontaneously during the course of the study were submitted for gross pathologic evaluation. no 131039 OONF T OFNT 1 At -14- Semen Evaluation. Semen evaluation was performed on the rabbits at the intervals Indicated in Table 2. Semen collections were performed prior to placing the animals in the chambers. Semen was collected in a graduated test tube from each rabbit by means of an artificial vagina. After collection, the volume of semen was obtained and its color was recorded. The semen was placed in a constant temperature bath at 37C for 15 minutes to allow it to liquify. The motility and ratio of live and dead sperm were determined after the semen had liquified. To assess motility, a large drop of semen diluted with warm saline was placed on a glass slide under a cover slip and examined at 400 X magnification. The first 100 sperm observed were ranked as follows: 1) progressively motile (moving from place to place), 2) non-progressively motile (twitching tails but staying in one place), and 3) non-motile (no movement). The ratio of live and dead sperm was 2 determined by staining a drop of semen with eosin-aniline blue stain and counting 100 sperm per specimen. Sperm counts were determined using a modification of a method using a Coulter Counter, Model ZBI described by Gordon et a^,, (1965 and 1967) or by using the hemocytometer method described by Miller (1955). For the Coulter Counter method a 10 yl aliquot of the semen sample was diluted with 1 ml of Isoton II (Coulter Electronics, Inc., Hialeah, Florida) in a 2 ml Autoanalyzer sample cup. Aniline blue, 5 g; eosin B, 0.75 g; sodium citrate. 2.9 g; water, 100 ml. DO 13104 0 roni- i or ni i a -15- Subsequently, 250 pi of the diluted semen was added to 24.75 ml of 3 diluent In a commercial blood cell counter vial. This second dilution was mixed and allowed to stand for approximately 10 minutes. Additional dilutions were made, as necessary, to insure that the concentration of sperm in the aliquot was within the range of accuracy of the Coulter Counter. The actual sperm count was determined using a Model ZBI Coulter Counter equipped with a Channelyzer (Coulter Electronics, Inc., Hlleah, Florida). The apperture size was 50 x 60 y; the counts were made with an amplifi cation setting of 1.0 and apperture current setting of 1.0. The i instrument was volumetrically calibrated with 2.9 y and 3.4 y diameter standard latex particles. Using these settings, the Threshold Factor was 0.74. If the sample count was too high or too low, different dilutions were made to maintain the sample count within the range of 3,000 to 7,500. The actual number of sperm per ml was calculated by taking the average of 5 sample counts, then adding the coincidence factor, sub tracting the background count, and multiplying this corrected value by the dilution factor. Sperm count/ml was also evaluated by hemocytometer count. Hemocytometer counts were used when the Coulter Counter could not give an adequate reading (Counts of 3000 or less could not be obtained on the Channelizer). 3 750 ml isoton II, 37.5 ml acetic acid, 0.15 gm saponin. DO 131041 OONF" T DFNT T At -16- Fertillty In Rats Male Rats: Groups of 20 male rats per exposure level were mated with unexposed females of reproductive age during the following weeks of the study: 2,4,7,10,12,14,16,19,24,29 and 41 (Table 2). All of the males used for the experiment were of proven fertility (able to sire at least one litter during a pre-exposure mating). Beginning on the first day of exposure of the indicated weeks, each male was placed with two female rats for 7 days, except while they were exposed in the inhalation chambers. Twelve days after the last day of cohabitation (except week 41), the females were sacrificed by carbon dioxide anesthesia and their uterine contents were examined. The number of corpora lutea, implantation sites, and resorption sites were recorded. The male fertility index was expressed as follows: Number of fertile males____________ . Male Fertility Index *= Number of males housed with females x For each litter, the following indices were calculated: Pre-Implantation Loss (Number of corpora lutea minus Number of implantation sites) x 100 Number of corpora lutea Post-Implantation Loss (%) Number of resorption sites x 100 Number of implantation sites The mean value for each male was calculated for each of these indices. 00 131040 OONF J DFNT TA -17- During the breeding in the 41st week, vaginal smears were obtained from each rat until sperm and/or a vaginal plug was detected in order to determine the day of gestation. At the end of the 7 days of mating or at the time both females were found to have sperm in the vagina, males were separated from the females. Each timed pregnant rat was sacrificed on its respective day 21 of gestation. All other female rats which did not exhibit sperm or a vaginal plug were sacrificed 20 days following the first day of cohabitation. The following parameters were noted at cesarean section: number of corpora lutea, number of implantations, number of resorptions, number of live and dead pups, sex of each fetus and external examination (including palate examination) of each fetus. The objective of this breeding was to determine whether DBCP-exposed male rats were able to sire pups which were grossly normal. After evaluation of these data, all exposed male rats were sacrificed during the 46th week of the study for pathologic examination. Female Rats: At the end of the 14 week exposure period, 20 exposed female rats per exposure level were placed in separate cages with an unexposed adult male rat for two consecutive 5-day periods, each with a different male. After the period of cohabitation the females were placed singly in delivery cages containing ground corn cob litter for nesting. The date of delivery (day zero) and the number of live and dead pups delivered were recorded. On the day after delivery (day 1), the number of live pups of each sex was recorded and the pups were examined externally for morphologic alterations and were then discarded. DO 1 31 0&3 r.ONF 1 dfnttw -18- A similar breeding of exposed female rats with unexposed male rats was performed again during the 33r<* and 34^ weeks due to poor survival of pups at the prior breeding interval. Following this breeding all exposed female rats were sacrificed during the 40til week of the study for pathologic examination. Fertility in Rabbits. During the 14 ^ week of the study, each male rabbit was allowed to mate with an unexposed female rabbit; the day of mating was considered to be day zero of gestation. Immediately after copulation, each doe was given an injection of 50 units of human chorionic gonadotrophin (W. A. Butler, Columbus, Ohio) in the lateral ear vein to induce ovulation. On day 28 of gestation, the females were killed with carbon dioxide. The number of corpora lutea, implantations, and resorptions were recorded. The male fertility index, the pre implantation loss, and the post-implantation loss were calculated. To evaluate whether the exposed male rabbits were able to sire normal pups, each exposed male rabbit was allowed to mate with two unexposed virgin female rabbits during the 41 week of the study. Immediately after copulation, each doe was given an injection of 50 units of human chorionic gonadotrophin in the lateral ear vein. On day 29 of gestation the females were sacrificed to evaluate the following parameters: number of corpora lutea, number of implantations, number of resorptions, number of live and dead pups, and external examination (including palate examination) of each pup. After evaluation of these data, exposed male rabbits were sacrificed during the 46^ week of the study for pathologic examination. no 131044 OONFTDFNTTA! -19- Clinical Observations. Hematologic evaluations were performed on groups of 1 to 4 rabbits per exposure level and 5 rats/sex/exposure level during the following weeks -2 (rabbits only), -1 (rats only), 9, and 13. Prothrombin times were determined on 3 to 4 rabbits per ex posure level (except the 10 ppm group) and 5 rats/sex/exposure level during the 9t*1 (rats only) and 14t^1 weeks of the study. Urinalyses^5 were conducted on 5 rats/sex/exposure level during the 9 til , 13 til , and 14C^ (males only) weeks of the study. Clinical chemistry determinations of serum urea nitrogen concentration, serum alkaline phosphatase activity, serum glutamic pyruvic transaminase activity, and serum glutamic oxaloacetic transaminase activity (rabbits only) were made on 3-4 rabbits/exposure level (except the 10 ppm group) and 5 rats/sex/exposure level. The clinical chemistry determinations were performed at the time of necropsy during the 14^ week of the study. The rats and rabbits were anesthetized with methoxyflurane and carbon dioxide, respectively; the trachea was clamped, and blood was obtained following decapitation. Cytogenetics. Bone marrow preparations for cytogenetic examination were made on 5 rats/sex/level of exposure at the termination of ex posure. These slides were not examined microscopically but were stored for possible future examination. ^CV - Microhematocrit Centrifuge, Clay-Adams Co., New York; RBC, WBC counts, Hgb-Coulter Counter Model ZBI and Hemoglobinometer, Coulter Electronic, Hialeah, Florida. kpH, sugar, protein, ketones, bilirubin, urobilinogen and occult blood - Multistix - Ames Company, Elkhart, Indiana. CBUN, AP, SGPT, SGOT - Centrifi Chem System 400, Methods File, Union Carbide Corporation, Rye, New York. DO 131045 CONF T DFN'T T Al. -20- Serum Hormone Determinations: The serum concentrations of FSH (follicle stimulating hormone) and testosterone were determined by radioimmuno assay at the Bioscience Laboratories, Van Nuys, California. FSH was monitored from 5 rats per sex at 4 and 14 weeks of the study and from 36 male rabbits at 14 and 46 weeks of the study. Testosterone was monitored from 5 male rats at 4 and 14 weeks and from 3-6 male rabbits at 14 and 46 weeks of the study. Heritable Translocation Test. During the first week post-exposure, 20 male rats/group were placed in individual cages containing one unexposed female rat for a period of 7 days. Subsequently, the female was allowed to deliver her litter in a delivery cage with corn cob bedding. The following data were recorded: the date of parturition, the number of live and dead pups on the day of parturition, and the number and sex of live pups on the day after delivery (day 1). On day 14, all female pups were removed and killed. At weaning, two male pups from each litter, selected by a table of random numbers, were saved as parents for the next generation. The remainder of the litter was killed immediately. At approximately 24 weeks of age, (42^ week of study) F^ males were mated with unexposed, sexually mature female rats. One male from each litter was selected (by a table of random numbers) for this mating, and was placed in a cage with two females for 7 days. The females were sacrificed approximately 12 days after the last day of cohabitation, and the number of corpora lutea, implantations, and resorptions were recorded. The incidence of pregnancy, the pre-implantation loss, and the post implantation loss were calculated. At the end of this evaluation, all ,F^ males were sacrificed. DO 131040 CONFTDFN1 TAt -21- Gross Necropsy Examination. A gross necropsy examination was performed on male and female rats and male rabbits including those j animals that were sacrificed during the exposure period, those that were held for the recovery portion of the study, and those that died or were killed moribund during the study. The first | i interim sacrifice was after 4 weeks of exposure (rats only) and 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 sacrifice 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. The rats that I were submitted alive were killed by decapitation following clamp ing of the trachea under methoxyfluorane anesthesia, while the rabbits that were submitted alive were killed by decapitation following CO2 anesthesia. Those animals that were submitted as part of the interim or terminal kills had been deprived of food overnight 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 illumination. A complete gross pathologic examination was performed by a veterinary pathologist. Prior no 131047 CONFTDFNTTAl -22- 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 rabhits 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 phosphate-buffered 10% formalin and those tissues routinely collected are listed in Table 49. 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 phosphate-buffered 10% 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. Tissue was collected in glutaraldehyde from the one rabbit in the 10 ppm group that was killed after 8 weeks of exposure and from all of the control and treated rabbits DO 13104B OONF TDFNT T At, -23- after 14 weeks exposure (interim kill) as well as all at the terminal kill of the recovery period. These tissues were collected from the testicles for possible future electron microscopy; howevert tissues from rats were not evaluated 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. r>n K?i04 9 <30NF T DFNT T At -24- Ultras true tural Examination of Testicular Tissue From Male Rabbits Testicular tissue was collected and examined ultrastructurally from most of the male rabbits on this study and summarized in Table 53. t 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 group which were also killed after 14 weeks, and 1 animal from the 10 ppm group which was killed after 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 timeof 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 3 tissue before cutting into 1 mm blocks, the slice was fixed for 1-6 hours in 2.5% phosphate-buffered glutaraldehyde fixative. 3 The 1 mm blocks were washed in phosphate buffer, and post-fixed in 1% phosphatebuffered osmium tetroxide. Dehydration was accom plished 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 u 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 CJO 131050 t'ONF TDFNT TAl -25- more desirable blocks for thin sectioning. Three blocks were selected and examined per animal. Thin sections, approximately 600-700 A 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 miscroscope. Development of negative sheets and printing was performed within this laboratory using standard techniques for Kodak AA89. film and Kodak Kodachrome paper. The grids were first examined by the electron microscropist 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 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 cell. Interstitial cells were also evaluated and graded for the number of lysosomes, and fat content on a semiquantitative basis. t DO 131051 OONF TDFNT TAl -26- Statistical Evaluation. Body weights, organ weights, clinical chemistry determinations, specific gravity of urine, hematologic parameters, numbers of corpora lutea and implantation sites and parameters concerning semen evaluations were evaluated by a one way analysis of variance; differences between experimental means and the control were examined using Dunnett's test (Steel and Torrie, 1960). Where appropriate, a transformation of the data or a nonparametric analysis of variance by ranks was used to evaluate these parameters. For body weight and food consumption data, statistical outliers were excluded from the calculation of the group means (Grubbs, 1969). The level of significance chosen for identification of statistical outliers was p<0.02. The level of reported signifi cance for all other parameters was p<0.05. The pre-implantation loss, number of resorptions, and post-implantations loss were analyzed by using the Wilcoxon test as modified by Haseman and Hoel (1974). The fertility indexes were analyzed by the Fisher's exact probability test (Siegel, 1956). (i Of.. CONFTDFNTTA! DO 1310 53 00NFTDFNT1A1 -27- RESULTS SPRAGUE-DAWLEY RATS Mortality, General Health and Demeanor. No deaths occurred during the exposure period among rats exposed to DBCP. However, several animals, both In control and treated groups, died during the late recovery phase of the study (discussed under Pathology). None of these deaths were attributed to DBCP exposure. There were no overt clinical signs of toxicity or changes In appearance of the rats of either sex during the course of the study that could be attributed to the exposure to DBCP. Body Weights. Mean weekly body weight data for male and female rats are presented in Table A and 5 respectively. In both males and females, a slight decrease in the body weight was observed during the entire exposure period at the high exposure level (10 ppm). Although these values were not statistically signi ficant compared to controls, it is considered that the decrease in body weight observed at the high level during exposure is related to DBCP. However, these rats recovered their body weight immediately after termination of DBCP exposure and remained consistently higher during the recovery period. During the second week of the study, a significant decrease in the body weight was observed among female rats exposed to 10 ppm DBCP. Also, several instances of statistically significantly increased body weights among DBCP exposed rats were observed: 0.1 ppm male no i^05A C.ONFTf')frNTTAl -28- rats at weeks 5,6,41,42 and 43; 10 ppm male rats at week 41; and 0.1 ppm female rats at week 4. All of these statistically significant deviations In body weights were considered random variations and were not attributed to exposure to DBCP. Reproductive Parameters - Male Rats. Fertility of male rats was not adversely affected by inhalation of DBCP (Table 6). Throughout the study, the percentage of males which fertilized at least 1 female was 85% or more in all groups during each mating period. Among the rats exposed to 1 ppm, the percentage of males with both females pregnant was markedly decreased during the 4^ week of exposure only (Table 7). This parameter was not significantly altered during any week at 0.1 or 10 ppm DBCP groups. The fertility indices observed in treated groups were within the historical control range for this strain of rat. The average number of corpora lutea/dam was significantly decreased during the 7t^1 week at 10 ppm, 14^ week at 0.1 and 1 ppm and 16^ week at 1 and 10 ppm DBCP groups (Table 8). No other statistically significant decreases from the control values were seen in other weeks. These changes were not considered biologically meaningful because these females were not exposed to DBCP. A statistically significant decrease in the average number of implantations/dam was observed during the 7 week at 10 ppm and during the 14^ week in all treated groups (Table 9). All of these were considered random variations and were unrelated to 00 131055 r.ONFTDFNTt Al -29- DBCF exposure because the total number of implantations are within the range for historical controls for Sprague-Dawley rats in this laboratory. Marked increases in the average number of resorptions were seen f~Vt *-v consistently at 10 ppm from the 4 through the 19 weeks of the study (Table 10). This was considered a treatment-related effect. It was Interesting to note that by the 24^ week of the study (10 weeks following the termination of exposure) the average number of resorptions at the high dose level was comparable to the control group, suggesting a reversal of the DBCP-induced effect. At the lower concentrations, the number of resorptions was com parable to controls. Statistically significant Increases in pre-implantation loss were seen in female rats bred to male rats exposed to 10 ppm DBCP during the 7^ (P=0.051) and 29^ weeks of exposure (Table 11); however, the control values during these weeks were relatively low compared to the range of control values observed in this study. At the lower concentrations, no increase in pre-implantation loss was observed. Statistically significant decreases in pre-implantation loss were seen on a sporadic basis in the 0.1 and 1 ppm groups. All of these were considered due to the biological variations which were not related to treatment. Post-implantation loss (the percentage of implantations resorbed) was significantly increased among the unexposed females bred by males exposed to 10 ppm of DBCP during weeks 4,7,10,12,14,16 and 19 no 131056 rONFTDFNTTAi -30- (Table 12). In the 10 ppm DBCP groups a statistically significant increase in post-implantation loss first appeared during the 4C** week of exposure and plateaued by the 7th week of exposure. Some evidence of reversibility was seen during the 19^ week of the study (fifth week post-exposure); during the 24tn week (tenth week post-exposure), the post-implantation loss of the 10 ppm rats was comparable to that of the control rats. In halation of 0.1 or 1 ppm DBCP did not significantly increase post-implantation loss. The post-implantation loss observed at the high dose level is interpreted as being mediated by DBCP exposure to male rats via the dominant lethal mechanism. The dominant lethality is a chromosomal aberration in treated male spermatozoa which results in death of the developing embryo. In order to assess whether the DBCP exposed male rats were able to sire normal pups, each exposed male rat was bred to two unexposed female rats for 7 days during the 41s t week of the study. Each timed pregnant rat was sacrificed on day 20 of gestation. The pups were observed for external malformations (including palate examination) and sexed. These data are presented in Table 13. No unique anomaly was observed among fetuses sired by the DBCP-treated males. The above results suggest that exposures up to 10 ppm DBCP did not affect the overall fertility of male rats as tested by breeding to unexposed female rats. However, the exposure of male rats to the high dose level (10 ppm) of DBCP induced a significant increase in post-implantation loss as early as D0 A 31057 OONF T DFN'T T Al -31- the 4t*1 week of exposure. This effect was evident up to 5 weeks post exposure (19^ week of study). The increase in post-implantation loss was interpreted as an indication of dominant lethality. It is signi ficant to note that continued maintenance of these treated male rats under laboratory conditions (without subsequent DBCP exposure) resulted in reversal of the dominant lethal effect by the 24^ week of the study h (10 week post-exposure). The no-effect level for the dominant lethal effect was established as 1 ppm DBCP. In addition, it was established that following recovery from the dominant lethal effect the exposed male rats were, able to sire pups which were normal in appearance. Reproductive Parameters - Female Rats. Female rats exposed to DBCP for 14 weeks were bred with unexposed male rats during weeks 15 and 16 of the study. Each female was housed with two different unexposed male rats, each for a 5-day period. These bred females were allowed to deliver at term. Data from these litters are presented in Table 14. Fertility of DBCP-exposed females was not significantly different from that of the control females. The average number of live pups per litter at birth (day zero) was generally higher among the DBCP treated litters than among the control litters. A trend (not statistically significant) toward an increase in the average number of dead pups/litter was seen among the DBCP-exposed groups. On day 1, the average number of live pups/litter among the DBCP-exposed groups was not significantly different from that of the controls. However, a higher incidence of litters with 4 or less pups was noted among the 10 ppm dams. no 13105A OONFTDFNTTAI -32- A trend toward a decrease In the gestation survival Index (the percentage of pups that were alive at birth) was noted among the litters of rats that Inhaled 10 ppm of DBCP when compared to the control group; however the differ ence was not statistically significant. The one day sur- vival Index (percentage of pups which survived for one day) was not significantly altered by exposure to DBCP. Compared i to the control group, there were proportionally more males among the offspring of rats exposed to 0.1 ppm DBCP but not among those exposed to the higher concentrations. This observation is not considered to be of toxicologic significance. The results of the examination of the pups at one day of I I age revealed no abnormalities which could clearly be attri buted to DBCP (Table 15). One pup with acaudla or short tall was observed in each of the experimental groups. Single incidences of hematoma (umbilical region), runts and an emaciated pup were observed in treated litters only. Such observations have been made historically in control litters at a low incidence in this laboratory. Hypothermia (as determined by touch) was observed in 5 pups at the 0.1 ppm and 3 pups at the 10 ppm DBCP level. This finding was not detected at the 1 ppm level or in the concurrent control litters. The significance of this observation is unclear at this time. Due to a slightly higher incidence of dead pups and the exclusive occurrence of some physical findings in the no 131059 CONFTDFNTTAI -33- litters exposed to DBCP, it was decided to rebreed these females with untreated males. Such breeding was conducted during weeks 33 and 34 of the study and the data are presented in Table 16. It is important to note that following rebreeding of these females all the parameters evaluated were generally comparable between control and DBCP treated litters. All the pups examined on day 1 were apparently normal. Heritable Translocation Study in Rats. The male rats, sired by DBCP exposed Fq male rats bred with unexposed female rats during the 15 ^ and h 16 weeks of the study were maintained in the laboratory until approxi mately 24 weeks of age. These adult F^ male rats were bred for 7 days __ j with 2 unexposed female rats during the 42" week of the study. No effect on fertility was evident as the control, 0.1, 1.0 and 10 ppm groups had a 100, 94, 100 and 90% fertility index, respectively. The bred females were sacrificed 12 days after the last day of cohabitation and the number of corpora lutea, implantations and resorptions were recorded. These data are summarized in Table 17. All of the parameters evaluated were comparable between the control and 0.1 and 10 ppm DBCP groups. In the 1 ppm group, rats exhibited a statistically significant increase in post-implantation loss accompanied with a slight but not statistically significant increase in pre-implantation loss. Because of the absence of a dose-response in the latter finding it was not con sidered related to DBCP exposure. no 131060 C ONF-' T DF NT T Al -34- Clinical Laboratory Findings Hematology; The results of hematologic evaluations of male and female rats are presented in Tables 18 and 19 respectively. Inhalation of DBCP had no significant effect in either sex on the following: packed cell volume, red blood cell count, hemoglobin and white blood cell differen tial count. Compared to the control group, white blood cell counts were significantly decreased during the 9^ week of exposure in all experi mental groups of males. During the 13 ^ week, a trend toward a decrease in white blood cell count was observed in all experimental groups of males, but only the 1 ppm males exhibited a statistically significant decrease. In comparison, females exposed to 10 ppm of DBCP had a statistically significant increase in white blood cell counts during the 9t*1 but not the 13^ week of exposure. These fluctuations were con sidered random variations unrelated to DBCP exposure because all these values were within the historical control range. Prothrombin time was generally comparable between all groups in males at 9 and 13 weeks and at 13 weeks in females (Table 20). However, a marked decrease in prothrombin time was observed in females at 9 weeks of exposure at the two lower exposure levels but not at the 10 ppm level. Due to the lack of a temporal or dose related effect on prothrombin time, these isolated decreases were not considered related to DBCP exposure. 0*1 od"' DO ^ -35- Cllnlcal ChemlBtry: Serum chemistry analyses at the 14^ week of the study are presented in Table 21, while serum follicle stimulating hormone (FSH) and testosterone level analyses at 4 and 14 weeks of exposure are presented in Table 22. None of the parameters evaluated exhibited any changes in either sex which were considered to be compound-related. Urinalysis: Data from urinalyses in male and female rats are presented in Tables 23 and 24 respectively. Except for urine specific gravity, all of the parameters evaluated were comparable between control and DBCP-exposed groups of both sexes. Statis tically significant increases in urine specific gravity were noted in males at 9 and 14 weeks of exposure at 1 ppm and at 14 weeks only in 0.1 ppm DBCP exposed rats. Such an effect was not discernible at 10 ppm in male rats or at any level among treated females. Hence, these changes were considered unrelated to DBCP exposure. Thus it is concluded that up to 10 ppm DBCP exposure to rats did not result in any compound-induced changes in the clinical laboratory parameters evaluated. Due to the absence of DBCPrelated changes in clinical laboratory parameters during the ex posure period, it was not considered necessary to evaluate them during the recovery. Organ Weights: The mean organ weights and organ/body weight ratios determined at various times during the study for male and female rats are present in Tables 25 and 26, respectively. 13l0hp CONF TDFNT TA1 T\36ar, At the 4-week sacrifice, the weights of the brain, heart, liver and kidneys of male rats were not significantly affected by exposure to DBCP (Table 25). The testes and epididymides of the 1 ppm rats (but not the 0.1 or 10 ppm rats) weighed statistically significantly less than those of the controls; however, when the weights of the testes and epididymides were expressed relative to body weight, no significant differences were evident. Based on the lack of a dose-response, this was not considered treatment related. At the 14-week sacrifice, both the absolute and relative weights of the testes and epididymides were significantly decreased at 10 ppm, and the relative kidney weights of the 10 ppm males were significantly greater than that of the controls. No other signifi cant changes in organ weights were found in males exposed to DBCP. However, by 46 weeks of the study (i.e. 32 weeks after termination of exposure) all organ weights in treated animals were comparable to controls, except the relative testes weight of the 10 ppm males which was significantly decreased when compared to the controls. In females, the only statistically significant difference in organ weights at the 4-week sacrifice was a decrease in relative liver weight at the 1 ppm group (Table 26). As in the males, a significant increase in relative kidney weight was observed at the 14-week sacrifice in the females exposed to 10 ppm of DBCP. The absolute weight of the heart of females exposed to 0.1 ppm was greater than that of the controls, but the relative weight of the heart was unaffected. All of these were considered random fluctuations un related to DBCP exposure. DO 131003 CONF T DENT T Al -37- A significant decrease in the weight of testes and epididymides was observed in rats exposed to 10 ppm DBCP for 1A weeks. However, ' a partial recovery in the weight of these organs was apparent when the DBCP-exposed rats were sacrificed 32 weeks after termination of exposure. Gross and Histopathologic Evaluation of Male and Female Rats The gross pathology observations are tabulated in Table 27 for the interim kills after A weeks of exposure, Table 29 for the interim kills after 1A weeks of exposure, and Tables 31 and 32 for the terminal kill at the end of the recovery period which followed the 1A weeks of exposure. In addition, the gross pathologic observation from animals that died during the recovery period are also tabulated in Tables 31 and 32. The histopathologic observations are listed in Table 28 for the interim kill after A weeks of exposure. Table 30 for the interim kill after 1A weeks of exposure, and in Tables 33 and 3A for the terminal kill at the end of the recovery period which followed the 1A weeks of exposure. Histopathologic observations from rats that died during the recovery period are also summarized in Tables 33 and 3A. A-Week Interim Kill. Five male and five female rats were killed after A weeks of exposure to DBCP. There were no grossly observed treatment-related alterations in either the male or the female rats after A 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. (Table 27). DO 131064 CONFTDFNTIAl -38- Histopathologic evaluation of tissues was limited to the male reproductlve 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 bralnj and I 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 spermatogenesis and loss of spermatogenlc 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 I I 1 of 5, 2 of 5, 0 of 5 and 0 of 5 rats from the 10 ppm, 1 ppm, 0.1 ppm and 0 ppm 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. (Table 28). 14-Week Interim Kill. Five male and 5 female rats were killed at the termination of the 14-week exposure period. Grossly observed altera tions 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 no 13106.5 OONFTDFNTTAl in size while 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 DBCF groups. The changes in these control rat testicles were considered to be incidental alterations which occurred spontantously, 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 (Table 29). Histopathologic evaluation of tissues was limited to the male repro ductive system which included the testicles, epididymides, prostate, coagulating glands, and seminal vesicles; the female reproductive system which included the ovaries, oviducts, uterus, and cervix; the liver; th kidneys; the urinary bladder; the brain; and the adrenal glands. Histopathologic changes that appeared to be treatment-related were observed in the testicles and In the adrenal glands (Table 30). The changes in the testicles consisted of individual seminiferous tubules with decreased spermatogenesis. Some lacked germinal cells and contained only or predominately Sertoli cells. Other tubules had some germinal cells, but they were decreased In amount. Approximately 50Z 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 DO K-nOBO CONF T OF NT T At -40- 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, -l interstitial edema, and multinucleated spermatids. Such changes are suggestive for an acquired lesion possibly due to circulatory distur bances. The alterations seen in these 2 control animals were clearly different than those seen in the testicles of the rats from the 10 ppm DBCP 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 ex perimental 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 no i3i Of-/ CONFTDFMTTAl -41- 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 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. In contrast, 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, there are several factors that make a correlation possible. These factors include the low background historical incidence for animals of this age and strain, the fact that similar but larger foci as well as nodular hyperplasias, were observed in the adrenal glands of the recovery rats, and that it is very unusual to see so many foci (3 of 5 male and 3 of 5 females) in rats of this age. Therefore, these adrenal gland changes in rats from the 10 ppm groups are considered to be exposurerelated alterations. There were a few other histopathologic observations made in the male and female rats, but these were typical of spontaneous naturallyoccurring changes commonly seen in rats of this age and strain and are not considered to be treatment-related. no 13106B oonftbfnttai -42- 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 induced 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. The cause of death of these rats is summarized in Table 35. 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 wer 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 2(^males in the 1 ppm group, 0 of 20 in the males from the control and 0.1 ppm groups (Table 31), 10 of 20 females in the 10 ppm group, 4 of 20 females in the 1 ppm group, and 1 of 20 females from the control and OO _ C.O^ 9 -43- 0.1 ppm groups (Table 32). Ovarian cysts were observed in 6 of the 20 (6 of 17 females at the terminal kill) females from the 10 ppm experi mental 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 the 14 weeks of exposure had testicles that were grossly decreased in size. At the 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 (Table 31). It is not possible to determine if the grossly observed testicular changes in the two male rats at the 10 ppm group are age-associated or due to DBCP treatment. In any case, 18 of 20 male rats from the 10 ppm group had grossly normal-appearing testicles suggesting a reversibility of the alterations that were seen grossly after 14 weeks of exposure. 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 reproduction system which included the testicles, epididymides, prostate, coagulating glands and seminal vesicles; the female repro ductive system which included the ovaries, oviducts and cervix; the DO 131070 rONFTOFNTTAl -44- 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. j Testicular changes consisted of either bilateral or unilateral atrophy (decreased spermatogenesis) of individual seminiferous tubules (Table 33). These 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 uni lateral or bilateral testicular alterations. Such alterations were slight and are 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 (Table 34). 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. DO 131071 C0NF10FNT T Al -45- A spectrum of lesions was 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 killed 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 hyperplastic 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 ppm or control recovery groups. Although similar lesions occasionally occur in aging rats of this strain, those observed in the present study were 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) were considered treatment-related alterations. Ectasia (dilatation) of adrenal cortical sinusoids and cortical hemato cyst 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. DO 13107? CONFTDFNT TAl -46- In contrast, similar changes were found in 0 of 60 males or 1 of 60 females from the 1, 0.1, and 0 ppm recovery groups combined. 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 hematocysts while none of the 20 rats from each of the 1, 0.1, or 0 ppm recovery 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. 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 were 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 group had mineral deposits in the brain. The pathogenesis of the mineral deposits is unknown. The brains from the animals from the 4 and 14-week interim kills were re examined for possible early alterations, but no changes were detected. DO 131073 OONF TDFNT 1AI -47- NEW ZEALAND WHITE RABBITS Mortality, General Health and Demeanor. Three male rabbits exposed to 10 ppm of DBCP died during the 8 weeks of exposure; gross examination at necropsy did not reveal the cause of death. Pasteurella-like pneumonic changes in lungs were evident at necropsy in two rabbits. Because of the high incidence of mortality noted among the 10 ppm rabbits, exposure of that group was terminated after 8 weeks, and one of the remaining 10 ppm rabbits was sacrificed. During the 11th week of the study (3 weeks post-exposure), an additional 10 ppm rabbit died with pneumonia. One rabbit exposed to 1 ppm DBCP died with severe rhinitis and Pasteurella-like bronchopneumonia during the 10th week of exposure. At 0.1 ppm, no deaths were observed. One control rabbit was sacrificed during the 7th week of the study due to an inner ear infection with secondary bone and brain inflammation; otherwise, no deaths occurred among the control group. Other surviving rabbits did not exhibit any signs of altered appearance which were considered to be compound-related. Body Weights: The weekly body weights of male rabbits exposed to DBCP are summarized in Table 36. Average body weights of the rabbits exposed to DBCP were not significantly different from those of the control rabbits during any week of the study. DO 131074 OONFTDFNTIAl -48- Semen Evaluation - Male Babbits: The sperm concentration and the volume of semem per ejaculate for male rabbits exposed to DBCP by inhalation are summarized in Tables 37 and 38( respectively. The average number of sperm/ml of semen (sperm count) was slightly decreased during the first few weeks of exposure among the rabbits that Inhaled 10 ppm of DBCF. Similar slight decreases in the average sperm count were seen at 0.1 and 1 ppm during the first and second weeks of^exposure, respectively. These decreases may have been related to the initial stress of placement in the exposure chambers. During the 7th week of exposure, a marked decrease in sperm count was noted in rabbits exposed to 10 ppm DBCP; only one 10 ppm rabbit had a sperm count above 50 million/ml. After 7 weeks of exposure, the average sperm count of the 10 ppm rabbits was significantly less than that of the controls and remained decreased for the rest of the study including the 38 week recovery period. Evidence of slight reversal at 10 ppm was first noted during the 38th week of the study (30 weeks after the last week of exposure). At 1 ppm, statistically significant decreases in sperm counts were seen during the 11th through 14th weeks of exposure; this effect was still evident during the 16th and 19th weeks of the study but reversal was noted by the 24th week (10 weeks post-exposure). no 131075 OONFTDFNT TA( -49" Ac 0.1 ppm, the average sperm count was statistically significantly less than that of the control rabbits during the 12th week of exposure; however, this decrease was not considered to be compoundrelated since sperm counts during subsequent weeks of exposure were comparable to those of the controls and were not considered toxicologically significant. There were no consistent changes in the volume of the ejaculate among the rabbits exposed to DBCP (Table 38). Although statistically significant decreases in the volume of semen were seen occasionally among the experimental rabbits, no value fell below the range of values seen in the control group and none were considered to be toxicologically significant. The motility data on sperm from rabbits are summarized in Tables 39-41. In evaluating motility, sperm were classified as progressively motile, non-progressively motile, or nonmo tile. Beginning the 8th week of the study, the semen of rabbits exposed to 10 ppm of DBCP had marked decreases in the percentage of progressively motile sperm compared to the control group (Table 39). This trend continued to persist throughout the study until termination. At the lower concentrations, no con- t sistent statistically significant decreases in the percentage of progressively motile sperm were observed. A significant increase in the percentage of progressively motile sperm was noted during the 19th week, but this was due to an unusually low control value. 00 131076 fONFTOFNTTAl -50- Significant decreases in the percentage of progressively motile spepn were observed sporadically at the 28th week in 0.1 ppm and 46th week in 1 ppm DBCF groups but were not considered toxicologlcally significant. i A significant increase in the percentage of non-progressively motili 1 sperm was seen only in the 0.1 ppm group during the 26th week of study and in the 1.0 ppm group during the 40th week of study (Table 40). At 10 ppm, increases in the percentage of non-motile sperm (Table 41) occurred in association with the decreases in progressive motility. This trend continued through study termination. Due to low sperm counts experienced at this dose level, the group mean values were not always i statistically significant. The percentage of non-motile sperm among, the 1 ppm rabbits was significantly greater than the control value during the 13th week of exposure only. No significant changes in the per centage of non-motile sperm were discerned in rabbits that Inhaled 0.1 ppm DBCP. It is important to note that considerable variation in motility of sperm was observed among all groups as well as in individual animals throughout the study. The percentage of sperm which were alive (as determined by eosin-aniline blue stain) among the 10 ppm rabbits was significantly decreased com pared to the control value from the 8th through the 11th weeks of the study (Table 42). During the ll1"*1 through 26C^ weeks of the study, sperm counts among the 10 ppm rabbits were generally too low to permit accurate quantification of the percentage of live sperm; however, most no 131,077 CONFTDFNTTA! -51- or all of the sperm were dead In the few 10 ppm rabbits which had sufficient numbers of sperm for this determination. At 1 ppm, statistically significant decreases In the percentage of live sperm were seen during the 8th, 12th and 13th weeks of exposure but not during subsequent weeks. The percentage of live sperm among the rabbits exposed to 0.1 ppm of DBCP was not significantly different from that of the control rabbits except during the 38th week (24 weeks post-exposure) of the study. This was considered random variation and not related to DBCP exposure. Reproductive Parameters - Male Rabbits. During the 14th week of study, each male rabbit was allowed to mate with a single unexposed female rabbit. Immediately after copulation each doe was given an injection (lateral ear vein) of 50 units of human chorionic gonadotrophin. The results of the matings are summarized in Table 43. DBCP did not appear to affect libido, as judged by the percentage of males which copulated. This is particularly significant because all five of the high dose rabbits copulated and these rabbits had a mean sperm count of 2 x 10^/ml during this week of study. None of the females which were mated with 10 ppm males were pregnant, indicating that the males were infertile six weeks after their last exposure to DBCP. The fertility of the 0.1 and 1 ppm rabbits was higher than the controls. DO 13107B CONFIOFNT!*1 -52- Exposure to 0.1 or 1 ppm DBCP had no significant effect on the average number of corpora lutea per dam or the average number of resorptions per litter. However, the mean number of Implantations/litter in the 1 ppm group was significantly less than that in the control group. In addition, a trend toward an increase in pre-implantation loss was noted among the 1 ppm rabbits, but this was not statistically significant. No significant evidence of an effect on post-implantation loss was discerned at 0.1 or 1 ppm of DBCP. To evaluate whether the exposed male rahbits were able to sire normal pups, each exposed male rabbit was again allowed to mate during the 41st week of the study with two unexposed virgin female rabbits. Immediately after copulation each doe was given an injection (lateral ear vein) of 50 units of human chorionic gonadotrophin. On day 29 of gestation, the females were sacrificed to evaluate the reproductive parameters and for external examination (including palate examination) of each pup. Results of this examination are presented in Table 44. As in the previous breeding interval, the libido, as judged by the percentage of males which copulated, continued to be comparable between the control and DBCP exposed rabbits. Fertility of 0.1 and 1 ppm DBCP exposed rabbits at this interval was 100%. It is interesting to note that two of five high dose (10 ppm) rabbits which were infertile at 14 weeks of the study had regained fertility at 41 weeks of the study (mean sperm count 27.2 x 10^/ml) All other reproductive parameters evaluated were comparable between all DO 131079 CONFTDFNTTAl -5-3- DBCP-exposed and control groups. It was significant to note that all pups delivered by cesarean section were apparently normal In appearance by external examination. These data clearly suggest that DBCP at 10 ppm affects fertility, however, a prolonged recovery period resulted In an Initiation of recovery in some animals. Equally significant Is the fact that these recovered animals were able to produce normal appearing pups. Hematology and Clinical Chemistry Determinations: The results of the hematologic and clinical chemistry evaluations in male rabbits are summarized in Tables 45 and 46. Hematologic evaluation during the 9th and 13th weeks of exposure did not reveal any significant changes among the rabbits inhaling 0.1 or.1 ppm of DBCP. Of the four 10 ppm rabbits originally scheduled for hematologic determinations, two died during the exposure and one was sacrificed after 8 weeks of exposure. In the latter case, hematologic values were obtained at sacrifice; these were consistent with the pre-exposure values for this animal. During the 9th and 13th weeks of the study, hematologic data from the single 10 ppm rabbit evaluated were comparable to those of the control rabbits. The average prothrombin time in rabbits was not altered signi ficantly by 14 weeks of exposure to 0.1 or 1 ppm of DBCP (Table 46). Analysis of serum samples from these same rabbits revealed no compound-related alterations in BUN, SGPT, AP or SGOT. Samples were not obtained from a 10 ppm rabbit at 14 weeks. DO 131080 OONF TDFNT IAl The serum levels of follicle stimulating hormone (FSH) and testosterone at 14 and 46 weeks of the study in male rabbits are presented in Table 47. A significant increase in serum FSH was observed in the 1 ppm rabbits at 14 weeks and in the 10 ppm rabbits at 46 weeks. No data wer available for 10 ppm rabbits at 14 weeks of the study because of ter mination of DBCP exposure to this group at 8 weeks. These significant increases in serum FSH were consistent with marked decreases in sperm concentration in these rabbits. FSH levels of the 0.1 ppm rabbits were unaffected throughout the study. The 1 ppm rabbits appeared to have recovered with respect to serum FSH by the 46th week of the study. This was in agreement with the recovery of semen concentration of sperm at this exposure level. The serum concentration of testosterone was comparable between control and DBCP-exposed rabbits at both the intervals monitored. Organ Weights: The mean organ weights and organ/body weight ratios determined during the 14th week interim sacrifice find the 46th week terminal sacrifice are presented in Table 48. At the 14-week sacrifice, the weights of the brain, heart, liver, kidney, and epididymides among the rabbits exposed to 0.1 or 1 ppm of DBCP were comparable to those of the control rabbits. Testes of the 1 ppm rabbits weighed approximately 50% of the control rabbits, both on an absolute and a relative basis, and the differences were statistically significant. At 0.1 ppm the testicular weights were comparable to those of the control rabbits. No 10 ppm rabbits were sacrificed during the 14th week of the study. 00 131081 OONFIOFNT TAt -55- However, the weight of the testes of the 10 ppm rabbit which died during the 8th week of exposure was 1.43 gm, approximately one-fourth of that of the control rabbits during the 14th week of the study. No other organs were weighed from this rabbit. One high dose rabbit was sacri ficed after 8 weeks of exposure, at which time exposure of DBCP to all high, dose rabbits were terminated due to higher mortality in this group. Body and organ weights for this rabbit are presented in Table 48. Again the weight of the testes was markedly decreased; In addition, a notable increase in the weight of the liver was observed in this rabbit. At the terminal sacrifice (46th week), the weights of the brain, heart, liver and kidney among the rabbits exposed to DBCP were comparable to those of the controls. Marked decreases in the weight of the testes were present at 1 and 10 ppm levels; however, this parameter was different from control values in rabbits exposed to 0.1 ppm of DBCP. The weight of epididymides at the 0.1 and 1 ppm levels were comparable to control, while at 10 ppm a slight decrease was apparent. 00 13108? OONFTDFNTTAl -56- Gross and Histopathologic Evaluation of Male Rabbits The gross pathologic observations for the rabbits are tabulated in Table 50 for the 10 rabbits at each exposure concentration. This 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 group); 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). Complete sets of tissues were evaluated from the control and 10 ppm 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 and their diagnoses for each of the rabbits at each dose level are given in Table 51. Six rabbits died or were killed moribund during this study (Table 52). Five of the six had pneumonia, rhinitis, pleuritis or other lesions that were consistent with a severe bacterial infection. Although cultures were not made on these rabbits, the most likely agent was Pasteurella multoclda which is a no 131083 OONFTDFNTTAL -57- common bacterial organism in rabbits causing a variety of disease syndromes. 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 spontaneous in nature. However, since more animals died in the 10 ppm group, it is possible that exposure to DBCP at this concentration 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. 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 alter ations could be assessed. Treatment-related changes were confined to the reproductive system and included atrophy of the testicles, atrophy of the epididymides, atrophy of the prostate, and atrophy of the accessory genitalia. In the 10 ppm rabbits, diffuse severe testicular atrophy was observed upon gross and histopathologic examination of these animals. Testicular alterations consisted of complete or nearly complete loss of spermatogenlc elements in nearly all of the seminiferous tubules. Sertoli cells were the predominant or the only cells lining most of the tissues. In addition, the tubules that still contained some evidence of germinal cells usually DO 131084 CONF T DFNT T Al -58- had debris present in the tubules. The fourth rabbit from the 10 ppm group was killed after 8 weeks of exposure. This 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 bilateral 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 was 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 were now confined to a smaller area due to the atrophy of the 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 regeneration in the testicles from the rabbits that had been ex posed 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 DO 131085 OONFTOFNT1 Al -59- 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 rabbits 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 longer. There were other gross and histopathologic alterations seen in the control and 10 ppm rabbits as well as in the tissues examined from the 0.1 and 1 ppm rabbits. These changes were not considered to be treatmentrelated, but rather spontaneous in nature. DO 131088 CONFIDENTIAL -60- Electron Microscopic Evaluation of Testicles From Male Rabbits An electron microscopic (ultrastructural) evaluation conducted on the testicles from the rabbits killed after the 8t^1, and 14^ week of exposure are summarized in Table 54. Those rabbits killed after the recovery period are presented in Table 55. 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 individual tubules normally are in different stages of spermatogenesis at any given time. Some tubules were active while others were 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. Qualitative Evaluation The normal rabbit testicle contains many seminiferous tubules. The relationship of the different cells within individual tubules is il lustrated 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. 00 1310B7 OONFTDFNT -61- 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 lumlna, 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 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 epididymides 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 30% of the tubules appeared normal. The remaining tubules were atrophic and varied from severe (complete or nearly complete) to slight atrophy. The types of changes present consisted of loss of spermatogonia, spermatocytes and sperma tozoa with normal-appearing Sertoli cells. There were abnormal sperma tozoa present in the tubules of control and treated rabbits and they had' DO 131088 CONF T OF NT T At -62- 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 appealed 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 number 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. DO 131089 OONFTDFNTT A! -63- Quantitative Evaluation In order to quantify the ultrastructural finding of an apparently Increased number of abnormal 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 54 for the rabbits examined at the end of the exposure periods (Interim kills) and Table 55 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 normal versus those which 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 54, but were 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 8week exposure period did not have spermatozoa or evidence of active spermatogenesis 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 (Table 55). Similarly, the rabbits exposed to 1 ppm of DBCP for 14 weeks 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. DO 131090 CONFTDFNTTAl -64- Therefore, rabbits exposed to either 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 the variability of such counts was 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%). " Attempts were made to quantify the breaks in the nuclear membranes of cap-phase spermatids as well as the number of lysosomes and the amount of fat in the interstitial cells. However, there was extensive vari ability in these parameters in both the control and exposed tissues. This variability was due to the inherent nature of the counting techniques, the artifacts and variability induced by fixation, and the variability inherent in the small sample size. Due to such factors, quantification of these parameters was not considered valid and therefore their evalua tion was confined to a qualitative examination. DO 131091 CONF TDFNTIAI -65- DISCUSSION Results of the present study clearly Indicate a potential for Inhaled DBCP to Interfere with spermatogenesis In rats and rabbits. Many of the effects observed were shown to be reversible, partially or completely. In both species. Exposure of male rats to DBCP had no effect on fertility. However, a significant dominant lethal effect was seen at 10 ppm, as evidenced by an increased incidence of resorptions among unexposed females mated with exposed males. This effect was evident within 4 weeks after the first exposure, indicating involvement of spermatids. After exposure, the time course for reversal of the dominant lethal effect was approximately the same as that required for this onset. In comparison, a dominant lethal effect was not clearly discerned in rabbits exposed to DBCP, although there was a trend toward an increase in pre-implantation loss among unexposed does mated with bucks exposed to 1 ppm of DBCP. Teramoto al., (1980) observed a dominant lethal effect in rats given oral doses of 10 or 50 mg/kg of DBCP for 5 days as evidenced by increased incidences of resorption sites and corresponding decreases in numbers of live embryos. When mice were tested in a similar manner at doses of 50 or 150 mg/kg, no dominant lethal effect was present. Thus there appears to be quite a range of species variation in rats, rabbits and mice with regard to the dominant lethal effect. H'O 13109? CONFTDFNTTAl -66Exposure of female rats to DBCP had no significant effect on their ability to become pregnant. Howevert among the females exposed to DBCP for 14 weeks before breeding, there was an unusually high incidence of litters with 4 or fewer pups at 10 ppm. Each of the experimental groups had one pup with acaudia or short tail* whereas none were seen in the control group. This malformation is not uncommon among the offspring of Spartan substrain Sprague-Dawley rats; the incidence of this defect in control groups from teratology studies conducted in this laboratory is 0.2% (13/6192) among fetuses and 2% (11/538) among litters. Treatment-related pathologic alterations were observed in male and female rats exposed to 10 ppm of DBCP 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 aSgreSates 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 were almost 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 to the formation of cortical hematocysts, dilated cortical sinusoids, foci of altered cortical cells and nodular hyperplastic lesions of the cortex in some rats. In addition, increased numbers of 00 131093 CONFTOFNTIAl -67- female rats with an ovarian cyst were present at 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. Our results are in agreement with Hasegawa, et al. (1979) who showed marked weight reduction of the epididymides and testes in rats exposed to 0.3-10 ppm DBCP. These authors also demonstrated recovery of testes weight within 1-2 months.after exposure to 0.3-3 ppm DBCP. However, after DBCP exposure of 8-10 ppm, recovery of testes weight and the number of spermatozoa were not observed after 4 months. In rabbits, decreases in sperm counts were seen at 1 and 10 ppm. The length of the spermatogenesis cycle in the rabbit is approximately 10 weeks. Thus, the sharp decline in sperm counts seen in the 10 ppm rabbits between the 8th through 10th weeks of the study indicated that DBCP affected primarily spermatogonia. This was confirmed histologi cally. Sperm counts were decreased to a lesser extent among the 1 ppm rabbits, and a longer period of exposure was required before an effect was observed. Histologically, the testes of the 1 ppm rabbits were less severely affected than the 10 ppm rabbits and a longer period of ex posure was required before an effect was observed. All of the 10 ppm rabbits appeared to be infertile when mated during the 14th week of the study (six weeks post-exposure). However, the fertility of the rabbits no 131094 CONF TDFNT TAl -68- exposed to 1 ppm for 14 weeks was unaffected, in spite of the fact that their average sperm count was less than half that of the control rabbits. Two of the 5 high dose male rabhlts regained their fertility when I evaluated at 41 weeks of the study. j Four of ten rabbits exposed to 10 ppm of DBCF died during or shortly after the period of exposure. In at least two cases, the cause of death was due to lung changes typical of Pasteurella Infection. It is possi ble that exposure to DBCF reduced the rabbits resistance to bacterial infection. A predisposition toward secondary infection was reported by Torkelson et al. (1961) in other species exposed to DBCP. Rakhmatullaev (1971) found changes in the microbial digesting function of the rats given 0.05 mg/kg/day of DBCP orally for eight months. Increased FSH levels were noted in rabbits exposed to DBCP. These Increases are believed to reflect a stimulated bio-feed-back mechanism which resulted from DBCP induced testicular damage. It is not likely that the testicular degeneration seen in this study was directly caused by changes in hormone levels. In this regard, Torkelson et al., (1961) showed that administration of testosterone, cortisone, or ACTH in com bination with exposure to DBCP did not protect against the effects of DBCP on the testes. Rabbits exposed to 10 ppm had testicular 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 DO ^ 3U>95 CONFIDENTIAL -69- (approximately 50Z reduction in size). Following the recovery period, the rabbits in both the 10 and 1 ppm groups had evidence of partial reversibility of the testicular atrophy. Electron microscopic evalua tion of testicular tissue confirmed the light microscopic effects and also Indicated increased numbers of 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. In the present study, the rabbit was considerably more sensitive than was the rat to the degenerative effects of inhaled DBCP on the testes. Torkelson et al., (1961) reported a similar species difference between rabbits and rats with regards to testicular weight. On the basis of the first probe study with DBCP (Burek et al., 1980), the dog appeared to be less susceptible than the rabbit but more susceptible than the rat. The reason for these species differences is not known. It is not known whether the differences in the metabolism and disposition of DBCP account for this species variation rather than differences in the intrinsic sensitivity of the germ cell. From this study it is clear that inhaled DBCP has considerable potential to adversely affect spermatogenesis and to reduce fertility at low concentrations. However, animal data regarding the reversibility of DBCP-impaired spermatogenesis is quite favorable. In rabbits, severe testicular damage was produced which resulted essentially in aspermia and nearly complete absence of spermatogonia; yet, partial reversibility occurred no 131090 CONF TDFNT T Al -70- withln 8-9 months of this severe insult. The dominant lethal effect observed in rats at 10 ppm was not present in male rats exposed to 1 ppm DBCP and was found to be reversible when the male rats were mated 5 weeks after cessation of exposure. In conclusion, exposure of rabbits to 1 and 10 ppm of DBCP by inhalation produced reduction in fertility as well as decreases in sperm count, motility and viability. In rats, no effect on fertility was observed, but a dominant lethal effect was evident at 10 ppm which tended to reverse by 5 weeks after termination of exposure. Testicular degenera tion and atrophy were observed in both species. The adverse effects of DBCP on spermatogenesis were shown to be completely reversible in both species at 1 ppm, however, at 10 ppm recovery was not complete under the conditions of the test. It is significant to note that male rats and rabbits displaying moderate testicular atrophy and other DBCP-Induced alterations were still fertile and upon breeding with unexposed females were able to sire normal appearing pups. Electron microscopy showed equivocal effects in the rabbits exposed to 0.1 ppm immediately following the 14-week exposure period, but not after the recovery period. Based upon these results, it was concluded that the no effect level of DBCP is approximately 0.1 ppm in both species. DO 131097 f'ONFTDFNTTAl -71- Tbls report was prepared and submitted by: Vv* S- K. S. Rao, D.V.M., Ph.D. Research Leader Toxicology Research Laboratory A ScWt I2&UJ80 B. A. Schwetz, D..v.ft, Ph.D. Director Toxicology Research Laboratory Burek, D.V.M., Fh.D. [plomate, American College of Veterinary Pathologists Diplomate, American College of Laboratory Animal Medicine Research Leader - Pathology Toxicology Research Laboratory fl. J. 7HuMOuj /SjQeafiZO J US .Murray, g/s. Biologist Toxicology Research Laboratory trOjLr. mP >hn, M.S. Senior Research Biologist Toxicology Research Laboratory B. M. Sutter %Q. Student Co-op Toxicology Research Laboratory juwWwk'? /f/kcsio D. A. Dittenber, B.S. M.T. (ASCP) Research Medical Technologist Toxicology Research Laboratory Medical Technologist Toxicology Research Laboratory (? d n R. R. Albee, H.T. (ASCP) Histotechnologist Toxicology Research Laboratory p TM aaavw(&A$) F. J. Murray, PW.D. Research Specialist Toxicology Research Laboratory /?.#. ttILv A. A. Crawford, B.S. Biologist Toxicology Research Laboratory M. M. Deacon, B.S. Biologist Toxicology Research Laboratory UJt PirftZ ftXa*-J9WfXlSi) W. J. Potts, Ph.D. S Research Specialist Toxicology Research Laboratory !? Z . J^/Bell, bTB. Biologist Toxicology Research Laboratory J3 /rbec&n JVE. BeyWr, B.S.^M.T. CAS CP) Medical Technologist Toxicology Research Laboratory ff. '?'? ZrAr C. M. Parker, M.S. Research Toxicologist Toxicology Research Westhollow Research Center Shell Development Company REVIEWED BY: /Z'decSD F. Quast, D.V.M., Ph.D. Diplomate, American College of Veterinary Pathologists Research Associate Toxicology Research Laboratory no 131098 GONFTDFNTTAl 72 1,2-DIRROMO-3-CHLOROPROPANE: INHALATION FERTILITY STUDY IN RATS AND RABBITS QUALITY ASSURANCE STATEMENT This report represents data generated prior to the enactment of the FDA Good Laboratory Practice Regulations. The study was conducted according to standards used in this laboratory at that time. The report accurately reflects all of the data generated. All data and reports are located at the submitting laboratory. Study Started; 28 Nov 77 Protocol Audited: Nov 77 Final Report Audited: 3 Sept 80 Study Dates Audited 9 Feb. 78 22 March 78 9 May 78 28 August 78 23 Jan. 80 3 Sept. 80 Report Issued; 19 Dec 80 Reported; Nov 77 Reported: 4 Sept 80 Reported 9 Feb. 78 28 March 78 11 May 78 28 Sept. 78 24 Jan. 80 4 Sept. 80 W. E. Hoover (Pate) Quality Assurance Toxicology Research Laboratory Health and Environmental Sciences, USA 1803 Building Dow Chemical U.S.A. Midland, MI 18640 no 131 09-3 o,onf t dfnt t Al -73- REFERENCES 1) Biles, R. W., Connor, T. H., Trieff, N. M. and Legator, M.S. (1978) The Influence of Contaminants on the Mutagenic Activity of DBCP. J. Environ. Path. Toxicol. 2, 301-312. 2) Blum, A. and Ames, B. (1977) Flame Retardant Additives as Possible Cancer Hazards. Science 195:17-23. 3) 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-Chloropropane (DBCP). Toxicology Research Laboratory, Dow Chemical U.S.A. Midland, MI. February 7, 1980. 4) Faydysh, E. V., Rakhmatullaev, N. N and Varshavskli, V. A. (1970) The Cytotoxic Action of Nemagon in a Subacute Experiment. Med. Zh. Uzbekistana 1_, 64-65. 5) Federal Register (1977) Occupational Exposure to l,2-dibromo-3Chloropropane Part VII. September 9. Pages 45536-45549. 6) Gordon, D. L., Moore, D. J., Thorslund, T. and Paulsen, C. A. (1965). The Determination of Size and Concentration of Human Sperm with an Electronic Particle Counter. J. Lab. Clin. Med. 65, 506-512. 7) Gordon, D.L., Herrigan, J. E., Moore, D. J. and Paulsen, C. A. (1967). Efficacy of Coulter Counter in Determining Low Sperm Concentrations. Am. J. Clin. Path. 4, 226-228. no 131100 OONF TDFNT T ftl -74- 8) Grubbs, F. E. (1969) Procedures for detecting outlying observations in samples. Technometrics 11: 1-21. 9) Hasegawa, H., Sato, M. and Okonogi, K. (1979) On the Toxicity of a Pesticide DBCP. Japn. J. Ind. Health 21, 661. j 10) Haseman, J. K. and Hoel, D. G. (1974). Tables of Gehan's Generalized Wilcoxin with Fixed Point Sensoring. J. Stat. Comput. Slmul. _3, 117-135. 11) Kapp, R. W. (1979). Mutagenicity of DBCP: In Vivo Cyto- genetics Study in the Rat. Presented at the Eighteenth ' I Annual Meeting of the Society of Toxicology, New Orleans, LA. 12) Lee, I. P. and Suzuki, K. (1979). Induction of Unscheduled DNA Synthesis in Mouse Germ Cells following DBCP Exposure. Mutat. Res. 6Q, 169-173. 13) Miller, S. E. (1955). in: A Textbook of Clinical Pathology Pub. The Williams and Wilkins Co. Baltimore, Md. 14) Prival, M., McCoy, E. and Rosenkranz, H. (1977). Tris(2,3dibromopropyl) phosphate: Mutagenicity of a widely used flame retardant. Science 195, 76-78. 15) Rakhmatullaev, N. N. (1971). Hygienic Characteristics of the Nematocide Nemagon in relation to Water Pollution Control. Hyg. Sanit. 36, 344-348. 131101 CONFTDFNTTA -75- 16) Reznik, Y. B. and Sprinchan, G. K. (1975). Experimental Data on the Gonadotoxlc Effect of Nemagon. Gig. Sanit. 6, 101-102. 17) Rosenkranz, H. (1975). Genetic Activity of l,2-dibromo-3chloropropane, a widely used fumigant. Bull. Env. Contain, Tox., 14, 8-12. 18) Ruddick, J. A. and Newsome, W. H. (1979). A Teratogenicity and Tissue Distribution Study of DBCP in the Rat. Bull. Environ. Contam. Toxicol. 21, 483-487. 19) Siegel, S. (1956). Non-Parametric Statistics for the Behavioral Sciences. McGraw-Hill Book Company, Inc., New York, New York. 20) Steel, R. G. D. and Torrie, H. H. (1960). Principles and Procedures of Statistics. McGraw-Hill Book Company, Inc., New York, New York, pp. 101-105 and 111-112. 21) Swierstra, E. E. and Foote, R. H. (1965). Duration of Spermatogenesis and Spermatozoan Transport in the Rabbit based on Cytological Changes, DNA Synthesis and Labelling with Tritiated Thymidine. Am. J. Anat. 116, 401. 22) Teramoto, S., Salto, R., Auyama, H. and Shirasu, Y. (1980) Dominant Lethal Mutation Induced in Male Rats by DBCP. Mutat. Res. 77, 71-78. no i _-n i o/' GONFTDFNTTA -7623) Torkelson, T. R., Sadek, S. E. and Rowe, V. K. (1961). Toxicologic Investigations of 1,2-dibromo-3-chlorpropane. Toxicol. Appl. Pharmacol. 3^ 545-559. 24) Whorton, D., Krauss, R. M., Marshall, S. and Milby, T. H. (.1977). Infertility in Male Pesticide Workers. Lancet 2: 1259-1261. DO 1 31 1 03 CONFT OFNTl Al -77- 1,2-DIBROMO-3-CHLOROPROPANE: INHALATION FERTILITY STUDY IN RATS AND RABBITS APPENDIX 1) GENERAL TABLES 2) TEXT RAT TABLES 3) TEXT RABBIT TABLES A) TEXT FIGURES 5) INDIVIDUAL ANIMAL DATA TABLES 1 to 3 A to 35 36 to 55 I to 8 A-l to A-AA DO 131104 fONFTDFNTTA -781.2-DIBROMO-3-CHLOROPROPANE: INHALATION FERTILITY STUDY IN RATS AND RABBITS GENERAL TABLES - I TO 3 00 1311^ OONFTOFNTTAl -79- Table 1 DBCP: INHALATION FERTILITY STUDY IN THE RAT AND RABBIT Chemical Analysis of DBCP DBCP Allyl chloride 1,2,5,6-Te trabromohexane 2-Chloropropane 1-Chloropropane Epichlorohydrin l-bromo-3-chloropropane Pre-exposure5 Post-exposure5 % by weight 97.3 96.60.4 0.5 0. 590.06 0.92 1.200.1 0.35 0. 380.04 0.03 0.040.004 0.81 1.000.1 0.11 0.100.01 aThe test material was analyzed for impurities by gas-liquid chromatography 12 days prior to the first day of exposure and 40 days after the last day of exposure. Analysis was performed by the Analytical Laboratories, Dow Chemical Company, Midland, MI. DO 131100 OONF T DFNT T Al -80- Table 2 DBCP: ISHALATXOS FERTILITY STUDY IH THE RAT AHD RABBIT Experimental Design Compound: 1,2 Dibromo-3-chloropropane Species: Rev Zeeland white rabbits (males) and Sprague Davley rats (males and females) Exposure: Inhalation, 6 hr/day, 5 days/week Level: 0, 0.1, 1.0, 10.0 ppa Group Sixes: 10 male rabbits, 35 male and 35 female rats per level of exposure RABBITS Pre-Exposure___________ Exposure (weeks)_______ (-2) -112 3 1 5 6 7 r 9 10 II 12 13 nr Body Weights Semen Evaluation Fertility Hematology Clinical Chemistry Histology FSH and Testosterone X XXXXXXXXXXXX X XXXXXXXXXXXX 16* 1 12 XX XX 12 X X 33 11 11 11 RATS Body Weights Males Females Fertility Males Females Hematology (males and females) Clinical Chemistry (males and feroles) Urinalysis Males Females Histology Males Females FSH and Testosterone (males and females) Bone Marrow (males and females) (Slide Preparation) XX XX XX XX rr XX XX 60 XXX XXX XXX XXX 80 80 XX XX 60 X X 60 kO kO kO 39 39 k0 lk 12 19 20 20 20 20 20 20 kO ko 10 X * Indicates that this parameter \as monitored. * * Indicate the number of animals evaluated. no 131107 OONFTDFNTTAi -fll- '-*> -J X 7> Table 2 {Continued) DBCP: INHALATION FERTILITY STUDY IN THE RAT AND RABBIT Experimental Design Compound: 1,2 Dibromo-3-chloro propane Species: New Zealand white rabbits (males) and Sprague Dawley rats (males and females) Exposure: Inhalation, 6 hr/day, 5 days/week Level: 0, 0.1, 1.0, 10.0 ppu Group Sizes; 10 male rabbits, 35 male and 35 female rats per level of exposure RABBITS PoBt-Exposure (weeks) 15 16 17 18 19 20 21 22 23 2*. 25 26 27 20 29 30 31 32 33 3*t 35 36 3t 30 39 W" fcl 1(2 1|3 44 li$ lib Body Weights Semen Evaluation Fertility Hematology Clinical Chemistry Histology FSH and Testosterone xxxxxxxxxxxxxxx xxxxxxxx X X X X X XXX XX X XXX X X X X X X X X X 22a 22 22 RATS Body Weights Males Females Fertility Males Females Hematology (males and females) Clinical Chemistry (males and females) UrlnalyBls Males Females Histology Males Females FSH and Testosterone (males and females) xxxxxxxxxxxxxxxxxxxxxxxxxxxxx XXXXXXXXXXXXXX X 00 00 80 80 79 78 77 75 x 7*i X - Indicates that this parameter was monitored. a Indicates the number of animals evaluated. CONF TOFNT T -82- Table 3 DBCP: INHALATION FERTILITY STUDY IN THE RAT AND RABBIT Inhalation Chamber Air Analysis for DBCP Target Concentration, ppm Nominal Concentration, ppm Analytical Concentration, ppmb Total Exposure Days Exposure Days within 10% of Mean Analytical Concentration Average Daily Temperature^ Average Daily Relative Humidityb 0 -- 70 70 ND ND 0.1 NDa 0 .101.003 70 70 782F 527% oCOM. ooH H 1.0 NDa 70 70 762F 576% 10.0 NDa 10.1.2 70 70 734F 466% aNominal concentrations could not be determined because of the nature of the vapor generation method (see text). bMeanStandard Deviation no i:-nioo CONF TOFNT 1 A!. 82a 1,2-DIBROMO-3-CHLOROPROPANE: INHALATION FERTILITY STUDY IN RATS AND RABBITS TEXT RAT TABLES - 4 TO 35 no CONFTDFNTTAl -83- TABLE 4 OBCP: INHALATION FERTILITY STUDY IN THE RATt RAT: Male Body weights wseteukdyOf --o~------------ in-- ppro-DBCPrns------------ rtr T9 mean s.d.)a Pre-Exposure - 1 511*30 Exposure 1 518133 2 519135 3 528136 4 526141 5 530138 6 537138 7 539136 8 54435 9 543128 10 544136 11 557136 12 561137 13 564136 14 561137 Post-Expos ure 15 572135 16 585137 17 586138 18 594140 19 594140 20 599140 21 611142 22 624153 23 635155 24 609142 25 634159 522136 - 519134 524143 537137 542136 554134* 561137* 559143 563138 558138 561138 569139 574140 578141 57U42 514136 514137 519139 517138 522138 534140 544142 539144 551146 552146 545148 556148 560149 563147 551148 526132 514135 506134 509132 509131 522132 529134 531131 537134 539135 523142 548134 550136 553137 546137 584135 595137 60H35 608138 606137 616137 632137 636140 645138 629136 636139 S68146 580148 581147 589149 585148 593150 604152 608156 619159 592159 612155 572139 580140 ' 589142 596139 591138 599140 610140 619141 631140 608140 62242 DO 131111 GONF TDFNT TAl -84- TABLE 4 (Continued) DBCP: INHALATION FERTILITY STtJDY IN THE RATt RAT; Male Body Haights week Of Study --g~-------------cnr~ ppre-DBCPo Tg mean * 757) Iff------ 26 62441 651*41 627*57 637*43 27 636*56 652*41 631*59 645*41 28 650*57 666*42 641*62 652*44 29 634*55 652*39 622*54 637*42 30 6434:57 660*38 627*58 647*42 31 645*57 660*38 633*60 650*45 32 65359 669*40 647*63 661*46 33 656*60 669*42 650*66 666*48 34 650*61 668*40 650*67 665*48 35 642*62 666*37 646*67 665*47 36 644*69 670*38 650*68 669*48 37 661*53 682*37 660*71 678*50 38 660*54 681*39 654*70 676*49 39 662*53 685*38 658*73 682*49 40 659*55 686*40 652*71 676*49 41 626*39 670*38* 645*51 661*48* 42 631*40 676*39* 650*51 662*53 43 630*41 677*41* 653*50 663*67 46*> 607*44 646*36 618*73 637*77 H O O ioJ TMale rats were exposed 1.0 or 10 ppm of DBCP by inhalation for 6 hr/day, S days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. ^Statistical outliers are excluded from calculation of the mean, Grubbs test, p < 0.02. ^Values for the 46th week represent fasted body weights taken prior to necropsy. `Significantly different from the control value by Dunnett's test, p < 0.05. See Table A-l for individual animal data. coNf^fnT1W -85- TABLE 5 DBCPt INHALATION FERTILITY STUDY IN THE RATt RAT; Female Body Weights Week of Study 0 Pre-Exposure - 1 29319 Exposure 1 294*17 2 29718 3 29819 4 300*19 5 307*19 6 310*20 7 311*19 8 31218 9 315*20 10 316*20 11 32419 12 323*19 13 322*19 14 328*20 Post-Exposure 15-I8b 19 348*31 20 346*28 21 348*23 22 349*21 23 347*22 24 346*21 25 348*20 26 354*22 PPO-DBCP 0.1 1.0 "Tg, mean * S.D.) 10 303*19 298*19 302*20 306*19 312*19* 315*20 318*20 318*22 320*21 322*20 324*20 330*22 333*24 333*23 335*21 288*22 291*16 298*19 299*19 302*18 309*18 311*19 314*19 315*18 318*18 321*21 327*20 328*21 327*22 330*22 294*21 289*20 285*18' 292*20 295*20 301*18 300*18 303*17 304*18 309*17 308*18 315*19 317*17 319*19 322*20 361*25 352*23 354*24 ' 348*22 354*20 349*23 351*22 359*23 366*25 361*22 361*22 359*19 356*19 358*22 354*23 363*26 348*24 344*24 340*33 341*27 345*23 343*23 346*25 354*30 DO 131113 CONF T DFNT 1 Al -86- TABLE 5 (Continued) DBCP: INHALATION FERTILITY STUDY IN THE RATt RAT; Female Body Weights Week Of Study 27 28 29 30 31 32 33-35b 40c 0 352123 35622 35424 35526 353124 35825 313123 ppm-DBCP 0.1 ~Tg, mean l 1.0 5.D.)* 35826 362123 360127 364130 356129 369130 365127 36428 362130 364126 369126 364129 324135 295161 io. 352130 357130 359131 365135 365139 362131 32H36 tFemale rats were exposed to 0, 0. 1, 1.0, or 10 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. Statistical outliers are excluded from calculation of the mean, Grubbs test, p < 0.02. ^Females were bred to unexposed male rats during weeks IS, 16 and 32, 33 of the post-exposure period. During weeks 16, 17, 18 and 33, 34, 35 females were pregnant and due to deliver their young. Body weights taken during these weeks are therefore not reported. cValues for the 40th week represent fasted body weights taken prior to necropsy. *Significantly different from the control value by Dunnett's test, p < 0.05. See Table A-2 for individual animal data. DO 131114 CONFTDFNT TAl -87- TABLE 6 DBCP: INHALATION FERTILITY STUDY IN THE RATf Fertility Index for DBCP Exposed Male Rats Week of study 2 4 7 10 12 14 16 19 24 29 41 ppm DBCP 0 100(20/20)a 100(20/20) 100(20/20) 95(19/20) 100(20/20) 100(20/20) 100(20/20) 100(20/20) 100(20/20) 100(20/20) 100(18/18) 0.1 100(18/18) 95(19/20) 95(19/20) 95(19/20) 95(19/20) 100(20/20) 100(20/20) 95(19/20) 95(19/20) 100(20/20) 95(19/20) 1.0 95(18/19) 95(19/20) 95(19/20) 90(18/20) 100(20/20) 95(19/20) 100(20/20) 100(20/20) 90(18/20) 85(17/20) 85(17/20) 10 95(19/20) 95(19/20) 90(18/20) 100(20/20) 95(19/20) 100(20/20) 100(20/20) 95(19/20) 100(20/20) 100(20/20) 89(17/19) "Male rats were exposed to 0, 0.1, 1.0, or 10 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. Each exposed male rat was housed with 2 unexposed females for a 7-day breeding period during the designated weeks of the study. aFertility Index (%) # fertile males_________ . nn # males housed with females x 1UU No value differed significantly from the control value by Fishers exact probability test, p <0.05. See Table A-3 through A-13 for individual animal data. 00 O0NF1^fNTI Al -88- TABLE 7 DBCP: INHALATION FERTILITY STUDY IN THE RAT1" Percentage of DBCP Exposed Males with Two Pregnancies Among Two Females Week of Study 2 4 7 10 12 14 16 19 24 29 41 ppm DBCP 0 65(13/20)a 75(15/20) 65(13/20) 65(13/20) 75(15/20) 75(15/20) 80(16/20) 80(16/20) 65(13/20) 65(13/20) 61(11/18) 0.1 44(8/18) 70(14/20) 60(12/20) 85(17/20) 65(13/20) 85(17/20) 80(16/20) 75(15/20) 55(11/20) 85(17/20) 50(10/20) 1.0 53(10/19) 45(9/20) 60(12/20) 70(14/20) 90(18/20) 75(15/20) 60(12/20) 85(17/20) 60(12/20) 60(12/20) 45(9/20) 10 60(12/20) 55(11/20) 70(14/20) 65(13/20) 70(14/20) 65(13/20) 80(16/20) 60(12/20) 60(12/20) 55(11/20) 47(9/19) "Male rats were exposed to 0, 0.1, 1.0, or 10 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. Each exposed male rat was housed with 2 unexposed females for a 7-day breeding period during the designated weeks of the study. a # males with 2 pregnant females x # males housed with females 1 No value differed significantly from the control by Fisher's exact probability test, p <0.05. See Tables A-3 through A-13 for individual animal data. no 1311 if-. OONFTOFNTTAi -89- TABLE 8 DBCPs INHALATION FERTILITY STUDY IN THE RAT* Numbers of Corpora Lutea Among Female Rats with DBCP Exposed Males ____________________________ ppm DBCP___________ Week of Study 1.0 10 2 15 2a 14 2 15 * 2 14 4 15 2 15 2 15 1 14 ; 7 16 * 1 15 1 15 * 2 14 : 10 14 2 15 2 15 3 14 ; 12 15 2 15 2 15 2 14 14 15 2 14 1* 14 2* 14 : 16 16 1 15 2 14 2* 14 19 14 1 15 2 15 2 14 : 24 14 1 14 1 14 1 15 29 14 2 14 2 14 1 15 : 41 14 + 2 14 + 2 14 + 1 14 ; e rats were exposed to 0, o.;L, 1.0, or 10 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. Each exposed male rat was housed with 2 unexposed females for a 7-day breeding period during the designated weeks of the study. aMean S.D. The average number of corpora lutea for the two female rats bred to each male was calculated. Group means were then calculated from these averaged values. *Significantly different from the control value by Dunnett's test, p <0.05. See Tables A-3 through A-13 for individual animal data. DO 131117 OONFTDFNTTAl -90- TABLE 9 DBCP: INHALATION FERTILITY STUDY IN THE RATf Numbers of Implantations Among Female Rats Mated with DBCP Exposed Males Week of Study 0 ppm DBCP 0.1 1.0 10 2 14 2a 14 1 13 4 13 2 4 13 3 14 3 15 2 13 3 7 15 1 14 2 14 2 13 2* 10 13 3 14 1 13 2 12 3 12 14 2 14 3 14 2 13 2 14 15 1 13 2* 13 2* 14 2* 16 14 4 13 3 13 2 14 3 19 14 2 14 2 14 3 14 1 24 14 1 13 2 14 2 14 1 29 14 1 14 1 14 2 13 1 41 13 2 13 2 13 2 12 2 tMale rats were exposed to 0, 0.1, 1.0, or 10 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. Each exposed male rat was housed with 2 unexposed females for a 7-day breeding period during the designated weeks of the study. aMean * S. D. The average number of implantations for the two female rats bred to each male was calculated. Group means were then calculated from these averaged values. *Significantly different from the control value by Dunnett's test, p <0.05. See Tables A-3 through A-13 for individual animal data. 00 10111ft OONF TDFNT T Ai -91- TABLE 10 DBCP: INHALATION FERTILITY STUDY IN THE RAT1" Numbers of Resorptions Among Female Rats Mated With DBCP Exposed Males Week of Study 2 4 7 10 12 14 16 19 24 29 41 ppm DBCP 0 1.1 * 1.2* 0.6 0.6 1.1 0.8 0.6 * 0.5 0.8 0.8 0.6 0.7 1.8 3.6 0.6 0.4 0.6 0.8 0.8 * 0.7 0.9 0.9 0.1 0.9 0.6 0.9 1.0 1.2 0.9 0.7 0.5 1.1 1.4 0.6 0.7 0.8 0.8 0.9 1.0 0.9 1.0 0.4 * 0.5 0.3 0.6 1.0 0.6 * 0.7 0.9 1.0 0.9 0.9 0.8 0.8 1.2 1.0 0.7 0.6 1.1 * 1.2 0.4 0.4 0.8 0.8 0.5 0.7 0.5 0.7 10, 1.0 1.0 1.6 1.4 2.6 1.1 2.5 1.6 2.1 1.2 2.3 1.7 2.0 1.6 1.5 + 1.2 0.6 0.6 0.9 1.0 0.6 1.0 +Male rats were exposed to 0, 0.1, 1.0, or 10 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. Each exposed male rat was housed with 2 unexposed females for a 7-day breeding period during the designated weeks of the study. aMean S.D. The average number of resorptions for the two female rats bred to each male was calculated. Group means were then calculated from these averaged values. Resorption data were transformed into percent and were analyzed statistically using a modified Wilcoxon test. See Tables A-3 through A-13 for individual animal data. DO 131119 CONFTDFNTTAL -92- TABLE 11 DBCP: INHALATION FERTILITY STUDY IN THE RAT1- Pre-Implantation Loss Among Female Rats Mated with DBCP Exposed Males * Week of Study 2 4 7 10 12 14 16 19 24 29 41 0 8 lla 13 14 77 7 10 12 10 36 11 23 7 10 78 57 8 10 ppm DBCP 0.1 1.0 2 4* 16 22 11 15 5 dt 9 * 10 12 10 12 7 11 12 15 11 dt 14 8 10* 6 10 6 7 12 19 7 13 6 8 6 dt 10 8 14 8 10 5 5 7 11 9 10 1C1 A: 10 10 7 7 14 16 13 llb 16 22 11 10 6 7 8 15 4 4 77 10 9* 6&7 tMale rats were exposed to 0, 0.1, 1.0, or 10 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. Each exposed male rat was housed with 2 unexposed females for a 7-day breeding period during the designated weeks of the study. aPre-implantation Loss (%) = I. CorPora#LggaQ;a*L^antation x i00 The average pre-implantation Loss for the 2 females bred to each male rat was* calculated. Group means were then calculated from these averaged values. Values are reported as mean standard deviation. bp=0.051, modified Wilcoxon test. Significantly different from control value by a modified Wilcoxon test, p <0.05. 00 irm?o .,, ,, . See Tables A-3 throuah A-13 for individual animal data. OONFTDFNTTAt -93- TABLE 12 DBCP: INHALATION FERTILITY STUDY IN THE RAT* Post Implantation Loss Among Female Rats Mated with DBCP Exposed Males Week of Study 2 4 7 10 12 14 16 19 24 29 41 __________________________ppm DBCP 0 8 ga C1.1 6 4* 1.01 8 14 44 8 10 7 10 7 6 10 12 87 54 53 68 66 11 18 97 45 45 55 7 10 78 88 53 78 33 4 6 8 13 6 6 6 5 3 4* 45 89 5 8 34 10 87 12 10 21 8* 21 14 19 14 17 13 16 15 11 9* 5 5 77 6 9 "^Male rats were exposed to 0, 0.1, 1.0, or 10 ppm of- DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. Each exposed male rat was housed with 2 unexposed females for a 7-day breeding period during the designated weeks of the study. apost-Implantation Loss <%) > T* Jgjg&twns x 100. The average post-implantation loss for the 2 females bred to each male rat was calculated. Group means were then calculated from these averaged values. Values are reported as mean standard deviation. *Significantly different from the control value by a modified Wilcoxon Test, p<0.05. See Tables A-3 through A-13 for individual animal data. no 131^1 OONF T DF NT T At -94- TABLE 13 DBCP: INHALATION FERTILITY STUDY IN THE RATf Incidence of Alterations Among Litters of Unexposed Female Rats Bred to DBCP Exposed Males during Week 41 of the Study No. of pups (litters) examined Exencephaly and Spina Bifida Short tail Bent tail Sex ratio of fetuses (M:F) ppm, DBCP 0 0.1 1.0 10.0 322(27) 330(26) 307(25) 316(26 Number of pups (litters) affected l(l)a 0(0) 0(0) 0(0) 1(1) 0(0) 52:48 51:49 0(0) 0(0) KD 49:51 0(0) 0(0) 0(0) 46:54 ""Male rats were exposed to 0, 0.1, 1.0, or 10 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. Each exposed male rat was housed with two unexposed females during the 41st week of the study. These females were sacrificed on day 20 of gestation and the fetuses were examined for external alterations and cleft palate. aThese alterations were observed in the same litter. No values differed significantly from the control value by a modified Wilcoxon test, p<0.05. See Table A-14 for individual animal data. DO 1311?? CONFTDFNTTAt -95- TABLE 14 DBCP: INHALATION FERTILITY STUDY IN THE RAT'*' Reproductive Parameters - Fertility Index and Survival Indicias for Female Rats Exposed To D8CP by Inhalation (Bred during week IS and 16 of the study period) No. of females t (no.) pregnant Live pups, day 0b Dead pups, day 0b AverageLitter size 'c Live pups, day lb'd Gestation survival index (l)b'e 1-Day survival index (%)b* Sex ratio of pups (M:F), day 1 0 l9a 74(14) 63 0.4 t 0.8 93 82 96 9 98 5 44 . 56 ppm DBCP 071170 20 20 70(14) 10 3 85(17) 9 3 1.0 2.3 0.8 1.2 11 3 94 10 2 9 2 92 19 92 12 95 14 99 3 57 a e 43 48 t 52 ID 20 75(15) 75 0.8 1.1 915 814 83 28 94 19 44 I 56 *Female rats were exposed to 0, 0.1, 1.0, or 10 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. Following termination of exposures (weeks 15 and 16 of the study) each female was housed with two different unexposed male rats, each for a 5-day period. *One control female died during the 15th week of the study. bMean standard deviation. cTotal number of pups born, alive plus dead. dIn some cases, the litter size was greater on day 1 than on day 0 because the dam was still delivering when the data were recorded on day 0. aThe percentage of newborn pups that were alive. ^The percentage of liveoorn pups that survived for one day. No values were significantly different from the control means by the appropriate statistical test, p <0.05. See Table A-15 for individual animal data. DO CONFTDFNT1AI -96- TABLE 15 DBCP: INHALATION FERTILITY STUDY IN THE RAT1" DBCP - Exposed Female Rats Bred to Unexposed Male Rats; Results of External Examination Of 1-Day Old Pups (Bred during week 15 and 16 of the study period) --------o-----------------o:r ------------170----------------- io-- No. of pups (litters) examined 108(14) 131(14) 157(17) 118(15) Number of pups (litters) affected Acaudia or short tail 0(0) 1(1) l(l)a l(l)a Hematoma, umbilical region 0(0) 0(0) 1(1) 0(0) Runts Emaciated pup Hypothermia as determined by touch 0(0) 0(0) 0(0) 1(1) 0(0) 5(1) 1(1) 0(0) 0(0) 0(0) Kl) 3(1) *Female rats were exposed to 0, 0.1, 1.0, or 10 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. Following termination of exposures (weeks 15 and 16) each female was housed with two different unexposed male rats, each for a 5-day period. aThe acaudate or shortened tail pups in the 1 and 10 ppm groups also had imperforate anus. No value differed significantly from the control value by a modified Wilcoxon test, p<0.05. See Table A-15 for individual animal data. DO 131174 C-ONF T OF NT T A1 -97- TABLE 16 DBCP: INHALATION FERTILITY STUDY IN THE RAT* Reproductive Parameters-Fertility Index and Survival Indicies for Female Rats Exposed to DBCP by Inhalation (Bred during week 33 and 34 of the study period) No. of females % (no.) pregnant Live pups, day 0b Dead pups, day 0b Average Litter Sizeb'c Live pups, day lb*d Gestation survival index (%)b'e 1-Day survival indexb'f Sex ratio of pups (M:F), day 1 0 19a 42(8) 4*4 0.3*0.5 64 5*4 95*9 92*22 47:53 ppm DBCP 0.1 1.0 20 20 45(9) 55(11) 8*4 6*4 0.1*0.3 0.40.7 8*4 7*4 8*4 6*4 96*11 89*30 97*7 100*0 56:44 37:63 10 19* 53(10) 5*5 0.2*0.4 6*5 6*5 83*35 99*3 48:52 *Female rats were exposed to 0, 0.1, 1.0, or 10 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. During weeks 33 and 34 of the study, each female was housed with two different unexposed male rats, each for a 5-day period. *One control female died during the 15th week of the study. One high dose female died during the 32nd week of the study. hfiean * standard deviation. cTotal number of pups born, alive plus dead. dln some cases, the litter size was greater on day 1 than on day 0 because the dam was still delivering when the data were recorded on day 0. eThe percentage of newborn pups that were alive. fThe percentage of liveborn pups that survived for one day. No external malformations were observed in the pups examined. No values were significantly different from the control means by the appropriate statistical methods, p<0.05. See Table A-16 for individual animal data. no c oN' :1DF^TTAI -98- TABLE 17 DBCP: INHALATION FERTILITY STUDY IN THE RATf HERITABLE TRANSLOCATION STUDY Reproductive Parameters for Unexposed Female Rats Hated with the F^ Males of DBCP Exposed Male Rats Fertility Index3 Average Corpora Lutea*3 Average Implantations'3 Average Resorptions'3 Pre-Implantation Loss'3*0 Post-Implantation Loss'3 0 100(17/17) 14*2 142 0.6*0.7 69 612 ppm DBCP 0.1 1.0 94(16/17) 100(19/19) 14*2 15*1 152 132 0.70.6 1.11.2 23 1114 54 1113* 10.0 90(18/20) 14*2 14 2 0.50.5 8H 44 ^Fq male rats were exposed to 0, 0.1, 1.0, or 10 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. During the first week post-exposure , each male rat was housed with an unexposed female rat. F^ males resulting from this mating were raised to maturity and housed with two unexposed females for 7 days. "Male Fertility Index (%) - - , housed^fcivfeiaie-- * 100 bMean S.D. The Average value for the two unexposed female rats bred to each F^ male was calculated. Group means were then calculated from the averaged values. cPre-implantation Lose (%) - - corpora^intenttimplantationa x 1## ^Post-implantation Loss (t) - /x^lfg^ltiSns * 100 `Significantly different from control value by a modified Wilcoxon test, p<0.05. S e Tabl A-17 for individual animal data. DO 1311 36 CONFTDFN1 TAl I -99TABLE 18 DBCP: INHALATION FERTILITY STUDY IN THE RATf Hale Rat: Hematologic Evaluation Week of Study ppm DBCP n PCV % RBC x 106/mm3 Hgb g/100 ml WBC x. 10J/mmJ WBC Differential Count (%) Neut Lymph Mono Eos in Baso -1 0 5 52 i la 8.6 0.7 16.0 1.0 20.3 4.2 8 89 2 1 0.1 5 49 1 2 9.0 0.5 15.9 0.4 21.5 1.5 9 85 5 1 1.0 5 50 0,5 8.8 0.2 16.2 0.3 19.9 2.0 10 88 1 1 10.0 5 48 3* 8.8 0.3 - 15.8 0.5 17.6 3.4 7 88 2 3 0 0 0 0 9 0 5 51 1 8.8 0.5 16.5 0.6 14.8 L'9* 11 84 4 1 0.1 5 54 3 9. 3 0.5 17. 3 1.2 10.6 3.3* 14 83 2 1 1.0 5 50 1 8. 8 0.4 16.7 0. 5 10.3 1.9* 12 86 1 1 10.0 5 52 2 8.9 0.5 16.6 0.3 10.1 1.4 16 80 3 1 0 0 0 0 13 0 5 50 2 8.8 0.6 16.6 0.5 19.9 2.9 15 81 2 2 0.1 5 50 3 6.6 0.7 16.6 1.1 17.5 5.3 18 78 2 2 1.0 5 52 2 8.8 0.3 17.2 0.4 14.0 2.2* 11 87 1 1 10.0 5 50 1 8.5 0.2 16.6 0.4 14.2 2.6 19 78 1 2 0 0 0 0 *Male rats were exposed to 0, 0.1, 1.0, or 10 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. aMean S. D. *Significantly different from the control value by Dunnett's test, p<0.05. See Table A-18 for individual animal data. DO 131107 CONFTDFNTTAl -100TABLE 19 DBCP: INHALATION FERTILITY STUDY IN THE RATf Female Rat; Hematologic Evaluation Week of Study ppm DBCP n PCV % RBC X lOvmnr Hgb g/100 ml WB^ C x *1 lOvinm3 WBC Differential Count (%> Neut Lymph Mono Eos in Baso -1 0 5 47 la 8.0 0.4 14.8 0.5 15.6 4.3 7 90 2 1 0.1 5 45 2 7.8 0.4 14.8 1.0 12.7 0.8. 9 88 1 2 1.0 5 49 2 8.2 0.6 15.5 0.8 11.1 1.5 6 92 1 1 10.0 5 49 3 8.7 0.6 16.2 t 1.0 11.6 2.3 8 90 1 1 0 0 0 0 9 0 5 50 dt 2 8.5 0.4 16.1 1.1 10.2 1.0 12 86 1 1 0.1 5 48 t 4 8.2 0.6 16.0 1.0 9.2 1.6 15 80 3 2 1.0 5 50 2 7.9 0.4 16.0 0.4 11.9 2.5. 9 88 2 1 10.0 5 49 2 8.1 0.4 15.9 0.4 14.1 3.1 11 85 1 3 0 0 0 0 13 0 5 48 dt 4 8.1 0.4 16.1 1.1 13.6 4.7 12 85 1 2 0.1 5 48 2 8.1 it 0.2 16.0 0.6 11.1 it 2.7 13 84 1 2 1.0 5 50 * 3 8.0 * 0.5 16.4 * 0.9 11.6 2.6 11 85 2 2 10.0 5 49 2 8.4 0.4 16.9 A 0.6 12.2 * 3.4 15 81 2 2 0 0 0 0 *Female rata were exposed to 0, 0.1, 1.0, or 10 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. aMean S.D. *Significantly different from the control value by Dunnett's test, p<0.05. See Table A-19 for individual animal data. no ioiipa CONF TDFNT TA!. 14 -101- TABLE 20 DBCP: INHALATION FERTILITY STUDY IN THE RAT1" Male and Female Rat: Prothrombin Time ppm DBCP Sex Week of Study n 0 n 0.1 n 1 n 10 Prothrombin time (seconds) M9 (5) 194a (5) 226 (5) 236 (4) 2211 M 13 (4) 151 (5) 162 (5) 162 (5) 141 F9 F 13 (5) 315 (5) 161 (5) 204 (5) 172 (5) 191* (5) 3312 (5) 161 (5) 152 tRats were exposed to 0f 0.1, 1.0, or 10 ppm of DBCP by inhalation for 6 hr/day, S days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. aMean S.D. *Significantly different from the control value by Dunnett's test, p <0.05. See Table A-20 for individual animal data. HO 101109 CONF TDFN'T TA -102- TABLE 21 DBCP: INHALATION FERTILITY STUDY IN THE RATf Male and Female Rat: Clinical Chemistry Values (14th Week of Study) 3ex ppm DBCP ri BUN, mq/lOOml SGPT, mU/ml AP, mU/m' M0 5 18 2a 26 3 58 7 M 0.1 5 19 2 41 35 88 + 80 M 1.0 5 16 2 29 6 58 18 M 10.0 5 17 3 28 4 67 11 F0 5 17 2 F 0.1 5 17 3 F 1.0 5 17 2 F 10.0 5 16 2 19 3 16 3 18 2 22 7 47 16 41 7 33 4 56 18 fRats were exposed to 0, 0.1, 1.0, or 10 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. aMean S.D. No value differed significantly from the control value by Dunnett's test, p <0.05. See Table A-21 for individual animal data. DO 131130 OONFTDFNTIAI -103TABLE 22 DBCP: INHALATION FERTILITY STUDY IN THE RAT* Male and Female Rat:___FSH and Testosterone levels Week of Study Sex ppm DBCP n FSII (nanogram/ml) Testosterone (nanogram/ml) 4 M 0 5 309 =fc 53a M 0.1 5 324 * 65 M 1.0 5 283 55 M 10.0 5 392 51 3.5 2.5 2.8 1.3 3.4 1.7 4.3 2.0 14 M 0 5 297 143 M 0.1 5 214 22 M 1.0 5 301 28 M 10.0 5 334 48 0.7 0.3 2.2 1.4 1.9 1.2 1.0 1.0 4 F 0 5 144 30 F 0.1 5 147 31 F 1.0 5 195 108 F 10.0 5 209 71 14 F 0 5 119 29 F 0.1 5 176 78 F 1.0 5 116 34 F 10.0 5 140 30 *Rats were exposed to 0, 0.1, 1.0, or 10 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. aMean S.D. zo ____ __ U _ No value differed significantly from the control value by Dunnett's test, p<.05. z> 0) z - See Tables A-22 and A-23 for individual animal data. ____ -104TABLE 23 DBCP: INHALATION FERTILITY STUDY IN THE RAT* Male Rat: Urinalysis Week of ppm Study DBCP n Specific Gravity PH Sugar Protein Ke tones Bilirubin Blood Urobilinogen 9 0 4 1.042 Jt 0.0 0 2a 6.0 7.0 Neg 1+ to 3+ 0.1 3 1.043 0.012 6.0 - 7.0 Neg 1+ to 3+ 1.0 4 1.060 0.006 6.0 - 7.0 Neg 2+ to 3 + 10.0 3 1.033 0.006 6.5 7.0 Neg 1+ to 3+ Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg 1.0 1.0 1.0 1.0 13 0 3 1.050 0.010 6.0 7.0 Neg 1+ to 3+ 0.1 2 1.054 0.023 6. 0 - 6.5 Neg 2+ to 3+ 1.0 3 1.053 0.013 6.5 - 7.0 Neg 3+ 10.0 4 1.034 + 0.014 6.5 7.0 Neg 1+ to 4 + Neg Neg Neg Neg Neg Neg Neg Small(l)b Neg Neg Neg Neg 1.0 1.0 1.0 1.0 14c 0 5 1.013 0.013 6.0 7.0 Neg Trace to 3+ Neg 0.1 5 1.047 0.007* 6.0 - 8.0 Neg 3+ Neg 1.0 4 1.034 0.012 6.0 - 8.0 Neg 2+ to 3+ Neg 10.0 5 1.018 0.007 6.0 - 8.0 Neg 2+ to 3+ Neg Neg Trace{1)b Neg Neg Neg Neg Neg Neg 1.0 1.0 1.0 1.0 *Male rats were exposed to 0, 0.1, 1.0, or 10 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. aMean S. D. b( ) indicates number of rats affected. cDue to difficulty in obtaining urine samples from male rats during the 13th week, additional urine samples were obtained at the time of necropsy in the 14th week. *Significantly different from the control value by Dunnett's test, p<0.05. See Table A-24 for individual animal data. -105TABLE 24 DBCP: INHALATION FERTILITY STUDY IN THE RAT* Female Rati Urinalysis Week of ppm Study DBCP n Specific Gravity PH Sugar Protein Ketones Bilirubin 9 0 5 1.038 0.008a 6.0 - 7.0 Neg Trace to 3+ Neg 0.1 5 1.050 0.009 6.0 - 6.5 Neg Trace to 2+ Neg 1.0 5 1.037 0.008 6.0 - 7.0 Neg Trace to 2+ Neg 10.0 5 1.033 0.015 6.0 - 7.0 Neg Trace to 2+ Neg Neg Neg Neg Neg Blood Neg Neg Neg Neg Urobilinogen 1.0 1.0 1.0 1.0 13 0 5 1.032 0.010 6.0 - 7.0 Neg Trace to 2+ Neg 0.1 5 1.042 0.012 6.0 - 6.5 Neg Trace to 3+ Neg 1.0 5 1.033 + 0.006 5.0 - 7.0 Neg Trace to 3+ Neg 10.0 5 1.036 0.005 5.0 - 6.5 Neg Trace to 2+ Neg Neg Neg Neg Neg Neg Neg Neg Neg 1.0 1.0 1.0 1.0 ^Female rats were exposed to 0, 0.1, 1.0, or 10 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. aMean S.D. No value differed significantly from the control value by Dunnett's test, p<0.05. See Table A-25 for individual animal data. no 131133 rONFTOFNTTAl 1 TABLE 25 DBCP: INHALATION FERTILITY STUDY IN THE RAT* Hale Rat: Organ Weights and Organ/Body Weight Ratios Determined at the Interim (4 weeks and 14 weeks) and Terminal (46 weeks) Sacrifices Week of ppm Body Wt. Study DBCP n ____ 6____ Brain 8 g/lOOg Heart 8 g/lOOfi Liver S g/lOOg Kidneys 8 g/lOOg Testes 8 s/100g Epididymides S s/ iook ti 0 5 541 * 40 1-9910.05 0.3710.03 1.63*0.12 0.30*0.02 19.4 * 1.6 3.59*0.19 3.96*0.12 0.74*0.04 4.37*0.17 0.81*0.04 1.57*0.06 0.29*0.02 4 0.1 5 529 35 1.9810.08 0.37*0.02 1.59*0.21 0.3010.02 17-7 * 2.5 3.34*0.28 3.57*0.51 0.67*0.06 4.23*0.13 0.80*0.07 1.49*0.07 0.2810.02 4 1.0 5 .536 t 42 2.000.08 0.37+0.03 1.51+0.06 0.28+0.01 19.6 + 3.2 3.64+0.28 3.74+0.27 0.70+0.06 3.97+0.14'*0.74i0.04 1.43+0.09'*0.2710.03 4 10.0 5 496 t 30 2.0310.09 0.4U0.01 1.4510.12 0.2910.02 18.8 + 1.2 3.80i0.15 3-7310.30 0.75+0.06 4.15+0.09 0.84+0.05 1.51+0.10 0.31+0.02 14 0 5 5 IT 45 1.99+0.03 0.39+0.03 1.57+0.12 0.30+0.01 14.2 + 1.6 2.75+0.24 3-50+0.42 0.68+0.06 4.04+0.38 0.79+0.13 1.45+0.15 0.28+0.02 14 0.1 5 538 i 48 2.0110.06 0.3810.03 1.6710.19 0.31+0.03 14.2 + 1.8 2.63+0.19 3.71+0.48 0.69+0.07 4.15+0.12 0.78+0.06 1.49+0.06 0.28+0.03 14 1.0 5 522 i 27 2.03+0.11 0.39+0.01 1.69+0.18 0.3210.04 14.4 i 1.4 2.75+0.15 3.76+0.48 0.7210.06 4.19+0.21 O.80+O.O4 1.4910.07 0.2910.02 14 10.0 5 492 20 1.93+0.06 0.39+0.02 1.48+0.05 0.30+0.02 15.0 + 1.4 3.04+0.17 3.97+0.29 0.81+0.06''2.7110.19''o. 5510.02''l. 1310. OB'*0.2310.01* 46 0 17 607 1 44 2.O61O.O6 0.3410.02 1.86i0.l4 0.3110.02 19.3012.70 3.1810.4i 5.0510.83 0.840.1T 4.4110.33 0.73+0.05 1.66i0.l4 0.2710.02 46 0.1 19 646 36 2.0810.06 0.32+0.02 1.86+0.15 0.29+0.02 19.84+2.54 3.0T+0.32 4.99+0.59 0.77+0.08 4.60+0.38 0.71+0.08 1.75+0.14 0.27+0.03 46 1.0 18 618 1 73 2.04l0.09 0.34l0.07 I.861O.21 0.3010.03 19*4813.36 3.161O.45 5-09ll.ll 0.83+0.16 4.48+0.40 0.7310.10 1.66^0.16 0.2&10.03 46 10.0 20 637 1 77 2.010.0T 0.3210.04 1.94i0.20 0.3U0.04 20.84i3.02 3.2710.26 5.4310.67 O.861O.17 4.1310.57 0.66i0.08*1.62i0.24 0.26i0.04 ^Hale rats were exposed to 0, 0.1, 1.0, or 10 ppm of DBCP by Inhalation for 6 hr/day, 5 days/week for ill weeks. Following termination of the exposure period, animals were maintained In the laboratory for recovery. Mean 1 S.D. 'significantly different frcn the control value by Dunnett's test, p<0.05. See Table A-26 for Individual animal data. TABLE 26 DBCP: INHALATION FERTILITY STUDY IN THE RAT* Female Rats; Organ Weights and Organ/Body Weight Ratloa Determined at the Interim (It weeks and lit weeks) and Terminal tUp weeks) Sacrifices Week of Study k k It It ppm DBCP 0 0.1 1.0 10.0 Body Wt. Brain n S _____ S_____ g/lOOg 5 285 + 50a 1.7710.07 0.6k+0.12 5 302 + 11 1.8k+0.08 0.640.0k 5 301 * 23 1.8k+0.08 0.61+0.03 5 279 1 20 1.81*0.06 0.650.05 Heart B g/100g 1.03+0.08 0.37+0.06 0.99+0.0k 0.33+0.01 0.99+0.08 0.33+0.02 0.9k0.09 0.3k+0.0k Liver S K/lOOg Kidneys e r/IOOk 11.15+1.38 3.98+0.6k 10.19+0.62 9.9k+1.17 3.38+0.21 3.30+0.22* 10.OBjO.k3 3.63+0.3k 2.240.17 0.80+0.lk 2.22+0.15 2.2k0.15 0.740.05 0.75+0.05- 2.lk+0.20 0.77*0.11 lit 0 5 303 * 33 1.81*0.03 0.60+0.07 0.97+0.06 0.32+0.02 7.88+1.02 2.60+0.1k 2.11+0.29 0.70+0.ok Ik 0.1 5 317 1 28 1.8510.Ok 0.5910.0k 1.12+0.11* 0.3510.03 7.950.61 2.5110.0k 2.3510.17 0.7k+0.06 lk 1.0 5 28k 1 12 1.8210.06 0.640.03 0.940.07 0.3310.01 7.0510.k2 2.k9+0.12 2.16+0.09 0.76+0.03 Ik 10.0 5 298 i lk 1.08+0.00 0.63+0.Ok 1.01+0.06 0.3k+0.03 8.k3+0.89 2.82+0.19 2.35+0.09 0.79*0.06* ko 0 19 313 1 23 1.8710.06 0.600.0k 1.2210.08 0.3910.03 ll.3kil.28 3.6ki0.k7 2.65*0.2k 0.65*0.08 kO 0.1 20 32k 35 1.8k+0.07 0.57+0.06 1.17+0.12 0.36+0.Ok 11.12*l.k2 3.kk+0.37 2.50*0.18 0.76*0.10 ko 1.0 19 295 * 61 1.65*0.05 0.66l0.19 1.1510.16 O.kOlO.Ok 10.53d3.26 3.55*0.51 2.5210.33 0.68*0. IT kO 10.0 IT 321 * 36 1.86i0.05 0.5910.05 1.20*0.10 0.38i0.0k 12.23+2.23 3.83*0.75 2.71*0.27 0.65*0.10 *Female rats vere exposed to 0, 0.1, 1.0, or 10 ppm of DBCP by Inhalation for 6 hr/day, 5 days/week for lk weeks. Following termination of the exposure period, animals were maintained In the laboratory for recovery. "Mean 1 S.D. "significantly different from the control value by Dunnett's test, p<0.05. See Table A-27 for individual animal data. * -108- Diagnosis Code E-l P-3 LL-8 Q-7 TABLE 27 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY Alb RECOVERY STUDY OF DBCP IN RATS AND RABBITS GROSS PATHOLOGIC OBSERVATIONS ON RATS FROM THE 4-WEEK INTERIM KILL Observations Number of rata per group GENERAL No vlaiblc lesions URINARY SYSTEM Mineralization of renal cortex or palvia FEMALE REPRODUCTIVE SYSTEM Clear fluid dietending uterine horn(a) INTEGUMENT AND SUBCUTANEOUS Abscess or Inflammation of preputial fi Expoaure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Mala 5 S 5 5 3 3 5 5 0 0.1 1.0 10.0 0 2 0 0 0 0.1 1.0 10.0 - 0 0.1 1.0 10.0 2 1 0 0 Fmoale 5 5 5 5 5 3 4 5 _ - * 0 2 1 0 - * - " - Indicates none examined or not applicable. 00 131136 CONFTDFNTTA1 Diagnosis Code T-l T-3e E-l -7 Pr-1 Pr-2, Pr-2m SV-1 CG-1 -109- TABLE 28 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RAIS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON RATS FROM THE 4-WEEK INTERIM mj. Exposure Laval Obaarvatlona (ppm)______ Number of rata per group 0 0.1 1.0 ___________________________________________________________ 10.0 MALE REPRODUCTIVE SYSTEM Teatea - Number of tlaeuee examined 0 0.1 1.0 10.0 No visible leaiona 0 0.1 1.0 10.0 Atrophy (decreaaed apermatogeneala of Individual eemlnlferoua tubulea, Includes Individual aeml- niferous tubulea containing predominantly aertoli cella) - focal or multifocal, alight 0 0.1 1.0 10.0 Male Fmule 5i 5 5 !; 5I s 5 5__________ 5____ 5 5 5 5 5 5 3 4 0 0 2 1 Epldldymidea - Number of tlaauea examined 0 0.1 1.0 10.0 No vialble leaiona 0 0.1 1.0 10.0 Aggregate of mononuclear lymphoid cells, peri- vascular - focal 0 0.1 1.0 10.0 Prostate - Number of tissues ""<0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Aggregate of mononuclear lymphoid cells - focal or multifocal. Interstitial 0 0.1 1.0 10.0 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 o 0.1 1.0 10.0 0 0.1 1.0 10.0 o 0.1 1.0 10.0 5i 5 51 5 5 5 4 5 0 0 1 0 5 5 5 5 4 3 4 4 1 2 1 1 5 5 5 5 5 5 5 3 5 5 5 5 5 5 5 5 r N (0 CONF TfJFNT TAi Diagnosis Code Ov-1 OD-l U-l C-l B-l A-l 110- TABLE 28 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCF IN RAIS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF tissues EXAMINED ON RATS FROM THE 4-WEEK INTERIM DLL ___________________ Observations Number of rata per group FEMALE REPRODUCTIVE SYSTEM Ovaries - Number of tissues examined No visible lesions Oviducts - Number of tissues No visible lesions Uterus - Number of tissues examined No visible lesions Cervix - Number of tissues examined No visible lesions Exposure Level (ppm)____________ Male Female 0 55 0.1 5 5 1.0 5 5 10.0_______________ 5__________ 5___ 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 -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. v DO CONFTDFNTTAl Dlagnoale Code A-2ua A-lAbe 111- TABLE 28 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCF IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMNm ON RATS FROM THE 4-WEEE INTERIM RILL ___________________ Observations Number of rate per group ENDOCRINE SYSTEM (cont'd) Adrenal Glenda (cont'd) Focus(1) of altered calls, cortex - unilateral, alight Increased vacuolization, cortex - bilateral, alight Exposure Level (PP) ___________ Male Female 0 55 0.1 5 5 1.0 55 10.0_______________5__________ 5____ 0 0.1 1.0 10.0 0 0.1 1.0 10.0 00 00 10 00 00 10 00 00 - Indicates none examined or not applicable. no 131139 CONF T DFNTJfy -112- Diagonal! Code A-4 D-l D-2 D-3 E-l E-2 L-l L-2 L-19 M-l XABLE 29 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITT AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS CROSS PATHOLOGIC OBSERVATIONS ON RATS FROM THE 14-WEEK INTERIM KILL ______________ Observations Number of rata par group ADRENAL GLANDS Unilateral absence of adrenal EYES Exophthalmua Intraocular cloudiness Cloudiness of cornca(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) Male Female 0 S5 0.1 5 5 1.0 5 5 10.0_______________5__________ 5 0 0.1 1.0 10.0 0 -o -1 -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 -o -0 -0 00 11 00 00 0 0.1 1.0 10.0 0 0.1 1.0 10.0 23 34 54 04 -2 -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 10.1 2 0 0 5 0 0 0 3 1 0 0 0 0 1 0 1 on 13! 140 r ONFTDFNTTA Diagnosi Code P-7 Q-l-(l) Q-4 0-7 -113- TABLE 29 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOUCITT AND RECOTERT STUDY OF DBCF IN RATS AND RABBITS CROSS PATHOLOGIC OBSERVATIONS ON RATS FROM THE 14-WEEK INTERIM KILL Observations Number of rate per group URINARY SYSTEM Focal dark, depressed foci or ares(s) in kidney Exposure Level (non) 0 0.1 1.0 1CU)55 0 0.1 1.0 10.0 Male Pul. 55 55 55 1- 0 0 0 INTECUMENT AND SUBCUTANEOUS Subcutaneous mass - inguinal, mamaxy or midcervical region Abscess of clitoral gland 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Abscess or inflamBstion of preputial gland 0 0.1 1.0 10.0 - Indicates none examined or not applicable. -0 -0 -0 -1 -1 -0 -0 -0 1 0 0 0 i_ ^ OA4fr Tr>FN 41 7 r*i -11*' Diagnosis Code L-l L-2, L-2s L-7s L-10 L-13m K-l K-2, K-2s K-3 K-4 K-5 TABLE 30 SUBCHRONIC IKEALAIION 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 Obaervetlone Exposure Level (ppm) Male Ffmi* Number of ret* per group 0 35 0.1 5 3 1.0 5 5 ____________________________________________________________________ifiafl_______________5 5 LIVER Number of tissues examined 0 0.1 1.0 10.0 55 55 55 53 No visible lesions 0 0.1 1.0 10.0 3* A3 35 34 Aggregate* of mononuclear, lymphoid or reticuloendothcllal cells - focal or multifocal 0 0.1 1.0 10.0 21 02 10 21 Biliary hyperplasia - focal or multifocal, slight 0 0.1 1.0 10.0 00 10 00 00 Coagulation necrosis and inflammation - focal 0 0.1 1.0 10.0 00 00 10 10 Chronic active Inflammation, portal triads - moderate 0 o.l 1.0 10.0 00 10 00 00 URINARY SYSTEM Kidneys - 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 cortlcomedullary 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 no ir?i i4p OONFTDFNTTA! Diagnosis Coda K-6va K-6s K-10 K-lls K-12 DB-1 T-l T-3s T-2u, sev -115' TABLE 30 (Continued) SOBCHRONIC INHALATION REPRODUCTIVE TOnCITT AND RECOVERT STODT OF DBCF IN RATS AND RABBITS 1 HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON RATS FROM THE 14-WEEK INTERIM KILL Observation* Number of rats par group Exposure Laval _______ (ppm)______ 0 0.1 1.0 10.0 yRINAKT SYSTEM (cont'd) Kidney (cont'd) Chronic progressive glomerulonephropathy - very alight 0 0.1 1.0 10.0 Chronic progressive glomerulonephropathy - slight 0 0.1 1.0 10.1 Inflammation, subacute, lnterstltium 0 0.1 1.0 10.0 Aggregates of mononuclear lymphoid cells, pelvis - focal or multifocal, slight 0 0.1 1.0 10.0 Aggregates of mononuclear lymphoid cells, perl- vascular - focal or multifocal 0 0.1 1.0 10.0 MalJ 5! 5 5 5 0 2 1 0 0 0 0 3 0 0 0i 0 0 0 0 0 0 0 0 0 Urinary 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 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Atrophy (decreased spermatogenesis of Individual seminiferous tubules - Includes Individual semlni- ferous tubules containing predominantly sertoli cells) - focal or multifocal, slight 0 0.1 1.0 10.0 Atrophy (generalised) - unilateral, severe 0 0.1 1.0 10.0 5 5 5 5 3 5 5 0 0 0 0 5 1 0 0 0 Fenalc 5 5 5 5 0 0 1 0 0 0 0 0 0 0 1 0 0 1 0 0 0 0 1 0 5 4 4 5 5 4 4 3 - " - - - - - " - Indicates none examined or not applicable. DO 101143 CONF TDFNTTA 116 Diagnosis Code T-2bav T-4u T-4b T-6u T-6b T-7u T-7b E-l E-2u E-2b TABLE 30 (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 rate per group MALE REPRODUCTIVE SYSTEM (cont'd) Teatea (cont'd) Atrophy (generalized) - bilateral, eevere Mineralization (intratubular calcification) - multifocal, unilateral Mineralization (Intratubular calcification) - multifocal, bilateral Edema, lnteratltlal - unilateral Edema, lnteratltlal - bilateral Locally increased multnucleated apermatlda - unilateral Locally increased multinucleated spermatids - bilateral Epididymides - Number of tissues examined No visible lesions Atrophy - unilateral Atrophy - bilateral Exposure Level (nom)____________ Male Female 0 55 0.1 5 5 1.0 5 5 ___ ISL5__________ 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 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. no 131144 C.ONF TOFN1 TAt Diagnosis Code E-3u E-3b SV-1 CC-1 Pr-1 Pr-2 Pr-4s TABLE 30 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITT AND RECOVER! 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) Epididymides (cont'd) Decreased sperm content, tubular limine - unilateral Decreased sperm content, tubular limine - bilateral Exposure Level ____ (PP*?_____ 0 0.1 1.0 li Male 5 5 3 5 0 0.1 1.0 10.0 0 0.1 1.0 10.0 1 0 0 0 1 0 0 0 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 3 5 3 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 3 5 4 5 3 5 4 5 Prostate - Number of tissues examined No visible lesions Aggregates of mononuclear lymphoid cells - focal or multifocal,interstitial Suppurative inflammation - focal, slight FEMALE REPRODUCTIVE SYSTEM Ovaries. - 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 o.l 1.0 10.0 0 0.1 1.0 10.0 3 5 5 3 5 3 3 2 0 0 0 2 0 0 0 1 Female 5 5 3 5 5 5 3 5 - Indicates none examined or not applicable. DO 131)45 CONFTDFNT TA[ -118 Diagonals Coda Ov-1 OD-1 U-l C-l B-l A-l TABLE 30 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITT 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 FEMALE REPRODUCTIVE SYSTEM (tout'd) Ovaries (cont'd) No visible lesions Exposure Level _____ (ppm)____________ Male 05 0.1 5 1.0 5 ___________________ S - Female 5 5 5 5 0 0.1 1.0 10.0 5 -5 -5 -5 Oviducts - Number of tissues examined No visible lesions Uterus - Number of tissues examined No visible lesions Cervix - Number of tissues examined No visible lesions 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 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 4 -3 -5 -5 .4 -5 -5 -5 5 -5 -5 -5 -5 -5 -5 -5 5 -5 -4 -4 5 -5 -4 -4 35 55 55 35 55 55 55 55 55 55 45 55 43 55 44 22 Indicates none examined or not applicable. -3. V- Z <? o c Diagnoala Coda A-2ua A-2ba A-5us TABLE 30 (Continued) SOBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCF IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON RATS FROM JHE 14-WEEK INTERIM KILL Obaervatlona Number of rata per group ENDOCRINE SYSTEM (cont'd) Adrenal Glanda (cont'd) Focua(i) of altered cella, cortex - unilateral, alight Focua(l) of altered cella, cortex - bilateral, alight Ectatic ainuaolds - multifocal, unilateral, alight Expoeure Level (ppm)Male Female 0 53 0.1 5 5 1.0 5 5 1(F055 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 - Indicate# none examined or not applicable. DO 131147 CONFTDFN1 I A! 120- Diagnosis Code A-2 B-l B-2 B-3 C-l D-3 D-4 D-5 D-6 E-l TABLE 31 SUBCHHONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STOUT OF DBC? IN HATS AND RABBITS CROSS PATHOLOGICAL OBSERVATIONS ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN WFi.n for QP 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(1) 0 0.1 1.0 10.0 CARDIOVASCULAR SYSTEM Pale streaks, 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 Terminal Kill 17 19 20 18 Cumulative Results 20 20 20 20 0 00 0 00 - 22 0 16 16 0 00 0 00 - 00 1 01 0 00 0 00 - 00 1 01 0 00 0 00 - 11 0 00 0 00 0 00 - 00 1 01 0 11 0 11 - 22 0 33 0 22 0 11 - 44 0 00 0 00 0 00 - 00 0 11 0 00 0 00 - 11 0 00 0 55 0 10 10 - 00 0 00 DO 131148 CONF TOFNT T Al 121' Diagnosis Code E-2 E-3 E-7 E-9 E-10 E-ll E-12 F-5 F-6 F-8 F-9 TABLE 31 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCF IN RATS AND RABBITS GROSS PATHOLOGICAL OBSERVATIONS ON HALE HATS EXPOSED TOR 14 WEEKS AND THEN HET-n ro CP TO 32 WEEKS OF RECOVERY Observations Number of rata per group GENERAL (cont'd) Nodule of necrotic omental or mesomctrlal fat Postmortem autolysis Exudate or porphyrin-like pigment accumulation lateral to external nares or around eyes Perineal soiling Depletion of adipose tisaue. 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 mucosa suggestive of hyperkeratosis Absence or decreased normal Ingests In gastrointestinal tract Small Intestinal maaa(es) or nodule(s) Mineralization of gastric wall 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 -- 0 0 - 0 1 0 - 1 0 1 2 0 0 - 0 1 0 - 0 1 1 - 0 2 1 o Terminal! Kill 17 19 , 20 18 0 1 1 0 0 0 0 0 0 0 1i '1 i 0 0 1 1 1 0 2 1 0 0 0 0 0 0 0 0 Cumulative Results 20 20 20 20 0 1 1 0 1 0 0 1 0 1 1 3 0 0 1 1 2 0 2 1 1 1 0 0 2 1 0 0 0 00 0 00 00 0 11 1 01 0 00 - 00 1 01 1 01 0 00 * 00 0 00 1 01 0 00 00 1 01 00 1 31149 C0NFTDFNTTA1 122- ' Diagnosis Code F-10 F-ll G^-l G-2 G-5 G-7 G-8 G-9 G-10 H-3 H-5 TABLE 31 (Continued) SDBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERT STUDY OF DBCP IN RATS AND RABBITS CROSS PATHOLOGICAL OBSERVATIONS ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN mj tor HP TO 32 WEEKS OF RECOVERY Observation* Number of rats per group GASTROINTESTINAL SYSTEM (cont'd) Gaseous distention of stomach and/or Intestinal tract Enlarged Peyer's Patch In small Intestine LIVER Diaphragmatic hernia Solitary to several red or darkened focus(1) or area(s) in liver Feu small pale foci or focus In liver Enlarged llvar Darkened or congested liver Firm liver Linear streak(s) or areas In liver LYMPHORETICULAR 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 no 131150 OONFTOFNTTAl -123- Diagnosis Code H-6 H-7 1-1 s J-l J-2 K-l K-2 K-3 K-4 L-l TABLE 31 (Continued) SOBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCF IN RATS AND RABBITS CROSS PATHOLOGICAL OBSERVATIONS ON MALE RATS EXPOSED FOB 14 ufhcr AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rats per group LYMPHORETICULAR SYSTEM (cont'd) Cyst replacing renal lymph node(s) Mottled renal lymph node(a) Exposure Level (pom) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 MUSCULOSKELETAL SYSTIM Demineralization of bones 0 0.1 1.0 10.0 PANCREAS Nodule(s) in region of pancreas Slight thlckenlng(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(1) on pituitary Enlarged pituitary Mottled pituitary Cyst 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-llke 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 IB Cunulatli Results 20 20 20 20 0 11 0 00 - 00 0 00 0 00 0 11 - 00 0 00 1 01 0 00 - 00 0 00 0 00 0 00 - 11 0 00 0 00 0 00 - 11 0 00 0 00 0 00 - 00 1 01 0 00 0 00 - 11 0 11 0 00 0 00 - 11 0 00 0 00 0 11 - 00 0 00 0 00 0 11 a- 0 0 0 22 DO 131151 CONFTDFNT TAl -124 Diagnosis Code L-2 L-S L-6 L-4 L-7 L-3 L-6 L-9 M-l M-2 TABLE 31 (Continued) SOBCHBONIC INHALATION REPRODUCTIVE TOIICITY ADD RECOVERY STUDY OF DBCF IN RATS AND RABBITS CROSS PATHOLOGICAL OBSERVATIONS ON HALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Observation* Number of rats per group TESTES (cont'd) Dark or tan appearance of testes Increased size of testes Edematous appearance of testes EPIDIDYMIDES Nodule of necrosis In epldldymal fat pad Abscess or inflammation of epididymides ACCESSORY SEX GLANDS Decreased size of accessory sex glands Dark focus on prostate Enlarged prostate RESPIRATORY SYSTEM Dark or red focus(1) 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 - Indicate* none examined or not applicable. Died or Rilled Moribund During Recovers Period 3 1 0 2 Terminal Rill 17 19 20 18 Cumulative Results 20 20 20 20 0 00 0 11 - 00 0 00 0 00 0 00 00 b 11 0 00 0 11 - 00 0 11 0 00 0 00 * 00 0 11 0 00 0 00 - 00 0 11 0 00 0 00 - 00 0 11 0 00 0 00 -e 1 1 0 00 0 00 1 01 - 00 0 00 0 55 0 11 - 10 10 0 11 1 12 0 00 . 00 0 00 DO 131 1 S? CONFTDFNIT TA! 125- Diagnosis Code M-3 M-4 M-5 N-l N-2 0-1 P-1 P-2 P-3 P-7 TABLE 31 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOUCITT AND RECOVER! STUDY OF DBCF IN RATS AND RABBITS CROSS PATHOLOGICAL OBSERVATIONS ON MALE rats gypnsm WYR 14 vtttz AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rats per group RESPIRATOR! SYSTEM (cont'd) Pulmonary congestion or dark color Pulmonary edema Mottled appearance of lungs SPLEEN Ectopic splenic tissue Enlarged spleen PARATHYROID GLANDS Enlarged parathyroids 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 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 Recoverv Period 3 1 0 2 Terminal Kill 17 19 20 18 10 00 0 00 10 10 -0 00 00 10 -0 01 00 00 -0 01 00 00 -0 01 10 00 -0 10 10 00 -0 10 14 02 5 15 01 00 -0 01 00 01 -1 00 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 C.ONF f oFNT T Al -126- Diagnosis Code P-8 P-9 P-10 P-19 P-6 0-1(1) 0-3(1) 0-6(1) 0-6(2) 0-7 TABLE 31 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVER! STUDY OF DBCP IN RATS AND RABBITS CROSS PATHOLOGICAL OBSERVATIONS ON MALE RATS EXPOSED TOR 14 WEEKS AND THEN RPTn row UP TO 32 WEEKS OF RECOVERY Obeervationa Number of rata per group Exposure Level (ppm) 0 0.1 1.0 10.0 KIDNEYS (cont'd) Dilated renal pelvia(e) (hydronepbroale) 0 0.1 1.0 10.0 Mottled appearance of kidney(t) 0 0.1 1.0 10.0 Cyat(i) in kidney 0 0.1 1.0 10.0 Pale depreaaed area on kidney 0 0.1 1.0 10.0 URINARY BLADDER Organized plug within urinary bladder 0 0.1 1.0 10.0 INTEGUMENT AND SUBCUTANEOUS Subcutaneoua maaa - Inguinal, masnary or mldcervical region - Number per rat: 1 0 0.1 1.0 10.0 Subcutaneoua maaa - body or limb region - Number per rat: 1 0 0.1 1.0 10.0 Cutaneoue nodule or maaa; body, head or limb region - Number per rat: 1 0 0.1 1.0 10.0 Cutaneoue nodule or maaa; body, head or limb region - Number per rat: 2 0 0.1 1.0 10.0 Abeceee or inflammation of preputial gland 0 0.1 1.0 10.0 - Indicate* none examined or not applicable. Died or Killed Moribund During Recovery Period 3 1 0 2 Terminal Kill 17 19 20 _____ IS______ Cumulative Result! 20 20 20 20 1 01 0 00 - 11 0 00 0 00 0 00 - 00 0 11 0 00 0 00 - 11 - 11 0 00 0 00 - 11 0 00 0 33 0 11 - 33 0 11 0 00 0 00 00 0 22 0 00 0 00 - 00 0 11 0 11 0 00 - 00 0 11 0 00 0 00 * 00 0 11 0 11 0 11 . 11 0 22 DO 101 "l C0NFTDFN1 T A1 -127 Diagnosis Code Q-8 Q-9 S-4 TABLE 31 (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 DP TO 32 WEEKS OF RECOVERY Observations Number of rats per group INTEGUMENT AND SUBCUTANEOUS feont'dl 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 Terminal Kill T -------- IT- 19 20 < 18 1 Cumulative 20 20 20 20 1 01 0 00 - 00 0 00 1 01 0 00 * 00 1 01 0 0.1 1.0 10.0 0 00 0 0, 0 me - 11 0 11 1 - Indicates none examined or not applicable. on i3u, ss CONFTDFNTTAl 124- TABLE 32 SUBCHRDNIC INHALATION REPRODUCTIVE TOXICITY AND RECOVEST STUDY OF DBCP IN RATS AND RABBITS CROSS PATHOLOGICAL OBSERVATIONS ON FINALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD row IIP TO 26 WEEKS OF RECOVERY Diagnosis Cods_____________________________ Observations Number of rats per group Exposure Died or Killed Level Moribund During Terminal Cumulative (oral Recovery Period Kill Results "0 ------------------------ 1*---------------19-------------------5o--------- 0.1 0 20 20 1.0 1 19 20 10.0__________________ 3______________17____________ 20 ADRENAL GLANDS A-2 Mottled sdrenal(s) and/or pinpoint focus(1) 0 0.1 1.0 10.0 A-3 Enlarged adrenal(s) 0 0.1 1.0 10.0 0 11 11 0 44 1 9 10 0 00 00 0 00 0 33 CENTRAL NERVOUS SYSTEM C-l Darkened, discolored or distorted area In 0 brain 0.1 1.0 10.0 C-2 Focal hemorrhage lesions on themeninges 0 0.1 1.0 10.0 0 00 00 0 00 1 01 0 00 11 0 00 0 00 EYES D-3 Cloudiness of cornea(s) 0 0.1 1.0 10.0 0 00 11 0 00 0 00 GENERAL E-l No visible lesions (NVL) 0 0.1 1.0 10.0 E-3 Postmortem autolysis 0 0.1 1.0 10.0 E-4 Vaginal discharge 0 0.1 1.0 10.0 E-3 Ascites - cloudy, dark or hemorrhage 0 0.1 1.0 10.0 E-6 Multiple nodules vlthln abdominal cavity 0 (possible pancreatic or mesothelial 0.1 involvement) 1.0 10.0 0 53 11 0 11 0 22 1 01 00 0 00 0 00 0 00 00 1 01 1 01 0 00 00 0 00 1 01 0 00 00 0 00 1 01 - Indicates none examined or not applicable. confVofmt^1 .129' Diagnosia Code E-7 E-B E-9 E-10 E-ll F-l F-2 F-3 F-4 F-5 F-6 TABLE 32 (Continued) SUBCHHONIC INHALATION REPRODUCTIVE TOXICITT AND RECOVEST STUDT OF DBCP IN RATS AMD RABBITS GROSS PATHOLOGICAL OBSERVATIONS ON FEMALE BATS EXPOSED TOR 14 MEEKS AND THEN HELP TOR tm TO 26 WEEKS OP RECOVERY Observation* Number of rate per group Exposure Level (ppm) 0 0.1 1.0 10.0 GENERAL (cont'd) Exudate or porphyrln-llka pigment acctnula- tion lateral to external nares or around eyea Diffuse paleness of tissues (anemia) Perineal soiling Depletion of adipose tissue, including serous atrophy of fat t 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 STSTEM 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 Ingest* 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. no i 3 1 1 57 OONF T DFNT 1 A1 -130- Diagnosis Code F-7 G-l 0-2 0-3 0-4 G-5 C-6 H-l H-2 H-3 H-4 TABLE 32 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCF IN RATS AND RABBITS CROSS PATHOLOGICAL OBSERVATIONS ON FTMAT.r rats EXPOSED FOR 14 WEEKS AND THEN held TOR UP TO 26 WEIRS 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(1) or area(a) in liver Diffuse paleness of liver Accentuated lobular pattern of liver Fev small pale foci or focus in liver Pale arca(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 LYMPHORETICULAR 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 Cumulative Results " 26 20 20 20 0 00 - 00 0 11 0 00 0 11 - 00 0 00 0 00 0 00 11 0 11 0 22 0 00 - 00 1 0 1. 0 00 0 00 - 00 1 01 0 00 0 00 - 00 0 11 0 00 0 00 - 00 0 11 0 00 0 00 * 00 0 00 1 01 0 00 - 00 0 00 1 01 0 00 - 00 0 00 0 11 0 00 - 00 0 00 0 11 DO 1311 SB C.ONF T OF NT 1 Al -131- Diagnosis Code J-l K-l LL-1 LL-2 LL-3 LL-4 LL-5 LL-6 LL-7 LL-8 TABLE 32 (Continued) SDBCHBONIC INHALATION REPRODUCTIVE 70XXCITT AND RECOVEII STDDT OF DBCF IN RATS AND RABBITS CROSS PATHOLOGICAL OBSERVATIONS OW TOOLE RATS EXPOSED FOR 14 WEEKS AND THEN w*TM won tn TO 26 HEEES OP RECOVER! Observation* Number of rets per group Exposure Died or Rilled Level Moribund During - (PP) 0 Recoverv Period "' i 0.1 0 1.0 l 10.0 3 Terminal Kill 19 20 19 17 PANCREAS Nodule(a) In region of pancreas 0 0.1 1.0 10.0 00 -0 00 10 PITUITARY GLAND Dark, red or hemorrhagic focus(1) on pituitary 0 0.1 1.0 10.0 00 -1 00 00 FEMALE REPRODUCTIVE SYSTEM Cyst In ovary Endometrial polyp(s) Dark or hyperemlc appearance to uterus or meaometrlal blood vessels Mass Involving uterus Cyst(s) in uterus Gravid uterus Implantation (fetal reabsorbtlon) sites within gravid uterus Clear fluid distending uterine hom(s) 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. -2 00 06 0 1 -1 01 00 04 - 16 0 13 0 13 00 -0 00 01 01 -0 00 00 00 -0 10 10 00 -0 00 10 00 0 00 01 Cumulative Results 20 20 20 20 0 0 0 1 0 1 0 0 1 2 0 6 1 1 1 0 4 16 13 13 0 0 0 1 1 0 0 0 0 0 1 1 0 0 0 1 0 0 0 1 - Indicates none examined or not applicable. no i.-ii i,^ CONFTDFN'T TA1 -132 Diagnosis Code LL-9 LL-10 LL-11 M-l M-2 N-l N-2 P-2 P-3 F-A P-5 TABLE 32 (Continued) SUBCHBONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN HATS AND RABBITS CROSS PATHOLOGICAL OBSERVATIONS ON FEMALE BATS EXPOSED FOR 14 WEEKS AND THEN TM FOB UP TO 26 WEEKS OF RECOVERY Observations Number of rats per group Exposure Level ^ (ppm) 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period i 0 1 3 Terminal Kill 19 20 19 17 Cumulative Results 20 20 20 20 FEMALE REPRODUCTIVE SYSTEM (coat'd) Distention of end congestion of uterine horns due to endometrlsl polyp(s) Endometrlsl hyperplasia Portion of plscents within vsgins 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 00 00 Oil 0 00 0 00 -11 Oil 0 00 0 00 -00 10 1 0 00 RESPIRATORY SYSTEM Dark or red focus(1) In lungs Few pale foci In lungs 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 33 -00 0 22 0 00 0 00 -11 10 1 0 00 SPLEEN Ectopic splenic tissue Enlarged spleen 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Oil -00 Oil Oil 00 0 10 10 0 0 1 1 KIDNEY Slight to moderate chronic renal disease (slightly pale, enlarged, roughened, etc.) Mineralisation of renal cortex or pelvis Pale appearance of kidneys Right kidney enlarged containing hemorrhage 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. 0 00 -00 0 00 Oil Oil -00 0 00 0 00 0 00 00 Oil Oil 10 0 00 00 1 0 0 0 DO 131 1 r.0 CONFTDFNT \ A[ 133- Diagnosis Code P-6 0-1(1) Q-l(2) 0-6 Q-5 0-6 R-l S-l T-l TABLE 32 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITT AND RECOVER! STOUT OF DBCP IN RAIS AND RABBITS CROSS PATHOLOGICAL OBSERVATIONS ON PPMAT.r. bats exposed FOR 14 WEEKS AND THEN TM FOR UP TO 26 Weets or RECOVERY Observations Number of rats per group URINART BLADDER Organized plug within urinary bladder INTEGUMENT AND SUBCUTANEOUS Subcutaneous mass - Inguinal, mammary or aidcervlcal region - number perrat: 1 Subcutaneous mass - Inguinal, mammary or mldcervlcal region - number perrat: 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 Died or Rilled Moribund During Recovery Period 1 0 1 3 J Terminal j Rill 19 20 19 17 Cumulatl' Results 20 20 20 20 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 55 44 0 33 3 25 0 00 00 0 00 0 33 0 00 00 0 11 0 00 0 11 00 0 00 0 11 0 00 11 0 00 0 00 0 0.1 1.0 10.0 0 00 00 0 11 0 00 0 0.1 1.0 10.0 0 00 00 1 01 0 00 0 0.1 1.0 10.0 0 00 00 0 11 0 00 - Indicates none examined or not applicable* 0fJ 1311m CONFTOFNTTA! 134- Diagnosis Coda A-l A-2u, A-2us, A-S A-2b. A-2bs A-3 A-4u A-4b, A-4bm, A-8b A-5u, A-5us A-Sb A-6, A-6u A-6b A-lib TABLE 33 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RAIS AND BABBITS HISTOPATHOLOGIC OBSERVATIONS AND HUMBER OF TISSUES EXAMINED ON MALE BATS EXPOSED FOR 14 wests and then Rnj) FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rata par group Exposure Level (ppm) 0 0.1 1.0 10.0 ENDOCRINE SYSTEM Adrenal Glands - Number of tisaues examined 0 0.1 1.0 10.0 No visible leslona 0 0.1 1.0 10.0 Focus(1) of altered cells, cortex - unilateral 0 0.1 1. 10.0 Focus(l) of altered cells, cortex - bilateral 0 0.1 1.0 10.0 Thrombus, adrenal blood vessel Nodular hyperplasia, cortex - multifocal, unilateral 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Nodular hyperplasia, cortex - multifocal, bilateral 0 0.1 1.0 10.0 Ectatlc sinusoids - multifocal, unilateral 0 0.1 1.0 10.0 Ectatlc sinusoids - multifocal, bilateral 0 0.1 1.0 10.0 Hematocyst , cortex - unilateral 0 0.1 1.0 10.0 Hosatocyst, cortex - bilateral 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 emulative 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. DO T3116? r.ONF 1 nFNl T At 135- DlegnoalA 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 XABLE 33 (Continued) SUBCHR0N1C INHALATION BEFBODUCTIVZ TOXICITT AMD BECOVZXY STOUT OF DBCP IN BATS AMD BABBITS HISTOPATHOLOGIC OBSERVATIONS AMD NUMBER OF Tttnv* etsmINED ON MALE BATS EXPOSED FOB 14 WEEKS AMD THEM HELD FOB OP TO 32 MEEKS OF RECOVER! ObeervAtiona Number of rata par group ENDOCRINE SYSTEM (coat'd) Adrenal Gland* (coat'd) Pheochromocytoma - unilateral Modular hyperplasia, medulla - focal, unilateral Aggregate of mononuclear lymphoid cell*, cortex - alight 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 tissue* examined No visible lesions Cyst Focus(1) of altered cells anterior portion Adenoma, anterior portion Pigmented (golden brown) macrophages, pars intermedia - focal, slight f^ncal 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 Killed Moribund During Recoverv 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 _. ._ -- Cumulatl* Result* 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. 00 OONFTDFNTTAl Diagnosis Code Th-1 Th-2s Th-3 Th-4m Th-5 PG-1 PG-2, PG-2b PG--3m TG-l -136- TABLE 33 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOUCITT AND RECOVER STUD! 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 par group Exposure Level (ppm) 0 0.1 1.0 10.0 . ENDOCRINE SYSTEM (cont'd) Thyroid Gland - Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Hyperplasia, parafollicular cells (C-cell) - focal, slight 0 0.1 1.0 10.0 Medullary thyroid carcinoma - solitary 0 0.1 1.0 10.0 Cervical blood vessels near thyroid. periarteritis - multifocal, moderate Ultimobranchial cyst 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 Terminal Cumulative Kill______ Results 17 20 19 20 20 20 18 20 3 16 19 1 01 0 00 2 18 20 3 14 17 0 -0 2 14 16 0 22 0 -0 - -- 0 33 0 11 0 -0 - 0 11 0 00 0 -0 - -0 11 0 00 1 -1 - ** 0 11 3 14 17 1 01 0 00 2 14 16 2 13 15 1 -1 - -* 1 14 15 1 01 0 -0 - -* 1 01 0 11 0 -0 - -0 00 3 17 10 00 2 18 1 12 0- - 1 15 no 1311b4 f.ONF TDFN 1 I 20 1 0 20 13 0 - 16 137- Diagnosis Code TG-2, TG-2a TG-3 TG--4 s TG-5a TG*6s TG-7, TG-7s SC-1 Es-1 TABLE 33 (Continual) SUBCHRONIC INHALATION REPRODUCTIVE TOHCITT AND RECOVEKT STUD! OF DBCP m RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 WEEKS AND THEM HELD FOR UP TO 32 WEEKS OF RECOVERY Observatlona Number of rata par 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 miltlfocal, slight 0 0.1 1.1 10.0 Foreign body granuloma or subacute inflsmnation, submucosa - focal 0 0.1 1.0 10.0 Salivaj^r Glands - Number of tissues examined No visible lesions 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Esophagus - Number of tissues examined No visible lesions 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 11 1- -- 02 10 0* -- 10 01 000 01 0a. 00 02 0 -- 00 00 1 - 01 3 16 10 00 2 -- 17 3 16 1* - 2 17 3 15 10 00 2 16 3 15 1- *_ 2 16 Cumulate Results 20 20 20 20 2 1 - 2 1 0 1 1 0 - 0 1 0 - 0 2 0 0 0 1 1 19 1 0 19 19 1 _ 19 18 1 0 18 18 1 _ 18 - Indicates none examined or not applicable. DO 131105, OONFIDFNT TAl -138- TABLE 33 (Continuad) SUBCHRONIC INHALATION REPRODUCTIVE TOUCH! AND RECOVER! STUD! OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EEPOSED FOR 1A WEEKS AND thth WFifl Fob BP TO 32 WEEKS OF RECOVER! Diagnosis Code _.... _ S-I S-2, S-2s S-3 S-A S-5 S-2 SI-1 SI-2 Observations Number of race per group GASTROINTESTINAL SYSTEM (coat'd) Stomach - Number of tissue* examined Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 No visible lesions Cystic dilatation, base of crypts. glandular portion ' 0 0.1 1.0 10.0 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. nicosa 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 Recovers Period 3 1 0 2 Terminal Kill 17 19 20 18 3 16 10 00 2 18 1 15 1-1 16 11 000 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. DO 131166 OONFTDFNT TA1 139 Diagnosis Code Ce-1 Ce-2 LI-1 LI-2 LI-3 L-l L-2. L-2va, L-2s L-3 L-4vs TABLE 33 (Continued) SUBCHHONIC INHALATION REPRODUCTIVE TOXICITT AND RECOVER! STUD! 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) Cecum (cont'd) No visible lesions 0 0.1 1.0 10.0 Intraluminal nematode parasites consistent with plnvorms 0 0.1 1.0 10.0 Lare_Intestine_ - Number of tissues examinedi No visible lealona Intraluminal nematode parasites consistent vith pinvents 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 Vacuolization consistent with fatty change - focal or multifocal, very Blight 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 Cumulative Results 20 20 20 20 1 14 15 - " -- 17 17 0 33 - --" 00 3 16 19 1 01 0 00 2 18 20 3 10 13 1 -1 - -" 1 11 12 0 66 00 - -" 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 131167 r.ONFinFNTT Al -140- Diagnosis Code L-4s L-4m L-5vs L-5a L--6, L-6s, L-6m L-19s L-7s L-8 L-9vs L*9s L~12s TABLE 33 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOCIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN Itnj FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rats per group GASTROINTESTINAL SYSTEM (cont'd) Exposure Level (ppm) 0 0.1 1.0 10,0 Liver (cond't) Vacuolization consistent with fatty change - focal or multifocal, slight Vacuolization consistent with fatty change - focal or niltifocal, moderate 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Extramedullary hematopoiesis - focal or multifocal, very slight 0 0.1 1.0 10.0 Extramedullary hematopoiesis - focal or multifocal, slight Focus(i) of altered hepatocytes Area of altered hepatocytes - slight Biliary hyperplasia - focal or multifocal, slight Herniated portion of liver, nodular Subacute inflammation - focal, very slight Subacute inflammation - focal, slight Atrophy, hepatic cords, centrilobular region - 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 Died or Killed Moribund During Recovery Period 3 1 0 2. Terminal Kill 17 19 . 20 18 18 0 12 *9 18 0 0 01 -0 01 01 00 -0 00 04 09 -9 09 06 07 -8 0 14 00 00 -1 00 02 02 2 02 01 00 -0 00 01 00 0 00 00 03 -1 01 00 00 -0 10 Cumulative Results 20 20 20 20 9 12 9 9 0 1 0 1 1 0 0 0 4 9 9 9 6 7 8 14 0 0 1 0 2 2 2 2 1 0 0 0 1 0 0 0 0 3 1 1 0 0 0 1 - Indiestea none examined or not applicable. DO 131168 CONF TDFNT TAt -141. Diagnosis Code L-13a L-14s L-15s L-18s Pa-1 Pa-2vs, Fa-2s Pa-3 Pa-5, Pa-5sev Pa-6a TABLE 33 (Continued) SOBCHR0NIC INHALATION REPRODUCTIVE TOXICITT AND RECOVERY STUDY OF DBCP IN RAIS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 WEEKS AND THTM VQR UP TO 32 WEEKS OF RECOVERY Obaervatlona Number of rata per group GASTROINTESTINAL SYSTEM (cont'd) Liver (cont'd) Chronic active Inflammation, portal triads - alight Dilated (telangiectatic) alnuaolda - alight 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 tlaauea 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 Periarteritis - focal or multifocal Fibrosis, Interstitial - focal, alight 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 Cimlatlve Results 20 20 20 20 0 00 0 22 - 00 0 00 0 00 0 00 - 11 0 00 0 00 0 11 - 11 0 00 0 00 0 00 - - 0 11 3 17 20 1 01 0 11 2 18 20 1 11 12 1 -1 ** 0 0 2 12 14 2 68 0 *, 0 - 00 0 44 1 01 00 - 00 1 01 0 00 00 - 11 0 11 0 00 00 - 00 0 11 3 17 20 1 01 0 00 2 18 20 qq 131 1 69 GONFTDFNT IAl 142- TABT.E 33 (Continued) SUBCHH0NIC INHALATION REPRODUCTIVE TOHCITT AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AMD NUMBER OF TISSUES EXAMINED ON MALE BATS Diagnosia Cod* NT-1 NT-2vs, NT-2s NT-3, NT-3s NT-3sev NT-4s NT-5 NT-6 NT-7* NT-8 Tr-1 Tr-2s Observation* Number of rats par group RESPIRATORY SYSTEM (cont'd) Exposure Level (ppm) 0 0.1 1.0 10.0 Nasal Turbinates (cont'd) No visible lesions 0 0.1 1.0 10.0 Aggregates of mononuclear lymphoid cells. auboicosa - focal or multifocal 0 0.1 1.0 10.0 Suppurative (acute) rhinltla - focal or niltlfocal, slight 0 0.1 1.0 10.0 Suppurative (acute) rhinitis - focal or multifocal, slight Chronic active Inflavation - focal, slight Malignant schwannoma - primary Fibrous osteodystrophy, probably secondary to severe chronic renal disease Acute Inflaudation with or without necrosis. mucosa and submucosa of olfactory portion of the dorsal medial turbinates 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 Adenocarcinoma 0 0.1 1.0 10.0 Trachea - Number of tissues examined No visible lesions Subacute inflammation, submucoss - multifocal, slight 0 0.1 1.0 10.0 0 0.1 1.0 10.0 G 0.1 1.0 10.0 -Indicate* none examined or not applicable. Died or Killed Moribund During Recovery Period 3 1 0 2 Terminal Kill 17 19 20 18 emulative Becults 20 20 20 20 1 23 0 -0 a- - 0 00 1 14 13 0 _1 - -1 17 18 1 01 1 _1 - _0 11 0 00 0 -0 - - 1 01 0 11 00 - -0 11 0 00 0 -0 - . 1 01 0 00 0 _0 -- 1 01 0 00 0 _0 - __ 0 22 0 00 0 *0 a. _ 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 00 131170 CONF TDFNTTAl -163- Diagnosia Code Tr-3s Tr-6 Lu-2, Lu-2s Lu-3s Lu-7a Lu-lOs Lu-4 Lu-5 Lu-6 a Lu-8a TABLE 33 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOnCITT AND RECOVER! STUD! OF DBCF IN RAXS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER Of TISSUES EXAMINED ON MALE RATS EXPOSED FOR 16 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVER! Observations Number of rats per group RESPIRATOR! SYSTEM (coat'd) Trachea (cont'd) Periarteritis, submucosa - focal, slight Aggregate of mononuclear lymphoid cells. aubtoucoaa - 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 calls. 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 Generalised 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 18 18 01 -2 05 11 10 -3 00 00 00 0 o1 30 00 a- 0 10 20 00 .0 10 17 01 -3 03 02 00 -6 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 101171 CONF TOFN'I TA! 144- Diagnosis Code Lu-9a Lu-lla Lu-12s Lu-13s Lu-14 Lu-15 Lu-16 Lu-17 Lu-18s PN-1 TABLE 33 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOUCITT AND RECOVERT STUDY OF DBCF IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 wragg AMD THEN HELD FOR UP TO 32 WEEK5 OF RECOVERY Observations Number of rata per group Exposure Level (ppm) 0 0.1 1.0 10.0 RESPIRATORY SYSTEM (cont'd) Lungs (cont'd) Granulomatous lnflamation - focal, slight 0 0.1 1.0 10.0 Chronic lnflamation, bronchiole - slight 0 0.1 1.0 10.0 Cholesterol clefts - focal, slight 0 0.1 1.0 10.0 Microgrsnuloma - 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 Chronic active lnflansstion - multifocal 0 0.1 1.0 10.0 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 Terminal Kill 17 19 20 18 01 00 -1 00 00 00 -0 01 00 00 -0 01 00 00 1 00 00 00 0 10 00 00 -0 10 00 00 0 10 00 00 -0 10 a0 00 0 01 3 16 l0 00 2 18 3 10 1_ _ 29 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 00 131\7p r^rOFNTTA( -^143- TABLE 33 (Continued) SUBCHROHIC INHALATION REPRODUCTIVE TOUCH! AND RECOVERT STUD! OF DBCP IN EATS AND RABBITS HISTOPAIHOLOCIC OBSERVATIONS AND NUMBER OP TISSUES EXAMTKTO OH HALE RATS EXPOSED FOR 14 WEEKS AND TPra "OR UP TO 32 WEEKS OP RECOVER! Diagnosis ... Code ...... .. PN-2va PN-Za SC-1 B-l B-2 B-3a, B-3b, B-3bs B-4 B-5m Observation* Number of rata par group NERVOUS SYSTEM (cont'd) Peripheral Nerve (cant'd) Peripheral neuropathy - very alight Peripheral neuropathy - alight Exposure Level (m>m) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Slnal Cord - Number of tlaauea examined No vialble leaIona 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Brain - Number of tlaauea examined No vialble lealona Malignant schwannoma, Infiltrating from primary alte In naaal turbinates. Mineralization, cerebrum - focal or multifocal Granular cell tumor located In menlngea. cerebrum, dorsal surface Vacuolization and degeneration of the cerebellum, midbrain, and cerebrum - multifocal, anderate 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 MUSCULOSKELETAL SYSTEM Skeletal Muscle - Number of tissues examined 0 0.1 1.0 10.0 - Indicate* none examined or not applicable. Died or Killed Moribund During Terminal Recovery Period mi t 3 17 1 19 0 20 2 ... . .- 18 Cumulative Reaulta 20 20 20 20 0 44 0 -0 - - 0 44 0 33 0 -0 - -0 33 3 17 20 1 0! 1 0 00 2 IS 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 34 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 DO 131173 f.ONFTDFNTTAl -146- Diagnosis Code SH-1 VB-1 VB-2, VB-2s VBM-1 K-4ua, K-4s K-4b K-Sus TABLE 33 (Continued) SU1CHHDNIC INHALATION REPRODUCTIVE TOXXCITT AND RECOVER? STUD! OP DBCF IN RAIS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON HALE RATS EXPOSED FOR 14 WEEKS AND THEM wwn fob UP TO 32 WEEKS OF RECOVER! Observations Number of rats per group MUSCULOSKELETAL SYSTEM (cont'd) Skeletal Muscle (cont'd) No visible lesions Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Vertebral Bone - Number of tissue* 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 1.0 10.0 URINARY SYSTEM Kidneys - Number of tissues examined Mineral deposits, cortex, medulla or cortlcomedullary Junction - focal or multifocal, unilateral Mineral depoalts, cortex, medulla or cortlcomedullary junction - focal or niltlfocal, 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 11 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 a* 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 DO 131174 CONFIOFNTTAL -147- Diagnosis Code K-5b, K-Sba K-6a, K-6bs K-6m, K-6bm K-6sev, tt-6b,sev K-Uua K-13us K~14us K-16 K-17us K-18 K-24 TABLE 33 (Continued) L )- SUBCHBONIC INHALATION REPRODUCTIVE TOIICITT AND RECOVER! STOUT OF DBCP IN BATS AND BABBITS HISTOPATHOLOGIC OBSERVATIONS AMP NUMBER OF TISSUES EXAMINED ON MALE RATS EIPOSED FOB 14 WEEKS AMD THEN HELD itP TO 32 WEEKS OFRECOVERV----- Observaciona Number of rata per group Expoaure Level (ppm) 0 0.1 1.0 10.0 URINARY SYSTEM (coat'd) Kidneys (coat'd) Mineral deposits, renal pelvia - focal of aailtifocal, bilateral 0 0.1 1.0 10.0 Chronic progressive glomerulonephropathy - alight 0 0.1 1.0 10.0 Chronic progreaaive glomerulonephropathy - moderate 0 0.1 1.0 10.0 Chronic progreaaive glomerulonephropathy - ever 0 0.1 1.0 10.0 Aggregate# of mononuclear lymphoid cella. pelvis - focal or multifocal, unilateral, alight 0 0.1 1.0 10.0 Vacuolization, pelvic epithelium - unilateral, alight 0 0.1 1.0 10.0 Hyperplasia, pelvic epithelium - unilateral, slight 0 0.1 1.0 10.0 Cyst, cortex 0 0.1 1.0 10.0 Hydrohephrosls - unilateral, alight 0 0.1 1.0 10.0 Adenoma, cortex 0 0.1 1.0 10.0 Focus or (pleomorphic) basophilic cella 0 0.1 1.0 10.0 - Indicates none examined or not applicable. Died nr Killed Moribund During Recovery Period 3 1 0 2 Terminal Kill 17 19 20 18 00 00 -0 11 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 emulative Rasuite 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 :r' no 131175 CONFTDFNTTAl -148- Diagnosis ode UB-1 H-l H-2a, H-5s, H-6s H-3 H-Avs H-4s ABV-1 ABV-2, ABV-2s, ABV-2m TABLE 33 (Continued) SCBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUB! OF DBCP IN RAIS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS tiPOSH) FOR 1* WEEKS AND THEN HELD TOR UP TO 32 WEEKS OF RECOVER! Observation* Number of rata per group Exposure Level (non) 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 leeiona 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 alight Aggregate of mononuclear lymphoid 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 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Anterior Mediastinal Blood Vessels Number of tlsaues 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 -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 -a 20 2 17 3 17 10 00 2 18 1 1* 11 14 21 0 - 1* 10 0<- 10 01 0- -- 00 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 l 0 1 1 0 - 0 1 0 - 0 20 1 1 19 17 1 0 16 2 0 1 2 - oo 13 3 1 7 ^ C.ONF- 1 OFNT 1 Al -149- Diagnosis Coda ABV-3 CBV-2 MBV-1 MBV-2 MBV-3 MF-1 MF-2 0-2 TABLE 33 (Continued) SUBCHRONXC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STOUT OF DBCF Dt RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR DP TO 32 WEEKS OF RECOVERY ,. Observation* Number of rata per froup Exposure Level (ppm) 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 Vessel* Number of tissues examined No visible lesions Periarteritis - focal or multifocal Sublntimal 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 of tissues examined No visible lesions Atrophy Strsngulatcd (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 - Indictees none examined or not applicable. Died or Killed Moribund During Recovery Period 3 1 0 2 Terminal Kill 17 19 20 18 - 10 0" -0 10 00 10 00 00 1--- 3 17 10 00 2 18 1 17 1-1 18 10 0-10 20 010 Cumulatlva Result* 20 20 20 20 1 0 0 1 0 1 0 0 1 - 20 1 0 20 18 1 - 19 1 0 1 2 0 1 3 17 20 1 12 0 11 2 18 20 3 17 20 1 01 * 00 1 18 19 0 00 0 00 - 00 1 01 0 00 0 00 e. 1 1 0 00 no 131177 CONF TDFNT TAl -150- Diagnosis Code 0-3 EA-2 EY-1 EY-2b, EY-2bs, EY-2bm EY-4um EY-3us, EY-3um T-l TABLE 33 (Continued) SUBCHRDN1C INHALATION REPRODUCTIVE TOXICITY AND RECOVER! STUDY OF DBCF IN RATS AND BABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HglJ* FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rata per group ABDOMINAL CAVITY (coat'd) Mesenteric Fat (cont'd) Necrosis and chronic lnflamsatlon of fat Exposure Level (nnm) 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 vascular!- cation - 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 Q.l 1.0 10.0 Died or Killed Moribund During Recovery Period 3 1 0 2 Terminal Kill 17 19 20 18 0 0 - 0 0 0 0 0 * - 3 1 0 2 2 0 0 1 1 1 0 0 - 0 0 0 0 3 1 0 2 1 1 1 0 1 0 0 0 0 0 1 " 1 17 2 6 17 15 2 5 16 0 0 0 0 0 0 1 0 2 0 0 1 17 19 20 18 12 14 15 5 Cumulative Results 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. no 101178 CONF T DF fv~ T A1 >151. Diagnosis Coda T-2um T-2bm T-2u,sev T-3u,vs T-3us T-3bs T-3um T-Aus 1*4UB T-Ab, T-Abs TABLE 33 (Continued) SDBCHRONIC INHALATION REPRODUCTIVE TOXXCXTT AMD RECOVER! STUD! OF DBCP IM RAIS AMD RABBITS HISTOPATHOLOGIC OBSERVATIONS AMD HUMBER OF TISSUES EIAMIMED OM MALE RATS moSED FOE 14 weeks amp unm helb ton HP TO 32 WEEKS OP RECOVER! Observations Number of rata par group MALE REPRODUCTIVE STSTB4 (cost'd) Exposure Level (ppm) 0 0.1 1.0 10.0 Tettea (cost'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 Indlvldual seminiferous tubules - includes Individual seminiferous tubules containing predominantly eertoli cells) - unilateral, very slight 0 0.1 1.0 10.0 Atrophy (decreased spermatogenesis of lndlvldual seminiferous tubules - Includes Individual seminiferous tubules containing predominantly sertoll cells) - unilateral, slight 0 0.1 1.0 10.0 Atrophy (decreased apermatogenasla of indlvldual aemlnlferoua tubules - Includes Individual seminiferous tubules containing predominantly aertoli cells) - bilateral, alight 0 0.1 1.0 10.0 Atrophy (decreased spermatogenesis of Indl- 0 vldual seminiferous tubules - includes 0.1 Individual aemlnlferoua tubules containing 1.0 predominantly sertoll cells) 10.0 - focal or multifocal, unilateral, moderate Mineralization (intratubular calcification) - unilateral, slight Mineralization (intratubular calcification) - unilateral, moderate Mineralization (intratubular calcification) - multifocal, bilateral 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 Recovers Period 3 1 0 2 Terminal Kill 17 19 20 18 J , i i emulative Results 20 20 20 20 0 11 0 00 * 00 0 11 0 00 0 00 00 1 12 0 00 0 11 - 00 0 00 0 11 0 00 * 00 0 00 0 11 0 22 - 55 0 88 0 11 0 11 - 00 0 AA 0 00 0 11 - 00 0 00 0 22 0 00 - 00 0 11 0 00 0 11 00 0 00 0 00 0 00 * 00 1 12 -Indicates none examined or not applicable. D 1 i7f79 Cn^rnFNTiAl -132- Diagnosis Code T-5b T-5bm T-6um T-6u,sev T-8u -1 E~3um E-3u,sev E-3b E-4s TABLE 33 (Continued) SUBCHK0N1C INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OP DBCP IN BATS AND BABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE bats EafOSED FOR 14 WEEKS Ann THEN HEin WJR OT TO 32 WEEKS OE pEOOVERY Observations Number of rate 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 funm) 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 Epididymides - Number of tissues examined No visible lesions Decreased sperm content In tubular lumina - unilateral, moderate Decreased sperm content In tubulsr lumina - unilateral, aevere 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 Recovery 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 -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. - DO "1 31 1 OO r.ONF I nFNT T Al -153- Diagnosis Code E-5u E-5b E-6, E-6u E-7ue PR-1 PR-3, FR-3s, PR-3m PR-5* PR-6 a CG-1 TABLE 33 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCF ZN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FDR UP TO 32 WEEKS OF RECOVERY Observations Number of rats per group Exposure Level (nnm) 0 0.1 1.0 10.0 MALE REPRODUCTIVE SYSTEM (cont'd) Epididymides (cont'd) Increased cellular debris in tubular lumloa - unilateral 0 0.1 1.0 10.0 Increased cellular debris in tubular liimina - bilateral 0 0.1 1.0 10.0 Periarteritis - focal 0 0.1 1.0 10.0 Aggregate of mononuclear lymphoid cells. perivascular - focal, unilateral, slight 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 3 1 0 2 0 e0 0 0 0 1 0 0 0 0 0 m 0 Terminal Kill 17 19 20 18 0 1 0 1 0 0 0 1 0 1 0 1 0 0 1 1 Prostate Gland - Number of tissues examined 0 3 17 0.1 1 19 1.0 0 20 10.0 1 17 No visible lesions 0 0.1 1.0 10.0 1 0 - 0 3 3 5 2 Corpora amylacea-llke bodies 0 2 14 - focal or multifocal 0.1 1 16 1.0 15 10.0 1 15 Papillary hyperplasia, glands - focal, slight 0 0.1 1.0 10.0 0 0 - 0 0 0 0 1 Hyperplasia, glands - focal, slight 0 0.1 1.0 10.0 0 0 - 0 0 1 0 0 Coagulating Gland Number of tissues examined No visible lesions 0 3 17 0.1 1 18 1.0 0 20 10.0 2 16 0 3 17 0.1 1 18 1.0 - 20 10.0 1 15 - Indlcatss none examined or not applicable. 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>0 131181 cONF T DFNT T A[ 154- Diagnosis Code CG-Z SV-1 SV-2 SV-3 PPG-2a, PPG-2m, FPG-2sev PPG-3m, PPG-3aev PPG-4 TY-2m TABLE 33 (Continued) SOBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERT STUDY OP DBCP IN RAIS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD TOR UP TO 32 WEEKS OP RECOv5y Observations Number of ret* per group MALE REPRODUCTIVE SYSTEM (cont'd) Coagulating Gland (cont'd) Atrophy Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 gwninal Veaiclea Number of tleauea examined No vlalble lesions Atrophy Corpora amylacea-lllte bodies - 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 pj-eputlal Gland - Number of tissues examined 0 0.1 1.0 10.0 Chronic lnflasmation - multifocal 0 0.1 1.0 10.0 Cystic dilatation, duct* 0 0.1 1.0 10.0 Abscess 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 - indicate* 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 12 3 17 20 1 18 19 0 20 20 2 17 19 3 17 20 1 18 19 - 20 20 1 16 17 0 00 0 00 * 00 1 1 .2 0 00 0 00 00 1 01 0 11 0 11 0 11 0 22 - 11 - 11 - 00 - 11 - 11 - 11 * 00 - 11 - 00 - 00 - 11 - 11 2 15 17 1 01 0 11 2 17 19 2 15 17 1 -1 - .1 1 1 17 18 1 3 T 1 ftp c ONFTDFNTTAi 155- Diagnosis Code TY-2av Sp-*1 Sp-2m Sp-3 Sp-As Sp-5s MLN-1 MLN-2 MLN-3a IABLE 33 (Continued) SOBtSSOHIC INHALATION REPRODUCTIVE TOXICITY AMD RECOVER! STOUT OF DBCP Ht RATS AMD RABBITS HISTOPATHOLOGIC OBSERVATIONS AMD NUMBER OF TISSUES etamtupti rot watv * EXPOSED FOR 14 weees inn then nvrn FOR UP TO 32 hefts OF RECOVERY Observations Number of rats per group LTMFHORETICULAR SYSTEM (cont'd) Thymus (cont'd) Atrophy - severe Exposure Level (non) 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 Lymph 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 2 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 a. 1 0 0 1 19 1 1 18 1A 1 0 17 3 0 0 1 1 0 0 0 - Indicates none examined or not applicable DO CONF TOFNT 1 Al -156- Dlagnoela Code HLN-4 MLN-5 Pa-4 Pa-7 K-20sev K-21 K-22 K-23 XABLE 33 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOZZCITT AND IECOTEKZ STOTT OF DBCP IN BATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISStTES EXAMINED ON MALI RATS EXPOSED FOR 14 WEEKS AND THEN hftj> FOE OP TO 32 MEEKS OF RECOVERY Observation* Number of rata per group LYMPHORETICULAR SYSTEM (cont'd) Me*enterlc Lymh Node* (cont'd) Reactive hyperplasia PLasmacytotl* of the medullary cords Exposure Level (ppm) .... 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 3 1 0 2 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0 - 0 0 0 - 0 Pancreatic Lymph Nodes Number of tissue* eremlned No visible lesions Free and phagocytlzad 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 0 0 0 0 - - - - Renal Lymph Nodes Number of tissues examined Cystic dilatation, sinusoids * sever* Free and phagocytlzed 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 0 0 0 0 - * * - - * * - Anterior Mediastinal Lymph Nodes Number of tissues examined 0 0.1 1.0 10.0 2 1 0 2 Terminal Kill 17 19 20 18 0 1 0 0 " 1 0 2 0 0 1 2 * 0 0 1 2 1 0 0 2 0 - 0 1 * 0 1 - 0 1 * 17 0 1 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 - Indicate* none examined or not applicable. DO 131184 OONF TDFNTTA! -157 Diagnosis. Code ALN-1 ALN-2 ALN-3, ALN-3s ALN-4 AX-2 SLN-1 LN-1 LN-2 TABLE 33 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDT OF DBCF IN BATS AND BABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TTSSIJES EXAMINED ON MALE BATS EXPOSED FOE 14 WEEKS AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rats par group LTMFHORETXCULAR SYSTEM (cont'd) Anterior Mediastinal Lymph Nodes (cont'd) No visible lesions Free and phagocytlzed red cells In the medullary sinuses Hematogenous pigment (hemosiderin), medullary sinuses Sinus histiocytosis Axillary Lymph Nodes Number of tissues examined Reactive hyperplasia Subcutaneous Lymph Nodes Number of tissues examined No visible lesions Lymph Nodes - (orlzin undetermined) Number of tissues examined No visible lesions Free and phagocytlzed 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 2 1 2 0 0 0 0 0 0 0 0 0 0 0 0 0 - - 0 0 0 1 - - 1 0 1 0 0 0 1 - Terminal] uu 17 19 20 18 i 10 0 16 6 0 2 4 * 0i 0 0 1 0 0 0 0 1 - - 1 5 0 0 8 5 8 0 0 0 1 _ 1 0 Emulative 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. no 131185 CONf T OF NT T -158- Diagnosis Code LN-3 Sk-1 Sk-2 Sk-3 Sk--4 Sk-5 Sk-6 Sq-1 Sq-2 TABLE 33 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCF IN RATS AND RABBITS HISTOPATHOLOCIC OBSERVATIONS AMD NUMBER OF TISSUES EXAMINED ON MALE RATS EXPOSED FOR 14 WEEKS AND THEN HEIJ) FOR UP TO 32 WEEKS OF RECOVERY Observations Number of rats par group Exposure Level (ppm) 0 0.1 1.0 10.0 LYMPHORETICULAR SYSTEM (cont'd) Lymph Nodes - (orlg.undetero.j (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 inflamation sad 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 caldflca- tlon, 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 till 17 19 20 18 emulative Results 20 20 20 20 - -- 1 "1 - -- 00 3 16 19 1 01 0 00 2 18 20 2 15 17 1 -1 - -- 1 17 18 1 01 0 -0 - -- 0 00 0 11 0 -0 -0 00 0 00 0 *0 - -1 01 0 00 0 -0 - -0 11 0 00 0 -0 - -0 11 3 16 19 1 01 0 00 2 18 20 1 01 0 -0 - *1 01 0 00 0 -0 - -0 22 r>0 131186 OONFTDFNTTAI Diagnosis Code Sq-3 MG-1 MG-2* MG-3 s TABLE 33 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXXCITI AND RECOVEBT STUDY OP DBCP IN BATS AND BABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OP 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) Subcutaneous (cont'd) Lipoma Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.1 Mammary Gland - Number of tissues examined No visible lesions Acinar hyperplasia - slight Ductal hyperplasia - 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 Died or Killed Moribund During Recovery Period 3 1 0 2 Terminal Kill 17 19 20 18 00 0-01 3 12 00 00 1 IS 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. DO 101 1 ft 7 CONF TDFNTTAt -160- TABLE 34 SUBCKEONIC INHALATION REPRODUCTIVE TOXICITT AND RECOVERT STUDT OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN WFT.n FOR UP TO j6 WEEKS OF RECOVERY Diagnosis Code Observations Number of rats par group ENDOCRINE SYSTEM Adrenals - Number of tissues examined A-l No visible lesions A-2s, A-2u, A-2us A-2b, A-2bs A-4u, A-4us A-4b Focus(1) of altered cells, cortex - unilateral Focus(1) of altered cells, cortex - bilateral Nodular hyperplasia, cortex - multifocal, unilateral Nodular hyperplasia, cortex - multifocal, bilateral A-5u A-5b A-6u, A-Uu, A-llus A-6b, A-lib Ectatic sinusoids - multifocal, unilateral Ectatic sinusoids - multifocal, bilateral Hematocyst, cortex - unilateral Hematocyst, cortex - bilateral - Indicates none examined or not applicable. Exposure Level (ppm) 0 0.1 1.0 10.0 Died or Eillad 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 0 0 0 1 0 1 3 4 0 0' 1 12 0 0 0 2 0 1 3 4 0 0 1 13 DO 131188 CONF TDFNTT A! TABLE 34 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND BECOVERT STUDY OF DBCF IN EATS AND BABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON FEMALE BATS EXPOSED FOR 14 WEEKS AND THEN wtfl mg UP TO 26 WEEKS OF RECOVERY Diagnosis Code A-12bs A-13bs P-1 P-3 P-4 TH-1 TH-5, TH-5e TH-6, TH-6 Observations Number of rats per group ENDOCRINE SYSTEM (coat'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 0.1 1.0 10.0 Focus or foci of altered cells, anterior portion 0 0.1 1.0 10.0 Adenoma, anterior portion 0 0.1 1.0 10.0 Thyroid Gland - Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Ultlmobranchial cyst 0 0.1 1.0 10.0 Parafollicular cell (C-cell) hyperplasia - focal 0 0.1 1.0 10.0 Parathyroid Glands 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 00 -0 10 00 emulative Results 20 20 20 20 0 0 1 0 0 00 * 00 0 11 0 00 1 19 20 0 11 1 01 3 16 19 1 17 18 - 11 1 -1 3 16 19 0 11 - 00 0 -0 0 00 0 1 1 - 00 0 -0 0 00 1 19 20 0 00 1 01 3 17 20 1 17 18 - -- 1 s- 1 2 13 13 0 11 - -- 0 -0 0 33 0 11 am - 0 *- 0 1 23 1 18 19 0 00 1 01 3 13 16 DO 1011R9 CONFTDFNT IAI -162' TABU 36 (Continued) SUBCHROHIC INHALATION REPRODUCTIVE TOIICITT AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND I8M mnj FOR UP TO 26 WEEKS OF RECOVERY Diagnosia Exposure Level Code_____________________________ Observations_______________________ (ppm) Number of rats per group 0 0.1 1.0 ________________________________________________________________________ 10-0 Parathyroid Glands (coat'd) PG-1 No visible lesions 0 0.1 1.0 10.0 PC-4 Altered cells - focal , 0 0.1 1.0 10.0 GASTROINTESTINAL SYSTEM Tongue - Number of tissues examined 0 0.1 1.0 10.0 TG--1 No visible lesions 0 0.1 1.0 10.0 TG-2 Periarteritis - focal ormultifocal 0 0.1 1.0 10.0 TG-4s. Aggregate of mononuclear lymphoid cells - focal, slight 0 0.1 1.0 10.0 TG-6s Subacute infTarnation, submucosa - focal or multifocal, slight 0 0.1 1.0 10.0 TG-7, TG-7s Foreign body granuloma or subacute inflammation, submucosa - focal 0 0.1 1.0 10.0 TG-8-s Fibrosis and suppurative Inflammation, lacrimal ducts of tongue - focal, slight 0 0.1 1.0 10.0 TG-9 Increased number of mast cells, musculature 0 0.1 1.0 10.0 TG-10 Squamous cell carcinoma 0 0.1 1.0 10.0 - Indicates none examined or not applicable. Died or Rilled Moribund During Terminal Cumulative Recovery Period______Kill________ Results 1 19 20 0 20 20 1 19 20 _____ 2___________ 12________ Zfi____ 1 17 18 11 3 13 16 0 11 00 0 00 1 19 20 0 00 1 12 3 17 20 1 11 12 1 01 1 16 15 0 0 0 0 0 0 0 0 00 1 01 0 11 0 00 1 01 0 11 0 00 0 00 0 00 0 00 0 11 0 00 0 11 0 00 no 131190 OONFTDFNTTAl. -163- TABLE 34 (Continued) f i SOBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCF IN RAIS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND HUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN mii ran m TQ 26 WEEKS OF RECOVERY Diagnosis Code SG-1 ES-1 S-l S-2s S-4 S-7 S-8 S-9 Observation* Number of rats par group Exposure Level (ppm) 0 0.1 1.0 10.0 GASTROINTESTINAL SYSTEM (cont'd) Salivary Glands - Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Esophagus - Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Stomach - Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Cystic dilatation, base of crypts. glsndulsr portion - slight 0 0.1 1.0 10.0 Submucosal edema, nonglandular mucosa 0 0.1 1.0 10.0 Hyperkeratosis, nonglandular portion 0 0.1 1.0 10.0 Ulcer, nonglandular portion 0 0.1 1.0 10.0 Subacute inflammation, nonglandular portion 0 0.1 1.0 10.0 Died or Killed Moribund During Recovery Period 1 0 1 3 Terminal Kill 1 19 20 19 17 Cumulative Results 20 20 20 20 - 1 18 19 0 00 0 00 3 17 20 1 18 19 - -* - -- 3 17 20 1 18 19 0 00 1 o1 3 14 17 1 18 19 * -- 1 -1 3 14 17 1 19 20 0 11 1 23 3 17 20 1 18 19 - 11 1 01 3 13 16 0 11 -- 00 0 00 0 44 0 00 - 00 0 11 0 00 0 00 - 00 0 22 0 00 0 00 - 00 0 11 0 00 0 00 - 00 0 11 0 00 Indicates none examined or not applicable. DO 131191 CONF T DFNT T Al -164- TABLE 34 (Continued) SUBCHRQNIC 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 O os a 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 1iiflamation, 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 plnworms 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 plnworm 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 - 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 1 19 20 0 00 1 01 3 17 20 1 19 20 - -1 -1 3 16 19 0 00 - -- 0 -0 0 11 0 17 17 0 00 0 00 2 12 14 _ 11 11 - -- -2 11 13 66 - -- -0 11 1 19 20 0 00 1 01 3 17 20 1 16 17 - -1 -1 3 16 19 0 33 - -0 -0 0 11 1 19 20 0 20 20 1 19 20 3 17 20 0 77 - 99 0 77 0 66 00 i o i > rONMDFNTTfl, -165- TABLE 34 (Continued) SUBCHHONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCF IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND HUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR UP TO 26 WEEKS OF RICOVERT Diagnosis Code L-2s L-4s L-4m L-5s L-6, L--6s L-19 L-7s L-9s L-lOs L-17 L-20 Observations Number of rats par group LIVER (cont'd) Aggregates of mononuclear lymphoid or reticuloendothelial cells focal or multifocal Exposure Level (com) 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 Vacuolizstlon consistent with fatty change - focal or Biltifocal, 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, alight 0 0.1 1.0 10.0 Subacute Inflammation - focal, slight 0 0.1 1.0 10.0 Coagulation necrosis and inflamnatlon - 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, centrllobular - multifocal 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 till 19 20 19 17 emulative Results 20 20 20 20 1 34 _ 00 0 11 0 11 0 66 - 77 0 44 2 8 10 1 01 00 0 22 0 00 0 53 * 44 0 66 2 46 0 11 - 11 0 33 0 11 0 00 * 00 0 00 0 11 0 00 - 00 0 11 0 00 0 00 - 00 0 00 0 11 1 01 - 00 0 00 0 00 0 11 - 00 0 00 0 00 0 00 0 00 0 00 2 02 DO 131193 OONF 1DFNT 1 Al 166- TABLE 34 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVER! STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN WETJ FOR UP TO 26 WEEKS OF RECOVERY Diagnosis Code Observations Number of rata 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-2s PA-9 PA-lOs PA-12s Atrophy, with or without influmation, acinar cells - focal or multifocal Cystic duct with associated fibrosis and chronlc-acdve Inflammation Increased cytoplasmic secretory macerlal - focal, slight Subacute inflammation - focal, slight PA-13 NT-1 Aggregates of mononuclear lymphoid cells, lnterstitium RESPIRATORY SYSTEM Nasal Turbinates Number of tissues examined No visible lesions NT-2s 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 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 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 a- 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 00 13 13 _ -1 IS 18 DO 131194 C.ONF- TDPNTTAl 167. Diagnosis Coda NT-7, NT-7s NT-9 NT-lOs NT-11, NT-lls NT-12 NT-13 NT-14 TR-1 TR-2s TABLE 34 (Conelimed) SUBCHBONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RAIS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND Tgra help for UP TO 26 WEEKS OF RECOVERY Observations Number of rata par group Exposure Level (ppm) 0 0.1 1.0 10.0 RESPIRATORY SYSTEM (cont'd) Nasal Turbinates (coat'd) Acute inflammation, with or without necroala, mucosa and submucosa. olfactory portion, dorsal medial turbinates 0 0.1 1.0 10.0 Ulceration, olfactory epithelium with or without adherent exudativa material, dorsal medial turbinates 0 0.1 1.0 10.0 Subacute Inflammation, respiratory epithelium 0 0.1 1.0 10.0 Subacute lnflamnation, 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 subacuta metaplasia and cuboids11ration, 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 Recovery Period 1 0 1 3 Terminal Kill 19 20 19 17 04 - 004 01 - a. 001 02 -- 000 09 -009 00 -- 010 00 -004 00 -0* 01 1 19 00 10 3 16 1 18 - 13 13 01 - 4. 0 a01 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. DO 131195 CONFTDFNT T At 168- TABLE 34 (Continued) SDBCSKOMIC INHALATION REPRODUCTIVE T0XICIT7 AND RECOVERT 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 TR-2m TR-4a LU-2s LU-3, LU-3a LU-7s LU-4 Observations Number of rats per group RESPIRATORY SYSTEM (cont'd) Trachea (cont'd) Subacute Inflammation, submucosa - multifocal, moderate Exposure 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, alight 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 LU-5m LU-6s LU-8s Edema, perivascular - focal or multifocal Alveolar histiocytosis - 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 UJ-19 Mineralization - focal 0 0.1 1.0 10.0 - Indicates none examined or not applicable. Died nr Killed Moribund During Recovery Period 1 0 1 3 Terminal Kill 19 20 19 17 Emulative 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 22 0 11 - 00 0 00 0 00 DO 131190 OONF TDFNT TAl -169- TABLE 34 (Continued) SUBCHRjONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPAIHOLOCIC 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 par group LU-20s RESPIRATORY SYSTEM (cont'd) Lungs (cont'd) Granuloma - focal, slight LU-21 PN-1 Medial hypertrophy, pulmonary artary - focal NERVOUS SYSTEM Peripheral Nerve Number of tissues examined No visible lesions Spinal 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 Glial cell tumor - Indictees 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 Rilled Moribund During Recoverv Period 1 0 1 3 Terminal Kill 19 20 19 17 1 i Cumulative Results 20 20 20 20 0 11 - 00 0 00 0 11 0 00 - 00 0 00 1 01 1 1 15 16 0 00 1 01 3 16 19 1 15 16 - *1 -1 3 16 19 1 18 19 0 00 1 01 3 17 20 1 18 19 - -- 1 -1 3 17 20 1 19 20 0 20 20 1 18 19 3 17 20 1 19 20 - 20 20 1 17 18 1 12 13 0 00 - 00 0 00 1 56 0 00 - 00 0 11 1 01 DO 131197 CONFTDFNTT Al 170- TABLE 34 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOHCXTT AMD RECOVERT STUDY OF DBCF IN RATS AMD RABBITS HISTOPATHOLOGIC OBSERVATIONS AMD NUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN FOR UP TO 26 WEEKS OF RECOVERY Diagnosis Cods SM-1 VB-l 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 Kidneys - 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 vlth eosinophilic cast formation - focal or multifocal. bilateral, 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 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 19 0 0 17 19 . - 17 IB 0 0 17 18 - 17 18 0 0 17 18 - 17 0 * * 0 19 20 19 17 1 1 1 0 1 2 1 0 3 1 1 1 Cumulative Results 20 20 20 20 20 0 1 20 20 - 1 20 19 0 1 20 19 * 1 20 19 0 1 20 19 * 1 19 0 - 0 1 20 20 20 20 1 1 1 0 1 2 2 1 3 1 1 1 CONFTDFNTT6L 171- TABLE 34 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY ADD RECOVERY STUDY OF DBCF IN RAIS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND HUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN FOR DP TO 26 WEEKS OF RECOVERY Diagnosis Code Observations Number of rats per group K-3us URINARY SYSTEM (cont'd) Kidneys (cont'd) Basophilic staining renal tubulaa - unilateral, slight K-3bs Basophilic staining renal tubules - bilateral, slight K-4s, K-4us, K-4m K-4b, K-4bs K-5s, K-5us Mineral deposits, cortex, medulla, or corticomedullary Junction - focal or multifocal. unilateral Mineral deposits, cortex, medulla, or corticomedullary Junction - focal or nultifocal. bilateral Mineral deposits, renal pelvis - focal or multifocal K-5b K-6vs, K-6bvs Mineral deposits, renal pelvis - focal or miltlfocal. bilateral Chronic progressive glomerulonephropethy - very slight K-6s, K-6bs Chronic progressive glomerulonephropethy - slight K-6bm Chronic progressive glosierulonephropachy - moderate K-8us Inflamnation, subacute, renal pelvis - unilateral, slight K-9us Inflammation, subacute, cortex - unilateral, slight - 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 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 11 - 00 0 00 0 00 0 11 - 00 0 00 0 11 1 34 - 22 0 33 2 46 0 66 - 33 0 44 1 45 0 44 - 22 0 22 0 22 0 00 - 11 0 00 0 00 0 00 V- 2 2 0 44 0 11 0 99 - 11 11 0 88 2 13 13 0 00 00 0 22 0 00 0 11 - 00 0 00 0 00 0 11 - 00 0 00 0 00 DO 131199 OONF T OF NT T At 172. TABLE 34 (Continued) SUBCHKjONXC INHALATION REPRODUCTIVE TOnCITT AMD RECOVERT STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEFTS Awn THEN HELD FOR UP TO 26 WEEKS OF RECOVERY Diagnosis Code K-lOus K-10bs K-llus K-ISs K-19u UB-1 H-l H-2s, H-6s Observations Number of rats per group URINARY SYSTEM (cont'd) Kidneys (cont'd) Inflammation, subacute, interstltlum - unilateral, slight Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Inflammation, subacute, interstltlum - 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 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 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Myocardial degeneration, with or without inf 1 agination - 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 61 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 I1 -- 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 no ir-iiooo CONFTDFNT TAl -173 TABLE 34 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOUCITT AND RECOVERT STUDY OF DBCF IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED OH FINALE RATS EXPOSED FOR 14 WEEKS AND THEN HPTJI FOR UP TO 26 WEEKS OF RECOVERY Diagnosis Code H**7s H-8a ABV-1 ABV-2 ABV-4 MBV-1 AC-1 Obaervatlons Number of rata per group CARDIOVASCULAR STSTDt (cont'd) Heart (cont'd) Mineralization, myocardium - wltlfocal, alight Exposure level (ppm) ... .. 0 0.1 1.0 10.0 Died or Rilled Moribund During Recovery Period 1 0 1 3 0 0.1 1.0 10.0 0 - 1 0 Endomyocardial dlaeaae, left ventricle - alight 0 0.1 1.0 10.0 0 - 0 0 Anterior Mediastinal Blood Veasela Number of tiaaues examined 0 0.1 1.0 10.0 1 0 1 3 No visible lesions 0 0.1 1.0 10.0 0 - 1 2 Periarteritis, small arterioles - focal or multifocal 0 0.1 1.0 10.0 0 - 0 0 Medial calcification, aorta - multifocal 0 0.1 1.0 10.0 1 - 0 0 Mesenteric Blood Vessels Number of tissues examined 0 0.1 1.0 10.0 1 0 1 3 No visible lesions 0 0.1 1.0 10.0 1 - 1 3 ABDOMINAL CAVITY Abdominal Cavity Lymphosarcoma, abdominal cavity, mesentery and serosal surface of numerous organs 0 0.1 1.0 10.0 0 0 0 1 Mesenteric Fat - Number of tissues examined 0 0.1 1.0 10.0 1 0 1 3 Terminal Elll 19 20 19 17 0 - 0 0 - 1 19 0 0 16 19 * - 15 0 - 0 1 0 - * 0 19 0 0 17 19 - 17 0 0 0 0 19 0 0 17 emulative 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 - Indictees none examined or not applicable. ir-npoi TONF TDFNT TA! `174. Diagnosis Code MF-1 MF-2 MF-3 ET-1 U-l U-3, U*3i, U-3bs U-3bm U-4, U-4s U-4bm J TABLE 34 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITT AMD RECOVERT STDDT OF DBCP IM RATS AMD RABBITS HISTOPATHOLOGIC OBSERVATIONS AMD NUMBER OF TISSUES EXAMINED OH FEMALE RATS EXPOSED FOR 14 WEEKS AMD THEM held FOR OP TO 26 WEEKS OF RECOVER! Observations Number of rats per group ABDOMINAL CAVITY (coat'd) Mesenteric Fat (cont'd) No visible lesions Atrophy Diffuse atrophy with mononuclear cell Inflamatlon HEAD REGION Eyes - Number of tissues examined No visible lesions FEMALE REPRODUCTIVE SYSTEM Uterus - Number of tissues examined No visible lesions Cystic endometrial hyperplasia - slight Cystic endometrial hyperplasia - moderate Squamous metaplasia Squamous metaplasia - 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 _____ 12______ Cmmlatli 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 - 1 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 44 22 55 S7 88 66 33 44 11 00 00 00 44 66 33 00 11 00 00 00 1 ^K1 A OONFTDFNTTAt -175- TABLE 34 (Continued) SUBOffiONIC INHALATION REPRODUCTIVE TOUCITT AND RECOVER! STUD! OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND HUMBER OP TISSPES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN HELD FOR OP TO 26 WEEKS OF RECOVERY Diagnosis Code 0-5 U-7, 0-7u 0-6, U-6s U-8eev 0-9 0-10s U-llsev 0-12 0-13sev C-l Observations Number of rats per group FEMALE REPRODOCTIVE SYSTEM (cont'd) Uterus (cont'd) Endometrial stromal polyp with focal necrosis and Inflammation Exposure Level . (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Endometrial stromal polyp 0 0.1 1.0 10.0 Hematogenous pigment 0 0.1 1.0 10.0 Granulomatous and necrotic placentitis - severe 0 0.1 1.0 10.0 Hemorrhage, oesometrial fat - xultlfocal 0 0.1 1.0 10.0 Suppurative endometritis - focal, slight 0 0.1 1.0 10.0 Suppurative inflammation and necrosis - transmural, severe 0 0.1 1.0 10.0 Placenta with severe coagulation necrosis 0 0.1 1.0 10.0 Transmural endometritis - focal, severe 0 0.1 1.0 10.0 Cervix - 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 Recovers Period 1 0 1 3 i Terminal Kill 1 19 20 19 17 Cumulative 20 20 20 20 0 11 00 0 00 0 00 0 11 - 00 0 22 0 00 0 <- 9 11 9 11 i 0 10 10 0 88 0 00 - 00 0 00 1 01 1 01 -w 0 0 0 00 0 00 0 00 00 0 00 0 11 0 00 00 1 01 0 00 0 00 00 1 01 0 00 0 00 - 00 0 00 1 01 z1 16 17 0 19 19 1 17 18 cfs tZ; 3 15 18 U- rc 1 16 17 ll. - 18 18 c z 1 17 18 c C 3 15 IB c 176- TABLE 34 (Continued) SUBCHROKIC INHALATION REPRODUCTIVE TOXICITY AMD RECOVERY STUDY OF DBCP IH RATS AMD RABBITS HIBTOPATHOLOCIC OBSERVATIONS AMD HUMBER OF TISSUES EXAMINED OK FEMALE RATS EXPOSED FOR 14 WEFTS AMD them HELP FOR UP TO 26 MEEKS OF RECOVERY Diagnosis Code C-2 OV-1 0V-2u OV-2b OV-3 OV-4 OD-1 0D-2u Observation* Number of race per group FEMALE REPRODUCTIVE SYSTEM (cont'd) Cervix (coat'd) Well-differentiated stromal cell aarcoaa. cubmucota 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 Mo visible lesions 0 0.1 1.0 10.0 Cyst - unilateral Q 0.1 1.0 10.0 Cyst - bilateral 0 0.1 1.0 10.0 Prominent corpora lutes - multifocal 0 0.1 1.0 10.0 Hemorrhage, mesovarlal 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 x.o 10.0 Clltoral Gland - Number of tissues examined 0 0.1 1.0 10.0 Indictees none examined or not Applicable Died or Killed Moribund During Recovery Period 1 0 1 3 Terminal Kill 19 20 19 17 00 1 00 00 1 19 0 20 1 18 3 17 0 IB * 19 0 18 2 10 01 -1 00 06 00 -0 00 01 00 -0 10 10 10 a- 0 00 00 1 18 0 17 1 16 3 14 1 18 - 17 1 16 3 13 00 -0 00 01 00 00 01 00 Cumulative Raaults 20 20 20 20 0 1 0 0 20 '20 19 20 18 19 18 12 1 1 0 6 0 0 0 1 0 0 1 1 1 0 0 0 19 17 17 17 19 17 17 16 0 0 0 1C c\ 0 r, 0 1 0d CO NF TDr- NT TAI -177- TABLE 34 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATBOLOCIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 wwrs AND THEM HTT.n TOW HP TQ 26 WEEKS OF RECOVERY Diagnosis Code CL-lu CL-2u TY-1 TY-2m TY-3a SP-1 SP-3 SP-5* Observations Number of rats per croup FEMALE REPRODUCTIVE SYSTEM (cont'd) Clitoral Gland (cont'd) Abscess - unilateral Exposure Laval (pom) 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 LYMFHQRETICULAR SYSTEM Thymus - Number of tissues examined No visible lesions 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Atrophy - moderate 0 0.1 1.0 10.0 Epithelial hyperplasia - focal, slight 0 0.1 1.0 10.0 Spleen - 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 - -- -1 - _ *1 - 1 19 00 10 2 16 00 -001 1 19 -12 15 01 "" 0* 01 1 19 00 11 3 17 0 19 -01 08 01 - 01 02 00 -00 01 emulative Results 20 20 20 20 - 1 - 1 - 20 0 1 18 0 0 1 20 - 1 17 1 " 0 1 20 0 2 20 19 - 1 8 1 - 1 2 0 " 0 1 - Indicates none examined or not applicable. DO 131 70S OONF T OF NT T A1  -178-; TABLE 34 (Continued) SUBCHBONIC INHALATION REPKODUCTIVE TOUCm AMD RECOVERY STUDY OP DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 WEEKS AND THEN HHLB FOR DP TO 26 WEEKS OF RECOVERY Diagnosis Coda SP-5m SF-5aev SP-6, SP-6s SP-7sev MLN-1 MLN-2 MLN-3 PA-7 Observations Number of rats per group LTMPHORETICULAR SYSTEM (cont'd) Spleen (cont'd) Increased extramedullary hematopoiesis - moderate Expoeure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Increased extramedullary hematopoiesis - severs 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 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 phagocytixed 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 phagocytiled 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 -0* 01 00 00 00 02 _ -. _ -2 Cumulative Results 20 20 20 20 1 - 0 2 0 a. 1 0 0 - 0 8 0 * 1 0 19 0 1 19 16 a. 1 17 1 0 0 2 0 1 0 0 0 2 - 2 - Indicates none examined or not applicable. DO 131 306 CONFTDFNTTAl -- -179' TABLE 34 (Continued) SUBCHR0NIC inhalation REPRODUCTIVE TOXIC1TT AND RECOVER! STUDY OF DBCP IN RAIS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON FEMALE RATS EXPOSED FOR 14 weeks Ann nmt mn n k m> tq 26 WEENS OF RECOVERY Diagnosis Code PA-11 ALN-1 ALN-2, ALN-2o ALN-3, ALN-3s, ALN-3m ALN-4 CLN-1 SIN-1 Exposure Laval _________________ Observations_______________________ (mm) Number of rad par group 0 0.1 1.0 _____________________________________________________ Iflafl-- LTMPHORETXCULAR SYSTEM (coat'd) Pancreatic Lymph Nodea (cont'd) Hematogenous pigment, medullary sinuses of pancreatic lymph nodes 0 0.1 1.0 10.0 Anterior Mediastinal Lvaroh Nodea Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Free and phagocytlzed red cells in the medullary sinuses 0 0.1 1.0 10.0 Hematogenous pigment(hemosiderin), medullary sinuses 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 Died or Killed Moribund During Terminal Recovery Period Kill 1 19 0 20 1 19 _____ 2____________ 1Z_ Cumulative Results 20 20 20 20 2 18 0 1 17 12 1 11 5 0 3 4 0 3 1 0 0 0 0 0 1 1 7 0 0 11 7 11 20 1 1 19 - Indicates none examined or not applicable. DO 1 3 1 7 0 7 CONFTDFNTTAl 180- TABLE 34 (Continued) subchronic inhalation reproductive toucitt and recovert study OP DBCP IN RATS AND RABBITS [ HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OP TISSUES EXAMINED OK FEMALE RATS EXPOSED TOR 14 WEEKS AND them OTtm PfiB tip TO 26 UFFgS or RECOVERY Diagnosis -- Code SK-l SK-5 SQ-6 MG-2 s MG-3s MG-5 KG-6 SQ-4 SQ-4(2) Observations Number of rata per group SKIN AND SUBCUTANEOUS (coat'd) Skin (coat'd) No visible lesions Epidermal inclusion cyst Subcutaneous - Number of tissues Tsmlnd Undifferentiated sarcoma Masmary Gland Number of tissues examined 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 Acinar hyperplasia - slight 0 0.1 1.0 10.0 Ductal hyperplasia - slight 0 0.1 1.0 10.0 Diffuse adnar hyperplasia asaodated with a latter atage of pregnancy 0 0.1 1.0 10.0 Intraductal nodular hyperplasia with assodated periductal connective tissue - focal 0 0.1 1.0 10.0 Fibroadenoma, mammary gland origin 0 0.1 1.0 10.0 Fibroadenoma, mammary gland origin, 2 in number 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 1 Cumulative 1 Results ' 20 20 1 20 20 1 19 20 - 00 1 1 2 17 19 0 00 - 11 0 *0 0 00 1 19 1 20 0 1 11 1 0 11 2 17 19 0 11 * 00 0 0 0 00 1 19 20 0 44 1 45 3 16 19 1 4S - 00 0 00 0 55 0 17 17 - 0 0 0 00 2 U 13 0 00 - 00 1 01 1 01 0 00 00 0 00 0 11 0 44 - 44 0 44 2 46 0 00 _ 00 0 00 0 11 DO 1 3 1 ?OR CONF TDFNT T At Diagnoaia Code SQ-5 SQ-7 SQ-8 181' * TABLE 34 (Continued) r SDBCHBONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN EATS AND BABBITS HISTOPATHOLOGIC OBSERVATIONS AND HUMBER OF TISSUES EXAMINED ON FEMALE BATS EXPOSED FOB 14 WEEKS AND THEN WEtn FOB HP TO 26 WEEKS OF RECOVERY Obaarvationa Number of rata per group SKIN AND SUBCUTANEOUS fcont'd) Expoaura Level (ppm) .... 0 0.1 1.0 10.0 Pled or Killed Moribund During Becovarv Period 1 0 1 3 Mammary Gland (cont'd) Galactocele formation, naimary gland origin 0 0.1 1.0 10.0 0 - 0 0 Papillary adenocarcinoma, aanmary gland origin 0 0.1 1.0 10.0 0 - 0 1 Adenocarcinoma, mammary gland origin 0 0.1 1.0 10.0 0 - 0 0 Terminal Kill 19 20 19 17 1 0 0 1 0 0 0 1 0 0 0 1 Cumulative Beaulta 20 20 20 20 1 0 0 1 0 0 0 2 0 0 0 1 -- ; t - Indicate* none examined or not applicable. DO 131709 DONF TDFNTT Al FatholosV No. 77-7471 77-7477 77-7487 77-7557 77-7680 77-7683 TABLE 35 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AMS RECOVERT STUD! OP DBCP IN RATS AND RABBITS CAUSE OF DEATH OR MORIBUND CONDITION OF RATS DYING OR ULLEP tnltlBmm DQRIHC THE RECOVERT PERIOD Exposure Cone. Sex <W) tfeeka After Lest Exposure Possible or Probsbls Cause of Death or Illness M0 M0 M0 M 0.1 M 10 H 10 28 Obesity and sudden death 27 Obesity and sudden death 23 Renal failure from severe chronic progressive renal dlseaae. 31 Obesity and sudden death. Also had a wall muclnoua adenocarcinoma of the email lntaatine. 23 Malignant schwannoma In tha naaal turbinates with local invasion to brain. 32 Renal failure from aevere chronic progreealve renal diaeaae. 77-7423 77-7566 77-7629 77-7633 77-7634 P0 P1 F 10 F 10 F 10 2 Nonmetaatatlc traneitional cell carcinoma of kidney. 23 Focal aevere, suppurative trsnsmursl Inflammation and necrosia of the uterua. 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 sacondary to a fibroadenoma of the mammary gland which waa ulcerated. DO 131710 r.ONFTDFNTTAt -1831,2-DIBROMO-3-CHLOROPROPANE: INHALATION FERTILITY STUDY IN RATS AND RABBITS TEXT RABBIT TABLES - 36 TO 55 no 131 on CONF TOFNTTAl -184- TABLE 36 OBCPt INHALATION FERTILITY STUDY IN THE KALE RABBIT1 Rabbiti Body Weights Week of Study Pre-exposure -2 -1 Exposure 1 2 3 4 5 6 7 8a 9 10 11 12 13 14 Post-Exposure 15 0 3.88 0.29 4.01 0.32 3.96 0.34 3.96 0.31 3.98 0.31 4.00 0.28 3.98 *0.27 3.95 0.26 3.94 0.35 4.03 0.21 3.95 0.20 4.00 0.25 3.96 0.31 3.99 0.31 3.93 0.33 3.88 0.38 3.94 0.25 ppm DBCP 0.1 1.0 TKg., mean s.d.) 3.91 0.57 3.92 0.44 4.06 0.44 4.12 0.42 3.75 0.42 3.71 0.40 3.74 0.42 3.75 0.46 3.77 0.48 3.77 0.47 3.81 0.49 3.81 0.50 3.81 0.46 3.86 0.48 3.85 0.46 3.95 0.39 3.89 0.41 3.93 0.39 4.02 0.38 4.02 0.39 4.02 0.43 3.98 0.46 3.89 0.54 3.96 0.50 3.90 0.49 3.86 0.50 3.93 0.42 3.98 0.50 3.91 0.52 3.62 0.58 3.87 0.59 4.00 0.48 3.94 0.42 4.13 0.56 10 3.88 0.44 3.94 0.42 3.89 0.43 3.82 0.39 3.83 0.41 3.83 0.41 3.82 0.39 3.81 0.44 3.86 0.54 3.81 0.47 3.61 0.30 3.64 0.26 3.84 0.51 3.86 0.52 3.91 0.53 3.94 0.51 3.92 0.50 no OONF TOFNTIAl -185- DBCP: TABLE 36 (Continued) INHALATION FERTILITY STUDY IN THE MALE RABBIT* Rabbit: Body Weights Week of Study 16 17 18 19 20 21 22 23 24 25 26 27 28 29 31 32 33 34 35 0 3.88 0.29 3.91 0.27 3.89 0.30 3.88 0.28 3.94 0.28 3.92 0.31 3.89 0.27 3.91 0.24 3.93 0.19 3.97 0.22 4.05 0.23 4.00 0.20 4.08 0.21 4.09 0.24 4.13 0.27 4.05 0.27 4.07 0.25 4.09 0.27 4.10 0.25 ' ppm DBCP __ 0.1 1.0 mean "375.) 3.93 0.47 4.00 0.43 4.02 0.55 4.14 0.54 4.14 0.52 4.21 0.49 4.15 0.45 4.05 0.47 4.19 0.43 4.26 0.47 4.20 0.42 4.27 0.46 4.21 0.41 4.16 0.65 4.27 0.45 4.28 0.45 4.24 0.45 4.32 0.45 4.30 0.39 4.36 0.42 4.30 0.42 4.32 0.46 4.28 0.37 4.32 0.47 4.31 0.40 4.32 0.52 4.34 0.41 4.27 0.63 4.43 0.43 4.37 0.41 4.34 0.62 4.27 0.62 4.37 0.45 4.27 0.62 4.27 0.41 4.14 0.78 4.32 0.42 4.10 0.79 10 3.87 0.39 3.90 0.43 3.97 0.50 3.97 0.50 4.02 0.45 3.97 0.38 3.99 0.46 3.93 0.39 3.92 0.40 3.95 0.42 3.95 0.43 3.96 0.43 4.02 0.43 4.04 0.49 4.09 0.49 4.08 0.48 4.10 0.50 4.07 0.55 4.11 0.52 DO fONF TDFNT I At -186- TABLE 36 (Continued) DBCP: INHALATION FERTILITY STUDY IN THE KALE RABBIT* Rabbit; Body Weights Week of Study 36 37 38 39 40 41 0 4.09 *0.28 4.11 *0.25 4.10 *0.26 4.16 *0.27 4.07 *0.33 4.08 *0.36 ppm DBCP 0.1 1.0 ^Hcg., mean S.b.) 4.33 *0.42 4.15 *0.78 4.29 *0.40 4.17 *0.78 4.32 *0.43 4.15 *0.76 4.39 *0.45 4.17 *0.78 4.37 *0.39 4.10 *0.77 4.37 *0.40 4.04 *0.88 ' 10 4.11 *0.50 4.08 *0.54 4.13 0.56 4.17 0.57 4.18 0.58 4.18 0.59 42 4.14 4.41 3.98 4.14 *0.35 *0.42 0.97 0.62 43 4.09 4.40 3.91 4.17 *0.39 0.42 1.05 0.61 44 4.12 4.45 3.95 4.23 0.41 0.46 1.07 0.62 45 4.08 4.36 3.84 4.20 0.42 0.44 1.01 0.58 46b 4.01 4.32 3.79 4.11 0.48 0.43 1.06 0.59 *Male rabbits were exposed to 0, 0.1 or 1. 0 ppm of DBCP by inhalation for 6 hr/day, 5 days/week Cor 14 weeks. Hale rabbits exposed to 10 ppm of DBCP were exposed for 8 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. `Exposures of rabbits to 10 ppm were terminated after 8 weeks due to toxicity of the test material. For the 10 ppm males,- the post exposure period begins on week 9. Values for the 46th week represent fasted body weights taken prior to necropsy. No value differed significantly from the control value, by Dunnett's test, p < 0.05. See Table A-28 for individual animal data. DO 131714 GONF TOFNT T Al 187- TABLE 37 DBCP: INHALATION FERTILITY STUDY IN THE HALE RABBIT1 Rabbit; Sperm Count ppm DBCP Week of Study 0 0.1 1,0 lp (millions of spetm/ml of semen, mean a S.D.) Pre-Exposure -2 -1 Exposure 1 2 3 4 5 6 7 8* 9 10 11 12 13 14 Post-Exposure 16 19 24 26 27 28 30 32 34 36 38 40 42 44 46 835 237 694 452 728 i 280 671 t 342 657 181 575 275 474 205 675 294 641 501 426 a 167 509 a 255 473 206 458 * 132 716 * 234 758 502 602 a 282 604 a 273 396 a 220 540 a 560 452 133 701 a 501 327 213 728 678 357 a 202 520 a 467 374 1 197 667 689 637 a 433 429 a 284 497 a 239 637 a 350 576 i 263 673 416 494 281 521 135 835 i 488 618 i 290 391 t 160 576 440 531 t 571 423 232 420 122 459 t 284 360 201 382 208* 738 t 376 498 499 448 157 500 190 691 121 629 115 415 259 409 308 526 244 628 a 24* 535 235 486 239 497 a 196 616 a 341 231 t 181 522 a 196 583 * 276 630 549 552 a 312 538 a 276 373 i 244* 465 231 467 t 126 353 186 473 165 386 251 301 1 167 510 a 122 376 288 204 a 131* 356 a 210* 248 a 217* 109 a 160* 292 a 210 199 a 221 532 a 411 328 a 180 359 a 189 542 a 261 411 a 327 394 a 299 544 a 301 471 a 155 382 a 442 488 a 544 559 a 587 395 a 313 430 a 107 579 a 468 546 a 198 503 a 255 347 a 141 392 a 281* 548 a 456 467 a 272 455 a 250 277 a 170* 124 a 254* 124 a 275* 7.2 a 7.0* 5.4 a 2.0* 2.4 a 3.4* 3.7 a 7.2* 1.9 a 2.7* 0.9 a 0.8* 0.3 a 0.2* 0.4 a 0.5* 1.8 a 3.5* 7.7 a 10.9* 5.1 a 9.6* 4.9 a 5.9* 6.0 a 7.0* 7.5 a 11.9* 1.7 a 2.1* 39.6 a 73.0* 28.7 a 44. lb 2.0 a 2.5* 8.4 a 8.6* 27.2 a 37.2* tMale rabbits were exposed to 0, 0.1, or 1.0 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Hale rabbits exposed to 10 ppm DBCP were exposed for 8 weeks. Following termination of the exposure period, animals were .maintained in the laboratory for recovery. aExposures of rabbits to 10 ppm were terminated after 8 weeks due to toxicity of the test material. For the 10 ppm males, the post exposure period begins on week 9. Significantly different from control at p<0.10 using Wilcoxon test. Small sample size makes statistical interpretation inconclusive. *Significantly different from the control value by Wilcoxon test, p <0.05. See Table A-29 for individual animal data. 00 131015 rONFTDFNTTAl -188- TABLB 38 DBCP: INHALATION FERTILITY STUDY IN THE MALE BABBIT1' Rabbit: Volume of Ejaculate ppm DBCP Week of Study 0 ( i L.O 10 (ml of semen, mean a s. 0.) Pre-Exposure -2 -1 Exposure 1 2 3 4 5 6 7 8* 9 10 11 12 13 14 Post-Exposure 16 19 24 26 27 28 30 32 34 36 38 40 42 44 46 0.6 a 0.2 0.4 4 0.2 0.7 0.4 0.8 * 0.4 0.8 0.5 0.7 a 0.3 0.7 a 0.4 1.1 4 0.3 0.9 0.4 0.8 0.4 1.0 0.4 1.3 0.4 1.0 4 0.4 1.1 a 0.6 0.8 a 0.3 0.7 a 0.2 0.9 i 0.2 1.1 0.6 1.0 0.2 0.9 0.2 0.7 0.3 0.7 t 0.3 0.7 a 0.2 0.6 a 0.2 0.7 0.3 0.7 a 0.2 1.2 a 0.6 0.6 0.2 0.7 0.3 0.9 0.2 0.7 0.2 0.7 4 0.4 0.5 4 0.2 1.0 * 0.5 1.0 4 0.5 0.9 a 0.6 1.1 4 0.6 0.8 4 0.4 1.1 a 0.7 1.0 a 0.6 1.0 a 0.5 1.4 a 0.2* 1.1 a 0.4 1.1 4 0.5 1.2 0.5 1.0 0.7 1.1 a 0.6 1.2 1 0.7 1.2 0.5 1.1 0.7 1.2 0.2 1.3 a 0.2 1.0 0.6 0.9 0.4 1.0 a 0.4 0.7 a 0.2 1.0 a 0.4 0.9 a 0.3 1.2 a 0.2* 1.0 a 0.4 0.9 a 0.3 1.2 a 0.4 0.6 4 0.2 0.4 4 0.2 0.5 4 0.2 0.8 4 0.5 1.0 4 0.4 0.8 4 0.3 0.9 4 0.3 1.1 a 0.5 1.0 a 0.4 0.9 4 0.3 0.8 t 0.4 0.8 a 0.4* 0.8 4 0.4 0.8 a 0.4 0.9 a 0.4 0.8 a 0.2 0.8 1 0.4 1.1 0.8 1.0 a 0.6 0.8 a 0.4 0.8 a 0.5 0.7 t 0.2 0.6 a 0.2 0.8 a 0.4 0.9 a 0.4 0.8 a 0.4 0.9 a 0.4 0.8 a 0.4 0.8 a 0.3 1.0 a 0.1 0.8 a 0.3 0.6 a 0.3 0.4 a 0.2 0.8 a 0.5 0.6 a 0.3 0.9 a 0.4 0.9 a 0.4 0.8 a 0.3 0.7 a 0.4 0.8 a 0.3 0.8 a 0.5 o.6 a 0.1* 0.8 a 0.4* 0.6 a 0.4 1.6 a 1.3 1.2 a 0.3 0.7 a 0.2 1.4 0.7 1.2 a 0.6 l.o a O.S 0.7 0.5 o.8 a O.S 0.5 t 0.4 0.7 0.4 0.9 a 0.5 0.7 a 0.2 l.o a 0.6 l.o a 0.7 0.9 a 0.5 o.s a 0.2 l.i a 0.6 1.2 a 0.4* ^Male rabbits vmre exposed to 0, 0. 1, or 1.0 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Male rabbits exposed to 10 ppm of DBCP were exposed for 8 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. Exposures of rabbits to 10 ppm wn terminated after 8 weeks due to toxicity of the test material. For the 10 ppm males, the post-exposure period begins on week 9. *Significantly different from the control value by Dunnett's test, p <0.05 See Table A-30 for individual animal data. no 131016 CONFIDENT IAl. 189- TABLE 39 DBCPi INHALATION FERTILITY STUDY IN THE MALE RABBITf Rabbltt Proportion of Progressively Motile Sperm Week of Study 0 ppm DBCP 0.1 1.0 10 Pre-Exposure -2 -1 Exposure 1 2 3 4 5 6 7 8a 9 10 11 12 13 14 Post-Exposure 16 19 24 26 27 28 30 32 34 36 38 40 42 44 46 (% Progressively Motile Sperm, mean a S.D.) 68 a 26 80 a 5 63 a 29 69 a 21 S3 a 24 71 a 13 61 a 15 47 a 29 64 20 49 a 25 37 14 42 a 27 62 a 20 56 a 24 50 31 45 a 24 35 a 36 17 21 63 a 16 58 a 33 21 a 27 67 a 35 30 a 31 45 a 37 46 31 54 a 25 49 a 25 72 a 22 57 a 32 50 a 38 56 a 8 60 a 33 78 a 6 60 a 28 57 a 34 42 a 20 51 a 28 56 a 16 48 a 35 58 a 23 54 a 28 47 a 33 48 a 36 44 a 31 40 a 28 34 a 24 38 a 31 19 a 34 52 a 23* 37 a 38 20 a 14 20 a 22 15 a 21* 14 a 20 19 a 26 44 a 37 32 a 23 37 a 36 63 a 38 53 a 35 56 a 26 39 a 31 52 a 36 77 a 6 62 a 30 52 a 34 53 a 27 50 a 30 56 a 19 58 a 24 62 a 19 46 a 31 39 a 20 24 a 22 37 a 27 46 a 30 35 a 21 36 a 10 50 a 34 56 a 26* 41 a 35 45 a 34 30 a 16 40 a 45 29 a 29 20 a 30 26 l 38 36 a 28 18 a 24 38 a 44 43 a 32 57 a 32 18 a 16* 74 a 8 55 a 38* 54 a 35 80 a 9 64 a 27 55 a 27 70 a 13 44 a 25 37 a 28 23 a 21 27 a 34 15 a 13* 3 a__b4* 0C 0C __ D _b __b 38c 3C 7C 21 a 21 0C 7a 6 18 a 21* 15 a 23 26 a 20* 20 a 22 20 a 14 11 a 16* *Male rabbits were exposed to 0, 01., or 1.0 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Male rabbits exposed to 10 ppm of C6CP were exposed for 8 weeks. Following termination of the exposure period, they were maintained in the laboratory for recovery. Exposures of rabbits to 10 ppm were terminated after 8 weeks due to toxicity of the test material. For the 10 ppm males the post exposure period begins on week 9. ^Insufficient number of sperm for determination. cNo mean calculated only a single value was available. "Significantly different from the control value by Dunnett't test p <0. OS. See Table A-31 for individual animal data. DO 13 V? M CONF IDFNT T Al 190- TABLE 40 DBCP: INHALATION FERTILITY STUDY IN THE MALE RABBIT1, Rabbit: Proportion of Non-Progressively Motile Sperm Week of Study Pre-Exposure -2 -1 Exposure 1 2 3 4 5 6 7 8" 9 10 11 12 13 14 Post-Exposure 16 19 24 26 27 28 30 32 34 36 38 40 42 44 46 ppm DBCP 0 1o.;i 1.13 10 ( Non-Progressively Motile Sperm , mean a S.D.) 85 11 4 19 a 15 23 t 22 31 20 18 a 13 21 18 40 a 28 21 a 13 36 22 49 a 20 32 a 18 31 21 18 13 38 27 30 1 14 43 a 36 65 31 31 1 19 32 22 56 28 16 14 48 a 25 18 12 34 20 34 4 18 34 * 23 21 a 23 38 4 31 44 a 35 33 4 13 64 11 i 3 17 13 32 32 37 23 32 a 26 29 a 18 33 a 29 27 a 26 30 a 22 31 a 24 25 a 16 38 a 28 39 a 28 38 a 25 46 a 29 57 4 33 37 i 30 49 a 32 64 a 5* 39 a 27 47 31 48 a 36 45 4 36 31 a 30 50 4 23 29 a 27 20 24 26 4 15 31 a 20 47 4 24 7a 5 10 a 2 20 22 34 22 22 21 37 a 35 26 1 17 23 a 24 23 a 12 32 25 38 a 22 40 a 23 36 1 27 26 18 34 22 37 a 16 37 a 38 29 1 20 45 * 32 24 a 12 48 14 52 42 27 a 22 29 a 30 65 39 53 a 22 41 36 61 43* 45 a 31 33 a 38 47 a 7 13 6* 10 1 3 26 a 32 15 t 8 21 23 23 19 14 a 10 35 t 21 33 a 16 40 a 24 42 a 33 25 a 19 18 a__b2 1C oc --O __b __b l?c 5C 58c 22 a li 6C 28 a 17 18 a 24 49 17 15 a 17 31 a 15 29 a io 37 a 9 fMale rabbits were exposed to 0, 0. 1, or 1.0 ppn of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Male rabbits exposed to 10 ppm of DBCP were exposed for 8 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. "Exposures of rabbits to 10 ppm were terminated after 8 weeks due to toxicity of the test material. For the 10 ppm males the post exposure period begins on week 9. ^Insufficient number of sperm for determination. cNo mean calculated only a single value was available. Significantly different from the control value by Dunnett's test, p <0.05. See Table A-32 for individual animal data. DO 1 3101 8 fONF TDFNTTAL -191- TABLE 4X DBCP: INHALATION FERTILITY STUDY IN THE MALE RABBIT* Rabbit; Proportion of Non-Motlle Sperm ppm DBCP Week of Study 0 0.1 1.0 ______ 10 Pre-Exposure -2 -1 Exposure 1 2 3 4 5 6 7 8* 9 10 11 12 13 14 Post-Exposure 16 19 24 26 27 28 30 32 34 36 38 40 42 44 46 ( Non-Motile Sperm, mean a S.D.) 24 28 94 18 24 84 15 19 11 6 17 9 13 t 9 15 17 16 16 13 a 9 27 a 20 7 3 26 a 12 11 9 26 21 22 a 34 24 27 65 11 a 20 24 28 18 a 24 22 a 15 36 a 29 21 a 11 13 a 12 16 a 14 7a7 8a5 6a3 10 9 33 36 11 t 6 23 26 11 5 21 29 18 i 8 15 5 20 10 15 a 9 16 9 22 a 18 27 a 29 19 a 24 21 a 30 26 a 30 16 13 24 28 12 a 13 14 a 22 15 a 18 40 a 35 38 a 41 38 a 33 36 a 38 24 a 34 19 a 32 34 a 45 18 a 18 20 a 28 14 a 11 14 a 17 40 42 13 8 17 a 22 14 19 25 30 15 11 18 16 19 9 15 a 13 22 a 31 23 a 33 36 a 31 27 a 23 28 a 19 31 a 17* 26 a 11 12 a 4 15 a 9 14 a 10 31 a 31 22 a 13 7a7 44 a 37 51 a 36 9a2 11 a 15 41 a 36 2a2 12 a 8 10 a 12 34 a 21* 12 a 6 34 a 45* 19 a 31 6a2 14 a 14 21 a 16 15 8 21 a 14 29 a 16 37 a 30 31 a 34 60 a 31* 79 a 13* __b 99c 100c __ D _b __b 45= 92= 35= 57 24 94= 66 a 22* 64 a 43* 36 a 20 59 a 25* 49 a 32* 51 a 21* 52 t 18* tMale rabbits were exposed to 0, 0.1, or 1.0 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Male rabbits exposed to 10 ppm of DBCP were exposed for 8 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. *Exposurea of rabbits to 10 ppm were terminated after 8 weeks due to toxicity of the test material. For the 10 ppm males, the post-exposure period begins on week 9. ^insufficient number of sperm for determination. cNo mean calculated: only a single value was available. *Significantly different from the control value by Dunnett's test, p <0.05. See Table A-33 for individual animal data. DO 131719 OONFTDFNTIAI -192- TABLE 42 DBCP: INHALATION FERTILITY STUDY IN THE HALE RABBIT* Rabbit; Viability of Sperm* ppm DBCP Week of Study 0 0.1 1.0 IQ (t live sperm, mean a S.D.) Pre-Exposure -2 -1 Exposure 1 2 3 4 5 6 7. 8b 9 10 11 12 13 14 Post-Exposure 16 19 24 26 27 28 30 32 34 36 38 40 42 44 46 87 9 93 * 3 88 15 92 a 5 76 a 21 88 a 6 78 a 12 89 a 5 88 a 5 88 a 5 87 a 11 83 i 16 88 5 84 10 86 14 83 a 13 90 a 5 8S a 22 79 a 8 96 a 4 88 a 12 96 a 2 86 a IS 82 a 15 82 a 11 85 a 11 86 a 12 84 a 14 67 a 22 81 a 16 90 a 6 88 * 28 88 * 8 71 a 25 87 a 9 84 a 12 80 a 14 81 a 5 86 a 6 87 a 10 85 a 8 88 t 12 90 a 6 84 a 18 89 a 6 78 a 18 87 a 6 93 a 4 92 a 3 86 a 7 96 a 2 86 a 24 76 a 29 82 a 15 89 a 6 79 a 23 81 a 22 53 a 20* 89 a 6 82 a 7 91 a 4 78 a 5 92 a 6 89 a 6 81 a 25 84 a 18 79 a 15 83 a 5 80 a 15 80 a 13* 86 a 10 73 a 25 83 a 9 82 a 11 79 a 13 69 a 22* 72 a 12* 74 a 17 84 a 8 92 a 8 87 a 16 92 a 5 95 a 4 89 a 11 82 a 17 86 a 13 62 a 31 89 a B 77 a 30 84 a 4 81 a 3 92 a 3 68 a 36 87 a 6 89 a 5 89 a 6 90 a 6 86 a 10 76 20* 78 a 8 82 a 8 81 a li 49 a 26* 53 a 36* 49 17* 31 a 14* _e 5d __ c 0d _c __ c 36d 51*j 47d 46 65* 34 47 a 17* 47 a 23* 53 a 10* 59 a 17* 66 a 8 72 a 1 70 a 13 *Male rabbits were exposed to 0, 0.1, or 1.0 ppm of DBCP by inhalation for 6 hr/day, S days/week for 14 weeks. Male rabbits exposed to 10 ppm of EBCP were exposed for 8 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. ^Determined by staining sperm with eosin-aniline blue stain. ^Exposures of rabbits to 10 ppm were terminated after 8 weeks due to toxicity of the test material. For the 10 ppm males, the post-exposure period begins on week 9. cInsufficient number of sperm for determination of the percentage of live sperm. ^No mean calculated; only a single value was available. Significantly different from the control value by Dunnett's test, p <0.05. See Table A-34 for individual animal data. DO CONFTDFNTTAt -193- TABLE 43 DBCP: INHALATION FERTILITY STUDY IN THE RABBIT* Observations Made at the Tine of Necropsy of bnexposed Female Rabbits Mated with DBCP Exposed Hales (14 Weeks) 0 No. of males 9 % (No. of males which copulated) 100(9) Male Fertility Index, t (No. Fertile Hales/No. Bred to Females) 67(6/9) Corpora Lutea/dama 10 * 1 Implantation/litter3 9*1 Resorptions/1itterA 0.7 * 0.8 t Pre-Implantation Lossa'" 9 15 % Post-Implantation LOSSa'c 89 ppm DBCP 0TT 170 10 9 90(9) 78(7) 100(9/9) 10 a 3 9*1 0.9 * 0.8 86(6/7) 8*4 6*2* 0.3 * 0.5 14 * 13 21 1 20 10 * 9 46 10 5 100(5) 0(0/5) -- -- -- -- *Male rabbits were exposed to 0, 0.1, or. 1.0 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Hale rabbits exposed to 10 ppm of DBCP were exposed for 8 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. During the 14th week of the study, each male rabbit was allowed to mate with one unexposed female rabbit. The females were sacrificed on day 28 of gestation. aMean * standard deviation. ^Pre-Implantation Loss - corpora lutea^minus ^implantations x 1(J0 cPost-implantation loss - - /JffSKKUs * 100 -- No data available. *significantly different from the control value by the appropriate statistical test, p <0.05. See Table A-35 for individual animal data. DO CONFtDFNTTAt -194- TABLE *4 DBCPt INHALATION FERTILITY STUDY XN THE HALE RABBIT* Observations Hade at the Tine ot Necropsy of unexposea Female kaboits Hated with DBCP-Exposed Males (41 Weeks) 0--------- cm-------- 175---------------- n-- No. of males 6 6 55 t (No. of males which copulated) 83 (S) 100(6) 80(4) 100(5) Male Fertility Index, * (No. males impregnating one female/number bred) 100(5/5) 100(6/6) 100(4/4) 40(2/5) , (No. males impregnating two females/ number bred) 80(4/5) 100(6/6) 100(4/4) 20(1/5) Corpora Lutea/Dama 10 a 1 10 2 10 1 12 3 Implantations/Litter4 8 1 2b 82 8*2 10 6 Re so rptions/Litter* 0.7 a 0.7 0.8 a 0.5 0.2 a 0.3 1.0 a 1.4 t Pre-Implantation Loss*'* 24 20 22 17 19 13 22 26 t Post-Implantation Loss*'d 16 * 24 15 a 12 3a3 7 a 10 tMale rabbits were exposed to 0, 0.1, or 1.0 ppm of EBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Hale rabbits exposed to 10 ppm of EBCP were exposed for 8 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. During the 41st week of the study, each male was allowed to mate with two unexposed female rabbits. The females were sacrificed on day 29 of gestation. aHean a standard deviation. b0ne fetus from a female bred to a control male exhibited multiple external malformations including short trunk, acaudia, rotated hind limbs, ectodactyly, and microdactyly. cpre-Implantation Loss - . corpora lutea minus 4 implantations 10,, corpora lutea * dpost-Implantation loss - / x 100 No value differed significantly from the control value by the appropriate statistical test. See Table A-36 for individual animal data. DO 131??? CONFIDENT TA1 TABLE 45 DBCP: INHALATION FERTILITY STUDY IN THE MALE RABBIT* Rabbit; Hematologic Evaluation Week of Study ppm DBCP n PCV % RBC x 10^/nTM^ Hgb g/100 ml WBC x 10J/mmJ WBC Differential Count (5) Neut Lymph Mono Eos in Baso -2 0 4 46 2a 6.8 0.8 14.7 0.8 9.4 2.0 30 61 5 1 0.1 4 43 1 6.4 0.5 14.0 0.4 9.9 2.5 40 56 2 1 1.0 4 42 2 6.2 1 0.6 13.9 0.8 8.4 1 0.8 24 69 4 1 10.0 4 44 1 6.5 0.2 14.4 0.6 9.5 1.9 26 66 4 2 3 2 2 2 8 10.0 1 40 6.2 12.4 12.2 66 25 6 1 2 9 0 3 44 i 3 6.6 0.6 14.2 0.4 10.8 1.0 41 52 3 1 0.1 4 38 5 5.6 0.8 12.1 0.9 15.8 7.2 51 40 4 2 1.0 4 37 5 5.6 0.4 11.9 1.7 12.2 2.7 55 34 6 0 10.0 1 43 5.8 14.4 7.7 43 50 3 0 3 3 5 4 13 0 3 38 * 2 5.9 0.5 12.9 1.2 11.9 1.6 49 43 5 1 0.1 4 40 10 5.8 1.6 12.7 3.0 12.9 5.8 59 36 2 1 1.0 4 37 6 5.8 0.3 12.1 2.2 10.7 2.0 51 41 3 1 10.0 1 44 6.1 14.6 6.6 35 53 1 2 3 2 4 9 *Male rabbits Were exposed to 0, 0.1, or 1.0 ppm of DBCP by inhalation for 6 hr/day, 5 day/week for 14 weeks. Male rabbits exposed to 10 ppm of DBCP were exposed for 8 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. aMean S.D. No value differed significantly from the control value by Dunnett's test, p<0.05. See Tables A-37 through A-41 for individual animal data. DO 131773 OONFTDFNTTAI -196- TABLE 46 DBCP: INHALATION FERTILITY STUDY IN THE MALE RABBIT* Rabbit; Clinical Chemistry Values Week of Study: 14 No. of rabbits3 Prothrombin time, sec. BUN, mg/100 ml SGPT, mU/Ml SGOT, mU/ml AP, mU/ml rt 00 ppm DBCP 0 0.1 1 10 34 0.5b 8.1 0.5 19 2 27 22 20 7 18 5 48 21 25 7 27 17 15 6 4 8.1 0.2 18 3 21 6 40 16 29 2 0 -- -- -- -- *Male rabbits were exposed to 0, 0.1, or 1.0 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Male rabbits exposed to 10 ppm of DBCP were exposed for 8 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. aA sample was not obtained from one rabbit in the 0.1 and 1 ppm groups each. bMean S.D. -- No data available. No value differed significantly from the control value by Dunnett's test, p <0.05. See Table A-42 for individual animal data. HO 131??4 r.ONFTDFNTTAl -197- DBCP: TABLE 47 INHALATION FERTILITY STUDY IN THE MALE RABBIT1- Rabbit: FSH and Testosterone Levels Week of Study ppm DBCP n FSH (nanogram/ml) Testosterone (nanogram/ml) 14 03 6.92.7a 1.21.1 0.1 4 5.63.4 1.44:1.6 1.0 4 15.14.6* 3.42.7 46 06 3.51.7 0.1 6 4.53.8 1.0 5 3.7*3.7 10.0 5 12.9*2.0* 1.40.9 3.42.7 0.80.6 1.0*1.0 "''Male rabbits were exposed to 0, 0.1f or 1.0 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Male rabbits exposed to 10 ppm of DBCP were exposed for 8 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. aMean S.D. *Significantly different from the control value by Dennett's test, p<0.05. See Table A-43 for individual animal data. no -131 2P5 CONFIDENT TAI. -198- TABLE 48 DBCP: INHALATION FERTILITY STUDY IN THE MALE RABBIT* Rabbit; Organ Weights and Organ/Body Weight Ratios Determined at the Interim (8 and 14 weeks) and Terminal (46 weeks) Sacrifices Week of ppm Body tft. Study DBCP n kg Brain g k/IOOk Heart g r/100r Liver g r/100r 8 10.0 1 4.45 10.95 0.25 8.58 0.19 162.61 3.65 14 0 3 3.82+0.62s- 9.831*08 0.26+0.04 8.12+0.50 0.22+0.03 99.73+25.60 2.61+0.48 14 0.1 4 3.9U0.50 9.84+0.67 0.25+0.04 7.23+2.31 0.18+0.05 94.82+33.28 2.36+0.56 14 1.0 4 3* 60+0.66 9.91+0.54 0.28+0.04 7.63+O.36 0.22+0.04 96.29+17.99 2.70+0.43 46 0 6 4.0010.48 9-9710.29 0.250.03 7.56+0.62 0.19+0.03 73.65+9.94 1.86+0.33 46 0.1 6 4.320.43 10.45+0.76 0.24+0.02 7.24+0.83 0.17+0.02 74.718.12 1.75+0.30 46 1.0 5 3.79+1.06 9.50+0.50 0.27+0.07 7.56+1.29 0.22+0.08 67.75+11.67 1.85+0.35 46 10.0 5 4.11+0.59 10.23+0.52 0.25+0.03 7051.01 0.170.01 70.0710.15 1.71+0.08 DO CONFTDFNTTAl f}. -199- TABLE 48 (Continued) DBCP: INHALATION FERTILITY STUDY IN THE MALE RABBITt Rabbit: Organ Weights and Organ/Body Weight Ratios Determined at the Interim (6 and lU veeks) and Terminal t46 weeks) Sacrifices Week of ppm Study DBCP n Kidney g g/lOOg Testes g g/lOOg Epididymides g g/lOOg 8 10.0 1 18.63 0.42 1*53 0.03 2.42 * 0.05 14 0 3 l4.910.80 0.40+0.05 6.780.95 0.20+0.05 2.650.07 0.080.01 14 0.1 4 17.09+3.25 0.43+0.05 6.01+1.31 0.150.03 3.24+0.56 0.08+0.01 14 1.0 4 17.57+3.12 0.49+0.08 3.330.47 0.10+0.03* 2.50+0.54 0.07+0.02 Adrenals g g/100g __b __b __b __b __b __b __b __b 46 0 6 17-1012.25 0.440.11 6.060.54 0.150.01 2.28+0.29 0.060.01 0.60+0.16 0.02+0.01 46 0.1 6 17.02+2.08 0.39+0.04 6.49+0.43 0.15+0.01 2.33+0.27 0.05+0.00 0.70+0.18 0.02+0.00 46 1.0 5 17.28+1.45 0.49+0.14 4.91117* 0.14+0.04 2.45+0.69 0.07+0.01 0.71+0.07 0.020.00 46 10.0 5 18.21+0.72 0.45+0.07 1.80+0.38* 0.05+0.01* 1.67+0.13 0.04+0.01 0.63+0.15 0.02+0.00 b~ z^ b o^ "Tl -* 5 -o ? *Male rabbits were exposed to 0, 0.1, or 1.0 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for l4 weeks. Male rabbits exposed to 10 ppm of DBCP were exposed for 8 weeks* Following termination of the exposure period, they were maintained in the laboratory for recovery. aMean + S.D. ^Adrenals for the 8 and 14 week Interim sacrifice were not weighed. Significantly different from the control value by Dunnett's test, p<0.05 -200- TABLE 49 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS TISSUES ROUTINELY COLLECTED AT NECROPSY AND PRESERVED IN 102 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 oviducts 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 DO 131728 CONFIDENTIAL -201- TABLE SO Diagnosis Code A-6 A-7 B-4 B-3 B-6 D-7 D-8 E-l E-3 E-5 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS GROSS PATHOLOGIC OBSERVATIONS ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKS* AND THEN W*t t> FOR UP TO 32 WEEKS OF RECOVERY Number of rabbits par group ADRENAL GLANDS Slightly raised pale focus(1) on adrenal Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Raised dark focus(1) on adrenal 0 0.1 1.0 10.0 CARDIOVASCULAR SYSTEM Serosangulneous fluid within the pericardial sac 0 0.1 1.0 10.0 Fibrlnoua or fibroua pericarditis (adhesions to eplcardium) 0 0.1 1.0 10.0 Heart Involved In a suppurative inflaamatory response with abscess formation 0 0.1 1.0 10.0 EYES Focal scar on eyelid 0 0.1 1.0 10.0 Purulent or mucoid 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 hemorrhaglc 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 D 1 1 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill Results 6 10 6 10 5 10 S 10 0- 0 1 1 * as 0 2 2 -- 0 01 1 0 .0 0 00 0* 000 -- -000 -- 0011 00 0-00 0--000 -*-000 -*0101 00 0-00 0 _01 1 -- - 0 0 0 --0000 00 0-00 0* _000 -- -101 -a - 0 0 0 0 001-01 0 *000 - -- 10 1 -- 0000 0 0 0-00 0 _000 -- -000 *- 0000 0 0 1-01 0 - . 01 1 -m 02 2 -- 0000 00 0-00 0 _000 -- _000 -- 0000 00 1-01 0- 000 -- -101 - 0000 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. 00 1 31 cO NFlnc.' 9 M/ f 202- TABLE 50 (Continued) .agnosia Cod* 7 9 -10 -11 13 14 -15 16 -17 18 SOBCHBONIC INHALATION REPRODUCTIVE TOXICITY AMD RECOVERY STDDT OF DBCF IM RATS AMD RABBITS GROSS PATHOLOGIC OBSERVATIONS ON male RABBITS EXPOSED FOR DP TO 14 WEEKS* AMD THEN FOR UP TO 32 WEEKS OF RECOVER! Number of rabbits per group GENERAL (cont'd) Exudate or porphyrin-like pig- meat accumulation lateral to external narea or around eyes Exposure Level . (ppm) 0 0.1 1.0 _ 10.0 00.1 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 Abscess at base of Incisor or molar tooth 0 0.1 1.0 10.0 Decubitus 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 throughout peritoneum and omentum 0 0.1 1.0 10.0 Yellowish, purulent lnflamnatory 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 -101 -*- 4 0 4 *1 3 04 100-0 1 0__11 2 --- 2 0 2 --0 13 4 000-1 1 0 _011 ---10 1 --1 1 2 4 00 0" 0 0 0_ 112 ---00 0 --10 2 3 000-0 0 1 _056 -.-0 4 4 --032 5 000-3 3 0-_0 1 1 .-.000 .-0 0 0 0 000-0 0 0_ 011 -- -10 1 ** 0 1 2 3 010-0 1 0 *000 -. -0 0 0 --001 1 000*00 0_ _ 0 0 0 ---00 0 -- 0 0 0 0 000-11 1._0 0 1 *--0 00 --0000 000 "0 0 *Top dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. - Indicate* none examined or not applicable. DO 131?30 CONFTDFNTTAl  -203- TABLE 50 (Continued) SUBCHROHIC INHALATION REPRODUCTIVE TOECITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS GROSS PATHOLOGIC OBSERVATIONS ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKS* AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY Exposure 8-Week 14-Week Level 0-8 Interim 8-14 Interim Terminal Cumulative (ppm) Weeks Kill Weeks Kill Kill Results Diagnosis Number of rabbits per group 0 1 0 0 3 6 10 ! Code 0.1 0 0 0 4 G 10 1.0 10.0 0 0 1 4 5 10 3 1 1 0 5 10 GASTROINTESTINAL SYSTEM F-6 Absence or decreased normal ingests 0 0- . 0 0 0 in gastrointestinal tract 0.1 ---00 0 i 1.0 - 1 0 0 1 10.0 10 0-0 1 F-8 Small intestinal mass(es) or 0 0 *00 0 nodule (a) 0.1 -*1 0 1 1.0 me 0 0 0 0 10.0 00 0-0 0 F-12 Mass(es) or nodule(s) in stomach 0 0_--0 1 1 ? 0.1 -- 0 0 0 1.0 - 0 0 0 0 10.0 00 0-0 0 F-13 Dark area or focus on gastric mucosa, suggestive of hemolysed blood admixed with bile 0 0.1 1.0 10.0 0 -00 0 -- -0 0 0 --10 0 1 000- 0 0 F-14 Pinpoint dark foci on stomach OUCOS& 0 0.1 1.0 10.0 0--00 0 --0 0 0 - 00 0 0 001-0 1 LIVER G-3 Diffuse paleness of liver 0 0.1 1.0 10.0 0--0 0 0 --0 0 0 --00 0 0 00 1- 0 1 G-4 Accentuated lobular pattern of 0 0_ 000 liver 0.1 --0 0 0 1.0 -* 001 1 10.0 00 0- 0 0 G-5 Few small pale foci or focus 0 0 00 0 in liver 0.1 ** -0 0 0 1.0 - - 0 0 1 1 10.0 0 0 0- 0 0 G-8 Darkened or congested liver 0 000 0 0.1 - -10 1 1 1.0 -- 101 2 i 10.0 010-- 1 i 0-9 Firm liver , i 0 0.1 1.0 10.0 0 000 --10 1 - 101 2 00 0-- 0 0 Top dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. 1J - Indicates none examined or not applicable. > DO 131701 i OONF TDFNT TAL -204- TABLE 50 (Continued) lagnoals Code -11 -12 -13 -14 -15 -15 -3 -8 1-9 1-10 SOBCHRONIC INHALATION REPRODUCTIVE TOZICITT AND RECOVERY STUDY OP DBCP IN RATS AND RABBITS GROSS PATHOLOGIC OBSERVATIONS ON KALE RABBITS EXPOSED FOR UP TO 14 WEEKS* AND THEN HELD FOR UP TO 32 WEEKS OF RECOVERY : 1 Number of rabbits per group Exposure Level (non) 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(1) In subcapsular region 0 of liver, suggestive of parasitic 0.1 leslon(s) 1.0 10.0 White focus(1) 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 nodular surface of liver 0 0.1 1.0 10.0 Atrophied liver (decreased size) 0 0.1 1.0 10.0 LYMPHORETICULAR SYSTEM Enlarged 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 Enlarged thoracic lymph node(s) 0 0.1 1.0 10.0 Edema of thoracic lymph node(s) 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 8-Week Interim Kill 0 0 0 1 8-14 Weeks 0 0 1 1 -* --0 00 me --0 00 _ --0 00 -0 10 _ --0 00 --* -1 00 14-Week Interim Kill 3 4 4 0 TermIns! Cumulative Kill Results 6 6 1100 5 I 10 5 10 1" 01 1 00 0 00 0 -0 0 00 0 01 1 00 0 -11 000 000 00 0 -1 1 0 0 :o 000 000 -0 1 000 101 000 -0 0 000 10 1 00 1 -0 0 0--10 1 --- 0 0 0 --0 10 1 000 -0 0 0*-1 0 1 ---00 0 --00 0 0 000- 0 0 0--00 0 ---00 0 --010 1 000 -0 0 0--00 0 ---00 0 --0 1 0 1 000"0 0 *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 OONFTDFNTTA! . i iL -205- TABLE 50 (Continued) Diagnosis Code 1-2 1-3 1-4 1-5 L-l L-2 L-6 L-9 L-10 L-ll subchronic inhalation reproductive toxicity and recovery study OF DBCP IN RAIS AND RABBITS GROSS 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 (pp) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Hock joint swollen and arthritic due to an inflammatory reaction 0 0.1 1.0 10.0 0-8 Weeks 1 0 0 3 8-Weak 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* - 0 1 1 ---00 0 -- 0 1 1 2 00 0-0 0 0 * - 0 1. 1 --- 00 0 -- 0 000 00 0 - 0 0 Generalized atrophy of muscle yflTTu> of hind Usb muscles 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0_ 0 1 1 .- - 00 0 -_ 00 1 1 000 -00 0_- 000 - - me 1 0 1 -- 0 0 0 0 00 0 - 0 0 MALE REPRODUCTIVE SYSTEM Decreased size of testlde(s) with or without minerallike laaions Dark tan appearance of teates 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0- -1 1 2 -- - 101 -- 0 4 2 6 111"58 0- - 000 -. - 0 0 0 --0 3 14 000 "5 5 Edematous appearance of testes 0 0.1 1.0 10.0 0- 0 1 1 - - 0 0 0 -- 0 0 0 0 000 *00 Enlarged prostate 0 0.1 1.0 10.0 0- - 0 1 1 -- -000 -- 0 0 0 0 000 -0 0 Edematous appearance of prostate Absence or severe atrophy of one testis 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 me - 0 1 1 --000 -- 0 0 1 1 00 0-1 1 0- - 0 0 0 - - - 0 0 0 *-0 0 1 1 00 0 * 00 *Top dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 week* of recovery. - Indicates none examined or not applicable. no 131033 CONF TDFNT TAl -206- TABLE 50 (Continued) iagnosis Code -12 -13 -14 -15 -16 -17 -18 -1 -2 -5 SOBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERT STUDY OF DBCP IN RATS AND RABBITS GROSS PATHOLOGIC OBSERVATIONS ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKS* AND THEN HELP FOR UP TO 32 WEEKS OF RECOVERY Number of rabblte per group MALE REPRODUCTIVE SYSTEM (cont'd) Flaccid teatide(s) Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Decreased else of prostace 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 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 Cunnilatlve Kill Results 6 10 6 10 5 10 5 10 0 - *. 0 - 1 1 --- 1 o 1 -*1 2 2 S 000-5 5 0 __ 00 0 ---10 1 --0 2 1 3 001*3 4 0__00 0 ---00 0 --011 2 000-4 4 0 - 00 0 -- 00 0 -e - 0 0 0 0 00 0-1 1 Prostate - filled with a yellowish fluid Decreased size of epididymis(Ides) Testicle - mottled In color with yellow to tan colored Btreaks 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 000 ---00 0 --000 0 000-11 0__000 ---00 0 *-000 0 0 1 1-0 2 0_m 10 1 --*00 0 *-000 0 0 0 0 -0 0 RESPIRATORY SYSTEM Dark or red focus(1) In lungs 0 0.1 1.0 10.0 0-31 - -- 24 - 0 3 3 0 0 0-4 Few pale foci in lungs 0 0.1 1.0 10.0 0--00 ---01 -* 000 000-0 Mottled appearance of lungs 0 0.1 1.0 10.0 0-00 ---01 -- 002 0 1 1-0 *Top dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of rtcovary. - Indicates none examined or not applicable. 4 6 6 4 0 1 0 0 0 1 2 2 DO 1 r-n ?34 C.ONF T DFN'T TAl t * It'! L1 -207 TABLE SO (Continued) Diagnosis Code M~6 M-7 W-8 M-9 M-10 M-ll M-12 H-14 M-L5 M-16 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS GROSS PATHOLOGIC OBSERVATIONS ON MALE RABBITS EXPOSED FOR OP TO 14 WEEKS* AND THEN HELD FOR OP TO 32 WEEKS OF RECOVERY 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 adhesions 0 0.1 1.0 10.0 Pulmonary atelectasis 0 0.1 1.0 10.0 Hyperemic and/or congested appearance 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 abscessatlon of thoracic cavity and lung 0 0.1 1.0 10.0 Red and hemorrhagic appearance of trachea 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 8-Week Interim Kill 0 0 0 1 8-14 Weeks 0 0 1 1 14-Week Interim Kill 3 4 4 0 Terminal emulative Kill Results 6 10 6 10 3 10 5 10 0- - 3 14 -- - 1 23 - 1 4 38 1 1 0 -13 0 - 2 1` 3 --- 02 2 -- 1 225 00 0"11 0* _ 011 *- - 0 00 -- 0011 01 1-02 0- * 011 --000 * 0 0 0 0 10 0* 01 0_ -1 01 -- 000 -- 0 123 10 1-02 0- -1 01 -- - 3 03 -- 0202 10 1"02 0 - 0 00 -- -0 00 -* - 1 0 0 1 10 0"01 0 _000 -* - 1 01 -- 0 011 00 1 -01 0- * 0 00 -- - 0 00 -- 1 001 00 0 -00 0- - 000 --- 000 - 1001 00 0 -00 *Top doee rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none examined or not applicable. DO 131735 OONFTDFNTTAl -208- TABLE SO (Continued) iagnosls Code -7 -8 '-9 '-10 -11 '-12 j-13 J-14 '-15 ?-16 SUBCHBONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVER! STUD! OF DBCP IN RATS AND RABBITS GROSS PATHOLOGIC OBSERVATIONS ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKS* AND THEN HELD FOR UP TO 32 WEEKS OF RECOVER! Number of rebblta 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 Dilated renal pelvis(ea) (hydronephrosis) 0 0.1 1.0 10.0 Mottled appearance of kldney(s) 0 0.1 1.0 10.0 Cyst(a) In kidney 0 0.1 1.0 10.0 Hypcremlc appearance of blood vessels of urinary bladder 0 0.1 1.0 10.0 Polypoid mass In bladder 0 0.1 1.0 10.0 Focal hemorrhagic areas on urinary bladder mucosa 0 0.1 1.0 10.0 Subcapsular white focus(1) In kidney 0 0.1 1.0 10.0 Hydroureter 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 - 012 3 000 "0 0 0-00 0 ---00 0 -*000 0 000-1 1 0--00 0 ---00 0 --000 0 000-2 2 0-*00 0 ---00 0 - * 0 0 0 0 00 0-1 1 0--00 0 -* -01 1 - 000 0 000-0 0 0--00 0 ---01 1 -000 0 000-0 0 0--00 0 - - - 0 0 0 -001 1 000-0 0 0--00 0 ---00 0 --001 1 000-0 0 0--00 0 - -00 0 -- 0 00 0 000-1 1 0 -00 0 -- 00 0 -*000 0 000-1 1 *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 131P36 C ONFTDFNTTAl 209- TABLE 50 (Continued) Diagnosis Code P-17 P-18 P-20 P-21 Q-8 Q-ll Q-12 Q-13 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERT STUDY OF DBCP IN RATS AND RABBITS CROSS PATHOLOGIC OBSERVATIONS ON HALE RABBITS EXPOSED FOR UP TO 14 WEEKS* AND THEN help 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 noseuatosls 0 0.1 1.0 10.0 Roughened or Irregular appearance of kidneys 0 0.1 1.0 10.0 Mass or nodule Involving kidney 0 0.1 1.0 10.0 INTEGUMENT AND SUBCUTANEOUS Subcutaneous edema 0 0.1 1.0 10.0 Subcutaneous abscess 0 0.1 1.0 10.0 Subcutaneous region containing suppurative necrotic debris and fluid suggestive for suppurative inflammation 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 Cuaulatlve Kill Results 6 10 6 10 5 10 5 10 0 - - 0 00 - - 0 00 * - 0 0 00 0 0 0 - 11 0 0 00 - - - 0 0 0 - 0 0 00 1 0 0 - 01 0 _ 0 00 - - 0 00 - - 0 0 00 0 0 0 - 11 0 - 0 00 - * - 0 00 - - 1 0 01 0 0 0 - 00 0 * - 0 00 *- 1 01 - - 0 0 00 0 0 0 - 00 0 -- _ 0 00 - * - 0 00 - - 1 0 01 0 0 0 - 00 0 _ _ 0 00 * - - 0 00 - - 0 0 00 0 0 1 - 01 0 _ 0 00 a- - * 1 0 1 - 0 0 00 0 0 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. HO 131737 CONFTDFNTTAl -210- TABLE 51 SOBCHRONIC INHALATION REPRODUCTIVE TOXXCITT AND RECOVER! STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC observations and number of tissoes examined on male rabbits ttposto FOR UP TO 14 WEEKS* AND THEN HELD FOR 32 WEEKS OF RECOVERT Exposure Level ______________________________________________________________ (ppm) Diagnosis Number of rabbits per group 0 Code 0.1 1.0 _______________________________ !_____________________ ,,___ 10-0 ENDOCRINE SYSTEM Adrenal a Number of tlseuea 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 Cumulativs r Kin Results i6 16 5 10 10 10 '3 10 1000 6 7 0000 1 1 00 10 0 1 30104 8 A-l A-2 ! i No visible lesions 0 0.1 1.0 10.0 1 67 _ _- 1 1 0-- 0 3- 1- 4 8 Malignant lymphoma, secondary 0 0 _ 00 site - bilateral 0.1 _ *- 0 0 1.0 _ 1- - 1 10.0 0 - 0 - 0 0 Pituitary Gland Number of tissues examined 0 1000 6 7 0.1 0 0 0 0 0 0 1.0 0 0 1 0 0 1 10.0 3 0 1 0 4 8 P-1 No visible lesions 01 * - 6 .7 0.1 _ -* * 1.0 _ 1-- 1 10.0 3 - 1 - 4 8 Thyroid Gland Number of tissues examined ) i TH-1 No visible lesions i i TH-2 Colloid cyst - focal, slight 0 1000 6 7 0.1 0 0 0 0 0 0 1.0 0 0 1 0 0 1 10.0 3 0 0 0 5 8 0 1*.5 6 0.1 _ * - - - - 1.0 1- - 1 10.0 3 - - - 4 . 7 0 0--- 1 1 0.1 - -- - * 1.0 - 0 - - 0 10.0 0 - - - 0 0 j TH-3 Atrophy with decreased secretory 0 0 a. _ - 0 0 contents - bilateral, moderate 0.1 - - - 1.0 0*- 0 10.0 0 - -1 1 Parathyroid Glands Number of tissues examined | i PG-,1 No visible lesions 0 0000 1 1 0.1 0 0 0 0 0 0 1.0 0 0 0 0 0 0 10.0 1 0 0 0 2 3 0 1- * - - 1 0.1 - - -e - " - 1.0 * _- - - 10.0 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. DO 131738 CONFIDFNTTAl -211- TABLE SI (Continued) Diagnosis Code PC-2 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVER! STUDY OF DBCP m RAIS 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 (ppm) 0 0.1 1.0 10.0 ENDOCRINE SYSTEM (cont'd) Parathyroid 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 8-14 Weeks 0 0 1 1 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill Reaults 6 10 6 10 5 10 5 10 ----00 --- - - -- - -- 0""* 11 SC-1 ES--1 ES-2s S-l S-2 GASTROINTESTINAL SYSTEM Salivary Glands Number of tissues examined 0 1000 6 0.1 0 0 0 0 0 1.0 0 0 1 0 0 10.0 3 0 1 0 5 No visible lesions 0 1---6 Oe 4. 1,0 _ _ 1 _ 10.0 3 - 1 - 5 Esophagus Number of tissues examined No visible lesions 0 10005 0.1 0 0 0 0 0 1.0 0 0 0 0 0 10.0 2 0 1 0 5 0 1*--4 0.1 " " " - " 10.0 2 - 1 - 5 Subacute inflammation, muscularis 0 0_ __ 1 - multifocal, slight 0.1 - - - - - 1.0 * -- - - 10.0 0 - 0 - 0 Stomach - 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 0.1 - - - - 1.0 * - 1 - 10.0 2 * - - 5 Reactive hyperplasia with associated 0 0-- _1 acute inflammation, edema and multi- o.l - - * - 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 "Top 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 HO 131039 CONF TDFNTTA! -212- TABLE 51 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AMD RECOVERY STUDY OF DBCP IN RATS AMD RABBITS* HISTOPATHOLOGIC OBSERVATIONS AMD HUMBER OF TISSUES EXAMINED ON MALE RABBITS t EXPOSED FOR UP TO 14 WEEKS' AMD THEN HELD FOR 32 WEEKS OF RECOVERY Exposure 8-Week 14-Week Level 0-8 Interim 8-14 Interim Terminal Cumulatl } (ppm) Weeks Kill Weeks Kill Kill Result Diagnosis Dumber of rabbits per group 0 1 0 0 3 6 10 Code 0.1 0 0 0 4 6 10 1.0 0 0 1 4 5 10 - 10.0 3 1 1 0 5 10 GASTROINTESTINAL SYSTEM (cont'd) Small Intestine 0 10 00 36 Number of tissues examined 0.1 0 0 0 0 0 0 1 1.0 0 0 1 0 0 1 10.0 3 0 1 0 5 9 SI-1 No visible lesions , i 0 1 --- 56 0.1 -- -- -- -- 1.0 - - 1 * - 1 10.0 3 - 1 " 5 9 LaTRe Intestine 0 10 00 56 1 Number of tissues examined 0.1 0 0 0 0 0 0 i 1.0 0 0 1 0 0 1 i 10.0 3 0 1 0 4 8 LI-1 No visible lesions 0 1- - - 56 0.1 - - - 1.0 - - 1 - - 1 10.0 3 - 1 * 4 8 Sacculus Rotundus Number of tissues examined 0 1000 56 0.1 0 0 0 0 0 0 1.0 0 0 0 0 0 0 10.0 0 0 0 0 5 3 SR-1 No visible lesions i 0 0--- 55 CL-1 1.0 _ -- - 10.0 - - - - 5 5 } \ SR-2 Granulomata and histiocytosis. 0 1-- 01 J submucosa - multifocal 0.1 - - - - * - 1.0 -- - * 10.0 - - - - 0 0 Gallbladder 0 0 0 00 44 Number of tissues examined 0.1 0 0 0 0 0 0 1.0 0 0 0 0 0 0 t 10.0 3 0 0 0 5 8 i GB-I No visible lesions 0 . - 33 0.1 - - - " * 1.0 - - - * 10.0 3 - - ms 5 8 CB-2m Subacute lnflaanatlon, submucosa 0 -_ -- 11 - diffuse, moderate 0.1 --" - 1.0 - * - * -- i i 10.0 0 - - " 0 0 t.IVER - Number of tissues examined 0 1 0 0 3 6 10 0.1 0 0 0 4 6 10 1.0 0 0 1 4 5 10 10.0 3 1 1 0 5 10 *Top dose rabbits (10 ppm) vere only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none examined or not applicable. DO 131?40 C ONFTDFNTTAI 213- TABLE 31 (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 REin FOR 32 WEEKS OF RECOVERY Dlagnoala Code L-l L-2va L-2s L-2ta L-3a L-3m L-4vs L--4 s L-4m L-Ss 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 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 - * o- 0 0 - 0` 2 .2 -0 00 0 100T1 2 Vacuolization of hepatocytes, con- 0 0- 000 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 -* - 0 0 1 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 0 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 predom- 0 1_10 2 inantly lymphoid cells 0.1 - - - 2 0 2 - slight 1.0 - - 0 1 0 1 10.0 0 0 0 " 0 0 Aggregates of mononuclear predom- 0 0_ 20 2 inantly lymphoid cells 0.1 - - - 0 0 0 - moderate 1.0 - - 1 1 0 2 10.0 0 0 0 00 Subacute Inflammation, periportal 0 0--00 0 - multifocal, very 0.1 - - * 0 1 1 slight 1.0 - - 0 0 1 1 10.0 0 0 0 - 0 0 Subacute inflaamation, periportal 0 0 _ a. 0 2 2 - multifocal, slight 0.1 - -* 0 1 1 1.0 - - 0 0 0 0 10.0 0 0 0 - 1 1 Subacute inflasmatlon, 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_*0 1 1 - multifocal, slight 0.1 -- - 0 0 0 1.0 * * 0 0 1 1 10.0 0 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. 00 131?41 OONFTnFNTTAI 214- TABLE 51 (Continued) SOBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED OH MALE RABBITS EXPOSED FOR UP TO 14 WEEKS AND THEN HELD FOR 32 WEEKS OF RECOVERY Diagnosis Code L-15 L-9* L--6a L-12 L-13 L-7s L-8 L-lOs L-14 Number of rabbits per group LIVER (cont'd) Subacute Inflammation, centrl lobular - multifocal, slight Subacute lnflaanatlon with focal fibrosis - 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 Centrllobular congestion with or 0 without hepatocellular degenera- 0.1 tlon, multifocal coagulation 1.0 necrosis and slight mononuclear and 10.0 polymorphonuclear Inflammation Diffuse congestion Coagulation necrosis - focal 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Biliary hyperplasia - focal, slight 0 0.1 1.0 10.0 Granulomata with mineralization. probably parasitic In origin - slight 0 0.1 1.0 10.0 Dilated (telangiectatic) sinusoids. subcapsular 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 Weeks 1 0 0 3 8-Week Interim till 0 0 0 1 8-14 Weeks 0 0 1 1 14-Week Interim Kill 3 4 4 0 Terminal Cumelatlt Kill Result! 6 10 6 10 3 10 5 10 0 0 00 _ 0 00 -- 0 0 11 00 0 - 00 0 0 00 - * _ 0 00 - - 0 0 11 0 0 0 _ 00 0 0 00 _ _ .p 1 0 1 -_ 0 0 11 0 0 0 " 00 0 -- -- 10 _0 -0 00 1- 00 00 00 02 0_ 0 00 -- -0 00 - - 0 0 00 10 0- 01 0 0 00 -- - 1 01 - -e 0 0 0 0 00 0- 00 4 0 0 00 - * -- 0 11 - 00 00 00 0 - 11 0_ 0 00 - - _ 0 0 0 -- 0 0 11 00 0 - 00 0 0 00 -- - 0 00 - - 0 0 00 00 0 - 11 10 0 0 67 00 0 0 00 00 1 0 01 30 1 0 59 "Top dose rabbit* (10 ppm) were only exposed for 8 week* and held for 38 weeks of recovery. - Indicate* none examined or not applicable. 00 i CONFTDFNTTAi -215- TABLE 51 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCF IN RAIS 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 Exposure Level _________________________________________________ (PR*)_____ Number of rabbits per group 0 0.1 1.0 JXL.Q___ PANCREAS (cont'd) PA-1 No visible lesions 0 0.1 1.0 10.0 0-8 Weeks 1 0 0 3 1 3 RESPIRATORY SYSTEM Trachea - Number of tissues examined 0 0.1 1.0 10.0 1 0 0 3 TR-1 No visible lesions 0 0.1 1.0 10.0 1 - 1 TR-2s Aggregates of mononuclear predomInanely lymphoid cells, submucosa - multifocal, slight 0 0.1 1.0 10.0 0 - 0 TR-3 Chronic active tracheitis 0 0.1 1.0 10.0 0 - 0 TR-4 Suppurative necrotizing tracheitis 0 0.1 1.0 10.0 0 * 1 TR-3 Mild acute tracheitis 0 0.1 1.0 10.0 0 - 1 Nasal Turbinates Number of tissues examined 0 0.1 1.0 10.0 1 0 0 2 NT-1 No visible lesions 0 0.1 1.0 10.0 0 " - 0 NT-2s Aggregates of mononuclear predomInantly lymphoid cells, submucosa - multifocal, slight 0 0.1 1.0 10.0 1 - 0 8-Week Interim Kill 0 0 0 1 8-14 Weeks 0 0 1 1 -- --1 "1 00 00 01 01 -- -- -0 -1 __ - a-0 -0 _--1 -0 _--0 -0 * -*0 -0 00 00 00 00 -. -- -w -- - -- -- -- 14-Week Interim Kill 3 4 4 0 Terminal <Cumulative Kill Results 6 10 6 10 5 10 5 10 -6 7 - am - 1 -5 9 06 7 00 0 001 05 9 56 -- -- 0 -46 _11 --0 -1 1 -0 0 -- - -- 1 -0 0 __ 0 0 -- -- 0 *0 1 0 0 --* -0 -01 06 7 00 0 00 0 05 7 -0 0 --- -1 1 67 -* * -- - -4 4 *Top doee rabbits (10 ppw) were only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none examined or not applicable. 00 131?43 confjDFnttai -216- * TABLE 51 (Continued) 1 I StJBCKRONIC 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 HEU)_EPR_32 WEEKS OF RECOVERY Diagnosis Cod* Exposure Level ________________________________________________ (pptt)_____ Number of rabbits per group 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! 3I 4 4 01 Terminal Kill 6 6 5 5 ;umulatl Result 10 10 10 10 RESPIRATORY SYSTEM (cont'd) 1 Nasal Turbinates (cont'd) NT-3* Acute Inflammation with associated 0 0__-11 foreign body 0.1 - - - * - - - focal, slight 1.0 T T - T T T 10.0 0 - " - 0 0 NT-4* Focal ulcer with chronic active in- 0 0_ _ll flamination, mucosa and submucosa 0.1 - - - - - - , - slight 1.0 - - - - - - 10.0 0 - -00 j NT-5 s Suppurative Inflammation - slight 0 0_ _11 0.1 - - - " j - 1.0 - - - | - -- 10.0 0 - " " | 0 0 NT-5m Suppurative inflammation - moderate 0 0- -- 1 1 0.1 - - - - - - 1.0 - - - -- 10.0 0 - - - 0 0 NT-5sev Suppurative inflammation - severe 0 0*- 00 0.1 - - - * - 1.0 - - - - - 10.0 0 - " - 1 1 NT-6m Suppurative necrotizing rhinitis 0 0- --0 0 - moderate 0.1 * - - - - - 1.0 - - - - - J 10.0 1 - 01 ' NT-6sev Suppurative necrotizing rhinitis 0 0 -- 0 0 - severe 0.1 - - - - - - l 1.0 - - - - - 10.0 1 - - * 0 1 i Lungs - Number of tissues examined 0 10 0l 68 0.1 0 0 0 1 0 1 1.0 0 0 1 0 2 3 10.0 3 1 1 0 5 10 LU-l No visible lesions I J 0 0_000 0.1 - - - 0 - 0 1.0 - 0 - 0 0 10.0 1 0 0 - 0 1 Ltf-Z* Aggregates of mononuclear predom- 0 1_ 0 67 ! lnantly lymphoid cells, peri- 0.1 * - 0*0 bronchial 1.0 - - 0 - 0 0 i - multifocal, slight 10.0 0 0 0 " 5 s 9 Top dose rabbits (10 ppm) were only exposed for 8 veeki and held for 38 weeks of`recovery. i - Indicates none examined or not applicable. 00 13)744 C-ONF T DFNT T A! < -217- TABLE 31 (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 LtJ-6 LD-9 LU-4s LU-5s, LU-Sm, LU-5sev LU-7 LU-8 LU-lOs PN-1 Number of rabbits per group RESPIRATORY SYSTEM (cont'd) Lunas (cont'd) Bronchophemaonla and/or bronchlo- litis - focal or multifocal Exposure Level (ppm)* 0 0.1 1.0 10.0 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 formation 0 0.1 1.0 10.0 Atelectasis - multifocal 0 0.1 1.0 10.0 Suppurative necrotizing pleurltis 0 0.1 1.0 10.0 Micro granulomata - multifocal, slight 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 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 Cumulativ Kill Results 6 10 6 10 5 10 5 10 0--10 1 ---0* 0 --0 -0 0 000"2 2 0__00 0 --- 1 1 -*1 - 0 1 100-0 1 0-- 00 0 --- 0-0 --0-0 0 100 01 0 _03 3 --*0- 0 -0-0 0 0 00 -2 2 0 011 --- 1 1 ._0- 2 2 010-1 2 0__00 0 ---0 0 --0-0 0 100-0 1 0_*00 0 - -- 0- 0 --0 -0 0 101 -0 2 0_ 000 --- 0- 0 - - 0 - 0 0 000 -1 1 100 04 5 000000 001 001 10103 5 1 -- 45 -- 1 1 1--1 - 3 5 `Top dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 week* of recovery. - Indicates none examined or not applicable. 00 331?45 CONF TDFNT 7A 218- TABLE 51 (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 Exposure Level . ____________________________________________ (PPm>_____ Number of rabbits per group 0 0.1 1.0 10.0 NERVOUS SYSTEM (cont'd) Spinal Cord Number of tissues examined 0 0.1 1.0 10.0 0-8 Weeks 1 0 0 3 1 0 0 2 SC-1 No visible lesions 0 0.1 1.0 10.0 1 - - 2 Brain - Number of tissues examined 0 0.1 1.0 10.0 1 0 0 3 B-l No visible lesions 0 0.1 1.0 10.0 0 - - 3 B-2 Chronic active meningitis and enceph-- 0 1 alltls, secondary to middle ear 0.1 - infection 1.0 - 10.0 0 B-3s Subacute inflammation, perivascular - multifocal, slight 0 0.1 1.0 10.0 0 - - 0 B--4s Glial nodules - multifocal, alight 0 0.1 1.0 10.0 0 - - 0 MUSCULOSKELETAL SYSTEM Skeletal Muscle Number of tissues examined 0 0.1 1.0 10.0 1 0 0 3 SM-1 No visible lesions 0 0.1 1.0 10.0 1 3 SM-2* Atrophy - alight 0 0.1 1.0 10.0 0 -- - 0 8-Week Interim Kill 0 0 0 1_ 8-14 Weeks 0 0 1 1 00 00 00 00 -- -* "* 00 00 01 01 -* -* -1 -1 *--0 -0 ---0 -0 ---0 -0 00 00 01 00 *-.1 -- --- -0 - 14-Week Interim Kill 3 4 4 0 Terminal Cumulate Kill Result! 6 10 6 10 S 10 5 10 056 000 000 0 35 -56 ---"35 0 67 0 00 001 059 -22 --- -1 -37 -01 - -" --0 - 00 -44 -* * - -0 - 22 -00 - "-0 -22 056 0 00 001 058 -45 * - -1 - 58 -11 --" --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. DO 131?4fc CONFTDFNT TA1  -219- TABLE 51 (Continued) Diagnosis Cods VB--1 VBM-1 VBM-2 M-l HK-lsev SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AMD RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AMD NUMBER OF TISSUES EXAMINED ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKS'* AND THEN HELD FOR 32 WEEKS OF RECOVERY ` Number of rabbits pet group MUSCULOSKELETAL SYSTEM (cont'd) Vertebral Bone Number of tissues examined No visible lesions Vertebral Bone Harrow Number of tissues examined No visible lesions Myeloid hyperplasia 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 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 0000 5 5 000 0 0 0 000 0 0 0 000 04 4 -*- - 5 5 -- - -* --- -- ----44 00005 5 000 000 000 000 00 0 04 4 --. 4 4 -- --- ---- * ---- 44 -*-* 1 1 - * - - " *" 10.0 - - - - 0 0 Mandible - Number of tissues examined 0 00 0 0 1 1 0.1 0 0 0 0 0 0 1.0 0 0 0. 0 0 0 10.0 0 0 0 0 0 0 Abscess 0 --*-1 1 0.1 - - - -- - - 1.0 -- - * - - 10.0 - - - - - - Hock - Number of tissues examined 0 00001 1 0.1 0 0 0 0 0 0 1.0 0 0 0 0 0 0 10.0 0 0 0 0 0 0 Chronic active inflssmation with 0 11 abscess formation 0.1 - * - - - - diffuse, severe 1.0 * - - - - 10.0 - - - - - - URINARY SYSTEM Kidneys - Number of tissues examined 0 1 0 0 3 6 10 0.1 0 0 0 4 6 10 1.0 0 0 1 4 5 10 10.0 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. . J '* & i i OO 131?47 CONFTOFNTTAl. -220- TABLE 51 (Continued) Diagnosis Code K-l K-2s K-5, K-5a K-3s K-3m K-8sev K-4s K-7* K-6 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AMD RECOVERY STUDY OF DBCF IN BATS AMD BABBITS HISTOPATHOLOGIC OBSERVATIONS AMD NUMBER OF TISSUES EXAMINED OM MALE BABBITS EXPOSED FOR OP TO 14 WEEKS* AMD TWffW mtl-n tor 32 WEEKS OF RECOVERY " , Number of rabbits per group URINARY SYSTEM (cont'd) Kidneys (cont'd) No visible lesions Exposure Level (ppm) 0 0.1 1.0 10.0 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, cortlcomedullary 0 junction - 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, intersltitum. with or without fibrosis - multifocal, moderate 0 0.1 1.0 10.0 Hydronephrosis - unilateral, severe 0 0.1 1.0 10.0 Dilated renal tubules with eosinophilic cast formation - multifocal, slight 0 0.1 1.0 10.0 Cyst, cortex - multifocal, bilateral. 0 slight 0.1 1.0 10.0 Malignant lymphoma, secondary site 0 0.1 1.0 10.0 Urinary Bladder Humber of tissues 0 0.1 1.0 10.0 0-8 Weeks 1 0 0 3 6-Week Interin Kill 0 0 0 1 8-14 Weeks 0 0 1 1 14-Week Interim Kill 3 A A 0 Terminal Comulatli Kill lesultc 6 10 6 10 5 10 5 10 0 - - 2 13 - - - 2 13 - - 0 2 02 3 0 1 - 04 1 - 4* 0 0 1 - - 0 22 - - 0 0 00 0 1 0 " 23 0 0 00 - - - 0 22 - - 0 1 3A 0 0 0 - 11 0 * 1 56 - 2 46 0 2 57 0 1 0 - 34 0 _ _ 0 00 - - - 0 00 0 0 00 0 0 0 * 11 0 - - 0 00 - - - 0 00 - - 0 0 00 0 0 0 - 11 0 _ _ 1 01 - - - 0 00 - * 0 0 00 0 0 0 - 00 0 _ _ 0 00 - * - 0 00 - - 0 0 00 0 0 0 - 11 0 _ - 0 00 - - 0 00 - 1 0 01 0 0 0 - 00 1 0 0 0 56 0 0 0 0 11 0 0 1 0 23 1 1 1 0 58 "Top dose rabbit* (10 ppm) were only exposed for 8 week* and held for 38 weeks of recovery. - Indicates none examined or not applicable. no :i r-n ?48 oonftdfntia; -221- TABLE 51 (Continued) Lagnosis Code 1-1 3--2 a 3-3s i-3m 3--4sev B-3m B-5sev B-6a B-6sev B-7a SUBCHRONIC INHALATION REPRODUCTIVE TOUCITY 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 ` Dunbar of rabbits per group URINARY SYSTEM (coat'd) Urinary Bladder (coat'd) No visible lesions Exposure Level (ppm) 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Aggregates of mononuclear predomlnantly lymphoid cells - multifocal, slight 0 0.1 1.0 10.0 Subacute inflemmatlcm, sucosa and submucosa - multifocal, slight 0 0.1 1.0 10.0 Subacute inflammation, mucosa and submucosa - multifocal, moderate 0 0.1 1.0 10.0 Chronic active inflammation, mucosa and submucosa - severe 0 0.1 1.0 10.0 Edema, mucosa and submucosa - moderate Edema, mucosa and submucosa - severe 0 0.1 1.0 10.0 0 0.1 1.0 10.0 Increased veecularlty, subnicoea - moderate 0 0.1 1.0 10.0 Increased vascularity, submucosa * revere 0 0.1 1.0 10.0 Hyperplasia, mucosa - sultlfocal, 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 Cumilatlve Kill Results 6 10 6 10 5 10 5 10 1-- -34 - --00 - 1 *01 1 1 1 " .2 5 0 - 11 - - - 0 0 --0 -00 000"00 0 - 4. - 1 1 --- -00 --0 -00 0 0 0 "00 0 - -0 0 -* - -0 0 -* 0 -00 000"11 0- 00 -- - - 1 1 --0 -2 2 000"22 0-- -00 --- -00 -- 0 -0 0 000 "11 0- -00 -* -*11 -- 0 2 2 000 "22 0_ - -00 --- -00 - - ,0 - 0 0 000 -1 1 0---00 --- 11 *-0 *2 2 00 0 11 0*- -00 -- - -00 --0 -00 00 0 11 *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?49 OONFTDFNTIAI 1L * -222- TABLE 51 (Continued) j SUBCHRONIC INHALATION REPRODUCTIVE TOZICITt AND RECOVER! STUDY 1 OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER 07 TISSUES EXAMINED ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKS" AND THEN HELD FOR 32 WEEKS OF RECOVERY ficposure 8-week 14-Week Level 0-8 Interim 8-14 Interim Terminal Cumulative |i Diagnosis Number of rabbles par group (ppm) 0 Weeks 1 Kill 0 Weeks 0 till 3 ' Kill 6 Results 10 Cods 0.1 0 0 0 416 10 1.0 10.0 0 0 1 4 5 10 3 1 1. 0 1 5 10 URINARY SYSTEM (coat'd) Urinary Bladder (coat'd) UB-7m Hyperplasia, mucosa 0 0__ 0 0 I - multifocal, moderate 0.1 - ms - 0 0 } 1.0 - - 0 0 0 10.0 0 0 0 - 1 1 UB-7sev Hyperplasia, mucosa 00 __ 0 0 ; - multifocal, severe 0.1 - - - - 1 1 1.0 - - 0 - 2 2 10.0 0 0 0 - 0 0 UB-Ssev Ulceration - multifocal, severe 0 0*__ 0 0 i 0.1 - - - , 1 1 1.0 - - 0 j2 2 10.0 0 0 0 10 0 Urethra - Number of tissues examined 0 0 0 "0 0 5 5 0.1 0 0 0 0 6 6 1.0 0 0 0 0 5 5 10.0 0 0 0 0 5 5 UA-1 No visible lesions 0_ __3 3 0.1 - - - - 3 3 1.0 - * - - 4 4 10.0 - - - - 2 2 i UA-2vs Subacute Inflammation, mucosa and 0 _ 00 submucosa - diffuse, very slight 0.1 - - - - 1 1 1.0 - am - am 0 0 10.0 - - - - 0 0 * UA-2s Subacute Inflammation, mucosa and 0 00 submucosa - diffuse, slight 0.1 - - - - 1 1 ] 1.0 - - - 0 0 10.0 - - - - 1 1 i UA-2m Subacute Inflammation, mucosa and 0 _ _1 1 submucosa - diffuse, moderate 0.1 , - -- 0 0 1.0 - _ *p - 0 0 * 10.0 - - - - 1 1 UA-2sev Subacute Inflammation, mucosa and 0 _0 0 subsucosa - diffuse, severe 0.1 - * * 0 0 1.0 - - * 0 0 1 10.0 - - -- 1 1 UA-3m Chronic active Inflammation, 0_ _ 11 ii mucosa and sutmucosa 0.1 . _ 1 1 - diffuse, moderate 1.0 - * - 1 1 i 10.0 - -" 0 0 . "top dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. i - Indicate* none examined or not applicable* i 11 no i 31 350 OONFTDFNTT Al 223- TABLE 31 (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 '10 14 WEEKS AND THEN HELD FOR 32 WEEKS OR RECOVERY lagnosls Code l-4m -1 2s -3 3-1 3-2s 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 No visible lesions 0 0.1 1.0 10.0 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 0 0.1 1.0 10.0 No visible lesions 0 0.1 1.0 10.0 Subacute Inflammation, aublntimal - focal, slight 0 0.1 1.0 10.0 Mesenteric Blood Vessels Number of tissues examined 0 0.1 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 3 10 5 10 --11 ----00 --- -0 0 "-- -0 0 10006 7 000000 001001 3 0105 9 1- 5 6 --- ---.1 -- 1 3-0 -5 8 0 _- _ 1 1 *.- *-- 0 -0 0-0-00 0---00 --- -- --0 --0 0- 1-01 100 0 5 6 000000 001 001 300058 1 * * -4 5 -- - - - -- 1 --1 3-- -58 0 *_11 - -- -- - -*0 --0 0-- -00 000 000 000 00 0 000 000 300003 aTop dose rabbits (10 ppm) were only exposed for 8 weeks end held for 38 weeks of recovery. - Indicates none examined or not applicable. ,n Conf^fN71ai -224 TABU 51 (Continued) SOBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERT STUDY OP DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON HALE RABBITS "exposed TOR UP TO 14 WEEKS'1 AND THEN HELD FOR 32 WEEKS OF RECOVERY Diagnosis Coda MBV-1 MF-1 0-1 LG-1 EY-1 EY-2s Number of rabbits per group Exposure Level (ppm) 0 0.1 1.0 10.0 CARDIOVASCULAR SYSTEM (cont'd) Mesenteric Blood Vessels (cont'd) No visible lesions 0 0.1 1.0 10.0 0-8 Weeks 1 0 0 8-Week Interim Kill 0 0 0 ______ 3____ ______ 1______ 8-14 Weeks 0 0 1 1 ABDOMINAL CAVITY Mesenteric Fat Number of tissues examined 0 0.1 1.0 10.0 0 00 0 00 0 01 3 00 No visible lesions 0 0.1 1.0 10.0 3 1 Omentum - Number of tissues examined 0 0.1 1.0 10.0 00 0 000 000 000 Parasitic granulomas with calclfication - multifocal 0 0.1 1.0 10.0 HEAD REGION Lacrimal Gland Number of tissues examined 0 0.1 1.0 10.0 Subacute inflammation 0 0.1 1.0 10.0 Eves - Number of tissues examined No visible lesions 0 0.1 1.0 10.0 0 0.1 1.0 10.0 10 00 00 30 1 0 0 1 1 Aggregates of mononuclear predominantly lymphoid cells, corneal scleral Junction - focal, unilateral, slight 0 0.1 1.0 10.0 0 0-0 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill Results 6 10 6 10 5 10 5 10 0 00 000 0 01 003 1 3 000 000 0 00 011 067 000 001 059 -56 0 11 "Top dose rabbits (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none examined or not applicable. f;0 13125? CONF TDENT TAl -225- TABU 51 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOUCHY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RABBITS EXPOSED FOR UP TO~(4 MEEKS AND THEN HELD FOR 32 WEEKS OF~ RECOVERY liagnosis Code ffi-1 IM-lsev \M-2 iH-3 iM-4 AMF-1 Number of rabbits per group HEAD REGION (cont'd) Middle Ear Number of tissues examined Exposure Level (ppm) 0 0.1 1.0 10.0 0-8 Weeks 1 0 0 ......... 3.... 0 0.1 1.0 10.0 1 0 0 0 Severe suppurative otitis media with necrotizing inflammation of the bone 0 0.1 1.0 10.0 1 - - THORACIC CAVITY Anterior Mediastinum Number of tissues examined Abscess formation - severe, multifocal 0 0.1 1.0 10.0 0 0.1 1.0 10.0 0 0 0 2 _ - 0 Localized suppurative anterior mediastlnltis 0 0.1 1.0 10.0 _ 0 No visible lesions 0 0.1 1.0 10.0 1 Suppurative necrotizing mediastlnltis 0 0.1 1.0 10.0 * - 1 Anterior Mediastinal Fat Number of tissues examined 0 0.1 1.0 10.0 1 0 0 0 No visible lesions 0 0.1 1.0 10.0 1 - 8-Week Interim Kill 0 0 0 1 0 0 0 0 - - 0 0 0 0 * - * - _ - - - - 0 0 0 0 _ - 8-14 Weeks 0 0 1 1 0 0 0 0 - 0 0 1 0 _ - 0 " _ 1 * - 0 - - 0 * 0 0 0 0 " - 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill Results 6 10 6 10 5 10 5 IQ_____ 0 -0 00 00 00 _ -*-- 1 0 0 0 1 " 0 00 1 01 012 002 *1-1 -11 -"0 -0-0 -01 -"0 _-0-0 -00 -*1 -- 0-0 -00 -"1 001 000 0 00 0 00 -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 1,31353 CONFTDFNTTAl -226- TABLE 51 (Continued) SOBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND HUMBER OF TISSUES EXAMINED ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKS AND THEN held FOR 32 WEEKS OF RECOVERY Diagnosis Code T-l T-2um T-2ba T-2ba T-2b,sev T-3 T-4us T-4bs T-4bm Number of rabbits par group Exposure 8-Week Level 0-8 Interim (ppm)________ Weeks Kill 0 10 0.1 0 0 1.0 0 0 10.0 ______ 2_____ _____ l_____ MALE REPRODUCTIVE SYSTEM Testes - Number of tissues examined 0 0.1 1.0 10.0 10 00 00 31 No visible lesions 0 0.1 1.0 10.0 Atrophy (decreased spermatogenesis) - unilateral, moderate 0 0.1 1.0 10.0 1 -w -* 00 0m -* -- 00 Atrophy (decreased spermatogenesis) - bilateral, alight 0 0.1 1.0 10.0 0_ . -- 00 Atrophy (decreased spermatogenesis) - bilateral, modarate 0 0.1 1.0 10.0 0 --- 00 Atrophy (decreased spermatogenesis) - bilateral, severe 0 0.1 1.0 10.0 0 .-- 31 Hypoplastic seminiferous tubules - focal 0 0.1 1.0 10.0 0 -- 00 Multlnucleeted spermatids - unilateral, slight 0 0.1 1.0 10.0 0* --- 10 Multlnuclaated spermatids - bilateral, alight 0 0.1 1.0 10.0 0 *-* 00 Multlnuclaated spermatids - bilateral, moderate 0 0.1 1.0 10.0 0 - -- 00 8-14 Weeks 0 0 1 1 0 0 1 1 _ 0 0 * 0 0 _ _ 1 0 _ 0 0 . 0 1 0 0 0 0 _ 1 0 . 0 0 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill Results 6 1* 6 If 5 IS 5 18 3 6 IS 4 6 IS 4 5 IS 0 5 IS 1 57 136 033 - 00 1 01 0 00 0 11 - 0 0 08 0 08 0 01 - 08 0 08 0 08 3 14 - 00 000 00a 10l - 5 18 101 0 08 0 08 -00 101 011 0 00 - 01 101 3 03 203 - 33 0 08 0 0a 1 0l 00 *Top dose rebblts (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none "< or not applicable. DO 131254 OONF T DF NT T Ai -227- TABLE 51 (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 WBEKSOF~RCOVERY iagnosia Code -5m -6u -6b, -6bs, -6bm -7b -8s :-9a :-9b >10us :-10bm Exposure Level . ....___________________ (PP)_____ Number of rabbits per group 0 0.1 1.0 ...10.0 MALE REPRODUCTIVE SYSTEM (cont'd) Teste# (cont'd) Atrophy, primarily subcapsular, probably secondary to severe stress and cachexia - bilateral, moderate 0 0.1 1.0 10.0 Necrotic debris In the lumen of the seminiferous tubules - unilateral 0 0.1 1.0 10.0 Necrotic debris In the lumen of the seminiferous tubules - bilateral 0 0.1 1.0 10.0 Increased prominence of Sertoli cells, secondary to decreased spermatogenesis - bilateral 0 0.1 1.0 10.0 Mononuclear predominately lymphoid cell Inflammation - focal, slight 0 0.1 1.0 10.0 Normal-appearing seminiferous tubules occupying less than 25Z of total sections - multifocal 0 0.1 1.0 10.0 Normal-appearing aaniniferous tubules occupying between 25Z and 50Z of total sections - multifocal 0 0.1 1.0 10.0 Dilated seminiferous tubules with decreased spermatic elements - unilateral, slight 0 0.1 1.0 10.0 Dilated seminiferous tubules with decreased spermatic elements - bilateral, moderate 0 0.1 1.0 10.0 Epididymides Number of tissues examined 0 0.1 1.0 10.0 0-8 Weeks 1 0 0 0 - 0 0 - 0 0 - 2 0 3 0 - 0 0 0 0 0 0 * 0 0 0 1 0 0 3 8-Week Interim Kill 0 0 0 1 8-14 Weeks 0 0 1 1 -- -- -0 00 _ -* -0 00 --1 00 --1 11 ** - -- -0 00 --0 00 *** *0 00 ---0 00 --0 00 00 00 01 11 14-Week Interim Kill 3 4 4 0 Terminal Cumulative Kill Results 6 10 6 10 5 10 5 10 01 1 00 0 000 00 101 000 000 -0 0 000 000 304 02 000 000 20 3 "05 000 000 101 00 000 000 00 0 *3 3 000 000 000 -2 2 000 000 01 1 -0 0 000 011 000 -0 0 3 6 10 4 6 10 4 3 10 0 5 10 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 131? 5 5 CONFTDFNTTAl -228- TABLE 51 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCF IN RATS AND RABBITS HISTOPATHOLDCIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKS AND THEN HELD FOR 32 WEEKS~OP~RBCOVERY Exposure Level 8-Week 14-Week L 0-3 Interim 8-14 Interim Terminal Cumulative i (ppm) _ Weeks Kill Weeks Kill 1 Kill Results Diagnosis Number of rabbits per group 0 1 0 0 3 16 10 Code 0.1 0 0 0 4 6 10 <* 1.0 10.0 0 0 1 4 15 10 3 1 1 0 5 10 MALE REPRODUCTIVE SYSTEM (cont'd) Epididymides (cont'd) E-l No visible lesions 0 0.1 1.0 10.0 1--2 69 - - * 4 6 10 -- 10 34 00 0" 00 E-2 Sperm granuloma i - focal 0 0.1 1.0 10.0 0* 1 01 --.0 00 -- 00 00 000- 00 E-3u Decreased sperm In tubular luaina - unilateral 0 0.1 1.0 10.0 0 _ _ 1 i0 1 -- -0 00 - * 0 0 10 0 00 0- 00 E-3b Decreased sperm In tubular lumina - bilateral 0 0.1 1.0 10.0 0__0 00 - - 4. 0 0 0 - 0 2 02 21 1- 04 E-3b,sev Decreased sperm In tubular luaina - bilateral, severe 0 0.1 1.0 10.0 0 4, 0 00 -* 0 00 -- 0 0 00 000- 53 f E-4us Epithelial hyperplasia 0 0_ _0 00 - unilateral, slight 0.1 1.0 -- 0 00 -- 0011 10.0 00 0- 00 j E-5us Vacuolization, mucosa 00 _0 00 , - multifocal, uni- 0.1 - _0 00 lateral, slight 1.0 - 0 0 22 J 10.0 00 0 - 00 E-6b Decreased in size (atrophy) 0 0 * 0 00 - bilateral 0.1 - * _ 0 0 0 1.0 - - 0 0 0 0 i 10.0 11 0- 57 E-7b Increased Intratubular, cellular. 0 0 0 00 j and/or proteinaceous debris 0.1 -- _0 00 j - bilateral 1.0 - , 0 0 0 0 10.0 00 0-5 5 t E-8b Questionable (equivocal) decrease 0 0 4, 0 0 0 j In sperm, tubular lumina 0.1 -- .0 00 i - bilateral 1.0 - 02 02 10.0 00 0- 00 aTop dose rabbit* (10 ppm) were only exposed for 8 weeks and held for 38 weeks of recovery. - Indicates none examined or not applicable. no 13J?56 OONFTDFNTTA1, -229- TABLE 51 (Continued) lagnosls Code 3-1 R-l R-2s R-3, R-3s R-4 'R-5* R-6s R-7 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER op TISSUES EXAMINED ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKS* AN" them M mn 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 No visible lesions 0 0.1 1.0 10.0 Aggregates of mononuclear predomlnantly lymphoid cells, submucosa - multifocal, slight 0 0.1 1.0 10.0 Squamous metaplasia, with or without keratIniration - 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 1 14-Week Interim Kill 3 4 4 0 TfTffllftll 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 3 10 1 * - 3 6 10 - - - 4 6 10 . . 1 4 5 10 3 1 1 - 5 10 1 0 0 3 6 10 0 0 0 4 6 10 0 0 1 4 5 10 31005 9 1--_ 1 6 8 ---13 4 -- 133 7 31-*5 9 0-. 2 0 2 ---0 0 0 -- 0 0 0 0 00- -0 0 0- -00 0 ---3 1 4 --01 0 1 00*"0 0 0 - a- 0 0 0 --- 02 2 -*0 01 1 0 0 * - 0 0 0---0 0 0 *--0 1 1 -*000 0 00 - 00 0-- 00 0 -- -0 1 1 -- 001 1 00-*0 0 0_ - 00 0 ---00 0 -0101 00--0 0 "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 131757 CONFTDFNTTAl -230- TABLE 51 (Continued) SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN HATS AND RABBITS HISTOPATHOLOGIC OBSERVATIONS AND NUMBER OF TISSUES EXAMINED ON MALE RABBITS EXPOSED FOR UP TO 14 WEEKS* AN" thfm win row 12 WEEKS OF RECOVERY Diagnosis Code Exposure 8-Week Number of rabbits per group Level (ppm) 0 0-8 ttoeks i Interim Kill 0 8-14 Weeks 0 0.1 0 0 0 1.0 0 0 1 ________________________________________________ UU2____________3____ ______ 1___________l____ LYMPHORETICULAR SYSTEM LS-1 Malignant lymphoma, primary alte 0 0 00 0.1 0 0 0 1.0 0 0 1 10.0 0 00 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 01 00 .0 Thvmua - Number of tissues examined 0 0 00 0 66 0.1 0 00 0 00 1.0 0 01 0 01 10.0 3 00 0 47 TY-1 No visible lesions 0 0.1 1.0 10.0 0 55 00 -44 TY-2sev Atrophy - severe 0 0.1 1.0 10.0 3 11 1- -1 -03 Spleen - Number of tissues examined 0 0.1 1.0 10.0 1000 00 0 0 00 1 0 3010 67 00 01 59 SF-1 No visible lesions 0 0.1 1.0 10.0 0 --0 3-1 66 0 59 SP-2 Acute splenitis 0 0.1 1.0 10.0 1 0 0-0 01 0 00 SP-3 Severe congestion 0 0.1 1.0 10.0 0 1 0-0 00 1 00 SP-4 Hemosiderin within histiocytes 0 0.1 1.0 10.0 0 1 0-0 00 1 00 SP-5 Malignant lymphoma, secondarysite 0 0.1 1.0 10.0 0 1 0-0 00 1 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. Do DONF TFNTtq1 231- 1ABLE SI (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 .agnosia Code N-l H-2 2J-3 JJ-1 JJ-2 1-1 C-2 Number of rabbits per group Exposure Level (ppm) 0 0.1 1.0 10.0 LYMPHORETICULAR SYSTEM (cont'd) Mesenteric Lymph Nodes Number of tissues examined 0 0.1 1.0 10.0 No visible lesions 0 Reactive lymphoid hyperplasia. paracortlcal zones and medullary cords 1.0 10.0 0 0.1 1.0 10.0 Free and phagocytlzed red blood cell, medullary sinuses Anterior Mediastinal Lymph Nodes Number of tissues examined No visible lesions Suppurative lymphadenitis 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 SKIN AND SUBCUTANEOUS Skin - Number of tissues examined 0 0.1 1.0 10.0 No visible lesions Subcutaneous abscess formation 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 10005 6 000000 001001 300025 0--_5 5 0_0 3- "25 1-- 01 - - ---- - *0- - 0 0 ---0 0 0*--00 --*--- - - 1-- 1 0-- 00 100023 000000 001001 1 00 03 4 1---2 3 - - -- - - . 0-- 0 1---3 4 0--*00 * ----- . - 1 -- 1 0 -- -0 0 10006 7 000000 001 10 2 2 0005 7 1---6 7 --*-" --10-1 2 ---5 7 0 - me 0 0 - - - *---1-1 0 - - -0 0 aTop dose rabbits (10 ppm) were only exposed for 8 weeks end held for 38 weeks of recovery. - Indicates none examined or not applicable. DO 131759 CONF TDFNTTA! TABLE 52 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP 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 Possible or Probable Cause of Death or Illness 7 weeks of exposure Severe suppurative otitis media with secondary bone and brain inflammation. 10 weeks of exposure Severe rhinitis and bronchopneumonia. 7 weeks of exposure Not determined. 7 weeks of exposure Severe rhinitis and bronchopneumonia 8 weeks of exposure Suppurative pleurltis and pneumonia. 8 weeks of exposure plus 3 weeks of recovery Severe pleurltis and eplcarditis. C O N F T O F N T rA l u a CO \) 'T' 6 -233- TABLE 53 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 6 3 3 3 OONFTDFNTT o a jj \> O' 3> 00 131^6? conftdfnttai. -234- r> o -o zo "n >--t --* o u) 'n -> Z 'O --t O' --+ jj 3> TABLE 34 Duration of Exposure 14 weeks 14 weeks 14 weeks 8 weeks SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS NUMBER OF ULTRASTRUCTURALLY ABNORMAL SPERMATOZOA IN RABBITS IMMEDIATELY AFTER EXPOSURE PERIOD 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 SIX 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 5%* 10% 18% - Mean Percent S.D. 53%a 103% 1812% - Without rabbit number 78-792 which bad a spontaneous unilateral testicular abnormality -235- TABLE 55 SUBCHRONIC INHALATION REPRODUCTIVE TOXICITY AND RECOVERY STUDY OF DBCP IN RATS AND RABBITS NUMBER OF ULTRASTRUCTURALLY ABNORMAL SPERMATOZOA IN RABBITS AFTER RECOVERY PERIOD Duration of Exposure Dose Level Pathology Number Number of Abnormal Spermatozoa Number of Normal Spermatozoa Total Number of Spermatozoa Counted Percent of Abnormal Spermatozoa Average Percentage Abnormal Spermatozoa Mean Percent S.D. 14 weeks exposure plus 32 weeks recovery 0 ppm 78-1732 78-1733 78-1734 78-1735 78-1736 78-1737 6 107 113 5% 9 163 172 51 8 72 80 101 4 72 76 51 0 67 67 01 6 83 89 71 overall 51 53% 14 weeks 0.1 ppm 78-1738 11 200 211 51 exposure 78-1739 9 109 118 81 plus 78-1740 6 102 108 61 32 weeks exposure overall 61 62% 14 weeks 1.0 ppm 78-1744 29 160 189 151 exposure 78-1745 28 52 80 351 plus 78-1746 11 39 50 221 32 weeks recovery overall 241 2410% 8 weeks 10 ppm 78-1749 5 19 24 211 exposure 78-1750 11 25 36 311 plus 78-1751 10 110 120 81 38 weeks recovery overall 201 20+12% 3> DO 1 3 1 2 6 4 CO NFIDENT! 1,2-DIBROMO-3-CHLOROPROPANE: INHALATION FERTILITY STUDY IN RATS AND RABBITS TEXT FIGURES - 1-9 DO 131?A5 CONFTDFNTTAL -237- 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 2t070X. 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. 00 OONFTDFNTTA! -238- 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 DBCF. 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 (1) within Sertoli cells (SC). BL basal lamella and PR *> primary spermatocyte. Original magnification 8.300X. DO 131767 CONFTDFNTTAl 239 DO 1 3 1 7 6 B CONFTDFNTTA 240 Pig. 2 no 131069 f.ONF TOFNT T Al Pig. 3 241 wiPvnK Fig. 5 131270 ' CONFrDFNTIAJ. 242 Fig. 7 243 Fig. 8 DO 13177? OONFTOFNTTAl 244 Fig. 9 ! I J J i 00 131773 OONFTDFNTTAI -2451,2-DIBROMO-3-CHLOROPROPANE: INHALATION FERTILITY STUDY IN RATS AND RABBITS INDIVIDUAL ANIMAL DATA TABLES A-l TO A-44 no 131374 CONFTDFNTIAL -246- Tlbl 4-1 mcp> xshautxoi raeriLrn study ii nz ratt IUT; mim Swtr !*** fyTM) gxpMur* Uv*l An1ml Dn Vii^>r Cootrol 77-7656 7*55 7*56 7*5T 7*58 7*59 7*60 7*61 7*62 7*63 7*6* 7%65 TW6 7*67 7*68 7*69 7*70 7*71 7*72 7*73 7*7* 7*73 7*76 7*tY 7*78 7*79 7*80 7*81 7*82 7*83 7*8* 7*85 7*86 7*87 7*88 -1 TSo.d *66.0 502>0 5T*.0 *80.0 500.0 302.0 *92.0 537-0 505.0 357.0 55**0 53**0 *97.0 *80.0 522.0 4TT.0 59T-0 323*0 *88.0 318.0 517*0 *79.0 6**.o* 510.0 526.0 *9*.0 331.0 *80.0 526.0 *92.0 5*0.0 522*0 *96.0 500.0 ""1 465.0 *77.0 512.0 568.0 *82.0 51*.0 513.0 505.0 5*k.o 518.0 566.0 373.0 5*8.0 505.0 *88.0 526.0 *85.0 613.0 529.0 *77.0 523.0 51*.0 *70.0 656.0* 501*0 327.0 516.0 5*2-0 *88.0 533.0 *98.0 5*7.0 526.0 500*0 *96.0 2 459*0 *73.0 519.0 573.0 *82.0 502.0 52*.0 502.0 536.0 509.0 371.0 568.0 566*0 496.0 *91.0 622.0 533.0 *70.0 533.0 521.0 *7*.0 661.0* 512.0 5**.0 5l*.0 52*.0 *91.0 5*6.0 502*0 5*1.0 532.0 503.0 502.0 *73.0 *80.0 533.0 587.0 51*.0 *81.0 51**0 503.0 315-0 5*8.0 56**0 58*.0 569.0 $00*0 538.0 496*0 462*0 632.0 538.0 *8*.0 5*3.0 5*1.0 *87.0 666.0* 517.0 5*9.0 530.0 552.0 *98.0 556.0 512.0 56O.O 5*2.0 522.0 507.0 A *62.0 *83.3 527.9 591.0 *85.2 518.8 523.3 503.0 5*2.8 *96.3 568.7 572.8 569-5 301.8 *92.3 538.9 *T*.0 618.5 526.0 *7*.* 337.1 532.* *75.9 6*3.1 506.2 5*2.8 516.5 5*9.1 *93.0 5*7-5 516.* 550.8 525-2 511.3 *9*.7 Weak of Studr ski --5 TrlT TtTT *76.* J16.6 523.* B "skr LA TfflJo 525.* 529.2 519.* *97-7 5*3.8 555.* 560.6 533.2 56}.* 606.I 617.7 616.* 22.3 618.3 616.O *99-0 518.5 53**0 319.8 *92.6 318.7 5*3-5 522-3 508.1 560.5 557.2 537.0 51*. 9 5a-6 553.1 535.0 510.7 517.1 537.3 5*2.3 505*9 533*1 563.8 5*6.5 5*7.5 560.3 568.9 562.7 373.5 573-8 509.6 518.7 513*2 sa.7 528.9 536.8 Sacrificed Sacrificed luiinead Sacrificed Sacrificed _ --. _ to 526.9 *8*.7 eH:S 5**.3 *91.2 5*0.2 *99.* 83 5*5.2 502.* 6*2.0 6**.3 637.6 6*3.5 650.0* 6*1.3 537-6 537.7 5*3.7 5*3.2 561.0 357*5 *78.* *83.3 500.2 502.3 507.7 505.5 561.0 565.5 556.9 3T3.2 568.* *88.T 5*2.6 550.2 535.5 5**.7 5*9.6 5*8.6 *91.5 *87.1 *80.9 *96.2 506.7 502.5 667.6* 509.3 685.6* 513.2 667.7* 5a. 1 T02.2* 52*.2 sar 101.3* 535-0 558.6 358.8 56*.0 565.3 556.* 55T.3 536.2 5*3.3 539.2 536.7 539.6 5*0.5 56k.0 56*.* 560.6 573.* 56*.0 560.3 *99. 52**1 518.1 533-1 533.7 S3*.} 567.3 562.* 558.1 5*6.* 559.3 561.7 52**6 535.7 526.0 391-9 5*7.5 5*7.6 565.3 5*5-* 52*.6 51*.S 579.* 512.1 5*7.8 517-2 572.1 539.* 517.9 507.6 552.* 5*7.* 317.* 531.6 5996 555.2 521.8 518.2 601.2 569-5 519*8 322.* n 532.1 571.6 628.1 }26.7 527.5 372.9 556.5 582.9 5*0.0 _ _ 95T-5 506.3 657.2 567.3 513-2 575.5 55**6 512*0 716.5* 553.1 573.9 555.5 582.2 5*9.0 568.9 533.1 612.7 577.9 518.7 528.* 12 MrM 5*1.* 582.8 6*1.7 529.6 53**1 3B*.0 559.6 585.5 551.3 u TB515 5*6.3 580.3 6*3.* 530.6 333-1 581.8 570.* 59*-9 330.* 14 5557 5*7.9 565.6 6*2.0. ;i*.6 3*2.* 587.9 373.* 387.* 3*1.2 wm _ to 5*8.6 51*.l 567.3 511.7 573.1 559.3 517.1 Ta.5* 56*.3 580.8 3*6.8 588.2 552.5 575.7 553.3 613.9 581.8 528.* 53*.T mm 3*6.3 519-8 639.3 371.7 sa.* 593*1 563.3 523.6 738.9* 556.3 583.5 5*1.6 577-5 553.1 565.2 575.1 617-8 375.6 528.7 528.7 __ 549-1 507*2 6*9.0 570-1 32*.6 588.7 563.0 518.8 720.3* 5**. 5 59*. 9 338.6 368.3 532.* 570.1 56*.* <22.8 581.2 532.* 505.7 . M*n 5U 13.D. *30 318 *33 519 135 528 36 526 1*1 530 *38 537 38 539 136 5** 133 5*3 128 5** 136 557 136 561 237 56* 236 56l 237 o.l TT-752* *60.0 *55.0 *58.0 *62.0 *63.8 *77.2 *87.* *88.5 *91.6 *86.1 *81.0 *92.8 *96.1 *95-5 *97-9 7525 7526 752T 520.0 52*. 0 56*.0 517*0 516.0 362.0 53*.0 5*1.0 579.0 5*6.0 575-0 5*5.0 5*9.6 5*7.8 583.6 555-3 561.5 593.3 567.9 568.2 601.6 576.9 353.9 598.1 571.9 56**7 609.* 553.3 5*6.1 592.5 563.3 552*5 599** 57*.7 539.* 599.0 566.8 559*1 618.9 598.* 559.8 621.1 389.2 557.6 617.9 7528 526.0 52*.0 5*5.0 55*.0 376.7 583.0 595.6 599.9 60*.3 612.6 621.2 610.2 633.3 6*7.2 621.0 7529 7530 T531 527.0 . 532.0 512.0 505-0 576.0 58*.0 5*6.0 520.0 600.0 5*8.0 528.0 610.0 565.1 535.0 62*. 3 $81.7 555.1 623.2 588.5 571.2 622.7 588.5 557.7 637.7 595.2 555.0 617.6 596.7 5*1.7 615.9 596.8 551-7 63**3 598.7 559.8 6*0.9 601.7 563.9 6*$.2 603.6 557.3 639.* 397.3 553.6 616.7 7532 7533 753* 560.0 562.0 *83.0 5**.0 555.0 *73-0 550.0 569.0 *82.0 569.0 561.0 *87.0 557.* 582.8 *95.* 56**7 577.8 595*5 601.6 Snnrlflend 5T*.6 61t1o.* 586.1 60t9o-2 579-9 622.8 -- 587.5 60t7o.1 607.9 63t5o.2 60* .2 631.I to 598.7 6*2.8 -- 596.5 636.0 7535 7536 7537 7538 51**0 *3*.0 *63.0 520.0 52*.0 531.0 *53.0 523.0 527*0 5*0.0 *62.0 528.0 5*0.0 550.0 *7*.0 5*9-0 5*9.8 55**9 *87.* 559.2 Sacrificed 8*crlflc*4 Secrifleed Sacrificed --> -- *-- -- -- to *- -- * -- -- to -- to -- to to to to to --to 7539 523.0 522*0 *58.0 52*.0 5*1.3 562.6 57**9 565.9 577.9 579.8 562.1 587.1 582.7 393.8 595-8 75*0 502.0 *89.0 *98.0 5U,0 510.3 528.1 532.* 531.5 5*1-1 339.5 5*9-6 5*9.6 337*8 552.5 52T.5 75*1 75*2 333*0 *70.0 525-0 *60.0 533.0 *73-0 5*6.0 *85.0 53T.* *96.8 5***3 *87.7 555.9 *90.6 552.9 *33.8 559.8 *73.5 552.1 *8*.5 5*2-0 *81.0 5*5-9 *83.7 3*9.* 300.9 5*7.0 *98.2 569.2 306.6 75*3 73** 75*5 522*0 506.0 536.0 5*3.0 500*0 5*1.0 *55-0 *79.0 550.0 51**0 $10.0 551.0 5*2.6 508.7 359*0 350.6 52T.3 572.8 556.* 539.5 569.6 533.5 5*3.0 575-1 556.1 5*6.2 580.1 563.6 536.2 581.8 S6*-6 5*0.2 566.2 570.* 5*0.5 585.2 388.8 3*1.5 59%.o 576.9 553.1 392.* 575.8 550.7 582.6 52:S73*6 *90.0 505.0 *37.0 *76.0 *97.1 313.* 526.8 530.5 327.1 53*.6 556.1 3*2.2 $31.1 316.8 75*7 73*8 513.0 5*8.0 *73.0 5*0.0 *96.0 561.0 500*0 569.0 505.6 565.* 515-1 576.* 522.* >7*.9 531.3 568.9 583.8 336.8 56*.5 3*0.6 561.7 338.3 575.0 3*8.6 392.0 5*6.3 580.1 562.7 366.6 73*9 7550 352.0 535.0 350.0 521*0 5*8.0 539.0 570.0 571.0 372.3 5*6.3 372.8 5*7.8 589.8 571.1 5*3.2 587.5 551.8 578.1 566.7 572.} 568.7 595.2 571.0 597.8 57* .5 610.7 592.1 581.6 376.0 7351 5*7.0 550.0 562.0 552.0 563.7 5T1-0 570.0 589.8 373-* 565.8 571.8 588.2 391-2 397-9 385.0 7332 520.0 509.0 516.0 531.0 5*3.0 539.9 5*9.3 557.* 55*.T 537.2 5*3.6 5*9.2 550.7 533.9 570.1 7353 735* 7698 7555 7556 *82.0 528.0 553.0 552-0 500.0 *76.0 510*0 536.0 533.0 *87.0 *76.0 539-0 550.0 5*6.0 500.0 *92.0 5**-0 }62.0 552.0 502*0 *92.6 5*5.5 553.5 5*0.5 502.7 321*8 567.0 367.7 5*9.* 508.3 *95.8 570.5 563.0 55*-2 518.1 *91.8 359-9 576.5 555.3 518.* *98.6 35**0 376.7 350.2 509.7 *97.9 560.8 556.3 331.6 501.6 :! 361.9 381.3 502.3 503-3 582.3 567.5 561.3 513.2 313*3 590.2 571-5 56*.8 515-7 525.5 589.6 576.0 572.* 523.7 *95.5 573.2 577.6 566.6 515-6 7357* 617.0 600.0 623.0 620.0 626.* 6l8.2 6*2.0 6**. 3 650.2 631.7 630.1 <30.3 6*3.* 6*9.1 655.1 Itou 522 519 52* 537 5*2 55* 561 559 363 558 361 569 57* 578 571 *36 .3* *3 ,37 36 *34 *37 *3 38 38 38 *39 *40 **1 *42 nn i3i?75 CONF TDFNTTAt -247- Table 4*1 (Continued) DOCTi DAAL4TZQI FCTTILTtT SlUDT l THK HAT* K4J; Hale ftodr tft-*) Leral PP Cootrol e IiIhI ----r TPIRT 7455 TfcSfi 7457 nj n?9 7460 7461 7462 n3 7* 7465 7466 7467 7468 7469 74TO T471 7472 T4T3 7474 7475 T4T6 7*77 T4T8 74T9 7480 7481 7482 7483 7484 7485 T486 7487 7488 Haas *3.0. 3 16 --fi----- IB ao 21 22 Sacrificed 8m rifle *d Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed 554.0 577.1 525.1 537.1 658.4 679.6 578.2 5T-7 533.3 535.8 589.2 573.1 523.2 737.8* 558.8 592.0 588.6 538.6 748.6* 574.6 590.7 606.3 555.2 570.3 597.2 609.1 566.5 574.4 597.8 613.1 575.1 582.3 629.0 64T.8 588.0 602.2 547.2 558.3 533.4 548.3 -- -- -- 574.2 543-9 663.0 594.3 537.1 594.5 586.0 531.3 750.2* 573.1 612.6 566.7 612.9 582.8 616.1 585.2 654.9 589-7 551.2 552.7 -** 584.5 553.0 694.6 601.6 558.2 608.8 587-3 530.7 755.6* 566.5 599.4 573.2 623*8 586.2 631.6 578.5 661.7 610.7 548.8 559-5 * -- 596.3 556.8 692.5 606.9 546.6 611.4 587.9 529.5 759.9* 596.8 612.8 563.7 619*6 586.0 619.9 584.5 660.1 617.6 544.9 560.5 -- -- _ 597.8 561.4 686.7 601.7 548-9 609.2 594.7 538.9 762.1* 597.5 621.1 571-9 621.5 597.0 630.6 595-3 674.6 628.4 548.6 563.6 -- -- _ 611.0 559.9 708.6 614.9 560.0 622.4 604.4 553.9 765.4* 605.6 618.6 583.6 638.7 6U.7 642.5 595.1 692.9 638.5 568.7 580.2 -- 616.6 581.2 713.0 601.5 581.0 630.9 597.0 553.4 767.4 603.7 641.5 592.3 637.7 631.4 647.0 604.8 693.9 655.6 565.9 569.8 572 585 586 59* 59* 599 6ll 624 *35 37 38 *o i*0 40 42 53 mm 620.6 586.0 725-7 621.7 581.9 647.8 606.1 567-4 784.7 6l6.5 649.6 601.4 654.2 627.8 664.3 617.1 10Q.Q 671.0 562-2 597.7 635 55 24 3T --zznr CP- -- CP* -- --to 599.9 568.2 699.5 612.9 564.1 612.8 593.1 549.7 766.3* 596.1 629.1 583.0 636.9 622.0 646.3 603.8 688.0 644.6 547.6 578.7 -- -- 611.2 577.5 707.2 611.8 570.9 624.7 596.1 766.6 766.6 601.2 638.6 590.8 630.1 624.4 652.4 610.3 688.6 653-0 556.2 592.1 609 634 1*2 159 -- mm 617.9 5T9.2 712.3 618.6 383.1 631.5 605*1 558.2 792.9* 610.0 657.1 616.3 632.3 642.5 656.2 624.6 692.8 666.6 557.8 599.5 -- 621.6 581.8 719.6 620.6 581.9 642.0 610.5 559.2 784.1 621.9 658.1 608.0 634.3 647.7 672.0 620.0 713.3 668.7 556.3 607.6 624 636 l4l 156 -- -- 636.6 596.8 740.9 640.9 599.3 652*8 623.8 380.1 798.4 637.9 667.5 617.3 673.3' 660.3 700.3 627.8 714.6 677.2 559.7 604.6 620.2 584.6 T14.S 629.1 571.8 639.2 6o8.o 565.7 780.8 622.1 645.7 597.2 646.2 640.9 681.0 622.0 690.1 676.6 545.5 598.1 650 634 157 155 77-7324 7525 7526 7527 7528 7529 7530 7531 7532 7533 753* T535 7536 7537 7538 7539 7540 75*1 75*2 75*3 75*4 75*5 7546 75*7 7548 75*9 7550 7551 7552 7553 7554 7698 7555 7556 7557 Mean 3*0. Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed 606.9 614.3 548.3 568.9 575.6 988.1 518.8 522.3 597.4 614.7 584.6 593-9 614.3 617.7 551.0 575.2 562.2 575.1 599.1 605-3 612.4 614.3 575-1 588.6 611.0 6l6*k 601.2 615.0 536.1 527.6 605.3 619.0 584.1 609.3 582.3 605.3 535-0 537.4 671.9 687.1 584 595 35 *37 _ -- -- e^ *** -- -- -- -- -** -- 612.6 590.0 589.1 528.6 617-5 600.2 621.4 582.5 571.8 615.7 625.5 603.2 629*0 613.3 542.3 629.0 610.6 602.1 549.8 685.7 601 *35 mm --_ --_ ---- -- _ ---- __ _ -- 624.8 611.0 597.3 535.2 607.8 600.4 632.6 579.4 573.8 630.9 645.6 611.3 633.5 627.2 543.8 626.6 621.1 602.3 952.8 TOO.O -- _ 615.5 595.5 593-6 530.7 611.3 599.3 628.9 578.6 577.0 633.3 646.4 618.0 634.1 626.4 338.7 630.7 622.6 .597.7 355.8 684.6 60S 606 *38 *37 _ e-- _ _ -- _ _ mm __ -- 625.0 606.1 606.9 333.8 618.5 603.5 643.0 588.6 581.6 639.9 646.9 631.8 639.8 626.2 560.9 639.3 632.8 624.2 565-4 702.3 616 *37 _ -- _ _ -- _ _ _ _ -- 642.3 630.1 643.2 579.7 634.3 614.7 642.4 602.2 597*1 655.2 676.5 641.6 652.4 636.8 562.0 666.9 640.9 637.9 361.3 714.9 632 *37 _ _ mm _ __ _ _ _ _ _ _ 654.2 643.7 603.6 354.6 650.6 625-5 657.8 606.6 599-4 660.6 670.1 667.6 658.4 643.3 561.5 673.9 646.4 6*0.9 982.0 718.J 636 ko ___ _ -- _ mm. __ _ _ 652.8 661.3 627.2 566.6 652.2 631.2 662.4 626.4 617.7 675.0 666.3 653.6 675.0 635.6 577.3 682.5 662.4 658.5 592.0 727.5 645 38 mm _ _ ___ _ _ 640.0 628.5 616.1 560.1 629-6 613.9 636.9 605*1 597.7 653.1 656.0 636.8 656.3 647.1 567.0 663.6 6*3.4 642.3 370.7 TU.i 629 *36 __ r ___ ___ _ __ r --m ___ ___ ___ ___ ___ 630.5 644.3 617.9 532.6 638.0 619.6 647.3 616.9 993.8 671.4 668.1 635-2 667.0 647.7 971.1 674.0 654.3 644.6 587.4 723.0 636 39 ___ ___ Its mm -rr __ __r wm 666.9 660.4 622.2 565.8 644.2 636.0 652.3 634.2 6i4.7 673.6 667.2 651.9 682.4 664.2 578.0 102*9 672.5 676.2 599-6 735.4 651 *41 mm ___ .__ _ 673-9 670.2 619.0 564.3 662.1 645.2 648.9 642.2 627*1 671.4 683.5 652-0 695*1 650.3 577-0 697*0 671.4 668.6 594.0 732.3 652 *41 _ ___ _ _ ST 676.2 685.4 637.3 912*1 663.6 651.4 658.4 647.1 640.7 683.4 703*9 679.5 704.4 680.9 5*7.1 719*2 674.7 682.0 617*8 753.7 666 *42 , _ ___ __ T_ __ ___ 11 664.5 656.4 631.6 580.6 648.2 627.7 $30.9 6)9.6 632.7 678.2 684.7 676.0 687.3 671.2 378.7 693.4 654.4 671*5 58T.8 733.5 652 *39 DO 131776 CONF TDFNT TAL -24*- MU <U1 (Continued) dscpi nuUTXOi fbrujtx studt ii m mi*1 MT: Hale Body tfelchta (trace) ttpetun LataI Ac1ml bc* uaber BmtfSI IT-7656' 7655 7656 7657 7658 7659 7660 7661 7662 7663 7666 7665 7666 7667 7668 7669 7670 7671 7672 7673 7676 7675 7676 7677 7678 7679 7680 7681 7682 7683 7686 7685 7686 7687 7688 TE5FIric#" Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sierifieid Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Saerlfleed Sacrificed 629.1 628.2 586.9 583.8 727.6 736.8 630.9 639.9 581.5 588.7 662.8 667.1 616.6 610.8 570.6 568.5 791.6 783.6 620.5 635.7 657.2 668.1 612.1 606.6 666.6 651.0 666.3 656.5 679.5 685.0 626.5 626.3 712.0 688.3 566.5 596.8 722.6 687.2 566.8 598.1 Meac 663 8.0. *57 665 *57 32 -- -- -- 632.7 597.2 738.2 665-8 601.3 677.6 616.1 586.1 806.7 661.6 672.0 625.7 657.6 653.6 692.6 636.8 728.6 703*9 558.0 595.2 653 *59 33 a-- _ -- 636.8 595.6 766.2 650.6 611.6 677.3 620.9 586.6 807.9 639.7 673.1 620.5 671.9 666.8 691.6 661.8 762.0 697.5 568.8 616.7 656 *60 36__ a 630.6 598.1 735.3 667.8 596.6 676.6 606.9 581.2 797.7 636*1 672.3 618.2 650.2 638.2 691.9 631.5 739.1 711.1 563.3 606.S 650 61 35 _ _ -- 630.7 576.7 767.0 662.0 596.9 651.3 598.1 571.8 766.6 636.8 657.7 609.7 663.I 629.0 692.3 639.6 733*0 698.5 513.7 605.8 662 *62 Veek of Stitdr 36 37 3B~ _J2_ __ ___ __ 629-9 596-7 739-6 662.3 602.0 663.3 602.5 579-6 773.1 666.2 669.0 608.6 656.2 636.6 692.0 632.9 738.5 711.6 656.9 612-2 666 *69 650.1 600.6 760.6 650.5 601.3 660.6 613.9 591.1 776.5 669.0 667.8 622.3 651.6 656.8 719.0 666.5 762.6 708.7 6O6.5 661 *53 637.3 609.7 769.0 669.7 590.6 669.7 601.5 595.6 769.8 669.3 675.1 616.6 661.3 659.3 708.9 661.0 767.7 690.7 Dead 613.9 660 *56 668.8 603.6 760.0 669.6 599-1 673.3 597.1 596.8 778.1 653.1 672.5 627.0 669.6 659.6 711.3 668.6 762.6 696.2 _ 616.I 662 53 ao i a " 111' a. _ a 633.0 608.2 758.5 656.2 599*1 667.6 589.5 586.6 768.8 667.3 672.0 629.3 666.8 639.8 718.3 662.6 761.3 696.0 609.9 659 *55 626.6 598.8 _b 623-5 591.2 666.5 586.2 573.6 _b 638.6 651.1 596.5 636.6 633.5 683.6 623.2 731.0 598.7 600.5 626 *39 62 _ 635*7 590.3 Dead 626.6 586.6 639-1 583.2 579.7 Dead 661.3 652-7 606.6 632.6 666.8 680.6 630.9 735.2 666.1 _ 600.9 631 *60 _ 626.1 593.2 613.0 591.2 S7.6 572.2 576.2 639.5 667.2 611.1 631.7 638.1 687.7 663.5 727.5 673.6 599.0 630 61 77-7526 7525 7526 7527 7528 7529 7530 7531 7532 7533 7536 7535 7536 7537 7538 7539 7560 7561 75*2 7363 75*6 75*5 7566 75*7 7568 7569 7550 7551 7552 7533 7556 7698 7555 7556 7557 Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Saerlfleed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed 606*3 683.1 673.0 679.6 635.T 665.I 581.6 582.0 660.6 656.7 636.5 661.9 663.0 658.3 665.3 638.9 661.0 661.2 683-3 66b*6 691*6 690.9 666.1 666*2 696*1 685.8 669.2 666.7 598.6 590.8 709.9 707.3 666*0 669.8 672.6 673.6 596.8 6o6*6 731.3 760.0 ex* -- -- -------- _ 691.7 693.3 666.5 585-3 666*b 66T.3 661.5 663.3 65126 693.2 689.3 672.9 7X1*0 665.0 588.7 722.6 683.5 683.7 623.7 769.2 _ __ _ _ ____a. 680.6 702.5 666.6 585.9 666.6 663.7 618.8 663.3 661.2 678.3 688.9 675.3 709.6 663.5 588.3 731.9 698.1 687.6 618.3 766.8 _ --_ _ __ -- <pu 676.6 699.3 651.6 386.1 671.T 661.3 672.9 $66.6 668.7 673.1 679*2 680.8 716.3 665.8 583.3 725*2 686.5 686.2 631.8 766.7 _ __ *__ 676.3 692.8 651.6 589.6 675.6 633.1 663.I 666.3 656.2 677.5 610.5 668.8 706.2 $58.3 592.5 T26.5 $90.2 $93.6 626.5 729.8 __ _ _ __ _ 675.T $98.0 $52.2 596.9 $56.9 $33.8 $$9.6 $53.0 659.1 $82.6 $89.6 $77.3 699.9 $$5.2 59T.6 732.6 691.5 $97.0 $25-7 760.0 _ _ __ 690.6 710.8 $59.6 591.1 6T2.0 $50.5 $81.6 $67.6 $$5.6 707.3 706.3 $90.0 708.7 $97.1 $33.5 768.0 700*0 696.5 632.6 736-7 _ __ ,_ _ 687.1 707-1 661.3 592.6 683.8 $50.7 678.1 662.3 665.6 698.2 706.7 681.7 718.8 675-0 615.2 765.0 696.5 708.0 639.2 752.6 wnmr _ _ _r 696.7 70T.5 676.6 600.6 681.6 66T.6 682.6 666.9 668.0 707.8 706.3 691.5 701.3 676.0 619.7 750.7 712.7 716.2 668.0 755.1 _ 701.9 718.3 672.6 600.6 688.7 665.7 682.5 6T0.1 662.9 703.8 103.8 $96.6 709*9 6T7.6 $16.7 765.7 711.8 726.6 660.5 T5T.1 _ _ _ ___ 667.6 696.6 657.7 990*3 670.8 636.3 682.7 $57.7 661.6 688.0 687.6 662.0 696.9 659*8 610.1 736.3 <83.3 T01*T $18.2 739.3 * 679*6 696*5 656.9 598.3 676.0 667.6 $83.2 660.0 653.0 709*6 68b. T 670.9 TDi.i 658.6 606.7 7*3.0 7X7*9 716.5 6S6.6 736.7 $91.2 703*9 659.5 601.2 672.8 629.8 679.6 665.1 650.6 703*5 695.8 665.O 705*5 661.6 606.5 792*9 723*2 628.9 7*7*2 690.5 Mean 660 S.D. *38 66o *36 669 *60 669 *62 668 *60 666 37 670 *38 662 *37 681 39 685 *38 686 *60 670 *38 676 *39 67T *61 bb _ _ *_ _ aa M _ _ _ _ _ 601* 575 597 5606 618 520 558 626 619 596 601 619 661 618 712 656 580 607 *66 665* 675 636 379 633 60S 669 662 662 609 656 660 662 637 JT6 717 660 693 622 Dud 666 *36 no 131P77 0ONFIDFNTTA1 249- fabla A->1 (Cootlunedl DBCP: XnULATXOI TOtTIUTI STUDY ZB T*tt fUXt Bat; Mild Bndr tfelaftta iiamam) Zarl Aoiaal ftiaber W-T593 739* 7595 7396 7397 7598 7599 7600 7601 7602 7603 760k 7605 7606 7607 7608 7609 7610 T6U 7612 7613 7616 7615 7616 7617 7618 7619 7620 7621 7622 7623 7626 7625 7626 7627 -1" "5553 560.0 666.0 510.0 500.0 677.0 668.0 525.0 560.0 577.0 588.0 500.0 698.0 690.0 520.0 500.0 683,0 676.0 655.0 525.0 565.0 520,0 686.0 502.0 552.0 516.0 683.0 503.0 550.0 533.0 696.0 610.0 560.0 516.0 508.0 Hmq 516 8. D. 236 -stray 530.0 539.0 566.0 668.0 679.0 515.0 516.0 507.0 509.0 676.0 680.0 65O.O 659.0 522.0 536.0 566.0 562.0 568.0 588.0 597.0 595.0 502.0 503.0 692.0 512.0 686.0 ta.o 517.0 520.0 508.0 515.0 678.0 678.0 671.0 675.0 656.0 658.0 529.0 535.0 566.0 561.0 506.0 695.0 680.0 688.0 692.0 698.0 555.0 560.0 510.0 518.0 676.0 676.0 502.0 506.0 552.0 556.0 535.0 568.0 683.0 686.0 613.0 619*0 566.0 556.0 518.0 536.0 5U.0 510.0 516 519 37 39 50SIS 503.0 682.0 920*0 515-0 687.0 629.0 502.0 561.0 556.0 576.0 696.O 520.0 682.0 526.0 515.0 685.O 683.O 655.0 539.0 569.0 510*0 690.0 698.0 566.0 515.0 687.0 503.0 566.0 560.0 696.0 627.0 561.0 563.0 526.0 517 38 6 533.S 536.2 690.6 526.5 522*1 685.9 653-2 510-9 571.8 567.5 608.0 518.1 527-3 696.6 528.9 676.9 681.6 662.1 525.6 555.2 699-7 689.6 503.6 556.9 512.3 678.6 507.0 553*9 567.8 698.6 622.8 561.6 512.7 5U.6 522 38 Vnk of Btadr 553*8 5I9.J B-----"57?nt -ski "IS u TO "5S53 im 556.3 569.6 576.8 586.5 573.1 511.3 589.6 613.9 503.3 505.0 508.6 518.7 519.0 317.3 322.5 523.6 569.2 562.7 55.l 572.8 561.6 556.3 581.7 580.0 522.1 533.3 508.9 529.6 525.7 515.1 330.6 535.6 502.6 693.6 696.8 698.3 690.6 692.9 679.8 688.2 667.0 687.1 693.1 689.9 691.9 881.2 692.3 501.6 528.9 569.8 553.6 563.0 572.6 375.5 575.2 583.8 578.1 592.1 6(12.7 619.7 627.5 623.8 626.6 630.1 607.3 619.3 632.3 666.6 656.5 656.3 669.8 656.8 tacrlflc*4 tacrine*4 _ __ tacrine*4 Sacrificed 8aerlflce4 _ _ __ mm 507.8 518.6 516.7 520.3 538.1 527-2 536.0 551.8 693.3 501.6 695.6 501.6 509-6 516.2 512.2 510.5 690.9 698.3 683.2 696.7 689.3 698.0 508.7 510.8 663.6 ' 670.2 663.8 672.5 681.0 655.9 663.5 661.8 538.8 552.2 561.3 552.2 556.0 538.3 560.6 563.9 556.8 566.1 569.9 563.3 578.6 572.6 596.7 597.0 515.9 523.0 697.6 509.0 522.3 502.1 521.8 522*2 502.6 510.2 501.8 515.6 515.3 505.7 519.1 523.5 523.0 522.6 517.6 562.3 563.0 606.6 562.6 562.9 580.1 589.5 589.5 603.9 601.6 522.6 616.7 612.5 535-6 560.6 537.3 569.2 566.6 556.3 566.6 573.8 687.7 686.1 683.6 699.8 690.9 687.7 699.2 685.0 526.1 525.6 515-3 532.5 532.5 511.8 523.1 333.5 571.1 581.8 583.3 596.6 590.6 591.5 590.7 589.6 363.9 576.6 576.8 592.0 588.9 57.6 601.9 608.6 513.5 525.9 527.8 532.3 533.3 556.6 538.6 561.6 666.7 663.1 638.8 669.9 651.9 569.6 656.8 665.0 562.0 587.6 560.7 563.7 573.5 638.2 580.6 586.6 552.6 569.7 553.7 580.5 569.8 567.9 569.3 561.6 530.3 561.T 53.0 550.5 557.9 552.5 567.1 567.3 536 60 566 62 539 66 551 66 552 66 585 68 556 68 560 69 --ir~ 598.1 527.0 572.0 539.1 695*6 512.3 586.9 635.6 660.3 _--a 560.0 526.2 506.6 667.6 569.2 612.8 561.6 566.5 553.8 612.9 569.9 691.5 536.9 596.6 610.6 952*7 659.9 572.8 576.1 576.6 570.2 520.6 570.7 316.1 505*3 503.9 636.6 650.5 __ _ 558.6 516.9 512.0 691.5 559*5 605.6 560.6 668.6 560.I 59T*1 560.1 687*1 537.1 585.6 596-8 526.7 636.2 575.8 559*9 559-0 563 551 67 68 77-7663 7666 7665 7666 7667 7668 7669 7670 7671 7672 7673 7676 7675 7676 7677 7678 7679 7680 7681 7682 7683 7686 7685 7686 7687 7688 7689 7690 7691 7692 7693 7696 7695 7696 7697 Main *s.o. 538.0 312.0 515.0 523.0 698.0 503.0 523.0 506.0 510.0 516.0 561.0 698.0 670.0 697.0 550.0 567.0 580.0 531.0 563.0 552.0 561.0 512.0 568.0 523.0 556.0 527.0 567.0 501.0 590.0 566.0 633.0 698.0 560.0 522.0 696.0 526 32 523.0 507-0 500.0 515.0 670.0 686.0 516.0 685.0 300.0 507.0 533.0 663.0 657.0 683.0 550.0 570.0 507.0 366.0 552.0 560.0 532.0 506.0 533.0 317.0 533.0 505.0 566.0 690.0 570.0 371.0 622.0 678.0 570.0 522-0 692.0 516 35 519.0 505.0 698.0 698.0 665-0 683.0 500.0 676.0 679*0 692.0 516.0 659.0 669.0 676.0 529-0 562*0 508.0 526.0 569.0 533.0 521.0 506.0 512.0 513.0 531.0 511.0 536.0 696.0 562.0 568.0 621.0 660.0 331.0 525-0 685.0 506 36 527.0 501*0 506.0 693.0 675.0 677.0 508.0 676.0 689.0 503.0 523.0 671.0 666.0 688.0 336.0 563.0 516.0 510.0 568.0 526.0 518.0 503.0 528.0 509.0 528.0 521*0 535.0 698.0 575.0 555.0 620.0 638.O 563.0 518.0 696.0 509 32 535-7 506.1 509.2 505.6 688.9 677-9 516.9 686.6 691.6 513.8 518*8 671.6 666.2 688.5 536.1 566.3 508.2 512.8 356.2 529*0 513-6 506.9 316.7 507.2 S3 527.2 5S3:I 550.6 616.8 652-3 567.8 517.5 606.3 509 31 552.8 355-7 516.3 518.3 509.9 511.6 502.9 310.3 696.6 500.3 698.2 693.7 530*0 527.7 687.3 697.1 506.0 508.5 327.2 531.6 Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed 568.6 583.6 515.T 528.1 506.7 560.2 563.1 510.2 5*3.0 5*6.5 5*0.2 331.0 516.7 530.9 535.8 5*0.3 519.1 516.5 537.8 5*3.6 500.0 5*1.6 5*5.0 5*6.6 513.0 517.8 571.2 586.5 5*9-6 535.8 633.6 633.6 675.0 617.8 5*8.8 537.0 507.5 *95.1 683.3 698.0 522 529, 32 3* 569.6 525-9 523.2 519. 500.8 528.3 531.5 *97.8 516-2 532.6 576.0 528.7 516.3 583.2 5*2.0 526.3 518.6 535-2 535-6 5*2.5 532.9 5*6.8 5U.8 596.8 552.6 668.0 *79-3 572.7 551-3 SOI. 2 531 31 575.8 535.0 526.5 523.1 502.8 698.5 536.6 502.6 315*8 5*3.5 -- 586.1 317.8 517.1 391.6 353.0 5*1.3 321.6 568.9 533.6 5*6.6 5*6.7 356.2 513.6 595.6 577.1 *56.3 678.3 596.5 555.6 507.6 53T 36 570.3 529-9 523-3 532.6 507.3 *90.3 313*6 505.* 513-5 531.2 598.3 533.3 527.1 591-6 556.0 5*6.0 528.8 551.7 536.7 551.6 551-7 5*6.3 520.6 606.7 596.5 656.9 686.2 590.6 566.8 516.8 539 35 578.0 5*3.9 536.0 526-5 518.9 693.1 5*0.5 523.2 508.3 531.9 e. *05.3 536.9 656.1 515.7 563.6 509.1 515-5 m 550.0 671.6 682.9 536.6 596.7 579.0 666.7 671.2 525*6 561.9 666.0 523 *2 586.7 5*0.1 526.8 526.9 522.5 501.7 5*7.7 529.8 518.1 5*7.8 619.6 557.8 532.3 557.8 592.7 379.5 5*6.9 5*6.0 532.7 5*7.7 5*7.6 557.6 538.6 609*0 595.8 668.0 *92.5 593.1 567.8 512*2 5*8 36 598.0 531.1 527.0 531.3 527.0 505.8 556.8 520.1 517-3 556.2 _ 612.0 552.3 53*.7 598.2 372.0 356.0 5*0.0 566.8 339.7 5*8.9 5*7.1 561.3 336.0 605-5 398.2 663.8 501.6 616.6 586.6 503.2 350 36 588.8 527.8 533.6 529.2 336.1 500.9 550.8 516.1 512.9 558.0 _ 619.2 552.3 5*5.5 595.6 590.3 562.8 5*1.6 566.2 539.1 532.7 556.6 569.5 536.8 609.7 612.2 678.1 *96.5 615.6 376.8 921.2 553 37 583.6 521-5 526.0 551.9 532.6 502.9 552-2 518.6 519.5 569.6 630.6 5*1.3 560.6 583.0 560.9 559-6 526.2 536-9 531-9 922.0 518.9 5*6.2 523-0 <06.0 608.3 666.8 *93-2 610.2 576.6 516.5 5*6 37 00 131P7S confident tai -4JV Mil* A-l (Continue) BBCP: DEAIATI01 mmLITI STODT O HIS MX* lUt; MU* Body tfalchtl (trtmt) txpOVUT* Ural taiatl ~fS" 77=7553 7391 7595 7596 7597 7598 7599 7600 7601 7602 7603 760k 7605 7606 7607 7606 7609 7610 7611 7612 7613 T61k 7615 T616 7617 7618 7619 7620 7621 7622 7623 762k 7625 7626 7627 ___ 15 ___ 16 WrinFa Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Burlfleid Sacrificed 9krifled Sacrificed Sacrificed Burlflead Sacrificed Sacrificed Sacrificed 56k. i 566.7 518.3 527.6 536.0 5kk.2 kT5.0 k87.6 5TT.2 586.9 61T.5 618.2 560.9 579.0 536.9 5k8.1 55k.2 559.7 6k3.6 659-6 57k.3 596.2 k99.6 509.7 556.3 566.6 615.6 635.6 623.1 633.0 539-2 656.9 65T521-.03 583.8 603.6 576.3 579.7 561.3 578.0 --iL ------ 18 566.8 537. k 5k5.1 k91.9 590.9 623.7 573.9 5kS.6 567.3 657.6 589.6 509.2 56k.8 617. k 633.8 551.6 683.5 607.7 585.2 57k.6 592.0 5k8.0 5k7-7 505.k 591.8 632.9 578.5 553.0 566.7 672.2 605.2 509.9 572.5 627.1 629*1 556.3 698.2 622.8 581.5 590.6 --H. 578.5 5kk.9 537.2 k90.1 592.3 627-1 572.0 55k. 2 5T3-k 668.8 603.8 510.0 566.1 628.8 636.3 557.6 673.5 616.8 591-3 579. k Nmb 568 16.0. 580 18 581 17 589 19 585 18 so 5k.3 5*7.8 536.5 507.7 602.3 610.1 576.3 566.6 576.1 675.6 602.6 502*0 572.1 610.8 611.3 83 636.8 606.6 386.3 593 50 Knfc of Study 21 22 _2_ 596.9 513.9 553.2 520.0 6l7*k 655-2 591.1 579.9 589.6 687.5 621.2 508.3 576.0 650.5 666.1 5T9.5 701.3 635.9 612.1 601.6 601 52 390.9 555.6 512.7 518.0 631.3 662.1 596.0 575.9 598.7 709*1 623.2 508.6 585.7 616.3 666.8 587.1 711.6 610.0 609.7 603.0 608 56 610.8 571.1 551.2 525.1 637.6 683.1 605.1 577.1 601.2 717.3 610.8 501.3 591.8 662.6 679.1 600.1 727.6 657.6 618.3 608.7 619 59 2t -2- 592.3 553.3 517.9 516.3 617.7 586.9 589.0 566.1 581.7 <88.1 611.7 122.7 577.7 636.6 666.6 581.1 678.2 627.5 609.5 591.9 606.8 565.6 353.0 528.5 633.3 657.9 588.3 586.1 599.3 707.1 636.3 192.3 592.8 615.5 678.2 592.9 707.7 616.2 619.8 609*6 592 59 612 55 __ L 616.3 571.5 373.1 512.1 652.6 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610.5 178.2 196.8 517.0 519.7 622.2 635.2 579.5 592.9 528.0 516.2 Main 572 |0 D. 59 580 do . 636*2 583.3 581.8 631.1 611.1 595.7 569.5 599.2 562.9 589.8 588.2 589.8 516.6 629-3 652.7 195.1 523.3 615.1 606.1 532.6 589 *12 611.7 597.7 595.3 631.5 616.I 593.7 575.7 606.2 569.6 589.9 596.2 609.5 561.6 631.7 650.1 503.8 531.2 611.0 612.2 518.5 596 39 630.7 583.0 571.6 632.7 607.1 601.0 562.3 592.1 562.5 581.1 585.6 595.0 563.1 629*0 665.7 306.? 531.1 611.1 607.5 558.7 591 38 * 639.8 588.8 598.9 633.3 611.6 599-0 570.0 600.1 572.9 600.1 600.2 601.1 561.9 619.2 669.5 505.9 536.2 651.1 616.0 561.9 599 10 -- 665.3 606.6 619.1 612.8 613.6 615.I 586.9 621.0 586.0 597.6 599.1 6O8.T 570.5 656.1 681.6 516.1 556.6 661.3 621.6 566.5 610 10 -- 667.1 625.6 629.2 657.5 621.6 628.5 603.0 619.2 583.2 610.1 600.0 620.3 576.6 671.9 TOO. 5 513*0 516.9 660.8 626.1 579.8 619 ll 680.2 631.0 638.9 670.2 637.8 613.1 612.9 623.8 606.1 630.3 620.1 632.9 390.6 677.0 709-1 551.2 558.3 676.2 637.7 587.3 631 10 w 653.1 601.2 616.1 652.1 599.9 628.0 589.0 601.1 575.1 601.1 392.1 601.1 562.2 666.9 690.2 513.2 517.7 619.6 619.6 561.7 608 10 w 677.0 622.7 621.1 657.8 618.1 630.6 601.1 621.1 591.1 618.9 603.2 625.2 580.7 672.1 698.3 537.1 333.3 671.7 617.1 579.3 622 -- 691.I 637.1 611.2 675.5 636.5 651.8 621.8 631-3 605-9 639.5 606.0 631.1 600.8 696.0 718.3 558.9 562.0 686.5 650.0 591.9 617 13 692.3 688.6 653.8 677.1 617.1 659.1 629.3 617.0 611.1 631.9 617-1 631.8 605.3 697.2 711.1 561.1 563.1 681.1 667*0 622.1 613 11 -- 710-5 660.6 660.1 689.6 657.7 675*1 613.6 651.5 622.1 650.9 622.2 656.0 609.T 712.7 729.9 5M 572.8 688.% 666.3 600.5 652 H -- 709-2 615.0 629.9 678.2 611.2 658.2 621.1 658.1 619.3 631.3 608.6 612.6 632-7 615.1 71T.2 561.2 551*9 679.1 650.8 579.2 637 12 no 131P79 CONFIDENTIAL -151- Tahla A-l (Coatlmm)) DBCPi UHAMTtOI nSTILITI BTUDT H m MI* Rat: Hala Body Weight* (pm) bpoitn Level Anlaal Mutter TT-TSM 7591 T595 7396 7597 7598 7599 7600 7801 7802 7603 7606 7605 7606 7607 7608 7609 7610 7611 7612 7613 7616 7615 7616 7617 7618 7819 7620 T621 7622 7623 7626 7625 7626 7627 Sac riflead Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed 618.6 627.7 572.1 570.8 562.6 662.9 692.8 615.6 5T3.6 569.3 560.7 669.1 TO6.7 619.6 601.1 607.0 605.7 706.3 666.8 616.9 721.6 669.6 685.5 696.7 616,1 626.5 667.8 T01.9 616,1 726.6 666.5 636.7 619.6 676.9 712.6 616.2 726.9 662.8 661.0 629.7 _JL_ _JL_ _JL_ _jju 662.1 580.7 583-2 561.7 673-3 726.8 626.1 627.3 625.7 737.0 667.8 690.3 627.2 697.1 723.1 626.1 737.2 687.5 652.T 665.7 668.7 572.3 5T9.6 567.2 680-5 735.9 630.7 625.8 638.2 769.6 675.6 693.9 627.9 706.2 722.6 626.9 751.6 686.5 663.I 663.8 669.9 587.9 579.2 562.5 676.6 730.8 627.9 619.9 638.0 766.8 667.5 685.7 626.1 706.8 736.2 630.2 753.8 696.1 657.2 636.8 665.1 581.5 583.6 557*0 669.3 732.6 627.3 623.6 628.0 T63.6 665.9 675.0 627*9 698.6 T16.8 626.1 769.7 686.8 650.5 638.9 636.2 589.5 590.3 555.1 692.9 767.T 626.1 620.3 621.5 737-2 662.6 682.2 636.0 712.3 719-1 626.8 769.1 688.9 666.9 663.3 659.6 590.9 589.6 588.8 688.9 730.1 633.1 631.9 637.7 809.6 669*7 679.5 652.6 707.1 722*6 6U.6 735.1 705.0 706.3 666.0 _J2_ J4_ _iL_ 656.3 586.8 589.6 556.2 692*1 736.5 626.9 632.7 626.8 756.6 658.9 671.5 651.7 706.1 733-6 625*0 767.6 TO6.3 669.1 651.8 650.6 583-T 586.7 561.6 689.0 737-7 636.7 632.1 633.6 753.6 662.8 686.7 651.0 705.5 733-6 615.8 T39*T 702*6 671*1 766.8 650.2 591.6 588.6 556.2 683.0 736.8 660.8 662.5 661.3 757.T 661.1 652.6 655.1 703.2 729.0 610.0 726.5 702.7 666.6 652.1 632.9 572.3 578.6 562.7 671*2 713.6 616.7 628.6 626.0 738.6 666.5 628.1* 639.1 681.7 706.3 602.1 686.7 689.9 662.5 635.6 663.2 577*8 586.0 567.7 6TB.6 705*9 626.9 622.3 623.6 736.0 638.7 626.6* 665.1 689.7 716.7 6O6.9 708.7 Too.o 656.6 651.9 653.7 575-6 585.6 550.5 686.9 716.6 623.0 632*2 632*0 729.0 661.9 621.0* 666.6 699.5 709.9 616.3 702.5 702.7 666.0 652.6 sr 6230 561 567 521 655 681 607 617 606 698 608 386 633 690 682 596 665 690 661 635 Hate 627 iS*D* d58 633 *60 6kT *63 650 *66 650 *67 6k6 *67 650 *68 660 ATI 651 170 658 *73 652 *71 615 *51 650 151 653 150 618 *73 77-7663 7666 7665 7666 T66T 7668 7669 7670 7671 7672 7673 76T6 7675 7676 76TT 7678 7679 7680 7681 7682 7683 7686 7685 7686 7687 7668 7689 7690 7691 7692 7693 7696 7695 7696 7697 Sacrificed Sacrificed Secrifleed Sacrificed Sacrificed Sacrificed Secrifleed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed 711.6 657.1 652.0 681.5 652.5 729-1 657.0 651.1 678.1 65k.8 668.6 630.7 611.8 618.0 613.0 666.5 631.5 613-1 626.2 6kl.2 623.2 650.5 608.5 622.9 662.0 59k. 6 68k. 3 699*0 726.8 726.0 565.1 567.6 572.3 569.1 693.5 696.9 657.1 665.1 598.9 605.2 Tk0.3 680.8 656.2 699.3 669.0 673.2 6k5.8 6k6.9 SkJ.T 6k5.0 611.0 676.6 612.0 717.5 7kk.2 578.3 582.k 691.1 676.7 607.6 718. k 689.5 671*1 700.8 680.3 672.7 6k8.T 652.3 6k6.T 66k.6 635.3 675.5 606.9 732.5 75k.2 585.7 581.3 686.6 683.k 613.5 Tk7.1 688.7 6T0.7 692.6 676.6 675.3 658.3 653.7 6kk.k 65k.3 626.7 672.7 610. k 736.5 7k9. k 592.7 575.0 689.3 680.7 606.9 7k6.7 691.0 660.8 692.5 679.3 669.2 655.8 6*8.2 650. k 6k8>7 617*1 669.9 609.I Tki.6 Tk6.7 39k.9 582.3 690.3 678.0 618.3 7k3.1 T01.0 618.9 693.3 702*1 67k.2 661.9 653.7 658.9 618-5 631.8 676.9 619.7 712.3 765.1 595.8 390.7 68T.1 693.1 620.1 753.0 710.1 Deed 701.1 710*1 686.6 659.1 653.8 663.1 658.1 631.2 713.1 60I.3 750.1 769.8 606.8 601.6 696.8 680.9 630.0 752.7 T2T.2 _ 668.6 706.3 675.1 659-5 652.1 660.2 653-7 613.5 698.0 612.6 752.1 766.2 601.1 602.6 687.8 683.5 631.1 757.8 739.1 671.7 721.8 681.8 668.1 631.2 665.O 657.7 653.7 701.3 629.8 757.9 766.6 612.3 60I.6 685.8 686.8 633.1 733.0 719.3 661.9 733.2 660.0 673-3 6I9.O 639.0 653.9 653.2 693.5 622.9 751*0 711.7 606.9 60I.9 681.3 679-2 627.3 TlO.l 732.1 _ 639.1 716.0 622.1 616.3 637.6 611.2 616.3 639.1 672.7 609.7 731.9 729.2 601.1 597.1 682.1 663.6 612.1 -- 733.3 731.8 631.3 726.7. 585.5 617.2 619.0 638.3 638.1 618.6 689.9 602.8 731.1 731.5 605.9 599.8 681.0 675.1 607. T 711.6 770.9 *mw 6U.6 TJ7.1 501.6 656.7 616.8 613.9 631.1 660.3 696.7 616.9 712.1 719.0 600.3 595.T 689.2 682.7 617*2 _ -- -- -- -- -- ** -- -- -- -- " -- -- 737* 759 -- 139 722 Deed 631 601 613 599 618 660 582 T08 736 589 566 630 655 613 Hate 6k7 18, Do k2 650 15 661 k6 666 kS 665 665 17 669 $18 678 150 676 iM 682 119 676 19 661 w 662 53 663 67 637 *77 7ml1* nti mn azpsaed to 0, 0-1. 1.0 or 10 ppm DSCP by Inhalation (nr 6 hr/day, 5 day* par wak 0>r 16 waaka. expoaur* period, animal* vara maintainad la tb* laboratory for racoTary. "Statistical outllar idantlfiad bf aaquantlal outlier teat. Alpha - 0,01; aalua not incited la calculation*. b*o wight takan. eA* dial * aar* being held nr nacropiy on wak 66 of th* study, cniaalc aara not wighad on vaak* 6A and 65. dvalua* fbr tbs 66tb wak rapreaent raatad body Wight* takan prior to naeropey. Pbllovin* termination of th* DO 131080 r.ONF TDFNT I A. mart nmun imhbaiahoi studt to mt* MTi Teila BoOr Malahta (ml to1ml Mutbtr T7-7*19 TWO 7*21 7*22 TW3 1*2* 7*25 7*26 1*27 7*20 7*29 7*30 7*31 7*32 7*33 7*3* 7*35 7*36 T*3T 7*38 7*39 T**0 7**1 T**2 T**3 7U1 T**5 T**6 T**T T**8 T**9 T*50 7*51 T*52 7*53 "350' 283.0 292.0 306.0 306.0 280.0 270.0 3Q*.0 291.0 317.0 900.0 2T0.0 293.0 2A1.0 280.0 283.0 292.0 333.0 268.0 290-0 260.0 286.0 300.0 300.0 265.0 305.0 327.0 2*7.0 322.0 265.0 303.0 300.0 253-0 320.0 303.0 ' 3ife*o 29*-0 291.0 29*.0 316.0 273.0 277*0 313.0 299-0 323-0 292-0 281.0 285-0 293-0 282.0 276.0 290.0 323.0 266.0 276.0 282.0 290*0 297.0 J0*.0 286.0 302.0 31T.0 250.0 31*. 0 263.0 300.0 29**0 260.0 32*.0 302.0 -sfo 285.0 29k.0 30*.0 30*.0 279.0 276.0 308.0 301.0 325.0 290.0 293-0 290.0 297.0 288.0 290.0 306.0 336.0 290.0 29*>0 288.0 287.0 298.0 312*0 263.0 302.0 325.0 2*6.0 321*0 282.0 30*.0 291*0 257.0 328.0 311*0 Hnb 293 S* 0* 119 29* 117 297 ns 291-0 289.0 298.0 297.0 283*0 281.0 31*. 0 30*.0 320.0 26T.0 281.0 286.0 298.0 282.0 283*0 299.0 331.0 292.0 28*.0 282.0 286.0 310.0 309.0 295.0 307.0 327.0 250.0 323.0 291*0 31*.0 29*.0 260.0 332.0 31T-0 thh: 291.7 288.3 295.3 296.8 293-1 267.8 321.9 307.6 332.5 288.0 289.* 292.5 305.9 29*.7 293.7 291.* 333.0 29*. 3 276.9 287.0 286.* 305.* 297.1 29*. 1 310.2 337.3 25*. 3 320.5 286.1 306.* 290-9 262.0 330.7 319.1 Veek OS Studr ikl T3HF 295.8 302.8 303.* 312.9 312.0 302*1 313.0 313.9 268.9 296.9 292.6 300*1 323.* 316.* 338.2 296.1 320.7 332-7 317.5 3*3.9 290.5 '301*0 299-3 293.8 315.2 302.3 305.* 318.0 306.9 309.6 292.T 317.1 3*6.3 293.0 276.9 289.3 298.2 332.1 328.0 298.6 292*0 285.7 313.7 356.1 311.6 313.* 303.2 30**5 302*2 301.6 3*2-5 30*.5 255.5 253-7 326.0 330.6 299-9 306.3 Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed 3^9-7 305.6 302.* 316.3 31*.7 292*1 292*6 327.9 3U-* 353.2 307.9 311*1 303.8 318.3 295.8 301.7 316.3 3*1.6 309.3 289.7 296.* 310.8 318.9 316.3 30*.9 310.6 3*5.5 25* .7 33**8 303-3 -- 3*2.3 306.* 302.3 Jlk.T 310.0 301.8 303.2 33*.6 316.6 3*3.* 303.9 300.2 310.1 321.7 290.9 302.9 31*.* 336.9 29T.7 293.3 295-* 306.3 318.0 31T.5 306.3 316.2 3*9.2 262.6 337-1 307.3 jfcy 308.1 30*.8 315*3 311*1 300.5 301.3 338.8 31*.6 35*.3 306.6 30*.9 312*6 323*1 301.1 308.0 317.8 3*5.0 293.* 269.5 300.5 308.7 320*2 321.6 318.0 316.7 3*8.8 262.5 3*5.* 3U.0 -- io w JU.k 312-* 318.0 311.0 310.* 29*.1 3*2-9 313-1 332.0 308.8 303-0 313.0 330.7 293.0 309.0 31*.0 3*1.2 302.0 292-7 311.3 311*2 326.5 313.5 311.* 320.5 3*9-7 255.3 33*.* 322.8 -- T1O1 *.2 313.9 327.2 319-3 311.8 312.8 3*5.* 320.3 356.6 30*.8 315.8 318.* 331.0 307.1 316.8 322.9 3*9.0 300*0 302.9 325.3 320.7 331-3 33*. 3 31*.* 325.2 360.2 271-1 358.6 311.3 -- i T5I7? 316.6 31**5 32*.7 328.3 319.8 303.8 351.8 325.3 362.0 310.6 313.7 31*.7 3*2.2 302.7 313.3 323.0 3*3.8 JOT-2 303.6 309-3 318.9 332.6 316.3 310.T 32*.5 353.* 267.9 3*3.5 328.8 -- 298 119 300 +19 307 +19 310 20 311 +19 312 +18 315 20 316 120 32* 119 323 19 3*2.6 32*.5 310-0 330.9 323.8 313.6 299.6 3*1.3 327.6 359.2 315.2 321-3 319-0 3*8.6 301.1 322.3 316.2 351.0 300.0 300.6 307.1 312.* 323.7 318.3 309.5 320.3 3*8.9 268.9 3*2.9 328.3 -- 322 19 1* ` 352.0 329.2 320-0 333.6 325.5 322.1 309.* 3*1.2 336.0 360.7 313.6 322.5 328.2 337.0 312.3 327.8 336.* 35**8 311*2 309.* 293.6 308.8 350.6 330.* 319.9 32k.B 362.3 273*9 35*. 5 327.1 " -- 326 20 77-7*89 7*90 7*91 7*92 T*93 7*9* 1*95 7*96 1*97 T*96 7*99 7500 7501 7502 7503 750* 7505 7506 750T 7308 7509 7510 7511 7512 7513 T51* 7515 7516 7517 T518 7519 7520 7521 7522 7523 Mmi a.D. 300.0 317.0 289.0 263.0 300.0 307.0 29*. 0 28*.0 305.0 298.0 316.0 282.0 307.0 331.0 265.0 30*.0 325.0 282.0 290.0 297.0 363.0 305.0 296.0 295.0 31*.0 337.0 285.0 330.0 326.0 293.0 310.0 291*0 285.0 290.0 299-0 303 *19 30*. 0 312.0 285.0 260.0 297.0 292.0 290.0 278.0 291.0 263.0 31*. 0 273.0 302.0 32 *.0 288.0 295-0 322*0 290.0 286.0 295.0 355.0 29T.0 300.0 290.0 306.0 337.0 285.0 323.0 31T.0 287*0 303.0 280.0 277.0 295.0 300.0 298 *19 295.0 316.0 29*.0 255.0 290*0 307.0 29*-0 266.0 309.0 290.0 316.0 28*.0 299.0 33*.0 26*.0 310*0 317.0 288.0 295.0 298.0 35*. 0 305.0 302.0 29**0 31*.0 3*2.0 293.0 3*1.0 320.0 295.0 300*0 291*0 280.0 269.0 300*0 302 *20 303.0 323.0 286.0 265*0 300.0 30T-0 298.0 285.0 302.0 296.0 326.0 282.0 305.0 33*.0 293.0 311*0 31*.o 289.0 316.0 315.0 366.0 3OT.0 307.0 296.0 317.0 339.0 296.0 333.0 320*0 301*0 309.0 296.0 26*. 0 296.0 305.0 306 *19 30*.0 327.1 296.2 268.2 311.8 307.5 305.7 301*0 322.9 299*2 3*2.7 285.5 306.* 338.6 292*1 313.6 325.2 307.3 306.0 31*. 0 360.0 310.7 317.9 306.9 319.* 358.5 299.1 331*5 322.* 29*.2 316.* 300.7 286.1 299.1 306.9 312 *19 309.0 320.8 32*.1 326.0 300.9 310.3 272.0 2T0*9 320.9 31T*0 30*. 1 303.6 305.1 305.2 303.1 318. k 309.9 309*9 306.5 331*1 332.* 335.5 268.9 280.6 309-3 308.0 3*2.5 353.8 292.9 316.0 327.* 296.7 297.1 323-9 320*2 300.* 308.3 307.3 308.* 313.9 367.1 31*.2 326.0 295*7 323.8 356.* 366.9 31**9 317.7 298.6 32*. 3 353.0 307.2 31**6 339-6 3*2.9 337.7 325-9 30*.3 305.1 Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed 315 *20 318 *20 313.2 33*. 8 302.1 269.6 325.6 299.9 30*.0 306.9 315-1 310*1 339.5 291*0 313.7 3*9.3 293.* 326.* 320.3 293.8 311-9 Slk.O 36*.0 32*.* 313-5 301-0 3*0.5 365.7 303.1 3*6.1 335.7 312*2 318 *22 326.1 330.5 302.3 276.* 315.1 30T.9 30*.3 313.2 307.7 316.1 336.2 293.0 306.3 3*5-8 298.5 32*.3 33*.T 296.0 31*>5 313.3' 372.2 319-5 320.9 301.* 338.2 367.6 307.7 Stf 310.0 325.1 333.9 305.8 263.7 323.2 299.* 302.3 315.8 310.8 319-9 33**2 306.5 316.2 35*.0 299.6 328.3 339*0 302.3 313.6 316.9 371.8 318.* 320.0 302.9 3*1.1 366.3 311*1 352.6 328.6 309.* as _ 320 *21 322 *20 319-* 3*0.3 305*1 283.0 331.6 31k.8 307-* 310.3 305-3 326.6 3Z7.T 298.* 319.* 339.9 306.2 337-* 329.5 318.3 322.3 339.6 376.* 333.5 31T.5 316.0 3*6.* 366.7 305.6 3*6.3 329.8 313.1 32* *20 328.6 3S1.T 9.5 269.5 332-5 32*.2 310.3 31*.* 321.3 3**-9 303.1 298.* 326.1 363-8 306.9 335.0 361.6 306.5 3*6.0 330.2 375.1 329.8 330.1 318.5 352.0 369.1 312.7 357.* 3*1.1 308.8 fc* 330 *22 326.* 3*8.* 316.5 287.3 33*.5 306.2 316.8 316.5 321.8 32k.6 365-9 307.2 323.* 361.0 308.7 3*5.* 35*.7 316.3 329-2 327.9 38*.T 335.7 316.3 309.3 350.3 377.5 318.* 370.* 355-2 32k.k 333 *2* 330.2 3*9.0 312.8 293.6 3*1.2 303-* 316.2 315.* 318.2 323.6 3*9.9 313.* 32*-1 363.2 307.7 3*5.7 3*5.2 307.2 322.6 327.0 363-1 339-7 326.9 318.2 3*9.1 381.3 316.8 380.6 350.9 325.0 _ 333 23 3*1.2 3*0.8 320.0 297*3 3*0.3 323.9 320.* 329-3 331.9 31*.2 351.6 31*.1 331.5 367.1 31*.2 3*9.8 3*9-1 321*8 33*-3 327.2 382.5 337.2 XJ*.8 317.7 3*9.8 387.5 312-0 362.5 33*.a 316.7 w 335 *21 no 131?81 C.ONF TDFNT I Al -251- -2XOHJ A (Continued) Mcpt muuoiOR Tarrant stodt u tk* mt* IUTi &ody Weiahti (arm) trpovure Lerel Aalaal CoP&tfrol 7*7TM^7b5e1r5 T120 T121 7122 7123 Tl21 T125 7126 T12T T12S 7129 T130 T131 7132 T133 T131 T135 T136 T13T T13S 7139 TllO TUl Tll2 TU3 Till Til; TU6 TUT T11S TU9 7150 T1S1 Tl52 T153 4M fi *S.D. JB159.V1 TSgJo7E 33S.T 371.1 3T5.5 Dead 339.0 353.1 375.0 305.X 336.3 356.9 361.9 319.3 333-6 360.5 351.3 395.S 321.1 3130 329.1 339*6 311.2 387.3 321.1 316.6 J3T-9 360.6 299.6 315.2 313.9 119.6 311.1 319.6 338.0 106.8 313.8 336.1 330.3 Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed 318 316 31 28 32811.3 316.6 356.2 367.8 T,B22KB 313.3 3U.8 370.7 326.3 335.5 356.2 357.6 385.6 335.8 31T.2 311.1 351.8 308.6 321.3 311.5 395.5 310.9 332.8 319.8 328.1 357.0 358.6 393.1 337.3 321.3 315.6 357.2 327.0 330.1 3U.2 381.8 313.5 336.7 318 319 23 421 32836.4 JU.5 311.0 36T-6 320*2 327-5 356.9 318.9 391-9 337-1 322*2 313.6 359.5 32T.6 325.1 3ll.l 388.1 336.5 332.3 3T 422 32716.9 313.3 312.T 365.0 V--It of Study T625}.^ 383.6 WqSA.T 336.8 313.1 319.6 335.5 355.3 358.0 361.2 369-3 361.8 319.6 327.0 331*1 310.9 395.8 3W.8 320.1 310.T 361.7 336.3 325.8 33T.8 381.6 335.0 328.7 316.9 321.1 355.1 315.2 393.0 362.6 336.5 339.2 367.9 313.2 311.6 337.3 382.2 330.3 321.8 321.7 332.3 361.8 319.1 398.0 356.1 328.0 318-6 366.I 315.8 312.2 36T.3 390.3 338.3 325-5 315.7 32T-1 351-0 311.3 386.1 359.3 320.1 315.1 36J.6 363.9 336.2 350.1 381.9 316.3 321.3 316 3M 351 352 421 420 422 23 3M48.1 319.0 372.2 361.T 326.6 326.3 351.3 31T.T 398.9 376.3 331.9 352.3 370.3 362.2 336.8 3W.T 379-2 319.6 321*8 345262 M2?i.l 336.8 365.0 36T-T 321*0 319.0 313.6 333.8 390.8 31T.1 320.9 369.1 3T6.1 365.1 335.5 317.2 371.9 358.9 JlO-i 34512k y7> 3 350.0 35T-T 363-3 321.6 321.5 353-3 352.7 392.3 315.0 321.1 351.0 369.1 372.9 321.1 362.8 382.3 311.8 325.9 355 426 1,a67.4. TSHT 355.8 319.8 351-1 351.1 361.0 361.0 322*0 325.6 359.0 313.6 100.1 311.0 329.6 319.1 3T1.6 353.2 320.1 353.0 386.8 31T.8 330.3 327.1 332.6 358.7 358.0 106.0 360.1 335.5 352.1 360.3 355.2 328.7 356.6 3*7.8 357.0 329.1 353 358 21 25 33-35T-150CT 291*0 311.1 331.2 -- 291*0 281.5 303.5 310.1 353.9 331.5 289.1 317.3 320.9 310.1 267.8 315.7 311.5 316.1 306.9 313 23 77.7X69 TI90 7191 7192 7193 T7119915 7196 TW 7198 7199 7500 7501 7502 7503 Tsoi 7505 7506 7507 7508 7509 T510 7511 7512 T513 7511 T5 7516 7517 7518 7519 7520 7521 7522 7523 373*0 368.3 361.1 301*1 366.6 3T1.3 351.5 305.2 390*3 371*6 322.5 319.3 370.7 338.9 397*9 321.1 365.2 381.6 351.2 368*7 393.1 357*1 338.T 375.1 371.1 353.3 323*6 333.0 362.9 333.5 38T.J 316.7 319*2 373*7 310.1 356.7 382.1 350.6 330*9 376.1 Secrlflced Sacrificed Secrlflced Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed Mt*A *&*D* 36l 25 352 23 365*9 376.1 358.8 303.1 3TT.T 359.2 331.5 326.7 353.8 339.0 382.1 320.9 353.3 391.2 315.8 361.9 391.3 310.8 330.6 361.3 -- *-- -- -- -- 351 21 351.2 368.1 319.6 317.7 372.2 312.2 3U-1 325.1 357-6 330.6 312.3 287.3 352.1 386.1 315.9 357.7 380.1 338.8 315.9 362.1 -- -- -- 318 22 361.7 371.5 317.9 313.6 361.3 338.8 312.1 327.1 356.3 315.T 380.6. 228.9b 358.0 386.0 333-T 358.1 381.9 310.6 338.9 380.2 355.1 361.1 351.3 310.5 367.8 313.9 339.8 325-T 3II.1 319.2 378.5 306.2 319.0 390.9 327.6 351.1 383.1 328.5 3l2.2 367.6 351 319 20 23 361.2 366.0 316.3 309.3 367.5 318.7 3M.5 322*8 361.2 316.5 382.3 312.0 350.T 38I.6 331.7 353.7 382.I 332.5 338.5 371.1 351 22 383.1 36T.6 35T.1 31T-3 375.5 351.9 317.5 339-6 370.5 351.8 381.3 325.3 3T9-7 387.2 331.3 339.1 399.8 330*0 351.1 373.1 359 23 396'2 369.6 311.8 311.9 380.8 350.7 338.1 328.8 371.8 356.3 385.0 320.8 366.5 388.3 329.8 375.2 396.8 331.1 315.6 378.1 358 126 383.5 383.5 351.6, 338.6 101.3 312.7 353.8 335.9 378.1 359.3 380.1 322.1 371.T 395.3 331.0 3M.5 389.1 312.1 3W.7 316.3 362 23 396.8 358.2 317.7 336.8 106.1 335.T 370.7 323.3 359*5 351.6 375.1 309.7 359.8 391.3 326.1 366.8 379.5 336.7 361.9 398.2 360 27 106.6 382.1 339.6 322*1 loS.T 3U.8 319.3 333.8 3T1.1 361.2 JI5.5 31T.5 363.1 10T.6 326.1 371.5 116.2 310.1 316.9 383.9 361 30 378.3 379*9 31k. 0 100.3 333*6 318.8 325.0 372.1 35T-9 3T3.1 308.3 362.7 390.2 325.7 316.T k06*8 331*1 310.2 381.T " 356 29 102.3 381.3 360.9 322.3 kll*k 3W.T j6k*i 33T.O 371*3 367*0 101.3 315.6 303*0 kib*6 328.3 101.5 313.9 319.2 397.9 369 331395..27s 301.1 293-1 368.1 329-0 306.1 26T.3 326.1 311.1 331.1 26T.9 33T.2 360.7 332.2 3TT.1 290.6 297.6 101.0 321 35 DO 131282 GONF TDFNTTAI -1H- TABLZ A-a (Continual) dbcpi niAiATmi rwTiLm studt n m has* MTi fgl4 Bodr Weight. (gui) miMi *"*, 77-755# 7559 T5fi0 7561 T562 7563 7566 7565 7566 7567 756# 7569 7570 7571 7572 7573 7576 7575 7576 7577 757# 7579 75#0 75#l 7582 7583 7586 7585 75#6 7587 7588 7589 7590 7591 7592 Mma +6*0. ,-i _ iltt.o 296.0 297.0 275-0 290.0 292.0 277.0 303.0 310.0 292.0 266.0 263.0 305.0 306.0 300*0 335.0 310*0 260.0 310*0 267.0 330.0 296.0 290.0 278.0 297.0 265.0 266.0 266.0 267*0 280.0 300.0 272.0 295-0 270.0 225*0 TSO 290*0 282.0 293*0 291*0 285.0 2T7.0 291*0 310.0 263.0 297.0 273-0 306.0 302.0 302*0 323.0 306.0 266.0 316.0 270*0 322*0 293.0 292*0 260.0 296.0 256.0 276.0 292*0 276.0 260.0 297.0 272.0 272.0 266.0 316.0 -2 325.6 316.0 265.0 296.0 290.0 261.0 266.0 307-0 323.0 305.0 315.0 293.0 311.0 306.0 306.0 325.0 315.0 266.0 313.0 275*0 336.0 299.0 295.0 291.0 295.0 256.0 262.0 266.0 271.0 262.0 302.0 276.0 297.0 266.0 323.0 288 222 291 *16 296 *19 332.0 298*0 295.0 267.0 290*0 267.0 302.0 336.0 305*0 312.0 290.0 308.0 301*0 306.0 332.0 313.0 265.0 317-0 271.0 325.0 293.0 292*0 266.0 305.0 265.0 275*0 307*0 276.0 269*0 300.0 275.0 279.0 296.0 331.0 326.3 307.5 296.6 295.1 295.2 286.6 292.9 305.8 362.8 300.3 318.0 289.8 313.2 306.9 308.2 335.3 316.5 285.3 323.0 287.3 319.6 296.5 303.5 290.1 315.6 275-9 271*1 302.6 279.1 290.9 311.6 276.5 278.8 309.5 330.8 299 19 302 *1# Week of Study "BE? 307.2 305.7 307.0 298.8 317.6 303.6 306.8 290.6 292.6 291.5 319.6 328.9 306.6 311.5 299.2 316.8 310.2 312.7 169.9 322*1 296.9 303.2 295.8 313.3 331.8 309.1 322.6 300.6 319.1 311.5 316.9 360.9 328.5 299*6 322.5 339*9 286.2 283.1 336.2 339.6 301.8 301.5 308.8 312.9 302*0 307.3 322.5 322.7 285.9 266.2 275.9 276.2 307.3 316.6 282.6 282.0 301.3 306.1 Sacrificed Sacrificed Sacrificed Sacrificed Sacrificed 319.3 308.0 306.1 308.7 290.1 308.7 332.8 338.T 306.5 320.0 306.6 336.0 326.3 313.5 362.1 336.6 306.1 329.9 302.3 360.0 301.7 310.0 298.2 319.5 206.0 286.3 311-9 288.9 297.7 -55TT 326.9 316.8 312.5 311.9 293-9 301.9 327.1 333.9 306.5 326.0 303.3 330-1 316.1 318.7 362.1 329.6 310.7 320.3 286.6 363.3 310.7 308.0 313-0 331.6 286.5 278.0 311.3 285.7 302.3 309 18 311 19 316 19 315 1# 325.1 313.1 310.7 316.6 297.5 307.9 333.7 336.0 312.6 322.7 306.3 336.1 320.6 323.0 360.5 323.7 320.7 326.8 269.0 366.3 306.0 313-0 306.2 336.2 288.1 266.0 310.9 296.9 316.3 318 18 10 375*5 329-7 320.6 316.1 319.7 299.8 299.2 330.1 366.5 320.1 330.3 328.0 352*7 327-0 323.5 363.2 327.0 302.8 332.5 291.6 362.3 315.0 320.5 313.6 336.6 2B1.3 285.6 312*6 291.3 309.7 -rfci in.! 323-5 313.6 323.8 303.6 320.6 330.5 331.9 338.0 3U.6 309.8 332.2 316.6 331.2 357.6 336.0 320.5 362.2 299.0 366.7 320.2 328.1 321*0 365.0 292-6 293.9 323.5 302.2 316.5 321 ZL 327 +20 377*1 335.6 327.8 320.6 310.6 302.9 309-0 338.5 353*3 329.9 367.1 323-0 360.0 333.5 332.9 366.6 166.9 311.1 139-2 291*6 352.6 321.2 331.1 327-2 337.9 296.I 296.2 317*9 295.6 312.0 Trfo 333.5 325.8 320.9 329.6 311*2 311*3 336.9 331.6 326.3 363.1 336.0 367.8 326.1 129.7 350.3 369.6 309.1 362.3 287.2 353.9 309*9 326.0 317.7 335.6 292.7 291*0 321*6 295.3 310*2 ll TTHI 137.0 331.8 319-5 331.1 307-5 313-3 332.5 369.0 331.6 351.2 320*6 366.9 130.5 326.9 376.1 363.9 319.6 369.3 288.6 361.3 316.7 335.1 329.9 369.9 292*6 299.7 325-6 300.5 315*2 15-1** , 328 21 327 +22 330 +22 77-7626 7629 7630 7631 7632 7633 7636 7635 7636 7637 7638 7639 7660 7661 7662 7663 7666 7665 7666 7667 7668 7869 7650 7651 7652 7653 7656 7655 7656 7657 7658 7659 7660 7661 7662 M**Q *8*0. 338.0 296.0 360.0 280.0 293.0 303.0 306.0 293*0 280.0 307.0 270*0 292*0 336.0 302.0 305.0 306.0 310.0 305.0 263.0 296.0 280.0 275.0 296.0 273.0 267.0 102.0 280.0 306.0 309.0 305.0 256.0 301.0 260.0 290*0 269.0 296 *21 315-0 268.0 331.0 260.0 267.0 300*0 313.0 290.0 266.0 296.0 263.0 266.0 331.0 292*0 300.0 290*0 319.0 292.0 263.0 293.0 260.0 276.0 265*0 272*0 303.0 266.0 260.0 302.0 300.0 297.0 250*0 305.0 256.0 292*0 260.0 269 too 268.0 266.0 326.0 269.0 266.0 307.0 306.0 299.0 279.0 302.0 262.0 265.0 318.0 297.0 266.0 273.0 299.0 263.0 259.0 295.0 270.0 272.0 266.0 261.0 296.0 267.0 277.0 302.0 302.0 287.0 265.0 292.0 255.0 266.0 267.0 265 *16 316.0 292*0 336.0 260.0 292*0 302.0 309.0 289.0 262.0 323.0 266.0 292.0 329.0 300*0 306.0 286.0 310*0 292.0 266.0 308.0 268.0 285.0 278.0 266.0 303.0 271*0 311.0 269*0 293.0 320*0 255.0 295.0 271*0 281.0 272.0 299.2 298.9 336.0 287.8 298.1 301.9 316.9 290.6 298.5 306.8 268.5 288.5 326.3 305.1 310.6 290.6 325-5 293.1 266.9 321*8 271*2 276.9 276.9 268.3 309.7 276.0 295.8 311.3 318.5 299.9 267.2 292*0 280.8 299.5 276.8 292 295 *20 *20 322.1 311*0 295.7 337.6 295.0 296.7 365.3 299.1 297.6 293.1 311.8 309.0 319.6 318.3 297*0 298.1 305.0 287*6 306.6 312*1 271*6 270.8 291.9 316.6 306.5 297.6 319*1 306.5 310*1 308.9 296.6 296.1 315.9 311*2 296.8 296.9 273*5 309.8 279.1 275.3 279.2 277.6 262.9 316.9 279.6 275.1 291*8 269.6 116.1 275*6 293.1 308.3 276.8 301.6 319.0 323.1 330.2 326.0 306.5 307.9 84crifled Sacrificed Sacrificed Sacrificed Sacrlflead 301 418 300 *16 310.5 306.9 336.9 297.9 291.7 310.0 320.9 302.6 299.6 312.6 273*9 299.3 321.8 310.8 315.3 302.6 317-7 316.8 270.0 310.8 280.6 280.7 280.3 276.1 315.8 276.6 301.3 325.2 317.3 312.6 --* -- 303 417 302.8 301.7 361.7 295.3 289.2 310*1 321.6 305.0 306.0 320*1 260.5 298.6 338.8 311.7 310.7 316.0 317-1 303.5 276.7 320*1 278.6 282.7 288.8 281.5 310.7 273.6 296.9 317.9 326.7 313.0 4P 306 418 328.5 303.3 362.1 300.6 299*6 319.3 330.9 311.3 308.5 330*1 283.2 306.6 337.3 316.3 317.0 302.6 113-1 306.7 279.1 321.0 291.6 287.5 288.5 291.5 317.2 275*6 307.8 330.1 320.9 316.9 -- 309 417 320.8 308.5 367.7 300.9 299.5 305-3 326.1 313.3 309.6 325.7 277.9 305.9 329-0 326.6 322.1 301.9 323*0 305.5 279.3 318.3 282.1 286.5 295.3 280.1 118.3 272*6 303.3 330*3 322.8 319.3 -- *4* 308 *16 323.1 316.3 355.3 306,7 306.1 326.7 366.O 316.2 316.6 315.7 286.6 313-7 365.8 336.2 321.8 306.3 31T.6 310.T 283*6 330.1 288.2 292.6 306.6 287.9 319.0 286.6 308.9 329.7 330.2 322-7 -- 315 419 326.3 306.7 369.7 308.6 310.1 328.0 115.7 315.5 117.7 332.6 282.0 310.5 350.6 327.3 336.5 309.5 J23.T 316.6 301.1 326.5 290.8 296.8 303.5 287.3 320.3 300.1 307.5 326.2 331.8 U6.8 --* -- 317 417 328.3 326.3 353.9 313.8 310.9 329.6 360.6 313.3 316.5 336.6 283.5 317.1 358.1 136.6 332.2 321.2 321.7 316.3 295.2 335.0 296.5 289*2 299.9 290.3 323.5 291*1 JOT. 2 329.6 336.9 326.1 ** -- 319 419 325.3 331.7 363.9 316.5 317.0 332.0 367.3 316.3 318.1 335-7 267.8 316.1 353-0 361.6 327.6 332.0 320.9 323-2 288.2 336.6 307.8 296.8 300*3 298.3 328.6 287.7 311.8 366.6 339.2 322.8 -- -- 322 *20 no 131? 8 3 CONFIDFNTIAt -2JJ- TAJLLK A-2 (Coetlcuad) CBCF: mrAMTIPl fPTIUTT STUD! IV ffX AATf MT; feaala Bodr tfalihrta (gw) Cxpooun Laval InInal gp* i*o W-7558 7959 7560 7561 7569 7563 756* 7565 7566 T56T 7568 7569 7570 7571 7579 7573 757* 7575 T5T6 T5TT 7578 7579 7580 7581 7589 7583 758* 7585 7586 7587 7588 7589 7590 7591 7599 Tjb 90 -sinr 351.0 371*3 365.7 351*9 363.9 355*1 369-3 3**-5 365.1 3*9.5 3*5.8 13*.1 36*.k 378.3 369.7 371.* 361,1 363.6 399.7 388.* 3*3.6 331.5 170.8 361.9 360.9 360.9 169.* 360.1 375*3 357.* 379*1 377*0 1*1. T 356.T *0*-9 383.5 307.* 308.3 Saerlflead ufUled Sacrificed aorlfload Sacrificed Saerlflead Baerlflenl Saerlflead Sacrificed Saerlflead Saerlflead Saerlflead Saerlflead Saerlflead herlflctd Tb 379-9 3*6-3 355.0 1*1.9 1*T.6 >3.5 369.8 377*3 360.0 387.3 3*1.3 367.5 353.9 353.9 36*.9 38**0 3*T.9 391-9 303.8 368.7 359.5 350.7 3*8.5 359.9 335.* 3*6.0 376.T 369.* 385.3 3*9.8 366.1 553*3 35*.6 363-7 381.9 3*3.T 301-0 sir.* Th 360*0 35*. 3 352-3 3*6.9 331*3 331*5 359.T 37**1 35T-3 3T*-3 3*1.3 369.1 359.9 3*T.* 370*3 316.5 3*6.5 369.9 312*1 *. VKS 360.8 3*9.6 3*T.O 3*5-7 335.* 3*2.0 3*7.8 378.5 359.0 383.9 3*0.* 375.1 359*9 3*%.* 365.9 389.8 3*9.7 ITS.* 30*.7 VHk Of study -*ihr Tint -reta 353*2 3*9.9 1*5.7 339*7 339*1 399.9 338.8 378.9 351*3 381.1 355.* 369.0 351.8 352-9 365.T 387.3 329-1 368.1 301.6 395.* 359*7 359.1 3*5.8 339.T 3*0.6 3*9-7 398-7 363.6 38*.6 379.5 361.8 159.9 3*9.9 369.5 *0k.6 3*1.8 181.0 301.1 153.* 157.9 350.9 3*7.8 3*6.5 337.8 11**7 397.8 *91.0 17*. 1 369.1 389.8 350.3 3*5.9 390-5 383.9 363.3 373-9 306.2 _ __ -20-- 11475 356.T 167.1 3*6.* 1*7.* 310.6 3*0.0 3*1.5 *16.8 176.7 319.0 15*0 363.* 353.5 359.5 375-0 *06.1 3*5*0 381.5 299-* -sib 35*.a 385.3 1*6.7 1*0.2 3*1.7 3*90 326.9 390.3 367*9 371*2 3*9.6 375 0 366.2 3Ual 372-0 *30.9 329*6 381.0 >99*2 _ 30wSTT 357*3 389.1 3*9.5 3590 3*5-2 369.6 310.1 396.0 383.1 378-* 3360 378.8 176.1 3*6.1 378.1 391*3 336.6 501.6 299.0 _ mm mm n lo}75 356.2 370*2 3*50 3550 36T.6 351-8 3*1.5 *07.* 381.6 38**0 3*5-1 393-* 379-7 3*90 187.6 399.6 1390 383-* 109.9 -""iSbi 357-9 373*7 3*5.* 357.* 37*.1 3**.6 339-0 *09.7 380.8 379*3 337*0 3820 370.1 3*9-T 377.8 116.8 335.2 335.T 303.9 389.2 ' 312.5 33*0 258.6 275*1 1*5-8 261.6 Dead 297.0 311.6 31T.6 3*7.0 33*.0 299-7 263.1 132.6 287.1 3*3-6 251-2 _ -- an _ _ ' _ _ fe. _ -- _ Haaa 15- D. 77-7620 7629 T630 7631 1632 T633 763* T635 7636 T63T 7636 T639 76*0 76*1 T6*2 76*3 76** 76*5 76*6 T6*T 76*8 76*9 7650 T651 1652 7653 765* 7655 7656 7657 7658 7659 7660 7661 7669 366 195 361 336.6 35*. 1 386.8 3330 331.8 33**8 361.2 395-2 333.* 3*5.1 307.7 335.* *02.9 3*5.* 3*0.6 3*1.8 390.8 327.* 337.6 357.8 32TO 3280 352.8 303.9 336.3 385.0 3*9.9 369.* 3*0.8 390.3 333.* 393.6 3*5-1 359.9 396.2 388.0 337.* 30*.6 363-T 3*80 Sueriflead Saerlflead Saerlflead Sacrificed Saerlflead Saerlflead Sacrificed flaerifle ad Sueriflead Sacrificed 5acriflead Saerlflead Sacrificed Saerlflead Saerlflead 361 +23 3*90 3*5.1 337.7 385*1 326.6 290.9 36*.T 3300 329.1 352.T 3010 25*0 395.9 355.1 350.9 3*1-6 3790 3**.3 301.1 353-7 359 19 333.T 33.6 331.2 386.1 326.9 337-9 36*0 3380 3*0.2 353.* 303.0 2T*-0 378.8 3*6.2 35*. 7 1*0.* 373.6 3*T.* 2990 3*8.3 356 19 337-6 3370 338.1 3810 321.2 3*5*0 373.9 3*2.6 3*10 369.0 299.1 1230 37*.2 3*9.0 350.1 355-6 380.6 1*6.7 3020 3*6.1 358 199 3*0.1 3*2-9 33*.8 386.9 326.2 1*7.9 36*0 338.* 3320 356.1 296.6 321.6 3750 3*8.0 3*1-9 3*8.3 378.3 1*3.9 300.1 315-T 35* 93 360.1 325-6 335.9 391-9 3290 1*7.6 35*.T 1*0.9 3390 362.6 100.2 326.2 186.2 350.7 350.1 3*8.9 391.8 3*0.8 977.8 3*50 363 96 375*0 135.6 331*T 395.* 311-7 353*7 3710 3*5.6 339-0 396.5 3010 326.9 3910 310.0 352.1 3510 *16.* 1*2.5 31*.* 3*2.1 365 97 3*0.0 335.1 325*8 *0*.T 325*6 35*.0 376.3 1*8-7 325.9 385.8 302.6 1150 *11-9 1T1.9 3510 353.6 39*.* 1*8.3 309.8 3*6.9 36* 98 36*0 3*TO 331.6 399-1 3*6.1 35*0 395.* 1*6.9 331.6 *07-2 305.6 336.9 *10.* 3T0.1 1530 3550 1860 336.0 307.6 3*7.* 369 30 3*2-9 355.* 1300 *0*.9 356.6 3650 *03.1 3*0.3 328.9 385.1 325*0 3230 *11-9 3790 3*9.8 362.9 *0T.0 3930 300.6 3*6.2 36* 96 3TT.0 3560 *02.* 327.9 3*8.9 390.* *26.3 3*30 35*0 3T9.2 3100 323.8 *25.2 368.0 3730 3TSO *11.6 350.8 3020 3*6.6 369 +26 3*70 1*60 *00.7 3260 1*5-8 --4 *69.2 3**. 2 360.0 380.6 309.0 330.6 *1*.9 358.0 37*.1 359.1 *13.* 355.6 319.2 350.8 36* 229 367.1 158.1 326.9 *03-5 139.* d 522.0* 3*5-9 3*8.5 3820 309.0 339*8 **1.T 371-1 369.0 36*0 396.8 357*2 333.6 35*0 .295 61 no.o X>*-S 3*5-0 309-0 0W4 2106*9.0* 371-9 975-9 997.1 389.1 108.5 315-* 39*. 7 38*.* 369.0 967.9 989-3 Maau 3*8 18.D. 19* 3*k 19* 3*0 3*1 3*5 1*3 1*6 15* 111 197 193 111 195 110 159 HO 157 130 359 HI 365 135 165 119 361 131 tta*l* TMta Pod to 0, 0.1, 1.0, or 10 nm of MOT for 6 hr/doy, 5 feya/aoak for 1* Mki aapoaun parlod, anlaala van aliUlMf lo tko Laboratory for neoniy. following tarwlaatlow of tfo rwlta m-a Oral to laiazpoaod felo rat. ferine * 15, 16, ao 39 . 33 of tba pat-oapaun print. Curiae vaaka 16, IT. 18 and 33 , 3*. 35 faoaloa van Pfeaant and duo to dalivar tkoir mine. ody wldkta tofeao dorlaa tbooo waoka an tharaftm aat nprtad. tStatlatleal fetllor Idantlflad by aaquantlal eutllor toat, alpha - 0-01; ralua aot lntludad. evaluaa tor tha *oth wak rap-vaant raatad body vaichta takM ja-lor to oaeropy, difo --ltfcrt takan. 321 136 T31?84 conftdfnttai 256- Animal Number Male TABLE A-3 DBCFi INHALATION FERTILITY STUDY IN THE RATr Individual Observations Made at the Tima of Necropsy of Unexpcreed Female Rata Mated with DBCP-Exposed Males Week of Studyi 2 Exposure Leveli 0 ppm Ear Number Male Ear Number Female Corpora Lutea Implantations A Pre-imp Resorptions Loss A Post-; Loss 77-7469 7470 7471 7472 7473 7474 7475 7476 7477 7478 7479 7480 7481 7482 7483 7484 7485 7486 7487 7488 1019 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1032 1033 1034 1035 1036 1037 1182 1039 1040 Mean * S. D. 1501 1502 1503 1504 1505 1506 1507 1508 1509 1510 1511 1512 1513 1514 1515 1516 1517 1518 1519 1520 1521 1522 1523 1524 1525 1526 1527 1528 1529 1530 1531 1532 1533 1534 1535 1536 1537 1538 1539 1540 15 - , 14 non-pregnant 14 16 16 . 14 16 19 non-pregnant 17 12 15 16 non-pregnant 15 16 non-pregnant 14 13 12 17 18 13 non-pregnant 15 14 13 12 11 13 non-pregnant non-pregnant 14 16 16 16 12 18 16 15*2 15 14 14 16 16 14 15 17 17 12 15 16 16 15 1 15 14 13 15 11 14 15 13 12 12 11 11 15 12 15 12 18 12 14*2 2 0 0 2 3 0 0 3 1 3 0 1 0 0 0 2 4 2 2 0 1 0 1 2 1 3 3 2 0 0 0 0 1.1*1.2 0 0 0 3 10 0 0 0 6 46 12 16 7 4 0 15 21 16 3 12 8*11 6 0 16 0 18 16 3 0 0 0 22 16 0 4 12 9 27 18 0 0 8*9 Total fertile males - 20 Total fertile males iropregnanting two females " 13 DO 131P85 00NFTDFN7 TAl -257. Animal Number Hale TABLE A-3 (Continued) DBCP: INHALATION FERTILITY STUDY IN THE RAT1, Individual observations Made at the Tima of Necropsy of Unexposed Female Rats Mated with fioc-'P-Exposed Males Week of Study: 2 Exposure Level: 0.1 ppm Ear Number Male Ear Number Female Corpora Lutea implantations X Pre-imp Resorptions Loss Posit-imp Loss 77-7539 7540 7541 7542 7543 7544 7545 7546 7547 7548 7549 7550 7551 7552 7553 7554 7698 7555 7556 7557 1057 1058 1059 1060 1062 1063 1064 1065 1066 1068 1069 1070 1072 1073 1074 1075 1175 1077 1078 1181 1541 1542 1543 1544 1545 1546 1547 1548 1549 1550 1551 1552 1553 1554 1555 1556 1557 1558 1559 1560 1561 1562 1563 1564 1565 1566 1567 1568 1569 1570 1571 1572 1573 1574 1500 1576 1577 1578 1579 1580 15 non-pregnant 15 16 16 16 non-pregnant 15 13 13 non-pregnant 16 16 killed, animal out of water killed, animal out of water non-pregnant 14 14 13 13 13 13 killed, animal out of water killed, animal out of water 13 13 11 11 15 15 non-pregnant 12 12 13 15 13 13 12 non-pregnant 13 12 13 14 13 non-pregnant 13 non-pregnant 14 15 16 11 13 16 13 15 13 11 non-pregnant 11 14 14 non-pregnant 16 16 15 14 1 0 2 1 1 2 0 0 1 0 2 0 1 1 0 2 0 1 1 0 1 1 1 1 1 0 07 1 36 08 06 0 14 00 1 04 1 0 13 04 04 0 IS 70 07 03 16 8 09 07 43 Mean S. D. 142 141 0. 90.6 24 64 Total fertile males 18 Total fertile males Impregnating two females 8 no i3i;>86 CONFIDENTI A! -258- TABLE A-3 (Continued) DBCP: INHALATION FERTILITY STUDY IN THE RATf Individual observations Made at the Time of Necropsy of Unexposed Female Rata Hated with DBCP-Exposed Males Week of Studyt 2 Exposure Levelt 1.0 ppm Animal Number Male Ear Number Male Ear Number Female Corpora Lutea Implantations Resorptions X Pre-imp Loss X Post-imp Loss 77-7608 7609 7610 7611 7612 7613 7614 7615 7616 7617 7618 7619 7620 7621 7622 7623 7624 7625 7626 7627 1097 . 1581 1582 1098 1583 1584 1099 1585 1586 1100 1587 1588 1101 1589 1590 1102 1591 1592 1103 1593 1594 1104 1595 1596 1105 1597 1598 1106 1599 1107 1600 1601 1602 1110 1603 1604 1111 1605 1606 1112 1607 1608 1113 1609 1610 1114 1611 1612 1115 1613 1614 1116 1615 1616 1117 1617 1618 1118 1619 1620 Mean S. D. 16 16 17 17 18 non-pregnant 18 13 13 18 18 15 14 non-pregnant 13 12 13 13 killed, animal out of water killed, animal out of water 18 18 13 12 12 12 13 13 17 17 non-pregnant 14 8 11 13 17 17 non-pregnant non-pregnant non-pregnant non-pregnant 19 13 12 4 non-pregnant non-pregnant 15 17 15 7 13 14 11 1 15 14 12 12 non-pregnant 10 5 16 11 15 15 15 IS 0 0 1 1 2 1 0 1 0 0 0 3 0 1 1 1 0 0 0 0 0 1 0 1 3 2 0 0 15*2 13*4 0.6*0.7 Total fertile males - 18 Total fertile males Impregnating two females - 10 0 0 0 7 4 4 0 0 22 0 32 67 0 26 49 0 40 0 16*22 0 6 10 7 4 0 12 0 10 6 0 0 0 0 50 8 39 0 8*14 00 131?87 CONFTDFNTTAl -259- TABLE A-3 (Continued) DBCP: INHALATION FERTILITY STUDY IN THE RAT* Individual Observations Made at the Time of Necropsy of Unexposed Female Rats Hated with DBCP-Exposed Males Week of Study: 2 Exposure Level: 10 ppm Animal Number Male Ear Number Male Ear Number Female Corpora Lutea implantations Resorptions X Pre-imp Loss X Post-imp Loss 77-7678 7679 7680 7681 7682 7683 7684 7685 7686 7687 7688 7689 7690 7691 7692 7693 7694 7695 7696 7697 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 Mean A S. D. 1621 1622 1623 1624 1625 1626 1627 1628 1629 1630 1631 1632 1633 1634 1635 1636 1637 1638 1639 1640 1641 1642 1643 1644 1645 1646 1647 1648 1649 1650 1651 1652 1653 1654 1655 1656 1657 1658 1659 1660 16 non-pregnant 13 non-pregnant 14 16 17 non-pregnant 11 12 13 13 non-pregnant 14 10 15 12 non-pregnant 17 14 15 15 16 15 16 17 12 14 non-pregnant non-pregnant 15 18 non-pregnant 17 11 12 16 17 non-pregnant 11 IS 13 16 16 14 11 13 11 13 12 10 15 12 17 14 15 14 16 14 16 13 10 11 14 18 17 11 7 16 14 10 14*2 13*2 0 1 4 4 2 2 1 2 0 0 0 1 0 0 0 1 3 0 3 0 1 0 0 0 1 2 0 1 0 1 2 1.0*1.0 6 0 0 18 0 8 14 0 0 0 4 4 12 19 4 0 21 9 9 7*7 0 8 25 14 13 9 0 4 0 0 14 10 4 0 3 12 7 4 20 8*7 Total fertile males 19 Total fertile males impregnating two females * 12 ^Male rats were exposed to 0, 0.1, 1.0, or 10 ppm of EBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. Each exposed male was housed with 2 unexposed females for a 7-day breeding period during the 2nd week of the study. aData inadvertantly were not recorded. The average values for the two female rats bred to each male were calculated. Group means were then calculated from these averaged values. DO 101788 OONF IDFNT TAt 260- TABLEA-4 dbcp: inhalation fertility study in the rat1" Individual Observations Made at the Time of Necropsy of Unexpoaaa Female Rata Mated wltft DBCP-Expoaed Malea week of Studys 4 Exposure Levelt 0 ppm Animal Number Hale Ear Number Male Ear Number Female Corpora Lutea Implantations Resorptions X Pre-imp Loss A Post-imp Loss 77-7469 7470 7471 7472 7473 7474 7475 7476 7477 7478 7479 7480 7481 7482 7483 7484 7485 7486 7487 7488 1019 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1032 1033 1034 1035 1036 1037 1182 1039 1040 Mean S. D. 1661 1662 1663 1664 1665 1666 1667 1668 1669 1670 1671 1672 1673 1674 1675 1676 1677 1678 1679 1680 1681 1682 1683 1684 1685 1686 1687 1688 1689 1690 1691 1692 1693 1694 1695 1696 1697 1698 1699 1700 13 18 13 13 15 16 15 16 non-pregnant 19 14 16 19 20 13 16 15 12 non-pregnant 18 12 17 13 non-pregnant 12 non-pregnant 16 15 15 14 14 15 13 non-pregnant 18 15 15 14 16 12 152 12 15 13 11 14 16 11 16 17 14 18 15 18 5 14 15 12 15 14 12 14 5 12 13 15 15 14 13 9 16 13 15 14 14 12 133 Total fertile males - 20 Total fertile males impregnating two females 15 1 1 2 1 1 0 0 0 0 1 0 0 0 0 2 0 0 1 0 1 0 0 2 1 0 0 0 1 0 1 1 1 2 0 1 060.6 12 8 4 14 10 0 16 37 0 17 14 0 58 19 0 6 31 12 0 6 1314 8 12 4 0 0 4 0 7 0 7 4 0 0 12 0 4 0 7 10 4 44 DO 131?89 FONFTDFNTTAl -261. TABLE A-4 (Continued) DBCPt INHALATION FERTILITY STUDY IN THE RAT* Individual Observations Made at the Ting of Necropsy of Unexposed Female Rats Mated with DBCP-Exposed Males Week of Studyi 4 Exposure Level: 0.1 ppm Animal Number Male Ear Number Male Ear Number Female Corpora Lutea Implantations Resorptions A Pre-imp Loss X Post-imp Loss 77-7539 7540 7541 7542 7543 7544 7545 7546 7547 7548 7549 7550 7551 7552 7553 7554 7698 7555 7556 75S7 1057 1058 1059 1060 1062 1063 1064 1065 1066 1068 1069 1070 1072 1073 1074 1075 1175 1077 1078 1181 Mean S. D. 1701 1702 1703 1704 1705 1706 1707 1708 1709 1710 1711 1712 1713 1714 1715 1716 1717 1718 1719 1720 1721 1722 1723 1724 1725 1726 1727 1728 1729 1730 1731 1732 1733 1734 1735 1736 1737 1738 1739 1740 18 non-pregnant non-pregnant non-pregnant 16 14 12 non-pregnant 16 17 14 13 13 15 non-pregnant 13 17 16 14 18 15 21 14 15 non-pregnant 16 13 15 15 15 16 16 14 non-pregnant 14 18 15 12 13 15 152 18 17 10 12 12 16 13 13 12 13 5 18 16 14 13 14 17 14 15 16 13 14 14 15 16 14 11 8 14 16 13 16 14 143 Total fertile males 19 Total fertile males impregnating two females * 14 0 0 1 2 0 1 0 0 0 1 0 0 0 0 2 2 0 0 0 1 0 1 1 1 4 1 2 7 0 0 1 2 1 0.91.0 00 14 0 16 4 10 62 0 14 13 0 0 4 4 6 21 32 0 4 1115 5 17 3 0 4 0 0 8 7 0 6 4 7 16 18 44 4 10 810 no 131?90 OONFTDFNTTAl  1 , / 1 i * , 1 j 1 i -262- * Animal Number Male TABLE A-4 (Continued) DBCP: INHALATION FERTILITY STUDY IN THE RAT* Individual Observations Made at the Time of necropsy of Unexposed Female Hats Mated with DBCF-Exposed Males Week of Study: 4 Exposure Level: 1.0 ppm Ear Number Male Ear Number Female Corpora Lutea Implantations Resorptions X Pre-imp Loss X Post-imp Loss 77-7608 7609 7610 7611 7612 7613 7614 7615 7616 7617 7618 7619 7620 7621 7622 7623 7624 7625 7626 7627 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1110 1111 1112 1113 1114 1115 1116 1117 1118 Mean * S. D. 1741 1742 1743 1744 1745 1746 1747 1748 1749 1750 1751 1752 1756 1757 1758 1759 1760 1761 1762 1763 1764 1765 1753 1754 1766 1767 1768 1769 1770 1771 1772 1773 1774 1775 1776 1777 1778 1779 1780 1781 non-pregnant 17 14 19 15 14 18 14 non-pregnant 16 15 non-pregnant 15 12 non-pregnant non-pregnant 12 14 16 non-pregnant 13 18 13 16 non-pregnant 16 non-pregnant 14 15 non-pregnant non-pregnant 15 14 non-pregnant 15 non-pregnant 16 17 11 14 15*1 17 11 8 16 15 17 15 16 14 15 13 16 14 15 12 16 13 15 14 14 13 14 14 16 18 16 15 15 15*2 3 1 6 1 0 0 2 2 0 1 0 2 1 0 1 0 0 1 0 0 0 1 1 1 2 0 1 1 0.9*1.0 0 40 0 3 0 7 0 0 6 10 3 12 0 13 7 0 0 3 0 5*9 18 42 3 6 12 0 4 10 0 4 4 0 0 0 7 7 6 6 7 7*10 Total fertile males 19 Total fertile males impregnating two females " 9 DO 131?91 CONFTDFNTTAI -263' TABLE A-4 (Continued) DBCP: INHALATION FERTILITY STUDY IN THE RAT* Individual Observations Made at the Tine of Necropsy of unexposed Female Rata Mated wltn DBCP-Exposed Males Week of Study: 4 Exposure Level: 10 ppm Animal Number Hale Ear Number Hale 77-7678 7679 7680 7681 7682 7683 7684 7685 7686 7687 7688 7689 7690 7691 7692 7693 7694 7695 7696 7697 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 Mean a S. D. Ear Number Female Corpora Lutea implantations 1782 1783 1784 1785 1786 1787 1788 1789 1790 1791 1792 1793 1794 1795 1796 1797 1798 1799 1800 1801 1802 1803 1804 1805 1806 1807 1808 1809 1810 1811 1812 1813 1814 1815 1816 1817 1818 1819 1820 1821 11 15 non-pregnant 14 20 12 non-pregnant 10 17 16 non-pregnant 14 13 16 15 15 19 non-pregnant 13 13 non-pregnant non-pregnant non-pregnant 13 14 13 19 non-pregnant 15 non-pregnant 13 non-pregnant 18 18 14 15 14 14 11 13 14*2 9 15 11 16 12 3 16 16 14 12 12 12 11 14 13 14 11 15 14 15 15 13 13 17 11 16 14 13 11 8 13*3 Resorptions X Pre- imp Loss 0 0 1 1 1 0 7 0 0 1 4 3 2 1 3 2 1 1 3 2 6 2 2 2 0 2 3 0 0 0 1.6*1.4 9 21 10 70 3 0 16 24 26 0 15 0 21 0 0 17 10 4 19 14*16 1 Post-imp ' Loss 1 0 9 7 0 22 0 20 22 7 1 18 9 14 13 40 15 14 6 10 0 12*10 Total fertile males 19 Total fertile males Impregnating two females 11 fMale rats were exposed to 0, 0.1, 1.0, or 10 ppm of EBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. Each exposed male was housed with 2 unexposed females for a 7-day breeding period during the 4th v^ek of the study. The average values for the two female rats bred to each male were calculated. Group means were then calculated from these averaged values. DO 131?92 C0NFI0FNT1 Ai -26*' Animal Number Hale TABLE A-5 DBCPt INHALATION FERTILITY STUDY IN THE RATf Individual Observations Hade at the Time of Necropsy of Unexpoaed Female Rats Hated with DBCP-fexposed hales week of Study: 7 Exposure Level: 0 ppm Ear Number Male Ear Number Female Corpora Lutea Implantations Resorptions X Pre-imp Loss X Post-imp Loss 77-7469 7470 7471 7472 7473 7474 7475 7476 7477 7478 7479 7480 7481 7482 7483 7484 7485 7486 7487 7488 1019 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1032 1033 1034 1035 1036 1037 1182 1039 1040 Mean 1 S. D. 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 B16 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 17 16 17 15 14 non-pregnant 15 12 12 15 17 non-pregnant 14 13 non-pregnant 17 non-pregnant 16 non-pregnant 16 14 13 non-pregnant 17 14 17 16 non-pregnant 15 16 15 15 16 14 15 16 14 18 18 15 16H 16 15 19 14 14 16 11 15 13 15 13 15 17 16 15 12 12 13 13 17 13 15 9 15 15 13 17 15 17 IS 17 18 15 1511 Total fertile males - 20 Total fertile males impregnating two females 13 1 2 1 0 0 3 0 3 1 0 2 2 1 1 1 0 0 2 1 0 3 4 0 0 1 1 0 1 0 1 0 3 0 1.10.8 6 4 0 4 6 12 4 0 0 6 11 24 4 19 22 0 10 0 3 0 717 10 2 0 10 14 0 14 6 6 7 0 15 4 23 14 4 4 4 4 8 716 DO 131? 9 3 0 ONFTDFNTTA! 265- TABLE A-5 (Continued) DBCP: INHALATION FERTILITY STUDY IN THE RAT1' Individual Observations Made at the Time of Necropsy of Unexposed Female Rats Mated wifcn DBUF-Exposed waxes Week of Study: 7 Exposure Level: 0.1 ppm Animal Number Hale Ear Number Male Ear Number Female Corpora Lutea Implantations Assorptions A Pre-imp Loss X Post-imp Loss 77-7539 7540 7541 7542 7543 7544 7545 7546 7547 7548 7549 7550 7551 7552 7553 7554 7698 7555 7556 7557 1057 1058 1059 1060 1062 1063 1064 1065 1066 1068 1069 1070 1072 1073 1074 1075 1175 1077 1078 1181 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 17 non-pregnant 16 15 17 non-pregnant 15 non-pregnant 16 18 14 14 14 14 15 14 15 14 12 non-pregnant 14 12 non-pregnant non-pregnant 16 16 17 15 non-pregnant 14 non-pregnant 14 16 14 14 14 non-pregnant IS 16 14 15 12 17 12 16 14 12 15 13 14 16 15 14 17 15 7 14 14 16 15 17 15 12 16 15 15 12 13 14 17 6 Mean S. D. 151 142 Total fertile males - 19 Total fertile males impregnating two females - 12 2 1 0 2 0 0 2 2 1 3 1 3 0 1 0 4 1 0 0 0 1 1 1 1 1 1 2 1 0 2 1 1.20.9 12 13 12 4 29 17 00 22 8 4 10 0 14 0 10 03 42 57 04 3 0 14 0 3 10 7 28 1012 0 6 8 6 7 12 0 14 1012 00 731094 COfVF Tr>FNTTAt -266- Animal Number Hale TABLE A-5 (C ntinued) DBCP: INHALATION FERTILITY STUDY IN THE RAT* Individual Observations Made at the Time of Necropsy of 0ne*Paed Female Rata Mated with DBCP-Exposed Males Week of Study: 7 Exposure Level: 1.0 ppm Ear Number Hale Ear Number Female Corpora Lutea Implantations X Pre-imp Resorptions Loss X Post-imp Loss 77-7608 7609 7610 7611 7612 7613 7614 7615 7616 7617 7618 7619 7620 7621 7622 7623 7624 7625 7626 7627 1097 1098 1099 1100 1101 110 2 1103 1104 1105 1106 1107 1110 1111 1112 1113 1114 1115 1116 1117 1118 Mean S. D. 881 non-pregnant 882 13 883 16 884 non-pregnant 885 17 886 non-pregnant 887 17 888 15 889 16 890 17 891 16 892 16 893 12 894 13 895 non-pregnant 896 16 897 13 898 16 899 16 901 12 902 16 903 14 904 16 905 non-pregnant 906 20 907 non-pregnant 908 13 909 non-pregnant 910 13 911 15 912 15 913 12 914 15 915 14 916 non-pregnant 917 non-pregnant 918 17 919 18 920 16 921 16 11 15 17 17 14 16 14 16 5 14 11 15 13 16 14 14 15 12 9 19 15 13 12 13 14 15 15 16 16 9 16 1S2 142 2 0 0 0 1 0 1 0 1 0 0 0 0 3 2 0 2 1 2 3 0 1 0 0 3 2 0 0 0 4 0 0.910.9 15 18 60 00 44 94 34 10 80 60 0 10 67 10 10 44 22 5 16 00 10 4 6 10 06 8 22 1012 0 22 87 Total fertile male 19 Total fertile males impregnating two females " 12 HO 13.1795 OONFTDFNTTA1 -267- TABLE A-S {Continued) DBCPi INHALATION FERTILITY STUDY IN THE RAT1, Individual Observations Made at the Tima oC Necropsy of Uncxposed Female Rata Mated with PBCP-^xposed Males' Week of Study: 7 Exposure Level: 10 ppm Animal Number Male Ear Number Male Ear Number Female Corpora Lutea implantations X Pre-imp Resorptions Loss * Post- Los 77-7678 7679 7680 7681 7682 7683 7684 7685 7686 7687 7688 7689 7690 7691 7692 7693 7694 7695 7696 7697 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 Mean s. D. 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 17 15 13 15 14 14 17 15 non-pregnant 15 14 13 12 15 13 14 16 non-pregnant 18 14 12 non-pregnant 13 12 17 19 9 13 14 13 non-pregnant non-pregnant 14 12 16 16 non-pregnant 13 non-pregnant non-pregnant 14*2 13 12 13 12 12 9 16 15 15 13 13 13 11 11 9 13 13 14 13 14 3 15 19 13 14 16 13 10 11 11 13 12 13*2 1 2 0 3 1 3 2 4 4 3 2 0 3 0 2 3 6 3 5 5 0 2 3 4 3 3 1 4 3 4 0 2 2.6*1.1 22 12 10 12 25 20 3 20 0 27 4 19 14 14 26 11 19 23 14 34 0 38 38 18 6 14 0 26 0 14 18 34 25 18 8 17 13*11 21*8 Total fertile males - 18 Total fertile males impregnating two females 14 tMale rats were exposed to 0, 0.1, 1.0, or 10 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. Each exposed male was housed with 2 unexposed females for a 7-day breeding period during the 7th week of the study. * The average values for the two female rats bred to each male were calculated. Group means were then calculated from these averaged values. fii I no I31?9b OONFTDFNn At. 268- Animal Number Male TABLE A-6 DBCPt INHALATION FERTILITY STUDY IN THE RATf Individual Observations Made at the Tima of Necropsy of Unexposed Female Rata Mated with DBCP-Expoaed Males- Week of Study: 10 Exposure Level: 0 ppm Ear Number Male Ear Number Female Corpora Lutea Implantations X Pre-imp Resorptions Loss A Post-imp Loss 77-7469 7470 7471 7472 7473 7474 7475 7476 7477 7478 7479 7480 7481 7482 7483 7484 7485 7486 7487 7488 1019 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1032 1033 1034 1035 1036 1037 1182 1039 1040 Mean S. D. 1825 1826 1827 1828 1829 1830 1831 1832 1833 1834 1835 1836 1837 1838 1839 1840 1841 1842 1843 1844 1845 1846 1847 1848 1849 1850 1851 1852 1853 1854 1855 1856 1857 1858 1859 1860 1861 1862 1863 1864 10 non-pregnant 15 16 non-pregnant 13 15 16 12 13 14 14 14 15 15 12 16 15 15 13 13 16 non-pregnant 18 16 13 non-pregnant non-pregnant 12 17 15 11 16 non-pregnant 12 non-pregnant 10 14 non-pregnant 11 14*2 9 16 15 13 15 14 10 13 14 10 13 15 13 1 14 13 16 13 13 13 16 15 13 12 18 15 11 15 12 10 14 6 13*3 Total fertile males - 19 Total fertile males impregnating two females - 13 0 0 1 1 4 0 1 0 0 0 1 1 1 0 0 1 2 0 0 2 1 0 1 0 1 0 1 0 1 1 0 0 0.6*0.5 10 3 0 6 8 14 4 10 12 0 10 11 3 0 0 6 0 0 45 7*10 0 4 8 14 5 0 8 4 4 6 8 6 4 3 4 0 8 5 0 5*4 00 131097 CONFTDFNT 1 Al 269 TABLE A-6 (Continued) C6CP: INHALATION FERTILITY STUDY IN THE RAT* Individual Observations Hade at the Time of Necropsy of Dnexposed Female Rata" Mated with DBCP-Exposed Males Week of Study* 10 Exposure Level* 0.1 ppm Animal Number Male Ear Number Male Ear Number Female Corpora Lutea Implantations A Pre-imp Resorptions Loss X Post-imp Loss 77-7S39 7540 7541 7542 7543 7544 7545 7546 7547 7548 7549 7550 7551 7552 7553 7554 7698 7555 7556 7557 1057 1058 1059 1060 1062 1063 1064 1065 1066 1068 1069 1070 1072 1073 1074 1075 1175 1077 1078 1181 Mean S. D. 1865 1866 1867 1868 1869 1870 1871 1872 1873 1874 1875 1876 1877 1878 1879 1880 1881 1882 1883 1884 1885 1886 1887 1888 1889 1890 1891 1892 1893 1894 1895 1896 1897 1898 1899 1900 1901 1902 1903 1904 17 14 17 14 13 14 20 25 non-pregnant non-pregnant 14 13 15 12 14 15 16 12 16 8 16 15 17 13 14 13 15 18 non^pregnant 14 15 14 15 11 16 15 13 15 non-pregnant 16 152 14 13 16 14 12 14 10 16 14 13 15 12 12 14 14 IS 15 4 14 14 17 13 13 13 14 18 14 15 14 13 14 14 15 14 17 16 141 1 2 1 1 1 0 1 0 1 1 2 0 1 0 0 1 2 0 0 0 1 1 0 0 0 0 1 0 3 0 0 0 2 2 0 1 0.70.5 12 3 4 43 0 0 10 6 28 10 0 4 4 0 0 6 6 0 0 711 11 6 4 5 8 6 4 4 6 0 7 0 0 7 10 0 6 7 6 53 Total fertile males 19 Total fertile males impregnating two females 17 DO 131?98 OONFTDFNTTAl 270- Animal Number Male TABLE A-6 (Continued) DBCP: INHALATION FERTILITY STUDY IN THE RAT* Individual Observations Made at the Tine of Necropsy of Unexpoaea female Rata Mateo witn DuC^-Exposed wales Week of Studyt 10 Exposure Leveli 1.0 ppm Ear Number Male Ear Number Female Corpora Lutea implantations X Pre-imp Resorptions Loss X Post-imp Loss 77-7608 7609 7610 7611 7612 7613 7614 7615 7616 7617 7618 7619 7620 7621 7622 7623 7624 7625 7626 7627 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1110 1111 1112 1113 1114 1115 1116 1117 1118 Mean S. D. 1905 1906 1907 1908 1909 1911 1912 1913 1914 1915 1916 1917 1918 1919 1920 1921 1922 1923 1924 1925 1926 1927 1928 1929 1930 1931 1932 1933 1934 1935 1936 1937 1938 1939 1940 1941 1942 1943 1944 1945 16 non-pregnant 25 non-pregnant 13 17 15 16 16 12 13 16 16 20 non-pregnant non-pregnant 17 16 14 17 13 14 15 non-pregnant 15 13 18 16 14 11 11 17 17 non-pregnant 10 12 11 12 non-pregnant non-pregnent 153 17 13 11 15 14 15 9 13 12 13 14 9 18 16 14 16 15 3 12 14 14 16 16 14 12 13 17 16 11 11 12 12 132 O' 0 2 48 0 14 2 06 1 0 22 0 1 14 1 0 34 5 00 0 03 0 2 39 0 0 20 04 0 06 0 20 1 00 0 26 04 1 20 1 0.810.8 12115 0 15 6 4 0 8 28 0 0 6 0 0 0 11 0 12 4 12 618 Total fertile males 18 Total fertile males impregnating two females 14 DO 131099 00NF TDFNTTA1, -271- TABLE a-6 (continued) DBCPs INHALATION FERTILITY STUDY IN THE RAT1, Individual Observations Made at the Time of Necropsy of frnexposed Female Rata Mated with dbcp-Exposed dales Week of Study: 10 Exposure Level: 10 ppm Animal Number Hale Ear Number Male Ear Number Female Corpora Lutea Implantations X Pre-imp Resorptions Loss iX Post-imp Loss 77-7678 7679 7680 7681 7682 7683 7684 7685 7686 7687 7688 7689 7690 7691 7692 7693 7694 7695 7696 7697 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 Mean S. D. 1946 1947 1948 1949 1950 1951 1952 1953 1954 1955 1956 1957 1958 1959 1960 1961 1962 1963 1964 1965 1966 1967 1968 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 15 13 14 17 16 non-pregnant non-pregnant 16 non-pregnant 14 14 12 non-pregnant 13 --a 12 14 11 14 14 14 11 7 15 16 16 15 13 14 12 16 non-pregnant __a 14 13 non-pregnant 16 non-pregnant 20 8 14*2 15 12 14 12 16 13 14 14 8 14 12 12 11 9 14 11 3 1 4 12 14 9 15 13 14 12 15 13 13 5 14 17 8 12*3 0 0 2 2 5 5 3 2 3 4 3 4 2 1 2 2 1 0 4 2 2 4 3 1 1 1 6 0 4 0 2 3 1 2.5*1.6 4 14 0 19 0 16 0 0 20 10 84 32 28 0 0 6 7 62 12 8 16*22 0 16 31 38 21 26 28 i 29 1 14 16 16 58 29 14 8 40 16 0 14 15 21*14 Total fertile malea * 20 Total fertile malea impregnating two femalea * 13 tMale rata were exposed to 0, 0.1, 1.0, or 10 ppm of EBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the expoaure period, animals were maintained in the laboratory for recovery. Each exposed male waa housed with 2 unexposed femalea for a 7-day breeding period during the 10th week of the study. aData inadvertently were not recorded. The average values for the two female rats bred to each male were calculated. Group means were then calculated from these averaged values. DO 131300 CONFIDENT TAl -272- TABLE A-7 DBCFt INHALATION FERTILITY STUDY IN THE RAT* Individual Observations Made at the Tine of Necropsy of Unexpoaed Female Rata Hated with-bBCP-Expoaed Males week of study 12 Exposure Levelt 0 ppm Animal Number Male Ear Number Male Ear Number Female Corpora Lutea Implantations X Pre-imp Resorptions Loss J Post- Los 77-7469 7470 7471 7472 7473 7474 7475 7476 7477 7478 7479 7480 7481 7482 7483 7484 7485 7486 7487 7488 1019 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1032 * 1033 1034 1035 1036 1037 1182 1039 1040 Mean * S. D. 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 2034 2035 2036 2037 2038 2039 2040 14 14 non-pregnant 13 16 14 10 15 17 14 non-pregnant 21 18 10 non-pregnant 18 17 17 non-pregnant 17 15 14 20 17 18 17 non-pregnant 14 13 16 16 14 15 14 14 11 13 13 12 16 15*2 11 13 16 14 12 5 13 16 16 16 16 10 17 13 17 15 16 12 18 15 16 14 8 13 13 15 15 13 13 15 8 13 14 12 13 14*2 Total fertile males * 20 Total fertile males impregnating two females 15 4 0 0 0 1 0 1 1 2 0 0 0 0 1 0 0 1 2 2 3 1 1 0 1 3 0 1 2 0 0 2 1 0 0 1 0.8*0.8 14 0 13 32 3 24 6 6 12 12 7 11 14 43 10 3 10 18 0 10 12*10 18 0 4 4 9 0 0 0 4 0 12 16 6 0 16 4 8 12 4 4 6*6 no 131001 CONFTDFNTTAL -273- TABLE A-7 (Continued) DBCPi INHALATION FERTILITY STUDY IN THE RATf Individual Observations Made at the Time of necropsy of Unexposed Female Rats Hated witft DBCP-Exposea Males Week of Studyi 12 Exposure Level: 0.1 ppm Animal Number Male Ear Number Male Ear Number Female Corpora Lutea Implantations X Pre-imp Resorptions Loss X Post-imp Loss 77-7539 7540 7541 7542 7543 7544 7545 7546 7547 7548 7549 7550 7551 7552 7553 7554 7698 7555 7556 7557 1057 1058 1059 1060 1062 1063 1064 1065 1066 1068 1069 1070 1072 1073 1074 1075 1175 1077 1078 1181 Mean S. D. 2041' 2042 2043 2044 2045 2046 2047 2048 2049 2050 2051 2052 2053 2054 2055 2056 2057 . 2058 2059 2060 2061 2062 2063 2064 2065 2066 2067 2068 2069 2070 2071 2072 2073 2074 2075 2076 2077 2078 2079 2080 non-pregnant 14 15 15 non-pregnant 13 22 17 17 non-pregnant 14 14 18 14 non-pregnant 16 16 16 13 17 15 15 18 16 non-pregnant 11 16 17 22 13 non-pregnant 15 19 10 18 17 non-pregnant non-pregnant 11 11 152 15 14 12 10 17 15 16 17 14 17 15 13 17 15 13 15 14 16 11 15 9 17 17 18 15 14 12 2 18 16 14 16 143 0 1 0 0 2 0 1 1 2 4 1 3 1 1 0 1 0 0 1 1 6 0 1 0 0 0 1 2 1 0 1 0 1.11.4 00 14 4 23 0 18 6 66 0 10 3 16 19 23 36 64 40 22 8 18 67 03 90 70 58 54 33 0 1114 4 1118 Total fertile males 19 Total fertile males impregnating two females 13 13130? CONFTDFNTTAI -274- TABLE A-7 (Continued) DBCPs INHALATION FERTILITY STUDY IN THE RATf Individual Qbaervationa Made at the Tine ot Necropsy of Unexposed Female Rats Hated with DBCF-Exposed Males Week of Studyt 12 Exposure Level: 1.0 ppm Animal Number Male Ear Number Male Ear Number Female Corpora Lutea Implantations A Pre-imp Resorptions Loss % Post-ii Loss 77-7608 . 7609 7610 7611 7612 7613 7614 7615 7616 7617 7618 7619 7620 7621 7622 7623 7624 7625 7626 7627 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1110 1111 1112 1113 1114 1115 1116 1117 1118 Mean S. D. 2081 2082 2083 2084 2085 2086 2087 2088 2089 2090 2091 2092 2093 2094 2095 2096 2097 2098 2099 2100 2101 2102 2103 2104 2105 2106 2107 2108 2109 2110 2111 2112 2113 2114 2115 2116 2117 2118 2119 2120 14 15 non-pregnant 15 18 15 15 16 13 13 14 13 13 14 14 5 11 13 16 19 14 16 12 13 19 19 21 18 17 17 13 14 16 non-pregnant 18 18 14 15 14 13 152 16 13 15 14 14 15 15 12 15 15 14 13 14 11 3 12. 13 12 16 15 14 11 12 15 13 12 14 17 14 14 14 19 18 15 14 15 14 13 142 Total fertile males - 20 Total fertile males impregnating two females * 18 1 1 0 0 0 2 1 2 1 0 2 3 1 5 0 1 1 0 0 0 0 1 0 1 3 0 0 1 2 0 2 1 4 4 0 2 0 3 1.21.0 6 0 14 3 4 0 0 30 0 20 6 8 26 32 9 0 0 8 0 0 810 7 0 0 10 12 7 15 22 16 0 0 4 15 0 10 7 5 24 6 12 97 DO 131303 CONFTDFNTIA l -275- Animal Number Hale TABLE A-7 (Continued) DBCPt INHALATION FERTILITY STUDY IN THE RATf Individual Observations Made at the Time of Necropsy of Unexposed Female Rats Mated with DBCP-Exposed Males Week of studyt 12 Exposure Level: 10 ppm Ear . Number Male Ear Number Female Corpora Lutea implantations X Pre-imp Resorptions Loss X Post-imp Loss 77-7678 7679 7680 7681 7682 7683 7684 7685 7686 7687 7688 7689 7690 7691 7692 7693 7694 7695 7696 7697 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 Mean * S. D. 2121 2122 2123 2124 2125 2126 2127 2128 2129 2130 2131 2132 2133 2134 2135 2136 2137 2138 2139 2140 2141 2142 2143 2144 2145 2146 2147 2148 2149 2150 2151 2152 2153 2154 21S5 2156 2157 2158 2159 2160 15 13 13 15 13 14 17 14 15 _a 12 13 19 13 15 non-pregnant non-pregnant 16 non-pregnant non-pregnant 12 13 15 12 dead 18 13 non-pregnant 12 non-pregnant 14 9 --a 16 13 13 15 18 15 13 14*2 14 14 15 15 15 15 16 15 14 1 15 13 14 13 12 11 11 11 13 10 13 10 12 15 .1.3a 13 15 11 18 17 10 14 13*2 0 1 3 2 0 1 1 2 3 1 2 0 7 1 2 4 1 3 0 4 2 3 1 1 7 i 2 4 2 4 1 0 2.1*1.2 44 0 16 04 3 10 7 60 06 13 29 20 17 31 36 12 15 28 23 0 0 19 8 3 16 11*10 18 20 15 30 8 30 8 24 18 5 19*14 Total fertile males - 19 Total fertile males impregnating two females 14 Male rats were exposed to 0, 0.1, 1.0, or 10 ppm of EBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. Each exposed male was housed with 2 unexposed females for a 7-day breeding period during the 12th week of the study. aData inadvertently were n t rec rded. The average values for the two female rats bred to each male were calculated. Group means were then calculated from these averaged values. DO 131304 CONFTDFNTTAl. -276- TABLE A-8 DBCP: INHALATION FERTILITY STUDY IN THE HAT1, Individual Observations Made at the Time of Necropsy of unexposed female Rats Mateo with DBCP-Exposed Males Week of Studyt 14 Exposure Level: 0 ppm Animal Number Male Ear Number Male Ear Number Female Corpora Lutea Implantations Resorptions X Pre-imp Loss X Post-imp Loss 77-7469 7470 7471 7472 7473 7474 7475 7476 7477 7478 7479 7480 7481 7482 7483 7484 7485 7486 7487 7488 1019 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1032 1033 1034 1035 1036 1037 1182 1039 1040 Mean a S. D. 2201 2202 2203 2204 2205 2206 2207 2208 2209 2210 2211 2212 2213 2214 2215 2216 2217 2218 2219 2220 2221 2222 2223 2224 2225 2226 2227 2228 2229 2230 2231 2232 2233 2234 2235 2236 2237 2238 2239 2240 16 15 15 12 13 14 15 18 16 non-pregnant non-pregnant 18 13 14 13 18 16 18 non-pregnant 12 15 16 13 10 12 non-pregnant 15 11 14 15 18 19 16 15 13 12 14 14 17 non-pregnant 152 16 17 17 12 15 14 16 17 17 16 13 15 14 16 16 16 12 17 16 15 10 15 16 14 14 17 14 13 16 13 13 16 13 16 16 151 0 0 0 0 0 0 0 0 0 2 0 1 0 0 0 0 2 2 0 2 1 1 0 0 0 0 1 0 1 0 1 0 1 1 1 0 00 00 00 30 00 11 12 04 60 60 0 17 06 0 12 07 00 00 27 4 63 04 47 66 36 4S o -H .Total fertile males 20 Total fertile males impregnating two females " 15 DO 131305 CONFTDFNTTAt -277- TABLE A-8 (Continued) DBCP: INHALATION FERTILITY STUDY IN THE RAT1, Individual Observations Made at the Time of Necropsy of Unexposed Female Rata Hated witn DBCP-Exposed Males Week of Study: 14 Exposure Level: 0.1 ppm Animal Number Male Ear Number Male Ear Number Female Corpora Lutea Implantations A Pre-imp Resorptions Loss 1A Post-imp Loss 77-7539 7540 7541 7542 7543 7544 7545 7546 7547 7548 7549 7550 7551 7552 7553 7554 7698 7S55 7556 7557 1057 1058 1059 1060 1062 1063 1064 1065 1066 1063 1069 1070 1072 1073 1074 1075 1175 1077 1078 1181 Mean * S. D. 2241 2242 2243 2244 2245 2246 2247 2248 2249 2250 2251 2252 2253 2254 2255 2256 2257 2258 2259 2260 2261 2262 2263 2264 2265 2266 2267 2268 2269 2270 2271 2272 2273 2274 2275 2276 2277 2278 2279 2280 13 14 13 15 12 15 10 11 12 14 14 9 non-pregnant 14 16 14 13 13 14 13 12 non-pregnant 13 12 16 12 15 16 17 11 15 11 12 16 16 16 15 non-pregnant 15 11 13 14 13 15 12 17 9 11 14 11 14 7 14 15 14 14 13 14 13 13 14 14 14 16 15 16 17 a 16 2 12 14 16 14 14 15 11 14*1 13*2 0 1 0 2 0 0 2 1 1 0 2 0 0 1 1 0 1 0 1 0 1 1 4 2 0 0 1 0 1 0 1 0 0 0 0 0 0 0.6*0.7 0 0 0 5 19 11 0 3 0 0 0 0 6 0 14 41 6 6 7 0 6*10 >4 6 0 16 4 7 0 7 1 4 4 0 7 20 0 3 3 4 0 0 0 4*5 Total fertile males - 20 Total fertile males Impregnating two females " 17 Do 13I306 CONF TDFNT TAI 278- TABLE A-8 (Continued) DBCPt INHALATION FERTILITY STUDY IN THE RAT1 Individual Observations Made at the Time of Necropsy of Unexposed Female Rata Mated with DBCP-Exposed Males Weak of Studyi 14 Exposure Level: 1>0 ppm Animal Number Male Ear Number Male Ear Number Female Corpora Lutea Implantations K Pre-imp Resorptions Loss X Post-imp Loss 77-7608 7609 7610 7611 7612 7613 7614 7615 7616 7617 7618 7619 7620 7621 7622 7623 7624 7625 7626 7627 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1110 1111 1112 1113 1114 1115 1116 1117 1118 Mean S. D. 2281 2282 2283 2284 2285 2286 2287 2288 2289 2290 2291 2292 2293 2294 2295 2296 2297 2298 2299 2300 2301 2302 2303 2304 2305 2306 2307 2308 2309 2310 2311 2312 2313 2314 2315 2316 2317 2318 2319 2320 12 non-pregnant 12 non-pregnant 15 9 11 16 15 16 non-pregnant 13 14 15 13 12 15 12 11 13 17 16 12 9 13 14 non-pregnant 17 17 14 15 14 14 14 10 15 14 14 non-pregnant non-pregnant 142 14 12 12 7 13 15 12 15 11 15 15 13 13 15 12 11 IS 15 15 13 ' 9 10 14 17 17 13 14 15 11 13 13 11 14 15 132 Total fertile males - 19 Total fertile males impregnating two females 15 1 2 0 0 0 0 0 2 0 0 1 2 0 1 0 1 0 0 0 0 0 1 1 1 1 0 1 2 2 1 0 1 0 1 0.70.6 07 0 17 21 0 30 13 0 15 0 04 0a 04 04 90 00 12 8 06 43 4 10 14 13 14 4 04 67 5S 00 131307 CONFIDENT TAl -279- TABLE A-8 (Continued) DBCP: INHALATION FERTILITY STUDY IN THE RAT* Individual Observations Made at the Time of Necropsy of "unexposed Female Rata Mated with DBCP-Exposed Males Week of Studyi 14 Exposure Leveli 10 ppm Animal Number Hale Ear Number Male Ear Number Female Corpora Lutea implantations X Pre-imp Resorptions Loss X Post-imp Loss 77-7678 7679 7680 7681 7682 7683 7684 7685 7686 7687 7688 7689 7690 7691 7692 7693 7694 7695 7696 7697 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 Mean a s. D. 2321 2322 2323 2324 2325 2326 2329 2330 2327 2328 2331 2332 2333 2334 2335 2336 2337 2338 2339 2340 2341 2342 23 43 2344 2345 2346 2347 2348 2349 2350 2351 2352 2353 2354 2355 2356 2357 2358 2359 2360 13 11 non-pregnant 12 14 15 non-pregnant 13 11 12 non-pregnant 18 15 13 14 14 non-pregnant 15 17 11 15 11 15 non-pregnant non-pregnant 15 16 15 15 non-pregnant 15 16 14 16 13 12 18 14 13 12 14*2 13 11 12 14 14 14 11 7 17 15 15 15 11 12 15 11 13 11 17 15 14 15 14 16 16 15 11 12 15 16 12 13 13 14*2 0 2 0 0 2 6 2 0 0 5 1 3 1 4 3 0 4 5 2 3 4 3 1 1 1 8 0 6 2 1 4 1 0 2. 3*1.7 0 0 4 0 21 6 0 10 20 6 6 0 0 6 7 0 16 4 12 0 6*7 9 0 7 43 9 0 20 14 33 10 38 12 20 25 7 6 26 32 20 4 17*13 Total fertile males - 20 Total fertile males impregnating two females 13 *Male rats were exposed to 0, 0.1, 1.0, or 10 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. Each exposed male was housed with 2 unexposed females for a 7-day breeding period during the 14th week of the study. The average values for the two female rats bred to each male were calculated. Group means were then calculated from these averaged values. DO 131308 OONFTDFNTTAl -280- Animal Number Kale TABLE A-9 DBCP: INHALATION FERTILITY STUDY IN THE RAT* Individual Observations Made at the Time of Necropsy of Unexposed Female Rats Mated with DBCP-Exposed Males Week of Study: 16 Exposure Level: 0 ppm Ear Number Male Ear Number Female Corpora Lutea Implantations X Pre-imp Resorptions Loss X Post-imp Loss 77-7469 7470 7471 7472 7473 7474 7475 7476 7477 7478 7479 7480 7481 7482 7483 7484 748S 7486 7487 7488 1019 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1032 1033 1034 1035 1036 1037 1182 1039 1040 Mean S. D. 2601 2602 2603 2604 2605 2606 2607 2608 2609 2610 2611 2612 2613 2614 2615 2616 2617 2618 2619 2620 2621 2622 2623 2624 2625 2626 2627 2628 2629 2630 2631 2632 2633 2634 2635 2636 2637 2638 2639 2640 15 15 15 16 16 15 16 non-pregnant 13 14 13 18 13 15 17 13 non-pregnant 17 15 20 12 15 12 14 16 non-pregnant 14 16 16 non-pregnant 20 15 19 18 15 15 16 13 15 18 16*1 13 16 16 16 16 15 0 8 12 14 17 13 15 17 17 15 16 20 15 14 4 17 14 16 16 16 19 16 16 17 14 15 16 11 16 16 14*4 1 0 0 0 2 3 16 0 0 1 0 0 2 1 4 1 0 0 1 0 1 9 0 1 0 1 0 0 7 2 1 0 1 0 0 0 1.8*3.6 6 0 0 100 26 3 0 0 12 0 4 34 12 0 0 2 11 4 8 6 11*23 4 0 16 0 0 4 7 15 7 0 4 39 0 3 6 0 28 4 3 0 7*10 Total fertile males 20 Total fertile males impregnating two females 16 DO 131309 CONFTOFNT TAl -281- TABLE A-9 (Continued) DBCPi INHALATION FERTILITY STUDY IN THE BAT1 individual observations Made at the Time of Necropay of dnexpoaed Female Rats Mated with DBCP-Exposed Males Week of Study: 16 Exposure Level: 0.1 ppm Animal Number Hale Ear Number Male Ear Number Female Corpora Lutea Implantations X Pre-imp Resorptions Loss X Post-imp Loss 77-7539 7540 7541 7542 7543 7544 7545 7546 7547 7548 7549 7550 7551 7552 7553 7554 7698 7555 7556 7557 1057 1058 1059 1060 1062 1063 1064 1065 1066 1068 1069 1070 1072 1073 1074 1075 1175 1077 1078 1181 2641* 2642 2643 2644* 2645 2646* 2647* 2648 2649 2650 2651 2652 2653 2654 2655 2656 2657 2658 2659 2660 2661 2662 2663 2664 2665 2666 2667 2668 2669 2670 2671 2672 2673 2674 2675 2676 2677 2678 2679 2680 14 15 15 15 15 15 14 15 17 18 16 15 12 13 11 17 11 13 17 14 14 18 14 non-pregnant 16 13 13 14 13 13 16 non-pregnant 18 non-pregnant 17 13 14 IS 14 14 17 14 14 15 17 18 14 15 12 14 5 13 11 12 16 12 13 18 13 15 14 13 15 13 3 4 17 13 13 Mean S. D. 15*2 133 Total fertile males - 20 Total fertile males impregnating two females - 16 2 2 0 0 0 0 2 1 1 0 2 1 0 2 0 0 0 0 0 0 0 1 0 2 1 0 0 2 1 1 1 4 0 0.80.8 0 0 7 7 4 0 0 6 4 40 4 10 4 7 7 0 38 75 6 12 12*19 14 13 0 0 0 10 3 10 7 0 00 3 0 10 0 24 25 6 16 7*8 D0 131310 CONF TOFNTIA1 282' TABLE A-9 (Continued) DBCPs inhalation fertility study IN THE RATt Individual Observations Made at the Time of Necropsy of Unexpoaed Female Rata Mated with DBCP-Expoaed Males Week of Study> 16 Exposure Level* 1.0 ppm Animal Number . Male Ear Number Male Ear Number Female Corpora Lutea Implantations A Pre-imp Resorptions Loss X Post-imp Loss 77-7608 7609 7610 7611 7612 7613 7614 7615 7616 7617 7618 7619 7620 7621 7622 7623 7624 7625 7626 7627 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1110 1111 1112 1113 1114 1115 1116 1117 1118 Mean a S. D. 2681 2682 2683 2684 2685 2686 2687 2688 2689 2690 2691 2692 2693 2694 2695 2696 2697 2698 2699 2700 2701 2702 2703 2704 2705 2706 2707 2708 2709 2710 2711 2712 2713 2714 2715 2716 2717 2718 2719 2720 15 15 14 non-pregnant 14 14 14 15 13 16 12 16 14 14 14 14 13 13 11 non-pregnant non-pregnant 15 11 non-pregnant 17 non-pregnant 13 13 14 non-pregnant 13 15 15 non-pregnant non-pregnant 11 14 18 15 16 14*2 15 14 13 14 14 12 16 14 15 15 12 14 14 13 15 14 14 12 14 9 18 11 13 6 12 15 15 11 16 16 15 14 132 Total fertile males 20 Total fertile males Impregnating two females - 12 2 0 1 0 0 0 0 2 0 1 1 10 0 2 0 0 2 0 1 1 2 2 1 0 0 1 2 0 2 0 5 0 1.ltl.2 4 7 0 7 3 12 0 4 0 0 7 18 0 8 57 4 0 0 12 6 713 6 8 0 0 7 8 36 8 7 0 7 11 11 13 0 4 13 0 6 16 8*8 i DO 131311 OONFTDFNTIAl. 283- Animal Number Male TABLE A-9 (Continued) DBCPi INHALATION FERTILITY STUDY IN THE RAT* Individual Observations Made at the Time of Necropsy of Unexposed Female Rats Mated with DBCP-Exposed Males Week of Study* 16 Exposure Level: 10 ppm Ear Number Male Ear Number Female Corpora Lutea Implantations X Pre-imp Resorptions Loss \X Post-imp Loss 77-7678 7679 7680 7681 7682 7683 7684 7685 7686 7687 7688 7689 7690 7691 7692 7693 7694 7695 7696 7697 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 Mean * S. D. 2721 2722 2723 2724 2725 2726 2727 2728 2729 2730 2731 2732 2733 2734 2735 2736 2737 2738 2739 2740 2741 2742 2743 2744 2745 2746 2747 2748 2749 2750 2751 2752 1753 2754 2755 2756 2757 2758 2759 2760 IS 15 15 15 14 14 15 10 13 14 14 16 13 17 11 14 non-pregnant 15 non-pregnant 16 14 12 17 14 16 11 15 13 15 14 16 non-pregnant 15 14 15 13 14 non-pregnant 14 15 14*1 14 15 16 15 8 1 15 13 12 16 15 16 15 15 13 14 14 16 14 11 14 15 16 13 12 13 14 14 17 15 14 8 13 12 13 IS 14*3 2 3 1 1 2 1 1 1 3 5 1 4 8 4 2 1 1 3 2 0 10 0 1 0 1 1 0 4 3 1 1 0 0 0 4 1 2.0*1.6 4 0 68 0 4 0 6 0 7 0 4 9 0 10 4 0 0 24 14 4 8*15 17 6 62 8 28 16 40 i 11 1 7 19 7 36 3 8 14 18 7 0 0 19 16*15 Total fertile males * 20 Total fertile males impregnating two females - 16 fMale rats were exposed to 0, 0.1, 1.0, or 10 ppm of EBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. Each exposed male was housed with 2 unexposed females for a 7-day breeding period during the 16th week of the study. `Animals lost ear tags and were not identifiable The average values for the two female rats bred to each male were calculated. Group means were then calculated from these averaged values. 00 13131? OONFTOFNTTAI 28A' TABLE A-10 DBCP: INHALATION FERTILITY STUDY IN THE RAT1, Individual Observations Made at the Time of Necropsy of '"unexposed Female Rata Mated with DBCF-Exposed Males Week of Studyt 19 Exposure Levels 0 ppm Animal Number Hale Ear Number Male Ear Number Female Corpora Lutea Implantations A Pre-imp Resorptions Loss X Post-imp Loss 77-7469 7470 7471 7472 7473 7474 7475 7476 7477 7478 7479 7480 7481 7482 7483 7484 7485 7486 7487 7488 1019 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1032 1033 1034 1035 1036 1037 1182 1039 1040 Mean * S. D. 3301 3302 3303 3304 3305 3306 3307 3308 3461 3310 3311 3312 3313 3314 3315 3316 3317 3318 3319 3320 3321 3322 3323 3324 3325 3326 3327 3328 3329 3330 3331 3332 3333 3334 3335 3336 3337 3338 3339 3340 13 non-pregnant non-pregnant 16 15 14 13 13 non-pregnant 14 14 14 14 11 13 17 14 12 12 17 16 17 18 12 non-pregnant 13 12 16 15 15 17 11 15 17 15 15 IS 17 16 15 14*1 14 12 13 13 8 14 15 10 14 14 13 16 17 13 13 15 18 16 17 15 12 13 15 16 IS 16 16 14 15 15 13 6 15 15 13 15 14*2 Total fertile males - 20 Total fertile males impregnating two females 16 1 1 1 0 1 0 1 2 1 2 0 1 0 1 0 1 0 1 2 0 0 0 1 0 0 2 0 0 0 1 1 0 0 0 1 0 0.6*0.4 0 25 10 19 0 14 0 0 4 0 0 8 0 0 0 3 6 36 6 10 7*10 7 8 4 6 7 14 7 3 4 4 9 0 0 4 6 0 4 4 0 4 5*3 DO 131313 C.ONT TDFNTTAl Animal Number Hale TABLE A-10 (Continued) DBCP: INHALATION FERTILITY STUDY IN THE RATT Individual Observations Made at the Time of Necropsy of Uhexposed Female Rata Mated with DBCP-Expoaed Malea Week of Studyt 19 Exposure Level: 0.1 ppm Ear Number Male Ear Number Female Corpora Lutea implantations X Pre-imp Resorptions Loss X Post-imp Loss 77-7539 7540 7541 7542 7543 7544 7545 7546 7547 7548 7549 7550 7551 7552 7553 7554 7698 7555 7556 7557 1057 1058 1059 1060 1062 1063 1064 1065 1066 1068 1069 1070 1072 1073 1074 1075 1175 1077 1078 1181 Mean s. D. 3341~ 3342 3343 3344 3345 3346 3347 3348 3349 3350 3351 3352 3353 3354 3355 3356 3357 3358 3359 3360 3361 3362 3363 3364 3365 3366 3367 3368 3369 3370 3371 3372 3373 3374 3375 3376 3377 3378 3379 3380 16 14 14 16 14 14 15 15 non-pregnant non-pregnant non-pregnant 14 17 19 non-pregnant 17 13 13 15 15 19 16 17 13 17 15 19 14 16 18 15 non-pregnant non-pregnant 14 16 18 13 12 13 12 15*2 17 13 15 16 IS 13 13 15 14 16 17 16 9 13 15 14 20 17 14 7 19 15 19 15 17 15 IS 11 17 17 13 14 11 13 14*2 0 1 0 1 1 0 0 0 0 0 2 3 2 0 2 0 0 1 0 2 3 0 0 1 0 1 1 4 0 2 0 1 0 0 0.9*1.0 4 0 4 6 0 8 6 16 4 0 32 0 0 8 0 21 3 0 8 6*8 4 3 4 0 0 6 19 11 6 3 14 8 4 4 7 36 6 4 0 7*8 Total fertile males 19 Total fertile males impregnating two females 15 DO 131314 OONFTDFNTT -286- Animal Number Male TABLE A-10 (Continued) DBCPi INHALATION FERTILITY STUDY IN THE RATf Individual Observations Made at the Time of Necropsy of Unexpoaed Female Rata Hated witft DBCF-Exposed Majefl Meek of Study* 19 Exposure Levels 1.0 ppm Ear Number Male Ear Number Female Corpora Lutea Implantations X Pre-imp Resorptions Loss X Post-imp Loss 77-7608 7609 7610 7611 7612 7613 7614 7615 7616 7617 7618 7619 7620 7621 7622 7623 7624 7625 7626 7627 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1110 1111 1112 1113 1114 1115 1116 1117 1118 Mean S. D. 3381 3382 3383 3384 3385 3386 3387 3388 3389 3390 3391 3392 3393 3394 3395 3396 3397 3398 3399 3475 3401 3402 3403 3404 3405 3406 3407 3408 3409 3410 3411 3412 3413 3414 3415 3416 3417 3418 3419 3420 13 13 14 15 16 17 15 17 19 18 13 17 14 12 10 11 18 non-pregnant 15 15 11 15 13 13 16 14 17 15 19 non-pregnant 15 13 non-pregnant 14 13 12 14 15 15 17 152 11 15 15 14 15 18 15 14 18 19 11 15 18 14 9 14 15 16 15 14 16 13 15 16 16 16 16 19 15 11 5 15 13 13 12 16 18 143 0 0 1 0 0 0 0 0 0 1 1 0 0 0 2 0 0 0 1 1 0 0 0 1 1 0 2 0 3 0 0 1 0 0 1 1 1 0.40.4 8 4 6 9 2 14 0 5 17 0 0 0 0 3 0 8 64 0 14 0 814 0 4 0 0 2 4 0 11 0 4 4 0 6 6 0 10 0 4 4 6 33 Total fertile males * 20 Total fertile males impregnating two females 17 13131s CONF TOFNT TAt 287- Animal Number Male TABLE A-10 (Continued) DBCP: INHALATION FERTILITY STUDY IN THE RAT* Individual Observations Made at the Time of Necropsy of Unexposed Female Rats Mated with pfaclP-Exposed Males' Meek of Study: 19 Exposure Level: 10 ppm Ear Number Male Ear Number Female Corpora Lutea Implantations % Pre-imp Resorptions Loss S post-imp Loss 77-7678 7679 7680 7681 7682 7683 7684 7685 7686 7687 7688 7689 7690 7691 7692 7693 7694 7695 7696 7697 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 Mean S. D. 3421 3422 3423 3424 . 3425 3426 3427 3428 3429 3430 3431 3432 3433 3434 3435 3436 3437 3438 3439 3440 3441 3442 3443 3444 3445 3446 3447 3448 3449 3450 3451 3452 3453 3454 3455 3456 3457 3458 3459 3460 15 17 11 non-pregnant non-pregnant 12 12 14 12 12 non-pregnant non-pregnant non-pregnant 11 14 13 13 non-pregnant 13 18 15 14 16 non-pregnant 14 14 16 12 non-pregnant 16 14 non-pregnant 12 16 12 15 15 13 15 13 142 15 18 12 12 14 16 12 11 11 14 13 15 15 14 16 15 14 12 15 16 11 14 13 12 15 14 17 18 11 14 14 141 0 1 1 0 0 4 3 1 2 0 0 4 1 .5 1 2. 2 1 0 0 6 3 2 0 0 1 0 1 0 1 1 1.51.2 0 0 0 0 4 0 0 0 11 0 12 7 4 12 7 3 0 8 4 44 3 8 0 12 17 18 0 27 22 10 14 4 28 21 15 0 4 3 7 119 Total fertile males 19 Total fertile males impregnating two females - 12 *Male rats were exposed to 0, 0.1, 1.0, or 10 ppm of OBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. Each exposed male was housed with 2 unexposed females for a 7-day breeding period during the 19th week of the study. The average values for the two female rats bred to each male were calculated. Group means were then calculated from these averaged values. f'O 131316 CONFTOFNriAl -288- TABLE A-11 DBCPt INHALATION FERTILITY STUDY IN THE RATf Individual Observations Made at the Time of Necropsy of Unexposet!"Female Rata Mated with DBCP-Exposed hales Week of Studyi 24 Exposure Levels 0 ppm Animal Number Male Ear Number Male Ear Number Female Corpora Lutea Implantations X Pre-imp Resorptions Loss X Post-imp Loss 77-7469 7470 7471 7472 7473 7474 7475 7476 7477 7478 7479 7480 7481 7482 7483 7484 7485 7486 7487 7488 1019 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1032 1033 1034 1035 1036 1037 1182 1039 1040 Mean S. D. 4001 4002 4003 4004 4005 4006 4007 4008 4009 4010 4011 4012 4013 4014 4015 4016 4017 4018 4019 4020 4021 4022 4023 4024 4025 4026 4027 4028 4029 4030 4031 4032 4033 4034 4035 4036 4037 4038 4039 4040 11 19 13 19 14 15 13 14 non-pregnant 13 20 11 16 non-pregnant 14 15 13 15 non-pregnant 13 13 15 15 14 13 non-pregnant 13 13 14 16 17 non-pregnant 16 non-pregnant 14 non-pregnant 13 13 19 15 14*1 13 19 12 15 13 16 12 14 13 15 12 16 13 14 14 13 14 14 11 15 13 14 14 13 14 15 15 12 10 14 13 17 14 14*1 Total fertile males - 20 Total fertile males impregnating two females - 13 0 0 0 1 1 0 0 0 1 2 3 2 0 0 2 2 0 0 0 0 1 1 0 0 0 0 0 0 0 1 1 1 0 0.6*0.8 00 14 4 44 40 08 12 19 0 12 70 6 14 00 14 , 4 0 o 4 7 00 30 12 0 25 0 29 0 08 93 7*8 4*6 00 131317 GONF TDFN7 T A1 289' Animal Number Kale TABLE A-ll (Continued) DBCP: INHALATION FERTILITY STUDY IN THE RATf Individual Observations Made at the Time of Necropsy of unexposed Female Rata Mated with DBCP-Exposed Males Week of Studyt 24 Exposure Level: 0.1 ppm Ear Number Male Ear Number Female Corpora Lutea Implantations JC Pre-imp Resorptions Loss !l jt Post-imp Loss 77-7539 7540 7541 7542 7543 7544 7545 7546 7547 7548 7549 7550 7551 7552 7553 7554 7698 7555 7556 7557 1057 1058 1059 1060 1062 1063 1064 1065 1066 1068 1069 1070 1072 1073 1074 1075 1175 1077 1078 1181 Kean S. D. 4041 4042 4043 4044 4045 4046 4047 4048 4049 4050 4051 4052 4053 4054 4055 4056 4057 4058 4059 4060 4061 4062 4063 4064 4065 4066 4067 4068 4069 4070 4071 4072 4073 4074 4075 4076 4077 4078 4079 4080 15 13 13 non-pregnant 18 11 non-pregnant 14 non-pregnant 17 16 13 15 non-pregnant 16 13 non-pregnant 11 13 15 14 12 12 non-pregnant 12 15 14 15 14 13 14 14 non-pregnant non-pregnant non-pregnant 13 11 non-pregnant 13 16 14x1 15 15 14 14 13 15 17 14 12 14 15 13 11 11 13 14 14 11 2 14 14 IS 14 11 14 12 12 13 15 17 132 1 0 1 3 2 2 0 1 0 0 7 0 0 2 0 0 0 0 2 1 1 1 0 0 0 0 1 0 3 1 0.91.0 0 ,4 07 11 18 0 13 00 10 4 70 3 24 1 0 !o 14 9 00 80 45 54 07 80 70 8 0 0 610 8 0 13 8x13 Total fertile males - 19 Total fertile males impregnating two females - 11 DO 131318 CONFTDFN1 TA1 L 290- TABLE A-ll (Continued) DBCPs INHALATION FERTILITY STUDY IN THE RAT* Individual Observations Hade at the Time of Necropsy of Unexposed Female Rata hated witft DBCP-Exposed Males Week of Study: 24 Exposurd Level: 1.0 ppm Animal Number Male 77-7608 7609 7610 7611 7612 7613 7614 7615 7616 7617 7618 7619 7620 7621 7622 7623 7624 7625 7626 7627 Ear Number Male 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1110 1111 1112 1113 1114 1115 1116 1117 1118 Mean S. D. Ear Number Female 4081 4082 4083 4084 4085 4086 4087 4088 4089 4090 4091 4092 4093 4094 4095 4096 4097 4098 4099 4100 4101 4102 4103 4104 4105 4106 4107 4108 4109 4110 4111 4112 4113 4114 4115 4116 4117 4118 4119 4120 Corpora Lutea Implantations 12 15 14 non-pregnant 14 18 14 non-pregnant non-pregnant non-pregnant non-pregnant 15 non-pregnant 16 11 non-pregnant 17 14 13 16 15 16 non-pregnant non-pregnant 13 16 14 18 15 IS non-pregnant 15 15 12 12 15 14 16 13 13 141 12 14 15 14 14 15 15 15 7 15 15 13 14 15 16 13 15 11 14 14 13 15 15 6 12 13 16 15 13 13 142 X Pre-imp Resorptions Loss 24 3 10 2 11 0 00 0 2 0 2 2 0 1 2 1 0 0 0 1 1 3 1 1 0 0 0 0 1 0 0 0.80.8 0 6 36 6 6 0 3 22 10 0 25 6 3 0 810 X Post-imp Loss 19 7 7 0 0 13 0 13 4 10 0 4 15 7 4 0 4 0 66 Total fertile males 18 Total fertile males impregnating two females " 12 DO 131319 CONF T DFNT T AL -291- TABLE A-ll (Continued) DBCP: INHALATION FERTILITY STUDY IN THE RATf Individual Observations Made at the Time of Necropsy of Unexposed Female Rata Mated with DBCP-Expoaed Males Weak of Study* 24 Exposure Level: 10 ppm Animal Number Male Ear Number Male Ear Number Female Corpora Lutea Implantations u Pre-imp Resorptions Loss X post-Imp Loss 77-7678 7679 7680 7681 7682 7683 7684 7685 7686 7687 7688 7689 7690 7691 7692 7693 7694 7695 7696 7697 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 Mean S. D. 4121 4122 4123 4124 4125 4126 4127 4128 4129 4130 4131 4132 4133 4134 4135 4136 4137 4138 4139 4140 4141 4142 4143 4144 4145 4146 4147 4148 4149 4150 4151 4152 4153 4154 4155 4156 4157 4158 4159 4160 14 non-pregnant 13 18 12 13 13 15 14 17 non-pregnant 16 18 14 13 14 15 non-pregnant 16 16 12 18 11 13 17 15 16 13 non-pregnant 15 16 14 non-pregnant 16 non-pregnant 11 15 non-pregnant 14 non-pregnant 13 13 16 14 13 13 16 14 14 IS 17 13 13 14 13 14 15 13 15 11 15 12 14 14 14 15 14 14 12 11 13 15 152 141 0 1 2 0 1 1 1 1 1 1 0 1 2 1 0 1 0 0 1 1 1 1 0 0 0 0 1 0 0 2 1 0 0* 60.6 70 6 10 04 07 97 67 64 0 11 13 0 94 84 06 18 4 60 00 64 25 0 0 18 13 a 00 77 55 Total fertile males * 20 Total fertile males impregnating two females " 12 tMale rats exposed to 0, 0.1, 1.0, or 10 ppn of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. Each exposed male was housed with 2 unexposed females for a 7-day breeding period during the 24th week of the study. The average values for the two female rats bred to each male were calculated. Group means were then calculated from these averaged values. 00 131370 CONF T DFNTTAl 292' Animal Number Hale TABLE A-12 DBCPt INHALATION FERTILITY STUDY IN THE RATt Individual Observations Made at the Time of Necropsy of Unexposed female Rata Mated witn DBCR-Exposed Male3 Week of Study: 29 Exposure Level: 0 ppm Ear Number Male Ear Number Female Corpora Lutea Implantations X Pre-imp Resorptions LOSS X Post-Imp Loss 77-7469 7470 7471 7472 7473 7474 7475 7476 7477 7478 7479 7480 7481 7482 7483 7484 7485 7486 7487 7488 1019 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1032 1033 1034 1035 1036 1037 1182 1039 1040 Mean S. D. 4201 4202 4203 4204 4205 4206 4207 4208 4209 4210 4211 4212 4213 4214 4215 4216 4217 4218 4219 4220 4221 4222 4223 4224 4225 4226 4227 4228 4229 4230 4231 4232 4233 4234 4235 4236 4237 4238 4239 4240 15 12 non-pregnant 14 12 12 non-pregnant 16 15 15 19 15 16 13 non-pregnant 16 13 13 16 15 16 17 13 14 non-pregnant 15 11 non-pregnant 13 non-pregnant 16 15 12 12 15 13 17 11 13 non-pregnant 14*2 13 13 14 14 13 15 14 15 15 IS 16 13 15 13 8 15 15 11 14 13 14 16 13 12 15 14 14 12 14 10 20 11 13 14*1 2 1 0 1 0 1 0 1 2 3 2 1 1 0 0 1 1 1 0 0 1 2 0 1 0 0 0 0 1 0 0 3 0 0.8*0.7 6 12 00 04 67 44 10 16 0 10 67 19 0 37 24 4 04 0 12 00 88 60 00 15 4 0 14 00 5*7 6*5 Total fertile males > 20 Total fertile males Impregnating two females 13 no ioi37i 00NF TDFN7 TAi -293- TABLE A-12 (Continued) DBCP: INHALATION FERTILITY STUDY IN THE RAT1, Individual Observations Hade at the Time of Necropsy of Unexposed Female Rata Hated with DBCP-Exposed Males Week of Study> 29 Exposure Leveli 0.1 ppra Animal Number Male Ear Number Male Ear Number Female Corpora Lutea Implantations X Pre-imp Resorptions Loss X Post-imp Loss 77-7539 7540 7541 7542 7543 7544 7545 7546 7547 7548 7549 7550 7551 7552 7553 7554 7698 7555 7556 7557 1057 1058 1059 1060 1062 1063 1064 1065 1066 1068 1069 1070 1072 1073 1074 1075 1175 1077 1078 1181 Mean * S. 4241 4242 4243 4244 4245 4246 4247 4248 4249 4250 4251 4252 4253 4254 4255 4256 4257 4258 4259 4260 4261 4262 4263 4264 4265 4266 4267 4268 4269 4270 4271 4272 4273 4274 4275 4276 4277 4278 4279 4280 15 13 13 16 13 15 13 17 17 13 non-pregnant 12 15 13 17 12 17 13 13 15 15 16 11 14 15 11 14 15 non-pregnant 14 17 19 13 15 12 14 12 12 non-pregnant 19 142 16 12 13 15 13 16 13 14 17 14 15 16 13 14 12 16 12 11 16 15 14 12 14 16 13 14 16 13 14 17 14 12 14 14 12 14 16 141 0 40 0 0 30 0 1 07 1 0 90 0 2 06 0 00 0 1 03 0 0 94 1 0 74 1 1 84 0 0 60 0 0 04 1 0 00 0 0 00 0 70 0 0 14 3 1 1 10 8 1 0 00 0 1 0 14 3 16 0 0 0.40.5 55 34 Total fertile males - 20 Total fertile males impregnating two females 17 DO 1313?? CONF TDFNT TAl -294- TABLE A-12 (Continued) DBCPi INHALATION FERTILITY STUDY IN THE RAT* Individual Observations Made at the Time of Necropsy of Unexposea Female Rats Hated with bBCP-Exposed Males Week of Study: 29 Exposure Level: 1.0 ppm Animal Number Male Ear Number Male Ear Number Female Corpora Lutea Implantations X Pre-imp Resorptions Loss X Post-imp toss 77-7608 7609 7610 7611 7612 7613 7614 7615 7616 7617 7618 7619 7620 7621 7622 7623 7624 7625 7626 7627 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1110 1111 1112 1113 1114 1115 1116 1117 1118 Mean * S, D. 4281 4282 4283 4284 4285 4286 4287 4288 4289 4290 4291 4292 4293 4294 4295 4296 4297 4298 4299 4300 4301 4302 4303 4304 4305 4306 4307 4308 4309 4310 4311 4312 4313 4314 4315 4316 4317 4318 4319 4320 17 11 non-pregnant non-pregnant 16 non-pregnant 13 16 18 12 IS 16 16 14 non-pregnant 15 13 13 11 16 16 non-pregnant non-pregnant non-pregnant 14 14 non-pregnant non-pregnant 14 non-pregnant 10 14 15 15 non-pregnant 17 17 15 12 11 141 14 12 15 13 19 14 13 15 16 13 15 15 14 12 1 15 15 14 12 14 11 15 14 15 17 15 15 10 12 142 Total fertile males 17 Total fertile males Impregnating two females - 12 1 1 1 0 0 0 1 0 0 3 2 0 0 1 0 0 0 0 0 0 0 2 1 1 0 0 2 0 0 0.50.7 9 6 0 11 0 10 0 4 48 6 7 0 0 4 0 6 4 711 8 7 0 4 0 18 0 4 0 0 0 0 6 7 0 6 0 45 Dn 1-313F3 CONF TDFNT -295- DBCPs TABLB A-12 (Continued) INHALATION FERTILITY STUDY IN THE RATr Animal Number Hale Unexposed Female Rats Mated with DBCP-Exposed Males Week of Study! 29 Exposure Levels 10 ppm Ear Number Kale Ear Number Female Corpora Lutea Implantations X Pire-imp Resorptions Loss 77-7678 7679 7680 7681 7682 7683 7684 7685 7686 7687 7688 7689 7690 7691 7692 7693 7694 7695 7696 7697 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 Mean t S. D. 4321 4322 4323 4324 4325 4326 4327 4328 4329 4330 4331 4332 4333 4334 4335 4336 4337 4338 4339 4340 4341 4342 4343 4344 4345 4346 4347 4348 4349 4350 4351 4352 4353 4354 4355 4356 4357 4358 4359 4360 14 non-pregnant 14 14 19 15 18 non-pregnant 14 13 14 16 non-pregnant 15 15 15 13 16 13 non-pregnant 16 16 13 14 18 non-pregnant 14 15 12 non-pregnant non-pregnant 15 16 14 12 16 non-pregnant 15 non-pregnant 16 152 14 11 14 13 14 11 13 12 12 15 14 15 14 13 14 11 16 IS 11 13 15 13 14 12 16 14 13 13 15 12 14 13*1 0 1 2 1 0 0 0 0 1 3 1 1 1 0 1 2 1 0 0 2 0 0 3 1 0 2 0 1 0 0 4 0.91.0 0 10 20 39 8 10 7 4 6 IS 3 11 17 7 0 0 10 3 20 12 10*9 i* Post-is Loss i 0 12 4 0 0 14 7 i1 4 18 3 a 0 10 8 0 7 4 0 28 7*7 Total fertile males - 20 Total fertile males impregnating two females 11 *Male rats were exposed to 0, 0.1, 1.0, or 10 ppm of EBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. Each exposed male was housed with 2 unexposed females for a 7-day breeding period during the 29th week of the study. The average values for the two female rats bred t each male were calculated. Group means were then calculated from these averaged values. J31374 OONFTDFNT TA! m- Animal Ntmbar Mala Sir Hubtr Ml Er Nunbvr Female 7MLE A-13 oocpi inhalation remun study ih tub rat* Individual Obtarvatloni Hada at tha Tlaa of Wacropay of Unaapoaad faaala Rata Hated with D6CP - Expoivd Malta Wtak 0( Studyi 41 Bxpoaura Lavali 0 ppa Corpora Lutaa Implantationa Itaaorptiona I Fra-lap Loaa 77-7469 7470 7471 7472 7473 7474 7475 7476 7477 7478 7479 7400 7481 7482 7483 7404 7485 748C 7487 7488 1019 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1032 1033 1034 1035 1036 1037 1182 1039 1040 Men * S.Da 3401 3402 3403 3404 3405 3406 3407 3408 3409 3410 3411 3412 3413 3414 3415 3416 3419 3420 3421 3422 3423 3424 3425 3426 3427 3428 3429 3430 3431 3432 3433 3434 3435 3436 3437 3438 16 15 10 non-pragnant 14 noi>*prtgn*nt 14 nort-prgn*nt 13 non-pragnant 13 13 14 13 16 dalivarad aarly daad, not brad 13 13 non-pragnant 12 14 16 14 12 16 18 16 12 ndn*pr9n*nt 12 15 16 11 14 dead, not bred 17 non-pragnant 15 13 10 14 11 14 13 13 13 14 17 11 13 13 16 IS 14 12 15 5 13 14 10 15 12 11 14 14 14 a 2 13 a 2 1 2 0 0 1 2 0 1 1 1 0 1 0 1 2 2. 0 0 0 3 0 1 3 0 0 2 0 0 0.9 * 0.9 10 0 0 21 0 0 4 0 8 0 3 0 39 10 17 12 0 18 8 a 10 Total fartila lain - 18 Total fartila aalaa iapragnating two foaalaa - 11 X Boat-lap Loaa 11 0 0 9 14 4 8 0 4 6 13 0 30 4 30 0 9 0 8a9 Sat Ratio H------------- P 58 47 64 10 4 55 84 7C 75 66 85 10 7 38 55 84 57 86 76 77 10 2 __a _a 11 58 49 34 96 7S 36 95 3 11 52 >48 no 131005 CONFTDFNTTAl m- Animal Number Hale Ear Number Hala Ear Hmbr Ftaala TABLE A-13 (Continued) DSCPi INHALATION rMTILITT STUDY IN THE RATf Individual Observations Hade at the Time of Necropsy of Unaapoaed female Kata Hated with peer - Exposed Hales Week of Study! 41 Exposure Levels 0.1 ppm Corpora Lutaa Implantations Resorptions X pre-imp Loss 77-7539 7540 7541 7542 7543 7544 7545 7546 7547 7548 7549 7550 7551 7552 7553 7554 7698 7555 7556 7557 1057 lost 1059 1060 1062 1063 1064 1065 1066 1068 1069 1070 1072 1073 1074 1075 1175 1077 1078 1181 Mean S.D. 3439 3440 3441 3442 3443 3444 3445 3446 3447 3448 3449 3450 3451 3452 3453 3454 3455 3456 3457 3458 3459 3460 3461 3462 3463 3464 3465 3466 3467 3468 3469 3470 3471 3472 3473 3474 3475 3476 3477 3478 9 14 11 18 non-pregnant non-pregnant 16 non-pregnant 12 13 11 13 14 non-pregnant non-pregnant 14 15 13 16 non-pragnant 12 17 15 13 14 17 non-pragnant 13 non-pragnant 17 17 13 14 non-pragnant 13 12 non-pragnant 16 non-pragnant ii 14 a 2 10 12 12 17 14 13 12 a 14 14 13 14 12 16 13 13 14 13 14 15 13 14 16 12 8 11 12 12 12 13 2 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 1 0 0 0 1 2 0 0 0 0 1 1 0 0.3 0.6 0 3 12 4 14 0 7 a 0 12 4 6 0 18 7 43 8 25 0 9 t 10 Total fartila males 19 Total fartila Bales impregnating two faoalas 10 x lest-imp Loss 8 13 30 0 0 0 0 o 6 0 4 0 8 14 0 0 4 8 0 58 No Sea Eat H-------- 6 5 6 10 4 7 6 7 cs 7C 7S 44 77 8 94 6S 7S 11 I 7 67 95 10 s S7 1 11 4 12 39 __a __ a 5 74 3t 7S 51 i 49 n0oNFT0FN1TAI c ws- Anlaal Number (tele Bit Nueber Mala Bar Ntabar Famala TRBLE A-13 (Continued) CSCPi XNBA1ATI0N rERTCUTT STUDY IN THE RATf Individual Obaerratlona Hada at the Tlae of Necropav of uneapoaoa regal* m iutw with peep - Expoaaa halei Week of Studyt 41 Exposure Lavalt 1.0 ppa Corpora Lutaa leolantatlona Reeorptlona X pre-lap Lose 77*760 7609 7610 7611 7612 7613 7614 7615 7616 7617 7618 7619 7620 7621 7622 7623 7624 7625 7626 7627 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1110 1111 1112 1113 1114 1115 1116 1117 1118 Naan S.D. 4 3479 3480 3481 3482 3483 3484 3485 3486 3487 3488 3489 3490 3491 3492 3493 3494 3495 3496 3497 3498 3499 3500 3501 3502 3503 3504 3505 3506 3507 3508 3509 3510 3511 3512 3513 3514 3515 3516 3517 3518 12 14 12 15 16 13 non-pregnant 16 non-pragnant 12 non-pregnant 14 14 13 non-pregnant non-pragnant 12 15 14 non-pragnant 14 non-pregnant non-pregnan t non-pregnant 13 17 non-pregnant non-pragnant non-pregnant 12 17 14 non-pregnant 12 15 non-pragnant 15 15 14 13 14 1 10 15 12 16 16 14 14 15 12 14 14 12 14 12 12 12 15 8 16 14 12 13 12 9 8 13 13 t 2 1 0 0 1 0 0 0 2 0 1 1 0 3 0 0 1 2 0 0. 2 0 0 0 0 1 0 0.5 1 0.7 8 0 0 13 0 14 0 4 14 14 10 33 3 0 13 30 22 10 10 Total fertile aalea - 17 Total fertile alee impregnating two feaalea - 9 X Mat-lap Loaa 5 3 0 0 13 0 7 10 0 0 See Ratio Ht 54 96 78 88 59 61 76 S7 67 76 57 65 66 84 10 0 7 0 0 0 6 3t4 56 58 44 6 10 66 57 85 66 63 43 67 49 i 51 00 '31^7 00NF t0FNTT$i -IM- Animal Niabar Hale car NuAbar Hale Bar Number Female TR8LE *-13 (Continual) CBCFt INHALATION miUTI STUDY IN THE RATf Individual Observations Hade at the Tine of Necropsy of unexpoaeo remaie Rata hatao with utxjp - Exposed hales- *sek of study; 41 Exposure Level* 10 ppm Corpora Lutes Implantations Nssorptions X Pre-imp Loss X Post-: Lost Sox Ratio s--------- 1 77-7678 7679 7680 7681 7682 7683 7684 7685 7686 7687 7688 7689 7690 7691 7692 7693 7694 7695 7696 7697 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 Mean e S.D. 3519 3520 3521 3527 3523 3524 3525 3526 3527 3528 3529 3530 3531 3532 3533 3534 3535 3536 3537 3538 3539 3540 3541 3542 3543 3544 3545 3546 3547 3548 3549 3550 3551 3552 3553 3554 3555 3556 17 14 14 14 dead, not bred noftpcgn*fit 13 15 fton-pragnant non-pregnant non-pregnant 11 noft-oragnant 12 20 12 non-oragnant 12 13 12 12 . 11 19 13 13 non-prgnant 13 Aditprgnant non-pragnant non-pregnant 13 non-pragnant 10 13 12 16 17 17 non-pregnant 15 14 12 13 12 13 11 12 17 13 12 13 12 12 13 16 13 13 12 13 10 7 11 15 14 16 14 a 2 12 e 2 0 1 6 1 0 0 0 0 0 0 0 0 0 0 1 0 0 1 0 1 2 3 0 0 2 0 0.6 * 1.0 6 10 8 13 0 8 0 0 0 s 0 8 0 0 27 12 $ 6a7 4 4 11 7t 29 2 4 7S 0 48 0 76 0 47 0 75 5 12 0 67 0 75 4 0 29 66 4 57 97 4 7 fi 39 0 10 2 a 57 20 44 22 1 3 65 7 5 10 S 0 5 11 6 a 44 i 54 Total fartlla males 17 Total fartlla mala* impregnating two females 9 rale rats were exposed to 0, 0.1. 1.0, or 10 ppm of COCP by inhalation for C hc/day, 5 days/waek for 14 weeks, following termination of the exposure period, animals were maintained in the laboratory for recovery. Each exposed male was housed with 2 unexposed females for a 7-day breeding period during the 41st week of the study. These females were sacrificed on day 20 of gestation and the fetuses were examined for external alterations and cleft palate. Females were not timed pregnant; therefore the pupa were smaller than day 20 and were not sexed. bpemale Inadvertently was C-eectioned on wrong day, therefore the pups were not sexed. The average values for the tw female rata bred to each male were calculated. Group means were then calculated from these averaged values. DO 131378 CONFTDFNTTAl 300- Tahl t-1* tBCPt IKAUTIOI TBI'IIUTI STUDY I* TBS SAT* tMlrt *'*-1 Uttar Buaaanr 01 fatal Altarctlona Amt llttara of Uaaipoaad >! Bata Brad to DBCP tnoaad Hajaa Din-inn **" kl f tha 8tu3r Fteaala Ear luabar: SrUrnal S*al&4tlofl Bnaacaphalf, apia* bifid* Short tail Baat uU Oatd fitui 3101 1<> 0 0 0 0 3*02 u 0 0 0 0 3*03 10 0 0 0 0 3*05 1* 0 0 0 0 SxpBra Laral: 0 pp. 3*0T 3*09 3*11 3*12 3*13 Victor of Fatuaaa Exaalaad 10 12 13 12 12 Vu^ar of Fttuaa* Affactad 01000 00 00 0 00000 01000 3*1* 13 0 0 0 0 3*15 IT 0 0 0 0 3*16 U 0 0 0 0 3*19 10 0 0 0 0 3*20 12 0 0 0 0 3*22 12 0 0 0 0 3*23 1* 0 0 0 0 ^*2* 13b 0 0 0 0 fuftla Ikr luibart External txaai&atlon Kxoaerpboljt apla* bifida. Short toll Boat tall Daad fatua 3*39 10 0 0 0 0 3**0 12 0 0 0 0 3**l 12 0 0 0 0 3**2 IT 0 0 0 0 Expoaura Loral: 0*1 pp* 3**5 3**T 3**4 }**9 3*50 ftabar of Fatuaaa Exaalnad 1* 13 12 a 1* lUr sf Fatoaaa Affactad 00000 00000 00000 00 00 0 3*51 1* 0 0 0 0 3*5* 13 0 0 0 0 3*55 l* 0 0 0 0 3*56 12 0 0 0 0 3*57 15* 0 0 0 0 3*59 13 0 0 0 0 3*60 13 0 0 0 0 3*61 __ C Expoaura Loral: 1.0 PI* Faaiala Bar Vuabar: 3*79 3*40 3*i 3*82 3*43 3*4* 3*46 1*48 3*90 3*91 3*92 3*95 3*96 3*97 3*99 3503 350k BrUmal Snaalaatloo 9 15 _b 15 Busbar of Fbtuaaa txaalnad 16 i* 1* 13 12 13 13 12 11 12 12 11 13 tuahar of Fatuaaa AffaeUd Exe*pb*lyf *piaa bifida 0 0 000000000000 0 0 Short tail 0 0 -- 0 0 0 0 0 0 0a 0 0 0 0 0 0 0 Bant tall 0 0-- 0 0 0 0 0 0 0 1 0 0 0 0 0 0 Daad fatua 00 000 00 00 00000 0 0 Expoaura Laral: 10 pp* Ffli Ear Vuatwr: 3519 3520 3521 3522 352* 3525 3529 3531 3532 3533 3535 3536 3537 3534 3539 35*0 35*1 External faaalnatlon Exaacapbalj, cpiaa bifida Short tail Bant tall Daad fatua 15 0 0 0 0 13 0 0 0 0 Ambar of Fatuaaa Exaalaad 6 12 12 13 U 12 17 13 12 13 12 12 12 16 13 fcabar of Fatuaaa Affactad 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 000 000000000 00 0000000000000 0 0  -301- Table A-ib (Continued) okpi hhaiatiom natiLirt study 3 the ratt Individual Litter Sugary of fetal Alteration* Aaona Litter* of Unexuoeed F*mlm R*tl JfH to Doer Ureoaed Hal-- burin* H-tb bl of the Study ExpoeUT* levels 0 PJM Femle Ear lunber: External Examination Exencepbaly, epina bifida Short tell Bent tail Dud fttua 3*85 lb 0 0 0 0 3*26 12 0 0 0 0 3*27 _,_h ** -- 3*28 2 0 0 0 0 3*29 3*30 3*32 3*33 3*3* fbaber of Fbtuaee Examined 13 13 T 15 12 unbar of Fttoaoo Affastad 00000 0 00 00 0 00 00 0 0000 3*35 9 0 0 0 0 3*36 lb 0 0 0 0 3bJT lb 0 0 0 0 E-atl* Zhr luab-r: External Examination tMoc-ptelj, -pinu Mfldu Short tall teat tell Dead fetue 3*62 13 0 0 0 0 3*63 1* 0 0 0 0 3*6* 15 0 0 0 0 Expocure levels 0*1 ppm 3*66 3*68 3*69 3*70 3*T1 3*T3 tabor of fatuaaa tzudaad 12 . 12 16 12 --* u tabor of fttnooo Affactad 0 0 00--0 0 0 1 0-- Q 0 0 0 0--0 0 0 0 0--0 3*T* 11 0 0 0 0 3b76 11 0 0 0 0 3b7 12 0 0 0 0 Femle Ear ltuabar: Exteral Exumtlon Exeacepbely, epina bifida Short tell Coat tell DMd ftt 3508 8 0 0 0 0 3509 16 0 0 0 0 3510 12 0 0 0 0 3512 12 0 0 0 0 xpoturo toroli 1.0 ppa 3513 3515 3516 3517 3510 lunber of Fetaeea Trainer* 13 12 9 T 13 tabor of rotuoeo Affoctod 0 0000 0 0000 0 0 0 0*0 0 0000 Eetel- Ear Suoter: txtanal EnalsutloB Exencephaly, epina bifida Short tail Bent tall Dead fetue 35*2 12 0 0 0 0 35** 12 0 0 0 0 35*8 12 0 0 0 0 3550 8 0 0 0 0 Expeouro toroli 10 ppa 3551 3552 3553 355* 3555 tabor of rotuooo Etealaod b U 15 12 16 tabor or rotuooo Affoctod 0 0000 00000 0 0000 0 0000 *Mtle rata wr expoeed to 0, 0,1* 1.0, or 10 ppa of DBCP by inhalation for 6 hr/dap, 5 day/vevk for lb mLa. Following termination of the expoeure period* aalael* were ablnteled la tbe laboratory for recovery- Each expoeed aala rt tme houaed with t*o wexpoead f--1m during tba bi*t mk of tba etudy* Thao* femlee vara eecrifleed on day 20 of geetntion and tba fetuee* ware n--laaj for external alteration* tod cleft palate* *fea*le delivered early papa ear* Included la external calculatloae only* bfeaalee were not tlned pregnant; therefore tba pupe *ere not included in tba external e--trffttttf-fm or ealculatlona* eFe--le Inadvertently vca C-eectlooed on wrong day; therefor* tba pupa were not included In tba external examination or calculation!* Total Fetoeea 322 J o o 1 1 330 0 1 0 0 307 0I 01 11 0 316 0 0 0 0 TOtal Litter* 27 1 0 0 1 26 0 1 0 0 25 0 0 1 0 26 0 0 0 0 no 131330 CONFTDFNT TAt -302- Animal Number 77-7tl9 7t20 7t21 7t22 7t23 7t2t 7t25 7t26 7t27 7>*29 7t29 7t30 7t31 7t32 7t33 7t3t 7t35 7*i36 T*37 7*f38 Ear huiber 1201b 1202 1203 120*t 1205 1206b 1207 1208 1209 1210 1211 1212 1213h 121*1 1215 1216 1217 1218 1219** 1220" Hean+3.D. Table A-15 DBCP: INHALATION FERTILITY STUDY IN THE RATf Reproductive Parameters-Fcrtlllty Index and Survival Indictee for Female Rata Exposed to DBCP by Inhalation (Bred during week 15 and 16 of the post-exposure period) Exposure Level: 0 ppo Litter Sire Ho. Dead Pups on Day 0 70 Did not deliver a litter B1 9 Dead 1 t0 10 3 Did not deliver a litter 80 15 1 Did not deliver a litter Did not deliver a litter 13 0 70 90 Did not deliver a litter 60 70 80 90 No. Live Pups on Day 01 67 77 88 13 76 88 l*t It t 10 77 99 66 77 t7 29 Sex Ratio Day 1 M:F 3:t 1:6 t:t 2:1 t:2 6:2 7:7 5:5 2:5 3:6 2:t 1:6 t:3 t:5 tb:56 Gestation Survival Index (5) 100 88 89 100 70 100 93 100 100 100 100 100 100 100 1-Day Survival Index (5) 100 100 100 100 86 100 100 100 100 100 100 100 88 100 9+3 0.t+0.8 6+3 8+2 96+9 Total pregnant female b it 98+5 Mjrphologlcal Alterations CONFTDFNTT CO CO Co I> -305- Anlnl Number TT-T620 7629 7630 7631 7632 7633 763* 7635 7636 7637 7636 7639 76*0 76*1 76*i2 76*3 76** 76*5 76*6 76*7 Bar Number 1306 1307 1198** 1309 1310 1311 1312 1313 131* 1315 1316 1317 1318 1319 1320 1321 1322 1323 132* 1325 Ke&rttS. D. Table A-15 (Continued) DBCP: INHALATION FERTILITY STUDY Iff THE RAT* Reproductive Parameters-Fertlllty Index and Survival Indielea for Female Rata Exposed to DBCP by Inhalation (Bred durlrg week 15 and l6 of the poet-expoeure period) Exposure Level: 10 ppm Litter Bite* No. Dead Pupa on Day 0 No. Live Pupa on Day 01 Sax Ratio Dir 1 H:F Geatation Survival Index (f) 1-Day Survival Index (5) Old not deliver a litter 12 __c 13 0 15 3 22 Did not deliver a litter Old not deliver a litter Did not deliver a litter 11 0 15 0 *0 52 13 0 10 12 0 11 2 * 3 13 9 3:6 13 8:5 12 5:7 0 0:0 11 6:5 11 7:* * 1:3 1 1:0 12 *:8 10 1 1 0:1 10 0 10 10 * :6 Did not deliver a litter 10 2 8 8 5:3 10 __c ,.c 10 3:7 *0 1* 2 * * 1:3 12 12 *:8 --c 100 . Bo 0 100 73 100 60 100 100 100 60 __c 100 86 _e 100 100 -- 100 100 100 33 92 100 100 100 100 100 **:56 9*5 0.8*1.1 7*5 a** 83*28 Total pregnant females * 15 9*119 Morphological Alterations 1 eaaclated pup 3 pupa exhibited hypothermia aa determined by touch 1M pup exhibited acaudla and Imperforate anua *Pemale rata wre axpoaed to 0, 0.1, 1*0 or 10 ppm of DBCP by inhalation for 6 hr/day, 5 days/veek for Ik weeks. Following termination of the exposure period, anlnala were maintained in the laboratory for recovery* Following termination of exposures (veeka 15 and 16 of the atudy) each female wa housed with two different unexpoaed male rats, each for a 5-day period. Total number of pups born, alive plus dead. t>ln some cases, the litter size wa greater on day 1 than on day 0 because the dam was still delivering when the data were recorded on day 0. cHo data were collected. ^Animal #77-750^ delivered 9 pups on an undetermined day. Since the age of the pups could not be verified, the dsta from tills animal were included In the calculation of % pregnant, and external calculations only. jO u> *N> CONFTDFNTTAL -306- Animal Humber 77-7*19 7*20 71(21 7U22 7>(23 7*2*1 7*25 7*26 7*27 7*28 7*29 7*30 7*31 7*32 7*33 7*3* 7*35 7*36 7*37 7*38 Bar Humber 1201 1202 1203 120* 1203 1206* 1207 1208 1209* 1210 1211b 1212 1213C 121* 1215 1216 1217 1218 1219 1220 MeanlS.D. Table A-l6 DBCP: INHALATIOH FERTILITY STUDY IK THE RATf Reproductive Paramcters-Fertlllty Index and Survival Indielea for Female Rata Exposed to DBCP by Inhalation (Bred during week 33 and 3*1 of the poat-expoBure period) Exposure Level: 0 ppm Utter Size* Ho. Dead Pups on Day 0 Ho. Live Pups on Day 01 Sex Ratio M:F Gestation Survival Index (%) 1-Day Survival Index ) did not deliver a litter did not deliver a litter 12 1 11 11 6:5 10 1 1 0:1 dead *0 2 * *:0 did not deliver a litter did not deliver a litter 10 0 5 9 *:5 did not deliver a litter 61 3 * 0:* did not deliver a litter 92 100 100 100 75 100 100 100 100 100 did not deliver a litter did not deliver a litter did not deliver a litter 70 did not deliver a litter 7 3 2:1 20 2 2 0:2 did not deliver a litter 100 100 *3 100 6* 0. 3*0.5 *7:53 *** 5** 95*9 Total pregnant females " 8 92*22 Morphological Alterations one pup devoid of milk In stomach C0NFTDFN1T jj U) T> Oj -307- Table A-l6 (Continued) DBCP: INHALATION F1RTILITY STUDY IN THE RATf Reproductive Parametcrs-Fertlllty Index and Survival. Indlcles for Female Rata Exposed to DBCP by Inhalation {Bred during week 33 and 34 of the post-exposure period) Exposure Level: 0-1 ppa Animal Humber 7T-7489 7490 7491 7492 7493 7494 7495 7596 7597 7499 7499 7500 7501 7502 7503 7504 7505 7506 7507 7508 Ear Number 1238 1237 123flb 1239 1240 1241 1242 1243 1244 1243 1197 1247 1248 1249 1250 1251 1252 1253 1254 1555 Mean+S.D. Utter Slre" No. Dead Pups on Day 0 90 did not deliver a litter 10 0 31 did not deliver a litter 90 did not deliver a litter did not deliver a litter 12 0 60 did not deliver a litter did not deliver a litter 20 did not deliver a litter did not deliver a litter 11 0 13 0 did not deliver a litter did not deliver a litter did not deliver a litter 8+4 0.1+0.3 Ho. Live Pups on Day 01 99 9 10 22 97 12 11 66 22 11 11 13 13 Sex Ratio M:F 5:4 4:6 2:0 5:2 8:3 3:3 1:1 8:3 4:9 Gestation Survival Index (f) 100 100 67 100 100 100 100 100 100 56:44 8+4 8+4 96+11 Total pregnant females " 9 1-Day Survival Index (5) 100 100 100 78 92 100 100 100 100 977 Morphological Alterations one pup appears emaciated DO 1 3 1 3 3 4 OONFTDFNTTAl -308- Table A-l6 (Continued) DBCP: INHALATION FERTILITY STUDY IN THE RAT^ Reproductive Paramcters-Fcrtlllty Index and Survival Indlclea for Female Rata Exposed to DBCP by Inhalation (Bred during veek 33 and 34 of the post-expoaure period) Exposure Level: 1.0 ppm An Inal Number 77-7559 7559 7560 7561 7562 7563 7564 7565 7566 Bar Niunber 1271 1200 1273 1274 1275 1276 1277 1278 1219* 7567 7568 7569 7570 7571 7572 7573 757* 7575 7576 7577 1280 1281 1282b 1283 1284 1285 1286 1287b 1288 1289 1290 MeaniS.D. o zs 2"U O --i >-> TO| Co 2 U) -t U) -* Cn Litter Slzea Ho. Dead Pups on Day 0 did not deliver a litter 22 15 1 60 did not deliver a litter 70 It 0 did not deliver a litter 70 70 did not deliver a litter 81 30 did not deliver a litter did not deliver a litter did not deliver a litter 90 did not deliver a litter 50 did not deliver a litter 7i4 0.4*0.7 Ho. Live Pups on Day 01 00 lit lit 66 77 It it 1l 77 67 33 Sex Ratio M:F 0:0 5:9 2:4 1:6 2:2 0:1 4:3 3:4 2:1 Gestation Survival Index (f) 0 93 100 100 100 14 100 88 100 6 9 3:6 100 5 5 1:4 100 37:63 61k 6*4 89130 Total pregnant females 11 1-Day Survival Index (J) 100 100 100 100 100 100 100 100 100 100 1000 Morphological Alterations one pup exhibited hypothermia as determined by touch, and was devoid of milk in stomach one pup devoid of milk in stomach one pup exhibited hypothermia as determined by touch n oo 5 2-->t CO -109- Table A-l6 (Continued) DBCP: IHRALATIOR PEKTILITY STUDY IK THE RAT* Reproductive Paranetere-rertlllty Index and Survival Indlclea for female Rate Bupoeed to DBCP by Inhalation {Bred during week 33 and 36 of the post-eipoeure period) Exposure Level: 10 ppa Anloal Jhusber 77-7628 7629 7630 7631 7632 7633 76* 7635 7636 7637 7638 7639 7660 7661 76*2 7663 7666 7665 7666 7667 Dir Riaber 1306 1307 1198 1309 1310 1311 1312 1313 1316 1315b 1316 1317 1318 1319 1320 1321 1322 1323 1326 1325 Hean8. D. Litter Size* Ho* Dead Pups on Day 0 Ho. Live Pups on Day 01 Bex Ratio M:F Gestation Survival Index (1) 21 1 anloal died before delivering anloal did not deliver a litter 10 1 13 0 13 anloal died before breeding did not deliver * litter did not deliver a litter did not deliver a litter 10 0 2 did not deliver a litter did not deliver a litter did not deliver a litter 30 3 20 2 90 12 0 9 12 11 0 did not deliver a litter did not deliver a litter 1 1j0 1 1:0 13 6:9 10 5:5 3 2:1 2 2:0 9 5:6 11 6:7 0 0:0 50 100 100 100 100 100 100 100 0 6B:52 65 0.2+0.6 5+5 6+5 83+35 Total pregnant feaalee 10 1-Day Survival Index Cl) 100 100 100 100 100 100 100 92 -- 99+3 Morphological Alterations ^Feule rats were exposed to 0, 0*1, 1+0 and 10 ppa of DBCP by inhalation for 6 hr/day * 5 days/week for U weeks* FollowItermination of the exposure period, an Inals were Maintained In laboratory for recovery* During weeks 33 and of the study, each fenale was housed with two different unexposed nale rats, each for a 5-day period* Total number of pups born, alive plus dead* ^Zn soae cases, the litter sits was greater on day 1 than on day 0 because the dan was still delivering when the data were recorded* cAnlnal #77-7*131 apparently escaped frcn the cage and delivered a litter-In-the-aninal holding room. All pups were ~ dead when they were discovered* Data from this an inal were Included In the calculation of % pregnant only, dAn leal 117-7566 exhibited excessive bleeding and labored delivery prior to death* On day 0, a single pup was delivered, on day 1 of lactation, an additional 6 pups, which were dead at the tlxie of examination were delivered by this female* -310- 4 o zz T\ ---t ow 'TX ^ zz -* '-i V Table A-17 DBCP: INHALATION FERTILITY STUDY IK THE RAT+ HERITABLE TRANSLOCATION STUDY IndlTldual Observations Made at the Time of Necropsy of Unexposed Female Rata Hated with Fi Halea of DBCP Exposed Hale Rata Exposure Level: 0 ppm An Inal Number DBCP Exposed Hales 77-7*69 7*70 7*71 7*72 7*73 7*7* 7*75 7*76 7*77 7*78 7*79 7*80 7*81 7*82 7*83 7*0* 7*85 7*86 7*87 7*88 Ear Number DBCP Exposed Males 1019 1021 1022 1023 102* 1025 1026 1027 1028 1029 1030 1032 1033 103* 1035 1036 1037 1182 1039 10*0 MeaniS.D. Ear Number Fj Male Ear Number Female Corpora Lutea Implantations 2313 3601 3602 16 1* 2316 3603 360* 13 18 2317 3605 3606 17 non-pregnant No Fi pups (3607. 3600 females were not bred) 2319 2321 3609 3610 3611 22 15 1* 3612 non-pregnant 232* 3613 1* 2326 361* 3615 15 non-pregnant 3616 1* 2327 3617 3618 12 non-pregnant 2329 2331 3619 3620 3621 3622 12 15 16 11 233* 3623 362* 13 1* 2335 2338 3625 3626 3627 3628 1* 1* 16 19 No Fi pupa (3629, 3630 females were not bred) 23*0 3631 1* 3632 13 23*1 3633 1* 363* 1* Ho Fj pupa (3637, 3638 females were not bred) 23*3 3635 16 3636 1* 23*6 3639 13 36*0 8 15 1* 12 16 1* 15 16 16 1* 15 1* 12 12 16 18 12 12 1* 13 1* 1* 15 16 13 1* 1* 15 13 13 3 Tnfnl 1*12 11 * 1*2 a IT Resorptions 1 0 0 0 2 0 1 0 1 2 0 0 0 0 0 1 0 0 0 2 1 2 0 1 0 0 0 0 0 3 O.60.7 * Pre-Imp Loss 3 10 18 16 0 0 0 0 0 0 * * 17 0 0 6 32 619 I Post-Imp Loss * 0 1* 3 0 10 0 0 0 k 0 7 10 ll 0 0 50 6112 80 131338 OONFTDFNT TA( -311- An Inal Humber DBCP Exposed Hales 77-7539 75>t0 75*(1 75*(2 T5**3 75*t*t 75*5 75*(6 75*7 75*8 75**9 7550 7551 7552 7553 755*i 7698 7555 7556 7557 Table A-17 (Continued) DBCP: INHALATION FERTILITY STUDY IN THE RAT* HERITABLE TRANSLOCATION STUDY Individual Observations Hade at the Time of Necropsy of Unexposed Female Rata Hated with Ft Hales of DBCP Exposed Hale Rata Exposure Level: 0.1 ppa Ehr Number DBCP Exposed Hales 1057 1058 1059 1060 1062 1063 106*1 1066 1066 1068 1069 1070 1072 1073 107*i 1075 1175 1077 1078 1181 Mean+S.D. Ear Number Fx Kale Ear Number Female Corpora Lutea Implantations 2201 36*11 13 220*1 36*12 36*13 17 13 2206 36*1*1 36*i5 15 11 2208 361*6 36U7 15 12 361*8 non-pregnant 2210 361*9 non-pregnant 3650 1*( 2212 3651 non-pregnant 3652 13 No Fi pups. (3653, 365*1 females were not bred) 2213 3655 3656 non-pregnant non-pregnant 2215 3657 12 3658 13 No F] pups. (3659, 3660 females were not bred) 2217 3661 12 3662 16 2220 3663 non-pregnant 366*1 16 2221 3665 15 3666 12 No Fi pups. (3667. 3668 females were not bred) 2223 3669 1*1 3670 non-pregnant 2225 3671 18 3672 non-pregnant 2228 3673 13 367*1 1*( 2229 3675 3676 18 17 2231 3677 13 3678 12 223* 3679 15 3680 16 12 16 lit 16 11 1*( 15 13 15 13 12 15 1*( 17 15 12 1*( 20 15 1*1 16 16 15 13 16 16 1*(2 152 Total fertile Bales 16 Resorptions 0 1 0 2 0 1 1 1 0 2 0 0 0 1 1 0 0 0 3 0 3 1 0 2 1 0 0.7+0.6 A Pre-Imp Loss 7 0 It 0 7 0 k 6 0 0 0 0 0 3 0 0 23 A Post-Imp Loss 3 6 h 7 8 0 8 0 6 l* 0 0 10 12 8 3 5i*( DO 1 3 1 3 3 9 O O NFIDFNTTAl -312- Table A-17 (Continued) DBCP: INHALATION FERTILITY STUDY IK THE RAT* HERITABLE TRANSLOCATION STUDY Individual Observations Hade at the Tine of Necropsy of Unexposed Female Rats ' Hated with Fi Halea of DBCP Exposed Hale Rata Exposure Level: 1.0 ppa An Inal Ituaber DBCP Exposed Halea 77-7608 7609 7610 7611 7612 7613 761H 7615 7616 7617 7618 7619 7620 7621 7622 7623 ?62li 7625 7626 7627 thr Humber DBCP Exposed Hales 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1110 1111 1112 1113 1114 1115 1116 1117 1118 Mean+S.D. Ear Number Fi Hale Ear Number Female Corpora Lutea Implantations 2235 3681 15 2238 3682 3683 17 16 3684 15 2239 3685 3686 17 non-pregnant 2242 3687 non-pregnant 3688 16 2243 3689 17 2245 3690 3691 15 non-pregnant 3692 13 No Fj pups. (3693, 3694 females vere not bred) 2247 3695 3696 13 non-pregnant 2250 2251 3697 3698 3699 3700 14 non-pregnant 14 16 2253 3701 non-pregnant 3702 15 2256 3703 15 3704 16 2257 3705 3706 18 14 2260 3707 18 3708 12 2261 3709 13 2263 3710 3711 17 non-pregnant 2266 3712 3713 16 16 2268 3714 3715 14 16 3716 15 2270 3717 13 3718 13 2271 3719 14 3720 12 13 13 15 13 17 16 16 14 12 13 13 14 15 13 14 15 14 14 11 13 10 11 12 16 15 16 15 15 13 12 1 15+1 13+2 Total fertile males 19 Resorptions 0 1 2 1 0 1 1 2 5 2 0 1 0 1 3 1 1 1 1 0 0 2 1 1 3 0 0 0 0 0 1 1.1+1.2 A Pre-Imp Loss 18 10 0 0 6 B 0 7 3 13 6 11 20 29 25 0 0 0 53 11+14 4 A Post-lap Loaa 4 10 0 6 10 42 15 0 M 8 14 7 k 9 8 13 0 0 50 11+13 -113- Tahla A1T (Continued) MCPt IttALATIOI VtRTlLm STUDT Hi THE RAT1, HERITABLE TRAHSLOCATIOI STUDT Individual Observation* mda at tN lcrgp*r of Unaspoiad f*ml* Rat* Mated with Ft Htiei of DSCP Iipowl mi* Rati txpoaon Level: 10 ppa Anlaal luafcar DBCP bpoaad felts T7-T6T8 7679 7680 7681 7682 TS83 7686 1665 7686 7687 7688 T689 7690 T6OT. T6SO 7693 769k 7695 7696 7697 br fiwbor DSCP bpoaad felas 1136 1137 1138 1139 11to 1161 1162 1163 1166 1165 1166 1167 1168 U69 U50 U51 1152 1153 1156 1155 Ear Ruabar Pi Mala 8273 2276 2277 2279 2282 2286 2286 2287 2290 2291 2293 2293 2298 2300 2301 2303 2305 2308 2309 2311 hr mtoar Pmal* 3721 3722 3723 3726 372S 3726 3727 3728 3729 3730 3T31 3732 3733 3736 3735 3736 3737 3738 3739 3T60 3761 3762 3763 3766 3765 3T66 3767 3768 3769 3750 3751 3752 3753 3T56 3755 3756 3757 3758 3759 3760 Corpora lutaa luplaatatlona 16 13 16 16 13 16 15 13 12 16 15 13 13 no(^pregnant 23 17 noo-pregnant 16 noi^pregnant 16 16 15 noo-pregnant U noo-pregnant noo-pregnant ooo-prcgnaat U 12 non-pregnant IT 20 16 noa-pregnant noo-pregnant 001^pregnant no0-pregnant 16 ooiwpregnant 15 12 10 u 12 16 16 16 13 16 9 15 16 15 15 17 IT 16 16 13 u 10 15 13 16 16 11 16 l*orption 1 1 0 2 2 0 0 0 0 0 1 1 0 0 0 1 0 1 1 1 0 1 0 0 1 0 0 HaaaS* D* l6t2 16i2 0.510.5 Total fertile ml** * 18 *Fq ml* rata vara exposed to 0, 0.1* 1*0, or 10 ppa of CP by Inhalation for 6 hr/day, 5 days/vaak for it vaeks* During tha firtt uaak poat*axpoaurat each ml* rat ai homed with an unaapoead fml rat* mlaa rsuiting fret this mtlng vara raisad to Hturlty sad housod with tuo \mxpo**d feaaleo for 7 day** Tha araraga value* tor tha too wexpoead fatal* rats brad to aaeh ?\ aal* vara calsulatad* Group m*n* vara than ealculatad fro* tha araragad valuta* A Pr*>l*9 Lo 22 10 0 k 22 0 0 18 0 0 6 0 k 0 27 0 31 0 Sill A to*t-flp Lots 9 0 7 0 0 T 0 0 0 e 9 0 T 0 6 0 0 b+4 00 131340 OONF T OF NT T Al -314- TABLE A-10 DBCP: INHALATION FERTILITY STUDY IN THE RATf Hale Rat: Hematologic Evaluation Week of Study: -1 An Inal Number ppm DBCP PCV RBC x Hgb WBC x WBC Differential Count % lO^/mo? k/100 ml 103/ma3 Heut Lymph Mono Eos In Baao 77-7454 7455 7V56 7457 7*158 Mean S.D. 0 $2.0 53.0 51.5 52.0 50.0 51.7 *1.1 8.05 9.82 8.77 8.60 8.02 8.65 *0.73 15.4 16.6 15.9 17.0 14.7 16.0 1.0 18.5 15.6 18.8 22.0 26.6 20.3 4.2 13 84 4 95 4 90 6 91 12 84 8 89 12 10 33 30 40 21 0 0 0 0 0 0 7524 7525 7526 7527 7528 0.1 50.0 *19.0 1)7.0 51.0 50.0 8.78 8.78 8.1)8 9-83 9.10 15.5 15.7 15.6 16.1 16.5 21.3 21.8 22.3 23.0 19.0 6 87 6 88 11 78 10 85 9 87 41 42 92 50 31 0 0 0 0 0 Mean 3. D. 7593 759*i 7595 7596 7597 Hean S.D. 1.0 1)9- * *1.5 *19.5 1)9.0 50.0 1)9.0 50.0 *9-5 0.5 8.99 *0.52 8.74 8.55 8.91 8.99 8.99 8.84 0.19 15.9 *0.4 16.5 15.8 16.1 16.3 16.4 16.2 10.3 21.5 1.5 21.0 22.0 17.8 20.9 17.7 19.9 *2.0 9 85 13 86 16 81 7 93 12 85 4 96 10 88 51 01 30 00 21 00 11 0 0 0 0 0 0 0 7660 10.0 1)7.0 8.45 15.4 15.6 14 80 51 0 7669 1)7.0 8.82 15.4 22.2 6 88 15 0 7670 45.0 8.58 15.8 17.8 6 90 13 0 7671 50.0 9*03 16.0 13.2 6 90 22 0 O 7672 52.0 9.04 16.6 19.0 3 91 33 0 Mean 48.2 8.76 15.8 17.6 7 88 23 0 S.D. *2.8 0.26 +0.5 3.4 jJ r.ONF TDFNTT -317- TABLE A-19 DBCP: INHALATION FERTILITY STUDY IN THE RATf Female Rat: Hematologic Evaluation Week of Stu4y: -1 Animal Number ppm DBCP PCV RBC x Hgb VBC x WBC Differential Count 5 ]t 106/BM? k/100 ml 10^/W Neut Lymph Mono Eos in Baao 7T_Tmii 7kk5 7kk6 7<*l*7 7LLS 0 k6.5 k7.0 k6.0 k7.5 k6.0 8.27 7.28 7.8k 8.23 8.11 Mean 3.D. k6.6 0.7 7.95 0.kl 751*1 7515 7516 7517 7518 0.1 k3.5 k5.0 k8.0 kk.O k6.0 7.56 8.10 8.30 7.22 7.90 Mean S.D. k5.3 1.8 7.82 +0.k3 7583 758k 7585 7586 7587 1.0 ka.o k7*5 52.0 k.5 k6.0 8.02 8.91 7.6k 8.8k 7-71 Mean 3 * D k8.6 +2.3 8.22 0.61 7653 10.0 k7.0 8.73 765k k7.0 7-93 7655 5k .0 9.51 7656 50.0 8.29 a 7657 k7.0 8.96 Mean 1a) S.D. 'jJ k9.0 +3.1 8.68 10.61 15.1 lk.2 lk.k 15.5 lk.6 lk.8 0.5 13.8 15.6 15.9 13.7 15.1 lk.8 +1.0 15.9 15-5 lk.7 16.6 15.0 15.5 +0.8 15.8 15.2 17.9 16.2 15.7 16.2 +1.0 13.7 17. k 22.0 11.0 13.7 15.6 ik.3 lk.O 11.8 12.8 12. k 12.7 12.7 0.8 12.0 12.9 11.5 9-6 9.6 11.1 +1*5 10. k 11.3 13.6 lk.O 8.5 11.6 2.3 k 90 17 79 k 96 6 92 3 90 7 90 7 89 8 87 6 93 lk 86 10 86 9 88 3 96 7 89 6 9k 10 88 5 93 6 92 19 79 k 95 3 96 9 90 8 90 8 90 2k 31 00 20 52 21 22 23 10 00 0k 12 01 k0 00 02 02 1l 11 01 10 01 11 11 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 C O N FID FN fT CONFTDFNTI Z> o LJ J> -318- Animal Number ppm DBCP 77-7>t^>t TliliS 7446 T*t*t7 7448 Mean 43.D. 7514 7515 7516 7517 7518 Mean JS.D. 7583 7584 7585 7586 7587 Kean S.D. 7653 7654 7655 7656 7657 Kean S.D. 0 0.1 1.0 10.0 TABLE A-19 (Continued) DBCP: INHALATION FERTILITY STUDY IN THE RAT^ Female Rat; Hematologic Evaluation Week of Study: 9 PCY 49*0 54.0 48.0 48.5 49.0 49.7 42.4 46.0 45.0 53.0 50.5 45.0 47.9 3.6 51.0 50.0 50.0 53.0 47.0 50.2 2.2 50.0 50.0 52.0 48.0 47.0 49.4 *1.9 RBC x 10/mu? 8.37 9.14 8.4l 8.62 7.99 8.51 40.42 8.12 7.65 8.88 8.66 7.46 8.15 40.62 7.43 8.37 8.02 8.21 7.43 7-89 0.43 B.78 7.80 8.32 7.83 7.85 8.12 0.43 Hgb g/100 ml 15.5 17.9 15-7 16.0 15-2 16.1 41.1 15.1 15.6 17.3 16.8 15.1 16.0 1.0 15.6 16.2 16.4 16.3 15.4 16.0 10.4 16.1 15.8 16.4 15.3 15.7 15.9 10.4 WBC x 10^/mm? 10.8 8.6 11.3 10.3 9-8 10.2 41.0 9.8 9.8 10.6 9-4 6.5 9.2 1.6 12.0 10.5 10.8 16.2 10.1 11.9 2.5 13.0 18.9 14.9 13.0 10.7 14.1 3.1 Neut 7 10 11 7 22 12 6 9 17 27 17 15 8 8 9 7 12 9 10 10 8 22 7 11 WBC Differential Count % Lymph Mono Eosln 90 1 2 89 0 1 86 3 0 91 1 1 75 2 1 86 1 1 87 4 3 88 2 1 83 0 0 63 6 4 78 1 4 80 3 2 87 5 0 90 1 1 90 1 0 91 1 1 85 2 1 88 2 1 86 1 3 86 1 3 87 2 3 75 0 3 91 1 1 85 1 3 Baso 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 -319- TABLB A-19 (Continued) DBCP: INHALATION FERTILITY STUDY IN THE KATt Female Rat: Hematologic Evaluation Meek of Study: 13 Animal Number PP* DBCP PCV BBC x Hgb WBC x WBC Differential Count % 106/mr3 g/100 ml 103/nm3 Heut Lymph Mono Eosln Baao 77-7kkk 7kk5 7kk6 7kk7 7kk8 0 k7.0 50.0 k3>0 52.0 50.0 8.17 8.17 7.51 7.90 8.67 15.7 17.1 lk.7 15.6 17.2 9.8 8.9 19. k 17.5 12.k 7 92 9 88 16 77 19 77 7 91 10 03 25 22 02 0 0 0 0 0 Mean S.D. k8.li *3.5 8.08 0.k2 16.1 *1.1 13.6 k.7 12 85 12 0 751k 7515 7516 7517 7518 0.1 k8.0 k7.0 52.5 k7.0 kfi.O 8.37 8.00 8.16 7.85 7-99 15-3 15.8 17.0 15.7 16.2 13.2 9-0 lk.O 11.7 7.6 9 86 20 79 11 87 17 80 10 88 k1 01 02 12 02 0 0 0 0 0 Mean S.D. k8.5 2.3 8.07 0.19 16.0 +0.6 11.1 2.7 13 6k 12 0 7503 758*1 7585 7586 7587 1.0 k9.5 k7.0 5k.5 51.0 k7.0 7.76 8.02 8.56 8.11 7.32 16.5 15.5 17-7 16.7 15.6 12. k 10.5 a.k 15.5 11. k 6 91 11 85 lk 85 16 75 8 90 21 0k 10 k5 22 0 0 0 0 0 Mean S.D. k9.8 3.1 7.95 +0.k6 16.k +0.9 11.6 +2.6 11 85 22 0 7653 765*1 7655 7656 7657 10.0 51.0 k9.0 52.0 k7.0 k6.5 a.ki 8.75 a.k5 7.85 8.65 17.3 16.9 17.7 16.2 16.5 9.3 11.8 17.2 13.8 8.9 11 83 22 69 16 78 7 93 16 81 k2 36 33 00 21 0 0 0 0 0 5 Mean k9.1 8.k2 16.9 12.2 15 81 22 0 S.D. 12.k 0.35 0.6 3.k r- 0) ^Female rats were exposed to 0. 0.1, 1.0. or 10 ppn of DBCP by Inhalation for 6 hr/day, 5 days/week for Ik weeks. Following termination of the exposure period, snlaale were aa lntained In the laboratory n>r recovery OONFTDFNTT -320- TABLB A-20 DBCP: INHALATION FERTILITY STUDY IN THE RATf Hale and Female Rats: Prothrombin Time Animal Number Hale Bate____________________________ ppm Prothrombin Time [seconds) DBCP 9 weeks 13 weeks 77-7k5k 7k55 7k56 7k 57 7k58 0 [lean t S.D. 752k 7525 7526 7527 7528 0.1 Hean t S.D. 7593 759k 7595 7596 7597 Mean 7668 7669 7670 7671 7672 1.0 10.0 Mean i S.D. 2k. 3 19.2 18.2 13.8 20.6 19-2 i 3.8 30.3 15.1 21.8 20.8 19.8 21.6 5.5 23.3 30.1 21.1 15.6 27-1 23.k + 5.6 16.1 16.3 39-5 18.1 __ & 22.5 11.k lk.2 15.8 __a, 15.3 lk.l lk.9 0.8 15-8 18.6 13.3 15-1 15-3 15.6 + 1.9 13.3 15.9 lk.9 16.3 18.6 15.8 + 1.9 lk.3 13.k lk.l 16.1 12.3 lk.O t l.k ___________________________ Female Rata Animal ppm Prothrombin Time (seconds) Number DBCP 9 weeks 13 weeks 77-kkkk 7kk5 7kk6 7kk7 7kk8 0 Kean S.D. 751k 7515 7516 7517 7518 0.1 Kean t S.D. 7583 758k 7585 7586 7587 Mean * S.D. 1.0 7653 765k 7655 7656 7657 10.0 Mean S.D. 23.6 29.6 35.1 35.8 33.1 31>k + 5.0 13.8 18.3 25.1 21.6 22.1 20.2 1 k.3 20.8 17.1 19.3 19.6 18.1 - 19.0 * l.k 25.1 27.3 28.1 31.1 5k.2 33-2 11.9 15.1 15-6 16.6 16.1 lk.6 15.6 + 0.8 lk.6 16.6 18.1 15.3 17.8 16.5 1.5 16.5 15.8 16.1 lk.3 16.1 15.8 + 0.9 11.8 15.1 15.6 16.5 lk.l lk.6 t 1.8 *Rata were exposed to 0, 0.1, 1.0, or 10 ppm of DBCP by Inhalation fbr 6 hr/day, 5 daya/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. aData not available, blood sample clotted. DO 1 3 1 3 4 5 CO NFIDFNT T I> n O Z? Z3 3 "H -* Z U! -H X* . -< O' I> -321- TABLE fl-gl DBCP: INHALATION FERTILITY STUDY IN THE RAT1 Hale and Female Rat; Clinical Cherniatry Values Animal Humber Hale Rata (l4th Week) ppm BUN, S0PT, DDCP mg/100 ml nil/ml AP, riJ/ml _______________________ Female Rata (l4th Week) Animal ppm ---------------- m:----------- .....flaw;-- Number DBCP fflg/100 ml nll/ml AP, mU/ml 77-7454 7455 7456 7457 7*>58 0 Hean S. D. 77-T52** 7525 7526 7527 7528 0.1 Mean S.D. 77-7593 759*1 7595 7596 7597 1.0 Mean S.D. 77-7668 7669 7670 7671 7672 10.0 Kean S.D. 16 20 18 20 16 18 2 19 20 20 19 16 19 2 18 15 IT l*i 1*1 16 a 2 1*1 1*1 22 17 17 17 + 3 28 29 25 23 23 26 3 25 103 30 2*1 23 41 35 2*i 2*i 36 27 36 29 6 23 31 31 23 30 28 + *t 52 65 67 52 5*t 58 7 60 232 5*t **6 *t9 88 80 66 37 58 I18 83 58 a 18 82 64 73 63 53 67 11 77-7444 7*i *t5 7446 7*t*t7 7448 0 Hean S.D. 77-751** 7515 7516 7517 7518 0.1 Hean S.D. 77-7583 7584 7585 7586 7587 1.0 Mean a S.D. 77-7652 7654 7655 7656 7657 10.0 Mean S.D. 16 16 21 18 16 17 t 2 18 14 13 20 18 17 3 15 17 19 19 IT 17 a 2 18 18 15 15 16 16 2 20 15 23 20 17 19 3 17 14 16 14 21 16 3 19 20 IT 15 19 18 a 2 22 14 19 33 23 22 7 36 46 74 42 36 47 16 38 49 48 38 33 41 7 39 29 31 35 30 33 a 4 53 65 34 81 45 56 18 *Rats were exposed to 0, 0.1, 1.0, or 10 ppm of DBCP by Inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained In the laboratory for recovery. -322' Table A-22 DBCP INHALATION FERTILITY STUDY IN THE RATf Male Rati PSH and Testosterone level* Week of AnInal ppm Study Number DBCP FSH(nanogram/ml) Testoaterone(nanoqram/ml) 77-7464 0 7465 7466 7467 7468 MeantS.D. 77-7534 0.1 7535 7536 7537 7538 MeaneS. D. 400 306 266 293 280 309153 320 333 320 233 416 324165 1.6 2.7 2.4 8.0 3.0 3.5*2.5 4.9 2.7 2.7 1.2 2.3 2.811.3 77-7603 1.0 7604 7605 7606 7607 MeanS.D. 266 233 233 350 333 283155 6.4 3.2 2.8 2.2 2.3 3.411.7 77-7673 10.0 7674 7675 7676 7677 MeanS. D. 383 450 433 375 320 392151 6.8 3.5 1.4 5.1 4.9 4.312.0 14 77-7454 0 7455 7456 7457 7458 MeamS.D. 193 533 200 333 226 2971143 0.6 0.6 0.8 1.2 0.4 0.710.3 77-7524 0.1 7525 7526 7S27 7528 MeanS.D. 220 233 180 206 233 214122 1.6 0.9 1.0 4.0 3.4 2.211.4 77-7593 1.0 7594 7595 7596 7597 MeamS.D. 306 333 320 266 280 301128 2.6 3.3 0.7 0.6 2.5 1.911.2 77-7668 10.0 7669 7670 7671 7672 MeaniS.D. 383 333 280 383 293 334148 0.6 0.4 0.7 2.7 0.4 1.011.0 fMale rats were exposed to 0, 0.1, 1.0, or 10 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. DO 131347 CONFTDFNTTAt -323- Table A-23 DBCP INHALATION FERTILITY STUDY IN THE RAT1 Female Rat; FSH levels week of Study Animal Number ppm DBCP FSB(nanoqram/ml) 77-7449 7450 7451 7452 7453 Mean*S.D. 0 113 173 113 173 147 144*30 77-7519 7520 7521 7522 7523 Mean*S.D. 77-7588 7589 7590 7591 7592 Mean*s. D. 77-7658 7659 7660 7661 7662 MeantS.D. 0.1 1.0 10.0 147 113 157 127 193 147*31 383 193 133 127 140 195*108 167 167 333 206 173 209*71 77-7444 7445 7446 7447 7448 MeanaS.D. 77-7514 7515 7516 7517 7518 MeanS.D. 77-7583 7584 7585 7586 7587 MeanaS. D. 0 0.1 1.0 100 83 133 120 157 119*29 167 280 226 87 120 176*78 113 100 70 140 157 116*34 77-7652 7653 7654 7655 7656 HeanSS.D. 10.0 167 147 120 167 100 140*30 fFemale rata were exposed to 0, 0.1, 1.0, or 10 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. DO 131348 OONFTDFNT TAt -324- TABLE A-24 DBCP: INHALATION FERTILITY STUDY IN THE RAT* Hale Rati Urinalysis Week of Study: 9 Animal Number ppm DBCP Specific Gravity P Sugai 7T-7454 T>t 55 7*56 7*t 57 7^58 Mean+S. D. 752*1 7525 7526 7527 7528 MeanlS. D. 7593 7594 7595 7596 7597 MeanS. D. 7668 7669 7670 T6T1 7672 MeantS.D. 0 0.1 1.0 10.0 1.040 6.5 Neg 1.044 6.0 Neg 1.042 7.0 Neg 1.040 7.0 Neg Unable to obtain a sample 1.042+0.002 Unable to obtain a sample 1.032 6.5 Neg Unable to obtain a sample 1.056 6.0 Neg 1.040 7-0 Neg 1.0430.012 Unable to obtain a sample 1.058 7.0 Neg 1.066 6.5 Neg 1.052 7*0 Neg 1.064 6.0 Neg 1.060+0.006 Unable to obtain a Bample 1.030 7.0 Neg 1.028 6.5 Neg 1.040 6.5 Neg Unable to obtain a sample 1.0330.006 Protein 2+ 1+ 1+ 3+ 1+ 3+ 3+ 2+ 3+ 2+ 2+ 2+ 1+ 3+ Ketones Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Bilirubin Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Blood Neg Neg Neg Neg Urobilinogen 1.0 1.0 1.0 1.0 Neg 1.0 Neg 1.0 Neg 1.0 >te8 1.0 Neg 1.0 Neg 1.0 Neg 1.0 Neg 1.0 Neg 1.0 Neg 1.0 DO 1 3 1 3 4 9 CONF TDFNTT, I> O O N F ID F N T T A L -325- TABLE A-24 (Continued) DBCP: INHALATION FERTILITY STUDY IN THE RAT* Male Rat; Urinalysis Week of Study: 13 Animal Number ppm DBCP rT-7454 7*i55 7*i56 7457 7*i 58 MeanlS.D. 7524 7525 7526 7527 7528 MeanlS.D. 7593 759*i 7595 7596 7597 MeaniS. D. 7668 7669 . 7670 7671 7672 MeantS. D. 0 0.1 1.0 10.0 Specific 0rarity _E*L Sugar Unable to obtain a sample 1.050 6.5 Neg 1.060 6.0 Neg 1.040 T.O Neg Unable to obtain a sample 1.05010.010 Unable to obtain a sample Unable to obtain a sample Unable to obtain a sample 1.070 6.0 Neg 1.038 6.5 Neg 1.05*H0.023 Unable to obtain a sample Unable to obtain a sample 1.05*) 6.5 Neg 1.066 7-0 Neg 1.040 7.0 Neg 1.053+0.013 Unable to obtain a sample 1.038 6.5 Neg 1.024 6.5 Neg 1.052 T.O Neg 1.022 6.5 Neg 1.0340.0l4 Protein 1+ 1+ 3+ 3+ 2+ 3+ 3+ 3+ ' 2+ 1+ 4+ 1+ Ketones Neg Neg Neg Heg Neg Heg Neg Heg Neg Neg Neg Heg Bilirubin Neg Reg Neg Neg Neg Neg Reg Neg Neg Neg Neg Neg Blood Neg Neg Neg Urobilinogen 1.0 1.0 1.0 Neg Small Neg Neg Neg Neg Neg Neg Neg 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 -326- TABLE A-2b (Continued) DBCP: INHALATION FERTILITY STUDY IN THE RAT* Male Rat: Urinalysis Veek of Study: lb* Animal Number pps DBCP rT-TliJlt 7*55 7456 7b57 7li58 MeaniS.D. 752* 7525 7506 7527 7528 Hean3.D> 7593 7591* 7595 7596 7597 MeanlS.D. 7666 7669 7670 7671 7672 MeanlS.D. 0 0.1 1.0 10.0 Specific Gravity pH Sugar 1.007 7.0 Neg 1.010 6.0 Neg 1.035 6.0 Neg 1.007 7-0 Neg 1.00k 7.0 Neg 1.01310.013 l.Obb 6.0 Neg 1.037 8.0 Neg 1.05b 7.0 Neg 1.052 6.0 Neg 1.050 6.0 Neg 1.0b7l0.007 1.050 1.02b 6.0 8.0 Neg Neg 1.036 6.0 Neg Unable to obtain a sample 1.026 6.0 Neg 1.031*10.012 1.02b 7-0 Neg 1.013 6.0 Neg 1.010 6.0 Neg 1.016 6.0 Neg 1.026 7.0 Neg 1.0l8l0.007 Protein 3+ 1+ 3+ 3+ Trace 3+ 3*3+ 3+ 3+ 3+ 2+ 3+ 3+ 3* 3* 2+ 3* 3* Ketones Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Bilirubin Neg Neg Neg Neg Neg Neg Heg Neg Neg Heg Neg Neg Neg Neg Neg Neg Neg Neg Neg Blood Neg Neg Neg Neg Trace Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Urobilinogen 1.0 1*0 1.0 1*0 1*0 1*0 1.0 1*0 1*0 1*0 1*0 1*0 1.0 1*0 1*0 1*0 1.0 1*0 1*0 *Male rate were exposed to 0, 0.1, 1.0, or 10 ppm of DBCP by Inhalation for 6 hr/dsy, 5 days/week for lit weeks. Following termination f the exposure period, animals were maintained in the laboratory for recovery. "Due to difficulty in obtaining urine samples from male rats during the 13th week, additional urine samples were obtained at the time f necropsy in the lbtta week. r.ONF TDFNT TAI n oo I> -328- TABLE A-25 (Continued) DBCP: INHALATION FERTILITY STUDY IN THE RAT* Female Rati Urinalysis Week of Study: 13 Animal Number ppm DBCP 7bb5 7bb6 7bb7 7bb8 Mean+S.D. 751b 7515 7516 7517 7518 MeanS.D. 7583 758b T585 7586 7587 MeanS. D. 7653 765b 7655 7656 7657 Mean+S. D. 0 0.1 1.0 10.0 Specific Gravity _25L 1.030 1.020 1.030 1.0b8 1.032 1.032+0.010 1.026 1.05b 1.050 1.03b 1.0b6 1.0b20.012 1.028 1.0b2 1.038 1.030 1.028 1.0330.006 l.ObO 1.038 1.036 l.ObO 1.026 1.0360.005 6.5 6.0 6.5 6.0 7-0 6.0 6.0 6.0 6.5 6.0 7.0 5-0 7.0 6.0 6.0 5.0 6.0 , 6.0 6.0 6.5 Sugar Neg Neg Neg Neg Neg Reg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Protein Trace 2+ 1+ 2* Trace Trace 1+ 2+ Trace 3+ Trace -Trace 3+ 1+ 1+ Trace 1+ 2+ 2+ 2+ Ketones Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Reg Neg Neg Neg Neg Neg Neg Neg Neg Neg Bilirubin Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Reg Neg Neg Neg Neg Neg Blood Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Keg Neg Neg Neg Neg Heg Neg Neg Heg Urobilinogen 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 *Female rats were exposed to 0, 0.1, 1.0, or 10 ppm Following termination of the exposure period. DBCP by inhalation for 6 hr/day, 5 days/week for lb weeks-- were relntained in the laboratory for recovery. -329- Table A-26 DBCP: INHALATION FESTILITT STUDY IK THE HATf Hale Rat; Individual Organ Weights and Organ/Body Weight Ratios Determined at the Interim (li weeks) Sacrifice Animal Humber Exposure Level PP" Final Bexhr Height (g) ___________________________________________Organ Heights (a and g/lOOg Body Height) BRAIN HEART LIVER KIDNEYS g/100g g/lOOg g/100g -s- g/100g TESTES g/100g 77-7A6A 7*165 7*i 66 7*i67 7*t 68 Mean 4S.D. 77-753*t 7535 7536 7537 7538 Mean 2S.D. 77-7603 760A 7605 7606 7607 Mean iS.D. 77-7673 767*1 7675 7676 7677 Mean IS.D. 0.0 0.1 1.0 10.0 569.0 573.0 569.0 502.0 *l92.0 5*tl.O 4A0.A *>95.0 550.0 555.0 1)87.0 559.0 529.2 35.1 608.0 318.0 527.0 1)97*0 529-0 535-8 2*12.3 519.0 1)71.0 1)66.0 1)88.0 53*) .0 *29.8 1.9*) 1.95 2.05 2.00 2.01 0.3*) 0.3*) 0.36 0.1)0 0.1)1 1.99 0.37 4O.O5 40.03 I.96 1.91 2.05 1.90 2.06 1.98 40.08 0.1)0 0.35 0.37 0.39 0.37 0.37 40.02 2.10 1.96 1.91 2.06 1.98 2.00 40.08 2.11 1.92 1.9*) 2.06 2.10 0.35 0.38 0.36 0.1)1 0.37 0.37 20.03 0.1)1 0.1)1 0.1)2 0.1)2 0.39 2.03 0.1)1 0.09 0.01 1.65 1.83 1.57 1.56 1.5*1 1.63 0.12 0.29 0.32 0.28 0.31 0.31 0.30 40.02 1.1)2 1.87 1.68 1.3*1 1.63 0.29 0.3*) 0.30 0.28 0.29 1.59 0.30 20.21 40.02 1.59 1.A6 1.55 l.H 1.51 1.51 20.06 0.26 0.28 0.29 0.29 0.29 0.28 40.01 1.1)9 1.1)7 1.25 1.51 1.5*1 0.29 0.31 0.27 0.31 0.29 1.1)5 0.29 0.12 0.02 19.28 21.33 20.1)2 17-17 18.80 3.39 3-72 3.59 3.*>2 3.82 19>*)0 1.59 16.36 19-53 16.15 1*).25 20.32 17.72 42.1)6 3.59 40.19 3.31 3.55 3.27 2.93 3.6*) 3.3*) 40.28 25-10 18.23 16.91 17-09 16.69 *).13 3.52 3.59 3.*)*) 3.53 19.60 23.15 18.73 17-83 18.63 18.0*) 20.81 3.6*) 40.28 3.61 3.79 *).00 3.70 3.90 16.81 3.80 1.18 0.15 *).12 3-92 *).08 3.86 3.90 3.98 4O.12 0.72 0.68 0.72 0.77 0.79 0.71) 40.0*) 3.29 3.76 3.56 2.9*1 *>30 3.57 20.51 3.99 3.51 3.1)0 3.80 3-99 3.7*) 20.27 3.61 3.78 3.79 3.32 *1.15 0.66 0.68 0.64 0.60 0.77 0.67 4O.06 0.66 0.68 0.65 0.76 0.75 0.70 20.06 0.70 0.80 0.81 0.68 0.78 3.73 0.75 0.30 0.06 *). 31 *).6o A. *>9 1). 21 1>.22 0.76 0.80 0.79 0.8A 0.66 *1.37 0.81 +0.17 40.0A A. 20 A.23 t>.06 A. 1)2 A. 23 0.85 0.77 0.73 0.91 0.76 A. 23 0.80 20.13 20.07 A.20 3.98 3.9A 3.95 3.80 O.69 0.77 0.75 0.79 0.72 3.97 0.7A 20.1A 20. OA A.29 A. 17 A.OA A. 15 A. 10 0.83 O.89 0.87 0.85 0.77 A.15 0.8A 0.09 0.05 EPIDIDYMIDES g/100g * 1.60 1.58 1.A7 1.63 __a 0.28 0.28 0.29 0.33 1.57 0.29 40.06 40.02 1.51 1.37 1.55 1.A8 1.5A 0.31 0.25 0.28 0.30 0.28 I.A9 0.28 20.07 20.02 1.A3 1.A2 1.30 1.A8 1.5A 0.2A 0.27 0.25 0.30 0.29 1.A3 0.27 20.09 20.03 1.6A 1.50 1.A8 1.38 1.57 0.32 0.32 0.32 0.28 0.29 1.51 0.31 0.10 0.02 CONFTDFNTT in 10 -330- Table A-26 (Continued) DBCP: INHALATION FERTILITY STUDY IN THE RAT* Hale Rati Individual Organ Weighta and Organ/Body Weight Ratlog Determined at the Interla (lk weeks) Sacrifice Animal Hunger Exposure Level ppm Final Body Height (g) ___________________________________________Organ Weights (g and g/lOOg Body Weight) BRAIN HEART LIVER KIDNEYS TESTES g/lOOg 6 g/lOOg K/100g g/lOOg -S- g/lOOg 77-7k5k 7*55 7k56 7k 57 71*58 Mean +S.D. 77-752** 7525 7526 7527 5828 Mean iS* D* 77-7593 759*t 7595 7596 7597 Mean iS.D. 77-7668 7669 7670 7671 7672 Mean S.D. 0.0 0.1 1.0 10.0 1*68.3 506.1 528.1* 586.6 1*91*.2 516.7 kk.7 V61.8 538.8 529.7 578.9 578.1 537.5 1*7.8 550.6 526.5 1*91.6 5kk.7 1*98.1* 522.1* 26.6 1*68.8 507.6 1*83.6 1*81.5 517.8 1*91.9 20.2 1.95 2.00 1-97 2.00 2.01 0.1*2 0.1*0 0.37 0.3l* o.ltl 1.99 0.39 0.03 0.03 1.96 .2.03 * 1.9*1 2.05 2.08 0.1*2 0.38 0.37 0.35 0.36 2.01 0.38 0.06 0.03 2.10 2.06 1.87 2.13 1.97 0.38 0.39 0.38 0.39 0.1*0 2.03 0.39 0.11 0.01 1.93 1.83 1.98 1.96 1.9k 0.1*1 0.36 0.1*1 0.1(1 0.37 1-93 0.06 0.39 0.02 1.50 1.51* 1.1*8 1.77 1.51* 0.32 0.30 0.28 0.30 0.31 1.57 0.30 0.12 0.01 1.1*6 1.59 1.85 1.88 1.56 0.32 0.30 0.35 0.32 0.27 1.67 0.31 0.19 0.03 1.55 I.9I* 1-79 1.66 1.50 0.28 0.37 0.36 0.30 0.30 1.69 0.32 0.18 0.01* 1.52 1.1*3 1.1*3 1.1*9 1.55 0.32 0.28 0.30 0.31 0.30 1.1*8 0.30 0.05 0.02 11*. 65 13-33 13.89 16.67 12.1*5 3.13 2.63 2.63 2.8k 2.52 Ik.20 2.75 1.60 0.2k 11.53 15. k3 13.66 16.16 lk. 10 2.50 2.86 2.58 2.79 2.1*1* lk. 18 2.63 1.79 0.19 16.53 lk.36 13.51 lk.k2 13.00 3.00 2.73 2.75 2.65 2.61 lk.36 2.75 1.35 0.15 12.89 15.6k lk.91 lk.8l 16.6k 2.75 3.08 3.08 3.08 3.21 lk.98 1.38 3.0k 0.17 3.58 3.32 3-29 k.19 3.12 0.76 0.66 0.62 0.71 0.63 3.50 0.68 0.k2 0.06 3.2k 3.63 3.81 k.l*8 3.kl 3.71 0.1*8 0.70 0.67 0.72 0.77 0.59 0.69 0.07 k.k9 3.92 3.1*2 3.70 3.26 0.82 0.7k 0.70 0.68 O.65 3.76 0.72 0.k8 0.06 k.15 3.83 3.67 3.8k k.38 0.89 0.75 0.76 0.80 O.85 3.97 0.81 0.29 0.06 k.k6 1.68b k.26 3.7k 3.71 0.95 0.33" 0.81 0.6k 0.75 k.Ok 0.79 0.38 0.13 k.Ok k.05 k.16 >*.35 k.15 0.87 0.75 0.79 0.75 0.72 k.15 0.78 0.12 0.06 k.20 k.52 3.9k k.lk k.17 0.76 0.86 0.80 0.76 0.8k k.19 0.80 0.21 0.0k 2.k8 2.77 2.82 2.53 2.93 0.53 0.55 0.58 0.53 0.57 2.71 0.19 0.55 0.02 EPIDIDYMIDES g/lOOg 1.1*6 0.98b l.k3 1.6k 1.27 0.31 0.19b 0.27 0.28 0.26 l.k5 0.28 0.15 0.02 l.k9 1.50 l.kl 1.58 l.k9 0.32 0.28 0.27 0.27 0.26 1.1*9 0.28 0.06 0.03 1.53 1.57 1.38 l-k6 1.52 l.k9 0.07 0.28 0.30 0.28 0.27 0.30 0.29 0.02 1.01 1.1k 1.11 1.18 1.22 0.22 0.22 0.23 0.25 0.2k 1.13 0.23 0.08_ 0.01 U) GO On I> CONFTDFNTT -331- Table A-26 (Continued) DBCP: INHALATION FERTILITY STUDY IN THE RAT'* Hale Rati Individual Organ Weights and Organ/Body Weight Ratloa Determined at the Terminal (1.6 veeka) BaerIfIce Aniaal Number Exposure Level PP Final Body Haight (g) BRAIN g/lOOg 77-7 >*69 7>*70 7** 72 74 73 7474 7t75 7U76 7478 7*79 7*i80 7*i8l 7*162 7*i83 7*18*1 7485 7I.66 7*i88 0.0 601 575 597 560 618 520 558 62*t 619 596 601 619 661 618 712 65*. 580 2.10 1.99 2.01 2.00 2.07 1.9*1 2.06 2.1*. 2.09 2.03 2.13 2.10 2.16 2.09 2.11 2.02 1.96 0.35 0.35 0.3*1 0.36 0.34 0.37 0.37 0.34 0.34 0.34 0.35 0.34 0.33 0.34 0.30 0.31 0.34 Mean S.D. 607 2.06 0.34 44 10.06 10.02 77-7539 75*iO 75*1 75*i2 75*t3 75*1*1 75*i5 7546 75*i7 75*i8 75*i9 7550 7551 7552 7553 755* 7696 7555 7556 0.1 665 675 636 579 633 602 6I.9 61.2 61.2 669 656 640 682 637 576 717 660 693 622 2.09 2.01 2.09 2.10 2.13 2.11 2.17 2.07 2.15 2.15 2.04 1.95 2.15 2.02 2.08 2.08 2.06 2.05 1.99 0.31 0.30 0.33 0.36 0.34 0.35 0.33 0.32 0.33 0.32 0.31 0.30 0.32 0.32 0.36 0.29 0.31 0.30 0.32 Mean ' *S.D. 646 2.08 0.32 *36 *0.06 *0.02 Organ Weights (g and g/lOOg Body Weight) HEART LIVER KIDNEYS g/lOOg g/lOOg g/lOOg TESTES g/100g 2.07 1.69 1.78 1.75 1.94 1.68 1.89 2.08 1.69 2.03 1.80 1*75 2.02 1.73 2.02 1.87 1.75 0.34 0.29 0.30 0.31 0.31 0.32 0.34 0.33 0.27 0.34 0.30 0.28 0.31 0.28 0.28 0.29 0.30 1.86 0.31 10.14 10.02 1.68 1.74 1.72 1.65 1.93 1.67 2.00 1.73 1.93 1.92 2.11 1.71 1.81 1.90 1.98 2.09 1.81 2.04 1.65 0.25 0.26 0.27 0.28 0.30 0.28 0.31 0.27 0.30 0.29 0.32 0.27 0.27 0.30 0.34 0.29 0.27 0.29 0.30 1.86 0.29 *0.15 *0.02 20.36 i7.ll 19.82 16.09 16.13 20.07 15.91 14.39 18.01 19.93 21.21 23.63 22.69 21.17 21.89 21.76 17.85 3.39 2.98 3.32 2.87 2.61 3.86 2.85 2.31 2.91 3.34 3-53 3.82 3.43 3-43 3.07 3.33 3.08 19.30 3.18 12.70 10.41 20.63 17.00 19.91 17.48 19.36 18.26 19.51 17.60 20.26 21.33 23.01 21.42 17.90 22.73 16.60 25.40 22.34 20.75 15.49 3.10 2.52 3.13 3.02 3.06 3.03 3.01 2.74 3.16 3.19 3-51 3.35 2.62 3.57 2.88 3.54 3.38 2.99 2.49 19.84 *2.54 3.07 *0.32 6.00 4.44 5.33 4.11 4.81 7.29 4.47 4.06 4.79 5.01 6.08 5.60 4.96 4.62 5.14 5.02 4.17 1.00 0.77 0.89 0.73 0.78 1.40 0.80 0.65 0.77 0.84 1.01 0.90 0.75 0.75 0.72 0.77 0.72 5.05 0.84 10.83 10.17 5.43 4.25 4.66 4.31 5.29 4.37 4.93 4.44 4.61 5.65 5.78 5.03 4.42 5-71 4.44 5.39 6.03 5.54 4.44 0.82 0.63 0.73 0.74 0.84 0.73 0.76 0.69 0.72 0.84 0.88 0.79 0.65 0.90 0.77 0.75 0.91 0.60 0.71 4.99 *0.59 0.77 *0.08 4.48 4.10 4.64 4.12 4.38 3.60 *1.48 4.78 4.85 4.04 4.71 4.63 4.78 4.26 4.4l 4.52 4.22 0.75 0.71 0.78 0.74 0.71 O.69 0.60 0.77 0.78 0.68 0.78 0.75 0.72 0.69 0.62 0.69 0.73 4.4i 0.73 10.33 10.05 4.39 4.95 4.42 4.64 4.5B 4.8l 4.46 4.55 5.22 4.96 4.18 4.32 4.88 4.42 5.28 5.01 3.91 4.38 4.05 0.66 0.73 0.70 0.80 0.72 0.80 0.69 0.71 0.81 0.74 0.64 0.68 0.72 0.69 0.92 0.70 0.59 0.63 0.65 4.60 0.71 *0.38 0.08 EPIDIDYMIDES g/lOOg 1.64 1.45 1.49 1.50 1.67 1.48 1.87 1.72 1.82 1.63 4.28* 1.64 1.72 1.77 1.64 1.79 1.60 0.27 0.25 0.25 0.27 0.27 0.28 0.34 0.28 0.29 0.27 0.71* 0.26 0.26 0.29 0.26 0.27 0.28 1.66 0.27 10.14 10.02 1.68 1.67 1.58 1.80 1.87 1.75 1.48 1.56 1.91 1.89 1.58 1.69 1.90 1.83 2.03 1.84 1.66 1.80 1.66 0.25 0.25 0.25 0.31 0.30 0.29 0.23 0.24 0.30 0.28 0.24 0.26 0.28 0.29 0.35 0.26 0.25 0.26 0.27 1.75 0.27 10.14 0.03 r>0 1 3 1 3 5 5 00NFTDFNTTAI n o *n 'll ^ 2 !*) H Cn -* O' -332- Table A-26 {Continued) DBCP: UHAUmOB FERTILITT STUDT IB THE RAT* Bale Rati Individual Origin Weights and Organ/Body Weight Ratios Detenelned at the Terminal {weeta) Sacrifice AnInal Ifunbar Exposure Level ppm Final Body Height (g) BRAlIt ft g/100g Organ Weights (g and g/lOOg Body Height) HEART LIVER KIDKBIB Jt g/100g g/lOOg g/lOOg TESTES g/100 EPIDIDIMDEB g/100g 77-7606 7609 7610 7611 7612 7613 761k 7615 7616 761T 7618 T619 7620 7621 7622 7623 762k 7625 7626 7627 1.0 623 561 56T 521 655 681 607 617 606 698 608 38k 633 690 682 596 665 690 6kl 635 2.05 2.06 2.11 1.92 2.05 2.05 2.21 1.95 2.00 2.00 2.05 2.30 2.01 1.91 2.03 1-93 2.02 2.09 2.06 2.02 0.33 0.37 0.3T 0.37 0.31 0.30 0.36 0.32 0.33 0.29 0.3k 0.60 0.32 0.28 0.30 0.32 0.30 0.30 0.32 0.32 1.92 1.62 1.73 1.7k 1.96 1-97 1.82 1.62 1.67 2.10 2.09 1.50 1.83 1.82 2.22 1.58 2.18 1.87 1.92 2.11 0.31 0.29 0.31 0.33 0.30 0.29 0.30 0.26 0.28 0.30 0.3k 0.39 0.29 0.26 0.33 0.27 0.33 0.27 0.30 0.33 19.9k 15.37 17-23 19.19 18.65 18.06 16.17 16.98 16.12 22.26 23.17 13-78 19.30 20.01 21.38 19. T5 28. k8 19.91 2k.11 19.85 3.20 2.7k 3.0k 3.66 2.85 2.65 2.66 2.75 2.66 3.19 3.81 3.59 3.05 2*90 3.13 3.31 k.26 2.89 3.76 3.13 5.16 k.23 k.k7 5.55 k.9k 5-38 k.26 k.15 k.k3 5.75 5.19 3.77 k.65 k.6l 5.71 k.29 8.95 5.10 6.3k k.95 O.83 0.75 0.79 1.07 0.75 0.79 0.70 0.67 0.73 0.82 O.85 0.98 0.73 0.67 0.8k 0.72 1.35 0.7k 0.99 0.78 k.k2 k.25 k.29 3.73 5.00 k.U k.57 k.6l k.33 k.90 3-93 k.27 k.07 5.19 5.15 k.19 k.8o k.38 k.79 k.53 0.T1 0.76 0.76 0.72 0.76 0.60 0.75 0.75 0.11 0.70 0.65 1.11 0.6k 0.75 0.76 0.70 0.72 0.63 0.75 0.71 1.69 1.73 1.60 l.k2 1.81 1.52 1.86 1*70 1.66 1.89 l.k6 l.k9 1.60 1.87 1.96 1.5k 1.8k 1.65 1.79 1.56 0.27 0.31 0.28 0.27 0.28 0*22 0.31 0.2a 0.27 0.27 0.2k 0.39 0.25 0.27 0.29 0.26 0.28 0.2k 0.28 0.25 Bean S* D* 618 2.0k 0.3k 1.86 0.30 19. k3 3.16 5.09 0.83 k.k8 0.73 1.68 0.26 73 0.09 0.07 0.21 0.03 3.36 0.k5 1.11 0.16 0.k0 0*10 0.16 0,03 77-7678 7679 7681 7682 768k 7685 7686 7687 7688 7689 7690 7691 7692 T693 769k 7695 7696 7697 10.0 T3T 759 k39 722 631 60k 613 599 618 660 582 708 736 589 566 630 655 615 2.05 2.10 1-91 2.02 2.01 2.08 2.0k 1.97 2.05 1.97 1.8k 2.03 2.09 2.0k 1.92 2.05 2.06 1.9T 0.28 0.28 O.kk 0.28 0.32 0.3k 0.33 0.33 0.33 0.30 0.32 0.29 0.26 0.35 0.3k 0.33 0.31 0.32 2.02 2.15 1.8k 1.72 1.86 1.9k 1.99 2.39* 1.63 2.02 1.61 1.90 2.26 1.76 1-79 2.21 2.11 2.13 0.27 0.26 0.k2 0.2k 0.29 0.32 0.32 O.kO* 0.26 0.31 0.28 0.27 0.31 0*30 0.32 0.35 0.32 0.35 2T.37 22.57 15.19 20.87 19.63 20.52 19-33 19.11 1T.07 23. k8 18. T3 2k.51 2k. 61 18.32 19.20 23.17 21.27 19.95 3.71 2.9T 3.k6 2.69 3.11 3.k0 3.15 3.19 2.76 3.56 3.22 3.k6 3.37 3.11 3.39 3.68 3.25 3.2k 6.57 5.32 6.23 ' 5.12 5.13 5.96 5.31 5.32 k.21 5.3k 5.13 6. k3 5.60 k.k8 k.99 6.30 5.36 k.69 0.89 0.70 l.k2 0.71 0.81 0.99 0.87 0.89 0.68 0.81 0.88 0.91 0.79 0.76 0.88 1.00 . 0.82 0.76 k.62 k.05 2.31 k.29 k.08 k.20 k.32 3.8k h.09 k.lk k.kO 6.kl k.3k k.78 k.30 k.2k k.76 3.k0 0.63 0.53 0.53 0.59 0.65 0*71 0.70 0.6k 0.66 0.63 0.76 0.91* 0.59 0.81 0.T6 O.67 0.73 0.55 1.51 1.62 0.78 1.53 1.62 1.57 1.51 1.68 1.71 1.69 1.85 2.29* 1.72 1.93 1.7k 1.68 1.71 1.62 0.20 0.21 0.18 0.21 0.26 0.26 0.25 0.28 0.28 0.26 0.32 0.32" 0.23 0.33 0.31 0.27 0.26 0.26 Heaa 6* Qs 637 2.01 0.32 1.9k 0.31 20.8k 3.27 5-k3 0.86 k.13 0.66 1.62 0.26 77 0.07 O.Ok 10.20 0.0k 3.02 0.26 0.67 0*17 0.57 0.08 0.2k 0,0k 3Hale rata were exposed to 0, 0.1, 1.0, or 10 ppa of DBCP by Inhalation (hr 6 hr.day, 5 daya/veek for It weeks. Following termination of the exposure period, entasis were ealntalned In the laboratory for recovery. The weights of the epldldyaldea of animal numbera 77-7k6k t T7-Tk6l were not Included In the statistical analysis due to Inproper processing. -333- Table A-27 DBCP; INHALATION FERTILITY STUDY Ilf THE RAT* ?i. Rat! Individual Organ Weights and Organ/Body Weight Ratios Determined at the Interim tU weeks) Sacrifice AnInal Number 77-7449 7*i50 7451 7*t52 7453 Mean +S.D. 77-7519 7520 7521 7522 7523 Mean iS.D. 77-7568 7589 7590 7591 7592 Mean 3.D. 77-7658 7659 7660 7661 7662 Mean iS.D. Exposure Level ppm0.0 0.1 1.0 10.0 Final Body Weight (g) 306.0 209.0 262.0 330.0 319.0 285.2 49*8 316.0 301.0 286.0 299.0 307.0 301.8 11.0 311.0 276.0 279.0 309*0 331.0 301.2 23.3 2*i7.0 292.0 281.0 299.0 276.0 279.0 20.0 __________________________________ Organ Weights (g and g/lOOg Body Weight) BRAIN HEART LIVER R g/100g g g7ioog g g/4Qg 1.78 1.77 1.65 1.79 1.85 1.77 0.07 1.77 1.85 1.88 1.7*i 1.94 1.8*1 0.08 1.9** 1.79 1.73 1.86 I.89 1.8*1 0.08 1.80 1.78 1.7B 1.92 1.79 1.81 0.06 0.58 0.85 0.63 0.5*1 0.58 0.64 +0.12 0.56 0.61 0.66 0.58 0.63 0.6l 0.04 0.62 0.65 0.62 0.60 0.57 0.61 0.03 0.73 0.61 0.63 0.64 0.65 0.65 0.05 1.03 0.98 0.96 1.02 1.16 1.03 +0.08 1.00 1.00 0.92 0.97 1.04 0.99 o.o4 1.11 0.89 0.94 1.02 1.00 0.99 0.08 0.93 0.85 1.10 0.93 0.91 0.94 0.09 0.34 0.47 0.37 0.31 0.36 0.37 +0.06 0.32 0.33 0.32 0.32 0.34 0.33 0.01 0.36 0.32 0.34 0.33 0.30 0.33 0.02 0.38 0.29 0.39 0.31 0.33 0.34 0.04 10.63 10.44 9.81 11.49 13-36 11.15 1.38 10.25 10.84 9.52 10.74 9.58 10.19 0.62 9.34 8.75 8.88 11.39 10.86 9.94 1.17 10.39 10.33 10.20 10.14 9-32 10.08 0.43 3.47 5.00 3.74 3.48 4.19 3.98 +0.64 3.24 3.60 3.35 3.59 3.12 3.38 0.21 3.16 3.17 3.18 3.69 3.28 3.30 0.22 4.21 3.54 3.63 3.39 3.38 3.63 0.34 KIDNEYS g gfioog 2.02 2.13 2.23 2.42 2.40 2.24 +0.17 2.12 2.36 2.02 2.29 2.33 2.22 0.15 2.37 2.14 2.08 2.42 2.19 2.24 0.15 2.38 2.15 2.05 2.25 1.86 2.14 0.20 0.66 1.02 0.85 0.73 0.75 0.80 +0.14 0.67 0.78 0.71 0.77 0.76 0.74 0.05 0.76 0.78 0.75 0.78 0.65 0.75 0.05 O.96 0.74 0.73 0.75 0.67 0.7T 0.11 DO 1 3 1 3 5 7 CONF T D F N T I -334- Animal Humber 77-7444 7445 7446 7447 7448 Hean +S.D. 77-7514 7515 7516 7517 7518 Mean S.D. 77-7503 7584 7585 7586 7587 Mean +S.D. 77-7652 7654 7655 7656 7657 Mean AS* D. Tabla A-27 {Continued) DBCP: INHALATION FERTILITY STUDY IK THE RATf Female Rati Individual Organ Weighta and Organ/Body Weight Ratloa Determined at the Interim (l4 weeks) Sacrifice Exposure Level ppm Final Body Height (g) 0.0 0.1 1.0 10.0 305.6 328.9 246.8 326.1 308.6 303.2 33.2 357-7 290.8 330.5 317.0 290.8 317.4 +28.3 280.2 271.1 304.4 278.7 284.4 283.8 +12.5 300.4 281.6 313-9 309.9 285.4 298.2 14.4 __________________________________ Organ Weights (a and g/lOOg Body Height) BRAIN ft g/lOOg HEART ft b7Ioob LIVER ft g/lOOg 1.86 1.81 1.78 1.81 1.81 1.81 +0.03 1.91 1.85 1.85 1.82 1.82 1.85 +0.04 1.71 1.65 1.87 1.85 1.82 1.82 +0.06 1.91 1.79 1.90 1.82 1.98 1.88 0.08 0.61 0.55 0.72 0.56 0.59 0.60 +0.07 0.53 0.64 0.56 0.57 0.63 0.59 +0.04 0.61 0.68 0.61 0.66 0.64 0.64 +0.03 0.64 0.64 0.61 0.59 0.69 0.63 0.04 0.98 1.03 O.87 1.02 0.95 0.97 +0.06 1.17 0.98 1.28 1.07 1.10 1.12 +0.11 0.89 0.88 1.06 0.94 0.93 0.94 +0.07 1.07 0.97 1.00 0.93 1.06 1.01 0.06 0.32 0.31 0.35 0.31 0.31 0.32 +0.02 0.33 0.34 0.39 0.34 0.30 0.35 +0.03 0.32 0.32 0.35 0.34 0.33 . 0.33 +0.01 0.36 0.34 0.32 0.30 0.37 0.34 0.03 7.64 9.33 6.50 8.19 7.73 7.68 +1.02 8.86 7.35 8.19 7.07 7.48 7-95 +O.61 6.47 7.05 7.62 7.20 6.91 7.05 +0.42 8.48 7.29 8.75 9.6? 7.97 8.43 0.89 2.50 2.84 2.63 2.51 2.50 2.60 +0.14 2.48 2.53 2.48 2.40 2.57 2.51 +0.04 2.31 2.60 2.50 2.58 2.43 2.49 +0.12 2.82 2.59 2.79 3.12 2.79 2.82 0.19 KIDNEYB g g/lOOg 2.30 2.27 1.61 2.14 2.25 2.11 +0.29 2.43 2.16 2.58 2.21 2.37 2.35 +0.17 2.08 2.14 2.25 2.07 2.25 2.16 +0.09 2.40 2.20 2.25 2.33 2.48 2.35 0.09 0.75 0.69 0.65 0.66 0.73 0.70 +0.04 0.68 0.74 0.78 0.70 0.01 0.74 +0.06 0.74 0.79 0.74 0.74 0.79 0.76 +0.03 0.80 0.81 0.72 0.75 0.07 0.79 0.06 Animal Number G^ ZO "n n Z 10 --t *J\ 77-7419 7420 7421 7422 7424 7425 7426 7427 7*i28 7429 7*i30 7431 7 **32 7433 7434 7 **35 7*i36 7**37 7** 30 Mean +3. D. 77-7**89 7**90 7**91 7**92 71*93 7494 71*95 7**96 7*197 71*98 71*99 7500 7501 7502 7503 750*t 7505 7506 7507 7508 Mean -335- Table A-27 (Continued) DBCP: INHALATION FERTILITY STUDY IH THE RAT* Female Rat: Indirldual Organ Heights and Organ/Bodf Weight Ratios Determined at the Terminal (1*0 weeks) Sacrifice Exposure Lerel ppm 0.0 0.1 Final Body Height (g) 352.8 291.0 31*t.*i 33**. 2 291.0 281.5 303.5 310.1 353-9 33**. 5 289.** 317.3 320.9 310.** 267.8 315.7 3*11.5 316.1* 306.9 313.3 23.3 335.7 3**9.2 301.1* 293.*t 368.1* 329.0 306. 4 287.3 328.1* 31>*.l 331.1 267.9 337.2 360.7 276.6 332.2 377.** 290.6 297.6 *101.0 32*1.3 BRAIN ft g^lOOg 1.68 1.80 1.86 2.01 1.88 1.82 1.89 1.83 1.87 1.86 1.96 1.80 1.93 1.9** 1.81 1.81 1.90 1.88 1.80 1.87 +0.06 1.81 1.95 1.85 1.80 1.83 1.75 1.71 1.87 1.92 1.79 1.08 1.87 1.9** 1.93 1.81 1.87 1.82 1.79 1.77 1.90 1.01* 0.53 0.62 0.59 0.60 0.65 0.65 0.62 0.59 0.53 0.56 0.68 0.57 0.60 0.63 0.68 0.57 O.56 0.59 0.59 0.60 +0.0** 0.5*t 0.56 0.61 0.61 0.50 0.53 0.56 0.65 0.58 0.57 0.57 0.70 0.58 0.5*1 0.65 0.56 0.1*8 0.62 0.59 0.1*7 0.57 Organ Heights (g and g/lOOg Body Height) HEART g B/lOOg LIVER ft b7ioo5 1.17 1.09 1.21 1.36 1.12 l.lt* 1.11 1.27 1.20 1.21 1.17 1.3*1 1.27 1.13 1.21 1.26 1.30 1.31 1.16 1.22 +0.00 1.22 1.21 1.32 0.85 1.17 1.16 1.22 1.08 1.33 1.15 1.25 1.11 1.23 1.26 1.03 1.35 1.27 1.01 1.00 1.00 1.17 0.33 0.37 0.38 0.1*1 0.38 0.1*0 0.37 0.1*1 0.36 0.36 0.1*0 0.1*2 0.1*0 O.36 0.1*5 0.1*0 0.30 0.1*1 0.38 0.39 +0.03 0.36 0.35 0.1*1* 0.29 0.32 0.35 0.1*0 0.38 0.1*0 0.37 0.38 0.1*1 0.36 0.35 0.37 0.1*1 0.3*1 0.35 0.36 0.27 0.36 10.01 9.20 9.53 9.29 11.23 U.55 11.23 10.53 13.1*2 9*81 12.51 10.99 12.87 10.73 11.55 12.55 12.59 12.50 12.51 11.3*t +1.28 10.88 1*1.30 9.60 8.87 11.77 11.11* 11.44 11.05 10.88 8.29 11.58 9.03 12.27 13.21 10.70 12.11 11.58 10.83 11.15 11.72 11.12 3.06 3.16 3-03 2.78 3.86 It. 10 3.70 3.1*0 3.79 2.93 1*.32 3.1*6 *1.01 3.1*6 *t. 31 3.98 3.69 3.95 4.08 3.61* +0.1*7 3* 2*t It.lO 3.19 3.02 3.19 3-39 3.73 3.85 3.31 2.61* 3.50 3.37 3.6** 3.66 3.87 3.65 3.07 3.73 3-75 2,92 3.1*1* KIDNEYS g/lOOl 2.56 2.1*7 2.69 2.57 2.1*2 2.7I1 2.61* 2.23 3.30 2.56 2.66 2.62 2.90 2.1*1* 2.69 2.89 2.94 2.60 2.1*0 2.65 +0.24 2.58 2.66 2.43 2.14 2.48 2.39 2.64 2.25 2.81 2.31 2.36 2.8l 2.44 2.68 2.46 2.54 2.53 2.50 2.74 2.30 2.50 0.73 0.85 0.66 0.77 0.83 0.97 0.07 0.72 0.93 0.77 0.92 0.83 0.90 0.79 1.00 0.92 0.86 0.82 0.78 0.85 +0.08 0.77 0.76 0.01 0.73 0.67 0.73 0.86 0.78 0.86 0.74 0.71 1.05 0.72 0.74 O.89 0.76 0.67 0.86 O.92 0.57 0.78 ow 2 r; _ 1> -316- Table A-27 (Continued) DBCP: INHALATION FERTILITY STUDY IN THE RAT* renale Rat: Individual Organ Weights and Organ/Body Weight Ratioa Doterained at the Teralnal (ko weeke) Sacrifice An Inal Huaber 7T-T558 7559 7560 7561 T56a 7563 756k 7565 756T 7568 7569 7570 7571 T5T2 75 T3 757k 75T5 7576 7577 Hean 16. Da 77-7620 7630 T631 7632 7635 7636 7637 7630 7639 76kO T6kl 76k2 T6k3 76k k T6k5 76k S T6kT Hean 43. D. Exposure Level PF 1.0 10.0 Final Bo<ty Weight (g) 198.0 320.2 312-5 33k.5 250.6 275-1 lk;.B 26k .6 29T.0 311.6 317.6 3k7.0 33k.0 299.7 263. k k32.6 207.1 3k3.6 251.2 29k.a 60.0 330.0 30k.O 3k 5.0 309.0 209.3 30k.k 371.9 275.9 297.1 302.1 300.5 315.k 32k.7 30k.k = 362.0 267.9 209.3 321.3 236.2 BRAIN g g/lOOg 1.02 1.03 1.02 1.0k 1.09 1.T9 1.91 1.0k 1-79 1.07 1.7T 1.60 1.95 1.07 1.02 1.00 1.75 1-93 1.00 1.05 0.05 1.06 1.01 1.98 1.00 l.Bo 1.03 1.00 1.02 1.0k 1.87 1.90 1*90 1.09 1.92 1.87 1.01 1.T0 1.06 40.05 0.92 0.56 0.50 0.55 0.T3 O.65 1.31 0.70 0.60 0.60 0.56 0.5k 0.5a 0.62 0.69 0.t3 0.61 O.56 0.T5 0.66 *0.19 0.57 0.59 0.57 0.61 0.62 0.60 0.51 0.66 0.62 0.k9 0.62 0.60 0.58 0.50 0.52 0.68 0.62 0.59 +0.05 Organ Weight* (g and g/lOOg Body Weight) HEART LIVER B B/100g g 8/lOOg 0.97 1.15 1.22 l.Hl 1.12 1.13 0.T0 1.10 1.16 1.21 1.13 1.39 1.26 1.13 1.11 1O0 1.21 l.k2 0.90 1.15 to. 16 1.13 1.25 1.07 1.25 1*2* 1.1k 1.2T 1.11 1.15 1.22 1.30 1.10 1.26 l.kT 1.06 1.06 1.18 1.20 40.10 0.k9 0.35 0.39 0.3k 0.k3 O.kl O.kO 0.k2 0.39 0.39 0.36 O.kO 0.30 0.38 0.k2 0.30 0. k2 O.kl 0.39 O.kO tO.Ok 0.3k O.kl 0.31 O.kO 0. k3 0.37 0.3k O.kO 0.39 0.32 0.k2 0.37 0.39 0.36 0.29 O.kO O.kl 0.30 +0. Ok 6.95 11.3k 10.9k 9.72 6.75 10.73 5.00 0.31 10.0k 9.80 10.23 12.02 11.50 12.33 8.T2 21.20 9.76 12.91 10.05 3.51 3.k6 3.50 2.91 2.61 3.90 k.03 3.1k 3.38 3.15 3.22 3.69 3. kk k. 11 3.31 k.92 3.k0 3.T6 k.00 10.53 3.26 13.23 Ik.kT 12.6k 11. kk 10.10 11.33 12.6k 10.5k 10.68 12. k9 11.99 12.32 11.k9 11.20 lk.k6j tU- 9.67 9.20 3.55 0.51 k.01 k.75 3.66 3.70 3.k9 3.72 3.k0 3.02 6.29 3.27 3.89 3.91 3.5k 2.91 3.99 3.61 3.10 12.23 12.23 3.03 +O.T5 KIDNEYS A g/lOOg 2.6k 2.50 2.56 2.65 2.11 2.93 1.8k 2.35 2.3k 2.k6 2.53 2.06 2.k5 2.90 2.07 2.73 2.kk 3.25 2.35 2.52 0.33 2.55 2.00 2.35 2.57 2.65 2.62 2.59 2.k0 3.13 3.25 3.11 2.O9 2.T1 2.09 2.63 2.3k 2.57 2.71 10.21 1.33 0.76 0.82 0.79 0.82 l.OT 1.26 0.09 0.79 0.79 0.80 0.62 0.T3 0.97 0.79 0.63 0.05 0.95 0.9k 0.00 0.17 0.77 0.92 0.68 0.83 0.92 0.66 0.70 0.87 1.05 0.05 1.01 0.92 0.63 0.75 0. T3 0.87 0.09 0.85 0.10 *mtl rata vara exposed to 0, 0.1, 1.0, or 10 ppa of DBCP by Inhalation (Or 6 hr/day, 5 daya/week for ill weeke. Following termination of tin exposure period, animal* warn mlntalned In the laboratory for recovery. -337- Table A-2fl DBCP: INHALATION FERTILITY STUDY IN THE MALE RABBIT* Rabbit; Body Weighta (kg.) Exposure Lerel-ppa Control Anlaal Number 81)>i 215 910 ISO 909 901 916 932 907 923 -2 -* 3.3*1 3.87 3.6? 3.85 l).01 >|.19 3.75 3.71 *-33 -1 **.31 3.56 3.95 3.95 3.52 4.12 *.21 *.23 3.75 **7 1 *.*5 *.26 3.50 3.51 3.9* 3.82 3.88 3.89 3.66 3.68 *.16 *.21 *.26 *.08 *.21 *.25 3-56^ 3.55 3.39b *.33 3 *.23 3.58 3-78 3.89 3.73 *.23 *.09 *.*2 3.56 *.30 k *.21 3.57 3.80 3-93 3.86 *.17 *.15 *.33 3.66 *.35 WEEK OF STUDY -2-- _2__ 8 *.07 3-57 3.81 3.91 3.86 *.18 *.18 *.*0 3.60 *.20 *.01 3.*6 3.81 3.82 3.85 *.17 *.20 *.33 3.72 *.10 *.03 3.2* 3.83 3-77 3.80 *.23 *.25 *.*3 3.70 *.13 *.09 DEAD 3.86 3.79 3.92 *.20 *.27 *.3* 3.75 *.05 -2__ *.11 -- 3.83 3.76 3.80 *.06 *._2a7 3_.7a9 10 *.26 -- 3.90 3.69 3.72 *.l* *.2* *.25 3.78 _a 11 *.30 -- 3.86 3.61 3.65 *.16 *.17 *.30 3_.6a3 12 *.32 ... 3.85 3.57 _a *.12 *.19 *.25 3_.6a0 13 *._33 3.87 3.*9 3.73 *.l* *.30 *.2* 3.55 3.7* 14 *.28 _ 3.85 3.27 3..a76 *.38 *.18 3.5* 3.7* Mean 3.88 *.01 3.96 3.96 3.98 *.00 3.98 3.95 3.9* *.03 3.95 *.00 3.96 3.99 3.93 3.88 +8, Da +O.29 +0.32 +0.3* +0.31 +0.31 +0.28 +0.27 +0.26 +0.35 +0.21 +0.20 +0.25 +0.31 +0.31 0.33 +0.38 0.1 91T 3.1)2 3.52 3.51 3.36 3.*0 3.33 3.23 3.30 3.27 3.2* 3.33 3.25 3.25 3.31 3.2* 3.*1 920 1).02 *.18 *.18 *.l* *.16 *.18 *.2* *.23 *.26 *.33 *.32 *.*1 *.*7 *.53 *.50 *.52 906 3.12 3.25 3.2* 3.22 3.29 3.19 3.20 3.20 3.16 3.16 3.1* 3.18 3.30 3.60 3.65 3.66 911 *1.70 *.35 3-7* 3.77 3-T6 3.82 3.89 3.86 3.9* 3.85 3.89 3.95 3.95 3.97 3.87 3.87 1128 *.78 *.35 *.22 *.0* *.25 *.*0 *.*3 *.*2 *.*6 *.38 *.*3 *.*1 *.*7 b.*8 *.50 *.** 913 3.75 3.88 3.33 3.35 3.36 3. *2 3. *2 3.*8 3.*6 3**5 3. *8 3.58 3.59 3.67 3.69 3.69 902 li.OT *.23 *.17 *.17 *.17 3.95 3-85 3.63 3-T7 3.88 3.99 *.01 *.07 *.07 *.11 *.16 928 915 912 3.7* *.15 3.25 3.87 *.27 3.26 3.67 *.22 3.2* 3.60 *.20 3.28 3.53 *.23 3.23 3.68 *.3* 3.23 3.70 *.*3 3-32 3.71 *.*8 3.36 3.80 *.5* 3**1 3.80 *.56 3.*0 3.88 _a 3.99 *.*2 3.39 3.91 *.15 3.3* 3.96 3..a98 3.96 3.95 3.*2 3.98 *.10 3. *3 Mean 3.91 3.92 3-75 3.71 3.7* 3.75 3.H 3.77 3.81 3.81 3.81 3.86 3.85 3.95 3.89 3.93 3.D. +0.57 40.** +0.*2 +0.*0 +0.*2 +0.*6 +0.*8 +0.*7 +0.*9 +0.50 +0.*6 +0.*B +0.*6 +0.39 +0.*1 +O.39 CONF TDFNTT 7s i> -338- Table A-28 (Continued) DBCP: INHALATION FERTILITY STUDY IN THE HALE RABBIT* Rabbit: Body Weights (kg.) Exposure Level-ppn Control Animal Number _1L. 16 _il_ lfl WEEK OF STUDY 20 21 22 23 2k _2L_ 26 _I_ 2fl _22_ 8kk k.05 k.ll k.13 k.lk k.15 k.22 k.22 k.13 k.07 k.lk k.15 k.22 k.09 k.19 k.3k 215 DEAD 910 3.91 3.85 3.80 3.8k 3.81 3-95 3.86 3.88 3.80 3.9k 3.99 k.Ok 3.95 k.01 k.01 180 SACRIFICED -- -- ------ ---- -- ---- ---- 909 SACRIFICED 901 k.02 3.97 k.03 k.01 k.03 k.ll k.10 k.ll k.18 k.08 k.22 k.20 k.22 k.35 k.32 916 SACRinCED 932 k.29 It.2k k.27 k.2k k.17 k.17 k.21 k.10 k.10 k.03 k.Ok k.23 k.17 k.2k k.23 907 3.55 3.k6 3.56 3.55 3.58 3.63 3.63 3.66 3.72 3-73 3.82 3.83 3.8k 3.6k 3.85 923 3-79 3.6k 3.67 3.5k 3-53 3.56 3.k9 3.k8 3.60 3.67 3.61 3.73 3.70 3.85 3.79 Mean 3.9k 3.88 3.91 3.89 3.88 3.9k 3.92 3.89 3.91 3.93 3.97 k.05 k.00 k.08 k.09 iS. D. 0.25 0.29 0.27 0.30 0.28 0.28 0.31 0.27 0.2k 0.19 0.22 0.23 0.20 0.21 0.2k 30 _a _a -- .a .a -a ,,a _a .a 0.1 917 SACRIFICED 920 SACRIFICED 906 SACRIFICED 911 1128 913 902 928 915 912 3.80 3-73 A. 50 k.59 3.75 3.73 k.22 k.2l It.06 k.07 SACRIFICED 3.28 3.2k 3.85 k.56 3.75 k.29 k.16 -- 3.37 k.Ok k.71 3-30 k.39 k.23 -- 3.k3 k.03 k_.6a3 k.kk k.20 -- 3.k5 k.12 k.7k 3-92 k.56 k.2k -- 3.57 k.l6 k.70 3.83 k.58 k.33 me 3.62 k.lk k.69 3.88 k.62 k.32 -- 3.6k k.06 k.8k 3.93 k.65 k.k5 -- 3.67 k.03 k.83 3.93 k.6k k.37 3.6k k.lk k.72 3-99 k.72 k.kk _ 3.80 k.10 k.82 k.02 k.T3 k.ko ~ 3.76 k.12 k.67 3.97 k.72 k.36 -- 3.83 k.15 k.69 3.91 k.T0 k.50 -- 3.86 k.18 k.8o 3.85 k.78 k--.51 3.9k .a _a _a _a .a -- a Mean B.D. 3.9k 3.93 k.00 k.02 k.15 k.19 k.20 k.21 k.2T k.2k k.30 k.30 k.28 k.31 k.3k 0.1(2 ;0.k7 0.k3 0.55 0.k5 0.k3 0.k2 0.kl 0.k5 0.k5 0.39 0.k2 0.37 +0.k0 0.kl _a 00 13130? 00NFTDFNTTAL -339- Table A-28 (Continued) DBCP: INHALATION FfHTILITI STUDY IR THE HALE RABBITt Rabbit: Body Weights (kg.) Exposure Level-pun Animal Humber Control 0 8AA 215 910 ISO 909 901 916 932 907 923 31 32 33 3A 35 36 WEEK OF STUDY 38 _32_ AO Ai A2 A3 AA JL5_ ke 4.34 A.27 Dead >1.15 A.03 SACRIFICED SACRIFICED A. 1*1. A. 33 SACRIFICED A.22 A. 21 3.91 3.81 3.71 3.66 A. 19 A.oA A.30 A.19 3.92 3.60 A.29 A.12 A.A2 A. 13 3.86 3-70 A.28 A.11 A.Ai A. 15 3.88 3.75 A.30 A. 16 A.AA A. 13 3.80 3.7A A.21 A.10 A.A6 A.20 3.88 3.78 A.22 A. 13 A.A7 A.12 3.91 3-73 A.39 A.25 A.A8 A.lA 3.93 3.76 A.28 A. 18 A.A8 A. 10 3.65 3.71 A. 39 A.25 A.A9 A.01 3.72 3.62 A.A2 A.31 A.50 A. 16 3.63 3.61 A.30 A.30 A.5A A. 12 3.75 3.50 A.33 A.lA A.60 A. 11 3.88 3.A5 A.38 A.2A A. 51 A.12 3.05 3.36 A.30c A.20 A.A6 A.12 3.01 3-lA Mean A. 13 A.05 A.07 A.09 A. 10 A.09 A.11 A. 10 A.16 A.07 A.08 A.lA A. 09 A.12 A.08 A. 01 *3.0. *0.27 *0.27 *0.23 *0.27 *0.25 *0.28 *0.2? *0.26 *0.27 *0.33 *0.36 *0.35 *0.39 0.Al *0.A2 ;to. A8 0.1 917 SACRIFICED 920 SACRIFICED 906 SACRIFICED 911 A.22 A.17 A.06 A.07 A.OA A.12 3.93 3.90 A.OA A. 07 A.03 a.ot A. 10 A. 12 A.02 3-96c 1120 913 902 920 A.92 3.96 A.83 A.6A A.86 3.93 A.80 A.51 A.OA 3.89 A. 89 A.55 A. 01 3.85 A.7A A. 16 A.01 3.68 A.82 A.39 A.81 3.83 A.83 A.AO A. 69 3.86 A. 78 A.A5 A.78 3.88 A.83 A.A9 A. 91 3.89 A.86 A.56 A.7A 3.9A A.85 A.53 A.80 3.93 A. T9 A.61 A. 82 3.91 A.87 A.68 A.06 3.95 A. 81 A.6A A.97 3.93 A. 87 a.ta A.79 3.83 A.03 A.63 A. 78 3.00 A.75 A.56 915 SACRIFICED 912 3.98 3.96 3.98 3.98 3.97 3.98 A. 01 A.06 A.07 A.07 A.08 A. 12 A.03 A.08 A.07 A.05 Mean A.A3 A.37 A.37 A. 27 A.32 A. 33 A.29 A. 32 A.39 A. 37 A. 37 A.Al A.AO A.A? A. 36 A. 32 13. D. 10.A3 10.Al +0.A5 10. Al 10.A2 +0.A2 40.Ao 10.A3 10. A? 10.39 10. AO +0.A2 +0.A2 40. A6 10. AA 40. A3 I)() 1 ^ 1 3 6 3 CONF TOFNT TA -3A0- Table A-2fl (Continued) DBCP: INHALATION FERTILITY STUDY IN THE HALE RABBIT* Rabbit: Body Weights (kg.) Exposure Animal WEEK OF STUDY Level-ppm Number -2 -1 _1____ 2 3 b 5 J[_ 7 a _2_ 10 11 12 13 lb 1.0 929 b.12 b.17 3.8b b.ll 3.89 3.90 3.66 3.72 3.80 3.89 3.90 3.8b 3.7b 3.39 3.80 3.86 931 1126 919 3.88 b.71 b.18 3*95 b.73 b.32 b. 11 b.bb b.18 3.95 b.37 b.19 3.95 b.b5 b.26 3.99 b.35 b.35 b.00 b.13 b.bO b.05 b.20 b.b7 3.89 3-81 b.35 3.81 3.63 b.15 3-75 3.51 b.02 3.76 3.23 b.25 3.76 DEAD b.32 3_.37 _a 3_.77 b.38 3.5b -- b.37 9**9 .170 b.55 b.10 b.53 b.18 b.bb b.13 b.b6 b.19 b.55 b.28 b.52 b.20 b.55 Jk b.58 b.30 b.58 b.3b b.53 b.38 b.52 _a b.5b b.38 b.58 b.36 b_.ba7 b.53 b.37 b.53 b.32 926 90b 930 932A 3b3 3.81 3.b2 b.bl 3.b6 3.89 3-53 b.b5 3.bo 3.86 3.b2 b.3b 3.37 3.82 3-37 b.35 3.38 3.71 3-37 b.35 3.28 3.b9 3.3b b.37 3.3i 3.b2 3.30 b.35 3.35 3. bo 3-23 b.33 3.39 3.26 3.2b b.3b 3. bo 3.13 3.2b b.bO 3.39 _a _a b.39 3.39 JtL _a b.b7 3_.3a5 3.23 jk 3.36 3.06 3.25 b.b5 3.36 2.9b 3.25 b.b5 3.38 _a Jk _a Haan b.06 b.12 b.02 b.02 b.02 3.98 3.89 3.96 3.90 3.86 3.93 3.98 3.91 3.62 3.07 b.00 8. D. 0.bb J0.b2 1O.38 10.39 l0.b3 0.b6 10.5b 10.50 l0.b9 10.50 30. b2 10.50 0.52 10.58 IO.59 i0.b8 10.0 91b 921 922 908 918 933 927 1125 925 92b b.2b 3-95 b.b2 3-95 3.67 3.71 3.60 3.10 3.57 b-57 b.22 b.09 b.b9 b.09 3.68 3.7b 3.77 3.20 3.63 b.53 b.b9 3.89 b.19 b.06 3.75 3.66 3.66 3.15 3.55 b.51 b.3b 3-73 b.18 b.00 3.67 3.59 3.70 3.10 3.55 b.32 b.33 3.81 b.27 3.98 3.60 3.57 3.67 3.10 3.55 b.38 b.36 3.8b b.16 b.00 3-70 3. b8 3*T3 3.08 3.50 b.39 b.21 3.61 b.25 b.01 3.70 3.b5 3.85 3.12 3.61 b.35 b.18 3. bo b.32 b.02 3.75 3.36 3.86 3.11 3.65 b.b2 b.21 3.52 DEAD DEAD 3.88 3.50 3.91 3.16 3.75 b.93 b.31 3.56 -- -- 3.89 3.b2 DEAD 3.18 3.80 b.b8 SACRIFICED 3.62 3.68 ---- ---- 3.93 3.87 3.bb 3.b7 ---- 3.21 3.29 3.85 3.90 _a Jk _ 3-T5 -- -- DEAD 3.53 -- 3.32 3.9b b.65 _ 3.80 -- -- -- 3.56 -- 3.32 3.9b b.69 _ 3.08 -- -- 3.63 -- 3.32 3.99 b.75 _ 3.92 -- -- -- 3.65 -- 3.37 b.Ob b.T3 Mean 3.88 3.9b 3.89 3.82 3.83 3.63 3.82 3.81 3.86 3.81 3.61 3.6b 3.8b 3.86 3.91 3.9b 8* D* iO.bb J0.b2 f0.b3 +0.39 ,O.bl 10.bl 10.39 IO.bb 10.5b i0.b7 10.30 10.26 0.51 10.52 0.53 10.51 C .O N F T D F N T T -341- Table A-26 (Continued) DBCP: INHALATION FERTILITY BTUDI IN THE KALE RABBIT* Babbit; Body Weights (kg.) Exposure Lerel-ppa 1.0 An Inal __________________________________________ WEEK OF BTUDI Nunber 15 lb lB _!2_ 20 21 22 23 24 _2L_ 26 ~W _22_ 929 931 1126 919 9*9 178 926 90l) 930 932A 3.7^ 3.75 SACRIFICED DEAD SACRIFICED 4.62 4.56 4.38 4.37 3.34 3.40 SACRIFICED SACRIFICED 4.57 4.63 3.81 4.49 4.38 3.40 4.62 3.93 4.50 4.45 3.49 4.66 3.89 4.47 4.37 3.45 _a 3.96 4.52 4.47 3.60 4.74 4.02 4.47 4.46 3.61 4.79 4.02 4.42 4.50 3.10 4.78 4.04 4.45 4.43 3.65 4.83 4.07 4.46 4.47 3.69 4.89 4.17 4.44 4.50 3.77 4.90 4.13 4.32 4.46 3.71 4.98 4.06 4.39 4.49 3.72 4.96 4.14 4.43 4.47 3.58 5.00 3.90 4.36 4.60 3.43 5.06 Kean 4.13 4.14 4.14 4.21 4.05 4.26 4.27 4.16 4.28 4.32 4.36 4.32 4.32 4.32 4.27 +S. D. +0.56 40.54 +O.52 +0.49 0.47 40.47 +0.46 0.65 +O.45 +0.45 40.42 +0.46 +0.47 +0.52 +O.63 30 .a _a _a _a .a _a .a 10.0 91>) 921 922 908 918 933 927 1125 925 921) Mean IS. D. SACRIFICED 3.94 3.96 DEAD DEAD DEAD 3.71 3.75 DEAD 3.24 3.30 4.07 4.01 4.62 4.35 3.98 3.76 3.26 4.10 4.40 4.01 3.80 3.25 4.21 4.60 4.04 3.80 3.25 4.15 4.60 4.08 3.98 3.29 4.23 4.51 4.15 4.00 3.31 4.21 4.17 4.13 4.00 3.21 4.23 4.38 4.15 4.07 3.25 4.20 3.96 4.21 4.04 3.25 4.20 3.92 4.28 4.08 3.23 4.18 4.00 4.26 4.06 3.21 4.21 4.01 4.29 4.10 3.22 4.17 4.02 4.44 4.15 3.29 4.19 4.04 4.53 4.19 3.24 4.26 4.00 3-92 3.87 3.90 3.97 3.97 4.02 3.97 3.99 3.93 3.92 3.95 3.95 3.96 4.02 4.04 0.50 :*0.39 40.43 40.50 40.50 40.45 40.38 40.46 40.39 40.4o 40.42 40.43 40.43 40.43 40.49 _a ,,a jk _a _a -* jk r.ONF ID F N T T o o Ok1 O' -Jt -342- Table A-38 (Continued) DBCP: INHALATION FHITILITI STUDY IN THE HALE RABBIT* Rabbit: Body Weights (kg.) Exposure Level-ppm 1.0 Animal Number 929 931 1126 919 949 178 926 904 930 932A _________________________________________________________ WEEK OF STUDY 31 32 33 34 J_ 3T _iL_ 3r~ _22_ 40 41 42 43 JET J*5_ IT 4.15 4.04 SACRIFICED DEAD -- SACRIFICED 4.41 4.33 4.69 4.60 3.40 3.37 SACRIFICED SACRIFICED 5.03 5.03 4.05 4.31 4.61 3.37 5.01 3.38 4.31 4.73 3.28 4.99 3-31 4.22 4.68 3.28 5-03 3.44 4.25 4.76 3.28 5-03 3.48 4.27 4.79 3.27 5.02 3.50 4.25 4.75 3.26 4.99 3.49 4.37 4.76 3.22 5.00 3.42 4.34 4.63 3.18 4.94 3.28 4.33 4.73 2.96 4.92 2.92 4.41 4.69 2.96 4.93 2.72 4.35 4.70 2.94 4.93 2.77 4.44 4.79 2.92 4.94 2.73 4.27 4.57 2.89 4.86 2.59c 4.27 4.60 2.82 4.78 Mean 4.34 4.27 4.27 4.14 4.10 4.15 4.17 4.15 4.17 4.10 4.04 3.98 3.91 3.95 3.84 3.79 iSeOe 10.62 10.62 10.62 10.78 10.79 180.78 0.78 10.76 0.78 10.77 10.88 30.97 1.05 1.07 1.01 +1.06 10.0 914 921 922 908 918 933 927 1125 925 924 Mean iS.D. SACRIFICED 4.57 4.53 DEAD DEAD DEAD -- 4.15 4.18 DEAD 3.26 3.27 4.30 4.28 4.19 4.16 4.59 -- 4.20 3.28 4.34 4.08 4.67 4.16 3.23 4.40 3.89 4.56 4.20 3.22 4.42 4.13 4.49 4.20 3.27 4.49 4.12 4.58 4.21 3.22 4.46 3-95 4.63 4.68 4.24 4.27 3.20 - 3.21 4.50 4.51 4.07 4.17 4.75 4.25 3.23 4.52 4.15 4.84 4.23 3.23 4.37 4.24 4.91 4.27 3.18 4.12 4.24 4.89 4.22 3.20 4.19 4.33 4.93 4.24 3.23 4.41 4.32 4.88 4.16 3.28 4.37 4.33 4.82<s 4.10 3.19 4.21 4.23 4.09 4.08 4.10 4.07 4.11 4.11 4.06 4.13 4.17 4.18 4.18 4.14 4.17 4.23 4.20 4.11 +0.49 +0.48 +0.50 +O.55 +O.52 +0.50 +0.54 +0.56 +O.57 +O.58 +O.59 +0.62 +0.61 +0.62 +O.58 +O.59 *Male rabbits ware exposed to 0, 0.1, or 1.0 ppm of DBCTP by Inhalation for 6 hr/day, 5 days/veek for 14 weeks. Male rabbits exposed to 10 ppm of DBCP were exposed for 8 weeks. Following termination of the exposure period, animals were salntalned in the laboratory for recovery. Sleight Inadvertently was not recorded. *)Tbe weight recorded was apparently Incorrect and therefore was not Included In the calculation of the mean. cValues fhr the 46th week represent fasted body weights taken prior to necropsy. I> n o 1 3 1 3 G6 gonftdfntt -343- Exposure Level--ppm Control Animal Nunfcer 844 215 910 180 909 901 916 932 907 923 l3D< 0.1 917 920 906 911 1128 913 902 928 915 912 Mean 8. D. Table A-29 DBCP: INHALATION FERTILITY STUDY IN THE HALE RABBIT^ Rabbit; 3perm Count (Hlllions/nl Semen) -2 999 741 714 758 6_76& 1291 1063 517 753 835 237 ^1 __ a 468 360 1850 646 761 653 532 393 587 694 452 _1 742 1390 690 358 787 404 786 748 776 602 728 280 _2 388 329 247 676 903 1246 1068 891 405 554 671 342 _3 718 531 __ a 514 767 992 689 370 751 580 657 181 Jt _ 300 315 450 655 609 993 1017 416 373 420" 301 193 319 582 358 306 765 513 709 699 575 474 275 205 Week of Study 6 _L _8 338 398 501 549 920 735 1356 602 618 734 342 Dead 601 5i4 1.7b 988 1783 558 394 591 312 -- 463 482 252 361 751 227 399 587 675 641 426 294 501 167 _2 424 -- 545 633 349 385 1002 __ a 224 a 509 255 10 437 -- 377 960 428 495 287 373 424 a 473 206 11 415 -- 463 570 431 724 404 303 358 a 458 132 12 789 -- 535 1110 787 76l 363 66s 716 234 13 458 -- 587 1508 109 802 457 702 557 1640 758 502 14 442 466 1099 549 130" 762 691 676 602 282 469 1106 893 370b a 764 483 375 ..a 347 608 619 569 1668 __ a 407 688 395 __ a 433 576 673 263 416 829 572 696 786 624 666 182 310 2.2b 274 354 ^ .a 322 65. 5a 638 553 512 613 __ a 494 521 28l 135 599 468 401 1644 1179 1190 1470 635 454 309 835 488 1070 503 343 600 370 1180 653 594 525 341 618 290 532 616 297 223 410 223 530 559 334 184 391 160 525 426 255 601 148 1329 1315 738 318 102 576 440 170 191 303 612 290 1873 1080 675 16.6> 99 600 433 675 698 a 557 217 415 120b 92 402 449 624 443 a .a 329 270 _a a 531 423 420 571 232 122 196 333 580 1020 262 757 499 597 171 172 459 284 431 517 529 430 183 192 456 654 12.2b 199 426 354 757 577 332 __ a 250 387 2.1b 357 759 1172 724 1232 519 1145 693 668 0.1b 665 368 371 wa 439 397 1758 196 582 0.2b 375 360 201 382 208 738 376 498 499 fO N F TDFNTTAl 10 CO Ch V! -344- Exposure Level--ptn Control * Animal Humber 644 215 910 lBo 909 901 916 932 907 923 Mean 23. D. Table A-29 (Continued) DBCP: IMHALATIOH FBtTILITT STUDY IH THE HALE RABBIT* Babbit; Spent Count (HUllone/al Semen) l6 24 26 786 434 Dead 472 110b Sacrificed Sacrificed 6l4 738 Sacrificed 210 495 1006 382 536 216 1638 19*0b -- 459 355 374 394 488 438 -- 644 276 415 ,a 604 396 540 452 273 +220 560 133 ZL 1457 1020 28 & 546 1926 0.8b 568 ____ 793 483 418 32-6b 466 249 375 _a 349 304 495 a 701 327 728 +501 +213 +678 Week of Study 32 34 36 3B 40 429 1422 0.6b 171 569 1882 70.0b 297 1115 544 443 486 241 357 +202 539 258 508 225 520 +467 449 451 515 192 374 +197 1063 418 334 10.6b 948 464 648 __ a 667 637 +689 433 "IT42 .....44 637 879 1102 148 340 513 666 564 902 92.4 276 391 604 __ a 426 a 2__7a9 429 497 637 +284 4239 350 0.1 917 Sacrificed __ _,, 920 Sacrificed 906 Sacrificed -- -- -- ---- M. 911 1128 913 902 928 509 701 396 232 244 --* 897 570 647 466 ,, a a 633 0.9b 212 588 91 146 859 240 271 634 a a 307 522 352 684 429 308 169 50.0b 314 680 550 187 400 0.0b 7.8b 688 289 319 890 559 86 340 504 760 637 433 299 691 593 714 747 602 1164 302 752 747 693 656 677 682 565 919 623 632 676 630 760 761 382 632 538 915 Sacrificed 912 504 409 596 730 644 410 471 651 658 535 645 357 296 451 678 Mean 3.D. 446 +157 500 190 691 1121 629 115 415 259 409 +308 526 1244 628 535 486 497 616 231 522 583 124 +235 239 H96 1341 1181 1196 +276 CONF TDFNTT a o OJ O' 0) O oz Zn o T1 ZV -I O' -1 -0 0> -345- Table A-29 (Continued) DBCP: INHALATION FERTILITY STUDY IN THE MALE RABBIT* Rabbit: Sperm Count (Mllllona/Kl Semen) Exposure Level--ppm 1.0 Animal Humber 929 931 1126 919 9*9 178 926 90ii 930 932A Kean S.D. 10.0 914 921 922 908 918 933 927 1125 925 924 Mean S. D. ______________________________________________________________ Week of Study -2 -1 _1 _2 _3 .2 _6 _8 303 310 878 287 674 580b 539 573 461 362 155 466 785 252 406 321 294 563 164 163 198 --ft 570 122 153 478 167 210 5U 142 503 363 417 608 861 570 628 330 269 230 350 --ft --ft 782 437 314 381 330 348 421 128 1124 346 400 553 366 197 560 130 7.8b 1419 --ft 648 659 372 444 381 384 453 381 --ft 356 151 302 155 460 148 --ft --ft 436 1317 690 854 0.9b 573 716 183 589 197 297 1299 --* 196 316 --ft 418 6ll 720 944 570 _ 442 532 605 703 449 --& 324 --ft --ft 519 630 552 538 373 465 467 353 473 386 301 510 549 312 276 +244 +231 126 +186 165 251 167 +122 10 341 216 188 262 256 149 156 513 609 1070 376 +288 11 12 13 14 201 107 Dead 338 345 96 25.8b 316 --ft 226 --ft -- 694 370 --ft 16.0b 485 318 382 291 26.4b -- 7.2b 213 420 7.6b 300 297 667 17.4b 17.2b -- 35.6b 352 0.8b 6.0b --ft 333 --ft 204 356 248 109 +131 +210 217 160 .a 94 342 --* 1428 1136 639 422 355 219 579 468 468 356 321 --ft 809 719 604 --ft --ft 546 198 695 661 497^ 0.2" 586 616 840 284 ft 352 210 236 193 .a 344 458 560 427 a --ft 503 347 255 l4i 590 486 266 4.6b 850 158 662 5.0b 398 501 655 633 423 8.9b 1701 366 Til 376 254 353 663 663 146 1.0b 972 398 373 459 502 494 693 562 741 13. ob 337 165 670 379 537 a 4l4 100b Dead Dead 0.5b --ft 452 357 244 369 641 5.8b -- __ 12.3? 43.4b Dead 19-8b 18.8b __a 685 0.6b -- -- 0.4b 26.2b -- 16.2b 9.0b a Sacrificed 1.0b --ft ---- ---- 3.2b Dead 15-6b 2.4b -- __ 2.2b 6.0b l4.1b 6.0b --ft 7.0b 0.2b -- -- -- 1.2b -- 7-5b 0.6b --ft 0.1b -- -- -- 0.5b -- 0.6b 0.6b 16.6b I.0b -- -- -- 0.1b -- 2.0b 0.6b 6.0b 392 548 467 455 277 124 124 7-2 5-4 2.4 3.7 1.9 281 456 272 250 170 254 275 7.0 2.0 3-4 7.2 2.7 -346- Exposure Level--ppm 1.0 Animal Ruriber 929 931 1126 919 9*9 ITS 926 90k 930 932A Mean S.D. 10.0 91k 921 922 90S 918 933 927 1125 925 92k Mean D* 1?-- 3 3T6 7.1b Sacrificed Dead -- Sacrificed 559 356 iSB k23 15.6b 11.2b Sacrificed Sacrificed 350 --* 292 210 199 221 Sacrificed O.kb O.kb Dead -- Dead _ Dead -- O.kb 0.2b Dead O.kb 0.2b 1.0b 0.05b 2.2b O.fib 0.9 10.B 0.3 0.2 Table A-29 (Continued) DBCP: IKHALATIOH FERTILITY STUDY IN THE HALE RABBIT1 Rabbit: Sperm Count (HlUlons/Ml Semen) 24 615 -- -- -- 1129 626 108 -- 182 532 kll 26 212 -- -- -- 298 64k 220 -- -- 267 328 180 3 389 -- -- -- 16k 530 161 -- -- 5k9 359 189 26 305 -- -- ~ 692 k75 321 -- -- 918 5k2 261 Week of Study 32 34 339 3.8b kl6 -- -- -- 25k 666 35k koo 186 kl3 960 688 993 100 kii 327 k2T 39k 299 __& 5kk 301 39k 3k7 693 573 3k9 k71 155 38 11.0b " kk9 23.6b 109k 40 __ a z 176 297 1300 332 382 442 179 488 5kk 42 __ a - 102 573 138k ire 559 587 44 __ a L 301 1_3a9 7kk 395 313 46 __ a j-i-- 316 446 __ a 528 k30 107 0.0b -- -- -- 0.0b -- 0.0b 0.9b 1.0b O.k 0.5 0.5b -- -- -- 0.05b -- 0.2b 8.1b 0.0b ,, 2k. kb -- -- -- 0.6b -- O.kb 13.2b 0.0b 1.8 7-7 3.5 10.9 _ 0.0b -- -- -- 0.7b -- __ a 19.5b 0.1b 5.1 9.6 k.Ob 0.1b 0.0b lk.kb 6.2b k.9 5-9 8.2b 6.0b 0.0b olkb 17.0b k.6b O.kb 0.9b 28.kb 2.0b 6.0 7.5 7.0 II.9 1.8b 2.0b 8.2b 0.05b 170b 0.2b 0.8b 5.2b 0.8b 11.8b 7.8b 6.5b 15.3b lOI 13.0b 1.7 39.6 28.7 2.1 73.0 kk.l 0.05b oTkb 3.6b 0.2b 5.6b 2.0 2*5 0.6b k.2b 0.2b 20.0b lk. lb 7.0b 2.1b lk?6b 92 23.2b 8.k 27.2 8.6 37.2 ^Male rabbits Here exposed to 0, 0.1 or 1.0 ppm of DBCP by inhalation DBCP were exposed for B weeks. Following termination of the exposure 6 hr/day, 5 daye/veek for lk weeks, tfale rabbits exposed to 10 ppm -lod, animals were maintained in the laboratory for recovery. *No sample, or Insufficient sample taken. buue to low spera concentration, counts were unable to be obtained via Coulter Counter, they were obtained via Hemocytometer. O jJ Nl O OONF T D F N T TAL -347 - Table A-30 DBCP: INHALATION FERTILITY STUDY IN THE HALE RABBIT1 Rabbit; Volume of Ejaculate (ml) Exposure Level--ppm Control Animal Number Bit It 215 910 ISO 909 901 916 932 90T 923 Heart S.D. -2 0.9 O.ll 0.9 __ a 1.0 0.7 0.5 0.5 0.ti 0.5 0.6 0.2 -1 __ b 0.1* 0.5 0.2 0.8 0.5 0.1 0.3 0.7 0.3 0.1 0.2 _1 0.9 0.7 ft. --81 1.5 0.3 0.3 0.8 0.5 0.7 0.1 _2 0.5 1.7 0.7 0-9 1.0 0.1 0.3 0.9 0.5 1.2 0.8 0.1 _3 1.5 0.3 0.3 0.3 1.0 0.8 0.3 1.0 1.0 1.5 0.8 0.5 _1 1.0 0.9 0.5 1.3 0.8 0.6 0.5 1.0 0.1 0.1 0.7 0.3 Jl 0.1 1.3 1.0 1.1 0.5 0.1 0.3 0.3 0.9 0.5 0.7 0.1 Week of Study X" JL 1.0 0.6 0.1 1.3 __b Dead 1.2 1.0 0.6 1.5 1-5 1.0 0.7 0.8 1.0 1.0 0.7 0.5 0.5 0.6 0.5 1-5 0.7 1.7 1.0 0.5 0.8 1.1 1.5 0.8 1.1 0.3 0-9 0.1 0.8 0.1 _2 1.2 -- 0.7 1.0 0.6 1.5 0.5 _b 1.2 __b 1.0 0.1 10 1.0 -- 0.8 1.1 0.8 1.1 2.0 1.6 1.3 __ b 1.3 0.1 11 1.0 -- 0.8 1.5 0.3 1.2 0.9 1.2 1.2 _b 1.0 0.1 12 0.6 -- 0.9 2.0 --b 0.6 0.5 1.5 1.6 --b 1.1 0.6 13 1.0 -- 1.0 1.0 0.2 0.8 0.8 1.0 1.0 0.6 0.8 0.3 11 0.7 -- 0.5 1.0 0.8 --b 0.5 1.0 0.7 0.5 0.7 0.2 0.1 917 0.8 0.5 1.3 1.8 1.5 1.1 1.0 1.5 1.5 2.0 1.2 1.5 2.0 1.5 2.3 1.5 920 906 0.1 a 0.5 1.0 1.5 1.1 1.7 1.0 0.7 1.2 1.1 1.5 0.7 1.6 1.3 1.5 1.5 2.0 1.0 1.5 1.5 1.5 0.6 1.2 0.3 1.0 1.5 1.0 1.8 1.3 1-5,1 911 1128 913 0.8 0.3 __ a 0.6 0.3 0.3 0.1 0.5 0.8 0.6 0.9 0.7 1.0 1.0 0.1 0.8 0.3 0.3 b 0.3 __ a 0.3 b 0.8 0.3 0.1 0.2 0.3 1.0 0.6 2.6 0.2 1.1 0.2 __ b 0.6 1-5b 1.5 0.3 1.5 1.1 2.0 b 0.8 0.5 2.0 0.6 902 0.1 0.1 1.5 0.1 0.5 1.3 0.7 0.1 0.5 1.0 1.5 1.1 1.0 0.9 0.3 1.0 928 915 912 1.0 1.5 0.5 O.Tv 0.5 1.0 0.1 0.7 0.7 1-5 0.1 2.0 1.7 0.8 1.5 1.1 1.5 1.1 0.5 0.6 1.5 0.1 0.8 0.1 0.3 1.2 1.5 0.7 0.5 1.6 __b __ b 1.1 1.0 1.1 1.5 0.3 1.0 1.1 0.1 1.5 1.1 0.2 1.5 1.5 0.2 0.9 Mean jS* D< 0.7 0.1 0.5 0.2 1.0 0.5 1.0 0.5 0.9 0.6 1.1 0.6 0.8 0.1 1.1 0.7 1.0 0.6 1.0 +0.5 1.1 0.2 1.1 0.1 1.1 0.5 1.2 0.5 1.0 0.7 1.1 0.6 L ^ ;ix L ou T> -348- Table A-30 (Continued) DBCP: INHALATION FEBTILITTt BTODI IN THE HALE RABBIT^ Babbit: Volume of Ejaculate 1 ml 1 Exposure Level--ppa Control 0.1 Animal Number 844 215 910 180 909 901 916 932 907 923 Mean +S. D. 917 920 906 911 1126 913 902 928 915 912 Mean 3. D. 16 22 1.0 Dead 0.8 -- 1.0 1.9 Sacrificed Sacrificed 0.9 1.5 Sacrificed 1.0 1.4 0.8 0.4 0.5 0.5 0.9 0.2 1.1 +0.6 21 1.0 -- 1.0 -- -- 1.3 -- 0.9 0.8 0.8 1.0 0.2 26 1.0 -- 0.5 -- -- 0.9 -- 0.9 1.0 . ,b SL 0.7 -- 0.1* __ __ 1.0 -- 0.7 1.2 0.4 0.9 0.2 0.7 0.3 Sacrificed Sacrificed Sacrificed 0.7 0.7 2.5 0.5 1.0 b 1.0 1.2 1.5 2.0 Sacrificed 1.0 1.0 1.2 0.7 1.2 0.5 -- -- 0.6 0.05 1.3 1.3 2.1 -- 1.3 1.1 0.7 ,, -- -- 1.2 b __b 1.2 1.5 -- 0.9 1.2 0.2 -- __. 1.3 1.2 1-5 1.3 1-5 __ o.B 1.3 0.2 0.6 -- 0.4 -- _ 0.7 -- 0.6 1.3 b 30 1.0 -- 0.7 H* __ -0.7 -- o.t* 0__-?b 0.7 0.3 0.7 0.2 -- -- 1.1 2.1 0.1* 0.5 1.3 -- 0.6 1.0 0.6 __ __ 0.6 1.0 0.7 0.6 1.6 --. o.T 0.9 0.1* Week of studv 32 34 36 0.6 0.9 0.8 ------ 0.3 0.3 0.1* __ -- ___ -- 0.7 1.2 0.7 -- __ -- 0.6 0.7 0.6 0.8 o.li 1.1 0.5 0.7 0.5 0.6 +0.2 0.7 +0.3 0.7 +0.2 __ -- 0.6 b __ b 1.3 1.3 -- 0.8 1.0 0.1| __ 0.8 0.5 1.0 0.6 0.7 __ 0.5 0.7 0.2 0.8 1.5 0.7 0.6 1.1* -- 1.0 1.0 0.1* 38 1.0 -- 1.6 1.4 -- 1.9 1.0 0.3 1.2 +0.6 __ 1.0 0.5 0.8 0.9 1.5 __ 0.8 0.9 0.3 40 0.8 --- 0.2 -- -- 0.6 __ 0.6 0.8 _b 42 1.0 1_.0_ 0.6 O.B 0.3 b 44 "TjT 1.0 1.0 __ 0.6 0_.8_ -- 1.0 0.4 0.8 1.0 mb 0.5 0.6 0.6 0.2 0.7 +0.3 0.9 0.2 0.7 +0.2 VI O __ 1.2 1.3 1.5 1.1 1.3 -- 0.9 1.2 0.2 1.5 0.3 0.8 1.0 1.2 0.9 1.0 0.4 1.0 0.7 0.5 O.T 1.4 1.0 0.9 0.3 1.0 1.4 1.5 1.0 1.5 0.5 1.2 0.4 DO 1 3 1 3 7 2 OONFTDFNT T I> .I -349- V Table A-30 (Continued) DBCP: INHALATION FERTILITY STUDY IN THE HALE RABBIT* Rabbit: Volume of Ejaculate (ml) Exposure Level--ppm 1.0 10.0 An 1ml Number 929 931 1126 919 949 178 926 904 930 932A Hean IS. D. 914 921 922 908 918 933 927 1125 925 924 Hean 3.0. -2 0.3 0.8 0.5 0.4 0.5 1.0 0.4 0.3 0.7 0.7 0.6 10.2 -1 _1 _2 0.8 0.4 --b 0.5 0.4 0.4 _b 0.3 0.3 __ b 0.7 0.6 0.4 __ a __ & 0.6 0.3 0.3 0.4 0.6 0.7 1.0 1.9 1.0 1.0 0.7 0.3 0.8 0.2 0.5 0.4 10.2 0.5 10.2 0.8 10.5 _3 1.2 0.9 2.0 0.8 1.0 1.5 0.7 0.8 0.6 __ b 1.0 10.4 _4 0.8 0.8 0.7 0.7 1.4 0.2 1.0 0.7 0.8 0.5 0.8 10.3 0.2 0.3 0.5 _b 0.5 0.4 1.3 1.0 0.5 0.5 0.6 0.3 0.3 0.3 0.6 __ & ,b 0.5 0.2 0.5 _b __ b 0.4 0.2 0.5 1.5 1.4 __ a 0.3 0.5 0.4 1---5.b 0.5 0.8 +0.5 0.4 0.6 1.0 0.4 0.3 0.8 0.2 0.8 -b 0.6 +0.3 0.5 0.8 1.5 1.0 0.5 0.8 0.7 0.8 1-9 1.0 0.9 +0.4 0.7 0.4 1.3 0.6 0.3 0.6 0.7 1.4 1.3 1.5 0.9 +0.4 JS. 0.8 1.0 1.5 1.0 0.6 0.4 0.8 0.5 1.1 1.1 0.9 10.3 0.8 0.6 1.0 0.4 0.7 0.4 1.1 0.6 1.5 1.0 0.8 +0.3 Week of Study JL 1.4 0.9 2.0 1.0 0.8 1.5 0.4 b 1.5 0.8 0.6 1.4 0.6 1.5 1.3 0.4 1.0 b 1.5 0.6 0.7 1.2 0.7 1.0 1.0 0.4 1.2 0-5 1.4 0.6 1.1 10.5 1.0 io.4 0.9 10.3 _2 1.4 0.8 0.6 0.4 0.5 b 1.2 ,, b __b 0.4 0.8 10.4 10 0.8 0.5 1.0 1.0 0.6 1.0 1.5 0.2 1.0 0.5 0.8 10.4 11 1.0 0.4 Dead 1.4 0.4 0.8 1.0 b 1.0 __b 0.8 10.4 12 0.7 1-5 -- 0.5 0.7 __ b 0.8 0.5 1.4 0.4 0.8 10.4 13 0.7 0.7 1.4 1.4 0.9 1.0 0.5 1.0 0.3 0.9 10.4 14 0.7 1.0 -- 0.8 0.9 0.6 1.1 . ,b 0.4 __b 0.8 10.2 o-5 0.3 0.8 0.4 0.3 0.8 1.4 1.0 1.0 __ b 0.7 +0.4 0.4 0.4 Dead Dead 1.0 __ b 1.2 0.8 1.2 0.8 0.8 +0.3 0.5 0.2 _ _ 0.4 1.0 Dead 1.0 1.5 __ b 0.8 +0.5 0.5 0.6 _ -- 0.8 0.5 -- 0.4 0.6 b 0.6 +0.1 Sacrificed 0_.7 0.2 _-- 0.5 Dead 0.8 0.8 ---- 0.6 0.5 1.5 __b 1.3 0.4 0.8 +0.4 0.6 +0.4 0.6 _ _ a __b 2.5 1.6 +1*3 _ 1.4 _ _ -- 1-5 -- 1.4 1.0 0.9 1.2 +0.3 _ 0.4 _ -- -- , 0.9 -- 0.8 1.0 0.5 0.7 +0.2 O oo zTi o *1 Z) ---7LJ --S U) > -350- Table A-30 (Continued) DBCP: INHALATION F(UTILITY STUDY IN THE HALE RABBIT^ Babbit: Volume of Ejaculate (ml) Exposure Level--ppm 1.0 AnInal Number 929 931 1126 919 9*9 178 926 90 k 930 932A Mean +S.D. lb 0.8 0.5 Sacrificed Dead --- Sacrificed 0.8 0.5 1.3 1.5 1.0 2.0 Sacrificed S0.a3crificed_ft 0.8 +0.4 1.1 +0.8 24 0.5 -- -- aw 0.8 0.8 2.0 -- 0.7 1.0 +0.6 26 0.5 -- -- -- 0.7 0.5 1.5 -- -- 1.0 0.6 +0.4 SL 0.5 --* -- -- 0.8 0.5 1.7 -- -- 0.4 0.8 +0.5 26 0.5 0.6 0.8 1.1 0.5 0.7 +0.2 30 0.5 0.8 0.4 1.0 0.5 0.6 +0.2 Week of Study 32 34 0.4 0.7 36 0.4 0.7 1.4 0.5 0.8 0.8 +0.4 0.7 0.7 1.5 0.8 0.8 0.4 Zb 0.9 +0.4 1.5 0.8 +0.4 36 0.6 0.6 1.1 0.6 1.5 0.9 +0.4 40 __ b 42 __ b 44 __ b 46 __ b 1.0 1.0 1.0 1.0 1.2 0.9 1.0 1.0 0.5 0.3 0.3 0.8 +0.4 0.8 0.8 +0.3 0.9 1.0 +0.1 0.4 0.8 +0.3 10.0 914 921 922 906 918 933 927 1125 925 924 Mean S.D. Sacrificed 1.4 1-5 Dead -- Dead -- Dead -- 1.4 Dead 0.9 -- 0.9 0.8 2.5 2.0 0.7 0.6 1.4 0.7 1.2 so. 6 1.4 -- -- -- 0.8 -- 1.0 1.6 0.2 1.0 JO.5 0.8 -- -- -- 0.4 -- 0.4 1.6 0.4 0.7 JO.5 1.3 -- -- -- 0.8 -- 0.2 1.2 0.4 0.8 J0.5 0.2 0.3 0.3 1.3 0.5 0.5 JO.4 1.3 0.6 0.3 1.0 0.4 0.7 0.4 1.7 0.7 0.5 1.3 0.5 0.9 0.5 0.9 0.5 0.4 1.0 0.8 0.7 0.2 1.0 0.4 0.5 1.5 1.7 1.0 0.6 1.5 0.3 0.2 1.5 1.5 1.0 0.7 1.5 O.T 0.4 1.4 0.4 0.9 0.5 0.7 0.6 0.8 1.0 1.0 0.8 0.2 2.0 0.5 0.7 1.4 0.8 1.1 0.6 1.7 0.8 1.0 1.5 1.0 1.2 0.4 tMale rabbits sere exposed to 0, 0.1 or 1.0 ppm of DBCP by Inhalation for 6 hr/day, 5 days/week for 111 veeks. Hale rabbits exposed to 10 ppm of DBCP were exposed for 6 weeks. Following termination of the exposure period animals were maintained In the laboratory for recovery. A sample wee taken, but no volume was recorded. b8o sample taken. 1)0 1 3 1 3 7 4 OONF TDFNTTAI 'i !------ 1 -351- Table A-31 DBCP: INHALATION FERTILITY STUDY IN THE HALE RABBIT* Babbit; Proportion of Progressively Motile Spam (%) Exposure Animal Level--ppm Number -2 ^1 _1 _2 _3 _b J. jT~ _2 10 11 12 13 lb Control 8bb 215 910 180 909 901 916 932 9T 923 0 & 69 61* 80 76 73 62 80 50 82 85 83 81 b 79 90 15 75. 79 . 75 70 71 65 65 73 82 82 81 77 13 79 78 82 60 76 81 65 7U 65 78 lit 83 l6 65 63 26 38 38 81 63 .62 83 b3 66 63 62 53 69 37 82 8b *7 68 79 58 66' 65 92 80 37 9 b8 79 2 32 bb 52 79 87 56 26 30 87 28 55 63 a Dead -- -- -- -- -- 6b 52 38 38 35 6b 85 3__7bw 68 8 60 25 69 3b 61 67 69a 31 5 8b 71 be 3b 81 62 79 90 55 2b 1_7_a 0 25 83 70 65 lb 88 67 37 88 bb b2 b5a 6_9_a 7b .a 30 75 25 -- b9 32 60 a 29 82 69 13 Mean 13. D. 68 126 80 *5 63 *29 69 121 53 tzk 71 *13 61 15 b7 29 6b *20 b9 *25 37 lib b2 *27 62 *20 56 2b 50 31 b5 2b 0.1 917 920 906 911 1128 913 902 928 915 912 8t> 83 75 77 0 51* 72 76 0 82 80 67 78 90 88 82 79a 79 91 68 lil 72 38 77 37 __a 6 83 65 75 0 5 63 75 20 2 59 __a 59 so 1*3 82 bo 61 31 7__9b 55 1*T 76 63 8U is b8 0 57 27 78 58 62 59 53 51 82 58 6b 60 52 19 2 66 81 82 10 20 15 31 85 86 bb 7b 76 82 7b 25 61 16 52 75 39 b5 8b b5 93 82 25 83 85 b60 __a so 21 __a 7 60 80 60 28 60 20 71 6b 0 68 __a 68 28 67 81 20 70 0 87 b7 18 17 35 3b 11 b9 32 8b 17 5 700 85 a 67 17 b7 b2 bl 35 71 56 0 58 2 _b _b 70 60 bb Mean 1S.D. 60 *33 78 *6 60 *28 57 3b b2 *20 51 *28 56 *16 b8 *35 58 23 5b *28 b7 33 b8 *36 bb *31 bo *28 3b *2b 3B *31 CONFTDFNTT o o -j -352- Table A-31 {Continued) DBCP: INHALATION FERTILITY STUDY IN THE HALE RABBIT^ Rabbit; Proportion of Progressively Hotile Sperm (%} Exposure Anleal Week of Study Level--ppa Number ~w~ 22 24 26 L 28 30 32 li 36 30 40 42 44 46 Control 641* 21 3 76 15 2 73 3 74 0 35 26 68 14 9 58 215 Dead 910 160 16 21 Sacrificed 75 -- 57 -- 56 -- 6 -- 80 -- 50 -- 64 -- 46 -- 79 -- 73 -- 70 -- 93 -- -- 909 Sacrificed 901 2 13 70 37 7 71 34 1 39 46 27 37 73 27 51 916 Sacrificed 932 77 57 65 86 0 91 7 91 87 89 78 96 94 88 65 907 923 84 12 1 8 58 33 94 56 __(L 3 93 24 53 __a __a 1 59 26 81 26 55 30 87,a 36 __a 3_1_a 62 Mean iS.D. 35 17 63 58 21 67 30 45 46 54 49 72 57 50 36 +21 +l6 33 27 35 31 37 31 25 25 +22 +32 38 56 +8 917 920 906 911 1128 913 902 928 915 912 Mean +S.D. Sacrificed Sacrificed Sacrificed 29 2 0 48 56 2,,9* 92 0 30 21 -i.* ,_b __a 0 6 0 0 0 27 0 21 _a __a 47 93 0 49 65 0 50 0 0 78 27 4 37 64 ,, b 93 0 22 49 3 3 84 74 62 26 57 44. 49 55 5 33 67 85 86 76 73 0 77 12 25 15 38 5 1 75 29 20 93 64 41 40 Sacrificed -- ___ ___ ---- -- -- ---- -- ---- -- 0 30 0 0 9 0 0 0 46 15 84 90 79 39 68 19 34 52 23 37 38 20 14 20 +22 15 21 l4 20 19 26 44 37 32 23 37 36 63 +38 53 35 56 26 39 31 DO 1 3 1 3 7 6 CONF- TD FN T T > -353- Table A-31 (Continued) DBCP: INHALATION FERTILITY BTODY IN THE HALE RABBIT* Rabbit: Proportion of Progesalvely Motile 8pern tit) Exposure Level--ppm 1.0 Animal Humber 929 931 1126 919 9>9 178 926 90It 930 932A Mean S.D. -2 77 n 0 79 0 72 73 0 70 70 52 +36 -1 _1 78 83 79 84 77 7* 78 82 87 83 10 --a 5 79 70 6*. 68 __& 62 77 62 +6 30 _2 69 26 63 84 7*i 72 77 0 __b 0 52 3*i _3 -- 0 3i 36 7*t 72 86 67 78 91 79 60 67 30 21 62 33 6l 6 __a 22 53 50 27 30 10.0 91<t 921 922 908 918 933 927 1125 925 92*i Mean jS# D* 73 73 78 88 80 0 7_9_a 71 0 77 0 63 __a 79 8l 0 68 66 80 28 68 73 72 83 --* 80 __a a 81 7* 55 5* +8 38 35 83 65 89 89 77 87 b 3*i 83 55 80 90 61 32 86 21 __a 82 a 90 80 6*. +9 27 25 61. 91 30 5 77 52 58 79 73 55 27 -1 58 69 6*i 59 81 31 1.6 19 65 70 56 19 60 86 8lt b 61. *.3 79 70 76 72 70 13 jb 79 1.2 89 76 15 *.0 1.0 --.a 65 72 58 +2*. 20 61. 30 17 73 63 50 10 69a H 25 J. 71 58 81 79 75 21 7__1& 55 *.7 62 19 ~J----- _2 68 33 76 1.8 79 W 60 79 0 66 a 22 26 67 *.5a _a 1.1 32 1.6 39 31 20 77 6 Dead Dead b a 61. 27 36 14 37 28 53 0 -- -- m_ib 21 Dead 7 3__2a 23 21 69 0 -- -- b 2 -- 5 6o a 27 3*. 10 11 12 22 10 57 58 63 2 0 Dead 10 67 58 0 12 3 55 65 a !| 16 30 32 50 51 a 1.1, _a 5 73 79 21. 37 1.6 22 27 30 Sacrificed __b _b ---- -- 0 9 D__ebad ---- 23 0 28 _a 6bk 15 3 13 +!. _ b -- _ -- b -- b a b __c 13 1.0 29 53 82 8 20 27 27 32 35 +21 _ b __ -- _ ib -- b __b 0 od ik 21. 29 *5 31 b *_._7a 1_*3a 36 +10 n_ b -- -- -- mmb b __b 0 od 1 IN JO 1 JNO J I> -35A- Table A -31 (Continued) DBCP: INHALATION FERTILITY STUDY IH THE MALE RABBIT* Rabbit: Proportion of Progesslvely Motile Bperm (5) o oo zo --nt r- Z) 10 'n z u> -1 NJ -< X 3> Exposure Level--ppm 1.0 10.0 Animal Humber 929 931 1126 919 9*>9 178 926 90k 930 932A Hean IS. 0. 91k 921 922 908 918 933 927 1125 923 92k Hean +S.D. HE H- 28 k6 Sacrificed Dead -- Sacrificed 7k 7k 72 80 77 25 Sacrificed Sacrificed 1 --a 50 56 3k *26 2k --K-- ZL 86 70 3k ------ ------ ____ -- -- 23 73 k 19 0 31 70 66 k6 ---- -- ------ 5 15 36 kl k5 30 *35 *3k *16 Sacrificed __b __b __b __b __b Dead -- ____ -- -- Dead -- -- -- -- Dead -- __b _b __ __b __b __b D_ebad --__b __b __ __b __b __b _b __b __b __b __b 38 _b __3b. __c __c __c 38d 3d 2 96 -- -- --- 10 8 83 -- -- k kO *k5 _,b -- -- __b Mi_b __7^b 7d 30 38 -- -- -- 68 38 0 -- -- 1 29 *29 _ 0 -- -- ___ kk -- __b 33 6 21 +21 Week of Study 32 3k _b 7 ---- ---- ---- 16 83 63 2 1 12 ---- ---- 0 --a 36 7k -- -- -- 52 17 3k -- -- k 20 26 36 *30 *38 *28 __ 0k0 ------ ------ -- _b __b ------ b b 38 b lk 3k b2 0 0& 7 18 +6 +21 30 " kO k _a ---- ---- ---- 58 1 0 88 2k 62 ---- ---- 20 18 38 *2k *kk k2 __a -- -- -- 79 55 33 -- -- 5 k3 *32 kk __a -- -- -- 82 68 --* -- -- 21 57 *32 _a -- -- -- 2k _31a -- -- 0 18 *16 _ 5 lk 6 5 0 -- -- ------ ---------- ---------- b 16 16 18 k -- -------- k9 28 23 lk 8 6 60 57 k3 38 0 13 0 19 3 15 26 20 20 11 23 +20 +22 +lk +16 *Male rabbits were exposed to 0. 0.1 ,'or 1.0 ppm of DHCP by Lnhalatlon for 6 hr/day. 5 days/week for lk weeks. Male rabbits exposed to 10 ppm were exposed for 8 weeks. following termination of the exposure period animals vere maintained in tbs laboratory for recovery* sRo sample taken. bInsufficient number of sperm to count fbr motility. -- --" cNo value e vere available fbr mean S.D. dHo mean taken: only a single value was available. '-- - --- ' CONF T o o O Ou -n ^ z OJ H N! i--[ -355- Table A-32 DBCP: INHALATION FERTILITY STUDY IN THE HALE RABBIT* Rabbit: Proportion of Hott-ProKeBBlvcly Motile 3pern (5) Exposure Level--ppn Control An Inal Number ew 215 910 ISO 909 901 916 932 90T 923 Mean 8.D. ____________________________________ _________________ Week of Study -2 -1 _i _2 _3 JT _6 _L _8 0 6 __a 2it 5 16 83 18 lit 18 32 10 1 U7 51! 7*i 25a 72 Dead 8 8 10 10 6 13 13 15 33 13 18 6 10 lit T 56 12 9 36 28 lh 20 28 55 7 81 hh b 15 5h T 6 It 21 2It 7 2 61 10 25 T 12 11 16 15 26 Ik 26 56 58 h3 16 21 20 19 39 11 8 hi 39 2 17 9 15 58 27 16 10 25 10 12 12 23 20 l>i 1 11 9 9 55 A 60 -- hO 2h 60 27 7--8a 5, 7,a 6 11 19 23 31 18 21 ho 21 36 h9 5 +h 15 +22 +20 13 +18 +28 13 +22 +20 10 10 -- 35 26 23 63 h9 39 10 ,_a 32 18 11 62 -- 59 32 31 8 25 25a 31 +21 12 25 -- 6 _9a h2 b 17 11 --a is *13 13 25 -- 9 37 76 29 77 10 65 18 38 27 lh 53 -- 37 33 23 --.a h3 16 16 15 30 lh 0.1 917 5 11 21 18 0 16 15 6k 36 51 25 11 58 h9 58 67 920 906 8 lh 96 6 76 6 22 27 18 11 1+0 9 18 77 2 36 6 9 55 5 3 13 10 30 7 38 72 60 hh 8 __a 911 1128 913 6 0 T 12 10 __a 8 6 *8 68 3li __a 35 lit 30 51 *3 78 37 7 21 5 7h k6 3 21 65 65 10 63 lh 26 3h __a 2h 79 15 32 si 5 95 --a 7h 88 13 55 902 U 16 26 12 I18 17 25 72 30 15 hO 59 h 5h 5h 2h 928 915 912 13 0 6 1__2a lit 10 11 19 25 62 __5b 2k h3 66 6 15 21 31 73 33 6 2 77 11 6 15 lh 8 58 13 --* hh ,a 26 h8 23 80 32 0 lh 21 b 68 _.b 2h h5 Mean 6 11 17 32 37 32 29 33 27 30 31 25 38 39 38 h6 S.D. h 3 *13 *32 *23 *26 *18 *29 26 *22 *2h *16 *28 *28 *25 *29 -35- Table A-32 (Continued) DBCP: INHALATION FERTILITY STUDY IN THE HALE RABBIT* Rabbit: Proportion of Non-ProReBBlvely Hotlie Sperm tit) Exposure Animal Week of Study IT-Level--ppm Number 21 24 26 n. 28 30 32 34 36 38 40 42 44 46 Control 844 61 89 9 39 20 11 63 5 61 61 43 26 81 82 38 215 Dead .... -- -- -- ---- -- -- -- -- -- --* -- 910 60 68 23 41 4o 35 7 20 22 36 9 8 30 5 42 180 Sacrificed 909 901 Sacrificed -- -- -- -- -- -- -- -- -- --- -- -- -- 7 81 25 59 85 26 66 20 35 33 72 59 23 6k 42 916 Sacrificed __ -- -- -- -- -- -- -- -- -- -- -- -- 932 IT 36 26 13 75 5 63 4 3 10 12 2 1 8 10 90T 923 9 62 96 19 40 64 6 __a 33 80 1 a 4__3a 29 33 31 49 17 45 37 34 10 _a 5.7^a 60 34 Mean +S.D. *3 65 31 32 56 16 46 18 34 34 34 21 38 44 33 36 31 19 +22 +28 14 +25 12 +20 +18 23 23 31 35 13 917 920 906 911 1128 913 902 928 915 912 Mean S. D. Sacrificed Sacrificed Sacrificed 64 19 94 76 69a 11 10 21 16 Sacrificed 76 70 -- -- 39 7 4l 32 79 -- 95 57 37 49 33 30 32 -- ------ -- -- -- -- -- -- -- -- ---- ---- ------ ------ -- -- 65 a 4ii9b 85 22 3 25 61 __a 49 3 48 30 40 14 11 57 48 __b 27 6 39 89 __a 0 0 81 a 7 15 2 42 31 47 49 65 25 5*t 30 24 83 64 IT 1 8 10 26 TO 70 53 52 87 15 65 78 4 27 39 57 --- -- -- -- -- - -- -- -- -- -- -- -- 58 51 70 97 8 30 75 22 4 17 56 22 64 39 47 48 45 31 50 29 20 26 31 47 5 27 31 36 36 30 23 27 24 15 20 24 DO 1 3 1 3 8 0 CONF TOFNT TAl r~ -357- Table A-32 (Continued) DBCP: imtALATIOH FERTILITY STUDY III THE KALE RABBIT* Rabbit: Proportion of Hon-Progrcslvely Motile Spent (it) Exposure Level--ppe Anleal Runber -1 _1 _2 _3 _T Week of Study 16 JL -nr- _2 10 n_ 12 13 14 1.0 929 6 13 12 24 0 24 32 16 23 25 64 38 76 24 53 41 931 1126 11 12 10 61 4o 0 a 11 37 4 9 10 33 21 15 42 18 28 32 14 42 3 31 3 17 13 42 15 Dead __ 919 14 11 8 11 9 2 32 3 6 38 3 62 25 18 16 17 9>t9 178 926 904 930 932A 0 9 12 0 6 12 96 __9a 81 15 11 15 . 7a 16 27 18 3 13 21 18 11 17 61 70 38 __b 25 38 66 86 78 __a 86 7 8 44 59 14 24 70 16 8 29 35 0 47 16 72 __a __a 64 9 22 27 0 49 57 18 0 __a 66 35 66 __a ,a 49 39 61 44 74 29 2_3a 5 75 12 _a 23 68 30 30 11 10 __a 10 47 35 62 __b 32 __a 26 _a Mean 7 10 20 34 22 37 26 23 23 32 38 40 36 26 34 37 S.D. 5 2 +22 +22 +21 35 17 +24 12 25 +22 23 27 18 +22 16 10.0 914 921 922 908 918 933 927 1125 925 924 Kean tB.D. 6 11 is 10 17 94 12 9 15 1 20 16 31 7 57 23 11 49 32 18 24 10 Sacrificed __b _b __b __b __b 7 23 9 14 4 4 0 65 Dead -- -- -- -- ---- 0 0 __b 17 61 31 Dead ___ -- -- -- ___ 20 __a 10 10 29 51 6 9 __b __b __b 0 Dead __ -- 13 0 25 16 1 12 27 29 __a 23 79 30 __b _b _b _b 22 9 68 32 64 30 13 27 is Dead __ ---- 18 8 12 8 10 60 .. a __& --- 14 25 12 19 9 61 13 33 48 76 53 77 20 24 47 12 24 __b _b _b __a _b __b 12 --* 8 __& 6 3 17 _ a 4l __a __a __b __b 1 0 13 10 26 15 21 23 14 35 33 40 42 25 18 +6 8 32 8 23 19 10 21 16 24 33 19 8 c 1<* 0<* n 0 i^7 2O --1 O CO Tf r-A 2 CO H 00 -H --1 3> n o o "H -* Z 'Si -t 3) '0 -358- Table A-32 (Continued) DBCP: INHALATION FHtTTLITY STUDY IN THE KALE RABBIT* Rabbit: Proportion of Hon-Progressively Hot11a Sperm tit) Exposure Level--ppa Animal Number Week of Study 2b 26 a 2fl 30 32 3b 36 38 bO b2 bb 1.0 929 63 b3 8 27 30 b 57 __b 82 21 50 __a --* a___ a 931 Sacrificed -- -- -- -- -- -- -- -- -- -- -- -- -- 1126 Dead -- -- -- ---- -- -- ---- -- -- ---- 919 Sacrificed -- __ -- -- -- ____ ____ -- __ __ 9b9 lb 20 b8 lb 6l 8b 21 73 6 b3 6 98 13 lb 55 1T8 926 11 5 76 19 62 7b 6 bT 18 15 b3 9 8 5 6 17 90 81 79 1 65 67 11 38 25 63 _9a b6 __& 90b Sacrificed -- -- -- -- -- -- -- -- -- -- smew 930 Sacrificed -- -- -- -- -- -- -- -- -- ___ ___ -- 932A 90 -* 77 bb b2 91 b3 20 a. 58 83 96 78 77 bl Mean iS.D. 37 29 b5 2b be 52 27 29 65 53 bl 61 b5 33 38 20 32 12 lb b2 22 30 39 22 36 b3 31 38 b7 7 10.0 91b 921 922 908 918 933 92T 1125 925 92b Kean S.D. Sacrificed b b b b____ ____ b b 10 6 10 0 33 1 b8 25 Dead -- ---- -- -- wees Dead -- -- Dead -- __b __b b____ b____ MS b____ b____ -r-- 2b b____ b____ b____ -- b___ b 23 -- 3b Dead -- ... __ -- we-- -- MS me* ee_ __b _b __b __b _b _b __b __b __b 22 35 10 36 lb b___ __b __b 17 5 58 18 __b b3 51 67 lb bo 36 __b b____ b____ __b b____ b____ 36 b____ 30 0 60 bb 10 38 c____ c____ __c lTd 5d 58d 22 ill 6<> 28 18 b9 15 31 29 +17 +2b 17 17 15 10 26 -- 3b bo 37 50 37 9 *Hale rabbits wre exposed to 0, 0*1, or 1.0 ppm of DBCP bjr Inhalation for 6 hr/day, 5 days/week fbr lb weeks. *hle rabbits exposed to 10 ppa DBCP were exposed for 8 weeks. Following termination of the exposure period animals were maintained In the laboratory for recovery. --aNo sample taken. ^Insufficient number of sperm to count for motility. cHo values were available for mean i s.D. dHo mean taken: only a single value was available. -359- Tnble A-33 DBCP: INHALATION FERTILITY STUDY IN THE HALE RABBITt Rabbit: Proportion of Hon-Hotlle Sperm (j) Exposure Level--pm An Inal Nunber Week of Stuctr -1 JL _2 _3 _4 J. _6 _1 _8 JL 10 11 12 13 14 Control 844 215 100 __a 7 10 15 8 48 3 68 5 7 37 10 9 17 1_9ft 0 Dead 10 -- 3 -- 10 -- 20 -- 12 -- 22 -- 910 19 10 10 12 11 21 24 37 3 35 22 27 6 30 6 16 180 909 901 34 U 14 8 5 4 8 40 81 6 11 3 15 7 13 24 11 11 19 8 14 14 17 7 !9wb 17 38 64 16 15 25 5 43 3 7 2 11 22 32 __a 19 49 9 35 16 _a 916 932 18 10 10 18 13 9 5 14 10 11 9 4 ll 22 7 9 10 2 5 37 __5a 51 37 12 5 _b 10 18 2 28 2 90T 923 13 10 67 9 11 0 15 4 5 7 19 11 8 7 9 4 54 2 2 1 __a 4_5a 6 _a 1_5a 5 7 15 72 Mean 24 9 18 8 15 11 17 13 15 16 13 27 7 26 11 26 +S.D. 28 +k +24 +4 +19 +6 19 +9 17 +16 9 +20 +3 +12 +9 21 0.1 917 11 9 12 7 100 8 23 34 20 10 30 5 14 16 8 22 920 906 9 16 6 6 4 19 29 15 14 16 15 15 2 9 7 3 l4 11 13 15 20 14 5 5 3 12 13 11 8 51 8 __a 911 1120 913 17 100 39 9a 11 1 24 11 10 __& 7 6 6 27 31 9 22 12 11 21 13 16 34 15 5 10 3__1a 10 31 53 a 66 59 16 1 15 68 12 95 6 28 _a 9 12 40 3 902 17 12 36 6 12 26 12 13 9 5 0 13 9 5 11 5 928 915 912 U 100 12 11 __a 49 84 6 16 14 7 16 b 11 10 7 16 27 19 17 8 36 9 12 7 37 19 25 22 4 22 16 . a 56 a6 5 12 59 100 3 16 21 b 3*. 6U Mean 33 11 23 11 21 18 15 20 15 16 22 27 19 21 26 16 38* D* +36 +6 26 +5 29 8 5 10 9 +9 18 +29 +24 30 +30 13 1 IN JO I dNO'J OU O CJ zn o O L) z US H 00 -H 3> -360- Table A-33 (Continued) DBCP: INHALATION rEBTILITI 8TUDI IN THE HALE RABBIT* Rabbit; Proportion of Hon-Motlie Spera (]t) Exposure Level--ppm Control Huofcer 81*1* 215 910 180 909 901 916 932 907 923 Mean S.D. ~W~ ia 18 8 Dead 1) 11 Sacrificed Sacrificed 91 6 Sacrificed 67 7 37 6 73 22 2b 34 *27 2b 2f> SL --2B~ 30 32 34 36 15 b6 78 16 3b 21 39 b 31 ------ -- -- -- -- -- 2 3 b 59 13 30 lb 18 12 -- -- -- -- -- -- -- ` -- -- ------------ ------ 5 __ b -- 8 -- 3 -- 0 -- 79 -- 26 -- 21 -- 1 -- 9 1 25 b 30 5 10 1 10 2 0 11 6 33 18 10 2 8 3 __a 17 __a --ft 66 25 31 37 6 11 2b 18 22 36 21 13 16 *5 *20 28 *2b 15 29 11 12 lb bS bb ST 659b -- -- -- ~* 19 17 2 12 -- -- -------- bb97 -- ---- 2 5 b 25 3 7 8 1* --ft --ft --ft --ft 7 8 6 10 *7 *5 3 *9 0.1 917 Sacrificed 920 Sacrificed 906 911 1128 913 902 928 Sacrificed 7 33 b2 5 1 5 --ft 30 _b 9 76 97 be 18 --ft b b 3 10 11 5 87 16 9 12 18 2b 5 79 --a 59 16 6 79 __a 100 9 16 5 16 100 2 9 19 21 b3 --ft 93 21 12 12 10 85 3 6 98 6 2 5b lb 7 89 5 9 31 lb 20 bB 1 3 915 912 Sacrificed 2b 0 5 b2 bO 30 3 92 2b 12 b 6 V 6 10 Hean +S.D. 2b 12 lb 15 bO 38 38 36 2b 19 3b 18 20 lb lb 28 13 22 18 35 bl 33 38 3b 32 b5 18 28 11 17 -361- Exposure Lercl---ppm 1.0 Animal Humber 929 931 1126 919 949 912769 904 930 932A Mean S.D. 10.0 914 921 922 900 910 933 92? 1125 925 924 Mean iS.D. Table A-33 (Continued) DBCP: IHHALAT10B FERTILITY STUDY IK THE HALE RABBIT* Rabbit; Proportion of Hon-Motlle Sperm (%) ______________________________________ ______ -________ Week of Study ^2 -1 _1 _2 _3 ~JT~ "3-- "X" .2 17 9 5 7 100 42 10 5 6 7 3 12 100 __9a 6 12 13 0 24 24 17 11 21 5 25 8 21 2 9 10 8 10 7 15 14 5 24 20 9 21 15 56 97 100 19 97 0. 9 9 7 6 22 0 22 12 6l 15 31 9 13 44 100 16 _a 15 100 24 7 00 10 6 29a 16 11 O99 62 ,b 13 1 1 8 22 __a 12 10 22 21 6 _1_3a 1_3a 6 11 26 23 6 20 4 3 20 __a --,a 7 4o 13 17 14 25 15 18 19 15 22 23 42 8 22 *19 30 11 16 *9 13 31 33 10 40 24 85 28 100 2289 19 11 5 36 31 11 14 9 Dead 9 23 16 72a 4_5_a 27 23 12 19 66 24 12 a 47 27 17 11 28 19 13 7 57 31 13 17 50 42 26 33 31 17 14 32 25 38 __7b 2_1a 3_1_a 26 11 21 9 1 10 14 6 a 7 1_0_0a 6 100 12 11 14 5 19 --* 12 "* 5 6 14 100 11 7 4 12 _& 11 12 34 19 6 *45 *31 5 20 2 10 _9_b 9 49 7 16 49 84 4 __a 19 4 _a 4 6 14 *2 *14 55 20 5 9 44 11 18 17 9 24 21 *16 9 7 23 13 12 45 15 02 7 90 Sacrificed __b __b __b b _b 16 5 Dead -- --_-- __b 28 30 52 16 8 D_eabd ..It b 56 -- __ __b 100 19 61 Dead __b __ __b __b . _ _b 0 23 18 Dead -- 11 15 11 29 40 10 16 __a 45 18 1..5a is 20 __a 53 2__5a 88 7_0b __b a _b __b _b _b _b 99 100 15 21 29 37 31 60 79 *0 14 *16 *30 34 *31 13 c 99* 100d DO 1 3 1 3 8 ? . OONFTDFNTTAl -362- Table A-33 (Continued) DBCP: INHALATION FffiTILITT STUDY IN THE KALE RABBITt Rabbit: Proportion of Non-Hotlie Sperm. (%) Exposure Level--ppm 1.0 Animal Number 929 931 1126 919 949 178 926 904 930 932A Mean yS.D. 10.0 914 921 922 908 916 933 927 1125 925 924 Mean B.D. ^________ 16 n 24 26 9 ii Sacrificed Dead -- Sacrificed 10 6 17 15 17 28 Sacrificed Sacrificed 9a 7 29 5 12 -- -- 18 3 13 81 19 -- -- 4l 12 15 14 31 4 +9 +10 131 27 36 35 7 12 -- -- 22 22 +13 _________ Week of Study 28 30 32 34 ~nr~~~w~ 40 i!i 44 IT 0 5 __b 11 5 46 a __a __a i 6 11 11 11 5 36 i 8 4 21 18 54 31 8 95 82 8 7 4 99 29 i 0 20 4 23a _2_31 ---------------- -- ------------ -- 5 56 80 38 15 4 17 2 59 7 44 51 9 11 41 2 12 10 34 7 137 +36 2 15 36 2 8 12 21 Sacrificed __b __b --b __b __ b __b 90 94 86 100 62 85 48 70 74 Dead Dead -- -- -- -- -- -- -- -- -- -- -- -- -- -- Dead __b __b __b __b __b __b 32 __b __b _b __b 80 61 48 62 _b ~b ~b ~b ~b "b ~b Zb Zb 40 b __b ,,b __b __b --b 45 92t __b 3__5bt 49 58 __b __b 43 68 15 100 16 27 40 62 26 43 4l 3 90 72 22 43 52 25 47 .c __c l5d 92d 35d 57 24 9>*d 66 22 a 36 43 20 59 49 25 32 51 52 21 18 *Male rabbits were exposed to 0, 0.1, or 1.0 ppm of DBCP by Inhalation for 6 hr/day, 5 days/week for lit weeks. Kale rabbits exposed 50 10 pp DBCP were exposed for B weeks. Following termination of the exposure period animals were maintained In the laboratory fbr recovery. ,aNo sample taken. bInsufficient number of sperm to count for motility. No values ware available fbr mean S.D. dKo mean taken: only a single value va* available. r.... DO 1 3 1 3 8 0 CONFTDFNTTA! D O 2 a0 --~nf D Ok) 2 -t 3) --< X> M -363- Table A-34 DBCP: INHALATION FERTILITY STUDY IN THE HALE RABBIT^ Rabbit; Viability of Sperm (5)a Exposure Level--ppm Animal Humber -1 _1 _2 _3 _4 Week of Study _6~ jB _2 10 11 12 13 14 Control 8ItA 93 __c 89 91 83 91 47 78 92 93 86 92 87 84 89 87 215 95 92 95 96 64 90 74 92 _.C Dead -- -- __ -- -- 910 88 89 90 88 31 89 90 94 82 79 63 88 92 84 75 87 180 909 901 89 70 86 96 89 91 45 94 97 82 97 96 73 80 90 75 83 92 81 88 73 85 87 93 82 85 __d 93 86 90 86 90 92 88 87 97 84 81 93 63 90 52 91 96 64 84 e 916 932 99 90 97 93 96 94 94 90 88 87 95 88 76 82 86 64 90 86 94 89 98 c 47 86 94 84 90 94 96 97 68 98 907 923 88 75 92 96 91 90 95 91 88 95 92 88 81 83 94 93 96 92 89 84 9_4c 76 _c 9_1c 84 _c 93 89 100 74 Mean +3. Da 87 93 88 +9 +3 15 & 76 5 +21 68 78 6 +12 89 5 88 88 87 83 88 84 86 83 +5 +5 11 +16 5 +10 14 +13 0.1 917 9k 86 84 89 66 87 86 82 94 77 94 92 92 82 80 82 920 94 92 92 94 59 90 73 95 93 86 91 96 86 92 83 86 906 99 96 75 89 96 82 83 94 95 90 92 98 81 92 76 911 1126 913 69 80 87 68 91 44 78 91 85 72 93 82 92 82 68 87 71 81 c 80 73 78 91 91 90 81 76 79 83 86 79 89 66 ,-C 60 84 96 --c 92 99 74 97 C 84 96 90 82 902 / 93 93 78 65 88 81 84 80 75 80 90 89 92 88 94 94 928 915 912 83 96 8 --b ..c 50 90 91 81 89 90 88 d 80 89 88 79 93 89 78 77 81 84 66 92 85 99 94 79 90 96 82 ,,, c c 98 85 94 36 90 84 88 96 __ <3 d __d 96 37 82 Kean 88 88 71 87 84 80 81 86 87 85 88 90 84 89 78 87 8. D. i8 8 25 9 112 14 5 16 10 8 +12 6 +16 6 +18 6 -364- Table A-34 (Continued) DBCP: IHHALATIOH FtETILITY STUDY IH THE KALE RABBIT* Rabbit: Viability of Sperm (j)a Exposure Level--ppm Control An Inal Humber 81* 215 910 180 909 901 916 932 90T 923 Kean +8. D. 0.1 91T 920 906 911 1120 913 902 928 915 912 Kean S.D. 16 24 26 ZL 80 76 89 76 Dead 90 92 66 99 97 Sacrificed -- -- -- Sacrificed 96 92 90 96 99 Sacrificed ---- 90 97 86 96 94 92 89 95 39 80 n 100 _C 93 69 90 85 79 96 88 +5 22 +8 4 12 Week of Study 28 30 32 34 A 38 40 J*2 44 93 59 01 61 88 73 85 68 94 __d 95 60 89 73 93 60 90 88 -------- -- __ __ __ 97 92 94 83 93 100 85 53 82 -------- -- -- -- __ 95. 95 90 09 09 94 92 76 54 98 88 __c 91 71 09 84 97 71 88 71 9_8c 42 +--C 8T 96 86 82 82 85 86 84 67 01 2 15 *5 11 11 12 14 22 16 Sacrificed _ _ __ ,, _ ,, _ _,,,,_ Sacrificed -- -- Sacrificed 97 91 85 9k 80 9_3c 94 n 90 __d 92 85 ,,0 43 21 92 64 88 88 90 . _C 99 __C 35 93 93 37 69 29 47 79 91 07 7_9_d 66 92 71 66 96 87 81 93 92 68 55 01 79 79 61 91 90 93 94 93 89 90 100 93 76 94 91 90 78 09 83 96 Sacrificed -- __ -- __ __ -- -- -- -- 95 93 93 96 97 97 90 93 80 96 34 96 87 93 93 92 86 96 06 76 02 89 79 61 53 89 82 91 4 +3 +7 2 +24 +29 *5 +6 23 +22 20 +6 7 +4 46 82 97 __ 92 -- 8T 90 _c 90 +6 _ 83 73 79 74 84 -- 76 78 +5 00 131388 CONFTDFNTTA O oZ zn o --t -1 oTl o-Aj z--t w'D o I-- Table A-3b (Continued) DBCP: INHALATION FERTILITI 61UDI IN THE HALE RABBIT* Rabbit: Viability of Sperm (]t)* Exposure Level--ppm 1.0 Animal Number 989 931 919 9*>9 178 926 90b 930 932A Kean S. D. ________________________ ______________ __________ Week of Study ~E-- 2k 26 27 28 30 32 91 99 97 93 98 95 9** __d 111 Sacrificed -- -- -- -- -- -- -- Sacrificed 82 95 100 95 97 89 96 86 90 68 92 95 95 87 70 72 67 31 89 81 78 95 97 9k 92 97 88 Sacrificed -- -- -- ~ ---' -- -- S70acrificedC -- 63 -- 83 -- 9b 96 57 93 __c 81) 92 87 92 95 89 82 86 62 +8 8 16 5 +1. +11 17 113 +31 ~3 100 93 ---- 92 81 78 2b 6>t 89 ---- 92 99 89 77 40 30 bo b2 ~w~~T5 _C __c __c _C -------- 79 8b 89 88 90 85 80 83 95 --c 2_7_c -------- 83 78 93 89 8b 81 92 68 k 3 3 +36 10.0 9lb 921 922 90S 918 933 927 1129 925 92b Mean S. D. Sacrificed __d __d __d __d __d __d __d _d __d 1*6 50 59 Dead -- -- -- -- -- -- -- -- -- -- --* Dead -- -- __ -- -- -- -- -- -- -- -- Dead _d __d __d __d __d __d 0 __d __d __d __d 30 Dead __d __d __d __d __d __d _d 36 _d 51 __d 1*7 __d 92 __ __d __d __d 59 __ 25 60 56 61* __ 68 62 _d __d __d __d __d __d __d 3b 35 38 111 7b 0* __e __6 36f 5lf kit I16 165 3bf *T 1*7 53 59 17 23 10 17 __d _d __d ------ ------ __d _d _d ---- 60 71 55 71 73 79 _d __d 77 66 72 70 8 1 13 *Male rabbits were exposed to 0, 0.1, or 1.0 ppm of DBCP by inhalation Tor 6 hr/day, 5 days/week for lit weeks. Hals rabbits exposed to 10 pp of DBCP were exposed for 8 weeks. Following termination of tbe exposure period, animals were maintained in the laboratory for recovery. `Determined by staining sperm with coeln-anlllne blue stain. bl(o slides were available fbr a viability count. cHo sample taken. dInsufficient number of sperm to count fbr viability. eHo values were available fbr mean t S.D. rNo mean taken: only a single value was available. Sthe value recorded was apparently incorrect and therefore was not included In the calculation of the mean. -347- Tiblt A-3S DACPt INHALATION FERTILITY STUDY XM TBS HALE RABBIT* Individual Obsarvatlons Mada at tha Tina of Nacropav of Unaxpoaad ranala Raooita Hatad with D6CF Expoitd Malas` MHk of Sttrtyi 14 Exposure Laval--pro Animal Number Mala Control >44 910 909 916 932 180 901 907 923 MtsntS.D. Animal Himbar Female 43 41 36 830 S3 IS 27 32 841 Corpora Lutaa implantations Resorptions ii 12 non-pragnant non-pregnant 10 non-pragnant 10 9 9 7 10 10 10 9 9 1 0 0 1 0 2 10*1 9*1 0.7*0.8 Total fartlla mm las 6 X Pre-Imp Loaa 36 17 0 0 0 0 9*IS X Poat-iap Loss 14 0 0 10 0 22 8*9 0.1 917 28 17 920 29 11 911 37 8 1128 12 11 902 13 7 913 47 11 928 48 12 915 20 8 912 16 10 11 9 8 9 7 10 10 8 7 0 1 0 2 1 1 1 2 0 MaanSS.D. 10*3 9*1 0.9*0.8 Total fertile mala* * 9 35 18 0 18 0 9 17 0 30 14*13 0 11 0 22 14 10 10 25 0 10*9 1.0 929 82* 9^ 3 931 39 7 S 919 30 14 9 949 87 $ 8 178 46 non-pragnant 930 33 10 S 93 2A 72 9 8 NeanaS.D. 8*4 6*2 0 0 1 0 0 1 0,3*0.5 10.0 921 59 933 44 112$ 52 924 61 925 62 Nn*S.D. non-pragnant non-pragnant non-pragnant non-pragnant non-pragnant _e _e _c 70tal fertile males - o ob 29 36 0 SO 11 21*20 --c 0 0 11 0 0 12 4*6 tN>l* rabbit* war* axposad to 0, O.X. or 1.0 ppm of DBCF by Inhalation for 6 hr/day, ! dayt/weak for 14 weeks. Mala rabbits sxposed to 10 ppm of DBCP warn sxposed for 4 weeks. Following tanlnatlon of tha axposur* parlod animals warm maintained in tba laboratory for recovery. During tha 14th week of tha study, aach aala rabbit was allowad bo aata with ona unaxposad female rabbit. Tha females wara aaerlflead on day 28 of gaatatlon. `Tha laft born of tha utacus from Animal ho. 12 waa not continuous. Tha antarlor portion of tha laft horn waa anlargad and was attachad to tba laft ovary. Tha poatarlor portion of tha laft horn was of normal alta. Both portions of tha laft horn did not hava any implantations. bAs tha laft utarlna horn was not continuous, only tha 3 corpora lutaa observed from tha right uterine horn ware included in thla summary. cno data available. no 131391 CONFTDFNTTAt -3M- Table A-36 OBCPi INHALATION FERTILITY STUDY IH THE HALS RABBIT1 Individual Observations Hade at tha Time of necropsy of unamosad mm mmhu Hated >tn mov exposed Hala Week of Study* 41 Exposure Laval--pf Animal Numbsr Mala Control 844 910 932 901 907 Maan*S.D, An las1 Huabar raaale corpora Lutaa taplantatlons Assorptions X Pra-lap Loss 223 237 218* 2322 184 2323 233 259 249 258 220 10 7 12 12 10 8 10 ii 10 7 91 non-pragnant 89 15 11 DalItsrad aarly 98 1 1 0 0 1 1 1 2 0 ioi 8*2 0.7*0.7 Total fartlla aalas S Total fartlla aalas Impregnating two faaalas * 4 15 20 CO 14 11 24*20 X PostLoss 1 11 0 f > 57 14 i0 16*24 911 1128 902 913 928 912 HeanmS.D. 949 178 926 932A MeanaS.D. 222 7 248 10 173 12 243 11 234 11 244 10 262 9 187 7 219 9 245 11 244 10 278 10 7 10 3 11 11 9 9 3 8 3 10 4 00 1 1 38 1 15 1 0 28 0 0 42 2 2 20 1 10S2 8*2 0.840.5 22el7 Total fartlla aalas - 4 total fertile aalas impregnating two faaalas 6 257 10 270 9 234 12 217 9 204 11 2344 9 2320 8 2347 8 10 9 5 10 5 9 5 8 10 0 0 29 0 0 2B 1 0 19 0 lOal 8*2 0.240.3 19413 total fartlla aalas - 4 total fartlla aalas impregnating two faaalas 4 5 21 10 0 1 34 [ l 18 15*12 5 0 6 0 3*3 921 933 1125 924 925 Mean*S.D. 256 B9i*pr*9<iant 277 non-pr*gnant 216 AMWprfgnant 261 non-pr*9n*nt 260 non-pr*gnant 271 non*prnntnt 276 10 6 238 non*pr*gnant 202 14 13 279 15 15 40 4 12*3 10*6 1.0*1.4 22*24 total fartlla aalas 2 total fartlla aalas iapragnatlng two faaalas - 1 0 14 7*10 fHala rabbits wars vxpoaad to 0, 0.1, or 1.0 ppa of DBCP by Inhalation for 4 hr/day, 5 days/waak for 14 waks. Hals rabbits axposad to 10 p(H of DBCP wars axpossd for 4 wsaka. Following tarainatlon of tha exposura parlod, anlaals wars aaintainad in tha laboratory for tacovary. During tha 41st waak of tha study, aach aala was allowad to aata with two unazposad feaale rabbits, tha faaalas wars sacrificed on day 29 of gaatation. *<kia fatus froa this fsaala axhlhitad aultipla axtarnal aalforaations, including short trunk, acaudia, rotated hind liabs, actodactyly, and alcrodactyly. 00 13139? CONFTDFNTIAl -369Table A-37 DBCP: INHALATION FERTILITY STUDY IN THE MALE RABBITt Rabbit: Hematologic Evaluation (Packed Cell Volume %) Animal Number Control 180 909 916 Mean+S.D. O-1 PPm 917 920 906 915 Mean+S.D. 1.0 ppm 931 919 904 930 MeanS.D. 10.0 ppm 914 908 927 924 Mean+S.D. -2 1*6.0 48.0 43.0 46+2 43*0 42.0 44.0 42.0 43+1 41.0 40.5 45.0 43.5 42+2 43.5 45.0 42.0 44.0 44+1 Week of Study _9_ 41.5 48.0 43.0 44+3 13 35-5 40.0 39-0 38+2 39-0 37.0 44.0 33.0 38+5 40.0 37.5 52.5 29-0 40+10 38.0 39.0 30.0 40.5 37+5 36.0 42.0 29*0 41.0 37+6 40.0a Died Died 43.0 43 43.5 44 *Male rabbits were exposed to 0, 0.1, or 1.0 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Male rabbits exposed to 10 ppm DBCP were exposed for 8 weeks. Following termination of the exposure period animals were maintained in the laboratory for recovery. aAfter 8 weeks of exposure hematological evaluation done on animal #914 prior to sacrificing. Not included in calculations. no conftdhhttai Animal Number Control 180 909 916 Mean^S.D. 0.1 ppm 917 920 906 915 Mean+S.D. i-P.pg* 931 919 904 930 Mean+S. D. 10.0 ppm 914 908 927 924 Mean+S. D. -370- Table A-38 DBCP: INHALATION FERTILITY STUDY IN THE MALE RABBIT1Rabbit: Hematologic Evaluation (R.B.C. x 10^) Week of Study -2 _2_ 13 6.67 7-63 6.01 6.80.8 6.21 7.23 6.21 6.6o.6 5*42 6.34 5.83 5-910.5 6.55 5-82 7.00 6.26 6.4+0.5 6.15 5.29 6.26 4-55 5.6+0.8 6.26 5.35 7-79 3.88 5*8+1.6 5.64 5.74 6.78 6.44 6.2+0.6 5.60 5-34 5.29 6.26 5.6+0.4 5.71 5-59 5.76 6.22 5.8+0.3 6.21 6.63 6.40 6.59 6.5+0.2 6.23a Died Died 5.83 5-8 6.06 6.1 ""Male rabbits were exposed to 0, 0.1, or 1.0 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for l4 weeks. Male rabbits exposed to 10 ppn of DBCP were exposed for 8 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. aAfter 8 weeks of exposures, hematological evaluation was done on animal prior to sacrificing. Not included in calculations. 00 131394 CONFTDFNTTAI Animal Number Control 180 909 916 MeanS.D. 0.1 ppm 917 920 906 915 Mean+S.D. 3- PPm 931 919 90 4 930 MeanlS.D. 10.0 ppm 914 908 927 924 MeanS.D. -371Table A-39 DBCP: INHALATION FERTILITY STUDY IN THE MALE RABBIT1" Rabbit: Hematologic Evaluation (Hemoglobin g/lOOml) Week of Study -2 9 13 15.0 15.2 13.8 14.7*0.8 13.9 14.7 14.0 14.20.4 11.6 13.9 13.1 12.91.2 13.8 13.6 l4.4 14.3 14.00.4 12.9 13.7 14.8 14.2 13.9*0.8 12.7 12.4 12.4 10.8 12.1*0.9 12.3 12.7 9*5 13.3 11.9*1.7 13.1 12.8 16.1 8.9 12.7*3.0 12.0 13.9 9.0 13.4 12.1*2.2 13.9 14.3 14.0 15.2 14.4+0.6 12.4a Died Died 14.4 14.4 14.6 14.6 ^Male rabbits were exposed to 0, 0.1, or 1.0 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for 14 weeks. Male rabbits exposed to 10 ppm of DBCP were exposed for 8 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. aAfter 8 weeks of exposures, hematological evaluation was done on animal #91^ prior to sacrificing. Not included in calculations. DO 131395 CONFTDFNTTAl -372Table A-40 DBCP: INHALATION FERTILITY STUDY IN THE MALE RABBIT1" Rabbit: Hematologic Evaluation (W.B.C. x lp3) Animal Number Control 180 909 916 MeantS.D. 0.1 ppm 917 920 906 915 MeanS.D. -I'0 PPfl 931 919 904 930 MeanS.D. 10.0 ppm 9lU 908 927 924 Mean+S.D. -2 11.6 7-7 8.8 9.42.0 9*8 7.1 13.2 9-4 9.9+2.5 8.7 8.4 7.2 9.1 8.40.8 10.2 11.6 9.2 7-0 9.51.9 Week of Study _2_ . 9-9 11.9 10.6 10.81.0 13.2 8.3 25.3 l6.4 15.8+7.2 10.2 9.5 13.9 15.1 12.2+2.7 12.2a Died Died 7.7 7.7 13 12.3 13.2 10.1 11.91.6 8.7 7.1 17-8 18.0 12.9+5.8 11.3 8.5 13.1 9.9 10.7+2.0 6.6 6.6 +Male rabbits were exposed to 0, 0.1 or 1.0 ppm of DBCP by inhalation for 6 hr/dsy, 5 days/week for l4 weeks. Male rabbits exposed to 10 ppm DBCP were exposed for 8 weeks. Following termination of the exposure period, animals were maintained in the laboratory for recovery. aAfter 8 weeks of exposures, hematological evaluation was done on animal #914 prior to sacrificing. Not included in calculations. DO 131396 CONFTDFNT TAl Table A-ltl DBCP: INHALATION FEHTILITT STUDTt 18 THE MALE RABBIT* Rabbit: Hematologic Evaluation (Differential W.B.C. t) Animal Number Control 180 909 916 Mean 0.1 ppm 917 920 906 915 Mean 1.0 ppm 931 919 90b 930 Mean 10.0 ppm 91b 908 927 92b can Beut. 28 32 31 30 Lym. 68 53 62 61 -2 Hon. 3 10 2 5 EOS. 0 1 2 1 BAS. 1 b 3 3 Heut. 36 b9 37 bl Week of Study ____9 Lym. Mon. EOS. 6o 2 0 38 6 2 60 1 0 52 3 1 BAS. 2 5 2 3 Beut. 62 b2 b3 b9 Lym. 28 50 50 b3 13 Mon. 9 b 1 5 EOS. 0 2 1 1 BAS. 1 2 5 3 bl 53 0 2 b 51 bb 2 1 2 39 57 1 0 3 31 65 0 2 2 3b 55 3 5 3 3b 61 1 2 2 3b 58 5 0 3 62 26 6 0 6 8b 8 b0b 52 b7 1 0 0 55 35 7 1 1 77 18 b 1 0 bO 56 2 1 2 51 bo b 2 3 59 36 2 1 2 32 6b 2 1 1 53 32 7 0 8 57 3b b 0 5 27 68 1 0 b 39 56 20 3 28 63 1 1 7 10 83 b 1 2 59 27 11 1 2 7b 19 6 0 1 27 60 9 1 3 69 20 5 0 6 b5 b6 3 2 b 2b 69 b 1 2 55 3b 6 0 5 51 bl 3 1 b 30 6b 3 2 1 66a 25` 6a 1* 2* 15 78 b 2 1 Died 37 57 b 0 2 Died 2b 65 3 5 3 b3 50 3 0 b 35 53 1 2 9 26 66 b 2 2 b3 50 3 0 b 35 53 1 2 9 *Male rabbits were exposed to 0, 0.1, or 1.0 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for lb weeks. Male rabbits exposed to 10 ppm of DBCP were exposed for 8 weeks. Following termination of the exposure period animals were smintalned In the laboratory for recovery. aAfter 8 weeks of exposures, hematological evaluation was done on animal #91** prior to sacrificing. Hot included -374- Table A-42 DBCP: INHALATION FERTILITY STUDY IN THE MALE RABBIT* Rabbit: Clinical Chemistry Values Week of Study: 14 | Animal Number Control 909 916 180 Mean+S.D. 0.1 ppm 917 920 906 915 MeantS.D. 1.0 ppm 919 904 931 930 MeanlS.D. Prothrombin Time Sec. BUN mg/100 ml 8.6 7.8 8.6 8.3+0.5 19 21 18 19+2 8.1 __ ,a 8.3 7.8 8.110.5 20 16 60 13 27122 7.6 8.0 __ a 8.6 8.U0.2 22 16 16 18 1813 SGPT niJ/ml 28 16 16 20+7 19 23 18 10 1815 27 22 13 22 21l6 SGOT nU/ml i AP nU/ml 71 30 43 48+21 21 36 24 20 257 46 18 16 27+17 1 1 18 22 11 9 156 61 24 34 43 40l6 30 26 28 31 292 *Male rabbits ware exposed to 0, 0.1, or 1.0 ppm of DBCP by inhalation for 6 hr/day, 5 days/week for l4 weeks. Male rabbits exposed to 10 ppm DBCP were exposed for 8 weeks* Following termination of the exposure period animals were maintained in the laboratory for recovery. aNo sample taken. DO 13-1398 CONFIDENT! Al Tahla A-kk (Continued) skp: ibhalatioi mram stodi nt to wli moit* jjabblti TmHiHAi.1 Qrasn Height, ai Organ/Body Height Ratios Ostamlnad at the Tttilnil (kb~aha) Scorifies Pltholofy Aalaal final Body lusher luaber Haight (kg)> BRAH g/lOQg HEART k/l<55i Oma Haightt (g and g/lOOa Boar Haight) ZalYEB g7166g KioMna DE7io5 TESTES /M0 EPIDIDYMIDES Mt222 AlttOULS tVbOOl Control 78-1732 1733 173 k 1735 1736 1737 8kk 910 901 932 907 923 MAE 8*0. 0.1 upa 1738 1739 17k0 17kl 17k2 17k3 913 928 912 902 1128 911 MEAI 1S.D* k.30 k.20 k.k6 k.12 3*81 3.1k k.oo ao.kS 3.80 k.56 k.05 k.75 k.78 3.96 k.32 10.V3 10.01 9.70 9-75 10.50 10.05 9*82 0*23 0.23 0*22 0*2$ 0.26 0*31 9*97 0*23 0.29 0.03 6.85 7.k9 7*50 8.51 7.00 7.98 0.16 0.18 0.17 0.21 0.18 0*25 7.56 0.19 0.62 0.03 86.50 76.22 7k.13 72.55 55.97 76.51 2*01 1.81 1.66 1.76 l.k7 2.kk 73.65 1.86 9.9k 0.33 17.30 17.k5 15.85 17*10 Ik .05 20.87 O.kO 0.k2 0.36 0.k2 0.37 0.66 17* 10 O.kk 2.25 0.11 5.83 6.k0 6.65 6.35 5-51 5.k3 0.1k 0*19 0*13 0.16 0.1k 0*1T 6.06 0*13 0.5k 0*01 2.22 2.80 2.a 2.25 1-90 2.30 0*03 0*07 0*03 0.05 0*05 0*07 1 2.28 0.06 0.29 0.01 0.32 0.61 0.69 0.6k 0.5k 0.81 0.01 0.01 0*02 0*02 0*01 0-03 0.60 0*02 0.16 0,01 9.96 10.80 10.96 9.k9 11.51 10.00 0.26 0.2k 0*27 0.20 0.2k 0.23 lo.ks 0.2k 0.76 0.02 6.96 8.12 6.98 6-ki a.ko 6.55 0.18 0.18 0*17 0.1k 0.18 0.17 7.2k 0.17 0.83 0.02 79.08 76.10 61.51 72.88 72.68 85.96 2.08 1.67 1*52 1.53 1.52 2.17 7k .71 1.75 8.12 0.30 12*91 18.29 17. U 18.58 17.52 17.73 0.3k O.kO 0.k2 0.39 0.3T 0.k5 1T*02 0.39 2.08 0.0k 6.30 6-kJ 6.00 6.25 7.23 6.69 0.17 0.1k 0.15 0.13 0.15 0.17 6.69 0*15 0-k3 0.01 2.12 2*70 2*09 2.39 2.60 2*10 0.06 0.06 0*03 0*03 0.03 0*03 2.33 0.03 0.27 0.00 0*70 0*91 0*31 Q.k9 0.68 0*91 0*02 0*02 0*01 0*01 0*01 0.02 0*70 0*02 0.18 0.00 17kS 17kk 17k5 17k6 17k7 i_EES 929 926 932k 9k9 178 KEAH 8. D. 10*0 troa 2.59 2.71 k.78 k.27 k.6o 3-79 11.06 9*01 9.39 9*10 10.19 9.81 0.35 0.35 0.19 0.2k 0.21 9-50 0.27 10-50 10.07 6.18 9.k5 6.91 8.27 7*01 0.2k 0.35 0.1k 0.19 0*15 7.56 0*22 11.29 0.08 62.83 19.68 71.31 78.75 75.98 2.k3 1.8k l.k9 1.8k 1.65 67.75 1.85 11.67 0.35 15.75 17.82 16.37 19.k8 17*00 0.61 0.66 0.3k - 0.k6 0.37 17.28 0.k9 *l.k5 0.lk 3.61 5-a 6.39 5.51 3.85 0.1k 0*19 0*13 0*13 0.08 k.91 0.1k 1.17 0.0k 1*33 2.20 2* a 3.21 3.09 0.06 0.08 0*03 0.08 0*07 2*k5 0*07 0.69 0.01 O.63 0.68 0.66 0.81 0.75 0*02 0.03 0*01 0.02 0.02 o.n 0*02 0*07 0.00 17k9 1T50 1751 1752 1753 921 925 92k 933 1125 MEAN +6*0, k.82 k.21 k.23 k.10 3.19 k.U iO.59 9.78 10-58 10.80 10. ko 9.60 0*20 0.25 0.26 0.25 0*30 10.23 0.25 +0.52 +0.03 8.k2 6.78 7.32 7.13 5.62 0.17 0.16 0.17 0.17 0.18 7.05 0.17 1.01 +0.01 79.08 77.56 69.33 70.85 53.53 1.6k l.Sk 1.6k 1.73 1.68 70.07 1.71 10.15 *0.08 19-18 18.2k 25.k2* 17.95 17.k8 O.kO 0.k3 0.60* O.kk 0.55 18.21 0.k5 10.72 10.07 2.10 I.89 l.k2 1.39 2*22 0.0k O.Ok 0.03 0*03 0*07 l.So 0*03 10.38 0.01 1.90 1.60 1.65 1.59 1.60 0.0k 0.0k O.Ok 0.0k 0.05 1.67 O.Ok 0.13 0*01 0-30 0.87 0.5k 0.59 0.65 0.01 0*02 0*01 0*01 0.02 0.63 0.02 IO.15 1O.00 flkl rabbits wrt expossd to 0, 0.1, or 1.0 pm of 1CF br Inhalation fbr 6 hr/day, 5 days/mak for lb vnU. iu rabbits exposed to 10 tm Of EBCP wars exposed for 8 mil. Pollovin* termination of tbs exposure parlod, anlmla vara mint*load la tba laboratory for recoTery. `Values rtiraaaat faatad body mighta taken prior to oacropay. ^Maan axcludaa aoiaal #916 baoauaa one taataa as severely atrophic. e Organ mights not used la calculations. DO 131399 GONFTDFNT TA1