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The objective of this study was to examine the effects of gestational and lactational exposure to Aroclor 1242 (0, 10, 25, 50, and 100 mg/kg-bw) on male fertility. Doses were administered to C57BL6 female mice orally every two days from two weeks before mating, during mating, and through gestation until postnatal day 21. Male B6D2F1 offspring were examined for anogenital distance, organ development, epididymal sperm count, sperm motility, and in vitro fertility at 16 and 45 weeks of age. Stomach samples of pups nursing from PCB-treated mothers in the 50 mg/kg dose group were analyzed for PCBs and chlorobiphenylols by high resolution gas chromatography coupled with low resolution mass spectrometry. It was estimated that the nursing pups were exposed to 0.2, 0.6, 1.2, and 2.4 mg/kg/day total PCBs in the 10, 25, 50, and 100 mg/kg dose groups, respectively. This exposure level approaches the maximum FDA recommended levels for PCBs in food and breast milk. The composition of the PCBs in the stomach samples was different from the parent mixture, as there was a higher proportion of heavily chlorinated congeners, as well as chlorobiphenylols. Anogenital distance at weaning, and liver, thymus, and testes weight at 16 and 45 weeks of age were not affected by PCB exposure. Epididymal sperm velocity and linearity were significantly increased in the 25 mg/kg dose group at 16 weeks of age. Sperm count was increased by 36% in this dose group (P = 0.06). By 45 weeks of age, average sperm count in this dose group was similar to that of controls. With the exception of the 50 mg/kg dose group at 16 weeks of age, sperm fertilizing ability in vitro was significantly decreased in all PCB-exposed groups at 16 and 45 weeks of age. These results suggest that fertility in the adult mouse is susceptible to developmental exposure to Aroclor 1242 and is independent of testis weight or epididymal sperm count.
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PMID:Effects of gestational and lactational exposure to Aroclor 1242 on sperm quality and in vitro fertility in early adult and middle-aged mice. 1139 Jan 73

Dimethylethoxysilane (DMES), a volatile liquid, is used by NASA to waterproof the heat-protective silica tiles and blankets on the Space Shuttle. Acute, 2-wk, and 13-wk inhalation exposures to DMES vapor were conducted in male and female Fischer 344 rats. In the acute study, rats were exposed to 4000, 2000, 1000, 500, or 0 (control) ppm DMES for 4 h and observed for 14 days. There were no deaths. Narcosis and ataxia were observed in rats of the two highest concentrations only. These signs disappeared within 1 h following exposure. There were no DMES-related gross or microscopic tissue lesions in rats of all exposure groups. In the 2-wk study, rats were exposed for 6 h/day, 5 days/wk to 3000, 1000, 300, 100, or 0 ppm DMES. During exposure, narcosis was observed in rats of the 3000 and 1000 ppm groups. There was a mild decrease in body weight gain in rats of the 3000 ppm group. A decrease in platelet count, an increase in bile acids, and reduced weights of the thymus, testis, and liver were observed in rats of the 3000 ppm group. Microscopically, hypospermatogenesis and spermatid giant cells were observed in the seminiferous tubules of the testes of rats exposed to 3000 ppm DMES. In the 13-wk study, rats were exposed 6 h/day, 5 days/wk to 2000, 600, 160, 40, or 0 ppm DMES. During exposure, rats of the 2000 ppm group exhibited mild narcosis and loss of startle reflex. Recovery from these central nervous system signs was rapid. Body weights were mildly decreased for rats of the 2000 ppm group. There were no exposure-related effects in hematology, serum chemistry, or urinalysis. Female rats of the 2000 ppm group had delayed estrous cycles (6 days compared to 5 days in control rats). Noteworthy organ weight changes in rats of the 2000 ppm group included decreases in thymus, liver, and testicular weights; however, pathologic lesions were observed in the testes only. Sperm motility, epididymal sperm count, and testicular spermatid count were dramatically reduced. Microscopic lesions included degeneration of the seminiferous tubular cells, pyknosis or absence of germ cells, and hypospermia in the epididymis. Rats of the 600 ppm group had a slight decrease in thymic weight and a transient decrease in body weight. Results of the acute, 2-wk, and 13-wk inhalation studies indicate DMES concentrations of 1000 ppm and higher produce narcosis that rapidly disappears following exposure. Repeated exposure of rats to DMES at either 3000 ppm for 2 wk or 2000 ppm for 13 wk caused testicular atrophy and hypospermia in male rats. Female rats exposed to 2000 ppm for 13 wk had delayed estrous cycles. Toxicological effects in rats of the 600 ppm group were minimal and equivocal. The 160 ppm concentration was a no-observable-effect level (NOEL) for 13 wk of exposure to DMES.
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PMID:Acute, 2-week, and 13-week inhalation toxicity studies on dimethylethoxysilane vapor in Fischer 344 rats. 1153 68

Experiments were conducted to determine the role of the aryl hydrocarbon receptor (AhR) in the development of control and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-exposed C57Bl/6 male mice. Male and female mice heterozygous for the AhR (Ahr+/-) were mated, and pregnant females were dosed orally on gestation day 13 with corn oil vehicle or TCDD (5 microg/kg). Pups were necropsied on postnatal day (PND) 21, 35, and 90. Comparison of vehicle-exposed wild-type (Ahr+/+) pups with vehicle-exposed AhR knockout (AhRKO; Ahr-/-) pups confirmed and extended previous reports that development of the liver, heart, spleen, thymus, and kidney is affected by absence of the AhR. Lung, submandibular gland, testis, and epididymis weights were also affected, indicating that the AhR plays a role in normal development of these organs as well. The presence or absence of the AhR had no effect on the incidence of hydronephrosis, daily sperm production, or cauda epididymal sperm numbers in vehicle-exposed mice. TCDD caused numerous effects in wild-type mice that were absent in AhRKO mice; specifically, hydronephrosis, increases in relative liver and heart weight, decreases in absolute heart and lung weight, and decreases in absolute and relative thymus, submandibular gland, epididymis, and testis weight. In several cases, TCDD produced one effect in wild-type mice (reductions in body weight and absolute thymus, submandibular gland, and epididymis weight on PND 21; and reductions in absolute and relative submandibular gland and absolute testis weight on PND 35) but caused the opposite effect in AhRKO mice. In yet other cases (reduced relative spleen weight on PND 21 and reductions in absolute and relative thymus weight on PND 35), TCDD produced similar effects in wildtype and AhRKO mice. There were also cases in which TCDD significantly affected AhRKO mice without significantly altering the same endpoint in wild-type mice; absolute liver, lung, and kidney weight were increased and relative submandibular gland weight was decreased on PND 21; relative heart weight was reduced and absolute lung weight increased on PND 35; and relative liver weight was decreased on PND 90. Although many effects of TCDD required the presence of the AhR, these results provide evidence either for multiple forms of the AhR in mice (one or more of which are still present in AhRKO mice), or for AhR-independent effects of low-level TCDD exposure.
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PMID:Role of the aryl hydrocarbon receptor in the development of control and 2,3,7,8-tetrachlorodibenzo-p-dioxin-exposed male mice. 1169 91

beta-Bromo-beta-nitrostyrene is a wide-spectrum biocide most frequently used as a fungicide to combat the formation of slime in paper and pulp mill operations. Toxicity studies were conducted by administering beta-bromo-beta-nitrostyrene (99% pure, trans isomer) to groups of 10 male and 10 female F344/N rats and B6C3F1 mice by gavage, 5 days per week for 4 weeks. Doses of 0, 37, 75, 150, 300, or 600 mg/kg were administered in a corn oil vehicle. The parameters evaluated included hematology, clinical chemistry (rats only), and histopathology. The genetic toxicity of b-bromo-b- nitrostyrene was evaluated in Salmonella typhimurium and in peripheral blood erythrocytes of mice. In addition, the absorption, distribution, metabolism, and excretion of b-bromo-b- nitrostyrene were studied in male F344 rats following intravenous, dermal, or oral administration. In the 4-week study in rats, two males in the 150 mg/kg group, one male and one female in the 300 mg/kg groups, and all rats in the 600 mg/kg groups died or were killed moribund before the end of the study. The mean body weight gains and absolute and relative thymus weights of male and female rats in the 300 mg/kg groups were lower than those of the controls. Hematology evaluations in rats indicated the development of a mild anemia and monocytosis consistent with and likely related to inflammatory and ulcerative lesions that occurred in the gastrointestinal tract. Clinical chemistry evaluations indicated lower alkaline phosphatase activities and serum total protein and albumin concentrations in treated rats than in the controls. Treatment-related lesions in rats were observed in the forestomach, glandular stomach, cecum, nasal passages, and testis. Males were generally affected at lower doses than females. The most prominent lesions were in the forestomach and were characterized by inflammation, hemorrhage, and necrosis in rats dying early. In rats surviving to the end of the study, forestomach lesions included necrosis, ulceration, and regenerative epithelial hyperplasia and hyperkeratosis. Inflammation of the glandular stomach and cecum also occurred in rats dying early. Inflammation and degeneration of the nasal passage in treated rats were attributed to reflux of the irritant chemical in the gavage fluid. Testicular degeneration was seen in rats dying early and was characterized by necrotic germ cells and a decreased number of spermatozoa in the epididymal tubules and by multinucleated syncytial cells in the seminiferous tubules. In the 4-week study in mice, one male in the 300 mg/kg group and all mice in the 600 mg/kg groups died or were killed moribund before the end of the study. No significant changes in final mean body weights or mean body weight gains were observed in males or females. Hematologic changes consistent with inflammatory lesions occurred in male and female mice in the 300 mg/kg groups. Treatment-related lesions in mice occurred in the forestomach, gallbladder, and testis. Forestomach lesions were similar to those described in rats and were only present in male and female mice given doses of 300 mg/kg or greater. At these dose levels, inflammation and degeneration/necrosis of the gallbladder mucosa also occurred in male and female mice, but these lesions were absent in the bile ducts or liver. Testicular degeneration occurred in mice dying early and was similar to that observed in rats. In comparative disposition and metabolism studies in male F344 rats, clear differences were found between the fate of b-bromo- b-nitrostyrene following oral administration and the fate of radiolabeled beta-bromo-beta-nitrostyrene following intravenous or dermal administration. Oral exposure resulted in significant absorption of nonhydrolyzed beta-bromo-beta-nitrostyrene and the formation of parent compound metabolites, primarily 1-phenyl-2-nitroethyl-1-sulfonic acid (PNSA), a product of a sulfation reaction at the alpha carbon. Following dermal exposure, a limited amount of beta-bromo-beta-nitrostyrene entered the systemic circulation (approximately 10% per 24 hours from a 10 mg/cm2 dose) although lower doses were more completely absorbed. Once beta-bromo-beta-nitrostyrene entered the circulation, significant amounts of the dose were hydrolyzed or bound to macromolecules. PNSA was not a major metabolite in dermal or intravenous studies. Regardless of the route of administration, only low levels of radioactive label from beta-bromo-beta-nitrostyrene were retained in tissues following exposure, and most beta-bromo-beta-nitrostyrene metabolites were excreted in the urine and feces within 24 to 48 hours. beta-bromo-beta-nitrostyrene was mutagenic in S. typhimurium strains TA98 and TA100 in the absence of exogenous metabolic activation (S9). No mutagenic activity was observed with S9 in either of these strains, and no mutagenic activity was observed in strains TA97 or TA1535, with or without S9. The frequency of micronucleated normochromatic erythrocytes was significantly increased in the peripheral blood of male mice, but not female mice, following 4 weeks of exposure to beta-bromo-beta-nitrostyrene by corn oil gavage. In summary, under the conditions of these 4-week gavage studies, rats were more sensitive to the toxic and irritant effects of beta-bromo-beta-nitrostyrene than mice, and males were more affected by beta-bromo-beta-nitrostyrene than females. Although the specific cause of the early deaths could not be determined, significant inflammation and necrosis developed in the forestomach of rats and mice, in the glandular stomach and cecum of rats, and in the gallbladder of mice. Similar lesions in the nasal passages of rats were attributed to reflux of gavage materials. The no-observed- adverse-effect level (NOAEL) for histopathologic lesions was 37 mg/kg per day for rats and 150 mg/kg per day for mice.
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PMID:NTP Toxicity Studies of beta-Bromo-beta-Nitrostyrene (CAS No. 7166-19-0) Administered by Gavage to F344/N Rats and B6C3F1 Mice. 1196 39

3,3',4,4'-Tetrachloroazobenzene is not commercially manufactured but is formed as an unwanted byproduct in the manufacture of 3,4-dichloroaniline and its herbicidal derivatives Propanil(R), Linuron(R), and Diuron(R). In addition, environmental contamination by 3,3',4,4'-tetrachloroazobenzene occurs from the degradation of chloranilide herbicides and the photolysis and biolysis of 3,4-dichloroaniline. 3,3',4,4'-Tetrachloroazobenzene was nominated by the United States Environmental Protection Agency for toxicity testing based on concerns over the potential for human exposure, the structural resemblance to 2,3,7,8-tetrachlorodibenzo-p-dioxin, and the reported dioxin-like effects of 3,3',4,4'-tetrachloroazobenzene. The toxicity of 3,3',4,4'- tetrachloroazobenzene was evaluated in 16-day and 13-week gavage studies in male and female F344/N rats and B6C3F1 mice. In addition to histopathology, evaluations included hematology (rats only), clinical chemistry, thyroid hormone analyses (rats only), cytochrome P(450)1A immunohistochemical staining in the liver (rats only), and assessments of male reproductive endpoints and estrous cycle length. Genetic toxicology studies included mutagenicity tests in Salmonella typhimurium and the determination of micronuclei in mouse bone marrow and peripheral blood erythrocytes. In the 16-day studies, groups of five male and five female rats received 3,3',4,4'-Tetrachloroazobenzene in corn oil by gavage 5 days a week at doses of 0, 12.5, 32, 80, 200, or 500 mg per kg body weight. Groups of five male and five female mice received 3,3',4,4'-Tetrachloroazobenzene in corn oil by gavage 5 days a week at doses of 0, 1, 3.2, 10, 32, or 100 mg/kg. Major effects included increases in liver, lung, and spleen weights of rats and liver and heart weights of mice and decreases in thymus weights of rats and mice. No effects were found on survival or mean body weight gains of rats or mice. Incidences of hematopoietic cell proliferation in the spleen were increased in all groups of dosed male rats, in female rats that received 32 mg/kg or greater, and in 100 mg/kg male and female mice. Renal tubule hyaline droplet accumulation in the cytoplasm of renal cortical epithelial cells and chronic nephropathy were observed microscopically in male rats in the 80, 200, and 500 mg/kg groups. Female mice in the 100 mg/kg group had atrophy of the thymus. In the 13-week studies, groups of 10 male and 10 female rats and mice received 3,3',4,4'-Tetrachloroazobenzene in corn oil by gavage 5 days a week at doses of 0, 0.1, 1, 3, 10, or 30 mg/kg. In the 13-week rat study, the major effects included a decrease in the mean body weight gain of 30 mg/kg females and final mean body weights of 30 mg/kg males and females, decreased thymus weights of males and females in the 10 and 30 mg/kg groups accompanied by thymic atrophy observed microscopically, increased incidences of hematopoietic cell proliferation in the spleen in 10 and 30 mg/kg males and females, a responsive anemia in 10 and 30 mg/kg males and females at week 13, and decreased platelet counts in 10 and 30 mg/kg males and females on day 21 and at week 13. Spleen weights were increased in 10 and 30 mg/kg males and females. Liver weights were increased in males that received 1 mg/kg or greater and in 10 and 30 mg/kg females. Furthermore, hepatic cytochrome P(450)1A staining presence and intensity were increased in 30 mg/kg males and females. Sharp decreases in circulating thyroxine concentrations were observed in males and females at all doses. In spite of this sharp decrease, thyroid-stimulating hormone concentrations were marginally increased. Incidences of hyperplasia of the forestomach were increased in males administered 3 mg/kg or greater and females administered 30 mg/kg. In the 13-week mouse study, the major effects included increases in liver and spleen weights of 10 and 30 mg/kg males and females and increased incidences of hyperplasia of the forestomach in males and females that received 1 mg/kg or greater. Furthermore, a decrease in thymus weight of 30 mg/kg males, an increase in centrilobular hypertrophy of hepatocytes in males that received 3 mg/kg or greater, and an increase in the incidences of hematopoietic cell proliferation in the spleen in males that received 3 mg/kg or greater were observed. A significant decrease in epididymal spermatozoal concentration was observed in 3 and 30 mg/kg males. 3,3',4,4'-Tetrachloroazobenzene was mutagenic in S. typhimurium strain TA97 in the presence of rat liver S9 activation enzymes; no mutagenic activity was detected in strain TA98, TA100, TA1535, or TA1537 with or without S9. In vivo, the frequency of micronucleated erythrocytes was significantly increased in peripheral blood samples from male and female mice given 3,3',4,4'-Tetrachloroazobenzene by gavage for 13 weeks. However, results of a 3-day exposure of up to 200 mg/kg by intraperitoneal injection did not demonstrate induction of micronuclei in bone marrow erythrocytes of male mice. In summary, 3,3',4,4'-Tetrachloroazobenzene caused typical dioxin-like effects, such as thymic atrophy, an increase in liver weights, induction of hepatic cytochrome P(450)1A, and decreased mean body weight gains. Furthermore, in the 13-week studies, a sharp decrease in circulating thyroxine concentrations was observed even at the lowest dose (0.1 mg/kg) tested in rats. Other effects included a decrease in epididymal spermatozoal concentration in mice, major effects on the hematopoietic system, and increased incidences of hyperplasia of the forestomach in 3 and 30 mg/kg males and 30 mg/kg females. A no-observable-adverse-effect-level (NOAEL) was not reached in rats. The NOAEL in mice was 0.1 mg/kg. Comparison of various dioxin-like effects in these studies with those reported in the literature indicate that 3,3',4,4'-Tetrachloroazobenzene is six to two orders of magnitude less potent than 2,3,7,8-tetrachlorodibenzo-p-dioxin.
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PMID:NTP Technical Report on the Toxicity Studies of 3,3',4,4'-Tetrachloroazobenzene (CAS No. 14047-09-7) Administered by Gavage to F344/N Rats and B6C3F1 Mice. 1198 82

3,3',4,4'-Tetrachloroazoxybenzene is not commercially manufactured but is present as a contaminant of 3,4-dichloroaniline and its herbicidal derivative Diuron(R). In addition, environmental contamination occurs when 3,3',4,4'-tetrachloroazoxybenzene is formed by the photolysis and biolysis of 3,4-dichloroaniline. 3,3',4,4'-Tetrachloroazoxybenzene was nominated by the United States Environmental Protection Agency for toxicity testing based on concerns over the potential for human exposure, the structural resemblance to 2,3,7,8-tetrachlorodibenzo-p-dioxin, and the reported dioxin-like effects of 3,3',4,4'-tetrachloroazoxybenzene. The toxicity of 3,3',4,4'-tetrachloroazoxybenzene was evaluated in 16-day and 13-week gavage studies in male and female F344/N rats and B6C3F1 mice. In addition to histopathology, evaluations included hematology (rats only), clinical chemistry, thyroid hormone analyses (rats only), hepatic cell proliferation (rats only), cytochrome P(450)1A immunohistological staining in the liver (rats only), and assessments of male reproductive endpoints and estrous cycle length. Additional genetic toxicology studies included mutagenicity tests in Salmonella typhimurium and the determination of micronuclei in mouse bone marrow and peripheral blood erythrocytes. In the 16-day studies, groups of five male and five female rats received 3,3',4,4'-tetrachloroazoxybenzene in corn oil by gavage at doses of 0, 12.5, 32, 80, 200, or 500 mg per kg body weight, 5 days a week. Groups of five male and five female mice received 0, 1, 3.2, 10, 32, or 100 mg/kg in corn oil by gavage, 5 days a week. Major effects in rats included increases in liver and lung weights, and decreases in mean body weights and body weight gains, heart weights, and thymus weights. Effects in mice included increases in liver weights and decreases in thymus weights. No effects on survival were observed. Treatment-related lesions included cytoplasmic alteration of hepatocytes, splenic hematopoietic cell proliferation, thymic atrophy, and nephropathy in rats and thymic atrophy, splenic hematopoietic cell proliferation, and hepatic foci of inflammation and necrosis in mice. In the 13-week studies, groups of 10 male and 10 female rats and mice received 3,3',4,4'- tetrachloroazoxybenzene in corn oil by gavage at doses of 0, 0.1, 1, 3, 10, or 30 mg/kg, 5 days a week. In the 13-week rat study, all males and seven females in the 30 mg/kg groups died. Decreases in final mean body weights and body weight gains were observed in 3 and 10 mg/kg males and 10 and 30 mg/kg females. Decreased thymus weights, accompanied by thymic atrophy observed microscopically, were observed at doses of 1 mg/kg or greater in males and females. Increased liver weights were observed in males and females administered 1 mg/kg or greater, and hepatic cytochrome P(450)1A staining was increased in 1 and 3 mg/kg males and 3, 10, and 30 mg/kg females. In addition, a responsive anemia and decreases in platelet counts were observed in dosed male and female rats. A marked decrease in circulating thyroxine concentrations was observed in dosed males and females. In spite of this sharp decrease, thyroid-stimulating hormone concentrations were marginally increased. A decrease in epididymal spermatozoal motility was observed in all dosed groups tested. In 10 mg/kg females, the estrous cycle length was increased. Major effects included increased incidences of hyperplasia of the forestomach in 3, 10, and 30 mg/kg males and 10 and 30 mg/kg females. Increased incidences of centrilobular degeneration and hematopoietic cell proliferation were observed in the liver of dosed males and females. Furthermore, chronic active inflammation of the lung vasculature and hematopoietic cell proliferation in the spleen were observed in dosed males and females. The increased severities of cardiomyopathy and nephropathy in males and the incidences of cardiomyopathy and nephropathy and severity of cardiomyopathy in females were 3,3',4,4'-tetrachloroazoxybenzene related. In the 13-week mouse study, the major effects included increases in liver weights in males administered 3 mg/kg or greater and females administered 1 mg/kg or greater. Hyperplasia of the forestomach and dilatation of hair follicles were observed in 10 and 30 mg/kg males and 30 mg/kg females. Furthermore, thymus weights were decreased in males administered 3 mg/kg or greater and in 10 and 30 mg/kg females. Increased incidences of centrilobular hypertrophy of hepatocytes were observed in 10 and 30 mg/kg males and females. Increased incidences of hematopoietic cell proliferation in the spleen were observed in 30 mg/kg males and in 10 and 30 mg/kg females. Increases in the incidences of thymocyte necrosis were observed in 10 mg/kg males and in 10 and 30 mg/kg females. The incidences of splenic pigmentation were increased in all dosed groups of males, and the severity of pigmentation increased with increasing dose in males and females. 3,3',4,4'-Tetrachloroazoxybenzene was not mutagenic in S. typhimurium strain TA97, TA98, TA100, or TA1535 with or without induced S9 metabolic activation enzymes. It did not induce significant increases in micronucleated erythrocytes in a three-exposure male mouse bone marrow micronucleus test up to dose levels of 200 mg/kg, but results of a 13-week peripheral blood micronucleus test conducted in male and female mice were positive. In summary, 3,3',4,4'-tetrachloroazoxybenzene caused typical dioxin-like effects, including thymic atrophy, increased liver weights, induction of hepatic cytochrome P(450)1A, and decreased mean body weight gains. Furthermore, a marked decrease in circulating thyroxine concentrations was observed in male and female rats, even at the lowest dose (0.1 mg/kg) in female rats. A decrease in epididymal sperm motility was observed at all doses in rats. Effects on the hematopoietic system occurred at doses including and lower than those that caused histopathologic alterations in the liver. A no-observable-adverse-effect-level (NOAEL) was not reached in rats. In male and female mice, the NOAEL was 1 and 0.1 mg/kg, respectively. Furthermore, treatment-related effects included increased incidences of hyperplasia of the forestomach epithelium in rats and mice, chronic active inflammation of the vasculature of the lung in rats, increased incidences and/or severities of cardiomyopathy and nephropathy in rats, and dilatation of the hair follicles in mice. Comparison of various dioxin-like effects in these studies with those reported in the literature indicate that 3,3',4,4'- tetrachloroazoxybenzene is six to two orders of magnitude less potent than 2,3,7,8-tetrachlorodibenzo-p-dioxin.
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PMID:NTP Technical Report on the Toxicity Studies of 3,3',4,4'-Tetrachloroazoxybenzene (CAS No. 21232-47-3) Administered by Gavage to F344/N Rats and B6C3F1 Mice. 1198 83

Isoprene, the 2-methyl analogue of 1,3-butadiene, has a high production volume and is used largely in the manufacture of synthetic rubber. Isoprene is also the major endogenous hydrocarbon exhaled in human breath. Two-week and 13-week inhalation toxicology studies were conducted in male and female F344/N rats and B6C3F1 mice to characterize potential adverse effects of isoprene. Male rats and male mice were also exposed to isoprene vapors for 6 months followed by a 6-month recovery period (stop- exposure protocol) to determine if isoprene produces a carcinogenic response similar to that of 1,3-butadiene after intermediate exposure durations. In addition to histopathology, evaluations included clinical pathology, tissue glutathione analyses, forelimb and hindlimb grip strength analyses, and sperm motility and vaginal cytology. Data from inhalation teratology studies of isoprene in rats and mice are also reported. In vitro genetic toxicity studies included assessments of mutagenicity in Salmonella typhimurium and sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells. In conjunction with the inhalation studies in mice, evaluations were also made of sister chromatid exchanges and chromosomal aberrations in bone marrow cells and micronuclei in peripheral blood of male mice exposed to isoprene for 12 days or 13 weeks. Target concentrations of isoprene in the inhalation chambers were 0, 438, 875, 1,750, 3,500, and 7,000 ppm in the 2-week studies; 0, 70, 220, 700, 2,200, and 7,000 ppm in the 13-week and stop-exposure studies; and 0, 280, 1,400, and 7,000 ppm in the teratology studies. In the 2-week studies, no changes related to chemical administration were observed in survival, body weight gain, clinical signs, hematologic or clinical chemistry parameters, or the incidence of gross or microscopic lesions in rats. In mice, there were no effects on survival; the mean body weight of males in the 7,000 ppm group was less than that of the controls. In mice, exposure to isoprene caused decreases in hematocrit values, hemoglobin concentrations, and erythrocyte counts, atrophy of the testis and thymus, cytoplasmic vacuolization of the liver, olfactory epithelial degeneration in the nasal cavity, and epithelial hyperplasia in the forestomach. Exposure to isoprene for 13 weeks produced no discernible toxicologic effects in rats. In the stop-exposure study, interstitial cell hyperplasia of the testis was observed in all male rats in the 7,000 ppm group after 6 months of exposure. Following the 6-month recovery period, male rats exposed to 700, 2,200, or 7,000 ppm isoprene had slightly greater incidences of interstitial cell adenomas of the testes than the controls. Exposure to isoprene for 13 weeks or 6 months produced no clear exposure-related effects on body weight gain in male or female mice; however, survival was decreased for male mice exposed to 7,000 ppm isoprene for 6 months. More notably, toxic and carcinogenic effects were induced at multiple organ sites in mice exposed to isoprene. After 6 months of exposure and 6 months of recovery, male mice exposed to 700 ppm or higher concentrations of isoprene had greater incidences of neoplasms of the liver (0 ppm, 7/30; 70 ppm, 3/30; 220 ppm, 7/29; 700 ppm, 15/30; 2,200 ppm, 18/30; 7,000 ppm, 17/28), lungs (2/30, 2/30, 1/29, 5/30, 10/30, 9/28), forestomach (0/30, 0/30, 0/30, 1/30, 4/30, 6/30), and harderian gland (2/30, 6/30, 4/30, 14/30, 13/30, 12/30) than the controls. In addition to the higher neoplasm incidences in male mice exposed to 700 ppm or greater, incidences of multiple neoplasms and/or neoplasms of greater malignancy were also higher than in the controls. Hematologic effects similar to those occurring in exposed mice in the 2-week study, plus greater mean cell volume values than in the controls, were observed after 24 days and after 13 weeks of exposure to isoprene. These hematologic effects, which were not accompanied by greater reticulocyte counts or a higher frequency of polychromatic erythrocytes than controls, were indicative of a nonresponsive, macrocytic anemia. In male mice in the stop-exposure study, partial hindlimb paralysis in the 7,000 ppm group and a dose-related decrease in grip strength were observed near the end of the 6-month exposure period. Other nonneoplastic effects in mice exposed to isoprene included spinal cord and sciatic nerve degeneration, skeletal muscle atrophy, degeneration of the olfactory epithelium, epithelial hyperplasia of the forestomach, increased estrous cycle length, testicular atrophy, and decreased epididymal weight, sperm head count, sperm concentration, and sperm motility. The inhalation teratology studies did not show maternal or developmental toxicity in Sprague-Dawley rats at exposures of up to 7,000 ppm isoprene; in CD-1® Swiss mice, exposure to isoprene resulted in lower fetal weights and a higher percentage of fetuses per litter with supernumerary ribs. Isoprene was not mutagenic in Salmonella typhimurium and did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells with or without exogenous metabolic activation; however, in mice, isoprene induced increases in the frequency of sister chromatid exchanges in bone marrow cells and in the frequency of micronucleated erythrocytes in peripheral blood. These inhalation studies showed that isoprene caused toxic effects in the testis of rats and at multiple organ sites in mice. In F344/N rats, exposure to 7,000 ppm isoprene for 6 months caused an increase in the incidence of testicular interstitial cell hyperplasia, and after 6 months of recovery there was a marginally increased incidence of benign testicular adenomas that may have been related to isoprene administration. No-observable-adverse-effect levels (NOAELs) for isoprene-induced toxic lesions in mice were: 70 ppm for nonresponsive, macrocytic anemia, decreased hindlimb grip strength, olfactory epithelial degeneration, and decreases in epididymal weights, spermatid head counts, sperm concentration, and sperm motility; 220 ppm for forestomach epithelial hyperplasia; 700 ppm for increased estrous cycle length; and 2,200 ppm for testicular atrophy, sciatic nerve degeneration, and muscle atrophy. A NOAEL was not achieved for spinal cord degeneration (less than 70 ppm) or developmental toxicity (less than 280 ppm, based on lower body weights of female fetuses). In addition, the 6-month inhalation exposure plus 6-month recovery (stop-exposure) study provided clear evidence of carcinogenicity of isoprene in the liver, lung, forestomach, and harderian gland of mice. Because these studies involved exposures of male rats and male mice to isoprene for only 6 months, they do not necessarily reveal the full carcinogenic potential of isoprene in these species. Most of the toxic and carcinogenic effects seen with isoprene were also caused by inhalation exposure to 1,3-butadiene. Synonyms: isopentadiene; 2-methyl-1,3-butadiene; beta-methylbivinyl.
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PMID:NTP technical report on the toxicity studies of Isoprene (CAS No. 78-79-5) Administered by Inhalation to F344/N Rats and B6C3F1 Mice. 1220 93

A tocotrienol (T3) mixture was intragastricaly administered to Sprague-Dawley rats, and the T3 levels in various tissues were measured 0, 4, 8 and 24 hr after the administration. In blood clots, brain, thymus, testes, vice-testes and muscles, T3 homologues were not detected at all. In epididymal adipose, renal adipose, subcutaneous adipose and brown adipose tissues and in the heart, the T3 levels were maintained or increased for 24 hr after the administration. In the serum, liver, mesenteric lymph node, spleen and lungs, the T3 levels were highest 8 hr after the T3 administration. These results suggest that the distribution and metabolism of T3 in the rat vary considerably among different tissues.
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PMID:Tocotrienol levels in various tissues of Sprague-Dawley rats after intragastric administration of tocotrienols. 1235 45

Gallium arsenide is used primarily to make light- emitting diodes, lasers, laser windows, and photodetectors and in the photoelectronic transmission of data through optical fibers. Gallium arsenide was nominated for study because of its widespread use in the microelectronics industry, the potential for worker exposure, and the absence of chronic toxicity data. Male and female F344/N rats and B6C3F1 mice were exposed to gallium arsenide particles (greater than 98% pure; mass median aerodynamic diameter = 0.8 to 1.0 &mgr;m) by inhalation for 16 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, and the frequency of micronuclei was determined in the peripheral blood of mice exposed to gallium arsenide for 14 weeks. 16-DAY STUDY IN RATS: Groups of five male and five female rats were exposed to particulate aerosols of gallium arsenide with a mass median aerodynamic diameter of approximately 1 &mgr;m at concentrations of 0, 1, 10, 37, 75, or 150 mg/m(3) by inhalation, 6 hours per day, 5 days per week, for 16 days. All rats survived to the end of the study. The final mean body weights of all exposed groups of males and females were similar to those of the chamber controls. Compared to chamber controls, the liver and lung weights of males exposed to 1 mg/m(3) or greater and females exposed to 10 mg/m(3) or greater were increased; the thymus weights of all exposed groups of males were decreased. Gallium arsenide particles were visible in the alveolar spaces and, to a lesser extent, within alveolar macrophages of exposed rats. Moderate proteinosis (surfactant mixed with small amounts of fibrin) and minimal histiocytic cellular infiltrate were observed in the alveoli of exposed males and females. Epithelial hyperplasia and squamous metaplasia of the larynx were observed primarily in males exposed to 150 mg/m(3). 16-DAY STUDY IN MICE: Groups of five male and four or five female mice were exposed to particulate aerosols of gallium arsenide with a mass median aerodynamic diameter of approximately 1 &mgr;m at concentrations of 0, 1, 10, 37, 75, or 150 mg/m(3) by inhalation, 6 hours per day, 5 days per week, for 16 days. The final mean body weights were similar among exposed and chamber control groups. Compared to chamber controls, the lung weights of males and females exposed to 10 mg/m(3) or greater were increased. Gallium ar senide particles were visible in alveolar spaces and macrophages in some mice exposed to 150 mg/m(3). Moderate proteinosis, mild epithelial hyperplasia, and histiocytic infiltration of the lung were observed in males and females exposed to 10 mg/m(3) or greater. In the larynx, mild squamous metaplasia was seen in mice exposed to 10 mg/m(3) or greater, and mild chronic inflammation occurred in mice exposed to 75 or 150 mg/m(3). 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed by inhalation to gallium arsenide particulate at concentrations of 0, 0.1, 1, 10, 37, or 75 mg/m(3), 6 hours per day, 5 days per week, for 14 weeks. All rats survived until the end of the study. The final mean body weight and body weight gain of males exposed to 75 mg/m(3) were significantly less than those of the chamber controls. Hematology and clinical chemistry results indicated that exposure to gallium arsenide induced a microcytic responsive anemia with an erythrocytosis and increased zinc protoporphyrin/heme ratios in exposed groups of rats. There were also increases in platelet and neutrophil counts, a transient decrease in leukocyte counts, and increases in the serum activities of alanine aminotransferase and sorbitol dehydrogenase. These changes were of greater magnitude in male rats. The lung weights of all exposed groups of rats were increased, while testis, cauda epididymis, and epididymis weights of males exposed to 37 or 75 mg/m(3) were generally less than those of chamber controls. Total spermatid heads and spermatid counts were significantly decreased in males exposed to 75 mg/m(3), while epididymal spermatozoa motility was significantly reduced in males ees exposed to 10 mg/m(3) or greater. Gallium arsenide particles were visible in alveolar spaces and macrophages in the lungs of exposed rats. Minimal to marked proteinosis and minimal histiocytic cellular infiltration of the alveoli were observed in all exposed groups; minimal squamous metaplasia in the larynx and lymphoid cell hyperplasia of the mediastinal lymph node were observed in some males and females exposed to 37 or 75 mg/m(3). Exposure-related increases in the incidences of plasma cell hyperplasia of the mandibular lymph node, testicular atrophy, epididymal hypospermia, bone marrow hyperplasia (males), and hemosiderosis in the liver were observed in the 37 and 75 mg/m(3) groups. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were exposed by inhalation to gallium arsenide particulate at concentrations of 0, 0.1, 1, 10, 37, or 75 mg/m(3), 6 hours per day, 5 days per week, for 14 weeks. One female mouse exposed to 75 mg/m(3) died before the end of the study. Final mean body weights and body weight gains of males in the 75 mg/m(3) group were signifi cantly less than the chamber controls. Hematology and clinical chemistry results indicated that exposure to gallium arsenide affected the circulating erythroid mass and induced a microcytic responsive anemia with an erythrocytosis and increased zinc protoporphyrin/heme ratios in male and female mice. There were also increases in platelet and neutrophil counts. Compared to the chamber controls, the lung weights of males exposed to 1 mg/m(3) or greater and females exposed to 10 mg/m(3) or greater were increased. Testis, cauda epididymis, and epididymis weights, total spermatid heads, spermatid counts, and concentration and motility of epididymal spermatozoa were generally decreased. Gallium arsenide particles were visible in alveolar spaces and macrophages in the lungs of mice exposed to 1 mg/m(3) or greater. Mild to marked proteinosis, histiocytic infiltration, and epithelial hyperplasia were observed in the alveoli of males and females exposed to 1 mg/m(3) or greater. Minimal to mild suppurative inflammation and granuloma in the lung and squamous metaplasia in the larynx were present in males and females exposed to 10 mg/m(3) or greater. Min imal hyperplasia was observed in the tracheobronchial lymph node of males exposed to 10 mg/m(3) or greater and females exposed to 37 or 75 mg/m(3). Exposure- related increases in the incidences of testicular atrophy, epididymal hypospermia, hematopoietic cell proliferation of the spleen, and hemosiderosis of the liver and spleen were observed in groups of male and female mice exposed to 10 mg/m(3) or greater. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed by inhalation to gallium arsenide particulate at concentrations of 0, 0.01, 0.1, or 1.0 mg/m(3), 6 hours per day, 5 days per week, for 105 weeks. Survival and Body Weights: Survival of exposed male and female rats was similar to the chamber controls. Mean body weights of males exposed to 1.0 mg/m(3) were generally less than those of the chamber controls throughout the study; females exposed to 1.0 mg/m(3) had slightly lower mean body weights during the second year. Pathology Findings: Compared to the chamber controls, the incidences of alveolar/bronchiolar neoplasms were significantly increased in females exposed to 1.0 mg/m(3) and exceeded the historical control ranges. Exposure-related nonneoplastic lesions in the lungs of male and female rats included atypical hyperplasia, alveolar epithelial hyperplasia, chronic active inflammation, proteinosis, and alveolar epithelial metaplasia. In the larynx of males exposed to 1.0 mg/m(3), the incidences of hyperplasia, chronic active inflammation, squamous metaplasia, and hyperplasia of the epiglottis were significantly increased. The incidences of benign pheochromocytoma of the adrenal medulla occurred with a positive trend in female rats, and the incidence was significantly increased in the 1.0 mg/m(3) group and exceeded the historical control range. The incidence of mononuclear cell leukemia was significantly increased in females exposed to 1.0 mg/m(3) and exceeded the historical control range. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed by inhalation to gallium arsenide particulate at concentrations of 0, 0.1, 0.5, or 1.0 mg/m(3), 6 hours per day, 5 days per week, for 105 (males) or 106 (females) weeks. Survival and Body Weights: Survival of male and female mice was similar to the chamber controls. Mean body weights of exposed groups of males were similar to those of the chamber controls throughout the study; mean body weights of exposed groups of females were greater than those of the chamber controls from week 13 until the end of the study. Pathology Findings: Exposure-related nonneoplastic lesions in the lung of all groups of exposed mice included suppurative focal inflammation, chronic focal inflammation, histiocyte cellular infiltration, alveolar epithelial hyperplasia, and proteinosis. Increased incidences of minimal lymphoid hyperplasia of the tracheobronchial lymph node occurred in mice exposed to 1.0 mg/m(3) and in 0.5 mg/m(3)mg/m(3) males. GENETIC TOXICOLOGY: Gallium arsenide was not mutagenic in several strains of Salmonella typhimurium, with or without S9 metabolic activation enzymes, and no increase in the frequency of micronucleated erythrocytes was observed in peripheral blood of male or female mice exposed to gallium arsenide by inhalation for 14 weeks. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity of gallium arsenide in male F344/N rats exposed to 0.01, 0.1, or 1.0 mg/m(3). There was clear evidence of carcinogenic activity in female F344/N rats based on increased incidences of benign and malignant neoplasms in the lung. Increased incidences of benign neoplasms of the adrenal medulla and increased incidences of mononuclear cell leukemia were also considered to be exposure related. There was no evidence of carcinogenic activity in male or female B6C3F1 mice exposed to 0.1, 0.5, or 1.0 mg/m(3). Exposure to gallium arsenide caused a spectrum of nonneoplastic lesions in the lung of rats and mice, the larynx of male rats and hyperplasia of the tracheobronchial lymph node in mice. Synonym: Gallium monoarsenide.
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PMID:NTP Toxicology and Carcinogenesis Studies of Gallium Arsenide (CAS No. 1303-00-0) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). 1256 48

1-Chloro-2-propanol and its positional isomer, 2-chloro-1-propanol, are used as chemical intermediates for the manufacture of propylene oxide, a starting material for production of polyurethane polyols and propylene glycol. The National Cancer Institute nominated 1-chloro-2-propanol for study because of potential for human exposure due to its residues in various foods that are fumigated with ethylene oxide or propylene oxide. Male and female F344/N rats and B6C3F1 mice were exposed to technical grade 1-chloro-2-propanol (75% to 76%% 1-chloro-2-propanol; 24% to 25%% 2-chloro-1-propanol) in drinking water for 14 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, Drosophila melanogaster, and mouse peripheral blood erythrocytes. Continuous breeding studies were conducted in Sprague-Dawley rats. 14-DAY STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were administered 1-chloro-2-propanol in drinking water at concentrations of 0, 100, 330, 1,000, 3,300, or 10,000 ppm for 14 days. Two 10,000 ppm females died before the end of the study. The final mean body weights and body weight gains of 3,300 and 10,000 ppm rats were significantly less than those of the controls; rats in the 10,000 ppm groups lost weight. Water consumption by the 3,300 and 10,000 ppm groups was significantly less than that by the controls throughout the study. The thymus weights of 10,000 ppm rats were significantly less than those of the controls. Exposure to 1-chloro-2-propanol caused cytoplasmic alteration and degeneration of the acinar cells and fatty change in the pancreas, atrophy of the bone marrow, and atrophy and hematopoiesis of the spleen in males and females. 14-DAY STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were administered 1-chloro-2-propanol in drinking water at concentrations of 0, 100, 330, 1,000, 3,300, or 10,000 ppm for 14 days. One male mouse in the 10,000 ppm group died before the end of the study. Mean body weight gains of 10,000 ppm mice were significantly less than those of the controls. Water consumption by 3,300 and 10,000 ppm males and females was significantly less than that by the controls throughout the study. Liver weights of 1,000, 3,300, or 10,000 ppm males and females were significantly greater and thymus weights of 10,000 ppm mice were significantly less than those of the controls. Exposure to 1-chloro-2-propanol caused hepatocellular vacuolization, cytoplasmic alteration and degeneration of the pancreas acinar cells, and atrophy of the spleen in males and females. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were administered 1-chloro-2-propanol at concentrations of 0, 33, 100, 330, 1,000, or 3,300 ppm (equivalent to average daily doses of approximately 5, 10, 35, 100, or 220 mg/kg) for 14 weeks. All rats survived to the end of the study. Mean body weight gains of 3,300 ppm rats were significantly less than those of the controls. Water consumption by the 3,300 ppm male and female rats was significantly less than that by the controls. A minimal to mild anemia was observed in exposed female rats. The cauda epididymis and epididymis weights of 3,300 ppm males were significantly less than those of the controls. The percentage of abnormal sperm in 3,300 ppm males and the concentration of epididymal sperm in 330 ppm males were significantly increased compared to the controls. Kidney and liver weights of males and females exposed to 100 ppm or more were generally greater than those of the controls. The incidences of acinar cell degeneration and fatty change of the pancreas in 1,000 and 3,300 ppm rats, hepatocytic metaplasia of the pancreatic islets in 3,300 ppm females, cytoplasmic vacuolization of the liver in 100, 1,000 and 3,300 ppm males, and renal tubule epithelium regeneration in 3,300 ppm females were increased compared to the controls. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were administered 1-chloro-2-propanol in drinking water at concentrations of 0, 33, 100, 33entrations of 0, 33, 100, 330, 1,000, or 3,300 ppm (equivalent to average daily doses of approximately 5, 15, 50, 170, or 340 mg/kg to males and 7, 20, 70, 260, or 420 mg/kg to females) for 14 weeks. One 330 ppm male died before the end of the study. Mean body weight gains of exposed groups were similar to those of the controls. A minimal anemia was observed in 3,300 ppm males. The right epididymis weight of 3,300 ppm males was significantly greater than that of the controls. Kidney weights of 3,300 ppm mice, liver weights of 1,000 ppm males and of all exposed groups of females, and thymus weights of 1,000 and 3,300 ppm females were greater than those of the controls. The incidences of pancreatic acinar cell degeneration and fatty change in 3,300 ppm males and females and cytoplasmic vacuolization of the liver in all groups of exposed females were significantly increased compared to the controls. The severities of renal tubule cytoplasmic vacuolization were greater in 1,000 and 3,300 ppm males than in the controls. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female F344/N rats were administered drinking water containing 0, 150, 325, or 650 ppm 1-chloro-2-propanol (equivalent to average daily doses of approximately 15, 30, or 65 mg/kg during the first several months of the study and 8, 17, or 34 mg/kg for the remainder of the 2-year study) for up to 105 weeks. Survival of all exposed groups was similar to that of the controls. Mean body weights of exposed rats were generally similar to those of the controls throughout most of the study. Water consumption by all exposed groups was similar to that by the controls. No treatment-related neoplasms or nonneoplastic lesions were observed in this study. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female B6C3F1 mice were administered drinking water containing 0, 250, 500, or 1,000 ppm 1-chloro-2-propanol (equivalent to average daily doses of approximately 45, 75, or 150 mg/kg to males and 60, 105, or 210 mg/kg to females during the first several months of the study and 25, 50, or 100 mg/kg for the remainder of the 2-year study) for up to 105 weeks. Survival of all exposed groups was similar to that of the controls. The mean body weights of all exposed mice were generally similar to those of the controls throughout the study. Water consumption by all exposed groups was similar to that by the controls. No treatment- related neoplasms or nonneoplastic lesions were observed in this study. GENETIC TOXICOLOGY: 1-Chloro-2-propanol is a demonstrated mutagen in vitro. It was weakly mutagenic in S. typhimurium strain TA100 in the presence of hamster or rat liver S9 activation enzymes and was positive, with and without S9, in TA1535. No mutagenic activity was detected in strains TA97, TA98, and TA1537, with or without S9. In cytogenetic tests with Chinese hamster ovary cells, 1-chloro-2-propanol induced high levels of sister chromatid exchanges and chromosomal aberrations in the presence and the absence of S9. The marked ability of 1-chloro-2-propanol to induce chromosomal effects in vitro was not seen in vivo. Positive results were obtained in a test in D. melanogaster for induction of sex-linked recessive lethal mutations in germ cells of males administered 1-chloro-2-propanol via injection; however, negative results were obtained when males were administered 1-chloro-2-propanol in feed. A subsequent germ cell reciprocal translocation test in D. melanogaster yielded negative results. Further, no induction of micronucleated erythrocytes was observed in peripheral blood of male and female mice administered 1-chloro-2-propanol via drinking water for 14 weeks. CONCLUSIONS: Under the conditions of these 2-year drinking water studies, there was no evidence of carcinogenic activity of technical grade 1-chloro-2-propanol in male or female F344/N rats exposed to 150, 325, or 650 ppm. There was no evidence of carcinogenic activity of technical grade 1-chloro-2-propanol in male or female B6C3F1 mice exposed to 250, 500, or 1,000 ppm. Synonyms: 1-Chloro-2-hydroxypropane, 1-chloroisopropyl alcohol, propylene-α-chlorohydrin, sec-propylene chlorohydrin
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PMID:NTP Toxicology and Carcinogenesis Studies of 1-Chloro-2-propanol (Technical Grade) (CAS NO. 127-00-4) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies. 1257 86

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