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PubMed1986

NTP Toxicology and Carcinogenesis Studies of Xylenes (Mixed) (60% m-Xylene, 14% p-Xylene, 9% o-Xylene, and 17% Ethylbenzene) (CAS No. 1330-20-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

The technical grade of xylenes (mixed) (hereafter termed xylenes) contains the three isomeric forms and ethylbenzene (percentage composition shown above). The annual production for 1985 was approximately 7.4 x 108 gallons. Xylenes is used as a solvent and a cleaning agent and as a degreaser and is a constituent of aviation and automobile fuels. Xylenes is also used in the production of benzoic acid, phthalate anhydride, and isophthalic and terephthalic acids as well as their dimethyl esters. Toxicology and carcinogenesis studies of xylenes were conducted in laboratory animals because a large number of workers are exposed and because the long- term effects of exposure to xylenes were not known. Exposure for the present studies was by gavage in corn oil. In single-administration studies, groups of five F344/N rats and B6C3F1 mice of each sex received 500, 1,000, 2,000, 4,000, or 6,000 mg/kg. Administration of xylenes caused deaths at 6,000 mg/kg in rats and mice of each sex and at 4,000 mg/kg in male rats. In rats, clinical signs observed within 24 hours of dosing at 4,000 mg/kg included prostration, muscular incoordination, and loss of hind limb movement; these effects continued through the second week of observation. Tremors, prone position, and slowed breathing were recorded for mice on day 3, but all mice appeared normal by the end of the 2- week observation period. In 14- day studies, groups of five rats of each sex were administered 0, 125, 250, 500, 1,000, or 2,000 mg/kg, and groups of five mice of each sex received 0, 250, 500, 1,000, 2,000, or 4,000 mg/kg. Chemical- related mortality occurred only at 2,000 mg/kg in rats and at 4,000 mg/kg in mice. Rats and mice exhibited shallow breathing and prostration within 48 hours following dosing at 2,000 mg/kg. These signs persisted until day 12 for rats, but no clinical signs were noted during the second week for mice. In 13- week studies, groups of 10 rats of each sex received 0, 62.5, 125, 250, 500, or 1,000 mg/kg, and groups of 10 mice of each sex received 0, 125, 250, 500, 1,000, or 2,000 mg/kg. No deaths or clinical signs of toxicity were recorded in rats. However, high dose male rats gained 15% less weight and females 8% less weight than did the vehicle controls. Two female mice died at the 2,000 mg/kg dose. Lethargy, short and shallow breathing, unsteadiness, tremors, and paresis were observed for both sexes in the 2,000 mg/kg group within 5- 10 minutes after dosing and lasted for 15- 60 minutes. Two- year toxicology and carcinogenesis studies were conducted by administering 0, 250, or 500 mg/kg xylenes in corn oil by gavage to groups of 50 F344/N rats of each sex, 5 days per week for 103 weeks. Groups of 50 B6C3F1 mice of each sex were administered 0, 500, or 1,000 mg/kg xylenes on the same schedule. Although the mortality was dose related in male rats (final survival: vehicle control, 36/50; low dose, 26/50; high dose, 20/50), many of the early deaths in the dosed males were gavage related. Body weights of the high dose male rats were 5%- 8% lower than those of the vehicle controls after week 59. The mean body weights of low dose and vehicle control male rats and those of dosed and vehicle control female rats were comparable. Survival rates of female rats and both sexes of dosed mice were not significantly different from those of the vehicle controls. The mean weights of dosed male and female mice were comparable to those of the vehicle controls. Hyperactivity lasting 5- 30 minutes was observed in high dose mice after dosing, beginning after week 4 and continuing through week 103. At no site was the incidence of nonneoplastic or neoplastic lesions in dosed rats or mice of either sex considered to be related to the administration of xylenes. Neither xylenes nor any of its components (o- xylene, m-xylene, p- xylene, or ethylbenzene) were mutagenic when tested with or without metabolic activation in Salmonella typhimurium strains TA100, TA1535, TA97, or TA98 with the preincubation protocol. In addition, ethylbenzene was tested in cytogenetic assays using cultured Cetic assays using cultured Chinese hamster ovary cells both with and without metabolic activation; neither sister- chromatid exchanges nor chromosomal aberrations were induced by ethylbenzene. An audit of the experimental data was conducted for the 2-year studies of xylenes. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenicity of xylenes (mixed) for male or female F344/N rats given 250 or 500 mg/kg or for male or female B6C3F1 mice given 500 or 1,000 mg/kg.

Journal Article↗

PubMed1985

NTP Toxicology and Carcinogenesis Studies of Propylene (CAS No. 115-07-1) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

Propylene is used as a starting material in the production of polypropylene plastics and various other chemicals, including acrylonitrile, isopropyl alcohol, propylene oxide, butyraldehyde, cumene, dodecane, nonene, and allyl chloride. The major derivatives are polypropylene (25%), acrylonitrile (15%), isopropyl alcohol (10%), and propylene oxide (10%). It is also a valuable feed-stock chemical for the production of gasoline. Other miscellaneous applications include use as a starting material for polymerization reactions to form vinyl chloride copolymers and low-molecular-weight homopolymers that are used as additives in lubricating oils and in the manufacture of hydroquinone. The chemical is also used as an aerosol propellant or component. The major end uses of propylene are in the production of fabricated plastics (50%) and fibers (15%). Toxicology and carcinogenesis studies of propylene (greater than 99% pure) were conducted by exposing groups of 50 F344/N rats and 49 or 50 B6C3F1 mice of each sex to propylene in air by inhalation at concentrations of 5,000 or 10,000 ppm, 6 hours per day, 5 days per week, for 103 weeks. Other groups of 50 rats and 50 mice of each sex in chambers received air only on the same schedule and served as chamber controls. The highest concentration of propylene that was considered safe for these studies was 10,000 ppm because of the risk of explosion that can occur at higher concentrations. The survival of exposed and control rats and mice was comparable. Throughout most of the studies, mean body weights of exposed male and female rats were slightly lower (0%-5%) than those of the controls, but the decrements were not concentration related. After week 59 of the study, mean body weights of 10,000-ppm male mice were usually slightly lower (5%) than those of the controls, whereas those in other exposed groups of male and female mice were generally comparable with those of the controls. No compound-related adverse clinical signs were observed in either species. An increased incidence of squamous metaplasia of the nasal cavity was observed in female rats exposed at the 5,000-ppm and 10,000-ppm concentrations (control, 0/49; low, 15/50; high, 6/50) and in male rats exposed at 5,000 ppm (2/50; 19/50; 7/50). Epithelial hyperplasia of the nasal cavity was increased in female rats exposed at the 10,000-ppm concentration (0/49; 4/50; 9/50); the incidences in male rats were 2/50, 2/50, and 5/50. Inflammation of the nasal cavity, characterized by an influx of lymphocytes, macrophages, and granulocytes into the submucosa and by granulocytes into the lumen, occurred at increased incidences in low concentration and high concentration male rats and in high concentration female rats. Chronic focal inflammation of the kidneys occurred at an increased incidence in low concentration and high concentration mice of each sex. Hemangiosarcomas were found in one low dose male mouse (liver), two high dose male mice (spleen), and three high dose female mice (subcutis, spleen, and uterus). Hemangiomas were found in one low dose and in one high dose female mouse (liver). Vascular tumors were not found in control mice of either sex. The low incidences of vascular tumors and their occurrence in a variety of organs suggest that they are not related to administration of propylene. The occurrence of uterine endometrial stromal polyps in female mice showed a positive trend (P<0.05; 0/47; 0/47; 3/48); the incidence in the 10,000-ppm group was not significantly greater than that in the concurrent control group, but the incidence was higher than the mean historical control rate (22/2,411, 0.9%) and was within the range (0%-6%) observed in studies throughout the Carcinogenesis Program. The occurrence of endometrial stromal polyps in three high concentration female mice was not considered to be clearly related to exposure to propylene. The incidence of male mice with alveolar/bronchiolar adenomas or carcinomas (combined) occurred with a negative trend (P<0.05; 16/50; 4/49; 7/50), and the reduced incidences in both exposed groups wegative trend (P<0.05; 16/50; 4/49; 7/50), and the reduced incidences in both exposed groups were less (P<0.05) than that in the control group. The control incidence of these tumors in an inhalation study conducted concurrently at the same laboratory was similar (15/50), suggesting a possible exposure-related decrease. The biologic significance of this decrease in male mice is difficult to assess; the incidences seen in these control and exposed animals are within the range of incidences (2&percnt;-34&percnt;; mean, 16.7&percnt;) observed in control male mice in other studies throughout the Carcinogenesis Program. An audit of the experimental data was conducted for these carcinogenesis studies on propylene. No data discrepancies were found that influenced the final interpretations. Under the conditions of these studies, there was no evidence of carcinogenicity in male and female F344/N rats or in male and female B6C3F1 mice exposed to propylene by inhalation at concentrations of 5,000 or 10,000 ppm for 103 weeks. In the nasal cavity, propylene induced squamous metaplasia of the respiratory epithelium in male and female rats and epithelial hyperplasia in female rats. Synonyms: propene; methylethylene; methylethene

Journal Article↗

PubMed1985

NTP Toxicology and Carcinogenesis Studies of HC Blue No. 1 (CAS No. 2784-94-3) in F344/N Rats and B6C3F1 Mice (Feed Studies).

Toxicology and carcinogenesis studies of HC Blue No. 1 (97% pure), a semipermanent hair dye, were conducted by administering the test chemical in feed for 103 weeks to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex. The dietary concentrations used were 0, 1,500, or 3,000 ppm for rats and male mice and 0, 3,000, or 6,000 ppm for female mice. These concentrations were selected on the basis of results from single-administration gavage studies and 14-day and 13-week feed studies. The survival of male and female rats and male mice was not affected by administration of HC Blue No. 1. Survival of high dose female mice was reduced (P<0.05); the early deaths in this group are believed to have been caused by hepatocellular carcinomas. Body weights of high dose rats and dosed mice were lower than those of the respective control groups; female rats and mice were more affected than were males. Administration of HC Blue No. 1 produced significant positive trends in the incidences of male rats with hepatocellular neoplastic nodules/carcinomas (neoplastic nodules: control, 0/49; low dose, 0/50; high dose, 3/50; neoplastic nodules/carcinomas: 1/49; 0/50; 6/50). In male and female mice, both doses of HC Blue No. 1 increased the incidences of hepatocellular carcinoma (male: 11/50; 20/50; 30/50; female: 1/50; 24/48; 47/49) and the low doses increased the incidences of hepatocellular adenomas (male: 4/50; 17/50; 10/50; female: 2/50; 11/48; 4/49). HC Blue No. 1 produced dose-related increases in the incidences of proliferative lesions of the lungs (adenomatous hyperplasia and alveolar/bronchiolar adenomas or carcinomas) in female rats (hyperplasia: 2/50; 5/49; 8/50; adenoma/carcinoma: 1/50; 3/49; 7/50). In male mice, HC Blue No. 1 at the 6,000-ppm dose increased the incidences of thyroid gland follicular cell hyperplasia and adenomas (hyperplasia: 3/47; 7/49; 14/50; adenoma: 0/47; 0/49; 5/50). HC Blue No. 1 was mutagenic in strains TA97, TA98, and TA100 of Salmonella typhimurium in the presence or absence of Aroclor-induced male Sprague-Dawley rat or Syrian hamster liver S9; HC Blue No. 1 was negative in strain TA1535. HC Blue No. 1 was mutagenic in the absence of activation in the L5178Y/TK+/- mouse lymphoma assay and induced unscheduled DNA synthesis in rat hepatocytes in vitro. An audit of the experimental data was conducted for these carcinogenesis studies on HC Blue No. 1. No data discrepancies were found that influenced the final interpretations. Under the conditions of these feed studies, there was equivocal evidence of carcinogenicity in male F344/N rats, since HC Blue No. 1 caused a marginal increase in the incidence of hepatocellular neoplastic nodules/carcinomas. For female F344/N rats, there was some evidence of carcinogenicity in that HC Blue No. 1 induced increased incidences of alveolar/bronchiolar neoplasms. There was clear evidence of carcinogenicity of HC Blue No. 1 for male and female B6C3F1 mice as shown by increased incidences of hepatocellular carcinomas. The incidences of follicular cell adenomas of the thyroid gland were also increased in male mice receiving HC Blue No. 1. Synonym: 2,2'((4-(methylamino)-3-nitrophenyl)imino)bis (ethanol)

Journal Article↗

PubMed1986

NTP Toxicology and Carcinogenesis Studies of Diglycidyl Resorcinol Ether (Technical Grade) (CAS No. 101-90-6) In F344/N Rats and B6C3F1 Mice (Gavage Studies).

Diglycidyl resorcinol ether (DGRE), a pale, yellow, translucent, amorphous solid at room temperature, is used as a liquid spray epoxy resin, as a diluent in the production of other epoxy resins used in electrical, tooling, adhesive, and laminating applications, and as a curing agent for polysulfide rubber. Approximately 3,000 workers are exposed to DGRE. The quantity of DGRE produced in the United States is not known. Toxicology and carcinogenesis studies of technical grade diglycidyl resorcinol ether (81% pure) were conducted by administering the chemical in corn oil by gavage to groups of 50 male and 50 female F344/N rats at doses of 25 or 50 mg/kg and to groups of 50 male and female B6C3F1 mice at doses of 50 or 100 mg/kg. A supplemental study of similar design in male and female rats (0 or 12 mg/kg) was started approximately 12 months later because of high mortality in the 50 mg/kg dose groups. Doses were administered five times per week for 103 weeks. Groups of 50 rats and 50 mice of each sex received corn oil by gavage on the same dosing schedule and served as vehicle controls. Throughout most of the primary study, mean body weights of high dose male and female rats and female mice were lower than those of the corresponding vehicle controls. In the supplemental study, body weights of both sexes of the dosed rats were unaffected by administration of DGRE. Survival of dosed rats of each sex in the primary study was dose related and was shorter (P<0.001) than that of the vehicle controls. No high dose male rats and only 1/50 high dose female rats lived to the end of the study. Bronchopneumonia was the most frequent cause of early death among the rats and may have resulted from the animals' aspiration of corn oil containing diglycidyl resorcinol ether. Survival of the dosed male rats in the supplemental study was reduced (P<0.005) when compared to controls. There was no significant difference in survival between dosed and control female rats in the supplemental study. Survival of dosed and control mice was comparable but poorer in females, with 20/50 (40%) of the controls, 13/50 (26%) of the low dose, and 10/50 (20%) of the high dose groups alive at the end of 2 years. These early deaths were due to suppurative and necrotizing inflammation of the reproductive tract, possibly caused by a Klebsiella sp. infection. The incidences of rats and mice with hyperkeratosis and hyperplasia of the forestomach were compound related. For rats and mice of each sex, incidences of animals with squamous cell papillomas, squamous cell carcinomas, or both occurred with statistically significant positive trends and the incidences observed in other organs in dosed groups relative to the controls. An audit of the experimental data was conducted for the 2-year studies of diglycidyl resorcinol ether. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, technical grade diglycidyl resorcinol ether caused hyperkeratosis and hyperplasia of the forestomach in rats and mice. DGRE was carcinogenic for male and female F344/N rats and for male and female B6C3F1 mice, causing both benign and malignant neoplasms of the forestomach. Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Positive Male Mice: Positive Female Mice: Positive Synonym: DGRE

Journal Article↗

PubMed1986

NTP Toxicology and Carcinogenesis Studies of C.I. Basic Red 9 Monohydrochloride (Pararosaniline) (CAS No. 569-61-9) In F344/N Rats and B6C3F1 Mice (Feed Studies).

C.I. Basic Red 9 monohydrochloride is a triphenylmethane dye used for coloring textiles, leather, and paper and as a biological stain. Toxicology and carcinogenesis studies were conducted by administering the test chemical in feed to groups of 50 male and 50 female F344/N rats and B6C3F1 mice for 103 weeks at concentrations of 0, 1,000, or 2,000 ppm for male rats and 0, 500, or 1,000 ppm for female rats and mice of each sex. The average daily doses of C.I. Basic Red 9 monohydrochloride were estimated to be 49 and 103 mg/kg for male rats, 28 and 59 for female rats, 196 and 379 mg/kg for male mice, and 149 and 407 mg/kg for female mice. Two lots of the test chemical were used in the 2-year studies with purities of 93% (water content approximately 9%) and 99%. In rats, the thyroid gland and pituitary gland were identified as target sites in the 13-week studies. Therefore, 10 additional rats of each sex were added to the control and high dose groups in the 2-year studies to examine the effects on these organs after 1 year of exposure. In the 1-year studies in rats, final mean body weights were slightly decreased in both sexes. The thyroid gland weight to body ratio of dosed males was 1.7 times that of the controls, and the concentration of serum thyroxin in male and female rats was significantly lower than that of the controls at week 52. Compound-related histopathologic effects included thyroid gland cysts in both sexes (1/10; 1/10) and thyroid gland follicular cell hyperplasia (1/10), adenomas (1/10), and carcinomas (1/10) and fatty metamorphosis of the liver (4/10, two of these with focal necrosis) in males; no effect was seen in the controls. The doses selected for the 2-year studies were based on the results of the 13-week studies. The absence of toxicologic signs, histopathologic changes, significant body weight depressions, or mortality after 13 weeks of exposure to C.I. Basic Red 9 monohydrochloride suggested that these concentrations would not shorten survival. However, throughout the 2-year studies, mean body weights of high dose rats and dosed mice were lower than those of the controls, and significantly reduced survival relative to controls was observed for high dose rats of each sex (P<0.001), low dose male mice (P<0.03), and low dose and high dose female mice (P<0.001). In the 2-year studies, several types of neoplastic lesions occurred with significantly increased incidences in dosed animals (see table page 12 of the Technical Report). High dose male rats had increased incidences of squamous cell carcinomas, trichoepitheliomas, and sebaceous adenomas of the skin. Greater incidences of follicular cell carcinomas and of follicular cell adenomas were found in the thyroid glands of high dose male rats than in controls, whereas in high dose female rats, the combined incidence of follicular cell adenomas or carcinomas was greater than that in controls. Dosed rats of each sex had increased incidences of subcutaneous fibromas, and high dose rats had increased incidences of Zymbal gland carcinomas. Hepatocellular carcinomas were the compound-related neoplasms common to both species; the incidences were increased in both high dose male rats and in dosed mice of each sex. Dosed female mice had an increased incidence of pheochromocytomas or malignant pheochromocytomas. In addition, marginally increased incidences of mammary gland tumors (23/50; 32/50; 32/50) in female rats, and malignant lymphomas (17/50; 24/50; 25/50) in female mice were observed. C.I. Basic Red 9 monohydrochloride was mutagenic in strains TA98 and TA100 of Salmonella typhimurium by the preincubational protocol with or without metabolic activation. It was not mutagenic in strains TA1535 and TA1537 in this system with or without metabolic activation. It was mutagenic in the L5178Y/TK+/- mouse lymphoma assay with or without metabolic activation. C.I. Basic Red 9 monohydrochloride did not induce chromosomal aberrations in Chinese hamster ovary cells; it did induce sister-chromatid exchanges in the presence of Aroclor 1254-induced male Sprague-Dawley rat li-induced male Sprague-Dawley rat liver S9. C.I. Basic Red 9 monohydrochloride also induced unscheduled DNA synthesis in F344 male rat hepatocytes in vitro. An audit of the experimental data was conducted for these 2-year studies of C.I. Basic Red 9 monohydrochloride. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year feed studies, there was clear evidence of carcinogenicity of C.I. Basic Red 9 monohydrochloride for male and female F344/N rats and for male and female B6C3F1 mice. In male rats, C.I. Basic Red 9 monohydrochloride caused squamous cell carcinomas, trichoepitheliomas and sebaceous adenomas of the skin, subcutaneous fibromas, thyroid gland follicular cell adenomas and follicular cell carcinomas, Zymbal gland carcinomas, and hepatocellular carcinomas. In female rats, C.I. Basic Red 9 monohydrochloride caused subcutaneous fibromas, thyroid gland follicular cell adenomas or carcinomas (combined), and Zymbal gland carcinomas. In male mice, C.I. Basic Red 9 monohydrochloride caused hepatocellular carcinomas. In female mice, C.I. Basic Red 9 monohydrochloride caused hepatocellular carcinomas and adrenal gland pheochromocytomas or malignant pheochromocytomas (combined). Exposure to C.I. Basic Red 9 monohydrochloride also may have been related to increased incidences of mammary gland tumors in female rats and hematopoietic system tumors in female mice. Synonyms: pararosaniline; benzeneamine 4-((4-aminophenyl)(4-imino-2,5-cyclohexadian-1-ylidene)methyl)-monohydrochloride paramagenta

Journal Article↗

PubMed1985

NTP Toxicology and Carcinogenesis Studies of Diallylphthalate (CAS No. 131-17-9) in F344/N Rats (Gavage Studies).

Diallylphthalate is widely used as a crosslinking agent for unsaturated polyesters. Diallylphthalate or diallylphthalate polyester blends are used primarily as plasticizers and carriers for adding catalysts and pigments to polyesters and in molding, electrical parts, laminating compounds, and impregnation of metal castings. Rubber compounds, epoxy formulations, and polyurethane foams may also contain diallylphthalate. Precise figures are not currently available, although annual production of diallylphthalate in the United States is known to exceed 5,000 pounds, and an estimated 57,000 pounds were imported into the United States in 1982. Toxicology and carcinogenesis studies of diallylphthalate (approximately 99% pure) were conducted by administering the test chemical in corn oil by gavage to groups of 50 male and 50 female F344/N rats at doses of 0 (vehicle control), 50, or 100 mg/kg 5 days per week for 103 weeks. The diallylphthalate doses used in the 2-year studies were chosen on the basis of 13-week studies, wherein doses of 200 or 400 mg/kg caused death, reductions in body weight gains, or periportal hepatocellular necrosis and fibrosis in both sexes. Mean body weights and survival of male and female rats administered diallylphthalate were essentially the same as those of the vehicle controls throughout the 2-year studies, although hepatotoxicity was produced in both sexes by the 100 mg/kg dose. Based on the results of the prechronic studies and the effects on the liver in the 2-year studies, the doses used in the 2-year studies were considered to be adequate for carcinogenicity testing. Male and female rats receiving the 100 mg/kg dose of diallylphthalate in the 2-year studies developed chronic liver diseases characterized by periportal fibrosis, periportal accumulation of pigment, and severe bile duct hyperplasia. Pigment accumulation also occurred at the 50 mg/kg dose in both sexes. Diallylphthalate administration increased the occurrence of mononuclear cell leukemia in female rats (P<0.05 by trend tests), and the increase in the 100 mg/kg dose female rats was greater (P</=0.05) than in the vehicle controls by pairwise comparisons (vehicle control, 15/50, 30%; low dose, 15/43, 35%; high dose, 25/49, 51%). An increased occurrence of mononuclear cell leukemia was not observed in male rats receiving diallylphthalate. A previous NTP carcinogenesis study (NTP TR 242) reported an increased incidence of lymphomas in male B6C3F1 mice receiving diallylphthalate by gavage for 2 years at doses of 0, 150, or 300 mg/kg. This increase was considered to be equivocally related to diallylphthalate administration. The incidences of hyperplasia and inflammatory lesions of the forestomach were increased in a dose-related fashion in both sexes of mice in that study, and uncommon forestomach papillomas were observed in 0%, 2%, and 4% of both sexes of mice. Because of the numerical increase in forestomach papillomas, the concomitant presence of forestomach hyperplasia, and the rarity of forestomach papillomas in vehicle control (corn oil gavage) B6C3F1 mice, the development of these proliferative lesions of the forestomach in mice may have been related to diallylphthalate administration. In the current study in rats, a squamous cell carcinoma was found in one high dose male rat. Diallylphthalate was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without activation by a 9,000 x g supernatant fraction from the livers of Aroclor 1254-treated male Sprague-Dawley rats or Syrian hamsters. Diallylphthalate did not induce sex-linked recessive lethal mutations in Drosophila melanogaster. An audit of the experimental data was conducted for these carcinogenicity studies on diallylphthalate. No data discrepancies were found that influenced the final interpretations. Under the conditions of this study, the administration of diallylphthalate by gavage in corn oil to male and female F344/N rats for 2 years caused chronic liver disease characterized by periportal fibrosis and pigment accumulation and an increasetal fibrosis and pigment accumulation and an increased severity of bile duct hyperplasia. The incidence of mononuclear cell leukemia was significantly increased in female rats receiving 100 mg/kg. Because of the variability in the incidence of this neoplasm in aged Fisher 344 rats and the difficulty in definitively diagnosing this lesion in Fisher 344 rats, this increase was considered to be equivocal evidence of carcinogenicity of diallylphthalate in female rats. There was no evidence of carcinogenicity in male rats. Synonym: DAP

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PubMed1985

NTP Toxicology and Carcinogenesis Studies of Chlorodibromomethane (CAS No. 124-48-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Toxicology and carcinogenesis studies of chlorodibromomethane (greater than 98% pure), a trihalomethane formed after chlorination of water supplies, were conducted by administering this test chemical in corn oil gavage five times per week for 104 weeks to groups of 50 male and 50 female F344/N rats at 0,40, or 80 mg/kg per day and to groups of 50 male and 50 female B6C3F1 mice for 105 weeks at doses of 0, 50, or 100 mg/kg per day. Survival of dosed male and female rats and female mice was comparable to that of the corresponding vehicle control groups. An overdose of chemical was given to low dose male and female mice at week 58; this overdose killed 35 male mice, whereas the female mice were apparently not affected. Because this mortality significantly reduced the number of survivors, the low dose male mouse group was considered to be inadequate for analysis of neoplasms. High dose male mice had lower survival than the vehicle controls (44/50 vs 29/50; P<0.001). At week 82, nine high dose male mice had died; the cause remains unknown. High dose male rats and dosed male and female mice had lower body weights compared with those of the vehicle controls. Compound-related nonneoplastic lesions were found in the liver and kidney in male and female rats and in male mice in the 13-week studies at the highest dose (250 mg/kg). In the 2-year studies, compound-related toxicity was seen primarily in the livers of male and female rats (fatty metamorphosis and ground-glass cytoplasmic changes) and in the male mice (hepatocytomegaly, necrosis, fatty metamorphosis) and female mice (calcification and fatty metamorphosis). Toxicity was also seen in the kidneys (nephrosis) of male mice and female rats. Administration of chlorodibromomethane significantly increased the incidence of hepatocellular adenomas (vehicle control, 2/50; low dose, 4/49; high dose, 11/50) and the combined incidences of hepatocellular adenomas or carcinomas (6/50; 10/49; 19/50) in high dose female mice. The incidence of hepatocellular carcinomas (vehicle control, 10/50; high dose, 19/50) was significantly increased in high dose male mice, although the combined incidence of hepatocellular adenomas or carcinomas (vehicle control, 23/50; high dose, 27/50) was marginally significant by the life table test but not by the incidental tumor test. Negative trends in several common rodent tumors were found in dosed animals in the 2-year studies. These neoplasms included fibroadenomas of the mammary gland in female rats, endometrial stromal polyps of the uterus in female rats, and malignant lymphomas in male mice. Chlorodibromomethane was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 in the presence or absence of Aroclor-induced male Sprague-Dawley rat or male Syrian hamster liver S9. An audit of the experimental data was conducted for the 2-year toxicology and carcinogenesis studies of chlorodibromomethane. No data discrepancies were found that influenced the final interpretations. Under the conditions of these gavage studies, there was no evidence of carcinogenicity in male or female F344/N rats receiving chlorodibromomethane at doses of 40 or 80 mg/kg five times per week for 104 weeks. Fatty metamorphosis and ground-glass cytoplasmic changes of the liver in male and female F344/N rats were related to administration of chlorodibromomethane. There was equivocal evidence of carcinogenicity for male B6C3F1 mice; chlorodibromomethane caused an increased incidence of hepatocellular carcinomas, whereas the combined incidence of hepatocellular adenomas or carcinomas was only marginally increased. Some evidence of carcinogenicity was observed for female B6C3F1 mice, since chlorodibromomethane caused an increased incidence of hepatocellular adenomas and an increased combined incidence of hepatocellular adenomas or carcinomas. Synonym: Dibromochloromethane

Journal Article↗

PubMed1986

NTP Toxicology and Carcinogenesis Studies of HC Red No. 3 [2,((Amino-2-nitrophenyl)amino)ethanol] (CAS No. 2871-01-4) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

oxicology and carcinogenesis studies of HC Red No. 3 (97% pure), a semipermanent hair dye, were conducted by administering the chemical in corn oil by gavage for 105 weeks to groups of 50 male and 50 female F344/N rats and for 104 weeks to groups of 50 male and 50 female B6C3F1 mice. The dosage regimen used for rats was 0, 250, or 500 mg/kg per day and for mice, 0, 125. or 250 mg/kg per day. Doses were administered 5 days per week. In prior 13-week studies, these doses produced no signs of toxicity when administered 5 days per week. In the 2-year studies, the administration of HC Red No. 3 did not affect body weight gains of male or female rats or mice. Body weight gains by all groups of female mice were reduced because of a reproductive tract infection. Survival of male and female rats and mice was not reduced by administration of HC Red No. 3. The survival of female mice, including vehicle controls, was reduced relative to historical survival rates due to a reproductive tract infection. The infection, accompanied by weight loss, high mortality, and suppurative inflammation of multiple organs, was found in 36/50 vehicle control, 32/50 low dose, and 29/50 high dose female mice. Klebsiella pneumoniae was isolated from infected tissues. Pigmentation of various tissues in both rats and mice was a common observation in both the 13-week and the 2-year studies. The pigment was not identified but was presumed to be a derivative of HC Red No. 3. Very minimal nephropathy was found in dosed female rats, but its relationship to HC Red No. 3 is equivocal. Mild nephrosis was found in dosed female mice, but this effect may have been secondary to the infection of the genital tract. There was an increase in the incidence of mammary gland fibroadenomas or cystadenomas in low dose female rats. The incidence of this lesion in high dose female rats was not increased (vehicle control, 14/50, 28%; low dose, 25/50, 50%; high dose, 11/50, 22%). Largely because of the lack of a dose response, the increased incidence in the low dose females was not considered to be due to HC Red No. 3. No increased incidences of neoplasms were seen in male rats. Transitional cell papillomas of the urinary bladder were detected in one high dose male rat, two low dose female rats, and one high dose female rat; none was observed in the vehicle controls. These uncommon neoplasms were found in animals that survived to the termination of the study and were not accompanied by other proliferative lesions. The incidence of hepatocellular adenomas or carcinomas (combined) was increased in high dose male mice, whereas the incidence of these neoplasms in low dose male mice was significantly lower than that in the vehicle controls (25/50; 15/50; 35/50). Hepatocellular carcinomas in three vehicle control, one low dose, and five high dose male mice metastasized to the lung. The incidences of liver neoplasms in dosed female mice were not significantly different from those in the vehicle control group. HC Red No. 3 was mutagenic in Salmonella typhimurium strains TA97, TA98, and TA100, but not in TA1535, in the presence or absence of Aroclor 1254-induced male Sprague-Dawley rat or male Syrian hamster liver S9 when tested by the preincubational protocol. An audit of the experimental data was conducted for these 2-year toxicology and carcinogenesis studies on HC Red No. 3. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies of HC Red No. 3, there was no evidence of carcinogenicity for male or female F344/N rats given 250 or 500 mg/kg per day. There was equivocal evidence of carcinogenicity for male B6C3F1 mice as indicated by an increased incidence of hepatocellular adenomas or carcinomas (combined) in the 250 mg/kg dose group. Poor survival coupled with lack of significant findings rendered the study in female B6C3F1 mice an inadequate study of carcinogenicity. Both sexes of both species may have been able to tolerate higher doses of HC Red No. 3. Therefore, the sensitivity of these studies for detecting chese studies for detecting carcinogenesis may have been limited. Synonym: 2,((amino-2-nitrophenyl)amino)ethanol

Journal Article↗

PubMed1985

NTP Toxicology and Carcinogenesis Studies of 8-Hydroxyquinoline (CAS No. 148-24-3) in F344/N Rats and B6C3F1 Mice (Feed Studies).

Carcinogenesis studies of 8-hydroxyquinoline (99% pure), a metal chelator and antimicrobial agent, were conducted by administering the test chemical in feed to groups of 50 male and 50 female F344/N rats and B6C3F1 mice at concentrations of 0, 1,500, or 3,000 ppm for 103 weeks. These concentrations were selected because the chemical at higher concentrations resulted in reduced feed consumption, decreases in mean body weights, and deaths in the 15-day and 13-week studies. The average daily doses were estimated to be 73 and 143 mg/kg for male rats, 89 and 166 mg/kg for female rats, 217 and 396 mg/kg for male mice, and 349 and 619 mg/kg for female mice. Survival of dosed male and female rats and mice in the 2-year studies was comparable to that of the corresponding controls. The high dose rats and mice of each sex exhibited slight decreases in mean body weights and decreased feed consumption. Compound-related gross or microscopic pathologic effects were not observed in either species in the 15-day or 13-week studies. In the 2-year studies, C-cell adenomas/carcinomas of the thyroid gland showed a positive trend (P=0.03) for male rats (control, 1/50; low dose, 1/49; high dose, 6/47). The incidence of C-cell neoplasms in the high dose was not significantly increased compared with the controls, and the occurrence of C-cell hyperplasia was not elevated (4/50; 3/49; 1/47). The incidence of alveolar/bronchiolar adenomas or carcinomas (combined) in male rats with a positive trend, and the incidence in the high dose group was greater than that in the controls (0/50; 3/50; 4/50). This marginal effect was not supported by an increase in epithelial hyperplasia (5/50; 5/50; 3/50). These marginal increases in male rats were not regarded as being related to the administration of 8-hydroxyquinoline. In in vitro tests, 8-hydroxyquinoline did not induce either unscheduled DNA synthesis in rat hepatocytes or transformation of BALB/c-3T3 cells. An audit of the experimental data for these carcinogenesis studies on 8-hydroxyquinoline was conducted. No data discrepancies were found that significantly influenced the final interpretations. Under the conditions of these studies, there was no evidence of carcinogenicity for male and female F344/N rats or for male and female B6C3F1 mice given 8-hydroxyquinoline in feed at concentrations of 1,500 or 3,000 ppm for 103 weeks. Synonyms: 8-quinolinol; oxine; hydroxybenzopyridine

Journal Article↗

PubMed1986

NTP Toxicology and Carcinogenesis Studies of o-Phenylphenol (CAS No. 90-43-7) Alone and with 7,12-Dimethylbenz(a)anthracene (CAS No. 57-97-6) in Swiss CD-1 Mice (Dermal Studies).

o-Phenylphenol is used primarily as a germicide and fungicide for citrus fruits and vegetables and was selected for carcinogenesis studies because of the potential for human exposure. Four-week studies were conducted in which groups of 10 male and 10 female Swiss Webster mice were given dermal applications to the dorsal interscapular region of 0, 6, 11, 21, 36, or 56 mg of o-phenylphenol in 0.1 ml of acetone. Doses were administered 3 days per week for 4 weeks, and animals were monitored for clinical changes. Reductions in body weights of acetone vehicle control were observed, but no compound-related changes in weight or survival occurred in male or female mice administered o-phenylphenol. o-Phenylphenol caused dose-related ulcerative lesions at the site of application. The severity of these lesions was judged not to be life threatening. Carcinogenesis studies were conducted to determine whether o-phenylphenol was a complete carcinogen for skin or a promoter in a two-stage initiation/promotion skin paint model. Groups of 50 Swiss CD-1 mice of each sex were used for up to 102 weeks. Five dose groups were used: an acetone vehicle control group; a positive control group initiated with 7,12-dimethylbenz(a)- anthracene (DMBA) and promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA); an initiator control group that received DMBA plus acetone; a group that received repeated applications of o-phenylphenol. The following doses were applied dermally to a clipped area on the dorsal interscapular region 3 days per week: o-phenylphenol - 55.5 mg/0.1 ml acetone; or TPA - 0.005 mg/0.1 ml acetone. DMBA was administered as a single dose at a concentration of 0.05 mg/0.1 ml acetone to the dorsal interscapular region. In the 2-year studies, mean body weights of the o-phenylphenol, DMBA/o-phenylphenol, and DMBA/TPA groups were not markedly different from those of mice that received DMBA/acetone. Similarly, there were no significant group differences in survival except for a decrease in survival in the positive control group (DMBA/TPA). Skin neoplasms classified as squamous cell papillomas, squamous cell carcinomas, basal cell tumors, basal cell carcinomas, keratoacanthomas, or sebaceous adenomas occurred in mice dosed with DMBA/acetone, DMBA/o-phenylphenol, or DMBA/TPA alone. However, the incidence of skin neoplasms in mice dosed with DMBA/acetone (15/100) was similar to that in mice dosed with DMBA/o-phenylphenol (17/100). The incidence of skin neoplasms in male and female mice dosed with DMBA/TPA (52/100) was substantially greater than those in mice dosed with either DMBA/acetone or DMBA/o-phenylphenol. Similarly, the mean time of appearance of skin papillomas occurred much earlier in the DMBA/TPA groups than in the DMBA/acetone or DMBA/o-phenylphenol groups. All groups had nonneoplastic lesions consisting of inflammation, ulceration, hyperkeratosis, and acanthosis at the site of application. These lesions were present in the acetone vehicle control group and, to a larger extent, in the o-phenylphenol, DMBA/o-phenylphenol, and DMBA/TPA groups. No skin neoplasms were observed in male or female mice receiving o-phenylphenol or in the acetone vehicle control groups. Moreover, a complete histopathologic review revealed no other neoplasms at any other site at significantly increased incidences in the groups receiving o-phenylphenol compared with the acetone vehicle controls. There were also no tumor-enhancing (or tumor-inhibiting) effects of o-phenylphenol and DMBA given in combination. o-Phenylphenol was weakly mutagenic in strains TA1535 of Salmonella typhimurium only in the absence of rat liver S9; it was not mutagenic in strains TA1537, TA98, or TA100. It was mutagenic in the mouse lymphoma L5178/TK+/- assay in the presence or absence of Aroclor 1254-induced male F344 rat liver S9. o-Phenylphenol did not induce sex-linked recessive lethal mutations in Drosophila melanogaster. o-Phenylphenol induced sister-chromatid exchanges in Chinese hamster ovary (CHO) cells only in the absence of rat liver S9. It did not induce chromosomal aberraterrations in CHO cells in the presence or absence of Aroclor 1254-induced male Sprague-Dawley rat liver S9. An audit of the experimental data was conducted for these 2-year studies of o-phenylphenol. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year dermal application studies, there was no evidence of carcinogenicity in male or female Swiss CD-1 mice administered o-phenylphenol alone or as a promoter following initiation with DMBA. o-Phenylphenol, however, caused nonneoplastic lesions, which included ulceration, inflammation, and hyperkeratosis, at the site of application.

Journal Article↗

PubMed1986

NTP Toxicology and Carcinogenesis Studies of 3-Chloro-2-methylpropene (Technical grade containing 5% dimethylvinyl chloride) (CAS No. 563-47-3) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Toxicology and carcinogenesis studies of technical-grade 3-chloro-2-methylpropene (containing 5% dimethylvinyl chloride), a widely used insecticide and a chemical intermediate, were performed on F344/N rats and B6C3F1 mice. In the 13-week studies, 50%-100% mortality occurred in groups of male and female rats receiving 400 mg/kg, male rats receiving 300 mg/kg, and male and female mice receiving 500-1,250 mg/kg. Inflammation and necrosis of the liver were seen in rats and mice, and necrosis of cortical tubules of the kidney was seen in mice. Based on these observations, groups of 50 male and 50 female rats were administered 3-chloro-2-methylpropene in corn oil by gavage at doses of 0, 75, or 150 mg/kg body weight, 5 days per week for 103 weeks, and groups of 50 male and 50 female mice received 3-chloro-2-methylpropene at 0, 100, or 200 mg/kg on the same schedule. In the 2-year studies, the mean body weight of high dose male rats was consistently 10%-15% lower than that of the vehicle control group, and late in the study there was a marginal reduction in survival of high dose male rats. Mean body weights and survival in low dose male rats and in both dosed groups of female rats were comparable to those of their vehicle control groups. Mean body weights of high dose male mice and of both dosed groups of female mice were slightly (5%-9%) lower than those of the vehicle controls, whereas survival in both male and female mice was not affected by 3-chloro-2-methylpropene administration. Dose-related increases in the incidence of forestomach inflammation were observed in male and female mice (male: vehicle control, 0/49; low dose, 9/49; high dose, 7/49; female: vehicle control, 2/50; low dose, 3/48; high dose, 9/44). Increased incidences of forestomach basal cell hyperplasia were observed in rats and mice of each sex. 3-Chloro-2-methylpropene induced forestomach squamous cell papillomas and squamous cell carcinomas in rats and mice as shown in the table. Invasion or metastasis of the squamous cell carcinomas to other organs was observed in two low dose male, three high dose male, and one high dose female mice. Renal tubular cell adenocarcinomas (1/49), renal transitional cell carcinomas (1/49), and transitional cell papillomas (1/49) of the urinary bladder were observed in high dose male rats, and renal tubular cell adenomas (1/50) and renal tubular cell adenocarcinomas (1/50) were seen in low dose male rats. These urinary tract neoplasms were not observed in vehicle controls. The incidences of inflammation of the nasal cavity and of nephropathy/nephrosis were greater in the two dosed groups than in the vehicle control groups of rats and mice of each sex. Negative trends or lower incidences of pheochromocytomas of the adrenal gland and C-cell adenomas or carcinomas (combined) of the thyroid gland were observed in dosed male rats. Negative trends were observed in the incidences of hepatocellular adenomas or carcinomas (combined) in dosed male mice and of hemangiomas or hemangiosarcomas (combined) in dosed female mice. 3-Chloro-2-methylpropene was weakly mutagenic in Salmonella typhimurium strain TA1537 with 10% rat liver S9; results in strain TA100 with 10% Syrian hamster liver S9 or with 10% or 30% rat liver S9 were judged equivocal. Mutagenicity tests with S. typhimurium strains TA1535 and TA98 were negative with or without metabolic activation. 3-Chloro-2-methylpropene was mutagenic in the mouse lymphoma L5178/TK+/- forward mutation assay without exogenous metabolic activation. Cytogenetics tests with cultured Chinese hamster ovary cells were positive for induction of chromosomal aberrations and sister-chromatid exchanges (SCE's) in the absence of rat liver S9. With metabolic activation, SCE levels remained significantly elevated, but the number of chromosomal aberrations was reduced. An audit of the experimental data was conducted for these 2-year carcinogenesis studies on 3-chloro-2-methylpropene. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, d the final interpretations. Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenicity for 3-chloro-2-methylpropene as shown by the increased incidences of squamous cell neoplasms in the forestomach of male and female F344/N rats and of male and female B6C3F1 mice. Synonyms: 2-methallyl chloride; methyl allyl chloride; b-methallyl chloride; pi-chloroisobutylene; isobutenyl chloride; 3-chloro-2-methyl-1-propene; 2-methyl-2-propenyl chloride

Journal Article↗

PubMed1986

NTP Toxicology and Carcinogenesis Studies of C.I. Disperse Blue 1 (A commercial dye containing approximately 50% 1,4,5,8-tetraaminoanthraquinone, and 20% water) (CAS No. 2475-45-8) in F344/N Rats and B6C3F1 Mice (Feed Studies).

C.I. Disperse Blue 1, a component of several semipermanent hair dyes, was studied as a commercial-grade product (minus lignosulfonate dispersants) containing approximately 50% 1,4,5,8-tetraaminoanthraquinone, 30% other compounds structurally related to 1,4,5,8-tetraaminoanthraquinone, and 20% water. C.I. Disperse Blue 1 was studied for toxicity and carcinogenicity in single-administration gavage, 14-day feed, 13-week feed, and 104-week feed studies. All studies used F344/N rats and B6C3F1 mice. In the single-administration gavage studies, no deaths occurred within 14 days at doses up to 3,000 mg/kg C.I. Disperse Blue 1 in rats or up to 2,000 mg/kg in mice. In the 14-day studies, rats and mice received dietary concentrations of up to 50,000 ppm. All male rats survived, and 2/5 female rats in the 50,000-ppm group died. All mice receiving 25,000 ppm or more died. Three of five males and 2/5 female mice in the 12,500-ppm groups died. In the 13-week studies, diets containing concentrations up to 20,000 ppm C.I. Disperse Blue 1 were fed to rats, and diets containing concentrations up to 10,000 ppm were fed to mice. No compound-related deaths of rats occurred; however, pathologic changes occurred at 2,500 ppm and higher and included urinary tract calculi, urinary bladder inflammation, hyperplasia of the urinary bladder transitional epithelium, and nephrosis, Compound-related deaths occurred at 10,000 ppm in mice of each sex. Pathologic changes included chronic inflammation and hyperplasia of the urinary bladder transitional epithelium and urinary tract calculi at dietary concentrations of 2,500 ppm and higher and nephrosis, myocardial necrosis, and testicular degeneration at 10,000 ppm. The renal lesions at 5,000 ppm were considered to be potentially life threatening. These composite findings from the short-term studies were used to identify target organs and to help select dietary concentrations for the longer term studies. In the 2-year studies in rats, groups of 50 animals of each sex were administered C.I. Disperse Blue 1 at dietary concentrations of 0, 1,250, 2,500, or 5,000 ppm. These dietary concentrations corresponded to 0, 45, 95, and 217 mg/kg per day for males and 0, 56, 111, and 240 mg/kg per day for females. Survival of males and females in the 5,000 ppm groups and males in the 2,500-ppm group was significantly reduced. Final body weights, as percent of controls, were: male-- low dose 100%; mid dose, 94%; high dose, 85%; female-- low dose, 99%; mid dose, 94%; high dose, 87%. Compound-related effects of feeding diets containing C.I. Disperse Blue 1 for 104 weeks to F344/N rats included urinary bladder neoplasms and calculi at the incidences noted in the table. Positive statistical associations existed between the presence of calculi and transitional cell neoplasms of the urinary bladder in male and female rats, leiomyomas or leiomyosarcomas (combined) in female rats, and squamous cell neoplasms in male rats. The increased incidence of pancreatic islet cell adenomas or carcinomas (combined) in high dose male rats was significant by survival-adjusted analyses (overall incidences: control, 1/49; low dose, 2/50; mid dose, 5/50; high dose, 3/50). In the 2-year studies in mice, 50 animals of each sex were administered diets containing C.I. Disperse Blue 1 at 0, 600, 1,200, or 2,500 ppm. These dietary concentrations corresponded to doses of 0, 112, 239, and 540 mg/kg per day for males and 0, 108, 235, and 520 mg/kg per day for females. Survival was comparable among control and dosed male or female mice. Final body weights, as percent of controls, were as follows: male-- low dose, 97%; mid dose, 98%; high dose, 101%; female-- low dose, 110%; mid dose, 104%; high dose, 91%. The incidences of hepatocellular adenomas or carcinomas (combined) were increased for dosed male mice (9/50; 21/50; 16/50) and for low dose female mice (3/50; 13/49; 3/50; 4/50). Alveolar/bronchiolar adenomas or carcinomas (combined) occurred with an increased incidence in high dose male mice (4/50; 9/49; 5/50; 11/50). Several nonneoplastic effects were increased incidence in high dose male mice (4/50; 9/49; 5/50; 11/50). Several nonneoplastic effects were detected in the kidneys of mid dose and high dose male and high dose female rats and of all dosed groups of male and female mice. These effects on the kidney included calculi, hydronephrosis, and epithelial hyperplasia in rats and casts and renal tubular degeneration in mice. C.I. Disperse Blue 1 was studied for mutagenicity in Salmonella typhimurium in the presence or absence of Aroclor 1254-induced male Sprague-Dawley rat or male Syrian hamster liver S9. C.I. Disperse Blue 1 was mutagenic in strain TA1535 in the presence of S9 and in strains TA97 and TA98 in the presence or absence of S9; it was not mutagenic in strain TA100. An audit of the experimental data was conducted for the 2-year toxicology and carcinogenesis studies of C.I. Disperse Blue 1. No data discrepancies were found that influenced the final interpretations. Under the conditions of these feed studies of C.I. Disperse Blue 1, there was clear evidence of carcinogenicity for male and female F344/N rats as shown by the increased occurrence of transitional cell papillomas and carcinomas, of leiomyomas and leiomyosarcomas, and of squamous cell papillomas and carcinomas of the urinary bladder. Urinary bladder calculi were observed in the groups of rats in which urinary bladder neoplasms were increased. Positive associations existed between the presence of calculi and transitional cell neoplasms in male and female rats, leiomyomas or leiomyosarcomas (combined) in female rats, and squamous cell neoplasms in male rats. A marginally increased occurrence of pancreatic islet cell adenomas or carcinomas (combined) was observed in male rats exposed to C.I. Disperse Blue 1. There was equivocal evidence of carcinogenicity of C.I. Disperse Blue 1 in male B6C3F1 mice as shown by marginally increased incidences of hepatocellular adenomas or carcinomas (combined) in dosed male mice and a marginally increased occurrence of alveolar/bronchiolar adenomas or carcinomas (combined) in high dose male mice. There was no evidence of carcinogenicity of C.I. Disperse Blue 1 in female B6C3F1 mice. Synonyms: C.I. 64500; 1,4,5,8-tetraamino-9,10-anthracenedione; 1,4,5,8-tetraaminoanthraquinone

Journal Article↗

PubMed1986

NTP Toxicology and Carcinogenesis Studies of Dimethyl Morpholinophosphoramidate (CAS No. 597-25-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Dimethyl morpholinophosphoramidate (DMMPA, greater than 99% pure) was developed for use as a simulant for the physical (but not biologic) properties of anticholinesterase agents in chemical defense training. Because of the potential for human exposure, the toxicity and carcinogenicity of DMMPA were investigated. Fourteen-day and 13-week studies were conducted to determine short-term toxicity, to identify target organs, and to establish doses for the 2-year toxicology and carcinogenesis studies. In the 14-day studies, groups of five male and five female F344/N rats were administered DMMPA in corn oil by gavage daily at 0, 313, 1,250, 2,500, or 5,000 mg/kg body weight for 14 consecutive days. All the rats receiving DMMPA at 2,500 or 5,000 mg/kg, except one male receiving 5,000 mg/kg, died before the end of the studies. Rats receiving DMMPA at doses of 1,250 mg/kg or less survived. The final mean body weights of the surviving dosed rats were within +/- 8% of those of the vehicle controls. Compound-related gross lesions were not found at necropsy. Groups of five B6C3F1 mice of each sex were given DMMPA by the same route on the same schedule at 0, 250, 500, 1,000, 2,000, or 4,000 mg/kg. All the mice given DMMPA at 2,000 or 4,000 mg/kg died before the end of the studies. Mice administered DMMPA at doses of 1,000 mg/kg or less survived. The final mean body weight of the male mice given DMMPA at 1,000 mg/kg was 14% greater than that of the vehicle controls, whereas that of the other dosed survivors was within 10% of that of the vehicle controls. Compound-related gross lesions were not found at necropsy. In the 13-week studies, groups of 10 male and 10 female F344/N rats and B6C3F1 mice were given DMMPA by gavage in corn oil at 0, 200, 400, 1,200, or 1,600 mg/kg body weight, 5 days per week for 13 weeks. All rats given DMMPA at 400 mg/kg or less survived, and no more than 3/10 died in any of the higher dose groups. The final mean body weights of the dosed male rats were 6% to 11% greater than that of the vehicle controls; weights of the dosed female rats were similar to that of the vehicle controls (-6% to 1%). There was a dose-related increase in liver weight/body weight ratio. All the mice given DMMPA at 1,600 mg/kg, except one female, died before the end of the 13-week studies; mice receiving DMMPA at 1,200 mg/kg or less survived. The final mean body weights of the dosed male mice were 3.4% to 6.9% greater than that of the vehicle controls. The final mean body weights of dosed female mice and vehicle controls were similar. Compound-related gross or histopathologic changes were not observed in rats or mice. In the 2-year toxicology and carcinogenesis studies, groups of 50 male and 50 female F344/N rats were given DMMPA in corn oil by gavage at doses of 0, 150, 300, or 600 mg/kg body weight, 5 days per week for 103 weeks. Groups of 50 male B6C3F1 mice were given DMMPA at 0, 150, 300 mg/kg body weight, and groups of 50 female B6C3F1 mice were given DMMPA at 0, 300, 600 mg/kg body weight on the same schedule. Doses of 300 or 600 mg/kg were originally selected for male mice for the 2-year study; because 19/50 high dose male mice died by week 19, all male mice were killed and doses of 0, 150, and 300 mg/kg were selected for the restart of the 2-year study in male mice. The survival of high dose male (22/50) and female (24/50) rats was reduced (P<0.025) relative to that of the male (37/50) and female (36/50) vehicle controls. Mean body weights were less than 10% lower in the mid dose and high dose male rats and in the high dose female rats than in the vehicle controls. DMMPA administration did not significantly affect body weight gain or survival of male and female mice. At the 600 mg/kg dose, increased (P<0.05) incidences of mononuclear cell leukemia occurred in both male rats (vehicle control, 14/50; 150 mg/kg, 21/50; 300 mg/kg, 19/50; 600 mg/kg, 25/50) and female rats (9/50; 13/50; 12/49; 18/50). DMMPA-related neoplastic or nonneoplastic lesions were not observed in the dosed mice. DMMPA was not mutagenic in strains TA100, TA1535ns were not observed in the dosed mice. DMMPA was not mutagenic in strains TA100, TA1535, TA1537, or TA98 of Salmonella typhimurium in the presence or absence of Aroclor 1254-induced male Sprague-Dawley rat or male Syrian hamster liver S9. DMMPA was mutagenic in the L5178Y/TK± mouse lymphoma assay in the absence of S9; it was not tested in the presence of S9. DMMPA induced chromosomal aberrations and sister-chromatid exchanges in Chinese hamster ovary cells in the absence of S9, but cytogenetic effects were not observed in the presence of Aroclor 1254-induced rat liver S9. An audit of the experimental data for these 2-year carcinogenesis studies on DMMPA was conducted. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenicity for male and female F344/N rats given dimethyl morpholinophosphoramidate, as indicated by increased incidences of mononuclear cell leukemia. There was no evidence of carcinogenicity for male and female B6C3F1 mice given dimethyl morpholinophosphoramidate at doses of 150 (male), 300, or 600 (female) mg/kg for 2 years. Synonyms: dimethyl morpholinophosphonate; phosphonic acid, morpholino, dimethyl ester; DMMPA; phosphonic acid, 4-morpholinyl-, dimethyl ester

Journal Article↗

PubMed1987

NTP Toxicology and Carcinogenesis Studies of Tetrakis(hydroxymethyl)phosphonium sulfate (THPS) (CAS No. 55566-30-8) and Tetrakis(hydroxymethyl)phosphonium chloride (THPC) (CAS No. 124-64-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Toxicology and carcinogenesis studies of tetrakis(hydroxymethyl)phosphonium sulfate (THPS) and tetrakis(hydroxymethyl)phosphonium chloride (THPC) were conducted because of the widespread use of these chemicals as flame retardants in cotton fabrics. THPS was available as a 72% aqueous solution and THPC as a 75% aqueous solution. Short-term gavage studies with a range of doses were conducted first to identify toxic effects and affected sites and to determine doses for the 2-year studies. The doses selected for the 14-day studies ranged from 12.5 to 200 mg/kg THPS for rats and mice, 9.4 to 150 mg/kg THPC for rats, and 18.8 to 300 mg/kg THPC for mice. Mortality and reduction in body weight gain occurred at the two highest doses in the 14-day studies. There was hind limb paralysis in some rats and mice dosed at the highest concentrations of THPS and THPC. In the 13-week studies, doses of THPS ranged from 5 to 60 mg/kg in rats and from 2 to 180 mg/kg in mice; doses of THPC ranged from 3.75 to 60 mg/kg in rats and from 1.5 to 135 mg/kg in mice. Mortality and reduction in body weight gain occurred at the two higher doses for both sexes and species. Vascular degeneration of hepatocytes or hepatocellular necrosis was a common histopathologic finding. Hind limb paralysis was noted in rats and mice receiving the highest dose of THPC, and axonal degeneration, characterized by swollen axon sheaths, missing or fragmented axons, and some proliferation of neurolemma cells, was observed in rats. These lesions were found in the sciatic nerve, dorsal roots of the caudal spinal nerves, and the tracts of the spinal cord, particularly in the dorsal column of the lumbar cord. Two-year studies were conducted in F344/N rats by administering 0, 5, or 10 mg/kg THPS or 0, 3.75, or 7.5 mg/kg THPC in deionized water by gavage to groups of 49 or 50 animals of each sex, 5 days per week for 103 or 104 weeks. Groups of 49 or 50 B6C3F1 mice were administered 0, 5, or 10 mg/kg THPS (each sex), 0, 7.5, or 15 mg/kg THPC (males), or 0, 15, or 30 mg/kg THPC (females). Survival of male rats was reduced for the low dose (after week 102) and the high dose (after week 67) groups given THPS compared with that of the vehicle controls; survival at terminal kill was as follows: vehicle control, 28/50; low dose, 13/50; high dose, 16/50. Survival of the high dose group of female rats given THPC was lower after week 70 than that of the vehicle controls (survival at terminal kill: 37/50; 34/50; 21/50). Mean body weights of rats dosed with THPS or THPC were comparable to those of the vehicle controls. There was no difference in survival or mean body weights between the vehicle controls and mice dosed with either THPS or THPC. No neurotoxicity or any other signs of clinical toxicity were observed. A nonneoplastic effect common to 13-week and 2-year exposure to THPS or THPC was an increase in the incidence of hepatocellular lesions, primarily cytoplasmic vacuolization. The incidences of this lesion in the two-year studies were dose related for all studies except for the mice receiving THPS. Other lesions observed included focal hyperplasia of the adrenal medulla in high dose male mice given THPS and follicular cell hyperplasia of the thyroid gland in high dose female mice given THPC. The increased incidences of hematopoietic system lesions observed in these studies were not considered biologically related to chemical exposure because the increases were marginal, no dose-response relationship was observed, and the incidences of these lesions are highly variable in untreated rats and mice. The incidences of mononuclear cell leukemia in low dose male rats administered THPS or THPC were somewhat greater than those in the vehicle controls (THPS: 30/50; 36/50; 20/50; THPC: 19/50; 25/50; 16/50). Low dose male mice administered THPS had an increased incidence of malignant lymphomas when compared with vehicle controls (2/50; 9/50; 0/50). These marginal increases in the incidences of hematopoietic system tumors were not considered related to chemical exposure, since they were signific were significant only by the life table tests and were not dose related. THPC demonstrated no mutagenic activity in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without metabolic activation. Both THPS and THPC induced forward mutations in mouse lymphoma L5178Y cells without metabolic activation; neither was tested in the presence of S9. THPC increased the frequency of sister-chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells in the presence and absence of exogenous metabolic activation. An audit of the experimental data was conducted for the 2-year studies of THPS and THPC. No discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenicity of THPS in either sex of F344/N rats or B6C3F1 mice given 5 or 10 mg/kg. There was no evidence of carcinogenicity of THPC in either sex of F344/N rats given 3.75 or 7.5 mg/kg, in male B6C3F1 mice given 7.5 or 15 mg/kg, or in female B6C3F1 mice given 15 or 30 mg/kg.

Journal Article↗

PubMed1986

NTP Toxicology and Carcinogenesis Studies of Chlorinated Trisodium Phosphate (CAS No. 56802-99-4)* in B6C3F1 Mice (Gavage Studies).

Two-year toxicology and carcinogenesis studies of chlorinated trisodium phosphate, an inclusion complex of trisodium phosphate and sodium hypochlorite used in various cleaning compounds, were conducted by administering 0, 500, or 1,000 mg/kg (dose volume: 10 ml/kg) of the chemical in water by gavage, 5 days per week for 103 weeks, to groups of 50 male and 50 female B6C3F1 mice. Groups of mice receiving 250 mg/kg were included in these studies but were removed after 6 months because of a lack of toxicity in the 500 and 1,000 mg/kg groups. Two-year studies were begun in male and female F344/N rats at doses of 0, 500, 1,000, or 2,000 mg/kg of chlorinated trisodium phosphate in water by gavage (10 ml/kg). The 2,000 mg/kg groups were killed at 15 weeks because of poor survival, and the other groups were killed at 35 weeks because of toxicity in the 1,000 mg/kg group. The doses selected for the 2-year studies were based on the general lack of adverse effects seen in the 14-day and 13-week studies in which rats received 0-1,000 mg/kg and mice received 0-2,000 mg/kg by gavage in water. No compound-related histopathologic effects were observed in the 14-day or the 13-week studies in mice. In the 2-year studies, survival and mean body weights of dosed and vehicle control male mice groups were comparable (survival-- vehicle control, 39/50; low dose, 35/50; high dose, 32/50). Survival of the dosed female mice was lower than that of the vehicle controls (30/50; 16/50; 21/50), although at week 80 survival of female mice was 42/50, 39/50, and 36/50. The mean body weights of the high dose female mice were lower than those of the vehicle control mice, primarily after week 32; final body weights were 11% lower in the high dose group compared with that in the vehicle controls. The lower survival and mean body weights of the dosed female mice may have been due to a greater incidence of uterine/ovarian infections in these mice rather than to a direct toxic effect of chlorinated trisodium phosphate. Nine of 20 vehicle control, 20/34 low dose, and 21/29 high dose female mice that died before the end of the studies had such infections. This reduced survival decreased the sensitivity of the study of female mice for detecting the presence or absence of carcinogenic effects. At no site was the incidence of neoplasms considered to be related to the administration of chlorinated trisodium phosphate. Minimal necrosis and fatty changes were observed in the livers of male mice. Kidneys in male mice were characterized by small, multifocal areas of mineralization, primarily in the cortex but not at the corticomedullary junction or in the tubes of the medulla. Neither effect was considered compound related. Five different types of ovarian neoplasms were found in six dosed female mice; because these lesions were from tissues of different embryonic origin, they were considered unrelated to administration of chlorinated trisodium phosphate. Chlorinated trisodium phosphate was weakly mutagenic in strain TA1535 of Salmonella typhimurium in the presence of Aroclor 1254-induced male Sprague-Dawley rat or male Syrian hamster liver S9. This compound was not mutagenic in strains TA97, TA98, or TA100. An audit of the experimental data was conducted for these 2-year studies of chlorinated trisodium phosphate. No data discrepancies were found that influenced the final interpretation of these experiments. Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenicity for either male or female B6C3F1 mice given chlorinated trisodium phosphate by gavage in water for 103 weeks at doses of 500 or 1,000 mg. Survival of dosed female mice was 78% and 72% after 80 weeks and 32% and 42% at the termination of the study. The studies in male and female F344/N rats were considered to be inadequate studies of carcinogenicity because the experiments were terminated at 35 weeks due to poor survival. Synonym: sodium hypochlorite phosphate

Journal Article↗

PubMed1985

NTP Toxicology and Carcinogenesis Studies of HC Blue No. 2 [2,2'-((4-((2-Hydroxyethyl)amino)-3-nitrophenyl)imino)bis(ethanol)] (CAS No. 33229-34-4) in F344/N Rats and B6C3F 1 Mice (Feed Studies).

Toxicology and carcinogenesis studies of HC Blue No. 2 (approximately 98% pure), a semipermanent hair dye, were conducted by administering the test chemical in feed for 103 weeks to groups of 50 F344/N rats of each sex and for 104 weeks to groups of 50 B6C3F 1 mice of each sex. The dietary concentrations used were 0, 5,000, or 10,000 ppm for male rats and male mice and 0, 10,000, or 20,000 ppm for female rats and female mice. These concentrations were selected on the basis of results from single-administration gavage and 14-day and 13-week feed studies. For the 2-year studies, the average daily doses were approximately 195 and 390 mg/kg in male rats, 465 and 1,000 mg/kg in female rats, 1,320 and 2,240 mg/kg in male mice, and 2,330 and 5,600 mg/kg in female mice. The survival of high dose male rats and male mice was better than that for controls, and the survival of dosed female rats was comparable to that of the controls. The survival of high dose female mice was reduced (P<0.05) relative to that of controls (control, 35/50; low dose, 27/50; high dose 19/50); this reduced survival was attributed to a reproductive tract infection. Final mean body weights relative to those of controls were depressed less than 10% in dosed male rats, whereas depressions of 13% and 22% were observed in the low dose and high dose groups of female rats. Final mean body weights for dosed male mice were within 5% of control values, but final mean body weights for dosed females were 15% (low dose) and 22% (high dose) lower than that of controls. A dose-related increase in the incidence of hyperostosis of the skull was detected in rats (male, 5/50, 8/50, 25/49; female, 2/50, 19/50, 49/50) and in 1/49 high dose male and 4/50 high dose female mice. Mixed mesenchymal neoplasms of the kidney were detected in 2/50 high dose female rats; none was observed in any other group of female or male rats. This tumor is considered uncommon and has not been found in 1,863 historical control female F344/N rats. A negative trend in fibroadenomas of the mammary gland was seen in female rats (20/50, 10/50, 4/50). A marginal (P=0.05) positive trend occurred in the incidence of lymphomas in male mice (1/50; 5/48; 8/49); the incidences in the dosed groups were not significantly greater than that in the controls when survival differences were taken into account. HC Blue No. 2 was mutagenic for strains TA97 and TA98 but not for strains TA100 or TA1535 of Salmonella typhimurium in the presence or absence of Aroclor 1254-induced male Sprague-Dawley rat or Syrian hamster liver S9. HC Blue No. 2 was mutagenic in the mouse lymphoma L5178Y/TK+/- assay in the presence of Aroclor 1254-induced male F344/N rat liver S9. An audit of the experimental data was conducted for these carcinogenic studies on HC Blue No. 2. No data discrepancies were found that influenced the final interpretations. Under the conditions of these studies, there was no evidence of carcinogenicity in male and female F344/N rats or in male and female B6C3F 1 mice receiving HC Blue No. 2 in the diet at concentrations of 0.5% and 1.0% for males and 1.0% and 2.0% for females for 2 years. HC Blue No. 2 administration caused a dose-related increase in the incidence of hyperostosis of the skull in male and female rats. Synonym: 2,2'-((4-((-hydroxyethyl)amino)-3-nitrophenyl)imino)bis(ethanol)

Journal Article↗

PubMed1986

NTP Toxicology and Carcinogenesis Studies of Isophorone (CAS No. 78-59-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Toxicology and carcinogenesis studies of isophorone (greater than 94% pure), a widely used solvent and chemical intermediate, were conducted by administering 0, 250, or 500 mg isophorone/kg body weight per day by gavage in corn oil to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex, 5 days per week for 103 weeks. Doses selected for the 2-year studies were based on the 16-day studies in which rats and mice of each sex received doses of 0-2,000 mg/kg per day and on 13-week studies in which rats and mice of each sex received doses ranging from 0 to 1,000 mg/kg per day by gavage in corn oil. No chemically related gross or histopathologic effects were observed in the 16-day or 13-week studies, but 1/5 high dose male rats, 4/5 high dose female rats, and all high dose male and female mice died during the 16-day studies. During the 13-week studies, 1/10 high dose female rats and 3/10 high dose female mice died. The high dose for the 2-year studies was set at 500 mg/kg per day for each sex of rats and mice, based mainly on the deaths in the 13-week studies. Throughout the 2-year study, the mean body weights of the high dose male rats averaged 5% lower than those of the vehicle controls. During the second year, the mean body weights of the female high dose rats averaged 8% lower than those of the vehicle controls, and the high dose female mice averaged 5% lower. The survival of high dose male rats was significantly lower than that of the vehicle controls after week 96 (final survival: vehicle control, 33/50; low dose, 33/50; high dose, 14/50). The survival of dosed female rats was poor (30/50; 23/50; 20/50), due in part to 20 gavage-related accidental deaths of dosed animals. The survival of male mice was also low (16/50; 16/50; 19/50), but there was a significant trend toward increased survival of dosed female mice relative to that of the vehicle controls (26/50; 35/50; 34/50). Dosed male rats showed a variety of proliferative lesions of the kidney (tubular cell hyperplasia: 0/50; 1/50; 4/50; tubular cell adenoma: 0/50; 0/50; 2/50; tubular cell adenocarcinoma: 0/50; 3/50; 1/50; epithelial hyperplasia of the renal pelvis: 0/50; 5/50; 5/50). Dosed male rats also exhibited increased mineralization of the medullary collecting ducts (1/50; 31/50; 20/50), and low dose male rats showed a more severe nephropathy than is commonly seen in aging F344/N rats. Carcinomas of the preputial gland were increased in high dose male rats (0/50; 5/50; 5/50). With the exception of a moderate increase in nephropathy (21/50; 39/50; 32/50), female rats did not show chemically related increased incidences of neoplastic or nonneoplastic lesions. In high dose male mice, isophorone exposure was associated with increased incidences of hepatocellular adenomas and carcinomas (18/48; 18/50; 29/50) and of mesenchymal tumors of the integumentary system (fibroma, fibrosarcoma, neurofibrosarcoma, or sarcoma: 6/48; 8/50; 14/50). An increased incidence of lymphomas or leukemias was noted in low dose male mice (8/48; 18/50; 5/50). Coagulative necrosis (3/48; 10/50; 11/50) and hepatocytomegaly (23/48; 39/50; 37/50) were observed more frequently in the livers of dosed male mice than in vehicle controls. No compound-related neoplastic or nonneoplastic lesions associated with isophorone exposure were seen in female mice. Isophorone was not mutagenic in strains TA100, TA1535, TA1537, or TA98 of Salmonella typhimurium in the presence or absence of Aroclor 1254-induced male Sprague-Dawley rat or male Syrian hamster liver S9. Isophorone was weakly mutagenic in the mouse L5178Y/TK+/- assay in the absence of S9; it was not tested in the presence of S9. Isophorone induced sister-chromatid exchanges in the absence of S9 in Chinese hamster ovary cells; it did not induce sister-chromatid exchanges in the presence of Aroclor 1254-induced male rat liver S9, and it did not induce chromosomal aberrations in Chinese hamster ovary cells in the presence or absence of S9. An audit of the experimental data was conducted for the 2-year toxicology and carcinogenesis studies of isophorcarcinogenesis studies of isophorone. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenicity of isophorone in male F344/N rats as shown by the occurrence of renal tubular cell adenomas and adenocarcinomas in animals given 250 or 500 mg/kg per day; carcinomas of the preputial gland were also observed at increased incidence in male rats given 500 mg/kg. There was no evidence of carcinogenicity in female F344/N rats given 250 or 500 mg/kg per day. For male B6C3F1 mice, there was equivocal evidence of carcinogenicity of isophorone as shown by an increased incidence of hepatocellular adenomas or carcinomas (combined) and of mesenchymal tumors in the integumentary system in animals given 500 mg/kg per day and by an increase in malignant lymphomas in animals given 250 mg/kg per day. There was no evidence of carcinogenicity of isophorone in female B6C3F1 mice given 250 or 500 mg/kg per day. Synonym: 3,5,5-trimethyl-2-cyclohexen-1-one

Journal Article↗

PubMed1984

NTP Toxicology and Carcinogenesis Studies of 1,3-Butadiene (CAS No. 106-99-0) in B6C3F1 Mice (Inhalation Studies).

1,3-Butadiene is used as an intermediate in the production of elastomers, polymers, and other chemicals. Of the 1,3-butadiene used in 1978, 44% was used to manufacture styrene-butadiene rubber (a substitute for natural rubber, produced by copolymerization of 1,3-butadiene with styrene), and 19% was used to produce polybutane elastomer (a substance that increases resistance of tire products to wear, heat degradation, and blowouts). Chloroprene monomer, derived from 1,3-butadiene, is used exclusively to manufacture neoprene elastomers for non-tire and latex applications. Commercial nitrile rubber, used largely in rubber hoses, seals, and gaskets for automobiles, is a copolymer of 1,3-butadiene and acrylonitrile. Acrylonitrile- butadiene- styrene resins, usually containing 20%-30% 1,3-butadiene by weight, are used to make parts for automobiles and appliances. Other polymer uses include specialty polybutadiene polymers, thermoplastic elastomers, nitrile barrier resins, and K resins(R). 1,3-Butadiene is used as an intermediate in the production of a variety of industrial chemicals, including two fungicides, captan and captofol. It is approved by the U.S. Food and Drug Administration for use in the production of adhesives used in articles for packaging, transporting, or holding food; in components of paper and paperboard that are in contact with dry food; and as a modifier in the production of semigrid and rigid vinyl chloride plastic food-contact articles. No information was located on the levels of monomer or on its elution rate from any of the commercially available polymers. It is not known if unreacted 1,3-butadiene migrated from packaging materials. Male and female B6C3F1 mice were exposed to air containing 1,3-butadiene (greater than 99% pure) at concentrations of 0-8,000 ppm in 15-day and 14-week inhalation studies. In the 15-day studies, survival was unaffected by dose, and no pathologic effects were observed; slight decreases in mean body weight occurred at the high concentrations. In the 14-week studies, mean body weight gain decreased with dose, and survival in the 5,000-ppm and 8,000-ppm groups of males was markedly reduced; no other compound-related effects were reported. Inhalation carcinogenesis studies of 1,3-butadiene were conducted by exposing groups of 50 male and female B6C3F1 mice 6 hours per day for 5 days per week to air containing the test chemical at concentrations of 0 (chamber controls), 625, or 1,250 ppm. These studies were planned for 103-week exposures but were terminated at week 60 for male mice and week 61 for female mice because of the rapidly declining survival, primarily due to neoplasia. Body weights were not affected by 1,3-butadiene. Significantly increased incidences of neoplasms at multiple sites were observed in mice exposed to 1,3-butadiene. Hemangiosarcomas of the heart occurred at increased incidences in exposed males and females (male: control, 0/50; low dose, 16/49; high dose, 7/49; female: 0/50; 11/48; 18/49). Hemangiosarcomas were also observed in the peritoneal cavity (one high dose male), subcutaneous tissue (two low dose females), and liver (one high dose female). Malignant lymphomas, diagnosed as early as week 20, were observed at increased incidences in exposed male and female mice (male: 0/50; 23/50; 29/50; female: 1/50; 10/49; 10/49). Alveolar/bronchiolar adenomas and alveolar/bronchiolar (both separately and combined) occurred at increased incidences in exposed male and female mice (combined incidences -- male: 2/50; 14/49; 15/49; female: 3/49; 12/48; 23/49). Epithelial hyperplasia of the forestomach occurred at increased incidences in dosed mice (male: 0/49; 5/40; 7/44; female: 0/49; 5/42; 9/49). Papillomas of the forestomach occurred in low dose male and in low dose and high dose female mice (male: 0/49; 5/40; 0/44; female: 0/49; 4/42; 10/49). Squamous cell carcinomas of the forestomach were observed in dosed mice (male: 0/49, 2/40, 1/44; female: 0/49, 1/42, 1/49). Acinar cell carcinomas of the mammary gland were observed at an increased incidence in high dose female reased incidence in high dose female mice (0/50; 2/49; 6/49); adenosquamous carcinomas were found in four low dose females. The incidences of granulosa cell tumors of the ovary were increased in dosed females (0/49; 6/45; 12/48). A granulosa cell carcinoma was observed in another high dose female. Gliomas were observed in two 68- to 69-week-old low dose and one high dose male mice; brain tumors are uncommon even in 2-year old mice. Liver necrosis occurred at increased incidences in dosed male and low dose female mice (male; 1/50, 8/49, 8/49; female: 6/50, 15/47, 6/49). Hepatocellular adenomas or carcinomas (combined) were observed at an increased incidence in high dose female mice (0/50, 2/47 5/49). No neoplastic lesions of the nasal cavity were observed at any dose level. The following nonneoplastic lesions of the nasal cavity occurred in mice exposed at 1,250 ppm: chronic inflammation (male, 35/50; female, 2/49); fibrosis (male, 33/50; female, 2/49); cartilaginous metaplasia (male, 16/50; female, 1/49); osseous metaplasia (male, 11/50; female, 2/49); and atrophy of the sensory epithelium (male, 32/50). No nonneoplastic lesions of the nasal cavity were found in the controls. The incidence of testicular atrophy (0/50, 19/49, 11/48) or ovarian atrophy (2/49, 40/45, 40/48) was increased in exposed male or female mice. An audit of the experimental data from these studies on 1,3-butadiene was conducted by the National Toxicology Program. No data discrepancies were found that influenced the final interpretation of these experiments. Under the conditions of these studies, there was clear evidence of carcinogenicity for 1,3-butadiene in male and female B6C3F1 mice, as shown by increased incidences and early induction of hemangiosarcomas of the heart, malignant lymphomas, alveolar/bronchiolar adenomas and carcinomas, and papillomas of the stomach in males and females; and of acinar cell carcinomas of the mammary gland, granulosa cell tumors of the ovary, and hepatocellular adenomas and adenomas or carcinomas (combined) in females. 1,3-Butadiene was associated with nonneoplastic lesions in the respiratory epithelium, liver necrosis, and testicular or ovarian atrophy. Synonyms: butadiene; biethylene; bivinyl; divinyl; erythrene; vinylethylene; pyrrolylene

Journal Article↗