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National Toxicology Program

Publications and source records attributed to National Toxicology Program.

At least 343 records · Page 19Linked to original sources
PubMed1993

NTP Toxicology and Carcinogenesis Studies of Acetaminophen (CAS No. 103-90-2) in F344 Rats and B6C3F1 Mice (Feed Studies).

Acetaminophen is a widely consumed analgesic found in several nonprescription pharmaceuticals. Toxicology and carcinogenesis studies were conducted by administering acetaminophen (purity >99%) in feed to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary cells. 14-DAY STUDIES: Rats were fed diets containing 0, 800, 1,600, 3,100, 6,200, or 12,500 ppm acetaminophen, and mice were fed diets containing 0, 250, 500, 1,000, 2,000, or 4,000 ppm acetaminophen. There were no deaths among any groups during the study; the final mean body weight of male rats that received 12,500 ppm was significantly lower than that of the controls. Final mean body weights of male and female mice and female rats that received acetaminophen were similar to those of the controls. Feed consumption by male and female rats that received 12,500 ppm acetaminophen was lower than that of the controls; feed consumption by all other exposed groups was higher than that of the controls. 13-WEEK STUDIES: Rats and mice were fed diets containing 0, 800, 1,600, 3,200, 6,200, 12,500, or 25,000 ppm acetaminophen. Two male and two female rats, and one male and one female mouse that received 25,000 ppm, and two male mice that received 12,500 ppm died from acetaminophen-related toxicity before the end of the studies. Final mean body weights of male and female rats and mice that received 12,500 or 25,000 ppm were lower than those of the controls. The patterns of feed consumption and reduced body weights that occurred among rats and mice that received diets containing 12,500 or 25,000 ppm were indicative of poor feed palatability. Acetaminophen-related lesions were observed in the liver (necrosis, chronic active inflammation, hepatocytomegaly), kidney (tubule cast, tubule necrosis, tubule regeneration), reproductive organs (atrophy of testis, ovary, and uterus), thymus and lymph nodes (lymphoid depletion) of rats that received 25,000 ppm, and of the live (chronic active inflammation, hepatocytomegaly) and testis (atrophy) of male rats receiving 12,500 ppm. Compound-related lesions in mice were found in the liver (hepatocytomegaly, focal calcification, pigmentation, necrosis) of males that received 6,200, 12,500, or 25,000 ppm and females that received 12,000 or 25,000 ppm. Dose selection for the 2-year studies was based on reduced body weights and the liver lesions observed in rats and mice at 12,500 and 25,000 ppm. 2-YEAR STUDIES: Diets containing 0, 600, 3,000, or 6,000 ppm acetaminophen were given continuously to groups of 60 rats and mice of each sex for up to 104 weeks. After 65 weeks of exposure, 10 animals from each group were evaluated for histopathology and for hematology, urinalysis, and clinical chemistry parameters. Survival and mean body weights of rats that received acetaminophen were similar to those of the controls throughout the study. The average severity of nephropathy was increased in exposed male and female rats. In males this was associated with an increased incidence of parathyroid hyperplasia (renal hyperparathyroidism). The incidence of focal renal tubule hyperplasia was also increased in exposed male rats. The incidence of mononuclear cell leukemia was increased in exposed female rats and was significantly increased in the 6,000 ppm group (9/50; 17/50; 15/50; 24/50). Survival of exposed and control mice was similar throughout the study. Mean body weights of mice that received acetaminophen were generally lower than those of the controls throughout the study. Although the incidence of thyroid follicular cell hyperplasia increased with dose among groups of exposed male and female mice, there was no increase in the incidence of follicular cell neoplasms. Renal tubule hyperplasia occurred in one low-dose and two high-dose males and a renal tubule adenoma was present in one low-dose and one high-dose male. GENETIC TOXICOLOGY: Acetaminophen was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98 witr TA98 with or without S9. In cytogenetic tests with Chinese hamster ovary cells, acetaminophen induced sister chromatid exchanges and chromosomal aberrations in both the presence and absence of S9. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of acetaminophen in male F344/N rats that received 600, 3,000, or 6,000 ppm. There was equivocal evidence of carcinogenic activity of acetaminophen in female F344/N rats based on increased incidences of mononuclear cell leukemia. There was no evidence of carcinogenic activity of acetaminophen in male and female B6C3F1 mice that received 600, 3,000, or 6,000 ppm. Nonneoplastic lesions associated with exposure to acetaminophen included increased severity of nephropathy and increased incidences of renal tubule hyperplasia and parathyroid hyperplasia in male rats, increased severity of nephropathy in female rats, and increased incidences of thyroid follicular cell hyperplasia in male and female mice. Synonyms: 4-Hydroxyacetanilide, N-Acetyl-p-aminophenol, Paracetamol

Journal Article↗
PubMed1993

NTP Toxicology and Carcinogenesis of 1,2,3-Trichloropropane (CAS No. 96-18-4) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

1,2,3-Trichloropropane is a colorless liquid used as a paint and varnish remover, solvent, and degreasing agent, and as a crosslinking agent in the synthesis of polysulfides and hexafluoropropylene. 1,2,3-Trichloropropane may be found as an impurity in certain nematocides and soil fumigants and as a contaminant of drinking and ground water. Studies on the toxic and carcinogenic effects of 1,2,3-trichloropropane were initiated because of the close structural relationship of this chemical to other short-chain halogenated compounds that were demonstrated to be carcinogenic in experimental animals, and because of the potential for human exposure. Toxicology and carcinogenicity studies were conducted by administering 1,2,3-trichloropropane (greater than 99% pure) in corn oil by gavage to groups of F344/N rats and B6C3FI mice for 17 weeks and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium strains, mouse lymphoma cells, and Chinese hamster ovary cells. 17-Week Studies: Groups of 20 male and 20 female rats received 1,2,3-trichloropropane in corn oil by gavage at doses of 8, 16, 32, 63, 125, or 250 mg/kg body weight 5 days per week for up to 17 weeks; 30 male and 30 female rats received corn oil alone and served as controls. Animals were evaluated at 8 or 17 weeks. All rats in the 250 mg/kg groups died by week 5. One male and four female rats in the 125 mg/kg groups died during the study. The mean body weight gains and final mean body weights of males receiving 63 mg/kg and of males and females receiving 125 mg/kg were lower than those of the controls. Hematocrit values, hemoglobin concentrations, and erythrocyte counts decreased with dose in males and females. Serum alanine aminotransferase, aspartate aminotransferase, and sorbitol dehydrogenase activities were significantly increased in some female rats receiving 125 mg/kg. Serum pseudocholinesterase activity decreased with dose in females. Increases in kidney and liver weights were related to chemical administration. The principal toxic lesions associated with the administration of 1,2,3-trichloropropane to rats were hepatocellular necrosis, karyomegaly, and biliary hyperplasia of the liver; renal tubule necrosis, regeneration, and karyomegaly of the kidney; and necrosis and inflammation of the nasal olfactory and respiratory epithelium. Groups of 20 male and 20 female mice received 1,2,3-trichloropropane in corn oil by gavage at doses of 8, 16, 32, 63, 125, or 250 mg/kg 5 days per week for up to 17 weeks; 30 male and 30 female mice received corn oil alone and served as controls. Sixteen male and seven female mice in the 250 mg/kg groups died by week 4. The final mean body weights and mean body weight gains of dosed mice were similar to those of the controls, except those of 250 mg/kg males, which were lower than those of controls. The principal toxic lesions associated with the administration of 1,2,3-trichloropropane were hepatocellular necrosis and karyomegaly of the liver; necrosis, regeneration, and hyperplasia of the bronchiolar epithelium in the lung; and acanthosis (hyperplasia) and hyperkeratosis of the forestomach epithelium. 2-Year Studies: Groups of 60 male and 60 female rats received 0, 3, 10, or 30 mg 1,2,3-trichloropropane/kg body weight in corn oil by gavage 5 days per week for up to 104 weeks. Selection of 30 mg/kg as the high dose in these studies was based on the following chemical-related effects in the 17-week studies: deaths and liver and kidney lesions at 125 and 250 mg/kg and reduced final mean body weights and mean body weight gains at 63 mg/kg or greater. Groups of 60 male and 60 female mice received 0, 6, 20, or 60 mg 1,2,3-trichloropropane/kg body weight in corn oil by gavage 5 days per week for up to 104 weeks. Selection of 60 mg/kg as the high dose was based on chemical-related deaths and lesions of the liver, lung, and forestomach at 125 and 250 mg/kg in the 17-week studies. 15-Month Interim Evaluations: Up to 10 rats and 10 mice from each dose group were evaluated at 15 months. Absolute and relative liver and kidned kidney weights of dosed rats were significantly greater than those of the controls. Chemical-related nonneoplastic lesions and neoplasms of the forestomach, oral mucosa, pancreas (males), kidney, mammary gland (females), preputial gland, and clitoral gland were observed in dosed rats. Chemical-related nonneoplastic lesions and neoplasms of the forestomach and liver (females) were observed in dosed mice. Survival and Body Weight in the 2-Year Studies: Survival of male and female rats receiving 10 or 30 mg/kg 1,2,3-trichloropropane was significantly lower than that of controls. Two-year survival rates of male rats were: control, 34/50; 3 mg/kg, 32/50; 10 mg/kg, 14/49; 30 mg/kg, 0/52; and of females were: 31/50, 30/49, 8/52, 0/52. At 30 mg/kg, survival was markedly reduced due to chemical-related neoplasms, and survivors were killed in weeks 67 (females) or 77 (males). Final mean body weights of 30 mg/kg rats were 13% lower for males and 12% lower for females than those of controls; mean body weights of 3 and 10 mg/kg rats were similar to controls. Survival rates of mice receiving 6, 20, or 60 mg/kg 1,2,3-trichloropropane were also significantly lower than those of controls. Two-year survival rates of male mice were: 42/52, 18/51, 0/54, 0/56; and of female mice were: 41/50, 13/50, 0/51, 0/55. Because of reduced survival at 20 and 60 mg/kg due to chemical-related neoplasms, survivors were killed in weeks 73 (60 mg/kg females), 79 (60 mg/kg males), or 89 (20 mg/kg males and females). Final mean body weights were 16% lower for 60 mg/kg males, 18~ lower for 60 mg/kg females, and 13% lower for 20 mg/kg males than those of controls. Final mean body weights of 6 mg/kg males and females and 20 mg/kg females were similar to controls. Neoplasms and Nonneoplastic Lesions in the 2-Year Studies: Administration of 1,2,3-trichloropropane to rats induced benign and malignant neoplasms of the oral mucosa (pharynx and tongue), forestomach, and preputial and clitoral glands in males and females; benign neoplasms of the exocrine pancreas and kidney in males, and malignant neoplasms of the mammary gland in females. The incidences of squamous cell papillomas and carcinomas of the oral mucosa were significantly increased in 10 and 30 mg/kg rats, while the incidences of squamous cell papillomas or carcinomas (combined) of the forestomach were significantly increased in all dosed groups. The incidence of pancreatic acinar adenoma was significantly increased in dosed males, but not in dosed females. Similarly, the incidence of adenoma of the kidney was significantly increased in 10 and 30 mg/kg male rats only. The incidences of adenoma or carcinoma (combined) of the preputial gland in 30 mg/kg males and of the clitoral gland in 10 and 30 mg/kg females (homologous organs) were significantly increased. The incidence of adenocarcinoma of the mammary gland was significantly increased in the 10 and 30 mg/kg females. The incidences of Zymbal's gland carcinomas were increased in 30 mg/kg males and females. Adenocarcinomas of the intestine occurred in small numbers of dosed rats and may have been chemical related. In mice, the incidence of squamous cell carcinoma of the oral mucosa was significantly increased only in 60 mg/kg females. In contrast, the incidences of squamous cell papilloma and carcinoma of the forestomach were significantly increased in all groups of dosed mice. The incidences of hepatocellular adenoma or carcinoma (combined) were significantly increased in all dosed groups of males and 60 mg/kg females. The incidences of harderian gland adenoma were significantly increased in 20 mg/kg males and in 60 mg/kg males and females. The incidences of uterine adenoma, adenocarcinoma, and stromal polyp were significantly increased in 60 mg/kg females. Genetic Toxicology: 1,2,3-Trichloropropane was mutagenic in vitro in the presence of S9 metabolic activation. At two laboratories, positive responses were obtained for mutagenicity in Salmonella typhimurium strains TA97, TA98, TA100, and TA1535 in the presence of S9; no mutagenic activity was observed in TA1537, with or without S9. 1,2,3-Trichloropropane induced trifluorothymidine resistance in L5178Y mouse lymphoma cells with, but not without, S9. In cultured Chinese hamster ovary cells, sister chromatid exchanges and chromosomal aberrations were induced by 1,2,3-trichloropropane; however, significant increases in the endpoints of both cytogenetic effects occurred only in the presence of S9. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of 1,2,3-trichloropropane in male F344/N rats based on increased incidences of squamous cell papillomas and carcinomas of the oral mucosa and forestomach, adenomas of the pancreas and kidney, adenomas or carcinomas of the preputial gland, and carcinomas of the Zymbal's gland. Adenomatous polyps and adenocarcinomas of the intestine may have been related to chemical administration. There was clear evidence of carcinogenic activity of 1,2,3-trichloropropane in female F344/N rats based on increased incidences of squamous cell papillomas and carcinomas of the oral mucosa and forestomach, adenomas or carcinomas of the clitoral gland, adenocarcinomas of the mammary gland, and carcinomas of the Zymbal's gland. Adenocarcinomas of the intestine may have been related to chemical administration. There was clear evidence of carcinogenic activity of 1,2,3-trichloropropane in male B6C3F1 mice based on increased incidences of squamous cell papillomas and carcinomas of the forestomach, hepatocellular adenomas or carcinomas of the liver, and harderian gland adenomas. Squamous cell papillomas of the oral mucosa may have been related to chemical administration. There was clear evidence of carcinogenic activity of 1,2,3-trichloropropane in female B6C3F1, mice based on increased incidences of squamous cell carcinomas of the oral mucosa, squamous cell papillomas and carcinomas of the forestomach, hepatocellular adenomas or carcinomas of the liver, harderian gland adenomas, and uterine adenomas, adenocarcinomas, and stromal polyps. Nonneoplastic lesions associated with exposure to 1,2,3-trichloropropane included increased severity of nephropathy in male rats and increased incidences of basal cell and squamous hyperplasia of the forestomach, acinar hyperplasia of the pancreas, renal tubule hyperplasia, and preputial or clitoral gland hyperplasia in male and female rats. Increased incidences of squamous hyperplasia of the forestomach and eosinophilic foci in the liver in male and female mice were chemical related. Synonyms: Allyl trichloride, glycerol tnchlorohydrin, glyceryl tnchlorohydrin, trichlorohydrin

Journal Article↗
PubMed1992

NTP Toxicology and Carcinogenesis Studies of HC Yellow 4 (CAS No. 59820-43-8) in F344 Rats and B6C3F1 Mice (Feed Studies).

HC Yellow 4 is used in semipermanent hair dyes. Toxicology and carcinogenesis studies were conducted by administering HC Yellow 4 (greater than 93% pure) in feed to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and Drosophila melanogaster. 14-Day Studies: Groups of five rats of each sex were given 0, 5,000, 10,000, 20,000, 40,000, or 80,000 ppm and groups of five mice of each sex were given 0, 1,250, 2,500, 5,000, 10,000, or 20,000 ppm HC Yellow 4 in feed for 14 days. All animals survived to the end of the studies. Final mean body weights of male rats that received 20,000 ppm or more, female rats that received 10,000 ppm or more, and female mice that received 20,000 ppm were significantly lower than those of the controls. The mean body weights of exposed and control groups of male mice were similar. No chemical-related decrease in feed consumption was observed. No chemical-related clinical findings or changes in absolute or relative organ weights occurred in rats or mice. No gross or microscopic changes were related to HC Yellow 4 administration in rats or mice. 13-Week Studies: Groups of 10 rats of each sex were fed diets containing 0, 2,500, 5,000, 10,000, 20,000, or 40,000 ppm and groups of 10 mice of each sex were fed diets containing 0, 5,000, 10,000, 20,000, 40,000, or 80,000 ppm HC Yellow 4 for 13 weeks. All rats survived to study termination. Chemical-related deaths occurred at the two highest dose levels in male and female mice. Final mean body weights of male rats that received 10,000 ppm or greater, female rats that received 20,000 or 40,000 ppm, and mice that received 10,000 ppm or greater were significantly lower than those of the controls. There were no biologically significant changes in absolute or relative organ weights. Mineralization of the renal papilla occurred in all male rats in the 40,000 ppm group. Thyroid pigmentation occurred in rats receiving 40,000 ppm and in mice at all dose levels. Uterine atrophy occurred in female rats in the 20,000 and 40,000 ppm groups and female mice in the 40,000 and 80,000 ppm groups. Lymphoid depletion and atrophy of the spleen occurred in male mice that received 40,000 or 80,000 ppm and female mice that received 80,000 ppm. Atrophy of the thymus occurred in male and female mice that received 40,000 or 80,000 ppm. 2-Year Studies: Groups of 70 male rats were fed diets containing 0, 2,500, or 5,000 ppm and groups of 70 female rats and 70 mice of each sex were fed diets containing 0, 5,000, or 10,000 ppm HC Yellow 4 for up to 2 years. Interim evaluations were performed on 10 rats and 10 mice from each dose group at 6 and 15 months. No biologically significant changes in absolute or relative organ weight or hematology or clinical chemistry values were found in these rats or mice. No compound-related lesions were seen in exposed rats. In exposed mice, pigmentation of the thyroid gland was observed at the 6-month interim evaluations; pigmentation and hyperplasia of the thyroid gland were seen at the 15-month interim evaluations. Body Weight, Survival, and Feed Consumption in the 2-Year Studies: The mean body weight of female rats that received 10,000 ppm was significantly lower than that of the controls. The mean body weights of mice receiving 10,000 ppm were 20% to 30% lower than those of the controls during the second year of the studies. The survival of exposed rats and mice was similar to that of the controls. Neoplasms and Nonneoplastic Lesions in the 2-Year Studies: Pituitary gland pars distalis adenomas were marginally increased in exposed male rats (0 ppm, 17/45; 2,500 ppm, 20/49; 5,000 ppm, 28/49), and there was a concomitant dose-related increase in the incidence of hyperplasia (8/45, 13/49, 18/49). There was no increase in the incidence of pituitary gland adenomas or carcinomas in female rats (34/49, 35/48, 30/49). In mice, no neoplasms were considered related to chemical administration. However, a dose-related incr, a dose-related increased incidence of thyroid gland pigmentation and follicular cell hyperplasia occurred in both sexes of mice. Genetic Toxicology: HC Yellow 4 was mutagenic in Salmonella typhimurium strains TA100, TA1537, and TA98 with and without exogenous metabolic activation (S9); the response in strain TA1535 without S9 was equivocal. HC Yellow 4 induced sister chromatid exchanges in Chinese hamster ovary cells in the absence but not the presence of S9 activation; no induction of chromosomal aberrations occurred in Chinese hamster ovary cells, with or without S9. HC Yellow 4 induced sex-linked recessive lethal mutations in germ cells of adult male Drosophila melanogaster when administered by injection; results of a reciprocal translocation test in D. melanogaster were negative. Conclusions: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity of HC Yellow 4 in male F344/N rats based on the increased incidence of pituitary gland adenomas and hyperplasia. The male rats may have been able to tolerate a slightly higher dose of the chemical. There was no evidence of carcinogenic activity of HC Yellow 4 in female F344/N rats given 5,000 or 10,000 ppm. There was no evidence of carcinogenic activity of HC Yellow 4 in male or female B6C3F1 mice given 5,000 or 10,000 ppm. There was a chemical-related increase in the incidence of thyroid gland pigmentation and follicular cell hyperplasia in mice. Synonym: N,O-di(2-hydroxyethyl)-2-amino-5-nitrophenol

Journal Article↗
PubMed1992

NTP Toxicology and Carcinogenesis Studies of Polysorbate 80 (CAS No. 9005-65-6) in F344/N Rats and B6C3F1 Mice (Feed Studies).

Polysorbate 80 is a nonionic surfactant used widely as an additive in foods, pharmaceutical preparations, and cosmetics as an emulsifier, dispersant, or stabilizer. Toxicity and carcinogenicity studies were conducted by administering polysorbate 80 (which met all compendial specifications) in feed to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium. 14-Day Studies: Groups of five rats and five mice of each sex received diets containing 0, 3,000, 6,000, 12,500, 25,000, or 50,000 ppm polysorbate 80. All animals survived to the end of the studies. The mean body weight change of male rats that received 50,000 ppm was significantly lower than that of the controls. The mean body weight changes in all other groups of dosed rats and in all groups of dosed mice were similar to those of the respective controls. No clinical findings or changes in absolute or relative organ weights in rats or mice were related to polysorbate 80 administration. 13-Week Studies: Groups of 10 rats and 10 mice of each sex received diets containing 0, 3,100, 6,200, 12,500, 25,000, or 50,000 ppm polysorbate 80. All animals survived to the end of the studies. The final mean body weights of dosed rats and mice were similar to those of the controls. No clinical findings, changes in absolute or relative organ weights, or gross or microscopic lesions in rats or mice were related to polysorbate 80 administration. 2-Year Studies: Doses for the 2-year studies were selected based on the lack of observed compound-related effects at the dose levels used in the 13-week studies. Groups of 60 rats and 60 mice of each sex received diets containing 0, 25,000, or 50,000 ppm polysorbate 80 for up to 103 weeks. 15-Month Interim Evaluations: Interim evaluations were performed on 7 to 10 rats and mice from each dose group at 15 months. There were no significant changes in absolute or relative organ weights. Incidences of hyperplasia and inflammation of the forestomach were increased in female mice that received 50,000 ppm. No other chemical-related lesions occurred in rats or male mice evaluated at 15 months. Body Weights, Clinical Findings, and Survival in the 2-Year Studies: The mean body weights in male and female rats and male mice administered polysorbate 80 were similar to those of the controls throughout the studies. The final mean body weight of female mice receiving 50,000 ppm was 11%lower than that of the controls. No clinical findings were associated with administration of polysorbate 80. The survival of dosed male rats was lower than that of the controls (0 ppm, 29/50; 25,000 ppm, 18/50; 50,000 ppm, 18/50); the survival of dosed female rats and male and female mice was similar to that of the respective controls (female rats: 23/50, 25/50, 25/50; male mice: 33/49, 34/50, 32/50; female mice: 30/50, 28/50, 26/50). Neoplasms and Nonneoplastic Lesions in the 2-Year Studies: The incidence of adrenal medulla pheochromocytoma was marginally increased in high-dose male rats (21/50, 19/50, 29/50). The incidence of hyperplasia of the adrenal medulla was increased in low-dose male rats but not in high-dose male rats (11/50, 22/50, 12/50). No chemical-related increases in the incidences of neoplasms occurred in male or female mice. The incidences of squamous hyperplasia and inflammation of the forestomach were significantly increased in high-dose male and female mice; forestomach ulcers were significantly increased in high-dose females. Genetic Toxicology: Polysorbate 80 was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, and TA98 with or without exogenous metabolic activation (S9). Conclusions: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity for polysorbate 80 in male F344/N rats based on an increased incidence of pheochromocytomas of the adrenal medulla. There was no evidence of carcinogenic activity for polysorbate 80 in female F344/N rats or in male or female B6C3F1 mice given 25,000 or 50, or 50,000 ppm. Administration of polysorbate 80 was associated with inflammation and squamous hyperplasia of the forestomach in male and female mice, and with ulcers of the forestomach in female mice. Synonyms: Glycol; sorbitan mono-9-octadecenoate poly(oxy-1,2-ethanediyl) derivatives; polyoxyethylene (20) sorbitan mono-oleate; sorethytan (20) mono-oleate; polyethylene oxide sorbitan mono-oleate Trade names: Alkamuls PSMO-20; Armotan PMO-20; Capmul POE-O; Drewmulse POE-SMO; Emsorb 2722; Glycosperse O-20; Glycosperse O20 Veg; Glycosperse O20X; Hetsorb O20; Industrol O20S; Laxan ESO; Liposorb O-20; Lonzest SMO-20; Montanox 80; Nikkol TO-10;Protasorb O-20; Sorbitan mono-oleate polyoxyethylene; Sorlate; Tween 80; Monitan; Olothorb; Sorbimacrogol Oleate 300; T-Maz 80

Journal Article↗
PubMed1992

Toxicology and Carcinogenesis Studies of g-Butyrolactone (CAS No. 96-48-0) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

g-Butyrolactone is an intermediate in the synthesis of polymers used as film formers in hair sprays, blood plasma extenders, and clarifying agents in beer and wine. Toxicology and carcinogenesis studies were conducted by administering g-butyrolactone (greater than 97% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex, 5 days per week for 16 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Drosophila melanogaster, and Chinese hamster ovary cells. 16-Day Studies: Groups of five rats of each sex received doses of 0, 75, 150, 300, 600, or 1,200 mg of g-butyrolactone per kg of body weight and groups of five mice of each sex received doses of 0, 87, 175, 350, 700, or 1,400 mg/kg. All male and female rats given 1,200 mg/kg and one male rat given 600 mg/kg died within 3 days. The mean body weight gain of female rats given 600 mg/kg was significantly lower than that of the controls. Mean body weight gains of the other female dose groups and all male dose groups were similar to those of the controls. All of the male and four female mice receiving 1,400 mg/kg died during the studies. Mean body weight gains of dosed mice were generally similar to those of the controls. Rats receiving 600 or 1,200 mg/kg and mice receiving 350 mg/kg or more became inactive or recumbent with irregular respiration following dosing. 13-Week Studies: Groups of 10 rats of each sex received doses of 0, 56, 112, 225, 450, or 900 mg of g-butyrolactone per kg of body weight and groups of 10 mice of each sex received doses of 0, 65, 131, 262, 525, or 1,050 mg/kg. One female and all male rats given 900 mg/kg died during the studies. The final mean body weight and mean body weight gain of male rats receiving 450 mg/kg were significantly lower than those of the controls; final mean body weights and body weight gains of all female rat dose groups were similar to those of the controls. There was an increased incidence of focal inflammation of the nasal mucosa in rats administered g-butyrolactone. Three male mice and one female receiving 1,050 mg/kg died from g-butyrolactone toxicity during the studies. The mean body weight gain and final mean body weight of high-dose male mice were lower than those of the controls; the mean body weight gains and final mean body weights of dosed female mice were similar to those of the controls. No lesions related to the administration of g-butyrolactone occurred in mice of either sex. 2-Year Studies: The doses administered to groups of 50 animals per sex were 0, 112, and 225 mg ofg-butyrolactone per kg of body weight for male rats; 0, 225, and 450 mg/kg for female rats; and 0, 262, and 525 mg/kg for male and female mice. Body Weight and Survival in the 2-Year Studies: The mean body weights of male rats administered g-butyrolactone were similar to those of the controls throughout the study. The mean body weight of high-dose females was lower than that of the controls after week 5 and was 10% to 20% lower than that of the controls throughout the second year. The survival of high-dose male rats was slightly higher than that of the controls (control, 24/50; low-dose, 27/50, high-dose, 32/50) due primarily to a lower incidence of mononuclear cell leukemia in the high-dose group (16/50, 15/50, 9/50). The survival of dosed females was similar to that of the controls (28/50, 27/50, 28/50). The mean body weights of dosed male mice were lower than those of the controls throughout the study, but the differences in mean body weights decreased when male mice were housed individually at week 67. The final mean body weights of dosed male mice were 6% lower than that of the controls. Mean body weights of dosed female mice were also lower than those of the controls throughout the study, and the final mean body weights were from 14% to 17% lower than that of the controls. The survival in high-dose male mice was significantly lower than that of the controls (35/50, 30/50, 12/50) due to bite wounds and fighting in high-dose males recovering from the sedative effects of g-becovering from the sedative effects of g-butyrolactone. The survival of female dosed mice was similar to that of the controls (38/50, 34/50, 38/50). Neoplasms and Nonneoplastic Lesions in the 2-Year Studies: No increased incidences of neoplasms or nonneoplastic lesions in male rats were related to the administration of g-butyrolactone for 2 years. In female rats, negative trends were observed in the incidences of cysts (42/50, 35/50, 23/50) and fibroadenomas of the mammary gland (22/50, 14/50, 6/50) and in cysts of the pituitary pars distalis (25/49, 13/37, 11/48). These decreases were considered to be related to g-butyrolactone administration. Increased incidences of proliferative lesions, primarily hyperplasia, of the adrenal medulla in low-dose male mice were associated with g-butyrolactone administration (pheochromocytoma, benign or malignant: 2/48, 6/50, 1/50; hyperplasia: 2/48, 9/50, 4/50). The incidence of hepatocellular neoplasms in both dose groups of male mice was lower than the incidence in the controls (hepatocellular adenoma or carcinoma: 24/50, 8/50, 9/50). Genetic Toxicology: g-Butyrolactone was not mutagenic, with or without exogenous metabolic activation (S9), in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537, nor did it induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster when administered in feed or by injection. Positive results were obtained, however, in cytogenetic tests with Chinese hamster ovary cells; g-butyrolactone induced sister chromatid exchanges and chromosomal aberrations in trials conducted in the presence of S9 activation. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of g-butyrolactone in male F344/N rats given 112 or 225 mg/kg or in female F344/N rats given 225 or 450 mg/kg in corn oil. There was equivocal evidence of carcinogenic activity of g-butyrolactone in male B6C3F1 mice based on marginally increased incidences of adrenal medulla pheochromocytomas and hyperplasia in the low-dose group. The sensitivity of the study in male mice to detect a carcinogenic effect was reduced by the low survival of the high-dose group associated with fighting. There was no evidence of carcinogenic activity of g-butyrolactone in female B6C3F1 mice given 262 or 525 mg/kg in corn oil. A decreased incidence of hepatocellular neoplasms in dosed male mice and decreased incidences of mammary gland fibroadenomas and cysts and pituitary cysts in female rats were associated with the administration of g-butyrolactone. Synonyms: Dihydro-2(3H)-furanone (8CI) (9CI), 1,2-butanolide, butyrolactone, 1,4-butanolide, 4-butyrolactone, 4-hydroxybutanoic acid lactone, g-hydroxybutyric acid cyclic ester, g-hydroxybutyric acid lactone, g-lactone 4-hydroxy-butanoic acid, butyric acid lactone, butyryl lactone, 4-hydroxybutyric acid lactone, tetrahydro-2-furanone, 4-butanolide, 4-deoxytetronic acid, g-hydroxybutyrolactone

Journal Article↗
PubMed1992

Toxicology and Carcinogenesis Studies of Resorcinol (CAS No. 108-46-3) in F344 Rats and B6C3F1 Mice (Gavage Studies).

Resorcinol is used in the manufacture of adhesives and dyes and as an ingredient in pharmaceutical preparations for the topical treatment of skin conditions. Toxicity and carcinogenicity studies were conducted by administering resorcinol (>99% pure) in water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 17 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary cells, mouse lymphoma cells, and Drosophila melanogaster. 17-Day Studies: Groups of five rats of each sex were administered 0, 27.5, 55, 110, 225, or 450 mg/kg resorcinol and groups of five mice of each sex were administered 0, 37.5, 75, 100, 300, or 600 mg/kg resorcinol in deionized water by oral gavage. No rats died during the studies. All female and four male mice receiving 600 mg/kg and one male receiving 300 mg/kg died as a result of resorcinol administration. Final mean body weights of dosed rats and mice were similar to those of the control groups. No gross or microscopic lesions attributable to resorcinol administration were observed. 13-Week Studies: Groups of 10 rats of each sex were administered 0, 32, 65, 130, 260, or 520 mg/kg resorcinol and groups of 10 mice of each sex were administered 0, 28, 56, 112, 225, or 420 mg/kg resorcinol in deionized water by oral gavage. All female and eight male rats receiving 520 mg/kg and eight mice of each sex receiving 420 mg/kg resorcinol died of chemical-related toxicity during the studies. The final mean body weights of dosed rats and mice were similar to those of the control groups. No chemical-related gross or microscopic lesions were observed. 2-Year Studies: Doses were selected for the 2-year studies based on the decreased survival observed in the 13-week studies. Groups of 60 male rats and male and female mice were administered 0, 112, or 225 mg/kg resorcinol in deionized water by gavage, five days per week for up to 104 weeks. Groups of 60 female rats were initially administered the same doses as male rats, but by week 22 of the study 16 of the high-dose females had died. Consequently, the female rat study was restarted using doses of 0, 50, 100, or 150 mg/kg. After 15 months of exposure interim evaluations were performed on 10 animals from each group. No chemical-related changes in clinical pathology parameters or incidence of neoplasms or nonneoplastic lesions were found during the 15-month interim evaluations. Body Weights and Survival in the 2-Year Studies: Mean body weights of high-dose male rats were 10% to 15% lower than those of the controls from week 87 to study termination. Mean body weights of high-dose female rats were 11% to 14% lower than those of controls from week 95 to study termination. Mean body weights of other dosed rat groups were similar to those of controls. Survival of high-dose male and female rats was significantly lower than controls. Decreased survival in high-dose groups was attributed to chemical-related toxicity. Mean body weights of high-dose female mice were 10% to 15% lower than those of controls from week 85 to study termination, whereas those of the remaining dosed mouse groups were similar to those of the controls. Survival of dosed mice was similar to that of controls. Clinical signs suggestive of a chemical-related effect on the central nervous system, including ataxia, recumbency, and tremors, were observed in rats and mice in the 2-year studies. Neoplasms and Nonneoplastic Lesions in the 2-Year Studies: There were no treatment-related increased incidences of neoplasms or nonneoplastic lesions in rats or mice administered resorcinol for 2 years. Mammary gland fibroadenomas occurred at significantly reduced incidences in all exposed groups of female rats (25/50, 14/50, 12/50, 9/50). The incidence of subcutaneous fibroma or sarcoma in high-dose male mice was significantly lower than for the controls (8/50, 6/50, 1/50). Genetic Toxicity: Resorcinol was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation (S9). Induor without exogenous metabolic activation (S9). Induction of trifluorothymidine resistance was observed in mouse L5178Y lymphoma cells treated with resorcinol in the absence of S9 activation; this test was not performed with S9. Resorcinol induced sister chromatid exchanges in Chinese hamster ovary cells with and without S9. Resorcinol was positive for induction of chromosomal aberrations in Chinese hamster ovary cells in the presence of S9; an equivocal response was obtained in this test in the absence of S9. No induction of sex-linked recessive lethal mutations was observed in the germ cells of male Drosophila melanogaster when resorcinol was administered in the feed, but an equivocal response was observed when the chemical was administered by injection. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of resorcinol in male F344/N rats given 112 or 225 mg/kg or female F344/N rats given 50, 100, or 150 mg/kg. There was no evidence of carcinogenic activity of resorcinol in male or female B6C3F1 mice given 112 or 225 mg/kg. Clinical signs suggestive of a chemical-related effect on the central nervous system, including ataxia, recumbency, and tremors, were observed in rats and mice in the 2-year studies. Synonyms: 1,3-benzenediol; m-dihydroxybenzene; resorcin

Journal Article↗
PubMed1992

NTP Technical Report on the Toxicology and Carcinogenesis Studies of 2,4-Diaminophenol Dihydrochloride (CAS NO. 137-09-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

2,4-Diaminophenol dihydrochloride is used in the manufacture of dyes and as a color accelerator in photographic developers. Toxicology and carcinogenesis studies were conducted by administering 2,4-diaminophenol dihydrochloride (greater than 97% pure) in corn oil by gavage to F344/N rats and B6C3F1 mice for 16 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma cells, Drosophila melanogaster, and Chinese hamster ovary cells. 16-Day Studies: Groups of five rats of each sex received doses of 0, 6, 13, 25, 50, or 100 mg/kg and groups of five mice of each sex received doses of 0, 13, 25, 50, 100, or 200 mg/kg of 2,4-diaminophenol dihydrochloride in corn oil by gavage. There were no deaths among rats during the 16-day studies and chemical exposure had no effect on final mean body weights. Organ weight differences were unrelated to chemical exposure. Renal tubule necrosis was present in male and female rats in the 25, 50, and 100 mg/kg dose groups. All male and four female mice that received 200 mg/kg, all males and three females that received 100 mg/kg, and two female mice that received 50 mg/kg died before the end of the studies. Final mean body weights of surviving dosed mice were similar to controls. Absolute liver weights were increased in female mice that received 50 and 100 mg/kg and relative liver weights were increased in all female dose groups. Renal tubule necrosis was present in the 100 mg/kg male and female dose groups. 13-Week Studies: Groups of ten male and female rats received doses of 0, 12, 25, 50, 100, or 200 mg/kg and groups of ten male and female mice received doses of 0, 5, 9, 19, 38, or 75 mg/kg of 2,4-diaminophenol dihydrochloride in corn oil by gavage. All female and nine male rats that received 200 mg/kg and four males and one female in the 100 mg/kg rat groups died before the end of the studies. Final mean body weights of male rats that received 50 or 100 mg/kg were significantly lower than controls. Relative kidney weights were significantly increased in all male dose groups; absolute and relative kidney and liver weights were significantly increased in females that received 50 and 100 mg/kg. Lesions in rats associated with chemical exposure included renal tubule necrosis in males that received 25 mg/kg and above and in females that received 100 or 200 mg/kg. Forestomach ulcers with acanthosis and hyperkeratosis were present at 50 mg/kg and above in both sexes. Pigment, presumably 2,4-diaminophenol dihydrochloride or a metabolite, was present in the duodenum and within the renal tubule epithelium of all dose groups. Splenic lymphoid depletion was present in both sexes and bone marrow hyperplasia was present in groups of males that received 100 or 200 mg/kg. Hemosiderin was present in Kupffer cells of males that received 100 or 200 mg/kg. The severity of splenic extramedullary hematopoiesis increased with dose in males. There were no deaths among mice attributed to chemical exposure. Final mean body weight of male mice that received 75 mg/kg was 8% lower than for the controls. Absolute and relative liver weights were increased in males that received 9 mg/kg or above and in all female dose groups. Absolute and relative kidney weights of 38 and 75 mg/kg male mice and all dosed female mice were significantly increased. Absolute heart weights were increased in the 19, 38, and 75 mg/kg female groups. Lesions in 75 mg/kg mice included increased incidences of renal tubule regeneration; forestomach acanthosis and hyperkeratosis occurred in 38 and 75 mg/kg groups. Hemosiderin was present in the spleen of mice from all dose groups and in hepatic Kupffer cells of female mice that received 38 or 75 mg/kg. Pigment was present in the duodenum of males and females that received 9 mg/kg and above and in the renal tubule epithelium of both sexes that received 75 mg/kg. 2-Year Studies: The 2-year studies were conducted by administering 2,4-diaminophenol dihydrochloride in corn oil by gavage to groups of 60 male and 60 female F344/N rats and B6C3F1 mice. Tence. Ten animals from each dose group were evaluated after 15 months. Rats received doses of 0, 12.5, or 25 mg/kg; mice received doses of 0, 19, or 38 mg/kg. Body Weight and Survival in the 2-Year Studies: Mean body weights of high-dose male and female rats and of high-dose male mice were lower than those of the respective controls. Survival of dosed rats and mice was similar to controls throughout the 2-year studies. Neoplastic and Nonneoplastic Effects in the 2-Year Studies: The severity of nephropathy increased in high-dose male rats. The incidence of renal tubule cell hyperplasia was increased in rats that received 2,4-diaminophenol dihydrochloride; however, there were no renal tubule cell neoplasms attributed to chemical exposure. Renal tubule cell hyperplasia was present in three high-dose male mice and a renal tubule adenoma was present in one of the high-dose males with hyperplasia; two additional high-dose males also had renal tubule adenomas. These are uncommon neoplasms in male mice and were considered related to chemical exposure. In a supplemental review of step-sectioned kidneys, six additional hyperplasia were seen in high-dose male mice and adenomas in three other high-dose males. A tubule cell carcinoma was present in one low-dose female mouse. The incidences of several nonneoplastic kidney lesions, including necrosis and renal tubule regeneration, were also increased in male and female mice. Pigment was observed in the lamina propria of the duodenum, the submucosa of the forestomach, and in pancreatic and mesenteric lymph nodes in dosed rats. Hemosiderin was present in the renal tubule epithelial cells of low- and high-dose rats. The incidence of forestomach acanthosis was increased in dosed male mice and pigment was present in liver Kupffer cells, in the lamina propria of the duodenum, and in the mesenteric lymph nodes of male and female mice. Pigment and hemosiderin were also present in the renal tubule epithelium of dosed mice. Genetic Toxicology: 2,4-Diaminophenol dihydrochloride was mutagenic in the Salmonella typhimurium strain TA98 in the presence of exogenous metabolic activation (S9); it was not mutagenic in strain TA98 in the absence of S9, nor was it mutagenic in strains TA100, TA1535, or TA1537 with or without S9. 2,4-Diaminophenol dihydrochloride was positive in the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y cells without S9; it was not tested with S9. No induction of sister chromatid exchanges or chromosomal aberrations was observed in Chinese hamster ovary cells treated with 2,4-diaminophenol dihydrochloride with and without S9. In the Drosophila melanogaster sex-linked recessive lethal assay, 2,4-diaminophenol dihydrochloride gave equivocal results when administered in the feed and negative results when administered by injection. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of 2,4-diaminophenol dihydrochloride in male or female F344/N rats that received 12.5 or 25 mg/kg. There was some evidence of carcinogenic activity of 2,4-diaminophenol dihydrochloride in male B6C3F1 mice based on increased incidences of renal tubule adenomas; there was no evidence of carcinogenic activity of 2,4-diaminophenol dihydrochloride in female B6C3F1 mice that received 19 or 38 mg/kg. Administration of 2,4-diaminophenol dihydrochloride to rats was associated with increased severity of nephropathy in males and females, increased incidence of nephropathy in females, and focal renal tubule hyperplasia in males and females. In mice, chemical exposure was associated with renal tubule necrosis and regeneration in males and females and forestomach acanthosis in males. Synonyms: Acrol, amidol, dianol

Journal Article↗
PubMed1992

Toxicology and Carcinogenesis Studies of 4,4'-Diamino-2,2'-Stilbenedisulfonic Acid Disodium Salt (CAS No. 7336-20-1) in F344 Rats and B6C3F1 Mice (Feed Studies).

4,4'-Diamino-2,2'-stilbenedisulfonic acid, disodium salt, is used in the synthesis of dyes and optical brighteners or fluorescent whitening agents. Toxicology and carcinogenesis studies were conducted by administering the chemical (approximately 14% water, 6% sodium chloride, 4% impurities, and 76% 4,4'-diamino-2,2'-stilbenedisulfonic acid) in feed to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary cells. 14-Day Studies: Groups of five rats and five mice of each sex were given 0, 6,250, 12,500, 25,000, 50,000, or 100,000 ppm 4,4'-diamino-2,2'-stilbenedisulfonic acid, disodium salt, in feed for 14 days. All rats and mice survived to the end of the studies. The mean body weight gain of male rats receiving 50,000 or 100,000 ppm and of female rats and male and female mice receiving 100,000 ppm was significantly lower than those of the respective controls. Clinical findings included diarrhea in the rats and mice receiving 100,000 ppm. There were no chemical-related changes in absolute or relative organ weights in rats or mice. There were no gross or microscopic lesions related to chemical administration in rats or mice. 13-Week Studies: Groups of 10 rats and 10 mice of each sex were given 0, 6,250, 12,500, 25,000, 50,000, or 100,000 ppm 4,4'-diamino-2,2'-stilbenedisulfonic acid, disodium salt, in feed for 13 weeks. One female rat, six male mice, and one female mouse in the 100,000 ppm dose groups died during the studies. Mean body weight gain was significantly decreased in male rats and female mice receiving 50,000 or 100,000 ppm, in male mice receiving 25,000, 50,000, or 100,000 ppm, and in female rats receiving 100,000 ppm. Clinical findings in rats that received 50,000 or 100,000 ppm and in mice that received 100,000 ppm included diarrhea, emaciation, and hyperemia of the perineum. There were no biologically significant changes in absolute or relative organ weights or clinical pathology results in rats or mice. Histopathologic lesions present in rats receiving 100,000 ppm were bone marrow hypercellularity and chronic inflammation of the anus and rectum. Ulcerative inflammation of the anus and rectum was observed in mice receiving 25,000 ppm and above. Female mice in the 6,250, 12,500, 25,000, and 50,000 ppm dose groups had increased incidences of cystic endometrial hyperplasia. 2-Year Studies: Doses selected for the 2-year studies were based on mortality, decreased body weight gains, and the presence of diarrhea and chronic inflammation of the anus/rectum in rats and mice during the 13-week studies. Groups of 60 rats of each sex were given 0, 12,500 or 25,000 ppm and groups of 60 mice of each sex were given 0, 6,250, or 12,500 ppm 4,4'-diamino-2,2'-stilbenedisulfonic acid, disodium salt, in feed for up to 103 weeks. Interim evaluations were performed on 10 rats and 10 mice from each dose group at 15 months. There were no biologically significant absolute or relative organ weight, clinical pathology, or histopathology findings in rats or mice administered 4,4'-diamino-2,2'-stilbenedisulfonic acid, disodium salt, in feed for 15 months. Body Weight, Feed Consumption, Survival, and Clinical Findings in the 2-Year Studies: Mean body weights were marginally decreased for high-dose male and female rats and female mice. Feed consumption by dosed rats and mice was similar to feed consumption by the controls throughout the studies. Survival was similar among control and treated groups of rats and mice. No clinical findings related to chemical administration were observed in rats or mice. Nonneoplastic and Neoplastic Effects in the 2-Year Studies: There were no chemical-related increased incidences of neoplasms at any site in rats. Ulcers of the forestomach or glandular stomach occurred in dosed rats (males: 1/50, 5/50, 4/50; females: 0/50, 1/50, 4/50), and may have been related to the administration of 4,4'-diamino-2,2'-stilbenedisulfonic acid, disodium salt. There were no chemical-related incidences ohemical-related incidences of neoplasms, nonneoplastic lesions, or other toxic effects in mice in the 2-year studies. Although the animals might have been able to tolerate slightly higher doses, results of the 13-week studies indicate that a doubling of the highest doses could not have been tolerated. Genetic Toxicology: 4,4'-Diamino-2,2'-stilbenedisulfonic acid was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98 with or without S9 metabolic activation. 4,4'-Diamino-2,2'-stilbenedisulfonic acid did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells in the presence or absence of S9. Conclusions: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of 4,4'-diamino-2,2'-stilbenedisulfonic acid, disodium salt, in male or female F344/N rats receiving 12,500 or 25,000 ppm. There was no evidence of carcinogenic activity of 4,4'-diamino-2,2'-stilbenedisulfonic acid, disodium salt, in male or female B6C3F1 mice receiving 6,250 or 12,500 ppm. Synonyms: Amsonic acid; diaminostilbene disulphonate (DASD); 2,2'-(1,2-ethenediyl)bis[5-amino-benzenesulfonic acid]; 2,2'-disulfo-4,4'-stilbenediamine; 2,2'-stilbenedisulfonic acid; 4,4'-diamino-2,2'-benzenesulfonic acid; 2,2'-(1,2-ethenediyl)bis(5-amino-) diaminostilbenedisulfonic acid; flavonic acid; p,p'-diaminostilbene-o,o'-disulfonic acid; 4,4'-diaminostilbene-2,2'-disulfonic acid

Journal Article↗
PubMed1992

Toxicology and Carcinogenesis Studies of C.I. Pigment Red 23 (CAS No. 6471-49-4) in F344 Rats and B6C3F1 Mice (Feed Studies).

C.I. Pigment Red 23 is a bluish red commercial dye used as a coloring agent in paints, inks, rubber, plastics, lacquers, and paper. Toxicology and carcinogenicity studies were conducted by feeding groups of rats and mice diets containing C.I. Pigment Red 23 (greater than 96% pure) for 17 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and in Chinese hamster ovary cells. 17-Day Studies: Groups of five rats and five mice of each sex were fed diets containing 0, 6,000, 12,500, 25,000, 50,000, or 100,000 ppm C.I. Pigment Red 23 for 15 to 17 days. All rats and all female mice lived until the end of the studies. Two male mice in the 12,500 ppm dose group died accidentally. No other deaths occurred among male mice. Final mean body weights of rats and mice receiving C.I. Pigment Red 23 were within 10% of those of the controls. Feed consumption by exposed animals was similar to that of the controls. Hematocrit value, hemoglobin concentration, and erythrocyte count were decreased in the 50,000 and 100,000 ppm groups of rats. A corresponding decrease was not seen in mice. Absolute and relative organ weights of exposed animals were generally similar to those of the controls. No chemical-related gross lesions were seen in rats or mice. 13-Week Studies: Groups of 10 rats and 10 mice of each sex were fed diets containing 0, 3,000, 6,000, 12,500, 25,000, or 50,000 ppm C.I. Pigment Red 23 for 13 weeks. All rats and mice lived until the end of the studies. Final mean body weights of rats and mice receiving C.I. Pigment Red 23 were within 10% of those of the controls. Feed consumption by exposed animals was similar to that of the controls. In 50,000 ppm male rats, hematocrit and hemoglobin concentrations and erythrocyte counts were significantly less than those of the controls. In female rats receiving 3,000, 6,000 and 50,000 ppm C.I. Pigment Red 23, lymphocyte counts were significantly higher than the control values. Leukocyte counts in 3,000 ppm females were also significantly increased. Female mice in the 6,000 ppm dose group had significantly lower hematocrit and hemoglobin concentrations than did untreated females. Hematology parameters in exposed males were similar to those of untreated males. There were no biologically significant differences in organ weights among dosed and control rats. Absolute and relative liver weights of male mice receiving 12,500 ppm C.I. Pigment Red 23 were significantly increased compared to those of the controls. Absolute and relative thymus weights for all but 12,500 ppm female mice were significantly lower than those of the controls. No chemical-related gross or histopathologic lesions occurred in rats or mice. 2-Year Studies: Survival, Body Weights, Feed Consumption, and Clinical Findings Because levels of C.I. Pigment Red 23 as high as 50,000 or 100,000 ppm in the feed did not adversely affect survival and mean body weights in the 17-day and 13-week studies, nor cause any chemical- related lesions, doses of 0, 10,000, 25,000, or 50,000 ppm were selected for the 2-year studies. Doses higher than 50,000 ppm (5%) are not used in 2-year studies because they may lead to excessive dilution of nutrients in feed which in turn could produce nutritional deficiencies. Survival rates of mid- and high-dose male and of high-dose female rats were significantly greater than those of the controls, due primarily to a chemical related decreased incidence of mononuclear cell leukemia in these groups (survival in male rats: control, 22/50, low-dose, 29/50, mid-dose, 36/50, high-dose, 35/51; female rats: 29/50, 34/50, 33/50, 40/50). Survival of mice was not affected by the administration of C.I. Pigment Red 23, although survival of low-dose male mice was significantly lower than that of controls (male mice: 29/51, 17/53, 27/52, 30/51; female mice: 35/50, 34/49, 36/50, 35/49). The decreased survival in the low- dose males was associated with evidence of body trauma and secondary septicemia caused by fighting. From approximately week 20 of the study, the group mean body weight, the group mean body weights of exposed female rats were consistently lower than those of controls; at week 101, mean body weights of mid- dose (25,000 ppm) and high-dose (50,000 ppm) females were 6% and 8% less, respectively. The final mean body weights of exposed male rats and male and female mice were similar to those of controls. Feed consumption values for exposed male and female rats and mice were similar to those of the controls and there were no clinical signs associated with the administration of C.I. Pigment Red 23. Pathology Findings: Renal tubule adenomas occurred in two high- dose male rats. Renal tubule carcinomas occurred in one high-dose male and one mid-dose male rat. No renal tubule neoplasms were seen in the controls. Renal tubule neoplasms are uncommon and have occurred in 8/499 (1.6%) untreated historical controls with a range of 0% to 6%. The residual halves of kidneys from control and high-dose males were step sectioned and examined; renal tubule adenomas were observed in a control male and in two additional high- dose males. Because of the low numbers of renal neoplasms, it is uncertain if they were related to chemical administration. The incidence of renal tubule hyperplasia (3/50, 6/48, 5/50, 8/50) and the mean severity of nephropathy were also slightly increased in high-dose male rats. The incidence of mononuclear cell leukemia occurred with a significant negative trend in exposed male and female rats. No chemical-related increases in the incidence of neoplasms were observed in mice of either sex. There was a chemical-related increase in the incidence of hyperplasia (male mice: 0/49, 1/48, 1/50, 7/48; female mice: 6/49, 14/49, 43/50, 47/49) and hyperkeratosis of the forestomach epithelium attributed to chemical administration. Genetic Toxicology: C.I. Pigment Red 23 was mutagenic in Salmonella typhimurium strains TA100, TA1537, and TA98 with and without exogenous metabolic activation (S9), but it was not mutagenic in strain TA1535. C.I. Pigment Red 23 induced sister chromatid exchanges in Chinese hamster ovary cells in the absence of S9, but not with S9 activation. The pigment was negative for the induction of chromosomal aberrations in Chinese hamster ovary cells both in the presence and absence of S9. Conclusions: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity of C.I. Pigment Red 23 in male F344 rats as evidenced by a marginally increased incidence of renal tubule cell neoplasms. There was no evidence of carcinogenic activity of C.I. Pigment Red 23 in female F344 rats fed diets containing 10,000, 25,000, or 50,000 ppm. Mononuclear cell leukemia occurred with a decreased incidence in male and female rats receiving C.I. Pigment Red 23. There was no evidence of carcinogenic activity of C.I. Pigment Red 23 in male and female B6C3F1 mice fed diets containing 10,000, 25,000 or 50,000 ppm. The severity of kidney nephropathy was increased in exposed male rats. In mice, C.I. Pigment Red 23 caused an increase in hyperkeratosis and epithelial hyperplasia of the fore- stomach. Synonyms: 2-Naphthalenecarboxamide; 3-hydroxy-4-((2-methoxy-5- nitrophenyl)azo)-N-(3- nitrophenyl); 3-hydroxy-4-((2-methoxy-5- nitrophenyl)azo)-3 -2-naphthanilide; Alkali Resistant Red Dark; Calcotone Red 3B; Carnation Red Toner B; CI 12355; Congo Red R- 138; Fenalac Red FKB Extra; Malta Red X2284; Naphthol Red B; Naphthol Red T Toner 35- 6001; Naphthol Red Deep 10459; Pigment Red BH; Rubescence Red MT-21; Sanyo Fast Red 10B; Sapona Red Lake RL-6280; Sengale Light Rubin RG; Textile Red WD-263

Journal Article↗
PubMed1992

Toxicology and Carcinogenesis Studies of Naphthalene (CAS No. 91-20-3) in B6C3F1 Mice (Inhalation Studies).

Naphthalene, a white, crystalline powder, is used as a moth repellent and in the manufacture of phthalic and anthranilic acids, naphthylamines, and synthetic resins. The 2-year studies were conducted by exposing groups of male and female B6C3F1 mice to naphthalene (>99% pure) vapor for 6 hours daily, 5 days per week, for 104 weeks. Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary cells. 2-Year Studies: Groups of male and female mice were exposed to atmospheres containing 0 (75 mice per group), 10 (75 mice per group), or 30 ppm (150 mice per group) naphthalene. Mice from each group were included for 14-day hematology evaluations (male: 0 ppm, 5 animals; 10 ppm, 4; 30 ppm, 10; female: 0 ppm, 4; 10 ppm, 5; 30 ppm, 10). Mean body weights of exposed mice were slightly lower than those of controls throughout the studies. Survival of male control mice was significantly less than that of exposed mice; the lower survival was the result of wound trauma and secondary infections related to fighting among the group-housed mice (0 ppm, 26/70, 37%; 10 ppm, 52/69, 75%; 30 ppm, 118/133, 89%). Survival of exposed female mice was similar to that of controls (59/69, 86%; 57/65, 88%; 102/135, 76%). Neoplastic and Nonneoplastic Effects in the 2-Year Studies: No increase in tumor incidence related to naphthalene administration was observed in male mice. In females, the incidence of pulmonary alveolar/bronchiolar adenomas was significantly greater in the high-dose group than in the controls (5/69, 7%; 2/65, 3%; 28/135, 21%). One other high-dose female had an alveolar/bronchiolar carcinoma. The combined incidence of alveolar/ bronchiolar adenomas and carcinomas in the high-dose females was above those for control female B6C3F1 mice from NTP feed, water, and inhalation studies (91/1,166, 7.8%, range 0%-16%). These lung tumors were attributed to naphthalene exposure. Nonneoplastic lesions attributed to naphthalene exposure were observed in the nose and lungs of mice of both sexes. In the nose, naphthalene exposure was associated with an increase in the incidence and severity of chronic inflammation, metaplasia of the olfactory epithelium, and hyperplasia of respiratory epithelium. Chronic inflammation in the lung was associated with chemical exposure. Genetic Toxicology: Naphthalene was negative for the induction of gene mutations in Salmonella typhimurium strains TA100, TA1535, TA1537, and TA98 with and without exogenous metabolic activation (S9). In cytogenetic tests with Chinese hamster ovary cells, naphthalene induced sister chromatid exchanges with and without S9 activation. Exposure to naphthalene induced a significant increase in chromosomal aberrations in Chinese hamster ovary cells in the presence of S9. Conclusions: Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity of naphthalene in male B6C3F1 mice exposed to 10 or 30 ppm. There was some evidence of carcinogenic activity of naphthalene in female B6C3F1 mice, based on increased incidences of pulmonary alveolar/ bronchiolar adenomas. In both male and female mice, naphthalene caused increased incidences and severity of chronic inflammation, metaplasia of the olfactory epithelium, and hyperplasia of the respiratory epithelium in the nose and chronic inflammation in the lungs. Synonyms: Naphthalin, Naphthene, Tar Camphor

Journal Article↗
PubMed1992

Toxicology and Carcinogenesis Studies of Quercetin (CAS No. 117-39-5) in F344 Rats (Feed Studies).

Quercetin is a member of a group of naturally occurring compounds, the flavonoids, which have a common flavone nucleus composed of two benzene rings linked through a heterocyclicpyrone ring. Quercetin is found in various plants, food products, and dyes of natural origin. The estimated average daily intake of quercetin by an individual in the United States is 25 mg. The Food and Drug Administration nominated quercetin for toxicity and carcinogenicity studies in the rat because it is a chemical that is widely distributed in foods. Quercetin was administered to rats by dosed feed since human exposure is by dietary consumption. Information in the literature showed that quercetin administered in the diet to rats at levels up to approximately 4% caused a minor body weight effect, whereas higher dose levels produced greater than 10% reduction in body weight gains relative to controls. Based on this information, the NTP 2-year studies were conducted by administering 0, 1,000, 10,000, or 40,000 ppm quercetin (>95% pure) in feed to groups of 50 male and female rats for 104 weeks. Ten additional animals per dose group were evaluated at 6 and 15 months. Body Weight, Survival, and Clinical Findings in the 2-Year Studies: Body weights of exposed male and female rats given 1,000 and 10,000 ppm were within 5% of controls throughout the studies. Reduced body weight gain in male and female rats receiving 40,000 ppm was observed by week 15 and the final mean body weights were 87% of controls at week 104. Survival and feed consumption were similar among exposed and control groups throughout the studies. The average amounts of quercetin consumed per day by the 1,000, 10,000 and 40,000 ppm dose groups after week 52 were 40, 400, and 1,900 mg/kg of body weight. Nonneoplastic and Neoplastic Effects in the 2-Year Studies: In male rats, the principal toxic effects associated with the dietary administration of quercetin for 2 years were observed in the kidney. There were dose-related increases in the severity of chronic nephropathy (control, 2.7; low-dose, 2.7; mid-dose, 3.0; high-dose, 3.2) and a slight increased incidence in focal hyperplasia of the renal tubule epithelium (1/50; 2/50; 3/50; 4/50). Parathyroid hyperplasia, indicative of renal secondary hyperparathyroidism, also increased incidence in dosed male rats (1/43, 6/45, 6/43, 17/43). The evaluation of single sections from the left and right kidneys revealed renal tubule adenomas in three male rats and adenocarcinomas in another male rat receiving 40,000 ppm quercetin; none were seen in the controls. Examination of additional step sections of the male rat kidney identified additional hyperplasia and adenomas in all dose groups (hyperplasia: 2/50, 2/50, 6/50, 8/50; adenoma: 1/50, 2/50, 7/50, 6/50). The overall incidence of renal tubule adenoma or adenocarcinoma combined in male rats was 1/50 in controls and 9/50 in the high-dose group. There was no apparent effect of quercetin on the kidney of female rats. A single renal tubule adenoma was seen in a female receiving 10,000 ppm; this neoplasm was not considered biologically significant. There was a statistically significant, dose-related decrease in the incidence of mammary gland fibroadenomas in exposed female rats (29/50, 27/50, 16/50, 9/50), which may in part be attributed to lower body weight gains. There was a treatment-related accumulation of yellow-brown granular pigment adsorbed to or absorbed by the epithelial cells of the glandular stomach, ileum, jejunum, and, to a lesser extent, the duodenum and colon. The severity of the pigmentation in these tissues increased with increased length of exposure. There were no other lesions considered to be related to chemical administration. Genetic Toxicology: Quercetin induced gene mutations in Salmonella typhimurium strains TA100 and TA98 with and without exogenous metabolic activation (S9). Positive results were also obtained in tests with and without S9 for induction of sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells. Conclusions: Under the conditionslls. Conclusions: Under the conditions of these 2-year feed studies there was some evidence of carcinogenic activity of quercetin in male F344/N rats based on an increased incidence of renal tubule cell adenomas. There was no evidence of carcinogenic activity of quercetin in female F344/N rats receiving 1,000, 10,000 or 40,000 ppm. The incidence of renal tubule hyperplasia and the severity of nephropathy were increased in exposed male rats. Synonyms: C.I. Natural Yellow 10; C.I. 75670; Cyanidelonon 1522; Flavin Meletin; Quercetine; Quercetol; Quertin; Quertine; Sophoretin; Xanthaurine; 3,3',4',5,7-Pentahydroxyflavone; 3,5,7,3',4'-Pentahydroxyflavone; 2-(3,4-Dihydroxyphenyl)-3,5,7-trihydroxy-4H-1-benzopyran-4-one

Journal Article↗
PubMed1992

Toxicology and Carcinogenesis Studies of C.I. Pigment Red 3 (CAS No. 2425-85-6) in F344/N Rats and B6C3F1 Mice (Feed Studies).

C.I. Pigment Red 3, a yellowish red solid, is widely used for coloring paints, inks, plastics, and rubber, and in textile printing. It is used in a wide range of consumer items such as wallpaper, typewriter ribbons, carbon paper, and art materials. Toxicology and carcinogenicity studies were conducted by feeding groups of F344/N rats and B6C3F1 mice of each sex diets containing C.I. Pigment Red 3 (97% pure) for 2 weeks, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and cultured Chinese hamster ovary cells. 2-Week Studies: Groups of five rats and five mice of each sex were given feed containing 0, 6,000, 12,500, 25,000, 50,000, or 100,000 ppm C.I. Pigment Red 3 for 2 weeks. No chemical-related deaths occurred in rats or mice. Final mean body weights of exposed rats and male mice were lower than controls; female mice that received 6,000 and 50,000 ppm had significantly increased final mean body weights compared to that of the controls. The feed consumption of treated rats and mice was slightly greater than that of the controls, suggesting that C.I. Pigment Red 3 had no adverse effects on the feed palatability. Dose-related decreases in erythrocyte counts and hematocrit values and an increase in reticulocyte counts were observed in rats. Changes in these parameters were observed in mice, but there were no clear, dose-related trends. 13-Week Studies: Groups of ten rats and ten mice of each sex were given feed containing 0, 3,000, 6,000, 12,500, 25,000, or 50,000 ppm C.I. Pigment Red 3 for 13 weeks. No chemical-related deaths were observed in rats or mice. The final mean body weights of exposed female rats were significantly lower than that of the controls; the final mean body weights of exposed male rats and exposed mice were similar to controls. There were significant increases in relative liver and kidney weights of exposed male rats. Increases in the relative liver weights in mice did not occur with a dose-related trend and thus they were not considered related to chemical administration. Sites for the toxicity of C.I. Pigment Red 3 were the bone marrow, kidney, liver, and spleen in rats. Lesions observed in rats included bone marrow hyperplasia, congestion and hematopoietic cell proliferation of the spleen, and iron-positive pigmentation of the spleen, kidney, and liver. Sites for the toxicity of C.I. Pigment Red 3 in mice were the liver, kidney, and spleen in males and the liver and spleen in females. Lesions noted among mice in the spleen were hematopoietic cell proliferation and iron-positive pigmentation. In the liver, there was hematopoietic cell proliferation in male and female mice. Cytomegaly occurred in the renal tubule epithelium of the male mouse kidney. 2-Year Studies: Doses selected for the 2-year feed studies were 0, 6,000, 12,500, and 25,000 ppm for rats and 0, 12,500, 25,000, and 50,000 ppm for mice. The dose selection for rats was based on body weight changes observed for females that received 50,000 ppm; the dose selection for mice was based on the lack of body weight depression or death at the doses tested during the 13-week studies. Concentrations higher than 50,000 ppm in the feed were not used because higher levels might have adversely affected the nutritional value of the diet during the 2-year studies. Body Weight, Feed Consumption, Clinical Findings, and Survival in the 2-Year Studies: Final mean body weights for male rats that received 25,000 ppm, female rats that received 12,500 and 25,000 ppm, and male and female mice that received 50,000 ppm were more than 10% lower than those of the controls. Feed consumption of exposed rats and mice was similar to that of the controls. No clinical findings indicative of toxicity were observed in rats or mice. The survival of low-dose male rats was greater than that of the controls (0 ppm, 28/50; 6,000 ppm, 40/50; 12,500 ppm, 28/50; 25,000 ppm, 20/50). Survival of exposed female rats and exposed male mice was similar to the controls; the survival of high-dose female mice was significantly decreased compared to thcompared to that of the controls (39/50, 37/50, 31/50, 25/50). The reduced survival in this dose group may have been due to the increased incidence of ovarian abscesses. Neoplasms and Nonneoplastic Lesions in the 2-Year Studies: Benign adrenal pheochromocytomas were significantly increased in the 12,500 and 25,000 ppm groups of male rats compared to the controls (22/50, 29/50, 35/50, 34/50). However, malignant neoplasms were not increased in incidence (6/50, 7/50, 10/50, 4/50). The incidence of adrenal pheochromocytomas in dosed groups exceeded the range for NTP historical controls for feed studies (22%-48%), and the increased incidence of this neoplasm was attributed to C.I. Pigment Red 3 administration. Squamous cell papillomas of the skin occurred with a positive trend in male rats (0/50, 4/50, 2/50, 6/50), and the incidence in the high-dose group was significantly greater than that of the controls. A poorly differentiated squamous cell carcinoma (diagnosed as carcinoma) was observed in a control male. The historical control rate for squamous cell papillomas in NTP feed studies is low (16/800 or 2%, range 0%-4%), and the higher incidence of this tumor in male rats may have been caused by the administration of C.I. Pigment Red 3. Hepatocellular adenomas occurred with a positive trend in female rats, with a significantly greater incidence in the high-dose group than in the control group (0/50, 0/50, 1/50, 10/50). This neoplasm has occurred in only one historical control group in NTP feed studies (3/800, range 0%-6%), and the increase in hepatocellular adenomas in female rats was attributed to chemical administration. Chemical-related nonneoplastic lesions observed in the livers of male and female rats included eosinophilic or mixed type foci of cellular alteration. Foci were often accompanied by angiectasis and cystic degeneration in males and by granulomas and cholesterol pigmentation in females. Chronic nephropathy occurred with increased severity in exposed male and female rats. The lesions were more severe in males than in females. Other lesions considered secondary to renal disease included parathyroid gland hyperplasia, fibrous osteodystrophy of the bone, and mineralization of various organs (stomach, intestine, heart, and blood vessels). The increased incidence of hyperplasia of the transitional epithelium of the renal papilla observed in treated rats was considered to be part of the chronic nephropathy. Zymbal's gland carcinoma incidences were marginally increased in the mid- and high-dose male rats (0/50, 0/50, 2/50, 3/50). The incidence in the high-dose group was outside the NTP historical control range (0%-4%), and the Zymbal's gland carcinomas may have been related to C.I. Pigment Red 3 administration. Mononuclear cell leukemias, mammary gland fibroadenomas, and preputial gland/clitoral gland adenomas occurred at lower incidences in exposed male and female rats. The decrease in mononuclear cell leukemia was attributed to the direct effect of C.I. Pigment Red 3 or its metabolites on the mechanism responsible for inducing leukemias in aging rats, while the decreased incidence of mammary gland fibroadenomas might be attributed to decreased body weights in female rats. The cause of the decreased incidences of preputial and clitoral gland tumors is unknown. Tubule adenomas of the renal cortex occurred at a significantly higher incidence in high-dose male mice than in controls (0 ppm, 0/50; 12,500 ppm, 0/50; 25,000 ppm, 0/50; 50,000 ppm, 6/50). Because this tumor occurred only in exposed males and was outside the range for NTP historical controls in feed studies (0%-2%), renal cortical tubule adenomas in male mice were considered to be related to the administration of C.I. Pigment Red 3. Follicular cell adenoma of the thyroid gland occurred with a positive trend in male mice (0/50, 0/49, 1/50, 5/50). Theincidence in the high-dose group was significantly greater than that in the controls. This chemical-related effect is supported by the increased incidence of follicular cell hyperplasia. Because the incidence of this tumor exceeded the range of the historical controls from NTP feed studies (0%-4%), the increase of follicular cell adenoma was attributed to chemical administration. Female mice receiving C.I. Pigment Red 3 had a significant increase in follicular cell hyperplasia but showed no increase in tumor incidence at this site. Focal renal tubule hyperplasia and cystic hyperplasia occurred in exposed male mice but not in the controls. Cytomegaly (karyomegaly) of the renal tubule epithelium was seen in all treated male mice. The severity of the accompanying chronic nephropathy was increased in both male and female mice. Genetic Toxicology: C.I. Pigment Red 3 was mutagenic in Salmonella typhimurium strains TA100 and TA98 in the presence of exogenous metabolic activation (S9); no increases in gene mutation were observed in strains TA1535 and TA1537, with or without S9. C.I. Pigment Red 3 did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells in either the presence or the absence of S9. Conclusions: Under the conditions of these 2-year feed studies, there was some evidence of carcinogenic activity of C.I. Pigment Red 3 in male F344/N rats as exhibited by increased incidences of benign pheochromocytomas of the adrenal gland. The marginal increase in the incidences of squamous cell papillomas of the skin and Zymbal's gland carcinomas may have been related to C.I. Pigment Red 3 administration. There was some evidence of carcinogenic activity of C.I. Pigment Red 3 in female F344/N rats as indicated by the increased incidence of hepatocellular adenomas. There was some evidence of carcinogenic activity of C.I. Pigment Red 3 in male B6C3F1 mice as exhibited by the increased incidences of tubule adenomas of the renal cortex and follicular cell adenomas of the thyroid gland. There was no evidence of carcinogenic activity of C.I. Pigment Red 3 in female B6C3F1 mice that received 12,500, 25,000, or 50,000 ppm. The incidences of mononuclear cell leukemia and preputial gland tumors in male rats and mononuclear cell leukemia, mammary gland fibroadenoma, and clitoral gland tumors in female rats were lower in the exposed groups. The incidences of liver foci were markedly increased in exposed male and female rats. The severity of chronic nephropathy was increased in male rats and to a lesser extent in female rats given C.I. Pigment Red 3. An increase in the severity of nephropathy was observed in male and female mice; cytomegaly (karyomegaly) of renal tubule epithelium was observed in male mice. Thyroid follicular cell hyperplasia occurred with an increased incidence in male and female mice receiving C.I. Pigment Red 3. Synonyms: 2-Naphthalenol, 1-((4-methyl-2-nitrophenyl)azo)-; Calcotone Toluidine Red YP; Fast Red A; Pigment Scarlet R; Recolite Fast Red RBL; Sengale Light Red B

Journal Article↗
PubMed1992

NTP Toxicology and Carcinogenesis Studies of Methyl Bromide (CAS: 74-83-9) in B6C3F1 Mice (Inhalation Studies).

Methyl bromide is widely used as a fumigant and pesticide. Toxicology and carcinogenesis studies were conducted by exposing groups of male and female B6C3F1 mice to methyl bromide (99.8% pure) by inhalation 6 hours per day, 5 days per week, for 14 days, 6 weeks, 13 weeks, or 2 years. Six-week and 13-week inhalation toxicity studies in F344/N rats were conducted concurrently with the mouse studies. Hematology parameters were measured during the 6-week, 13-week, and 2-year studies. Quantitative neurobehavioral testing was performed during the 14-day, 13-week and 2-year studies. Genetic toxicology studies were conducted for gene mutation induction in Salmonella typhimurium and for induction of sister chromatid exchanges in mouse bone marrow cells and of micronuclei from peripheral blood erythrocytes. 14-Day Studies: Groups of five B6C3F1 mice of each sex were exposed to 0, 12, 25, 50, 100, or 200 ppm methyl bromide by inhalation 6 hours per day, 5 days per week for 2 weeks. Only four female mice and one male mouse survived 10 exposures at 200 ppm. No deaths occurred at the lower doses. Neurobehavioral effects including trembling and paralysis were noted in all groups, but were most pronounced in the three highest dose groups. Red urine was noted in the mice exposed to 200 ppm. 13-Week Studies : Groups of 10 mice of each sex were exposed to 0, 10, 20, 40, 80, or 120 ppm methyl bromide by inhalation 6 hours per day, 5 days per week for 13 weeks. Additional groups of eight to 17 mice were concurrently exposed for neurobehavioral and genetic toxicology studies. The final mean body weight of males exposed to 120 ppm was significantly (12%) lower than that of the controls. Four of 24 males exposed to 120 ppm died during the study. Groups of 10 rats of each sex were exposed to 0, 30, 60, or 120 ppm methyl bromide by inhalation 6 hours per day, 5 days per week for 13 weeks. Additional groups of eight rats were concurrently exposed for neurobehavioral studies. Final mean body weights of rats exposed to 120 ppm were 12% lower than those of the controls for males and 13% lower for females. No rats died as a result of methyl bromide exposure during the studies. Special 6-Week Target Organ Toxicity Studies: Neither the 14-day nor the 13-week studies provided strong evidence for specific organ toxicity. Six-week studies were therefore conducted to identify target organs for the 2-year studies. Groups of 20 rats and mice of each sex were exposed to methyl bromide by inhalation for 6 hours per day, 5 days per week for 6 weeks at a dose of 160 ppm. Mortality rates exceeded 50% in the male mice after eight exposures, in female mice after six exposures, and in male rats after 14 exposures. Only the female rat group survived 30 exposures with less than 50% mortality. The study identified the brain, kidney, nasal cavity, heart, adrenal gland, liver, and testis as the primary organs to examine for toxicity in the 2-year methyl bromide inhalation studies. 2-Year Studies: Groups of 70 B6C3F1 mice of each sex were exposed to methyl bromide by inhalation at 0, 10, 33, or 100 ppm for 6 hours per day, 5 days per week for up to 103 weeks. Additional groups of 16 mice were included for neurobehavioral evaluations throughout the 2-year studies. By 20 weeks (139 days), 27 males and 7 females exposed to 100 ppm had died and methyl bromide exposure was discontinued for the remaining mice in this dose group. Ten female mice from the 100 ppm group predesignated for the 15-month interim evaluation were killed on schedule and all other high-dose animals were allowed to live to term (24 months) for evaluation of chronic toxicity and carcinogenicity. Clinical signs indicative of neurotoxicity, including tremors, abnormal posture, tachypnea, and hind leg paralysis, persisted in these high-dose mice until the end of the studies. Final mean body weights of surviving 100 ppm males and females were markedly lower (33% and 31%) than those of the controls. Neurobehavioral changes occurred in male and female mice initially exposed to 100 ppm methyl bromide, with more prnitially exposed to 100 ppm methyl bromide, with more pronounced changes observed in males. In general, these animals were less active and manifested a heightened sensitivity in the startle response than mice in other dose groups. Exposure to methyl bromide was not carcinogenic under the conditions of these studies. However, there was an increase in the incidence of several nonneoplastic lesions in the brain, heart, bone (sternum), and nose. Degenerative changes in the cerebellum and cerebrum occurred in males and females exposed to 100 ppm. Myocardial degeneration and cardiomyopathy were observed in the hearts of mice exposed to 100 ppm. An increased incidence of sternal dysplasia was seen in treated animals, particularly in those exposed to 100 ppm. An increased incidence of olfactory epithelial necrosis and metaplasia within the nasal cavity was seen in the mice exposed to 100 ppm, particularly males. Genetic Toxicology: Methyl bromide was positive for induction of gene mutations in Salmonella typhimuriumstrain TA100, with and without exogenous metabolic activation; negative results were obtained with TA98 in this assay. In vivo, methyl bromide induced sister chromatid exchanges in bone marrow cells and micronuclei in peripheral erythrocytes of female mice exposed by inhalation for 14 days. No significant increase in either sister chromatid exchanges or micronuclei was observed in male or female mice exposed to methyl bromide by inhalation for 4, 8, or 12 weeks. Conclusions: Under the conditions of these 2-year inhalation studies, methyl bromide caused degenerative changes in the cerebellum and cerebrum, myocardial degeneration and cardiomyopathy, sternal dysplasia, and olfactory epithelial necrosis and metaplasia. Toxic effects persisted although exposure to methyl bromide in the 100 ppm group terminated after 20 weeks. There was no evidence of carcinogenic activity of methyl bromide in male or female B6C3F1 mice exposed to 10, 33, or 100 ppm. Synonym: Bromomethane

Journal Article↗
PubMed1992

NTP Toxicology and Carcinogenesis Studies of C.I. Direct Blue 15 (CAS No. 2429-74-5) in F344 Rats (Drinking Water Studies).

C.I. Direct Blue 15 is one of five chemicals being evaluated in 2-year carcinogenicity and toxicity studies as part of the NTP's Benzidine Dye Initiative. This Initiative was designed to evaluate representative benzidine congeners, benzidine congener-derived dyes, and benzidine-derived dyes. The dye, industrial grade C.I. Direct Blue 15, was chosen for study as a product to which workers are potentially exposed. Because of the high salt content, the dye was desalted prior to use. The purity was determined to be approximately 50%, with high-performance liquid chromatography indicating one major peak and approximately 35 impurities. Toxicology and carcinogenesis studies were conducted by administering the dye, C.I. Direct Blue 15, in drinking water to groups of F344/N rats of each sex for 14 days, 13 weeks, or 22 months. Planned as 24-month studies, the 22-month studies were terminated early because of rapidly declining animal survival, which was due primarily to neoplasia. These studies were performed only in rats because studies of benzidine congeners were being performed in mice at the National Center for Toxicological Research (NCTR). Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary cells. 14-Day Studies: Rats were given C.I. Direct Blue 15 in drinking water at doses of 1,250, 2,500, 5,000, 10,000, or 30,000 ppm. All control and treated rats survived. Body weight gain in high-dose females was less than that in controls. Water consumption declined as the dose increased. Male and female rats receiving 30,000 ppm had slight degeneration and necrosis of individual hepatocytes in the liver, and females also had mild to moderate renal tubule degeneration and thymic lymphoid depletion. 13-Week Studies: C.I. Direct Blue 15 was administered in drinking water at doses of 0, 1,250, 2,500, 5,000, 10,000, or 30,000 ppm to male rats, and at doses of 0, 630, 1,250, 2,500, 5,000, or 10,000 ppm to female rats. Seven of 10 male rats receiving 30,000 ppm died; all rats in the other groups survived until the end of the studies. Mean final body weights of males receiving 10,000 or 30,000 ppm were 92% and 69% of those of controls, and mean final body weights of females receiving 5,000 or 10,000 ppm were 97% and 94% of those of controls. Tissues from treated animals were stained blue. Compound-related lesions were seen in the kidney and liver of male rats given 30,000 ppm and in the kidney of males and females given 10,000 ppm. The renal lesions included necrosis, degeneration, pigmentation and regeneration of the tubule epithelium, and tubule mineralization. Liver lesions included centrilobular hepatocellular degeneration, fatty metamorphosis, and individual cell necrosis with slight periportal hepatocellular hypertrophy. Lymphoid depletion in the thymus was also seen in the high-dose males. Based on the results of the 14-day and 13-week studies, the high dose chosen for the 22-month studies was 2,500 ppm. 22-Month Studies: At study initiation, 70 rats of each sex were given 0 or 2,500 ppm C.I. Direct Blue 15, 45 rats of each sex were given 630 ppm, and 75 rats of each sex were given 1,250 ppm. Interim evaluations were made at 9 and 15 months. The average amounts of compound consumed per day by the six dose groups after week 52 of the studies were estimated to be 45, 90, and 215 mg/kg for male rats and 50, 100, and 200 mg/kg for female rats. Survival and Body Weights: The studies were terminated at 22 months due to extensive mortality associated with chemical-related neoplasia. Survival of control, 630, 1,250, and 2,500 ppm males at 22 months was 37/50, 8/35, 11/65, and 2/50; survival of females was 40/50, 13/35, 22/65, and 4/50. At 22 months, the mean final body weights of the 630, 1,250, and 2,500 ppm groups were 95%, 91%, and 81% of those of the control for male rats and 91% of those of the control for all female dose groups. Histopathologic Effects in the 22-Month Studies: At the 9-month interim evaluations, one adenoma of the Zymbal's gland was seen in a high-dose male rat, and three carcinmbal's gland was seen in a high-dose male rat, and three carcinomas of the clitoral gland were seen in the high-dose females. At the 15-month interim evaluations, Zymbal's gland neoplasms were seen in low- and high-dose males and all treated female dose groups. Mid- and high-dose males and females also had preputial or clitoral gland neoplasms, and a few neoplasms were present in the skin, small and large intestine, liver, and oral cavity of treated animals at 15 months. At the end of the study, neoplasms related to chemical administration were found in the Zymbal's gland, skin, oral cavity, and the preputial or clitoral gland in both male and female rats. Neoplasms related to chemical administration were also seen at other sites including the small and large intestine, liver, uterus, and brain. The incidence of mononuclear cell leukemia was also increased in treated rats. Genetic Toxicology: C.I. Direct Blue 15 was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, and TA98 when tested in a standard preincubation protocol with or without exogenous metabolic activation; however, when a specialized reductive metabolism protocol was used, C.I. Direct Blue demonstrated mutagenic activity in Salmonella strain TA1538. C.I. Direct Blue 15 did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells with or without S9 activation; reductive metabolism was not used in these cytogenetic tests. Conclusions: Under the conditions of these 22-month drinking water studies, there was clear evidence of carcinogenic activity of C.I. Direct Blue 15 (desalted industrial grade) in male F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, preputial gland, liver, oral cavity, and small and large intestine. Increased incidences of mononuclear cell leukemia and neoplasms of the brain may have been related to chemical administration. There was clear evidence of carcinogenic activity of C.I. Direct Blue 15 in female F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, clitoral gland, liver, oral cavity, small and large intestine, and uterus, and by mononuclear cell leukemia. Synonyms: Airedale Blue D, Aizen Direct Sky Blue 5BH, Amanil Sky Blue, Atlantic Sky Blue A, Atul Direct Sky Blue, Azine Sky Blue 5B, Belamine Sky Blue A, Benzanil Sky Blue, Benzo Sky Blue S, Benzo Sky Blue A-CF, Cartasol Blue 2GF, Chloramine Sky Blue A, Chloramine Sky Blue 4B, Chrome Leather Pure Blue, C.I. 24400, Cresotine Pure Blue, Diacotton Sky Blue 5B, Diamine Blue 6B, Diamine Sky Blue, Diaphtamine Pure Blue, Diazol Pure Blue 4B, 3,3'-[(3,3'-dimethoxy[1,1'-biphenyl]-4,4'-diyl)bis(azo)]bis[5-amino-4-hydroxy-2,-naphthalenedisulfonic acid] tetrasodium salt, Diphenyl Brilliant Blue, Diphenyl Sky Blue 6B, Direct Blue 10G, Direct Blue HH, Direct Pure Blue, Direct Pure Blue M, Direct Sky Blue (6CI), Direct Sky Blue A, Direct Sky Blue 5B, Enianil Pure Blue AN, Fenamin Sky Blue, Hispamin Sky Blue 3B, Kayafect Blue Y, Kayaku Direct Sky Blue 5B, Mitsui Direct Sky Blue 5B, Naphtamine Blue 10G, Niagara Blue 4B, Niagara Sky Blue, Nippon Direct Sky Blue, Nitto Direct Sky Blue 5B, Paper Blue S, Phenamine Sky Blue A, Pontamine Sky Blue 5BX, Shikiso Direct Sky Blue 5B, Sky Blue 4B, Sky Blue 5B, Tertrodirect Blue F, Vondacel Blue HH

Journal Article↗
PubMed1992

NTP Toxicology and Carcinogenesis Studies of Monochloroacetic Acid (CAS No. 79-11-8) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Monochloroacetic acid, a colorless crystalline material, is used as a postemergence contact herbicide and as an intermediate in the synthesis of other organic compounds. Toxicology and carcinogenicity studies were conducted by administering monochloroacetic acid (99% pure) in deionized water by gavage to groups of F344/N rats and B6C3F1 mice of each sex once daily, 5 days per week for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma L5178Y cells, Chinese hamster ovary cells, and Drosophila melanogaster. 16-Day Studies: Groups of five rats of each sex received 0, 7.5, 15, 30, 60, or 120 mg monochloroacetic acid/kg body weight. Doses administered to mice were 0, 15, 30, 60, 120, or 240 mg/kg to groups of five males and 0, 30, 60, 120, 240, or 480 mg/kg to groups of five females. One of five male rats given 120 mg/kg died during the studies. Clear nasal discharge, lacrimation, or both, were observed in all groups of male and female rats receiving monochloroacetic acid. No compound-related gross lesions were observed in rats. All male mice given 240 mg/kg and all females given 240 or 480 mg/kg died during the studies. Hypoactivity, piloerection, ataxia, and lacrimation were observed in mice given 240 or 480 mg/kg. No compound-related gross lesions were observed in mice at necropsy. 13-Week Studies: Groups of 20 rats of each sex received 0, 30, 60, 90, 120, or 150 mg/kg monochloroacetic acid, and groups of 20 mice of each sex received doses of 0, 25, 50, 100, 150, or 200 mg/kg. Three to five animals in each dose group were killed at weeks 4 and 8 for the evaluation of hematology parameters. Compound-related deaths occurred in rats in the three highest dose groups (all males given 120 or 150 mg/kg, 9/10 males given 90 mg/kg, and all females given 90 to 150 mg/kg) and in mice given 200 mg/kg (all males and 2/10 females). Final mean body weights of surviving rats and mice receiving monochloroacetic acid were similar to those of controls. In rats, dose-related increases in blood urea nitrogen, alanine aminotransferase, and aspartate aminotransferase levels were observed, and relative liver and kidney weights were elevated. There were no compound-related changes in the various hematologic or clinical pathology parameters in mice. A dose-related increase in the incidence and severity of cardiomyopathy was observed in male and female rats receiving monochloroacetic acid, and hepatocellular cytoplasmic vacuolization was observed in the high-dose mice that died during the studies. 2-Year Studies: Based on the mortality and compound-related histopathologic lesions observed in the 13-week studies, doses selected for the 2-year studies of monochloroacetic acid were 0, 15, or 30 mg/kg, administered to groups of 70 rats of each sex, and 0, 50, or 100 mg/kg, administered to groups of 60 mice of each sex. Interim evaluations were conducted on 10 rats per dose group after 6 months of treatment with monochloroacetic acid and on seven rats per dose group after 15 months of treatment. Body Weight and Survival in the 2-Year Studies: Mean body weights of low- and high-dose female and low-dose male rats receiving monochloroacetic acid were within 10% of those of controls throughout the studies; however, after week 30, the mean body weights of high-dose male rats were 4% to 8% less than those of controls. In mice, the mean body weights of dosed males were similar to controls, but those of low- and high-dose females were 6% to 10% less than control values after week 52. Survival of high-dose male and dosed female rats and high-dose male mice was significantly lower than that of controls (male rats: control, 27/53; low-dose, 21/53; high-dose, 16/53; female rats: 37/53; 19/53; 26/53; male mice: 46/60; 39/60; 21/60; female mice: 42/60; 40/60; 44/60). Neoplasms and Nonneoplastic Lesions in the 2-Year Studies: There was no compound-related increase in the incidence of neoplasms or nonneoplastic lesions in rats given monochloroacetic acid for 2 years. The incidence of uterine stromal polypss. The incidence of uterine stromal polyps in low- and high-dose female rats was slightly higher than that in controls (2/60; 7/57; 10/60). However, the incidence in the controls was unusually low, and those in the dosed groups were well within the range for NTP historical controls (mean: 21%, range: 10%-38%). Further, because the only malignant stromal neoplasm occurred in a control animal, the polyps were not considered to be related to the administration of monochloroacetic acid. Similarly, there was no monochloroacetic acid-related increase in the incidence of neoplasms in male or female mice, and malignant lymphoma occurred with a significant negative trend in dosed female mice. Increases in the incidence of inflammation of the mucosa of the nasal passages, respiratory epithelial metaplasia of the olfactory epithelium of the nose, and focal squamous cell hyperplasia of the forestomach occurred in dosed male and female mice. Genetic Toxicology: Monochloroacetic acid was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98, with or without exogenous metabolic activation (S9). It induced trifluorothymidine resistance in L5178Y cells in the absence of S9 and induced sister chromatid exchanges without S9 in Chinese hamster ovary cells. Monochloroacetic acid did not induce a significant increase in chromosomal aberrations in Chinese hamster ovary cells, with or without S9. Monochloroacetic acid administered in feed was negative for the induction of sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster; however, when it was administered by injection, the results were equivocal. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity for monochloroacetic acid in male or female F344/N rats given 15 or 30 mg/kg. There was no evidence of carcinogenic activity for monochloroacetic acid in male or female B6C3F1 mice given 50 or 100 mg/kg. Monochloroacetic acid administration was associated with inflammatory lesions of the nasal mucosa, metaplasia of the olfactory epithelium, and squamous cell hyperplasia of the forestomach in male and female mice. Synonyms: Chloroacetic acid, a-chloroacetic acid, chloroethanoic acid

Journal Article↗
PubMed1992

NTP Toxicology and Carcinogenesis Studies of Chlorinated Water (CAS Nos. 7782-50-5 and 7681-52-9) and Chloraminated Water (CAS No. 10599-90-3) (Deionized and Charcoal-Filtered) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies).

Chlorine and chloramine are used as disinfectants in water supplies to prevent the spread of waterborne diseases. The U.S. Environmental Protection Agency and the U.S. Congress, through the Safe Drinking Water Acts and Amendments, initiated studies to determine the most effective way to disinfect water supplies and, at the same time, minimize any potential long-term health effects associated with direct chemical exposure or indirect chemical exposure through the formation of byproducts. As part of this evaluation, 2-year studies of chlorinated or chloraminated deionized charcoal-filtered drinking water were conducted in F344/N rats and B6C3F1 mice to determine the potential toxicity and carcinogenicity associated with prolonged exposure and eliminate possible confounding effects of byproducts of chlorination. Chlorinated Water Studies: Water containing 0, 70, 140, or 275 ppm chlorine (based on available atomic chlorine) was provided to groups of 70 F344/N rats or B6C3F1 mice of each sex for up to 2 years. Groups of 10 rats or mice of each sex were predesignated for evaluation at 14 or 15 weeks and 66 weeks. Survival at 2 years of rats and mice receiving chlorinated water was similar to that of the controls. Mean body weights of dosed male rats, high-dose female rats, and dosed mice were slightly lower than those of their respective control groups. There was a dose-related decrease in water consumption by rats and mice. Water consumption by high-dose rats during the second year of the studies was 21% lower than controls for males and 23% lower than controls for females; water consumption by high-dose mice was 31% lower than controls for males and 26% lower than controls for females. The incidence of mononuclear cell leukemia in mid-dose, but not high-dose, female rats was significantly higher than that in controls (control, 8/50; low-dose, 7/50; mid-dose, 19/51; high-dose, 16/50). The proportion of female rats that died of leukemia before the end of the study and the mean time for observation of animals dying with leukemia were similar among all dose groups and controls. Although the marginal increase in leukemia incidence in the mid- and high-dose female rats suggested a possible association with the administration of chlorinated water, the incidence of leukemia was not clearly dose related. There was no indication of reduced latency of leukemia, and the incidence of leukemia in concurrent controls was less than the mean for historical controls; furthermore, there was no supporting evidence of an effect in male rats. Thus, the marginal increase in leukemia incidence in female rats was considered equivocal evidence of carcinogenic activity. There were no neoplasms or nonneoplastic lesions in male rats or in male or female mice that were clearly associated with the consumption of chlorinated water. Chloraminated Water Studies: Water containing 50, 100, or 200 ppm chloramine was provided to groups of 70 F344/N rats or B6C3F1 mice of each sex for up to 2 years. The same control groups were used for the chlorinated water and chloraminated water studies. Groups of 9 or 10 rats or mice of each sex were evaluated at 14 or 15 weeks and 66 weeks. Survival at 2 years of rats and mice receiving chloraminated water was similar to that of the controls. Mean body weights of high-dose rats and dosed mice were lower than those of their respective control groups. There was a dose-related decrease in water consumption by rats and mice. Water consumption during the second year of the studies by high-dose rats was 34% lower than controls for males and 31% lower than controls for females; water consumption by high-dose mice was 42% lower than controls for males and 40% lower than controls for females. Mononuclear cell leukemia occurred with a marginally increased incidence in the mid- and high-dose female rats receiving chloraminated water (control, 8/50; low dose, 11/50; mid dose, 15/50; and high dose, 16/50). As in female rats receiving chlorinated water, the proportion of female rats that died of leukemia before the end of the study and t that died of leukemia before the end of the study and the mean time for observation of animals dying with leukemia were similar among all dose groups and controls. The marginal increase in leukemia incidence in females receiving chloraminated water was considered equivocal evidence of carcinogenic activity for the same reasons given for female rats receiving chlorinated water. There were no neoplasms or nonneoplastic lesions in male rats or in male or female mice that were clearly associated with the consumption of chloraminated water. Conclusions: Under the conditions of these 2-year drinking water studies, there was no evidence of carcinogenic activity of chlorinated water in male F344/N rats receiving 70, 140, or 275 ppm. There was equivocal evidence of carcinogenic activity of chlorinated water in female F344/N rats based on an increase in the incidence of mononuclear cell leukemia. There was no evidence of carcinogenic activity of chlorinated water in male or female B6C3F1 mice receiving 70, 140, or 275 ppm. Under the conditions of these 2-year drinking water studies, there was no evidence of carcinogenic activity of chloraminated water in male F344/N rats receiving 50, 100, or 200 ppm. There was equivocal evidence of carcinogenic activity of chloraminated water in female F344/N rats based on an increase in the incidence of mononuclear cell leukemia. There was no evidence of carcinogenic activity of chloraminated water in male or female B6C3F1 mice receiving 50, 100, or 200 ppm.

Journal Article↗
PubMed1992

NTP Toxicology and Carcinogenesis Studies of Ethylene Thiourea (CAS: 96-45-7) in F344 Rats and B6C3F1 Mice (Feed Studies).

Ethylene thiourea is a white crystalline solid used extensively in the rubber industry as an accelerator in the vulcanization of elastomers. It is also a trace contaminant and metabolic degradation product of a widely used class of ethylene bisdithiocarbamate fungicides. Ethylene thiourea is known to produce thyroid neoplasms in rats and liver neoplasms in mice following long-term administration; thus, it was chosen by the National Toxicology Program in an investigation of the potential value of perinatal exposures in assessing chemical carcinogenicity. Chronic toxicity and carcinogenicity studies of ethylene thiourea, 99% pure, were conducted in F344/N rats and B6C3F1 mice of each sex. The studies were designed to determine 1) the effects of ethylene thiourea in rats and mice receiving adult exposure only (a typical carcinogenicity study), 2) the toxic and carcinogenic effects of ethylene thiourea on rats and mice receiving perinatal exposure only (dietary exposure of dams prior to breeding and throughout gestation and lactation), and 3) the effects of combined perinatal and adult exposure to ethylene thiourea. STUDIES IN F344/N RATS: In a preliminary study to determine the perinatal dietary concentrations for the 2-year studies, female F344/N rats were fed 0, 8, 25, 83, or 250 ppm ethylene thiourea in the feed beginning 2 weeks prior to breeding and continuing throughout gestation and lactation, and the pups were fed at these same concentrations up to 9 weeks postweaning. Based on decreased survival of rat pups between postnatal days 0 to 4 and reduction in body weight gains in male weanling rats receiving 250 ppm, dietary concentrations of 0, 9, 30, and 90 ppm were selected for the perinatal (F0) exposure levels in the 2-year studies. Groups of 10 male and 10 female rats, 8 to 9 weeks of age, were fed diets containing 0, 60, 125, 250, 500, or 750 ppm ethylene thiourea for 13 weeks to determine the adult dietary concentrations. Because of reduced weight gains and decreased feed consumption in rats receiving 500 or 750 ppm ethylene thiourea, dietary concentrations of 0, 25, 83, and 250 ppm were selected for the adult (F1) exposure during the 2-year studies. In the 2-year studies, perinatal and adult exposures to ethylene thiourea were applied separately and together to groups of male or female rats as shown in the following table. The principal toxic effects of ethylene thiourea involved the thyroid gland. Serum levels of thyroxine (T4) and/or triiodothyronine (T3) were significantly decreased in rats receiving adult concentrations of 83 or 250 ppm, and thyrotropin (thyroid-stimulating hormone, TSH) was significantly increased at these concentrations. In male and female rats receiving adult-only exposure of 83 or 250 ppm, the incidences of follicular cell hyperplasia or follicular cell adenoma of the thyroid gland were significantly increased relative to the controls. The incidences of follicular cell carcinoma were significantly increased in the 250 ppm groups, and carcinomas occurred more frequently in males than in females. Exposure Groups of Rats in the 2-Year Feed Studies of Ethylene Thiourea a F1 Concentration (ppm)b F0(ppm)c 0 25 83 250 0 60 -- 60 60 9 -- 60 -- -- 30 -- -- 60 -- 90 60 -- 60 60 a Ten rats from each group were sacrificed and evaluated at 9 months b Concentration of ethylene thiourea in feed given to rats beginning at 8 weeks of age for 24 months c Concentration of ethylene thiourea in feed through breeding, gestation, and lactation until pups were 8 weeks of age Perinatal-only exposure to 90 ppm had no effect on the incidence of thyroid neoplasms in these studies, although there was a marginal increase in follicular cell hyperplasia relative to the controls. However, for groups of rats receiving combined perinatal and adult exposure (F0:F1), males and females receiving concentrations of 90:250 ppm ethylene thiourea had significantly increased incidences of thyroid follicular cell neoplasms relative to those receiving adult-only exposure to 250 ppm. Further, groups of male rats receiving 90:83 ppm 83 ppm showed a significantly increased incidence of follicular cell hyperplasia. Final mean body weights of males and survival of males and females receiving combined perinatal (90 ppm) and adult (250 ppm) exposure were lower than those receiving adult-only exposure of 250 ppm. Thus, in rats, combined perinatal and adult exposure slightly enhanced the toxicity and proliferative effects on the thyroid gland observed with adult-only exposure to ethylene thiourea. Neoplasms of the Zymbal's gland were marginally increased in rats receiving 90:250 ppm (males - 0:0, 1/50; 90:250, 5/50; females - 0:0, 1/50; 90:250, 4/50). Mononuclear cell leukemia occurred with a significant trend in groups of male and female rats receiving perinatal exposure of 90 ppm and increasing adult concentrations (90:0, 90:83, and 90:250 ppm), and for female rats without perinatal exposure (0:0, 0:83, and 0:250 ppm). The incidences of mononuclear cell leukemia in males receiving 90:83 ppm and males and females receiving 90:250 ppm were statistically significant relative to the respective 0:0 ppm groups. Low incidences of renal tubule cell adenomas occurred in most dose groups of male rats, but not in the highest dose group or the controls. STUDIES IN B6C3F1 MICE: In a preliminary study to determine the perinatal dietary concentrations for the 2-year studies, adult female C57BL/6N mice were fed 0, 33, 100, 330, or 1,000 ppm ethylene thiourea in the feed beginning 2 weeks prior to breeding and continuing throughout gestation and lactation and up to 9 weeks postweaning. Because of reduced survival of mouse pups at postnatal day 28 and lower final mean body weights in weanlings receiving perinatal exposure of 1,000 ppm, dietary concentrations of 0, 33, 110, and 330 ppm were selected for the perinatal exposure levels in the 2-year studies. Groups of 10 male and 10 female mice, 8 to 9 weeks of age, were fed diets containing 0, 125, 250, 500, 1,000, or 2,000 ppm ethylene thiourea for 13 weeks to determine the adult dietary concentrations. Moderately severe diffuse follicular cell hyperplasia in the thyroid gland and centrilobular cytomegaly of the liver occurred in mice receiving 2,000 ppm. Because the severity of the thyroid lesion (and degree of hypothyroidism) at this concentration was considered potentially life threatening in 2-year studies, dietary concentrations of 0, 100, 330, and 1,000 ppm ethylene thiourea were selected for adult exposure during the 2-year studies. In the 2-year studies, perinatal and adult exposures to ethylene thiourea were applied separately and together to groups of male or female mice as shown in the following table. Exposure Groups of Mice in the 2-Year Feed Studies of Ethylene Thiourea a F1 Concentration (ppm)b F0(ppm)c 0 100 330 1,000 0 69 -- 60 60 33 -- 34/29d -- -- 110 -- -- 60 -- 330 60 -- 60 60 a Ten mice from each group except the 33:100 ppm group were sacrificed and evaluated at 9 months b Concentration of ethylene thiourea in feed given to mice beginning at 8 weeks of age for 24 months c Concentration of ethylene thiourea in feed through breeding, gestation, and lactation until pups were 8 weeks of age d 34 males and 29 females assigned to group The principal toxic effects of ethylene thiourea in mice occurred in the thyroid gland, liver, and pituitary gland. Serum levels of T3 were significantly decreased in groups of mice receiving adult concentrations of 1,000 ppm; TSH was significantly increased in mice receiving 330 and 1,000 ppm. The incidences of follicular cell hyperplasia and neoplasia increased principally in males receiving 1,000 ppm and in females receiving 330 or 1,000 ppm. Follicular cell carcinomas were significantly increased in mice receiving 1,000 ppm. Incidences of centrilobular hepatocellular cytomegaly (males and females), hepatocellular adenoma (females), hepatocellular carcinoma (males and females), and adenoma or carcinoma combined (males and females) also were significantly increased in mice receiving F1 concentrations of 330 or 1,000 ppm. In the pituitary gland, incidences of focal hyperplasia (males) or adenoma (males and females) of the pars distalis were significantly increased in groups of mice receiving 1,000 ppm ethylene thiourea. Perinatal exposure to concentrations of 330 ppm had no effect on the incidences of nonneoplastic lesions or neoplasms in mice. For groups of mice receiving combined perinatal and adult exposure, females receiving F0:F1 concentrations of 330:330 ppm had significantly increased incidences of follicular cell adenoma relative to those receiving adult-only exposure to 330 ppm. Similarly, male mice receiving F0:F1 concentrations of 330:330 ppm had significantly increased incidences of follicular cell hyperplasia. Thus, in mice, perinatal exposure slightly enhanced the proliferative effects on the thyroid gland of adult exposure. There were no effects of perinatal exposure in mice at sites other than in the thyroid gland. CONCLUSIONS: 2-Year Adult-Only Exposure:Under the conditions of these 2-year adult-only dietary exposures, there was clear evidence of carcinogenic activity of ethylene thiourea in male and female F344/N rats, as shown by increased incidences of thyroid follicular cell neoplasms. There was clear evidence of carcinogenic activity of ethylene thiourea in male and female B6C3F1 mice as shown by increased incidences of thyroid follicular cell neoplasms, hepatocellular neoplasms, and adenomas of the pars distalis of the pituitary gland. Nonneoplastic lesions associated with the administration of ethylene thiourea included follicular cell hyperplasia in rats and mice and follicular cell cytoplasmic vacuolation, centrilobular hepatocellular cytomegaly, and focal hyperplasia of the pars distalis of the pituitary gland in mice. Other effects associated with the administration of ethylene thiourea included decreased serum levels of T4 and/or T3 in rats and increased serum levels of TSH in rats and mice. Perinatal-Only Exposure:Perinatal exposure alone had no effect on the incidences of neoplasms in rats or mice after 2 years. Animals may have been able to tolerate higher perinatal exposure concentrations. Combined Perinatal and 2-Year Adult Exposures:Combined perinatal and 2-year adult dietary exposure to ethylene thiourea confirmed the findings of the 2-year adult-only exposures for the incidences of neoplasms in the thyroid gland of rats and mice and the liver and pituitary gland of mice. In male and female rats, combined perinatal and adult exposure to 90:250 ppm was associated with marginal increases, relative to the untreated (0:0 ppm) controls, in Zymbal's gland neoplasms and mononuclear cell leukemia, which may have been related to chemical administration. In rats receiving adult exposure to 250 ppm ethylene thiourea, perinatal exposure to 90 ppm was associated with a slightly enhanced incidence of thyroid neoplasms compared to adult-only exposure. However, increasing perinatal exposure from 0 to 90 ppm had no effect on incidences of thyroid neoplasms in rats receiving adult exposure to 83 ppm. Increasing perinatal exposure from 0 to 330 ppm was associated with a marginally increased incidence of thyroid neoplasms in female mice receiving adult exposure to 330 ppm, but there were no enhancing effects of perinatal exposure in mice receiving adult exposure to 1,000 ppm. Synonyms: 2-Imidazolidinethione; Imidazoline-2-thiol; 2-mercaptoimidazoline; N,N'-ethylenethiourea; 1,3-ethylenethiourea; 2-imadazoline-2-thiol

Journal Article↗
PubMed1991

Toxicology and Carcinogenesis Studies of C.I. Acid Red 114 (CAS No. 6459-94-5) in F344/N Rats (Drinking Water Studies).

C.I. Acid Red 114 is one of five chemicals being evaluated in 2-year carcinogenicity and toxicity studies as part of the NTP's Benzidine Dye Initiative. This Initiative was designed to evaluate representative benzidine congeners, benzidine congener-derived dyes, and benzidine-derived dyes. C.I. Acid Red 114 was nominated for study because of the potential for human exposure during production of bisazobiphenyl dyes and because benzidine, a structurally related chemical, is a known human carcinogen. Toxicology and carcinogenesis studies were conducted by administering desalted, industrial grade C.I. Acid Red 114 in drinking water to groups of F344/N rats of each sex for 13 days, 13 weeks, 9 or 15 months, or 2 years. These studies were performed only in rats because studies of benzidine congeners were being performed in mice at the National Center for Toxicological Research (NCTR). Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary cells, and Drosophila melanogaster. 13-Day Studies: Rats were exposed to C.I. Acid Red 114 in drinking water at doses of 0, 10,000, 20,000, or 30,000 ppm. All control and dosed rats survived except one male rat in the 20,000 ppm dose group. Final mean body weights in the three dosed groups were 94%, 83%, or 77% of controls for males and 92%, 88%, or 80% of controls for females. Water consumption declined with increased dose. Clinical findings included red stained fur, ears, and tail in all test animals. On gross necropsy, organs and tissues were also stained red. 13-Week Studies: C.I. Acid Red 114 was administered in drinking water at doses of 0, 600, 1,200, 2,500, 5,000, or 10,000 ppm. All control and dosed animals survived until the end of the study. Final mean body weights in the five dosed groups were 97%, 89%, 87%, 87%, or 85% of controls for males and 97%, 94%, 94%, 92%, or 89% of controls for females. Water consumption was decreased in dosed animals. As was seen in the 13-day studies, major organs and tissues from treated animals were stained red. Kidney toxicity characterized by regeneration and karyomegaly of tubule epithelial cells with chronic inflammation was observed in female rats at doses of 1,200 ppm or above. Treatment-related increases in relative liver weights and elevated liver enzyme levels were seen in males and females, centrilobular pallor in the liver was seen in all male dose groups. Because of these body weight differences, decreases in water consumption, and organ toxicity, the doses chosen for the 2-year studies were 70,150, and 300 ppm for males and 150, 300, and 600 for females. 2-Year Studies: Male rats received doses of 0, 70, 150, or 300 ppm of C.I. Acid Red 114, and female rats received 0, 150, 300, or 600 ppm. Seventy animals were in the control and high-dose groups, 45 in the low-dose groups, and 75 in the mid-dose groups. Ten animals were evaluated from the control and high-dose groups at 9 months, and ten animals from all dose groups were evaluated at 15 months. The average amount of compound consumed per day was 4, 8, or 20 mg/kg for males and 9, 20, or 70 mg/kg for females. Survival and Body Weights: Survival at 105 weeks for male rats receiving 0, 70, 150, or 300 ppm was 24/50, 15/35, 26/65, and 1/50; for females receiving 0, 150, or 300 ppm, survival was 36/50, 13/35, and 6/64. All female rats receiving 600 ppm died by week 89. The decreased survival in treated groups was due primarily to the development of chemical-related neoplasms. Of the surviving animals, the final mean body weights for males receiving 70 or 150 ppm were 94% and 90% of control and for females receiving 150 or 300 ppm, 99% and 84% of control. These weight differences began in the second year of the studies and were attributed in part to the development of neoplasms in the dosed groups. Histopathologic Effects in the 2-Year Studies: At 9 and 15 months, a few neoplasms were seen in the liver, lung, clitoral gland, skin, Zymbal's gland, oral cavity epithelium, and small and large intestine, and the number of neoplasms at these sites increased as gland, skin, Zymbal's gland, oral cavity epithelium, and small and large intestine, and the number of neoplasms at these sites increased as the studies progressed. At 2 years, there was a clear carcinogenic response in the skin, Zymbal's gland, and liver of male and female rats, and in the clitoral gland, oral cavity epithelium, small and large intestine, and lung in female rats. Treatment-related increases were also seen in the incidence in neoplasms of the oral cavity epithelium, adrenal gland, and lung of male rats, and in mononuclear cell leukemia and in neoplasms of the mammary gland and adrenal gland in female rats. The incidence of these neoplasms was generally lower, but was significant and considered to be marginally related to chemical treatment. The same neoplastic effects have been previously observed in some or all of the NTP studies with dimethoxybenzidine, dimethylbenzidine, or C.I. Direct Blue 15. Genetic Toxicology: In a standard preincubation protocol, C.I. Acid Red 114 was mutagenic in Salmonella typhimurium strain TA98 in the presence of induced hamster liver S9, and an equivocal response was noted in strain TA100 with hamster liver S9. However, no significant mutagenic activity was noted in strains TA1535 or TA1537 with or without S9 activation. In a modified S. typhimurium gene mutation test which employed reductive metabolism followed by oxidative metabolism with S9 liver enzymes, C.I. Acid Red 114 was strongly mutagenic in strain TA1538. C.I. Acid Red 114 did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells with or without S9 activation; reductive metabolism was not used in these cytogenetic tests. No increase in sex-linked recessive lethal mutations was observed in germ cells of male Drosophila melanogaster administered C.I. Acid Red 114 by feeding or injection. Conclusions: Under the conditions of these 2-year drinking water studies, there was clear evidence of carcinogenic activity of C.I. Acid Red 114 for male F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, and liver. Increased incidences of neoplasms of the oral cavity epithelium, adrenal gland, and lung may have been related to chemical administration. There was clear evidence of carcinogenic activity for female F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, clitoral gland, liver, oral cavity epithelium, small and large intestines, and lung. Increased incidences of mononuclear cell leukemia, mammary gland adenocarcinoma, and adrenal gland pheochromocytomas may have been related to chemical administration. Synonyms: 1,3-Naphthalenedisulfonic acid, 8-((3,3'-dimethyl-4'-((4-(((4-methylphenyl)sulfonyl)oxy)phenyl)azo)(1,1'-bipheny)-4-yl)azo)-7-hydroxy, disodium salt, Acid Leather Red BG, Acid Red 114, Amacid Milling Red PRS, Benzyl Fast Red BG, Benzyl Red BR, Cerven Kysela, C.I. 23635, Erionyl Red RS, Folan Red B, Kayanol Milling Red RS, Leather Fast Red B, Levanol Red GG, Midlon Red PRS, Milling Red B, Milling Red BB, Milling Red SWB, NCI C61096, Polar Red RS, Sandolan Red N-RS, Sella Fast Red RS, Sulphonol Fast Red R, Supranol Fast Red GG, Supranol Red PBX-CF, Supranol Red R, Telon Fast Red GG, Tertracid Milling Red B, Vondamol Fast Red RS

Journal Article↗