UMLS:C0023418 - FACTA Search

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N,N-Dimethylaniline is used as a chemical intermediate in the synthesis of dyestuffs. Toxicology and carcinogenesis studies were conducted by administering N,N-dimethylaniline (greater than 98% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 2 weeks, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma cells, and Chinese hamster ovary (CHO) cells. Two-Week and Thirteen-Week Studies: In the 2-week studies, doses were 94-1,500 mg/kg; deaths of rats and mice were observed in groups given doses of 750 or 1,500 mg/kg. The final mean body weights of male rats that received 375 or 750 mg/kg were 15% or 47% lower than that of vehicle controls; final mean body weights of other groups of rats and mice were similar to those of vehicle controls. Compound-related clinical signs observed included cyanosis in rats and lethargy and tremors in rats and mice. Splenomegaly occurred in nearly all dosed groups of rats and mice, and the incidences were dose related. In the 13-week studies, doses were 32-500 mg/kg; no compound-related deaths occurred. The final mean body weights of male rats that received 250 or 500 mg/kg were 15% or 27% lower than that of vehicle controls. The final mean body weights of all groups of dosed female rats and male and female mice were within 12% of those of vehicle controls. Compound-related clinical signs included lethargy in rats and mice and cyanosis in rats. Splenomegaly was observed in all dosed groups of rats and mice; the severity was dose related. Compound-related extramedullary hematopoiesis and hemosiderosis occurred in the kidney or testis of dosed rats and liver and spleen of dosed rats and mice. Two-year studies were conducted by administering 0, 3, or 30 mg/kg N,N-dimethylaniline in corn oil by gavage, 5 days per week for 103 weeks, to groups of 50 rats of each sex. The lower dose was selected to be one-tenth the higher dose to increase the likelihood that one dose would cause only a minimal nonneoplastic response. Groups of 50 mice of each sex were administered 0, 15, or 30 mg/kg on the same schedule. Body Weight and Survival in the Two-Year Studies: Mean body weights of vehicle control and dosed rats and mice were similar throughout the studies. Survival rates of all respective groups were similar after 2 years, except for the lowered survival of vehicle control female rats (vehicle control, 21/50; low dose 32/50; high dose, 36/50). This may reflect the large number (24/50) of vehicle control female rats killed when observed to be in a moribund state. Final survival for other groups was as follows: male rats--29/50; 32/50; 28/50; male mice-- 34/50; 30/50; 34/50; female mice--35/50; 39/50; 33/50. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: In these 2-year studies, the spleen was the expected site of chemical-related effects. Fatty metamorphosis and fibrosis in the spleen of high dose male rats were increased (fatty metamorphosis: vehicle control, 0/49; low dose, 1/49; high dose, 10/50; fibrosis: 5/49; 2/49; 22/50). Splenic hemosiderosis and hematopoiesis were present at an incidence greater than 85% in all groups of rats; however, the severity of the lesions was greater in dosed groups than in vehicle controls. Sarcomas of the spleen were seen in 3/50 high dose male rats, and an osteosarcoma was seen in another high dose male rat. One additional high dose male rat had a sarcoma of the thymus. Splenic sarcomas are uncommon in corn oil vehicle control male F344/N rats (NTP historical incidence 3/2,081, 0.1%), and thus, these neoplasms in high dose male rats (4/50, 8%) were considered to be chemically related. Lower incidences of mononuclear cell leukemia (which apparently originates in the spleen) were seen in dosed male and female rats than in vehicle controls (male: 13/50; 4/50; 3/50; female: 11/50; 7/50; 0/50). The incidence of squamous cell papillomas of the forestomach in high dose female mice was marginally greater than that in vehicle controls (2/50; 2/50; 8/50). No malignant forestomacin vehicle controls (2/50; 2/50; 8/50). No malignant forestomach neoplasms were observed. Genetic Toxicology: N,N-Dimethylaniline was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 in the presence or absence of exogenous metabolic activation. In the mouse lymphoma assay, N,N-dimethylaniline produced a positive response with and without metabolic activation. In CHO cells, N,N-dimethylaniline induced both sister chromatid exchanges (SCEs) and chromosomal aberrations in the presence of exogenous metabolic activation. Without activation, an increase in chromosomal aberrations was observed, but no increase in SCEs occurred. Conclusions: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of N,N-dimethylaniline for male F344/N rats, as indicated by the increased incidences of sarcomas or osteosarcomas(combined) of the spleen. There was no evidence of carcinogenic activity of N,N-dimethylaniline for female F344/N rats given 3 or 30 mg/kg body weight by gavage for 2 years. There was no evidence of carcinogenic activity of N,N-dimethylaniline for male B6C3F1 mice given 15 or 30 mg/kg body weight by gavage for 2 years. There was equivocal evidence of carcinogenic activity of N,N-dimethylaniline for female B6C3F1 mice, as indicated by an increased incidence of squamous cell papillomas of the forestomach. Both rats and mice could have tolerated doses higher than those used in these studies. There were decreased incidences of mononuclear cell leukemia in dosed male and high dose female rats. Compound-related splenic fibrosis, hemosiderosis, and fatty metamorphosis were increased in male rats. Synonyms: dimethylaminobenzene; N,N-dimethylbenzeneamine; dimethylaniline; dimethylphenylamine; N,N-dimethylphenylamine
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PMID:Toxicology and Carcinogenesis Studies of N,N-Dimethylaniline (CAS No. 121-69-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1269 81

Nitrofurazone is a synthetic furan derivative, active against a broad spectrum of bacteria, which has been widely used in veterinary and human medicine. Toxicology and carcinogenesis studies were conducted by feeding diets containing nitrofurazone (99% pure) to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Fourteen-Day and Thirteen-Week Studies: Groups of five males and five females of each species were fed diets containing 0, 630, 1,250, 2,500, 5,000, or 10,000 ppm for 14 consecutive days. Early deaths occurred in all groups of rats receiving 5,000 or 10,000 ppm nitrofurazone. The surviving rats in the lower two dose groups gained weight, but weight gain was decreased as the dose of nitrofurazone was increased. Feed consumption by rats of each sex was decreased at all doses above 630 ppm. In all dosed groups, clinical signs of toxicity included rough hair coats and lethargy. At doses of 2,500 ppm and above, rats of each sex exhibited intermittent episodes of seizures and lethargy. All mice that received 2,500, 5,000, or 10,000 ppm nitrofurazone and 3/5 males that received 1,250 ppm died before the end of the 14-day studies; the surviving dosed mice (except females at 630 ppm) lost weight. A dose-related decrease in feed consumption was observed at all doses above 630 ppm. Clinical signs included rough hair coats and convulsive seizures. In the 13-week studies, groups of 10 rats of each sex were given diets containing 0, 150, 310, 620, 1,250, or 2,500 ppm nitrofurazone. No deaths were observed and all animals gained weight, but the magnitude of weight gain was dose dependent with decrements in final mean body weight for the highest dose group reaching 55% in males and 36% in females. Other evidence of chemically related toxicity included convulsive seizures, osteoporosis, degenerative arthropathy, and gonadal hypoplasia in both sexes at the two highest doses. Groups of 10 mice of each sex were given diets containing 0, 70, 150, 310, 620, or 1,250 ppm nitrofurazone for 13 weeks. Early deaths were observed in the two highest dose groups of each sex. The final mean body weights of male and female mice in the 1,250-ppm groups were about 20% lower than those of the controls; weight gains of the other dosed mice were comparable to those of the controls. Stimulus-induced convulsive seizures were observed for all mice in the two highest dose groups. Testicular hypoplasia was observed in the two highest dose groups of male mice. Body Weight and Survival in the Two-Year Studies: Dietary concentrations for the 2-year studies were 0, 310, or 620 ppm for rats and 0, 150, or 310 ppm for mice (50 animals per dose group). Mean body weights of high dose male rats were lower than those of the controls after week 39; mean body weights of low dose male rats and of the controls were comparable throughout the study. Final mean body weights of low and high dose female rats were 9% and 21% lower than those of the controls. Dosed rats consumed less feed than did the controls. The average amount of nitrofurazone consumed per day was approximately 11-12 or 24-26 mg/kg by low or high dose male and female rats. The survival of the high dose group of male rats was lower than that of the controls after week 92 (final survival-- male: control, 33/50; low dose, 30/50; high dose, 20/50; female: 28/50; 37/50; 31/50). Mean body weights of dosed mice were similar to or somewhat greater than those of controls throughout most of the studies. The average daily feed consumption by dosed mice was similar to that of controls. The average amount of nitrofurazone consumed per day was approximately 14-16 or 29-33 mg/kg for low or high dose male and female mice. The survival of the high dose group of male mice was lower than that of the controls after week 88 (final survival-- male: 39/50; 31/50; 27/50; female: 39/50; 40/50; 35/50). In mice of each sex, nitrofurazone administration induced stimulus-sensitive convulsive seizures beginning at week 4 or 5 for high dose mice and week 24 for low dose female mice. These seizures were low dose female mice. These seizures were observed primarily in the first year of the study. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Degenerative changes involving the vertebral and femoro-tibial (knee) joints were observed at increased incidences in dosed rats. The degenerative changes primarily affected the articular cartilage and were similar to those seen in the 13-week studies. Degeneration of the sternal synchondroses was increased in high dose female rats. The osteoporosis seen in the 13-week studies was not observed in the 2-year studies. Testicular degeneration, characterized by atrophy of the germinal epithelium and aspermatogenesis, was observed at increased incidences in dosed male rats (control, 12/50; low dose, 49/50; high dose, 47/50). Adenomas of the sebaceous glands and trichoepitheliomas or sebaceous adenomas (combined) of the skin were observed in high dose male rats (0/50; 0/50; 5/50). Carcinomas of the preputial gland were increased in dosed male rats (1/50; 8/50; 5/50). The incidences of preputial gland adenomas or carcinomas (combined) in dosed male rats were not statistically greater than that in the controls (9/50; 16/50; 7/50). However, in the low dose group, the incidence is greater than the highest incidence observed in historical untreated control groups (9/50). In addition, hyperplasia of the preputial gland was observed in six low dose male rats in which neither adenomas nor carcinomas occurred. The incidence of mesotheliomas of the tunica vaginalis in low dose male rats was greater than that in the controls (0/50; 7/50; 2/50). Fibroadenomas of the mammary gland occurred at markedly increased incidences in dosed female rats (8/49; 36/50; 36/50). Three adenocarcinomas were also observed (1/49; 0/50; 2/50). Ovarian atrophy (7/47; 44/50; 38/50) and tubular cell hyperplasia of the ovary (1/47; 23/50; 21/50) were observed at markedly increased incidences in dosed female mice. The incidences of benign mixed tumors (0/47; 17/50; 20/50), granulosa cell tumors (1/47; 4/50; 9/50), and granulosa cell tumors or luteomas (combined) (3/47; 6/50; 9/50) of the ovary were increased in exposed female mice. Mononuclear cell leukemia in rats occurred with negative trends (male: 21/50; 23/50; 6/50; female: 15/49; 2/50; 2/50). In female mice, the incidences of adenomas or carcinomas (combined) of the anterior pituitary gland occurred with a negative trend (10/50; 7/50; 2/49). The incidences of testicular interstitial cell tumors were decreased in dosed male rats (45/50; 30/50; 28/50). Genetic Toxicity: Nitrofurazone was mutagenic in Salmonella typhimurium strains TA98 and TA100 both with and without exogenous metabolic activation. The responses in strains TA1535 and TA1537 were more varied: nitrofurazone was mutagenic in strain TA1535 only in the presence of S9 and produced no consistent increase in gene reversions in strain TA1537 with or without S9. In the absence of metabolic activation, nitrofurazone induced forward mutations at the TK+/- locus of mouse L5178Y lymphoma cells; the chemical was not tested with S9. Treatment of cultured Chinese hamster ovary cells with nitrofurazone in the absence of S9 produced a dose-related increase in sister chromatid exchanges and chromosomal aberrations; with S9, sister chromatid exchanges were increased, but no induction of chromosomal aberrations was observed. Audit: The data, documents, and pathology materials from the 2-year studies of nitrofurazone were audited at the NTP Archives. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity of nitrofurazone for male F344/N rats as shown by the occurrence of sebaceous gland adenomas and trichoepitheliomas of the skin, mesotheliomas of the tunica vaginalis, and preputial gland tumors. There was clear evidence of carcinogenic activity of nitrofurazone for female F344/N rats as shown by a markedly increased incidence of fibroadenomas of the mammary gland. There was no evidence of carcinogenic activity for male B6C3F1 mice fed diets containing nitrofurazone at concentrations of 150 or 310 ppm. There was clear evidence of carcinogenic activity of nitrofurazone for female B6C3F1 mice as shown by increased incidences of benign mixed tumors and granulosa cell tumors of the ovary. Administration of nitrofurazone was associated with decreased incidences of mononuclear cell leukemia in male and female rats, testicular interstitial cell tumors in male rats, and pituitary gland neoplasms in female mice. Convulsive seizures in mice of each sex, ovarian atrophy in female mice, testicular degeneration in rats, and degeneration of articular cartilage in rats were all associated with the administration of nitrofurazone. Synonyms: 5-nitro-2-furaldehyde semicarbazone; 2-[(5-nitro-2-furanyl)methylene]hydrazine carboximide Trade Names: Aldomycin; Amifur; Chemfuran; Coxistat; Furacin; Furacinetten; Furaplast; Furazol W; Furesol; Furracoccid; Mammex; Nefco; Nifuzon; Nitrofural; Vabrocid
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PMID:NTP Toxicology and Carcinogenesis Studies of Nitrofurazone (CAS No. 59-87-0) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1273 99

N-Phenyl- 2- naphthylamine, formerly used as a antioxidant in the rubber industry, was selected for toxicology and carcinogenesis studies because at the time of nomination (1976) it had a large annual production and widespread human exposure. Additional reasons for selection included it structural similarity and possible metabolism to the known human urinary bladder carcinogen, 2-naphthylamine. Toxicology and carcinogenesis studies were conducted by feeding diets containing N-phenyl-2-naphthylamine (approximately 98% pure and containing less than 1 ppm 2-naphthylamine) at various concentrations to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Fourteen-Day and Thirteen-Week Studies: In 14-day studies, 3/5 male and 4/5 female rats that received 50,000 ppm N-phenyl-2-naphthylamine died before the end of the studies. Final mean body weights of rats that received 12,500 ppm or more were considerably lower (18%-57%) than those of the controls. Arched backs, rough coats, and diarrhea were observed for males that received 12,500 ppm or more and for females that received 25,000 or 50,000 ppm. All mice were alive at the end of the studies, and no compound-related clinical signs of toxicity were observed in mice given feed containing up to 20,000 ppm. In 13-week studies, deaths occurred in 4/10 male and 9/10 female rats that received the highest dose (40,000 ppm) of N-phenyl-2-naphthylamine. Final mean body weights of rats that received 5,000-40,000 ppm were 9%-60% lower than those of the controls. The liver weight to body weight ratios increased with increasing dose, with the ratios for male rats at 10,000 ppm or more and for female rats at 5,000 ppm being greater (P<0.05) than those of controls. A compound-related nephropathy occurred in rats and was characterized by renal tubular epithelial degeneration and hyperplasia. Other effects in rats included hematopoietic hypoplasia or atrophy of the femoral bone marrow, testicular hypospermatogenesis, lymphoid degeneration of the thymus, and lymphoid depletion of the spleen. In mice, 2/10 males and 7/10 females that received 40,000 ppm died before the end of the 13-week studies. The final mean body weights of mice that received 10,000, 20,000, or 40,000 ppm were 9%-32% lower than those of the controls. The liver weight to body weight ratios for mice increased with increasing dose. Those for male mice at 10,000 ppm or more and for female mice at 20,000 ppm or more were greater (P<0.05) than those for the controls. Nephropathywas observed at increased incidences and severity in dosed mice. Because of kidney lesions, liver enlargement, lower weight gain, and increased mortality in the shorter term studies, dietary concentrations of N-phenyl-2-naphthylamine selected for the 2-year studies in rats and mice were 0, 2,5000, and 5,000 ppm. Body Weight and Survival in the Two-Year Studies: The mean body weights of dosed rats were lower than those of the controls throughout the studies (12% and 16% lower for dosed males and 15% and 31% lower for dosed females at the end of the studies). The average daily feed consumption for rats was 94%-87% that of the controls for dosed males and 88% that of the controls for dosed females. The estimated average amount of N-phenyl-2-naphthylamine consumed per day was 100 mg/kg and 225 mg/kg for male rats and 120 mg/kg and 260 mg/kg for female rats. The survival of the high dose group of male rats was greater (P<0.05) than that of the controls after week 101 (male: control, 24/50; low dose, 28/50; high dose, 34/50; female: 26/50; 44/50; 38/50). Final mean body weights of high dose male and female mice were lower (male, 9%; female, 23%) than those of the controls. The estimated average daily feed consumption by dosed mice was within 10% that of the controls. The average amount of N-phenyl-2-naphthylamine consumed per day was approximately 500 or 1,000 mg/kg for male mice and 450 or 900 mg/kg for female mice. No significant differences in survival were observed between any groups of mice of either sex (male: control, 33/50; male mice. No significant differences in survival were observed between any groups of mice of either sex (male: control, 33/50; low dose, 36/50; high dose, 28/50; female: 36/50; 30/50; 35/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: As in the 13-week studies, the kidney was the principal target for toxic effects of N-phenyl-2-naphthylamine. Mineralization of the kidney, necrosis of the renal papilla, and epithelial hyperplasia and calculi of the kidney pelvis were observed at increased incidences in high dose female rats. Hydronephrosis, atrophy, fibrosis, and chronic focal inflammation of the kidney were observed at increased incidences in high dose female rats. Cysts and acute suppurative inflammation of the kidney were observed at increased incidences in dosed male and high dose female rats. No compound-related renal neoplasms were observed in rats. Nuclear enlargement of renal tubular epithelial cells and nephropathy were observed at increased incidences in high dose female mice. Atypical tubular cell hyperplasia occurred in two high dose female mice. A tubular cell adenoma was found in one high dose female mouse, and a tubular cell adenocarcinoma was found in another high dose female mouse. No renal neoplasms were observed in dosed male mice. Neoplasms of several organs occurred in rats with negative trends and/or at significantly lower incidences in high dose groups. These included thyroid gland C-cell neoplasms in males and females and mammary gland fibroadenomas, pituitary gland adenomas, and mononuclear cell leukemia in females. The lack of carcinogenicity in rats may be related to an inability to metabolize this compound to the known animal and human carcinogen 2-napththylamine. Genetic Toxicity: N-Phenyl-2-naphthylamine was not mutagenic in the Salmonella typhimurium/microsome assay with strains TA97, TA98, TA100, or TA1535 with or without induced hamster or rat liver S9. The chemical did not induce chromosomal aberrations in cultured Chinese hamster ovary (CHO) cells with or without metabolic activation. No increase in sister chromatid exchanges (SCEs) was observed in the absence of metabolic activation; in the presence of rat liver S9, the SCE results were judged to be equivocal. Data Audit: The data, documents, and pathology materials from the 2-year studies of N-phenyl-2-naphthylamine were audited at the NTP Archives. The audit findings show thatthe conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity for male or female F344/N rats fed diets containing 2,500 or 5,000 ppm N-phenyl-2-naphthylamine. Decreased incidences of several neoplasms were observed in dosed rats: thyroid gland C-cell neoplasms in males and females and mononuclear cell leukemia, pituitary gland adenomas, and mammary gland fibroadenomas in females. There was no evidence of carcinogenic activity for male B6C3F1 mice fed diets containing 2,500 or 5,000 ppm N-phenyl-2-naphthylamine. There was equivocal evidence of carcinogenic activity of N-phenyl-2-naphthylamine for female B6C3F1 mice as indicated by the occurrence of two rare kidney neoplasms. Chemical-related nonneoplastic lesions (nephropathy, karyomegaly, and hyperplasia) occurred in the kidney of rats and mice. Synonyms: N-(2-naphthyl)aniline; 2-naphthylphenylamine; b-naphthylphenylamine; 2-phenylaminonaphthalene; phenyl-b-naphthylamine; N-phenyl-b-naphthylamine Trade Names: Aceto PBN; Agerite Powder: Antioxidant 116; Neosone D; Neozon D; Nilox PBNA; Nonox D; PBNA; Stabilizator AR
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PMID:NTP Toxicology and Carcinogenesis Studies of N-Phenyl-2-naphthylamine (CAS No. 135-88-6) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1273 3

Toxicology and carcinogenesis studies of technical-grade 2-mercaptobenzothiazole (96%-97% pure), a rubber accelerant and preservative, were conducted by administering the chemical by gavage in a corn oil vehicle to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. 2-Mercaptobenzothiazole was nominated for study by the National Institute of Environmental Health Sciences and the National Institute for Occupational Safety and Health. Sixteen-Day and Thirteen-Week Studies: In 16-day studies, mean body weight gains of rats receiving 2,500 mg/kg were 6-7 g lower than those of vehicle controls; 4/5 male and 5/5 female mice dosed with 3,000 mg/kg and 4/5 female mice dosed with 1,500 mg/kg died; lethargy and prostration occurred in most of these animals after gavage. Based on these results, doses were selected for both species in the 13-week studies were 0, 94 (mice only), 188, 375, 750, and 1,500 mg/kg. In the 13-week studies, no chemical-related deaths occurred in rats, but body weight gains in males dosed with 1,500 mg/kg and in females dosed with 750 or 1,500 mg/kg were lower than those in the vehicle control groups. Hepatomegaly occurred at the two highest doses in males and at all doses in females; however, no microscopic pathologic changes were noted in any tissue. More than half the mice dosed with 1,500 mg/kg died, but no compound-related body weight changes occurred. Clinical signs in mice were dose related and included lethargy in animals dosed with 375 mg/kg and lacrimation, salivation, and clonic seizure in some dosed with 750 or 1,500 mg/kg. No association between these clinical signs of toxicity and gross or microscopic pathologic effects were observed. Doses selected for the 2-year studies were 0, 375, and 750 mg/kg for male rats and for mice of each sex and 0, 188, or 375 mg/kg for female rats. Body weight and Survival in the Two-Year Studies: Fifty animals of each species and sex were administered 2-mercaptobenzothiazole in corn oil by gavage 5 days per week for 103 weeks. Administration of 2-mercaptobenzothiazole resulted in decreased survival in dosed male rats (vehicle control, 42/50; low dose, 22/50; high dose, 20/50) and in the high dose group of female mice (37/50; 39/50; 22/50) but not in female rats (28/50; 31/50; 25/50) or in male mice (38/50; 33/50; 30/50). No effect on body weight gain in dosed rats was observed; in dosed mice, minor reductions occurred between weeks 3 and 64, withrecovery thereafter. Postgavage lethargy and prostration occurred frequently in dosed rats and mice. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: The severity of nephropathy was increased in dosed male rats. Ulcers and inflammation of the forestomach were prevalent in dosed rats, as were increased incidences of epithelial hyperplasia and hyperkeratosis in male rats, but no neoplasms of the forestomach were observed. There were no increases of nonneoplastic lesions in mice which were considered to be compound related. The incidences of a variety of tumors were increased in rats dosed with 2-mercaptobenzothiazole; some of the increased incidences were not dose related. In low dose male rats, increased incidences (P<0.01) were observed for mononuclear cell leukemia (7/50; 16/50; 3/50) and pancreatic acinar cell adenomas (2/50; 13/50; 6/49). Increased tumor incidences with dose-related trends (P<0.05) included pituitary gland adenomas in females (15/49; 24/50; 25/50), preputial gland adenomas or carcinomas (combined) in males (1/50; 6/50; 5/50), adrenal gland pheochromocytomas or malignant pheochromocytomas (combined) in males (18/50; 27/50; 24/49), and pheochromocytomas in females (1/50; 5/50; 6/50). These tumors were observed at significantly greater incidences (P</=0.05) in the high dose groups than in the vehicle controls. An increased incidence (P=0.028) of hepatocellular adenomas or carcinomas (combined) was observed only in low dose female mice (4/50; 12/49; 4/50). No significant increases in tumor incidences were seen in male mice. Genetic Toxicology: 2-Mercaptobenzothgy: 2-Mercaptobenzothiazole was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without metabolic activation. In the presence of rat liver S9, 2-mercaptobenzothiazole increased the frequency of chromosomal aberrations and sister chromatid exchanges (SCEs) in Chinese hamster ovary (CHO) cells, as well as mutations at the TK locus of mouse L5178Y lymphoma cells. Audit: The data, documents, and pathology materials from the 2-year studies of 2-mercaptobenzothiazole were audited at the NTP Archives. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of 2-mercaptobenzothiazole for male F344/N rats, indicated by increased incidences of mononuclear cell leukemia, pancreatic acinar cell adenomas, adrenal gland pheochromocytomas, and preputial gland adenomas or carcinomas (combined). There was some evidence of carcinogenic activity for female F344/N rats, indicated by increased incidences of adrenal gland pheochromocytomas and pituitary gland adenomas. There was no evidence of carcinogenic activity of 2-mercaptobenzothiazole for maleB6C3F1 mice dosed with 375 or 750 mg/kg. There was equivocal evidence of carcinogenic activity for female B6C3F1 mice, indicated by increased incidences of hepatocellular adenomas or carcinomas (combined). Synonyms and Trade Names: Captax; Dermacid; Mertax; Thiotax; 2(3H)-benzothiazolethione; 2-benzothiazolyl mercaptan
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PMID:NTP Toxicology and Carcinogenesis Studies of 2-Mercaptobenzothiazole (CAS No. 149-30-4) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1273 4

4-Hexylresorcinol, which is used as an anthelmintic and antiseptic, was nominated by the National Cancer Institute for study. Toxicology and carcinogenesis studies were conducted by administering 4-hexylresorcinol (greater than 99% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Sixteen-Day and Thirteen-Week Studies: In the 16-day studies, groups of five rats and five mice of each sex were administered 0, 31.3, 62.5, 125, 250, or 500 mg/kg 4-hexylresorcinol. Survival was not affected. Decreased body weights were seen in male rats that received 250 or 500 mg/kg 4-hexylresorcinol. No other effects were observed. In the 13-week studies, groups of 10 rats and 10 mice of each sex were administered 0, 62.5, 125, 250, 500, or 1,000 mg/kg of the chemical, 5 days per week. All rats and male mice and 9/10 female mice that received 1,000 mg/kg died before the end of the studies. Final mean body weights of male rats that received 250 or 500 mg/kg were 22% or 38% lower than that of the vehicle controls; final mean body weights of female rats that received 250 or 500 mg/kg were 16% or 9% lower. No compound-related gross or microscopic pathologic effects were observed in rats. No body weight effects were observed for mice. Mild to moderate nephropathy was dose related in male and female mice. Based on these results, 2-year toxicology and carcinogenesis studies of 4-hexylresorcinol were conducted by administering 0, 62.5, or 125 mg/kg to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex, 5 days per week. Body Weight and Survival in the Two-Year Studies: Mean body weights of high dose male rats were 7%-11% lower than those of the vehicle controls throughout the study. Mean body weights of low dose male and dosed female rats were similar to those of the vehicle controls. The body weights of dosed male and dosed female mice were comparable to those of vehicle controls except during the last 16 weeks of the studies, when body weights were 6%-16% lower in the dosed groups. No significant differences in survival were observed between any groups of rats or mice of either sex (male rats: vehicle control, 30/50; low dose, 29/50; high dose, 33/50; female rats: 28/50; 32/50; 30/50; male mice: 36/50; 26/50; 30/50; female mice: 35/50; 32/50; 35/50). Nonneoplastic and Neoplastic Lesions in the Two-Year Studies: Two astrocytomas and an oligodendroglioma were observed in high dose male rats, a glioma was observed in one low dose male rat, and an oligodendroglioma was observed in one vehicle control male rat. These neoplasms were not considered to be related to 4-hexylresorcinol administration. Focal medullary hyperplasia of the adrenal gland was observed at increased incidences in dosed male mice (5/50; 16/50; 10/49). Pheochromocytomas in male mice occurred with a marginal upward trend (1/50; 2/50; 5/49). Historically, these neoplasms are observed in about 1% of corn oil vehicle control B6C3F1 male mice. The incidences of neoplasms of the harderian gland in male mice were slightly increased over those in the vehicle controls (adenomas or carcinomas, combined: 0/50; 4/50; 3/50). Decreases were observed in the incidences of mononuclear cell leukemia in dosed male (12/49; 7/50; 1/50) and female (16/50; 3/50; 2/50) rats, hepatocellular adenomas or carcinomas (combined) in dosed male mice (21/50; 9/50; 9/50), and circulatory system tumors in male (10/50; 4/50; 2/50) and female (6/50; 2/49; 0/50) mice. These decreased incidences of tumors in rats and mice are considered to be possibly related to 4-hexylresorcinol administration. The incidences and severity of nephropathy (male: 39/50; 43/50; 47/50; female: 7/50; 40/49; 47/50) and incidences of osteosclerosis (male: 5/50; 5/50; 15/50; female: 21/50; 25/49; 40/50) were increased in both dosed male and female mice and are considered to be related to chemical exposure. Genetic Toxicology: 4-Hexylresorcinol was not mutagenic for Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without S9 metabolic activation. 4-Hexylre, TA1535, or TA1537 with or without S9 metabolic activation. 4-Hexylresorcinol induced forward mutations at the TK locus in mouse L5178Y cells in the presence of S9; no response was observed in the absence of metabolic activation. In cytogenetic assays with cultured Chinese hamster ovary (CHO) cells, 4-hexylresorcinol caused an increase in the frequency of sister chromatid exchanges (SCEs) in the absence of metabolic activation; no induction of SCEs was observed in the presence of S9. Chromosomal aberrations were not induced in CHO cells with or without metabolic activation. Data Audit: The data, documents, and pathology materials from the 2-year studies of 4-hexylresorcinol were audited at the NTP Archives. The audit findings show that the conduct of the studies is documented appropriately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of 4-hexylresorcinol for male or female F344/N rats given doses of 62.5 or 125 mg/kg. There was equivocal evidence of carcinogenic activity of 4-hexylresorcinol for male B6C3F1 mice, as shown by marginally increased incidences of pheochromocytomas (and hyperplasia) of the adrenal medulla and of harderian gland neoplasms. There was no evidence of carcinogenic activity for female B6C3F1 mice given doses of 62.5 or 125 mg/kg 4-hexylresorcinol. Decreased incidences of three tumors types were considered related to 4-hexylresorcinol administration: mononuclear cell leukemia in male and female rats, hepatocellular neoplasms in male mice, and circulatory system tumors in male and female mice. Synonyms: 4-hexyl-1,3-benzenediol; 4-hexyl-1,3-dihydroxybenzene
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PMID:NTP Toxicology and Carcinogenesis Studies of 4-Hexylresorcinol (CAS No. 136-77-6) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1273 6

Diallylphthalate is widely used as a crosslinking agent for unsaturated polyesters. Diallylphthalate or diallylphthalate polyester blends are used primarily as plasticizers and carriers for adding catalysts and pigments to polyesters and in molding, electrical parts, laminating compounds, and impregnation of metal castings. Rubber compounds, epoxy formulations, and polyurethane foams may also contain diallylphthalate. Precise figures are not currently available, although annual production of diallylphthalate in the United States is known to exceed 5,000 pounds, and an estimated 57,000 pounds were imported into the United States in 1982. Toxicology and carcinogenesis studies of diallylphthalate (approximately 99% pure) were conducted by administering the test chemical in corn oil by gavage to groups of 50 male and 50 female F344/N rats at doses of 0 (vehicle control), 50, or 100 mg/kg 5 days per week for 103 weeks. The diallylphthalate doses used in the 2-year studies were chosen on the basis of 13-week studies, wherein doses of 200 or 400 mg/kg caused death, reductions in body weight gains, or periportal hepatocellular necrosis and fibrosis in both sexes. Mean body weights and survival of male and female rats administered diallylphthalate were essentially the same as those of the vehicle controls throughout the 2-year studies, although hepatotoxicity was produced in both sexes by the 100 mg/kg dose. Based on the results of the prechronic studies and the effects on the liver in the 2-year studies, the doses used in the 2-year studies were considered to be adequate for carcinogenicity testing. Male and female rats receiving the 100 mg/kg dose of diallylphthalate in the 2-year studies developed chronic liver diseases characterized by periportal fibrosis, periportal accumulation of pigment, and severe bile duct hyperplasia. Pigment accumulation also occurred at the 50 mg/kg dose in both sexes. Diallylphthalate administration increased the occurrence of mononuclear cell leukemia in female rats (P<0.05 by trend tests), and the increase in the 100 mg/kg dose female rats was greater (P</=0.05) than in the vehicle controls by pairwise comparisons (vehicle control, 15/50, 30%; low dose, 15/43, 35%; high dose, 25/49, 51%). An increased occurrence of mononuclear cell leukemia was not observed in male rats receiving diallylphthalate. A previous NTP carcinogenesis study (NTP TR 242) reported an increased incidence of lymphomas in male B6C3F1 mice receiving diallylphthalate by gavage for 2 years at doses of 0, 150, or 300 mg/kg. This increase was considered to be equivocally related to diallylphthalate administration. The incidences of hyperplasia and inflammatory lesions of the forestomach were increased in a dose-related fashion in both sexes of mice in that study, and uncommon forestomach papillomas were observed in 0%, 2%, and 4% of both sexes of mice. Because of the numerical increase in forestomach papillomas, the concomitant presence of forestomach hyperplasia, and the rarity of forestomach papillomas in vehicle control (corn oil gavage) B6C3F1 mice, the development of these proliferative lesions of the forestomach in mice may have been related to diallylphthalate administration. In the current study in rats, a squamous cell carcinoma was found in one high dose male rat. Diallylphthalate was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without activation by a 9,000 x g supernatant fraction from the livers of Aroclor 1254-treated male Sprague-Dawley rats or Syrian hamsters. Diallylphthalate did not induce sex-linked recessive lethal mutations in Drosophila melanogaster. An audit of the experimental data was conducted for these carcinogenicity studies on diallylphthalate. No data discrepancies were found that influenced the final interpretations. Under the conditions of this study, the administration of diallylphthalate by gavage in corn oil to male and female F344/N rats for 2 years caused chronic liver disease characterized by periportal fibrosis and pigment accumulation and an increasetal fibrosis and pigment accumulation and an increased severity of bile duct hyperplasia. The incidence of mononuclear cell leukemia was significantly increased in female rats receiving 100 mg/kg. Because of the variability in the incidence of this neoplasm in aged Fisher 344 rats and the difficulty in definitively diagnosing this lesion in Fisher 344 rats, this increase was considered to be equivocal evidence of carcinogenicity of diallylphthalate in female rats. There was no evidence of carcinogenicity in male rats. Synonym: DAP
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PMID:NTP Toxicology and Carcinogenesis Studies of Diallylphthalate (CAS No. 131-17-9) in F344/N Rats (Gavage Studies). 1274 96

1,4-Dichlorobenzene is commonly used as a space deodorant in toilets and for moth control. Because of its extensive production and use and the absence of carcinogenicity data, carcinogenesis studies were conducted by administering 1,4-dichlorobenzene (greater than 99% pure) in corn oil by gavage (5 days per week) to male F344/N rats at doses of 0, 150, or 300 mg/kg and to female F344/N rats and male and female B6C3F1 mice at doses of 0, 300, or 600 mg/kg per day for 2 years (50 animals per group). Fourteen-day and 13-week studies were performed to characterize the toxicity, identify affected sites, and set doses for the 2-year studies. Clinical chemistry and hematologic studies were performed during the 13-week studies to assess the effects of 1,4-dichlorobenzene on the liver, kidney, and hematopoietic system and to assess whether the compound produced hepatic porphyria. Two 13-week studies were performed in rats. In the first study, rats were dosed with 300-1,500 mg/kg 1,4-dichlorobenzene. Because histologic changes were observed in the kidney of male rats at all doses, a second 13-week study was performed at doses of 38-600 mg/kg. In the 13-week studies, survival was decreased in groups of male rats given 1,200 or 1,500 mg/kg and in female rats given 1,500 mg/kg. Weight gain was decreased in male rats receiving doses of 300 mg/kg or more and in female rats given doses of 1,200 or 1,500 mg/kg. Doses of 1,200 or 1,500 mg/kg produced degeneration and necrosis of hepatocytes, hypoplasia of the bone marrow, lymphoid depletion of the spleen and thymus, and epithelial necrosis of the nasal turbinates in male and female rats. Renal tubular cell degeneration was observed in male rats receiving 300 mg/kg or more in the first study, but only slight changes were seen at 300 mg/kg in the second study. Liver weight to brain weight ratios were increased at 900 mg/kg or more for both male and female rats. The kidney weight to brain weight ratio was increased in male rats receiving doses of 600 mg/kg or more. Administration of 1,4-dichlorobenzene to rats for 13 weeks produced slight but statistically significant decreases in the hematocrit, red blood cell count, and hemoglobin level in all males receiving doses of 300-1,200 mg/kg. No clear hematologic changes were observed in female rats. 1,4-Dichlorobenzene produced minimal changes in clinical chemistry parameters in the 13-week studies. Serum cholesterol levels were increased by doses of 600 mg/kg or more in male rats and 900 mg/kg or more in female rats. Serum triglycerides were reduced by doses of 300 mg/kg or more in male rats. The blood urea nitrogen level was increased slightly in male rats dosed with 900 mg/kg or more. Urinary porphyrins were increased slightly in male rats administered 1,200 or 1,500 mg/kg and female rats receiving 1,200 mg/kg. However, these increases were modest and indicative of a mild porphyrinuria rather than hepatic porphyria. Liver porphyrins were not increased at any dose. Two 13-week studies were performed in mice. The doses selected for the first study were 600-1,800 mg/kg. Survival was decreased in male and female mice receiving doses of 1,500 mg/kg or more, and body weight gain was decreased at all doses. Hepatocellular degeneration was observed in both sexes at all doses, and the liver weight to brain weight ratio was increased at doses of 900 mg/kg or more. Serum cholesterol levels were increased in male mice at doses of 900 mg/kg or more, whereas serum protein and triglycerides were increased at doses of 1,500 mg/kg or more. These relatively modest clinical chemistry changes probably reflect the hepatic effects of this compound. The white blood cell count was reduced significantly in male mice receiving doses of 600 mg/kg or more and female mice receiving 1,000 mg/kg or more, but this effect was not dramatic. Hepatic porphyria was not found in mice at any dose in the 13-week study. Because hepatic effects were seen in all dose groups in the first study, a second 13-week study was performed at doses of 85-900 mg/kg. In this study, hepatocellularellular cytomegaly was observed im male and female mice at doses of 675 mg/kg or more but not at 338 mg/kg. Renal damage was not observed in mice in either 13-week study. Based on the histopathologic findings in the kidney of male rats and in the liver of both sexes of rats and mice in the 13-week studies, the doses selected for the 2-year studies were 150 and 300 mg/kg for male rats and 300 and 600 mg/kg for female rats and male and female mice. In the 2-year studies, survival of female rats and of both sexes of mice was comparable to that of the vehicle controls; survival of high dose male rats was significantly lower than that of the vehicle controls (vehicle control, 32/50; low dose, 31/50; high dose, 20/50). Mean body weights of high dose male rats were 5&percnt;-8&percnt; lower than those of vehicle controls after week 38, and those of high dose female rats were 5&percnt;-7&percnt; lower than those of vehicle controls after week 55. Mean body weights of mice dosed with 1,4-dichlorobenzene were comparable to those of vehicle controls throughout the studies. Administration of 1,4-dichlorobenzene to male rats increased the average seveity of nephropathy and caused epithelial hyperplasia of the renal pelvis (1/50; 30/50; 31/50), mineralization of the collecting tubules in the renal medulla (4/50; 46/50; 47/50), and focal hyperplasia of renal tubular epithelium (0/50; 1/50; 9/50). There were increased incidences of nephropathy in both low and high dose female rats compared with vehicle controls (21/49; 32/50; 41/49). 1,4-Dichlorobenzene produced a dose-related increase in the incidence of tubular cell adenocarcinomas of the kidney in male rats (1/50; 3/50; 7/50); one tubular cell adenoma was observed in a high dose male rat. These malignant tumors are uncommon in male F344/N rats. They have been diagnosed in only 4/1,098 (0.4&percnt;) corn oil gavage controls in previous NTP studies. There were no tubular cell tumors in dosed or vehicle control female rats. There was a marginal increase in the incidence of mononuclear cell leukemia in dosed male rats compared with that in vehicle controls (5/50; 7/50; 11/50). 1,4-Dichlorobenzene increased the incidences of nonneoplastic liver lesions in male and female mice, including alteration in cell size (cytomegaly and karyomegaly), hepatocellular degeneration, and individual cell necrosis. 1,4-Dichlorobenzene also increased the incidences of nephropathy in male mice and renal tubular regeneration in female mice. 1,4-Dichlorobenzene increased the incidences of hepatocellular carcinomas in high dose male (14/50; 11/49; 32/50) and female (5/50; 5/48; 19/50) mice and hepatocellular adenomas in dosed male (5/50; 13/49; 16/50) and high dose female (10/50; 6/48; 21/50) mice. Hepatoblastomas were observed in four high dose male mice but not in vehicle controls. This rare tumor has not occurred in 1,091 male vehicle control mice in NTP studies. An increase in thyroid gland follicular cell hyperplasia was observed in dosed male mice (1/47; 4/48; 10/47), and there was a marginal positive trend in the incidence of follicular cell adenomas of the thyroid gland in female mice (0/48; 0/45; 3/46). Pheochromocytomas (benign or malignant, combined) of the adrenal gland occurred with a positive trend in dosed male mice, and the incidence in the high dose group was significantly greater than in vehicle controls (0/47; 2/48; 4/49). The incidence of adrenal gland medullary hyperplasia in male mice was 2/47; 4/48; and 4/49. Focal hyperplasia of the adrenal gland capsule was also observed in dosed male mice (11/47;21/48; 28/49). 1,4-Dichlorobenzene was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without activation by Aroclor 1254-induced male Sprague-Dawley rat or male Syrian hamster liver S9 when tested according to a preincubational protocol at concentrations up to 100 ug/plate. 1,4-Dichlorobenzene did not induce forward mutations in the mouse lymphoma L5178Y/TK± assay in the absence of exogenous metabolic activation; however, the results were equivocal in this system in the presence of metabolic activation. 1,4-Dichlorobenzene did not produce an increase in sister-chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells in culture with or without exogenous metabolic activation. No increase in micronucleated cells was seen in erythrocytes of mice from the first 13-week studies. An audit of the experimental data was conducted for the 2-year studies of 1,4-dichlorobenzene. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, 1,4-dichlorobenzene produced clear evidence of carcinogenicity for male F344/N rats, as shown by an increased incidence of renal tubular cell adenocarcinomas. There was no evidence of carcinogenicity for female F344/N rats receiving doses of 300 or 600 mg/kg. There was clear evidence of carcinogenicity for both male and female B6C3F1 mice, as shown by increased incidences of hepatocellular carcinomas and hepatocellular adenomas. Marginal increases were observed in the incidences of pheochromocytomas of the adrenal gland in male mice. Nonneoplastic effects in the kidney of male and female rats, in the liver of male and female mice, and in the thyroid gland and adrenal gland of male mice were also associated with the administration of 1,4-dichlorobenzene. Synonyms: p-dichlorobenzene; para-dichlorobenzene; para-chlorophenyl chloride
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PMID:NTP Toxicology and Carcinogenesis Studies of 1,4-Dichlorobenzene (CAS No. 106-46-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1274 34

Mirex (95% pure), formerly used a systemic insecticide and as a fire retardant, was studied for toxicologic and carcinogenic effects by administering diets containing 0, 0.1, 1.0, 10, 25, or 50 ppm mirex to groups of 52 F344/N rats of each sex for 104 weeks. Doses selected for the 2-year studies were based primarily on the effects on body weights and survival of rats in a 26-week study. During the first 6 months of the 2-year study, because of good survival and the absence of observable toxic effects in female rats, additional groups (termed second study) of 52 F344/N female rats were started at higher dietary concentrations of 0, 50, and 100 ppm mirex. Based on feed consumption data, the estimated average intake per day was 0, 0.007, 0.075, 0.75, 1.95, and 3.85 mg mirex/kg body weight for male rats and female rats in the first study, and 0, 3.9, and 7.7 mg/kg for female rats in the additional study. Body Weights, Feed Consumption, and Survival in Two-Year Studies: Mean body weights of male rats that received 25 or 50 ppm mirex were 5%-18% lower than those of the controls throughout most of the study; mean body weights of female rats that received 50 or 100 ppm mirex were 4%-18% lower than those of the controls after week 40; mean body weights of groups receiving 0.1, 1.0, or 10 ppm were similar to those of controls. Feed consumption by dosed male rats was 83%-91% that by controls, and that by dosed female rats was 86%-99% that by controls. The top dietary exposure groups of rats received the equivalent of 3.85 mg mirex/kg body weight, whereas the 100-ppm group of female rats (second study) averaged 7.7 mg/kg. At the end of the study, survival of male rats that received 25 or 50 ppm of mirex was lower than that of controls, whereas survival of all dosed groups of female rats was similar to that of controls (male: control, 44/52; 0.1 ppm, 37/52; 1 ppm, 36/52; 10 ppm, 37/52; 25 ppm, 19/52; 50 ppm, 15/52; female-- first study: 38/52; 38/52; 35/52; 41/52; 35/52; female-- second study: control, 44/52; 50 ppm, 44/52; 100 ppm, 39/52). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: The most notable compound-related effects were observed in the liver of male and female rats. Fatty metamorphosis, cytomegaly, angiectasis (males only), and necrosis of the liver were observed at increased incidences in dosed rats. The incidences of of neoplastic nodules of the liver were dose related, and in the 10-, 25-, and 50-ppm groups of males and the 50- and 100-ppm groups of females (second study), they were markedly greater than those in controls (52/group-- male: control, 3; 0.1 ppm, 5; 1 ppm, 5;10 ppm, 14; 25 ppm, 15; 50 ppm, 26; female (second study): control, 2; 50 ppm, 23; 100 ppm, 30). In the first study in female rats, the incidences of neoplastic nodules were not significantly different between control and dosed groups (10; 5; 4; 5; 9; 7). The 10 neoplastic nodules of the liver seen in the control group (19%) was significantly greater than the mean incidence observed historically (57/2,015; 2.8%). The incidences of hepatocellular carcinomas in control and dosed groups were relatively low and were not significantly different between groups. The incidences of pheochromocytomas of the adrenal gland occurred with a positive trend in male rats (8/51; 7/52; 13/52; 11/52; 18/51, 19/51); the incidences in the 25- and 50-ppm male rats were greater than that in controls; malignant pheochromocytomas were observed in 2 controls and in 2 mirex-exposed male rats. The incidence of pheochromocytomas in 50-ppm female rats in the first study was marginally greater than that in controls (control, 1/51; 50 ppm, 6/52); this borderline increase was not observed in the second female rat study and thus is not considered to be due to the dietary administration of mirex. Nephropathy occurred at similar incidences in control and mirex-exposed groups of male and female rats; however, the severity of this nonneoplastic lesion was judged to be slightly greater in the groups given 25, 50, or 100 ppm mirex (male: severe vs. moderate in controls; femas given 25, 50, or 100 ppm mirex (male: severe vs. moderate in controls; female: moderate to severe vs. moderate). Hyperplasia of the transitional epithelium of the kidney pelvis was observed in dosed male rats (0/51; 2/51; 2/52; 5/52; 14/51; 9/52). Transitional cell papillomas of the renal pelvis in male rats occurred with a positive trend (P<0.02) (0/51; 0/51; 0/52; 1/51; 3/52). The highest incidence previously observed in untreated male F344/N rats in NTP studies is 1/48, and the mean historical incidence is 5/1,968 (0.3&percnt;). In both the first and second studies in female rats, the incidence of mononuclear cell leukemia showed dosed-related increases (first study: 8/52; 8/52; 11/52; 14/52; 18/52; 18/52; second study: 6/52; 9/52; 14/52). When the data from both studies are combined, the incidences are significantly increased in the 10-, 25-, 50-, and 100-ppm groups. The mean historical incidence is 19&percnt; (375/2,021). For the thyroid gland, there was a positive trend for follicular cell neoplasms in male rats (0/51; 1/50; 0/47; 1/47; 0/35; 4/49) and a negative trend for C-cell neoplasms in male rats (8/51; 6/50; 4/47; 7/47; 3/35; 0/49) and infemale rats in the first study (12/50; 13/50; 7/48; 9/47; 6/48; 2/46). Neither observation is considered to be associated with the dietary administration of mirex. Genetic Toxicology: Mirex was not mutagenic in the Salmonella typhimurium-microsome assay when tested in a preincubation protocol in the presence or absence of exogenous metabolic activation in strains TA98, TA100, TA1535, or TA1537. Mirex did not induce either 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 of mirex, there is clear evidence of carcinogenic activity for male and female F344/N rats, as primarily indicated by marked increased incidences of benign neoplastic nodules of the liver, as well as by increased incidences of pheochromocytomas of the adrenal gland and transitional cell papillomas of the kidney in males and by increased incidences of mononuclear cell leukemia in females. Nonneoplastic effects induced by mirex include cytomegaly, fatty metamorphosis, angiectasis (males only), and cellular necrosis in the liver. Synonyms and Trade Names: 1,1a,2,2,3,3a,4,5,5,5a,5b,6-dodecachlorooctahydro-1,3,4-metheno-1H-cyclobta[cd]pentalene; hexachloropentadiene dimer; dodecachloropentacyclodecane; perchloropentacyclodecane; hexachlorocyclopentadiene dimer; Dechloranereg.; Ferriamicidereg.
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PMID:NTP Toxicology and Carcinogenesis Studies of Mirex (1,1a,2,2,3,3a,4,5,5,5a,5b,6-Dodecachlorooctahydro-1,3,4- metheno-1H-cyclouta[cd]pentalene) (CAS No. 2385-85-5) in F344/N Rats (Feed Studies). 1274 40

4,4'-Methylenedianiline is used primarily as a chemical intermediate in the closed system production of isocyanates and polyisocyanates. These chemicals are used extensively in the manufacture of rigid polyurethane foams for thermal insulation and in the production of semiflexible polyurethane foams for automobile safety cushioning. The saturated isocyante of 4,4'-methylenedianiline [4,4'-methylene-bis(cyclohexylisocyanate)] is an intermediate in the production of light-stable, high-performance polyurethane coatings. 4,4'-Methylenedianiline is also a curing agent for epoxy resins and urethane elastomers, a dye intermediate, and a corrosion inhibitor. NTP Carcinogenesis studies of 4,4'-methylenedianiline dihydrochloride (98.6% pure) were conducted by administering this chemical in the drinking water of F344/N rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex received drinking water containing 150 or 300 ppm 4,4'-methylenedianiline dihydrochloride (dosage expressed as the free base) for 103 weeks. Groups of 50 rats and 50 mice of each sex, given drinking water adjusted with 0.1N HCl to the pH (3.7) of the 300-ppm formulation, served as controls. Survival was comparable among groups except for male mice receiving the high dose of 4,4'-methylenedianiline dihydrochloride; survival in that group was lower (P=0.006) than that in controls. Mean body weight was reduced in high dose female rats and in high dose male and female mice. Water consumption was reduced in a dose-related manner in both sexes of rats. No compound-related clinical effects were observed. Compound-related nonneoplastic lesions of the thyroid in female rats included follicular cysts and hyperplasia. The incidence of thyroid follicular cell hyperplasia was elevated in high dose male and female mice. The incidences of thyroid neoplasms in the high dose groups were elevated compared with those of the control groups for both sexes of both species. Thyroid follicular cell carcinoma was increased in male rats (controls, 0/49; low dose, 0/47; high dose, 7/48, 15%: P</=0.012). Follicular cell adenoma was increased in high dose female rats (0/47; 2/47, 4%; 17/48, 35%: P<0.001), in high dose male mice (0/47; 3/49, 6%; 16/49, 33%: P<0.001), and in high dose female mice (0/50; 1/47, 2%; 13/50, 26%: P<0.001) as compared with controls. In female rats, thyroid C-cell adenoma was also elevated in a dose-related manner (0/47; 3/47, 6%; 6/48, 13%, P</=0.029). Dose-related increases in nonneoplastic lesions were observed for male rats (nonspecific liver dilatation) and for male and female rats (fatty metamorphosis and focal cellular change). Liver degeneration was present in 80% of the low dose and 60% of the high dose male mice but was not found in the controls. Neoplastic nodules of the liver were observed at greater incidences (P</=0.002) for low and high dose male rats as compared with controls (control, 1/50, 2%; low dose, 12/50, 24%, P</=0.002; high dose 25/50, 50%, P<0.001). Hepatocellular adenoma was increased in a dose-related manner in dosed female mice (3/50, 6%; 9/50, 18%; 12/50, 24%, P<0.011). Hepatocellular carcinoma was observed in greater incidence in dosed male mice (10/49, 20%; 33/50, 66%, P<0.001; 29/50, 58%, P<0.001) and in high dose female mice (1/50, 2%; 6/50, 12%; 11/50, 22%, P=0.002). Male rats had a dose related increase in kidney mineralization. Nephropathy was increased in dosed mice of both sexes; renal papillary mineralization was greater in high dose male mice and female mice than in the controls. Other tumors that were elevated in dosed animals included adrenal pheochromocytomas in male mice (control, 2/48, 4%; low dose, 12/49, 24%, P</=0.006; high dose, 14/49, 29%; P</=0.001), alveolar/bronchiolar adenoma in female mice (1/50, 2%; 2/50, 4%; 6/49, 12%, P</=0.05) and malignant lymphomas in female mice (13/50,26%; 28/50, 56%, P=0.002; 29/50, 58%; P=0.001). Uncommon tumors were observed in dosed animals at low incidences but may be important because the historical control incidences are very low; bile duct adenoma in 1/50 high dose male (13/50,26&percnt;; 28/50, 56&percnt;, P=0.002; 29/50, 58&percnt;; P=0.001). Uncommon tumors were observed in dosed animals at low incidences but may be important because the historical control incidences are very low; bile duct adenoma in 1/50 high dose male rats (historical control 3/3,663), transitional-cell papillomas of the urinary bladder in female rats (historical control, 3/3,664, 0.08&percnt;; low dose, 2/50, 4&percnt;; high dose, 1/50, 2&percnt;) and granulosa cell tumors of the ovary in female rats (historical control, 11/3,642, 0.3&percnt;; low dose, 3/50, 6&percnt;; high dose, 2/50, 4&percnt;). Decreases in tumor incidences were observed for leukemia in male rats (control, 12/50, 24&percnt;; low dose, 6/50, 12&percnt;; high dose, 5/50, 10&percnt;, P=0.048) and alveolar or bronchiolar adenomas (combined) in male mice (12/49, 24&percnt;; 9/49, 18&percnt;; 3/49, 6&percnt;, P≤0.011). Under the conditions of these studies, 4,4'-methylenedianiline dihydrochloride was carcinogenic for F344/N rats and B6C3F1 mice of each sex, causing significantly increased incidences of thyroid follicular cell carcinomas in male rats, thyroid follicular cell adenomas in female rats and in mice of each sex, C-cell adenomas of the thyroid gland in female rats, neoplastic nodules in the liver of male rats, hepatocellular carcinomas in mice of each sex, adenomas of the liver and malignant lymphomas in female mice, and adrenal pheochromocytomas in male mice. Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Positive Male Mice: Positive Female Mice: Positive
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PMID:NTP Carcinogenesis Studies of 4,4'-Methylenedianiline Dihydrochloride (CAS No. 13552-44-8) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies). 1275 Jul 45

Diallyl phthalate is a widely used crosslinking agent for unsaturated polyesters. Diallyl phthalate or diallyl phthalate polyester blends are used primarily as plasticizers and carriers for adding catalysts and pigments to polyesters and in molding, electrical parts, laminating compounds, and impregnation of metal castings. Rubber compounds, epoxy formulations, and polyurethane foams may also contain diallyl phthalate. Annual production of diallyl phthalate in the United States exceeds 5,000 pounds; precise figures are not available. A NTP Carcinogenesis bioassay of diallyl phthalate (99% pure) was conducted by administering 0 (vehicle control), 150, or 300 mg/kg diallyl phthalate in corn oil by gavage, 5 days per week for 103 weeks, to groups of 50 male and 50 female B6C3F1 mice. Survival rates and mean body weights of dosed mice were not different from those of the controls, and pathological lesions unrelated to proliferative changes were not observed. Therefore, a maximally tolerated dose for the purposes of carcinogenicity testing may not have been achieved. The incidences of lymphoma and either lymphoma or leukemia in dosed male mice were no significantly greater than those in the controls according to pairwise comparisons (P=0.051 to P=0.096), but the trend tests were statistically significant by either life table or incidental tumor analysis (P=0.031 to P=0.045). The incidence of lymphomas in the high-dose male mice was 12/50 (24%) in comparison with 6/50 (12%) in the controls. Recent historical incidences at the performing laboratory and in the NTP Bioassay Program were 18/120 (15%) and 71/661 (11%), respectively. Since the incidence of high-dose male mice with leukemia was not significantly greater than that of concurrent or historical controls at the performing laboratory by pairwise comparisons, this marginal increase was considered only to be equivocally related to diallyl phthalate administration. Increased incidences of squamous cell papillomas, hyperplasia, and inflammatory lesions of the forestomach were observed in diallyl phthalate-dosed mice of both sexes in a dose-related manner. Papillomas of the forestomach were observed in 0%, 2%, and 4% of the control, low-dose, and high-dose mice of both sexes. The recent historical incidence of this tumor in gavage control mice from both the performing laboratory and other laboratories within the Bioassay Program was less than 1%. Forestomach hyperplasia was diagnosed in 0%, 15%, and 18%, and in 8%, 2%, and 29% of the control, low-dose, and high-dose male and female mice, respectively; chronic inflammation of the forestomach was diagnosed in 0%, 9%, and 16% and in 4%, 2%, and 18% of the control, low-dose, and high-dose male and female mice, respectively. Because of the numerical elevation of the forestomach papillomas in the high-dose mice of both sexes, the concomitant observation of dose related forestomach hyperplasia, and the rarity of this tumor in corn oil (gavage) control B6C3F1 mice, the development of squamous cell papillomas of the forestomach may have been related to diallyl phthalate administration. Under the conditions of this bioassay, the development of chronic inflammation and hyperplasia of the forestomach in both male and female B6C3F1 mice was considered to be related to the administration of diallyl phthalate. The development of squamous cell papillomas of the forestomach may also have been related to chemical administration, but the available data are insufficient to indicate a clear cause and effect relationship. An increase in the incidence of male mice with lymphomas was observed, but this increase was considered only to be equivocally related to diallyl phthalate administration. The results of this bioassay, therefore, do not indicate that diallyl phthalate is carcinogenic in B6C3F1 mice, although a maximum tolerated dose may not have been achieved. A carcinogenicity study by the National Toxicology Program of diallyl phthalate in male and female Fisher 344/N rats, employing daily gavage doses of 0 (vehicle control), 50, or 100 mg/kg boicology Program of diallyl phthalate in male and female Fisher 344/N rats, employing daily gavage doses of 0 (vehicle control), 50, or 100 mg/kg body weight is currently being evaluated. Levels of Evidence of Carcinogenicity: Male Mice: Equivocal Female Mice: Equivocal
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PMID:NTP Carcinogenesis Bioassay of Diallyl Phthalate (CAS No. 131-17-9) in B6C3F1 Mice (Gavage Study). 1275 Jul 51

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