Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001430 (adenoma)
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1,2-Dihydro-2,2,4-trimethylquinoline (monomer) is used as an antioxidant in styrene-butadiene and nitrile-butadiene rubbers and latexes. It was nominated by the National Cancer Institute as part of a review of chemicals used in the manufacture and processing of rubber, during which potential occupational and consumer exposure to this compound can occur. It was selected for evaluation because it is a derivative of quinoline, a known rodent carcinogen, and was regarded as having potential carcinogenic activity. Because of the pattern of use and exposure, dermal administration was considered most appropriate. Male and female F344/N rats and B6C3F1 mice received topical applications of 1,2-dihydro-2,2,4-trimethylquinoline in acetone (greater than 90% pure) for 13 weeks or 2 years. Groups of female SENCAR mice received 1,2-dihydro-2,2,4-trimethylquinoline (greater than 90% pure) during a 1-year dermal initiation/promotion study to determine the tumor initiation or promotion potential of the chemical. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse peripheral blood cells. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were topically administered 0, 5, 20, 50, 100, or 200 mg 1,2-dihydro-2,2,4-trimethylquinoline/kg body weight in acetone, 5 days per week for 13 weeks. In addition, there were 10 male and 10 female untreated controls. All rats survived to the end of the study. Final mean body weights and mean body weight gains of treated male and female rats were similar to those of the vehicle controls except those of 200 mg/kg males, which were significantly lower than those of the vehicle controls. The only notable clinical observation was skin discoloration of treated rats. In the 200 mg/kg groups, absolute and relative liver weights of males and absolute liver weights of females were significantly greater than those of the vehicle controls. There were no significant differences in hematology or clinical chemistry parameters, reproductive tissue parameters, or estrous cycle characterization between treated and control groups. Histopathologic lesions of the skin at the site of application included acanthosis and hyperkeratosis in 100 and 200 mg/kg males and 200 mg/kg females. Cytoplasmic vacuolization of hepatocytes of mild to moderate severity was observed in the livers of all 200 mg/kg males and was considered treatment related. Based on the incidence and severity of skin and liver lesions observed in 200 mg/kg rats in the 13-week study, 100 mg/kg was selected as the high dose for the 2-year rat study. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were topically administered 0, 2.5, 5, 10, 20, or 50 mg 1,2-dihydro-2,2,4-trimethylquinoline/kg body weight in acetone, 5 days per week for 13 weeks. In addition, there were 10 male and 10 female untreated controls. All mice except one 2.5 mg/kg female survived to the end of the study. Final mean body weights and mean body weight gains of male and female mice were similar to those of the vehicle controls. There were no treatment-related clinical observations. There were no significant differences between treated and control groups in organ weights, hematology and clinical chemistry parameters, reproductive tissue parameters, or estrous cycle characterization. Histopathologic lesions of the skin at the site of application included acanthosis (epidermal hyperplasia), hyperkeratosis, and parakeratosis, all ranging from minimal to mild in severity. Minimal to mild fibrosis and subchronic inflammation were observed in the dermis. Based on the incidences and severities of skin lesions observed in 20 and 50 mg/kg mice in the 13-week study, 10 mg/kg was selected as the high dose for the 2-year mouse study. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female F344/N rats were topically administered 0, 36, 60, or 100 mg 1,2-dihydro-2,2,4-trimethylquinoline/kg body weight in acetone, 5 days per week for 103 (males) or 104 (females) weeks. Ten rats per group were evaluated after 15 moed after 15 months of treatment. Survival and Body Weights Survival of treated rats was similar to that of controls. Mean body weights of 60 mg/kg males and 100 mg/kg males and females were slightly lower than those of the controls after week 21. Mean body weights of 36 mg/kg males and females and 60 mg/kg females were generally similar to those of the controls throughout the study. Pathology Findings: No skin neoplasms were attributed to treatment with 1,2-dihydro-2,2,4-trimethylquinoline. Several nonneoplastic skin lesions were determined to be treatment related. Incidences of acanthosis at the site of application in all treated groups of males and in 100 mg/kg females at the 15-month interim evaluation were significantly greater than those in the controls. At the end of the 2-year study, incidences of acanthosis at the site of application in 60 and 100 mg/kg males and females and hyperkeratosis at the site of application in 60 mg/kg females were significantly greater than those in the controls. Absolute and relative right kidney weights of 60 and 100 mg/kg male rats were significantly greater than those of the controls at the 15-month interim evaluation. Incidences of renal tubule adenoma and adenoma or carcinoma (combined) in all treated groups of males were significantly greater than those in the controls. These incidences exceeded the range from the historical controls in 2-year NTP feed studies. An extended (step section) evaluation of the kidneys of male rats did not reveal an additional increase in neoplastic response because additional adenomas and hyperplasias were observed in the controls as well as in treated groups. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female B6C3F1 mice were topically administered 0, 3.6, 6, or 10 mg 1,2-dihydro-2,2,4-trimethylquinoline/kg body weight in acetone, 5 days per week for 103 (males) or 104 (females) weeks. Nine or ten mice per group were evaluated after 15 months of treatment. Survival and Body Weights: Survival of treated mice was similar to that of controls. Mean body weights of treated male and female mice were similar to those of the controls throughout the study. Pathology Findings: No neoplasms or nonneoplastic lesions were attributed to treatment with 1,2-dihydro-2,2,4-trimethylquinoline. 1-YEAR INITIATION/PROMOTION STUDY IN FEMALE SENCAR MICE: Groups of 30 female SENCAR mice were topically administered varying initiation/promotion treatments as outlined in the table below. Survival, Body Weights, and Clinical Findings: Survival in all treated groups was similar to that of the respective controls, except in the 2.5 mg 7,12-dimethylbenz(a)anthracene (DMBA)/0.5 mg 12-O-tetradecanoylphorbol-13-acetate (TPA) group in which survival was significantly lower than that of the controls. Mean body weights of all treated groups were similar to those of the respective controls throughout the study. No clinical observations were associated with 1,2-dihydro-2,2,4-trimethylquinoline treatment; however, mice promoted with TPA showed signs of irritation and papilloma at the site of application. Pathology Findings: Initiation and promotion with acetone alone was not associated with any skin lesions at the site of application. The incidences of acanthosis and chronic inflammation were increased in all groups promoted with TPA regardless of the initiator treatment; however, the incidences of nonneoplastic lesions were low in all other groups. Incidences of squamous cell papillomas and squamous cell carcinomas were markedly increased in the DMBA/TPA positive control group; however, no response was observed in groups initiated with DMBA and promoted with 5, 10, or 25 mg/kg 1,2-dihydro-2,2,4-trimethylquinoline or in the group initiated with 1,2-dihydro-2,2,4-trimethylquinoline and promoted with TPA. GENETIC TOXICOLOGY: 1,2-Dihydro-2,2,4-trimethylquinoline was not mutagenic in any of several strains of Salmonella typhimurium, with or without S9 metabolic activation. 1,2-Dihydro-2,2,4-trimethylquinoline induced sister chromatid exchanges in cultured Chinese hamster ovary cells in the absence of S9, but not in the presence of S9. However, no increase in the frequency of chromosomal aberrations was observed in cultured Chinese hamster ovary cells treated with 1,2-dihydro-2,2,4-trimethylquinoline, with or without S9. No increase in the frequency of micronucleated erythrocytes was noted in peripheral blood of male or female mice exposed topically to 1,2-dihydro-2,2,4-trimethylquinoline for 13 weeks. CONCLUSIONS: Under the conditions of these 2-year dermal studies, there was some evidence of carcinogenic activity of 1,2-dihydro-2,2,4-trimethylquinoline in male F344/N rats, based on increased incidences of renal tubule adenoma and adenoma or carcinoma (combined). There was no evidence of carcinogenic activity of 1,2-dihydro-2,2,4-trimethylquinoline in female F344/N rats receiving 36, 60, or 100 mg/kg, or in male or female B6C3F1 mice receiving 3.6, 6, or 10 mg/kg. Exposure of rats to 1,2-dihydro-2,2,4-trimethylquinoline by dermal application in acetone for 2 years resulted in acanthosis in males and females and hyperkeratosis in females at the site of application. No nonneoplastic lesions in male or female mice were attributed to treatment with 1,2-dihydro-2,2,4-trimethylquinoline. Synonyms: 2,2,4-Trimethyl-1,2-dihydroquinoline; acetone anil; methylquinoline Trade names: Agerite Resin D; Flectol A; Flectol H; Flectol Pastilles; Vulkanox HS/LG; Vulkanox HS/Powder
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PMID:NTP Toxicology and Carcinogenesis Studies of 1,2-Dihydro-2,2,4-Trimethylquinoline (CAS No. 147-47-7) in F344/N Rats and B6C3F1 Mice (Dermal Studies) and the Dermal Initiation/Promotion Study in Female Sencar Mice. 1258 20

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