NTP technical report on the toxicology and carcinogenesis studies of β-Picoline (CASRN 108-99-6) in F344/N rats and B6C3F1/N mice (Drinking water studies)
Special study groups of 10 male and 10 female rats were exposed to the same concentrations for 23\sdays for determinations of cytochrome P450 enzyme activity. All rats survived to the end of the study. Mean body weights of males and females exposed to 625 or 1,250\smg/L were significantly less than...
| Corporate Author: | |
|---|---|
| Format: | eBook |
| Language: | English |
| Published: |
Research Triangle Park, North Carolina
National Toxicology Program, Public Health Service, U.S. Department of Health and Human Services
August 2014, 2014
|
| Series: | NTP TR
|
| Online Access: | |
| Collection: | National Center for Biotechnology Information - Collection details see MPG.ReNa |
| Summary: | Special study groups of 10 male and 10 female rats were exposed to the same concentrations for 23\sdays for determinations of cytochrome P450 enzyme activity. All rats survived to the end of the study. Mean body weights of males and females exposed to 625 or 1,250\smg/L were significantly less than those of the controls. Water consumption by 625 and 1,250\smg/L males and females was less than that by the controls at weeks 1 and 13 due to poor palatability. On day 23, hepatic 7-pentoxyresorufin-O-dealkylase activity was significantly increased in 312\smg/L or greater males and in 156\smg/L or greater females compared to that in the controls. Absolute liver weights of 625 and 1,250\smg/L males and absolute and relative liver weights of 625 and 1,250\smg/L females were significantly less than those of the controls. GENETIC TOXICOLOGY: β-Picoline was tested in three independent bacterial gene mutation studies; all studies gave negative results in S. typhimurium or E. coli tester strains, with and without exogenous metabolic activation. In vivo, no significant increases in the frequencies of micronucleated erythrocytes were observed in peripheral blood of male or female B6C3F1/N mice treated with β-picoline in drinking water for 3 months. CONCLUSIONS: Under the conditions of these 2-year drinking water studies, there was no evidence of carcinogenic activity (see Explanation of Levels of Evidence of Carcinogenic Activity; see summary of the peer review panel comments and the public discussion on this Technical Report in Appendix M) of β-picoline in male F344/N rats exposed to 156.25, 312.5, or 625\smg/L. There was some evidence of carcinogenic activity of β-picoline in female F344/N rats based on increased incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined). There was equivocal evidence of carcinogenic activity of β-picoline in male B6C3F1/N mice based on increased incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined). There was clear evidence of carcinogenic activity of β-picoline in female B6C3F1/N mice based on the increased incidences of alveolar/bronchiolar adenoma or carcinoma (combined) in the lung and of hepatocellular carcinoma and hepatoblastoma in the liver. Exposure to β-picoline caused increased incidences of nonneoplastic lesions of the lung in female mice and the nose in male and female mice. Synonyms: β-methylpyridine; 3-methylpyridine; m-methylpyridine; m-picoline Mean body weights and water consumption were generally similar among exposed and control groups of male and female mice. Lung weights of 1,250\smg/L females were significantly less than those of the controls. No histopathologic lesions were attributed to β-picoline exposure. TWO-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to 0, 156.25, 312.5, or 625\smg β-picoline/L drinking water for 104 or 105 weeks (equivalent to average daily doses of approximately 6, 12, or 22\smg β-picoline/kg body weight to males and 7, 14, or 26\smg/kg to females). Survival and mean body weights were generally similar among exposed and control groups of male and female mice. Decreased water consumption was evident in 625\smg/L males and females compared to controls throughout the 2-year study. The incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined) were significantly increased in the lung of 625\smg/L female rats. TWO-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to 0, 312.5, 625, or 1,250\smg β-picoline/L drinking water for 105 weeks (equivalent to average daily doses of approximately 26, 50, or 92\smg β-picoline/kg body weight to males and 18, 37, or 68\smg/kg to females). Survival of all exposed groups was similar to that of the control groups. Mean body weights of 1,250\smg/L males were 10% less than those of the control group after week 57, and those of 1,250\smg/L females were generally 10% less after week 13. Water consumption by exposed groups of males and females was similar to that by controls during the first 13 weeks of the study; water consumption by 625 and 1,250\smg/L males and 1,250\smg/L females was less than that in the controls after week 13. In the liver of females, there were significantly increased incidences of hepatocellular adenoma in the 312.5\smg/L group and hepatocellular carcinoma in all exposed groups. The combined incidences of hepatocellular carcinoma or hepatoblastoma were significantly increased in all exposed females. In the lung, the incidence of alveolar/bronchiolar adenoma in 625\smg/L males was significantly increased. The incidences of alveolar/bronchiolar adenoma occurred with a positive trend in females. The incidences of alveolar/bronchiolar carcinoma were increased in all exposed groups of females. The incidence of alveolar/bronchiolar adenoma or carcinoma (combined) was significantly increased in 1,250\smg/L females. The incidence of alveolar epithelium hyperplasia was significantly increased in 1,250\smg/L females. In the nose, there were significantly increased incidences of olfactory epithelium respiratory metaplasia in 625\smg/L males and 1,250\smg/L males and females; the incidence of olfactory epithelium atrophy was significantly increased in 1,250\smg/L females. β-Picoline is used as a solvent in the synthesis of pharmaceuticals, resins, dyes, rubber accelerators, and insecticides. β-Picoline was nominated by the National Institute of Environmental Health Sciences for toxicological evaluation and carcinogenicity studies based on its high production volume and potential for human exposure. Male and female F344/N rats and B6C3F1/N mice were exposed to β-picoline (greater than 96% pure) in drinking water for 3 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes.THREE-MONTH STUDY IN RATS: Groups of 10 male and 10 female core study rats were exposed to 0, 78, 156, 312, 625, or 1,250\smg β-picoline/L drinking water for 14\sweeks (equivalent to average daily doses of approximately 6, 11, 22, 38, or 70\smg β-picoline/kg body weight to males and 6, 12, 23, 38, or 64\smg/kg to females). The Markov transition matrix analyses of estrous cyclicity indicated female rats in the 312 and 625\smg/L groups had a significantly higher probability of extended estrus than the control females, suggesting a potential for β-picoline to be a reproductive toxicant in female rats exposed to these concentrations. The severity of chronic progressive nephropathy was increased in 625 and 1,250\smg/L males and that of hyaline droplet accumulation in proximal renal tubules was increased in 1,250\smg/L males. The concentrations of renal α2u-globulin were significantly increased in 312\smg/L or greater males compared to the controls. THREE-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to 0, 78, 156, 312, 625, or 1,250\smg β-picoline/L drinking water for 14\sweeks (equivalent to average daily doses of approximately 10, 20, 37, 77, or 148\smg β-picoline/kg body weight to males and 9, 18, 38, 72, or 134\smg/kg to females). All mice survived to the end of the study. |
|---|---|
| Physical Description: | 1 PDF file (various pagings) illustrations |