National Toxicology Program

National Toxicology Program
https://ntp.niehs.nih.gov/go/37177

Abstract for TR-580 β-Picoline

Toxicology and Carcinogenesis Studies of β-Picoline (CASRN 108-99-6) in F344/N Rats and B6C3F1/N Mice (drinking water studies)

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Abstract

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.

3-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 mg β-picoline/L drinking water for 14 weeks (equivalent to average daily doses of approximately 6, 11, 22, 38, or 70 mg β-picoline/kg body weight to males and 6, 12, 23, 38, or 64 mg/kg to females). Special study groups of 10 male and 10 female rats were exposed to the same concentrations for 23 days 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 mg/L were significantly less than those of the controls. Water consumption by 625 and 1,250 mg/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 mg/L or greater males and in 156 mg/L or greater females compared to that in the controls. Absolute liver weights of 625 and 1,250 mg/L males and absolute and relative liver weights of 625 and 1,250 mg/L females were significantly less than those of the controls. The Markov transition matrix analyses of estrous cyclicity indicated female rats in the 312 and 625 mg/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 mg/L males and that of hyaline droplet accumulation in proximal renal tubules was increased in 1,250 mg/L males. The concentrations of renal α2u-globulin were significantly increased in 312 mg/L or greater males compared to the controls.

3-MONTH STUDY IN MICE

Groups of 10 male and 10 female mice were exposed to 0, 78, 156, 312, 625, or 1,250 mg β-picoline/L drinking water for 14 weeks (equivalent to average daily doses of approximately 10, 20, 37, 77, or 148 mg β-picoline/kg body weight to males and 9, 18, 38, 72, or 134 mg/kg to females). All mice survived to the end of the study. Mean body weights and water consumption were generally similar among exposed and control groups of male and female mice. Lung weights of 1,250 mg/L females were significantly less than those of the controls. No histopathologic lesions were attributed to β-picoline exposure.

2-YEAR STUDY IN RATS

Groups of 50 male and 50 female rats were exposed to 0, 156.25, 312.5, or 625 mg β-picoline/L drinking water for 104 or 105 weeks (equivalent to average daily doses of approximately 6, 12, or 22 mg β-picoline/kg body weight to males and 7, 14, or 26 mg/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 mg/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 mg/L female rats.

2-YEAR STUDY IN MICE

Groups of 50 male and 50 female mice were exposed to 0, 312.5, 625, or 1,250 mg β-picoline/L drinking water for 105 weeks (equivalent to average daily doses of approximately 26, 50, or 92 mg β-picoline/kg body weight to males and 18, 37, or 68 mg/kg to females). Survival of all exposed groups was similar to that of the control groups. Mean body weights of 1,250 mg/L males were 10% less than those of the control group after week 57, and those of 1,250 mg/L females were generally 10% less after week 13. Water consumption by exposed groups of males and females was similar to that by con-trols during the first 13 weeks of the study; water consumption by 625 and 1,250 mg/L males and 1,250 mg/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 mg/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 mg/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 mg/L females. The incidence of alveolar epithelium hyperplasia was significantly increased in 1,250 mg/L females.

In the nose, there were significantly increased incidences of olfactory epithelium respiratory metaplasia in 625 mg/L males and 1,250 mg/L males and females; the incidence of olfactory epithelium atrophy was significantly increased in 1,250 mg/L females.

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 of β-picoline in male F344/N rats exposed to 156.25, 312.5, or 625 mg/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


Summary of the 2-Year Carcinogenesis and Genetic Toxicology Studies of β-Picoline
  Male
F344/N Rats
Female
F344/N Rats
Male
B6C3F1 Mice
Female
B6C3F1 Mice
Concentrations in drinking water 0, 156.25, 312.5, or 625 mg/L 0, 156.25, 312.5, or 625 mg/L 0, 312.5, 625, or 1,250 mg/L 0, 312.5, 625, or 1,250 mg/L
Body weights Exposed groups generally similar to the control group Exposed groups similar to the control group 1,250 mg/L group 10% less than the control group after week 57 1,250 mg/L group generally 10% less than the control group after week 13
Survival rates 33/50, 31/50, 32/50, 24/50 30/50, 32/50, 33/50, 30/50 24/50, 26/50, 27/50, 33/50 38/50, 32/50, 35/50, 33/50
Nonneoplastic effects None None Nose: olfactory epithelium, metaplasia, respiratory (8/50, 12/50, 30/50, 41/50) Lung: alveolar epithelium, hyperplasia (2/50, 4/50, 3/49, 8/50)
Nose: olfactory epithelium, metaplasia, respiratory (2/49, 2/44, 7/49, 14/47); olfactory epithelium, atrophy (1/49, 2/44, 2/49, 7/47)
Neoplastic effects None Lung: alveolar/bronchiolar adenoma (0/50, 3/50, 2/50, 5/50); alveolar/bronchiolar adenoma or carcinoma (0/50, 4/50, 2/50, 5/50) None Liver: hepatocellular carcinoma (11/49, 20/50, 26/50, 23/50); hepatoblastoma (1/49, 3/50, 4/50, 4/50)
Lung: alveolar/bronchiolar adenoma (5/50, 6/50, 4/49, 11/50); carcinoma (7/50, 8/50, 10/49, 13/50); alveolar/bronchiolar adenoma or carcinoma (11/50, 13/50, 13/49, 21/50)
Equivocal findings None None Lung: alveolar/bronchiolar adenoma (6/50, 11/50, 16/50, 8/50); alveolar/bronchiolar adenoma or carcinoma (14/50, 19/50, 21/50, 15/50) None
Level of evidence of carcinogenic activity No evidence Some evidence Equivocal evidence Clear evidence
Genetic Toxicology
Assay Results
Bacterial gene mutations:
 
Negative in S. typhimurium TA97, TA98, TA100, TA1535, and TA1537 with and without S9; negative in E. coli strain WP2 uvrA/pKM101 with and without S9
Micronucleated erythrocytes
Mouse peripheral blood in vivo:
Negative in males and females

 


Date: August 2014

Pathology Tables, Survival and Growth Curves from NTP 2-year Studies

Target Organs & Incidences from 2-year Studies

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