2-methylpyridine

Endpoint summary

Description of key information

Repeated dose oral toxicity has been well studied for pyridine and 3-methylpyridine, representative members of a chemical category, and a reliable study exists for repeated dose inhalation toxicity for 3-methylpyridine.   The oral toxicity studies are two year bioassay data in rats (F344 and Wistar) and mice (B6C3F1).  NOAELs are established.   

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

7 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

adequate

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

1 105 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

adequate

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

A category of pyridine and alkyl pyridine derivatives is comprised of pyridine (CAS 110 -86 -1), 2-methylpyridine (CAS 109 -06 -8), 3-methylpyridine (CAS 108 -99 -6) and 4-methylpyridine (CAS 108 -89 -4). The foundation of the category is a common functional group (the pyridine unsaturated ring structure) and similar physico-chemical properties, environmental fate and toxicity, and mammalian toxicity. Similar toxicological properties derive from physico-chemical parameters and common pathways of metabolism and elimination among all members of the category. Three of four members of this category have harmonized classification and labelling. Read-across for non-harmonized endpoints is adequate for risk assessment purposes.

The U.S. National Toxicology Program (NTP) has undertaken 2-year carcinogenicity/chronic toxicity assays of pyridine, as well as of 3-methylpyridine, in drinking water of rats and mice. These substances comprise a chemical category along with 2-methylpyridine and 4-methylpyridine. For pyridine and 3-methylpyridine, F344 rats displayed a strain-specific nephrotoxicity involving alpha-2-microglobulinemia. Humans do not develop kidney toxicity by an alpha-2-microglobulin-mediated mechanism of action; hence this toxicity is not relevant to humans.

A second strain of rat which is not susceptible to this toxicity, Wistars, were added as a supplemental group in the dosing of pyridine. Actual doses from consuming drinking water were comparable between the two strains, at 7, 14 and 33 mg/kg bw/d for F344, and 8, 17 and 36 mg/kg bw/d in Wistars. Nontumorigenic findings in the F344 study were nephrotoxicity due to alpha-2-microglobulinemia, and in Wistar rats, hepatic centrilobular liver degeneration/necrosis and fibrosis in male rats. The NOAELs were 7 and 8 mg/kg bw/d for F344 and Wistar rats, respectively. 3 -Methylpyridine also resulted in nephrotoxicity due to alpha-2-microglobulinemia in F344 rats. For pyridine, tumors were observed in each strain of rat and mouse, but none were consistent over the 3 species. The NTP concluded that there was some evidence of carcinogenic activity of pyridine in F344 and Wistar rats, and in C3H6F1 mice. The International Agency for Cancer Research (IARC) reviewed this data and epidemiologic evidence and concluded that pyridine was not able to be classified as a human carcinogen. Consumption of 3-methylpyridine resulted in lung adenomas and carcinomas, primarily in mice, and liver tumours in female mice. The NOAELs are higher for 3-methylpyridine, at 12 to 77 mg/kg bw/d. The NOAELs of pyridine were used for development of DNELs for the chemical category. The methylpyridines have been investigated in subchronic and subacute studies in rats. The NOAEC was determined to be greater than 380 mg/m³.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
experimental study according to a guideline method

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
experimental study using a valid protocal

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver; urogenital: kidneys

Repeated dose toxicity: inhalation - systemic effects (target organ) digestive: liver

Justification for classification or non-classification

No specific target organ toxicity is proposed for pyridine and methylpyridines as a result of repeated dose exposure. The toxicity observed in chronic studies of pyridine in rats is either strain specific and not relevant to humans, or is a reflection of gastroenterologic (liver) adaptation. The toxicity observed in chronic studies of 3-methylpydine is tumour development (lung, after oral exposure) or liver, not relevant to humans. There is a question about whether inhalation of orally-consumed 3 -methylpyridine may have contributed to the development of lung tumors. There is insufficient evidence to classify for specific target organ toxicity.