Initial hazard assessment of 1,4-dichlorobutane: Genotoxicity tests, 28-day repeated-dose toxicity test, and reproductive/developmental toxicity screening test in rats

Regul Toxicol Pharmacol. 2020 Apr:112:104610. doi: 10.1016/j.yrtph.2020.104610. Epub 2020 Feb 4.

Abstract

1,4-Dichlorobutane (1,4-DCB) is used as raw materials for drugs, pesticides, fragrances, and chemical fibers, and being used as a solvent. Its toxicity data was insufficient for screening assessment under the Japanese Chemical Substances Control Law. We conducted toxicity tests and hazard classification for screening assessment 1,4-DCB showed negative in the Ames test, positive in the in vitro chromosomal aberrations test with metabolic activation, and negative in the in vivo mouse bone-marrow micronucleus test. The 28-day repeated-dose toxicity study, where male and female rats were administered 1,4-DCB by gavage at 0, 12, 60, and 300 mg/kg/day, showed significant effects on the liver and pancreas from 12 mg/kg/day and kidney at 300 mg/kg/day. Based on periportal hepatocellular hypertrophy and decreased zymogen granules in pancreas, the lowest observed adverse effect level (LOAEL) of 12 mg/kg/day was obtained. The reproductive/developmental toxicity screening study, in which male and female rats were administered 1,4-DCB by gavage at dose of 0, 2.4, 12, and 60 mg/kg/day for 42-46 days, showed that the delivery index was decreased at 60 mg/kg/day without maternal toxicity. Based on the general toxicity, we classified this chemical as hazard class 2, with a D-value (Derived No Effect Level) of 0.002 mg/kg/day.

Keywords: CAS no. 110-56-5; Chemical substances control low; D-value; Existing chemical substance; Halogenated hydrocarbon; Hazard class.

MeSH terms

  • Administration, Oral
  • Animals
  • CHO Cells
  • Cells, Cultured
  • Chromosome Aberrations / drug effects*
  • Cricetulus
  • Dose-Response Relationship, Drug
  • Female
  • Hydrocarbons, Halogenated / administration & dosage
  • Hydrocarbons, Halogenated / toxicity*
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Pancreas / drug effects
  • Pancreas / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Reproduction / drug effects*
  • Toxicity Tests

Substances

  • Hydrocarbons, Halogenated
  • 1,4-dichlorobutane