Abstract for TR-300

Toxicology and Carcinogenesis Studies of 3-Chloro-2-methylpropene (Technical grade containing 5% dimethylvinyl chloride) in F344/N Rats and B6C3F1 Mice (Gavage Studies)

CASRN: 563-47-3
Chemical Formula: C4H7Cl
Molecular Weight: 90.5523
Synonyms/Common Names: 2-Methallyl chloride; methyl allyl chloride; b-methallyl chloride; pi-chloroisobutylene; isobutenyl chloride; 3-chloro-2-methyl-1-propene; 2-methyl-2-propenyl chloride
Report Date: June 1986

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Toxicology and carcinogenesis studies of technical-grade 3-chloro-2-methylpropene (containing 5% dimethylvinyl chloride), a widely used insecticide and a chemical intermediate, were performed on F344/N rats and B6C3F1 mice. In the 13-week studies, 50%-100% mortality occurred in groups of male and female rats receiving 400 mg/kg, male rats receiving 300 mg/kg, and male and female mice receiving 500-1,250 mg/kg. Inflammation and necrosis of the liver were seen in rats and mice, and necrosis of cortical tubules of the kidney was seen in mice. Based on these observations, groups of 50 male and 50 female rats were administered 3-chloro-2-methylpropene in corn oil by gavage at doses of 0, 75, or 150 mg/kg body weight, 5 days per week for 103 weeks, and groups of 50 male and 50 female mice received 3-chloro-2-methylpropene at 0, 100, or 200 mg/kg on the same schedule.

In the 2-year studies, the mean body weight of high dose male rats was consistently 10%-15% lower than that of the vehicle control group, and late in the study there was a marginal reduction in survival of high dose male rats. Mean body weights and survival in low dose male rats and in both dosed groups of female rats were comparable to those of their vehicle control groups. Mean body weights of high dose male mice and of both dosed groups of female mice were slightly (5%-9%) lower than those of the vehicle controls, whereas survival in both male and female mice was not affected by 3-chloro-2-methylpropene administration.

Dose-related increases in the incidence of forestomach inflammation were observed in male and female mice (male: vehicle control, 0/49; low dose, 9/49; high dose, 7/49; female: vehicle control, 2/50; low dose, 3/48; high dose, 9/44). Increased incidences of forestomach basal cell hyperplasia were observed in rats and mice of each sex. 3-Chloro-2-methylpropene induced forestomach squamous cell papillomas and squamous cell carcinomas in rats and mice as shown in the table. Invasion or metastasis of the squamous cell carcinomas to other organs was observed in two low dose male, three high dose male, and one high dose female mice.

Renal tubular cell adenocarcinomas (1/49), renal transitional cell carcinomas (1/49), and transitional cell papillomas (1/49) of the urinary bladder were observed in high dose male rats, and renal tubular cell adenomas (1/50) and renal tubular cell adenocarcinomas (1/50) were seen in low dose male rats. These urinary tract neoplasms were not observed in vehicle controls.

The incidences of inflammation of the nasal cavity and of nephropathy/nephrosis were greater in the two dosed groups than in the vehicle control groups of rats and mice of each sex.

Negative trends or lower incidences of pheochromocytomas of the adrenal gland and C-cell adenomas or carcinomas (combined) of the thyroid gland were observed in dosed male rats. Negative trends were observed in the incidences of hepatocellular adenomas or carcinomas (combined) in dosed male mice and of hemangiomas or hemangiosarcomas (combined) in dosed female mice.

3-Chloro-2-methylpropene was weakly mutagenic in Salmonella typhimurium strain TA1537 with 10% rat liver S9; results in strain TA100 with 10% Syrian hamster liver S9 or with 10% or 30% rat liver S9 were judged equivocal. Mutagenicity tests with S. typhimurium strains TA1535 and TA98 were negative with or without metabolic activation. 3-Chloro-2-methylpropene was mutagenic in the mouse lymphoma L5178/TK+/- forward mutation assay without exogenous metabolic activation. Cytogenetics tests with cultured Chinese hamster ovary cells were positive for induction of chromosomal aberrations and sister-chromatid exchanges (SCE's) in the absence of rat liver S9. With metabolic activation, SCE levels remained significantly elevated, but the number of chromosomal aberrations was reduced.

An audit of the experimental data was conducted for these 2-year carcinogenesis studies on 3-chloro-2-methylpropene. No data discrepancies were found that influenced the final interpretations.

Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenicity for 3-chloro-2-methylpropene as shown by the increased incidences of squamous cell neoplasms in the forestomach of male and female F344/N rats and of male and female B6C3F1 mice.