Toxicology studies of allyl bromide (CAS No. 106-95-6) in genetically modified (FVB Tg.AC hemizygous) mice and carcinogenicity studies of allyl bromide in genetically modified [B6.129-Trp53tm1Brd (N5) Haploinsufficient] mice (dermal and gavage studies)

Abstract

Allyl bromide is primarily used as a starting material/chemical intermediate in organic synthesis and as an intermediate in the manufacture of polymers/resins, synthetic perfumes, pharmaceuticals, agricultural chemicals, and other allyl compounds. It has been described as an insecticidal fumigant used in crop protection. Male and female FVB/N and C57BL/6 mice received allyl bromide (greater than 99% pure) by gavage and dermal application, respectively, for 2 weeks, and FVB/N, C57BL/6, Tg.AC hemizygous, and p53 haploinsufficient mice received allyl bromide by gavage for 40 weeks. Genetic toxicology studies were conducted in Salmonella typhimurium and mouse peripheral blood erythrocytes. 2-WEEK STUDIES IN FVB/N MICE: Groups of five male and five female FVB/N mice were dermally administered 0, 7.5, 15, 30, 60, or 120 mg allyl bromide/kg body weight in acetone, 5 days a week for 2 weeks. The survival and mean body weights of all dosed groups of males and females were similar to those of the vehicle controls. There were no increases in the incidences of lesions in dosed mice. 2-WEEK STUDIES IN C57BL/6 MICE: Groups of five male and five female FVB/N mice were administered 0, 7.5, 15, 30, 60, or 120 mg allyl bromide/kg body weight in corn oil by gavage, 5 days a week for 2 weeks. Three 120 mg/kg male mice died prior to the end of the study. Mean body weights of all dosed groups of males and females were similar to those of the vehicle controls. Liver weights of 30 and 60 mg/kg males were significantly greater than those of the vehicle controls. Nonneoplastic lesions of the forestomach, including hyperplasia, inflammation, degeneration, and hyperkeratosis of the forestomach epithelium, were observed in dosed mice. 40-WEEK STUDIES IN FVB/N MICE: Groups of 15 male and 15 female FVB/N mice were administered 0 or 8 mg allyl bromide/kg body weight in corn oil by gavage, 5 days a week for 40 weeks. Survival of dosed mice was similar to that of the vehicle controls. Mean body weights of dosed mice were within 10% of those of the vehicle controls throughout most of the study. There were no chemical-related gross or microscopic findings in dosed mice. 40-WEEK STUDIES IN Tg.AC HEMIZYGOUS MICE: Groups of 15 male and 15 female Tg.AC hemizygous mice were administered 0, 0.5, 1, 2, 4, or 8 mg allyl bromide/kg body weight in corn oil by gavage, 5 days a week for 40 weeks. Survival of dosed mice was similar to that of the vehicle controls. Mean body weights were generally similar between dosed and vehicle control mice throughout the study. In female mice, there were increased numbers of cutaneous and mucocutaneous masses (gross observations) on the body, particularly the vaginal and vulvar area, and these papillomas were observed earlier in the dosed groups. There were positive trends in the incidences of squamous cell papilloma of the vulva and of all skin sites in females. 40-WEEK STUDIES IN C57BL/6 MICE: Groups of 15 male and 15 female C57BL/6 mice were administered 0 or 8 mg allyl bromide/kg body weight in corn oil by gavage, 5 days a week for 40 weeks. Survival of dosed mice was similar to that of the vehicle controls. Mean body weights and organ weights were similar between dosed and vehicle control mice throughout the study. There were no chemical-related gross or microscopic findings in dosed mice. 40-WEEK STUDIES IN p53 HAPLOINSUFFICIENT MICE: Groups of 15 male and 15 female p53 haploinsufficient mice were administered 0, 0.5, 1, 2, 4, or 8 mg allyl bromide/kg body weight in corn oil by gavage, 5 days a week for 40 weeks. Survival of dosed mice was similar to that of the vehicle controls. Mean body weights of dosed mice were within 10% of those of the vehicle controls throughout most of the study. Mean body weights of 8 mg/kg females were 11% to 15% greater than those of the vehicle controls from week 26 to week 33, and those of 4 mg/kg females were generally less after week 21. There were no chemical-related gross or microscopic findings.

Genetic toxicology: Allyl bromide was mutagenic in S. typhimurium strain TA100, with and without exogenous metabolic activation (S9). No mutagenicity was detected in S. typhimurium strain TA98, with or without S9, over the same concentration range tested with TA100. The frequency of micronucleated erythrocytes was assessed in male and female mice for each of the four mouse strains administered allyl bromide by corn oil gavage for 40 weeks. Results in all four studies were concluded to be negative; in addition, no significant changes in the percentages of polychromatic erythrocytes (reticulocytes) among total erythrocytes were observed in any of the four strains of mice.

Conclusions: Under the conditions of this study, there was no evidence of carcinogenic activity in male or female p53 haploinsufficient mice administered allyl bromide at 0, 0.5, 1, 2, 4, or 8 mg/kg per day by corn oil gavage, 5 days a week for 40 weeks. There was a marginal increase in the incidence of squamous cell papillomas, primarily of the vulva, in female Tg.AC mice administered allyl bromide by corn oil gavage for 40 weeks. No treatment-related neoplasms were seen in male Tg.AC hemizygous mice administered allyl bromide by gavage at 0.5, 1, 2, 4, or 8 mg/kg, 5 days per week for 40 weeks.