NTP Toxicology and Carcinogenesis Studies of 1,2-Epoxybutane (CAS No. 106-88-7) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).
1,2-Epoxybutane was selected for study because it is a short-chain epoxide that had been shown to be mutagenic and because no carcinogenicity data were available. Approximately 8 million pounds of 1,2-epoxybutane are produced annually in the United States. The chemical is used primarily as a stabilizer in chlorinated hydrocarbon solvents. Single-Exposure, Fourteen-Day, and Thirteen-Week Studies: Single-exposure, 14-day, 13-week, and 2-year studies were conducted in F344/N rats and B6C3F1 mice. The chemical was greater than 99% pure and was administered as a vapor by the inhalation route to mimic worker exposure; room air was used as the control exposure during these studies. Exposures were 6 hours per day (5 days per week), except in the single-exposure studies (4 hours). Additional studies were performed to evaluate the potential for genetic damage in bacteria and in mammalian cells. In the single-exposure studies, the chemical was administered at exposure concentrations of 400-6,550 ppm in rats and 400-2,050 ppm in mice. In the 14-day studies, rats and mice were exposed at 400-6,400 ppm, and in the 13-week studies, rats and mice were exposed at 50-800 ppm. All rats in the single-exposure studies at 6,550 ppm died; compound-related deaths were not seen in other dosed groups. All mice at 2,050 ppm and 4/5 mice of each sex at 1,420 ppm died; compound-related mortality was not seen in other dosed groups. In the 14-day studies, all rats at 3,200 and 6,400 ppm and 2/5 female rats at 1,600 ppm died; all mice at 1,600, 3,200, and 6,400 and 1/5 male mice at 800 ppm died. Final mean body weights of surviving rats exposed at 800 or 1,600 ppm were 12%-33% lower than those of the controls; final mean body weights of surviving mice at 800 ppm were 10%-12% lower than those of the controls. Compound-related lesions included pulmonary hemorrhage and rhinitis in rats at 1,600 ppm and nephrosis in mice at 800 and 1,600 ppm. In the 13-week studies, no compound-related mortality was observed in rats; all mice exposed at 800 ppm died. No compound-related clinical signs were seen in rats or in surviving mice. The final mean body weight of rats exposed at 800 ppm was 23% lower than that of controls for males and 16% lower for females. Final body weights of surviving mice were unaffected by exposure. Inflammation of the nasal turbinates was seen in rats at 800 ppm but not at lower exposure concentrations. Renal tubular necrosis was seen in mice at 800 ppm but not at lowerconcentrations. Inflammation of the nasal turbinates was observed in female mice at 100, 200, 400, and 800 ppm and in male mice at 200, 400, and 800 ppm. The highest exposure concentration selected for the 2-year studies in rats was 400 ppm because of body weight effects and nasal lesions observed at 800 ppm. The highest concentration selected for the 2-year studies in mice was 100 ppm because the nasal lesions seen at 200 and 400 ppm were considered to be potentially life threatening. Two-Year Studies: The 2-year toxicology and carcinogenesis studies of 1,2-epoxybutane were conducted by exposing groups of 50 animals per species and sex to the chemical by inhalation, 6 hours per day 5 days per week. Rats were exposed at concentrations of 0, 200, or 400 ppm for 103 weeks and mice at 0, 50, or 100 ppm for 102 weeks. Body Weight and Survival in the Two-Year Studies: The survival of all groups of dosed rats was at least 50% until week 98, but final survival was reduced in the dosed groups (final survival-- male: control, 30/50; low dose, 18/50; high dose, 23/50; female: 32/50; 21/50; 22/50). Mean body weights of control and exposed male rats were similar until week 86; thereafter, mean body weights of high dose male rats were 4%-8% lower than those of controls. Mean body weights of high dose female rats were 5%-10% lower than those of controls after week 22. Survival in male mice was comparable among groups (final survival: 41/50; 45/50; 33/50). Survival in female mice was greater than 50% in all groups at week 86 and then was reduced in high dose females toward the end of the stin all groups at week 86 and then was reduced in high dose females toward the end of the study (final survival: 29/50; 25/50; 9/50). This decreased survival was associated with suppurative inflammation of the ovary and uterus. Klebsiella oxytoca was isolated from these ovarian/uterine lesions. Mean body weights of high dose male mice were 10&percnt;-14&percnt; lower than those of the controls after week 69; mean body weights of low dose male mice were 4&percnt;-8&percnt; lower than those of the controls after week 86. Mean body weights of high dose female mice were 13&percnt;-23&percnt; lower than those of the controls after week 60, and mean body weights of low dose female mice were 12&percnt;-16&percnt; lower than those of the controls after week 73. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Dosed rats had nonneoplastic lesions of the nasal cavity including inflammation, epithelial hyperplasia, squamous metaplasia, hyperostosis of the nasal turbinate bone, and atrophy of the olfactory epithelium. Seven papillary adenomas of the nasal cavity were seen in highdose male rats and two in high dose female rats. The historical incidences of nasal cavity adenomas in untreated male and untreated female F344/N rats are less than 0.1&percnt;. The incidences of alveolar/bronchiolar carcinomas (0/50; 1/50; 4/49) and adenomas or carcinomas (combined) (0/50; 2/50; 5/49) were increased in high dose male rats; no increased incidences of these tumors were observed in dosed female rats. Dosed mice had increased incidences of nonneoplastic lesions of the nasal cavity but no significant increase in the incidence of neoplastic lesions of the nasal cavity. The nonneoplastic lesions included suppurative inflammation (empyema), epithelial hyperplasia, erosion, regeneration, and squamous metaplasia in the nasal cavity; atrophy of the olfactory sensory epithelium; hyperplasia of the nasal gland (Bowman's glands); and inflammation and hyperplasia of the nasolacrimal duct. A single squamous cell papilloma was seen in the incisive duct of one high dose male mouse. Genetic Toxicology: 1,2-Epoxybutane was mutagenic in Salmonella typhimurium strains TA100 and TA1535 when tested with a preincubational protocol with or without rat liver S9, indicating that it is a direct-acting mutagen capable of inducing base-pair substitutions in prokaryotes; it did not cause gene reversion in strains TA1537 or TA98. 1,2-Epoxybutane induced forward mutations at the TK locus of cultured mouse L5178Y lymphoma cells with and without metabolic activation. Both chromosomal aberrations andsister chromatid exchanges were induced in cultured Chinese hamster ovary cells after exposure to 1,2-epoxybutane in the presence and absence of metabolic activation. 1,2-Epoxybutane, when fed to male Drosophila, caused significant increases in the number of sex-linked recessive lethal mutations and reciprocal translocations in the germ cells. Data Audit: An audit of the experimental data was conducted for the 2-year studies of 1,2-epoxybutane. No data discrepancies were found that influenced the final interpretations. Conclusions: Under the conditions of these 2-year inhalation studies, there was clear evidence of carcinogenic activity of 1,2-epoxybutane for male F344/N rats, as shown by an increased incidence of papillary adenomas of the nasal cavity, alveolar/bronchiolar carcinomas, and alveolar/bronchiolar adenomas and carcinomas (combined). There was equivocal evidence of carcinogenic activity for female F344/N rats, as shown by the presence of papillary adenomas of the nasal cavity. There was no evidence of carcinogenic activity for male or female B6C3F1 mice exposed at 50 or 100 ppm. 1,2-Epoxybutane exposure was associated with adenomatous hyperplasia and inflammatory lesions of the nasal cavity in rats and inflammatory lesions of the nasal cavity in mice. Synonyms: 1-butene oxide; 1,2-butene oxide; butylene oxide; 1,2-butylene oxide; ethyl ethylene oxide; ethyl oxirane