Toxicology and Carcinogenesis Studies of 1,2-Epoxybutane(CAS No. 106-88-7) in F344/N Rats and B6C3F1 Mice (InhalationStudies)
Chemical Formula: C4H8O
1,2-Epoxybutanewas selected for study because it is a short-chain epoxide that had beenshownto be mutagenic and because no carcinogenicity data were available.Approximately 8 million pounds of 1,2-epoxybutaneare produced annually in the United States. The chemical is used primarily asa stabilizer in chlorinated hydrocarbon solvents.
Single-exposure,14-day,13-week,and 2-yearstudies were conducted in F344/N rats and B6C3F1 mice. The chemical wasgreater than 99% pure and was administered as a vapor by the inhalationrouteto mimic worker exposure; room air was used as the control exposure duringthese studies. Exposures were 6 hours per day (5 days per week), except inthesingle-exposurestudies (4 hours). Additional studies were performed to evaluate the potentialfor genetic damage in bacteria and in mammalian cells. In thesingle-exposurestudies, the chemical was administered at exposure concentrations of400-6,550ppm in rats and 400-2,050ppm in mice. In the 14-daystudies, rats and mice were exposed at 400-6,400ppm, and in the 13-weekstudies, rats and mice were exposed at 50-800ppm.
All rats in the single-exposurestudies at 6,550 ppm died; compound-relateddeaths were not seen in other dosed groups. All mice at 2,050 ppm and 4/5miceof each sex at 1,420 ppm died; compound-relatedmortality was not seen in other dosed groups.
In the 14-daystudies, all rats at 3,200 and 6,400 ppm and 2/5 female rats at 1,600 ppmdied;all mice at 1,600, 3,200, and 6,400 and 1/5 male mice at 800 ppm died. Finalmean body weights of surviving rats exposed at 800 or 1,600 ppm were12%-33%lower than those of the controls; final mean body weights of surviving mice at800 ppm were 10%-12%lower than those of the controls. Compound-relatedlesions included pulmonary hemorrhage and rhinitis in rats at 1,600 ppm andnephrosis in mice at 800 and 1,600 ppm.
In the 13-weekstudies, no compound-relatedmortality was observed in rats; all mice exposed at 800 ppm died. Nocompound-related clinical signs were seen in rats or in surviving mice. Thefinal mean body weight of rats exposed at 800 ppm was 23% lower than that ofcontrols for males and 16% lower for females. Final body weights of survivingmice were unaffected by exposure. Inflammation of the nasal turbinates wasseen in rats at 800 ppm but not at lower exposure concentrations. Renaltubular 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 highestexposure concentration selected for the 2-yearstudies in rats was 400 ppm because of body weight effects and nasal lesionsobserved at 800 ppm. The highest concentration selected for the 2-yearstudies in mice was 100 ppm because the nasal lesions seen at 200 and 400ppmwere considered to be potentially life threatening.
The 2-yeartoxicology and carcinogenesis studies of 1,2-epoxybutanewere conducted by exposing groups of 50 animals per species and sex to thechemical by inhalation, 6 hours per day 5 days per week. Rats were exposedatconcentrations of 0, 200, or 400 ppm for 103 weeks and mice at 0, 50, or 100ppm for 102 weeks.
Body Weight and Survival in the Two-YearStudies:
The survival of all groups of dosed rats was at least 50% until week98, 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 untilweek 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 ratswere5%-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 atweek 86 and then was reduced in high dose females toward the end of thestudy(final survival: 29/50; 25/50; 9/50). This decreased survival was associatedwith suppurative inflammation of the ovary and uterus. Klebsiellaoxytoca was isolated from these ovarian/uterine lesions. Mean bodyweightsof high dose male mice were 10%-14%lower than those of the controls after week 69; mean body weights of low dosemale mice were 4%-8%lower than those of the controls after week 86. Mean body weights of highdosefemale mice were 13%-23%lower than those of the controls after week 60, and mean body weights of lowdose female mice were 12%-16% lower than those of the controls after week73.
Nonneoplastic and Neoplastic Effects in the Two-YearStudies:
Dosed rats had nonneoplastic lesions of the nasal cavity includinginflammation, epithelial hyperplasia, squamous metaplasia, hyperostosis ofthenasal turbinate bone, and atrophy of the olfactory epithelium. Seven papillaryadenomas of the nasal cavity were seen in highdose male rats and two in highdose female rats. The historical incidences of nasal cavity adenomas inuntreated male and untreated female F344/N rats are less than 0.1%. Theincidences of alveolar/bronchiolar carcinomas (0/50; 1/50; 4/49) andadenomasor carcinomas (combined) (0/50; 2/50; 5/49) were increased in high dose malerats; no increased incidences of these tumors were observed in dosed femalerats.
Dosed mice had increased incidences of nonneoplastic lesions of the nasalcavity but no significant increase in the incidence of neoplastic lesions ofthe nasal cavity. The nonneoplastic lesions included suppurativeinflammation(empyema), epithelial hyperplasia, erosion, regeneration, and squamousmetaplasia in the nasal cavity; atrophy of the olfactory sensory epithelium ;hyperplasia of the nasal gland (Bowman's glands); and inflammation andhyperplasia of the nasolacrimal duct. A single squamous cell papilloma wasseen in the incisive duct of one high dose male mouse.
1,2-Epoxybutanewas mutagenic in Salmonella typhimurium strains TA100 and TA1535whentested with a preincubational protocol with or without rat liver S9, indicatingthat it is a direct-actingmutagen capable of inducing base-pairsubstitutions in prokaryotes; it did not cause gene reversion in strains TA1537or TA98. 1,2-Epoxybutane induced forward mutations at the TK locus ofculturedmouse L5178Y lymphoma cells with and without metabolic activation. Bothchromosomal aberrations andsister chromatid exchanges were induced inculturedChinese hamster ovary cells after exposure to 1,2-epoxybutanein the presence and absence of metabolic activation. 1,2-Epoxybutane, whenfedto male Drosophila, caused significant increases in the number of sex-linkedrecessive lethal mutations and reciprocal translocations in the germ cells.
An audit of the experimental data was conducted for the 2-yearstudies of 1,2-epoxybutane. No data discrepancies were found that influenced the final interpretations.
Under the conditions of these 2-yearinhalation studies, there was clear evidence of carcinogenic activity of1,2-epoxybutane for male F344/N rats, as shown by an increased incidence ofpapillary adenomas of the nasal cavity, alveolar/bronchiolar carcinomas, andalveolar/bronchiolar adenomas and carcinomas (combined). There wasequivocalevidence of carcinogenic activity for female F344/N rats, as shown by thepresence of papillary adenomas of the nasal cavity. There was noevidenceof carcinogenic activity for male or female B6C3F1 mice exposed at 50 or100 ppm. 1,2-Epoxybutaneexposure was associated with adenomatous hyperplasia and inflammatorylesionsof the nasal cavity in rats and inflammatory lesions of the nasal cavity inmice.
Synonyms: 1-butene oxide; 1,2-butene oxide; butylene oxide; 1,2-butyleneoxide;ethyl ethylene oxide; ethyl oxirane
Report Date: March 1988