Tertiary-butyl acetate metabolism, toxicity, and human health considerations

Abstract

Tertiary-butyl acetate (TBAC) (CAS No. 540-88-5) is an organic solvent with a potential for occupational and environmental exposure as a result of its use in industrial coatings, adhesives, inks, and degreasers. The objective of these studies was to extend the toxicological database upon which health hazard and risk assessments of TBAC can be made. The metabolism of TBAC was studied in rats exposed by inhalation for 6 h to concentrations of 100 or 1000 ppm. There was an evidence of partial saturation of TBAC absorption and metabolism at some concentration below 1000 ppm. Approximately 5% of the low dose and 26% of the high dose was expired without change within 12 h, while the retained material was rapidly metabolised and excreted, mostly in the urine, within 24 h. Very little radioactivity remained in the tissues after day 7. The metabolism of TBAC appears to follow two major routes: hydroxylation of the tertiary-butyl moiety to form 2-hydroxymethylisopropyl acetate and ester hydrolysis to form tertiary-butyl alcohol (TBA). A minor route involves oxidation of the acetate moiety. Based on the proportion of metabolites that can clearly be assigned to one or the other major pathway, hydroxylation of the tertiary-butyl moiety prevails at 100 ppm, while hydrolysis of the ester bond predominates at 1000 ppm. Based on nose-only inhalation exposure of rats to TBAC for 6 h, the LC50 for males and females combined is approximately 4200 ppm. Clinical signs included exaggerated breathing, staggering, tremors, and lethargy approximately 1 h after the exposure, but all surviving rats appeared normal from 24 h until the end of the 14 day observation period. An LC50 was not identified for mice. After exposure of whole body for 6 h to 3000 ppm, the highest concentration tested, all mice were prostrate for most of the exposure time, but there were no deaths. Groups of five male and five female Sprague-Dawley rats were exposed nose-only to 0, 100, 400, or 1600 ppm TBAC 6 h day−1 5 days wk−1 for 2 weeks. There were no effects on body weight, feed or water consumption, or necropsy findings. Male rats exposed to 1600 ppm had increased liver weights and hypertrophy of centrilobular hepatocytes. An increased proportion of cortical tubule cells with hyaline droplet accumulation was observed in all treated groups of males. Groups of five male and five female CD-1 mice were exposed whole body to 0, 190, 375, 750, or 1500 ppm TBAC 6 h day−1 for 14 consecutive days. There were no effects on body weight, feed consumption, or necropsy findings. Liver weights were increased in female mice at 750 and 1500 ppm. Minimal hypertrophy of centrilobular hepatocytes was found in female mice at 375, 750, and 1500 ppm and in male mice at 1500 ppm TBAC. TBAC did not induce gene mutations in bacterial tests with strains of S. typhimurium and E. coli. Further, there was no evidence of clastogenic activity from tests either for the induction of chromosomal aberrations in human lymphocytes in vitro in the presence or absence of S9 mix or for the induction of micronuclei in bone marrow cells of rats exposed by inhalation for 6 h to 1600 ppm TBAC. These results are relevant to human health risk assessment and are discussed in the context of previous studies. The weight of the scientific evidence supports the conclusion that TBAC has lower acute toxicity than previously suggested, that it is rapidly excreted when inhaled, and that neither TBAC nor its TBA metabolite are genotoxic or potential human carcinogens.