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

Abstract

Tertiary-butyl acetate (TBAC) 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 LC 50 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 À1 5 days wk À1 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 À1 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 bo...

tert‐Butyl acetate [MAK Value Documentation, 2014]

“…As the radioactivity detected in the tissues after exposure to a concentration ten times higher was less than ten times higher, the authors concluded that there might have been a partial saturation of absorption and metabolism at the higher concentrations (Cruzan and Kirkpatrick 2006).…”

“…Based on the proportion of metabolites that are formed, tert-butyl acetate is primarily hydroxylated at 100 ml/m 3 (altogether 24% of all metabolites), while ester hydrolysis prevails at 1000 ml/m 3 (altogether 23% of all metabolites), 70% to 80% of the ester being cleaved. Oxidation of the acetate unit (1.3% at 100 ml/m 3 ; 0.6% at 1000 ml/m 3 ) is a third metabolic pathway, but it is of minor relevance; glucuronidation is another minor route (Figure 1; Cruzan and Kirkpatrick 2006).…”

“…Only 0.6% and 3% of the inhaled amount, respectively, was identified as CO 2 . Exhalation during exposure was not determined (Cruzan and Kirkpatrick 2006).…”

Scientific Opinion on the evaluation of the substances currently on the list in the annex to Commission Directive 96/3/EC as acceptable previous cargoes for edible fats and oils – Part III of III

“…Hydroxylation of the tert-butyl side chain appears to predominate at lower exposures whilst hydrolysis predominates at higher exposures. Oxidation of the acetate side chain can also occur to a minor extent (Cruzan and Kirkpatrick, 2006). tert-Butanol is not a substrate for alcohol dehydrogenase and is metabolised only slowly, either by glucuronide conjugation of the hydroxyl group, with excretion in the urine, or oxidation of one or more of the alkyl substituents, which can be catalysed by P450 enzymes.…”

“…In the absence of any human counterpart to this protein at levels sufficient to support a toxicologically relevant interaction, this carcinogenic response is considered not relevant to humans (Cruzan and Kirkpatrick, 2006;TERA, 2009). The follicular cell adenomas in female mice were accompanied by follicular cell hyperplasia.…”