This CICAD on n-butyl, isobutyl, sec-butyl, and tert-butyl acetates was prepared by Toxicology Advice and Consulting Ltd and the Centre for Ecology and Hydrology. The health effects sections were based on the Dutch Expert Committee on Occupational Standards and Swedish Criteria Group for Occupational Standards Basis for an Occupational Standard (Stouten and Bogaerts, 2002). Data identified as of September 2000 were considered in this source document. A comprehensive literature search of several online databases was conducted by Toxicology Advice and Consulting Ltd in January 2004 to identify any references published subsequent to those incorporated in the source document. The environmental and ecotoxicological sections were prepared by the Centre for Ecology and Hydrology from a review of the literature. Information on the nature of the peer review and the availability of the source document is presented in Appendix 2. Information on the peer review of this CICAD is presented in Appendix 3. This CICAD was considered and approved as an international assessment at a meeting of the Final Review Board, held in Hanoi, Viet Nam, on 28 September -1 October 2004. Participants at the Final Review Board meeting are presented in Appendix 4. The International Chemical Safety Cards for n-butyl acetate (IPCS, 2003a) isobutyl acetate (IPCS, 20036), sec-butyl acetate (IPCS, 2003c), and tert-butyl acetate (IPCS, 2002), produced by the International Programme on Chemical Safety in a separate, peer-reviewed process, have also been reproduced in this document.
The butyl acetate isomers n-butyl acetate (CAS No. 123-86-4), isobutyl acetate (CAS No. 110-19-0), sec-butyl acetate (GAS No. 105-46-4), and tert-butyl acetate (CAS No. 540-88-5) are colourless, flammable liquids with fruity odours.
Butyl acetates can occur naturally, and they are present in various plant tissues. They may be released to the environment from industrial plants during their manufacture and use, as well as following their use as solvents in products suck as lacquers, inks, coatings, and adhesives. n-Butyl acetate is used as a food flavorant and in materials for food contact use. Butyl acetates may also be formed in the atmosphere as a product of the photo-chemical oxidation of other chemicals.
Butyl acetates released to the environment are likely to volatilize to the atmosphere, where they will undergo photochemical oxidation reactions with hydroxyl radicals and chlorine atoms. Butyl acetates in solution will undergo hydrolysis reactions, at a rate determined by the pH of the solution. Butyl acetates are readily biodegradable. Their physicochemical properties suggest that butyl acetates will not bind to soil or be bioaccumulated.
Butyl acetates have been detected in river water, but the concentrations were not quantified. They have also been detected in air samples from industrial and chemical waste sites at concentrations up to 4.8 ug/m3. Exposure of the general population may occur from domestic sources, with n-butyl acetate concentrations up to 23 ug/m3 imported in household air. Occupational exposure to butyl acetate particles and vapour may occur in work Places involving printing, lacquering, or glueing. Mean occupational air concentrations as measured by personal air sampling ranged up to 413 mg/m3.
It is expected that the butyl acetates are readily absorbed by the respiratory tract, the sin, and the gastrointestinal tract, although no published quantitative data were identified. n-Butyl acetate, isobutyl acetate, and me-butyl acetate may be readily hydrolysed to acetic acid and their respective alcohols (n-butanol, isobutanol, and sec-butanol) in the blood, liver, small intestine, and respiratory tract. tert-Butyl acetate is less readily hydrolysed, with about 20?/. of the inhaled isomer being metabolized by a different pathway involving hydroxylation to produce 2-hydroxyisopropyl acetate. Where appropriate, data on the alcohols relevant to an assessment of toxic hazard and risk of butyl acetates have been included in this CICAD. n-Butyl acetate is probably excreted via exhaled air and urine both as the unchanged compound and as metabolites after transformation in the body. Humans exposed to atmospheres containing n-butyl acetate at a concentration of 200 mg/m3 were reported to excrete 50% of the inhaled compound in the exhaled air.
Data on the acute inhalation toxicity of n-butyl acetate are highly inconsistent, with LC50 values ranging from 740 to above 45 000 mg/m3. The explanation for the inconsistent results is not known. However, the results of a recent well designed and performed experiment indicate that the toxicity of n-butyl acetate following a single 4-h inhalation is low, with no deaths occurring at exposures up to approximately 45 000 mg/ m3. Additionally, n-butyl acetate has low acute toxicity by the oral and dermal routes. Oral "values in mule and female rats were 13.1 and 11.0 g/kg body weight, respectively, whereas no deaths occurred in rabbits exposed by the dermal route to 14.4 g/kg body weight. Data (where available) on the other isomers indicate low toxicity by the inhalation, oral, and dermal routes.
Most results indicate that n-butyl, isobutyl, and tert-butyl acetate are, at mast, only slightly irritating to the skin and eyes, although there is some indication of more severe irritation with certain exposure conditions. No data on irritation were identified for sec-butyl acetate. n-Butyl acetates and Isobutyl acetate have been tested for skin sensitization potential, with negative results.
Published data on systemic toxicity following repeated exposure are limited to n-butyl acetate. The principal effect observed following inhalation exposure was a reduction in activity levels at 7200 mg/m3 and above, with a NOAEC of 2400 mg/m3. However, a 13-week neurotoxicity study in which rats were exposed by inhalation to atmospheres containing up to 14 000 mg/m3 found no evidence of neurotoxicity in functional observational battery, motor activity, and scheduled-controlled operant behaviour tests or on microscopic examination of nervous system tissues.
Only limited studies (with only one tested concentration) are available on the reproductive and developmental toxicity of n-butyl acetate. Although there were signs of developmental toxicity reported, maternal toxicity was also present. Data from a develop-mental toxicity study with the major metabolite, n-butanol, suggest that it is rot a developmental toxin. No data were identified on the other butyl acetate isomers. Studies with the key metabolites isobutanol and sec-butanol indicate lack of specific reproductive or developmental toxicity.
None of the butyl acetate isomers has been tested in long-term carcinogenicity studies. Results (where avail-able) from genotoxicity studies, however, indicate a lack of activity. Although the metabolite tert-butanol has
given same evidence of carcinogenicity in rats and mice, genotoxicity assays with this compound again failed to show any activity.
Human studies indicate that n-butyl acetate expo-sure via inhalation may be slightly irritating to the eyes, nose, and throat. Sensitivity to odour occurs at concentrations several orders of magnitude lower than levels at which nose, and throat irritation are reported. Isobutyl acetate (2?/. in petrolatum) was not irritating when applied as a 48-h covered patch No, or only very limited, data concerning effects on humans were available on the other isomers.
Based on the limited data set for n-butyl acetate, a tolerable concentration of 0.4 mg/m3 has been derived. This is based on results from the 13-week inhalation study in rats providing the lowest NOAEC. An uncertainty factor of 1000 is used, allowing for interspecies extrapolation, intraspecies variability, and extrapolation from medium-term to long-term exposure. The only available study in which representative levels of n-butyl acetate in households were identified reported values up to 0.02 mg/ and , which is 20 limes less than the tolerable concentration. Occupational exposure levels, however, may exceed this tolerable concentration.
Acute toxicity data suggest that butyl acetate has moderate to low toxicity to aquatic organisms. An EC50 value of 675 mg/litre was reported for growth of green algae exposed to n-butyl acetate for 72 h. Twenty-four-hour LC50/EC50 values for aquatic invertebrates exposed to n-butyl acetate and Isobutyl acetate were 72.8-205 mg/litre and 250-1200 mg/litre, respectively. Ninety-six hour LC50 values for fish ranged from 18 to 185 mg/litre for n-butyl acetate. Forty-eight-hour LC50 values for fish exposed to Isobutyl acetate ranged from 71 to 141 mg/litre. NOEC values for growth of lettuce exposed to tert-butyl acetate were 100 mg/litre (14-day NOEC in soil) and 32 mg/litre (16-day NOEC in hydroponic solution).
