Human health screening level risk assessments of tertiary-butyl acetate (TBAC): Calculated acute and chronic reference concentration (RfC) and Hazard Quotient (HQ) values based on toxicity and exposure scenario evaluations

Abstract

A screening level risk assessment has been performed for tertiary-butyl acetate (TBAC) examining its primary uses as a solvent in industrial and consumer products. Hazard quotients (HQ) were developed by merging TBAC animal toxicity and dose-response data with population-level, occupational and consumer exposure scenarios. TBAC has a low order of toxicity following subchronic inhalation exposure, and neurobehavioral changes (hyperactivity) in mice observed immediately after termination of exposure were used as conservative endpoints for derivation of acute and chronic reference concentration (RfC) values. TBAC is not genotoxic but has not been tested for carcinogenicity. However, TBAC is unlikely to be a human carcinogen in that its non-genotoxic metabolic surrogates tertiary-butanol (TBA) and methyl tertiary butyl ether (MTBE) produce only male rat α-2u-globulin-mediated kidney cancer and high-dose specific mouse thyroid tumors, both of which have little qualitative or quantitative relevance to humans. Benchmark dose (BMD)-modeling of the neurobehavioral responses yielded acute and chronic RfC values of 1.5 ppm and 0.3 ppm, respectively. After conservative modeling of general population and near-source occupational and consumer product exposure scenarios, almost all HQs were substantially less than 1. HQs exceeding 1 were limited to consumer use of automotive products and paints in a poorly ventilated garage-sized room (HQ = 313) and occupational exposures in small and large brake shops using no personal protective equipment or ventilation controls (HQs = 3.4–126.6). The screening level risk assessments confirm low human health concerns with most uses of TBAC and indicate that further data-informed refinements can address problematic health/exposure scenarios. The assessments also illustrate how tier-based risk assessments using read-across toxicity information to metabolic surrogates reduce the need for comprehensive animal testing.

Keywords:

• Tertiary-butanol (t-butanol)
• methyl tertiary butyl ether (MTBE)
• metabolism
• genotoxicity
• neurotoxicity
• chronic progressive nephropathy
• thyroid
• α-2u-globulin
• occupational
• consumer product
• solvent
• screening level risk assessment
• tier-based toxicity testing

Acknowledgements

The authors acknowledge Michael Gargas and Lisa Sweeney (Environmental Health Effects Research Naval Medical Research Unit, Dayton, OH) for providing reviews of the benchmark dose analyses. The authors acknowledge comments provided by the anonymous journal peer reviewers in improving the final version of this manuscript.

Declaration of interest

The employment affiliation of the authors has been noted on on the title page of this paper. Development of this review and analysis was supported in-part by a contract from Lyondell Basell to Exponent, Inc., the employer of the lead author (JSB). TBAC is a commercial product of LyondellBasell. The participation of co-authors MIB and DBP was conducted as part of their employment responsibilities with LyondellBasell, a manufacturer of TBAC. Co-authors WF, DBM, and CRK are consultants to LyondellBasell, and also received contract support from LyondellBasell to develop a toxicology review and screening level risk review for TBAC that was subjected to an unpublished peer consultation provided by Toxicology Excellence for Risk Assessment (TERA; http://www.tera.org/Peer/TBAC/index.html); the peer consultation document and review was a partial basis for the current review and analysis. WF was an author on the TBAC subchronic studies (Faber et al. 2014) which were conducted at WIL Research Laboratory with contract support from LyondellBasell. DBM was the author of the TBA cancer and mode of action review (McGregor, 2010) which was supported by a contract from LyondellBasell. A final draft of the manuscript was reviewed by internal LyondellBasell health sciences, communications, legal and business representatives, and was subjected to technical and editorial reviews by Exponent, Inc. staff. The authors have sole responsibility for the content and writing of this paper. The interpretation and views expressed in the paper are not necessarily those of the authors’ employers.

Supplementary material available online

Supplementary Tables 1 & 3.