EPA’s Response to Select Interagency Comments on the Interagency Science Consultation 

Draft of the IRIS Toxicological Review of tert-Butyl Alcohol

May 2016

Purpose: The Integrated Risk Information System (IRIS) assessment development process of May 

2009 includes two steps (Step 3 and 6b) where the Executive Office of the President and other 

federal agencies can comment on draft assessments. Comments on the Interagency Science 

Consultation draft of the IRIS Toxicological Review of tert-Butyl Alcohol (tert-butanol) (Step 3) 

were provided by the National Toxicology Program (NTP), and jointly by the Office of Management 

and Budget (OMB) and the Office of Science and Technology Policy (OSTP). The following are EPA’s 

responses to select interagency comments. All interagency comments were taken into 

consideration in revising the draft assessment prior to release for public comment (Step 4a).

For a complete description of the IRIS process, including Interagency Science Consultation, visit the 

IRIS website at www.epa.gov/iris.

Select Interagency Science Consultation Comments and Responses:

Topic #1: Confusion regarding α2u-globulin nephropathy - OMB commented that there was 

contradictory language in the assessment regarding the conclusions related to α2u-globulin 

nephropathy and kidney effects.

EPA Response: EPA has revised and added text in the document to improve the clarity of 

the α2u-globulin mode-of-action (MOA) analysis, discussion, and conclusions presented in Sections 

1.2.1, 1.3.1, 1.3.2, 2.2.8, 2.3.1, 2.3.4, and 2.4, as well as the Executive Summary. Noncancer kidney 

endpoints that are considered part of the α2u-globulin nephropathy pathological sequence are 

specific to the male rat, and are not relevant for human health assessment. Thus, these endpoints 

are not considered in the hazard identification and dose-response assessment for tert-butanol. With 

respect to carcinogenicity, EPA concluded that α2u-globulin nephropathy was likely responsible for 

some but not all of the kidney tumors. Thus, these tumors were considered in the characterization 

of the carcinogenic potential of tert-butanol. Because α2u-globulin nephropathy was not the sole 

MOA for kidney tumors, and the relative contribution of this process to tumor development could 

not be ascertained, the kidney tumors were not considered in the dose-response assessment for 

cancer risk. 

Topic #2: PBPK modeling – NTP commented that it is not clear why reversible protein binding in the 

blood was added in the PBPK model to account for the fact that 60% of the radiolabeled tert-butanol 

in whole blood is in plasma.
EPA Response: EPA has revised the document to better explain how the PBPK model was 

modified. As described in Appendix B.2.2. of the Supplemental Information, the model 

includes reversible binding of tert-butanol in the blood to improve the fit of the model to 

the tert-butanol blood concentrations measured after i.v. dosing data of Poet et al. (1997). 

The impact of this modification is that the bound tert-butanol is not considered free tertbutanol in blood. 

Topic #3: Evidence that tert-butanol is a developmental toxicant is weak – NTP commented 

that the evidence for tert-butanol being a developmental toxicant is weak and if it occurs at all is at 

extraordinarily high doses and likely to be of limited human relevance. 

EPA Response: Exposure to tert-butanol during gestation resulted in increased fetal loss, 

decreased fetal body weight, and increases in skeletal variations in exposed offspring. As 

noted by NTP, these effects were observed at relatively high doses (e.g., 1000 mg/kg-day), 

and while skeletal variations were noted, no malformations were reported. At these same 

doses, the mothers also had body weight losses or gains (or both), decreased food 

consumption, and clinical signs of intoxication. Therefore, determining whether tertbutanol exposure results in specific developmental toxicity or whether the fetal effects are 

due to maternal toxicity is difficult. The observed maternal effects are minimal, however, 

and thus, the developmental effects observed in the fetuses are not discounted as being 

secondary to maternal toxicity (U.S. EPA, 1991). Overall, the evidence is considered 

suggestive of developmental toxicity. Although EPA considered there to be some evidence 

for developmental toxicity, these effects were observed at high doses which also affected 

the mothers, and there was a lack of consistency across some endpoints. In addition, no 

adverse effects were reported in one- and two-generation developmental studies on the 

parent compound of tert-butanol, ethyl tertiary butyl ether (ETBE) (Gaoua, 2004a, b). Due 

to the limited evidence for developmental toxicity, EPA did not carry the developmental 

endpoints forward for dose-response analysis. 

References

Gaoua, W. (2004a). Ethyl tertiary butyl ether (ETBE): prenatal developmental toxicity study by the 

oral route (gavage) in rats. (CIT Study No. 24860 RSR). unpublished study for Totalfinaelf 

on behalf of the ETBE Producers' Consortium. 

Gaoua, W. (2004b). Ethyl tertiary butyl ether (ETBE): Two-generation study (reproduction and 

fertility effects) by the oral route (gavage) in rats. (CIT Study No. 24859 RSR). unpublished 

study for Totalfinaelf on behalf of the ETBE Producers' Consortium. 
Poet, TS; Valentine, JL; Borghoff, SJ. (1997). Pharmacokinetics of tertiary butyl alcohol in male and 

female Fischer 344 rats. Toxicol Lett 92: 179-186. 

U.S. EPA (U.S. Environmental Protection Agency). (1991). Guidelines for developmental toxicity risk 

assessment. (EPA/600/FR-91/001). Washington, DC: U.S. Environmental Protection 

Agency, Risk Assessment Forum. 

http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=23162.