Charge to the Science Advisory Board for the

IRIS Toxicological Review of tert-butyl alcohol

September 2014

Introduction

The U.S. Environmental Protection Agency (EPA) is seeking a scientific peer review of draft 

Toxicological Review of tert-butyl alcohol (tert-butanol) developed in support of the Agency’s 

online database, the Integrated Risk Information System (IRIS). IRIS is prepared and maintained by 

EPA’s National Center for Environmental Assessment (NCEA) within the Office of Research and 

Development (ORD). 

IRIS is a human health assessment program that evaluates scientific information on effects that may 

result from exposure to specific chemical substances in the environment. Through IRIS, EPA 

provides high quality science-based human health assessments to support the Agency’s regulatory 

activities and decisions to protect public health. IRIS assessments contain information for chemical 

substances that can be used to support hazard identification and dose-response assessment, two of 

the four steps in the human health risk assessment process. When supported by available data, IRIS 

provides health effects information and toxicity values for health effects (including cancer and 

effects other than cancer) resulting from chronic exposure. IRIS toxicity values may be combined 

with exposure information to characterize public health risks of chemical substances; this risk 

characterization information can then be used to support risk management decisions. 

There is no existing IRIS assessment for tert-butanol. IRIS is developing this assessment in tandem 

with that of ethyl tert-butyl ether (ETBE) because tert-butanol is a major metabolite of ETBE, so 

data from one compound may be informative as to the toxicity of the other compound. The draft 

Toxicological Review of tert-butanol is based on a comprehensive review of the available scientific 

literature on the noncancer and cancer health effects in humans and experimental animals exposed 

to tert-butanol. Additionally, appendices for chemical and physical properties, toxicokinetic 

information, and other supporting materials are provided as Supplemental Information (see 

Appendices A to C) to the draft Toxicological Review. 

The draft assessment was developed according to guidelines and technical reports published by 

EPA (see Preamble), and contain both qualitative and quantitative characterizations of the human 

health hazards for tert-butanol, including a cancer descriptor of the chemical’s human carcinogenic 

potential, noncancer toxicity values for chronic oral (reference dose, RfD) and inhalation (reference 

concentration, RfC) exposure, and cancer risk estimates for oral and inhalation. 
Charge questions on the draft tert-butanol Toxicological Review

1. Literature search/study selection. Is the literature search strategy well documented? Please 

identify additional peer-reviewed studies that might have been missed.

2. Physiologically-based pharmacokinetic (PBPK) modeling. In Appendix B, the draft 

assessment describes the development of an EPA PBPK model for tert-butanol in rats that was 

adapted from published models for MTBE (Blancato et al., 2007) and tert-butanol (Leavens and 

Borghoff, 2009). 

2a. Does this PBPK model adequately represent the toxicokinetics? Are the model assumptions 

and parameters clearly presented and scientifically supported? Are the uncertainties in the 

model structure appropriately considered and discussed? 

2b. The concentration of tert-butanol in the blood was selected as the dose metric to derive the 

BMCL. Is the choice of dose metric appropriate? Does this PBPK model adequately estimate 

the internal dose of tert-butanol in rats?

3. Hazard identification. In section 1, the draft assessment evaluates the available human, 

animal, and mechanistic studies to identify the types of toxicity that can be credibly associated 

with tert-butanol exposure. The draft assessment uses EPA’s guidance documents (see 

http://www.epa.gov/iris/backgrd.html/) to reach the following conclusions.

3a. Kidney toxicity (section 1.1.1, 1.2.1). The draft assessment concludes that kidney toxicity is 

a human hazard of tert-butanol exposure. Do the available human, animal, and mechanistic

studies support this conclusion, giving due consideration to the mode of action analyses for 

alpha2u-globulin nephropathy and chronic progressive nephropathy? 

3b. Thyroid toxicity (sections 1.1.2, 1.2.1). The draft assessment concludes that thyroid 

toxicity is a potential human hazard of tert-butanol exposure. Do the available human, 

animal, and mechanistic studies support this conclusion?

3c. Developmental toxicity (sections 1.1.3, 1.2.1). The draft assessment concludes that there 

is suggestive evidence of developmental toxicity as a potential human hazard of tert-butanol 

exposure. Do the available human, animal, and mechanistic studies support this conclusion?

3d. Other types of toxicity (sections 1.1.3, 1.1.5, 1.2.1). The draft assessment concludes that 

the evidence does not support other types of noncancer toxicity as a potential human 

hazard of tert-butanol exposure. Are there other types of noncancer toxicity that can be

credibly associated with tert-butanol exposure? 

3e. Cancer (sections 1.1.1, 1.1.2, 1.1.4, 1.2.2). The draft assessment concludes that there is 

“suggestive evidence of carcinogenic potential” for tert-butanol by all routes of exposure. Do 

the available human, animal, and mechanistic studies support this conclusion, giving due 

consideration to the mode of action analyses for alpha2u-globulin nephropathy, chronic 

progressive nephropathy, and thyroid follicular cell tumors? 

4. Dose-response analysis. In section 2, the draft assessment uses the available human, animal, 

and mechanistic studies to derive candidate toxicity values for each hazard that is credibly

associated with tert-butanol exposure in section 1, then proposes an overall toxicity value for 
each route of exposure. The draft assessment uses EPA’s guidance documents (see 

http://www.epa.gov/iris/backgrd.html/) in the following analyses.

4a. Oral reference dose for effects other than cancer (section 2.1). The draft assessment 

proposes an overall reference dose of 1x10-1 mg/kg-d based on kidney transitional 

epithelial hyperplasia. Is this value scientifically supported, giving due consideration to the 

intermediate steps of selecting studies appropriate for dose-response analysis, calculating 

points of departure, and applying uncertainty factors? 

4b. Inhalation reference concentration for effects other than cancer (section 2.2). The draft 

assessment proposes an overall reference concentration of 9x10-1 mg/m3 based on kidney 

transitional epithelial hyperplasia, using a PBPK model to extrapolate the oral point of 

departure to an inhalation point of departure. Is this value scientifically supported, giving 

due consideration to the intermediate steps of selecting studies appropriate for doseresponse analysis, calculating points of departure, route-to-route extrapolation, and 

applying uncertainty factors? 

4c. Oral slope factor for cancer (section 2.3). The draft assessment proposes an oral slope 

factor of 1x10-2 per mg/kg-d based on kidney tumors in rats. Is this value scientifically 

supported, giving due consideration to the intermediate steps of selecting studies 

appropriate for dose-response analysis and calculating points of departure?

4d. Inhalation unit risk for cancer (section 2.4). The draft assessment proposes an inhalation 

unit risk of 1x10-3 per mg/m3 based on kidney tumors in rats, using a PBPK model to 

extrapolate the oral point of departure to an inhalation point of departure. Is this value 

scientifically supported, giving due consideration to the intermediate steps of selecting 

studies appropriate for dose-response analysis, calculating points of departure, and routeto-route extrapolation? 

5. Executive summary. Does the executive summary clearly and appropriately present the major 

conclusions of the assessment?

Charge question on the public comments

6. In [DATE TBD], EPA asked for public comments on an earlier draft of this assessment. Appendix

D summarizes the public comments and this assessment’s responses to them. Please comment 

on EPA’s responses to the scientific issues raised in the public comments.