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Draft Charge to the Science Advisory Board for the

IRIS Toxicological Review of tert-Butyl Alcohol

April 2016

Introduction

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

chemicals 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 chemicals; 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 toxicokinetic information, dose-response modeling, 

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 contains 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 a cancer risk estimate for oral exposure. 
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Charge questions on the draft Toxicological Review of tert-butanol

1. Literature search/study selection and evaluation. The section on Literature Search Strategy 

| Study Selection and Evaluation describes the process for identifying and selecting pertinent 

studies. Please comment on whether the literature search strategy, study selection 

considerations, and study evaluation considerations are appropriate and clearly described. 

Please identify additional peer-reviewed studies that the assessment should consider.

2. Toxicokinetic modeling. In Appendix B, the draft assessment describes a physiologicallybased pharmacokinetic (PBPK) model for tert-butanol in rats that EPA modified (Salazar et al., 

2015) from published models for MTBE (Blancato et al., 2007) and tert-butanol (Leavens and 

Borghoff, 2009). 

2a. Does this PBPK model (Salazar et al., 2015) 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 daily average concentration of tert-butanol in the blood was selected as the dose 

metric for the dose-response assessment. Is the choice of dose metric appropriate? Does 

this PBPK model adequately estimate the internal dose of tert-butanol in rats?

3. Hazard identification and dose-response assessment. In Chapter 1, the draft assessment 

evaluates the available human, animal, and mechanistic studies to identify health outcomes that 

may result from exposure to tert-butanol. In Chapter 2, the draft assessment develops 

organ/system-specific reference values for the health outcomes identified in Chapter 1, then 

selects overall reference values for each route of exposure. The draft assessment uses EPA’s 

guidance documents (see http://www.epa.gov/iris/basic-information-about-integrated-riskinformation-system#guidance) to reach the following conclusions.

[Note: As suggested by the Chemical Assessment Advisory Committee panel that reviewed the 

draft IRIS assessment of benzo[a]pyrene, the charge questions in this section are organized by 

health outcome, with a question on each hazard identification followed by questions on the 

corresponding organ/system-specific toxicity values. This suggestion, however, entails some 

redundancy, as some questions apply equally to multiple health outcomes.]

3a. Kidney effects.

i) Kidney hazard (Sections 1.2.1, 1.3.1). The draft assessment concludes that kidney 

effects are potential human hazards of tert-butanol exposure. Please comment on 

whether the available human, animal, and mechanistic studies support this conclusion, 

giving due consideration to the relationships between several observed endpoints and 

the alpha2u-globulin process and/or chronic progressive nephropathy. Please 

comment on whether this selection is scientifically supported and clearly described.

ii) Kidney-specific oral toxicity values (Section 2.1.1). Please comment on whether the 

selection of the NTP (1995) study that describes kidney effects is scientifically 

supported and clearly described.

iii) Points of departure for kidney endpoints (Section 2.1.2). Please comment on 

whether the calculation of points of departure from endpoints reported in NTP (1995) 
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study, including transitional epithelial hyperplasia, is scientifically supported and 

clearly described. 

iv) Uncertainty factors for kidney endpoints (Section 2.1.3). Please comment on 

whether the application of uncertainty factors to these points of departure is 

scientifically supported and clearly described.

v) Kidney-specific oral reference dose (Section 2.1.4). Please comment on whether the 

organ/system-specific oral reference dose derived for kidney effects is scientifically 

supported and clearly characterized.

vi) Kidney-specific inhalation toxicity values (Sections 2.2.1–2.2.3). The draft 

assessment uses a PBPK model to derive inhalation toxicity values from the 2-year oral 

NTP (1995) study. Please comment on whether the selection of the 2-year oral NTP 

(1995) study (with application of toxicokinetic modeling to extrapolate from oral to 

inhalation exposures) over the 13-week inhalation NTP (1997) study is scientifically 

supported and clearly described. Please comment as to whether calculation of points of 

departure from the NTP (1995) study, as well as application of uncertainty factors to 

both inhalation and oral exposure-derived points of departure, are scientifically 

supported and clearly described.

vii) Kidney-specific inhalation reference concentration (Section 2.2.4). Please comment 

on whether the organ/system-specific inhalation reference concentration derived for 

kidney effects is scientifically supported and clearly characterized.

3b. Developmental effects

i) Developmental hazard (Section 1.2.3). The draft assessment concludes that there is 

suggestive evidence of developmental effects associated with tert-butanol exposure. 

Please comment on whether the available human, animal, and mechanistic studies 

support this conclusion. 

ii) Neurodevelopmental hazard (Section 1.2.4). The draft assessment states that, at this 

time, there is inadequate information to draw conclusions regarding

neurodevelopmental toxicity. Please comment on whether the available human, 

animal, and mechanistic studies support this conclusion. 

3c. Reproductive effects

i) Reproductive hazard (Section 1.2.5). The draft assessment states that, at this time, no 

conclusions are drawn in regard to reproductive system toxicity. Please comment on 

whether the available human, animal, and mechanistic studies support this conclusion.

3d. Other toxicological effects (Section 1.2.6). The draft assessment states that, at this time,

there is inadequate information to draw conclusions regarding other health hazards that 

may be associated with tert-butanol exposure. Please comment on whether the available 

human, animal, and mechanistic studies support these conclusions.

3e. Cancer.

i) Cancer hazard (Sections 1.2.1, 1.2.2, 1.3.2). There are plausible scientific arguments 

for more than one hazard descriptor, as discussed in Section 1.3.2. The draft 

assessment concludes that there is suggestive evidence of carcinogenic potential for 

tert-butanol. Please comment on whether the available human, animal, and 
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mechanistic studies support this conclusion in accordance with the relevant U.S. EPA 

Guidelines (2005). 

ii) Cancer modes of action:

(1) Kidney (Sections 1.2.1, 1.3.2). A mode of action for the alpha2u-globulin process was 

evaluated (U.S. EPA, 1991); the draft assessment concludes that tert-butanol weakly 

induces this process, and that this process is not solely responsible for the renal 

tubule nephropathy and carcinogenicity observed in male rats. A chronic 

progressive nephropathy mode of action was also evaluated; the draft assessment 

concludes that although chronic progressive nephropathy was indicated in the 

induction of renal tubule toxicity, it does not induce renal tubule tumors in male 

rats. Overall, the draft assessment concludes that other, unknown processes 

contribute to renal tubule nephrotoxicity and carcinogenicity, and that the kidney 

tumors in male rats are relevant to human cancer hazard identification. Please 

comment on whether the available human, animal, and mechanistic studies support 

this conclusion in accordance with the relevant U.S. EPA Guidelines (1991).

(2) Thyroid (Sections 1.2.2, 1.3.2). An anti-thyroid mode of action was evaluated (U.S. 

EPA, 1998); the draft assessment concludes that the evidence is inadequate to 

determine if an antithyroid MOA is operating, and that the thyroid tumors in male 

and female mice are relevant to human cancer hazard identification. Please 

comment on whether the available human, animal, and mechanistic studies support 

this conclusion in accordance with the relevant U.S. EPA Guidelines (1998).

iii) Cancer oral toxicity values (Section 2.3.1). As noted in EPA’s 2005 Guidelines for 

Carcinogen Risk Assessment:

“When there is suggestive evidence, the Agency generally would not 

attempt a dose-response assessment, as the nature of the data 

generally would not support one; however, when the evidence 

includes a well-conducted study, quantitative analyses may be useful 

for some purposes, for example, providing a sense of the magnitude 

and uncertainty of potential risks, ranking potential hazards, or 

setting research priorities.” 

Please comment on whether the draft assessment adequately explains the rationale for 

quantitative analysis, and whether the selection of the NTP (1995) study for this 

purpose is scientifically supported and clearly described.

iv) Points of departure for cancer (Sections 2.3.2, 2.3.3). Because the relative 

contribution of α2u-globulin nephropathy and other processes to kidney 

tumorigenesis in male rats could not be determined, the draft assessment concludes 

that the rat kidney tumors cannot be used in dose-response analysis (U.S. EPA. 1991). 

Because evidence was inadequate to determine if an antithyroid MOA is operating, the 

draft assessment uses linear extrapolation below the points of departure bases upon 

thyroid tumors (U.S. EPA, 1998). Please comment on whether the calculation of points 

of departure and oral slope factors is scientifically supported in accordance with the 

relevant U.S. EPA Guidelines (1991, 1998, 2005), and clearly described.

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

and mechanistic studies to derive candidate values and organ/system-specific toxicity values 

for each hazard that is credibly associated with tert-butanol exposure in Chapter 1, then selects 

an overall toxicity value for each route of exposure. The draft assessment uses EPA’s guidance 

documents (see http://www.epa.gov/iris/basic-information-about-integrated-riskinformation-system#guidance) in the following analyses.
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4a. Oral reference dose for effects other than cancer (Sections 2.1.5, 2.1.6). The draft 

assessment derives an overall oral reference dose of 1×10-1 mg/kg-day based on kidney 

transitional epithelial hyperplasia as described in NTP (1995). Please comment on whether 

this selection is scientifically supported and clearly described.

4b. Inhalation reference concentration for effects other than cancer (Sections 2.2.5–2.2.6).

The draft assessment derives an overall inhalation reference concentration of 9×10-1 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. Please comment on whether this 

selection is scientifically supported and clearly described. 

4c. Oral slope factor for cancer (Sections 2.3.3–2.3.4). The draft assessment derives an oral 

slope factor of 5×10-4 per mg/kg-day based on the thyroid follicular cell adenoma or 

carcinoma response in male and female mice. Is this value scientifically supported and 

clearly described?

4d. Inhalation unit risk for cancer (Section 2.4). No inhalation unit risk was derived in the 

draft assessment. There are no chronic inhalation studies for tert-butanol. No mouse PBPK 

model is available to extrapolate the oral thyroid tumor results to the inhalation route. If the 

available data might support an inhalation unit risk, please describe how one might be 

derived.

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

conclusions of the assessment?