**Charge to the Science Advisory Board for the IRIS Toxicological Review of**  tert

- **but yl alcoh**  **ol**

**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 Deve lopment (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 healt h 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 fou r 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 t ert

- 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 ch emical 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 w as 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 addition al peer

- reviewed studies that might have been missed.

2. **Physiologically**

**- based pharmacokinetic (PBPK) modeling.**  In Appendix B, the draft assessment describes the develo pment of a n EPA PBPK model for tert

- butanol in rats that was adapted from p ublished 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 assess ment 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 guid ance documents (see http://www.epa.gov/iris/backgrd.html /) to reach the following conclusions.

3 a. **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 availa ble human, animal , and mechanistic studies support this conclusio n , giving due consideration to the mode of action analyses for alpha2u

- globulin nephropathy and chronic progressive nephropathy ?

3 b. **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 toxici ty as a potential human hazard of tert

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

3d. **Other types**  **of toxic ity**  (section s 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 c an 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 ac tion 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 foreach route of exposure. The draft assessment uses EPA’s guidance documents (see http://www.epa.gov/iris/backgrd.html/) in the following analyses.

4 a. **Oral reference dose for effects other than cancer** (section 2 .1). The draft assessment proposes an overall reference do se of 1 x10 -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 departur e, and applying uncertainty factors ?

4 b. **Inhalation reference**  **concentration for effects other than cancer**  (section 2. 2 ). The draft assessment proposes an overall reference concentration of 9 x10 -1 mg/m 3 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 dose

response analysis, calc ulating points of departure, route

- to

- route extrapolation, and applying uncertainty factors?

4 c. **Oral slope factor for cancer** (section 2.3). The draft assessment proposes an oral slope factor of 1 x10 -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/m 3 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 suppor ted, giving due consideration to the intermediate steps of selecting studies appropriate for dose

- response analysis, calculating points of departure , and route

to

- route extrapolation ?

5. **Executive summary** . Does the executive summary clearly and appropriat ely 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.