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Draft Charge to External Reviewers for the IRIS Tox icological Review of n-Butanol

June 2011

The U.S. Environmental Protection Agency (EPA) is s eeking an external peer review of the scientific basis supporting the human health assess ment of n-butanol that will appear on the Agency’s online database, the Integrated Risk Infor mation System (IRIS). IRIS is prepared and maintained by the EPA’s National Center for Environ mental Assessment (NCEA) within the Office of Research and Development (ORD). An exist ing IRIS assessment of n-butanol which includes a chronic reference dose (RfD) was posted to the database in 1990.

The current draft health assessment includes an RfD and reference concentration (RfC). Below is a set of charge questions that address scientifi c issues in the assessment of n-butanol. Please provide detailed explanations for responses to the charge questions. Please consider the accuracy, objectivity, and transparency of EPA’s an alyses and conclusions in your review.

General Charge Questions:

1. Is the Toxicological Review logical, clear and c oncise? Has EPA clearly synthesized the

scientific evidence for noncancer and cancer hazard ?

2. Please identify any additional studies that would make a s ignificant impact on the conclusions of the Toxicological Review and should be considered i n the assessment of the noncancer and cancer

hazard of n-butanol.

Chemical-Specific Charge Questions:

(A) Oral reference dose (RfD) for n-butanol

1. A chronic RfD for n-butanol has been derived fro m the oral drinking water developmental toxicity study (Sitarek et al., 1994) in Wistar IMP :DAK rats. Please comment on whether the selection of this study as the principal study is s cientifically supported and clearly described. Please identify and provide the rationale for any o ther studies that should be selected as the principal study.

2. Visceral malformations in litters from female Wi star IMP:DAK rats were selected as the

critical effect. Please comment on whether the sel ection of this critical effect is scientifically supported and clearly described. Please identify a nd provide the rationale for any other endpoints that should be selected as the critical e ffect.

3. Benchmark dose (BMD) modeling methods were appli ed to the litter visceral malformation data to derive the point of departure (POD) for the RfD. Has the BMD modeling been appropriately conducted and clearly described? Is the benchmark response (BMR) selected for use in deriving the POD (i.e. a 10% increase in inc idence of visceral malformations in litters) scientifically supported and clearly described?

4. Please comment on the rationale for the selectio n of the uncertainty factors (UFs) applied to2

the POD for the derivation of the RfD. If changes to a UF are proposed, please identify and provide a rationale(s).

(B) Inhalation reference concentration (RfC) for n- butanol

1. A chronic RfC for n-butanol has been derived fro m a 90 days inhalation in rats (Korsak et al., 1994). Please comment on whether the selection of this study as the principal study is scientifically supported and clearly described. Pl ease identify and provide the rationale for any other studies that should be selected as the princi pal study.

2. Impaired neurobehavioral function in male Wistar rats was selected as the critical effect for

the RfC. Please comment on whether the selection o f this critical effect is scientifically supported and clearly described. Please identify a nd provide the rationale for any other endpoints that should be selected as the critical e ffect.

3. The NOAEL/LOAEL approach was used to derive the POD for the RfC. Please comment on whether this approach is scientifically supported a nd clearly described.

4. PBPK modeling was used to extrapolate the POD fr om rats to humans. Please comment on whether the PBPK modeling for interspecies extrapol ation has been appropriately conducted and clearly described. Are the model assumptions, para meter values, and selection of dose metrics scientifically supported?

5. Please comment on the rationale for the selectio n of the UFs applied to the POD for the derivation of the RfC. If changes to a UF are prop osed, please identify and provide a rationale(s).

(C) Carcinogenicity of n-butanol

1. Under the EPA’s 2005 Guidelines for Carcinogen Risk Assessment (www.epa.gov/iris/backgrd.html), there is inadequate information to assess the carcinogenic potential of n-butanol. Is the cancer weight of evidence cha racterization scientifically supported and clearly described?

2. EPA did not derive a quantitative estimate of th e carcinogenic potential of n-butanol. Do the data support an estimation of a cancer slope factor for n-butanol? If a quantitative estimate is proposed, please identify the data set and a descri ption of the method that should be used.