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Draft Charge to External Reviewers for the 

Toxicological Review of Hexachloroethane

March 2010

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

scientific basis supporting the human health assessment for hexachloroethane that will appear on 

the Agency’s online database, the Integrated Risk Information System (IRIS). IRIS is prepared 

and maintained by the EPA’s National Center for Environmental Assessment (NCEA) within the 

Office of Research and Development (ORD). An existing IRIS assessment for hexachloroethane 

was posted on the database in 1987. 

The current draft health assessment includes a chronic reference dose (RfD), reference 

concentration (RfC), and a carcinogenicity assessment. Below is a set of charge questions that 

address scientific issues in the assessment of hexachloroethane. Please provide detailed 

explanations for responses to the charge questions.

General Charge Questions:

1. Is the Toxicological Review logical, clear and concise? Has EPA clearly and objectively 

represented and synthesized the scientific evidence for noncancer and cancer hazards?

2. Please identify any additional studies that would make a significant impact on the conclusions 

of the Toxicological Review and should be considered in the assessment of the noncancer and 

cancer health effects of hexachloroethane.

Chemical-Specific Charge Questions:

(A) Oral reference dose (RfD) for hexachloroethane

1. A 16-week dietary exposure study of hexachloroethane in F344 rats by Gorzinski et al. (1985) 

was selected as the basis for the derivation of the RfD. Kidney effects were observed in male rats 

in this study at doses below the range of exposure tested in the available chronic NTP (1989) 

study. Please comment on the scientific justification for the use of the subchronic Gorzinski et al.

(1985) study as the principal study for the derivation of the RfD. Is the rationale for this selection 

scientifically justified and clearly described in the document? Please identify and provide the 

rationale for any other studies that should be selected as the principal study.

2. An increase in the incidence of nephrotoxicity as indicated by atrophy and degeneration of renal 

tubules in male rats (Gorzinski et al., 1985) was selected as the critical effect for the RfD. Please 

comment on whether the selection of this critical effect is scientifically justified and clearly 

described. Please identify and provide the rationale for any other endpoints that should be 

considered in the selection of the critical effect.
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3. Benchmark dose (BMD) modeling was applied to the atrophy and degeneration of renal tubules

data to derive the point of departure (POD) for the RfD. Has the BMD modeling been 

appropriately conducted? Is the benchmark response (BMR) selected for use in deriving the POD 

(i.e., a 10% increased incidence of nephrotoxicity as indicated by atrophy and degeneration of 

renal tubules in male rats compared with controls) scientifically justified and clearly described. 

Please identify and provide the rationale for any alternative approaches (including the selection of 

the BMR, model, etc.) for the determination of the POD and discuss whether such approaches are 

preferred to EPA’s approach.

4. Please comment on the rationale for the selection of the uncertainty factors (UFs) applied to the 

POD for the derivation of the RfD. Are the UFs scientifically justified and clearly described in the 

document? Please provide a detailed explanation. If changes to the selected UFs are proposed, 

please identify and provide a rationale. 

(B) Inhalation reference concentration (RfC) for hexachloroethane

1. A 6-week inhalation exposure study in rats by Weeks et al. (1979) was selected as the basis for 

the derivation of the RfC for hexachloroethane. Please comment on whether the selection of this 

study as the principal study is scientifically justified. Is the rationale for this selection clearly

described in the document? Please identify and provide the rationale for any other studies that 

should be selected as the principal study.

2. Neurobehavioral effects in Sprague-Dawley rats (Weeks et al., 1979) were selected as the 

critical effect for the RfC. Please comment on whether the selection of this critical effect is 

scientifically justified and clearly described in the document. Please identify and provide the 

rationale for any other endpoints that should be considered in the selection of the critical effect.

3. The NOAEL/LOAEL approach was used to derive the POD for the RfC. Please comment on 

whether this approach is scientifically justified and clearly described. 

4. Please comment on the rationale for the selection of the UFs applied to the POD for the 

derivation of the RfC. Are the UFs scientifically justified and clearly described in the document?

Please provide a detailed explanation. If changes to the selected UFs are proposed, please 

identify and provide a rationale.

(C) Carcinogenicity of hexachloroethane

1. Under the EPA’s 2005 Guidelines for Carcinogen Risk Assessment (www.epa.gov/iris/backgrd.htm), the Agency concluded that hexachloroethane is likely to be carcinogenic to humans. Is 

the cancer weight of evidence characterization scientifically justified and clearly described?

2. A two-year oral gavage cancer bioassay in F344 rats (NTP, 1989) was selected for the 

development of an oral slope factor. Please comment on whether the selection of this study for 

quantification is scientifically justified and clearly described. Please identify and provide the 

rationale for any other studies that should be considered.
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3. EPA selected the renal tubule tumor data in male rats from the NTP (1989) two-year oral 

gavage cancer bioassay to serve as the basis for the quantitative cancer assessment for 

hexachloroethane. Please comment on whether the rationale for this selection has been 

scientifically justified and clearly described. Please identify and provide the rationale for any other 

endpoints that should be considered to serve as the basis for the quantitative cancer assessment.

4. EPA concluded that the mode of action for kidney tumors observed following oral exposure to 

HCE is unknown. An analysis of the mode of action data for kidney tumors is presented in the 

Toxicological Review. Based on this analysis, EPA determined that HCE-induced kidney tumors 

could not be attributed to the accumulation of a2u-globulin. Please comment on the scientific 

support for these conclusions. Please comment on whether the analysis is scientifically justified 

and clearly described. 

5. The oral cancer slope factor was calculated by linear extrapolation from the POD (lower 95% 

confidence limit on the dose associated with 10% extra risk for renal tumors in male rats). Has the 

modeling approach been appropriately conducted and clearly described?