Draft Charge to the Science Advisory Board for the
IRIS Toxicological Review of ethyl tertiary butyl ether (ETBE)
August 2016
Introduction
The U.S. Environmental Protection Agency (EPA) is seeking a scientific peer review of draft
Toxicological Review of ethyl tertiary butyl ether (ETBE) 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 ETBE. IRIS is developing this assessment in tandem with
that of tert-butyl alcohol (tert-butanol) 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 ETBE 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 ETBE. 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 ETBE, 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.

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Charge questions on the draft ETBE Toxicological Review
1.	Literature search/study selection and evaluation. The section on Literature Search Strategy
I 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 physiologically-
based pharmacokinetic (PBPK) model for ETBE 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 (Salazar etal., 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 rate of ETBE metabolism 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 ETBE 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 ETBE. 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-risk-
info rmation-svstem#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 toxicity.
i)	Kidney hazard (Sections 1.2.1,1.3.1). The draft assessment concludes that kidney
effects are potential human hazards of ETBE 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.
ii)	Kidney-specific oral toxicity values (Section 2.1.1). The draft assessment selects four
studies (Suzuki etal. (2012), Miyata etal. (2013), Gaoua etal. (2004b), and Fujii etal.
(2010)) to quantify kidney effects. Is this selection of studies scientifically supported
and clearly described?

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iii)	Points of departure for kidney endpoints (Section 2.1.2). Are the calculation of
points of departure from endpoints reported in Suzuki et al. (2012), Miyata et al.
(2013), Gaouaetal. (2004b), and Fujii etal. (2010) studies, including urothelial
hyperplasia, scientifically supported and clearly described?
iv)	Uncertainty factors for kidney endpoints (Section 2.1.3). Is 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). Is 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). Are the points of
departure from the Saitoetal. (2013), Medinsky etal. (1999), andJPEC (2008b)
studies, as well as application of uncertainty factors are scientifically supported and
clearly described?
vii)	Kidney-specific inhalation reference concentration (Section 2.2.4). Is the
organ/system-specific inhalation reference concentration derived for kidney effects is
scientifically supported and clearly characterized?
3 b. Liver effects
i) Liver hazard (Section 1.2.2). The draft assessment concludes that there is suggestive
evidence of liver effects associated with ETBE exposure. Please comment on whether
the available human, animal, and mechanistic studies support this conclusion.
3 c. Reproductive effects
i) Reproductive hazard (Section 1.2.3). 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. Developmental effects
i) Developmental hazard (Section 1.2.4). The draft assessment concludes that the
developmental toxicity evidence is slight and uncertain, and the toxicological
significance is unknown. Do the available human, animal, and mechanistic studies
support this statement?
3e. Other types of toxicity (Section 1.2.6). The draft assessment concludes that, at this time,
there is inadequate information to draw conclusions regarding other health hazards that
may be associated with ETBE exposure. Do the available human, animal, and mechanistic
studies support these statements?
3f. Cancer
i) Cancer hazard (Sections 1.2.1,1.2.2,1.2.5,1.3.2). There are plausible scientific
arguments for more than one hazard descriptor, as discussed in Section 1.3.2. The draft

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assessment concludes that there is suggestive evidence of carcinogenic potential for
ETBE. Please comment on whether the available human, animal, and mechanistic
studies support this conclusion in accordance with the EPA Cancer Guidelines (2005).
ii)	Cancer modes of action (Sections 1.2.2,1.3.2). A mode of action for the nuclear
hormone receptors (i.e. PPARa, PXR and/or CAR) was evaluated and the draft
assessment concludes that there is inadequate evidence to determine the role these
pathways play, if any, in ETBE-induced liver carcinogenesis. Acetaldehyde-mediated
genotoxicity was also evaluated as a possible MOA, but while suggestive, the available
data overall are insufficient to establish acetaldehyde-mediated mutagenicity as a MOA
for ETBE-induced liver tumors. Overall, the draft assessment concludes that the data
are inadequate to establish a nuclear hormone receptor- or acetaldehyde-mediated
MOA for liver carcinogenesis, and in accordance with the EPA Cancer Guidelines (2005),
the liver tumors induced by ETBE are relevant to human hazard identification. Do the
available human, animal, and mechanistic studies support this conclusion?
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."
The draft assessment uses a PBPK model to derive an oral toxicity value from the 2-year
inhalation Saito et al. (2013) study. Does the draft assessment adequately explain the
rationale for quantitative analysis? Is the selection of the Saito et al. (2013) study for
this purpose scientifically supported and clearly described?
iv)	Cancer inhalation toxicity values (Section 2.4.1). 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."
Does the draft assessment adequately explain the rationale for quantitative analysis? Is
the selection of the Saito et al. (2013) study for this purpose scientifically supported?
v)	Points of departure for cancer (Sections 2.3.2, 2.3.3, 2.4.2, 2.4.3). Because an MOA
could not be established for liver carcinogenesis, the draft assessment uses linear
extrapolation below the points of departure based upon liver tumors. Please discuss
whether the calculation of points of departure and oral and inhalation slope factors is
scientifically supported in accordance with the EPA Cancer Guidelines (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 ETBE exposure in Chapter 1, then selects an

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overall toxicity value for each route of exposure. The draft assessment uses EPA's guidance
documents fhttp://www.epa.gov/iris/basic-information-about-integrated-risk-information-
svstem#guidance] in the following analyses.
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 5x101 mg/kg-day based on kidney
urothelial hyperplasia as described in Suzuki et al., 2012. Is this selection is scientifically
supported and clearly described?
4b. Inhalation reference concentration for effects other than cancer (Sections 2.2.5,
2.26). The draft assessment proposes an overall reference concentration of 9x10°
mg/m3 based on kidney urothelial hyperplasia as describe in Saito et al., 2013. Is 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 9x10 4 per mg/kg-day based on the liver adenoma or carcinoma
response in male rats, using a PBPK model to extrapolate the inhalation point of
departure to an oral point of departure. Is this value scientifically supported and clearly
described?
4d. Inhalation unit risk for cancer (Sections 2.4.3, 2.4.4). The draft assessment derives an
inhalation unit risk of 8x10 5 per mg/m3 based on liver adenomas and carcinoma in
male rats. Is this value scientifically supported and clearly described?
5. Executive summary. Does the executive summary clearly and appropriately present the major
conclusions of the assessment?

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