vvEPA
EPA/635/R-17/332
IRIS Assessment Plan
www.epa.gov/iris
IRIS Assessment Plan for Ethylbenzene
[CASRN 100-41-4]
September 2017
Integrated Risk Information System
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency

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IRIS Assessment Plan for Ethylbenzene
DISCLAIMER
This document is a preliminary draft for review purposes only. This information is
distributed solely for the purpose of pre-dissemination review under applicable information quality
guidelines. It has not been formally disseminated by EPA. It does not represent and should not be
construed to represent any Agency determination or policy. Mention of trade names or commercial
products does not constitute endorsement or recommendation for use.
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Ethylbenzene
CONTENTS
AUTHORS | CONTRIBUTORS	v
1.	INTRODUCTION	1
2.	SCOPING AND INITIAL PROBLEM FORMULATION	2
2.1. BACKGROUND	2
2.2.SCOPING SUMMARY	2
2.3. PROBLEM FORMULATION	4
3.	OVERALL OBJECTIVE, SPECIFIC AIMS AND DRAFT POPULATIONS, EXPOSURES,
COMPARATORS, AND OUTCOMES (PECO) FRAMEWORK	8
3.1.	SPECIFIC AIMS	8
3.2.	DRAFT PECO FRAMEWORK	9
3.3.	ASSESSMENT APPROACH	10
3.4.	KEY SCIENCE ISSUES	11
REFERENCES	12
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Ethylbenzene
TABLES
Table 1. EPA program or regional office interest in an updated ethylbenzene assessment	2
Table 2. Heat map of ethylbenzene (EB) human database	6
Table 3. Heat map of ethylbenzene (EB) animal database	7
Table 4. Draft PECO framework for the ethylbenzene assessment	9
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IRIS Assessment Plan for Ethylbenzene
AUTHORS | CONTRIBUTORS
Assessment Team
Paul Reinhart (co-Assessment Manager)
George Woodall (co-Assessment Manager)
Andrew Hotchkiss
U.S. EPA/ORD/NCEA
Executive Direction
Tina Bahadori
Mary Ross
Kris Thayer
Vincent Cogliano
John Vandenberg
Emma Lavoie
Samantha Jones
NCEA Center Director
NCEA Deputy Center Director
IRIS Division Director
IRIS Division Director (2010-2017)
Research Triangle Park Division Director
Assistant Center Director for Scientific Support
NCEA Associate Director for Health (acting)
Contributors and Production Team
Hillary Hollinger
Ryan Jones
Vicki Soto
Dahnish Shams
Maureen Johnson
HERO Librarian
HERO Director
Project Management Team
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IRIS Assessment Plan for Ethylbenzene
1. INTRODUCTION
The Integrated Risk Information System (IRIS) Program is undertaking a reassessment of
the health effects of ethylbenzene. EPA included ethylbenzene on the December 2015 multiyear
agenda for the IRIS program fhttps://www, ep a. gov /iris /iris- agenda! as an ongoing agency priority
for assessment development because of interest by multiple program or regional offices.
IRIS assessments provide high quality, publicly available information on the toxicity of
chemicals to which the public might be exposed. These assessments are not regulations, but
provide a critical part of the scientific foundation for decisions made in EPA program and regional
offices to protect public health.
Before beginning an assessment, the IRIS Program consults with EPA program and regional
offices to define the scope of the assessment, including the nature of the hazard characterization
needed, identification of the most important exposure pathways, and level of detail needed to
inform program and regional office decisions. Based on the scope defined by EPA, the IRIS Program
undertakes problem formulation activities to frame the scientific questions that will be the focus of
the assessment, which is conducted using systematic review methodology.
This document presents the draft assessment plan for ethylbenzene, including a summary
of the IRIS Program's scoping and initial problem formulation conclusions, objectives and specific
aims of the assessment, draft PECO (Populations, Exposures, Comparators, and Outcomes)
framework that outlines the evidence considered most pertinent to the assessment, assessment
approach, and identification of key areas of scientific complexity. Brief background information on
uses and potential for human exposure is provided for context.
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Ethylbenzene
2. SCOPING AND INITIAL PROBLEM FORMULATION
2.1. BACKGROUND
Ethylbenzene, also known as phenylethane, is an aromatic hydrocarbon present in crude
petroleum and gasoline. It is used in the production of styrene monomer flPCS. 19961. primarily as
a chemical intermediate. Ethylbenzene also is used as an industrial solvent and a diluent in the
paint industry and in the manufacture of synthetic rubber, acetophenone, and cellulose acetate
(Cal/EPA. 19971. It is present in naphtha and asphalt and as an impurity in xylene solvents
fCal/EPA. 19971.
Individuals that may be exposed are those living near manufacturing and processing
facilities, petroleum refineries, and hazardous waste sites where ethylbenzene has been detected or
those using well water downgradient from leaking underground storage tanks fATSDR. 20101.
An assessment of ethylbenzene is available on the IRIS website
https://cfpub.epa.gov/ncea/iris2/chemicalLanding.cfm7substance nmbr=51 (U.S. EPA. 19911. An
oral RfD of 1 x 101 mg/kg-day was posted in 1987 based on hepatic and renal toxicity. An
inhalation RfC of 1 mg/m3 was posted in 1991 based on developmental toxicity. In 1988 the cancer
weight of evidence for ethylbenzene was categorized as "Group D," that is, not classified concerning
its potential to cause cancer in humans, due to a lack of animal and human data. Since then, several
relevant studies on ethylbenzene toxicity have been completed and new data have become
available.
2.2. SCOPING SUMMARY
During scoping the IRIS Program met with EPA program and regional offices that had
interest in an updated IRIS assessment for ethylbenzene to discuss specific assessment needs.
Table 1 provides a summary of input from this outreach.
Table 1. EPA program or regional office interest in an updated ethylbenzene
assessment
Program or
regional
office3
Oral
Inhalation
Statutes/
Regulations
Description of
authority/Regulation
Anticipated
uses/Interest
OLEM


Comprehensive
Environmental
Response,
Compensation
Authorizes EPA to promulgate
regulations designating as
hazardous substances those
substances which, when released
Ethylbenzene is a
hazardous substance
under CERCLA.
Releases of
EPA Regions


This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Ethylbenzene
Program or
regional
office3
Oral
Inhalation
Statutes/
Regulations
Description of
authority/Regulation
Anticipated
uses/Interest



and Liability Act
(CERCLA)-
Sections 102 and
103
into the environment, may
present substantial danger to
public health or welfare or the
environment. EPA must also
promulgate regulations
establishing the quantity of any
hazardous substance the release
of which must be reported under
Section 103.
ethylbenzene in
excess of 1000 pounds
must be reported (40
CFR 302.4).
OAR

V
Clean Air Act
(CAA) - Section
112
Section 112 (b) defines the
original list of 189 hazardous air
pollutants (HAP). Under 112(c) of
the CAA, EPA must identify and
list source categories that emit
HAP and then set emission
standards for those listed source
categories under CAA section
112(d).
Section 112(d) states that the
EPA must establish NESHAPs for
each category or subcategory of
major sources and area sources
of HAPs [listed pursuant to
Section 112(c)], The standards
must require the maximum
degree of emission reduction that
the EPA determines to be
achievable by each particular
source category. Different criteria
for maximum achievable control
technology (MACT) apply for new
and existing sources. Less
stringent standards, known as
generally available control
technology (GACT) standards, are
allowed at the Administrator's
discretion for area sources.
Ethylbenzene is listed
as a HAP under
Section 112 (42 U.S.C.
§ 7412) of the
CAA.
There are a number of
source-specific
NESHAPs that are
applicable to
ethylbenzene
including:
-	Organic Liquids
Distribution (40 CFR
Part 63, Subpart EEEE)
-	Shipbuilding and Ship
Repair (Surface
Coating; 40 CFR Part
63 Subpart II)
-	Municipal Solid
Waste Landfills (40
CFR Part 63 Subpart
AAAA).
OW
V

Clean Water Act
(CWA) - Sections
304/307
EPA is required to develop and
revise list of toxic pollutants or
combination of pollutants. From
time to time, EPA may revise
taking into account toxicity of the
pollutant, its persistence,
degradability, the usual or
potential presence of the
affected organisms in any waters,
Ethylbenzene is
identified on the list of
toxic pollutants under
section 307 of the
Clean Water Act.
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Program or
regional
office3
Oral
Inhalation
Statutes/
Regulations
Description of
authority/Regulation
Anticipated
uses/Interest




the importance of the affected
organisms, and the nature and
extent of the effect of the toxic
pollutant on such organisms.

OCSPP
V
V
Toxic Substances
Control Act (TSCA)
-Section 6(b)
EPA is directed to identify and
begin risk evaluations on 10
substances drawn from the 2014
update of the TSCA Work Plan for
Chemical Assessments.
Ethylbenzene was
identified on the 2014
update of the TSCA
Work Plan for
Chemical
Assessments, and may
be among the next
chemicals to be
evaluated.
aOLEM (Office of Land and Emergency Management); OW (Office of Water); OAR (Office of Air and Radiation);
OCSPP (Office of Chemical Safety and Pollution Prevention)
2.3. PROBLEM FORMULATION
A public science meeting on the scoping and problem formulation activities for
ethylbenzene was held on September 3-4, 2014 (U.S. EPA, 20141. Although an ATSDR Toxicological
Profile was published on ethylbenzene in 2010 (ATSDR, 20101. the discussion from the public
meeting indicated that a comprehensive assessment of ethylbenzene was warranted based on such
considerations as the size of the new evidence base and the time since EPA conducted an
assessment.
Following the initial literature search and screening, identified studies were reviewed and
sorted into bins according to the type(s) of health outcomes and/or health effects reported. This
was done to appropriately direct the study reports to subject matter experts for the next stages in
the IRIS Assessment Development Process, namely study evaluation, data extraction, evidence
synthesis and integration, and dose-response analysis. The initial results of the binning process are
shown below. Heat maps indicating the number of studies for each endpoint/health outcome
category are shown for the 36 studies in humans (Table 2), and separately for the 47 studies in
animals (Table 3).
Many studies report on more than one health effect/outcome category; therefore, there is
not a one-to-one correspondence between the total number of studies across all endpoints and the
total number of studies identified in the screening process. The upper set of values in each row in
both Table 2 and Table 3 indicate the number of studies that examined the endpoint while the
lower set of values indicate number of studies reporting response measurements from
ethylbenzene exposure. Blanks indicate that no studies were identified in the systematic literature
search and screening for that specific effect category. When studies were identified that examined
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IRIS Assessment Plan for Ethylbenzene
1	the effect (upper values) but no effects were observed, zeroes were shown in the lower set of values
2	to indicate the lack of an ethylbenzene-specific, exposure-related effect
3
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IRIS Assessment Plan for Ethylbenzene
Table 2. Heat map of ethylbenzene (EB) human database

Cardiovascular
Dermal
Developmental
Endocrine/
Exocrine
Gastrointestinal
Hematological
Hepatic
Immunological
Musculoskeletal
Nasal
Neurological
Pulmonary
Renal
Reproductive
Ocular
Other effects3
Human studies - inhalation exposure
Occupational
Epidemiological Studies

1 1
0 0

1
1

General Population
1
2
5

1


1
9


2 2
4

2 2
Epidemiological Studies
1
0
2
0
0
7

0 0
2

1
2
Controlled Exposure
Studies

1
0

7
6



5
4
2
2
Case Reports and
Case Series Reports

Human studies-oral exposure
Occupational
Epidemiological Studies

General Population
Epidemiological Studies

Controlled Exposure
Studies

Case Reports and
Case Series Reports

Human studies - dermal/multiple routes or unknown (biomarker) exposure
Occupational
Epidemiological Studies

1 1
0 0

1
0
General Population
Epidemiological Studies
1
1

1
0
1
1

2
1

1
0
Controlled Exposure
Studies

Case Reports and
Case Series Reports

1
0

Heat map key
Number of studies that examined the endpoint



0 12 3 4
5-9
10-14


Number of studies reporting response measurements from ethylbenzene exposure.

0 12 3 4
5-9
10-14
15+

aOther includes body weight, clinical signs, and other observations (not organ specific).
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IRIS Assessment Plan for Ethylbenzene
Table 3. Heat map of ethylbenzene (EB) animal database

Cardiovascular
Dermal
Developmental
Endocrine/
Exocrine |
Gastrointestinal
Hematological
Hepatic
Immunological
Musculoskeletal
Nasal
Neurological
Pulmonary
Renal
Reproductive
Ocular
Other effects3
Animal studies - inhalation exposure
Chronic
6
2

6
2
6
7 6
2 2 2
6 6 6
2
7
0 0
1
0 0
5
0 0 0 0
1
2
3
0
4
Subchronic
3
1


3
3 3

6
3
2
3
4
3
7
3 3
7
0 0
0
0 0

6
1
0 0
1 1
6
0 0
1
Short-term
9
4
1
8
6 7

17
9 6 9
18
13
16
10
7
23
0 0
0
1
0
2
10
0 0 0
9
2
5
0 0
8
Acute

1
1
4
4
3
3

1
1
2
2
Multigenerational


3



3

3 3

3


1



2

2
1

1
Gestational
2


12
2


6 5

2
5 6
12

11
0

10
0


4
3

0 0
3 3
4
Animal studies - oral exposure
Chronic
2


2
1 1

2 2
111
2 2 2

2
0
0
0 0

1
0 0
1
0 0
1
0 0
1
Subchronic
1 1


1
1 1

2
1
2
1
2
1
2
1
2 2
0 0
0
0
1

2
1
0 0 0 0
2
0 0
2
Short-term
1
0

1
0

1
0
2
1
1
0

1
0

1
1
2
1

2
2
Acute

1
1

1
1

1
1

1
1
Multigenerational

Gestational

Heat map k
Number of
0
ey
studies that examined endpoint



1
2
3
4
5 to 9
10 to 14
15+

Number of
0
studies reporting response measurements from ethylbenzene exposure.

1
2
3
4
5 to 9
10 to 14
15+

aOther includes body weight, clinical signs, and other observations.
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IRIS Assessment Plan for Ethylbenzene
1	3. OVERALL OBJECTIVE, SPECIFIC AIMS AND DRAFT
2	POPULATIONS, EXPOSURES, COMPARATORS,
3	AND OUTCOMES (PECO) FRAMEWORK
4	The overall objective of this assessment is to identify adverse health effects and
5	characterize exposure-response relationships for these effects of ethylbenzene to support
6	development of toxicity values. This assessment will use systematic review methods to evaluate
7	the epidemiological and toxicological literature, including consideration of relevant mechanistic
8	evidence. The evaluations conducted in this assessment will be consistent with relevant EPA
9	guidance.3 The systematic review protocol will be disseminated after review of the draft
10	assessment plan and will reflect changes made to the specific aims and the PECO framework in
11	response to public input
12	3.1. SPECIFIC AIMS
13	• Identify epidemiological (i.e., human) and toxicological (i.e., experimental animal) literature
14	reporting effects of exposure to ethylbenzene as outlined in the PECO framework.
15	• Use an iterative approach to determine which mechanistic studies are most important to
16	summarize, based on factors such as robustness of the evidence in humans and animals,
17	likelihood to influence evidence synthesis conclusions for human health, and directness or
18	relevance of the model systems for understanding potential human health hazards. When
19	summarizing individual mechanistic studies is not critical, this information will generally be
20	summarized by relying on other published authoritative sources, such as public health
21	agency reports and expert review articles.
22	• Conduct study evaluations (risk of bias and sensitivity) for individual epidemiological and
23	toxicological studies. Studies with critical deficiencies will be considered uninformative and
24	not considered further.
25	• Extract data on relevant health outcomes from epidemiological and toxicological studies
26	included based on the study evaluation
27	• Synthesize the evidence across studies assessing similar health outcomes using a narrative
28	approach or meta-analysis (if appropriate).
aEPA guidance documents: http://www.epa.gov/iris/basic-information-about-integrated-risk-information-
svstem#guidance/.
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IRIS Assessment Plan for Ethylbenzene
1	• For each health outcome, express confidence in conclusions from across studies (or subsets
2	of studies) within human and animal evidence streams, evaluating each evidence stream
3	separately.
4	• For each health outcome, integrate results across evidence streams (human and animal) to
5	conclude whether a substance is hazardous to humans. Identify and discuss issues
6	concerning potentially susceptible populations and life stages. Biological support from
7	mechanistic studies and nonmammalian model systems will be considered based on the
8	iterative prioritization approach outlined in the PECO framework.
9	• Derive toxicity values as supported by the available data.
10	• Characterize uncertainties and identify key data gaps and research needs such as
11	limitations of the evidence base, limitations of the systematic review, and consideration of
12	dose relevance and pharmacokinetic differences when extrapolating findings from higher-
13	dose animal studies to lower levels of human exposure.
14
15	3.2. DRAFT PECO FRAMEWORK
16	A PECO framework is used as an aid to focus the research question(s), search terms, and
17	inclusion/exclusion criteria in a systematic review. The draft PECO framework for ethylbenzene
18	(Table 4) was based on (1) nomination of the chemical for assessment, (2) discussions with
19	scientists in EPA program and regional offices to determine the scope of the assessment that will
20	best meet Agency needs, and (3) preliminary review of the health effects literature for
21	ethylbenzene to identify the major health hazards associated with exposure and key areas of
22	scientific complexity.
23
Table 4. Draft PECO framework for the ethylbenzene assessment
24
PECO Element
Evidence
Populations
Human: All populations and life stages (e.g., children, general population, occupational,
or high exposure from an environmental source). The following study designs will be
considered most informative: controlled exposure, cohort, case-control, cross-sectional,
and ecological. Note: Case reports and case series will be tracked during study screening
but are not the primary focus of this assessment. They may be retrieved for full-text
review and subsequent evidence synthesis if no or few more informative study designs
are available. Case reports also can be used as supportive information to establish
biologic plausibility for some target organs and health outcomes.
Animal: Non-human mammalian animal species (whole organism) of anv life stage
(including preconception, in utero, lactation, peripubertal and adult stages).
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IRIS Assessment Plan for Ethylbenzene

Nonmammalian model svstems/in vitro/in silico: Non-mammalian model svstems (e.g..
fish, amphibians, birds, Caenorhabditis elegans, etc.); human or animal cells, tissues, or
biochemical reactions (e.g., ligand-binding assays) with in vitro exposure regimens;
bioinformatics pathways of disease analysis; or high-throughput screening data. These
studies are tagged during title and abstract screening and an iterative approach is used to
prioritize their inclusion for full-text retrieval and evidence synthesis based on likelihood
to impact evidence synthesis conclusions for human health3
Exposures
Human: Exposure to ethvlbenzene (CASRN 100-41-4). including occupational exposures,
alone or as a mixture by any route.

Animal: Exposure to ethvlbenzene (CASRN 100-41-4) alone bv anv route. Studies
employing chronic exposures will be considered the most informative. Studies involving
exposures to mixtures will be included only if they include an arm with exposure to
ethylbenzene alone.

Nonmammalian model svstems/in vitro/in silico: Exposure to ethvlbenzene via growth
or assay medium.
Comparators
Human: Anv comparison or reference group exposed to: lower levels of ethvlbenzene.
no exposure to ethylbenzene, or to ethylbenzene for shorter periods of time.

Animal: Quantitative exposure versus lower or no exposure with concurrent vehicle
control group.

Non-mammalian model svstems / in vitro / in silico: Quantitative exposure versus
lower or no exposure with concurrent vehicle control group.
Outcomes
All health outcomes (both cancer and noncancer). In general, endpoints related to
clinical diagnostic criteria, disease outcomes, histopathological examination, or other
apical/phenotypic outcomes will be prioritized for evidence synthesis over outcomes
such as biochemical measures.
aNote: An iterative approach is used to prioritize evidence from nonmammalian model systems (e.g., fish,
amphibians, birds, C elegans), in vitro, in silico, and other types of mechanistic studies based on likelihood to
impact evidence synthesis conclusions for human health. Evidence from these studies will be tagged preliminarily
during title/abstract screening as "Other Informative Studies" or "Supporting Information" according to hazard
categories or types of mechanistic outcomes/pathways. These studies are prioritized for full-text retrieval and
evidence synthesis to focus on those studies most important to summarize, based on factors such as robustness
of the evidence in humans and animals, directness or relevance of the model systems, and concentrations tested.
For example, if robust epidemiological or nonhuman mammalian evidence is available, the need to conduct a
thorough assessment of individual non-mammalian and mechanistic studies could be diminished unless
controversial issues need to be resolved, e.g., issues related to applicability of animal evidence to humans or the
shape of the dose-response curve at low exposure levels.
1
2	3.3. ASSESSMENT APPROACH
3	This assessment will use a modular approach. Toxicity values not requiring advanced
4	quantitative methods (e.g., physiologically based pharmacokinetic [PBPK] modeling) will be
5	derived first When more complex modeling approaches will be required to develop a toxicity
6	value, progress on developing those values shall be handled once the models have been developed
7	and evaluated by EPA. Based on the ample database for inhalation studies, EPA anticipates an RfC
8	for ethylbenzene can be derived without the need for PBPK modeling. The very limited database
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1	for oral studies, however, might necessitate use of PBPK modeling to develop an RfD. Dermal
2	toxicity values will not be derived based on the survey of needs (see Table 1). Evaluation of cancer
3	endpoints could be complex and, therefore, might require more time to assess than noncancer
4	endpoints. For this reason, a cancer assessment might be developed separately from RfC or RfD
5	toxicity values.
6 3.4. KEY SCIENCE ISSUES
7	Based on the preliminary literature survey, the following key scientific issues and potential
8	mode-of-action hypotheses were identified that warrant evaluation in the assessment
9	• Toxicokinetics of ethylbenzene.
10
11
• Human relevance for cancer and noncancer hazards observed in experimental systems (e.g.,
rat renal toxicity and tumors, mouse lung toxicity and tumors).
12	• Mechanisms of neurotoxicity including ototoxicity.
13
14
° Reversibility, persistence, or potential for progression of the neurobehavioral or
ototoxic effects after humans are removed from ethylbenzene exposure.
15
O
The relevance of ototoxicity to humans at lower exposure levels.
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REFERENCES
ATSDR (Agency for Toxic Substances and Disease Registry). (2010). Toxicological profile for
ethylbenzene [ATSDR Tox Profile]. (PB2010100004). Atlanta, GA: U.S. Department of
Health	and	Human	Services,	Public	Health	Service.
http://www.atsd r.cdc.gov/ToxProfiles/tp.asp?id=383&tid=66.
Cal/EPA (California Environmental Protection Agency). (1997). Public health goal for
ethylbenzene in drinking water. Pesticide and Environmental Toxicology Section; Office
of Environmental Health Hazard Assessment; California Environmental Protection
Agency.
IPCS (International Programme on Chemical Safety). (1996). Environmental health criteria 186:
Ethylbenzene [WHO EHC]. (CIS/98/00236). Geneva: United Nations Environment
Programme, International Labour Organisation, and the World Health Organization.
http://www.inchem.org/documents/ehc/ehc/ehcl86.htm.
U.S. EPA (U.S. Environmental Protection Agency). (1991). Ethylbenzene - Integrated Risk
Information	System	[EPA	Report].	Washington	DC.
http://www.epa.gov/iris/subst/0051.htm.
U.S. EPA (U.S. Environmental Protection Agency). (2014). Scoping and problem formulation for
the identification of potential health hazards for the Integrated Risk Information System
(IRIS) toxicological review of ethylbenzene [CASRN 100-41-4] [EPA Report]. (EPA/635/R-
14/198). Washington, DC. http://nepis.epa.gov/Exe/ZvPURL.cgi?Dockev=P100L2BQ.txt.
This document is a draft for review purposes only and does not constitute Agency policy.
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