TOXICOLOGICAL PROFILE FOR
 

ETHYLBENZENE
 


 


 


 


 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
 

Public Health Service
 

Agency for Toxic Substances and Disease Registry
 

November 2010 
 

ETHYLBENZENE ii 

DISCLAIMER 

The use of company or product name(s) is for identification only and does not imply endorsement by the 

Agency for Toxic Substances and Disease Registry. 
 

ETHYLBENZENE iii 

UPDATE STATEMENT
 

A Toxicological Profile for Ethylbenzene, Draft for Public Comment was released in October 2007. This 

edition supersedes any previously released draft or final profile. 

Toxicological profiles are revised and republished as necessary. For information regarding the update 

status of previously released profiles, contact ATSDR at: 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology and Environmental Medicine/Applied Toxicology Branch
 

1600 Clifton Road NE
 

Mailstop F-62
 

Atlanta, Georgia 30333
 
ETHYLBENZENE iv 

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FOREWORD 


This toxicological profile is prepared in accordance with guidelines* developed by the Agency for 

Toxic Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA). The 

original guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised 

and republished as necessary. 

The ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health 

effects infonnation for these toxic substances described therein. Each peer-reviewed profile identifies and 

reviews the key literature that describes a substance's toxicologic properties. Other pertinent literature is 

also presented, but is described in less detail than the key studies. The profile is not intended to be an 

exhaustive document; however, more comprehensive sources of specialty information are referenced. 

The focus ofthe profiles is on health and toxicologic infonnation; therefore, each toxicological 

profile begins with a public health statement that describes, in nontechnical language, a substance's 

relevant toxicological properties. Following the public health statement is infonnation concerning levels 

of significant human exposure and, where known, significant health effects. The adequacy of infonnation 

to detennine a substance's health effects is described in a health effects summary. Data needs that are of 

significance to protection of public health are identified by ATSDR. 

Each profile includes the following: 

(A) The examination, summary, and interpretation ofavailable toxicologic infonnation and 

epidemiologic evaluations on a toxic substance to ascertain the levels of significant human 

exposure for the substance and the associated acute, subacute, and chronic health effects; 

(B) 	A determination ofwhether adequate infonnation on the health effects of each substance is 

available or in the process of development to detennine levels ofexposure that present a 

significant risk to human health ofacute, subacute, and chronic health effects; and 

(C) Where appropriate, identification oftoxicologic testing needed to identifY the types or levels 

ofexposure that may present significant risk of adverse health effects in humans. 

The principal audiences for the toxicological profiles are health professionals at the Federal, State, 

and local levels; interested private sector organizations and groups; and members ofthe public. 

This profile reflects ATSDR's assessment ofall relevant toxicologic testing and infonnation that 

has been peer-reviewed. Staffs ofthe Centers for Disease Control and Prevention and other Federal 

scientists have also reviewed the profile. In addition, this profile has been peer-reviewed by a 

nongovernmental panel and was made available for public review. Final responsibility for the contents 

and views expressed in this toxicological profile resides with ATSDR. 

// 7\\ /) ;/A~-'0/.L.-- /r:../C~--(Xj 

Thomas R. Frieden, M.D., M.P.H. 


Administrator 


Agency for Toxic Substances and 


Disease Registry 

"Legislative Background 

The toxicological profiles are developed under the Comprehensive Environmental Response, 

Compensation, and Liability Act of 1980, as amended (CERCLA or Superfund). CERCLA section 

104(i)(1) directs the Administrator of ATSDR to " ...effectuate and implement the health related 

authorities" ofthe statute. This includes the preparation oftoxicological profiles for hazardous 

substances most commonly found at facilities on the CERCLA National Priorities List and that pose the 

most significant potential threat to human health, as determined by ATSDR and the EPA. Section 

104(i)(3) ofCERCLA, as amended, directs the Administrator ofATSDR to prepare a toxicological profile 

for each substance on the list. In addition, A TSDR has the authority to prepare toxicological profiles for 

substances not found at sites on the National Priorities List, in an effort to " ...establish and maintain 

inventory of literature, research, and studies on the health effects oftoxic substances" under CERCLA 

Section 104(i)(IXB), to respond to requests for consultation under section 104(i)(4), and as otherwise 

necessary to support the site-specific response actions conducted by A TSDR. 
 

 

 

 

ETHYLBENZENE vii 

QUICK REFERENCE FOR HEALTH CARE PROVIDERS 

Toxicological Profiles are a unique compilation of toxicological information on a given hazardous 

substance. Each profile reflects a comprehensive and extensive evaluation, summary, and interpretation 

of available toxicologic and epidemiologic information on a substance. Health care providers treating 

patients potentially exposed to hazardous substances will find the following information helpful for fast 

answers to often-asked questions. 

Primary Chapters/Sections of Interest 

Chapter 1: Public Health Statement: The Public Health Statement can be a useful tool for educating 

patients about possible exposure to a hazardous substance. It explains a substance’s relevant 

toxicologic properties in a nontechnical, question-and-answer format, and it includes a review of 

the general health effects observed following exposure. 

Chapter 2: Relevance to Public Health: The Relevance to Public Health Section evaluates, interprets, 

and assesses the significance of toxicity data to human health. 

Chapter 3: Health Effects: Specific health effects of a given hazardous compound are reported by type 

of health effect (death, systemic, immunologic, reproductive), by route of exposure, and by length 

of exposure (acute, intermediate, and chronic). In addition, both human and animal studies are 

reported in this section. 

NOTE: Not all health effects reported in this section are necessarily observed in the clinical 

setting. Please refer to the Public Health Statement to identify general health effects observed 

following exposure. 

Pediatrics: Four new sections have been added to each Toxicological Profile to address child health 

issues: 

Section 1.6 How Can (Chemical X) Affect Children?
 

Section 1.7 How Can Families Reduce the Risk of Exposure to (Chemical X)?
 

Section 3.7 Children’s Susceptibility
 

Section 6.6 Exposures of Children
 

Other Sections of Interest: 

Section 3.8 Biomarkers of Exposure and Effect 

Section 3.11 Methods for Reducing Toxic Effects 

ATSDR Information Center 

Phone: 1-800-CDC-INFO (800-232-4636) or 1-888-232-6348 (TTY) Fax: (770) 488-4178 

E-mail: cdcinfo@cdc.gov Internet: http://www.atsdr.cdc.gov 

The following additional material can be ordered through the ATSDR Information Center: 

Case Studies in Environmental Medicine: Taking an Exposure History—The importance of taking an 

exposure history and how to conduct one are described, and an example of a thorough exposure 

history is provided. Other case studies of interest include Reproductive and Developmental 

Hazards; Skin Lesions and Environmental Exposures; Cholinesterase-Inhibiting Pesticide 

Toxicity; and numerous chemical-specific case studies. 
 

 

 

 

 

 

ETHYLBENZENE viii 

Managing Hazardous Materials Incidents is a three-volume set of recommendations for on-scene 

(prehospital) and hospital medical management of patients exposed during a hazardous materials 

incident. Volumes I and II are planning guides to assist first responders and hospital emergency 

department personnel in planning for incidents that involve hazardous materials. Volume III— 

Medical Management Guidelines for Acute Chemical Exposures—is a guide for health care 

professionals treating patients exposed to hazardous materials. 

Fact Sheets (ToxFAQs) provide answers to frequently asked questions about toxic substances. 

Other Agencies and Organizations 

The National Center for Environmental Health (NCEH) focuses on preventing or controlling disease, 

injury, and disability related to the interactions between people and their environment outside the 

workplace. Contact: NCEH, Mailstop F-29, 4770 Buford Highway, NE, Atlanta, 

GA 30341-3724 • Phone: 770-488-7000 • FAX: 770-488-7015. 

The National Institute for Occupational Safety and Health (NIOSH) conducts research on occupational 

diseases and injuries, responds to requests for assistance by investigating problems of health and 

safety in the workplace, recommends standards to the Occupational Safety and Health 

Administration (OSHA) and the Mine Safety and Health Administration (MSHA), and trains 

professionals in occupational safety and health. Contact: NIOSH, 200 Independence Avenue, 

SW, Washington, DC 20201 • Phone: 800-356-4674 or NIOSH Technical Information Branch, 

Robert A. Taft Laboratory, Mailstop C-19, 4676 Columbia Parkway, Cincinnati, OH 45226-1998 

• Phone: 800-35-NIOSH. 

The National Institute of Environmental Health Sciences (NIEHS) is the principal federal agency for 

biomedical research on the effects of chemical, physical, and biologic environmental agents on 

human health and well-being. Contact: NIEHS, PO Box 12233, 104 T.W. Alexander Drive, 

Research Triangle Park, NC 27709 • Phone: 919-541-3212. 

Referrals 

The Association of Occupational and Environmental Clinics (AOEC) has developed a network of clinics 

in the United States to provide expertise in occupational and environmental issues. Contact: 

AOEC, 1010 Vermont Avenue, NW, #513, Washington, DC 20005 • Phone: 202-347-4976 

• FAX: 202-347-4950 • e-mail: AOEC@AOEC.ORG • Web Page: http://www.aoec.org/. 

The American College of Occupational and Environmental Medicine (ACOEM) is an association of 

physicians and other health care providers specializing in the field of occupational and 

environmental medicine. Contact: ACOEM, 25 Northwest Point Boulevard, Suite 700, Elk 

Grove Village, IL 60007-1030 • Phone: 847-818-1800 • FAX: 847-818-9266. 
ETHYLBENZENE ix 

CONTRIBUTORS 

CHEMICAL MANAGER(S)/AUTHOR(S): 

Jessilynn Taylor, M.S.
 

Henry Abadin, M.S.P.H.
 

Heraline Hicks
 

Oscar Tarrago, M.D., M.P.H.
 

Diana Cronin
 

ATSDR, Division of Toxicology and Environmental Medicine, Atlanta, GA
 

Julie M. Klotzbach, Ph.D., 

Mario Citra, Ph.D., 

Gary Diamond, Ph.D.,
 

Lisa Ingerman, Ph.D., DABT,
 

Antonio Quiñones-Rivera, Ph.D.
 

SRC, Inc., North Syracuse, NY
 

THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS: 

1.	 Health Effects Review. The Health Effects Review Committee examines the health effects 

chapter of each profile for consistency and accuracy in interpreting health effects and classifying 

end points. 

2.	 Minimal Risk Level Review. The Minimal Risk Level Workgroup considers issues relevant to 

substance-specific Minimal Risk Levels (MRLs), reviews the health effects database of each 

profile, and makes recommendations for derivation of MRLs. 

3.	 Data Needs Review. The Applied Toxicology Branch reviews data needs sections to assure 

consistency across profiles and adherence to instructions in the Guidance. 

4.	 Green Border Review. Green Border review assures the consistency with ATSDR policy. 
ETHYLBENZENE x 

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ETHYLBENZENE xi 

PEER REVIEW
 

A peer review panel was assembled for ethylbenzene. The panel consisted of the following members: 

Draft for Public Comment: 

1.	 John DeSesso, Ph.D., Senior Fellow, Noblis, Falls Church, VA; 

2.	 James McDougal, Ph.D., Professor and Director of Toxicology Research, Boonshoft School of 

Medicine, Wright State University, Department of Pharmacology and Toxicology, Dayton, OH; 

3.	 Andrew Salmon, Ph.D., Senior Toxicologist and Chief, Air Toxicology and Risk Assessment 

Unit, Office of Environmental Health Hazard Assessment, California Environmental Protection 

Agency, Oakland, CA. 

Revised Minimal Risk Levels: 

4.	 John DeSesso, Ph.D., Senior Fellow, Noblis, Falls Church, VA; 

5.	 Brent Finley, Ph.D., DABT, Principal Health Scientist and Vice President, ChemRisk, San 

Francisco, CA; 

6.	 Andrew Salmon, Ph.D., Senior Toxicologist and Chief, Air Toxicology and Risk Assessment 

Unit, Office of Environmental Health Hazard Assessment, California Environmental Protection 

Agency, Oakland, CA. 

These experts collectively have knowledge of ethylbenzene's physical and chemical properties, 

toxicokinetics, key health end points, mechanisms of action, human and animal exposure, and 

quantification of risk to humans. All reviewers were selected in conformity with the conditions for peer 

review specified in Section 104(I)(13) of the Comprehensive Environmental Response, Compensation, 

and Liability Act, as amended. 

Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer 

reviewers' comments and determined which comments will be included in the profile. A listing of the 

peer reviewers' comments not incorporated in the profile, with a brief explanation of the rationale for their 

exclusion, exists as part of the administrative record for this compound. 

The citation of the peer review panel should not be understood to imply its approval of the profile's final 

content. The responsibility for the content of this profile lies with the ATSDR. 
ETHYLBENZENE xii 

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ETHYLBENZENE xiii 

CONTENTS
 

DISCLAIMER ................................................................................................................................ ii
 

UPDATE STATEMENT............................................................................................................... iii
 

FOREWORD .................................................................................................................................. v
 

QUICK REFERENCE FOR HEALTH CARE PROVIDERS ..................................................... vii
 

CONTRIBUTORS......................................................................................................................... ix
 

PEER REVIEW ............................................................................................................................. xi
 

CONTENTS................................................................................................................................. xiii
 

LIST OF FIGURES .................................................................................................................... xvii
 

LIST OF TABLES....................................................................................................................... xix
 

1. PUBLIC HEALTH STATEMENT............................................................................................ 1
 

1.1 WHAT IS ETHYLBENZENE?......................................................................................... 1
 

1.2 WHAT HAPPENS TO ETHYLBENZENE WHEN IT ENTERS THE 

ENVIRONMENT?............................................................................................................ 2
 

1.3 HOW MIGHT I BE EXPOSED TO ETHYLBENZENE?................................................ 2
 

1.4 HOW CAN ETHYLBENZENE ENTER AND LEAVE MY BODY?............................. 3
 

1.5 HOW CAN ETHYLBENZENE AFFECT MY HEALTH?.............................................. 4
 

1.6 HOW CAN ETHYLBENZENE AFFECT CHILDREN? ................................................. 4
 

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO
 

ETHYLBENZENE?.......................................................................................................... 5
 

1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN
 

EXPOSED TO ETHYLBENZENE?................................................................................. 6
 

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT
 

MADE TO PROTECT HUMAN HEALTH? ................................................................... 6
 

1.10 WHERE CAN I GET MORE INFORMATION? ............................................................. 7
 

2. RELEVANCE TO PUBLIC HEALTH ..................................................................................... 9
 

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO 

ETHYLBENZENE IN THE UNITED STATES .............................................................. 9
 

2.2 SUMMARY OF HEALTH EFFECTS............................................................................ 10
 

2.3 MINIMAL RISK LEVELS (MRLs) ............................................................................... 15
 

3. HEALTH EFFECTS................................................................................................................ 33
 

3.1 INTRODUCTION........................................................................................................... 33
 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE ........................ 33
 

3.2.1 Inhalation Exposure .................................................................................................. 34
 

3.2.1.1 Death .................................................................................................................. 34
 

3.2.1.2 Systemic Effects................................................................................................. 35
 

3.2.1.3 Immunological and Lymphoreticular Effects .................................................... 66
 

3.2.1.4 Neurological Effects........................................................................................... 66
 

3.2.1.5 Reproductive Effects.......................................................................................... 69
 

3.2.1.6 Developmental Effects ....................................................................................... 70
 

3.2.1.7 Cancer................................................................................................................. 72
 
 

 

ETHYLBENZENE	 xiv 

3.2.2 Oral Exposure ........................................................................................................... 74
 

3.2.2.1 Death .................................................................................................................. 74
 

3.2.2.2 Systemic Effects................................................................................................. 74
 

3.2.2.3 Immunological and Lymphoreticular Effects .................................................... 82
 

3.2.2.4 Neurological Effects........................................................................................... 83
 

3.2.2.5 Reproductive Effects.......................................................................................... 83
 

3.2.2.6 Developmental Effects ....................................................................................... 84
 

3.2.2.7 Cancer................................................................................................................. 84
 

3.2.3 Dermal Exposure ...................................................................................................... 84
 

3.2.3.1 Death .................................................................................................................. 84
 

3.2.3.2 Systemic Effects................................................................................................. 84
 

3.2.3.3 Immunological and Lymphoreticular Effects .................................................... 87
 

3.2.3.4 Neurological Effects........................................................................................... 87
 

3.2.3.5 Reproductive Effects.......................................................................................... 87
 

3.2.3.6 Developmental Effects ....................................................................................... 87
 

3.2.3.7 Cancer................................................................................................................. 87
 

3.3 GENOTOXICITY ........................................................................................................... 87
 

3.4 TOXICOKINETICS........................................................................................................ 91
 

3.4.1 Absorption................................................................................................................. 92
 

3.4.1.1 Inhalation Exposure............................................................................................ 92
 

3.4.1.2 Oral Exposure..................................................................................................... 93
 

3.4.1.3 Dermal Exposure................................................................................................ 94
 

3.4.2 Distribution ............................................................................................................... 95
 

3.4.2.1 Inhalation Exposure............................................................................................ 95
 

3.4.2.2 Oral Exposure..................................................................................................... 96
 

3.4.2.3 Dermal Exposure................................................................................................ 96
 

3.4.3 Metabolism ............................................................................................................... 96
 

3.4.4 Elimination and Excretion ...................................................................................... 100
 

3.4.4.1 Inhalation Exposure.......................................................................................... 100
 

3.4.4.2 Oral Exposure................................................................................................... 102
 

3.4.4.3 Dermal Exposure.............................................................................................. 103
 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD)
 

Models.................................................................................................................... 104
 

3.5 MECHANISMS OF ACTION ...................................................................................... 121
 

3.5.1 Pharmacokinetic Mechanisms ................................................................................ 121
 

3.5.2 Mechanisms of Toxicity ......................................................................................... 122
 

3.5.3 Animal-to-Human Extrapolations........................................................................... 124
 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS.............. 125
 

3.7 CHILDREN’S SUSCEPTIBILITY............................................................................... 126
 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT ........................................................ 128
 

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Ethylbenzene .................... 129
 

3.8.2 Biomarkers Used to Characterize Effects Caused by Ethylbenzene ...................... 130
 

3.9 INTERACTIONS WITH OTHER CHEMICALS ........................................................ 130
 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE................................... 131
 
ETHYLBENZENE xv 

3.11 METHODS FOR REDUCING TOXIC EFFECTS....................................................... 132
 

3.11.1 Reducing Peak Absorption Following Exposure................................................. 132
 

3.11.2 Reducing Body Burden ....................................................................................... 133
 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects.............................. 133
 

3.12 ADEQUACY OF THE DATABASE............................................................................ 133
 

3.12.1 Existing Information on Health Effects of Ethylbenzene.................................... 134
 

3.12.2 Identification of Data Needs................................................................................ 134
 

3.12.3 Ongoing Studies .................................................................................................. 143
 

4. CHEMICAL AND PHYSICAL INFORMATION ............................................................... 147
 

4.1 CHEMICAL IDENTITY............................................................................................... 147
 

4.2 PHYSICAL AND CHEMICAL PROPERTIES............................................................ 147
 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL............................................ 151
 

5.1 PRODUCTION ............................................................................................................. 151
 

5.2 IMPORT/EXPORT ....................................................................................................... 156
 

5.3 USE................................................................................................................................ 156
 

5.4 DISPOSAL .................................................................................................................... 156
 

6. POTENTIAL FOR HUMAN EXPOSURE........................................................................... 159
 

6.1 OVERVIEW.................................................................................................................. 159
 

6.2 RELEASES TO THE ENVIRONMENT...................................................................... 162
 

6.2.1 Air ........................................................................................................................... 162
 

6.2.2 Water....................................................................................................................... 166
 

6.2.3 Soil .......................................................................................................................... 166
 

6.3 ENVIRONMENTAL FATE.......................................................................................... 167
 

6.3.1 Transport and Partitioning ...................................................................................... 167
 

6.3.2 Transformation and Degradation ............................................................................ 169
 

6.3.2.1 Air..................................................................................................................... 169
 

6.3.2.2 Water ................................................................................................................ 170
 

6.3.2.3 Sediment and Soil............................................................................................. 174
 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT..................... 175
 

6.4.1 Air ........................................................................................................................... 175
 

6.4.2 Water....................................................................................................................... 181
 

6.4.3 Sediment and Soil ................................................................................................... 184
 

6.4.4 Other Environmental Media ................................................................................... 184
 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE........................... 186
 

6.6 EXPOSURES OF CHILDREN..................................................................................... 190
 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES ................................. 193
 

6.8 ADEQUACY OF THE DATABASE............................................................................ 194
 

6.8.1 Identification of Data Needs ................................................................................... 194
 

6.8.2 Ongoing Studies...................................................................................................... 197
 

7. ANALYTICAL METHODS ................................................................................................. 199
 

7.1 BIOLOGICAL MATERIALS....................................................................................... 199
 

7.2 ENVIRONMENTAL SAMPLES.................................................................................. 203
 
ETHYLBENZENE xvi 

7.3 ADEQUACY OF THE DATABASE............................................................................ 209
 

7.3.1 Identification of Data Needs ................................................................................... 210
 

7.3.2 Ongoing Studies...................................................................................................... 212
 

8. REGULATIONS, ADVISORIES, AND GUIDELINES ...................................................... 215
 

9. REFERENCES ...................................................................................................................... 221
 

10. GLOSSARY ........................................................................................................................ 255
 

APPENDICES 

A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS............................................... A-1 

B. USER’S GUIDE.....................................................................................................................B-1 

C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS ........................................................C-1 

D. INDEX .................................................................................................................................. D-1 
 

 

 

 

 

ETHYLBENZENE xvii 

LIST OF FIGURES
 

3-1. Levels of Significant Exposure to Ethylbenzene - Inhalation ...............................................55 

3-2. Levels of Significant Exposure to Ethylbenzene - Oral ........................................................79 

3-3. Metabolic Scheme for Ethylbenzene in Humans ................................................................. 97
 

3-4. Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK)
 

Model for a Hypothetical Chemical Substance ................................................................. 106
 

3-5. Schematic Representation of the Model of Dermal Absorption......................................... 119
 

3-6. Existing Information on Health Effects of Ethylbenzene................................................... 135
 

6-1. Frequency of NPL Sites with Ethylbenzene Contamination.............................................. 160
 

6-2. Major Degradation Pathways for Ethylbenzene in the Atmosphere .................................. 171
 

6-3. Major Degradation Pathways for Ethylbenzene in Water, Sediment, and Soil.................. 172
 
ETHYLBENZENE xviii 

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ETHYLBENZENE xix 

LIST OF TABLES
 

2-1. Human Equivalent Concentrations (HECs) for CAP Threshold Shifts................................ 19
 

2-2. Human Equivalent Concentrations (HECs) for Auditory Effects in Sprague-Dawley
 

Rats Exposed to Ethylbenzene 6 Hours/Day, 6 Days/Week for 4 or 13 Weeks.................. 22
 

2-3. Internal Dose Metrics for Male and Female F344/N Rats Exposed to Ethylbenzene 

6 Hours/Day, 5 Days/Week for 104 Weeks......................................................................... 25
 

2-4. Effects on Serum Liver Enzymes, Liver Weights, and Liver Histopathology in Male
 

and Female Rats Exposed to Oral Ethylbenzene for 13 Weeks........................................... 28
 

2-5. Benchmark Doses and Human Equivalent Doses for Liver Effects Using Arterial
 

Ethylbenzene Concentration (MCL) Dose Metric............................................................... 30
 

2-6. Benchmark Doses (BMDs) and Human Equivalent Doses (HEDs) for Liver Effects 

Using MRAMKL Internal Dose Metric............................................................................... 31
 

3-1. Levels of Significant Exposure to Ethylbenzene - Inhalation ...............................................36 

3-2. Levels of Significant Exposure to Ethylbenzene - Oral ........................................................75 

3-3. Levels of Significant Exposure to Ethylbenzene - Dermal ...................................................86 

3-4. Genotoxicity of Ethylbenzene In Vivo.................................................................................. 88
 

3-5. Genotoxicity of Ethylbenzene In Vitro................................................................................. 89
 

3-6. Parameter Values for Tardif et al. (1997) Ethylbenzene PBPK Models............................ 108
 

3-7. Parameter Values for Nong et al. (2007) Ethylbenzene Mouse Physiologically-based
 

Pharmacokinetic Model ..................................................................................................... 112
 

3-8. Parameter Values for Dennison et al. (2003) Ethylbenzene PBPK Model ........................ 116
 

3-9. Parameters Used in the Shatkin and Brown PBPK Model of Dermal Absorption of
 

Ethylbenzene...................................................................................................................... 120
 

3-10. Ongoing Studies on Ethylbenzene.................................................................................... 144
 

4-1. Chemical Identity of Ethylbenzene .................................................................................... 148
 

4-2. Physical and Chemical Properties of Ethylbenzene ........................................................... 149
 

5-1. Ethylbenzene Production in the United States from 1983 to 2005 ..................................... 152
 
 

 

ETHYLBENZENE xx 

5-2. Facilities that Produce, Process, or Use Ethylbenzene....................................................... 153
 

5-3. Manufacturers and Annual Production Capacity of Ethylbenzene .................................... 155
 

6-1. Releases to the Environment from Facilities that Produce, Process, or Use 

Ethylbenzene...................................................................................................................... 163
 

6-2. Ethylbenzene Concentrations in Ambient Air Samples Collected in the United States .... 180
 

6-3. Distribution of Blood Ethylbenzene Concentrations in Children (ng/mL) ........................ 192
 

6-4. Ongoing Research Regarding the Environmental Fate and Exposure to Ethylbenzene..... 198
 

7-1. Analytical Methods for Determining Ethylbenzene in Biological Samples....................... 200
 

7-2. Analytical Methods for Determining Ethylbenzene in Environmental Samples ............... 204
 

7-3. Analytical Methods for Determining Biomarkers of Ethylbenzene in Biological
 

Materials ............................................................................................................................ 211
 

7-4. Analytical Methods for Determining Environmental Degradation Products of
 

Ethylbenzene...................................................................................................................... 213
 

8-1. Regulations, Advisories, and Guidelines Applicable to Ethylbenzene .............................. 217
 
 

 

 

 

 

ETHYLBENZENE 1 

1. PUBLIC HEALTH STATEMENT 

This public health statement tells you about ethylbenzene and the effects of exposure to it. 

The Environmental Protection Agency (EPA) identifies the most serious hazardous waste sites in the 

nation. These sites are then placed on the National Priorities List (NPL) and are targeted for long-term 

federal clean-up activities. Ethylbenzene has been found in at least 829 of the 1,689 current or former 

NPL sites. Although the total number of NPL sites evaluated for this substance is not known, the 

possibility exists that the number of sites at which ethylbenzene is found may increase in the future as 

more sites are evaluated. This information is important because these sites may be sources of exposure 

and exposure to this substance may be harmful. 

When a substance is released either from a large area, such as an industrial plant, or from a container, 

such as a drum or bottle, it enters the environment. Such a release does not always lead to exposure. You 

can be exposed to a substance only when you come in contact with it. You may be exposed by breathing, 

eating, or drinking the substance, or by skin contact. 

If you are exposed to ethylbenzene, many factors will determine whether you will be harmed. These 

factors include the dose (how much), the duration (how long), and how you come in contact with it. You 

must also consider any other chemicals you are exposed to and your age, sex, diet, family traits, lifestyle, 

and state of health. 

1.1 WHAT IS ETHYLBENZENE? 

Colorless liquid 

that smells like 

gasoline 

You can smell ethylbenzene in the air at 2 parts of ethylbenzene per million 

parts of air (2 ppm). It evaporates at room temperature and burns easily. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 2 

1. PUBLIC HEALTH STATEMENT 

Used in industry 

and in consumer 

products 

Ethylbenzene is found naturally in oil. Large amounts of ethylbenzene are 

produced in the United States, most of which is used to make styrene. 

Ethylbenzene is also used in fuels and solvents. 

Consumer products containing ethylbenzene include: 

• gasoline 

• paints and inks 

• pesticides 

• carpet glues 

• varnishes and paints 

• tobacco products 

• automotive products 

For more information on the physical and chemical properties of ethylbenzene and its production, 

disposal, and use, see Chapters 4 and 5. 

1.2 WHAT HAPPENS TO ETHYLBENZENE WHEN IT ENTERS THE ENVIRONMENT? 

Most commonly 

found in air 

Ethylbenzene moves easily into the air from water and soil. Ethylbenzene in 

soil can also contaminate groundwater. 

Rapidly broken 

down in air 

Air: Ethylbenzene in air is broken down in less than 3 days with the aid of 

sunlight. 

Water: In surface water such as rivers and harbors, ethylbenzene breaks 

down by reacting with other compounds naturally present in water. 

Soil: In the soil, ethylbenzene is broken down by soil bacteria. 

For more information on ethylbenzene in the environment, see Chapter 6. 

1.3 HOW MIGHT I BE EXPOSED TO ETHYLBENZENE? 

Air If you live in a city or near many factories or heavily traveled highways, you 

may be exposed to ethylbenzene in the air. Releases of ethylbenzene into 

the air occur from burning oil, gas, and coal and from industries using 

ethylbenzene. 

The median levels of ethylbenzene in air are: 

• 0.62 ppb in city and suburban locations 

• 0.01 ppb in rural locations 

• 1 ppb in indoor air 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 3 

1. PUBLIC HEALTH STATEMENT 

Water Ethylbenzene is infrequently detected in private and public groundwater 

wells used for drinking water. Higher levels of ethylbenzene may be found in 

private residential wells near landfills, waste sites, or leaking underground 

fuel storage tanks. 

People with ethylbenzene-contaminated tap water could be exposed by 

drinking the water or eating foods prepared with it. Exposure could also 

result from breathing in ethylbenzene while showering, bathing, or cooking 

with contaminated water. 

Soil Background levels in soils have not been reported. Ethylbenzene may get 

into the soil by gasoline or other fuel spills and poor disposal of industrial 

and household wastes. 

Workplace air Gas and oil workers may be exposed to ethylbenzene either through skin 

contact or by breathing ethylbenzene vapors. Varnish workers, spray 

painters, and people involved in gluing operations may also be exposed to 

high levels of ethylbenzene. Exposure may also occur in factories that use 

ethylbenzene to produce other chemicals. 

Consumer 

products 

You might be exposed to ethylbenzene by using any of the following 

products: 

• gasoline 

• carpet glues 

• varnishes and paints 

• tobacco products 

• automotive products 

For more information on human exposure to ethylbenzene, see Chapter 6. 

1.4 HOW CAN ETHYLBENZENE ENTER AND LEAVE MY BODY? 

Rapidly enters 

your body 

When you breathe air containing ethylbenzene, it enters your body rapidly 

and almost completely through your lungs. Ethylbenzene in food or water 

may also rapidly and almost completely enter your body through the 

digestive tract. It may enter through your skin when you come into contact 

with liquids containing ethylbenzene. 

Typically leaves 

your body within 

2 days 

Once in your body, ethylbenzene is broken down into other chemicals. Most 

of these other chemicals leave your body in the urine within 2 days. 

Small amounts of ethylbenzene can also leave your body through the lungs 

and in feces. 

For more information on how ethylbenzene enters and leaves the body, see Chapter 3. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 4 

1. PUBLIC HEALTH STATEMENT 

1.5 HOW CAN ETHYLBENZENE AFFECT MY HEALTH? 

Scientists use many tests to protect the public from harmful effects of toxic chemicals and to find ways 

for treating persons who have been harmed 

The effect of ethylbenzene on human health depends on how much ethylbenzene is present, how you are 

exposed to it, and the length of exposure. 

Short-term Humans: Exposure to high levels of ethylbenzene in the air for short 

exposure in air periods can cause eye and throat irritation. Exposure to higher levels can 

result in vertigo and dizziness. 

Animals: Exposure to very high levels (about 2 million times the usual level 

in urban air) can cause death. 

Long-term Hearing: Exposure to relatively low concentrations of ethylbenzene for 

exposure in air several days to weeks resulted in potentially irreversible damage to the 

inner ear and hearing of animals. 

Kidney: Exposures to relatively low concentrations of ethylbenzene for 

several months to years caused in kidney damage in animals. 

Reproduction: There is no clear evidence that ethylbenzene affects fertility. 

Cancer: An increase in kidney tumors in rats and lung and liver tumors in 

mice were found after they were exposed to ethylbenzene in air for 2 years. 

The International Agency for Research on Cancer (an expert group that is 

part of the World Health Organization) has determined on that long-term 

exposure to ethylbenzene may cause cancer in humans. 

Long-term 

exposure by 

ingestion 

Hearing: Rats exposed to large amounts of ethylbenzene by mouth had 

severe damage to the inner ear. 

Short-term eye 

and skin contact 

Irritation: Liquid ethylbenzene caused eye damage and skin irritation in 

rabbits. 

Further information on the health effects of ethylbenzene in humans and animals can be found in 

Chapters 2 and 3. 

1.6 HOW CAN ETHYLBENZENE AFFECT CHILDREN? 

This section discusses potential health effects in humans from exposures during the period from 

conception to maturity at 18 years of age. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 5 

1. PUBLIC HEALTH STATEMENT 

Children are likely 

to have similar 

effects as adults 

No information is available about the effect of exposure to ethylbenzene on 

children. It is likely that children would show the same health effects as 

adults. We do not know whether children will have effects at the same 

exposure levels as adults. 

In immature animals, exposure to inhaled ethylbenzene produced small 

decreases in weight gain. 

Birth defects We do not know whether ethylbenzene causes birth defects in people. 

Minor birth defects and low birth weights have occurred in newborn animals 

whose mothers were exposed air contaminated with ethylbenzene. 

Exposure from 

breast milk 

We do not know whether ethylbenzene can accumulate in breast milk. 

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO ETHYLBENZENE?
 

Limit children’s 

exposure to 

consumer 

products 

containing 

ethylbenzene 

Use adequate ventilation to minimize exposure to ethylbenzene vapors from 

consumer products such as 

• gasoline 

• pesticides 

• varnishes and paints 

• newly installed carpeting 

• automotive products 

Sometimes older children sniff household chemicals in an attempt to get 

high. Your children may be exposed to ethylbenzene by inhaling products 

containing it, such as paints, varnishes, or gasoline. Talk with your children 

about the dangers of sniffing chemicals. 

Store household Always store household chemicals in their original labeled containers out of 

chemicals out of reach of young children to prevent accidental poisonings. Never store 

reach of young household chemicals in containers children would find attractive to eat or 

children drink from, such as old soda bottles. 

Gasoline should be stored in a gasoline can with a locked cap. 

Follow directions 

on label 

Always follow directions on household products (for example, use only with 

adequate ventilation.) 

Limit exposure to 

tobacco smoke 

Ethylbenzene is a component of tobacco smoke. Avoid smoking in 

enclosed spaces such as inside the home or car in order to limit exposure to 

children and other family members. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE	 6 

1. PUBLIC HEALTH STATEMENT 

1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO 

ETHYLBENZENE? 

Can be measured 

in blood and 

breath 

Ethylbenzene can be measured in blood and in the breath of people 

exposed to ethylbenzene. 

This should be done within a few hours after exposure occurs because 

these metabolites leave the body very quickly. 

Metabolites can 

be measured in 

urine 

The presence of ethylbenzene breakdown products (metabolites) in urine 

might indicate that you were exposed to ethylbenzene; however, these 

breakdown products can also form when you are exposed to other 

substances, such as styrene. 

The detection of these metabolites in your urine cannot be used to predict 

the kind of health effects that might develop from that exposure. 

You should have this test done within a few hours after exposure occurs 

because these metabolites leave the body very quickly. 

For more information on the different substances formed by ethylbenzene breakdown and on tests to 

detect these substances in the body, see Chapters 3 and 7. 

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH? 

The federal government develops regulations and recommendations to protect public health. Regulations 

can be enforced by law. The EPA, the Occupational Safety and Health Administration (OSHA), and the 

Food and Drug Administration (FDA) are some federal agencies that develop regulations for toxic 

substances. Recommendations provide valuable guidelines to protect public health, but cannot be 

enforced by law. The Agency for Toxic Substances and Disease Registry (ATSDR) and the National 

Institute for Occupational Safety and Health (NIOSH) are two federal organizations that develop 

recommendations for toxic substances. 

Regulations and recommendations can be expressed as “not-to-exceed” levels, that is, levels of a toxic 

substance in air, water, soil, or food that do not exceed a critical value that is usually based on levels that 

affect animals; they are then adjusted to levels that will help protect humans. Sometimes these not-toexceed levels differ among federal organizations because they used different exposure times (an 8-hour 

workday or a 24-hour day), different animal studies, or other factors. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 7 

1. PUBLIC HEALTH STATEMENT 

Recommendations and regulations are also updated periodically as more information becomes available. 

For the most current information, check with the federal agency or organization that provides it. 

Some regulations and recommendations for ethylbenzene include the following: 

Levels in drinking 

water set by EPA 

The EPA has determined that exposure to ethylbenzene in drinking water at 

concentrations of 30 ppm for one day or 3 ppm for 10 days is not expected 

to cause any harmful effects in a child. 

The EPA has determined that lifetime exposure to 0.7 ppm ethylbenzene is 

not expected to cause any harmful effects. 

Levels in surface 

water set by EPA 

If you eat fish and drink water from a body of water, the water should 

contain no more than 0.53 ppm ethylbenzene. 

Levels in 

workplace air set 

by OSHA 

OSHA set a legal limit of 100 ppm ethylbenzene in air averaged over an 

8-hour work day. 

For more information on regulations and advisories, see Chapter 8. 

1.10 WHERE CAN I GET MORE INFORMATION? 

If you have any more questions or concerns, please contact your community or state health or 

environmental quality department, or contact ATSDR at the address and phone number below. 

ATSDR can also tell you the location of occupational and environmental health clinics. These clinics 

specialize in recognizing, evaluating, and treating illnesses that result from exposure to hazardous 

substances. 

Toxicological profiles are also available on-line at www.atsdr.cdc.gov and on CD-ROM. You may 

request a copy of the ATSDR ToxProfilesTM CD-ROM by calling the toll-free information and technical 
 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 8 

1. PUBLIC HEALTH STATEMENT 

assistance number at 1-800-CDCINFO (1-800-232-4636), by e-mail at cdcinfo@cdc.gov, or by writing 

to: 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology and Environmental Medicine
 

1600 Clifton Road NE
 

Mailstop F-62
 

Atlanta, GA 30333
 

Fax: 1-770-488-4178
 

Organizations for-profit may request copies of final Toxicological Profiles from the following: 

National Technical Information Service (NTIS)
 

5285 Port Royal Road
 

Springfield, VA 22161
 

Phone: 1-800-553-6847 or 1-703-605-6000
 

Web site: http://www.ntis.gov/
 
 

 

 

 

 

 

 

ETHYLBENZENE 9 

2. RELEVANCE TO PUBLIC HEALTH
 

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO ETHYLBENZENE IN THE 

UNITED STATES 

Ethylbenzene is widely distributed in the environment. It is primarily used for the production of styrene, 

which is the monomeric unit for polystyrene materials. Ethylbenzene is also used as a solvent and in the 

manufacture of several organic compounds other than styrene; however, these uses are very minor in 

comparison to the amounts used for styrene production. The production volume of ethylbenzene is 

typically among the highest of all chemicals manufactured in the United States. In 2005, nearly 12 billion 

pounds of ethylbenzene were produced domestically, with historical levels ranging anywhere from 

approximately 7 to 13 billion pounds annually. Routine human activities, such as driving automobiles, 

boats, or aircraft, and using gasoline powered tools and equipment as well as paints, varnishes, and 

solvents release ethylbenzene to the environment. Environmental and background levels of ethylbenzene 

are generally small and therefore, have minimal impact on public health. Trace levels of ethylbenzene are 

found in internal combustion engine exhaust, food, soil, water, and tobacco smoke, but usually at levels 

well below those that have been shown to exhibit toxic effects in laboratory animals or human exposure 

studies. 

Ethylbenzene is not considered highly persistent in the environment. It partitions primarily to air and 

removal via photochemically generated hydroxyl radicals is an important degradation mechanism. The 

half-life for this reaction in the atmosphere is approximately 1–2 days. Biodegradation under aerobic 

conditions and indirect photolysis are important degradation mechanisms for ethylbenzene in soil and 

water. Based on a vapor pressure of 9.53 mm Hg and Henry’s law constant of 7.9x10-3 atm-m3

/mol, 

volatilization from water and soil surfaces is expected to be an important environmental fate process for 

ethylbenzene. If released to soil, ethylbenzene is expected to possess moderate mobility based on a soil 

adsorption coefficient (Koc) value of 240. 

Ethylbenzene is ubiquitous in ambient air, primarily as a result of automobile emissions. The median 

level of ethylbenzene in city and suburban air was reported as 2.7 μg/m3 (0.62 ppb). In contrast, the 

median level of ethylbenzene measured in rural locations was 0.056 μg/m3 (0.013 ppb). Ethylbenzene 

levels in indoor air tend to be higher than corresponding levels monitored in outdoor air, as a result of 

contributions from environmental tobacco smoke (ETS) and various consumer products, in addition to the 

permeation indoors of ethylbenzene from attached garages or outside air. One study analyzed the 

components of ETS for the 50 top-selling U.S. cigarette brand styles in 1991 and for the University of 
 

 

 

 

 

 

 

 

ETHYLBENZENE 10 

2. RELEVANCE TO PUBLIC HEALTH 

Kentucky Research cigarette, K1R4F. The ethylbenzene concentrations measured were 8.68 μg/m3 for 

full-flavor cigarettes, 8.24 μg/m3 for full-flavor, low-tar cigarettes, and 8.72 μg/m3 for ultra-low-tar 

cigarettes. The mean ethylbenzene concentration for all cigarettes was 8.50 μg/m3

. One study reported a 

maximum outdoor air concentration of 7.4 μg/m3 (1.7 ppb) for ethylbenzene at four residential locations, 

while indoor air concentrations at these same homes ranged from 5 to 110 μg/m3 (1–25.3 ppb). 

Ethylbenzene is also released to the air during processing of crude oil. 

Ethylbenzene is detected infrequently in surface water. Data from the EPA STOrage and REtrieval 

Database (STORET), indicated that ethylbenzene was detected in <3% of the surface water samples 

analyzed in the United States from January 2005 to March 2007, with a maximum concentration of 2 ppb. 

Ethylbenzene can also be present in groundwater, particularly near current or former landfills, hazardous 

sites, or gas stations. Oil- and gasoline-contaminated sites have also been found to have relatively high 

ethylbenzene concentrations in soil. 

Ethylbenzene was identified in 82 different food items at a maximum concentration of 0.129 ppm in data 

obtained from the FDA Total Diet Study Market Basket Surveys collected between September 1991 and 

October 2003. Trace concentrations of ethylbenzene have been reported in split peas (0.013 mg/kg 

[ppm]), lentils (0.005 mg/kg [ppm]), and beans (mean concentration 0.005 mg/kg [ppm]; maximum 

concentration 0.011 mg/kg [ppm]). 

The general population is primarily exposed to ethylbenzene from the inhalation of ambient air. This is 

due to the direct release of ethylbenzene into the air by the burning of fossil fuels or industrial processes, 

and partitioning into the air from other media (e.g., soil, surface water). This partitioning of ethylbenzene 

into the air or water would play a role in exposure to populations living near hazardous waste sites. In 

addition to inhalation exposure, ingestion of ethylbenzene may also occur because trace amounts have 

been found in water supplies and various food items. 

2.2 SUMMARY OF HEALTH EFFECTS 

In humans, eye irritation was observed after exposure to 10,000 ppm ethylbenzene for a few seconds. 

Volunteers reported irritation and chest constriction after acute-duration exposures to 2,000 ppm 

ethylbenzene. These symptoms worsened as the concentration was increased to 5,000 ppm. Human 

exposures in the range of 2,000–5,000 ppm ethylbenzene were associated with dizziness and vertigo. 

Complete recovery occurs if exposure is not prolonged. Momentary ocular irritation, a burning sensation, 
 

 

 

ETHYLBENZENE 11 

2. RELEVANCE TO PUBLIC HEALTH 

and profuse lacrimation were observed in humans exposed to 1,000 ppm ethylbenzene. Workers exposed 

occupationally to solvent mixtures that included ethylbenzene showed an increased incidence of hearing 

loss compared to unexposed individuals. Respiratory effects were not observed in two patients exposed 

to 55.3 ppm ethylbenzene for 15 minutes. An increase in the mean number of lymphocytes and a 

decrease in hemoglobin levels were observed during a 1-year period in workers exposed chronically to 

solvents including ethylbenzene. However, no adverse hematological effects were observed in workers 

exposed to ethylbenzene for 20 years. Although no information on ethylbenzene concentrations was 

reported, an estimated concentration of 6.4 mg/m3 was derived from a mean post-shift in urinary mandelic 

acid concentration in workers, based on the relationship between ethylbenzene concentrations in air and 

urinary mandelic acid concentration in a chamber-exposed group. No liver lesions or differences in liver 

function tests between exposed and nonexposed workers were observed and no cases of malignancy in 

workers were reported. However, given the low exposure concentration, this study had limited the power 

to detect any effect. No other studies in humans exposed to ethylbenzene were located. Given that little 

data in humans are available, it is assumed that adverse effects observed in animals are relevant to 

humans. 

Acute-duration and intermediate-duration studies in animals suggest that the auditory system is a sensitive 

target of ethylbenzene toxicity. Significant losses of outer hair cells (OHCs) in the organ of Corti have 

been observed in rats after acute-duration exposure ≥400 ppm and intermediate-duration inhalation 

exposure to ≥200 ppm ethylbenzene. These OHC losses have been observed up to 11 weeks after 

termination of the exposure, suggesting that these effects may be irreversible. Significant deterioration of 

auditory thresholds is also observed in animals affected with OHC losses. Auditory deficits have also 

been observed in animals after an intermediate-duration oral exposure to ethylbenzene. An almost 

complete loss of the three rows of outer hair cells in the organ of Corti was observed in rats 10 days after 

the last dose (900 mg/kg/day) in an acute-duration study. Effects on the central nervous system, such as 

moderate motor activation, narcotic effects, changes in posture and arousal, and salivation and prostration 

have been observed in animals after acute- and intermediate-duration exposure to ≥400 ppm

ethylbenzene. 

Results of 4- and 13-week studies indicate that intermediate-duration oral exposure to ethylbenzene 

produces effects to the liver. Effects indicative of liver toxicity observed included increased activity of 

serum liver enzymes (alanine aminotransferase and γ-glutamyl transferase) in males (≥250 mg/kg/day)

and females (750 mg/mg/day), increased absolute and relative liver weights (≥250 mg/kg/day in males 

and females), and a dose-related increase in the incidence of centrilobular hepatocyte hypertrophy 
 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 12 

2. RELEVANCE TO PUBLIC HEALTH 

(≥250 mg/kg/day in males and females). Increased bilirubin (≤250 mg/kg/day in males and 

750 mg/kg/day in females), total protein (750 mg/kg/day in females), albumin (750 mg/kg/day in males 

and females), globulins (750 mg/kg/day in females), and cholesterol (≤250 mg/kg/day in males and 

females), and decreased prothrombin time (750 mg/kg/day in males and ≥250 mg/kg/day in females) were

considered by study investigators as adaptive effects in the liver. In males in the 75 mg/k/day group, 

relative liver weight was significantly increased by 4% compared to controls; however, no 

histopathological changes, or increases in absolute liver or serum liver enzyme activities were observed at 

this dosage. Given that ethylbenzene is a microsomal enzyme inducer, and the absence of histopathology 

and other evidence of liver injury at the 75 mg/kg/day dosage, the small increase in relative liver weight 

in male rats was at this dosage not considered evidence for an adverse effect on the liver. Results of the 

4-week gavage study in rats were similar to those of the 13-week study, identifying no-observed-adverseeffect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) values of 250 and 

750 mg/kg/day, respectively, for liver effects. Observed effects consistent with hepatotoxicity included 

increased absolute and relative liver weights (≥250 mg/kg/day in males and 750 mg/kg/day in females),

increased incidence of hepatocyte centrilobular (≥250 mg/kg/day in males and 750 mg/kg/day in 

females), and increase serum liver enzyme activity (alanine aminotransferase) (750 mg/kg/day in males 

and females). Histopathological changes characterized by cloudy swelling of parenchymal cells of the 

liver and an increase in liver weight were observed in female rats administered 408 mg/kg/day by gavage 

for 6 months. No other hepatic changes were reported. No liver effects were observed in female rats 

administered 136 mg/kg/day. However, this study was poorly reported and did not provide adequate 

descriptions of study methods or results. 

Guinea pigs exposed to sublethal concentrations of ethylbenzene (≤10,000 ppm for <100 minutes)

showed “moderate” pulmonary edema and congestion. These findings had disappeared in animals after a 

4–8-day recovery period, suggesting that these pathological effects in the lung are reversible. A 50% 

respiratory depression was observed in mice exposed to ≥1,432 ppm for 5–30 minutes. Respiratory 

depression has not been reported in humans exposed to ethylbenzene. Nasal and eye irritation was 

evident in animals exposed to 1,000 ppm for ≥3 minutes. An NTP study did not observe weight or 

histopathological effects in the lungs of rats or mice exposed to 782 ppm or rabbits exposed to 1,610 ppm 

ethylbenzene for 4 weeks. Absolute and relative lung weight was increased in rats, but not mice, exposed 

to ≥250 ppm for 13 weeks; no treatment-related histopathological effects were observed. Another study 

did not report pulmonary injury in rats, guinea pigs, rabbits, or monkeys exposed to 600–2,200 ppm 

ethylbenzene for approximately 6 months; however, only two animals were used in some of the dose 

groups in rabbits and monkeys. In the NTP study, no treatment-related histopathological effects were 
 

 

 

 

 

 

 

 

ETHYLBENZENE 13 

2. RELEVANCE TO PUBLIC HEALTH 

noted in respiratory tissue in rats or female mice exposed to up to 750 ppm ethylbenzene for 2 years. 

Although an increase in alveolar epithelial hyperplasia was noted in male mice in the 750-ppm group the 

incidence fell within historical controls for the conducting laboratory. The available data on adverse 

respiratory effects associated with ethylbenzene exposure in animals and the limited data available in 

humans suggest that respiratory effects in humans could result following inhalation exposure to high 

concentrations of ethylbenzene. Respiratory effects from low-level exposure, such as that found in the 

outdoor air, appear to be less likely. 

Developmental effects have been reported in the offspring of pregnant animals exposed to ethylbenzene 

during gestation. The best reported studies available suggest that developmental effects are generally 

observed at concentrations of approximately ≥1,000 ppm. Significant increases in the incidence of fetal 

skeletal variations were observed in the offspring of pregnant rats exposed to 2,000 ppm and reductions in 

fetal body weight were observed in the offspring of pregnant rats exposed to ≥1,000 ppm ethylbenzene

during gestation. Maternal toxicity, manifested as reduced body weight gain, was also observed in rats 

exposed to ≥1,000 ppm. No developmental effects were observed at concentrations of ≤500 ppm. In 

contrast, an increased incidence of fetuses with extra ribs was observed in the offspring of rats exposed to 

100 ppm during gestation, but not when the animals were exposed to 100 ppm during pre-mating and 

gestation. No other significant increases in major malformations or minor anomalies were observed. 

Neurodevelopmental assessments conducted on F2 rat offspring indicated no effects in a functional 

observational battery assessment, fore- or hind-limb grip strength, swimming ability, motor activity, 

startle response, or learning and memory assessments at 500 ppm. 

The number of implantations or live fetuses per litter and the percentage of resorptions or non-live 

implants per litter were unaffected in pregnant rats exposed to 2,000 ppm ethylbenzene during gestation. 

In a two-generation study, estrous cycle length was significantly reduced in F0, but not F1, females 

exposed to 500 ppm or in rats or mice exposed to 975 ppm ethylbenzene for 90 days. Reproductive 

parameters were not affected in F0 or F1 males or females at 500 ppm ethylbenzene. Exposure of rats 

and rabbits to 100 or 1,000 ppm ethylbenzene for 3 weeks during prior to mating or gestation or both 

resulted in no conclusive evidence of reproductive effects in either species. Assessments of reproductive 

organs conducted following intermediate- and chronic-duration exposure to ethylbenzene have not 

observed histopathological changes in the testes of rats, mice, or rabbits exposed to concentrations as high 

as 2,400 ppm ethylbenzene for 4 days or in rats or mice exposed to 782 ppm ethylbenzene or rabbits 

exposed to 1,610 ppm for 4 weeks. No effect was observed on spermatid counts, sperm motility, weight 

of the caudal epididymis, or testicular morphology in rats or mice exposed to 975 ppm ethylbenzene for 
 

 

 

 

ETHYLBENZENE 14 

2. RELEVANCE TO PUBLIC HEALTH 

90 days. No adverse histopathological effects were seen in the testes of rats or guinea pigs exposed to 

concentrations up to 1,250 or 600 ppm, respectively, for 6–7 months. 

Other systemic effects have been observed in animals after acute-, intermediate-, and chronic-duration 

exposures to ethylbenzene. Eye irritation and lacrimation have been observed after acute-duration 

exposures in rats, mice, and guinea pigs exposed to ≥1,000 ppm ethylbenzene. Lacrimation was observed

in rats exposed to 382 ppm for 4 weeks. In contrast, no ocular effects were seen in rats or mice after a 

13-week exposure to 975 ppm ethylbenzene. Mild irritation, reddening, exfoliation, and blistering have 

been reported in rabbits when ethylbenzene was applied directly on the skin. Slight irritation of the eye 

and corneal injuries were observed in rabbits when ethylbenzene was instilled onto the eyes. 

One study examined the possible association between occupational exposure to ethylbenzene and 

increased cancer risk; no cases of malignancy were observed in workers exposed to ethylbenzene for 

20 years. Animal studies have found increased incidences of neoplasms in rats and mice following 

inhalation or oral exposure, which are considered relevant to humans. The inhalation studies conducted 

by NTP found clear evidence of carcinogenic activity in male rats based on increased incidences of renal 

tubule neoplasm's and testicular adenomas, some evidence of carcinogenic activity in female rats based 

on increased incidences of renal tubule adenomas, some evidence of carcinogenic activity in male mice 

based on increased incidences of alveolar/bronchiolar neoplasms, and some evidence of carcinogenic 

activity in female mice based on increased incidences of hepatocellular neoplasms. In a reevaluation of 

the histopathology of rat kidneys from the NTP study, another study confirmed the NTP findings and 

suggested that the increased incidence of kidney tumors in rats in the high-dose group was related to a 

chemical-induced exacerbation of chronic progressive nephropathy (CPN) with a minor contributing 

factor in male rats being α2μ-globulin nephropathy. The author suggests that since CPN is an age-related 

disease of rodents without a counterpart in humans, the kidney results of the NTP study are not relevant to 

humans for risk assessment purposes. However, in an analysis of the association between CPN and renal 

tubule cell neoplasms in male F344 rats, it was concluded that the association between CPN and renal 

tubule cell neoplasms is marginal. Results of this analysis suggest that the number of renal tubule cell 

neoplasms secondary to CPN would be few. An increase in the total number of malignant tumors was 

observed in rats orally exposed to ethylbenzene; however, data on specific tumor types were not provided. 

On the basis of the NTP study, IARC has classified ethylbenzene as a Group 2B carcinogen (possibly 

carcinogenic to humans). In the most recent carcinogenicity assessment by the EPA conducted in 1991, 

ethylbenzene was classified as Group D (not classifiable as to human carcinogenicity) due to the lack of 
 

 

 

 

 

 

 

 

ETHYLBENZENE 15 

2. RELEVANCE TO PUBLIC HEALTH 

animal bioassays and human studies; however, the EPA assessment predated the NTP study. Ethylbenzene is not included in the DHHS’s 11th Report on Carcinogens. 

Acute- and intermediate-duration studies provide strong evidence that ototoxicity is a sensitive effect 

following inhalation exposure to ethylbenzene. A more detailed discussion of this effect follows. The 

reader is referred to Section 3.2, Discussion of Health Effects by Route of Exposure, for additional 

information on other effects. 

A study of workers exposed occupationally to solvent mixtures that include ethylbenzene (mean exposure 

level 1.8 ppm) showed a 58% incidence of hearing loss compared to 36% in the reference (unexposed) 

group. The role of ethylbenzene in the observed losses cannot be ascertained from this study given that 

ethylbenzene was only one of several solvents, most of which were present at mean concentrations 1.5– 

3.5 times higher than ethylbenzene. Consistent with the outcome of occupational studies showing hearing 

loss, significant and persistent adverse auditory effects have been shown in animals after acute- and 

intermediate-duration inhalation exposures to ethylbenzene and after acute-duration oral exposures. 

OHCs in the organ of Corti (located in the cochlea) are a sensitive target of toxicity of ethylbenzene. 

Significant losses of OHCs in the organ or Corti were observed in male rats after acute-duration 

inhalation exposure to ≥400 ppm and intermediate-duration inhalation exposure to ≥200 ppm ethylbenzene. These losses in OHC were observed 8–11 weeks after the last exposures. Inhalation of 

≥400 ppm ethylbenzene for 5 days or 4 weeks also resulted in a significant deterioration of auditory 

thresholds. The magnitude of the shifts in auditory thresholds observed after the first 4 weeks of exposure 

did not change during a 13-week exposure period or after an 8-week post-exposure recovery period. 

Inner hair cells were affected by ethylbenzene only at ≥600 ppm in the intermediate-duration study. 

Guinea pigs exposed to ethylbenzene at 2,500 ppm for 5 days did not show auditory deficits or losses in 

outer hair cells, whereas significant deficits and hair cell loss were observed in rats exposed to ethylbenzene at 550 ppm. An almost complete loss of OHC was reported in male rats 10 days after an acuteduration oral exposure to ethylbenzene. The mechanisms of the species differences between rats and 

guinea pigs are not understood. However, given the observations of hearing loss in workers exposed to 

1.8 ppm ethylbenzene, the rat appears to be an appropriate animal model. 

2.3 MINIMAL RISK LEVELS (MRLs) 

Estimates of exposure levels posing minimal risk to humans (MRLs) have been made for ethylbenzene. 

An MRL is defined as an estimate of daily human exposure to a substance that is likely to be without an 
 

 

 

 

 

ETHYLBENZENE 16 

2. RELEVANCE TO PUBLIC HEALTH 

appreciable risk of adverse effects (noncarcinogenic) over a specified duration of exposure. MRLs are 

derived when reliable and sufficient data exist to identify the target organ(s) of effect or the most sensitive 

health effect(s) for a specific duration within a given route of exposure. MRLs are based on 

noncancerous health effects only and do not consider carcinogenic effects. MRLs can be derived for 

acute, intermediate, and chronic duration exposures for inhalation and oral routes. Appropriate 

methodology does not exist to develop MRLs for dermal exposure. 

Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA 1990a), 

uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional 

uncertainties inherent in the application of the procedures to derive less than lifetime MRLs. As an 

example, acute inhalation MRLs may not be protective for health effects that are delayed in development 

or are acquired following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic 

bronchitis. As these kinds of health effects data become available and methods to assess levels of 

significant human exposure improve, these MRLs will be revised. 

Inhalation MRLs 

•	 An MRL of 5 ppm has been derived for acute-duration inhalation exposure (14 days or less) to 

ethylbenzene. 

There is limited information on the acute toxicity of ethylbenzene in humans. Acute exposures to 

≥1,000 ppm resulted in ocular irritation, a burning sensation, and profuse lacrimation (Cometto-Muniz 

and Cain 1995; Thienes and Haley 1972; Yant et al. 1930). Volunteers exposed to 2,000 ppm reported 

irritation and chest constriction with worsening symptoms when the concentration was increased to 

5,000 ppm (Yant et al. 1930). Studies in laboratory animals identify ototoxicity as the most sensitive end 

point for acute-duration inhalation exposure to ethylbenzene. Damage to the outer hair cells (OHCs) of 

the organ of Corti and, in some cases, significant reductions in auditory thresholds were observed in rats 

exposed to ≥400 ppm ethylbenzene by inhalation for 5 days (Cappaert et al. 1999, 2000, 2001, 2002).

Loss of OHCs appeared to be concentration-related as losses were 52–66% in animals exposed to 

800 ppm ethylbenzene (Cappaert et al. 1999), 40–75% at 550 ppm, and approximately 25% at 400 ppm 

(Cappaert et al. 2000, 2001). OHC losses in rats exposed to 300 ppm were small (12%) and not 

statistically significant (Cappaert et al. 2000). Auditory thresholds in rats exposed to ethylbenzene at 

≥400 ppm were significantly affected in the mid-frequency region; however, an increasingly broader 

range of frequencies was affected with increasing concentrations of ethylbenzene (Cappaert et al. 1999, 

2000). Auditory assessments indicate that effects were evident shortly after exposure and persisted for up 
 

 

 

 

ETHYLBENZENE 17 

2. RELEVANCE TO PUBLIC HEALTH 

to 11 weeks (termination of the observation period) (Cappaert et al. 1999, 2000, 2001, 2002), suggesting 

that the auditory effects might be irreversible. Cappaert et al. (2002) demonstrated a significant species 

difference in the susceptibility of rats and guinea pigs to the ototoxic effects of ethylbenzene, with guinea 

pigs showing no auditory deficits or losses in OHCs at 2,500 ppm ethylbenzene after 5 days (Cappaert et 

al. 2002). 

Neurological effects were observed after acute-duration exposure to ethylbenzene at concentrations equal 

to or higher than those that elicited auditory effects in animals. Effects observed after acute-duration 

exposure to ethylbenzene include moderate activation of motor behavior in rats exposed to 400 ppm 

(Molnar et al. 1986) and reduced activity and prostration and shallow breathing in rats and mice at 

1,200 ppm (Ethylbenzene Producers Association 1986a). Rats or mice exposed to ≥2,000 ppm showed 

posture changes, reduced grip strength, reduced motor coordination (Tegeris and Balster 1994), narcotic 

effects (Molnar et al. 1986), and neurotransmission disturbances in the forebrain and hypothalamus 

(Andersson et al. 1981). Mice exposed to 4,060 ppm for 20 minutes showed a 50% reduction in 

respiratory rate (Nielsen and Alarie 1982). A 50% respiratory depression observed in mice at 1,432 ppm 

was attributed to sensory irritation (De Ceaurriz et al. 1981). 

Increased liver weight was reported after acute-duration exposure in rats exposed to ≥400 ppm

ethylbenzene (Ethylbenzene Producers Association 1986a; Toftgard and Nilsen 1982), but not in mice at 

1,200 ppm or rabbits at 2,400 ppm (Ethylbenzene Producers Association 1986a). At these same levels 

and exposure durations, induction of microsomal enzymes and related ultrastructural changes (e.g., 

proliferation of the smooth endoplasmic reticulum) were observed. These effects occurred in the absence 

of histopathological changes to the liver. Therefore, the effects on the liver appear to be related to 

induction of microsomal enzymes in smooth endoplasmic reticulum. An increase in relative kidney 

weight was also observed in rats exposed to ≥1,200 ppm (Ethylbenzene Producers Association 1986a;

Toftgard and Nilsen 1982), but not in mice at 1,200 ppm or rabbits at 2,400 ppm (Ethylbenzene Producers 

Association 1986a). However, increased kidney weights occurred in the absence of histological changes 

(Ethylbenzene Producers Association 1986a). No histopathological alterations were observed in the lungs 

of surviving rats, mice, or rabbits exposed to 1,200, 400, or 2,400 ppm ethylbenzene, respectively, for 

4 days (Ethylbenzene Producers Association 1986a). 

The observed damage to the auditory capacity of rats exposed to ethylbenzene during acute-duration 

studies reported in Cappaert et al. study (2000) was chosen as a critical effect to derive the acute-duration 

inhalation MRL. In the study by Cappaert et al. (2000), Wag/Rij rats (8 rats/group; sex not provided) 
 

 

 

ETHYLBENZENE 18 

2. RELEVANCE TO PUBLIC HEALTH 

were exposed to 0, 300, 400, or 550 ppm ethylbenzene (99% pure) 8 hours/day for 5 days. Potential 

auditory effects were examined by measuring distortion product otoacoustic emissions (DPOAE), 

compound action potential (CAP), and hair cell counts at five locations of the organ of Corti 3–6 weeks 

after the last ethylbenzene exposure. Exposed animals did not show clinical signs of intoxication and 

there were no significant differences in terminal body weight between exposed and control rats. DPOAE 

amplitude growth curves showed a significant reduction in rats exposed to 550 ppm, but not to 300 or 

400 ppm ethylbenzene. Effects were significant at 5.6, 8, and 11.3 kHz, but not at other frequencies. The 

DPOAE thresholds were significantly shifted (increased stimulus was needed to elicit the threshold 

response) at 5.6, 8, 11.3, and 16 kHz in rats in the 550-ppm group. DPOAE threshold shifts were not 

observed in other exposure groups. Animals exposed to 550 ppm showed a significant shift in the CAP 

amplitude growth curves at 8, 12, and 16 kHz. In the 400-ppm group, the CAP growth curves were 

affected only at 12 kHz and there was no effect in animals in the 300-ppm group. CAP thresholds were 

significantly shifted at 8, 12, and 16 kHz in the 550-ppm group and at 12 and 16 kHz in the 400-ppm 

group. There was no significant deterioration of CAP thresholds in the 300-ppm group. Significant OHC 

losses of approximately 33 and 75% were observed in the 550-ppm group in the auditory regions 

corresponding to 11 and 21 kHz, respectively. In the 400-ppm group, significant losses (25%) were 

observed in the 11 kHz region. OHC losses in the 21 kHz region in the 300-ppm group were 

approximately 12%, but were not statistically significantly different from controls. This study identifies a 

NOAEL of 300 ppm and a LOAEL of 400 ppm for significant deterioration in CAP auditory thresholds 

and significant OHC losses. 

The point of departure for an acute-duration inhalation MRL was identified using benchmark dose (BMD) 

analysis of the CAP auditory threshold data using data from this study provided by Dr. Cappaert to 

ATSDR. The largest effects on CAP threshold occurred in response to 8, 12, and 16 kHz stimuli and, on 

this basis, these data were selected for BMD modeling. The BMD modeling was run using an internal 

dose metric (time-averaged arterial blood concentration of ethylbenzene, MCA), which was simulated 

using a physiologically-based pharmacokinetic (PBPK) model. Using MCA as the dose metric, the CAP 

threshold shift data were fit to all available continuous models in EPA’s Benchmark Dose Software 

(BMDS, version 2.1.1) using a benchmark dose response (BMR) of 1 standard deviation. Details of the 

BMD modeling and PBPK models are present in detail in Appendix A. At the 8 kHz frequency, the Hill, 

polynomial (2- and 3-degree), and power models provided adequate fit to the data. Of these models, the 

polynomial (3-degree) model provided the best fit to the data. At 12 and 16 kHz frequencies, only the 

Hill model provided an adequate fit to the data. The 95% lower confidence limit on the benchmark 

concentration (BMDLMCA) for these three models are presented in Table 2-1. 
 

 

 

 

ETHYLBENZENE 19 

2. RELEVANCE TO PUBLIC HEALTH 

Table 2-1. Human Equivalent Concentrations (HECs) for CAP Threshold Shifts 

Effect Model BMCLMCA (μmol/L) HECa (ppm) 

CAP threshold shift at 8 kHz Polynomial (3-degree) 102.63 178.52 

CAP threshold shift at 12 kHz Hill 89.47 163.80 

CAP threshold shift at 16 kHz Hill 81.10 154.26 

a

Calculated using a reference human body weight of 70 kg and the assumption of 14-day continuous exposure. 

BMCLMCA = 95% lower confidence limit on the benchmark concentration associated with a benchmark response of 

1 standard deviation estimated using an MCA (time-weighted arterial blood concentration of ethylbenzene) dose 

metric; CAP = compound action potential 
 

 

 

 

 

ETHYLBENZENE 20 

2. RELEVANCE TO PUBLIC HEALTH 

To select the point of departure for the acute-duration inhalation MRL, human equivalent concentrations 

(HECs) were predicted from the BMCLMCA values in Table 2-1 for CAP threshold data at 8, 12, and 

16 kHz using the human PBPK model (estimation of the HEC values is described in Appendix A). The 

lowest HEC of 154.26 ppm was selected as the point of departure. This HEC was divided by an 

uncertainty factor of 30 (3 for extrapolation from animals to humans with dosimetric adjustments and 10 

for human variability) resulting in an acute-duration inhalation MRL of 5 ppm. 

•	 An MRL of 2 ppm has been derived for intermediate-duration inhalation exposure (15–364 days) 

to ethylbenzene. 

Several studies in animals, but no studies in humans, have examined the toxicity of ethylbenzene 

following intermediate-duration inhalation exposure. The available animal studies suggest that 

ototoxicity is the most sensitive end point of ethylbenzene toxicity. Rats exposed to ≥400 ppm

ethylbenzene via inhalation for 4 or 13 weeks showed significant increases in auditory thresholds. These 

threshold shifts persisted unchanged for the duration of the exposure period and during an 8-week postexposure recovery period (Gagnaire et al. 2007). Cell counts conducted in the organ of Corti after the 

8-week recovery period showed significant losses of outer hair cells in rats exposed to ≥200 ppm.

Concentration-related losses of inner hair cells (IHC) (14 and 32%) were observed in animals in the 

600 and 800 ppm groups, respectively, with occasional IHC losses in the 400 ppm group. 

Systemic effects have been observed at concentrations equal to or higher than those that elicited ototoxic 

effects in rats. Increased liver, kidney, lung, and spleen weights have been observed in animals exposed 

to ethylbenzene concentrations in the 250–1,000 ppm range (Cragg et al. 1989; Elovaara et al. 1985; 

NIOSH 1981; NTP 1992; Wolf et al. 1956). However, the changes in organ weight have not been 

associated with histological alterations. One study (Cragg et al. 1989) reported a small, but statistically 

significant, increase in platelet counts in male rats and leukocyte counts in female rats exposed to 

782 ppm ethylbenzene for 4 weeks. Developmental effects have been observed in rats exposed to 

≥1,000 ppm. Increases in the occurrence of skeletal malformations (NIOSH 1981; Saillenfait et al. 2003) 

and decreases in fetal body weight (Saillenfait et al. 2003, 2006, 2007) have been observed at 

≥1,000 ppm. The NOAEL for these effects is 500 ppm (NIOSH 1981; Saillenfait et al. 2003, 2006, 

2007). Developmental landmarks and neurodevelopment were not statistically or biologically 

significantly affected in the offspring of rats exposed to up to 500 ppm ethylbenzene in a two-generation 

reproductive toxicity study (Faber et al. 2006, 2007). 
 

 

 

ETHYLBENZENE 21 

2. RELEVANCE TO PUBLIC HEALTH 

Thus, the available intermediate-duration inhalation studies suggest that ototoxicity is the most sensitive 

effect of ethylbenzene. Ototoxicity observed in the study by Gagnaire et al. (2007) was selected as the 

critical effect to derive the intermediate-duration inhalation MRL. In the Gagnaire et al. (2007) study, 

male Sprague-Dawley rats (14 rats/exposure group) were exposed to 0, 200, 400, 600, and 800 ppm 

ethylbenzene (99% pure) 6 hours/day, 6 days/week for 13 weeks. Ototoxicity was assessed based on 

effects on neurophysiological measurements after 4, 8, or 13 weeks of exposure and after a 8-week 

recovery period and cochlear total hair cell counts were measured at the end of the 8-week recovery 

period. There were no significant differences in body weight gain between the surviving treated animals 

and controls. Audiometric thresholds at 2, 4, 8, and 16 kHz were significantly higher in animals exposed 

to 400, 600, and 800 ppm ethylbenzene than in controls. The effect was evident at week 4, did not change 

throughout the exposure period, and was not reversed after 8 weeks of recovery. No shift in audiometric 

thresholds was observed in rats in the 200 ppm group; however, the morphological assessment of the 

organ of Corti showed significant losses (up to 30% of the outer hair cells in the mid frequency region) in 

the third row of the OHC in four of eight rats exposed to 200 ppm. A concentration-related loss in third 

row OHC (OHC3) was evident with almost complete loss observed in the 600 and 800 ppm groups. The 

data suggest that the extent of the damage at each concentration was greatest in the OHC3 followed, in 

decreasing order, by damage in OHC2, OHC1, and IHC. There was no significant hair cell loss in the 

control animals. 

Auditory threshold shifts and OHC loss are selected as the critical effects following intermediate-duration 

inhalation exposure to ethylbenzene. BMD analysis was conducted for these end points using a data set 

provided to ATSDR by Dr. Gagnaire. The data for auditory thresholds at 4, 8, and 16 kHz in rats exposed 

for 4 or 13 weeks and OHC loss at the end of the recovery period were fit to all available continuous 

models in EPA’s BMDS (version 2.1.1) using a time-averaged arterial blood concentration of 

ethylbenzene (MCA) as the dose metric and a BMR of 1 standard deviation change from control. The 

BMD modeling and the PBPK model used to estimate the MCA dose metric are described in 

Appendix A. 

Most of the available BMD models did not adequately fit the auditory threshold data; however, with the 

exception of the auditory thresholds at 16 kHz in rats exposed to ethylbenzene for 13 weeks, one BMD 

model fit each data set often when the highest two dose groups were dropped. The BMCLMCA values 

estimated from these models are presented in Table 2-2. None of the BMD models adequately fit the 

OHC loss data. HECs corresponding to specific BMCLMCA values were simulated using a human PBPK 

model (described in Appendix A). The HECs of the BMCLMCA values (Table 2-2) ranged from 63.64 to 
 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 22 

2. RELEVANCE TO PUBLIC HEALTH 

Table 2-2. Human Equivalent Concentrations (HECs) for Auditory Effects in 

Sprague-Dawley Rats Exposed to Ethylbenzene 6 Hours/Day,
 

6 Days/Week for 4 or 13 Weeks
 

Effect Model BMCLMCA μmol/L) HECa (ppm) 

Auditory thresholds at 4 kHz 

following 4 weeks of exposure 

Auditory thresholds at 8 kHz 

following 4 weeks of exposure 

Auditory thresholds at 16 kHz 

following 4 weeks of exposure 

Auditory thresholds at 4 kHz 

following 13 weeks of exposure 

Auditory thresholds at 8 kHz 

following 13 weeks of exposure 

Power (two highest doses dropped); 33.12 87.13 

nonconstant variance 

2-Degree polynomial (two highest 19.94 63.64 

doses dropped); nonconstant 

variance 

Power (two highest doses dropped); 27.31 77.77 

nonconstant variance 

Hill (all doses); nonconstant variance 28.59 79.95 

Power (two highest doses dropped); 29.71 81.79 

nonconstant variance 

a

Calculated using a reference human body weight of 70 kg and the assumption of 364-day continuous exposure. 

BMCLMCA = 95% lower confidence limit on the benchmark concentration associated with a benchmark response of 

1 standard deviation estimated using an MCA (time-weighted arterial blood concentration of ethylbenzene) dose 

metric 
 

 

 

 

 

 

 

 

 

ETHYLBENZENE 23 

2. RELEVANCE TO PUBLIC HEALTH 

87.13 ppm; the lowest HEC of 63.64 ppm was selected as the point of departure for the MRL. This HEC 

was divided by an uncertainty factor of 30 (3 for extrapolation from animals to humans with dosimetric 

adjustments and 10 for human variability) resulting in an intermediate-duration inhalation MRL of 2 ppm. 

•	 An MRL of 0.06 ppm has been derived for chronic-duration inhalation exposure (365 days or 

more) to ethylbenzene. 

The chronic toxicity of inhaled ethylbenzene has been examined humans and in 2-year bioassays in rats 

and mice (NTP 1999). Hematological effects (increased average number of lymphocytes and decreased 

hemoglobin) were observed in workers exposed to solvents containing ethylbenzene (Angerer and Wulf 

1985). In rats, concentration-related increases in the severity of nephropathy were observed in female rats 

exposed to ≥75 ppm and in male rats exposed to 750 ppm (NTP 1999). Increases in the incidence of renal 

tubule hyperplasia were also observed in male and female rats exposed to 750 ppm. The lowest LOAEL 

identified in mice was 250 ppm for hyperplasia of pituitary gland pars distalis observed in females; at 

750 ppm, thyroid follicular cell hyperplasia was observed in male and female mice and hypertrophy and 

necrosis of the liver were observed in male mice (NTP 1999). These studies identify the kidney as a 

sensitive target following chronic-duration inhalation exposure to ethylbenzene and the NTP (1999) rat 

study was selected as the basis of the MRL. 

In the NTP (1999) study, groups of male and female F344/N rats (50 animals/sex/dose group) were 

exposed to 0, 75, 250, or 750 ppm ethylbenzene by inhalation 6 hours/day, 5 days/week, for 104 weeks. 

Animals were observed twice daily and clinical findings were recorded monthly. Body weights were 

measured throughout the study and a complete necropsy and microscopic examination of major tissues 

and organs were performed on all rats. Survival of male rats in the 750 ppm group was significantly less 

than that of the chamber controls. No clinical findings were attributed to ethylbenzene exposure. 

Although the incidence of nephropathy (47/50, 43/50, 47/50, and 48/50 in males and 38/50, 42/50, 43/50, 

46/49 in females) was not significantly different between the groups, significant increases in the severity 

of the nephropathy were observed in females at ≥75 ppm and in males at 750 ppm. The nephropathy

severity scores in the 0, 75, 250, and 750 ppm groups were 2.3, 2.4, 2.3, and 3.5 in males, respectively, 

and 1.3, 1.6, 1.7, and 2.3 in females, respectively. Additionally, a significant increase in the incidence of 

renal tubule hyperplasia was observed in male rats exposed to 750 ppm. The incidences of renal tubule 

adenoma and adenoma or carcinoma (combined) in the 750-ppm group were significantly greater than the 

incidence in control animals. An increase in the incidence of cystic degeneration of the liver was also 

observed in male rats at 750 ppm. 
 

 

 

 

 

 

 

 

 

ETHYLBENZENE 24 

2. RELEVANCE TO PUBLIC HEALTH 

Increased severity of chronic progressive nephropathy observed in female rats exposed to ≥75 ppm (NTP

1999) was selected as the critical effect for the MRL. BMD analysis was considered for determining the 

point of departure for the MRL; however, none of the available continuous exposure BMD models fit the 

data (standard errors calculated using the raw severity score data). Thus, a NOAEL/LOAEL approach 

was selected for calculating the point of departure; application of BMD analysis was precluded because 

standard errors or standard deviations were not provided for the nephropathy severity ratings. A PBPK 

model was developed (see Appendix A for details) to simulate two internal dose metrics for kidney 

effects: time-averaged arterial blood concentration of ethylbenzene (MCA) and time-averaged rate of 

metabolism of ethylbenzene expressed per kg body mass (MRAMKB). Both metrics were explored 

because current knowledge of the mechanisms of toxicity of ethylbenzene does not include an 

understanding of the relative contribution of parent compound or metabolites as proximate toxic agents in 

kidney. The internal dose metrics (MCA and MRAMKB) for each exposure level are presented in 

Table 2-3. 

Human equivalent concentrations (HECs) corresponding to LOAELMCA and LOAELMRAMKB in female rats 

was estimated using a human PBPK model (described in Appendix A). The HECs were 17.45 ppm for 

the MCA dose metric and 52.68 ppm for the MRAMKB dose metric. Because there is limited 

information to determine whether the observed renal toxicity in female rats exposed to ethylbenzene is 

due to ethylbenzene or its metabolites, the lowest HEC value (17.45 ppm) was selected as the point of 

departure for the MRL. The HECMCA of 17.45 ppm was divided by an uncertainty factor of 300 (10 for 

the use of a LOAEL, 3 for extrapolation from animals to humans with dosimetric adjustments, and 10 for 

human variability) resulting in a chronic-duration inhalation MRL of 0.06 ppm. 

Oral MRLs 

No studies describing acute-duration oral exposure of humans to ethylbenzene were found in the 

literature. Two animal studies have examined the acute oral toxicity of ethylbenzene. An almost 

complete loss of the three rows of OHCs in the organ of Corti were reported in male rats administered 

900 mg/kg/day (the only dose tested) by gavage for 2 weeks (Gagnaire and Langlais 2005). These losses 

were observed 10 days after the last dose. Although losses of OHCs have also been observed in acuteduration inhalation studies (Cappaert et al. 1999, 2000, 2001, 2002), Gagnaire and Langlais (2005) did 

not have a control group to establish the magnitude of the effects relative to unexposed animals; the study 

was used to rank the ototoxicity of 21 solvents administered by gavage. Nevertheless, the OHC losses 

observed in the ethylbenzene-treated animals were among the highest observed among the 21 organic 
 

ETHYLBENZENE 25 

2. RELEVANCE TO PUBLIC HEALTH 

Table 2-3. Internal Dose Metrics for Male and Female F344/N Rats Exposed to 

Ethylbenzene 6 Hours/Day, 5 Days/Week for 104 Weeks
 

Arterial ethylbenzene 

Exposure level (ppm) concentration (MCA, μmol/L) MRAMKB (μmol/hour/kg body weight) 

Malea 

0 0 0 

75 4.12 8.92 

250 27.66 23.64 

750 146.77 43.05 

Femaleb 

0 0 0 

75 4.16 10.00 

250 28.72 26.04 

750 150.68 46.49 

a

Time weighted average body weight of 0.43 kg. b

Time weighted average body weight of 0.27 kg. 

MCA = time-averaged arterial blood concentration; MRAMKB = time averaged rate of ethylbenzene metabolism 

expressed per kg body mass 
 

 

ETHYLBENZENE 26 

2. RELEVANCE TO PUBLIC HEALTH 

solvents tested (Gagnaire and Langlais 2005). The 900 mg/kg/day dose was considered a serious LOAEL 

for ototoxicity. In the second study, doses of 500 or 1,000 mg/kg ethylbenzene decreased luteinizing 

hormone, progesterone, and 17 β-estradiol levels, increased stromal tissue with dense collagen bundles 

and reduced lumen in the uterus, and delayed the estrus cycle in female rats during the diestrus stage 

(Ungvary 1986). Interpretation of the results of this study is limited by the poor reporting of the study 

methods and results and the lack of statistical analysis. Because the only dose tested in the Gagnaire and 

Langlais (2005) study is a serious LOAEL, an acute-duration oral MRL cannot be derived for 

ethylbenzene. 

•	 An MRL of 0.4 mg/kg/day has been derived for intermediate-duration oral exposure (15–
 

364 days) to ethylbenzene.
 

The intermediate-duration oral database for ethylbenzene is limited to a study conducted by Mellert et al. 

(2007) evaluating the effects of oral exposure of rats to ethylbenzene for 4 and 13 weeks, and a poorly 

reported 6-month exposure study in rats (Wolf et al. 1956). The 4- and 13-week studies by Mellert et al. 

(2007) found effects consistent with hepatotoxicity including increased absolute and relative liver 

weights, increased incidence of hepatocyte centrilobular hypertrophy, and increased serum liver enzyme 

activities in rats administered ≥250 mg/kg/day. Kidney effects, including increases in increases in

relative kidney weight and hyaline droplet nephropathy were observed in males administered 

≥250 mg/kg/day; however, these effects were most likely secondary to increases of α2μ-globulin 

accumulation, and, therefore, considered not relevant to humans. Wolf et al. (1956) also reported liver 

effects (characterized by cloudy swelling of parenchymal cells of the liver and an increase in liver weight) 

in female rats administered 408 mg/kg/day by gavage for 6 months. No other hepatic changes were 

reported. However, this study was poorly reported and did not provide adequate descriptions of study 

methods or results. 

Based on evidence of hepatotoxicity (increased serum liver enzyme activity, absolute and relative liver 

weights, dose-related increased incidence of centrilobular hepatocyte hypertrophy), and the lack of 

evidence for adverse effects in other tissues or organ systems at lower oral intermediate-duration dosages, 

liver effects were selected as the basis for deriving the intermediate oral MRL. The principal study 

(Mellert et al. 2007) identified NOAEL and LOAEL values for hepatotoxicity of 75 and 250 mg/kg/day, 

respectively, in rats administered ethylbenzene for 13 weeks. In this study (Mellert et al. 2007), groups of 

10 male and 10 female Wister rats were administered ethylbenzene (no vehicle) by gavage at doses of 0, 

75, 250, or 750 mg/kg/day for 13 weeks. The total daily dose of ethylbenzene was administered as split 

morning/evening half doses. Animals were examined daily for mortality and clinical signs and food and 
 

 

 

 

 

 

 

ETHYLBENZENE 27 

2. RELEVANCE TO PUBLIC HEALTH 

water consumption and body weights were recorded weekly. A detailed clinical examination 

(ophthalmology and a functional observational battery [FOB]) and assessment of motor activity were 

conducted during the last week of treatment. After 13 weeks, urinalysis was conducted and blood 

samples were obtained and analyzed for hematology and clinical chemistry; organ weights were recorded 

and gross histopathologic examinations of the liver, kidney, and pancreas were conducted on animals in 

all groups. A comprehensive histopathological examination of tissues was performed in the control and 

750 mg/kg/day groups. No mortalities were observed during the course of the study. Clinical signs (postdosing salivation) in treated animals were observed in all animals administered ≥250 mg/kg/day and in 

one animal administered 75 mg/kg/day. Terminal body weight in males was significantly decreased by 

14% compared to controls in the 750 mg/kg/day group. Mean corpuscular volume was increased in males 

and females and platelet count was reduced in females treated with 750 mg/kg/day. Prothrombin time 

was significantly decreased (<8% compared to controls) in females administered ≥250 mg/kg/kg, but no 

changes in prothrombin times were observed in males in any treatment group. Effects indicative of liver 

toxicity (summarized in Table 2-4) included increased activity of serum liver enzymes (alanine 

aminotransferase and γ-glutamyl transferase), increased absolute and relative liver weights, and a doserelated increase in the incidence of centrilobular hepatocyte hypertrophy. Although some alterations in 

other serum chemistry parameters were found, the study investigators considered them to be due to 

adaptive effects in the liver. 

Renal effects in males included increased serum creatinine (750 mg/kg/day), increased incidences of 

transitional epithelial cells and granular and epithelial cell casts in the urine (≥250 mg/kg/day), increased 

absolute and relative kidney weights (≥250 mg/kg/day), and a dose-related increase in severity of hyaline 

droplet nephropathy (≥250 mg/kg/day). Adverse renal effects in males were most likely related to

accumulation of α2μ-globulin accumulation, and, therefore, considered not relevant to humans. Absolute 

kidney weight was significantly increased by 7 and 13% in females administered 250 and 750 mg/kg/day, 

respectively, compared to controls. However, since no histopathological findings or alterations in 

urinalysis parameters were observed, increased kidney weight in females was not considered adverse. 

Absolute and relative thymus weights were decreased in females treated with ≥250 mg/kg/day, but no 

histopathological findings were observed. Histopathological examination of all other tissues did not 

reveal any abnormalities. Results of the FOB did not reveal consistent treatment-related effects. NOAEL 

and LOAEL values of 250 and 750 mg/kg/day, respectively, were identified based on hepatotoxicity in 

male and female rats. 
 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 28 

2. RELEVANCE TO PUBLIC HEALTH 

Table 2-4. Effects on Serum Liver Enzymes, Liver Weights, and Liver
 

Histopathology in Male and Female Rats Exposed to Oral
 

Ethylbenzene for 13 Weeks
 

Dose group (mg/kg/day) 

Parameter 0 75 250 750 

Males 

ALT(μkat/L) 0.62±0.12a 0.70±0.12 0.89±0.26b 1.11±0.23b 

GGT (nkat/L) 2±3 6±6 10±6b 10±6b 

Absolute liver weight (g) 8.02±0.55 8.26±0.81 10.25±0.98b 9.88±0.98b 

Liver/body weight (%) 2.26±0.08 2.36±0.08b 3.01±0.14b 3.31±0.13b 

Centrilobular hepatocyte 1/10 1/10 6/10c 8/10b 

hypertrophy (incidence) 

Females 

ALT(μkat/L) 0.58±0.18 0.55±0.08 0.60±0.12 0.73±0.19c 

Absolute liver weight (g) 5.40±0.30 5.72±0.53 6.11±0.36b 7.15±0.50b 

Liver/body weight (%) 2.63±0.13 2.70±0.16 3.03±0.12b 3.52±0.18b 

Centrilobular hepatocyte 0/10 0/10 5/10c 10/10b 

hypertrophy (incidence) 

a

values are mean±standard deviation.
 b

p≤0.01.
 c

p≤0.05.
 

ALT = alanine aminotransferase; GGT = γ-glutamyl transferase 

Source: Mellert et al. 2007 
 

 

 

 

 

 

 

ETHYLBENZENE 29 

2. RELEVANCE TO PUBLIC HEALTH 

Based on evidence of hepatotoxicity (increased serum liver enzyme activity, absolute and relative liver 

weights, and incidence of centrilobular hepatocyte hypertrophy), the liver was identified as the most 

sensitive target for oral ethylbenzene, with NOAEL and LOAEL values of 75 and 250 mg/kg/day, 

respectively. Since serum liver enzyme activities were increased in the 250 and 750 mg/kg/day groups in 

males, but only in the 750 mg/kg/day group in females, males appeared more sensitive than females to 

hepatic effects of oral ethylbenzene. 

To determine the point of departure for derivation of the intermediate-duration MRL, data sets for serum 

liver enzymes (alanine aminotransferase and γ-glutamyl transferase), absolute liver weight, relative liver 

weight, and centrilobular hepatocyte hypertrophy in male rats were evaluated for suitability for BMD 

modeling using EPA’s BMDS (version 2.1.1). A PBPK model was developed to simulate two internal 

dose metrics for liver effects: time-averaged concentration of ethylbenzene in liver (MCL) and timeaveraged rate of metabolism of ethylbenzene in liver (MRAMKL). The assumption of using the MCL 

metric is that the liver response is correlated with the time-averaged concentration of ethylbenzene in 

liver. The assumption in using the MRAMKL metric is that the liver response is correlated with the timeaveraged rate of production of ethylbenzene metabolites in liver. Both metrics were explored because 

current knowledge of the mechanism of toxicity of ethylbenzene does not include an understanding of the 

relative contributions of parent compound or metabolites as proximate toxic agents in liver. Detailed 

discussions of the BMD modeling and PBPK model are presented in Appendix A. 

Using the MCL and MRAMKL dose metrics, data for alanine aminotransferase, γ-glutamyl transferase, 

absolute liver weight, and relative liver weight were analyzed using all available continuous variable 

BMD models and a BMR of 1 standard deviation change from control and incidence data for centrilobular 

hepatocyte hypertrophy were analyzed using all available dichotomous BMD models and the extra risk 

option with a BMR of 10% extra risk. The BMD analysis identified nine BMDL values that could be 

used as the point of departure for the intermediate-duration oral MRL; these values are presented in 

Tables 2-5 and 2-6. For each end point and dose metric, human equivalent doses (HEDs) were estimated 

from the BMDL value using the human PBPK model (discussed in Appendix A); the HEDs are 

summarized in Tables 2-5 and 2-6. 

The lowest HEDs were calculated from the BMDLMCL and BMDLMRAMKL for centrilobular hepatocyte 

hypertrophy. Because there is limited information to determine whether the observed hepatic effects are 

due to ethylbenzene or its metabolites, the lowest HED value (10.68 mg/kg/day) was selected as the point 

of departure for the MRL. The HED was divided by an uncertainty factor of 30 (3 for extrapolation from 
 

 

 

 

ETHYLBENZENE 30 

2. RELEVANCE TO PUBLIC HEALTH 

Table 2-5. Benchmark Doses and Human Equivalent Doses for Liver Effects 

Using Arterial Ethylbenzene Concentration (MCL) Dose Metric
 

BMDL HEDa 

Effect Model (μmol/L) (mg/kg/day) 

Increased alanine aminotransferase Hill (all doses); constant variance 7.49 11.82 

Increased γ-glutamyl transferase Inadequate fit to all models 

Increased absolute liver weights Linear (highest dose dropped); 32.17 31.82 

constant variance 

Increased relative liver weights Linear (highest dose dropped); 13.53 18.47 

constant variance 

Centrilobular hepatocyte Log logistic 6.61 10.68 

hypertrophy 

a

Calculated using a reference human body weight of 70 kg and the assumption that the daily dose was delivered in 

16 dose splits/24 hours (i.e., only exposed during waking hours). 

BMDL = 95% lower confidence limit on the benchmark dose; HED = human equivalent dose; MCL = time-averaged 

concentration of ethylbenzene in liver 
 

 

 

 

ETHYLBENZENE 31 

2. RELEVANCE TO PUBLIC HEALTH 

Table 2-6. Benchmark Doses (BMDs) and Human Equivalent Doses (HEDs) for
 

Liver Effects Using MRAMKL Internal Dose Metric
 

BMDL HEDb 

Effect Modela (μmol/hour/kg liver) (mg/kg/day) 

Increased alanine 3-Degree polynomial; nonconstant 391.02 31.06 

aminotransferase variance 

Increased γ-glutamyl transferase Linear; constant variance 737.62 111.37c 

Increased absolute liver weights Hill; constant variance 548.01 48.62 

Increased relative liver weights 2-Degree polynomial; constant 390.47 31.01 

variance 

Centrilobular hepatocyte Multistage (3-degree polynomial) 206.91 15.48 

hypertrophy 

a

All doses used for BMD modeling.

b

Calculated using a reference human body weight of 70 kg and the assumption that the daily dose was delivered in 

16 dose splits/24 hours (i.e., only exposed during waking hours).
 c

Approximate value, value is very close to the metabolism Vmax.
 

BMDL = 95% lower confidence limit on the benchmark dose; MRAMKL = time-averaged rate of metabolism of
 

ethylbenzene in liver
 
ETHYLBENZENE 32 

2. RELEVANCE TO PUBLIC HEALTH 

animals to humans using dosimetric adjustments and 10 for human variability), resulting in an 

intermediate-duration oral MRL of 0.4 mg/kg/day. 

No studies describing the non-carcinogenic effects of chronic-duration oral exposure to ethylbenzene in 

humans were located. Available chronic-duration oral exposure studies in animals (Maltoni et al. 1985, 

1997) did not evaluate comprehensive noncancer end points and, therefore, do not provide suitable data 

for derivation of a chronic-duration oral MRL. 
 

 

 

ETHYLBENZENE 33 

3. HEALTH EFFECTS 

3.1 INTRODUCTION 

The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and 

other interested individuals and groups with an overall perspective on the toxicology of ethylbenzene. It 

contains descriptions and evaluations of toxicological studies and epidemiological investigations and 

provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health. 

A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile. 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 

To help public health professionals and others address the needs of persons living or working near 

hazardous waste sites, the information in this section is organized first by route of exposure (inhalation, 

oral, and dermal) and then by health effect (death, systemic, immunological, neurological, reproductive, 

developmental, genotoxic, and carcinogenic effects). These data are discussed in terms of three exposure 

periods: acute (14 days or less), intermediate (15–364 days), and chronic (365 days or more). 

Levels of significant exposure for each route and duration are presented in tables and illustrated in 

figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowestobserved-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies. 

LOAELs have been classified into "less serious" or "serious" effects. "Serious" effects are those that 

evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute respiratory distress 

or death). "Less serious" effects are those that are not expected to cause significant dysfunction or death, 

or those whose significance to the organism is not entirely clear. ATSDR acknowledges that a 

considerable amount of judgment may be required in establishing whether an end point should be 

classified as a NOAEL, "less serious" LOAEL, or "serious" LOAEL, and that in some cases, there will be 

insufficient data to decide whether the effect is indicative of significant dysfunction. However, the 

Agency has established guidelines and policies that are used to classify these end points. ATSDR 

believes that there is sufficient merit in this approach to warrant an attempt at distinguishing between 

"less serious" and "serious" effects. The distinction between "less serious" effects and "serious" effects is 

considered to be important because it helps the users of the profiles to identify levels of exposure at which 

major health effects start to appear. LOAELs or NOAELs should also help in determining whether or not 
 

 

 

 

 

 

 

ETHYLBENZENE 34 

3. HEALTH EFFECTS 

the effects vary with dose and/or duration, and place into perspective the possible significance of these 

effects to human health. 

The significance of the exposure levels shown in the Levels of Significant Exposure (LSE) tables and 

figures may differ depending on the user's perspective. Public health officials and others concerned with 

appropriate actions to take at hazardous waste sites may want information on levels of exposure 

associated with more subtle effects in humans or animals (LOAELs) or exposure levels below which no 

adverse effects (NOAELs) have been observed. Estimates of levels posing minimal risk to humans 

(Minimal Risk Levels or MRLs) may be of interest to health professionals and citizens alike. 

A User's Guide has been provided at the end of this profile (see Appendix B). This guide should aid in 

the interpretation of the tables and figures for Levels of Significant Exposure and the MRLs. 

3.2.1 Inhalation Exposure 

3.2.1.1 Death 

No studies were located regarding lethality in humans following inhalation exposure to ethylbenzene. 

Matsumoto et al. (1992) reported the case of a 44-year-old man who died 9 days after exposure to 

gasoline vapors for at least 10 hours in an enclosed car. The patient’s clothing was saturated with 

gasoline, but there was no apparent ingestion of gasoline. The patient suffered chemical burns over 50% 

of the total body surface area, and the cause of death was reported as multiple organ failure. Ethylbenzene was detected in the patient’s blood (estimated initial blood concentration of 2.6 μg/mL). 

However, since gasoline contains approximately 1.4% (by weight) ethylbenzene (Agency for Toxic 

Substances and Disease Registry 1995), it is unlikely that death was due to ethylbenzene exposure. 

Studies on the lethality of inhaled ethylbenzene have been conducted using several animal models, with 

exposure times ranging from a few hours to 2 years. The LC50 values obtained from acute inhalation 

exposure studies were 13,367 ppm following a 2-hour exposure (Ivanov 1962) and 4,000 ppm following a 

4-hour exposure (Smyth et al. 1962); 100% mortality was observed following exposure to 16,698 ppm for 

2 hours (Ivanov 1962) and exposure to 8,000 ppm for 4 hours (Smyth et al. 1962). Inhalation exposure of 

Fischer 344 rats and B6C3F1 mice to ethylbenzene for 6 hours/day for 4 days produced lethality at 

concentrations of 1,200 and 2,400 ppm, respectively, although exposure to concentrations up to 

2,400 ppm was not lethal to rabbits (Ethylbenzene Producers Association 1986a). In intermediateduration exposure studies, inhalation exposure of rats and mice to 782 ppm or rabbits to 1,610 ppm 
 

 

 

 

 

ETHYLBENZENE 35 

3. HEALTH EFFECTS 

ethylbenzene for 4 weeks did not produce lethality (Cragg et al. 1989). No mortality was observed in rats 

or mice exposed to 782 ppm or rabbits exposed to 1,610 ppm ethylbenzene for 4 weeks (Cragg et al. 

1989) or in rats or mice exposed to 975 ppm ethylbenzene for 90 days (NTP 1992). Survival of male rats, 

but not female rats or male or female mice, exposed to 750 ppm ethylbenzene for 2 years was 

significantly decreased (NTP 1999); survival in male rats exposed to 75 or 250 ppm ethylbenzene was not 

affected. 

The LC50 values and all reliable LOAEL values for death in rats and mice following acute- or chronicduration exposure are recorded in Table 3-1 and plotted in Figure 3-1. 

3.2.1.2 Systemic Effects 

Little data are available on the systemic effects of inhaled ethylbenzene in humans. Most of the 

information available is from case reports in which quantitative data on exposure concentrations and 

durations were not reported. In addition, most of the available studies have confounding factors (e.g., 

simultaneous exposures to other toxic substances) and insufficient reporting of important study details. In 

general, the systemic effects observed in humans were respiratory tract and ocular irritation, and possible 

ototoxicity (hearing loss) and hematological alterations (increased lymphocyte counts and decreased 

hemoglobin concentration) (Angerer and Wulf 1985; Cometto-Muñiz and Cain 1995; Thienes and Haley 

1972; Yant et al. 1930). 

Several studies were located on the systemic effects of ethylbenzene in animals following inhalation 

exposure. Acute- and intermediate-duration exposure to inhaled ethylbenzene is associated with 

respiratory irritation, changes to the liver (increased organ weights and induction of microsomal 

enzymes), and effects on the hematological system (decreased platelets and increased leukocyte counts). 

Chronic exposure is associated with adverse effects to the liver (necrosis and hypertrophy), kidney 

(nephropathy and hyperplasia), and endocrine system (thyroid and pituitary hyperplasia). 

No studies were located describing cardiovascular, gastrointestinal, musculoskeletal, renal, endocrine, 

dermal, body weight, or metabolic effects in humans, or dermal effects in animals after inhalation 

exposure to ethylbenzene. 
513

2400

63

4000

514

1200

520

50600

Table 3-1 Levels of Significant Exposure to Ethylbenzene - Inhalation 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

ACUTE EXPOSURE Death 

1 Rat 

(Fischer- 344) 

4 d 6 hr/d 

System 

NOAEL 

(ppm) 

Less Serious 

(ppm) 

LOAEL 

Serious 

(ppm) 

2400 M (100% mortality by 

day 3) 

Reference Chemical Form 

Ethylbenzene Producer

Association 1986a 

2 Rat 

(NS) 

4 hr 4000 M (LC50) Smyth et al. 1962 

3 Mouse 

(B6C3F1) 

4 d 6 hr/d 1200 M (4/5 animals died by day 3) Ethylbenzene Producer

Association 1986a 

Systemic 

4 Rat 

(Wistar) 

2 wk 5 d/wk 6 hr/d 

Hepatic 50 M (induction of 

UDP-glucuronyl transferase and D-glucuronyllactone dehydrogenase) 

Elovaara et al. 1985 

Renal 600 M (increase in relative 

kidney weights) 
59

2000

400

400

1200

400 12001200

3

2000

20002000

4

1432

Table 3-1 Levels of Significant Exposure to Ethylbenzene - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

5 Rat 

(Fischer- 344) 

4 d 6 hr/d Resp 2000 M Ethylbenzene Producer

Association 1986a 

Hepatic 400 M (increased liver weight) Renal 400 M 1200 M (increased relative kidney 

weight) 

Ocular 400 M 1200 M (lacrimation) Bd Wt 1200 M 

6 Rat 

(SpragueDawley) 

3 d 6 hr/d Resp 2000 M Toftgard and Nilsen 198

Hepatic 2000 M (increased relative liver 

weight, and induction of nadph-cytochrome reductase and 7-ethoxycoumarin o-deethylase) 

Renal 2000 M (increased relative kidney 

weight) 

7 Mouse 

(Swiss) 

5 min Resp 1432 M (RD50) De Ceaurriz et al. 1981 
57

400

400

48

4060

433

2000

60

240024002400

400

2400

954

800

953

300

400

Table 3-1 Levels of Significant Exposure to Ethylbenzene - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

8 Mouse 

(B6C3F1) 

4 d 6 hr/d Ocular 400 M (lacrimation) Ethylbenzene Producer

Association 1986a 

Bd Wt 400 M 

9 Mouse 

(SwissWebster) 

30 min Resp 4060 M (RD50) Nielsen and Alarie 1982 

10 Mouse 

(CFW) 

20 min Ocular 2000 M (lacrimation and 

palpebral closure) 

Tegeris and Balster 199

11 Rabbit 

(New Zealand) 

4 d 6 hr/d 

Neurological 

12 Rat 

(Wag/Rij/Cpb/H 

8 hr/d 5 d 

Resp Hepatic Renal Ocular Bd Wt 

2400 M 

2400 M 

2400 M 

2400 M 

400 M (lacrimation) 

800 M (loss of outer hair cells 

and hearing loss) 

Ethylbenzene ProducerAssociation 1986a Cappaert et al. 1999 

13 Rat 

(Wag/Rij) 

8 hr 5 d 

b

300 400 (loss of outer hair cells 

and shifts in hearing thresholds) 

Cappaert et al. 2000 
968

300 400

955

550

516

1200 2400

2

200

400

2180

517

400

1200

434

2000

Table 3-1 Levels of Significant Exposure to Ethylbenzene - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) 

LOAEL 

Less Serious 

(ppm) 

Serious 

(ppm) 

Reference Chemical Form 

14 Rat 

(albino Wag/Rij) 

8 hr/d 5 d 300 400 (loss of outer hair cells) Cappaert et al. 2001

15 Rat 

(Wag/Rij) 

8 hr/d 5 d 550 F (loss of outer hair cells Cappaert et al. 2002 and shifts in hearing 

thresholds) 

16 Rat 

(Fischer- 344) 

4 d 6 hr/d 1200 M Ethylbenzene Producer

Association 1986a 2400 M (salivation, prostration) 

17 Rat 

(CFY) 

4 hr 200 M 400 M (moderate activation in Molnar et al. 1986

motor behavior) 

2180 M (narcotic effects) 

18 Mouse 

(B6C3F1) 

4 d 6 hr/d 400 M Ethylbenzene Producer

Association 1986a 1200 M (prostration and reduced activity) 

19 Mouse 

(CFW) 

20 min 2000 M (postural changes, Tegeris and Balster 199

decreased arousal and rearing, distrubed gait, decreased mobility, righting reflex, decreased grip strength, increased landing foot splay, impaired psychomotor coordination) 
455

2400

456

2400

457

1200

458

2400

Table 3-1 Levels of Significant Exposure to Ethylbenzene - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

20 Rabbit 

(New Zealand) 

4 d 6 hr/d 

Reproductive 

21 Rat 

(Fischer- 344) 

4 d 6 hr/d 

2400 M 2400 M 

Ethylbenzene ProducerAssociation 1986a Ethylbenzene ProducerAssociation 1986a 

22 Mouse 

(B6C3F1) 

4 d 6 hr/d 1200 M Ethylbenzene Producer

Association 1986a 

23 Rabbit 

(New Zealand) 

4 d 6 hr/d 2400 M Ethylbenzene Producer

Association 1986a 
424

782782782382

782

782382

782

78278299

382

782

Table 3-1 Levels of Significant Exposure to Ethylbenzene - Inhalation (continued) Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) 

INTERMEDIATE EXPOSURE Systemic 

24 Rat 4 wk 

5 d/wk (Fischer- 344) 6 hr/d 

System 

Resp Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Ocular Bd Wt 

LOAEL 

NOAEL 

(ppm) 

Less Serious 

(ppm) 

Serious 

(ppm) 

Reference Chemical Form 

782 Cragg et al. 1989 

782 

782 382 782 (increased platelet 

counts in males; increased mean total leukocyte counts in males and females) 

782 

382 782 (increased absolute and 

relative liver weight) 

782 

782 

99 382 (sporadic incidence of 

lacrimation) 

782 
6

50300

600

530

98597 95997 959985

Table 3-1 Levels of Significant Exposure to Ethylbenzene - Inhalation (continued) Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) 

25 Rat 

(Wistar) 

5-16 wk 5 d/wk 6 hr/d 

26 Rat 

(Wistar) 

3 wk 5 d/wk 7 hr/d Gd 1-19 

LOAEL 

System 

NOAEL 

(ppm) 

Less Serious 

(ppm) 

Serious 

(ppm) 

Reference Chemical Form 

Hepatic 50 M (induction of Elovaara et al. 1985 

UDP-glucuronyl transferase and D-glucuronyllactone dehydrogenase) 

Renal 300 M (increase in microsomal 

enzyme activity and glutathione) 

Bd Wt 600 M Resp 985 F NIOSH 1981 

Hepatic 97 F 959 F (increased liver weight) 

Renal 97 F 959 F (increased kidney weight) Bd Wt 985 F 
90

99

246

97597597597599

246

246

498

975975975

958

250

250 1000

Table 3-1 Levels of Significant Exposure to Ethylbenzene - Inhalation (continued) Exposure/ LOAEL 

Duration/ 

a 

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (ppm) (ppm) (ppm) Chemical Form 

27 Rat 

(F344/N) 

90 d 5 d/wk 6 hr/d 

Resp 99 F 246 F (increased absolute and 

relative lung weight) 

NTP 1992 

Cardio 975 Gastro 975 Hemato 975 Musc/skel 975 Hepatic 99 M 246 M (increased absolute and 

relative liver weight) 

Renal 246 M 498 M (<10% increase in 

absolute and relative kidney weight) 

Endocr 975 

Ocular 975 Bd Wt 975 

28 Rat 

SD 

6 hr/d Gd 6-20 Hepatic 250 F (increased absolute and relative liver weight, 

moderate to marked hepatocellular hypertrophy) 

Saillenfait et al. 2006, 2

Bd Wt 250 F 1000 F 
988

500500

419

782782782782782382

782

782782782782

Table 3-1 Levels of Significant Exposure to Ethylbenzene - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

29 Rat 

(CD) 

6 hr/d 7 d/wk Hemato 500 F Stump 2004 

Bd Wt 500 F 

30 Mouse 

(B6C3F1) 

4 wk 5 d/wk 6 hr/d 

Resp 782 Cragg et al. 1989 

Cardio Gastro Hemato Musc/skel Hepatic 

782 

782 782 782 

382 782 (increased absolute and 

relative liver weight) 

Renal Endocr Ocular Bd Wt 

782 

782 782 782 
91

975975975975975498

740

740

975

975975975

Table 3-1 Levels of Significant Exposure to Ethylbenzene - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

31 Mouse 

(B6C3F1) 

90 d 5 d/wk 6 hr/d 

Resp 975 NTP 1992 

Cardio 975 Gastro 975 Hemato 975 Musc/skel Hepatic 

975 498 M 740 M (increased absolute and 

relative liver weight) 

Renal 740 F 975 F (increased relative kidney 

weight) 

Endocr 975 

Ocular 975 Bd Wt 975 
429

1610161016101610161016101610161016101610

528

96299

962

962962962

425

782

Table 3-1 Levels of Significant Exposure to Ethylbenzene - Inhalation (continued) Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) 

32 Rabbit 4 wk 

5 d/wk (New 

Zealand) 6 hr/d

33 Rabbit Gd 1-24 

7 d/wk (New 

Zealand) 7 hr/d

Immuno/ Lymphoret 

34 Rat 4 wk 

5 d/wk (Fischer- 344) 6 hr/d 

System 

Resp Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Ocular Bd Wt Resp Hepatic Renal Bd Wt Other 

LOAEL 

NOAEL 

(ppm) 

Less Serious 

(ppm) 

Serious 

(ppm) 

Reference Chemical Form 

1610 Cragg et al. 1989 

1610 

1610 

1610 1610 1610 1610 1610 1610 

1610 

962 F NIOSH 1981 

99 F 962 F (increased absolute and 

relative liver weights in pregnant rabbits) 

962 F 962 F 962 F 782 Cragg et al. 1989 
531

97

959

549

975

987

500

420

782

550

975

Table 3-1 Levels of Significant Exposure to Ethylbenzene - Inhalation (continued) 

a 

Key to Species 

Figure (Strain) 

35 Rat 

(Wistar) 

36 Rat 

(F344/N) 

37 Rat 

(CD) 

38 Mouse 

(B6C3F1) 

39 Mouse 

(B6C3F1) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

3 wk 5 d/wk 7 hr/d Gd 1-19 

97 F 959 F (increased spleen 

weight) 

NIOSH 1981 

90 d 5 d/wk 6 hr/d 

975 NTP 1992 

6 hr/d 7 d/wk 500 F Stump 2004 

4 wk 5 d/wk 6 hr/d 

782 Cragg et al. 1989 

13 wk 5 d/wk 6 hr/d 

975 NTP 1992 
430

1610

426

99

382

957

200

600

551

975

421

782

552

975

Table 3-1 Levels of Significant Exposure to Ethylbenzene - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

40 Rabbit 

(New Zealand) 

4 wk 5 d/wk 6 hr/d 

Neurological 

41 Rat 

(Fischer- 344) 

4 wk 5 d/wk 6 hr/d 

1610 

99 382 (sporadic incidence of 

salivation) 

Cragg et al. 1989 Cragg et al. 1989 

42 Rat 

(SD) 

6 hr/d 6 d/wk 13 wk 

c

200 M 600 M (complete loss of third 

row outer hair cells and hearing loss) 

Gagnaire et al. 2007 

43 Rat 

(F344/N) 

90 d 5 d/wk 6 hr/d 

975 NTP 1992 

44 Mouse 

(B6C3F1) 

4 wk 5 d/wk 6 hr/d 

782 Cragg et al. 1989 

45 Mouse 

(B6C3F1) 

90 d 5 d/wk 6 hr/d 

975 NTP 1992 
431

1610

427

782

959

500

75

985

553

975

Table 3-1 Levels of Significant Exposure to Ethylbenzene - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

46 Rabbit 

(New Zealand) 

4 wk 5 d/wk 6 hr/d 

1610 Cragg et al. 1989 

Reproductive 

47 Rat 

(Fischer- 344) 

4 wk 5 d/wk 6 hr/d 

782 Cragg et al. 1989 

48 Rat 

(Crl-CD) 

6 hr/d 70 d 500 Faber et al. 2006 

49 Rat 

(Wistar) 

3 wk 5 d/wk 7 hr/d Gd 1-19 

985 F NIOSH 1981 

50 Rat 

(F344/N) 

90 d 5 d/wk 6 hr/d 

975 NTP 1992 
422

782

554

975

432

1610

77

962

960

500

Table 3-1 Levels of Significant Exposure to Ethylbenzene - Inhalation (continued) 

a 

Key to Species 

Figure (Strain) 

51 Mouse 

(B6C3F1) 

52 Mouse 

(B6C3F1) 

53 Rabbit 

(New Zealand) 

54 Rabbit 

(New Zealand) 

Developmental 

55 Rat 

(Crl-CD) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

4 wk 5 d/wk 6 hr/d 

782 Cragg et al. 1989 

13 wk 5 d/wk 6 hr/d 

975 NTP 1992 

4 wk 5 d/wk 6 hr/d 

1610 Cragg et al. 1989 

Gd 1-24 7 d/wk 7 hr/d 

962 F NIOSH 1981 

6 hr/d 70 d 500 F Faber et al. 2006 
961

500

76

97

959

966

500

1000

967

250

1000

527

962

Table 3-1 Levels of Significant Exposure to Ethylbenzene - Inhalation (continued) 

a 

Key to Species 

Figure (Strain) 

56 Rat 

(Crl-CD) 

57 Rat 

(Wistar) 

58 Rat 

(SpragueDawley) 

59 Rat 

(SpragueDawley) 

60 Rabbit 

(New Zealand) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

6 hr/d 70 d 500 F Faber et al. 2007 

3 wk 5 d/wk 7 hr/d Gd 1-19 

97 F 959 F (extra rib, supemumerary 

ribs) 

NIOSH 1981 

6 hr/d Gd 6-20 500 F 1000 F (decreased fetal body weight) Saillenfait et al. 2003 

6 hr/d Gd 6-20 250 F 1000 F (slight decrease in fetal body weight) Saillenfait et al. 2006, 2

Gd 1-24 7 d/wk 7 hr/d 

962 F NIOSH 1981 
980

750

971

750750750750750

75

750750750

Table 3-1 Levels of Significant Exposure to Ethylbenzene - Inhalation (continued) Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) 

CHRONIC EXPOSURE Death 

61 Rat 6 hr/d 

5 d/wk (F344) 2 yr 

Systemic 

62 Rat 6 hr/d 

5 d/wk (F344) 2 yr 

System 

Resp Cardio Hemato Musc/skel Hepatic Renal Endocr Dermal Bd Wt 

LOAEL 

NOAEL 

(ppm) 

Less Serious 

(ppm) 

Serious 

(ppm) 

Reference Chemical Form 

750 M (decreased survival) NTP 1999 

750 NTP 1999 

750 

750 750 

750 

d

75 F (increased severity of 

nephropathy) 

750 

750 

750 
970

750750750750250

750

75075

250750

750750

965

750

Table 3-1 Levels of Significant Exposure to Ethylbenzene - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

63 Mouse 

(F344) 

6 hr/d 5 d/wk 2 yr 

Resp 750 NTP 1999 

Cardio 750 Gastro 750 Musc/skel Hepatic 

750 250 M 750 M (hypertrophy and 

necrosis) 

Renal 750 Endocr 75 F 250 F (hyperplasia in pituitary 

gland pars distalis) 

750 (thyroid follicular cell 

hyperplasia) 

Dermal 750 

Cancer 

64 Rat 

(F344) 

6 hr/d 5 d/wk 2 yr 

Bd Wt 750 

750 M (CEL: renal tubule 

adenoma or carcinoma) 

NTP 1999 
972

750

Table 3-1 Levels of Significant Exposure to Ethylbenzene - Inhalation (continued) Exposure/ LOAEL 

Duration/ 

a 

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (ppm) (ppm) (ppm) Chemical Form 

65 Mouse 

(F344) 

6 hr/d 5 d/wk 2 yr 

750 (CEL: 

alveolar/bronchiolar adenoma or carcinoma 

NTP 1999 

and hepatocellular adenoma or carcinoma) 

a The number corresponds to entries in Figure 3-1. b Used to derive an acute-duration inhalation minimal risk level (MRL) of 5 ppm based on a BMCL using an internal dose metric to simulate time averaged arterial bconcentration of ethylbenzene (81.10 μmol/L); a human equivalent concentration (HEC) of the BMCL was estimated using a human PBPK model. The BMCL(HECdivided by an uncertainty factor of 30 (3 for extrapolation from animals to humans with dosimetric adjustment and 10 for human variability). c Used to derive an intermediate-duration inhalation minimal risk level (MRL) of 2 ppm based on a BMCL using an internal dose metric to simulate time averaged aconcentration of ethylbenzene (19.94 μmol/L); a human equivalent concentration (HEC) of the BMCL was estimated using a human PBPK model. The BMCL(HECdivided by an uncertainty factor of 30 (3 for extrapolation from animals to humans with dosimetric adjustment and 10 for human variability). d Used to derive a chronic-duration inhalation minimal risk level (MRL) of 0.06 ppm based on an internal dose metric (averaged arterial blood concentration of ethylthe LOAEL; a human equivalent concentration (HEC) of the LOAEL(MCA) was estimated using a human PBPK model. The LOAEL(HEC) (17.45 ppm) was divided factor of 300 (10 for use of a LOAEL, 3 for extrapolation from animals to humans with dosimetric adjustment and 10 for human variability). Bd Wt = body weight; Cardio = cardiovascular; CEL = cancer effect level; d = day(s); Endocr = endocrine; F = Female; Gastro = gastrointestinal; Gd = gestation dayhematological; hr = hour(s); LC50 = lethal concentration, 50% kill; LOAEL = lowest-observed-adverse-effect level; M = male; min = minute(s); Musc/skel = musculono-observed-adverse-effect level; NS = not specified; RD50 = exposure concentration producing a 50% decrease in respiratory rate ; Resp = respiratory; wk = wee
Figure 3-1 Levels of Significant Exposure to Ethylbenzene - Inhalation 

Acute (≤14 days) 

Systemic 

ppm 

Death 

Respiratory 

Hepatic 

Renal 

Ocular 

Body Weight 

Neurological 

Reproductive 

10000 

2r 9m

1r 11h 11h 11h 11h 16r 20h 21r 23h 17r 5r 6r 6r 6r 10m 19m 

7m 

3m 5r 5r 5r 18m 16r 22m 

1000 

12r 

4r 15r 

5r 5r 8m 5r 11h 8m 18m 13r 14r 17r 

13r		 14r 

17r 

100 

4r 

10 

1 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans Minimal Risk Level

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans for effects

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans other than

q-Cow a-Sheep g-Guinea Pig Cancer 

ETHYLBENZENE 3. HEALTH EFFECTS 55
Figure 3-1 Levels of Significant Exposure to Ethylbenzene - Inhalation (Continued)
 

Intermediate (15-364 days)
	

Systemic 

ppm Respiratory 

Cardiovascular 

Gastrointestinal 

Hematological 

Musculoskeletal 

Hepatic 

Renal 

10000 

32h 32h 32h 32h 32h 32h 32h
	

1000
	 31m 26r 33h 31m 27r 31m 27r 31m 27r 31m 27r 26r 33h 31m 26r 33h

30m 24r 30m 24r 30m 24r 30m 24r 30m 24r 30m 31m 24r 30m 31m 24r

29r 31m 27r 

24r 30m 24r 

25r 

27r 27r 28r 27r 

100 27r 26r 27r 33h 26r 

25r 

10 

1 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans Minimal Risk Level

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans for effects

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans other than

q-Cow a-Sheep g-Guinea Pig Cancer 

ETHYLBENZENE 3. HEALTH EFFECTS 56
Figure 3-1 Levels of Significant Exposure to Ethylbenzene - Inhalation (Continued)
 

Intermediate (15-364 days)
	

Systemic
	

Endocrine 

Ocular 

Body Weight 

Other 

Immuno/Lymphor 

Neurological 

Reproductive 

ppm 

Developmental 

10000 

32h 32h 32h 40h 46h 53h 

1000 31m 27r 31m 27r 31m 26r 27r 28r 33h 33h 39m 35r 36r 45m 43r 52m 49r 50r 54h 57r 58r 59r 60

30m 24r 30m 30m 24r 38m 34r 44m 51m 47r 

25r 42r 

29r 37r 48r 55r 56r 58r 

24r
	 41r 

28r
	 59r 

42r 

100 24r 35r 41r 57r 

10 

1 1 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans Minimal Risk Level

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans for effects

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans other than

q-Cow a-Sheep g-Guinea Pig Cancer 

ETHYLBENZENE 3. HEALTH EFFECTS

h

57
Figure 3-1 Levels of Significant Exposure to Ethylbenzene - Inhalation (Continued)
 

Chronic (≥365 days)
	

Systemic 

Death 

Respiratory 

Cardiovascular 

Gastrointestinal 

Hematological 

Musculoskeletal 

Hepatic 

Renal 

Endocrine 

Dermal 

Body Weight 

Cancer * 

ppm 

1000 

61r 63m 62r 63m 62r 63m 62r 63m 62r 63m 62r 63m 63m 62r 63m 62r 63m 62r 65m 64r 

63m 63m 

100 

62r 63m 

10 

1 

0.1 

*Doses represent the lowest dose tested per study that produced a tumorigenic 

0.01 response and do not imply the existence of a threshold for the cancer endpoint. 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans Minimal Risk Level

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans for effects

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans other than

q-Cow a-Sheep g-Guinea Pig Cancer 

ETHYLBENZENE 3. HEALTH EFFECTS 58
 

 

 

 

 

 

 

 

 

ETHYLBENZENE 59 

3. HEALTH EFFECTS 

The systemic effects observed after inhalation exposure are discussed below. The highest NOAEL values 

and all reliable LOAEL values for systemic effects in each species and duration category are recorded in 

Table 3-1 and plotted in Figure 3-1. 

Respiratory Effects. Male volunteers reported throat and nasal irritation and feelings of “chest 

constriction” during a 6-minute inhalation exposure to 2,000 ppm ethylbenzene (Yant et al. 1930). More 

severe throat and nasal irritation were reported immediately upon exposure to 5,000 ppm ethylbenzene. 

No data on pulmonary function were reported (Yant et al. 1930). No bronchospastic response was 

observed in two subjects challenged with 55 ppm ethylbenzene for 15 minutes in an inhalation chamber, 

based on comparison of pre- and post-exposure pulmonary function tests (Moscato et al. 1987). 

Results of acute studies in animals indicate that inhalation of ethylbenzene produces adverse respiratory 

effects ranging from irritation to pulmonary congestion. Nasal irritation (based on nose rubbing) was 

observed in guinea pigs exposed to 1,000 ppm for 3 and 8 minutes and to 2,000, 5,000, and 10,000 ppm 

for 480, 30, and 10 minutes, respectively (Yant et al. 1930). Gross histopathology revealed congestion 

and edema in the lungs of animals that died after exposure to 10,000 ppm ethylbenzene, with less severe 

effects observed in surviving animals. Pulmonary congestion also was observed in rats and mice that died 

during exposure a 4-day exposure to 2,400 and ≥1,200 ppm ethylbenzene, respectively (Ethylbenzene 

Producers Association 1986a). A 50% reduction in breathing rate was observed in mice exposed to 

1,432 ppm for 5 minutes (De Ceaurriz et al. 1981) and 4,060 ppm for 30 minutes (Nielsen and Alarie 

1982). No adverse respiratory effects were observed in rats exposed to 2,000 ppm for 3 days (Toftgard 

and Nilsen 1982) or in rats, mice, and rabbits exposed to 1,200, 400, or 2,400 ppm, respectively, for 

4 days (Ethylbenzene Producers Association 1986a). 

Adverse respiratory effects attributed to intermediate- or chronic-duration inhalation exposures to 

ethylbenzene have been observed in animals. Relative lung weight was increased in male rats exposed to 

975 ppm for 90 days, although increased absolute and relative lung weights were observed only in female 

rats exposed to 246 ppm ethylbenzene, but not to higher concentrations (NTP 1992). Pulmonary lesions 

(inflammatory cell infiltrate) were observed in male rats exposed to ≥246 ppm for 90 days (NTP 1992). 

However, the NTP Pathology Working Group considered these effects to be more typical of an infectious 

agent than a response to the test compound; therefore, pulmonary findings were not attributed to 

ethylbenzene exposure. No histopathological changes were observed in rats exposed to 2,200 ppm, 

guinea pigs or rabbits exposed 1,250 ppm, or monkeys exposed to 600 ppm ethylbenzene for 6 months 

(Wolf et al. 1956); however, the utility of this study is limited by a general lack of study details (e.g., no 
 

 

 

 

 

 

 

ETHYLBENZENE 60 

3. HEALTH EFFECTS 

exposure or control data were provided) and the small size of exposure groups (1–2 rabbits or monkeys 

per group). No histopathological findings clearly attributable to ethylbenzene were observed in 

respiratory tissue of rats or mice exposed to up to 750 ppm ethylbenzene for 2 years (NTP 1999). 

Although the incidences of edema, congestion, and hemorrhage observed in male rats in the 750 ppm 

group were increased relative to control rats, observations were considered to be agonal changes in 

moribund animals and not directly related to chemical toxicity (NTP 1999). 

Cardiovascular Effects. Intermediate and chronic exposure of animals to inhaled ethylbenzene does 

not appear to produce adverse cardiovascular effects, based on results of histopathological examinations. 

No adverse histopathological effects were reported in cardiac tissue of rats or mice exposed to 782 ppm or 

rabbits exposed to 1,610 ppm ethylbenzene for 4 weeks (Cragg et al. 1989). Similarly, no cardiovascular 

effects were observed in rats or mice exposed to 975 ppm ethylbenzene for 90 days (NTP 1992) or in rats 

exposed to 2,200 ppm, guinea pigs or rabbits exposed to 1,250 ppm, or monkeys exposed to 600 ppm 

ethylbenzene for 6 months (Wolf et al. 1956). No adverse histopathological findings were observed in 

cardiovascular tissues of rats or mice exposed to 750 ppm ethylbenzene for 2 years (NTP 1999). 

Gastrointestinal Effects. No adverse effects on the gastrointestinal system have been observed 

following intermediate or chronic inhalation exposure of animals. No changes in gross appearance or 

adverse histopathological effects were observed in the intestines of rats and mice exposed to 782 ppm or 

rabbits exposed to 1,610 ppm ethylbenzene for 4 weeks (Cragg et al. 1989). No adverse histopathological 

changes in gastrointestinal tissue were observed in rats or mice exposed to ≤975 ppm ethylbenzene for

90 days (NTP 1992) or in rats or mice exposed to ≤750 ppm ethylbenzene for 2 years (NTP 1999). 

Hematological Effects. Two studies involving long-term monitoring of workers occupationally 

exposed to ethylbenzene were located (Angerer and Wulf 1985; Bardodej and Cirek 1988). Angerer and 

Wulf (1985) reported increased lymphocyte count and decreased hemoglobin concentration in male 

varnish workers exposed to a mixture of solvents, including ethylbenzene, compared to an unexposed 

control group. Workers were employed for an average of 8.2 years and exposed to an average 

ethylbenzene concentration of 1.64 ppm. Average lymphocyte levels increased (41.5–68.8%) and 

average hemoglobin values decreased (5.2–7.1%) in exposed workers, compared to unexposed controls. 

However, due to concomitant exposure to other chemicals (xylenes, lead, toluene), the relationship of 

adverse hematological effects to inhaled ethylbenzene cannot be established. No adverse hematological 

effects were seen in male workers employed at an ethylbenzene manufacturing facility over a 20-year 

period, compared to unexposed control workers (Bardodej and Cirek 1988). Although no information on 
 

 

 

 

 

 

ETHYLBENZENE 61 

3. HEALTH EFFECTS 

ethylbenzene concentrations was reported, an estimated concentration of 6.4 mg/m3 was derived from a 

mean post-shift in urinary mandelic acid concentration in workers, based on the relationship between 

ethylbenzene concentrations in air and urinary mandelic acid concentration in a chamber-exposed group 

(Bardodej and Bardodejova 1988). However, given the low exposure concentration, this study had 

limited power to detect any effect. 

Studies using animal models yield conflicting results regarding hematological effects of inhaled 

ethylbenzene. Platelet count was significantly decreased in male rats and mean total leukocyte count was 

significantly increased in female rats exposed to 782 ppm ethylbenzene for 4 weeks; hematological 

effects were not observed in male or female rats exposed to ≤382 ppm, mice exposed to ≤782 ppm, or 

rabbits exposed to ≤1,610 ppm (Cragg et al. 1989). Similarly, no hematological effects were observed in

female rats exposed to ≤500 ppm ethylbenzene vapor daily for 28 days, based results of complete blood 

count with differential and assessments of erythrocyte morphology and hemoglobin content (Stump 

2004). No adverse hematological effects were observed in rats or mice exposed to 975 ppm ethylbenzene 

for 90 days (NTP 1992), or in rats exposed to ≤2,200 ppm, guinea pigs or rabbits exposed ≤1,250 ppm, or

monkeys exposed to ≤600 ppm ethylbenzene for 6 months (Wolf et al. 1956).

Musculoskeletal Effects. No musculoskeletal effects have been observed in laboratory animals 

exposed to inhaled ethylbenzene for intermediate or chronic durations. No bone tissue abnormalities 

were observed upon histopathological examination of tissue from rats and mice exposed to 782 ppm and 

rabbits exposed to 1,610 ppm for 4 weeks (Cragg et al. 1989). Similarly, no adverse effect on bone tissue 

was observed in rats or mice exposed to 975 ppm ethylbenzene for 90 days (NTP 1992) or 750 ppm for 

2 years (NTP 1999). 

Hepatic Effects. No adverse effects on liver function, as measured by serum liver enzyme activities, 

were observed in male workers employed at an ethylbenzene manufacturing facility over a 20-year period 

(Bardodej and Cirek 1988). Although no information on ethylbenzene concentrations was reported, an 

estimated concentration of 6.4 mg/m3 was derived as described above under hematological effects 

(Section 3.2.1.3). Given the low exposure concentration, this study had limited the power to detect any 

effect. 

Results of studies in laboratory animals have found various effects on the liver, including induction of 

cytochrome P-450, changes in liver weight (at least in part related to induction of cytochrome P-450), 

changes in hepatocyte ultrastructure consistent with induction of smooth endoplasmic reticulum, and 
 

 

 

ETHYLBENZENE 62 

3. HEALTH EFFECTS 

histopathological changes, including hepatocyte necrosis. Increased liver weights, induction of hepatic 

drug metabolizing enzymes, and changes in hepatocyte ultrastructure (consistent with induction of 

smooth endoplasmic reticulum) have been observed in rats following acute inhalation exposure to 

ethylbenzene. Concentration-related increases in absolute and relative liver weights were reported in 

male rats exposed to ≥400 ppm ethylbenzene for 3–4 days, although no histopathological changes were 

observed (Ethylbenzene Producers Association 1986a). Increased relative liver weight, increased hepatic 

concentration of cytochrome P-450, and induction of hepatic microsomal enzymes (NADPH-cytochrome 

reductase, 7-ethoxycoumarin O-deethylase) were reported in rats exposed to 2,000 ppm ethylbenzene 

concentrations for 3 days (Toftgard and Nilsen 1982). Similarly, hepatic drug metabolizing enzymes 

(UDP glucuronyl-transferase, D-glucuronolactone dehydrogenase) were increased in male rats exposed to 

50 ppm ethylbenzene for 2 weeks, and ethyoxycoumarin o-deethylase was increased at 300 ppm 

(Elovaara et al. 1985). Electron microscopy showed changes in hepatocyte ultrastructure consistent with 

induction of cytochrome P-450 (e.g., smooth endoplasmic reticulum proliferation, slight degranulation of 

rough endoplasmic reticulum) in rats exposed to 600 ppm ethylbenzene for 2 weeks (Elovaara et al. 

1985). Hepatic changes following acute exposure to ethylbenzene are consistent with induction of 

hepatic microsomal enzymes. 

Similar hepatic effects (liver weights, induction of hepatic drug metabolizing enzymes, and changes in 

hepatocyte ultrastructure) also have been reported in laboratory animals exposed to inhaled ethylbenzene 

for intermediate exposure durations. Significant increases in relative liver weight were observed in 

female rats exposed to ≥250 ppm ethylbenzene for 15 days (Saillenfait et al. 2006), rats and mice exposed

to 782 ppm ethylbenzene for 4 weeks (Cragg et al. 1989), pregnant and nonpregnant rats and pregnant 

rabbits exposed to 1,000 ppm ethylbenzene for 3 weeks prior to mating and throughout gestation (NIOSH 

1981), and rats and mice exposed to 246 and 740 ppm ethylbenzene, respectively, for 90 days (NTP 

1992). Increased liver weight was also observed in rats exposed to 400 ppm, and guinea pigs and 

monkeys exposed to 600 ppm ethylbenzene for 6 months (Wolf et al. 1956). Hepatic microsomal 

enzymes (total cytochrome P-450 protein, 7-ethoxycoumarin O-deethylase, aminopyrine N-demthylase) 

were induced in rats exposed to 50 ppm ethylbenzene for 16 weeks and changes in hepatocyte 

ultrastructure (e.g., smooth endoplasmic reticulum proliferation, slight degranulation of rough 

endoplasmic reticulum) in rats exposed to ethylbenzene from 2 to 15 weeks (Elovaara et al. 1985). 

Other histopathological findings in animals exposed to inhaled ethylbenzene were moderate to marked 

hypertrophy of periportal hepatocytes with clear cytoplasm in female rats exposed to ≥250 ppm

ethylbenzene for 15 days (the investigators noted that minimal hypertrophy was observed in controls) 
 

 

 

 

 

 

 

ETHYLBENZENE 63 

3. HEALTH EFFECTS 

(Saillenfait et al. 2006) and a cloudy swelling of hepatocytes of rats exposed to 2,200 ppm for 6 months 

(Wolf et al. 1956). Slight, statistically significant increases in relative liver weights (≤7% compared to

controls) were observed in male and female B6C3F1 mice exposed to 750 ppm, but not 75 ppm, 

ethylbenzene vapor for 1 or 4 weeks (Stott et al. 2003). Histopathological assessment showed 

hepatocellular hypertrophy, mitotic figures, and S-phase DNA synthesis in mice exposed to 750 ppm 

ethylbenzene vapor for 1 or 4 weeks, but serum activities of hepatic enzymes (alanine transaminase, 

asparatate transpeptidase, alkaline phosphatase, and γ-glutamyl trnaspeptidase) were not elevated 

compared to controls. No histopathological changes in the liver were observed in rats or mice exposed to 

246 and 740 ppm, respectively, for 90 days (NTP 1992). 

Chronic exposure of mice, but not rats, to inhaled ethylbenzene for 2 years produced hepatic toxicity, as 

indicated by histopathological changes (syncytial alterations of hepatocytes, hepatocellular hypertrophy, 

and hepatocyte necrosis) (NTP 1999). Syncytial alterations (enlarged hepatocytes with multiple nuclei), 

which were concentration-related in incidence and severity, were observed at in male mice exposed to 

≥75 ppm ethylbenzene, and hepatocyte hypertrophy and necrosis were observed in male mice exposed to 

750 ppm. In female mice exposed to 750 ppm ethylbenzene for 2 years, the incidence and severity of 

eosinophilic foci, which was considered to be a preneoplastic lesion, was increased. 

Renal Effects. Renal effects of acute and intermediate exposure to inhaled ethylbenzene are primarily 

limited to minimally adverse effects, including increased kidney weight in rats and mice and induction of 

microsomal enzymes in rats. However, chronic exposure of male and female rats results in more serious 

renal effects, including nephropathy, renal tubule hyperplasia, and renal tubular adenomas and 

carcinomas (see Section 3.2.1.7, Cancer). In addition, effects associated with accumulation of 

α2μ-globulin and hyaline droplets have been observed in male rats exposed to inhaled ethylbenzene. 

Accumulation of α2μ-globulin in the renal tubule epithelial cells of male rats is associated with tubular 

epithelial necrosis, regenerative proliferation, and renal tumors. This accumulation is not observed in 

female rats, mice, or humans (which lack that protein), or in male rats, which are genetically lacking 

α2μ-globulin. Adverse effects in male rats associated with renal accumulation of α2μ-globulin are 

therefore not considered relevant to humans (EPA 1991d). However, since renal toxicity of chronic 

exposure to inhaled ethylbenzene has been observed in female rats, renal effects associated with 

ethylbenzene are relevant to humans. 

Acute exposure to inhaled ethylbenzene had been reported to produce increases in kidney weight, induce 

renal microsomal enzymes, and enhance renal hyaline droplets in rats of both sexes. In male rats only, 
 

 

 

 

 

 

ETHYLBENZENE 64 

3. HEALTH EFFECTS 

this accumulation includes α2μ-globulin, but evidently other proteins are involved in females, and 

probably also in the males. Relative kidney weight was significantly increased (11–20%) in male rats 

exposed to 2,000 ppm for 2 days (Toftgard and Nilsen 1982) and 1,200 ppm ethylbenzene for 4 days 

(Ethylbenzene Producers Association 1986a), and in male and female rats exposed to 750 ppm 

ethylbenzene (6–7%), but not at 75 ppm, for 1 week (Stott et al. 2003). Although no change in renal 

histopathology accompanied increased kidney weight in rats exposed to 1,200 ppm ethylbenzene for 

4 days (Ethylbenzene Producers Association 1986a), increased accumulation of α2μ-globulin and hyaline 

droplets were observed after 1 week in the kidneys of male rats exposed to 750 ppm ethylbenzene 

compared to controls (Stott et al. 2003). Renal congestion was reported in rats and mice that died during 

exposure to 2,400 or 1,200 ppm ethylbenzene, respectively (Ethylbenzene Producers Association 1986a). 

Induction of renal cytochrome P-450 microsomal enzymes (7-ethoxycoumarin, O-deethylase, UDP 

glucuronyl-transferase, NADPH-cytochrome c reductase) was reported in rats following a 3-day exposure 

to 2,000 ppm ethylbenzene (Toftgard and Nilsen 1982). 

Renal effects of intermediate-duration exposure to inhaled ethylbenzene are similar to those observed 

following acute exposure (increased kidney weight, induction of renal microsomal enzymes, and changes 

associated with accumulation of α2μ-globulin). Several studies have shown that exposure of rats or mice 

to inhaled ethylbenzene for durations of 4 weeks –7 months increases relative kidney weight (Elovaara et 

al. 1985; NIOSH 1981; NTP 1999; Stott et al. 2003; Wolf et al. 1956). Concentration-related increases in 

renal microsomal enzymes (7-ethoxycoumarin O-deethylase, UDP glucuronyl-transferase) and renal 

glutathione concentration were reported in rats following a 5–16-week exposure to ethylbenzene at 

concentrations ranging from 50 to 600 ppm (Elovaara et al. 1985). Histopathological changes in the 

kidney include α2μ-globulin-associated changes (nuclear-size and staining variations and vacuolation or 

decreased amount of cytoplasm) in male rats exposed to 750 ppm for 4 weeks (Stott et al. 2003) and 

swelling of the tubular epithelium in rats exposed to 600 ppm ethylbenzene for up to 7 months (Wolf et 

al. 1956). 

Chronic exposure of male and female rats, but not mice, to inhaled ethylbenzene for 2 years resulted in 

nephropathy and renal tubule hyperplasia (NTP 1999). Although age-related nephropathy was observed 

in control rats, the severity was increased compared to controls in female rats exposed to ≥75 ppm and 

male rats exposed to 750 ppm. The incidence of renal tubular hyperplasia (considered as a preneoplastic 

effect) was increased in male and female rats exposed to 750 ppm. NTP (1999) concluded that 

ethylbenzene may have exacerbated the development of age-related nephropathy in rats and that renal 
 

 

 

 

 

 

 

ETHYLBENZENE 65 

3. HEALTH EFFECTS 

tubular lesions were related to exposure. Additional information pertaining to renal carcinogenesis is 

provided in Section 3.2.1.7. 

Endocrine Effects. Adverse endocrine effects, based on histopathological examinations of endocrine 

tissues, have not been observed in laboratory animals exposed to inhaled ethylbenzene for 4 weeks to 

6 months (Cragg et al. 1989; NTP 1992; Wolf et al. 1956), although chronic exposure is reported to 

produce hyperplasia of the thyroid and pituitary (NTP 1999). Mice exposed to 750 ppm ethylbenzene for 

2 years showed an increased incidence of follicular cell hyperplasia in the thyroid gland. In female mice 

exposed to ≥250 ppm ethylbenzene, the incidences of hyperplasia of the pituitary gland pars distalis were 

significantly greater than those in the control group. No effects on other endocrine tissues were observed 

in mice and no effects on any endocrine tissue were observed in rats exposed to 750 ppm ethylbenzene for 

2 years (NTP 1999). 

Ocular Effects. Ocular effects observed in humans and animals after inhalation exposure to 

ethylbenzene are presumed to be due to direct contact of the eyes with ethylbenzene vapor. These effects 

are discussed in Section 3.2.3.2. 

Body Weight Effects. Studies in animals examined body weight effects in acute-, intermediate-, and 

chronic-duration inhalation exposure to ethylbenzene. Mean body weight was not affected in rats or mice 

exposed to 400 ppm or in rabbits exposed to 2,400 ppm ethylbenzene for 4 days (Ethylbenzene Producers 

Association 1986a). Rats exposed to 1,200 ppm showed a mean body weight that was lower than in 

control animals. No effect on body weight was observed in rabbits after 7 days of exposure to 750 ppm 

(Romanelli et al. 1986). 

No changes in body weight were observed in pregnant rats or rabbits exposed to 985 and 962 ppm 

ethylbenzene, respectively, for 3 weeks prior to mating and throughout gestation (NIOSH 1981). A 

decrease in body weight gain of 26–48% at weeks 2, 5, and 9, but not at week 16 was observed in male 

rats exposed to 600 ppm ethylbenzene for 16 weeks (Elovaara et al. 1985). No adverse effect on body 

weight was observed in rats or mice exposed to 782 ppm or rabbits exposed to 1,610 ppm ethylbenzene 

for 4 weeks (Cragg et al. 1989). In female rats exposed to up to 500 ppm ethylbenzene daily for 28 days, 

no effects on body weight were observed (Stump 2004). No effect on body weight was observed in rats 

and mice exposed to 975 ppm ethylbenzene for 90 days (NTP 1992). Similarly, no biologically 

significant effect on body weight was observed in rats and mice exposed to concentrations of 

ethylbenzene of up to 750 ppm for 2 years (NTP 1999). 
 

 

 

 

 

 

ETHYLBENZENE 66 

3. HEALTH EFFECTS 

3.2.1.3 Immunological and Lymphoreticular Effects 

Angerer and Wulf (1985) reported increased lymphocyte counts in male varnish workers exposed to a 

mixture of solvents, including ethylbenzene, compared to an unexposed control group. Workers were 

employed for an average of 8.2 years and exposed to an average ethylbenzene concentration of 1.64 ppm. 

Average lymphocyte levels increased (41.5–68.8%) in exposed workers, compared to unexposed controls. 

However, due to concomitant exposure to other chemicals (xylenes, lead, toluene), the relationship of 

adverse hematological effects to inhaled ethylbenzene cannot be established. 

Mean total leukocyte count was significantly increased in female rats expose to 782 ppm ethylbenzene, 

but not ≤382 ppm, for 4 weeks (Cragg et al. 1989). Absolute and relative spleen weights were increased

in pregnant rats exposed to 1,000 ppm ethylbenzene during pre-mating and gestation or gestation alone, 

although histopathological changes were not observed (NIOSH 1981). Spleen weight was not affected in 

rabbits exposed to 1,000 ppm during gestation (NIOSH 1981). No histopathological changes were 

observed in bone marrow (sternum), lymph nodes, thymic region, or spleen of rats or mice exposed to 

782 ppm or rabbits exposed to 1,610 ppm ethylbenzene for 4 weeks (Cragg et al. 1989). In female rats 

exposed to ethylbenzene at concentrations up to 500 ppm for 6 hours/day, no effects were observed on 

humoral immunity (as assessed by the IgM antibody-forming response to the T cell-dependent antigen 

sheep erythrocytes), thymus or spleen weight, or blood leukocyte populations (Stump 2004). No 

treatment-related effect on the histopathology of several lymphoreticular tissues, including bronchial 

lymph nodes, regional lymph nodes, mandibular and mesenteric lymph nodes, mediastinal lymph nodes, 

spleen, or thymus were observed in rats and mice exposed to 975 ppm ethylbenzene for 90 days (NTP 

1992) or 750 ppm for 2 years (NTP 1999). 

The highest NOAELs for immunological and lymphoreticular effects in each species for intermediate- or 

chronic-duration exposure are reported in Table 3-1 and plotted in Figure 3-1. 

3.2.1.4 Neurological Effects 

Symptoms of dizziness accompanied by vertigo have been observed in humans acutely exposed to air 

concentrations of ethylbenzene ranging from 2,000 to 5,000 ppm for 6 minutes (Yant et al. 1930). 

Workers exposed occupationally for a mean of 13 years to solvent mixtures that include ethylbenzene 

(mean ethylbenzene exposure level 1.8 ppm) showed a 58% incidence of hearing loss compared to 
 

 

 

 

 

 

ETHYLBENZENE 67 

3. HEALTH EFFECTS 

36% in the reference group (Sliwinska-Kowalska et al. 2001). Hearing losses (expressed as increased 

hearing thresholds) were observed at all frequencies and appeared to range from 3 to 8 dB. The role of 

ethylbenzene in the observed losses cannot be ascertained from this study given that ethylbenzene was 

only one of several solvents, most of which were present at mean concentrations 1.5–3.5 times higher 

than ethylbenzene. 

Neurological effects have been observed in several animals following acute-duration exposure to inhaled 

ethylbenzene, although there is considerable variability in species sensitivity. In general, central nervous 

system depression is associated with acute exposure to higher concentrations, whereas stimulation of the 

motor nervous system is associated with lower concentrations. The most serious adverse neurological 

effect associated with acute- and intermediate-duration inhalation exposure to ethylbenzene is ototoxicity, 

characterized by deterioration in auditory thresholds and alterations of cochlear morphology. 

Clinical signs of general central nervous system depression or increased motor activity have been 

observed in animals acutely exposed to inhaled ethylbenzene. Moderate activation in motor behavior was 

observed in rats following a 4-hour inhalation exposure to levels of ethylbenzene ranging from 400 to 

1,500 ppm, whereas narcotic effects were observed at higher ethylbenzene concentrations (2,180– 

5,000 ppm) (Molnar et al. 1986). This study is limited by a lack of methodological detail and appropriate 

statistical analysis. Central nervous system depression (unconsciousness) and ataxia were observed in 

guinea pigs exposed to 2,000 ppm ethylbenzene for acute-duration periods (Yant et al. 1930). Salivation, 

prostration, and/or reduced activity were observed in rats and mice exposed to 2,400 or 1,200 ppm 

ethylbenzene, respectively, for 4 days (Ethylbenzene Producers Association 1986a). However, rabbits 

exposed to 2,400 ppm ethylbenzene for the same period showed no adverse behavioral effects. Exposure 

of mice to ethylbenzene for 20 minutes to ≥2,000 ppm produced changes in posture; decreased arousal 

and rearing; increased ease of handling; disturbances of gait, mobility, and righting reflex; decreased 

forelimb grip strength; increased landing foot splay; and impaired psychomotor coordination (Tegeris and 

Balster 1994). These acute effects were short-lived and more pronounced during exposure than after 

exposure, with recovery beginning within minutes of removal from the exposure chamber. Sensorimotor 

reactivity also decreased. Acute exposure of rats and mice to 245 and 342 ppm, respectively (Frantik et 

al. 1994), resulted in a 30% depression of evoked electrical activity in the brain immediately after 

exposure. 

General signs of neurotoxicity have not been observed in animals exposed to inhaled ethylbenzene for 

intermediate or chronic durations, although ethylbenzene concentrations evaluated in intermediate- and 
 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 68 

3. HEALTH EFFECTS 

chronic-duration studies were lower than those evaluated in acute studies. No behavioral changes, 

clinical signs of neurotoxicity or histopathological alterations of neurological tissues were observed in 

rats or mice exposed to concentrations of up to 782 ppm or rabbits exposed to concentrations up to 

1,610 ppm ethylbenzene for 4 weeks. Sporadic salivation was noted in rats at doses of ≥382 ppm (Cragg 

et al. 1989). In a 90-day study (NTP 1992), rats and mice showed no adverse histopathological effects on 

brain tissue at doses up to 975 ppm. No adverse effects were noted in the brain tissues of rats and mice 

exposed to concentrations of ethylbenzene of up to 750 ppm for 2 years (NTP 1999). 

Ototoxic effects of inhaled ethylbenzene have been observed following acute- or intermediate-duration 

exposure of rats. Effects are characterized by deterioration in auditory thresholds and alterations of 

cochlear morphology. Male rats exposed to ethylbenzene at 800 ppm, 8 hours/day for 5 days showed 

significant deterioration in auditory thresholds (threshold shifts were 10–20 and 17–28 dB using two 

methods) 1 and 4 weeks after the exposure had ceased (Cappaert et al. 1999). The magnitude of the 

increase in thresholds did not change between assessments conducted on post-exposure weeks 1 and 4; 

threshold shifts were evident at all tested frequencies (1–24 kHz). Eight to 11 weeks after exposure, a 

significant loss (52–66%) of outer hair cells (OHCs) in the organ of Corti in the auditory region 

corresponding to 11–21 kHz was observed. No loss of inner hair cells (IHCs) was found in the exposed 

animals (Cappaert et al. 1999). Similarly, auditory threshold shifts (approximately 15–30 dB) and OHC 

losses (25–75%) were observed 3–6 weeks after exposure in male rats exposed to 400 or 550 ppm 

ethylbenzene, 8 hours/day for 5 days. Auditory thresholds and OHC counts were not affected in rats 

exposed to 300 ppm ethylbenzene (Cappaert et al. 2000, 2001). Cappaert et al. (2002) demonstrated a 

significant species difference in the susceptibility of rats and guinea pigs to the ototoxic effects of 

ethylbenzene. Guinea pigs exposed to ethylbenzene at 2,500 ppm, 6 hours/day for 5 days did not show 

auditory deficits or losses in OHCs. There was no loss of IHCs in either species (Cappaert et al. 2002). 

Auditory deficits persisted unchanged throughout the 13-week exposure period and the 8-week postexposure recovery period in rats exposed to ≥400 ppm ethylbenzene (Gagnaire et al. 2007). Histological 

assessments conducted after the 8-week recovery period showed significant losses in OHCs in rats 

exposed to ≥200 ppm ethylbenzene, 6 hours/day, 6 days/week for 13 weeks (Gagnaire et al. 2007). IHC 

losses (14–32%) were observed in rats exposed to 600 and 800 ppm ethylbenzene, but only occasionally 

in rats exposed to 400 ppm (Gagnaire et al. 2007). 

The highest NOAEL values and all reliable LOAEL values for neurological effects in each species and 

duration category are recorded in Table 3-1 and plotted in Figure 3-1. 
 

 

 

 

 

 

ETHYLBENZENE 69 

3. HEALTH EFFECTS 

3.2.1.5 Reproductive Effects 

No studies were located regarding reproductive effects in humans following inhalation exposure to ethylbenzene. 

No adverse effects on reproduction were observed in female rats and rabbits exposed to approximately 

100 or 1,000 ppm ethylbenzene for 3 weeks prior to mating and throughout gestation (NIOSH 1981). 

Reproductive function and outcome was assessed in a 2-generation reproductive toxicity study in rats 

exposed to 25, 100, or 500 ppm ethylbenzene starting with a pre-mating exposure of ≥70 days and 

continuing through gestation day 20, lactation day 5–21, and postnatal day 21 (Faber et al. 2006). On 

lactational days 1–4 for F0 and F1 dams, inhalation exposure was discontinued and oral ethylbenzene (in 

corn oil at doses of 0, 26, 90, or 342 mg/kg/day) was administered; inhalation exposure was re-initiated 

on lactational day 5 and maintained for the remainder of the exposure period. Oral exposure on 

lactational days 1–4 was intended to provide the same maternal blood concentrations as inhalation 

exposure. Estrous cycle length was significantly reduced in F0 rats in the 500-ppm group (4.0 days vs. 

4.4 days in controls), but was not altered in the F1 females. Reproductive parameters (mating or fertility 

indices, gestation length, number of implantation sites, number of births/litter, and litter size) were not 

affected in F0 or F1 females (or males, as appropriate) exposed to 25–500 ppm ethylbenzene. 

No treatment-related histopathological changes were noted in the testes of rats, mice, or rabbits exposed 

to concentrations as high as 2,400 ppm ethylbenzene for 4 days (Ethylbenzene Producers Association 

1986a). No testicular histopathological abnormalities were reported in rats and mice exposed to 782 ppm 

and rabbits exposed to ethylbenzene concentrations as high as 1,610 ppm for 4 weeks (Cragg et al. 1989). 

NTP (1992) reported no effect on sperm or testicular morphology or on the length of the estrous cycle in 

rats or mice exposed to 975 ppm ethylbenzene for 90 days. Mice showed a decrease in epididymal 

weight in the 1,000-ppm group; however, this observation was not considered biologically significant 

since there was no significant difference in spermatid counts, sperm motility, or weight of the caudal 

epididymis among treated and control animals. Inhalation exposure of male monkeys and rabbits to 

600 ppm ethylbenzene for 6 months produced degeneration of germinal epithelium in the testes of one 

monkey and one rabbit (Wolf et al. 1956). No adverse histopathological effects were seen in the testes of 

rats or guinea pigs exposed to concentrations up to 1,250 or 600 ppm, respectively, for 6–7 months (Wolf 

et al. 1956). In a 2-generation reproduction study, no effects were observed on sperm number, motility, 

and morphology in F0 and F1 rats exposed to 25–500 ppm ethylbenzene (Faber et al. 2006). 
 

 

 

 

 

 

 

 

ETHYLBENZENE 70 

3. HEALTH EFFECTS 

The highest NOAEL values and all reliable LOAEL values for reproductive effects in each species for 

acute-, intermediate-, and chronic-duration are recorded in Table 3-1 and plotted in Figure 3-1. 

3.2.1.6 Developmental Effects 

No studies were located regarding developmental effects in humans following inhalation exposure to 

ethylbenzene. 

The developmental effects of inhaled ethylbenzene have been studied in rats (NIOSH 1981; Ungváry and 

Tátrai 1985), mice (Ungváry and Tátrai 1985), and rabbits (NIOSH 1981; Ungváry and Tátrai 1985) 

exposed during gestation or pre-mating and gestation; rats exposed from pre-gestation through lactation 

(Faber et al. 2006); and in a 2-generation reproduction study in rats (Faber et al. 2007). Results of studies 

in rats indicate that ethylbenzene produces reduced fetal weight, skeletal anomalies, and anomalies and 

delayed development of urogenital tract; skeletal and urogenital anomalies were observed in the presence 

of maternal toxicity (Faber et al. 2006; NIOSH 1981; Ungváry and Tátrai 1985). Studies conducted by 

Faber et al. (2006, 2007) and NIOSH (1981) are of high quality and guideline-compliant. However, 

usefulness of the Ungváry and Tátrai (1985) study is hampered by incomplete descriptions of the results 

and because an analysis of the results on a per litter basis was not provided. 

In rats, continuous inhalation exposure to ethylbenzene on gestational days 7–15 to concentrations 

ranging from 138 to 552 ppm resulted in fetal resorption and skeletal retardation (Ungváry and Tátrai 

1985). Retarded skeletal development was observed in 13, 26, 30, and 35% of fetuses exposed to 138, 

276, and 552 ppm ethylbenzene, respectively. Increased incidence of extra ribs and anomalies of the 

urinary tract (specific effects not reported) were observed in 7% of fetuses at 552 ppm, compared to 1% 

in controls. Maternal toxicity was reported to be moderate and dose-dependent, but data were not 

presented. In this same study, the incidence of anomalies of the uropoietic apparatus (not specified) was 

observed in the offspring of mice exposed to 115 ppm ethylbenzene on gestation days 6–15. Anomalies 

of the uropoietic apparatus were not observed in other developmental studies (Faber et al. 2006, 2007; 

Saillenfait et al. 2003, 2006, 2007). In rabbits continuously exposed to ethylbenzene on gestation days 7– 

20, decreases in female fetal body weights were observed at 115 ppm and an increase in abortions 

(3/3 does aborted compared to 0/60 in controls) were observed at 230 ppm. The Ungváry and Tátrai 

(1985) study did not include sufficient details regarding the adverse fetal effects, dictating caution in the 

interpretation of study findings. 
 

 

 

 

 

ETHYLBENZENE 71 

3. HEALTH EFFECTS 

In a NIOSH sponsored study conducted by Andrews et al. (NIOSH 1981), increases in the incidences of 

fetuses with extra ribs were observed in the offspring of rats exposed to 100 or 1,000 ppm ethylbenzene 

through gestation day 19 or 1,000 ppm during pre-mating and gestation. The incidence of supernumerary 

ribs was increased only in the offspring of rats exposed to 1,000 ppm during gestation. Reduced pup 

crown-rump length and an increased incidence of supernumerary ribs were observed in the offspring of 

rats exposed to 1,000 ppm during gestation, but not in the offspring of rats exposed to 1,000 ppm during 

pre-mating and gestation. No other significant increases in major malformations or minor anomalies were 

observed. There was some evidence of maternal toxicity (increased relative liver, kidney, and spleen 

weights) in rats exposed to 1,000 ppm ethylbenzene during pre-mating and gestation or gestation only 

(NIOSH 1981). 

Statistically significant reductions in fetal body weight were observed in the offspring of pregnant rats 

exposed to ≥1,000 ppm ethylbenzene during gestation (Saillenfait et al. 2003, 2006, 2007), but not in rats

exposed to 500 ppm (Saillenfait et al. 2003) or 250 ppm (Saillenfait et al. 2006, 2007). A significant 

increase in the number of fetuses with fetal malformations (mostly skeletal variations) was observed in 

the offspring of rats exposed to ≥1,000 ppm ethylbenzene (Saillenfait et al. 2003, 2006, 2007). On a per

litter basis, a significant increase in the incidence of fetal malformations was observed only at 2,000 ppm 

(Saillenfait et al. 2003). Maternal toxicity was observed in rats exposed to ≥1,000 ppm, as indicated by

significant reductions in maternal weight gain compared to control animals (Saillenfait et al. 2003, 2006, 

2007). 

Survival from birth to postnatal days (PND) 4 and 21 was not affected in F1 or F2 offspring of pregnant 

rats exposed to ethylbenzene at 25, 100, or 500 ppm during premating, mating, gestation, and lactation 

(Faber et al. 2006). A statistically significant delay in balanopreputial separation was observed in F1 

males in the 500 ppm group, although the mean age at separation in that group (44.7 days) was similar to 

that observed in historical controls (44.8 days). No exposure-related macroscopic findings or changes in 

organ weight in F1 pups necropsied on PND 21 were observed. 

Results of a 2-generation reproduction study in rats show that the mean age at acquisition of vaginal 

patency was significantly reduced in F1 females at 25, 100, and 500 ppm; however, the values in the 

treated groups (33.3–33.9 days) were similar to the historical control value (33.4 days) in the conducting 

laboratory (Faber et al. 2006). F2 generation pups (which were not exposed to ethylbenzene by 

inhalation) did not show differences from controls in the age at preputial separation or vaginal patency 
 

 

 

 

 

 

 

 

ETHYLBENZENE 72 

3. HEALTH EFFECTS 

(Faber et al. 2007). Developmental landmarks (pinna detachment, hair growth, incisor eruption, and eye 

opening) were not affected in F1 male or female pups exposed to 25–500 pm ethylbenzene (Faber et al. 

2006); however, in the F2 generation, statistically significant delays in hair growth were observed in 

males and females in all exposure groups and eye opening was significantly delayed in males the 25 and 

100 ppm groups, but not in the 500 ppm group (Faber et al. 2007). Neurodevelopmental tests conducted 

on subsets of the F2 offspring (Faber et al. 2007) did not show statistically significant differences from 

controls in a functional observational battery assessment or in fore- or hind-limb grip strength. Although 

the data suggest an increase in motor activity in F2 males and females in the 25–500 ppm groups on 

PNDs 13 and 17, there were no statistical differences in motor activity on PNDs 13, 17, and 21 between 

exposed and control animals (Faber et al. 2007). A statistically significant increase in motor activity was 

observed on PND 61 in F2 females in the 25 ppm group only. Startle response was not affected in F2 rats 

of either sex on PND 20 or females on PND 60; F2 males showed statistically lower startle responses, but 

this was attributed to highly variable and abnormal responses in some control animals. Swimming ability, 

learning, and memory assessments conducted in a Biel water maze did not reveal any significant effects 

in F2 animals in any of the exposure groups (Faber et al. 2007). No morphometric or histologic effects in 

brains of F2 animals were observed from any exposure group on PND 21 or 72 (Faber et al. 2007). 

Reduced fetal weight was observed in female rats exposed to 115 ppm during gestation (Ungváry and 

Tátrai 1985). In the offspring of rabbits exposed to ethylbenzene, no treatment-related effects were 

observed in fetal size, placental weight, or intrauterine growth retardation and there were no significant 

incidences of major malformations, minor anomalies, or common variants observed in the absence of 

maternal toxicity (NIOSH 1981). 

The highest NOAEL values and all reliable LOAEL values for developmental effects in each species and 

duration category are recorded in Table 3-1 and plotted in Figure 3-1. 

3.2.1.7 Cancer 

No association has been found between the occurrence of cancer in humans and occupational exposure to 

ethylbenzene. No cases of malignancy were observed in workers exposed to ethylbenzene monitored for 

20 years (Bardodej and Cirek 1988). No information on ethylbenzene concentrations was reported, 

although an estimated concentration of 6.4 mg/m3 was derived as described above under hematological 

effects (Section 3.2.1.3). However, no clear conclusions can be drawn from this study due to the lack of 

measured ethylbenzene concentrations. Furthermore, the low exposure concentration limited the power 
 

 

 

 

 

ETHYLBENZENE 73 

3. HEALTH EFFECTS 

of this study to detect any effect. No other studies were found regarding cancer effects in humans 

exposed to ethylbenzene by inhalation. 

Information concerning the carcinogenicity of ethylbenzene in animals comes from an NTP-sponsored 

bioassay in male and female rats and mice exposed to 0, 75, 250, or 750 ppm ethylbenzene for up to 

2 years (NTP 1999). NTP (1999) concluded that ethylbenzene showed clear evidence of carcinogenic 

activity in male rats based on increased incidences of renal tubule neoplasms and testicular adenomas, 

some evidence of carcinogenic activity in female rats based on increased incidences of renal tubule 

adenomas, some evidence of carcinogenic activity in male mice based on increased incidences of 

alveolar/bronchiolar neoplasms, and some evidence of carcinogenic activity in female mice based on 

increased incidences of hepatocellular neoplasms (NTP 1999). 

Pathological findings in male and female rats exposed to 750 ppm ethylbenzene showed significant 

increases in the incidence of renal tubule adenoma and adenoma or carcinoma (combined) compared to 

control animals. An extended histopathological evaluation of the kidneys showed significant increases in 

the incidence of nephropathy and of renal tubular hyperplasia (a preneoplastic lesion) in male rats 

exposed to 750 ppm; in female rats, nephropathy was observed at concentrations ≥75 ppm and renal

tubular hyperplasia was only observed at a concentration of 750 ppm. In a reevaluation of the 

histopathology of rat kidneys from the NTP study, Hard (2002) confirmed the NTP (1999) findings and 

suggested that the increase incidence of kidney tumors in rats in the high-dose group was related to a 

chemical-induced exacerbation of chronic progressive nephropathy (CPN), with a minor contributing 

factor in male rats being α2μ-globulin nephropathy. However, in an analysis of the association between 

CPN and renal tubule cell neoplasms in male F344 rats, Seely et al. (2002) concluded that the association 

between CPN and renal tubule cell neoplasms is marginal. Results of this analysis suggest that the 

number of renal tubule cell neoplasms secondary to CPN would be few (Seely et al. 2002). The incidence 

of interstitial cell adenoma in the testes of males exposed to 750 ppm was significantly greater than in the 

control group and slightly exceeded the historical control range for inhalation studies. The incidence of 

bilateral testicular adenoma was also significantly increased in males exposed to 750 ppm. 

In male mice, the incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or 

carcinoma (combined) were significantly greater in males exposed to 750 ppm than in the controls. No 

significant increased in the incidence of neoplastic lung lesions was observed in female rats. The 

incidences of hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined) were 
 

 

 

 

 

 

 

 

ETHYLBENZENE 74 

3. HEALTH EFFECTS 

significantly greater in female mice exposed to 750 ppm than in the control group. Hepatocellular 

adenomas or carcinomas were not observed in male mice. 

3.2.2 Oral Exposure 

3.2.2.1 Death 

No studies were located regarding death in humans following oral exposure to ethylbenzene. 

Lethality has been observed in laboratory animals following ingestion of ethylbenzene. The oral LD50 for 

gavage administration of ethylbenzene was reported to be 4,769 mg/kg ethylbenzene in rats (Smyth et al. 

1962). In another oral study with rats exposed to ethylbenzene, the LD50 was reported to be 

approximately 3,500 mg/kg ethylbenzene (Wolf et al. 1956). The usefulness of these data is limited since 

the study methodology was not provided. 

An oral LD50 value for rats is recorded in Table 3-2 and plotted in Figure 3-2. 

3.2.2.2 Systemic Effects 

No studies were located describing respiratory, cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, endocrine, dermal, ocular, body weight, or metabolic effects in humans or gastrointestinal, musculoskeletal, endocrine, dermal, ocular, body weight, or metabolic effects in animals after 

oral exposure to ethylbenzene. 

The highest NOAEL values and all reliable LOAEL values are recorded in Table 3-2 and plotted in 

Figure 3-2. 

Respiratory Effects. No clinical signs of respiratory effects or histopathological findings in 

respiratory tissues were observed in male and female rats exposed to 750 mg/kg/day by gavage for 4 or 

13 weeks (Mellert et al. 2007). No respiratory effects were observed in female rats orally exposed to 

680 mg/kg ethylbenzene by gavage for 6 months (Wolf et al. 1956). The utility of this study is limited 

because of poor protocol description. 
13

4769

963

900

981

75075075075

250

75

250

Table 3-2 Levels of Significant Exposure to Ethylbenzene - Oral 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

ACUTE EXPOSURE Death 

System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

1 Rat 

(CarworthWistar) 

once (G) 4769 M (LD50) Smyth et al. 1962 

Neurological 

2 Rat 

(SD) 

1 x/d 5 d/wk 2 wk 

900 M (complete loss of outer 

hair cells in cochlea) 

Gagnaire and Langlais 

(G) 

INTERMEDIATE EXPOSURE Systemic 

3 Rat 

(Wistar) 

4 wk 7 d/wk 2 x/d (GO) 

Resp 750 Mellert et al. 2007 

Cardio 750 Hemato 750 Hepatic 75 M 250 M (increased absolute and 

relative liver weights, increased incidence of centrilobular hepatocyte hypertrophy) 

Renal 75 M 250 M (hyaline droplet 

nephropathy) 
984

750750250

750

75

250

75

250

Table 3-2 Levels of Significant Exposure to Ethylbenzene - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

4 Rat 

(Wistar) 

13 wk 7 d/wk 2 x/d (GO) 

Resp 750 Mellert et al. 2007 

Cardio 750 Hemato 250 750 (increased mean 

corpuscular volume in males and females, decreased platelet counts in females) 

Hepatic 

b

75 250 (increased serum liver 

enzymes in males, increased absolute and relative liver weights in males and females, increased incidence of centrilobular hepatocyte hypertrophy in males and females) 

Renal 75 M 250 M (hyaline droplet 

nephropathy) 
29

680136

408

136

408

989

500

982

750

Table 3-2 Levels of Significant Exposure to Ethylbenzene - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

5 Rat 6 mo 

5 d/wk 1 x/d (GO) 

Hemato 680 F Wolf et al. 1956 

Hepatic 136 F 408 F (increased liver weight; 

cloudy swelling of parenchymal liver cells) 

Renal 136 F 408 F (increased kidney weight; 

cloudy swelling of kidney tubular epithelium) 

Neurological 

6 Rat 

(CD) 

2 x/d 13 wk (G) 

500 Barnett 2006 

7 Rat 

(Wistar) 

4 wk 7 d/wk 2 x/d (GO) 

750 Mellert et al. 2007 
985

750

983

750

986

750

Table 3-2 Levels of Significant Exposure to Ethylbenzene - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

8 Rat 

(Wistar) 

Reproductive 

9 Rat 

(Wistar) 

10 Rat 

(Wistar) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

13 wk 7 d/wk 2 x/d (GO) 

750 Mellert et al. 2007 

4 wk 7 d/wk 2 x/d (GO) 

750 Mellert et al. 2007 

13 wk 7 d/wk 2 x/d (GO) 

750 Mellert et al. 2007 

a The number corresponds to entries in Figure 3-2. b Used to derive an intermediate-duration oral MRL of 0.4 mg/kg/day based on a BMDL using an internal dose metric to simulate time averaged liver concentration (6.61 μmol/L); a human equivalent dose (HED) of the BMDL was estimated using a human PBPK model. The BMDL(HED) (10.68 mg/kg/day) was divided by an un30 (3 for extrapolation from animals to humans with dosimetric adjustment and 10 for human variability). Cardio = cardiovascular; d = day(s); F = Female; (G) = gavage; (GO) = gavage in oil; Hemato = hematological; LD50 = lethal dose, 50% kill; LOAEL = lowest-obserlevel; M = male; mo = month(s); NOAEL = no-observed-adverse-effect level; Resp = respiratory; wk = week(s); x = time(s) 
Figure 3-2 Levels of Significant Exposure to Ethylbenzene - Oral
	

Acute (≤14 days)
	

Death 

mg/kg/day 

Neurological 

10000 

1r 

1000 

2r 

100 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans Minimal Risk Level

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans for effects

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans other than

q-Cow a-Sheep g-Guinea Pig Cancer 

ETHYLBENZENE 3. HEALTH EFFECTS 79
Figure 3-2 Levels of Significant Exposure to Ethylbenzene - Oral (Continued)

Intermediate (15-364 days) 

Systemic 

Respiratory 

Cardiovascular 

Hematological 

Hepatic 

Renal 

mg/kg/day 

Neurological 

Reproductive 

1000 

3r 4r 3r 4r 3r 4r 7r 8r 9r 10r 5r 

6r 

5r 5r 

4r 3r 4r 3r 4r 

5r 5r 

100 

3r 4r 3r 4r 

10 

1 

0.1 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans Minimal Risk Level

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans for effects

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans other than

q-Cow a-Sheep g-Guinea Pig Cancer 

ETHYLBENZENE 3. HEALTH EFFECTS 80
 

 

 

 

 

 

 

 

ETHYLBENZENE 81 

3. HEALTH EFFECTS 

Cardiovascular Effects. No histopathological findings were made in cardiac tissue from male and 

female rats exposed to 750 mg/kg/day by gavage for 4 or 13 weeks (Mellert et al 2007) or from female 

rats exposed to 13.6–680 mg/kg via gavage for 6 months (Wolf et al. 1956) 

Hematological Effects. Decreased platelet count was observed in females administered 

750 mg/kg/day and increased mean corpuscular volume was observed in males and females exposed to 

≥250 mg/kg/day ethylbenzene by gavage for 13 weeks (Mellert et al 2007). No effects on hematological 

parameters were observed in rats treated for 4 weeks (Mellert et al. 2007). No adverse effects on bone 

marrow counts or histopathology were reported in female rats orally exposed to 13.6–680 mg/kg 

ethylbenzene by gavage for 6 months (Wolf et al. 1956). The usefulness of this study is limited by the 

poorly described and limited results that were provided. 

Hepatic Effects. Effects indicative of liver toxicity were observed in male and female rats exposed to 

oral ethylbenzene for 4 and 13 weeks (Mellert et al. 2007). After 4 weeks of exposure, observed effects 

consistent with hepatotoxicity included increased absolute and relative liver weights (≥250 mg/kg/day in 

males and 750 mg/kg/day in females), increased incidence of hepatocyte centrilobular hypertrophy 

(≥250 mg/kg/day in males and 750 mg/kg/day in females), and increase serum liver enzyme activity 

(alanine aminotransferase) (750 mg/kg/day in males and females) (Mellert et al. 2007). After 13 weeks of 

exposure, increased activity of serum liver enzymes (alanine aminotransferase and γ-glutamyl transferase) 

in males (≥250 mg/kg/day) and females (750 mg/mg/day), increased absolute and relative liver weights 

(≥250 mg/kg/day in males and females), and a dose-related increase in the incidence of centrilobular 

hepatocyte hypertrophy (≥250 mg/kg/day in males and females) were observed. Increased bilirubin 

(≤250 mg/kg/day in males and 750 mg/kg/day in females), total protein (750 mg/kg/day in females), 

albumin (750 mg/kg/day in males and females), globulins (750 mg/kg/day in females), and cholesterol 

(≤250 mg/kg/day in males and females), and decreased prothrombin time (750 mg/kg/day in males and 

≥250 mg/kg/day in females) were considered by study investigators as adaptive effects in the liver. In

males in the 75 mg/kg/day group, relative liver weight was significantly increased by (4% compared to 

controls); however, no histopathological changes, or increases in absolute liver or serum liver enzyme 

activities were observed at this dosage. Given that ethylbenzene is a microsomal enzyme inducer, and the 

absence of histopathology and other evidence of liver injury at the 75 mg/kg/day dosage, the small 

increase in relative liver weight in male rats was at this dosage not considered evidence for an adverse 

effect on the liver (Mellert et al. 2007). Histopathological changes characterized by cloudy swelling of 

parenchymal cells of the liver and an increase in liver weight were observed in female rats administered 

408 mg/kg/day for 6 months (Wolf et al. 1956). No other hepatic changes were reported. No liver effects 
 

 

 

 

 

 

ETHYLBENZENE 82 

3. HEALTH EFFECTS 

were observed in female rats administered 136 mg/kg/day. No conclusions could be drawn from these 

results because of serious weaknesses in the methodology and reporting of the data, including incidence 

data and statistical analyses. 

Renal Effects. Renal effects in males administered ethylbenzene by gavage for 13 weeks included 

increased serum creatinine (750 mg/kg/day), increased incidences of transitional epithelial cells and 

granular and epithelial cell casts in the urine (≥250 mg/kg/day), increased absolute and relative kidney

weights (≥250 mg/kg/day), and a dose-related increase in severity of hyaline droplet nephropathy 

(≥250 mg/kg/day) (Mellert et al. 2007). Adverse renal effects in males were most likely related to 

accumulation of α2μ-globulin accumulation, and, therefore, considered not relevant to humans. Similar 

renal findings were observed in male rats exposed for 4 weeks (administered ethylbenzene by gavage for 

13 weeks). Absolute kidney weight was significantly increased by 7 and 13% in females administered 

250 and 750 mg/kg-day, respectively, compared to controls. However, since no histopathological 

findings or alterations in urinalysis parameters were observed, increased kidney weight in females was 

not considered evidence for renal toxicity in female rats. The only animal study that investigated renal 

effects following ethylbenzene exposure involved female rats administered 13.6–680 mg/kg/body weight 

ethylbenzene by gavage for 6 months (Wolf et al. 1956). Histopathological changes characterized as 

cloudy swelling of the tubular epithelium in the kidney and an increase in kidney weight were observed at 

the 408 mg/kg/day dose level. No other renal changes were reported. As in hepatic effects, no 

conclusions could be drawn from these results because of serious weaknesses in the methodology and 

reporting of the data (e.g., no data on the number of animals with renal effects). Furthermore, no 

statistical analysis was performed. 

3.2.2.3 Immunological and Lymphoreticular Effects 

No studies were located regarding immunological effects in humans following oral exposure to ethylbenzene. 

Absolute and relative thymus weights were significantly decreased in females treated with 

≥250 mg/kg/day for 13 weeks, but no histopathological findings were observed (Mellert et al. 2007). 

Therefore, effects were not considered adverse. 
 

 

 

 

 

 

ETHYLBENZENE 83 

3. HEALTH EFFECTS 

3.2.2.4 Neurological Effects 

No studies were located regarding neurological effects in humans following oral exposure to ethylbenzene. 

Significant ototoxic effects were observed in male rats administered 900 mg/kg/day (the only dose tested) 

by gavage for 2 weeks (Gagnaire and Langlais 2005). The authors reported an almost complete loss of 

the three rows of OHCs in the organ of Corti 10 days after the last exposure to ethylbenzene. This study 

did not have a control group to clearly establish the magnitude of the effects relative to unexposed 

animals; nevertheless, this study showed that the losses observed in ethylbenzene-exposed animals were 

among the highest observed among 21 organic solvents tested (Gagnaire and Langlais 2005). No 

ethylbenzene-related behavioral changes were observed in female rats administered 13.6–680 mg/kg/day 

ethylbenzene by gavage for 6 months (Wolf et al. 1956). No other parameters were investigated. The 

utility of this study is limited because the monitored behavioral changes were not reported, and the study 

protocol was poorly described. 

In male and female rats exposed to 75–750 mg/kg/day ethylbenzene by gavage for 13 weeks, no 

neurological effects were observed, based on negative results of motor activity tests and a functional 

observational battery (FOB) (Mellert et al. 2007). Similarly, no neurological effects were observed in 

male or female rats admininistered 50–500 mg/kg/day ethylbenzene by gavage for 13 weeks, based on 

negative findings for FOB and motor activity assessments and for histopathology to neurological tissues 

(Barnett 2006). However, assessments of ototoxicity were not conducted in these studies. 

3.2.2.5 Reproductive Effects 

No studies were located regarding reproductive effects in humans following oral exposure to 

ethylbenzene. 

The only available reproduction study reported that acute oral exposure to 500 or 1,000 mg/kg ethylbenzene decreases peripheral hormone levels and may block or delay the estrus cycle in female rats 

during the diestrus stage (Ungváry 1986). Decreased levels of hormones, including luteinizing hormone, 

progesterone, and 17 β-estradiol, were accompanied by uterine changes, which consisted of increased 

stromal tissue with dense collagen bundles and reduced lumen. No dose response was noted. The study 

is limited by the absence of statistical analysis of the data. 
 

ETHYLBENZENE 84 

3. HEALTH EFFECTS 

No histopathological findings of reproductive tissues were observed in male and female rats exposed to 

750 mg/kg/day by gavage for 4 or 13 weeks (Mellert et al. 2007). 

3.2.2.6 Developmental Effects 

No studies were located regarding developmental effects in humans or animals following oral exposure to 

ethylbenzene. 

3.2.2.7 Cancer 

No studies were located regarding carcinogenic effects in humans following oral exposure to 

ethylbenzene. 

The carcinogenicity of ethylbenzene by the oral route has been evaluated in a chronic-duration study in 

Sprague-Dawley rats (Maltoni et al. 1985). A statistically significant increase in total malignant tumors 

was reported in females and in combined male and female groups exposed to 500 mg kg/day via gavage 

for 104 weeks and observed until after week 141. No data on specific tumor type were presented, only 

one dose was tested, and no information on survival was provided. 

3.2.3 Dermal Exposure 

3.2.3.1 Death 

No studies were located regarding lethal effects in humans following only dermal exposure to ethylbenzene. Matsumoto et al. (1992) reported the case of a 44-year-old man who died 9 days after being 

massively exposed to gasoline (which contained ethylbenzene) dermally and by inhalation for ≥10 hours.

The dermal LD50 in rabbits exposed to liquid ethylbenzene (applied to clipped skin subsequently covered 

with an impervious plastic film) was calculated to be 15,433 mg/kg/body weight (Smyth et al. 1962). No 

additional studies were located regarding death in animals following dermal exposure to ethylbenzene. 

3.2.3.2 Systemic Effects 

No studies were located regarding respiratory, cardiovascular, gastrointestinal, hematological, 

musculoskeletal, hepatic, renal, endocrine, body weight, or metabolic effects in humans or animals after 

dermal exposure to ethylbenzene. 
 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 85 

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The systemic effects observed after dermal exposure to ethylbenzene are discussed below. The highest 

NOAEL values and all reliable LOAEL values for each species and duration category are recorded in 

Table 3-3. 

Dermal Effects. No studies were located regarding dermal effects in humans following dermal 

exposure to ethylbenzene. 

Liquid ethylbenzene applied directly to the skin of an unspecified number of rabbits caused irritation 

characterized by reddening, exfoliation, and blistering (Wolf et al. 1956). Mild dermal irritation (grade 2 

on a scale of 10) was also noted in New Zealand White rabbits 24 hours after application of ethylbenzene 

to clipped skin (Smyth et al. 1962). 

Ocular Effects. Ocular effects observed in humans and animals after inhalation exposure are assumed 

to be due to exposure of the mucous membranes of the eye to ethylbenzene vapor. Volunteers reported 

eye irritation and burning, and profuse lacrimation, which gradually decreased with continued exposure to 

1,000 ppm for 1–6 minutes (Yant et al. 1930). Upon entering the chamber with an ethylbenzene 

concentration of 2,000 or 5,000 ppm, the volunteers also experienced severe eye irritation. 

Cometto-Muñiz and Cain (1995) reported eye irritation in humans after exposure to ethylbenzene vapor. 

Eye irritation was observed at 10,000 ppm. 

Liquid ethylbenzene applied directly to the eyes of rabbits for an unspecified duration caused slight 

irritation of conjunctival membranes (Wolf et al. 1956) and slight corneal injury (Smyth et al. 1962; Wolf 

et al. 1956). 

Irritant effects from exposure to ethylbenzene vapor have been reported in animals. Tegeris and Balster 

(1994) reported lacrimation and palpebral closure in mice after 20 minutes of exposure to 2,000 ppm 

ethylbenzene. Eye irritation was observed in guinea pigs exposed to 1,000 ppm for 8 minutes, and in 

animals exposed to 2,000, 5,000, and 10,000 ppm for 480, 30, and 10 minutes, respectively (Yant et al. 

1930). Lacrimation was observed in rats exposed to 1,200 ppm ethylbenzene and in mice and rabbits 

exposed to 400 ppm ethylbenzene for 4 days (Ethylbenzene Producers Association 1986a). After 4 weeks 

of exposure to 382 ppm, rats showed sporadic lacrimation, whereas mice and rabbits showed no ocular 

effects at 782 and 1,610 ppm, respectively (Cragg et al. 1989). No ocular effects were seen in rats or 

mice after a 13-week exposure to 975 ppm ethylbenzene (NTP 1992). 
502 mg/kg/day

503 mg902

ppm

903

ppm

Table 3-3 Levels of Significant Exposure to Ethylbenzene - Dermal 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

ACUTE EXPOSURE 

Death 

(New Zealand) Rabbit 24 hr 

System NOAEL Less Serious 

LOAEL 

15433 M 

mg/kg/day 

Serious 

(LD50) 

Reference Chemical Form 

Smyth et al. 1962 

Systemic 

(New Zealand) Rabbit 24 hr Dermal 8.67 

mg 

(grade 4 skin irritation) Smyth et al. 1962 

INTERMEDIATE EXPOSURE 

Systemic 

(F344/N) Rat 13 wk 

5 d/wk 6 hr/d 

Ocular 975 B 

ppm 

NTP 1992 

(B6C3F1) Mouse 13 wk 

5 d/wk 6 hr/d 

Ocular 975 B 

ppm 

NTP 1992 

B = males and females; d = day(s); hr = hour(s); LD50 = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; M = male; NOAEL = no-observed-advparts per million; wk = week(s) 
 

 

 

 

 

 

ETHYLBENZENE 87 

3. HEALTH EFFECTS 

No studies were located regarding the following health effects in humans or animals after dermal 

exposure to ethylbenzene: 

3.2.3.3 Immunological and Lymphoreticular Effects 

3.2.3.4 Neurological Effects 

3.2.3.5 Reproductive Effects 

3.2.3.6 Developmental Effects 

3.2.3.7 Cancer 

3.3 GENOTOXICITY 

Holz et al. (1995) reported no increase in sister chromatid exchanges, DNA adduct formation, 

micronuclei, or DNA single-strand breaks in the peripheral lymphocytes of workers exposed to low levels 

of ethylbenzene and other aromatic hydrocarbons (benzene, toluene, and xylene) in a styrene plant. 

Chromosomal aberrations were observed in peripheral blood lymphocytes of workers concomitantly 

exposed to ethylbenzene (0.2–13.1 mg/m3

) and benzene (0.4–15.1 mg/m3) (Sram et al. 2004). Although a 

reduction in exposure (reduced ethylbenzene and benzene concentrations not reported) reduced 

chromosomal aberrations, due to concomitant exposure to benzene, an association between chromosomal 

damage and ethylbenzene exposure cannot be established. No significant alterations in micronuclei 

formation were observed in peripheral blood erythrocytes of B6C3F1 mice exposed to 500–1,000 ppm 

ethylbenzene 6 hours/day, 5 days/week for 13 weeks (NTP 1992, 1999) or in polychromatic erythrocytes 

in the bone marrow of NMRI mice administered two daily doses of 0.37–0.75 mL/kg via intraperitoneal 

injection (Mohtashamipur et al. 1985). Similarly, inhalation exposure of B6C3F1 mice to 375–1,000 ppm 

ethylbenzene for 6 hours did not induce DNA repair (as assessed by unscheduled DNA synthesis) in 

hepatocytes (Clay 2001). The in vivo genotoxicity data in laboratory animals are shown in Table 3-4. 

The genotoxic potential of ethylbenzene has been investigated primarily using in vitro assays in 

Salmonella typhimurium, Escherichia coli, Saccharomyces cerevisiae, Chinese hamster ovary cells, 

mouse lymphoma cells, Syrian hamster embryo cells, and human lymphocytes. Results of these in vitro 

genotoxicity studies are shown in Table 3-5. The available data indicate that ethylbenzene is not 

mutagenic in bacteria (Dean et al. 1985; Degirmenci et al. 2000; Florin et al. 1980; Kubo et al. 2002; 

Nestmann et al. 1980; NTP 1986, 1999; Zeiger et al. 1992) or yeast cells (Dean et al. 1985; Nestmann and 

Lee 1983) in the presence or absence of metabolic activation. Ethylbenzene was found to induce forward 
 

 

ETHYLBENZENE 88 

3. HEALTH EFFECTS 

Table 3-4. Genotoxicity of Ethylbenzene In Vivo 

Species (test system) End point Results Reference 

B6C3F1 mice (inhalation Micronuclei formation in – NTP 1992, 1999 

exposure 6 hours/day, peripheral blood 

5 days/week for erythrocytes 

13 weeks) 

NMRI mice Micronuclei formation in – Mohtashamipur et al. 1985 

(intraperitoneal injection) polychromatic bone 

marrow erythrocytes 

B6C3F1 mice (inhalation Unscheduled DNA – Clay 2001 

6 hours) synthesis in hepatocytes 

– = negative result; DNA = deoxyribonucleic acid 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 89 

3. HEALTH EFFECTS 

Table 3-5. Genotoxicity of Ethylbenzene In Vitro 

Results 

With Without 

Species (test system) End point activation activation Reference 

Prokaryotic organisms: 

Salmonella typhimurium Gene mutation – – Dean et al. 1985a

; Florin et 

(plate incorporation assay) al. 1980b; Nestmann et al. 

1980c 

S. tymphimurium (plate Gene mutation – – NTP 1986d
 

incorporation assay; strains
 

TA87, TA98, TA100,
 

TA1537; TA1538)
 

S. tymphimurium (plate Gene mutation – – Zeiger et al. 1992d (results
 

incorporation assay; strains also published in NTP 1992,
 

TA97, TA98, TA100, 1999)
 

TA1535)
 

Escherichia coli WP2, Gene mutation – –	 Dean et al. 1985a 

WP2uvrA 

Eukaryotic organisms: 

Saccharomyces cerevisiae Gene mutation – – Dean et al. 1985 

JD1 gene conversion assay 

S. cerevisiae Dy, Gene mutation – No data Nestmann and Lee 1983 

XV185-14C 

Mammalian cells: 

Mouse lymphoma cells Gene mutation No data +	 McGregor et al. 1988 

(results also published in 

NTP 1992, 1999) 

Mouse lymphoma cells Gene mutation – – Seidel et al. 2006
 

Mouse lymphoma cells Gene mutation – – Wollny 2000
 

Rat liver (RL4) epithelial type Chromosome – – Dean et al. 1985
 

cells damage 

Chinese hamster ovary cells Chromosome – – NTP 1992, 1999 

damage 

Syrian hamster embryo cells Micronuclei No data + Gibson et al. 1997 

formation 

Human lymphocytes Sister chromatid Not ±e Norppa and Vainio 1983a 

exchange applicable 

Chinese hamster ovary cells Sister chromatid – – NTP 1986, 1992, 1999 

exchange 

Syrian hamster embryo cells Cell No data + Kerckaert et al. 1996 

transformation 
 

 

 

 

ETHYLBENZENE 90 

3. HEALTH EFFECTS 

Table 3-5. Genotoxicity of Ethylbenzene In Vitro 

Results 

With Without 

Species (test system) End point activation activation Reference 

Human lymphocytes	 DNA single strand No data + Chen et al. 2008 

breaks 

Human lymphocytes	 DNA double No data – Chen et al. 2008 

strand breaks 

a

Concentrations of ethylbenzene tested: 0, 0.2, 2, 20, 500, or 2,000 μg/plate (>99% pure)
	 b

Concentrations of ethylbenzene tested: 0, 3, 31, 318, or 3,184 μg/plate (0, 0.03, 0.3, 3, or 30 μmole/plate)
	 c

Concentrations of ethylbenzene tested: 0.4 mg/plate
 d

Concentrations of ethylbenzene tested: 0, 10, 33, 110, 333, 666, or 1,000 μg/plate
	 e

Also cytotoxic.
 

C = negative result; + = positive result; ± = weakly positive 
 

 

 

 

 

 

 

ETHYLBENZENE 91 

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mutations in mouse lymphoma cells at 80 mg/L without metabolic activation (McGregor et al. 1988; 

results also reported in NTP 1992, 1999); this concentration was near the lethal concentration of 

100 mg/L. Similarly, no alterations in the occurrence of forward mutations in mouse lymphoma cells 

(with or without activation) were observed at concentrations of ≤50 mg/L (Seidel et al. 2006). A third

study examining the occurrence of forward mutations in mouse lymphoma cells (Wollny 2000) found a 

positive response at cytotoxic concentrations (34.4 and 68.8 μg/mL without metabolic activation and 

825 μg/mL with activation); however, two replications of the experiment failed to find a positive 

mutagenic response. A weak positive response was observed when ethylbenzene was tested for sister 

chromatid exchanges in human lymphocytes (Norppa and Vainio 1983a); however, the positive response 

was only observed at a cytotoxic concentration. Ethylbenzene also failed to induce sister-chromatid 

exchanges in Chinese hamster ovary cells (NTP 1986, 1999) or chromosomal aberrations in Chinese 

hamster cells (NTP 1986, 1999) or rat liver cells (Dean et al. 1985). A positive dose-related increase in 

the occurrence of micronuclei formation were observed in Syrian hamster embryo cells tested at 

ethylbenzene concentrations of 25–200 μg/mL (Gibson et al. 1997). A significant increase in 

morphological cells transformations was also observed in Syrian hamster embryo cells exposed to 150 or 

200 μg/mL for 7 days (Kerckaert et al. 1996); the 200 μg/mL concentration resulted in significant 

cytotoxicity. In this same study, no significant alterations the percent cell transformations were observed 

when the cells were incubated with ethylbenzene for 24 hours. A series of studies conducted by Chen et 

al. (2008) evaluated the potential of ethylbenzene to induce DNA damage in human lymphocytes. A 

significant increase in single strand breaks was observed at 100 and 200 μM; no alterations in double 

strand breaks were found at 200 μM. The study also found a significant decrease in DNA damage in cells 

pre-treated with spin traps, suggesting that the DNA damage may be due to the generation of free 

radicals. 

In general, the results of available in vivo and in vitro genotoxicity studies suggest that ethylbenzene is 

not genotoxic. Excluding studies that found results at cytotoxic or near cytotoxic concentrations, a few 

studies have found positive results. The significance of these positive findings is not known. 

3.4 TOXICOKINETICS 

Ethylbenzene is absorbed from the lungs, gastrointestinal tract, and through the skin. Absorbed 

ethylbenzene is rapidly eliminated (blood t1/2 1 hour) by metabolism and excretion of metabolites. The 

major metabolic pathways are side chain and ring hydroxylation with subsequent formation of 

O-glucuronide and sulfate conjugates. Conjugates, mandelic acid and phenylglyoxylic acid are the 
 

 

 

 

ETHYLBENZENE 92 

3. HEALTH EFFECTS 

primary excreted metabolites. The distribution of ethylbenzene to tissues has been modeled as a flowlimited process (i.e., clearance from blood to tissues can be predicted by tissue blood flow) with rapid 

equilibrium achieved between blood and tissues. Measured blood:tissue partition coefficients in the rat 

are approximately as follows: fat, 36; liver, 2; and muscle, 0.6. These values predict the same order for 

tissue concentrations for any given blood concentration; however, this order has not been verified 

experimentally with simultaneously measured blood and tissue ethylbenzene concentrations in vivo. 

3.4.1 Absorption 

3.4.1.1 Inhalation Exposure 

Inhalation studies in humans demonstrate that ethylbenzene is rapidly absorbed via this route (Bardodej 

and Bardodejova 1970; Gromiec and Piotrowski 1984; Knecht et al. 2000; Tardif et al. 1997). A steadystate blood:alveolar air concentration ratio of approximately 30 was achieved within 1 hour of initiating 

exposure (Tardif et al. 1997). Volunteers exposed for 8 hours to ethylbenzene at concentrations of 23– 

85 ppm were shown to retain 64% of the inspired vapor, with only trace amounts detected in expired air at 

the end of the exposure period (Bardodej and Bardodejova 1970). Another inhalation study that involved 

humans exposed to similar levels of ethylbenzene demonstrated mean retention rates of 49% (Gromiec 

and Piotrowski 1984). The differences may be attributable to human variability in absorption rates 

although they could also be due to differences in methodology. 

An initial concentration of ethylbenzene in blood of 2.6 μg/mL and a half-life of 27.5 hours were 

estimated in a 44-year-old man who died after a massive inhalation and dermal exposure of ≥10 hours to 

gasoline (Matsumoto et al. 1992). This absorption value may have been slightly overestimated, however, 

because possible contributions from dermal exposure were not addressed. 

In a study conducted in Italy, blood concentrations of ethylbenzene in non-smoking policemen working as 

traffic wardens showed no significant differences between before and after work shift values or from 

blood ethylbenzene concentrations in policemen working indoors (Fustinoni et al. 1995). Indoor and 

outdoor mean air concentrations (measured by personal air samplers) were 21 and 37 mg/m3

, respectively. 

Before and after shift blood ethylbenzene concentrations were 140 and 163 ng/L in indoor workers, 

respectively, and were 158 and 184 ng/L in outdoor workers, respectively. 

Ethylbenzene concentrations in whole blood collected from workers at the end of their work shifts 

correlated significantly with the average concentrations of occupational exposure to ethylbenzene (Kawai 
 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 93 

3. HEALTH EFFECTS 

et al. 1992). The maximum ethylbenzene concentration in air in the workplace was 5 ppm (Kawai et al. 

1992). 

Inhalation studies in animals exposed to ethylbenzene showed results similar to those found in humans 

(Chin et al. 1980b; Freundt et al. 1989; Fuciarelli 2000; Romer et al.1986; Tardif et al. 1997). HarlanWistar rats rapidly absorbed radiolabeled ethylbenzene during respiration, with a retention rate of 44% 

(Chin et al. 1980b). This absorption value may have been slightly overestimated, however, because 

possible contributions from dermal exposure were not addressed. Concentrations of ethylbenzene in the 

blood of rats and guinea pigs exposed to ethylbenzene at 550 ppm for 8 hours reached 23 and 3 μg/mL, 

respectively. Ethylbenzene concentrations in blood after the last of three daily exposures (8 hours each) 

had diminished to 6 μg/mL in rats and to <2 μg/mL in guinea pigs (Cappaert et al. 2002). In mice, 

steady-state blood ethylbenzene concentrations achieved within 2 hours of initiating inhalation exposures 

were approximately 0.71 mg/L at 75 ppm, 2.3 mg/L at 200 ppm, and 20 mg/L at 500 ppm (Charest-Tardif 

et al. 2006). These data indicate that the disposition of inhaled ethylbenzene between guinea pigs may be 

different from that in rats and mice. Ethylbenzene concentrations in blood in adult rats and their offspring 

increased at a rate that was greater than proportional to dose (Faber et al. 2006). Ethylbenzene levels in 

maternal blood, collected on PND 22, after a 6-hour exposure to 25, 100, or 500 ppm, were 0.11, 0.56, 

and 11 mg/L, respectively. The mean concentrations in the blood of pups (males/females), culled from 

the dams sampled above, in the 25-, 100-, and 500-ppm groups were 0.021/0.025, 0.26/0.24, and 

11.4/12.7 mg/mL, respectively (Faber et al. 2006). 

No studies describing factors specifically affecting absorption of ethylbenzene following inhalation 

exposure were available. 

3.4.1.2 Oral Exposure 

No studies were located regarding the absorption of ethylbenzene in humans following oral exposure. 

Studies in animals, however, indicate that ethylbenzene is quickly and effectively absorbed by this route. 

Recovery of ethylbenzene metabolites in the urine of rabbits administered a single dose of 593 mg/kg was 

between 72 and 92% of the administered dose 24 hours following exposure (El Masry et al. 1956). 

Similarly, 84% of the radioactivity from a single oral dose of 30 mg/kg ethylbenzene administered to 

female rats was recovered within 48 hours (Climie et al. 1983). Ethylbenzene was detected at 0.49, 3.51, 

and 18.28 mg/L in maternal blood of rats 1 hour after the last of four daily administrations of 26, 90, or 

342 mg/kg/day (distributed over three equal doses), respectively; however, ethylbenzene was not detected 
 

 

 

 

 

ETHYLBENZENE 94 

3. HEALTH EFFECTS 

(limit of detection: 0.006 mg/L) in blood of weanlings culled from the same dams (Faber et al. 2006). It 

is unclear if the latter finding is due to low transfer of ethylbenzene to milk or if the 1-hour exposure-tosampling time-lapse was too long to allow detection of ethylbenzene. 

3.4.1.3 Dermal Exposure 

Studies in humans dermally exposed to liquid ethylbenzene demonstrate rapid absorption through the 

skin, but absorption of ethylbenzene vapors through the skin appears to be minimal (Dutkiewicz and 

Tyras 1967; Gromiec and Piotrowski 1984). Absorption rates of 24–33 mg/cm2

/hour and 0.11– 

0.23 mg/cm2

/hour have been measured for male subjects exposed to liquid ethylbenzene and ethylbenzene 

from aqueous solutions, respectively (Dutkiewicz and Tyras 1967). The average amounts of 

ethylbenzene absorbed after volunteers immersed one hand for up to 2 hours in an aqueous solution of 

112 or 156 mg/L ethylbenzene were 39.2 and 70.7 mg ethylbenzene, respectively. These results indicate 

that skin absorption could be a major route of uptake of liquid ethylbenzene or ethylbenzene in water. In 

contrast, ethylbenzene metabolite levels in urine following dermal exposure to 150–300 ppm (650– 

1,300 mg/m3

) ethylbenzene vapors for two hours did not differ from values taken prior to exposure, 

indicating minimal, if any, dermal absorption of ethylbenzene vapors (Gromiec and Piotrowski 1984). 

Susten et al. (1990) conducted in vivo percutaneous absorption studies of ethylbenzene in mice. Results 

showed total absorption (sums of radioactivity found in the excreta, carcass, skin application site, and 

expired breath) was 3.4% of the nominal dose. The total percentage recovered (includes wipe of skin 

area, ethylbenzene 0.03%) was 95.2%. The amount of ethylbenzene absorbed at an estimated contact 

time of 5 minutes was 148.55 μg with an absorption rate of 37 μg/cm2

/minute. 

The volumes of ethylbenzene absorbed in rats treated dermally for 24 hours with aqueous solutions of 

ethylbenzene (neat [99% pure], saturated, 2/3 or 1/3 saturated), were 0.24, 0.20, 0.18, and 0.17 mL, 

respectively (Morgan et al. 1991). Peak blood level during exposure to neat ethylbenzene was reported at 

5.6 μg/mL, attained after 1 hour of exposure, which decreased during the remainder of the exposure 

period. The concentration of ethylbenzene in the blood was highest after exposure to saturated aqueous 

solutions, followed by the 2/3 and 1/3 saturated solutions. 

Results of dermal penetration studies in excised rat skin indicate that the penetration rate of pure 

ethylbenzene (Tsuruta 1982) is faster than that of ethylbenzene from JP-8 jet fuel (McDougal et al. 2000). 

The penetration rates of pure liquid ethylbenzene following 3-, 4-, and 5-hour exposure durations in rat 
 

 

 

 

 

 

ETHYLBENZENE 95 

3. HEALTH EFFECTS 

skin were approximately 2.38, 3.12, and 3.22 μg/cm2/hour (calculated by ATSDR from reported data on 

exposure area, exposure time, and mass transfer); these rates are substantially lower than the rate of 

dermal absorption determined for humans (Tsuruta 1982). This might be attributed to differences 

between in vitro and in vivo testing and/or differences in rat versus human skin. McDougal et al. (2000) 

reported an ethylbenzene flux of 0.377 μg/cm2

/hour (0.0004 mg/cm2/hour) for ethylbenzene and a 

permeability coefficient of 3.1x10-4 cm/hour during a 4-hour period in excised rat skin which had 

received 2 mL of JP-8 fuel containing approximately 1,200 μg ethylbenzene/mL fuel (0.15% w/w). It 

was recognized that the choice of vehicle (JP-8) could affect dermal penetration of ethylbenzene. The 

steady state flux, permeability, and diffusivity values of ethylbenzene in pig skin treated with JP-8 ex vivo 

were 1.04 μg/cm2

/hour, 0.06x10-3 cm/hour, and 715x10-6 cm2/hour (Muhammad et al. 2005). 

3.4.2 Distribution 

3.4.2.1 Inhalation Exposure 

In humans exposed for 2 hours to a mixture of industrial xylene containing 40.4% ethylbenzene, the 

estimated solvent retention in adipose tissue was 5% of the total uptake (Engstrom and Bjurstrom 1978). 

Since there was no indication of differences in turnover rates of chemicals within the mixture, it is likely 

that the retention of ethylbenzene in adipose tissue was approximately 2% of the total uptake. No studies 

were located concerning the distribution of ethylbenzene in humans following exposure to ethylbenzene 

alone. However, studies by Pierce et al. (1996) suggest that in vitro, the partitioning of ethylbenzene 

from air into human adipose tissue is similar to that observed in rats. 

Studies conducted in rats and mice have shown that inhaled ethylbenzene accumulates in adipose tissue 

(Elovaara et al. 1982; Engstrom et al. 1985; Fuciarelli 2000). In rats and mice exposed to 750 ppm 

ethylbenzene for 6 hours/day, concentrations of ethylbenzene in mesenteric adipose were 20–60 times 

higher than steady-state blood concentrations, whereas concentration in liver were similar to blood 

(Fuciarelli 2000). Concentrations of ethylbenzene in perirenal adipose tissue were reported to increase, 

although not linearly, with increasing concentrations of ethylbenzene (Engstrom et al. 1985) and in a 

mixture of solvent vapors containing ethylbenzene (Elovaara et al. 1982). The less-than-linear increase of 

ethylbenzene in adipose tissue with increasing dose was partially attributed to the induction of drugmetabolizing enzymes occurring with increasing exposure concentrations, altered blood flow to adipose 

tissue, changes in lung excretion, and changes in the distribution of ethylbenzene in different tissues. 

Ethylbenzene was shown to be efficiently distributed throughout the body in rats following inhalation 

exposure to radiolabeled ethylbenzene (Chin et al. 1980b). The highest amounts of radioactivity in 
 

 

 

 

ETHYLBENZENE 96 

3. HEALTH EFFECTS 

tissues 42 hours after exposure to 230 ppm ethylbenzene for 6 hours were found in the carcass, liver, and 

gastrointestinal tract, with lower amounts detected in the adipose tissue. 

3.4.2.2 Oral Exposure 

No studies were located regarding distribution of ethylbenzene in humans or animals following oral 

exposure. 

3.4.2.3 Dermal Exposure 

No studies were located regarding distribution in humans following dermal exposure to ethylbenzene. 

The percentages of absorbed doses following dermal application of [14C]-ethylbenzene in hairless mice 

were: 15.5%, carcass; 4.5%, application site; 14.3%, expired breath; and 65.5%, excreta (Susten et al. 

1990). 

3.4.3 Metabolism 

The metabolism of ethylbenzene has been studied in humans and other mammalian species. The data 

demonstrate that ethylbenzene is metabolized mainly through hydroxylation and then through conjugation 

reactions from which numerous metabolites have been isolated. Figure 3-3 summarizes the proposed 

metabolic pathway for ethylbenzene in humans (Engstrom et al. 1984). The major urinary metabolites 

have been identified (Kiese and Lenk 1974; Sullivan et al. 1976). Comparisons of in vitro data with data 

from intact animals indicate that liver microsomal enzymes participate in ethylbenzene hydroxylation 

(McMahon and Sullivan 1966; McMahon et al. 1969; Sams et al. 2004). In microsomes prepared from 

human liver, hydroxylation of ethylbenzene to 1-phenylethanol is catalyzed by cytochrome P-450 

isoforms CYP2E1 and CYP2B6 (Sams et al. 2004). Adrenal cortex may be a major site of extra-hepatic 

ethylbenzene metabolism (Greiner et al. 1976). No significant qualitative differences in metabolism 

between oral and inhalation routes were reported in humans or animals. The metabolism of ethylbenzene 

has been found to vary with species, sex, and nutritional status. These differences are described below. 

In humans exposed via inhalation, the major metabolites of ethylbenzene are mandelic acid 

(approximately 64–71%) and phenylglyoxylic acid (approximately 19–25%) (Bardodej and Bardodejova 

1970; Engstrom et al. 1984; Knecht et al. 2000; Jang et al. 2001; Tardif et al. 1997). Based on data from 

human, animal, and in vitro studies, the metabolic pathway for ethylbenzene in humans was proposed 
ETHYLBENZENE 97 

3. HEALTH EFFECTS 

Figure 3-3. Metabolic Scheme for Ethylbenzene in Humans 

O O OH OH 

C C C CH OH C COOH 

CH3 CH 2

2OH 

H H 

Acetophenone omega-Hydroxyacetophenone 1-Phenyl-1,2-ethanediol Mandelic acid 

O 

O C COOH 

O OH C 

CH C 3 C CH3 CH3 MAINLY Phenylglyoxyilic acid H GLUCURONIDES 

HO OH 

I-Phenylethanol p-Hydroxyacetophenone m-Hydroxyacetophenone 

CH2CH3 GLUCURONIDES 

SULFATES 

MAINLY 

Ethylbenzene GLUCURONIDES 

CH2CH3 

O -

CH2CH3 

GLUCURONIDES URINE SULFATES 

HO

4-Ethylphenol 

Source: Engstrom et al. 1984 
 

 

 

 

 

 

ETHYLBENZENE 98 

3. HEALTH EFFECTS 

(Engstrom et al. 1984). This pathway is shown in Figure 3-3. Evidence indicates that the initial step in 

this metabolic pathway is oxidation (hydroxylation) of the side chain of ethylbenzene to produce 

1-phenylethanol. Microsomal preparations from rat liver have shown that the oxidation of ethylbenzene 

proceeds with the incorporation of atmospheric oxygen, as opposed to oxygen from water molecules 

(McMahon et al. 1969). Filipovic et al. (1992) have shown that cytochrome P-450(cam) from Pseudomonas 

putida provides a useful metabolic model for ethylbenzene hydroxylation, converting ethylbenzene to 

1-phenylethanol at 98%. 1-Phenylethanol is conjugated to glucuronide, which then is either excreted or 

converted to subsequent metabolites. Oxidation of 1-phenylethanol yields acetophenone, which is both 

excreted in the urine as a minor metabolite and further transformed. Continued oxidation of the side 

chain leads to the sequential formation of 2-hydroxyacetophenone, 1-phenyl-1,2-ethanediol, mandelic 

acid, and phenylglyoxylic acid. Minor pathways (e.g., ring hydroxylation) include glucuronide and 

sulfate conjugation with hydroxylated derivatives to form glucuronides and sulfates that are excreted in 

the urine. Analysis of urine from humans exposed to ethylbenzene via the inhalation route showed that 

approximately 70 and 25% of the retained dose of ethylbenzene is excreted as mandelic acid and 

phenylglyoxylic acid, respectively (Bardodej and Bardodejova 1970; Engstrom et al. 1984). Additional 

metabolites detected in human urine include 1-phenylethanol (4%), p-hydroxyacetophenone (2.6%), 

m-hydroxyacetophenone (1.6%), and trace amounts of 1-phenyl-1,2-ethanediol, acetophenone, 

2-hydroxyacetophenone, and 4-ethylphenol. Following dermal exposure of humans, however, excretion 

of mandelic acid was shown to be only 4.6% of the absorbed dose (Dutkiewicz and Tyras 1967), which 

may indicate differences in the metabolic fate between inhalation and dermal exposure routes. However, 

the small percentage of absorbed dose accounted for limits the interpretation. No animal data were 

located which could confirm these metabolic differences following dermal exposure. Generally, ethylbenzene metabolites and intermediates are thought to be only slightly toxic, since no adverse effects from 

human experimental exposure have been reported (Bardodej and Bardodejova 1970). 

Qualitative and quantitative differences in the biotransformation of ethylbenzene in animals as compared 

to humans have been reported (Bakke and Scheline 1970; Climie et al. 1983; El Masry et al. 1956; 

Engstrom et al. 1984, 1985; Smith et al. 1954a, 1954b; Sollenberg et al. 1985). The major metabolites of 

ethylbenzene differ from species to species, and different percentages of the metabolites are seen in 

different species. The principal metabolic pathway in rats is believed to begin with oxidation 

(hydroxylation) of the side chain as in humans (Climie et al. 1983; Engstrom et al. 1984, 1985; Smith et 

al. 1954a). In rats exposed by inhalation or orally to ethylbenzene, the major metabolites were identified 

as benzoic acids and glycine conjugates (e.g., hippuric acid; approximately 38%), 1-phenylethanol 

(approximately 25%), and mandelic acid (approximately 15–23%), with phenylglyoxylic acid making up 
 

 

 

 

 

 

 

ETHYLBENZENE 99 

3. HEALTH EFFECTS 

only 10% of the metabolites (Climie et al. 1983; Engstrom et al. 1984, 1985; Fuciarelli 2000). The 

urinary excretion rate of mandelic acid in rats exposed to 250 ppm ethylbenzene, 6 hours/day for 15 days 

was the same after the first exposure as it was after the last exposure. In contrast, excretion in the 1,000 

ppm group was 2–5 times higher after the last exposure than it was after the first exposure (Saillenfait et 

al. 2006). Both in vivo studies using rats and in vitro studies using rat liver microsomes showed that 

4-ethylphenol was also produced from ethylbenzene, perhaps by rearrangement of corresponding arene 

oxides (Bakke and Scheline 1970; Kaubisch et al. 1972). Kaubisch et al. (1972) also showed that 

2-hydroxyethylbenzene was produced from ethylbenzene in vitro in the presence of rat liver microsomes. 

The level of ethylbenzene exposure was shown to affect the metabolic pattern. This was thought to be 

due either to selective enzymatic induction in the biotransformation of ethylbenzene or to delayed 

excretion of certain metabolites with increasing doses. 

Acetophenone was detected (quantitative data were not provided) in blood of rats and guinea pigs 

exposed to ethylbenzene in air at 500 ppm, 8 hours/day for 3 days (Cappaert et al. 2002). Further 

clarification of ethylbenzene metabolic pathways was provided by Sullivan et al. (1976). Using 

intraperitoneally dosed rats, the authors demonstrated that the conversion of 1-phenylethanol to mandelic 

acid initially involves oxidation to acetophenone. Acetophenone was considered to be the precursor of 

mandelic acid, benzoylformic acid, and benzoic acid. A similar study in which rabbits were 

intraperitoneally injected with a single dose of 250 mg ethylbenzene/kg body weight was conducted by 

Kiese and Lenk (1974). This study showed that between 1 and 10% of the dose was excreted as 

1-phenylethanol in the urine and <1% was excreted in the urine as 2-hydroxyacetophenone, p-hydroxyacetophenone, and m-hydroxyacetophenone. 

Rabbits given an oral dose of ethylbenzene showed the major metabolic pathway to be hydroxylation of 

the α-carbon to 1-phenylethanol, which is oxidized further to a number of intermediates and metabolites 

(El Masry et al. 1956; Smith et al. 1954a). Many of these intermediates are subsequently conjugated to 

glucuronides and sulfates and excreted. In rabbits, the most important metabolite is hippuric acid, which 

is probably formed by oxidative decarboxylation of phenylglyoxylic acid (El Masri et al. 1958). 

Oxidation of the methyl group of ethylbenzene was also shown to occur, as evidenced by the presence of 

phenaceturic acid in the urine. A slight increase in the excretion of thioether suggests that glutathione 

conjugation may also play a minor role. 

The nutritional status of animals was demonstrated to have a marked effect on ethylbenzene metabolism 

in rats (Nakajima and Sato 1979). The in vitro metabolic activity of liver microsomal enzymes on ethyl-
 

 

 

ETHYLBENZENE 100 

3. HEALTH EFFECTS 

benzene was shown to be significantly enhanced in fasted rats despite a marked loss of liver weight. No 

significant increases in the microsomal protein and cytochrome P-450 contents were detected in fasted 

rats compared with fed rats. In addition, the metabolic rate in fasted males was significantly higher than 

in fasted females, but the difference in rates decreased following food deprivation for 3 days. These 

results suggest possible sex differences in the rate of ethylbenzene metabolism. However, it is not known 

if such differences exist in the normally fed rats. 

Metabolism of ethylbenzene has not been studied in children or immature animals. However, some 

members of two of the enzyme superfamilies involved in conjugation of phase I ethylbenzene metabolites 

are known to be developmentally regulated. In humans, UDP glucuronosyltransferase activity does not 

reach adult levels until about 6–18 months of age, although the development of this activity is isoform 

specific. Activity of sulfotransferases seems to develop earlier, although again, it is isoform specific. The 

activity of some sulfotransferase isoforms may even be greater during infancy and early childhood than in 

adults (Leeder and Kearns 1997). 

3.4.4 Elimination and Excretion 

3.4.4.1 Inhalation Exposure 

Excretion of ethylbenzene has been studied in humans and in a number of animal species. Ethylbenzene 

has been shown to be rapidly metabolized and then eliminated from the body, primarily as urinary 

metabolites. The major metabolic products have been previously described in Section 3.4.3. 

Elimination of ethylbenzene has been studied in volunteers exposed by inhalation (Bardodej and 

Bardodejova 1970; Dutkiewicz and Tyras 1967; Engstrom and Bjurstrom 1978; Gromiec and Piotrowski 

1984; Knecht et al. 2000; Tardif et al. 1997; Yamasaki 1984) and in humans exposed by inhalation in the 

occupational setting (Holz et al. 1995; Jang et al. 2001; Kawai et al. 1991, 1992; Ogata and Taguchi 

1988). Elimination of ethylbenzene in exhaled air in volunteers exposed to 33 ppm ethylbenzene 

exhibited multi-phasic kinetics with an early-phase half time of <1 hour (Tardif et al. 1997). This 

elimination rate is similar to the rate of elimination of ethylbenzene from blood following cessation of 

exposure (Knecht et al. 2000; Tardif et al. 1997) and is considerably faster than the rate of elimination 

(i.e., urinary excretion) of the metabolites, mandelic acid (t1/2≈3–5 hours) and phenylgloxylic acid 

(t1/2≈10–12 hours) (Gromiec and Piotrowski 1984; Knecht et al. 2000; Tardif et al. 1997). Elimination of 

mandelic acid was reported to be biphasic, with half-lives of 3.1 hours for the rapid phase and 25 hours 

for the slow phase (Gromiec and Piotrowski 1984). During the 8-hour exposure, 23% of the retained 
 

 

 

 

 

 

 

 

 

ETHYLBENZENE 101 

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ethylbenzene was eliminated in the urine, and 14 hours following termination of exposure an additional 

44% of the retained ethylbenzene was eliminated. The highest excretion rate of urinary metabolites in 

humans exposed to ethylbenzene by inhalation occurred 6–10 hours after the beginning of exposure 

(Gromiec and Piotrowski 1984; Yamasaki 1984). 

Concentrations of ethylbenzene metabolites in before-shift and after-shift urine were significantly higher 

in workers exposed to 85 to >921 ppm ethylbenzene in a styrene plant than in control workers exposed to 

33.4–66.8 ppm (Holz et al. 1995). 

A statistically significant correlation was observed between urinary excretion of mandelic acid and 

ethylbenzene exposure in workers exposed to mixed solvents (including an ethylbenzene time-weighted 

average [TWA] of 0.9 ppm) in a metal-coating factory (Kawai et al. 1991). No correlation was observed 

between ethylbenzene exposure and phenylglyoxylic acid urinary excretion. In a study of chronicduration exposure at lower levels (2.1 and 2.3 ppm for geometric and arithmetic mean, respectively), no 

significant correlation was observed between ethylbenzene exposure and urinary excretion of 

phenylglyoxylic acid and mandelic acid (Kawai et al. 1992). 

In animals, elimination of 14C-ethylbenzene following inhalation exposure is rapid and occurs primarily 

via urinary excretion (Chin et al. 1980a, 1980b; Engstrom et al. 1984, 1985) and to a much lesser degree 

via the feces, and expired “gasses” and carbon dioxide (Chin et al. 1980b). Rats exposed to 230 ppm 

radiolabeled ethylbenzene for 6 hours via inhalation excreted virtually all of the radioactivity within 

24 hours after the onset of exposure (Chin et al. 1980a, 1980b). Ninety-one percent of the radioactivity 

was recovered, primarily in the form of urinary metabolites. In a similar inhalation experiment using rats 

exposed to 300 or 600 ppm, urinary excretion was reported to be 83 and 59% of the absorbed dose within 

48 hours after the onset of exposure, with 13% eliminated during the first 6 hours of exposure (Engstrom 

et al. 1984). 

Quantitative differences between species in the percentages of metabolites excreted in the urine were also 

reported by Chin et al. (1980a). In this report, urinary metabolites in dogs and rats exposed to 

ethylbenzene by inhalation were studied. Although similarities in the types of metabolites recovered 

following inhalation exposure were reported, quantitative differences, albeit minor ones, were noted in the 

ratio of metabolites present in the urine. These results were attributed to differences in metabolism 

between dogs and rats. 
 

 

 

 

 

 

ETHYLBENZENE 102 

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Elimination of inhaled ethylbenzene from blood, fat, liver, and lung tissue following inhalation exposures 

is biphasic in rats and mice (Fuciarelli 2000). The terminal phase for blood is approximately 4–7 times 

slower than the initial phase. For example, in male rats exposed to 75 ppm for 6 hours, the initial and 

terminal elimination half-times were approximately 77 and 493 minutes, respectively. Blood elimination 

kinetics of inhaled ethylbenzene are dependent on exposure concentration, with decreasing clearance of 

ethylbenzene from blood in association with increasing exposure concentration. In female mice, rate 

constants for ethylbenzene measured at the conclusion of 4-hour exposures to concentrations ranging 

from 75 to 1,000 ppm were 0.21 minute-1 (t1/2=3.3 minute) at 75 ppm and 0.011 minute-1 (t1/2=63 minutes) 

at 1,000 ppm; similar decreases in elimination rate were observed in male mice (Charest-Tardif et al. 

2006). Elimination half-life values increased approximately 2-fold, with the 10-fold increase in exposure 

concentration, and the ratio of the area under the curve (AUC) for ethylbenzene in blood/exposure 

concentration increased 10–20-fold (Fucareli 2000). The concentration dependence on elimination is 

consistent with a capacity limitation in metabolism of ethylbenzene. Elimination rates measured in mice 

after 1 or 7 days of 4-hour exposures to 75 ppm ethylbenzene were similar; however, elimination rates 

increased following 7 days of exposure to 750 ppm (e.g., 0.016 minute-1, t1/2=43.3 minutes, female mice), 

compared to 1 day of exposure (0.061 minute-1, t1/2=11.4 minutes, female mice; Charest-Tardif et al. 

2006). These observations are consistent with induction of metabolic clearance of ethylbenzene in 

association with repeated exposures to 750 ppm. Elimination rates of ethylbenzene from blood were 

faster in mice compared to rats. In rats exposed to 75 ppm ethylbenzene for 6 hours, the rate for the 

initial phase of elimination was 0.00902 minute-1 (t1/2=76.8 minutes) in male rats and 0.0102 minute-1 

(t1/2=68.1 minutes) in female rats. In mice the elimination rates were 0.0596 minute-1 (t1/2=11.6 minutes) 

in male mice, and 0.109 minute-1 (t1/2=6.36 minutes) in female mice (Fuciarelli 2000). 

3.4.4.2 Oral Exposure 

No studies were located regarding the excretion of ethylbenzene metabolites in humans following oral 

exposure to ethylbenzene. 

Elimination of ethylbenzene and its metabolites in animals after oral exposure has been shown to be 

similar to that following inhalation exposure. Female rats administered a single oral dose of 30 mg 

radiolabeled ethylbenzene/kg/body weight showed very rapid elimination, mostly in the urine (Climie et 

al. 1983). Eighty-two percent of the radioactivity was detected in the urine, while 1.5% was detected in 

the feces. The major metabolites were mandelic acid (23%) and hippuric acid (34%), with 1-phenylethyl 

glucuronide detected as a minor metabolite. Relatively minor metabolites (e.g., 4-ethylphenol, 2-phenyl-
 

 

 

ETHYLBENZENE 103 

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ethanol, 1-phenylethanol) were shown to be excreted in the urine of male rats exposed to a single oral 

dose of 100 mg/kg ethylbenzene administered by gavage in oil (Bakke and Scheline 1970). No data on 

the major metabolites were provided in this study. 

In a similar study in which male rats were given single oral doses of 350 mg/kg/body weight ethylbenzene, the excretion of mandelic acid and phenylglyoxylic acid was detected in the first urine sample 

after exposures. Peak concentration was reached within 17 hours, and ethylbenzene was virtually 

eliminated 48 hours following the onset of exposure (Sollenberg et al. 1985). 

As in inhalation experiments, quantitative and qualitative differences between species were shown to exist 

in the percentages of metabolites excreted in the urine. Rabbits orally exposed to ethylbenzene excreted 

large amounts of glucuronide conjugates in the urine (El Masry et al. 1956; Smith et al. 1954a, 1954b) 

instead of mandelic acid, hippuric acid, and phenylglyoxylic acid, which are the major metabolites in rats 

(see above). Glucuronide conjugates accounted for 32% of the administered dose, with mandelic acid 

making up only 2% of the administered dose (El Masry et al. 1956). These results were confirmed in a 

study by Smith et al. (1954a, 1954b), who detected 32% of a single oral dose of ethylbenzene 

(433 mg/kg) administered to rabbits as glucuronide conjugates excreted in the urine. 

3.4.4.3 Dermal Exposure 

In humans, the pattern of excretion of ethylbenzene metabolite following dermal exposure has been 

shown to differ significantly from the pattern in which humans have been exposed by inhalation. Dermal 

absorption of ethylbenzene in aqueous solutions was estimated as the difference of the ethylbenzene 

concentrations in solution before and after exposure. The urinary excretion of mandelic acid in humans 

dermally exposed to ethylbenzene for 2 hours was only 4.6% of the absorbed ethylbenzene (Dutkiewicz 

and Tyras 1967). Urine was collected periodically during the 2-hour exposure period and a 10-hour 

follow-up. Interpretation is difficult due to the small percentage of absorbed dose accounted for. No 

ethylbenzene was reported to be excreted in exhaled air. No further details on the excretion patterns were 

provided. 

Susten et al. (1990) conducted in vivo percutaneous absorption studies of ethylbenzene in Hairless mice. 

Results showed total absorption (sums of radioactivity found in the excreta, carcass, skin application site, 

and expired breath) was 3.4% of the nominal dose. The absorbed dose collected in expired breath during 

the first 15 minutes of ethylbenzene application was 9.3%. The percentage of absorbed doses following 
 

 

 

 

ETHYLBENZENE 104 

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dermal application of [14C]-ethylbenzene are as follows: 15.5% in the carcass; 4.5% at the application 

site; 14.3% in expired breath; and 65.5% in excreta. 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models 

Physiologically based pharmacokinetic (PBPK) models use mathematical descriptions of the uptake and 

disposition of chemical substances to quantitatively describe the relationships among critical biological 

processes (Krishnan et al. 1994). PBPK models are also called biologically based tissue dosimetry 

models. PBPK models are increasingly used in risk assessments, primarily to predict the concentration of 

potentially toxic moieties of a chemical that will be delivered to any given target tissue following various 

combinations of route, dose level, and test species (Clewell and Andersen 1985). Physiologically based 

pharmacodynamic (PBPD) models use mathematical descriptions of the dose-response function to 

quantitatively describe the relationship between target tissue dose and toxic end points. 

PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to 

delineate and characterize the relationships between: (1) the external/exposure concentration and target 

tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen and 

Krishnan 1994; Andersen et al. 1987). These models are biologically and mechanistically based and can 

be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from 

route to route, between species, and between subpopulations within a species. The biological basis of 

PBPK models results in more meaningful extrapolations than those generated with the more conventional 

use of uncertainty factors. 

The PBPK model for a chemical substance is developed in four interconnected steps: (1) model 

representation, (2) model parameterization, (3) model simulation, and (4) model validation (Krishnan and 

Andersen 1994). In the early 1990s, validated PBPK models were developed for a number of 

toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen 

1994; Leung 1993). PBPK models for a particular substance require estimates of the chemical substancespecific physicochemical parameters, and species-specific physiological and biological parameters. The 

numerical estimates of these model parameters are incorporated within a set of differential and algebraic 

equations that describe the pharmacokinetic processes. Solving these differential and algebraic equations 

provides the predictions of tissue dose. Computers then provide process simulations based on these 

solutions. 
 

 

 

 

ETHYLBENZENE 105 

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The structure and mathematical expressions used in PBPK models significantly simplify the true 

complexities of biological systems. If the uptake and disposition of the chemical substance(s) are 

adequately described, however, this simplification is desirable because data are often unavailable for 

many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty. The 

adequacy of the model is, therefore, of great importance, and model validation is essential to the use of 

PBPK models in risk assessment. 

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the 

maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994). 

PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in 

humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste 

sites) based on the results of studies where doses were higher or were administered in different species. 

Figure 3-4 shows a conceptualized representation of a PBPK model. 

If PBPK models for ethylbenzene exist, the overall results and individual models are discussed in this 

section in terms of their use in risk assessment, tissue dosimetry, and dose, route, and species 

extrapolations. 

Several models have been developed that simulate the kinetics of inhaled ethylbenzene in animals and 

humans (Dennison et al. 2003; Haddad et al. 1999, 2000, 2001; Jang et al 2001; Nong et al. 2007; Tardif 

et al. 1997). The Dennison et al. (2003) and Tardif et al. (1997) inhalation models have been incorporated 

into models of gasoline component mixture models (Dennison et al. 2004, 2005; Haddad et al. 2001). An 

extension of the Tardif et al. (1997) model has been reported that includes simulation of gastrointestinal 

absorption (i.e., transfer of ingested ethylbenzene to liver) of ethylbenzene in rats (Faber et al. 2006). A 

model of dermal absorption ethylbenzene in human has also been reported (Shatkin and Brown 1991). 

Models that simulate kinetics of ingested ethylbenzene have not been reported. In general, all of the 

inhalation models of have similar structures, with the major conceptual differences being the simulation 

of metabolism and excretion of metabolites. The Nong et al. (2007) mouse model simulates metabolism 

of ethylbenzene in liver, lung, and richly perfused tissues, whereas all other models attribute all 

ethylbenzene metabolism to the liver. The Nong et al. (2007) mouse model also simulated changes in 

ethylbenzene blood kinetics in mice that occurred with repeated exposure to ethylbenzene at exposure 

concentrations >75 ppm. These changes were attributed to induction of cytochrome P450 and were 

simulated as an increase in Vmax for metabolism of ethylbenzene in liver. The Jang et al. (2001) human 

model simulates excretion of the ethylbenzene metabolite, mandelic acid, whereas other models do not 
 

 

ETHYLBENZENE 106 

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Figure 3-4. Conceptual Representation of a Physiologically Based 

Pharmacokinetic (PBPK) Model for a Hypothetical
 

Chemical Substance
 

Lungs 

Liv er 

F at 

S lo w ly 

perfus ed 

tis s ues 

R ic h ly 

perfus ed 

tis s ues 

K idney 

S k in 

V 

E 

N 

O 

U 

S 

B 

L 

O 

O 

D 

A 

R 

T 

E 

R 

I 

A 

L 

B 

L 

O 

O 

D 

V m a x 

K m 

Inges tion 

Inhaled c hem ic al E x haled c hem ic al 

GI 

T ra c t 

F ec es 

U rin e

 C h e m ic a ls 

contacting skin 

Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a 

hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin, by inhalation, or by 

ingestion, metabolized in the liver, and excreted in the urine or by exhalation. 

Source: adapted from Krishnan and Andersen 1994 
 

 

 

 

 

 

ETHYLBENZENE 107 

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simulate the urinary elimination pathway. The Tardif et al. (1997), Dennison et al. (2003), and Nong et 

al. (2007) models are described in greater detail in the sections that follow. Complete documentation of 

the Jang et al. (2001) model was not available for providing a detailed description of the model, although 

it appears to be conceptually similar to the Tardif et al (1997) and Dennison et al. (2003) models. 

The Tardif et al. (1997; Haddad et al. 1999, 2000, 2001) Model 

Description of the Model. Tardif et al. (1997) developed a PBPK model for simulating the kinetics 

of ethylbenzene, toluene, and xylene in blood following inhalation exposures to the individual chemicals 

or the ternary mixture (in rats and humans). The structure of the model is essentially identical the generic 

model depicted in Figure 3-4, with tissue compartments limited to lungs, liver, fat, richly perfused tissues 

(RPT), and poorly perfused tissues (SPT). All metabolism was attributed to the liver and represented as 

functions of the concentration of parent compound in liver venous blood, affinity constant (Km), and 

maximum reaction velocity (Vmax). Transfers of parent compound between blood and tissues were 

assumed to be flow-limited, with clearance represented by tissue blood flow (L/hour). Parameters for the 

ethylbenzene model are presented in Table 3-6. Tissue: air partition coefficients for ethylbenzene were 

derived from vial equilibrium studies of isolated rat tissues. Tissue:blood partition coefficients were 

derived from measured tissue:air and blood:air partition coefficients (i.e., tissue:blood=tissue:air/ 

blood:air; Tardif et al. 1997). Metabolism parameter values for ethylbenzene were derived by fitting the 

model to observations of blood ethylbenzene kinetics measured in rats during and following 4-hour 

exposures to ethylbenzene in a dynamic exposure chamber (Tardif et al. 1996). Physiological parameters, 

cardiac output (QC), alveolar ventilation rate (QP), and metabolism Vmax were allometrically scaled 

across species (i.e., rat to human) as a function of body weight (BW, scaling factor=BW0.75). A blood:air 

partition coefficient for humans was estimated from vial equilibrium measurements made on isolated 

human blood; human tissue:blood partition coefficients were derived based on tissue:air coefficients for 

the rat (Tardif et al. 1997). 

Subsequent enhancements of the Tardif et al. (1997) model included simulation of kinetics of an inhaled 

quaternary mixture that included benzene, ethylbenzene, toluene, and xylene (Haddad et al. 1999) or 

mixtures of the latter quaternary mixture with dichloromethane (Haddad et al. 2000, 2001). In the 

development of the quaternary mixture model, values for Vmax and Km for ethylbenzene were re-estimated 

by fitting data on kinetics of ethylbenzene in venous blood following 4-hour exposures to ethylbenzene 

(50, 100, or 200 ppm; Haddad et al. 1999; Tardif et al. 1997). The resulting estimates were similar to the 

original estimates reported in Tardif et al. (1997): Vmax=6.39 mg/hour-kg) and Km=1.04 mg/L. 
 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 108 

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Table 3-6. Parameter Values for Tardif et al. (1997) Ethylbenzene PBPK Models 

Parameter Definition Rat model Human model 

Physiological parameters 

VLC Liver volume (fraction of body) 0.049 0.026 

VFC Fat volume (fraction of body) 0.09 0.19 

VSC Slowly-perfused tissue volume (fraction of body) 0.72 0.62 

VRC Richly-perfused tissue volume (fraction of body) 0.05 0.05 

QCC Cardiac output (L/hour-kg BW) 15a 18a 

QPC Alveolar ventilation rate (L/hour-kg body weight) 15a 18a 

QLC Liver blood flow (fraction of cardiac output) 0.25 0.26 

QFC Fat blood flow (fraction of cardiac output) 0.09 0.05 

QSC Slowly-perfused blood flow (fraction of cardiac output) 0.15 0.25 

QRC Richly-perfused blood flow (fraction of cardiac output) 0.51 0.44 

Chemical parameters 

PB Blood:air partition coefficient 42.7 28.0 

PL Liver:blood partition coefficient 1.96b (83.8) 2.99b 

PF Fat:blood partition coefficient 36.44b (1,556) 55.57b 

PS Slowly-perfused partition coefficient 0.61b (26.0) 0.93b 

PR Richly-perfused partition coefficient 1.41b (60.3) 2.15b 

VmaxC Maximum rate of metabolism (mg/hour-kg body weight) 7.3a,c 7.3a,c 

KmC Michaelis-Menten coefficient for metabolism (mg/L) 1.39c 1.39c 

a

Scaled to body weight (BW0.75) b

Tissue:blood partition coefficients calculated based on reported, experimentally determined (vial equilibrium),
 

tissue:air partition coefficients for rats (values in parentheses) and blood:air coefficient (PB) measured in rat or
 

human blood; tissue:blood=tissue:air/blood:air.
 c

Values derived by optimization to data on blood ethylbenzene concentrations in rats exposed to ethylbenzene 

(dynamic chamber).
 
 

 

 

 

 

ETHYLBENZENE 109 

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Although the Tardiff et al. (1997) model was developed to simulate kinetics of inhaled ethylbenzene, 

Faber et al. (2006) reported an extension of the model that includes simulation of gastrointestinal 

absorption (i.e., transfer of ingested ethylbenzene to liver) of ethylbenzene in rats. The gastrointestinal 

absorption rate constant of 0.18 hour-1 was estimated by iteratively adjusting the ate constant to achieve 

agreement with observed blood ethylbenzene kinetics in following a gavage dose of ethylbenzene 

(180 mg/kg), in corn oil, administered to adult female rats. 

Validation of the Model. Optimization of the metabolism parameters against observed blood 

kinetics of ethylbenzene in rats exposed for 4 hours to 100 or 200 ppm ethylbenzene achieved predicted 

blood concentration of ethylbenzene that were within 1–2 standard deviations (SD) of the observations. 

Most of the validation efforts reported in Tardif et al. (1997) were directed at exploring how well the 

mixture model predicted observed blood kinetics of ethylbenzene, toluene, or xylene in rats during and 

following exposures to binary or ternary mixtures of the chemicals. Interactions were simulated as 

competitive, noncompetitive, or uncompetitive inhibition of metabolism, with the values of the inhibition 

constants derived by fitting the model to observed blood kinetics during and following exposures to 

binary mixtures. Although the mixture model achieved predictions similar to observations (i.e., within 1– 

2 SD of observations), this outcome would have been highly influenced by the parameter values selected 

for each of the individual chemicals, including fitted interaction constants. A more direct evaluation of 

the ethylbenzene model was explored by comparing predictions of the human model (allometrically 

scaled from the rat) to ethylbenzene concentrations in blood and in exhaled air observed in human 

subjects who were exposed to ethylbenzene (33 ppm) for 7 hours/day on 4 different days (Tardif et al. 

1991, 1997). Predicted blood and exhaled air concentrations of ethylbenzene (at steady-state and 

following cessation of exposure) in subjects exposed to ethylbenzene were within 1–2 SD of 

observations. The Tardif et al. (1997) model has been incorporated into a mixtures model of JP-8 vapor 

and its components (Campbell and Fisher 2007). The model included simulations of the kinetics of mxylene and ethylbenzene, with other aromatic components of JP-8 vapor represented as a lumped 

component. Interactions between m-xylene and ethylbenzene were simulated as competitive inhibition of 

metabolism. The mixtures model predicted kinetics liver concentrations of ethylbenzene in rats during 

and following 4-hour exposures to JP-8 vapor (380–2,700 mg/m3

) that were similar to observed kinetics 

(i.e., predicted liver concentrations were within 1–2 SD of observations). 

Risk Assessment. The ethylbenzene model predicts blood kinetics of ethylbenzene and kinetics of 

metabolism of ethylbenzene that occur in association with inhalation exposures. These predictions are 
 

 

 

 

ETHYLBENZENE 110 

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potentially useful for predicting inhalation-derived internal doses of ethylbenzene in rats and/or humans 

(e.g., blood concentrations, liver concentrations of parent compound, or amounts of total metabolites 

formed in the liver), and for making extrapolations of these internal dose metrics across species. The 

applicability any of the above dose metrics to risk assessment will depend on the mechanism for the 

specific toxicity end point being assessed, and contribution of the parent compound and/or metabolism 

metabolites to toxicity (see Section 3.5.2, Mechanisms of Toxicity). 

The Tardif et al. (1997) ethylbenzene model has been incorporated into a mixtures model for 

alkylbenzenes (ethylbenzene, toluene, m-xylene), benzene, and dichloromethane (DCM), (Haddad et al. 

2001). This mixture model has been applied to the derivation of interaction coefficients for various 

endpoints of dichloromethane toxicity (i.e., hypoxia, central nervous system effects, and cancer) based on 

predictions of corresponding relevant DCM internal dose metrics (i.e., carboxyhemoglobin concentration, 

area under concentration-time curve for DCM in richly perfused tissues; time-integrated amount of DCM 

conjugated with GSH). Interactions were simulated as dose addition, with internal dose metrics 

representing dose and the sole interaction mechanism assumed to be competitive inhibition of cytochrome 

P-450-mediated metabolism of DCM. The Tardif et al. (1997) model also has been incorporated into a 

mixtures model of JP-8 vapor and its components (Campbell and Fisher 2007). The model included 

simulations of the kinetics of m-xylene and ethylbenzene, with other aromatic components of JP-8 vapor 

represented as a lumped component. Interactions between m-xylene and ethylbenzene were simulated as 

competitive inhibition of metabolism. The Tardif et al. (1997) mixtures model was also utilized to 

evaluate occupational exposure limits for ethylbenzene, toluene, m-xylene for hypothetical exposures to 

ternary mixtures of the chemicals (Dennison et al. 2005). These analyses demonstrate the potential utility 

of the ethylbenzene model for predicting metabolic interactions with other chemicals that share a common 

mechanism of metabolic elimination, and the potential impacts of such interactions on risk (e.g., hazard 

index, cancer risk, occupation exposure limits). 

Target Tissues. The Tardif et al. (1997) ethylbenzene model was calibrated and evaluated to predict 

blood kinetics of ethylbenzene that occur in association with inhalation exposures. Essential to this 

prediction is the accurate prediction of rates of metabolism of ethylbenzene, which, in the model, is 

attributed solely to the liver. The model has potential utility for predicting, in addition to blood kinetics 

of ethylbenzene, kinetics of concentrations of ethylbenzene in important toxicity target tissues, including 

liver and richly perfused tissues (which includes kidney and central nervous system), and rates of 

metabolism of ethylbenzene and total amount of metabolites formed in liver. The model does not 

simulate, specifically, the kidney or central nervous system. 
 

 

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Species Extrapolation. The Tardif et al. (1997) model was initially developed and calibrated to 

simulate kinetics of inhaled ethylbenzene in the rat, and was allometrically scaled to the human. The 

scaled human model was evaluated for predicting ethylbenzene blood concentrations observed in human 

subjects who were exposed to ethylbenzene (33 ppm) for 7 hours/day on 4 different days (Tardif et al. 

1991). Predicted blood concentrations of ethylbenzene in subjects exposed to ethylbenzene were within 

1–2 SD of observations. Studies of the robustness of the model for predicting ethylbenzene kinetics in 

other species (after allometric scaling to those species) were not located. 

Interroute Extrapolation. The Tardiff et al. (1997) model was developed to simulate kinetics of 

inhaled ethylbenzene in rats and humans. An extension of the model that includes a gastrointestinal 

absorption rate constant enables simulation of gavage dosing in rats administered ethylbenzene in corn oil 

(Faber et al. 2006). The gastrointestinal model has not been evaluated for applications to human oral 

exposures. Studies that evaluated the model for predicting ethylbenzene kinetics following dermal 

exposure were not located. 

The Nong et al. (2007) Model 

Description of the Model. Nong et al. (2007) developed a PBPK model for simulating the kinetics 

of inhalation exposures of ethylbenzene in mice. The structure of the model is essentially identical to the 

Tardif et al. (1997) model (Figure 3-4, with tissue compartments limited to lungs, liver, fat, richly 

perfused tissues, and poorly perfused tissues), with the addition of metabolism of ethylbenzene in richly 

and poorly perfused tissues (Km, Vmax). Parameter values are presented in Table 3-7. Values for Vmax in 

naive (not induced) liver were derived my allometric scaling (BW0.75) of values estimated for the rat and 

values for Km in liver were assumed to be the same as in the rat (Haddad et al. 2000). The value for Vmax 

was subsequently optimized against data on venous blood kinetics in mice exposed to ethylbenzene 

concentrations ranging from 75 to 1,000 ppm (Nong et al. 2007). The model overpredicted observations 

in animals exposed to 750 ppm; adequate fit was achieved by upward adjustment of the Vmax by a factor 

of 3. This adjustment achieved adequate fit to blood kinetics observed in animal repeatedly exposed 

(12 days) to 75 or 750 ppm and was adopted to account for induction of cytochrome P450 in animals 

exposed repeatedly to ethylbenzene at concentrations >75 ppm (Nong et al. 2007). The value for Vmax in 

lung was derived from estimates made in in vitro preparation of mouse lung microsomes (Nong et al. 

2007) and was scaled to lung weight. Values for Km in lung and Vmax and Km in richly perfused tissues 

were derived by optimization against data on venous blood kinetics in mice exposed to ethylbenzene 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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Table 3-7. Parameter Values for Nong et al. (2007) Ethylbenzene Mouse 

Physiologically-based Pharmacokinetic Model
 

Parameter Definition Male Female 

Physiological parameters 

VLC Liver volume (fraction of body) 0.06 0.06 

VLUC Lung volume (fraction of body) 0.0073 0.0073 

VFC Fat volume (fraction of body) 0.1 0.1 

VSC Slowly-perfused tissue volume (fraction of body) 0.70 0.70 

VRC Richly-perfused tissue volume (fraction of body) 0.05 0.05 

QCC Cardiac output (L/hour-kg BW) 24a 24a 

QPC Alveolar ventilation rate (L/hour-kg body weight) 16a 16a 

QLC Liver blood flow (fraction of cardiac output) 0.25 0.25 

QLUC Lung blood flow (fraction of cardiac output) 1.00 1.00 

QFC Fat blood flow (fraction of cardiac output) 0.09 0.09 

QSC Slowly-perfused blood flow (fraction of cardiac output) 0.15 0.15 

QRC Richly-perfused blood flow (fraction of cardiac output) 0.51 0.51 

Chemical parameters 

PB Blood:air partition coefficient 42.8 65.4 

PL Liver:blood partition coefficient 1.38b (72.9) 1.12b (72.9) 

PLU Lung:blood partition coefficient 1.21b (63.8) 0.98b (63.8) 

PF Fat:blood partition coefficient 26.84b (1417) 21.67b (1417) 

PS Slowly-perfused partition coefficient 0.86b (45.6) 0.70b (45.6) 

PR Richly-perfused partition coefficient 1.38b,c (72.9) 1.12b,c (72.9) 

VmaxCL Maximum rate of metabolism in liver for exposures 7.3d 7.3d 

≤75 ppm (mg/hour-kg body weight) 

KmCL Michaelis-Menten coefficient for metabolism in liver 1.04 1.04 

(mg/L) 

VmaxCL Maximum rate of metabolism in liver for repeated 19.2d 19.2d 

exposures >75 ppm (mg/hour-kg body weight) 

KmCL Michaelis-Menten coefficient for metabolism in liver 1.04 1.04 

(mg/L) 

VmaxCLU Maximum rate of metabolism in lung (mg/hour-kg body 13.4d 13.4d 

weight) 

KmCLU Michaelis-Menten coefficient for metabolism in lung 5.57 4.35 

(mg/L) 
 

 

 

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Table 3-7. Parameter Values for Nong et al. (2007) Ethylbenzene Mouse 

Physiologically-based Pharmacokinetic Model
 

Parameter Definition	 Male Female 

VmaxCRP	 Maximum rate of metabolism in rapidly perfused tissue 17.4d 12.9d 

(mg/hour-kg body weight) 

KmCRP	 Michaelis-Menten coefficient for metabolism in rapidly 2.33 1.15 

perfused tissue (mg/L) 

a

Scaled to body weight (BW0.75). b

Tissue:blood partition coefficients calculated based on reported, experimentally determined (vial equilibrium),
 

tissue:air partition coefficients for rats (values in parentheses) and blood:air coefficient (PB) measured in rat or
 

human blood; tissue:blood=tissue:air/blood:air.
 c

Values shown are for liver; values reported for tissue:air were as follows: brain, 51.44; heart, 61.16; and kidney,
 

68.53 corresponding values for tissue:blood were: brain, 0.97 (male), 0.79, female); heart, 1.16 (male), 

0.94 (female); and kidney, 1.30 (male), 1.05 (female). d

Scaled to body weight (BW0.74). 
 

 

 

ETHYLBENZENE 114 

3. HEALTH EFFECTS 

concentrations ranging from 75 to 1,000 ppm (Nong et al. 2007). Tissue:air partition coefficients for 

ethylbenzene were derived from vial equilibrium studies of isolated tissues, and included blood:air 

coefficients determined in male (52.8±3 standard error [SE]) and female (65.4±5 SE) mice. Tissue:blood 

partition coefficients for male and female mice were derived from measured gender-specific blood:air 

partition coefficients and tissue:air coefficitent (i.e., tissue:blood=tissue:air/blood:air). Physiological 

parameters, cardiac output (QC) and alveolar ventilation rate (QP), and metabolism Vmax were 

allometrically scaled as a function of body weight. 

Validation of the Model. Metabolism parameters were optimized against observed blood kinetics of 

ethylbenzene in mice exposed for 4 hours to 75 or 1,000 ppm ethylbenzene. The optimized model was 

evaluated against observations of blood, liver, lung, and fat concentrations of ethylbenzene in male or 

female mice repeatedly exposed to 750 ppm ethylbenzene (12 days, 6 hours/day) and predictions were 

within 1–2 SDs of the observations. 

Risk Assessment. The Nong et al. (2007) model predicts blood kinetics of ethylbenzene and kinetics 

of metabolism of ethylbenzene that occur in association with inhalation exposures. These predictions are 

potentially useful for predicting inhalation-derived internal doses of ethylbenzene in mice and/or humans 

(e.g., blood concentrations, liver concentrations of parent compound, or amounts of total metabolites 

formed in the liver), and for making extrapolations of these internal dose metrics across species. 

However, a human model that includes simulation of metabolism of ethylbenzene in lung and rapidly 

perfused tissue has not been reported. The applicability any of the above dose metrics to risk assessment 

will depend on the mechanism for the specific toxicity end point being assessed, and contribution of the 

parent compound and/or metabolism metabolites to toxicity (see Section 3.5.2, Mechanisms of Toxicity). 

Target Tissues. The Nong et al. (2007) ethylbenzene model was calibrated and evaluated to predict 

blood, liver, lung, and fat kinetics of ethylbenzene that occur in association with inhalation exposures to 

mice. The model has potential utility for predicting, in addition to blood kinetics of ethylbenzene, 

kinetics of concentrations of ethylbenzene in important toxicity target tissues, including liver and richly 

perfused tissues (which includes kidney and central nervous system), and rates of metabolism of 

ethylbenzene and total amount of metabolites formed in liver, lung, and other rapidly perfused tissues 

(e.g., brain, heart, kidney). The model does not simulate, specifically, the kidney or central nervous 

system. 
 

 

 

 

 

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Species Extrapolation. The Nong et al. (2007) model was initially developed and calibrated to 

simulate ethylbenzene kinetics in the mouse. The model could be allometrically scaled to other species 

(e.g., humans). Studies of the robustness of the model for predicting ethylbenzene kinetics in other 

species (after allometric scaling to those species) were not located. 

Interroute Extrapolation. The Nong et al. (2007) model was developed to simulate kinetics of 

inhaled ethylbenzene. Studies that evaluated the model for predicting ethylbenzene kinetics following 

oral or dermal exposure were not located. 

The Dennison et al. (2003, 2004) Model 

Description of the Model. Dennison et al. (2003, 2004) developed a PBPK model for simulating the 

blood and elimination kinetics of components of gasoline, including benzene, ethylbenzene, n-hexane, 

toluene, o-xylene, and other volatile components (represented as a single lumped composition) in rats. 

The structure of the model is essentially identical the generic model depicted in Figure 3-4, with tissue 

compartments limited to lungs, liver, fat, richly perfused tissues (RPT), and slowly perfused tissues 

(SPT). All metabolism was attributed to the liver and represented as functions of the concentration of 

parent compound in liver venous blood, affinity constant (Km), and maximum reaction velocity (Vmax). 

Transfers of parent compound between blood and tissues were assumed to be flow-limited, with clearance 

represented by tissue blood flow (L/hour). Parameters for the ethylbenzene portion of the model are 

presented in Table 3-8. Partition coefficients for ethylbenzene were derived from vial equilibrium studies 

of isolated rat tissues (Tardif et al. 1997). Metabolism parameter values for ethylbenzene were derived by 

fitting the model to observations of blood ethylbenzene kinetics measured in rats during closed-chamber 

exposure to ethylbenzene (approximately 2,000 ppm starting chamber concentration; Dennison et al. 

2003). Physiological parameters, cardiac output (QC), and alveolar ventilation rate (QP), and metabolism 

Vmax were allometrically scaled to body weight (BW, scaling factor=BW0.74) 

Validation of the Model. Optimization of the metabolism parameters for rats against observed 

closed chamber air concentration kinetics achieved predicted elimination kinetics of ethylbenzene that 

were similar to observations (Dennison et al. 2003). Validation efforts reported in Dennison et al. (2004) 

were directed at exploring how well the mixture model predicted observed closed chamber air kinetics of 

ethylbenzene, toluene, or xylene during exposures of rats to gasoline (1, 10, 100, 1,000 ppm). 

Interactions were simulated as competitive inhibition of metabolism, with the values of the inhibition 

constants derived by fitting to chamber air concentration kinetics during exposures to binary mixtures. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 116 

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Table 3-8. Parameter Values for Dennison et al. (2003) Ethylbenzene PBPK Model 

Parameter Definition Rat model 

Physiological parameters 

VLC Liver volume (fraction of body) 0.037 

VFC Fat volume (fraction of body, scaled to body weight) 0.036(body weight)+0.205 

VSC Slowly-perfused tissue volume (fraction of body) 0.91-remaininga 

VRC Richly-perfused tissue volume (fraction of body) 0.054 

VLBV Lung blood volume (fraction of body) 0.002 

QCC Cardiac output (L/hour-kg body weight) 15b 

QPC Alveolar ventilation rate (L/hour-kg body weight) 15b,c 

QLC Liver blood flow (fraction of cardiac output) 0.183 

QSC Fat blood flow (fraction of cardiac output) 0.07 

QFC Slowly-perfused blood flow (fraction of cardiac output) 0.237d 

QRC Richly-perfused blood flow (fraction of cardiac output) 0.51 

Chemical parameters 

PB Blood:air partition coefficient 42.7e 

PL Liver:blood partition coefficient 1.96e 

PF Fat:blood partition coefficient 36.4e 

PS Slowly-perfused partition coefficient 0.609e 

PR Readily-perfused partition coefficient 1.96 

VmaxC Maximum rate of metabolism (mg/hour-kg body weight) 7.6b,f 

KmC Michaelis-Menten coefficient for metabolism (mg/L) 0.10f 

a

VSC=0.91-(VLC+VFC+VRC+VLB) b

Scaled to body weight (BW0.74) c

QPC varied with exposure: 14.9 at 500 ppm, 13.1 at 1,000 ppm, and 12.5 at 1,500 ppm.

d

QSC=1-(QLC+QFC+QRC)
 e

Tissue:blood partition coefficients calculated based on reported, experimentally determined (vial equilibrium)
 

tissue:air partition coefficients for rats (Tardif et al. 1997). f

Values derived by optimization to data on blood ethylbenzene concentrations in rats exposed to ethylbenzene 

(closed chamber).
 
 

 

 

 

 

ETHYLBENZENE 117 

3. HEALTH EFFECTS 

Although the mixture model achieved predictions similar to observations, this outcome would have been 

highly influenced by the parameter values selected for each of the individual chemicals (or lumped 

chemicals), including fitted interaction constants and, therefore, does not directly address the validity of 

the ethylbenzene model. 

Risk Assessment. The Dennison et al. (2003) ethylbenzene model predicts blood kinetics of 

ethylbenzene and kinetics of metabolism of inhaled ethylbenzene. These predictions are potentially 

useful for predicting internal doses of inhaled ethylbenzene in rats (e.g., blood concentrations, liver 

concentrations of parent compound, or amounts of total metabolites formed in the liver). The 

applicability any of the above dose metrics to risk assessment will depend on the mechanism for the 

specific toxicity endpoint being assessed, and contribution of the parent compound and/or metabolism to 

toxicity. Current knowledge of the mechanism of toxicity of ethylbenzene does not include an 

understanding of the relative contributions of parent compound or metabolites as proximate toxic agents 

in the major end points of ethylbenzene toxicity (i.e., kidney, liver, otic, cancer). 

The Dennison et al. (2003) ethylbenzene model has been incorporated into a mixtures model for gasoline 

(benzene, ethylbenzene, n-hexane, toluene, o-xylene, and other volatile components). In the mixtures 

model, chemical interactions were attributed to competitive inhibition of metabolism and inhibition 

constants were derived by fitting model predictions of closed chamber air concentration kinetics during 

exposures to binary mixtures. The model was used to predict the effect of increasing exposure 

concentration to gasoline on blood concentrations and amounts of individual mixture components 

metabolized (Dennison et al. 2004). 

Target Tissues. The Dennison et al. (2003) ethylbenzene model was calibrated and evaluated to 

predict elimination (i.e., metabolism) kinetics of ethylbenzene that occur in association with inhalation 

exposures. Essential to this prediction is the accurate prediction of rates of metabolism of ethylbenzene, 

which, in the model, is attributed solely to the liver. The model has potential utility for predicting, in 

addition to elimination kinetics of ethylbenzene, kinetics of concentrations of ethylbenzene in important 

toxicity target tissues, including liver, richly perfused tissues (which includes kidney and central nervous 

system), and rates of metabolism of ethylbenzene and total amount of metabolites formed in liver. The 

model does not simulate, specifically, the kidney or central nervous system. 

Species Extrapolation. The Dennison et al. (2003) ethylbenzene model was developed and 

calibrated to simulate ethylbenzene kinetics in the rat; however, it could be allometrically scaled to the 
 

ETHYLBENZENE 118 

3. HEALTH EFFECTS 

human. Studies of the robustness of the model for predicting ethylbenzene kinetics in species other than 

the rat (after allometric scaling to those species) were not located. 

Interroute Extrapolation. Studies that evaluated the model for predicting ethylbenzene kinetics 

following oral or dermal exposure were not located. 

The Shatkin and Brown (1991) Model 

Description of the Model. Shatkin and Brown (1991) described a model of dermal absorption of 

several nonpolar organic nonelectrolytes in dilute aqueous solution, one of which was ethylbenzene. The 

structure of the model is depicted in Figure 3-5; model parameters are presented in Table 3-9. The model 

includes three compartments: stratum corneum, viable epidermis, and blood. Transfers of ethylbenzene 

in solution through the fully hydrated stratum corneum and viable epidermis are assumed to be diffusive, 

with passage through the stratum corneum being the rate-limiting step. A uniform thickness of 40 μm

was assumed for the stratum corneum, with adjustments for different body parts. Immersion of the hand 

or of the full body was assumed for the predicted models. The viable epidermis was assumed to be 

200 μm, although the thickness was varied to test the outcome of the model. Transfer from the viable

epidermis to blood was assumed to be flow-limited. Elimination from blood (i.e., distribution to tissues, 

excretion to urine and air, and metabolism) was represented with a single first-order rate constant. A 

sensitivity analysis revealed a relatively high influence of epidermal blood flow (as expected for flowlimited transfer to blood), epidermal thickness (increasing thickness decreased absorption), and stratum 

corneum fat (increasing fat content decreased absorption). 

Validation of the Model. Model predictions were compared to the estimates of dermal absorption of 

ethylbenzene in humans (Dutkiewicz and Tyras 1967, 1968). In this study, adult males (n=7) immersed 

their hands into a bath solution of 151 mg/L ethylbenzene for 1 hour and the absorbed dose was estimated 

from the change in concentration of the exposure bath. The model predicted absorption of 34–37% of the 

bath ethylbenzene in 1 hour, compared to the observed mean absorption of 39% (range, 0.33–0.54). The 

simulated kinetics of absorption were not reported or compared to observations. 

Risk Assessment. The Shatkin and Brown (1991) model is potentially useful for predicting dermal 

absorption of ethylbenzene in risk assessment applications. An example of one application is prediction 

of the dermal-absorbed dose of ethylbenzene for a bathing scenario (20-minute immersion in 0.1 mg 

ethylbenzene/L); the predicted absorbed dose, 0.47–0.50 mg, was higher than the absorbed dose predicted 
Figure 3-5. Schematic Representation of the Model of Dermal Absorption 

Bath to SC to Epidermis to 

SC rate epidermis rate blood rate 

Bathtub Blood Excreted 

Elimination rate 

Stratum corneum Epidermis 

SC to bath rate Epidermis to SC rate Blood to epidermis rate 

Urine 

Outer Stratum Viable Exhaled breath Blood reservoir corneum epidermis Organ storage 

Metabolism 

Source: Shatkin and Brown 1991 

ETHYLBENZENE 119 

3. HEALTH EFFECTS 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 120 

3. HEALTH EFFECTS 

Table 3-9. Parameters Used in the Shatkin and Brown PBPK Model of Dermal
 

Absorption of Ethylbenzene
 

Parametera Value Reference 

Stratum corneum/water NG Calculated from Roberts et al. 1975 

partition coefficient (Km) 

Stratum corneum diffusion NG Calculated from Guy and Maibach 

coefficient (Dsc) 1984 

Skin surface 320 cm2 (adult, hands and forearms) Dutkiewicz and Tyras 1967, 1968 

NG (adult, body) Guy and Maibach 1984 

Skin surface (infant) 1,900 cm2 Guy and Maibach 1984 

Epidermis diffusion coefficient 3.6x10-4 cm2

/minute Scheuplein 1976; Scheuplein et al. 

(De) 1969 

Stratum corneum thickness 0.004 cm Blank and Scheuplein 1969 

(Hsc) 

Epidermis thickness (He) 0.02–0.1 cm Blank and McAuliffe 1985; Blank 

and Scheuplein 1969; Guy et al. 

1982 

Epidermal blood flow (Feb) 280 mL/minute–m2 Wade et al. 1962 

(adult, at rest) 

Epidermal blood flow (Feb) 4,000 mL/minute–m2 Rowell 1986 

(adult, heavy exercise) 

Epidermis/blood partition 2.75 Shatkin and Brown 1991 

coefficient (Keb) 

Stratum corneum/epidermis NG Shatkin and Brown 1991 

partition coefficient (Ksc/e) 

Blood volume (Vb) (adults) 5,000 mL Shatkin and Brown 1991 

Blood volume (Vb) (infants) 693 mL Shatkin and Brown 1991 

Fat in blood 0.7–0.9% Brown and Hattis 1989 

Fat in stratum corneum 3–6% Raykar et al. 1988 

Fat in epidermis 2–2.5% Scheuplein 1976 

Elimination rate constant (Ke) 0.1 minute -1 Hagemann 1979 

Octanol/water partition 2,230 Shatkin and Brown 1991 

coefficient (Kow) 

a

Taken from Shatkin and Brown 1991. All parameters used were either taken from published experimental work of 

others or calculated from previously reported mathematical relationships. 

NG = value not given 
 

 

 

ETHYLBENZENE 121 

3. HEALTH EFFECTS 

for ingestion of 2 L of water at the same concentration, or from inhalation during a 20-minute shower 

(Shatkin and Brown 1991). The model may be useful in predicting absorbed doses of ethylbenzene 

resulting from bathing, swimming, and other activities (Shatkin and Brown 1991). 

Target Tissues. The Shatkin and Brown (1991) model was developed to simulate dermal absorption 

of ethylbenzene (and other volatile organics); it does not predict concentrations of ethylbenzene in 

specific tissues, other than skin. However, if the model were integrated into PBPK models of the 

distribution and elimination of absorbed ethylbenzene (e.g., Dennison et al. 2003; Tardif et al. 1997), the 

combined models might be useful for predicting internal doses of ethylbenzene associated with dermal 

exposures. 

Species Extrapolation. The Shatkin and Brown (1991) model was developed to simulate dermal 

absorption of ethylbenzene in humans and has been evaluated with observations in humans. The major 

physiological parameters in the model are scalable or could be determined in different species (e.g., 

dermal thickness, dermal fat content, dermal blood flow), and the chemical parameters could be evaluated 

in other species (e.g., partition coefficients) or predicted from physical-chemical properties (e.g., diffusion 

coefficients). These features improve the feasibility of scaling the model to other species. 

Interroute Extrapolation. The Shatkin and Brown (1991) model, in combination with existing 

PBPK ethylbenzene inhalation models (e.g., Dennison et al. 2003; Tardif et al. 1997), may have utility for 

estimating dermal exposures (i.e., concentration, time) that would be expected to yield equivalent 

absorbed doses from inhalation exposures. 

3.5 MECHANISMS OF ACTION 

3.5.1 Pharmacokinetic Mechanisms 

Studies of the in vitro metabolism of ethylbenzene in microsomes prepared from human liver have 

identified high and low affinity catalytic pathways for the initial hydroxylation to 1-phenylethanol (Sams 

et al. 2004). In human liver microsomes, the high affinity pathway exhibited a lower Km and lower Vmax 

(Km=8 M, Vmax=689 pmol/minute/mg protein) than the low affinity pathway (Km=391 M, 

Vmax=3,039 pmol/min/mg protein) and was inhibited by diethyldithiocarbamate. Studies conducted in 

microsomes prepared from insect cells expressing recombinant human isoforms of cytochrome P-450 also 

revealed a relatively high affinity, low Vmax catalysis by CYP2E1and lower affinity, higher Vmax catalysis 
 

 

 

 

 

 

 

ETHYLBENZENE 122 

3. HEALTH EFFECTS 

by CYP1A2 and CYP2B6, suggesting that the latter two isoforms may contribute to the low affinity 

pathway observed in human liver microsome (Sams et al. 2004). 

Blood kinetics of inhaled ethylbenzene have been successfully modeled with assumptions of flow-limited 

transfer of ethylbenzene to tissues and capacity-limited elimination by metabolism (Dennison et al. 2003, 

2004; Tardif et al. 1997, see Section 3.4.5). These models have been successfully scaled from the rat to 

humans by applying species physiological parameter values (e.g., tissue volumes) and partition 

coefficients (i.e., blood:air partition coefficient) and allometrically scaling flows (i.e., cardiac output, 

alveolar ventilation rate) and metabolism parameters (i.e., Km, Vmax) to body weight (Tardif et al. 1997). 

These studies suggest a general similarity of the distribution and elimination kinetics in rats and humans. 

The robustness of these models for predicting ethylbenzene kinetics in other species has not been 

reported; however, the blood elimination kinetics of inhaled ethylbenzene in the mouse show similarities 

to that in the rat (e.g., nonlinearity of clearance with exposure concentration, similar elimination halftimes (Charest-Tardif et al. 2006; Tardif et al. 1997). 

3.5.2 Mechanisms of Toxicity 

Mechanisms of ototoxicity, toxicity to the liver and kidney, and carcinogenicity have not been identified. 

However, studies on ethylbenzene and ethylbenzene metabolites provide some insights regarding the 

potential roles of parent compound and metabolites in ethylbenzene-induced effects. As reviewed in 

Section 3.2.1.4 (Inhalation Exposure, Neurological Effects), inhalation exposure of animals to 

ethylbenzene produces hearing loss through irreversible loss of OHC in the organ of corti (Cappaert et al. 

1999, 2000, 2001, 2002; Gagnaire and Langali 2005; Gagnaire et al. 2007). Cappaert et al. (2002) 

attributed the lack of ototoxicity (based on auditory thresholds and histological assessment of cochlea) in 

guinea pigs exposed to inhaled ethylbenzene to lower circulating levels of ethylbenzene, relative to levels 

producing ototoxicity in rats. Results of a 3-month oral study on phenylglyoxylic acid, a major 

ethylbenzene metabolite, show that this metabolite did not produce ototoxicity, based on 

electrophysiological tests, in rats exposed to drinking water at approximately 293 mg/kg/day (Ladefoged 

et al. 1998). Although this study provides supporting evidence that phenylglyoxylic acid is not ototoxic, 

animals were not evaluated for OHC loss in this study. Furthermore, Pryor et al. (1991) proposed that 

hearing loss caused by toluene, which is structurally similar to ethylbenzene, was caused by parent 

compound, rather than metabolites; pretreatment of rats with phenobarbital, which induces cytochrome 

P450 metabolism of toluene, prevented ototoxicity. Taken together, results of these studies suggest that 

ethylbenzene, rather than metabolites, may be responsible for ototoxicity. 
 

 

 

 

 

 

 

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Regarding possible mechanisms of carcinogenicity, results of the NTP (1999) bioassay on ethylbenzene 

provided clear evidence of carcinogenicity in male rats based on renal tubule neoplasms, some evidence 

in female rats based on renal tubule adenomas, some evidence in male mice based on alveolar/bronchiolar 

neoplasms, and some evidence in female mice based on hepatocellular neoplasms; in addition, testicular 

neoplasms were increased in male rats. In contrast, results of an NTP (1990) 2-year bioassay on 

1-phenylethanol, a primary oxidative metabolite of ethylbenzene, provided some evidence of 

carcinogenicity in male rats based on increased incidences of renal tubular cell adenomas and adenomas 

or adenocarcinoma (combined), but no evidence of carcinogenicity in female rats or male or female mice. 

These results suggest that carcinogenic activity of ethylbenzene may be, at least in part, attributed to the 

parent compound and/or reactive oxidative metabolites in the 4-ethylphenol pathway, rather than the 

1-phenylethanol pathway. 

Ethylbenzene has been shown to exert adverse central nervous system effects on both humans (Yant et al. 

1930) and animals (Cragg et al. 1989; Ethylbenzene Producers Association 1986a; Molnar et al. 1986; 

Tegeris and Balster 1994; Yant et al. 1930). In vivo animal studies of ethylbenzene toxicity at the cellular 

level indicate that changes in brain levels of dopamine and other biochemical alterations, and in evoked 

electrical activity in the brain may be involved in ethylbenzene central nervous system toxicity 

(Andersson et al. 1981; Frantik et al. 1994; Mutti et al. 1988; Romanelli et al. 1986). 

The molecular mechanism(s) of ethylbenzene-induced ototoxicity has not been established. Results of a 

recent in vitro study suggest that ototoxicity induced by low concentrations of ethylbenzene may be 

mediated through nicotinic acetylcholine receptors (van Kleef et al. 2008). Using human heteromeric 

α9α10 nicotinic acetylcholine receptors expressed in Xenopus oocytes, ethylbenzene inhibited 

acetylchloline-mediated ion currents under conditions of low receptor occupancy. Based on in vitro 

studies conducted with toluene, Cappaert et al. (2001) briefly speculated that increased intracellular 

calcium levels might be responsible for the obliteration of outer hair cells exposed to solvents such as 

ethylbenzene. 

In vitro studies of the mechanism of toxicity have focused on the effect of ethylbenzene on cell 

membranes, particularly that of the astrocyte (Engelke et al. 1993; Naskali et al. 1993, 1994; Sikkema et 

al. 1995; Vaalavirta and Tähti 1995a, 1995b). In a review by Sikkema et al. (1995), changes in the 

structure and integrity of the cell membrane after partitioning of ethylbenzene into the lipid bilayer may 

be a mechanism of toxicity. Changes in the integrity of the cell membrane may subsequently affect the 
 

 

 

 

 

 

 

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function of membrane, particularly as a barrier and in energy transduction, and in the formation of a 

matrix for proteins and enzymes. 

The work of Vaalavirta and Tähti (1995a, 1995b) and Naskali et al. (1993, 1994) has investigated the 

effect of ethylbenzene on the membrane of the rat astrocyte, as an in vitro model for the membranemediated effects of solvents on the central nervous system. Cultured astrocytes from the cerebella of 

neonatal Sprague-Dawley rats were sensitive to the effects of ethylbenzene, as measured by the inhibition 

of activity of Na+, K+-ATPase, and Mg++-ATPase (Vaalavirta and Tähti 1995a, 1995b). This effect was 

found to be dose-dependent (Naskali et al. 1994). Inhibition of these membrane-bound enzymes that 

regulate the ion channels of the membrane may disturb the ability of the cells to maintain homeostasis. 

Experiments with rat synaptosome preparations, similar to those using microsomal preparations by 

Engelke et al. (1993), showed that membrane fluidity was increased after exposure to ethylbenzene. 

ATPase and acetylcholinesterase activity were also decreased, as seen in the astrocyte preparations. 

3.5.3 Animal-to-Human Extrapolations 

Species differences have been shown for ethylbenzene metabolism. In humans exposed via inhalation, 

the major metabolites of ethylbenzene are mandelic acid (approximately 70% of the absorbed dose) and 

phenylglyoxylic acid (approximately 25% of the absorbed dose), which are excreted in the urine 

(Bardodej and Bardodejova 1970; Engstrom et al. 1984). Evidence indicates that the initial step in this 

metabolic pathway is oxidation of the side chain of ethylbenzene to produce 1-phenylethanol. In rats 

exposed by inhalation or orally to ethylbenzene, the major metabolites were identified as hippuric and 

benzoic acids (approximately 38%), 1-phenylethanol (approximately 25%), and mandelic acid 

(approximately 15–23%), with phenylglyoxylic acid making up only 10% of the metabolites (Climie et al. 

1983; Engstrom et al. 1984, 1985). In rabbits, the most important metabolite is hippuric acid, which is 

probably formed by oxidative decarboxylation of phenylglyoxylic acid (El Masri et al. 1958). Rabbits 

have been shown to excrete higher levels of glucuonidated metabolites than do humans or rats (El Masry 

et al. 1956; Smith et al. 1954a, 1954b). Thus, there are no animal models of ethylbenzene metabolism 

that are completely consistent with human metabolism. However, of the experimental models 

investigated, rats appear to be a more appropriate model than rabbits. 

Models of the pharmacokinetic mechanisms and mechanisms of toxicity of ethylbenzene have focused on 

cellular processes (see Sections 3.5.1 and 3.5.2, above). In these, humans and animals appear to be 

similar. Although some species differences exist with respect to toxicity, adverse effects observed after 
 

 

 

 

 

 

 

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ethylbenzene exposure in both humans and animals seem to be similar in scope (i.e., respiratory, hepatic, 

renal, and neurological). Rats may be more sensitive than mice or rabbits (Cragg et al. 1989; NTP 1992). 

Thus, the rat may be the most appropriate animal model for studying the mechanism of toxicity of 

ethylbenzene as it relates to human health effects assessment. 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS 

Recently, attention has focused on the potential hazardous effects of certain chemicals on the endocrine 

system because of the ability of these chemicals to mimic or block endogenous hormones. Chemicals 

with this type of activity are most commonly referred to as endocrine disruptors. However, appropriate 

terminology to describe such effects remains controversial. The terminology endocrine disruptors, 

initially used by Thomas and Colborn (1992), was also used in 1996 when Congress mandated the EPA to 

develop a screening program for “...certain substances [which] may have an effect produced by a 

naturally occurring estrogen, or other such endocrine effect[s]...”. To meet this mandate, EPA convened a 

panel called the Endocrine Disruptors Screening and Testing Advisory Committee (EDSTAC), and in 

1998, the EDSTAC completed its deliberations and made recommendations to EPA concerning endocrine 

disruptors. In 1999, the National Academy of Sciences released a report that referred to these same types 

of chemicals as hormonally active agents. The terminology endocrine modulators has also been used to 

convey the fact that effects caused by such chemicals may not necessarily be adverse. Many scientists 

agree that chemicals with the ability to disrupt or modulate the endocrine system are a potential threat to 

the health of humans, aquatic animals, and wildlife. However, others think that endocrine-active 

chemicals do not pose a significant health risk, particularly in view of the fact that hormone mimics exist 

in the natural environment. Examples of natural hormone mimics are the isoflavinoid phytoestrogens 

(Adlercreutz 1995; Livingston 1978; Mayr et al. 1992). These chemicals are derived from plants and are 

similar in structure and action to endogenous estrogen. Although the public health significance and 

descriptive terminology of substances capable of affecting the endocrine system remains controversial, 

scientists agree that these chemicals may affect the synthesis, secretion, transport, binding, action, or 

elimination of natural hormones in the body responsible for maintaining homeostasis, reproduction, 

development, and/or behavior (EPA 1997b). Stated differently, such compounds may cause toxicities that 

are mediated through the neuroendocrine axis. As a result, these chemicals may play a role in altering, 

for example, metabolic, sexual, immune, and neurobehavioral function. Such chemicals are also thought 

to be involved in inducing breast, testicular, and prostate cancers, as well as endometriosis (Berger 1994; 

Giwercman et al. 1993; Hoel et al. 1992). 
 

 

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No studies were located regarding endocrine disruption in humans or animals after exposure to 

ethylbenzene. Nishihara et al. (2000) concluded that ethylbenzene was not estrogenic as established in an 

in vitro yeast two-hybrid assay. No additional in vitro studies were located regarding endocrine 

disruption of ethylbenzene. 

3.7 CHILDREN’S SUSCEPTIBILITY 

This section discusses potential health effects from exposures during the period from conception to 

maturity at 18 years of age in humans, when all biological systems will have fully developed. Potential 

effects on offspring resulting from exposures of parental germ cells are considered, as well as any indirect 

effects on the fetus and neonate resulting from maternal exposure during gestation and lactation. 

Relevant animal and in vitro models are also discussed. 

Children are not small adults. They differ from adults in their exposures and may differ in their 

susceptibility to hazardous chemicals. Children’s unique physiology and behavior can influence the 

extent of their exposure. Exposures of children are discussed in Section 6.6, Exposures of Children. 

Children sometimes differ from adults in their susceptibility to hazardous chemicals, but whether there is 

a difference depends on the chemical (Guzelian et al. 1992; NRC 1993). Children may be more or less 

susceptible than adults to health effects, and the relationship may change with developmental age 

(Guzelian et al. 1992; NRC 1993). Vulnerability often depends on developmental stage. There are 

critical periods of structural and functional development during both prenatal and postnatal life, and a 

particular structure or function will be most sensitive to disruption during its critical period(s). Damage 

may not be evident until a later stage of development. There are often differences in pharmacokinetics 

and metabolism between children and adults. For example, absorption may be different in neonates 

because of the immaturity of their gastrointestinal tract and their larger skin surface area in proportion to 

body weight (Morselli et al. 1980; NRC 1993); the gastrointestinal absorption of lead is greatest in infants 

and young children (Ziegler et al. 1978). Distribution of xenobiotics may be different; for example, 

infants have a larger proportion of their bodies as extracellular water, and their brains and livers are 

proportionately larger (Altman and Dittmer 1974; Fomon 1966; Fomon et al. 1982; Owen and Brozek 

1966; Widdowson and Dickerson 1964). The infant also has an immature blood-brain barrier (Adinolfi 

1985; Johanson 1980) and probably an immature blood-testis barrier (Setchell and Waites 1975). Many 

xenobiotic metabolizing enzymes have distinctive developmental patterns. At various stages of growth 

and development, levels of particular enzymes may be higher or lower than those of adults, and 
 

 

 

 

 

 

 

 

 

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sometimes unique enzymes may exist at particular developmental stages (Komori et al. 1990; Leeder and 

Kearns 1997; NRC 1993; Vieira et al. 1996). Whether differences in xenobiotic metabolism make the 

child more or less susceptible also depends on whether the relevant enzymes are involved in activation of 

the parent compound to its toxic form or in detoxification. There may also be differences in excretion, 

particularly in newborns who all have a low glomerular filtration rate and have not developed efficient 

tubular secretion and resorption capacities (Altman and Dittmer 1974; NRC 1993; West et al. 1948). 

Children and adults may differ in their capacity to repair damage from chemical insults. Children also 

have a longer remaining lifetime in which to express damage from chemicals; this potential is particularly 

relevant to cancer. 

Certain characteristics of the developing human may increase exposure or susceptibility, whereas others 

may decrease susceptibility to the same chemical. For example, although infants breathe more air per 

kilogram of body weight than adults breathe, this difference might be somewhat counterbalanced by their 

alveoli being less developed, which results in a disproportionately smaller surface area for alveolar 

absorption (NRC 1993). 

There are no data describing the effect of exposure to ethylbenzene in children. Respiratory and eye 

irritation, and dizziness are the most prevalent signs of exposure to high levels of ethylbenzene (Yant et 

al. 1930), and it is expected that children would also exhibit these effects, as well as other effects 

observed in adults. Minor birth defects have occurred in newborn rats, but not rabbits, whose mothers 

were exposed by breathing air contaminated with ethylbenzene (NIOSH 1981; Ungváry and Tátrai 1985). 

These defects consisted of urinary tract anomalies (not specified) and supernumerary ribs. 

Supernumerary ribs were observed in the presence of minimal maternal changes. Although 

developmental effects were reported in the offspring of animals exposed to <500 ppm ethylbenzene 

(Ungváry and Tátrai 1985) several longer duration studies have shown developmental effects at 

biologically or statistically significant levels only in the offspring of rats exposed to >500 ppm 

ethylbenzene (Faber et al. 2006, 2007; Saillenfait et al. 2003, 2006, 2007). Furthermore, the report by 

Ungváry and Tátrai (1985) lacks pertinent experimental details, including specific data on the urinary 

tract anomalies, dictating caution in the interpretation of study findings. Section 3.2.1.6, Developmental 

Effects, contains a more detailed discussion of these results. It is not known whether these developmental 

effects observed in animals would be observed in people. Ethylbenzene has been detected in human 

breast milk at unspecified concentrations (Pellizzari et al. 1982), but no pharmacokinetic experiments 

have been done to confirm that it is actually transferred to breast milk in mammals. No specific 

information was found concerning ethylbenzene concentrations in placenta, cord blood, or amniotic fluid. 
 

 

 

 

 

 

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Since there is no information about health effects in children, it is unknown whether they differ from 

adults in their susceptibility to health effects from ethylbenzene. However, in general, the principle that 

early-in-life exposures may increases susceptibility to carcinogens may apply to ethylbenzene (EPA 

2005). 

There is no specific information about the metabolism of ethylbenzene in children or immature adults. 

However, since two of the enzyme families responsible for the conjugation and elimination of 

ethylbenzene metabolites are developmentally regulated, it is possible that the activity of these enzymes 

would differ in children or immature animals compared to adults. In humans, UDP 

glucuronosyltransferase activity does not reach adult levels until about 6–18 months of age, although the 

development of this activity is isoform specific. Activity of sulfotransferases (which is also isoform 

specific) seems to develop earlier. The activity of some sulfotransferase isoforms may even be greater 

during infancy and early childhood than in adulthood (Leeder and Kearns 1997). In addition, agedependence of elimination kinetics (e.g., glomerular filtration and tubular secretion of organic anion 

metabolites of ethylbenzene), potentially, could contribute to age-related differences in sensitivity to 

ethylbenzene. 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT 

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 

1989). 

A biomarker of exposure is a xenobiotic substance or its metabolite(s) or the product of an interaction 

between a xenobiotic agent and some target molecule(s) or cell(s) that is measured within a compartment 

of an organism (NAS/NRC 1989). The preferred biomarkers of exposure are generally the substance 

itself, substance-specific metabolites in readily obtainable body fluid(s), or excreta. However, several 

factors can confound the use and interpretation of biomarkers of exposure. The body burden of a 

substance may be the result of exposures from more than one source. The substance being measured may 

be a metabolite of another xenobiotic substance (e.g., high urinary levels of phenol can result from 

exposure to several different aromatic compounds). Depending on the properties of the substance (e.g., 

biologic half-life) and environmental conditions (e.g., duration and route of exposure), the substance and 

all of its metabolites may have left the body by the time samples can be taken. It may be difficult to 

identify individuals exposed to hazardous substances that are commonly found in body tissues and fluids 
 

 

 

 

 

 

 

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(e.g., essential mineral nutrients such as copper, zinc, and selenium). Biomarkers of exposure to 

ethylbenzene are discussed in Section 3.8.1. 

Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an 

organism that, depending on magnitude, can be recognized as an established or potential health 

impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of 

tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial 

cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung 

capacity. Note that these markers are not often substance specific. They also may not be directly 

adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused 

by ethylbenzene are discussed in Section 3.8.2. 

A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism's ability 

to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or 

other characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in the 

biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are 

discussed in Section 3.10, Populations That Are Unusually Susceptible. 

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Ethylbenzene 

Information on ethylbenzene concentrations in human tissue or fluids is available. Exposure to 

ethylbenzene may be determined by the detection of mandelic acid and phenylglyoxylic acid in urine 

(Bardodej and Bardodejova 1970) or by direct detection of ethylbenzene in whole human blood (Antoine 

et al. 1986; Ashley et al. 1992; Cramer et al. 1988) or urine (Wang et al. 2007). However, mandelic acid 

and phenylglyoxilic acid are also metabolites of styrene (Agency for Toxic Substances and Disease 

Registry 1992). 

The 1982 National Human Adipose Tissue Survey conducted by EPA measured ethylbenzene in 96% of 

the 46 composite samples analyzed for volatile organic compounds (EPA 1986). A wet tissue 

concentration range of not detected (detection limit=2 ng/g) to 280 ng/g was reported, but an average 

concentration was not provided. 

Numerous studies indicate that environmental exposures to ethylbenzene can result in detectable levels in 

human tissues (Antoine et al. 1986; Cramer et al. 1988; Pellizzari et al. 1982; Wolff 1976; Wolff et 
 

 

 

 

 

 

 

 

 

ETHYLBENZENE 130 

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al. 1977) and in expired air (Conkle et al. 1975; Engstrom and Bjurstrom 1978; EPA 1984e). Analysis of 

blood specimens from a test population of 250 patients (Antoine et al. 1986) and composite samples 

obtained from blood donations of laboratory personnel with potentially low-level exposure (Cramer et 

al. 1988) indicated ethylbenzene concentrations in the blood to range from below detection limits to 

59 ppb. Similarly, ethylbenzene was detected in 8 of 12 milk samples from lactating women living in 

various urban areas of the United States with high probability of emissions of pollutants (Pellizzari et al. 

1982). Subcutaneous fat samples taken from individuals exposed to an average of 1–3 ppm ethylbenzene 

in the workplace contained ethylbenzene levels as high as 0.7 ppm (Wolff 1976; Wolff et al. 1977). 

Studies examining the correlation of ethylbenzene concentrations in ambient air with concentrations 

measured in expired or alveolar air have also been conducted (Conkle et al. 1975; Engstrom and 

Bjurstrom 1978; EPA 1984e). Ethylbenzene concentrations in breath samples were reported to correlate 

well with ethylbenzene concentrations in indoor samples taken with personal air monitors (EPA 1984e). 

A correlation was also found between ethylbenzene uptake and ethylbenzene concentrations in alveolar 

air during, but not after, inhalation exposure in volunteers (Engstrom and Bjurstrom 1978). Rates of 

ethylbenzene expiration measured in volunteers with no known previous exposure to ethylbenzene ranged 

from 0.78 to 14 μg/hour, with higher rates detected in smokers than in nonsmokers (Conkle et al. 1975). 

3.8.2 Biomarkers Used to Characterize Effects Caused by Ethylbenzene 

For more information on biomarkers for renal and hepatic effects of chemicals see ATSDR/CDC 

Subcommittee Report on Biological Indicators of Organ Damage (Agency for Toxic Substances and 

Disease Registry 1990) and for information on biomarkers for neurological effects see OTA (1990). 

No specific biomarkers of effect for ethylbenzene were identified. Most of the information on humans is 

from case reports in which the effects are general and non-specific, such as eye and throat irritation and 

chest constriction (Yant et al. 1930). 

3.9 INTERACTIONS WITH OTHER CHEMICALS 

The metabolism of ethylbenzene includes pathways involving mono-oxygenases (e.g., cytochrome P-450) 

and formation of glucuronide and sulfate conjugates. Therefore, the metabolism of ethylbenzene could be 

markedly altered by inhibitors (e.g., carbon monoxide, SKF 525A) and inducers (e.g., phenobarbital, 

described above) of drug-metabolizing enzymes (Gillette et al. 1974) and by the availability of 

conjugation reactants (e.g., glucuronic acid, sulfate) that facilitate the excretion of ethylbenzene 
 

 

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metabolites. Mono-oxygenases (MOs) are a class of enzymes involved in the detoxication of xenobiotics, 

including ethylbenzene. Substances that induce or inhibit MO enzymes may alter the toxicity of ethylbenzene by increasing the rate of production of its metabolites. Compounds that affect glucuronic acid 

availability could also affect the excretion rate of ethylbenzene metabolites. 

Numerous studies have demonstrated interactions between ethylbenzene and chemicals that inhibit 

cytochrome P-450 (e.g., carbon monoxide; Maylin et al. 1973), compete with ethylbenzene for 

metabolism by cytochrome P-450 (e.g., alkylbenzenes, ethanol; Angerer and Lehnert 1979; Elovaara et al. 

1984; Engstrom et al. 1984; Romer et al. 1986), or induce cytochrome P-450 (e.g. phenobarbital; Maylin 

et al. 1973; McMahon and Sullivan 1966). Competitive inhibition of metabolism by alkylbenzenes, 

including ethylbenzene, has been introduced into PBPK models of alkylbenzene mixtures and gasoline 

component mixtures (Dennison et al. 2003, 2004; Haddad et al. 2001; Tardif et al. 1997). 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

A susceptible population will exhibit a different or enhanced response to ethylbenzene than will most 

persons exposed to the same level of ethylbenzene in the environment. Reasons may include genetic 

makeup, age, health and nutritional status, and exposure to other toxic substances (e.g., cigarette smoke). 

These parameters result in reduced detoxification or excretion of ethylbenzene, or compromised function 

of organs affected by ethylbenzene. Populations who are at greater risk due to their unusually high 

exposure to ethylbenzene are discussed in Section 6.7, Populations with Potentially High Exposures. 

Even though ethylbenzene is not known to bioaccumulate (Aster 1995; Meylan et al. 1999; Nuns and 

Benville 1979; Ogata et al. 1984), human and animal studies suggest that several factors can contribute to 

an increased probability of adverse health effects following ethylbenzene exposure (NIOSH/OSHA 

1978). Exposure to ethylbenzene has been shown to produce hearing loss and animals; therefore, 

individuals with pre-existing hearing loss (e.g., congenital or infection-related) or individuals 

participating in activities that may result in hearing loss (e.g., sharpshooting) may be more susceptible to 

the ototoxic effects of ethylbenzene. Exposure of individuals with impaired pulmonary function to ethylbenzene in air has been shown to exacerbate symptoms because of ethylbenzene's irritant properties. 

Because ethylbenzene is detoxified primarily in the liver and excreted by the kidney, individuals with 

liver or kidney disease might be more susceptible to ethylbenzene toxicity, as would persons taking 

medications or other drugs (e.g., alcohol) that are known hepatotoxins. Persons with dermatitis or other 
 

 

 

 

 

 

 

 

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skin diseases may be at greater risk, since ethylbenzene is a defatting agent and may aggravate these 

symptoms. Children’s susceptibility is discussed in Section 3.7. 

In summary, groups that might be more susceptible to the toxic effects of ethylbenzene are individuals 

with hearing loss and diseases of the respiratory system, liver, kidney, or skin; young children; fetuses; 

pregnant women; and individuals taking certain medications such as hepatotoxic medications or drugs. 

3.11 METHODS FOR REDUCING TOXIC EFFECTS 

This section will describe clinical practice and research concerning methods for reducing toxic effects of 

exposure to ethylbenzene. However, because some of the treatments discussed may be experimental and 

unproven, this section should not be used as a guide for treatment of exposures to ethylbenzene. When 

specific exposures have occurred, poison control centers and medical toxicologists should be consulted 

for medical advice. The following texts provide specific information about treatment following exposures 

to ethylbenzene: 

Leikin JB, Poloucek FP. 2002. Poisoning and toxicology handbook. Hudson, OH: Lexi-Comp, Inc., 

554. 

Proctor NH, Hughes JP. 1978. Chemical hazards of the workplace. Philadelphia, PA: J.B. Lippincott 

Company, 251-252. 

3.11.1 Reducing Peak Absorption Following Exposure 

Human exposure to ethylbenzene can occur by inhalation, oral, or dermal contact. General 

recommendations for reducing absorption of ethylbenzene following exposure include removing the 

exposed individual from the contaminated area and removing the contaminated clothing. Removal of the 

patient from the source of contamination is an initial priority along with proper ventilation and cardiac 

monitoring. If the eyes and skin were exposed, they should be flushed with water. Emesis or lavage is 

not recommended following oral exposure due to the risk of aspiration pneumonia (Leikin and Paloucek 

2002). Activated charcoal may be administered to adsorb ethylbenzene (Leikin and Paloucek 2002). 

Benzodiazepines may be used to control seizures (Leikin and Paloucek 2002). Administration of 

catecholamines should be avoided due to the risk of ventricular arrhythmia (Leikin and Paloucek 2002). 
 

 

 

 

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3.11.2 Reducing Body Burden 

Following absorption into the blood, ethylbenzene is rapidly distributed throughout the body. The initial 

stage of ethylbenzene metabolism in humans is the formation of 1-phenylethanol via hydroxylation of the 

of the side chain. Further oxidation leads to the formation of mandelic acid and phenylglyoxylic acid, the 

major urinary metabolites of ethylbenzene in humans. Detoxication pathways generally involve the 

formation of glucuronide or sulfate conjugates of 1-phenylethanol or its subsequent metabolites. Urinary 

excretion is the primary route of elimination of metabolized ethylbenzene. Studies in humans and 

animals indicate that urinary excretion occurs in several phases, with half-lives of hours. Hence, 

ethylbenzene and its metabolites have relatively short half-lives in the body, and while some of these 

metabolites are clearly toxic, substantial body burdens are not expected. 

No methods are currently used for reducing the body burden of ethylbenzene. It is possible that methods 

could be developed to enhance the detoxication and elimination pathways. 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects 

Treatments interfering with the mechanism of action for toxic effects have not been identified. 

3.12 ADEQUACY OF THE DATABASE 

Section 104(I)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of ethylbenzene is available. Where adequate information is 

not available, ATSDR, in conjunction with the National Toxicology Program (NTP), is required to assure 

the initiation of a program of research designed to determine the health effects (and techniques for 

developing methods to determine such health effects) of ethylbenzene. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 
 

 

 

 

 

 

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3.12.1 Existing Information on Health Effects of Ethylbenzene 

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 

ethylbenzene are summarized in Figure 3-6. The purpose of this figure is to illustrate the existing 

information concerning the health effects of ethylbenzene. Each dot in the figure indicates that one or 

more studies provide information associated with that particular effect. The dot does not necessarily 

imply anything about the quality of the study or studies, nor should missing information in this figure be 

interpreted as a “data need”. A data need, as defined in ATSDR’s Decision Guide for Identifying 

Substance-Specific Data Needs Related to Toxicological Profiles (Agency for Toxic Substances and 

Disease Registry 1989), is substance-specific information necessary to conduct comprehensive public 

health assessments. Generally, ATSDR defines a data gap more broadly as any substance-specific 

information missing from the scientific literature. 

Figure 3-6 graphically describes the existing health effects information on ethylbenzene by route and 

duration of exposure. Little information concerning humans exposed via inhalation to ethylbenzene is 

available. Most of the information concerning health effects in humans is reported in occupational 

studies, which are difficult to interpret given the limitations of the studies (e.g., simultaneous exposure to 

other hazardous substances, unquantified exposure concentrations, and exposure probably occurring by a 

combination of routes). No data were available concerning human health effects following oral exposures 

to ethylbenzene. Dermal effects in humans exposed to ethylbenzene vapors include respiratory and 

ocular irritation. 

In animals, the lethality of ethylbenzene is documented for all routes of exposure. Systemic, 

immunologic, neurologic, developmental, and reproductive effects have been reported following acute-, 

intermediate-, or chronic-duration inhalation exposures to ethylbenzene. Limited data on the health 

effects resulting from oral or dermal exposure to ethylbenzene were located. 

3.12.2 Identification of Data Needs 

In general, data on the toxic effects of ethylbenzene in humans and animals are limited. In many areas for 

which studies have been conducted, the lack of reliable data precludes any definitive conclusions from 

being drawn. 

Acute-Duration Exposure. The database for acute-duration inhalation exposure to ethylbenzene is 

largely composed of inhalation studies in laboratory animals with a limited number of human studies. 
Figure 3-6. Existing Information on Health Effects of Ethylbenzene 

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Existing Studies 

ETHYLBENZENE 135 

3. HEALTH EFFECTS 
 

 

 

 

ETHYLBENZENE 136 

3. HEALTH EFFECTS 

The available acute-duration studies in humans (Sliwinska-Kowalska et al. 2001; Yant et al. 1930) and 

animals (Andersson et al. 1981; Cappaert et al. 1999, 2000, 2001, 2002; Ethylbenzene Producers 

Association 1986a; Molnar et al. 1986; Tegeris and Balster 1994; Yant et al. 1930) indicate that the 

nervous system, and particularly the auditory system, is sensitive to the toxic effects of ethylbenzene. 

The available reports and studies in humans are of limited use for dose-response assessment because 

insufficient information was provided to clearly characterize the exposure to ethylbenzene or because 

exposures were for mixtures of solvents, not ethylbenzene alone. Ethylbenzene is an acute ocular and 

respiratory irritant in humans (Cometto-Muñiz and Cain 1995; Thienes and Haley 1972; Yant et al. 

1930); however, animal studies suggest that acute sublethal inhalation exposures do not result in 

pulmonary histopathology (Ethylbenzene Producers Association 1986a). Developmental and 

reproductive effects were reported in animals exposed to ethylbenzene by inhalation during gestation 

(Ungváry and Tátrai 1985); however, the latter study is limited by incomplete description of the results 

and the absence of an analysis on a per litter basis. Increased organ weight (liver, kidneys) has been 

observed in a number of studies in animals (Ethylbenzene Producers Association 1986a; Toftgard and 

Nilsen 1982); however, no findings are made upon microscopic examination of the liver or kidneys 

(Ethylbenzene Producers Association 1986a). An acute-duration inhalation MRL was derived based on 

ototoxicity in animals. No studies describing acute-duration oral exposure of humans to ethylbenzene 

were found in the literature. Although two animal studies have examined the acute oral toxicity of 

ethylbenzene (Gagnaire and Langlais 2005; Ungvary 1986), they were not adequate for the derivation of 

an acute-duration oral MRL. Mild irritation (Smyth et al. 1962), reddening, exfoliation, and blistering 

(Wolf et al. 1956) have been reported in rabbits when ethylbenzene was applied directly on the skin. 

Slight irritation of the eye (Wolf et al. 1956) and corneal injuries (Smyth et al. 1962; Wolf et al. 1956) 

were observed in rabbits when ethylbenzene was instilled onto the eyes. There is a data need for 

additional acute-duration oral and dermal toxicity studies in animals exposed to ethylbenzene. 

Intermediate-Duration Exposure. The database of intermediate-duration inhalation studies 

includes several studies in animals, but no studies in humans. It has been shown that the auditory system 

is sensitive to the toxic effects of ethylbenzene after intermediate-duration inhalation exposure (Gagnaire 

et al. 2007). Systemic effects have been observed at concentrations equal to or higher than those that 

elicited ototoxic effects in rats. Effects at even higher concentrations include neurological and 

hematological effects (Cragg et al. 1989; Wolf et al. 1956) and increased organ weight (Cragg et al. 1989; 

Elovaara et al. 1985; NIOSH 1981; NTP 1992; Wolf et al. 1956). Organs showing increased weight did 

not show treatment-related histopathological effects (Cragg et al. 1989; NTP 1992). Developmental 

and/or reproductive effects have been reported in offspring of animals following intermediate-duration 
 

 

 

 

 

 

ETHYLBENZENE 137 

3. HEALTH EFFECTS 

inhalation exposures to ethylbenzene during gestation (Faber et al. 2006, 2007; NIOSH 1981; Saillenfait 

et al. 2003, 2006, 2007) at concentrations that were higher than those that elicited ototoxic effects. An 

intermediate-duration inhalation MRL was derived based on the observed ototoxic effects in animals 

(Gagnaire et al. 2007). The intermediate-duration oral database for ethylbenzene is limited to the critical 

study by Mellert et al. (2007) evaluating the effects of oral exposure of rats to ethylbezene for 4 and 13 

weeks, and a poorly reported 6-month exposure study in rats (Wolf et al. 1956). Results of the 13-week 

gavage study in rats observed effects indicative of liver toxicity, including increased activity of serum 

liver enzymes (alanine aminotransferase and γ-glutamyl transferase), increased absolute and relative liver 

weights, and a dose-related increase in the incidence of centrilobular hepatocyte hypertrophy. Results of 

the 4-week exposure study in rats are similar to those observed in the 13-week study, showing that the 

liver is the primary target organ for oral ethylbenzene; effects consistent with hepatotoxicity, including 

increased absolute and relative liver weights, increased incidence of hepatocyte centrilobular, and 

increased serum liver enzyme activity (alanine aminotransferase) (Mellert et al. 2007). Wolf et al. (1956) 

reported slight weight and histopathological effects in the liver and kidney of female rats. An 

intermediate-duration oral MRL was derived based on the observed liver effects in animals exposed for 

13 weeks (Mellert et al. 2007). 

Chronic-Duration Exposure and Cancer. The database of chronic-duration/carcinogenicity 

inhalation studies with ethylbenzene includes a chronic duration study in rats and mice (NTP 1999) and a 

limited number of studies in humans. Hematological effects were observed in workers exposed to 

solvents containing ethylbenzene (Angerer and Wulf 1985), but no hematological effects, liver lesions or 

effects on liver function, or cases of malignancy were reported in a study of workers exposed chronically 

(>20 years) to ethylbenzene (Bardodej and Cirek 1988). The severity of nephropathy was significantly 

increased in female and male rats exposed to ≥75 or 750 ppm ethylbenzene, respectively, for 2 years 

(NTP 1999). At higher concentrations rats showed significant increases in renal tubule hyperplasia; male 

rats showed an increased incidence of interstitial cell adenoma in the testis. Effects observed in male or 

female mice exposed to ethylbenzene for 2 years include an increased incidence of hyperplasia of the 

pituitary gland pars distalis, increased incidence of follicular cell hyperplasia in the thyroid gland, an 

increased incidence of syncytial alterations of the hepatocytes, hypertrophy, and hepatic necrosis, and an 

increased incidence of eosinophilic foci (NTP 1999). Ethylbenzene showed clear evidence of 

carcinogenic activity in male rats based on increased incidences of renal tubule neoplasms, some evidence 

of carcinogenic activity in female rats based on increased incidences of renal tubule adenomas, some 

evidence of carcinogenic activity in male mice based on increased incidences of alveolar/bronchiolar 

neoplasms, and some evidence of carcinogenic activity in female mice based on increased incidences of 
 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 138 

3. HEALTH EFFECTS 

hepatocellular neoplasms (NTP 1999). The 2-year inhalation study in rats suggests that an increase in the 

severity of nephropathy in female rats is the most sensitive end point of ethylbenzene exposure. This end 

point was selected to estimate a chronic-duration inhalation MRL. There is no need to conduct additional 

carcinogenicity studies of ethylbenzene via inhalation. A statistically significant increase in total 

malignant tumors was reported in female rats and in combined male and female groups exposed to 500 

mg kg/day via gavage for 104 weeks (Maltoni et al. 1985). No data on specific tumor type were 

presented, only one dose was tested, and no information on survival was provided. It might be useful to 

conduct a toxicity and carcinogenicity study of ethylbenzene administered orally to at least two animal 

species. It might be useful to conduct chronic-duration studies in at least two species with an emphasis in 

ototoxic effects. 

Genotoxicity. There are limited data on the genotoxicity of ethylbenzene in humans. Two studies 

examined potential genotoxic effects in workers (Holz et al. 1995; Sram et al. 2004); the interpretation of 

these results is limited by co-exposure to other chemicals (e.g., benzene, toluene, styrene). In vivo 

genotoxicity studies in laboratory animals did not cause significant alterations in micronuclei formation 

(Mohtashamipur et al. 1985; NTP 1992, 1999) or unscheduled DNA syntheseis (Clay 2001). Data are 

available regarding the genotoxic potential of ethylbenzene from in vitro assays in bacteria, yeast, and 

mammalian cell cultures (Dean et al. 1985; Degirmenci et al. 2000; Florin et al. 1980; Kubo et al. 2002; 

Nestmann and Lee 1983; Nestmann et al. 1980; NTP 1986, 1999; Zeiger et al. 1992). The results 

generally indicate that ethylbenzene is not mutagenic. Similarly, in vitro genotoxic assays in mammalian 

cells were negative when noncytotoxic concentrations were used (Dean et al. 1985; McGregor et al. 1988; 

NTP 1986, 1999; Seidel et al. 2006; Wollny 2000). However, some studies did not cause genotoxic 

alterations at concentrations not associated with cytotoxicity (Chen et al. 2008; Gibson et al. 1997); it is 

not known whether these positive results reflect a genotoxic response in a particular test system or 

whether they are outliers. Independent confirmation or refutation of these studies, as well as further 

genotoxicity studies, especially in mammalian systems, would help provide clarification of these 

conflicting results. 

Reproductive Toxicity. No studies were located regarding reproductive effects in humans following 

inhalation exposure to ethylbenzene. Reproductive end points have been assessed after acute- (Ungváry 

and Tátrai 1985) and intermediate-duration exposures of animals exposed during gestation (Saillenfait et 

al. 2003, 2006, 2007) and in a two-generation reproductive toxicity study (Faber et al. 2006, 2007). 

Effects on reproductive organs (Cragg et al. 1989; NTP 1992, 1999; Wolf et al. 1956) in animals exposed 

to ethylbenzene have also been evaluated. The only available oral-exposure reproduction study reported 
 

 

 

 

 

 

ETHYLBENZENE 139 

3. HEALTH EFFECTS 

decreased hormone levels and blockage or delay of the estrus cycle in female rats (Ungvary 1986). 

Additional inhalation exposure reproductive toxicity studies are not deemed necessary at this time. It 

might be useful to conduct additional oral exposure reproductive toxicity studies in at least two species. 

Developmental Toxicity. No studies of developmental effects in humans following inhalation 

exposure to ethylbenzene were located. The available studies have reported developmental effects in the 

offspring of animals exposed to ethylbenzene during gestation (NIOSH 1981; Saillenfait et al. 2003, 

2006, 2007; Ungváry and Tátrai 1985). The report by Ungváry and Tátrai (1985) has many deficiencies, 

including poor reporting of the experimental conditions and poor description of the maternal and fetal 

observations. Maternal toxicity has been generally reported at the highest doses tested (Saillenfait et al. 

2003, 2006, 2007; Ungváry and Tátrai 1985). Biologically or statistically significant developmental or 

neurodevelopmental effects were not observed in the offspring of animals in a two-generation inhalation 

study (Faber et al. 2006, 2007). No studies were located regarding developmental effects in humans and 

animals following oral or dermal exposure to ethylbenzene. A data need exists for oral and dermal 

developmental toxicity studies. 

Immunotoxicity. No studies were found regarding immunological effects in humans following 

inhalation exposure to ethylbenzene. No effects on humoral immune function were observed in female 

rats exposed to ethylbenzene vapor for 28 days (Stump 2004). Studies also were located that examined 

organs of the immune system in animals after intermediate- (Cragg et al. 1989; NIOSH 1981; NTP 1992) 

or chronic-duration (NTP 1999) exposure to ethylbenzene. No studies were located regarding 

immunological effects in humans or animals following oral or dermal exposure to ethylbenzene. No 

additional immunological studies are deemed to be necessary at this time. 

Neurotoxicity. Human studies have established that acute exposure to ethylbenzene may result in 

dizziness and vertigo (Yant et al. 1930) and that hearing loss is significantly increased in workers exposed 

to solvent mixtures that include ethylbenzene (Sliwinska-Kowalska et al. 2001). The role of ethylbenzene 

in the observed hearing losses cannot be ascertained from this study given that ethylbenzene was only one 

of several solvents. 

Animal studies indicate that the auditory system is the most sensitive target of ethylbenzene toxicity after 

acute- (Cappaert et al. 1999, 2000, 2001, 2002) or intermediate-duration (Gagnaire et al. 2007) inhalation 

exposures and after acute-duration oral exposures to ethylbenzene (Gagnaire and Langlais 2005). The 

effects of ethylbenzene on the central nervous system have been assessed in animals after acute-duration 
 

 

 

 

ETHYLBENZENE 140 

3. HEALTH EFFECTS 

exposure to ethylbenzene (Ethylbenzene Producers Association 1986a; Molnar et al. 1986; Tegeris and 

Balster 1994; Yant et al. 1930). Neurobiochemical and electrical activity alterations have been reported 

in animals after acute-duration exposure to ethylbenzene (Andersson et al. 1981; Frantik et al. 1994; 

Mutti et al. 1988; Romanelli et al. 1986). No adverse histopathological findings were observed in brain 

tissue of animals after intermediate- (NTP 1992) or chronic-duration (NTP 1999) exposure to 

ethylbenzene. No studies were located regarding neurological effects in humans following oral exposure 

to ethylbenzene. Ototoxicity is also observed in animals after acute-duration oral exposure to 

ethylbenzene (Gagnaire and Langlais 2005). Additional studies are needed to establish the mechanism of 

action by which ethylbenzene elicits ototoxicity, as no information establishing the mechanism of 

ethylbenzene-induced ototoxicity was identified. Furthermore, due to the large differences between rats 

and guinea pigs in susceptibility to ethylbenzene-induced ototoxicity, additional studies on hearing and 

ear physiology in rodents are needed to evaluate which species is most similar to humans. No studies 

were located regarding neurological effects in humans or animals following dermal exposure to 

ethylbenzene. Additional inhalation studies are needed to establish an intermediate-duration NOAEL for 

ototoxic effects. Additional studies are also needed to characterize the concentration-response pattern for 

ototoxicity after acute- and intermediate-duration oral exposures to ethylbenzene. 

Epidemiological and Human Dosimetry Studies. The few available epidemiological studies on 

the health effects of ethylbenzene were primarily limited to occupational studies in which quantitative 

estimates of exposure were lacking and other limitations (e.g., multiple exposure routes, simultaneous 

exposure to other hazardous chemicals) were present. Studies using volunteers exposed to low concentrations of ethylbenzene have provided useful information on effects of acute-duration inhalation 

exposure on the central nervous system (Yant et al. 1930). No studies were available in which humans 

were exposed orally or dermally to ethylbenzene. Epidemiological studies conducted in populations 

exposed to ethylbenzene alone may provide useful information on the effects of ethylbenzene in humans. 

Emphasis should be placed in the detection of ototoxic effects as this end point is the most sensitive effect 

observed in animal studies. 

Biomarkers of Exposure and Effect. Sensitive methods are available for determining ethylbenzene and ethylbenzene metabolites in biological tissues and fluids. However, limited data are 

available associating levels of ethylbenzene in human tissues and fluids with adverse health effects. 

Additional animal or epidemiological studies evaluating the association between levels in tissue or fluids 

and adverse health effects would be useful to devise more sensitive and more specific early biomarkers of 

effect. 
 

 

 

 

 

 

ETHYLBENZENE 141 

3. HEALTH EFFECTS 

Exposure. Exposure to ethylbenzene can be monitored through levels of ethylbenzene in breath, blood, 

or tissue, or levels of its metabolites, mandelic or phenylglyoxylic acid in urine. A statistically significant 

correlation was observed between urinary excretion of mandelic acid and ethylbenzene exposure in 

workers exposed to mixed solvents (including an ethylbenzene TWA of 0.9 ppm) in a metal-coating 

factory (Kawai et al. 1991). However, neither one of the metabolites is specific to ethylbenzene. 

Additional studies to identify a biomarker or biomarkers of exposure specific to ethylbenzene are needed. 

Effect. There are currently no known specific biomarkers of effect for ethylbenzene. Development of 

methods to identify biomarkers that would indicate toxic effects, and the extent of those toxic effects after 

exposure to ethylbenzene, would be helpful in managing health effects that occur after significant 

exposure to ethylbenzene. 

Absorption, Distribution, Metabolism, and Excretion. Ethylbenzene is absorbed by humans 

following inhalation (Bardodej and Bardodejova 1970; Gromiec and Piotrowski 1984) and dermal 

(Dutkiewicz and Tyras 1967) exposures. Absorption rates were 49–64% by inhalation. Dermal 

absorption rates were in the range of 24–33 and 0.11–0.23 mg/cm2

/hour for male subjects exposed to 

liquid ethylbenzene and ethylbenzene from aqueous solutions, respectively (Dutkiewicz and Tyras 1967). 

Animal data support these findings and indicate that absorption rates are high following oral exposures as 

well (Climie et al. 1983; El Masry et al. 1956). 

Only one study (Engstrom and Bjurstrom 1978) is available that outlines the distribution of ethylbenzene 

in humans following inhalation exposure. This study indicates rapid distribution to adipose tissues 

throughout the body. Inhalation studies in animals support these results (Elovaara et al. 1982; Engstrom 

et al. 1985). Ethylbenzene is accumulated primarily in the intestine, liver, kidney, and fat, which provides 

some basis for ethylbenzene-induced effects observed in the liver and kidney. No data on distribution of 

ethylbenzene following dermal exposure were located. Such information would be useful because 

absorption of liquid ethylbenzene via this route is rapid in humans and because the potential exists in 

humans for dermal exposure. 

The metabolism of ethylbenzene in humans and animals has been studied. Although some differences in 

the metabolic pattern according to route of exposure, sex, nutritional status (Nakajima and Sato 1979), 

and species (Bakke and Scheline 1970; Climie et al. 1983; El Masry et al. 1956; Engstrom et al. 1984, 

1985; Smith et al. 1954a, 1954b; Sollenberg et al. 1985) have been documented, pharmacokinetic data 
 

 

 

 

 

ETHYLBENZENE 142 

3. HEALTH EFFECTS 

show no significant differences in metabolism between oral and inhalation routes in either humans or 

animals (Climie et al. 1983; Engstrom et al. 1984, 1985). Further studies that correlate these differences 

in metabolism with differences in health effects would be useful. Data on metabolism following dermal 

exposure are sparse, because it is difficult to accurately measure absorption of volatile compounds. 

Additional data on metabolism following dermal exposure would be useful as these exposures could 

occur both from contaminated soil or groundwater. 

Ethylbenzene has been shown to be rapidly eliminated from the body following inhalation exposure 

(primarily in the urine) in both humans and animals. These studies (Gromiec and Piotrowski 1984; 

Yamasaki 1984) are sufficient to characterize the elimination of ethylbenzene following inhalation 

exposure. A small number of studies in animals exposed orally and humans exposed dermally support 

these findings. Further studies on elimination of ethylbenzene via these exposure routes would be useful, 

especially because differences in the excretion patterns have been observed with different routes of 

exposure. 

PBPK models have been developed for predicting ethylbenzene kinetics (including metabolism) in rats 

and humans exposed by inhalation (Dennison et al. 2003, 2004; Tardif et al. 1997) and in rats exposed to 

gavage doses of ethylbenzene in corn oil (Faber et al. 2006). 

Comparative Toxicokinetics. Quantitative and qualitative variations in the absorption, distribution, 

metabolism, and excretion of ethylbenzene were observed depending on exposure routes, sex, nutritional 

status, and species, as previously outlined. Further studies that focus on these differences and their 

implications for human health would be useful. Additionally, in vitro studies using human tissue and 

PBPK modeling would contribute significantly to the understanding of the kinetics of ethylbenzene, since 

they would provide information on half-lives and saturation kinetics associated with the metabolism of 

ethylbenzene. 

Methods for Reducing Toxic Effects. No information was found that specifically addressed the 

reduction of toxic effects after absorption of ethylbenzene. Development of clinical procedures for 

minimizing the effects of ethylbenzene on the respiratory, hepatic, and renal systems, and the central 

nervous system would be useful in situations where significant exposure had occurred. 
 

 

 

 

ETHYLBENZENE 143 

3. HEALTH EFFECTS 

Children’s Susceptibility. Data needs relating to both prenatal and childhood exposures, and 

developmental effects expressed either prenatally or during childhood, are discussed in detail in the 

Developmental Toxicity subsection above. 

There are no data describing the effects of ethylbenzene exposure in children or developing postnatal 

animals. Data needs relating to development are discussed in more detail above under developmental 

effects. In order to evaluate whether ethylbenzene presents a unique hazard to children, additional 

information on the health effects, pharmacokinetics, metabolism, and mechanism of action in children is 

needed. It is unknown whether children differ from adults in their susceptibility to health effects from 

exposure to ethylbenzene. Pharmacokinetic studies investigating whether ethylbenzene or its active 

metabolites cross the placenta or are transferred into breast milk would be useful. Studies to determine 

whether there are specific biomarkers of exposure in children would be helpful in monitoring the 

exposure of children to this chemical. In addition, information describing methods of reducing toxic 

effects and decreasing body burden in children might be helpful. 

Child health data needs relating to exposure are discussed in Section 6.8.1, Identification of Data Needs: 

Exposures of Children. 

3.12.3 Ongoing Studies 

Ongoing studies pertaining to ethylbenzene have been identified and are shown in Table 3-10 (FEDRIP 

2007). In addition, the American Chemistry Council is conducting investigations on the mode of action 

of ethylbenzene-induced mouse lung tumors, including the role of ethylbenzene ring-oxidation to 

cytotoxic quinine metabolites. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 144 

3. HEALTH EFFECTS 

Table 3-10. Ongoing Studies on Ethylbenzene 

Investigator Affiliation Research description Sponsor 

Thrall KD 

Backes WL 

Burke J 

Davis-Hoover W 

Venosa A 

Vroblesky DA 

Jayarao BM 

Sylva TY 

Holm RH 

Miknis F 

Starr RC 

Friesen DT 

Battelle Pacific 

Northwest 

Laboratories 

Louisiana State 

University 

Environmental 

Protection 

Agency 

Environmental 

Protection 

Agency 

Environmental 

Protection 

Agency 

Department of the 

Interior, U.S. 

Geological 

Survey, Water 

Resources 

Division 

Pennsylvania 

State University, 

Veterinary 

Science 

University of 

Hawaii, Molecular 

Biosciences and 

Biosystems 

Harvard 

University, 

Department of 

Chemistry 

FETC-MGN 

Idaho National 

Engineering and 

Environmental 

Laboratory 

Bend Research, 

Inc. 

Dermatopharmacokinetics of paint solvents. 

Identify conditions under which individuals 

may be susceptible to alkylbenzene-induced 

toxicity. 

A critical review and probabilistic model input 

distribution development for 

microenvironmental exposures to benzene. 

Determining if biologically active in situ 

BioNets could bioremediate methyl-tert-butyl 

ether and BTEX contaminated groundwater. 

Treatability of co-mingled groundwater plume 

contaminated with polycyclic aromatic 

hydrocarbons. 

Remediation of JP-4 contamination using 

hydraulic containment and in situ 

biodegradation at the Defense Fuel Supply 

Center, Charleston, South Carolina. 

Bioreporter-based technology for detection of 

organic toxicants directly from milk and milk 

products. 

Application of bioremediation to hydrocarbon 

contaminated soils. 

Transformations catalyzed by the 

molybdenum and tungsten oxotransferases 

and hydroxylases. 

Noncatalytic concept for the direct conversion 

of fossil fuels and hydrocarbon-containing 

materials to transportation fuels with 

simultaneous reduction in the heteroatom 

content. 

Development and testing of an in situ system 

for remediating groundwater contaminated 

with BTEX. 

High-performance membranes for gas, vapor, 

and liquid separations. 

National Institute for 

Occupational safety 

and Health 

National Institute of 

environmental 

Health Sciences 

Environmental 

Research 

Laboratories 

Risk Management 

Resource Library 

Risk Management 

Resource Library 

Department of the 

Interior, U.S. 

Geological Survey, 

Water Resources 

Division 

Pennsylvania State 

University, 

Veterinary Science 

University of Hawaii, 

Molecular 

Biosciences and 

Biosystems 

National Science 

Foundation 

Office of Fossil 

Energy 

Office of Fossil 

Energy 

Office of Energy 

Research 
 

 

 

 

 

 

ETHYLBENZENE 145 

3. HEALTH EFFECTS 

Table 3-10. Ongoing Studies on Ethylbenzene 

Investigator Affiliation Research description Sponsor 

Sibold J Golden 

Technologies 

Company, Inc. 

Investigating the use of ceramic membranes 

in dehydrogenation reactions. 

Energy Efficiency, 

Department of 

Energy 

Ittrell J SE, Inc. Advanced low temperature emissions control 

technology for MTB destruction. 

SE, Inc. 

aPierre R Recision 

Combustion, Inc 

Investigating ano-zeolite coatings on microlith 

substrates for high selectivity chemical 

reactions. 

Recision 

Combustion, Inc. 

BTEX = benzene, toluene, ethylbenzene, and xylenes 

Source: FEDRIP 2007 
ETHYLBENZENE 146 

3. HEALTH EFFECTS 

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ETHYLBENZENE 147 

4. CHEMICAL AND PHYSICAL INFORMATION 

4.1 CHEMICAL IDENTITY 

Ethylbenzene is an aromatic hydrocarbon that occurs naturally in petroleum and is a component of 

aviation and automotive fuels. It is used as a solvent and in the production of synthetic rubber and 

styrene. Information regarding the chemical identity of ethylbenzene is located in Table 4-1. 

4.2 PHYSICAL AND CHEMICAL PROPERTIES 

Ethylbenzene is a colorless liquid with an aromatic odor. Information regarding the physical and 

chemical properties of ethylbenzene is located in Table 4-2. Ethylbenzene is a flammable and 

combustible liquid. Vapors are heavier than air and may travel to a source of ignition and flash back. 

Liquid ethylbenzene floats on water and may travel to a source of ignition and spread fire. Combustion 

may produce irritants and toxic gases (HSDB 2009; NFPA 1994). Ethylbenzene may accumulate static 

electricity and will react with oxidizing materials (HSDB 2009; NFPA 1994). 
Table 4-1. Chemical Identity of Ethylbenzene 

Characteristic Information Reference 

Chemical name Ethylbenzene Budavari and O'Neil 1989 

Synonym(s) EB; ethyl benzene; benzene, ethyl-; HSDB 2009 

ethylbenzol; phenylethane; 

etilbenzene; ethylbenzeen; 

aethylbenzo; etylobenzen 

Registered trade name(s) No data 

Chemical formula C8H10 Cannella 2007 

Chemical structure CH Cannella 2007 3 

CH2 

Identification numbers: 

CAS registry 100-41-4 Cannella 2007 

NIOSH RTECS NIOSH/DA0700000 NIOSH 2009; RTECS 2009 

EPA hazardous waste F003 HSDB 2009 

OHM/TADS 7216709 HSDB 1995 

DOT/UN/NA/IMDG shipping UN 1175; IMDG 3.2 HSDB 2009 

HSDB 84 HSDB 2009 

NCI NCI-C56393 HSDB 2009 

STCC 49 091 63 HSDB 2009 

CAS = Chemical Abstracts Service; DOT/UN/NA/IMDG = Department of Transportation/United Nations/North 

America/International Maritime Dangerous Goods Code; EPA = Environmental Protection Agency; 

HSDB = Hazardous Substances Data Bank; NCI = National Cancer Institute; NIOSH = National Institute for 

Occupational Safety and Health; OHM/TADS = Oil and Hazardous Materials/Technical Assistance Data System; 

RTECS = Registry of Toxic Effects of Chemical Substances; STCC = Standard Transport Commodity Code 

ETHYLBENZENE 148 

4. CHEMICAL AND PHYSICAL INFORMATION 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 149 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Ethylbenzene 

Property Information	 Reference 

Molecular weight 106.17 Lide 1994 

Color Colorless Welch et al. 2005 

Physical state Liquid Welch et al. 2005 

Melting point -94.975 °C Cannella 2007 

Boiling point 136.19 °C Cannella 2007 

Density at 20 °C/4 °C 0.8670 Welch et al. 2005 

at 25 °C/25 °C 0.8671 Cannella 2007 

Odor Sweet, gasoline-like CHRIS 1985 

Odor threshold: 

Water 0.029 mg/L	 Amoore and Hautala 1983 

0.140 mg/L Rosen et al. 1963; Verschueren 1983 

Air 2.3 ppm Amoore and Hautala 1983 

2–2.6 mg/m3 Verschueren 1983 

Solubility: 

Water at 0 °C 197 mg/L Polak and Lu 1973 

at 15 °C 140 mg/L Verschueren 1983
 

at 20 °C 152 mg/L Verschueren 1983
 

at 25 °C 160 mg/L Amoore and Hautala 1983
 

at 25 °C 177 mg/L Polak and Lu 1973
 

at 25 °C 208 mg/L Bohon and Claussen 1951
 

Organic solvents	 Miscible with usual organic solvents Budavari and O'Neil 1989 

Soluble in alcohol and ether Lide 1994 

Partition coefficients: 

Log Kow 4.34 EPA 1982 

3.13	 Yalkowsky and Valvani 1976 

3.15 Hansch et al. 1995
 

Log Koc 2.22 (calculated) Chiou et al. 1983
 

2.38 (measured)	 Hodson and Williams 1988 

2.40 (calculated)	 Vowles and Mantoura 1987 

Vapor pressure 

at 20 °C 7 mm Hg Verschueren 1983 

at 25 °C 1.27 kPa (9.53 mm Hg) Mackay and Shiu 1981 

at 25.9 °C 10 mm Hg Sax and Lewis 1989 

at 30 °C 12 mm Hg Verschueren 1983 
 

 

 

 

 

 

ETHYLBENZENE 150 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Ethylbenzene 

Property Information Reference 

Henry's law constant: 

at 20 °C 6.6x10-3 atm-m3/mol EPA 1982 

at 20 °C 8.7x10-3 atm-m3/mol Lyman et al. 1982 

at 25 °C 8.43x10-3 atm-m3/mol Mackay et al. 1979 

at 25 °C 7.9x10-3 atm-m3

/mol Mackay and Shiu 1981 

Autoignition temperature 810 °F (432 °C) Cannella 2007; NFPA 1994; 

Flash point 15 °C Cannella 2007 

Flammability limits 0.8 (lower) vol% –6.7 (upper) vol% NIOSH 2005 

Conversion factors 1 mg/m3

=0.230 ppm NIOSH 2005; Verschueren 1983 

(25 °C, 1 atm) 1 ppm=4.34 mg/m3 
 

 

 

 

 

 

ETHYLBENZENE 151 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

5.1 PRODUCTION 

Ethylbenzene is primarily produced by the alkylation of benzene with ethylene in liquid-phase slurry 

reactors promoted with aluminum chloride catalysts or by vapor-phase reaction of benzene with dilute 

ethylene-containing feedstock with a boron trifluoride catalyst supported on alumina (Cannella 2007; 

Clayton and Clayton 1981; HSDB 2009; Welch et al. 2005; Ransley 1984). Newer versions of the 

method employ synthetic zeolites in fixed-bed reactors as catalysts for alkylation in the liquid phase or 

narrow pore synthetic zeolites in fixed-bed reactors in the vapor phase (Welch et al. 2005). Other 

methods of manufacturing ethylbenzene include preparation from acetophenone, dehydrogenation of 

naphthenes, catalytic cyclization and aromatization, separation from mixed xylenes via fractionation, 

reaction of ethylmagnesium bromide and chlorobenzene, extraction from coal oil, and recovery from 

benzene-toluene-xylene (BTX) processing(Clayton and Clayton 1981; HSDB 2009; Ransley 1984; Welch 

et al. 2005). Commercial grades of ethylbenzene may contain small amounts of m-xylene, p-xylene, 

cumene, and toluene (HSDB 2009). 

Ethylbenzene is traditionally ranked as one of the top 50 chemicals produced in the United States. 

Table 5-1 shows the historical production volumes of ethylbenzene from 1983 to 2005 (C&EN 1994a, 

1994b, 1995, 2006; Kirschner 1995). 

Table 5-2 lists the facilities in each state that manufacture or process ethylbenzene, the intended use, and 

the range of maximum amounts of ethylbenzene that are stored on site. There are currently 

3,755 facilities that produce, process, or use ethylbenzene in the United States. The data listed in 

Table 5-2 are derived from the Toxics Release Inventory (TRI06 2008). These data should be used with 

caution however since only certain types of facilities are required to report (EPA 1995d). Therefore, this 

is not an exhaustive list. 

Currently, there are eight major producers of ethylbenzene in the United States, with a combined annual 

production capacity of approximately 15.8 billion pounds (SRI 2006). These producers and their 

respective plant locations are provided in Table 5-3. 
ETHYLBENZENE 152 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-1. Ethylbenzene Production in the United States from 1983 to 2005 

Production in thousands of Production in billions of 

Year metric tons pounds 

1983 3,583 7.9 

1984 3,447 7.6 

1985 3,357 7.4 

1986 4,082 9.0 

1987 4,218 9.3 

1988 4,491 9.9 

1989 4,173 9.2 

1990 3,810 8.4 

1991 5,171 11.4 

1992 5,035 11.1 

1993 5,352 11.8 

1994 5,398 11.9 

1995 6,194 13.7 

1996 4,699 10.4 

1997 5,432 12.0 

1998 5,743 12.7 

1999 5,945 13.1 

2000 5,968 13.2 

2001 4,642 10.2 

2002 5,412 11.9 

2003 5,578 12.3 

2004 5,779 12.7 

2005 5,251 11.6 

Source: C&EN 1994a, 1994b, 1995, 2006; Kirschner 1995 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 153 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-2. Facilities that Produce, Process, or Use Ethylbenzene 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

AK 21 0 49,999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 12 

AL 109 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

AR 50 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

AS 1 100,000 999,999 9 

AZ 34 100 9,999,999 1, 2, 4, 5, 7, 8, 9, 10, 11, 12, 13 

CA 238 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

CO 32 0 9,999,999 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13 

CT 37 0 999,999,999 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14 

DE 18 0 49,999,999 1, 2, 3, 6, 7, 8, 10, 11, 12, 13 

GA 86 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

GU 8 100 9,999,999 2, 3, 4, 7, 9, 12 

HI 23 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 9, 10, 12, 13, 14 

IA 56 0 9,999,999 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13 

ID 4 1,000 999,999 1, 5, 7, 9, 11, 12 

IL 156 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

IN 134 0 49,999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14 

KS 90 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

KY 91 0 49,999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14 

LA 235 0 999,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MA 44 100 499,999,999 1, 2, 4, 5, 7, 8, 9, 10, 11, 12, 14 

MD 54 100 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

ME 17 0 49,999,999 2, 3, 4, 7, 9, 10, 11, 12 

MI 185 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MN 79 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MO 95 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MP 8 0 999,999 2, 3, 4, 7, 9 

MS 73 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MT 19 10,000 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 13, 14 

NC 68 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

ND 11 1,000 9,999,999 1, 2, 3, 4, 6, 7, 9, 10, 12 

NE 22 0 9,999,999 1, 2, 3, 7, 8, 10, 11, 12 

NH 16 0 999,999 2, 7, 9, 10, 11, 12, 13 

NJ 102 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

NM 30 1,000 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13 

NV 15 100 999,999 1, 2, 4, 7, 8, 9, 11, 12 

NY 85 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

OH 172 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

OK 59 100 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 154 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-2. Facilities that Produce, Process, or Use Ethylbenzene 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

OR 36 0 9,999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13 

PA 145 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

PR 58 100 10,000,000,000 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

RI 19 0 999,999,999 1, 2, 4, 7, 8, 9, 10, 11, 12 

SC 55 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

SD 8 100 99,999 7, 10, 11 

TN 81 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

TX 412 0 10,000,000,000 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

UT 45 100 9,999,999 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13 

VA 69 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

VI 9 10,000 49,999,999 1, 2, 3, 4, 6, 7, 8, 9, 12 

VT 5 0 999,999 7, 11 

WA 69 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

WI 73 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

WV 60 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

WY 34 1,000 9,999,999 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14 

a

Post office state abbreviations used 

b

Amounts on site reported by facilities in each state 

c

Activities/Uses: 

1. Produce 6. Impurity 11. Chemical Processing Aid 

2. Import 7. Reactant 12. Manufacturing Aid 

3. Onsite use/processing 8. Formulation Component 13. Ancillary/Other Uses 

4. Sale/Distribution 9. Article Component 14. Process Impurity 

5. Byproduct 10. Repackaging 

Source: TRI06 2008 (Data are from 2006) 
 

 

 

 

 

 

ETHYLBENZENE 155 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-3. Manufacturers and Annual Production Capacity of Ethylbenzene 

Annual capacity 

Manufacturer Plant location (millions of pounds) 

Chevron Phillips Chemical Company St. James, Louisiana 2,083 

Pascagoula, Mississippi 289 

Cos-Mar Company Carville, Louisiana 2,822 

The Dow Chemical Company Freeport, Texas 1,896 

INEOS America Texas City, Texas 1,124 

Lyondell Chemical Company Channelview, Texas 3,245 

NOVA Chemical Corporation Bayport, Texas 1,940 

Sterling Chemicals Incorporated Texas City, Texas 1,920 

Westlake Styrene Corporation Sulphur, Louisiana 450 

Total capacity 15,769 

Source: SRI 2006 
 

 

 

 

 

 

 

 

 

ETHYLBENZENE 156 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

5.2 IMPORT/EXPORT 

According to the Chemical Marketing Reporter, import volumes were negligible in 2002 and were 

4.95x107 kg (109 million pounds) in 2003 (CMR 2004). Import volumes for ethylbenzene have been 

relatively small as compared to annual production, typically representing ≤1% of the annual domestic

production volume. 

U.S. exports for 2002 and 2003 were reported as 1.86x107 kg (41 million pounds) and 1.50x107 kg 

(33 million pounds), respectively (CMR 2004). Export volumes for ethylbenzene have been relatively 

small, typically representing ≤1% of the annual domestic production volume.

5.3 USE 

Ethylbenzene is used primarily as a precursor in the production of styrene (ACGIH 2002; Cannella 2007; 

Ransley 1984; Verschueren 1983). It is estimated that >99% of the ethylbenzene manufactured in the 

United States is ultimately used in styrene production, while the remainder is exported or sold in solvent 

applications (CMR 2004; HSDB 2009; Welch et al. 2005). Ethylbenzene is also used as a solvent, a 

constituent of asphalt and of naphtha, and in fuels (ACGIH 2002; Verschueren 1983) as well as in the 

manufacture of acetophenone, cellulose acetate, diethylbenzene, ethyl anthraquinone, ethylbenzene 

sulfonic acids, propylene oxide, and α-methylbenzyl alcohol (HSDB 2000; Verschueren 1983; Welch et 

al. 2005). 

5.4 DISPOSAL 

Regulations governing the treatment and disposal of wastes containing ethylbenzene are detailed in 

Chapter 8. Recommended methods for the disposal of ethylbenzene include burial in a landfill and rotary 

kiln incineration, liquid injection incineration, and fluidized bed incineration (EPA 1981d; HSDB 2009). 

Ethylbenzene may be disposed of by adsorbing it in vermiculite, dry sand, earth, or a similar material and 

then by burial in a secured sanitary landfill or by atomizing in a suitable combustion chamber (IRPTC 

1985). Ethylbenzene is a good candidate for liquid injection incineration at a temperature range of 650– 

1,600 °C and a residence time of 0.1–2 seconds; a candidate for rotary kiln incineration at a temperature 

range of 820–1,600 °C and a residence time of seconds for gases and liquids and hours for solids; and a 

good candidate for fluidized bed incineration at a temperature range of 450–980 °C and a residence time 

of seconds for gases and liquids, and longer for solids (HSDB 2009). 
ETHYLBENZENE 157 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

The following waste water treatment technologies have been investigated for disposal of ethylbenzene; 

biological treatment, air and steam stripping, or activated carbon treatment (HSDB 2009). Spent ethylbenzene solvents and still bottoms from the recovery of these solvents are designated hazardous wastes 

and, as such, are subject to the Resource Conservation and Recovery Act (RCRA) of 1976 handling and 

record-keeping requirements (EPA 1992c). 

According to the TRI, in 2006, an estimated 141,972 pounds (64,455 kg) were transferred off-site, which 

includes releases to publicly owned treatment works (POTWs) (TRI06 2008). No additional information 

was located on the trends in disposal methods related to ethylbenzene. 
ETHYLBENZENE 158 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

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6. POTENTIAL FOR HUMAN EXPOSURE 

6.1 OVERVIEW 

Ethylbenzene has been identified in at least 829 of the 1,689 hazardous waste sites that have been 

proposed for inclusion on the EPA National Priorities List (NPL) (HazDat 2007). However, the number 

of sites evaluated for ethylbenzene is not known. The frequency of these sites can be seen in Figure 6-1. 

Of these sites, 825 are located within the United States, 2 are located in the Commonwealth of Puerto 

Rico, and 2 are located in the Virgin Islands (not shown). 

Ethylbenzene is an aromatic hydrocarbon naturally present in crude petroleum. It is also a combustion 

byproduct of biomass. It is widely distributed in the environment because of human activities such as the 

use of fuels and solvents (which account for the bulk of emissions) and through chemical manufacturing 

and production activities. Because of its volatile nature, ethylbenzene tends to partition to the atmosphere 

when it is released to the environment; therefore, exposure to this chemical is most likely to occur by 

inhalation. However, it is also present in trace amounts in some water supplies and food items. Thus, 

ingestion also may be an important exposure pathway in some cases. Exposures from contaminated water 

may also occur via inhalation and dermal absorption during showering and other household activities 

(Beavers et al. 1996). 

Physical, chemical, and biological processes can remove ethylbenzene from the medium of concern and 

reduce human exposures. In the atmosphere, ethylbenzene exists primarily in the vapor phase. Vapor 

phase ethylbenzene is removed from air by reacting with photochemically produced hydroxyl radicals, 

with an approximate half-life of 2 days. Photolytic transformations may also take place in surface water 

in the presence of naturally occurring humic materials (sensitized photolysis). Biologically induced 

transformations take place largely in soil and surface water in the presence of oxygen; however, anaerobic 

degradation can also occur in soil, sediment, and groundwater, but at a much slower rate than aerobic 

biodegradation. Although chemical transformations can result in reduced exposures to ethylbenzene in 

the atmosphere, one toxic by-product of ethylbenzene photodegradation, peroxyacetylnitrate (PAN), may 

be of concern. Ethylbenzene, as well as a variety of other hydrocarbons, has been implicated in the 

atmospheric formation of PAN in smog (Yanagihara et al. 1977). 

The kinetics of partitioning and/or transformation processes are site-specific and depend upon many 

external factors. For example, the extent of biodegradation observed in an environmental medium 

depends upon the type and population of microorganisms present, the concentration of ethylbenzene, the 
ETHYLBENZENE 160 

6. POTENTIAL FOR HUMAN EXPOSURE 

Figure 6-1. Frequency of NPL Sites with Ethylbenzene Contamination 
 

ETHYLBENZENE 161 

6. POTENTIAL FOR HUMAN EXPOSURE 

presence of other compounds that may act as a substrate, and the presence or absence of oxygen. 

Biodegradation in soil will also compete with transport processes such as volatilization and infiltration to 

groundwater. Because ethylbenzene migration is only moderately retarded by adsorption onto soil, 

leaching of the compound to an anaerobic environment (groundwater) before biotransformation in soil is 

possible and may allow ethylbenzene to persist in an aquifer. 

Although information is limited on dietary exposures, ethylbenzene does not appear to significantly 

bioaccumulate in aquatic or terrestrial food chains, and human exposure through this route is not likely to 

be of concern. 

Exposure of the general population to ethylbenzene is possible through contact with gasoline, automobile 

emissions, solvents, pesticides, printing ink, varnishes, coatings, and paints. Cigarette smoke also has 

been identified as a source of exposure to this chemical. Ethylbenzene is widely present at low 

concentrations in rural, suburban, and urban atmospheres with the highest concentrations generally 

detected in areas of gasoline stations, tunnels, highways, and parking lots. Ethylbenzene is also present in 

indoor air. Very often ethylbenzene levels in indoor air exceed the levels typically found in outdoor air 

(Dodson et al. 2008). Occupational exposures are expected within the petroleum industry; within 

industries using solvents, paints, and coatings; and during the manufacture and handling of ethylbenzene 

and styrene (which is manufactured from ethylbenzene). 

Several groups within the general population may have potentially higher exposures to ethylbenzene by 

inhalation, oral, or dermal contact with contaminated drinking water or soil. These groups include 

individuals living near manufacturing and processing facilities, petroleum refineries, and hazardous waste 

disposal sites and those working or residing in high traffic areas. Exposures associated with the 

consumption of contaminated drinking water as well as with inhalation and dermal exposure during 

showering and bathing in contaminated water would be expected for individuals that derive their primary 

drinking water supply from residential wells downgradient of uncontrolled landfills, hazardous waste 

sites, and leaking underground storage tanks that are contaminated with ethylbenzene. Individuals living 

near these sites may also be exposed via dermal contact with, or ingestion of soil contaminated with 

ethylbenzene. 
 

 

 

 

 

ETHYLBENZENE 162 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.2 RELEASES TO THE ENVIRONMENT 

The Toxics Release Inventory (TRI) data should be used with caution because only certain types of 

facilities are required to report (EPA 2005). This is not an exhaustive list. Manufacturing and processing 

facilities are required to report information to the TRI only if they employ 10 or more full-time 

employees; if their facility is included in Standard Industrial Classification (SIC) Codes 10 (except 1011, 

1081, and 1094), 12 (except 1241), 20–39, 4911 (limited to facilities that combust coal and/or oil for the 

purpose of generating electricity for distribution in commerce), 4931 (limited to facilities that combust 

coal and/or oil for the purpose of generating electricity for distribution in commerce), 4939 (limited to 

facilities that combust coal and/or oil for the purpose of generating electricity for distribution in 

commerce), 4953 (limited to facilities regulated under RCRA Subtitle C, 42 U.S.C. section 6921 et seq.), 

5169, 5171, and 7389 (limited S.C. section 6921 et seq.), 5169, 5171, and 7389 (limited to facilities 

primarily engaged in solvents recovery services on a contract or fee basis); and if their facility produces, 

imports, or processes ≥25,000 pounds of any TRI chemical or otherwise uses >10,000 pounds of a TRI

chemical in a calendar year (EPA 2005). 

6.2.1 Air 

Estimated releases of 4,586,441 pounds (~2,081 metric tons) of ethylbenzene to the atmosphere from 

1,485 domestic manufacturing and processing facilities in 2006, accounted for about 82% of the estimated 

total environmental releases from facilities required to report to the TRI (TRI06 2008). These releases are 

summarized in Table 6-1. 

The majority of ethylbenzene releases to the environment occur to the atmosphere. Because of its 

frequent use, and production in manufacturing operations, ethylbenzene is an important industrial 

chemical. Ethylbenzene is consistently ranked among the top 50 chemicals produced in the United States, 

with total production ranging from approximately 11 to 13 billion pounds annually (C&EN 1995, 2006; 

Kirschner 1995). In 2005, 11.6 billion pounds of ethylbenzene were produced by U.S. manufacturers 

(C&EN 2006). Its release can occur during manufacturing, processing, and handling. In 1978, emissions 

of ethylbenzene in the United States from catalytic reformate production alone were estimated at over 

2 million pounds (Fishbein 1985). Ethylbenzene is also released to the air during processing of crude oil 

(Bratveit et al. 2007). Fuels and solvents, however, are considered to account for the bulk of emissions 

(Fishbein 1985). Exposure to ethylbenzene increases in areas high traffic areas (Smith et al. 2008). 

Ethylbenzene has been measured from tail pipe emissions of gasoline-powered vehicles at a weighted 

average rate of 12 mg/km (considering both catalyst and noncatalyst equipped cars) (Hampton et al. 
ETHYLBENZENE 163 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-1. Releases to the Environment from Facilities that Produce, Process, or
 

Use Ethylbenzenea
 

Reported amounts released in pounds per yearb 

Total release 

Statec RFd Aire Waterf UIg Landh Otheri On-sitej Off-sitek On- and off-site 

AK 11 4,790 9 0 374 0 5,168 5 5,173 

AL 37 249,191 560 0 228 349 249,751 577 250,328 

AR 17 63,827 5 0 78 0 63,833 77 63,910 

AZ 19 33,661 12 0 0 0 33,673 0 33,673 

CA 99 91,863 11 500 1,733 1,407 92,331 3,184 95,515 

CO 10 2,435 0 0 10 0 2,435 10 2,445 

CT 12 4,504 1 0 10 729 4,505 739 5,244 

DE 3 7,175 0 0 1 0 7,175 1 7,176 

FL 39 104,231 8 0 5 268 104,239 273 104,512 

GA 33 80,852 1 0 229 1,742 80,853 1,971 82,824 

GU 2 2,436 0 0 0 255 2,436 255 2,691 

HI 10 3,312 53 0 170 78 3,365 248 3,613 

IA 25 72,532 0 0 3 0 72,535 0 72,535 

ID 2 111 No data 0 0 0 111 0 111 

IL 69 173,154 170 0 1,300 1,449 173,355 2,718 176,073 

IN 75 265,514 571 0 109 1,098 266,095 1,197 267,292 

KS 19 71,934 96 14 22,148 0 86,545 7,647 94,192 

KY 39 147,354 24 0 33,281 20,709 147,411 53,957 201,368 

LA 68 272,307 935 170 3,774 0 273,286 3,900 277,187 

MA 18 6,917 28 0 2,251 2,078 9,194 2,080 11,274 

MD 20 13,195 5 0 1 0 13,200 1 13,201 

ME 5 1,841 3 0 0 124 1,844 124 1,968 

MI 66 363,099 3 0 12,317 574 363,107 12,886 375,993 

MN 22 73,380 13 0 141 10 73,393 151 73,544 

MO 48 214,512 1 0 45 246 214,513 291 214,804 

MP 3 255 0 0 5 5 260 5 265 

MS 21 171,586 33 0 0 0 171,619 0 171,619 

MT 6 5,406 4 0 86 0 5,414 82 5,496 

NC 25 31,809 0 0 4 807 31,811 809 32,620 

ND 2 5,000 0 0 1 0 5,001 0 5,001 

NE 8 2,830 0 0 54 0 2,855 29 2,884 

NH 4 410 1 0 0 0 410 0 410 

NJ 41 37,281 230 0 2,010 8 38,247 1,282 39,529 

NM 8 10,585 5 5 186 1,334 10,772 1,343 12,115 

NV 4 2,821 No data 0 0 0 2,821 0 2,821 

NY 51 37,634 11 0 20 1,693 37,645 1,713 39,358 

OH 99 289,303 303 0 2,618 701 290,754 2,171 292,925 

OK 18 72,700 9 20 270 262 72,977 284 73,261 
 

ETHYLBENZENE 164 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-1. Releases to the Environment from Facilities that Produce, Process, or
 

Use Ethylbenzenea
 

Reported amounts released in pounds per yearb 

Total release 

Statec RFd Aire Waterf UIg Landh Otheri On-sitej Off-sitek On- and off-site 

OR 16 35,640 1 0 0 3 35,641 3 35,644 

PA 64 149,523 118 0 1,570 1,427 149,641 2,997 152,637 

PR 10 15,209 10 0 5 47 15,224 47 15,271 

RI 5 1,224 3 0 7 33 1,227 40 1,267 

SC 17 48,768 55 31 52 4,565 48,823 4,648 53,471 

SD 4 40,119 No data 0 0 0 40,119 0 40,119 

TN 33 412,260 45 0 502 250 412,306 751 413,057 

TX 158 627,282 1,625 843,929 13,835 2,262 1,462,679 26,254 1,488,933 

UT 15 6,812 5 0 98 97 6,822 190 7,012 

VA 25 66,825 99 0 180 79 66,924 259 67,183 

VI 3 12,390 3 0 12 0 12,393 12 12,406 

VT 1 608 No data 0 0 0 608 0 608 

WA 19 30,388 11 0 169 36 30,536 68 30,605 

WI 37 61,033 0 0 14 6,013 61,034 6,026 67,060 

WV 14 75,811 9 0 15 398 75,820 413 76,233 

WY 6 10,800 No data 0 261 0 10,805 256 11,061 

Total 1,485 4,586,441 5,088 844,670 100,181 51,134 5,445,543 141,972 5,587,515 

a

The TRI data should be used with caution since only certain types of facilities are required to report. This is not an 

exhaustive list. Data are rounded to nearest whole number.
 b

Data in TRI are maximum amounts released by each facility.
 c

Post office state abbreviations are used.
 d

Number of reporting facilities.

e

The sum of fugitive and point source releases are included in releases to air by a given facility.
 f

Surface water discharges, waste water treatment-(metals only), and publicly owned treatment works (POTWs) (metal
 

and metal compounds).
 g

Class I wells, Class II-V wells, and underground injection. h

Resource Conservation and Recovery Act (RCRA) subtitle C landfills; other on-site landfills, land treatment, surface 

impoundments, other land disposal, other landfills.

i

Storage only, solidification/stabilization (metals only), other off-site management, transfers to waste broker for 

disposal, unknown

j

The sum of all releases of the chemical to air, land, water, and underground injection wells.

k

Total amount of chemical transferred off-site, including to POTWs.
 

RF = reporting facilities; UI = underground injection 

Source: TRI06 2008 (Data are from 2006) 
 

 

 

 

 

 

 

 

 

ETHYLBENZENE 165 

6. POTENTIAL FOR HUMAN EXPOSURE 

1983). Exposures to ethylbenzene can also occur while individuals are traveling in the passenger 

compartment of automobiles, and the chemical has been found at much higher concentrations during 

automobile engine malfunctions (Lawryk and Weisel 1996; Lawryk et al. 1995). Starting gasolinepowered vehicles in attached garages can contribute to increased indoor ethylbenzene exposure (Dodson 

et al. 2008). Emissions from gasoline-powered vehicles were found to be somewhat higher than from 

diesel trucks (Hampton et al. 1983). Similarly, ethylbenzene has been measured in jet fuel emissions 

(Katzman and Libby 1975) and has been reported in waste incinerator stack emissions (Jay and Steiglitz 

1995; Junk and Ford 1980). Ethylbenzene has also been shown to be released into the atmosphere from 

volatile organic compound (VOC)-laden waste water in municipal sewer systems (Quigley and Corsi 

1995). 

Emissions of ethylbenzene can arise from transport of hot asphalt from a manufacturing plant to a paving 

site and from subsequent road paving operations. Kitto et al. (1997) measured the emissions of volatile 

organic compounds from Type I and Type II hot asphalts. At 150 °C, the concentration of the ethylbenzene emissions from Type I asphalt was 800 μg/m3

; at 200 °C, the concentration was 2,200 μg/m3, an 

increase by a factor of 2.8. At 150 °C, the concentration of the ethylbenzene emissions from Type II 

asphalt was 7,000 μg/m3

; at 200 °C, the concentration was 21,000 μg/m3, an increase by a factor of 3. 

Mukund et al. (1996) conducted chemical mass balance source apportionment modeling on a data set of 

142 3-hour integrated air samples collected at six different sites in three separate campaigns during the 

summer of 1989 in Columbus, Ohio. The contributions (± standard error) to the observed atmospheric 

levels of ethylbenzene from the sources considered, expressed as percentage of measured average 

concentration, were: 55±11 from vehicle exhaust; 0.7±0.2 from gasoline vapor; 0±3 from natural gas; 

20±4 from industrial solvents; and 0±1 from the dry cleaning/degreasing/waste water composite source. 

These five sources contributed an estimated 76±12% of the measured average concentration of 1.1 μg/m3

. 

Ethylbenzene releases to the air especially in indoor environments can occur with the use of consumer 

products such as pesticides, liquid process photocopiers and plotters, solvents, carpet glue, paints, 

varnishes, automotive products, adhesives, and fabric and leather treatments that contain ethylbenzene 

(Hodgson et al. 1991; Lillo et al. 1990; NAS 1980; Otson et al. 1994; Sack et al. 1992; Wallace et al. 

1987b). Indoor exposure to ethylbenzene may also result from the start-up of gasoline-powered engines 

in attached garages (Dodson et al. 2008). Ethylbenzene (in addition to other aromatic hydrocarbons, such 

as benzene, styrene, and xylenes) has also been measured in cigarette smoke (Barrefors and Petersson 

1993; Wallace et al. 1986, 1987c). An analysis of indoor air in a home using gasoline-contaminated tap 
 

 

 

ETHYLBENZENE 166 

6. POTENTIAL FOR HUMAN EXPOSURE 

water found that exposures to ethylbenzene could occur via inhalation during showering and other 

household activities (Beavers et al. 1996). Ethylbenzene concentrations in the shower area were often 

one to two orders of magnitude higher than in other areas of the home. Ethylbenzene has been identified 

in air samples collected at 121 of the 829 NPL hazardous waste sites respectively, where it was detected 

in some environmental media (HazDat 2007). 

6.2.2 Water 

Estimated releases of 5,088 pounds (~2.3 metric tons) of ethylbenzene to surface water from 

1,485 domestic manufacturing and processing facilities in 2006, accounted for <1% of the estimated total 

environmental releases from facilities required to report to the TRI (TRI06 2008). An additional 

141,972 pounds (~64.4 metric tons) were transferred off-site or released to publicly owned treatment 

works (POTWs) (TRI06 2008). These releases are summarized in Table 6-1. 

Releases to water can occur as a result of industrial discharges (Snider and Manning 1982), fuel spillage 

(Gschwend et al. 1982; Tester and Harker 1981), leaking petroleum pipelines or underground storage 

tanks (Cotruvo 1985), landfill leachate (Barker 1987; Beavers et al. 1996; Chen and Zoltek 1995; 

Hallbourg et al. 1992), and the inappropriate disposal of wastes containing ethylbenzene (Eiceman et al. 

1986). Ethylbenzene has been detected in both surface water and groundwater (EPA 2007i; Jin et al. 

2007). Ethylbenzene emissions to oceans occur as a result of offshore oil production, hydrocarbon 

venting, oil field brines, and tanker oil spills (Sauer et al. 1978). Sauer and Tyler (1995) reported that 

ethylbenzene was one of the most commonly detected VOCs in motor vehicle waste fluids released from 

routine vehicle maintenance shops entering catch basins and septic tanks in Wisconsin. Ethylbenzene 

was detected at a mean concentration of 11 ppb (range 3–98 ppb) in catch basin waste water, 1.5 ppb 

(range 7–23 ppb) in septic tank effluent, and 8 ppb (range 9–53 ppb) in septic tank sludge. 

Ethylbenzene has been identified in surface water at 123 sites and groundwater collected at 557 of the 

829 NPL hazardous waste sites respectively, where it was detected in some environmental media (HazDat 

2007). 

6.2.3 Soil 

Estimated releases of 100,181 pounds (~45.4 metric tons) of ethylbenzene to soils from 1,485 domestic 

manufacturing and processing facilities in 2006, accounted for about 2% of the estimated total 

environmental releases from facilities required to report to the TRI (TRI06 2008). An additional 
 

 

 

 

 

ETHYLBENZENE 167 

6. POTENTIAL FOR HUMAN EXPOSURE 

844,670 pounds (~383.2 metric tons), constituting about 15% of the total environmental emissions, were 

released via underground injection (TRI06 2008). These releases are summarized in Table 6-1. 

Ethylbenzene can be released to soils through the spilling of gasoline and other fuels (Sauer and Tyler 

1995; Tester and Harker 1981); through the disposal of solvents and household products such as paint, 

cleaning and degreasing solvents, varnishes, and pesticides; through emissions from leaking underground 

or aboveground storage tanks, well pumping units, or pipelines(Cotruvo 1985; Soukup et al. 2007); and 

leaching from landfills or contaminated industrial sites (Barker 1987; Soukup et al. 2007). 

Ethylbenzene has been identified in soil and sediment samples collected at 469 and 144 of the 829 NPL 

hazardous waste sites respectively, where it was detected in some environmental media (HazDat 2007). 

6.3 ENVIRONMENTAL FATE 

6.3.1 Transport and Partitioning 

The large vapor pressure and Henry’s law constant of ethylbenzene (Table 4-2) suggests a moderate to 

strong tendency for ethylbenzene to partition into the atmosphere where it will exist predominantly in the 

vapor phase (Eisenreich et al. 1981; Mackay 1979; Masten et al. 1994). Depending upon site-specific 

conditions, releases to surface soil can result in substantial losses to the atmosphere in addition to 

subsurface infiltration. Since it has a moderately high vapor pressure, ethylbenzene will evaporate fairly 

rapidly from dry soil. Vapor phase transport will occur from subsurface releases (i.e., from leaking 

underground storage tanks) and during migration through unsaturated soil pore spaces (Rhue et al. 1988). 

Atmospheric reaction with hydroxyl radicals can limit the atmospheric transport of ethylbenzene (Dewulf 

and van Langenhove 1997). 

The large Henry's law constant (Table 4-2), which measures partitioning between water and air, indicates 

that a significant proportion of ethylbenzene will partition from water into air (Mackay 1979; Masten et 

al. 1994). Ethylbenzene dissolved in surface water, soil pore water, or groundwater will thus migrate into 

an available atmospheric compartment until its saturated vapor concentration is reached. The 

volatilization half-life of ethylbenzene in a constructed wetland (length=228 m, width=60 m, depth=0.5– 

1.5 m) located in Phoenix, Arizona ranged from approximately 40 to 200 hours (Keefe et al. 2004). 

Based on log Koc values in the range of 2.2–2.4 (Table 4-2) and using the classification scheme of Swann 

et al. (1983), ethylbenzene is classified as having moderate mobility in soils. Sorption and retardation by 
 

 

 

 

 

 

 

 

ETHYLBENZENE 168 

6. POTENTIAL FOR HUMAN EXPOSURE 

soil organic carbon content will occur to a moderate extent, but sorption is not significant enough to 

completely prevent migration in most soils. Particularly in soils with low organic carbon content, 

ethylbenzene will tend to leach into groundwater. Mobility is also possible in aquifers that contain very 

little solid-phase organic matter, a condition common to sand and gravel aquifers (Ptacek et al. 1984). 

Sorption and desorption experiments performed by Dewulf et al. (1996) demonstrated that the sorption 

process of ethylbenzene on marine sediments is reversible and that the sorption is even lower than 

expected from the log Kow data and the organic carbon content of the sediment. They concluded that the 

marine sediment compartment is not an important sink for the VOCs investigated when they are released 

to water. 

When ethylbenzene is part of a complex mixture of hydrocarbons associated with a petroleum spill or 

leak, the proportion of ethylbenzene that will bind to soil versus the amount that will migrate toward 

groundwater depends primarily on the type of soil, the biological environment in the soil, the particular 

petroleum product in which the ethylbenzene is dissolved, the size of the spill, and the amount of rainfall 

(Stokman 1987; Soukup et al. 2007). For example, the solubility of ethylbenzene varies in accordance 

with the presence of other petroleum products (Ptacek et al. 1984). While the pure compound solubility 

of ethylbenzene in water is 180 mg/L, its solubility in water equilibrated with JP-jet fuel is 10.6 mg/L 

(Burris and MacIntyre 1984). Potter (1993) also reported that the equilibrium aqueous solubility of 

ethylbenzene was 2.4 mg/L with gasoline, 0.18 mg/L with diesel fuel, and 0.007 mg/L with #6 fuel oil 

equilibrated with groundwater. Both of these authors calculated the solubility concentrations of 

ethylbenzene in water equilibrated with various petroleum products. In addition, solvent spills of 

chemicals such as ethylbenzene may enhance the mobility of other organic chemicals, which do strongly 

adsorb to soil (Rao et al. 1985). No information was found concerning bioavailability of ethylbenzene 

from soil for human dermal or oral uptake. 

Boyd et al. (1990) reported that corn residues high in organic matter that were left on the surface of a no 

tillage field, adsorbed a significantly greater amount of ethylbenzene as compared with surface soil. The 

authors suggested that the highly lipophilic plant cuticle appears to be the sorptive component. Kango 

and Quinn (1989) also reported that humic acid adsorbed higher amounts of ethylbenzene and xylenes 

ranging from 40 to 77 times greater than soil. 

Once in the atmosphere, ethylbenzene will be transported until it is removed by physical or chemical 

processes. Physical removal processes, which involve partitioning into clouds or rainwater, are relevant 

to ethylbenzene, which has been measured in Los Angeles rainwater (Kawamura and Kaplan 1983). The 
 

 

 

 

 

ETHYLBENZENE 169 

6. POTENTIAL FOR HUMAN EXPOSURE 

concentrations of several dissolved organic chemicals in rainwater and in the atmosphere during rainfall 

events were measured by Ligocki et al. (1985). The authors found that the concentration of ethylbenzene 

in rain water was approximately equal to the inverse of the dimensionless Henry's law constant 

(Table 4-2) at atmospheric temperatures. This indicates that ethylbenzene is removed from the 

atmosphere through precipitation, but it can re-enter the atmospheric environment upon evaporation. 

In comparison to chemicals such as polychlorinated biphenyls (PCBs), DDT, and other chlorinated 

pesticides, which are of great concern with respect to bioaccumulation, ethylbenzene does not 

significantly bioaccumulate in aquatic food chains. A measured bioconcentration factor (BCF) of 15 was 

reported for ethylbenzene in goldfish (Ogata et al. 1984). A BCF value of 53 was estimated in fish, using 

a log Kow of 3.15 and a regression derived equation (Meylan et al. 1999). A 3% weighted average lipid 

content in fish and shellfish was assumed by EPA in the calculation. The calculated BCF is a theoretical 

value based on known constants, and is a conservative estimate of the bioconcentration of this chemical in 

fish. A calculated BCF of 167 was also estimated for fathead minnows (Pimephales promelas) (ASTER 

1995). In a shellfish study, the ethylbenzene concentration in clam tissue was 5 times higher than that 

measured in water after an 8-day continuous-flow exposure to the water-soluble fraction of Cook Inlet 

crude oil (Nunes and Benville 1979). 

Ethylbenzene has also been found to partition into human tissues; primarily as a result of inhalation 

exposures (see Section 6.5). Ethylbenzene has been detected in human adipose tissue (Sections 3.4.2.1 

and 3.8.1), blood (Section 3.4.1.1), and in breast milk (Section 3.7). No information was located 

concerning the bioavailability of ethylbenzene from contaminated soil or sediment either with respect to 

dermal exposure or oral intake via consumption of soil particles from unwashed hands. 

6.3.2 Transformation and Degradation 

6.3.2.1 Air 

Ethylbenzene undergoes atmospheric transformations through reaction with photochemically generated 

hydroxyl radicals (Atkinson et al. 1978; Ohta and Ohyama 1985; Ravishankara et al. 1978), NO3 radicals 

(Atkinson et al. 1987), and atomic oxygen (Grovenstein and Mosher 1970; Herron and Huie 1973). Gas 

phase reactions with ozone and structurally similar molecules such as toluene have been observed 

(Atkinson and Carter 1984). The predominant degradation pathway for ethylbenzene in the atmosphere 

occurs via reaction with hydroxyl radicals and nitrate radicals (which are only present during non daylight 

hours), with the other degradation mechanisms being of only minor importance. The rate constant for the 
 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 170 

6. POTENTIAL FOR HUMAN EXPOSURE 

vapor phase reaction of ethylbenzene with photochemically generated hydroxyl radicals was measured as 

7.1x10-12 cm3 per molecule-second (Kwok and Atkinson 1994). This corresponds to an atmospheric halflife of approximately 2 days using a hydroxyl radical concentration of 5x105 hydroxyl radicals per cm3

. 

The rate constant for the degradation of ethylbenzene with nitrate radicals was measured as 6x10-16 cm3 

per molecule-second (Atkinson et al. 1987). Using a nighttime nitrate radical concentration of 

5x108 nitrate radicals per cm3

, a half-life of approximately 26 days is estimated. Atmospheric degradation 

occurs more rapidly during summer months as opposed to winter since the concentration of hydroxyl 

radicals in the atmosphere peaks during summer (Ravishankara et al. 1978; Singh et al. 1981), and is also 

faster under photochemical smog conditions (Dilling et al. 1976). Oxidation by-products from the 

reaction with hydroxyl radicals and nitrogen oxides include ethylphenols, benzaldehyde, acetophenone, 

and m- and p-nitroethylbenzene (Hoshino et al. 1978). The major degradation pathways for ethylbenzene 

in the atmosphere are summarized in Figure 6-2. 

Experiments conducted with various hydrocarbons on the formation of photochemical aerosols or the 

haze associated with smog revealed that aromatics such as ethylbenzene produced only low yields of 

aerosol when compared with more reactive compounds such as alkenes (O'Brien et al. 1975). The 

formation of PAN is related to the photoreactivity of the reacting hydrocarbon. The photoreactivity of 

ethylbenzene is intermediate relative to other atmospheric hydrocarbons, and it is less reactive than 

gasoline, toluene, and alkenes such as propene (Yanagihara et al. 1977). 

6.3.2.2 Water 

In surface water, transformations of ethylbenzene may occur through two primary processes— 

photooxidation and biodegradation. Since ethylbenzene does not contain hydrolysable functional groups 

at environmental pH (pH 5–9), hydrolysis is not considered an important environmental fate process. 

Although ethylbenzene does not absorb light in the environmental ultraviolet spectrum, it is capable of 

undergoing photooxidation in water through an indirect reaction with other light-absorbing molecules, a 

process known as sensitized photolysis. The compounds 1-methylphenyl ketone (acetophenone), 

1-phenylethanol, and benzaldehyde were identified as degradation products from the laboratory 

photooxidation of ethylbenzene in both distilled water and seawater with anthraquinone used as a 

sensitizer (Ehrhardt and Petrick 1984). In the environment, similar degradation is expected to occur in the 

presence of ubiquitous, naturally occurring humic material sensitizers. The major degradation pathways 

for ethylbenzene in water are summarized in Figure 6-3. 
Figure 6-2. Major Degradation Pathways for Ethylbenzene in the Atmosphere 

CH3 CH3 H CH3 

CH2 CHOH C O C O 

Hydroxyl 

+ 

radicals 

Ethylbenzene 1-Phenylethanol Benzaldehyde Acetophenone 

CH3 

CH2 

OH Nitrogen
 

radicals
 

Ethyl phenols
 

CH3 

CH3 CH2 

CH2
 

Nitrogen
 

+ 

oxides NO2 NO2 

m-Nitroethylbenzene p-Nitroethylbenzene 

Source: Hoshino et al. 1978 

ETHYLBENZENE 171 

6. POTENTIAL FOR HUMAN EXPOSURE 
Figure 6-3. Major Degradation Pathways for Ethylbenzene in Water, Sediment, 

and Soil 

CH3 CH3 H CH3 

CH2 CHOH C O C O 

Photooxidation 

+ 

Ethylbenzene 1-Phenylethanol Benzaldehyde Acetophenone 

OH 

CH2 HC O COOH 

CH C C 2 CH H2COOH H2COOH 2 CH2

OH OH 

Aerobic 

Ring fusion 

transformation 

HO 

2-Phenethyl alcohol Phenylacetaldehyde Phenyl acetic acid o-Hydroxyphenol- 2,5-Dihydroxyphenyl acetic acid acetic acid 

(homogentisic acid) 

CH3 CH3 CH2OH 

CH2COOH 

HC OH C O C O

Aerobic Ring fusion 

transformation
 

NO2
 OH 

1-Phenylethanol Acetophenone p-Hydroxyphenylacetic acid
 

CH3 CH3 CH3 

CH2 CH2 CH2

OH OH
 Aerobic
 

+
 Ring fusion
 

transformation
 

OH OH
 

o-Ethylphenol m-Ethylphenol 3-Ethylcatechol 

CH2OH
 

CH2 CH2
 CHOH 

Aerobic 

transformation 

Styrene 1-Phenyl-1,2-ethanediol 

Anaerobic
 

May be degraded under denitrifying conditions
 

transformation
 

Source: Burback and Perry 1993; Ehrhardt and Petrick 1984; Van der Linden and Thijsse 1965 

ETHYLBENZENE 172 

6. POTENTIAL FOR HUMAN EXPOSURE 
 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 173 

6. POTENTIAL FOR HUMAN EXPOSURE 

Biodegradation in aerobic surface water will compete with sensitized photolysis and transport processes 

such as volatilization. Volatilization and biodegradation of ethylbenzene in seawater have been observed 

by Gschwend et al. (1982), Masten et al. (1994), and Wakeham et al. (1983). Migration from surface 

water to subsurface soil with low amounts of oxygen or to aquifers with lower microbial populations, 

however, will limit the rate of transformation. No significant disappearance of ethylbenzene during 

11 weeks of incubation with bacteria under low oxygen (anoxic) conditions was observed by Bouwer and 

McCarty (1983). Slow degradation of ethylbenzene was reported in anaerobic aquifer materials known to 

support methanogenesis, although a long acclimation period or lag time was required (Wilson et al. 1986). 

Less than 1% of the initial concentration of ethylbenzene remained after 120 weeks, indicating that, given 

sufficient time, ethylbenzene will be essentially completely biodegraded. 

Laboratory microcosm tests were conducted to determine optimum conditions for ethylbenzene biodegradation by aquifer microorganisms under denitrifying condition (Hutchins 1991). Ethylbenzene was 

degraded to <5 μg/L when present as a sole source substrate and stoichiometric calculations indicated that

nitrate removal was sufficient to account for 70–80% of the compound being mineralized. Biodegradation did not occur without the presence of nitrate, and nitrate removal was minimal without the 

presence of the ethylbenzene over a 55-day incubation period. In a laboratory microcosm containing 

aquifer material and groundwater from the North Bay site in Ontario, Canada, no significant loss of ethylbenzene was observed compared to unamended controls over a period of 187 days. In another experiment 

conducted at the North Bay site that used in situ biodegradation columns, ethylbenzene was completely 

degraded in at least 1 of the 8 in situ columns in <100 days (Acton and Barker 1992). In all cases, the 

authors attributed the ethylbenzene attenuation to biodegradation by methanogenic and fermentative 

bacteria. In another study using a laboratory scale flow-through aquifer column system, low dissolved 

oxygen (<1 mg/L) conditions were initiated with the nitrate-amended column influent in order to mimic 

contaminated groundwater conditions distal from a nutrient injection well (Anid et al. 1993). The authors 

reported that 40% of the ethylbenzene was removed after several months of operation. In a similar study, 

using batch incubations seeded with four different aquifer materials, ethylbenzene was not degraded 

within 4 months in any of the denitrifying enrichments tested, even though nitrate reduction occurred. 

Burback and Perry (1993) reported than Mycobacterium vaccae can catabolize a number of major 

groundwater pollutants, including ethylbenzene. At a concentration of 100 ppm, ethylbenzene was not 

measurably degraded; however, at 50 ppm, 80% of the added ethylbenzene was degraded. A product 

peak of 4-ethylphenol was detected as well as a small amount of 1-phenylethanol. 
 

 

 

 

 

ETHYLBENZENE 174 

6. POTENTIAL FOR HUMAN EXPOSURE 

The contrast between biodegradation rates in the presence or absence of oxygen was demonstrated by a 

biofilm reactor study designed to simulate an aquifer (Bouwer and McCarty 1984). Continuous-flow 

laboratory column studies under aerobic and methanogenic conditions were performed with mixed 

bacterial cultures on glass beads. In the aerobic biofilm column, 99% of the ethylbenzene initially present 

was degraded within a 20-minute detention time, while under methanogenic (anaerobic) conditions, only 

7% was degraded within a 2-day detention time. 

6.3.2.3 Sediment and Soil 

Biodegradation of ethylbenzene by aerobic soil microbes has been reported by various researchers. The 

common soil microorganism Pseudomonas putida is able to utilize ethylbenzene as a sole source of 

carbon and energy (Fukuda et al. 1989; Gibson et al. 1973). In some instances, co-oxidation or cometabolism was observed (i.e., ethylbenzene was degraded by Nocardia sp. in the presence of other 

compounds that are more readily metabolized by the microorganism) (Jamison et al. 1970; 

Van der Linden and Thijsse 1965). Yadav and Reddy (1993) reported that the white-rot fungus 

Phanerochaete chrysosporium efficiently degraded ethylbenzene as well as other benzene, toluene, ethylbenzene, and xylenes (BTEX) compounds when these chemicals were added either individually or as a 

composite mixture. In addition, substantially greater degradation of all the BTEX compounds was 

observed in static rather than in shaken liquid cultures. Furthermore, degradation was greater at 25 °C 

than at 37 °C, but pH variations between 4.5 and 7 had little effect on the extent of the degradation. Chen 

and Taylor (1995) reported that two thermophilic bacterial strains, Thermus aquaticus and an unidentified 

Thermus sp. degraded ethylbenzene (in a mixture with other BTEX chemicals) by 18% after 45 days of 

incubation at 70 °C and by 32% after 45 days of incubation at 60 °C, respectively. Zappi et al. (1996) 

reported that ethylbenzene degraded rapidly in a pilot scale bioslurry reactor under aerobic conditions. 

The initial concentration (0.35 mg/kg) was degraded by 94% in 2 days. 

Biotic transformations by aerobic soil microbes involve oxidation of the ethyl side chain to form phenylacetic acid (Van der Linden and Thijsse 1965) and 1-phenylethanol (Bestetti and Galli 1984); ring 

hydroxylation to form 2,3-dihydroxy-1-ethylbenzene (Gibson et al. 1973), 2-hydroxyphenlacetic acid, 

4-hydroxyphenylacetic acid, and 2,5- and 3,4-dihydroxyphenylacetic acid (Van der Linden and Thijsse 

1965); and ultimate ring cleavage to form straight chain carboxylic acids such as fumaric and acetoacetic 

acids (Van der Linden and Thijsse 1965). The major degradation pathways for ethylbenzene are 

summarized in Figure 6-3. 
 

 

 

 

 

 

 

 

 

ETHYLBENZENE 175 

6. POTENTIAL FOR HUMAN EXPOSURE 

Anaerobic degradation of ethylbenzene based on observations from studies conducted under anaerobic 

conditions in other media and as discussed above (Bouwer and McCarty 1983, 1984; Wilson et al. 1986), 

would be much slower than that observed under aerobic conditions. Ramanand et al. (1995) studied the 

biodegradation of several organic pollutants including ethylbenzene in soil columns under denitrifying 

conditions. These authors reported that one of the significant factors governing biodegradation is the 

availability of suitable electron acceptors. The biodegradation of ethylbenzene, toluene, and xylenes has 

been demonstrated in laboratory samples obtained from subsurface habitats or in pure cultures under 

dinitrifying conditions (Hutchins 1991; Hutchins et al. 1991). Ramanand et al. (1995) reported that soil 

column bacteria, after sufficient acclimation time, metabolized 100–500 μM of toluene and ethylbenzene

in <6 days under denitrifying conditions. These compounds were successfully degraded under anoxic 

conditions by the addition of nitrate and by stimulating the indigenous soil denitrifying bacteria. 

The kinetics of biodegradation appear to be site specific, and depend upon factors such as the type and 

population of microbes present, the environmental temperature, the concentration of ethylbenzene, the 

presence of other compounds that may act as a substrate, and the amount of oxygen and electron 

acceptors present. Biodegradation in soil will also compete with migration processes such as 

volatilization and infiltration to groundwater. 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

Reliable evaluation of the potential for human exposure to ethylbenzene depends in part on the reliability 

of supporting analytical data from environmental samples and biological specimens. Concentrations of 

ethylbenzene in unpolluted atmospheres and in pristine surface waters are often so low as to be near the 

limits of current analytical methods. In reviewing data on ethylbenzene levels monitored or estimated in 

the environment, it should also be noted that the amount of chemical identified analytically is not 

necessarily equivalent to the amount that is bioavailable. The analytical methods available for monitoring 

ethylbenzene in a variety of environmental media are detailed in Chapter 7. 

6.4.1 Air 

Ambient air levels of volatile organic compounds, including ethylbenzene, were monitored as a part of a 

multi-media study known as the Lower Rio Grande Valley Environmental Scoping Study. Monitoring 

was performed at a “central” site and at a “border” site in the Brownsville, Texas, air shed in the spring 

and summer of 1993. The median ambient concentration of ethylbenzene at the central site was 

0.80 μg/m3 (0.18 ppbv) (n=22; range=0.20–1.7 μg/m3 [0.046–0.39 ppbv]) in the spring and 0.4 μg/m3 
 

 

 

 

 

 

 

 

 

ETHYLBENZENE 176 

6. POTENTIAL FOR HUMAN EXPOSURE 

(0.09 ppb) (n=14; range=0.2–1.0 μg/m3 [0.04–0.2 ppbv]) in the summer. These concentrations are either 

lower or comparable to those found in previous EPA and other monitoring investigations (Ellenson et al. 

1997). The median indoor concentration of ethylbenzene for nine Rio Grande Valley residences 

measured in the spring was 1.00 μg/m3 (0.230 ppbv) compared to a median outdoor concentration of 

0.70 μg/m3 (0.16 ppbv); in the summer, the median indoor concentration of ethylbenzene for five 

residences was 1.40 μg/m3 (0.321 ppbv) compared to a median outdoor concentration of 0.35 μg/m3 

(0.080 ppbv) (Mukerjee et al. 1997). The mean indoor concentration of ethylbenzene at the homes of 

46 high school students residing in New York City was 3.57 μg/m3 (0.821 ppbv) in the winter months as 

compared to a mean indoor concentration of 1.99 μg/m3 (0.458 ppbv) during the summer months (Kinney 

et al. 2002). The corresponding mean outdoor levels of ethylbenzene were 1.27 (0.292 ppbv) and 

1.88 μg/m3 (0.432 ppbv) in the winter and summer months, respectively. 

An update of the 1980 National Ambient Volatile Organic Compounds (VOC) database prepared for EPA 

summarized concentrations of ethylbenzene by site type (EPA 1988c). Median values are reported 

because they are less biased by a few high or low concentrations and, thus, may better represent the data 

than would average values. The median indoor concentration of ethylbenzene detected at 95 locations 

was 1.0 ppbv (4.4 μg/m3

) (mean 2.9 ppbv), while personal air monitoring of 1,650 individuals found a 

median concentration of 1.3 ppbv (5.6 μg/m3

) (mean 3.2 ppbv). 

Of particular interest is that personal air monitoring of indoor air found higher concentrations of ethylbenzene than those observed in outdoor air. This was also observed during the Total Exposure 

Assessment Methodology (TEAM) Study conducted by EPA between 1979 and 1985 in an effort to 

measure exposures to 20 VOCs in personal air, outdoor air, and drinking water. The major cause for the 

higher personal air concentrations was felt to be the presence of ethylbenzene sources in the home. In the 

TEAM study, tobacco smoke was reported to be a main source of exposure to volatile aromatic 

compounds such as ethylbenzene (Wallace et al. 1987a, 1987c). Based on the results of a stepwise 

regression carried out on data collected during the fall in New Jersey from 352 participants, overnight 

geometric mean ethylbenzene exposures of persons living in homes with smokers were approximately 

1.5 times the geometric mean exposures of persons living in homes without smokers. The amount of 

ethylbenzene measured in mainstream smoke of a single cigarette containing 16 mg of tar and nicotine 

was 8 μg (Wallace et al. 1987c). Wallace et al. (1989) reported that a maximum outdoor air concentration

of ethylbenzene of 7.4 μg/m3 (1.7 ppbv) was detected in nine outdoor samples collected at each of three 

houses while maximum indoor air concentrations at these same residences ranged from 5 to 110 μg/m3 
 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 177 

6. POTENTIAL FOR HUMAN EXPOSURE 

(1–25.3 ppbv). Mean personal exposures averaged 28 μg/m3 (6.4 ppbv) (range 4.6–144 μg/m3 [1.0– 

33.1 ppbv]) and the personal/outdoor ratio for ethylbenzene was 16. 

The poor quality of indoor air has been linked to a number of symptoms (headache; nausea; irritation of 

the eyes, mucous membranes, and respiratory system; drowsiness; fatigue; and general malaise) which 

have been defined as "sick building" syndrome. Kostiainen (1995) identified over 200 VOCs in the 

indoor air of 26 normal houses. Ethylbenzene was detected in 100% of the houses studied at an average 

concentration of 3.2 μg/m3 [0.74 ppbv] (median 2.41 μg/m3 [0.554 ppbv], minimum 0.62 μg/m3 

[0.14 ppbv], and maximum 10.54 μg/m3 [2.42 ppbv] concentration). The median concentration of ethylbenzene (2.41 μg/m3 [0.554 ppbv]) in these normal houses was lower in all but one case than ethylbenzene concentrations detected in houses with "sick building" syndrome where the concentrations 

ranged from 2.25 to 747.24 μg/m3 (0.517–172 ppbv). 

A nationwide study of indoor air concentration of 26 VOCs was conducted in Canada in 1991 (Fellin and 

Otson 1994). These authors reported that mean indoor ethylbenzene concentrations were 6.46 μg/m3 

(1.48 ppbv), 8.15 μg/m3 (1.87 ppbv), 4.35 μg/m3 (1.00 ppbv) , and 13.98 μg/m3 (3.21 ppbv) in the winter, 

spring, summer and fall months, respectively and that the concentrations declined with an increase in 

ambient air temperature. At ≤0, 0–15, and ≥15 °C, the mean ethylbenzene concentrations were 

12.76 μg/m3 (2.93 ppbv), 7.78 μg/m3 (1.79 ppbv), and 6.46 μg/m3 (1.48 ppbv), respectively. These 

authors concluded that indoor sources of ethylbenzene (primarily from household products) are likely to 

have a more significant influence on indoor air concentrations than climatic variables. 

Concentrations of ethylbenzene were measured in soil gas, and indoor and outdoor air of a home located 

near a landfill in California (Hodgson et al. 1992). During the first sampling in September, ethylbenzene 

concentrations were not detected in soil gas or outdoor air, but were detected at 0.6 ppbv (3 μg/m3

) in 

basement air. In October, ethylbenzene concentrations averaged 3.3 ppbv (14 μg/m3

) in soil gas, 0.8 ppbv 

(4 μg/m3

) in basement air, and 0.7 ppbv (3 μg/m3) in bedroom air. In this study, the authors found that the 

existence of soil gas contamination alone is not sufficient to result in significantly elevated indoor 

exposures. The entry rate of ethylbenzene and VOCs form the soil into the house was low. The limited 

entry that occurred at the conditions of the study was apparently the result of diffusive and advective flux 

of VOC through the cement blocks used in the basement wall construction. The authors suggest that there 

is a general need to identify variables associated with residential sites with the highest potential for 

significantly elevated indoor exposures resulting from soil gas contamination. 
 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 178 

6. POTENTIAL FOR HUMAN EXPOSURE 

Indoor VOC concentrations were analyzed in 12 California office buildings as part of the California 

Healthy Building Study (Daisey et al. 1994). These authors reported that ethylbenzene was detected at a 

geometric mean of 0.50 μg/m3 (0.11 ppbv) (range 0.27–0.98 μg/m3 [0.062–0.22 ppbv]). These authors 

also reported that an estimated 82% of indoor air concentrations were contributed from motor vehicle 

emissions. Hodgson et al. (1991) reported that concentrations of ethylbenzene in indoor air of a new 

office building ranged from 7 to 18.7 μg/m3 (2–4.30 ppbv) over the course of a 14-month sampling 

period. Furthermore, ethylbenzene indoor air concentrations were higher than those in outdoor air and 

that the dominant source of VOCs in the building was liquid-process photocopiers and plotters which 

emitted a characteristic mixture of C10–C11 isoparaffinic hydrocarbons. 

VOC concentrations were monitored both indoors and outdoors, including garages, basements, and 

common spaces, for 55 Boston area residences as part of the Boston Exposure Assessment in 

Microenvironmental (BEAM) study. Indoor and outdoor arithmetic mean ethylbenzene concentrations of 

2.4 and 0.42 μg/m3

, respectively, were reported. Arithmetic mean ethylbenzene concentrations in 

garages, basements, and common hallways were 35, 4.1, and 2.1 μg/m3

, respectively. VOC 

concentrations also varied seasonally, tending to be higher in summer than winter (arithmetic mean 

ethylbenzene concentrations of 0.06 and 0.04 μg/m3

, respectively). Attached garages attributed to 

approximately 20–40% of gasoline-associated indoor VOC concentrations, while basements contributed 

approximately 10–20% and common hallways contributed 5–10% of indoor concentrations (Dodson et al. 

2008). 

Wadden et al. (1995) reported average VOC concentrations for indoor air monitored in a sheetfed offset 

printing shop. These authors reported mean ethylbenzene concentrations ranging from 0.27 to 

0.84 mg/m3 (0.062–0.19 ppmv) based on 12 1-hour samples. 

Levels of ethylbenzene monitored in ambient air show great variation (Jonsson et al. 1985). Generally, 

air concentrations are much lower in rural areas than in urban areas, where vehicle emissions are thought 

to be a major contributor of ethylbenzene to ambient air. Ethylbenzene concentrations range from below 

detection limits in rural areas to 100 μg/m3 (23.0 ppbv) on busy urban streets (Jonsson et al. 1985). Kelly 

et al. (1994) reported a median concentration of ethylbenzene of 1.1 μg/m3 (0.25 ppbv) for 8,723 samples 

collected from 93 locations throughout the United States. 

Ambient air concentrations reported for Deer Park, Texas suggest a correlation between high traffic areas 

and VOC concentrations. The mean ethylbenzene concentration for 12 sites was 0.51 μg/m3 (0.12 ppbv). 
 

 

 

 

 

 

 

 

 

ETHYLBENZENE 179 

6. POTENTIAL FOR HUMAN EXPOSURE 

High correlations between toluene, ethylbenzene, and xylenes suggest petroleum-related sources (Smith 

et al. 2008). 

Median outdoor air concentrations of ethylbenzene for 6 remote and 122 rural locations are reported as 

0.156 and 0.013 ppbv (0.679 and 0.056 μg/m3

), respectively (EPA 1988c). Median concentrations of 

0.62 ppbv (2.7 μg/m3

) were reported for 886 suburban and 1,532 urban locations. The daily median 

concentration of ethylbenzene considering all site types including source dominated areas and workplace 

air was 0.60 ppbv (2.6 μg/m3

). Table 6-2 lists some monitoring results reported for ethylbenzene in 

various cities. 

Ethylbenzene concentrations at four locations along U.S. Highway 70 near Raleigh, North Carolina, 

during the month of May were reported to range from 10 to 16 ppbv (44–70 μg/m3

) that were corrected to 

include upwind concentrations (Zweidinger et al. 1988). 

Concentrations of ethylbenzene were measured in two tunnels: the Fort McHenry Tunnel in Baltimore, 

Maryland (June 18–24, 1992) and the Tuscarora Mountain Tunnel in Pennsylvania (September 2–8, 

1992) (Zielinska et al. 1996). These authors reported minimum and maximum ethylbenzene 

concentrations (on a carbon basis) for the Fort McHenry Tunnel of 6.3 and 89.2 ppbC (0.79 and 

11.2 ppbv) for bore #3, respectively, and 0.5 and 114.1 ppbC (0.06 and 14.26 ppbv) for bore #4, 

respectively, and concentrations for the Tuscarora Tunnel of 1.2 and 11.1 ppbC (0.15 and 6.04 ppbv) , 

respectively. The total number of light-duty vehicles (LDV) and heavy-duty vehicles (HDV) that passed 

through each tunnel was 12,273 LDV and 187 HDV for bore #3 and 11,788 LDV and 2,417 HDV for 

bore #4 of the Fort McHenry Tunnel and 4,887 LDV and 1,041 HDV for the Tuscarora Tunnel. 

Ethylbenzene is released during processing of crude oil. Bratveit et al. (2007) reported air concentrations 

ranging from an average of 0.01–0.09 ppm of ethylbenzene over a 12-hour period, with individual 

measurements reported as high as 1.11 ppm (Bratveit et al. 2007). 

Ethylbenzene and other VOCs have been found to be removed from waste water in municipal sewers and 

were emitted to the ambient atmosphere prior to entering a downstream waste water treatment facility in 

Toronto, Ontario (Quigley and Corsi 1995). These authors measured concentrations of ethylbenzene 

during four monitoring events and found that concentrations ranged from not detectable to 5 ppm. 

Headspace concentrations of ethylbenzene exhibited a significant weekday/weekend trend. Significant 

emissions of all VOCs monitored occurred during three of the four monitoring events. Ethylbenzene had 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 180 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. Ethylbenzene Concentrations in Ambient Air Samples Collected in the 

United States
 

Location Concentration Comments Reference 

Downey, 

California 

4.6±3.7 ppb (mean±SD) 

16.1 ppba 

February 18–27, 1984; 

n=100 

Singh et al. 1985 

Los Angeles, 3–12 ppb (range) September 29– Grosjean and Fung 

California November 13, 1981 1984 

Riverside, 

California 

1.3±0.8 ppb (mean±SD) 

4.0 ppba 

July 1–13, 1980; 

n=100 

Singh et al. 1985 

Denver, 

Colorado 

2.2±3.1 ppb (mean±SD) 

18.5 ppba 

June 15–28, 1980; 

n=100 

Singh et al. 1985 

Chicago, 

Illinois 

0.8±1.2 ppb (mean±SD) 

9.5 ppba 

April 20–May 2, 1981; 

n=100 

Singh et al. 1985 

St. Louis, 

Missouri 

0.6±0.5 ppb (mean±SD) 

2.1 ppba 

May 29–June 9, 1980; 

n=100 

Singh et al. 1985 

Camden, 0.17 ppb (mean) July 6–August 16, 1981; Harkov et al. 1983 

New Jersey n=35 

Elizabeth, 0.26 ppb (mean) July 6–August 16, 1981; Harkov et al. 1983 

New Jersey n=37 

Newark, 0.33 ppb (mean) July 6–August 16, 1981; Harkov et al. 1983 

New Jersey n=38 

Staten Island, 

New York 

1.7±2.5 ppb (mean±SD) 

17.2 ppba 

March 26–April 5, 1981; 

n=100 

Singh et al. 1985 

Staten Island, 

New York 

2.7±4.2 ppb (mean±SD) 

16.7 ppba 

April 25–May 1, 1984; 

n=100 

Singh et al. 1985 

Philadelphia, 

Pennsylvania 

0.8±0.8 ppb (mean±SD) 

7.3 ppba 

April 4–22, 1983 

n=100 

Singh et al. 1985 

Pittsburgh, 

Pennsylvania 

0.8±1.6 ppb (mean±SD) 

10.5 ppba 

April 7–17, 1981; 

n=100 

Singh et al. 1985 

Houston, 

Texas 

1.5±1.6 ppb (mean±SD) 

8.2 ppba 

March 8–17, 1984; 

n=100 

Singh et al. 1985 

Jones State Forest, 2.8 ppbb January 4–6, 1978 EPA 1979 

Texas 

a

Maximum measured concentration
 b

Median concentration in 10 bag samples (median concentration in 5 can samples was 1.0 ppb)
 

n = number of samples; SD = standard deviation 
 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 181 

6. POTENTIAL FOR HUMAN EXPOSURE 

the second highest emissions during all periods and ranged from 7 to 14 g/hour (62–130 kg/year) for 

event 1 and from 1 to 13 g/hour (9–115 kg/year) for event 2. Ethylbenzene emissions at five municipal 

treatment facilities ranged from 0.08 to 93 g/day (0.003–3.9 g/hour). Results of this study suggest that 

sewers that accept VOC-laden waste water, and that are characterized by significant ventilation and drop 

structures, can be significant sources of VOC emissions (including ethylbenzene) relative to municipal 

waste water treatment facilities. 

Assmuth and Kalevi (1992) reported that ethylbenzene was detected in municipal solid waste landfill gas 

at minimum and maximum concentrations of 6.6–7.6 mg/m3 (1.5–1.7 ppmv), <0.1–9.6 mg/m3 (<0.02– 

2.2 ppmv), 0.2–1.2 mg/m3 (0.04–0.28 ppmv), and 85–98 mg/m3 (20–22 ppmv) at four different landfill 

sites in Finland. Concentrations of ethylbenzene measured in a biogas collection system at the Miron 

Quarry Municipal Waste Landfill Site in Montreal, Quebec ranged from 2 to 36 mg/m3 (0.5–8.3 ppmv) 

(Goldberg et al. 1995). 

6.4.2 Water 

The median ethylbenzene concentration in ambient surface waters in the United States in 1980–1982 was 

<5.0 μg/L (ppb) according to EPA's STORET water quality database (Staples et al. 1985). The chemical 

was detected in 10% of the 1,101 samples collected during that period. Ethylbenzene was also detected in 

7.4% of the 1,368 industrial effluent samples collected during 1980–1982 at a median concentration of 

<3.0 μg/L (ppb). More recent data from the STORET database indicated that ethylbenzene was only

detected in 15 out of 548 surface water samples obtained from January 2005 to March 2007, at a 

maximum concentration of 2 ppb (EPA 2007i). 

From 1989 to 1993, New York City municipal waste waters were analyzed to determine the frequency of 

detection of organic priority pollutants, including ethylbenzene (Stubin et al. 1996). Ethylbenzene was 

detected in 14 of 84 (17%) influent samples at concentrations ranging from 1 to 11 μg/L (ppb) and in only

1 of 84 (1%) effluent samples at a concentration of 2 μg/L (ppb).

Ethylbenzene and other VOCs have been detected in waste water in municipal sewers prior to entering a 

downstream waste water treatment facility in Toronto, Ontario (Quigley and Corsi 1995). These authors 

measured concentrations of ethylbenzene in waste water during several monitoring events and found that 

concentrations ranged from 0.059 to 0.086 mg/L (ppm) in one event and from 7 to 11 mg/L (ppm) in 

another event. The authors also determined that the stripping efficiency across two drop structures with 
 

 

 

 

 

 

 

 

 

ETHYLBENZENE 182 

6. POTENTIAL FOR HUMAN EXPOSURE 

waste water fall heights of 1.4–3 meters within the sewer system removed 31–36% of the ethylbenzene in 

the waste water. Results of this study suggest that sewers that accept VOC-laden waste water, and that 

are characterized by significant ventilation and drop structures, can be significant sources of VOC 

emissions (including ethylbenzene) relative to municipal waste water treatment facilities. 

As part of EPA's Nationwide Urban Runoff Program, ethylbenzene was measured in 4% of the municipal 

runoff samples collected in 15 cities throughout the United States (Cole et al. 1984). The measured ethylbenzene concentration range was 1–2 μg/L (ppb). Ethylbenzene was detected in 41 out of 249 (16.5%)

storm water runoff samples collected at 46 different sampling locations in North Carolina over a 1-year 

period (Borden et al. 2002). The mean, median, and maximum ethylbenzene levels were 0.10, 0.07, and 

0.36 μg/L (ppb), respectively. 

Ethylbenzene was measured in seawater at an average concentration of 0.011 μg/L (ppb) and a

concentration range of 0.0018–0.022 μg/L (ppb) over a 15-month observation period at Vineyard Sound, 

Massachusetts (Gschwend et al. 1982). Ethylbenzene also has been reported in surface waters of the Gulf 

of Mexico at a concentration range of 0.0004–0.0045 μg/L (ppb) (Sauer et al. 1978). 

Ethylbenzene has been detected in a relatively remote location (Mt. Mitchell, North Carolina) in cloud 

water at a mean concentration of 170 ng/L (range 0–450 ng/L) (Aneja 1993). The average concentration 

of ethylbenzene in precipitation was 34 ng/L. Ethylbenzene has also been detected in snow samples from 

two remote sites in the province of Québec, Canada (Kos and Ariya 2006). Ethylbenzene levels reported 

in μg/L±3σ were: 2.65±1.28 (Resolute Bay); 0.22±0.02 (Gaspé Peninsula); and 0.31±0.06 (Gaspé 

Peninsula). 

From 1989 to 1990 and from 1992 to 1993, ethylbenzene was monitored in wetland-treated leachate water 

at a municipal solid waste landfill in central Florida (Chen and Zoltek 1995). During the first sampling 

period, ethylbenzene was detected in surface water samples ranging from 0.06 to 0.09 ppb and in 

groundwater samples ranging from 0.06 to 9.75 ppb. During the second sampling period (1992–1993), 

ethylbenzene was not detected in surface water samples, but was detected in groundwater samples at 

concentrations ranging from below detection limits to 10.55 ppb. Ethylbenzene was detected in a study of 

three landfills in central Florida (Hallbourg et al. 1992). These authors reported concentrations of ethylbenzene in groundwater of 1.63–9.75, <1–83.8, and <1–8.6 μg/L (ppb) at the three different landfill sites. 

The mean concentration of ethylbenzene detected in landfill leachate from these disposal areas was 

17.5 μg/L.
 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 183 

6. POTENTIAL FOR HUMAN EXPOSURE 

Ethylbenzene was measured in all three drinking water plants sampled as part of the New Orleans Area 

Water Supply Study conducted by EPA in 1974 (Keith et al. 1976). The reported concentrations were 

1.6, 1.8, and 2.3 μg/L (ppb). The 1982 Ground Water Supply Survey conducted by EPA reported ethylbenzene in only 3 out of 466 random samples at a mean concentration of 0.8 μg/L (ppb) and a maximum 

concentration of 1.1 μg/L (ppb) (Cotruvo 1985). Chemical monitoring of 617 private and 1,174 public 

groundwater wells in the state of Wisconsin revealed that ethylbenzene was detected in 3 community and 

12 private wells. The concentration of ethylbenzene detected exceeded the state's recommended drinking 

water advisory limit of 1,400 μg/L (ppb) in 9 of the 12 private wells, but no exceedences were observed 

in the public wells (Krill and Sonzongni 1986). 

Ethylbenzene was infrequently detected in a comprehensive survey conducted by the United States 

Geological Survey (USGS) of volatile organic compounds in private and public groundwater wells used 

for drinking water (USGS 2006). Ethylbenzene was identified in 18 out of 3,497 aquifer samples at a 

median concentration of 0.035 μg/L for the 18 samples having positive detections. In an analysis of

domestic groundwater wells, the median concentration of ethylbenzene was reported as 0.041 μg/L for

samples having positive detections. Ethylbenzene was identified in 7 out of 1,083 samples obtained from 

public wells across the United States at a median concentration of 0.32 μg/L for samples having positive

detections. 

Although ethylbenzene does not appear to be a frequent contaminant in public water supplies, private 

residential wells near landfills, hazardous waste sites, or gas stations are more likely to contain detectable 

levels of this compound. Ethylbenzene was listed as one of the 58 most frequently detected chemicals 

associated with groundwater contamination near superfund sites (Knox and Canter 1994). Ethylbenzene 

was listed as having a medium priority with respect to its frequency of occurrence. Ethylbenzene has 

been detected in wells downgradient from landfills in Southern Ontario at concentrations ranging from 

12 to 74 μg/L (ppb) (Barker 1987). Ethylbenzene was detected at levels of 1–22, 1–5, and <1 μg/L in

groundwater 0–37, 50–114, and 170–254 meters, respectively, downgradient from a municipal landfill 

located in Grindsted, Denmark (Baun et al. 2000). Ethylbenzene was detected in groundwater from a 

representative monitoring well on a former gas-compressor site near South Lovedale, Oklahoma at a 

concentration of 220 μg/L (Jin et al. 2007). 

Borden and Yanoschak (1990) compared ground and surface water quality impacts associated with North 

Carolina sanitary landfills. These authors found that ethylbenzene was detected at ≈25% of the waste 
 

 

 

 

 

ETHYLBENZENE 184 

6. POTENTIAL FOR HUMAN EXPOSURE 

water effluents (receiving secondary treatment) and only 3% of the groundwater sampled in the vicinity 

of sanitary landfill sites. Groundwater monitoring at 479 hazardous waste disposal sites indicated that 

ethylbenzene, like the other 9 VOCs monitored, was detected at more than 100 of the 479 sites tested 

(Plumb 1991). Ethylbenzene was also one of the VOCs detected in groundwater samples from hazardous 

waste sites in all 10 EPA regions. Rosenfeld and Plumb (1991) reported that ethylbenzene was detected 

in groundwater at 19% of wood-treatment industry sites based on its frequency of detection and average 

concentration. Groundwater near an underground coal gasification site in northeastern Wyoming 

contained concentrations of ethylbenzene ranging from 92 to 400 μg/L (ppb) (Stuermer et al. 1982). 

Groundwater samples near a fuel spill in the Great Ouse Basin in Great Britain contained ethylbenzene 

concentrations as high as 1,110 μg/L (ppb) (Tester and Harker 1981).

6.4.3 Sediment and Soil 

The median ethylbenzene concentration (dry weight) detected in sediment in the United States in 1980– 

1982 was 5 μg/kg (ppb) according to EPA's STORET water quality database (Staples et al. 1985). The

compound was detected in 11% of 350 sediment samples analyzed. More recent data from the STORET 

database indicated that ethylbenzene was identified, but not quantified, in 25 out of 68 sediment samples 

obtained from January 2005 to March 2007 (EPA 2007i). 

Ethylbenzene concentrations were analyzed in contaminated soil samples obtained from the site of a 

former crude oil and natural gas production facility near Los Angeles, California. Concentrations ranged 

from the limit of detection (0.005 mg/kg) to 160 mg/kg. Subsurface samples were collected from 

trenches, boreholes, and excavations; the highest concentrations were found in samples obtained through 

a borehole (Soukup et al. 2007). 

6.4.4 Other Environmental Media 

Data from the FDA Total Diet Study Market Basket Surveys collected between September 1991 and 

October 2003 indicate that ethylbenzene was detected in 82 different food items at a maximum 

concentration of 0.129 ppm (FDA 2006b). In a previous Market Basket Survey, ethylbenzene was 

identified in 15 out of 234 table-ready food items at an average concentration of 0.0146 ppm and a range 

of 0.00637–0.0387 ppm (Heikes et al. 1995). Trace concentrations of ethylbenzene have been reported in 

split peas (0.013 mg/kg [ppm]), lentils (0.005 mg/kg [ppm]), and beans (mean concentration 0.005 mg/kg 

[ppm]; maximum concentration 0.011 mg/kg [ppm]) (Lovegren et al. 1979). Ethylbenzene was reported 

as one of 227 organic chemicals present in roasted filbert nuts (Kinlin et al. 1972). Gorna-Binkul et al. 
 

 

 

 

 

 

 

 

ETHYLBENZENE 185 

6. POTENTIAL FOR HUMAN EXPOSURE 

(1996) reported concentrations of ethylbenzene in orange peel (0.0236 μg/g [ppm] dry weight) and in 

parsley leaves (0.2567 μg/g [ppm] dry weight). The author reported that the differences in concentrations

of the VOCs were dependent on the plant species and the morphological part of the plant analyzed. In 

underground parts (i.e., roots and bulbs) not directly exposed to polluted ambient air during growth, no 

VOC concentrations were detected. Biedermann et al. (1995) reported concentrations of several VOCs in 

extra virgin olive oil collected in northwest Italy. These authors measured ethylbenzene levels in raw 

olives of 6 μg/kg (ppb), which increased with time as they were milled to 25 μg/kg (ppb). Levels in the

finished olive oils ranged from 11 to 27 μg/kg (ppb) depending on the preparation method used. These

authors reported that while some of the ethylbenzene was accumulated in the olives in the orchards, a 

larger proportion was accumulated as a result of exposure of the oil to air in the milling areas. Ethylbenzene concentrations in olive oil increased from 6 to 235 ppb after 2 days of exposure. The authors 

concluded that the production process increased the concentration of ethylbenzene in the oil as a result of 

uptake from the air that was likely to be contaminated with gasoline vapors associated with small vehicles 

used to move the olives from area to area within the olive oil mill. 

Ethylbenzene was also found to migrate from thermoset polyester cooking containers (composed of crosslinking chains of styrene) into belly pork during cooking (Gramshaw and Vandenburg 1995). Migration 

ranged from <6 to 34 μg/kg for ethylbenzene. The authors also found that the migration measured during 

the second use of the cookware was generally higher than that during the first use. These authors also 

reported that ethylbenzene concentrations in food cooked in foil-covered dishes was higher than that in 

the same food cooked uncovered. This was especially true for ethylbenzene that was more volatile than 

the styrene tested. Ehret-Henry et al. (1994) also reported migration of ethylbenzene from polystyrene 

containers into dairy products. Concentrations of ethylbenzene were 2–4 μg/kg for yogurt and 4 μg/kg for

chocolate dessert. 

Sack et al. (1992) conducted a survey of VOCs in 1,159 household items, including automotive products, 

household cleaners and polishes, paint related products, fabric and leather treatments, cleaners for 

electronic equipment, oils, greases, and lubricants, adhesive-related products, and miscellaneous products. 

Ethylbenzene was detected in 157 of 658 (24%) of the products tested. The highest mean ethylbenzene 

concentrations and percentage of products in each category in which ethylbenzene was detected are as 

follows; 7.2% w/w (wet weight) in 7.5% of automotive products, 2.4% w/w in 47.8% of paint-related 

products, and 1.0% w/w in 11.8% of fabric and leather treatments. 
 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 186 

6. POTENTIAL FOR HUMAN EXPOSURE 

Hodgson et al. (1996) determined the contribution of environmental tobacco smoke (ETS) to 

concentrations of VOCs in smoking environments. These authors reported that the average emission 

factor for ethylbenzene for six brands of cigarettes was 101 μg/cigarette (range 83–142 μg/cigarette). The

average concentration of ethylbenzene in five smoking areas ranged from 1.3 to 8.7 μg/m3 (0.3–2 ppbv). 

Martin et al. (1997) determined the ETS yield of selected analytes, including ethylbenzene, for the 50 topselling U.S. cigarette brand styles in 1991 and for the University of Kentucky Research cigarette, K1R4F. 

The ETS was generated by smokers in an environmental test chamber. The ethylbenzene concentrations 

measured were 8.68 μg/m3 for full flavor cigarettes, 8.24 μg/m3 for full flavor low tar cigarettes, and 

8.72 μg/m3 for ultra-low-tar cigarettes. The mean ethylbenzene concentration for all cigarettes was 

8.50 μg/m3

. The mean ethylbenzene yields by tar category weighted by market share were 

81.18 μg/cigarette for full flavor cigarettes, 76.79 μg/cigarette for full flavor low tar cigarettes, and

81.66 μg/cigarette for ultra low tar cigarettes. The mean ethylbenzene yield for all cigarettes was 

79.57 μg/cigarette.

Ethylbenzene was not detected (at a detection limit of 0.025 mg/kg [ppm] wet weight) in any of the 

97 biota samples collected from all STORET stations in 1980–1983 (Staples et al. 1985). Ethylbenzene 

was detected at low concentrations (0.8 ng/g [0.8 ppb]) in oyster tissue, but not in clam tissue from Lake 

Pontchartrain at Passes, Louisiana (Ferrario et al. 1985). The highest average ethylbenzene concentration 

measured in tissue of bottomfish from Commencement Bay in Tacoma, Washington was reported as 

0.01 mg /kg (ppm) (Nicola et al. 1987). 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

The highest exposure to ethylbenzene for the general public is most likely to occur via inhalation 

associated with the use of self-service gasoline pumps or while driving a gasoline-powered motor vehicle 

especially in high traffic areas or in tunnels (Lawryk et al. 1995; Smith et al. 2008). Backer et al. (1997) 

performed a study that measured exposures associated with the pumping two different blends of fuel 

under cold conditions in Fairbanks, Alaska. The subjects in the study had significantly higher levels of 

gasoline components in their blood after pumping gasoline than before. The changes in VOC levels in 

blood were similar whether the individuals pumped regular or oxygenated gasoline. Prior to pumping 

regular gasoline, the median concentration of ethylbenzene in blood was 0.10 ppb (n=26) with a range of 

0.02–0.73 ppb; after pumping, the median concentration was 0.16 ppb with a range of 0.06–1.40 ppb. 

Before pumping an oxygenated fuel blend that was 10% ethanol, the median concentration of 
 

 

 

 

 

 

 

 

ETHYLBENZENE 187 

6. POTENTIAL FOR HUMAN EXPOSURE 

ethylbenzene in blood was 0.11 ppb (n=22) with a range of 0.04–0.55 ppb; after pumping, the ethanol 

blend, the median concentration was 0.16 ppb with a range of 0.06–0.64 ppb. 

Janasik et al (2008) studied ethylbenzene exposure in six male volunteers who were subjected to an 

exposure chamber containing ethylbenzene as well as toluene, xylene, and mesitylene at concentrations 

emulating Polish occupational exposure standards of 100 mg/m3

. Blood and urine samples obtained from 

the volunteers were analyzed. Ethylbenzene concentrations in the blood ranged from 20 to 200 μg/L, 

while urine concentrations ranged from 1 to 152 μg/L (Janasik et al. 2008).

Lawryk and Weisel (1996) measured in-vehicle concentrations of selected gasoline-derived volatile 

organic compounds on 113 commutes through suburban New Jersey and 33 New Jersey/New York 

commutes. In a typical suburban commute, the mean in-vehicle concentration of ethylbenzene was 

11.5±18.8 μg/m3 (2.64±4.32 ppbv; n=52) under low ventilation conditions and 8.5±11.2 μg/m3 

(1.9±2.57 ppbv; n=43) under high ventilation conditions. On the New Jersey turnpike and in the Lincoln 

Tunnel, the mean in-vehicle concentrations of ethylbenzene were 8.8±10.8 μg/m3 (2.0±2.48 ppbv; n=32) 

and 14.3±10.2 μg/m3 (3.29±2.34 ppbv; n=32), respectively. 

Ethylbenzene is ubiquitous in urban and rural atmosphere resulting from vehicular and industrial 

emissions (EPA 1988c). Tobacco smoke also provides a general source of exposure to ethylbenzene in 

indoor air (Wallace et al. 1987c). Wallace et al. (1989) also reported that two activities, painting and the 

use of automotive products (carburetor cleaner), led to increased indoor exposure to ethylbenzene by 

100-fold. Indoor exposure to ethylbenzene may also be increased resulting from the start-up of gasolinepowered engines in attached garages (Dodson et al. 2008). Information on exposure from foods is 

limited, but is not likely to be a significant source of ethylbenzene for the general population. 

Human exposure to styrene and ethylbenzene was assessed by considering inhalation exposure (including 

cigarette smoking) and food intake (Tang et al. 2000). The daily exposure to ethylbenzene for the general 

population was calculated as 1.8 μg/kg bodyweight/day, with up to 99% of the exposure due to inhalation

routes and only 1–2% caused by food consumption. 

One-half of the household drinking water used in the United States is supplied by groundwater, and 

contamination of groundwater by petroleum products is an increasingly common problem (Beavers et al. 

1996). Beavers et al. (1996) conducted a study in a New England household that used groundwater 

contaminated by gasoline from a leaking underground storage tank. A total daily dose of 379 μg 
 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 188 

6. POTENTIAL FOR HUMAN EXPOSURE 

ethylbenzene (204 μg ingested and 175 μg inhaled) was estimated for an exposed subject compared to a

median daily dose of 32 μg for unexposed subjects. Of the 175 μg inhaled by the exposed subject, 108 μg 

was attributed to shower activities. The exposed subject and the three non-exposed subjects all were 

smokers. 

The 1982 National Human Adipose Tissue Survey conducted by EPA measured ethylbenzene in 96% of 

the 46 composite samples analyzed for VOCs (EPA 1986). A wet tissue concentration range of not 

detected (detection limit=2 ng/g) to 280 ng/g (ppb) was reported, but an average concentration was not 

provided. 

Ethylbenzene has been detected in breast milk samples collected from 8 of 12 women from various cities 

in the United States; however, the concentrations were not reported (Pellizzari et al. 1982). The 

12 women sampled in the study were residents of Bayonne, New Jersey (6 women), Jersey City, New 

Jersey (2 women), Bridgeville, Pennsylvania (2 women), and Baton Rouge, Louisiana (2 women). 

Mean and median concentrations of ethylbenzene detected in 631 blood samples from participants in the 

Third National Health and Nutrition Examination Survey (NHANES III 1998–1994 data) were 0.11 and 

0.06 ppb (95 percentile value of 0.25 ppb), respectively (Ashley et al. 1994). In an earlier study (Ashley 

et al. 1992), these authors reported a mean ethylbenzene concentration of 0.12 ppb in 13 blood samples. 

Hajimiragha et al. (1989) conducted a study of 13 nonsmokers and 14 smokers with no known 

occupational or hobby-related exposure to volatile organic hydrocarbons. These authors reported a mean 

and median ethylbenzene concentration of 651 ng/L (0.651 ppb) and 431 ng/L (0.431 ppb) for the 

nonsmokers and 837 ng/L (0.837 ppb) and 533 ng/L (0.533 ppb) for the smokers. Ethylbenzene 

concentrations tended to occur at higher concentrations in the blood of smokers than in nonsmokers; 

however, the difference was not significant. Ashley et al. (1995) also reported that smoking elevated the 

blood levels of ethylbenzene and was highly correlated with blood levels of 2,5-dimethylfuran. These 

authors reported a mean concentration of 0.10 ng/mL (ppb) (median 0.048 ng/mL; range from below 

detection limit to 2.7 ng/mL) for nonsmokers and a mean concentration of 0.17 ng/mL (ppb) (median 

0.16 ng/mL; range 0.036–0.88 ng/mL) for smokers. To aid in understanding the kinetics of uptake and 

elimination of volatile organics (including ethylbenzene), Ashley and Prah (1997) measured blood 

concentrations before, during, and after exposure of five individuals to a mixture of volatile organics in a 

controlled chamber. The half-lives of the compounds measured were <0.5 hour, but the elimination time 

courses were multiexponential and suggested that, with repeated exposure, bioaccumulation may occur in 

humans. 
 

 

 

 

 

 

 

 

 

ETHYLBENZENE 189 

6. POTENTIAL FOR HUMAN EXPOSURE 

Occupational exposure to ethylbenzene in the petroleum industry has been reported in a study that 

measured ethylbenzene concentrations in air for 49–56 workers during the summer of 1984 (Rappaport et 

al. 1987). The average air concentrations of ethylbenzene measured over the full work shift for gasoline 

service station attendants, transport drivers, and outdoor refinery personnel were comparable at 0.063, 

0.079, and 0.079 mg/m3

, respectively (14.5, 18.2, and 18.2 ppbv, respectively). The authors noted that 

exposures of service station attendants were significantly lower when vapor recovery systems were 

present. Crude oil process operators at an offshore processing plant near Norway were found to be 

exposed to 0.01–0.09 ppm of ethylbenzene in air during a full 12-hour work shift. Short-term exposure to 

ethylbenzene was dependent upon the specific work task and ranged from <0.01 to 1.11 ppm. Workers 

on the flotation package were found to be exposed to the highest ethylbenzene concentrations (Bratveit et 

al. 2007). 

Personal air monitoring of 35 varnish workers (spraymen) has revealed an average ethylbenzene 

concentrations of 4.0 ppm, while the average concentration in blood was 61.4 μg/L (Angerer and Wulf

1985). Concentrations of ethylbenzene were monitored in auto paint shops in Spain that used organic 

solvents (de Medinilla and Espigares 1988). These authors reported air concentrations of ethylbenzene 

ranging from 0.50 to 125.0 mg/m3 (0.12–28.75 ppmv). 

The indoor air of screen printing plant workrooms located directly below houses in Amsterdam, Holland 

was found to contain median TWA concentrations of ethylbenzene ranging from <0.03 mg/m3 (7 ppbv) to 

1.30 mg/m3 (299 ppbv) and maximum TWA concentrations ranging from 0.11 mg/m3 (25 ppbv) to 

3.21 mg/m3 (738 ppbv) (Verhoeff et al. 1988). 

Spray-painting and gluing operations can also result in exposure to ethylbenzene; personal air monitoring 

of workers measured average exposures of approximately 0.50 ppmv (2.2 mg/m3

) (Whitehead et al. 

1984). Most of the operations measured during the study were performed in ventilation hoods. 

Holz et al. (1995) reported that ethylbenzene air concentrations detected from air sampling in all areas of 

a styrene production facility located in the former German Democratic Republic ranged from 365 to 

2,340 μg/m3 (0.08–0.53 ppmv). 

According to the National Occupational Exposure Study (NOES) conducted by NIOSH from 1981 to 

1983, an estimated 201,838 workers were potentially exposed to ethylbenzene in the workplace (NIOSH 
 

 

 

 

 

 

 

ETHYLBENZENE 190 

6. POTENTIAL FOR HUMAN EXPOSURE 

1990). The NOES database does not contain information on the frequency, concentration, or duration of 

occupational exposure to any of the chemicals listed. The survey provides only estimates of the numbers 

of workers for whom potential exposure in the workplace is an issue. 

The Occupational Safety and Health Administration (OSHA) has set a Permissible Exposure Limit (PEL) 

based on a TWA of 100 ppm (≈435 mg/m3 at 1 atm and 25 °C) in the workplace (OSHA 1974). The 

American Conference of Governmental Industrial Hygienists also recommends a Threshold Limit Value 

(TLV-TWA) of 100 ppm (≈435 mg/m3

) for occupational exposures (ACGIH 1992). The recommended 

exposure limit (REL) for occupational exposures (TWA) set by the NIOSH is also 100 ppm 

(≈435 mg/m3

) for ethylbenzene based on a 10-hour average workday and a 40-hour workweek (NIOSH 

2005). 

6.6 EXPOSURES OF CHILDREN 

This section focuses on exposures from conception to maturity at 18 years in humans. Differences from 

adults in susceptibility to hazardous substances are discussed in Section 3.7, Children’s Susceptibility. 

Children are not small adults. A child’s exposure may differ from an adult’s exposure in many ways. 

Children drink more fluids, eat more food, breathe more air per kilogram of body weight, and have a 

larger skin surface in proportion to their body volume. A child’s diet often differs from that of adults. 

The developing human’s source of nutrition changes with age: from placental nourishment to breast milk 

or formula to the diet of older children who eat more of certain types of foods than adults. A child’s 

behavior and lifestyle also influence exposure. Children crawl on the floor, put things in their mouths, 

sometimes eat inappropriate things (such as dirt or paint chips), and spend more time outdoors. Children 

also are closer to the ground, and they do not use the judgment of adults to avoid hazards (NRC 1993). 

Children can be exposed to ethylbenzene by inhalation in urban and rural atmospheres contaminated by 

vehicular and industrial emissions. Tobacco smoke also provides a general source for exposure of 

children to ethylbenzene in indoor air, especially in the homes where one or both parents smoke. 

Children may also be exposed to ethylbenzene-containing consumer products, such as carpet glues, 

paints, and varnishes. Household activities, such as painting, can lead to short-term exposures to higher 

levels of ethylbenzene if ventilation is inadequate. The limited information available on exposure from 

foods indicates that food is not likely to be a significant source of ethylbenzene for children. 
 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 191 

6. POTENTIAL FOR HUMAN EXPOSURE 

Ethylbenzene is heavier than air, and since young children are closer to the ground or floor because of 

their height, during accidental exposures they may be exposed to more ethylbenzene vapors than adults. 

A 2- year monitoring study (2000–2001) involving 134 children aged 6–10 was conducted in 

Minneapolis, Minnesota in order to assess exposure to VOCs, including ethylbenzene (Sexton et al. 

2005). The distribution of ethylbenzene measured in the blood of these children (416 samples) is 

provided in Table 6-3. Comparing these data to monitoring results from NHANES III, the levels of 

ethylbenzene in children’s blood is approximately 2 or more times lower than in non-occupationally 

exposed adults (Sexton et al. 2005). Ethylbenzene has been detected in breast milk samples collected 

from 8 of 12 women from various cities in the United States; however, the concentrations were not 

reported (Pellizzari et al. 1982). The 12 women sampled in the study were residents of Bayonne, New 

Jersey (6 women); Jersey City, New Jersey (2 women); Bridgeville, Pennsylvania (2 women); and Baton 

Rouge, Louisiana (2 women). No direct pharmacokinetic experiments have been done to investigate 

whether significant amounts of ethylbenzene are transferred to breast milk in mammals. No studies were 

located that expressed the level of ethylbenzene or its metabolites in amniotic fluid, meconium, cord 

blood or neonatal blood. 

Although no data were found in the literature, it is possible that children playing near hazardous waste 

sites could be dermally exposed to ethylbenzene in soil or orally exposed by hand-to-mouth activity 

and/or soil pica. Ethylbenzene, however, is only moderately adsorbed by soil. Since it has a moderately 

high vapor pressure, it will evaporate fairly rapidly from dry soil. However, under certain soil conditions, 

ethylbenzene may persist for longer periods of time; it has been detected in soil samples collected at 

469 of the 829 NPL hazardous waste sites where it has been detected in some environmental media 

(HazDat 2007). It was also detected in high concentrations in soil at a former crude oil and natural gas 

production facility, which was being considered for redevelopment (Soukup et al. 2007). No information 

was found concerning dermal and oral bioavailability of ethylbenzene in soil. 

In the home, intentionally sniffing solvents could lead to high levels of exposure. Household products 

containing ethylbenzene, such as gasoline, paints, and glue, are widely available to children. Radhouame 

et al. (2008) studied inhalant abuse among 40 male and 4 female children and young adults (aged 11– 

23 years) suspected of drug abuse in Tunisia. Solvent metabolites were measured in urine samples to 

indicate exposure to VOC compounds through sniffing of various products. The authors concluded that 

the particular children in the study abused substances that ultimately resulted in high toluene and hexane 

exposures, as opposed to those resulting in high ethylbenzene exposure (Chakroun et al. 2008). However, 

abuse of household products could still be a concern for exposure of children to ethylbenzene. 
 

ETHYLBENZENE 192 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-3. Distribution of Blood Ethylbenzene Concentrations in 

Children (ng/mL)
 

Percentage 

Sampling above 

period Samples detection limit 10th 25th 50th 75th 90th 95th 99th 

February 2000 92 79.1 0.02 0.02 0.03 0.05 0.07 0.08 0.12 

May 2000 86 66.7 0.01 0.02 0.03 0.04 0.05 0.07 0.17 

February 2001 63 61.1 0.02 0.02 0.02 0.03 0.03 0.03 0.04 

May 2001 88 98.9 0.03 0.04 0.05 0.06 0.08 0.09 0.10 

Source: Sexton et al. 2005 
 

 

 

 

 

ETHYLBENZENE 193 

6. POTENTIAL FOR HUMAN EXPOSURE 

No information was found concerning differences in the weight-adjusted intakes of ethylbenzene by 

children. 

No exposures of children to ethylbenzene by contamination of workers’ homes were found in the 

Workers’ Home Contamination Study conducted under the Worker’s Family Protection Act (NIOSH 

1995). 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

In addition to individuals who are occupationally exposed to ethylbenzene (see Section 6.5), there are 

several groups within the general population that may receive potentially high exposures (higher than 

background levels) to ethylbenzene. These populations include individuals living in proximity to sites 

where ethylbenzene is produced or used in manufacturing or sites where ethylbenzene is disposed, and 

includes individuals living near the 829 NPL hazardous waste sites where ethylbenzene has been detected 

in some environmental media (HazDat 2007). Ethylbenzene has been detected in air and groundwater at 

121 and 557 NPL hazardous waste sites, respectively. 

Individuals living or working near petroleum refineries or chemical manufacturing plants may receive 

higher inhalation exposures than those experienced by the general population. Residents living in the 

vicinity of gasoline stations, high traffic areas, tunnels, parking lots, and highways may also receive a 

higher than average inhalation exposure since ethylbenzene is a component of gasoline (Smith et al. 

2008). Residential wells downgradient of leaking underground storage tanks, landfills, and hazardous 

waste sites contaminated with petroleum products and solvents may contain high levels of ethylbenzene. 

If these residential wells are the primary source of drinking water, this may pose a risk to human health 

via consumption of contaminated water as well as increased inhalation of and dermal contact with ethylbenzene during showering and bathing. A study of indoor air in a home using gasoline-contaminated 

drinking water found that exposures to ethylbenzene could occur via inhalation during showering and 

other household activities (Beavers et al. 1996). Ethylbenzene concentrations in shower air were often 

one to two orders of magnitude higher than non-shower air. These authors reported a total daily 

household dose of ethylbenzene of 379 μg, with 204 μg derived from ingestion of drinking water and 175 

μg derived from inhalation (108 μg from shower-related inhalation and 67 μg from non-shower-related 

inhalation) to the exposed subject living in the home. The daily dose of ethylbenzene for an unexposed 

smoker by comparison was estimated to be 32 μg.
 

 

 

 

 

 

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6. POTENTIAL FOR HUMAN EXPOSURE 

6.8 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of ethylbenzene is available. Where adequate information is 

not available, ATSDR, in conjunction with NTP, is required to assure the initiation of a program of 

research designed to determine the health effects (and techniques for developing methods to determine 

such health effects) of ethylbenzene. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

6.8.1 Identification of Data Needs 

Physical and Chemical Properties. The physical and chemical properties of ethylbenzene are well 

characterized (see Table 4-2) and allow prediction of the transport and transformation of the compound in 

the environment (Amoore and Hautala 1983; Bohon and Claussen 1951; Chiou et al. 1983; EPA 1982; 

Hansch and Leo 1979; Hodson and Williams 1988; Mackay and Shiu 1981; Polak and Lu 1973; Sutton 

and Calder 1975; Verschueren 1983). No additional studies are needed at the present time. 

Production, Import/Export, Use, Release, and Disposal. According to the Emergency 

Planning and Community Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required 

to submit substance release and off-site transfer information to the EPA. The TRI, which contains this 

information for 2006, became available in May of 2008. This database is updated yearly and should 

provide a list of industrial production facilities and emissions. 

Ethylbenzene has numerous uses (ACGIH 2002; Ransley 1984; Verschueren 1983), and production of the 

chemical has steadily increased since 1983 (C&EN 1994a, 1994b, 1995, 2006; Kirschner 1995). Releases 

occur from a variety of common sources including manufacturing and production (TRI06 2008), fuels, 

automobile exhaust, and fumes from paints, varnishes, solvents, carpet glue, and hot asphalt (Fishbein 

1985; Hampton et al. 1983; Junk and Ford 1980; Katzman and Libby 1975; Kitto et al. 1997; Mukund et 

al. 1996; NAS 1980; Wallace et al. 1987b). Ethylbenzene also is released from waste waters to the 
 

 

 

 

ETHYLBENZENE 195 

6. POTENTIAL FOR HUMAN EXPOSURE 

atmosphere in municipal sewer systems (Quigley and Corsi 1995). Therefore, the potential for human 

exposure to ethylbenzene is considerable. The medium most likely to be contaminated is air, although 

ethylbenzene has also been detected in trace amounts in water supplies. Some ethylbenzene-containing 

wastes are designated as hazardous and are subject to EPA handling and recordkeeping requirements. 

Recommended methods for the disposal of ethylbenzene include burial in a landfill and rotary kiln 

incineration, liquid injection incineration, and fluidized bed incineration (EPA 1981d). No data need is 

identified at this time. 

Environmental Fate. Ethylbenzene is primarily partitioned to and transported in air (Dewulf and 

van Langenhove 1997; Eisenreich et al. 1981; Mackay 1979; Masten et al. 1994). The partitioning and 

transport processes in water, soil, and aquatic life are also well characterized (ASTER 1995; Dewulf et al. 

1996; Kawamura and Kaplan 1983; Ligocki et al. 1985; Swann et al. 1983). Transformation and 

degradation processes have also been well characterized in air (Atkinson and Carter 1984; Atkinson et al. 

1978; Grovenstein and Mosher 1970; Herron and Huie 1973; Hoshino et al. 1978; O'Brien et al. 1975; 

Ohta and Ohyama 1985; Ravishankara et al. 1978; Yanagihara et al. 1977), water (Acton and Barker 

1992; Anid et al. 1993; Bouwer and McCarty 1984; Burback and Perry 1993; Ehrhardt and Petrick 1984; 

Gschwend et al. 1982; Hutchins 1991; Masten et al. 1994; Wakeham et al. 1983; Wilson et al. 1986), and 

in soil and sediment (Bestetti and Galli 1984; Chen and Taylor 1995; Hutchins 1991; Hutchins et al. 

1991; Jamison et al. 1970; Ramanand et al. 1995; Van der Linden and Thijsse 1965; Yadav and Reddy 

1993; Zappi et al. 1996). No data need is identified at this time. 

Bioavailability from Environmental Media. Ethylbenzene is absorbed following inhalation, oral, 

and dermal exposures. Information is available on its absorption from air and water, but little data exist 

regarding dermal bioavailability and absorption from soil and food. Due to its large vapor pressure and 

Henry’s law constant, ethylbenzene is expected to volatilize fairly rapidly from soil surfaces. Based on 

the moderate affinity of ethylbenzene for soil, especially soils with relatively high organic carbon content, 

the amount of ethylbenzene in bioavailable form in soil is expected to be low to moderate. Because of the 

low BCF values calculated for ethylbenzene, food chain bioaccumulation would not be expected to be 

significant sources of ethylbenzene exposure. No data need is identified at this time. 

Food Chain Bioaccumulation. Limited data suggests that ethylbenzene does not bioconcentrate in 

aquatic organisms (Ogata et al. 1984), and is not likely to bioaccumulate in aquatic or terrestrial food 

chains. However, little information on food residues in commercially important fish and shellfish species 
 

 

 

ETHYLBENZENE 196 

6. POTENTIAL FOR HUMAN EXPOSURE 

is currently available. Additional monitoring data regarding the levels of ethylbenzene would be helpful 

for several commercially important fish and shellfish species. 

Exposure Levels in Environmental Media. Reliable monitoring data for the levels of 

ethylbenzene in contaminated media at hazardous waste sites are needed so that the information obtained 

on levels of ethylbenzene in the environment can be used in combination with the known body burden of 

ethylbenzene to assess the potential risk of adverse health effects in populations living in the vicinity of 

hazardous waste sites. 

An extensive amount of atmospheric monitoring data exists (EPA 1988c; Goldberg et al. 1995; Kinney et 

al. 2002; Kostiainen 1995; Mukerjee et al. 1997; Quigley and Corsi 1995; Wallace et al. 1987a, 1987c; 

Zielinska et al. 1996; Zweidinger et al. 1988). Ethylbenzene has also been detected in surface water and 

groundwater (Barker 1987; Borden and Yanoschak 1990; Chen and Zoltek 1995; Cole et al. 1984; 

Cotruvo 1985; Gschwend et al. 1982; Krill and Sonzongni 1986; Quigley and Corsi 1995; Staples et al. 

1985; Stubin et al. 1996; Stuermer et al. 1982; Tester and Harker 1981), sediment (Staples et al. 1985), a 

limited number of foodstuffs (Ferrario et al. 1985; Górna-Binkul et al. 1996; Kinlin et al. 1972; Lovegren 

et al. 1979; Nicola et al. 1987), and in cigarette smoke (Hodgson et al. 1996; Martin et al. 1997; Wallace 

1986; Wallace et al. 1987c). Continued monitoring data at or around hazardous waste sites are needed in 

order to assess human exposure for populations residing in these areas. 

Exposure Levels in Humans. Ethylbenzene and its metabolites have been detected in human blood 

(Angerer and Wulf 1985; Ashley et al. 1994), urine (Bardodej and Bardodevova 1970; Dutkiewicz and 

Tyras 1967; Engstrom and Bjurstrom 1978; Gromiec and Piotrowski 1984; Kiese and Lenk 1974; 

Sullivan et al. 1976; Yamasaki 1984), breast milk (Pellizzari et al. 1982), and adipose tissue (Engstrom 

and Bjurstrom 1978; EPA 1986). Most of the monitoring data have come from occupational studies of 

specific worker populations exposed by inhalation. Members of the general population can be exposed to 

ethylbenzene through inhalation of fumes while pumping gas, riding in gasoline-powered vehicles, and 

routinely starting vehicles in enclosed garages (Backer et al. 1997; Dodson et al. 2008; Lawryk and 

Weisel 1996; Lawryk et al. 1995), as well as exposure to ethylbenzene-containing consumer products 

(Hodgson et al. 1991; Lillo et al. 1990; NAS 1980; Otson et al. 1994; Sack et al. 1992; Wallace et al. 

1987b). Additional information regarding the general population’s exposure to ethylbenzene would be 

useful. Dietary intake is expected to be insignificant as compared to inhalation exposure (Tang et al. 

2000). Oral exposures are likely to be low, except for the consumption of contaminated drinking water 

by populations living in the vicinity of hazardous waste sites, leaking underground storage tanks, or 
 

 

 

 

 

 

 

 

ETHYLBENZENE 197 

6. POTENTIAL FOR HUMAN EXPOSURE 

municipal landfills. This information is necessary for assessing the need to conduct health studies on 

these populations. 

Exposures of Children. Children are exposed to ethylbenzene by the same routes that affect adults. 

Biomonitoring data suggest that blood levels of ethylbenzene are lower in children than non--

occupationally exposed adults (Sexton et al. 2005). Ethylbenzene has been detected in breast milk 

samples collected from 8 or 12 women from various cities in the United States; however, the 

concentrations were not reported (Pellizzari et al. 1982). There do not appear to be any childhood 

specific means to decrease exposure to ethylbenzene, aside from educating children about the dangers of 

inhalant abuse (Chakroun et al. 2008). A data need exists to determine current ethylbenzene residues and 

their sources in breast milk of members of the general population. 

Child health data needs relating to susceptibility are discussed in Section 3.12.2, Identification of Data 

Needs: Children’s Susceptibility. 

Exposure Registries. No exposure registries for ethylbenzene were located. This substance is not 

currently one of the compounds for which a sub-registry has been established in the National Exposure 

Registry. The substance will be considered in the future when chemical selection is made for subregistries to be established. The information that is amassed in the National Exposure Registry facilitates 

the epidemiological research needed to assess adverse health outcomes that may be related to exposure to 

this substance. 

6.8.2 Ongoing Studies 

The Federal Research in Progress (FEDRIP 2007) database provides additional information obtainable 

from a few ongoing studies that may fill in some of the data needs identified in Section 6.8.1. These 

studies are summarized in Table 6-4. 

As part of the Third National Health and Nutrition Evaluation Survey (NHANES III), the Environmental 

Health Laboratory Sciences Division of the National Center for Environmental Health, Centers for 

Disease Control and Prevention, will be analyzing human blood samples for ethylbenzene and other 

volatile organic compounds. These data will give an indication of the frequency of occurrence and 

background levels of these compounds in the general population. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 198 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-4. Ongoing Research Regarding the Environmental Fate and Exposure to 

Ethylbenzene
 

Investigator Affiliation Description Sponsor 

Thrall KD Battelle Pacific The overall research objective for this NIOSH 

Northwest Laboratories, project is to expand prior studies to 

Richland, Washington evaluate the percutaneous absorption of 

compounds commonly encountered 

within similar industries (styrene and 

ethylbenzene) along with focused 

studies to evaluate the dermal 

bioavailability of compounds with both 

lipophilic and hydrophilic properties. 

Burke J EPA The development of a human exposure EPA 

model has been initiated to characterize 

population exposures to air toxics in 

support of risk assessment activities in 

the National Air Toxics Program. This 

research will develop probabilistic inputs 

for exposure to chemicals such as 

benzene and ethylbenzene for use in the 

model. 

EPA = Environmental Protection Agency; NIOSH = National Institute for Occupational Safety and Health 

Source: FEDRIP 2007 
 

 

 

 

 

 

ETHYLBENZENE 199 

7. ANALYTICAL METHODS 

The purpose of this chapter is to describe the analytical methods that are available for detecting, 

measuring, and/or monitoring ethylbenzene, its metabolites, and other biomarkers of exposure and effect 

to ethylbenzene. The intent is not to provide an exhaustive list of analytical methods. Rather, the 

intention is to identify well-established methods that are used as the standard methods of analysis. Many 

of the analytical methods used for environmental samples are the methods approved by federal agencies 

and organizations such as EPA and the National Institute for Occupational Safety and Health (NIOSH). 

Other methods presented in this chapter are those that are approved by groups such as the Association of 

Official Analytical Chemists (AOAC) and the American Public Health Association (APHA). 

Additionally, analytical methods are included that modify previously used methods to obtain lower 

detection limits and/or to improve accuracy and precision. 

7.1 BIOLOGICAL MATERIALS 

Ethylbenzene can be determined in biological fluids, and tissues, and breath using a variety of analytical 

methods. Representative methods are summarized in Table 7-1. Most analytical methods for biological 

fluids and tissues use headspace gas chromatographic (GC) analysis. Breath samples are usually 

collected on adsorbent traps or in sampling bags or canisters, and then analyzed by GC. 

The headspace method involves equilibrium of volatile analytes such as ethylbenzene between a liquid or 

solid sample phase and the gaseous phase. The gaseous phase is then analyzed by GC. There are two 

main types of headspace methodology: static (equilibrium) headspace and dynamic headspace, which is 

usually called the "purge-and-trap" method (Seto 1994). The static headspace technique is relatively 

simple, but may be less sensitive than the purge-and-trap method. The purge-and-trap method, while 

providing increased sensitivity, requires more complex instrumentation and may result in artifact 

formation (Seto 1994). Generally, an inert gas such as helium is passed over the biological sample at 

elevated temperature, and the purged volatile organic compound (VOC) is trapped onto an adsorbent 

polymeric resin (Tenax). The organic compound is thermally desorbed from the adsorbent followed by 

identification and quantitation using various detectors; flame ionization detection (FID) and mass 

spectrometry (MS) are used most often. Other sample preparation methods have been used, but less 

frequently. Solvent extraction permits concentration, thereby increasing sensitivity, but the extraction 

solvent can interfere with analysis. Direct aqueous injection is a very rapid method, but sensitivity is low 

and matrix effects can be a serious problem. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 200 

7. ANALYTICAL METHODS 

Table 7-1. Analytical Methods for Determining Ethylbenzene in Biological
 

Samples
 

Sample Analytical Sample Percent 

matrix Preparation method method detection limit recovery Reference 

Whole blood Whole blood samples Capillary 0.015– 114–118 Ashley et al. 1992, 

were collected by GC/MS 0.020 ppb 1994 

venipuncture, sealed, and 

refrigerated. Extraction 

accomplished using a 

closed system purge and 

trap sampler 

Blood Direct analysis via inertial GC/MS <1 ppb No data St-Germain et al. 

spray extraction interface 1995 

Blood Automated head space Capillary 0.002 μg/mL 90–110 Otson and 

GC/FID (estimated) Kumarathasan 1995 

Blood	 Extraction using dynamic cap GC/FID 50 ng/L 39 Fustinoni et al. 1996 

headspace purge and trap (calculated) 

system followed by 

thermal desorption to the 

GC 

Blood	 Capillary blood samples GC/FID 2.7 μg/L No data Janasik et al. 2008 

extracted, sealed, mixed, 

and refrigerated. Gas 

phase sampled with 

gastight syringe and 

injected on column 

Urine Purge and trap Capillary No data 64–123 for Michael et al. 1980 

GC/MS model 

compounds 

Urine	 Extraction using dynamic Capillary 50 ng/L 61 Fustinoni et al. 1996 

headspace purge and trap GC/FID (calculated) 

system followed by 

thermal desorption to the 

GC 

Urine Extracted to headspace GC/FID 0.48 μg/L No data Janasik et al. 2008 

Mother’s Purge and trap Capillary No data 35–88 for Michael et al. 1980 

milk GC/MS model 

compounds 

Brain tissue Modified headspace (full Capillary 0.038 nmoles/ 80–120 Schuberth 1996 

(post evaporation technique) GC-ITD sample 

mortem) 

Fat tissue Add saline; freeze; thaw GC/FID; No data No data Wolff et al. 1977 

to 0 °C prior to analysis; confirmation 

add CS2; inject into GC GC/MS 

Adipose Purge and trap Capillary No data 13–80 for Michael et al. 1980 

tissue GC/MS halogenated hydrocarbons 

Breath Collection via spirometer Capillary low μg/m3 77–82 Thomas et al. 1991 

into passivated canisters GC/MS levels 
 

 

 

 

 

ETHYLBENZENE 201 

7. ANALYTICAL METHODS 

Table 7-1. Analytical Methods for Determining Ethylbenzene in Biological
 

Samples
 

Sample Analytical Sample Percent 

matrix Preparation method method detection limit recovery Reference 

Breath Collection via spirometer Capillary 0.2 μg/m3 No data Riedel et al. 1996 

onto charcoal traps; GC/MS-SIM (1 L sampled) 

microwave desorption 

FID = flame ionization detector; GC = gas chromatography; HPLC = high performance liquid chromatography; 

ITD = ion trap detector; MS = mass spectrometry; SIM = selected ion monitoring 
 

 

 

 

 

 

ETHYLBENZENE 202 

7. ANALYTICAL METHODS 

A spirometer is usually used for the collection of breath samples. The device is used to provide clean air 

for inhalation and a mechanism for pumping exhaled breath into the collection media (Pellizzari et al. 

1985). The breath samples are collected into Tedlar bags with subsequent adsorption onto Tenax traps 

(Pellizzari et al. 1985) or into passivated stainless steel canisters (Thomas et al. 1991). The Tenax traps 

are analyzed by thermal desorption GC techniques, and canister samples are analyzed by GC as well. 

A sensitive and reliable method for identification and quantitation of ethylbenzene in samples of whole 

blood taken from humans following exposure to VOCs has been developed by Ashley and coworkers at 

the Centers for Disease Control and Prevention (Ashley et al. 1992, 1994). The method involves purgeand-trap of a 10-mL blood sample with analysis by capillary GC/MS. Anti-foam procedures were used, 

as well as special efforts to remove background levels of VOCs from reagents and equipment (Ashley et 

al. 1992). The method is sensitive enough (ppt levels) to determine background levels of VOCs in the 

population and provides adequate accuracy (114–118% recovery) and precision (16–44% relative 

standard deviation [RSD]) for monitoring ethylbenzene in the population. Using GC/FID to analyze 

capillary blood samples, Janasik et al. (2008) achieved a detection limit of 2.7 μg/L for ethylbenzene.

Few methods are available for the determination of ethylbenzene in body fluids and tissues other than 

blood. A modified dynamic headspace method for determination of ethylbenzene in urine, mother's milk, 

and adipose tissue has been reported (Michael et al. 1980). Volatiles swept from the sample are analyzed 

by capillary GC/FID. Acceptable recovery was reported for model compounds, but detection limits were 

not reported (Michael et al. 1980). Ethylbenzene in brain tissue may be determined using a headspace, 

capillary/ion trap detector (ITD) technique (Schuberth 1996). Recovery was good (80–120%) as was 

precision (≈20% RSD); the detection limit was reported as 4 ng/sample (0.038 nmoles) (Schuberth 1996). 

Janasik et al. (2008) achieved a detection limit of 0.48 μg/L for detection of ethylbenzene in urine using

GC/FID. Biological monitoring for exposure to VOCs can also be based on identification of metabolites 

in urine, as analyzed by GC (Janasik et al. (2008). Sensitive, reliable methods are available for measuring 

ethylbenzene in breath. Exhaled breath is collected using a spirometer. The exhaled breath is collected 

into Tedlar bags for later transfer to adsorption tubes (Wallace et al. 1982), into passivated canisters 

(Thomas et al. 1991), or directly onto adsorbent traps (Riedel et al. 1996). The spirometer system, using 

adsorption onto Tenax traps and analysis by thermal desorption/capillary GC/MS techniques, was fieldtested over the course of a very large exposure study (EPA 1987). The quantitation limit was ≈1 μg/m3

, 

recovery was 91–100%, and the precision for duplicate samples was ≤30% RSD (EPA 1987). Advances

in the methodology include development of a more compact system with collection in 1.8-L canisters 
 

 

 

 

 

 

ETHYLBENZENE 203 

7. ANALYTICAL METHODS 

(Thomas et al. 1992). Recovery of ethylbenzene is 92–104%, precision for duplicate samples is <3% 

RSD, and the detection limit was estimated as 3 μg/m3 for ethylbenzene (Thomas et al. 1992). 

7.2 ENVIRONMENTAL SAMPLES 

Methods are available for determining ethylbenzene in a variety of environmental matrices. A summary 

of representative methods is shown in Table 7-2. Validated methods, approved by agencies and 

organizations such as EPA, ASTM, APHA, and NIOSH, are available for air, water, and solid waste 

matrices. Gas chromatography is the most widely used analytical technique for quantifying 

concentrations of ethylbenzene in environmental matrices. Various detection devices used for GC include 

FID, MS, and the photoionization detector (PID). Because of the complexity of the sample matrix and the 

low concentration of VOCs in most environmental media, sample preconcentration is generally required 

prior to GC analysis. Air samples may be collected and concentrated on adsorbent or in canisters for 

subsequent analysis. Methods suitable for determining trace amounts of ethylbenzene in aqueous and 

other environmental media include three basic approaches to the pretreatment of the sample: gas purgeand-trap technique, headspace gas analysis, and extraction with organic solvent. 

Gas purge-and-trap is the most widely used method for the isolation and concentration of VOCs in 

environmental samples (Lesage 1993). The purge-and-trap technique offers advantages over other 

techniques in that it allows facile isolation and concentration of target compounds, thereby improving 

overall limits of detection and recovery of sample. Detection limits of <1 μg of ethylbenzene per liter of 

sample have been achieved (APHA 1995c; EPA 1984c, 1991b, 1992a). A serious drawback of this 

technique, particularly for quantitative analysis, is interference by impurities found in the stripping gas 

(EPA 1994c). 

A purge-and-trap method with GC/FID analysis (Otson and Williams 1982) or GC/MS (Otson and Chan 

1987) has been reported for the analysis and quantitation of ethylbenzene in environmental samples. 

Detection limits of <0.1 μg/L for GC/FID analysis and 0.1 μg/L were reported. Accuracy was also good,

74–88% (Otson and Chan 1987; Otson and Williams 1982). 

Extraction with organic solvents (liquid-liquid extraction) provides a simple, rapid screening method for 

semi-quantitative determination of ethylbenzene in aqueous samples containing limited number of VOCs, 

but is less effective for aqueous samples containing large numbers of VOCs. Furthermore, interference 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 204 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Ethylbenzene in Environmental
 

Samples
 

Analytical Sample Percent 

Sample matrix Preparation method method detection limit recovery Reference 

Occupational air Collection on charcoal GC/FID 0.001– Bias -7.6% NIOSH 1994a 

adsorbent tube; 

desorption with CS2 

0.01 mg/ 

samplea (NIOSH Method 

1501) 

Occupational air Organic vapor passive GC/MS 0.01 ppm No data Bratveit et al. 

dosimeter badges; 2007 

desorbed using CS2 

Ambient air Collection on Tenax 

adsorbent; thermal 

Capillary 

GC/MS 

20 ng 

estimateda 

No data EPA 1988a 

(Method TO-1) 

desorption 

Ambient air Collection in passivated Capillary No data No data EPA 1988b 

stainless steel canisters GC/MS or 

PID or FID 

(Method TO-14) 

Ambient air Collection on Tenax Capillary 2 nga No data Pellizzari et al. 

adsorbent; thermal GC/MS 1993 

desorption (IARC Method 6) 

Ambient air Collection in canisters GC/MS 0.2 ppbv bias -8.1% McClenny and 

Fortune 1995 

(CLP Method) 

Ambient air Collection on Capillary 0.036 ppbv 102 Oliver et al. 

multisorbent traps; GC/MS 1996 

automated 

preconcentration 

Ambient air Collection on Capillary 0.25 ppbv 98 Oliver et al. 

multisorbent traps; GC/FID 1996 

thermal desorption with 

modified cryofocussing 

Indoor air Collection on Tenax GC/MS 0.05–0.2 μg/m3 No data Kostianinen 

acsorbent; thermal 1995 

desorption 

In-vehicle air Collection on Tenax or Capillary No data No data Lawryk and 

multisorbent traps; GC/MS-SIM Weisel 1996 

thermal desorption 

Flue gas Collection on adsorbent Capillary 0.05 μg/m3 No data Jay and Steiglitz 

traps using probe; GC/FID (estimated) 1995 

thermal desorption 

Product Collection on charcoal Capillary No data No data Wadden et al. 

emissions traps; desorption with GC/FID 1995 

CS2 

Tobacco smoke Collection on fused-silica No data No data Barrefors and 

multisorbent traps; PLOT column Petersson 1993 

thermal desorption GC/MS 
 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 205 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Ethylbenzene in Environmental
 

Samples
 

Analytical Sample Percent 

Sample matrix Preparation method method detection limit recovery Reference 

Snow SPME using DVB­ GC/MS 0.20 μg/L No data Kos and Ariya 

coated PDMS fiber with 2006 

a film thickness of 

65 μm 

Drinking water Purge and trap GC/PID 0.01–0.04 μg/L 98–101 EPA 1991a 

(EPA Method 

502.2) 

Drinking water Purge and trap GC/PID; 0.002 μg/L 93 EPA 1991b 

confirmation 

on second 

column or 

(EPA Method 

503.1) 

GC/MS 

Drinking water Purge and trap GC/MS 1–2 μg/L No data EPA 1991c 

(EPA Method 

524.1) 

Drinking water Purge and trap Capillary 0.06 μg/L 96–99 EPA 1992a 

GC/MS (EPA Method 

524.2) 

Drinking water Purge and trap GC/FID or low μg/L 84–114 ASTM 1999b 

GC/MS (ASTM Method 

D 3871) 

Drinking water Direct injection GC/FID ~1 mg/L No data ASTM 1999a 

(ASTM Method 

D 2908) 

Waste water Purge and trap GC/PID; 0.2 μg/L 98 EPA 1984c 

confirmation 

on second 

column 

(EPA Method 

602) 

Waste water Purge and trap GC/MS 7.2 μg/L 100–103 EPA 1999 

(EPA Method 

624) 

Water Closed-loop stripping Capillary 50 ng/L No data APHA 1995a 

GC/MS (instrumental) (Method 6040B) 

Waste water Purge and trap GC/MS 7.2 μg/L APHA 1995b 

(Method 6210B) 

Waste water Purge and trap GC/PID; 0.2 μg/L 93 APHA 1995c 

confirmation 

on second 

(Method 6220B) 

column or 

GC/MS 

Waste water Purge and trap GC/PID 0.01–0.05 μg/L 93 APHA 1995d 

(Method 6220C) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 206 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Ethylbenzene in Environmental
 

Samples
 

Sample matrix Preparation method 

Analytical 

method 

Sample 

detection limit 

Percent 

recovery Reference 

Solid waste Direct injection or purge 

and trap 

Capillary 

GC/PID 

~1 μg/L (soil, 

sediment); 

~0.1 mg/kg 

(wastes) 

101 EPA 1994d 

(SW846 Method 

8021A) 

Solid waste Purge and trap Capillary 

GC/PID 

~1 μg/L (soil, 

sediment); 

~0.1 mg/kg 

(wastes) 

101 EPA 1995a 

9SW846 Method 

8021B, 

proposed) 

Solid waste Purge and trap Capillary 

GC/MS 

~5 μg/kg (soil, 

sediment) 

99 EPA 1994e 

(SW846 Method 

8260A) 

Solid waste Various options 

including purge and 

trap, headspace, closed 

system vacuum 

distillation 

Capillary 

GC/MS 

purge and trap: 

~5 μg/kg (soil 

and sediment); 

~0.5 mg/kg 

(wastes) 

90–112 

(purge and 

trap) 

EPA 1995b 

(SW846 Method 

8260B, 

proposed) 

Plant foliage Solvent extraction; 

filtration 

Capillary 

GC/SM-SIM 

50 pg/μL 

extract 

No data Keymeulen et al. 

1991 

Fish Solvent extraction; 

cleanup on florisil 

column; solvent 

microextraction 

GC/FID 5 μg/gb 98–102 Karasek et al. 

1987 

Fish and sediment Homogenization; 

freezing and vacuum 

extraction 

Capillary 

GC/MS 

25 ppbb Sediments, 

97 recovery; 

fish, 76% 

average for 

all analytes 

Hiatt 1981, 1983 

Eggs Headspace Capillary 

GC/PID; 

confirmation 

by GC/MS 

0.002 μg/mL 94 (white); 

49 (whole); 

21 (yolk) 

Stein and 

Narang 1990 

Fruits and 

vegetables 

Solvent extraction; 

filtration 

Capillary 

GC/MS-SIM 

No data No data Górna-Binkul et 

al. 1996 

Olives and olive 

oil 

Headspace Capillary 

GC/MS 

Low μg/kg 

levels 

No data Biedermann et 

al. 1995 
 

 

 

 

ETHYLBENZENE 207 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Ethylbenzene in Environmental
 

Samples
 

Sample matrix Preparation method 

Analytical 

method 

Sample 

detection limit 

Percent 

recovery Reference 

Cooked meat Azeotropic distillation 

using Kilens-Nickerson 

estractor 

Capillary 

GC/MS 

6 μg/kg No data Gramshaw and 

Vandenburg 

1995 

Food containers 

(polystyrene) 

Incubation with DMF; 

headspace 

Capillary 

GC/FID; 

confirmation 

10 ppm 96–102 Sugita et al. 

1995 

GC/MS 

a

Sample detection limit will depend upon volume sampled. Value is estimated instrumental detection limit.

b

Method detection limits were not provided; estimates cited are based on lowest concentrations used for method 

performance evaluation. 

CS2 = carbon disulfide; DMF = dimethylformamide; DVB = divinylbenzene; FID = flame ionization detector; GC = gas 

chromatography; MeOH = methanol; MS = mass spectrometry; PDMS = polydimethylsiloxane; PID = photoionization 

detector; PLOT = pourous-layer open tubular; SIM = selected ion monitoring; SPME = solid phase microextraction; 

UV = ultraviolet spectrophotometry 
 

 

 

 

 

 

 

 

 

ETHYLBENZENE 208 

7. ANALYTICAL METHODS 

from the organic extraction solvent (hexane) makes it more difficult to completely identify all 

components (Karasek et al. 1987; Otson and Williams 1981). 

Ethylbenzene may be determined in occupational air using collection on multisorbent cartridges, solvent 

desorption and analysis by GC/FID (NIOSH 1994a). Accuracy is very good (-7.6% bias); detection limits 

depend upon the amount of air sampled. Ambient air samples may also be collected on adsorbent traps 

(EPA 1988a; Pellizzari et al. 1993) or in stainless steel canisters (EPA 1988b; McClenny and Fortune 

1995). Recovery for Tenax traps is very good, ranging from 91 to 100% (EPA 1987), and detection limits 

of 0.01 ppm have been reported (Bratveil et al. 2007). Little information on accuracy is available for 

multisorbent traps, but good recovery (102%) has been reported (Oliver et al. 1996). Bias of -8.1% for 

canister collection has been reported (McClenny and Fortune 1995). Detection limits depend upon the 

amount of air sampled, but values in the sub-ppb range have been reported (Kostiainen 1995; McClenny 

and Fortune 1995; Oliver et al. 1996). Organic vapor passive dosimeter badges may be used to determine 

personal exposure; the hydrocarbons are desorbed and analyzed by GC with GC/MS. Detection levels of 

0.01 ppm for ethylbenzene have been reported (Bratveit et al. 2007). Purge-and-trap methodology is used 

most often for determination of ethylbenzene in water and hazardous wastes (Lesage 1993). The method 

was developed by Bellar and Lichtenberg (1974) for waste water. An inert gas is bubbled through the 

sample to strip out volatile components. The analytes in the gas stream are adsorbed onto sorbent traps, 

then thermally desorbed into the GC column. Very low detection limits for drinking water are reported 

for the purge-and-trap method with GC/PID (0.002–0.04 μg/L) (EPA 1991b). Accuracy is very good 

(93–101% recovery) (EPA 1991b). While the method is quite selective, confirmation using a second GC 

column or GC/MS is recommended (EPA 1991b). A sensitive (0.06 μg/L) and reliable method (96–99% 

recovery; <10% RSD) for drinking water uses capillary column GC/MS (EPA 1992a). Purge-and-trap 

methodology with analysis by GC/PID or GC/MS is used for waste waters (APHA 1995b, 1995c, 1995d; 

EPA 1984c, 1999). The detection limits are lower for GC/PID (0.2 μg/L) (EPA 1984c) than for GC/MS 

(7.2 μg/L) (EPA 1984b), but confirmation on a second column is recommended (EPA 1984c) when PID

is used. Recovery and precision are very good (98–103% recovery; ≤10% RSD) (EPA 1984c, 1999).

Soil, sediment, and solid waste samples are difficult to analyze. Volatilization during sample handling 

and homogenization can result in ethylbenzene losses. The wet sample is usually dispersed in a solvent, 

then added to water for purge-and-trap/GC analysis (EPA 1994c; Minnich et al. 1997) or analyzed by 

high performance liquid chromatography (HPLC) (Dawson et al. 2008). Capillary GC/PID or GC/MS 

analysis provides detection limits in the low ppb range for soil and sediment and in the sub-ppm range for 
 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 209 

7. ANALYTICAL METHODS 

solid wastes (EPA 1994d, 1994e, 1995a, 1995b). Minnich et al. (1997) reported detection limits as low as 

1.7 ng/g using the GC method. 

Few methods are available for the determination of ethylbenzene in fish and biota. A method for the 

determination of ethylbenzene in fish at low ppm levels using solvent extraction with GC/FID analysis 

has been reported (Karasek et al. 1987). A procedure to identify and quantify ethylbenzene in fish 

samples by vacuum distillation with capillary column GC/MS has been reported (Hiatt 1981, 1983). 

Recovery of 98–102% from spiked fish tissue was reported, but detection limits were not reported (Hiatt 

1981). Purge-and-trap/capillary GC/MS has also been used for the determination of ethylbenzene in fish. 

Performance data for fish tissue samples were not reported (Dreisch and Munson 1983). 

Few methods are available for the determination of ethylbenzene in food. Available methods involve 

solvent extraction (Górna-Binkul et al. 1996), headspace purge (Biedermann et al. 1995), and azeotropic 

distillation (Gramshaw and Vandenburg 1995) followed by capillary GC/MS or GC/PID analysis. 

Detection limits are in the low μg/kg range (Biedermann et al. 1995; Gramshaw and Vandenburg 1995).

Little performance data are available. Recoveries from 21% (egg yolk) to 94% (egg white) were reported 

for headspace/capillary GC/PID analysis of eggs (Stein and Narang 1990). 

Screening methods and field-portable methods may be useful analytical tools. Soil screening for 

petroleum hydrocarbons, including ethylbenzene, can be conducted using immunoassay procedures (EPA 

1995e). Sensitivity is in the ppm range. Solid phase microextraction (SPME) has been tested as a 

screening method for water (Shirey 1995). The method is used in conjunction with capillary GC 

techniques. Portable GCs have been used for field monitoring of air (Berkley et al. 1991), water (Driscoll 

and Atwood 1993), soil (Driscoll and Atwood 1993), and hazardous waste (Overton et al. 1995). There 

are several studies that compare portable GC methods with laboratory methods (Berkley et al. 1991; 

Driscoll and Atwood 1993). 

7.3 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of ethylbenzene is available. Where adequate information is 

not available, ATSDR, in conjunction with NTP, is required to assure the initiation of a program of 
 

 

 

 

ETHYLBENZENE 210 

7. ANALYTICAL METHODS 

research designed to determine the health effects (and techniques for developing methods to determine 

such health effects) of ethylbenzene. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

7.3.1 Identification of Data Needs 

Methods for Determining Biomarkers of Exposure and Effect. 

Exposure. Exposure to ethylbenzene can be determined by the detection of mandelic acid and 

phenylglycolic acid in urine or by direct detection of ethylbenzene in human blood. Environmental 

exposures to ethylbenzene can result in detectable levels in human tissues. Existing methods for the 

determination of ethylbenzene in blood have the sensitivity necessary (0.008–0.012 ppb) (Ashley et al. 

1992) to detect and measure low to trace levels of ethylbenzene in blood that might be present in the 

general population, as well as concentrations of ethylbenzene that might be associated with specific health 

effects. Methods for measurement of ethylbenzene in exhaled breath are sensitive enough (low μg/m3

) 

(Thomas et al. 1991) to provide background levels of ethylbenzene in the general population as well as to 

measure exposure. Additional performance information would be helpful, as would further development 

of a portable breath collection system. Information on levels of ethylbenzene in tissues is limited and the 

existing methods are not as well characterized. Improvements in the sensitivity of the methods for 

measuring concentrations of ethylbenzene in tissues and additional performance data would be helpful. 

Methods for measuring metabolites and biomarkers for ethylbenzene are shown in Table 7-3. Methods 

exist for measuring ppm levels of ethylbenzene metabolites in urine (Ogata and Taguchi 1987, 1988; 

Sollenberg et al. 1985). They are sufficiently sensitive for measuring occupational exposure to 

ethylbenzene. These analytical methods are reliable and precise, but may not be sensitive enough to 

measure non-occupational exposure. Improvements in the sensitivity of the methods for measuring 

concentrations of ethylbenzene in tissues, and improvements in the sensitivity for measurement of 

metabolites in urine would allow better assessment of the correlation between levels in these media and 

observed health effects. 
 

 

 

 

 

 

 

 

 

ETHYLBENZENE 211 

7. ANALYTICAL METHODS 

Table 7-3. Analytical Methods for Determining Biomarkers of Ethylbenzene in 

Biological Materials
 

Sample Analytical Sample detection Accuracy permatrix Sample preparation method limit cent recovery Reference 

Urine (MA) Dilution; centrifugation HPLC/UV MA 5 ng injected MA 100–102 Ogata and 

Taguchi 1988 

Urine (MA MeOH addition; HPLC PGA 8.5x103 μg/L PGA 101 Ogata and 

and PGA) centrifugation MA 10x103 μg/L MA 102.6 Taguchi 1987 

Urine (MA 

and PGA) 

Filtration; solvent 

extraction; evaporation 

HPLC/UV MA, PGA 

1.5x103 μg/L 

No data Sollenberg et al. 

1985 

and dissolution 

Urine (MA 

and PGA) 

Filtration; solvent 

extraction; evaporation 

ITP MA 6.1x103 μg/L 

PGA 3.0x103 μg/L 

No data Sollenberg et al. 

1985 

and dissolution 

HPLC = high performance liquid chromatography; ITP = isotachophoresis; MA = mandelic acid; 

PGA = phenylglyoxylic acid; UV = ultraviolet (detection) 
 

 

 

 

 

ETHYLBENZENE 212 

7. ANALYTICAL METHODS 

Effect. No specific biomarkers of effect for ethylbenzene were identified. 

Methods for Determining Parent Compounds and Degradation Products in Environmental 

Media. Sensitive methods are available for measuring background levels of ethylbenzene in air, water, 

and wastes, the media of most concern for exposure of the general population and those populations 

located near hazardous waste sites. Few methods are available for measuring levels of ethylbenzene in 

fish, plants and biota. Detection limits in the low ppb range have been reported (Dreisch and Munson 

1983; Hiatt 1981; Karasek et al. 1987; Keymeulen et al. 1991), but other performance data are generally 

lacking. Few methods are available for measuring levels of ethylbenzene in food. Little performance 

data are available for the available methods. Although several good analytical methods are available for 

detecting ethylbenzene in some environmental media, validated, reliable methods for measuring 

ethylbenzene in fish and foods are needed. These would be helpful in evaluating the potential for human 

exposure and health effects that might result from ethylbenzene contamination. 

Methods for detecting environmental degradation products of ethylbenzene in environmental media are 

summarized in Table 7-4. Although methods are available for detecting major environmental degradation 

products (1-phenylethanol, acetophenone, benzaldehyde, for example) in reaction mixtures, it is not 

known whether these methods have the sensitivity and specificity for application to environmental media. 

Sensitive, reliable methods for determining degradation products in air, water, and waste would be 

helpful. 

7.3.2 Ongoing Studies 

The Environmental Health Laboratory Sciences Division of the National Center for Environmental 

Health, Centers for Disease Control and Prevention, is developing methods for the analysis of 

ethylbenzene and other volatile organic compounds in blood. These methods use purge and trap 

methodology, high-resolution gas chromatography, and magnetic sector mass spectrometry, which give 

detection limits in the low ppt range. 
 

 

ETHYLBENZENE 213 

7. ANALYTICAL METHODS 

Table 7-4. Analytical Methods for Determining Environmental Degradation 

Products of Ethylbenzene
 

Sample 

matrix Preparation method 

Analytical 

method 

Sample 

detection limit 

Accuracy percent recovery Reference 

Reaction 

mixtures 

Solvent extraction; 

concentration 

Capillary 

GC/FID 

No data No data Ehrhardt and 

Petrick 1984 

Reaction 

mixtures 

Centrifugation; solvent 

extraction; 

concentration 

GC/FID; 

confirmation 

GC/MS 

No data No data Fukuda et al. 1989 

FID = flame ionization detector; GC = gas chromatography; MS = mass spectrometry 
ETHYLBENZENE 214 

7. ANALYTICAL METHODS 

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ETHYLBENZENE 215 

8. REGULATIONS, ADVISORIES, AND GUIDELINES 

MRLs are substance specific estimates, which are intended to serve as screening levels, are used by 

ATSDR health assessors and other responders to identify contaminants and potential health effects that 

may be of concern at hazardous waste sites. 

ATSDR has derived an acute-duration inhalation MRL of 5 ppm for ethylbenzene based on a BMCL for 

auditory threshold shifts observed in rats exposed to ethylbenzene 8 hours/day for 5 days (Cappaert et al. 

2000). The BMCL was estimated using an internal dose metric to simulate time averaged arterial blood 

concentration of ethylbenzene; a human equivalent concentration (HEC) of the BMCL was estimated 

using a human PBPK model. This BMCLHEC of 154.26 ppm was divided by an uncertainty factor of 

30 (3 for animal to human extrapolation with dosimetric adjustment and 10 for human variability). 

ATSDR has derived an intermediate-duration inhalation MRL of 2 ppm for ethylbenzene based on a 

BMCL for auditory threshold shifts observed in rats exposed to ethylbenzene 6 hours/day, 6 days/week 

for 4–13 weeks (Gagnaire et al. 2007). The BMCL was estimated using an internal dose metric to 

simulate time averaged arterial blood concentration of ethylbenzene; a HEC of the BMCL was estimated 

using a human PBPK model. This BMCLHEC of 63.64 ppm divided by an uncertainty factor of 30 (3 for 

animal to human extrapolation with dosimetric adjustment and 10 for human variability). 

ATSDR has derived a chronic-duration inhalation MRL of 0.06 ppm for ethylbenzene based on a LOAEL 

for a significant increase in the severity of nephropathy in female rats exposed to ethylbenzene by 

inhalation for 6 hours/day, 5 days/week for 104 weeks (NTP 1999). Using a PBPK model, an internal 

dose metric (time averaged arterial blood concentration of ethylbenzene, MCA) of the LOAEL of 75 ppm 

was simulated. The HEC of this LOAELMCA (17.45 ppm) was divided an uncertainty factor of 300 

(10 for use of a LOAEL, 3 for animal to human extrapolation with dosimetric adjustment, and 10 for 

human variability). 

The EPA inhalation reference concentration (RfC) (verified in 1991) for ethylbenzene is 1 mg/m3 

(equivalent to 0.23 ppm), based on developmental toxicity seen in rats and rabbits exposed to 

4,340 mg/m3

 (Hardin et al. 1981; IRIS 2007; NIOSH 1981). 

ATSDR has derived an intermediate-duration oral MRL of 0.4 mg/kg/day for ethylbenzene based on a 

BMDL for hepatotoxicity (centrilobular hepatocyte hypertrophy) in male rats exposed to ethylbenzene by 
ETHYLBENZENE 216 

8. REGULATIONS, ADVISORIES, AND GUIDELINES 

gavage for 13 weeks (Mellert et al. 2007). The BMDL was estimated using an internal dose metric to 

simulate time averaged liver concentrations of ethylbenzene; a HED of the BMDL was estimated using a 

human PBPK model. This BMDLHED of 10.68 mg/kg/day was divided by an uncertainty factor of 30 

(3 for animal to human extrapolation with dosimetric adjustment and 10 for human variability). 

The EPA oral reference dose (RfD) for ethylbenzene is 0.1 mg/kg/day, based on the LOAEL for liver and 

kidney toxicity in rats administered 291 mg/kg/day ethylbenzene via gavage 5 days/week for 182 days 

(Wolf et al. 1956). The RfD was calculated by dividing the NOAEL of 97 mg/kg/day by an uncertainty 

factor of 1,000 (10 for use of a subchronic study, 10 for interspecies extrapolation, and 10 for intraspecies 

variability). 

The international and national regulations, advisories, and guidelines regarding ethylbenzene in air, water, 

and other media are summarized in Table 8-1. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 217 

8. REGULATIONS, ADVISORIES, AND GUIDELINES 

Table 8-1. Regulations, Advisories, and Guidelines Applicable to Ethylbenzene 

Agency Description Information Reference 

INTERNATIONAL 

Guidelines: 

IARC Carcinogenicity classification Group 2Ba IARC 2006 

WHO Air quality guidelines 

Drinking water quality guidelines 

No data 

0.3 mg/Lb 

WHO 2000 

WHO 2004 

NATIONAL 

Regulations and 

Guidelines: 

a. Air 

ACGIH TLV (8-hour TWA) 100 ppm ACGIH 2006 

STEL (15-minute TWA) 125 ppm 

EPA AEGL-1, -2, -3 No data EPA 2007a 

Hazardous air pollutant Yes EPA 2007c 

42 USC 7412 

NIOSH REL (10-hour TWA) 100 ppm NIOSH 2005 

STEL (15-minute TWA) 125 ppm 

IDLH 800 ppm 

OSHA PEL (8-hour TWA) for general industry 100 ppm OSHA 2006c 

29 CFR 1910.1000 

PEL (8-hour TWA) for shipyard industry 100 ppm OSHA 2006a 

29 CFR 1915.1000 

PEL (8-hour TWA) for construction 

industry 

100 ppm OSHA 2006b 

29 CFR 1926.55, 

Appendix A 

b. Water 

EPA Designated as hazardous substances 

in accordance with Section 311(b)(2)(A) 

of the Clean Water Act 

Yes EPA 2007b 

40 CFR 116.4 

Designated as a toxic pollutant 

pursuant to Section 307(a)(1) of the 

Clean Water Act 

Yes EPA 2007g 

40 CFR 401.15 

Drinking water standards and health 

advisories 

EPA 2006a 

1-Day health advisory for a 10-kg 

child 

30 mg/L 

10-Day health advisory for a 10-kg 

child 

3 mg/L 

DWEL 3 mg/L 

Lifetime 

10-4 Cancer risk 

0.7 mg/L 

No data 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 218 

8. REGULATIONS, ADVISORIES, AND GUIDELINES 

Table 8-1. Regulations, Advisories, and Guidelines Applicable to Ethylbenzene 

Agency Description Information Reference 

NATIONAL (cont.) 

EPA National primary drinking water 

standards 

EPA 2003 

MCLG 0.7 mg/L 

MCL 0.7 mg/Lc 

Public health goal 0.7 mg/L 

Reportable quantities of hazardous 

substances designated pursuant to 

Section 311 of the Clean Water Act 

1,000 pounds EPA 2007d 

40 CFR 117.3 

Water quality criteria for human health 

consumption of: 

EPA 2006b 

Water + organism 0.53 mg/L 

Organism only 2.1 mg/L 

c. Food 

EPA Inert pesticide ingredients in pesticide 

products 

List 2d EPA 2004 

FDA Bottled water requirement 0.7 mg/L FDA 2006a 

21 CFR 165.110 

EAFUS No data FDA 2007b 

d. Other 

ACGIH Carcinogenicity classification A3e 

Biological exposure indices (end of shift 

at end of workweek); sum of mandelic 

acid and phenyl glyoxylic acid in urine 

1.5 g/g creatininef 

ACGIH 2006 

EPA Carcinogenicity classification Class Dg IRIS 2007 

Oral slope factor No data 

Inhalation unit risk No data 

RfC 1 mg/m3 

RfD 

Master Testing List 

0.1 mg/kg/day 

Yesh EPA 2007j 

Superfund, emergency planning, and 

community right-to-know 

Designated CERCLA hazardous 

substance 

Yesi EPA 2007e 

40 CFR 302.4 

Reportable quantity 1,000 pounds 

Effective date of toxic chemical 

release reporting 

01/01/87 EPA 2007f 

40 CFR 372.65 

TSCA health and safety data reporting 

requirements 

Yes EPA 2007h 

40 CFR 716.120 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE 219 

8. REGULATIONS, ADVISORIES, AND GUIDELINES 

Table 8-1. Regulations, Advisories, and Guidelines Applicable to Ethylbenzene 

Agency Description Information Reference 

NATIONAL (cont.) 

NTP Carcinogenicity classification No data NTP 2005 

a

Group 2B: possibly carcinogenic to humans 

b

Concentrations of the substance at or below the health based guideline value may affect the appearance, taste, or 

odor of the water, leading to consumer complaints. 

c

Potential health effects from exposure above the MCL include liver or kidneys problems; and the common sources of 

contaminant in drinking water is from the discharge from petroleum refineries.

d

List 2: potentially toxic other ingredients and high priority for testing inerts 

e

A3: confirmed animal carcinogen with unknown relevance to humans 

f

ACGIH (2006) has submitted notice of intended changes for ethylbenzene in which the BEI will be lowered to 

0.7 g/g creatinine. g

Class D: not classifiable as to human carcinogenicity 

h

Ethylbenzene was recommended to the Master Testing List (MTL) by the U.S. EPA’s Office of Pollution Prevention 

and Toxics on the basis of the Screening Information Data Sets (SIDS). Styrene was added to the MTL in 1993 and 

the chemical testing program is currently underway by way of a VTA. The testing needs include health effects, 

environmental effects, and environmental fate and exposure. The Office of Air and Radiation recommended 

ethylbenzene to the MTL in 1995 on the basis that ethylbenzene is a hazardous air pollutant. EPA is in the process 

of determining the testing needs for the following: acute toxicity, neurotoxicity, developmental toxicity, reproductive, 

and immunotoxicity

i

Designated CERCLA hazardous substance pursuant to Section 311(b)(2) and Section 307(a) of the Clean Water and 

Section 112 of the Clean Air Act. 

ACGIH = American Conference of Governmental Industrial Hygienists; AEGL = Acute Exposure Guideline Levels; 

BEI = biological exposure indices; CERCLA = Comprehensive Environmental Response, Compensation, and Liability 

Act; CFR = Code of Federal Regulations; DWEL = drinking water equivalent level; EAFUS = Everything Added to 

Food in the United States; EPA = Environmental Protection Agency; FDA = Food and Drug Administration; 

IARC = International Agency for Research on Cancer; IDLH = immediately dangerous to life or health; 

IRIS = Integrated Risk Information System; MCL = maximum contaminant level; MCLG = maximum contaminant level 

goal; NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program; 

OSHA = Occupational Safety and Health Administration; PEL = permissible exposure limit; REL = recommended 

exposure limit; RfC = inhalation reference concentration; RfD = oral reference dose; STEL = short-term expsoure 

limit; TLV = threshold limit values; TSCA = Toxic Substances Control Act; TWA = time-weighted average; 

USC = United States Code; WHO = World Health Organization 
ETHYLBENZENE 220 

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10. GLOSSARY 

Absorption—The taking up of liquids by solids, or of gases by solids or liquids. 

Acute Exposure—Exposure to a chemical for a duration of 14 days or less, as specified in the 

Toxicological Profiles. 

Adsorption—The adhesion in an extremely thin layer of molecules (as of gases, solutes, or liquids) to the 

surfaces of solid bodies or liquids with which they are in contact. 

Adsorption Coefficient (Koc)—The ratio of the amount of a chemical adsorbed per unit weight of 

organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium. 

Adsorption Ratio (Kd)—The amount of a chemical adsorbed by sediment or soil (i.e., the solid phase) 

divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a 

fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or 

sediment. 

Benchmark Dose (BMD)—Usually defined as the lower confidence limit on the dose that produces a 

specified magnitude of changes in a specified adverse response. For example, a BMD10 would be the 

dose at the 95% lower confidence limit on a 10% response, and the benchmark response (BMR) would be 

10%. The BMD is determined by modeling the dose response curve in the region of the dose response 

relationship where biologically observable data are feasible. 

Benchmark Dose Model—A statistical dose-response model applied to either experimental toxicological 

or epidemiological data to calculate a BMD. 

Bioconcentration Factor (BCF)—The quotient of the concentration of a chemical in aquatic organisms 

at a specific time or during a discrete time period of exposure divided by the concentration in the 

surrounding water at the same time or during the same period. 

Biomarkers—Broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers of susceptibility. 

Cancer Effect Level (CEL)—The lowest dose of chemical in a study, or group of studies, that produces 

significant increases in the incidence of cancer (or tumors) between the exposed population and its 

appropriate control. 

Carcinogen—A chemical capable of inducing cancer. 

Case-Control Study—A type of epidemiological study that examines the relationship between a 

particular outcome (disease or condition) and a variety of potential causative agents (such as toxic 

chemicals). In a case-controlled study, a group of people with a specified and well-defined outcome is 

identified and compared to a similar group of people without outcome. 

Case Report—Describes a single individual with a particular disease or exposure. These may suggest 

some potential topics for scientific research, but are not actual research studies. 

Case Series—Describes the experience of a small number of individuals with the same disease or 

exposure. These may suggest potential topics for scientific research, but are not actual research studies. 
 

 

 

 

ETHYLBENZENE 256 

10. GLOSSARY 

Ceiling Value—A concentration of a substance that should not be exceeded, even instantaneously. 

Chronic Exposure—Exposure to a chemical for 365 days or more, as specified in the Toxicological 

Profiles. 

Cohort Study—A type of epidemiological study of a specific group or groups of people who have had a 

common insult (e.g., exposure to an agent suspected of causing disease or a common disease) and are 

followed forward from exposure to outcome. At least one exposed group is compared to one unexposed 

group. 

Cross-sectional Study—A type of epidemiological study of a group or groups of people that examines 

the relationship between exposure and outcome to a chemical or to chemicals at one point in time. 

Data Needs—Substance-specific informational needs that if met would reduce the uncertainties of human 

health assessment. 

Developmental Toxicity—The occurrence of adverse effects on the developing organism that may result 

from exposure to a chemical prior to conception (either parent), during prenatal development, or 

postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point 

in the life span of the organism. 

Dose-Response Relationship—The quantitative relationship between the amount of exposure to a 

toxicant and the incidence of the adverse effects. 

Embryotoxicity and Fetotoxicity—Any toxic effect on the conceptus as a result of prenatal exposure to 

a chemical; the distinguishing feature between the two terms is the stage of development during which the 

insult occurs. The terms, as used here, include malformations and variations, altered growth, and in utero 

death. 

Environmental Protection Agency (EPA) Health Advisory—An estimate of acceptable drinking water 

levels for a chemical substance based on health effects information. A health advisory is not a legally 

enforceable federal standard, but serves as technical guidance to assist federal, state, and local officials. 

Epidemiology—Refers to the investigation of factors that determine the frequency and distribution of 

disease or other health-related conditions within a defined human population during a specified period. 

Genotoxicity—A specific adverse effect on the genome of living cells that, upon the duplication of 

affected cells, can be expressed as a mutagenic, clastogenic, or carcinogenic event because of specific 

alteration of the molecular structure of the genome. 

Half-life—A measure of rate for the time required to eliminate one half of a quantity of a chemical from 

the body or environmental media. 

Immediately Dangerous to Life or Health (IDLH)—The maximum environmental concentration of a 

contaminant from which one could escape within 30 minutes without any escape-impairing symptoms or 

irreversible health effects. 

Immunologic Toxicity—The occurrence of adverse effects on the immune system that may result from 

exposure to environmental agents such as chemicals. 
 

 

 

ETHYLBENZENE 257 

10. GLOSSARY 

Immunological Effects—Functional changes in the immune response. 

Incidence—The ratio of individuals in a population who develop a specified condition to the total 

number of individuals in that population who could have developed that condition in a specified time 

period. 

Intermediate Exposure—Exposure to a chemical for a duration of 15–364 days, as specified in the 

Toxicological Profiles. 

In Vitro—Isolated from the living organism and artificially maintained, as in a test tube. 

In Vivo—Occurring within the living organism. 

Lethal Concentration(LO) (LCLO)—The lowest concentration of a chemical in air that has been reported 

to have caused death in humans or animals. 

Lethal Concentration(50) (LC50)—A calculated concentration of a chemical in air to which exposure for 

a specific length of time is expected to cause death in 50% of a defined experimental animal population. 

Lethal Dose(LO) (LDLO)—The lowest dose of a chemical introduced by a route other than inhalation that 

has been reported to have caused death in humans or animals. 

Lethal Dose(50) (LD50)—The dose of a chemical that has been calculated to cause death in 50% of a 

defined experimental animal population. 

Lethal Time(50) (LT50)—A calculated period of time within which a specific concentration of a chemical 

is expected to cause death in 50% of a defined experimental animal population. 

Lowest-Observed-Adverse-Effect Level (LOAEL)—The lowest exposure level of chemical in a study, 

or group of studies, that produces statistically or biologically significant increases in frequency or severity 

of adverse effects between the exposed population and its appropriate control. 

Lymphoreticular Effects—Represent morphological effects involving lymphatic tissues such as the 

lymph nodes, spleen, and thymus. 

Malformations—Permanent structural changes that may adversely affect survival, development, or 

function. 

Minimal Risk Level (MRL)—An estimate of daily human exposure to a hazardous substance that is 

likely to be without an appreciable risk of adverse noncancer health effects over a specified route and 

duration of exposure. 

Modifying Factor (MF)—A value (greater than zero) that is applied to the derivation of a Minimal Risk 

Level (MRL) to reflect additional concerns about the database that are not covered by the uncertainty 

factors. The default value for a MF is 1. 

Morbidity—State of being diseased; morbidity rate is the incidence or prevalence of disease in a specific 

population. 

Mortality—Death; mortality rate is a measure of the number of deaths in a population during a specified 

interval of time. 
 

 

 

ETHYLBENZENE 258 

10. GLOSSARY 

Mutagen—A substance that causes mutations. A mutation is a change in the DNA sequence of a cell’s 

DNA. Mutations can lead to birth defects, miscarriages, or cancer. 

Necropsy—The gross examination of the organs and tissues of a dead body to determine the cause of 

death or pathological conditions. 

Neurotoxicity—The occurrence of adverse effects on the nervous system following exposure to a 

chemical. 

No-Observed-Adverse-Effect Level (NOAEL)—The dose of a chemical at which there were no 

statistically or biologically significant increases in frequency or severity of adverse effects seen between 

the exposed population and its appropriate control. Effects may be produced at this dose, but they are not 

considered to be adverse. 

Octanol-Water Partition Coefficient (Kow)—The equilibrium ratio of the concentrations of a chemical 

in n-octanol and water, in dilute solution. 

Odds Ratio (OR)—A means of measuring the association between an exposure (such as toxic substances 

and a disease or condition) that represents the best estimate of relative risk (risk as a ratio of the incidence 

among subjects exposed to a particular risk factor divided by the incidence among subjects who were not 

exposed to the risk factor). An OR of greater than 1 is considered to indicate greater risk of disease in the 

exposed group compared to the unexposed group. 

Organophosphate or Organophosphorus Compound—A phosphorus-containing organic compound 

and especially a pesticide that acts by inhibiting cholinesterase. 

Permissible Exposure Limit (PEL)—An Occupational Safety and Health Administration (OSHA) 

allowable exposure level in workplace air averaged over an 8-hour shift of a 40-hour workweek. 

Pesticide—General classification of chemicals specifically developed and produced for use in the control 

of agricultural and public health pests. 

Pharmacokinetics—The dynamic behavior of a material in the body, used to predict the fate 

(disposition) of an exogenous substance in an organism. Utilizing computational techniques, it provides 

the means of studying the absorption, distribution, metabolism, and excretion of chemicals by the body. 

Pharmacokinetic Model—A set of equations that can be used to describe the time course of a parent 

chemical or metabolite in an animal system. There are two types of pharmacokinetic models: data-based 

and physiologically-based. A data-based model divides the animal system into a series of compartments, 

which, in general, do not represent real, identifiable anatomic regions of the body, whereas the 

physiologically-based model compartments represent real anatomic regions of the body. 

Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically based doseresponse model that quantitatively describes the relationship between target tissue dose and toxic end 

points. These models advance the importance of physiologically based models in that they clearly 

describe the biological effect (response) produced by the system following exposure to an exogenous 

substance. 
 

 

 

 

 

 

 

 

 

ETHYLBENZENE 259 

10. GLOSSARY 

Physiologically Based Pharmacokinetic (PBPK) Model—Comprised of a series of compartments 

representing organs or tissue groups with realistic weights and blood flows. These models require a 

variety of physiological information: tissue volumes, blood flow rates to tissues, cardiac output, alveolar 

ventilation rates, and possibly membrane permeabilities. The models also utilize biochemical 

information, such as air/blood partition coefficients, and metabolic parameters. PBPK models are also 

called biologically based tissue dosimetry models. 

Prevalence—The number of cases of a disease or condition in a population at one point in time. 

Prospective Study—A type of cohort study in which the pertinent observations are made on events 

occurring after the start of the study. A group is followed over time. 

q1*—The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the 

multistage procedure. The q1* can be used to calculate an estimate of carcinogenic potency, the 

incremental excess cancer risk per unit of exposure (usually μg/L for water, mg/kg/day for food, and 

μg/m3 for air). 

Recommended Exposure Limit (REL)—A National Institute for Occupational Safety and Health 

(NIOSH) time-weighted average (TWA) concentration for up to a 10-hour workday during a 40-hour 

workweek. 

Reference Concentration (RfC)—An estimate (with uncertainty spanning perhaps an order of 

magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups) 

that is likely to be without an appreciable risk of deleterious noncancer health effects during a lifetime. 

The inhalation reference concentration is for continuous inhalation exposures and is appropriately 

expressed in units of mg/m3 or ppm. 

Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of the 

daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious 

effects during a lifetime. The RfD is operationally derived from the no-observed-adverse-effect level 

(NOAEL, from animal and human studies) by a consistent application of uncertainty factors that reflect 

various types of data used to estimate RfDs and an additional modifying factor, which is based on a 

professional judgment of the entire database on the chemical. The RfDs are not applicable to 

nonthreshold effects such as cancer. 

Reportable Quantity (RQ)—The quantity of a hazardous substance that is considered reportable under 

the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). Reportable 

quantities are (1) 1 pound or greater or (2) for selected substances, an amount established by regulation 

either under CERCLA or under Section 311 of the Clean Water Act. Quantities are measured over a 

24-hour period. 

Reproductive Toxicity—The occurrence of adverse effects on the reproductive system that may result 

from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related 

endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior, 

fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of 

this system. 

Retrospective Study—A type of cohort study based on a group of persons known to have been exposed 

at some time in the past. Data are collected from routinely recorded events, up to the time the study is 

undertaken. Retrospective studies are limited to causal factors that can be ascertained from existing 

records and/or examining survivors of the cohort. 
 

 

 

 

ETHYLBENZENE 260 

10. GLOSSARY 

Risk—The possibility or chance that some adverse effect will result from a given exposure to a chemical. 

Risk Factor—An aspect of personal behavior or lifestyle, an environmental exposure, or an inborn or 

inherited characteristic that is associated with an increased occurrence of disease or other health-related 

event or condition. 

Risk Ratio—The ratio of the risk among persons with specific risk factors compared to the risk among 

persons without risk factors. A risk ratio greater than 1 indicates greater risk of disease in the exposed 

group compared to the unexposed group. 

Short-Term Exposure Limit (STEL)—The American Conference of Governmental Industrial 

Hygienists (ACGIH) maximum concentration to which workers can be exposed for up to 15 minutes 

continually. No more than four excursions are allowed per day, and there must be at least 60 minutes 

between exposure periods. The daily Threshold Limit Value-Time Weighted Average (TLV-TWA) may 

not be exceeded. 

Standardized Mortality Ratio (SMR)—A ratio of the observed number of deaths and the expected 

number of deaths in a specific standard population. 

Target Organ Toxicity—This term covers a broad range of adverse effects on target organs or 

physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited 

exposure to those assumed over a lifetime of exposure to a chemical. 

Teratogen—A chemical that causes structural defects that affect the development of an organism. 

Threshold Limit Value (TLV)—An American Conference of Governmental Industrial Hygienists 

(ACGIH) concentration of a substance to which most workers can be exposed without adverse effect. 

The TLV may be expressed as a Time Weighted Average (TWA), as a Short-Term Exposure Limit 

(STEL), or as a ceiling limit (CL). 

Time-Weighted Average (TWA)—An allowable exposure concentration averaged over a normal 8-hour 

workday or 40-hour workweek. 

Toxic Dose(50) (TD50)—A calculated dose of a chemical, introduced by a route other than inhalation, 

which is expected to cause a specific toxic effect in 50% of a defined experimental animal population. 

Toxicokinetic—The absorption, distribution, and elimination of toxic compounds in the living organism. 

Uncertainty Factor (UF)—A factor used in operationally deriving the Minimal Risk Level (MRL) or 

Reference Dose (RfD) or Reference Concentration (RfC) from experimental data. UFs are intended to 

account for (1) the variation in sensitivity among the members of the human population, (2) the 

uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from 

data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using lowestobserved-adverse-effect level (LOAEL) data rather than no-observed-adverse-effect level (NOAEL) data. 

A default for each individual UF is 10; if complete certainty in data exists, a value of 1 can be used; 

however, a reduced UF of 3 may be used on a case-by-case basis, 3 being the approximate logarithmic 

average of 10 and 1. 

Xenobiotic—Any chemical that is foreign to the biological system. 
 

 

 

 

 

ETHYLBENZENE A-1 

APPENDIX A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS 

The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) [42 U.S.C. 

9601 et seq.], as amended by the Superfund Amendments and Reauthorization Act (SARA) [Pub. L. 99– 

499], requires that the Agency for Toxic Substances and Disease Registry (ATSDR) develop jointly with 

the U.S. Environmental Protection Agency (EPA), in order of priority, a list of hazardous substances most 

commonly found at facilities on the CERCLA National Priorities List (NPL); prepare toxicological 

profiles for each substance included on the priority list of hazardous substances; and assure the initiation 

of a research program to fill identified data needs associated with the substances. 

The toxicological profiles include an examination, summary, and interpretation of available toxicological 

information and epidemiologic evaluations of a hazardous substance. During the development of 

toxicological profiles, Minimal Risk Levels (MRLs) are derived when reliable and sufficient data exist to 

identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration for a 

given route of exposure. An MRL is an estimate of the daily human exposure to a hazardous substance 

that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration 

of exposure. MRLs are based on noncancer health effects only and are not based on a consideration of 

cancer effects. These substance-specific estimates, which are intended to serve as screening levels, are 

used by ATSDR health assessors to identify contaminants and potential health effects that may be of 

concern at hazardous waste sites. It is important to note that MRLs are not intended to define clean-up or 

action levels. 

MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty factor 

approach. They are below levels that might cause adverse health effects in the people most sensitive to 

such chemical-induced effects. MRLs are derived for acute (1–14 days), intermediate (15–364 days), and 

chronic (365 days and longer) durations and for the oral and inhalation routes of exposure. Currently, 

MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method 

suitable for this route of exposure. MRLs are generally based on the most sensitive chemical-induced end 

point considered to be of relevance to humans. Serious health effects (such as irreparable damage to the 

liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. Exposure to a level 

above the MRL does not mean that adverse health effects will occur. 

MRLs are intended only to serve as a screening tool to help public health professionals decide where to 

look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that 
ETHYLBENZENE A-2 

APPENDIX A 

are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of 

the lack of precise toxicological information on the people who might be most sensitive (e.g., infants, 

elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR 

uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health 

principle of prevention. Although human data are preferred, MRLs often must be based on animal studies 

because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes 

that humans are more sensitive to the effects of hazardous substance than animals and that certain persons 

may be particularly sensitive. Thus, the resulting MRL may be as much as 100-fold below levels that 

have been shown to be nontoxic in laboratory animals. 

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the 

Division of Toxicology and Environmental Medicine, expert panel peer reviews, and agency-wide MRL 

Workgroup reviews, with participation from other federal agencies and comments from the public. They 

are subject to change as new information becomes available concomitant with updating the toxicological 

profiles. Thus, MRLs in the most recent toxicological profiles supersede previously published levels. 

For additional information regarding MRLs, please contact the Division of Toxicology and 

Environmental Medicine, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road NE, 

Mailstop F-62, Atlanta, Georgia 30333. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE A-3 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Ethylbenzene 

CAS Numbers: 100-41-4 

Date: June 2010 

Profile Status: Final Draft Post-Public Comment 

Route: [x] Inhalation [ ] Oral 

Duration: [x] Acute [ ] Intermediate [ ] Chronic 

Graph Key: 13 

Species: Rat 

Minimal Risk Level: 5 [ ] mg/kg/day [x] ppm 

Reference: Cappaert NLM, Klis SFL, Baretta AB, et al. 2000. Ethyl benzene-induced ototoxicity in rats: 

A dose-dependent mid-frequency hearing loss. J Assoc Res Otolaryngol 1(4):292-299. 

Experimental design: Wag/Rij rats (8 rats/group; sex not provided) were exposed to 0, 300, 400, or 

550 ppm ethylbenzene (99% pure) 8 hours/day for 5 days. Animal weight was recorded weekly. 

Measurement of Distortion Product Otoacoustic Emissions (DPOAE), Compound Action Potential 

(CAP), and hair cell counts were conducted 3–6 weeks after the last ethylbenzene exposure. 

DPOAE: Stimuli were delivered to the ear canal via a probe system incorporating two speakers and a 

low-noise microphone. The microphone signal was amplified and the response to the stimulus was 

measured. DPOAE amplitude growth curves with stimulus levels were obtained from both ears. Growth 

functions were obtained at 4, 5.6, 8, 11.3, 16, and 22.6 kHz. The DPOAE threshold, defined as the 

stimulus level required to elicit a response of 0 dB SPL DPOAE was determined for each of the six 

frequencies. 

CAP: CAP was conducted immediately after DPOAE measurements. Auditory-evoked responses were 

recorded via a silverball electrode at the apex of the cochlea after presenting tone bursts of 1, 2, 4, 8, 12, 

16, and 24 kHz. An isoresponsive criterion of 1 μV level was used to define CAP thresholds. CAP 

amplitude was defined as the difference between the first negative peak and the summating potential in 

the electrophysiologic response. Hair cell counts: Immediately after conducting the 

electrocochleography (CAP) cochleas were removed and bisected longitudinally. Hair cell counts were 

conducted on five locations of the organ of Corti. Outer hair cell (OHC) loss was determined and 

expresses as a percentage of the expected number of OHC in different auditory regions. 

Effect noted in study and corresponding doses: Rats did not show signs of ill health. There were no 

significant differences in terminal body weight between exposed and control rats. 

DPOAE: DPOAE amplitude growth curves showed a significant reduction in rats exposed to 550 ppm, 

but not 300 or 400 ppm ethylbenzene. Effects were significant at 5.6, 8, and 11.3 kHz, but not at other 

frequencies. The DPOAE thresholds were significantly shifted (increased stimulus was needed to elicit 

the threshold response) at 5.6, 8, 11.3, and 16 kHz in rats in the 550-ppm group. DPOAE threshold shifts 

were not observed in other exposure groups. 

CAP: Animals exposed to 550 ppm showed a significant shift in the CAP amplitude growth curves at 8, 

12, and 16 kHz. In the 400-ppm group, the growth curves were affected only at 12 kHz and there was no 

effect in animals in the 300-ppm group. CAP thresholds were significantly shifted at 8, 12, and 16 kHz in 

the 550-ppm group and at 12 and 16 kHz in the 400-ppm group. There was no deterioration of CAP 

thresholds in the 300-ppm group. Significant OHC losses of approximately 33 and 75% were observed in 
 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE A-4 

APPENDIX A 

the 550-ppm group in the auditory regions corresponding to 11 and 21 kHz, respectively. In the 400-ppm 

group, significant losses (25%) were observed in the 11 kHz region. OHC losses in the 21 kHz region in 

the 300-ppm group were approximately 12%, but were not statistically significant. 

Dose and end point used for MRL derivation: BMCL1SD of 81.10 μmol/L for CAP auditory shifts using 

an internal dose metric of time-averaged arterial blood concentration of ethylbenzene. 

[] NOAEL [ ] LOAEL [x] BMCL 

The point of departure for an acute-duration inhalation MRL was identified using BMD analysis of the 

CAP auditory threshold data from the Cappaert et al. (2000) study. The data were presented graphically 

in the paper; however, Dr. Cappaert provided individual animal data for the CAP thresholds (presented in 

Figures 3 and 4 in the published paper) to ATSDR (data on OHC loss were not available). Data from 

Figure 4 included measurements of CAP thresholds in response to auditory stimuli ranging from 1 to 

24 kHz. The largest effects on CAP threshold occurred in response to 8, 12, and 16 kHz stimuli and, on 

this basis, these data were selected for BMD modeling. The raw data set from Dr. Cappaert was used to 

make the following calculations: 

1.	 Control group mean (±SD) CAP threshold: mean CAP stimulus threshold (dB SPL, defined 

as ≥1 μV CAP) of control group;

2.	 Individual animal threshold shift in response to ethylbenzene exposure: mifference between 

threshold for each animal exposed to ethylbenzene and the control group mean threshold; and 

3.	 Ethylbenzene exposure group mean (±SD) threshold shift: mean (±SD) of individual 

threshold shifts for each ethylbenzene exposure group. These group mean responses (mean 

CAP threshold shift, dB) were used as the response metric in BMD modeling. 

Code for an ethylbenzene inhalation PBPK model was developed from documentation provided in Tardif 

et al. (1997) with revised metabolism parameter values reported in Haddad et al. (1999, 2001) (see 

Appendix E for additional information on the PBPK model). This model reproduces model output 

reported in Tardif et al. (1997) for venous blood and alveolar air concentrations of ethylbenzene in rats 

and humans and output reported in Appendix R of American Chemistry Council (2007, Krishnan 

simulations) of human steady-state venous blood and alveolar air concentrations for exposure 

concentrations ranging from 1 to 50 ppm. For cochlear effects, the assumption was made that 

ethylbenzene, rather than a metabolite, is the toxic agent. Although there are no data for ethylbenzene, 

support of this assumption comes from studies of toluene (Pryor et al. 1991) and styrene (Ladefoged et al. 

1998), which found that ototoxicity was most likely due to the action of the parent compound rather than 

a metabolite. The dose metric simulated for the cochlear effects was time-averaged arterial blood 

concentration of ethylbenzene (MCA) because there are no validated models for simulating ethylbenzene 

levels in cochlea tissue or enodolymph. Using MCA for this end point assumes that tissue dosimetry and 

response would be correlated with time averaged arterial ethylbenzene concentrations (or average x time, 

AUC), which would be expected to correlate with time-averaged tissue concentration. 

The CAP threshold shift data (summarized in Table A-1) were fit to all available continuous models in 

EPA’s Benchmark Dose Software (BMDS, version 2.1.1) using MCA as the dose metric. The following 

procedure for fitting continuous data was used. The simplest model (linear) was first applied to the data 

while assuming constant variance. If the data were consistent with the assumption of constant variance 

(p≥0.1), then the fit of the linear model to the means was evaluated and the polynomial, power, and Hill 

models were fit to the data while assuming constant variance. Adequate model fit was judged by three 

criteria: goodness-of-fit p-value (p>0.1), visual inspection of the dose-response curve, and scaled residual 
 

 

 

 

ETHYLBENZENE A-5 

APPENDIX A 

at the data point (except the control) closest to the predefined BMR. Among all the models providing 

adequate fit to the data, the lowest BMCL (95% lower confidence limit on the benchmark concentration) 

was selected as the point of departure when the difference between the BMCLs estimated from these 

models were more 3-fold; otherwise, the BMCL from the model with the lowest Akaike’s Information 

Criterion (AIC) was chosen. If the test for constant variance was negative, then the linear model was run 

again while applying the power model integrated into BMDS to account for nonhomogenous variance. If 

the nonhomogenous variance model provided an adequate fit (p≥0.1) to the variance data, then the fit of

the linear model to the means was evaluated and the polynomial, power, and Hill models were fit to the 

data and evaluated while the variance model was applied. Model fit and point of departure selection 

proceeded as described earlier. If the test for constant variance was negative and the nonhomogenous 

variance model did not provide an adequate fit to the variance data, then the data set was considered 

unsuitable for modeling. For all models, a BMR of 1 standard deviation change from the control was 

used. This default BMR was used because there are insufficient mechanism of action data to determine 

what level of response constitutes a biologically significant effect in the cochlea. 

Table A-1. CAP Threshold Shifts in Wag/Rij Rats Exposed to Ethylbenzene 

8 Hours/Day for 5 Days 

Frequency Exposure Arterial ethylbenzene Number 

(kHz) level (ppm) concentration (MCA, μmol/L) Mean (dB) SD of rats 

8 

0 0 0.00 5.66 7 

300 76.11 -3.45 11.09 8 

400 119.00 4.36 9.94 7 

550 198.10 23.93 6.11 8 

12 

0 0 0.00 6.30 7 

300 76.11 -3.51 11.31 8 

400 119.00 14.79 9.53 7 

550 198.10 30.62 5.78 8 

16 

0 0 0.00 7.18 7 

300 76.11 -0.35 10.43 8 

400 119.00 15.57 12.00 7 

550 198.10 21.84 7.37 8 

CAP = compound action potential; MCA = time-averaged arterial blood concentration of ethylbenzene;
 

SD = standard deviation 

Source: Cappaert et al. 2000 

The model predictions for CAP threshold shifts at 8, 12, and 16 kHz are summarized in Table A-2. At the 

8 kHz frequency, the Hill, polynomial (2- and 3-degree), and power models provided adequate fit to the 

data. Of these models, the polynomial (3-degree) model (Figure A-1) had the lowest AIC. At 12 and 

16 kHz frequencies, only the Hill model provided an adequate fit to the data; the models are presented in 

Figures A-2 and A-3. 
 

 

 

 

 

 

 

 

 

ETHYLBENZENE A-6 

APPENDIX A 

Table A-2. Model Predictions for CAP Threshold Shifts in Wag/Rij Rats Exposed 

to Ethylbenzene 8 Hours/Day for 5 Days 

Variance Means BMC1SD BMCL1SD 

Model p-valuea p-valuea AIC (μmol/L) (μmol/L) 

8 kHz frequency 

Constant variance 

Hillb 0.17 0.41 163.26 121.43 104.55 

Linearc 0.17 0.00 174.14 NA NA 

Polynomial (2-degree)b 0.17 0.14 164.53 105.93 91.96 

Polynomial (3-degree)b 0.17 0.46 162.12 128.00 102.63 

Powerb 0.17 0.24 163.94 136.36 101.61 

12 kHz frequency 

Constant variance 

Hillb 0.19 0.40 163.36 111.59 89.47 

Linearc 0.19 0.00 176.02 NA NA 

Polynomial (2-degree)b 0.19 0.03 167.42 NA NA 

Polynomial (3-degree)b 0.19 0.01 169.42 NA NA 

Powerb 0.19 0.01 169.32 NA NA 

16 kHz frequency 

Constant variance 

Hillb 0.42 0.94 168.39 110.51 81.10 

Linearc 0.42 0.04 172.72 NA NA 

Polynomial (2-degree)b 0.42 0.03 173.35 NA NA 

Polynomial (3-degree)b 0.42 0.03 173.35 NA NA 

Powerb 0.42 0.03 173.12 NA NA 

a

Values <0.10 fail to meet conventional goodness-of-fit criteria. b

Coefficients restricted to be positive.
 c

Power restricted to ≥1.
	

AIC = Akaike Information Criterion; BMC = benchmark concentration associated with a 1 standard deviation 

benchmark response; BMCL = 95% lower confidence limit on the BMC; CAP = compound action potential; NA = not
 

applicable, model does not provide adequate fit to the data
 

Source: Cappaert et al. 2000
 
Figure A-1. Predicted (3-Degree Polynomial Model with Constant Variance) and 

Observed CAP Threshold Shifts at 8 kHz * 

*BMD and BMDL indicated are associated with a change of 1 standard deviation from control 

and are in units of umol/L. 

Figure A-2. Predicted (Hill Model with Constant Variance) and Observed CAP 

Threshold Shifts at 12 kHz* 

*BMD and BMDL indicated are associated with a change of 1 standard deviation from control and are 

in units of umol/L. 

ETHYLBENZENE A-7 

APPENDIX A 
Figure A-3. Predicted (Hill Model with Constant Variance) and Observed CAP 

Threshold Shifts at 16 kHz* 

*BMD and BMDL indicated are associated with a change of 1 standard deviation from control and are in 

units of umol/L. 

 

ETHYLBENZENE A-8 

APPENDIX A 

The BMDL1SD values estimated from the BMD model with the lowest AIC for CAP threshold data at 8, 

12, and 16 kHz were 102.3, 89.47, and 81.10 μmol/L, respectively. The lowest BMDL1SD of 

81.10 μmol/L was selected as the point of departure. 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[x] 3 for extrapolation from animals to humans with dosimetric adjustment 

[x] 10 for human variability 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? Not applicable 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: 

HECs were predicted from the BMCL1SD values (estimated from the model with the lowest AIC values) 

for CAP threshold data at 8, 12, and 16 kHz using the human PBPK model. The BMCL values for the 

internal dose metric (MCA) were converted to HEC values by iterative simulation of human inhalation 

exposures. Exposure concentrations were varied until the simulated value for the internal dose metric was 

within 0.01% of the BMCL. The HECs for BMCL1SD values are presented in Table A-3. 
 

 

 

ETHYLBENZENE A-9 

APPENDIX A 

Table A-3. Human Equivalent Concentrations (HECs) for CAP Threshold Shifts 

Effect Model BMCL1SD (μmol/L) HECa (ppm) 

CAP threshold shift at 8 kHz Polynomial (3-degree) 102.63 178.52 

CAP threshold shift at 12 kHz Hill 89.47 163.80 

CAP threshold shift at 16 kHz Hill 81.10 154.26 

a

Calculated using a reference human body weight of 70 kg and the assumption of 14-day continuous exposure. 

BMCLMCA = 95% lower confidence limit on the benchmark concentration associated with a benchmark response of 

1 standard deviation estimated using an MCA (time-weighted arterial blood concentration of ethylbenzene) dose 

metric; CAP = compound action potential 

Was a conversion used from intermittent to continuous exposure? The PBPK models used to estimate 

internal dose metrics and HECs adjusted for intermittent exposure. 

Other additional studies or pertinent information that lend support to this MRL: There is limited 

information on the acute toxicity of ethylbenzene in humans. Acute exposures to ≥1,000 ppm resulted in 

ocular irritation, a burning sensation, and profuse lacrimation (Cometto-Muniz and Cain 1995; Thienes 

and Haley 1972; Yant et al. 1930). Volunteers exposed to 2,000 ppm reported irritation and chest 

constriction with worsening symptoms when the concentration was increased to 5,000 ppm (Yant et al. 

1930). Studies in laboratory animals identify ototoxicity as the most sensitive end point for acuteduration inhalation exposure to ethylbenzene. Damage to the OHCs of the organ of Corti and, in some 

cases, significant reductions in auditory thresholds were observed in rats exposed to ≥400 ppm 

ethylbenzene by inhalation for 5 days (Cappaert et al. 1999, 2000, 2001, 2002). Loss of OHCs appeared 

to be concentration-related as losses were 52–66% in animals exposed to 800 ppm ethylbenzene 

(Cappaert et al. 1999), 40–75% at 550 ppm, and approximately 25% at 400 ppm (Cappaert et al. 2000, 

2001). OHC losses in rats exposed to 300 ppm were small (12%) and not statistically significant 

(Cappaert et al. 2000). Auditory thresholds in rats exposed to ethylbenzene at ≥400 ppm were 

significantly affected in the mid-frequency region; however, an increasingly broader range of frequencies 

were affected with increasing concentrations of ethylbenzene (Cappaert et al. 1999, 2000). Auditory 

assessments indicate that effects were evident shortly after exposure and persisted for up to 11 weeks 

(termination of the observation period) (Cappaert et al. 1999, 2000, 2001, 2002), suggesting that the 

auditory effects might be irreversible. Cappaert et al. (2002) demonstrated a significant species difference 

in the susceptibility of rats and guinea pigs to the ototoxic effects of ethylbenzene with guinea pigs 

showing no auditory deficits or losses in OHCs at 2,500 ppm ethylbenzene after 5 days (Cappaert et al. 

2002). 

Neurological effects were observed after acute-duration exposure to ethylbenzene at concentrations equal 

to or higher than those that elicited auditory effects in animals. Effects observed after acute-duration 

exposure to ethylbenzene include moderate activation of motor behavior in rats exposed to 400 ppm 

(Molnar et al. 1986) and reduced activity and prostration and shallow breathing in rats and mice at 

1,200 ppm (Ethylbenzene Producers Association 1986a). Rats or mice exposed to ≥2,000 ppm showed 

posture changes, reduced grip strength, reduced motor coordination (Tegeris and Balster 1994), narcotic 

effects (Molnar et al. 1986), and neurotransmission disturbances in the forebrain and hypothalamus 

(Andersson et al. 1981). Mice exposed to 4,060 ppm for 20 minutes showed a 50% reduction in 

respiratory rate (Nielsen and Alarie 1982). A 50% respiratory depression observed in mice at 1,432 ppm 

was attributed to sensory irritation (De Ceaurriz et al. 1981). 
ETHYLBENZENE A-10 

APPENDIX A 

Increased liver weight was reported after acute-duration exposure in rats exposed to ≥400 ppm 

ethylbenzene (Ethylbenzene Producers Association 1986a; Toftgard and Nilsen 1982), but not in mice at 

1,200 ppm or rabbits at 2,400 ppm (Ethylbenzene Producers Association 1986a). At these same levels 

and exposure durations, induction of microsomal enzymes and related ultrastructural changes (e.g., 

proliferation of the smooth endoplasmic reticulum) were observed. These effects occurred in the absence 

of histopathological changes to the liver. Therefore, the effects on the liver appear to be related to 

induction of microsomal enzymes in smooth endoplasmic reticulum. An increase in relative kidney 

weight was also observed in rats exposed to ≥1,200 ppm (Ethylbenzene Producers Association 1986a; 

Toftgard and Nilsen 1982), but not in mice at 1,200 ppm or rabbits at 2,400 ppm (Ethylbenzene Producers 

Association 1986a). However, increased kidney weights occurred in the absence of histological changes 

(Ethylbenzene Producers Association 1986a). No histopathological alterations were observed in the lungs 

of surviving rats, mice, or rabbits exposed to 1,200, 400, or 2,400 ppm ethylbenzene, respectively, for 

4 days (Ethylbenzene Producers Association 1986a). 

Agency Contacts (Chemical Managers): Jessilynn Taylor, Henry Abadin, Heraline Hicks 
 

 

 

 

 

ETHYLBENZENE A-11 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Ethylbenzene 

CAS Numbers: 100-41-4 

Date: June 2010 

Profile Status: Final Draft Post-Public Comment 

Route: [x] Inhalation [ ] Oral 

Duration: [ ] Acute [x] Intermediate [ ] Chronic 

Graph Key: 42 

Species: Rat 

Minimal Risk Level: 2 [ ] mg/kg/day [x] ppm 

Reference: Gagnaire F, Langlais C, Grossman S, et al. 2007. Ototoxicity in rats exposed to 

ethylbenzene and to two xylene vapors for 13 weeks. Arch Toxicol 81:127-143. 

Experimental design: Male Sprague-Dawley rats (14 rats/exposure group) were exposed to 0, 200, 400, 

600 and 800 ppm ethylbenzene (99% pure), 6 hours/day, 6 days/week, for 13 weeks. Ototoxicity was 

assessed based on effects on neurophysiological measurements and cochlear total hair cell counts. For the 

neurophysiologic assessments, rats were surgically fitted with electrodes (active electrode was placed at 

the lamba point over the inferior colliculus, the reference electrode was placed posterior to the bregma 

and to the right of the midline, and the ground electrode was placed over the nasal bone). Exposure to 

ethylbenzene was conducted starting 3–4 weeks after implantation of the electrodes and neurophysiological measurements were conducted at the end of 4th, 8th, and 13th week of exposure and at the 

end of the 8th week of recovery (week 21). Brainstem auditory responses were evoked with 

50 microsecond clicks at 10 clicks/second presented in 5 dB steps. The evoked activity was analyzed for 

10 ms following each click. Audiometric thresholds were determined at 2, 4, 8, and 16 kHz by inspection 

of the auditory brainstem responses. Following the 8th week of recovery (post-exposure) eight rats/group 

were sacrified. The organ of Corti and the basilar membrane were dissected from the cochlea and 

prepared for total hair cell counts (cytocochleograms). Four left and four right cochleas were prepared in 

this manner in all groups including controls. 

Effect noted in study and corresponding doses: In the 800 ppm group, one rat lost its head plug and could 

not undergo neurophysiological testing, one rat died for unknown reasons and another rat was sacrificed 

due to a large neck tumor. There were no significant differences in body weight gain between the 

surviving treated animals and controls. 

Audiometric thresholds at 2, 4, 8, and 16 kHz were significantly higher in animals exposed to 400, 600, 

and 800 ppm ethylbenzene than in controls (p<0.05). The effect was evident at week 4, did not increase 

significantly throughout the exposure period, and was not reversed after 8 weeks of recovery. No shift in 

audiometric thresholds was observed in rats in the 200 ppm group. 

The morphological assessment of the organ of Corti (conducted after an 8-week recovery period) showed 

significant losses (up to 30% of the OHC in the mid frequency region) in the third row of the OHC in 

4/8 rats exposed to 200 ppm. A dose related loss in third row OHC (OHC3) was evident with almost 

complete loss observed in the 600- and 800-ppm groups. The data suggest that the extent of the damage 

at each dose was greatest in the OHC3 followed, in decreasing order, by damage in OHC2, OHC1, and 

inner hair cells (IHC). There was no significant hair loss in the control animals. The LOAEL for OHC3 

loss was 200 ppm. A NOAEL was not established. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE A-12 

APPENDIX A 

Dose and end point used for MRL derivation: BMDL1SD of 19.94 μmol/L for auditory shifts using an 

internal dose metric of time-averaged arterial blood concentration of ethylbenzene. 

[] NOAEL [ ] LOAEL [x] BMCL 

Auditory threshold shifts and OHC loss are selected as the critical effects following intermediate-duration 

inhalation exposure to ethylbenzene. Because these data are only presented graphically in the Gagnaire’s 

paper, the data are not suitable for BMD analysis. However, Dr. Gagnaire has provided to ATSDR the 

individual animal data for these end points; these data are summarized in Tables A-4 and A-5. 

Table A-4. Auditory Thresholds in Male Sprague-Dawley Rats Exposed to 

Ethylbenzene 6 Hours/Day, 6 Days/Week for 4 or 13 Weeks 

Frequency Exposure Exposure Arterial ethylbenzene Mean Number 

(kHz) duration (weeks) level (ppm) concentration (MCA, μmol/L) (dB SPL) SD of rats 

4 

4 

0 0 33 4 14 

200 20.97 31 4 13 

400 64.26 52 11 14 

600 118.07 75 7 14 

800 177.98 74 6 14

 13 

0 0 31 4 14 

200 20.97 31 5 13 

400 64.26 59 8 14 

600 118.07 74 8 14 

800 177.98 73 7 14 

8 

4 

0 0 22 4 14 

200 20.97 23 5 13 

400 64.26 40 11 14 

600 118.07 69 8 14 

800 177.98 68 6 14

 13 

0 0 22 4 14 

200 20.97 21 4 13 

400 64.26 44 15 14 

600 118.07 71 9 14 

800 177.98 67 7 14 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE A-13
 

APPENDIX A 

Table A-4. Auditory Thresholds in Male Sprague-Dawley Rats Exposed to 

Ethylbenzene 6 Hours/Day, 6 Days/Week for 4 or 13 Weeks 

Frequency Exposure Exposure Arterial ethylbenzene Mean Number 

(kHz) duration (weeks) level (ppm) concentration (MCA, μmol/L) (dB SPL) SD of rats 

16 

4 

0 0 21 3 14 

200 20.97 20 4 13 

400 64.26 40 16 14 

600 118.07 70 6 14 

800 177.98 68 5 14

 13 

0 0 18 3 14 

200 20.97 18 4 13 

400 64.26 46 18 14 

600 118.07 74 9 14 

800 177.98 67 7 14 

MCA = time-averaged arterial blood concentration of ethylbenzene; SD = standard deviation; SPL = sound pressure 

level 

Source: Gagnaire et al. 2007 

Table A-5. Percent OHC Loss in Male Sprague-Dawley Rats Exposed to 

Ethylbenzene 6 Hours/Day, 6 Days/Week for 13 Weeksa 

Exposure level Arterial ethylbenzene Number of 

(ppm) concentration (MCA, μmol/L) Mean (% loss) SD rats 

0 0 0.346 0.159 7 

200 20.97 3.67 4.24 8 

400 64.26 67.12 12.26 8 

600 118.07 85.58 7.68 8 

800 177.98 90.81 7.36 8 

a

Evaluation conducted at the end of the 8-week recovery period. 

MCA = time-averaged arterial blood concentration of ethylbenzene; OHC = outer hair cell; SD = standard deviation 

Source: Gagnaire et al. 2007 

Code for an ethylbenzene inhalation PBPK model was developed from documentation provided in Tardif 

et al. (1997) with revised metabolism parameter values reported in Haddad et al. (1999, 2001) (see 

Appendix E for additional information on the PBPK model). This model reproduces model output 

reported in Tardif et al. (1997) for venous blood and alveolar air concentrations of ethylbenzene in rats 

and humans and output reported in Appendix R of American Chemistry Council (2007, Krishnan 

simulations) of human steady-state venous blood and alveolar air concentrations for exposure 
ETHYLBENZENE A-14 

APPENDIX A 

concentrations ranging from 1 to 50 ppm. For cochlear effects, the assumption was made that 

ethylbenzene, rather than a metabolite, is the toxic agent. Although there are no data for ethylbenzene, 

support of this assumption comes from studies of toluene (Pryor et al. 1991) and styrene (Ladefoged et al. 

1998), which found that ototoxicity was most likely due to the action of the parent compound rather than 

a metabolite. The dose metric simulated for the cochlear effects was time-averaged arterial blood 

concentration of ethylbenzene (MCA) because there are no validated models for simulating ethylbenzene 

levels in cochlea tissue or endolymph. Using MCA for this endpoint assumes that tissue dosimetry and 

response would be correlated with time averaged arterial ethylbenzene concentrations (or average x time, 

AUC), which would be expected to correlate with time-averaged tissue concentration. 

For the BMD analysis, the auditory threshold and percent OHC loss data were fit to all available 

continuous models in EPA’s BMDS (version 2.1.1) using MCA as the dose metric. The following 

procedure for fitting continuous data was used. The simplest model (linear) was first applied to the data 

while assuming constant variance. If the data were consistent with the assumption of constant variance 

(p≥0.1), then the fit of the linear model to the means was evaluated and the polynomial, power, and Hill 

models were fit to the data while assuming constant variance. Adequate model fit was judged by three 

criteria: goodness-of-fit p-value (p>0.1), visual inspection of the dose-response curve, and scaled residual 

at the data point (except the control) closest to the predefined BMR. Among all the models providing 

adequate fit to the data, the lowest BMCL (95% lower confidence limit on the benchmark concentration) 

was selected as the point of departure when the difference between the BMCLs estimated from these 

models were more 3-fold; otherwise, the BMCL from the model with the lowest AIC was chosen. If the 

test for constant variance was negative, the linear model was run again while applying the power model 

integrated into the BMDS to account for nonhomogenous variance. If the nonhomogenous variance 

model provided an adequate fit (p≥0.1) to the variance data, then the fit of the linear model to the means 

was evaluated and the polynomial, power, and Hill models were fit to the data and evaluated while the 

variance model was applied. Model fit and point of departure selection proceeded as described earlier. If 

the test for constant variance was negative and the nonhomogenous variance model did not provide an 

adequate fit to the variance data, then the data set was considered unsuitable for modeling. For data sets 

that did not provide an adequate fit to the available models, the highest or two highest doses were dropped 

and the models were fit to the modified data set. ATSDR considered this an acceptable procedure 

because the BMD modeling was used to predict the response at low doses. For all models, a BMR of 

1 standard deviation change from the control was used. This default BMR was used because there are 

insufficient mechanism of action data to determine what level of response constitutes a biologically 

significant effect in the cochlea. 

The model predictions for auditory threshold after 4 and 13 weeks of exposures are presented in Tables 

A-6 and A-7. None of the BMD models provided an adequate fit (as assessed by the goodness-of-fit 

criteria) to the OHC loss data. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE A-15 

APPENDIX A 

Table A-6. Model Predictions for Changes in Auditory Thresholds in Male
 

Sprague-Dawley Rats Exposed to Ethylbenzene 6 Hours/Day,
 

6 Days/Week for 4 Weeks 

Variance Means BMC1SD BMCL1SD 

Model p-valuea p-valuea AIC (μmol/L) (μmol/L) 

4 kHz frequency 

All doses 

Constant variance 

Linearb 0.0004 <0.0001 382.99 NA NA 

Nonconstant variance 

Linearb

 0.002 <0.0001 435.85 NA NA 

Highest dose dropped 

Constant variance 

Linearb 0.0002 0.0001 286.70 NA NA 

Nonconstant variance 

Linearb 0.007 <0.0001 312.35 NA NA 

2 Highest doses dropped 

Constant variance 

Linearb <0.0001 0.001 216.31 NA NA 

Nonconstant variance 

Hillc Failed to generate a model output; the number of observations 

were less than the number of parameters for the Hill model 

Linearb

 0.66 <0.0001 207.43 NA NA 

Polynomial (2-degree)c

 0.66 0.010 194.79 NA NA 

Powerc

 0.66 0.21 189.65 58.75 33.12 

8 kHz frequency 

All doses 

Constant variance 

Linearb

 0.002 <0.0001 387.55 NA NA 

Nonconstant variance 

Linearb

 0.004 <0.0001 438.09 NA NA 

Highest dose dropped 

Constant variance 

Linearb

 0.001 0.002 291.87 NA NA 

Nonconstant variance 

Linearb

 0.02 <0.0001 392.73 NA NA 

2 Highest doses dropped 

Constant variance 

Linearb 0.0003 0.05 211.83 NA NA 

Nonconstant variance 

Hillc Failed to generate a model output; the number of observations 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE A-16 

APPENDIX A 

Table A-6. Model Predictions for Changes in Auditory Thresholds in Male
 

Sprague-Dawley Rats Exposed to Ethylbenzene 6 Hours/Day,
 

6 Days/Week for 4 Weeks 

Variance Means BMC1SD BMCL1SD 

Model p-valuea p-valuea AIC (μmol/L) (μmol/L) 

were less than the number of parameters for the Hill model 

Linearb

 0.61 0.01 200.49 

Polynomial (2-degree)c

 0.61 0.69 194.10 30.34 19.94 

Powerc

 0.61 NA 195.94 NA NA 

16 kHz frequency 

All doses 

Constant variance 

Linearb

 <0.0001 <0.0001 404.82 NA NA 

Nonconstant variance 

Linearb

 <0.0001 <0.0001 447.85 NA NA 

Highest dose dropped 

Constant variance 

Linearb

 <0.0001 0.002 310.22 NA NA 

Nonconstant variance 

Linearb

 <0.0001 <0.0001 315.43 NA NA 

2 Highest doses dropped 

Constant variance 

Linearb

 <0.0001 0.03 235.61 NA NA 

Nonconstant variance 

Hillc Failed to generate a model output; the number of observations 

were less than the number of parameters for the Hill model 

Linearb

 0.20 0.00 203.91 NA NA 

Polynomial (2-degree)c

 0.20 0.07 195.17 NA NA 

Powerc

 0.20 0.84 191.99 58.34 27.31 

a

Values <0.10 fail to meet conventional goodness-of-fit criteria. b

Coefficients restricted to be positive.
 c

Power restricted to ≥1.
 

AIC = Akaike Information Criterion; BMC = benchmark concentration associated with a benchmark response of 

1 standard deviation; BMCL = 95% lower confidence limit on the BMC; NA = not applicable, model failed to provide 

an adequate fit to the data; SD = standard deviation
 

Source: Gagnaire et al. 2007
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE A-17 

APPENDIX A 

Table A-7. Model Predictions for Changes in Auditory Thresholds in Male
 

Sprague-Dawley Rats Exposed to Ethylbenzene 6 Hours/Day,
 

6 Days/Week for 13 Weeks 

Variance Means BMC1SD BMCL1SD 

Model p-valuea p-valuea AIC (μmol/L) (μmol/L) 

4 kHz frequency 

All doses 

Constant variance 

Linearb 0.05 <0.0001 385.41 NA NA 

Nonconstant variance 

Hillc

 0.64 0.93 322.34 54.91 28.59 

Linearb

 0.64 <0.0001 437.05 NA NA 

Polynomial (2-degree)c 0.64 0.0001 419.18 NA NA 

Polynomial (3-degree)c 0.64 <0.0001 419.88 NA NA 

Polynomial (4-degree)c

 0.64 <0.0001 414.64 NA NA 

Powerc

 0.64 <0.0001 375.90 NA NA 

8 kHz frequency 

All doses 

Constant variance 

Linearb

 <0.0001 <0.0001 408.00 NA NA 

Nonconstant variance 

Linearb

 <0.0001 <0.0001 447.64 NA NA 

Highest dose dropped 

Constant variance 

Linearb

 <0.0001 0.01 310.79 NA NA 

Nonconstant variance 

Linearb

 0.001 <0.0001 402.37 NA NA 

2 Highest doses dropped 

Constant variance 

Linearb

 <0.0001 0.01 233.73 NA NA 

Nonconstant variance 

Hillc Failed to generate a model output, the number of observations 

were less than the number of parameters for the Hill model 

Linearb

 0.78 <0.0001 213.91 NA NA 

Polynomial (2-degree)c

 0.78 0.03 201.59 NA NA 

Powerc

 0.78 0.54 197.02 58.29 29.71 

16 kHz frequency 

All doses 

Constant variance 

Linearb

 <0.0001 <0.0001 434.87 NA NA 

Nonconstant variance 
 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE A-18 

APPENDIX A 

Table A-7. Model Predictions for Changes in Auditory Thresholds in Male
 

Sprague-Dawley Rats Exposed to Ethylbenzene 6 Hours/Day,
 

6 Days/Week for 13 Weeks 

Variance Means BMC1SD BMCL1SD 

Model p-valuea p-valuea AIC (μmol/L) (μmol/L) 

Linearb <0.0001 <0.0001 474.46 NA NA 

Highest dose dropped 

Constant variance 

Linearb

 <0.0001 0.03 322.19 NA NA 

Nonconstant variance 

Linearb

 0.0001 <0.0001 416.55 NA NA 

2 Highest doses dropped 

Constant variance 

Linearb

 <0.0001 0.01 245.83 NA NA 

Nonconstant variance 

Hillc Failed to generate a model output, the number of observations 

were less than the number of parameters for the Hill model 

Linearb

 0.34 <0.0001 211.61 NA NA 

Polynomial (2-degree)c

 0.34 0.06 198.11 NA NA 

Powerc

 0.34 NA 196.52 NA NA 

a

Values <0.10 fail to meet conventional goodness-of-fit criteria. b

Coefficients restricted to be positive.
 c

Power restricted to ≥1.
 

AIC = Akaike Information Criterion; BMC = benchmark concentration associated with a benchmark response of 

1 standard deviation; BMCL = 95% lower confidence limit on the BMC; NA = not applicable, model failed to provide 

an adequate fit to the data; SD = standard deviation
 

Source: Gagnaire et al. 2007
 

Most of the available BMDS models did not adequately fit the auditory threshold data; however, with the 

exception of the auditory thresholds at 16 kHz in rats exposed to ethylbenzene for 13 weeks, one BMD 

model fit each data set often when the highest two dose groups were dropped. In rats exposed to 

ethylbenzene for 4 weeks, the power with nonconstant variance, 2-degree polymonial with nonconstant 

variance, and power models adequately fit the auditory shift data assessed at 4, 8, or 16 kHz, respectively; 

these models are shown in Figures A-4, A-5, and A-6. The Hill model with nonconstant variance (Figure 

A-7) and the power model with nonconstant variance (FigureA- 8) adequately fit the auditory threshold 

shift data assessed at 4 and 8 kHz, respectively, for rats exposed for 13 weeks. 

The BMDL1SD values estimated from the BMD model with the lowest AIC for changes in auditory 

threshold for each frequency and duration ranged from 19.94 to 33.21 μmol/L. Although there is a degree 

of uncertainty associated with the BMD models in which the two highest doses were dropped, the narrow 

range of BMCL values estimated from the truncated data sets and the full data set supports this approach. 

The lowest BMDL1SD of 19.94 μmol/L (estimated using auditory threshold data at 8 kHz following 

4 weeks of exposure) was selected as the point of departure. 
Figure A-4. Predicted (Power Model with Nonconstant Variance) and Observed 

Changes in Auditory Threshold at 4 kHz (4-Week Exposure)* 

Two highest doses dropped 

*BMCs and BMCLs indicated are associated with a change of 1 standard deviation from the control, and are in 

units of μmol/L. 

ETHYLBENZENE A-19 

APPENDIX A 
Figure A-5. Predicted (2-Degree Polynomial Model with Nonconstant Variance) 

and Observed Changes in Auditory Threshold at 8 kHz (4-Week Exposure)* 

Two highest doses dropped 

*BMDs and BMDLs indicated are associated with a change of 1 standard deviation from the control, and are in units 

of μmol/L. 

ETHYLBENZENE A-20 

APPENDIX A 
Figure A-6. Predicted (Power Model) and Observed Changes in Auditory 

Threshold at 16 kHz (4-Week Exposure)* 

Two highest doses dropped 

*BMDs and BMDLs indicated are associated with a change of 1 standard deviation from the control, and are in units 

of μmol/L. 

Figure A-7. Predicted (Hill Model with Nonconstant Variance) and Observed 

Changes in Auditory Threshold at 4 kHz (13-Week Exposure)* 

*BMDs and BMDLs indicated are associated with a change of 1 standard deviation from the control, and are in units 

of μmol/L. 

ETHYLBENZENE A-21 

APPENDIX A 
Figure A-8. Predicted (Power Model with Nonconstant Variance) and Observed 

Changes in Auditory Threshold at 8 kHz (13-Week Exposure)* 

Two highest doses dropped 

*BMDs and BMDLs indicated are associated with a change of 1 standard deviation from the control and are in units of 

μmol/L. 

 

ETHYLBENZENE A-22 

APPENDIX A 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[x] 3 for extrapolation from animals to humans with dosimetric adjustment 

[x] 10 for human variability 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? Not applicable 

If an inhalation study in animals, list conversion factors used in determining human equivalent 

concentration: The human PBPK model was used to predict HECs corresponding to specific BMCL 

values. The BMCL values for the internal dose metric (MCA) were converted to HEC values by iterative 

simulation of human inhalation exposures. Exposure concentrations were varied until the simulated value 

for the internal dose metric was within 0.01% of the BMCL. The HECs for BMCL1SD values estimated 

from the models providing adequate fit are listed in Table A-8. The HECs of the BMCL1SD values ranged 

from 63.64 to 87.13 ppm; the lowest HEC of 63.64 ppm was selected as the point of departure for the 

MRL. 
 

ETHYLBENZENE A-23 

APPENDIX A 

Table A-8. Human Equivalent Concentrations for Auditory Effects in SpragueDawley Rats Exposed to Ethylbenzene 6 Hours/Day, 6 Days/Week for 4 or 

13 Weeks 

BMCLMCA 

Effect Model μmol/L) HECa

 (ppm) 

Auditory thresholds at 4 kHz Power (two highest doses 33.12 87.13 

following 4 weeks of exposure dropped); nonconstant variance 

Auditory thresholds at 8 kHz 2-Degree polynomial (two highest 19.94 63.64 

following 4 weeks of exposure doses dropped); nonconstant 

variance 

Auditory thresholds at 16 kHz Power (two highest doses 27.31 77.77 

following 4 weeks of exposure dropped); nonconstant variance 

Auditory thresholds at 4 kHz Hill (all doses); nonconstant 28.59 79.95 

following 13 weeks of exposure variance 

Auditory thresholds at 8 kHz Power (two highest doses 29.71 81.79 

following 13 weeks of exposure dropped); nonconstant variance 

a

Calculated using a reference human body weight of 70 kg and the assumption of 364-day continuous exposure. 

BMCLMCA = 95% lower confidence limit on the benchmark concentration associated with a benchmark response of 

1 standard deviation estimated using an MCA (time-weighted arterial blood concentration of ethylbenzene) dose 

metric 

Was a conversion used from intermittent to continuous exposure? The PBPK models used to estimate 

internal dose metrics and HECs adjusted for intermittent exposure. 

Other additional studies or pertinent information that lend support to this MRL: Several studies in 

animals, but no studies in humans, have examined the toxicity of ethylbenzene following intermediateduration inhalation exposure. The available animal studies suggest that ototoxicity is the most sensitive 

end point of ethylbenzene toxicity. Rats exposed to ≥400 ppm ethylbenzene via inhalation for 4 or 

13 weeks showed significant increases in auditory thresholds. These threshold shifts persisted unchanged 

for the duration of the exposure period and during an 8-week post-exposure recovery period (Gagnaire et 

al. 2007). Cell counts conducted in the organ of Corti after the 8-week recovery period showed 

significant losses of outer hair cells in rats exposed to ≥200 ppm. Concentration-related losses of inner 

hair cells (IHC) (14 and 32%) were observed in animals in the 600 and 800 ppm groups, respectively, 

with occasional IHC losses in the 400 ppm group. 

Systemic effects have been observed at concentrations equal to or higher than those that elicited ototoxic 

effects in rats. Increased liver, kidney, lung, and spleen weights have been observed in animals exposed 

to ethylbenzene concentrations in the 250–1,000 ppm range (Cragg et al. 1989; Elovaara et al. 1985; 

NIOSH 1981; NTP 1992; Wolf et al. 1956). However, the changes in organ weight have not been 

associated with histological alterations. One study (Cragg et al. 1989) reported a small, but statistically 

significant, increase in platelet counts in male rats and leukocyte counts in female rats exposed to 

782 ppm ethylbenzene for 4 weeks. Developmental effects have been observed in rats exposed to 

≥1,000 ppm. Increases in the occurrence of skeletal malformations (NIOSH 1981; Saillenfait et al. 2003) 

and decreases in fetal body weight (Saillenfait et al. 2003, 2006, 2007) have been observed at 

≥1,000 ppm. The NOAEL for these effects is 500 ppm (NIOSH 1981; Saillenfait et al. 2003, 2006, 

2007). Developmental landmarks and neurodevelopment were not statistically or biologically 
ETHYLBENZENE A-24 

APPENDIX A 

significantly affected in the offspring of rats exposed to up to 500 ppm ethylbenzene in a two-generation 

reproductive toxicity study (Faber et al. 2006, 2007). 

Agency Contacts (Chemical Managers): Jessilynn Taylor, Henry Abadin, Heraline Hicks 
 

 

 

 

 

 

 

ETHYLBENZENE A-25 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Ethylbenzene 

CAS Numbers: 100-41-4 

Date: June 2010 

Profile Status: Final Draft Post-Public Comment 

Route: [x] Inhalation [ ] Oral 

Duration: [ ] Acute [ ] Intermediate [x] Chronic 

Graph Key: 62 

Species: Rat 

Minimal Risk Level: 0.06 [ ] mg/kg/day [x] ppm 

Reference: NTP. 1999. NTP technical report on the toxicology and carcinogenesis studies of 

ethylbenzene in F344/N rats and B6C3F1 mice (inhalation studies). Research Triangle Park, NC: 

National Toxicology Program, U.S. Department of Health and Human Services. NTP TR 466. 

Experimental design: Groups of F344/N rats (50 animals/sex/dose group) were exposed to 0, 75, 250, or 

750 ppm ethylbenzene by inhalation for 6 hours/day, 5 days/week for 104 weeks. Animals were observed 

twice daily and clinical findings were recorded monthly. Body weights were recorded at the initiation of 

the study, weekly for the first 13 weeks, at week 16, monthly through the end of exposure, and prior to 

terminal necropsy. Animals that survived to study termination were killed by asphyxiation with CO2. A 

complete necropsy and microscopic examination were performed on all rats and mice that survived to 

study termination or died early. The tissues examined included the adrenal gland, blood vessel (aorta), 

bone and marrow, brain, clitoral gland, esophagus, gall bladder, harderian gland, heart, large intestine 

(cecum, colon, and rectum), small intestine (duodenum, jejunum, ileum), kidney, liver, lung, lymph nodes 

(mandibular and mesenteric), mammary gland, nose, ovary, pancreas, parathyroid gland, preputial gland, 

prostate gland, salivary gland, spleen, stomach (forestomach and glandular stomach), testis with 

epididymis and seminal vesicle, thymus, thyroid gland, trachea, urinary bladder, and uterus. 

Effect noted in study and corresponding doses: Survival of male rats in the 750-ppm group was 

significantly less than that of control animals. Survival was not affected in rats in other exposure groups 

or in mice at any ethylbenzene concentration. No clinical findings were attributed to ethylbenzene 

exposure in rats or mice. Although the incidence of nephropathy (47/50, 43/50, 47/50, and 48/50 in males 

and 38/50, 42/50, 43/50, and 46/49 in females) was not significantly different between the groups, 

significant increases in the severity of the nephropathy were observed in females at ≥75 ppm and in males 

at 750 ppm. The nephropathy severity scores in the 0, 75, 250, and 750 ppm groups were 2.3, 2.4, 2.3, 

and 3.5 in males, respectively, and 1.3, 1.6, 1.7, and 2.3 in females, respectively. Additionally, significant 

increases in the incidences of renal tubule hyperplasia were observed in male rats exposed to 750 ppm. 

The incidences of renal tubule adenoma and adenoma or carcinoma (combined) in the 750 ppm group 

were significantly greater than the incidence in control animals. An increase in the incidence of cystic 

degeneration of the liver was also observed in male rats at 750 ppm. 

Dose and end point used for MRL derivation: The critical effect for chronic exposure to ethylbenzene is 

increased severity of chronic progressive nephropathy in female rats exposed to 75 ppm and higher (NTP 

1999). BMD analysis was considered for determining the point of departure for the MRL; however, none 

of the available continuous exposure BMD models fit the data (standard errors were calculated using the 

raw severity score data). Thus, a NOAEL/LOAEL approach was selected for calculating the point of 

departure. 
 

 

ETHYLBENZENE A-26 

APPENDIX A 

[ ] NOAEL [x] LOAEL 

Code for an ethylbenzene inhalation PBPK model was developed from documentation provided in Tardif 

et al. (1997) with revised metabolism parameter values reported in Haddad et al. (1999, 2001). This 

model reproduces model output reported in Tardif et al. (1997) for venous blood and alveolar air 

concentrations of ethylbenzene in rats and humans and output reported in Appendix R of American 

Chemistry Council (2007, Krishnan simulations) of human steady-state venous blood and alveolar air 

concentrations for exposure concentrations ranging from 1 to 50 ppm. Two internal dose metrics were 

simulated for kidney effects: time-averaged arterial blood concentration of ethylbenzene (MCA) and 

time-averaged rate of metabolism of ethylbenzene expressed per kg body mass (MRAMKB). Both 

metrics were explored because current knowledge of the mechanisms of toxicity of ethylbenzene does not 

include an understanding of the relative contribution of parent compound or metabolites as proximate 

toxic agents in kidney. The assumption in using the MCA metric for this end point is that tissue 

dosimetry and response would be correlated with time-averaged arterial ethylbenzene concentration (or 

average x time, AUC), which would be expected to correlate with time-averaged kidney concentration. 

The assumption in using the MRAMKB metric is that the kidney response is correlated with the timeaveraged rate of whole-body production of ethylbenzene metabolites. In the model, all metabolism is 

attributed to the liver (the model does not have a kidney compartment); therefore, the rate of metabolism 

in the liver is the only representation of whole body metabolism that can be simulated. The internal dose 

metrics (MCA and MRAMKB) for each exposure level are presented in Table A-9. 

Table A-9. Internal Dose Metrics for Male and Female F344/N Rats Exposed to 

Ethylbenzene 6 Hours/Day, 5 Days/Week for 104 Weeks 

Arterial ethylbenzene 

Exposure level (ppm) concentration (MCA, μmol/L) MRAMKB (μmol/hour/kg body weight) 

Malea

 0 0 0 

75 4.12 8.92

 250 27.66 23.64

 750 146.77 43.05
 

Femaleb

 0 0 0 

75 4.16 10.00

 250 28.72 26.04

 750 150.68 46.49
 

a

Time weighted average body weight of 0.43 kg. 

b

Time weighted average body weight of 0.27 kg. 

MCA = time-averaged arterial blood concentration; MRAMKB = time averaged rate of ethylbenzene metabolism 

expressed per kg body mass 

Uncertainty Factors used in MRL derivation: 

[x] 10 for use of a LOAEL 

[x] 3 for extrapolation from animals to humans with dosimetric adjustment 

[x] 10 for human variability 
 

 

ETHYLBENZENE A-27 

APPENDIX A 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? Not applicable. 

If an inhalation study in animals, list conversion factors used in determining human equivalent 

concentration: The human PBPK model was used to predict HECs corresponding to LOAELMCA and 

LOAELMRAMKB in female rats. The MCA and MRAMKB dose metrics were converted to HEC values by 

iterative simulation of human inhalation exposures. Exposure concentrations were varied until the 

simulated value for the internal dose metric was within 0.01% of the LOAEL. The HECs were 

17.45 ppm for the MCA dose metric and 52.68 ppm for the MRAMKB dose metric. Because there is 

limited information to determine whether the observed renal toxicity in female rats exposed to 

ethylbenzene is due to ethylbenzene or its metabolites, the lowest HEC value (17.45 ppm) was selected as 

the point of departure for the MRL. 

Was a conversion used from intermittent to continuous exposure? The PBPK models used to estimate 

internal dose metrics and HECs adjusted for intermittent exposure. 

Other additional studies or pertinent information that lend support to this MRL: The chronic toxicity of 

inhaled ethylbenzene has been examined humans and in 2-year bioassays in rats and mice conducted by 

NTP (1999). Hematological effects (increased average number of lymphocytes and decreased 

hemoglobin) were observed in workers exposed to solvents containing ethylbenzene (Angerer and Wulf 

1985). In rats, concentration-related increases in the severity of nephropathy were observed in female rats 

exposed to ≥75 ppm and in male rats exposed to 750 ppm (NTP 1999). Increases in the incidence of renal 

tubule hyperplasia were also observed in male and female rats exposed to 750 ppm. The lowest LOAEL 

identified in mice was 250 ppm for hyperplasia of pituitary gland pars distalis observed in females; at 

750 ppm, thyroid follicular cell hyperplasia was observed in male and female mice and hypertrophy and 

necrosis of the liver were observed in male mice. 

Agency Contacts (Chemical Managers): Jessilynn Taylor, Henry Abadin, Heraline Hicks 
 

 

 

 

ETHYLBENZENE A-28 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Ethylbenzene 

CAS Numbers: 100-41-4 

Date: June 2010 

Profile Status: Final Draft Post-Public Comment 

Route: [ ] Inhalation [x] Oral 

Duration: [ ] Acute [x] Intermediate [ ] Chronic 

Graph Key: 4 

Species: Rat 

Minimal Risk Level: 0.4 [x ] mg/kg/day [ ] ppm 

Reference: Mellert W, Deckardt K, Kauffmann W, et al. 2007. Ethylbenzene: 4- and 13-week rat oral 

toxicity. Arch Toxicol 81:361-370. 

Experimental design: Groups of 10 male and 10 female Wister rats were administered ethylbenzene (no 

vehicle) by oral gavage at doses of 0, 75, 250, or 750 mg/kg/day for 13 weeks. The total daily dose of 

ethylbenzene was administered as split morning/evening half doses. Animals were examined daily for 

mortality and clinical signs. Food and water consumption and body weights were recorded weekly. A 

detailed clinical examination [ophthalmology and a functional observational battery (FOB)] and 

assessment of motor activity were conducted during the last week of treatment. After 13 weeks, 

urinalysis was conducted and blood samples were obtained and analyzed for hematology and clinical 

chemistry; organ weights were recorded and gross histopathologic examinations of the liver, kidney, and 

pancreas were conducted on animals in all groups. A comprehensive histopathological examination of 

tissues was performed in the control and 750 mg/kg/day groups. 

Effect noted in study and corresponding doses: Clinical signs (post-dosing salivation) in treated animals 

were observed in all animals administered ≥250 mg/kg/day and in one animal administered 75 mg/kg/day. 

Terminal body weight in males was significantly decreased by 14% compared to controls in the 

750 mg/kg/day group. Mean corpuscular volume was increased in males and females and platelet count 

was reduced in females treated with 750 mg/kg/day. Effects indicative of liver toxicity included 

increased activity of serum liver enzymes (alanine aminotransferase and γ-glutamyl transferase) in males 

(≥250 mg/kg/day) and females (750 mg/mg/day), increased absolute and relative liver weights 

(≥250 mg/kg/day in males and females), and a dose-related increase in the incidence of centrilobular 

hepatocyte hypertrophy (≥250 mg/kg/day in males and females) (Table A-10). Increased bilirubin 

(≤250 mg/kg/day in males and 750 mg/kg/day in females), total protein (750 mg/kg/day in females), 

albumin (750 mg/kg/day in males and females), globulins (750 mg/kg/day in females), and cholesterol 

(≤250 mg/kg/day in males and females), and decreased prothrombin time (750 mg/kg/day in males and 

≥250 mg/kg/day in females) were considered by study investigators as adaptive effects in the liver. In 

males in the 75 mg/k/day group, relative liver weight was significantly increased by (4% compared to 

controls); however, no histopathological changes or increases in absolute liver or serum liver enzyme 

activities were observed at this dosage. Given that ethylbenzene is a microsomal enzyme inducer and the 

absence of histopathology and other evidence of liver injury at the 75 mg/kg/day dosage, the small 

increase in relative liver weight in male rats at this dosage was not considered indicative of an adverse 

effect on the liver. 
 

 

ETHYLBENZENE A-29
 

APPENDIX A 

Table A-10. Effects on Serum Liver Enzymes, Liver Weights, and Liver 

Histopathology in Male and Female Rats Exposed to Oral 

Ethylbenzene for 13 Weeks 

Dose group (mg/kg/day) 

Parameter 0 75 250 750 

Males 

ALT (μkat/L) 0.62±0.12a

 0.70±0.12 0.89±0.26b 1.11±0.23b 

GGT (nkat/L) 2±3 6±6 10±6b

 10±6b 

Absolute liver weight (g) 8.02±0.55 8.26±0.81 10.25±0.98b

 9.88±0.98b 

Liver/body weight (%) 2.26±0.08 2.36±0.08b

 3.01±0.14b 3.31±0.13b 

Centrilobular hepatocyte 1/10 1/10 6/10c

 8/10b 

hypertrophy (incidence) 

Females 

ALT(μkat/L) 0.58±0.18 0.55±0.08 0.60±0.12 0.73±0.19c 

Absolute liver weight (g) 5.40±0.30 5.72±0.53 6.11±0.36b

 7.15±0.50b 

Liver/body weight (%) 2.63±0.13 2.70±0.16 3.03±0.12b

 3.52±0.18b 

Centrilobular hepatocyte 0/10 0/10 5/10c

 10/10b 

hypertrophy (incidence) 

a

values are mean±standard deviation.
 b

p≤0.01.
 c

p≤0.05. 

ALT = alanine aminotransferase; GGT = γ-glutamyl transferase 

Source: Mellert et al. 2007 

Renal effects in males included increased serum creatinine (750 mg/kg/day), increased incidences of 

transitional epithelial cells and granular and epithelial cell casts in the urine (≥250 mg/kg/day), increased 

absolute and relative kidney weights (≥250 mg/kg/day), and a dose-related increase in severity of hyaline 

droplet nephropathy (≥250 mg/kg/day). Adverse renal effects in males were most likely related to 

accumulation of α2μ-globulin, and, therefore, considered not relevant to humans. Absolute kidney 

weight was significantly increased by 7 and 13% in females administered 250 and 750 mg/kg/day, 

respectively, compared to controls; however, since no histopathological findings or alterations in 

urinalysis parameters were observed, the increased kidney weight in females was not considered 

indicative of an adverse kidney effect in female rats. Absolute and relative thymus weights were 

decreased in females treated with ≥250 mg/kg/day, but no histopathological findings were observed. 

Results of the FOB did not reveal consistent treatment-related effects. 

Dose and end point used for MRL derivation: Based on evidence of hepatotoxicity (increased serum liver 

enzyme activity, absolute and relative liver weights, and incidence of centrilobular hepatocyte 

hypertrophy), the liver was identified as the most sensitive target for oral ethylbenzene, with NOAEL and 

LOAEL values of 75 and 250 mg/kg/day, respectively. Since serum liver enzyme activities were 

increased in the 250 and 750 mg/kg/day groups in males, but only in the 750 mg/kg/day group in females, 

males appeared more sensitive than females to hepatic effects of oral ethylbenzene. BMD analysis was 

used to identify points of departure for several liver endpoints (alanine aminotransferase activity, 
 

ETHYLBENZENE A-30 

APPENDIX A 

γ-glutamyl transferase activity, absolute liver weight, relative liver weight, and centrolobular hepatocyte 

hypertrophy) using the two internal dose metrics. 

[ ] NOAEL [ ] LOAEL [X] BMDL 

To determine the point of departure for derivation of the intermediate-duration MRL, a PBPK model was 

used to estimate internal dose metrics and data sets for serum liver enzymes, absolute and relative liver 

weight, and centrilobular hepatocyte hypertrophy (Table A-10) in male rats were evaluated for suitability 

for BMD modeling. Code for an ethylbenzene inhalation PBPK model was developed from 

documentation provided in Tardif et al. (1997) with revised metabolism parameter values reported in 

Haddad et al. (1999, 2001). This model reproduces model output reported in Tardif et al. (1997) for 

venous blood and alveolar air concentrations of ethylbenzene in rats and humans and output reported in 

Appendix R of American Chemistry Council (2007, Krishnan simulations) of human steady-state venous 

blood and alveolar air concentrations for exposure concentrations ranging from 1 to 50 ppm. The model 

was extended to implement first-order gastrointestinal absorption kinetics as described in Faber et al. 

(2006). For liver effects, the model simulated two internal dose metrics: time-averaged concentration of 

ethylbenzene in liver (MCL) and time-averaged rate of metabolism of ethylbenzene in liver (MRAMKL). 

The assumption of using the MCL metric is that the liver response is correlated with the time-averaged 

concentration of ethylbenzene in liver. The assumption in using the MRAMKL metric is that the liver 

response is correlated with the time-averaged rate of production of ethylbenzene metabolites in liver. 

Both metrics were explored because current knowledge of the mechanism of toxicity of ethylbenzene 

does not include an understanding of the relative contributions of parent compound or metabolites as 

proximate toxic agents in liver. 

Data for changes in alanine aminotransferase and γ-glutamyl transferase, absolute liver weight and 

relative liver weight were analyzed using all available continuous variable models in EPA BMDS 

(version 2.1.1). BMDs and the 95% lower confidence limit on the BMD (BMDLs) associated with a 

BMR of 1 standard deviation change from the control were calculated for all models. The data were fit to 

BMD models using the MCL and MRAMKL internal dose metrics. The following procedure for fitting 

continuous data was used. The simplest model (linear) was first applied to the data while assuming 

constant variance. If the data were consistent with the assumption of constant variance (p≥0.1), then the 

fit of the linear model to the means was evaluated and the polynomial, power and Hill models were fit to 

the data while assuming constant variance. Adequate model fit was judged by three criteria: goodnessof-fit p-value (p>0.1), visual inspection of the dose-response curve, and scaled residual at the data point 

(except the control) closest to the predefined BMR. Among all the models providing adequate fit to the 

data, the lowest BMCL (95% lower confidence limit on the benchmark concentration) was selected as the 

point of departure when the difference between the BMCLs estimated from these models were more 

3-fold; otherwise, the BMCL from the model with the lowest AIC was chosen. If the test for constant 

variance was negative, the linear model was run again while applying the power model integrated into the 

BMDS to account for nonhomogenous variance. If the nonhomogenous variance model provided an 

adequate fit (p≥0.1) to the variance data, then the fit of the linear model to the means was evaluated and 

the polynomial, power and Hill models are fit to the data and evaluated while the variance model is 

applied. Model fit and point of departure selection proceeded as described earlier. If the test for constant 

variance was negative and the nonhomogenous variance model did not provide an adequate fit to the 

variance data, then the data set was considered unsuitable for modeling. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE A-31 

APPENDIX A 

As summarized in Table A-11, the alanine aminotransferase activity data only adequately fit the Hill 

model (Figure A-9) and absolute liver weight data only fit the linear model with nonconstant variance 

(Figure A-10) when MCL was used as the internal dose metric. Three models fit the data (using MCL as 

the internal dose metric) for relative liver weight when the highest dose was dropped (linear, 2-degree 

polynomial, and power models); the linear model is presented in Figure A-11. No models meet adequate 

fit criteria for γ-glutamyl transferase when MCL was used as the internal dose metric. 

Table A-11. Model Predictions for Changes in Alanine Aminotransferase, 

γ-Glutamyl Transferase, and Absolute and Relative Liver Weight Using 

Liver Ethylbenzene Concentration (MCL) Dose Metric in Male Rats 

Exposed to Ethylbenzene Via Gavage for 13 Weeks Dose Metric 

Variance Means BMD1SD BMDL1SD 

Model p-valuea p-valuea AIC (μmol/L) (μmol/L) 

Alanine aminotransferase 

 All doses 

 Constant variance

 Linearb 0.02 0.04 -83.16 NA NA 

 Nonconstant variance 

Hillc

 0.34 0.83 -93.15 21.34 7.49

 Linearb

 0.34 0.001 -82.16 NA NA 

 Polynomial (2-degree)b 0.34 0.001 -82.16 NA NA 

 Polynomial (3-degree)b

 0.34 0.001 -82.16 NA NA 

 Powerc

 0.34 0.001 -82.16 NA NA 

γ-Glutamyl transferase Inadequate fit to all models 

Absolute liver weight

 All doses 

 Constant variance

 Hillc

 0.28 NA 33.68 NA NA 

 Linearb

 0.28 <0.0001 56.22 NA NA 

 Polynomial (2-degree)b

 0.28 <0.0001 56.22 NA NA 

 Polynomial (3-degree)b

 0.28 <0.0001 56.22 NA NA 

 Powerc

 0.28 <0.0001 56.22 NA NA 

 Highest dose dropped

 Constant variance

 Hillc Failed to generate a model output; the number of observations were 

less than the number of parameters for the Hill model 

Linearb

 0.20 0.87 19.46 42.31 32.17

 Polynomial (2-degree)b

 0.20 0.87 19.46 42.31 32.17

 Powerc

 0.20 0.87 19.46 42.31 32.17 

Relative liver weight 

 All doses 

 Constant variance 
 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE A-32 

APPENDIX A 

Table A-11. Model Predictions for Changes in Alanine Aminotransferase, 

γ-Glutamyl Transferase, and Absolute and Relative Liver Weight Using 

Liver Ethylbenzene Concentration (MCL) Dose Metric in Male Rats 

Exposed to Ethylbenzene Via Gavage for 13 Weeks Dose Metric 

Variance Means BMD1SD BMDL1SD 

Model p-valuea p-valuea AIC (μmol/L) (μmol/L)

 Hillc 0.15 NA -130.06 NA NA 

 Linearb

 0.15 <0.0001 -60.07 NA NA 

 Polynomial (2-degree)b

 0.15 <0.0001 -60.07 NA NA 

 Polynomial (3-degree)b

 0.15 <0.0001 -60.07 NA NA 

 Powerc

 0.15 <0.0001 -60.07 NA NA 

 Highest dose dropped

 Constant variance

 Hillc Failed to generate a model output; the number of observations were 

less than the number of parameters for the Hill model 

Linearb

 0.11 0.39 -102.26 16.74 13.53

 Polynomial (2-degree)b

 0.11 0.39 -102.26 16.74 13.53

 Powerc

 0.11 0.39 -102.26 16.74 13.53 

a

Values <0.10 fail to meet conventional goodness-of-fit criteria. b

Coefficients restricted to be positive.
 c

Power restricted to ≥1.
 

AIC = Akaike Information Criterion; BMD1SD = benchmark dose associated with the benchmark response of 

1 standard deviation (SD); BMDL = 95% lower confidence limit on the BMD; MCL = time-averaged concentration of 

ethylbenzene in liver; NA = not applicable, model does not provide adequate fit to the data
 
Figure A-9. Predicted (Hill Model with Nonconstant Variance) and 

Observed Changes in Alanine Aminotransferase Levels Using 

MCL Internal Dose Metric* 
 

*BMD and BMDL indicated are associated with a change of 1 standard deviation from control and are in units of 

umol/L. 

Figure A-10. Predicted (Linear Model with Constant Variance) and Observed 

Changes in Absolute Liver Weight Using MCL Internal Dose Metric* 

Highest dose dropped 

*BMD and BMDL indicated are associated with a change of 1 standard deviation from control and are in units of 

umol/L. 

ETHYLBENZENE A-33 

APPENDIX A 
Figure A-11. Predicted (Linear Model with Constant Variance) and 

Observed Changes in Relative Liver Weight Using MCL Internal 

Dose Metric* 

 

 

 

 

 

ETHYLBENZENE A-34 

APPENDIX A 

Highest dose dropped 

*BMD and BMDL indicated are associated with a change of 1 standard deviation from control and are in units of 

umol/L. 

The model predictions using the MRAMKL internal dose metric are summarized in Table A-12. Several 

models fit the alanine aminotransferase data, the 3-degree polynomial model with nonconstant variance 

had the lowest AIC and is illustrated in Figure A-12. The linear, 2-degree polynomial, 3-degree 

polynomial, and power models all meet adequate fit criteria to the γ-glutamyl transferase data; Figure 

A-13 shows the fit of the linear model. The Hill model (Figure A-14) was the only model which provided 

adequate fit to the absolute liver weight data. Several models fit the relative liver weight data, the 

2-degree polynomial model provided the best fit, as judged by the AIC; this model is shown in Figure 

A-15. 

Table A-12. Model Predictions for Changes in Alanine Aminotransferase,
 

γ-Glutamyl Transferase, Absolute Liver Weight, and Relative Liver 

Weight in Male Rats Exposed to Ethylbenzene via Gavage for 

13 Weeks Using MRAMKL Internal Dose Metric 

Model 

Alanine aminotransferase 

Variance 

p-valuea 

Means 

p-valuea AIC 

BMD1SD 

(μmol/hour/kg 

liver) 

BMDL1SD 

(μmol/hour/kg 

liver) 

 All doses 

Constant variance

 Linearb 0.02 0.14 -85.87 NA NA 

Nonconstant variance 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE A-35 

APPENDIX A 

Table A-12. Model Predictions for Changes in Alanine Aminotransferase,
 

γ-Glutamyl Transferase, Absolute Liver Weight, and Relative Liver 

Weight in Male Rats Exposed to Ethylbenzene via Gavage for 

13 Weeks Using MRAMKL Internal Dose Metric 

BMD1SD BMDL1SD 

Variance Means (μmol/hour/kg (μmol/hour/kg 

Model p-valuea p-valuea AIC liver) liver) 

Hillc 0.34 NA -90.93 NA NA 

 Linearb

 0.34 0.26 -92.47 438.99 307.25

 Polynomial (2-degree)b 0.34 0.65 -92.98 771.05 387.82 

Polynomial (3-degree)b

 0.34 0.81 -93.14 804.09 391.02

 Powerc

 0.34 0.61 -92.93 778.16 388.97 

γ-Glutamyl transferase

 All doses 

Constant variance

 Hillc

 0.14 NA 180.82 NA NA 

Linearb

 0.14 0.73 177.46 1,072.23 737.62

 Polynomial (2-degree)b

 0.14 0.73 177.46 1,072.23 737.62

 Polynomial (3-degree)b

 0.14 0.73 177.46 1,072.23 737.62

 Powerc

 0.14 0.73 177.46 1,072.23 737.62 

Absolute liver weight

 All doses 

Constant variance 

Hillc

 0.28 0.31 31.68 602.99 548.01

 Linearb

 0.28 0.05 34.73 NA NA 

 Polynomial (2-degree)b

 0.28 0.01 36.61 NA NA 

 Polynomial (3-degree)b

 0.28 0.01 36.61 NA NA 

 Powerc

 0.28 0.02 36.29 NA NA 

Relative liver weight 

 All doses 

Constant variance

 Hillc

 0.15 NA -130.06 NA NA 

 Linearb

 0.15 <0.0001 -107.43 NA NA 

Polynomial (2-degree)b

 0.15 0.96 -133.98 531.76 390.47 
 

 

Figure A-12. Predicted (3-Degree Polynomial with Nonconstant Variance) 

and Observed Changes in Alanine Aminotransferase Using MRAMKL 

Internal Dose Metric* 

*BMD and BMDL indicated are associated with a change of 1 standard deviation from control and are in units of 

μmol/hour/kg liver. 

ETHYLBENZENE A-36 

APPENDIX A 

Table A-12. Model Predictions for Changes in Alanine Aminotransferase,
 

γ-Glutamyl Transferase, Absolute Liver Weight, and Relative Liver 

Weight in Male Rats Exposed to Ethylbenzene via Gavage for 

13 Weeks Using MRAMKL Internal Dose Metric 

BMD1SD BMDL1SD 

Variance Means (μmol/hour/kg (μmol/hour/kg 

Model p-valuea p-valuea AIC liver) liver) 

 Polynomial (3-degree)b 0.15 0.80 -132.00 540.34 485.79

 Powerc

 0.15 0.83 -132.02 547.45 416.38
 

a

Values <0.10 fail to meet conventional goodness-of-fit criteria. b

Coefficients restricted to be positive.
 c

Power restricted to ≥1.
 

AIC = Akaike Information Criterion; BMD = maximum likelihood estimate of the dose associated with the selected
 

benchmark response of 1 standard deviation (SD); BMDL = 95% lower confidence limit on the BMD; 

MRAMKL = time-averaged rate of metabolism of ethylbenzene in liver; NA = not applicable, model does not provide 

adequate fit to the data.
 

Source: Mellert et al. 2007
 
Figure A-13. Predicted (Linear Model with Nonconstant Variance) and Observed 

Changes in γ-Glutamyl Transferase Using MRAMKL Internal Dose Metric* 

*BMD and BMDL indicated are associated with a change of 1 standard deviation from control and are in units of 

μmol/hour/kg liver. 

Figure A-14. Predicted (Hill Model with Constant Variance) and Observed 

Changes in Absolute Liver Weight Using MRAMKL Internal Dose Metric* 

*BMD and BMDL indicated are associated with a change of 1 standard deviation from control and are in units of 

μmol/hour/kg liver. 

ETHYLBENZENE A-37 

APPENDIX A 
 

Figure A-15. Predicted (2-Degree Polynomial Model with Constant Variance) and 

Observed Changes in Relative Liver Weight Using MRAMKL Internal Dose Metric*
 

*BMD and BMDL indicated are associated with a change of 1 standard deviation from control and are in units of 

μmol/hour/kg liver. 

ETHYLBENZENE A-38 

APPENDIX A 

Data for the incidence of centrilobular hepatocyte hypertrophy were analyzed using all available 

dichotomous models in the EPA BMDS (version 2.1.1) using the extra risk option. The multistage model 

was run for all polynomial degrees up to n-1 (where n is the number of dose groups including control). 

Adequate model fit was judged by three criteria: goodness-of-fit p-value (p>0.1), visual inspection of the 

dose-response curve, and scaled residual at the data point (except the control) closest to the predefined 

BMR. Among all the models meeting adequate fit criteria, the lowest BMDL was selected as the point of 

departure when the difference between the BMDLs estimated from these models were more than 3-fold; 

otherwise, the BMDL from the model with the lowest AIC was chosen. BMDs and lower bounds on the 

BMD (BMDLs) associated with a BMR of 10% extra risk were calculated for all models. The data were 

fit to BMD models using the MCL and MRAMKL dose metrics. The BMD models using the MCL dose 

metric are summarized in Table A-13. As assessed by the chi-square goodness-of-fit statistic, most of the 

models using the MCL dose metric provided adequate fit to the data. The BMDs ranged from 16.51 to 

127.56 μmol/L and the BMDLs ranged from 6.61 to 76.55 μmol/L. Because the range of BMDLs was 

greater than threefold; the lowest BMDL was selected as a point of departure. The log logistic model 

estimated the lowest BMDL of 6.61 μmol/L; the fit of this model is presented in Figure A-16. 
 

 

 

 

 

 

 

 

ETHYLBENZENE A-39 

APPENDIX A 

Table A-13. Model Predictions for the Incidence of Centrilobular Hepatocyte 

Hypertrophy in Male Rats Exposed to Ethylbenzene via Gavage for 

13 Weeks Using MCL Internal Dose Metric 

Model 

Gammab 

χ

2

 Goodness-of-fit 

p-valuea AIC 

0.13 44.25 

BMD10 (μmol/L) 

48.12 

BMDL10 (μmol/L) 

26.42 

Logistic 

Log Logistic 

Log Probit 

Multistage (1-degree 

polynomial)c 

Multistage (2-degree 

polynomial)c 

Multistage (3-degree 

polynomial)c 

Probit

0.04 

0.59 

0.07 

0.13

0.13

0.13

 0.04 

46.66 

41.50 

44.67 

44.25 

44.25 

44.25 

46.62 

127.56 

16.51 

NA 

48.12 

48.12 

48.12 

NA 

76.55 

6.61 

NA 

26.42 

26.42 

26.42 

NA 

Weibullb

 0.13 44.25 48.12 26.42 

Quantal-Linear 0.13 44.25 48.12 26.42 

a

Values <0.10 fail to meet conventional goodness-of-fit criteria. b

Power restricted to ≥1.
 c

Betas restricted to ≥0. 

AIC = Akaike Information Criteria; BMD = benchmark dose associated with the selected benchmark response of 

10% extra risk; BMDL = 95% lower confidence limit on the BMD; NA = not applicable, the data did not adequately fit 

the model
 

Source: Mellert et al. 2007
 
Figure A-16. Predicted (Log Logistic Model) and Observed Incidence of 

Centrilobular Hepatocyte Hypertrophy*
 

*BMDs and BMDLs indicated are associated with 10% extra risk and are in units of μmol/L. 

The BMD models using the MRAMKL dose metric are presented in Table A-14. All models provided 

adequate fit to the data (χ

2 p>0.1). Comparing across models, a better fit is generally indicated by a lower 

AIC. As assessed by AIC, the multistage 3-degree polynomial model (Figure 17) provided the best fit to 

the data. The BMD10 and BMDL10 predicted by this model for the data on centrilobular hepatocyte 

hypertrophy in male rats were 704.21 and 206.91 μmo/hour/kg liver, respectively. 

Because there is limited information to determine whether the observed hepatic effects are due to 

ethylbenzene or its metabolites, the lowest BMDL value (6.61 μmol/L, MCL dose metric) was selected as 

the point of departure for the MRL. 

ETHYLBENZENE A-40 

APPENDIX A 
 

 

 

 

 

 

 

 

 

ETHYLBENZENE A-41 

APPENDIX A 

Table A-14. Model Predictions for the Incidence of Centrilobular Hepatocyte 

Hypertrophy in Male Rats Administered Ethylbenzene Via Gavage for 

13 Weeks Using MRAMKL Internal Dose Metric 

Model 

Gammab 

χ

2

 Goodness-offit p-valuea

0.99

 AIC 

42.47 

BMD10 

(μmol/hour/kg liver) 

937.22 

BMDL10 

(μmol/hour/kg liver) 

283.42 

Logistic 

Log Logistic 

LogProbit

Multistage (1-degree 

polynomial)c 

Multistage (2-degree 

polynomial)c

Multistage (3-degree 

polynomial)c 

Probit

0.62 

0.98 

1.00 

0.18

 0.65 

0.93 

0.55 

41.38 

42.47 

42.47 

44.50 

41.42 

40.61 

41.64 

480.93 

961.63 

973.00 

178.95 

483.71 

704.21 

426.74 

300.24 

313.44 

332.90 

113.79 

179.74 

206.91 

278.66 

Weibullb

 0.88 42.49 849.57 267.67 

Quantal-Linear 0.18 44.50 178.95 113.79 

a

Values <0.10 fail to meet conventional goodness-of-fit criteria b

Power restricted to ≥1 c

Betas restricted to ≥0 

AIC = Akaike Information Criteria; BMD = benchmark dose associated with the selected benchmark response; 

BMDL = 95% lower confidence limit on the BMD 

Source: Mellert et al. 2007 
Figure A-17. Predicted (Multistage, 3-Degree Polynomial Model) and Observed 

Incidence of Centrilobular Hepatocyte Hypertrophy* 

*BMDs and BMDLs indicated are associated with 10% extra risk and are in units of μmol/hour/kg liver. 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a less serious LOAEL 

[x] 3 for extrapolation from animals to humans with dosimetric adjustments 

[x] 10 for human variability 

ETHYLBENZENE A-42 

APPENDIX A 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? Not applicable. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: For 

each end point and dose metric, human equivalent doses (HEDs) were predicted for the BMDL value with 

the lowest AIC (if multiple BMD models met the adequate fit criteria) using the human PBPK model. 

The BMDL values for the internal dose metrics (MCL and MRAMKL) were converted to HED values by 

iterative simulation of human oral exposures. Exposure doses (mg/kg/day) were varied until the 

simulated value for the internal dose metric was within 0.01% of the BMDL. The HEDs are summarized 

in Tables A-15 and A-16. 
 

 

 

 

 

 

 

 

ETHYLBENZENE A-43
 

APPENDIX A
 

Table A-15. Human Equivalent Doses for Liver Effects Using MCL Internal Dose 

Metric
 

BMDL HEDa 

Effect Model (μmol/L) (mg/kg/day) 

Increased alanine aminotransferase Hill (all doses); constant variance 7.49 11.82 

Increased γ-glutamyl transferase Inadequate fit to all models 

Increased absolute liver weights Linear (highest dose dropped); 32.17 31.82 

constant variance 

Increased relative liver weights Linear (highest dose dropped); 13.53 18.47 

constant variance 

Centrilobular hepatocyte Log logistic 6.61 10.68 

hypertrophy 

a

Calculated using a reference human body weight of 70 kg and the assumption that the daily dose was delivered in 

16 dose splits/24 hours (i.e., only exposed during waking hours). 

BMDL = 95% lower confidence limit on the benchmark dose; HED = human equivalent dose; MCL = time-averaged 

concentration of ethylbenzene in liver 

Table A-16. Human Equivalent Doses for Liver Effects Using MRAMKL Internal 

Dose Metric 

BMDL HEDb 

Effect Modela (μmol/hour/kg liver) (mg/kg/day) 

Increased alanine aminotransferase 3-Degree polynomial; 

nonconstant variance 

391.02 31.06 

Increased γ-glutamyl transferase Linear; constant variance 737.62 111.37c 

Increased absolute liver weights Hill; constant variance 548.01 48.62 

Increased relative liver weights 2-Degree polynomial; 

constant variance 

390.47 31.01 

Centrilobular hepatocyte 

hypertrophy 

Multistage (3-degree 

polynomial) 

206.91 15.48 

a

All doses used for BMD modeling.

b

Calculated using a reference human body weight of 70 kg and the assumption that the daily dose was delivered in 

16 dose splits/24 hours (i.e., only exposed during waking hours).
 c

Approximate value, value is very close to the metabolism Vmax.
 

BMDL = 95% lower confidence limit on the benchmark dose; MRAMKL = time-averaged rate of metabolism of
 

ethylbenzene in liver
 

Was a conversion used from intermittent to continuous exposure? The PBPK models used to estimate 

internal dose metrics and HEDs adjusted for intermittent exposure. 

Other additional studies or pertinent information that lend support to this MRL: The intermediateduration oral database for ethylbenzene is limited to a study conducted by Mellert et al. (2007) evaluating 

the effects of oral exposure of rats to ethylbenzene for 4 and 13 weeks, and a poorly reported 6-month 
 

 

 

 

 

 

 

ETHYLBENZENE A-44 

APPENDIX A 

exposure study in rats (Wolf et al. 1956). The 4- and 13-week studies by Mellert et al. (2007) found 

effects consistent with hepatotoxicity including increased absolute and relative liver weights, increased 

incidence of hepatocyte centrilobular hypertrophy, and increased serum liver enzyme activities in rats 

administered ≥250 mg/kg/day. Kidney effects, including increases in increases in relative kidney weight 

and hyaline droplet nephropathy were observed in males administered ≥250 mg/kg/day; however, these

effects were most likely secondary to increases accumulation of accumulation of α2μ-globulin 

accumulation, and, therefore, considered not relevant to humans. Wolf et al. (1956) also reported liver 

effects (characterized by cloudy swelling of parenchymal cells of the liver and an increase in liver weight 

were observed in female rats administered 408 mg/kg/day by gavage for 6 months (Wolf et al. 1956). No 

other hepatic changes were reported. However, this study was poorly reported and did not provide 

adequate descriptions of study methods or results. 

Although no additional data are available regarding the effects of intermediate oral exposure to 

ethylbenzene, results of an acute-duration oral study indicate that ethylbenzene is ototoxic (Gagnaire and 

Langlais 2005). In male rats administered 900 mg/kg/day (the only dose tested) by gavage for 2 weeks, 

an almost complete loss of the three rows of OHCs in the organ of Corti was observed in male rats 

(Gagnaire and Langlais 2005). The 4- and 13-week oral studies by Mellert et al. (2007) did not examine 

the cochlea or measure auditory function. 

Acute (Cappaert et al. 1999, 2000, 2001, 2002) and intermediate (Gagnaire et al. 2007) inhalation studies 

and an acute oral study (Gagnaire and Langlais 2005) have identified ototoxicity as a sensitive effect of 

ethylbenzene exposure. Although intermediate-duration oral studies have not examined this potential 

endpoint, a comparison of the human equivalent dose for liver effects following oral exposure and the 

human equivalent concentration for ototoxicity following inhalation exposure can be made using the 

PBPK model developed for MRL derivation. The human PBPK model predicts that the HED 

(10.68 mg/kg/day) would result in an internal dose of 1.92 μmol/L for MCA (the relevant internal dose 

metric for ototoxicicty). The HEC that corresponds to an MCA of 1.92 μmol/L is 8.37 ppm. Therefore, 

the HED of 10.68 mg/kg/day would be equivalent to human equivalent air concentration of 8.37 ppm. 

This air concentration is about 8-fold lower than the HEC of 63.64 ppm used to derive the intermediateduration inhalation MRL, suggesting that the liver is a more sensitive target of oral toxicity than the 

cochlea. 

Agency Contacts (Chemical Managers): Jessilynn Taylor, Henry Abadin, Heraline Hicks 
 

 

 

 

 

 

 

 

ETHYLBENZENE B-1 

APPENDIX B. USER'S GUIDE 

Chapter 1 

Public Health Statement 

This chapter of the profile is a health effects summary written in non-technical language. Its intended 

audience is the general public, especially people living in the vicinity of a hazardous waste site or 

chemical release. If the Public Health Statement were removed from the rest of the document, it would 

still communicate to the lay public essential information about the chemical. 

The major headings in the Public Health Statement are useful to find specific topics of concern. The 

topics are written in a question and answer format. The answer to each question includes a sentence that 

will direct the reader to chapters in the profile that will provide more information on the given topic. 

Chapter 2 

Relevance to Public Health 

This chapter provides a health effects summary based on evaluations of existing toxicologic, 

epidemiologic, and toxicokinetic information. This summary is designed to present interpretive, weightof-evidence discussions for human health end points by addressing the following questions: 

1.	 What effects are known to occur in humans? 

2.	 What effects observed in animals are likely to be of concern to humans? 

3.	 What exposure conditions are likely to be of concern to humans, especially around hazardous 

waste sites? 

The chapter covers end points in the same order that they appear within the Discussion of Health Effects 

by Route of Exposure section, by route (inhalation, oral, and dermal) and within route by effect. Human 

data are presented first, then animal data. Both are organized by duration (acute, intermediate, chronic). 

In vitro data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also 

considered in this chapter. 

The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using 

existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer 

potency or perform cancer risk assessments. Minimal Risk Levels (MRLs) for noncancer end points (if 

derived) and the end points from which they were derived are indicated and discussed. 

Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public 

health are identified in the Chapter 3 Data Needs section. 

Interpretation of Minimal Risk Levels 

Where sufficient toxicologic information is available, ATSDR has derived MRLs for inhalation and oral 

routes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are not 

meant to support regulatory action, but to acquaint health professionals with exposure levels at which 

adverse health effects are not expected to occur in humans. 
 

 

 

 

 

 

 

ETHYLBENZENE B-2 

APPENDIX B 

MRLs should help physicians and public health officials determine the safety of a community living near 

a chemical emission, given the concentration of a contaminant in air or the estimated daily dose in water. 

MRLs are based largely on toxicological studies in animals and on reports of human occupational 

exposure. 

MRL users should be familiar with the toxicologic information on which the number is based. Chapter 2, 

"Relevance to Public Health," contains basic information known about the substance. Other sections such 

as Chapter 3 Section 3.9, "Interactions with Other Substances,” and Section 3.10, "Populations that are 

Unusually Susceptible" provide important supplemental information. 

MRL users should also understand the MRL derivation methodology. MRLs are derived using a 

modified version of the risk assessment methodology that the Environmental Protection Agency (EPA) 

provides (Barnes and Dourson 1988) to determine reference doses (RfDs) for lifetime exposure. 

To derive an MRL, ATSDR generally selects the most sensitive end point which, in its best judgement, 

represents the most sensitive human health effect for a given exposure route and duration. ATSDR 

cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available 

for all potential systemic, neurological, and developmental effects. If this information and reliable 

quantitative data on the chosen end point are available, ATSDR derives an MRL using the most sensitive 

species (when information from multiple species is available) with the highest no-observed-adverse-effect 

level (NOAEL) that does not exceed any adverse effect levels. When a NOAEL is not available, a 

lowest-observed-adverse-effect level (LOAEL) can be used to derive an MRL, and an uncertainty factor 

(UF) of 10 must be employed. Additional uncertainty factors of 10 must be used both for human 

variability to protect sensitive subpopulations (people who are most susceptible to the health effects 

caused by the substance) and for interspecies variability (extrapolation from animals to humans). In 

deriving an MRL, these individual uncertainty factors are multiplied together. The product is then 

divided into the inhalation concentration or oral dosage selected from the study. Uncertainty factors used 

in developing a substance-specific MRL are provided in the footnotes of the levels of significant exposure 

(LSE) tables. 

Chapter 3 

Health Effects 

Tables and Figures for Levels of Significant Exposure (LSE) 

Tables and figures are used to summarize health effects and illustrate graphically levels of exposure 

associated with those effects. These levels cover health effects observed at increasing dose 

concentrations and durations, differences in response by species, MRLs to humans for noncancer end 

points, and EPA's estimated range associated with an upper- bound individual lifetime cancer risk of 1 in 

10,000 to 1 in 10,000,000. Use the LSE tables and figures for a quick review of the health effects and to 

locate data for a specific exposure scenario. The LSE tables and figures should always be used in 

conjunction with the text. All entries in these tables and figures represent studies that provide reliable, 

quantitative estimates of NOAELs, LOAELs, or Cancer Effect Levels (CELs). 

The legends presented below demonstrate the application of these tables and figures. Representative 

examples of LSE Table 3-1 and Figure 3-1 are shown. The numbers in the left column of the legends 

correspond to the numbers in the example table and figure. 
 

 

 

 

 

 

 

 

ETHYLBENZENE B-3 

APPENDIX B 

LEGEND 

See Sample LSE Table 3-1 (page B-6) 

(1) Route of Exposure. One of the first considerations when reviewing the toxicity of a substance 

using these tables and figures should be the relevant and appropriate route of exposure. Typically 

when sufficient data exist, three LSE tables and two LSE figures are presented in the document. 

The three LSE tables present data on the three principal routes of exposure, i.e., inhalation, oral, 

and dermal (LSE Tables 3-1, 3-2, and 3-3, respectively). LSE figures are limited to the inhalation 

(LSE Figure 3-1) and oral (LSE Figure 3-2) routes. Not all substances will have data on each 

route of exposure and will not, therefore, have all five of the tables and figures. 

(2) Exposure Period. Three exposure periods—acute (less than 15 days), intermediate (15– 

364 days), and chronic (365 days or more)—are presented within each relevant route of exposure. 

In this example, an inhalation study of intermediate exposure duration is reported. For quick 

reference to health effects occurring from a known length of exposure, locate the applicable 

exposure period within the LSE table and figure. 

(3) Health Effect. The major categories of health effects included in LSE tables and figures are 

death, systemic, immunological, neurological, developmental, reproductive, and cancer. 

NOAELs and LOAELs can be reported in the tables and figures for all effects but cancer. 

Systemic effects are further defined in the "System" column of the LSE table (see key number 

18). 

(4) Key to Figure. Each key number in the LSE table links study information to one or more data 

points using the same key number in the corresponding LSE figure. In this example, the study 

represented by key number 18 has been used to derive a NOAEL and a Less Serious LOAEL 

(also see the two "18r" data points in sample Figure 3-1). 

(5) Species. The test species, whether animal or human, are identified in this column. Chapter 2, 

"Relevance to Public Health," covers the relevance of animal data to human toxicity and 

Section 3.4, "Toxicokinetics," contains any available information on comparative toxicokinetics. 

Although NOAELs and LOAELs are species specific, the levels are extrapolated to equivalent 

human doses to derive an MRL. 

(6) Exposure Frequency/Duration. The duration of the study and the weekly and daily exposure 

regimens are provided in this column. This permits comparison of NOAELs and LOAELs from 

different studies. In this case (key number 18), rats were exposed to “Chemical x” via inhalation 

for 6 hours/day, 5 days/week, for 13 weeks. For a more complete review of the dosing regimen, 

refer to the appropriate sections of the text or the original reference paper (i.e., Nitschke et al. 

1981). 

(7) System. This column further defines the systemic effects. These systems include respiratory, 

cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and 

dermal/ocular. "Other" refers to any systemic effect (e.g., a decrease in body weight) not covered 

in these systems. In the example of key number 18, one systemic effect (respiratory) was 

investigated. 

(8) NOAEL. A NOAEL is the highest exposure level at which no harmful effects were seen in the 

organ system studied. Key number 18 reports a NOAEL of 3 ppm for the respiratory system, 

which was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm (see 

footnote "b"). 
 

 

 

 

 

ETHYLBENZENE B-4 

APPENDIX B 

(9) LOAEL. A LOAEL is the lowest dose used in the study that caused a harmful health effect. 

LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help 

readers identify the levels of exposure at which adverse health effects first appear and the 

gradation of effects with increasing dose. A brief description of the specific end point used to 

quantify the adverse effect accompanies the LOAEL. The respiratory effect reported in key 

number 18 (hyperplasia) is a Less Serious LOAEL of 10 ppm. MRLs are not derived from 

Serious LOAELs. 

(10)	 Reference. The complete reference citation is given in Chapter 9 of the profile. 

(11)	 CEL. A CEL is the lowest exposure level associated with the onset of carcinogenesis in 

experimental or epidemiologic studies. CELs are always considered serious effects. The LSE 

tables and figures do not contain NOAELs for cancer, but the text may report doses not causing 

measurable cancer increases. 

(12)	 Footnotes. Explanations of abbreviations or reference notes for data in the LSE tables are found 

in the footnotes. Footnote "b" indicates that the NOAEL of 3 ppm in key number 18 was used to 

derive an MRL of 0.005 ppm. 

LEGEND 

See Sample Figure 3-1 (page B-7) 

LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the 

reader quickly compare health effects according to exposure concentrations for particular exposure 

periods. 

(13)	 Exposure Period. The same exposure periods appear as in the LSE table. In this example, health 

effects observed within the acute and intermediate exposure periods are illustrated. 

(14)	 Health Effect. These are the categories of health effects for which reliable quantitative data 

exists. The same health effects appear in the LSE table. 

(15)	 Levels of Exposure. Concentrations or doses for each health effect in the LSE tables are 

graphically displayed in the LSE figures. Exposure concentration or dose is measured on the log 

scale "y" axis. Inhalation exposure is reported in mg/m3 or ppm and oral exposure is reported in 

mg/kg/day. 

(16)	 NOAEL. In this example, the open circle designated 18r identifies a NOAEL critical end point in 

the rat upon which an intermediate inhalation exposure MRL is based. The key number 18 

corresponds to the entry in the LSE table. The dashed descending arrow indicates the 

extrapolation from the exposure level of 3 ppm (see entry 18 in the table) to the MRL of 

0.005 ppm (see footnote "b" in the LSE table). 

(17)	 CEL. Key number 38m is one of three studies for which CELs were derived. The diamond 

symbol refers to a CEL for the test species-mouse. The number 38 corresponds to the entry in the 

LSE table. 
ETHYLBENZENE B-5 

APPENDIX B 

(18)	 Estimated Upper-Bound Human Cancer Risk Levels. This is the range associated with the upperbound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived 

from the EPA's Human Health Assessment Group's upper-bound estimates of the slope of the 

cancer dose response curve at low dose levels (q1*). 

(19)	 Key to LSE Figure. The Key explains the abbreviations and symbols used in the figure. 
SAMPLE

1 → Table 3-1. Levels of Significant Exposure to [Chemical x] – Inhalation 

LOAEL (effect) Exposure 

Key to frequency/ NOAEL Less serious Serious (ppm) 

figurea Species duration System (ppm) (ppm) Re

2 3 4 

→ INTERMEDIATE EXPOSURE 

5 6 7 8 9 10 

→ Systemic ↓ ↓ ↓ ↓ ↓ ↓

18 Rat 13 wk Resp 3b 10 (hyperplasia) 

→ 5 d/wk Nit

6 hr/d 

CHRONIC EXPOSURE 

Cancer 11 

↓

38 Rat 18 mo 20 (CEL, multiple W

5 d/wk organs) 7 hr/d 

39 Rat 89–104 wk 10 (CEL, lung tumors, NT

5 d/wk nasal tumors) 6 hr/d 

40 Mouse 79–103 wk 10 (CEL, lung tumors, NT

5 d/wk hemangiosarcomas) 6 hr/d 

12 → a The number corresponds to entries in Figure 3-1. b Used to derive an intermediate inhalation Minimal Risk Level (MRL) of 5x10-3 ppm; dose adjusted for intermittent ex

by an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). 

ETHYLBENZENE B-8 

APPENDIX B 

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ETHYLBENZENE C-1 

APPENDIX C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS 

ACGIH American Conference of Governmental Industrial Hygienists 

ACOEM American College of Occupational and Environmental Medicine 

ADI acceptable daily intake 

ADME absorption, distribution, metabolism, and excretion 

AED atomic emission detection 

AFID alkali flame ionization detector 

AFOSH Air Force Office of Safety and Health 

ALT alanine aminotransferase 

AML acute myeloid leukemia 

AOAC Association of Official Analytical Chemists 

AOEC Association of Occupational and Environmental Clinics 

AP alkaline phosphatase 

APHA American Public Health Association 

AST aspartate aminotransferase 

atm atmosphere 

ATSDR Agency for Toxic Substances and Disease Registry 

AWQC Ambient Water Quality Criteria 

BAT best available technology 

BCF bioconcentration factor 

BEI Biological Exposure Index 

BMD/C benchmark dose or benchmark concentration 

BMDX dose that produces a X% change in response rate of an adverse effect 

BMDLX 95% lower confidence limit on the BMDX 

BMDS Benchmark Dose Software 

BMR benchmark response 

BSC Board of Scientific Counselors 

C centigrade 

CAA Clean Air Act 

CAG Cancer Assessment Group of the U.S. Environmental Protection Agency 

CAS Chemical Abstract Services 

CDC Centers for Disease Control and Prevention 

CEL cancer effect level 

CELDS Computer-Environmental Legislative Data System 

CERCLA Comprehensive Environmental Response, Compensation, and Liability Act 

CFR Code of Federal Regulations 

Ci curie 

CI confidence interval 

CL ceiling limit value 

CLP Contract Laboratory Program 

cm centimeter 

CML chronic myeloid leukemia 

CPSC Consumer Products Safety Commission 

CWA Clean Water Act 

DHEW Department of Health, Education, and Welfare 

DHHS Department of Health and Human Services 

DNA deoxyribonucleic acid 

DOD Department of Defense 

DOE Department of Energy 

DOL Department of Labor 
 

 

ETHYLBENZENE C-2 

APPENDIX C 

DOT Department of Transportation 

DOT/UN/ Department of Transportation/United Nations/ 

NA/IMDG North America/Intergovernmental Maritime Dangerous Goods Code 

DWEL drinking water exposure level 

ECD electron capture detection 

ECG/EKG electrocardiogram 

EEG electroencephalogram 

EEGL Emergency Exposure Guidance Level 

EPA Environmental Protection Agency 

F Fahrenheit 

F1 first-filial generation 

FAO Food and Agricultural Organization of the United Nations 

FDA Food and Drug Administration 

FEMA Federal Emergency Management Agency 

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act 

FPD flame photometric detection 

fpm feet per minute 

FR Federal Register 

FSH follicle stimulating hormone 

g gram 

GC gas chromatography 

gd gestational day 

GLC gas liquid chromatography 

GPC gel permeation chromatography 

HPLC high-performance liquid chromatography 

HRGC high resolution gas chromatography 

HSDB Hazardous Substance Data Bank 

IARC International Agency for Research on Cancer 

IDLH immediately dangerous to life and health 

ILO International Labor Organization 

IRIS Integrated Risk Information System 

Kd adsorption ratio 

kg kilogram 

kkg metric ton 

Koc organic carbon partition coefficient 

Kow octanol-water partition coefficient 

L liter 

LC liquid chromatography 

LC50 lethal concentration, 50% kill 

LCLo lethal concentration, low 

LD50 lethal dose, 50% kill 

LDLo lethal dose, low 

LDH lactic dehydrogenase 

LH luteinizing hormone 

LOAEL lowest-observed-adverse-effect level 

LSE Levels of Significant Exposure 

LT50 lethal time, 50% kill 

m meter 

MA trans,trans-muconic acid 

MAL maximum allowable level 

mCi millicurie 
ETHYLBENZENE C-3 

APPENDIX C 

MCL maximum contaminant level 

MCLG maximum contaminant level goal 

MF modifying factor 

MFO mixed function oxidase 

mg milligram 

mL milliliter 

mm millimeter 

mmHg millimeters of mercury 

mmol millimole 

mppcf millions of particles per cubic foot 

MRL Minimal Risk Level 

MS mass spectrometry 

NAAQS National Ambient Air Quality Standard 

NAS National Academy of Science 

NATICH National Air Toxics Information Clearinghouse 

NATO North Atlantic Treaty Organization 

NCE normochromatic erythrocytes 

NCEH National Center for Environmental Health 

NCI National Cancer Institute 

ND not detected 

NFPA National Fire Protection Association 

ng nanogram 

NHANES National Health and Nutrition Examination Survey 

NIEHS National Institute of Environmental Health Sciences 

NIOSH National Institute for Occupational Safety and Health 

NIOSHTIC NIOSH's Computerized Information Retrieval System 

NLM National Library of Medicine 

nm nanometer 

nmol nanomole 

NOAEL no-observed-adverse-effect level 

NOES National Occupational Exposure Survey 

NOHS National Occupational Hazard Survey 

NPD nitrogen phosphorus detection 

NPDES National Pollutant Discharge Elimination System 

NPL National Priorities List 

NR not reported 

NRC National Research Council 

NS not specified 

NSPS New Source Performance Standards 

NTIS National Technical Information Service 

NTP National Toxicology Program 

ODW Office of Drinking Water, EPA 

OERR Office of Emergency and Remedial Response, EPA 

OHM/TADS Oil and Hazardous Materials/Technical Assistance Data System 

OPP Office of Pesticide Programs, EPA 

OPPT Office of Pollution Prevention and Toxics, EPA 

OPPTS Office of Prevention, Pesticides and Toxic Substances, EPA 

OR odds ratio 

OSHA Occupational Safety and Health Administration 

OSW Office of Solid Waste, EPA 

OTS Office of Toxic Substances 
ETHYLBENZENE C-4 

APPENDIX C 

OW Office of Water 

OWRS Office of Water Regulations and Standards, EPA 

PAH polycyclic aromatic hydrocarbon 

PBPD physiologically based pharmacodynamic 

PBPK physiologically based pharmacokinetic 

PCE polychromatic erythrocytes 

PEL permissible exposure limit 

pg picogram 

PHS Public Health Service 

PID photo ionization detector 

pmol picomole 

PMR proportionate mortality ratio 

ppb parts per billion 

ppm parts per million 

ppt parts per trillion 

PSNS pretreatment standards for new sources 

RBC red blood cell 

REL recommended exposure level/limit 

RfC reference concentration 

RfD reference dose 

RNA ribonucleic acid 

RQ reportable quantity 

RTECS Registry of Toxic Effects of Chemical Substances 

SARA Superfund Amendments and Reauthorization Act 

SCE sister chromatid exchange 

SGOT serum glutamic oxaloacetic transaminase 

SGPT serum glutamic pyruvic transaminase 

SIC standard industrial classification 

SIM selected ion monitoring 

SMCL secondary maximum contaminant level 

SMR standardized mortality ratio SNARL suggested no adverse response level 

SPEGL Short-Term Public Emergency Guidance Level 

STEL short term exposure limit 

STORET Storage and Retrieval 

TD50 toxic dose, 50% specific toxic effect 

TLV threshold limit value 

TOC total organic carbon 

TPQ threshold planning quantity 

TRI Toxics Release Inventory 

TSCA Toxic Substances Control Act 

TWA time-weighted average 

UF uncertainty factor 

U.S. United States 

USDA United States Department of Agriculture 

USGS United States Geological Survey 

VOC volatile organic compound 

WBC white blood cell 

WHO World Health Organization 
ETHYLBENZENE C-5 

APPENDIX C 

> greater than ≥ greater than or equal to 

= equal to 

< less than ≤ less than or equal to 

% percent α alpha β beta γ gamma δ delta 

μm micrometer 

μg microgram q1

* cancer slope factor 

– negative 

+ positive 

(+) weakly positive result 

(–) weakly negative result 
ETHYLBENZENE C-6 

APPENDIX C 

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ETHYLBENZENE D-1 

APPENDIX D. INDEX
 

absorbed dose........................................................................................ 96, 98, 101, 103, 118, 121, 124, 129
 

acetylcholine ............................................................................................................................................. 123
 

acetylcholinesterase .................................................................................................................................. 124
 

adenocarcinoma ........................................................................................................................................ 123
 

adipose tissue .............................................................................................................. 95, 141, 169, 196, 202
 

adsorbed .................................................................................................................................... 168, 191, 208
 

adsorption...................................................................................................................................... 9, 161, 202
 

aerobic........................................................................................................................... 9, 159, 173, 174, 175
 

alanine aminotransferase (see ALT) ............................................................... 11, 27, 28, 29, 30, 31, 81, 137
 

ALT (see alanine aminotransferase) ........................................................................................................... 28
 

ambient air .............................................................................................................. 9, 10, 130, 177, 178, 185
 

anaerobic................................................................................................................... 159, 161, 173, 174, 175
 

bioaccumulation........................................................................................................................ 169, 188, 195
 

bioavailability ........................................................................................................... 168, 169, 191, 195, 198
 

bioconcentration factor ............................................................................................................................. 169
 

biodegradation................................................................................................... 144, 159, 170, 173, 174, 175
 

biomarker .................................................................................. 128, 129, 130, 140, 141, 143, 199, 210, 212
 

body weight effects..................................................................................................................................... 65
 

breast milk..................................................................................... 5, 127, 143, 169, 188, 190, 191, 196, 197
 

cancer ........................................................................................................................ 4, 14, 72, 110, 117, 127
 

carcinogen........................................................................................................................................... 14, 219
 

carcinogenic .......................................................................................... 14, 16, 32, 33, 73, 84, 123, 137, 219
 

carcinogenicity................................................................................................ 14, 73, 84, 122, 123, 137, 219
 

carcinoma.............................................................................................................................................. 23, 73
 

carcinomas ............................................................................................................................................ 63, 74
 

cardiovascular ........................................................................................................................... 35, 60, 74, 84
 

cardiovascular effects............................................................................................................................ 60, 81
 

chromosomal aberrations ...................................................................................................................... 87, 91
 

clearance ..................................................................................................................... 92, 102, 107, 115, 122
 

death................................................................................................................................ 4, 33, 34, 35, 74, 84
 

deoxyribonucleic acid (see DNA)............................................................................................................... 88
 

dermal effects........................................................................................................................................ 35, 85
 

developmental effects ................................................................................. 13, 70, 72, 84, 87, 127, 139, 143
 

DNA (see deoxyribonucleic acid)....................................................................... 63, 87, 88, 90, 91, 129, 138
 

dopamine................................................................................................................................................... 123
 

elimination half-time......................................................................................................................... 102, 122
 

elimination rate ................................................................................................................................. 100, 102
 

endocrine................................................................................................................... 35, 65, 74, 84, 125, 126
 

endocrine effects ......................................................................................................................................... 65
 

estrogenic .................................................................................................................................................. 126
 

fetus........................................................................................................................................................... 126
 

gastrointestinal effects ................................................................................................................................ 60
 

general population............................................................................... 10, 161, 187, 193, 196, 197, 210, 212
 

genotoxic................................................................................................................................. 33, 87, 91, 138
 

genotoxicity................................................................................................................................... 87, 91, 138
 

germinal epithelium .................................................................................................................................... 69
 

groundwater .................2, 3, 10, 142, 144, 159, 161, 166, 167, 168, 173, 175, 182, 183, 184, 187, 193, 196
 

growth retardation....................................................................................................................................... 72
 

half-life............................................................................................................ 9, 92, 102, 128, 159, 167, 170
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ETHYLBENZENE D-2 

APPENDIX D 

hematological effects .................................................................................... 11, 60, 61, 66, 72, 81, 136, 137
 

hepatic effects ............................................................................................................. 29, 61, 62, 81, 82, 130
 

hydrolysis.................................................................................................................................................. 170
 

hydroxyl radical .................................................................................................................... 9, 159, 167, 169
 

immune system ......................................................................................................................................... 139
 

immunological ........................................................................................................................ 33, 66, 82, 139
 

Kow .................................................................................................................................... 120, 149, 168, 169
 

LD50....................................................................................................................................................... 74, 84
 

lymphoreticular........................................................................................................................................... 66
 

metabolic effects ............................................................................................................................. 35, 74, 84
 

micronuclei ................................................................................................................................... 87, 91, 138
 

milk ......................................................... 5, 94, 127, 130, 143, 144, 169, 188, 190, 191, 196, 197, 200, 202
 

musculoskeletal effects ............................................................................................................................... 61
 

neonatal............................................................................................................................................. 124, 191
 

neoplasm ..................................................................................................................................................... 14
 

neoplastic .................................................................................................................................................... 73
 

neurobehavioral......................................................................................................................................... 125
 

neurodevelopmental.................................................................................................................................. 139
 

neurological effects........................................................................................... 66, 68, 83, 87, 122, 130, 140
 

neurophysiological...................................................................................................................................... 21
 

nuclear......................................................................................................................................................... 64
 

ocular effects................................................................................................................................... 14, 65, 85
 

partition coefficients ........................................................................... 92, 107, 108, 113, 114, 116, 121, 122
 

pharmacodynamic ..................................................................................................................................... 104
 

pharmacokinetic.................................................................. 18, 104, 105, 106, 124, 126, 127, 141, 143, 191
 

photolysis.............................................................................................................................. 9, 159, 170, 173
 

placenta ............................................................................................................................................. 127, 143
 

rate constant ...................................................................................................... 102, 109, 111, 118, 120, 169
 

renal effects..................................................................................................................................... 27, 63, 82
 

reproductive effects..................................................................................... 13, 69, 70, 83, 87, 134, 136, 138
 

respiratory effects............................................................................................................................ 13, 59, 74
 

retention .......................................................................................................................................... 92, 93, 95
 

salivation......................................................................................................................................... 11, 27, 68
 

solubility ................................................................................................................................................... 168
 

systemic effects............................................................................................................. 14, 35, 59, 74, 84, 85
 

thyroid..................................................................................................................................... 23, 35, 65, 137
 

toxicokinetic................................................................................................................................................ 33
 

tumors ................................................................................................................... 4, 14, 63, 73, 84, 138, 143
 

vapor phase ....................................................................................................................... 151, 159, 167, 170
 

vapor pressure ....................................................................................................................... 9, 167, 191, 195
 

volatilization ................................................................................................................. 9, 161, 167, 173, 175
 

weanlings .................................................................................................................................................... 94