TOXICOLOGICAL PROFILE FOR 

XYLENE 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES 

Public Health Service 

Agency for Toxic Substances and Disease Registry
 

August 2007 
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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. 
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UPDATE STATEMENT 

A Toxicological Profile for Xylene, Draft for Public Comment was released in September 2005. 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-32 

Atlanta, Georgia 30333 
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v 

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 information for the hazardous substance described therein. Each peer-reviewed profile identifies 

and reviews the key literature that describes a hazardous 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 of the profiles is on health and toxicologic information; 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 information concerning levels 

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

to determine 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 and EPA. 

Each profile includes the following: 

(A) The examination, summary, and interpretation of available toxicologic information and 

epidemiologic evaluations on a hazardous substance to ascertain the levels of significant 

human exposure for the substance and the associated acute, subacute, and chronic health 

effects; 

(B) A determination of whether adequate information on the health effects of each substance is 

available or in the process of development to determine levels of exposure that present a 

significant risk to human health of acute, subacute, and chronic health effects; and 

(C) Where appropriate, identification of toxicologic testing needed to identify the types or levels 

of exposure 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 of the public. 

This profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that 

has been peer-reviewed. Staff of the 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 is being made available for public review. Final responsibility for the 

contents and views expressed in this toxicological profile resides with ATSDR. 
vi 

The toxicological profiles are developed in response to the Superfund Amendments and 

Reauthorization Act (SARA) of 1986 (Public Law 99-499) which amended the Comprehensive 

Environmental Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund). This 

public law directed ATSDR to prepare toxicological 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. The availability of the revised priority 

list of 275 hazardous substances was announced in the Federal Register on December 7, 2005 (70 FR 

72840). For prior versions of the list of substances, see Federal Register notices dated April 17, 1987 

(52 FR 12866); October 20, 1988 (53 FR 41280); October 26, 1989 (54 FR 43619); October 17, 1990 (55 

FR 42067); October 17, 1991 (56 FR 52166); October 28, 1992 (57 FR 48801); February 28, 1994 (59 

FR 9486); April 29, 1996 (61 FR 18744); November 17, 1997 (62 FR 61332); October 21, 1999 (64 FR 

56792); October 25, 2001 (66 FR 54014); and November 7, 2003 (68 FR 63098). Section 104(i)(3) of 

CERCLA, as amended, directs the Administrator of ATSDR to prepare a toxicological profile for each 

substance on the list. 
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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. 
XYLENE 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. 
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CONTRIBUTORS 

CHEMICAL MANAGER(S)/AUTHOR(S): 

Mike Fay, Ph.D. 

John F. Risher, Ph.D. 

Jewell D. Wilson, Ph.D. 

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

Margaret Fransen, Ph.D. 

Daniel Plewak, BS. 

Lisa Ingerman, Ph.D., DABT 

Syracuse Research Corporation, 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. 
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PEER REVIEW 

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

1. Dr. Bruce Jarnot, Private Consultant, Prince Frederick, Maryland; 

2. Dr. Kannan Krishnan, Professor of Occupational and Environmental Health, University of 

Montreal, Pierrefonds, Canada; and 

3. Dr. Steven Lewis, President, Lewis Environmental Consulting Services, Washington, New 

Jersey. 

These experts collectively have knowledge of xylene'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. 
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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 XYLENE?..................................................................................................................1 

1.2 WHAT HAPPENS TO XYLENE WHEN IT ENTERS THE ENVIRONMENT?.....................2 

1.3 HOW MIGHT I BE EXPOSED TO XYLENE? .........................................................................3 

1.4 HOW CAN XYLENE ENTER AND LEAVE MY BODY? ......................................................4 

1.5 HOW CAN XYLENE AFFECT MY HEALTH? .......................................................................5 

1.6 HOW CAN XYLENE AFFECT CHILDREN? ..........................................................................6 

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO XYLENE? ......................7 

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

EXPOSED TO XYLENE? ..........................................................................................................7 

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH?.................................................................................................8 

1.10 WHERE CAN I GET MORE INFORMATION? .......................................................................9 

2. RELEVANCE TO PUBLIC HEALTH .................................................................................................11 

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO XYLENE IN THE 

UNITED STATES.....................................................................................................................11 

2.2 SUMMARY OF HEALTH EFFECTS......................................................................................12 

2.3 MINIMAL RISK LEVELS (MRLs) .........................................................................................17 

3. HEALTH EFFECTS..............................................................................................................................27 

3.1 INTRODUCTION.....................................................................................................................27 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE ..................................27 

3.2.1 Inhalation Exposure ..............................................................................................................29 

3.2.1.1 Death ............................................................................................................................29 

3.2.1.2 Systemic Effects...........................................................................................................30 

3.2.1.3 Immunological and Lymphoreticular Effects...............................................................72 

3.2.1.4 Neurological Effects.....................................................................................................72 

3.2.1.5 Reproductive Effects....................................................................................................78 

3.2.1.6 Developmental Effects .................................................................................................79 

3.2.1.7 Cancer...........................................................................................................................82 

3.2.2 Oral Exposure........................................................................................................................82 

3.2.2.1 Death ............................................................................................................................82 

3.2.2.2 Systemic Effects...........................................................................................................83 

3.2.2.3 Immunological and Lymphoreticular Effects.............................................................106 

3.2.2.4 Neurological Effects...................................................................................................106 

3.2.2.5 Reproductive Effects..................................................................................................107 

3.2.2.6 Developmental Effects ...............................................................................................108 

3.2.2.7 Cancer.........................................................................................................................108 
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3.2.3 Dermal Exposure.................................................................................................................109 

3.2.3.1 Death ..........................................................................................................................109 

3.2.3.2 Systemic Effects.........................................................................................................109 

3.2.3.3 Immunological and Lymphoreticular Effects.............................................................115 

3.2.3.4 Neurological Effects...................................................................................................116 

3.2.3.5 Reproductive Effects..................................................................................................116 

3.2.3.6 Developmental Effects ...............................................................................................116 

3.2.3.7 Cancer.........................................................................................................................117 

3.3 GENOTOXICITY ...................................................................................................................117 

3.4 TOXICOKINETICS................................................................................................................122 

3.4.1 Absorption...........................................................................................................................123 

3.4.1.1 Inhalation Exposure....................................................................................................123 

3.4.1.2 Oral Exposure.............................................................................................................124 

3.4.1.3 Dermal Exposure ........................................................................................................125 

3.4.2 Distribution .........................................................................................................................126 

3.4.2.1 Inhalation Exposure....................................................................................................126 

3.4.2.2 Oral Exposure.............................................................................................................129 

3.4.2.3 Dermal Exposure ........................................................................................................129 

3.4.3 Metabolism..........................................................................................................................129 

3.4.4 Elimination and Excretion...................................................................................................134 

3.4.4.1 Inhalation Exposure....................................................................................................134 

3.4.4.2 Oral Exposure.............................................................................................................136 

3.4.4.3 Dermal Exposure ........................................................................................................136 

3.4.4.4 Other Routes of Exposure ..........................................................................................137 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ...........138 

3.5 MECHANISMS OF ACTION ................................................................................................ 152 

3.5.1 Pharmacokinetic Mechanisms............................................................................................. 152 

3.5.2 Mechanisms of Toxicity......................................................................................................154 

3.5.3 Animal-to-Human Extrapolations.......................................................................................157 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS ........................157 

3.7 CHILDREN’S SUSCEPTIBILITY.........................................................................................158 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT ..................................................................162 

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Xylene ...........................................163 

3.8.2 Biomarkers Used to Characterize Effects Caused by Xylene .............................................164 

3.9 INTERACTIONS WITH OTHER CHEMICALS .................................................................. 164 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE............................................. 168 

3.11 METHODS FOR REDUCING TOXIC EFFECTS................................................................. 170 

3.11.1 Reducing Peak Absorption Following Exposure ............................................................170 

3.11.2 Reducing Body Burden...................................................................................................171 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects .........................................171 

3.12 ADEQUACY OF THE DATABASE......................................................................................172 

3.12.1 Existing Information on Health Effects of Xylene .........................................................173 

3.12.2 Identification of Data Needs ...........................................................................................175 

3.12.3 Ongoing Studies..............................................................................................................184 

4. CHEMICAL AND PHYSICAL INFORMATION..............................................................................185 

4.1 CHEMICAL IDENTITY.........................................................................................................185 

4.2 PHYSICAL AND CHEMICAL PROPERTIES......................................................................185 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL..........................................................189 

5.1 PRODUCTION .......................................................................................................................189 
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5.2 IMPORT/EXPORT .................................................................................................................200 

5.3 USE..........................................................................................................................................200 

5.4 DISPOSAL..............................................................................................................................200 

6. POTENTIAL FOR HUMAN EXPOSURE .........................................................................................203 

6.1 OVERVIEW............................................................................................................................203 

6.2 RELEASES TO THE ENVIRONMENT................................................................................205 

6.2.1 Air .......................................................................................................................................206 

6.2.2 Water...................................................................................................................................214 

6.2.3 Soil ......................................................................................................................................216 

6.3 ENVIRONMENTAL FATE....................................................................................................217 

6.3.1 Transport and Partitioning...................................................................................................217 

6.3.2 Transformation and Degradation ........................................................................................218 

6.3.2.1 Air...............................................................................................................................218 

6.3.2.2 Water ..........................................................................................................................219 

6.3.2.3 Sediment and Soil.......................................................................................................221 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT...............................222 

6.4.1 Air .......................................................................................................................................222 

6.4.2 Water...................................................................................................................................232 

6.4.3 Sediment and Soil ...............................................................................................................235 

6.4.4 Other Environmental Media................................................................................................237 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE .....................................239 

6.6 EXPOSURES OF CHILDREN...............................................................................................249 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES ...........................................253 

6.8 ADEQUACY OF THE DATABASE......................................................................................253 

6.8.1 Identification of Data Needs ...............................................................................................254 

6.8.2 Ongoing Studies ..................................................................................................................257 

7. ANALYTICAL METHODS ...............................................................................................................259 

7.1 BIOLOGICAL MATERIALS.................................................................................................259 

7.2 ENVIRONMENTAL SAMPLES............................................................................................ 266 

7.3 ADEQUACY OF THE DATABASE......................................................................................268 

7.3.1 Identification of Data Needs ...............................................................................................269 

7.3.2 Ongoing Studies ..................................................................................................................270 

8. REGULATIONS AND ADVISORIES ...............................................................................................271 

9. REFERENCES ....................................................................................................................................277 

10. GLOSSARY ......................................................................................................................................325 

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 
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LIST OF FIGURES 

3-1. Levels of Significant Exposure to Xylene - Inhalation....................................................................... 56 

3-2. Levels of Significant Exposure to Xylene - Oral................................................................................ 97 

3-3. Metabolic Scheme for Xylenes—Humans .......................................................................................130 

3-4. Metabolic Scheme for Xylenes—Animals.......................................................................................132 

3-5. Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) Model for a 

Hypothetical Chemical Substance....................................................................................................140 

3-6. PBPK Model for Inhaled m-Xylene .................................................................................................140 

3-7. PBPK Model to Describe Dermal Absorption of o-Xylene .............................................................146 

3-8. PBPK Model for Lactational Exposure to Volatile Organic Compounds (Including o-, m-, 

p-Xylenes) Following Maternal Occupational Inhalation Exposure................................................149 

3-9. Existing Information on Health Effects of Total Xylenes................................................................174 

6-1. Frequency of NPL Sites with Xylene Contamination ......................................................................204
 
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LIST OF TABLES 

3-1. Levels of Significant Exposure to Xylene - Inhalation....................................................................... 31 

3-2. Levels of Significant Exposure to Xylene - Oral................................................................................ 84 

3-3. Levels of Significant Exposure to Xylene - Dermal......................................................................... 110 

3-4. Genotoxicity of Xylene In Vivo........................................................................................................118 

3-5. Genotoxicity of Xylene In Vitro .......................................................................................................119 

3-6. Partition Coefficients for Xylenes....................................................................................................127 

3-7. Human Parameters Used in the PBPK Inhalation Model for m-Xylene...........................................142 

3-8. Rat and Human Parameters Used in the PBPK Dermal Model for o-Xylene .................................. 145 

3-9. Human Parameters Used in the PBPK Lactational Model for o-, m-, p-Xylene ..............................148 

4-1. Chemical Identity of m-Xylene, o-Xylene, p-Xylene, and Mixed Xylene .......................................186 

4-2. Physical and Chemical Properties of m-Xylene, o-Xylene, p-Xylene, and Mixed Xylene ..............187 

5-1. Producers of Xylene and Estimated Annual Capacities ...................................................................190
 

5-2. Facilities that Produce, Process, or Use Xylene (Mixed) .................................................................191 

5-3. Facilities that Produce, Process, or Use m-Xylene ...........................................................................194 

5-4. Facilities that Produce, Process, or Use o-Xylene ............................................................................196 

5-5. Facilities that Produce, Process, or Use p-Xylene ............................................................................198 

5-6. U.S. Import and Export Data on Xylenes.........................................................................................201 

6-1. Releases to the Environment from Facilities that Produce, Process, or Use Xylene (Mixed)..........207 

6-2. Releases to the Environment from Facilities that Produce, Process, or Use m-Xylene....................209 

6-3. Releases to the Environment from Facilities that Produce, Process, or Use o-Xylene.....................210 

6-4. Releases to the Environment from Facilities that Produce, Process, or Use p-Xylene.....................212 

6-5. Xylene Concentrations in Outdoor Air.............................................................................................223 

6-6. Xylene Concentrations in Indoor Air ...............................................................................................228 

6-7. Xylene Concentrations in Groundwater ...........................................................................................236 
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6-8. Average Personal Air, Outdoor Air, and Breath Concentrations Measured During the 1984 

TEAM Study ....................................................................................................................................240 

6-9. Average Personal Air, Indoor Air, Outdoor Air, and Breath Concentrations from the 1987 

TEAM Study ....................................................................................................................................241 

6-10. Concentrations of Xylene in Consumer Products...........................................................................244 

6-11. Percentage Breakdown of NIOSH Occupational Exposure Estimates from the NOES 

Database.........................................................................................................................................250 

6-12. Personal, Indoor, and Outdoor Air Exposures of Inner-city Children in Minneapolis, 

Minnesota to Xylenes ....................................................................................................................252 

7-1. Analytical Methods for Determining Xylene in Biological Materials..............................................260 

7-2. Analytical Methods for Determining Xylene in Environmental Samples........................................262 

8-1. Regulations and Guidelines Applicable to Xylenes .........................................................................272 
XYLENE 1 

1. PUBLIC HEALTH STATEMENT 

This public health statement tells you about xylene 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. Xylene has been found in at least 840 of the 1,684 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 xylene 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 harm you. 

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 xylene, 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 XYLENE? 

In this report, the terms xylene, xylenes, and total xylenes will be used interchangeably. There 

are three forms of xylene in which the methyl groups vary on the benzene ring: meta-xylene, 

ortho-xylene, and para-xylene (m-, o-, and p-xylene). These different forms are referred to as 

isomers. Drawings of the three different isomers are shown in Chapter 4. The term total xylenes 

refers to all three isomers of xylene (m-, o-, and p-xylene). Mixed xylene is a mixture of the 

three isomers and usually also contains 6–15% ethylbenzene. Xylene is also known as xylol or 

dimethylbenzene. Xylene is primarily a synthetic chemical. Chemical industries produce xylene 
XYLENE 2 

1. PUBLIC HEALTH STATEMENT 

from petroleum. Xylene also occurs naturally in petroleum and coal tar and is formed during 

forest fires, to a small extent. It is a colorless, flammable liquid with a sweet odor. 

Xylene is one of the top 30 chemicals produced in the United States in terms of volume. It is 

primarily used as a solvent (a liquid that can dissolve other substances) in the printing, rubber, 

and leather industries. Along with other solvents, xylene is also widely used as a cleaning agent, 

a thinner for paint, and in varnishes. Xylene is used, to a lesser extent, as a material in the 

chemical, plastics, and synthetic fiber industries and as an ingredient in the coating of fabrics and 

papers. Isomers of xylene are used in the manufacture of certain polymers (chemical 

compounds), such as plastics. Xylene is found in small amounts in airplane fuel and gasoline. 

Xylene evaporates and burns easily. Xylene does not mix well with water; however, it does mix 

with alcohol and many other chemicals. Most people begin to smell xylene in air at 0.08– 

3.7 parts of xylene per million parts of air (ppm) and in water at 0.53–1.1 ppm. Additional 

information regarding chemical and physical properties and use of xylene can be found in 

Chapters 4 and 5. 

1.2 WHAT HAPPENS TO XYLENE WHEN IT ENTERS THE ENVIRONMENT? 

Xylene is a liquid, and it can leak into soil, surface water (creeks, streams, rivers), or 

groundwater. Xylene can enter the environment when it is made, packaged, shipped, or used. 

Most xylene that is accidentally released evaporates into the air, although some is released into 

rivers or lakes. Xylene can also enter soil, water, or air in large amounts after an accidental spill 

or as a result of an environmental leak during storage or burial at a waste site. 

Since xylene evaporates easily, most xylene that gets into soil and water (if not trapped 

underground) is expected to go into the air where it is broken down by sunlight into other less 

harmful chemicals within a couple of days. For this reason, xylene is rarely found in high 

concentrations in topsoil or surface water (river, creeks) unless there has been a recent spill or 

continuing source of contamination. Any xylene that does not evaporate quickly from soil or 
XYLENE 3 

1. PUBLIC HEALTH STATEMENT 

water is broken down by small organisms. Only very small amounts are taken up by plants, fish, 

and birds. 

Xylene below the soil surface may travel down through the soil and enter underground water 

(groundwater). Xylene may remain in groundwater for several months before it is finally broken 

down by small organisms. If a large amount of xylene enters soil from an accidental spill, a 

hazardous waste site, or a landfill, it may travel through the soil and contaminate drinking water 

wells. More information on what happens to xylene in the environment can be found in 

Chapters 5 and 6. 

1.3 HOW MIGHT I BE EXPOSED TO XYLENE? 

Xylene is primarily released from industrial sources, in automobile exhaust, and during its use as 

a solvent. Hazardous waste disposal sites and spills of xylene into the environment are also 

possible sources of exposure. You are most likely to be exposed to xylene by breathing it in 

contaminated air. Typical levels of xylene measured in outdoor air in the United States range 

from 1 to 30 parts of xylene per billion parts of air (a part per billion [ppb] is one thousandth of a 

part per million [ppm]; one ppm equals 1,000 ppb). Typical levels of xylene measured in indoor 

air range from 1 to 10 ppb. 

Xylene is sometimes released into water and soil as a result of the use, storage, and transport of 

petroleum products. Little information exists about the amount of xylene in surface water and 

soil. However, levels of xylene in contaminated groundwater have been reported to be as high as 

10,000 ppb. 

You may be exposed to xylene by drinking or eating xylene-contaminated water or food. Xylene 

is not commonly found in drinking water. When it is, the levels of xylene are typically below 

2 ppb. Xylene has been found in many types of foods at levels ranging from 1 to 100 ppb. 

You may also come in contact with xylene from a variety of consumer products, including 

gasoline, paint, varnish, shellac, rust preventives, and cigarette smoke. Breathing vapors from 
XYLENE 4 

1. PUBLIC HEALTH STATEMENT 

these types of products can expose you to xylene. In some cases, indoor levels of xylene can be 

higher than outdoor levels, especially in buildings with poor ventilation. Skin contact with 

products containing xylene, such as solvents, lacquers, paint thinners and removers, and 

pesticides may also expose you to xylene. 

Besides painters and paint industry workers, others who may be exposed to xylene include 

biomedical laboratory workers, distillers of xylene, wood processing plant workers, automobile 

garage workers, metal workers, and furniture refinishers. Workers who routinely come in 

contact with xylene-containing solvents in the workplace are the population most likely to be 

exposed to high levels of xylene. Additional information on the potential for human exposure 

can be found in Chapter 6. 

1.4 HOW CAN XYLENE ENTER AND LEAVE MY BODY? 

Xylene is most likely to enter your body when you breathe xylene vapors. Xylene may also 

enter your body if eat or drink xylene-contaminated food or water. Less often, xylene enters the 

body through the skin following direct contact. Xylene is rapidly absorbed by your lungs after 

you breathe air containing it. The amount of xylene retained ranges from 50 to 75% of the 

amount of xylene that you inhale. Physical exercise increases the amount of xylene absorbed by 

the lungs. Absorption of xylene in the gut after eating food or drinking water containing it is 

both rapid and complete. Absorption of liquid xylene through the skin also occurs rapidly 

following direct contact with xylene, but absorption of xylene vapor through the skin is only 

about 12% of the amount absorbed by the lungs. At hazardous waste sites, the most likely ways 

you can be exposed are: breathing xylene vapors, drinking well water contaminated with xylene, 

and direct contact of the skin with xylene. Xylene passes into the blood soon after entering the 

body. 

In people and laboratory animals, xylene is chemically changed, primarily in the liver, into a 

different form that is more water soluble and is rapidly removed from the body in urine. Some 

unchanged xylene also leaves in the breath from the lungs within a few seconds after xylene is 

absorbed. Small amounts of breakdown products of xylene have appeared in the urine of people 
XYLENE 5 

1. PUBLIC HEALTH STATEMENT 

as soon as 2 hours after breathing air containing xylene. Usually, most of the xylene that is taken 

in leaves the body within 18 hours after exposure ends. About 4–10% of absorbed xylene may 

be stored in fat, which may prolong the time needed for xylene to leave the body. Additional 

information on how xylene can enter and leave your body can be found in Chapter 3. 

1.5 HOW CAN XYLENE 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. 

One way to learn whether a chemical will harm people is to determine how the body absorbs, 

uses, and releases the chemical. For some chemicals, animal testing may be necessary. Animal 

testing may also help identify health effects such as cancer or birth defects. Without laboratory 

animals, scientists would lose a basic method for getting information needed to make wise 

decisions that protect public health. Scientists have the responsibility to treat research animals 

with care and compassion. Scientists must comply with strict animal care guidelines because 

laws today protect the welfare of research animals. 

Scientists have found that the three forms of xylene have very similar effects on health. No 

health effects have been noted at the background levels that people are exposed to on a daily 

basis. Short-term exposure of people to high levels of xylene can cause irritation of the skin, 

eyes, nose, and throat; difficulty in breathing; impaired function of the lungs; delayed response to 

a visual stimulus; impaired memory; stomach discomfort; and possible changes in the liver and 

kidneys. Both short- and long-term exposure to high concentrations of xylene can also cause a 

number of effects on the nervous system, such as headaches, lack of muscle coordination, 

dizziness, confusion, and changes in one's sense of balance. Some people exposed to very high 

levels of xylene for a short period of time have died. Most of the information on health effects in 

humans exposed for long periods of time is from studies of workers employed in industries that 

make or use xylene. Those workers were exposed to levels of xylene in air far greater than the 

levels normally encountered by the general population. Many of the effects seen after their 
XYLENE 6 

1. PUBLIC HEALTH STATEMENT 

exposure to xylene could have been caused by exposure to other chemicals that were in the air 

with xylene. 

Results of studies in animals indicate that large amounts of xylene can cause changes in the liver 

and harmful effects on the kidneys, lungs, heart, and nervous system. Short-term exposure to 

very high concentrations of xylene causes death in animals, as well as muscular spasms, 

incoordination, hearing loss, changes in behavior, changes in organ weights, and changes in 

enzyme activity. Animals that were exposed to xylene on their skin had irritation and 

inflammation of the skin. Long-term exposure of animals to low concentrations of xylene has 

not been well studied, but there is some information that long-term exposure of animals can 

cause harmful effects on the kidney (with oral exposure) or on the nervous system (with 

inhalation exposure). 

Information from animal studies is not adequate to determine whether or not xylene causes 

cancer in humans. Both the International Agency for Research on Cancer (IARC) and EPA have 

found that there is insufficient information to determine whether or not xylene is carcinogenic 

and consider xylene not classifiable as to its human carcinogenicity. 

Additional information regarding the health effects of xylene can be found in Chapters 2 and 3. 

1.6 HOW CAN XYLENE AFFECT CHILDREN? 

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

conception to maturity at 18 years of age. 

The effects of xylenes have not been studied in children, but it is likely that they would be 

similar to those seen in exposed adults. Although there is no direct evidence, children may be 

more sensitive to acute inhalation exposure than adults because their narrower airways would be 

more vulnerable if the surrounding tissue became swollen. (One study suggested that the 

narrower airway in women compared to men could be the reason women had more breathing 

difficulty than men after breathing xylene.) 
XYLENE 7 

1. PUBLIC HEALTH STATEMENT 

Although there are no conclusive studies in humans, it is possible that exposure of pregnant 

women to high levels of xylene may cause harmful effects to the fetus. Animal studies showed 

that xylene absorbed by the mother can cross the placenta and reach the fetus. The unborn 

animals may have reduced body weight and delayed bone mineralization if the level of xylene is 

high enough to be toxic to the mother. Some animal studies have shown that newborn babies 

that were exposed to xylene during pregnancy have problems after birth with motor coordination 

and the ability to orient themselves in their surroundings. In general, these developmental effects 

occur at exposure levels much higher than those typically seen in the background environment, 

levels high enough to also harm the mother. 

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

If your doctor finds that you have been exposed to substantial amounts of xylene, ask whether 

your children might also have been exposed. Your doctor might need to ask your state health 

department to investigate. 

Exposure to xylene as solvents (in paints or gasoline) can be reduced if the products are used 

with adequate ventilation and if they are stored out of the reach of small children. 

Sometimes older children sniff household chemicals in attempt to get high. Talk with your 

children about the dangers of sniffing xylene. 

If products containing xylene are spilled on the skin, then the excess should be wiped off and the 

area cleaned with soap and water. 

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

EXPOSED TO XYLENE? 

Medical tests are available to determine if you have been exposed to xylene at higher-thannormal levels. After xylene has been absorbed, some of its breakdown products can be measured 

in the urine. However, a urine sample must be provided very soon (within hours) after exposure 
XYLENE 8 

1. PUBLIC HEALTH STATEMENT 

ends because xylene quickly leaves the body. These tests may be available in certain doctors' 

offices. Available tests can only indicate exposure to xylene; they cannot be used to predict 

which health effects, if any, will develop. More information about xylene detection can be found 

in 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-to-exceed 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. 

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 xylene include the following: 

To protect people from the potential harmful health effects of xylene, EPA regulates xylene in 

the environment. 
XYLENE 9 

1. PUBLIC HEALTH STATEMENT 

The EPA estimates that, for an adult of average weight who drinks 2 L of water each day for a 

lifetime (70 years), exposure to 7 ppm xylene in drinking water is unlikely to result in harmful 

noncancerous health effects. 

Exposure to 40 ppm xylene in water for 1 or 10 days is unlikely to present a health risk to a small 

child. 

The EPA has set a legally enforceable maximum level of 10 ppm of xylene in water that is 

delivered to any user of a public water system. 

OSHA regulates levels of xylene in the workplace. The maximum allowable amount of xylene 

in workroom air during an 8-hour workday in a 40-hour workweek is 100 ppm. 

More information on government regulations for xylene can be found in 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 
XYLENE 10 

1. PUBLIC HEALTH STATEMENT 

and technical 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-32 

 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/ 
XYLENE	 11 

2. RELEVANCE TO PUBLIC HEALTH 

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO XYLENE IN THE UNITED 

STATES 

Xylenes (mixtures of ortho-, meta-, and para-isomers) are used as industrial solvents, synthetic 

intermediates, and solvents in commercial products such as paints, coatings, adhesive removers, and paint 

thinners; they are also a component of gasoline. Xylenes are released to the atmosphere primarily as 

fugitive emissions from industrial sources (e.g., petroleum refineries, chemical plants), in automobile 

exhaust, and through volatilization from their use as solvents. Discharges into waterways and spills on 

land result primarily from use, storage, and transport of petroleum products and waste disposal. 

When xylene is released to soil or surface water, it is expected to volatilize into the atmosphere where it is 

quickly degraded. The half-life for xylene in the atmosphere is 8–14 hours. Any xylene in soil or surface 

water that does not volatilize quickly may undergo biodegradation. Xylene may also leach into 

groundwater where biodegradation becomes the primary removal process. Half-lives measured for 

xylene in groundwater range from 25 to 287 days. Degradation rates in groundwater will vary depending 

on differences in conditions such as temperature, presence of oxygen, and presence of electron acceptors. 

Xylene is primarily detected in air. Typical xylene concentrations range from 1 to 30 ppb in outdoor air 

and from 1 to 10 ppb in indoor air. Xylene has been detected in <5% of samples collected during 

groundwater surveys conducted in the United States. Median xylene concentrations of ≤2 ppb have been 

reported in 406 urban and 2,542 rural drinking water wells or monitoring wells in the United States. Less 

than 6% of drinking water samples collected during drinking water surveys contained xylene; the mean 

concentrations in positive samples were typically <2 ppb. Xylene has been detected in all kinds of foods 

(e.g., meat, fruit, dairy, fish, vegetables, grains), with typical concentrations ranging from 1 to 100 ppb. 

Because individual xylene isomers are used in large amounts in industrial settings, people who work at or 

live near these locations may receive a higher exposure to one xylene isomer compared to the other 

isomers. However, since xylenes are present as a mixture in gasoline and in the solvent components of 

commonly used commercial products (paint, coatings, etc.), exposure of the general population is 

expected to be primarily to xylenes as a mixture, and not to the separate xylene isomers. 

Inhalation appears to be the major route of exposure to xylene, although exposure through the use or 

consumption of groundwater is also likely in areas where there is subsurface gasoline contamination. 
XYLENE 12 

2. RELEVANCE TO PUBLIC HEALTH 

During exposures to xylene vapor, a small amount of dermal absorption also occurs, ≤2% of the amount 

inhaled. Humans may also be exposed to xylene through smoking, consumption of xylene-contaminated 

foods, and dermal contact with consumer products containing xylene. Children are expected to be 

exposed to xylene by the same routes as adults. Since xylene has a low affinity for adsorption onto soil 

and dust particles and a high volatilization rate, the risk of exposure for small children from ingesting soil 

or dust is likely to be low. The average daily intake of total xylene (sum of o-, m-, and p-xylene intakes) 

for the general population is estimated as 0.3–8.6 μg/kg/day from inhalation exposure and 0.06 μg/kg/day 

from ingestion of drinking water assuming typical low background levels. Based on a maximal 

concentration of 1.5 mg/L in drinking water, the maximal daily consumption of xylenes from drinking 

water would be 0.04 mg/kg/day. These exposure levels are below the minimal risk levels (MRLs) 

established for xylenes (see Section 2.3 and Appendix A). 

See Chapter 6 for more detailed information regarding concentrations of xylenes in environmental media. 

2.2 SUMMARY OF HEALTH EFFECTS 

Xylenes, because of their lipophilic properties, are rapidly absorbed by all routes of exposure, rapidly 

distributed throughout the body, and, if not metabolized, quickly eliminated in exhaled air. In humans, 

absorption has been estimated as >50% through the lungs following inhalation exposure and <50% 

through the gastrointestinal system. In humans exposed by inhalation, up to 2% of the absorbed dose may 

be absorbed through the skin. The major pathway for metabolism involves mixed function oxidases in 

the liver, resulting mainly in the formation of isomers of methylhippuric acid that are eliminated in the 

urine and are used as an index of exposure for occupational monitoring. Background urinary levels of 

methylhippuric acids in nonexposed workers are <2 mg/g creatinine. Xylenes tend not to accumulate in 

the body, but they may be sequestered briefly in fat tissues due to their lipophilicity; elimination of xylene 

is slower in individuals with a greater percentage of body fat. The primary effects of xylene exposure 

involve the nervous system by all routes of exposure, the respiratory tract by inhalation exposure, and, at 

higher oral exposure levels, hepatic, renal, and body weight effects. No adverse health effects have been 

associated with the background levels of xylene to which the general population is typically exposed (see 

Section 2.1). Isomers of xylene have similar toxicokinetic properties and elicit similar toxicological 

effects, with no single isomer consistently exhibiting the greatest potency, depending on the end point. 

This issue is discussed further in the introduction to Section 2.3 and in Section 3.2. 
XYLENE 13 

2. RELEVANCE TO PUBLIC HEALTH 

Information on the toxicity of xylene in humans comes from case reports, occupational studies, and 

studies on volunteers. At acute-duration inhalation concentrations as low as 50 ppm, xylenes produce 

irritant effects on the eyes, skin, and mucous membranes; impaired respiratory function; and mild central 

nervous system effects, including headache and dizziness. Increases in subjective reports of eye irritation, 

sore throat, and neurological effects (anxiety, forgetfulness, inability to concentrate, and a sensation of 

intoxication) were noted following chronic-duration occupational exposure at 14 ppm. Irritation of the 

eye may occur from contact with xylene vapor or from direct contact with xylene liquid, in which case 

photophobia, redness of the conjunctiva, and partial loss of the conjunctival and corneal epithelia have 

been reported. Slight-to-moderate eye irritation has also been observed in rabbits following direct 

instillation with ≥23 mg/kg mixed xylenes. With increasing airborne xylene concentrations of 100– 

400 ppm, other neurological effects reported in acutely exposed human subjects include retardation of 

response times and impairments in memory and body balance. Acute exposure to an estimated 10,000 

ppm xylenes elicited tremors, mental confusion, and depressant effects (narcosis) on the central nervous 

system that caused at least one fatality due to respiratory failure. All of these effects are related to the 

lipophilic properties of xylenes, which interfere with the integrity of cell membranes and alter neuronal 

function. In addition to neurological and respiratory effects, an increase in the reporting of nausea was 

noted following controlled exposure to m-xylene at 50 ppm. Symptoms of nausea and vomiting have also 

been noted in workers exposed to xylene vapors. 

Other effects of xylene exposure involve the liver and kidney in humans and animals and body weight 

effects in laboratory animals. Hepatic effects (elevated serum transaminases and hepatocellular 

vacuolation) were observed in a limited number of case reports describing effects of acute exposure to an 

estimated 700–10,000 ppm mixed xylene, but were not observed in workers with chronic occupational 

exposure at 14 ppm. Hepatic effects in laboratory animals exposed orally at ≥750 mg/kg/day or by 

inhalation at ≥300 ppm include increases in liver weight, serum enzyme levels, and cytochrome P-450 

levels, but no histopathology. However, a number of authors characterized the hepatic effects in animals 

as adaptive rather than adverse. Information on renal effects (distal renal tubular acidemia and abnormal 

clinical chemistry values) of xylene in acutely exposed humans is confounded by exposure to other 

compounds or uncertainties as to the duration of exposure. No alterations in renal serum biochemistry 

values were observed in workers exposed to 14 ppm mixed xylene for several years. Renal effects in 

repeatedly exposed laboratory animals include increases in renal enzyme activity, cytochrome P-450 

content, and increased kidney-to-body-weight ratios following inhalation exposure at 50–2,000 ppm or 

oral exposure and increased chronic nephropathy in rats exposed at ≥750 mg/kg/day. However, no renal 

effects were observed in rats exposed via inhalation to 810 ppm mixed xylenes for 13 weeks, gavage 
XYLENE 14 

2. RELEVANCE TO PUBLIC HEALTH 

doses of 1,000 mg/kg/day 5 days/week for 13 weeks, or gavage doses of 800 mg/kg/day to m- or p-xylene 

for 90 consecutive days. It is not known whether the variability in induction of renal effects from mixed 

xylene is related to variations in the relative amounts of o-xylene or ethylbenzene or variations in the 

strains of rats tested. Decreased body weight gain has been observed in laboratory animals repeatedly 

exposed by inhalation at ≥700 ppm or by oral dosing or at ≥700 mg/kg/day; a 5–8% reduction in body 

weight gain observed in male rats exposed at 500 mg/kg during the last year of a 2-year study is not 

considered biologically significant. Dermal exposure of humans to xylene causes skin irritation, dryness 

and scaling of the skin, and vasodilation. In addition, one case report demonstrated the possibility that 

contact urticaria can develop after several months of occupational exposure to 100 ppm xylene vapors. 

Dermal effects of m-xylene, o-xylene, or mixed xylenes in laboratory animal studies included skin 

irritation (erythema and edema) at topical doses as low as 2.3 mg/kg and more serious effects (eschar 

formation in some animals and epidermal thickening) at topical doses of ≥114 mg/kg. Rat skin that 

developed moderate erythema after treatment with m- or o-xylene exhibited increases in transepidermal 

water loss and increases in pro-inflammatory cytokines (interleukin 1-alpha and tumor necrosis factoralpha). 

Available studies of developmental or reproductive toxicity from occupational exposure to xylenes are 

not definitive because of the small number of subjects and/or concurrent exposure to other chemicals. In 

general, developmental studies in animals reported adverse fetal effects only at concentrations that caused 

maternal toxicity. Developmental effects in laboratory animals exposed to ≥350 ppm xylenes by 

inhalation include delayed ossification of the skeleton at maternally toxic concentrations and reduced fetal 

body weight, which is also influenced by maternal body weight effects. Postnatal neurobehavioral 

deficits (decreased rotarod performance) have been observed in rats gestationally exposed to m-xylene at 

500 ppm. Oral exposure to 2,060 mg/kg/day of mixed xylene has been associated with cleft plate and 

decreased fetal weight. Dermal exposure of rats to xylene has been associated with biochemical changes 

in fetal and maternal brain tissue. No reproductive effects were found in rats following inhalation of 

500 ppm xylene before mating and during gestation and lactation. Histopathological examination 

following intermediate and chronic oral bioassays revealed no adverse effects on the reproductive organs 

of rats and mice dosed with mixed xylene 5 days/week at 800 and 1,000 mg/kg/day, respectively. 

There is no definitive evidence for carcinogenic effects of xylene in humans. Epidemiological studies 

looking for associations with xylene exposure and specific cancers either reported no cases or a limited 

number of cases exposed to xylene and/or reported concurrent exposure to multiple solvents. Two-year 

cancer bioassays in rats and mice exposed by oral gavage provided no evidence for carcinogenicity of 
XYLENE 15 

2. RELEVANCE TO PUBLIC HEALTH 

mixed xylene. The Department of Health and Human Services (DHHS) has not classified xylene as to its 

carcinogenicity. Both IARC and EPA have determined that xylene is not classifiable as to its 

carcinogenicity in humans, due to inadequate evidence for the carcinogenicity of xylenes in humans and 

animals. 

The following sections discuss the most sensitive effects of exposure to xylenes: neurological and 

respiratory. These effects, as well as other adverse effects, are discussed in greater detail in Chapter 3. 

Neurological Effects. The neurotoxicity of xylenes has been examined in short- and long-term 

inhalation studies in humans and animals and acute-duration oral studies in animals and appears to be 

related to the interference of unmetabolized xylene with neuronal membranes. Mild central nervous 

system effects (subjective symptoms of intoxication, headache, fatigue, and dizziness) have been 

observed following acute-duration exposure of humans to m-xylene at 50 ppm and chronic-duration 

occupational exposure to mixed xylene at 14 ppm. Results of experimental studies with humans indicate 

that acute inhalation exposure to 100 ppm mixed xylene or 200 ppm m-xylene causes impaired short-term 

memory, impaired reaction time, performance decrements in numerical ability, and alterations in 

equilibrium and body balance. These experimental studies are supported by case reports and occupational 

studies that described similar neurological effects at higher exposure levels. Isolated cases of 

unconsciousness, amnesia, brain hemorrhage, and seizures have been associated with accidental acute 

inhalation exposure to unknown concentrations of xylene (estimated in one case as 10,000 ppm). 

Neurological impairment has also been reported in experimental studies with laboratory animals with a 

similar range of concentration-related severities as in humans. The range of thresholds for specific 

neurological end points suggests that specific neuronal pathways or regions of the central nervous system 

may vary in their vulnerability to xylene exposure. Studies in animals have shown that mixed xylene and 

individual isomers are neurotoxic at airborne concentrations ranging from 50 to 2,000 ppm. A decreased 

latency of the paw-lick response was reported in rats exposed to 50 ppm m-xylene for 3 months. 

Decreased motor performance and impaired learning have been reported in rats exposed to concentrations 

between 100 and 3,000 ppm. Loss of cochlear hair cells and/or hearing deficits have been observed in 

rats exposed by inhalation acutely to ≥1,450 ppm mixed xylene and in rats exposed for 13 weeks to 

900 ppm p-xylene, but not other isomers or 1,000 ppm mixed xylenes. Changes in the levels of brain 

enzyme activities or neurotransmitters have been noted with acute exposure to 2,000 ppm with m- or 

o-xylenes. Severe neurotoxicity was observed in rats, mice, and gerbils following acute- or intermediateduration inhalation exposure to the various xylene isomers at concentrations in excess of 1,000 ppm. 
XYLENE 16 

2. RELEVANCE TO PUBLIC HEALTH 

These effects included narcosis, prostration, incoordination, tremors, muscular spasms, and labored 

respiration. All three xylene isomers elicited biphasic response rates in operant behavior studies in mice 

exposed for 30 minutes: increased responses at ≥1,400 ppm and half-maximal responses at 5,179– 

6,176 ppm. Motor coordination was impaired at concentrations above 2,000 ppm for the para isomer and 

above 3,000 ppm for the meta and ortho isomers. 

Animal studies have shown that oral exposure to xylenes at high concentrations (single doses of 

≥4,000 mg/kg or repeated dosing at 2,000 mg/kg/day for 2 weeks) may result in nervous system effects 

such as tremors, respiratory depression, weakness, lethargy, unsteadiness, and hyperactivity. 

Hyperactivity was also observed in all mice after oral dosing with 1,000 mg/kg mixed xylene during 

weeks 4–103. Rats dosed with p-xylene, but not m- or o-xylene at 900 mg/kg/day, 5 days/week for 

2 weeks, experienced significant loss of cochlear hair cells associated with hearing at medium frequencies 

(10–25 kHz). 

Respiratory Effects. Numerous studies in humans identified the respiratory tract as a sensitive target 

of xylenes following short- or long-term inhalation exposure. Subjective symptoms of nose and throat 

irritation were noted following single exposures to xylene vapor at concentrations between 50 and 

700 ppm, repeated intermediate-duration exposure at 100 ppm, or chronic-duration occupational exposure 

at 14 ppm. Mild increases in the subjective severity scores for breathing difficulty and small changes in 

measured pulmonary physiology parameters (reduced forced vital capacity) were observed following 

acute-duration exposure to m-xylene at 50 ppm. Labored breathing with impaired pulmonary function 

was reported following chronic occupational exposure to unspecified concentrations of xylene vapor. 

Severe lung congestion with pulmonary hemorrhages and edema was noted in a worker who died 

following inhalation of paint fumes containing an estimated 10,000 ppm xylene for an undetermined time 

(<18 hours) and in one case of suicide by ingestion of an undetermined amount of xylene. 

Animal data from acute- and intermediate-duration inhalation studies provide supporting evidence for the 

respiratory effects observed in humans following inhalation exposure to xylene. Respiratory effects noted 

in laboratory animals exposed for a few minutes at concentrations of ≥690 ppm include a 50% reduction 

in respiratory rate, labored breathing, irritation of the upper respiratory tract, pulmonary edema, and 

pulmonary inflammation. Irritation of the upper respiratory tract induced a reflex pause in the expiratory 

phase of respiration that resulted in an overall reduction in respiratory rate. Decreased metabolic capacity 

of the lungs was reported to be related to 45–80% decreases in the activities of metabolizing enzymes 

(cytochrome P-450) following acute exposure to mixed xylenes or individual isomers at concentrations 
XYLENE 17 

2. RELEVANCE TO PUBLIC HEALTH 

between 75 and 2,000 ppm. The toxicological significance of the reduction in metabolizing enzymes is 

not established, but may be related to the lessened ability to reduce cellular concentrations of xylene. 

2.3 MINIMAL RISK LEVELS (MRLs) 

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

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

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 1990), 

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. 

Toxicological data from comparative studies demonstrate that, in some cases, the effects and effect levels 

of the three isomers are similar; e.g., body weight findings in the acute oral study by Condie et al. (1988) 

or the alveolar concentration levels associated with anaesthetic effects as described by Fang et al. (1996). 

Other studies have indicated different orders of relative toxicity for the isomers, but there is no consistent 

pattern indicating that a particular isomer is the most potent for all end points, and the differences in 

effect levels among the isomers may be small. For example, the ortho isomer was most potent in assays 

on operant behavior (Moser et al. 1985) and motor coordination in rats (Korsak et al. 1990) and in a 

developmental toxicity assay in rats in which mixed xylenes had the same effect levels (Saillenfait et al. 

2003). The para isomer, however, was most potent in a different test for motor performance, the inverted 

screen test (Moser et al. 1985), and in ototoxicity assays in rats (Gagnaire et al. 2001). Given the lack of 

consistency among the different end points, the most sensitive effect by mixed xylenes or any isomer was 

chosen as the basis for MRL for mixed xylenes and all isomers for that duration and route of exposure. 
XYLENE	 18 

2. RELEVANCE TO PUBLIC HEALTH 

Inhalation MRLs 

•	 An MRL of 2 ppm has been derived for acute-duration inhalation exposure (14 days or less) to 

mixed xylenes 

The database for acute-duration inhalation exposure to xylenes includes a number of studies in humans 

and laboratory animals. Studies in humans identify neurological and respiratory effects as the most 

sensitive end points for acute-duration inhalation exposure. Effects observed in humans at 50–690 ppm 

included irritation of the respiratory tract (breathing difficulty, discomfort in nose and throat, reduced 

forced air capacity), neurotoxicity (dizziness, headache, impaired short-term memory, increase in reaction 

times), and eye irritation (Carpenter et al. 1975a; Dudek et al. 1990; Gamberale et al. 1978; Nelson et al. 

1943; NIOSH 1981). Other neurological effects in humans included altered visual evoked potentials 

following repeated exposure to 200 ppm m-xylene and impaired body balance following a single 4-hour 

exposure at 400 ppm (Savolainen et al. 1984; Seppalainen et al. 1989). 

Acute-duration neurological effects in animals were observed at concentrations of 113 ppm and higher. 

These included transiently decreased operant responses in rats repeatedly exposed to 113 ppm mixed 

xylene (Ghosh et al. 1987), altered responses to electric shock in rats and mice exposed once to 230– 

320 ppm o-xylene (Vodickova et al. 1995), and decreased axonal transport in rats repeatedly exposed to 

800 ppm mixed xylene (Padilla and Lyerly 1989). Effects related to motor incoordination were observed 

following exposures to mixed xylenes or individual isomers in the range of 1,010–1,982 ppm (Carpenter 

et al. 1975a; De Ceaurriz et al. 1983; Korsak et al. 1988, 1990, 1993). Sensory-related changes (altered 

visual- or auditory-evoked potentials or hearing losses) occurred at exposures in the range of 1,400– 

1,600 ppm p-xylene (Crofton et al. 1994; Dyer et al. 1988; Pryor et al. 1987; Rebert et al. 1995). Other 

neurological effects included disturbances in brain catecholamine or dopamine following repeated 

exposure to mixed xylene or individual isomers at 2,000 ppm (Andersson et al. 1981), narcosis in rats at 

≥1,940 ppm (Molnar et al. 1986), and ataxia and seizures in cats exposed to 9,500 ppm mixed xylene 

(Carpenter et al. 1975a). 

The lowest effect levels for other end points affected by acute-duration inhalation exposure in animals 

were higher than the lowest-observed-adverse-effect level (LOAEL) for neurological effects. Rat 

developmental effects (reduced fetal body weight and delayed ossification) were observed at xylene 

exposures in the range of 350–2,000 ppm (Saillenfait et al. 2003; Ungvary et al. 1980b); maternal body 

weight effects were observed at 700 ppm (Ungvary et al. 1980b). Acute-duration respiratory effects in 
XYLENE 19 

2. RELEVANCE TO PUBLIC HEALTH 

animals include decreases in lung surfactant following exposure to mixed xylenes or individual isomers at 

1,000 ppm or higher (Elovaara et al. 1987; Patel et al. 1978; Toftgard and Nilsen 1982) and decreased 

respiratory rates in mice briefly exposed to m- or o-xylene at concentrations of 1,361–2,700 ppm (De 

Ceaurriz et al. 1981; Korsak et al. 1990, 1991, 1993). Increased mortality has been reported in rodents 

repeatedly exposed to at 700 ppm (Ungvary et al. 1980b) or once to ≥2,010 ppm (Bonnet et al. 1979; 

Cameron et al. 1938; Carpenter et al. 1975a; Harper et al. 1975; Hine and Zuidema 1970). 

Neurological and respiratory effects are selected as co-critical effects of acute-duration inhalation 

exposure since they occurred at the lowest tested exposure level of 50 ppm. Ernstgard et al. (2002) was 

selected as the principal study for acute-duration inhalation exposure because it provides the lowest 

LOAEL for the co-critical effects. In this study, 28 men and 28 women were exposed to 0 or 50 ppm 

m-xylene in sessions separated by 2 weeks. There were difficulties with recruitment for the study; only 

10%/sex out of the original selected group of 1,000/sex agreed to participate and the drop-out rate was 

high (~72%) because of failure to pass the screening medical examination or a change in life 

circumstances. Strengths of the study include that subjects served as their own controls, exposures were 

controlled (with respect to solvent concentration, duration, temperature, and humidity), results were 

analyzed for statistical significance, and a third exposure condition (150 ppm 2-propanol) resulted in a 

qualitatively different pattern of adverse effects compared to m-xylene exposure. During exposure (3, 60, 

and 118 minutes from the start of exposure) and post-exposure (140 and 350 minutes from onset), the 

subjects rated the level of perceived discomfort using a visual analogue scale (0–100 mm) in a 

questionnaire with 10 questions. Pulmonary function measurements were conducted prior to exposure, 

immediately after exposure, and 3 hours post-exposure. Nasal swelling was assessed by acoustic 

rhinometry before, immediately after, and 3 hours after the end of exposure. Nasal lavages obtained 

before and 3 hours after the end of exposure were evaluated for markers of inflammation. Eye blinking 

was measured throughout exposure by electromyography, and color vision was assessed before, 

immediately after, and 3 hours post-exposure. Compared to air-exposure, exposure to m-xylene at 

50 ppm resulted in small statistically significant increases in the average rating of self-reported symptoms 

for local irritant effects (discomfort in the eyes and nose), other respiratory effects (breathing difficulty in 

both sexes and discomfort in the throat or airways in women), and neurological effects (feeling of 

intoxication in both sexes, and headache, fatigue, and dizziness in men). All self-reported symptoms 

were characterized as minimal. Although the subjects were not blinded with respect to the exposure 

conditions, there was only a weak correlation between ratings of smell and ratings of symptoms; the 

authors conclude that it was unlikely that the perceived exposure by itself significantly affected symptom 

ratings. Small statistically significant changes were observed in objective measures of respiratory 
XYLENE	 20 

2. RELEVANCE TO PUBLIC HEALTH 

function in exposed women, but not men, 3 hours after the end of the exposure to m-xylene; forced vital 

capacity was reduced by 2.81% (45-fold more than air exposure) and other parameters dependent on 

forced vital capacity were likewise altered. The authors indicated that these measured respiratory effects 

in women were of uncertain significance, but could be explained by possible effects of estrogen or the 

narrower airways in women compared to men. A minimal LOAEL of 50 ppm is identified for 

neurological and respiratory effects in humans exposed to m-xylene. An uncertainty factor of 30 was 

applied to the LOAEL of 50 ppm (3 for the use of a minimal LOAEL and 10 for human variability). The 

resulting MRL of 2 ppm is considered to be protective to human health under acute-duration (≤14 days) 

inhalation exposures to mixed xylenes or individual isomers. 

•	 An MRL of 0.6 ppm has been derived for intermediate-duration inhalation exposure (15– 

364 days) to mixed xylenes. 

The database for intermediate-duration inhalation to xylenes includes one controlled-exposure study in 

humans and several animal bioassays. Effects in humans exposed to 100–150 ppm p-xylene for 1– 

7.5 hours/day, 5 days/week for 4 weeks included increased reporting of subjective symptoms of 

irritation of the nose and throat (NIOSH 1981). This study found no significant alterations in objective 

measures of neurological function (electroencephalography, tests of motor activity, and cognitive 

performance) and no alterations in pulmonary function in human subjects, but the study was limited in 

that some group sizes were small (n=2). Animal toxicity bioassays that tested at concentrations below 

100 ppm reported no clinical signs of neurotoxicity or no adverse effects liver enzymes or brain weight 

(Hillefors-Berglund et al. 1995; Jajte et al. 2003; Jenkins et al. 1970). In a special neurobehavioral 

assay, a LOAEL of 50 ppm was identified for reduced mean latency of the paw-lick response 

(indicative of increased sensitivity to pain) in rats exposed to m-xylene for 3 months (Korsak et al. 

1994). Other neurobehavioral effects (impaired rotarod performance, passive avoidance learning) were 

observed following exposure to 100 ppm m-xylene for 4 weeks to 6 months (Gralewicz and Wiaderna 

2001; Gralewicz et al. 1995; Korsak et al. 1994); some neurological impairment persisted for 5– 

9 weeks after exposure (Gralewicz and Wiaderna 2001). Other neurological effects included 

distribution of astroglia cells in the brain of Mongolian gerbils exposed to 160 ppm mixed xylene for 

4 months (Rosengren et al. 1986), delayed maxillary ossification and impaired rotarod performance in 

rats gestationally exposed to 200 ppm technical-grade xylene for 6 hours/day (Hass and Jakobsen 

1993), and impaired motor coordination and spatial orientation following gestational exposure at 

500 ppm (Hass et al. 1995, 1997). Neurological effects at higher concentrations included tremors in 

dogs exposed to 780 ppm o-xylene for 6 hours/day, 5 days/week for 6 weeks (Jenkins et al. 1970), 

alterations in brain neurotransmitters following continuous exposure to 800 ppm mixed xylenes for 
XYLENE 21 

2. RELEVANCE TO PUBLIC HEALTH 

30 days (Honma et al. 1983), and auditory effects in rats (hearing loss or decreases in auditory 

brainstem responses) following exposure to ≥800 ppm mixed xylenes or 900 ppm p-xylene for 

13 weeks (Gagnaire et al. 2001, 2006; Nylen and Hagman 1994; Pryor et al. 1987). 

Non-neurological effects were observed at higher concentrations. Cardiovascular effects (increased 

thickness of coronary microvessels) were observed in rats exposed to 230 ppm mixed xylenes 

6 hours/day, 5 days/week for 4 weeks (Morvai et al. 1987). Hepatic effects (increased liver weight) were 

observed at a LOAEL of 600 ppm in rats discontinuously exposed to mixed xylenes for 4 weeks 

(Toftgard et al. 1981). In rats exposed gestationally to mixed xylenes or o-xylene, a LOAEL of 500 ppm 

was identified for decreased fetal body weights in the absence of maternal toxicity (Bio/dynamics 1983). 

LOAELs for adult body weight effects were 1,000 ppm or higher (Tatrai et al. 1981). Increased deaths 

among squirrel monkeys and rats were noted following discontinuous intermediate-duration exposure to 

780 ppm o-xylene (Jenkins et al. 1970), but no systemic effects were noted in rats or dogs exposed to 

810 ppm mixed xylenes (Carpenter et al. 1975a). 

Neurotoxicity is selected as the critical effect of intermediate-duration inhalation exposure to xylenes, 

since it occurs at the lowest effect levels and may persist after exposures cease. The study by Korsak et 

al. (1994) on m-xylene was selected as the principal study because it provides the lowest LOAEL 

(50 ppm) for the critical effect, neurotoxicity. In this study, groups of 12–24 male Wistar rats were 

exposed to 0, 50, or 100 ppm m-xylene, 6 hours/day, 5 days/week for 3 months. Before the study and at 

the end of each month of exposure, rats were evaluated for motor coordination using the rotarod 

performance test. The level of analgesia was tested at termination in the paw-lick response to hot-plate 

test at 54 °C. An increase in the failure rate on the rotarod performance test was concentration-related 

and statistically significant at 100 ppm, but not at 50 ppm. Mean latency of the paw-lick response was 

significantly reduced by 28% at 50 ppm compared to controls; this effect is considered minimal. The rat 

minimal LOAEL of 50 ppm was converted to a human equivalent following the EPA (1994) dosimetric 

equation for an extra-respiratory effect from an inhaled category 3 gas: LOAELHEC = LOAELADJ × λa/λh, 

where λa and λh are blood:air partition coefficients for rats and humans, respectively. Reported blood:air 

partition coefficients for m-xylene are 39.9 for male Wistar rats and 26.4 for humans (Sato and Nakajima 

1979). Since the rat value is higher than the human, the default value of 1 was used for λa/λh (EPA 1994). 

The minimal LOAELHEC is therefore 50 ppm. An uncertainty factor of 90 was applied to the minimal 

LOAELHEC of 50 ppm (3 for the use of a minimal LOAEL, 3 for extrapolation from animals to humans 

using dosimetric adjustment, and 10 for human variability). The resulting MRL of 0.6 ppm is considered 
XYLENE	 22 

2. RELEVANCE TO PUBLIC HEALTH 

to be protective to human health under intermediate-duration inhalation exposures to mixed xylenes or 

individual isomers. 

•	 An MRL of 0.05 ppm has been derived for chronic-duration inhalation exposure (>1 year) to 

mixed xylenes. 

The database for chronic-duration inhalation toxicity of xylene contains two studies that provide 

quantitative exposure information. An occupational study reported a LOAEL of 14 ppm for subjective 

respiratory and neurological effects in workers exposed to mixed xylenes for an average of 7 years 

(Uchida et al. 1993). This study examined 175 workers (107 men, 68 women) who were exposed to 

mixed xylenes (approximately 50% m-xylene, 30% p-xylene, and 15% o-xylene) during the manufacture 

of boots or rubber-coated wires. Subjects were selected between 1989 and 1991 from a group of 

994 solvent-exposed workers who were supplied with diffusion samplers for one 8-hour workday; 

exposures were corroborated by measurements of xylene metabolites in urine. Subjects were evaluated 

for subjective symptoms in a questionnaire and also examined for objective parameters (serum 

biochemistry, hematology, and urinalysis). The final group of 175 exposed workers included those 

showing at least 70% of their solvent exposure to be from xylene and having completed all tests. The 

time-weighted average (TWA) (arithmetic mean) for xylenes was 21 ppm for an average of 7 years 

(geometric mean, 14 ppm); one man was exposed to 175 ppm. Xylenes represented at least 70% of the 

total solvent exposure, other chemicals being 3.4 ppm ethylbenzene (a typical component of commercial 

mixed xylene), 1.2 ppm toluene and rarely, n-hexane. No subjects were exposed to benzene, and the level 

of toluene exposure was low enough to be insignificant. The control group included 241 non-exposed 

workers (116 men, 125 women) in the same factories or elsewhere. Exposed workers showed a 

significant increase in the reporting of subjective symptoms including increased anxiety, forgetfulness, 

inability to concentrate, eye and nasal irritation, and sore throats. A concentration-relationship was 

reported for eye irritation, sore throat, and floating sensation, the last being indicative of central nervous 

system effect. There were no alterations in renal or hepatic serum parameters. This study has a few 

limitations: the lack of precise information on the duration of exposure and the lack of information as to 

how the workers used xylene on the job. Reliance on subjective symptoms might be considered a 

limitation of the study, except that these same symptoms were noted in the principal study for acuteduration inhalation exposure (Ernstgard et al. 2002). 

The only other chronic-duration study was for rats exposed to 1,096 ppm o-xylene 8 hours/day, 

7 days/week for 1 year (Tatrai et al. 1989). Hepatic changes included increases in liver weight and 

microsomal activity and proliferating endoplasmic reticulum, but no histopathological lesions. Body 
XYLENE	 23 

2. RELEVANCE TO PUBLIC HEALTH 

weight was reduced by 11% in exposed rats. Calculation of a chronic-duration inhalation MRL from this 

rat study would not be appropriate since the study did not examine neurological effects, which are the 

most critical end points for inhalation exposure to xylene. 

Respiratory and neurological effects are the co-critical effects of chronic-duration inhalation exposure to 

xylenes since they occurred at the lowest tested concentrations. The study of Uchida et al. (1993) was 

selected as the principal study for the chronic-duration inhalation MRL since it identified the lowest 

LOAEL of 14 ppm (geometric mean) for the co-critical effects. The geometric mean was used because it 

provides a better measure of central tendency than the arithmetic mean. The LOAEL of 14 ppm was 

divided by a total uncertainty factor of 100 (10 for the use of a LOAEL and 10 for human variability) and 

a modifying factor of 3 to account for lack of supporting studies evaluating the chronic neurotoxicity of 

xylene. The resulting MRL of 0.05 ppm is considered to be protective to human health under chronicduration (>1 year) inhalation exposures to mixed xylenes or individual isomers. 

Oral MRLs 

•	 An MRL of 1 mg/kg/day has been derived for acute-duration oral exposure (≤14 days) to mixed 

xylenes. 

Evaluation of the limited database for acute-duration oral exposure to xylenes suggests that neurotoxicity 

represents the most sensitive end point in laboratory animals; no quantitative human data are available. 

Effects observed in acute-duration oral studies in rats included altered visually evoked potentials 

following a single dose of 250 mg/kg p-xylene (Dyer et al. 1988), reduced pulmonary microsomal activity 

following a single dose of 1,000 mg/kg/day p-xylene (Patel et al. 1978), and reduced body weight gain 

following repeated dosing with 1,000 mg/kg/day mixed xylenes or 2,000 mg/kg/day o- or p-xylene 

(Condie et al. 1988; NTP 1986). Repeated gavage dosing with p-xylene, but not m- or o-xylene, at 

900 mg/kg/day, 5 days/week for 2 weeks, resulted in significant loss of cochlear hair cells associated with 

hearing at midrange frequencies (10–25 kHz) (Gagnaire and Langlais 2005). Repeated exposure to mixed 

xylenes at 2,000 mg/kg/day, resulted in impaired respiration (shallow and/or labored breathing) in rats 

and mice and increased mortality (NTP 1986). At 2,060 mg/kg/day, developmental toxicity (cleft palate) 

was observed in mice gestationally exposed to mixed xylenes (Marks et al. 1982). Serious neurological 

effects (coma, incoordination, prostration, decreased hindleg movement) were observed in rats that 

received single oral gavage doses of ≥4,000 mg/kg mixed xylenes (Muralidhara and Krishnakumari 1980; 

NTP 1986). 
XYLENE	 24 

2. RELEVANCE TO PUBLIC HEALTH 

Neurotoxicity was selected as the critical effect for acute-duration oral exposure to xylene because it was 

observed at the lowest exposure level and demonstrated dose-related increases in severity. The study by 

Dyer et al. (1988) was selected as the principal study, since it provides the lowest LOAEL for the critical 

effect. In this study, male Long-Evans rats with electrodes implanted for recording of brain visual 

potentials were dosed orally in two different experiments. In the first experiment, groups of 10–11 rats 

received single doses of p-xylene at doses of 0, 500, 1,000, or 2,000 mg/kg in corn oil and were tested 

75 minutes later for potentials evoked in response to a single flash in 128 trials. The latencies and 

amplitudes of the P1, N1, P2, N2, P3, and N3 waveforms were determined. Based on the results of this 

experiment, groups of 14–16 rats were dosed at 0, 125, or 250 mg/kg and tested 45 minutes later to record 

the N3 waveform. Forty-five minutes after administration of 250 mg/kg, the amplitude of the N3 peak 

was decreased by 47% (statistically significant). At higher doses (500, 1,000, and 2,000 mg/kg), the 

N3 peak was not observed until 75 minutes after dosing. Thus, 125 mg/kg is a NOAEL and 

250 mg/kg/day is a LOAEL for suppression of visual evoked brain potentials in rats exposed once to 

p-xylene. An uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human 

variability) was applied to the NOAEL. The resulting MRL of 1 mg/kg/day is considered to be protective 

to human health under acute-duration oral exposures to mixed xylenes or individual isomers. 

•	 An MRL of 0.4 mg/kg/day has been derived for intermediate-duration oral exposure (≥14 days to 

1 year) to mixed xylenes. 

The intermediate-duration oral toxicity of xylenes has been investigated in several oral gavage bioassays 

in rodents exposed to mixed xylene (Condie et al. 1988; NTP 1986), m-xylene (Elovaara et al. 1989; 

Wolfe 1988a), and p-xylene (Wolfe 1988b). The observed effects include increases in minimal chronic 

nephropathy and 17–37% increases in relative hepatic weight in rats exposed to ≥750 mg/kg/day mixed 

xylene (Condie et al. 1988); 27–46.3% increases in serum transaminase levels in rats exposed to 750– 

1,500 mg/kg/day mixed or m-xylene (Condie et al. 1988; Elovaara et al. 1989; Wolfe 1988a); reduced 

levels of cytochrome P-450 in the lung in rats exposed to 800 mg/kg m-xylene (Elovaara et al. 1989); 15– 

25% decreases in body weight gain in rats exposed to 800–1,000 mg/kg/day mixed, m-, or p-xylene (NTP 

1986; Wolfe 1988a, 1988b); hyperactivity or increased aggressiveness subsequent to dosing with mixed 

xylene in rats at 1,500 mg/kg/day or mice at 1,000 mg/kg/day (Condie et al. 1988; NTP 1986); and 11% 

increased relative spleen weight, 16% increased relative kidney weight, and increased hematological 

effects (mild polycythemia and leukocytosis) in female rats dosed with 1,500 mg/kg/day mixed xylene 

(Condie et al. 1988). No hepatic effects were noted in F344 rats given mixed xylene at doses as high as 

1,000 mg/kg/day or B6C3F1 mice dosed at ≤2,000 mg/kg/day 5 days/week for 13 weeks (NTP 1986) or in 

Sprague-Dawley rats dosed with p-xylene at 800 mg/kg/day for 90 days (Wolfe 1988b). No renal effects 
XYLENE	 25 

2. RELEVANCE TO PUBLIC HEALTH 

were observed in rats or mice exposed to mixed xylene in studies by NTP (1986) or in rats exposed to 

m- or p-xylene (Wolfe 1988a, 1988b). The lack of hepatic or renal effects in some studies may be related 

to strain differences, exposure differences (discontinuous vs. continuous), or isomer specificities. 

A limitation of standard intermediate-duration oral bioassays for xylene is that no testing was conducted 

for sensitive neurological effects. The only overt neurological effect of long-term exposure to xylene was 

hyperactivity noted in all male and female B6C3F1 mice (50/sex/group) immediately after oral gavage 

dosing 5 days/week with 1,000 mg/kg (710 mg/kg/day duration adjusted) mixed xylene (9.1% o-, 60.2% 

m-, and 13.6% p-xylene plus 17% ethylbenzene) in corn oil beginning at week 4 of the 103-week NTP 

(1986) bioassay; hyperactivity was not observed at 500 mg/kg (360 mg/kg/day, duration-adjusted). 

Survival was not significantly affected by treatment with xylene during the first year. Neurotoxicity 

(hyperactivity) observed during the first year of that study (weeks 4–51) is selected as the critical effect of 

intermediate-duration exposure because it was observed at the lowest LOAEL (710 mg/kg/day, adjusted 

for intermittent exposure). Selection of neurotoxicity as the critical effect is consistent with other MRLs 

for xylene. The NTP (1986) study is selected as the principal study for intermediate-duration exposure to 

xylene because it provides the lowest adverse effect level, a LOAEL of 710 mg/kg/day, and a NOAEL of 

500 mg/kg (360 mg/kg/day, duration-adjusted) for the critical effect. A total uncertainty factor of 

100 (10 for extrapolation from animals to humans, and 10 for human variability) and a modifying factor 

of 10 (for the lack of testing for sensitive neurological end points and lack of developmental and multigenerational data) were applied to the duration-adjusted NOAEL. The resulting MRL of 0.4 mg/kg/day is 

considered to be protective to human health under intermediate-duration oral exposures to mixed xylenes 

or individual isomers. 

•	 An MRL of 0.2 mg/kg/day has been derived for chronic-duration oral exposure (≥1 year) to 

mixed xylenes. 

The available animal studies involving chronic-duration oral exposure to xylenes do not clearly identify 

toxic effects other than 5–8% decreases in body weight gain (not biologically significant) and 

unexplained reduced survival in male F344 rats at 500 mg/kg (NTP 1986) and transient hyperactivity 

associated with gavage administration in male and female B6C3F1 mice at 1,000 mg/kg/day (NTP 1986). 

These studies are standard cancer/toxicology bioassays involving administration of mixed xylenes (13.6% 

p-xylene, 60.2% m-xylene, 9.1% o-xylene, and 17% ethylbenzene) by gavage in corn oil to groups of 

50 animals/sex, 5 days/week for 103 weeks (NTP 1986). Animals were examined twice daily and clinical 

signs were recorded daily for the first 16 months, then once a month thereafter. Body weights were 

recorded weekly for the first 12 weeks and then once every 4 weeks thereafter. At termination, all 
XYLENE 26 

2. RELEVANCE TO PUBLIC HEALTH 

animals were subjected to gross necropsy and histological examinations. Comprehensive histological 

examination of major tissues and organs revealed no exposure-related increased incidences of 

pathological lesions in rats or mice. 

In the absence of data associating health effects in humans with chronic-duration oral exposure to 

xylenes, the animal bioassays provide a minimal basis for deriving an MRL for humans chronically 

exposed to xylenes. A NOAEL of 500 mg/kg was identified for hyperactivity in mice, but this was not 

selected as the basis for the chronic-duration MRL because that dose decreased survival in male rats. 

Therefore, the rat NOAEL of 250 mg/kg was selected as the basis of the MRL. The NOAEL was first 

adjusted for discontinuous exposure (5 days/7 days), resulting in a duration-adjusted NOAEL of 

179 mg/kg/day. An uncertainty factor of 100 (10 for extrapolation between animals and humans and 

10 for human variability) and a modifying factor of 10 were applied to the duration-adjusted NOAEL to 

account for the lack of testing for sensitive neurological end points (the most sensitive effects in 

inhalation studies and acute oral studies) and lack of developmental and multi-generational data. The 

resulting chronic-duration oral MRL of 0.2 mg/kg/day is considered to be protective to human health 

under chronic-duration (>1 year) oral exposures to mixed xylenes or individual isomers. 
XYLENE 27 

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 xylene. 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. 

Commercial xylene is a mixture of three isomers of xylene (m-, o-, and p-xylene) with <20% ethylbenzene. In the following discussion of the health effects of xylene, the effects of both the mixture and 

the individual isomers are presented. Where possible, the effects of individual isomers will be identified 

and presented separately. 

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 
XYLENE 28 

3. HEALTH EFFECTS 

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 

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 change from the last edition of this profile is that a single MRL is derived for each duration (acute, 

intermediate, or chronic) of inhalation or oral exposure that applies equally to mixed xylenes and to the 

individual isomers, rather than having specific MRLs for each chemical entity. This convention is in 

accordance with occupational exposure levels promulgated by agencies such as ACGIH, NIOSH, and 

OSHA (see Table 8-1) and is supported by several lines of evidence. The isomers have similar chemical 

properties such as log Kow (see Table 4-2), resulting in similar absorption, distribution, and excretion 

patterns (see Section 3.4 and Table 3-6). The tissue:air partition coefficients (liver, fat, and muscle) and 

the blood:air partition coefficients, as well as the estimated hemoglobin binding constants, for the three 

isomers of xylene are almost identical or comparable (Adams et al. 2005; Poulin and Krishnan 1996a, 

1996b). The xylene isomers are metabolized by the same enzymes, resulting in an isomer of 

methylhippuric acid as the predominant metabolite in each case (see Section 3.4.3). In addition, 

physiologically based pharmacokinetic (PBPK) models based on the characteristics of m-xylene have 

been shown to be able to simulate the kinetics of mixed xylenes (Tardif et al. 1993a, 1995). 

Toxicological data from comparative studies, as discussed by EPA (2003), demonstrate that, in some 

cases, the effects and effect levels of the isomers are similar; e.g., body weight findings in the acute oral 

study by Condie et al. (1988) or the alveolar concentration levels associated with anaesthetic effects as 

described by Fang et al. (1996). Other studies have indicated different orders of relative toxicity for the 

isomers, but there is no consistent pattern indicating that a particular isomer is the most potent for all end 

points, and the differences in effect levels among the isomers may be small. For example, the ortho 

isomer was most potent in assays on operant behavior (Moser et al. 1985) and motor coordination in rats 
XYLENE 29 

3. HEALTH EFFECTS 

(Korsak et al. 1990), and in a developmental toxicity assay in rats in which mixed xylenes had the same 

effect levels (Saillenfait et al. 2003). On the other hand, the para isomer was most potent in a different 

test for motor performance, the inverted screen test (Moser et al. 1985), and in ototoxicity assays in rats 

(Gagnaire and Langlais 2005; Gagnaire et al. 2001). Given the lack of consistency among the different 

end points, the most sensitive effect by mixed xylenes or any isomer was chosen as the basis for the MRL 

for mixed xylenes and all isomers for that duration and route of exposure. 

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 

One report was located regarding death in humans following acute inhalation exposure to xylene 

(composition unspecified) (Morley et al. 1970). One of three men died after breathing paint fumes for 

several hours that contained an estimated atmospheric concentration of 10,000 ppm xylene. Xylene 

comprised 90% of the solvent in the paint (small amounts of toluene were also present), with the total 

solvent comprising 34% of the paint by weight. An autopsy of the man who died showed severe 

pulmonary congestion, interalveolar hemorrhage, and pulmonary edema; the brain showed hemorrhaging 

and evidence of anoxic damage. Clinical signs noted in the two exposed men who survived included 

solvent odor of the breath, cyanosis of the extremities, and neurological impairment (temporary 

confusion, amnesia). Both men recovered completely. The authors hypothesized that anoxia did not 

contribute to the effects observed in the survivors because the flow of oxygen into the area in which the 

men were working should have been adequate. The study was inconclusive for evaluating the toxic 

effects of xylene because the subjects were concurrently exposed to other chemicals in the paint. No 

studies were located regarding mortality in humans after intermediate or chronic inhalation exposure to 

mixed xylene or xylene isomers. 

Acute inhalation LC50 values have been determined in animals for xylene and its isomers (Bonnet et al. 

1979; Carpenter et al. 1975a; Harper et al. 1975; Hine and Zuidema 1970; Ungvary et al. 1980b). The 

4-hour LC50 value for mixed xylene in rats ranged from 6,350 ppm (Hine and Zuidema 1970) to 

6,700 ppm (Carpenter et al. 1975a). The 4-hour LC50 value for p-xylene in rats was reported to be 

4,740 ppm (Harper et al. 1975). In mice, the 6-hour LC50 values for m-, o-, and p-xylene were determined 

to be 5,267, 4,595, and 3,907 ppm, respectively (Bonnet et al. 1979). These data suggest that p-xylene 
XYLENE 30 

3. HEALTH EFFECTS 

may be slightly more toxic than the other xylene isomers. According to the toxicity classification system 

of Hodge and Sterner (1949), these values indicate that mixed xylene and its isomers are slightly toxic by 

acute inhalation. 

Mice appear to be more sensitive than rats to the lethal effects of the m- and o-isomers of xylene 

(Cameron et al. 1938). While no rats died following a 24-hour exposure to 2,010 ppm m-xylene, 6 of 

10 mice died as a result of a similar exposure. Similarly, a 24-hour exposure of rats to 3,062 ppm 

o-xylene resulted in a death rate of only 1 in 10, whereas in mice, 4 of 10 died. It is unclear whether 

differential sensitivities exist for the p-isomer of xylene in mice and rats (Cameron et al. 1938). 

Information regarding lethality following intermediate-duration exposures is limited to the results of a 

single study examining mortality in rats, guinea pigs, monkeys, and dogs following intermittent and 

continuous exposure to o-xylene (Jenkins et al. 1970). Continuous exposure to 78 ppm o-xylene for 90– 

127 days resulted in the death of only 1 of 15 rats. Intermittent exposure to 780 ppm o-xylene resulted in 

deaths of 3 of 15 rats; none of the 15 guinea pigs, 3 monkeys, or 2 dogs died. No data were located 

regarding death following chronic-duration exposure to mixed xylene or its isomers. 

All LC50 values and LOAEL values from each reliable study for death in each species and duration 

category are recorded in Table 3-1 and plotted in Figure 3-1. 

3.2.1.2 Systemic Effects 

No human or animal data were available regarding dermal effects following inhalation exposure to mixed 

xylene or xylene isomers. The systemic effects observed after inhalation exposure to xylene are discussed 

below. The highest NOAEL value and all LOAEL values from each reliable study for systemic effects in 

each species and duration category are recorded in Table 3-1, and are plotted in Figure 3-1. 

Respiratory Effects. Self-reported symptoms of respiratory irritation and impaired performance in 

tests of pulmonary function have been observed in studies of volunteers exposed to xylene for short 

periods of time under controlled conditions. In humans, nose and throat irritation has been reported 

following exposure to mixed xylene at 200 ppm for 3–5 minutes (Nelson et al. 1943), to m-xylene at 

50 ppm for 2 hours (Ernstgard et al. 2002), and to p-xylene at 100 ppm for 1–7.5 hours/day for 5 days 

(NIOSH 1981). However, no increase in reports of nose and throat irritation and no change in respiratory 

rate were seen in a study of subjects exposed to mixed xylene at a concentration of 396 ppm for 
12

3062

891

19650

143

6700

39

4740

43

6350

759

700

36

3907

37

5267

38

4595

11

3062

Table 3-1 Levels of Significant Exposure to Xylene - Inhalation 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

ACUTE EXPOSURE Death 

1 Rat 

Wistar 

24 hr 

System 

NOAEL 

(ppm) 

Less Serious 

(ppm) 

LOAEL 

Serious 

(ppm) 

3062 (1/10 died) 

Reference Chemical Form 

Cameron et al. 1938 ortho 

2 Rat 

(Wistar) 

12 hr 19650 (8/10 died) Cameron et al. 1938 

para 

3 Rat 

HarlanWistar 

4 hr 6700 M (LC50) Carpenter et al. 1975a 

mixed 

4 Rat 

CD 

4 hr 4740 F (LC50) Harper et al. 1975 

para 

5 Rat 

Long- Evans 

4 hr 6350 M (LC50) Hine and Zuidema 1970 

mixed 

6 Rat 

CFY 

7 d 24 hr/d 700 F (4/30 died) Ungvary et al. 1980b 

meta 

7 Mouse 

SPF-Of1 

6 hr 3907 F (LC50) Bonnet et al. 1979 

para 

8 Mouse 

SPF-Of1 

6 hr 5267 F (LC50) Bonnet et al. 1979 

meta 

9 Mouse 

SPF-Of1 

6 hr 4595 F (LC50) Bonnet et al. 1979 

ortho 

10 Mouse 

NS 

24 hr 3062 (4/10 died) Cameron et al. 1938 

ortho 
19

19650

8

2010

77

460 690230 460

883

5050

98

299

601

396396

Table 3-1 Levels of Significant Exposure to Xylene - Inhalation (continued) 

a 

Key to Species 

Figure (Strain) 

11 Mouse 

NS 

12 Mouse 

NS 

Systemic 

13 Human 14 Human 15 Human 16 Human 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

12 hr 19650 (9/10 died) Cameron et al. 1938 

para 

24 hr 2010 (6/10 died) Cameron et al. 1938 

meta 

0.25 hr Resp 460 690 (throat irritation) Carpenter et al. 1975a 

mixed 

Ocular 230 460 (eye irritation) 

2 hr Resp 50 (decreased forced vital 

capacity; increased severity score for throat/airway discomfort, breathing difficulty, nose irritation) 

Ernstgard et al. 2002 meta 

Ocular 50 (slight eye irritation) 

2 or 3 d 70 min/d Cardio 299 M Gamberale et al. 1978 

mixed 

30 min Resp 396 M Hastings et al. 1986 

mixed 

Ocular 396 M 
462

200200200

207

200200

96

100

100100100

100

788

100

789

200

Table 3-1 Levels of Significant Exposure to Xylene - Inhalation (continued) 

Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) 

17 Human 2-6 d 

5-5.5 hr/d 

18 Human 3-5 min 19 Human 5 d 

1-7.5 hr/d 

20 Human 7 hr 21 Human 7 hr 

System 

Resp Cardio Hemato Resp 

Ocular 

Resp Cardio Hemato Renal Ocular Cardio Cardio 

LOAEL 

NOAEL 

(ppm) 

Less Serious 

(ppm) 

Serious 

(ppm) 

Reference Chemical Form 

200 M 200 M 200 M 

Laine et al. 1993 meta 

200 (nose and throat 

irritation) 

Nelson et al. 1943 mixed 

200 (eye irritation) 

100 F (nose and throat 

irritation) 

NIOSH 1981 para 

100 F 100 F 100 F 

100 F (eye irritation) 

100 M Ogata et al. 1970 

para 

200 M Ogata et al. 1970 

meta 
754

200200

94

15000

732

750

583

75

772

1000

773

1000

729

300

Table 3-1 Levels of Significant Exposure to Xylene - Inhalation (continued) 

a 

Key to 

Figure 

22 23 24 25 26 27 28 

Species 

(Strain) 

Human Rat HarlanWistar Rat Wistar Rat NS Rat SpragueDawley Rat SpragueDawley Rat NS 

Exposure/ 

Duration/ 

Frequency 

(Route) 

4 d 3.67 hr/d 0.75 hr 1 or 2 wk 5 d/wk 6 hr/d 24 hr 4 d 4 hr/d 4 hr 1, 3, or 5 d 6 hr/d 

LOAEL 

NOAEL Less Serious Serious Reference

System (ppm) (ppm) (ppm) Chemical Form 

Resp 200 M Seppalainen et al. 1989 

meta 

Cardio 200 M Hemato 15000 M Carpenter et al. 1975a 

mixed 

Hepatic 750 M Elovaara 1982 

meta 

Resp 75 M (decrease in P-450 and 

7-ethoxycoumarin O-deethylase activity) 

Elovaara et al. 1987 meta 

Resp 1000 F (decreased pulmonary 

microsomal activity) 

Patel et al. 1978 para 

Resp 1000 F (decreased pulmonary 

microsomal activity) 

Patel et al. 1978 para 

Resp 300 M (transiently decreased 

surfactant levels) 

Silverman and Schatz 1para 
726

1600

745

20002000

746

2000

747

20002000

748

2000

760

700350

700

Table 3-1 Levels of Significant Exposure to Xylene - Inhalation (continued) 

Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) 

29 Rat 

Fischer- 344 

1 or 3 d 6 hr/d 

30 Rat 

SpragueDawley 

3 d 6 hr/d 

31 Rat 

SpragueDawley 

3 d 6 hr/d 

32 Rat 

SpragueDawley 

3 d 6 hr/d 

33 Rat 

SpragueDawley 

3 d 6 hr/d 

34 Rat 

CFY 

7 d 24 hr/d Gd 7-14 

LOAEL 

System 

NOAEL 

(ppm) 

Less Serious 

(ppm) 

Serious 

(ppm) 

Reference Chemical Form 

Hepatic 1600 M Simmons et al. 1991 

para 

Resp 2000 M (decreased cytochrome Toftgard and Nilsen 198

P-450) para 

Renal 2000 M (decreased relative 

kidney weight) 

Resp 2000 M (decreased cytochrome Toftgard and Nilsen 198

P-450) meta 

Resp 2000 M (decreased cytochrome Toftgard and Nilsen 198

P-450) ortho 

Renal 2000 M (decreased relative 

kidney weight) 

Resp 2000 M (decreased cytochrome Toftgard and Nilsen 198

P-450) mixed 

Hepatic 700 F Ungvary et al. 1980b 

meta 

Bd Wt 350 F 700 F (16% decrease in body 

weight gain) 
761

700700

762

700700

728

2764

140

460

1300

102

1467

723

2440

849

2513

Table 3-1 Levels of Significant Exposure to Xylene - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

35 Rat 

CFY 

7 d 24 hr/d Gd 7-14 

Hepatic Bd Wt 

700 F 700 F 

Ungvary et al. 1980b ortho 

36 Rat 

CFY 

7 d 24 hr/d Gd 7-14 

Hepatic Bd Wt 

700 F 700 F 

Ungvary et al. 1980b para 

37 Rat 

Wistar 

9 d 5 hr/d Hemato 2764 Wronska-Nofer et al. 19

mixed 

38 Mouse 

SwissWebster 

1 min Resp 460 M 1300 M (50% decrease in 

respiratory rate) 

Carpenter et al. 1975a mixed 

39 Mouse 

Swiss Of1 

5 min Resp 1467 M (50% decrease in 

respiratory rate) 

De Ceaurriz et al. 1981 ortho 

40 Mouse 6 min Resp 2440 M (50% decrease in 

respiratory rate) 

Korsak et al. 1988 mixed 

41 Mouse 

Balb/C 

6 min Resp 2513 M (32% decrease in 

respiratory rate) 

Korsak et al. 1990 ortho 
850

2626

851

2700

465

1361

476

12081208

774

1000

756

460 690

725

100

Table 3-1 Levels of Significant Exposure to Xylene - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

42 Mouse 

Balb/C 

6 min Resp 2626 M (transient 46% decrease 

in respiratory rate) 

Korsak et al. 1990 para 

43 Mouse 

Balb/C 

6 min Resp 2700 M (transient 57% decrease 

in respiratory rate) 

Korsak et al. 1990 meta 

44 Mouse 

Balb/c 

once 6 min Resp 1361 M (50% decrease in respiratory rate) Korsak et al. 1993 meta 

45 Mouse 

C3H/H3J 

4 d 6 hr/d Hepatic 

Bd Wt 

1208 F 1208 F 

Selgrade et al. 1993 para 

46 Rabbit 

New Zealand 

2 d 4 hr/d Resp 1000 M (decreased pulmonary microsomal activity) Patel et al. 1978 para 

Neurological 

47 Human 0.25 hr 460 690 (dizziness) Carpenter et al. 1975a 

mixed 

48 Human 4 hr 100 M (increased reaction time) Dudek et al. 1990 

mixed 
884

50

97

299

99

299

602

396

463

200

95

100

790

200

110

69

Table 3-1 Levels of Significant Exposure to Xylene - Inhalation (continued) 

a 

Key to Species 

Figure (Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

2 hr once 

b

50 (increased severity 

scores for headache, dizziness in males; intoxication in males and females) 

Ernstgard et al. 2002 meta 

2 d 70 min/d 299 M Gamberale et al. 1978 

mixed 

1 d 70 min/d 299 M (impairment in reaction time and short-term 

memory after exercising; not without exercising) 

Gamberale et al. 1978 mixed 

30 min 396 M Hastings et al. 1986 

mixed 

2-6 d 5-5.5 hr/d 200 M Laine et al. 1993 

meta 

5 d 1-7.5 hr/d 100 F (dizziness) NIOSH 1981 

para 

7 hr 200 M Ogata et al. 1970 

meta 

49 Human 50 Human 51 Human 52 Human 53 Human 54 Human 55 Human 

Human 4 hr 69 M Olson et al. 1985 

para 

56 
183

281

752

400

753

200

117

2000

118

2000

119

2000

120

2000

Table 3-1 Levels of Significant Exposure to Xylene - Inhalation (continued) 

a 

Key to 

Figure 

57 58 59 60 61 62 63 

Species 

(Strain) 

Human Human Human Rat SpragueDawley Rat SpragueDawley Rat SpragueDawley Rat SpragueDawley 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

2 x/dose 1 x/wk 4 hr/x 4 hr 

281 M 

400 M (impaired body balance 

and reaction times) 

Savolainen 1980 meta Savolainen et al. 1984 meta 

4 d 3.67 hr/d 200 M (altered visual evoked potentials) Seppalainen et al. 1989 meta 

3 d 6 hr/d 2000 M (increased brain levels of catecholamine) Andersson et al. 1981 para 

3 d 6 hr/d 2000 M (increased dopamine and catecholamine in brain) Andersson et al. 1981 mixed 3 d 6 hr/d 2000 M (increased brain levels of catecholamine) Andersson et al. 1981 meta 3 d 6 hr/d 2000 M (increased brain levels of catecholamine) Andersson et al. 1981 ortho 
757

580 1300

873

1800

768

800

1600

78

113

79

99

80

114

722

2010

2870

Table 3-1 Levels of Significant Exposure to Xylene - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

64 65 

Rat NS 

4 hr 

Rat (Long- Evans) 

5 d 8 hr/d 

580 M 1300 M (incoordination) 

1800 M (18-30 dB increased in 

mid-range auditory thresholds) 

Carpenter et al. 1975a mixed Crofton et al. 1994 mixed 

66 Rat 

Long- Evans 

4 hr 800 M 1600 M (altered visual evoked 

potentials) 

Dyer et al. 1988 para 

67 Rat 

F344 

1 d 3 x/d 2 hr/x 

113 M (transiently decreased 

operant responding) 

Ghosh et al. 1987 mixed 

68 69 

Rat F344 Rat F344 

5 hr 3 d 6 hr/d 

99 M 

114 M (transiently decreased 

operant responding) 

Ghosh et al. 1987 mixed Ghosh et al. 1987 mixed 

70 Rat 

NS 

4 hr 2010 M 2870 M (impaired rotarod 

performance) 

Korsak et al. 1988 mixed 
846

3000

847

3000

848

3000

466

1982

103

1940

104

2180

105

2100

501

800

Table 3-1 Levels of Significant Exposure to Xylene - Inhalation (continued) 

a 

Key to 

Figure 

71 72 73 74 75 76 77 78 

Species 

(Strain) 

Rat Rat NS Rat Rat Wistar Imp:DAK Rat NS Rat Rat Rat NS 

Exposure/ LOAEL 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) Serious (ppm) 

6 hr 3000 M (impaired rotarod 

performance) 

6 hr 3000 M (impaired rotarod 

performance) 

6 hr 3000 M (impaired rotarod 

performance) 

once 4 hr 1982 M (EC50 for decreased rotarod performance) 

4 hr 1940 M (narcosis) 4 hr 2180 M (narcosis) 4 hr 2100 M (narcosis) 1.5 wk 5 d/wk 6 hr/d 

800 M (decreased axonal 

transport) 

Reference Chemical Form 

Korsak et al. 1990 ortho Korsak et al. 1990 para Korsak et al. 1990 meta Korsak et al. 1993 meta Molnar et al. 1986 para Molnar et al. 1986 ortho Molnar et al. 1986 meta Padilla and Lyerly 1989 mixed 
806

400

800

100

1700

185

1450

874

1700

2000

888

230

113

102

192

875

250

500

Table 3-1 Levels of Significant Exposure to Xylene - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

79 Rat 

NS 

1, 3, 8, 13 d 5 d/wk 6 hr/d 

400 M 800 M (decreased axonal 

transport) 

Padilla and Lyerly 1989 para 

80 Rat 

NS 

4 hr 1700 M Pryor et al. 1987 

mixed 

81 Rat 

NS 

8 hr 1450 M (hearing loss) Pryor et al. 1987 

mixed 

82 Rat 

(Long- Evans) 

5 d 8 hr/d 1700 M 2000 M (50% decreased integrated amplitude of 

brainstem auditory evoked potentials at 16 kHz) 

Rebert et al. 1995 mixed 

83 Rat 

(albino) 

4 hr once 230 M (18% inhibition of electrically evoked 

seizure discharge) 

Vodickova et al. 1995 ortho 

84 Rat 

F344 

2 hr 102 M 192 M (decreased 

self-stimulation behavior) 

Wimolwattanapun et al. mixed 

85 Mouse 

(SwissWebster) 

5 min 250 M 500 M (decreased response 

rate for schedule-controlled operant behavior) 

Bowen et al. 1998 meta 
116

1010

889

320

755

9500

6

775

513

775

876

500

Table 3-1 Levels of Significant Exposure to Xylene - Inhalation (continued) 

a 

Key to Species 

Figure (Strain) 

86 Mouse 

Swiss Of1 

87 Mouse 

(albino) 

88 Cat 

NS 

Reproductive 

89 Rat 

(CFY) 

Developmental 

90 Rat 

(CFY) 

91 Rat 

(Wistar) 

Exposure/ LOAEL 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) Serious (ppm) 

4 hr 1010 M (altered behavior in 

swimming test) 

4 hr once 320 F (11% decreased duration of response

 to electric shock) 

2 hr 9500 M (salivation, ataxia, 

seizures, anesthesia) 

8 d 24 hr/d Gd 7-15 

775 (8% decreased fertility; 

increased resorptions) 

8 d 24 hr/d Gd 7-14 

775 (postimplantation loss) 

Gd 7-20 6 hr/d 500 F (delayed air righting reflex, impaired motor 

coordination on Rotarod; impaired memory in Morris water maze) 

Reference Chemical Form 

De Ceaurriz et al. 1983 ortho Vodickova et al. 1995 ortho Carpenter et al. 1975a mixed Balogh et al. 1982 mixed Balogh et al. 1982 mixed Hass et al. 1995 mixed 
877

500

57

1612

878

500

1000

879

100

500

880

500

1000

881

100

500

899

438

784

Table 3-1 Levels of Significant Exposure to Xylene - Inhalation (continued) 

a 

Key to 

Figure 

92 93 94 95 96 97 98 

Species 

(Strain) 

Rat (Wistar) Rat SpragueDawley Rat (SpragueDawley) Rat (SpragueDawley) Rat (SpragueDawley) Rat (SpragueDawley) Rat CFY 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

Gd 7-20 6 hr/d 500 F (increased latency in Morris water maze 

persisting to 28 weeks) 

Hass et al. 1997 mixed 

10 d 6 hr/d Gd 7-16 

1612 F Rosen et al. 1986 

para 

Gd 6-20 6 hr/d 500 1000 (6% decrease in fetal body weight) Saillenfait et al. 2003 meta 

Gd 6-20 6 hr/d 100 500 (5% decrease in fetal body weight) Saillenfait et al. 2003 ortho 

Gd 6-20 6 hr/d 500 1000 (5-6% decrease in fetal body weight) Saillenfait et al. 2003 para 

Gd 6-20 6 hr/d 100 500 (4% decrease in fetal body weight) Saillenfait et al. 2003 mixed 

9 d 24 hr/d Gd 7-15 

438 F 784 F (increased fetal death 

and resorption) 

Ungvary and Tatrai 198mixed 
62

35

350

63

350

700

64

350 700

66

691

735

780

158

780

Table 3-1 Levels of Significant Exposure to Xylene - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

99 Rat 

CFY 

8 d Gd 7-14 24 hr/d 

35 350 (9% decrease in fetal 

weight) 

Ungvary et al. 1980b ortho 

100 Rat 8 d 

24 hr/d Gd 7-14 

350 F 700 F (fetal and maternal 

weight decreased, decreased implantation) 

Ungvary et al. 1980b meta 

101 Rat 

CFY 

8 d 24 hr/d Gd 7-14 

350 F 700 F (postimplantation loss) Ungvary et al. 1980b 

para 

102 Rat 

CFY 

24-48 hr Gd 9 and 10 691 (27% decrease in fetal weight) Ungvary et al. 1981 para 

INTERMEDIATE EXPOSURE Death 

103 Monkey 

Squirrel 

6 wk 5 d/wk 8 hr/d 

780 M (1/2 died) Jenkins et al. 1970 

ortho 

104 Rat 

SpragueDawley LongEvans 

6 wk 5 d/wk 8 hr/d 

780 (3/12 died) Jenkins et al. 1970 

ortho 
187

20

100

15015015020 100

141

810810810810810810810810810

24

300

Table 3-1 Levels of Significant Exposure to Xylene - Inhalation (continued) 

Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) 

Systemic 

105 Human 4 wk 

5 d/wk 1-7.5 hr/d (I) 

106 Rat 10 wk 

NS 5 d/wk

6 hr/d 

107 Rat 5, 9, 14, or 

NS 18 wk

5 d/wk 6 hr/d 

System 

Resp Cardio Hemato Renal Ocular Resp Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Bd Wt Hepatic 

LOAEL 

NOAEL 

(ppm) 

Less Serious 

(ppm) 

Serious 

(ppm) 

Reference Chemical Form 

20 100 M (nose and throat 

irritation) 

NIOSH 1981 para 

150 M 150 M 150 M 

20 M 100 M (eye irritation) 

810 M Carpenter et al. 1975a 

mixed 

810 M 810 M 810 M 810 M 810 M 810 M 810 M 810 M 300 M Elovaara et al. 1980 

mixed 
864

1800

866

1800

868

1800

861

1000

863

9292

157

7878787878

Table 3-1 Levels of Significant Exposure to Xylene - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

108 Rat 

(SpragueDawley) 

13 wk 6 d/wk 6 hr/d 

Bd Wt 1800 M Gagnaire et al. 2001 

meta 

109 Rat 

(SpragueDawley) 

13 wk 6 d/wk 6 hr/d 

Bd Wt 1800 M Gagnaire et al. 2001 

ortho 

110 Rat 

(SpragueDawley) 

13 wk 6 d/wk 6 hr/d 

Bd Wt 1800 M Gagnaire et al. 2001 

para 

111 Rat 

(Wistar) 

3 mo 5 d/wk 6 hr/d 

Bd Wt 1000 M Gralewicz et al. 1995 

meta 

112 Rat 

(Wistar) 

5 mo 5 d/wk 5 hr/d 

Hepatic Bd Wt 

92 M 

92 M 

Jajte et al. 2003 meta 

113 Rat 

SpragueDawley LongEvans 

90-127 d 24 hr/d Resp 78 Jenkins et al. 1970 

ortho 

Cardio Hemato Hepatic Renal 

78 78 78 78 
159

780780780780780

467

10001000

856

50

100

100

153

230

460

100

Table 3-1 Levels of Significant Exposure to Xylene - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

114 Rat 

SpragueDawley LongEvans 

6 wk 5 d/wk 8 hr/d 

Resp 780 Jenkins et al. 1970 

ortho 

Cardio Hemato Hepatic Renal 

780 

780 

780 780 

115 Rat 

Wistar 

3 mo 5 d/wk 6 hr/d 

Hemato Bd Wt 

1000 M 1000 M 

Korsak et al. 1992 meta 

116 Rat 

(Wistar) 

3 mo 5 d/wk 6 hr/d 

Hemato 50 M 100 M (19% decreased 

erythrocytes; 35% increased leukocytes) 

Korsak et al. 1994 meta 

Bd Wt 100 M 

117 Rat 

CFY 

4 wk 5 d/wk 6 hr/d 

Cardio 230 M (increased wall thickness 

in coronary micro-vessels) 

Morvai et al. 1987 mixed 

118 Rat 

Wistar 

6 mo 5 d/wk 6 hr/d 

Hepatic 100 M Rydzynski et al. 1992 

meta 
461

1000

743

1096

1096

92

600

1

810810810810810810810810

172

150

Table 3-1 Levels of Significant Exposure to Xylene - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

119 Rat 

Wistar 

3 mo 5 d/wk 6 hr/d 

Hepatic 1000 M Rydzynski et al. 1992 

meta 

120 Rat 

CFY 

6 mo 7 d/wk 8 hr/d 

Hepatic 1096 M Tatrai et al. 1981 

ortho 

Bd Wt 1096 M (12% decrease in body 

weight) 

121 Rat 

SpragueDawley 

4 wk 5 d/wk 6 hr/d 

Hepatic 600 M (11% increase in relative 

liver weight) 

Toftgard et al. 1981 mixed 

122 Dog 13 wk 

5 d/wk 6 hr/d 

Resp 810 M Carpenter et al. 1975a 

mixed 

Neurological 

123 Human 4 wk 

5 d/wk 1-7.5 hr/d 

Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr 

810 M 810 M 810 M 810 M 810 M 810 M 810 M 150 M NIOSH 1981 

para 
168

78

170

780

865

1800

867

1800

869

450

900

1800

906

500

1000

Table 3-1 Levels of Significant Exposure to Xylene - Inhalation (continued) 

a 

Key to Species 

Figure (Strain) 

124 Monkey 

Squirrel 

125 Monkey 

Squirrel 

126 Rat 

(SpragueDawley) 

127 Rat 

(SpragueDawley) 

128 Rat 

(SpragueDawley) 

129 Rat 

(SpragueDawley) 

Exposure/ LOAEL 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) Serious (ppm) 

90-127 d 24 hr/d 78 M 

6 wk 5 d/wk 8 hr/d 

780 M 

13 wk 6 d/wk 6 hr/d 

1800 M 

13 wk 6 d/wk 6 hr/d 

1800 M 

13 wk 6 d/wk 6 hr/d 

450 M 900 M (loss of cochlear hair 

cells without functional hearing loss) 

1800 M (extensive cochlear hair 

cell loss; altered auditory evoked potentials; persistent 35-42 dB hearing loss) 

13 wk 6 d/wk 6 hr/d 

500 M 1000 M (13-19 dB hearing losses 

in 2-16 kHz frequencies; in all rats, significant loss of outer hair cells of cochlea) 

Reference Chemical Form 

Jenkins et al. 1970 ortho Jenkins et al. 1970 ortho Gagnaire et al. 2001 meta Gagnaire et al. 2001 ortho Gagnaire et al. 2001 para Gagnaire et al. 2006 mixed 
907

500

1000

858

100

862

100

854

80

731

800

468

1000

Table 3-1 Levels of Significant Exposure to Xylene - Inhalation (continued) 

a 

Key to Species 

Figure (Strain) 

130 Rat 

(SpragueDawley) 

131 Rat 

(Wistar) 

132 Rat 

(Wistar) 

133 Rat 

(SpragueDawley) 

134 Rat 

Albino 

135 Rat 

Wistar 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

13 wk 6 d/wk 6 hr/d 

500 M 1000 M (in all rats, significant 

loss of hair cells in outer rows of organ of Corti) 

Gagnaire et al. 2006 mixed 

4 wk 5 d/wk 6 hr/d 

100 M (impaired passive and 

active avoidance learning) 

Gralewicz and Wiadernmeta 

3 mo 5 d/wk 6 hr/d 

100 M (learning deficit in radial 

arm maze test) 

Gralewicz et al. 1995 meta 

4 wk 5 d/wk 6 hr/d 

80 M Hillefors-Berglund et al. 

mixed 

30 d 24 hr/d 800 M (decreased acetylcholine in striatum, increased 

glutamine in midbrain, and norepinephrine in hypothalmus) 

Honma et al. 1983 mixed 

3 mo 5 d/wk 6 hr/d 

1000 M (decreased rotarod 

performance and spontaneous motor activity) 

Korsak et al. 1992 meta 
469

100

857

50

464

1009

101

800

182

300

174

300

111

1600

Table 3-1 Levels of Significant Exposure to Xylene - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

136 Rat 

Wistar 

6 mo 5 d/wk 6 hr/d 

100 M (decreased rotarod 

performance and spontaneous motor activity) 

Korsak et al. 1992 meta 

137 Rat 

(Wistar) 

3 mo 5 d/wk 6 hr/d 

c

50 M (decreased latency of 

paw-lick response) 

Korsak et al. 1994 meta 

138 Rat 

SpragueDawley 

61 d 7 d/wk 8 hr/d 

1009 M (reversible decrease in 

auditory brainstem response) 

Nylen and Hagman 199mixed 

139 140 

Rat Fischer- 344 Rat Wistar 

6 wk 7 d/wk 14 hr/d 18 wk 5 d/wk 6 hr/d 

300 M (decreased membrane 

lipids in axon membranes) 

800 M (hearing loss) Pryor et al. 1987 

mixed Savolainen and Seppala1979 mixed 

141 Rat 

Wistar 

18 wk 5 d/wk 6 hr/d 

300 M (transient decreases in 

preening behavior) 

Savolainen et al. 1979a mixed 

142 Mouse 

NMRI- BOM 

7 wk 5 d/wk 4 hr/d 

1600 F (decreased 

alpha-adrenergic binding in brain) 

Rank 1985 meta 
164

78

166

780

106

160

7

1000

60

250

500

Table 3-1 Levels of Significant Exposure to Xylene - Inhalation (continued) 

a 

Key to Species 

Figure (Strain) 

143 Dog 

Beagle 

144 Dog 

Beagle 

145 Gerbil 

Mongolian 

Reproductive 

146 Rat 

SpragueDawley 

Developmental 

147 Rat 

CD 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

90-127 d 24 hr/d 6 wk 5 d/wk 8 hr/d 

78 M 

780 M (tremor) 

Jenkins et al. 1970 ortho Jenkins et al. 1970 ortho 

3 mo 30 d/mo 24 hr/d 

160 (regional increases in 

DNA and astro-glial proteins) 

Rosengren et al. 1986 mixed 

61 d 7 d/wk 18 hr/d 

1000 Nylen et al. 1989 

mixed 

166 d 7 d/wk 6 hr/d 

250 500 F (7% decrease in fetal 

weight) 

Bio/dynamics 1983 mixed 
470

1414

141414

14

508

1096

1096

Table 3-1 Levels of Significant Exposure to Xylene - Inhalation (continued) 

Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) 

CHRONIC EXPOSURE Systemic 

148 Human average 

7 yr 8 hr/d 

149 Rat 1 yr 

CFY 7 d/wk

8 hr/d 

LOAEL 

System 

NOAEL 

(ppm) 

Less Serious 

(ppm) 

Serious 

(ppm) 

Reference Chemical Form 

Resp 14 M (nose and throat 

irritation) 

Uchida et al. 1993 mixed 

Gastro 14 M (increased prevalence of 

nausea and poor appetite) 

Hemato 14 M Hepatic Renal 

14 M 14 M 

Ocular 14 M (eye irritation) Hepatic 1096 M Tatrai et al. 1981 

ortho 

Bd Wt 1096 M (12% decrease in body 

weight) 
471

14

Table 3-1 Levels of Significant Exposure to Xylene - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) 

LOAEL 

Less Serious 

(ppm) 

Serious 

(ppm) 

Reference Chemical Form 

Neurological 

150 Human average 

7 yr 8 hr/d 

d

14 (increased prevalence of 

anxiety, forgetfulness, inability to concentrate and other subjective symptoms) 

Uchida et al. 1993 mixed 

a The number corresponds to the entries in Figure 3-1. b Used to derive an acute-duration minimal risk level (MRL) for mixed xylenes based on a minimal LOAEL of 50 ppm for m-xylene in humans; concentration divided factor of 30 (3 for use of a minimal LOAEL and 10 for human variability). c Used to derive an intermediate-duration minimal risk level (MRL) for mixed xylenes based on a minimal LOAEL of 50 ppm for m-xylene in rats; this LOAEL was cohuman equivalent concentration using a dosimetric adjustment (EPA 1994). The human equivalent LOAEL of 50 ppm was divided by an uncertainty factor of 90 (3 minimal LOAEL, 3 for extrapolation from animals to humans with dosimetric adjustment, and 10 for human variability). d Used to derive a chronic-duration minimal risk level (MRL) for mixed xylenes based on a LOAEL of 14 ppm (geometric mean) for mixed xylenes in humans; concean uncertainty factor of 100 (10 for use of a LOAEL and 10 for human variability) and a modifying factor of 3 to account for the lack of supporting studies evaluating neurotoxicity of xylene. Bd Wt = body weight; Cardio = cardiovascular; d = day(s); dB = decibel; EC50 = effective concentration; Endocr = endocrine; F = Female; Gastro = gastrointestinalday,50%; hemato = hematological; hr = hour(s); KHz = kilohertz; LC50 = lethal concentration, 50%; LOAEL = lowest-observed-adverse-effect level; M = male; min = month(s); Musc/skel = musculoskeletal; NOAEL = no-observed-adverse-effect level; Resp = respiratory; x = time(s); wk = week(s); yr = year(s) 
Death 

Respiratory Cardiovascular Hematological 

Figure 3-1 Levels of Significant Exposure to Xylene - Inhalation
	

Acute (≤14 days)
	

Systemic 

ppm 

100000 

11m 2r 

10000 

3r 

8m 9m 4r

7m 

10m 1r 

12m 

1000 

100 

10 

1 

23r 

5r 

40m 41m 42m 43m 

30r 31r 32r 33r 

37r 

38m 39m 44m 

26r 27r 46h 

6r 13 

13 17 38m 

28r 15 

18 19 22 18 21 22 18 

16 16 20 16 

25r 

14 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 
Hepatic 

Renal Ocular Body Weight Neurological 


 



 
 



 


Figure 3-1 Levels of Significant Exposure to Xylene - Inhalation (Continued)
 

Acute (≤14 days)
	

Systemic 

ppm 

100000 

10000 88c 

30r 32r 60r 61r 62r 63r 65r 29r 66r 

45m 45m 64r

1000 86m

24r 66r 34r 35r 36r 34r 35r 36r 47 64r

13 47 85m

17 53 58 34r 50 51 87m 57 

13 85m

19 54 55 59 

67r 100 16 16 48 52 

56 

14 49 

10 

1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Levels

 for effects

 other than

 Cancer 
Neurological 

Reproductive Developmental 

Figure 3-1 Levels of Significant Exposure to Xylene - Inhalation (Continued)

Acute (≤14 days) 

ppm 

100000 

10000 

70r 71r 72r 73r

70r 74r 75r 76r 77r 82r 80r 82r 93r 81r 

1000 94r 96r 

78r 79r 89r 90r 98r 100r 

91r 92r 94r 95r 96r 97r 98r 79r 99r 100r 

83r 84r 

69r 100 68r 84r 95r 97r

99r 

10 

1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 
Developmental 

Figure 3-1 Levels of Significant Exposure to Xylene - Inhalation (Continued)
 

Acute (≤14 days)
	

ppm 

100000 

10000 

1000 

101r 102r 

101r 

100 

10 

1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 
Death 

Respiratory Cardiovascular Gastrointestinal Hematological Musculoskeletal Hepatic Renal 

Figure 3-1 Levels of Significant Exposure to Xylene - Inhalation (Continued)
 

Intermediate (15-364 days)
	

Systemic 

ppm 

10000 

120r 1000 115r 119r 

103k 104r 122d 106r 114r 122d 106r 114r 122d 106r 122d 106r 114r 122d 106r 122d 106r 114r 122d

121r 

107r 

117r 

105 105 105 

100 105 116r 118r 112r 113r 113r 113r 113r 

116r 

105 

10 

1 

0.1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level 

for effects

 other than

 Cancer 
Renal 

Endocrine Ocular Body Weight Neurological 

Figure 3-1 Levels of Significant Exposure to Xylene - Inhalation (Continued)
 

Intermediate (15-364 days) 

Systemic 

ppm 

10000 

108r 109r 110r 126r 127r 128r 142m 

120r 1000 111r 115r 129r 130r 135r 138r 128r 106r 122d 106r 106r 114r 144d 125k 134r 139r

129r 130r 128r 

140r 141r 

123 145e

100 105 116r 131r 132r 136r 112r 113r 143d 124k 133r

137r 

105 

10 

1 

0.1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 
Reproductive 

Developmental 

Figure 3-1 Levels of Significant Exposure to Xylene - Inhalation (Continued)
 

Intermediate (15-364 days)
	

ppm 

10000 

1000 146r 

147r 

147r 

100 

10 

1 

0.1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 
Respiratory 

Gastrointestinal Hematological Hepatic Ocular Body Weight Neurological 


 
 
 
 
 


Renal 

Figure 3-1 Levels of Significant Exposure to Xylene - Inhalation (Continued)

Chronic (≥365 days) 

Systemic 

ppm 

10000
	

149r 149r 1000
	

100
	

148
	 148
	 148
	 148
	 148
	 148
	 150
	

10
	

1
	

0.1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 
XYLENE 64 

3. HEALTH EFFECTS 

30 minutes (Hastings et al. 1986). Slight, but statistically significant increases in the average rating for 

subjective symptoms of respiratory effects were observed following exposure to m-xylene at 50 ppm 

(Ernstgard et al. 2002) for discomfort in the nose in both sexes after 60 and 118 minutes, in discomfort in 

the throat or airways in women after 60 minutes, and in breathing difficulty in men at 118 minutes and 

women at both timepoints. Small but statistically significant changes in objective tests of pulmonary 

function were reported in women, but not men, measured 3 hours after the end of the 2-hour exposure: 

decreased forced vital capacity (FVC), increased forced expiratory flow at 75% FVC (FEF75), and 

increased ratio of forced expiratory volume in 1 minute (FEV1) to forced vital capacity (FEV1/FVC). 

This study is the basis for the acute-duration inhalation MRL for which respiratory and neurologic 

toxicity are the critical effects. Chest x-rays obtained from volunteers exposed to a time-weightedaverage (TWA) concentration of 200 ppm m-xylene for 3.67 hours/day for 4 days showed no adverse 

effects on the lungs (Seppalainen et al. 1989). Also, no effects on pulmonary ventilation volume were 

observed in volunteers exposed to 150 ppm p-xylene for 5 days/week in a 4-week trial (NIOSH 1981). 

At much higher concentrations, however, the lung may be adversely affected. An autopsy revealed that 

exposure to an estimated 10,000 ppm of xylene produced severe lung congestion with focal intra-alveolar 

hemorrhage and pulmonary edema in one worker who died following exposure to xylene fumes for 

several hours while painting (Morley et al. 1970). Another worker exposed in the same incident exhibited 

patchy diffuse opacities in radiograms and moist rales in both lungs; a third exposed worker showed no 

evidence of lung effects. Case reports indicate that acute-duration inhalation exposure to mixed xylene 

and p-xylene has been associated with irritation of the nose and throat (Carpenter et al. 1975a; Klaucke et 

al. 1982; Nelson et al. 1943; Nersesian et al. 1985; NIOSH 1981). A worker at a chemical company who 

was exposed to heated xylene from a pressurized hose experienced throat pain and dyspnea (Narvaez and 

Song 2003). 

Chronic occupational exposure of workers to an unspecified concentration of vapors of mixed xylene has 

also been associated with labored breathing and impaired pulmonary function (Hipolito 1980; Roberts et 

al. 1988). A significant (p<0.01) increase in the prevalence of nose and throat irritation was reported by 

workers chronically exposed to mixed xylene vapors at a geometric mean TWA concentration of 14 ppm 

(Uchida et al. 1993). This study is the basis for the chronic-duration inhalation MRL for which 

respiratory and neurological toxicity are the critical effects. 

Adverse respiratory effects noted in rats, mice, and guinea pigs following acute and intermediate 

inhalation exposure to xylene are similar to those observed in humans. They include decreased 
XYLENE 65 

3. HEALTH EFFECTS 

respiration, labored breathing, irritation of the respiratory tract, pulmonary edema, pulmonary 

hemorrhage, and pulmonary inflammation (Carpenter et al. 1975a; De Ceaurriz et al. 1981; Furnas and 

Hine 1958; Korsak et al. 1990). Exposure to concentrations of 2,440 ppm mixed xylene for 6 minutes 

(Korsak et al. 1988) to 1,467 ppm o-xylene for 5 minutes (De Ceaurriz et al. 1981), or to 1,361 ppm 

m-xylene for 6 minutes (Korsak et al. 1993) produced a 50% decrease in respiratory rate in mice. 

Comparison of the individual xylene isomers showed that the irritant effects of m- and o-xylene as 

quantified by measurements of respiratory rate in mice are more pronounced than those of p-xylene, with 

o-xylene having the most prolonged effect (Korsak et al. 1990). In rats that died as a result of exposure to 

9,900 ppm mixed xylene for 4 hours, atelectasis, hemorrhage, and edema of the lungs were observed 

(Carpenter et al. 1975a). Biochemical changes detected in the lungs after acute-duration intermittent 

exposure include transiently decreased lung surfactant levels at 300 ppm p-xylene (Silverman and Schatz 

1991) and decreased pulmonary microsomal enzyme activities at 2,000 ppm mixed xylene, 75–2,000 ppm 

m-xylene, 2,000 ppm o-xylene, or 1,000 or 3,400 ppm p-xylene (Day et al. 1992; Elovaara et al. 1980, 

1987; Patel et al. 1978; Silverman and Schatz 1991; Toftgard and Nilsen 1982). The LOAEL of 75 ppm 

for m-xylene was based on decreased P-450 and 7-ethoxycoumarin O-deethylase activities noted in the 

lungs of rats exposed for 24 hours (Elovaara et al. 1987). The decrease in pulmonary microsomal activity 

by selective inactivation of enzymes can result from damage to lung tissue caused by the toxic metabolite 

of xylene, a methylbenzaldehyde (Carlone and Fouts 1974; Patel et al. 1978; Smith et al. 1982); the 

selective inactivation of enzymes may also result in anoxia. 

No effect on absolute or relative lung weights was observed in male rats intermittently exposed to 

m-xylene at concentrations as high as 100 ppm for 13 weeks (Korsak et al. 1994). No histopathological 

changes in the lungs were evident in rats, dogs, guinea pigs, or monkeys following intermediate exposure 

for 90–127 days to concentrations of 78 ppm o-xylene on a continuous basis (Jenkins et al. 1970) or 

13 weeks to 810 ppm mixed or 6 weeks to 780 ppm o-xylene, 5 weeks to 300 ppm m-xylene, or for 

5 days to 300 ppm p-xylene on an intermittent basis (Carpenter et al. 1975a; Elovaara et al. 1987; Jenkins 

et al. 1970; Silverman and Schatz 1991). 

No animal studies were located that evaluated the respiratory effects of mixed xylene or single xylene 

isomers following chronic inhalation exposure. 

An acute-duration inhalation MRL of 2 ppm was calculated for mixed xylenes based on a LOAEL for 

neurological and respiratory effects in human subjects exposed to 50 ppm m-xylene for 2 hours 

(Ernstgard et al. 2002; see footnote in Table 3-1). A chronic-duration inhalation MRL of 0.05 ppm was 
XYLENE 66 

3. HEALTH EFFECTS 

calculated for mixed xylenes based on a LOAEL of 14 ppm for subjective neurological and respiratory 

symptoms in workers exposed to mixed xylene 8 hours/day, 5 days/week for an average of 7 years 

(Uchida et al. 1993; see footnote in Table 3-1). 

Cardiovascular Effects. Limited human data are available regarding the cardiovascular effects of 

xylene following inhalation exposure. Although tachycardia was reported by one of nine persons exposed 

to unidentified levels of xylene as a result of its use in a sealant in a heating duct, no effects on heart rate, 

blood pressure, or cardiac function were noted in humans exposed to ≤299 ppm mixed xylene for an acute 

duration (70 minutes to 7 hours) (Gamberale et al. 1978), 200 ppm m-xylene (Ogata et al. 1970; 

Seppalainen et al. 1989), or 150 ppm p-xylene (NIOSH 1981; Ogata et al. 1970). Furthermore, two 

survivors exposed to an estimated 10,000 ppm xylene in an industrial accident had normal pulse, blood 

pressure, and heart sounds upon hospitalization. Chronic occupational exposure to xylene along with 

other chemical agents has resulted in complaints of heart palpitations, chest pain, and an abnormal 

electrocardiogram (ECG) (Hipolito 1980; Kilburn et al. 1985). However, the contribution of other 

chemical exposures to these effects cannot be eliminated. 

Data regarding cardiovascular effects in animals are limited. Morphological changes in coronary 

microvessels (increased wall thickness) were noted in rats exposed to 230 ppm xylene (unspecified 

composition) for 4 weeks (Morvai et al. 1987). Other effects seen in rats inhaling unspecified (lethal) 

concentrations of xylene of unknown composition included ventricular repolarization disturbances and 

occasional arrhythmias; the toxicity of unknown components was not reported (Morvai et al. 1976). 

However, no adverse effects on the heart were observed upon histopathological examination of rats and 

dogs exposed intermittently for 10–13 weeks to mixed xylene at concentrations as high as 810 ppm 

(Carpenter et al. 1975a) or rats, guinea pigs, dogs, or monkeys exposed to o-xylene at 78 ppm on a 

continuous basis for 90–127 days or 780 ppm on an intermittent basis for 6 weeks (Jenkins et al. 1970). 

No effect on absolute or relative heart weights was observed in male rats intermittently exposed to 

m-xylene at concentrations as high as 100 ppm for 13 weeks (Korsak et al. 1994). No information was 

located regarding cardiovascular effects in animals after chronic exposure to mixed xylene or its 

individual isomers. 

Gastrointestinal Effects. Symptoms of nausea, vomiting, and gastric discomfort have been noted in 

workers exposed to xylene vapors (concentration unspecified) (Goldie 1960; Hipolito 1980; Klaucke et al. 

1982; Nersesian et al. 1985; Uchida et al. 1993). These symptoms subsided after cessation of the xylene 

exposure. Anorexia and vomiting were also observed in a patient admitted to the hospital after sniffing 
XYLENE 67 

3. HEALTH EFFECTS 

paint containing xylene and other unknown substances over a 2-week period in an effort to become 

intoxicated (Martinez et al. 1989) and nausea was more frequently reported in males acutely exposed to 

m-xylene for 2 hours, as compared to controls (Ernstgard et al. 2002). 

Limited data were located regarding gastrointestinal effects in animals. No lesions were observed in the 

gastrointestinal tract of rats and dogs exposed to concentrations as high as 810 ppm mixed xylene for 

13 weeks (Carpenter et al. 1975a). No studies were located regarding gastrointestinal effects in animals 

after acute or chronic inhalation exposure to mixed xylene or the isomers of xylene. 

Hematological Effects. Human data are limited regarding the effects of xylene on the blood. 

Female volunteers had normal blood counts after exposure to 100 ppm p-xylene for 1–7.5 hours/day for 

5 days (NIOSH 1981). Hemoglobin content of the blood was unaffected in two workers exposed to an 

estimated 10,000 ppm of mixed xylene in an industrial accident (Morley et al. 1970). Decreased white 

blood cell counts were observed in two women with chronic occupational exposure to xylene (Hipolito 

1980; Moszczynski and Lisiewicz 1983, 1984a), but exposure to other chemicals cannot be ruled out as 

an alternative explanation for the effects observed. 

Previously, chronic occupational exposure to xylene by inhalation was thought to be associated with a 

variety of hematological effects (NIOSH 1975). However, exposure in all cases was to solvent mixtures 

known or suspected to contain benzene as well. Because benzene is an agent known to cause leukemia 

and other blood dyscrasias in humans (Agency for Toxic Substances and Disease Registry 2005), these 

effects cannot be solely attributed to xylene. 

An occupational study in which no benzene exposure was involved (Uchida et al. 1993) found no 

hematological effects (red blood cell, white blood cell and platelet counts, and hemoglobin concentrations 

were unchanged). Workers (175) were exposed to a geometric mean TWA of 14 ppm xylene for an 

average of 7 years, and mixed xylene exposure accounted for 70% or more of the total exposure (Uchida 

et al. 1993). This study suggests that occupational exposure to relatively low concentrations of xylenes 

does not cause hematological effects. 

No effect on erythrocyte fragility was observed in rats exposed to 15,000 ppm mixed xylene for 

45 minutes (Carpenter et al. 1975a). No adverse hematological effects have been observed in rats 

exposed to 2,764 ppm mixed xylene for 5 hours/day for 9 days (Wronska-Nofer et al. 1991). In rats 

intermittently exposed to 100 ppm m-xylene for 90 days, erythrocyte counts were reduced by 18.5% and 
XYLENE 68 

3. HEALTH EFFECTS 

leukocyte counts were increased by 35% (Korsak et al. 1994). Increases in leukocyte count were reported 

in rats and dogs exposed intermittently to 780 ppm o-xylene for 6 weeks (Jenkins et al. 1970), but it is 

unknown whether these increases were statistically significant. However, no effects on hematological 

parameters were observed in rats or dogs following intermediate-duration intermittent exposure to 

concentrations as high as 810 ppm of mixed xylene (Carpenter et al. 1975a) or in guinea pigs exposed to 

78 ppm o-xylene continuously or 780 ppm o-xylene intermittently (Jenkins et al. 1970) for an 

intermediate duration. 

Musculoskeletal Effects. A 1993 occupational study indicates that workers exposed to xylenes 

(geometric mean TWA 14 ppm) reported reduced grasping power and reduced muscle power in the 

extremities more frequently than the unexposed controls (Uchida et al. 1993). This effect was a 

neurological effect rather than a direct effect on the muscles. No additional data were available regarding 

musculoskeletal effects in humans following inhalation exposure to mixed xylene or its individual 

isomers. Animal data regarding musculoskeletal effects following xylene inhalation are limited but 

provide no indication that xylene produces musculoskeletal effects. No lesions were observed in the 

skeletal muscle of rats and dogs exposed for an intermediate exposure to concentrations as high as 

810 ppm mixed xylene (Carpenter et al. 1975a). 

Hepatic Effects. Human data regarding hepatic effects following inhalation of xylene are limited to 

several case and occupational studies (Klaucke et al. 1982; Morley et al. 1970; Uchida et al. 1993); other 

occupational studies involve exposure to other compounds such as toluene (Dolara et al. 1982; Kurppa 

and Husman 1982). Two of these studies suggest that acute-duration exposure to high levels of xylene 

may result in hepatic toxicity. Two painters who survived exposure to an estimated 10,000 ppm of xylene 

and several workers who were exposed to an estimated 700 ppm of xylene had transiently elevated serum 

transaminase levels (Klaucke et al. 1982; Morley et al. 1970). The one painter who died had hepatocellular vacuolation following exposure to xylene for 18.5 hours. An occupational study in which 

workers were exposed an average of 7 years to >70% mixed xylenes (geometric mean TWA 14 ppm) 

found no changes in serum biochemistry values that reflect liver function (total bilirubin, aspartate 

aminotransferase, alanine aminotransferase, gamma glutamyl transpeptidase, alkaline phosphatase, and 

leucine aminopeptidase) (Uchida et al. 1993). This study suggests that low-level occupational exposure 

to xylenes does not result in hepatic effects. 

Animal studies using rats indicate that mixed xylene, m-xylene, o-xylene, or p-xylene generally induce a 

wide variety of hepatic enzymes, as well as increased hepatic cytochrome P-450 content in rats (Elovaara 
XYLENE 69 

3. HEALTH EFFECTS 

1982; Elovaara et al. 1980; Patel et al. 1979; Savolainen et al. 1978; Selgrade et al. 1993; Toftgard and 

Nilsen 1981, 1982; Toftgard et al. 1981; Ungvary et al. 1980a). Following acute exposures to mixed 

xylene (Savolainen et al. 1978; Ungvary 1990; Wisniewska-Knypl et al. 1989), m-xylene (Elovaara 1982; 

Ungvary et al. 1980b), o-xylene (Tatrai and Ungvary 1980; Ungvary et al. 1980a), or p-xylene (Patel et al. 

1979; Simmons et al. 1991; Ungvary et al. 1980b), effects have been observed including increased 

relative liver weight (Simmons et al. 1991; Tatrai and Ungvary 1980; Ungvary et al. 1980a, 1980b), 

cytochrome P-450 content (Simmons et al. 1991; Ungvary 1990; Ungvary et al. 1980a; WisniewskaKnypl et al. 1989), microsomal protein (Elovaara 1982), microsomal enzyme activity (Elovaara 1982; 

Savolainen et al. 1978; Ungvary 1990; Ungvary et al. 1980a; Wisniewska-Knypl et al. 1989), 

proliferation of the endoplasmic reticulum (Ungvary 1990; Wisniewska-Knypl et al. 1989), and decreased 

hexobarbital sleep time (Ungvary 1990; Ungvary et al. 1980a). Similar changes were observed in rabbits 

and mice (Ungvary 1990). Although histopathological examination of livers in most studies showed no 

adverse effects (Elovaara 1982; Simmons et al. 1991; Ungvary et al. 1980b), minor histopathological 

changes suggesting mild hepatic toxicity included decreased glycogen content, dilation of the cisterns of 

the rough endoplasmic reticulum, separation of ribosomes from the membranes, variously shaped 

mitochondria, and increased autophagous bodies (Tatrai and Ungvary 1980; Ungvary 1990). Also, 

increased serum transaminases were observed following a 4-hour exposure of rats to 1,000 ppm p-xylene 

(Patel et al. 1979). 

Many similar hepatic effects appear after intermediate-duration exposure to mixed xylene or o-xylene. 

They include increased absolute and/or relative hepatic weight in rats (Kyrklund et al. 1987; Tatrai and 

Ungvary 1980; Tatrai et al. 1981; Toftgard et al. 1981; Ungvary 1990; Ungvary et al. 1980a), increased 

cytochrome P-450 (Tatrai et al. 1981; Ungvary 1990; Ungvary et al. 1980a); increased microsomal 

enzyme activity (Elovaara et al. 1980, 1987; Tatrai et al. 1981; Toftgard et al. 1981; Ungvary 1990; 

Ungvary et al. 1980a), proliferation of the smooth and rough endoplasmic reticulum (Rydzynski et al. 

1992; Tatrai and Ungvary 1980; Tatrai et al. 1981; Ungvary 1990) and decreased hexobarbital sleeping 

time because of enhanced metabolism of the drug (Tatrai et al. 1981; Ungvary 1990; Ungvary et al. 

1980a). Similar effects were observed in rabbits and mice (Ungvary 1990). As in the acute studies, 

several intermediate-duration studies in rats, guinea pigs, monkeys, or dogs, reported no effect on serum 

transaminases (Carpenter et al. 1975a; Tatrai et al. 1981) or hepatic morphology (Carpenter et al. 1975a; 

Jenkins et al. 1970). Ultrastructural examination of livers showed only minor changes: decreased hepatic 

glycogen in rats (Tatrai and Ungvary 1980; Ungvary 1990; Ungvary et al. 1980b), ultrastructural changes 

in hepatic rough endoplasmic reticulum and mitochondria in rats (Tatrai and Ungvary 1980; Ungvary 

1990), increased autophagous bodies (Tatrai et al. 1981; Ungvary 1990), and changes in the distribution 
XYLENE 70 

3. HEALTH EFFECTS 

of hepatocellular nuclei in rats (Tatrai and Ungvary 1980). Some authors have characterized the hepatic 

changes as adaptive rather than adverse (Tatrai and Ungvary 1980; Ungvary 1990). No effects on hepatic 

microsomal proteins, cytochrome P-450, lipid peroxidation (as indicated by levels of malondialdehyde), 

triglycerides, serum enzymes (AST, ALT, SDH), or absolute or relative liver weights were observed in 

rats exposed to m-xylene at concentrations as high as 100 ppm for 13 weeks (Korsak et al. 1994). No 

changes in the levels of lipid peroxidation (malondialdehyde levels), glutathione, or glutathione-Stransferase activity were observed in rats intermittently exposed to 92 ppm m-xylene for 5 months (Jajte 

et al. 2003). 

Increased liver weight and microsomal enzyme activity were reported in a study in which rats were 

exposed to 1,096 ppm o-xylene for 1 year (Tatrai et al. 1981). Electron microscopic examination of liver 

revealed a proliferation of the endoplasmic reticulum and only very minor effects on mitochondria as 

exemplified by increased numbers of peroxisomes. 

Renal Effects. Although urinalyses (using a dip-stick technique) of volunteers exposed to p-xylene at 

100 ppm for 5 days or up to 150 ppm in a multi-week exposure paradigm showed no adverse effects on 

the kidneys (NIOSH 1981), limited data from case reports and occupational studies suggest that 

inhalation exposure to solvent mixtures containing xylene may be associated with adverse renal effects in 

humans (Martinez et al. 1989; Morley et al. 1970). These effects included increased blood urea (Morley 

et al. 1970), distal renal tubular acidemia (Martinez et al. 1989), and decreased urinary clearance of 

endogenous creatinine (Morley et al. 1970). Other studies that reported increased urinary levels of 

β-glucuronidase (Franchini et al. 1983), or increased urinary excretion of albumin, erythrocytes, and 

leukocytes (Askergren 1981, 1982) are confounded by concurrent exposure to substantial amounts of 

toluene, a known renal toxicant. 

In an occupational study in which the exposure was predominantly to mixed xylenes (geometric mean 

TWA 14 ppm) for an average of 7 years (Uchida et al. 1993), no effects on measures of kidney function 

(serum creatinine or urinalysis for urobilinogen, sugar, protein, and occult bleeding) were noted. This 

study suggests that low-level occupational exposure to xylenes does not result in kidney effects. 

The renal effects of mixed xylene and o-xylene following inhalation exposure have been evaluated in 

acute and intermediate studies with rats, guinea pigs, dogs, and monkeys (Carpenter et al. 1975a; 

Elovaara 1982; Jenkins et al. 1970; Toftgard and Nilsen 1982). Effects noted in these studies at xylene 

concentrations of 50–2,000 ppm have included increased renal enzyme activity, increased renal 
XYLENE 71 

3. HEALTH EFFECTS 

cytochrome P-450 content, and increased kidney-to-body weight ratios (o-xylene-exposed rats) (Elovaara 

1982; Toftgard and Nilsen 1982). However, histopathologic examination of rats, guinea pigs, dogs, and 

monkeys did not reveal any renal lesions after inhalation of 810 ppm mixed xylene or 78 ppm o-xylene 

for an intermediate period of 13 weeks and 90–127 days, respectively (Carpenter et al. 1975a; Jenkins et 

al. 1970). No effect on absolute or relative kidney weights was observed in male rats intermittently 

exposed to m-xylene at concentrations as high as 100 ppm for 13 weeks (Korsak et al. 1994). 

No studies were located regarding renal effects following chronic inhalation exposure to mixed xylene or 

its isomers. 

Endocrine Effects. No human data were available regarding endocrine effects following inhalation 

exposure to mixed xylene or xylene isomers. Inhalation exposure to 810 ppm mixed xylene for 13 weeks 

produced no adverse adrenal, thyroid, or parathyroid effects in the dog (Carpenter et al. 1975a). No effect 

on absolute or relative adrenal weights was observed in male rats intermittently exposed to m-xylene at 

concentrations as high as 100 ppm for 13 weeks (Korsak et al. 1994). 

Ocular Effects. Human data indicate that acute inhalation exposures to 460 ppm mixed xylene and 

100 ppm p-xylene vapors produce mild and transient eye irritation (Carpenter et al. 1975a; Hastings et al. 

1986; Klaucke et al. 1982; Nelson et al. 1943; Nersesian et al. 1985; NIOSH 1981). This effect is 

probably the result of direct contact of the xylene vapor with the eye and as such is described under 

Ocular Effects in Section 3.2.3.2. 

No animal data were available regarding ocular effects following inhalation exposure to mixed xylenes or 

xylene isomers. 

Body Weight Effects. No studies were located regarding body weight effects in humans following 

inhalation exposure to mixed xylenes or xylene isomers. 

A number of intermediate-duration intermittent inhalation studies of xylene have examined body weight 

effects in animals (Carpenter et al. 1975a; Gagnaire et al. 2001, 2006; Gralewicz and Wiaderna 2001; 

Jajte et al. 2003; Korsak et al. 1992, 1994; Rosengren et al. 1986; Tatrai et al. 1981). Except for the study 

by Tatrai et al. (1981) in which a 12% decrease in body weight was observed in rats exposed to 

1,096 ppm o-xylene for 6 months, no significant adverse effects on body weight were noted. 
XYLENE 72 

3. HEALTH EFFECTS 

Metabolic Effects. Metabolic acidosis was reported in a man who sniffed paint containing xylenes, 

but other solvents in the paint may have contributed to the effect (Martinez et al. 1989). No data were 

located concerning metabolic effects in animals following inhalation exposure to xylenes. 

3.2.1.3 Immunological and Lymphoreticular Effects 

Limited data were available regarding immunological and lymphoreticular effects of xylene in humans. 

Decreased lymphocytes (Moszczynski and Lisiewicz 1983, 1984a) and decreased serum complement 

(Smolik et al. 1973) have been observed in workers exposed to xylene. However, no determination can 

be made regarding the association between inhalation of xylene and immunological effects from the 

available human studies, because workers were concurrently exposed to other chemical agents. 

Acute exposure (4 days, 4 hours/day) of mice to 1,208 ppm p-xylene had no effect on natural killer cell 

activity, although mortality from murine cytomegalovirus was increased (Selgrade et al. 1993). The 

investigators (Selgrade et al. 1993) attributed the enhanced virus susceptibility to increased liver toxicity 

rather than to an effect on the immune system. Intermittent exposure of rats and dogs to mixed xylenes 

for 10 or 13 weeks at concentrations as high as 810 ppm resulted in no effect on spleen weight (Carpenter 

et al. 1975a). 

3.2.1.4 Neurological Effects 

The neurological effects of xylene in humans following inhalation exposure have been evaluated in a 

number of experimental studies, case reports, and occupational studies. Results of experimental studies 

with humans indicate that acute inhalation exposure to mixed xylene or m-xylene causes impaired shortterm memory, impaired reaction time, performance decrements in numerical ability, and alterations in 

equilibrium and body balance (Carpenter et al. 1975a; Dudek et al. 1990; Gamberale et al. 1978; 

Riihimaki and Savolainen 1980; Savolainen and Linnavuo 1979; Savolainen and Riihimaki 1981a; 

Savolainen et al. 1979b, 1984, 1985a). 

Dizziness was reported by the majority of subjects exposed to 690 ppm mixed xylene for 15 minutes, but 

in only one of six persons exposed at 460 ppm (Carpenter et al. 1975a). In objective measures of 

neurological function, exposure to 100 ppm mixed xylene for 4 hours resulted in prolonged reaction time 

(Dudek et al. 1990) and exposure to 299 ppm mixed xylene for 70 minutes during exercise resulted in 

impaired short-term memory and reaction time (Gamberale et al. 1978). No impairment in performance 

tests was observed in sedentary subjects exposed at 299 ppm for 70 minutes (15 men) (Gamberale et al. 
XYLENE 73 

3. HEALTH EFFECTS 

1978) or at 396 ppm for 30 minutes (10 men) (Hastings et al. 1986). The difference between the effects 

in the absence and presence of exercise may be due to increased xylene respiratory uptake during 

exercise. 

Slight, but statistically significant, increases in the average rating for subjective symptoms of neurological 

effects were observed following exposure to 50 ppm m-xylene vapor compared to controls (Ernstgard et 

al. 2002). After 60 and 118 minutes of exposure, severity ratings for feelings of intoxication were 

elevated in men and women, and ratings for headache were elevated in men. The ratings for dizziness 

were increased in exposed men after 118 minutes of exposure. (This study was chosen as the basis for the 

acute-duration inhalation MRL, for these subjective neurological effects and changes in objective and 

subjective measures of respiratory function.) Electroencephalograms obtained from nine men exposed to 

m-xylene at 200 ppm (TWA) for 4 hours showed only minor changes (Seppalainen et al. 1991). These 

changes were characterized as a slight increase in alpha-wave frequency and percentage early in the 

exposure period and a decrease in exercise-induced increases in theta and delta waves indicating central 

nervous system effects. Studies using the m-isomer of xylene have also indicated that some tolerance 

may occur during acute exposures. While exposure to stable concentrations of m-xylene for 7 hours or 

4 hours, twice a week in the range of up to approximately 280 ppm had no effect on body sway, 

coordination, or reaction time (Ogata et al. 1970; Savolainen 1980; Savolainen et al. 1980b), exposure for 

6 hours or 6–9 days to levels fluctuating between 64 and 400 ppm produced impairment in human body 

balance and/or reaction time (Savolainen and Linnavuo 1979; Savolainen and Riihimaki 1981a; 

Savolainen et al. 1979b, 1980a, 1984, 1985a). A 3-hour exposure of nine male volunteers to m-xylene at 

200 ppm during exercise resulted in a slight but significant (p<0.05) change in the N135 component of a 

pattern visual evoked potential (Seppalainen et al. 1989). Laine et al. (1993) saw no clear effects on 

visual reaction times or auditive choice reaction times in nine male volunteers exposed to levels of 

m-xylene fluctuating between 135 and 400 ppm (TWA 200 ppm) with or without exercise. Levels of 

m-xylene fluctuating between 135 and 400 ppm produced a slight decrease in the latency of visual evoked 

potentials (Seppalainen et al. 1989), but no clear effects on visual reaction times or auditory choice 

reaction times (Laine et al. 1993). 

Objective measures of neurological function (electroencephalography, tests of motor activity and 

cognitive performance) in humans are not affected by acute or intermediate, intermittent or continuous 

inhalation exposure to p-xylene for 4 hours or up to 7 hours for 5 days at concentrations ranging from 

69 to 150 ppm (NIOSH 1981; Olson et al. 1985). Differences in such factors as the xylene isomer, the 

neurological parameter, exposure conditions and concentrations, rapid development of tolerance, and total 
XYLENE 74 

3. HEALTH EFFECTS 

xylene uptake may account for the variability in results. However, some sex difference in subjective 

reports of central nervous system effects was observed (NIOSH 1981). Three women exposed to 

p-xylene at 100 ppm for 1–7.5 hours/day, for 5 days, showed no effects on electroencephalograms, 

evoked potentials, or cognitive performance, but frequently reported headache and dizziness as a result of 

exposure (NIOSH 1981). In contrast, four men exposed at concentrations of up to 150 ppm p-xylene 

under the same exposure conditions reported no increase in headaches or dizziness. 

Available case reports and occupational studies together provide suggestive evidence that acute and 

chronic inhalation exposure to xylene or solvent mixtures containing xylene may be associated with 

neurological effects; however, most studies are difficult to evaluate because the exposure conditions 

either have not been well characterized or the subjects may have been exposed to other chemicals in 

addition to xylene. The neurological symptoms observed in these studies include headache, nausea, 

dizziness, difficulty concentrating, impaired memory, slurred speech, ataxia, fatigue, agitation, confusion, 

tremors, labored breathing, and sensitivity to noise (Arthur and Curnock 1982; Goldie 1960; Gupta et al. 

1990; Hipolito 1980; Klaucke et al. 1982; Martinez et al. 1989; Morley et al. 1970; Nersesian et al. 1985; 

Roberts et al. 1988). In several case reports, isolated instances of unconsciousness, amnesia, brain 

hemorrhage, and epileptic seizure have been associated with acute inhalation exposure to solvent mixtures 

containing xylene (Arthur and Curnock 1982; Goldie 1960; Martinez et al. 1989; Morley et al. 1970). 

Long-term occupational exposure (≥10 years) to mixed solvents among spray painters was associated 

with an increase in depression and "loss of interest," but no significant effects on psychological 

performance tests or CAT-scan measures of brain atrophy (Triebig et al. 1992a, 1992b). Workers 

exposed to mixed solvents for <10–>30 years exhibited significantly reduced conduction velocities in the 

radial and tibial nerves, as well as duration-related increases in symptoms of numbness, cramps, and 

weakness (Jovanovic et al. 2004). Because other chemicals were present with xylenes in many of these 

studies, the effects observed cannot be conclusively attributed to xylene exposure. 

Another occupational study in which xylene exposure was most well defined and represented 70% of the 

solvent exposure (Uchida et al. 1993) reported an increase in subjective symptoms including an increased 

prevalence of anxiety, forgetfulness, inability to concentrate, and dizziness among workers exposed to an 

average TWA concentration of 21 ppm (14 ppm geometric mean) of mixed xylenes for an average of 

7 years. No objective measures of neurological impairment were tested in this study. Subjective 

symptoms of neurological and respiratory toxicity in this study were selected as co-critical effects for the 

chronic-duration inhalation MRL. 
XYLENE 75 

3. HEALTH EFFECTS 

Results of experimental studies with animals also provide evidence that mixed xylene and its isomers are 

neurotoxic following inhalation exposure. Signs of neurotoxicity observed in rats, mice, dogs, cats, and 

gerbils following acute and intermediate inhalation exposure to the various xylene isomers include 

narcosis, prostration, incoordination, tremors, muscular spasms, labored breathing, behavioral changes, 

hyperreactivity to stimuli, altered visual evoked potentials, elevated auditory thresholds, hearing loss, and 

decreased acetylcholine in midbrain and norepinephrine in hypothalamus (suggestive of effect on motor 

control, sleep, and memory maintenance) (Andersson et al. 1981; Bushnell 1989; Carpenter et al. 1975a; 

De Ceaurriz et al. 1983; Furnas and Hine 1958; Ghosh et al. 1987; Honma et al. 1983; Korsak et al. 1988, 

1990; Kyrklund et al. 1987; Molnar et al. 1986; Pryor et al. 1987; Rank 1985; Rosengren et al. 1986; 

Savolainen and Seppalainen 1979; Savolainen et al. 1978, 1979b; Wimolwattanapun et al. 1987). 

Exposure levels associated with neurological effects in animals are well defined. A comparative study 

determined that the minimal alveolar concentrations needed to induce anesthesia in rats were similar for 

all three isomers (0.00118, 0.00139, and 0.00151 atm, respectively, for o-, m-, and p-xylene), but only 

p-xylene also induced excitation (strong tremors) (Fang et al. 1996). Acute exposure to unspecified levels 

of mixed xylene resulted in respiratory paralysis (Morvai et al. 1976), 1,600 ppm p-xylene produced 

hyperactivity (Bushnell 1989), and 1,300 ppm mixed xylene produced incoordination in rats, which did 

not persist after exposure ended; no overt signs of toxicity were noted at 580 ppm (Carpenter et al. 

1975a). All three xylene isomers produced narcosis in rats after 1–4 hours of exposure to concentrations 

of approximately 2,000 ppm (Molnar et al. 1986). No behavioral signs of xylene intoxication were 

observed in dogs or monkeys exposed continuously to 78 ppm o-xylene for up to 127 days, but dogs 

exposed to 780 ppm o-xylene intermittently for 6 weeks exhibited tremors during exposure (Jenkins et al. 

1970). 

The neurotoxicity of xylenes has been evaluated in neurobehavioral tests on animals exposed by 

inhalation. Mice exposed for 30 minutes by inhalation to any of the isomers exhibited impaired operant 

performance at the same minimal effective concentration, 1,400 ppm, but the median effective 

concentrations varied to a limited degree—5,179 ppm for o-xylene, 5,611 ppm for p-xylene, and 

6,176 ppm for m-xylene (Moser et al. 1985). The order of potency was different for impairment of motor 

coordination in mice undergoing the inverted screen test, with a minimal effective concentration of 

2,000 ppm for p-xylene and 3,000 ppm for the two other isomers (Moser et al. 1985); the median 

effective concentrations were 2,676, 3,640, and 3,790 ppm, respectively, for p-, o-, and m-xylene. Acute 

exposures to concentrations inducing behavioral changes in rats and mice ranged from 114 ppm for 

effects of mixed xylene on operant conditioning or self-stimulation behavior (Ghosh et al. 1987; 
XYLENE 76 

3. HEALTH EFFECTS 

Wimolwattanapun et al. 1987), 500 ppm for reduced response rate in schedule-controlled operant 

behavior in mice exposed to m-xylene (Bowen et al. 1998), to 1,010 ppm for o-xylene-induced 

immobility in a "behavioral despair swimming test" (De Ceaurriz et al. 1983). Exposure of male rats to 

230 ppm o-xylene for 4 hours shortened the duration of response (extension of hindlimbs) to an applied 

electrical shock by 18.8% (Vodickova et al. 1995); doubling the exposure concentration correspondingly 

doubled the magnitude of the response. In the same report, exposure of female mice to 320 ppm o-xylene 

for 2 hours shortened the duration of response (velocity of tonic extension, i.e., the reciprocal of the 

latency) was reduced by 11%; unlike rats, exposure at twice the concentration, increased the magnitude of 

the response by a factor of 3.7. Impaired rotarod performance was observed in rats acutely exposed to 

mixed xylene and the individual xylene isomers at concentrations of ≥3,000 ppm (Korsak et al. 1990). In 

intermediate-duration inhalation studies with rats, exposure to 100 ppm m-xylene intermittently for 3 or 

6 months or to 1,000 ppm for 3 months showed decreased rotarod performance and decreased 

spontaneous activity (Korsak et al. 1992, 1994). The effect was greater following the 3-month exposure 

at 1,000 ppm than the 6-month exposure at 100 ppm suggesting that for effects on motor activity, 

concentration is more important than duration of exposure. The persistence of neurological effects of 

xylene was examined in some studies that evaluated tested animals some weeks after the last exposure. 

Rats intermittently exposed to 100 ppm m-xylene for 4 weeks exhibited impaired passive avoidance 

learning (tested 5 weeks after exposure) and impaired acquisition, but not retention, of the two-way active 

avoidance response (tested 9 weeks after exposure) (Gralewicz and Wiaderna 2001). Exposure had no 

lasting effect in tests for short-term memory, responsiveness to a thermal stimulus (paw-lick latency), or 

spontaneous activity (open-field test) or the retention of a learned active avoidance response. 

Sensory deficits resulting from xylene exposure have been observed under controlled testing conditions. 

Acute exposure to 1,600 ppm, but not 800 ppm p-xylene depressed the amplitude of visual evoked 

potentials (Dyer et al. 1988). Hearing deficits have been reported in animals exposed to xylene for acute 

or intermediate durations. Hearing loss occurred in rats exposed to 1,450 ppm mixed xylene for 8 hours, 

whereas exposure to 1,700 ppm for 4 hours produced no effects on hearing (Pryor et al. 1987) indicating 

that the duration of exposure is important for the observation of ototoxic effects in conditioned avoidance 

tests. In rats acutely exposed to 1,800 ppm mixed xylenes, 18–30 dB hearing losses were observed at 

mid-range frequencies (Crofton et al. 1994). The amplitude of brainstem auditory evoked potentials was 

reduced by 50% in rats acutely exposed at 2,000 ppm, but not at 1,700 ppm (Rebert et al. 1995). Hearing 

loss was also evident after exposure for 6 weeks to 800 ppm mixed xylene (Pryor et al. 1987). In rats 

exposed intermittently to 900 ppm p-xylene for 13 weeks, there was some hair cell loss in the organ of 

Corti, but no effect on auditory neurophysiology (Gagnaire et al. 2001). At 1,800 ppm, extensive 
XYLENE 77 

3. HEALTH EFFECTS 

ototoxicity (altered brainstem auditory evoked potentials, measurable hearing loss [deficits of 35–42 dB] 

and significant hair cell loss in the organ of Corti) was observed as early as the fourth week and did not 

improve during an 8-week recovery period; neither o-xylene nor m-xylene were ototoxic in this study. 

All rats exposed for 13 weeks to 1,000 or 2,000 ppm mixed xylenes containing ethylbenzene exhibited 

significant irreversible ototoxicity including hearing deficits and loss of hair cells (Gagnaire et al. 2006). 

Exposures to these mixtures at 250 or 500 ppm resulted in a small loss of hair cells in one of eight rats per 

group, but no effect on auditory thresholds. According to the authors, ethylbenzene contributes 

significantly to the ototoxicity of technical xylene. 

Changes in neuronal cells and brain biochemistry have been noted in animals following exposure to 

xylenes. Acute exposure to p-xylene caused decreased axonal transport at concentrations as low as 

800 ppm (Padilla and Lyerly 1989); however, no such decrease was apparent 3 days after exposures had 

ceased. At 1,600 ppm, however, the decrease in axonal transport persisted for 13 days after exposure. 

Acute inhalation of 2,000 ppm mixed xylene produced increased dopamine and/or noradrenaline levels in 

the hypothalamus of rats; no behavioral changes were assessed (Andersson et al. 1981). Levels of these 

catecholamines in the hypothalamus of rats were also increased following inhalation of 2,000 ppm m-, o-, 

or p-xylene (Andersson et al. 1981). Brain concentrations of deoxyribonucleic acid (DNA) and/or 

astroglial proteins increased in rats (at 300–320 ppm) and gerbils (at 160 ppm) after intermediate 

continuous exposure of 3–4.5 months to xylene (Rosengren et al. 1986; Savolainen and Seppalainen 

1979). In addition, increased levels of brain enzymes, changes in axon membranes, and behavioral 

changes occurred in rats after exposure to 300 ppm of mixed xylene for 18 weeks (Savolainen and 

Seppalainen 1979; Savolainen et al. 1979a). Alterations in neurotransmitter levels were observed in some 

brain areas at 800 ppm mixed xylene for 30 days (Honma et al. 1983). However, no significant long-term 

alterations in fatty acid levels were noted in the brains of rats after intermediate-duration exposure of 

30 or 90 days to 320 ppm mixed xylene (Kyrklund et al. 1987). At 1,600 ppm m-xylene for 7 weeks, 

decreased α-adrenergic binding compared to the controls was observed in the hypothalamus of exposed 

mice (Rank 1985). No persistent changes in brain weight or weights of the caudate-putamen or 

subcortical limbic areas, or in agonist binding to the dopamine D2 receptor in those regions occurred in 

rats exposed to 80 ppm p-xylene for 4 weeks and examined 5 weeks after the last exposure (HilleforsBerglund et al. 1995). 

No animal studies were located regarding neurological effects following chronic inhalation exposure to 

mixed xylene or its isomers. 
XYLENE 78 

3. HEALTH EFFECTS 

The highest NOAEL values and all LOAEL values for each reliable study for neurological effects in each 

species and duration category are recorded in Table 3-1 and plotted in Figure 3-1. An acute-duration 

inhalation MRL of 2 ppm was calculated for mixed xylenes based on a LOAEL for subjective 

neurological effects and measured and subjective respiratory effects in human subjects exposed to 50 ppm 

m-xylene for 2 hours (Ernstgard et al. 2002; see footnote in Table 3-1). An intermediate-duration 

inhalation MRL of 0.6 ppm was calculated for mixed xylenes based on a minimal LOAEL of 50 ppm for 

decreased mean latency of the paw-lick response in rats exposed to m-xylene for 6 hours/day, 

5 days/week for 3 months (Korsak et al. 1994; see footnote in Table 3-1). A chronic-duration inhalation 

MRL of 0.05 ppm was calculated for mixed xylenes based on a LOAEL of 14 ppm for subjective 

neurological and respiratory symptoms in workers exposed to mixed xylene 8 hours/day, 5 days/week for 

an average of 7 years (Uchida et al. 1993; see footnote in Table 3-1). 

3.2.1.5 Reproductive Effects 

A few occupational studies evaluated reproductive effects in workers exposed to xylenes. A case-control 

study of spontaneous abortions among Finnish workers for whom there was biomonitoring data for 

exposure to organic solvents found no statistically significant increase in the odds ratio associated with 

exposure to xylene (Lindbohm et al. 1990). Spontaneous abortions in early pregnancy were significantly 

increased among 37 women exposed to xylene and formalin in pathology or histology laboratories 

(Taskinen et al. 1994). Although the increased odds ratio (OR=3.1; 95% confidence interval=1.3–7.5) for 

spontaneous abortion was statistically significant for women exposed to xylene at least 3–4 days/week, 

the analysis cannot be considered definitive because of simultaneous exposure to other solvents and 

chemicals. A cross-sectional study among 1,408 petrochemical workers in China reported an increased 

prevalence of oligomenorrhea among workers exposed to organic solvents, but the contribution of xylene 

cannot be definitively determined as all workers who were exposed to xylene were also exposed to other 

solvents such as benzene, toluene, and styrene (Cho et al. 2001). 

Continuous exposure of CFY rats for 8 days on days 7–14 during pregnancy to 775 ppm mixed xylene 

produced an increased number of resorptions without any maternal toxicity; reduced fertility was also 

observed (Balogh et al. 1982). However, no adverse reproductive effects were noted following inhalation 

exposure of male and female CD rats to mixed xylene at concentrations as high as 500 ppm during 

premating, mating, pregnancy, and lactation (Bio/dynamics 1983). No effect on absolute or relative 

testicular weights was observed in rats intermittently exposed to m-xylene at concentrations as high as 

100 ppm for 13 weeks (Korsak et al. 1994). Inhalation exposure of male Sprague-Dawley rats to 
XYLENE 79 

3. HEALTH EFFECTS 

1,000 ppm mixed xylene for 61 days produced no alterations in testes, accessory glands, or circulating 

male hormone levels (Nylen et al. 1989). Strain differences may account for the differential response to 

mixed xylene in these studies. The highest NOAEL and LOAEL values for each reliable study for 

reproductive effects in rat for each duration category are recorded in Table 3-1 and plotted in Figure 3-1. 

3.2.1.6 Developmental Effects 

Although the human data regarding the developmental effects of xylene suggest a possible relationship 

between solvent (unspecified) exposure and developmental toxicity, these data are limited for assessing 

the relationship between inhalation of xylene and developmental effects because the available studies 

involved concurrent exposure to other solvents in addition to xylene in the workplace (Holmberg and 

Nurminen 1980; Kucera 1968; Taskinen et al. 1989; Windham et al. 1991), and because of the small 

number of subjects ranging from 9 to 61 (Taskinen et al. 1989; Windham et al. 1991). 

Both mixed xylene and the individual isomers produce fetotoxic effects in laboratory animals. Effects of 

mixed xylene observed in rats, mice, and rabbits included increased incidences of skeletal variations in 

fetuses, delayed ossification, fetal resorptions, hemorrhages in fetal organs, and decreased fetal body 

weight (Balogh et al. 1982; Bio/dynamics 1983; Hass and Jakobsen 1993; Hudak and Ungvary 1978; 

Litton Bionetics 1978a; Mirkova et al. 1983; Ungvary 1985; Ungvary and Tatrai 1985). Balogh et al. 

(1982) reported delayed ossification in all exposure levels (53–775 ppm), but as the incidences were 

inversely related to dose, this end point is not included in LSE Table 3-1. The levels at which these 

effects were observed depended upon the composition and concentration of mixed xylene, the time of 

exposure, and the choice of strain and test species used. In addition, animals in a number of studies were 

exposed 24 hours/day (Balogh et al. 1982; Hudak and Ungvary 1978; Ungvary 1985; Ungvary and Tatrai 

1985), whereas animals in other studies (Bio/dynamics 1983; Hass and Jakobsen 1993; Litton Bionetics 

1978a; Mirkova et al. 1983) were exposed 6 hours/day. The study conducted by Litton Bionetics (1978a) 

used a formulation of mixed xylene with a comparatively high percentage (36%) of ethylbenzene. 

Developmental effects were reported following maternal exposure to concentrations as low as 12 ppm 

mixed xylene in rats (Mirkova et al. 1983), but the health of the test animals may have been compromised 

due to poor animal husbandry. This is suggested by the relatively low conception rates and the high 

incidence of fetal hemorrhages seen in the controls. Maternal toxicity was observed at 775 ppm in the 

study by Balogh et al. (1982) and at 138 ppm in the study by Ungvary (1985); however, no maternal 

toxicity occurred at exposure levels of 100–400 ppm in the studies by Bio/dynamics (1983), Hass and 

Jacobsen (1993), Hudak and Ungvary (1978), and Litton Bionetics (1978a). Insufficient evidence was 
XYLENE 80 

3. HEALTH EFFECTS 

presented to determine whether maternal toxicity occurred in the studies by Mirkova et al. (1983) and 

Ungvary and Tatrai (1985). Many of the studies (Balogh et al. 1982; Bio/dynamics 1983; Hudak and 

Ungvary 1978; Mirkova et al. 1983; Ungvary 1985; Ungvary and Tatrai 1985) had limitations that made 

them difficult to assess (e.g., unknown composition of xylene and insufficient number of doses to form a 

dose-response relationship; lack of detail with regard to both methods and data obtained). Furthermore, 

several of these studies (Balogh et al. 1982; Ungvary and Tatrai 1985; Ungvary et al. 1980b) reported the 

incidence of fetal effects, such as delayed skeletal ossification and extra ribs, on the basis of total fetuses 

per exposure group, but not on a per-litter basis. Without litter-specific results, it is not possible to adjust 

for possible covariance with litter size, as reported by Litton Bionetics (1978a). Given the uncertainty of 

the significance of these effects, increases in the incidences of delayed ossification or skeletal variants 

were not used to establish NOAELs or LOAELs unless litter-specific data were provided. Based on the 

reliable data in these reports (fetal weight, fetal death, implantation losses), developmental toxicity in rats 

occurred at concentrations of ≥350 ppm; these effects are noted in Table 3-1. 

A number of studies reported neurobehavioral deficits in rats resulting from exposure to xylene during 

gestation. ATSDR considers these effects to be serious. Hass and Jakobsen (1993) reported decreased 

rotarod performance in 1- and 2-day-old rat pups exposed to 200 ppm mixed xylenes 6 hours/day on 

gestation days 4–20. Female offspring of rats exposed to 500 ppm mixed xylenes for 6 hours/day on 

gestation days 7–20 showed significant reductions in absolute brain weight after weaning and 

neurobehavioral deficits (delayed air righting reflex, nonsignificant trends for reduced motor coordination 

in the Rotarod test, and increased latencies in the Morris water maze test) (Hass et al. 1995). Hass et al. 

(1995) suggested that the delayed air righting reflex and impaired spatial navigation in the water maze 

(locating a re-situated platform) may have been related to ototoxicity, since both tasks involve the 

vestibular system and cochlear hair cells. The latency in locating a moved platform was significantly 

increased in the first learning trial by exposed offspring tested at week 28, but was not significantly 

different from controls at 55 weeks (Hass et al. 1997). 

Inhalation of o- or p-xylene at concentrations similar to those at which mixed xylene caused fetal toxicity, 

produced decreased fetal weight, skeletal retardation, and post-implantation loss in rats, mice, and rabbits 

following maternal acute exposure during gestation days 7–14/15 (Ungvary and Tatrai 1985; Ungvary et 

al. 1980b, 1981); no maternal toxicity was observed. A NOAEL value of 1,612 ppm p-xylene for 

developmental effects was determined from one study with rats (Rosen et al. 1986). The large variation 

in concentrations of xylene producing developmental effects and those producing no developmental 

effects may be influenced by a number of factors (e.g., strain and species of animal, purity of xylene, 
XYLENE 81 

3. HEALTH EFFECTS 

method of exposure, exposure pattern and duration, etc.). For example, Rosen et al. (1986) exposed 

animals for 6 hours/day, whereas animals were exposed 24 hours/day in studies by Ungvary and Tatrai 

(1985) and Ungvary et al. (1980b, 1981). No information on maternal toxicity was available for the 

studies by Ungvary and Tatrai (1985) or Ungvary et al. (1981); however, in the studies by Rosen et al. 

(1986) and Ungvary et al. (1980b), signs of maternal toxicity in rats following inhalation of the isomers 

included decreased weight gain, decreased food consumption, and increased liver-to-body weight ratios. 

m-Xylene was the only isomer that resulted in lasting maternal growth inhibition or maternal mortality 

(Ungvary et al. 1980b). Thus, it is difficult to determine from these studies whether mixed xylenes are 

selectively toxic to the fetus or the observed developmental toxicity was secondary to maternal toxicity. 

As mentioned above, retardation in skeletal growth or variations, in the absence of litter-specific data, 

were not used to determine NOAELs or LOAELs for exposure to specific isomers of xylene (Ungvary et 

al. 1980b). 

Results of a well-documented comparative standard developmental toxicity assay in rats exposed for 

6 hours/day on gestational days 6–20, suggest that developmental toxicities of m- and p-xylene are 

secondary to maternal toxicity (Saillenfait et al. 2003). Statistically significant maternal effects (reduced 

‘corrected weight gain’—body weight gain exclusive of gravid uterus weight) and fetal toxicity (reduced 

fetal weight) occurred at exposures of ≥1,000 ppm, but not 500 ppm for these two isomers. Both m- and 

p-xylene at 2,000 ppm induced significant increases in delayed ossification, a skeletal variation related to 

retarded growth, although the affected bones were different for the two isomers. Dams exposed at 

≥1,000 ppm to o-xylene or mixed xylenes showed similar effects, although the reduced corrected weight 

gain for mixed xylenes was only significant for gestational days 6–13. However, both o-xylene and 

mixed xylene caused significantly reduced fetal body weights at 500 ppm, the maternal NOAEL. 

Exposure to mixed xylenes did not elicit any developmental structural anomalies at concentrations as high 

as 2,000 ppm, whereas o-xylene elicited increases in the percent of fetuses per litter with skeletal 

variations (incomplete ossification) at 2,000 ppm and in the percent of fetuses with any variation at 

1,000 ppm. This assay did not include testing for postnatal neurobehavioral effects. 

The highest NOAEL value and all LOAEL values from each reliable study for developmental effects in 

each species and duration category are recorded in Table 3-1 and plotted in Figure 3-1. 
XYLENE 82 

3. HEALTH EFFECTS 

3.2.1.7 Cancer 

Human data regarding cancer are limited to three occupational studies and one population-based study. 

Two studies examined the cancer and leukemia risks among solvent-exposed workers and suggested a 

possible relationship between coal-based xylene exposure and leukemia (Arp et al. 1983; Wilcosky et al. 

1984). Both contain limitations (e.g., small number of subjects ranging from 9 to 85 male workers, no 

exposure concentrations, unknown composition of xylene) that preclude a definitive conclusion regarding 

inhalation of xylene and cancer. A retrospective cohort mortality study evaluated 14,457 workers at an 

aircraft maintenance facility, 108 of whom had been exposed to xylene (Spirtas et al. 1991; Stewart et al. 

1991). In this study, evaluations of deaths from multiple myeloma or non-Hodgkin’s lymphoma revealed 

no cases among xylene-exposed workers, representing 1,837 and 444 person-years of exposure, for men 

and women, respectively (Spirtas et al. 1991; Stewart et al. 1991). A population-based case-control study 

that estimated job-related exposure to xylene reported limited evidence of increased risks for cancers of 

the colon and rectum following high exposure to xylene (Gerin et al. 1998). The authors indicated that 

the marginally significant excesses in rectal cancer in xylene-exposed workers may have been due to the 

confounding effect of exposure to styrene or another material associated with styrene exposure. 

Limitations of this study included a lack of information on exposure concentrations and the composition 

of xylene, a small number of cases, and the fact that most of the xylene-exposed workers were also 

exposed to toluene and benzene. 

No studies were located regarding cancer in animals exposed via inhalation to mixed xylene or xylene 

isomers. 

3.2.2 Oral Exposure 

3.2.2.1 Death 

Death in humans following accidental or intentional ingestion of xylene was reported by Abu Al Ragheb 

et al. (1986). Levels of xylene found in blood and gastric and duodenal contents were 110, 8,800, and 

33,000 mg/L, respectively, indicating ingestion of a large, but undetermined, quantity of xylene. Death 

was attributed to respiratory failure secondary to depression of the respiratory center in the brain. 

Mortality was observed in laboratory animals following the ingestion of mixed xylene or isomers of 

xylene. Reported acute oral LD50 values in rats for mixed xylene range from 3,523 mg/kg when 

administered in corn oil (NTP 1986) to 8,600 mg/kg when administered undiluted (Hine and Zuidema 
XYLENE 83 

3. HEALTH EFFECTS 

1970). It appears that the absorption of xylene was enhanced by corn oil due to its greater lipophilicity. 

The acute oral LD50 values for mixed xylene administered in corn oil to male and female mice were 

5,627 and 5,251 mg/kg, respectively (NTP 1986). The acute oral LD50 for m-xylene (neat) in rats was 

6,661 mg/kg (Smyth et al. 1962). According to a study by Gerarde (1959), m-xylene may be slightly less 

toxic than the other two isomers, since a single oral dose of 4,320 mg/kg of m-xylene resulted in death in 

3/10 rats, whereas 4,400 mg/kg of o-xylene or 4,305 mg/kg of p-xylene produced death in 7/10 and 

6/10 rats, respectively. In acute-duration repeated-dose gavage studies, mortality was observed in 8 of 

10 rats given 2,000 mg/kg mixed xylene and 10 of 10 mice given 4,000 mg/kg mixed xylene in corn oil 

for 14 days (NTP 1986) and in 2 females from a group of 10 male and 10 female rats that received 

2,000 mg/kg/day p-xylene for 10 days (Condie et al. 1988). 

Survival was significantly lowered in male rats exposed to mixed xylene 5 days/week at chronic oral 

doses of 500 mg/kg but not at 250 mg/kg (NTP 1986); females were not affected. Although mortality 

appeared to be dose related in the treated rats, many of the early deaths were related to an error in gavage 

methodology; non-accidental deaths occurred with an incidence of 22% in controls, 32% at 

250 mg/kg/day, and 38% at 500 mg/kg/day. 

All LD50 values and LOAEL values from each reliable study for death in each species and duration 

category are recorded in Table 3-2 and plotted in Figure 3-2. 

3.2.2.2 Systemic Effects 

The systemic effects observed after oral exposure to xylene are discussed below. The highest NOAEL 

value and all LOAEL values from each reliable study for systemic effects in each species and duration 

category are recorded in Table 3-2 and plotted in Figure 3-2. 

Respiratory Effects. Limited information was located regarding respiratory effects in humans 

following oral exposure to mixed xylene or xylene isomers. Postmortem examination of a man who 

committed suicide by ingesting xylene showed pulmonary congestion and edema (Abu Al Ragheb et al. 

1986). Death resulted from centrally mediated respiratory depression. 

A single oral dose of 4,000 mg/kg in mice or daily oral dosing of rats and mice by gavage with mixed 

xylene for 14 days at 2,000 mg/kg/day resulted in shallow and labored breathing immediately after 

dosing, but no compound-related effects were observed in the lungs at necropsy (NTP 1986). Mice given 
504

2000

25

4305

26

4400

27

4320

44

8640

93

5950

3

2000

35

3523

47

6661

Table 3-2 Levels of Significant Exposure to Xylene - Oral 

Exposure/ LOAEL 

Duration/ 

a 

Key to 

Figure 

Species 

(Strain) 

Frequency 

(Route) 

ACUTE EXPOSURE Death 

1 Rat 

SpragueDawley 

10 d 1 x/d (GO) 

System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

2000 F (2/20 died) 

2 Rat 

NS 

once (GO) 4305 (6/10 rats died) 

3 Rat 

NS 

once (GO) 4400 (7/10 died) 

4 Rat 

NS 

once (GO) 4320 (3/10 died) 

5 Rat 

Long- Evans 

once (G) 8640 M (LD50) 

6 Rat 

Albino-Wistar 

CFT 

once (GO) 5950 F (4/6 died) 

7 Rat 

F344/N 

14 d 1 x/d (GO) 

2000 (8/10 died) 

8 Rat 

F344/N 

once (GO) 3523 M (LD50) 

9 Rat 

CarworthWistar 

once (G) 6661 M (LD50) 

Reference Chemical Form 

Condie et al. 1988 para Gerarde 1959 para Gerarde 1959 ortho Gerarde 1959 meta Hine and Zuidema 1970 mixed Muralidhara and Krishn1980 mixed NTP 1986 mixed NTP 1986 mixed Smyth et al. 1962 meta 
34

56275251

4

4000

503

200020002000

505

200020001000

2000

506

200020001000

2000

Table 3-2 Levels of Significant Exposure to Xylene - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

10 Mouse 

B6C3F1 

11 Mouse 

B6C3F1 

Systemic 

12 Rat 

SpragueDawley 

13 Rat 

SpragueDawley 

14 Rat 

SpragueDawley 

Exposure/ 

Duration/ 

Frequency 

(Route) 

once (GO) 14 d 1 x/d (GO) 10 d 1 x/d (GO) 10 1 x/d (GO) 10 d 1 x/d (GO) 

System 

Hemato RenalBd WtHematoRenalBd WtHematoRenalBd Wt

LOAEL 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

5627 M (LD50) 

b

5251 F (LD50) 

NTP 1986 mixed 

4000 (10/10 died) NTP 1986 

mixed 

2000 Condie et al. 1988 

meta 

2000 

2000 

2000 Condie et al. 1988 

para 

2000 

1000 2000 M (13% decrease in body 

weight) 

2000 Condie et al. 1988 

ortho 

2000 

1000 2000 M (14% decrease in body 

weight) 
766

1000 2000

780

1000

2000

500

1000

771

1000

781

1000 20002000

742

1000

2000

767

125

250

Table 3-2 Levels of Significant Exposure to Xylene - 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 

15 Rat 

Long- Evans 

once (GO) Other 1000 M 2000 M (mild hypothermia) Dyer et al. 1988 para 

16 Rat 

F344/N 

14 d 1 x/d (GO) 

Resp 1000 2000 (shallow and labored 

breathing) 

NTP 1986 mixed 

Bd Wt 500 1000 M (18% decrease in body 

weight gain in males) 

17 Rat 

SpragueDawley 

once (GO) Resp 1000 F (decreased pulmonary microsomal activity) Patel et al. 1978 para 

18 Mouse 

B6C3F1 

Immuno/ Lymphoret 

19 Rat 

SpragueDawley 

14 d 1 x/d (GO) 10 d 1 x/d (GO) 

Resp Bd Wt 

1000 

2000 1000 2000 (11% decrease in relative 

thymus weight) 

2000 (shallow breathing) NTP 1986 

mixed Condie et al. 1988 para 

Neurological 

20 Rat 

Long- Evans 

once (GO) 

c

125 M 250 M (suppressed visual 

evoked potentials) 

Dyer et al. 1988 para 
902

900

903

900

904

900

785

5950

782

4000

136

2000

Table 3-2 Levels of Significant Exposure to Xylene - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to 

Figure 

Species 

(Strain) 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) Serious (mg/kg/day) 

21 Rat 

(SpragueDawley) 

2 wk 5 d/wk 1 x/d (GO) 

900 M 

22 Rat 

(SpragueDawley) 

2 wk 5 d/wk 1 x/d (GO) 

900 M (partial loss of outer hair 

cells in cochlea responsive to medium frequencies: 10-25 kHz) 

23 Rat 

(SpragueDawley) 

2 wk 5 d/wk 1 x/d (GO) 

900 M 

24 Rat 

Albino- Wistar 

once (GO) 5950 F (coma) 

25 Rat 

F344/N 

once (GO) 4000 (decreased hindleg movement, 

incoordination, prostration) 

26 Mouse 

B6C3F1 

1 x/d 5 d/wk 13 wk (GO) 

2000 (weakness, lethargy, 

unsteadiness, tremors, and partial paralysis) 

Reference Chemical Form 

Gagnaire and Langlais meta Gagnaire and Langlais para Gagnaire and Langlais ortho Muralidhara and Krishn1980 mixed NTP 1986 mixed NTP 1986 mixed 
69

1030 2060

525

2000

507

750

1500

150

750

150

750

1500

Table 3-2 Levels of Significant Exposure to Xylene - Oral (continued) 

a 

Key to 

Figure 

Species 

(Strain) System 

Exposure/ 

Duration/ 

Frequency 

(Route) 

LOAEL 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Developmental 

27 Mouse 

CD-1 

10 d Gd 6-15 3 x/d (GO) 

1030 F 2060 F (cleft palate) Marks et al. 1982 

mixed 

28 Mouse 

ICR/SIM 

5 d 1 x/d Gd 8-12 (GO) 

INTERMEDIATE EXPOSURE Systemic 

29 Hemato Rat SpragueDawley 90 d 1 x/d (GO) 

2000 F 

750 F 1500 F (mild polycythemia and 

leukocytosis; increased spleen weight) 

Seidenberg et al. 1986 meta Condie et al. 1988 mixed 

Hepatic 150 750 (14% increase in serum 

alanine aminotransferase in females, 14-17% increase in relative liver weight in both sexes) 

Renal 150 F 750 F (minimal chronic 

nephropathy in 6/10 females) 

Bd Wt 1500 
701

800800

133

10001000100010001000100010001000500

1000

Table 3-2 Levels of Significant Exposure to Xylene - Oral (continued) 

Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) 

30 Rat 

NS 

3.5 wk 5 d/wk 1 x/d (GO) 

31 Rat 

F344/N 

13 wk 5 d/wk 1 x/d (GO) 

System 

Resp Hepatic Resp Cardio Gastro Hemato Musc/skel Hepatic Renal Ocular Bd Wt 

LOAEL 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

800 M (decreased cytochrome 

P-450) 

Elovaara et al. 1989 meta 

800 M (increased plasma SGPT 

and relative liver weight) 

1000 NTP 1986 

mixed 

1000 

1000 

1000 1000 1000 1000 1000 

500 M 1000 M (15% decrease in body 

weight gain) 
195

800800800800800800

800

800800800200

800

Table 3-2 Levels of Significant Exposure to Xylene - 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 

32 Rat 

SpragueDawley 

13 wk 7 d/wk 1 x/d (GO) 

Resp 800 Wolfe 1988a 

meta 

Cardio 800 Gastro 800 Hemato 800 Musc/skel Hepatic 

800 800 F 800 M (37% increased serum 

alanine aminotransferase) 

Renal 800 Dermal 800 Ocular 800 Bd Wt 200 M 800 M (body weight gain 

decreased by 15%) 
193

800800800800800800800800800800

2

20002000200020002000200020002000

Table 3-2 Levels of Significant Exposure to Xylene - Oral (continued) 

Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) 

33 Rat 13 wk 

Sprague 7 d/wk -Dawley 1 x/d

(GO) 

34 Mouse 13 wk 

B6C3F1 5 d/wk

1 x/d (GO) 

System 

Resp Cardio Gastro Hemato Musc/skel Hepatic Renal Dermal Ocular Bd Wt Cardio Gastro Hemato Musc/skel Hepatic Renal Ocular Bd Wt 

LOAEL 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

800 Wolfe 1988b 

para 

800 

800 800 800 

800 800 800 

800 800 ( 

2000 NTP 1986 

mixed 

2000 

2000 2000 2000 2000 2000 

2000 
741

750

1500

130

1000

191

800

190

800

150

500

1000

132

1000

192

800

Table 3-2 Levels of Significant Exposure to Xylene - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

Neurological 

35 Rat 

SpragueDawley 

36 Rat 

F344/N 

37 Rat 

SpragueDawley 

38 Rat 

SpragueDawley 

39 Mouse 

B6C3F1 

Reproductive 

40 Rat 

F344/N 

41 Rat 

SpragueDawley 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

90 d 1 x/d (GO) 

750 M 1500 M (increased 

aggressiveness) 

Condie et al. 1988 mixed 

13 wk 5 d/wk 1 x/d (GO) 

1000 NTP 1986 

mixed 

13 wk 7 d/wk 1 x/d (GO) 

800 Wolfe 1988a 

meta 

13 wk 7 d/wk 1 x/d (GO) 

800 Wolfe 1988b 

para 

103 wk 5 d/wk 1x/d (GO) 

d

500 1000 (hyperactivity weeks 

4-52) 

NTP 1986 mixed 

13 wk 5 d/wk 1 x/d (GO) 

1000 NTP 1986 

mixed 

13 wk 7 d/wk 1 x/d (GO) 

800 Wolfe 1988a 

meta 
194

800

135

2000

145

500

Table 3-2 Levels of Significant Exposure to Xylene - 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 

42 Rat 

SpragueDawley 

13 wk 7 d/wk 1 x/d (GO) 

800 Wolfe 1988b 

para 

43 Mouse 

B6C3F1 

13 wk 5 d/wk 1 x/d (GO) 

CHRONIC EXPOSURE Death 

44 Rat 

F344/N 

103 wk 5 d/wk 1 x/d (GO) 

2000 

500 M (survival decreased by 

16%) 

NTP 1986 mixed NTP 1986 mixed 
148

500500500500500500500500500250

500

Table 3-2 Levels of Significant Exposure to Xylene - 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 

Systemic 

45 Rat 

F344/N 

103 wk 5 d/wk 1 x/d (GO) 

Resp 500 NTP 1986 

mixed 

Cardio 500 Gastro 500 Hemato 500 Musc/skel 500 Hepatic 500 Renal 500 Dermal 500 Ocular 500 Bd Wt 250 500 M (body weight decreased 

5-8% after week 59) 
152

1000100010001000100010001000100010001000

146

500

147

500

Table 3-2 Levels of Significant Exposure to Xylene - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

46 Mouse 

B6C3F1 

Neurological 

47 Rat 

F344/N 

Reproductive 

48 Rat 

F344/N 

Exposure/ 

Duration/ 

Frequency 

(Route) 

103 wk 5 d/wk 1 x/d (GO) 103 wk 5 d/wk 1 x/d (GO) 103 wk 5 d/wk 1 x/d (GO) 

System 

Resp Cardio Gastro Hemato Musc/skel Hepatic Renal Dermal Ocular Bd Wt 

LOAEL 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

1000 NTP 1986 

mixed 

1000 

1000 

1000 1000 1000 1000 1000 1000 

1000 

e

500 NTP 1986 

mixed 

500 NTP 1986 

mixed 
151

1000

Table 3-2 Levels of Significant Exposure to Xylene - 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 

49 Mouse 

B6C3F1 

103 wk 5 d/wk 1 x/d (GO) 

1000 NTP 1986 

mixed 

a The number corresponds to the entries in Figure 3-2. b Differences in levels of health effects and cancer effects between male and females are not indicated in Figure 3-2. Where such differences exist, only the levels most sensitive gender are presented. c Used to derive an acute-duration minimal risk level (MRL) for mixed xylenes based on a NOAEL of 125 mg/kg/day p-xylene. The NOAEL was divided by an unce100 (10 for extrapolation from animals to humans and 10 for human variability). d Used to derive an intermediate-duration minimal risk level (MRL) for mixed xylenes based on a NOAEL of 500 mg/kg and a LOAEL of 1000 mg/kg for mice exposxylenes 5 days/week. The NOAEL was adjusted for intermittent exposure (5 days/7 days) and divided by an uncertainty factor of 100 (10 for extrapolation from aniand 10 for human variability) and a modifying factor of 10 to account for the lack of testing for sensitive neurological endpoints and lack of developmental and multi-e Used to derive a chronic-duration minimal risk level (MRL) for mixed xylenes based on a NOAEL of 250 mg/kg in rats exposed to mixed xylenes 5 days/week. At decrease in survival was observed, thus the next lowest dose was selected as the basis of the MRL. The NOAEL of 250 mg/kg/ was adjusted for intermittent exposdays) and divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human variability) and a modifying factor of 10 to account testing for sensitive neurological endpoints and lack of developmental and multi-generational data. Bd Wt = body weight; Cardio = cardiovascular; d = day(s); F = Female; Gastro = gastrointestinal; Gd = gestational day; hemato = hematological; LD50 = lethal dose= lowest-observed-adverse-effect level; M = male; Musc/skel = musculoskeletal; NOAEL = no-observed-adverse-effect level; Resp = respiratory; SGPT = serum glutransaminase; x = time(s); wk = week(s) 
Death 

Respiratory Hematological Renal Body Weight Other 

Figure 3-2 Levels of Significant Exposure to Xylene - Oral
	

Acute (≤14 days)
	

Systemic 

mg/kg/day 

10000 5r 

9r 6r 10m 

2r 3r 4r 11m 8r 

1r 7r 18m 16r 12r 13r 14r 12r 13r 14r 18m 12r 13r 14r 15r 

1000 18m 16r 17r 13r 14r 16r 15r 

16r 

100 

10 

1 

0.1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 
Immuno/Lymphor 

Neurological Developmental 

Figure 3-2 Levels of Significant Exposure to Xylene - Oral (Continued)
 

Acute (≤14 days)
	

mg/kg/day 

10000 

24r 

25r 

19r 26m 27m 28m 

1000 19r 27m 21r 22r 23r 

20r 

20r 

100 

10 

1 

0.1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 
Respiratory 

Cardiovascular Gastrointestinal Hematological Musculoskeletal Hepatic Renal 

Figure 3-2 Levels of Significant Exposure to Xylene - Oral (Continued)

Intermediate (15-364 days) 

Systemic 

mg/kg/day 

10000 

34m 34m 34m 34m 34m 34m 

29r 

1000 31r 31r 31r 31r 31r 31r 31r 

30r 32r 33r 32r 33r 32r 33r 29r 32r 33r 32r 33r 29r 30r 32r 32r 33r 29r 32r 33r

29r 29r 

100 

10 

1 

0.1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 
Dermal 

Ocular Body Weight Neurological Reproductive 

Figure 3-2 Levels of Significant Exposure to Xylene - Oral (Continued)

Intermediate (15-364 days) 

Systemic 

mg/kg/day 

10000 

34m 34m 43m 

29r 35r 

1000 31r 31r 39m 36r 40r 

32r 33r 32r 33r 32r 33r 35r 37r 38r 41r 42r

31r 39m 

32r 

100 

10 

1 

0.1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 
Death 

Respiratory Cardiovascular Gastrointestinal Hematological Musculoskeletal Hepatic Renal Dermal Ocular Body Weight NeurologicalReproductive 

Figure 3-2 Levels of Significant Exposure to Xylene - Oral (Continued)
 

Chronic (≥365 days)
	

Systemic 

mg/kg/day 

10000 

1000 46m 46m 46m 46m 46m 46m 46m 46m 46m 46m 49m 

44r 45r 45r 45r 45r 45r 45r 45r 45r 45r 45r 47r 48r

45r 

100 

10 

1 

0.1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 
XYLENE 102 

3. HEALTH EFFECTS 

daily oral doses of 2,000 mg/kg/day, 5 days/week, for 13 weeks exhibited similar effects 15–60 minutes 

after dosing (NTP 1986). Histopathological examination of the lungs and mainstem bronchi of rats and 

mice administered mixed xylene 5 days/week at doses as high as 1,000 mg/kg in rats and 2,000 mg/kg in 

mice for 13 weeks or 500 mg/kg in rats and 1,000 mg/kg in mice for up to 2 years revealed no adverse 

effects (NTP 1986). Gross and histopathological examination of rats administered m- or p-xylene for 

13 weeks at doses as high as 800 mg/kg/day revealed no treatment-related effects (Wolfe 1988a, 1988b). 

Decreased pulmonary microsomal enzyme activity was observed in rats after a single oral dose of 

1,000 mg/kg of p-xylene (Patel et al. 1978) and decreased pulmonary cytochrome P-450 content were 

observed in rats after gavage dosing with 800 mg/kg/day, 5 days/week, for 3 weeks (Elovaara et al. 1989), 

suggesting some direct toxicity of xylene in the lungs. Selective inactivation of enzymes can result in 

damage to tissue caused by the toxic metabolite of xylene, a methylbenzaldehyde (Carlone and Fouts 

1974; Patel et al. 1978; Smith et al. 1982). The formation of the methylbenzaldehydes has not been 

confirmed in humans. 

Cardiovascular Effects. Limited information was located regarding cardiovascular effects in 

humans following oral exposure to mixed xylene or its isomers. Postmortem examination showed no 

adverse effects on the heart or coronary arteries of a man who committed suicide by ingesting a large but 

unknown quantity of xylene (Abu Al Ragheb et al. 1986). No adverse cardiovascular effects were noted 

following histopathological examination of the heart in rats and mice exposed 5 days/week to mixed 

xylene at ≈63–2,000 mg/kg for 13 or 103 weeks (NTP 1986). No treatment-related effects were noted 

upon gross or histopathological examination of the heart in rats administered m- or p-xylene at doses as 

high as 800 mg/kg/day for 13 weeks (Wolfe 1988a, 1988b). 

Gastrointestinal Effects. No superficial erosions, deep ulcerations, or other lesions were observed 

during postmortem examination of the gastric mucosa of a person who died following ingestion of a 

"large quantity" of xylene (Abu Al Ragheb et al. 1986). Histopathological examination of rats 

administered doses 5 days/week as high as 1,000 mg/kg of mixed xylene and mice administered doses as 

high as 2,000 mg/kg of mixed xylene for 13 weeks or in rats and mice administered doses as high as 

500 and 1,000 mg/kg, respectively, for 2 years revealed no adverse effects on the stomach, small 

intestine, or colon (NTP 1986). Administration of p-xylene up to 800 mg/kg/day for 13 weeks also had 

no significant effect on gastrointestinal organs of rats (Wolfe 1988a, 1988b). 
XYLENE 103 

3. HEALTH EFFECTS 

Hematological Effects. No studies were located regarding hematological effects in humans 

following oral exposure to mixed xylene or xylene isomers. Exposure of rats to 2,000 mg/kg/day 

p-xylene for 10 days resulted in no effects detectable in routine hematological analysis (Condie et al. 

1988). Exposure to o- and m-xylene at 2,000 mg/kg/day for 10 days produced a decrease in the spleen 

weight of male rats (Condie et al. 1988); however, hematological analyses in these rats were normal. 

Mild polycythemia and leukocytosis in both male and female rats and an increase in spleen weight in 

females were observed in rats exposed to 1,500 mg/kg/day mixed xylene for 90 days (Condie et al. 1988). 

No effects were observed upon histopathological examination of the bone marrow following exposure to 

800 mg/kg/day of p-xylene in rats and mice (Wolfe 1988a), or on administration 5 days/week of 

1,000 mg/kg mixed xylene in rats for 13 weeks (NTP 1986), 2,000 mg/kg mixed xylene in mice for 

13 weeks (NTP 1986), or 500 mg/kg mixed xylene in rats and 1,000 mg/kg in mice for 2 years (NTP 

1986). 

Musculoskeletal Effects. No studies were located regarding musculoskeletal effects in humans 

following oral exposure to mixed xylene or xylene isomers. In two animal bioassays, no musculoskeletal 

effects were observed in rats and mice upon histopathological examination of the femur, sternebrae, or 

vertebrae following intermediate or chronic exposure 5 days/week to mixed xylene up to 2,000 mg/kg for 

mice and 1,000 mg/kg for rats for 13 weeks and 1,000 mg/kg for mice or 500 mg/kg for rats for 

103 weeks (NTP 1986). No adverse effects were observed in the sternum (with marrow), thigh 

musculature, or femur upon histopathological examination of rats administered m- or p-xylene at doses up 

to 800 mg/kg/day for 13 weeks (Wolfe 1988a, 1988b). 

Hepatic Effects. No studies were located regarding hepatic effects in humans following oral exposure 

to mixed xylene or xylene isomers. In general, studies in animals have shown mild changes in the liver in 

response to oral exposure to mixed xylene. These changes included increased activity of liver enzymes 

and ultrastructural changes indicative of increased metabolic activity, but no evidence of 

histopathological changes in the liver tissue (Ungvary 1990). In acute and intermediate studies with rats, 

oral exposure to mixed xylene (Condie et al. 1988; Ungvary 1990) and its isomers (Condie et al. 1988; 

Elovaara et al. 1989; Pyykko 1980) has been associated with hepatic enzyme induction and increased 

hepatic weight. In the study by Condie et al. (1988), acute exposure to p-xylene at 250 mg/kg/day and 

m- and o-xylene at 1,000 mg/kg/day for 10 days caused increases in liver weight. Administration of 

doses of 1,060 mg/kg/day of all three xylene isomers for 3 days also produced increased cytochrome 

b5 content and increased activities of liver enzymes in rats (Pyykko 1980), with the different isomers 

showing different enzyme induction potencies. Increased liver weight was observed with m- and 
XYLENE 104 

3. HEALTH EFFECTS 

o-xylene, but not p-xylene, and increased cytochrome P-450 was observed only with m-xylene. 

Administration of mixed xylene to rats for 90 days caused 13.8–27% increases in relative liver weight 

ratios at doses between 750 and 1,500 mg/kg/day (Condie et al. 1988); a statistically significant 5.7% 

increase in relative liver weight in male rats at 150 mg/kg/day is not biologically significant. No 

treatment-related histopathological changes were observed in the liver, but mild increases in serum 

transaminases were observed at 750 mg/kg/day. Similar increases in serum alanine aminotransferase 

were observed following ingestion of 800 mg/kg/day of m-xylene for 3 or 13 weeks (Elovaara et al. 1989; 

Wolfe 1988a). No effects were noted upon histopathological examination of the liver of rats and mice 

that were administered mixed xylene 5 days/week for a chronic or intermediate period of time with doses 

as high as 2,000 mg/kg for mice; 1,000 mg/kg for rats for 13 weeks; and 1,000 mg/kg for mice and 

500 mg/kg for rats for 103 weeks (NTP 1986). Administration of doses as high as 800 mg/kg/day of 

p-xylene in rats for 13 weeks produced no adverse hepatic effects (Wolfe 1988b). 

Renal Effects. No studies were located regarding renal effects in humans following oral exposure to 

mixed xylene or xylene isomers. Data are available for renal effects in laboratory animals following 

acute-duration exposure to individual isomers, but not to mixed xylene (Condie et al. 1988; Pyykko 

1980). At 1,060 mg/kg/day for 3 days, increases in kidney weight were observed with m-xylene and 

increases in microsomal enzyme content and activity were observed with all three isomers (Pyykko 

1980). No effects on urine parameters were noted after a 10-day exposure to 2,000 mg/kg/day of any of 

the isomers (Condie et al. 1988). The majority of studies using mixed xylene or its isomers for 

intermediate or chronic durations also showed no adverse effects on the kidneys. The only toxic change 

observed was increased hyaline droplet change in males (not relevant to humans) and increased early 

chronic nephropathy in females at 150–1,500 mg/kg/day mixed xylene for 90 days; the incidence in 

females at 150 mg/kg/day was not statistically significant. Although urine from these rats were normal 

(Condie et al. 1988), continued hyaline droplet accumulation can result in cell damage. Increased relative 

kidney weight was also observed in male rats given mixed xylene at 750 mg/kg/day and in female rats at 

1,500 mg/kg/day for 90 days (Condie et al. 1988). Similarly, increased kidney weight and microsomal 

enzyme activity were observed in rats exposed to 800 mg/kg/day of m-xylene, 5 days/week, for 3 weeks 

(Elovaara et al. 1989). Increased relative kidney weight was also observed in male rats administered 

800 mg m-xylene/kg/day for 13 weeks (Wolfe 1988a, 1988b). Histopathology of the kidneys and urinary 

bladder were normal. Also, no adverse effects were noted upon histopathological examination of the 

kidneys of rats and mice following intermediate or chronic exposure 5 days/week to doses of mixed 

xylene as high as 2,000 mg/kg (for 13 weeks in mice) and 1,000 mg/kg (for 103 weeks in mice) (NTP 

1986). 
XYLENE 105 

3. HEALTH EFFECTS 

Endocrine Effects. No studies were located regarding endocrine effects in humans or animals 

following oral exposure to mixed xylene or xylene isomers. 

Dermal Effects. No studies were located regarding dermal effects in humans following oral exposure 

to mixed xylene or xylene isomers. Limited information was located regarding dermal effects in animals. 

No adverse effects were noted during microscopic examination of the skin of rats and mice administered 

mixed xylene 5 days/week at doses as high as 2,000 mg/kg in mice and 1,000 mg/kg for rats for an 

intermediate (13 weeks) period of time or as high as 1,000 mg/kg for mice and 500 mg/kg for rats for a 

chronic (103 weeks) period of time (NTP 1986). The skin of rats administered doses as high as 

800 mg/kg/day of m- or p-xylene for 13 weeks appeared normal upon histopathological examination 

(Wolfe 1988a, 1988b). 

Ocular Effects. No studies were located regarding ocular effects in humans following oral exposure 

to mixed xylenes or xylene isomers. Histopathological examination of the eyes of rats and mice orally 

exposed to mixed xylenes (NTP 1986) or to m- or p-xylene (Wolfe 1988a, 1988b) for 13 or 103 weeks 

showed no effects. No additional data regarding ocular effects in animals following oral exposure to 

xylenes were available. 

Body Weight Effects. Effects on body weight were observed in several acute studies of the effects of 

mixed xylene and its isomers (Condie et al. 1988; NTP 1986; Pyykko 1980). Exposure to m-, o-, and 

p-xylene for 3 days resulted in weight losses of between 2.5 and 3 times that observed in control rats 

(Pyykko 1980). A 14-day exposure of rats and mice to mixed xylene resulted in an 18% decrease in body 

weight gain in male rats at 1,000 mg/kg/day and an 89% decrease in bodyweight gain in male mice at 

2,000 mg/kg/day (NTP 1986). Body weights of male rats given 2,000 mg/kg/day o- or p-xylene, but not 

m-xylene, for 10 days showed 14% and 13% decreases, respectively, relative to controls (Condie et al. 

1988). No significant body weight changes were observed in male or female rats dosed daily with 

≤1,500 mg/kg/day mixed xylenes for 13 weeks (Condie et al. 1988), but a 16% decrease was noted in 

female mice dosed 5 days/week for 13 weeks at 2,000 mg/kg (NTP 1986). Body weights were decreased 

by 25% in males (with reduced food consumption) and by 15.5% in females (with normal food 

consumption) treated by daily oral gavage with 800 mg m-xylene/kg/day for 13 weeks (Wolfe 1988a). In 

a parallel study with p-xylene, body weights were reduced by 21% in males and by 11% in females 

treated at 800 mg/kg/day, although food consumption was significantly higher than controls (Wolfe 

1988b). Body weight in male rats at 1,000 mg/kg and in female mice at 2,000 mg/kg mixed xylene were 
XYLENE 106 

3. HEALTH EFFECTS 

decreased 15% and 16%, respectively, in a 13-week study (NTP 1986). After week 59 in a 2-year study, 

mean body weights were reduced by 5–8% in male rats exposed by oral gavage 5 days/week to 

500 mg/kg mixed xylenes, but this change is not biologically significant (NTP 1986). No body weight 

effects were observed in female rats exposed at doses as high as 500 mg/kg or in mice exposed at doses as 

high as 1,000 mg/kg/day (NTP 1986). 

3.2.2.3 Immunological and Lymphoreticular Effects 

No studies were located regarding immunological or lymphoreticular effects in humans after oral 

exposure to mixed xylene or xylene isomers. The only information suggesting a possible toxic effect of 

mixed xylene or its isomers on the immune system was a decrease in spleen and thymus weight observed 

in rats exposed for 10 days to 2,000 mg/kg/day p-xylene (Condie et al. 1988). Organ weight changes 

were not accompanied by histopathological changes. 

The NOAEL and LOAEL values for immunological effects of p-xylene in rats are recorded in 

Table 3-2 and plotted in Figure 3-2. 

3.2.2.4 Neurological Effects 

Information concerning possible neurological effects associated with the ingestion of xylene is limited. 

Xylene produced a coma that persisted for more than 26 hours in a person who accidentally ingested an 

unknown amount (Recchia et al. 1985). The composition of the xylene was also unknown. 

Clinical signs consistent with central nervous system toxicity have been observed in rats and mice 

following oral exposure to mixed xylene. A single oral dose of 4,000 mg/kg caused incoordination, 

prostration, decreased hindleg movement, and hunched posture in rats and tremors, prostration, and/or 

slowed breathing in mice (NTP 1986). In 13-week gavage assays in rats, neurotoxic signs included 

hyperactivity, convulsions, salivation, and epistaxis following exposure to 800 mg/kg/day m- or p-xylene 

(Wolfe 1988a, 1988b) and increased aggression following exposure to 1,500 mg/kg/day mixed xylenes 

(Condie et al. 1988). Clinical signs observed in mice in the hour after gavage dosing with mixed xylenes 

included weakness, lethargy, unsteadiness, tremors, and partial paralysis of hindlimbs at 2,000 mg/kg in a 

13-week assay and hyperactivity at 1,000 mg/kg beginning week 4 in 13-week and 2-year assays (NTP 

1986). Mild sedation at 2,000 mg/kg and increases in latency of several peaks in flash-evoked potentials 

at doses of 250 mg/kg and higher were observed following single doses of p-xylene; no effect was seen at 
XYLENE 107 

3. HEALTH EFFECTS 

125 mg/kg/day (Dyer et al. 1988). This NOAEL was used to derive an MRL of 1 mg/kg/day for acute 

oral exposure to mixed xylenes or individual xylene isomers. 

Histological damage to the outer hair cells of the organ of Corti provided evidence of ototoxicity in rats 

exposed by oral gavage to p-xylene, but not m- or o-xylene, at a dose of 900 mg/kg/day, 5 days/week for 

2 weeks (Gagnaire and Langlais 2005). The losses of hair cells occurred in the area of the cochlea 

responsive to medium frequencies (10–25 kHz). No histopathology of the brain or spinal cord was 

observed in rats or mice administered mixed xylenes 5 days/week at doses as high as 1,000 mg/kg (rats) 

or 2,000 mg/kg/day (mice) for 13 weeks or 1,000 mg/kg for 2 years (NTP 1986). Similarly, no 

neurohistopathology was observed in rats administered doses of m- or p-xylene as high as 800 mg/kg/day 

for 13 weeks, although the brain-to-body weight ratio was increased in males dosed with 800 mg/kg/day 

of m-xylene (Wolfe 1988a, 1988b). 

An acute-duration oral MRL of 1 mg/kg/day for mixed xylenes or individual isomers was calculated 

based on a NOAEL of 125 mg/kg and a LOAEL of 250 mg/kg for altered visual evoked brain potentials 

in male Long-Evans rats given single gavage doses of p-xylene (Dyer et al. 1988; NTP 1986) as described 

in the footnote in Table 3-2. An intermediate-duration oral MRL of 0.4 mg/kg/day for mixed xylenes or 

individual isomers was calculated based on a NOAEL of 500 mg/kg and a LOAEL of 1,000 mg/kg for 

hyperactivity in male and female B6C3F1 mice dosed with mixed xylenes by gavage 5 days/week for 4– 

51 weeks (NTP 1986) as described in the footnote in Table 3-2. 

The highest NOAEL value and all LOAEL values from each reliable study for neurological effects in rats 

and mice and for each exposure duration are recorded in Table 3-2 and plotted in Figure 3-2. 

3.2.2.5 Reproductive Effects 

No studies were located regarding reproductive effects in humans following oral exposure to mixed 

xylene or individual isomers. 

No studies in animals directly examining reproductive function following oral administration of mixed 

xylene or its isomers were located; however, histological examination of rats and mice administered 

mixed xylene 5 days/week at doses as high as 1,000 mg/kg in rats and 2,000 mg/kg in mice for 13 weeks 

revealed no adverse effects on the prostate/testes (male), ovaries/uterus, or mammary glands (female) 

(NTP 1986). The reproductive system organs of rats administered doses of m- or p-xylene as high as 
XYLENE 108 

3. HEALTH EFFECTS 

800 mg/kg/day appeared comparable to controls after 13 weeks of treatment (Wolfe 1988a, 1988b). In 

chronic studies, no adverse histopathological changes were observed in the reproductive organs in rats at 

doses as high as 500 mg/kg and in mice at doses as high as 1,000 mg/kg administered 5 days/week for 

103 weeks (NTP 1986). The highest NOAEL value from each reliable study for reproductive effects are 

recorded in Table 3-2 and plotted in Figure 3-2. 

3.2.2.6 Developmental Effects 

No studies were located regarding developmental effects in humans following oral exposure to mixed 

xylene or xylene isomers. 

Significantly increased incidences of cleft palate and decreased fetal body weight were reported following 

maternal oral exposure during gestation days 6–15 to doses of 2,060 mg/kg/day mixed xylene in mice 

(Marks et al. 1982). Mixed xylene was also toxic to the dams, producing 31.5% mortality at 

3,100 mg/kg/day. It is unclear whether the observation of cleft palate in this study is associated with 

maternal toxicity or a predisposition of mice under stress to give birth to offspring with this birth defect. 

In a teratology screening study, 2,000 mg/kg/day of m-xylene produced no evidence of fetal toxicity in 

mice (Seidenberg et al. 1986). Given the limited amount of animal data, no conclusion can be made 

regarding the relationship between oral exposure of xylene and adverse developmental effects. The 

highest NOAEL value and all LOAEL values from each reliable study for developmental effects are 

recorded in Table 3-2 and plotted in Figure 3-2. 

3.2.2.7 Cancer 

No data were located regarding cancer in humans following oral exposure to mixed xylene or xylene 

isomers. 

The carcinogenicity of mixed xylene following oral exposure has been evaluated in chronic studies with 

rats and mice; however, no animal studies were available on the carcinogenic effects of m-, o-, or 

p-xylene following oral exposure. Results of the chronic oral studies with mixed xylene have been 

negative (NTP 1986) or equivocal (Maltoni et al. 1983, 1985). In a chronic bioassay, rats and mice of 

both sexes received mixed xylene by gavage at 0, 250, or 500 mg/kg and 0, 500, or 1,000 mg/kg, 

respectively, 5 days/week for 103 weeks. The interpretation of the results of the NTP bioassay was 

compromised by the large number of gavage-related deaths early in the study in the high-dose male rats. 

In the other chronic study (Maltoni et al. 1983, 1985), male and female rats were fed xylene (unspecified) 
XYLENE 109 

3. HEALTH EFFECTS 

by gavage at 0 or 500 mg/kg, 4–5 days/week for 104 weeks. The Maltoni studies were weakened because 

of methodological flaws such as failure to report site-specific neoplasia, insufficient toxicity data, and 

absence of statistical analyses. Therefore, given the limited data, no definitive conclusion can be made 

regarding the carcinogenicity of mixed xylene in animals following oral exposure. 

3.2.3 Dermal Exposure 

In addition to studies that have directly examined the health effects of dermal exposure to xylene, a 

number of reports of health effects resulting from occupational exposure to xylene have been included in 

this section. Dermal contact with xylene is likely in many occupational situations, and absorption of 

xylene has been demonstrated in humans (Engstrom et al. 1977; Riihimaki 1979b; Riihimaki and Pfaffli 

1978). The results of the occupational studies must be interpreted with caution, however, because of 

coexposure to other compounds. 

3.2.3.1 Death 

No reports of death in humans following dermal exposure to xylene were located. Limited animal data 

suggest that mixed xylene and m-xylene can cause death when applied dermally (Hine and Zuidema 

1970; Smyth et al. 1962). The acute dermal LD50 in rabbits has been determined to be 3,228 mg/kg/day 

for m-xylene and >114 mg/kg/day for mixed xylene for 4 hours or more (Hine and Zuidema 1970; Smyth 

et al. 1962). 

The LD50 value for death in rabbits as a result of acute-duration exposure to m-xylene is recorded in 

Table 3-3. 

3.2.3.2 Systemic Effects 

No studies were located regarding musculoskeletal, endocrine, or body weight effects in humans or 

animals following dermal exposure to mixed xylenes or xylene isomers. The systemic effects that were 

observed after dermal exposure to xylene are discussed below. All LOAEL values from each reliable 

study for systemic effects in each species and duration category are recorded in Table 3-3. 

Respiratory Effects. Case reports of dryness of the throat (Goldie 1960) in painters and decreased 

pulmonary function and dyspnea in histology technicians with chronic exposure to xylene (Hipolito 1980) 

have been published. It is likely that these effects represent direct effects of xylene or other solvents on 
807

mg/kg

45 mg/kg908

mg/day

901

mg

Table 3-3 Levels of Significant Exposure to Xylene - Dermal 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

ACUTE EXPOSURE 

Death 

Hall Mouse once 

System NOAEL Less Serious 

LOAEL 

57 

mg/kg 

Serious 

(8/120 died) 

Reference Chemical Form 

Pound and Withers 196mixed 

Albino New 

Zealand Rabbit 24 hr 

3228 M 

mg/kg 

(LD50) Smyth et al. 1962 

meta 

Systemic 

(hairless) Rat 4 d 

5 x/d Dermal 66 

mg/day 

(2-fold increase in 

transepidermal water loss, moderate erythema 

5-fold increase in pro-inflammatory cytokine TNF-alpha) 

Ahaghotu et al. 2005; S2006 

(hairless) Rat 1 hr Dermal 199 M 

mg 

(2-fold higher transepidermal water loss, 30% reduced moisture content, moderate erythema, 2.5-fold increase in pro-inflammatory TNF-alpha) 

ortho 

Chatterjee et al. 2005 meta 
mixed 

909

mg/day

886

mg/kg

887

μg/kg

808

mg/kg

73 mg/kg/day787

mg

Table 3-3 Levels of Significant Exposure to Xylene - Dermal (continued) 

Exposure/ LOAEL 

Duration/ 

Species Frequency Reference (Route) (Strain) System NOAEL Less Serious Serious Chemical Form 

Rat(hairless)Rat(Fischer- 344)Mouse(BALB/c)MouseHallGn PigDunkinHartleyRabbitNS

4 d 5 x/d 1 hr once once once 3 d 3 x/d once 

Dermal 64.8 M 

mg/day 

(2-fold increase in transepidermal water loss, 22% reduced wate content, moderate erythema, 5.7-fold increase in pro-inflammatory TNF-alpha) 

Dermal 1200 M 

mg/kg 

(separation of epidermis 

and dermis) 

Dermal 3136 F 

μg/kg 

(skin edema) 

Dermal 57 

mg/kg 

(edema, irritation, 

scaliness of skin) 

Dermal 2.3 F 

mg/kg/day 

(skin irritation) 

Ocular 87 

mg 

(mild irritation of eyes) 

Chatterjee et al. 2005 meta 

Gunasekar et al. 2003 meta Iyadomi et al. 2000 meta Pound and Withers 196mixed Anderson et al. 1986 mixed Consumer Product Test1976 
82 mg/kg

mg

88 mg900 mg75 mg76

mg/kg

Table 3-3 Levels of Significant Exposure to Xylene - Dermal (continued) 

Exposure/ LOAEL 

Duration/ 

Species Frequency Reference (Route) (Strain) System NOAEL Less Serious Serious Chemical Form 

New Zealand white Rabbit once Dermal 

Ocular 87 M 

mg 

(moderately irritating to the conjunctiva) 

114 M 

mg/kg 

(moderate to severe skin irritation) 

Hine and Zuidema 1970 mixed 

New Zealand white Rabbit once Ocular 87 M 

mg 

(eye irritation) Hine and Zuidema 1970 

mixed 

(New Zealand) Rabbit once Ocular 87 

mg 

(minimal eye irritation) Kennah et al. 1989 

mixed 

New Zealand albino Rabbit once Ocular 432 

mg 

(eye irritation) Smyth et al. 1962 

meta 

Albino 

Rabbit once Dermal 2.3 

mg/kg 

(skin irritation) Smyth et al. 1962 

meta 

d = day(s); F = Female; hr = hour(s); LD50 = lethal dose, 50% kill;LOAEL = lowest-observed-adverse-effect level; M = male; NOAEL = no-observed-adverse-effect necrosis factor; x = time(s) 
XYLENE 113 

3. HEALTH EFFECTS 

the respiratory tissues and they are discussed in more detail in Section 3.2.1.2. No studies were located 

regarding respiratory effects in animals following dermal exposure to mixed xylene or xylene isomers, 

although some of the inhalation studies also involved exposure via dermal route as well. 

Cardiovascular Effects. Cases of flushing, chest pains, and palpitations in histology technicians 

have been reported (Hipolito 1980). These studies also involved exposure via inhalation route. It is 

unclear whether these effects are directly attributable to xylene exposure because of possible exposure to 

other chemicals. No studies were located regarding cardiovascular effects in animals after dermal 

exposure to mixed xylene or xylene isomers. 

Gastrointestinal Effects. Gastric discomfort in painters (Goldie 1960) and nausea in histology 

technicians (1980) have been reported; these studies also involved exposure via inhalation route. 

However, other chemicals in the workplace may have contributed to these effects. No studies were 

located regarding gastrointestinal effects in animals following dermal exposure to mixed xylene or xylene 

isomers. 

Hematological Effects. Decreased white blood cell count has been observed in histology technicians 

(Hipolito 1980) and in workers with occupational exposure to benzene, toluene, and xylene (Moszczynski 

and Lisiewicz 1983, 1984a); these studies also involved exposure via inhalation route. However, 

chemicals other than xylene may have caused these decreases. No studies were located regarding 

hematological effects in animals following dermal exposure to mixed xylene or xylene isomers. 

Hepatic Effects. When compared with unexposed controls, workers with occupational exposure via 

dermal and inhalation routes to toluene, xylene, and pigments had significantly increased urinary 

D-glucaric acid content in the urine indicating hepatic microsomal enzyme induction (Dolara et al. 1982). 

Serum antipyrine half-life was increased, suggesting possible hepatotoxicity. No effect on serum 

aminotransferases was observed in workers exposed to a mixture of solvents (Kurppa and Husman 1982). 

These studies also involved exposure via inhalation route. These studies are limited in that multiple 

chemical exposures occurred and the effects observed cannot be directly attributed to xylene. No studies 

were located regarding hepatic effects in animals following dermal exposure to mixed xylene or xylene 

isomers. 

Renal Effects. Occupational exposure to a mixture of mainly xylene and toluene resulted in elevated 

albumin, erythrocytes, and leukocytes in the urine (Askergren 1981, 1982). In addition, increased 
XYLENE 114 

3. HEALTH EFFECTS 

β-glucuronidase was observed in the urine of painters (Franchini et al. 1983). However, these studies are 

limited in that the effects observed may be attributable to exposure to toluene, which is a known renal 

toxicant, and that inhalation as well as dermal exposure could have occurred. No studies were located 

regarding renal effects in animals following dermal exposure to mixed xylene or xylene isomers. 

Dermal Effects. Acute dermal exposure of human subjects to undiluted m-xylene in hand immersion 

studies has been associated with transient skin erythema (irritation), vasodilation of the skin, and dryness 

and scaling of the skin (Engstrom et al. 1977; Riihimaki 1979b). Urticaria was reported in a female 

cytology worker exposed predominantly to xylene vapors (Palmer and Rycroft 1993). Because this 

response probably had an immunological component, it is discussed further in the Immunological and 

Lymphoreticular Effects section. 

Mild-to-severe skin irritation was noted in rabbits, guinea pigs, and mice treated topically with mixed 

xylene (2.3–114 mg/kg/day), m-xylene (65–199 mg/day) or o-xylene (66 mg/day) in acute studies 

(Ahaghotu et al. 2005, isomer identified in personal communication by Singh 2006; Anderson et al. 1986; 

Chatterjee et al. 2005; Consumer Products Testing 1976; Food and Drug Research Labs 1976a; Hine and 

Zuidema 1970; Pound and Withers 1963; Smyth et al. 1962). The extent of the irritation appeared to 

increase with duration of exposure; the most severe dermal irritation ratings were obtained in the longest 

exposures of 10-days (Hine and Zuidema 1970). Application of 0.250 mL (1,200 mg/kg) of m-xylene to 

the skin of rats for 1 hour resulted in a significant increase in oxidative species and DNA fragmentation 

(increased low-molecular-weight DNA) within 2 hours (Gunasekar et al. 2003; Rogers et al. 2001). 

Treatment with m- or o-xylene increased levels of inducible nitric oxide synthetase and tumor necrosis 

factor-alpha (TNF-alpha), a pro-inflammatory cytokine, in skin, as well as plasma levels of interleukin-1­

alpha (IL-1alpha) (Ahaghotu et al. 2005; Chatterjee et al. 2005; Gunasekar et al. 2003). Dermal swelling 

following application of 69 mg m-xylene to the ear of mice resulted in significant increases in the 

thickness of the ear as measured 0.5–25 hours after application (Iyadomi et al. 2000); peak thickness was 

observed 6 hours after treatment. Histopathological effects of exposure to m- or o-xylene included 

swelling and disruption of the stratum corneum, granulocyte infiltration of the epidermis, and separation 

of the epidermis and dermis, with evidence of local inflammation (accumulation of mast cells, plasma 

cells) (Ahaghotu et al. 2005; Chatterjee et al. 2005; Gunasekar et al. 2003). Impairment of skin function 

was evident in the increase in transepidermal water loss in hairless rats following occlusive exposure (199 

mg for 1 hour) or unocclusive exposure (64.8 mg/day in 5 divided daily fractions over 4 days) to 

m-xylene or unocclusive exposure (66 mg/day in 5 divided doses, for 4 days) to o-xylene and the 

reduction in skin moisture content observed in rats treated unocclusively as above with m-xylene 
XYLENE 115 

3. HEALTH EFFECTS 

(Ahaghotu et al. 2005; Chatterjee et al. 2005). Moderate-to-marked irritation and moderate necrosis were 

observed in rabbits with a 2–4-week dermal exposure to undiluted xylene (Wolf et al. 1956). No chronic 

animal studies evaluating the dermal effects of xylene were located. 

Ocular Effects. There are a few case reports in humans describing the effects of direct contact of the 

eye with heated xylene from a pressurized hose in one case or with paint containing xylene as the solvent 

in two cases (Ansari 1997; Narvaez and Song 2003). Both kinds of exposures resulted in photophobia, 

redness of the conjunctiva, and partial loss of the conjunctival and corneal epithelia. The effects in the 

two men exposed to paint were characterized as equivalent to grade II chemical burns and, with medical 

therapy, largely reversed after about a week (Ansari 1997). The other case also experienced 

subconjunctival hemorrhage, more extensive loss of the corneal epithelium, and xylene keratopathy 

(melting of the corneal stroma), the latter of which persisted to 4 weeks following the initial injury 

(Narvaez and Song 2003). It is possible combined thermal, physical, and chemical injury increased the 

severity of ocular effects in this case. 

Several studies in humans have reported on ocular effects of exposure to xylene vapor. In the controlled 

exposure situations, eye irritation was reported at concentrations of mixed xylene as low as 200 ppm for 

3–5 minutes (Nelson et al. 1943) and of p-xylene as low as 100 ppm for 1–7.5 hours/day for 5 days 

(NIOSH 1981). Case reports have also demonstrated transient eye irritation in humans exposed to vapors 

of mixed xylene or p-xylene (Carpenter et al. 1975a; Hastings et al. 1986; Klaucke et al. 1982; Nelson et 

al. 1943; Nersesian et al. 1985; NIOSH 1981). Eye irritation was more frequently reported by workers 

exposed to mixed xylene (geometric mean TWA 14 ppm) than by the controls (Uchida et al. 1993). 

Instillation of 0.1 mL (87 mg) of mixed xylene or 0.5 mL (432 mg) of m-xylene into the eyes of rabbits 

resulted in slight-to-moderate eye irritation (Consumer Products Testing 1976; Hine and Zuidema 1970; 

Kennah et al. 1989; Smyth et al. 1962). No corneal effects were observed in these studies. 

3.2.3.3 Immunological and Lymphoreticular Effects 

Limited data were located regarding immunological and lymphoreticular effects in humans following 

dermal exposure to xylene. Occupational exposure to benzene, toluene, and xylene resulted in decreased 

serum complement (Smolik et al. 1973) and in decreased lymphocytes, but there was no effect on 

lymphocyte reactions when stimulated with phytohemagglutinin (Moszczynski and Lisiewicz 1983, 

1984a). Interpretation of these studies is limited in that chemicals other than xylene may have accounted 
XYLENE 116 

3. HEALTH EFFECTS 

for the effects observed. Exposures via inhalation and dermal routes also may have occurred. Contact 

urticaria was reported in a female cytology worker exposed for several months predominantly to 

<100 ppm xylene vapors (Palmer and Rycroft 1993). A closed patch test resulting in severe erythema and 

wealing provides evidence that the effect was a result of direct contact of xylene vapor with the skin and 

suggests that the reaction was immunological. 

No studies were located regarding immunological or lymphoreticular effects in animals after dermal 

exposure to mixed xylene or xylene isomers. 

3.2.3.4 Neurological Effects 

Occupational exposure to xylene has been reported to result in headache, dizziness, malaise, a feeling of 

drunkenness, irritability, fine tremor, dysphasia, hyperreflexia, and/or impaired concentration and 

memory (Goldie 1960; Hipolito 1980; Kilburn et al. 1985; Roberts et al. 1988). These studies are limited, 

however, because other chemical exposures in the workplace may have been responsible for the effects 

observed and that exposures via inhalation and dermal routes may have occurred. 

As described in a brief report, pregnant rats dermally exposed to xylene (form not specified) at 

2,000 mg/kg/day throughout gestation showed a statistically significant 27% reduction, compared to 

controls, in motor activity in an open field test, suggesting a neurotoxic effect of xylene (Mirkova et al. 

1979). In this study, dosing at 200 or 2,000 mg/kg/day reduced brain cholinesterase activities in dams by 

35–38% compared to controls; fetal brain cholinesterase was also reported to be ‘inhibited’ at those doses. 

The report did not discuss whether any measures were taken to prevent ingestion of the test material. 

3.2.3.5 Reproductive Effects 

No studies were located regarding reproductive effects in humans or animals after dermal exposure to 

mixed xylene or xylene isomers. 

3.2.3.6 Developmental Effects 

The human data regarding the developmental effects of xylene suggest a possible relationship between 

occupational solvent exposure and developmental toxicity (Holmberg and Nurminen 1980; Kucera 1968; 

Taskinen et al. 1989; Windham et al. 1991). However, these data are limited for assessing the 

relationship between dermal exposure to xylene and developmental effects because the available studies 
XYLENE 117 

3. HEALTH EFFECTS 

involved concurrent exposure to other chemical agents in addition to xylene in the workplace (Holmberg 

and Nurminen 1980; Kucera 1968; Taskinen et al. 1989; Windham et al. 1991), because few subjects 

were tested (Taskinen et al. 1989; Windham et al. 1991), and because it is extremely difficult to have a 

pure dermal exposure since such exposure in the absence of respiratory protection is accompanied by 

inhalation exposure. 

As described in a brief report, dermal exposure of pregnant rats to doses as low as 200 mg/kg/day of 

xylene (unspecified concentration and isomer) throughout gestation produced decreases in enzyme 

activity (cholinesterase, cytochrome oxidase) in fetal and maternal brain tissue (Mirkova et al. 1979). 

3.2.3.7 Cancer 

Studies of workers occupationally exposed to solvents have examined the cancer and leukemia risks and 

suggest a possible relationship between coal-based xylene exposure and leukemia (Arp et al. 1983; 

Wilcosky et al. 1984). Both contain limitations (e.g., small number of subjects, no exposure 

concentrations, unknown composition of xylene and possible exposure to benzene and other chemicals) 

that preclude a definitive conclusion regarding dermal exposure to xylene and cancer; development of 

these studies probably also involved exposure via inhalation. 

Limited information was located regarding the carcinogenicity of dermal exposure to xylene in animals 

(Berenblum 1941; Pound 1970; Pound and Withers 1963). Application of xylene (concentration, purity, 

and amount unspecified) to the skin for 25 weeks resulted in no increase in skin tumors, and did not 

potentiate the number of skin tumors produced by benz[a]pyrene (Berenblum 1941). However, two 

studies showed that a single xylene pretreatment slightly enhanced the number of tumors produced by a 

combination of ultraviolet light irradiation (initiation) and croton oil (promotion) (Pound 1970) or 

urethane (initiation) and croton oil (promotion) (Pound and Withers 1963). These findings suggest that 

xylene may be a promoter for skin cancer and might also act as initiator or cocarcinogen. These studies 

are limited in that tumors other than skin tumors were not assessed and untreated controls were not used. 

Furthermore, it is not known whether the xylene was analyzed for the presence of other aromatic 

hydrocarbons such as benzene that are known to be tumorigenic. 

3.3 GENOTOXICITY 

The preponderance of data from testing in vivo (Table 3-4) and in vitro (Table 3-5) indicates that xylenes 

are not mutagenic and do not induce chromosomal anomalies. A few studies indicate that DNA 
XYLENE 118 

3. HEALTH EFFECTS 

Table 3-4. Genotoxicity of Xylene In Vivo 

Species (test Exposure route; 

system) End point dose Results Reference Isomer 

Mammalian cells: 

 Human peripheral Sister chromatid Inhalation – Haglund et al. Not reported 

lymphocytes exchange and (occupational 1980 

chromosomal exposure) 

abberations 

 Human peripheral Sister chromatid Inhalation – Pap and Varga Mixed xylene 

lymphocytes exchange (occupational 1987 

exposure) 

 Human peripheral Sister chromatid Inhalation (three – Richer et al. Mixed xylene 

lymphocytes exchange exposures; 1993 

40 ppm, 

7 hours/day) 

 Mouse reticulocytes Chromosomal Oral (single – Feldt 1986 Mixed xylene 

aberrations or exposure); 

Micronuclei ≤1,000 mg/kg 

formation 

 Rat (Fischer 344) DNA damage Dermal (250 μL; + Rogers et al. m-Xylene 

skin 1 hour) 2001 

Rat bone marrow Chromosomal Intraperitoneal – Litton Bionetics Mixed xylene 

aberrations (single exposure) 1978b (11.4% 

o-xylene, 0.3% 

p-xylene, 36.1% 

ethylbenzene) 

Rat bone marrow Chromosomal Intraperitoneal – Litton Bionetics Mixed xylene 

aberrations (five exposures) 1978b (0.3% p-xylene, 

36.1% ethylbenzene) 

Mouse bone marrow Micronuclei Intraperitoneal – Mohtashami­ m-Xylene, 

polychromatic- formation (two exposures pur et al. 1985 o-xylene, 

erythrocyte assay at ≤650 mg/kg) p-xylene 

(micro-nucleus test) 

 Rat sperm-head Sperm-head Intraperitoneal – Washington et o-Xylene 

morphology assay abnormalities (two exposures al. 1983 

at 435 mg/kg) 

– = negative result 

+ = positive result 
XYLENE 119 

3. HEALTH EFFECTS 

Table 3-5. Genotoxicity of Xylene In Vitro 

Results 

With Without 

Species (test system) End point activation activation Reference Isomer 

Prokaryotic organisms: 

Salmonella typhimurium 

TA97, TA98, TA100, TA1535/ 

plate incorporation assay 

S. typhimurium TA98, TA100, 

TA1535, TA1537/plate 

incorporation assay 

S. typhimurium TA98, TA100, 

UTH8414, UTH8413/plate 

incorporation assay 

S. typhimurium TA98, TA100, 

TA1535, TA1537, TA1538/ 

plate incorporation assay 

S. typhimurium TA98, TA100, 

TA1535, TA1537/spot and 

plate incorporation assays 

S. typhimurium TA98, TA100, 

TA1535, TA1537, TA1538/ 

suspension and plate 

incorporation assays 

S. typhimurium TA98, TA100, 

TA1535, TA1537, TA1538/ 

plate incorporation assay 

S. typhimurium TA1535/ 

pSK1002 (umuC-lacZ gene 

expression) 

Escherichia coli WP2uvrA/ 

plate incorporation assay 

E. coli WP2 (λ) (Ionii, sulA1, 

trpE65, uvrA155, IamB+), 

microscreen prophageinduction assay 

E. coli WP2, WP2uvrA, WP67, 

CM611, WP100, 

W3110polA+, p3478pola-/ 

DNA repair microsuspension 

assay 

Bacillus subtilis H17, 

M45/modified rec assay 

Eukaryotic organisms: 

Saccharomyces cerevisiae 

D4/suspension and plate 

incorporation assays 

Reverse – 

Mutation 

Reverse – 

Mutation 

Reverse – 

Mutation 

Reverse – 

Mutation 

Reverse – 

Mutation 

Reverse – 

Mutation 

Reverse – 

Mutation 

SOS induction – 

Mutation – 

Mutation – 

DNA damage – 

DNA damage – 

Mitotic gene – 

conversion 

– NTP 1986 Mixed 

xylene 

– Haworth et al. m-Xylene; 

1983 o-xylene; 

p-xylene 

– Connor et al. m-Xylene; 

1985 o-xylene; 

p-xylene 

– Bos et al. 1981 m-Xylene; 

o-xylene; 

p-xylene 

– Florin et al. 1980 m-Xylene; 

p-xylene 

– Litton Bionetics Mixed 

1978b xylene 

– Shimizu et al. p-Xylene 

1985 

– Nakamura et al. Mixed 

1987 xylene 

– Shimizu et al. p-Xylene 

1985 

– DeMarini et al. Mixed 

1991 xylene 

– McCarroll et al. Not reported 

1981b (technical 

grade) 

– McCarroll et al. Not reported 

1981a (technical 

grade) 

– Litton Bionetics Mixed 

1978b xylene 
XYLENE 

3. HEALTH EFFECTS 

120 

Table 3-5. Genotoxicity of Xylene In Vitro 

Species (test system) End point 

Results 

With 

activation 

Without 

activation Reference Isomer 

Mammalian cells: 

Cultured mouse lymphoma 

cells (L5178Y, TK+/-) 

Cultured human lymphocytes 

Cultured human lymphocytes 

Cultured human lymphocytes 

Cultured Chinese hamster 

ovary cells 

Cultured Syrian hamster 

embryo cells-Simian 

adenovirus SA7 

Forward – – 

mutation 

Sister chromatid Not tested – 

exchange and 

chromosomal 

aberrations 

Sister chromatid Not tested – 

exchange 

DNA-damage Not tested +T 

(comet assay) 

Sister chromatid – – 

exchange and 

chromosomal 

aberrations 

Enhanced viral – 

transformation 

Litton Bionetics Mixed 

1978b xylene 

Gerner-Smidt Not reported 

and Friedrich 

1978 

Richer et al. Mixed 

1993 xylene 

Morrozzi et al. Mixed 

1999 xylene 

Anderson et al. Mixed 

1990 xylene 

Casto 1981 Mixed 

xylene 

– = negative result; +T = damage associated with cytotoxcity (14% viability) 
XYLENE 121 

3. HEALTH EFFECTS 

fragmentation may occur if cells are exposed to levels that cause cytotoxicity, presumably related to the 

activity of nucleases within dying cells. 

Limited human data are available regarding the genotoxic effects of mixed xylene following inhalation 

exposure. No inhalation studies were located regarding the genotoxicity of m-, o-, or p-xylene in humans 

and animals. Results of studies by Pap and Varga (1987) and Richer et al. (1993) suggest that inhalation 

exposure of humans to mixed xylene is not associated with the induction of sister chromatid exchanges or 

chromosomal aberrations in peripheral lymphocytes. Results of other investigations were also negative 

for chromosomal aberrations in humans or rats exposed by inhalation to xylene; however, as the isomeric 

composition of the xylene in these studies was not reported (Haglund et al. 1980; Zhong et al. 1980), it is 

difficult to assess the contribution of the individual isomers of xylene. The rat study was limited by the 

lack of details regarding exposure concentrations and duration of exposure. 

No studies were located regarding genotoxic effects in humans after oral exposure to mixed xylene or 

xylene isomers. No chromosomal aberrations or change in the incidence of micronuclei were observed in 

reticulocytes isolated from mice receiving oral doses of xylenes as high as 1,000 mg/kg within a 24-hour 

period (Feldt 1986). 

No studies were located regarding genotoxic effects in humans after dermal exposure to mixed xylene or 

xylene isomers. A significant increase in lower molecular weight genomic DNA was detected in the skin 

of rats that received a dermal application of 250 μL (1,200 mg/kg) m-xylene for 1 hour (Rogers et al. 

2001). Electrophoretic patterns indicative of DNA fragmentation appeared 2 hours after exposure ended 

and coincided with the significant increase in oxidative species in skin cells. Although the level of 

oxidative species subsequently was reduced—the authors speculate as a result of endogenous antioxidant 

activity—lower molecular weight DNA levels remained significantly elevated at 4 and 6 hours after 

exposure. DNA fragmentation coincided with histopathological evidence of skin irritation, inflammation, 

and separation of the epidermis and dermis (Gunasekar et al. 2003). 

The absence of genotoxic effects following parenteral in vivo exposure to xylene has been reported in the 

bone marrow chromosomal aberration test with rats (Litton Bionetics 1978b), the bone marrow 

micronucleus test with mice (Mohtashamipur et al. 1985), and the sperm morphology test with rats 

(Washington et al. 1983). 
XYLENE 122 

3. HEALTH EFFECTS 

Mixed xylene, and the individual xylene isomers, have been tested for genotoxicity in a variety of shortterm in vitro assays. Results of standard mutagenicity assays indicate that mixed xylene and xylene 

isomers are not mutagenic in bacteria, yeast, or mammalian cells (Bos et al. 1981; Connor et al. 1985; 

DeMarini et al. 1991; Florin et al. 1980; Haworth et al. 1983; Litton Bionetics 1978b; McCarroll et al. 

1981a, 1981b; NTP 1986; Shimizu et al. 1985). Mixed xylenes did not induce umu gene expression, part 

of the SOS response to DNA damage, in Salmonella typhimurium TA1535/pSK1002 (Nakamura et al. 

1987). Mixed xylene did not induce chromosomal anomalies (chromosomal aberrations or sister 

chromatid exchanges) in cultured mammalian cells (Anderson et al. 1990; Gerner-Smidt and Friedrich 

1978; Richer et al. 1993). Increased DNA damage in human lymphocytes exposed to a single 

concentration of mixed xylene (5 μM) was associated with reduced cell viability (14% of controls) and 

likely caused by nuclease activity in the dying cells (Morozzi et al. 1999). Mixed xylenes did not enhance 

the adenovirus transformation of hamster embryo cells (Casto 1981). 

No mutagenic activity was demonstrated for any of the various metabolites of xylene in bacterial test 

systems. S. typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538, with and without S9 

metabolic activation, have been used to test the mutagenic activity of p-xylenol (Epler et al. 1979; Florin 

et al. 1980; Hejtmankova et al. 1979; Pool and Lin 1982), m-xylenol (Epler et al. 1979; Florin et al. 

1980), and o-methylbenzyl alcohol (Bos et al. 1981). 2,4-Dimethylphenol has been evaluated in a gene 

reversion assay with Escherichia coli strain Sd-4-73 (Szybalski 1958). 

In summary, genotoxicity studies on mixed xylene and the individual isomers of xylene have provided 

consistently negative results in a variety of in vitro and in vivo assays and test systems (bacteria, yeast, 

insects, cultured mammalian cells, mice, rats, and humans). Thus, there is sufficient evidence to conclude 

that mixed xylene, m-xylene, o-xylene, and p-xylene are nonmutagenic. Xylenes may cause DNA 

fragmentation at cytotoxic concentrations because of nucleases released from lysosomes in moribund 

cells. There is also limited evidence from bacterial test systems that suggests that xylene metabolites, 

specifically m-xylenol, p-xylenol, 2,4-dimethylphenol, and o-methylbenzyl alcohol, are also 

nonmutagenic. 

3.4 TOXICOKINETICS 

Studies in humans and animals have shown that xylenes are well absorbed by the inhalation and oral 

routes. Approximately 60% of inspired xylene is retained and approximately 90% of ingested xylene is 

absorbed. Absorption of xylene also occurs by the dermal route, but to a much lesser extent than by the 
XYLENE 123 

3. HEALTH EFFECTS 

inhalation and oral routes especially following exposure to xylene vapor. Following absorption, xylene is 

rapidly distributed throughout the body by way of the systemic circulation. In the blood, xylene is 

primarily bound to serum proteins. Xylene accumulates primarily in adipose tissue. All three isomers of 

xylene are primarily metabolized by oxidation of a methyl group and conjugation with glycine to yield the 

methylhippuric acid. In humans exposed to xylene, >90% of the absorbed xylene is excreted in the urine 

as the methylhippuric acid. Aromatic hydroxylation of xylene to xylenol occurs to only a limited extent 

in humans. Less than 2% of an absorbed dose is excreted in the urine as xylenol. Other minor 

metabolites found in urine include methylbenzyl alcohol and glucuronic acid conjugates of the oxidized 

xylene. Metabolism in animals is qualitatively similar, but glucuronide conjugates make up a larger 

proportion of the urinary excretion products (see Figures 3-3 and 3-4). In addition, methylbenzaldehyde 

(the product of the action of alcohol dehydrogenase on methylbenzyl alcohol) has been detected in 

animals, where it may exert toxic effects, but its presence has not been confirmed in humans. In humans, 

about 95% of the absorbed xylene is excreted in the urine, with about 5% excreted unchanged in the 

exhaled air. Elimination from most tissue compartments is rapid, with slower elimination from muscle 

and adipose tissue. 

3.4.1 Absorption 

3.4.1.1 Inhalation Exposure 

Xylenes are very soluble in blood and are therefore absorbed easily into the systemic circulation during 

inhalation exposure (Astrand 1982). Evidence for absorption of xylene by humans following inhalation 

exposure is provided by the observation that urine metabolites increase in proportion to exposure (Inoue 

et al. 1993; Jonai and Sato 1988; Kawai et al. 1991; Ogata et al. 1970; Riihimaki and Pfaffli 1978; 

Riihimaki et al. 1979b; Sedivec and Flek 1976b; Senczuk and Orlowski 1978; Wallen et al. 1985) and in 

proportion to increased ventilatory rates during exercise (Astrand 1982; Astrand et al. 1978; Bergert and 

Nestler 1991; Engstrom and Bjurstrom 1978; Riihimaki and Savolainen 1980; Riihimaki et al. 1979b). 

Absorption of the retained isomers appears to be similar, regardless of exposure duration or dose. The 

alveolar air concentrations of xylenes in male volunteers exposed at rest to 100 ppm mixed xylenes for 

70 minutes reached equilibrium within 10 minutes (Gamberale et al. 1978). 

Many authors have measured the retention of xylene in the lungs following inhalation exposure. It is this 

retained xylene that is available for absorption into the systemic circulation. In experimental studies with 

human subjects, retention of the various isomers was similar following inhalation of m-, o-, or p-xylene, 

and averaged 63.6% (Sedivec and Flek 1976b). Other authors have estimated that between 49.8 and 
XYLENE 124 

3. HEALTH EFFECTS 

72.8% of inhaled xylene is retained (David et al. 1979; Ogata et al. 1970; Riihimaki and Pfaffli 1978; 

Riihimaki and Savolainen 1980; Wallen et al. 1985). Pulmonary retention does not appear to differ on the 

basis of sex (Senczuk and Orlowski 1978). However, one study reported that uptake of m-xylene during a 

2-hour exposure at 200 mg/m3

 was slightly higher in women than in men (Ernstgard et al. 2003). The 

enhanced pulmonary ventilation and cardiac output associated with physical exertion can increase the 

amount of xylene retained and subsequently absorbed into the body (Astrand et al. 1978; Riihimaki et al. 

1979b). The study by Astrand et al. (1978) suggests that retention efficiency decreases as exposure 

duration increases. 

In pregnant mice, approximately 30% of an administered inhalation dose of 600 ppm p-xylene was 

absorbed following a 10-minute exposure period (Ghantous and Danielsson 1986). Absorption was not 

quantified in other animal studies, but absorption can be inferred from the observed effects on pulmonary 

microsomal enzymes and the appearance of methylhippuric acid in the urine following inhalation of 

xylene (Carlsson 1981; David et al. 1979; Elovaara 1982; Elovaara et al. 1987; Patel et al. 1978). 

3.4.1.2 Oral Exposure 

Limited information is available on the absorption of xylene in humans and animals following ingestion. 

Excretion of urinary metabolites indicated that absorption had occurred following oral doses of either 

40 or 80 mg/kg of o-xylene or m-xylene in humans (Ogata et al. 1979). Although absorption was not 

fully quantified, recovery of specific metabolites demonstrated that at least 34% of o-xylene and 53% of 

m-xylene had been absorbed from the administered doses of 40 mg/kg. 

Measurement of urinary metabolites in rats over 24 hours demonstrated almost complete absorption (87– 

92%) following oral gavage dosing with 1.8 g m-xylene, or 1.74 g o- or p-xylene (Bray et al. 1949). 

Experiments in which 0.15 mL of radiolabelled m-xylene (0.27 mg/kg) was administered by oral gavage 

in 5% aqueous gum acacia to male and female rats indicated that absorption was rapid (Turkall et al. 

1992); peak blood levels of radioactivity were observed within 20 minutes. The half-life of absorption of 

m-xylene was twice as fast in females than in males, although the total amount absorbed over 24 hours— 

the area under the curve (AUC) for plasma radioactivity—was the same in both sexes (about 0.2% of the 

initial dose/mL/hour). When m-xylene was first adsorbed to 0.5 g of a sandy soil before mixing with the 

vehicle and gavage administration, the absorption half-life was twice as long in female rats but unaffected 

in males (Turkall et al. 1992); adsorption to clay soil did not produce a biologically significant difference 
XYLENE 125 

3. HEALTH EFFECTS 

from m-xylene administered alone. Adsorption to sandy soil doubled the peak blood levels of 

radioactivity and increased the plasma AUC by 75% in female rats, but had no such effects in males. 

3.4.1.3 Dermal Exposure 

Results of experimental studies with humans indicate that m-xylene is absorbed following dermal 

exposure; however, the extent of penetration and absorption of m-xylene through skin is not nearly as 

great as that resulting from inhalation (Engstrom et al. 1977; Riihimaki 1979b; Riihimaki and Pfaffli 

1978). Dermal absorption may occur via exposure to m-xylene vapors, as well as through direct dermal 

contact with the solvent (Dutkiewicz and Tyras 1968; Engstrom et al. 1977; Kezic et al. 2000; Loizou et 

al. 1999; Riihimaki 1979b; Riihimaki and Pfaffli 1978). Absorption of m-xylene through the skin was 

measured at a maximal permeation rate, occurring between 15 and 25 minutes at a flux of 

46 nmol/cm2

/minute (Kezic et al. 2001). In humans, the estimated absorption rate following immersion 

of both hands in m-xylene for 15 minutes was approximately 2 μg/cm2

/minute (Engstrom et al. 1977). 

Another study measured a rate of absorption of 75–160 μg/cm2

/minute when xylene was applied to 

forearm skin (Dutkiewicz and Tyras 1968). Absorption of m-xylene vapor through the skin has been 

estimated at between 0.1 and 2% of the inhaled dose (Kezic et al. 2000; Loizou et al. 1999; Riihimaki and 

Pfaffli 1978). Dermal permeability constants averaging 0.25 cm/hour were calculated from exposure of 

subjects to 600 ppm m-xylene for 3.5 hours (McDougal et al. 1990; Riihimaki and Pfaffli 1978). In 

human subjects exposed to 6770 ppm m-xylene vapor on the hand and forearm the average flux through 

the skin was 0.091 mg/L/hour for a 20-minute exposure, falling to 0.061 mg/L/hour for a 180-minute 

exposure (Kezic et al. 2004). Simultaneously, the maximal flux into the blood was 0.034 mg/L/hour after 

20 minutes, rising to 0.063 mg/L/hour after a 180-minute exposure. Maximum permeation rates of 

m-xylene vapor were achieved within 90 minutes (Kezic et al. 2004). Dermal absorption of m-xylene 

following topical administration or exposure to vapor was 3 times greater in subjects with atopic 

dermatitis compared to normal subjects (Engstrom et al. 1977; Riihimaki and Pfaffli 1978). 

Limited information is available regarding the absorption of xylene following dermal exposure in 

animals. Permeability of rat skin to m-xylene was estimated from blood levels obtained during dermal 

exposure to liquid m-xylene (Morgan et al. 1991; Skowronski et al. 1990) or m-xylene vapors (McDougal 

et al. 1990). Peak blood levels of m-xylene were reached within 2 hours of topical application from 

sealed dermal enclosures in rats and slowly declined during the 24-hour observation period (Morgan et al. 

1991); an average of 562 mg (0.65 mL) was absorbed across a 3.1 cm2

 area of skin (1% of total surface 

area) from the initial volume of 2 mL over 24 hours. The total amount absorbed was reduced when 
XYLENE 126 

3. HEALTH EFFECTS 

m-xylene was administered in aqueous solution (Morgan et al. 1991). Dermal permeability constants 

calculated for rats exposed to 5,000 ppm m-xylene averaged 0.723 cm/hour, about 3 times greater than 

those calculated for humans (McDougal et al. 1990); the flux was calculated as 0.0151 mg/cm2

/hour. 

Skin:air partition values for a series of solvents including m-xylene correlated well with permeability 

constants (McDougal et al. 1990), but not with octanol-water partition coefficients. m-Xylene adsorbed 

on sandy soil or clay soils showed lower peak absorption than for m-xylene alone and clay soil 

significantly prolonged the absorption half-life, but the total amount absorbed over an unspecified period 

was unchanged (Abdel-Rahman et al. 1993; Skowronski et al. 1990). 

Dermal penetration rates of xylene have been estimated using excised skin of rats exposed to liquid or 

vapor. The absorption of o-xylene by excised abdominal skin from rats increased with the time of contact 

(Tsuruta 1982); the penetration rate was estimated to be 0.006 mg/cm2

/hour. The flux of o-xylene 

through the dorsal skin of hairless rats was measured as 0.22 mg/cm2

/hour (Ahaghotu et al. 2005). The 

skin:air partition coefficient for m-xylene was found to be 50.4±1.7 using rat skin in vitro exposed to 

203 ppm m-xylene vapor (Mattie et al. 1994); the concentration of m-xylene in the skin reached 

equilibrium in 2 hours. Dermal absorption studies using excised skin are not directly comparable to in 

vivo studies because of the lack of an intact blood supply, but diffusion through the skin appears to be the 

limiting factor rather than removal from the skin by the blood (McDougal et al. 1990). 

3.4.2 Distribution 

Results of experiments to derive tissue:air partition coefficients for xylene indicate that the isomers are 

expected to have similar distributions in the body (Table 3-6). Factors influencing the distribution of 

xylene in blood are discussed in Section 3.5.1. 

3.4.2.1 Inhalation Exposure 

In human subjects exposed by inhalation to ≤44 ppm deuterium-labeled xylene isomers for 2 hours, peak 

blood xylene concentrations were highest exactly at the end of exposure and then declined (Adams et al. 

2005). Absorbed xylene in venous blood was distributed in cells (12%) and serum (88%), with about 9% 

of the total amount in blood associated with protein-free serum (Riihimaki et al. 1979b). Following 

systemic circulation, xylene is distributed primarily to adipose tissue. Estimates of the amount of xylene 

accumulated in human adipose tissue range from 4 to 10% of the absorbed dose (Astrand 1982; Engstrom 

and Bjurstrom 1978; Riihimaki et al. 1979b). It has been suggested that following prolonged 
XYLENE 127 

3. HEALTH EFFECTS 

Table 3-6. Partition Coefficients for Xylenes 

Partition coefficienta 

Reference Species m-Xylene o-Xylene 

Blood:Air 

p-Xylene 

Gargas et al. 1989 Rat (male F-344) 46±1.5 44.3±2.0 41.3±3.5 

Kaneko et al. 1991a Rat (male Wistar) 39.9±7.18b NR NR 

Kumarathasan et al. Rat (male 40.3±1.4 NR 37.0±0.4 

1998 Sprague-Dawley) 

Thrall et al. 2002c Rat 37.8 

Sato and Nakajima Human 26.4±0.9b

 31.1±2.3b 37.6±3.5b 

1979 

Pierce et al. 1996 Human 31.9±0.45 35.2±0.45 39.0±0.70 

Thrall et al. 2002c Human 34.0 

Fat:Air 

Gargas et al. 1989 Rat (male F-344) 1,859±93 1,877±132 1,748±65 

Kaneko et al. 1991a 

Pierce et al. 1996 

Rat (male Wistar) 

Rat (male F-344) 

2,050±459b 

2,325±194 

NR 

2,930±260 

NR 

NR 

Kumarathasan et al. 

1998 

Rat (male 

Sprague-Dawley) 

1,970±34 NR 1,863±37 

Pierce et al. 1996 Human 1,919±53 2,460±63 

Liver:Air 

2,019±102 

Gargas et al. 1989 Rat (male F-344) 90.9±4.4 108±7 90.0±4.3 

Kaneko et al. 1991a 

Kumarathasan et al. 

1998 

Rat (male Wistar) 

Rat (male 

Sprague-Dawley) 

79.9±9.42b 

66.8±6.6 

NR 

NR 

Muscle:Air 

NR 

62.1±5.0 

Gargas et al. 1989 Rat (male F-344) 41.9±5.7 51.5±6.7 38.4±4.1 

Kaneko et al. 1991a 

Kumarathasan et al. 

1998 

Rat (male Wistar) 

Rat (male 

Sprague-Dawley) 

79.7±20.2b 

41.3±0.1 

NR 

NR 

Milk:Air 

NR 

43.21±3.4 

Fisher et al. 1997 Human 133±54.58 for o-, m-, p-xylenes 

a

Mean ± standard error unless otherwise noted 

b

Mean ± standard deviation 

c

As reported in Thrall and Woodcock 2003 

NR = not reported 
XYLENE 128 

3. HEALTH EFFECTS 

occupational exposure to xylene, significant amounts of the solvent could accumulate in adipose tissue 

(Astrand 1982; Engstrom and Bjurstrom 1978). 

Studies in mice (Bergman 1983; Ghantous and Danielsson 1986) and rats (Carlsson 1981; Ito et al. 2002) 

indicate that the distribution of m- or p-xylene and their metabolites is characterized by high uptake in 

lipid-rich tissues, such as brain and fat. High uptake also occurs in well-perfused organs, such as the liver 

and kidney. Using low-temperature (cryogenic) whole-body autoradiography of male mice exposed by 

inhalation to 14C-labeled m-xylene for 10 minutes, Bergman (1983) observed a high level of 

unmetabolized m-xylene (volatile radioactivity) in body fat, bone marrow, white matter of the brain, 

spinal cord, spinal nerves, liver, and kidney immediately after exposure. High levels of metabolites 

(nonvolatile radioactivity) were present in the blood, liver, lung, kidney, and adrenal medulla. 

Unmetabolized m-xylene persisted in the central nervous system and spinal nerves for up to 1 hour postexposure, whereas a considerable amount persisted in body fat at 4–8 hours after exposure. Metabolites 

were detectable post-exposure in the adrenal medulla for 0.5 hours, in the liver for 2 hours, in the kidney 

for up to 8 hours, in bile for 2–8 hours, in the intestinal lumen for up to 24 hours, and in the nasal mucosa 

and bronchi for 2–24 hours. No radioactivity was detectable by 48 hours. In male Sprague-Dawley rats 

exposed to 2,000 ppm m-xylene vapor 4 hours/day for 5 consecutive days, m-xylene concentrations were 

measured in tissues by gas chromatography (Ito et al. 2002). The highest concentrations of m-xylene 

were observed in peri-intestinal fat and subcutaneous fat, whereas concentrations more than 40 times 

lower were detected in lung, spleen, testis, heart, kidney, liver, and psoas muscle. In the brain subdivided 

into four parts, the concentration of m-xylene was 3–6 times lower than in subcutaneous fat. The uneven 

distribution of inhaled m-xylene in the brain was associated with changes in GABAA receptor binding 

(discussed in Section 3.5.2). 

According to an intermediate-duration animal study, the level of xylene stored in body fat may decrease 

as exposure continues due to an increase in metabolic rate possibly by inducing its own metabolism 

(Savolainen et al. 1979a). Levels of m-xylene in perirenal fat of rats exposed to 300 ppm technical xylene 

decreased from 67.6 to 36.6 μg/g tissue as exposure duration increased from 5 to 18 weeks (Savolainen et 

al. 1979a). 

p-Xylene and o-xylene have been shown to readily cross the placenta and were distributed in amniotic 

fluid and embryonic and fetal tissues (Ghantous and Danielsson 1986; Ungvary et al. 1980b). The level 

detected in fetal tissues (brain, liver, lung, and kidney), which are low in lipids, was only 2% of that 
XYLENE 129 

3. HEALTH EFFECTS 

detected in the maternal brain tissue, which contains large amounts of lipids (Ghantous and Danielsson 

1986). Also, higher levels were detected in fetal tissues than in amniotic fluid (Ungvary et al. 1980b). 

3.4.2.2 Oral Exposure 

No studies were located regarding distribution in humans following oral exposure to mixed xylene or 

xylene isomers. In rats administered m-xylene by gavage, fat contained the highest tissue concentration 

of radioactivity; approximately 0.3% of the administered dose was found per gram of fat in females and 

0.1% per gram of fat in males (Turkall et al. 1992). 

3.4.2.3 Dermal Exposure 

No studies were located regarding distribution of xylene in humans following dermal exposure to mixed 

xylene or individual isomers. Extremely limited information was located regarding distribution in 

animals following dermal absorption. After topical administration, m-xylene was rapidly detectable in 

plasma, reaching peak concentrations in about 2 hours (Skowronski et al. 1990). About 0.003% of the 

initial dose was detected per gram of subcutaneous fat 48 hours after exposure. 

3.4.3 Metabolism 

The biotransformation of xylene in humans proceeds primarily by the oxidation of a side-chain methyl 

group by microsomal enzymes (mixed function oxidases) in the liver to yield toluic acids (methylbenzoic 

acids). These toluic acids conjugate with glycine to form toluic acids (methylhippuric acids) that are 

excreted into the urine (Astrand et al. 1978; Norstrom et al. 1989; Ogata et al. 1970, 1979; Riihimaki et al. 

1979a; Sedivec and Flek 1976b; Senczuk and Orlowski 1978). This metabolic pathway accounts for 

almost all of the absorbed dose of xylene, regardless of the isomer, route of administration, administered 

dose, or duration of exposure. Minor metabolic pathways that account for <10% of the absorbed dose 

include the elimination of unchanged compound in the exhaled breath and in the urine, and the urinary 

elimination of methylbenzyl alcohols, o-toluylglucuronides (o-toluic acid glucuronide), xylene 

mercapturic acid (Norstrom et al. 1988), and xylenols (dimethylphenols). Dimethylphenylmercapturic 

acid (DPMA) was detected in only 9 out of 27 samples of exposed workers and occurred at a ratio of only 

0.0003% compared to the main metabolite, methylhippuric acid (Gonzalez-Reche et al. 2003). The 

metabolism of the various xylene isomers in humans is presented in Figure 3-3. 
3. HEALTH EFFECTS 

Figure 3-3. Metabolic Scheme for Xylenes—Humans 

free o-toluic acid? 

urine 

conjugates o-isomer (sulphoconjugate + o-toluylglucoronide) 

(trace - 1%) 

CH3 CH3 CH3 o-, m-, p- H4C6 H4C6 H4C6

CH isomers CONHCH2COOH 2OH COOH 

methylbenzylalcohols methylbenzoic acids methylhippuric acids (urine) (o-, m-, p- isomers) (o-, m-, p- toluic acids) (o-, m-, p- toluric acids) 

(ortho - 97.1% 

oxidation CH3-group meta - 72-99.2% 

para - 95.1%) 

urine (traces) 

unchanged 

exhalation 

urine (ortho - 0.0046% unchanged 

(ortho - 5.3% meta - 0.0047% 

C6H4(CH3)2 

meta xylenes - 4-5.8% para - 0.0026%) 

para - 3.5% 

mixture - 4.5%) 

aromatic 

hydroxylation urinary excretion as sulphates + etherglucuronides? 

HOC6H3(CH3)2 

xylenols 

(dimethylphenols) 

urinary excretion of 2,3-, 3,4-, 2,4-, and 2,5-xylenols,
 

respectively, from o-, m-, and p-xylene
 

(ortho - 0.86%
 

meta - 1.98%
 

para - 0.05%)
 

Sources: derived from Astrand et al. 1978; Ogata et al. 1980; Riihimaki et al. 1979a, 1979b; Sedivec and Flek 1976b; 

Senczuk and Orlowski 1978; Toftgard and Gustafsson 1980 

XYLENE 130 
XYLENE 131 

3. HEALTH EFFECTS 

 In physiologically based pharmacokinetic (PBPK) modeling of blood concentration data from male 

subjects exposed by inhalation to 0–44 ppm of deuterium-labeled xylene isomers for 2 hours, the rate of 

hepatic metabolism was held constant scaled to body weight (Adams et al. 2005). Simulations revealed 

that apparent systemic clearance of isomers sometimes exceeded that predicted by the hepatic blood flow 

parameter, suggesting that extrahepatic tissues could play a significant role in xylene metabolism in 

certain individuals. 

The metabolism of xylene in animals is qualitatively similar to that of humans, though quantitative 

differences do exist (Bakke and Scheline 1970; Bray et al. 1949; Ogata et al. 1979; Sugihara and Ogata 

1978; van Doorn et al. 1980). The metabolism of the various isomers in animals is presented in 

Figure 3-4. The major quantitative difference between animals and humans occurs in the metabolism of 

the metabolic intermediate methylbenzoic acid (toluic acid). In rats given m-, o-, or p-xylene by 

intraperitoneal injection, 10–56.6% of the administered dose of o-xylene was excreted in the urine as 

o-toluylglucuronide, whereas approximately 1% of the administered doses of m- and p-xylene was 

metabolized to the appropriate toluylglucuronide (Ogata et al. 1979; van Doorn et al. 1980). The amounts 

of m-methylhippuric acid and p-methylhippuric acid excreted in the urine accounted for 49–63 and 64– 

75% of the administered dose, respectively (Ogata et al. 1979; Sugihara and Ogata 1978). Similar results 

were seen in rats administered m-xylene by gavage (Turkall et al. 1992). In studies with rabbits, 60% of 

an administered o-xylene dose, 81% of an m-xylene dose, and 88% of a p-xylene dose were excreted in 

the urine as methylhippuric acids (Bray et al. 1949). Minor quantities of methylbenzyl alcohols and 

xylenols have also been detected in the urine of experimental animals administered xylene isomers 

(Bakke and Scheline 1970; Ogata et al. 1979; Turkall et al. 1992; van Doorn et al. 1980). In a study of 

metabolites formed by aromatic hydroxylation, rats administered 100 mg/kg doses of xylene isomers 

eliminated 0.1% of a dose of o-xylene in the urine as 3,4-xylenol and 0.03% as 2,3-xylenol, 0.9% of a 

dose of m-xylene as 2,4-xylenol, and 1% of a dose of p-xylene as 2,5-xylenol (Bakke and Scheline 1970); 

A trace of the methylbenzyl alcohol was also detected in the urine of rats given o- and m-xylene, but not 

in rats given p-xylene. In rats administered m-xylene by the dermal route, the major metabolite in the 

urine over a 24-hour period was identified as methylhippuric acid (82.3%), with xylenol comprising 7.2% 

and unchanged m-xylene comprising 3.8% of the urinary products (Skowronski et al. 1990). In rats given 

m-xylene adsorbed onto sandy soil, the proportion of xylenol present in the urine over the first 12 hours of 

excretion was significantly increased. 

Studies in animals have also shown that the metabolism of xylene may be influenced by prior exposures 

to xylene (Elovaara et al. 1989). Pretreatment of rats with m-xylene increased the percentage of 
3. HEALTH EFFECTS 

Figure 3-4. Metabolic Scheme for Xylenes—Animals 

o-, m-, pisomers 

free o-toluic acid? 

urine 

p-tolualdehyde 

conjugates CH3 (sulphoconjugate + o-toluylglucoronide) 

H4C6 (ortho - 10-56.6% 

CHO meta - 1.3% 

para - 0.6%) 

CH3 CH3 CH3 o-, m-, p- H4C6 H4C6 H4C6

CH isomers CONHCH2COOH 2OH COOH 

methylbenzylalcohols methylbenzoic acids methylhippuric acids (urine) (o-, m-, p- isomers) (o-, m-, p- toluic acids) (o-, m-, p- toluric acids) 

(ortho - 15.9-60% 

oxidation CH3-group meta - 49-80.2% 

para - 64-75%) 

urine (traces) 

unchanged 

exhalation unchanged C6H4(CH3)2 urine (ortho - 0.0046% 

(ortho - 5.3% meta - 0.0047% 

meta xylenes - 4-5.8% para - 0.0026%) 

para - 3.5% 

mixture - 4.5%) 

aromatic 

hydroxylation urinary excretion as sulphates + etherglucuronides? 

HOC6H3(CH3)2 

xylenols 

(dimethylphenols) 

urinary excretion of 2,3- and 3,4-, 2,4-, and 2,5-xylenols, 

respectively, from o-, m-, and p-xylene
 

(ortho - 0.13%
 

meta - 0.9%
 

para - 1.0%)
 

Sources: derived from Bakke and Scheline 1970; Bray et al. 1949; Ogata et al. 1980; Sugihara and Ogata 1978; 

Toftgard and Gustafsson 1980; van Doorn et al. 1980 

XYLENE 132 
XYLENE 133 

3. HEALTH EFFECTS 

methylhippuric acid and thioethers in the urine by approximately 10%. A toxic metabolite of xylene in 

rats and rabbits appears to be methylbenzaldehyde (tolualdehyde) (Carlone and Fouts 1974; Patel et al. 

1978; Smith et al. 1982). It is formed by the action of alcohol dehydrogenase on methylbenzyl alcohol in 

lung and liver tissues (Elovaara et al. 1987); the presence of methylbenzaldehyde has not been confirmed 

in humans. Lung tissue can be damaged by this intermediate because of its selective inactivation of 

enzymes involved in microsomal electron transport (mixed function oxidases, cytochrome P-450) 

(Elovaara et al. 1987). 

The differences in xylene metabolism observed between humans and animals may, in part, be explained 

by differences in the size of the doses given to humans and animals in experimental studies (David et 

al. 1979; Ogata et al. 1979; van Doorn et al. 1980). The formation of glucuronic acid derivatives may be 

an emergency mechanism that is activated when the organism can no longer conjugate all acids with 

glycine (Ogata et al. 1979; Sedivec and Flek 1976b; van Doorn et al. 1980). Humans dosed with 

19 mg/kg xylene excreted only methylhippuric acids in the urine, whereas rabbits exposed to 600 mg/kg 

excreted both methylhippuric acids and derivatives of glucuronic acid (Sedivec and Flek 1976b). The 

second-phase conjugation of the main oxidized intermediate (methylbenzoic acid with glycine to form 

methylhippuric acid) may be the rate-limiting step in humans. The maximum rate of glycine mobilization 

limits the rate of conjugation to a level below 200 μmol/minute (Riihimaki et al. 1979a, 1979b). If this 

limit is approached, other elimination pathways may be activated, such as conjugation with glucuronic 

acid or aromatic hydroxylation to form xylenols. The capacity of the first-phase oxidation reaction, 

encompassing both side-chain and aromatic oxidation, is not known. Aromatic oxidation of xylene could 

possibly produce toxic intermediates and phenolic end-metabolites (Riihimaki et al. 1979b); however, this 

is a minor metabolic pathway. 

Using a low-temperature (cryogenic), whole-body autoradiography technique for mice exposed by 

inhalation to radiolabeled m-xylene for 10 minutes, Bergman (1983) observed high levels of metabolites 

(non-volatile radioactivity) in the blood, liver, lung, kidney, and adrenal medulla immediately after 

exposure. Metabolites were detectable post-exposure in the adrenal medulla for 0.5 hours, in the liver for 

2 hours, in the kidney for up to 8 hours, in bile for 2–8 hours, in the intestinal lumen for up to 24 hours, 

and in the nasal mucosa and bronchi for 2–24 hours. No radioactivity was detectable 48 hours after 

exposure, indicating that there was no significant binding of xylene metabolites to tissue macromolecules. 
XYLENE 134 

3. HEALTH EFFECTS 

3.4.4 Elimination and Excretion 

3.4.4.1 Inhalation Exposure 

In humans, about 95% of absorbed xylene is biotransformed and excreted as urinary metabolites, almost 

exclusively as methylhippuric acids; the remaining 5% is eliminated unchanged in the exhaled breath 

(Astrand et al. 1978; Ogata et al. 1979; Pellizzari et al. 1992; Riihimaki et al. 1979b; Sedivec and Flek 

1976b; Senczuk and Orlowski 1978). Less than 0.005% of the absorbed dose of xylene isomers is 

eliminated unchanged in the urine, and <2% is eliminated as xylenols (Sedivec and Flek 1976b). The 

excretion of methylhippuric acids is rapid and a significant amount is detected in the urine within 2 hours 

of exposure. The amount of methylhippuric acid increases with time. Differences in the amount of the 

metabolites excreted depend on the interpersonal differences in lung ventilation and retention, not on the 

isomer of xylene (Sedivec and Flek 1976b). 

There appear to be at least two distinct phases of elimination, a relatively rapid one (half-life, 1 hour) and 

a slower one (half-life, 20 hours). These phases of elimination are consistent with the distribution of 

xylene into three main tissue compartments; the rapid and slower elimination phases correspond to 

elimination from the muscles and the adipose tissue, respectively, whereas the elimination of xylene from 

the parenchymal organs is so rapid that the available studies could not monitor it (Ogata et al. 1970; 

Riihimaki et al. 1979a, 1979b). It is also possible that the renal excretion of the most common xylene 

metabolite, methylhippuric acid, takes place via the tubular active secretion mechanism of organic acids. 

Renal excretion is not a rate-limiting step in the elimination of absorbed xylene under normal 

physiological conditions (Riihimaki et al. 1979b). Physiologically based pharmacokinetic modeling 

suggests that the urinary excretion of m-methylhippuric acid following m-xylene exposure of humans is 

linear at concentrations up to 500 ppm, and that elimination of m-methylhippuric acid is slower in 

individuals with a greater percentage of body fat (e.g., women) (Kaneko et al. 1991a, 1991b). Systemic 

clearance rates in male subjects following inhalation of ≤44 ppm deuterium-labeled xylene isomers for 

2 hours ranged between 116 and 129 L/hour (Adams et al. 2005). The terminal half-life averaged 

34 hours for all three isomers among all subjects, but varied widely among individuals from 12 to 

108 hours. 

Volunteers acutely exposed by inhalation to 100 or 200 ppm m-xylene for 7 hours excreted 54 and 61%, 

respectively, of the administered dose by 18 hours after exposure ended (Ogata et al. 1970). Following 

intermittent acute exposure of men and women to 23, 69, or 138 ppm m-xylene, excretion of 

m-methylhippuric acid peaked 6–8 hours after exposure began. It decreased rapidly, regardless of 
XYLENE 135 

3. HEALTH EFFECTS 

exposure level or sex, after exposure had ended. Almost no xylene or m-methylhippuric was detected 

24 hours later (Senczuk and Orlowski 1978). Following exposure to 200 mg/m3 

m-xylene for 2 hours, 

small differences in elimination were noted between genders (Ernstgard et al. 2003). Women excreted 

31% more (AUC) unmetabolized m-xylene in exhaled air than men, whereas men excreted 37% more 

(AUC) m-methylhippuric acid in urine than women. 

Exercise increased the amount of xylene absorbed and thus increased the amount of m-methylhippuric 

acid and 2,4-xylenol eliminated in the urine of men exposed to m-xylene (Riihimaki et al. 1979b). No 

evidence of saturation of metabolism of xylene was observed at exposures as high as 200 ppm (Riihimaki 

et al. 1979b). The excretion of m-methylhippuric acid appeared to correspond very closely to the 

estimated xylene uptake and expired xylene represented about 4–5% of the absorbed xylene in all 

exposure groups (Riihimaki et al. 1979b). Urinary excretion of methylhippuric acid correlated well with 

exposure (Kawai et al. 1992; Lapare et al. 1993; Skender et al. 1993), and based on a study of workers 

occupationally exposed to mixed xylenes (geometric mean TWA 14 ppm), Inoue et al. (1993) estimated a 

slope of 13 mg methylhippuric acid/L/ppm (11.1 mg/g creatinine/ppm) for all three isomers. A sexrelated difference in the urinary excretion of methylhippuric acids was not observed (Inoue et al. 1993). 

A few studies have evaluated the kinetics of elimination of the metabolites of xylene following inhalation 

exposure of experimental animals. The primary urinary metabolite is methylhippuric acid (David et al. 

1979). A dose-relationship in the urinary elimination of m-methylhippuric acid in rats was observed 

immediately after exposure to 50 or 500 ppm m-xylene for 6 hours (Kaneko et al. 2000). Another study 

found the increase of urinary elimination of methylhippuric acid metabolites to be linear in rats exposed 

for 5 hours to mixed xylene between 75 and 150 ppm, but non-linear between exposures at 150 and 

225 ppm (Tardif et al. 1992). Concomitantly, there were non-linear increases in the amount of xylene 

excreted unchanged in exhaled air, indicating possible saturation of metabolism at 225 ppm. 

Using a low-temperature (cryogenic), whole-body autoradiography technique for mice exposed by 

inhalation to radiolabeled m-xylene for 10 minutes, Bergman (1983) observed elimination of metabolites 

(non-volatile radioactivity) in bile and feces. Clearance of metabolites was completed in the adrenal 

medulla by 0.5 hours, in the liver after a little over 2 hours, in the kidney after 8 hours, in bile after 

8 hours, in the intestinal lumen after 24 hours, and in the nasal mucosa and bronchi after 24 hours. No 

radioactivity was detectable 48 hours after exposure. 
XYLENE 136 

3. HEALTH EFFECTS 

3.4.4.2 Oral Exposure 

Limited information is available on the elimination of the metabolites of xylene following ingestion in 

humans. In an unspecified number of male volunteers given oral doses of 40 mg/kg/day of o-xylene or 

m-xylene, the molar (mol) excretion ratios (total excretion [mol] in urine during appropriate interval/dose 

administered [mol] x 100[%]) for o-methylhippuric acid and m-methylhippuric acid were 33.1 and 53.1, 

respectively (Ogata et al. 1979). More of the m-xylene is eliminated as methylhippuric acid than the 

ortho derivative for o-xylene. The molar excretion ratio for o-toluic acid glucuronide (o-toluylglucuronide) was 1.0 in men given o-xylene as an oral dose of 40 mg/kg/day. The amounts of 

o-methylhippuric acid (o-toluic acid) and of o-toluic acid glucuronide excreted in the urine attained 

maximal levels in 3–6 hours of exposure, while that of m-methylhippuric acid attained peak levels in 1– 

3 hours (Ogata et al. 1979). These results indicate that the major elimination pathway of o-xylene is the 

formation of o-methylhippuric acid in humans. The formation of o-toluic acid glucuronide is a minor 

pathway for the elimination of o-toluic acid, but would be available in the event of saturation of the major 

pathway. 

Excretion of radioactivity by rats following an oral dose of m-xylene showed most excretion occurred in 

the urine during the first 12 hours after dosing (50–59% of the dose), with a total of 96.2% eliminated in 

urine in males and 73.7% in urine in females over 48 hours (Turkall et al. 1992). Approximately 8 and 

22% of the total dose was excreted in exhaled air by males and females, respectively, during the first 

12 hours. m-Methylhippuric acid comprised 67–75% of the urinary radioactivity, with xylenol 

comprising 2–18%, and unchanged xylene comprising approximately 1%. When m-xylene adsorbed onto 

sandy soil matrix was administered, the excretion of radioactivity in urine and exhaled air in female rats 

was significantly decreased compared to m-xylene during the first 12 hours (Turkall et al. 1992). In 

males given xylene in a sandy or clay soil matrix, the excretion of radioactivity was increased in exhaled 

air during the first 12 hours. In a study of aromatic hydroxylation products of xylene metabolism, rats 

administered 100 mg/kg doses of xylene isomers eliminated 1% or less of the administered dose as 

xylenols in the urine, along with trace amounts of methylbenzyl alcohols for o- and m-xylene only (Bakke 

and Scheline 1970). 

3.4.4.3 Dermal Exposure 

The elimination of m-xylene has been studied in human subjects exposed dermally either to liquid or to 

vapor. The elimination of liquid m-xylene absorbed dermally in humans following a 15-minute exposure 

was through the exhaled breath and urine (Engstrom et al. 1977; Riihimaki and Pfaffli 1978). Elimination 
XYLENE 137 

3. HEALTH EFFECTS 

in the exhaled breath followed a two-phase elimination curve with a rapid half-life of 1 hour and a longer 

half-life of 10 hours. In human subjects who immersed both hands in m-xylene for 15 minutes, the rate of 

excretion of m-methylhippuric acid was approximately 50 μmol/hour at 2 hours and 2 μmol/hour 3 hours 

later (Riihimaki 1979b). In male subjects whose hand and forearm were exposed dermally to 6,770 ppm 

m-xylene vapor for up to 3 hours, elimination of xylene in the exhaled breath was detected within 

10 minutes and continued up to several hours after the exposure ended (Kezic et al. 2004). 

In rats receiving a dermal application of 15 mg of radiolabeled m-xylene per cm2

, elimination over 

48 hours was primarily in unmetabolized expired air (61.9% of the initial dose), with 42.7% excreted as 

metabolites in the urine and 0.1% in feces (Skowronski et al. 1990). The majority of the excretion in 

expired air occurred within the first 12 hours, with excretion in the urine occurring primarily during the 

first 24 hours; fecal excretion was detected the second day. If m-xylene was applied to the skin in the 

form of a sandy soil matrix, the excretion was similar to that seen with m-xylene alone, but if the 

m-xylene was applied adsorbed onto clay soil matrix, approximately equal amounts were excreted in 

exhaled air and in the urine (46 and 53%, respectively). 

3.4.4.4 Other Routes of Exposure 

Limited information was available on the elimination of xylene metabolites in rats following 

intraperitoneal injection (Ogata et al. 1979; Sugihara and Ogata 1978; van Doorn et al. 1980). The 

urinary metabolites of xylene are similar regardless of route of exposure; however, the amounts of the 

various metabolites differ. The elimination profile of xylene isomers is related more to absorption than it 

is with dose or duration of exposure. In rats, 49–62.6% of various doses of m-xylene or 64–75% of 

various doses of p-xylene were excreted in the urine as m-methylhippuric acid or p-methylhippuric acid, 

respectively (Sugihara and Ogata 1978). Urinary excretion of o-toluic acid glucuronide and 

o-methylhippuric acid accounted for 57 and 16%, respectively, of single intraperitoneal dose of 1,240 mg 

o-xylene/kg give to rats (Ogata et al. 1979). The amount of o-toluic acid glucuronide and 

o-methylhippuric acid excreted reached a maximum 8–24 hours after dosing. Mercapturic acid 

derivatives were present in the urine of rats following an intraperitoneal dose of m-, o-, or p-xylene 

(Tanaka et al. 1990; van Doorn et al. 1980). The percentages ranged from 0.6% (p-xylene) to 10–29% 

(o-xylene). 
XYLENE 138 

3. HEALTH EFFECTS 

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. 

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 
XYLENE 139 

3. HEALTH EFFECTS 

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 3-5 shows a conceptualized representation of a PBPK model. 

If PBPK models for xylene 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. 

Kaneko et al. (1991a) Inhalation Exposure Model 

Kaneko et al. (1991a) developed a PBPK model for inhalation of m-xylene by rats and humans, based on 

the trichloroethylene model of Endoh et al. (1989). The model simulates concentrations of m-xylene in 

seven modeled tissue compartments and the amount of metabolites formed (Figure 3-6 and Table 3-7). 

Description of the Model. The model consists of compartments for lung (lung arterial blood and 

one-third of the tidal volume), liver, fat (adipose tissues and yellow bone marrow), slowly-perfused 

tissues (red bone marrow), richly-perfused tissues (brain, heart, kidneys and glandular tissues), muscle 

(muscle and skin), and gastrointestinal tract (portal system excluding the liver), plus an arteriovenous 

shunt. Model parameters included tissue volumes and blood flows, calculated for each compartment 

based on values by Davis and Mapleson (1981), and several values that were determined experimentally 

for adult male Wistar rats: partition coefficients, metabolic constants (Vmax and Km), and the rate constant 

for urinary excretion of m-methyl hippuric acid. The concentration flowing out of a given compartment 

(in venous blood) was set as equilibrated with the concentration in that compartment. All metabolism of 

m-xylene was assumed to occur in the liver and was expressed as a Michaelis-Menten process. The 

metabolism of m-xylene considered only the main pathway, (i.e., the conversion to m-toluic acid, which is 

conjugated to glycine and excreted in the urine as m-methylhippuric acid); the pathway from m-xylene to 

coefficients for rat blood, lung, brain, heart, kidney, testis, intestine, spleen, liver, fat, and muscle were 

determined by vial equilibration, and tissue/blood values were calculated by dividing the tissue/air 
3. HEALTH EFFECTS 

Figure 3-5. Conceptual Representation of a Physiologically Based 

Pharmacokinetic (PBPK) Model for a 

Hypothetical Chemical Substance 

Inhaled chem ic al E x haled chem ic al 

Lungs 

Liver 

F a t 

S lo w ly 

perfu sed 

tissues 

R ic h ly 

perfu sed 

tissues 

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 

Ingestion 

GI 

T ra c t 

F e c e s 

U rin e

 C hem ic als 

contacting skin 

XYLENE 140 

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 
3. HEALTH EFFECTS 

Figure 3-6. PBPK Model for Inhaled m-Xylene 

Inhaled Air Exhaled Air Lung 

Richly Perfused 

Tissues 

Poorly Perfused 

Tissues 

Muscle 

Fat 

Shunt 

Gastrointestinal 

Liver 

m-Toluic Acid 

m-Methylhippuric 

Acid 

m-Methylhippuric 

Acid in Urine 

XYLENE 141 

Source: adapted from Kaneko et al. (1991a) 
XYLENE 142 

3. HEALTH EFFECTS 

Table 3-7. Human Parameters Used in the PBPK Inhalation Model for m-Xylene 

Tissue volume (percent body weight) 

Lung 

 Richly perfused 

 Slowly perfused 

Muscle 

Fat 

 Gastrointestinal tract 

Liver 

Cardiac output (L/minute) 

Blood flow (percent cardiac output) 

Lung 

 Richly perfused 

 Slowly perfused 

Muscle 

Fat 

 Gastrointestinal tract 

Liver 

Shunt 

Air flow 

Alveolar ventilation (L/hour)b

Partition coefficients 

 Lung:blood 

 Richly perfused:blood 

 Slowly perfused:blood 

 Muscle:blood 

Fat:blood 

 Gastrointestinal tract:blood 

 Liver:blood 

Blood:air 

Metabolic constants 

Vmax 

c

 (mmol/minute) 

Km 

d

 (mmol/L) 

Kex 

d

 (per minute) 

calculateda

3 

8.5 

41.5 

21.1 

1.9 

2.3 

0.296 (bw)0.7 

100 

37.9 

6.3 

11.4 

5.3 

17.1 

6.9 

15.1 

 0.296 (bw)0.7 

4.09 

4.42 

2.01 

3.01 

77.8 

4.67 

3.02 

26.4 

Vmax1 = 1.394x10-3(bw)0.7 Vmax2 = 1.115x10-2(bw)0.7 

Km1 = 0.033 Km2 = 0.330 

0.012 

Source: Adapted from Kaneko et al. (1991a) 

a

Lung volume = functional residual capacity + one third tidal volume + (volume arterial blood x blood:air partition 

coefficient + volume of lung tissue x lung:air partition coefficient. b

Set equal to cardiac output. 

c

Rat Vmax and Km were determined experimentally for two different exposure concentrations. Rat Vmax1
 

(0.6 x 10-3 mmol/minute) and Vmax2 (4.8 x 10-3 mmol/minute) values were corrected for body surface area (body 

weight)0.7. d

Set equal to experimentally determined rat value. 

bw = body weight 
XYLENE 143 

3. HEALTH EFFECTS 

coefficient by the blood/air coefficient. The richly perfused coefficient was set equal to that of the liver. 

Human coefficients were calculated as the rat tissue/air partition coefficients divided by the human 

blood/air coefficient reported by Sato and Nakajima (1979). Metabolic rate constants were 

experimentally determined for high and low concentrations. For the human model, cardiac output and 

metabolic rate constants were estimated from rat values using a (body weight)0.70 scalar, but the rat Km 

was used directly. Simulations were performed for a 70-kg man inhaling 100 ppm m-xylene for 6 hours 

as reported by Riihimaki et al. (1979b). The blood concentration was set equivalent to the concentration 

flowing out of the richly-perfused compartment. 

Validation of the Model. The model parameters were optimized against the human data of Riihimaki 

et al. (1979b). Comparisons of model simulations against data from studies other than those used in 

model development were not presented. 

Additional Predictions. Kaneko et al. (1991b) used the model to evaluate the relationship of external 

and internal doses of m-xylene and determine the effects of body weight, body fat content, sex, and 

physical activity on blood concentrations and urinary excretion of metabolite. Several different exposure 

scenarios were simulated: continuous exposure of a 70-kg male to 50 ppm for 8 hours, intermittent 

exposure of a 70-kg male to 100 ppm for 1 hour 4 times at 1-hour intervals, continuous exposure of a 

70-kg male for 8 hours to various concentrations between 0 and 4,000 ppm. In the simulation, larger 

bodies absorbed more m-xylene, and excreted more metabolite, but there was no significant change in 

blood concentration. Increased physical activity increased both the blood concentration of m-xylene and 

the rate of urinary excretion of metabolite. The concentration of m-xylene in the blood during exposure 

was lower in women than in men, but was higher in women 10 hours after exposure. The rate of urinary 

excretion of metabolite was lower in women both during and after exposure. 

Adams et al. (2005) Inhalation Exposure Model 

Adams et al. (2005) developed a PBPK model for inhalation of deuterium-labeled xylene isomers in 

humans, using biomonitoring data (isomer levels in blood and exhaled air) to quantify the kinetics of each 

isomer in adult Caucasian men. The model simulates concentrations in six modeled tissue compartments 

and assumes systematic clearance of xylenes by metabolism primarily in the liver, but also in the lung. 

Description of the Model. The model consists of compartments for lung blood, adipose tissue, 

slowly perfused tissue, rapidly perfused tissue, and liver. The model used subject-specific values for 
XYLENE 144 

3. HEALTH EFFECTS 

body weight, adipose tissue fraction, and exposure concentration. Cardiac output and all blood flows 

were scaled to (body weight)0.74 . Published values were used for fractional tissue compartment volumes, 

fractional blood flows, tissue/blood partition coefficients, and hepatic metabolic constants. Alveolar 

ventilation, blood flows, and blood/air partition coefficients were assigned as Bayesian parameters to be 

optimized during model fitting. As xylene was assumed to diffuse rapidly into tissues, the transfer of 

xylene from arterial blood to tissues was assumed to be flow-limited. Changes in the amount of xylenes 

in nonmetabolizing tissues, in the metabolizing hepatic compartment, and the mass balance of xylene in 

the lung (including a metabolic component varying from 0 to 25% of hepatic metabolism) were defined 

by a series of simultaneous differential equations. Extrahepatic metabolism was indicated when the 

apparent systematic clearance of xylenes exceeded hepatic blood flow. 

Validation of the Model. The model parameters were optimized against human data collected by the 

investigators (Adams et al. 2005). Twenty-seven male Caucasian volunteers were exposed at rest to 

atmospheres containing 0–40 ppm each of 2

H10-meta-, 2H10-ortho-, and 2H10-para-xylene for 2 hours 

through a gated mouthpiece. Eight subjects experienced replicate exposures (at a minimal 2-week 

interval), bringing the total number of exposures to 37. Inhaled and exhaled breath concentrations of 

deuterium-labeled isomers were measured continuously during exposure. Doses were estimated for all 

subjects as the product of exposure concentration, exposure duration, and model-fitted subject-specific 

alveolar ventilation rates. Blood concentrations of isomers were measured in 1 venous blood sample 

collected before exposure and in 15–20 samples collected at the end of exposure for 4 days; collection 

frequency was every 15 minutes for the first several hours to every 12 hours after day 1. Model-fitted 

values for systemic clearance, terminal half-lives, and blood:air partition coefficients were similar to 

values reported by other investigators (Pierce et al. 1996; Sato 1988; Wallen et al. 1985). Subjects 

exposed during multiple sessions showed significant intra-individual variability in respiratory and blood 

physiology parameters as well as metabolism rates. The study authors suggested that differences in diet, 

alcohol consumption, and stress could affect variation in these parameters. 

Thrall and Woodstock (2003) Dermal Exposure Model 

Thrall and Woodstock (2003) adapted a PBPK model for binary inhalation exposures to toluene and 

m-xylene by Tardif et al. (1993a) to construct a PBPK model for dermal exposures to o-xylene in rats and 

humans (Table 3-8 and Figure 3-7). 
XYLENE 145 

3. HEALTH EFFECTS 

Table 3-8. Rat and Human Parameters Used in the PBPK Dermal Model for 

o-Xylene 

Rat Human 

Body weight (kg) 0.2–0.25 83.9, 48.5, 80.7 

Tissue volume (percent body weight) 

Liver 4 4 

Fat 8 30.7, 22.3, 26.4 

 Richly perfused 5 5 

 Slowly perfused 64 Variable 

 Total skin 10 10 

Cardiac output (L/hour) 5.4 348 

Blood flow (percent cardiac output) 

Liver 25 25 

Fat 5 6 

 Richly perfused 51 49 

 Slowly perfused 15 15 

 Total skin 5 5 

Air flow 

Alveolar ventilation (L/hour) 5.4 348 

Partition coefficients 

Saline:air 2.6 2.6 

Blood:air 37.8 34.0 

 Liver:blood 3.4 3.8 

Fat:blood 55.7 61.9 

 Muscle:blood 2.0 2.2 

Skin:air 65.4 65.4 

Metabolic constants 

Vmax (mg/kg/hour) 8.4 8.4 

Km (mg/L) 0.2 0.2 

Source: Adapted from Thrall and Woodstock (2003) 
3. HEALTH EFFECTS 

Figure 3-7. PBPK Model to Describe Dermal Absorption of o-Xylene 

Lung Blood 

Inhaled Air Alveolar Air Exhaled Air 

Richly Perfused Tissues 

Slowly Perfused Tissues 

Skin 

Fat 

Liver 

Dermal Exposure 

Metabolites 

XYLENE 146 

Source: adapted from Thrall and Woodstock (2003) 
XYLENE 147 

3. HEALTH EFFECTS 

Description of the Model. The model consists of compartments for lung, blood, richly perfused 

tissues, slowly perfused tissues, skin, fat, and liver. The skin compartment represents exposed skin, 

whereas nonexposed skin is incorporated into the slowly perfused compartment. Total skin volume (10% 

of body weight) was assumed to receive 5% of the total cardiac output. The volume and blood flow for 

exposed skin were calculated according to the methods of Jepson and McDougal (1997). Model 

parameters were as presented in Table 3-8. Metabolism was assumed to occur in the liver. Dermal 

exposure was simulated by relating the rate of change in the concentration of xylene in the skin 

compartment to the rate of penetration through the skin (the flux) and the rate of delivery because of 

blood flow and the arterial concentration (the perfusion) (Thrall et al. 2000). The model also considered 

the amount of xylene lost through evaporation from nonoccluded skin. The kinetics of dermal absorption 

was determined empirically in experiments in rats and humans based on the appearance of xylene in 

exhaled air. A total of 400 μg of o-xylene in aqueous solution (0.02%) was applied to the skin of rats 

under an occlusive covering for 4 hours. Human subjects submerged their lower legs into a hydrotherapy 

tub containing 500 μg/L o-xylene (a concentration 400 times lower than for rats) for 10–30 minutes and 

were monitored unexposed for an additional 30 minutes. An algorithm was used to vary the skin 

permeability coefficient to achieve an optimal fit to the time course data for each subject and then 

averaged. The calculated skin permeability rate constants of 0.058±0.009 cm/hour for rat and 

0.005±0.001 cm/hour for human adequately described the respective individual dermal exposure data 

sets. Both species rapidly absorbed aqueous xylene through the skin as shown by the chemical’s 

appearance in exhaled air within a few seconds of exposure. 

Validation of the Model. The dermal PBPK model was used to simulate the exhaled breath data 

from experiments in humans dermally exposed for 3 minutes to undiluted m-xylene (Kezic et al. 2001). 

The calculated skin permeability coefficient was identical to the average value of 0.005 cm/hour derived 

by Thrall and Woodstock (2003). Simulation of blood concentration data from F344 rats dermally 

exposed to saturated m-xylene for 24 hours (Morgan et al. 1991) resulted in a calculated skin permeability 

coefficient of 0.0727 cm/hour, which was in the range of values determined by Thrall and Woodstock 

(2003). 

Fisher et al. (1997) Lactational Model for Inhalation Exposure 

Fisher et al. (1997) adapted the PBPK model of Ramsey and Andersen (1984) to create a lactational 

model for maternal occupational exposure to volatile organic solvents, including o-, m-, and p-xylenes 

(Table 3-9 and Figure 3-8). 
XYLENE 148 

3. HEALTH EFFECTS 

Table 3-9. Human Parameters Used in the PBPK Lactational Model for 

o-, m-, p-Xylene 

Human 

Body weight (kg) 60 

Tissue volume (percent body weight) 

Liver 1.5 

Fat 25 

 Richly perfused 10 

 Slowly perfused 54 

 Milk (mL) 10–125 

Cardiac output (L/hour) 15 x body weight0.74 

Blood flow (percent cardiac output) 

Liver 29 

Fat 10 

 Richly perfused 35 

 Slowly perfused 19 

Milk 7 

Air flow 

Alveolar ventilation (L/hour) 24 x body weight0.74 

Milk compartment 

Rate of ingestion of breast milk by nursing infant (per hour) 20 

Rate of breast milk production at 1.5–3.0 months lactation (L/hour) 0.06 

Partition coefficients 

 Liver:blood 2.14 

Fat:blood 41.28 

Milk:blood 2.98 

 Richly perfused:blood 2.14 

 Slowly perfused:blood 0.97 

Metabolic constants 

Vmax 

a

 Not reported 

Km

a

 Not reported 

Source: Adapted from Fisher et al. (1997) 
3. HEALTH EFFECTS 

Figure 3-8. PBPK Model for Lactational Exposure to Volatile Organic Compounds 

(Including o-, m-, p-Xylenes) Following Maternal Occupational Inhalation 

Exposure 

Inhaled Air 

Lung 

Exhaled Air 

Richly Perfused Tissues 

Slowly Perfused Tissues 

Fat 

Liver 

Milk 

Nursing 

VMAX KM 

XYLENE 149 

Infant Chemical Exposure 

Source: adapted from Fisher et al. (1997) 
XYLENE 150 

3. HEALTH EFFECTS 

Description of the Model. In addition to the standard compartments for lung, richly- and slowlyperfused tissues, fat, and lung (the site of metabolism), the model contained a milk compartment. Milk 

production was described as a zero-order process at 0.06 L/hour. Milk letdown from nursing (infant 

nursing rate) was described as a first order process (20/hour). The milk volume in mammary tissue was 

0.125 L before nursing and 0.010 L at the end of nursing. The equation describing the rate of change in 

the amount of chemical ingested by the nursing infant included terms for the chemical concentration in 

milk, the amount of milk in the mammary tissue lumen, the infant nursing rate, and a switch to turn on or 

off nursing over 24 hours. Integration of this equation provided the cumulative amount of chemical 

ingested by a nursing infant in 24 hours. Partition coefficients for blood:air and milk:air were 

experimentally derived to calculate the milk:blood partition coefficient (Table 3-9). The human 

tissue:blood coefficient for xylenes was calculated by dividing the rat tissue:air coefficients of Gargas et 

al. (1989) by the human blood:air coefficient. The published paper did not report the constants (Vmax and 

Km) used to describe the rate of metabolism of xylenes in humans, so it appears that the authors may have 

assumed zero metabolism for xylenes. 

The lactational model was used to simulate lactational transfer of xylenes following maternal exposure for 

8 hours at the threshold limit value (TLV) of 100 ppm. The model predicted that approximately 1–2% of 

inhaled xylenes would be transferred to milk and that the daily intake for a 10 kg infant would be 

6.59 mg. 

Interaction Models 

In addition to those described above, a number of PBPK models have been developed for exposures to 

xylene in the presence of other chemicals. Tardif et al. (1993a, 1995) first developed a PBPK model for 

inhalation exposures to binary mixtures of m-xylene and toluene in the rat and later adapted the model for 

humans. The models based on parameters for m-xylene were found to adequately simulate the kinetics of 

mixed xylenes as well. A later model was developed for inhalation of a ternary mixture of alkyl benzenes 

(m-xylene, toluene, and ethylbenzene) in rats and humans (Tardif et al. 1997). Haddad et al. (2000) 

validated a PBPK model for inhalation of mixtures of benzene, toluene, ethyl benzene, and m-xylene 

(BTEX), with the addition of a model for dichloromethane. Kaneko et al. (1995) modeled the effect of 

phenobarbital pretreatment with exposure to m-xylene orally or intraperitoneally at the same doses or by 

inhalation. The interactions between xylene and the other chemicals are presented in Section 3.9. 
XYLENE 151 

3. HEALTH EFFECTS 

MacDonald et al. (2002) used PBPK modeling to estimate central nervous system effects following 

exposure to a time-weighted-average 100 ppm of m-xylene for 8 hours. The model incorporated the 

inhalation PBPK model for m-xylene by Kaneko et al. (1991a) and a model for ingested ethanol by Derr 

(1993). Other components included a competitive enxyme (CYP2E1) inhibition model for the two 

chemicals, as well as a population PBPK simulation model derived from statistical distributions of the 

PBPK model parameters with Monte Carlo sampling. Finally, since central nervous system effects were 

assumed to be dependent on blood levels of m-xylene, a pharmacodynamic (PD) threshold model was 

included for peak venous concentrations of m-xylene. The deterministic PBPK model for m-xylene was 

validated against available human data (Loizou et al. 1999; Riihimaki et al. 1982b). The population 

PBPK-PD model for m-xylene was run to establish the population distribution for peak venous blood 

m-xylene concentrations (CV,max) following exposure at the U.K. occupational exposure standard of 

100 ppm over 8 hours and for a 4-hour exposure at 200 ppm that elicited central nervous system 

disturbances in healthy volunteers (Savolainen et al. 1985a). The corresponding 80th percentile on the 

CV,max cumulative frequency distribution, 20.35 μmol/L, was selected as the pharmacokinetic/ 

pharmcodynamic threshold for central nervous system depression elicited by exposure to m-xylene. 

Simulations were also reported for blood levels of ethanol alone, combined m-xylene and ethanol, and 

population PBPK-PD modeling for the combined exposure scenario. In the model simulations, increasing 

exposure to ethanol increased the probability of central nervous system effects from exposure to 

m-xylene. 

PBPK modeling has been employed to assess possible toxicological interactions between chemicals, such 

as inhalation exposure to m-xylene and methylchloroform (Tardif and Charest-Tardif 1999). 

Haddad et al. (2001) developed a PBPK modeling-based risk assessment approach for mixtures of volatile 

chemicals that would incorporate pharmacokinetic interactions, such as changes in hepatic metabolism, 

among components of the mixture. 

Model Applications 

In deriving a chronic-duration inhalation reference concentration (RfC) for xylenes, the EPA (2003) 

examined the application of the inhalation PBPK models for m-xylene developed by Tardif and 

colleagues (Haddad et al. 1999; Tardif et al. 1991, 1992, 1993a, 1993b, 1995) to extrapolate rat exposure 

levels from the intermediate-duration inhalation study by Korsak et al. (1994) to human equivalent 

exposure levels. Using a time-weighted-average steady-state concentration of m-xylene in blood as the 
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internal dose surrogate, it was found that model-predicted human equivalent concentrations (46.5 mg/m3) 

were similar, although not identical, to human equivalent concentrations (39 mg/m3

) calculated from rat 

experimental exposure levels using the 1994 EPA default cross-species dosimetric equations (EPA 2003). 

EPA (2003) noted that, as neurobehavioral effects were the targets in the study by Korsak et al. (1994), 

the brain concentration of xylene would have been a more optimal dose surrogate, but the model did not 

include such a compartment. 

Pelekis et al. (2001) used the PBPK models of Tardif et al. (1993a, 1995) to examine possible differences 

between children and adults with respect to estimated blood and tissue doses following inhalation 

exposure to xylene. The model simulations incorporated published physiological parameters for a 10-kg 

1-year-old child and high and low values for adults. The simulations revealed that the parameters having 

a significant effect on within-species variability of tissue and blood doses following inhalation exposures 

were the body weight, ventilation rate, fraction of cardiac output flowing to the liver, blood:air partition 

coefficient, and hepatic extraction ratio. 

Jang and Droz (1997) used PBPK modeling to evaluate possible ethnic differences in metabolism in 

individuals exposed by inhalation to 100 ppm m-xylene for 6 hours (Jang et al. 1997). No significant 

differences were noted between six Caucasians and six Asians in metabolic clearance of methylhippuric 

acid. 

3.5 MECHANISMS OF ACTION 

3.5.1 Pharmacokinetic Mechanisms 

Absorption. The isomers of xylene are expected to have similar absorption behavior because of their 

relatively small molecular size and similar chemical properties. Penetration of xylenes is rapid by all 

routes of exposure because of the lipophilic nature of the chemicals, as indicated by the log Kow values 

(see Table 4-2). The similar blood-air partition coefficients for the xylene isomers also reflect the 

expected similarities in absorption from inhaled air through the lung (Table 3-6). PBPK modeling of 

human data revealed little inter-subject variability with respect to blood:air partition coefficients (Adams 

et al. 2005). 

Distribution. Distribution of xylenes is rapid throughout the body although their water solubility is 

low (Table 4-2). Xylenes, because of their lipophilic properties, are readily distributed to fat and tissues 

rich in cell membranes, such as the brain. The lipophilic nature of xylenes is generally responsible for 
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their penetration across the placenta to fetal tissues and for distribution into milk (Fisher et al. 1997). 

Distribution of xylenes is a simple diffusion process. As shown by PBPK modeling, the factors affecting 

tissue and blood distributions of inhaled xylenes include the body weight (since several physiological 

parameters are scaled to body weight), ventilation rate, fraction of cardiac output flowing to the liver, 

blood:air partition coefficient, and hepatic extraction ratio (Pelekis et al. 2001). In addition, hepatic blood 

flow can be significantly affected by changes in posture, exercise, and thermal stress (Adams et al. 2005). 

All of these factors may contribute to intra- and inter-individual variations in tissue distributions of 

xylenes (Adams et al. 2005; Pelekis et al. 2001). 

In developing a tissue composition-based algorithm for predicting tissue:air partition coefficients for 

volatile organic compounds, including isomers of xylene, Poulin and Krishnan (1996a, 1996b) uncovered 

an anomaly regarding blood compared to other tissues. The algorithm was based on tissue composition 

with respect to water and total lipid content by weight, and phospholipids and neutral lipids as fractions of 

total lipids. For liver, muscle, and adipose tissue, the algorithm, which used the solubilities of chemicals 

in water, neutral lipid, and phospholipid, predicted tissue:air partition coefficients that were similar to 

values in the published literature (ratios of predicted vs experimental between 0.93 and 1.57 for xylene 

isomers on average). For blood, however, the algorithm seriously underpredicted the partition 

coefficients of hydrophobic organic compounds, for xylenes by a factor of 5, indicating that solubility 

characteristics alone could not account for partitioning. Poulin and Krishnan (1996b) suggested that 

retention of hydrophobic organic compounds in blood was partly the result of reversible binding to 

hydrophobic holes in hemoglobin molecules. Association constants (Ka) of 1,512, 1,853, and 1,609 per 

mole were calculated for reversible binding to hemoglobin by o-, m-, and p-xylene, respectively (Poulin 

and Krishnan 1996b). 

In PBPK modeling of data from humans exposed by inhalation, fitted values for partitioning between 

blood and slowly perfused tissues exhibited significant inter-individual variability, ranging from 0.68 to 

13.78 for m-xylene (mean 3.05±3.77), 0.65–17.44 for o-xylene (mean 2.88±3.37), and 0.55–12.27 for 

p-xylene (2.25±2.58) (Adams et al. 2005). The basis for this variability is not understood. 

Metabolism. Phase I metabolism of xylenes is primarily by the oxidation of side-chain methyl groups 

by mixed function oxidases in the liver, forming methylbenzoic (toluic) acids. Phase II metabolism is 

primarily through conjugation with glycine, which is rate limiting in humans (Riihimaki et al. 1979a, 

1979b). In the absence of glycine, minor pathways are employed, such as conjugation with glucuronic 

acid or aromatic hydroxylation to form xylenols. In humans, hepatic microsomal CYP2E1 is the primary 
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enzyme involved with the metabolism of xylenes to methylbenzylalcohols, the dominant pathway leading 

to the formation of methylhippuric acid isomers (Tassaneeyakul et al. 1996); human CYP1A2 causes the 

ring hydroxylation of m-xylene to form 2,4-dimethylphenol. 

Inter-individual variations in rates of metabolism of xylenes may be affected by lifestyle differences. 

Treatment with ethanol prior to xylene exposure increases rates of xylene metabolism by the liver, 

presumably by inducing hepatic microsomal enzymes (Tardif et al. 1994; Wisniewska-Knypl et al. 1989). 

Excretion. The lipophilic properties of unmetabolized xylene are responsible for the diffusion out of 

the lungs into exhaled breath. The water solubility of conjugated metabolites of xylene is responsible for 

their transported out of the body in urine. As estimated by PBPK modeling of human data, systemic 

clearance of m-xylene (fitted average of 131 L/hour) proceeds more rapidly than for o-xylene 

(116 L/hour) or p-xylene (119 L/hour) (Adams et al. 2005). 

3.5.2 Mechanisms of Toxicity 

The lipophilic effects of xylenes, which dissolve lipid membranes, is responsible for the irritant effects on 

eyes, mucous membranes and skin (Riihimaki 1979b). In addition, the lipophilicity of xylenes is 

responsible for their narcotic and anaesthetic properties, which are similar for the three isomers (Fang et 

al. 1996). The para isomer differs in also eliciting excitation reactions in rats (Fang et al. 1996). The 

mechanism of anesthetics in general is not well understood, but probably relates to intercalation of the 

chemical into neuronal cell membranes, changing membrane properties that affect transmission of nerve 

impulses (Desi et al. 1967; EPA 1985a; Gerarde 1959; Savolainen and Pfaffli 1980; Tahti 1992). The 

mechanism could be either by a disruption of the lipid environment in which membrane proteins function 

or by direct interaction with the hydrophobic/hydrophilic conformation of proteins in the neuronal 

membrane. A statistically significant 28% increase in binding (fmol/mg tissue) of radiolabeled t-butylbicyclophosphorothionate, a ligand to the picrotoxin/convulsant binding stite of GABAA receptors, was 

observed in the molecular layer of the cerebellum of rats exposed by inhalation to m-xylene at a high 

concentration (Ito et al. 2002). The results of this study suggest that the high concentration of m-xylene in 

the cerebellum (see Section 3.2.2.1) increased GABA release and/or enhanced GABAA receptor function, 

consequently increasing GABAA receptor binding activity. The increased inhibitory effect of GABAergic 

neurotransmission in the cerebellum is consistent with the adverse effect of m-xylene on motor 

coordination (Ito et al. 2002). 
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Changes in levels of various neurotransmitters and lipid composition have been observed in several brain 

areas following acute- and intermediate-duration exposure to xylene (Andersson et al. 1981; Honma et al. 

1983; Savolainen and Seppalainen 1979). It is unclear whether these represent direct effects of xylene or 

are secondary changes resulting from nonspecific central nervous system depression. Some authors have 

also suggested that metabolic intermediates, such as arene oxides or methylbenzaldehyde, may be 

responsible for the toxic effects of xylene (Savolainen and Pfaffli 1980). Oxidation of xylene to these 

intermediates by microsomal enzyme systems may occur within brain cells (Savolainen and Pfaffli 1980). 

Acute-duration oral or intermediate-duration inhalation exposures to high concentrations of p-xylene, but 

not the other isomers, results in death of cochlear hair cells and hearing loss in rats (Gagnaire and 

Langlais 2005; Gagnaire et al. 2001). The reason for the isomer-specificity of the effect is not known, but 

Gagnaire and Langlais (2005) have indicated that ototoxicity from exposure to aromatic solvents is 

generally associated with structural constraints: the presence of a single short side chain on the benzene 

ring. They imply that the meta- and ortho- placements of a second short side chain in xylene interfere 

with ototoxic potency, whereas the para- position does not. Direct effects of xylene on the brain may be 

responsible for degraded performance of rats in tests of motor coordination, but the precise brain areas 

affected have not been identified (Gralewicz and Wiaderna 2001; Gralewicz et al. 1995; Korsak et al. 

1990, 1992, 1993, 1994). 

Inhibition of pulmonary microsomal enzymes has been observed by several investigators (Elovaara et al. 

1987; Foy and Schatz 2004; Foy et al. 1996; Park et al. 1994; Patel et al. 1978; Silverman and Schatz 

1991; Smith et al. 1982; Stickney et al. 1989). The exact mechanism of the enzyme inhibition is 

unknown but has been attributed to the formation of a toxic reactive metabolite (such as methylbenzaldehyde) that binds directly to microsomal protein and inactivates the microsomal enzymes (Patel et al. 

1978; Smith et al. 1982). Direct effects on microsomal membrane fluidity and/or lipid content do not 

appear to be involved (Stickney et al. 1989). Inhalation exposure to m-xylene for 6 hours caused a 

condensation-dependent reduction in cytochromes CYP 2B1, 2E1, and 4B1 in the lung and 2B1 and 2E1 

in the nasal mucosa (Vaidyanathan et al. 2003). 

The cytotoxicity of m-xylene has been associated with reductions in cellular antioxidant status (Coleman 

et al. 2003). In rat dermal fibroblasts cultured in a collagen matrix (dermal equivalents), exposure to 

m-xylene caused duration- and concentration-related reductions in viability, endogenous catalase activity, 

and endogenous thiol levels (thiols detected with 5,5-dithiobis[2-nitrobenzoic acid], DTNB). 

Supplementation with the antioxidant N-acetylcysteine, a hydroxyl radical scavenger as well as a 
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precursor to glutathione, increased survival of cultured fibroblasts exposed to m-xylene. These results 

suggest that hydroxyl radicals may play a role in xylene-induced cytotoxicity. 

The mechanism for xylene's toxic effects on the kidneys is also unknown, but may be related to formation 

of reactive metabolites and subsequent irritation or direct membrane fluidization (EPA 1985a). Support 

for the former idea is provided in several experiments using porcine proximal tubular cells (LLC-PK1, an 

established cell line) cultured in the presence of p-xylene (Al-Ghamdi et al. 2003a, 2003b, 2004). 

Treatment for up to 48 hours with 5 mM p-xylene reduced cell viability, increased the activity of 

CYP2E1, and increased the release of malondialdehyde (indicative of lipid peroxidation), but did not 

cause an increase in DNA fragmentation (Al-Ghamdi et al. 2003a). Disulfuram, an inhibitor of CYP2E1, 

reduced the activity of this enzyme, as well as the release of malondialdehyde occurring from treatment 

with p-xylene. Experiments using a free radical scavenger (catalase) also counteracted the effect of 

p-xylene. These experiments suggest that renal toxicity of p-xylene may be related to its metabolism by 

CYP2E1, which generates the production of oxidative intermediates and subsequent necrosis; the authors 

suggest that this mechanism would be relevant to acute high-level exposures to xylene. Results of 

additional experiments with LLC-PK1 cells treated for 96 hours with 1 mM p-xylene suggested that 

nephrotoxicity from xylene may involve induction of apoptosis through the activation of mitochondrial 

caspase-9 and caspase-3 (Al-Ghamdi et al. 2003b, 2004); typical features of apoptosis, DNA 

fragmentation and upregulation of Bax protein compared to Bcl-2 protein (increasing the ratio of 

Bax/Bcl-2), were observed with xylene treatment. In humans exposed to solvent mixtures containing 

xylene and a substantial proportion of toluene, a number of effects were noted (lysozymuria and increased 

urinary excretion of beta-glucuronidase, albumen, erythrocytes and leukocytes) that are attributable to 

renal injury (Askergren, 1982; Franchini et al. 1983). However, these effects are likely caused by 

toluene, which is a known renal toxicant. 

Developmental toxicity of m- and p-xylenes in standard animal bioassays is largely related to maternal 

toxicity (Saillenfait et al. 2003). Effects on fetal body weight and delay of skeletal ossification are both 

growth related and impaired by compound-induced reductions in maternal body weight. The reason that 

fetal body weight effects occur at doses lower than the maternal LOAEL for o-xylene and mixed xylenes 

is not known. The fact that mixed xylenes did not elicit the skeletal variants or delayed ossification seen 

with the individual isomers at the same concentration suggests that the effects of the isomers are not 

additive. Thus, it is possible that there may be isomer-specific targets relating to skeletal development, as 

indicated by the slightly different pattern of effects; for example, the incidence of incomplete ossification 
 

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in thoracic vertebral centra was significantly elevated in fetuses exposed to m-xylene, but not the other 

isomers. 

The mechanism of neurobehavioral deficits observed in rats exposed gestationally following maternal 

inhalation to m-xylene is not known (Hass and Jakobsen 1993; Hass et al. 1995, 1997). Toxicity to 

vestibular structures involved with balance or hippocampal neurons involved with sensory processing 

have been suggested as targets associated with impaired motor coordination and spatial navigation 

following xylene exposure (Hass et al. 1997). 

Xylenes have not been shown to be mutagenic in short-term bioassays, but DNA degradation was 

reported in the skin of rats exposed dermally to m-xylene (Rogers et al. 2001). Penetration of liquid 

xylene may impair the integrity of cell membranes, resulting in release of nucleases from membranebound lysosomal stores and concomitant fragmentation of DNA. This process appears to be associated 

with cell death. 

3.5.3 Animal-to-Human Extrapolations 

In general, toxic effects of xylenes observed in humans, such as depression of the central nervous system 

and irritant effects, are also observed in animals. These similarities are to be expected given that they are 

a consequence of the chemical properties of unmetabolized xylenes and are not likely to be affected by 

minor species differences in cell type. Toxicokinetic processes, including metabolic pathways for 

xylenes, are similar in animals and humans, but would be limited by physiological differences in 

respiration. EPA (1994) has provided guidance for extrapolating from inhalation exposure in animals to 

human equivalent exposure levels in humans. PBPK models (see Section 3.4.5) have been employed to 

estimate human equivalent exposures for toxicity in exposed rats. 

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 
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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). 

No in vivo or in vitro studies were located regarding endocrine disruption in human and/or animals after 

exposure to mixed xylenes or individual isomers of xylene. Evidence for endocrine effects has not been 

seen in studies on reproductive, developmental, or chronic toxicity of xylenes. 

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 most 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. 
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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 

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 
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alveoli being less developed, which results in a disproportionately smaller surface area for alveolar 

absorption (NRC 1993). 

No data are available regarding the effects of exposure to xylenes in children, but it is expected that 

children would experience the same effects as exposed adults. In controlled acute inhalation experiments 

on m-xylene, one reason offered for the greater impairment in respiratory function (reduced forced vital 

capacity) in exposed women to compared to exposed men was that the airways in women are narrower 

and therefore more sensitive to swelling (Ernstgard et al. 2002). On this basis, it is likely that children 

exposed to xylenes by inhalation would be more sensitive to respiratory impairment than exposed adults. 

A few epidemiological studies on laboratory workers suggested that maternal exposure to xylenes might 

increase the frequency of spontaneous abortion, but the validity of the association is confounded by 

simultaneous exposure to other chemicals (Lindbohm et al. 1990; Taskinen et al. 1994). 

The lipophilic properties of xylenes suggest that the absorption and distribution in children are likely to 

be similar to those of adults. PBPK modeling estimated that about 1–2% of xylene absorbed from 

maternal occupational inhalation exposure at 100 ppm would be transferred to breast milk (Fisher et al. 

1997). The daily intake of xylene by a 10-kg nursing infant under this scenario was estimated to be 

6.59 mg. Studies in mice have demonstrated that xylene absorbed by pregnant females is transferred to 

the fetus, but that uptake by fetal tissues was lower than in maternal tissues (Ghantous and Danielsson 

1986). The most reliable developmental toxicity assay in rats exposed by inhalation indicated that 

fetotoxicity (reduced fetal weight and delayed ossification, a skeletal variation that is affected by impaired 

growth) from maternal exposure to m- and p-xylene only occurs at maternally toxic exposure levels 

(Saillenfait et al. 2003); exposure to o-xylene or mixed xylenes resulted in fetal body weight effects at 

concentrations below the LOAEL for maternal effects. The pattern of skeletal variations (i.e., the bones 

affected) was slightly different for each isomer and no serious malformations were observed at 

concentrations as high as 2,000 ppm. No significant increase in skeletal variations was noted for 

gestational exposure to mixed xylenes, suggesting that the effect of the isomers was not additive 

(Saillenfait et al. 2003). Other developmental inhalation studies reported skeletal variations and delayed 

ossification at lower concentrations, but the results were not considered for determining NOAEL or 

LOAEL values because fetal effects were not reported on a per-litter basis and little information on 

maternal toxicity was provided (see Section 3.2.1.6). Fetal toxicity in oral rodent studies occurred at 

relatively high doses near the maternal effect level (Marks et al. 1982). A potentially serious 

developmental effect of xylene is impaired neurobehavioral function, which has been observed in rats 
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gestationally exposed at a level (500 ppm) that was not toxic to dams (Hass and Jakobson 1995; Hass et 

al. 1997). In these studies, motor coordination was impaired and deficiencies in a water maze test for 

spatial navigation persisted to postnatal week 28 in the offspring of exposed dams. These results suggest 

that in humans, excess maternal exposure to xylene might result in postnatal neurobehavioral deficits 

even if no overt structural anomalies occurred. 

The main phase I metabolizing enzyme for xylene, CYP2E1, is present in the fetus and in children. The 

presence of CYP2E1 facilitates the elimination of xylene from the body. Total fetal liver CYP content is 

a relatively constant 30% of the adult level from the end of the first trimester of gestation up to 1 year of 

age (EPA 2001b). mRNA for CYP2E1 has been detected in human first-trimester placentas (Hakkola and 

Saarinen 1996). Low levels of CYP2E1 protein have been detected in human fetal brain as early as 

gestational day 46, substantially increasing around day 50 (Boutelet-Bochan et al. 1997; Brzezinski et al. 

1999). In the fetal liver, CYP2E1 protein was not detectable at 10 weeks of gestation, but was present at 

16 weeks (Carpenter et al. 1996). Additionally, there is some evidence that maternal alcohol consumption 

induces placental CYP2E1 in humans (Rasheed et al. 1997). Hepatic levels of CYP2E1 mRNA increase 

significantly during the first 24 hours after birth, largely resulting from demethylation that allows 

transcription to proceed (Vieira et al. 1996). Major accumulations of CYP2E1 occur between 1 and 

3 months of age and values comparable to those of adults are achieved sometime between 1 and 10 years 

of age (EPA 2001b; Vieira et al. 1996). Thus, elimination of xylene metabolites in exposed children 

would be expected to be similar to exposed adults. 

Aside from the model described above (and in Section 3.4.5) for lactational transfer to nursing infants by 

Fisher et al. (1997), no PBPK models have been developed for children or for fetuses or pregnant women 

exposed to xylenes. 

Ginsberg et al. (2004) considered developmental and pharmacokinetic differences between adults and 

children that could impact risk assessments of children exposed to toxicants. The higher inhalation rate 

per respiratory surface area in children compared to adults might result in an apparent higher dose to the 

lungs in children for the first several years compared to adults exposed to xylene at the same atmospheric 

concentration. As the stratum corneum of the epidermis is well-developed in newborn infants, dermal 

absorption of xylene by newborns would be generally expected to be similar to adults. The one exception 

is for the infants born prematurely, in which the stratum corneum attains a normal thickness only by the 

second postnatal week. The relatively larger ratio of liver weight to body weight in children, especially 

during the first 2 years postnatally, and the lower body lipid content for the first 3 months postnatally, 
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compared to adults, would suggest that retention of absorbed xylene is lower and systemic clearance of 

absorbed xylene is faster in young children than in adults. These factors are countered by the possibly 

lower rates of metabolism of xylenes during the first two postnatal months (see above). The larger brain 

weight to body weight ratios in children, especially during the first two postnatal years, suggests that 

proportionally more xylene may be delivered to the brain of children, rendering them more vulnerable to 

the neurotoxic effects of xylene than similarly exposed adults. No compound-specific experimental data 

are available to confirm these suppositions regarding the exposure of children to xylenes. 

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). 

Due to a nascent understanding of the use and interpretation of biomarkers, implementation of biomarkers 

as tools of exposure in the general population is very limited. 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 (e.g., essential mineral nutrients such as 

copper, zinc, and selenium). Biomarkers of exposure to xylene 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 
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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 xylene 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 Xylene 

Xylene levels in the blood and levels of its metabolite, methylhippuric acid, in the urine are the primary 

markers used to detect exposure to xylene. Xylene is very soluble in the blood and is readily absorbed 

into the circulation during exposure (Astrand 1982). Measurement of blood levels of xylene is limited by 

the rapid metabolism of xylene. Moreover, there are no data on background concentrations of xylene in 

blood or urine. Xylene and xylene isomers have been detected at concentrations of up to 400 nM in urine 

of workers exposed to xylene at geometric mean concentration of 1.9 ppm with a maximum concentration 

of 27.3 ppm (Takeuchi et al. 2002). Xylenes are metabolized almost exclusively to methylhippuric acids 

in humans. Detection of methylhippuric acid in the urine is the most widely used indicator of xylene 

exposure (ACGIH 1986). A strong association has been shown between urinary methylhippuric acid 

concentrations and exposure to xylene (Daniell et al. 1992; Jonai and Sato 1988; Kawai et al. 1991); 

during an 8-hour workshift, a concentration of 57.8 mg/L of methylhippuric acid isomers (i.e., all isomers 

combined) was found to correlate with exposure to 3.8 ppm (geometric mean concentration) of total 

xylenes (Kawai et al. 1991). In a study of Chinese men and women occupationally exposed to mixed 

xylenes, Inoue et al. (1993) estimated that 13 mg of methylhippuric acid would be excreted in a liter of 

urine for each ppm of xylene exposure (or 11.1 mg/g creatinine/ppm). This relationship was true for both 

men and women as well as for mixed and individual isomers. Within 2 hours of an inhalation exposure, 

methylhippuric acid may be detected in the urine (Sedivec and Flek 1976b). The excretion of 

methylhippuric acid is complete within 1 or 2 days of exposure to xylene, limiting the utility of this 

biomarker to the detection of only very recent exposures. With chronic exposure to xylene, the 

metabolism is enhanced, further limiting the time following exposure that xylene levels may be measured 

in the blood (Savolainen et al. 1979a). Since the methylhippuric acid background levels in persons not 

exposed to xylenes are very low, methylhippuric acids are specific markers for xylenes, except for 
XYLENE 164 

3. HEALTH EFFECTS 

exposure to alkyl toluenes in which the number of carbon atoms in the alkyl group is odd. A minor 

metabolite of xylene, N-acetyl-S-xylyl cysteine (a trioether), may also be detected in the urine (Tanaka et 

al. 1990; van Doorn et al. 1980); however, it is at such low levels in the urine during experimental 

exposures that it is ineffective as a biomarker (Norstrom et al. 1988). For additional information on the 

kinetics of xylene absorption, distribution, metabolism, or excretion, see Section 3-4. 

3.8.2 Biomarkers Used to Characterize Effects Caused by Xylene 

The following changes are potential biomarkers of effect for xylenes; however, none of the changes are 

unique to xylene exposure. Xylenes have been observed to enhance the activity of a variety of 

microsomal enzymes and increase hepatic cytochrome P-450 content (Elovaara 1982; Elovaara et al. 

1980; Patel et al. 1979; Savolainen et al. 1978; Tatrai et al. 1981; Toftgard and Nilsen 1981, 1982; 

Toftgard et al. 1981). Scores consistent with memory impairment and decreased reaction time have been 

observed using standard intelligence tests and measures of reaction time (Gamberale et al. 1978; 

Riihimaki and Savolainen 1980; Savolainen and Riihimaki 1981a; Savolainen et al. 1979b, 1984, 1985a). 

These effects are likely to be elicited by any solvent that has anaesthetic properties. Erythema of the skin 

is a biomarker of dermal exposure to xylene, but this is a common reaction to compounds with irritant 

properties (Ahaghotu et al. 2005; Anderson et al. 1986; Chatterjee et al. 2005; Hine and Zuidema 1970; 

Pound and Withers 1963; Smyth et al. 1962). Increases in blood levels of interleukin 1-alpha, as 

demonstrated in rats, may represent a biomarker of inflammatory processes in skin following dermal 

exposure to xylene, but might apply to any chemical that elicits dermal irritation (Ahaghotu et al. 2005; 

Chatterjee et al. 2005). 

3.9 INTERACTIONS WITH OTHER CHEMICALS 

The interaction of xylene with alcohol, drugs (aspirin, phenobarbitol), and various solvents (1,1,1-trichlorethane, benzene, toluene, ethylbenzene, methyl ethyl ketone) has been evaluated in experimental 

studies with humans and animals. Xylene has a high potential to interact with numerous substances 

because the isomers induce microsomal enzymes in the liver (Blanchard and Morris 1994; Liira et al. 

1991), while microsomal enzymes in the lungs are inhibited by xylene exposure (Blanchard and Morris 

1994; Elovaara et al. 1987; Patel et al. 1978; Silverman and Schatz 1991; Toftgard and Nilsen 1982). 

Which enzymes will be affected is isomer dependent. For example, m-xylene is a more potent inducer of 

P-450 2B enzymes than p-xylene (Backes et al. 1993). The isomer differences, as well as organ 

differences in effects on xenobiotic metabolizing enzymes, make it difficult to predict the interaction of 

xylene with other substances. 
XYLENE 165 

3. HEALTH EFFECTS 

The effects from combined exposure to xylene and ethanol have been studied most extensively because of 

the reasonable expectancy that some workers will consume alcoholic beverages and subsequently might 

be exposed to xylene occupationally by inhalation. Results of studies with humans and animals indicate 

that metabolic interaction between xylene and ethanol occurs. Co-administered ethanol appears to inhibit 

the metabolism of xylene, probably by competition for mixed function oxidases, resulting in elevated 

blood levels of xylene and decreased excretion of methylhippuric acid (Elovaara et al. 1980; Riihimaki et 

al. 1982a, 1982b; Romer et al. 1986; Savolainen 1980; Savolainen et al. 1978, 1979b, 1980b). A kinetic 

study in rats (Kaneko et al. 1993) suggests that ethanol inhibition of xylene metabolism occurs only at 

high airborne concentrations (500 ppm). Paradoxically, ethanol pretreatment has a synergistic effect on 

metabolism of xylene as a result of the induction of microsomal enzymes in the liver (Wisniewska-Knypl 

et al. 1989). Ethanol pretreatment (137 g taken orally) enhanced the metabolism of m-xylene in human 

subjects exposed at 400 ppm, but had no effect at 100 ppm (Tardif et al. 1994). This would enhance the 

metabolic capacity of the liver and modify biological effects of other chemicals that are either detoxified 

or converted to toxic metabolites by the microsomal enzymes. In summary, it cannot be stated with 

certainty whether alcohol and xylene would interact to produce synergistic or antagonistic effects in 

humans and animals because there are reasons why both would occur. MacDonald et al. (2002) used 

PBPK modeling to evaluate the likelihood of central nervous system effects in people exposed to a timeweighted-average concentration of 100 ppm m-xylene for 8 hours and also exposed to ethanol. In the 

model simulations, increasing exposure to ethanol increased the probability of central nervous system 

effects from exposure to m-xylene. Combined exposure to m-xylene and ethanol increased lipid 

peroxidation in the rat liver (Jajte et al. 2003). 

Kaneko et al. (1995) modeled the effect of phenobarbital pretreatment (80 mg/kg/day for 3 days) with 

exposure to m-xylene orally or intraperitoneally at 8.6 or 86.4 mg/kg or by inhalation for 6 hours at 40 or 

400 ppm. Phenobarbital treatment increased the metabolism of inhaled m-xylene at 400 ppm. This was 

related to a decrease in xylene blood concentrations and increased urinary excretion. Phenobarbital had 

no significant effect on metabolism of ingested xylene. The metabolism of m-xylene was not affected by 

coexposure to n-butyl alcohol in rats exposed by inhalation for 7 hours to 100 ppm of each chemical 

(Swiercz et al. 1995). 

Combined exposure to ethanol and xylene results in macrocytosis and decreased erythrocyte membrane 

fluidity (Wronska-Nofer et al. 1991). These effects were not observed when either chemical was 
XYLENE 166 

3. HEALTH EFFECTS 

administered alone. It is unclear whether this interaction is pharmacological or pharmacokinetic in 

nature. 

Acute inhalation exposure to a mixture of toluene and xylene resulted in more-than-additive respiratory 

and central nervous system toxicity (Korsak et al. 1988, 1992). Elevated blood levels of xylene and 

toluene and decreased excretion of the major metabolites of xylene and toluene in the urine (Tardif et al. 

1992) suggest mutual metabolic inhibition. However, simultaneous exposures in humans indicate that a 

threshold exists for this interaction (Tardif et al. 1991). No increase in blood levels of these substances 

was observed during combined exposures to 50 ppm toluene and 40 ppm xylene over 3 consecutive days, 

whereas increases in blood levels and levels in exhaled air were observed during a combined 4-hour 

exposure to 95 ppm toluene and 80 ppm xylene. Thus, combined exposures at below threshold level are 

unlikely to produce greater than additive toxicity (Tardif et al. 1991). Physiologically based toxicokinetic 

modeling studies using rat data suggests that the interaction between toluene and xylene is competitive, 

with toluene a more potent inhibitor of xylene metabolism than xylene is of toluene metabolism (Tardif et 

al. 1993a, 1993b, 1995). PBPK modeling studies of ternary mixtures predicted that humans exposed to 

permissible levels for the mixture (33 ppm m-xylene, 17 ppm toluene, and 33 ppm ethylbenzene), would 

not exhibit biologically significant metabolic inhibition of the components (Tardif et al. 1997). In these 

ternary simulations, after 0.5–8 hours of exposure, the concentration of xylene in alveolar air was slightly, 

but significantly higher than expected compared to exposure of xylene alone; the blood concentration of 

xylene following exposure to the ternary mixture was slightly elevated in venous blood after 5.5–8 hours 

of exposure. Studies in rats exposed to binary or ternary mixtures (m-xylene and toluene with or without 

ethylbenzene) at component concentrations of 100 or 200 ppm demonstrated that the kinetics of 

metabolism was less affected by metabolic interactions when metabolism was near saturation (Tardif et 

al. 1996). 

Exposure to xylene combined with benzene or ethylbenzene may also produce mutual inhibition of the 

metabolism of both solvents (Engstrom et al. 1984; Nakajima and Sato 1979b). Ethylbenzene is found in 

commercial xylene. In contrast, ethyl acetate exposure in combination with exposure to m-xylene caused 

a reduction in blood xylene levels (Freundt et al. 1989). 

Combined exposures to m-xylene and methyl ethyl ketone (2-butanone) produced a synergistic induction 

of microsomal enzymes in rats (Liira et al. 1991), but in humans, inhibited the metabolism of m-xylene to 

methylhippuric acid, resulting in corresponding increases in levels of xylene in blood and fat (Liira et al. 

1988, 1991). While the side-chain oxidation of xylene to methylhippuric acid was inhibited, an increase 
XYLENE 167 

3. HEALTH EFFECTS 

in ring oxidation (xylenol production) was observed (Liira et al. 1991), indicating that the inhibition was 

specific to a particular oxidation reaction. Thus, it is not known as to whether 2-butanone and m-xylene 

would interact to produce additive or antagonist effects in humans and animals. 

Inhalation of m-xylene following pretreatment with phenobarbital was associated with both increased 

pulmonary retention of m-xylene and increased urinary excretion of m-methylbenzoic acid (David et al. 

1979). Combined inhalation of 1,1,1-trichloroethane (methylchloroform) and m-xylene had no effect on 

the metabolism of m-xylene, as indicated by blood concentrations of the parent compound and urinary 

concentrations of m-methylhippuric acid (Tardif and Charest-Tardif 1999). Surprisingly, inhalation of 

m-xylene and 1,1,1-trichloroethane has been associated with slight improvements in certain 

psychophysiological parameters, including reaction time and equilibrium in humans as compared with 

pre-exposure measurements (Savolainen et al. 1982a, 1982b), and impairment in others such as visual 

evoked potentials and equilibrium (Savolainen et al. 1982a; Seppalainen et al. 1983). Also, a protective 

effect of xylene on n-hexane-induced testicular atrophy and peripheral nerve effects were observed when 

rats were exposed to n-hexane and xylene simultaneously (Nylen and Hagman 1994; Nylen et al. 1989), 

although combined exposure to xylene and n-hexane increased loss of auditory sensitivity (Nylen and 

Hagman 1994; Nylen 1996). Bromobenzene, which requires metabolic activation, showed greater 

toxicity to the liver in p-xylene exposed rats, while lung toxicity was not affected (Day et al. 1992). 

Following concurrent exposure to 100 ppm m-xylene and 1,500 mg aspirin orally in human subjects, the 

urinary excretion of metabolites conjugated to glycine (m-methylhippuric acid and salicyluric acid, 

respectively) was reduced by 50% for both compounds (Campbell et al. 1988). The authors speculate that 

the cause was competition for the enzymes involved in conjugation with glycine (acyl-CoA synthetase 

and glycine N-acylase), resulting in saturation of the conjugation pathway for both chemicals (Campbell 

et al. 1988). Administration of aspirin to pregnant rats during inhalation exposure to xylene caused 

greater-than-additive potentiation of maternal and fetal toxic effects (Ungvary 1985). This was postulated 

to be due to the interference with metabolism of aspirin by xylene and vice versa. 

Oral exposure to a relatively high dose of sodium benzoate, a food additive, 3 hours before intraperitoneal 

injection of o-xylene altered the metabolism of o-xylene in rats (Moriwaki et al. 2005). Pre-treatment 

with sodium benzoate (more than twice the amount of o-xylene on a molar basis) reduced the excretion of 

o-methylhippuric acid but increased the excretion of o-toluic acid conjugates and unmodified o-xylene in 

urine. These changes were attributed to competition for the enzymes involved in glycine conjugation 

(benzoyl-Coenzyme A synthetase and benzoyl-CoA:glycine N-acyltransferase). 
XYLENE 168 

3. HEALTH EFFECTS 

Exposure to xylene has been shown to inhibit several microsomal enzymes in the lung (Blanchard and 

Morris 1994; Elovaara et al. 1987; Patel et al. 1978; Silverman and Schatz 1991; Toftgard and Nilsen 

1982). m-Xylene administered intraperitoneally or exposure to o-xylene by inhalation altered the 

pulmonary microsomal metabolism of benzo[a]pyrene in rats, resulting in inhibition of its detoxification 

and increased production of toxic, mutagenic metabolites (bay region diols) (Park and Schatz 1999; 

Stickney et al. 1991). One study suggested that xylene acts as a promotor or cocarcinogen for the 

induction of skin tumors in mice, but the purity of the tested material was not reported (Pound 1970). If 

verified, these findings could be relevant in combined human exposures to xylene and polyaromatic 

hydrocarbons present in cigarette smoke and combustion emissions and especially to petrochemical 

workers who could be exposed to xylene, crude oils (promotor), and ultraviolet light (initiator). 

Dilution in polyethylene glycol 600 (PEG 600) increased the severity of eye irritation elicited by xylene 

and other aromatic compounds in rabbits compared to the undiluted compounds (Kennah et al. 1989). 

Undiluted xylene (not specified but presumed to be mixed isomers) elicited only minimal eye irritation 

whereas dilutions in PEG 600 resulted in slight or moderate irritation (3–5-fold increases in Draize 

scores); similar increases were observed with toluene and styrene. Because other diluents (cellosolve 

acetate or methyl isobutyl ketone) did not have the same effect, the study authors proposed that the 

aromatic compounds interacted with PEG 600 to form a more potent ocular irritant. 

In addition to interacting with other chemicals, exposure to xylene at high concentrations has also been 

shown to increase the effects of a virus. Acute exposure of mice to 1,208 ppm (but not 595 ppm) 

p-xylene (4 days, 4 hours/day) increased the mortality resulting from the murine cytomegalovirus 

(Selgrade et al. 1993). This effect was a result of potentiation of the liver damage cause by the virus 

rather than an immunological effect. 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

A susceptible population will exhibit a different or enhanced response to xylene than will most persons 

exposed to the same level of xylene 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 xylene, or compromised function of organs 

affected by xylene. Populations who are at greater risk due to their unusually high exposure to xylene are 

discussed in Section 6.7, Populations with Potentially High Exposures. 
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3. HEALTH EFFECTS 

Available data indicate that subsets of the human population may be unusually susceptible to the toxic 

effects of xylene. Pregnant women, fetuses, and very young children may be at greater risk of adverse 

health effects from xylene exposure than the population in general (Barlow and Sullivan 1982; Holmberg 

and Nurminen 1980; Hudak and Ungvary 1978; Kucera 1968; Marks et al. 1982; Mirkova et al. 1983; 

Ungvary et al. 1980b, 1981). Although no human studies were located indicating maternal or fetal 

toxicity following mixed xylene exposure, animal studies that involved exposure to m-xylene and aspirin 

or xylene alone suggest there may be a relationship between exposure to the agents and developmental 

effects (Hudak and Ungvary 1978; Marks et al. 1982; Ungvary 1985; Ungvary et al. 1980b, 1981). In 

summary, although it is not clear how toxic xylene might be to fetuses and infants, for safety's sake 

caution is urged. The ability of fetuses and very young children to metabolize certain xenobiotics, 

including possibly xylene, is reduced because of their immature enzyme detoxification systems 

(Calabrese 1978). Thus, for pregnant women exposed to xylene, ingestion of aspirin is likely to 

potentiate adverse effects of xylene in both the mother and the offspring. 

People with subclinical and clinical epilepsy are at increased risk of seizures if exposed to xylene because 

of its excitatory central nervous system effects (Arthur and Curnock 1982; Goldie 1960; Riihimaki and 

Hanninen 1987). It has also been demonstrated in human (Goldie 1960; Riihimaki et al. 1982a; 

Savolainen 1980; Savolainen et al. 1978, 1980b) and animal studies (Elovaara et al. 1980; Savolainen et 

al. 1979b) that alcohol consumption potentiates xylene toxicity. Some people appear particularly 

susceptible to the interaction and may develop dizziness, nausea, and dermal flush (Riihimaki et al. 

1982b; Savolainen et al. 1980b). 

People with clinical or subclinical renal, hepatic, or cardiac disease may be more susceptible to the effects 

of xylene. Evidence from occupational and case studies indicates that exposure to high levels of xylene 

might cause renal impairment and some hepatic effects, as well as cardiac manifestations, including 

tachycardia and ECG abnormalities (Goldie 1960; Hipolito 1980; Morley et al. 1970; NIOSH 1975; Von 

Burg 1982). However, exposure to xylene in these studies was confounded with exposure to other 

chemical agents. 

Limited human data suggest that people with respiratory diseases, such as asthma, could potentially be at 

risk with regard to the adverse effects of xylene following inhalation exposure (Hipolito 1980; Morley et 

al. 1970). 
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3. HEALTH EFFECTS 

3.11 METHODS FOR REDUCING TOXIC EFFECTS 

This section will describe clinical practice and research concerning methods for reducing toxic effects of 

exposure to xylene. 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 xylene. 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 

xylene: 

Ellenhorn MJ, Barceloux DG, eds. 1988. Medical toxicology: Diagnosis and treatment of human 

poisoning. New York, NY: Elsevier, 1422-1426, 1730-1731. 

IPCS. 1992. Xylene. Poisons information. Monograph 565. International Programme on Chemical 

Safety. http://www.inchem.org/documents/pims/chemical/xylene.htm. April 7, 2005. 

3.11.1 Reducing Peak Absorption Following Exposure 

General recommendations reported for reducing absorption following acute high-dose exposure to xylene 

include removal of the patient from the source of exposure to fresh air and decontamination of the skin 

with mild soap and water (Bronstein and Currance 1988; Ellenhorn and Barceloux 1988; Goldfrank et al. 

1990; Stutz and Janusz 1988). When the eyes have been involved, copious rinsing with tepid water or 

normal saline has been used for decontamination (Bronstein and Currance 1988; Stutz and Janusz 1988). 

Strategies for reducing xylene absorption following ingestion are limited because light petroleum 

products such as xylene cause severe aspiration pneumonitis (Ellenhorn and Barceloux 1988; IPCS 1992). 

Gastric lavage is the preferred method recommended for emptying the stomach contents, as long as a 

cuffed endotracheal tube is used to limit the possibility of aspiration (Goldfrank et al. 1990). Induction of 

emesis (vomiting) with syrup of ipecac is generally not recommended, especially in pediatric cases 

(Goldfrank et al. 1990); emesis is contraindicated if unprovoked emesis has already occurred or if the 

patient is not alert or has an impaired gag reflex (Ellenhorn and Barceloux 1988; Goldfrank et al. 1990). 

The only circumstances in which emesis is recommended are when very large quantities have been 

ingested, such as in a suicide attempt (Ellenhorn and Barceloux 1988; Goldfrank et al. 1990), or another 

highly toxic substance has been ingested together with xylene (Goldfrank et al. 1990). In summary, 

gastric lavage is recommended to reduce xylene absorption from the gastrointestinal tract only when one 

is certain that aspiration is not likely to occur. 
XYLENE 171 

3. HEALTH EFFECTS 

Although the use of activated charcoal and/or cathartics to limit intestinal absorption is recommended in 

some treatment protocols (Stutz and Janusz 1988), their use has been reported to be equivocal (Ellenhorn 

and Barceloux 1988). No studies have shown that activated charcoal is effective in adsorbing petroleum 

distillates or that cathartics are effective in speeding excretion (Goldfrank et al. 1990). Furthermore, 

because of low viscosity, oil-based cathartics may increase aspiration pneumonitis and absorption 

(Goldfrank et al. 1990). 

3.11.2 Reducing Body Burden 

In acute exposure situations, most xylene absorbed by the body is excreted in the urine or exhaled air 

within a day after exposure (see Section 3.4.4). However, charcoal hemoperfusion has been used to speed 

the removal of xylene from the body and to reverse its acute toxicity (Recchia et al. 1985). Sevcik et al. 

(1992) also used hemoperfusion and hemodialysis in an attempt to speed removal of xylene. Whether the 

relative gain from these treatment methods is worth the potential risks of invasive treatment remains to be 

established. A small percentage of absorbed xylene is retained in body fat. It has been suggested that 

over a prolonged period of exposure, significant amounts of xylene could accumulate in adipose tissue 

(Astrand 1982; Engstrom and Bjurstrom 1978). However, xylene has been shown to induce its own 

metabolism with the result that greater amounts of metabolites are excreted and less is available for 

storage (Elovaara et al. 1989; Savolainen et al. 1979a). No information was located regarding methods 

for reducing adipose stores of xylene; removal of xylene from adipose tissue is slow, limited by the 

lipophilic nature of the chemical and the poor vascular perfusion of adipose tissue (Riihimaki et al. 

1979b). Use of agents known to induce microsomal enzyme activity is a possible experimental method 

for enhancing excretion of xylene released from adipose stores by increasing the gradient of diffusion. 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects 

No information was located on established therapies designed to interfere with the mechanism of action 

of xylene. However, some speculation is possible regarding areas for future research in this regard. For 

example, the central nervous system toxicity of xylene is believed to be similar to that produced by other 

nonspecific central nervous system depressants (Desi et al. 1967; EPA 1985a; Gerarde 1959; Savolainen 

and Pfaffli 1980; Tahti 1992). If circulating xylene levels could be reduced, then the central nervous 

system toxicity may likewise be reduced (see Section 3.11.2). 

Since the exact metabolite responsible for the pulmonary toxicity of xylene has not been identified, it is 

difficult to speculate on steps to avert its synthesis or speed its excretion. In animals, selective 
XYLENE 172 

3. HEALTH EFFECTS 

inactivation of enzymes can result in damage to tissue caused by the toxic metabolite of xylene, 

methylbenzaldehyde. This effect has not been confirmed in humans. Decreased pulmonary microsomal 

enzyme activity was seen in rats administered a single dose or repeated doses of p-xylene for 3 weeks 

(Elovaara et al. 1989; Patel et al. 1978). However, the inhibition of pulmonary microsomal enzymes 

decreases to some extent with continued exposure to xylene (Silverman and Schatz 1991); this may 

indicate that xylene-induced activation of metabolizing enzymes and thereby acceleration of its own 

metabolism (Elovaara et al. 1989) may be limiting the production of the toxic metabolite. 

At least one in vitro study indicated that cytotoxicity caused by m-xylene is associated with reductions in 

cellular antioxidants and that supplementation with N-acetylcysteine partially ameliorates these effects 

(Coleman et al. 2003). N-acetylcysteine has been employed as a therapeutic antagonist for 

acetaminophen poisoning, but its effectiveness for reducing toxicity of xylenes in vivo has not been 

assessed. 

The available information on the mechanisms of renal and fetotoxicity is insufficient to allow speculation 

on potential means for blocking these effects. 

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 xylene 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 xylene. 

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. 
XYLENE 173 

3. HEALTH EFFECTS 

3.12.1 Existing Information on Health Effects of Xylene 

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 

xylene are summarized in Figure 3-9. The purpose of this figure is to illustrate the existing information 

concerning the health effects of xylene. 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. 

People may be exposed to xylene at hazardous waste sites by inhalation of contaminated air, drinking 

contaminated water, or dermal contact with contaminated water or subsurface soils and sediments. 

Volatilization of xylene from surface water and soil occurs rapidly; therefore, inhalation is the most likely 

route of exposure to xylene at these sites. The human health effects of xylene by inhalation exposure 

have been studied to the greatest extent. There is little information available regarding health effects in 

humans following oral or dermal exposure to xylene. The bulk of the information on health effects in 

humans associated with dermal exposure comes from reports of occupational exposures, which are likely 

to be combined inhalation and dermal exposures. As noted above, ingestion of xylene may be of concern 

because of the potential for xylene to contaminate sources of drinking water (groundwater) and certain 

soils. Dermal exposure to xylene is of concern not only because of potential workplace exposures, but 

also because members of the general public are potentially exposed to xylene contained in paints, glues, 

and other household products. As noted above, dermal exposure to soils and water contaminated with 

xylene at waste sites could also occur. 

Human fatalities following both inhalation and ingestion of xylene have been reported in the literature. 

Acute inhalation exposure of humans to xylene has resulted in hepatic and cardiovascular effects as well 

as neurologic effects. Very limited data regarding the systemic health effects of intermediate-duration 

human exposure to xylene were located in the literature. Also, very limited human carcinogenicity data 

were reported in the literature. Very little information is available on the chronic systemic, immunologic, 

developmental, reproductive, and genotoxic health effects of xylene exposure in humans. Interpretation 

of the large number of human studies examining the health effects of inhaled xylene vapor is difficult 
3. HEALTH EFFECTS 

Figure 3-9. Existing Information on Health Effects of Total Xylenes 

Inhalation 

Oral 

Dermal 

Human 

Death 

Acute 

Intermediate 

Chronic 

Immunologic/Lymphoretic 

Neurologic 

Reproductive 

Developmental 

Genotoxic 

Cancer 

Systemic 

Inhalation 

Oral 

Dermal 

Existing Studies 

Death

Acute 

Intermediate 

Chronic 

Immunologic/Lymphoretic 

Neurologic 

Reproductive 

Developmental 

Genotoxic 

Cancer 

Systemic 

Animal 

XYLENE 174 
XYLENE 175 

3. HEALTH EFFECTS 

because of study design limitations, such as inadequate characterization of exposure and concurrent 

exposure to other solvents such as toluene and benzene. 

Studies conducted on experimental animals have been fairly extensive (Figure 3-9) and have focused on 

the adverse health effects following inhalation and oral exposure to xylene. Data are comprehensive on 

neurological and systemic effects. There are several developmental studies in animals, although most 

have limitations. Limited information exists on the carcinogenicity of mixed xylenes. A large number of 

studies on the genotoxicity of xylene are available, with the majority reporting negative results. 

3.12.2 Identification of Data Needs 

Acute-Duration Exposure. There are acute exposure data in humans and/or animals that indicate 

that the central nervous system (Andersson et al. 1981; Arthur and Curnock 1982; Bushnell 1989; 

Carpenter et al. 1975a; De Ceaurriz et al. 1983; Dudek et al. 1990; Dyer et al. 1988; Ernstgard et al. 2002; 

Furnas and Hine 1958; Gamberale et al. 1978; Ghosh et al. 1987; Klaucke et al. 1982; Korsak et al. 1988; 

Martinez et al. 1989; Molnar et al. 1986; Morley et al. 1970; Muralidhara and Krishnakumari 1980; 

Nersesian et al. 1985; NIOSH 1981; NTP 1986; Padilla and Lyerly 1989; Pryor et al. 1987; Savolainen 

and Linnavuo 1979; Savolainen et al. 1978, 1979b, 1984, 1985a; Seppalainen et al. 1989; 

Wimolwattanapun et al. 1987) and possibly the developing fetus (Balogh et al. 1982; Hudak and Ungvary 

1978; Marks et al. 1982; Ungvary 1985; Ungvary and Tatrai 1985; Ungvary et al. 1980b, 1981) are the 

major targets of acute xylene toxicity by the inhalation and oral routes. Limited information is available 

on the nervous system effects of dermal exposure to xylenes (Goldie 1960; Hipolito 1980; Kilburn et al. 

1985; Roberts et al. 1988). Death has been observed to occur as a result of exposure by inhalation, oral, 

and dermal exposure, and lethal and nonlethal levels of total xylenes have been determined (Abu Al 

Ragheb et al. 1986; Bonnet et al. 1979; Cameron et al. 1938; Carpenter et al. 1975a; Condie et al. 1988; 

Dyer et al. 1988; Furnas and Hine 1958; Gerarde 1959; Harper et al. 1975; Hine and Zuidema 1970; 

Morley et al. 1970; Muralidhara and Krishnakumari 1980; NTP 1986; Pound and Withers 1963; Smyth et 

al. 1962; Ungvary et al. 1980b; Wolf et al. 1956). Acute studies have demonstrated that xylene is 

irritating to the skin and eyes (Anderson et al. 1986; Carpenter et al. 1975a; Consumer Products Testing 

1976; De Ceaurriz et al. 1981; Engstrom et al. 1977; Ernstgard et al. 2002; Food and Drug Research Labs 

1976a; Hine and Zuidema 1970; Klaucke et al. 1982; Nelson et al. 1943; Nersesian et al. 1985; NIOSH 

1981; Pound and Withers 1963; Riihimaki 1979b; Smyth et al. 1962; Wolf et al. 1956). Inhalation of 

xylenes has also been shown to cause irritation of the respiratory tract and dyspnea (Carpenter et al. 
XYLENE 176 

3. HEALTH EFFECTS 

1975a; De Ceaurriz et al. 1981; Ernstgard et al. 2002; Furnas and Hine 1958; Klaucke et al. 1982; Korsak 

et al. 1988; Morvai et al. 1976; Nelson et al. 1943; Nersesian et al. 1985; NIOSH 1981). 

Data were sufficient to determine an acute-duration inhalation MRL for mixed xylenes based on increased 

respiratory effects (slight irritation and impaired lung function) and subjective neurological symptoms 

(headache, dizziness, feeling of intoxication) in humans exposed to m-xylene (Ernstgard et al. 2002). The 

acute oral MRL for mixed xylenes is based on a NOAEL for neurological effects in rats exposed to 

p-xylene (Dyer et al. 1988). Additional information on the effects observed after acute dermal exposure 

is needed due to the likelihood that acute duration skin contact with xylenes could occur in the home, 

workplace, and possibly at hazardous waste sites. Pharmacokinetic data and toxicity data indicate that 

xylene is absorbed through the skin (Dutkiewicz and Tyras 1968; Engstrom et al. 1977; Kezic et al. 2001; 

McDougal et al. 1990; Morgan et al. 1991; Riihimaki 1979b; Riihimaki and Pfaffli 1978; Skowronski et 

al. 1990), although the relative absorption by this route is difficult to ascertain because of the rapid 

evaporation of xylenes from the skin. A PBPK model has been developed for dermal exposure (Thrall 

and Woodstock 2003). Additional acute-duration inhalation and oral studies clarifying which nervous 

system effects are the most sensitive are needed to provide critical, reliable guidance values for acute 

exposure. 

Intermediate-Duration Exposure. Intermediate-duration inhalation, oral, and dermal studies have 

identified the central nervous system (Condie et al. 1988; Goldie 1960; Honma et al. 1983; Jenkins et al. 

1970; NTP 1986; Pryor et al. 1987; Rank 1985; Savolainen and Seppalainen 1979; Savolainen et al. 

1979a), liver (Condie et al. 1988; Elovaara et al. 1989; Ungvary 1990), kidneys (Condie et al. 1988), and 

possibly the developing fetus (Bio/dynamics 1983; Mirkova et al. 1979, 1983; Taskinen et al. 1989) as the 

primary targets of intermediate-duration xylene exposure. Very few studies were located that examined 

the effects associated with intermediate-duration dermal exposure to xylenes (Mirkova et al. 1979; Wolf 

et al. 1956). Pharmacokinetic data indicate that absorption of xylenes occurs through the skin; however, 

it is difficult to determine whether similar end points would be expected after repeated dermal exposure to 

xylenes. Human skin may be repeatedly exposed to xylene as a result of occupational and home use. 

Repeated exposure of the skin to contaminated media at hazardous waste sites may also occur. Therefore, 

a well-designed and well-conducted intermediate-duration dermal study may help to better characterize 

the potential health hazards associated with repeated dermal exposure to xylenes. 

An intermediate-duration inhalation MRL was derived based on a NOAEL for decreased rotarod 

performance in rats discontinuously exposed to m-xylene for 3 months (Korsak et al. 1994). Data were 
XYLENE 177 

3. HEALTH EFFECTS 

sufficient to determine an intermediate-duration oral MRL for mixed xylenes based on a LOAEL for 

hyperactivity in animals (Condie et al. 1988). Deficiencies of the intermediate-duration oral toxicity 

database include the lack of testing for neurobehavioral effects, which appear to be the most sensitive end 

points in acute-duration oral toxicity studies, and lack of developmental and multi-generational data. 

Additional intermediate-duration oral studies that identify a NOAEL and LOAEL for sensitive 

neurobehavioral effects are needed to provide reliable guidance values for intermediate-duration 

exposure. 

Chronic-Duration Exposure and Cancer. Few human (Arp et al. 1983; Askergren 1981, 1982; 

Askergren et al. 1981b, 1981c; Brasington and Thorpe-Swenson 1991; Dolara et al. 1982; Franchini et al. 

1983; Gupta et al. 1990; Hipolito 1980; Holmberg and Nurminen 1980; Kilburn et al. 1985; Kucera 1968; 

Kurppa and Husman 1982; Moszczynski and Lisiewicz 1983, 1984a; Roberts et al. 1988; Smolik et al. 

1973; Triebig et al. 1992a, 1992b; Uchida et al. 1993; Wilcosky et al. 1984) or animal studies (Tatrai et 

al. 1981; Maltoni et al. 1983, 1985; NTP 1986) were available regarding the health effects associated with 

chronic exposure to xylenes. The central nervous system (Gupta et al. 1990; Hipolito 1980; NTP 1986; 

Roberts et al. 1988) and the kidney (Askergren 1981, 1982; Askergren et al. 1981b, 1981c; Franchini et 

al. 1983) appear to be the primary targets of chronic xylene exposure. However, the study by Uchida et 

al. (1993) suggests that in healthy individuals, kidney effects are unlikely to occur at concentrations 

below those that cause neurological effects and eye and respiratory tract irritation. A chronic-duration 

inhalation MRL was derived based on the subjective neurological and respiratory effects noted in the 

Uchida et al. (1993) study. It is not clear if the effects noted in this study were a result of exposure at the 

TWA (14 ppm) or a result of short-term exposure at higher concentrations. Studies that focus on 

neurological effects with different exposure scenarios resulting in the same TWA may help to distinguish 

between effects caused by transient exposure to higher concentrations and those caused by stable lowlevel exposure. A chronic-duration oral MRL was calculated based on a NOAEL for decreased body 

weight at a dose that reduced survival in rats exposed to mixed xylenes for 2 years (NTP 1986). No 

specific target organ was identified in this study and there is uncertainty as to the NOAEL because there 

is no information on sensitive neurobehavioral effects. No chronic dermal studies of xylenes were 

identified. Since the inhalation and oral routes of exposure are the most important for individuals living 

near hazardous waste sites or in occupational settings, additional inhalation and oral studies are needed to 

provide critical, reliable guidance values for chronic exposure to xylenes. 

Few epidemiological studies were available regarding the development of cancer in humans following 

inhalation, oral, or dermal exposure to mixed xylene or xylene isomers (Arp et al. 1983; Wilcosky et al. 
XYLENE 178 

3. HEALTH EFFECTS 

1984). Several oral carcinogenicity bioassays involving lifetime exposure have been conducted with 

mixed xylene in rats and mice (Maltoni et al. 1983, 1985; NTP 1986); however, all of these bioassays 

contained limitations that preclude a definitive conclusion regarding the carcinogenicity of xylene. 

Several dermal studies are available in which xylene (unspecified isomeric content) was evaluated for its 

ability to enhance tumor induction by tumor-initiating and tumor-promoting agents (Berenblum 1941; 

Pound 1970; Pound and Withers 1963); however, these studies are less than lifetime and have often 

involved exposures to more than one chemical agent. No animal cancer bioassays involving inhalation 

exposure to mixed xylene or isomers of xylene have been conducted. Because the issue of the potential 

carcinogenicity of xylenes has not been resolved, additional bioassays are needed. Chronic inhalation 

exposure to low levels is needed in these studies because chronic exposure by this route may be 

encountered in the workplace, home, or in the vicinity of hazardous waste sites. 

Genotoxicity. Limited data are available regarding the genotoxicity of inhalation of xylenes in 

humans (Haglund et al. 1980; Pap and Varga 1987; Richer et al. 1993). No data are available regarding 

the potential genotoxicity of xylenes in humans following oral or dermal exposure. Animal studies 

examining the genotoxicity of inhalation (Zhong et al. 1980) or oral (Feldt 1986) exposure to xylenes 

have been almost uniformly negative. The only positive assay was for DNA fragmentation in skin of rats 

exposed dermally (Rogers et al. 2001); this effect appears to be related to cell death. Also, a variety of in 

vitro assays (Anderson et al. 1990; Bos et al. 1981; Connor et al. 1985; DeMarini et al. 1991; Epler et al. 

1979; Florin et al. 1980; Gerner-Smidt and Friedrich 1978; Haworth et al. 1983; Hejtmankova et al. 1979; 

Litton Bionetics 1978b; McCarroll et al. 1981a, 1981b; NTP 1986; Pool and Lin 1982; Richer et al. 1993; 

Shimizu et al. 1985) produced negative results. Because of the large number of negative studies that 

exist, additional in vivo or in vitro assays of the genotoxicity potential of xylenes are not needed. 

Reproductive Toxicity. One epidemiological study suggested that paternal exposure to xylenes in 

the workplace may increase the likelihood of abortions; however, this study was limited by the size of the 

sample population (Taskinen et al. 1989). Only one animal inhalation study has been conducted to test 

the potential reproductive toxicity of mixed xylene (Bio/dynamics 1983). No studies of reproductive 

function have been conducted on either mixed xylene or the individual xylene isomers in animals 

following exposure via oral or dermal routes. Histopathological examination of reproductive organs of 

rats and mice following intermediate (NTP 1986; Wolfe 1988a, 1988b) and chronic (NTP 1986) oral 

bioassays revealed no adverse effects; however, given the high potential for human exposure to xylene 

and its isomers and their ability to cross the placenta (Ghantous and Danielsson 1986; Ungvary et al. 

1980b), additional studies in animals and epidemiological studies in humans are needed to assess more 
XYLENE 179 

3. HEALTH EFFECTS 

fully the reproductive toxicity of xylene and its isomers. A multi-generation reproductive toxicity study 

in animals is needed, possibly combined with a study examining developmental neurotoxicity end points. 

Developmental Toxicity. Congenital defects of the central nervous system in children whose 

mothers were exposed occupationally to mixed xylene vapors were reported in two case studies 

(Holmberg and Nurminen 1980; Kucera 1968). However, the studies have many limitations, and no 

conclusion can be made. Animal inhalation, oral, and dermal studies have provided some information on 

the developmental effects of xylene and its isomers (Balogh et al. 1982; Bio/dynamics 1983; Hudak and 

Ungvary 1978; Litton Bionetics 1978a; Marks et al. 1982; Mirkova et al. 1979, 1983; Rosen et al. 1986; 

Seidenberg et al. 1986; Ungvary 1985; Ungvary and Tatrai 1985; Ungvary et al. 1980b, 1981); however, 

the quality of many of these studies precludes drawing conclusions. An inhalation developmental study 

in rats evaluated all three isomers and mixed xylenes using standard contemporary protocols, and found 

all tested xylenes could produce developmental toxicity (Saillenfait et al. 2003). Ingestion of aspirin by 

pregnant rats exposed to xylene have been shown to potentiate adverse maternal and fetal effects 

(Ungvary 1985). The most critical developmental studies in animals relate to neurobehavioral deficits 

observed in offspring following inhalation exposure of dams to xylenes, since these effects persist for 

months (Hass and Jakobsen 1993, 1995; Hass et al. 1997). No developmental neurobehavioral studies of 

xylenes have been conducted in animals exposed orally. Such studies are needed to better assess the 

potential of developmental toxicity and dose-response relationships associated with oral exposure to 

xylene. More information is needed on the mechanism of xylene-induced developmental toxicity, 

particularly of the developing nervous system, because this appears to be a sensitive target of xylene 

exposure. Such a study could be combined with a multi-generational reproductive toxicity study. 

Immunotoxicity. Several occupational studies have been conducted to evaluate the immunological 

effects of xylene (Moszczynski and Lisiewicz 1983, 1984a; Smolik et al. 1973); however, workers in 

these studies were exposed to other chemical agents in addition to xylene. No animal studies involving 

exposure by any route have been conducted to examine directly the immunotoxicity of mixed xylene or 

the xylene isomers, although a decrease in thymus weight was observed in one oral study (Condie et al. 

1988). Inhalation exposure studies in animals employing only xylene or its isomers may remove 

uncertainties about the immunotoxicity potential of xylene. One case report indicates that dermal 

sensitization to xylene is possible (Palmer and Rycroft 1993). Dermal sensitization tests would provide 

additional information on whether an allergic response to xylene is likely, since the potential for skin 

contact by humans occurs in occupational settings and in soil and water at hazardous waste sites. 
XYLENE 180 

3. HEALTH EFFECTS 

Neurotoxicity. Human and animal studies regarding neurologic effects have been conducted 

following inhalation, oral, and dermal exposures to xylene (Andersson et al. 1981; Carpenter et al. 1975a; 

Condie et al. 1988; Dyer et al. 1988; Ernstgard et al. 2002; Gagnaire and Langlais 2005; Gagnaire et al. 

2001, 2006; Gamberale et al. 1978; Gralewicz and Wiaderna 2001; Gralewicz et al. 1995; Klaucke et al. 

1982; Korsak et al. 1990, 1991, 1992, 1993, 1994; Morley et al. 1970; NIOSH 1981; NTP 1986; Nylen 

and Hagman 1994; Ogata et al. 1970; Savolainen et al. 1984, 1985a; Wolfe 1988a, 1988b) (see Sections 

3.2.1.4 and 3.2.2.4 for additional data). Data from such studies indicate that xylene adversely affects the 

nervous system; all inhalation MRLs and the acute oral MRL are based, at least in part, on neurological 

effects of xylene. The majority of studies in humans and animals concentrated on the neurobehavioral 

effects of xylene. Further studies attempting to elucidate the mechanism of action of xylenes on the 

nervous system are needed to increase understanding of the neurotoxic effects produced by high 

concentrations of xylenes. An occupational study of workers exposed to low concentrations of mixed 

solvents including xylenes for 10–44 years found no significant effects on CAT-scan measures of brain 

atrophy (Triebig et al. 1992a), but specific information on xylene is not available. Additional wellconducted studies in animals on the histopathologic changes of the central nervous system following 

intermediate or chronic exposure are needed to provide useful information on permanent structural 

alterations induced by xylene. More epidemiological and/or animal data are needed to better assess 

sensitive neurological end points (subjective effects, behavior, performance) for intermediate and chronic 

exposures by both inhalation and oral routes. The priorities in descending order of need are chronic oral 

> intermediate oral = chronic inhalation > intermediate inhalation. 

Epidemiological and Human Dosimetry Studies. Limited epidemiological studies (Arp et al. 

1983; Askergren 1981, 1982; Askergren et al. 1981b, 1981c; Dolara et al. 1982; Franchini et al. 1983; 

Gupta et al. 1990; Holmberg and Nurminen 1980; Kilburn et al. 1985; Kucera 1968; Kurppa and Husman 

1982; Moszczynski and Lisiewicz 1983, 1984a; Smolik et al. 1973; Taskinen et al. 1989; Uchida et al. 

1993; Wilcosky et al. 1984) and no human dosimetry studies on any of the xylenes have been conducted. 

Much of the available information on the effects of xylene in humans comes from case reports (Abu Al 

Ragheb et al. 1986; Arthur and Curnock 1982; Brasington and Thorpe-Swenson 1991; Goldie 1960; 

Hipolito 1980; Klaucke et al. 1982; Martinez et al. 1989; Morley et al. 1970; Nersesian et al. 1985; 

Roberts et al. 1988) and occupational studies in which subjects were exposed to other chemical agents in 

addition to xylene (Arp et al. 1983; Askergren 1981, 1982; Askergren et al. 1981b, 1981c; Dolara et al. 

1982; Franchini et al. 1983; Gupta et al. 1990; Holmberg and Nurminen 1980; Jovanovic et al. 2004; 

Kilburn et al. 1985; Kucera 1968; Kurppa and Husman 1982; Moszczynski and Lisiewicz 1983, 1984a; 

Smolik et al. 1973; Taskinen et al. 1989; Uchida et al. 1993; Wilcosky et al. 1984). The best 
XYLENE 181 

3. HEALTH EFFECTS 

characterization of exposure, verified with urinary metabolite measurements, was conducted in the 

occupational study by Uchida et al. (1993); subjects were exposed to 70% xylene with little involvement 

of other chemicals, besides ethylbenzene, a component of mixed xylene. Many of the case reports and 

occupational studies were also limited because exposure conditions were not well characterized. 

Additional well-designed and well-controlled epidemiological studies of people living near waste sites or 

industries using xylene, or occupational studies in which xylene exposure conditions are better 

characterized, may be useful to better describe potential neurotoxic effects and their dose-response 

relationships. Epidemiological studies examining the nervous system, reproductive outcome, and renal 

effects associated with xylene exposure would be particularly useful since these have been shown to be 

sensitive end points. 

Human Sensory Studies on Oral Exposure. A sensory study is needed using human subjects on 

the detection of taste and smell thresholds for drinking water containing mixed xylenes. This data need is 

prompted by the observation that the guidance values for xylene (0.6–1 mg/kg/day) translated to typical 

daily water consumption (2 L/day) are only slightly below the maximum solubility of xylene in water 

(~145 mg/L). Information on the detectability of xylene at maximum solubility would be a useful rule of 

thumb for public health communications. This information might allow individuals to rule out water 

contamination at levels of concern in many situations. 

Biomarkers of Exposure and Effect. 

Exposure. Methods are available for determining xylene and its metabolite, methylhippuric acid, in 

biological tissues and fluids (Daniell et al. 1992; Jonai and Sato 1988; Kawai et al. 1991; Sedivec and 

Flek 1976b). These biomarkers of exposure are specific for xylene exposure and are sufficient for 

determining recent exposure to xylenes but are incapable of distinguishing short-term from intermediateand chronic-duration exposures. It would be useful to determine if a biomarker of longer-term exposure 

could be derived, although it is not known whether one could be found. 

Effect. No specific biomarkers of effects have been identified for xylenes. Xylenes have been 

demonstrated to cause a number of adverse health effects including central nervous system depression 

(Gamberale et al. 1978; Riihimaki and Savolainen 1980; Savolainen and Linnavuo 1979; Savolainen and 

Riihimaki 1981b; Savolainen et al. 1979b, 1984, 1985a). A number of neurological and cognitive 

function tests exist and have been used to identify central nervous system changes produced by xylenes. 

However, until the mechanism for nervous system disruption is identified, it is unlikely that a specific test 
XYLENE 182 

3. HEALTH EFFECTS 

could predict xylene-specific intoxication. Similarly, xylene treatment of the skin elicits increases in proinflammatory cytokines in blood (interleukin 1-alpha) and skin (tumor necrosis factor-alpha) (Ahaghotu 

et al. 2005; Chatterjee et al. 2005; Gunasekar et al. 2003), but these responses are not specific to xylene 

exposure. Assessment of hepatic enzyme induction is difficult without obtaining liver tissue. 

Demonstration of enhanced metabolism of substances by the microsomal enzyme system could be 

interpreted as microsomal induction; however, a large number of substances other than xylenes also 

induce enhanced enzyme activity. Renal impairment also has been associated with high levels of xylene 

exposure. Increased excretion of albumin, leukocytes, and erythrocytes demonstrates kidney damage of 

the type ascribed to xylene exposure, but these effects are not specific for xylenes. However, limited data 

are available associating levels of xylene in human tissues and fluids with adverse health effects. 

Available human studies have focused on the blood concentrations of m-xylene associated with central 

nervous system effects. Additional animal studies evaluating the association between xylene (or xylene 

metabolite) levels in other human tissues or fluids and adverse health effects are needed. 

Absorption, Distribution, Metabolism, and Excretion. The absorption, metabolism, and 

excretion of xylenes following inhalation, oral, and dermal exposures in humans and/or animals have 

been well characterized (Astrand 1982; Engstrom et al. 1977; Inoue et al. 1993; Jonai and Sato 1988; 

Kawai et al. 1991; Kezic et al. 2001; Ogata et al. 1970, 1979; Riihimaki 1979b; Riihimaki and Pfaffli 

1978; Riihimaki et al. 1979a, 1979b; Skowronski et al. 1990). The distribution of xylene has been well 

characterized in animals and identified to a small extent in humans. The database for absorption, 

distribution, and excretion of xylene isomers in humans and/or animals after inhalation exposure is most 

extensive. The database for oral and dermal exposures is not as extensive but has been well described. 

Differences in the rate of metabolism of xylenes after short-term or chronic exposure have been 

identified. Differences in the toxicokinetics of xylene seen when exposure occurs with xylene adsorbed 

to sandy or clay soil have also been examined. Dermal penetration and resulting doses of xylene could be 

better characterized. 

Although a number of route-specific PBPK models are available, a model is needed that would enable 

route-to-route extrapolation from intermediate- or chronic-duration inhalation data for oral exposure. 

Such a model would help address uncertainties in existing oral exposure data resulting from experimental 

bolus delivery to animals. Since environmental oral exposures involve consumption of contaminated 

drinking water during the course of a day, toxicity values based on bolus dosing would tend to 

overestimate risk. 
XYLENE 183 

3. HEALTH EFFECTS 

Comparative Toxicokinetics. The target organs and adverse health effects of xylenes are similar 

across species. Toxicokinetic studies have been performed in humans, rats, mice, rabbits, and monkeys 

(Adams et al. 2005; Astrand et al. 1978; Bakke and Scheline 1970; Bray et al. 1949; Ogata et al. 1979; 

Patel et al. 1978; Smith et al. 1982; Sugihara and Ogata 1978; van Doorn et al. 1980). There is reasonable 

correlation between the end points examined in these studies. The metabolism of m- and p-xylenes is 

similar in rats and humans. However, a difference in the metabolism of o-xylene in rats and in humans 

exists. Whereas o-xylene is almost exclusively metabolized to o-methylhippuric acid in humans, 10–56% 

of o-xylene is also conjugated by glucuronide and glutathione in rats. Toxic metabolic intermediates of 

xylene such as benzaldehyde found in rats have not been found in humans. Additional studies are needed 

to determine whether other differences exist in the metabolism of xylenes among species. Although 

Inoue et al. (1993) did not observe a sex-related difference in excretion in men and women occupationally 

exposed to xylenes, sex-related differences in the toxicokinetics of xylene have been identified in animals. 

Additional studies concerning sex/genetic factors controlling xylene metabolism in humans might by 

useful. 

Methods for Reducing Toxic Effects. Current methods used for reducing toxic effects of xylenes 

after acute exposures concentrate on decreasing absorption (HSDB 2007). Additional research on 

speeding excretion of xylene and reducing its concentration at its target organs are needed. As future 

research identifies the mechanisms underlying the toxic effects of xylenes, additional methods may be 

developed for combating the effects of xylene at the molecular level. 

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 studies examining health effects in children 

exposed to xylenes, but the effects are likely to be the same as those observed in exposed adults. As 

mentioned in the Developmental Toxicity and Neurotoxicity subsections, there is a need for more data on 

neurological (neurobehavioral) effects of xylenes in laboratory animals. Studies in rats indicated that 

inhalation exposure to xylenes during gestation can affect neurobehavioral performance of offspring 

(Hass and Jakobson 1995; Hass et al. 1997). Studies in laboratory animals exposed by the oral route 

could identify dose-response relationships for neurological effects that would help in the assessment of 

health risks for children exposed to drinking water containing xylene. 

There is currently insufficient age-specific information relevant to the absorption, distribution, 

metabolism, and elimination of xylenes in children. Although the absorption and distribution of xylenes 
XYLENE 184 

3. HEALTH EFFECTS 

are driven by their lipophilic properties and diffusion, and the main metabolizing enzyme (CYP2E1) is 

available at adult levels in children by year 1 (Vieira et al. 1996), not enough information is available for 

children <1 year old. No data are available relative to the possible contribution of other microsomal 

enzymes to xylene metabolism in young animals. The elimination of xylene and its metabolites from the 

body is relatively rapid and expected to be similar in children and adults. However, the balance between 

factors tending to facilitate xylene clearance in children (lower body fat content, larger liver-to-body 

weight ratio) and factors tending to slow clearance (immaturity of enzyme systems) is not well 

understood. Data are especially needed to compare pulmonary metabolism of xylenes to hepatic 

metabolism, since the contribution of pulmonary metabolism may be significant for inhalation exposures 

(Adams et al. 2005). These suggestions are consistent with the recommendations of the peer consultation 

meeting of the Voluntary Children’s Chemical Evaluation Program (VCCEP 2006). PBPK modeling 

studies indicate that xylenes can be excreted into breast milk (Fisher et al. 1997), but no PBPK models 

have been developed for children, fetuses, or pregnant women exposed to xylenes. Placental transfer of 

xylenes has been demonstrated in mice, but uptake by fetal tissues was lower than in maternal tissues 

(Ghantous and Danielsson 1986). Elimination of xylene and its metabolites is so rapid that there does not 

seem to be a need for pediatric-specific methods to reduce peak absorption. 

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 

The Federal Research in Progress database (FEDRIP 2006) listed research by Dr. Karla Thrall on the 

assessment of human exposure to volatile organic chemicals, including xylene, at Superfund sites. The 

study, which is supported by the National Institute of Environmental Health Sciences, is intended to 

extend existing PBPK models to describe uptake kinetics and brain dosimetry following exposure. The 

results of this research program are intended to improve the extrapolation from animal studies to relevant 

human exposure situations and to develop biomarkers of susceptibility and response in potentially 

exposed populations. Dr. Steven Dewey is developing methods for quantifying exposure of fetal 

macaques after administration of positron-labeled inhalants such as C11toluene to the macaque mother. 

This research, sponsored by the National Institute on Drug Abuse, could be useful in the future for 

evaluating fetal and postnatal behavioral deficits resulting from maternal exposure to such inhalants. 
XYLENE 185 

4. CHEMICAL AND PHYSICAL INFORMATION 

4.1 CHEMICAL IDENTITY 

Information regarding the chemical identity of m-, o-, and p-xylene and mixed xylene is located in 

Table 4-1. Commercial or mixed xylene generally contains about 40–65% m-xylene and up to 20% each 

of o-xylene, p-xylene, and ethylbenzene (Fishbein 1985). 

4.2 PHYSICAL AND CHEMICAL PROPERTIES 

Information regarding the physical and chemical properties of m-, o-, and p-xylene and mixed xylene is 

located in Table 4-2. 
CH3 CH3 CH3 

CH3 

CH3 

CH3 

CH3 CH

XYLENE 186 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of m-Xylene, o-Xylene, p-Xylene, and Mixed Xylenea 

Characteristics Mixed xylene m-Xylene o-Xylene p-Xylene 

Synonyms/trade 

names 

Dimethylbenzene; 

xylol; benzene, 

1,3-Dimethylbenzenec

; benzene, 

1,2-Dimethylbenzenec

; benzene, 

1,4-Dimethylbenzenec

; 

dimethyl-; ksylen 1-3-dimethyl-; m-di­ 1,2-dimethyl-; o-di­ benzene, 1,4-di­

(Polish); xiloli 

(Italian); xylenen 

(Dutch); xylole 

(German); methyl 

tolueneb

; Violet 3b 

methylbenzene; 

m-methyltoluene; 

1,3-xylene; m-xylolc

; 

meta-xylenec 

methylbenzene; 

o-methyltolueneb

; 

1,2-xylene; o-xylolc

; 

ortho-xylenec 

methyl-; p-dimethylbenzene; 

p-methyltoluene; 

1,4-xylene; 

p-xylolc

; 

para-xylenec 

Chemical formula C8H10 C8H10 C8H10 C8H10 

Chemical structure 

3 

Identification numbers: 

 CAS registry 1330-20-7 108-38-3 95-47-6 106-42-3 

 NIOSH RTECS ZE2100000d

 ZE2275000d ZE2450000d ZE2625000d

 EPA hazardous U239; F003 U239; F003 U239; F003 U239; F003 

waste 

 DOT/UN/NA/IMCO UN 1307; UN 1307; IMCO3.2; UN 1307; IMCO3.2; UN 1307; 

shipping IMCO3.2; IMCO3.3 IMCO3.3 IMCO3.2; 

IMCO3.3 IMCO3.3 

HSDB 4500 135 134 136 

NCI C55232 No data No data No data 

STCC 49 093 50 49 093 50 49 093 50 49 093 51 

a

All information obtained from HSDB 2007 except where noted. 

b

Lewis 2000 

c

NIOSH 2005 

d

RTECS 2007 

CAS = Chemical Abstracts Services; DOT/UN/NA/IMCO = Department of Transportation/United Nations/North 

America/Intergovernmental 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; RTECS = Registry of Toxic Effects of Chemical Substances; STCC = Standard 

Transport Commodity Code 
XYLENE 187 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of m-Xylene, o-Xylene, p-Xylene, and
 

Mixed Xylenea
 

Property 

Molecular weight 

Color 

Mixed xylene 

106.16b 

Clearc

 m-Xylene

 106.16b

 Colorlessc

 o-Xylene

 106.16b

 Colorlessc

 p-Xylene 

106.16b 

 Colorlessc 

Physical state 

Melting point 

Boiling point 

Density at 20 °C/4 °C 

Liquidc 

No data 

137–140 °Cb 

0.864 g/cm3e

 Liquidc 

-47.8 °Cd

 139.1 °Cd

 0.864 g/cm3e

 Liquidc

 -25.2 °Cd

 144.5 °Cd

 0.880 g/cm3e

 Liquidc 

 13.2 °Cd 

 138.4 °Cd 

 0.8611 g/cm3e 

Odor Sweet Sweet Sweet Sweet 

Odor threshold: 

Water No data No data No data No data 

Air 0.0045 mg/L 

(1.0 ppm)g 

0.05 ppmf

 0.05 ppmf 0.05 ppmf 

Solubility: 

Water at 25 °C 106 mg/Li

 161 mg/Lj 178 mg/Lj 162 mg/Lj 

Organic solvent(s) Miscible with alcohol 

and etherb 

Miscible with 

alcohol, ether, and 

other solventsb 

Miscible with 

alcohol and 

etherb 

Soluble in alcohol, 

ether, and other 

organic solventsb 

Partition coefficients: 

 Log Kow

 Log Koc 

Vapor pressure 

 No data 3.2k

 No data 2.22l 

6.72 mmHg at 21°C e 8.29 mmHg at 

25 °Cm 

3.12k

 2.11l 

6.61 mmHg at 

25 °Cn 

3.15k

 2.31l 

8.84 mm Hg at 25 °Cm 

Henry's law constant No data 7.18x10-3 atmm3

/molj 

5.18x10-3 atmm3

/molj 

6.90x10-3 atm-m3

/molo 

Autoignition 

temperature 

Flashpoint 

464 °C (867 °F) 

29 °C (CC)b 

527 °C 

 27 °C (CC)b 

463 °C 

 32 °C (CC)b 

528 °C 

 27 °C (CC)b 

Flammability limits No data 1.1B7.0% 1.0–7.0% 1.1–7.0% 

NFPA Flammability 

Classification 

3p 3p 3p 3p 

NFPA Reactivity 

Classification 

0q 0q 0q 0q 
XYLENE 188 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of m-Xylene, o-Xylene, p-Xylene, and
 

Mixed Xylenea
 

Property Mixed xylene m-Xylene o-Xylene p-Xylene 

Air conversion factorsr 1 ppm = 4.34 mg/m3l 1 ppm = 1 ppm = 1 ppm = 4.34 mg/m3l; 

4.34 mg/m3s; 4.34 mg/m3l; 1 ppm = 4.41 mg/m3t; 

1 ppm = 1 ppm = 1 mg/m3

 = 0.23 ppmt 

4.41 mg/m3t; 4.41 mg/m3t; 

1 mg/m3

 = 1 mg/m3 = 

0.23ppms 0.23 ppmt 

a

All information obtained from HSDB 2007 unless otherwise noted. 

b

O’Neil et al. 2001 

c

Lewis 1997 

d

Lide 2005 

e

Lewis 2001 

f

CHRIS 1999 

g

Carpenter et al. 1975a 

h

Gerarde 1959 

i

Yalkowsky and He 1992 

j

Sanemasa et al. 1982 

k

Hansch et al. 1995 

l

Abdul et al. 1987 

mChao et al. 1983 

n

AIChE 1996 

o

Foster et al. 1994 

p

Classified by the NFPA as a liquid that can be ignited under almost all normal temperature conditions. q

Classified by the NFPA as a liquid that is normally stable even under fire exposure conditions and that is not reactive 

with water. 

r

In air, ppb is a volume-to-volume ratio for vapor-phase compounds like xylenes. When air monitoring data are 

reported in terms of ppb or ppm, it is understood that this is equivalent to ppbv or ppmv (parts per billion or parts per 

million volume-to-volume ratio). 

s

Sandmeyer 1981 

t

Verschueren 2001 

CC = closed cup; NFPA = National Fire Protection Association; TOC = tag open cup 
XYLENE 189 

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

5.1 PRODUCTION 

U.S. manufacturers had an estimated annual production capacity of 18 billion pounds of mixed xylene in 

2006 (SRI 2006). This figure is based on maximum plant production volumes. Table 5-1 lists producers 

of mixed xylene and their estimated annual capacities. In 1990 and 1991, U.S. production of xylene 

totaled 6.2 and 6.1 billion pounds, respectively (Reisch 1992). These figures represent the total amount of 

mixed xylene actually produced by U.S. manufacturers based on data from trade associations and industry 

sources. The production of mixed xylene during the year 1995 was reported to be 9.5 billion pounds 

(Cannella 1998). According to data collected under the Toxic Substances Control Act Inventory Update 

Rule, the total production volume of mixed xylene reported by U.S. manufacturers has remained above 

1 billion pounds during each reporting year (1986, 1990, 1994, 1998, and 2002) (EPA 2002a). 

Table 5-2 summarizes the number of facilities in each state that manufactured or processed mixed xylene 

in 2004, the ranges of maximum amounts on site, if reported, and the activities and uses as reported in the 

Toxics Release Inventory (TRI) (TRI04 2006). The data listed in this table should be used with caution 

since only certain types of facilities are required to report. This is not an exhaustive list. 

The 2006 estimated U.S. annual production capacities of o- and p-xylene were 1 and 11 billion pounds, 

respectively (SRI 2006). These figures are based on maximum plant production volumes. Table 5-1 lists 

producers of o- and p-xylene and their estimated annual capacities. Production capacity data for m-xylene 

were not reported. 

According to estimates, over 943 million and 5.2 billion pounds of o- and p-xylene, respectively, were 

produced in the United States in 1990 (Reisch 1992; USITC 1991). The production volumes of o-xylene 

reported by United States manufacturers during 1986, 1990, 1994, 1998, and 2002 were within the ranges 

of >500 million pounds–1 billion pounds, >1 billion pounds, >500 million pounds–1 billion pounds, 

>1 billion pounds, and >500 million pounds–1 billion pounds, respectively (EPA 2002a). The ranges of 

production volumes reported during these years have remained unchanged for both m-xylene (>100– 

500 million pounds) and p-xylene (>1 billion pounds). 

It is not clear whether there is any relationship between the amounts of xylene isomers produced at an 

individual facility and the total amount of mixed xylenes produced at the same facility. Sources reporting 

production and capacity data do not specify whether companies that report amounts of both mixed 
XYLENE 190 

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

Table 5-1. Producers of Xylene and Estimated Annual Capacitiesa 

Annual capacity (millions of pounds) 

Producers Location(s) Mixed xylene m-Xylene o-Xylene p-Xylene 

BP America, Inc. Texas City, Texas 2,215 NR — 2,693 

 Whiting, Indiana 1,735 — — — 

 Decatur, Alabama — — — 2,420 

Chevron Phillips Pascagoula, Mississippi 1,025 — — 1,001 

Chemical Company LP 

Olefins and Polyolefins 

Business Unit 

Chevron Phillips Guayama, Puerto Rico 639 — 150 727 

Chemical Puerto Rico 

Core Inc. 

CITGO Petroleum Corpus Christi, Texas 538 — — — 

Corporation 

ConocoPhillips Alliance, Louisiana 432 — — — 

Refining, Marketing & 

Transportation Division 

 Sweeny, Texas 1,049 — — — 

ExxonMobil Chemical Baytown, Texas 1,710 — 280 1,316 

Company 

 Beaumont, Texas 705 — — 606 

 Chalmette, Louisiana 505 — 150 419 

Flint Hills Resources Corpus Christi, Texas 397 NR 397 1,322 

L.P. 

Corpus Christi, Texas 1,677 — — — 

HOVENSA, L.L.C. St. Croix, Virgin Islands 833 — — — 

Lyondell-Citgo Refining, Houston, Texas 765 — — 399 

LP 

Marathon Petroleum Catlettsburg, Kentucky 183 — — — 

LLC 

 Texas City, Texas 73 — — — 

Shell Chemical Deer Park, Texas 355 — — — 

Company 

Sunoco, Inc. Marcus Hook, Pennsylvania 187 — — — 

 Toledo, Ohio 377 — — — 

Westville, New Jersey 441 — — 

Total Petrochemicals Port Arthur, Texas 855 — — — 

USA, Inc. 

Valero Energy Corpus Christi, Texas 500 — — — 

Corporation 

Corpus Christi, Texas 652 — — — 

Three Rivers, Texas 361 — — — 

Totals 18,209 NR 976 10,903 

a

Derived from SRI 2006 

— = not produced; NR = the xylene was produced, but the amount was not reported 
XYLENE 191 

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

Table 5-2. Facilities that Produce, Process, or Use Xylene (Mixed) 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

AK 26 10,000 499,999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12 

AL 181 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

AR 97 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

AS 2 1,000 9,999,999 9, 11 

AZ 64 0 9,999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13 

CA 307 0 999,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

CO 65 100 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

CT 73 0 49,999,999 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13 

DE 29 0 99,999,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13 

FL 99 0 999,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 

GA 140 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

GU 4 1,000,000 9,999,999 2, 3, 4, 7, 9, 12, 13 

HI 20 100 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14 

IA 121 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

ID 21 100 9,999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12 

IL 255 0 10,000,000,000 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

IN 234 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

KS 158 0 999,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

KY 135 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

LA 253 0 999,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MA 95 0 49,999,999 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

MD 69 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

ME 30 100 49,999,999 2, 3, 4, 6, 7, 8, 9, 10, 11, 12 

MI 289 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MN 117 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MO 147 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 

MP 6 100 999,999 2, 3, 4, 7, 9 

MS 135 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

MT 32 100 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

NC 140 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

ND 26 100 49,999,999 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12 

NE 67 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

NH 41 0 999,999 2, 3, 6, 7, 8, 9, 10, 11, 12, 13 

NJ 199 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

NM 35 100 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

NV 27 100 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 

NY 161 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

OH 300 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 
XYLENE 192 

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

Table 5-2. Facilities that Produce, Process, or Use Xylene (Mixed) 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

OK 107 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

OR 73 0 49,999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13 

PA 224 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

PR 89 0 10,000,000,000 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

RI 48 0 49,999,999 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12 

SC 100 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

SD 35 0 99,999,999 2, 3, 7, 8, 10, 11, 12 

TN 166 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

TX 535 0 10,000,000,000 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

UT 87 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

VA 125 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

VI 11 100,000 10,000,000,000 1, 2, 3, 4, 5, 6, 7, 8, 9, 12 

VT 12 100 999,999 5, 7, 10, 11, 12 

WA 121 0 10,000,000,000 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

WI 170 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

WV 85 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

WY 42 100 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 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 

2. Import 

3. Onsite use/processing 

4. Sale/Distribution 

5. Byproduct 

6. Impurity 

7. Reactant 

8. Formulation Component 

9. Article Component 

10. Repackaging 

11. Chemical Processing Aid 

12. Manufacturing Aid 

13. Ancillary/Other Uses 

14. Process Impurity 

Source: TRI04 2006 (Data are from 2004) 
XYLENE 193 

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

xylenes and the individual isomers have separated the amounts of the isomers from the mixed xylenes (in 

which case, they would be counting these amounts twice) or whether they are reporting total amounts of 

mixed xylenes and xylene isomers separately that are finished and ready for use. 

Tables 5-3, 5-4, and 5-5 list the U.S. facilities that manufacture or process m-, o-, and p-xylene, 

respectively, with their corresponding location, range of amounts on site, and activities and uses. This 

information is based on the release data reported to the TRI for 2004 (TRI04 2006). The data listed in 

these tables should be used with caution since only certain types of facilities are required to report and the 

actual figures may be higher. 

Mixed xylene consists of a mixture of ethylbenzene and the m-, o-, and p-isomers of xylene; m-xylene 

predominates. In addition to ethylbenzene, mixed xylene may contain nonxylene hydrocarbons, such as 

benzene, toluene, trimethylbenzene, phenol, thiophene, and pyridine; the combined volume of these 

nonxylene hydrocarbons is only a fraction of a percentage point of the composition of mixed xylene 

(Gerarde 1960; Riihimaki and Hanninen 1987; Sandmeyer 1981). Current formulations of mixed xylene 

are relatively free (<0.001%) of benzene contamination (Gosselin et al. 1984; Riihimaki and Hanninen 

1987). The exact composition of mixed xylene depends on the manufacturing method used. Currently, 

nearly all mixed xylene is produced as a catalytic reformate of petroleum and consists of approximately 

44% m-xylene, 20% o-xylene, 20% p-xylene, and 15% ethylbenzene (HSDB 2007; NIOSH 1975). 

Mixed xylene may also be manufactured from coal tar, yielding a mixture of approximately 45–70% 

m-xylene, 23% p-xylene, 10–15% o-xylene, and 6–10% ethylbenzene (HSDB 2007). Other production 

processes include gasoline pyrolysis and disproportionation of toluene, both of which produce a mixture 

free of ethylbenzene, and recovery from coke-oven light oil (HSDB 2007; NIOSH 1975; Ransley 1984). 

The xylene isomers are produced from mixed xylene. m-Xylene is obtained from mixed xylene via 

crystallization to remove p-xylene and fractionation to remove o-xylene and ethylbenzene, or via 

complexing with hydrofluoric acid and boron trifluoride (HSDB 2007). o-Xylene is isolated from mixed 

xylene via distillation but can also be produced by the isomerization of m-xylene (HSDB 2007). 

p-Xylene is derived from mixed xylene by crystallization, solvent extraction, or adsorption (HSDB 2007; 

Lewis 2001). 
XYLENE 194 

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

Table 5-3. Facilities that Produce, Process, or Use m-Xylene 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

AL 16 1,000 499,999,999 1, 2, 3, 4, 5, 6, 7, 10, 11, 12, 13 

AR 10 100 9,999,999 7, 8, 9, 11, 12 

AZ 2 10,000 99,999 10, 12 

CA 35 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

CO 1 1,000,000 9,999,999 1, 4 

CT 2 10,000 99,999 10 

DE 1 10,000 99,999 7, 12 

FL 7 1,000 9,999,999 2, 3, 10, 11, 12 

GA 7 100 999,999 1, 4, 7, 10, 11, 13 

GU 2 0 9,999 9 

HI 7 1,000,000 9,999,999 1, 2, 5, 7, 10, 12, 13, 14 

IA 8 100 99,999 8, 9, 10, 11, 12 

IL 21 100 49,999,999 1, 2, 3, 5, 6, 7, 9, 11, 12 

IN 7 100 9,999,999 6, 7, 8, 11, 12 

KS 10 100 999,999 5, 6, 7, 9, 10, 12 

KY 9 1,000 99,999 1, 4, 5, 10, 11, 12 

LA 17 1,000 49,999,999 1, 2, 3, 4, 5, 6, 7, 9, 12, 13, 14 

MA 2 0 99,999 2, 3, 7, 10 

MD 2 10,000 99,999 3, 4, 5, 11 

MI 5 100 99,999 7, 8, 10, 11, 12 

MN 3 1,000 99,999 7, 10 

MO 10 1,000 999,999 2, 7, 9, 10, 11, 12 

MS 21 1,000 99,999,999 1, 2, 3, 4, 5, 6, 7, 10, 11, 12, 13, 14 

MT 1 10,000 99,999 2, 4 

NC 9 0 999,999 1, 3, 5, 6, 7, 8, 10, 12 

NE 9 100 999,999 2, 3, 7, 11, 12 

NH 3 0 99,999 7, 11, 12 

NJ 10 1,000 49,999,999 2, 3, 6, 7, 10, 11, 12 

NM 6 100,000 9,999,999 1, 2, 3, 4, 7, 9, 12 

NV 1 100,000 999,999 9 

NY 8 0 99,999 2, 3, 6, 7, 9, 10, 11 

OH 7 1,000 999,999 6, 7, 8, 9, 10, 11, 12 

OK 3 1,000 9,999,999 4, 7, 9, 12 

OR 3 1,000 99,999 7, 10, 12 

PA 20 100 49,999,999 1, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13 

PR 18 1,000 10,000,000,000 1, 2, 3, 4, 5, 6, 7, 9, 10, 12, 13 

SC 9 1,000 999,999 6, 7, 10, 11, 12 

TN 20 100 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

TX 71 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 
XYLENE 195 

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

Table 5-3. Facilities that Produce, Process, or Use m-Xylene 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

UT 5 1,000 9,999,999 1, 4, 9, 10 

VA 6 1,000 9,999,999 1, 2, 4, 9, 10, 11, 12 

WA 1 100 999 12 

WI 6 0 99,999 6, 7, 8, 10, 11, 12, 13 

WV 3 10,000 9,999,999 1, 4, 6, 7, 8 

a

Post office state abbreviations used 

b

Amounts on site reported by facilities in each state 

c

Activities/Uses: 

1. Produce 

2. Import 

3. Onsite use/processing 

4. Sale/Distribution 

5. Byproduct 

6. Impurity 

7. Reactant 

8. Formulation Component 

9. Article Component 

10. Repackaging 

11. Chemical Processing Aid 

12. Manufacturing Aid 

13. Ancillary/Other Uses 

14. Process Impurity 

Source: TRI04 2006 (Data are from 2004) 
XYLENE 196 

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

Table 5-4. Facilities that Produce, Process, or Use o-Xylene 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

AL 25 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 10, 11, 12, 13 

AR 9 0 9,999,999 2, 3, 7, 9, 10, 12 

AZ 3 1,000 99,999 3, 7, 10, 12 

CA 46 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13 

CO 2 10,000 9,999,999 1, 4, 12 

CT 4 0 999,999 7, 10, 11, 12 

DE 2 100,000 999,999 7, 10, 11 

FL 2 1,000 9,999,999 7, 12 

GA 15 0 999,999 7, 10, 11, 12 

GU 2 0 9,999 9 

HI 7 1,000,000 9,999,999 1, 2, 5, 7, 10, 12, 13, 14 

IA 7 0 99,999 8, 10, 11, 12 

IL 19 0 49,999,999 2, 3, 6, 7, 10, 11, 12 

IN 5 100 99,999 7, 10, 11, 12 

KS 11 1,000 9,999,999 1, 2, 3, 4, 6, 7, 9, 10, 12 

KY 1 10,000 99,999 10 

LA 24 0 10,000,000,000 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13 

MA 6 0 99,999 2, 3, 7, 9, 10, 12 

MD 3 1,000 99,999 2, 3, 4, 5, 6, 10, 11 

MI 7 0 99,999 1, 5, 6, 7, 9, 10, 11, 12, 13 

MN 1 0 99 2, 3, 12 

MO 14 0 49,999,999 2, 3, 6, 7, 9, 10, 12 

MS 17 1,000 99,999,999 1, 2, 3, 4, 5, 6, 7, 10, 12, 13, 14 

MT 1 10,000 99,999 2, 4 

NC 12 0 999,999 1, 2, 3, 5, 7, 10, 11, 12, 13 

NE 8 100 99,999 2, 3, 7, 11, 12 

NH 2 0 99 11, 12 

NJ 24 0 99,999,999 2, 3, 4, 6, 7, 9, 10, 11, 12 

NM 2 100,000 9,999,999 1, 2, 3, 4, 7, 12 

NY 6 0 99,999 2, 3, 9, 10, 11, 12 

OH 11 0 99,999 2, 3, 7, 8, 9, 10, 11, 12 

OK 1 0 0 7, 10, 12 

PA 26 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

PR 25 1,000 10,000,000,000 1, 2, 3, 4, 5, 6, 7, 10, 11, 12, 13 

RI 4 10,000 999,999 7, 10, 12 

SC 10 1,000 9,999,999 6, 10, 11, 12, 14 

TN 22 0 49,999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13 

TX 76 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

UT 5 10,000 9,999,999 1, 3, 4, 9 
XYLENE 197 

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

Table 5-4. Facilities that Produce, Process, or Use o-Xylene 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

VA 2 10,000 9,999,999 1, 2, 4, 9, 12 

WA 4 100 9,999,999 6, 7, 8, 12, 13 

WI 6 1,000 999,999 10, 12 

WV 7 100 9,999,999 1, 2, 3, 4, 6, 7, 8, 10 

a

Post office state abbreviations used 

b

Amounts on site reported by facilities in each state 

c

Activities/Uses: 

1. Produce 

2. Import 

3. Onsite use/processing 

4. Sale/Distribution 

5. Byproduct 

6. Impurity 

7. Reactant 

8. Formulation Component 

9. Article Component 

10. Repackaging 

11. Chemical Processing Aid 

12. Manufacturing Aid 

13. Ancillary/Other Uses 

14. Process Impurity 

Source: TRI04 2006 (Data are from 2004) 
XYLENE 198 

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

Table 5-5. Facilities that Produce, Process, or Use p-Xylene 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

AL 14 1,000 499,999,999 1, 2, 3, 4, 5, 6, 7, 11, 12, 13 

AR 6 1,000 9,999,999 7, 9, 10 

AZ 1 10,000 99,999 12 

CA 33 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13 

CO 2 100,000 9,999,999 1, 4 

DE 1 10,000 99,999 7, 12 

FL 1 1,000 9,999 10 

GA 6 100 99,999 2, 3, 7, 10, 11, 12 

HI 7 1,000,000 9,999,999 1, 2, 5, 7, 10, 12, 13, 14 

IA 6 0 99,999 8, 10, 11 

IL 7 0 999,999 1, 6, 7, 10, 11, 13 

IN 1 10,000 99,999 7 

KS 4 1,000 99,999 7, 10, 12 

KY 1 1,000 9,999 12 

LA 11 0 49,999,999 1, 3, 4, 6, 7, 13 

MA 3 1,000 99,999 7, 9, 10 

MD 1 10,000 99,999 3, 4, 5 

MI 2 1,000 99,999 7, 9 

MN 1 1,000 9,999 11 

MO 2 1,000 9,999 10, 12 

MS 9 1,000 99,999,999 1, 2, 3, 4, 5, 7, 12, 13, 14 

MT 1 10,000 99,999 2, 4 

NC 12 0 499,999,999 1, 2, 3, 5, 6, 9, 10 

NE 9 100 99,999 2, 3, 7, 11, 12 

NH 1 0 99 12 

NJ 6 100 9,999,999 3, 6, 7, 9, 10, 11, 12 

NM 2 100,000 999,999 1, 2, 3, 4, 7, 12 

NY 7 100 999,999 6, 7, 9, 10, 11 

OH 2 1,000 99,999 8, 11, 12 

PA 17 100 49,999,999 1, 3, 4, 5, 7, 8, 9, 12, 13 

PR 10 10,000 10,000,000,000 1, 2, 3, 4, 6, 10 

SC 6 10,000 499,999,999 6, 12, 14 

TN 20 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 

TX 61 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

UT 5 10,000 9,999,999 1, 3, 4, 9, 10 

VA 1 1,000,000 9,999,999 1, 4, 12 

VI 6 100,000 10,000,000,000 1, 2, 3, 4, 6, 7 

WA 1 100 999 12 
XYLENE 199 

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

Table 5-5. Facilities that Produce, Process, or Use p-Xylene 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

WI 4 1,000 99,999 7, 11, 12 

WV 5 1,000 9,999,999 1, 4, 6, 7, 8, 10 

a

Post office state abbreviations used 

b

Amounts on site reported by facilities in each state 

c

Activities/Uses: 

1. Produce 

2. Import 

3. Onsite use/processing 

4. Sale/Distribution 

5. Byproduct 

6. Impurity 

7. Reactant 

8. Formulation Component 

9. Article Component 

10. Repackaging 

11. Chemical Processing Aid 

12. Manufacturing Aid 

13. Ancillary/Other Uses 

14. Process Impurity 

Source: TRI04 2006 (Data are from 2004) 
XYLENE 200 

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

5.2 IMPORT/EXPORT 

Available import and export data for mixed, o-, m-, and p-xylene are shown in Table 5-6. Amounts of 

U.S. imports and exports reported for mixed xylenes appear to be independent of the amounts reported for 

the individual xylene isomers. U.S. imports and exports of total xylenes during 2005 were approximately 

1.3 billion liters and 280 million liters, respectively (USDOC 2005). 

5.3 USE 

Approximately 70% of mixed xylene is used in the production of ethylbenzene and the m-, o-, and 

p-isomers. The remaining mixed xylene is used as a solvent, in products such as paints and coatings, or 

blended into gasoline (Fishbein 1988; HSDB 2007; NCI 1985; Riihimaki and Hanninen 1987). 

The xylene isomers are used primarily for internal industrial operations as solvents and intermediates in 

synthetic reactions. m-Xylene is a chemical intermediate in the production of isophthalic acid and 

isophthalonitrile; isophthalic acid, in turn, is used in the manufacture of polyesters. o-Xylene is a 

chemical intermediate in the synthesis of phthalic anhydride (for plasticizers), phthalonitrile, 

4,4-(trifluoro-1-(trifluoromethyl) ethylidene) diphthalic anhydride (for polyimide polymers), o-toluic 

acid, vitamins, and pharmaceuticals. p-Xylene is a chemical intermediate for the synthesis of dimethyl 

terephthalate, terephthalic acid (for polyesters), dimethyl tetrachloroterephthalate, vitamins, and 

pharmaceuticals. Both o-xylene and p-xylene are used as components of insecticides (HSDB 2007; 

Lewis 2001). 

5.4 DISPOSAL 

Various methods of incineration are used in the disposal of xylene isomers, such as fluidized bed rotary 

kiln and liquid injection incinerator methods (EPA 1981a; HSDB 2007). The addition of a more 

flammable solvent has been suggested to make the process easier (HSDB 2007). 

Criteria for the disposal of xylenes are currently subject to significant revision. Under the Resource 

Conservation and Recovery Act, waste product, off-specification batches, and spill residues of xylenes 

>1,000 pounds are subject to handling, reporting, and recordkeeping requirements. This applies also to 

spent xylene solvents and still bottoms from the refining of these solvents (EPA 1980b, 1981b). 
XYLENE 201 

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

Table 5-6. U.S. Import and Export Data on Xylenesa

 Import Export 

Year Mixed o-Xylene m-Xylene p-Xylene Mixed o-Xylene m-Xylene p-Xylene Reference 

1986 284 3 NA 141 NA NA NA NA HSDB 2007 

1995 713 47 6 343 713 90 37 713 Canella 1998 

2000 1,302b 3 51 189 141c 50 NA 152 USDOC 2005 

2005 1,303b

 0 11 0 263c 10 NA 12 USDOC 2005 

a

Values reported in millions of liters 

b

Reported as "Other Xylenes NESOI" 

c

Reported as "Other Xylenes NESOI (except o- or p-Xylene)"
 

NA = data not available 
XYLENE 202 

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

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XYLENE 203 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.1 OVERVIEW 

Xylene has been identified in at least 840 of the 1,684 hazardous waste sites that have been proposed for 

inclusion on the EPA National Priorities List (NPL) (HazDat 2006). However, the number of sites 

evaluated for xylene is not known. The frequency of these sites can be seen in Figure 6-1. Of these sites, 

835 are located within the United States, 2 are located in the Commonwealth of Puerto Rico (not shown), 

1 is located in Guam (not shown), and 2 are located on the Virgin Islands (not shown). 

Xylenes are released to the atmosphere primarily as fugitive emissions from industrial sources (e.g., 

petroleum refineries, chemical plants), in automobile exhaust, and through volatilization from their use as 

solvents. Discharges into waterways and spills on land result primarily from use, storage, and transport of 

petroleum products and waste disposal. When xylenes are released to soil or surface water, they are 

expected to volatilize into the atmosphere. However, based on the mobility of these substances in soil, 

xylenes may also leach into groundwater, where they may persist for several months. 

Xylene is rapidly transformed in the troposphere where photooxidation by hydroxyl radicals is the 

dominant process. Xylene is stable to hydrolysis and oxidation in the aquatic environment, but is 

expected to undergo biodegradation. However, based on the volatility of xylene, biotransformation of 

this substance in surface waters is not expected to compete with its evaporation into the air. Xylene is 

also expected to volatilize from soil surfaces. Biodegradation is an important process in subsurface soils 

and groundwater where volatilization is hindered. Xylene is not expected to adsorb strongly to soil; 

however, soil adsorption increases as organic matter content increases. Xylene has been found to 

bioaccumulate to very modest levels (e.g., bioconcentration factors of <100), and food-chain 

biomagnification has not been observed. 

As is expected based on the partitioning and environmental fate of xylenes, these substances are primarily 

detected in air. Typical xylene concentrations range from 1 to 30 ppb in outdoor air and from 1 to 10 ppb 

in indoor air (see note at the end of Table 4-2). According to groundwater surveys conducted in the 

United States, xylenes are generally detected in <5% of groundwater samples. However, xylene 

concentrations in contaminated groundwater have been reported as high as 10,000 ppb. Little data are 

available reporting the concentrations of xylene in soil or surface water. Less than 6% of drinking water 

samples collected during U.S. drinking water surveys contained xylenes. Mean concentrations in positive 

XYLENE 205 

6. POTENTIAL FOR HUMAN EXPOSURE 

samples were typically <2 ppb. Xylene has been detected in a variety of foods with typical 

concentrations ranging from 1 to 100 ppb. 

Because individual xylene isomers are used in large amounts in industrial settings, people who work at or 

live near these locations may receive a higher exposure to one xylene isomer compared to the other 

isomers. However, since xylenes are present as a mixture in gasoline and in the solvent components of 

commonly used commercial products (paint, etc.), exposure of the general population is expected to be 

primarily to xylenes as a mixture, and not to the separate xylene isomers. 

Xylene or its metabolites have been detected in human urine, blood, and expired air samples among 

members of the general population. Human exposure to xylene is believed to occur via inhalation of 

indoor and workplace air, inhalation of automobile exhaust, ingestion of contaminated drinking water, 

smoking, and inhalation and dermal absorption of solvents containing xylene. 

When analyzing biological and environmental samples for xylene, it is difficult to separate the m- and 

p-isomers. Therefore, the concentrations of these two isomers are typically reported together as a sum 

(m-/p-xylene). 

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 2005g). 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 2005g). 
XYLENE 206 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.2.1 Air 

Estimated releases of mixed xylenes, m-xylene, o-xylene, and p-xylene to the atmosphere were 

34.8 million pounds (16,000 metric tons), 0.5 million pounds (240 metric tons), 0.6 million pounds 

(290 metric tons), and 1.4 million pounds (640 metric tons), respectively, to the atmosphere from 2,794, 

58, 67, and 39 domestic manufacturing and processing facilities, respectively, in 2004. These releases 

accounted for about 91, 93, 95, and 98% of the estimated total environmental releases of mixed xylenes, 

m-xylene, o-xylene, and p-xylene, respectively, from facilities required to report to the TRI (TRI04 2006). 

These releases are summarized in Tables 6 1, 6-2, 6-3, and 6-4, respectively. 

Xylene has been identified in air samples collected at 143 of the 840 NPL hazardous waste sites where it 

was detected in some environmental media (HazDat 2006). 

Most annual releases of xylene are refinery losses into the atmosphere during the production, 

transportation, and processing of petroleum. Other significant sources of xylene emissions are from the 

use of solvents, as a component of automobile exhaust gases, evaporation of gasoline into the air during 

its transportation and distribution, and releases from the chemical industry (Merian and Zander 1982). 

Based on vapor pressures of 6–8 mm Hg (AIChE 1996; Chao et al. 1983; Lewis 2000), volatilization 

from soil or surface water is also expected to be an important pathway for xylenes to enter the 

atmosphere. 

Releases of xylenes are associated with outgassing from landfills where disposal of industrial, hazardous, 

and mixed municipal wastes occur. In Finland during 1989–1990, all three xylene isomers were detected 

in gases released from closed municipal landfills at average concentrations of 0.86, 3.6, and 1.2 mg/m3 

(0.20, 0.83, and 0.28 ppm) for the o-, m-, and p-isomers, respectively (Assmuth and Kalevi 1992). 

Concentrations of all of the xylene isomers in off-gases from an active landfill were 30–35 times higher. 

In 1987–1988, air emissions of mixed xylene from facilities in the Houston, Texas, ship channel 

industrial area were 551 tons per year (LaGrone 1991). The emissions resulted in an ambient 

concentration in this area of 1.6 parts per billion volume (ppbv). The mean concentrations of o-xylene 

and m-/p-xylene in landfill gas from the Fresh Kills Municipal Solid-waste Landfill in New York City 

(Staten Island) were 2.17 and 5.97 ppmv, respectively (Eklund et al. 1998). 

Eitzer (1995) measured volatile organic compound (VOC) emissions at eight municipal solid waste 

compositing facilities. Respective mean p-xylene and m-/o-xylene concentrations were 1 and 2 μg/m3 
XYLENE 207 

6. POTENTIAL FOR HUMAN EXPOSURE 

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

Use Xylene (Mixed)a
 

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 10 22,415 41 0 820 0 23,268 7 23,275 

AL 76 2,051,596 190 50 27,628 12,182 2,078,986 12,660 2,091,646 

AR 35 571,748 46 0 74 0 571,794 74 571,868 

AZ 27 87,092 0 0 5,901 768 87,097 6,664 93,761 

CA 155 504,919 266 204 28,895 8,789 529,014 14,059 543,074 

CO 19 70,584 0 0 10 479 70,584 489 71,073 

CT 20 18,978 3 0 3 6,759 18,981 6,762 25,743 

DE 9 93,557 0 0 51 0 93,557 51 93,608 

FL 67 457,196 29 0 1 549 457,225 550 457,775 

GA 67 1,070,406 252 0 589 755 1,071,198 805 1,072,003 

GU 3 4,407 1 0 0 1,417 4,408 1,417 5,825 

HI 11 25,708 43 0 1,710 2,795 25,758 4,498 30,256 

IA 62 883,083 0 0 0 0 883,083 0 883,083 

ID 4 39,534 No data 0 0 0 39,534 0 39,534 

IL 134 1,287,226 296 0 6,483 6,504 1,288,763 11,746 1,300,509 

IN 165 2,964,117 469 0 11,642 2,469 2,973,971 4,726 2,978,698 

KS 52 773,525 146 293 1,033 50 774,006 1,041 775,047 

KY 82 1,159,382 484 0 138,771 25,662 1,160,156 164,143 1,324,299 

LA 80 1,096,942 710 27,957 13,236 7,374 1,127,021 19,199 1,146,219 

MA 43 68,132 152 0 139 24,187 68,284 24,326 92,610 

MD 23 102,410 266 0 139 250 102,677 388 103,065 

ME 8 14,187 80 0 0 1,820 14,266 1,820 16,086 

MI 137 2,768,110 27 0 49,160 155,142 2,777,445 194,994 2,972,439 

MN 45 655,287 30 0 597 70 655,354 630 655,984 

MO 77 1,797,940 0 0 510 1,748 1,797,940 2,258 1,800,198 

MP 2 587 0 0 0 10 587 10 597 

MS 47 1,056,657 50 0 1,826 0 1,058,407 126 1,058,533 

MT 8 41,341 5 0 75 5,600 41,357 5,664 47,021 

NC 62 609,558 0 0 558 4,296 609,558 4,854 614,412 

ND 5 60,533 1 4 13 0 60,534 17 60,551 

NE 19 231,469 No data 0 26,437 510 231,469 26,947 258,416 

NH 6 32,052 No data 0 0 500 32,052 500 32,552 

NJ 77 262,906 1,454 0 20,425 6,810 270,720 20,876 291,596 

NM 13 71,564 5 25 230 5,468 71,824 5,468 77,292 

NV 9 3,149 No data 0 902,695 0 905,844 0 905,844 

NY 76 278,303 366 0 1,492 7,499 278,675 8,985 287,660 
XYLENE 208 

6. POTENTIAL FOR HUMAN EXPOSURE 

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

Use Xylene (Mixed)a
 

Reported amounts released in pounds per yearb 

Total release 

Statec

 RFd Aire Waterf UIg Landh Otheri On-sitej

 Off-sitek 

On- and 

off-site 

OH 184 2,367,513 90 2,114 226,194 7,205 2,370,589 232,528 2,603,117 

OK 37 471,134 47 109 560 50 471,566 333 471,899 

OR 25 252,626 1,001 0 1,038 20,770 254,416 21,019 275,435 

PA 147 1,080,111 725 0 11,167 18,372 1,080,857 29,517 1,110,375 

PR 16 45,826 2 0 0 6 45,828 6 45,834 

RI 9 8,395 6 0 0 7,305 8,401 7,305 15,706 

SC 40 1,028,025 627 0 3,172 14,124 1,029,472 16,476 1,045,948 

SD 16 399,993 No data 0 0 0 399,993 0 399,993 

TN 86 1,918,718 80 0 1,137 9,962 1,918,799 11,098 1,929,897 

TX 271 3,517,712 18,881 1,098,590 27,896 75,766 4,517,614 221,231 4,738,845 

UT 23 135,919 1,000 0 1,051 2,141 137,169 2,942 140,111 

VA 58 886,351 255 0 575 5 886,856 330 887,185 

VI 3 49,114 0 0 1,089 0 49,114 1,089 50,203 

VT 1 1,880 No data 0 0 0 1,880 0 1,880 

WA 30 175,968 4 0 596 137 176,299 405 176,705 

WI 80 830,359 5 0 25,478 1,665 855,764 1,743 857,507 

WV 25 396,903 418 0 4,524 65 397,321 4,589 401,910 

WY 8 25,986 0 0 69 0 26,055 0 26,055 

Total 2,794 34,829,134 28,554 1,129,345 1,545,689 448,034 36,883,391 1,097,365 37,980,757 

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: TRI04 2006 (Data are from 2004) 
XYLENE 209 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. Releases to the Environment from Facilities that Produce, Process, or 

Use m-Xylenea
 

Reported amounts released in pounds per yearb 

Total release 

Statec

 RFd Aire Waterf UIg Landh Otheri On-sitej

 Off-sitek On- and off-site 

AL 1 201,000 22,000 0 250 0 223,250 0 223,250 

AR 1 1,137 No data 0 5 0 1,137 5 1,142 

CA 1 0 No data No data 0 No data No data 0 0 

FL 1 4,505 No data 0 0 0 4,505 0 4,505 

GA 4 38,421 No data 0 0 0 38,421 0 38,421 

IA 3 14,891 No data 0 0 0 14,891 0 14,891 

IL 2 6,271 4 0 173 0 6,276 173 6,449 

IN 4 2,835 No data 0 0 0 2,835 0 2,835 

KS 1 39,870 No data 0 0 0 39,870 0 39,870 

KY 2 2,535 No data 0 0 0 2,535 0 2,535 

LA 2 1,463 0 0 213 0 1,463 213 1,676 

MO 1 933 0 0 0 0 933 0 933 

MS 1 30,100 25 0 1,006 0 30,126 1,005 31,131 

NE 2 11,265 No data 0 0 0 11,265 0 11,265 

NJ 1 0 No data No data 0 No data No data 0 0 

NM 2 190 No data 0 0 0 190 0 190 

NY 1 920 No data 0 0 0 920 0 920 

OK 1 500 1 0 0 0 501 0 501 

PA 1 0 No data No data 0 No data No data 0 0 

PR 1 11,530 0 0 0 0 11,530 0 11,530 

SC 2 33,508 No data 0 0 0 33,508 0 33,508 

TN 1 500 No data 0 0 0 500 0 500 

TX 21 118,647 2,149 10,190 2,569 1,397 132,711 2,242 134,953 

UT 1 0 No data No data 0 No data No data 0 0 

Total 58 521,021 24,180 10,190 4,216 1,397 557,366 3,638 561,004 

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: TRI04 2006 (Data are from 2004) 
XYLENE 210 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-3. Releases to the Environment from Facilities that Produce, Process, or 

Use o-Xylenea
 

Reported amounts released in pounds per yearb 

Total release 

Statec

 RFd Aire Waterf UIg Landh Otheri On-sitej

 Off-sitek 

On- and 

off-site 

AL 4 224,186 9,500 0 252 0 233,938 0 233,938 

AR 2 29,007 0 82 5 0 29,089 5 29,094 

CA 2 114 0 0 0 0 114 0 114 

FL 1 0 No data 0 0 No data No data 0 0 

GA 4 598 No data 0 3 0 598 3 601 

IA 2 2,247 No data 0 0 0 2,247 0 2,247 

IL 3 110,203 4 0 0 0 110,207 0 110,207 

IN 1 424 No data 0 0 0 424 0 424 

KS 2 17,966 No data 0 0 0 17,966 0 17,966 

KY 1 0 No data 0 0 No data No data 0 0 

LA 2 2,739 0 0 2 0 2,739 2 2,741 

MD 1 0 No data 0 0 0 0 0 0 

MO 2 5,161 5 0 5 0 5,171 0 5,171 

MS 1 16,400 25 0 503 0 16,425 503 16,928 

NC 2 3,383 18 0 0 0 3,401 0 3,401 

ND 1 0 No data 0 0 No data No data 0 0 

NE 2 1,144 No data 0 0 0 1,144 0 1,144 

NJ 3 509 No data 0 0 0 509 0 509 

NY 2 45,231 No data 0 0 0 45,231 0 45,231 

PA 2 0 No data 0 0 No data No data 0 0 

PR 2 4,658 0 0 0 0 4,658 0 4,658 

SC 1 12 No data 0 0 0 12 0 12 

TN 2 16,509 No data 0 0 0 16,509 0 16,509 

TX 20 162,940 1 25,174 1,096 614 189,107 718 189,825 

UT 1 0 No data 0 0 No data No data 0 0 
XYLENE 211 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-3. Releases to the Environment from Facilities that Produce, Process, or 

Use o-Xylenea
 

Reported amounts released in pounds per yearb 

Total release 

Statec

 RFd Aire Waterf UIg Landh Otheri On-sitej

 Off-sitek 

On- and 

off-site 

WI 1 1,452 0 0 0 0 1,452 0 1,452 

Total 67 644,883 9,553 25,256 1,866 614 680,941 1,231 682,172 

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: TRI04 2006 (Data are from 2004) 
XYLENE 212 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-4. Releases to the Environment from Facilities that Produce, Process, or 

Use p-Xylenea
 

Reported amounts released in pounds per yearb 

Total release 

Statec

 RFd Aire Waterf UIg Landh On-sitej

 Off-sitek On- and off-site 

AL 1 380,000 360 0 4,150 380,610 3,900 384,510 

AR 2 354 0 0 5 354 5 359 

CA 1 12,862 No data 0 0 12,862 0 12,862 

GA 1 11,410 No data 0 0 11,410 0 11,410 

IA 2 487 No data 0 0 487 0 487 

IN 1 2,496 No data 0 0 2,496 0 2,496 

KS 1 8,284 No data 0 0 8,284 0 8,284 

KY 1 0 No data No data 0 No data 0 0 

LA 1 0 No data 0 0 0 0 0 

MS 1 123,000 25 0 503 123,025 503 123,528 

NC 3 1,032 No data 0 0 1,032 0 1,032 

NE 1 423,442 268 0 2,550 423,710 2,550 426,260 

PA 1 0 No data No data 0 No data 0 0 

PR 1 18,338 0 0 0 18,338 0 18,338 

SC 3 276,970 0 0 0 276,970 0 276,970 

TN 2 24,482 No data 0 0 24,482 0 24,482 

TX 15 136,545 2,144 10,539 1,724 150,479 473 150,952 

UT 1 0 No data No data 0 No data 0 0 

Total 39 1,419,702 2,797 10,539 8,932 1,434,539 7,431 1,441,970 

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: TRI04 2006 (Data are from 2004) 
XYLENE 213 

6. POTENTIAL FOR HUMAN EXPOSURE 

(0.23 and 0.46 ppb) in background air; 910 and 2,600 μg/m3 (209 and 600 ppb) in tipping air; 1,600 and 

3,700 μg/m3

 (370 and 850 ppb) in shredder air; 110 and 250 μg/m3 (25 and 58 ppb) in indoor air; 250 and 

420 μg/m3

 (56 and 97 ppb) in digester air; 250 and 520 μg/m3 (58 and 120 ppb) in fresh compost air; 

76 and 86 μg/m3

 (18 and 20 ppb) in mid-aged compost air; 31 and 55 μg/m3 (7.1 and 13 ppb) in old 

compost air; and 4 and 6 μg/m3

 (0.92 and 1.4 ppb) in curing compost air. 

The mean concentration of xylene in the post combustion region of a German incineration plant (prior to 

any emission reduction) was 7.881 μg/m3

 (1.816 ppb) (Zimmermann et al. 2001). Jay and Stieglitz 

(1995) reported xylene concentrations of 7.77 and 1.79 μg/m3

 (1.79 and 0.412 ppb) in the emissions of a 

municipal waste incineration plant at an unspecified location in Germany. Schauer et al. (2001) reported 

emissions of o-xylene and m-/p-xylene during pine wood burning of 18.1 and 60.0 mg per kg of wood 

burned, respectively. 

o-Xylene was identified in the volatile emissions of a waste water treatment plant in Broward County, 

Florida with an emission rate of approximately 16 mg/s (1,400 g/day) (Tansel and Eyma 1999). The 

volatile emissions of xylenes measured in five municipal waste water treatment plants in Ontario, Canada 

were 770, 129, 213, 408, and 0.16 g/day (Quigley and Corsi 1995). The volatile emissions of total 

xylenes from four publicly owned treatment works servicing the Los Angeles, California area were 3,683, 

215, 294, and 72 kg/year (Mayer et al. 1994) 

Xylenes have been detected among other VOCs in the emissions of newly built homes (Hodgson et al. 

2000; Zabiegala et al. 1999). The geometric mean (range) concentrations of m-/p-xylene in the indoor air 

of four manufactured houses and seven site built houses in the eastern and southeastern United States 

were 1.0 ppb (0.5–2.7 ppb) and 3.9 ppb (1.4–11.5 ppb), respectively (Hodgson et al. 2000). The 

geometric mean (range) emission rates of m-/p-xylene from these houses were 3.2 μg/m2

-hour (<1.5– 

9.1 μg/m2

-hour) and 9.5 μg/m2-hour (<4.1–24.2 μg/m2-hour), respectively. Brown et al. (1994) reported 

weighted average geometric mean and 98th percentile m-/p-xylene concentrations of 280 and 2,700 μg/m3 

(65 and 620 ppb), respectively, in seven new dwellings, 25 and 240 μg/m3

 (5.8 and 55 ppb), respectively, 

in four new office buildings, and 9 and 85 μg/m3

 (2 and 20 ppb), respectively, in one new school building. 

The concentration of m-/p-xylene in volatiles released from a tufted textile floor covering with styrenebutadiene rubber backing ranged from 85.1 to 155 ng/L (19.6–35.7 ppt) (Sollinger et al. 1994). 

o-Xylene and m-/p-xylene emission rates from diesel-powered medium duty trucks have been measured 

as 830 and 2,330 μg/km (0.83 and 2.33 mg/km), respectively (Schauer et al. 1999). Schauer et al. (2002) 
 

 

XYLENE 214 

6. POTENTIAL FOR HUMAN EXPOSURE 

reported tailpipe o-xylene and m-/p-xylene emission rates of 5,410 and 14,300 μg/km (5.41 and 

14.3 mg/km), respectively, for catalyst-equipped gasoline-powered vehicles and 562,000 and 

1,720,000 μg/km (562 and 1,720 mg/km), respectively, for noncatalyst-equipped gasoline-powered 

vehicles. Mean o-xylene and m-/p-xylene tail pipe emission rates from cars that use a catalyst were 

0.0042–0.0110 and 0.0054–0.0270 g/km (4.2–11 and 5.4–27 mg/km), respectively, compared to mean 

emission rates of 0.0330 and 0.0868 g/km (33 and 86.8 mg/km), respectively, from a car that did not use a 

catalyst (Chan et al. 1995). These authors reported mean o-xylene and tail pipe emission rates of 

approximately 0.010 g/km (10 mg/km) from noncatalyst motorcycle engines and 0.016 g/km (37 mg/km) 

from a catalyst motorcycle engine. Mean m-/p-xylene tail pipe emission rates were approximately 

0.028 g/km (28 mg/km) from the noncatalyst motorcycle engines and 0.037 g/km (37 mg/km) from the 

catalyst motorcycle engine. Gabele (1997) reported that o-xylene and m-/p-xylene made up 1.58 and 

4.55%, respectively, of total organic emissions in the exhaust of 10 four-stroke lawnmower engines. 

o-Xylene and m-/p-xylene emission values measured in the Craeybeckx tunnel in Antwerp, Belgium were 

0.148 and 0.307 g/kg carbon, respectively, under highway conditions and 0.216 and 0.442 g/kg carbon, 

respectively, under congested conditions (De Fré et al. 1994). Average concentrations in the tunnel air 

were 17 μg/m3

 (3.9 ppb) for o-xylene and 34 μg/m3 (7.8 ppb) for m-/p-xylene, compared to background 

concentrations of 1.0 μg/m3

 (0.23 ppb) for o-xylene and 2.4 μg/m3 (0.55 ppb) for m-/p-xylene. The 

authors estimated total yearly vehicle emissions in Belgium of 824 metric tons/year (1.82 million 

pounds/year) for o-xylene and 1,690 metric tons/year (3.72 million pounds/year) for m-/p-xylene based on 

the congested traffic emissions data. Vehicle emission rates measured in the Los Angeles roadway tunnel 

in 1993 were 200 mg/L of consumed fuel for o-xylene and 557 mg/L of consumed fuel for m-/p-xylene 

(Fraser et al. 1998b). Lawryk and Weisel (1996) measured mean o-xylene and m-/p-xylene in vehicle 

concentrations of 20.7 and 52.9 μg/m3

 (4.77 and 12.2 ppb), respectively, in the Lincoln Tunnel and 

12.5 and 31.4 μg/m3

 (2.88 and 7.47 ppb), respectively, on the New Jersey Turnpike. 

6.2.2 Water 

Estimated releases of mixed xylenes, m-xylene, o-xylene, and p-xylene to surface water were 

29,000 pounds (13 metric tons), 24,000 pounds (11 metric tons), 10,000 pounds (4.3 metric tons), and 

3,000 pounds (1.3 metric tons), respectively, to the atmosphere from 2,794, 58, 67, and 39 domestic 

manufacturing and processing facilities, respectively, in 2004. These releases accounted for <0.1, 4.3, 

1.4, and <0.1% of the estimated total environmental releases of mixed xylenes, m-xylene, o-xylene, and 
XYLENE 215 

6. POTENTIAL FOR HUMAN EXPOSURE 

p-xylene, respectively, from facilities required to report to the TRI (TRI04 2006). These releases are 

summarized in Tables 6-1, 6-2, 6-3, and 6-4. 

Xylene has been identified in groundwater and surface water samples collected at 556 and 150 of the 

840 NPL hazardous waste sites, respectively, where it was detected (HazDat 2006). 

Xylenes may be introduced into groundwater by fuel oil, gasoline, or solvent spills, infiltration of polluted 

surface waters, leaking underground petroleum storage tanks, or leaching from disposed wastes (Giger 

and Schaffner 1981). 

The mean concentrations of xylenes in three groundwater monitoring wells at a Shell Oil service station 

site in San Diego, California were 0.39, 1.23, and 19.35 mg/L (ppm) (Odermatt 1994). Groundwater 

extract from an oil spill site in northern Virginia contained xylene at a concentration of 2.8 ppm 

(Mushrush et al. 1994). 

A total xylene concentration (concentration includes ethylbenzene) of 1.2 ppb was detected in effluent 

from containment ponds in the containment area of an oil spill that accumulated along the banks of the 

Atigun River, Alaska (Lysyj et al. 1980). Treated effluents from offshore oil drilling platforms in the 

Gulf of Mexico contained an average concentration of 0.3 mg/L (ppm) (concentration includes 

ethylbenzene) (Lysyj et al. 1980). 

The mean influent concentrations of o-xylene and m-/p-xylene upstream of the Metropolitan Wastewater 

Treatment Plant of St. Paul, Minnesota were 4.09 and 9.03 μg/L (ppb), respectively, in grab samples and 

4.04 and 2.64 μg/L (ppb), respectively, in composite samples (Balogh et al. 1998). Final effluent from a 

Los Angeles County waste-water treatment plant, sampled between November 1980 and August 1981, 

contained o-xylene and p-xylene at concentrations of 40 and 30 μg/L (ppb), respectively (Gossett et 

al. 1983). 

All three xylenes have been detected in the leachate from landfills at concentrations ranging from 10 to 

4,400 μg/L (ppb) for hazardous waste landfills and from 3.7 to 38 μg/L (ppb) for domestic landfills (Först 

et al. 1989a, 1989b). Roy (1994) reported a concentration range of 2.5–320 μg/L (ppb) for xylenes in 

municipal landfill leachate. The concentration of xylenes detected in 6 of 13 landfills sampled in 

Minnesota ranged from 1.3 to 950 μg/L (ppb) (Roy 1994). The concentration of o-xylene and 

m-/p-xylene in groundwater samples collected at the Orange County Landfill in central Florida range 
XYLENE 216 

6. POTENTIAL FOR HUMAN EXPOSURE 

from 0.04 to 38.78 μg/L (ppb) and from 0.10 to 3.18 μg/L (ppb), respectively (Chen and Zolteck 1995). 

The concentration of o-xylene and m-/p-xylene in surface water samples at this site ranged from 0.07 to 

0.09 μg/L (ppb) and from 0.07 to 0.10 μg/L (ppb), respectively. 

Xylenes are also released to waterways through the use of gasoline powered outboard boat engines 

(Gabele 2000; Juttner 1994). The rates of release of o-xylene and m-/p-xylene to water by an unleaded 

gasoline powered four-stroke outboard motor were 3.7 and 7.1 mg/minute, respectively (Juttner 1994). 

The aqueous emission rates of xylenes from a two-stroke outboard engine and a four-stroke outboard 

engine range from 0.27 to 0.86 g/kW-hour (0.075–0.24 kg/kJ) and from 0.07 to 0.09 g/kW-hour (0.019– 

0.025 kg/kJ), respectively (Gabele 2000). 

6.2.3 Soil 

Estimated releases of mixed xylenes, m-xylene, o-xylene, and p-xylene to soil were 1.5 million pounds 

(700 metric tons), 4,200 pounds (1.9 metric tons), 2,900 pounds (1.3 metric tons), and 8,900 pounds 

(4.0 metric tons), respectively, to the atmosphere from 2,794, 58, 67, and 39 domestic manufacturing and 

processing facilities, respectively in 2004. These releases accounted for 4, 0.8, 0.4, and 0.6% of the 

estimated total environmental releases of mixed xylenes, m-xylene, o-xylene, and p-xylene, respectively, 

from facilities required to report to the TRI (TRI04 2006). 

An additional 1.1 million pounds (510 metric tons) of mixed xylenes, 10,000 pounds (4.6 metric tons) of 

m-xylene, 25,000 pounds (11.4 metric tons) of o-xylene, and 11,000 (4.8 metric tons) of p-xylene, 

constituting about 3, 1.8, 3.7, and 0.7%, respectively of the total environmental emissions, were released 

via underground injection (TRI04 2006). These releases are summarized in Tables 6-1, 6-2, 6-3, and 6-4. 

Xylene has been identified in soil and sediment samples collected at 469 and 139 of the 840 NPL 

hazardous waste sites, respectively, where it was detected (HazDat 2006). 

No quantitative information was available in the literature regarding total releases of xylene to soil. 

Atmospheric xylene may reach soils either by wet deposition by precipitation or through dry deposition of 

material adsorbed to particulate matter in air. Xylene may also reach soils from the introduction of manmade wastes (e.g., landfills) or as a result of accidental releases (e.g., spills). 
XYLENE 217 

6. POTENTIAL FOR HUMAN EXPOSURE 

Xylene was detected in only 4 out of 30 sediment samples collected adjacent to combined sewer overflow 

outfalls along the lower Passaic River in New Jersey at concentrations of 15, 7, 6, and 5 μg/kg (ppb) 

(Iannuzzi et al. 1997). 

6.3 ENVIRONMENTAL FATE 

The environmental fate (transport, partitioning, transformation, and degradation) is expected to be similar 

for each of the xylene isomers based on the similarities of their physical and chemical properties. 

6.3.1 Transport and Partitioning 

Based on Henry’s law constants of 0.005–0.007 atm-m3

/mol (Foster et al. 1994; Sanemasa et al. 1982), 

volatilization is expected to be the dominant transport mechanism for xylenes in surface water. The halflife associated with the volatilization of o-xylene from surface waters at a depth of 1 meter is reported to 

be 5.6 hours (Mackay and Leinonen 1975). This value will vary in accordance with turbulence and water 

depth. Once xylenes enter the atmosphere, they undergo rapid photooxidation such that washout and 

long-range atmospheric transport are not expected to be important processes. 

Soil organic carbon sorption coefficient (Koc) values ranging from 25.4 to 540 indicate that xylenes are 

mobile in soil and will not adsorb strongly to organic matter, although adsorption does increase with 

increasing organic matter (Green et al. 1981; Kango and Quinn 1989; Nathwani and Phillips 1977; Seip et 

al. 1986; Swann et al. 1983). Based on the Henry’s law constants and vapor pressures (6.6–8.8 mm Hg) 

(AIChE 1996; Chao et al. 1983; Lewis 2000), xylenes that are released to soil are expected to volatilize if 

near the surface. However, the mobility of xylenes in soil indicates that these substances may also leach 

into groundwater, especially when volatilization is hindered as is the case with underground releases from 

gasoline storage tanks. 

When xylene was spilled at an application depth of 7.2 cm (2.9 inches) or less on loam-textured soil at 

moisture contents ranging from 0.15 to 0.26 kg/kg, 1–4% volatilized, 0.5–35% leached, 50–85% 

degraded, and 6–12% remained after about 80 days in the soil (Aurelius and Brown 1987). Most of the 

observed volatilization occurred immediately after application. A greater percentage of xylene initially 

evaporated when it was applied to the wet soil compared to the dry soil. However, after the initial 

retention in the dry soil, there was less moisture to entrap the subsurface soil and prevent it from later 

volatilizing or degrading. The xylene that remained in the wet soil after the initial evaporation was then 

blocked by the moisture and was less able to volatilize or degrade. Therefore, xylene is expected to 
XYLENE 218 

6. POTENTIAL FOR HUMAN EXPOSURE 

evaporate more rapidly when spilled onto wet soil than when spilled onto dry soil; however, removal is 

expected to be more complete in the dry soil after the initial retention period. 

Xylene moves through unsaturated (drier) soil faster than water and other polar solvents (Amoozegar et 

al. 1986; Barbee and Brown 1986). For example, diffusion coefficients of approximately 0.02 and 

0.005 cm2

/second were measured in dry and wet (12–15%) cores taken from the first natural barriers at 

the Los Alamos National Laboratory chemical waste site (Fuentes et al. 1991). Additional field data 

suggesting that concentrated organics may leach 10–1,000 times faster than water in unsaturated soil were 

provided by Griffin et al. (1984). This increased conductivity is probably due to cracks in the soil through 

which the organics move rapidly (Aurelius and Brown 1987). 

Measured log octanol-water partition coefficient (log Kow) values are 2.77, 3.15, and 3.20 for o-, p-, and 

m-xylene, respectively (Chiou et al. 1982; Gherini et al. 1989). The rapid oxidation of xylene isomers to 

their corresponding polar metabolites seems to preclude bioconcentration in higher animal systems and, 

therefore, bioaccumulation up the food chain is unlikely (NRC 1980). Bioconcentration factors (BCFs) 

for o-, m-, and p-xylenes have been estimated to be 45, 105, and 95, respectively (EPA 1985a). 

Bioconcentration of xylene has been observed in shrimp (Pandalus platyceros) (Sanborn and Malins 

1980), manila clams (Tapes semidecussata) (Nunes and Benville 1979), and eels (Anguilla japonica) 

(Ogata and Miyake 1978). A bioconcentration factor of 6 has been reported for tissue uptake in clams 

throughout an 8-day exposure to o-, m-, and p-xylenes (Nunes and Benville 1979), and bioconcentration 

factors of 21.4, 23.6, and 23.6 have been reported for eels exposed to 50 ppm of o-, m-, and p-xylenes, 

respectively (Ogata and Miyake 1978). Tissue levels reached a steady state after 10 days. The green alga 

Selenastrum capricornutum has bioconcentration factors of 257, 251, and 218 for p-, m-, and o-xylenes, 

respectively (Herman et al. 1991). Bioconcentration has been predicted for all isomers of xylene because 

of their tendency to partition into the octanol phase of the octanol-water system (EPA 1978). Scientists 

generally regard BCFs below 20 as indicative of little or no bioconcentration, 20–100 as equivocal, and 

<1,000 as indicative of modest bioconcentration. 

6.3.2 Transformation and Degradation 

6.3.2.1 Air 

Xylene is transformed in the atmosphere by photooxidation. Based on experimental reaction rate 

constants of 13.7x10-12–23.6x10-12 cm3

/molecule-sec (Atkinson 1989; Kwok and Atkinson 1995), the 

calculated half-life of xylenes in air is 8–14 hours using a hydroxyl radical concentration of 
 

 

 

XYLENE 219 

6. POTENTIAL FOR HUMAN EXPOSURE 

5.00x105 molecules/cm3 and a 12-hour day (Atkinson 1990). The transformation of xylene by reaction 

with hydroxyl radicals prevails over that of reaction with ozone (half-life 3–78 years) and nitrate radicals 

(half-life 80–220 days) (Atkinson and Carter 1984; Atkinson et al. 1982, 1984, 1991; ECETOC 1986; 

Fox et al. 1984; Mill 1980; Roberts et al. 1984). Direct photolysis is not expected because xylene does 

not significantly absorb light at wavelengths >290 nm (Jori et al. 1986). Major photodegradation 

products formed by the cleavage of the aromatic ring in the presence of nitric oxide are: o-tolualdehyde, 

methylglyoxal, 4-nitro-o-xylene, and 2,3-dimethylphenol for o-xylene; 2,6-dimethylphenol, 

2,4-dimethylphenol, methylglyoxal, and m-tolualdehyde for m-xylene; and p-tolualdehyde and 

2,5-dimethylphenol for p-xylene (Atkinson et al. 1991; Gery et al. 1987). Glyoxal and methylglyoxal 

may form approximately 30–50% of the photooxidation products (Tuazon et al. 1986). o-Xylene also 

forms formaldehyde, acetaldehyde, biacetyl nitrate, and peroxyacetylnitrate (Bandow and Washida 1985; 

Darnall et al. 1979; Shepson et al. 1984; Takagi et al. 1980). The products of photoreaction with 

hydroxyl radicals are ultimately degraded to carbon dioxide and water after absorption in the hydrosphere 

(Guisti et al. 1974). 

6.3.2.2 Water 

The primary removal process for xylene in surface water is expected to be volatilization. Xylenes are not 

expected to undergo hydrolysis, and biodegradation is not fast enough to be a competing process 

(Rathbun 1998). However, biodegradation is expected to an important removal process for xylenes in 

groundwater since volatilization is hindered under these conditions (Rathbun 1998). 

Data describing the degradation of xylenes in surface waters are limited. The first-order degradation-rate 

coefficients for o-xylene and m-/p-xylene in a strip-pit pond formed as a result of coal-mining operations 

were 3.6 and 6.5 day-1, respectively, after amendment with nutrients (Bouwer 1989; Rathbun 1998). 

These rate coefficients correspond to half-lives of approximately 4.6 and 2.6 hours, respectively. Clapp et 

al. (1994) observed the biodegradation of priority pollutants in waste water treated in both an activated 

sludge reactor and a biological aerated filter reactor. Influent concentrations were 1.929 μg/L (ppb) for 

o-xylene and 5.53 μg/L (ppb) for m-/p-xylene, while effluent and percent removal concentrations were 

<1.2 μg/L (ppb) and >38%, respectively, for o-xylene and <1.2 μg/L (ppb) and >78%, respectively, for 

m-/p-xylene in both types of reactors. 

The majority of xylene biodegradation studies have examined the fate of this substance in groundwater. 

During a field experiment conducted at Base Borden in Ontario, Canada, xylenes were degraded to 50% 
 

 

XYLENE 220 

6. POTENTIAL FOR HUMAN EXPOSURE 

of initial concentrations (1,080–1,290 μg/L (ppb)) in a shallow sand aquifer in approximately 20–40 days 

(Barker 1987). The authors reported similar results in aerobic laboratory biodegradation tests. 

Biodegradation of xylenes is expected to be slower under anaerobic conditions. The aerobic 

biodegradation half-lives of o-, m-, and p-xylene in an unconfined, uncontaminated aquifer after injection 

with 100% PS6 gasoline were 116, 70, and 100 days, respectively (API 1994). The gasoline was injected 

above a landfill leachate zone. Although biodegradation of petroleum hydrocarbons (including xylene) 

spilled in northern Alaska was observed, the authors concluded that this process is likely to be limited by 

a short annual thaw season (Braddock and McCarthy 1996). 

The half-life of xylenes measured in groundwater from an anaerobic aquifer in Seal Beach, California was 

approximately 25 days (Beller et al. 1995). Xylene degradation metabolites observed by these authors 

included the methylated homologs of benzylsuccinic acid, benzylfumaric acid, and E-phenylitaconate 

(Beller 2000; Beller et al. 1995). o-Xylene was anaerobically degraded by approximately 75–100% 

30 days in groundwater after it was injected into contaminated aquifers (Reusser et al. 2002). Detection 

of methylbenzylsuccinic acid in the same wells following injection was additional evidence of xylene 

biodegradation. Between 92 and 95% of xylene released from a gasoline spill at an underground storage 

tank site was degraded over a distance of 80 m from the spill location (Kao and Wang 2001). The major 

removal process was biodegradation under iron-reducing conditions. Thierrin et al. (1995) measured a 

half-life of 125–170 days for xylenes under anoxic groundwater conditions. The first-order anaerobic 

biodegradation rate constants for o-, m-, and p-xylene were 0.028–0.11, 0.026–0.10, and 0.017– 

0.067 week-1 (corrected for dilution), respectively, in an underground gasoline storage tank spill plume at 

the Sleeping Bear Dunes National Lakeshore in Michigan. These rate constants correspond to half-lives 

of 7–25 weeks for o-xylene, 7–27 weeks for m-xylene, and 10–41 weeks for p-xylene (Wilson et al. 

1994). Hunt et al. (1997) did not observe anaerobic biodegradation of xylenes at Sleeping Bear Dunes 

National Lakeshore and reported that this process may be hindered by the presence of acetate and other 

non-BTEX organic carbon. These authors did observe anaerobic biodegradation of xylenes in 

groundwater at a site near Rocky Point, North Carolina. Weidemeier et al. (1995a) concluded that BTEX 

was biodegraded both aerobically and anaerobically at two U.S. air force bases (AFB) (Hill AFB and 

Patrick AFB) with sulfite reduction being the primary removal mechanism at Hill AFB and 

methanogenesis being the primary removal mechanism at Patrick AFB. Greater than 99% of xylene at 

the Hill AFB site was degraded after traveling 305 m downgradient from the contamination source. Only 

38% of xylene (34% o-xylene, 60% m-xylene, and 21% p-xylene) at the Patrick AFB site was degraded 

after traveling 98 m downgradient from the contamination source. Differences in the degradation rates 
XYLENE 221 

6. POTENTIAL FOR HUMAN EXPOSURE 

and half-lives reported in these studies are most likely due to differences in study conditions such as 

temperature, presence of oxygen, and presence of electron acceptors. 

6.3.2.3 Sediment and Soil 

If xylene is released to soil, the dominant removal process is expected to be volatilization. However, in 

situations where volatilization is hindered, biodegradation is expected to be an important fate process. 

o-Xylene in vials containing unsaturated soil was biodegraded within 5 days after a lag period of 10 days 

(English and Loehr 1991). However, subsequent additions of o-xylene to the soil were degraded without 

a lag period. The half-life after the sixth addition to the soil was less than 3 hours. o- and p-Xylene 

applied to a soil microcosm at 3 μL/g (2.6 mg/g) were aerobically degraded in less than 25 days (Tsao et 

al. 1998). CO2 production measured during the experiment ranged from approximately 35–65%. 

p-Xylene, at an initial concentration of 45 ppm, was completely degraded in natural potting soil 

microcosm in less than 27 days at 20 °C (Eriksson et al. 1999). It was not degraded at 6 °C. 

Elshahed et al. (2001) reported that xylenes were degraded anaerobically in an aquifer microflora 

laboratory test under sulfate-reducing conditions, but not under methanogenic conditions. m-Xylene was 

completely degraded in less than 25 days under sulfate-reducing conditions. The authors proposed that 

the successive metabolites involved in the ultimate anaerobic degradation of xylenes are methylbenzylsuccinic acid, toluic acid, phthalic acid, and benzoic acid (finally degraded to carbon dioxide). 

The first-order biodegradation rate constants for xylene calculated from data collected at a gasoline spill 

site in Beaufort, South Carolina ranged from 0.10 to 0.31 d-1 near the water table (Lahvis et al. 1999). 

These rates correspond to half-lives of 2–7 days. Sovik et al. (2002) calculated first-order biodegradation 

rate constants of 0.1–0.11 d-1 for xylene applied to a lysimeter trench at the Gardermoen delta north of 

Oslo, Norway. These rates correspond to half-lives of 6–7 days. 

Total VOCs (including xylene) added to sewage sludge-amended fields were reduced to a concentration 

similar to that in control fields within 36 days in a plowed plot and within 8 days in a pasture plot (Wilson 

and Jones 1996; Wilson et al. 1997). The half-lives calculated for o-xylene and m-/p-xylene were 7.6 and 

5.8 days, respectively, in the plowed plot and 0.7 and 0.3 days, respectively, in the pasture plot. During a 

laboratory soil study conducted by these authors, 92.6% of the total VOC concentration was lost after 

65 days from an unsterilized treatment compared to 88.1% loss from a sterilized treatment. This indicates 
XYLENE 222 

6. POTENTIAL FOR HUMAN EXPOSURE 

that abiotic factors, such as volatilization, are primarily responsible for this degradation, with 

biodegradation accounting for approximately 5% of the loss. 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

Reliable evaluation of the potential for human exposure to xylene depends in part on the reliability of 

supporting analytical data from environmental samples and biological specimens. Concentrations of 

xylene 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 xylene 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 xylene in a 

variety of environmental media are detailed in Chapter 7. 

6.4.1 Air 

Since one of the largest sources of xylene release into the atmosphere is auto emissions, atmospheric 

concentrations are related to urbanization. Ambient air concentrations of xylene in industrial and urban 

areas of the United States have been reported to range from 0.003 to 0.38 mg/m3

 (1–88 ppb) (Merian and 

Zander 1982). Median o-xylene concentrations calculated from a compilation of atmospheric data on 

organic chemicals were 0.41 μg/m3

 (0.094 ppb) in rural/remote areas (114 observations), 5.2 μg/m3 

(1.2 ppb) in urban/suburban areas (1,885 observations), and 3.5 μg/m3

 (0.81 ppb) in source-dominated 

areas (183 observations) (EPA 1983). The median concentrations for the combined m- and p-isomers 

were 0.38 μg/m3

 (0.088 ppb) in rural/remote areas (115 observations), 12 μg/m3 (2.8 ppb) in 

urban/suburban areas (1,911 observations), and 7.4 μg/m3

 (1.7 ppb) in source-dominated areas 

(186 observations) (EPA 1983). Air samples in highly industrialized areas of Illinois (Chicago and East 

St. Louis) between 1986 and 1990 had mean concentrations of 3.9–16 μg/m3

 (0.90–3.7 ppb) (for m- and 

p-xylene combined) and 2.9–3.3 μg/m3

 (0.67–0.76 ppb) (for o-xylene and styrene combined). Levels in 

rural areas of Illinois were 1.2 μg/m3

 (0.28 ppb) (for m- and p-xylene combined) and 1.1 μg/m3 (0.25 ppb) 

(for o-xylene and styrene combined). Paints (including automobile paint), chemical plants, and vehicle 

exhaust were the major sources of these chemicals (Sweet and Vermette 1992). Concentrations of 

xylenes measured in outdoor air at various locations are listed in Table 6-5. Based on these data, typical 

xylene concentrations in outdoor air range from 1 to 30 ppb. 

Air samples collected at 12 cities around the United States between 1979 and 1984 contained average 

concentrations of 1.0–10.2 ppb for m-/p-xylene and 0.3–4.2 ppb for o-xylene (Singh et al. 1985). In 
XYLENE 223 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-5. Xylene Concentrations in Outdoor Air 

Type of Concentration (ppb) 

Location value o-Xylene m-/p-Xylene Total xylenesa Reference 

Urban 

 Urban/suburban Median 1.2 2.8 4 EPA 1983 

United States 

 Industrial/Urban Range — — 1–88b Merian and Zander 

United States 1982 

 Urban 12 U.S. Mean 0.3–4.2 1.0–10.2 — Singh et al. 1985 

cities 

39 U.S. cities Range 0.9–79 1.3–338 7.2c

 EPA 1989 

39 U.S. cities Median 8.0 20.0 28.0 Mohamed et al. 2002 

9 major U.S. cities Median 0.3–3.1 0.7–8.6 — Mohamed et al. 2002 

Chicago, East St. Mean 0.67–0.76d 0.9–3.7 — Sweet and Vermette 

Louis 1992 

Los Angeles Range 4–13 11–45 — Grosjean and Fung 

1984 

Las Vegas Range 0–1.1 0–0.46 — Tran et al. 2000 

Phoenix Mean 1.07 2.92 3.99 Zielinska et al. 1998 

Tucson Mean 0.46 1.21 1.67 Zielinska et al. 1998 

Columbus, Ohio Mean 0.31 0.82 1.1 Spicer et al. 1996 

Rural 

 Rural Median 0.094 0.088 0.18 EPA 1983 

United States 

 Rural Illinois Mean 0.25d

 0.28 0.53d Sweet and Vermette 

1992 

Rural Arizona Mean 0.30, 0.43 0.82, 1.13 1.12, 1.56 Zielinska et al. 1998 

Mixed Locations 

25 sites in Mean 0.18 1.18e 1.36 Pratt et al. 2000 

Minnesota 

Southern Mean 1.7 4.5 6.2 Fraser et al. 2000 

California 

 Approximately Median 0.51 1.96e 0.51 EPA 1993; Kelly et al. 

100 U.S. locations 1994 

Remote 

Remote Arizona Mean 0.02 0.03 0.05 Zielinska et al. 1998 

 North Atlantic Mean 0.003 0.0068e 0.0098 Eichmann et al. 1979

 Indian Ocean Mean 0.00021 0.00028e 0.00049 Eichmann et al. 1980 

Pacific Ocean Range 0.01–0.77 <0.05–0.31 — Greenberg and 

Zimmerman 1984 
XYLENE 224 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-5. Xylene Concentrations in Outdoor Air 

Location 

 Brazilian 

Rainforest 

Type of 

value 

Range 

o-Xylene 

— 

Concentration (ppb) 

m-/p-Xylene Total xylenesa Reference 

— <0.05–0.12b Greenberg and 

Zimmerman 1984 

a

Unless otherwise indicated, total xylene concentrations listed here are the sum of the o-xylene and m-/p-xylene 

concentrations. 

b

Range of total xylenes reported in source 

c

Median total xylenes concentration reported in source

d

Includes styrene 

e

Sum of m- and p-xylene concentrations (reported separately in source) 
XYLENE 225 

6. POTENTIAL FOR HUMAN EXPOSURE 

1981, atmospheric concentrations of m-/p-xylene and o-xylene, measured at a downtown Los Angeles 

location, were 11–45 and 4–13 ppbv, respectively (Grosjean and Fung 1984). Between 1984 and 1986, 

ambient air monitoring was conducted in 39 cities nationwide. All three isomers of xylene were detected 

in all cities at a median concentration of 7.2 ppb (range, 1.3–338 ppb for m-/p-xylene and 0.9–79 ppb for 

o-xylene) (EPA 1989). In 1990, o-xylene was measured at 4.2–6.9 μg/m3

 (0.97–1.6 ppb) in ambient 

outdoor air in Atlanta, Georgia (EPA 1991a). 

o-Xylene and m-/p-xylene were detected in ambient air at Las Vegas, Nevada at concentrations of 0– 

4.6 and 0–2.0 μg/m3

 (0–1.1 and 0–0.46 ppb), respectively (Tran et al. 2000). Trost et al. (1997) reported 

urban air concentrations of o-xylene and m-/p-xylene of 0.5 and 1.2 ppbv, respectively, in Boston, 

Massachusetts, 0.5 and 0.9 ppbv, respectively, in Chicago, Illinois, 1.1 and 2.9 ppbv, respectively, in Los 

Angeles, California, and 18 and 38 ppbv, respectively, in Houston, Texas. Mean concentrations of 

o-xylene and m-/p-xylene were 1.07 and 2.92 ppbv, respectively, in urban air from Phoenix, Arizona, 

0.46 and 1.21 ppbv, respectively, in urban air from Tucson, Arizona, 0.30 and 0.82 ppbv, respectively, in 

rural air from Payson, Arizona, 0.43 and 1.13 ppbv, respectively, in rural air from Casa Grande, Arizona, 

and 0.02 and 0.03 ppbv, respectively in remote mountain top air near Hillside, Arizona (Zielinska et al. 

1998). The mean (maximum) concentrations of o-xylene and m-/p-xylene in 142 air samples collected in 

the Columbus, Ohio area were 0.31 ppb (1.22 ppb) and 0.82 ppb (3.88 ppb), respectively (Spicer et al. 

1996). Concentrations of xylenes in snow samples collected in Denver, Colorado during February, 1995 

were <10, 86, 47, 32, and 38 ng/L (Bruce and McMahon 1996). Mohamed et al. (2002) reported median 

o-xylene and m-/p-xylene concentrations of 8.0 and 20.0 ppb, respectively, measured in the air of 39 U.S. 

cities. Median o-xylene and m-/p-xylene concentrations reported for nine major U.S. cities were 0.3– 

3.1 and 0.7–8.6 ppb, respectively. 

The mean and median concentrations of xylenes in air samples collected at 25 sites across Minnesota were 

0.79 and 0.5 μg/m3

 (0.18 and 0.12 ppb), respectively, for o-xylene, 2.94 and 1.87 μg/m3 (0.686 and 0.43 ppb), 

respectively, for m-xylene, and 2.11 and 1.36 μg/m3

 (0.49 and 0.31 ppb), respectively, for p-xylene (Pratt et 

al. 2000). The observed ambient mean concentrations of o-xylene and m-/p-xylene in Southern California 

based on data from Los Angeles, Azusa, and Claremont, California were 7.3 and 19.6 μg/m3

 (1.7 and 

4.5 ppb), respectively (Fraser et al. 2000). EPA (1993) and Kelly et al. (1994) reported the ambient air 

concentrations of o-, m-, and p-xylene that were measured in 104, 98, and 102 U.S. locations, respectively. 

Median concentrations were 2.2 μg/m3 (0.51 ppb) in 8,542 samples for o-xylene, 4.2 μg/m3

 (0.97 ppb) in 

8,431 samples for m-xylene, and 4.3 μg/m3

 (0.99 ppb) in 3,597 samples for p-xylene. 
XYLENE 226 

6. POTENTIAL FOR HUMAN EXPOSURE 

Mean concentrations of o-xylene and m-/p-xylene measured in vehicle tunnels were 61.79 and 148.04 ppb 

carbon, respectively, in the Caldecott tunnel of San Francisco, California, 17 and 34 μg/m3

 (3.9 and 

7.8 ppb), respectively, in the Craeybeckx tunnel in Antwerp, Belgium, 39.6 and 69.8 μg/m3

 (9.12 and 

16.1 ppb), respectively, in the Zefun tunnel of Taipei, Taiwan, and 74.4 and 104.0 μg/m3

 (17.1 and 

24.0 ppb) respectively, in the Lishin motorcycle tunnel of Taipei, Taiwan (De Fré et al. 1994; Hsieh et al. 

1999; Zielinska and Fung 1994). 

Mean in-vehicle concentrations of o-xylene and m-/p-xylene reported by Leung and Harrison (1999) for 

several locations in the United States were 2.5 and 2.7 ppb, respectively, in Birmingham, Alabama, 

1.7 and 4.8 ppb, respectively, during the winter in Boston, Massachusetts, 2.6 and 7.1 ppb, respectively, 

during the summer in Raleigh, North Carolina, and 2.1 and 5.5 ppb, respectively, during the winter in 

New Jersey. The mean and range of xylene concentrations measured in the cabins of automobiles with 

gasoline engines in Germany were 6.2 and 1.4–22.6 μg/m3

 (1.4 and 0.3–5.2 ppb), respectively, for 

o-xylene and 19.1 and 3.9–66.3 μg/m3

 (4.4 and 0.9–15 ppb), respectively, for m-/p-xylene (Ilgen et al. 

2001c). The mean and range of xylene concentrations in the cabins of automobiles with diesel engines 

were 2.7 and 1.0–5.9 μg/m3

 (0.6 and 0.2–1.4 ppb), respectively, for o-xylene and 7.9 and 3.2–15.2 μg/m3 

(1.8 and 0.7–3.5 ppb), respectively, for m-/p-xylene. Mean in-vehicle concentrations during suburban 

New Jersey-New York City commutes were 10.1 μg/m3

 (2.33 ppb) for o-xylene and 22.5 μg/m3 

(5.18 ppb) for m-/p-xylene with high ventilation and 14.5 μg/m3

 (3.34 ppb) for o-xylene and 34.6 μg/m3 

(7.97 ppb) for m-/p-xylene with low ventilation. The mean (range) xylene concentration measured in the 

air inside patrol cars was 4.5 ppb (1.4–12.1 ppb) compared to a concentration of 1.0 ppb (0.04–2.4 ppb) in 

air at an ambient site and 1.0 ppb (0.4–1.9 ppb) in roadside air (Riediker et al. 2003). 

Chan et al. (1994) reported the concentrations of VOCs that commuters were exposed to in Taipei, 

Taiwan during the spring of 1992. The mean, median, and maximum concentrations of o-xylene were 95, 

90, and 265 μg/m3

 (22, 21, and 61 ppb), respectively, in the bus, 161, 140, and 405 μg/m3 (37, 32, and 

93 ppb), respectively, in the car, and 244, 225, and 467 μg/m3

 (56, 52, and 108 ppb), respectively, on a 

motorcycle. The mean, median, and maximum concentrations of m-/p-xylene were 149, 141, and 

480 μg/m3

 (34, 32, and 111 ppb), respectively, in the bus, 240, 212, and 479 μg/m3 (55, 49, and 110 ppb), 

respectively, in the car, and 362, 350, and 698 μg/m3

 (83, 81, and 161 ppb), respectively, on a motorcycle. 

Jo and Choi (1996) reported higher concentrations of xylenes in urban vehicles compared to suburban 

vehicles during commutes in Korea. Mean, median, and maximum concentrations of o-xylene were 22.8, 

17.7, and 90.1 μg/m3

 (5.2, 4.1, and 21 ppb), respectively, in urban automobiles and 16.6, 12.4 and 
XYLENE 227 

6. POTENTIAL FOR HUMAN EXPOSURE 

65.6 μg/m3 (3.8, 2.9, and 15 ppb), respectively, in urban buses. Mean, median, and maximum 

concentrations of m-/p-xylene were 28.9, 23.2, and 82.7 μg/m3

 (6.7, 5.3, and 19 ppb), respectively, in 

urban automobiles and 23.1, 16.3, and 64.3 μg/m3

 (5.3, 3.8, and 15 ppb), respectively, in urban buses. 

Mean, median, and maximum concentrations of o-xylene were 13.1, 11.0, and 33.9 μg/m3

 (3.0, 2.5, and 

7.8 ppb), respectively, in suburban automobiles and 9.5, 7.5, and 36.4 μg/m3

 (2.2, 1.7, and 8.4 ppb), 

respectively, in suburban buses. Mean, median, and maximum concentrations of m-/p-xylene were 18.6, 

14.9, and 47.0 μg/m3

 (4.3, 3.4, and 11 ppb), respectively, in suburban automobiles and 12.5, 9.8, and 

34.2 μg/m3

 (2.9, 2.3, and 7.9 ppb), respectively, in urban buses. 

Xylene has also been detected in remote locations. Average background levels of o-, m-, and p-xylene, 

measured over the North Atlantic in 1977, were 13, 21, and 9.2 ng/m3

 (0.003, 0.0048, and 0.002 ppb), 

respectively (Eichmann et al. 1979). Similar measurements over the Indian Ocean gave average 

concentrations of 0.9, 1.1, and 0.15 ng/m3

 (0.21, 0.25, and 0.03 ppt), respectively (Eichmann et al. 1980), 

while over the Pacific Ocean, concentrations ranged from below the detection limit (0.05 ppbv) to 

0.31 ppbv for m- and p-xylene and from 0.01 to 0.77 ppbv for o-xylene (Greenberg and Zimmerman 

1984). All three xylene isomers were detected in the air of the Brazilian rainforest in 1979–1980, at 

concentrations ranging from below the detection limit (0.05 ppbv) to 0.12 ppbv (Greenberg and 

Zimmerman 1984). The concentrations of o-xylene and the combination of m- and p-xylene measured in 

Antarctic snow collected near the coast of the Ross Sea ranged from 1 to 80 ng/L and from 8 to 198 ng/L, 

respectively (Desideri et al. 1994, 1998). It is unlikely that xylenes were carried to these locations by 

long-range atmospheric transport since the half-life of these substances in air is 8–14 hours. One 

explanation given for the presence of xylenes in the remote oceanic locations was that they were being 

released in marine aerosols from contaminated ocean water (Desideri et al. 1994, 1998; Eichmann et al. 

1979, 1980). However, sources of this marine contamination were not identified. 

Recent studies have indicated that xylene is also a common but low contaminant of indoor air both at 

home and in the workplace. Xylene concentrations measured in indoor air are listed in Table 6-6. Based 

on these data, the concentrations of xylene in indoor air typically range from 1 to 10 ppb. 

Concentrations of m- and p-xylene measured in homes at 15 locations in the United States ranged from 

10 to 47 μg/m3

 (2.3–10.8 ppb) (Seifert and Abraham 1982). Similar results were reported during a 1981 

study of the correlation between breath concentration and personal and outdoor air concentrations of 

350 New Jersey residents (Wallace et al. 1986). The weighted median indoor air concentrations of 

o-xylene and the combined m- and p-xylene isomers were 4.9 and 14 μg/m3

 (1.1 and 3.2 ppb), 
XYLENE	 228 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-6. Xylene Concentrations in Indoor Air 

Concentration (ppb) 

Type of m-/p- Total 

Location value o-Xylene Xylene xylenesa Reference 

U.S. Locations 

15 homes Range — 2.3–10.8 — Seifert and Abraham 

1982 

Homes of 350 New Jersey Median 1.1 3.2 4.3 Wallace et al. 1986 

residents 

Homes of 36 students in Kinney et al. 2002 

New York City
 

Summer Mean 0.52 1.48 2.0 

Winter (30 students) Mean 0.77 2.40 3.2 

Library of Congress in Mean 0.7 1.7b

 2.4 b NIOSH 1990a 

Washington, DC 

50 “normal” houses Median 0.41 1.3b

 1.71b Kostiainen 1995 

7 “sick” houses Median 0.77 2.2b 2.97b

 Kostiainen 1995 

 “Sick” building Range 0.99–1.6 2.8–5.1 — Weschler et al. 1990 

Office buildings in United Shields et al. 1996 

States 

50 telecommunications Geometric 0.65c

 0.99 1.64c
 

offices mean 

9 data centers Geometric 1.1c

 1.5 2.6c
 

mean 

11 administrative Geometric 0.81c

 1.11 1.92c
 

offices mean 

Canadian homes Fellin and Otson 1994 

 Winter (185 homes) Mean 0.94 3.72d

 4.66 

Spring (178 homes) Mean 1.59 4.73d

 6.32 

 Summer (197 homes) Mean 0.70 2.43d

 3.13 

Fall (194 homes) Mean 1.89 8.10d

 9.99 

U.K. Indoor locations Kim et al. 2001 

 64 homes Mean 0.44 1.64d

 2.08 

 12 offices Mean 0.41 1.08d

 1.49 

6 restaurants, 6 pubs Mean 1.4, 1.6 5.1, 5.7d

 6.5, 7.3 

8 department stores, Mean 0.81, 1.4, 2.81, 4.9, 3.62, 6.3, 

6 cinemas, 3 perfume 0.55 1.91d 2.46 

shops 

 6 libraries Mean 0.76 2.81d

 3.57 

 8 labs Mean 0.18 0.58d

 0.76 
XYLENE 229 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-6. Xylene Concentrations in Indoor Air 

Concentration (ppb) 

Type of m-/p- Total 

Location value o-Xylene Xylene xylenesa Reference 

German homes Ilgen et al. 2001 

 Rural homes (summer) Mean 0.16 0.744 0.904 

 Rural homes (winter) Mean 0.36 1.1 1.46 

Urban homes (summer) Mean 0.36 1.09 1.45 

Urban homes (winter) Mean 0.64 1.91 2.55 

a

Unless otherwise indicated, total xylene concentrations listed here are the sum of the o-xylene and m-/p-xylene 

concentrations. 

b

Does not include m-xylene concentration because it was not reported in the source. c

Includes styrene 

d

Sum of m- and p-xylene concentrations (reported separately in source) 
XYLENE 230 

6. POTENTIAL FOR HUMAN EXPOSURE 

respectively. Breath concentrations showed significant correlation with personal air concentrations but 

only weak correlation with outdoor air concentrations. Concentrations in indoor air were usually higher 

than in outdoor air, indicating that the source of the xylene was building materials or household products 

(e.g., cleaning agents) (Wallace et al. 1986, 1987b). However, in areas where heavy automotive traffic 

has increased outdoor xylene concentrations, ventilating homes by leaving windows open may actually 

result in additional increases in indoor xylene levels (Hung and Liao 1991). That indoor sources of 

xylene contribute significantly to the levels of these chemicals in interior spaces was also demonstrated in 

an indoor air monitoring study conducted in February and March 1989 on the premises of the Library of 

Congress in Washington, DC. p-Xylene and o-xylene were present at mean levels of 7.2 μg/m3

 (1.7 ppb) 

and 3.2 μg/m3

 (0.7 ppb) in indoor air and 3.2 μg/m3 (0.7 ppb) and 1.2 μg/m3 (0.3 ppb) in outdoor air, 

respectively (NIOSH 1990a). 

Analysis of a building with "sick building syndrome" in the summer of 1987 showed significant 

differences in the concentrations of xylenes in indoor and outdoor air. Combined m- and p-xylene 

concentrations were 12–22 μg/m3

 (2.8–5.1 ppb) and 3.9 μg/m3 (0.9 ppb) for indoor and outdoor air, 

respectively, while o-xylene concentrations were 4.3–6.8 μg/m3

 (0.99–1.6 ppb) for indoor air and 

2.8 μg/m3

 (0.64 ppb) for outdoor air. Higher levels of the xylenes were detected during autumn for indoor 

but not outdoor samples. Potential sources were tobacco smoke and other consumer products including 

carpet adhesive (Weschler et al. 1990). Kostianen (1995) measured the concentrations of VOCs in the 

indoor air of 50 “normal” houses and 38 “sick” houses. Median concentrations of o-xylene and p-xylene 

in the “normal” houses were 1.8 and 5.77 μg/m3

 (0.41 and 1.3 ppb), respectively. Concentrations were 

only provided for 7 of the 38 “sick” houses. o-Xylene concentrations in these houses ranged from 1.74 to 

1,100 μg/m3

 (0.40–253 ppb) with median and geometric mean values of 3.35 and 8.74 μg/m3 (0.77 and 

2.01 ppb), respectively. p-Xylene concentrations ranged from 5.46 to 2,240 μg/m3

 (1.26–516 ppb) with 

median and geometric mean values of 9.53 and 23.9 μg/m3

 (2.20 and 5.51 ppb), respectively. 

Ilgen et al. (2001b) measured geometric mean o-xylene and m-/p-xylene concentrations of 0.68 and 

3.23 μg/m3

 (0.16 and 0.744 ppb), respectively, in German rural homes and 1.56 and 4.74 μg/m3 (0.36 and 

1.09 ppb), respectively, in German urban homes during the summer. Winter o-xylene and m-/p-xylene 

concentrations were 1.57 and 4.97 μg/m3

 (0.36 and 1.1 ppb), respectively, in the rural homes, and 

2.78 and 8.27 μg/m3

 (0.64 and 1.91 ppb), respectively, in the urban homes. 

Fellin and Otson (1994) measured seasonal indoor air concentrations of VOCs in Canadian homes during 

1991. The mean concentrations of o-, m-, and p-xylene were 4.09, 11.21, and 4.96 μg/m3

 (0.94, 2.58, and 
XYLENE 231 

6. POTENTIAL FOR HUMAN EXPOSURE 

1.14 ppb), respectively, in 185 homes during the winter, 6.89, 13.17, and 7.38 μg/m3 (1.59, 3.03, and 

1.70 ppb), respectively, in 178 homes during the spring, 3.03, 6.81, and 3.73 μg/m3

 (0.698, 1.57, and 

0.86 ppb), respectively, in 197 homes during the summer, and 8.19, 26.03, and 9.12 μg/m3

 (1.89, 6.00, 

and 2.10 ppb), respectively, in 194 homes during the fall. 

Graham et al. (2004) studied the effect of vehicle emission infiltration from an attached garage on the 

concentrations of VOCs in house air. The median levels of xylenes measured in 15 Canadian homes 

before and after running a warm vehicle in the garage during the afternoon were 18 and 34.5 ng/L, 

respectively. Median levels in these houses before and after running the vehicles following a cold start in 

the morning were 22.1 and 47.8 ng/L, respectively. Median concentrations of xylenes measured in the 

garage were 274 ng/L after running the vehicles in the afternoon and 1,001 ng/L after running the vehicles 

in the morning. 

The mean concentrations of o-xylene and m-/p-xylene were 1.52 and 4.46 μg/m3

 (0.350 and 1.03 ppb), 

respectively, in the home outdoor air and 3.36 and 10.4 μg/m3

 (0.774 and 2.40 ppb), respectively, in the 

home indoor air of 36 students from west central Harlem in New York City during the winter (Kinney et 

al. 2002). o-Xylene and m-/p-xylene concentrations during the summer were 2.00 and 5.77 μg/m3 

(0.461 and 1.33 ppb) respectively, in the home outdoor air and 2.27 and 6.44 μg/m3

 (0.523 and 1.48 ppb), 

respectively, in the home indoor air of 30 students from this area. Mean o-xylene and m-/p-xylene 

concentrations measured in the personal air of the students were 2.24 and 6.71 μg/m3

 (0.516 and 

1.55 ppb), respectively, during the winter and 3.93 and 10.9 μg/m3 (0.906 and 2.51 ppb), respectively, 

during the summer. 

Jo et al. (2003) did not observe a large difference in xylene indoor air concentrations at high apartment 

floors compared to the air at low floors. In contrast, the concentrations of other chemicals such as methyl 

tertiary butyl ether, toluene, and benzene were higher in the air at the lower floors. Median o-xylene and 

m-/p-xylene concentrations were 4.6 and 13.1 μg/m3

 (1.1 and 3.02 ppb), respectively, in air from low 

floors compared to 4.8 and 14.2 μg/m3

 (1.1 and 3.27 ppb), respectively, in air from high floors. The type 

of ventilation used in the apartment buildings was not indicated. 

Ilgen et al. (2001b) reported that xylene concentrations in the indoor air of homes dramatically increased 

after redecoration, painting, and varnishing. Elevated o-xylene and m-/p-xylene levels attributed to these 

activities ranged from 11.2 to 103.8 μg/m3

 (2.6–23.9 ppb) and from 28.5 to 352.4 μg/m3 (6.6–81 ppb), 

respectively, compared to normal levels ranging from 0.7 to 1.4 μg/m3

 (0.16–0.32 ppb) and from 2.6 to 
XYLENE 232 

6. POTENTIAL FOR HUMAN EXPOSURE 

5.9 μg/m3 (0.60–1.4 ppb), respectively. Leung and Harrison (1998) reported xylene concentrations 

measured in various microenvironments. Values were highest in the painted room and traffic tunnel 

microenvironments with mean o-xylene concentrations of 9.0 and 5.1 ppb, respectively, and mean 

m-/p-xylene concentrations of 24.6 and 22.7 ppb, respectively. 

In the United Kingdom, Kim et al. (2001) measured xylene concentrations in the air of 64 homes, 

12 offices, 6 restaurants, 6 pubs, 8 department stores, 6 cinemas, 3 perfume shops, 6 libraries, and 8 labs. 

Mean concentrations at these locations were 0.8–6.9 μg/m3

 (0.18–1.6 ppb) for o-xylene, 1.9–18.3 μg/m3 

(0.44–4.2 ppb) for m-xylene, and 0.6–6.5 μg/m3

 (0.14–1.5 ppb) for p-xylene. Mean concentrations 

reported for each location are listed in Table 6-6. These authors also measured xylene in the air of 

12 train stations, 12 coach stations, 12 trafficked roads, 18 trains, 18 busses, and 35 cars. Xylene levels 

were highest in the cars, with mean concentrations of 54.2, 127.2, and 52.5 μg/m3

 (12.4, 29.3, and 

12.1 ppb) for o-, m-, and p-xylene, respectively. Mean concentrations at the other locations were 3.5– 

13.2 μg/m3

 (0.81–3 ppb) for o-xylene, 10.1–32.3 μg/m3 (2.3–7.4 ppb) for m-xylene, and 3.5–11.6 μg/m3 

(0.81–2.7 ppb) for p-xylene. 

Shields et al. (1996) measured the VOC concentrations in the air of 70 outdoor locations, 50 telecommunications offices, 11 administrative offices, and 9 data centers throughout the United States. The 

geometric mean concentrations of m-/p-xylene at these locations were 2.7, 4.3, 4.6, and 6.7 μg/m3

 (0.62, 

0.99, 1.1, and 1.5 ppb), respectively. The geometric mean concentrations of o-xylene (reported in 

combination with styrene) at these locations were 1.4, 2.8, 3.5, and 4.8 μg/m3

 (0.32, 0.65, 0.81, and 

1.1 ppb) respectively. The concentration of o-xylene and m-/p-xylene measured in the air of three 

photocopy centers ranged from 0.5 to 16.8 ppb and from 0.7 to 9.4 ppb, respectively (Stefaniak et al. 

2000). The concentrations of xylene in 22 air samples collected from nonproduction departments of 

6 pulp, paper, and paper product mills ranged from <1 to 82 ppm with mean and median concentrations of 

23 and 17 ppm, respectively (Teschke et al. 1999). 

6.4.2 Water 

Limited monitoring data are available on ambient concentrations of xylenes in surface waters. In view of 

the rapid volatilization of xylenes, their presence in surface waters is unlikely to be significant. Surface 

waters generally contain average xylene concentrations of <1 ppb total xylenes except in areas where 

there are fuel processing activities, such as petroleum refining (ECETOC 1986; Otson et al. 1982b; Sauer 
XYLENE 233 

6. POTENTIAL FOR HUMAN EXPOSURE 

et al. 1978). Typical surface water concentrations range from not detected to 2 μg/L (ppb) (Otson et al. 

1982b; Sauer et al. 1978). 

According to 1999–2005 nationwide U.S monitoring data from the STORET database, mixed xylenes 

were detected in 1,252 out of 9,189 water samples with a median (range) concentration of 5.5 μg/L (ppb) 

(0.05–75,000 μg/L [ppb]) (EPA 2005h). o-Xylene was detected in 414 out of 3,623 STORET water 

samples with a median (range) concentration of 0.32 μg/L (ppb) (0.001–2,400 μg/L [ppb]). m-Xylene 

was detected in 76 out of 532 STORET water samples with a median (range) concentration of 0.5 μg/L 

(ppb) (0.02–2.18 μg/L [ppb]). p-Xylene was detected in 73 out of 526 STORET water samples with a 

median (range) concentration of 0.5 μg/L (ppb) (0.01–2 μg/L [ppb]). m-/p-Xylene was detected in 

358 out of 3,147 STORET water samples with a median (range) concentration of 0.53 μg/L (ppb) (0.004– 

4,300 μg/L [ppb]). 

The concentrations of o-xylene measured in estuarine water from Humber, Tyne, Wear, and Tweed, 

United Kingdom were all <10 ng/L (ppt); however, o-xylene was detected at Tees, United Kingdom at 

concentrations up to 1,340 ng/L (ppt) (Dewulf and Van Langenhove 1997). This high concentration of 

o-xylene was attributed to the use of this isomer as an intermediate in the production of phthalic 

anhydride. Concentrations of o-xylene and the combination of m- and p-xylene in estuarine water from 

Sheldt, Netherlands/Belgium were 21.0 and 23.0 ng/L (ppt), respectively. Mixed xylenes have been 

detected in estuarine water from Brazos, United States at concentrations ranging from 1 to 56 ng/L (ppt). 

Xylenes have been detected in beach, bay, shelf sea, and coastal waters in locations around the world. 

o-Xylene concentrations were 1.8–42 ng/L (ppt) at Vineyard Sound, United States, 210 ng/L (ppt) at La 

Pineda, Spain, 0.3–10.1 ng/L (ppt) at the Gulf of Mexico, 4.0 ng/L (ppt) at Vilanova/Sitges, Spain, 

6.1 ng/L (ppt) at Barcelona, Spain, <1–13 ng/L (ppt) at the Campeche Shelf, <10–35 ng/L (ppt) at the 

North Sea, and 9.8–11.9 ng/L (ppt) at the Belgian Continental Shelf. The concentrations of m-/p-xylene 

at these locations were 2.5–66, 34, 27–24.4, 72, 15, 22–59, <10–50, and 11.0–15.1 ng/L (ppt), 

respectively. The concentration of o-xylene was <10 ng/L (ppt) in water samples from five coastal 

locations in the United Kingdom. 

Xylenes were detected in stormwater samples collected from basins around the state of North Carolina at 

mean, median, and maximum concentrations of 0.15, 0.08, and 2.37 μg/L (ppb), respectively, for 

o-xylene and 0.14, 0.09, and 1.62 μg/L (ppb), respectively, for m-/p-xylene (Borden et al. 2002). 

Concentrations of detected xylene in 592 stormwater samples from 16 cities and metropolitan areas across 
XYLENE 234 

6. POTENTIAL FOR HUMAN EXPOSURE 

the United States ranged from 0.2 to 15 μg/L (ppb) with a median concentration of 0.4 μg/L (ppb) 

(percent detected not reported) (Delzer et al. 1997). 

Data on the occurrence of xylene in public drinking water supplies are available from several federal, 

regional, and state surveys (EPA 1985a). In most cases, <6% of the groundwater and surface water 

systems sampled contained detectable levels of xylenes (EPA 1985a). Typical xylene concentrations (all 

isomers) ranged from 0.2 to 9.9 μg/L (ppb) with mean concentrations of <2 μg/L (ppb) (EPA 1985a; 

Keith et al. 1976; Williams et al. 1982). The Unregulated Contaminant Information System (URCIS) 

database round 1 contains public water system contaminant data for a 24-state cross-section (EPA 2001a). 

o-Xylene was detected in 2.41% of 1,450 surface water public water systems and 1.69% of 12,638 

groundwater public water systems. m-Xylene was detected in 2.12% of 1,276 surface water public water 

systems and 1.47% of 10,145 groundwater public water systems. p-Xylene was detected in 2.36% of 

1,230 surface water public water systems and 1.49% of 8,956 groundwater public water systems. Total 

xylenes were detected in 10.75% of 670 surface water public water systems and 2.51% of 8,841 

groundwater public water systems. The 99th percentile concentrations of o-, m-, p-, and total xylenes for 

the round 1 data were <5.0, <4.0, <5.0, and 0.6 μg/L (ppb), respectively. The California EPA Office of 

Drinking Water quality-monitoring database contains drinking water contaminant data for both surface 

water and groundwater sources throughout the state of California (Storm 1994). According to these data, 

xylene has been detected in 23 out of 11,589 California public drinking water sources (0.2%) with mean 

and median detected concentrations of 22.91 and 3.80 μg/L (ppb), respectively. 

The migration of petroleum products from leaking underground storage tanks and pipelines poses a 

groundwater contamination problem. Gasoline-contaminated groundwater in Los Angeles contained 

levels of xylenes as high as 153 μg/L (ppb) (Karlson and Frankenberger 1989). Contaminated 

groundwater from a New Jersey industrial site contained xylenes at a concentration of 3.68 mg/L (ppm) 

(Adey et al. 1996). 

The concentration of o-xylene in groundwater collected from a sampling well at a crude oil spill site in 

north central Minnesota was 269 μg/L (ppb) (Eganhouse et al. 1996). The concentrations of total xylenes 

detected in the leachate plume of a closed landfill in Norman, Oklahoma were 0–1 μg/L (ppb) 

(Eganhouse et al. 2001). The concentration of xylenes measured in groundwater from a hydrocarboncontaminated site in Southern California was 1,010 μg/L (ppb) (Kent and Spycher 1994). The 

concentrations of m-xylene and the combination of o- and p-xylene measured at the Biscayne Aquifer 

Superfund site study area were 20 and 23 μg/L (ppb), respectively (Canter and Sabatini 1994). 
XYLENE 235 

6. POTENTIAL FOR HUMAN EXPOSURE 

Seventeen out of 338 water samples collected from four sites in Iowa using drain tiles, observations wells, 

or lysimeters contained xylene with a mean concentration of 3.0 μg/L (ppb) and a maximum 

concentration of 5 μg/L (ppb) (Wang et al. 1995). Xylenes were detected above a minimum detection 

limit of 0.2 μg/L (ppb) in approximately 15% of groundwater samples collected from 30 wells located 

throughout the Denver, Colorado area with a maximum concentration of 33 μg/L (ppb) (Bruce and 

McMahon 1996). During the National Water Quality Assessment Program of the U.S. Geological 

Survey, mixed xylenes were detected above a reporting level of 0.2 μg/L (ppb) in 2.2% (9 of 406) of 

urban wells with median and maximum detected concentrations of approximately 2 and 50 μg/L (ppb), 

respectively (Kolpin et al. 1997; Squillace et al. 1999). Mixed xylenes were detected above 0.2 μg/L 

(ppb) in 0.9% (23 of 2,542) of rural wells with median and maximum detected concentrations of 

approximately 0.5 and 200 μg/L (ppb), respectively. Concentrations of xylenes measured in groundwater 

are listed in Table 6-7. 

Concentrations of o-xylene and the combination of m- and p-xylene in Antarctic pack ice located at the 

coast of the Ross Sea range from 10 to 20 ng/L (ppt) and from 29 to 54 ng/L (ppt), respectively (Desideri 

et al. 1998). 

6.4.3 Sediment and Soil 

Although several investigators (Aurelius and Brown 1987; Barbee and Brown 1986; Griffin et al. 1984) 

refer to leaching of xylene from waste disposal sites as a source of xylene levels in groundwater samples, 

little data are available on actual measurements of xylene in soil. The rapid volatilization of this chemical 

makes its presence in surface soils unlikely. According to 1999–2005 nationwide U.S. monitoring data 

from the STORET database, mixed xylene was detected in 90 out of 528 soil samples with a median 

(range) concentration of 0.038 mg/kg (0.001–190 mg/kg) (EPA 2005h). 

The concentrations of o-xylene and m-/p-xylene ranged from <0.05 to 3.2 ng/g (ppb) (mean 0.89 ng/g 

[ppb]) and from 0.08 to 5.2 ng/g (ppb) (mean 1.4 ng/g [ppb]) in sediment samples collected from seven 

rivers and a port located in the Niigata Perfecture, Japan (Kawata et al. 1997). The concentration of 

xylenes measured in an aquifer matrix from a hydrocarbon-contaminated site in Southern California was 

5,300 μg/kg (ppb), respectively (Kent and Spycher 1994). According to 1999–2005 nationwide U.S. 

monitoring data from the STORET database, mixed xylene was detected in 14 out of 165 sediment 

samples with a median (range) concentration of 0.087 mg/kg (0.001–41 mg/kg) (EPA 2005h). 
XYLENE 236 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-7. Xylene Concentrations in Groundwatera 

Percent Positive concentration (ppb) 

Location detected Mean Median Maximum Reference 

General surveys 

4 sites in Iowa 5 3.0 — 10,000 Wang et al. 1995 

30 wells around 15 — — 33 Bruce and McMahon 1996 

Denver, Colorado 

406 urban U.S. wells 2.2 — 2.0 50 Squllace et al. 1999 

2,542 rural U.S. wells 0.9 — 0.5 200 Squllace et al. 1999 

Individual contaminated 

sites 

Los Angeles site — — — 153 Karlson and 

(gasoline Frankenberger 1989 

contamination) 

New Jersey industrial — 3,680b — — Adey et al. 1996 

site 

Minnesota crude oil — 269c — — Eganhouse et al. 1996 

spill site 

Leachate from closed — — — 1 Eganhouse et al. 2001 

Oklahoma landfill 

 Southern California — 1,010b — — Kent and Spycher 1994 

site 

 Biscayne Aquifer — 43d — — Canter and Sabatini 1994 

Superfund site 

a

Reported in sources as concentrations of xylene unless otherwise specified b

Value reported by source as single concentration of xylenes at that site c

Value reported by source as single concentration of o-xylene at that site (m- and p-xylene not reported)
 d

Value is the sum of reported single o- and p-xylene concentrations at that site (m-xylene not reported) 
XYLENE 237 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.4.4 Other Environmental Media 

Xylene has been detected in cigarette smoke, consumer products, and some foods. The gas phase 

delivery of p-xylene in ultra-low tar delivery cigarette smoke ranges from <0.01 to 8 μg/cigarette, while 

the ranges for m- and o-xylene are <0.01–20 and <0.005–10 μg/cigarette, respectively (Higgins et al. 

1983). Data were not located for regular strength or unfiltered cigarettes. The 1,095 household products 

surveyed by the Consumer Product Safety Commission (Fishbein 1985) contained an average of 9.5% 

mixed xylene. The largest number of products containing mixed xylene were household aerosols and 

paints, varnishes, shellac, and rust preventatives. The concentrations of o-xylene measured in interior 

alkyd primer and three interior alkyd enamel paints were 1.39, 4.91, 5.48, and 6.92 mg/g (1,390, 4,910, 

5,480, and 6,920 ppm) (Fortmann et al. 1998). The concentrations of p-xylene in these paints were 0.23, 

0.73, 1.45, and 1.36 mg/g (230, 730, 1,450, and 1,360 ppm). 

Xylene has been detected in distillates of rainbow trout and in carp tissue samples from three rivers not 

known to be contaminated (Hiatt 1983). The estimated tissue concentrations of m- and p-xylene in 

rainbow trout and carp were 0.05 and 0.12 mg/kg (ppm), respectively (Hiatt 1983). 

Eggs, whether stored or used fresh, contained detectable levels of all three xylene isomers when 

scrambled (Matiella and Hsieh 1991). The polystyrene packing case in which some of the eggs had been 

stored also contained detectable levels of the xylene. Actual concentrations of o-, m-, and p-xylene were 

4.0, 7.0, and 3.0 ng/g (ppb), respectively, in supermarket eggs packed in polystyrene, 3.0. 8.0, and 

2.7 ng/g (ppb), respectively, in fresh eggs not stored, and 2.0, 3.0, and 1.3 ng/g (ppb), respectively, in 

fresh eggs stored in polystyrene for 2 weeks. 

o-Xylene was detected above 3.72 ppb in 32 of 234 table-ready food items analyzed during a Total Diet 

Study conducted by the FDA with an average concentration of 8.15 ppb (range 3.72–23.5 ppb) (Heikes et 

al. 1995). m-/p-Xylene was detected in 64 out of the 234 food items with an average concentration of 

64 ppb (range 6.20–114 ppb). The concentrations of o-xylene in sandwich cookies, margarine, butter, and 

cake doughnuts measured during this study were 6.31, 21.7, 12.5, and 23.5 ppb, respectively. The 

concentrations of m- and p-xylene together in these foods were 12.9, 114, 54.8, and 35.0 ppb, 

respectively. 

The mean and range of m-/p-xylene concentrations were 0.24 and 0.01–0.75 ng/mL, respectively, in 

19 whole milk samples, 0.08 and 0.02–0.33 ng/mL, respectively, in eight 2% milk samples, and 0.27 and 
XYLENE 238 

6. POTENTIAL FOR HUMAN EXPOSURE 

0.01–0.56 ng/mL, respectively, in five 1% milk samples collected in Las Vegas, Nevada (Hiatt and Pia 

2004). The mean and range of o-xylene concentrations were 0.18 and 0.01–0.62 ng/mL, respectively, in 

the whole milk samples, 0.08 and 0.02–0.29 ng/mL, respectively, in the 2% milk samples, and 0.21 and 

0.01–0.40 ng/mL, respectively, in the 1% milk samples. 

Both o- and m-xylene were detected in the aroma concentrates of cured beef (Ramarathnam et al. 1991) as 

well as in the volatile fraction of raw beef (King et al. 1993). Only o-xylene was detected in cured 

chicken. None of the xylene isomers were detected in the uncured meat samples. o-, m-, and p-Xylene 

have been detected in the headspace of frankfurter sausages at unspecified concentrations (Chevance and 

Farmer 1999). Ho et al. (1983) identified o-xylene as a volatile flavor compound in fried bacon. 

o-Xylene has also been identified in the volatiles of fried chicken (Tang et al. 1983). Wu and Liou (1992) 

measured reported o-, m-, and p-xylene concentrations of 1.85, 0.99, and 0.72 ppb, respectively, in duck 

meat, 14.91, 4.29, and 5.97 ppb, respectively, in duck fat, 1.90, 9.61, and 10.64 ppb, respectively, in 

Cantonese style roasted duck, and 10.29, 18.09, and 21.23 ppb, respectively, in Cantonese style duck 

gravy. 

The concentrations of o-, m-, and p-xylene were measured to be 132 ng/g (ppb), not detected, and 

79.4 ng/g (ppb), respectively, in Korean anchovy; 102 ng/g (ppb), 378 ng/g (ppb), and not detected, 

respectively in Korean big eyed herring; not detected, 124 ng/g (ppb), and not detected, respectively, in 

Korean hair tail viscera; and 58.6, 99.9, and 39.0 ng/g (ppb), respectively in Korean Shrimp pastes (Cha 

and Cadwallader 1995). Chung (1999) reported measured o-, m-, and p-xylene concentrations of 31.4, 

53.8, and 36.0 μg/kg (ppb), respectively, in the leg meat of crabs (C. feriatus), 23.6, 40.1, and 2.8 μg/kg 

(ppb), respectively, in the body meat of the crabs, and 199.7, 329.4, and 234.6 μg/kg (ppb), respectively, 

in the carapace meat of the crabs. Misharina and Golovnya (1992) also detected xylenes among the 

volatile components of shrimp and crabmeat. o- and m-Xylene have been identified in the volatiles of 

cooked mussels (Leguen et al. 2000). 

Xylene (unspecified isomers) has been identified as a volatile component of Beaufort cheese from the 

French Alps (Dumont and Adda 1978). o-, m-, and p-Xylene have been identified as volatile components 

of Idaho Russet Burbank baked potatoes, chickpea (Cicer arietinum L.) seed, and peaches (Coleman et al. 

1981, Rembold et al. 1989, Takeoka et al. 1988). o-Xylene was detected in dry beans, split peas, and 

lentils at mean concentrations of 9 ppb (0–25 ppb), 8 ppb, and 3 ppb, respectively (Lovegren et al. 1979). 

Jenkins et al. (2004) found little difference in the mean concentrations of total xylenes in hazelnuts that 

had been previously treated with xylene compared to control hazelnuts that had not been treated (0.65– 
XYLENE 239 

6. POTENTIAL FOR HUMAN EXPOSURE 

1.43 ng/g [ppb] compared to 1.49 ng/g [ppb]). o-, m-, and p-xylene have all been detected in the volatiles 

of roasted filberts (Kinlin et al. 1972). The concentration of p-xylene in three apricots and two plums 

ranged from not detected to 2 μg/kg (ppb) while concentrations of this substance ranged from not detected 

to 9 μg/kg (ppb) in their interspecific hybrid progeny (Gomez et al. 1993). 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

Because individual xylene isomers are used in large amounts in industrial settings, people who work at or 

live near these locations may receive a higher exposure to one xylene isomer compared to the other 

isomers. However, since xylenes are present as a mixture in gasoline and in the solvent components of 

commonly used commercial products (paint, coatings, etc.), exposure of the general population is 

expected to be primarily to xylenes as a mixture, and not to the separate xylene isomers. 

The California Total Exposure Assessment Methodology (TEAM) Study conducted in 1984 in Los 

Angeles County (an urban area) and Contra Costa County (a rural area) monitored volatile organic 

compounds in ambient (outdoor) air, personal air, and breath samples for 188 people (Wallace et al. 

1988). (Personal air is defined as air samples which were collected using a sampling vest worn by the 

participant with the pump and collection cartridge placed close to the breathing level.) In Los Angeles, 

all three xylene isomers were detected in each air type; higher levels were measured during the winter for 

all air types and all xylene isomers compared with summer levels. Average concentrations (in μg/m3 

[ppb]) are listed in Table 6-8. 

Smoking was determined to be the major determinant for the presence of xylene in breath and personal 

air, with concentrations in the breath of smokers more than double those of nonsmokers. Auto-related 

situations, such as pumping gasoline and exposure to exhaust, as well as type of employment also 

contributed significantly to increased concentrations of xylene in breath and personal air (Wallace et al. 

1988). A second TEAM study in 1987, of the same Los Angeles families, showed similar trends in 

relative concentrations of xylene in personal, indoor, and outdoor air (Wallace et al. 1991). Again, 

outdoor concentrations were lower than indoor concentrations which, in turn, were lower than personal air 

samples. Mean xylene concentrations (in μg/m3

 [ppb]) are listed in Table 6-9. 

Studies by Ashley et al. (1995) and Wallace et al. (1987a) supported the argument that xylene exposure is 

greater for individuals who smoke cigarettes. The reported mean (median) concentrations of o-xylene 

and m-/p-xylene were 0.13 ng/mL (0.086 ng/mL) and 0.41 ng/mL (0.19 ng/mL), respectively, in the blood 
XYLENE 240 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-8. Average Personal Air, Outdoor Air, and Breath Concentrations 

Measured During the 1984 TEAM Study
 

Location 

Los Angeles 

(February) 

Sample type 

Personal air 

 Outdoor air 

Breath 

m-/p-Xylene (ppb) 

28 (6.5) 

24 (5.5) 

3.5 (0.8) 

o-Xylene (ppb) 

13 (3.0) 

11 (2.5) 

1.0 (0.2) 

Los Angeles 

(June) 

Personal air 

 Outdoor air 

Breath 

24 (5.5) 

9.4 (2.2) 

2.8 (0.6) 

7.2 (1.7) 

2.7 (0.6) 

0.7 (0.2) 

Contra Costa 

(June) 

Personal air 

 Outdoor air 

Breath 

11 (2.5) 

2.2 (0.5) 

2.5 (0.6) 

4.4 (1.0) 

0.7 (0.2) 

0.6 (0.1) 

TEAM Study = The California Total Exposure Assessment Methodology Study 

Source: Wallace et al. 1988 
XYLENE 241 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-9. Average Personal Air, Indoor Air, Outdoor Air, and Breath 

Concentrations from the 1987 TEAM Study
 

Date Sample type m-/p-Xylene (ppb) o-Xylene (ppb) 

February Personal air 43 (9.9) 16 (3.7) 

Indoor 30 (6.9) 12 (2.8) 

 Outdoor 18 (4.2) 6.5 (1.5) 

Breath (median value) 2.5 (0.6) 0.8 (0.2) 

July Personal air 27 (6.2) 9.2 (2.1) 

Indoor 12 (2.8) 4.3 (1.0) 

 Outdoor 7.4 (1.7) 2.8 (0.6) 

Breath (median value) 0.7 (0.2) 0.25 (0.1) 

TEAM Study = The California Total Exposure Assessment Methodology Study 

Source: Wallace et al. 1991 
XYLENE 242 

6. POTENTIAL FOR HUMAN EXPOSURE 

of 126 nonsmokers and 0.18 ng/mL (0.14 ng/mL) and 0.53 mg/mL (0.42 mg/mL), respectively, in the 

blood of 42 smokers (Ashley et al. 1995). The unweighted geometric mean concentrations of o-xylene 

and m-/p-xylene were 1.55 and 5.5 μg/m3

, respectively, in the breath of 200 smokers in New Jersey and 

California compared to 0.8 and 2.1 μg/m3

, respectively, in the breath of 322 nonsmokers from these 

locations (Wallace et al. 1987a). The unweighted geometric mean daytime personal air exposures of 

o-xylene and m-/p-xylene were 7.8 and 22 μg/m3

, respectively, for the smokers and 6.5 and 16 μg/m3, 

respectively, for the nonsmokers. The weighted geometric mean overnight indoor air concentrations of 

o- and m-/p-xylene were 5.5 and 14.9 μg/m3

, respectively, in the homes of the smokers and 4.9 μg/m3 and 

13.4 μg/m3

, respectively, in the homes of the nonsmokers. Heavner et al. (1995, 1996), however, came to 

a different conclusion, reporting that there was no significant difference between xylene exposure in 

smoking and nonsmoking homes. Median exposures reported for o-, m-, and p-xylene were 1.51, 3.61, 

and 1.11 μg day/m3

, respectively, at the homes of 15 smokers and 1.63, 3.22, and 1.12 μg day/m3, 

respectively, at the homes of 35 nonsmokers. It should be noted, however, that Heavner et al. (1995, 

1996) studied a relatively small subject population (49 subjects) compared to Ashley et al. (1995) 

(168 subjects) and Wallace et al. (1987a) (522 subjects). 

Individuals are expected to be exposed to xylenes by breathing the air inside homes and buildings since 

these substances are commonly found in indoor air. Exposure may also arise from ingestion of 

contaminated drinking water. Common activities identified with increased potential exposure include 

pumping gasoline, visiting service stations, traveling in a car, painting, scale model building, pesticide 

use, and smoking (Wallace et al. 1986, 1987b). 

Blood levels of o-xylene and m-/p-xylene were 0.080 and 0.32 μg/L, respectively, in 86 commuters from 

Mexico City, 0.082 and 0.24 μg/L, respectively, in 14 commuters from Stamford, Connecticut, 0.20 and 

0.44 μg/L, respectively, in 26 commuters from Fairbanks, Alaska, 0.045 and 0.14 μg/L, respectively, in 

19 commuters from Albany, New York, and 0.094 and 0.16 μg/L, respectively (Lemire et al. 2004). 

Jo and Moon (1999) studied the exposure of South Korean housewives who live near roadside service 

stations to VOCs. For housewives who lived within 30 m of a service station, mean o-, m-, and p-xylene 

concentrations were 9.8, 7.0, and 12.7 μg/m3

 (2.3, 1.6, and 2.9 ppb), respectively, in indoor air, 6.0, 4.1, 

and 8.8 μg/m3

 (1.4, 0.9, and 2.0 ppb), respectively, in outdoor air, and 3.3, 3.4, and 2.4 μg/m3 (0.8, 0.8, 

and 0.6 ppb), respectively, in breath samples. For housewives who lived 60–100 m from a service 

station, mean o-, m-, and p-xylene concentrations were 12.2, 8.5, and 15.5 μg/m3

 (2.8, 2.0, and 3.6 ppb), 

respectively, in indoor air, 3.7, 2.3, and 5.7 μg/m3

 (0.9, 0.5, and 1.3 ppb), respectively, in outdoor air, and 
XYLENE 243 

6. POTENTIAL FOR HUMAN EXPOSURE 

4.1, 4.0, and 3.2 μg/m3 (0.9, 0.9, and 0.7 ppb), respectively, in breath samples. The mean and range of 

concentration of xylenes that 25 individuals were exposed to while riding or operating an open sleigh 

snowmobile were 2.00 and <0.05–13.0 mg/m3

 (0.5 and <0.1–3.0 ppb), respectively (Eriksson et al. 2003). 

Of 237 consumer products tested for m-xylene and 221 products tested for o- and p-xylene, 101 products 

contained m-xylene and 93 products contained o- and p-xylene at concentrations >0.1% weight (EPA 

1991b; Sack et al. 1992). The concentrations and percentage of positive detects are listed in Table 6-10. 

Based on the estimates of EPA (1983) of median atmospheric concentrations of (see Section 6.4.1) and 

assuming inhalation of 23 m3

/day by a 70-kg adult, the daily o-xylene intakes from air for adults exposed 

to the median levels in rural, urban, and source-dominated areas would be 0.0001, 0.0017, and 

0.0012 mg/kg/day, respectively. The median m- and p-xylene intakes would be 0.0001, 0.0039, and 

0.0024 mg/kg/day, respectively (EPA 1985a). Assuming a typical ambient air xylene concentration of 

4.0 ppb, the average daily intake of xylene from air is estimated to be 353 μg (HSDB 2007). 

General population exposure to xylene can also occur through dermal contact with the many consumer 

products containing xylene, including cleaning solvents, insecticides, lacquers, paint thinners and 

removers, and pesticides (EPA 1985a; Fishbein 1985; Gleason et al. 1969). Dermal absorption is 

reported to be minor following exposure to xylene vapor but may be significant following contact with 

the liquid (EPA 1985a). The percutaneous absorption rate of m-xylene in humans is approximately 

2 μg/cm2

/minute through the skin of the hands (Engstrom et al. 1977). 

Assuming a maximum concentration of total xylenes (m-, o-, and p-xylene) (1.5 mg/L) and a daily intake 

of 2 L of drinking water, the adult maximum daily intake for total xylenes through consumption of 

drinking water is estimated to be 3 mg/day or 0.04 mg/kg/day (EPA 1985a). 

Mean and median concentrations of o-xylene detected in 711 blood samples from participants in the Third 

National Health and Nutrition Examination Survey (NHANES III) were 0.14 and 0.11 ppb, respectively 

(Ashley et al. 1994, 1996). m- and p-Xylene were detected together in 649 blood samples with mean and 

median concentrations of 0.37 and 0.19 ppb, respectively. o- and p-Xylene blood levels of 0.094 and 

0.16 μg/L (ppb), respectively, were reported for the nonsmoking subset (546 individuals) of participants 

in NHANES III (Lemire et al. 2004). 
XYLENE 244 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-10. Concentrations of Xylene in Consumer Products 

m-Xylene o-/p-Xylene 

Concentration of Concentration of 

Product Percent detected xylene Percent detected xylene 

Automotive 26.7 10.6 10.0 31.0 

products 

Household 33.3 1.4 0.0 0.0 

cleaners, polishers 

Paint-related 60.3 4.2 58.2 2.8 

products 

Fabric and leather 0.0 0.0 33.3 0.1 

treatments 

Oils, greases, and 9.3 0.2 11.9 0.2 

lubricants 

Adhesive-related 9.1 0.2 9.1 0.2 

products 

Source: Sack et al. 1992 
XYLENE 245 

6. POTENTIAL FOR HUMAN EXPOSURE 

The mean and range of xylene concentrations measured in whole blood specimens collected from 

250 hospital patients were 5.2 and 0.5–160 ppm (5,200 and 500–160,000 ppb), respectively (Antoine et 

al. 1986). Mean and median concentrations of m-xylene measured in blood samples of 25 individuals 

living in Italy (including both smokers and non smokers) were 719 and 457 ng/L (0.719 and 0.457 ppb), 

respectively (Perbellini et al. 2002). Mean and median m-xylene concentrations in the urine of these 

individuals were 106 and 96 ng/L (0.106 and 0.096 ppb), respectively. The mean and range of xylene 

concentrations in the blood of the occupants of approximately 57 rural homes in northern Germany were 

229 and 71–1,113 ng/L (0.229 and 0.071–1.113 ppb), respectively, with corresponding indoor air 

concentrations of 9.29 and 3.64–54.64 ng/L (2.1 and 0.8–12.5 ppb) (Ilgen et al. 2001a). The mean and 

range of xylene concentrations in the blood of the occupants of approximately 57 urban homes in northern 

Germany were 262 and 89–1,301 ng/L (0.262 and 0.089–1.301 ppb), respectively, with corresponding 

indoor air concentrations of 9.29 and 1.84–87.79 ng/L (2.1 and 0.4–20.2 ppb), respectively. 

Xylenes were detected in eight milk samples collected from mothers at hospitals in Bayonne, New Jersey; 

Jersey City, New Jersey; Pittsburgh, Pennsylvania; Baton Rouge, Louisiana; and Charleston, West 

Virginia (EPA 1980a). Concentrations in these samples were not reported. 

Occupational exposure to mixed xylenes may occur during their production as well as their end use as 

industrial solvents. Occupational exposures result from inhalation or dermal exposure and are usually 

associated with process, storage, or fugitive emissions at petroleum chemical, paint, and plastics plants 

(Bratveit et al. 2004; Fishbein 1985, 1988). Average daily intake of xylenes from individual occupational 

exposure sources has not been estimated. Results of a study of solvent exposures in 1981 involving 

eighty-nine workers in seven plants of three companies applying paints and glues, primarily by spraying, 

showed that most solvent spraying activities surveyed showed only low-to-moderate exposures to xylene 

relative to the TLV in the presence of ordinary general room ventilation (Whitehead et al. 1984). The 

TWA concentrations of xylene for high-aromatic spraying in booths (3.5 ppm), solvent wiping (0.7 ppm), 

and paint mixing (3.7 ppm) were well below the TLV for xylene (100 ppm) (Whitehead et al. 1984). 

The ranges of concentrations of o-xylene and m-/p-xylene were 65–1,900 μg/m3

 (15–440 ppb) and 180– 

5,800 μg/m3

 (41–1,300 ppb), respectively, in the personal air of 24 service station attendants, 2.0– 

44 μg/m3

 (0.5–10 ppb) and 71–120 μg/m3 (16–28 ppb), respectively, in the personal air of 6 street 

vendors, and 16–28 μg/m3

 (3.7–6.5 ppb) and 44–80 μg/m3 (10–18 ppb), respectively, in the personal air 

of 7 office workers in Mexico City during their work shifts (Romieu et al. 1999). Mean (range) 

concentrations of o-xylene and m-/p-xylene in the blood of the service station attendants were 0.39 (0.16– 
 

 

XYLENE 246 

6. POTENTIAL FOR HUMAN EXPOSURE 

1.2 μg/L) and 1.4 (0.50–4.7) μg/L (ppb), respectively, at the beginning of the work shift and 0.45 (0.15– 

6.3) and 1.3 (0.36–16) μg/L (ppb), respectively, at the end of the work shift. Mean (range) concentrations 

of o-xylene and m-/p-xylene in the blood of the street vendors were 0.18 (0.13–0.30) and 0.75 (0.41–1.1) 

μg/L (ppb), respectively, at the beginning of the work shift and 0.15 (0.083–0.20) and 0.53 (0.25–0.70) 

μg/L (ppb), respectively, at the end of the work shift. Mean (range) concentrations of o-xylene and 

m-/p-xylene in the blood of the street vendors were 0.15 (0.081–0.31) and 0.55 (0.37–0.81) μg/L (ppb), 

respectively, at the beginning of the work shift and 0.10 (0.073–0.21) and 0.39 (0.19–0.73) μg/L (ppb), 

respectively, at the end of the work shift. 

The ranges of concentrations of xylenes detected in the perimeter air, pump air, and breathing zone air 

were <0.001–0.066 ppm (<1.0–66 ppb) at two full service stations in New Jersey, 0.001–0.014 ppm (1.0– 

4.0 ppb) at three self-serve service stations in New York, and <0.001–0.281 ppm (<1.0–281 ppb) at five 

self-serve service stations in Connecticut (API 1994). 

The American Petroleum Institute (API 1995) studied the exposure of service station attendants and 

mechanics to fuel components at six stations in New York, three stations in Minnesota, four stations in 

Arizona, and three stations in Oregon in 1994. During the wintertime, xylene was detected above 0.01– 

0.30 ppm in only 1 of the 59 short-term exposure cases involving attendants. It was not detected above 

the detection limit (0.01–0.03 ppm) in 51 long-term exposure cases involving attendants. Xylene was 

detected above 0.09–0.15 ppm in 7 of 44 short term winter exposure cases involving mechanics with a 

median (range) concentration of 1 ppm (1–6.4 ppm). It was detected above 0.01–0.02 ppm in 3 out of 

44 long-term exposure cases involving mechanics with a median (range) concentration of 1 ppm (1– 

2.2 ppm). During the summertime, xylene was detected above 0.09–0.16 ppm in 44 of the 60 short-term 

exposure cases involving attendants with a median (range) concentration of 0.15 ppm (0.09–7.70 ppm). It 

was detected above 0.01–0.06 ppm in 52 out of 54 long-term exposure cases involving attendants with a 

median (range) concentration of 0.05 ppm (0.01–0.83 ppm). Xylene was detected above 0.08–0.16 ppm 

in 18 of 44 short term summer exposure cases involving mechanics with a median (range) concentration 

of 0.15 ppm (0.08–30.0 ppm). It was detected above 0.01–0.02 ppm in 35 out of 42 long-term exposure 

cases involving mechanics with a median (range) concentration of 0.1 ppm (0.01–1.60 ppm). 

During a study of exposure to gasoline components during loading and delivery, the mean exposure of 

tanker drivers to xylene was measured to be 0.8–4 mg/m3

 (Hakkola and Saarinen 1996). 
XYLENE 247 

6. POTENTIAL FOR HUMAN EXPOSURE 

The mean (median, range) concentrations of xylene in the blood of thirteen workers occupied in the 

production of paints containing xylene and 10 workers occupied in paint spraying were 380 μg/L 

(403 μg/L, 63–715 μg/L) and 130 μg/L (74 μg/L, 49–308 μg/L), respectively, after an 8-hour work shift 

(Kramer et al. 1999). The mean (median, range) concentrations of xylene in the air during the shifts were 

29 μg/L (30 μg/L, 5–58 μg/L) for the production workers and 8 μg/L (7 μg/L, 3–21 μg/L) for the spraying 

workers. The mean (median, range) concentrations of the methylhippuric acid metabolites in urine were 

1,221 mg/L (1,168 mg/L, 194–2,333 mg/L) for the production workers and 485 mg/L (397 mg/L, 65– 

1,633 mg/L) for the spraying workers. Moen and Hollund (2000) measured xylene concentrations 

ranging from 0.2 to 0.8 ppm in the air of six car painting garages. Vincent et al. (1994) reported that the 

mean (range) concentrations of xylenes in personal air during painting operations in an aeronautical 

workshop were 30.9 mg/m3

 (14.3–46.5 mg/m3) after day 1, 87.0 mg/m3 (38.7–160.0 mg/m3) after day 2, 

and 122.2 mg/m3

 (68.3–167.0 mg/m3) after day 3. 

o-Xylene and m-/p-xylene concentrations in the inhaled air were 5.3 and 15.9 μg/m3

, respectively, in the 

inhaled air of individuals who spent less than 3 hours/day in workshops and warehouses compared to 

30.4 and 114 μg/m3

, respectively, for individuals who spent more than 3 hours/day in these places 

(Hoffmann et al. 2000). The concentrations of o-xylene and m-/p-xylene were 5.4 and 16.2 μg/m3

, 

respectively, in the inhaled air of individuals who work where no paints or lacquers are used, 12.7 and 

38.4 μg/m3

, respectively, in the inhaled air of individuals who work where paints or lacquers are used 

occasionally, and 41.8 and 171 μg/m3

, respectively, in the inhaled air of individuals who work where 

paints or lacquers are used frequently. 

Holz et al. (1995) reported that exposure of workers at a styrene plant to air concentrations of 6.0– 

44.1 μg/m3

 for o-xylene and 5.6–64.0 μg/m3 for m- and p-xylene together did not result in increased 

breath concentrations compared to non-exposed individuals. o-Xylene and m- and p-xylene 

concentrations were 3.4 and 3.7 μg/m3

, respectively, in the breath of exposed workers after their shift 

compared to 3.5 and 4.0 μg/m3

, respectively, in the breath of non-exposed controls. The differences in 

mean concentrations of the metabolites o-methyl hippuric acid and m- and p-methyl hippuric acid 

together in the urine of workers before their shift to mean concentrations in their urine after their shift 

were 0.6 and 8.1 mg/g creatinine, respectively, for the exposed workers and 0.2 and 2 mg/g creatinine, 

respectively, for the non-exposed controls. 

Pedersen and Higgins (1995) reported the vapor concentrations of xylenes that individuals were exposed 

to while taking part in various activities. Measured vapor concentrations of xylenes were 10.83 ppm 
XYLENE 248 

6. POTENTIAL FOR HUMAN EXPOSURE 

during varnishing and sealing household wooden doors, 0.92 ppm during activity in a paint mixing booth, 

0.069 ppm during automotive break and rotor cleaning, 0.04 ppm during emptying/cleaning a fuel oil 

holding tank, 0.21 ppm during activity in a printing shop, 1.680 ppm during cleaning firearms, 2.264 ppm 

during refinishing furniture, and below the detection limit (not specified) during activity in a beauty salon, 

application of hairspray, activities in an autorepair shop, and activity in a traffic sign painting shop. The 

concentrations of xylenes measured in various work areas were 0.124 ppm in a paint booth mixing room, 

1.100 ppm in a household remodeling bathroom, 0.102 ppm in a household paint stripping room, and 

below the detection limit (not specified) in a wooden door staining room, a traffic sign painting room, and 

a traffic sign stripping room. 

The average concentrations of xylene vapors that 60 material handling personnel and 51 laboratory 

personnel were exposed to while working at treatment, storage, and disposal facilities were 1.61 and 

0.16 ppm, respectively (Pedersen and Higgins 1995). The average work area vapor concentration at these 

facilities was 0.47 ppm. 

The concentrations of xylene in the exhaled breath of shipyard workers commonly exposed to organic 

solvents ranged from <1 to 10.6 ppm (Katsuyama et al. 1998). The mean (range) concentrations of the 

metabolite methylhippuric acid in the urine of these workers were 0.09 g/g creatinine (0.02–0.40 g/g 

creatinine) before their work shift and 0.22 g/g creatinine (0.02–1.41 g/g creatinine) after their work shift. 

The mean concentrations of o-xylene and m-/p-xylene in the breath of four dry cleaning workers ranged 

from 4.5 to 9.0 and from 7.6 to 17.7 μg/m3

 (1.0–2.1 and 1.8–4.1 ppb), respectively compared to mean 

concentrations of 3.7 and 6.5 μg/m3

 (0.9 and 1.5 ppb), respectively, in the breath of their housewives (Jo 

and Kim 2001). Mean air concentrations measured inside different dry cleaning stores ranged from 

16.6 to 85.2 μg/m3

 (3.8–19.6 ppb) for o-xylene and from 33.8 to 161 μg/m3 (7.8–37.0 ppb) for 

m-/p-xylene. 

The National Occupational Exposure Survey (NOES), conducted by NIOSH from 1980 to 1983, indicated 

that 1,106,789 workers, including 211,806 women, in 74,063 plants were potentially exposed to mixed 

xylene in the workplace in 1980 (NIOSH 1990c). An estimated 5,596 workers (including 1,314 women) 

in 331 plants, 16,863 workers (including 1,194 women) in 1,610 plants, and 1,160 workers (including 

545 women) in 178 plants were potentially exposed to o-, m-, and p-xylene, respectively. The largest 

numbers of workers exposed to mixed xylene were employed in the machinery (except electrical), special 

trade contractors, fabricated metal products, and health services industries (as assemblers, janitors, 
XYLENE 249 

6. POTENTIAL FOR HUMAN EXPOSURE 

cleaners, painting and paint-spraying machine operators, and automobile mechanics). The largest 

numbers of workers exposed to o-xylene were employed in the chemical and allied products industry (as 

machine operators [not specified], chemical technicians, production inspectors, checkers, and examiners). 

The largest numbers of workers exposed to m-xylene were employed in the electric, gas, and sanitary 

services and business services industries (as electrical power installers and repairers, supervisors, 

plumbers, pipe fitters, steam fitters, order clerks, and chemists [except biochemists]). The largest 

numbers of exposed workers exposed to p-xylene were employed in the health services industries (as 

clinical laboratory technologists and technicians). These estimates were derived from observations of the 

actual use of mixed xylene and the individual xylene isomers and the use of trade name products known 

to contain xylene (see Table 6-11 for percentage breakdown). 

The NOES database does not contain information on the frequency, level, or duration of exposure of 

workers to any of the chemicals listed therein. The survey only provides estimates of workers potentially 

exposed to the chemicals. 

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 are expected to be exposed to xylenes by the same routes that affect adults. Since xylenes have 

a low affinity for adsorption onto soil and dust particles and a high volatilization rate, the risk of exposure 

for small children from ingesting soil or dust is likely to be low. 
XYLENE 250 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-11. Percentage Breakdown of NIOSH Occupational Exposure Estimates 

from the NOES Databasea 

NOES
 

Chemical Actualb

 Trade name 

o-Xylene 96% 4% 

m-Xylene 23% 77% 

p-Xylene 75% 25% 

Total xylenes 19% 81% 

a

Derived from NIOSH 1976, 1990c 

b

Actual observations are surveyor observations in which the surveyor observed the use of the specific agent. 

NIOSH = National Institute for Occupational Safety and Health; NOES = National Occupational Exposure Survey 
XYLENE 251 

6. POTENTIAL FOR HUMAN EXPOSURE 

During the Minnesota Children’s Pesticide Exposure Study (MCPES), xylene was detected in personal, 

indoor, and outdoor air samples collected from households with children (Adgate et al. 2004a). During 

the School Health Initiative: Environment, Learning, Disease (SHIELD) study, the concentrations of 

xylene were measured in the outdoor home air, indoor school air, indoor home air, and personal air of 

113 children from two inner-city schools in Minneapolis, Minnesota (Adgate et al. 2004b). Mean and 

median exposure concentrations reported in these studies were below 7 μg/cm3

 for both m-/p- and 

o-xylene. The data are listed in Table 6-12. 

Sexton et al. (2006) analyzed blood samples collected from 43 inner-city children 3–6 years of age living 

in Minneapolis, Minnesota. Mean, minimum, and maximum concentrations in 50 blood samples were 

0.32, 0.09, and 1.40, ng/mL, respectively, for m-/p-xylene and 0.06, 0.02, and 0.22 ng/mL, respectively, 

for o-xylene. 

During a study of the exposure of Danish children to benzene, toluene, and xylenes, the median 

concentration of xylenes was 18 μg/m3

 (4.1 ppb) in front door air samplers and 17 μg/m3 (3.9 ppb) in 

personal air samplers of 56 children living in Copenhagen. Median concentrations for 40 Danish children 

living in rural areas were 2.6 μg/m3

 (0.6 ppb) in front door air samplers and 13 μg/m3 (3.0 ppb) in 

personal air samplers (Raaschou-Nielsen et al. 1997). The authors concluded that riding in cars and 

activities involving exposure to gasoline vapors were factors contributing to the exposure of these 

children to xylenes. 

Minoia et al. (1996) studied the exposure of school children living in three Italian towns with 

50,000 inhabitants or less (Treviglio-Lombardy; Poggibonsi-Tuscany and Valenza-Piedmont) to xylenes. 

Mean indoor air concentrations within the children’s homes in these three towns were 18.5, 24.1, and 

11.7 μg/m3 (4.3, 5.6, and 2.7 ppb), respectively, which correspond to mean inhaled doses of 92.5, 120.5, 

and 58.5 μg/day, respectively. Mean personal air concentrations (referred to as “indoor + outdoor”) for 

children living in Treviglio, Poggibonsi, and Valenza were 20.2, 21.2, and 12.7 μg/m3

 (4.7, 4.9, and 

2.9 ppb), respectively, which correspond to inhaled doses of 101.0, 106.0, and 63.5 μg/day, respectively. 

Mean concentrations of xylene measured in urine samples were 316 ng/L for 144 children living in 

Treviglio, 112 ng/L for 96 children living in Poggibonsi, and 123 ng/L for 139 children living in Valenza. 
XYLENE 252 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-12. Personal, Indoor, and Outdoor Air Exposures of Inner-city Children in 

Minneapolis, Minnesota to Xylenesa
 

Study Type of sample Number of samplesb m/p-Xylene (μg/m3)

c o-Xylene (μg/m3

)

d 

MCPESe 

Personal 73 6.3 2.5 

Home Indoor 101c

 5.1 2.2 

Home Outdoor 100c

 0.5 1.5 

SHIELDf

 Winter 

School outdoor 8 2.3 0.8 

School indoor 39 2.3 0.8 

Personal 93 3.7 1.2 

Home indoor 93 3.5 1.1 

Spring 

School outdoor 10 2 0.7 

School indoor 47 1.2 0.4 

Personal 88 3.3 1.1 

Home indoor 88 2.9 1 

a

Data are from Adgate et al. 2004a, 2004b. 

b

Xylene isomers were detected in 100% of all samples unless otherwise specified. 

c

m/p-Xylene was detected above 0.5 μg/m3 in 99% of the home outdoor samples. d

o-Xylene was detected above 0.3 μg/m3 in 98% of the home indoor and home outdoor samples. e

Values reported for MCPES are mean concentrations. 

f

Values reported for SHIELD are median concentrations. 

MCPES = Minnesota Children’s Pesticide Exposure Study; SHIELD = School Health Initiative: Environment, 

Learning, Disease 
XYLENE 253 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

Among persons not occupationally exposed to xylenes, the highest exposure levels result from smoking 

and from contact with consumer products containing xylene (Wallace et al. 1988, 1991). Populations 

living near chemical waste sites where xylene is improperly stored are also likely to be at risk of increased 

exposure to xylene vapors via inhalation or dermal contact. 

Workers in certain occupational groups appear to have the greatest potential for exposure to high 

concentrations of xylenes. Based on the available case reports of xylene toxicity in humans, painters (or 

paint industry workers) and laboratory workers appear to be most frequently affected (EPA 1985a). In 

general, workers involved in the distillation and purification of xylene or employed in industries using 

xylene as a raw material (e.g., gasoline component) may be at higher risk of exposure (EPA 1985a). The 

use of xylene in improperly ventilated areas is often the cause for toxic levels of exposure, and increased 

exposures or breath concentrations have been observed for wood processing plant workers, gas station 

employees, metal workers, and furniture refinishers. 

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 xylene 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 xylene. 

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. 
XYLENE 254 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.8.1 Identification of Data Needs 

Physical and Chemical Properties. The physical and chemical properties of xylene have been well 

studied, and reliable information is available. On this basis, further studies of the physical-chemical 

properties of xylene are not essential 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 2004, became available in May of 2006. This database is updated yearly and should 

provide a list of industrial production facilities and emissions. 

Potential for human exposure to xylene is expected to be quite high based on the high volume of 

production and the widespread domestic and industrial uses of xylene. 

Recent estimates of xylene production capacity indicate that over 18 billion pounds of mixed xylene and 

over 13 billion pounds of xylene isomers may be produced in the United States each year (SRI 2006). 

Further information on the amounts of xylenes used in various products would be helpful in estimating 

human exposure to xylenes from consumer products. 

Xylenes are widely used in industry as solvents and as precursors of other products (i.e., polyester). Data 

describing releases of xylenes to the environment (TRI04 2006) and the presence of xylenes in gasoline, 

paint products, insecticides, and cigarette smoke have been well documented (Wallace et al. 1991). 

Information on the occurrence of xylenes in food are available and have been included. 

Because of its widespread use and release into the environment, xylene has been distributed to most 

environmental media. It has been detected in air (Wallace et al. 1991), surface water, sediments (Otson 

et al. 1982b), drinking water (EPA 1985a), and aquatic organisms (Hiatt 1983). Very little data are 

available that report actual levels of xylenes in soil. Information on the most recent distribution of xylene 

are needed to estimate exposure. 

Incineration is the primary method for disposal of xylene, although information on the disposal methods 

is not detailed (HSDB 2007). Information on the amount of xylene disposed of by incineration as well as 
XYLENE 255 

6. POTENTIAL FOR HUMAN EXPOSURE 

the amount of xylene disposed of or abandoned at hazardous waste sites is important for estimating the 

potential human exposure. Criteria for the disposal of xylenes are currently subject to frequent revision. 

Environmental Fate. The environmental fate of xylene has been well studied. Volatilization of 

xylene is the dominant fate process. Xylene released to surface water primarily volatilizes (Mackay and 

Leinonen 1975). Xylene also adsorbs to soils and sediments and leaches into groundwater (Gherini et al. 

1989). Photooxidation appears to be the most important transformation process in the atmosphere and in 

surface soils (Anderson et al. 1991; Jori et al. 1986). Biodegradation is likely to be the only significant 

degradation process for xylene in subsurface soils and aquatic systems (EPA 1984a, 1985a; Haigler et al. 

1992). Additional data on the partitioning of xylene released to soil and on longevity and the rates of 

biotransformation in soils and sediments, are important to further define potential pathways of human 

exposure. 

Bioavailability from Environmental Media. Xylene is absorbed during inhalation (Morley et al. 

1970), oral (Abu Al Ragheb et al. 1986; Ogata et al. 1979), and dermal contact (Riihimaki and Pfaffli 

1978; Skowronski et al. 1990). Approximately 50% of the xylene that is inhaled is absorbed into the 

body (Riihimaki and Savolainen 1980; Wallen et al. 1985), while 90% of ingested xylene is absorbed 

(Bray et al. 1949). However, limited information was found in the available literature regarding the 

bioavailability of xylene from contaminated media such as soil (Turkall et al. 1992) and sediments to 

which the xylene is sorbed or from contaminated surface waters. This information is needed to estimate 

human exposure from contaminated environmental media. 

Food Chain Bioaccumulation. Xylenes are bioconcentrated in aquatic organisms to a limited extent 

(Nunes and Benville 1979; Ogata and Miyake 1978). The degree of concentration is believed to be 

limited by the rapid metabolism and excretion of xylene from some aquatic species. However, additional 

data on the bioconcentration of xylene by aquatic organisms from contaminated surface waters and 

sediments would be useful. No information was found in the literature regarding the bioconcentration of 

xylene in plants or biomagnification of xylene among food chain trophic levels. Although 

bioconcentration has been predicted for all isomers of xylene because of their tendency to partition into 

the octanol phase of the octanol-water system, the rapid oxidation of xylene during metabolism seems to 

preclude bioconcentration in higher animal systems. Thus, biomagnification is not expected to be 

important for xylene. However, data on the bioaccumulation of xylene in commercially important fish 

and shellfish are needed since consumption of contaminated fish and shellfish may be a potential source 

of human exposure. 
XYLENE 256 

6. POTENTIAL FOR HUMAN EXPOSURE 

Exposure Levels in Environmental Media. Reliable monitoring data for the levels of xylene in 

contaminated media at hazardous waste sites are needed so that the information obtained on levels of 

xylene in the environment can be used in combination with the known body burden of xylene to assess 

the potential risk of adverse health effects in populations living in the vicinity of hazardous waste sites. 

Levels of xylene in air and groundwater have been determined (Kolpin et al. 1997; Squillace et al. 1999; 

EPA 1991a; Wallace et al. 1991). However, there are limited monitoring data on xylene levels in soil and 

surface waters (EPA 1985a). More monitoring data are needed to better characterize ambient 

concentrations of xylene in soils and surface water, particularly in the vicinity of hazardous waste sites 

and petroleum refineries. 

The available data allow characterization of human exposure to xylene from most exposure pathways, 

particularly air (Wallace et al. 1988, 1991). Estimates of human intake of xylene from contaminated air 

and drinking water have been made based on background levels that have been recorded. 

Exposure Levels in Humans. Xylene has been detected in human blood, urine, and exhaled breath. 

However, exposure associated with living or working near hazardous waste sites and refineries has not 

been assessed. The most important human exposure sources, workplace and ambient air, are well 

understood (Fishbein 1985, 1988; Wallace et al. 1988, 1991). Additional monitoring programs involving 

analysis of human breath or urine are needed to assess the magnitude of exposures and in estimating the 

average daily dose associated with various sources, particularly for populations in the vicinity of 

hazardous waste sites. 

Several sectors of the work force have the greatest levels of exposure to xylene. Total xylene exposure 

has been found to be greatest among those employed in the machinery (except electrical), special trade 

contracting, fabricated metal products, and health services industries (as assemblers, janitors and cleaners, 

painting and paint-spraying machine operators, and automobile mechanics) (EPA 1985a). More current 

information on occupational exposure are needed. 

This information is necessary for assessing the need to conduct health studies on these populations. 

Exposures of Children. Little data are available regarding exposures of children to xylene. Two 

foreign studies and three studies conducted in the United States have been located. The U.S. studies focus 
 

 

XYLENE 257 

6. POTENTIAL FOR HUMAN EXPOSURE 

primarily on children living in Minnesota. Additional data reporting the exposures of children living in 

other areas of the United States to xylenes would be helpful. 

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 xylene 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 2006) database and the Federal Research and Development 

(FED R&D 2005) database provide 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 below. 

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 xylene 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. 

Kate Scow (University of California Davis) is studying the relationship between microbial communities 

and the anaerobic biodegradation of contaminant mixtures in aquifer groundwater. Chemicals of focus 

will include toluene and xylene. This study will include both microcosm and field studies. 

T.Y. Sylva and C.M. Kinoshita (University of Hawaii) is studying the application of bioremediation to 

hydrocarbon contaminated soils. Laboratory soil biodegradation studies will be performed on organic 

compounds commonly found in petroleum products (including xylene). 
XYLENE 258 

6. POTENTIAL FOR HUMAN EXPOSURE 

Alfred Spormann (Stanford University) is studying the microbial degradation of aromatic hydrocarbons 

under anaerobic conditions. Anaerobic biodegradation studies on BTEX compounds will be examined to 

gain additional knowledge of microbial metabolism and for evaluating and enhancing intrinsic 

bioremediation. 
XYLENE 259 

7. ANALYTICAL METHODS 

The purpose of this chapter is to describe the analytical methods that are available for detecting, 

measuring, and/or monitoring xylene, its metabolites, and other biomarkers of exposure and effect to 

xylene. 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. 

The analytical methods used to quantify xylene in biological and environmental samples are summarized 

below. Table 7-1 lists the applicable analytical methods used for determining xylene in biological fluids 

and tissues. Table 7-2 lists the methods used for determining xylene in environmental samples. 

7.1 BIOLOGICAL MATERIALS 

Extensive commercial, industrial, and domestic use of volatile organic chemicals such as xylene virtually 

assures that the general population will be exposed to this class of chemicals to some extent. The 

determination of trace amounts of xylene in biological tissues and fluids has been restricted to only a 

limited number of analytical methods. These include gas chromatography coupled with mass 

spectrometry (GC/MS), gas chromatography coupled with hydrogen flame ionization detection (GC/FID), 

and high-performance liquid chromatography (HPLC). 

Xylene can be detected at parts-per-trillion (ppt) levels in whole human blood using a purge and trap 

apparatus followed by GC/MS; however, this method does not distinguish between m- and p-xylene 

(Ashley et al. 1992). Antifoam agents are frequently used, although a method has been developed that 

does not require this additive (Cramer et al. 1988). The use of a dynamic headspace purge at room 

temperature reduces the absolute recoveries of the late eluting compounds. An advantage of this GC/MS 

technique is that it can be used in conjunction with selected ion monitoring to obtain better sensitivity of 

target compounds (such as NPL Pollutants) at ppt levels (Cramer et al. 1988). 
XYLENE 260 

7. ANALYTICAL METHODS 

Table 7-1. Analytical Methods for Determining Xylene in Biological Materials 

Sample Analytical Sample Percent 

matrix Preparation method method detection limit recovery Reference 

Human Adsorb directly to Amberlite GC/FID No data 77B98 Norstrom 

blood XAD 2 resin; extract with (m-xylene) and 

carbon disulfide Scheepers 

1990 

Human Purge and trap sample on GC/MS 1 ng/mL No data Cramer et 

blood Tenax TA trap (m-xylene) al. 1988 

Human Purge and trap sample on GC/MS 5.2 ng/mL No data Antoine et 

blood sorbent al. 1986 

0.019 ng/mL No data Ashley et al. 

(m-, p-xylene); 1992 

0.035 ng/mL 

(o-xylene) 

Tissues and Saturate sample with sodium GC/FID 0.05 mg/100 g No data Bellanca et 

body fluids chloride and seal in a vial; and (m-, p-xylene); al. 1982 

inject into gas chromatograph GC/MS 0.01 mg/100 g 

(o-xylene) 

Urine Derivatize or methylate GC/FID <0.25 g/L 110.7 (m-MHA) de Carvalho 

sample with HCl and et al. 1991 

methanol; cool; extract with 

chloroform 

Urine Extract sample with THA-OH; GC/FID 1 ng (o-, p-, 94.2 (o-MHA); Kataoka et 

alkylate with isopropyl m-MHA) 96.0 (m-MHA); al. 1991 

bromide; wash with silver 97.6 (p-MHA) 

sulfate; dry; redissolve in ethyl 

acetate 

Urine Adsorb to filter paper; extract HPLC 4 ng (o-MHA 99B99.9 Astier 1992 

with methanol; dilute with and m-MHA) (o-MHA); 

mobile phase or water 97.2B99.9 

(m-MHA) 

Urine Adsorb to Sep-Pack C18 HPLC 10 μg/mL 94.7B96.1 Tanaka et 

cartridge; elute with methanol (xyl-m) (xyl-m) al. 1990 

Urine Acidify with H2SO4; extract HPLC 0.1 μmol (o-, p-, 91 (o-MHA); Tardif et al. 

with methyl-t-butyl ether; m-MHA) 107 (m-MHA); 1989 

concentrate 113 (p-MHA) 

Urine Acidify with HCl, saturate with HPLC/ UV 0.2 mg/mL 98 NIOSH 1994 

sodium chloride; extract with (methyl hippuric (Method 

ethyl acetate; dry and acid; method 8301) 

redissolve in distilled water does not 

distinguish 

between p- and 

m- isomers) 

Urine Acidify sample and extract GC/FID 5 mg/L 81.5 (o-MHA); Caperos 

with ethyl acetate and 82.2 (m-MHA); and 

methylating solution 84.8 (p-MHA) Fernandez 

1977 
XYLENE 261 

7. ANALYTICAL METHODS 

Table 7-1. Analytical Methods for Determining Xylene in Biological Materials 

Sample Analytical Sample Percent 

matrix Preparation method method detection limit recovery Reference 

Urine Adjust pH of sample to 2.0; GC/FID No data 98 (m-MHA) Engstrom et 

extract with ethylacetate al. 1976 

Urine Acidify sample with HCl and GC/FID No data 88.7B95 Morin et al. 

extract with ethylacetate; add (m-MHA); 1981 

methanol to ethylacetate 79.3B82 

extract; methylate extract with (p-MHA) 

diazomethane in diethyl ether 

solution 

Urine Acidify sample HPLC No data CV=4.8 Astier 1992 

Urine Acidify sample with HCl; HPLC 0.1 mg/mL No data Poggi et al. 

extract with n butyl (m-MHA) 1982 

chloride:isopropanol (9:1) 

Urine Adjust pH of sample to 2.0; HPLC 0.02 μg/sample No data Sugihara 

extract with methyl ethyl (m-MHA); and Ogata 

ketone; add phenacyl bromide 0.02 μg/sample 1978 

solution to extract and heat (p-MHA) 

Urine Add sample specimen to HPLC 6 mg/L (o-MHA); 102 (o-MHA); Ogata and 

methanol; centrifuge 8 mg/L 102.4 (m-MHA); Taguchi 

(m-MHA); 99.5 (p-MHA) 1987 

8 mg/L (p-MHA) 

Urine Acidify sample; extract with TLC 6 μg/mL 100 (m-MHA) Bieniek and 

chloroform and concentrate (m-MHA) Wilczok 

1981 

Exhaled Trap sample on charcoal GC/FID 0.06 ppm 90 Glaser and 

breath cloth; desorb with carbon (m-xylene) Arnold 1989; 

disulfide Glaser et al. 

1990 

Exhaled Sorb to Tenax TA tube; GC/FID 0.03 ppm 60 (m-xylene) Glaser et al. 

breath thermally purge 1990 

Exhaled Sorb to Tenax GC tube; dry; GC/MS 0.50 μg/m3 No data Pellizzari et 

breath thermally desorb al. 1988 

Whole body Kill mice and inject with GC/FID No data 86 (m-xylene) Tsuruta and 

(mice) solvent sample; homogenize Iwasaki 

sample in liquid nitrogen; 1984 

evaporate liquid nitrogen and 

extract with carbon disulfide 

Fish Freeze sample; homogenize GC/MS No data No data Hiatt 1983 

in liquid nitrogen; vacuum equipped 

distillation with fusedsilica 

capillary 

column 

CV = coefficient of variation; GC/FID = gas chromatography/flame ionization detector; GC/MS = gas 

chromatography/mass spectrometry; HCl = hydrochloric acid; HPLC = high performance liquid chromatography; 

H2SO4 = sulfuric acid; MHA = methylhippuric acid; THA-OH = tetrahexyl ammonium hydroxide; TLC = thin-layer 

chromatography; UV = ultra violet; xyl-m = N acetyl-s-xylyl-L-cysteine 
XYLENE 262 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Xylene in Environmental Samples 

Sample Analytical Sample 

matrix Preparation method method detection limit Percent recovery Reference 

Air Collect sample on porous GC/FID 0.1 ppm No data Brown 1988b 

polymer adsorbent; 

thermally desorb 

Air Sorption to a tube GC/MS 4.0 ng/tube 93B103 (o-xylene); Chan et al. 

containing Tenax, (5B50-L air 90.8 (p-, m-xylene) 1990 

Ambersorb XE 340, and sample) 

charcoal; thermally desorb 

Air Draw sample through GC/PID 0.3 ppb No data Hester and 

copper tubing with a Meyer 1979 

diaphragm pump 

Air Absorption on Tenax GC GC/MS No data No data Hampton et al. 

air sampler 1982 

Air Collect on coconut shell GC/FID 2.6 mg No data NIOSH 1994 

charcoal personal sampler; (Method 1501) 

desorb with carbon 

disulfide 

Air Pump air sample through GC/FID <0.05 ppm 51B86 (o-xylene); Brown 1988a; 

charcoal tubes; extract (o-xylene); 51B86 (p-xylene) Otson et al. 

charcoal with carbon <0.05 ppm 1983 

disulfide (p-xylene) 

Air Collect sample in Tedlar GC/FID No data No data Lonneman et 

bags by means of an al. 1974 

automated sequential large 

air sampler 

Air Collect air on activated GC/FID 1 μg/μL 92B100 Esposito and 

charcoal; desorb with 

carbon disulfide; shake with 

LC/UV No data 92B104 Jacobs 1977 

75% H2SO4 

Air Collect sample in GC­ 1.3 pg/sample No data Nutmagul et al. 

pressurized stainless steel FID/PID (o-xylene) 1983 

cannister 

Air Collect sample in a GC­ <1 ppm No data Pleil et al. 1988 

pressurized cannister FID/ELCD 

and 

GC/MS 

Air Collect sample on silica GC No data >99% Whitman and 

gel; extract with isopropyl Johnston 1964 

benzene 

Drinking Purge and trap on sorbent GC/FID <1 μg/L 75 (o-xylene); 87 Otson and 

water (o-xylene); (m-xylene) Williams 1982 

<1 μg/L 

(m-xylene) 
XYLENE 263 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Xylene in Environmental Samples 

Sample Analytical Sample 

matrix Preparation method method detection limit Percent recovery Reference 

Drinking Extract sample in hexane GC/FID 2 μg/L 80B96 (o-xylene); Otson and 

water (o-xylene); 80B83 (m-xylene); Williams 1981 

2 μg/L 78B85 (p-xylene) 

(m-xylene); 

2 μg/L 

(p-xylene) 

Water Purge and trap; methyl- GC/MS 0.06 μg/L 94 (o-xylene); NEMI 2005 

silicone-coated packing is (o-xylene); 94 (m-xylene); (EPA Method 

recommended; desorb 0.03 μg/L 97 (p-xylene) 524.2) 

thermally (m-xylene); 

0.06 μg/L 

(p-xylene) 

Water Purge and trap; desorb GC/MS 0.24 μg/L 94 (o-xylene) NEMI 2005 

thermally (o-xylene); 100 (m-xylene) (ASTM D5790) 

0.48 μg/L 100 (p-xylene) 

(m-xylene); 

0.48 μg/L 

(p-xylene) 

Water Purge and trap; desorb GC/MS 0.03 μg/L 106 (o-xylene) NEMI 2005 

thermally (o-xylene) (Standard 

Methods 

6200B) 

Water Purge and trap; desorb GC/ELCD 0.02 μg/L 68 (o-xylene) NEMI 2005 

thermally (o-xylene) (Standard 

Methods 

6200C) 

Ground- Solid-phase microextration GC/FID 1 μg/L No data Arthur et al. 

water (methyl-silicone fiber 1992 

coated with methyl-silicone 

film) 

Water Purge and trap; methyl- GC­ 0.01B0.05 μg/L 90 (o-xylene) APHA 1992 

silicone-coated packing is PC/PID 90 (m-xylene) (equivalent to 

recommended; desorb 85 (p-xylene) EPA Method 

thermally 503.1) 

Water Purge and trap; methyl- GC­ 0.02 μg/L 99 (o-xylene) NEMI 2005 

silicone-coated packing is CC/PID (o-xylene); 100 (m-xylene) (EPA Method 

recommended; desorb 0.01 μg/L 99 (p-xylene) 502.2) 

thermally (m-xylene); 

0.01 μg/L 

(p-xylene) 

Soil Extract sample with GC No data No data Anderson et al. 

methanol; centrifuge 1991 
XYLENE 264 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Xylene in Environmental Samples 

Sample 

matrix Preparation method 

Analytical 

method 

Sample 

detection limit Percent recovery Reference 

Sediment 

(clay) 

Shake sample with water; 

purge and trap on Porapak 

N cartridges; elute with 

MeOH 

GC 

ECD/PID 

GC/ELCD 

7 ng/g; 

1 ng/g 

70B77 (p-xylene); 

68B79 (o-xylene) 

No data 

Amin and 

Narang 1985 

Various Direct injection, purge and 

trap, or vacuum distillation 

GC/PID 0.02 μg/L 

(o-xylene); 

0.01 μg/L 

(m-xylene); 

0.01 μg/L 

(p-xylene) 

99 (o-xylene) 

100 (m-xylene) 

99 (p-xylene) 

NEMI 2005 

(EPA Method 

8021B) 

Various Direct injection, purge and 

trap, or vacuum distillation 

GC/ELCD No data No data NEMI 2005 

(EPA Method 

8021B) 

Various Purge and trap, azeotropic 

distillation, vacuum 

distillation, head space, or 

direct injection 

GC/MS NA 106 (o-xylene) 

106 (m-xylene) 

97 (p-xylene) 

NEMI 2005 

(EPA Method 

8260B) 

Waste Extract waste with hexane GC/MS No data No data Austern et al. 

1975 

Waste Add sample to a small 

volume of ethanol and 

GC/FID No data No data Austern et al. 

1975 

dilute with water or raw 

wastewater; adjust the pH; 

extract with Freon-TF 

CC = capillary column; ELCD = electron capture detector; FID = flame ionization detector; GC = gas 

chromatography; H2SO4 = sulfuric acid; MeOH = methanol; MS = mass spectrometry; LC = liquid chromatography; 

PC = packed column; PID = photoionization detector; UV = ultraviolet spectrometry 
XYLENE 265 

7. ANALYTICAL METHODS 

To overcome the low recoveries obtained with the purge and trap method, another extraction procedure is 

recommended that uses Amberlite XAD-2 adsorbent resin present in the blood collection tube when the 

sampling takes place. This method dispenses with the readsorption of the hydrocarbon from the sampling 

tube to the polymer and gives recoveries of 77–98% (Norstrom and Scheepers 1990). 

The use of GC/FID followed by a combination of packed and open tubular capillary GC and GC/MS to 

detect and quantify the isomers of xylene in human tissues and fluids has been reported in the literature. 

Brain, liver, lung, kidney, and blood samples of individuals who died following occupational exposure to 

several organic solvents were analyzed using a combination of capillary columns (Bellanca et al. 1982). 

The sensitivity and resolution of the isomers of xylene were increased, and detection limits of 0.05 mg, 

0.05 mg, and 0.01 mg per 100 grams of sample were obtained for m-, o-, and p-xylene, respectively 

(Bellanca et al. 1982). Despite this increased resolving power, adequate separation of m- and p-xylene 

was unattainable. 

Exposure to xylene may also be indicated by its presence in exhaled breath. Xylene in mainstream breath 

may be determined by exhaling through a charcoal cloth (Glaser and Arnold 1989); xylene in sidestream 

breath is trapped using a two-stage Tenax TA sorbent sampler (Glaser et al. 1990) or a Tenax GC 

cartridge (Pellizzari et al. 1988). The Tenax cartridge is dried over calcium sulfate, and then the xylene is 

thermally desorbed for GC/MS. Correlations with carbon dioxide measurements were 90 and 60% for 

mainstream and sidestream breath, respectively (Glaser et al. 1990), with a quantification limit of 

400 μg/m3

 of m-xylene for a 50-L sample (Glaser and Arnold 1989). The detection limit (LOD) was 

0.50 μg/m3

 with a quantification limit 5 times the LOD for a 15-L breath sample (Pellizzari et al. 1988). 

In addition to direct measurement of xylene in biological tissues and fluids, it is also possible to 

determine the concentration of its metabolites in biological fluids. A simple, sensitive, and specific 

automated HPLC technique was developed for direct and simultaneous quantification of o-, m-, and 

p-methylhippuric acids, the metabolites of o-, m-, and p-xylene, respectively (Ogata and Taguchi 1987; 

Sugihara and Ogata 1978; Tardif et al. 1989). A possible disadvantage of the HPLC technique is that at 

low concentrations (<0.6 mg/L) in urine, these methylhippuric acids may not be distinguishable from 

similar compounds. However, addition of a mobile phase, consisting of mixture of acetonitrile and 1% 

phosphoric acid, has been used to distinguish between xylene metabolites and other solvents such as 

benzene and toluene in the urine (Astier 1992). Use of methanol as a solvent for the urine obviates the 

need for the customary ethylether extraction step and allows direct urine injection for HPLC (Ogata and 

Taguchi 1988). N-Acetyl-S-xylyl-L-cysteine, a mercapturic acid, is also a urinary metabolite of xylene 
XYLENE 266 

7. ANALYTICAL METHODS 

that may be detected by direct HPLC (Tanaka et al. 1990). The HPLC method recommended by NIOSH 

(1994) does not distinguish between p- and m-methylhippuric acids. 

Other techniques that have been successful in quantitatively determining urinary concentrations of 

metabolites of xylene include GC/FID, GC/MS, and thin layer chromatography (TLC). GC/FID and 

GC/MS offer the possibility of excellent analytical sensitivity and specificity for urinary metabolites of 

xylene (Caperos and Fernandez 1977; de Carvalho et al. 1991; Engstrom et al. 1976; Kataoka et al. 1991; 

Kira 1977; Morin et al. 1981; Poggi et al. 1982). However, most GC analytical methods require the 

urinary metabolites to be chemically transformed into methyl esters or trimethyl silyl derivatives using 

ethylacetate or diazomethane. This transformation, however, is problematic and may subsequently cause 

low reproducibility (Caperos and Fernandez 1977; Engstrom et al. 1976; Morin et al. 1981; Poggi et al. 

1982). The methylhippuric acid metabolites of the xylene isomers may be distinguished using an 

extractive alkylation procedure followed by capillary GC analysis (Kataoka et al. 1991). An extraction 

method using less toxic reagents (hydrochloric acid with methanol) has been developed (de Carvalho et 

al. 1991). 

A simple and highly reproducible TLC method has been developed for the detection and separation of mor p-methylhippuric acid in the urine of individuals exposed to a mixture of volatile organic solvents 

(Bieniek and Wilczok 1981). However, the authors noted that this analytical technique is time 

consuming. Furthermore, the developing agent used in this technique (p-dimethylamine benzaldehyde in 

acetic acid) has the disadvantage that it is irritating to the eyes and mucous membranes. The sensitivity of 

this method was reported to be 6 μg hippuric acid per 1 mL urine with a recovery of 100%. 

When measuring hippuric acids in the urine of workers exposed to xylenes, NIOSH (1994) recommends 

that a complete spot voiding sample be collected at the end of the shift after 2 days of exposure. As a 

preservative, a few crystals of thymol should be added to the sample. It should be stored at 4 °C if 

analysis is within 1 week. The sample should remain stable for 2 months if it is stored at -20 °C. 

7.2 ENVIRONMENTAL SAMPLES 

A gas chromatograph equipped with an appropriate detector is the basic analytical instrument used for 

determining environmental levels of xylene. Precautions in the isolation, collection, and storage of 

xylene in environmental media are necessary to prevent loss of the volatile xylene compounds to the air. 
 

 

XYLENE 267 

7. ANALYTICAL METHODS 

The most common method for detecting aromatic hydrocarbons in air is the adsorption of the vapors to 

either activated charcoal with extraction using carbon disulfide or adsorption to a polymer adsorbent, such 

as Tenax GC, with thermal desorption. Each method is then followed by injection of the desorbed sample 

into a gas chromatograph equipped with FID (Brown 1988a, 1988b; NIOSH 1994). The activated 

charcoal method requires a 12-L air sample, while the polymer adsorbent uses a smaller 5-L sample for 

determination of the xylene in the sub-parts-per-million range. A GC/MS method has also been 

developed which uses an adsorbent tube with layers of Tenax, Amberlite, and charcoal (Chan et al. 1990). 

The use of a molecular sieve to remove water vapor prior to adsorption has been recommended to 

increase recovery of the hydrocarbons (Whitman and Johnston 1964). A computer-controlled, high-speed 

GC system has been developed for rapid analysis of volatiles in air (and other media with appropriate 

vapor generation). The system combines an electrically heated cold-trap inlet (with a vacuum 

backflushing device on the GC) with a conventional FID. The advantage of the system is that a complete 

analysis cycle requires only 10 seconds to detect p-xylene at a level of 13.4 ppb (Rankin and Sacks 1991). 

A differential optical absorption spectrophotometer has also been used to monitor o-xylene in air; this 

method gives a correlation coefficient of approximately 0.66 when compared with standard GC methods 

(EPA 1991a). 

An automated gas chromatograph with photoionization detector (GC/PID) has been developed by Hester 

and Meyer (1979) to identify gas-phase hydrocarbons (including xylene) for complex systems such as 

vehicle exhaust gas. The GC/PID method allows for measurement of sub-parts-per-billion level 

concentrations of air contaminants and does not require trapping or freeze-concentration of samples 

before analysis. These latter preconcentration steps are usually necessary because of the limited 

sensitivity of FID techniques commonly used in the analysis of environmental samples. A limitation of 

the GC/PID technique is that m- and p-xylene are detected but not well separated. GC/PID in tandem 

with FID was used to obtain a more sensitive method to determine xylene levels in the air. A detection 

limit of 1.3x10-12 g of o-xylene per sample was achieved (Nutmagul et al. 1983). 

A purge and trap gas chromatographic method involving photoionization detection has been developed by 

EPA to analyze volatiles in water (APHA 1992; NEMI 2005). A confirmatory analysis by a second 

analytical column or by GC/MS is advised by EPA. The purge and trap gas chromatographic method can 

detect the isomers of xylene and has a detection limit for o-, m-, and p-xylene of 0.2 ppb (Otson and 

Williams 1981, 1982; Saunders et al. 1975). A purge and trap method using GC/MS has also been used 

to detect xylene in waste water (Koe and Tan 1990). 
XYLENE 268 

7. ANALYTICAL METHODS 

Emissions of volatile organic compounds from surface waters, including ponds at hazardous waste 

treatment facilities, may be directly measured by the use of enclosure methods (such as a flux chamber or 

surface impoundment simulator connected to collection canisters) followed by GC with the effluent split 

between FID and an electron capture detector. Emission rates of 0.5 mg/minute/m2

 could be measured 

using the surface impoundment simulator with a precision of 3% relative standard deviation (Gholson et 

al. 1991). 

GC using both electron capture detection (ECD) and PID has been employed to determine xylene levels 

in sediment samples (Amin and Narang 1985). The authors indicated that their method involved transfer 

of samples between containers, and a considerable loss of volatile compounds was obtained. 

A procedure has been developed to characterize volatile xylene compounds from fish samples by GC/MS 

using a fused-silica capillary column (FSCC) and vacuum distillation (Hiatt 1983). The FSCC provides a 

more attractive approach than packed columns for chromatographic analysis of volatile aromatic organic 

compounds. An FSCC can be heated to a higher temperature (350 °C) than that recommended for packed 

column, thereby improving the resolution (in ppb levels) of compounds and reducing column retention 

times. A physical limitation for compounds that can be detected, however, is that the vapor pressure of 

the compound must be >0.78 torr (≈50 °C) in the sample chamber (Hiatt 1983). 

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 xylene 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 xylene. 

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. 
XYLENE 269 

7. ANALYTICAL METHODS 

7.3.1 Identification of Data Needs 

Methods for Determining Biomarkers of Exposure and Effect. 

Exposure. The methods for determining xylene levels in blood and tissue samples and exhaled breath, 

GC/MS or GC/FID, have sufficient sensitivity to measure xylene levels associated with background 

levels of exposure as well as xylene levels at which biological effects occur. GC/MS has been employed 

to detect o-xylene at ppm levels in the blood (Ashley et al. 1992; Cramer et al. 1988). However, 

development of a GC/MS method that incorporates a less rigorously heated purge would be useful. 

Heated purges currently used in GC/MS have the disadvantage of reducing the absolute recoveries of 

volatile organic solvents. Better resolution and sensitivity are achievable with the application of a 

capillary GC/MS column and selection of an appropriate detector or detector combination as an 

alternative to the packed column approach currently in use. Also, there is a growing need for analytical 

methods to efficiently separate and quantify trace levels of the isomers of xylene in biological media. 

Analytical methods are also available to detect and quantify the xylene metabolites present in the urine 

which have been correlated with exposure levels (Kawai et al. 1991; Ogata et al. 1979). These methods, 

HPLC (Astier 1992) and GC (coupled with MS or FID) (de Carvalho et al. 1991; Kataoka et al. 1991; 

Poggi et al. 1982), have been well characterized with respect to their precision, accuracy, reliability, and 

specificity and have sufficient sensitivity to measure xylene metabolite levels associated with biological 

effects. However, these methods may not be sensitive enough to measure metabolite levels associated 

with background exposure levels. 

Currently, no methods are available to quantitatively correlate monitored levels of xylene in tissues with 

exposure levels or toxic effects in humans, although simultaneous measurement of xylene in exhaled 

breath and ambient air may prove instrumental in indicating exposure, particularly in the workplace 

(Glaser et al. 1990). These methods would provide the ability to evaluate possible health effects in 

humans resulting from exposure to xylene. 

Effect. No specific biomarkers of effect have been clearly associated with xylene exposure. Some 

biological parameters such as hepatic microsomal enzyme activities and central nervous system activity 

have been tentatively linked with xylene exposure. However, insufficient data exist to adequately assess 

the analytical methods associated with measurement of these potential biomarkers. 
XYLENE 270 

7. ANALYTICAL METHODS 

Methods for Determining Parent Compounds and Degradation Products in Environmental 

Media. Methods for determining xylene and its degradation products in environmental media would 

help to identify contaminated areas and to determine whether the levels at contaminated sites constitute a 

concern for human health. Standardized methods are available to detect xylene in air (Brown 1988a, 

1988b; Chan et al. 1990; Rankin and Sacks 1991), waste water (Koe and Tan 1990), drinking water 

(Otson and Williams 1981, 1982), fish (Hiatt 1983), and clay sediments (Amin and Narang 1985). There 

is growing need for simultaneously achieving lower (less than ppb) detection limits, separating the m- and 

p-isomers of xylene, and obtaining an adequate sample recovery. Such methods would provide useful 

information for assessing the biological effects of exposure to xylene and for delineating dose-response 

relationships. A combination of capillary gas chromatography coupled to a multi-detector system, 

nuclear magnetic resonance (NMR) spectroscopy, and infra-red (IR) spectroscopy would be useful to 

accurately identify and measure the isomers of xylene in complex environmental systems. 

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 xylene and 

other volatile organic compounds in blood. These methods use purge and trap methodology, highresolution gas chromatography, and magnetic sector mass spectrometry, which give detection limits in the 

low parts per trillion (ppt) range. 

No other ongoing studies concerning the identification of xylene in biological materials or environmental 

samples were identified. 
XYLENE 271 

8. REGULATIONS AND ADVISORIES 

The international and national regulations and guidelines regarding xylenes in air, water, and other media 

are summarized in Table 8-1. 

ATSDR has derived inhalation and oral MRLs that apply to mixed xylenes and the individual isomers. 

An acute-duration inhalation MRL of 2 ppm is based on a minimal LOAEL of 50 ppm (217 mg/m3

) for 

mild objective and subjective respiratory effects and subjective neurological effects in subjects exposed to 

m-xylene vapor for 2 hours (Ernstgard et al. 2002); an uncertainty factor of 30 was applied to the minimal 

LOAEL. An intermediate-duration inhalation MRL of 0.6 ppm is based on a minimal LOAEL of 50 ppm 

(217 mg/m3

) for a small decrease in the latency of the paw-lick response in male rats exposed to m-xylene 

vapor 6 hours/day, 5 days/week for 3 months (Korsak et al. 1992); an uncertainty factor of 90 was applied 

to the human equivalent minimal LOAEL. A chronic-duration inhalation MRL of 0.05 ppm is based on a 

LOAEL of 14 ppm (geometric mean) for mild subjective respiratory and neurological symptoms in 

workers exposed to 70% xylene 8 hours/day, 5 days/week for 1–7 years (Uchida et al. 1993); an 

uncertainty factor of 100 and modifying factor of 3 was applied to the LOAEL. An acute-duration oral 

MRL of 1 mg/kg/day is based on a NOAEL of 125 mg/kg and a LOAEL of 250 mg/kg for alteration of 

visual evoked brain potentials in rats exposed to p-xylene for 45 minutes (Dyer et al. 1988); an 

uncertainty factor of 100 was applied to the NOAEL. An intermediate-duration oral MRL of 

0.4 mg/kg/day is based on a NOAEL of 500 mg/kg/day (duration-adjusted, 360 mg/kg/day) and a LOAEL 

of 1,000 mg/kg/day (duration-adjusted, 710 mg/kg/day) for hyperactivity in mice immediately after oral 

gavage dosing with mixed xylene (plus 17% ethylbenzene) 5 days/week during weeks 4–51 of a 2-year 

study (NTP 1986); an uncertainty factor of 100 was applied to the duration-adjusted NOAEL. In 

addition, a modifying factor of 10 was applied to account for the lack of testing for sensitive neurological 

effects and lack of developmental and multi-generational data. A chronic-duration oral MRL of 

0.2 mg/kg/day is based on a NOAEL of 250 mg/kg/day (duration-adjusted, 179 mg/kg/day) for the lack of 

any overt neurological toxicity or systemic toxicity in rats that received oral gavage doses of mixed 

xylene (plus 17% ethylbenzene) 5 days/week for 2 years (NTP 1986); an uncertainty factor of 100 was 

applied to the duration-adjusted NOAEL of 179 mg/kg/day. In addition, a modifying factor of 10 was 

applied for the lack of testing for sensitive neurological end points and lack of developmental and multigenerational data. Specific details about the MRL derivations are in Appendix A. 

EPA (IRIS 2005) has derived an inhalation reference concentration (RfC) for mixed xylenes of 0.1 mg/m3 

(0.02 ppm) based on a NOAEL of 50 ppm (217 mg/m3

) and a LOAEL of 100 ppm (434 mg/m3) for 
XYLENE 272 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Xylenes 

Agency Description Information Reference 

INTERNATIONAL 

Guidelines: 

IARC Carcinogenicity classification Group 3a

 IARC 2004 

WHO Air quality guidelines No data WHO 2000 

Drinking water quality guidelines 0.5 mg/Lb

 WHO 2004 

NATIONAL 

Regulations and Guidelines: 

a. Air 

ACGIH TLV (TWA) 435 mg/m3 ACGIH 2004 

STEL 655 mg/m3 

EPA Hazardous air pollutant (isomers and Yes EPA 2004b 

mixture) 42 USC 7412

 NAS/NRC AEGL-1c EPA 2007 

10, 30, and 60 minutes, 4 and 8 hours 130 ppm 

AEGL-2c 

10 minutes 2500 ppmd 

30 minutes 1300 ppmd 

60 minutes 920 ppmd 

4 hours 500 ppm 

8 hours 400 ppm 

AEGL-3c 

10 minutes 7,200 ppme 

30 minutes 3,600 ppmd 

60 minutes 2,500 ppmd 

4 hours 1,300 ppmd 

8 hours 1,000 ppmd 

NIOSH REL (15-minute ceiling limit) 435 mg/m3 NIOSH 2005
 

IDLH 3,906 mg/m3
 

STEL 655 mg/m3 

OSHA PEL (8-hour TWA) for general industry 435 mg/m3

 OSHA 2005c 

29 CFR 1910.1000 

PEL (8-hour TWA) for construction 435 mg/m3

 OSHA 2005b 

industry 29 CFR 1926.55 

PEL (8-hour TWA) for shipyard industry 435 mg/m3

 OSHA 2005a 

29 CFR 1915.1000 

b. Water 

EPA Designated as hazardous substances in Yes EPA 2005b 

accordance with Section 311(b)(2)(A) of 40 CFR 116.4 

the Clean Water Act 
XYLENE 

8. REGULATIONS AND ADVISORIES 

273 

Agency 

Table 8-1. Regulations and Guidelines Applicable to Xylenes 

Description Information Reference 

NATIONAL (cont)

 EPA Drinking water standards and health 

advisories 

1-day HA (10-kg child) 

10-day HA (10-kg child) 

DWEL 

National primary drinking water 

standards (total xylenes) 

MCLG 

MCL 

Reportable quantities of hazardous 

substances designated pursuant to 

Section 311 of the Clean Water Act 

c. Food 

EPA Exemption from the requirement of a 

tolerance 

Xylenes applied as an emulsion 

Maximum residue of xylenes in potable 

water system/return flows of treated 

irrigation water into receiving rivers 

and streams 

FDA Bottled drinking water 

d. Other 

 ACGIH Carcinogenicity classification 

Biological exposure indices 

Methylhippuric acids in urine (end of 

shift) 

EPA Carcinogenicity classification 

Inhalation unit risk 

Oral slope factor 

RfC 

RfD 

40 mg/L 

40 mg/L 

7.0 mg/L 

10 mg/L 

10 mg/L 

100 pounds 

Initial concentration not 

to exceed 750 ppm 

10 ppm 

10 mg/L 

A4f 

1.5 g/g creatinine 

Data are inadequate for 

an assessment of the 

carcinogenic potential 

Not applicable 

Not applicable 

0.1 mg/m3 

0.2 mg/kg/day 

EPA 2004a 

EPA 2002b 

EPA 2005c 

40 CFR 117.3 

EPA 2005f 

40 CFR 180.1025 

FDA 2006 

21 CFR 165.110 

ACGIH 2004 

IRIS 2005 
XYLENE 

8. REGULATIONS AND ADVISORIES 

274 

Agency 

Table 8-1. Regulations and Guidelines Applicable to Xylenes 

Description Information Reference 

NATIONAL (cont) 

EPA Superfund, emergency planning, and 

community right-to-know 

Designated CERCLA hazardous EPA 2005d 

substance 40 CFR 302.4 

 Reportable quantity 

Xylenes and p-xylenes 100 pounds 

m-Xylenes and o-xylenes 1,000 pounds 

Effective date of toxic chemical release 01/01/87 EPA 2005e 

reporting 40 CFR 372.65 

NTP Carcinogenicity classification No data NTP 2005 

a

Group 3: Not classifiable as to carcinogenicity 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

AEGL-1 is the airborne concentration of a substance above which it is predicted that the general population, 

including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic nonsensory
 

effects. AEGL-2 is the airborne concentration of a substance above which it is predicted that the general population, 

including susceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or 

an impaired ability to escape. AEGL-3 is the airborne concentration of a substance above which it is predicted that 

the general population, including susceptible individuals, could experience life-threatening health effects or death. d

Values denoted as having safety considerations against the hazard of explosion; the Lower Explosive Limit 

(LEL)=9,000 ppm and each value should be >10% LEL. Safety considerations against the hazard(s) of explosion(s) 

must be taken into account. 

e

Extreme safety considerations against the hazard(s) of explosion(s) must be taken into account. f

A4: Not classifiable as a human carcinogen 

ACGIH = American Conference of Governmental Industrial Hygienists; AEGL = acute exposure guideline level; 

CERCLA = Comprehensive Environmetnal Response, Compensation, and Liability Act; CFR = Code of Federal 

Regulations; DWEL = drinking water equivalent level; EPA = Environmental Protection Agency; FDA = Food and 

Drug Administration; HA = health advisory; IARC = International Agency for Research on Cancer; IDLH = immediately 

dangerous to life or health; IRIS = Integrated Risk Informatin System; MCL = maximum contaminant level; 

MCLG = maximum contaminant level goal; NAS/NRC = National Academy of Sciences/National Research Council; 

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 exposure 

limit; TLV = threshold limit values; TWA = time-weighted average; USC = United States Code; WHO = World Health 

Organization 
XYLENE 275 

8. REGULATIONS AND ADVISORIES 

impaired motor coordination (decreased rotarod performance) in male rats exposed to m-xylene vapor 

6 hours/day, 5 days/week for 3 months (Korsak et al. 1992); an uncertainty factor of 300 was applied to 

the NOAEL. EPA (IRIS 2005) has derived an oral reference dose (RfD) for mixed xylenes of 

0.2 mg/kg/day, based on a NOAEL of 250 mg/kg/day and a LOAEL of 500 mg/kg/day for dose-related 

decrease in body weight and increase in mortality in male rats treated by oral gavage 5 days/week for 

2 years (NTP 1986); an uncertainty factor of 1,000 was applied to the NOAEL. 
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XYLENE 325 

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. 
XYLENE 326 

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. 
XYLENE 327 

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. 
XYLENE 328 

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. 

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 
XYLENE 329 

10. GLOSSARY 

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. 

Risk—The possibility or chance that some adverse effect will result from a given exposure to a chemical. 
XYLENE 330 

10. GLOSSARY 

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. 
XYLENE 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 
XYLENE 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-32, Atlanta, Georgia 30333. 
XYLENE A-3 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Xylenes (mixed xylenes, ortho-, meta-, and para-xylenes) 

CAS Numbers: 1330-20-7, 95-47-6, 108-38-3, 106-42-3 

Date: August 2007 

Profile Status: Final 

Route: [X] Inhalation [ ] Oral 

Duration: [X] Acute [ ] Intermediate [ ] Chronic 

Graph Key: 49 

Species: Human 

Minimal Risk Level: 2 [ ] mg/kg/day [X] ppm 

[Note: A single acute-duration inhalation MRL has been derived based on data for m-xylene that applies 

to mixed xylenes and all of the individual isomers. The justification for deriving a common value is that 

the isomers have similar toxicokinetic properties and elicit similar toxicological effects, with no isomer 

consistently exhibiting the greatest potency, depending on the end point. Further discussion of this 

rationale is presented in Section 3.2.] 

Reference: Ernstgard L, Gullstrand E, Lof A, et al. 2002. Are women more sensitive than men to 

2-propanol and m-xylene vapors? Occup Environ Med 59:759-767. 

Experimental design: Fifty-six healthy volunteers (28 per sex) between the ages of 20 and 49 years were 

exposed to 50 ppm (200 mg/m3

) m-xylene, clean air (controls), or 150 ppm 2-propanol in a dynamic 

exposure chamber for 2 hours. Each subject experienced the three treatments. Sessions were separated 

by intervals of 2 weeks. The experiment was initially designed to be balanced with two men and two 

women exposed on each occasion with all six possible orders of treatment represented. (Schedule 

changes by the volunteers resulted in imbalances in treatment orders, but ANOVA analysis indicated that 

the imbalance had no significant effect on the results.) Subjects rated the level of perceived discomfort 

using a visual analog scale (0–100 mm) in a questionnaire with 10 questions during exposure (3, 60, and 

118 minutes from the start of exposure), and post-exposure (140 and 350 minutes from onset). Items 

included discomfort in eyes, nose, throat, or airways; breathing difficulty; solvent smell; headache; 

fatigue; nausea; dizziness; and feeling of intoxication. Pulmonary function measurements were 

conducted via spirometer prior to exposure, immediately after exposure, and 3 hours post-exposure. 

These included vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in one second 

(FEV1), peak expiratory flow (PEF), and forced expiratory flow in 25, 50, or 75% of FVC (FEF25, FEF50, 

FEF75). Nasal swelling was assessed by acoustic rhinometry before, immediately after, and 3 hours after 

the end of exposure. Nasal lavages obtained before and 3 hours after the end of exposure were evaluated 

for markers of inflammation (lysozyme, albumin, myeloperoxidase, and eosinophilic cationic protein). 

Eye blinking was measured throughout exposure by electromyography and color vision was assessed 

before, immediately after, and 3 hours post-exposure. 

Effect noted in study and corresponding doses: Statistically significant increases, compared to airexposure, in the average rating of self-reported symptoms resulting from exposure to m-xylene at 50 ppm 

were observed for discomfort in the eyes and nose, detection of solvent smell, and feeling of intoxication 

in both sexes after 60 and 118 minutes, in discomfort in the throat or airways in women after 60 minutes, 

in breathing difficulty and nausea in men at 118 minutes and women at both timepoints, in headache and 

fatigue in men at both timepoints, and in dizziness in men at 118 minutes. All of the statistically 

significant increases in the subjective ratings were minimal except for detection of solvent smell, which 

was moderate. 
XYLENE A-4 

APPENDIX A 

Statistically significant minimal changes, compared to air-exposure, were observed in objective measures 

of respiratory function (percent change from pre-exposure measurements) in women, but not men, 3 hours 

after the end of the exposure to m-xylene: FVC reduced by 2.81% (compared to reduced by 0.06% for air 

exposure, p<0.01), FEV1/FVC increased by 1.09% (compared to decreased by 0.34% for air exposure, 

p<0.03), and FEF75 increased by 3.32% (compared to decreased by 5.53% for air exposure, p<0.04). No 

statistically significant change was observed immediately after exposure. Irrespective of exposure 

condition, there were diurnal changes in lung function (FVC and FEV1) that were more pronounced in 

women than in men. There were no solvent-related changes in nasal volume or cross-sectional area, but 

ANOVA revealed a sex-dependent decrease in nasal volume over time (greater in women) irrespective of 

exposure condition. Exposure to m-xylene did not induce significant adverse changes in other 

parameters. 

Dose and end point used for MRL derivation: 

[ ] NOAEL [X] LOAEL 

The minimal LOAEL of 50 ppm m-xylene is for slight respiratory effects (reduced forced vital capacity, 

increased discomfort in throat and airways in females, and breathing difficulty in both sexes) and 

subjective symptoms of neurotoxicity (headache, dizziness, a feeling of intoxication). The LOAEL is 

minimal because the magnitude of the changes was small. The data were not suitable for benchmark dose 

analysis because a single exposure level was tested. 

Uncertainty Factors used in MRL derivation: 30 

[X] 3 for use of a minimal LOAEL 

[ ] 10 for extrapolation from animals to humans 

[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: 

Not applicable. 

Was a conversion used from intermittent to continuous exposure? Not applicable. 

Other additional studies or pertinent information that lend support to this MRL: The database for acuteduration inhalation exposure to xylenes includes a number of studies in humans and laboratory animals. 

Studies in humans identify neurological and respiratory effects as the most sensitive end points for acuteduration inhalation exposure. Effects observed in humans at 50–690 ppm included irritation of the 

respiratory tract (breathing difficulty, discomfort in nose and throat, reduced forced air capacity), 

neurotoxicity (dizziness, headache, impaired short-term memory, increase in reaction times), and eye 

irritation (Carpenter et al. 1975a; Dudek et al. 1990; Gamberale et al. 1978; Nelson et al. 1943; NIOSH 

1981). Other neurological effects in humans included altered visual evoked potentials following repeated 

exposure to 200 ppm m-xylene and impaired body balance following a single 4-hour exposure at 400 ppm 

(Savolainen et al. 1984; Seppalainen et al. 1989). 

Acute-duration neurological effects in animals were observed at concentrations of 113 ppm and higher. 

These included transiently decreased operant responses in rats repeatedly exposed to 113 ppm mixed 

xylene (Ghosh et al. 1987), altered responses to electric shock in rats and mice exposed once to 230– 

320 ppm o-xylene (Vodickova et al. 1995), and decreased axonal transport in rats repeatedly exposed to 

800 ppm mixed xylene (Padilla and Lyerly 1989). Effects related to motor incoordination were observed 
XYLENE A-5 

APPENDIX A 

following exposures to mixed xylenes or individual isomers in the range of 1,010–1,982 ppm (Carpenter 

et al. 1975a; De Ceaurriz et al. 1983; Korsak et al. 1988, 1990, 1993). Sensory-related changes (altered 

visual- or auditory-evoked potentials or hearing losses) occurred at exposures in the range of 1,400– 

1,600 ppm p-xylene (Crofton et al. 1994; Dyer et al. 1988; Pryor et al. 1987; Rebert et al. 1995). Other 

neurological effects included disturbances in brain catecholamine or dopamine following repeated 

exposure to mixed xylene or individual isomers at 2,000 ppm (Andersson et al. 1981), narcosis in rats at 

≥1,940 ppm (Molnar et al. 1986), and ataxia and seizures in cats exposed to 9,500 ppm mixed xylene 

(Carpenter et al. 1975a). 

The lowest effect levels for other end points affected by acute-duration inhalation exposure in animals 

were higher than the lowest LOAEL for sensitive end points in humans. Rat developmental effects 

(reduced fetal body weight and delayed ossification) were observed at xylene exposures in the range of 

350–2000 ppm (Saillenfait et al. 2003; Ungvary et al. 1980b); maternal body weight effects were 

observed at 700 ppm (Ungvary et al. 1980b). Acute-duration respiratory effects in animals include 

decreases in lung surfactant following exposure to mixed xylenes or individual isomers at 1,000 ppm or 

higher (Elovaara et al. 1987; Patel et al. 1978; Toftgard and Nilsen 1982) and decreased respiratory rates 

in mice briefly exposed to m- or o-xylene at concentrations of 1,361–2,700 ppm (De Ceaurriz et al. 1981; 

Korsak et al. 1990, 1991, 1993). Increased mortality has been reported in rodents repeatedly exposed to 

at 700 ppm (Ungvary et al. 1980b) or once to ≥2,010 ppm (Bonnet et al. 1979; Cameron et al. 1938; 

Carpenter et al. 1975a; Harper et al. 1975; Hine and Zuidema 1970). 

Respiratory and neurological effects are selected as co-critical effects of acute-duration inhalation 

exposure since they occurred at the lowest tested exposure level of 50 ppm. Ernstgard et al. (2002) was 

selected as the principal study for acute-duration inhalation exposure because it provides the lowest 

LOAEL for the co-critical effects. 

Agency Contacts (Chemical Managers): Mike Fay, Ph.D.; John F. Risher, Ph.D.; Jewell D. Wilson, 

Ph.D. 
XYLENE A-6 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Xylenes (mixed xylenes, ortho-, meta-, and para-xylenes) 

CAS Number: 1330-20-7, 95-47-6, 108-38-3, 106-42-3 

Date: August 2007 

Profile Status: Final 

Route: [X] Inhalation [ ] Oral 

Duration: [ ] Acute [X] Intermediate [ ] Chronic 

Graph Key: 137 

Species: Rat 

Minimal Risk Level: 0.6 [ ] mg/kg/day [X] ppm 

[Note: A single intermediate-duration inhalation MRL has been derived based on data for m-xylene that 

applies to mixed xylenes and all of the individual isomers. The justification for deriving a common value 

is that the isomers have similar toxicokinetic properties and elicit similar toxicological effects, with no 

isomer consistently exhibiting the greatest potency, depending on the end point. Further discussion of 

this rationale is presented in Section 3.2.] 

Reference: Korsak Z, Wisniewska-Knypl J, Swiercz R. 1994. Toxic effects of subchronic combined 

exposure to n-butyl alcohol and m-xylene in rats. Int J Occup Med Environ Health 7:155-166. 

Experimental design: Groups of 12–24 male Wistar rats were exposed to m-xylene at 0, 50, or 100 ppm, 

for 6 hours/day, 5 days/week for 3 months. Before the start of the study and at the end of each month of 

exposure, rats were examined for motor coordination (rotarod performance). The level of analgesia was 

tested at termination in the paw-lick response to hot-plate test at 54 °C. 

Effect noted in study and corresponding doses: A dose-related increase in the failure rate on the rotarod 

performance test was observed. The change at 100 ppm was significantly different (p≤0.05) from 

controls. There was no change in severity over time. Increased sensitivity to pain was indicated by a 

significant decrease (p≤0.05) compared to controls in the latency of the paw-lick response at 50 and 

100 ppm: 12.2±3.1, 8.7±3.8, and 8.6±2.7 seconds, respectively, for control, 50, and 100 ppm. The 

50 ppm concentration of m-xylene is a LOAEL and serves at the basis for the intermediate inhalation 

MRL for xylenes. 

Dose and end point used for MRL derivation: 

[ ] NOAEL [X] LOAEL 

The low concentration of 50 ppm was a minimal LOAEL for a statistically significant decrease in the 

mean latency of the paw-lick response. The LOAEL is considered minimal because the effect was subtle, 

differing from the control by <29%, and did not significantly increase in severity with dose. The data 

were not suitable for benchmark dose analysis because the response was essentially a plateau. 

Uncertainty Factors used in MRL derivation: 90 

[X ] 3 for use of a minimal LOAEL 

[X] 3 for extrapolation from animals to humans using 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. 
XYLENE A-7 

APPENDIX A 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: The 

minimal rat LOAEL was converted to a human equivalent following the EPA (1994) dosimetric equation 

for an extra-respiratory effect from an inhaled category 3 gas: minimal LOAEL(HEC) = minimal rat 

LOAEL × λa/λh, where λa and λh are blood:air partition coefficients for rats and humans, respectively. 

Reported blood:air partition coefficients for m-xylene are 39.9 for Wistar rats and 26.4 for humans (Sato 

and Nakajima 1979). Since the rat value is higher than the human, the default value of 1 was used for 

λa/λh (EPA 1994). The minimal LOAELHEC is therefore 50 ppm. 

Was a conversion used from intermittent to continuous exposure? No. The rapid clearance of xylene 

from the body does not justify such a conversion. 

Other additional studies or pertinent information that lend support to this MRL: The database for 

intermediate-duration inhalation to xylenes includes one controlled-exposure study in humans and several 

animal bioassays. Effects in humans exposed to 100–150 ppm p-xylene 1–7.5 hours/day, 5 days/week for 

4 weeks included increased reporting of subjective symptoms of irritation of the nose and throat (NIOSH 

1981). This study found no significant alterations in objective measures of neurological function 

(electroencephalography, tests of motor activity, and cognitive performance) and no alterations in 

pulmonary function in human subjects, but the study was limited in that some group sizes were small 

(n=2). Animal toxicity bioassays that tested at concentrations below 100 ppm reported no clinical signs 

of neurotoxicity or no adverse effects on brain weight (Hillefors-Berglund et al. 1995; Jenkins et al. 

1970). In a special neurobehavioral assay, a LOAEL of 50 ppm was identified for decreased latency of 

the paw-lick response in rats exposed to m-xylene for 3 months (Korsak et al. 1994); impaired rotarod 

performance was noted in this study at 100 ppm, but not at 50 ppm. Other intermediate-duration studies 

also reported neurobehavioral effects (impaired rotarod performance, passive avoidance learning) 

following exposure to 100 ppm m-xylene for 4 weeks to 6 months (Gralewicz and Wiaderna 2001; 

Gralewicz et al. 1995; Korsak et al. 1994); some neurological impairment persisted for 5–9 weeks after 

exposure (Gralewicz and Wiaderna 2001). Other effects included distribution of astroglia cells in the 

brain of Mongolian gerbils exposed to 160 ppm mixed xylene for 4 months (Rosengren et al. 1986), 

delayed maxillary ossification and impaired rotarod performance in rats gestationally exposed to 200 ppm 

technical-grade xylene for 6 hours/day (Hass and Jakobsen 1993), and impaired motor coordination and 

spatial orientation following gestational exposure at 500 ppm (Hass et al. 1995, 1997). Neurological 

effects at higher concentrations included tremors in dogs exposed to 780 ppm o-xylene for 6 hours/day, 

5 days/week for 6 weeks (Jenkins et al. 1970), alterations in brain neurotransmitters following continuous 

exposure to 800 ppm mixed xylenes for 30 days (Honma et al. 1983), and auditory effects in rats (midrange hearing loss, death of hair cells of the Cochlea, or decreases in auditory brainstem responses) 

following exposure to ≥800 ppm mixed xylenes or 900 ppm p-xylene for 13 weeks (Gagnaire et al. 2001; 

Nylen and Hagman 1994; Pryor et al. 1987). 

Non-neurological effects were observed at higher concentrations. Cardiovascular effects (increased 

thickness of coronary microvessels) were observed in rats exposed to 230 ppm mixed xylenes 

6 hours/day, 5 days/week for 4 weeks (Morvai et al. 1987). Hepatic effects (increased liver weight) were 

observed at a LOAEL of 600 ppm in rats discontinuously exposed to mixed xylenes for 4 weeks 

(Toftgard et al. 1981). In rats exposed gestationally to mixed xylenes or o-xylene, a LOAEL of 500 ppm 

was identified for decreased fetal body weights in the absence of maternal toxicity (Bio/dynamics 1983). 

LOAELs for adult body weight effects were 1,000 ppm or higher (Tatrai et al. 1981). Increased deaths 

among squirrel monkeys and rats were noted following discontinuous intermediate-duration exposure to 

780 ppm o-xylene (Jenkins et al. 1970), but no systemic effects were noted in rats or dogs exposed to 810 

ppm mixed xylenes (Carpenter et al. 1975a). 

Agency Contacts (Chemical Managers): Mike Fay, Ph.D.; John F. Risher, Ph.D.; Jewell D. Wilson, 

Ph.D. 
XYLENE A-8 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Xylenes (mixed xylenes, ortho-, meta-, and para-xylenes) 

CAS Number: 1330-20-7, 95-47-6, 108-38-3, 106-42-3 

Date: August 2007 

Profile Status: Final 

Route: [X] Inhalation [ ] Oral 

Duration: [ ] Acute [ ] Intermediate [X] Chronic 

Graph Key: 150 

Species: Human 

Minimal Risk Level: 0.05 [ ] mg/kg/day [X] ppm 

[Note: A single chronic-duration inhalation MRL has been derived based on data for mixed xylene that 

applies to mixed xylenes and all of the individual isomers. The justification for deriving a common value 

is that the isomers have similar toxicokinetic properties and elicit similar toxicological effects, with no 

isomer consistently exhibiting the greatest potency, depending on the end point. Further discussion of 

this rationale is presented in Section 3.2.] 

Reference: Uchida Y, Nakatsuka H, Ukai H, et al. 1993. Symptoms and signs in workers exposed 

predominantly to xylenes. Int Arch Occup Environ Health 64:597-605. 

Experimental design: 175 workers (107 men, 68 women) were exposed to mixed xylenes in Chinese 

factories during the production of rubber boots or plastic coated wire, or in printing work. Two hundred 

forty-one nonexposed workers (116 men, 125 women) were recruited from the same or other factories as 

a comparison population. Exposures, measured with a diffusive sampler, indicated that xylenes 

accounted for >70% total exposure, with m-xylene accounting for 50% of the xylene exposure, followed 

by p- and o-xylenes. Toluene exposure and ethylbenzene exposure were about 1 and 3 ppm, respectively, 

with no benzene exposure. Subjects were evaluated for subjective symptoms in a questionnaire and also 

examined for objective parameters (serum biochemistry, hematology, and urinalysis). Exposures were 

corroborated by measurements of xylene metabolites in urine. 

Effect noted in study and corresponding doses: The TWA (arithmetical mean) for xylenes was 21 ppm 

for an average of 7 years (geometric mean 14 ppm). One man was exposed to 175 ppm. Subjective 

symptoms included increased prevalence of anxiety, forgetfulness, inability to concentrate, eye and nasal 

irritation, dizziness, and sore throats. Exposure and urinary metabolites are further described in Inoue et 

al. (1993). The findings of hematology (red blood cell, platelet and white blood cell counts, hemoglobin), 

serum biochemistry (total protein, albumin, aspartate aminotransferase, alanine aminotranferase gammaGTP, alkaline phosphatase, leucine aminopeptidase, lactate dehydrogenase, amylase, BUN, creatinine), 

and urinalysis were normal, indicating no liver or kidney effects. The geometric mean of 14 ppm, a 

LOAEL for subjective effects, is used as the basis of the chronic-duration MRL. 

Dose and end point used for MRL derivation: 

[ ] NOAEL [X] LOAEL 

The LOAEL of 14 ppm, the TWA geometric mean, was for subjective symptoms of neurotoxicity 

(anxiety, forgetfulness, floating sensation) and respiratory toxicity (nasal irritation and sore throat) and 

eye irritation. The geometric mean was chosen over the arithmetical mean because it is a better 

representation of central tendency. The data were not suitable for benchmark dose analysis because a 

single average exposure level was reported. 
 

 

 

 

XYLENE A-9 

APPENDIX A 

Uncertainty Factors used in MRL derivation: 

[X] 10 for use of a LOAEL 

[ ] 10 for extrapolation from animals to humans 

[X] 10 for human variability 

Modifying Factors used in MRL derivation: 

[X] 3 to account for the lack of supporting studies evaluating the chronic neurotoxicity of xylene. 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? No. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 

Was a conversion used from intermittent to continuous exposure? No. The rapid clearance of xylene 

from the body does not justify such a conversion. 

Other additional studies or pertinent information that lend support to this MRL: Although no other 

chronic-duration inhalation data are available for humans, the database for shorter duration exposures 

supports the findings of Uchida et al. (1993). Neurotoxicity (dizziness, headache, impaired short-term 

memory, increased reaction times), irritation of the respiratory tract (breathing difficulty, discomfort in 

nose and throat, reduced forced air capacity), and eye irritation have been reported in humans acutely 

exposed to ≥50 ppm m-xylene or mixed xylenes or ≥100 ppm p-xylene (Carpenter et al. 1975a; Dudek et 

al. 1990; Ernstgard et al. 2002; Gamberale et al. 1978; Nelson et al. 1943; NIOSH 1981). Repeated 

intermediate-duration exposure to ≥100 ppm p-xylene also increased the reporting of subjective 

symptoms for irritation of the nose and throat (NIOSH 1981). 

Studies in animals also confirm that the nervous system is a sensitive target of inhalation exposure to 

xylene; respiratory function has not been assessed in animals at low concentrations. The most sensitive 

effects observed in acute-duration studies involved impaired neurological performance (operant 

responses) in rats exposed to 113 ppm mixed xylenes (Ghosh et al. 1987) and altered responses to electric 

shock in rats and mice exposed to 230–320 ppm o-xylene (Vodickova et al. 1995). The most sensitive 

effects in intermediate-duration studies were for increased sensitivity to pain in rats exposed to 50 ppm 

m-xylene (Korsak et al. 1994) and impairments in rotarod performance and passive avoidance learning in 

rats exposed to ≥100 ppm m-xylene (Gralewicz and Wiaderna 2001; Gralewicz et al. 1995; Korsak et al. 

1994). In addition, rats exposed during gestation to ≥160 ppm mixed xylene exhibited neurological 

impairments after birth (degraded rotarod performance, motor coordination, and spatial orientation) (Hass 

and Jakobsen 1993; Hass et al. 1995; Hass et al. 1997). Conversely, the most sensitive non-neurological 

effects in inhalation assays in animals were developmental effects in rats acutely-exposed at 350 ppm 

(Ungvary et al. 1980b) and cardiovascular effects in rats exposed for an intermediate duration at 230 ppm 

(Morvai et al. 1987). 

Acute exposure of volunteers to 50 ppm xylene and 50 ppm toluene appeared to reduce the neurological 

effects of xylenes (Dudek et al. 1990). Therefore, it is unlikely that the low concentration of toluene 

(1 ppm) reported in the Uchida et al. (1993) contributed to the observed effects. 

The only other chronic-duration inhalation study was for rats exposed to 1,096 ppm o-xylene 8 hours/day, 

7 days/week for 1 year (Tatrai et al. 1981). Hepatic changes included increases in liver weight and 

microsomal activity and proliferating endoplasmic reticulum, but no histopathological lesions. Body 

weight was reduced by 11% in exposed rats. Calculation of a chronic-duration inhalation MRL from this 
XYLENE A-10 

APPENDIX A 

rat study would not be appropriate since the study did not examine neurological effects, which are the 

most critical end points for inhalation exposure to xylene. 

Agency Contacts (Chemical Managers): Mike Fay, Ph.D.; John F. Risher, Ph.D.; Jewell D. Wilson, 

Ph.D. 
XYLENE A-11 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Xylenes (mixed xylenes, ortho-, meta-, and para-xylenes) 

CAS Number: 1330-20-7, 95-47-6, 108-38-3, 106-42-3 

Date: August 2007 

Profile Status: Final 

Route: [ ] Inhalation [X] Oral 

Duration: [X] Acute [ ] Intermediate [ ] Chronic 

Graph Key: 20 

Species: Rat 

Minimal Risk Level: 1 [X] mg/kg/day [ ] ppm 

[Note: A single acute-duration oral MRL has been derived based on data for p-xylene that applies to 

mixed xylenes and all of the individual isomers. The justification for deriving a common value is that the 

isomers have similar toxicokinetic properties and elicit similar toxicological effects, with no isomer 

consistently exhibiting the greatest potency, depending on the end point. Further discussion of this 

rationale is presented in Section 3.2.] 

Reference: Dyer RS, Bercegeay MS, Mayo LM. 1988. Acute exposures to p-xylene and toluene alter 

visual information processing. Neurotoxicol Teratol 10:147-153. 

Experimental design: Male Long-Evans rats had electrodes implanted in their skulls and were allowed to 

recover from surgery for 1 week prior to exposure and testing for visual processing. Two different 

experiments were conducted. p-Xylene (99.8% pure) was diluted in corn oil and administered by gavage 

at 1 mL/kg. Groups of 10–11 rats received single doses of p-xylene at doses of 0, 500, 1,000, or 

2,000 mg/kg in corn oil and were tested 75 minutes later. Based on the results of this experiment, groups 

of 14–16 rats were dosed at 0, 125, or 250 mg/kg and tested 45 minutes later. The eyes of exposed rats 

were treated with topical atropine (1% in saline) 10 minutes prior to visual testing, which took place in a 

rectangular box with three mirrored sides. A trial consisted of the response to a single strobe-generated 

flash. Trials were presented at 0.3 Hz and a total of 128 trials were averaged for each flash-evoked 

potential. The latencies and amplitudes of the P1, N1, P2, N2, P3, and N3 waveforms were determined in 

the first experiment and the N3 waveform measured in the second experiment. 

Effect noted in study and corresponding doses: Forty-five minutes after administration of 250 mg/kg, the 

amplitude of the N3 peak was decreased by 47% (statistically significant). At higher doses (500, 1,000, 

and 2,000 mg/kg), the N3 peak was not observed until 75 minutes after dosing. At 2,000 mg/kg, mild 

sedation and hypothermia (1 °C) were observed. Increased latencies were observed for the P1, N1, and 

P2 peaks, but this effect was attributed to the hypothermia. Effects on the N3 amplitude were still 

apparent 8 hours post dosing. By 16 hours post dosing, recovery was complete. Amphetamines (0.6, 1.2, 

or 2.5 mg/kg) produced effects on the N3 amplitude similar to p-xylene. The study authors suggested that 

the effects of xylene may be secondary to changes in arousal or excitability. No effects were noted at 

125 mg/kg/day, and this NOAEL serves as the basis for the acute oral MRL for xylenes. 

Dose and end point used for MRL derivation: 

[X] NOAEL [ ] LOAEL 

The NOAEL of 125 mg/kg/day was for alteration of visual evoked potentials. The data were not suitable 

for benchmark dose analysis because the responses at 250 mg/kg/day (reduction in N3 peak amplitude) 

and ≥500 mg/kg/day (delay in N3 peak appearance) were not comparable. 
XYLENE A-12 

APPENDIX A 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[X] 10 for extrapolation from animals to humans 

[X] 10 for human variability 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? No. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 

Was a conversion used from intermittent to continuous exposure? Not applicable. 

Other additional studies or pertinent information that lend support to this MRL: Evaluation of the limited 

database for acute-duration oral exposure to xylenes suggests that neurotoxicity represents the most 

sensitive end point in laboratory animals; no quantitative human data are available. Effects observed in 

acute-duration, single-dose oral studies included altered visually evoked potentials in rats receiving 

250 mg/kg p-xylene (Dyer et al. 1988) and reduced pulmonary microsomal activity in rats receiving 

1,000 mg/kg p-xylene (Patel et al. 1978). In rats exposed 5 days/week for 2 weeks, a significant loss of 

Cochlear hair cells responsible for detecting midrange frequencies was observed following gavage dosing 

with 900 mg/kg/day p-xylene but not m- or o-xylene (Gagnaire and Langlais 2005). Reduced body 

weight gain was observed in rats following repeated dosing for 13 weeks with 1,000 mg/kg mixed 

xylenes or 2,000 mg/kg/day o- or p-xylene (Condie et al. 1988; NTP 1986). Repeated exposure to mixed 

xylenes at 2,000 mg/kg/day resulted in impaired respiration (shallow and/or labored breathing) in rats and 

mice and increased mortality (NTP 1986). At 2,060 mg/kg/day, developmental toxicity (cleft palate) was 

observed in mice gestationally exposed to mixed xylenes (Marks et al. 1982). Serious neurological 

effects (coma, incoordination, prostration, decreased hindleg movement) were observed in rats that 

received single oral gavage doses of ≥4,000 mg/kg mixed xylenes (Muralidhara and Krishnakumari 1980; 

NTP 1986). 

The database for inhalation studies on xylene supports neurotoxicity as the sensitive target following 

short- or long-term exposure. Neurotoxicity was manifest as self-reported symptoms of headache, 

dizziness, and a feeling of intoxication in human subjects acutely-exposed to 50 ppm m-xylene (Ernstgard 

et al. 2002) and decreased operant responses in rats exposed to 113 ppm mixed xylene (Ghosh et al. 

1987). Conversely, the most sensitive non-neurological effects in animals were developmental effects in 

rats exposed at 350 ppm (Ungvary et al. 1980b). 

Neurotoxicity was selected as the critical effect for acute-duration oral exposure to xylene because it was 

observed at the lowest exposure level and demonstrated dose-related increases in severity. The study by 

Dyer et al. (1988) was selected as the principal study, since it provides the lowest LOAEL for the critical 

effect. 

Agency Contacts (Chemical Managers): Mike Fay, Ph.D.; John F. Risher, Ph.D.; Jewell D. Wilson, 

Ph.D. 
XYLENE A-13 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Xylenes (mixed xylenes, ortho-, meta-, and para-xylenes) 

CAS Number: 1330-20-7, 95-47-6, 108-38-3, 106-42-3 

Date: August 2007 

Profile Status: Final 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [X] Intermediate [ ] Chronic 

Graph Key: 39 

Species: Mouse 

Minimal Risk Level: 0.4 [X] mg/kg/day [ ] ppm 

[Note: A single intermediate-duration oral MRL has been derived based on data for mixed xylenes that 

applies to mixed xylenes and all of the individual isomers. The justification for deriving a common value 

is that the isomers have similar toxicokinetic properties and elicit similar toxicological effects, with no 

isomer consistently exhibiting the greatest potency, depending on the end point. Further discussion of 

this rationale is presented in Section 3.2.] 

Reference: NTP. 1986. National Toxicology Program technical report on the toxicology and 

carcinogenesis studies of xylenes (mixed) (60% m-xylene, 14% p-xylene, 9% o-xylene, and 17% 

ethylbenzene) (CAS No. 1330-20-7) in F344/N rats and B6C3F1 mice (gavage studies). Research 

Triangle Park, NC: U.S. Department of Health and Human Services, Public Health Service, National 

Institutes of Health, National Toxicology Program. NTP TR 327. NIH Publication No. 87-2583. 

Experimental design: B6C3F1 mice (50/sex/dose) were administered 500 or 1,000 mg/kg/day mixed 

xylenes (9.1% o-, 60.2% m-, and 13.6% p-xylene, and 17% ethylbenzene) in corn oil by gavage, 

5 days/week for 103 weeks. Mice were observed twice daily for mortality and clinical signs; clinical 

signs were recorded daily for 16 months and monthly thereafter. Body weights were recorded weekly for 

the first 12 weeks and once a month thereafter. Animals in a moribund condition and those surviving to 

103 weeks were sacrificed humanely. All animals were subjected to gross necropsy at termination; all 

gross lesions and a full range of tissues in each animal were examined for histopathology. 

Effect noted in study and corresponding doses: There were no significant treatment-related effects of 

mixed xylene on body weight, survival, or the incidence of neoplastic or non-neoplastic lesions in mice 

receiving doses as high as 1,000 mg/kg/day, 5 days/week for 104 weeks. The only effect of treatment 

with mixed xylenes was hyperactivity in high-dose male and female mice, consistently observed during 

the half-hour period following administration in weeks 4–103. Hyperactivity observed from week 4 to 

week 51 is considered an overt neurological effect of intermediate-duration exposure to mixed xylene. 

Dose and end point used for MRL derivation: 

[X] NOAEL [ ] LOAEL 

The NOAEL of 500 mg/kg/day for hyperactivity in male and female mice was adjusted for intermittent 

exposure (5 days/7 days), resulting in a duration-adjusted NOAEL of 360 mg/kg/day. The data were not 

suitable for benchmark dose analysis because the incidence of hyperactivity at the LOAEL was 100% and 

provides no information as to the shape of the low end of dose-response curve. 
XYLENE A-14 

APPENDIX A 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[X] 10 for extrapolation from animals to humans 

[X] 10 for human variability 

Modifying Factor used in MRL derivation: 

[X ] 10 for the lack of testing for sensitive neurological end points and lack of developmental 

and multi-generational data. 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? No. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 

Was a conversion used from intermittent to continuous exposure? Yes. The mouse NOAEL of 

500 mg/kg was multiplied by 5 days/7 days, resulting in a duration-adjusted mouse NOAEL of 

360 mg/kg/day. 

Other additional studies or pertinent information that lend support to this MRL: The intermediateduration oral toxicity of xylenes has been investigated in several oral gavage bioassays in rodents exposed 

to mixed xylene (Condie et al. 1988; NTP 1986), m-xylene (Elovaara et al. 1989; Wolfe 1988a), and 

p-xylene (Wolfe 1988b). The observed effects include increases in minimal chronic nephropathy and– 

17–37% increases in relative hepatic weight in rats exposed to ≥750 mg/kg/day mixed xylene (Condie et 

al. 1988); 27–46.3% increases in serum transaminase levels in rats exposed to 750–1,500 mg/kg/day 

mixed or m-xylene (Condie et al. 1988; Elovaara et al. 1989; Wolfe 1988a); reduced levels of cytochrome 

P-450 in the lung in rats exposed to 800 mg/kg/day m-xylene (Elovaara et al. 1989); 15–25% decreases in 

body weight gain in rats exposed to 800–1,000 mg/kg/day mixed, m-, or p-xylene (NTP 1986; Wolfe 

1988a, 1988b); hyperactivity or increased aggressiveness subsequent to dosing with mixed xylene in rats 

at 1,500 mg/kg/day or mice at 1,000 mg/kg/day (Condie et al. 1988; NTP 1986); and 11% increased 

relative spleen weight, 16% increased relative kidney weight, and increased hematological effects (mild 

polycythemia and leukocytosis) in female rats dosed with 1,500 mg/kg/day mixed xylene (Condie et al. 

1988). No hepatic effects were noted in F344 rats given mixed xylene at doses as high as 

1,000 mg/kg/day or B6C3F1 mice dosed at ≤2,000 mg/kg/day 5 days/week for 13 weeks (NTP 1986) or in 

Sprague-Dawley rats dosed with p-xylene at 800 mg/kg/day for 90 days (Wolfe 1988b). No renal effects 

were observed in rats or mice exposed to mixed xylene in studies by NTP (1986) or in rats exposed to 

m- or p-xylene (Wolfe 1988a, 1988b). The lack of hepatic or renal effects in some studies may be related 

to strain differences, exposure differences (discontinuous vs. continuous), or isomer specificities. 

A limitation of standard intermediate-duration oral bioassays for xylene is that no testing was conducted 

for sensitive neurological effects. The only overt neurological effect of long-term exposure to xylene was 

hyperactivity noted in male and female mice immediately after dosing with 1,000 mg/kg (710 mg/kg/day, 

duration adjusted) mixed xylene beginning at week 4 of the 2-year NTP (1986) bioassay; hyperactivity 

was not observed at 500 mg/kg (360 mg/kg/day, duration adjusted). Neurotoxicity (hyperactivity) 

observed during the first year of that study (week 4–51) is selected as the critical effect of intermediateduration exposure because it was observed at the lowest LOAEL (710 mg/kg/day, duration-adjusted). 

Selection of neurotoxicity as the critical effect is consistent with the inhalation-exposure database. The 

most sensitive effects from inhalation exposure to xylenes were neurotoxicity: for the acute duration, 

self-reported symptoms of headache, dizziness, and feeling of intoxication in human subjects exposed to 
XYLENE A-15 

APPENDIX A 

50 ppm m-xylene (Ernstgard et al. 2002); for the intermediate duration, increased sensitivity to pain in 

rats exposed to 50 ppm m-xylene (Korsak et al. 1994); and for the chronic duration, increased reporting of 

symptoms of anxiety, forgetfulness, and a floating sensation in workers exposed to 14 ppm mixed xylene 

(Uchida et al. 1993). The most sensitive acute inhalation effect in animals was impairment of operant 

responses observed following exposure to ≥113 ppm m-xylene (Ghosh et al. 1987). Conversely, the most 

sensitive LOAELs for non-neurological effects in inhalation studies were for developmental effects in rats 

following acute exposure at ≥350 ppm (Ungvary et al. 1980b) or for cardiovascular effects in rats 

following intermediate exposure at ≥230 ppm (Morvai et al. 1987). 

The NTP (1986) study is selected as the principal study for intermediate-duration exposure to xylene 

because it provides the lowest adverse effect level, a LOAEL of 710 mg/kg/day, and a NOAEL of 

500 mg/kg (360 mg/kg/day, duration adjusted) for the critical effect. 

Agency Contacts (Chemical Managers): Mike Fay, Ph.D.; John F. Risher, Ph.D.; Jewell D. Wilson, 

Ph.D. 
XYLENE A-16 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Xylenes (mixed xylenes, ortho-, meta-, and para-xylenes) 

CAS Number: 1330-20-7, 95-47-6, 108-38-3, 106-42-3 

Date: August 2007 

Profile Status: Final 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [ ] Intermediate [X] Chronic 

Graph Key: 47 

Species: Rat 

Minimal Risk Level: 0.2 [X] mg/kg/day [ ] ppm 

[Note: A single chronic-duration oral MRL has been derived based on data for mixed xylenes that applies 

to mixed xylenes and all of the individual isomers. The justification for deriving a common value is that 

the isomers have similar toxicokinetic properties and elicit similar toxicological effects, with no isomer 

consistently exhibiting the greatest potency, depending on the end point. Further discussion of this 

rationale is presented in Section 3.2.] 

Reference: NTP. 1986. National Toxicology Program technical report on the toxicology and 

carcinogenesis studies of xylenes (mixed) (60% m-xylene, 14% p-xylene, 9% o-xylene, and 17% 

ethylbenzene) (CAS No. 1330-20-7) in F344/N rats and B6C3F1 mice (gavage studies). Research 

Triangle Park, NC: U.S. Department of Health and Human Services, Public Health Service, National 

Institutes of Health, National Toxicology Program. NTP TR 327. NIH Publication No. 87-2583. 

Experimental design: F344/N rats (50/sex/dose) were administered 250 or 500 mg/kg/day mixed xylenes 

(9.1% o-, 60.2% m-, and 13.6% p-xylene, and 17% ethylbenzene) in corn oil by gavage, 5 days/week for 

103 weeks. Rats were observed twice daily for mortality and clinical signs; clinical signs were recorded 

daily for 16 months and monthly thereafter. Body weights were recorded weekly for the first 12 weeks 

and once a month thereafter. Animals in a moribund condition and those surviving to 103 weeks were 

sacrificed humanely. All animals were subjected to gross necropsy at termination; all gross lesions and a 

full range of tissues in each animal were examined for histopathology. 

Effect noted in study and corresponding doses: No adverse effects were noted in male or female rats 

treated at the low dose of 250 mg/kg/day. At 500 mg/kg, body weights were 5–8% lower in male rats 

after week 59, but the differences from controls were not biologically significant. In addition, survival at 

termination was significantly lower compared to controls in male rats treated at 500 mg/kg/day. No other 

treatment-related non-neoplastic or neoplastic effects were observed in male or female rats. 

Dose and end point used for MRL derivation: 

[X] NOAEL [ ] LOAEL 

The MRL is based on a NOAEL of 250 mg/kg. Although no histopathology was observed in any organ, 

including the nervous system, in rats exposed to 500 mg/kg, this dose was not used as the basis for MRL 

derivation because survival was decreased in male rats at this dose level. Therefore, the next lowest dose 

level was used as the basis for the MRL. The NOAEL of 250 mg/kg was adjusted for intermittent 

exposure (5 days/7 days), resulting in a duration-adjusted NOAEL of 179 mg/kg/day. The data were not 

suitable for benchmark dose analysis because of the lack of measurable adverse effects aside from 

lethality. 
XYLENE A-17 

APPENDIX A 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[X] 10 for extrapolation from animals to humans 

[X] 10 for human variability 

Modifying Factor used in MRL derivation: 

[X] 10 for the lack of testing for sensitive neurological end points and lack of developmental and 

multi-generational data. 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? No. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 

Was a conversion used from intermittent to continuous exposure? Yes. The NOAEL of 250 mg/kg/day 

was multiplied by 5 days/7 days, resulting in a duration-adjusted NOAEL of 179 mg/kg/day. 

Other additional studies or pertinent information that lend support to this MRL: In the absence of data 

associating health effects in humans with chronic-duration oral exposure to xylenes, the animal bioassays 

provide a minimal basis for deriving an MRL for humans chronically exposed to xylenes. The parallel 

NTP (1986) oral gavage study in B6C3F1 mice reported no significant treatment-related effects of mixed 

xylene on body weight, survival, or the incidence of neoplastic or non-neoplastic lesions in mice 

receiving doses as high as 1,000 mg/kg/day, 5 days/week for 104 weeks. The only effect of treatment 

with mixed xylenes was hyperactivity in high-dose male and female mice, consistently observed during 

the half-hour period following administration in weeks 4–103. 

Histopathology in specific target organs was not observed in rats or mice exposed to mixed xylene for 

2 years (NTP 1986). Limitations of these studies include the lack of organ weight data, and the lack of 

hematology, urinalysis, or clinical chemistry data that might identify target organs for xylene. The lack of 

neurobehavioral analysis is also a deficiency, given that neurotoxicity was the most sensitive effect 

following acute-, intermediate-, or chronic-duration inhalation exposure, as well as acute-duration oral 

exposure to xylenes (Dyer et al. 1988; Ernstgard et al. 2002; Korsak et al. 1994; Uchida et al. 1993). The 

sensitive neurotoxic effects in animals were revealed by specialized neurobehavioral or neurophysiological tests and would not be apparent in standard toxicity assays. 

Agency Contacts (Chemical Managers): Mike Fay, Ph.D.; John F. Risher, Ph.D.; Jewell D. Wilson, 

Ph.D. 
XYLENE A-18 

APPENDIX A 

This page is intentionally blank. 
XYLENE	 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. 
XYLENE 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. 
XYLENE	 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"). 
XYLENE	 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. 
XYLENE	 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 → INTERMEDIATE EXPOSURE 

5 6 7 8 9 10 

3 → Systemic ↓ ↓ ↓ ↓ ↓ ↓

3b 18 Rat 13 wk Resp 10 (hyperplasia) 

4 → 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). 

XYLENE B-8 

APPENDIX B 

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XYLENE 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 benchmark dose 

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 

DOT Department of Transportation 

DOT/UN/ Department of Transportation/United Nations/ 

NA/IMCO North America/Intergovernmental Maritime Dangerous Goods Code 
XYLENE C-2 

APPENDIX C 

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 

MCL maximum contaminant level 

MCLG maximum contaminant level goal 

MF modifying factor 
XYLENE C-3 

APPENDIX C 

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 

OW Office of Water 

OWRS Office of Water Regulations and Standards, EPA 

PAH polycyclic aromatic hydrocarbon 
XYLENE C-4 

APPENDIX C 

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 
XYLENE 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 
XYLENE C-6 

APPENDIX C 

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XYLENE D-1 

APPENDIX D. INDEX 

absorbed dose...................................................................................................... 12, 123, 126, 129, 134, 163
 

acetylcholine ...............................................................................................................................................75 

adipose tissue .................................................................................... 123, 126, 128, 134, 139, 143, 153, 171 

adsorbed .................................................................................................... 124, 126, 131, 136, 137, 182, 216 

adsorption.................................................................................................... 12, 124, 193, 203, 217, 249, 267 

aerobic.......................................................................................................................................................220 

alanine aminotransferase (see ALT) ................................................................................................... 68, 104 

ALT (see alanine aminotransferase) ...........................................................................................................70 

ambient air ........................................................................................................................ 225, 243, 256, 269 

anaerobic........................................................................................................................... 220, 221, 257, 258 

aspartate aminotransferase (see AST).........................................................................................................68 

AST (see aspartate aminotransferase).........................................................................................................70 

bioaccumulation................................................................................................................................ 218, 255 

bioavailability ...........................................................................................................................................255 

bioconcentration factor ..................................................................................................................... 203, 218 

biodegradation..................................................................................... 11, 203, 219, 220, 221, 222, 257, 258 

biomarker .................................................................................................. 162, 163, 164, 181, 184, 259, 269 

blood cell count................................................................................................................................... 67, 113 

body weight effects ............................................................... 12, 13, 14, 18, 21, 71, 105, 106, 109, 156, 160 

breast milk......................................................................................................................... 148, 160, 184, 249 

cancer ...................................................................................................... 5, 6, 14, 25, 82, 108, 117, 159, 177 

carcinogen.................................................................................................................................................274 

carcinogenic ................................................................................................................ 6, 14, 17, 27, 108, 273 

carcinogenicity........................................................................................ 6, 14, 108, 117, 173, 175, 178, 274 

cardiovascular ..................................................................................................................... 66, 102, 113, 173 

cardiovascular effects.......................................................................................................... 66, 102, 113, 173 

cholinesterase.................................................................................................................................... 116, 117 

chromosomal aberrations .......................................................................................................... 120, 121, 122
 

clearance ..................................................................................... 70, 131, 134, 143, 144, 152, 154, 162, 184
 

cognitive function .....................................................................................................................................181 

death........................................................................................ 6, 27, 29, 30, 80, 83, 109, 155, 157, 178, 274 

deoxyribonucleic acid (see DNA)...............................................................................................................77 

dermal effects.............................................................................................................................. 30, 105, 115 

developmental effects ................................................................... 7, 18, 79, 80, 81, 108, 116, 169, 179, 183 

DNA (see deoxyribonucleic acid)....................... 77, 114, 117, 118, 119, 120, 121, 122, 156, 157, 163, 178 

dopamine............................................................................................................................................... 18, 77 

endocrine..................................................................................................................... 71, 105, 109, 157, 158 

endocrine effects ......................................................................................................................... 71, 105, 158 

erythema...................................................................................................................................... 14, 114, 116 

fetal tissue ......................................................................................................................... 128, 153, 160, 184 

fetus................................................................................................................. 7, 81, 158, 160, 161, 175, 176 

gastrointestinal effects .......................................................................................................... 66, 67, 102, 113 

general population............................................................................. 5, 11, 12, 162, 205, 239, 257, 259, 274
 

genotoxic..................................................................................................................................... 27, 121, 173 

genotoxicity....................................................................................................................... 121, 122, 175, 178 

groundwater ................................................ 2, 3, 11, 173, 203, 215, 217, 219, 220, 234, 235, 255, 256, 257 

half-life................................................................ 11, 113, 124, 126, 134, 137, 162, 217, 218, 220, 221, 227 

hematological effects ............................................................................................................ 24, 67, 103, 113 
XYLENE D-2 

APPENDIX D 

hepatic effects ................................................................................................... 13, 24, 68, 69, 103, 113, 169
 

hydrolysis.......................................................................................................................................... 203, 219 

hydroxyl radical ........................................................................................................................ 155, 203, 218 

immune system ................................................................................................................................... 72, 106 

immunological ...................................................................................... 27, 72, 106, 114, 115, 116, 168, 179 

immunological effects................................................................................................................. 72, 106, 179 

Kow ...................................................................................................................................... 28, 152, 187, 218 

LD50............................................................................................................................................... 82, 83, 109 

leukemia........................................................................................................................................ 67, 82, 117 

lymphoreticular................................................................................................................... 72, 106, 115, 116 

metabolic effects .........................................................................................................................................72 

micronuclei ...............................................................................................................................................121 

milk ................................................................................................................................... 150, 153, 237, 245 

musculoskeletal effects ....................................................................................................................... 68, 103 

neurobehavioral................................................... 14, 20, 75, 80, 81, 152, 157, 158, 160, 177, 179, 180, 183 

neurological effects............................................................ 13, 15, 18, 19, 20, 21, 22, 23, 25, 72, 73, 74, 75, 

76, 77, 78, 106, 107, 116, 176, 177, 180, 183, 271 

neurotransmitter ..........................................................................................................................................77 

non-Hodgkin’s lymphoma ..........................................................................................................................82 

norepinephrine ............................................................................................................................................75 

nuclear.......................................................................................................................................................270 

octanol-water partition coefficient.................................................................................................... 126, 218 

ocular effects............................................................................................................................... 71, 105, 115 

odds ratio.....................................................................................................................................................78 

partition coefficients ............................................................................. 21, 28, 126, 139, 143, 144, 152, 153 

pharmacodynamic ............................................................................................................................. 138, 151 

pharmacokinetic.................................................................. 28, 131, 134, 138, 139, 140, 151, 159, 161, 166 

photolysis ..................................................................................................................................................219 

placenta ................................................................................................................................. 7, 128, 153, 178 

rate constant ...................................................................................................... 139, 143, 147, 218, 220, 221
 

renal effects............................................................................................... 13, 24, 70, 71, 104, 113, 114, 181 

reproductive effects....................................................................................................... 14, 78, 107, 108, 116 

respiratory effects................................................ 13, 16, 18, 19, 30, 64, 65, 78, 83, 109, 113, 176, 177, 271 

retention .............................................................................................. 76, 123, 134, 153, 162, 167, 217, 268 

salivation...................................................................................................................................................106 

sequestered..................................................................................................................................................12 

solubility ........................................................................................................................... 152, 153, 154, 181 

systemic effects............................................................................................................... 21, 30, 83, 109, 175
 

thyroid.........................................................................................................................................................71 

toxicokinetic.................................................................................................................. 12, 27, 166, 182, 183 

tremors ........................................................................................................................ 13, 16, 20, 74, 75, 106 

tumors ............................................................................................................................................... 117, 168 

vapor pressure ........................................................................................................................... 206, 217, 268 

volatility ....................................................................................................................................................203 

volatilization ................................................................. 11, 12, 203, 206, 217, 219, 221, 222, 232, 235, 249